Triethylamine, Ethanol — Mediated Disciplined Reactions of S-Benzylisothiouronium Chloride with Unsaturated 2-Oxazolin-5-ones: Synthesis of (Z)-2-Amino-4-arylmethylene-2-imidazolin-5-ones, 5-Benzoylamino-2-benzylthio-6-oxo-4,4-spirocyclohexyl-1,4,5,6-tetrahydropyrimidine, and Their Structure

Abstract

Triethylamine-mediated condensation of S-benzylisothiouronium chloride with [~1-4-arylmethylene-Z-pheny~-2-oxazalin-5ones (4) in ethanol gives [Z)-2-amino-4-arylmethylene-2-imidazol-in-5-ones (11, whereas the similar reaction with 4-cyclohexylidene-Z-phenyl-Z-oxazalin-5-0ne[~) produces 5-benaoylamino-2-benzy-lthi0-6-oxo-4.4-~pir0~yclahexyl-1,4.5.6-tetrahydropyrimidine (5) which on aminolyses with arylamines affords the corresponding 2arylamino derivatives(l6).Counter-attack reagents1 are of considerable importance in synthetic organic chemistry, but their scope in many reactions does not seem to have been properly explored. With an appropriate choice of the substrates, reagents, and the reaction conditions, i t may be possible to carry out many multi-step syntheses in the same flask involving highly ordered conversions, resembling biochemical changes, follawing definite protocols. We propose to call such transformations as "disciplined reactions'' and in this article present a navel one-pot synthesis a f the title campaundsI~1 and (151, using the reactions of 4-arylmethylene-2-phenyl-2-oxazolin-5-ones(41and 4 -c y c l o h e x y l i d e n e -2 -p h e n y 1 -2 -o x a z o l i~] , respectively, with S -b e n z y l i~~t h i o~r~n i~m chloride[E) in ethanol containing triethylamine. -It should be noted that several 2-aminoimidazole alkaloids have Deen isolated from marine sponges. 2-5 Some o f these, for example aplysinopsin-type alkaloids [L~.4.5 which contain a 3-indolylmethylene group at the 4[51-position of the imidazole ring, have generated interest because of their reported cytotaxicity against cancer and for affecting neurotransmission. These compounds are related to creatinine, an important end product of nitrogen metabolism in human beings, which belongs t o a class of heterocycles called gly~ocyamidines.~'~The stereochemistry of aplysinapsin-type alkaloids (11 has been investigated and it has been found that the configuration at the olefinic centre depends on the Substituent present in the m~l e c u l e .~'~T h e stable isomers were amenable to phota-i~omerisation to the less stable isomers which in turn were thermolabile. Synthesis o f 1 was carried out by the condensation o f indole-3-carboxaldehyde (i,Y=01 with the corresponding 2-iminoimidaaolidin-5-0nes[?l.~ In our approach. (21-4-[3indolylrnethylene]-2-phenyl-Z-oxazalin-5-ane ( 5 ) was used as a substrate and when heated with 6 in ethanol in the presence of triethylamine furnished a sulphurfree compound which has been characterised as 2-amino-4-(3-indolylmethylenel-2imidazolin-5-one ( G I on the basis o f its spectral data and chemical reactions.

Solid-Phase Synthesis of 2-Aminoimidazolones

“…The S -methyl isothiourea 4 was generated from Rink Amide MBHA resin in a procedure identical with that outlined in Scheme 1. Treatment of 4 with the oxazolone 9 and sodium ethoxide yielded the unsaturated 2-aminoimidazolone 10 . The long reaction times (10 h) were necessary to ensure that the product was completely deacylated.…”