Pyrrole Aldehydes and Ketones

These are stable compounds which do not polymerise or autoxidise. For the most part, pyrrole aldehydes and ketones are typical aryl ketones, though less reactive -such ketones can be viewed as vinylogous amides. They can be reduced to alkylpyrroles by the Wolff-Kishner method, or by sodium borohydride via elimination from the initial alcoholic product. Treatment of acylated 1-phenylsulfonylpyrroles with t-butylamine-borane effects conversion to the corresponding alkyl derivatives.  

13- and a-Acylpyrroles can be equilibrated one with the other using acid for N-alkyl-C-acylpyrroles, the equilibrium lies completely on the side of the 3-isomer.  

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Aldehydes and Ketones. Pyrrole aldehydes and ketones are somewhat less reactive than the corresponding benzenoid derivatives. The aldehydes do not undergo Cannizzaro or Perkin reactions but condense with a variety of compounds that contain active methylene groups. They also react with pyrroles under acidic conditions to form dipyrryhnethenes (26). The aldehydes can be reduced to the methyl or carbinol stmctures. The ketones undergo normal carbonyl reactions. 

Pyrrole aldehydes and ketones are important sources of alkylpyrroles, formed from them by WolfF-Kishner reduction 232 -3, 33i, More recently, lithium aluminium hydride has been used for this purpose32 233, 332 -5 Direct addition of the carbonyl compound to the reagent gives the alkyl-pyrrole, whilst inverse addition allows preparation of the carbinol. Carboxylic acids and their esters are also reduced by lithium aluminium hydride to alkylpyrroles. In contrast to pyrrole aldehydes unsubstituted at nitrogen, 2-and 3-formyl-1-methylpyrroles are reduced by lithium aluminium hydride only to the carbinol stage sa. The difference is explained by the mechanism... 

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

An important extension of the Knorr pyrrole synthesis developed by Cushman utilizes ketone enolates and BOC-protected a-amino aldehydes and ketones. Two examples (37, 38) are shown. 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

Pyrrole reacts with aldehydes and ketones under acidic conditions to form polymeric compounds. In many cases these are intractable resin-like materials however, with appropriate carbonyl compounds, interesting cyclic tetramers can be formed in very good yields. 

Pyrrole reacts with aldehydes and ketones and an acid catalyst to form resins, probably linear polymers however, surprisingly, from an entrop-ic point of view, with acetone (propanone) and hydrochloric acid the product is a cyclic tetramer. Possibly the two methyl groups in the developing side chains force it to bend and thus bite its own tail (Scheme 6.7). 

When the reactions of pyrroles and indoles with aldehydes are catalyzed by hydriodic acid, the initially formed carbinols or azafulvenes are reduced to yield the corresponding alkylpyrroles and alkylindoles (68CJC3291,70CJC139). The reductive alkylation of the pyrrole ring, using a range of aliphatic and aromatic aldehydes and ketones, may also be accomplished with phosphonium iodide, with hydrochloric acid and zinc amalgam, or with tin(II) bromide in hydrobromic acid. 

The regioselective photoaddition of aliphatic aldehydes and ketones to pyrroles provides a route to 3-pyrrolylcarbinols and 3-vinylpyrroles in yields varying from 15 to 50% (79JOC2949) (see also Section 3.05.1.7.2). 

The Schotten-Baumann acylation of pyrroles and indoles is discussed in Section 3.05.1.2.6 and reactions of the heteroaryl anions with aldehydes and ketones are presented in Section... 

The formation of 3-pyrrolylcarbinols (280) from the photochemically induced reaction of pyrrole, or its 1-alkyl derivatives, with aliphatic aldehydes and ketones is thought to proceed via an oxetane intermediate (279) (79JOC2949). In contrast, the analogous reaction of 1 -phenylpyrrole with benzophenone leads to the formation of the diphenyl(2-pyrrolyl)car-binol, whilst the oxetane (281) has been isolated from the photoaddition of 1-benzoylpyrrole and benzophenone (76JHC1037, B-77MI30500). 2-Benzoyl-1-methylpyrrole undergoes a normal Paterno-Buchi photocyclization with 2,3-dimethylbut-2-ene, via the n -> v triplet... 

Pyrrole, like thiophene, does not react with benzophenone to give the corresponding oxetane. However, pyrrole reacts with aliphatic aldehydes and ketones to the corresponding 3-pyrryl carbinols. The alcohols derive from the cleavage of the corresponding oxetanes (Scheme 3.48) [94]. The yields increase when A -methylpyrrole is used as substrate, while the reactivity is depressed in the presence of substituents on the pyrrole ring. 

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