Highly chemoselective and stereoselective synthesis of Z-enol silanes

Article abstract of DOI:10.1021/ja802844v

Three-component nickel-catalyzed couplings of enals, alkynes, and silanes have been developed as a new entry to enol silanes. The enol silane and a trisubstituted alkene are both formed with >98:2 stereoselectivity, and the reaction tolerates a broad range of functionality including aldehydes, ketones, esters, free hydroxyls, and basic secondary amines. A mechanistic pathway involving the formation of a metallacycle that possesses an η¹ nickel O-enolate motif explains the high level of stereoselection. Copyright

Full text of DOI:10.1021/ja802844v

Published on Web 06/07/2008
Highly Chemoselective and Stereoselective Synthesis of Z-Enol Silanes
Ananda Herath and John Montgomery*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received April 17, 2008; E-mail: jmontg@umich.edu
Table 1. Range of Silanes Tolerated in Enol Silane Generation
Enol silanes are broadly useful in a range of synthetic transforma-
tions including Mukaiyama aldol reactions, Mannich reactions, and
metalation to more reactive enolates for subsequent alkylation.1 The
ability to selectively prepare a single alkene stereoisomer renders enol
silanes especially valuable in stereospecific transformations. Whereas
enolization/silylation sequences of ketones, esters, and amides are well-
developed, the corresponding transformations involving aldehydes are
limited due to the well-recognized problem of self-condensation
competing with enolization. However, powerful strategies for aldol
reactions of aldehyde-derived enol silanes have recently emerged,1 thus
suggesting that novel preparative entries to the requisite starting
materials could greatly expand the range of possible applications.
entry
R3SiH
yield (ratio)a
1
2
3
4
Et3SiH
t-BuMe2SiH
Ph3SiH
91% (>98:2)
85% (>98:2)
88% (>98:2)
81% (>98:2)b
PhMe2SiH
a A ratio of >98:2 indicates that no other stereo- or regioisomer was
detected at a level greater than 2%. b The aldehyde derived from enol
silane hydrolysis was obtained as the product of this reaction.
The direct enolization of aldehydes is typically accomplished by
the combination of silyl triflates with amine bases.1 Whereas at least
modestly Z-selective reactions are typically observed, obtaining high
selectivity is often challenging. Enone conjugate additions are well-
known to be accelerated by silyl chlorides.2 Similarly, enal conjugate
addition/electrophilic silylation sequences are sometimes successful,
and these procedures uniformly generate E-enol silanes.3 A feature of
each of the above-mentioned strategies for enol silane generation is
that electrophilic silylation is involved, and site-selective enol silane
installation following these methods is unknown in the presence of
reactive groups that would undergo silylation or silyl-mediated
chemical transformations. The alkylation of allyloxy carbanions
provides an alternate strategy for Z-enol silane synthesis;4 however,
strongly basic conditions are required that would also render poor
compatibility with reactive functional groups. The Ru-catalyzed
coupling of alkynes with allyloxysilanes does provide excellent
functional group compatibility, and E-enol silanes are selectively
produced by this method.5 Herein, we describe a new method for enol
silane installation via the nickel-catalyzed three-component coupling
of enals, alkynes, and silanes that is completely Z-selective, tolerant
of a broad range of reactive functional groups including free alcohols,
aldehydes, ketones, and secondary amines, and efficient with a good
range of synthetically versatile silane structures. Additional, the
exceptional Z-selectivity of enol silane installation provides compelling
evidence for the involvement of nickel η1 O-enolates in catalytic
reactions of R,ꢀ-unsaturated carbonyls.
Previous work in our laboratory has demonstrated that a variety of
reaction manifolds are accessible in nickel-catalyzed additions of
enones or enals with alkynes, including reductive coupling, reductive
cycloaddition, and coupling via redox isomerization.6 Silane reducing
agents have not been utilized in any of these classes of reactions;
however, we recognized that participation of silanes would potentially
allow production of highly functionalized enol silanes that would be
useful in the broad classes of reactions described above. Additionally,
the functional group tolerance of other silane-based reductive couplings
developed in our laboratory and elsewhere suggests that the generation
of enol silanes by a nickel-catalyzed reductive process involving silanes
would allow installation of a broad array of functionality.6a
coupling of enals (1.0 equiv), alkynes (1.5 equiv), and silanes (2.0
equiv) is broadly efficient with a catalyst derived from Ni(COD)2 (10
mol %) and PCy3 (20 mol %) in THF. Under these conditions, Z-enol
silanes are exclusively produced with >98:2 stereoselectivity, and the
trisubstituted alkene is installed with similarly exceptional stereose-
lectivity. Our initial studies focused on evaluating the scope of silanes
that efficiently participate in couplings of E-hex-2-enal with phenyl
propyne (Table 1). Indeed, most silanes examined were efficient
participants with this combination of substrates. Couplings with
triethylsilane, tert-butyldimethylsilane, and triphenylsilane proceeded
smoothly to afford the Z-enol silanes in high chemical yield and >98:2
Z-selectivity (Table 1, entries 1-3). Whereas these products were
completely stable in standard silica gel chromatographic separations,
the product of coupling with dimethylphenylsilane was unstable to
purification, and the corresponding aldehyde was directly obtained via
chromatographic purification (Table 1, entry 4). This particular silane
is therefore most convenient when the aldehyde is directly desired.
Unfortunately, couplings with trichlorosilane and tris(trimethylsilyl-
)silane, which are particularly useful in Mukaiyama aldol reactions,1
were unsuccessful due to catalyst decomposition with the former and
sluggish reactivity with the latter.
Upon establishing the range of silanes that efficiently participates
in this process, we next examined the scope of enal and alkyne
structures that may be utilized (Table 2). In addition to the aromatic
alkyne depicted (Table 1), a nonaromatic internal alkyne and a terminal
alkyne also effectively participated (Table 2, entries 1 and 2).
Crotonaldehyde and cinnamaldehyde were efficient participants with
a range of silanes (Table 2, entries 2-5), whereas acrolein underwent
efficient couplings only with triphenylsilane (Table 2, entries 6 and
7). As noted above, coupling with dimethylphenylsilane led to enol
silane hydrolysis upon purification (Table 2, entry 5). With the aim of
illustrating chemoselectivity that would not be possible with most other
methods for enol silane generation (Scheme 1), we examined a number
of functionalized alkynes in couplings with E-hex-2-enal, and excep-
tional functional group tolerance was observed. For example, the
reaction cleanly tolerates the ester functionality of ynoates (Table 2,
entry 8), free hydroxyls (Table 2, entries 9 and 10), isolated ketones
(Table 2, entry 11), isolated aldehydes (Table 2, entry 12), and basic
secondary amines (Table 2, entry 13). This combination of substrates
illustrates a range of Z-enol silanes that are likely inaccessible by any
Considering the potential impact of such a procedure based on the
above considerations, we screened a variety of substrates, ligands,
silanes, and reaction conditions and found that the three-component
9
8132 J. AM. CHEM. SOC. 2008, 130, 8132–8133
10.1021/ja802844v CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope and Functional Group Tolerance of Enol Silane
nickel enolates. On this basis, we propose that the transformation
described herein proceeds via this precise hapticity and structure of
the metallacycle as evidenced by the exclusive Z-selectivity of the
process. If a C-bound enolate, η3-enolate, or oxyallyl species were
involved,8 then the E-isomer of the enol silane product would be
expected. For example, the Mackenzie and Marshall methods involving
conjugate additions to enals and the Jamison method involving alkene
additions to enals each produce E-enol silanes via electrophilic
silylation.3 Therefore, a catalytic cycle for the method disclosed herein
can rationally be proposed that involves oxidative cyclization of the
enal and alkyne to afford metallacycle 2 with the η1, O-enolate
structural motif. The silane may promote the rate of this process,9 but
it does not impede formation of the nickel-oxygen bond as evidenced
by the stereochemical considerations noted above. σ-Bond metathesis
of the nickel-oxygen bond and the silane would afford intermediate
3, followed by C-H reductive elimination to afford the observed
product 1. Whereas metallacycle 2 with an η1 O-enolate motif was
previously proposed in numerous reactions and rigorously character-
ized,7 the acquisition of the Z-enol silane products in this study provides
the first evidence of its true involvement in a catalytic process rather
than simply being a nonproductive catalyst resting state.
Generationa
In summary, the first method of enol silane synthesis via reductive
coupling of enals and alkynes has been demonstrated. Noteworthy
features of the process include exceptional Z-selectivity and functional
group tolerance and applicability to a broad range of silane substitution
patterns. The catalytic involvement of metallacyclic intermediates that
possess an η1 O-enolate motif provides a clear rationale for the reaction
stereoselectivity. We anticipate that this novel entry to functionalized
enol silanes will facilitate advances with emerging technologies in
Mukaiyama aldol reactions.
Acknowledgment. The authors wish to acknowledge receipt
of NSF Grant CHE-0718250 in support of this work.
Supporting Information Available: Full experimental details and
copies of NMR spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Mukaiyama, T. In Organic Reactions; Wiley, New York, 1982; Vol 28,
p 203. (b) Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40,
4759. (c) Denmark, S. E.; Bui, T. J. Org. Chem. 2005, 70, 10190. (d) Boxer,
M. B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48. (e) Boxer, M. B.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 2762. (f) For an organocatalytic
strategy that avoids enol silane synthesis, see: Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (g) For an enal reductive
aldolization strategy, see: Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691.
(2) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368. (b)
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019.
(3) (a) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F. Angew. Chem., Int. Ed. 2008, 47,
1893. (b) Johnson, J. R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M. J. Am.
Chem. Soc. 1991, 113, 6172. (c) Grisso, B. A.; Johnson, J. R.; Mackenzie,
P. B. J. Am. Chem. Soc. 1992, 114, 5160. (d) Marshall, J. A.; Herold, M.;
Eidam, H. S.; Eidam, P. Org. Lett. 2006, 8, 5505. (e) Ikeda, S.-i.; Sato, Y.
J. Am. Chem. Soc. 1994, 116, 5975. (f) Ikeda, S.-i.; Yamamoto, H.; Kondo,
K.; Sato, Y. Organometallics 1995, 14, 5015.
a A ratio of >98:2 indicates that no other stereo- or regioisomer was
detected at a level greater than 2%. b Isomer ratio refers the regiochemistry
of alkyne insertion. c Me2PhSiH was used as reducing agent. d Isomer ratio
refers to relative stereochemistry of the two stereocenters.
Scheme 1. Mechanism of Enol Silane Generation
(4) Still, W. C.; Macdonald, T. L. J. Am. Chem. Soc. 1974, 96, 5561.
(5) Trost, B. M.; Surivet, J. P.; Toste, F. D. J. Am. Chem. Soc. 2001, 123, 2897.
(6) (a) Review: Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (b)
Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099. (c)
Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997,
119, 4911. (d) Herath, A.; Montgomery, J. J. Am. Chem. Soc. 2006, 128,
14030. (e) Herath, A.; Thompson, B. B.; Montgomery, J. J. Am. Chem. Soc.
2007, 129, 8712. (f) Herath, A.; Li, W.; Montgomery, J. J. Am. Chem. Soc.
2008, 130, 469. (g) Related work: Chang, H.-T.; Jayanth, T. T.; Wang, C.-
C.; Cheng, C.-H. J. Am. Chem. Soc. 2007, 129, 12032.
(7) (a) Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J.
J. Am. Chem. Soc. 2000, 122, 6775. (b) Mahandru, G. M.; Skauge, A. R. L.;
Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am.
Chem. Soc. 2003, 125, 13481. (c) Amarasinghe, K. K. D.; Chowdhury, S. K.;
Heeg, M. J.; Montgomery, J. Organometallics 2001, 20, 370. (d) Hratchian,
H.; Chowdhury, S. K.; Gutie´rrez-Garc´ıa, V. M.; Amarasinghe, K. K. D.; Heeg,
M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23, 4636.
(8) (a) Ca´mpora, J.; Maya, C. M.; Palma, P.; Carmona, E.; Gutie´rrez, E.; Ruiz,
C.; Graiff, C.; Tiripicchio, A. Chem.—Eur. J. 2005, 11, 6889. (b) Ogoshi,
S.; Nagata, M.; Kurosawa, H. J. Am. Chem. Soc. 2006, 128, 5350.
(9) Ogoshi, S.; Oka, M.-a.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11802.
other method and complements the powerful Trost procedure that is
E-selective.5 The tolerance of simple aldehydes is particularly note-
worthy since this suggests that substrates such as that produced in entry
12 would be useful candidates for subsequent Lewis base or Lewis
acid promoted intramolecular aldol additions.
In other classes of nickel-catalyzed couplings of enals and alkynes,
we proposed that seven-membered oxametallacyclic species were key
intermediates, and two examples of such species were fully character-
ized by X-ray crystallographic and NMR analysis.7 Those structural
studies clearly identified the η1, O-bound nature of the metallacyclic
JA802844V
9
J. AM. CHEM. SOC. VOL. 130, NO. 26, 2008 8133