M. Chaumontet, Riccardo Piccardi, O. Baudoin
2009
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Angewandte Chemie
Abstract
Dihydroisoquinolines (DHIQ) constitute synthetically strategic molecules in this context, since they are precursors to both isoquinolines and tetrahydroisoquinolines. Whereas a range of new methods have been developed for the synthesis of 1,2-DHIQ, efforts have focused on the parent 3,4-DHIQ to a much lesser extent. Classical syntheses of 3,4-DHIQ involve Bischler-Napieralski-type reactions that rely on an electrophilic aromatic substitution (SEAr) step. [5] However, for the purpose of introducing broader structural diversity onto this motif, the development of conceptually different synthetic alternatives is of great interest. We envisioned the construction of a variety of 3-aryl-3,4-DHIQ 5 from iminoBCB 4 (BCB = benzocyclobutene) by thermal tandem electrocyclic ring-opening/6p-electrocyclization via o-xylylene intermediate A (Scheme 1). 7] In turn, imines 4 would arise from amino-BCB 3, which should be accessible from BCBesters 2 by hydrolysis and Curtius rearrangement. BCB 2 can be readily synthesized from bromobenzenes 1 by the palladium-catalyzed C H activation of methyl groups that was developed recently in our group. Amino-BCB 3a–d (Table 1) were synthesized from the corresponding aryl bromides 1. The construction of the cyclobutene ring by Pd-catalyzed C H activation/intramolecular C C coupling was carried out in good yield as described earlier (Scheme 1, step a). After ester hydrolysis (Scheme 1, step b), the corresponding carboxylic acids underwent a Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA, Scheme 1, step c). Amino-BCB 3e (Table 1, entry 12) was obtained from the corresponding BCB-nitrile by hydrolysis to the primary amide and PhI(OCOCF3)2-mediated Hofmann rearrangement [10] (see the Supporting Information). Amino-BCBs, such as 3, have limited thermal stability when R = H, and therefore they have very rarely been isolated and employed in synthesis. In this case, the presence of a quaternary benzylic carbon (R1⁄46 H), which is also necessary for the C H activation step (a), stabilized the molecule, probably by raising the energy barrier for the cyclobutene ring-opening, which allowed us to isolate the free amines 3 and to engage them in the next step. Thus amino-BCB 3 was treated with one equivalent of an aromatic aldehyde (Scheme 1, step d) and the corresponding imines 4 underwent the thermal tandem electrocyclic ringopening/ring-closing process (Scheme 1, step e). It was anticipated that the presence of the R alkyl substituent would favor inward rotation of the imine group to give the Z isomer of the o-xylylene intermediate (Scheme 1, A) that was Scheme 1. Overall strategy for the synthesis of dihydroisoquinolines. Reagents and conditions: a) Pd(OAc)2 (10 mol%), P(tBu)3 (20 mol%), K2CO3, DMF, 140 8C; b) NaOH, MeOH/H2O, reflux; c) diphenylphosphoryl azide (DPPA), Et3N, toluene, reflux, then aq. HCl, 80 8C; d) ArCHO (1 equiv), MgSO4, CH2Cl2, reflux; e) DMF, 160 8C.