Hydrazones, oxidative cyclization

Unsaturated ketones react with phenyUiydrazines to form hydrazones, which under acidic conditions cyclize to pyrazolines (35). Oxidation, instead of acid treatment, of the hydrazone with thianthrene radical cation (TH " ) perchlorate yields pyrazoles this oxidative cyclization does not proceed via the pyrazoline (eq. 4). 

In contrast to the relatively limited number of non-fused 1,2,4-triazole syntheses that were reported in 1996, the preparation of several ting-fused 1,2,4-triazole-containing structures were published. For example, the frrst practical synthesis of fused[a]triazolo[l,4]benzodiazepine-5,11-diones 16 via the hydrazone IS was reported (Y = H, Cl, Me R = H, Me, Ph X = O, S) <96JHC275>. Oxidative cyclization of N-heteroarylamidines allowed the preparation of... 

Most preparations can be divided into two distinct routes (Scheme 47), either a condensation pathway (route A), or an oxidative cyclization starting from the corresponding hydrazone (route B). 

Oxidative cyclization of hydrazones to fused [l,2,4]triazoles by means of cupric chloride was already discussed above for a related pyridazine derivative. The same method was also applied successfully for ring closure of 428 to 429 in good to excellent yields (Scheme 53) <2005T5942>. 

An unusual one-pot intramolecular sulfoxide alkylation-elimination reaction was found by Gibson et al. <2001SL712>. These authors found that treatment of 459 with potassium bis-trimethylsilylamide resulted in a ring closure to 460 in acceptable yield. Furthermore, Batori and Messmer found an effective method for preparation of [l,2,3]triazolo[l,5- ]pyrimidinium salts <1994JHC1041> oxidative cyclization of hydrazones 461 by 2,4,4,6-tetrabromo-2,5-cyclohexadienone gave rise to the quaternary salts 462. Under certain reaction conditions, the formation of 6-bromo-salts 462 (R6 = Br) was also experienced. As neither the starting compound nor the quaternary triazolopyridinium salt underwent bromination in this position, the authors assumed that this bromination process occurred on one of the intermediates in the course of the above-mentioned cyclization reaction. 

Hydrazones 285 are oxidatively cyclized by IBD to form 286. Similar cyclization is accessible by using lead tetra-acetate as an oxidant, but results are inferior to those with IBD [89JCS(P1)543]. 

Oxidation of chalcone phenylhydrazone 13 leads to a pyrazole and the expelled proton catalyses formation of a pyrazoline from the chalcone phenyl-hydrazone [43]. The latter undergoes further anodic oxidation (p. 308). In the presence of pyridine as a proton acceptor, the pyrazole becomes the major product. A further example of oxidative cyclization is the conversion of a-oximino phenylhydrazones to 1,2,3-triazole-l-oxides 14 [44]. 

The mixed hydrazones (667), prepared from diacetyl monobenzoyl hydrazone and arylhydrazines, undergo oxidative cyclization to 2-aryl-jV-benzoyl-4,5-dimethyl-l,2,3-triazol-l-ylimines (668) in 32-76% yield upon treatment with lead tetraacetate in acetonitrile (Scheme 132) <92JOC2252>. The cychzation of bishydrazones to 1,2,3-triazoles can also occur in acidic or basic media. For instance, the tetrahydrobenzo[ /]triazol-4-one (669) is prepared by the base-catalyzed cyclization of the corresponding a-hydrazono oxime (Equation (53)) <85HCA1748>. 3-Methyl-1,2-cyclohexanedione reacts... 

The analogous hydrazones (383), however, gave only the acyclic adducts (384) (220). The latter failed to cyclize when heated in ethanol but did undergo oxidative cyclization when treated with Pd on carbon to give 385. 

Hydrazones 10 derived from aldose monosaccharides (9) and 2-hydrazinopyrimidine (8) gave, upon oxidative cyclization with bromine in methanol, the corresponding 3-(alditol-l-yl)-l,2,4-triazolo[4,3-a]pyrim-idines 11 [97JHC(34)1115] (Scheme 7). 

A number of 3-(alditol-l-yl)-5-methyl-7-oxo-l,2,4-triazolo[4,3-a]pyrim-idines l,2,4-triazolo[4,3-a]pyrimidines acyclo C-nucleosides (30) were synthesized (95PHA784) by oxidative cyclization of the corresponding aldehydo-sugar pyrimidin-2-ylhydrazones 27 with bromine in water. The alternative structure 29 was eliminated based on finding that acetylation of 30 afforded the same acetylated acyclo C-nucleosides 31 as those obtained by oxidative cyclization of the (A3-acetyl-poly-0-acetyl)hydrazones 28. Compounds 31 were also obtained by one-pot oxidative cyclization and acetylation of 27. In contrast to the oxidation and concurrent bromination of 19 to 25, it was possible to avoid nuclear bromination of 27 and 28 by performing the reaction in the absence of light (Scheme 13). 

A stereoselective synthesis of 3-( 1,2,4-triazolo[4,3-A ]azin-3-yl)-bicyclo[2.2.1 ]heptanones 58 starting from (l/ )-(+)camphor 56 has been described. The reaction comprises oxidative cyclization of the intermediate hydrazones 57 with methanolic bromine <02TA821>. 

A convenient synthesis of 1,2,3-thiadiazoles starts with the thioanilide derivative 544, which is converted into the hydrazone 545. Oxidative heterocyclization by treatment with hydrogen peroxide gives exclusively the 1,2,3-thiadiazoline 546 (Scheme 245) <2003S2559>. This method has been extended to include arylhydrazono thioacetamides, such as 547, which undergo oxidative cyclization using bromine to afford 2-aryl-l,2,3-thiadiazol-5(2//)imines 543 (Scheme 246) <2004RJ0818, CHEC-III(5.07.9.5)482>. 

Hydrazinonicotinic acid or its A/ -oxide cyclizes to pyrazolo[4,3-c]pyridin-3-one in refluxing hydrochloric acid (65AJC379). The phenylhydrazone (313) and cyanoacetamide react in the presence of base to give a mixture of the substituted pyridines (314) and (315). After separation these can be cyclized to the pyrazolopyridines (316) and (317). The protonated benzylic methoxy group is displaced in a nucleophilic attack by the hydrazone nitrogen (Scheme 92) (62LA(657)156). 

As a specific kind of intramolecular amination, one can consider the oxidative cyclization of arylhydrazones of benzazolyl-2-ketones by the action of N-bromosuccinimide (67AG272) [Eq. (22)]. This reaction occurs most easily for hydrazones of benzimidazoles, and this process is more difficult in the case of benzothiazoles weakly basic hydrazones of benzo-xazolyl-2-ketones do not take part in this conversion. 

The 1,2,4-triazole ring of 267 was formed by oxidative cyclization of aldehydo-sugar lepidin-2-yl-hydrazones (266) with iron(III) chloride (94MI6) (Scheme 80). 

Oxidative cyclization of (5,6-diphenyl-l,2,4-triazin-3-yl)hydrazones of aldose monosaccharides (820) and concurrent acetylation of the alditolyl chain hydroxyls provided the corresponding O-acetylated 3-(alditol-l-yl)-... 

When the iminophenylacetic acid (12.1) in acetonitrile is heated or allowed to stand for two days at ambient temperature, it is converted into an indole-3-carboxylic acid [2999]. Oxidative cyclization of the aminoalkene (12.2) oorurs under mild conditions (temperature of 23 C or lower) to give the hydrazone of an indole-3-carboxaldehyde [3843]. A number of 2,S-disub tituted indoles are accessible from the dilithium derivative of a 2-trimethylsilylmethylbenzanilide and an ester the latter is synthesized from a 4-substituted nitrobenzene in three stages [3824]. 

Nitrobenzaldehyde methylhydrazone undergoes oxidative cyclization to a betaine JV-oxide in high yield. Although the yield in this particular conversion is very high, it is worth considering the use of the phenyliodo diesters (review of the use of these and similar reagents [3714]). The reactions of hydrazones have been reviewed [2384]. 

Cinnolines may be formed by the cyclization of 2-hydrazone or 2-hydrazonophosphorane derivatives of 3-(2-fluoro- or chlorophenyl)-3-oxopropionates (Scheme 87), which are prepared from the oxopropionates via reaction with /i-toluenesulfonyl azide and treatment of the diazo derivatives with phosphines. Simple hydrazones undergo cyclization by displacement of fluoride under thermal or basic conditions, and reaction of chloro compounds is successful under basic conditions, though Wolff-Kishner reduction may compete in the absence of a methyl group on the terminal nitrogen. The diazo compounds cyclize, via tri- -butylphosphazines, more readily than do the hydrazones and base catalysis is not required it may be that cyclization proceeds via a phosphonium salt, with subsequent hydration and elimination of tri- -butylphosphine oxide. The triphenylphosphazines do not cyclize, but are labile intermediates to the hydrazones <88Cpbi321>. 

Triaza-Compounds. 2-(Ethoxymethyleneamino)pyridine is converted into the triazolopyridine (564) by the action of hydroxylamine-O-sulphonic acid. Anodic oxidation of the hydrazone Ar NHN=CHAr (Ar =p-NO2C6H4, Ar = /7-MeC6H4) in the presence of pyridine and tetraethyl-ammonium perchlorate affords the salt (565). Oxidative cyclization of the pyridylhydrazone PyCH=NNHPy (Py = 2-pyridyl) by means of mercury(II) acetate yields compound (566). 2,4,6-Triphenylpyrylium fluoroborate reacts with amidrazones ArC(NH2)=NNH2 in the presence of triethylamine to give the pyrazolopyrimidines (567). The tricyclic compound (568) is... 

Hydrazones (93) derived from the condensation of various aldehydes and 3-substituted 4-amino-3-sulfonyl[l,2,4]triazoles, on oxidative cyclization, afford the corresponding fully conjugated heterocycles (95) (Table 9 and Equation (23)). 

Hydrazone 69 (R = H) derived from 3-hydrazino-5//-l,2,4-triazino[5,6-6]indole (67, R = H) and aldose monosaccharides (68) produced the acyclo C-nucleoside (70, R = H) upon oxidative cyclization with iron(III) chloride (92BCJ546). The poly-O-acetyl derivatives of the 10-methyl and 10-ethyl congeners (70, R = Me or Et) were obtained in one step from the corresponding hydrazones (69, R = Me or Et) by cyclization with a mixture of bromine in acetic acid, anhydrous sodium acetate, and acetic anhydride (97UP1) (Scheme 22). 

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