Direct Copper(I) Iodide Dimethyl Sulfide Catalyzed Conjugate Addition of Alkenyl Groups from Vinylzirconocene Reagents

Article abstract of DOI:10.1021/ol036141y

(Equation presented) Cul·0.75DMS complex is an excellent catalyst for the direct conjugate addition of alkenyl groups from vinylzirconocene reagents to αβ-unsaturated aldehydes and ketones. The presence of the catalyst with an alkenylzirconocene, at +40°C in THF, circumvents the need for making discrete alkenylcopper reagents. The catalyst is superior in terms of product yields and alkene flexibility in comparison to other copper(I) sources as well as the nickel(II)-catalyzed conjugate addition. This simple one-pot procedure shows that only 1 equiv of the vinylzirconocene is needed.

Full text of DOI:10.1021/ol036141y

ORGANIC
LETTERS
2004
Vol. 6, No. 1
107-110
Direct Copper(I) Iodide Dimethyl Sulfide
Catalyzed Conjugate Addition of Alkenyl
Groups from Vinylzirconocene Reagents
Amer El-Batta, Taleb R. Hage, Steve Plotkin, and Mikael Bergdahl*
Department of Chemistry, San Diego State UniVersity,
San Diego, California 92182-1030
bergdahl@sciences.sdsu.edu
Received November 1, 2003
ABSTRACT
CuI‚0.75DMS complex is an excellent catalyst for the direct conjugate addition of alkenyl groups from vinylzirconocene reagents to r,â-
unsaturated aldehydes and ketones. The presence of the catalyst with an alkenylzirconocene, at +40 °C in THF, circumvents the need for
making discrete alkenylcopper reagents. The catalyst is superior in terms of product yields and alkene flexibility in comparison to other
copper(I) sources as well as the nickel(II)-catalyzed conjugate addition. This simple one-pot procedure shows that only 1 equiv of the
vinylzirconocene is needed.
Organocopper reagents are some of the most versatile
compounds available for creating carbon-carbon bond
connections.1 Specifically, the copper-promoted conjugate
addition of vinyl groups to R,â-unsaturated carbonyl com-
pounds is a very useful transformation in organic synthesis.2
Although organocuprate chemistry routinely takes advantage
of milder organometallic nucleophiles,1d the vinylcopper
reagents commonly originate from the corresponding orga-
nolithium and organomagnesium compounds.1c These reac-
tive and strongly basic precursors, in the synthesis of the
corresponding cuprate reagents, occasionally complicate the
experimental procedures and might limit tolerance of other
functional groups. Moreover, a stoichiometric quantity of the
copper(I) source makes the reaction less appealing, particu-
larly for scale-up. To activate the vinylzirconocene reagent
and simultaneously utilize the copper(I) source as the catalyst,
Lipshutz2a introduced MeLi,2g Me2CuLi,2c or Me3ZnLi.2b
Thus, less basic but sufficiently nucleophilic reagents have
been required to generate discrete alkenylcuprate reagents.
Hydrozirconation of alkynes, utilizing Schwartz’s reagent3a
{Cp2Zr(H)Cl},3b is a superb protocol for making regiose-
lective vinylzirconocene reagents. Although the valuable
vinylzirconium intermediates have been used in various
coupling reactions,4 there is no method available for utilizing
a combination of the vinylzirconocene and a catalytic amount
of copper(I) source directly in the conjugate addition of
(1) (a) Krause, N. Modern Organocopper Chemistry; Wiley-VCH:
Weinheim, 2002. (b) Taylor, R. J. K.; Casy, G. In Organocopper
Reagents-A Practical Approach; Taylor, R. J. K., Ed.; Oxford University
Press: New York, 1994. (c) Perlmutter, P. Conjugate Addition Reactions
in Organic Synthesis; Pergamon Press: Oxford, 1992. (d) Nakamura, E.;
Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750-3771.
(2) (a) Lipshutz, B. H. Acc. Chem. Res. 1997, 30, 277-282. (b) Lipshutz,
B. H.; Wood, M. R. J. Am. Chem. Soc. 1993, 115, 12625-12626. (c)
Lipshutz, B. H.; Keil, R. J. Am. Chem. Soc. 1992, 114, 7919-7920. (d)
Wipf, P.; Smitrovich, J. H.; Moon, C.-W. J. Org. Chem. 1992, 57, 3178-
3186. (e) Lipshutz, B. H.; Keil, R.; Barton, J. C. Tetrahedron Lett. 1992,
33, 5861-5864. (f) Lipshutz, B. H.; Kato, K. Tetrahedron Lett. 1991, 32,
5647-5650. (g) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990,
112, 7440-7441. (h) Babiak, K. A.; Behling, J. R.; Dygos, J. H.;
McLaughlin, K. T.; Ng, J. S.; Kalish, V. J.; Kramer, S. W.; Shone, R. L.
J. Am. Chem. Soc. 1990, 112, 7441-7442.
(3) (a) Yoshifuji, M.; Loots, M. J.; Schwartz, J. Tetrahedron Lett. 1977,
1303-1306. (b) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson,
B. T.; King, S. M. Tetrahedron Lett. 1987, 28, 3895-3898.
(4) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853-12910. (b)
Negishi, E.; Takahashi, T. Synthesis 1988, 1-19. (c) Negishi, E.; Takahashi,
T. Aldrichimica Acta 1985, 18, 31-48. (d) Negishi, E. Acc. Chem. Res.
1982, 15, 340-348.
10.1021/ol036141y CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

alkenyl groups.5 Our results using the copper(I)-based
catalysts were inspired from the CuBr‚DMS (DMS )
dimethyl sulfide)-catalyzed conjugate addition of an alkyl-
zirconocene reported by Wipf.6 Furthermore, our finding that
the CuI‚0.75DMS complex allows for the conjugate addition
of monosilylcopper reagents7 to occur in THF motivated us
to explore the idea of transferring alkenyl groups from
vinylzirconocenes directly utilizing CuI‚0.75DMS in 1,4-
additions.
Table 1. Influence of Copper Source on 1,4-Addition
We now report that by adding 10 mol % of CuI‚0.75DMS8
to 1.0 equiv of an alkenylzirconocene, it is possible to
conduct a direct transfer of the vinyl groups to R,â-
unsaturated aldehydes and ketones in high yields (54-97%).
The process reported herein is a simple protocol having a
very good economy of group transfer (Scheme 1).
Scheme 1
a 1.0 equiv of alkyne versus benzalacetone. b Based on isolated and
purified material (%). c Aldrich ultrapure grade (99.999%). d 60 equiv
of DMS added to 99.999% grade CuI. e 2 equiv of PR3 added to
99.999% grade CuI. f CuI purified via CuI‚S(i-Pr)2 and used as the solid
CuI‚0.75S(i-Pr)2 complex.
The catalytic efficiency of the CuI‚0.75DMS complex
prevailed when compared to various other copper sources
in the conjugate addition of 1-hexenylzirconocene to ben-
zalacetone (Table 1). The catalytic efficiency is furthermore
illustrated from the result using 1 mol % of CuI‚0.75DMS
(entry 4) and demonstrated in the acquired high yield (entry
2) compared to the yield obtained using the 99.999% grade
CuI (entry 5).
Although the yield increased by adding excess DMS to
CuI (entry 6), the yield was nonetheless lower than when
employing the DMS-purified CuI complex. Replacing DMS
with the more basic phosphines (entry 7) or the bulkier
diisopropyl sulfide9 (entry 8) resulted in lower yields. Copper
salts purified via their DMS complex render these salts more
soluble in THF or diethyl ether, which in turn amplifies
reactivity and stability, particularly in neat dimethyl sulfide.10
Less soluble and less efficient Cu(I) catalysts also included
CuBr, CuCl, CuCN, and CuOTf. It is worth mentioning the
formation of copper mirror precipitation in the low yielding
reactions, which suggests that the specific alkenylzirconium/
copper(I) combinations sometimes were unstable under the
conditions specified. Exposing a styrylzirconocene reagent
to 100 mol % CuCl3a at 20 °C in the absence of enone gave
69% of 1,4-diphenylbutadiene (Scheme 2). Under similar
Scheme 2
(5) Loots, M. J.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 8045-8046.
For an initial observation that CuOTf facilitates the 1,4-addition of vinyl
groups, see ref 3a.
reaction conditions using 100 mol % CuI‚0.75DMS, the rate
of formation of the coupling product decreased. However,
in the presence of 10 mol % CuI‚0.75DMS and 1 equiv of
2-cycohexenone at 40 °C, formation of diene product did
not occur,11 which suggests that the carbonyl group in the
enone has a stabilizing effect on the vinylzirconocene copper-
(I) complexation in the conjugate addition.
The efficiency of the CuI‚0.75DMS complex in conjugate
additions is further illustrated for a number of enones and
enals (Table 2). Treatment of various alkynes with Schwartz’s
reagent, Cp2Zr(H)Cl, in THF at 40 °C for 10 min afforded
(6) (a) Wipf, P.; Smitrovich, J. H. J. Org. Chem. 1991, 56, 6494-6496.
(b) Wipf, P.; Takahashi, H. Chem. Commun. 1996, 2675-2676.
(7) Dambacher, J.; Bergdahl, M. Chem. Commun. 2003, 144-145.
(8) The CuI‚DMS complex is unstable and loses rapidly DMS to form
the more stable CuI‚0.75DMS stoichiometry, as determined by elemental
analysis. For a discussion on the stability of CuI‚DMS complex, see:
Eriksson, M.; Hjelmencrantz, A.; Nilsson, M.; Olsson, T. Tetrahedron 1995,
51, 12631-12644. See also: Eriksson, M.; Iliefski, T.; Nilsson, M.; Olsson,
T. J. Org. Chem. 1997, 62, 182-187. For CuI purified via its dimethyl
sulfide complex, see: House, H. O.; Chu, C.-Y.; Wilkins, J. M.; Umen, M.
J. J. Org. Chem., 1975, 40, 1460-1469.
(9) For some initial conjugate additions in the presence of (i-Pr)2S, see:
Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318-7319. Clark,
R. D.; Heathcock, C. H. Tetrahedron Lett. 1974, 1713-1715.
(10) Bertz, S. H.; Dabbagh, G. Tetrahedron 1989, 45, 425-434.
1
(11) Based on H NMR data obtained from crude reaction mixtures.
108
Org. Lett., Vol. 6, No. 1, 2004

basis of the lack of formation of diene in the presence of
enone (Scheme 3). Furthermore, the π-base complexation
Table 2. Conjugate Additions of Vinyl Groups
Scheme 3
of the Zr-alkene to Cu(I) is more favored with iodide as a
π-donor ligand compared to bromide. The formation of a
putative alkylvinyl-cuprate13 intermediate could next undergo
a fast reductive elimination step to form the zirconium
enolate product. In the case of the alkenylzirconocenes,
CuBr‚DMS fails to achieve a promising yield whereas CuI‚
0.75DMS produces a very high yield.
In sharp contrast, the conjugate addition of alkylzir-
conocenes using CuBr‚DMS6a produced a high yield of
product, but the corresponding conjugate addition employing
CuI‚0.75DMS did not produce any 1,4-addition product
(Scheme 4).
Scheme 4
a 1.0 equiv of alkyne versus enone. b 40 °C. c Based on isolated and
purified material (%). d 10 mol % CuI‚0.75DMS versus alkyne. e 100 mol
% CuI‚0.75DMS, trans:cis ratio 20:1.
In summary, a novel method utilizing CuI‚0.75DMS as a
catalyst in conjugate addition of alkenyl groups derived from
vinylzirconocene reagents to R,â-unsaturated aldehydes and
ketones has been developed. While the simple CuI‚0.75DMS
complex is required only in catalytic amounts, no additional
transmetalation steps are required in order to obtain high
yields in the conjugate addition step. We show that our
conjugate addition method works extraordinarily well for
internal and terminal alkynes, as well as NHBoc-substituted
alkynes. The catalytic efficiency of the CuI‚0.75DMS
complex is currently being explored with various types of
R,â-unsaturated substrates. Further synthetic developments
will be reported in due course.
the corresponding vinylzirconocenes,3a which subsequently
were exposed to 10 mol % CuI‚0.75DMS and the substrates
at 20 °C. Increasing the temperature of the resulting mixture
to 40 °C afforded the 1,4-adducts in high yields after the
time indicated. The results illustrated exemplify the excep-
tional capability and synthetic potential of this novel
conjugate addition method. Addition of the 1-hexenyl group
to crotonaldehyde yielded the corresponding adduct in 90%,
which suggests that there is not much oligomerization of the
zirconium enolate. The results illustrated show that the
catalytic amount of CuI‚0.75DMS is a better catalyst
compared to the reported5 nickel(II)-catalyzed conjugate
additions of vinylzirconocenes in terms of catalytic ef-
ficiency, product yields, and the flexibility of various
vinylzirconocene reagents.
(12) There is no evidence for the formation of a discrete alkenylcopper
compound via a Zr f Cu transmetalation step. For an extensive mechanistic
study using alkylzirconocenes in conjugate additions, see: Wipf, P.; Xu,
W.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M. Tetrahedron 1994,
50, 1935-1954.
(13) A few stable copper(III) species have been isolated, see: (a) Willert-
Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem.
Commun. 1989, 1633-1634. (b) Naumann D.; Roy, T.; Tebbe, K.-F.;
Crump, W. Angew. Chem. 1993, 105, 1555-1556. (c) Naumann D.; Roy,
T.; Tebbe, K.-F.; Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482-
1483. (d) Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996,
519, 7-20.
Although the mechanism for the CuI‚0.75DMS-catalyzed
conjugate addition of alkenyl groups is quite obscure, there
seems to be a mechanistic resemblance to the proposed CuBr‚
DMS-catalyzed conjugate addition of alkyl groups from
alkylzirconocenes reported by Wipf.12 Thus, a simultaneous
three-component transition state is postulated partly on the
Org. Lett., Vol. 6, No. 1, 2004
109

Acknowledgment. This work was funded by the SDSU
Foundation. The authors thank Dr. LeRoy Lafferty and Ms.
Wen Zhao for technical assistance and Dr. Andrew Cooksy
and Dr. Hong-Chang Liang at SDSU for helpful discussions.
The authors also thank a reviewer for providing guidance
on our proposed mechanism.
Supporting Information Available: Experimental pro-
cedures and spectral data (1H NMR, 13C NMR, MS, and IR)
for pertinent compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL036141Y
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