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

All articles of this category

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

Full Text

References

References and Notes

<A NAME="RU31905ST-1A">1a</A> Luzzio FA. Piatt Zachert D. Tetrahedron Lett. 1998, 39: 2285

<A NAME="RU31905ST-1B">1b</A> Campbell JB. Dedinas RF. Trumbower-Walsh SA. J. Org. Chem. 1996, 61: 6205

<A NAME="RU31905ST-1C">1c</A> Decroix B. Pigeon P. . Tetrahedron Lett. 1996, 37: 7707

<A NAME="RU31905ST-1D">1d</A> Decroix B. Pigeon P. Othman M. Tetrahedron 1997, 53: 2495

<A NAME="RU31905ST-1E">1e</A> Allin SM. Northfield CJ. Page MI. Slawin AMZ. Tetrahedron Lett. 1997, 38: 3627

<A NAME="RU31905ST-1F">1f</A> Kundu NG. Khan MW. Tetrahedron Lett. 1997, 38: 6937

<A NAME="RU31905ST-1G">1g</A> Kitching MS. Clegg W. Elsewood MRJ. Griffin RJ. Golding BT. Synlett 1999, 997

<A NAME="RU31905ST-2A">2a</A> Nannin G. Griraldi PN. Molgora G. Biasoli G. Spinelli F. Logemann L. Dradi E. Zanni G. Buttinoni A. Tommasini R. Arzneim. Forsch. 1973, 23: 1090

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.

<A NAME="RU31905ST-3">3</A> Schmahl H.-J. Denker L. Plum C. Chahoud I. Nau H. Arch. Toxicol. 1996, 11: 749

<A NAME="RU31905ST-4">4</A> Plowman J. Paull KD. Atassi G. Harrison S. Dykes D. Kabbe N. Narayan VL. Yoder O. Invest. New Drugs 1988, 6: 147

<A NAME="RU31905ST-5A">5a</A> Ganesan A. Wang H. Tetrahedron Lett. 1998, 39: 9097

<A NAME="RU31905ST-5B">5b</A> Anzani M. Capelli A. Vomero S. Heterocycles 1994, 38: 103

<A NAME="RU31905ST-6">6</A> Horii Z. Iwata C. Tamura Y. J. Org. Chem. 1961, 26: 2273

<A NAME="RU31905ST-7">7</A> Orito K. Horibata A. Nakamura T. Ushito H. Nagasaki H. Yuguchi M. Yamashita S. Tokuda M. J. Am. Chem. Soc. 2004, 126: 14342

<A NAME="RU31905ST-8">8</A> Hoarau C. Couture A. Deniau E. Grandclaudon P. Synthesis 2000, 655

<A NAME="RU31905ST-9A">9a</A> Späth E. Lintner J. Ber. Dtsch. Chem. Ges. B 1936, 69: 2727

<A NAME="RU31905ST-9B">9b</A> Barrios I. Camps P. Comes-Franchini M. Muñoz-Torrero D. Ricci A. Sánchez L. Tetrahedron 2003, 59: 1971

<A NAME="RU31905ST-10">10</A> See for mechanical study: Decker M. Nguyen TTH. Lehmann J. Tetrahedron 2004, 60: 4567

<A NAME="RU31905ST-11">11</A> Lesimple P. Bigg DCH. Synthesis 1991, 306

See ref. 6 for preparation of 6i.

<A NAME="RU31905ST-13">13</A> Kornblum N. Smiley RA. Blackwood RK. Iffland DC. J. Am. Chem. Soc. 1955, 77: 6269

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

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.

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.