Pyrroles N-substituted

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

The condensation of primary amines with 2,5-dialkoxytetra-hydrofurans to give in one step N-substituted pyrroles is applicable to a variety of substituted aliphatic and aromatic amines.6 The method, largely developed by Clauson-Kaas and associates, has the advantages of simplicity, mild conditions, and generally excellent yields from readily available starting materials. 

Table 1. N-substituted pyrroles employed in the preparation of redox-Modified polypyrrole films on electrodes...

Anodic cyanations of N-substituted pyrrole or 2-methylpyrrole derivatives take place in the a-position to the nitrogen atom (Scheme 111) [209] and at the side chain with 2,5-dimethyl or 2,3,4,5-tetramethylpyrrole derivatives (Scheme 112). 

The silylation of heteroarenes was also reported [96]. Silylation of thiophene or furan with 11 occurs selectively at the ot-position in the presence of [Ir(COD) (OMe)]2/2-ferf-butyl-l,10-phenanthroline (tbphen, 17). Silylation of pyrrole or indole under the same conditions was unsuccessful presumably due to the presence of the acidic N-H bond. Accordingly, N-substituted pyrrole and indole undergo silylation with 11, to selectively give 3-substituted products (Scheme 7). 

Numerous N-substituted pyrroles undergo at elevated temperatures a conversion to C-substituted compounds. However, an analogous reaction course is not feasible since N-methylpyrrole also reacts with CF3SCI to give C-substituted derivatives ... 

No deprotonation of carbon occurs with pyrroles unsubstituted on nitrogen, so in order for carbanion formation to occur, protection of the nitrogen is essential. However, once protected, the a-lithiation of N-substituted pyrroles occurs readily (790R1 84MI2), and in the case of AT-methylpyr-role, both 2-mono and 2,5-dilithiation can occur, depending upon the reaction conditions (Scheme 5) [79JCS(P1)2845 82SC231]. 

When N-substituted pyrrole 37 and trithiazyl trichloride (NSCfis are heated at reflux in carbon tetrachloride, IH-pyrrolo[2,3-r 4,5-. V-Substituted pyrrolo[2,3-f]-l,2,5-thiadi-azole 38 is believed to be an intermediate in this reaction (Equation 2). The enamine character of the carbon-carbon double bond of 38 is presumed to be enhanced compared to pyrrole 37, rendering 38 more reactive toward (NSCfis. 

In addition, in fuel compositions or lubricating oil compositions, poly(isobutyl) N-substituted pyrrole compounds are particularly useful as a detergent-dispersants. The additives can be synthesized via a carbocationic polymerization (5). 

Anodic oxidation of pyrrole and N-substituted pyrroles results in the formation of polypyrroles in an oxidized state, which can be useful for the preparation of conducting organic polymers.185-188 Oxidation of 2,5-di-substituted pyrroles produces soluble products and no layer of polymers.187 One of the proposed applications of such a layer of conducting polymer is the protection of semiconductor electrodes from photocorrosion.189-191... 

In methanolic cyanide, N-substituted pyrroles193 are substituted in the 2-position by a cyano group on anodic oxidation. Methoxylation, which is often observed as a side reaction in the anodic oxidation in methanolic cyanide, was suppressed completely. When N-substituted pyrroles carry a methyl group in the 2- and 5-positions, a side-chain cyanation occurs.193,194... 

N-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloadditions with carbonyl compounds to give oxetanes. Furan and benzophenone give the oxetane (192). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 193), via an intermediate oxetane which undergoes rearrangement under the reaction conditions (79JOC2949). 

N-Substituted pyrroles, furans and thiophenes can be 2-lithiated, and these lithio derivatives are important synthetic intermediates (Section 3.3.3.8). 2-Mercuri and 2-palladio derivatives are also important (Sections 3.3.3.8.8 and 3.3.3.8.9). 

The light-induced rearrangement of 2-phenyl- to 3-phenyl-thiophene may occur by a similar mechanism an equilibrium between the bicyclic intermediate (26) and the cyclopro-penylthioaldehyde (27) has been suggested (Scheme 2). The formation of N-substituted pyrroles on irradiation of either furans or thiophenes in the presence of a primary amine supports this suggestion (Scheme 3). Irradiation of 2-phenylselenophene yields, in addition to 3-phenylselenophene, the enyne PhC=C—CH=CH2 and selenium. Photolysis of 2-phenyltellurophene furnishes solely the enyne and tellurium (76JOM(108)183). 

The chemical consequences of /3-protonation are illustrated further by the ring-opening reactions of furans with methanoiic hydrogen chloride and of N-substituted pyrroles with hydroxylamine hydrochloride (Scheme 11) (82CC800). 

Furan has the greater reactivity in cycloaddition reactions compared with pyrrole and thiophene the latter is the least reactive diene. However, N-substituted pyrroles show enhanced dienic character compared with the parent heterocycle. 

The development of methods to effect nucleophilic addition to carbon-carbon double bonds by prior activation with metal cations has been applied, at least in a preliminary way, as a method of pyrrole ring closure. The conversion of butadienes to N-substituted pyrroles can be accomplished in two stages. In acetic add, 1,4-dienes react with PdnCl2 to give tr-allyl complexes with introduction of acetate at C-4. The ir-allyl complexes then react with amines to give a l-amino-4-acetoxy-2-butene (equation 70). When the addition of the amine is carried out in the presence of a silver salt and triphenylphosphine, a pyrrole is isolated, probably by cyclization of the amino-substituted allyl-Pd complex (equation 71) (81CC59). Although this procedure is attractive in terms of the simplicity of the... 

Thermal addition (105°-142°) of DMAD to other N-substituted pyrroles (19a-d)80 83 gave azabicycloheptadienes (20) in yields of 30-45% lower temperatures sufficed for 19e-h. The reversibility of the addition was demonstrated for 20f, 60% of which after 9 hours at 65° in carbon tetrachloride was converted back into 19f compound 20h, however, was unaffected. The azabicycloheptadiene 20 (R = C02Et) undergoes cycloaddition with 1 mole of 2,4,6-trimethylbenzonitrile oxide at both double bonds to give 26 and 27, and both these products... 

Huisgen and co-workers486,490 have described a useful synthesis of N-substituted pyrroles (41) from mesoionic oxazolones (39) via the intermediates 40, which were not isolated. A variety of acetylenic esters (phenylpropiolic, propiolic, tetrolic, and DMAD) were used. The kinetics of these reactions have been studied.491 The addition of carbon... 

Azole N-oxides la-c-16a-c are structurally derived from N-substituted pyrrole, furan, thiophene, etc. by replacing one, two, or three ring carbon atoms with sp2 hybridized nitrogen atoms, one of which is attached to an oxygen atom. The azole N-oxides la-c-16a-c are shown in Scheme 1. The scheme also shows the possible azole N-oxide structures that have been reported. 

G. Trebicka, A. Chemoselective N-alkylation of 2-hydroxycarbazole as a model for the synthesis of N-substituted pyrrole derivatives containing acidic functions. Tetrahedron 1995, 51, 5681-5688. 

Pyrrole synthesis.2 This reagent effects coupling of a,f)-unsaturated imines with an ester or DMF to form N-substituted pyrroles in 34-78% yield. 

Extrusion of sulfur dioxide from a ring-fused dihydiothiophene derivative provides an exceptionally easy method for the preparation of heterocyclic o-dimethylene compounds. These compounds are valuable intermediates in intermolecular Diels-Alder reactions. This extrusion method was used to prepare the o-dimethylene compounds 44-46 <95CC1349> as well as quinolinone derivative 47 <95TL5983>. TTie dihydrothiophene dioxide moiety also played an important role in the formation of the intramolecular Diels-Alder reaction of N-substituted pyrrole 48 <95CC807>. 

Jiang S, Lu H, Liu S et al (2004) N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 48 4349-4359... 

Cong XJ, Tan JJ, Liu M et al (2010) Computational study of binding mode of N-substituted pyrrole derivatives to HIV-1 gp41. Prog Biochem Biophys 37 904-915... 

There are examples of preferential arylation of N-substituted pyrroles, thiophenes and furans in the 2-position. A preparatively useful reaction of this type is the o-nitrophenylation of thiophene (Scheme 40). A phase transfer catalytic technique has been recommended for this reaction <77TLi87i). 

The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31100). 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 N- substituted pyrroles, the closure of the intermediate... 

The acid sensitivity of pyrrole dictates the use of acetyl nitrate as nitrating agent the main product is the 2-nitro derivative together with some of the 3-nitro compound. The nitration of N-substituted pyrroles yields relatively more -substituted product, and with electron-withdrawing groups such as acetyl or ethoxycarbonyl at the 2-position,... 

The thermal reactions of pyrroles include the rearrangement of N-substituted pyrroles to C-substituted derivatives (Scheme 163). The rearrangement of iV-acylpyrroles has also been reported to occur in the vapor phase, on irradiation. 

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