Substituted pyrroles 3-dimethyl

The hexahydropyrrolo[l,2- ]imidazole chloro cycloadducts 57a-c, as a 1/1 mixture of stereoisomers, underwent an elimination on treatment with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dimethyl sulfoxide (DMSO) at 100°C. It was not possible to isolate the desired dihydropyrroles 58a-c and a second elimination occurred to form the T-substituted pyrroles 59a-c respectively (Scheme 4) <1998J(P1)2061>. 

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 protonation of acetyl- and formyl-pyrroles occurs on the carbonyl group (Skylar et al., 1966). So, for example, in the nmr spectrum of 2,4-dimethyl-3-acetyl-pyrrole in concentrated acid the vinyl (C-5) proton resonance is retained, although there is exchange in deuteriated acid (Melent eva et al., 1971). The behaviour of carbethoxy-substituted pyrroles is more complicated, however. While 3-carbethoxy derivatives [168] and the 2-carbethoxy derivatives unsubstituted at the 5-position [169] protonate at the a-position of the ring and are not exceptional, the 2-carbethoxy derivatives with a methyl group at the 5-position [170] give evidence in the nmr... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

Porphyrins dissolved in SDS micelles have also been applied towards the determination of pKa values of the central atoms, which are around 5.5 for alkyl substituted porphyrins, but drop to 4.8 for divinyl substituted protoporphyrin dimethyl ester and to 3.0 for porphyrins with two p-pyrrolic carbethoxy or formyl substituents. 

Simple pyrroles do not react as 4n components in Diels-Alder cycloadditions exposure of pyrrole to benzyne, for example, leads only to 2-phenylpyrrole, in low yield. However A-substitution, particularly with an electron-withdrawing group, does allow such reactions to occur, for example adducts with arynes are obtained using l-trimethylsilylpyrrole. Whereas pyrrole itself reacts with dimethyl acetylenedicar-boxylate only by a-substimtion, even at 15 kbar, ° A-acetyl- and A-alkoxycarbonyl-pyrroles give cycload-ducts, addition being much accelerated by high pressure or by aluminium chloride catalysis. The most popular A-substituted pyrrole in this context has been A-Boc-pyrrole, with benzyne (from diazotization of anthranilic acid) for example, a 60% yield of the cycloadduct is obtained. ... 

Synthesis of bis(pyrrole) monomers. The condensation of ethyl diacetyl succinate with amines to give dialkyl esters of N substituted pyrroles proceeds in near quantitative yields to the bis(dicarboethoxy dimethyl pyrrole). 

Pyrroles are exceptionally nucleophilic heterocycles and undergo electrophilic substitution reactions with very weak electrophiles. The reactivity of pyrrole may be compared with that of N,(V-dimethyl-aniline or phenol all three compounds couple with the benzenediazonium ion. It is no surprise, therefore, that Mannich reactions of pyrrole and substituted pyrroles have been studied in considerable detail. We will concentrate our attention on recent studies. 

Under these reaction conditions the carbonyl group of the 4-acctyl substituent is also reduced. In contrast, the corresponding 3,4- and 3,5-dimethyl-substituted pyrroles give the saturated pyrrolidines in 85% and 79%, respectively28. 

Reactions of 2,3-di(methoxycarbonyl)-2/f-azirine with keto-stabilized and ester-stabilized ylides give, respectively, substituted pyrroles and iminophos-phoranes (76). A similar reaction of the ketene-stabilized ylide (77) with 3.3-dimethyl-2-phenyl-l-azirine forms the oxaphospholene (78). ... 

TABLE 1.78. 2-ACYL-1-METHYI 5-SUBSTITUTED PYRROLE-3.4-DICARBOXYLIC ACID DIMETHYL ESTERS FROM 2,5-DISUBSTITUTED OXAZOLES, METHYLTRIFLATE,... 

In anolher three-component process, Nair successfully (rapped the intermediate 18 formed between isocyanides 16 and dimethyl acetylenedicarboxylate (DMAD, 17) with N-tosylimines 19 to afford amino substituted pyrroles 20 <01 JOC4427>. 

The azomethine ylide represents one of the most reactive and versatile classes of 1,3-dipoles and is trapped readily by a range of dipolarophiles, forming substituted pyrroles or pyrrolidines (Coldham and Hufton 2005). Synthesis of aziridines by reaction of a fluorocarbene with imines under ultrasonic irradiation was described previously (Konev et al. 2005). This reaction proceeds by the formation of an azomethine ylide (9), which can be trapped with dimethyl maleate (13) to produce pyrrolidines (14) or pyrrole rings (15) in moderate yields (Scheme 8.5). 

In 2009, the general asymmetric coupling of substituted pyrroles (110) and indoles (208) with 2-acylimidazole substrate of type 200 was extended to other catalyst complexes such as 0.15-0.3 mol % of copper 4,4 -dimethyl-2,2 -bipyridine [Cu(dmbpy)]/DNA complexes [1.4—7 ug/niL DNA base pairs] in aqueous media. Good enantioselectivities (83-93%) of the corresponding adducts 202 and 209, respectively, were observed using sources of DNA such as st-DNA (salmon testes-DNA) and DNA-1 with the self-complimentary sequence of d(TCAGGGCCCTGA)2. A key limitation of this approach was the requirement of at least 5 1 ratio of arene to 200 to achieve good conversion to the adducts (no scheme provided) ... 

For preparative purposes the Gattermann reaction is much more useful. It was first usedS5 to prepare ethyl 2-formyl-3,5-dimethyl- and ethyl 3-formyl-2,5-dimethyl-pyrrole-4-carboxylate, by means of hydrogen cyanide and hydrogen chloride in ether. Later applications sometimes involved minor changes such as the use of chloroform as solvent, or of Adams modification of the reaction . Formylation generally occurs at an a-position, but if none is open there is usually no difficulty in jS-substitution. Pyrrole-2-aldehyde cannot be made this way, for it reacts further to form dyestuffs, but several 1-alkylpyrroles have been satisfactorily formylated . The initial... 

Substituted pyrroles such as ethyl 2,4-dimethyl-3- or 2,5-dimethyl-3-carboxylate are hydroxymethylated at the empty nuclear position by formalin and sodium hydroxide or potassium cyanide . Similarly, the initial carbinols from pyrroles and aldehydes can he isolated if they are stabilized in any other way an example is the carbinol (17) which, like others of its class, can be obtained from the appropriate pyrrole and chloral hydrate in the presence of hydrochloric acid . 

Ar= Ph, 2-MePh, 3-MjPh, 4-MePh, 4-MeOPh, 3-ClPh, 4-ClPli, 4-NO2PI1, CHjPh, 1-Naph SCHEME 3 Synthesis of 2,5-dimethyl-N-substituted pyrrole using [HMIM]HS04 as catalyst. 

Li et al. [44] reported a simple and efficient method for the preparation of 2,5-dimethyl-N-substituted pyrroles (9) using the ionic liquid [HM1MJHS04 as catalyst at 25-30 °C under ultrasonic irradiation (frequency of 40 kHz and a nominal power of 250W) (Scheme 3) the authors studied the effect of different cosolvents such as ethanol, methanol, and acetonitrile, and tiie best result was obtained with methanol (87% yield). This method has the advantages of reducing the response time and avoidance of toxic catalysts moreover, tiie catalyst was recovered and reused. 

Satyanarayana and Sivakumar [51] developed a simple, rapid, and efficient synthesis of 2,5-dimethyl-N-substituted pyrrole derivatives (15) by tiie Paal-Knorr reaction [45,46] by means of the one-pot condensation of 1,4-dicarbonyl compoxmds (13) and substituted primary amines (14) using uranyl nitrate hexahydrate as catalyst under ultrasonic irradiation (Scheme 5). The authors studied tiie reaction of methanol, ethanol, acetonitrile, dichlorometh-ane, or chloroform in solvents, as well as in the absence of solvent. The best yields were obtained with methanol under sonication for 5 min. 

SCHEME 5 Synthesis of 2,5-dimethyl-IV-substituted pyrrole using uranyl nitrate hexahydrate as catalyst. 

V.S.V. Satyanarayana, A. Sivakumar, Ultrasound-assisted synthesis of 2,5-dimethyl-N-substituted pyrroles catalyzed by uranyl nitrate hexa-hydrate, Ultrason. Sonochem. 18 (2011) 917-922. 

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