Bachelor Thesis Chemistry

Hydrogenation of Prochiral Imines with RhodiumIII

METAMORPhos Half-Sandwich Complexes

Complex synthesis and deployment in a new route towards chiral amines

by

N.P. van Leest

10167293

27th June 2014

Daily supervisor Drs. S. Oldenhof

Supervisor Prof. Dr. J.N.H. Reek

Second examiner Dr. J.H. van Maarseveen

Research group Homogeneous, Supramolecular and Bio-Inspired Catalysis

Research institute Van 't Hoff Institute for Molecular Sciences

Universiteit van Amsterdam

1

Summary

Several chiral and achiral rhodium(III) METAMORPhos complexes were synthesised and applied in the

hydrogenation of prochiral imines. METAMORPhos ligand 8 was successfully bound to rhodium in an

anionic and bidentate fashion to yield complex 9 after addition of NaOAc to a neutral monodentate

bound species. Using the same approach with chiral ligand 1 was unfortunately unsuccessful and led

to the formation of mixtures. However, chiral complex 5 was effectively obtained as a cationic

complex with -BArF as the counterion. Complexes 5 and 9 were used in the hydrogenation of (in situ)

generated prochiral imines with H2 to yield a racemic product of the desired amine. However, it was

found that the used complexes were unstable towards H2, which indicated the presence and activity

of rhodium nanoparticles as the catalyst in the hydrogenation reaction. The transfer hydrogenation

of an in situ generated prochiral imine with ammonium formate towards a chiral amine was shown to

be successful by using complex 5 and 9. A chiral additive was added to achiral complex 9 in an

attempt to obtain an enantioenriched product. Unfortunately, no enantiomeric excess of the chiral

amine product could be determined. It was also found that the transfer hydrogenation was selective

for the imine, since no ketone hydrogenation towards the alcohol was observed.

Samenvatting

Verschillende chirale en achirale rhodium(III) METAMORPhos complexen zijn gesynthetiseerd en

gebruikt in de hydrogenatie van prochirale imines. METAMORPhos ligand 8 is succesvol gebonden

aan rhodium op een tweevoudige en anionische manier om complex 9 te geven na additie van

NaOAc aan een neutraal monodentate gebonden complex. Helaas was deze aanpak niet succesvol

met het chirale ligand 1 omdat dit een mengsel van complexen gaf. Complex 5 is echter wel als een

kationisch complex verkregen met -BArF als tegenion. Complexen 5 en 9 zijn toegepast in the

hydrogenatie van (in situ) gemaakte prochirale imines met H2 en gaven een racemisch mengsel van

het gewenste amine als product. Het is echter gebleken dat de gebruikte complexen niet stabiel zijn

met H2, wat aangaf dat in de hydrogenatie reactie waarschijnlijk rhodium nanodeeltjes aanwezig en

actief waren als katalysator. De transfer hydrogenatie van een in situ gemaakt en prochiraal imine

met ammonium formaat, om een chiraal amine te maken, is mogelijk gebleken door de complexen 5

en 9 te gebruiken. Een chiraal additief is toegevoegd aan achiraal complex 9 in een poging om de

vorming van een product met enantiomere overmaat te bevorderen. Het is helaas niet mogelijk

gebleken om de enantiomere overmaat van het chirale amine product te bepalen. Het is ook

gebleken dat de transfer hydrogenatie selectief was voor het imine omdat keton hydrogenatie naar

het alcohol niet werd waargenomen.

2

3

Table of contents

Summary 1

Samenvatting 1

1 Introduction 4

2 Results and discussion 9

2.1 Complex synthesis 9

2.1.1 Influence of the solvent on the complex structure 9

2.1.2 Coordination of the ligand in a bidentate and anionic fashion 11

2.1.3 Synthesis of other complexes 12

2.2 Imine and amine synthesis 14

2.2.1 Synthesis of imine 10 and racemic amine 11 14

2.2.2 Synthesis of imine 12 and racemic amine 13 15

2.3 Catalytic hydrogenation of imines 10 and 12 16

2.3.1 Hydrogenation of in situ generated imine 10 16

2.3.2 Hydrogenation of imine 12 19

2.3.3 Catalyst stability under molecular hydrogen 21

2.4 Catalytic transfer hydrogenation of imines 22

2.4.1 Catalyst stability under reaction conditions 22

2.4.2 Transfer hydrogenation of in situ generated imine 18 23

3 Conclusion 26

4 Outlook 28

5 Acknowledgements 29

6 References 30

7 List of Abbreviations 32

8 Experimental Section 33

8.1 Synthesis of complexes, imines and racemic amines 33

8.2 Standard procedures for catalysis reactions 38

4

1 Introduction

Chiral amines are widely encountered in pharmaceuticals, dyes, natural products and chemicals used

in the agricultural industry.1,2,3 The synthesis of these nitrogen containing and often high valued end

products should preferentially proceed in a single chemo-, regio- and enantiocontrolled step, since

usually only one of the enantio- or diastereomers is desired, and should start from cheap and widely

available starting materials.

Several synthetic routes towards enantioenriched amines are available, for instance the

reductive amination,1,4 biocatalytic approaches,2 amination of C-H bonds,5 hydroamination of

allenes,6 carbanion addition to a variety of imines,7 allylic amination,8 hydroaminoalkylation of

unactivated olefins9 and the conjugate amine addition by organocatalysis,10 see Scheme 1.

Scheme 1 Various procedures for the synthesis of chiral amines wherein LG is a leaving group and R(conjugated) means an R group which is in conjugation with the alkene moiety. Detailed reaction conditions are omitted and can be found in the following references.

1,2,5,6,7,8,9,10

The reductive amination of carbonyl compounds is one of the most important reactions in

the synthesis of amines.11 This reaction proceeds via nucleophilic attack of a primary or secondary

amine onto a carbonyl functionality to yield a carbinolamine as the addition product. In a protic

5

solvent the hydroxyl group of the carbinolamine is protonated to produce water as a leaving group

and an iminium ion intermediate, which is in equilibrium with the corresponding imine when a

primary amine is used as the starting material. A weak acid can also be used to enhance the cleavage

of H2O in a catalytic fashion. Subsequent reduction of the imine bond with H2 yields the alkylated

amine as the product, which can be seen in Scheme 2.

Scheme 2 The reductive amination of a carbonyl compound and the involved intermediates in neutral to weakly acidic and protic media.

11

Homogeneous catalysis is a powerful approach to perform the reduction of (in situ

generated) imines in a stereoselective fashion (see the last step in Scheme 2).3 Different ruthenium,12

rhodium13 and iridium14 complexes have already been used for the (a)symmetric hydrogenation of

imines with H2. For example, in 1992 Burk et al.15 reported the enantioselective hydrogenation of

different in situ generated imines with [Rh(Et-DuPHOS)]+ and enantiomeric excesses up to 97% were

obtained. More recently, the asymmetric hydrogenation of imines was also reported with first row

transition metals, namely chiral P-N-P' pincer iron(II)16 and dinuclear 2,2'-bis(diphenylphosphino)-

1,1'-binaphtyl (BINAP) cobalt17 complexes.

Besides the reduction of the carbon-nitrogen double bond in an imine by using molecular

hydrogen, several examples have been reported in which a hydrogen donor is used.4 This reaction is

commonly known as a transfer hydrogenation. The use of stable hydrogen donors is less hazardous

and more straightforward to use in comparison to molecular hydrogen. However, industrial

processes will still favour the use of molecular hydrogen due to waste and separation prevention and

a higher atom economy.18

The first transfer hydrogenation of imines was achieved in 1992 by Wang et al.19 Several

imines were reduced to amines by a ruthenium(II) catalyst under basic conditions and with

2-propanol as the hydrogen donor and solvent (see Scheme 3). Four years later, Uematsu et al.4

6

reported the first asymmetric transfer hydrogenation of imines, using formic acid as the hydrogen

donor and a chiral ruthenium(II) complex as the catalyst (see Scheme 3).

Scheme 3 Top: the first reported transfer hydrogenation, by Wang et al.19

Bottom: the first reported asymmetric transfer hydrogenation, by Uematsu et al.

4

In the transition metal catalysed transformation of prochiral imines to chiral amines the

ligand plays an essential role. Phosphorous based ligands are often utilized to obtain enantioenriched

products, which includes the asymmetric hydrogenation of imines. A novel class of interesting

supramolecular sulfonamido-phosphoramidite (METAMORPhos) ligands was reported by Patureau et

al. in 2008.20 METAMORPhos ligands can be synthesised by the condensation reaction of a

sulfonamide with a chlorophosphine or chlorophosphite. It was shown that these ligands reside in a

PIII and PV tautomeric equilibrium, which depends on the basicity of the phosphorus atom and the

acidity of the nitrogen atom, which are regulated by the choice of the sulfonamide and

chlorophosphine.20,21 For example, when an electron withdrawing functionalized sulfonamide is used

(e.g. trifluorosulfonamide), the nitrogen atom becomes more acidic which results in an equilibrium

shift towards the PV tautomer. Other interesting features are that these ligands can coordinate in a

neutral or anionic and mono- or bidentate fashion to a metal centre due to proton-responsive

properties, which will be further explained below. Scheme 4 illustrates the PIII and PV tautomeric

equilibrium of a METAMORPhos ligand and its neutral and anionic coordination to a rhodium metal

centre. It can be seen that protonation of the anionic ligand yields the neutral ligand, which can be

changed back to the anionic ligand by deprotonation. The rhodium centre does not change in

oxidation state during this (de)protonation.

7

Scheme 4 On the top: equilibrium between the PIII

and PV tautomer of a METAMORPhos ligand. On the bottom:

protonation of the anionically bound ligand (red) to form the neutral ligand (blue). The rhodium centre does not change oxidation state.

20,21

It has been shown that rhodium, iridium and ruthenium based METAMORPhos complexes

are active catalysts in the asymmetric hydrogenation of various functionalized alkenes20,22,23 and a

cyclic imine,24 base-free dehydrogenation of formic acid25 and heterolytic cleavage of molecular

hydrogen.21 The proton-responsive role of the METAMORPhos ligands, meaning that they are able to

bind or release a proton and thus switch between the neutral and anionic form, is important for the

proceeding of the previously named reactions and also means that during a reaction the metal centre

does not have to change in oxidation state. It is therefore envisioned that in analogy to the

heterolytic cleavage of H2 with a ruthenium-based half-sandwich complex by Terrade et al.21 and the

dehydrogenation of formic acid by Oldenhof et al.25 proton-responsive rhodium METAMORPhos

complexes can potentially be used for the (transfer) hydrogenation of imines.

The complex depicted in Scheme 5 was previously shown to be active in the reductive

amination of acetone by using benzylamine and H2 and is structure-wise comparable to other half-

sandwich complexes that are active in the heterolytic cleavage of H2.21 A transfer hydrogenation

might also be possible by using HCOOH to give protonation of the ligand and the generation of a

hydride at the rhodium centre together with the release of CO2, which is the net addition of H2 to the

complex and could result in the transfer hydrogenation of an (in situ generated) imine.

8

Scheme 5 Hydrogenation of an in situ generated imine with H2 and a rhodium(III) METAMORPhos complex.

The research described in this report addresses the questions whether the reductive

amination of prochiral ketones is feasible with half-sandwich rhodium(III) METAMORPhos complexes

and if there is a difference between the direct- (using H2) and transfer hydrogenation (using HCOOH)

to perform the reductive step. The role of the complex in the catalysis and if the introduction of

chirality leads to enantioselectivity in the product is also studied. Chirality is introduced via two

methods: the direct introduction of a chiral ligand by applying a 1,1'-bi-2-naftol (BINOL)

METAMORPhos complex (see Box A in Scheme 6) or by the addition of a chiral additive in the form of

a chiral phosphoric acid to an achiral METAMORPhos complex (see Box B in Scheme 6). The choice

for this additive was made because chiral phosphoric acids have been successfully applied in the

asymmetric reduction of imines,14 and could potentially also interact with the METAMORPhos ligand

when bound in an anionic state. This report will also describe and discuss the synthesis of different

(novel) complexes and imines and will provide an outlook on further research.

Scheme 6 The asymmetric direct and transfer hydrogenation by using a chiral BINOL METAMORPhos complex or an achiral complex with a BINOL based phosphoric acid as additive.

9

2 Results and discussion

The results obtained from different experiments will be discussed in this chapter. The synthesis of

several half-sandwich rhodium(III) METAMORPhos complexes will be discussed first, followed by the

synthesis of two prochiral imines, from which one will be used as a substrate in catalysis, and the

corresponding racemic amines after reduction with NaBH4. This chapter will conclude with two

sections about the (asymmetric) direct hydrogenation and the transfer hydrogenation of prochiral

imines with the described METAMORPhos complexes.

2.1 Complex synthesis

The synthesis of several half-sandwich rhodium(III) METAMORPhos complexes will be presented and

discussed in this section. First, the influence of the solvent on the complex structure will be

discussed, followed by several attempts to obtain a complex with an anionically bonded chiral

METAMORPhos ligand. This section will finish with an overview of the synthesised complexes.

2.1.1 Influence of the solvent on the complex structure

The standard procedure for the synthesis of a neutral rhodium(III) METAMORPhos complex starts by

neutral coordination of the phosphorous atom, from for example racemic ligand 1 (rac), to rhodium

and yields complex 2, as can be seen in Scheme 7. This reaction proceeds in quantitative yields for

different ligands within 30 minutes by stirring a solution of the ligand and the commercially available

rhodium precursor [RhCp*Cl2]2 at room temperature.

Scheme 7 Neutral coordination of racemic METAMORPhos ligand 1 to a rhodium centre to yield complex 2. The BINOL moiety will be showed in the rest of the report as depicted on the left bottom and is used as a racemate unless explicitly stated otherwise.

10

Figure 1 shows different 31P{1H} NMR signals, (162 MHz, Chloroform-d) δ 132.94 (d, J = 200.4

Hz), 121.38 (d, J = 217.6 Hz) and (162 MHz, Toluene-d8) δ 121.96 (d, J = 217.3 Hz), that were

observed when complex 2 was dissolved in toluene-d8 and CDCl3 and are comparable to the 31P NMR

signals that were previously found in comparable complexes.20 The observed doublets were found to

be due to the coupling of the phosphorous atom with the rhodium centre and thereby confirm

phosphorous coordination to rhodium. In toluene-d8 only a single doublet was observed, which was

characterised by 1H NMR spectroscopy to be the neutral complex 2. Triethylamine could not be

removed by evaporation and was still observed in the 1H NMR spectrum, showing a characteristic

downfield shift and thereby indicating the partial deprotonation of the ligand. In contrast to the 31P

NMR spectrum in toluene-d8, the CDCl3 solution showed two distinct doublets. Since chloroform is a

more polar solvent than toluene it is suggested that the additional signal (δ=132.94 ppm) originates

from the cationic complex 3. It was found that the complexes 2 and 3 are in a dynamic equilibrium

between the neutral mono and bidentate ligand, since switching back to toluene-d8 gave only the

initially observed doublet.

Figure 1 31

P NMR spectrum of complex 2 in toluene-d8 (top) and CDCl3 (bottom), in which also complex 3 can be seen.

11

2.1.2 Coordination of the ligand in a bidentate and anionic fashion

The ligand in complex 4 is anionically bound to rhodium in a bidentate fashion. This coordination of

the ligand was desired due to the then assessable proton-responsive property of the ligand, which is

illustrated in Scheme 8. It was envisioned that an anionic binding mode gave complexes that could be

used for the heterolytic cleavage of H2 and subsequent imine reduction via the complex towards an

amine, as was shown in Scheme 5.21

Scheme 8 Proton-responsive behavior of the anionically bonded bidentate ligand in complex 4.

Previously obtained rhodium half-sandwich complexes in which the ligand is anionically and

bidentate bonded (for example the complex in Scheme 5) were obtained simple by the addition of

sodium acetate (NaOAc) to a monodentate P-coordinated complex. This approach was also applied

to make the desired complex 4 (Scheme 8). In this reaction protonated triethylamine was envisioned

to be abstracted from complex 3 by NaOAc in order to promote anionic bonding of the ligand to

rhodium and yield complex 4 with the precipitation of sodium chloride, see reaction A in Scheme 9.

However, even with a large excess of NaOAc this reaction did not lead to satisfactory conversion

towards complex 4 according to 31P NMR spectroscopy. Longer reaction times and higher reaction

temperatures did not give complex 4 in better yields.

In previous experiments it was shown that NaBArF, KPF6 and AgBF4 were successful in the

abstraction of a chloride anion from complex 2 to create a vacant site and a cationic complex. These

complexes are similar to complex 3, but have -BArF (5), -PF6 (6) or -BF4 as the counterion and do not

show the equilibrium with complex 2, since they poorly coordinate in contrast to Cl-. It was thus

reasoned that conversion towards complex 4 could potentially be achieved by first creating the

cationic complexes 5 and 6. Conversion of 2 towards 5 was proven to be quantitative because a

single doublet was clearly observed at δ 134.92 ppm in 31P NMR spectroscopy, but poorly proceeded

towards 6 (see reaction B and C in Scheme 9). After addition of NaOAc to the formed complex 5, full

conversion towards complex 4 was expected but only moderate conversion was observed.

12

Scheme 9 The formation of complex 3, 5 and 6 from 2 and the formation of complex 4 from 3 and 5. The structure of complex 4 is proposed. TEAH

+ = protonated triethylamine.

2.1.3 Synthesis of other complexes

Another approach towards complex 4 was by initially deprotonating the ligand prior to complexation.

The sodium salt of the phosphite based ligand (7) was prepared and attempted to coordinate in a

bidentate and anionic fashion to rhodium to form complex 4, but with inconclusive results (reaction

A in Scheme 10). As can be seen, the phosphite based ligand 1 (R) (R enantiomer of the BINOL

moiety) was previously obtained as the triethylamine adduct.21 It was discussed in the previous

section that the abstraction of protonated triethylamine from this chiral phosphite based ligand was

proven to be problematic, since anionic bidentate coordination of the ligand was not easily achieved

(see Scheme 9). However, the synthesis of the cationic complex 5 from this ligand and [RhCp*Cl2]2

proceeds in quantitative yield after the addition of NaBArF, see reaction B in Scheme 10.

METAMORPhos ligand 8 could be obtained in the neutral form and was used to make complex 9, see

reaction C in Scheme 10. The ligand in this complex was found to be bonded in the desired bidentate

and anionic fashion to the rhodium centre, which was previously shown by drs. S. Oldenhof. This

coordination mode of the ligand and the structure of the complex were also previously confirmed by

a crystal structure, see Figure 2.

13

Scheme 10 Synthesis of three complexes 4, 5 (R) and 9 starting from two phosphite based METAMORPhos ligands 1 and 7 (reaction A and B) and one phosphine based METAMORPhos ligand 8.

Figure 2 Crystal structure of complex 9, in which the METAMORPhos ligand is bound in an anionic and bidentate fashion. Hydrogen atoms are omitted for clarity. Grey: carbon, red: oxygen, blue: nitrogen, yellow: sulfur, orange: phosphorus, green: chloride, turquoise: rhodium.

14

2.2 Imine and amine synthesis

This section provides an overview of the synthesis of two imines and the reduction with NaBH4 to

give the corresponding racemic amines. The amines were used as references for analysis of the

performed catalytic studies and one of the imines was used as a substrate in catalysis.

2.2.1 Synthesis of imine 10 and racemic amine 11

Scheme 11 Reaction equation for the formation of imine 10 from benzylamine and 2-butanone. See Table 1 for the reaction conditions.

N-(butan-2-ylidene)-1-phenylmethanamine (imine 10) was synthesised by the condensation reaction

of benzylamine and 2-butanone, see Scheme 11. The conversion of this reaction was followed in time

with 1H NMR spectroscopy and several reaction conditions were applied: different solvents,

temperatures and the addition of a drying agent in order to drive the equilibrium towards the

desired imine, see Table 1.

Table 1 The conversion towards 10 at different reaction conditions. a: conversion was determined by the imine/amine ratio in

1H NMR spectroscopy. b: adapted procedure from Orito et al.

26 c: 2-butanone (1 eq) and Na2SO4

were added after 16h. d: Na2SO4 was added after 18h.

Entry Solvent Temp. (°C) Drying agent Reaction time (h) Conversion (%)a

1 MeOH 30 - 22 48.3 2 EtOH rt Na2SO4 2 46.7 20 63.7 117 65.4

3b DCM rt Na2SO4 16c 62.9 18d 69.9 45d 71.9

115 76.3

It can be seen in Table 1 that the use of DCM gave a higher conversion towards imine 10 after

22 hours than when MeOH or EtOH were used as a solvent. Also, it seems that the formation of

imine 10 proceeds faster at room temperature than at 30 °C. The highest conversion was obtained by

the use of two equivalents of 2-butanone with respect to benzylamine and an excess Na2SO4 as water

scavenger, which can be explained by the fact that both favour an equilibrium shift towards the

15

imine due to Le Châteliers principle.27 However, even after 115 hours, no full conversion could be

obtained. Imine 10 was obtained as a brown oil after co-evaporation with toluene with an E/Z ratio

of 3.5/1 in all experiments and a yield of 22.1% in the case of entry 3 in Table 1.

Racemic N-benzylbutan-2-amine (11) was synthesised according to a literature procedure for

comparison with products obtained during catalysis. Amine 11 was obtained by the reduction of

imine 10 with NaBH4 as a light brown oil with 69.1% yield after extraction with DCM and

concentration under reduced pressure, see Scheme 12.26

Scheme 12 Synthesis of amine 11 from imine 12 with NaBH4.

2.2.2 Synthesis of imine 12 and racemic amine 13

1-phenyl-N-(1-phenylethylidene)methanamine (imine 12) was synthesised according to a literature

procedure by the amination of acetophenone with benzylamine in the presence of sodium hydrogen

carbonate and molecular sieves in toluene at 80 °C, see Scheme 13.28

Scheme 13 Synthesis of imine 12 from benzylamine and acetophenone. a: E/Z ratio changes to 25/1 after distillation and precipitation from n-pentane at -20 °C.

After 66 hours a conversion of 88.5% benzylamine towards imine 12 with an E/Z mixture of

ratio 12/1 was observed by 1H-NMR spectroscopy. Imine 12 was isolated as a white solid after

distillation and subsequent precipitation from n-pentane at -20 °C with an isolated yield of 21.2% and

an E/Z ratio that was shifted towards 25/1. This was interpreted as an isomerisation towards the

thermodynamically more stable E isomer or the favoured crystallisation from n-pentane of the E

isomer above the Z isomer.

16

Racemic N-benzyl-1-phenylethanamine (amine 13) was synthesised by the reduction of imine

12 with NaBH4 (see Scheme 14) to obtain a reference for later catalysis studies. The isolated product

was obtained as a light brown oil after extraction with DCM with a yield of 25.8% after 15 hours.

Scheme 14 Hydrogenation of imine 12 with NaBH4 to yield amine 13.

2.3 Catalytic hydrogenation of imines 10 and 12

The hydrogenation of the in situ generated imine 10 and the previously obtained imine 12 towards

amine 11 and 13 respectively will be discussed in this chapter. Since imine 10 and 12 are both

prochiral, the emphasis was on the hydrogenation towards the enantioenriched amines. Several

chiral and achiral complexes with chiral additives were screened for activity and selectivity in this

reaction. Also, the stability of a rhodium METAMORPhos complex (9) towards molecular hydrogen

was examined.

2.3.1 Hydrogenation of in situ generated imine 10

The hydrogenation of the in situ generated imine 10 towards amine 11 was accomplished with three

rhodium(III) METAMORPhos complexes, and can be seen in Scheme 15. Complex 5 (R) was used as

the cation because it was shown that this complex could easily be obtained with quantitative yield

form complex 2 (R). An appropriate amount of silver tetrafluoroborate (AgBF4) was added to the

reaction mixtures to abstract chlorides on complexes 2, 5 (R) and 9. Complex 2 was used as a

racemate, but complex 5 (R) was used as the R enantiomer and to achiral complex 9 two equivalents

of (R)-BINOL phosphoric acid (14) was added as an additive in an attempt to induce the formation of

an enantioenriched product. The results from this reaction are shown in Table 2.

17

Scheme 15 Hydrogenation of the in situ generated imine 10 by complex 2, 5 (R) and 9, additive 14 was added to achiral complex 9 in attempt to obtain an enantioenriched product.

Table 2 Results from the hydrogenation of in situ generated imine 10. All reactions were carried out under 30 bar H2 in methanol. Benzylamine and 2-butanone were added in a 1/1 ratio. a: conversion based on the amine / 2-butanone ratio. See also Scheme 15.

Entry Catalyst Additive Temperature (°C)

Reaction time (h)

Conversion (%)

ee (%)

1 2 (1.7 mol%) - 30 42 72.3a 0 2 5 (R) (5.0 mol%) - 40 18 >99.9 0 3 9 (2.0 mol%) 14 (3.4 mol%) 40 18 >99.9 0

After depressurisation of the reaction vials, all solutions were found to be brown with a black

precipitation. The reaction products were analyzed by 1H NMR spectroscopy after concentration

under reduced pressure and confirmed the formation of amine 11. 2-butanol was expected as a by-

product due to the hydrogenation of 2-butanone but was not observed. Entry 2 and 3 (Table 2) both

reached complete conversion of the substrate, but entry 1 did only reach 72.3% conversion despite a

longer reaction time. The lower conversion in entry 1 could be assigned to the used complex, catalyst

loading and/or the reaction temperature, from which the last two are lower than in entry 2 and 3.

18

In order to determine if an enantioenriched product was obtained in entry 2 and 3 (see Table

2), chiral gas chromatography (GC) and 1H NMR spectroscopy were used. Enantiomers cannot be

distinguished with NMR spectroscopy but diastereomers can be identified, therefore chiral shift

reagents were used in 1H NMR analysis.29 The enantiomeric excess can then be determined by

comparing the integrals of the signals from the obtained diastereomers. It was reasoned that the

product in entry 1 was obtained as a racemic mixture, since the used catalyst 2 is also racemic. The

reaction products of entry 2 and 3 were thus compared to entry 1 and the previously obtained

racemate of amine 11. Mosher's reagent (-methoxy--trifluoromethylphenylacetic acid) was used

as a shift reagent together with 1% pyridinium p-toluenesulfonate. Also a Lewis basic lanthanide

complex (tris[3-heptafluoropropylhydroxymethylene)-(+)camphorato]europium(III) derivative) was

used to attempt to distinguish the two enantiomers with 1H-NMR spectroscopy, but without

satisfactory results in the case of entry 2 and 3 in Table 2 (see the top of Figure 3). The discrimination

between the two enantiomers by using Mosher's reagent with racemic amine 11 and the reaction

products gave the best results, but no full separation of signals was observed, as can be seen in the

middle of Figure 3. Also, GC separation with a chiral column was unfortunately not sufficient to

determine the enantiomeric excess but strongly indicates, in combination with 1H-NMR

spectroscopy, the formation of a racemic product.

Figure 3 Part of the 1H NMR spectra of the reaction product of entry 3 in Table 2. The reaction product (amine

11) on the bottom. In the middle amine 11 with Mosher's reagent and 1% pyridinium p-toluenesulfonate and on the top with tris[3-heptafluoropropylhydroxymethylene)-(+)camphorato]europium(III) derivative as the shift reagent.

19

It was reasoned that in situ formation of imine 10 may not be completely sufficient, as was

also seen in the synthesis of the imine, and that minor by-products could give problems in the

analysis of the reaction product. Imine 12 was previously isolated and it was reasoned that using this

imine as the substrate would reduce the formation of minor by-products in comparison to the in situ

generated imine and thus simplify the analysis, so that enantiomeric excesses could be determined.

2.3.2 Hydrogenation of imine 12

Scheme 16 Hydrogenation of imine 12 towards amine 14 with different complexes and additives. Additive 16: CF3 groups are on the meta position. Additive 17: iPr groups are on the ortho and para position. See also Table 3.

The hydrogenation of imine 12 towards amine 13 was performed with a chiral and an achiral catalyst,

5 (R) and 9 respectively. Chiral phosphoric acids 14, 15, 16 and 17 were added to the reaction

mixture with achiral catalyst 9, to investigate whether chirality could be induced. Several bulky

phosphoric acids were utilized since bulky groups on the 2,2’ position of the BINOL moiety were

shown to have a significant influence on the enantioselectivity obtained.14 Also, a control experiment

20

was performed with the catalyst precursor [RhCp*Cl2]2. The reaction conditions, catalysts and

additives are shown in Scheme 16 and Table 3.

Table 3 The hydrogenation of imine 12 at 40 °C and under 30 bar H2 for 18 hours. The catalyst loading was 6.5 mol% and the additive loading was 10.0 mol% with respect to the imine. See also Scheme 16.

Entry Catalyst Additive Solvent

1 5 (R) - DCM/MeOH 2 5 (R) - DCM/MeOH 3 5 (R) 14 DCM/MeOH 4 9 15 MeOH 5 9 16 MeOH 6 9 17 MeOH 7 9 17 MeOH 8 [RhCp*Cl2]2 - DCM

The reaction mixtures were analysed by 1H NMR spectroscopy after concentration under reduced

pressure and conversion towards product 13 for entries 1-8 was observed. The conversions were

difficult to determine since several products were obtained. It was therefore focused on to analysing

the reaction mixtures further to establish whether enantiomeric excess in the formation of amine 13

was obtained. HPLC separation of the reaction product with a chiral column (using heptane/iPr/DEA

in a 97/1/2 ratio as eluent) did not lead to conclusive results about the formed product but suggested

the formation of amine 13. Due to peak tailing and slight changes in the retention times no

enantiomeric excess could be determined.

1H NMR spectroscopy with a mixture of the reaction products from entry 1-7 in Table 3 and a

chiral shift reagent, which is known from literature, was performed to analyze whether enantiomeric

excess was obtained.30 The used shift reagent was a mixture of (R)-BINOL and triphenoxyborane in a

4/1 ratio respectively with respect to the amine, leading to the formation of a chiral ammonium

borate salt. Although at first the results with this shift reagent looked promising, using pure previous

obtained racemic amine 13, analysis of the reaction mixtures proved to be more challenging. The 1H

NMR spectra became more difficult and therefore did not lead to conclusive results about the

enantiomeric excess of the product.

Because a black precipitation was observed in all reaction vials, which could indicate the

decomposition of the used complexes under the reaction conditions, the stability of the catalyst

towards molecular hydrogen was investigated. If the catalyst would show low stability towards

molecular hydrogen the reaction could be performed by nanoparticles.

21

2.3.3 Catalyst stability under molecular hydrogen

Complex 9 and AgPF6 were dissolved in CDCl3 under inert conditions and subsequently pressurized

with 5 bar of H2. Upon addition of H2 the orange solution turned completely to a brown suspension

with black precipitate within the timescale of minutes. An immediately measured 1H and 31P NMR

spectrum showed a species with a hydride: 31P NMR δ 66.31 (d, J = 128.6 Hz) and 1H NMR δ -10.37

(s). Shortly after, no signal could be observed by 1H and 31P NMR spectroscopy which confirmed the

decomposition of the complex, and thus low stability of the complex towards molecular hydrogen.

Since a similar brown/black precipitation was observed in earlier described catalysis

experiments which were also performed under inert conditions, next to the fact that no

enantiomeric excess could be observed, it was concluded that catalyst decomposition had occurred

and the reaction presumably was performed by rhodium nanoparticles. Because the nanoparticle

catalysed hydrogenation of imines is not of interest for this report the choice was made to look for

another approach in order to perform the hydrogenation reaction without the use of molecular

hydrogen.

22

2.4 Catalytic transfer hydrogenation of imines

It was shown in the previous chapter that complex 9 was not stable towards molecular hydrogen.

But, because the net addition of hydrogen is necessary to reduce an imine bond and yield an amine,

an alternative approach was investigated. It was already known that ammonium formate could serve

as a hydrogen and nitrogen donor in the reductive amination of carbonyl compounds. This reaction is

known in organic chemistry as the Leuckart reaction and proceeds at high temperatures.31

The reaction of acetophenone with ammonium formate as the hydrogen and nitrogen donor

to yield chiral amine 19 (1-phenylethylamine) was investigated, see Scheme 17. It was envisioned

that in situ formation of imine 18 was followed by the transfer hydrogenation of the imine bond

towards the amine. It was investigated whether stereoselectivity could be induced by the use of

rhodium(III) METAMORPhos complexes 5 (R) and 9 with chiral additive 14. The stability of one of the

used complexes towards ammonium formate was first tested to ensure catalyst stability under the

used reaction conditions.

Scheme 17 Envisioned reaction between acetophenone and ammonium formate to yield chiral amine 19 via imine 18.

2.4.1 Catalyst stability under reaction conditions

The stability of complex 9 towards ammonium formate was tested by the addition of 55 equivalents

HCOONH4 to a solution of complex 9 in methanol-d4. This gave a colour change from orange to

yellow and yielded another complex, as was shown by 31P and 1H NMR spectroscopy. 1H NMR

spectroscopy showed that the complex did not decompose and a new complex with a hydride at δ -

11.40 ppm (dd, J = 41.4, 22.7 Hz) was formed. This double doublet showed the formation of a

rhodium-hydride bond, in which the hydride couples with rhodium and the phosphorous in the

ligand. A proton originating from the protonated ligand (NH or OH) was unfortunately not clearly

observed in the same 1H NMR spectrum. The stability of complex 9 at higher temperatures was

tested by refluxing 9 in CDCl3 after the addition of an excess ammonium formate. Because no

decomposition was observed with 1H and 31P NMR spectroscopy this led to the assumption that this

complex was stable at the used reaction conditions.

23

2.4.2 Transfer hydrogenation of in situ generated imine 18

Scheme 18 Reductive amination of acetophenone by 10 equivalents HCOONH4 and complex 5 (R), 9 and additive 14.

The transfer hydrogenation of in situ generated imine 18 towards chiral amine 19 was attempted

with chiral complex 5 (R) and achiral complex 9. To the achiral complex, R-BINOL phosphoric acid (14)

was added as a chiral additive in an attempt to initiate the formation of an enantioenriched product.

Also, a control experiment was performed wherein no catalyst or additive was added and a control

experiment in which the rhodium precursor [RhCp*Cl2]2 was used as a catalyst. An overview of the

reaction, conditions and results can be seen in Scheme 18 and Table 4. The transfer hydrogenation of

imine 12 with ammonium formate and chiral complex 5 (R) was also tested but did not led to

satisfactory results.

Table 4 Results from the catalysis experiments in the reductive amination of acetophenone with 10 equivalents of HCOONH4 in methanol at 70 °C. a: conversion of acetophenone is based on the amine 19 : acetophenone ratio. b: small signals of unidentified product(s) were observed in

1H NMR spectroscopy. N.D.: not determined.

Entry Catalyst Additive Reaction time (h)

Conversion towards amine 19a (%)

ee (%)

1 - - 19 0b - 2 [RhCp*Cl2]2

(0.7 mol%) - 19 >99.9 -

3 5 (R) (1.1 mol%) - 22.5 88.9 N.D. 4 9 (2.0 mol%) 14 (6.0 mol%) 5.5 23.4 N.D.

24

In entry 2, 3, and 4 of Table 4 the major product which was observed with 1H NMR

spectroscopy was the desired amine 19. It is remarkable that 1-phenylethanol was not observed as a

product, which indicates the selective transfer hydrogenation of the imine intermediate and not of

acetophenone. The conversions in Table 4 were determined by the acetophenone : amine ratio in 1H

NMR spectroscopy, but in all entries the formation of trace amounts of unidentified by-product(s)

was observed. However, it was found that amine 19 could be isolated after extraction with

dichloromethane from a concentrated NaCl solution in H2O, which was brought to pH 10 by Na2CO3.

It can also be seen in Table 4 that the addition of a rhodium complex is necessary to obtain

the chiral amine 19 and acceptable conversion of acetophenone. The control reaction in entry 1 did

not yield amine 19 but the formation of small amounts of unidentified products and the conversion

of acetophenone was low. However, the control reaction in entry 2, in which [RhCp*Cl2] was used as

the catalyst, gave quantitative conversion of acetophenone towards amine 19 in 19 hours. Also, the

use of complex 5 (R) and complex 9 with additive 14 were found to convert acetophenone to amine

19.

The use of chiral complex 5 (R) yielded a lower conversion of acetophenone than [RhCp*Cl2]2

in a longer reaction time and with a higher catalyst loading. This leads to the assumption that

[RhCp*Cl2]2 is more active than complex 5 (R) under the used reaction conditions. A mixture of

complex 9 and additive 14 (entry 4) yielded a conversion of 23.4% after 5.5 hours, which is expected

to be in the same range as the conversions of the reactions in entry 2 and 3 at that time. It has not

been possible to determine whether the formed amine was enantioenriched. Several attempts to

determine whether enantiomeric excess was obtained with triphenylborate and R-BINOL as a

chemical shift reagent failed due to the difficulty of the obtained 1H NMR spectra after the addition

of the shift reagent. HPLC with a chiral column (using heptane/iPr/DEA in a 97/1/2 and 98/1/1 ratio

as eluent) was tried to separate the two enantiomers but insufficient time was available to develop a

high quality and reliable method for the separation. The obtained spectra showed peak tailing and

slight variations in the retention times.

The conversion of acetophenone towards amine 19 with 10 equivalents HCOONH4 and 1.0

mol% catalyst 9 in methanol was followed at room temperature, 40 °C and 70 °C with 1H NMR

spectroscopy, see Table 5. The reaction mixture was heated from room temperature to 40 °C after 23

hours and kept at that temperature for 2 hours, at which a conversion of 19.8% acetophenone

towards amine 19 was observed. Subsequent heating to 70 °C yielded a conversion of 41.2% after 1

hour and 89.3% 45 minutes later. As with the previous experiments, trace amounts of side product(s)

were observed with 1H NMR spectroscopy.

25

Table 5 Conversion of acetophenone towards amine 19 with complex 9 at different temperatures and reaction times. rt: room temperature. The total reaction time is the sum of all reaction times at the different temperatures, since entry 1-4 are all obtained by the heating of one experiment. a: conversion of acetophenone is based on the amine 19 : acetophenone ratio.

Entry Temperature (°C) Time at temperature (h)

Total reaction time (h)

Conversion (%)

1 rt 23 23 0 2 40 2 25 19.8 3 70 1 26 41.2 4 70 1.8 27.8 89.3

Because after 23 hours at room temperature no conversion of acetophenone was observed,

it was assumed that catalyst 9 was not active at this temperature. When comparing the results in

entry 4, Table 4 with entry 4, Table 5, the higher conversion of acetophenone of the latter within a

shorter time at elevated temperatures and a lower catalyst loading was found remarkable. This could

mean that additive 14 had a negative effect on the reaction rate or catalyst stability.

To summarise, it was thus shown that complex 5 (R), 9 and [RhCp*Cl2]2 are very active and

selective catalysts in the transfer hydrogenation of in situ generated imine 18 and that this reaction

only proceeds at elevated temperatures and gives selective the desired amine 19 and no ketone

reduction towards the alcohol. Unfortunately, no enantiomeric excess could be determined from the

reaction product.

26

3 Conclusion

This study was set out to answer the question whether the reductive amination of prochiral

substrates could be achieved by using different half-sandwich rhodium(III) METAMORPhos

complexes with H2 or HCOONH4 as the hydrogen source and if enantiomeric excess in the product

could be induced. Besides this, the synthesis of rhodium(III) METAMORPhos complexes and their

stability towards the applied reaction conditions was examined and the successful synthesis and

isolation of two imines and amines was performed.

It was found that monodentate coordination of phosphite functionalised METAMORPhos

ligand 1 towards a rhodium(III) centre yields a dynamic equilibrium between neutral complex 2 and

cationic complex 3, which is influenced by the polarity of the solvent. The anionic and bidentate

coordination of the ligand towards rhodium was found to be challenging for the chiral phosphite

based ligands 1 (rac) and 1 (R) by using NaOAc as a base, even though this approach appeared to be

successful for the formation of complex 9 from ligand 8. However, it was shown that cationic

complexes 5 (rac) and 5 (R) could be obtained in quantitative yield by the reaction of 2 with NaBArF,

which is the reason that these complexes were used in catalysis.

The anionic and bidentate coordination of the achiral phosphine based ligand 8 was

established due to the lower acidity of the nitrogen atom in comparison to the chiral phosphite

based ligands 1 (rac) and 1 (R). This difference in acidity of the nitrogen atom implies that the latter

could only be obtained as the base adduct, whereas the phosphine based ligand (8) can be obtained

in the neutral from. Decoordination of the base from the phosphite based ligand (1 (rac) and 1 (R)) in

order to promote anionic bidentate binding was thus found to be less successful than deprotonation

of the neutral phosphine based ligand 8.

The hydrogenation of in situ generated imine 10 by using molecular hydrogen was

established with good to quantitative conversion to a racemic mixture of the desired amine. The

hydrogenation of imine 12 was less successful and led to testing of the catalyst stability towards the

reaction conditions. Unfortunately, it was found that the rhodium(III) METAMORPhos complexes

decomposed under the influence of molecular hydrogen which led to the assumption that the

catalysis was performed by rhodium nanoparticles, a reaction that is known in literature.32 It can also

be concluded that the envisioned heterolytic cleavage of H2 to form a stable complex which could

hydrogenate the imine was not possible.

In order to perform a transfer hydrogenation, the stability of the complexes towards

ammonium formate was tested. It was found that the addition of HCOONH4 to a rhodium(III)

METAMORPhos complex yielded a complex upon which a hydride was observed by 1H NMR

27

spectroscopy. This complex was found to be stable, even at elevated temperatures and is expected

to be active the transfer hydrogenation of imines.

Upon addition of complex 5 (R), 9 or [RhCp*Cl2]2 to a mixture of ammonium formate and

acetophenone, conversion towards the desired 1-phenylethylamine (19) as the product was

observed. Quantitative conversion towards the desired amine was achieved with [RhCp*Cl2]2 after 19

hours, but good conversions towards 19 were also found for rhodium(III) METAMORPhos complexes

5 (R) and 9. It was also found that additive 14 has an influence on the reaction rate or the stability of

complex 9, since a lower conversion was observed upon the addition of 14. Because no ketone

hydrogenation towards the alcohol was observed it was concluded that the transfer hydrogenation

with the used complexes is selective for the in situ generated imine 18. Determination of the

enantiomeric excess of the reaction product in the asymmetric catalysis reactions was unfortunately

not successful, which is why it cannot be answered if chirality on the ligand or in an additive leads to

an enantioenriched product.

28

4 Outlook

Several questions arise due to the performed study and the obtained results, but unfortunately no

time was available to do more experiments to answer some of these questions. The research

described in this report covers a variety of different experiments; complex, imine and amine

synthesis, catalysis using molecular hydrogen and a hydrogen donor (HCOOH4N) and several (High

Pressure)-NMR spectroscopy experiments. Due to this variety of experiments some insights have

been obtained that need further research or more time consuming in depth experiments to answer

several questions.

First of all, an accurate method to determine the enantiomeric excess of the reaction product

should be developed. Preferably, this should be a GC or HPLC method, due to the ease of analysis

and use. It can then be determined if chirality in the ligand or in an additive induces the formation of

an enantioenriched product. Since it was shown that [RhCp*Cl2]2 was active in the transfer

hydrogenation reactions it could also be tested if the addition of chiral additives to this precursor

could yield an enantioenriched product, which would be of great interest due to the ease of use.

In order to obtain more insight in the reactivity and stability of half-sandwich rhodium(III)

METAMORPhos complexes, structural analysis studies should be undertaken to determine the

absolute configuration of all the used complexes. These include High Resolution Mass Spectrometry,

crystallography, detailed NMR spectroscopy studies and computational calculations. Information

about the structure of the complex could then be used to explain reactivity and stability of the

complexes. A suitable method for the anionic and bidentate coordination of the chiral phosphite

based ligands to rhodium should also be developed, so that the proton-responsive properties of the

METAMORPhos ligands are fully assessable.

Time resolved spectroscopy methods could be used to answer the question why catalyst

decomposition was observed after pressurisation with H2, and maybe how this could be avoided. This

analytic method could also be used to obtain insight in the mechanism of the transfer hydrogenation

reaction. Because a hydride was observed in 1H NMR spectroscopy after the addition of ammonium

formate to complex 9 it should be examined how this hydride complex is is involved in the reaction.

The reaction conditions for the transfer hydrogenation should be optimised and more

hydrogen donors and substrates should be tested for activity. After this, kinetic studies could be

performed to obtain insight in the reaction mechanism and answer the question why the

hydrogenation of an imine is preferred above a ketone. These results can give insight in how to

further optimize the catalyst structure and reaction conditions. Since the formation of

enantioenriched amines is of great interest the focus should be on the use of chiral complexes and

additives.

29

Since this research was performed in a short period of time and only general results could be

obtained, as mentioned before, it is strongly encouraged to look further into the reductive amination

reaction with these complexes. If the reaction can be optimized with rhodium(III) METAMORPhos

complexes, research should be done on the possibility to use more abundant transition metals like

iron or cobalt. This could be of great interest for the industry and scientific world.

5 Acknowledgements

First of all, I would like to thank Sander Oldenhof because he learned me countless things, ranging

from laboratory skills to writing this report, thinking about the usefulness of my experiments and

results and making a plan to answer my research questions. Besides this I really appreciate the time

and effort you took to answer all my questions and showing me a glimpse of what doing research is

all about. Thank you, also for the many laughs and the great time.

I would like to thank Joost Reek, Bas de Bruin and Jarl Ivar van der Vlugt for their

contributions during the mini meetings. I would also like to thank Joost Reek for being my supervisor

and Jan van Maarseveen for being my second examiner. And last but not least; the whole HOMKAT

group for their contributions at the mini meetings, helping me with all my questions and for the great

time.

30

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32

7 List of Abbreviations

Ac Acetate

NaBArF Sodium tetrakis[3,5-bis(triflouomethyl)phenyl]borate

BINOL 1,1'-bi-2-naftol

DCM Dichloromethane

DEA Diethylamine

ee Enantiomeric excess

eq Equivalent

EtOH Ethanol

GC Gas Chromatography

h Hours

HPLC High Pressure Liquid Chromatography

iPr iso-Propyl

MeOH Methanol

Molsieves Molecular sieves

NMR Nuclear Magnetic Resonance

Ph Phenyl

Rac Racemate

rt Room temperature

TEA Triethylamine

THF Tetrahydrofuran

33

8 Experimental Section

All reactions were carried out in dry glassware under nitrogen atmosphere by using standard Schlenk

techniques, unless stated otherwise. Solution additions or transfers were performed via syringes. All

chemicals and solvents were bought commercially at Sigma Aldrich, Biosolve or Strem (for

[RhCp*Cl2]2) and used without further purification. Pentane, THF and Et2O were distilled from sodium

benzophenone ketyl, CH2Cl2 and methanol were distilled from CaH2, toluene was distilled from

sodium and kept under nitrogen atmosphere prior to use. METAMORPhos ligands 1 (rac), 1 (R), 7 and

9 were synthesised prior to this study and checked for purity before use and were filtered over

neutral Al2O3 if needed. (R)-BINOL phosphoric acids 15, 16, 17 and 18 were generously donated by

the Synthetic Organic Chemistry Group at the UvA. Nuclear Magnetic Resonance spectra (1H, 1H{31P}

and 31P{1H}) were measured on a Varian Mercury300 (1H: 300.1 MHz), a Bruker AV400 (1H: 400 MHz,

31P, 162 MHz), a Varian Inova500 (1H: 500 MHz, 31P: 202.3 MHz) or a Bruker DRX300 (1H: 300 MHz,

31P: 122 MHz). Chemical shifts in 1H NMR spectra are referenced to the solvent signal (7.27 ppm for

CDCl3, 3.31 ppm for CD3OD, 5.32 ppm for CD2Cl2 or 2.08 for toluene-d8). Gas chromatography was

performed on a Shimadzu 17A GC with a Supelco SPB fused silica capillary column (30 m, 0.32 mm, 2

m) or a Thermo Electron Corporation Trace GC Ultra with chiral Supelco β-DEX 225 column. High

Pressure Liquid Chromatography was performed on a Shimadzu (Column oven: CTO-10A VP, injector:

SIL-10A VP and liquid chromatograph: LC-10AT VP) with UV-VIS detector (SPD-10A VP) and a chiral

OD-H column.

8.1 Synthesis of complexes, imines and racemic amines

METAMORAPhos ligand 1 (rac) (28.1 mg; 0.050 mmol; 2.0 eq) and

[RhCp*Cl2]2 (15.60 mg; 0.025 mmol; 1.0 eq) were dissolved in

dichloromethane (3.0 mL), upon which the red solution was stirred for 30

minutes at room temperature followed by concentration under reduced

pressure at room temperature, to yield a red product. For structural

analysis 31P- and 1H-NMR spectra were measured in D-toluene and CDCl3. In

the latter a second complex was visible, which was assigned as complex 3.

Complex 2: 31P{1H} NMR (162 MHz, Toluene-d8) δ 121.96 (d, J = 217.3 Hz),

1.75 (ligand oxide). 1H NMR (400 MHz, Toluene-d8) δ 8.00 (d, J = 8.8 Hz,

2H), 7.90 – 7.53 (m, 6H), 7.45 – 7.11 (m, 2H), 6.87 (m, 2H), 2.36 (qd, J = 7.3,

1.8 Hz, 6H), 1.46 (d, J = 5.2 Hz, 15H), 0.63 (t, J = 7.3 Hz, 9H). Complex 2 and

3: 31P{1H} NMR (162 MHz, Chloroform-d) δ minor: 132.94 (d, J = 200.4 Hz),

major: 121.38 (d, J = 217.6 Hz), 3.09 (ligand oxide). 1H NMR (400 MHz,

34

Chloroform-d) δ 8.10 – 7.75 (m, 6H), 7.67 – 7.27 (m, 4H), 7.25 – 6.93 (m,

2H), 3.00 (qd, J = 7.3, 1.4 Hz, 6H), 1.66 (d, J = 5.3 Hz, 7H), 1.62 (s, 4H), 1.52

(d, J = 5.4 Hz, 1H), 1.44 (d, J = 5.0 Hz, 3H), 1.20 (t, J = 7.3 Hz, 9H). 1H{31P}

NMR (400 MHz, Chloroform-d) δ 8.12 – 7.77 (m, 6H), 7.66 – 7.26 (m, 4H),

7.25 – 6.88 (m, 2H), 3.00 (qd, J = 7.3, 1.3 Hz, 6H), 1.66 (s, 7H), 1.62 (s, 4H),

1.52 (s, 1H), 1.44 (s, 3H), 1.20 (t, J = 7.3 Hz, 9H).

Typically, METAMORPhos ligand 1 (R) (28.18 mg; 0.050 mmol; 2.0 eq) and

[RhCp*Cl2]2 (15.61 mg; 0.025 mmol; 1.0 eq) were dissolved in

dichloromethane (2.0 mL), upon which the red solution was stirred for 45

minutes at room temperature. NaBArF (44.5 mg, 0.050 mmol, 2.0 eq) was

added and stirred for 2.5 hours. The red solution was dried under reduced

pressure yielding a red solid, 5 (R). Isolated yield: 28.6 mg, 0.020 mmol,

78.9%. 31P{1H} NMR (162 MHz, Chloroform-d) δ 134.92 (d, J = 205.2 Hz). 1H

NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 8.9 Hz, 1H), 8.04 (d, J = 8.9 Hz,

1H), 8.00 – 7.94 (m, 2H), 7.78 – 7.63 (m, 9H), 7.59 – 7.31 (m, 11H), 7.14 (s,

1H), 2.91 (m, 6H), 1.40 (d, J = 5.3 Hz, 15H), 1.08 (t, J = 7.3 Hz, 9H). 1H{31P}

NMR (400 MHz, Chloroform-d) δ 8.14 – 7.95 (m, 4H), 7.77 – 7.67 (m, 9H),

7.61 – 7.35 (m, 11H), 7.28 (s, 1H), 2.94 (m, 6H), 1.43 (s, 15H), 1.10 (t, J = 7.3

Hz, 9H).

Typically, METAMORPhos ligand 1 (rac) (29.92 mg; 0.053 mmol; 2.2 eq)

and [RhCp*Cl2]2 (14.86 mg; 0.024 mmol; 1.0 eq) were dissolved in

dichloromethane (2.0 mL), upon which the red solution was stirred for 45

minutes at room temperature. NaBArF (44.00 mg, 0.050 mmol, 2.1 eq)

was added and the red solution was stirred for 16 hours. After 16.5 hours

the mixture was concentrated under reduced pressure to yield a mixture

of a red and yellow fluffy solid, which was washed with Et2O, dissolved in

DCM and gave a red solid (5 (rac)) after drying. 31P{1H} NMR (162 MHz,

Chloroform-d) δ 137.93 (d, J = 205.4 Hz), 3.00. 1H NMR (400 MHz,

Chloroform-d) δ 8.13 – 7.88 (m, 4H), 7.72 (m, 9H), 7.63 – 7.16 (m, 11H),

2.85 (dq, J = 7.1, 2.2 Hz, 6H), 1.66 (s, 4H), 1.43 (d, J = 5.3 Hz, 11H), 1.07 (t, J

= 7.3 Hz, 9H). 1H{31P} NMR (400 MHz, Chloroform-d) δ 8.16 – 7.88 (m, 4H),

7.76 – 7.67 (m, 9H), 7.64 – 6.94 (m, 11H), 2.93 – 2.80 (m, 6H), 1.66 (s, 4H),

1.43 (s, 15H), 1.07 (t, J = 7.3 Hz, 9H).

35

METAMORPhos ligand 1 (rac) (26.90 mg; 0.048 mmol; 2.0 eq) and

[RhCp*Cl2]2 (14.70 mg; 0.024 mmol; 1.0 eq) were dissolved in

dichloromethane (2.0 mL), upon which the red solution was stirred for 20

minutes at room temperature. KPF6 (8.40 mg, 0.046 mmol, 1.9 eq) was

added and stirred for 90 hours after which a crude NMR sample was

taken. This products was not isolated. 31P{1H} NMR (162 MHz, Methanol-

d4) δ 133.38 (d, J = 203.5 Hz), 122.46 (d, J = 215.9 Hz), 119.53 (d, J = 219.8

Hz), 0.13 , -143.37 (sep, 710.3 Hz). 1H NMR (400 MHz, Methanol-d4) δ 8.15

– 7.79 (m, 6H), 7.54 – 6.83 (m, 6H), 2.91 (q, J = 7.3 Hz, 6H), 1.66 (d, J = 5.5

Hz, 8H), 1.52 (d, J = 5.5 Hz, 1H), 1.41 (d, J = 5.1 Hz, 6H), 1.12 (t, J = 7.3 Hz,

9H). Large solvent peak at δ = 5.32 ppm.

This synthesis was not successful to make complex 4. To a stirring solution

of ligand 1 with Et4N+ as base instead of the usual Et3NH+ (50.0 mg, 0.09

mmol, 1.0 eq) in tetrahydrofuran (1.0 mL), NaH (7.90 mg, 0.30 mmol, 3.7

eq) in tetrahydrofuran (2.0 mL) was slowly added. Immediate gas

development and a colour change to yellow was observed. The solution

was filtered over a column (Titan 3, PVDF, 0.45 µm) and dried under

reduced pressure yielding a slightly yellow solid. A part from this solid

(approximately 21.84 mg, 0.045 mmol, 2.0 eq) was dissolved in

tetrahydrofuran (1.25 mL), dried under reduced pressure, washed with

dichloromethane (2.0 mL) and again dried under reduced pressure. The

obtained ligand (7) was dissolved in dichloromethane (2.0 mL), [RhCp*Cl2]2

(14.48 mg; 0.023 mmol; 1.0 eq) was added and the red solution was

stirred at room temperature for 16 hours and subsequently dried under

reduced pressure to yield a red thick oil. 31P{1H} NMR (162 MHz,

Chloroform-d) δ 132.97 (d, J = 200.3 Hz). A good 1H NMR spectrum was

not obtained.

36

Typically, METAMORPhos ligand 8 (42.85 mg; 0.108 mmol; 2.1 eq) and

[RhCp*Cl2]2 (32.26 mg; 0.052 mmol; 1.0 eq) were dissolved in

dichloromethane (4.0 mL), upon which the red solution was stirred for 50

minutes at room temperature. NaOAc (85.31 mg, 1.04 mmol, 10.0 eq) was

added and stirred for 21 hours. The solution was filtered over a column

(Titan 3, PVDF, 0.45 µm) and silica plug, dried under reduced pressure and

washed with pentane to yield a red solid. Isolated yield: 68.8 mg, 0.103

mmol, 95.1%. 31P NMR (162 MHz, Chloroform-d) δ 66.54 (d, J = 128.8 Hz).

1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.3 Hz, 2H), 7.63 (dd, J =

12.0, 7.0 Hz, 4H), 7.46 – 7.37 (m, 6H), 7.11 (d, J = 8.2 Hz, 2H), 2.55 (t, J =

7.7 Hz, 2H), 1.49 (d, J = 3.2 Hz, 15H), 1.35 – 1.18 (m, 4H), 0.88 (t, J = 7.3 Hz,

3H). 1H{31P} NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.3 Hz, 2H), 7.63

(d, J = 7.0 Hz, 4H), 7.41 (d, J = 7.8 Hz, 6H), 7.11 (d, J = 8.2 Hz, 2H), 2.55 (t, J

= 7.7 Hz, 2H), 1.49 (s, 15H), 1.40 – 1.14 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H).

For all three methods: 3.5/1 mixture of E/Z isomers; 1H NMR (400 MHz,

Chloroform-d) δ 7.35 – 7.19 (m, 5H); major isomer: δ 4.49 (s, 2H), 2.35 (q, J

= 7.4 Hz, 2H), 1.91 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H); minor isomer 4.51 (s, 2H),

2.08 (s, 3H), 1.11 (t, J = 7.7 Hz, 3H).

Method 1 Benzylamine (0.57 mL, 560.31 mg, 5.23 mmol, 1.0 eq) and 2-butanone (0.45 mL,

362.25 mg, 5.02 mmol, 1.0 eq) were dissolved in methanol (15.0 mL) and stirred at 30 °C for 22.5

hours, after which the brown solution was concentrated under reduced pressure. Conversion: 48.3%

to an E/Z mixture with ratio 3.5/1.

Method 2 This experiment was performed under atmospheric conditions. 2-butanone (0.90 mL,

0.72 g, 10.0 mmol, 1.0 eq) and benzylamine (1.10 mL, 1.08 g, 10.1 mmol, 1.0 eq) were added to

Na2SO4 (15 g) in ethanol (20 mL) and stirred at room temperature for 117 h, after which the brown

solution was concentrated under reduced pressure. Conversion: 65.4% to an E/Z mixture with ratio

3.5/1.

Method 3 This experiment was performed under atmospheric conditions. 2-butanone (3.60 mL,

2.90 g, 40.19 mmol, 1.0 eq) and benzylamine (4.80 mL, 4.72 g, 44.04 mmol, 1.1 eq) were dissolved in

dichloromethane (60.0 mL). To this solution Na2SO4 (8.0 g) was added. The colourless solution was

stirred at room temperature for 16 hours and then filtered over paper. The mixture was

concentrated under reduced pressure, yielding a colourless liquid. After 1H-NMR analysis, 2-

butanone (3.60 mL, 2.90 g, 40.19 mmol, 1.0 eq) and Na2SO4 (7.5 g) were added and dissolved in

dichloromethane (60 mL). The mixture was stirred at room temperature for 2 hours, after which

37

more Na2SO4 (7.5 g) was added. After continuously stirring for 27 hours again more Na2SO4 (30.0 g)

was added, this step was repeated after 70 hours. After a total of 116 hours stirring the mixture was

filtered over paper and dried under reduced pressure, followed by co-evaporation with toluene (3x

50 mL) and concentration under reduced pressure. Conversion: 76.3%, isolated yield: 1.57 g, 9.72

mmol, 22.1% of an E/Z mixture with ratio 3.5/1.

Imine 10 (1.65 g, 10.23 mmol, 1.0 eq) was dissolved in methanol (20.0 mL)

and NaBH4 (190.60 mg, 5.04 mmol, 0.5 eq) was added slowly under stirring

at room temperature. After 75 minutes the yellow solution was

concentrated under reduced pressure and dissolved in dichloromethane,

yielding a yellow solution with white precipitate. The mixture was washed

with H2O (3x 15 mL) followed by drying of the dichloromethane fraction

with Na2SO4, filtration and concentration under reduced pressure to yield a

mixture of imine 10 and amine 11 (69.1% conversion). 1H NMR (400 MHz,

Chloroform-d) δ 7.52 – 6.99 (m, 5H), 3.84 – 3.69 (m, 2H), 2.60 (dt, J = 12.7,

6.2 Hz, 1H), 1.59 – 1.45 (m, 1H), 1.35 (dt, J = 13.9, 7.2 Hz, 1H), 1.07 (d, J =

6.3 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). Which is in accordance to literature.33

NaHCO3 (21.0 g, 250.0 mol, 5.0 eq), benzylamine (5.43 mL, 5.34 g, 49.84

mmol, 1.0 eq) and acetophenone (5.84 mL, 6.00 g, 50.00 mmol, 1.0 eq)

were dissolved in toluene (60.0 mL). To this mixture molecular sieves (3-4 Å,

8.0 g) were added and the flask was shaken and equipped with a reflux

condenser before heating to 80 °C for 66 hours. The brown solution with

white precipitate was cooled to room temperature, filtered over celite and

the residue was washed with toluene (3x 15.0 mL), after which the filtrate

was concentrated under reduced pressure. To remove impurities, the

brown liquid was distilled under reduced pressure. Upon addition of ice-

cold n-pentane (15.0 mL) the solution turned yellow. After shaking and

cooling to -20 °C a white solid precipitated. After decantation of the

supernatant the solid was washed with ice-cold n-pentane (2x 10.0 mL) and

dried under reduced pressure. Yield: 2.22 g, 10.61 mmol, 21.2%. 25/1

mixture of E/Z isomers; 1H NMR (400 MHz, Chloroform-d) δ 7.90 – 7.83 (m,

2H), 7.45 – 7.31 (m, 7H), 7.30 – 7.21 (m, 1H); major isomer: δ 4.74 (s, 2H),

2.33 (s, 3H); minor isomer: δ 4.43 (s, 2H) 2.37 (s, 3H). Which is in

accordance to literature.28

38

Imine 12 (496.4 mg, 2.37 mmol, 1.0 eq) was dissolved in methanol (15.0

mL) and NaBH4 (48.30 mg, 1.28 mmol, 0.5 eq) was added slowly under

stirring at room temperature. After 15 hours the colourless solution was

concentrated under reduced pressure, yielding a white solid. The solid was

dissolved in dichloromethane and washed with H2O (3x 15 mL) followed by

drying of the dichloromethane fraction with Na2SO4. After filtration,

washing of the residue with dichloromethane (3x 15.0 mL) and

concentration under reduced pressure a light brown oil was obtained. 1H

NMR (400 MHz, Chloroform-d) δ 7.35 – 7.14 (m, 10H), 3.76 (q, J = 6.7 Hz,

1H), 3.58 (m, 2H), 1.49 (s, 1H), 1.32 (d, J = 6.5, 3H). Which is in accordance

to literature.28

8.2 Standard procedures for catalysis reactions

In a standard hydrogenation experiment of the (in situ generated) imine, the catalyst and an additive

(if desired) were dissolved in methanol (1.0 mL). AgBF4 (approximately 2 eq with respect to the

catalyst), 2-butanone and benzylamine (in a 1/1 ratio) or imine 12 were added to the solution. The

vial was purged by N2 and subsequently flushed with H2 in an autoclave and pressurised (30 bar H2),

heated to the desired temperature and stirred for the reported amount of time. After cooling to

room temperature and depressurisation, the reaction products were filtered over a column (Titan 3,

PVDF, 0.45 µm) and dried under air or reduced pressure. See Scheme 15, Scheme 16, Table 2 and

Table 3 for specific reaction conditions, used catalysts, additives and relative concentrations. The

reaction products were compared to the earlier obtained amines to determine conversions.

In a standard transfer hydrogenation experiment, HCOONH4, a catalyst and additive (if

desired) were dissolved in MeOH (5.0 - 10.0 mL) in a Schlenk. Acetophenone or imine 13 was added

and the solution was degassed by N2 and subsequent heating to the desired temperature under

stirring for the desired reaction time. The reaction mixture was cooled to room temperature and

concentrated under reduced pressure. The product mixture was dissolved in a concentrated NaCl in

H2O solution and brought to pH 10 by the addition of Na2CO3. The product was extracted with ethyl

acetate and subsequently dried with Na2SO4, followed by filtration and concentration under reduced

pressure. See Table 4, Table 5 and Scheme 18 for specific reaction conditions, used catalysts,

additives and relative concentrations. The reaction products were determined by comparison to the

previously obtained amine 13 or to a measured 1H NMR spectrum of (S)-(-)-1-phenylethylamine for

the products of the reductive amination of acetophenone. 1H NMR (400 MHz, Chloroform-d) δ 7.31 –

7.11 (m, 5H), 4.02 (q, J = 6.6 Hz, 1H), 1.42 – 1.34 (br. s, 2H), 1.30 (d, J = 6.6 Hz, 3H).