Bishydrazone

A synthesis of an indolo[3,2-fl]carbazole (2) was reported in 1951—the first preparation of a compound belonging to this class (Scheme 13). This was accomplished commencing with cyclohexanone, via conversion to the bishydrazone 108, which underwent Fischer indolization in glacial acetic acid to furnish the octahy-dro derivative 109. After a final dehydrogenation step, the desired product 2 was obtained (51JCS809). 

As expected, 1,4-dinitrobutane (12.73) reacts with two equivalents of benzenedi-azonium chloride in aqueous ethanolic NaOH. The bishydrazone 12.74 can be isolated in high yield (Rembarz and Ernst, 1967). 

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 bishydrazones of the 1,2-diketones from inositols have also been converted into triazoles.222,223 The conversion of arylosazones into the corresponding osotriazoles requires the presence of an oxidant, and it is obvious that simple removal of aniline from the osazone, as suggested by the equation, is not involved. In addition to copper(II) sulfate, the reagent most commonly used, other oxidizing heavy-metal salts, such as ferric sulfate and chloride,224 and mercuric acetate,223 have been used, as well as halogens225 and nitro-sulfonates.226 The osazone acetates are converted into osotriazoles by nitrous acid,227 which decomposes the unacetylated osazones to the aldosuloses228 and the osazone formazans are cyclized with warm... 

Under the same conditions the 6,7-dodecanedione bishydrazone is converted to 36% 6-dodecyne and 19% 6-dodecene (35% Z, 65% E) . Remarkably no hexanonitrile is found in this case. In the oxidation of 1,2-bishydrazones to alkynes so far the chemical oxidants copper(II)salts mercuric oxide or nickel peroxide are superior to the nickel hydroxide electrode. 

Unsubstituted 4//-pyran (5) and 4//-thiopyran (7) with 2,4-dinitrophenyl-hydrazine afford identical bishydrazones 503.18,19 Analogous product 504 was obtained from 4//-pyran derivative 68 (X = EtO, Y = Me), whereas a slightly modified precursor possessing Y = Ph provided monohydrazone 505.86... 

Oxidation of 1,2-bishydrazones (494) is now known to give triazoles (495) and not dihydro-1,2,3,4-tetrazines. Possibly the latter are intermediates but are aromatized by ring contraction. 

Different results, depending on the structure of the initial 2-benzopyry-lium salt, were obtained also in reactions with phenylhydrazine. Thus, the 1,3-dimethyl-substituted cation 35 is converted into an isoquinolinium salt 174(R = Ph)(70KGS1308), whereas the 1,3-diphenyl derivative 178 forms an indole 180 via the bishydrazone 179 by the Fischer reaction (71CB2984). 

Figure 9-24. The oxidation of the nickel(ii) complex formed from the template condensation of biacetyl bishydrazone with formaldehyde gives a neutral, conjugated complex, in which the ligand is doubly deprotonated.

In some cases a whole series of dehydrogenation reactions may proceed sequentially to yield aromatic or highly conjugated products. An example of this is seen in the aerial oxidation of the nickel(n) complex of the macrocycle formed by the template condensation of biacetyl bishydrazone with formaldehyde. The product of the oxidation is the fully aromatic dianionic macrocyclic complex (Fig. 9-24). 

Compound 34 is obtained by bishydrazone formation from hydroxyiminoace-tophenone (33) and 4,4 -dihydrazinostilbene-2,2 -disulfonic acid followed by cyclization with urea [60],... 

Pure (6) can be prepared via the oxidative decomposition of the bishydrazone (7) with mercuric oxide 6) or thermal decomposition of the selenadiazole (8)7). 

If a very reactive cycloalkyne is synthesized, the necessary fast reaction at low temperature, must be worked up in a short period. These conditions are met by the oxidative decomposition of bishydrazones with lead tetraacetate in dichloro-methane. By this method the most strained, but still isolable cycloalkyne 3,3,7,7-tetramethylcycloheptyne (10) was prepared8), which on standing at room temperature... 

With hydrazine hydrochloride, thioindoxyl-1,1-dioxide has been reported to afford the azine (110) by prior formation of a bishydrazone.132 Murexide (111), a purple indicator used in compleximetric titrations, is formed from ammonium acetate, glacial acetic acid, and alloxantin (152 R = H). The murexide test is well known for detecting uric acid and other purines.133... 

The reaction of 1,2-dibromocycloalkenes (13) with magnesium in the presence of l,3-diphenylbenzo[c]furan (16) affords a cycloalkyne adduct (17). Also, the mercuric oxide oxidation of bishydrazone, which has been used extensively in the preparation of open-chain and medium or large cyclic acetylenes " , is adapted for small ring bishydrazones (18) . Treatment of 18 with mercuric oxide in the presence of 16 or of phenyl azide results in the adducts, 17 and 19, respectively. It seems... 

Table 1. Yields of cycloalkyne adducts. I Grignard reaction II oxidation of bishydrazone III base elimination of bromomethylene derivative IV oxidation of aminotriazole V photolysis of tosylaminotriazole anion...

Krebs and coworkers have synthesized 3,3,6,6-tetramcthyl-l-thiacycloheptyne (55) . The thiacycloheptanedione (53) derived from the corresponding acyloin was converted into the bishydrazone (54). Oxidation of 54 with mercury(ii) oxide gave 55 in 5-5% yield together with the ew-olefin (56, 6-9%). In the absence of oxygen... 

The synthesis of 3,3,7,7-tetramethylcycloheptyne (64), a carbocyclic analogue of 55, has also been performed. The bishydrazone (63) derived from tetramethyl-cycloheptane-l,2-dione (62) was oxidized with lead tetraacetate and 64 was obtained together with 65, 66, 67 and 68. The last compound (68) is a dimer of 64 with... 

Cyclooctyne (75) can be prepared according to the usual rhethods of synthesis of acetylenic compounds. For instance, oxidation of the bishydrazone of cyclooctane-1,2-dione (74) " " or debromination of 1,2-dibromocyclooctene (76) with magnesium or the photolysis of the anion of I-tosyIamino-1,2,3-triazole derivative (77) gave cyclooctyne (75). 

Macrocyclic acetylenes containing one acetylenic linkage have been prepared by the oxidation of bishydrazones of macrocyclic 1,2-diones - >. This method has been used for the synthesis of 1,7-cyclododecadiyne starting from cyclododecyn-1,2-dione . 

Diketones have also been converted into alkynes, most commonly through the bishydrazone derivatives. Originally, cyclodeca-l,2-dione was converted into cyclodecyne by initial bishydrazone formation and subsequent oxidation with mercury(II) oxide (Scheme 76). More recently, cyclic... 

The bishydrazones of DHA and related compounds have been studied and used to synthesize a number of nitrogen derivatives of DHA (18-23), Thus the bisphenylhydrazone of DHA is reduced by hydrogen/platinum to 2,3-diamino-2,3-dideoxyascorbic acid, which in turn can be converted to a variety of acyl derivatives. The structure of DHA phenylosazone is a hexenonelactone (24),... 

The nitrogen derivatives of L-ascorbic acid or its dehydro derivative, and the rationale for interest in these derivatives, are reviewed. In particular, the reactions of dehydro-L-ascorbic acid (DHA) with o-phenylenediamine or its substituted derivatives are surveyed as well as the reactions of DHA with hydrazines, which yield monohydrazones or bishydrazones. Further conversion of these initial derivatives into a variety of nitrogen heterocyclic compounds is evaluated. The reactions of i.-ascorbic acid with amino acids are also examined. 

The reaction of 38 with various hydrazines gave the corresponding mixed bishydrazones (42), which could be rearranged into other heterocycles (25,26), The bishydrazones could not be isolated with... 

Treatment of DHA or 38 with the corresponding arylhydrazine afforded the bis(arylhydrazone) (41) (33-40), Similarly, aroylhydra-zines and semicarbazide condensed readily with DHA to give the corresponding bishydrazone (41,42) and bis(semicarbazone) (43,44), A series of derivatives related to sulfa drugs (45) was prepared by the reaction of DHA with hydrazines having such moieties. 

The bishydrazones are now known to be in the 1,4-lactone form, showing that no opening of the lactone ring in DHA occurred during the reaction. However, at one time (38) the 1,5-lactone was the preferred form, since the IR spectra of the bishydrazones showed a carbonyl lactone band at a frequency lower than that expected for a... 

Another controversial aspect of the bishydrazone structure concerns the hydrazone residues. The bishydrazone was proposed to have the structure 46, which mutarotates in solution to 47 (47). More recently, on the basis of a comparative study of the spectroscopic properties of the bis(phenylhydrazone) with some related compounds, the bishydrazone was assigned the structure 2,3-dideoxy-3-phenylazo-2-phenylhydrazino-L-threo-hex-2-enone-l,4-lactone (48) (48). However, this latter structure was inconsistent with its NMR spectra (49). 

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