Pyrrole aldehydes, reduction

The Cram modification has not been greatly exploited in multistep synthetic endeavors, possibly because of the above-mentioned need to preform and isolate the hydrazone intermediate coupled with very slow addition of the hydrazone. This latter requirement is particularly inconvenient when milligram quantities are involved. The aldehyde in a triterpenoid (partial structure 18) was successfully reduced to the corresponding methyl group using the Cram method, albeit in low yield (32%). Notably, the hydrazone (lO mg) was not added slowly. The Cram process was not successful for the reduction of the cyclo-butanone (19) (the Huang-Minlon process succeeded), or the pyrrole aldehydes (20) and (21). ... 

Vilsmeier-Haack Formylation with N,N-Dimethylformamide. In the presence of phosphorus oxychloride (POCI3), the—CHO group of N,N-dimethylformamide can be attached to the pyrrole ring (Scheme 7.7). This is a highly useful process for the synthesis of pyrrole aldehydes, which are precursors of pyrrole acids by oxidation, of pyrryl carbinols by reductions with LiAHtj, and of other products (Scheme 7.7). 

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... 

Epoxidation of glycal 134 with DMDO followed by in situ reduction of the pyrrole aldehyde and subsequent attack on the epoxide afforded the spiroacetal core of acortatarin B in high yield as a single diastereomer. Cleavage of the TlPS-ethers with TBAF then afforded the natural product 38 in excellent yield. 

Reduction of amides to aldehydes was accomplished mainly by complex hydrides. Not every amide is suitable for reduction to aldehyde. Good yields were obtained only with some tertiary amides and lithium aluminum hydride, lithium triethoxyaluminohydride or sodium bis 2-methoxyethoxy)aluminum hydride. The nature of the substituents on nitrogen plays a key role. Amides derived from aromatic amines such as JV-methylaniline [1103] and especially pyrrole, indole and carbazole were found most suitable for the preparation of aldehydes. By adding 0.25 mol of lithium aluminum hydride in ether to 1 mol of the amide in ethereal solution cooled to —10° to —15°, 37-60% yields of benzaldehyde were obtained from the benzoyl derivatives of the above heterocycles [1104] and 68% yield from N-methylbenzanilide [1103]. Similarly 4,4,4-trifluorobutanol was prepared in 83% yield by reduction of N-(4,4,4-trifluorobutanoyl)carbazole in ether at —10° [1105]. 

Lactonization of the suitable hydroxy acids or their derivatives is the most common synthetic method for benzoxepinenones with fused pyrrole rings. Therefore, reduction of the formyl group in the ester aldehyde 121 with sodium borohydride gives a mixture of alcohol 122 (80% yield) and lactone 123 (19%). Further heating of the open-chain product 122 in refluxing ethanol affords cyclic lactone 123 quantitatively (Scheme 25 (1998T11079)). 

Reductive ring closure of l-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,l-c][l,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R = H) or ester (R = Et) 205 followed by CDI or thermal cyclization (1992JHC1005). 

The carbonyl reactivity of pyrrole-, furan-, thiophene- and selenophene-2- and -3-carbaldehydes is very similar to that of benzaldehyde. A quantitative study of the reaction of Af-methylpyrrole-2-carbaldehyde, furan-2-carbaldehyde and thiophene-2-carbaldehyde with hydroxide ions showed that the difference in reactivity between furan- and thiophene-2-carbaldehydes was small but that both of these aldehydes were considerably more reactive to hydroxide addition at the carbonyl carbon than A-methylpyrrole-2-carbaldehyde (76JOC1952). Pyrrole-2-aldehydes fail to undergo Cannizzaro and benzoin reactions, which is attributed to mesomerism involving the ring nitrogen (see 366). They yield 2-hydroxymethylpyrroles (by NaBH4 reduction) and 2-methylpyrroles (Wolff-Kishner reduction). The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

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. 

An intramolecular reaction with primary amine as the nucleophile that was prepared in situ by the reduction of the nitro group in pyrrole 1319 resulted in the pyrrolo[2,Tf]benzo[/ ]diazepine 1320, which indicates that the amino group reacts via condensation with the aldehyde group rather than via substitution of the chloro group (Equation 287) <2005T5831>. 

Treatment of the substrate 461 with 4-chloroaniline in the presence of a dibutyliodotin hydride complex caused initial reductive amination of the aldehyde functionality to provide an intermediate which underwent annulation to the pyrrole 462 (Equation 127) <2004SL137>. Access to /3-fluoropyrrole derivatives has been gained by reactions of a,a-difluoro-7-iodo-7-trimethylsilyl ketones with aqueous ammonia, followed by treatment with potassium fluoride <1995TL5119>. 

The oximes of the 1-butyl and 1-phenyl aldehydes (148) were reduced with zinc and hydrochloric acid to give 1-butyl- and l-phenyl-3-aminomethyl-4-methyl-7-azaindole, in 63 and 65% yield, respectively. Reduction of the 1-phenyl oxime with lithium aluminum hydride, however, was accompanied by reduction of the pyrrole ring to give the corresponding 3-aminomethyl azaindoline in 80% yield. 9... 

In a study focusing on the synthesis and reactions of 2-(2-aminoethyl)pyrroles, a preparation of the tricyclic ring-system 64 was accomplished by reduction of the succinimides 65, followed by cyclization of the intermediates 66. Moreover, 2-(2-aminoethyl)pyrroles were demonstrated to undergo cyclization with aldehydes to provide 4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines <03T5265>. 

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