Synthesis of N-(Purin-8-yl)arylamines

David H. Swenson, Karam El-Bayoumy, Gong Huey Shuie, Stephen S. Hecht, Emerich Fiala, Fred F. Kadlubar, J. Pat Freeman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Methods for direct synthesis of N-(purin-8-yl)arylamines were investigated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophilic metabolites of arylamines with DNA and have not been readily available by direct synthesis. Ability to generate significant quantities of this class of DNA adduct by synthetic means would facilitate basic research in molecular toxicology. Two routes with common thiourea intermediates were developed for this purpose. In the first route, 6-hydroxy-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p-toluidine to form corresponding 2,4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60–70% yields. The thiourea intermediates were converted to carbodiimides and isolated in 20–25% yields after treatment with HgO in dimethylformamide. The carbodiimides were cyclized at 125 °C in dimethylformamide under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65–75% yields. In the second route, direct reaction of p-tolyl isothiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triaminopyrimidine in dimethylformamide and triethylamine led to the formation of 2,4-diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diamino-5-(tolylthioureido)aminopyrimidine, respectively, in 77–79% yields. Methylation of the two thiourea derivatives by methyl iodide in dimethylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71% and 84% yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)-p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5–7 h at 80–90 °C, in 70% and 62% yields, respectively. The most efficient synthesis of the thioureas would appear to proceed by coupling the triaminopyrimidine precursor with the easily prepared dithiocarbamate derivatives of the arylamine followed by conversion to a methylisothiuronium and thermal cyclization of the methylated intermediate. These routes should be directly applicable to polynuclear arylamines and suitably blocked diaminoarenes.

Original languageEnglish (US)
Pages (from-to)480-485
Number of pages6
JournalChemical Research in Toxicology
Volume6
Issue number4
DOIs
StatePublished - Jan 1 1993

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Dimethylformamide
Thiourea
Derivatives
Carbodiimides
Methylation
DNA Adducts
Cyclization
Metabolites
Heating
Toxicology
Salts
Hot Temperature
4-toluidine
DNA
Research

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Swenson, D. H., El-Bayoumy, K., Shuie, G. H., Hecht, S. S., Fiala, E., Kadlubar, F. F., & Freeman, J. P. (1993). Synthesis of N-(Purin-8-yl)arylamines. Chemical Research in Toxicology, 6(4), 480-485. https://doi.org/10.1021/tx00034a014
Swenson, David H. ; El-Bayoumy, Karam ; Shuie, Gong Huey ; Hecht, Stephen S. ; Fiala, Emerich ; Kadlubar, Fred F. ; Freeman, J. Pat. / Synthesis of N-(Purin-8-yl)arylamines. In: Chemical Research in Toxicology. 1993 ; Vol. 6, No. 4. pp. 480-485.
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abstract = "Methods for direct synthesis of N-(purin-8-yl)arylamines were investigated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophilic metabolites of arylamines with DNA and have not been readily available by direct synthesis. Ability to generate significant quantities of this class of DNA adduct by synthetic means would facilitate basic research in molecular toxicology. Two routes with common thiourea intermediates were developed for this purpose. In the first route, 6-hydroxy-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p-toluidine to form corresponding 2,4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60–70{\%} yields. The thiourea intermediates were converted to carbodiimides and isolated in 20–25{\%} yields after treatment with HgO in dimethylformamide. The carbodiimides were cyclized at 125 °C in dimethylformamide under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65–75{\%} yields. In the second route, direct reaction of p-tolyl isothiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triaminopyrimidine in dimethylformamide and triethylamine led to the formation of 2,4-diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diamino-5-(tolylthioureido)aminopyrimidine, respectively, in 77–79{\%} yields. Methylation of the two thiourea derivatives by methyl iodide in dimethylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71{\%} and 84{\%} yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)-p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5–7 h at 80–90 °C, in 70{\%} and 62{\%} yields, respectively. The most efficient synthesis of the thioureas would appear to proceed by coupling the triaminopyrimidine precursor with the easily prepared dithiocarbamate derivatives of the arylamine followed by conversion to a methylisothiuronium and thermal cyclization of the methylated intermediate. These routes should be directly applicable to polynuclear arylamines and suitably blocked diaminoarenes.",
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Swenson, DH, El-Bayoumy, K, Shuie, GH, Hecht, SS, Fiala, E, Kadlubar, FF & Freeman, JP 1993, 'Synthesis of N-(Purin-8-yl)arylamines', Chemical Research in Toxicology, vol. 6, no. 4, pp. 480-485. https://doi.org/10.1021/tx00034a014

Synthesis of N-(Purin-8-yl)arylamines. / Swenson, David H.; El-Bayoumy, Karam; Shuie, Gong Huey; Hecht, Stephen S.; Fiala, Emerich; Kadlubar, Fred F.; Freeman, J. Pat.

In: Chemical Research in Toxicology, Vol. 6, No. 4, 01.01.1993, p. 480-485.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis of N-(Purin-8-yl)arylamines

AU - Swenson, David H.

AU - El-Bayoumy, Karam

AU - Shuie, Gong Huey

AU - Hecht, Stephen S.

AU - Fiala, Emerich

AU - Kadlubar, Fred F.

AU - Freeman, J. Pat

PY - 1993/1/1

Y1 - 1993/1/1

N2 - Methods for direct synthesis of N-(purin-8-yl)arylamines were investigated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophilic metabolites of arylamines with DNA and have not been readily available by direct synthesis. Ability to generate significant quantities of this class of DNA adduct by synthetic means would facilitate basic research in molecular toxicology. Two routes with common thiourea intermediates were developed for this purpose. In the first route, 6-hydroxy-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p-toluidine to form corresponding 2,4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60–70% yields. The thiourea intermediates were converted to carbodiimides and isolated in 20–25% yields after treatment with HgO in dimethylformamide. The carbodiimides were cyclized at 125 °C in dimethylformamide under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65–75% yields. In the second route, direct reaction of p-tolyl isothiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triaminopyrimidine in dimethylformamide and triethylamine led to the formation of 2,4-diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diamino-5-(tolylthioureido)aminopyrimidine, respectively, in 77–79% yields. Methylation of the two thiourea derivatives by methyl iodide in dimethylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71% and 84% yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)-p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5–7 h at 80–90 °C, in 70% and 62% yields, respectively. The most efficient synthesis of the thioureas would appear to proceed by coupling the triaminopyrimidine precursor with the easily prepared dithiocarbamate derivatives of the arylamine followed by conversion to a methylisothiuronium and thermal cyclization of the methylated intermediate. These routes should be directly applicable to polynuclear arylamines and suitably blocked diaminoarenes.

AB - Methods for direct synthesis of N-(purin-8-yl)arylamines were investigated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophilic metabolites of arylamines with DNA and have not been readily available by direct synthesis. Ability to generate significant quantities of this class of DNA adduct by synthetic means would facilitate basic research in molecular toxicology. Two routes with common thiourea intermediates were developed for this purpose. In the first route, 6-hydroxy-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p-toluidine to form corresponding 2,4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60–70% yields. The thiourea intermediates were converted to carbodiimides and isolated in 20–25% yields after treatment with HgO in dimethylformamide. The carbodiimides were cyclized at 125 °C in dimethylformamide under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65–75% yields. In the second route, direct reaction of p-tolyl isothiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triaminopyrimidine in dimethylformamide and triethylamine led to the formation of 2,4-diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diamino-5-(tolylthioureido)aminopyrimidine, respectively, in 77–79% yields. Methylation of the two thiourea derivatives by methyl iodide in dimethylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71% and 84% yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)-p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5–7 h at 80–90 °C, in 70% and 62% yields, respectively. The most efficient synthesis of the thioureas would appear to proceed by coupling the triaminopyrimidine precursor with the easily prepared dithiocarbamate derivatives of the arylamine followed by conversion to a methylisothiuronium and thermal cyclization of the methylated intermediate. These routes should be directly applicable to polynuclear arylamines and suitably blocked diaminoarenes.

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Swenson DH, El-Bayoumy K, Shuie GH, Hecht SS, Fiala E, Kadlubar FF et al. Synthesis of N-(Purin-8-yl)arylamines. Chemical Research in Toxicology. 1993 Jan 1;6(4):480-485. https://doi.org/10.1021/tx00034a014