.
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Table 1: Optimization of the reaction conditions .[a]
Entry Substrate [{RhCp*Cl2}2] CsOAc Allene 3a Yield[b] [%]
[mol%]
[equiv]
[equiv]
1[c]
2
3
4
5
1
2.5
2.5
0.5
0.25
0
0.3
0.3
0.3
0.3
0.3
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.1
0
62
64
19
2a
2a
2a
2a
2a
2a
0
6
7
0.5
0.5
92 (78)[d]
56
[a] Reaction conditions: 1 or 2a (0.4 mmol), allene 3a, [{RhCp*Cl2}2],
CsOAc, MeOH (2 mL), RT, 16 h. [b] Yields of isolated products; ratio of
4aa to other isomers: >99:1 based on GC–MS analysis. [c] 608C.
[d] 4 mmol scale based on 2a.
Scheme 3. RhIII-catalyzed annulation of N-pivaloyloxyarene amides 2
with cyclohexylallene (3a). General reaction conditions: 2 (0.4 mmol),
3a (0.8 mmol), [{RhCp*Cl2}2] (0.5 mol%), CsOAc (0.8 mmol), MeOH
(2 mL), RT. [a] [{RhCp*Cl2}2] (2.5 mol%). [b] 408C. [c] Ratio of 4 to
other isomers .
It should be noted that 4aa was the only isomer detected,
indicating a highly regio- and stereoselective reaction. The
newly formed exocyclic double bond allows for further
functionalization (vide infra). Gratifyingly, comparable cata-
lytic activity was achieved with a much lower catalyst loading
(0.5 mol% of dimer) (entries 3 and 4). Omission of RhIII
completely shut down the reactivity, demonstrating its
importance (entry 5). We also found that increasing the
CsOAc loading to 2 equiv considerably accelerated the
reaction and improved the yield to 92%.[15i,21] Notably, this
procedure is practical and scalable as 78% yield was obtained
when the reaction was conducted on a 4.0 mmol scale.
Attempts to lower the allene loading failed and the yield
decreased significantly (entry 7).
when the catalyst loading was simply increasedto 2.5 mol%,
the corresponding product 4la was obtained in 78% yield. As
another strong point, heterocycles are very well tolerated,
leading to valuable products. Electron-rich heterocycles like
furan 2m and thiophene 2n, which could potentially be
oxidized under oxidative conditions, gave the cyclized prod-
À
ucts in excellent yields. It is worth mentioning that the C H
activation took place exclusively at the a position of the furan
when 2m was employed. Owing to the prevalence of pyridine
À
in natural products and pharmaceuticals, the direct C H
À
Intriguingly, the regioselectivity of the C N bond-forma-
functionalization of pyridine represents a challenging but
attractive method. We were pleased to find that nicotinic (2p)
and isonicotinic acid (2o) derivatives are suitable substrates
providing the corresponding products in good yields under
slightly modified conditions.[22] A 1:1 mixture of regioisomers
4pa and 4pa’ was observed when a nicotinic acid derivative
was applied. It is surprising that the 3,5-dimethylbenzamide
derivative, in which both of the ortho positions are potentially
shielded, was found to react readily. However, an unusual
regioselectivity of the allene partner was observed in this case,
and the 3-substituted isoquinolone 6qa was obtained in 67%
yield, implying that the reaction outcome is sensitive to the
steric properties of the arene partner.
tion step (Scheme 1, type B) was in sharp contrast with that
observed in other preactivation strategies (Scheme 1,
type A),[3–5,17] wherein the nucleophilic attack or reductive
elimination predominantely occurred at the more substituted
end of the p-allyl metal intermediate. This unique feature
might arise from the steric hindrance of the Cp* ligand, and
the complete reversal of the selectivity may also benefit from
the rather mild conditions of this reaction.
The optimized reaction conditions were applicable to
a broad range of electron-poor and -rich aromatic substrates
(Scheme 3). Many valuable functional groups such as
methoxy (4ea), ester (4ha), chloro (4 fa), bromo (4ga), iodo
(4ka), and nitro (4ia) were well tolerated, providing ample
opportunity for further derivatization of the products. In the
reactions of meta-substituted substrates, good regioselectivity
The substrate scope was further extended to include
a
wide variety of mono- and multisubstituted allenes
(Scheme 4). Monosubstituted allenes bearing hydroxy
(4bb), ester (4ac), and silyl ether (4ad) functional groups
can be smoothly transformed into the desired products. In
accordance with previous observations,[3–5,17] an allene with an
À
favoring activation of the less hindered C H bond was
observed (4ja and 4ka). The ortho substituent retarded the
reaction, possibly because of steric interference. However,
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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