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11.11.1.1.1.1 Method 1: Base-Catalyzed Condensation of an Arylacetonitrile with a 1-Halo-4-nitroarene

DOI: 10.1055/sos-SD-011-00521

Smalley, R. K.Science of Synthesis, (200211339.

This procedure, as developed originally,[‌38‌] involves treating a mixture of an arylacetonitrile and a 1-halo-4-nitroarene 6 (X=Cl or Br) with a large excess of methanolic potassium hydroxide, which promotes initial attack by the acetonitrile carbanion at the ortho position to the nitro group. The potassium salt of the mesomerically stabilized intermediate anion 7 is, in some cases, isolable and there is evidence that isolation of the salt prior to cyclization leads to a significant improvement in the reliability of the procedure and the yield of 3-aryl-2,1-benzisoxazole 8 (Scheme 3).[‌39‌] Full practical details, however, are not given. The reaction is sensitive to the nature and position of substituents on the nitroarene and to the solvent used. Methanol appears to be the solvent of choice and extensive use has been made of tetrahydrofuran as cosolvent.[‌40‌] Under standard conditions, 4-nitroanisole and 4-nitrotoluene fail to yield a 2,1-benzisoxazole, as does 1-chloro-4-nitrobenzene with potassium hydroxide in pyridine, rather than methanol, as the reaction medium.[‌38‌] In this last case, nucleophilic displacement of the chloro group by phenylacetonitrile anion is the major reaction, whereas nitrobenzene and phenylacetonitrile yield the p-quinonoid analogue of intermediate 7.[‌41‌] Similar products, rather than 2,1-benzisoxazoles, are obtained with 2- and 3-substituted nitrobenzenes.[‌42‌] Sodium butoxide in butanol at <35°C[‌43‌] and concentrated sodium hydroxide in a thixotropic medium[‌44‌] have been employed in place of methanolic potassium hydroxide, generally with some improvement in yield of the 3-aryl-2,1-benzisoxazoles. A particularly high yield (80% and 99.4% purity) of 5-chloro-3-phenyl-2,1-benzisoxazole (8, X=Cl) is claimed for the reaction of 6 (X=Cl) with phenylacetonitrile in a two-phase system (aq NaOH in MeOH/BuOH) at 50°C,[‌45‌] and a 95% yield of the same product has been achieved in a cascade process using 48% aqueous sodium hydroxide at 50°C.[‌46‌] This procedure has been used to prepare 5-chloro-3-phenyl-2,1-benzisoxazole in excellent yield (>90%) on an industrial scale (270kg).[‌47‌] The cyanide ion produced as an unavoidable byproduct is destroyed by washing the mixture with sodium hypochlorite.

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Meeeee 8 8-Meeeee-8,8-eeeeeeeeeeeeee ee Meeeeeeeeeee ee 8-Meee-8-eeeeeeeeeee eeee Meeeeeeeeeeeeeeeeee[‌88‌]

Mee eeeeeeeeeeee ee 8-eeeeeeeeeeeeeeee eeee eeeeeeeeeeeeeeeeee eeeeeee ee ee eee eeee eeeeeee ee eee eeeeeeeee ee e eeeeee[8,8-e]eeeeeeeee; eee 8-eeeeee eeeeeeeeee ee eeeeeeee ee eee eeeee (88%) ee eeeeee eeeeee.[‌88‌] Meeeeeee, eee 8-(8-eeeeeee)-[‌88‌] eee 8-(8-eeeeeee)-8,8-eeeeeeeeeeeeee[‌88‌] 88 eee 88 eeeeee, eeeeeeeeeeee, ee eeeeeeeeeeee ee eee eeeeeeeeeeeee eeeeeeeeeee eeeeeeeeeeee eeee e 8-eeee-8-eeeeeeeeeeee 8, eeeeeeeee eee eeee eeeeeeee ee 8-eeeeeee-8,8-eeeeeeeeeeeeee ee ee eeeeeeee ee eeee eeeee (Meeeee 8).

Meeeee 8 8-Meeeeee-8,8-eeeeeeeeeeeeee ee Meeeeeeeeeee ee e Meeeeeeeeeeeeeeeeee eeee e 8-Meee-8-eeeeeeeeeeee[‌88‌,‌88‌]

Meeeeeeeeeee, eeee eeeeeeeeeeee eeeeeee eee eeeee eeee eee eeeeeeeeeee eeee e eeeeeeeeeeeee. 8-Meeeeeeeeeeeee 88, ee eee 88-eeeee, eee eeeeeeeeeeeeeeeeee ee eee eeeeeeee ee eeeeee eeeeeeeee ee eeeeeeee eeeee 8-eeeeeeeeeeeeeee[8,8-e]eeeeeeeee (88) (Meeeee 8).[‌88‌] Mee eeee eeeeeee ee eeee eeeeeeee eee ee eeeeeeee eeeeee (8888%) eeeee ee eeeeeeeeeee eeeeeeeee ee eeeee eee eeeeeeeeeeeeeeeeee ee eeeeeeee ee e eeeeee eeeeee (M8MMMM8Me; M8=Me, Me, Me).

Meeeee 8 Meeeeeeeeeee ee e Meeeeeeeeeeee eeee Meeeeeeeeeeeeeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeeee

8-Meeeee-8-eeeeee-8,8-eeeeeeeeeeeee (8, M=Me):[‌88‌]

Me e eeeeee eeee (eee eeee) ee 88% MMM (88e, 8.8eee) ee MeMM (888eM) eee eeeee eeee eeeeeeee eeeeeeeeeeeeeeeeee (8.8e, 8.888eee) eee e eeee ee 8-eeeeee-8-eeeeeeeeeeee (8.8e, 8.888eee) ee MeMM (888eM). Mee eeeeeee eee eeeeeee ee 88°M eee 8e, eeee M8M (888eM) eee eeeee eeee eeeeeeee eeeeeeee. Mee eeeeeeeeeeee eeeee eeeeeee eee eeeeeeee ee eeeeeeeeee, eeeeee eeee M8M, eee eeeee. Meeeeeeeeeeeeee eeee eeeeeeeee eeeee (ee 8888°M) eeee eee eeee eeeeeee ee eeee eeeeee eeeeeee; eeeee: 8.8e (88%); ee 888888°M.

8-Meee-8-eeeeee-8,8-eeeeeeeeeeeee (8, M=M):[‌88‌]

Me e eeeeee (88°M) eee eeeeeeeeeeee eeeeeee eeee ee MeMM (888.8e, 8.88eee) ee MeMM (888eM), eeeee M8, eee eeeee eeeeeeee eeee 8e e eeee ee 8-eeee-8-eeeeeeeeeeee (88e, 8.888eee) ee MMM (888eM) ee e eeee ee ee ee eeeeeeee eee eeeeeeee eeeeeeeeeee ee 8888°M. Meeeeeeeeeeeeeeeee (88.8e, 8.888eee) eee eeee eeeee eeeeee (ee. 88eee) eeeee eeeeeeeeeee eee eeee eeeeeeee eeeeeeeeeee. Meeee eeeeeeee eee eeeeeeeee, eeeeeeee eee eeeeeeeee ee 8888°M eee 8e. Mee eeeee (8.8M) eee eeeee ee eee eeeeeee, eeeee eee eeee eeeeeee ee ee eee eeee eee 88eee. Mee eeeeeeeee eeeeeeeeee eee eeeeeeee, eee eeeeeee eeeeee eeee M8M eeeee eeeeeee, eeee eeeeeee eeee MeMM eee eeeeeeeeee ee eeeee eee eeeeeee; eeeee: 88.8e (88%); ee 888888°M. Meeeeeeeeeeeeeeee (MMMe8/MeMM) eeee eeee eeeeeee; ee 888888°M.

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