The gem-dimethyl effect on reactivities in cyclizations through tetrahedral intermediates. Cyclization of methyl-substituted methyl amides of 5-(p-nitrophenyl)hydantoic acids

Koedjikov, Asen H.; Blagoeva, Iva B.; Pojarlieff, Ivan G.; Kirby, Anthony J.

doi:10.1039/p29960002479

Cited by 14 publications

(16 citation statements)

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“…These authors assume rate determining attack of the ureido group on the protonated amide function to give a tetrahedral intermediate (k −2 and T of Scheme 2), however, without the support of any experimental proof. Our study of the cyclization of hydantoic acid N-methylamides 3 and amides 4 when R = p-nitrophenyl showed acid catalysis below pH 2-3. No definite answer could be given as to which is the r.d.s.…”

Section: Introductionmentioning

confidence: 67%

“…If amides 2 were formed, these would give rise to absorption at 330 nm, characteristic of the p-nitrophenylureido group. 3 UV-Spectrophotometry is of course insensitive to small amounts of impurities so product analysis was further carried out by means of 1 H NMR. The reaction was followed in 0.03 M DCl in 1 : 1 DMSOd 6 -D 2 O; organic solvent was added to overcome poor solubility in water.…”

Section: Resultsmentioning

confidence: 99%

“…1 In the case of the oxygen analogues, the hydantoic acid amides, the mechanism of cyclization under acid catalysis is less well understood 2-4 as opposed to the more extensively studied base catalyzed cyclization. [3][4][5] In moderately concentrated acids above H o of −1 (the Hammett acidity function), Kaválek et al 2 observed saturation kinetics due to protonation of the ureido group, which eliminates its nucleophilicity, and also due to considerable protonation of the amide moiety. These authors assume rate determining attack of the ureido group on the protonated amide function to give a tetrahedral intermediate (k −2 and T of Scheme 2), however, without the support of any experimental proof.…”

Section: Introductionmentioning

confidence: 99%

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Hydrolysis of 4-imino-imidazolidin-2-ones in acid and the mechanism of cyclization of hydantoic acid amides

et al. 2007

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The hydrolysis of iminohydantoins generates the same tetrahedral intermediate as that obtained in the cyclization of hydantoic acid amides to hydantoins. The ratio of the products of imine hydrolysis under kinetic control is determined by the relative height of the barriers of the breakdown of to amide or to hydantoin. Thus the partitioning of products unequivocally proves which is the rate determining step in the cyclization reaction-formation or breakdown of . UV and 1H NMR monitoring of the acid catalyzed hydrolysis of four 5-substituted 4-imino-1-methyl-3-(4-nitrophenyl)imidazolidin-2-ones found hydantoins as the only products. The kinetics of hydrolysis of imines were measured in 0.001-1 M HCl. Contrary to the remaining imines, 1,5-dimethyl-4-imino-3-(4-nitrophenyl)imidazolidin-2-one is readily oxidized as stock solution in THF containing peroxides to 1,5-dimethyl-5-hydroxy-4-imino-3-(4-nitrophenyl)imidazolidin-2-one . In all cases, hydrolysis was found to be zero order with respect to [H+]. As imines are fully protonated under the acidity studied, this is evidence of a transition state of a single positive charge. Comparison of imine hydrolysis rates with previous data on rates of cyclization of the corresponding amides of hydantoic acids allowed conditions (acid concentration, substitution pattern-gem-dimethyl effect) to be found that guaranteed kinetic control of the products obtained. Thus it was unequivocally proven that formation of the tetrahedral intermediate is rate determining in the cyclization of hydantoic acid amides. The small steric effects upon methyl substitution at 5-C and a solvent kinetic isotope effect kH/kD of 1.72 favour a mechanism for imine hydrolysis whereby the rate is limited by water attack on the protonated imine concerted with proton transfer from attacking water to a second water molecule.

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Section: Introductionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hydrolysis of 4-imino-imidazolidin-2-ones in acid and the mechanism of cyclization of hydantoic acid amides

et al. 2007

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“…It was noteworthy that utilization of 2,2‐dimethylpropane‐1,3‐diamine 5 i led to a remarkable reaction efficiency, resulting in the formation of cyclopentapyridopyrimidin‐6‐carboxylate 10 i in 90 % yield by the gem‐dimethyl effect of diamine 5 i (Scheme 2). [14] In the case of benzene‐1,2‐diamine 5 j , the result was almost no reaction while the reaction time was prolonged to 5 days. We finally explored a possibility for cyclohexane‐1,2‐diamine 5 k with genipin 1 , which resulted in a smooth reaction to give the expected product 10 k in 81 % good yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Tricyclic Methyl Cyclopentapyridopyrimidin‐6‐carboxylates and Cyclopentaimidazopyridin‐6‐carboxylates from Genipin

et al. 2022

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An effective one‐pot reaction was successfully developed for the synthesis of tricyclic methyl cyclopentapyridopyrimidin‐6‐carboxylates and cyclopentaimidazopyridin‐6‐carboxylates from genipin with a variety of diamines, including aliphatic, sterically hindered substituted and N‐substituted diamines, and cyclohexane‐1,2‐diamine under nitrogen atmosphere. The tricyclic and tetracyclic methyl cyclopentapyridopyrimidin‐6‐carboxylate or cyclopentaimidazopyridin‐6‐carboxylate were successfully afforded in good to excellent yields. This facile and efficient one‐pot reaction involved N‐substitution reaction, cyclization, sequential dehydration, and final N‐substitution reaction in four‐step reactions. The reactivity tendency of diamines was also determined from the isolated yields of products in this work. On the other hands, we also evaluated genipin with amines and diamines under air atmosphere to determine the potential colour variation range areas. Fortunately, we firstly isolated the unstable methyl dihydro‐2H‐cyclopenta[c]pyridine‐4‐carboxylate intermediates 3 a–b and assigned by simple spectrum analysis technique.

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“…This results from strain in the open compound being relieved in the ring because the bonds forming the cycle are forced into unfavourable conformations thus leaving more freedom for the substituents. In cyclizations through tetrahedral intermediates 4 giving rigid products such as hydantoins flexibility is gradually lost along the reaction path and the GMDE will influence both steps of Scheme 1. If k f2 is rate determining the GDME can shift the overall transition state towards the first stage, k f1 , by making k r1 < k f2 .…”

Section: Introductionmentioning

confidence: 99%

The gem-dimethyl effect in reactions through tetrahedral intermediates: cyclizations of some ethyl 2,3-disubstituted-5-(p-nitrophenyl) hydantoates

Koedjikov¹,

Ivanov²,

Pojarlieff³

2001

Arkivoc

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Dedicated to Professor Oswald Tee on the occasion of his 60th birthday (received 13 Sep 01; accepted 25 Oct 01; published on the web 02 Nov 01) AbstractThe kinetics of cyclization for 3-ethyl-, 3-isopropyl-and 3-hexyl-substituted hydantoates 2-UE to the corresponding hydantoins 2-Hyd were studied in an attempt to examine the gem-dimethyl effect (GDME) in a case where the tetrahedral center of the intermediate T is not fully screened. However, in these congested compounds, the increase in strain in the open chains paralleled that of the intermediates resulting in meager rate enhancements -an interpretation confirmed by MM3 calculations. In the case of the largest substituent 2d-UE a new reaction appeared in the rate profile, together with substantial changes concerning the points of transition from r.d. formation to breakdown of T in the OH -and general base catalysis. All these agree with the concept that the GDME tends to shift the transition state to an earlier step of the cyclization reaction.

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The gem-dimethyl effect on reactivities in cyclizations through tetrahedral intermediates. Cyclization of methyl-substituted methyl amides of 5-(p-nitrophenyl)hydantoic acids

Cited by 14 publications

References 22 publications

Hydrolysis of 4-imino-imidazolidin-2-ones in acid and the mechanism of cyclization of hydantoic acid amides

Hydrolysis of 4-imino-imidazolidin-2-ones in acid and the mechanism of cyclization of hydantoic acid amides

Synthesis of Tricyclic Methyl Cyclopentapyridopyrimidin‐6‐carboxylates and Cyclopentaimidazopyridin‐6‐carboxylates from Genipin

The gem-dimethyl effect in reactions through tetrahedral intermediates: cyclizations of some ethyl 2,3-disubstituted-5-(p-nitrophenyl) hydantoates

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