Polysubstituted pyrroles

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... 

Katritzky offers a general one-pot alternative approach to polysubstituted pyrroles utilizing disubstituted olefins of which a wider variety is commercially available compared to acetylenes . Thus, thioamides 32 were subjected to Mannich condensation with aldehydes and BtH to yield functionalized thioamides 33 which were then treated with base... 

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. 

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... 

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. ... 

In a process similar to Ishii s previously developed samarium catalyzed multicomponent process <98JOC6234>, Ranu describes an efficient three-component coupling of a,(3-unsaturated aldehydes or ketones 12, an amine 13 and a nitroalkane 14 on the surface of silica gel or alumina without any solvent under microwave irradiation affording the polysubstituted pyrroles 15 <01T4767>. 

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). ... 

Takaya and co-workers found that the low-valent Rh4(CO)i2 complex was an effective catalyst for the addition of isocyanoacetates, e.g., 313, to 1,3-dicarbonyl compounds, e.g., 312, to give polysubstituted pyrroles such as 314. The authors... 

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. 

The addition/oxidative cyclization of alkynes with amines in the presence of an AgBp4 catalyst and a PIDA oxidant leads to polysubstituted pyrroles (Schane 11.3). The reaction corresponds to the construction of a pyrrole fragment, which also provides a new method for the formation of C-C bonds (Liu et al. 2010). 

Multicomponent reactions continue to be a popular way to achieve rapid construction of polysubstituted pyrrole skeletons. Cyanopyrrole 59 was synthesized in moderate to good yields from gem-dicyano olefin 56, piperidine (57), and tert-butyl isocyanide (58) without the need for a catalyst. Although the reaction is limited to cyanopyrroles, the nitrile moiety is a useful handle for further chemical transformations (130L4246). 

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). 

A polysubstituted pyrrole (XVIl) has been reported to have weak anorexigenic activity in dogs.67... 

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

Polysubstituted pyrroles have been reported fromreaetion of a-azido chalcones and 1,3-dicarbonyl compounds in the presenee of indium triehloride. ... 

An interesting approach to polysubstituted pyrroles was elaborated based on the enamine 402, which on heating with S2CI2 or SCI2 in chlorobenzene led to the thiazine 403 in good yields [132], Subsequent refluxing of 403 with triethylamine in ether afforded the pyrrole 405 in 57 % yield by sulfur extrusion from the intermediate 404 and acidic workup. Employing one pot technique, the pyrrole 405 was synthesized in 56 % overall yield calculated on the enamine 402. Other bases (LDA, 5-BuLi, KH, EtONa) can also be used for conversion of 403 to 405 [133]. 

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... 

Mn(OAc)3 can be used as a catalyst to promote efficient formation of a wide variety of polysubstituted pyrroles from vinyl azides and 1,3-dicarbonyl compounds (eq 21). ... 

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. 

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