“…Formylation of 2-chloropyrrole (1) with phosphorus oxychloride in dimethylformamide60'61 gave a white, crystalline material, which was shown by ir, uv, NMR, and mass spectral analyses to be 5-chloropyrrole-2-carboxaldehyde (28). No evidence was obtained for the presence of any 4substituted products.…”
Following the confirmation that both 2-chloropyrrole (1.) and 2-bromopyrrole (2) were unstable species, a number of 1-alkyl-and C-alkyl-2-halopyrroles were synthesized to investigate the range of instability. The l-alkyl-2halopyrroles synthesized were 2-chloro-1 -methylpyrrole ( 14), 2-bromo-l-methylpyrrole (15), l-benzyl-2-chloropyrrole (47), and l-benzyl-2-bromopyrrole (46). The C-alkyl-2-halopyrroles synthesized were 5-chloro-2-methylpyrrole (26), 2-tertbutyl-5-chloropyrrole (36), 5-chloro-2,3,4-trimethylpyrrole (29), and 5-bromo-2,3,4-trimethylpyrrole (20). Also synthesized were the 1-methyl derivatives of 26 and 29. Electrophilic substitution of 2-chloroand 2-bromopyrroles (1 and 2) under the conditions for formylation and diazo coupling was examined. In the case of the latter reaction no crystalline compounds could be isolated, but diazo coupling of 2-chloro-1 -methylpyrrole ( 14) gave rise to exclusive a substitution. Formylation of 2-chloropyrrole (1) gave the «-substituted derivative but 2-bromopyrrole (2) gave a product arising from the displacement of bromine, 5-chloropyrrole-2-carboxaldehyde (28), in addition to 5-bromopyrrole-2-carboxaldehyde (41).Electrophilic substitution of simple pyrrole derivatives occurs regioselectively at the 2 position2 and at a rate considerably faster than in the furan and thiophene series.3 The simple electrophilic substitution reactions such as nitration,4 sulfonation,5 and formylation6 therefore give rise to the 2-substituted product almost2 to the exclusion of the 3-substituted derivative. In all cases these products are well-characterized compounds with clearly defined physical constants.7 However, 2-chloropyrrole (1) and 2-bromopyrrole (2), the expected products of halogenation, are poorly characterized compounds. In addition, there is evidence that these compounds are quite unstable.Mazzara and Borgo,8 using sulfuryl chloride in ether as the chlorinating agent, were the first to report the synthesis of 1. Attempted isolation indicated that both l8 and 2,5dichloropyrrole (3)9 were probably labile. This observation was supported by the work of Hess and Wissing,10 who heated the pyrrolyl Grignard (4) reagent11 with chlorine in ether and obtained a highly unstable yellow oil. More recently, a Russian group6 prepared 2-chloropyrrole (1) but no comment was made as to the stability of the product. Further evidence for the instability of 2-chloropyrrole (1) comes from the work of Hodge and Rickards.12 Decarboxylation of 5-chloropyrrole-2-carboxylic acid (5) under re-
“…Formylation of 2-chloropyrrole (1) with phosphorus oxychloride in dimethylformamide60'61 gave a white, crystalline material, which was shown by ir, uv, NMR, and mass spectral analyses to be 5-chloropyrrole-2-carboxaldehyde (28). No evidence was obtained for the presence of any 4substituted products.…”
Following the confirmation that both 2-chloropyrrole (1.) and 2-bromopyrrole (2) were unstable species, a number of 1-alkyl-and C-alkyl-2-halopyrroles were synthesized to investigate the range of instability. The l-alkyl-2halopyrroles synthesized were 2-chloro-1 -methylpyrrole ( 14), 2-bromo-l-methylpyrrole (15), l-benzyl-2-chloropyrrole (47), and l-benzyl-2-bromopyrrole (46). The C-alkyl-2-halopyrroles synthesized were 5-chloro-2-methylpyrrole (26), 2-tertbutyl-5-chloropyrrole (36), 5-chloro-2,3,4-trimethylpyrrole (29), and 5-bromo-2,3,4-trimethylpyrrole (20). Also synthesized were the 1-methyl derivatives of 26 and 29. Electrophilic substitution of 2-chloroand 2-bromopyrroles (1 and 2) under the conditions for formylation and diazo coupling was examined. In the case of the latter reaction no crystalline compounds could be isolated, but diazo coupling of 2-chloro-1 -methylpyrrole ( 14) gave rise to exclusive a substitution. Formylation of 2-chloropyrrole (1) gave the «-substituted derivative but 2-bromopyrrole (2) gave a product arising from the displacement of bromine, 5-chloropyrrole-2-carboxaldehyde (28), in addition to 5-bromopyrrole-2-carboxaldehyde (41).Electrophilic substitution of simple pyrrole derivatives occurs regioselectively at the 2 position2 and at a rate considerably faster than in the furan and thiophene series.3 The simple electrophilic substitution reactions such as nitration,4 sulfonation,5 and formylation6 therefore give rise to the 2-substituted product almost2 to the exclusion of the 3-substituted derivative. In all cases these products are well-characterized compounds with clearly defined physical constants.7 However, 2-chloropyrrole (1) and 2-bromopyrrole (2), the expected products of halogenation, are poorly characterized compounds. In addition, there is evidence that these compounds are quite unstable.Mazzara and Borgo,8 using sulfuryl chloride in ether as the chlorinating agent, were the first to report the synthesis of 1. Attempted isolation indicated that both l8 and 2,5dichloropyrrole (3)9 were probably labile. This observation was supported by the work of Hess and Wissing,10 who heated the pyrrolyl Grignard (4) reagent11 with chlorine in ether and obtained a highly unstable yellow oil. More recently, a Russian group6 prepared 2-chloropyrrole (1) but no comment was made as to the stability of the product. Further evidence for the instability of 2-chloropyrrole (1) comes from the work of Hodge and Rickards.12 Decarboxylation of 5-chloropyrrole-2-carboxylic acid (5) under re-
“…Although both 2,3-didehydrothiophene ( 37 ) and 3,4-didehydrothiophene ( 2 ), the most mentioned of the five-membered hetarynes, had been suggested as reactive intermediates by Wittig in the early 1960's, the validity of such a claim was soon questioned. 54bc, Subsequently, the hetaryne 37 was generated from flash vacuum thermolysis (FVT) of thiophene-2,3-dicarboxylic anhydride and accordingly trapped . By way of contrast, evidence for the existence of 3,4-didehydrothiophene ( 2 ) has never been obtained despite many experimental attempts. 54c,59ac,− Thus, the question has remained open for over 30 years. …”
3,4-Bis(trimethylsilyl)thiophene (1a) was synthesized by three routes: (a) 1,3-dipolar cycloaddition; (b) modification of 3,4-dibromothiophene; and (c) intermolecular thiazole-alkyne Diels-Alder reaction. 3,4-Bis(trimethylsilyl)thiophene (1a) can function as a versatile building block for the construction of unsymmetrically 3,4-disubstituted thiophenes utilizing its stepwise regiospecific mono-ipso-substitution followed by palladium-catalyzed cross-coupling reactions. In this manner, thiophenes 15, 16, 17a-j, 19a,b, 20, 22a-c, 23a,b, 24a-d, 25a-c, and 27a-j were prepared. The thiophene-3,4-diyl dimer 28 and thiophene-3,4-diyl tetramer 29 were also realized by palladium-catalyzed self-coupling reaction of organoboroxines. The stannylthiophene 31, formed by conversion of the C-Si bond to a C-Sn bond via boroxine 26c underwent both carbonylative coupling and lithiation followed by quenching with electrophiles to afford unsymmetrically 3,4-disubstituted thiophenes 33 and 36a-c as well. Moreover, 3,4-bis(trimethylsilyl)thiophene (1a) can be used as the starting material for the generation of the highly strained cyclic cumulene 3,4-didehydrothiophene (2), whose existence was substantiated by its trapping reaction with several alkenes.
“…If a suitably located bromine or iodine atom is present, heavy‐halogen migrations can be observed. Such processes have been investigated more or less extensively by the groups of Gronowitz (thiophenes),71, 72 van der Plas (isothiazoles,73 pyrazoles,74 thiophenes75), Reinecke (thiophenes),76, 77 Shibuya (thiophenes),78 Taylor (thiophenes),79 Fröhlich (furans,80, 81 thiophenes82, 83), and Quéguiner (pyridines,84, 85 quinolines86).…”
Section: Regioflexibility In Halogen–metal Exchangementioning
This review describes a concept aimed at rational and maximal structure proliferation. To this end, simple aromatic or heterocyclic starting materials, often bulk chemicals, are converted into all regionisomerically possible polar organometallic intermediates (mostly lithiated species), which then may be combined with any of the countless electrophiles to provide attractive new building blocks, particularly functionalized derivatives. The practical implementation relies on a set ("toolbox") of sophisticated recipes developed by mechanistically guided modification of the two most prominent exchange methods used for the generation of polar organometallic compounds: hydrogen-metal and halogen-metal interconversion. These mutant methods ("old methods in a new outfit") amplify the existing options for organic synthesis by ensuring maximum regioflexibility. At the same time they offer new insight into factors that govern organometallic reactivity and provide hints on how to alter or finetune this reactivity judiciously.
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