Kinetics and mechanism of rearrangement and methanolysis of acylphenylthioureas

Abstract

S-Acyl-1-phenylthioureas and their 3-methyl derivatives are rearranged to 1-acyl derivatives of thiourea in methanolic solution. The rearrangement of the 1-acyl-1-phenyl derivative to the thermodynamically more stable 3-acyl derivative is subject to specific base catalysis. The rearrangement of acetyl group is about 2 orders of magnitude slower than that of benzoyl group. 1-Acetyl-l-phenylthiourea undergoes base-catalyzed methanolysis (giving phenylthiourea and methyl acetate) instead of the rearrangement. The methanolysis rates of l-acyl-3-phenylthioureas and their N-methyl derivatives have been measured. The acetylthioureas react at most 3x faster than the benzoyl derivatives. The methyl group at the nitrogen adjacent to acyl group accelerates the solvolysis by almost 2 orders of magnitude; the methyl group at the other nitrogen atom retards the solvolysis by almost 1 order of magnitude. Replacement of hydrogen atom by methyl group at the phenyl-substituted nitrogen increases acidity of the phenylacetylthiourea by 2 orders of magnitude. The same replacement at the benzoyl-substituted nitrogen increases the acidity by 3 orders of magnitude, the increase in the case of the acetyl derivative being as large as 4 orders of magnitude.

Regioselective Synthesis of 2-Imino-1,3-thiazolidin-4-ones by Treatment ofN-(Anthracen-9-yl)-N′-ethylthiourea with Bromoacetic Acid Derivatives

“…Scheme 4. The reaction course followed on treatment of thiourea 1 with bromoacetyl bromide; initially the sulfur atom combines with the more reactive acid bromide group to form the isothiouronium ion, [22Ϫ24] which subsequently isomerises by S Ǟ N acetyl migration; [22Ϫ25] the migration occurs through the imine [22] and so the reaction profile is dominated by the imine equilibrium, which heavily favours the nitrogen atom bearing the anthracenyl group; subsequent nucleophilic intramolecular attack by the sulfur atom on the α-carbon atom effects cyclisation and yields the product Although the regioselectivity for bromoacetyl bromide might appear to be good, it is actually poor in comparison to the results of Kaválek, [23] who reported effectively exclusive regioselectivity in a comparison between N-methyl-NЈ-phenyl-disubstituted thiourea and NЈ-phenyl-monosubstituted thiourea (in both cases the benzoyl/acetyl group preferentially migrated from the sulfur atom to the nitrogen atom bearing the phenyl moiety). This was a kinetic result, as they were also able, subsequent to this, to effect NЈ Ǟ N migration of the benzoyl or acetyl group to yield the thermodynamic product, showing that this is also a facile reaction.…”

“…If the product distribution were determined solely by the imine equilibrium, then almost exclusive formation of 3 would be expected. Of course, isomerisation after the S Ǟ N migration [23] Ϫ i.e., N Ǟ NЈ migration of the acetyl group Ϫ could occur. Alternatively, the less than exclusive regioselectivity could be the result of a contribution from the cyclic sulfonium ion produced by the sulfur atom displacing the α-bromine atom prior to any S Ǟ N migration.…”

Regiospecific Synthesis, Structure and Electron Ionization Mass Spectra of 1,3‐Thiazolidin‐4‐ones Containing the Acridine Skeleton.

“…On stirring of the reaction mixture at room temperature, the spiro isomer 7b transformed stepwise to the pure condensation product 8b (the reaction was followed by 1 H NMR in deuteriochloroform at 12, 24, 48 and 96 h, by observing the growth of the CH 2 S signal at 3.78 ppm). The migration of the Sacyl group to nitrogen in isothioureas is well known and has been studied in depth kinetically [20,21,22]. The process could be formally explained by the cleavage of the C9'-C5 bond of the spiro ring and a subsequent cyclization of the open form intermediate obtained with a simultaneous release of methanol.…”

Regiospecific synthesis, structure and electron ionization mass spectra of 1,3‐thiazolidin‐4‐ones containing the acridine skeleton

“…The cyclization of the S-acylated isothiourea hydrobromides 9a-i to the reversed regioisomers 11a-i occurred in the presence of triethylamine, after rearrangement of the bromoacetyl group onto the nitrogen atom bearing acridine skeleton via intermediates 10a-i. The migration of the Sacyl group to nitrogen in isothioureas is well known and has been studied in depth kinetically [20,21,22]. Regrouping is accelerated by base towards the preferred neutral imino but not the amino nitrogen [20] bearing the acridinyl group, which is the more stable imino tautomeric form of isothiourea as had been proved by an ab initio calculation for S-bromoacetyl-N-phenyl-N´-n-propylisothiourea [19].…”

“…The high rate of 9a-i formation in contradition to slow formation of intermediates 6a-i indicated that other than the Br-CH 2 reaction centre, namely the bromocarbonyl carbon had been attacked by the sulfur nucleophile. Indeed, a strong kinetic evidence for a primary S-acylation in reactions of thioureas with acetyl or benzoyl chlorides was described by Pratt and Kaválek [20][21][22]. The structural proof of 9a-i was hampered by their fast transformation Regiospecific Synthesis, Structure and Electron Ionization Mass Spectra Jul-Aug 2005 909…”