type of transformation can result in the formation of more
valuable nitrogen-containing compounds including aza-
heterocycles, but most olefin substrates were limited to
functionalized R,β-unsaturated carbonyl compounds,8aÀh
enol derivatives,8i and allylboranes8j or allylsilanes.8k In
comparison, the use of an unactivated olefin as one of the
π-coupling partners is highly uncommon possibly due to
its poor reaction activity.9 Additionally, unactivated ole-
fins easily react with N-aryl imines to produce heterocycles
via aza-DielsÀAlder cyclization10 instead of linear cou-
pling. Nevertheless, Tamaru reported that Ni(0)-catalyzed
reductive coupling of unfunctionalized dienes with aldi-
mines using Et2Zn as a reductant and this transformation
could realize the homoallylation of aldimines in which
a CÀC bond was formed between the R-carbon atom of
the alkene and the aldimine carbon atom (Scheme 1a).11
Moreover, Krische also reported that Ru(II)-catalyzed
reductive coupling of dienes with aldehydes could furnish
homoallyl alcoholsinwhichaCÀC bond formationoccurs
highly regioselectively at the γ-carbon atom of dienes
(Scheme 1b).4c
δ-unsaturated R-amino acid derivatives in which a CÀC
bond formation occurs highly regioselectively at the
γ-carbon atom of dienes (Scheme 1b). Most of the pro-
ducts described in this report are R-branched allyl sub-
stituted R-amino acid derivatives, and their corresponding
derivatives could be further used as fundamental building
blocks in many pharmacologically active molecules such
as Cyclomarin A14 and antimalarial lipopeptides.12b The
previous synthesis of R-branched allylic R-amino acid
derivatives generally suffers from tedious reaction steps
and harsh reaction conditions.12b,14,15
The Ru(II)-catalyzed reductive coupling of iminoester
1a (0.20 mmol) with isoprene 2a (0.80 mmol) was first
investigated using RuH2(CO)(PPh3)2 (10 mol %) as the
catalyst in toluene (3.0 mL) at 130 °C for 24 h, and we
quickly found that this transformation could provide a
12% yield of a branched-chain R-amino acid derivative
(3a) in the absence of any additives (Table 1, entry 1).
Considering the Ni-catalyzed homoallylation of aldimines
with dienes is involved in the hydrogen-transfer process in
the presence of Et2Zn,11 we tried to conduct this reaction
further to screen various hydrogen sources to achieve
satisfying yields (entries 2À6). To our delight, i-PrOH
could afford 3a in 70% yield (entry 6). Then, we investi-
gated the effect of various Ru salts on the reductive
coupling reaction. Among the tested Ru catalysts (entries
6À11), Ru-hydride catalysts were effective catalysts for
this transformation, and RuHCl(CO)(PPh3)3 provided 3a
in up to 90% isolated yield (compare entries 6 and 11).
However, other nonhydride ruthenium catalysts such as
RuCl3 gave trace amounts of 3a (entries 7 and 9). Finally,
we also investigated other reaction conditions to define the
reaction parameters and found that variation of the cata-
lyst loading (entry 12) and lower reaction temperature
(entry 13) all resulted in poorer yields (see Supporting
Information for more details).
Scheme 1. Transition-Metal-Catalyzed Reductive Coupling of
Imine or Aldehyde/Diene
On the other hand, R-imino esters have served as versa-
tile acceptors of nucleophiles, and their corresponding
addition reaction with organometallic reagents, Mannich
donors, etc. provided a concise synthetic approach to
R-amino acid derivatives.12 Our research interests in ex-
ploring methods for the rapid assembly of R-substituted
R-amino acid derivatives13 prompted us to investigate the
direct coupling reaction of olefins with R-imino esters.
Herein, we disclose the first Ru(II)-catalyzed diene/
iminoester reductive coupling reaction to give various γ,
Having established an efficient reaction protocol that
enables the smooth reductive coupling transformation
of particular isoprene, we next investigated its scope with
regard to the N-aryl iminoester coupling partner. As
shown in Table 2, aryl substitution on the imine nitrogen
(R1) showed no deleterious electronic effects, and the
substrates with a para-electron donating group (4-MeO,
4-Me) or electron withdrawing group (such as 4-Cl, 4-Br,
4-NO2, 3-CO2Et) on the phenyl ring afforded the
R-branched-chain allyl-R-amino acid derivatives in good
to excellent yields (54À90%, entry 1). It is worth noting
that the nitro-group-containing R-imino ester (1g) also
gave a 17% yield of the unexpected product 3g-2 in which
a CÀC bond was formed between the β-carbon atom of
isoprene and the imine carbon atom (entry 1). Compared
with the N-phenyl imino ester (1c), N-(1-naphthyl)-R-
iminoester (1h) underwent a slightly worse conversion
and provided a moderate yield of 3h (50%, entry 2)
possiblly due to the higher steric hindrance around the
(9) (a) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc.
Chem. Res. 2007, 40, 1394. (b) Komanduri, V.; Grant, C. D.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 12592. (c) Barchuk, A.; Ngai, M.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12644. (d) Barchuk, A.;
Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432.
(10) Selected examples: (a) Zhu, Z. B.; Shao, L. X.; Shi, M. Eur. J.
Org. Chem. 2009, 2576. (b) Xie, M.; Liu, X.; Zhu, Y.; Zhao, X.; Xia, Y.;
Lin, L.; Feng, X. Chem.;Eur. J. 2011, 17, 13800.
(11) Kimura, M.; Miyachi, A.; Kojima, K.; Tanak, S.; Tamaru, Y.
J. Am. Chem. Soc. 2004, 126, 14360.
(12) Selected examples: (a) Hatano, M.; Horibe, T.; Ishihara, K.
J. Am. Chem. Soc. 2010, 132, 56. (b) Ghosh, S. K.; Somanadhan, B.; Tan,
K. S.-W.; Butler, M. S.; Lear, M. J. Org. Lett. 2012, 14, 1560.
(13) (a) Zhu, S.; Dong, J.; Fu, S.; Jiang, H.; Zeng, W. Org. Lett. 2011,
13, 4914. (b) Chen, J.; Lu, X.; Lou, W.; Ye, Y.; Jiang, H.; Zeng, W.
J. Org. Chem. 2012, 77, 8541.
(14) Schultz, A. W.; Oh, D. C.; Carney, J. R.; Williamson, R. T.;
Udwary, D. W.; Jensen, P. R.; Gould, S. J.; Fenical, W.; Moore, B. S.
J. Am. Chem. Soc. 2008, 130, 4507.
(15) Edagwa, B. J.; Taylor, C. M. J. Org. Chem. 2009, 74, 4132.
B
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