Heine reaction

The synthesis of proline containing tripeptides constrained with phenylalanine-like aziridine and dehydrophenylalanine residues was accomplished in the laboratory of J. Iqbal.These tripeptides show -turn structure in solution and are good models for studying the mechanism of HIV protease. The aziridine rings in these tripeptides were stereoselectively transformed via the Heine reaction in two steps to the corresponding dehydrophenylalanine containing tripeptides, which also prefer to form -turn structures in solution. 

The first part of the mechanism includes the conversion of the carboxylic acid functionality to the acyl halide by the phosphorous trihalide. The acyl halide easily tautomerizes to the corresponding enol in the presence of a catalytic 

A convenient one-pot procedure for the preparation of a-bromo thioesters from carboxylic acids based on the HVZ reaction was developed by H.-J. Liu and co-workers.The neat carboxylic acid was mixed with 0.4 equivalents of PBrs, the resulting mixture was heated to 100-120 °C in an oil bath and 1.2 equivalents of liquid bromine was added in 1.5h. In the same flask, now containing the a-bromo acyl bromide, the solution of the thiol in dichloromethane was added to give the desired a-bromo thioesters in high yield. 

1 -Bromo-cyclohexanecarbothioic acid S-fert-butyi ester 

In order to determine the structure of the photochemical rearrangement product of carvone camphor in methanol, and to prove its structure, the research team of T. Gibson subjected the bicyclic carboxylic acid product to a degradation sequence, which commenced with the HVZ reaction, followed by dehydrohalogenation, dihydroxylation and glycol cleavage. 

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N-Acylaziridine-2-carboxylates readily rearrange to oxazolines under thennal, acidic, or nucleophilic conditions [91, 123-127]. Treatment of trans-aziridine-2-car-boxylate 176 (Scheme 3.63) with Nal in acetonitrile, for example, resulted in ring-expansion product 177 through the so-called Heine reaction. The reaction involves initial opening of the aziridine ring by iodide and subsequent oxazoline ring-closure by Sn2 displacement of the resultant iodide intermediate [127]. 

In this aforementioned Heine reaction the initial ring opening takes place by iodide ions. Subsequent ring closure by S 2 displacement of iodide by reaction with the negative oxygen center then leads to the products. This process proceeds with double inversion at the same carbon atom, thus with net retention. Hydrolysis of these oxazolines gives j9-hydroxy-a-amino acids (Scheme 31) [1,38]. The stereochemical course of ring expansion is the same as that observed in Scheme 29. 

Heine reaction Intramolecular ring expansion of substituted N-acylazirdines to the corresponding substituted oxazolines. 198... 

Much like with total synthesis, the Gabriel-Heine aziridine isomerization has not found widespread application within the medicinal chemistry community, despite its ability to efficiently generate a variety of azoles. DeWald and coworkers at Parke-Davis used the Gabriel-Heine reaction in the preparation of potential antipsychotics. Compound 27 was rearranged upon exposure to sodium iodide in acetone to provide compounds of type 28 in moderate to good yield, which were evaluated as nondopamine-binding antipsychotics. 

Variant AIq of synthesis of imidazo[l,2-fl]quinoxalines can be exemplified by the rearrangement of 2-(aziridino)quinoxaline derivatives 109a, b by the Gabriel-Heine reaction (Heine 1962). This method has been used to synthesize, for the first time, dihydroimidazo[l,2-a]quinoxalines 110a, b (Scheme 4.51) (Heine and Brooker... 

Scheme 4.51 The Gabriel-Heine reaction 2-(aziridin-l-yl)quinoxalines for the synthesis of imidazo[l,2-a]quinoxalines...

Hein UR, Chantraine-Hess S, Worm M, Zuberbier T, Henz BM Evaluation of systemic provocation tests in patients with suspected allergic and pseudo-allergic drug reactions. Acta Derm Venereol 1999 79 139-142. 

Transition-metal chemistry is currently one of the most rapidly developing research areas. The record of investigation for compounds with metal silicon bonds is closely comparable to that for silicones it was in 1941 when Hein discovered the first metal silicon complex, followed by Wilkinson in 1956. A milestone in the development of this chemistry was Speier s discovery of the catalytic activity of nobel metal complexes in hydrosilylation reactions in 1977. Hydrosilylation is widely used in modem organic syntheses as well as in the preparation of organo functionalized silicones. Detailed investigations of the reaction mechanisms of various catalysts continue to be subject of intense research efforts. 

HEINES, T.S., L.K.PETERS An analytical investigation of effect of a first order chemical reaction on the dispersion of pollutants in the atmosphere. Atmospheric Environment 7 (1972) S. 153-162. 

Hepatic Effects. The liver is a common target organ for substituted furan compounds (Boyd 1981). Ten days of oral exposure of female mice to a dose of 591 mg/kg/day of 2,3-benzofuran altered the activity of several hepatic enzymes, decreasing the rate of reactions which activate electrophiles and increasing the rate of reactions which deactivate electrophiles (Cha et al. 1985 Heine et al. 1986). No toxicity was reported in this study (Cha et al. 1985 Heine et al. 1986). Liver damage was seen in rats exposed to... 

Nabeya110 found that the same reaction occurred in acetic acid, and Heine et al.m reported that sodium iodide in acetone effectively promoted the rearrangement. Tisler112 utilized this procedure to produce a variety of 2-arylamino-2-thiazolines. 

When the aziridine nitrogen is substituted, Michael-type addition to the acetylene is not possible. Reactions are then usually preceded by ring cleavage with the formation of an azomethine ylid. The product obtained depends on the nitrogen substituent. Heine and co-workers 45,46 used m-l,2,3-triphenylaziridine (27) with DMAD, DEAD, EP, and EPP. The DMAD gave 98% of compound 28 after refluxing in toluene... 

As an example of rearrangements induced by a reaction on the metal, the rearrangement of tri-tr-phenylchromium (1) to bis(biphenyl)chromium(0) (3) and benzenebiphenylchromium(O) (2) (Hein s complexes) can be discussed (1,12). The tr complex (1) is prepared by the reaction of three equivalents of phenylmagnesium bromide with one equivalent of tris-tetrahydro-furanchromium(III) chloride. 

The structure of the products enabled Heine and Henzel [106] to propose that the intermediate of the reactions described is an azomethine ylide (Scheme 1.38). 

Brenk, R., Stubbs, M.T., Heine, A., Reuter, K., Klebe, G. Flexible adaptations in the structure of the tRNA modifying enzyme tRNA-guanine transglycosylase and their implications for substrate selectivity, reaction mechanism and structure-based drug design. ChemBiochem 2003, 4, 1066-1077. 

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