NH-Pyrrole

FIGURE 26.5 Initial polymerization step (dimerization) (examples X = NH, pyrrole X = S, thiophene). 

For the heterohelicenes, where isomers are possible, a new way for abbreviation is introduced by giving after the number in brackets the correct sequence of benzene and hetero rings, using symbols B = benzene, S = thiophene, NH = pyrrole, N = pyridine (the position of the hetero atom is indicated by the position number), O = furan etc. 

A process for the selective preparation of NH-pyrrole from oximes of aliphatic and alicyclic ketones and acetylene in an autoclave under pressure (yield 70-80%) with DMSO containing up to 10% of water as a solvent (120-140°C, 1-2 hr, 10% KOH) has been developed (76MIP1). According to Mikhaleva and co-workers (79ZOR602), the pyrroles were obtained... 

It is not possible (88KGS350) to obtain 1-vinylazaindole 40 having a nitroxyl group from oximes 39 (X = OH, 6). In these two cases, only the corresponding NH-pyrrole (R = H, X = 6) is formed at 50-65°C. When the temperature rises (95°C), the oxime 39 (X = 6) is converted to 1-vinylazaindole 40 (R = CH=CH2) with the loss of the radical center (X = H). This may be an indication of the vinylation of pyrroles in the KOH/DMSO system to involve a one-electron stage. 

Recently, (88ZOR1789) in the synthesis of pyrroles from ketoximes and acetylene (KOH/DMSO, 95°C, 5 hr, atmospheric pressure), the formation of dipyrrylethanes (98a-c) along with the normal products, NH-pyrroles and /V-vinylpyrroles, was observed in a number of cases. 

Basic hydrolysis of the l/7-pyrrole-2-carboxylate 1280, obtained in 71% yield by a procedure similar to described <2000JOC2479> (by alkylation of the corresponding NH-pyrrole with 3,4-dimethoxyphenethyl methanesulfonate (N2, NaH, DMF, 70 °C, 12 h)), with NaOH in aqueous EtOH produces the respective pyrrole carboxylic acid 1281 in 90% yield and in an analytically pure form (Scheme 246) <2003T207>. When the acid 1281 was heated with lead tetraacetate in refluxing ethyl acetate, a 52% yield of ningalin B hexamethyl ether 1282, the multidrug-resistant reversal agent, a marine natural product derivative, was obtained. 

Progesterone dioxime 51 reacted with acetylene in a superbasic system to afford dipyrrole 52 in 7% yield. The reaction was accompanied by prototropic migration of the double bonds in the steroid fragment and vinylation of the NH-pyrrole groups (Equation (14)) (03RJ01406). 

The success of this approach to construction of the pyrrole nucleus comes by complementing existing methods for the synthesis of pyrroles, enabling one to easily synthesize pyrroles with alkyl, aryl and hetaryl substituents, as well as various annulated pyrroles. Por the first time this reaction makes available practically an unlimited series of N-vinylpyr-roles which are readily protected NH-pyrroles and pyrrole ring-carriers and monomers having a wide and as yet almost unrealized synthetic potential. 

For the catalysis by DMAP of the t-butoxylcarbonylation of alcohols, amides, carbamates, NH-pyrroles, etc., see Di-t-butyl Dicarbonate. 

The NH pyrrole proton is acidic with a pATa of 17.5. As a consequence, bases such as NaH, Grignard reagents, n-BuLi, and NaOEt readily deprotonate pyrrole. For instance, alkylation of 4-nitro-pyrrole-2-ester was achieved by treatment of the pyrrole with sodium ethoxide in the presence of... 

Direct debenzylation of pyrroles 137 using Pd-catalyzed hydrogenation proved unsuccessful, but it was shown that if NH-pyrrole is required, debenzylation was easier to achieve on the dihydropyrrole intermediate 139, using 1-chloroethyl chloroformate. The debenzylated dihydropyrrole 140 can then be aromatized in the usual manner by treatment with DDQ to form 3-SF5-4-(3-thienyl)-AM-pyrrole (141) (Scheme 41). 

Scheme 8.128), and aromatic and aliphatic amines 367 (Scheme 8.129). In addition, the authors demonstrated that this protocol could be further extended to the syntheses of 1,2,3,5-tetrasubstituted- as well as NH-pyrroles by the in situ removal of various N - and C-protecting groups. According to the proposed mechanism, the Ru (Il)-catalyzed three-component synthesis of pyrroles 369 proceeds via two competitive pathways occurring simultaneously and involving the amination reaction after or prior to the propargylic substitution step. 

TB A cation deep within the cavity of 40 is thought to reflect the co-complexation of the chloride anion by the - NH pyrrolic groups, which results in the formation of a tighter ion pair. The presumably stabilizing interactions observed in the solid state were preserved in solution as evidenced by NMR spectroscopic analyses carried out in CDCI3 [81]. 

Recently, Guan et al. developed a novel Cu(OAc)2-promoted oxidative coupling of enamides with electron-deficient alkynes for the synthesis of multisubstituted NH pyrroles. This reaction tolerates a wide range of functional groups and is a reliable procedure for the rapid elaboration of readily available enamides into a variety of diester-substituted NH pyrroles. The reaction proceeded through C-H and N-H bond functionalization of enamides CU/O2 system [22]. They also developed an efficient CuBr-catalyzed homocoupling of ketoxime carboxylates for the synthesis of symmetrical pyrroles [23] (Scheme 8.10). 

Scheme 8.10 Cu(OAc)2-promoted oxidative coupling of enamides with electron-deficient alkynes for the synthesis of multisubstituted NH pyrroles.

Synthesis of N-vinylpyrroles from symmetric and asymmetric ketoximes is generally carried out in autoclave (10-20 atm, 120°C-140°C, 1-3 h) with a large excess acetylene, KOH-ketoxime ratio being 0.1-0.3 [185]. Preferable ketoxime-DMSO ratio is 1 8-16. NH-pyrroles are successfully obtained when acetylene is passed through the reaction mixture (atmospheric pressure, 93°C-100°C, 6-10 h, 40%-100% KOH from the ketoxime weight) in the presence of DMSO containing 4%-10% of water that suppresses vinylation reaction [186]. 

The study of the reaction between the oxime of A -pregnen-3p-ol-20-one and acetylene has allowed to find out the conditions (KOH/DMSO, 100°C, 5 h, initial acetylene pressure at room temperature 14 atm) ensuring not only formation of the pyrrole ring but also exhaustive vinylation of NH-pyrrole and hydroxyl functions (Scheme 1.40) [212]. 

The reaction smoothly proceeds also at 100°C in the presence of 30% (from ketoxime weight) KOH in DMSO in autoclave under initial acetylene pressure of 8-16 atm. The maximum pressure reached at the reaction temperature is 20-25 atm. Then, intensive consumption of acetylene begins, and pressure quickly decreases. As it was already noted, initially, N-unsubstituted pyrroles are formed, which further are vinylated in the presence of acetylene excess. If it is necessary to obtain the corresponding NH-pyrrole, the synthesis is carried out with calculated amount of acetylene or with its lack. LiOH appears to be a selective catalyst of the pyrrole ring construction, the application of which does not require strict dosing of acetylene. 

The reaction is expectedly accompanied by the addition of NH-pyrroles to propyne or allene to deliver N-2-propenylpyrroles (Scheme 1.111). 

It is intriguing that dihydropyrrolium cafions are not detected in the case of the corresponding NH-pyrroles. It can be explained by the inaease of electrophilicity of the pyrrole ring after the introduction of acceptor substituent CHXMe. Also, the addition of HX to the pyrrole ring is not obsCTved for 3-alkyl-N-vinylpyrroles, likely due to electron-donating effect of the alkyl substituent lowering the electrophilicity of the pyrrole ring. 

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