合成路线1

Bromination of 1,2-diethoxy-3-fluorobenzene (XIII) with NBS in acetonitrile gives 1-bromo-3,4-diethoxy-2-fluorobenzene (XVI), which undergoes bromide displacement with CuCN in DMF at 155 °C to yield 3,4-diethoxy-2-fluorobenzonitrile (XVII). Metalation of compound (XVII) with BuLi in the presence of tetramethylpiperidine (TMP) in THF at –10 °C followed by reaction with DMF and quenching with AcOH leads to 3,4-diethoxy-2-fluoro-6-formylbenzonitrile (XVIII). Reduction of aldehyde (XVIII) with NaBH(OAc)3 in EtOAc at 40 °C provides the benzylic alcohol (XIX), which is then activated as the mesylate (XX) by means of MsCl and Et3N in DME. Condensation of mesylate (XX) with phthalimide (XXI) by means of t-BuOK in DMF furnishes the N-substituted phthalimide (XXII), which is finally subsubjected to hydrazinolysis and subsequent cyclization in the presence of HCl in THF. Also, the isoindole (X) can be obtained by direct cyclization of the cyano mesylate (XX) with NH3 in toluene in a pressure vessel .
Alternatively, isoindole (X) can be prepared by metalation of 3,4-diethoxy-2-fluorobenzonitrile (XVII) with MeLi in the presence of TMP in THF, followed by alkylation with MeI to afford 3,4-diethoxy-2-fluoro-6-methylbenzonitrile (XXIII), which is then brominated with NBS by means of AIBN in refluxing CCl4 to yield 6-(bromomethyl)-3,4-diethoxy-2-fluorobenzonitrile (XXIV). Benzylic bromide (XXIV) can also be prepared by treatment of primary alcohol (XIX) with PBr3 in DME. Subsequent cyclization of the benzonitrile (XXIV) with NH3 in toluene affords 3-amino-5,6-diethoxy-4-fluoroisoindole (X) .