Electron-Transfer-Induced Reductive Cleavage of Phthalans:  Reactivity and Synthetic Applications

Abstract

The behavior of phthalan (1a) was investigated under conditions of electron transfer from alkali metals in aprotic solvents. Reaction with lithium in the presence of a catalytic amount of naphthalene in THF led to the reductive cleavage of an arylmethyl carbon−oxygen bond, with formation of a stable dilithium compound. Trapping of this intermediate with several electrophiles (alkyl halides, carbonyl derivatives, CO2) was successful. The extension of this procedure to several substituted phthalans (1b − i) was investigated, and the regiochemistry as well as the synthetic usefulness of these reactions are discussed.

The Oxa‐Pictet–Spengler Reaction: A Highlight on the Different Efficiency between Isochroman and Phthalan or Homoisochroman Derivative Syntheses

“…[6][7][8][9][10][11][12][13][14][15][16][17][18] In recent years, these compounds were studied for their antihistamine, [21] antidepressant, [22][23][24] and other biological or pharmacological activities. [19,20] Moreover, some phthalan derivatives are uti-lized in the agricultural industry as herbicides [25] and fungicides; [26][27][28] other uses include colorants [29] and perfumes. [30] Many methods to synthesize phthalans have been reviewed.…”

“…[31,32] Most of these are based on a nucleophilic substitution reaction, which results in intramolecular cyclization. Starting compounds are, for example, o-phthalyl alcohol [33][34][35][36][37] or o-phthalyl halides. [38][39][40][41][42][43] We synthesized hydroxyphthalans under the same conditions used for the synthesis of isochromans (see Experimental Section), but in some cases the temperature was increased to 38°C.…”

5-Bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran

“…The title compound, (I), is an intermediate in the synthesis of the antidepressant drug citalopram (Liechti et al, 2000). More generally, phthalans show distinctive redox chemistry (Azzena et al, 1996). We have previously deposited (CSD-260624; Cambridge Structural Database; Allen, 2002) data for a poor quality structure from a twinned crystal of (I).…”

1-(4-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

“…Comment 1,3-Dihydroisobenzofuran (or phthalan) is used for the preparation of 1,2-di(lithiomethyl)benzene (Almena et al, 1995). Electron-transfer-induced reductive cleavage of phthalans has been reported (Azzena et al, 1996). The title compound, (I), 4-¯uorophenyl-5-phthalan carbonitrile, is a key intermediate in the synthesis of citalopram, which is a versatile antidepressant (Liechti et al, 2000).…”

“…Experimental 5-Bromo-3H-isobenzofuran-1-one (1.0 g ,4.7 mmol) was subjected to a Grignard reaction with 4-¯uorophenyl magnesium bromide (1.12 g, 5.6 mmol) in tetrahydrofuran (20 ml) at 273±278 K. The resulting product was treated with sodium borohydride (0.19 g ,5.2 mmol) in methanol (5 ml) to obtain the diol, which was cyclized with p-toluene sulfonic acid monohydrate (0.1 g, 0.5 mmol) in toluene (10 ml) to obtain the cyclized product. The cyclized product was re¯uxed with CuCN (0.5 g, 5.6 mmol) in dimethylformamide (5 ml) to obtain the title compound (Bigler et al, 1977). X-ray quality crystals of (I) were obtained after recrystallization from solution in acetonitrile.…”