Pyrrole-2-carbaldehydes, 5-substituted

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). 

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). 

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 furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31 too). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxy-pyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield A-substituted pyrroles, the closure of the intermediate... 

Milkiewicz and coworkers [16] prepared a series of novel tetra-substituted furo[3,2-b Ipyrroles from the methyl or ethyl 3-bromo-2-phcnyllliro 3,2-/ pyrrole-5-carboxylate 40, which was prepared from 3-bromo-2-phenylfuran-2-carbaldehyde 39. The compounds 40 were subjected to a Suzuki coupling with 4-chlorophenyl boronic acid to form 41, which was treated with a variety of alkylating agents to afford the corresponding esters 42. The esters were then saponified to acids 43 (Scheme 6). 

Scheme 13 a 6-Substituted-4-oxochromene-3-carbaldehydes 84, TsOH b methyl 2-formyl-fum 3,2-7) pyrrole-5-carboxylales 80, TsOH [24]... 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

Iodo-li/-pyrrole-2-carbaldehyde, used in the synthesis of nucleoside derivatives, was prepared via protection of the aldehyde group in l//-pyrrole-2-carbaldehyde with an iminium salt for the efficient w f -directed electrophilic substitution of the starting pyrrole followed by a treatment of the iminium salt with N-iodosuccinimide in acetonitrile then with sodium bicarbonate (57% two-step total yield) <2003BML4515>. 

Photochemical substitution of some iodo-substituted pyrroles 597 in the presence of aromatic compounds depends on the structure of the pyrrole and on reaction conditions and gives the corresponding aryl derivatives 598 and/or dehalogenated product 599 (Scheme 120) <1997J(P1)2369>. Use of 4,5-diiodopyrrole-2-carbaldehyde 597 (R = I, = H, R = CHO) as substrate and irradiation in benzene, w-xylene, thiophene and 2-chlorothiophene as solvents gives solely the corresponding 5-aryl derivatives 598 in good yields (57-100%). There is no competition between 4-and 5-substitution. 

The substituted pyrrole-2-carbaldehydes 888 and the 5-(17/-pyrrol-2-ylmethyl)-l//-pyrrole-2-carbaldehydes 891 are oxidized by hydrogen peroxide under mild conditions to give pyrrol-2-ones 889, 890 and 892 (Equations 218... 

The Michael-addition of l//-pyrrole-2-carbaldehyde 1311 to Cr(CO)3-complexed aryl allenylphosphonates 1312 followed by an intramolecular Horner-Emmons-Wadsworth olefmation in boiling THE gives rise to arene Cr(CO)3-substituted 3-(l-methylethylidene)-3//-pyrrolizines 1313 and 1314 in moderate to good yields (Scheme 251) <1998T1457>. 

The photochemical heteroarylation of thiophenes has been further exemplified. Irradiation of 4,5-diiodopyrrole 2-carbaldehyde with thiophene or 2-chlorothiophene leads to the pyrrole-substituted thiophenes in high yield (Equation 18) <1997J(P1)2369>. Similarly, irradiation of 4(5)-nitro-2-iodoimidazole in the presence of thiophene or 2-chlorothiophene produces the imidazole-substituted thiophenes 54 in good yields <1998J(P1)271>. 

Structural changes affect seriously an electrophilic substitution orientation in pyrroles owing to their low positional selectivity in reactions with electrophiles. Thus, in contrast to thiophene, selenophene, and, especially, furan analogues, even a relatively weak type 11 substituent in position 2 of the pyrrole ring is capable of overcoming the a-oiienting effect of the heteroatom and directs an electrophile preferably to the position 4 (68JCS(B)392). N-(p-Nitrophenyl)pyrrole-2-carbaldehyde... 

Methylpyrrole is one of the four pyrroles isolated in the pyrolysis of trigonelline by Viani and Horman (1974). It was also formed by heating D-xylose with methylamine (Kato, 1966), from a cysteine/ cystine ribose browning system (Mulders, 1973c). Kato and Fujimaki (1968) observed the formation of A -substituted pyrrole-2-carbaldehydes when D-xylose reacted thermally with various amines or amino acids (glycine, alanine, 3-alanine, leucine). The intermediate 3,4-dideoxypentosulos-3-ene would either give 2-furaldehyde (mainly with a-amino acids) or substituted pyrrole-2-carbaldehydes and melanoidins (with 3-alanine or other amines). 

Under strongly basic conditions (generation of dichlorocarbene from chloroform and potassium hydroxide), electrophilic substitution of pyrrole by dichlorocarbene dominates, leading eventually to pyr-role-2-carbaldehyde. In a weakly basic medium (generation of dichlorocarbene by heating sodium tri-chloroacetate), the [2+1] cycloaddition prevails. The primary product eliminates hydrogen chloride to give 3-chloropyridine. 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

Organometallic intermediates continue to be important in the synthetic methodology for substitution of pyrroles and indoles. Numerous lithiation techniques have been reported and provide a range of useful reaction conditions. The pyrrolyl dimer (120) (really a dimeric equivalent of pyrrole-2-carbaldehyde) can be lithiated at the 5- and 5 -positions. Electrophilic substitution then yields 5-substituted pyrrole-2-carbaldehydes (121) (Scheme 34) <88TL777>. The related monomeric ald-iminium salts (122) yield similar products after anion formation, bromination, lithiation, and electrophilic attack (Scheme 35) <88HCA2053>. In a similar process, the dimer (120) can be brominated at C-4 and converted into 4-substituted pyrrole-2-carbaldehydes <88TL3215>. 

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