2.5- Disubstituted pyrroles, formation

Tertiary A-allylthioamides have been converted into thioamidium salts by the formation of complexes with Lewis acid. Further treatment with lithium hexamethyldisilazide (LiHMDS) affords the corresponding 1,2-disubstituted pyrroles (Scheme 25).52... 

Banwell s group has provided an alternative strategy [32] for obtaining the lamellarin framework and it is presented in Scheme 10. The methodology involves the formation of a 2,4-disubstituted pyrrole (53) containing an acid... 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

An interesting non-oxidative transformation of pyrrolidine into pyrroles was reported <07JOC1518>. Heating pyrrolidine and aldehydes in toluene in a pressurized vessel led to the formation of 1,3-disubstituted pyrroles 38. 

An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

Treatment of azidoketones 8 with triphenylphosphine led to the formation of pyrrolidine 9 via a Staudiner-aza-Wittig reductive cyclization <05JOC4751>. The latter were converted into 2,3-disubstituted pyrroles 10 upon heating. Azidoketones 8 were prepared by the novel condensation of 1,3-bis-sUyl enol ethers 6 with azidoacetal 7. This sequence was exploited for the synthesis of a cyclododecyl-fused pyrrole. 

Reported examples of the second reaction occur at the j8-position in an a,a -disubstituted pyrrole. Whilst for the second reaction there is no evidence to indicate the intermediate formation of ethyl methylenemalonate, followed by Michael addition, pyrroles can participate in such additions. Examples are the ready reaction with ethynyl ketones , with quinones" and with acrylic esters (in the presence of boron trifluoride etherate)" ... 

The formation of 5-(2 -pyrrolyl)-l-pyrrolines (54) by dimerization has not been observed to occur, and indeed could not occur without substituent elimination, with 2,5-disubstituted pyrroles [see the example of the dimerization of (56) above]. The dimerizatipn involves electrophilic attack by a j8-protonated pyrrole cation upon the conjugate base, as for example... 

An efficient Cu-catalyzed cycloisomerization of alkynyl imines into the 2-monosubstituted and 2,5-disubstituted pyrroles was reported by Gevorgyan and coworkers (Scheme 8.3). This methodology was efficient to the synthesis of various types of fused heteroaromatic compounds and even synthesis of ( ) monomorine. A C(sp )-H of the substrate was activated during this copper-catalyzed pyrrole formation [12]. Moreover, they also realized the... 

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]. 

Mercury(II) acetate tends to mercurate all the free nuclear positions in pyrrole, furan and thiophene to give derivatives of type (74). The acetoxymercuration of thiophene has been estimated to proceed ca. 10 times faster than that of benzene. Mercuration of rings with deactivating substituents such as ethoxycarbonyl and nitro is still possible with this reagent, as shown by the formation of compounds (75) and (76). Mercury(II) chloride is a milder mercurating agent, as illustrated by the chloromercuration of thiophene to give either the 2- or 2,5-disubstituted product (Scheme 25). 

The addition of trithiazyl trichloride (NSC1)3 to 2,5-disubstituted furans and to N-2,5-trisubstituted pyrroles has led to the formation of isothiazole derivatives <96JHC1419>. 

Studies by Heinze etal. on donor-substituted thiophenes or pyrroles [33] such as methylthio (= methylsulfonyl) or methoxy-substituted derivatives provide further clear evidence for this reaction pathway. They found, for instance, that 3-methylthiothiophene or 3-methoxythio-phene (2) undergo a fast coupling reaction. However, deposition processes or insoluble film formation could not be detected in usual experiments with these compounds, even at high concentrations. Similarly, the corresponding 3,3 -disubstituted bithiophenes (2a) do not polymerize, but the anodic oxidation of 4,4 -disubstituted bithiophenes (2c) produces excellent yields of conducting polymers. 

The reactions of 2-hydroxy-2-(3-indolyl)ethanoamides and of ethyl 2-hydroxy-2-(2-pyrrolyl) ethanoates with trialkyl ortho-esters follow similar routes with the initial formation of the enol ethers (295) and (297), followed by an ortho- Claisen rearrangement to give the 2,3-disubstituted indoles (296) and pyrroles (298) (79JOC1885,80TL4335). 

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