.
Angewandte
Communications
Table 1: Optimization of reaction conditions.
Table 2: Scope for aryl and heteroaryl substrates.[a]
Entry
Catalyst (x mol%)
Additive
t
Yield [%][a]
[h]
(8a:8a’)
1[b]
2
[(Cp*RhCl2)2] (2.5)
[(Cp*RhCl2)2] (0.5)
[(Cp*RhCl2)2] (1.0)
[(Cp*RhCl2)2] (1.0)
[(RuCl2{p-cymene})2] (3.0)
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
0.2
12
4.0
10
8
98 (29:1)
98 (27:1)
98 (54:1)
98 (98:1)
96 (3:1)
3
4[c]
5
1
[a] Yields determined by H NMR spectroscopy. [b] Reaction at 608C.
[c] Reaction at 0.01m. The entry in bold marks optimized reaction
conditions. Cp*=pentamethylcyclopentadienyl.
regioselectivity (54:1) and reaction time (4 h) was achieved by
using 1 mol% of catalyst at RT (Table 1, entry 3). The
regioselectivity could be further improved under high-dilu-
tion conditions (0.01m), although a longer reaction time (10 h)
was again needed (Table 1, entry 4). A ruthenium catalyst
([(RuCl2{p-cymene})2], 3.0 mol%)[11] also gave the isoquino-
lones in excellent yields, however, with poor regioselectivity
(3:1; Table 1, entry 5). The structure of 8a was unambiguously
[a] Yields of isolated products are given. [b] Isolated as a 10:1 mixture of
regioisomers. [c] Reaction at 608C. [d] 2.5 mol% [(Cp*RhCl2)2] used;
reaction at 608C. [e] 2.2 mmol scale reaction was also performed in the
presence of 0.5 mol% catalyst at RT to complete in 3 h in 98% yield.
[f] Regioselectivity of 11:1. TMS=trimethylsilyl.
1
assigned by H/13C NMR spectroscopy and X-ray crystallog-
raphy.[12]
It is noteworthy that this intramolecular rhodium-cata-
ꢀ
ꢀ
lyzed C H/N O bond functionalization reaction provides
isoquinolones with reverse regioselectivity compared to the
reported intermolecular version. In the latter case, when
internal alkynes substituted with alkyl and aryl groups are
employed, aryl groups are typically installed at the 3 position
of isoquinolones.[5–8,13] In contrast, our intramolecular reac-
tion allows the installation of aryl groups at the 4 position of
isoquinolones. This reverse regioselectivity offers a great
synthetic potential for the construction of benzoindolizidine
and indolizidine frameworks [Eq. (3)].
608C (8m and 8n). Variation of the substituents on the phenyl
group or replacement of the phenyl group with an alkyl group
(such as methyl) showed that the electronic environment of
the alkyne moiety had little impact on the reaction efficiency;
8p, 8q, and 8r were obtained in 98%, 97%, and 97% yield,
respectively. The reaction with TMS-protected alkyne turned
out to be more efficient than that with phenyl-substituted
alkyne and afforded 8o in excellent yield, thus providing
a useful handle for further transformation.
With the optimal conditions in hand, we surveyed various
substrates to determine the scope of the reaction. The
annulation reactions proceeded smoothly to afford isoquino-
lones and heteroaryl analogues in good to excellent yields
(Table 2). Awide range of important functional groups on the
aryl moieties of benzamides 7, such as chloro, bromo, nitro,
ester, and cyano groups, were well tolerated under the
reaction conditions. Substrates with both electron-donating
and electron-withdrawing groups at the para position of aryl
groups participated in this reaction; electron-deficient sub-
strates generally reacted faster than electron-rich ones (8a–
g). Reactions with ortho-substituted benzamides also
smoothly proceeded to give the corresponding products in
excellent yields, albeit with diminished reaction rates (8h and
8i). meta-Substituted benzamides smoothly reacted to give
the corresponding isoquinolones in excellent yields with
regioisomers (8j and 8k) in a ratio of approximately 10:1.
Extension of this reaction to heteroaryl carboxamides, such as
thiophene and indole, proved successful when the reaction
was performed in the presence of 2.5 mol% of catalyst at
Next, we investigated the length of the tethers between
the oxygen atom and the alkyne. All of the substrates with
three-carbon-atom tethers gave the corresponding isoquino-
lones in excellent yields (8a–q). Furthermore, a rigid tether
bearing an aryl group was well tolerated (8u). While the
substrate with the two-carbon-atom tether also afforded 8s in
high yield with 11:1 regioselectivity, that with the four-carbon-
atom tether was less effective and provided 8t in moderate
yield.
In 2010, Li and co-workers reported the rhodium(III)-
catalyzed synthesis of 2-pyridones through oxidative alkene
2
[14]
ꢀ
C(sp ) H activation of N-arylacrylamides.
While this
represents a remarkable progress, the regioselectivity of the
coupling with unsymmetrical alkynes is moderate. Later,
Rovis et al. developed a new rhodium(III) catalyst with
a
bulkier ligand (1,3-di-tert-butylcyclopentadienyl) to
improve regioselectivity, still favoring the normal regioselec-
tivity in which aryl groups are substituted adjacent to nitrogen
atoms.[15] We reasoned that our new intramolecular rhodium-
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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