Pyrrolodiazines. 6. Palladium-Catalyzed Arylation, Heteroarylation, and Amination of 3,4-Dihydropyrrolo[1,2-a]pyrazines

Abstract

The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids and 6-bromo- and 6,8-dibromo-3,4-dihydropyrrolo[1,2-a]pyrazines afforded 6-substituted and 6,8-disubstituted 3,4-dihydropyrrolo[1,2-a]pyrazines in good yields. Stille and Negishi coupling reactions have been used to prepare 6-heteroaryl-substituted derivatives in moderate yields by employing heteroaryl halides and 6-metalated 3,4-dihydropyrrolo[1,2-a]pyrazines as reaction partners. A variety of cyclic secondary amines have also been incorporated at position C-6 of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine in the presence of the palladium catalyst Pd(2)(dba)(3) in conjunction with BINAP as ligand. This amination reaction is one of the few reported examples of such a palladium-catalyzed transformation on a pyrrole ring, although the reaction could not be extended to less nucleophilic amines.

Palladium‐Catalysed Cross‐Coupling and Related Reactions Involving Pyrroles

“…Type I Pd 0 ‐catalysed C–N bond‐forming reactions between C ‐halogenated pyrroles and amines, and so leading to C ‐aminated pyrroles, have only been reported recently 31,32. The conversion 17 + 18 → 19 shown in Scheme is indicative and highlights the great potential of this sort of process.…”

“…C2‐Zincated pyrroles, which are readily generated through transmetallation of the corresponding C2‐lithiated species using ZnCl 2 , engage in Pd 0 ‐catalysed cross‐coupling with a range of aryl and acyl halides to give the expected products 31,64,68–70. A reaction reported by Fürstner and Weintritt during the course of their synthesis of the antitumour agent roseophilin68 serves to highlight the utility of these sorts of processes.…”

“…It took another thirteen years before Bailey demonstrated89 that N ‐methyl‐C2‐(tri‐ n ‐butylstannyl)pyrrole would engage in true Type II Stille cross‐coupling reactions with iodobenzene to form N ‐methyl‐C2‐phenylpyrrole which was obtained in 54 % yield. With the advent of various effective protocols for the formation of C2‐(tri‐ n ‐butylstannyl)pyrroles31,90–95 and the corresponding C3‐isomers,77,95 the title couplings have enjoyed widespread use not least because of the capacity they offer to prepare heavily substituted pyrroles96,97 and/or products where the fragment attached to the pyrrole is itself heavily substituted 98,99. The cross‐coupling of the C2‐stannylated pyrrole 88 with bromobenzene ( 89 ), so as to provide the tetrasubstituted pyrrole 90 (Scheme ), is illustrative 96…”

“…Thus, for example, as part of one of a number of programs108 aimed at developing syntheses of the immunosuppressive agent undecylprodigiosine and related systems, the cross‐coupling of boronic acid 95 with pyrrole 96 , bearing a triflate group at C2, was carried out and so delivering product 97 (Scheme ) 108a. Related couplings involving C2‐halogenated and C2‐,C5‐dihalogenated pyrroles have also been reported,31,109–112 including in the assembly of tetrasubstituted pyrroles and phenyl‐pyrrole mixed polymers 109,110…”

Cross‐Coupling Reactions on Azoles with Two and More Heteroatoms

“…[130] Scheme 61. Low catalyst loadings could be applied in the cross-coupling of 2-bromothiazole 165 with 1-phenyl-6-(tributylstannyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (181), giving 45 % of the desired product 182 (Scheme 61).…”