The first general synthesis of N-substituted 1,2-benzisoxazolin-3-ones

Article abstract of DOI:10.1016/S0040-4039(00)00164-7

A convenient synthesis of the title compounds has been developed. Key synthetic steps include: (1) conversion of the readily available salicylic acid derivatives to the corresponding N-substituted salicylhydroxamic acids; (2) cyclization of the hydroxamic acids under Mitsunobu conditions to give the title compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00164-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2295–2298
The first general synthesis of N-substituted
1,2-benzisoxazolin-3-ones
Guo-qiang Shi ∗
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065-0900, USA
Received 14 December 1999; revised 8 January 2000; accepted 11 January 2000
Abstract
A convenient synthesis of the title compounds has been developed. Key synthetic steps include: (1) conversion
of the readily available salicylic acid derivatives to the corresponding N-substituted salicylhydroxamic acids; (2)
cyclization of the hydroxamic acids under Mitsunobu conditions to give the title compounds. © 2000 Elsevier
Science Ltd. All rights reserved.
Synthesis of heterocyclic compounds has been a central and important theme in modern medici-
nal chemistry. During our recent structure–activity relationship studies, we became interested in the
synthesis of a series of N-substituted benzisoxazolin-3-ones (1). With their good chemical stability
and structural rigidity, this class of compounds may serve as a general structural motif for medicinal
chemistry applications. It was surprising, however, that no general method exists for their synthesis.
Direct N-alkylation of the known 3-hydroxy-1,2-benzisoxazole,1 the tautomeric form of N-unsubstituted
1,2-benzisoxazolin-3-one, was disqualified by the predominance of O-alkylation,2 while a previous
attempt at the ring closure of N-phenyl salicylhydroxamic acids led only to degradation via Lossen
rearrangement.3,4 Herein, we would like to report a convenient and general method for the synthesis
of N-substituted 1,2-benzisoxazolin-3-ones.
Our approach for the synthesis of the title compounds involves the use of two readily available starting
materials, salicylic acids and N-alkyl- or N-arylhydroxamines, and features the use of the Mitsunobu
reagent5 for cyclodehydration. As outlined in Scheme 1, salicylic acid (2) was converted to the acid
chloride after acetylation of the phenolic hydroxy group. The ortho-acetoxy acid chloride was then
treated with appropriate N-alkyl or N-arylhydroxyamine to produce N-substituted benzohydroxamic acid
3 with concomitant removal of the neighboring acetyl group in a selective manner such that a remote
acetoxy group as in 3g and 3h (entries 7 and 8, Table 1) was not affected under the reaction conditions.
The ring closure of o-hydroxyhydroxamic acid 3 was the key step. The attempted cyclodehydration
with carbonyldiimidazole6 or thionyl chloride1,4 led either to no reaction at low temperature or complex
∗
Corresponding author. Fax: (732) 594-8080; e-mail: guoqiang_shi@merck.com (G. Shi)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00164-7
tetl 16444

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Table 1
Synthesis of N-substituted benzisoxazolin-3-ones from salicylic acids and hydroxamines

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products at elevated temperature due to competing side reactions including the Lossen degradation.
Fortunately, the desired ring closure was smoothly effected with the use of the Mitsunobu reagent (Ph3P-
DEAD), affording product 1 in high yield (Scheme 1 and Table 1).7
Scheme 1.
As summarized in Table 1, a variety of compounds with a benzene, naphthalene and pyridine ring fused
to the N-substituted isoxazolinone have been prepared following the general synthetic sequence outlined
in Scheme 1. Several functional groups are well tolerated throughout the entire synthetic sequence.
No degradation products arising from the Lossen rearrangement were observed except for substrate 4
(Scheme 2) in which the presence of the free hydroxyl group para to the reaction center appeared to
have completely diverted the reaction course to Lossen rearrangement, giving rise to benzoxazolinone
7 as the only isolated product. This is probably because the p-hydroxyl group in 4 was sufficiently
electron donating to force the migration of the phenyl group (path A, Scheme 2), giving the isocyanate
intermediate4 6 that subsequently cyclized to afford 7, whilst other aromatic substituents including the
acetoxy group was generally less activating so that the attack on the nitrogen by the ortho hydroxyl group
(path B) prevailed giving the desired benzisoxazolinones. It should be emphasized that the use of the
Mitsunobu reagent must also contribute to the control of the desired pathway since as mentioned above
other cyclization reagents led to the Lossen rearrangement even for substrates without a para hydroxyl
group.
Scheme 2.
In conclusion, we have developed a convenient and general method for the synthesis of N-substituted
1,2-benzisoxazolin-3-ones. Noteworthy is the high efficiency and the ease with which all synthetic steps
can be executed as well as the ready availability of the starting materials, which may make this method
useful for combinatorial synthesis.

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References
1. Boeshagen, H. Chem. Ber. 1967, 100, 594.
2. A small amount of N-alkylation product was obtained when a primary halide was used as the electrophile. However the
desired N-alkylation product became essentially negligible when secondary halides was used. Similar results have been
mentioned in a few patents. (a) Nagano, M.; Sakai, J.; Mizukai, M.; Nakamura, N.; Misaka, E.; Kobayashi, S.; Tomita,
K. JP 79:54073772; Chem. Abstr. 91:211401. (b) Slawik, T.; Bien, I. PL 92:15571; Chem. Abstr. 94:244786.
3. (a) Kalkote, U. R.; Goswami, D. D. Aust. J. Chem. 1977, 30, 1847. (b) Sheradsky, T.; Avramovici-Grisaru, S. Tetrahedron
Lett. 1978, 2325.
4. For a review of the Lossen rearrangement, see: Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376.
5. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
6. Friary, R.; Sunday, B. R. J. Heterocycl. Chem. 1979, 16, 1277.
7. Typical procedure: 2h→3h: 2,4-dihydroxy-3,5-dipropylbenzoic acid (2h) (0.48 g, 2 mmol) in CH2Cl2 (20 mL) was treated
at 0°C with pyridine (0.96 mL, 12.0 mmol) and acetyl chloride (0.43 mL, 6.0 mmol). The reaction mixture was warmed
to 25°C over 30 min and then poured into water (20 ml). The resulting biphasic mixture was stirred for 1 h, acidified with
1N HCl and extracted with ethyl acetate. The crude 2,4-diacetoxy-3,5-dipropylbenzoic acid obtained was heated with oxalyl
chloride (0.52 mL, 6.0 mmol) in CH2Cl2 (5 mL) for 1 h. After removal of the volatiles, the acid chloride was taken up
in methylene chloride (20 mL) and added to a vigorously stirred mixture of aqueous sodium carbonate (0.5N, 16 mL), i-
PrNHOH·HCl (0.67 g, 6.0 mmol) and THF (20 mL), and then cooled at 0°C. The mixture was further stirred at 25°C for 1 h
before it was acidified with 0.5N hydrochloric acid to pH 2 and extracted with ethyl acetate. The crude product was purified
by chromatography on silica gel eluting with 7:3 hexane:ethyl acetate to give hydroxamic acid 3h (0.48 g, 72%). 3h→1h:
To a solution of compound 3h (0.48 g, 1.42 mmol) and triphenylphosphine (0.63 g, 1.7 mmol) in THF (20 mL) was added
dropwise diethyl azodicarboxylate (0.30 g, 1.7 mmol) at 0°C. The reaction mixture was warmed to 25°C over 30 min and
quenched with a 1:1 mixture of methanol:acetic acid (0.1 mL). Concentration and chromatography on silica gel eluting with
7:3 hexane:ethyl acetate gave 1h as an oil (0.42 g, 92%). 1H NMR (CDCl3, 500 MHz) δ 7.58 (s, 1H), 4.28 (heptet, J=7.2 Hz,
1H), 2.81 (t, J=7.0 Hz, 2H), 2.68 (t, J=7.1 Hz, 2H), 2.40 (s, 3H), 1.70–1.57 (m, 4H), 1.32 (d, J=7.2 Hz, 6H), 0.99 (t, J=7.3 Hz,
3H), 0.97 (t, J=7.6 Hz, 3H). Anal. calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.55; H, 7.95; N, 4.33.