Pyrroles reductive alkylation

Pyrrole has been condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 22). Although acid-catalyzed hydroxy-methylation is not a practical possibility, by addition of a reducing agent to the reaction mixture overall reductive alkylation can be achieved (Scheme 23). 

Fluormated pyrroles are obtained from 2,5-dimethylpyrrole by reductive alkylation with perfluoroaldehyde hydrates [174] (equation 149)... 

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 use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(l//)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with l-chloro-3-iodopropane or 1-chloro -iodobu-tane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178). 

Changing the position of the electron-withdrawing group (either an amide or ester) to the C-3 of pyrrole allowed access via regioselective reductive alkylations to the corresponding 4-alkyl-2-pyrrolines 924 (Equation 224) and 925 (Equation 225) in good yields <1998TL3075>. Reduction of 3-substituted pyrroles was more difficult to achieve than that of the 2-substituted isomers. 

Coal is characterised by a non-uniform molecular structure within which aromatic structural units can be distinguished. They are composed of one to five condensed or directly joined aromatic rings substituted by heterocyles and aliphatic (mainly methyl) groups. Nitrogen is involved in pyridine and pyrrole rings and a part of sulphur in thiophene rings. C- and 0-alkylation may occur by the reductive alkylation reactions of coal. Lazarov et al. (1984) presented a structural model which fits the values of the structural parameters obtained by H and NMR spectroscpy of alkylated coal. 

It has been reported [434,435] on the alkylation of ammonia, aliphatic, and some aromatic amines by primary and secondary alcohols upon heating under hydrogenation on Raney Ni. However, the data on alkylation of indole or pyrrole in similar conditions were absent until the work [433]. In this work, it has been shown that reductive alkylation may also be affected by other primary alcohols (e.g., butanol), although in the latter case, reduction proceeds with greater difficulty than in ethanol N-butyloctahydroindole is detected in the reaction mixture only by chromatography. 

Pyrrole- and Furan-fused Thio diens and Related Compounds.— The interest in the chemistry of thienopyrroles is still increasing. Starting from 2-amino-3-carbonyl-substituted thiophens obtained by the Gewald reaction, the A -ethoxy-carbonylmethyl derivative (245) was prepared either by direct alkylation with ethyl bromoacetate, or by reductive alkylation with methyl glyoxalate. The compounds (245) were then ring-closed directly, or after acetylation, to the... 

Photoreaction of 2-pyridone with aliphatic and aromatic amines leads to addition of the amines at C4 and C6 to give mixtures of dihydropyridone products (Scheme 15). All of these reactions appear to derive from a single electron transfer process. Tertiary aliphatic amines such as triethylamine 150 yield pyridones 151 and 152 (2 1) plus the reductively coupled pyridone dimer 153. Pyrrole 154 leads to a similar mixture of 4- and 6-substituted dihydropyridones 155 and 156 (1 1). Dimethylpyrrole 157 and indole 158 lead to analogous products of 4- and 6-substition of the pyridone (at C3 of the pyrrole 157). N-Methyl pyrrole 159, however, does not yield photoproducts. When the N-methyl pyrrole is alkyl substituted at C2 (160), addition to the pyridone yields 161 and 162 (1 1). ... 

Diborane reduction of pyrrole and indole ketones affords the corresponding alkyl-pyrroles and -indoles <68X1145). 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Although the synthesis of multiple-pyrrolyl compounds can be achieved by SnAt reactions of perfluoroaromatics with pyrrolylsodium at ambient temperature <96JOC9012>, deleterious side reactions are often observed during attempted A-alkylations of the alkali salts of pyrrole. A protocol has therefore been developed for the preparation of N-arylmethylenepyrroles by reduction of the corresponding AT-acyl derivatives by treatment with sodium borohydride/boron trifluoride etherate in a sealed tube <96S457>. ... 

In another example of a radical process at the pyrrole C-2 position, it has been reported that reductive radical cycloaddition of l-(2-iodoethyl)pyrrole and activated olefins, or l-(oj-iodo-alkyl)pyrroles 34 lead to cycloalkano[a]pyrroles 35 via electroreduction of the iodides using a nickel(II) complex as an electron transfer catalyst <96CPB2020>. Thus, it appears the radical chemistry of pyrroles portends to be a fertile area of research in the immediate or near future. 

A Sml2-induced reductive cyclization of (V-(alkylketo)pyrroles provided an entry into medium ring 1,2-annelated pyrroles <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to a-(pyrrol-2-yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <060L2007>. 

The HOPG (highly oriented pyrolytic graphite) carbon electrode chemically modified with (5[-phenylalanine at the basal surface led to 2% ee in the reduction of 4-acetylpyridine [377]. A cathode modified with a chiral poly(pyrrole) reduced 4-methylbenzophenone or acetophenone in DMF/LiBr and phenol as proton donor to 1-phenylethanol with up to 17% ee [382]. Alkyl aryl ketones have been reduced to the corresponding alcohols at a Hg cathode in DMF/water in the presence of (1R,2S)-A,A-dimethylephedrinium tetrafluorobo-rate (DET), producing (5 )-l-phenylethanol with 55% ee from acetophenone. Cyclovoltammetry supports an enantioselective protonation of the intermediate (PhCOH(CH3)) [383]. 

Pyrrolo[l,2-(7][l,2,5]benzotriazepin-ll-one 329 is the product of a sequence starting from N-(2-nitrophenyl)-lH-pyrrol-l-amine 327. The pathway included alkylation, reduction of the nitro group, formation of the isocyanate from intermediate 328 and intramolecular thermal cyclization (Scheme 69 (2000JHCl539)). 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

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