Douglas G. Neilson

Formation of 4-hydroxy-3-(α-hydroxybenzyl)-4-phenyl-2-pyrazolin-5-one from the interaction of 3,6-bis-(α-hydroxybenzyl)-s-tetrazine with potassium hydroxide in methanol

4-Hydroxy-3-(α-hydroxybenzyl)-4-phenyl-2-pyrazolin-5-one has been obtained from the reaction of methanolic potassium hydroxide with 3,6-bis-(α-hydroxybenzyl)-s-tetrazine and its structure proved by an alternative synthetic route. The mechanism of the rearrangement has been shown to involve a hydride transfer to a further tetrazine molecule which undergoes reduction to the dihydro-derivative.

The preparation of 3-benzyl-6-(α-methylbenzyl)- and 3,6-bis(α-methylbenzyl)-s-tetrazines by alkylation of 3,6-dibenzyl-s-tetrazine and a study of their rearrangements to imidazo[1,2-b]-s-tetrazines in alkali

3,6-Dibenzyl-s-tetrazine (1a) can be alkylated with methyl iodide after treatment with LDA in tetrahydrofuran to give a mixture of 3-benzyl-6-(α-methylbenzyl)- and 3,6-bis(α-methylbenzyl)-s-tetrazines (1c) and (18) separable by chromatography. 3,6-Dibenzyl-s-tetrazine on treatment with potassium hydroxide in benzyl alcohol yields, among other products, 3-benzyl-7-benzyloxy- and 3,7-dibenzyl-6-phenylimidazo[1,2-b]-s-tetrazines (8b) and (5a), the 7-benzyloxy group being generated from the solvent but the 7-benzyl group having the parent tetrazine (1a) as its precursor. Similar treatment of 3-benzyl-6-(α-methylbenzyl)-s-tetrazine (1c) but with methanol as solvent yields the related 7-methoxy-3-(α-methylbenzyl)-6-phenylimidazo[1,2-b]-s-tetrazine (8c) along with a novel compound assigned the structure of a substituted 1,2,4-triazolo[1′,5′ : 4,5]pyrazino[1,2-b]-s-tetrazine (15). 3,6-Bis(α-methylbenzyl)-s-tetrazine (18) is stable to alkali except when prolonged reaction times are employed when it breaks down to acetophenone, by way of an alkylidene hydrazide intermediate (19). Mechanisms are proposed for each of these reactions.

The preparation and absolute configuration of the optically active forms of the diastereoisomers of 2-(1-phenylethyl)amino-1-phenylethanol and their use as chiral auxiliaries in the asymmetric reduction of acetophenone with modified lithium aluminium hydrides

(1S,2S)-(–)-2-(1-Phenylethyl)amino-1-phenylethanol (4b)(α-form) and the(1S,2R)-(+)-diastereoisomer (4f)(β-form) were prepared by lithium aluminium hydride reduction of the optically active amides derived from the appropriate mandelic acids and 1-phenylethylamines. The preparative methods give the absolute stereochemistry. The aminoethanols (4) were used along with the lower alcohols to prepare chirally modified lithium aluminium hydrides which were in turn used to reduce acetophenone. The optical yields varied, giving at best, under low temperature conditions and use of [LiAlH(OMe)(PhCHOCH2NCH(Me)Ph)] a 25% optical yield.

Cyclisation reactions of α-hydroxy-imidates with oxalyl chloride and NN′-dicyclohexylcarbodi-imide

α-Hydroxy-imidate salts reacted with oxalyl chloride to form morpholine-2,3,5-triones, whereas the free bases gave oxazolidine-2,4-diones with the same reagent. Although imidate bases did not react with NN′-dicyclohexylcarbodi-imide, their salts gave 2-cyclohexylimino-oxazolidin-4-ones.

An investigation into the mechanism of formation of oxadiazoles and arylidenehydrazides from the action of methanolic potassium hydroxide on 1,4-dihydro-s-tetrazines.

3,6-Diaryl- and 3,6-dibenzyl-1,4-dihydro-s-tetrazines have been shown to be inert to methanolic alkali under nitrogen. Oxadiazoles derived from these substances by the action of alkali in methanol in air result from alkali attack on the tetrazines themselves and not on the reduced derivatives as previously believed. 1,4-Dihydro-3,6-bis(α-hydroxybenzyl)-s-tetrazine is likewise stable to alkali under nitrogen but on exposure to air yields the benzylidene derivative of mandelohydrazide. Mechanisms are here proposed for the formation of the oxadiazoles and hydrazides.

Rearrangement reactions of 1,3,6-triaryl-1,4-dihydro-s-tetrazines leading to 2,4-diarylquinazolines, 1-anilino-3,5-diaryl-1H-1,2,4-triazoles, 1,3,5-triaryl-1H-1,2,4-triazoles, and 2,5-diaryl-1H-1,3,4-oxadiazoles. X-Ray structure determination of 6-isopropyl-2,4-diphenylquinazoline

1,3,6-Triaryl-1,4-dihydro-s-tetrazines (2c–g) rearrange on heating at ca. 200 °C to 2,4-diaryl-quinazolines (for which an X-ray determination was carried out on the 6-isopropyl compound) and 1-anilino-3,5-diaryl-1H-1,2,4-triazoles as major products. Hydrolysis in chloroform solution of the title compounds (2) and their 1 -alkyl analogues gives rise to 1 -aryl (or alkyl)-3,5-diaryl-1H-1,2,4-triazoles and 2,5-diaryl-1,3,4-oxadiazoles.

The role of lithium amides as reducing agents in a novel pathway to 3,6-diarylpyridazines by ring transformations of 3,6-diaryl-s-tetrazines

3,6-Diaryl-s-tetrazines undergo two competing reactions when treated with lithium amides. The first, direct nucleophilic attack and addition of lithium amide to the tetrazine, appears to be predominant when a less hindered amide is used, and moderate quantities of tetrazine are then regenerated on quenching. The competing reaction, which is seen more clearly with a bulkier amide such as lithium di-isopropyl-amide, involves reduction of tetrazine to a dihydro derivative with concomitant formation of imine from the amide: this imine is then attacked by further amide and gives rise to a charged intermediate which reacts with more tetrazine to form a pyridazine.

Investigations into the mechanism of the action of alkali in methanol on 3,6-dibenzyl-s-tetrazines and their 1,4-dihydro-derivatives: the role of s-tetrazines as hydride acceptors and an X-ray determination of the structure of 3,6-bis(4-chlorobenzyl)-1,4-dihydro-s-tetrazine

Evidence is presented for the mechanism of the reaction of potassium hydroxide with 3,6-dibenzyl-s-tetrazines in which some tetrazine molecules act as hydride acceptors to become dihydro-derivatives which, in turn, react with alkali in a competing reaction to form the corresponding 1,3,4-oxadiazoles. The known action of alkali on 3,6-dibenzyl-1,4-dihydro-s-tetrazines to form 1,3,4-oxadiazoles has been shown to require the presence of an oxidising agent and tetrazine can play this role. The structures of the dihydro-derivatives of s-tetrazines have been in doubt, being called 1,2-and/or 1,4-compounds almost at random, but an X-ray determination of the structure of the dihydro-derivative of 3,6-bis(4-chlorobenzyl)-s-tetrazine has shown conclusively that it exists as the 1,4-dihydrocompound.

Synthesis and X-ray determination of the structure of 3-benzyl-7-methoxy-6-phenylimidazo[1,2-b]-s-tetrazines prepared by the action of potassium hydroxide in methanol on 3,6-dibenzyl-s-tetrazines

Compounds with the novel imidazo[1,2-b]-s-tetrazine structure have been obtained by the action of alkali in methanol on 3,6-dibenzyl-s-tetrazines, and their molecular structure has been confirmed by X-ray analysis.

Reactions of 1,2- and 1,3-amino-alcohols with imidate salts and with ortho esters

ω-Hydroxy-N-substituted amidines have been shown to be the intermediates in the formation of 2-oxazolines and 5,6-dihydro-4H-1,3-oxazines from the reactions of imidates and 1,2- and 1,3-amino-alcohols respectively. 1,2- and 1,3-Amino-alcohols also react with ortho esters to give 2-oxazolines and 5,6-dihydro-4H-1,3-oxazines, but N-acylamino-alcohols give rise to oxazolidines with ortho esters.