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Synlett 2006(5): 0801-0803  
DOI: 10.1055/s-2006-933114
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short and Efficient Synthesis of Isoindolin-1-ones

Takayuki Tsuritani*a, Satoshi Kiia, Atsushi Akaoa, Kimihiko Satoa, Nobuaki Nonoyamaa, Toshiaki Masea, Nobuyoshi Yasudab
a Process Research, Banyu Pharmaceutical Co. Ltd., 9-1, Kamimutsuna 3-Chome, Okazaki, Aichi 444-0858, Japan
b Merck Research Laboratories, Department of Process Chemistry, P.O. Box 2000, Rahway, NJ 07065, USA
Fax: +81(564)517086; e-Mail: takayuki_tsuritani@merck.com;
Further Information

Publication History

Received 26 December 2005
Publication Date:
09 March 2006 (online)

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Abstract

Here, we report a short and efficient synthesis of iso­indolin-1-ones. Base-induced cyclization of o-hydroxymethyl­benzamides, which was easily prepared from the corresponding phthalides and amines, led predominantly to N-alkylation in good yield. The reaction proceeded under mild conditions and bromine and nitrile substituents were tolerated. The selectivity is explained by HASB theory.

Key words

lactams - cyclizations - lactones - phosphate - N-selective alkylation

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See ref. 6 for preparation of 6i.

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When 1 equiv of Grignard reagent was employed, O-protected compound 8 was obtained predominantly in entry 5.

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Typical Experimental Procedure. To a three-necked 50-mL round-bottomed flask equipped with dropping funnel were charged DMI (15 mL) and o-hydroxymethylbenzamide 6a (1.35 g, 5.00 mmol). The resulting solution was cooled to 0 °C, and then 1.98 M of i-PrMgCl-THF (5.63 mL, 11.15 mol, 2.23 equiv to 6a) was added dropwise. The resulting solution was warmed to ambient temperature and stirred for 0.5 h. The solution was cooled to 0 °C, and then ClP(O)(NMe2)2 (0.94 mL, 6.50 mmol, 1.3 equiv to 6a) was added dropwise. The mixture was warmed to ambient temperature, and stirred for 14 h. The resulting solution was quenched by 2 N aq HCl (10 mL). The mixture was extracted with i-PrOAc (3 × 10 mL), and the combined i-PrOAc extracts were washed with H2O (2 × 10 mL) and dried over anhyd Na2SO4. Removal of the solvent and subsequent silica gel chromatography (heptane and EtOAc) afforded the corresponding lactam 1a in a pure form.

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Spectroscopic Data for New Compounds.
Compound 6c: IR (neat): 1673, 1608, 1510, 1451, 1411, 1356, 1308, 1274, 1242, 1175, 1033, 1007, 837, 813, 768, 673 cm-1. 1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H), 4.22 (s, 2 H), 4.72 (s, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.53 (s, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H). 13C NMR (CDCl3): δ = 45.82, 48.77, 55.27, 114.18, 125.21, 125.93, 126.12, 128.75, 129.50, 131.47, 131.72, 142.97, 159.21, 167.38.
Compound 6f: IR (neat): 1658, 1460, 1409, 1367, 1303, 1234, 1057, 764, 737, 686 cm-1. 1H NMR (300 MHz, CDCl3): δ = 4.86 (s, 2 H), 7.18-7.21 (m, 1 H), 7.41-7.46 (m, 2 H), 7.48-7.53 (m, 2 H), 7.58-7.60 (m, 1 H), 7.86-7.89 (m, 2 H), 7.92-7.94 (m, 1 H). 13C NMR (CDCl3): δ = 50.71, 119.46, 122.59, 124.15, 124.46, 128.37, 129.14, 132.05, 133.24, 139.50, 140.09, 167.49.
Compound 6g: IR (neat): 2227, 1677, 1610, 1447, 1409, 1230, 1060, 877, 839, 770, 677 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.32 (d, J = 6.8 Hz, 6 H), 4.41 (s, 2 H), 4.69 (sept, J = 6.8 Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.77 (s, 1 H), 7.94 (d, J = 8.2 Hz, 1 H). 13C NMR (CDCl3): δ = 20.75, 43.12, 44.90, 114.56, 118.31, 124.45, 126.75, 132.09, 137.32, 141.51, 165.88.