Dual Role of Silanol Groups in Cyclopropanation and Hiyama-Denmark Cross-Coupling Reactions L.-P. B. Beaulieu, L. B. Delvos, A. B. Charette* Département de Chimie, Université de Montréal, P.O. Box. 6138, Station Downtown Montréal, Québec, Canada H3C 3J7 Org. Lett. 2010, 12 (6), 1348-1351.
The cyclopropane unit: - Present in several bioactive natural products as well as synthetic drugs. - The Simmons-Smith reaction is one of the most important preparative method. The Hiyama-Denmark cross-coupling reaction: - Pd-catalysed cross-coupling reaction involving organosilicon compounds. - Probably not the most famous cross-coupling reaction, but good alternative to Stille or Suzuki-Miyaura methods. 2
Introduction To couple both reaction by using Di-tert-butoxy(alkenyl)silanols as substrates: The silanol group will bear two distinct roles: - Directing group during the cyclopropanation. - Mediator for the transmetalation event during the cross-coupling. 3
Discovered in 1958. The original Simmons-Smith cyclopropanation involves CH 2 I 2 and Zn-Cu couple. Allows cyclopropanation of a wide range of alkenes: simple alkenes, α,β-unsaturated ketones and aldehydes, electron rich alkenes (enol ethers, enamines, etc.). - Stereospecific (stereochemical information in the alkene substrates translated to the products). - Highly diastereoselective (occurs from the less hindered face on chiral substrates). - Strongly directed by functional groups containing heteroatoms (OH, OAc, OMe, NHR, ) with delivery of the alkylidene from the face of the double bond having the closest proximity with the FG. - Tolerant with many sensitive functional groups. - Non-coordinating solvents used (DCM, DCE). Poceeding through a «butterfly-type» transition structure: H. Lebel, J-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977-1050. 4
The Simmons-Smith cyclopropanation Zinc carbenoids: - Furukawa (1966): Et 2 Zn + CH 2 I 2 in DCM or DCE. Schlenk-type equilibria: Et 2 Zn + CH 2 I 2 EtZnCH 2 I + EtI EtZnCH 2 I + CH 2 I 2 Zn(CH 2 I) 2 + EtI 2 ICH 2 ZnI Zn(CH 2 I) 2 -ZnI 2 - Iodomethylzinc trifluoroacetate: CF 3 CO 2 ZnCH 2 I (more reactive than Furukawa s one towards unfunctionalised olefins). - Iodomethylzinc phenoxides: 2,4,6-Cl 3 C 6 H 2 OZnCH 2 I (more reactive as well). Other carbenoids: - Molander (1987): Sm(Hg) + CH 2 I 2 (chemoselective cyclopropanation of allylic alcohols in presence of other olefins). - Yamamoto (1985): i-bu 3 Al + CH 2 I 2 (cyclopropanation of unfunctionalised olefins in presence of allylic alcohols). H. Lebel, J-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977-1050. 5
The Simmons-Smith cyclopropanation Cyclopropanation of allylic alcohols: Occurs via an oxygen group-assisted delivery of the reagent from a conformation in which minimisation of the A (1,3) strain is the predominant controlling element. Furukawa s conditions: unfavorable nonbonded interactions arising from the bulky zinc alkoxide substituent in B, C and D. H. Lebel, J-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977-1050. 6
The Simmons-Smith cyclopropanation Only few examples in the literature. Reaction also enhanced by the presence of the hydroxy group on the silicon: K. Hirabayashi, A. Mori, T. Hiyama, Tetrahedron Lett. 1997, 38 (3), 461-464. Chiral alkenylsilanols: chirality of the silicon efficiently transferred to the alkenyl carbons diastereoselective cyclopropanation (Y. Yamamura, F. Toriyama, T. Kondo, A. Mori, Tetrahedron: Asymmetry 2002, 13, 13-15). 7
Originally (1988): Pd-catalysed cross-coupling involving organosilicons with organic halides (or triflates) in presence of an activating agent as fluoride or hydroxide (Hiyama cross-coupling reaction). Highly chemo-, stereo- and regioselective reaction, compatible with a wide range of sensitive groups. C-Si bond much less polarised than C-Metal bond (M = Li, B, Al, Zn, Sn, Mg ) need of an activating agent to promote the transmetalation (rate-determining step) by generating a pentacoordinated silicate and then increasing the nucleophilicity of the organic group linked to the silicon. First examples: Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 920-923 - Tris(diethylamino)sulfonium difluorotrimethylsilicate (TASF) better than TBAF, CsF or KF. - HMPA (with aryl halides) or THF + P(OEt) 3 (with vinyl halides). T. Hiyama, Y. Hatanaka, Pure & Appl. Chem. 1994, 66 (7), 1471-1478. 8
The Hiyama-Denmark cross-coupling reaction R 3 Si-R used with R = F or OAlk to increase the reaction rate. 9
The Hiyama-Denmark cross-coupling reaction Cross-coupling of alkenyl fluorosilanes: - Complexation of the halogen of Pd to Si of the unsaturated silicate to give coordinately saturated silicate. - C-Pd bond formation producing β-cationic silicate. - Then path a: transmetalation favored by R 1 and/or R 2 cation-stabilising groups and negatively charged hexacoordinated silicate group (enhanced β-effect). Then reductive elimination to give the ipso-substitution. - Path b: 1,3-migration of R from Pd to β-carbon favored when nucleophilicity of R enhanced by EDG-substituent. Then β-h-elimination, hydropalladation and elimination to give the cine-substitution. T. Hiyama, Y. Hatanaka, Pure & Appl. Chem. 1994, 66 (7), 1471-1478. 10
The Hiyama-Denmark cross-coupling reaction Biaryls and diaryl ketones synthesis: Trimethylsilylation: Cross-coupling with triflates: T. Hiyama, Y. Hatanaka, Pure & Appl. Chem. 1994, 66 (7), 1471-1478. 11
The Hiyama-Denmark cross-coupling reaction Alkenylsilanols can also be used: offer many advantages - Easily available. - Stable and easy to handle. - Easy modulation of the substituents on the silicon. S. E. Denmark, R. F. Sweis, Acc. Chem. Res. 2002, 35, 835-846. S. E. Denmark, D. Wehrli, Org. Lett. 2000, 2 (4), 565-568. 12
The Hiyama-Denmark cross-coupling reaction 2001: fluoride-free cross-coupling of organosilanols to overcome the incompatibility of some functional groups with fluoride (Si-protecting groups for instance). Economical motivation to replace TBAF by another cheaper cross-coupling promoter (TBAF. 3H 2 O: 734 CHF/mol Aldrich). First mechanistic proposal: Based on the Hiyama mechanism: generation of the pentacoordinated silicon by attachement of a second molecule of silyloxide i (prerequisite for transmetalation). S. E. Denmark, R. F. Sweis, J. Am. Chem. Soc. 2001, 123, 6439-6440. 13
The Hiyama-Denmark cross-coupling reaction S. E. Denmark, R. F. Sweis, J. Am. Chem. Soc. 2001, 123, 6439-6440. 14
The Hiyama-Denmark cross-coupling reaction Mechanistic investigations through a full kinetic analysis provide revision of the first mechanistic proposal: Does not involve any pentacoordinated siliconate, unlike other nucleophilic-activated organosilicon crosscoupling reactions. Reaction is first-order in silanolate and Si-O-Pd linkage has here a critical importance for the transmetalation. Intermediate isolated and heated up to 100 C to provide the biaryl product in quantitative yield. neutral arylpalladium (II) silanolate complex can undergo direct transmetalation! S. E. Denmark, R. F. Sweis, J. Am. Chem. Soc. 2004, 126, 4876-4882. S. E. Denmark, J. Org. Chem. 2009, 74, 2915-2927. 15
The Hiyama-Denmark cross-coupling reaction Hiyama (1995) Denmark (2005) S. E. Denmark, J. H.-C. Liu, Angew. Chem. Int. Ed. Early View, March 24, 2010 DOI: 10.1002/anie.200905657 Denmark (2009) 16
First try: cross-coupling of a cyclopropylsilanol with bromobenzene using Hiyama s conditions. Modulation of the nature of the substituents on the silicon: introduction of more electron-withdrawing substituents (alkoxide groups, -I effect) to enhance the stabilisation of the pentacoordinated siliconate intermediate formed with TBAF and then facilitate the transmetalation. Preparation of Di-tert-butoxy(alkenyl)silanols: 17
Charette et al. results 18
Charette et al. results First attempt with (±)-Di-tert-butoxy((1S,2R)-2-phenylcyclopropyl)silanol: Insufficient reactivity of the organosilane in the cross-coupling solved by generating the trifluorosilane in situ: 19
Charette et al. results 20
Charette et al. results First cyclopropylsilanes to be reacted in the Hiyama-Denmark cross-coupling. Nature of the substituents on the silicon atom has a profound effect on reactivity in the cross-coupling. Dual role of the silanol: directing group during the cyclopropanation and mediator for the coupling transmetalation. Next steps: Development of fluoride-free conditions. Development of asymmetric cyclopropanation conditions. 21