Pyrrole-2-carbaldehyde

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 diazepine with fused pyrrole ring 250c is the product of the condensation of orflzo-phenylenediamine with pyrrole carbaldehyde 249 in 36% yield (Equation (31) (2006T6018)). 

Pyrrolo-benzoxazepines with other fusion modes. As with diazepine, benzoxazepine with the fused pyrrole ring 250a can be prepared by condensing ortho-amino phenol (X = O) with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 (2006X6018)). 

This method of reduction is applicable also to heterocyclic aldehydes. For instance, 2-pyrrolemethanol can be prepared from 2-pyrrolecarbaldehyde in 59% yield by the inverse method 349 but reduction of polysubstituted pyrrole-carbaldehydes is impossible or possible only with great difficulty.350... 

Sulfonamides have also seen great success as partners in the Clauson-Kaas reaction. Similar to amides the pyrroles generated are protected by the starting sulfonamides. Karousis and co-workers reported a successful example of this procedure with 3-formyl-2,5-dimethoxytetrahydrofuran 7 to generate tosyl-protected pyrrole carbaldehyde 8. The tosyl-protecting group was later removed under mildly basic conditions (K2CO3, MeOH at room temperature). 

Although the same theoretical studies indicate very small energy differences between the syn and anti conformers of the 3-carbaldehydes of furan, thiophene and pyrrole with a slight preference for the syn conformer, in chloroform solution the furan- and thiophene-3-carbaldehydes adopt the anti conformers to the extent of 100 and 80% respectively (82X3245). However, A-substituted 3-(trifluoroacetyl)pyrroles exist in solution as mixtures of rotational isomers (80JCR(S)42). 

Pyrrole and alkylpyrroles can be acylated by heating with acid anhydrides at temperatures above 100 °C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacetyl-pyrrole on heating with acetic anhydride at 150-200 °C. iV-Acylpyrroles are obtained by reaction of the alkali-metal salts of pyrrole with an acyl halide. AC-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

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 iV-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... 

According to computational studies, pyrrole-2-carbaldehyde 200 is more stable than the corresponding tautomer 201 by 7.05 kcal/mol (CNDO/2) and 18.9 kcal/mol (STO-3G) (90MI5). 

In 1970, Hiraoka reported that 2-cyanopyrrole, irradiated in methanol with a low-pressure mercury arc for 20 h, gave a mixture of 3-cyanopyrrole and pyrrole-2-carbaldehyde [70JCS(CC)1306]. l-Methyl-2-cyanopyrrole (38) also gave this reaction (Scheme 15) [71JCS(CC)1610]. In this case, the author isolated the product of the isomerization 39, the product of the shift in C-2 of the IV-methy 1 group 40, and a third product that was assumed to be derived from the addition of methanol to the Dewar pyrrole 41. The reaction depends on the temperature used in fact, no reaction occurred when the reaction was performed at -68°C. This result is in agreement with the presence of a thermal-activated step [78JCS(CC)131]. More... 

Cyclization of /V-carbethoxyhydrazone 57 and ALformylhydrazone 58 of pyrrole-2-carbaldehyde gave 59 (73CC35 80JHC631) by base-catalyzed cyclodehydration. The expected substitution product at 6-position was obtained from the reaction of 58 with N-bromosuccinimide (Scheme 15). 

An efficient synthesis of rigid tricyclic (5 5 5) nitrogen heterocycles 64 has been achieved via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole derivatives <2004JOC1207> and the trienes 477 were prepared by the acylaton of amines 475 with the anhydride 476. The amines 475 were in turn prepared starting from pyrrole-2-carbaldehyde. The triene 477 on heating in toluene at 80 °C for 15 h underwent the IMDA to afford the tricyclic compound 64 as a single diastereomer in quantitative yield. The sterically bulky N-substitutent on the triene 477 promoted cycloaddition under milder condition at 65 °C in toluene to provide the tricyclic compound 64 in quantitative yield (Scheme 108). 

The reactions of substituted furo[3,2- ]pyrrole-5-carbohydrazides with 5-arylfuran-2-carbaldehydes, 4,5-disubsti-tuted furan-2-carbaldehydes, and thiophene-2-carbaldehyde have been studied <2005CEC622>. The advantage of microwave (MW) irradiation on some of these reactions was reflected in the reduced reaction time and increased yields (Table 8). The series of substituted hydrazones 241-246 was obtained from these... 

Substituted hydrazones 254 and 255 were synthesized by the reaction of the corresponding furo[3,2- ]pyrrole-5-carbohydrazides with 6-substituted 4-oxochromene-3-carbaldehydes 252 and methyl 2-formylfuro[3,2- ]pyrrole-5-car-boxylates 253 under MW irradiation as well as by the classical method(C). The beneficial effect of the MW irradiation on these reactions was a shortening of the reaction time and an increase in the yields <2005CCC2101> (Scheme 25). 

The condensation of furo[3,2- ]pyrrole-type aldehydes 8g and 265-267 with hippuric acid was carried out in dry acetic anhydride catalyzed by potassium acetate as is shown in Scheme 26. The product methyl and ethyl 2-[( )-(5-oxo-2-phenyl-l,3-oxazol-5(4//)-ylidene)methyl]furo[3,2- ]pyrrol-5-carboxylates 268a-d were obtained. The course of the reaction was compared with the reaction of 5-arylated furan-2-carbaldehydes with hippuric acid. It was found that the carbonyl group attached at G-2 of the fused system 8 is less reactive than the carbonyl group in 5-arylated furan-2-carbaldehydes in this reaction <2004MOL11>. The configuration of the carbon-carbon double bond was determined using two-dimensional (2-D) NMR spectroscopic measurements and confirmed the (E) configuration of the products. 

Methyl 2-[3-(trifluoromethyl)phenyl]-4/7-furo[3,2-4]pyrrole-5-carboxylate 81a was made by thermolysis of the corresponding methyl 2-azido-3- 5-[3-(trifluoromethyl)phenyl]-2-furyl propenoate 378, which was formed by condensation of 5-[3-(trifluoromethyl)phenyl]furan-2-carbaldehyde 377 with methyl azidoacetate under sodium meth-oxide catalysis (Scheme 40) <2006KGS825>. 

Knoevenagel condensation of the corresponding 3-methylfuran-2-carbaldehyde 379 and 3-methybenzo[4]furan-2-carbaldehyde 382 with diethyl malonate followed by bromination with iV-bromosuccinimide (NBS) in the presence of dibenzoyl peroxide afforded bromides 380 and 383, respectively. Treatment of 380 and 383 with benzylamine, isopropylamine, /-butylamine 3-hydroxypropylamine, aniline and -toluidine in ethanol yielded furo[2,3-c]pyrroles 381 and benzo[4,5]furo[2,3-c]pyrroles 384, respectively (Scheme 41). The yields of furopyrroles 381 are only moderate (16-46%), because these compounds are highly sensitive to acid, and partially polymerized upon silica... 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-f]pyrrole ring system 387 <2003T1477> and its derivatives was accomplished using the same synthetic sequence (Scheme 42). Starting with 2-methyl-benzo[ ]thiophene-3-carbaldehyde 388, an intermediate 389 was obtained. Treatment of bromo compound 389 with sodium azide in ethanol led to the stable triazoline 390. 1,3-Dipolar cycloreversion of 390 was induced by a catalytic amount of />-TsOH to give the parent 2//-benzo[4,5]thieno[2,3-c]pyrrole 387. Alternatively, direct treatment of bromo compound 389 with excess ammonia furnished 387 in one step. Compound 387 was treated with di-/-butyl dicarbonate and 4-dimethylaminopyridine (DMAP) to give iV-BOC derivative 391. Reaction of 389 with... 

Early work on the experimentally established conformational preferences in solution for a variety of other 2-substituted heterocycles is summarized in Table 30. Most of these conclusions have been deduced either from dipole moment measurements in benzene or by the use of lanthanide induced shifts for chloroform solutions. The aforementioned MO studies correctly predict the preferred conformations, (63, R = H) or (64, R = H), of pyrrole-2-carbaldehyde, thiophene-2-carbaldehyde and furfural in the gas phase. 

The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, gives a bicyclic intermediate which can be transformed to either 3-chloropyridine (155) or pyrrole-2-carbaldehyde (156). Indole gives a mixture of 3-chloroquinoline (157) and indole-3-carbaldehyde (158). The optimum conditions involve phase transfer (76S249, 76S798). Benzofuran reacts with dichlorocarbene in hexane solution to give the benzopyran (159), whereas benzothiophene fails to react. 

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. 

A second type of route from pyrroles to indoles involves construction of a vinylpyrrole suitable for [4 + 2] cycloaddition leading to a dihydro- or tetrahydro-indole (Scheme 19) (80JOC4515, 81T1597). The dihydro systems can be easily aromatized. 2-Nitrovinylpyrroles, which are readily available by condensation of pyrrole-2-carbaldehyde with nitromethane, give fully aromatic indoles on reaction with dienophiles (equation 139) (73JCS(P1)2450). The aromatization results from elimination of nitrous acid and a further dehydrogenation. 

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