preparation and activity of multidentate beta-amino
TRANSCRIPT
Preparation and Activity of Multidentate beta-Amino Sulfoxide Ligands and Expedited Catalytic Preparation of Bupropion
by
Erwin J. Remigio
A Thesis presented to
The University of Guelph
In partial fulfilment of requirements for the degree of
Master of Science in
Chemistry
Guelph, Ontario, Canada
© Erwin J. Remigio, January, 2017
ii
ABSTRACT
PREPARATION AND ACTIVITY OF MULTIDENTATE BETA-AMINO SULFOXIDE
LIGANDS
Erwin Javier Remigio Advisor: University of Guelph, 2017 Professor A. L. Schwan
Amino sulfoxide (and related derivative) functionalities have seen an increased
utility in the field of asymmetric synthesis. Many chiral ligands have incorporated these
moieties to successfully catalyze carbon-carbon bond forming reaction. In this work, an
N-Boc heteroaryl (2-pyridyl and 8-quinolyl) multidentate amino sulfoxide motif has been
constructed through diastereoselective sulfenate anion-based chemistry and traditional
sulfide oxidation to access the complementary diastereomer. The 2-pyridyl sulfenate
anion provided low diastereoselectivity (d.r. = 1.3:1), while the 8-quinolyl sulfenate anion
provided one lone diastereomer. Unfortunately, the diastereopure sulfoxides generated
via sulfide oxidation were not accessed due to difficulties in recrystallization. These
ligands were further diversified by condensation with an additional heteroaryl aldehyde
(2-picolinaldehyde and salicylaldehyde) to form their imine derivatives, which provided
an additional coordination site. In total, five ligands were prepared and probed for
reactivity in the asymmetric Henry (nitroaldol) reaction. Two ligands were probed as a
diastereomeric mixture, while the remaining three were probed as diastereopure
iii
ligands. In some cases high yields were obtained (as high as 99%), however as a
whole, these ligands failed to impart any meaningful enantioselectivity (as high as ee =
32%). The reactivity of the sulfenate anion was also further investigated. Here, lithiated
sulfenate anions were complexed with chiral PyBox ligands in an attempt to generate
enantiopure sulfoxides. Unfortunately, the resultant sulfoxides were accessed in low
yields with poor accompanying enenatioselectivities (49 – 56%; ee = 0 – 1.4%).
Moreover, attempts to generate a [SO]-2 species were unsuccessful and led only to the
expected products arising form reaction with the heteroaryl sulfenate anions.
iv
Acknowledgements
First and foremost, I would like to acknowledge Professor Adrian Schwan for
being an excellent supervisor. Thank you for giving me the opportunity to work in your
research group. I have learned a great deal about professionalism, life, and research
under your guidance. The experience I have gained form working under your
supervision is truly invaluable. I would also like to thank the committee members,
Professor William Tam and Professor Marcel Schlaf, for their guidance and feedback.
I owe many thank to Professor France-Isabelle Auzanneau and Jeffrey Davidson
for their guidance and expertise in dealing with HPLC systems and also for allowing me
to use your lab group’s analytical HPLC system.
In addition, I would also like to thank Dr. Kate Stuttaford and Steve Seifried for
their help and willingness to troubleshoot our HPLC system.
I would like to acknowledge Vibrant Pharma Inc. and Dr. Jaipal Nagireddy for
giving us the opportunity to work in collaboration in the Bupropion project. It has been
an invaluable experience to work alongside an industrial client.
In regards to this project, I would like to thank Rebecca Sydor for the work she
put forth in the Bupropion project. Her hard work and diligence helped guide us towards
optimal reaction conditions for Bupropion synthesis.
I would also like to acknowledge my fellow colleagues, past and present, in the
Schwan group. Thank you to Monika Kulak, Dr. Mohanad Shkoor, Marshall Lindner,
Alex Dean, Ashley Chrismas, Marina Lazarakos, Daniel Mok, Matt Sing, Joe Findlay,
v
and Michelle Michalski. Thank you for all of the support and feedback you have
provided me.
I would like thank the neighbouring Tam group and 2nd-Floor Island for putting up
with my non-sense, for lending a helping hand, and for providing useful feedback.
I am very grateful for the funding that NSERC has provided, which has made
these projects possible.
I would like to thank all of my friends and family who have provided a wonderful
and supporting environment for me. Thank you for shaping me into the person I am. I
hope to make you all proud.
vi
Table of Contents
ABSTRACT ii
Acknowledgements iv
Table of Contents vi
List of Abbreviations ix
List of Figures x
List of Schemes xi
List of Tables xvii
Chapter 1: Introduction 1
1.0 Introduction 2
1.1 Asymmetric catalysis 2
1.2 β-Amino thiol and disulfide ligands 2
1.3 Sulfonamide moiety in chiral ligands 5
1.4 Incorporation of the sulfoxide moiety in chiral ligands 8
1.5 Optically pure sulfoxide ligands 11
1.6 Accessing the sulfoxide moiety through sulfenate anion chemistry 29
Chapter 2: Results and Discussion 32
2.0 Results and Discussion 33
2.1 Chiral ligand design and synthesis 33
2.2 Synthesis of β-amino electrophile 34
vii
2.3 Heteroaryl thiols 37
2.4 Traditional oxidative synthesis of β-amino sulfoxide ligands 39
2.5 Sulfenate anion chemistry 45
2.6 Attempts towards enantioselective sulfoxide generation 48
2.7 Attempts towards [SO]-2 extrusion 51
2.8 β-Amino sulfoxide ligands and related derivatives 53
2.9 Probing chiral ligands for catalytic activity in the Henry (nitroaldol) reaction 55
2.10 Proposed model for observed stereoinduction 59
2.11 Future work 61
2.12 Conclusion 64
ABSTRACT lxvi
Chapter 3: Introduction 68
3.0 Introduction 69
3.1 Traditional synthetic pathway towards α-amino carbonyl compounds 69
3.2 Direct C-N oxidative coupling reactions 74
Chapter 4: Results and Discussion 80
4.0 Results and Discussion 81
4.1 Conclusion 96
Chapter 5: Experimental 97
5.0 Experimental 98
5.1 General experimental 98
5.2.0 Amino sulfoxide ligands and related compounds 99
viii
5.3.0 Experimental: Synthesis of Bupropion 124
Chapter 5: References 129
ix
List of Abbreviations
BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)
Bn benzyl
Boc tert-butyloxycarbonyl
DCCA dichloroisocyanuric acid
d.r. diastereomeric ratio
E+ electrophile
ee enantiomeric excess
hd 1,5-hexadiene
HFIP hexafluoroisopropanol
HPLC high pressure liquid chromatography
IPA isopropanol
L* ligand
mCPBA meta-chloroperbenzoic acid
NMR nuclear magnetic resonance
Nu nucleophile
ODNs 2,4-dinitrophenylsulfonate
PG protecting group
PyBox pyridine bis(oxazoline)
SET single electron transfer
Ts para-toluene sulfonate (tosylate)
x
List of Figures
Figure 1. Proposed 5-membered chelate transition state to rationalize favoured
production of (S)-product. 15
Figure 2. Probing the effectiveness of the sulfoxide moiety. 19
Figure 3. Enhanced reactivity of the (SS) sulfoxide conformation. 20
Figure 4. Proposed internal complexation transition state to account for observed
sulfenate diastereoselectivity with homochiral amino electrophiles. 31
Figure 5. Chiral amino sulfoxide ligands 54
Figure 6. Copper (II) coordination sites 60
Figure 7. 1H NMR of isolated by-product and corresponding predicted chemical
structure. 82
Figure 8. 1H NMR spectrum of the crude reaction mixture containing Bupropion
and 3’-chloropropiophenone. 84
xi
List of Schemes
Scheme 1. Test reactions for the asymmetric reduction of benzaldehyde with
diethyl zinc with amino thiol and amino disulfide ligands. 4
Scheme 2. Ligand screening between amino thiol and corresponding amino
disulfide ligands. 5
Scheme 3. Comparison of amino disulfide and amino thiol ligand. 5
Scheme 4. Selection of lone pair by the activated metal-ligand complex in
aldehydes (top) and ketones (bottom). 6
Scheme 5. Substrate scope tests enantioselective alkylzinc additions to ketones
in presence of Ti(OiPr)4. 7
Scheme 6. Asymmetric alkynation of ketones via isoborneol-10 sulfonamide
lewis acid catalyst. 8
Scheme 7. The first application of the sulfoxide moiety in asymmetric catalysis,
which was employed as a diastereomeric mixture. 9
Scheme 8. Diastereomeric bis-sulfoxide ligand employed in an asymmetric
hydrogenation reaction. 10
Scheme 9. Multidentate sulfoxide ligand used for asymmetric hydrogenation (hd
= 1,5-hexadiene). 11
xii
Scheme 10. Optically pure sulfoxide ligands employed in asymmetric aldehyde
alkylation. 12
Scheme 11. Proposed active catalytic species with 1-5 12
Scheme 12. Catalytic cycle for the palladium-catalyzed Tsuji-Trost allylic
substitution. 13
Scheme 13. Test reaction for the palladium-catalyzed Tsuji-Trost allylic
substitution and examination of the reactivity of sulfur moiety in different
oxidation states. 14
Scheme 14. Test reaction for the palladium-catalyzed Tsuji-Trost allylic
substitution. 15
Scheme 15. Test reaction for the palladium-catalyzed Tsuji-Trost allylic
substitution using complementary (RS, S) and (SS, S) sulfoxide diastereomer
ligands. 16
Scheme 16. Proposed 9-membered transition states to rationalize
enenatioselectivity in (RS, S) and (SS, S) sulfoxide diastereomer ligands. 17
Scheme 17. Test reaction for the palladium-catalyzed Tsuji-Trost allylic
substitution using amido phospino sulfoxide ligand. 18
Scheme 18. Enhanced catalytic activity of an amino sulfane over its
diastereomeric amino sulfoxide counterpart. 20
Scheme 19. Endo and exo adducts and respective enantiomers for the
asymmetric Diels-Alder cycloaddition. 21
xiii
Scheme 20. Test reaction for asymmetric Diels-Alder cycloaddition and the
proposed active catalytic species. 22
Scheme 21. Proposed 6-membered transition state to rationalize Re-face
approach leading to (R)-endo product. 23
Scheme 22. Proposed 6-membered transition state to rationalize Si-face
approach leading to (S)-endo product. 24
Scheme 23. Addition of methyl group to lock p-tol group in equatorial position. 24
Scheme 24. Proposed transition state to favour diene approach from the Re-face
in either conformation to afford the (S)-product. 25
Scheme 25. Enzyme-mediated de-symmetrisation sulfane with CAL-B lipase and
vinyl acetate to access the de-symmetrized sulfoxide. 26
Scheme 26. Test reaction for the Aza-Henry reaction 27
Scheme 27. Test reaction for Simmons-Ingold cyclopropanation 27
Scheme 28. Imino (Schiff-base) sulfoxide ligands used in the Henry reaction. 28
Scheme 29. Probing the importance of the sulfoxide moiety 29
Scheme 30. O- and S- sulfenate anion alkylation 30
Scheme 31. Retrosynthethic approach towards the construction of heteroaryl
amino sulfoxide ligands. 34
Scheme 32. Reduction of N-Boc protected L-phenylalanine 34
xiv
Scheme 33. Synthesis of amino iodide electrophile and formation of cyclic by-
product. 36
a Dissolve iodine in DCM and transfer resultant solution to Ph3P and imid. in DCM.
36
Scheme 34. Attempts towards SNAr substitutions with potassium thioacetate and
potassium thiocyanate. 38
Scheme 35. Reduction of sulfonyl chloride moiety to a thiol vial Ph3P. 39
Scheme 36. Thiolate substitution to access amino sulfane compounds 40
Scheme 37. Removal of N-Boc protecting group via trifluoroacetic acid. 43
Scheme 38. Reported synthesis of N-Ts protected amino sulfoxide ligands 44
Scheme 39. N-Ts protected amino sulfoxides 44
Scheme 40. Conditions for sulfanyl acrylate oxidations 47
Scheme 41. Addition-elimination mechanism for the generation of a lithiated
sulfenate anion. 47
Scheme 42. Heteroaryl sulfenate anion substitution with homochiral amino
electrophile 48
Scheme 43. Lithiated intramolecular sulfenate complexation 49
Scheme 44. Spirocyclic chiral Lewis acid catalyst for enantioselective sulfoxide
formation. 49
xv
Scheme 45. Enantioselective sulfoxide formation attempts with chiral PyBox
ligands 51
Scheme 46. Proposed mechanism of SO extrusion. 52
Scheme 47. Attempts towards [SO]-2 extrusion via double nBuLi addition and
release. 53
Scheme 48. Imino sulfoxide ligand synthesis 55
Scheme 49. Probing of other aldehydes as substrates in the Henry reaction under
optimized conditions. 59
Scheme 50. Proposed model for observed stereoinduction and preference for the
(R)-isomer. 61
Scheme 51. Future work towards ligand diversification. 63
Scheme 52. Common synthetic pathway towards α-amino carbonyl compounds
(X = C(O)OR, Y = N or O, Z = lone pair of electrons if Y = O, or Z = C(O)OR if Y = N).
70
Scheme 53. Enantioselective α-amination via tin enolate and silver (I)/BINAP
system. 70
Scheme 54. Asymmetric α-amination via chiral magnesium bis(sulfonamide)
enolate complex. 71
Scheme 55. Photoredox catalytic cycle. 73 Scheme 56. Proline-catalyzed amination via enamine intermediate. 74
xvi
Scheme 57. NBS-mediated α-amination of aryl ketones. 75
Scheme 58. Cu(II)-mediated oxidative α-amination of carbonyl compounds. 76
Scheme 59. Proposed I2 radical coupling mechanism 78
Scheme 60. Retrosynthetic approach of Bupropion via direct C-N coupling. 78
Scheme 61. Traditional synthesis of Bupropion. 79
Scheme 62. Failed synthesis of Bupropion via Cu(II)-mediated oxidative coupling.
81
Scheme 63. Test reaction of direct C-N coupling of 3’-chloropropiophenone and
morpholine via Cu(II)-mediated oxidative coupling. 82
Scheme 64. Proposed synthesis of Bupropion. 83
Scheme 65. Proposed ionic mechanism for the synthesis of Bupropion. 91
Scheme 66. Summary of synthetic efforts towards Bupropion. 95
xvii
List of Tables
Table 1. Substitution attempts on the amino mesylate 36
Table 2. Oxidation conditions of amino sulfane compounds 41
Table 3. Diastereomeric ratio of recrystallization fractions 43
Table 4. Solvent screening reactions for the Henry Reaction with nitromethane. 57
a Determined by chiral HPLC, Chiralcel OD-H column 0.8 mL/min; 85/15 (v/v)
Hexanes/IPA 57
Table 5. Solvent screening reactions for the Henry Reaction with nitroethane 58
Table 6. Solvent screening reaction trials. (Reaction entries expect #2 and #3
were performed by Rebecca Sydor.) 85
Table 7. Acid and iodine source screening reactions. (Reaction entries in this
table were performed by Rebecca Sydor.) 86
Table 8. Oxidant screening reactions. (Reaction entries in this table were
performed by Rebecca Sydor.) 87
Table 9. Screening reactions with aqueous saturated thiosulfate wash during
aqueous work-up. (Reaction entries in this table were performed by Rebecca
Sydor.) 88
xviii
Table 10. Screening reactions performed in screw-top glass pressure vessel and
comparable control reactions. (All reaction entries expect #1 were performed by
Rebecca Sydor.) 89
Table 11. Probing other suitable reagents for α-amination of 3’-
chloropropiophenone. (All reaction entries expect 4 were performed by Rebecca
Sydor.) 90
Table 12. Reaction screening trials with extra equivalents of reagents added.
(Entries marked with asterisk were performed by Rebecca Sydor.) 94
Table 13. Optimized reaction conditions tested with larger scale reactions. 95
1
Chapter 1: Introduction
2
1.0 Introduction
1.1 Asymmetric catalysis
Asymmetric carbon-carbon bond forming reactions are a central component of
synthetic organic chemistry. They play a large role in modern pharmaceutical chemistry
and natural product synthesis, due to the complex and often multiple stereogenic
centres that are typically sought. Given its importance, the field of asymmetric catalysis
has demanded similar attention regarding the development of highly stereoselective
catalysts. Often, chiral-at-metal complexes are utilized to impart stereoselectivity for
these asymmetric transformations.1-3 Here, the active catalytic species is formed from
the coordination of a chiral ligand and an active metal centre.1 The active species can
then form a chelate involving the substrates involved. The designs of chiral ligands
require the consideration of electronic and steric conformations of the chelate to bring
about stereoselectivity.1
1.2 β-Amino thiol and disulfide ligands
The use sulfur in the design of chiral ligands has garnered an increasing amount
of attention.2-6 Sulfur-carrying starting materials are generally commercially available,
and possess a high stability, allowing for facile handling. Naturally, with the
incorporation of a sulfur moiety in chiral ligands, its various oxidation states for use in
asymmetric catalysis have been probed. Moreover, chiral-at-metal complexes often
3
offer an additional accompanying complexing atom to aid in metal coordination to form
an active catalyst. As such, nitrogen atoms are a commonly used, due to the wide array
of natural chirally pure nitrogen containing species, and their commercial availability.5,6
For instance, a series of β-amino thiol ligands, derived from L-valine, were
reported by Anderson et al..7 These ligands were probed for their asymmetric catalytic
activity in addition of organozinc reagents to an aldehyde centre. Previous successful
amino thiol ligands, also used for this reaction, have shown increased catalytic activity
over their related alcohol analogues. This promising feature was thought to arise from
an increased polarizability of the sulfur atom compared to oxygen, and a softer
coordination site, more suited towards transition metal complexation. These ligands
relied on chiral influences by the iso-propyl group and by the differential substitution on
the nitrogen atom, which upon complexation could potentially become a stereogenic
centre, through restricted conformation. Overall, results were modest during their
benchmark reactions using benzaldehyde and diethyl zinc, with enantioselectivities
reaching upwards of 82% for the (R)-stereoisomer. Interestingly, the amino thiol ligands,
which contained mismatched N-substitution, yielded an appreciable improvement in
enantioselectivity over their matched counterparts, thus suggesting that nitrogen itself
could have the potential to be stereogenic (Scheme 1).
In the same report, the authors oxidized the reported amino thiol ligands into their
corresponding disulfides in order to probe them for catalytic activity. Unfortunately, their
activity was generally less efficient with decreased enantioselectivity (ee = 80%).
However the trend of mismatched N-substitution was also observed.7
4
Scheme 1. Test reactions for the asymmetric reduction of benzaldehyde with diethyl zinc with amino thiol and amino disulfide ligands.
The literature has provided conflicting results regarding the effectiveness of
amino thiol ligands in comparison to their disulfide counterparts. Kang et al. reported a
set of ligands with impressive results that were slightly more effective in their amino thiol
form as opposed to the disulfide.8 Along with decreased enantioselectivity, reaction
times with the disulfides were often twice as long. However, in most cases the decrease
in effectiveness was only marginal (Scheme 2).
The literature also provides cases where the opposite trend can be found. Hof et
al. have reported a set of amino disulfide ligands more effective than their thiol
counterpart (Scheme 3).9
H
O
ZnEt2+L*
Et
OH
L* =
1R2RN SH
R1 = R2 = Ph: 85%, ee = 74%R1 = R2 = Bn: 91%, ee = 58%R1 = iPr, R2 = Me: 81%, ee = 72%R1 = Ph, R2 = Me: 89%, ee = 82%
L* =
1R2RN S S NR1R2
R1 = R2 = Bn: 67%, ee = 38%R1 = R2 = Ph: 67%, ee = 59%R1 = Ph, R2 = Me: 85%, ee = 80%
5
Scheme 2. Ligand screening between amino thiol and corresponding amino disulfide ligands.
Scheme 3. Comparison of amino disulfide and amino thiol ligand.
1.3 Sulfonamide moiety in chiral ligands
A related, but more challenging reaction is the 1,2-addition of organozinc
reagents to ketones. This reaction has proved to be more difficult in imparting
stereoselectivity than its aldehyde counterpart, due to the reduced ability of ketones to
coordinate to a Lewis acid catalyst through steric interactions.5,6 Moreover, aldehydes
have a greater propensity to differentiate which oxygen lone pair is coordinated to the
R H
OZnEt2+ L*
R Et
OH
L* =
R = Ph: 90%, ee = 100%R = pClC6H4: 92%, ee = 100%R = oMeOC6H4: 92%, ee = 99%R = 2-Naph: 98%, ee = 99%
L* =HS N
Ph Ph
S N
Ph Ph
SN
PhPh
R = Ph: 92%, ee = 99%R = pClC6H4: 93%, ee = 99%R = oMeOC6H4: 91%, ee = 99%R = 2-Naph: 93%, ee = 98%
HS
Ph Me
S NHMe
Ph Me
S
L* =L* =
MeHN NHMe
PhMe
H
O
ZnEt2+L*
Et
OH
95%, ee = 80% 75%, ee = 86%
6
active catalyst due to lessened steric hindrance of the aldehyde hydrogen compared to
a ketone’s carbon based functionality. In the case of ketones, discrimination between
oxygen lone pairs is greatly reduced since both syn- and anti-coordination tend to have
comparable environments (Scheme 4).5,6
Scheme 4. Selection of lone pair by the activated metal-ligand complex in aldehydes (top) and ketones (bottom).
The reactions of ketones with selected nucleophiles can produce tertiary
alcohols, which are important targets in synthetic chemistry. These products can
typically be accessed via ketone reduction with organolithium or Grignard reagents.
However these protocols require typically harsh conditions and functional group
compatibility suffers. Unlike the organozinc reaction with aldehydes, ketones are not
sufficiently reactive, but difficulties can be overcome through the addition of Ti(OiPr)4
along with the chiral ligand.5,6
The Ti(OiPr)4 is proposed to exchange its own alkoxide for an alkyl group from
the zinc species, allowing the titanium to be the active Lewis acid catalyst, while also
being the carrier of the nucleophilic alkyl reagent (1-1).6 For this reaction the
sulfonamide moiety has been extensively incorporated into the chiral ligands used.
Specifically, the isoborneol-10 sulfonamide motif has been a central component to the
design of these ligands, and has been reported numerous times in various ligand
R H
OMLx
R H
O MLx
R' R"
OMLx
R' R"
O MLx
7
designs. An early chiral isoborneol-derived sulfonamide ligand reported by Yus et al.
was quite successful in catalyzing enantioselective alkylzinc additions to ketones in the
presence of Ti(OiPr)4.10 The ligand performed rather well for simple ketone substituents
and alkylzinc reagents. However, the process was troubled by long reaction times and
high catalyst loading (20 mol%) (Scheme 5). In their report, the authors also postulated
a dinuclear titanium complex as the active catalytic species; one titanium centre carried
the ligand and ketone, while the other carried the alkyl nucleophile, and both metal
centres were bridged by two alkoxides.
Scheme 5. Substrate scope tests enantioselective alkylzinc additions to ketones in presence of Ti(OiPr)4.
A report form Lu et al. utilized this same isoborneol-10 sulfonamide motif for the
alkynation of ketones to produce valuable tertiary propargylic alcohols.11 Screening
reactions, which varied substituents at various positions on the isoborneol ring and N-
O
SO2NHTi
O
ArR
H
O
O
iPr
iPr
Ti
Et
OiPrOiPrOiPr
Ar R
H
O L*ZnEt2
Ti(iOPr)4
Active catalytic species:
R1 R2
OZnR32+
Ti(OiPr)4
L* R1 R2
R3 OH
OH
SO2NH
L* =
R1 = Ph, R2 = R3 = Et: 63%, ee = 84%R1 = Ph, R2 = Me, R3 = Et: 85%, ee = 86%R1 = Ph, R2 = nBu, R3 = Et: 78%, ee = 86%R1 = Ph, R2 = Et, R3 = Me: 85%, ee = 86%
1-1
8
sulfonamide position of the ligand, led to the use of the same ligand reported by Yus et
al. In this report, the reduced reactivities of ketones and organozinc species was aided
by the addition of the stronger Lewis acid, Cu(OTf)2, in catalytic amounts.11 Overall, this
ligand was able to promote excellent enantioselectivities for the formation tertiary
propargylic alcohols (Scheme 6).
Scheme 6. Asymmetric alkynation of ketones via isoborneol-10 sulfonamide lewis acid catalyst.
1.4 Incorporation of the sulfoxide moiety in chiral ligands
A recent review from Trost and Roa delved into the development of chiral
sulfoxide ligands, and concluded that their use in asymmetric catalysis has much more
left to be explored.12 The sulfoxide functionality offers many distinct characteristics: (I) it
possesses a high optical stability, (II) it efficiently carries chiral information, (III) it can be
accessed in both enantiomeric forms, and (IV) it benefits from a large steric and
electronic differentiation between its surrounding carbon and oxygen environment.12
Ph
OZnMe2
+Cu(OTf)2
L* PhOH
OH
SO2NH
L* =R = H: 92%, ee = 88%R = Br: 65%, ee = 96%R = Cl: 94%, ee = 97%R = F: 91%, ee = 96%
R PhH
Ph
R
9
Moreover, the sulfoxide presumably places the location of stereogenecity close to the
reaction centre, which can assist the surrounding chiral carbon backbone. Furthermore,
this highly polarized functionality lends the potential to differentiate between S- and O-
coordination with ‘hard’ and ‘soft’ metals.12,13
James et al. were the first to report a chiral ligand, which included the sulfoxide
functionality in 1976.14 This novel ligand was employed for the hydrogenation of itaconic
acid to form methylsuccinic acid. Although the yields and enantioselectivities were less
than promising, it led them to design two more generations of catalyst for asymmetric
hydrogenation, each with varying design for coordinating groups. The first ligand
disclosed was employed as a diastereomeric mixture and featured an additional chiral
carbon stereocentre (1-2).14 Unfortunately, the results were less than ideal and low
yields with poor accompanying stereoselectivities were reported (Scheme 7).
Scheme 7. The first application of the sulfoxide moiety in asymmetric catalysis, which was employed as a diastereomeric mixture.
The second-generation sulfoxide ligand 1-3 reported from this research group
featured a bis-sulfoxide motif still as a diastereomeric mixture, designed in part to
enhance its chelating capabilities.15 Furthermore, during screening reactions, the
HO
OOH
OHO
OOH
ORuCl3•H2O, L*H2
N,N-dimethylacetamide50 ˚C
50%, 12% ee
L* = SO
d.r. = 1:1
1-2
10
substrates were varied in order to test any additional substrate chelating effects.
Itaconic acid underwent the most stereoselective transformation (ee = 25%). However,
atropic and 2-acetamidoacrylic acid underwent hydrogenation with significantly lower
selectivities, which suggested that the presence of an additional carboxylate group aids
the asymmetric transformation (Scheme 8).
This prompted the design of a third generation of sulfoxide-based ligand 1-4,
which incorporated a carboxylate group, once again as a diastereomeric mixture. In
contrast to the previous two reactions this catalyst system utilized a rhodium system and
iPrOH as the hydrogen source.16 Overall, the presence of the carboxylate group
seemingly provided increased enantioselectivities for the hydrogenation (Scheme 9).
Scheme 8. Diastereomeric bis-sulfoxide ligand employed in an asymmetric hydrogenation reaction.
HO
OOH
OHO
OOH
O
RuCl2(DMSO)4, L*H2
N,N-dimethylacetamide50 ˚C
L* =
d.r. = 1:1
HO
O
Ph
HO
O
HN
O
HO
O
Ph
HO
O
HN
O
49%, ee = 25%
17%, ee = 4%
52%, ee = 7%
SO
SO
OO
1-3
11
Scheme 9. Multidentate sulfoxide ligand used for asymmetric hydrogenation (hd = 1,5-hexadiene).
1.5 Optically pure sulfoxide ligands
It was not until 1993, that Carreño et al. employed enantiopure β-
hydroxysulfoxide ligands in the alkylation of aromatic aldehydes (Scheme 10).17 A
variety of ligands were reported and varied in carbon skeleton flexibility as well as
crowding around the β-hydroxy centre. Results were modest, but the absolute chirality
of the sulfoxide was given appreciation upon the authors proposing a plausible
mechanism. It was suggested that the sulfinyl oxygen coordinated with the organozinc
species in order to create a more stable six-membered transition state 1-5 (as opposed
to a five-membered ring) (Scheme 11). Interestingly, pre-treatment of one of the ligands
with AlMe3 increased stereoselectivity, however its involvement was not probed further.
R
R'
O
R
R'
OH[RhCl(hd)2], L*
iPrOH, reflux
R = H, R' = Me: 45%, ee = 63%R = H, R' = Et: 21%, ee = 71%R = Me, R' = Me: 31%, ee = 75%
SO
HN
O
OH
OL* =
1-4
12
Scheme 10. Optically pure sulfoxide ligands employed in asymmetric aldehyde alkylation.
Scheme 11. Proposed active catalytic species with 1-5
As the sulfoxide moiety was continually incorporated into chiral ligands, it was
paired increasingly with adjacent amine and amine-derived functionalities. Moreover,
the stereogenecity of the sulfur centre itself garnered further attention. This was
highlighted in a report from Williams et al., which further displayed the versatility of the
chiral configuration of the sulfoxide.18 The reported ligands were screened against the
extensively studied Pd-catalyzed Tsuji-Trost allylic substitution, presumably due to its
well-defined catalytic cycle (Scheme 12).6 While many successful sulfur-based ligands
H
O
ZnEt2+L*
Et
OH
OHSO OH
SO
SOHO
SOHO
ee = -9% ee = 22% ee = 11% ee = 45%* when pre-treated
with AlMe3 ee = 55%
L* =
SO
ZnO
RR
HEt
Zn EtO
Et
Ph
H
SO
ZnO
RR
HEt
Zn Et
Et
PhCHO
Proposed active catalytic species:
1-5
13
have successfully imparted stereoselectivity in this transformation, phosphorous-based
ligands have still shown to be the most effective.6
Scheme 12. Catalytic cycle for the palladium-catalyzed Tsuji-Trost allylic substitution.
During ligand evaluation, the diastereomeric pairs each provided noticeably
different results (Scheme 13).18 Although the (SS) isomer proved to be more effective
than its complementary pair, the sulfoxide’s presence was found to be nonessential, as
evidenced by the superior performance of the sulfane ligand. This suggested that the
palladium interacts with the ligand through either of the sulfane’s enantiotopic lone-pairs
to form a diastereopure catalyst, and possesses the potential to readily switch to a
preferred configuration upon palladium binding. Moreover, the ineffectiveness of the
sulfone-based ligand, which can only coordinate through its sulfonyl oxygen, further
supports S-Pd coordination.18
X
X
PdL L'
PdL L'
Nu
PdL L'
NuPd
S**S
L L'
XNu
decoordination coordination
oxidativeaddition
nucleophilicaddition
L, L' = ligandS* = solvent/vacantX = leaving groupNu = nucleophile
14
Scheme 13. Test reaction for the palladium-catalyzed Tsuji-Trost allylic substitution and examination of the reactivity of sulfur moiety in different oxidation states.
In 1997, Hiroi et al. reported a set of β-amino sulfoxide ligands for use in
asymmetric allylation.19 These ligands utilized the sulfoxide as the lone source of
chirality. In their communication, a variety of ligands were prepared, however only the
(SS)-sulfoxide was probed for catalytic activity. Their reported ligands performed with
moderate efficiency, however it was highlighted that rotationally restricted ligands (1-6)
offered improved stereoselectivities during this coupling (Scheme 14).19
Such an observation from these ligands was rationalized by the proposed
formation of a rigid 5-membered palladacyclic chelate ring, favoured by the planar
phenyl connector. Here, the sulfinyl electron lone pair is the coordination point. A 6-
membered chelate ring is certainly feasible, but the planar influence of the phenyl ring
could act to discourage that. Once the 5-membered chelate 1-7 has been established,
the coordination would provide a chiral environment allowing a nucleophilic attack from
a sulfinyl oxygen approach manner to afford the favoured (S)-product (Figure 1).
Ph Ph
OAc
MeO OMe
O O
Ph Ph
OMeMeO
O O
+[{Pd(n3-allyl)Cl}2], L*
KOAc
CH2Cl2
S O N
O
SO
N
O
S N
O
SO2 N
OL* =
96%, ee = 88% 42%, ee = 55% 69%, ee = 93% 0%, ee = n/a
15
Scheme 14. Test reaction for the palladium-catalyzed Tsuji-Trost allylic substitution.
Figure 1. Proposed 5-membered chelate transition state to rationalize favoured production of (S)-product.
Another communication from Hiroi et al. reports a chiral ligand which combined
the amido sulfoxide and phosphine functionalities, which was utilized to couple dimethyl
malonate and rac-(E)-1,3,-diphenylallyl (Scheme 15).20 Interestingly, they also provided
a more in-depth screening on complementary sulfoxide diastereomers. While neither
ligand displayed exceptional effectiveness, the marked difference in their catalytic ability
was rather intriguing. In comparing the complementary sulfinyl diastereomers, the (R)-
diastereomer (1-8) resulted in a low 53% yield, but was accompanied by a moderate
S
N
O
OtBu
O OOAc+ OtBu
O O[PdCl(π−allyl)2]
L* =
Yield = 25% (S)ee = 50%
*
1-6
NSO
Pd
16
stereoselectivity with ee = 74% for the (S)-product. The (S)-diastereomer (1-9) resulted
in a similar 58% yield, however it was essentially non-stereoselective (ee = 2%)
(Scheme 15).
Scheme 15. Test reaction for the palladium-catalyzed Tsuji-Trost allylic substitution using complementary (RS, S) and (SS, S) sulfoxide diastereomer ligands.
Such significant differences in stereoselectivity were proposed to arise from
different conformational preferences of the π-allyl group to the 9-membered
palladacyclic complex between either diastereomer, largely due to steric interactions
(Scheme 16).20 In the complex formed from the (R)-diastereomer 1-10, which provided
greater asymmetric control, the chelate resulted in a matched M-type π-allyl
conformation. In this favourable conformation, the phenyl π-allyl phenyl groups are
located in favourable locations, with regards to the sulfoxide and phosphine
substituents. Here, the C3 terminus is the favoured point of attack, since it is placed
trans to the better π-accepting phosphine moiety. In the complementary (S)-
N
O
S Bn
O
N
O
S Bn
O PPh2PPh2
L* =
(RS,S)Yield = 53%ee = 74%
(SS,S)Yield = 58%ee = 2%
Ph Ph
OAc
MeO OMe
O O
Ph Ph
OMeMeO
O O
+[PdCl(π−allyl)2]
1-8 1-9
17
diastereomer, an equilibrium exits between the M- and W-type allyl conformation
chelate (1-11, 1-12), to manage the steric interactions between the π-allyl phenyl
groups. Attack at the C3 terminus is still certainly favoured, however the M- and W-π-
allyl equilibrium results in a near racemic mix of (R) and (S)-products (Scheme 16).20
Scheme 16. Proposed 9-membered transition states to rationalize enenatioselectivity in (RS, S) and (SS, S) sulfoxide diastereomer ligands.
Recently, Xiao et al. reported an effective ligand (1-13) for use in this reaction,
which incorporated amido sulfoxide functionalities with a phosphine moiety (Scheme
17).21 In the benchmark test, which coupled dimethyl malonate with rac-(E)-1,3,-
diphenylallyl acetate in the presence of Pd catalyst, K2CO3 and Cs2CO3, the authors
reported a 99% GC-yield along with 99% ee for the (S)-product. While impressive, these
screening reactions were performed at a small scale (0.3 mmol of rac-(E)-1,3,-
diphenylallyl acetate and 0.9 mmol of malonate) and investigation of these parameters
at a larger scale would serve to increase the relevance of these observed results.
Interestingly, they were able to obtain the enantiomeric (R)-product with mono-α-
PdPS
N
Ph
Ph
OR Pd
PS
N
Ph
Ph
RO
O O
Ph Ph Ph Ph1 Ph Ph13
PdPS
N
Ph
Ph
RO
O
1 3
(R)
(R)(S)(S)
3
(S)
Nu Nu Nu1-10 1-11 1-12
M-conformation M-conformation W-conformation
18
substituted dimethyl malonate substrates, in similarly high yields and ee’s, although the
authors did not investigate this occurrence further.
Scheme 17. Test reaction for the palladium-catalyzed Tsuji-Trost allylic substitution using amido phospino sulfoxide ligand.
During the development of these ligands, Xiao et al. designed a series of control
experiments to evaluate the sulfoxide moiety’s contribution to the ligands
stereoselective ability. The low catalytic activity of analogous sulfane and sulfone
derivatives of the efficient ligand highlighted the importance of its presence as a chiral
auxiliary (Figure 2). However, in these control and subsequent substrate scope
experiments, only the (RS)-diastereomer was examined for catalytic activity.21 Despite
the limited screening of the chiral sulfoxide influence, its effectiveness certainly offers a
remarkable improvement over amino-derived sulfoxide ligands previously used for this
reaction.
PPh2
NH SO
OBr
L* =
Ph Ph
OAc
MeO OMe
O O
Ph Ph
OMeMeO
O O
+[Pd(C3H5)Cl]2 / L*K2CO3, Cs2CO3
CH2Cl2
Yield = 99% (S) ee = 99%
1-13
19
Figure 2. Probing the effectiveness of the sulfoxide moiety.
The inclusion of the sulfoxide moiety in chiral ligands continued to provide varied
results in regards to their efficacy and such ligands were still probed mostly as a curious
afterthought once amino sulfane ligands had been prepared. For instance, a set of
amino sulfoxide ligands 1-14 for the asymmetric hydrogen transfer to ketones was
reported by Petra et al., and was merely included in their optimization tests for their
already successful amino sulfane ligands.22 Unfortunately, such curiosity was met with
both low yields and ee values in the transformation (Scheme 18).
In that same communication from Petra et al., another set of amino sulfoxide
ligands, derived from their successful corresponding amino sulfane, was probed for
catalytic activity. In accessing the amino sulfoxide ligands, both diastereomers were
obtained and tested in the asymmetric hydrogenation of acetophenone. While the
reported stereoselectivities were modest at best, it displayed versatility of the sulfoxide
stereogenicity in imparting enantioselectivity in the resulting product. As such, the (RS)
PPh2
NH SO
OBr
L* =
3 hoursYield = 99% (S) ee = 99%
PPh2
NH SO
60 hoursYield = 5% (R) ee = 54%
PPh2
NH O2SO
60 hoursYield = 4% (R)ee = 38%
OMe
20
and (SS) sulfoxide diastereomers (1-15, 1-16) afforded (R) and (S) gem-phenylethanol,
respectively, while the sulfane only obtained the (S) alcohol (Figure 3).22
Scheme 18. Enhanced catalytic activity of an amino sulfane over its diastereomeric amino sulfoxide counterpart.
Figure 3. Enhanced reactivity of the (SS) sulfoxide conformation.
Amino sulfoxide ligands have also seen an increased utility in the Diels-Alder
reaction.6,12 This reaction is yet another significant carbon-carbon bond forming reaction
that has a diverse utility in asymmetric synthesis. This [4+2] cycloaddition can quickly
afford complex stereogenic centres from readily available compounds. In the
cycloaddition shown in Scheme 19, a complex mixture of four chiral compounds is
O OHHCO2H / Et3N[IrCl(COD)]2
L*
S NH2
Me
L* =
S NH2
Me
L* =
O
>99% Yield, 65% ee (Rs) = 32% Yield, 32% ee(Ss) = 9% Yield, 2% ee
1-14
S NH2
MeL* =
S NH2
Me
OO
(Rs) = 56% Yield (R)-gem-phenylethanol, 27% ee
(Ss) = 99% Yield (S)-gem-phenylethanol, 65% ee
1-15 1-16
21
readily afforded, which the next few examples utilized as their test reaction. As such,
asymmetric catalysis for this reaction certainly faces challenges in these stereoselective
syntheses.6,12
Scheme 19. Endo and exo adducts and respective enantiomers for the asymmetric Diels-Alder cycloaddition.
Khiar et al. first reported the use of chirally pure sulfoxide-based ligands, which
featured C2-symmetric bis(sulfoxide) motif (Scheme 20).23 The ligand successfully
imparted diastereoselectivity for the endo-adduct (96:4 endo/exo), however
enantioselectivity remained modest (ee = 56%). The ligand was postulated to form a
chelate through the sulfinyl oxygens in order to form an octahedral iron complex 1-17,
which provided enantioselectivity by limiting the diene to an underneath approach from
the less hindered side.23
To this point, amino sulfoxide and related N-derivatives had not yet been
frequently incorporated into ligands for this reaction. The work of Hiroi and co-workers
has helped bring more attention to those functionalities in ligand design.19,20,24-31 Their
work summarized two sets of chiral ligands that both utilize the oxazoline and sulfoxide
O N
OO Catalyst
H
RR
H
HR
(R)
(R)(S)
(S)
endo
exo
O N
OOR =
+
R
H
22
moieties, but contrast each other in the amount of rotational freedom. Their results
displayed promise; however they highlighted the challenges regarding cycloadditions of
this nature. In their 2002 communication, the reported ligands with more rotational
freedom consistently delivered great yields (often as high as 93%), with equally
impressive endo-diastereoselectivity (as high as dr = 93%).31 Their reported ligands
were also able to impart enantioselectivity for the endo-diastereomers by variation of the
substituents present on the oxazoline moiety, however the results for either enantiomer
were moderate at best (ee = 57% for (S)-endo, 66% for (R)-endo).31
Scheme 20. Test reaction for asymmetric Diels-Alder cycloaddition and the proposed active catalytic species.
In the (S)-selective ligand, the formation of a six membered copper chelate was
proposed. The chelate utilized the nitrogen and sulfinyl oxygen coordination points and
its most stable conformation 1-18 (Scheme 21) alleviates any steric clashes between
H
O NOO
78%, 96:4 endo/exo, ee = 56%
S SO OL* =
FeI
I
OOOO
SS
N
O
Proposed active catalytic species:
1-17
23
the tert-butyl group and the copper chelate coordinated to the dienophile. In this
conformation, the diene is afforded by an approach from the sterically less crowded Re-
face affording the (R)-endo-product, by way of the axial sulfinyl p-tolyl and tert-butyl
placements (Scheme 21).31
Scheme 21. Proposed 6-membered transition state to rationalize Re-face approach leading to (R)-endo product.
The (R)-selective ligand was also proposed to proceed through a 6-membered
chelate. However, the more flexible benzyl of 1-19 group does not create the same
interaction with the copper coordinated dienophile, and the opposite chair conformer is
preferred, with the sulfinyl p-tolyl in its equatorial position. Here, the diene approach
from the Si-face is favoured to afford the (S)-endo-product (Scheme 22).31
This model was further supported by the results of an analogous (R)-selective ligand
with an additional gem-dimethyl functionality (1-20) (Scheme 23). This ligand resulted in
SO N
O
Cu
OS
N O O Cu
SO H
N
X X
Re-face
XX 1-18
Re-face
Cu
O O
N
Cu
O O
NO O
Cu
X X= or
24
similar enantioselectivity, rationalized by the presence of the new methyl groups to lock
the sulfinyl p-tolyl in the equatorial position.31
Scheme 22. Proposed 6-membered transition state to rationalize Si-face approach leading to (S)-endo product.
Scheme 23. Addition of methyl group to lock p-tol group in equatorial position.
An earlier communication from Hiroi et al. reported yet another set of imino
sulfoxide ligands.29 Similarly, a high yield and diastereoselectivity for the endo-product
was observed. Moreover, a drastically improved enantioselectivity was reported,
reaching 92% ee for the (S)-product. Its effectiveness was rationalized through the
formation of a 6-membered chelate, where the sulfinyl oxygen and imine were the
coordination points (Scheme 24). Although an equilibrium exists between the two
SO N
O Cu
OS
N O
XX
Si-face
Si-face 1-19
SO N
OCu
OS
N O
XX
1-20
25
dienophile-coordination modes, 1-21 and 1-22, the ligands design favours an approach
of the diene from the Re-face in either conformation.29
Scheme 24. Proposed transition state to favour diene approach from the Re-face in either conformation to afford the (S)-product.
These few selected examples of nitrogen-based sulfoxide ligands are just a few
examples of their utility for asymmetric transformation. There have been many effective
ligands reported, and have been applied to a variety of carbon-carbon bond forming
reactions.
The Kiełbasinski group reported a highly versatile tridentate amino sulfoxide
ligand, along with a unique way of accessing its enantiopure sulfoxide centre.32-37 This
ligand motif continues to find utility in increasing amounts of C-C bond forming reaction,
through variation of substituents around the ligand’s amino centre. The construction of
this ligand utilizes traditional oxidation of bis(2-hydroxymethylphenyl) sulfane to afford
the corresponding prochiral sulfoxide. Next it is subjected to enzyme-mediated de-
SO
Mg
N O
OMe
OO
ON
SO
Mg
N O
OMe
OO
O N
Re-face
Re-face
1-211-22
26
symmetrization sulfane with CAL-B lipase and vinyl acetate to access the de-
symmetrized sulfoxide 1-23 in excellent yields and stereoselectivities, which served as a
framework to access the desired amino sulfoxide ligands. (Scheme 25).33
This ligand has been utilized for the Aza-Henry reaction with outstanding results
and required no additional metal salts (Scheme 26).34 Recently, this ligand motif has
been reported for use in the asymmetric Simmons-Smith under Sharpless conditions,
and was the first of its kind to utilize a sulfoxide-based ligand (Scheme 27).32
Scheme 25. Enzyme-mediated de-symmetrisation sulfane with CAL-B lipase and vinyl acetate to access the de-symmetrized sulfoxide.
SOHO O
S
HO OH
S*OHO OH
NaIO4
EtOH/H2O 1:1,rt
Olipase,(CAL-B)
CHCl3
O
O
98% Yield, 98% ee
1-23
1. (MeSO2)2O, Et3N, CH2Cl22. R-NH2
SOHO NHR
Amino sulfoxide ligandaccessed via CAL-B
lipase de-symmetrization
27
Scheme 26. Test reaction for the Aza-Henry reaction
Scheme 27. Test reaction for Simmons-Ingold cyclopropanation
Recently, Xiao et al. reported an imino sulfoxide ligand for use in this asymmetric
transformation.38 This ligand’s structural motif has served them well, and was in fact the
basis for their highly efficient amido sulfoxide ligands used in the Tsuji-Trost reaction
(Scheme 16 and Figure 1). In the initial screening parameters, these imino sulfoxide
ligands were able to achieve high yields with great stereoselectivity (up to 94%, ee =
85%), and results further improved upon optimization (Scheme 28).38
SOHO
HN
R
H
N Boc
R
HN Boc
NO2L*, Et3NMeNO2, toluene, 35 ˚C
L* = R = H: 97%, ee = 94%R = Me: 97%, ee = 96%R = MeO: 98%, ee = 94%R = NO2: 91%, ee = 86%R = Br: 95%, ee = 94%
SOHO NL* =
R2
R1 OH
R2
R1 OH*
*
L*, Et2AlCl, Et2Zn, CH2I2
DCM, rt
MeO
OH
Cl
OH
OH
Substrate Yield eeAbsolute
Configuration
91%
89%
92%
92%
94%
90%
1S,2S
1S,2S
1S,2S
28
Scheme 28. Imino (Schiff-base) sulfoxide ligands used in the Henry reaction.
Despite screening only one sulfoxide diastereomer 1-24, they have reported an
extensive analysis of the influence of the ligand’s moieties in this transformation. The
related sulfonyl ligand performed poorly, indicating that the coordination to the copper
centre likely occurs through the sulfur lone-pairs. Moreover, although the sulfane
derivative was able to deliver high yields, the significant decline of enantioselectivity
suggests that the stereogenic sulfinyl centre allows for proper discrimination of metal to
sulfoxide lone-pair coordination (Scheme 29).38
R H
O Cu(OAc)2•H2O, L*
tBuOH R
OHNO2
L* =
SNO
OH
R = 4-NO2Ph: 94%, ee = 93%R = 2-NO2Ph: 95%, ee = 96%R = 4-CF3Ph: 96%, ee = 94%R = 2,4-Cl2Ph: 98%, ee = 95%R = 2-OMePh: 92%, ee = 94%
1-24
29
Scheme 29. Probing the importance of the sulfoxide moiety
1.6 Accessing the sulfoxide moiety through sulfenate anion chemistry
In the selected examples above, the sulfoxide functionality was frequently
accessed through conventional sulfane oxidation. While this is certainly a reliable
protocol to access the sulfoxide, it offers little control over the resultant stereochemistry.
While the presence of other chiral centres may help in directing sulfur stereogenicity, the
resulting stereoinduction varies greatly from substrate to substrate.6,12,13 As a result,
recrystallization protocols have been used to access isomerically pure sulfoxides. Flash
column chromatography has also been able to separate sulfoxide isomers, however its
separation once again varies heavily with the compounds structure.6,12,13
The Schwan group has made significant inroads in the exploration of the
sulfenate anion chemistry.39-43 While this nucleophilic species can undergo “hard” O-
alkylation, the focus has mainly been in its “soft” alkylation, largely due to the ability to
H
O Cu(OAc)2•H2O, L*
tBuOH
OHNO2
L* =
SNO
OH
O2N O2N
O2SN
OH
SN
OH
94%, ee = 85% 59%, ee = 0% 94%, ee = 34%
30
form another stereocentre (Scheme 30).39,40,44 This conceptually novel method of
simultaneously introducing a sulfur and oxygen has seen a rapid increase of interest
and presents an alternate pathway to access the sulfoxide group.
Scheme 30. O- and S- sulfenate anion alkylation
The work of Söderman and Schwan in regards to sulfenate anion chemistry has
resulted in a highly diastereoselective synthesis of (RC, SS) or (SC, RS) β-amino
sulfoxides.42,43 The sulfenate anion was accessed via a nucleophilic addition-elimination
mechanism from a 2-sulfinyl acrylate precursor. In short, a homochiral amino iodide
electrophile was utilized in directing stereogenicity at the sulfur centre in the resulting
sulfoxide. The (S)-β-amino iodide electrophiles yielded (RS,SC)-β-amino sulfoxides,
whereas (R)-β-amino iodide electrophiles yielded (SS,RC)-β-amino sulfoxides. A
thorough optimization concluded that sulfenates typically required an aromatic
substituent to be efficiently released from its 2-sulfinyl acrylate form. This method of
generating sulfoxides provided moderate to high yields (up to 91%), and diastereomeric
ratios as high as 94:6.42,43 Such diastereoselectivity was rationalised through internal
complexation of the lithium counterion with the electrophile’s nitrogen lone pair to create
a stable chair form to impart stereoselectivity (Figure 4).43
R S O M R SO
M
R'-XS-Alkylation
R'-XO-Alkylation
R S O R'R SO
R'
31
Figure 4. Proposed internal complexation transition state to account for observed sulfenate diastereoselectivity with homochiral amino electrophiles.
Building on these results, we propose to build heteroaryl β-amino sulfoxide
ligand, and probe them for catalytic activity in the Henry reaction. We propose to build
these ligands using traditional oxidative syntheses and sulfenate anion chemistry, with
the aim of probing diastereopure conformations of each of these chiral ligands.
SO Li N
HetI
BnH
HBoc
via:
32
Chapter 2: Results and Discussion
33
2.0 Results and Discussion
2.1 Chiral ligand design and synthesis
The overall ligand design of the multidentate β-aminosulfoxide ligands can be
deconstructed into two fragments consisting of a nucleophilic source of sulfur, and an
electrophilic amine-containing alkyl group. In an attempt to access diastereopure
compounds, two pathways were envisioned for the construction of these amino-
sulfoxide ligands (Scheme 31). The first pathway begins with the construction of an β-
aminosulfane intermediate, which is to be followed by oxidation to access the β-
aminosulfoxide target (left, Scheme 31). The second pathway involves generation of the
heteroaryl sulfenate anion, which would lead directly to the desired target (right, Scheme
31). Reports from Söderman and Schwan indicate that the sulfenate anion reacted with
an N-Boc amino-acid based electrophile would favour a diastereomeric (SS,RC)
outcome. While the traditional oxidative approach typically lacks diastereoselectivity,
this method may provide a means of accessing the complementary (RS,RC)
diastereomer. Finally, upon accessing the targeted ligand, the N-Boc protecting group
will be removed to yield the desired ligand for use in catalytic studies.
34
Scheme 31. Retrosynthethic approach towards the construction of heteroaryl amino sulfoxide ligands.
2.2 Synthesis of β-amino electrophile
The preparation of the electrophilic amine-containing portion began with the
reduction of N-Boc protected L-phenylalanine as the initial source of chirality. It was
envisioned that upon reduction the hydroxyl group would be converted to a mesylate,
thus providing a suitable leaving group (Scheme 32).
Scheme 32. Reduction of N-Boc protected L-phenylalanine
Despite the facile acquisition of this mesylated amino compound 1-25, it proved
to be unsuitable as an electrophile for our purposes. Its reaction with both sulfenate and
thiolate nucleophiles were unsuccessful. Trial reactions with p-tolyl sulfenate anions with
varying amounts of mesylated electrophile resulted in no sulfoxide generation and
recovery of the electrophile (Table 1, entries 1-3). It can be envisioned that the presence
HetAr S*O Bn
NHBocHetAr SH LGBn
NHBoc HetAr S OM LGBn
NHBoc++
Followed by oxidation of corresponding sulfane
Traditional Oxidation Sulfenate Anion
HetAr = 2-pyridyl, 8-quinolyl
HO
ONHBoc
Bn
HO NHBoc
BnO NHBoc
Bn
SMeO O
1. EtOC(O)Cl, Et3N,THF, 0 ˚C to rt
2. NaBH4, H2O,0 ˚C to rt
MsCl, Et3N,0 ˚C to rt
(81%) (94%)1-25
DCM
35
of Li+ ions, arising from the required addition of nBuLi, could potentially complex with the
similarly “hard” nucleophilic oxygens form the mesylate moiety, creating steric bulk, and
thereby preventing sulfenate attack. Alternatively, the complexation effect may position
the sulfenate in a manner that precludes backside substitution on the mesylate.
Similarly, thiolate reactions starting 2-mercaptopyridine provided a similar outcome
(Entries 4 & 5, Table 1).
Due to the unsuccessful reactions of sulfur-based nucleophiles with these
mesylated compounds, further investigation with them was not pursued, and efforts to
access an iodinated electrophile, similar to those in the sulfenate reactions reported by
Söderman and Schwan, were made. The initial synthesis of this electrophile proved to
be more difficult, due to their lower yields, difficulty in purification, and the potential
formation of a recalcitrant by-product.
Initial reaction conditions described the addition of an iodine solution in DCM to a
solution of Ph3P and imidazole in DCM (Scheme 33). However, the iodine never fully
dissolved before it was transferred. This led to unreacted Ph3P, which typically co-eluted
with the iodinated product during flash column chromatography, even with low-polarity
mobile phases (95:5 hexanes/EtOAc). Upon formation of the amino iodide it was not
particularly stable. It had a tendency to react intramolecularly when heated or subjected
to aqueous work-up, resulting in the formation of benzylated cyclic carbamate 1-26
through the loss of the N-Boc group (Scheme 33).
36
Table 1. Substitution attempts on the amino mesylate
Scheme 33. Synthesis of amino iodide electrophile and formation of cyclic by-product. a Dissolve iodine in DCM and transfer resultant solution to Ph3P and imid. in DCM.
S OLi
Nucleophile
N
SH
Equivalents ElectrophileEntry
1.0
1.5
2.0
1.0
1.0
1
2
3
4
5
Conditions
Sulfenate generation
from 2-sulfinylacrylate a
Hünig's base
Et3N, K2CO3
NucleophileMsO
Bn
NHBoc NuBn
NHBoc
aS*
ptol
O CO2Me nBuLi
(1.0 equiv)+
HO NHBoc
BnI NHBoc
BnPh3P, imid, I2,DCM
0 ˚C to rt
IBn
NH
O OO
NH
O
Bn
ONH
O
Bn
H
BH +
BB
Intramolecular formation of by-product:
(73%)
1-26
37
In order to create a more favourable outcome, Ph3P, imidazole, and iodine were
placed in the same reaction vessel, and cooled to -78 ˚C, before solvent was added.
This mixture was stirred until all iodine appeared to be in solution, which would allow
complete reaction with Ph3P. Upon addition of the amino alcohol and a slow
temperature increase to ambient conditions, the crude reaction mixture contained no
Ph3P as confirmed by TLC. To circumvent by-product formation, the crude reaction
mixture was placed directly under reduced pressure, concentrated, and subsequently
loaded into a short silica plug for facile purification (10 g silica/1 g crude material; eluted
with 90:10 hexanes/EtOAc; yield = 67 – 73%). While the yields for this reaction were
only marginally increased, these updated conditions allow for quicker and undemanding
access to this amino iodide electrophile.
2.3 Heteroaryl thiols
The amino iodide electrophile proved to be a suitable electrophile for both
sulfenate and thiolate nucleophiles. Both of the proposed pathways for our ligand
construction began with either 2-mercaptopyridine or 8-mercaptoquinoline (1-27). While
the former is readily accessible, the latter is very costly and multi-gram quantities are
not commercially available. Consequently, more cost-effective precursors were sought.
One protocol began with 8-bromoquinoline, which was treated in separate experiments,
with potassium thioacetate and potassium thiocyanate with the goal of effecting an SNAr
substitution. Traditionally, this reaction requires the presence of strong electron-
38
withdrawing groups (e.g. p/o-NO2) on the arene to invoke nucleophilic attack at the ipso-
position.45,46 Here, it was hypothesized that the present quinolyl system could act as the
analogous electron-withdrawing group (Scheme 34). Unfortunately, all attempts towards
an SNAr reaction proved unsuccessful, as starting material failed to react (confirmed via
TLC).
An alternative pathway to access 8-mercaptoquinoline began with the reduction
of its corresponding sulfonyl chloride derivative. A report from Akamanchi et al. detailed
a quick and efficient reduction of this moiety using Ph3P (Scheme 35).47 With their
method, the reduction of 8-quinoline sulfonyl chloride yielded a 72% yield of the
corresponding thiol. No mechanism was included in their report, however one can
envision that the reaction proceed employing Ph3P as the principal reducing agent. The
use of base allows for the access of the corresponding thiolate and acidification affords
the desired thiol 1-27 (Scheme 35).
Scheme 34. Attempts towards SNAr substitutions with potassium thioacetate and potassium thiocyanate.
N
BrK-S-X
N
S X
Key Intermediate
HydrolysisN
SH
K-S-X Conditions
K-S-CN
K-S-C(O)Me
K-S-C(O)Me
DMSO, rt
DMSO, 80 ˚C
DMSO, 80 ˚C
1-27
39
Scheme 35. Reduction of sulfonyl chloride moiety to a thiol vial Ph3P.
2.4 Traditional oxidative synthesis of β-amino sulfoxide ligands
In order to access the desired amino-sulfoxide ligands via traditional oxidative
means, the corresponding sulfane 1-28 must first be accessed (Scheme 36). The
optimal conditions for this substitution utilize two equivalents of Hünig’s base and two
equivalents of the amino iodide electrophile. It is imperative that the reaction takes place
under an inert atmosphere, to prevent thiolate oxidation and heteroaryl disulfide
formation. In addition, the single equivalent excess of electrophile aids to drive the
desired substitution reaction forward. Similar reactions, which lacked meticulous effort in
maintaining an inert atmosphere and only one equivalent of electrophile, consequently
formed the disulfide compounds. These by-products have very similar polarities to their
8-quin SO O
Cl PPh3(1st equiv)
8-quin SO O
8-quin SO
O+ PPh3Cl
Ph3P(2nd equiv) Ph3P(O)
8-quin SO
O PPh3
8-quin SO
PPh38-quin S O PPh3Ph3P
(3rd equiv)
8-quinSPh3PPh3P(O)
HO8-quin S
H+
NSH
(76%)
Ph3P(O)
- Cl-
1-27
40
corresponding amino-sulfane compounds, which resulted in an arduous purification via
flash-column chromatography and a need for recrystallization afterwards.
Scheme 36. Thiolate substitution to access amino sulfane compounds
Various oxidation protocols were utilized on the amino-sulfane compounds to
probe for any diastereoselective preferences during sulfoxide generation (Table 2).
While diastereomeric ratios of corresponding amino-sulfoxides 1-29 were similar and
modest at best, they provided insight into the effectiveness of each protocol for use in
future sulfane oxidations. Trials of various oxidation procedures led us to prefer
mCPBA-mediated oxidations. These provided the highest yields and typically consumed
nearly all of the starting heteroaryl amino-sulfane materials. Moreover, these reactions
required the least time compared to the other methods (8 - 10 hours). Over-oxidation to
the corresponding sulfone is sometimes a concern when using mCPBA, however this
was circumvented by starting the oxidation at -78 ˚C for the first 3 hours and then raising
it to -35 ˚C until the reaction was complete.
Although oxidations with NaIO4 hold promise due to their undemanding
conditions, its utility in this case was diminished. With this protocol appreciable amounts
of both heteroaryl amino sulfanes were still present after a 48-hour reaction time. The
sluggishness could be attributed to the requisite 1:1 water/MeOH solvent system, which
HetArSH I
NHBoc
Bn Hünig's Base(2 equiv)
DCM, 0 ˚C to rt+
(2 equiv)
SNHBoc
Bn
HetAr
HetAr:2-pyridyl = 93%8-quinolyl = 96%
1-28
41
provide less than ideal solubility for starting materials. Similarly, oxidations with aqueous
H2O2 in hexafluoroisopropanol (HFIP) also yielded comparably poor results, in which a
48-hour reaction time left unreacted starting material.
With a preferred method of oxidation in hand, diastereomeric mixtures of the
target heteroaryl amino-sulfoxide ligands were accessed. Although these ligands were
oxidized without any appreciable diastereoselectivity, the literature has provided many
examples where diastereopure sulfoxides were isolated from a diastereomeric mix via
recrystallization protocols. Recent communications from van Leeuwen et al. and Xiao et
al. highlighted this and reported the isolation of at least one diastereopure β-amino-
sulfoxide from a mixture.21,22,38
Table 2. Oxidation conditions of amino sulfane compounds
a d.r. determined via 1H NMR analysis
S NHBoc
Bn
HetAr S* NHBoc
Bn
HetAr
O[O]
Entry HetAr [O] d.r.a
2-pyridyl
2-pyridyl
2-pyridyl
8-quinolyl
8-quinolyl
8-quinolyl
1
2
3
4
5
6
mCPBA
NaIO4
H2O2; HFIP
mCPBA
NaIO4
H2O2; HFIP
Yield (%)
1.4 : 1.0
1.0 : 1.2 95
50
1.0 : 1.3
1.0 : 1.3 63
86
1.0 : 1.0
1.0 : 1.0
45
53
1-29
42
Despite having a similar β-amino-sulfoxide motif, the newly acquired ligands
could not be separated by this method. Both amino-sulfoxide ligands were each
recrystallized in a variety of solvent system at varying temperatures which include:
hexanes/EtOAc, pentane/EtOAc, Et2O, pentane/DCM, toluene, toluene/EtOAc,
pentane/EtOH, and Et2O/EtOH. Despite numerous attempts, crystals that formed over
the duration of the recrystallization always contained a diastereomeric mix, with an
expected tendency to favour the diastereomer formed in slight excess during oxidation.
A d.r. = 1.0:2.1 and 1.0:2.3 for the 2-pyridyl and 8-quinolyl-based ligands was obtained
using a pentane/DCM system. However, the reproducibility was very difficult, and
repeated recrystallization on the isolated fractions proved difficult due to minimal
quantities initially isolated. Furthermore, once the mother liquors were re-concentrated
and subjected to further recrystallization, they failed to yield any further separation.
Difficulty in separation arose due the similar rates of crystal formation of each
diastereomer from solution. Therefore a different approach towards recrystallization was
taken (Table 3). Upon initial uniform crystal formation (Fraction 1; typically within the first
five minutes), the hot mother liquor was then decanted, into another heated vessel
(Fraction 2), and this was repeated one final time (Fraction 3). This process was
repeated three times for each heteroaryl amino-sulfoxide ligand. This yielded a better
initial results in the first fraction, however subsequent fractions led to the
recrystallization of both diastereomers as previously observed.
Unfortunately, recrystallization was thus an ineffective method of isolating
diastereopure ligands. Nonetheless, the removal of the N-Boc moiety was carried out, to
43
access their free-base forms for use in catalytic trials (Scheme 37). Recrystallization
attempts with the free-base amino-sulfoxide compounds again yielded disappointing
results, and seemingly again caused by similar rates of precipitation of each
diastereomer from solvent.
Table 3. Diastereomeric ratio of recrystallization fractions
Scheme 37. Removal of N-Boc protecting group via trifluoroacetic acid.
A communication from Jiang et al. offered a potential solution to the problem at
hand. The report featured the synthesis and purification of a series of diastereopure β-
amino-sulfoxide ligands, which possessed carbon chirality arising from amino acid
backbones and an N-Ts moiety (Scheme 38). Upon accessing N-Ts β-amino-sulfoxide
N
S*O
NHBoc
Bn
N
S*O
NHBoc
Bn
Fraction initial d.r. = 1.0 : 1.3 initial d.r. = 1.0 : 1.2
1
2
3
1.0 : 2.1 1.0 : 2.3
1.0 : 1.1
1.1: 1.0
1.0 : 1.2
1.0: 1.1
DCM, 0 ˚C to rtS* NH2
Bn
HetAr
HetAr:2-pyridyl (1-L1m) = 78%8-quinolyl (1-L2m) = 81%
OS* NHBoc
Bn
HetAr
O CF3C(O)OH(excess)
44
1-30 through non-diastereoselective means, simple flash-column chromatography
proved to be sufficient for isolation of diastereomeric compounds.48
Scheme 38. Reported synthesis of N-Ts protected amino sulfoxide ligands
Aiming to isolate diastereopure compounds, the free-base hetereoaryl amino-
sulfoxide ligands at hand were subjected to N-tosylation (Scheme 39). Disappointingly,
TLC analysis of both heteroaryl compounds in 10:90 MeOH/DCM yielded only one UV-
active spot, indicating failure to separate. In addition, recrystallization of 1-31 resulted in
a rapid and quantitative precipitation of both diastereomers. Although tosylated
compounds are known to crystallize easily, a newly introduced N-Ts moiety on the
heteroaryl amino-sulfoxide compounds could perhaps override each diastereomers
mildly different individual tendency to form crystals or precipitate from solution.
Scheme 39. N-Ts protected amino sulfoxides
tBu S NHTs
Bn
NH2
BnHO
mCPBA
DCM, 0 ˚C tBu S* NHTs
BnO
initial d.r. = 1.2 : 1.0
1-30
DCM, 0 ˚C to rtS* NHTs
Bn
HetAr
HetAr:2-pyridyl = 93%8-quinolyl = 86%
OS* NH2
Bn
HetAr
O TsCl
1-31
45
Unfortunately, ligands constructed via traditional oxidative means did not yield
diastereomerically pure compounds. Nonetheless, these diastereomeric mixtures of
ligands can still be probed for catalytic activity and comparison of results from a
diastereopure ligand can offer insight to the effectiveness of each configuration.
2.5 Sulfenate anion chemistry
To construct the proposed heteroaryl amino-sulfoxide ligands via the sulfenate
pathway, the necessary heteroaryl sulfenate anion was generated from a 2-sulfinyl
acrylate precursor, as previously reported by the Schwan group. The synthesis of the
sulfenate synthon began with a Michael addition of the heteroaryl thiols to methyl
propiolate, which resulted in a mixture of cis- and trans-2-sulfanyl acrylates 1-32. These
were then subjected to different oxidation procedures to yield the requisite sulfinyl
acrylates 1-33 (Scheme 40). Oxidation with mCPBA, while maintain a cold temperature,
once again proved to be the most efficient way of oxidation. As seen before, allowing
this reaction to reach room temperature resulted in an undesired mixture of unreacted
sulfanes, sulfoxides, and sulfone. Similarly, oxidations with NaIO4 and H2O2/HFIP
yielded sluggish reaction rates and messy crude reaction mixtures.
The heteroaryl sulfenate anion was generated through an addition/elimination
mechanism using n-butyl lithium as a nucleophile. Upon sulfenate release, two
equivalents of the amino iodide electrophile in solution were added rapidly (Scheme 41).
With this sulfoxidation method, Söderman and Schwan reported excellent
46
diastereoselectivities when using similar aryl sulfenates and amino electrophiles and X-
ray crystallography studies confirmed an absolute stereochemistry of (SS,RC) of their
major diastereomers.42,43 Furthermore, they rationalized that such diastereoselectivity
arose from an internal complexation of the lithium counterion with the nitrogen lone-pair
of the amino electrophile, in turn creating a stable chair transition state 1-34.43 Here, a
similar rationale was adopted due to the similarities between their compounds and our
targets (Scheme 41).
However, results obtained from the 2-pyridyl sulfenate anion provided less than
promising results. A diastereomeric ratio of 1.0:0.7 was obtained and such reaction
favoured the same diastereomer that mCPBA oxidation provided. The Schwan group
has synthesized this molecule previously and 1H NMR spectroscopy comparisons
suggest the same major isomer was formed in both cases. In contrast, the 8-quinolyl
sulfenate anion provided one lone diastereomer, which was assumed to possess
(SS,RC) chirality (Scheme 42).
47
Oxidant Conditions 2-pyridyl 8-quinolyl
NaIO4 1:1 MeOH/H2O Slow reaction time
H2O2 HFIP Slow reaction
time, messy crude reaction material
Slow reaction time
mCPBA DCM, -78 ˚C to rt Mixture of starting material, sulfoxide and sulfone formed, messy crude reaction material
Complete consumption of starting material, only sulfoxide formed
mCPBA DCM, -78 ˚C 3 hours, 35 ˚ C till completion
Complete consumption of starting material, only sulfoxide formed
Scheme 40. Conditions for sulfanyl acrylate oxidations
Scheme 41. Addition-elimination mechanism for the generation of a lithiated sulfenate anion.
HetAr SH C(O)OMe+1. Et3N, DCM, 0 ˚C to rt
2. H3O+HetAr S C(O)OMe HetAr S* C(O)OMe
O[O]
HetAr:2-pyridyl = 84% 8-quinolyl = 87%
HetAr:2-pyridyl = 81% 8-quinolyl = 77%
1-331-32
HetAr SO
OMe
O
nBuLi
nBu LiHetAr S
OOMe
OnBu Li
HetAr SO
Li HetAr SO Li
HetAr S OLi
-78 ˚CC(O)OMe
nBu
I NHBoc
Bn
-78 ˚C to rtS NHBoc
Bn
HetAr
O
SO Li N
HetArI
BnH
HBoc
1-34
48
Scheme 42. Heteroaryl sulfenate anion substitution with homochiral amino electrophile
2.6 Attempts towards enantioselective sulfoxide generation
Given the excellent diastereoselectivity demonstrated by the 8-quinolyl sulfenate
anion, the stereoselective capacity of these heteroaryl sulfenates was further
investigated. These heteroaryl sulfenates feature an additional N-coordination group,
which could form an intramolecular rigid, cyclic complex. Perrio et al. have proposed a
similar intramolecular sulfenate model, 1-35, of complexation in their attempts towards
stereoselective sulfoxide generation (Scheme 43).49
S NHBoc
BnO
N
S NHBoc
BnO
N
82%; d.r. = 1:072%; d.r. = 1.0:0.7
HetAr SO
OMe
O I NHBoc
Bn S NHBoc
Bn
HetAr
O1. nBuLi, THF, -78 ˚C2.
-78 ˚C to rt
49
Scheme 43. Lithiated intramolecular sulfenate complexation
In probing this model, it was suggested that the lithiated sulfenate could be
complexed further with an additional chiral ligand to form 1-36. The lithium counterion
should favour an O-Li coordination, allowing the formation of a spirocyclic lithium centre,
and in turn the possibility for sulfur lone pair discrimination leading to stereochemical
induction (Scheme 44).49-52
Scheme 44. Spirocyclic chiral Lewis acid catalyst for enantioselective sulfoxide formation.
Investigation of this concept began with the generation of the sulfenate anion
from the prerequisite 2-sulfinyl acrylates. A solution of chiral PyBox ligand (10 mol%,
catalytic quantity) was then introduced, in the hope of forming the chiral complex. The
SOLi
Me
N(Me)2Me
H NMe Me
S OLi
Proposed model:
1-35
R-X
S ON Li
X
XHetAr S
OOMe
O
nBuLi-78 ˚C HetAr
SOLi
L*S ON Li
Proposed activecatalytic species
Lone-pair discrimination
1-36
50
N-coordination sites were chosen for the propensity to coordinate with the similarly
“hard” lithium cation.49,51 The reaction protocol was completed by the addition of the
benzyl bromide in solution and a slow increase to room temperature while stirring for 10
hours (Scheme 45).
Attempts at stereoselective sulfoxide formation were unsuccessful and
accompanied by low yields of the heteroaryl benzyl sulfoxide. The low yields of product
suggest that if complexation was to occur successfully, it does not efficiently facilitate
the alkylation at the stereogenic sulfur centre, let alone with any appreciable
enantioselectivity. Moreover, this lack of stereoselectivity suggests that the complexed
sulfenate anion reacts at a slower rate than one without the PyBox ligands. The
literature suggests that such complexation is viable, and these results here only show a
limited screening of parameters. Another report from Perrio et al. investigated the use of
(–)-spartene as a lithiathed suflenate complexing agent for stereoselective sulfoxide
generation. Similarly, complexed sulfenate anions delivered lower yields and low
enantioselectivities (4 – 59% yields; 0 – 23% ee). Interestingly, they noted that as the
reaction temperature increased, the sulfenate anion delivered higher yields albeit with
lower accompanying %ee values.51
51
Scheme 45. Enantioselective sulfoxide formation attempts with chiral PyBox ligands
2.7 Attempts towards [SO]-2 extrusion
One final investigation probing the reactivity of these 2-sulfinyl acrylates
attempted to invoke [SO]-2 extrusion from these compounds. The concept of SO
extrusion has been reported by Hu et al. from 2-pyridyl sulfoxides for use in the Julia-
Kocienski olefination.53 Previously, the authors reported that gem-difluorosulfones can
display increased reactivity for this olefination, and as such, their related gem-
difluorosulfoxide derivatives 1-37 were probed for use in this reaction. Interestingly, the
presence of the gem-fluorides yielded an unexpected major product 1-38, which was
thought to arise from the mechanism in Scheme 46 involving SO extrusion.53
HetArSO
OMe
OHetAr
S*O
NN
OO
N
Q
1-L* PyBox1 =
nBuLi-78 ˚C, THF HetAr
SOLi
SO
N Li
N
N
N-78 ˚C to r.t.,
THF
BnBrL*
PyBox
THF
NN
OO
N
1-L* PyBox2 =
HetAr L* Yield (%) Ee
2-pyridyl 1-L*PyBox1 50 0%
2-pyridyl 1-L*PyBox 2 49 0.9%(S)
8-quinolyl 1-L*PyBox 1 55 1.4% (R)
8-quinolyl 1-L*PyBox 2 56 0%
52
Scheme 46. Proposed mechanism of SO extrusion.
To invoke a related [SO]-2 extrusion with the heteroaryl sulfinyl acrylates in hand,
sulfenate anion 1-39 was generated through normal means. However, an additional
equivalent of nBuLi and was added aiming for an ipso-nucleophilic attack to form 1-40
Moreover, the temperature was raised to room temperature before the benzyl bromide
electrophile was added. It was proposed that a similar addition-elimination pathway
would invoke [SO]-2 extrusion (Scheme 47). The resulting sulfur monoxide dianion would
be expected to react with benzyl halide in consecutive reactions.
N
S CHXY
O 1. LiHMDS (2 equiv), DMF -78 ˚C, then HCl (2M)
2. DBU (2 equiv), DMF, rt
If X = Y = For X = H, Y = F
If X = Y = H
Ar
O
Ar+
ArAr
Y X
N
S
O
OYF
ArAr
N
O
F
Ar Ar
NO
SO
F YArAr
N
O
Ar ArS
F Y
N
O
O - F-
ArAr
Y SO
N
O
X S O
ArAr N
O
X S O
ArArN
O
F
Ar Ar
Via:
- SO
1-37
1-38
1-38
53
Scheme 47. Attempts towards [SO]-2 extrusion via double nBuLi addition and release.
Unfortunately, 1H NMR analysis of crude reaction mixtures provided no evidence
of dibenzylsulfoxide formation nor the accompanying butylpyridine (Scheme 47).
Specifically, the aromatic region of each spectrum displayed only one set of heteroaryl
aromatic peaks corresponding to the heteroaryl benzyl sulfoxide compound. The first
experiment utilized the 2-pyridyl sulfinyl acrylate and its failure could perhaps be
attributed to the potential insufficient electron delocalization, which prevents the second
nucleophilic ipso-substitution. Thus, the quinolyl sulfinyl acrylate underwent similar
treatment, however similar results were obtained. Given the presence of the heteroaryl
benzyl sulfoxide, the second ipso-substitution could be attributed as the barrier for [SO]-2
extrusion.
2.8 β-Amino sulfoxide ligands and related derivatives
HetArSO
OMe
O
HetArSO
1. nBuLi (2 equiv.)2. BnBr-78 ˚C to r.t.
THF
Not observed:
BnS
Bn
O
SO
OMe
ON N
S OLi
BuLi N
S OLi
Bu
S OLi
Li
Li
nBuLinBuLi nBuLi
N
Bu
Via proposed mechanism shown with 2-pyridylsulfinyl acrylate:
1-39 1-40
HetAr:2-pyridyl = 40%8-quinilyl = 50%
54
In summary, two diastereomeric mixtures of ligands (1-L1m, 1-L2m, Figure 5)
were prepared via traditional oxidative means while one diastereopure ligand (1-L2,
Figure 5) was accessed via sulfenate anion chemistry, and subsequently subjected to
N-Boc deprotection (Scheme 48).
Figure 5. Chiral amino sulfoxide ligands
Ligand L2 was further modified through condensation with an additional
heteroaryl aldehyde. A report from Xiao et al. showcased the effectiveness of the β-
imino sulfoxide moieties. Given the similar structures of these ligands, the opportunity to
follow suit was presented. As such, diastereopure 1-L2 underwent condensation with
salicylaldehyde and 2-picolinaldehyde to yield 1-L3 and 1-L4, respectively (Scheme 48).
These newly accessed ligands offer a new imine moiety, as well as an additional
coordination site to a metal centre.
S NH2
BnO
NS* NH2
Bn
N
S* NH2
Bn
N
1-L1m 1-L2m 1-L2
OO
55
Scheme 48. Imino sulfoxide ligand synthesis
2.9 Probing chiral ligands for catalytic activity in the Henry (nitroaldol) reaction
The chiral ligands were probed for asymmetric catalytic activity in the Henry
reaction. A review of the literature led to the initial screening conditions.37,38,54-57 Ligand
screening tests within the literature have reported excellent yields and
enantioselectivities with the use of alcoholic solvents and Cu(OAc)2�H2O as the
catalyst.37,38,54,55 Although initial screening reactions with various alcohols led to
moderate to excellent yields, they were accompanied by low enantioselectivities (Table
4). Ligands 1-L1m – 1-L4 were screened within many solvents and did not yield any
promising results. However these screening reactions can offer insight into their
SNHBoc
BnO
N
SNH2
BnO
DCM, 0 ˚C to rt
CF3C(O)OH(excess)
N
1-L2 = 82%
H
O
3:1 DCM/MeOHNa2SO4, reflux
OH
H
O
3:1 DCM/MeOHNa2SO4, reflux
N
S N
BnO
N
1-L3; 91%
OH
S N
BnO
N N
1-L4; 89%
56
catalytic activities. These chiral ligands all favoured the formation of the (R)-isomer
(Table 4). In general, the imino sulfoxide ligands (1-L3 and 1-L4) led to higher yields
and ee’s than their corresponding free base form (1-L2) and nitromethane as a solvent
gave to the highest observed enantioselectivities (Entries 16 and 25, Table 4).
Although the complementary diastereomer of 1-L2 was not able to isolated as a
diastereopure ligand, the results from a reaction catalyzed by a diastereomeric mixture
indicate that it does not possess any more catalytic activity (1-L2m: 40% yield, 3.4% ee;
1-L2: 44% yield, 14% ee; Entries 3 and 7, Table 4).
These ligands underwent further screening in the Henry reaction using a
nitroethane (Table 5). Here, the emergence of diastereomeric nitro alcohols allowed the
use of 1H NMR to determine a diastereomeric ratio. Unfortunately, these ligands failed
to impart any appreciable diastereoselectivity, and as such the enantioselectivities from
these reactions were not pursued. Moreover, unlike when nitromethane was used as the
solvent, a nitroethane solvent system failed to improve the diastereomeric ratio (Table 5,
entries 3 and 8).
57
Table 4. Solvent screening reactions for the Henry Reaction with nitromethane.
Entry L* Solvent Yield (%) ee (%)a
1 1-L1m MeNO2 37 2.4
2 1-L2m EtOH 55 3.2 3 1-L2m MeNO2 40 3.4 4 1-L2 Toluene 3 24 5 1-L2 MeCN 36 6.7 6 1-L2 CH2Cl2 trace -- 7 1-L2 MeNO2 34 14 8 1-L2 THF 20 10 9 1-L2 DMF 76 11 10 1-L2 EtOH 79 17 11 1-L2 iPrOH 61 6.7 12 1-L2 tBuOH 41 17 13 1-L3 Toluene 35 27 14 1-L3 MeCN 13 21 15 1-L3 CH2Cl2 38 29 16 1-L3 MeNO2 52 29 17 1-L3 THF 72 23 18 1-L3 DMF 99 1.7 19 1-L3 EtOH 50 15 20 1-L3 iPrOH 79 17 21 1-L3 tBuOH 72 15 22 1-L4 Toluene 32 24 23 1-L4 MeCN 59 14 24 1-L4 CH2Cl2 14 25 25 1-L4 MeNO2 73 32 26 1-L4 THF 89 17 27 1-L4 DMF 99 8.8 28 1-L4 EtOH 68 11 29 1-L4 iPrOH 92 13 30 1-L4 tBuOH 91 14
a Determined by chiral HPLC, Chiralcel OD-H column 0.8 mL/min; 85/15 (v/v) Hexanes/IPA
O2N
H
O
O2N
OHNO2
L* (12 mol%) Cu(OAc)2•H2O (10 mol %)
MeNO2 (10 equiv.)Solvent, rt48 hours
58
Table 5. Solvent screening reactions for the Henry Reaction with nitroethane
Entry L* Solvent Yield (%) anti:syna 1 1-L1m EtNO2 2 1-L2m EtOH 40 1.21:1.0 3 1-L-2m EtNO2 62 1.29:1.0 4 1-L2 EtOH 64 1.37:1.0 5 1-L2 DMF 46 1.53:1.0 6 1-L3 EtOH 62 1.03:1.0 7 1-L3 DMF 55 1.56:1.0 8 1-L3 EtNO2 71 1.20:1.0
9 1-L4 EtOH 74 1.0:1.0 10 1-L4 DMF 77 1.05:1.0
a determined via 1H NMR analysis
To this point, only 4-nitrobenzaldehyde had been utilized in the Henry reaction.
Although results from the screening reactions, did not yield any exceptional results,
these trials suggested that either ligand 1-L3 or 1-L4 with Cu(OAc)2�H2O in
nitromethane would offer marginally improved enantioselectivities (Table 4, entry 16 and
25). Thus, 4-methylbenzaldehyde, 4-bromobenzaldehyde, and 2-
thiophenecarboxaldehyde were probed as substrates under those conditions (Scheme
50). Unfortunately, none of these substrates were able to produce the nitro alcohol
product. After 48 hours, TLC analysis indicated that no reaction had taken place.
O2N
H
O
O2N
OHL* (12 mol%) Cu(OAc)2•H2O (10 mol%)
EtNO2 (10 equiv.)Solvent, rt48 hours
NO2 O2N
OH
NO2
+
anti syn
59
Therefore, 10 mol% of Et3N was added to each reaction with the aim of moving the
reaction forward. However, after an additional 24 hours, TLC and 1H NMR analysis
again indicated that no desired product had been formed.
Disappointingly, the scope of these ligands for this reaction therefore appears to
be very limited. The failure of 4-bromobenzaldehyde to react suggests that this catalyst
system requires a greater electron deficiency in order to yield the desired product.
Moreover, enhanced reactivity of 4-nitrobenzaldehyde suggests that it is not a suitable
screening substrate, since it is not an accurate indicator of catalytic activity.
Scheme 49. Probing of other aldehydes as substrates in the Henry reaction under optimized conditions.
2.10 Proposed model for observed stereoinduction
All ligands probed in the Henry reaction using a nitromethane nucleophile led to a
preference for the R isomer, albeit with low enantioselectivity (Table 4). However, the
diastereopure quinolyl amino sulfoxide ligands (1-L3 and 1-L4) provided the highest
observed enantioselectivities (ee = 29%, 32%; Entry 16 and 25, Table 4). To rationalize
this stereoselectivity, three assumptions were made. (1) Although these ligands have
Ar H
O
N
SO
N
Bn
H
OH
1-L3
1-L3 (12 mol%)Cu(OAc)2•H2O (10 mol%),
MeNO2, rt, 48 hours
(10 mol% Et3Nafter 48 hours)
+ MeNO2(10 equiv)
Ar
OHNO2*
Not observed
Ar:4-Me-C6H44-Br-C6-H42-thienyl
60
multiple possible coordination sites, a bidentate coordination mode is assumed for these
hypothesized models; (2) The lone pair of the sulfoxide moiety coordinates with the
copper centre; (3) The imine nitrogen is the other coordination site in this hypothesized
bidentate system.
Upon disruption of an octahedral Cu(II) centre, the impact of the Jahn-Teller
effect is seen.58,59 This results in four possible strong coordination sites arranged in a
square-planar fashion around the copper centre, and an additional two possible weak
coordination sites above and below the plane (1-41, Figure 6).55,58,59 A communication
from Evans et al., which investigated a Cu(II)-bis(oxazoline)-catalyzed Henry reaction,
proposed that the most reactive transition state would place nucleophilic nitromethyl
group in a weak coordination site perpendicular to the plane while the electrophile would
be located in the strong coordination site along the plane.55
Figure 6. Copper (II) coordination sites
Thus, adopting a similar model with these amino sulfoxide ligands would first
place the S and N coordinating groups in a cis-orientation along the plane. Coordination
of the nucleophile and electrophile, in the reactive manner proposed by Evans et al.,
would result in chelate 1-42 (Scheme 50). The orientation of the electrophile in chelate
CuX X
X X
Y
Y
X = Strong coordination siteY = Weak coodination site
1-41
61
1-42 would result in the slightly favoured (R)-isomer. However, equilibrium between
chelate 1-42 and 1-43 can be envisioned, where the electrophile conformation is
reversed, since the -OAc group would provide a minimal steric hindrance. Chelate 1-43
would thus result in the (S)-isomer, and this equilibrium also serves to explain the low
enantioselecitivites obtained.
Scheme 50. Proposed model for observed stereoinduction and preference for the (R)-isomer.
2.11 Future work
Although the chemistry towards the access of these chiral sulfoxide ligands has
been established, accessing the pyridyl system in a diastereopure form requires further
investigation. Jiang et al. reported that the N-Ts moiety led to facile isolation of
diastereomers via flash chromatography, while this strategy did not yield separation for
the synthesized ligands, it gives insight as to how additional auxiliary groups could
CuS O
N OAcBn
H
ON
O
H
NO
NO2
CuS O
N OAc
XBn
H
ON
O
H
NONO2
H
NO2
HOO2N
H
NO2
HOO2N
HetAr
(R)
(S)
1-42 1-43
62
potentially bring about an efficient separation. For example, condensing the free base of
these ligands with a chiral aldehyde could introduce another chiral centre, which could
affect diastereomeric separation via achiral chromatography or recrystallization
techniques.
The 8-quinolyl sulfenate anion brought about an interesting outcome upon its
reaction with the chiral amino iodide electrophile. It is believed that one lone
diastereomer was produced based on the model that Schwan and Söderman had
reported.42,43 However, the chirality assignments for the sequent amino sulfoxide ligand
are only based on that analogy and an X-ray crystal structure determination would be
needed to determine its true stereochemical configuration.
The synthesized ligands were only screened for the Henry reaction. Although
they did not provide promising results, their effectiveness towards other reactions
remains to be established. Amino sulfoxide ligands have been probed against a variety
of reactions, from hydrogenations to cyclopropanations, and have been met with
success. Some of these examples serve to guide which reactions to probe next.15,32
The lack of stereochemical induction brought about by these ligands could arise from
their lack of rigidity. Substituting the phenylalanine carbon skeleton with that of a proline
would result in a rigid pentacyclic structure within the ligand 1-41 (Scheme 51a).
Moreover, the introduction of steric groups at the alpha position could help form a more
rigid ligand (1-42). A similar structural motif has been reported by Xiao et al. and those
reported ligands have seen success in the Henry reaction and Tsuji-Trost reaction.21,38
This motif can be accessed in a similar way using aziridine substrates. This chemistry
63
with a thiolate nucleophile has already been established, however the sulfenate
pathway must still be investigated for its viability (Scheme 51b).38
The free-base form of these amino sulfoxide ligands offers an additional site for
derivation, and potential to include additional components to match the requirements to
a reaction. For example, many ligands utilized in the Tsuji-Trost reaction and
asymmetric Michael additions include a phosphine moiety. This could easily be
introduced via diphenylphosphinobenzaldehyde (1-43) condensation with a ligand in its
free base form to access 1-44 (Scheme 51c).
Scheme 51. Future work towards ligand diversification.
HetAr S OMI N
Boc
*+ HetAr S*
O
NBoc
*
HetAr S OMN
R R'+ HetAr S*
O
R
R
NPG
HetAr S*O
NH2
Bn HetAr S*O
N
Bn
H
P(Ph)2O
H
P(Ph)2
+- H2O
a.
b
c
* * * *
PG
1-41
1-42
1-43 1-44
64
2.12 Conclusion
The desired amino sulfoxide targets were accessed through the complementary
traditional oxidative means and sulfenate anion chemistry. Moreover, the ligand design
was diversified via the introduction of an addition heteroaryl aldehyde to access their
imino-derivative. Despite the failure to access diastereopure configurations of each
ligand, the 8-quinolyl sulfenate anion fortunately generated only one diastereomer and
allowed for the access of more diastereopure derivatives.
The sulfenate anion itself provides an opportunity to generate optically enriched
sulfoxides via chiral Lewis acid induction. Although the attempts outlined here did not
yield any promising results, the literature is continually providing more examples of the
chiral sulfenate anion complexes.49-52 Promising chiral inductions have been slow to
develop, however a recent communication from Tan et al. reported enantioselectivities
as high as 94% with the use of chiral halogenated pentanidium salt.50 Despite the poor
results, the literature supports that this is a viable concept, and further screening will
hopefully lead to a more favourable outcome.
The synthesized chiral sulfoxide ligands unfortunately do not appear to have
much ability to influence the stereochemical outcome in the Henry reaction. Although
only one copper salt was screened, the literature suggests that other options are not as
viable. However, a thorough solvent screening with nitromethane and nitroethane
nucleophiles indicated that a slight improvement in enantioselectivity can be achieved
by using nitromethane as a solvent.
65
Overall, only a small segment of sulfenate anion reactivity and the capabilities of
the sulfoxide moiety in chiral induction have been probed. However these findings can
help influence and direct future research in these rapidly growing areas of interest.
lxvi
ABSTRACT
EXPEDITED CATALYTIC SYNTHESIS OF BUPROPION
Erwin Javier Remigio Advisor: University of Guelph, 2017 Professor A. L. Schwan
α-Amino carbonyl compounds represent a diverse group of synthetically valuable
compounds ranging from synthetically valuable compounds, ranging from synthetic
building blocks to biologically significant natural products. Moreover, the presence of
this motif in pharmaceutical compounds, such as Bupropion, make this a desirable
synthetic target. A common pathway to access this family of compounds involve an
enol-type nucleophile and an electrophilic nitrogen species (e.g. azodicarboxylates and
nitroso compounds). This pathway has been extensively investigated, however it
presents an inherent drawback, which requires additional post-functionalization in order
to access the desired α-amino target. Recently, the literature has provided examples of
direct C(sp3)-N bond forming reaction via catalytic oxidative means. Specifically, the
catalytic Cu(II)-mediated and I2 radical oxidative coupling methodologies, reported by
MacMillan et al. and Guo et al., respectively, have shown promise towards the facile
acquisition of α-amino aryl ketones. Here, these methodologies were probed for their
utility towards Bupropion synthesis, via the coupling of tbutyl amine and 3’-
lxvii
chloropropiopheone. The Cu(II)-mediated pathway did not seem to be compatible with
primary amines, and was not able to be generate Bupropion. In contrast, the I2-
mediated pathway was able to yield the desired target. In this system, NH4I in catalytic
amounts and sodium percarbonate in ethyl acetate, led to generation of Bupropion. An
extensive optimization led us to conclude that a reloading the reaction system with
additional sodium percarbonate and amine led to a complete reaction. This reaction was
probed with various iodine and acidic components (e.g. I2/AcOH, and I2/Phenol) in place
of NH4I to successfully yield Bupropion. As such, an alternative ionic mechanism was
proposed in order to account for unfavourable bond dissociation enthalpies required for
the originally proposed radical coupling. Unfortunately, isolation of Bupropion via flash-
column chromatography proved to be problematic. Therefore efforts were put forth
towards reaction optimization to force the complete consumption of the starting ketone
substrate, and its direct subsequent isolation as an HCl salt. Acquisition of HCl salt
proved to be successful, however it was accompanied by the unavoidable formation of
the corresponding tbutyl ammonium salt.
68
Chapter 3: Introduction
69
3.0 Introduction
3.1 Traditional synthetic pathway towards α-amino carbonyl compounds
Carbonyl compounds possessing an α-amine functionality are a diverse group of
synthetically valuable compounds. They represent significant synthetic building blocks
to biologically significant targets due to their capacity for additional chemistry.60
Moreover, this structural motif itself is present in many natural products and
pharmaceutical compounds.61 Specifically, the α-amino ketone motif is found in many
commonly prescribed drugs, making it an attractive synthetic target.
α-Amino ketones are commonly accessed through the reaction of a nucleophilic
enol, or related derivative with an electrophilic source of nitrogen, which typically
contains electron-withdrawing groups to achieve this reactivity (e.g. azodicarboxylates
and nitroso-compounds) (Scheme 52).60,61 This pathway offers opportunities for
stereoinductive interventions via chiral Lewis acids, whether the chemistry occurs
through a chiral metal enolate, the activation of the nitrogenated electrophile, and in
some instances, both. This reactivity offers much utility due to the need for enantiopure
compounds in drug synthesis.
A communication from Yamamoto et al. reported successful enantioselective α-
amination with tin enolates and a silver (I)/BINAP system complexed to
nitrosobenzene62. However, this electrophile can present chemoselectivity challenges
due to potential lone pair coordination of either the nitrogen or oxygen atoms. However,
it was reported that a 2:1 silver (I)/binap complex led exclusively attack at the nitrogen
70
centre, leading to the α-amino adduct. This catalytic system offered effective α-
aminations from cyclic tin enolates (Scheme 53).62
Scheme 52. Common synthetic pathway towards α-amino carbonyl compounds (X = C(O)OR, Y = N or O, Z = lone pair of electrons if Y = O, or Z = C(O)OR if Y = N).
Scheme 53. Enantioselective α-amination via tin enolate and silver (I)/BINAP system.
OHN Y
X
Z
ON Y
XZ+
N NRO(O)C
C(O)ORAr
N O
OHN Y
X
ZO ML*
N YX
Z
ML*
Via Lewis acid activation:
OSnBu3
Ph NO
+O
NOH
Ph
10 mol%(R)-binap•(AgOTf)2
EtOCH2CH2OEt-78 ˚C
O O
N NO
NOH
Ph
OH
Ph Ph
OH
95%; >99% ee 97%; 98% ee 96%; 97% ee
71
In another example, Evans and Nelson utilized a chiral magnesium
bis(sulfonamide) enolate complex 2-1 to facilitate asymmetric α-amination with di-tert-
butyl azodicarboxylate.63 Their method required the addition of the carbamate moiety to
their initial carbonyl substrate to act as an additional coordinating group to facilitate the
stereoselective nucleophilic attack.
The authors hypothesized a reactive intermediate, where the spirocyclic
magnesium centre allowed for the sulfonyl p-xylene to block the top-showing face of the
assumed E-enolate, permitting only addition from the rear-showing Si-face. Although the
reaction was sluggish and took upwards of three days in some cases, this catalytic
system afforded excellent yields and enantioselectivities (Scheme 54).63
Scheme 54. Asymmetric α-amination via chiral magnesium bis(sulfonamide) enolate complex.
Mg
N
NSO2
H
HO2S
O
O
ON
ArH
Prevents exposure fromincoming electrophiles
Proposed reactive intermediate:
NAr
O
O
O ML* (10 mol%)pTsNHMe (20 mol%)N
NBoc
Boc+
DCM-75 ˚C - -65 ˚C
N ArO
O
O
BocNNHBoc
N N
Ph Ph
O2S SO2Mg
ML* =
2-1
Ar:Ph = 92 %; ee = 86%4-F-C6H4 = 97%; ee = 90%4-OMe-C6H4 = 93%; ee = 86%
72
A report from MacMillan et al. utilized the general reactivity pattern shown in
Scheme 52 towards α-amino aldehyde, however it was achieved via a novel photoredox
mechanism (Scheme 55).64 The authors utilized a chiral electron-rich enamine for
stereoinduction. The radical amine coupling partner was generated from a carbamate
possessing an N-dinitrophenylsulfonate (ODNs) activation handle, chemoselectively
activated by a common household light bulb. The catalytic cycle begins with enamine
formation from the aldehyde and imidazolidinone catalyst. Upon its formation it is able to
couple with the electrophilic nitrogen radical (2-2) to form 2-3. Oxidation of 2-3 via a
photoexcited N-ODNs, N-methyl carbamate (2-4), results in a single electron transfer
(SET) to form the iminium ion (2-5), which is hydrolyzed to regenerate the
imidazolidinone catalyst and enantioenriched α-amino aldehyde. Moreover, this is a key
propagation step, which excites and subsequently delivers another carbamyl radical for
coupling (Scheme 55). Overall, they reported good to moderate yields, with outstanding
enantioselectivities.
Jørgensen et al. were the first to report such aminations using an enamine with a
chiral auxiliary (2-6) (Scheme 56).60 Here, L-proline was utilized to form the chiral
enamine, and its reaction with an azodicarboxylate resulted in impressive results. The
authors rationalized that the nitrogen lone pair and carboxylic acid proton of the proline-
enamine intermediate were able to direct the incoming azodicarboxylate electrophile. A
Zimmerman-Traxler-type transition state has been postulated and it rationalized the
formation of a stable chair conformation 2-7 to explain the observed stereoinductive
effects (Scheme 56).60
73
HR1
O
N C(O)OMe
ODNs
NH
NO
•HOTf (30 mol%)
2,6-lutidine(1:1) DMSO/CH3CN
26W CFL
HR1
N C(O)OMe
O
+
Hnhex
N C(O)OMe
O
HCH2-C6H4-4-OMe
N C(O)OMe
O
HiPr
N C(O)OMe
O
71%; ee = 90% 79%; ee = 91% 67%; ee = 94%
H
O
R1
N
NH
OEt
HR1
N
NEtO
HR1
N
NEtO
NR2(C(O)OR3
R2 N
R3
O
HR1
N
NEtO
NR2(CO2R3)
HR1
N
NEtO
NR2(C(O)OR3
HR1
NR2(C(O)OR3O
DNsON
R3
OR2
DNsON
R3
OR2
*DNsO
N
R3
OR2
R2 N
R3
O
SO3NO2
NO2
Imidazolidinone catalyst
hv
+
α−amino aldehyde 2-3
2-5
2-4
2-2
1
Catalytic Cycle:
Scheme 55. Photoredox catalytic cycle.
74
Scheme 56. Proline-catalyzed amination via enamine intermediate.
3.2 Direct C-N oxidative coupling reactions
The literature provides many effective approaches for carrying out the general
pattern of reactivity shown in Scheme 52. However this approach towards the α-
amination of carbonyl compounds all share a common disadvantage, which requires the
post-functionalization of the newly acquired amine-moiety. As such, efforts towards a
direct C(sp3)-N coupling have been undertaken, however the inherent nucleophilic
character of both the α-carbonyl centre and the amine present a challenge towards this
goal.65-67
MacMillan et al. provided a versatile one-pot strategy towards the direct coupling
of α-keto carbon centres and amines.66 Their approach utilized the alcohol precursor to
the respective ketone, N-bromosuccinimide (NBS), and open-air conditions to drive the
reaction forward (Scheme 57) A thorough investigation of their reactions using NMR
H Et
O
EtO(O)C NN C(O)OEt
+L-Proline (10 mol%)
DCM, rt H
ON
Me
HN
C(O)OEt
C(O)OEt
77%; ee = 90%
H
N C(O)OH EtO(O)C NN C(O)OEt
N N H
N
O O
EtO(O)CH
EtO(O)C
Proposed transition state:Via:
2-6 2-7
75
experiments led them to postulate that the alcohol initially reacts with NBS to form a
reactive hypobromite species 2-8. Its inherent reactivity allows for facile oxidation of this
species to release a bromide ion and form the ketone 2-9. In solution, the bromide is
capable of acquiring a proton to form HBr, which is further oxidized to elemental
bromine by the open-air conditions. The ketone is then subsequently α-brominated, and
the morpholine is able to directly attack the α-keto centre and afford 2-10 (Scheme 57).
Scheme 57. NBS-mediated α-amination of aryl ketones.
Ar
OH
O
HN
+Ar
O
N
O
NBS (1.3 equiv)
1,4-dioxane, rtopen-air
OHNBr
O
O
HN OO
O Br
H
O O
Br
O
N
O
O
HN
HBr
Br2
Br-
HBr +1/2O2 → 1/2 H2O + 1/2Br2Br-
2-8 2-9
2-10
Ar:Ph = 90%4-tBu-C6H4 = 70%4-Cl-C6H4 = 80%3-CF3-C6H4 = 70%2-thienyl = 40%
*
*
*
*
76
Another communication from MacMillan et al. further expanded the scope of
direct C(sp3)-amine coupling.65 Similarly, the α-brominated species 2-11 was generated
however it was accessed via a copper-bound enolate 2-12. The subsequent release of
HBr and 2 moles CuBr in the presence of air allowed for the regeneration of the Cu(II)
species. In addition to aryl ketones, this report successfully incorporated the morpholine
moiety onto α-aryl esters under the similar conditions (Scheme 58).
Scheme 58. Cu(II)-mediated oxidative α-amination of carbonyl compounds.
X RO
X RO
Br
X RO
N
O
HN
O
X BrO
R
CuCu
Br
2 CuBr
2 CuBr2
1/2 O2 + 2 HBr2 H2O
HBr
Catalytic cycle:
CuBr2 (10 mol%)
DMSO, 50 ˚Copen-air
X
OR
O
HN
+X
OR
N
O
2-11
2-12
X = 2-furyl, R = Me: 93%X = 4-CF3-C6H4, R = Me: 70%X = MeO, R = Ph: 81%X = MeO, R = 4-NHTs-C6H4: 70%X = MeO, R = 3-MeO-C6H4: 71%
*
**
77
Recently, Guo et al. achieved this direct C-N amine coupling via a one-pot
oxidative radical coupling pathway (Scheme 59).67 Their reaction system required the
presence of an iodide source, a weak acid (NH4I acts as both), oxidant, and weak base
(Na2CO2�1.5H2O2 acts as both). In contrast to the generation of an α-halogenated
species, these authors suggested a carbocation as the reactive electrophilic species.
The authors reported that the catalytic cycle begins with the oxidation of iodide anions to
elemental iodine. Iodine was reported to undergo homolytic cleavage, which continued
to abstract an α-hydrogen from the ketone substrate, and a subsequent single electron
transfer (SET) from the radical ketone species provides the reactive carbon electrophile
2-13 for nucleophilic attack. After the initial hydrogen abstraction, the HI by-product is
then transformed into the key elemental iodine species either by treatment with base
followed by oxidation of the anions or through simple oxidation (Scheme 59).
With these new and direct one-pot C-N bond-forming reactions, the synthesis of
small molecule α-aminated ketone compounds can be potentially revisited. Bupropion
((±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride), known
on the market as WellbutrinTM or ElontrilTM, is a commonly prescribed anti-depressant
drug. In addition, it has seen utility in smoking-cessation and obesity treatments. It
exerts its effects as a norepinephrine-dopamine reuptake inhibitor (NDRI, which is a
mechanism atypical compared to many antidepressants. Bupropion has a relatively
simple structure containing an α-tbutyl amino group. With these new methods in hand,
an expeditious protocol could potentially be constructed by simply coupling 3’-
chloropropiophenone and tbutyl amine (Scheme 60).
78
Scheme 59. Proposed I2 radical coupling mechanism
Scheme 60. Retrosynthetic approach of Bupropion via direct C-N coupling.
2 I
2 HIH2O2
I2
2 I-
H2O2
Base
R R'O
R R'O
R R'O
R R'O
N
O
HN
O
- H+
SET
R R'O R R'
O
N
OO
HN
NH4I (15 mol%)Na2CO3•1.5H2O2 (2 equiv)
MeCN, 50 ˚C+
Catalytic cycle:
[O]2-13
R = Ph, R' = Me: 92%R = 4-CF3-C6H4, R' = Me: 85%R = 4-MeO-C6H4, R' = Me: 80%R = 2-furyl, R' = Et: 66%R = 2-thienyl, R' = Et: 75%
*
*
Cl
O
NH • HCl
Bupropion HClCl
O
NH
Via direct C(sp3)-N coupling
Cl
O
+NH2
**
79
The synthesis of Bupropion is carried out as a two-step procedure. 3’-
chloropropiophenone is first subjected to an excess of liquid bromine in DCM to access
the α-brominated intermediate, which is prone to degradation and is also a lachrymator,
as most α-halogenated ketones are. This intermediate is then reacted with tbutyl amine
in DMF at 60 ˚C (Scheme 61) to access the desired product.68
Scheme 61. Traditional synthesis of Bupropion.
The work of MacMillan et al. and Guo et al. offer promising potential to expedite
the acquisition of Bupropion. The use of a one-pot system would reduce the amount of
solvent and reagents used in its synthesis, thereby resulting a more cost-effective,
efficient, and green synthesis. Given Bupropion’s prevalence of use, synthetic
improvements can potentially applied to its industrial preparation. These efforts were of
interest to our industrial client, Vibrant Pharma Inc. and as such this project was
undertaken with their partnership along with fellow laboratory technician, Rebecca
Sydor, who was under my supervision.
Cl
OBr2 (excess)
DCM, 0 ˚C to rt
Cl
O
Br
Must isolate- unstable- lachrymator
DMF,60 ˚C
NH2
Cl
O
NH
**
80
Chapter 4: Results and Discussion
81
4.0 Results and Discussion
In our hands, the synthetic method provided by MacMillan et al. was unable to afford
Bupropion (Scheme 62). The reaction was performed with 3’-chloropropiophenone and
tbutyl amine using their reported conditions. After a 36-hour reaction time, TLC analysis
displayed plenty of starting material. Although newer UV-active spots had formed, 1H
NMR of the crude reaction mixture only indicated the major presence starting material
along with indiscernible peaks in the aliphatic region.
Scheme 62. Failed synthesis of Bupropion via Cu(II)-mediated oxidative coupling.
The report from MacMillian et al. did not probe 3’-chloropropiophenone as a
substrate, so we examined this compound’s reactivity using with morpholine instead, as
they had originally reported. This substrate required a considerably longer reaction time,
and resulted in low yields of the expected α-amino aryl ketone 2-14 (Scheme 63)
(These sets of reactions were performed by Rebecca Sydor.)
This reaction with morpholine provided an interesting and initially unidentified by-
product 2-15 that the authors did not mention (Figure 6). First, an assumption was
made, that the original carbon skeleton was retained in this by-product. Based on 1H
Cl
O
Cl
O
NH
NH2
+
(3 equiv)
CuBr2 (10 mol%)
DMSO, rtopen-air
*
82
NMR analysis, this by-product seemed to contain two morpholine moieties, however
one of them seemed to be in a more polarized environment, due to the two 4H
multiplets, clearly separated by 0.650 ppm. Interestingly, the aromatic region was far
more condensed than usual and the characteristic peak pattern of a meta-disubstituted
phenyl ring was lost. Finally, a lone downfield singlet at 6.39 ppm was reasoned to
belong to an alkenyl proton. Unfortunately, efforts to maximize the yields of either this
by-product or the expected α-morpholine adduct were unsuccessful.
Scheme 63. Test reaction of direct C-N coupling of 3’-chloropropiophenone and morpholine via Cu(II)-mediated oxidative coupling.
Figure 7. 1H NMR of isolated by-product and corresponding predicted chemical structure.
Cl
O
Cl
O
N+
(3 equiv)
CuBr2 (10 mol%)
DMSO, rtopen-airO
HN
OCl
N
Br
H
NO
O
X
Possible by-product
2-14 2-15
*
83
The synthetic method towards α-amino aryl ketones provided by Guo et al. led to
more promising results. An initial trial reaction utilized their reported procedure and
provided trace amounts of the desired product formation as indicated by 1H NMR. This
trial was carried through in acetonitrile and formed a 1M solution with respect to the
starting material, however that volume was not sufficient in solvating all of the reactants
(Entry 1, Table 6, Scheme 64).
Scheme 64. Proposed synthesis of Bupropion.
In Figure 7 a sample 1H NMR spectrum of the reaction of Entry 3 (Table 6), which
contains both starting material and Bupropion is shown. The diagnostic signal at 4.33
ppm (q, J = 7.2 Hz, 1H) arises from Bupropion and indicates the α-proton where the
new C-N bond has been created. The signal at 2.99 ppm (q, J = 7.2 Hz, 2H) is indicative
of the starting material, 3’-chloropropiophenone, and indicates the protons from its α-
position. Initial attempts to isolate Bupropion via flash-column chromatography were
unsuccessful. These difficulties could be attributed to the acidic environment provided
by the silica gel, which could allow the newly added amino group to become protonated
allowing for its degradation. Due to the difficulty in isolating Bupropion as a free base,
NH4I (15 mol%)Na2CO3•1.5H2O2 (2 equiv)
MeCN, 50 ˚CCl
O
Cl
O
NH
NH2
+
(3 equiv)
*
84
crude reaction materials were characterized via 1H NMR and a ratio of Bupropion to
starting material was used to characterize effectiveness of screening trials. The
integration of the starting material signal at 2.99 ppm was halved to account for relative
contribution of protons compared to Bupropion. Moreover, efforts were placed towards
complete consumption of starting material in order to allow for facile isolation of
Bupropion as an HCl salt.
Figure 8. 1H NMR spectrum of the crude reaction mixture containing Bupropion and 3’-chloropropiophenone.
Increasing the volume of solvent used (0.5 M from 1.0 M wrt ketone) led to
improved product formation (e.g. Entry 3, Table 6). A variety of solvents were tested
during the screening procedures. A non-polar solvent (e.g. toluene) was not a suitable
environment for this reaction to proceed (Entry 10, Table 6). Likewise, polar-protic
alcoholic environments also led to no product formation (Entries 4-9, Table 6). A trial
reaction that utilized polar-aprotic solvents provided identical results (Entries 11-13,
Table 6). Surprisingly, ethyl acetate proved to be an effective solvent, despite its
85
potential reactivity as it bears potentially available hydrogens alpha to the carbonyl
moiety (Entries 15-18, Table 6). Furthermore, it provided better solvation even with less
solvent added (1.0 M from 0.5 M wrt ketone, Entry 18, Table 6). However when DMSO
was added as a co-solvent, product formation was inhibited (Entry 14-18, Table 6).
These solvent screening reactions summarized that a reaction temperature of 50 ˚C and
mildly polar aprotic solvent is required for this reaction (e.g. MeCN, EtOAc). A highly
polar aprotic solvent (e.g. DMF, DMSO) could potentially interfere with the reaction via
complexation of the iodine, which must be re-oxidized to drive the reaction forward.
Similarly polar-protic solvents could interfere with the iodine via H-bond interactions
preventing them from re-oxidation, while non-polar solvents do not provide enough
stabilization of these species.
Table 6. Solvent screening reaction trials. (Reaction entries expect #2 and #3 were performed by Rebecca Sydor.)
Entry Solvent Temp. (˚C)
Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 MeCN rt 48 --- No --- 2 MeCN 50 36 Less solvent Trace --- 3 MeCN 50 36 --- Yes 1.0 : 0.7 4 MeOH rt 48 -- No --- 5 EtOH rt 48 --- No --- 6 EtOH 50 28 --- No --- 7 IPA rt 36 --- No --- 8 tBuOH rt 48 --- No --- 9 tBuOH 50 48 --- No --- 10 Toluene rt 48 --- No --- 11 DMF 80 48 --- No --- 12 DMF 80 48 TBAI was used in
place of NH4I No ---
13 DMSO rt 48 --- No --- 14 EtOAc/D
MSO (4:1)
50 48 --- No ---
86
15 EtOAc rt 48 --- Yes 1.0 : 3.2 16 EtOAc 40 48 --- Yes 1.0 : 1.2 17 EtOAc 50 28 --- Yes 1.0 : 0.3 18 EtOAc 50 28 Less solvent
added Yes 1.0 : 0.2
The role of the acidic and iodinated components in this reaction material was also
investigated. Trial reactions, which replaced the NH4I catalyst with TBAI led to no
product formation, which suggested the need for an acidic component in this reaction
(Entry 12, Table 7). Reaction trials, which increased the concentration of iodine and
protons separately both led to significantly increased product formation (Table 7).
Although the presence of a strong acid led to product formation, relatively weaker acids
led to more desirable results (Entries 7 and 8, Table 7).
Table 7. Acid and iodine source screening reactions. (Reaction entries in this table were performed by Rebecca Sydor.)
Entry Solvent Temp.
(˚C) Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 50 28 Additional 15 mol% of I2 added after 12 hours
Yes 1.0 : 0.2
2 EtOAc 50 28 7.5 mol% NH4I catalyst
Yes 1.0 : 2.1
3 EtOAc 50 28 25 mol% NH4I catalyst
Yes 1.0 : 0.3
4 EtOAc 50 48 25 mol% NH4I catalyst, upscale (__ mmol)
Yes 1.0 : 0.2
5 EtOAc 50 28 TBAI was used in place of NH4I
No ---
6 EtOAc 50 48 4Å M.S. added to reaction mixture
Yes 1.0 : 0.6
7 EtOAc 50 48 Addition of 15 mol% AcOH
Yes 1.0 : 0.08
8 EtOAc 50 48 Addition of 15 mol% TFA
Yes 1.0 : 0.3
87
Guo et al. reported that the oxidant, sodium percarbonate, is required to generate
radical iodine species to drive this reaction forward. Different varieties of oxidant were
screened in an attempt to further optimize the reaction for our purposes.
Dichloroisocyanuric acid (DCCA) is an inexpensive oxidizer commonly used as a
swimming pool disinfectant and generates the oxidant hypochlorous acid (HOCl).69
Reaction trials with DCCA led to product formation, however it was not as effective in
consuming the starting material (Entry 1, Table 8). Next, an open-air environment was
probed in an attempt to use atmospheric oxygen as the oxidant to increase atom-
economy and to access a greener procedure however Entries 2-4 from Table 3
suggested that this was not a suitable oxidant.
Table 8. Oxidant screening reactions. (Reaction entries in this table were performed by Rebecca Sydor.)
Entry Solvent Temp.
(˚C) Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 50 28 DCCA was used in place of percarbonate
Yes 1.0 : 0.9
2 EtOAc 50 48 1 equiv. percarbonate, under air instead of argon, additional wash of sat. aq. Na2S2O3 during work-up
Yes 1.0 : 1.4
3 EtOAc 50 48 Under air instead of Ar(g)
No ---
4 EtOAc 50 48 No percarbonate, under air instead of Ar(g)
No ---
88
Crude reaction mixtures after aqueous work-up (aq. sat. NaHCO3, water, brine)
all displayed a dark-brown colour, characteristic of excess iodine. In an attempt to
reduce iodine to its corresponding anions, aqueous saturated thiosulfate washes were
incorporated into the work-up procedure. Although the resulting crude reaction materials
appeared to contain less iodine, the comparative increase of starting material in these
reactions suggested that aqueous thiosulfate washes led to degradation of Bupropion
(Table 9).
Table 9. Screening reactions with aqueous saturated thiosulfate wash during aqueous work-up. (Reaction entries in this table were performed by Rebecca Sydor.)
Entry Solvent Temp. (˚C)
Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 61 48 4 equiv. amine Yes 1.0 : 0.1 2 EtOAc 50 48 Na2SO4 added to
reaction mixture, additional wash of sat. aq. Na2S2O3 during work-up
Yes 1.0 : 1.0
3 EtOAc 50 48 4 equiv. amine, additional wash of sat. aq. Na2S2O3 during work-up
Yes 1.0 : 3.9
Only a few reaction conditions resulted in near complete consumption of starting
materials after 48 hours. In an attempt to expedite the rate of reaction, screening
reactions were carried out in a screw-top pressure vessel (Entries 1-4, Table 10).
Unfortunately, the standard conditions performed under increased pressure were unable
to yield any Bupropion. Additional catalyst and/or acid were required produce any
desirable results, however the consumption of starting material was only moderate
89
(Entries 3 and 4, Table 10). Comparable reactions, which took place at atmospheric
pressure led to increased product formation, which suggest that atmospheric pressures
are more favourable to this reaction.
Table 10. Screening reactions performed in screw-top glass pressure vessel and comparable control reactions. (All reaction entries expect #1 were performed by Rebecca
Sydor.)
Entry Solvent Temp.
(˚C) Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 50 48 Reaction done in pressure vessel
Yes ---
2 EtOAc 50 48 25 mol% NH4I catalyst, addition of 15 mol% AcOH, pressure vessel
Yes 1.0 : 3.5
3 EtOAc 50 48 25 mol% NaI used in place of NH4I, addition of 15 mol% AcOH, pressure vessel
Yes 1.0 : 3.5
4 EtOAc 50 48 15 mol% NaI used in place of NH4I, addition of 15 mol% AcOH, pressure vessel
Yes 1.0 : 1.3
5 EtOAc 50 48 25 mol% NaI used in place of NH4I, addition of 15 mol% AcOH
Yes 1.0 : 0.6
6 EtOAc 50 48 15 mol% NaI used in place of NH4I, addition of 15 mol% AcOH
Yes 1.0 : 0.3
These screening procedures have summarized that a weak acid, an iodine
source, and the percarbonate oxidant are required to carry this reaction forward. An
attempt to broaden compatible reagents for this reaction resulted in a new set of
conditions that led to promising results. 15 mol% each of elemental iodine and acetic
90
acid (Conditions #2) were used in place of NH4I and 1H NMR analysis of the crude
reaction mixture indicated product formation and complete consumption of the starting
material (Entry 1, Table 11). Similarly, 15 mol% each of elemental iodine and phenol
also led to product formation, although in lower yields of Bupropion (Conditions #3,
Entry 4, Table 11).
Table 11. Probing other suitable reagents for α-amination of 3’-chloropropiophenone. (All reaction entries expect 4 were performed by Rebecca Sydor.)
Entry Solvent Temp. (˚C)
Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 50 48 Conditions #2a Yes 1:0 2 EtOAc 50 48 Conditions #2,
0.10 equiv each of I2 and AcOH
Yes 1.0:0.07
3 EtOAc 50 48 Conditions #2, 0.075 equiv each of I2 and AcOH
Yes 1:0.11
4 EtOAc 50 48 Conditions #3b, Additional equiv. each of amine and percarbonate added after 48 hours (3 mmol scale)
Yes 1.0:1.7
a I2 (15 mol%), AcOH (15 mol%), sodium percarbonate (2 equiv), tbutyl amine (3 equiv), EtOAc b I2 (15 mol%), PhOH (15 mol%), sodium percarbonate (2 equiv), tbutyl amine (3 equiv), EtOAc
Guo et al. proposed a radical catalytic mechanism to account the α-amination of
their substrates. They proposed that I- was oxidized to I2 and underwent homolytic
cleavage to produce radical iodine species, which in turn can abstract a hydrogen atom
from the α-carbonyl position of an aryl ketone. However, bond dissociation enthalpies of
either I2 or HI (151 kJ/mol and 298 kJ/mol, respectively) neither match nor exceed the
91
energy required to abstract a hydrogen from the α-position of an aryl ketone
(PhC(O)CH2R = ~388 kJ/mol).70 To account for the discrepancies between the bond
dissociation enthalpies of these species, an ionic mechanism is proposed for this α-
amination reaction and accounts for the compatibility of other reagents for this reaction
summarized in Table 6. The presence of a weak acid helps facilitate formation of the
enol species 2-16, which in turn can form an α-iodinated species 2-17. Upon
nucleophilic attack from tbutyl amine, the desired product, Bupropion is formed. The
catalytic I2 is regenerated from oxidation of 2HI or 2I- (Scheme 65).
Scheme 65. Proposed ionic mechanism for the synthesis of Bupropion.
To this point, only a few reaction conditions had resulted in complete
consumption of starting material after 48 hours to yield Bupropion. In an attempt to
complete the reaction in this time frame extra equivalents of certain reagents were
added after a period of time to help facilitate the reaction. The addition of 3 equivalents
of amine over a span of 30 hours provided a low formation of the desired product,
indicating that at least a three-equivalent excess at the start is required to efficiently
I2
[O]2 I-
2HI
[O]
Base
Cl
O
Cl
OH
Cl
OIH+
+ HI
Cl
OI tBuNH2 + HI
Cl
O
NH
I2 Regenaration of I2
2-16 2-17
2-17
*
**
92
drive the reaction forward (Entry 1, Table 12). However, the addition of an additional
equivalent of amine after 24 hours led to the production of Bupropion and complete
consumption of starting material (Entry 4, Table 12). Similarly, an additional equivalent
of percarbonate after 24 hours also led to full consumption of starting material (Entry 6,
Table 12). Additional amounts of catalyst, via I2, AcOH, or NH4I, led to improvements
however were not as effective as the addition of more amine and oxidant (Entry 7 and 9,
Table 12).
With an optimized approach that allowed for complete consumption of starting
material, the scalability of this protocol was probed. Considering the scale of these
reactions previous improvements were employed as well as longer reaction times.
These reactions containing different sources of acid and iodine, and which were
reloaded with amine and percarbonate, resulted in product formation and complete
consumption of starting material (Scheme 66, Table 13).
Due to the difficulty of isolating Bupropion as a free-base via flash-
chromatography and to better serve the industrial client, efforts were placed towards
formation of its corresponding HCl salt. The first attempt combined HCl in IPA (1:1 v/v)
and this mixture was used to dissolve the crude product before removing the excess
under reduced pressure to isolate the salts. A second method dissolved the crude
product in toluene before delivering a saturated solution of HCl in IPA. This method
delivered the desired HCl salt, however this method was less reproducible due to the
difficulty in removing toluene. Both methods led to the desired HCl salt however they
were accompanied with an unwanted by-product. 1H NMR analysis of these HCl salts
93
depicted a resonance consistent with an α-tbutyl amino group, and no other protons
attached to a carbon. However, this resonance yielded an integration over 9 protons.
This excess was reasoned to arise from a t-butyl ammonium salt from the
disengagement of the amino group upon protonation. 1H NMR analysis of a separate
tbutyl ammonium salt sample confirmed this impurity. This by-product could have
formed during the acidification of the crude reaction material and as such, efforts to
keep this mixture cold were made. However, this was not sufficient in preventing
formation of this impurity. It should also be noted, that it was ensured that all excess
amine was evaporated from reaction mixtures, before the generation of the
corresponding HCl salt
94
Table 12. Reaction screening trials with extra equivalents of reagents added. (Entries marked with asterisk were performed by Rebecca Sydor.)
Entry Solvent Temp.
(˚C) Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 MeCN 50 30 Amine added in 3 portions over 30 hours
Yes 1.0 : 20
2* EtOAc 50 48 Additional 2 equiv. of amine added after 24 hours
Yes 1.0 : 0.1
3* EtOAc 50 48 Additional 2 equiv. of amine added after 24 hours, upscale (25 mmol)
Yes 1.0 : 0.3
4* EtOAc 50 48 Additional equiv. of amine added after 24 hours
Yes 1 : 0
5 EtOAc 50 72 Additional equiv. of amine added after 24 hours, upscale (36 mmol)
Yes 1.0 : 0.3
6* EtOAc 50 48 Additional equiv. of percarbonate added after 28 hours
Yes 1 : 0
7* EtOAc 50 48 Additional 10 mol% NH4I added after 28 hours
Yes 1.0 : 0.5
8 EtOAc 50 48 Additional 10 mol% AcOH added after 28 hours
Yes 1.0 : 0.4
9 EtOAc 50 48 Additional 10 mol% I2 added after 28 hours
Yes 1.0 : 0.3
10 EtOAc 50 72 Additional equiv. each of amine and percarbonate added after 48
Yes 1 : 0
95
hours, upscale (75 mmol)
Scheme 66. Summary of synthetic efforts towards Bupropion.
Table 13. Optimized reaction conditions tested with larger scale reactions.
Entry Solvent Temp. (˚C)
Time (hours)
Notes Prod. Formation
Prod. : Starting Material
1 EtOAc 50 96 Additional equiv. each of amine and percarbonate added after 48 hours, upscale (69 mmol scale)
Yes 1 : 0
2 EtOAc 50 96 Conditions #2, Additional equiv. each of amine and percarbonate added after 48 hours, upscale (68 mmol scale)
Yes 1 : 0
3 EtOAc 50 72 Conditions #3, Additional equiv. each of amine and percarbonate added after 48 hours, upscale (18 mmol scale)
Yes 1 : 0
Conditions #1NH4I (15 mol%)
Na2CO3•1.5H2O2 (2 equiv)
EtOAc, 50 ˚C
Cl
O
Cl
O
NH
NH2
+
(3 equiv)
Conditions #2I2 (15 mol%), AcOH (15 mol%)
Na2CO3•1.5H2O2 (2 equiv)
Conditions #3I2 (15 mol%), PhOH (15 mol%)
Na2CO3•1.5H2O2 (2 equiv)
96
4.1 Conclusion
Overall, the synthetic pathway provided by Guo et al. led to a set of conditions
that allowed for the access of Bupropion (Scheme 15). Moreover, modifications led to
the use of less expensive reagents (e.g. I2, AcOH, phenol) and an industrially viable
solvent choice with EtOAc. Despite these improvements, difficulties arose in the
isolation of the Bupropion, both as its free-base and its HCl salt. Nevertheless, the
chemistry was passed onto Vibrant Pharma Inc. for further modification and scale-up.
97
Chapter 5: Experimental
98
5.0 Experimental
5.1 General experimental
All reactions were carried out in flame-dried glassware under argon unless
specified otherwise. Thin layer chromatography (TLC) was performed on glass-backed
plates coated with Silica Gel 60, which contained a fluorescent indicator. The plates
were visualized under UV light. Flash column chromatography was performed with silica
gel particle size 30 – 60 (mesh 230 – 400) supplied by Silicycle ®.
Infrared (IR) spectra were obtained on a FT-IR spectrometer as a neat film. 1H NMR and
13C NMR Spectra were recorded on a Bruker Avance 300 (300 MHz 1H, 75 MHz 13C), a
Bruker Avance 400 (400 MHz 1H, 100.6 MHz 13C), or a Bruker Avance 600 (600 MHz
1H, 150.9 MHz 13C). Chemical shifts (ppm) and coupling constants (J, Hz) were
obtained from first order analysis of one-dimensional spectra. The proton spectra are
reported as follows δ (multiplicity, coupling constant J, number of protons). 1H NMR data
are reported using standard abbreviations: singlet (s), doublet (d), triplet (t), doublet of
doublet (dd), quartet (q), and multiplet (m). 1H NMR and 13C NMR chemical shifts are
referenced to CHCl3. Analytical thin-layer chromatography (TLC) was performed using
0.25 mm, extra-hard layer layer, 60 Å F254 glass-backed silica gel plates and were
visualized under UV light (254 nm). Pressure vessel reactions were carried out in
heavy-walled cylindrical vessels with an internal thread and a 15 mm Teflon ® bushing
as a pressure seal. HPLC experiments were performed using a Chiralcel OD-H (0.46
cm x 25 cm) column with iPrOH/hexanes as the eluent. Elemental analyses were
99
performed by MWH Laboratories of Pheonix, AZ. High-resolution mass spectrometry
was performed by Queen’s University Mass Spectrometry Facility in Kingston, ON.
5.2.0 Amino sulfoxide ligands and related compounds
5.2.1 General procedure for the preparation of aryl thiol from the corresponding
sulfonyl chloride
In a three-neck round bottom flask equipped with a drying tube, argon gas inlet,
and reflux condenser, 8-quinolinesulfonyl chloride (1.0 equiv.) was stirred in anhydrous
toluene (0.1 M, wrt sulfonyl chloride). Ph3P (3.0 equiv.) was added in five portions over
10 minutes. After complete addition of Ph3P, the reaction mixture stirred for 3 hours.
Water was added to the reaction mixture until all solids dissolved, and the mixture
stirred for an additional 30 minutes. The aqueous layer was discarded. The organic
layer was extracted four times with a 10% NaOH aqueous solution. The aqueous layers
were combined and toluene was added and the two-phase mixture was stirred. Water
was added to the mixture to dissolve remaining solids, and the toluene was discarded.
The aqueous layer was then acidified with a 1 M HCl solution until pH = 5 was reached.
The acidified aqueous layer was extracted with CH2Cl2. The organic layers were
combined and then washed with water, and brine. It was then dried over anhydrous
MgSO4, and concentrated under reduced pressure to afford pure product.
100
8-Mercaptoquinoline (1-27)47
Obtained as a viscous purple liquid, 76% yield; 1H NMR (400 MHz,
CDCl3), δ: 8.94 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.16 (dd, J = 8.0 Hz, 1.6 Hz,
1H), 7.72 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.59 (dd, J = 8.2, 1.2 Hz, 1H), 7.46 (dd, J = 8.4
Hz, 4.4 Hz, 1H), 7.42 (app, t, J = 2.8 Hz, 1H), 5.65 (s, 1H); 13C NMR (100 MHz, CDCl3),
δ: 149.50, 143.78, 136.97, 134.80, 128.84, 127.16, 126.63, 124.61, 121.78.
5.2.2 General procedure for the preparation of N-Boc Protected L-Phenylalanine
derived amino alcohol.
N-Boc-L-Phenylalanine was stirred in anhydrous THF (0.1 M wrt amino acid) and
cooled to 0 ˚C. Ethyl chloroformate (1.2 equiv.) was added to the reaction mixture,
followed by dropwise addition of Et3N. The reaction mixture was stirred for 2 hours or
until disappearance of starting material (confirmed via TLC). The solids were filtered off
and the filtrate was added dropwise to NaBH4 (1.5 equiv.) in water (0.25 M wrt hydride)
at 0 ˚C. The mixture was stirred overnight while warming to room temperature. The
reaction was quenched with a 1 M HCl solution until pH = 6 was reached. The acidified
aqueous solution was extracted five times with EtOAc, and the combined organic layers
were washed three times with water, twice with saturated aq. NaHCO3, and once with
brine. It was then dried over anhydrous MgSO4, concentrated under reduced pressure,
and the residue recrystallized with hexanes and EtOAc to afford pure product.
NSH
101
N-Boc-(R)-phenylalaninol71
Obtained as a white solid, yield: 81%; mp = 98 - 100 ˚C (lit mp =
96 – 97 ˚C).71 1H NMR (400 MHz, CDCl3), δ: 7.30 – 7.20 (m, 5H),
4.77 (br. d, J = 7.6 Hz, 1H), 3.87 (br. s, 1H), 3.69 (dd, J = 10.8 Hz, 3.6 Hz, 1H), 3.57 (dd,
J = 10.8 Hz, 5.2 Hz, 1H), 2.85 (d, J = 7.2, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3),
δ: 156.17, 137.77, 129.28, 128.57, 128.10, 126.55, 79.74, 64.45, 53.72, 37.43, 28.33;
IR (cm-1, neat): 3357, 2979, 2932, 1687, 1528, 1367, 1251, 1169.
5.2.3 General procedure for the preparation of N-Boc Protected L-phenylalanine
derived amino iodide.
Ph3P (1.0 equiv.), imidazole (1.0 equiv.) and I2 (1.1 equiv.) were cooled to -78 ˚C.
Anhydrous CH2Cl2 (0.1 M wrt Ph3P) was added, and after addition the mixture was
stirred and the temperature was raised slowly to -30 ºC. N-Boc protected amino alcohol
(1.0 equiv) in anhydrous CH2Cl2 (0.1 M wrt to amino alcohol) was added dropwise. The
reaction mixture was stirred and while warming to room temperature. Upon
disappearance of starting material (confirmed via TLC), the reaction mixture was filtered
to remove the phosphine oxide and the filtrate was concentrated under reduced
pressure without heat. The crude mixture was run through a short silica column (20 g
silica/1g crude) to afford pure product.
HO NH
Bn
O
O
102
(2R)-N-Boc-1-Phenyl-3-iodopropan-2-amine71
Obtained as a white solid, 72% yield; mp = 120 – 123 ˚C (lit mp =
121 – 122 ˚C).71 1H NMR (300 MHz, CDCl3), δ: 7.34 – 7.22 (m,
5H), 4.69 (br. s, 1H), 3.61 (br. s, 1H), 3.38 (dd, J = 10.1 Hz, 4.3 Hz, 1H), 3.18 (dd, J =
10.2 Hz, 3.8 Hz, 1H), 2.92 (dd, J = 13.5 Hz, 5.7 Hz, 1H), 2.78 (dd, J = 13.6 Hz, 8.0 Hz,
1H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3), δ: 154.74, 136.96, 129.34, 128.60,
126.76, 79.76, 50.94, 40.54, 28.25, 13.84; IR (cm-1, neat): 3328, 2976, 1666, 1536,
1445, 1436, 1365, 1274, 1171.
5.2.4 General procedure for the preparation of N-Boc protected heteroaryl amino
sulfanes (1-28)
Heteroaryl thiols (1.0 equiv) and N-Boc protected amino iodide (2.0 equiv) were
loaded in a round bottom flask. The flask was evacuated and then purged with inert
argon gas three times, and an argon filled balloon was utilized to keep a constant
pressure of argon. Anhydrous CH2Cl2 (10 mL/mmol thiol) was added and the solution
was cooled to 0 ˚C, which was followed by dropwise addition of N,N-
diisopropylethlyamine (2.0 equiv). The reaction was stirred overnight, while the
temperature slowly rose to room temperature. The reaction mixture was washed three
I NH
Bn
O
O
103
times with water, and once with brine. It was dried over anhydrous MgSO4,
concentrated under reduced pressure, and purified by flash column chromatography.
N-Boc-1-Phenyl-3-(2-pyridylsulfanyl)propan-2-amine
Obtained as a white solid, 93% yield; mp = 80 – 81 ˚C. 1H
NMR (400 MHz, CDCl3), δ: 8.39 (d, J = 4.4 Hz, 1H), 7.50
(td, J = 7.6 Hz, 1.6 Hz, 1H), 7.31 – 7.28 (m, 1H), 7.25 – 7.20 (m, 5H), 7.01 – 6.98 (m,
1H), 5.87 (br. d, J = 5.6 Hz, 1H), 4.07 (s, 1H), 3.32 (dd, J = 14.4 Hz, 4.4 Hz, 1H), 3.25
(dd, J = 14.0 Hz, 7.2 Hz, 1H), 3.12 (dd, J = 13.6, 4.8 Hz, 1H), 2.87 (dd, J = 13.6 Hz, 8.4
Hz, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3), δ: 158.71, 155.60, 149.10, 137.96,
136.07, 129.46, 128.41, 126.36, 122.47, 119.67, 78.85, 52.84, 40.26, 33.41, 28.32; IR
(cm-1, neat): 3426, 2975, 1686, 1648, 1557, 1162. TOF MS EI calculated for
[C19H24N2O2S]+: 344.1559; found: 344.1556.
N-Boc-1-Phenyl-3-(8-quinolylsulfanyl)propan-2-amine
Obtained as a white solid, 96% yield; mp = 89 – 90 ˚C. 1H
NMR (300 MHz, CDCl3), δ: 8.96 (dd, J = 4.2 Hz, 1.7 Hz,
1H), 8.21 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 7.58 (d, J = 7.9 Hz,
1H), 7.53 (d, J = 6.8 Hz, 1H), 7.43 (m, 1H), 7.41 (m, 1H), 7.28 – 7.20 (m, 5H), 5.38 (d, J
= 7.2 Hz, 1H), 4.22 (d, J = 5.3 Hz, 1H), 3.20 – 3.15 (m, 2H), 3.12 – 3.08 (m, 1H), 3.04
N
SBn
NH
O
O
N
SBn
NH
O
O
104
(dd, J = 13.6 Hz, 7.6 Hz, 1H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3), δ: 155.16,
149.28, 145.57, 137.53, 137.05, 136.47, 129.34, 128.32, 128.29, 126.57, 126.40,
125.81,124.66, 121.50, 79,16, 50.90, 39.38, 34.82, 28.24; IR (cm-1, neat): 3326, 2988,
1679, 1642, 1532, 1199.
5.2.5 General procedure for the preparation of N-Boc protected heteroaryl amino
sulfoxides (1-29)
5.2.5.1 mCPBA oxidation
N-Boc protected heteroaryl amino sulfanes (1.0 equiv) in anhydrous CH2Cl2 (0.5
M, wrt starting material) were stirred and cooled to -78 ˚C. To this, a solution of mCPBA
(1.0 equiv, 72% active) in anhydrous CH2Cl2 (0.05 M, wrt mCPBA) was added via
canula. The reaction mixture was stirred for an additional 3 hours at -78 ˚C, before
raising the temperature to -35 ˚C and stirring overnight. The reaction mixture was
concentrated under reduced pressure to reduce its volume by half. The reaction mixture
was washed twice with 4:1 solution of saturated aq. Na2S2O3 and NaHCO3, twice with a
saturated aq. NaHCO3, twice with water, and once brine. It was then dried over
anhydrous MgSO4, concentrated under reduced pressure, and purified by flash column
chromatography.
105
5.2.5.2 NaIO4 oxidation
N-Boc protected amino sulfanes (1.0 equiv) in MeOH/water solution (1:1 v/v) was
stirred, and CH2Cl2 was added dropwise until starting material had fully dissolved. To
this, NaIO4 (1.0 equiv) was added slowly. The reaction was stirred and its progress was
tracked via TLC. The reaction mixture was filtered through a Büchner funnel and the
filtrate was extracted three times with CH2Cl2. The combined organic layers were
washed three times with water, and once with brine. It was then dried over anhydrous
MgSO4, concentrated under reduced pressure, and purified by flash column
chromatography.
5.2.5.3 H2O2 oxidation
N-Boc protected heteroaryl amino sulfanes (1.0 equiv) in HFIP (1.0 M, wrt
starting material) at room temperature. To this, 30% aqueous H2O2 (2.0 equiv) was
added and the reaction’s progress was tracked via TLC. Excess H2O2 was quenched
with saturated aq. Na2S2O3. The reaction mixture was extracted three times with EtOAc,
and the combined organic layers were dried over anhydrous MgSO4, concentrated
under reduced pressure, and purified by flash column chromatography.
106
N-Boc-1-Phenyl-3-(2-pyridylsulfinyl)propan-2-amine71
Obtained as a diastereomeric mixture. White solid. Total
yield: 45 – 86 %; mp = 90 – 94 ˚C. Major isomer: 1H NMR
(400 MHz, CDCl3), δ: 8.61 (d, J = 4.6 Hz, 1H), 7.99 (s, 1H),
7.96 – 7.90 (m, 1H), 7.39 – 7.35 (m, 1H), 7.25 – 7.19 (m, 5H), 4.90 (d, J = 6.1 Hz, 1H),
4.39 (m, 1H), 3.43 (dd, J = 13.5 Hz, 4.6 Hz, 1H), 3.12 (dd, J = 13.7, 7.6, 1H), 3.03 –
2.98 (m, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3), δ: 164.53, 155.01, 149.57,
137.99, 136.95, 129.47, 128.45, 126.62, 124.54, 119.98, 79.43, 57.86, 48.07, 40.31,
28.23. Minor isomer: 1H NMR (400 MHz, CDCl3), δ: 8.59 (d, J = 4.7 Hz, 1H), 8.01 (s,
1H), 7.96 – 7.90 (m, 1H), 7.39 – 7.35 (m, 1H), 7.32 – 7.27 (m, 5H), 5.55 (d, J = 6.6 Hz,
1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.99 – 2.94 (m, 2H); 13C NMR (100 MHz, CDCl3), δ:
164.45, 154.74, 149.57, 137.93, 136.95, 129.36, 128.51, 126.62, 124.45, 119.78, 79.43,
58.10, 49.09 40.31, 28.27. Both diastereomers: IR (cm-1, neat): 3466, 2987, 1685, 1632,
1560, 1100, 1042.
N-Boc-1-Phenyl-3-(8-quinolylsulfinyl)propan-2-amine
Obtained as a diastereomeric mixture. Off-white solid. Total
yield: 96%; mp = 120 – 123 ˚C. Major diastereomer: 1H
NMR (600 MHz, CDCl3), δ: 8.70 (s, 1H), 8.15 (m, 1H), 8.09 N
S*O Bn
NH
O
O
N
S*Bn
NH
O
O
O
107
(m, 1H), 7.80 (m, 1H), 7.59 (m, 1H), 7.34 (m, 1H), 7.17 – 7.05 (m, 5H), 5.39 (s, 1H),
4.36 (s, 1H), 3.56 (m, 1H), 3.13 (m, 1H), 2.91 (m, 1H), 2.82 (m, 1H), 1.25 (s, 9H); 13C
NMR (150 MHz, CDCl3), δ: 154.52, 149.51, 143.12, 141.11, 137.15, 135.96, 129.96,
129.84, 129.35, 129.18, 127.65, 126.21, 126.19, 121.71, 78.71, 58.41, 50.15, 39.49,
27.21. Minor diastereomer: 1H NMR (600 MHz, CDCl3), δ: 8.75 (s, 1H), 8.27 (d, J = 7.2
Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.76 (app. J = 7.8 Hz, 1H),
7.49 – 7.45 (m, 1H), 7.34 – 7.17 (m, 5H), 4.23 (br. s, 1H), 3.62 (br. s, 1H), 3.25 (br. s,
1H), 3.06 (br. s, 1H), 2.94 (br. s, 1H), 1.37 (s, 9H); 13C NMR (150 MHz, CDCl3), δ:
149.93, 143.96, 136.34, 130.30, 129.70, 129.07, 128.94, 128.32, 128.10, 127.32,
126.74, 126.53, 126.45, 122.08, 78.62, 57.45, 53.79, 41.56, 28.44. Both diastereomers:
IR (cm-1, neat): 3289, 2976, 2929, 1708, 1495, 1169, 1044, 1025.
5.2.6 General procedure for the preparation of heteroaryl amino sulfoxides (N-
Boc de-protection)
To a solution of chiral N-Boc protected heteroaryl amino sulfoxide stirring in
anhydrous CH2Cl2 (0.05 M wrt starting material) at 0˚C, trifluoroacetic acid (5 mL/mmol
starting material) was added dropwise. The resulting solution was stirred, and while the
temperature was slowly raised to room temperature. The excess reagent and solvent
were removed under reduced pressure. Hexane was added and swirled around in the
flask and was removed under reduced pressure, and this process was repeated twice
more. The resulting oil was re-dissolved in CH2Cl2 and washed three times with a
108
saturated aq. NaHCO3, twice with water, and once with brine. It was then dried over
anhydrous MgSO4, concentrated under reduced pressure, and purified by flash column
chromatography.
1-Phenyl-3-(2-pyridylsulfinyl)propan-2-amine (Ligand 1-L1m)
Obtained as a diastereomeric mixture. Viscous off-white oil. Total
yield: 81%. Major diastereomer: 1H NMR (600 MHz, CDCl3), δ:
8.61 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.95 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.40
(m, 1 H), 7.29 - 7.23b (m, 5H), 3.77 (m, 1H), 3.29 (dd, J = 13.6 Hz, 4.6, 1H), 3.02 (dd, J
= 13.2 Hz, 3.0 Hz, 1H), 2.97 (dd, J = 13.3 Hz, 7.9 Hz, 1H), 2.76 (dd, J = 13.4 Hz, 8.4 Hz,
1H), 1.73 (s, 2H); 13C NMR (150 MHz, CDCl3), δ: 165.01, 149.52, 138.07, 137.64,
129.36, 128.59, 126.67, 124.54, 119.61, 61.84, 49.52, 43.97. Minor diastereomer: 1H
NMR (600 MHz, CDCl3), δ: 8.55 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.94 (td, J
= 7.6 Hz, 1.6 Hz, 1H), 7.40 (m, 1 H), 7.34 (m, 3H), 7.11 (app d, J = 8.4 Hz, 2H), 3.61 (m,
1H), 3.15 (dd, J = 13.3 Hz, 9.9 Hz, 1H), 3.02 (dd, J = 13.2 Hz, 3.0 Hz, 1H), 2.83 (dd, J =
13.5 Hz, 5.8 Hz, 1H), 2.72 (dd, J = 13.6 Hz, 8.1 Hz, 1H), 1.73 (s, 2H). 13C NMR (150
MHz, CDCl3), δ: 164.67, 149.59, 137.90, 137.49, 129.19, 128.59, 126.63, 124.38,
119.90, 61.54, 58.24, 44.41. Both diastereomers: IR (cm-1, neat): 3374, 3042, 2903,
1584, 1499, 1028.
N
S*Bn
NH2
O
109
1-Phenyl-3-(8-quinolylsulfinyl)propan-2-amine (Ligand 1-L2m)
Obtained as a diastereomeric mixture. Off-white solid. Total yield:
81%; mp = 114 – 118 ˚C. Major diastereomer: 1H NMR (600 MHz,
CDCl3), δ: 8.84 (dd, J = 4.2 Hz, 1.8 Hz, 1H), 8.30 (dd, J = 7.2 Hz,
1.4 Hz, 1H), 8.25 (m, 1H), 7.95 (m, 1H), 7.76 (m, 1H), 7.50 (dd, J = 8.3 Hz, 4.3 Hz, 1H),
7.31 – 7.23 (m, 5H), 3.90 (m, 1H), 3.64 (dd, J = 13.4 Hz, 4.7 Hz, 1H), 3.07 (m, 1H), 2.89
(dd, J = 13.15 Hz, 7.6 Hz, 1H), 2.78 (dd, J = 13.4 Hz, 8.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3), δ: 150.02, 143.71, 141.37, 137.78, 136.26, 130.19, 129.56, 129.04, 128.52,
128.35, 126.59, 126.39, 122.01, 62.07, 49.79, 44.21. Minor diastereomer (Ligand L2
accessed via sulfenate anion pathway, Section 1.4.11.1): 1H NMR (600 MHz, CDCl3), δ:
8.77 (dd, J = 4.3 Hz, 1.7 Hz, 1H), 8.28 (dd, J = 7.2 Hz, 1.4 Hz, 1H), 8.27 (dd, J = 8.4 Hz,
1.7 Hz, 1H), 7.94 (dd, J = 8.2 Hz, 1.3 Hz, 1H), 7.62 (dd, J = 8.0 Hz, 7.3 Hz, 1H), 7.47
(dd, J = 8.3 Hz, 4.3 Hz, 1H), 7.11 – 7.08 (m, 3H), 6.98 (m, 2H), 3.63 – 3.61 (m, 1H),
3.47 (dd, J = 13.2 Hz, 10.0 Hz, 1H), 3.06 (dd, J = 13.2 Hz, 2.2 Hz, 1H), 2.72 – 2.61 (m,
2H), 2.03 (s, 2H); 13C NMR (100 MHz, CDCl3), δ: 150.19, 143,82, 141.41, 137.90,
136.44, 130.38, 129.19, 128.51, 128.28, 126.84, 126.74, 126.55, 122.19, 60.86, 48.81,
44.34. Both diastereomers: IR (cm-1, neat): 3364, 3060, 3028, 2918, 1593, 1493, 1034.
N
S*O Bn
NH2
110
5.2.7 General procedure for the preparation of N-Ts protected heteroaryl amino
sulfoxides (1-31)
A mixture of anhydrous CH2Cl2 (0.1 M wrt amino sulfoxide), free base heteroaryl
amino sulfoxide (1.0 equiv), tosyl chloride (1.2 equiv) was stirred at 0 ˚C. Et3N (1.5
equiv) was added dropwise, and the temperature of the resulting solution was raised
slowly to room temperature. The solution was stirred until disappearance of starting
material (verified via TLC). The solvent was removed under reduced pressure and
triturated with hexanes.
N-Ts-1-Phenyl-3-(2-pyridylsulfinyl)propan-2-amine
Obtained as a diastereomeric mixture. White solid. Total
yield: 93%; mp = 168 – 170 ˚C. Major isomer: 1H NMR
(400 MHz, CDCl3), δ: 8.61 (d, J = 4.5 Hz, 1H), 7.95 (m,
1H), 7.89 (m, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.42 (m, 1H), 7.24 – 7.20 (m, 3H), 7.23 (m,
2H), 7.05 (m, 2H), 5.45 (d, J = 5.6 Hz, 1H), 3.92 (m, 1H), 3.27 (dd, J = 13.6 Hz, 6.3 Hz,
1H), 3.12 (m, 1H), 3.08 (m, 1H), 3.01 (m, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3),
δ: 163.92, 149.66, 143.45, 138.24, 136.24,135.71, 129.62, 129.44, 128.72, 127.19,
126.91, 124.84, 119.95, 58.14, 52.00, 40.84, 21.55. Minor isomer: 1H NMR (400 MHz,
CDCl3), δ: 8.53 (d, J – 4.5 Hz, 1H), 7.93 (m, 1H), 7.85 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H),
7.42 (m, 1H), 7.24 – 7.20 (m, 3H), 7.18 (m, 2H), 7.09 (m, 2H), 6.09 (d J = 6.8 Hz, 1H),
N
S*Bn
NH
O O2S
111
3.99 (m, 1H), 3.12 (m, 1H), 3.03 (m, 1H), 2.98 (m, 1H), 2.87 (dd, J = 13.8 Hz, 3.8 Hz,
1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3), δ: 164.00, 149.55, 143.35, 138.19,
137.18, 135.98, 129.60, 129.41, 128.72, 127.20, 126.96, 124.70, 119.91, 57.17, 52.10,
41`.15, 21.55. Both diastereomers: IR (cm -1, neat): 3060, 2923, 1453, 1423, 1327,
1157, 1086, 1035; Analysis calculated for C21H22N2O3S2; C, 60.85; H, 5.35; found C,
60.85; H, 5.35.
N-Ts-1-Phenyl-3-(8-quinolylsulfinyl)propan-2-amine
Obtained as a diastereomeric mixture. White solid. Total
yield: 86%; mp = 171 – 172 ˚C. Major isomer: 1H NMR
(400 MHz, CDCl3), δ: 8.88 (dd, J = 4.29 Hz, 1.57 Hz, 1H),
8.29 (dd, J = 8.3 Hz, 1.5 Hz, 1H), 8.26 (m, 1H), 7.99 (m, 1H), 7.83 (d, J = 8.2 Hz, 2H),
7.79 (app t, J = 7.7 Hz), 7.54 (m, 1H), 7.29 (d, J = 8.2 Hz), 2H) 7.21 – 7.08 (m, 5H), 5.99
(d, J = 4.8 Hz, 1H), 3.93 (m, 1H), 3.62 (dd, J = 13.5, 6.3 Hz, 1H), 3.44 (dd, J = 13.7 Hz,
8.9 Hz, 1H), 3.24 (dd, J = 14.0 Hz, 7.4 Hz, 1H), 3.15 (dd, J = 14.0 Hz, 7.4 Hz, 1H), 2.41
(s, 3H); 13C NMR (100 MHz, CDCl3), δ: 150.18, 143.33, 142.77, 140.85, 137.00, 136.78,
136.62, 136.10, 130.51, 129.71, 129.60, 128.53, 128.21, 126.73, 126.63, 126.56,
122.28, 58.66, 53.49, 41.34, 21.57. Minor isomer: 1H NMR (400 MHz, CDCl3), δ: 8.81
(dd, J = 4.3 Hz ,1.6 Hz, 1H), 8.24 (m, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.69 (app t, J =
N
S*Bn
NH
O O2S
112
7.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.51 (m, 1H), 7.21 – 7.08 (m, 5H), 7.19 (m, 2H),
3.93 (m, 1H), 3.33 (dd, J = 13.7 Hz, 4.4 Hz, 1H), 3.03 (m, 1H), 3.02 (m, 1H), 2.81 (dd, J
= 13.8 Hz, 2.76 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3), δ: 150.03, 143.31,
140.47, 136.78, 136.62, 136.43, 130.42, 129.64, 129.52, 128.39, 128.14, 127.43,
127.16, 126.70, 126.62, 126.55, 122.25, 58.16, 52.80, 40.24, 21.54 .Both
diastereomers: IR (cm -1, neat): 3061, 3029, 1595, 1493, 1455, 1328, 1202, 1086,
1044; TOF MS EI calculated for [C25H24N2O3S2]+: 464.1228; found: 464.1223.
5.2.8 General procedure for the synthesis of heteroaryl sulfanyl acrylates (1-32)41
Heteroaryl thiols (1.0 equiv) and methyl propiolate (1.3 equiv) were stirred in
anhydrous CH2Cl2 (0.25 M wrt thiol). The mixture was cooled to 0 ˚C and this was
followed by dropwise addition of Et3N (1.1 equiv). The solution was stirred, while the
temperature was slowly raised to room temperature over 60 minutes.. A 10% solution of
HCl(aq) was added when the reaction had reached completion, as confirmed by TLC. The
organic layer was separated. The aqueous layer was extracted by CH2Cl2 (3 x 50 mL)
and organic layers were combined. The organic layer was washed three times with
water, and three times with brine. The organic layer was dried of anhydrous MgSO4,
concentrated under reduced pressure, and purified by flash column chromatography.
113
2-Carbomethoxyethenyl 2-pyridyl sulfane
Obtained as mixture of (E) and (Z) isomers. Straw-coloured
solid. Total yield: 81%, mp = 79 – 90 ˚C. Major isomer (Z): 1H
NMR (400 MHz, CDCl3), δ: 8.57 (d, J = 10.3 Hz, 1H), 8.53 (dd, J = 4.9 Hz, J = 1.8 Hz,
1H), 7.62 (td, J = 7.9 Hz, 1.8 Hz, 1H), 7.33 (m, 1H), 7.14 (dd, J = 7.4 Hz, 4.9 Hz, 1H),
6.12 (d, J = 10.3 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3), δ: 167.25, 155.10,
149.63, 142.28, 136.84, 123.29, 121.50, 113.40, 51.54. Minor isomer (E): 1H NMR (400
MHz, CDCl3), δ: 8.60 (d, J = 15.9 Hz, 1H), 8.53 (dd, J = 4.9 Hz, 2.0 Hz, 1H), 7.58 (m,
1H), 7.27 (m, 1H), 7.14 (dd, J = 4.8 Hz, 0.9 Hz, 1H), 6.14 (d, J = 15.9 Hz, 1H), 3.75 (s,
3H); 13C NMR (100 MHz, CDCl3), δ: 165.58, 154.11, 150.12, 142.24, 136.94, 123.16,
121.35, 116.79, 51.54. Both isomers: IR (cm-1, neat): 3042, 2948, 1700, 1574, 1417,
1162, 1120, 1089.
2-Carbomethoxyethenyl 8-quinolyl sulfane
Obtained as mixture of (E) and (Z) isomers. Straw-coloured
solid. Total yield: 81%, mp 80 – 88 ˚C. Major isomer (Z): 1H
NMR (300 MHz, CDCl3), δ: 9.02 (d, J = 4.1 Hz, 1H), 8.20 (d, J =
8.3 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.56 (m, 1H), 7.49 (d, J =
10.2 Hz, 1H), 7.23 (m, 1H), 6.01 (d, J = 10.2 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz,
N
S CO2Me
N
S CO2Me
114
CDCl3), δ: 166.78, 150.48, 148.44, 146.44, 136.55, 135.92, 131.55, 128.92, 128.38,
126.45, 121.84, 113.57, 50.83. Minor isomer (E): 1H NMR (300 MHz, CDCl3), δ: 8.98 (m,
1H), 8.20 (d, J = 8.3 Hz, 1H), 8.04 (d J = 15.1 Hz, 1H), 7. 86 (m, 1H), 7.79 (m, 1H), 7.49
(m, 1H), 7.45 (m, 1H), 5.95 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H); 13C NMR (75 MHz,
CDCl3), δ: 165.66, 150.46, 146.42, 145.21, 136.58, 132.53, 131.10, 128.79, 128.26,
126.70, 122.02, 117.27, 51.51. Both isomers: IR (cm-1, neat): 3028, 2948, 1689, 1564,
1212, 1169. Analysis calculated for C13H11NO2S; C, 63.65; H, 4.52; found C, 63.46; H,
4.71.
5.2.9 General procedure for the preparation of heteroaryl sulfinyl acrylates (1-33)
5.2.9.1 mCPBA oxidation
Heteroaryl sulfanyl acrylates (1.0 equiv.) in anhydrous CH2Cl2 (0.5 M, wrt starting
material) were stirred and cooled to -78 ˚C. To this, a solution of mCPBA (1.0 equiv,
72% mCPBA) in anhydrous CH2Cl2 (0.05 M, wrt mCPBA) was added via canula. The
resulting solution was stirred, and while the temperature was slowly raised to room
temperature. The excess reagent and solvent were removed under reduced pressure.
Hexane was added and swirled around in the flask and was removed under reduced
pressure, and this process was repeated twice more. The resulting oil was re-dissolved
in CH2Cl2 and washed three times with a saturated aq. NaHCO3, three times with water,
115
and once with brine. It was then dried over anhydrous MgSO4, concentrated under
reduced pressure, and purified by flash column chromatography.
2-Carbomethoxyethenyl 2-pyridyl sulfoxide71
Obtained as mixture of (E) and (Z) isomers. Total yield: 84%,
mp = 83 – 89 ˚C. Major isomer (Z), straw-coloured oil: 1H NMR
(300 MHz, CDCl3), δ: 8.68; (dd, J = 4.7 Hz, 1.7 Hz, 1H), 8.01
(dt, J = 7.9 Hz, 1.1 Hz, 1H), 7.93 (td, J = 7.5 Hz, 1.7 Hz, 1H), 7.41 (dd, J = 7.4 Hz, 1.2
Hz, 1H), 6.90 (d, J = 10.3 Hz, 1H), 6.41 (d, J = 10.3 Hz, 1H), 3.84 (s, 3H); 13C NMR (100
MHz, CDCl3), δ: 164.26, 163.54, 152.44, 150.33, 137.93, 126.30, 125.15, 120.88, 52.34.
Minor isomer (E), pale-yellow solid: 1H NMR (300 MHz, CDCl3), δ: 8.65 (d, J = 4.7 Hz,
1H), 7.94 (m, 1H), 7.91 (m, 1H), 7.85 (d, J = 15.1 Hz, 1H), 7.41 (m, 1H), 6.72 (d, J =
15.1 Hz), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3), δ: 164.00, 162.53, 150.74, 149.84,
138.55, 124.86, 124.13, 118.96, 52.16; Both isomers: IR (cm-1, neat): 3049, 2592,
1728,1575, 1435, 1220, 1038.
(E)-2-Carbomethoxyethenyl quinolyl sulfoxide
Obtained as a dark-brown solid. Yield: 87%, mp = 108 -110 ˚C.
1H NMR (300 MHz, CDCl3), δ: 8.97 (dd, J = 4.3 Hz, 1.7 Hz, 1H),
N
S* CO2Me
O
N
S* CO2Me
O
116
8.31 (d, J = 15.1 Hz, 1H), 8.28 (dd, J = 8.4 Hz, 1.7 Hz, 1H), 8.18 (dd, J = 7.3 Hz, 1.4 Hz,
1H), 7.98 (dd, J = 8.2 Hz, 1.3 Hz, 1H), 7.68 (dd, J = 8.0 Hz, 7.4 Hz, 1H), 7.57 (dd, J =
8.4 Hz, 4.3 Hz, 1H), 6.78 (d, J = 15.1 Hz, 1H), 3.71 (s, 3H); 13C NMR (75 MHz, CDCl3),
δ: 164.93, 151.06, 150.74, 143.90, 140.01, 136.56, 130.60, 128.44, 127.26, 125.55,
123.38, 122.56, 52.69; IR (cm-1, neat): 3062, 2951, 1725, 1294, 1271, 1071. Analysis
calculated for C13H11NO3S; C, 59.76; H, 4.24; found C, 59.73; H, 4.25.
5.2.10 General procedure for lithiated heteroaryl sulfenate anion generation
Heteroaryl sulfinylacrylates (1.0 equiv.) in anhydrous THF (0.2 M, wrt starting
material) were stirred and cooled to -78 ˚C. The solution was treated with dropwise
addition of nBuLi (1.6 M in hexane, 1.0 equiv.), and stirred for 15 minutes. To this, a
solution of electrophile in anhydrous THF (0.25 M, wrt electrophile) was added quickly.
The solution was stirred for an additional 3 hours at -78 ˚C, and stirred overnight while
slowly warming to room temperature. The reaction mixture was concentrated under
reduced pressure, dissolved in CH2Cl2, and the organic layer was washed three times
with water, and once with brine. It was then dried over anhydrous MgSO4, concentrated
under reduced pressure, and purified by flash column chromatography.
117
5.2.10.1 Preparation of N-Boc protected heteroaryl amino sulfoxides (1-29)
(SS,2RC)-N-Boc-1-Phenyl-3-(2-pyridylsulfinyl)propan-2-amine71
A mixture of 2-Carbomethoxyethenyl 2-pyridyl sulfoxide,
nBuLi, and (2R)-N-Boc-1-Phenyl-3-iodopropan-2-amine
afforded a diastereomeric mixture of amino sulfoxides.
Total yield: 72%, d.r. = 1.0:0.7. White solid.
(SS,2RC)-N-Boc-1-Phenyl-3-(8-quinolylsulfinyl)propan-2-amine
A mixture of 2-Carbomethoxyethenyl 8-quinolyl sulfoxide,
nBuLi, and (2R)-N-Boc-1-Phenyl-3-iodopropan-2-amine
afforded one sulfoxide diastereomer. Obtained as an off-
white solid. Yield: 82%, mp = 121 – 122 ˚C. See analysis of minor diastereomer of N-
Boc-1-Phenyl-3-(8-quinolylsulfinyl)propan-2-amine. Removal of N-Boc protecting
group afforded Ligand 1-L2 Analysis calculated for C18H18N2OS (1-L2); C, 69.65; H,
5.85; found C, 70.00; H, 5.83.
N
SBn
NH
O
O
O
N
SO Bn
NH
O
O
118
5.2.10.2 Attempts towards enantioselective sulfoxide formation of heteroaryl
benzyl sulfoxide
Upon generation of the lithiated heteroaryl sulfenate anion in cold conditions as
indicated above, a solution of chiral PyBox ligand (10 mol% in 5 mL anhydrous THF)
was quickly added to the reaction mixture. The solution was stirred for an additional 30
minutes at -78 ˚C, before a solution of benzyl bromide in anhydrous THF (0.25 M) was
added quickly. The solution was stirred for an additional 3 hours at -78 ˚C, and stirred
overnight while slowly warming to room temperature. The reaction mixture was
concentrated under reduced pressure, dissolved in CH2Cl2, and the organic layer was
washed three times with water, and once with brine. It was then dried over anhydrous
MgSO4, concentrated under reduced pressure, and purified by flash column
chromatography.
NN
OO
N
L* PyBox1 =
NN
OO
N
L* PyBox2 =
119
2-Pyridyl benzyl sulfoxide
A mixture of 2-carbomethoxyethenyl 2-pyridyl sulfoxide, nBuLi,
PyBox ligand and benzyl bromide afforded an enantiomeric
mixture of sulfoxides. Obtained as an off-white solid. Yield: 50%,
mp = 87 – 89 ˚C (lit. mp = 86 – 89 ˚C)72. 1H NMR (300 MHz, CDCl3), δ: 8.67 (d, J = 4.7
Hz, 1H), 7.78 (app t, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (m, 1H), 7.26 – 7.01
(m, 5H), 4.39 (d, J = 13.1 Hz, 1H), 4.08 (d, J = 13.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3), δ: 163.55, 149.24, 137.57, 130.19, 129.20, 128.21, 128.06, 124.53, 120.53,
59.76; IR (cm-1, neat): 3058, 2922, 1602, 1576, 1422, 1051. Determined by chiral HPLC
analysis (Chiralcel OD-H, hexane/isopropanol, 70;30 v.v, 0.5 mL/min, 20 ˚C, UV 220
nm): Retention times: tr = 16.648 for (R)-isomer, tr = 19.526 for (S)-isomer).
8-Quinolyl benzyl sulfoxide
A mixture of 2-Carbomethoxyethenyl 8-quinolyl sulfoxide, nBuLi,
PyBox ligand and benzyl bromide afforded an enantiomeric
mixture of sulfoxides. Obtained as a yellow solid. Yield: 56%, mp
= 90 – 91 ˚C (lit. mp = 94 – 95 ˚C).73 1H NMR (400 MHz, CDCl3), δ: 8.99 (dd, J = 4.2 Hz,
1.7 Hz, 1H), 8.28 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 7.91(dd, J = 8.2 Hz, 1.3 Hz, 1H), 7.83
(dd, J = 7.2 Hz, 1.3 Hz, 1H), 7.21 (m, 1H), 7.16 (m, 1H) 7.26 – 7.13 (m, 3H), 6.91 (m,
2H), 4.60 (d, J = 12.9 Hz, 1H), 4.28 (d, J = 12.9 Hz, 1H); 13C NMR (75 MHz, CDCl3), δ:
N
S*O
S*
N
O
120
150.15, 144.11, 140.51, 136.43, 130.24, 130.05, 127.99, 127.91, 127.85, 127.38,
126.50, 121.95, 59.59; IR (cm-1, neat): 3030, 2926, 1561, 1046; Analysis calculated for
C16H13NOS; C, 71.88; H, 4.90; found C, 71.65; H, 5.08. Determined by chiral HPLC
analysis (Chiralcel OD-H, hexane/isopropanol, 70;30 v.v, 0.5 mL/min, 20 ˚C, UV 220
nm): Retention times: tr = 15.288 for (R)-isomer, tr = 18.174 for (S)-isomer.)
5.2.10.3 Attempts towards the release of lithiated [SO]-2
Upon generation of the lithiated heteroaryl sulfenate anion in cold conditions, an
additional equivalent of nBuLi was added to the reaction mixture. The solution was
stirred and slowly raised to room temperature over 3 hours, before a solution of benzyl
bromide in anhydrous THF (0.25 M) was added quickly and allowed to stir overnight.
The reaction mixture was concentrated under reduced pressure, dissolved in CH2Cl2,
and the organic layer was washed three times with water, and once with brine. It was
then dried over anhydrous MgSO4, concentrated under reduced pressure, and purified
by flash column chromatography. Attempts with either 2-carbomethoxyethenyl pyridyl
sulfoxide or 2-carbomethoxyethenyl quinolyl sulfoxide were unsuccessful and the
corresponding benzyl bromides from Section 1.4.11.2 were isolated.
121
5.2.11 General procedure for the preparation of quinolyl imino sulfoxides
A mixture of anhydrous CH2Cl2/methanol (3:1) (0.25 M wrt free base amino
sulfoxide), aryl aldehyde (1.0 equiv) and anhydrous Na2SO4 (0.5 g/mmol amino
sulfoxide) was refluxed for 4 h. The solution was filtered and the solvent was evaporated
under reduced pressure. The resulting residue was re-dissolved in CH2Cl2 and washed
three times with water, and once with brine. It was then dried over anhydrous MgSO4,
concentrated under reduced pressure, and triturated with diethyl ether to afford pure
product.
Ligand 1-L3
A mixture of (SS,2RC)-1-phenyl-3-(8-quinolylsulfinyl)propan-2-
amine, and 2-formylphenol afforded Ligand 1-L3. Obtained as
a yellow solid. Yield: 91%; mp = 133 – 134 ˚C. 1H NMR (600
MHz, CDCl3), δ: 8.93 – 8.92 (dd, J = 4.1 Hz, 1.4 Hz, 1H), 8.26 (d, J = 7.1 Hz, 1H), 8.23
(s, 1H), 8.21 (m, 2H), 7.95 (d, J = 8.0 1H), 7.75 (app t, J = 7.6 Hz, 1H), 7.51 (dd, J = 8.3
Hz, 4.2 Hz, 1H), 7.32 (app t, J = 7.0 Hz), 7. 21 – 7.13 (m, 4H), 7.08 (d, J = 7.1 Hz), 7.02
(d, J = 8.3 Hz), 6.86 (app t, J = 7.3 Hz), 4.23 (m, 1H), 4.02 (dd, J = 12.9 Hz, 10.5 Hz,
1H), 3.08 (dd, J = 12.9 Hz, 2.4 Hz, 1H), 2.99 (m, 2H); 13C NMR (150 MHz, CDCl3), δ:
166.78, 150.38, 143.96, 142.16, 137.12, 136.26, 132.59, 131.90, 130.20, 129.57,
128.52, 127.97, 126.62, 126.11, 122.14, 118.82, 117.03, 65.99, 61.55, 42.91; IR (cm-1,
N
SO Bn
N
H
OH
122
neat): 3442, 3060, 2918, 1644, 1494, 1106, 1046; [𝛼]!!" 426.4 𝑐 = 0.01 . Analysis
calculated for C25H22N2O2S; C, 72.44; H, 5.35; found C, 72.66; H, 5.57.
Ligand 1-L4
A mixture of (SS,2RC)-1-phenyl-3-(8-quinolylsulfinyl)propan-2-
amine, and 2-formylpyridine afforded Ligand 1-L4. Obtained
as an off-white solid. Yield: 89% yield; mp = 123 – 125 ˚C. 1H
NMR (600 MHz, CDCl3), δ: 8.91 (dd, J = 4.2 Hz, 1.68 Hz, 1H), 8.66 (d J = 4.5 Hz, 1H),
8.29 (s, 1H), 8.28 (d, J = 7.4 Hz), 8.23 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 8.04 (d, J = 7.9 Hz,
1H), 7.94 (d, J = 7.0 Hz, 1H), 7.78 (m, 1H), 7.75 (m, 1H), 7.51 (dd, J = 8.3 Hz, 4.3 Hz,
1H), 7.32 (m, 1H), 7.16 (m, 2H), 7.12 (m, 3H), 4.33 (m, 1H), 4.07 (dd, J = 12.9 Hz, 9.8
Hz, 1H), 3.10 (dd, J = 12.9 Hz, 2.9 Hz, 1H), 3.01 – 2.99 (m, 2H); 13C NMR (150 MHz,
CDCl3), δ: 163.57, 154.21, 150.14, 149.52, 143.85, 142.42, 137.42, 136.41, 136.17,
130.07, 129.55, 128.19, 128.04, 126.64, 126.37, 126.26, 124.77, 122.21, 121.96, 66.59,
60.61, 42.51; IR (cm-1, neat): 3029, 2920, 1628, 1580, 1279, 1046; [𝛼]!!" 59.7 𝑐 = 0.05 .
TOF MS EI calculated for [C24H21N3OS]+: 399.1405; found: 399.1401.
5.2.12 General procedure for the Henry reaction
Chiral amino sulfoxide ligands (12 mol%) and Cu(OAc)2�H2O (10 mol%) were
stirred in solvent (0.1 M wrt aldehyde) in a round-bottom flask. The mixture was stirred
N
SO Bn
N
H N
123
at room temperature for 2 hours, then nitroalkyl (10 equiv.) and aldehyde (1 equiv.) were
successively added. The resulting solution was stirred for the specified time. The volatile
components were removed under reduced pressure and purified by flash column
chromatography. Trial reactions with ligands 1-L1m, and 1-L2m were carried out using
20 mol% each of chiral ligand and Cu(OAc)2�H2O.
5.2.12.1 Henry reaction products with nitromethane
2-Nitro-1-(4-nitrophenyl)-ethanol
A mixture of chiral ligand, 4-nitro-benzaldehyde, and
nitromethane afforded an enantiomeric mixture. Obtained as an
off-white solid, mp = 83 – 84 ˚C (lit. mp = 83 – 84 ˚C).38 1H
NMR (300 MHz, CDCl3), δ: 8.30 (d, J = 9.0 Hz, 2H), 8.26 (d = 9.0, 2H), 5.63 – 5.58 (m,
1H), 4.65 – 4.54 (m, 1H), 3.10 (s, 1H); 13C NMR (75 MHz, CDCl3), δ: 148.05, 144.85,
126.53, 124.11, 80.51, 69.86; IR (cm-1, neat): 3612, 2813, 1554, 1519,1349, 1084.
5.2.12.2 Henry reaction products with nitroethane
O2N
OHNO2*
124
anti/syn-1-(4-nitropehenyl)-2-nitropropan-1-ol
A mixture of chiral ligand, 4-nitro-
benzaldehyde, and nitroethan afforded an
enantiomeric mixture. Obtained as an
straw-coloured solid, mp = 83 – 85 ˚C (lit mp = 84 – 85 ˚C).74 Anti-diastereomer: 1H
NMR (400 MHz, CDCl3), δ: 8.28 – 8.25 (m, 2H), 7.61 – 7.57 (m, 2H), 5.57 (m, 1H), 4.74
– 4.69 (m, 1H), 2.95 (d, J = 3.6 Hz, 1H), 1.5 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3), δ: 147.91, 145.31, 126.96, 123.96, 86.73, 72.80, 11.85. Syn-diastereomer: 1H
NMR (400 MHz, CDCl3), δ: 8.29 – 8.25 (m, 2H), 7.62 – 7.57 (m, 2H), 5.21 – 5.17 (dd, J
= 8.8 Hz, 4.4 Hz, 1H), 4.80 – 4.75 (m, 1H), 2.95 (d, J = 4.4 Hz, 1H), 1.40 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3), δ: 148.30, 145.13, 127.86, 124.11, 87.70, 75.01,
16.24. Both diastereomers: IR (cm-1, neat): 3526, 3114, 2917, 1550, 1520, 1349.
5.3.0 Experimental: Synthesis of Bupropion
5.3.1 General procedure for the copper-mediated α-amination of 3’-
chloropropiophenone
CuBr2 was (10 mol%) dissolved in DMSO (1.0 M wrt aryl ketone) in a closed
vessel before 3’-chloropropiophenone was added. This solution was stirred for 15
O2N
OH
NO2
antiO2N
OH
NO2
syn
125
minutes and alkyl amine (3.0 equiv) was added. The reaction was stirred for the
specified time at room temperature. The crude reaction mixture was diluted with water
and extracted three times with Et2O. The combined organic layer was washed three
times with water and brine. It was then dried over anhydrous MgSO4, concentrated
under reduced pressure, and purified by flash-column chromatography.
5.3.1.1 α-Amination using tBuNH2
A mixture of CuBr2, 3’-chloropropiophenone, tBuNH2 did not yield product.
5.3.1.2 α-Amination using morpholine
2-morpolino-1-(3-chlorophenyl)propan-1-one (2-14)
A mixture of CuBr2, 3’-chloropropiophenone, morpholine afforded the
α-amino aryl ketone. Obtained as a viscous pale-white oil. Yield: 3.6 –
19%. 1H NMR (400 MHz, CDCl3), δ: 8.08 (t, J = 1.2 Hz, 1H), 7.99 (dt, J
= 7.6 Hz, 1.2 Hz, 1H), 7.54 (dd, J = 7.9, 1.9 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 4.04 (q, J =
6.8 Hz,1 H), 3.73 (- 3.64 (m, 4H), 2.64 – 2.53 (m, 4H), 1.29 (d, J = 6.8 Hz, 3 H).
Cl
O
N
O
126
Predicted by-product (2-15)
Obtained as a yellow oil. 1H NMR (400 MHz, CDCl3), δ: 7.44
(t, J = 1.6 Hz, 1H), 7.38 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 7.33 (m,
1H), 7.31 (m, 1H), 6.45 (s, 1H), 3.82 (m, 4H), 3.73 – 3.68 (m,
8H), 3.15 (m, 4H).
5.3.2 General procedure for the I2 mediated α-amination of 3’-
chloropropiophenone
NH4I (15 mol%), sodium percarbonate (2.0 equiv), and 3’-chloropropiophenone
(1.0 equiv) were stirred in solvent (0.5 M wrt aryl ketone) at room temperature before
the mixture was heated to 50 ˚C and stirred for the specified time. The crude reaction
mixture was concentrated under reduced pressure, and re-dissolved in CH2Cl2. The
organic layer was washed three times with saturated aq. NaHCO3, twice with water, and
once with brine. It was dried over anhydrous MgSO4, and concentrated under reduced
pressure.
2-tert-butylamino-1-(3-chlorophenyl)propan-1-one (Bupropion)
Conditions #1: A mixture of NH4I (15 mol%), sodium percarbonate (2.0
equiv), and 3’-chloropropiophenone (1.0 equiv) were stirred in EtOAc
Cl
O
NH
Cl
N
Br
H
NO
O
X
127
(0.5 M wrt aryl ketone. Conditions #2: A mixture of I2 (15 mol%), AcOH (15 mol%),
sodium percarbonate (2.0 equiv), and 3’-chloropropiophenone (1.0 equiv) were stirred in
EtOAc (0.5 M wrt aryl ketone). Conditions #3: A mixture of I2 (15 mol%), PhOH (15
mol%), sodium percarbonate (2.0 equiv), and 3’-chloropropiophenone (1.0 equiv) were
stirred in EtOAc (0.5 M wrt aryl ketone). Obtained as viscous brown oil. 1H NMR (400
MHz, CDCl3), δ: 7.96 (t, J = 1.7 Hz, 1H), 7.8 (dt, J = 8.9 Hz, 1.2 Hz, 1H), 7.55 (s, 1H),
7.58 (dd, J = 8.0 Hz, 2.1 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H); 4.33 (q, J = 7.1 Hz, 1H), 1.26
(d, J = 7.2 Hz, 3H), 1.05 (s, 9H).
5.3.3 General procedure for the preparation of Bupropion HCl salt
HCl gas was bubbled into IPA to afford a saturated acidic solution. This was used
to dissolved crude mixtures of Bupropion while stirring at 0 ˚C. This reaction was
concentrated under reduced pressure and this process was repeated twice more. The
resultant viscous liquid was triturated with hexanes and EtOAc to afford the HCl salt.
Bupropion HCl
Obtained as a dark-orange solid. Yield = 67-78%, mp = 233 – 235
˚C. 1H NMR (300 MHz, CDCl3), δ: 8.40 (s, 1H), 8.00 (s, 1H), 7.97
(d, J = 7.9 Hz, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 5.02 (q, J = 7.2 Hz, 1H), 1.89 (d, J = 7.2 Hz, 3H), 1.47 (s, 9H); 13C NMR (75 MHz,
Cl
O
NHHCl
128
CDCl3), δ: 194.38, 136.11, 135.52, 133.07, 130.93, 129.00, 127.02, 59.46, 53.64, 26.58,
18.47.
129
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