Multicomponent, one-pot sequential synthesis of 1,3,5- and 1,3,5,5-substituted barbiturates

Alessandro Volonterio, Matteo Zanda

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Carbodiimides and malonic acid monoethylesters readily react to afford N-acylurea derivatives that could be cyclized in situ by addition of a suitable base. This process represents a general and straightforward one-pot sequential synthesis of 1,3,5-trisubstituted barbiturates in very mild conditions (organic solvent/2 N NaOH aqueous solution, 20 degrees C). Performing the reaction in the presence of an electrophile resulted in the formation of fully substituted (namely, 1,3,5,5-tetrasubstituted) barbiturates through a three-component one-pot sequential process. The latter, however, occurred only with highly reactive electrophiles, such as benzyl and, in some instances, allyl halides. In order to expand the scope of the process, we sought to develop a general method for the C-alkylation of 1,3,5-trisubstituted barbiturates. We found that C-alkylation occurred upon treatment of 1,3,5-trisubstituted barbiturates with an alkyl halide in CH3CN at 120 degrees C in the presence of anhydrous K2CO3 affording the target 1,3,5,5-tetrasubstituted barbiturates in good yields. The multicomponent process was accomplished by combining the three steps in a one-pot sequential fashion, i.e., the condensation of carbodiimides with malonic acid monoethylesters, the cyclization of the resulting N-acylureas, and the C-alkylation of the resulting 1,3,5-substituted barbiturates. A detailed study of the influence of the structure of the reactants on the reaction outcome and mechanism is presented. By selective N'-deprotection of 1,3,5,5-tetrasubstituted barbiturates, the corresponding 1,5,5-trisubstituted barbiturates were also prepared.
Original languageEnglish
Pages (from-to)7486-7497
Number of pages12
JournalJournal of Organic Chemistry
Volume73
Issue number19
Early online date28 Aug 2008
DOIs
Publication statusPublished - 3 Oct 2008

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Barbiturates
Alkylation
Carbodiimides
Cyclization
Organic solvents
Condensation
Derivatives

Keywords

  • Alkylation
  • Barbiturates
  • Carbodiimides
  • Cyclization
  • Malonates

Cite this

Multicomponent, one-pot sequential synthesis of 1,3,5- and 1,3,5,5-substituted barbiturates. / Volonterio, Alessandro; Zanda, Matteo.

In: Journal of Organic Chemistry, Vol. 73, No. 19, 03.10.2008, p. 7486-7497.

Research output: Contribution to journalArticle

Volonterio, Alessandro ; Zanda, Matteo. / Multicomponent, one-pot sequential synthesis of 1,3,5- and 1,3,5,5-substituted barbiturates. In: Journal of Organic Chemistry. 2008 ; Vol. 73, No. 19. pp. 7486-7497.
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AU - Volonterio, Alessandro

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N2 - Carbodiimides and malonic acid monoethylesters readily react to afford N-acylurea derivatives that could be cyclized in situ by addition of a suitable base. This process represents a general and straightforward one-pot sequential synthesis of 1,3,5-trisubstituted barbiturates in very mild conditions (organic solvent/2 N NaOH aqueous solution, 20 degrees C). Performing the reaction in the presence of an electrophile resulted in the formation of fully substituted (namely, 1,3,5,5-tetrasubstituted) barbiturates through a three-component one-pot sequential process. The latter, however, occurred only with highly reactive electrophiles, such as benzyl and, in some instances, allyl halides. In order to expand the scope of the process, we sought to develop a general method for the C-alkylation of 1,3,5-trisubstituted barbiturates. We found that C-alkylation occurred upon treatment of 1,3,5-trisubstituted barbiturates with an alkyl halide in CH3CN at 120 degrees C in the presence of anhydrous K2CO3 affording the target 1,3,5,5-tetrasubstituted barbiturates in good yields. The multicomponent process was accomplished by combining the three steps in a one-pot sequential fashion, i.e., the condensation of carbodiimides with malonic acid monoethylesters, the cyclization of the resulting N-acylureas, and the C-alkylation of the resulting 1,3,5-substituted barbiturates. A detailed study of the influence of the structure of the reactants on the reaction outcome and mechanism is presented. By selective N'-deprotection of 1,3,5,5-tetrasubstituted barbiturates, the corresponding 1,5,5-trisubstituted barbiturates were also prepared.

AB - Carbodiimides and malonic acid monoethylesters readily react to afford N-acylurea derivatives that could be cyclized in situ by addition of a suitable base. This process represents a general and straightforward one-pot sequential synthesis of 1,3,5-trisubstituted barbiturates in very mild conditions (organic solvent/2 N NaOH aqueous solution, 20 degrees C). Performing the reaction in the presence of an electrophile resulted in the formation of fully substituted (namely, 1,3,5,5-tetrasubstituted) barbiturates through a three-component one-pot sequential process. The latter, however, occurred only with highly reactive electrophiles, such as benzyl and, in some instances, allyl halides. In order to expand the scope of the process, we sought to develop a general method for the C-alkylation of 1,3,5-trisubstituted barbiturates. We found that C-alkylation occurred upon treatment of 1,3,5-trisubstituted barbiturates with an alkyl halide in CH3CN at 120 degrees C in the presence of anhydrous K2CO3 affording the target 1,3,5,5-tetrasubstituted barbiturates in good yields. The multicomponent process was accomplished by combining the three steps in a one-pot sequential fashion, i.e., the condensation of carbodiimides with malonic acid monoethylesters, the cyclization of the resulting N-acylureas, and the C-alkylation of the resulting 1,3,5-substituted barbiturates. A detailed study of the influence of the structure of the reactants on the reaction outcome and mechanism is presented. By selective N'-deprotection of 1,3,5,5-tetrasubstituted barbiturates, the corresponding 1,5,5-trisubstituted barbiturates were also prepared.

KW - Alkylation

KW - Barbiturates

KW - Carbodiimides

KW - Cyclization

KW - Malonates

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VL - 73

SP - 7486

EP - 7497

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 19

ER -