Selective Mono-reduction of Pyrrole-2,5 and 2,4-Dicarboxylates

Abstract

Pyrrole-2,5-dicarboxylates were rapidly and selectively reduced to the corresponding mono-alcohol using 3 eq of diisobutylaluminum hydride at 0°C. Pyrrole-2,4-dicarboxylate showed the same reactivity; however, the selectivity decreased with pyrrole-3,4-dicarboxylate. When the nitrogen atom of the pyrrole-2,5-dicarboxylate is protected with a benzyl group, selective mono-reduction does not occur. Considering that furan-2,5-dicarboxylates did not give the corresponding mono-alcohol under the same conditions, the unprotected nitrogen atom of pyrrole apparently plays an important role in this selective mono-reduction. Key words pyrrole dicarboxylate; diisobutylaluminum hydride (DIBAH); selective reductionThe pyrrole ring is an important heterocycle in fields such as medicinal, material and natural product chemistry. Much attention has been focused on highly substituted pyrroles including 3,4-diaryl groups found in a class of alkaloids [1][2][3][4][5][6][7][8][9][10][11][12] ( Fig. 1). We previously reported a synthetic reaction of 3,4-diarylpyrrole-2,5-dicarboxylates from α-diazoesters through a [3,3]-sigmatropic rearrangement of azine, which was also applied to the formal syntheses of polycitones (1) and permethyl storniamide (3b) 13,14) (Chart 1). This reaction is a very concise method but is not directly applicable to the preparation of unsymmetric pyrrole found in Ningalin B (4b) 8) and lamellarins (5).9-12) Such a limitation could be compensated by an efficient desymmetrization. Boger and Patel reported that hydrolysis of pyrrole dicarboxylate 6 gave mono acid 7 in good yield upon treatment with an equivalent of lithium hydroxide at room temperature 15) (Chart 2, example 1). Panda and colleagues applied this method to the desymmetrization of pyrrole dicarboxylate 8 for generating mono acid 9, which was a synthetic intermediate of sapphyrin 16) (example 2). In another case, Yanagisawa and colleagues reported desymmetrization of N-benzyl pyrrole dicarboxylate 10 by treatment with diisobutylaluminum hydride (DIBAH) at a low temperature 17) (example 3). These methods showed acceptable selectivity but needed a very long reaction time. To our knowledge selective mono-reduction of N-non-protected pyrrole dicarboxylates has not been reported so far. We describe here rapid and selective mono-reduction of N-non-protected pyrrole dicarboxylates, which was found during our independent trial to obtain unsymmetric pyrroles.Pyrrole dicarboxylate 12a was subjected to reduction with DIBAH in tetrahydrofuran (THF) at room temperature (Table 1, entry 1). In this case, 12a was completely consumed and mono-alcohol 13a was obtained in 63% yield. Changing solvent to toluene resulted in an increased yield of 13a at 0°C (entry 2). Interestingly, there was almost not reduction of second ester group despite highly excess addition of DIBAH (entry 3).To evaluate the scope of such selectivity, we next carried out reactions of several 3,4-diaryl pyrrole dicarboxylates with DIBAH in toluene at 0°C (Table 2). Thorough and careful experiments ...

Regioselective Reduction of 1H-1,2,3-Triazole Diesters

“…Dimethyl pyrrole-2,4-dicarboxylate was selectively reduced to form ethyl 4-(hydroxymethyl)-1H-pyrrole-2-carboxylate (A of Scheme 1) using diisobutylaluminum hydride (DIBAH). The selectivity of the reduction was not as effective for dimethyl pyrrole-3,4-dicarboxylates and did not occur for dimethyl furan-2,4-dicarboxylate, suggesting a role of the pyrrole nitrogen in complexing with the reagent and a neighboring carbonyl oxygen [12]. Dimethyl pyridine-2,5-dicarboxylate has been selectively reduced at C(2) using NaBH 4 /CaCl 2 in ethanol/THF to form methyl 6-(hydroxymethyl)-3pyridinecarboxylate (B of Scheme 1) [13].…”

“…Prior work on the NaBH 4 reduction of diethyl 2,4-pyrroledicarboxylate took place regioselectively at the C(4) ester group. Diethyl 2,5-pyrroledicarboxylate gave predominate conversion to the diol [12].…”

“…Selective reduction of diesters to form hydroxy esters using lithium borohydride (LiBH 4 ), relying upon differences in steric effects, has been reported [19]. Another example using DIBAH was for selective reduction of diesters by formation of an aldehyde monoester [12,20]. Esters were Molecules 2021, 26, 5589 2 of 14 reduced using NaBH 4 -CaCl 2 [13,21] or by NaBH 4 with added sodium methoxide (NaOMe) via sodium monomethoxyborohydride (NaBH 3 OCH 3 ), wherein the authors propose that the active reagent of NaBH 4 in methanol is indeed (NaBH 3 OCH 3 ) [22].…”