Vicinal functionalization of propiolate esters via catalytic carbocupration: Stereoselective formation of substituted vinyl silanes

Article abstract of DOI:10.1021/ol100854j

(Figure presented) The vicinal functionalization of propiolate esters via a catalytic carbocupration-silicon group migration sequence has been investigated. We have observed that catalyst loadings as low as 5 mol % allow for good yields and excellent diastereoselectivities (>20:1) with a series of Grignard reagents for the synthesis of substituted E-vinyl silanes.

Full text of DOI:10.1021/ol100854j

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2750-2753
Vicinal Functionalization of Propiolate
Esters via Catalytic Carbocupration:
Stereoselective Formation of Substituted
Vinyl Silanes
Amanda J. Mueller Hendrix and Michael P. Jennings*
Department of Chemistry, The UniVersity of Alabama,
Tuscaloosa, Alabama 35487-0336
jenningm@bama.ua.edu
Received April 14, 2010
ABSTRACT
The vicinal functionalization of propiolate esters via a catalytic carbocupration-silicon group migration sequence has been investigated. We
have observed that catalyst loadings as low as 5 mol % allow for good yields and excellent diastereoselectivities (>20:1) with a series of
Grignard reagents for the synthesis of substituted E-vinyl silanes.
The stereoselective synthesis of multifunctional alkenes
within a single reaction flask remains a challenging task to
organic chemists. While many methods currently exist, high
levels of diastereoselectivity still can be difficult to obtain.
Some of the more successful reaction processes include
olefination of complex aldehydes with Horner-Wadsworth-
Emmons (HWE) stabilized phosphonate esters, the Still-Gennari
modification of the HWE reaction, and the classical stabilized
Wittig ylide reagents to name a few.1 In addition, olefin
synthesis by means of transition metal catalysis has carved a
significant niche in the modern context of organic chemistry.
For example, there are numerous examples of Heck, Negishi,
Stille, and Suzuki couplings catalyzed by Pd, accompanied by
Mo, W, and Ru promoted olefin metatheses.2,3
A less utilized method for the synthesis of stereodefined
olefins centers on the partial reduction of propiolate esters
with cuprate complexes (i.e., Gilman or Kharash reagents).
Initially reported in 1969 by Corey and Katzenellenbogen,
the stoichiometric carbocupration of ethyl propiolate with a
variety of Gilman reagents and subsequent electrophiles
provided R,ꢀ-unsaturated esters with high levels of diaste-
reoselectivity.4 It was observed that reaction conditions (i.e.,
solvent and temperature) played a vital role in determining
the E/Z ratio of the final alkene products. Subsequent to this
report, there have been a multitude of investigations into the
stoichiometric carbocupration of propiolate esters.5 However,
one area that has garnered little attention is the catalytic
(4) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
1851.
(1) (a) Horner, L.; Hoffman, H.; Wippel, H. G. Chem. Ber. 1958, 91,
61. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733. (c) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (d)
For a review on stabilized Wittig reagents, see: Maryanoff, B. E.; Reitz,
A. B. Chem. ReV. 1989, 89, 863.
(5) (a) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750.
(b) Woodward, S. Chem. Soc. ReV. 2000, 29, 393. (c) Lipshutz, B. H.;
Sengupta, S. Org. React. 1992, 41, 135. (d) Nakamura, E.; Kuwajima, I.
J. Am. Chem. Soc. 1984, 106, 3368. (e) Nakamura, E.; Aoki, S.; Sekiya,
K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056. (f) Frantz,
D. E.; Singleton, D. A. J. Am. Chem. Soc. 2000, 122, 3288. (g) Nilsson,
K.; Andersson, T.; Ullenius, C. J. Organomet. Chem. 1997, 545-546, 591.
(h) Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N.
Chem.sEur. J. 1998, 4, 2051. (i) Klein, J.; Levene, R. J. Chem. Soc., Perkin
Trans. 2 1973, 1971. (j) Marino, J. P.; Linderman, R. J. J. Org. Chem.
1981, 46, 3696.
(2) Negishi, E.-I.; de Meijere, A., Eds. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley: New York, 2002; 2 Vols
.
(3) For a leading review on Mo and W metathesis, see: (a) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (b) For a
recent review on Ru metathesis, see: Vougioukalakis, G. C.; Grubbs, R. H.
Chem. ReV. 2010, 110, 1746
.
10.1021/ol100854j  2010 American Chemical Society
Published on Web 05/13/2010

carbocupration of such substrates utilizing Kharash reagents.
Recently, we have reported on the stereoselective synthesis
of both E and Z R,ꢀ-unsaturated esters via catalytic car-
bocupration of propiolate esters. The diastereoselectivity
diverges from a common TMS allenolate depending on
reaction conditions such as temperature and the proton source
used to quench the highly reactive intermediate.6 We also
recently expanded the scope of the TMS allenolate as a potent
nucleophile by demonstrating a vicinal functionalization of
propiolate esters via a tandem catalytic carbocupration-
Mukaiyama aldol reaction sequence.7 During this process,
we observed that excess TMSOTf did not promote the second
carbon-carbon bond formation as desired but instead
facilitated a tautomerization of the TMS allenolate to a
stereodefined R-TMS-R,ꢀ-unsaturated ester upon allowing
the reaction to warm to rt. Armed with this curious silyl
group migration and the synthetic potential of the formed
products, we chose to further investigate this reaction, and
our results are presented herein.8
chemistry was initially established by 1D NOE experiments
on the purified ester 2. The remaining mass balance was a
mixture of both E and Z R,ꢀ-unsaturated ester isomers
(arising from the proton quench of the intermediate TMS
allenolate). Increasing the amount of TMSOTf to 2.3 and
even further to 3.3 equiv furnished much greater yields (86%
and 92%) of vinyl silane 2, while maintaining the high level
of diastereoselectivity of >20:1 for the E isomer. Increasing
the catalyst loading to 10 and 20 mol % had limited effects
on the yield and stereoselectivity of 2 when using 3.3 equiv
of TMSOTf. A significant solvent effect was observed by
switching from THF to MTBE or Et2O as the yields of 2
significantly dropped from 92% down to 15% and 0%,
respectively. In addition, a slight change in yield for 2 was
observed when the initial carbocupration was performed at
a warmer temperature. Thus, initial carbocupration at -40
and -10 °C followed by warming to rt afforded yields of
85% and 80%, while maintaining comparable diastereose-
lectivities of 2 (>20:1 for the E isomer). Lastly, portionwise
addition of TMSOTf did have a slight effect on the overall
yield of 2 (see Table 1, examples 10 and 11) but did not
diminish the E-olefin selectivity.
As shown in Table 1, we initially examined the equiva-
lency of TMSOTf needed to perform the tautomerization
With standardized reaction conditions in hand from Table
1, we next investigated a variety of silanes with respect to
their catalytic activities and migratory aptitude. As delineated
in Table 2, all of the TMS halide Lewis acids (i.e., TMSCl,
Table 1. Vicinal Functionalization of 1a via a Catalytic
Carbocupration-Silicon Group Migration Sequence
Table 2. Vicinal Functionalization of 1a via a Catalytic
Carbocupration-Silicon Group Migration Sequence with
Various Silane Promoters
entry CuI·2LiCl mol % TMSOTf equiv solvent yield %a E/Zb
1
5
5
1.3
THF
THF
THF
THF
THF
Et2O
MTBE
THF
THF
THF
THF
43c
86
92
95
98
0
>20/1
>20/1
>20/1
>20/1
>20/1
---
2
2.3
3
5
3.3
4
10
20
5
3.3
5
3.3
6
3.3
7
5
3.3
15c
80
85
72c
90
>20/1
>20/1
>20/1
>20/1
>20/1
entry
CuI·2LiCl mol %
R3SiX
yield %a
E/Zb
8d
9e
10f
11g
5
3.3
5
3.3
1
2
3
4
5
6
7
5
5
5
5
5
5
5
TMSCl
TMSBr
TMSI
TESOTf
TESCl
TBSOTf
TBSCl
b
67c
80
89
88
32c
0
>20/1
>20/1
>20/1
>20/1
>20/1
N/A
5
1.3 then 1
1.3 then 2
5
a Purified, isolated yield of vinyl silane. E/Z ratio determined by H
NMR (360 or 500 MHz) from the crude reaction mixture. c Remaining mass
balance was the R,ꢀ-unsaturated ester from the proton quench of the TMS
allenolate. d Reaction ran at -10 °C. e Reaction ran at -40 °C. f Reaction
ran with 1.3 equiv of TMSOTf followed by addition of 1 equiv before
warming to rt. g Reaction ran with 1.3 equiv of TMSOTf followed by
addition of 2 equiv before warming to rt.
b
1
0
N/A
a Purified, isolated yield of vinyl silane. E/Z ratio determined by H
NMR (360 or 500 MHz) from the crude reaction mixture. c Remaining mass
balance was the R,ꢀ-unsaturated ester from the proton quench of the TMS
allenolate or decomposed material.
1
from the TMS allenolate to the R-TMS-R,ꢀ-unsaturated ester
(2).
Br, I) exhibited high levels of activity with yields ranging
from 67 to 89% using 3.3 equiv for either the desired vinyl
silane 2 and/or the side-product R,ꢀ-unsaturated ester.
Interestingly, it appeared that TMS migration via tautomer-
ization is dependent on Lewis acidity. For example, TMSCl-
mediated carbocupration of 1a provided only a 67% yield
for vinyl silane 2, whereas TMSBr and TMSI afforded
greater yields of 80 and 89% for 2, presumably via the
identical TMS allenolate intermediate. Keeping in mind that
Thus, under our standard catalytic carbocupration reaction
conditions as previously described for ethyl propiolate (1a)
and PhMgBr, 1.3 equiv of TMSOTf provided only a 43%
yield of the desired vinyl silane 2 with a d.r. of >20:1 for
the E isomer upon warming the reaction to rt. The stereo-
(6) (a) Mueller, A. J.; Jennings, M. P. Org. Lett. 2007, 9, 5327. (b)
Jennings, M. P.; Sawant, K. B. Eur. J. Org. Chem. 2004, 3201.
(7) Mueller, A. J.; Jennings, M. P. Org. Lett. 2008, 10, 1649.
(8) Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 4799.
Org. Lett., Vol. 12, No. 12, 2010
2751

TMSOTf furnished compound 2 in 92% yield, there appears
to be a direct correlation between the Lewis acidity of the
silane promoter and tautomerization of the TMS allenolate.
It should be noted that all three TMS halides (and TMSOTf)
provided selectively the E isomer of vinyl silane 2 with a
>20:1 ratio. Similarly, catalytic carbocupration utilizing either
TESCl or TESOTf as the additive proceeded fairly smoothly
to consume 1a but provided mixed results with respect to
the TES group migration from the allenolate to the vinyl
silane. The yields of the R-TES-R,ꢀ-unsaturated ester 3
varied from 32% with TESCl to 88% with TESOTf with
very high levels of diastereoselectivity (>20:1) for the E
isomer. Once again, it appeared that Lewis acidity played
an important and key role in tautomerizing the TES allenolate
to vinyl silane 3. Lastly, we examined TBSCl and OTf as
carbocupration-isomerization additives but observed no forma-
tion of either the desired vinyl silane or even the R,ꢀ-unsaturated
ester, although all of the starting material 1a was consumed. It
is our belief that both TBS additives do not promote even the
initial catalytic carbocupration, and the excess Grignard reagent
simply helped to decompose ester 1a.
chemistry. Thus, compounds 2-9 are simply an olefin reduction
and deprotonation away from a series of stabilized Peterson
reagents, and silanes 6 and 9 could serve as precursors for
higher-order nucleophilic allyl silanes.10,11
With the information of Tables 1-3 in hand, we decided
to examine two more substrates as shown in Scheme 1. As
Table 3. Vicinal Functionalization of 1a via a Catalytic
Carbocupration-Silicon Group Migration Sequence with
Various Grignard Reagents and TMSOTfa b
,
With the scope somewhat defined by the silane additives
for the catalytic carbocupration-tautomerization sequence
in Tables 1 and 2, we chose to further investigate the above-
mentioned reaction with a series of Grignard reagents
coupled with ester 1a. Given the utility of the final product
vinyl silanes, we were quite hopeful for a general stereo-
selectiVe synthesis of such compounds, as they have eluded
synthetic chemists.9 Much to our delight, the carbocupra-
tion-TMS tautomerization readily proceeded with 5 mol %
of the CuI·2LiCl catalyst and 3.3 equiv of TMSOTf with a
variety of aromatic Grignard reagents (1.2 equiv) to afford
compounds 4-5 and 7-8 in very good yields ranging from
88 to 93%. In addition, all of the ꢀ-aromatic-R-TMS-R,ꢀ-
unsaturated esters were virtually a single isomer, >20:1 for
1
the E diastereomer as determined by H NMR. Likewise,
two aliphatic Grignard reagents performed admirably as well.
The addition of hexyl MgBr to 1a under the standard reaction
conditions led to the corresponding product 6 in a 93% yield
with a diastereoselectivity of greater than 20:1 for the E
isomer. Similarly, MeMgBr mirrored the reactivity and
outcome of that of the hexyl derived Grignard reagent with
1a and provided the very simple methyl synthon 9 in 85%
yield as a single E isomer as well. Unfortunately, the
attempted addition of alkenyl and alkynyl Grignard reagents
did not proceed and led only to the decomposition of 1a.
There are a couple of key points that merit further discussion.
The first is that all of the tandem reaction processes occur in
very high yield. The lowest yield is 85% for both aromatic as
well as aliphatic Grignard reagents. Also, products 2-9 are
formed and isolated as single diastereomers. Given the nature
that two bond forming processes are taking place in a single
flask in such high yields and diastereoselectivities, we feel this
reaction is quite remarkable. Also, the final product R-TMS-
R,ꢀ-unsaturated esters are incredibly useful synthons in organic
a
1
E/Z ratio determined by H NMR (360 or 500 MHz) from the crude
reaction mixture. b Yields are of the isolated, pure compounds.
(9) (a) Hartzell, S. L.; Rathke, M. W. Tetrahedron Lett. 1976, 17, 2737.
(b) Sato, Y.; Takeuchi, S. Synthesis 1983, 9, 734. (c) Boeckman, R. K., Jr.;
Chinn, R. L. Tetrahedron Lett. 1985, 26, 5005.
2752
Org. Lett., Vol. 12, No. 12, 2010

Scheme 1
Figure 1. Key NOE enhancements for 2 and 11.
both the silane methyl groups and ꢀ-vinylic proton provided
conclusive proof for the assigned E-olefin geometry. In
1
addition, the H NMR chemical shifts of 2-10 mirror that
of similar vinyl silanes as synthesized by Zweifel.11b For
example, the resonance of the vinyl proton in 6 is upfield
(∼6.1 ppm), strongly suggesting the E-isomer in accordance
to Zweifel’s observations of E- and Z-isomeric vinyl silane
compounds. The resonance of the Z-isomer was shown to
be roughly 1 ppm downfield at ∼7.1 ppm.11b On the basis
of the NOE experiment results for 2 and by analogy to
Zweifel’s observations, the stereochemistry of the remaining
vinyl silanes 3-10 was assigned as the E-isomer. The relative
stereochemical determination of 11 was also determined in
a similar fashion. Much to our delight, a strong NOE for
both the silane methyl groups and the ꢀ-methyl protons
provided persuasive proof for the assigned E-olefin geometry.
anticipated and analogous to 1a, the catalytic carbocupration-
TMS tautomerization of methyl propiolate (1b) readily
proceeded under the standard reaction conditions and fur-
nished the R-TMS-ꢀ-phenyl-R,ꢀ-unsaturated ester 10 in 90%
yield as a single diastereomer. While all of the successful
examples to this point have been propiolate esters that lack
substitution at the ꢀ-carbon, we deemed it prudent to
investigate ethyl 2-butynoate (1c) under the standardized
reaction conditions. Much to our delight and surprise, the
catalytic carbocupration of 1c with 5 mol % of CuI·2LiCl
catalyst, 1.2 equiv of PhMgBr, and 3.3 equiv of TMSOTf
readily proceeded to the presumed TMS allenolate interme-
diate, and subsequent tautomerization furnished the tetra-
substituted alkene 11 in 85% yield and as a single diaste-
reomer (>20:1 for the E-isomer). This result is quite
remarkable given that Knochel reported that a similar
stoichiometric reaction did not provide high levels of
diastereoselectivity (the greatest dr was 88:12 for one
example).10 The result greatly expands this catalytic reaction
process to include stereodefined tetrasubstituted R-TMS-ꢀ,ꢀ-
disubstituted-R,ꢀ-unsaturated esters.
In conclusion, we have shown that vicinal functionalization
of propiolate esters via a catalytic carbocupration-silicon
group migration sequence with catalyst loadings as low as
5 mol % allows for good yields and excellent diastereose-
lectivities (>20:1) with a series of Grignard reagents for the
synthesis of substituted E-vinyl silanes. Future directions of
investigation will include further developments into the
catalytic vicinal functionalization of ynoates with other
electrophiles. Also, we are currently examining the broad
synthetic utility of the stereodefined vinyl silane products in
the context of natural product synthesis. Results from these
studies will be reported in due course.
As shown in Figure 1, the olefin geometry of 2 was
1
determined by means of H NMR. The strong 1D NOE for
Acknowledgment. Support for this project was provided
by the University of Alabama and the National Science
Foundation CAREER program under CHE-0845011.
(10) (a) Hartzell, S. L.; Sullivan, D. F.; Rathke, M. W. Tetrahedron
Lett. 1974, 15, 1403. (b) Shimoji, K.; Taguchi, H.; Oshima, K.; Yamamoto,
H.; Nozaki, H. J. Am. Chem. Soc. 1974, 96, 1620. (c) Yamamoto, K.; Tomo,
Y.; Suzuki, S. Tetrahedron Lett. 1980, 21, 2861. (d) Larson, G. L.;
Fernandez de Kaifer, C.; Seda, R.; Torres, L. E.; Ramirez, J. R. J. Org.
Chem. 1984, 49, 3385. (e) Tsuge, O.; Kanemasa, S.; Ninomiya, Y. Chem.
Lett. 1984, 1993. (f) Cooke, M. P., Jr. J. Org. Chem. 1987, 52, 5729. (g)
Gillies, M. B.; Tønder, J. E.; Tanner, D.; Norrby, P.-O. J. Org. Chem. 2002,
67, 7378.
Supporting Information Available: The general reaction
procedure and full NMR data (1H and 13C) for all of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) (a) Albaugh-Robertson, P.; Katzenellenbogen, J. A. J. Org. Chem.
1983, 48, 5288. (b) Najafi, M. R.; Wang, M.-L.; Zweifel, G. J. Org. Chem.
1991, 56, 2468.
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