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A DROP IN THE OCEANA DROP IN THE OCEAN-- The MIZOROKIThe MIZOROKI--HECK ReactionHECK Reaction
A DROP IN THE OCEAN A DROP IN THE OCEAN
Reporter: Yang ShouliangSupervisors: Prof. Yang
Prof. ChenProf. Tang2011-12-23 1
PrologueProloguegg
CO2Me
OH ReacitvityReacitvityNOHC
O
OH H
Daphniglaucin C
ReacitvityReacitvityRegioselectivityRegioselectivityElectronic effectElectronic effect
2
ProloguePrologueggThanks toLi YLi Yong
M h iMechanism Catalyst & LigandR i l i iRegioselectivityStereoselectivityC b l &Carbocycles &Heterocycles
iDomino ProcessesOther Metals……
3
ProfProf. Martin Oestreich. Martin Oestreich2011-today, Professor, Technische Universität Berlin
2010, Visiting Fellow at the Australian National University (w/ Prof. Dr. Michael S. Sherburn)
2006 2011 P f W tfäli h Wilh l2006-2011, Professor Westfälische Wilhelms-Universität Münster
2005-2006, Visiting Professor at Cardiff University,
Martin Martin OestreichOestreich
, g y,(w/ Prof. Dr. Thomas Wirth)
2001-2005, Habilitation, Albert-Ludwigs-Universität F ib (P f D R i h d B ü k )
Transition MetalTransition Metal--Catalyzed Catalyzed Freiburg (Prof. Dr. Reinhard Brückner)
1999-2001, Postdoc, University of California at Irvine, (Prof. Dr. Larry E. Overman)
yyCarbonCarbon––Element bond formationElement bond formation
Asymmetric Asymmetric IntramolecularIntramolecularMizorokiMizoroki HeckHeck ( y )
1996-1999, PhD, Westfälische Wilhelms-Universität Münster (Prof. Dr. Dieter Hoppe)
MizorokiMizoroki--HeckHeck
SiliconSilicon--Stereogenic Silanes in Stereogenic Silanes in Asymmetric CatalysisAsymmetric Catalysis
4
1991-1996, Diploma, Philipps-Universität Marburg (Prof. Dr. Paul Knochel)
NonNon--Enzymatic (Dynamic) Kinetic Enzymatic (Dynamic) Kinetic ResolutionResolution
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
5
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
6
Prof. Heck Prof. Heck –– Nobel Prize (2010)Nobel Prize (2010)( )( )1931, born in Springfield, Massachusetts1952, bachelor's degree at the UCLA1954, doctor of philosophy at the UCLA
with Dr. Saul Winstein1954 1956 P td ETH i Z i h S it l d1954-1956, Postdoc, ETH in Zurich, Switzerland
and UCLA1957, Hercules Corporation in Wilmington, Delaware1971 retirement Professor at the1971-retirement, Professor at the
University of Delaware
X
Aryl, Benzyl & Styryl Halides
XX
7
Heck, R. F. J. Am. Chem. Soc. 1968, 90.Heck, R. F., Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
Aryl, Benzyl & Styryl Halides
In Memory of Prof. In Memory of Prof. MizorokiMizorokiyy
Following Contribution:
1) Pd particles; 2) PhI > PhBr >> PhCl; 3) PPh3
8
Mizoroki, T., Mori, K. and Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.Mori, K., Mizoroki, T. and Ozaki, A. Bull. Soc. Chem. Jpn. 1973, 46, 1505.
MizorokiMizoroki--Heck ReactionHeck Reaction
Definition:The palladium-catalyzed arylation or
alkenylation of olefins is referred to as the Mizoroki-Heck reaction
9
DevelopmentDevelopmentpp
Substrates extensionSubstrates extension
RN2+ >R-I > R-OTf ≈ Br >>Cl > OTs ≈ OPO(OR)2
R- Cl : By Prof. Hartwig & Prof. Fu
Unactivated
11
Alkyl Halides:
DevelopmentDevelopmentpp For aryl iodides, activated aryl bromides
Reliable, high yielding, allow for simple scale-up and are easily optimized. Ligand free, Any form of Pd0 or Pd II, TON & TOF (SRPCs)
But for unactivated aryl bromides & activated aryl chlorides
Herrmann–Beller pincer palladacycle
12
palladacycle pincer palladacycle.
SRPCs(slow-release precatalysts)
AchievementAchievement1970s-now:
Substrates scope
C t l t & Li d Catalyst & Ligand
Regioselectivity
Stereoselectivity
Ri C i Ring Construction
Application
Domino Process
15
Other metals…………
AchievementAchievement1970s-now:
Substrates scope
C t l t & Li d Catalyst & Ligand
Regioselectivity
Stereoselectivity
Ri C i Ring Construction
Application
Domino Process
16
Other metals…………
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
17
RegioselectivityRegioselectivityg yg y
IntermolecularIntermolecularIntermolecularIntermolecular
Which one is favored?Which one is favored?
18
Which one is favored?Which one is favored?Electronic Electronic vsvs Steric effectsSteric effects
RegioselectivityRegioselectivityg yg y
EWGElectron-poor Alkenes:
steric
l t ielectronic
Electron-rich Alkenes:
EDG
steric electronic
EDG
steric electronicAlkyl substituent Alkenes:
alkyl
steric electronic
19
ElectronElectron--Poor AlkenesPoor Alkenesββ--selectivity: Matchedselectivity: Matched
Darses, S., Pucheault, M. and Genet, J. P. Eur. J. Org. Chem. 2001, 1121.
20Pastre, J. C. and Correia, C. R. D. Org. Lett. 2006, 8, 1657.
RegioselectivityRegioselectivityg yg y
EWGElectron-poor Alkenes:
steric
electronicelectronic
Electron-rich Alkenes:
EDG
steric electronic
EDG
steric electronicAlkyl substituent Alkenes:
alkyl
steric electronic
21
Electronic Electronic vsvs Steric effectsSteric effectsWhich one dominates?Which one dominates?
Cationic Route Cationic Route vsvs Neutral RouteNeutral Route
22Cationic route Cationic route vsvs Neutral routeNeutral route
ElectronElectron--Rich AlkenesRich Alkenes
Strongly coordinatingStrongly coordinatingStrongly coordinating Strongly coordinating bidentatebidentate ligands:ligands:
DPPP dmphen
24Cabri, W., Candiani, I., Bedeschi, A. and Santi, R. J. Org. Chem. 1993, 58, 7421.
Silver or Thallium SaltsSilver or Thallium Salts
Silver salts: AgOAc et al
HIV-1 protease inhibitor
Silver salts: AgOAc et al.
HIV-1 protease inhibitor1. Rare triflates2. Silver salt: expensive3. Thallium salt: toxic
25Hulten, J., Andersson, H. O., Schaal, W. et al. J. Med. Chem. 1999, 42, 4054.
Increasing Polarity of Reaction SystemIncreasing Polarity of Reaction Systemg y yg y y1. Pd(OAc)2,DPPPDMF/Water
Br + O
H2O/DMF 1.5/2.5Microwave heating
1.0 h at 122 oC OBr +
62%= 99:1
2. H+
Vallin, K. S. A., Larhed, M. and Hallberg, A.. J. Org. Chem. 2001, 66, 4340.
Water as the sole solvent
Arvela R K Pasquini S and Larhed M J Org Chem 2007 72 6390
26
Arvela, R. K., Pasquini, S. and Larhed, M., J. Org. Chem. 2007, 72, 6390.
Ionic LiquidsIonic LiquidsIonic LiquidsIonic Liquids
([bmim][BF4]
To stablize Br-:
No participation
28Mo, J., Xu, L. and Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.
HydrogenHydrogen--Bond DonorsBond Donorsy gy g[HNEt3][BF4]
nBu4NBr
29Mo, J. and Xiao, J. L. Angew. Chem. Int. Ed. 2006. 415, 4152.
HydrogenHydrogen--Bond DonorsBond Donorsy gy g
30
1 (2.0 equiv), 2 (1.0 mmol), [HNEt3][BF4] (1.5 equiv), Pd(OAc)2 (2.5 mol%), dppp (5.0 mol %), and iPr2NH (1.5 quiv) in [bmim][BF4] (2 mL) at 115 o C; 100 % conversion and > 99:1 regioselectivity
HydrogenHydrogen--Bond DonorsBond Donorsy gy g
31
1 (2.0 equiv), 2 (1.0 mmol), [H2NiPrt3][BF4] (1.5 equiv), Pd(OAc)2 (2.5 mol%), dppp (5.0 mol %), and NEt3 (1.5 quiv) DMF (2 mL) at 100 o C; 100 % conversion and > 99:1 regioselectivity
Synthetic ApplicationSynthetic Applicationy ppy ppn
Pd(OAc)2 (5 0 mol%) O n
OTf
Br
R
NO(3.0 equiv)
Pd(OAc)2 (7.5 mol%)R
NOPd(OAc)2 (5.0 mol%)
HBF4P(t-Bu)3 (10 mol%)Pyridine (2.0 equiv)
Mo(CO)6, Bu4NCl
Dioxane MWR
NO
n = 1, 3
Wu, X., Nilsson, P. and Larhed, M. J. Org. Chem. 2005, 70, 346.
Br
R = H, 5-F,4-Me, Naphthyl
( )2 ( )DPPP (15 mol%)Et3N (1.1 equiv)
DMF, 110 oC, 16 h
Br Dioxane, MW160 oC, 30 min
42-88%O
26-78%
Wu, X., Nilsson, P. and Larhed, M. J. Org. Chem. 2005, 70, 346.
32Arefalk, A., Wannberg, J., Larhed, M. and Hallberg, A. J. Org. Chem. 2006, 71, 1265.
Additive: Additive: LiClLiCl
--SelectivitySelectivity
OTf
OBu
OBuOBu
SelectivitySelectivity
NO2
+OBu
NO
+
NO2NO2
33
Andersson, C. M. and Hallberg, A. J. Org. Chem. 1988, 53, 2112.
ββ--directing Influence of tBudirecting Influence of tBu33P & P & ClCl--ββ ggt-Bu3P precursor: [(tert-Bu)3PH]BF4 (‘Fu salt’)
alkyl
34Datta, G. K., von Schenck, H., Hallberg, A. and Larhed, M. J. Org. Chem. 2006, 71, 3896.
AllylicAllylic Alkenes Alkenes -- Internal Internal yy
35Olofsson, K., Larhed, M. and Hallberg, A. J. Org. Chem. 2000, 65, 7235.Thermal heating Microwave heating
Internal of Internal of AllylicAllylic AlkenesAlkenesyyIonic liquidIonic liquid
ββ--stabilizing effect of silicon stabilizing effect of silicon
36
Mo, J., Xu, L.J., Ruan, J. W. et al. Chem. Commun. 2006, 3591.Olofsson, K., Larhed, M. and Hallberg, A. J. Org. Chem. 1998, 63, 5076.
TerminalTerminal -- TBAB & BuTBAB & Bu44NClNCl
Bouquillon, S., Ganchegui, B., Estrine, B. et al. J. Organomet. Chem. 2001, 634, 153.
37
Yum, E. K., Yang, O. K., Kang, S. K. et al. Bull. Korean Chem. Soc. 2004, 25, 1091.
AllylicAllylic Alkenes Alkenes -- Terminal Terminal yyAryl bromides as coupling partners and Tedicyp as ligand
Berthiol, F., Doucet, H. and Santelli, M. Tetrahedron Lett. 2004, 45, 5633.
I+PhBF
Pd(OAc)2 (2.0 mol%)NaHCO3 (2.0 equiv)
PhI+PhBF4
-OH+
CH3CN/H2O (5:1)rt, 0.5 h
83%
Ph OH
38
Ph O
Kang, S. K., Lee, H. W., Jang, S. B. et al. J. Org. Chem. 1996, 61, 2604.
AllylicAllylic Alkenes Alkenes –– TerminalTerminalyyCationic Route Cationic Route
Jeffery, T. J. Chem. Soc., Chem. Commun., 1991, 324.
39
Berthiol, F., Cacchi, S., Ciattini, P. G. et al. Tetrahedron Lett. 1992, 33, 3073.
Chelation Controlled Chelation Controlled RegioselectivityRegioselectivityg yg y
Reversal of regioselectivity ( to )b it b d di tiby nitrogen-based directing group
Pd(OAc)2P( t l l) Pd+
BnO
NI OBnnC4H9
+P(o-tolyl)3
AgNO3, Et3NCH3CN, 100 oC
NPd
Arn-C4H9
NC H
> 93 : 7nC4H9
73%
H2, Pd/CNHO
nC4H9NMeO
60
:
40
40
PreclamolO
40
Nilsson, K. and Hallberg, A. J. Org. Chem. 1992, 57, 4015.
TriarylationTriarylationyy
Amino auxiliary:
Regioselectivity
-complex formation
Nilsson P Larhed M and Hallberg A J Am Chem Soc 2001 123 8217
Alkene insertion
41
Nilsson, P., Larhed, M. and Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217.
ApplicationApplicationpppp
DiazonamideDiazonamide
42
Jeong, S., Chen, X. and Harran, P. G. J. Org. Chem. 1998, 63, 8640.
Representative substrates Representative substrates pp
RegioselectivityRegioselectivityDi t l ti itDi t l ti it
43
DiastereoselectivityDiastereoselectivityEnantioselectivityEnantioselectivity
Good StereoselectivityGood Stereoselectivityyy
syn carbopalladation
44
syn β-hydrogen eliminationItami, K., Mineno, M., Muraoka, N. and Yoshida, J. J. Am. Chem. Soc. 2004, 126, 11778.
EnantioselectivityEnantioselectivityyy
Nilsson, P., Larhed, M. and Hallberg, A. J. Am. Chem. Soc. 2003, 125, 3430.
45
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
46
Heck Heck -- SuzukiSuzuki
TimeGreenGreen
ElegantEfficiency
47Couty, S., Liegault, B., Meyer, C. and Cossy, J. Org. Lett. 2004, 6, 2511.
Efficiency
Heck Heck -- StilleStille -- ElectrocyclizationElectrocyclizationyy
48
Salem, B. and Suffert, J. Angew. Chem. Int. Ed. 2004, 43, 2826.
Heck Heck -- TrujiTruji--TrostTrostjjTowards the synthesis Towards the synthesis of of pumiliotoxinpumiliotoxin CC
49
Daly, J. W. J. Med. Chem. 2003, 46, 445.Flubacher, D. and Helmchen, G. Tetrahedron Lett. 1999, 40, 3867.
Heck Heck -- CC--H activationH activation
X
R1
MeMe
Me
S
X = S, O2nd-generation light-1st-generation light-
Me
2nd generation lightdriven molecular motor
g gdriven molecular motor
one stepone step
50
Gericke, K. M., Chai, D. I., Bieler, N., Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 1447.
Heck Heck –– CO insertionCO insertion
52Artman, G. D. III and Weinreb, S. M. Org. Lett. 2003, 5, 1523.
Domino ProcessesDomino ProcessesFour Four vsvs six membered ringsix membered ring
53
Zhang, Y. and Negishi, E. I. J. Am. Chem. Soc. 1989, 111, 3454.Zhang, Y., Wu, G. Z., Agnel, G. and Negishi, E. I. J. Am. Chem. Soc., 1990, 112, 8590.
Domino Domino MizorokiMizoroki––Heck ReactionsHeck Reactions
scopadulcic acid A
Two quaternary carbons
54
Fox, M. E., Li, C., Marino, J. P. Jr. and Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467.
Domino ProcessesDomino Processes
55
Overman, L. E., Paone, D. V. and Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702.
First Three Membered RingFirst Three Membered Ringgg
Schweizer, S., Song, Z. Z., Meyer, F. E. et al. Angew. Chem. Int. Ed. 1999, 38, 1452.
CN- as nucleophilep
56Pinto, A., Jia, Y., Neuville, L. and Zhu, J. Chem. Eur. J. 2007, 13, 961.
Carbon as NucleophileCarbon as Nucleophilepp
Other nucleophile?
57Vittoz, P., Bouyssi, D., Traversa, C. et al. Tetrahedron Lett. 1994, 35, 1871.
Dongol, K. G. and Tay, B. Y. Tetrahedron Lett. 2006, 47, 927.
Nitrogen Atom as NucleophileNitrogen Atom as Nucleophileg pg p
V S b h M V G i R D M ij A E J O Ch 2002 19 3268
58
Von Seebach, M. V., . Grigg, R., De Meijere, A. Eur. J. Org. Chem. 2002, 19, 3268.
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
59
ConclusionConclusion
ROTfDPPP
[HNEt3][BF4]
Cationic Route vs Neutral Route
DMF/H2OIonic liquid
RX, AgOAc TlOAc Neutral Route qTlOAc
LiCl, TBAB,
60
, ,nBu4NCl, tBu3P
ConclusionConclusion
Heck - Suzukik S ill l li i
Regioselectivity Diastereoselectivity Enantioselectivity
Heck - Stille - ElectrocyclizationHeck - Truji-trostHeck - CO insertionHeck - C-H
61
y Heck - C-HDomino HeckHeck - Anion Capture
ContentsContents
IntroductionIntroductionIntroductionIntroduction
RegioselectivityRegioselectivity & Product Outcome& Product OutcomeRegioselectivityRegioselectivity & Product Outcome & Product Outcome
Domino ProcessesDomino ProcessesDomino ProcessesDomino Processes
ConclusionConclusionConclusionConclusion
AcknowledgmentAcknowledgmentAcknowledgmentAcknowledgment
62