Lithiated Azafulvenes by Halogen/Metal Interchange of Brominated 6‐(Diisopropylamino)‐1‐azafulvene Derivatives. Novel synthesis of 5‐mono‐ and 4,5‐disubstituted 1H‐pyrrole‐2‐carbaldehydes

Abstract

The first known lithiated 1-azafulvene derivatives were generated by low-temperature halogen/metal interchange, with r-BuLi, from the corresponding brominated 6-diisopropylamino compounds 3b and 12. These Li species reacted with sundry electrophilic reagents to give products which, on basic hydrolysis, were converted into 5-mono-or 4,s-disubstituted pyrrole-2-carbaldehydes 10 and 16, respectively.The generation of pyrroles lithiated on a C-atom requires the presence of a N-substituent, and if a formal N-unsubstituted lithiopyrrole is desired, this N-substituent of which several types have been utilized [ 1-71 must be readily removable. It was of interest to us to examine the possibility of effecting C-metalation of the pyrrole nucleus in the absence, at least in the formal sense, of a protecting group for the N-atom'). We have now devised two complementary strategies which demonstrate that this is indeed a viable concept. The first of these, which has already been disclosed in preliminary form [lo], involves the lithiation of the readily available dimer of 6-(dimethylamino)-1-azafulvene and of the corresponding 3-bromo derivative. The lithiated species thus generated have provided access to a great variety of 4-or 5-mono-and 4,5-disubstituted 1H-pyrrole-2-carbaldehydes. A description of the second synthetic strategy constitutes the subject of this communication.The 3,4-disubstituted 6-(dimethylamino)-2-halo-I-azafulvenes, synthesized twenty years ago by von Dobeneck and coworkers [ 1 11, are readily hydrolyzed to the corresponding aldehydes under mildly alkaline conditions. It was, therefore, apparent that, if the proclivity for nucleophilic addition to C(6) of azafulvenes could be overcome [12] and barring stability problems, halogen/Li exchange of a 3,4-unsubstituted congener (see 3) would generate a lithiated 1-azafulvene derivative, functionally equivalent to 5-lithio-1 H -pyrrole-2-carbaldehyde. -doctoral fellow, 1987-1988. Syntex Research post-doctoral fellow, 1985-1986 have reported that 3,4-dlodo-lH-pyrrole is converted into the 1,3-dilithio derivative with BuLi (2 equiv.) in THF solution (-78") containing tetramethylethylenediamine, as judged by the formation of 4-iodo-lH-pyrrole-3-carbaldehyde (45 % yield), after quenching with dimethylformamide. This does not promise to be a generally useful process since 2-bromo-1H-pyrrole is not lithiated on a C-atom even with excess t-BuLi [9].

Substrate Controlled Regioselective Bromination of Acylated Pyrroles Using Tetrabutylammonium Tribromide (TBABr3)

“…Typically, electrophilic substitution of pyrroles can be predictably directed by groups in the C-2 position, where electron withdrawing (EWG) groups generally favor the C-4-substituted product whereas electron donating (D) groups favor reaction at C-5 to form the major products (Figure ). − However, regioselective bromination is nontrivial and presents a major challenge, especially for C-5 monobromopyrroles containing an electron withdrawing group in the C-2 position (Figure ). − A notable exception was reported by Feldman, and subsequently others, where the C-5 monobrominated pyrrole was the major product when methanol was used as an additive with electrophilic brominating reagents such as NBS. ,− Intrigued by these observations, we investigated the possibility of regioselectively monobrominating pyrroles bearing carbonyl functionalities in the C-2 position.…”

Iminopyrrole‐Based Self‐Assembly: A Route to Intrinsically Flexible Molecular Links and Knots

“…Without a proton scavenger, the likely outcome is proton transfer to the imine group producing 2‐A‐H + . Several reports described that 2 might undergo tautomerisation in the presence of a metal cation, transforming into the corresponding, neutral amine‐azafulvene ligand in 2‐B [90–94] …”

Iminopyrrole‐Based Self‐Assembly: A Route to Intrinsically Flexible Molecular Links and Knots

“…Several reports described that 2 might undergo tautomerisation in the presence of a metal cation, transforming into the corresponding, neutral amine-azafulvene ligand in 2-B. [90][91][92][93][94] To verify whether iminopyrrole synthons can be exploited for self-assembly of MIMs, the formation of [2]catenane 7-M, trefoil knot 8-M, [55] and Borromean rings 9-M [31] has been evaluated. Pyridine analogues of these synthetic targets were previously obtained with high yields using 2,6-diformylpyridine and two similar diamines, 5 and 6 (Scheme 2).…”