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. 2013 Sep 9;69(36):7719-7731.
doi: 10.1016/j.tet.2013.04.127.

Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocycles

David M Arnold  1 , Matthew G Laporte, Shelby M Anderson, Peter Wipf
Affiliations

Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocycles

David M Arnold et al. Tetrahedron. .

Abstract

2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bi-pyrimidine, pyrimido-aminotriazine, and pyrimido-sulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets.

Keywords: Atwal-Biginelli reaction; Guanidines; Pyrimidines; Quinazolines; Screening library.

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Figures

Fig. 1
Fig. 1
The 4H-pyrimido[1,2-a]pyrimidine and imidazo[1,2-a]pyridine scaffolds 1 and 2, and selected biologically active derivatives.
Fig. 2
Fig. 2
X-ray structure of 38d (CCDC 932463).
Fig. 3
Fig. 3
X-ray structure of 44 (CCDC 935121). Due to static disorder in the ethyl ester group, the five ethyl hydrogen positions are uncertain and are therefore not shown.
Fig. 4
Fig. 4
HF-6-311G* structures of anti- (top) and syn- (bottom) 46.
Scheme 1
Scheme 1
Overview of heterocycles obtained by condensation of guanidines with bis-electrophiles.
Scheme 2
Scheme 2
Thiourea methylation followed by aminolysis of the thioimidate provides access to 2-aminodihydropyrimidines.
Scheme 3
Scheme 3
2-Step preparation of 2-aminopyrimidine 13•HCl from PMB-protected guanidine 11.
Scheme 4
Scheme 4
Preparation of 2-aminopyrimidines from guanidine hydrochloride.
Scheme 5
Scheme 5
Synthesis of 4H-pyrimido[1,2-a]pyrimidine-3-carboxylates
Scheme 6
Scheme 6
Synthesis of 8-heteroaryl-4H-pyrimido[1,2-a]pyrimidine-3-carboxylates.
Scheme 7
Scheme 7
One-pot Sonogashira coupling - cyclocondensation for the synthesis of 8-aryl-4H-pyrimido[1,2-a]pyrimidine-3-carboxylates.
Scheme 8
Scheme 8
Synthesis of 2-morpholino-6H-pyrimido[1,2-a][1,3,5]triazine-7-carboxylates 40-43 and 4-oxo-3,4,6,9-tetrahydropyrimido[2,1-c][1,2,4,6]thiatriazine-7-carboxylate 2,2-dioxides 44-45.
Scheme 9
Scheme 9
A second Atwal-Biginelli cyclocondensation reaction converts 2-aminopyrimidine 13•TFA into pyrimidopyrimidine 46.
Scheme 10
Scheme 10
Atwal-Biginelli cyclocondensation reactions with guanidine-quinazolines 47a-d.
See this image and copyright information in PMC

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