readily available starting materials for the synthesis of 3-
hydroxyisoindolin-1-ones.
Deng and Li demonstrated a palladium-catalyzed oxidative
acylation reaction of 2-arylpyridines and alcohols in the pre-
sence of tert-butyl hydroperoxide as an oxidant.16c Li and
Kwong also reported a palladium-catalyzed oxidative cou-
pling of acetanilides and aldehydes to provide ortho-acyl
acetanilides.16d Recently, we described the rhodium-catalyzed
oxidative acylation of tertiary benzamides and aldehydes to
afford aryl ketones (Scheme 1).17
Scheme 1. Transition-Metal-Catalyzed Oxidative Acylation
and Intramolecular Cyclization
As part of an ongoing research program directed toward
the development of transition-metal-catalyzed carbonÀ
carbon bond forming reactions,18 we became interested
in developing an efficient synthetic route to 3-hydroxy-
isoindolin-1-ones from secondary benzamides and alde-
hydes via CÀH bond activation followed by amino-
cyclization. In this paper, we report the rhodium-catalyzed
regioselective ortho-acylation and intramolecular cyclization
sequence in the presence of silver carbonate as an oxidant to
prepare 3-hydroxyisoindolin-1-ones in good to high yields.
We initiated our investigation by exploring the coupling
of a variety of N-substituted benzamides (1aÀh) with
4-(trifluoromethyl)-benzaldehyde (2a); selected results are
summarized in Table 1. The cationic rhodium complex
derived from [Cp*RhCl2]2 and AgSbF6 catalyzed the cou-
pling of N-methyl benzamide (1a) and aryl aldehyde 2a in the
presence of Ag2CO3 as an oxidant to yield compound 3a in
34% yield (Table 1, entry 1). Further screening of N-mono-
substituted amides indicated that N-isopropyl benzamide
(1b) was the most effective in affording the 3-hydroxyiso-
indolin-1-one 3b, as shown in entries 2À8. However, the use
of other oxidants, such as AgOAc, K2S2O8, benzoquinone,
and t-BuO2H, was relatively ineffective in the coupling of 1b
and 2a (Table 1, entries 9À12). A screening of solvents re-
vealed that the best yield was obtained with THF and that
other oxygen-containing solvents, such as 1,4-dioxane and
THP, were less effective (Table 1, entries 13 and 14). After
further optimization, the best results were obtained by
increasing the amount of Ag2CO3 (300 mol %) and
the reaction temperature (150 °C) to afford the desired
3-hydroxyisoindolin-1-one 3b in 83% yield, as shown in
entry 16.
Having established the optimized reaction conditions,
the substrate scope was examined with respect to the
aldehyde (Scheme 2). The coupling of benzamide 1b and
aldehydes 2iÀm with para- or meta-substituted electron-
withdrawing groups afforded the corresponding products
3iÀm in moderate to high yields. This reaction was also
compatible with halogen-substituted aldehydes 2nÀp fur-
nishing the corresponding products 3nÀp in good yields.
Particularly noteworthy was the tolerance of the reaction
conditions to chloro and bromo groups, which provide a
versatile synthetic handle for further functionalization of
the products. In addition, 2-naphthaldehyde 2q and benz-
aldehyde 2r also smoothly underwent reaction to gener-
ate the corresponding products 3q and 3r, respectively.
Transition-metal-catalyzed CÀH bond functionaliza-
tions have emerged as powerful tools in organic synthesis,
since such methods avoid the necessity of multistep pre-
paration of preactivated starting materials and lead to an
improved overall efficiency of the desired transformation.9
In particular, the combination of transition metals and
directing groups is a useful strategy for facilitating CÀH
bond cleavage10 and has provided valuable conversions of
CÀH bonds to CÀX (X = carbon,11 oxygen,12 nitogen,13
and halogen14) bonds. Recently, remarkable progress has
been made in the transition-metal-catalyzed oxidative cou-
pling of two different aryl CÀH bonds for the construction
of areneÀarene linkages.15 However, cross-coupling reac-
tions between aryl CÀH and aldehyde CÀH bonds to form
corresponding aryl ketones remain relatively unexplored.16
Cheng et al. described a palladium-catalyzed cross-coupling
reaction of aromatic compounds containing a pyridine
directing group and aldehydes to afford aryl ketones.16a Li
and co-workers reported the palladium-catalyzed sp2Àsp2
coupling of 2-phenylpyridine with aliphatic aldehydes.16b
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Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Yu, J. Q.; Shi, Z. J.
CÀH Activation; Springer: Berlin, Germany, 2010.
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