Nitriles 1-pyrrolines

Enamine salts react with many nucleophilic reagents. The reaction with the cyanide ion is noteworthy. l-Methyl-2-ethyl-2-cyanopyrrolidine (170) is formed on treatment of alkali cyanide with l-methyl-2-ethyl-.d -pyrrolin-ium perchlorate (242). The reduction of the tertiary nitrile (170) with... 

Independent work by Schmid93 and by Padwa94 on the photochemistry of 2H-azirines has shown that irradiation of such systems leads in the first instance to the formation of nitrile ylids (nitrilium betaines). Subsequent 1,3-addition to a variety of dipolarophiles affords five-membered heterocycles. These additions take place in a stereospecific and regioselective manner thus, irradiation of the diphenyl-2f/-azirine 117 in the presence of dimethyl maleate leads to the formation of the two isomeric 1-pyrrolines... 

Photoelimination of carbon dioxide from the 2-oxazolin-5-one 474 in the presence of methyl acrylate affords the cis- and frans-l-pyrrolines 475 and 476.394 A nitrile ylid is believed to be involved in this and other analogous transformations.395... 

Cyclic imidate esters, 2-ethoxypyrrolin-5-one and 2-ethoxy-1II -indol-3-one, undergo 1,3-dipolar cycloaddition reactions with nitrile oxides, the reaction site being at the pyrroline C=N bond (317). Rigid and sterically congested pyrroline spiro compounds 148 demonstrate complete diastereofacial selection in site and regiospecific cycloaddition reactions with nitrile oxides to give products 149 (318). 

The cyano-substituted nitrile ylides 123 have been generated via 1,1-elimination reactions. For example, the benzyhdene derivative 122 (R=Ph) eliminated benzene on vapor phase pyrolysis to give 123 (R=Ph), which reacted via 1,5-electrocycli-zation [see also (66)] to give the isoindole 124 (41%) (67). In a similar way, 122 [R=(CH2)3CH=CH2] gave the corresponding nitrile yhde that reacted via intramolecular cycloaddition to give the pyrroline derivative 126. 

Thus, N-metalated azomethine ylides of the cyano-stabilized type are important in the stereoselective synthesis of pyrrolines. These reactive intermediates are regarded as synthetic equivalents of nonstabilized nitrile ylides. 

The photolytic ring opening of 2//-azirines yields nitrile ylides which can be trapped as pyrrolines (97) (73JA1945). 

From a secondary amide, formation of a nitrile ylid because of plausible elimination of trimethylsilanol prior to cyclization might be expected. However, it is possible that this elimination occurs after cyclization. Thus, the true 1,3-dipole would be the imidate methylide. In any case, the final product will be a A -pyrroline.458... 

This above result was only obtained with maleimide as the dipolarophile. With dimethyl fumarate and fumaronitrile, A2-pyrrolines are obtained, probably because of the acidity of the hydrogen atoms a- to ester and nitrile functionalities. Reaction with alkynes produces pyrrole derivatives in good to excellent yields and with aromatic aldehydes leads regioselectively to oxazolidines in moderate yields.263... 

By contrast, addition of hydrogen cyanide to J -pyrrolines yields stable nitriles, which are reduced by lithium aluminum hydride to diamines and can be saponified to acids318 (Scheme 14). 

Pyrrolines X -piperideines. A convenient, general synthesis of A -pyrroIincs is based on the reduction of suitable nitriles with DIBAH (equation 1). 

Bicyclic A(0-Mti-homonucleoside analogues such as 591 were synthesized through 1,3-dipolar cycloaddition of an enantiopure 3-hydroxy-l-pyrroline A -oxide and protected allyl alcohol and subsequent introduction of thymine by a Mitsunobu reaction <2003T5231>. Furthermore, isoxazole, isoxazoline, and isoxazolidine analogues of (7-nucleo-sides such as 592-594 were synthesized by 1,3-dipolar cycloaddition of nitrile oxides and nitrones derived from uracil-5-carbaldehydes with suitable dipolarophiles <2003T4733, 2006T1494>. 

If the internal nucleophile is an alkenic group, then 5,6-dihydropyridine (Scheme 18) " or 1-pyrroline (Scheme 19) rings are produced. In a recent development of the latter process, the diol (44) follows the same sequence to yield the carbenium ion (45 R = Bn). However, this now cyclizes onto the aromatic group originating from the nitrile component and produces the tetrahydrobenz indole (46) in good yield, with the conventional pyrroline structure (47) now being only a minor product. Compound (46), present as a tautomeric mixture, was rapidly autoxidized to (48 Scheme 20). A further unusual variant of this process is the production of small quantities of the 3-azabicyclo[3.3.0]octanes (49) and (50) from Ritter reaction of l-vinylbicyclo(2.1.1]hexane (equation 32). ... 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated by LDA in THF, by NaH in THF, by thallium(I) ethoxide in refluxing THF, or by electrochemical technique to oc,P-unsaturated esters provides a preparation of substituted 2-(alkoxycarbonyl)cyclopropylphosphonates in moderate to good yields via a tandem Michael addition-cyclization sequence (Scheme 8.47). The cyclopropanation has also been achieved via oxidation with iodine in the presence of KF-AI2O3. Nitrile ylides prepared from acyl chlorides and diethyl isocyanomethylphosphonate in the presence of Et3N react with methyl acrylates by a 1,3-dipolar cycloaddition to give phosphoryl pyrrolines or pyrroles. ... 

Two entirely different methods utilizing A -pyrrolines as intermediates have been published. Storesund and Kolsaker prepared heavily substituted pyrrolizidines by base-catalyzed dimerization of nitriles. Initial reaction of the dinitrile starting material (97) is presumed to generate a cyclopropane... 

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