2- Formylpyrrole

Reaction of pyrrole with carbenes yields enlarged ring systems as well as 2-formylpyrrole [1003-29-8] (40). 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. 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 substituted methylene derivative, prepared from a 2-formylpyrrole and a ma-lonic acid derivative, was used in a synthesis of chlorophyll. It is cleaved under drastic conditions (coned alkali). ... 

Formylpyrrole oxidatively adds to [Os3(CO)lo(AN)2] by its formyl group giving rise to product 59 followed by cleavage of the C—H bond of this moiety [86JOM(311)371 90OM6]. The complex 59 easily decomposes to 47 and 48. Species 59 further reacts with triethylamine to yield 60 (97P3775). 

Under basic conditions (Triton B), in the presence of acrolein, 2-formylpyrrole derivative 216 underwent iV-alkylation by 1,4-addition followed by intramolecular aldolization-crotonization leading to 377-pyrrolizine 217 (Scheme 52)... 

Pyrrolizin-3-ones 75 were synthesized in one step from 2-formylpyrrole derivatives 228 and hydrocinnamoyl chloride in the presence of 4-dimethylaminopyridine (DMAP) and T,iV-diisopropylethylamine (DIPEA), in low to moderate yields (Scheme 57) <2002TL3673>. 

Similarly, the Vilsmeier reaction (reagents POCl and A, A -dimethyl-formamide) gives 2-formylpyrrole (Scheme 6.5). 

In a similar manner, the cyclohydrocarbonylation of A -l-allyl-2-formylpyrrole 80a-c afforded 7-formyl-5,6-dihydroin-dolizine 84a-c in good yield through one-pot cascade hydroformylation-aldol condensation process (Scheme 13)." ... 

H2SO4 alone destroys ring), (ii) Reimer-Tiemann formylation 2-pyrrolecarboxaldehyde (2-formylpyrrole),... 

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 higher acidity of pyrroles and indoles bearing electron-withdrawing substituents at the a- or /3-positions permits their alkylation under mildly basic conditions, but although the thallium salt of 2-formylpyrrole is Af-alkylated, the corresponding alkylation of the thallium salts of ethyl pyrrole-2-carboxylate yields a complex mixture of products resulting from iV-alkylation and transesterification (B-77MI30502). N-Alkylation of pyrrolyl and indolyl esters is most conveniently effected under phase-transfer conditions. 

The apparent fickleness of the acyl-pyrroles and -indoles in their reaction with carbanions to form new C—C bonds arises from the contribution made by the zwitterionic structure, e.g. (410b), to the resonance hybrid and the choice of the reaction conditions is critical for a successful nucleophilic reaction. Thus, formyl-pyrroles and -indoles do not normally undergo the Cannizzaro reaction nor do they form stable cyanohydrins or undergo benzoin-type reactions. However, surprisingly, 2-formylpyrrole reacts with arylaldehydes in the presence of potassium cyanide to yield (428), which is easily oxidized to (429) (B-77MI30505). It is noteworthy that the presence of an ester substituent adjacent to the formyl group modifies the mesomeric interaction to such an extent to allow the formation of (430) in low yield, as a result of an initial benzoin-type self-condensation (Scheme 76) (68BSF637). 

The products of the base-catalyzed Stobbe condensation of 3-formylindole and of 2-formylpyrroles undergo acid-catalyzed cyclization to yield l-hydroxycarbazole-3-carboxylic esters and 4-hydroxyindole-6-carboxylic esters, respectively (73JPR295, 74JPR386, 76JPR816). The analogous condensation of dimethyl homophthalate with 2-formyi-l-methylpyrrole and with 3-formylindole produces (443 Hetero= l-methyl-2-pyrrolyl, 3-indolyl), (444) and (445) under acidic conditions (76JHC83). 

Pyrrolizinones have also been synthesized by ring closure of the Knoevenagel product from 2-formylpyrroles and diethyl malonate (B-77MI30505). 

The Wittig reaction has been used to synthesise the cis and trans isomers of styrylpyrroles (B-77MI30505) and l,2-bis(2-pyrrolyl)ethylenes have been prepared in good yield from the reaction of 2-formylpyrroles with triphenyl(2-pyrrolylmethylene)phosphorane (81UP30500). 

In contrast with the relatively facile nucleophilic substitution reactions at the 2-position of the indole system, only 3-iodoindole has been reported to react with silver acetate in acetic acid to yield 3-acetoxyindole (59JOC117). This reaction is of added interest as 3-iodo-2-methylindole fails to react with moist silver oxide (72HC(25-2)127). It is also noteworthy that the activated halogen of ethyl 3-bromo-4-ethyl-2-formylpyrrole-5-carboxylate is not displaced during the silver oxide oxidation of the formyl group to the carboxylic acid (57AC(R)167>. 

These highly colored compounds (free base, yellow, Amax 400-450 nm salt, orange-red, Amax 500-550 nm) were used extensively in Fischer s procedures. The method of choice for synthesis of dipyrrylmethenes, for example (123), involves the acid catalyzed condensation of a 2-unsubstituted pyrrole (124) with a 2-formylpyrrole (125). This is a very satisfactory method which often proceeds in quantitative yield. An alternative method, used less for... 

Most of the methods of formation of [2.2.3]cyclazines have been described already the intramolecular condensation of indolizines in Sections 3.08.1 and 3.08.4, the cycloaddition to indolizines in Section 3.08.3.5, the cycloaddition to methylenepyrrolizines in Section 3.08.6.2.1 and a multistep synthesis from 2-formylpyrrole and l,2-bis(hetero) substituted ethylenes in Section 3.08.6.3.1. 

In the intervening two decades, pyrrolizine research has increased and new synthetic methods have accumulated. In 1964 E. E. Schweizer synthesized the parent compound 3//-pyrrolizine (I) from 2-formylpyrrole with vinyltriphen-ylphosphonium bromide.2 This simple route, suitable for a compound of the instability of 3//-pyrrolizine, proved to be a versatile synthetic method. 

Intramolecular condensation of either 2-formylpyrrole or 2-benzoylpyrrole with phenacyl bromide gave pyrrolizin-3-ones 52a39 and 52b,40 respectively. JV-Acylpyrroles presumably are intermediates. Similarly, 5-alkoxy-2-for-mylindoles (53) were converted to benzopyrrolizines (54) by treatment with methyl vinyl ketone in the presence of trimethylbenzylammonium hydroxide in dioxane 41 From diketone 55 a mixture of pyrrolizines [56a (25%) and 56b (11%)] was obtained.42... 

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