A highly stereoselective TMSOTf-mediated catalytic carbocupration of alkynoates

Article abstract of DOI:10.1021/ol702546w

(Chemical Equation Presented) The TMSOTf-mediated catalytic carbocupration of ynoates has been investigated. It has been shown that catalyst loadings as low as 5 mol % readily allow for high yields and diastereosetectivities for a series of aromatic Grignard reagents. In addition, we have been successful in vicinally functionalizing 1a via initial TMSOTf-mediated catalytic carbocupration followed by a secondary electrophilic capture of the TMS allenoate intermediate.

Full text of DOI:10.1021/ol702546w

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5327-5329
A Highly Stereoselective
TMSOTf-Mediated Catalytic
Carbocupration of Alkynoates
Amanda J. Mueller and Michael P. Jennings*
Department of Chemistry, The UniVersity of Alabama, Tuscaloosa, Alabama 35487-0336
jenningm@bama.ua.edu
Received October 30, 2007
ABSTRACT
The TMSOTf-mediated catalytic carbocupration of ynoates has been investigated. It has been shown that catalyst loadings as low as 5 mol
% readily allow for high yields and diastereoselectivities for a series of aromatic Grignard reagents. In addition, we have been successful in
vicinally functionalizing 1a via initial TMSOTf-mediated catalytic carbocupration followed by a secondary electrophilic capture of the TMS
allenoate intermediate.
The first stoichiometric carbocupration of alkynoates was
reported by Corey and afforded stereodefined R,â-unsaturated
esters with high levels of diastereoselectivities and yields.1
Subsequent to this paper, considerable attention has been
given to understanding organocuprate additions to such
substrates.2 Most notably, it has been shown that Lewis acid
additives such as TMSCl not only accelerate the carbocu-
pration of alkynoates, but also isomerize the intermediate
vinyl cuprate to the TMS allenoate thus releasing the bound
organocuprate.3 With this in mind, we have been interested
in developing a diastereoselective carbocupration of R,â-
acetylenic esters that utilizes only a catalytic amount of Cu-
(I) catalyst. As described in Figure 1, syn-carbocupration of
ethyl propiolate (1a) with the diphenyl magnesiocuprate
should furnish the vinyl cuprate that would then be isomer-
Figure 1. Catalytic carbocupration via a TMS allenoate.
(1) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
1851.
(2) (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.;
ized, by addition of TMSOTf, to the TMS allenoate via
Sengupta, S. Org. React. 1992, 41, 135.
release of the organocuprate.4 Presumably, the byproduct
(3) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368.
(b) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am.
Chem. Soc. 1987, 109, 8056. (c) Frantz, D. E.; Singleton, D. A. J. Am.
Chem. Soc. 2000, 122, 3288. (d) Nilsson, K.; Andersson, T.; Ullenius, C.
phenyl cuprate would then be transformed into diphenyl
cuprate by means of PhMgBr addition and, in turn, complete
J. Organomet. Chem. 1997, 545-546, 591. (e) Nilsson, K.; Andersson, T.;
Ullenius, C.; Gerold, A.; Krause, N. Chem. Eur. J. 1998, 4, 2051. (f) Klein,
J.; Levene, R. J. Chem. Soc., Perkin Trans. 2 1973, 1971. (g) Marino, J.
P.; Linderman, R. J. J. Org. Chem. 1981, 46, 3696.
the catalytic cycle. Final protonation of the TMS allenoate
(4) Jennings, M. P.; Sawant, K. B. Eur. J. Org. Chem. 2004, 3201.
10.1021/ol702546w CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

(after organocuprate consumption) should provide the desired
ester product.
as the quenching source led to a decrease in E selectivity as
shown in entry 4.
Switching the Lewis acid from TMSCl to TMSOTf and
maintaining TFA as the proton source revealed additional
degradation of the E selectivity but provided a comparable
yield. Further lowering the catalyst loading to 20 mol %
slightly improved the overall yield, but dramatically altered
the selectivity providing the Z product in a 5:1 ratio. Much
to our delight, dropping the catalyst loading down even
further to 5 mol % led to a 91% yield and an exceptional
13:1 ratio for the (Z)-ethyl cinnamate product (entry 8). It is
worth noting in entry 9, that even at 3 mol % high levels of
diastereoselection were observed, but the yield did decrease
from 91% to 81%. A series of other proton sources were
examined (entries 10-14), but led to inferior results with
respect to both yield and diastereoselectivity. It is worth
noting that the TMSOTf-promoted catalytic carbocupration
of 1a proceeded with high yields in THF, but not significantly
in other ethereal solvents such as Et2O and MTBE. With
this information in hand, we subsequently examined the
scope and limitations of the TMSOTf-promoted catalytic
carbocupration of 1a.
Our initial concern with selective protonation of the TMS
allenoate has since been resolved as described in our previous
work.4 Although we had modest success (g20:1 (E)-
selectivity at 50 mol % loading) with the TMSCl-promoted
carbocupration of ynoates, we elected to further investigate
the catalytic carbocupration of propiolate esters with
TMSOTf as the Lewis acid additive. Our initial reasoning
behind using TMSOTf was its increased Lewis acidity
compared to TMSCl. We surmised that TMSOTf would lead
to amplified catalytic efficiency and allow for a much lower
catalyst loading. Herein we report that not only does
TMSOTf allow for catalytic carbocupration of propiolate
esters with 5 mol % of Cu(I), but also the incorporation of
TFA as the proton source provides selectively (Z)-substituted
R,â-unsaturated esters. This new catalytic protocol provided
products that are complementary to our previous catalytic
system and the Corey stoichiometric procedure.1,4 In addition
to a proton quench, we have also established that the
intermediate TMS allenoate can undergo highly diastereo-
selective carbon-carbon, deuterium, and silyl bond forming
processes in a single flask.
As shown in Table 2, the reactions readily proceeded with
As shown in Table 1, we initially observed that TMSCl
Table 2. TMSOTf-CuI‚2LiCl-Catalyzed Carbocupration
(5 mol %) of 1a and 1b with Various Grignard Reagentsa
Table 1. CuI‚2LiCl Promoted Carbocupration of 1a with
PhMgBr
no.
mol %
TMS-X
quench
yield, %
Ea
Z
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15b
16c
50
40
30
30
30
20
10
5
3
5
5
5
Cl
Cl
Cl
Cl
NH4Cl
NH4Cl
NH4Cl
TFA
TFA
TFA
91
90
87
76
81
85
84
91
81
85
55
71
57
63
<5
<5
20
12
9
3
2
1
1
1
1
1
1
1
1
1
1
1
1
1
5
6
13
12
7
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
TFA
TFA
TFA
NH4Cl
PPTS
TfOH
CSA
HCl
TFA
TFA
4
5
6
6
5
5
5
5
1
a E/Z ratio determined by 1H NMR (360 or 500 Mhz) from the crude
reaction mixture. b Reaction run in Et2O. c Reaction run in tBuOMe.
readily promoted the catalytic carbocupration of ethyl
propiolate (1a) at high catalyst loadings with PhMgBr. The
reaction afforded good yields and diastereoselectivities of
(E)-ethyl cinnamate after quenching with NH4Cl. However,
proton addition to the TMS allenoate intermediate with TFA
a E/Z ratio determined by 1H NMR (360 or 500 Mhz) from the crude
reaction mixture. b Reaction quenched with CF3COOD (g95% deuterium
incorporation).
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Org. Lett., Vol. 9, No. 25, 2007

ortho-, meta-, and para-substituted aryl Grignard reagents
to provide the R,â-unsaturated esters in good to excellent
yields (73-91%). In addition, high levels of diastereoselec-
tivities were observed (10:1 f 13:1 for the Z product) for
all of the reactions irrespective of steric or electronic
differences resident in the arene. For example, both 4-fluoro-
and 4-methoxyphenyl magnesium bromide readily underwent
catalytic carbocupration of 1a and afforded the ester products
in good yields and high levels of Z diastereoselectivity (12-
13:1). A few other table entries are notable. The first is that
the sterically hindered mesityl Grignard reagent underwent
Z-selective catalytic carbocupration in 75% yield with
TMSOTf, whereas when TMSCl was used as the Lewis acid
promoter no reaction with 1a was observed. Second, quench-
ing the TMS allenoate with TFA-D readily allowed for the
chemo- and diastereoselective introduction of a deuterium
atom R to the carbonyl moiety as predicted. Under the
standard reaction conditions for 1a, the â-methyl ynoate (1b)
showed equal reactivity toward PhMgBr with a comparable
88% yield but with a slightly diminished 1/5 E/Z ratio.
Nonetheless, the TMSOTf-mediated catalytic carbocupration
of substituted ynoates was shown to be quite feasible, and
also provided products that are complementary to our
previous catalytic system and the Corey stoichiometric
procedure.1,4 Last, we were pleased to observe that aliphatic
Grignard reagents underwent catalytic carbocupration and
provided a yield (84%) comparable to that of the aromatic
counterparts. However, the diastereoselectivity was signifi-
cantly lower (2:1) in favor of the Z product.
Scheme 1
yet to be reported.5 In addition to the carbon-carbon bond-
forming process, capturing the allenoate with a second
equivalent of TMSOTf furnished the (E)-stereodefined vinyl
silane 3 in an outstanding yield of 88%.6
In conclusion, we have shown that not only does TMSOTf
allow for catalytic carbocupration of propiolate esters with
5 mol % of Cu(I), but also the incorporation of TFA as the
proton source provides selectively (Z)-substituted R,â-
unsaturated esters. Future directions of investigation will
include increasing the Z selectivity for aliphatic Grignard
reagents and further developments into the catalytic vicinal
functionalization of ynoates with other electrophiles. Results
from these studies will be reported in due course.
Acknowledgment. The authors would like to thank The
University of Alabama for financial support of this work.
In addition to a proton quench, we have also established
that the intermediate TMS allenoate can undergo highly
diastereoselective carbon-carbon and silyl bond forming
processes in a single flask. As shown in Scheme 1, we have
been successful in vicinally functionalizing 1a via initial
TMSOTf-mediated catalytic carbocupration followed by a
secondary electrophilic capture of the TMS allenoate inter-
mediate. Thus, trapping of the TMS allenoate with PhCHO
and the external addition of BF3‚OEt2 afforded the aldol
adduct 4 in 55% overall yield as a single stereoisomer. To
the best of our knowledge, a Mukaiyama aldol reaction
between a TMS allenoate of this type and an aldehyde has
Supporting Information Available: General reaction
procedures and tabulated 1H NMR data for all of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702546W
(5) (a) Crimmins, M. T.; Nantermet, P. G. J. Org. Chem. 1990, 55, 4235.
(b) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2006, 128, 15382.
(6) (a) Boeckman, R. K., Jr.; Chinn, R. L. Tetrahedron Lett. 1985, 41,
5005. (b) Hartzell, S. L.; Rathke, M. W. Tetrahedron Lett. 1976, 31, 2737.
(c) Hartzell, S. L.; Sullivan, D. F.; Rathke, M. W. Tetrahedron Lett. 1974,
29, 1403.
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