A3-Pyrrolines

The marine natural product dynosin A (92) is a new member of the aerugi-nosin family and a novel inhibitor of thrombin and Factor Vila. In Hanessian s total synthesis of 92 [66], both the dihydroxyoctahydroindole 88 and the A3 pyrroline moiety 91 were prepared by RCM-based routes (Scheme 17). 

A complex product containing three A3-pyrrolines is obtained from the cooligomerization of diphenylbutadiyne with diaryl and dicyclohexyl carbo-... 

A3-Pyrroline formation with carbonyl insertion also occurs during the reaction of /V-sulfinylarylamines with diphenylcyclopropenone in the presence of nickel carbonyl (Scheme 36).64 Phenyl isocyanate does not give a pyrroline product under these reaction conditions, hence the SO-CO exchange probably occurs within an intermediate metallocycle. The reaction... 

Reduced pyrroles have trivial names the dihydro derivatives, of which there are three types, are designated as A1- (11), A2 - and A3-pyrrolines, and the tetrahydropyrroles are called pyrrolidines. 

A3-Pyrrolines, e.g. (176), are formed on the reduction of pyrroles and simple alkylpyrroles with zinc and acid. These are derived from the corresponding a-protonated species (66JA1335). 

The photosensitized reaction of pyrrole and oxygen yields 5-hydroxy-A3-pyrrolin-2-one, probably by way of an intermediate cyclic peroxide (Scheme 45) (76JA802). 

Among the less widely exploited interconversion processes are those involving thermal reactions with ethyl azidoformate, which convert furan into Af-ethoxycarbonyI-A3-pyrrolin-2-one, and thiophenes into /V-ethoxycarbonylpyrroles (Scheme 96a) (64TL2185). The boron trifluoride catalyzed reaction of l,3-diphenylbenzo[c]furan with Af-sulfinylaniline results in the replacement of the oxygen by an /V-phenyl group (Scheme 96b) (63JOC2464). 

The polymeric pyrrolic autoxidation products probably result from the oxidized monomeric systems, which are analogous in structure to those isolated from photooxidation and peroxide oxidation reactions. Thus, for example, analysis of the products of the autoxidation of 1-methylpyrrole (Scheme 47) would suggest that 1 -methyl-A3-pyrrolin-2-one (153) is initially formed from a radical reaction of the pyrrole with triplet oxygen. This reaction sequence should be compared with that proposed for the oxidation of pyrroles with hydrogen peroxide (Scheme 50), which yields (181), (182) and (183) as the major isolable products. The acid-catalyzed reaction of a pyrrole with its oxidation product e.g. 153) also results in the formation of polymeric material and the formation of pyrrole black is probably a combination of oxidation and acid-catalyzed polymerization processes. 

The reduction of pyrroles by zinc in acetic acid or hydrochloric acid gives, initially, as the major product, A-pyrroline, together with A1- and A2-pyrrolines, all of which are further reduced to pyrrolidine (Scheme 54) (B-77MI30507). Reduction of 2,5-disubstituted pyrroles produces both the cis- and the trans- A3-pyrrolines, (206) and (207). 

Chemical reduction of pyrroles by hydriodic acid and phosphorus leads to the formation of pyrrolidines (B-77MI30507) except when the 2-position is substituted by electron-withdrawing groups, which reduce the ease of protonation at the 3-position and, consequently, promote the formation of 2-substituted A3-pyrrolines (cf. Scheme 54) (B-74MI30500, 79MI30504). The analogous reduction of indole-2-carboxamide yields indoline-2-carboxamide (72HC(25-l)l). 

Radical benzylation of pyrrole produces 2-benzylpyrrole (B-77MI30500), whilst indoles react to give low yields of the 1- and 3-mono-, together with the 1,3- and 2,3-di-benzylated indoles (65JCS4253). Similarly, radical methylation of 2-nitropyrrole (B-77MI30500) has been reported to yield C-substitution products, whereas, in contrast, 2,5-bis(triphenylmethyl)-A3-pyrroline is obtained from the addition of triphenylmethyl radicals to pyrrole. 

A3-Pyrrolines are obtained, as the major product, by the reduction of pyrroles by zinc in hydrochloric acid via the initial protonation of the ring at the 2-position. The minor products are the A1- and A2-isomers, which result from the reduction of the 3-protonated species. As shown in Scheme 54 (Section 3.05.1.5), there is a tautomeric equilibrium between the A1- and A2-pyrrolines, which is catalyzed by the acidic medium, but there is no evidence of a tautomeric equilibrium between these isomers and the A3-pyrrolines. The tautomeric mixture of the A1- and A2-pyrrolines can inter-react to yield the 3-(2-pyrrolidinyl)-A -pyrroline and any attempt to isolate the pure A -pyrroline results in the... 

Grigg, R., Martin, W., Morris, J. and Sridharan, V., Synthesis of A3-pyrrolines and A3-tetrahydropyridines via microwave-accelerated ring-closing metathesis, Tetrahedron Lett., 2003, 44(26), 4899-4901. 

The first article on the desilylative route to azomethine ylids appeared in 1979.385 It deals with the action of methyl trifluorosulfonate on iV-(trimethylsilylmethyl)benzylide-nimine to form the corresponding iminium salt which reacts with DMAD in the presence of cesium fluoride to yield corresponding A3-pyrroline. 

When the precursor is derived from malononitrile, reaction with maleimide leads to the expected a-cyano pyrrolidine adduct. However, methyl propiolate gives 3-carbomethoxy pyrrole, probably due to the acidity of hydrogen a- to the cyano group in the intermediate A3-pyrrolinic adduct first formed.171... 

Azaazulen-3-one (5) and its benzo derivative (170) were obtained from A3-pyrroline-2-ones in a similar way (Scheme 15) (83MI1). Both of these 3-ones are highly colored and very unstable, in contrast to the isomeric 4-azaazulen-5-one (6), whose synthesis is shown in Scheme 16 (73CB1993). 

Three dihydropyrrole 33-35 and one tetrahydropyrrole 36 ring systems can occur. Trivial names for the dihydropyrroles are A1-, A2-, and A3-pyrroline, where A indicates the position of the remaining double bond. Tetrahydropyrroles are known as pyrrolidines. Systematic naming of the reduced rings is illustrated by the following examples 2,3-dihydro-furan 37 (X = 0) and 2,5-dihydrothiophene 38 (X = S). 2,3,4,5-Tetrahydrofuran 39 is the well-known solvent THF. Tetrahydrothiophene 40 has an unpleasant smell and is sometimes used as an odorant in natural gas. 

In contrast to ketenes, keteneimines readily undergo metal-catalyzed [3+21-cycloadditions with methylenecyclopropanes. Depending on the substituents in both educts, pyrroles, a-methylene-A3-pyrrolines or iminocyclopentenes can be synthesized selectively in good to excellent yields. The substituent of the imino group determines... 

The primary cycloadducts, 2,4-dimethylene-N-phenyl-pyrrolidines, normally iso-merize to pyrroles during the reaction (Eq. 103). Only with geminally disubstituted methylenecyclopropanes, a-methylene-A3-pyrrolines are formed (Eq. 104)217). 

---