A Short and Efficient Synthesis of Isoindolin-1-ones

Takayuki Tsuritani; Satoshi Kii; Atsushi Akao; Kimihiko Sato; Nobuaki Nonoyama; Toshiaki Mase; Nobuyoshi Yasuda

doi:10.1055/s-2006-933114

LETTER

A Short and Efficient Synthesis of Isoindolin-1-ones

Takayuki Tsuritani*^a, Satoshi Kii^a, Atsushi Akao^a, Kimihiko Sato^a, Nobuaki Nonoyama^a, Toshiaki Mase^a, Nobuyoshi Yasuda^b
^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;

Abstract

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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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References

References and Notes

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2b

Hisamitsu Pharmaceutical Co., Inc. Japan Kokai Tokyo Koho 149257, 1980; Chem. Abstr. 1981, 94, 174879; address: P. J. Kocienski, School of Chemistry, Univerity of Leeds, Leeds LS2 9JT, UK.

3 Schmahl H.-J. Denker L. Plum C. Chahoud I. Nau H. Arch. Toxicol. 1996, 11: 749

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12

See ref. 6 for preparation of 6i.

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14

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

15

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.

16

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.