Takeshi Yamakawa and Naohiko Yoshikai
stereochemistry of 3i is tentative and is based on the as-
sumption of a syn-hydroarylation mechanism. In the former
reaction, the unreacted alkene was recovered as an E/Z mix-
ture (1:1), whereas only the E-isomer was recovered in the
latter.
The relevance of the present catalytic species and reaction
pathways to the chemistry of well-defined cobalt-NHC com-
plexes[14] remains unclear, and it appears premature to give
an unambiguous interpretation of the above observations.
Nevertheless, some mechanistic speculations can be made.
Alkene isomerization typically proceeds through hydrome-
Next, the reaction of [D]-1a with 4-methoxyallylbenzene
2b under the same reaction conditions afforded 3i in 59%
yield, where deuterium incorporation into the 2-position
was observed to a modest extent (0.49D in total) with low
diastereoselectivity (Scheme 5c). Note also that the deuteri-
um content of the unreacted indole substrate decreased to
77%, while the unreacted alkene was recovered exclusively
as (E)-5i with minor (<10%) deuterium incorporation into
the b-position. More strikingly, the reaction of [D]-1a and 1-
homoallyl-4-methoxybenzene 8 resulted in virtually no sig-
nificant deuterium incorporation into any position of the hy-
droarylation product 3x (Scheme 5d), while the deuterium
content of the unreacted indole decreased to 54%.[13]
To probe the origin of the above anomalous observations,
control experiments were performed with a modified cata-
lytic system using [D7]-iPrMgBr instead of CyMgBr
(Scheme 6). The reaction of 1a alone resulted in significant
incorporation of deuterium (40%), presumably from the b-
position of the Grignard reagent, into the C2 position of the
recovered indole (42% yield; Scheme 6a). The rest of 1a
largely underwent reduction of the imine moiety by the
Grignard reagent. On the other hand, the reaction of 2b
alone cleanly afforded (E)-5i with only slight deuterium in-
corporation into the olefinic and allylic positions
(Scheme 6b). The reaction of 1a and 2b under the modified
catalytic system resulted in partial and diastereoselective
deuterium incorporation into the C2-Ha position of the hy-
droarylation product 3i (Scheme 6c).
À
talation–b-hydride elimination or allylic C H activation-re-
ductive elimination.[15] While the control experiment in
Scheme 6b does not allow us to distinguish between these
mechanisms, we speculate that the latter is more likely in
light of a related Co–NHC–Grignard catalytic system for
alkene isomerization.[12] Alkene hydroarylation with a low-
valent transition metal catalyst is generally considered to in-
À
volve three major steps, that is, C H oxidative addition to
À
the metal center, alkene insertion into the M H bond, and
[1]
À
C C bond-forming reductive elimination. While we also
prefer this mechanistic framework,[4] the H/D exchange of
1a caused by [D7]-iPrMgBr (Scheme 6a) and the low deute-
rium incorporation into 3x (Scheme 5d) apparently indicate
further mechanistic complexity. We speculate that the cobalt
precatalyst and the secondary Grignard reagent give rise to
a low-valent cobalt hydride species, and that this putative
species undergoes exchange of hydrogen atoms with the
indole substrate, thus interfering with the incorporation of
the original C2-H atom into the hydroarylation product.
The regio- and diastereoselective deuterium incorporation
observed for (Z)- and (E)-5i (Scheme 5a, b) may point to
regio- and stereoselective (most likely syn-selective) inser-
À
tion of these alkenes into the Co H bond. Upon the alkene
insertion, the resulting alkylcobalt intermediate would
prefer to undergo reductive elimination rather than b-hy-
dride elimination because the latter pathway would deterio-
rate the diastereoselectivity of the deuterium incorporation.
In summary, we have reported on a Co–NHC–CyMgBr
catalytic system for the indole alkylation reaction with aryl-
substituted alkenes to afford 1,1-diarylalkane derivatives
with exclusive regioselectivity. Allyl-, homoallyl-, and bisho-
moallylbenzene derivatives are amenable to the regiocon-
À
vergent C C bond formation through a tandem alkene iso-
merization–hydroarylation sequence. The Co–DMPU–
tBuCH2MgBr catalytic system allows complementary, linear-
selective alkylation. Deuterium-labeling experiments shed
light on the involvement of the secondary alkyl Grignard re-
À
agent in the C H activation process. We speculate that the
secondary alkyl Grignard reagents also play important roles
À
in other relevant cobalt-catalyzed C H functionalization re-
actions.[4b,10e,16] Extension of the substrate scope is currently
underway to establish a general synthetic approach to 1,1-di-
arylalkanes.[17]
Experimental Section
Typical Procedure: Synthesis of 1-Methyl-2-(1-phenylpropyl)-1H-indole-3-
carbaldehyde (3a)
Scheme 6. Control experiments using deuterated Grignard reagent. The
number of protons on each carbon atom was determined by 1H NMR
spectroscopy using the integration of the indole C4-H (a, c) or the me-
thoxy CH3 (b) as the reference.
To a solution of (E)-N-(4-methoxyphenyl)-1-(1-methyl-1H-indol-3-yl)me-
thanimine (1a, 52.9 mg, 0.20 mmol), allylbenzene (2a, 35.5 mg,
Chem. Asian J. 2014, 9, 1242 – 1246
1245
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