A R T I C L E S
Ohmiya et al.
Scheme 1. Metal-Mediated Allylic Substituions
formed through σ-π-σ isomerization of the allylmetal
intermediates.
While rather rare, R-selective allylic substitutions mediated
by transition metal complexes have also been reported. For
example, certain low-valent rhodium, ruthenium, and iron
complexes preferentially deliver R-substitution products in
reactions between allylic carbonates and soft carbon nucleophiles
such as malonate anions (Scheme 1c).7-9 The reactions of
R-chiral allylic compounds generally proceed with retention of
configuration. A mechanistic hypothesis to explain this regi-
oselectivity is summarized in Scheme 1c: strongly nucleophilic
(low-valent) transition metal complexes (M) attack the allylic
substrates in an SN2′ manner to form (σ-allyl)metal complexes,
which undergo a second SN2′ displacement with a carbon
nucleophile (R-). As with γ-selective substitution using orga-
nometallic reagents (R-M-) (Scheme 1b), however, the regi-
oselectivity of these R-substitution reactions is not always
complete.7,9 As shown in Scheme 1c, concomitant γ-substitution
proceeds through σ-π-σ allylic isomerization, which occurs
before the attack of the carbon nucleophile (R-).
In order to develop an alternative to existing regioselective
allylic substitutions, we contrived new γ-selective strategies
based on reaction pathways that proceed without forming the
problematic allylmetal species (Scheme 1d). We assumed that
an organometallic species (R-M) that is less nucleophilic than
M and R-M- in Scheme 1a-c would undergo carbometalation
across the C-C double bond (insertion) rather than oxidative
addition to form an allylmetal species with a higher metal
oxidation state. Regioselectivity in the carbometalation reaction
would be induced either by stereoelectronic effects that stabilize
the σ (Cꢀ-M) orbital through interactions with the σ* (CR-OX)
orbital or with the assistance of intramolecular coordination by
the leaving group (OX). ꢀ-Elimination of M-OX from the
alkylmetal intermediate would afford a formal SN2′ product.10
Furthermore, we knew that electrophilic or less nucleophilic
organometallic species could be prepared by a well established
transmetalation reaction between an acetoxopalladium(II) com-
plex and organoboronic acids.11
(7) For Rh-catalyzed R-selective allylic substitutions with carbon nucleo-
philes, see: (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998,
39, 1725–1728. (b) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc.
1998, 120, 5581–5582. (c) Evans, P. A.; Leahy, D. K. J. Am. Chem.
Soc. 2003, 125, 8974–8975. (d) Evans, P. A.; Lawler, M. J. J. Am.
Chem. Soc. 2004, 126, 8642–8643. (e) Evans, P. A.; Uraguchi, D.
J. Am. Chem. Soc. 2003, 125, 7158–7159. (f) Ashfeld, B. L.; Miller,
K. A.; Martin, S. F. Org. Lett. 2004, 6, 1321–1324. The stereospeci-
ficity of the Rh catalysis has been explained based on the [σ+π] nature
of the allyl (enyl) ligand.
product is in some cases contaminated with a small but
significant amount of the corresponding R-isomer, while in other
cases regioselectivity is almost lost.5,6 According to the
hypothetical mechanism shown in Scheme 1b, the R-isomer is
(5) The reaction of MeCu(CN)Li and cis-1-D-5-methyl-2-cyclohexenyl
acetate, which is a regiochemically unbiased substrate, showed 96:4
γ/R-selectivity: See ref 26b. For selected papers on γ-selective and
stereoselective allylic substitution reactions with stoichiometric alky-
lcopper(I) reagents with excellent 1,3-chirality transfer, see: (a)
Yanagisawa, A.; Nomura, N.; Noritake, Y.; Yamamoto, H. Synthesis
1991, 1130–1136. (b) Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii, S.;
Yamamoto, Y. J. Org. Chem. 1989, 54, 4055–4061. (c) Breit, B.;
Demel, P.; Studte, C. Angew. Chem., Int. Ed. 2004, 43, 3786–3789.
(d) Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P.
Angew. Chem., Int. Ed. 2005, 44, 4627–4631.
(8) For Ru-catalyzed R-selective allylic substitution with soft carbon
nucleophiles, see: Kawatsura, M.; Ata, F.; Hayase, S.; Itoh, T. Chem.
Commun. 2007, 4283–4285.
(9) For Fe-catalyzed R-selective allylic substitutions with soft carbon
nucleophiles, see: (a) Yanagisawa, A.; Nomura, N.; Yamamoto, H.
Synlett 1991, 513–514. (b) Plietker, B. Angew. Chem., Int. Ed. 2006,
45, 1469–1473. (c) Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 6053–
6056.
(10) For studies in this line [Cu-catalyzed γ-selective allylic and propargylic
substitutions with bis(pinacolato)diboron], see: (a) Ito, H.; Kawakami,
C.; Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034–16035. (b)
Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem.
Soc. 2007, 129, 14856–14857. (c) Ito, H.; Kosaka, Y.; Nonoyama,
K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424–
7427. (d) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008,
130, 15774–15775.
(6) When either arylcopper reagents or cinnamyl alcohol derivatives were
employed, the γ-selectivity is considerably reduced. See: refs 5c and
29. For allylic substitution reactions with stoichiometric arylcopper(I)
reagents with excellent γ-selectivity, see: (a) Harrington-Frost, N.;
Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel, P. Org. Lett. 2003,
5, 2111–2114. (b) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.;
Hyodo, T.; Kobayashi, Y. Org. Lett. 2008, 10, 1719–1722. (c)
Recently, Tomioka et al. reported the highly γ-selective, enantiose-
lective substitution of cinnamyl bromides with aryl Grignard reagents.
See: Selim, K. B.; Matsumoto, Y.; Yamada, K.; Tomioka, K. Angew.
Chem., Int. Ed. 2009, 48, 8733–8735.
(11) For a mechanistic study of the formation of a (σ-aryl)palladium(II)
intermediate by transmetalation with arylboronic acid and Pd(OAc)2,
see:Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996,
61, 2346–2351.
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880 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010