Acylhydrazines

Acylhydrazine derivatives of this general type provide one of the most convenient routes to a variety of 1,3,4-oxadiazoles, and the scope and limitations of this method are discussed in Chapter 4.23. 

Treatment of a mixture of 6-methoxy-9-chloro-7//- and 6-methoxy-9-chloro-5//-pyrido[2,3-c]-azepine (20) (see Section 3.2.1.5.5.1) with 1-acylhydrazines yields 3-substituted 5//-pyrido[2,3-c][l,2,4]triazolo[4,3-a]azepines, e.g. 21.191 Likewise, with sodium azide in dimethyl sulfoxide, the tetrazolo[4,5- ]azepine 22 is formed in good yield. 

Heating 4-(dimethylamino)-l//-l, 5-benzodiazepin-2(3//)-one with acylhydrazines affords tri-azolobenzodiazepinones 23.300... 

However, the switchover from an A2 to an A1 hydrolysis is a very common mechanistic pathway in strong acid media, probably more common than the pure A2 mechanism. Excess acidity analyses have shown that thioacetic acid, several thiobenzoic acids, and many thiolbenzoate and thionbenzoate esters show this sort of mechanism switch.179 Acylals and thioacylals also show this behavior,116 with thioacylals using two water molecules and acylals one. Many hydroxamic acids react this way,127,216 as do esters of various types,41,217,218 episulfoxides219 and aryloxatriazoles.220 Acylhydrazines can also show a mechanism switch of this sort, although with these substrates the situation is somewhat more complex.221... 

A new synthesis of fervenulins 341 in a single step was developed (77JA7358 78JA7661) by the photolysis of 6-azido-l,3-dimethyIuracil 372 in the presence of acylhydrazines. Their reaction could not be effected by heating, suggesting that photochemical activation is required. Thermol-... 

Thus, (dimorpholinophosphoryl)formonitrile oxide undergoes 1,3-addition reactions with HC1, HI, primary and secondary amines, acylhydrazines, and even with thiourea or thiosemicarbazide (Scheme 1.13) (98). The former gives (dimor-pholinophosphoryl)isothiocyanate and urea. Those products might arise from a retro destruction of the unstable 1,3,5-oxathiazoline. The latter transforms to the isothiocyanate, the product of addition of a second molecule of thiosemicarbazide. (98). 

A ring closure to triazoloquinazoles described by Blank et al. <2003EJ0182> also followed by a domino cycliza-tion pathway o-isothiocyanatobenzonitrile 452 was treated with acylhydrazines to give the intermediate 453, in which the formation of two N-C bonds occurs, as indicated by the arrows, to yield 454. Compound 455 - closely related to the already-mentioned intermediate 453 - was also reported to undergo cyclization in an ethanolic solution under reflux conditions to give 456 <1994AP469>. 

Acylhydrazines R1 CONF1NF1R2 (R1 = Ph or PhCH2 R2 = Bu, PhCH2 or Ph) are produced by the action of hydroxamic acids R ONHOH on the primary amines R2NH2 in the presence of tosyl chloride or 2-chloro-l-methylpyridinium chloride94. O-(Diphenylphosphinoyl)-A-arylhydroxylamines 77 (R = NO2, Ac, Tos or CN) react with A-methylaniline to afford the hydrazine derivatives 7895. 

Diazomethane is also produced in the reaction of acylhydrazines with dichloro-carbene, but the process is less efficient, as only one equivalent of diazomethane is produced from two equivalents of the acylhydrazine. However, the procedure provides a useful route to symmetrical AUV -diacylhydrazines (Scheme 7.25) [11],... 

The malonate derivative (93) reacted with acylhydrazine (94) to give a mixture of diacylhydrazine monoenamine (95) and oxadiazole (88c), (Scheme 6) which was also formed from (95) on heating <88LA909). 

Representatives of this novel class of meso-ionic compounds in which the exocyclic substituent f (see Table I) is a stabilized carbanionoid residue [-C(CN)C02Me or -C(CN)2l have been recently synthesized. Base-catalyzed (potassium carbonate or triethylamine) condensation of AT-acylhydrazines (147) with 3,3-dichloroacrylonitriles (165) yield the greenish-yellow meso-ionic l,3,4-oxadiazol-2-enes (164) directly. 

The kinetics of the acid hydrolysis of isosydnones (146) to N-acylhydrazines (147, X = O) has been examined in detail and the mechanism has been discussed. ... 

An extremely interesting and novel method has been described (91TL133). The principle involved is the intramolecular Diels-Alder addition of a 2,4-dienoic acid amide with an azodicarbonyl moiety. /V-Sorbyl-proline (27) was condensed with an acylhydrazine to form (28). Oxidation of this with lead tetraacetate (LTA) in boiling benzene resulted in the piperazinedione (30). This must have come about via (29), which could undergo an intramolecular Diels-Alder reaction. The structure and stereochemistry of (30) were confirmed by X-ray crystallography. The two new chiral centers have the R configuration as shown in (Scheme 9). 

Oxidation of acylhydrazines with /-butyl hypochlorite in acetone at —50°C to -78°C [110] (Eq. 51). This procedure is apparently suitable for azo... 

Closely related are the syntheses from various sulfur-containing derivatives of 2-pyridylhydrazine by which it is possible to obtain the 3-thiol (or thione) 6180 or 3-methylaminotriazolopyridine (62).88 By use of dithio-carbamates instead of acylhydrazines, the iminoether synthesis gives the tetrahydrotriazolopyridine-3-thiol (or thione) 63.89-92 Cyclization of the amidine 64 gives 3-anilinotriazolopyridine (65).93... 

Synthesis of l,2,4-triazolo[l,5-c]quinazolines from nonquinazoline intermediates is also known. Thus, the two heterocyclic rings were formed by the reaction of acylhydrazines with 2-ureidobenzonitriles (89JPR-537), 2-ethoxycarbonylaminobenzonitriles (329) (87USP4713383), or 2-isocyanatobenzonitrile (87CZ373) to give the title compounds (e.g. 330). 

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