A study of the synthesis of benzo [1,2-b:4,3-b'] dipyrroles

Author:
Laurino, Joseph Philip, Department of Chemistry, University of Virginia
Advisors:
Sundberg, Richard, As-Chemistry, University of Virginia
Vines, Sterling N., Department of Chemical Engineering, University of Virginia
Mcgarvey, Glenn, As-Chemistry, University of Virginia
Carey, Francis A., Department of Chemistry, University of Virginia
Abstract:

Two synthetic approaches to the benzo [1,2-b: 4,3-b']-dipyrrole ring system of the antitumor antibiotic CC-1065 were investigated. The first route involved the conversion of anilines to indoles. N-Methanesulfonyl-N-(2,2-diethoxyethyl) anilines were cyclized to indoles with titanium tetrachloride in aromatic solvents. The temperature required to effect cyclization was substituent dependent. Meta-substituted anilines afforded mixtures of 4– and 6– substituted indoles. Yields for the alkyl, alkoxy, and haloindoles ranged from 60-90%. Ortho-substituted anilines failed to cyclize. The cyclization of the isoelectronic 6– membered ring system was investigated and the importance of stereoelectronic effects in this general electrophilic aromatic substitution reaction evaluated. The failure of ortho-substituted anilines to cyclize precluded the use of this synthetic approach for the synthesis of the benzodipyrrole ring system.

The second approach involved the conversion of substituted pyrroles to the benzo [ 1 ,2-b: 4,3-b'] dipyrrole ring system. Central to this scheme was the condensation of the lithium derivatives of N-unsubstituted-4-bromopyrrole-2- carboxylates with 1-substituted pyrralidine-2,3-diones. The condensations of ethyl 4-bromo-5- (5,5-dimethyl-1,3-dioxan-2-y1) pyrrole-2-carboxylate, ethyl 4-bromo-5- [ (hydroxyimino) - methyl] pyrrole-2-carboxylate, 4 -bromopyrrole-2,5-dicarboxylic acid 5-monomethyl ester, 4-bromo-5-(3-methylisoxazol-5-yl) pyrrole-2-carboxylate, and ethyl 4-bromo-- pyrrole-2-carboxylate with both 1-benzyl-2,3-dioxopyrrolidine and 1-allyl-2,3-dioxopyrrolidine were investigated.

Ethyl 4-(1-benzyl-3-hydroxypyrrolidin-2-on-3-y1) pyrrole- 2-carboxylate and ethyl 4-(1-benzyl-3-hydroxypyrrolidin- 2-on-3-y1)-5-(3-methylisoxazol-5-y1) pyrrole-2-carboxylate and the corresponding allyl derivatives were elaborated to intermediates which could potentially be cyclized to the benzodipyrrole ring system. The acylation of the 5-position of ethyl 4- (1-benzyl-2-oxopyrrolidin-3-y1)- pyrrole-2-carboxylate proved exceedingly difficult. The base catalyzed cyclization of ethyl 4-(1-benzyl-2-oxopyrrolidin- 3-y1)-5-acetylpyrrole-2-carboxylate to the phenoclic Benzodipyrrole was also unsuccessful.

Another possible method for cyclizing ethyl 4-(1- benzylpyrrolidin-2-on-3-y1) pyrrole-2-carboxylate to the benzo [1,2-b:4,3-b'] dipyrrole ring system, which involved the condensation of the corresponding thiolactam derivative with either a β-keto ester or an ∝ --cyanoester, was investigated. The non-catalytic reduction of the ∝ -hydroxyketone functionality of both ethyl 4-(1-benzyl-2-oxo-3-hydroxypyrrolidin-3-yl) pyrrole-2-carboxylate and ethyl 4- (1-benzyl -2·-oxo-3-hydroxypyrrolidin-3-y1)-5-(3-methylisoxazol-5-y1) pyrrole-2-carboxylate was examined. Under a variety of reduction conditions, these reactants eliminated water to form ethyl 4- (1-benzyl- Δ3 -pyrrolin-2-on-3-y1) pyrrole-2- carboxylate and ethyl 4-(1-benzyl- Δ3 -pyrrolin-2-on-3-y1)-5- (3-methylisaxazol-5-y1) pyrrole-2-carboxylate, respectively. Attempts to reduce these pyrrolines under non-catalytic conditions are described.

The deallylation of ethyl 4-(1-allyl- Δ3 -pyrrolin-2-on- 3-y1) pyrrole-2-carboxylate and ethyl 4-- ( 1-allyl -- Δ3 - pyrolin-2-on-3-y1)-5-(3-methylisoxazol-5-y1) pyrrole-2-carboxylate were investigated. The former reaction was successfully effected by use of Wilkinson's catalyst which gave an Nethoxypropyl derivative in ethanol. The latter reaction was unsuccessful because of a competing rearrangement of the isoxazole ring to give the oxazole.

Degree:
PHD (Doctor of Philosophy)
Keywords:
Ring formation (Chemistry), Pyrroles, Derivatives, Synthesis, Indole, Heterocyclic compounds
Language:
English
Rights:
All rights reserved (no additional license for public reuse)
Issued Date:
1986