A DROP IN THE OCEAN - old.chem.pku.edu.cnold.chem.pku.edu.cn/zyang/uploads/allimg/140607/201233117219547.pdf · Prof. Martin Oestreich 2011-today, Professor, Technische Universität

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






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

Brief MechanismBrief Mechanism

10

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)

Development Development -- StereoselectivityStereoselectivitypp yy

13

Total SynthesisTotal Synthesisyy

14

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






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


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.


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


Cationic route:

23

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.

WaterWater

27

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






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.

MechanismMechanism

51

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






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






62

AcknowledgmentAcknowledgmentgg

Prof Yang & Prof Chen & Prof TangProf. Yang & Prof. Chen & Prof. Tang

Mr. Sun Tanwen, Ms. Xu Lingmin, Mr. Li Yong

Mr. Yu Ruocheng

63

Documents

A DROP IN THE OCEAN - old.chem.pku.edu.cnold.chem.pku.edu.cn/zyang/uploads/allimg/140607/201233117219547.pdf · Prof. Martin Oestreich 2011-today, Professor, Technische Universität