compounds in general is reflected, for instance, by
antidopaminergic,7 anxiolytic,8 hypnotic,9 antimicrobial,10
antiviral,11 and antitumoral12 activities.
or apparative requirements. Most noticeable, they are not
particularly well suited for the preparation of compound
libraries. Therefore, the search for an operational con-
venient, modular, and broadly applicable isoindolinone
synthesis still represents a challenging research task.
Inspired by the surprisingly facile formation of the
isoindolinone 2 from the highly functionalized ortho-
formylbenzophenone 1 we decided to probe this novel
type of lactamization reaction as a general new entry to
isoindolinones also using less complex substrates.
To prepare a variety of different 2-acylbenzaldehydes
of type 6 we employed the protocol developed by Kotali et
al.21 which proved to be highly reliable. For this purpose,
a series of N-acylhydrazines (3) were condensed with
salicylic aldehyde (4) to form N-aroylhydrazones 5, which
were then oxidized with lead tetraacetate to give the
desired substrates (6) in typically 45À70% overall yield
(Scheme 2).
Figure 1. Natural products and biologically active compounds
containing the isoindolin-1-one moiety.
Scheme 2. Preparation of 2-Acylbenzaldehydes According to
Kotali
While early methods for the synthesis of isoindolinones
are based on condensation reactions13 the growing im-
portance of this compound class is reflected by the recent
development of novel approaches exploiting, for instance,
radical cyclization,14 ortho-lithiation/cyclization,15 Pd-cata-
lyzed cyclo-carbonylation,16 In-mediated allylation/cycliza-
tion of N-sulfinyl imines,17 Pd-catalyzed R-substitution of
isoindolinones,18 Rh-catalyzed arylation of 2-formylbenzo-
ate-derived N-tosylimines,19 and Ni(0) mediated cyclization
of N-benzoylaminals.20
We started our study with ortho-formylbenzophenone
(6a) as a model substrate which can be considered as a
most simple pestalone analog. Initial attempts to convert
6a into the corresponding isoindolinone rac-7a under the
conditions used before for the conversion of 1 into rac-2,
i.e. by treating a 1,4-dioxane solution of 6a with aqueous
NH3/NH4Cl solution (pH = 8.0) at room temperature,3
resulted only in the formation of undefined, highly polar
(possibly oligomeric) products. Treatment of 6a with
unbuffered aqueous NH3 (4 equiv) was also not successful
(Scheme 3).
Nevertheless, most of the existing methods suffer from
certain limitations with respect to yield, substrate scope,
(11) (a) Maugeri, C.; Alisi, M. A.; Apicella, C.; Cellai, L.; Dragone,
P.; Fioravanzo, E.; Florio, S.; Furlotti, G.; Mangano, G.; Ombrato, R.;
Luisi, R.; Pompei, R.; Rincicotti, V.; Russo, V.; Vitiello, M.; Cazzolla,
N. Bioorg. Med. Chem. 2008, 16, 3091–3107. (b) Zhao, X. Z.; Maddali,
K.; Marchand, C.; Pommier, Y.; Burke, T. R. Bioorg. Med. Chem. 2009,
17, 5318–5324.
(12) Muller, G. W.; Chen, R.; Huang, S. Y.; Corral, L. G.; Wong,
L. M.; Patterson, R. T.; Chen, Y.; Kaplan, G.; Stirling, D. I. Bioorg.
Med. Chem. Lett. 1999, 9, 1625–1630.
(13) (a) Thiele, J.; Schneider, J. Ann. Chem. 1909, 369, 287–299. (b)
Grigg, R.; Gunaratne, H. Q. N.; Sridharan, V. J. Chem. Soc., Chem.
Commun. 1985, 17, 1183–1184. For a review, see:(c) Takahashi, I.;
Hatanaka, M. Heterocycles 1997, 45, 2475–2499.
Scheme 3. Treatment of 6a and 6b with Ammonia
ꢀ
(14) Lopez-Valdez, G.; Olguın-Uribe, S.; Millan-Ortız, A.; Gamez-
´ ´
~
Montano, R.; Miranda, L. D. Tetrahedron 2011, 67, 2693–2701.
(15) Smith, K.; El-Hiti, G.; Hegazy, A. Chem. Commun. 2010, 46,
2790–2792.
ꢀ
ꢀ
(16) (a) Marosvoelgyi-Hasko, D.; Takacs, A.; Riedl, Z.; Kollar, L.
Tetrahedron 2011, 67, 1036–1040. (b) Orito, K.; Miyazawa, M.; Nakamura,
T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.;
Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71, 5951–5958.
(17) Sun, X.; Liu, M.; Xu, M.; Lin, G. Org. Lett. 2008, 10, 1259–1262.
ꢀ
(18) (a) Perard-Viret, J.; Prange, T.; Tomas, A.; Royer, J. Tetrahe-
Interestingly, 2-(2-hydroxybenzoyl)benzaldehyde (6b),
which more closely resembles the core functionality of
dron 2002, 58, 5103–5108. (b) Li, P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2011, 50, 6396À6400.
(19) (a) Wang, Z.; Feng, C.; Xu, M.; Lin, G. J. Am. Chem. Soc. 2007,
129, 5336. (b) Kurihara, K.; Yamamoto, Y.; Miyaura, N. Adv. Synth.
Catal. 2009, 351, 260–270.
(21) (a) Kotali, A.; Papapetrou, M.; Dimos, V.; Harris, P. Org. Prep.
Proced. Int. 1998, 30, 177–181. (b) Kotali, A.; Tsoungas, P. G. Tetra-
hedron Lett. 1987, 28, 4321–4322.
(20) Shacklady-McAtee, D. M.; Dasgupta, S.; Watson, M. P. Org.
Lett. 2011, 13, 3490–3493.
Org. Lett., Vol. 13, No. 19, 2011
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