α-olefins as alkenylmetal equivalents in catalytic conjugate addition reactions

Article abstract of DOI:10.1002/anie.200705163

(Chemical Equation Presented) In the presence of a silyl triflate and an amine base, a nickel-phosphine complex catalyzes the direct conjugate addition of ethylene, α-olefins, and aryl alkenes to unsaturated aldehydes and ketones. The enolsilane products are isolated in good to very high yield, and in very high stereoselectivity for some cases. The alkene is a functional equivalent of an alkenylmetal reagent in the transformation.

Full text of DOI:10.1002/anie.200705163

Angewandte
Chemie
DOI: 10.1002/anie.200705163
Catalytic Coupling Reactions
a-Olefins as Alkenylmetal Equivalents in Catalytic Conjugate Addition
Reactions**
Chun-Yu Ho, Hirohisa Ohmiya, and Timothy F. Jamison*
First documented over a century ago, conjugate additions are
among the most utilized organic reactions. In carbon–carbon
bond-forming variants, the nucleophile is typically organo-
metallic. Earlier technology employed enolate, organo-
lithium, Grignard, or organocopper reagents; more recently,
organozinc and organoboron compounds have enhanced this
transformation significantly.[1,2] Despite increased functional
group tolerance, an organometallic or an organometalloid
compound is nonetheless required in these powerful methods.
Herein we describe a novel conjugate addition reaction in
which a simple, unactivated alkene (ethylene, an a-olefin, or
styrene) takes the place of the organometal reagent [Eq. (1)].
Thus, although an alkene is not an alkenylmetal reagent per
se, it functions as one in this carbon–carbon bond-forming
process.
the transformation reported herein (catalytic 1,4-addition of a
simple alkene to unsaturated carbonyl groups) appears to be
Lewis acid promoted conjugate addition of electron-rich
alkenes.[6,7] In these cases migration of the double bond of the
alkene nucleophile occurs, which is in contrast to the Ni-
catalyzed reactions described below.
Ogoshi et al. reported that stoichiometric amounts of
[Ni(cod)2] (cod = 1,5-cyclooctadiene) and trimethylsilyl tri-
fluoromethanesulfonate (Me3SiOTf) effected intramolecular
coupling of an alkene and an aldehyde, and shortly thereafter,
we reported that a-olefins are excellent nucleophiles in
intermolecular carbonyl addition reactions catalyzed by a
complex derived from [Ni(cod)2] and a phosphine or an N-
heterocyclic carbene.[8] Depending on the nature of the
ligand, addition occurs at either the terminus or the 2-position
of the alkene. The latter provides direct access to allylic
alcohol derivatives and the former yields products of a
carbonyl–ene-like reaction. With the aim of broadening the
scope of alkenes as nucleophiles in carbon-carbon bond-
forming reactions, we turned our attention to electrophiles
containing unsaturated carbonyl functional groups.
Catalyzed polymerization of alkenes is one of the most
important industrial processes,[3] and Ni-catalyzed two-alkene
coupling reactions have also received significant attention,
including hydrovinylation.[4] Montgomery and co-workers
found that nickel complexes catalyze a wide variety of
conjugate addition reactions,[5] but the closest precedent to
To focus on issues of alkene reactivity in initial studies, we
selected ethylene as the coupling partner and decided to
address issues of regioselectivity in subsequent experiments.
Triethylsilyl trifluoromethansesulfonate (Et3SiOTf) and cata-
lytic amounts of [Ni(cod)2] and Bu3P afford good to excellent
yields of the conjugate addition product, isolated as the
enolsilane (Table 1, entries 1–4). Moreover, the stereoselec-
tivity with respect to formation of the enolsilane is at least
92:8. Unsaturated ketones are also effective electrophiles
(Table 1, entries 5–11), but proceed with lower selectivity in
some cases.
As demonstrated in Table 1, entry 9, electron-rich enones
are superior electrophiles, and certain heterocycles are also
tolerated (Table 1, entries 10,11). Despite reduced selectivity,
reactions with furan- and thiophene-containing enones pro-
ceed in high chemical yield. Overall, most of the above cases
are highly selective, and thus the transformation represents a
direct and stereoselective assembly of tetrasubstituted siloxy-
alkenes.[9,10]
[*] Dr. C.-Y. Ho,[+] Dr. H. Ohmiya, Prof. Dr. T. F. Jamison
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-0253
E-mail: tfj@mit.edu
Homepage: http://web.mit.edu/chemistry/jamison
[+] Current address: Center of Novel Functional Molecules
The Chinese University of Hong Kong
Shatin, NT, Hong Kong SAR (P.R. China)
Several observations regarding the optimum reaction
conditions are noteworthy. Increasing either the ethylene
pressure from 1 atm to 2 atm, or the scale of the reaction by
fourfold resulted in only a marginal reduction in yield
(Table 1, entries 2 and 6). Out of 25 additives investigated
(see the Supporting Information), Bu3P (Bu3P = tributyl-
phosphine) was by far the most effective ligand for coupling
reactions of ethylene. Toluene is the superior solvent; for
example, ethereal solvents such as Et2O, THF, and 1,4-
dioxane completely suppress the coupling reaction.
[**] Support for this work was provided by the National Institute of
General Medical Sciences (GM-063755). C.-Y.H. and H.O. thank the
Croucher Foundation and the JSPS, respectively, for postdoctoral
fellowships. We are grateful to Dr. Li Li for obtaining mass
spectrometric data for all compounds (MIT Department of
Chemistry Instrumentation Facility, which is supported in part by
the NSF (CHE-9809061 and DBI-9729592) and the NIH
(1S10RR13886-01)).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 1893 –1895
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1893

Communications
Table 1: Ni-catalyzed conjugate addition reactions of alkenes.[a]
alkynes), the fact that 1-octene functions as a 2-alkenyl
organometallic reagent highlights a particularly useful aspect
of this reaction.
Entry R1
R2
R3
Major
Yield [%][b] E/Z (2)[b]
product
Aryl alkenes, in contrast, afford the opposite alkene
regioselectivity (Table 1, entries 13,14). Coupling at the 2-
position of styrene is not observed; carbon–carbon bond
formation at the 1-position occurs exclusively, whether the
electrophile is an enal or an enone.
The trends and observations noted above suggest a
general mechanistic framework (Scheme 1). The proposed
sequence of events is based largely on a crystal structure of a
complex derived from [Ni(cod)2], Cy3P (Cy3P = tricyclohex-
1
2
H
Me
n-hexyl
H
2a
2b
52
76
95:5
95:5
58[c]
64[d]
83
95:5[c]
95:5 [d]
8:92
3
PhCH2
2c
2d
4[e,f]
97
7:93
5
6
Me
nPr
P
2e
2 f
h
90
94
86[d]
78
70
94
95
95
67[i]
70
55
95:5
90:10
90:10[d]
13:87
n.d.
ylphosphine),
a 1,3-diene, and benzaldehyde reported
7
iPr
Ph
Me
nBu
Et
2g
2h
2i
recently by Ogoshi et al.[11] We believe that the alkene
(ethylene shown) and the electrophile (enal or enone 1)
afford an oxa-p-allyl nickel complex (A) during the formation
of the carbon–carbon bond. The silyl triflate reacts with this
species to give an enolsilane and a NiII complex (B) that
undergoes rapid b-hydride elimination. Release of product 2
and Et3N abstraction of TfOH from complex C affords a Ni0
species (not shown) to complete the catalytic cycle.
8[g]
9[h]
10
p-anisyl
2-furyl
2-thienyl 2k
H
91:9
2j
75:25
75:25
95:5
81:19
91:9
11
12[f]
13[f]
14[f]
n-hexyl n-hexyl
Ph
2l
3a
3b
n-hexyl
Me
H
p-anisyl
[a] See the Supporting Information and Equation (1). Standard con-
ditions (entries 1–11): Et3N (1.5 mmol) and the enal or enone
(0.25 mmol) were added to a solution of [Ni(cod)2] (0.075 mmol) and
Bu3P(0.15 mmol) in toluene (1.5 mL) at 23 8C under ethylene (1 atm).
Triethylsilyl trifluoromethanesulfonate (0.44 mmol) was added dropwise
at 08C. The mixture was stirred for 48 h at 458C and purified by
chromatography (SiO2). In some cases CyPPh2 (Cy=cyclohexyl;
entry 12) or tricyclopentylphosphine (entries 13,14) was used in place
The E/Z selectivity thus appears to be dictated by two
factors that in most cases reinforce each other. The placement
of R2 and R3 substituents away from each other and the
chairlike chelation of Ni in complex A are consistent with the
observed sense of alkene geometry. The superior perfor-
mance of electron-rich enals and enones is consistent with the
fact that reaction with silyl triflate is a critical step in the cycle.
Mackenzie and co-workers reported Ni-catalyzed conjugate
addition reactions between alkenyltributyltin reagents and
a,b-unsaturated aldehydes that are assisted by chlorotrialkyl-
silanes and likely proceed via 1-((trialkylsilyl)oxy)allylnick-
el(II) intermediates.[7] In this vein, it is possible that the silyl
triflate and enal (or enone) first combine and the resulting
species then undergoes coupling with the alkene. Morken and
co-workers proposed a similar sequence of events in Ni-
catalyzed coupling reactions between allylboron reagents and
enones.[12]
1
of Bu3P. [b] Determined by H NMR spectroscopy. [c] Ethylene pressure
was 2 atm. [d] Fourfold larger scale (1 mmol enal used). [e] Compound
1d added over 48 h. [f] Reaction time 72 h; a lower yield was obtained
after a 24 h reaction time. [g] A dihydropyran from hetero-Diels–Alder
reaction of 2 equiv of 1h was isolated (13%). [h] Reaction time 24 h.
[i] Combined yield of 2l and 2l’ (product ratio of 2l:2l is 79:21;
compound 2l’ is the result of the addition to the 1-position of 1-octene).
See the text and the Supporting Information.
Significant effort was expended to reduce the rather high
catalyst loading (30 mol%), however, small decreases in the
amount of [Ni(cod)2] resulted in a significantly reduced yield.
For example, 2b was afforded in 49% yield when 15 mol%
[Ni(cod)2] was used (76% yield under standard conditions).
Similarly, a 63% yield of 2 f was obtained at 20 mol% catalyst
loading, down from 94% yield at 30 mol% catalyst loading.
Other critical variables are the amounts of Et3N and
Et3SiOTf employed. Decreasing or increasing the former
lowered the yield or completely suppressed the reaction, and
reducing the amount of Et3SiOTf from 1.75 to 1.25 equiv-
alents decreased the yield of 2b from 76% to 47% under
otherwise identical conditions. Additionally, Me3SiOTf can be
used in place of Et3SiOTf, but this substitution tends to
diminish the product yield.
With the caveat that different ligands are used in coupling
reactions of a-olefins (CyPPh2) and styrene (PCy3), our
working hypothesis for the complementary regioselectivity in
Unactivated monosubstituted olefins are also good cou-
pling partners in this reaction. For example, 1-octene and 2-
hexylacrolein are combined in 67% yield, and with very high
enolsilane E/Z selectivity (Table 1, entry 12). Coupling occurs
in approximately 4:1 regioselectivity, favoring coupling at the
2-position of the alkene. Since there are comparatively a
greater number of general methods for the preparation of 1-
alkenyl organometallics (e.g., hydrometalation of terminal
Scheme 1. Proposed mechanistic framework.
1894
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1893 –1895

Angewandte
Chemie
Metal-Catalyzed Polymerization”: Chem. Rev. 2000, 100(4)
(Guest Ed.J. A. Gladysz); c) J. S. Yeston, Science 2005, 309,
2139b.
these two cases is as follows: It is possible that the
regioselectivity observed for styrene (coupling at the alkene
1-position) is due primarily to an electronic consideration,
specifically, the formation of a benzylic Ni species. In
conctrast, the sense of selectivity for a-olefins is that resulting
from avoidance of steric repulsion between the Ni–ligand
complex and the alkene substituent. We have proposed an
explanation similar to the latter for the behavior of a-olefins
in other Ni-catalyzed coupling reactions that we have devel-
oped.[8b–f]
Several aspects of this transformation are noteworthy.
First, it is a rare example of selective conjugate addition of an
alkenyl equivalent to an unsaturated aldehyde. Typically, in
such reactions 1,2-addition is favored, or one observes
complex mixtures.[1] The high E/Z selectivity in most cases
also merits further comment. Enolsilanes are starting materi-
als in a wide range of enantioselective transformations
leading to carbonyl compounds with quaternary stereogenic
centers in the a-position, in many cases with very high
enantioselectivity.[13,14] The double bond configuration is
generally critical for high facial selectivity, and thus the Ni-
catalyzed conjugate addition reaction provides rapid access to
important tri- and tetrasubstituted enolsilanes that would
otherwise be difficult to prepare with high selectivity by
enolization of an aldehyde or ketone[9] (Table 1, entry 2,
compare allyl vs. n-hexyl). Finally, the products derived from
ethylene possess a monosubstituted alkene that is an excellent
substrate for catalytic olefin cross-metathesis reactions.[15]
This combination therefore affords products that are regio-
complementary to those of the Ni-catalyzed conjugate
addition reaction with aliphatic, monosubstituted alkenes
(e.g., 1-octene).
[4] a) Review: T. V. Rajan Babu, Chem. Rev. 2003, 103, 2845; see
also: b) Ru-catalyzed hydrovinylation of 2,4-dienoate esters (not
conjugate addition: vinyl group and hydrogen add to 4- and 5-
position, respectively): Z. He, C. S. Yi, W. A. Donaldson, Synlett
2004, 1312; catalyzed hydrovinylation of enoates or enones with
double bond migration: c) Ni: G. Muller, J. I. Ordinas, J. Mol.
Catal. A 1997, 125, 97; d) Ru: C. S. Yi, Z. He, D. W. Lee,
Organometallics 2001, 20, 802.
[5] a) Review: J. Montgomery, Angew. Chem. 2004, 116, 3980;
Angew. Chem. Int. Ed. 2004, 43, 3890; b) A. Herath, B. B.
Thompson, J. Montgomery, J. Am. Chem. Soc. 2007, 129, 8712.
[6] a) Thermal: C. J. Albisetti, N. G. Fisher, M. J. Hogsed, R. M.
Joyce, J. Am. Chem. Soc. 1956, 78, 2637; Lewis acid promoted:
b) G. Bꢀchi, E. Koller, C. W. Perry, J. Am. Chem. Soc. 1964, 86,
5646; c) B. B. Snider, E. A. Deutsch, J. Org. Chem. 1983, 48,
1822.
[7] Enal- and enone-derived coupling reactions of allylnickel
complexes (stoichiometric in Ni, sunlamp irradiation): J. R.
Johnson, P. S. Tully, P. B. Mackenzie, M. Sabat, J. Am. Chem. Soc.
1991, 113, 6172.
[8] a) S. Ogoshi, M. Oka, H. Kurosawa, J. Am. Chem. Soc. 2004, 126,
11802; b) S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc. 2005, 127,
14194; c) C.-Y. Ho, S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc.
2006, 128, 5362; d) S.-S. Ng, C.-Y. Ho, T. F. Jamison, J. Am.
Chem. Soc. 2006, 128, 11513; e) C.-Y. Ho, T. F. Jamison, Angew.
Chem. 2007, 119, 796; Angew. Chem. Int. Ed. 2007, 46, 782;
f) Isocyanates as electrophiles: K. D. Schleicher, T. F. Jamison,
Org. Lett. 2007, 9, 875.
[9] Preparation of geometrically defined enolsilanes from aldehydes
and ketones: a) H. O. House, L. J. Czuba, M. Gall, H. D.
Olmstead, J. Org. Chem. 1969, 34, 2324; b) C. H. Heathcock,
C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, J. Lampe,
J. Org. Chem. 1980, 45, 1066; c) E. J. Corey, A. W. Gross,
Tetrahedron Lett. 1984, 25, 495; d) P. L. Hall, J. H. Gilchrist,
D. B. Collum, J. Am. Chem. Soc. 1991, 113, 9571; e) S. E.
Denmark, S. M. Pham, J. Org. Chem. 2003, 68, 5045.
[10] (E)-2-methyl cinnamaldehyde also undergoes coupling with
ethylene; however, a significant amount of 1,2-addition occurs
together with the usual 1,4-addition. See the Supporting
Information for details.
Our current efforts include expanding the scope and the
utility of the conjugate addition of monosubstituted alkenes
to unsaturated carbonyl compounds. More broadly, we
continue to explore catalytic reactions that utilize simple,
widely available chemical feedstocks, including a-olefins, and
provide important synthetic intermediates in a single oper-
ation.
[11] S. Ogoshi, K.-i. Tonomori, M.-a. Oka, H. Kurosawa, J. Am.
Chem. Soc. 2006, 128, 7077.
[12] J. D. Sieber, S. Liu, J. P. Morken, J. Am. Chem. Soc. 2007, 129,
2214.
Received: November 8, 2007
Published online: January 28, 2008
[13] General reviews: a) P. Brownbridge, Synthesis 1983, 85; b) I.
Kuwajima, E. Nakamura, Acc. Chem. Res. 1985, 18, 181; c) D. J.
Berrisford, Angew. Chem. 1995, 107, 192; Angew. Chem. Int. Ed.
Eng. 1995, 34, 178.
À
Keywords: C C coupling · conjugate additions · enolsilanes ·
nickel · olefins
.
[14] Protonation: a) K. Ishihara, D. Nakashima, Y. Hiraiwa, H.
Yamamoto, J. Am. Chem. Soc. 2003, 125, 24; Alpha chlorination:
b) Y.-H. Zhang, K. Shibatomi, H. Yamamoto, J. Am. Chem. Soc.
2004, 126, 15038; fluorination: c) D. Cahard, C. Audouard, J. C.
Plaquevent, N. Roques, Org. Lett. 2000, 2, 3699; Epoxidation:
d) F. A. Davis, A. C. Sheppard, B. C. Chen, M. S. Haque, J. Am.
Chem. Soc. 1990, 112, 6679; e) A. Ishii, J. Kojima, K. Mikami,
Org. Lett. 1999, 1, 2013; dihydroxylation: f) K. Morikawa, J.
Park, P. G. Andersson, T. Hashiyama, K. B. Sharpless, J. Am.
Chem. Soc. 1993, 115, 8463; Aldol: g) D. A. Evans, C. E. Masse,
J. Wu, Org. Lett. 2002, 4, 3375; h) D. A. Evans, J. Wu, C. E.
Masse, D. W. C. MacMillan, Org. Lett. 2002, 4, 3379.
[15] Reviews: a) R. H. Grubbs, Tetrahedron 2004, 60, 7117; b) K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4564;
Angew. Chem. Int. Ed. 2005, 44, 4490.
[1] a) G. H. Posner, An Introduction to Synthesis UsingOrgano-
copper Reagents, Wiley-Interscience, New York, 1980; b) P.
Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992; catalyzed conjugate addition: c) F.
Lopez, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res. 2007, 40,
179; d) J. Christoffers, G. Koripelly, A. Rosiak, M. Rössle,
Synthesis 2007, 1279; e) S. B. Tsogoeva, Eur. J. Org. Chem. 2007,
1701.
[2] For pioneering work in chlorotrimethylsilane-modified dialkyl-
cuprate conjugate addition reactions, see: a) E. J. Corey, F. J.
Hannon, N. W. Boaz, Tetrahedron 1989, 45, 545; b) Y. Horiguchi,
M. Komatsu, I. Kuwajima, Tetrahedron Lett. 1989, 30, 7087.
[3] a) Alpha Olefins Applications Handbook (Eds.: G. R. Lappin,
J. D. Sauer), Marcel Dekker, New York, 1989; b) “Frontiers in
Angew. Chem. Int. Ed. 2008, 47, 1893 –1895
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1895