Polysubstituted pyrrole synthesis

Chiba and coworkers developed a Cu(NTf2)2-catalyzed synthesis of pyrroles from a-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides [19]. Jiao and coworkers reported a copper- or nickel-catalyzed highly selective denitrogenative annula-tion of vinyl azides with acetaldehydes to 2,4- and 3,4-diaryl-substituted pyrroles. Cu(OAc)2 could catalyze the formation of 2,4-diaryl-substituted pyrroles. This selective polysubstituted pyrrole synthesis could proceed under mild conditions without any acidic or basic conditions [20] (Scheme 8.8). 

Liu W, Jiang H, Huang L (2010) One-pot silver-catalyzed and PIDA-mediated sequential reactions Synthesis of polysubstituted pyrroles directly from alkynoates and amines. Org Lett 12(2) 312—315... 

The development of new and simple methods for the synthesis of diversely polysubstituted pyrroles from readily available building blocks still remains an open... 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

Arndtsen and co-workers developed an isocyanide-mediated three-component synthesis ofthe polysubstituted pyrroles 97, wherein an acyclic imine was activated in situ by acylation [54]. Thus, reaction of an imine, an acyl chloride, an alkyne, and an isocyanide in the presence of PrNEt2 afforded 97 in good to excellent yields (Scheme 5.29). A complex reaction sequence involving formation ofthe N-acyliminium by [4 + 1] followed by [3 + 2] cycloadditions and a retro-cycloaddition was proposed to account the formation of 97. The isocyanide participated actively in this reaction sequence however, it was not incorporated in the final adduct since it was lost as isocyanate by a retro-D-A reaction. The aliphatic imine was shown to be an appropriate substrate, at least in one case, leading to the corresponding pyrrole (R2 = isopropyl) in 72% yield. Azenes participated in this reaction in a similar manner. Thus, the isoquinoline 94 was converted to the benzo-fused pyrrole 98 in 50% yield. 

A practical synthesis of polysubstituted pyrrole-2-carboxylic esters is via the corresponding benzyl esters, the other functional groups are not affected under hydrogenolysis conditions. ... 

A range of pyridine-type hydroxyl heterocycles are brominated effectively with NBS/PPhs while NBS is used as a synthesis of pyridines.Polysubstituted pyrroles,4 furans, 4 pyrrolidin-2-ones,4 thiophenes, and 3,4-disubstituted indoles have also been prepared using NBS as a key reagent. 3-Methyl indole derivatives of general structure 12 are brominated in the methyl group to 13 with NBS under radical conditions. Under ionic conditions bromination occurs at the 2-position of the indole structure (12) to give products with general stracture 14 (eq 38). ... 

Toste and coworkers have discovered a gold(I)-catalyzed acetylenic Schmidt reaction for the synthesis of polysubstituted pyrroles 38 (SchemeAlB). In this reaction, it was suggested that the metal plays two roles. It both activates the alkyne bond (cf. 39) and also stabilizes the n-intermediate 40 by electron donation. This powerful reaction tolerates both alkyl and aryl groups, and alkyne chemoselectivity was complete starting from a 1,5-enyne. 

SCHEME 6.53 Catalyst-free synthesis of polysubstituted pyrroles 360 and proposed mechanism. 

For another approach where dialkyl acetylenedicarboxylates were used in the synthesis of polysubstituted pyrroles, see N. Bhunia, B. Das, Synthesis 2013,45,1045-1050. One-pot synthesis of pentasubstituted pyrroles from propargyUc alcohols, amines, and dialkyl acetylenedicarboxylates tandem amination, propargylation and cycloisomerization catalyzed by molecular iodine. 

For other example of catalyst free multicomponent synthesis of pyrroles, see X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou, S.-J. Ji, Org. Lett. 2013, 15, 4246- 249. Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction. 

The pyrrole nucleus is the characteristic structural motif of numerous natural (stor-niamide A, lamellarin P, marinopyrrole B) and synthetic products [24], Many poly-functionalized pyrroles are known to display interesting biological activities [25], In addition, pyrroles were observed to inhibit cytokine-mediated diseases and were also found to have some apphcations in materials chemistry [26], The growing importance and wide usefiilness of polysubstituted pyrroles have kept in focus the search for new methods for the efficient synthesis of these heterocycles. 

Pal et al. [26] reported an iodine-catalyzed four-component reaction of 1,3-dicar-bonyl compounds, amines, aldehydes, and nitroalkanes affording polysubstituted pyrroles 3 under a metal-free condition. This is the first example of Grob and Ca-menisch s pyrrole synthesis [27] catalyzed by iodine via one-pot four-component reaction (Scheme 10.2). 

Scheme 24 Synthesis of polysubstituted pyrrole and pyrrolin-4-one derivatives...

Katritzky AR, Huang T-B, Voronkov MV, Wang MG, Kolb H (2000) Efficient one-pot synthesis of polysubstituted pyrroles. J Org Chem 65 8819-8821... 

L. Nagarapu, R. MallepalH, L. Yeramanchi, R. Bantu, Polyethylene glycol (PEG-400) as an efficient and recyclable reaction medium for one-pot synthesis of polysubstituted pyrroles under catalyst-free conditions. Tetrahedron Lett. 52 (2011) 3401-3404. 

Radha Krishna Murthi [53] accessed to a faster and efficient metal-free synthesis of polysubstituted pyrroles (23) in good yields under ultrasoxmd assistance. Starting materials were p-keto esters (19), benzylamines (20), aromatic aldehydes (21), and nitromethane (22) in the presence of amberlyst-15 as a reusable catalyst via a four-component reaction (Scheme 7). 

SCHEME 7 Synthesis of polysubstituted pyrroles catalyzed by amberlyst-15. 

The cycloaddition of a-metalated methyl isocyanides onto the triple bond of electron-deficient acetylenes to 2,3,4-trisubstituted pyrroles in 17-97% yield was realized in de Meijere group (Scheme 8.6). Several copper could catalyze the polysubstituted pyrrole formation. Moreover, they also developed a new copper catalyst system for the synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides in 5-88% yield [16,17]. 

CuOTf-catalyzed synthesis of polysubstituted pyrroles from a-diazoketones, nitroalkenes, and amines was reported by Lu, Wang, and coworkers. The corresponding polysubstituted pyrroles could be obtained in moderate yields using air as the oxidant. This cascade process of the polysubstituted pyrrole formation involves an NH insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide [21] (Scheme 8.9). 

Scheme 8.9 CuOTf-catalyzed synthesis of polysubstituted pyrroles from diazoketones, nitroalkenes, and amines.

Another efficient method for the synthesis of polysubstituted pyrroles was described by Li et al. They found that CuI/iV,iV-dimethylglycine-catalyzed reaction of amines with y-bromo-substituted y,5-unsaturated ketone 126 underwent a condensation/coupling process to afford pyrroles 127 (Scheme 45) [82]. 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

The introduction of substituents at the 3-position of pyrrole has been actively pursued in recent years due to the importance of this class of compound in natural product synthesis. In contrast to the significant number of preparations of polysubstituted 3-arylpyrroles, there have been relatively few syntheses of simple 3-arylpyrroles. A literature survey on the preparation of 3-arylpyrroles showed that the methods reported include the reductive cycliza-tion of 2-arylsuccinonitriles, the base-induced ring-closure of arylvinamidinium salts, and... 

Formyl-l//-pyrroles have also been used as synthons for the preparation of polysubstituted 4-(l//-pyrrol-3-yl)-1,4-dihydropyridines 1307-1310 under the conditions of the standard and modified Hantzsch s dihydropyridine synthesis or by regioselective alkylation of the 1,4-dihydropyridine skeleton (Scheme 250) <2005ARK127>. 

Using a [3H-2] annulation of 2-(benzotiiazol-l-ylmethyl) pyrroles with enones and enals, Katritzky and colleagues fashioned a novel synthesis of polysubstituted indoles (Scheme 6, equations 1 and 2) [36, 37]. The requisite pyrroles were fashioned in three steps from propargylbenzo-ttiazole as shown. In a modified C-3 benzotriazole-mediated reaction, Katritzky and coworkers developed a different... 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

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