3-formylpyrrol

Erba et al. (102) observed a novel formation of pyrrole imines 181 from the 1,3-dipolar cycloaddition of mtinchnones 179 and 5-amino-l-aryl-4,5-dihydro-4-methylene-1,2,3-triazoles 180 (Table 10.4). Treatment with benzaldehyde yielded 3-formylpyrroles (182). The reaction presumably involves loss of carbon dioxide, nitrogen, and morpholine from the initial cycloadduct. Unsymmetrical mtinchnones behave regioselectively and furnish products derived from bonding between C(2) of... 

In substituted 4-formylpyrazoles (14), the N (R),0-trans form prevails (84ZOR1790) in the conformational mixture the same conformational preference of 3-formylpyrrole is thus found. It is nevertheless hard to argue about the role played by the second nitrogen atom, in view also of the effects due to the substituents R and R on the heterocyclic ring. 

In an extensive ab initio study, the preferred conformers for substituted pyrroles are predicted to be, inter alia NCCH trans and C(2)CCH cis for 2- and 3-methylpyrroles [i.e. a methyl C—H bond eclipsing the pyrrole C(2)—C(3) bond) NCCO cis and C(2)CCO cis for 2- and 3-hydroxymethylpyrroles pyramidal at nitrogen for aminopyrroles planar OH trans for hydroxypyrroles planar trans for vinylpyrroles, and planar cis (syn) for formylpyr-roles. In agreement with experiment the energy difference between the two rotamers for 3-formylpyrrole is much smaller than for the 2-isomer (79NJC473). 

Addition reactions. 3-Aryl- and 3-formylpyrroles are alkylated by heating with the xanthates (XCH2SC=S)OEt and dilauroyl peroxide. The activated carbon chain CH2X (X = CN, COOEt, Ac,...) is introduced to C-2. ... 

When 2,5-dimethoxy-2,5-dihydrofuran was reacted with syngas in the presence of a heterogeneous rhodium catalyst, 3-formyl-2,5-dimethoxytetrahydrofuran was formed in excellent yields (Scheme 4.48) [95]. Treatment of the product with ethyl carbamate produced JV-(ethoxycarbonyl)-3-formylpyrrole, which was after saponification and decarboxylation transformed into 3-formylpyrrole. 

C2H5O O PTSA = p-Toluenesulfonic acid Scheme 4.48 Synthesis of 3-formylpyrrole via hydroformylation. 

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). 

The 1,3-oxazepine (848) is thermally labile the main products are formylpyrroles but some 3-hydroxy-2-phenylpyridine is obtained (75TL1067). The benzoxazepines of type (849) are intermediates in the photochemical breakdown of quinoline iV-oxides and can sometimes be isolated. They normally break down to give 3-hydroxyquinolines (66TL2145, 67CPB663), but compound (849) can be converted by methylamine into the diaminoquinoline (850) (67TL5237). The benzoxazepinone (851) with sodamide forms a mixture of three isoquinoline... 

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 Vilsmeier-Haack formylation procedure (Scheme 24) provides the most effective synthesis of formylpyrroles and indoles. Reaction of the heterocycles with the immonium cation (72), derived from DMF or (V-methylformanilide with an acid chloride, such as phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, benzoyl chloride or bromotriphenylphosphonium bromide, yields the intermediate heteroarylimmonium salt (73). Under suitable reaction conditions, this salt may be isolated from the reaction involving phosphorus oxychloride as an impure chlorophosphate (78TH30500) or precipitated from the reaction system as the thermally unstable perchlorate by the addition of sodium... 

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. 

Halogenomethylpyrroles have been oxidized with lead(IV) salts or by chromium trioxide to yield the formylpyrroles, whilst catalytic hydrogenolysis or zinc-acetic acid reduction produces the 2-methylpyrroles (B-77MI30504). The methyl derivatives are also obtained by hydride reduction of trifluoromethyl-pyrroles and -indoles, and trifluoromethylindoles are converted into the carboxylic esters by ethanol under basic conditions (74JOC1836). 

---