Hydrazones reaction with azides

Reactions of this type were first studied by Curtius and co-workers . For example, diethyl malonate and /(-toluenesulphonyl azide reacted in the presence of cold sodium ethoxide to give the sodium salt of the 5-hydroxytrizizole (296) . Acidification gave the 5-triazolone (297) which isomerized to the diazo compound (298) (overall yield 90%). (The same product could be obtained in 85% yield without base by heating the azide and malonate at 100° and a pressure of 20 mm) . This reaction provided the basis for the so-called diazo-transfer reaction, an extremely useful method of synthesizing diazo compounds, which has been reviewed. The reaction has been formulated as shown in equation (134), and has been extended to the synthesis of azides by a diazo transfer to amine anions/i-Toluenesulphonyl azide reacts with hydrazone... 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Amino-5-aryl-l,3,4-oxadiazoles form stable N-nitrosamines (71c) which are converted into hydrazines (7ld) with zinc in acetic acid. Treatment of the hydrazine (71d) with nitrous acid yields the corresponding azide and with benzaldehyde a hydrazone is formed (B-61MI42300). On heating in benzene or in nitrobenzene, the nitrosamine (71c) undergoes the Gomberg-Bachmann reaction to yield 2,5-diaryl-l,3,4-oxadiazoles (73JCS(P1)1357). 

Pyridazines were obtained also by photolysis of 1-phenyl-l-vinyl azide in the presence of iron pentacarbonyl (3,6-di-phenylpyridazine was obtained in 1.1% yield) (78HCA589) or by thermal decomposition of an allenic hydrazonate (81JA7011). Acetylenic hydrazides can be transformed into pyridazines [84BSF(2)129], and thermal cyclization of dialkali metal salts of cu-hydroxyketone tosylhydrazones afforded pyridazines in moderate yield (85TL655). Propionyl phenylhydrazine, after reaction with 4-bromobutyronitrile, converts into a pyridazine (87SC1253). 

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

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>. 

The main direct synthetic routes to 2,5-disubstituted tetrazoles which have been developed are (i) diazotization of substituted hydrazidines, (ii) the reaction of aromatic azides with hydrazones, (iii) heterocyclic rearrangements involving preferential ring interconversions, (iv) displacements from formazans or tetrazolium salts. Most of the recent work also falls into these general areas. 

Chloro- and 2, 6 -dichloro-4-nitrodiphenyl ethers were converted into the corresponding 4 -sulfonyl chlorides by reaction with excess chlorosulfonic acid (five equivalents). " The comparatively poor yields of the sulfonyl chlorides obtained may be due to their susceptibility towards hydrolysis, as a result of the presence of the electron-withdrawing groups. Several sulfonyl derivatives of diphenyl ethers, e.g. azides, hydrazides and hydrazones showed pronounced algaecidal activity. 

Figure 5.35 ABH reacts with aldehyde-containing compounds through its hydrazide end to form hydrazone linkages. Glycoconjugates may be labeled by this reaction after oxidation with sodium periodate to form aldehyde groups. Subsequent photoactivation with UV light causes transformation of the phenyl azide to a nitrene. The nitrene undergoes rapid ring expansion to a dehydroazepine that can couple to nucleophiles, such as amines.

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

Diazo compounds have previously been prepared by a variety of methods. Some of these methods Include hydrazone oxidations, the reaction of diazomethane with acid chlorides,4 the reaction of activated methylene compounds with tosyl azide, decomposition of N-nitroso compounds, ... 

Oxidative cleavage of hydrazones. Carbonyl compounds can be regenerated from 2,4-dinitrophenylhydrazones, tosylhydrazones, or N-methyl-N-tosylhydra-zones in 80-95% yield by oxidation with sodium nitrite in TFA or HOAc (0-5°, 1-2 hours). In the case of tosylhydrazones, the other product of cleavage has been identified as tosyl azide, the product of reaction of tosylhydrazine with nitrous acid. 

To date, four bioorthogonal reactions have been used to label glycans on cells and in lysates hydrazone/oxime formation with ketones, thiol alkylation with maleimides, Staudinger ligation of azides with triaryl phosphines, and copper-catalyzed or strain-promoted [3+2] cycloadditions of alkynes and azides (Figure 5) (25, 26, 32, 34, 35). While each reaction has been used extensively, most recent applications have employed azido- or alkynyl-sugars due to their superior metabolic incorporation and efficient ligations. 

Azide synthesis (2, 415). In the definitive paper3 describing the conversion of primary amines into azides by a diazo transfer reaction, methyllithium is preferred to methylmagnesium chloride as the base. The reaction has been extended to hydrazones. Thus, when the hydrazones of benzophenone, fluorenone, and acetophenone are treated with methylmagnesium chloride and then with tosyl azide, the corresponding diazoalkanes are obtained in about 20% yield. 

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