Highly enantioselective and regioselective nickel-catalyzed coupling of allenes, aldehydes, and silanes

Article abstract of DOI:10.1021/ja0521831

A complex derived from Ni(cod)₂ and NHC-IPr catalyzes a three-component coupling reaction involving allenes, aldehydes, and organosilanes and transfers the axial chirality of the allene to a stereogenic center in the product with very high fide

Full text of DOI:10.1021/ja0521831

Published on Web 04/29/2005
Highly Enantioselective and Regioselective Nickel-Catalyzed Coupling of
Allenes, Aldehydes, and Silanes
Sze-Sze Ng and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received April 5, 2005; E-mail: tfj@mit.edu
Table 1. Nickel-Catalyzed, Enantioselective Three-Component
Catalytic, stereoselective multicomponent coupling reactions
assemble highly functionalized molecules in a single operation from
very simple precursors.1 We and others have developed several such
reactions that involve catalytic reductive coupling of alkynes with
common functional groups, such as aldehydes,2 epoxides,3 and
imines.4 Allenes,5 however, have received far less attention in this
context.6 Moreover, nearly all existing classes of intermolecular
reactions between allenes and aldehydes involve the coupling of
an sp2-hybridized carbon with the carbonyl group, affording either
homoallylic alcohols (multicomponent coupling reactions)6 or
homopropargylic alcohols (allenylmetal additions).7 We report here
a rare example of the alternative, that is, the intermolecular addition
of an electrophile to the central, sp-hybridized,8 and ostensibly least
nucleophilic carbon of an unactivated allene (eq 1).9 Among
intermolecular transition-metal-catalyzed multicomponent coupling
reactions involving allenes and aldehydes, these are the first that
give allylic (as opposed to homoallylic6) alcohol derivatives, the
first that are reductive (instead of alkylative6), and finally, the first
that are highly enantioselective.10
Coupling of Allenes, Aldehydes, and Organosilanesa
In examining combinations of allenes, aldehydes, and reducing
agents, we found that a species derived from Ni(cod)2 and
tricyclopentylphosphine (Cyp3P) catalyzed a novel, efficient, and
selective three-component coupling process11 when Et3SiH was used
(Table 1, entry 1). The ratio of allylic and homoallylic products
(i.e., coupling at the sp vs an sp2 carbon) was >95:5, and only the
Z allylic alcohol was detected,12 but there was significant erosion
of enantiomeric purity, from 95 to 62% ee.
The use of the imidazolinyl carbene ligand NHC-IPr13,14 (1,
entry 2) completely eliminated this limitation, a case of a
dependence of enantioselectivity upon the nature of an achiral
ligand. Chirality transfer is commonly observed in intramolecular
reactions of enantiomerically enriched allenes,15 but the vast major-
ity of intermolecular examples16 involve allenylmetal additions.5,7c
Moreover, only achiral, racemic, or 1:1 mixtures of diastereomeric
allenes were used in all previous multicomponent coupling reac-
tions.6 Thus, the transfer of allene axial chirality in such processes
is now documented for the first time.
a See eq 1. Standard conditions: to a solution of Ni(cod)2 (20 mol %)
and 1 (40 mol %) in THF at -78 °C were added the allene (100 mol %),
aldehyde (300 mol %), and silane (300 mol %). The mixture was warmed
to ambient room temperature over 6 h, stirred 12 h, and purified by
chromatography (SiO2). Absolute configuration determined by Mosher ester
analysis. See Supporting Information. b Ratio of allylic to the sum of all
homoallylic products. c Determined by 1H NMR of unpurified reaction
mixtures. d Isolated yield of allylic alcohol shown. e Determined by chiral
g
HPLC. f Cyp3P (20 mol %) was used in place of 1. 1H NMR of crude
reaction mixture indicated a 94:6 ratio of 3f:3a (reductive dechlorination).
the user flexibility with respect to which silyl “protective group”
is incorporated (entries 9 and 10).
Two aspects of the complete preference for the Z alkene geometry
deserve further comment. In related reductive coupling reactions
involving alkynes, E allylic alcohols are formed exclusively (cis
addition of H and RCHO across the triple bond).2 Allenes and
alkynes are thus complementary to one another in this regard.
Second, the Z geometry corresponds to attachment of the aldehyde
to the more hindered face of the allene. In a similar vein, the site
Other noteworthy features include the compatibility of these
carbon-carbon bond-forming reactions with Lewis basic ethers,
esters, and aryl chlorides (entries 5-7) and, in the case of
differentially substituted 1,3-allenes, the complete site selectivity
(which double bond reacts) in the formation of the allylic product
(entries 8-11). Other organosilanes can also be employed, giving
9
7320
J. AM. CHEM. SOC. 2005, 127, 7320-7321
10.1021/ja0521831 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
selectivity observed with allenes 2b and 2c (entries 8-11) suggests
addition across the more hindered double bond.
Acknowledgment. Support for this work was provided by the
National Institute of General Medical Sciences (GM-063755). We
also thank the NIGMS (GM-072566), NSF (CAREER CHE-
0134704), Amgen, Boehringer Ingelheim, Bristol Myers-Squibb,
GlaxoSmithKline, Johnson & Johnson, Merck Research Labora-
tories, Pfizer, the Sloan Foundation, Wyeth, and the Deshpande
Center (MIT) for generous financial support. 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)).
The results of a deuterium labeling experiment provided infor-
mation critical to the development of an explanation for these
surprising results. We repeated a previous experiment (entry 8),
using Et3SiD (97% D) in place of Et3SiH (eq 2). Slightly lower
allylic:homoallylic selectivity (89:11) was observed, but 2H-3g had
the same enantiomeric excess, Z/E ratio, and site selectivity as that
of 3g. Deuterium incorporation occurred at a single site and with
>95:5 diastereoselectivity. The configuration was assigned as R
by converting 2H-3g to the known 2-2H-cyclohexylacetic acid,
1
esterifying with methyl (R)-mandelate, and comparing H NMR
Supporting Information Available: Experimental procedures and
data for all new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
spectra of the product (4) and the corresponding unlabeled ester.17
References
(1) Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005. (b) Ramo´n, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2005, 44, 1602-1634.
(2) Nickel: (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119,
9065-9066. (b) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000,
2, 4221-4223. (c) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am.
Chem. Soc. 2003, 125, 3442-3443. (d) Review: Montgomery, J. Angew.
Chem., Int. Ed. 2004, 43, 3890-3908. (e) Rhodium: Jang, H.-Y.;
Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4664-
4668.
(3) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076-8077.
(4) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364-
1367. (b) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43,
3941-3944.
(5) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; Vols. 1-2.
(6) (a) Anwar, U.; Grigg, R.; Rasparini, M.; Sridharan, V. Chem. Commun.
2000, 645-646. (b) Ha, Y.-H.; Kang, S.-K. Org. Lett. 2002, 4, 1143-
1146. (c) Hopkins, C. D.; Malinakova, H. C. Org. Lett. 2004, 6, 2221-
2224. (d) Montgomery, J.; Song, M. Org. Lett. 2002, 4, 4009-4011. (e)
Kang, S.-K.; Yoon, S.-K. Chem. Commun. 2002, 2634-2635. (f) Wu,
M.-S.; Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem. Soc. 2003, 125,
12426-12427.
The results of this experiment can be accounted for by the
sequence of events shown in Scheme 1. Back-bonding likely
induces significant deformation from linearity of the allene, and of
the four isomeric 1:1:1 complexes of Ni, NHC-IPr (L), and allene
2b, only A places the large Ni-L complex on the less hindered
allene face and less substituted double bond. The sense of induction
may be explained by benzaldehyde coordination away from the
methyl group with the Ph group placed between L and (cyclohexyl)-
methylidene, reorganization to allow overlap between a C-Ni bond
and π*, and oxidative addition to give metallacycle B.
Scheme 1
(7) (a) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3927-3929.
(b) Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Org. Chem. 1982, 47, 2225-
2227. (c) Marshall, J. A. Chem. ReV. 2000, 100, 3163-3186.
(8) (a) Taylor, D. R.; Wright, D. B. J. Chem. Soc., Perkin Trans. 1 1973,
956-959. (b) Trost, B. M.; Pinkerton, A. B.; Seidel, M. J. Am. Chem.
Soc. 1999, 121, 10842-10843. (c) Holemann, A.; Reissig, H.-U. Org.
Lett. 2003, 5, 1463-1466. (d) Takimoto, M.; Kawamura, M.; Mori, M.
Org. Lett. 2003, 5, 2599-2601. (e) Yang, F.-Y.; Shanmugasundaram, M.;
Chuang, S.-Y.; Ku, P.-J.; Wu, M.-Y.; Cheng, C.-H. J. Am. Chem. Soc.
2003, 123, 12576-12583.
(9) Coupling of the allene sp carbon with carbonyl groups is much more
common in intramolecular reactions, where geometric constraints of ring
closure play a substantial role. See volume 2 of ref 5 for examples.
(10) (a) See ref 6c for an isolated example of highly enantioselective coupling,
and refs 5 and 7c for enantioselective allenylmetal addition.
(11) For examples of Ni-catalyzed multicomponent coupling reactions of
allenes, see ref 6d-f and (a) Satyanarayana, N.; Alper, H.; Amer, I.
Organometallics 1990, 9, 284-286. (b) Wu, M.-S.; Rayabarapu, D. K.;
Cheng, C.-H. J. Am. Chem. Soc. 2003, 125, 12426-12427.
We believe that there is a direct link between the selectivity for
the Z alkene geometry and the sense of induction of deuterium
labeling. σ-Bond metathesis between B and Et3SiD could afford
η3-allyl-Ni complex C. Reductive elimination with retention leads
to the observed Z alkene and R configuration at the labeled carbon.
Conversely, the alternative complex (D) gives the opposite sense
of selectivity in both cases (E and S, respectively). Our explanation
for the absence of this product is the severe 1,3-interaction between
the Me and Cy groups present in D.
(12) Established by nOe experiments and comparison to related Z and E allylic
alcohols: (a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2001, 66, 4333-4339. (b) Colby, E. A.; Jamison, T. F. J. Org.
Chem. 2003, 68, 156-166.
(13) Review: Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(14) Ni-NHC-catalyzed aldehyde additions. (a) Alkynes: Mahandru, G. M.;
Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698-3699. (b)
1,3-Dienes: Sawaki, R.; Sato, Y.; Mori, M. Org. Lett. 2004, 6, 1131-
1133.
Finally, the overall site selectivity avoids formation of the more
congested alkene (Cy vs Me), and this bias appears to be operative
in the transition state of reductive elimination from C.
(15) (a) Gibbs, R.; Bartels, K.; Lee, R. W. K.; Ojamura, W. H. J. Am. Chem.
Soc. 1989, 111, 3717-3725. (b) Shepard, M. S.; Carreira, E. M. J. Am.
Chem. Soc. 1997, 119, 2597-2605. (c) Wender, P. A.; Glorius, F.;
Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc. 1999, 121,
5348-5349. (d) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am.
Chem. Soc. 1999, 121, 9895-9896. (e) In-depth discussion: Brummond,
K. M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156-5163.
(16) (a) Waters, W. L.; Linn, W. S.; Caserio, M. C. J. Am. Chem. Soc. 1968,
90, 6741-4025. (b) Ikeda, I.; Honda, K.; Osawa, E.; Shiro, M.; Aso, M.;
Kanematsu, K. J. Org. Chem. 1996, 61, 2031-2037. (c) Ma, S.; Ren, H.;
Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817-4830.
In summary, this enantioselective, three-component coupling
occurs by way of a previously unobserved process in allene-
aldehyde reactions and is promoted by a Ni-NHC complex that
transfers the axial chirality of the allene to the product with very
high fidelity. This catalyst also possesses the qualities necessary
to induce a surprising sense and degree of Z/E and site selectivity.
The implementation of this single-step formation of synthetically
useful, silyl-protected Z allylic alcohols in the synthesis of complex
molecules is currently under investigation.
(17) See Supporting Information and (a) Brown, J. M.; Parker, D. Tetrahedron
Lett. 1981, 22, 2815-2818. (b) Fleming, I.; Jones, G. R.; Kindon, N. D.;
Landais, Y.; Leslie, C. P.; Morgan, I. T.; Peukert, S.; Sarkar, A. K. J.
Chem. Soc., Perkin Trans. 1 1996, 1171-1196.
JA0521831
9
J. AM. CHEM. SOC. VOL. 127, NO. 20, 2005 7321