Nickel-Catalyzed Multicomponent Coupling of Alkynes. -Recent development in methodologies and applications. Zhenjie Lu. Department of Chemistry, MSU

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1 i ickel ickel-catalyzed Multicomponent Coupling of Alkynes -ecent development in methodologies and applications Zhenjie u Department of Chemistry, MSU January 28, 2004

2 Background Introduction Conjugate addition using cuprates - well established reactions 3 i CuC 3 Cu(C)i 3 3 i CuC 3 Cu(C)i 3 Stoichiometric copper complex must be used. Alkenylcuprate are thermally unstable. The loss of double bond stereochemistry may occur. Conjugate addition using nickel-catalyzed transmetallation process 3 4 ZrCp 2 ()Cl ClCp 2 Zr 3 1) 4 2) 3 +, i(0) 4 3 up to 84% yield 1. Carey, F. A.; Sundberg,. J. Advanced rganic Chemistry. Part B, 2001, Schwartz, J.; oots, M. J.; Kosugi,. J. Am. Chem. Soc. 1980, 102, 1333.

3 Discovery of ickel-catalyzed Coupling eaction with Alkynes 'Zn ' hydrolysis cat. i ' 2 Zn cat. i 2 Zn, TMSCl '' ' TMS ' " hydrolysis ' ' Conjugate addition Tandem coupling " 1. Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, Ikeda, S.; Yamamoto,.; Kondo, K; Sato, Y. rganometallics. 1995, 14, 5015.

4 ickel Catalyzed Multi-Component Coupling of Alkynes - A General Scheme + '' ' + 2 Zn cat. i TMSCl ' " "E" "u" ' " "E", "u" i(0) "u" ' "E" " "E" = enone, enal, aldehyde, imine, C 2, epoxide "u" = (M) 1. Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, Ikeda, S.; Yamamoto,.; Kondo, K; Sato, Y. rganometallics. 1995, 14, 5015.

coupling of enones or enals with alkynes Professor Timothy F.

imines and epoxides with alkynes Professor Shin-ichi Ikeda agoya City University

5 Major Contributors in the Field i ickel Professor John Montgomery Wayne State University Intramolecular coupling of enones or enals with alkynes Professor Timothy F. Jamison Massachusetts Institute of Technology Asymmetric coupling of aldehydes, imines and epoxides with alkynes Professor Shin-ichi Ikeda agoya City University Intermolecular coupling of enones or enals with alkynes Professor Miwako Mori okkaido University Coupling of C 2 with alkynes, and aldehydes with dienes

6 utline 4 n n intra 3 intra 4 3 inter 4 i(0), (M) + 3 inter 3 C C

7 Intramolecular Coupling of Alkynes and Enones intramolecular 4 i(0), (M) n intermolecular 4 3

8 Intramolecular Coupling of Enones or Enals and Alkynes Intramolecular Cyclization of Enones with Alkynes 3 single cyclization 3 (M) without 3 (M) [2+2+2] 3 E + E [3+2]

9 Intramolecular Coupling of Enones or Enals with Alkynes Single Cyclization of Enone and Alkyne Bu 2 Zn or BuZnCl i(cd) 2 (5 mol%) Bu 2 Zn or BuZnCl i(cd) 2 (5 mol%) P 3 (25 mol%) a b Bu Alkylative coupling eductive coupling entry ligand a yield, % b yield, % Bu P 3 Bu Bu P 3 Bu Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099.

10 Intramolecular Coupling of Enones or Enals with Alkynes Proposed chanism i(cd) 2 i i 3 A ZnBu 2 (transmetallation) BuZn n i with P 3 without P 3 b reductive coupling reductive elimination BuZn n i C β- elimination B reductive elimination Bu a alkylative coupling 1. Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, Montgomery, J.; blinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, Montgomery, J. Acc. Chem. es. 2000, 33, 467.

11 Intramolecular Coupling of Enones or Enals with Alkynes X-ray Structures of ickel-metallocycles i i i A B X-ray structures of the nickel-metallocycles supported the proposed mechanism. Amarasinghe, K. K. D.; Chowdhury, S. K.; eeg, M. J.; Montgomery, J. rganometallics. 2001, 20, 370.

12 Intramolecular Coupling of Enones or Enals with Alkynes Total Synthesis of Isogeissoschizoid Skeleton P(Et 2 ) 1 Et 3 Cl TIPS 1 TIPS 2 Zn i(cd) 2 (10 mol%) toluene/c 3 C 84%(95:5dr) ( +_ )-isogeissoschizoid 2 TIPS Fornicola,. S.; Subburaj, K.; Montgomery, J. rg. ett. 2002, 4, 615.

13 Intramolecular Coupling of Enones or Enals with Alkynes Alkylative Coupling - Vinyl Zr as Coupling Partner + Cp 2 ClZr 2.5 equiv. i(cd) 2 (10 mol%) 3 ZnCl 2 (20 mol%) 3 entry 3 yield, % 1 C C (C 2 ) 4 TBS 75 4 C i, Y.; Amarasighe, K. K. D.; Montgomery, J. rg. ett. 2002, 4, 1743.

14 Intramolecular Coupling of Enones or Enals with Alkynes Total Synthesis of Isodomoic Acid G Cp 2 ClZr TIPS i(cd) 2 (10 mol%) ZnCl 2 (20 mol%), 0 o C 70% TIPS 2 C 2 C 2 C Isodomoic acid G i, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J. rg. ett. 2003, 5, 3771.

15 Intramolecular Coupling of Enones or Enals with Alkynes Discovery of [2+2+2] Cyclization i(cd) 2 (20 mol%) P 3 (40 mol%), Zn TF, 25 o C a alkylative coupling b reductive coupling c dimerization Zn yield of a yield of b yield of c (n-bu) 2 Zn trace (t-bu) 2 Zn none Proposed mechanism 1 i(cd) 2 (20 mol%) i i P 3 1 i c Seo, J.; Chui,. M. P.; eeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 476.

16 Intramolecular Coupling of Enones or Enals with Alkynes [2+2+2] Cyclization i(cd) 2 (20 mol%) P 3, TF, 25 o C 3 entry 2 product Yield (%) , 4:1dr 3 36 Seo, J.; Chui,. M. P.; eeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 476.

17 Intramolecular Coupling of Enones or Enals with Alkynes [3+2] Cyclization i(cd) 2 (100 mol%) TMEDA i E + E A not observed entry electrophile product (yield,%) entry electrophile product (yield,%) % 4 Cl 72% 2 I 72% % 72% Single diastereomer obtained in entry 1~4. 1. Chowdhury, S. K.; Amarasinghe, K. K. D.; eeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, Mahandru, G. M.; Skauge, A...; Chowdhury, S. K.; Amarasinghe, K. K. D.; eeg, M. J; Montgomery, J. J. Am. Chem. Soc. 2003, 125,

18 Intramolecular Coupling of Enones or Enals with Alkynes Proposed chanism of [3+2] Cyclization i(cd) 2 (100 mol%) i i TMEDA A' A E + E E C i E i 2 1 B Mahandru, G. M.; Skauge, A...; Chowdhury, S. K.; Amarasinghe, K. K. D.; eeg, M. J; Montgomery, J. J. Am. Chem. Soc. 2003, 125,

19 Intramolecular Coupling of Enones or Enals with Alkynes Cyclization of β- substituted enal Cascade Cyclization i(cd) 2 (100 mol%) TMEDA i i 1 61% A B single diastereomer Cyclization of α- substituted enal i(cd) 2 (100 mol%) TMEDA i i % C D single diastereomer Mahandru, G. M.; Skauge, A...; Chowdhury, S. K.; Amarasinghe, K. K. D.; eeg, M. J; Montgomery, J. J. Am. Chem. Soc. 2003, 125,

20 Intramolecular Coupling of Enones or Enals with Alkynes Proposed chanism of Two Cyclizations i(cd) 2 / i E + i E i i E E i [3+2] [2+2+2] 1. Chowdhury, S. K.; Amarasinghe, K. K. D.; eeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, Montgomery, J.; Amarasinghe, K. K. D.; Chowdhury, S. K.; blinger, E.; Seo, J.; Savchenko, A. V. Pure. Appl. Chem. 2002, 74, 129.

21 Intramolecular Coupling of Enones or Enals with Alkynes Summary of Intramolecular Coupling i(0) i i 3 2Zn/ 3 () E E + = TMEDA = P 3 [3+2] [2+2+2]

22 Intermolecular Coupling of Enones and Alkynes intramolecular 4 i(0), (M) n intermolecular 4 3

23 Intermolecular Coupling of Enones or Enals and Alkynes Catalytic Enantiomeric Intermolecular Coupling TMS i(acac) 2 (5 mol%) + *(10 mol%) Zn, TMSCl n n n < triglyme entry n alkyne product yield, % ee, % * t-bu 1 1 Et Et Et Et 2 2 Et Et Et Et 3 1 Si 3 Si 3 60 (100%regioselectivity) 63 Ikeda, S. I.; Cui, D. M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712.

24 Intermolecular Coupling of Enones or Enals and Alkynes Cyclic Cotrimerization TMS, Proposed mechanism i(0) (10mol%) TMSCl (M) + i(acac) 2 (5 mol%) P 3 (10 mol%) 3 Al/, egioselectivity is highly substrate dependent. i Al i Al A i trimerization product i C 1. Ikeda, S. I.; Mori,.; Sato, Y. J. Am. Chem. Soc. 1997, 119, Ikeda, S. I. Acc. Chem. es. 2000, 33, 511. B

25 Intermolecular Coupling of Enones or Enals and Alkynes Control of egioselectivity in Trimerization with the Same Alkyne n + 2 equiv. 1)i(acac) 2 (10 mol%) / 3 Al/ 2)DBU, in air + + n n n a b c entry ligand n yield, % (a + b) ratio (a : b) 1 P 3 2 Bu 83 92:8 A 2 A 2 Bu :0 3 P 3 1 TMS 33 0:100 4 A 1 TMS 69 96:4 5 P 3 1 t-bu 45 11:89 6 A 1 t-bu :0 1. Mori,.; Ikeda, S. I.; Sato, Y. J. Am. Chem. Soc. 1999, 121, Ikeda, S. I.; Kondo,.; Mori,. Chem. Commun. 2000, 815.

26 Intermolecular Coupling of Enones or Enals and Alkynes Control of Enantioselectivity in Trimerization with the Same Alkyne X + i(acac) 2 (5 mol%) * (10 mol%) 3 Al/ (40 mol%) TF, rt X A higher yield lower ee or B lower yield higher ee entry X ligand product yield, % ee, % 1 A C 2 n-bu Bu 2 B egioselectivity > 95:5 in every example. Ikeda, S. I.; Kondo,.; Arii, T.; dashima, K. Chem. Commun. 2002, A C 2 t-bu 4 B t Bu A C 2 t-bu 6 B t Bu Bu t Bu t Bu

27 Intermolecular Coupling of Enones or Enals and Alkynes Summary of Intermolecular Coupling i i(0) *,TMSCl, Zn i 3 Al/, * trimerization

28 Coupling of Aldehydes and Alkynes intramolecular i(0), (M) + 3 intermolecular n 3

29 Coupling of Aldehydes and Alkynes Introduction to The Coupling of Aldehydes and Alkynes i i (M) A i i? (M) B Tsuda, T.; Kiyoi, T.; Saegusa, T. J. rg. Chem. 1990, 35, 2554.

30 Coupling of Aldehydes and Alkynes Catalytic eductive Coupling of Aldehydes 3 < 2 equiv. + i(cd) 2 (10 mol%) Bu 3 P (20 mol%) Et 3 B (200 mol%) toluene, rt 3 entry 3 product yield, %(regioselectivity) 1 n-ex ex 76% (96:4) 2 o-tolyl 83% (93:7) 3 n-pr Pr 85% (92:8) 4 n-ept Si 3 ept 89% (>98:2) Si 3 uang, W. S.; Chan, J.; Jamison, T. F. rg. ett. 2000, 2, 4221.

31 Coupling of Aldehydes and Alkynes Proposed chanism 3 + n i(0) large substituent i 3 small substituent (or tether chain) 3 i 4 (M) (transmetallation) n i (M) 3 1 D = PBu 3 β- elimination n i 4 (M) 3 1 C = TF 4 3 reductive coupling 3 alkylative coupling blinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065.

32 Coupling of Aldehydes and Alkynes Catalytic Asymmetric Coupling of Aliphatic Alkynes + 3 < 2 equiv. i(cd) 2 (10 mol%) * (10 mol%) Et 3 B (200 mol%) EtAc, rt 3 a + 3 b Fe P A entry ligand 3 product yield,% (a : b) ee, a (%) ee, b (%) 1 A i-pr Cy 65 (2.2:1) A n-pr Cy 30 (2.2:1) A n-pr n-pr /A Proposed mechanism i-pr Cy i BEt 3 P Fe Cy P i 3 β- elimn. i-pr BEt 3 Cy P 3 i BEt 2 i-pr reductive elimn. Cy i-pr Colby, E. A.; Jamison, T. F. J. rg. Chem. 2003, 68, 156.

33 Coupling of Aldehydes and Alkynes Catalytic Asymmetric Coupling of Aromatic Alkynes + 3 < 2 equiv. i(cd) 2 (10 mol%) * (20 mol%) Et 3 B (200 mol%) EtAc:DMI(1:1) 3 a + 3 b P 2 (+)-MDPP entry 3 alkyne yield,%(a : b) ee of a (%) 1 i-pr 95 (>95:5) 90 2 i-pr C 2 Boc 60 (>95:5) 96 DMI 3 n-pr 4 82 (>95:5) (91:9) 73 5 i-pr Miller, K. M.; uang, W. S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.

34 Coupling of Aldehydes and Alkynes Proposed Model for Enantio- and egioselectivity sterically disfavored, electronically favored sterically and electronically disfavored i P i P sterically favored electronically disfavored A i P B i P sterically and electronically favored C D D P 3 i Et 3 B major 1. Miller, K. M.; uang, W. S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, Whittall, I..; umphrey, M. G.; Samoc, M.; uther-davies, B.; ockless, D. C.. J. rganomet. Chem. 1997, 544, 189.

35 Coupling of Aldehydes and Alkynes Total Synthesis of (-)-Terpestacin + 3 Si Co(C) 3 TIPS I Si 3 Co(C) 3 1 P Ac 2 2 TBS 1 Fe ()-A i(cd) 2 (10 mol%) ()-A (10 mol%), Et 3 B 70% combined (dr 3:1; regio: 2:1) TBS 3 Si 2 (-)- Terpestacin Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,

36 Coupling of Aldehydes and Alkynes Total Synthesis of (+)-Allopumiliotoxin 339A SEM + Br Bn i(cd) 2 (10 mol%) PBu 3, Et 3 Si, TF 93% (+)-Allopumiliotoxin-339A Bn TES Tang, X.Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950.

37 Coupling of Aldehydes and Alkynes Two-Step Four-Component Coupling i(acac) 2 ( mol%) DIBA- TMSCl Bu 3 Sn 3 via 4 i(cd) 2 / ( mol%) Zn or 3 B via i i entry 3 % yield of 1 % yield of 2 (dr) 1 n-hexyl (Et 3 B) PBu ( 2 Zn) none 63 74(2.7:1) 3 ( 2 Zn) none 67 80(5.3:1) ozanov, M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124, 2106.

38 Coupling of Aldehydes and Alkynes Summary of Coupling eaction Between Aldehydes and Alkynes i i(0) inter/ intramolecular i reductive coupling *, 3 B alkylative coupling Zn 2 or B 3

39 Coupling of ther Electrophile Equivalents and Alkynes ther Electrophile Equivalents i(0), (M) 3 i 2 (M) C i 4 i i C (M) (M) (M)

40 Coupling of ther Electrophile Equivalents and Alkynes Coupling of Alkynes and C 2 + C 2 1)1 equiv. i(cd) 2 2 equiv. DBU 2) 2Zn or ZnX C 2 53 ~ 81% yield C 2 =, Bz, Bu,, alkylative product; = Et, major product is reductive coupling product. An efficient way to prepare β,β -disubstituted α,β-unsaturated acid under mild conditions. Proposed mechanism + C 2 i(0) i C i A -ZnX i Zn X C ZnX i B ZnX Takimoto, M.; Shimizu, K.; Mori, M. rg. ett. 2001, 3, 3345.

41 Coupling of ther Electrophile Equivalents and Alkynes Total Synthesis of Erythrocarine Boc Boc C Br Si 3 1)C 2, 1.1equiv. i(cd) equiv. DBU, 0 o C TMS2)C 2 2 ZnCl 69%(2 steps) TMS C 2 ( +_ )-Erythrocarine Ac Shimizu, K.; Takimoto, M. Mori, M. rg. ett. 2003, 5, 2323.

42 Coupling of ther Electrophile Equivalents and Alkynes Imine as Electrophile Equivalent i(cd) 2 (5 mol%) Cyp 3 P (5 mol%) Et 3 B (300 mol%) Ac/ Et 3 a b 4 entry product yield (%) a : b regioselectivity Et 1 o-tol Et 2 (p-cf 3 )C :6 90: :4 89:11 Et 3 C :6 91:9 Et 4 npr npr Et Bu 5 npr c-c 6 11 npr 91 94:6-52 >96:4-1. Patel, S. J.; Jamison, T. F. Angew.Chem. Int. Ed. 2003, 42, Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymm. 2003, 14, 3619.

43 Coupling of ther Electrophile Equivalents and Alkynes Imine as Electrophile Equivalent Proposed mechanism + Ar i(cd) 2 (5 mol%) (+)-MDPP (20 mol%) Et 3 B (300 mol%) Ac/ P 2 (+)-MDPP Et a Ar + b Ar ee of a ee of b p-clc P-CF 3 C Ar Et a BEt 2 Ar 2 a and b were isolated in identical ee. 1. Patel, S. J.; Jamison, T. F. Angew.Chem. Int. Ed. 2003, 42, Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymm. 2003, 14, i P 3 3 P Et i BEt2 reductive elimination Ar + Ar Et 3 B i P 3 Ar BEt 2 1 Ar P 3 i BEt2 β- elimination b P 3 i BEt2 BEt 2 Ar reductive elimination Ar

44 Coupling of ther Electrophile Equivalents and Alkynes Epoxide as Electrophile Equivalent i(cd) 2 (10 mol%) Bu 3 3 P (20 mol%) + 3 Et 3 B (200 mol%) < up to 71% yield, 3 = aryl, alkyl > 95:5 regioselectivity = alkyl > 99% ee Proposed mechanism + 3 n i-p 3 3 P i A 3 P 3 i B 3 Et 3 B i P 3 Et i P 3 BEt 2 BEt Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076.

45 Multicomponent Coupling of Alkynes Summary 3 n n intra 3 inter 3 i(0), (M) + 3 intra inter * 3 C 2 C 2 *

46 Multicomponent Coupling of Alkynes ecent Applications in Total Synthesis ( +_ )-Isogeissoschizoid Skeleton 2 C 2 C i 3 i 3 2 C Isodomoic acid G X i (-)-Terpestacin (+)-Allopumiliotoxin-339A ( +_ )-Erythrocarine

47 Multicomponent Coupling of Alkynes Future Development Alkylative coupling of aldehyde 3 4 i(0), 4 (M) 3 (More complicated 4 ) Coupling of ketone for the generation of tetra-substituted alkene & tertiary allylic alcohol i(0), 5 (M) 3 4

48 Multicomponent Coupling of Alkynes Future Development Tandem coupling-aldol condensation TMS n Mukaiyama aldol n Control of absolute stereochemistry * or E 2 i(0) i(0), 3 (M) chiral * [2+2+2] [3+2] 3 ()

49 Acknowledgement Professor William Wulff Professor Jetze Tepe Wulff Group mbers: Friends: Jie Mannish Chunrui Zhensheng Gang Keith Kostas Yu Victor Glenn Vijay ewman eddy Alex Feng Yana Jun Tao Chang ingling Xiaoyu ei Jason

Catalytic Reductive Coupling Reactions. Erin Vogel Michigan State University 3:00 p.m. 28 September 2005

Catalytic Reductive Coupling Reactions. Erin Vogel Michigan State University 3:00 p.m. 28 September 2005 Catalytic eductive Coupling eactions rin Vogel Michigan State University 3:00 p.m. 28 September 2005 eductive ydrogenation 3P h P3 P3 Wilkinson s Complex 3P P3 h P3 2 P3 P3 h P3 P3 3P h P3 fast P3 h 3P