Lithiation of the dimer of 3-bromo-6-dimethylamino-1-azafulvene. efficacious synthesis of 4-mono- and 4,5-disubstituted pyrrole-2-carboxaldehydes

Muchowski, Joseph M.; Hess, Petr

doi:10.1016/0040-4039(88)85125-6

Cited by 21 publications

(7 citation statements)

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“…General experimental conditions were as described previously . 4-Bromopyrrolo-2-carboxaldehyde ( 8b ), 4-methylpyrrolo-2-carboxaldehyde ( 8c ), 4-butylpyrrolo-2-carboxaldehyde 32 ( 8d ), 4-allylpyrrolo-2-carboxaldehyde 32 ( 8e) , 4-methoxycarbonylpyrrolo-2-carboxaldehyde ( 8f ), 4-acetyl-3,5-dimethylpyrrolo-2-carboxaldehyde ( 8g ), 5-methylpyrrolo-2-carboxaldehyde ( 8h ), 5-(imidazol-1-ylmethyl)pyrrolo-2-carboxaldehyde ( 8i ), and 4-ethyl-3,5-dimethylpyrrolo-2-carboxaldehyde ( 8j ) were prepared following previously published methods.…”

Section: Methodsmentioning

confidence: 99%

Pyrrolodiazines. 5. Synthesis, Structure, and Chemistry of Pyrrolo[1,2-c]pyrimidine. Dipolar Cycloaddition of Pyrrolo[1,2-c]pyrimidinium Ylides

et al. 1999

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An improved synthesis of pyrrolo[1,2-c]pyrimidines, including the parent system, was accomplished via sequential condensation of substituted pyrrole-2-carboxaldehydes with tosylmethyl isocyanide (TOSMIC), followed by desulfonylation of the formed tosylpyrrolo[1,2-c]pyrimidines. Based on the ab initio calculations performed on the pyrrolo[1,2-c]pyrimidine 1a, some of the basic chemistry was investigated, including electrophilic substitution, addition of organolithium reagents, metalation with lithium diisopropylamide (LDA) and subsequent reaction with electrophiles, and formation of salts by quaternization of the nonbridgehead nitrogen. Azomethine ylides generated from pyrrolo[1,2-c]pyrimidinium salts undergo 1,3-dipolar cycloaddition with suitable dipolarophiles to give new dipyrrolo[1,2-a;1‘,2‘-c]pyrimidine derivatives, with high regio- and stereoselectivity.

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Section: Methodsmentioning

confidence: 99%

Pyrrolodiazines. 5. Synthesis, Structure, and Chemistry of Pyrrolo[1,2-c]pyrimidine. Dipolar Cycloaddition of Pyrrolo[1,2-c]pyrimidinium Ylides

et al. 1999

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“…Muchowski et al have shown that lithiation and electrophilic substitution of a 6-dimethylamino-1-azafulvene dimer and subsequent hydrolysis lead in five steps to 4-mono-and 4,5-disubstituted pyrrole-2-carbaldehydes. 21,22 However, the disadvantage of this method is that the synthesis of the azafulvene derivative involves a 4-monosubstituted pyrrole-2-carbaldehyde. Up to now, the main synthetic pathway leading to pyrrole 2,5-dialdehydes is a four step reaction starting from di-a-free pyrroles.…”

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confidence: 99%

New One-Step Synthesis of 3,4-Disubstituted Pyrrole-2,5-dicarbaldehydes

Tardieux¹,

Bolze²,

Gros³

et al. 1998

Synthesis

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“…This process is, however, associated with the inconvenience of requiring the separate preparation of each 2-substituted pyrrole, and has the limitation that a deactivating substituent (at C-2) gives rise to a mixture in which the 4-formylated compound (kinetic product) is a significant or even the major component (1, 4,6). We have devised two complementary routes to 5-substituted pyrrole-2-carboxaldehydes based on the generation of 5-lithiopyrrole-2-carboxaldehyde equivalents of a nature such that there is no need for pyrrole ~-~r o t e c t i o n .~ One of these involves the lithiation of the easily prepared 6-(dimethylamino)-1-azafulvene dimer and its 3-bromo derivative (8). The other concerns the bromine-lithium exchange of the stable monomeric 2-bromo-6-(diisopropy1amino)-1-azafulvenes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 5-substituted pyrrole-2-carboxaldehydes. Part I. Generation of formal 5-lithiopyrrole-2-carboxaldehyde equivalents by bromine–lithium exchange of 2-bromo-6-(diisopropylamino)-1-azafulvene derivatives

Berthiaume¹,

Bray²,

Hess³

et al. 1995

Can. J. Chem.

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Abstract:The first known lithiated 1-azafulvene derivatives, e.g., 8 and 13a, were generated by a lowtemperature bromine-lithium exchange procedure with tert-butyllithium. These lithio species show substantial stability at 5-90°C because, at these temperatures, the sterically demanding 6-diisopropylamino moiety, unlike the dimethylamino group, completely inhibits nucleophilic addition to C-6. At higher temperatures, the addition of tert-butyllithium to C-6 is significant and it can become the dominant process. The lithio species 8 is a useful formal equivalent of 5-lithiopyrrole-2-carboxaldehyde since, on reaction with electrophilic reagents and subsequent hydrolysis, a wide variety of regiochemically pure 5-substituted pyrrole-2-carboxaldehydes is formed. The 6-dialkylamino-1-azafulvenes described herein exist predominantly or exclusively as the syn conformer in solution at room temperature. This conformational preference is confirmed by a significance NOE effect between H-4 and H-6 in the parent diisopropylamino compound 3f. The origin of the syn conformational preference stems from a substantial contribution of the charge-separated form 16 to the ground state structure of these compounds, a phenomenon that is strongly supported by variable temperature NMR measurements on 2-bromo-6-diisopropylamino-1 -azafulvene (3c).Key words: 2-bromo-6-diisopropylamino-1-azafulvenes, stereochemistry, lithiation, pyrrole-2-carboxaldehydes. R6sum6: On a prCpar6 les premiers dCrivCs 1-azafulvtne lithits connus, 8 et 13a, par une mCthode dlCchange du brome et du lithium, basse temptrature, utilisant du terf-butyllithium. Ces esptces lithiCes presentent une stabilitC importante 2 des tempkratures 5 -90°C parce que, i ces temphatures, la portion 6-diisopropylamino, qui posstde une demande stCrique importante par rapport B celle du groupe dimCthylamino, inhibe complbtement I'addition nucltophile en C-6. A des tempkratures plus ClevCes, l'addition du tert-butyllithium en C-6 devient importante et, dans quelques cas, elle peut devenir prkdominante. L'espbce lithike 8 est un equivalent formel utile du 5-lithiopyrrole-2-carboxaldChyde puisque, par rCaction avec des rCactifs Clectrophiles et hydrolyse substquente, il y a formation d'une grande variCtC de pyrrole-2-carboxaldthydes substituCs en position 5 rtgiochimiquement purs. En solution, &la tempkrature ambiante, les 6-dialkylamino-lazafulvbnes dCcrits dans le prksent travail existent exclusivement ou d'une f a~o n prbdominante comme conform5res syn. Cette prCfCrence conformationnelle est confirmte par un EON important entre les H-4 et H-6 du composC parent diisopropylamino 3f. La prCfCrence conformationnelle syn provient d'une contribution Received December 12, 1994. This paper is dedicated to Professor Charles W. Jefford, Universiv of Geneva, on the occasion of his 65th birthday. Syntex Research Postdoctorate Fellow, 1987-1989. Syntex Research Postdoctorate Fellow, 1987 Author to whom correspondence may be addressed. Telephone: (415) Can. J. Chem. Vol. 73, 1995 substantielle ...

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Lithiation of the dimer of 3-bromo-6-dimethylamino-1-azafulvene. efficacious synthesis of 4-mono- and 4,5-disubstituted pyrrole-2-carboxaldehydes

Cited by 21 publications

References 7 publications

Pyrrolodiazines. 5. Synthesis, Structure, and Chemistry of Pyrrolo[1,2-c]pyrimidine. Dipolar Cycloaddition of Pyrrolo[1,2-c]pyrimidinium Ylides

Pyrrolodiazines. 5. Synthesis, Structure, and Chemistry of Pyrrolo[1,2-c]pyrimidine. Dipolar Cycloaddition of Pyrrolo[1,2-c]pyrimidinium Ylides

New One-Step Synthesis of 3,4-Disubstituted Pyrrole-2,5-dicarbaldehydes

Synthesis of 5-substituted pyrrole-2-carboxaldehydes. Part I. Generation of formal 5-lithiopyrrole-2-carboxaldehyde equivalents by bromine–lithium exchange of 2-bromo-6-(diisopropylamino)-1-azafulvene derivatives

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