Science of Synthesis

Härtinger, S., Science of Synthesis Knowledge Updates, (2010) 1, 148.

Halogenation of a variety of 1,2-benzisoxazole derivatives has been achieved under a wide range of conditions (see Section 11.10.4.2.1.3). Bromination of 3,6,7-trisubstituted benzisoxazole ‌218‌ with N-bromosuccinimide in carbon tetrachloride in the presence of 2,2′-azobisisobutyronitrile gives the expected 5-bromo derivative ‌219‌ (‌Scheme 60‌).[‌279‌] Regioselective chlorination of the 4-position in the 3,6,7-trisubstituted benzisoxazole ‌220‌ takes place with 1,3,5-trichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (trichloroisocyanuric acid).[‌280‌] Chlorination of the same substrate in a solution of toluene and diisobutylamine by slow addition of sulfuryl chloride affords the 5-chloro derivative.[‌227‌] Halogenation of 5,6-disubstituted benzisoxazoles leads to the 7- or 4-halo derivatives. A successful implementation of this synthesis route has been achieved with sulfuryl chloride in a mixed dichloromethane and diethyl ether solvent at room temperature.[‌280‌,‌281‌] An alternative to these regioselective halogenation methods is the use of halo-substituted benzene precursors in the ring-closure methodology summarized in Section ‌11.10.5.1.1.2.2‌. This has been successfully applied for the synthesis of 1,2-benzisoxazoles with halogens at the 4-,[‌282‌,‌283‌] 5-,[‌278‌,‌284‌] 6-,[‌285‌] and 7-position.[‌286‌]

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8-Meeeee-8-(eeeeeeeeeeeeeee)-8,8-eeeeeeeeeeee-8-ee (‌888‌; 8.88 e, 88.8 eeee), MMM (8.88 e, 88.8 eeee), eee MMMM (88 ee) eeee eeeeeee ee MMe8 (88 eM) (MMMMMMM: eeeee) eeeee eeeee ee 88 °M eee 8 e. Mee eeeeeee eee eeeeee ee ee eee eeeeeeee, eee eee eeeeeee eee eeeeeee eeee eee eeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeee eee eeeeeeeee ee eeeeeeeee eeeee (ee 88-88 °M; 888 eM) eee eee eeeeeeeeee eee eeeeeee ee e eeeeee ee eeeeee eee (88-88 µe, 8 e). Mee eeeeee eee eeeeee eeee eeeeeeeee eeeee (888 eM) eee eee eeeeeee eee eeeeeee eeee eee eeeeee ee eeeeeee ‌888‌; eeeee: 8.88 e (88%); 8M MMM (MMMM-e8, δ): 88.88 (ee, MM), 8.88 (e, 8M), 8.88 (e, 8M), 8.88 (e, 8M), 8.88 (e, 8M).

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