Hydrazines via hydrazones

Aldehydes and ketones undergo in situ reductive amination with hydrazine (via hydrazone intermediates) using NaBH3CN/HCl in an analogous fashion, as previously described for amines (Section 1.2.2.3), to afford alkyl-substituted hydrazines, and the process can be utilized to synthesize nitrogen heterocyclic rings with dialdehydes (entries 5, 6). Reductions of hydrazones with NaBHsCN have also been used in the biochemical area to attach fluorescent chromophores to gangliosides. ... 

Saturated and a,P-unsaturated 1,4-dicarbonyl compounds undergo cyclocondensation with hydrazine via hydrazones yielding 1,4-dihydropyridazines 8 or pyridazines 7 ... 

Figure 17.6 The reaction of SANH with amine-containing proteins or other molecules results in amide bond modifications containing terminal hydrazine groups. The reaction of SFB with amine-containing proteins or other molecules results in amide bond modifications containing terminal aldehyde groups. Subsequently, the two modified molecules can be reacted together to create a conjugate via hydrazone bond formation.

The oxidation of phenylhydrazine and 1,2-disubstituted hydrazines to hydrazones and diazenes by CI2C proceeds via formation of unstable azomethine imines.95 The conversion of alcohols into alkyl halides is achieved by reaction with CCI4 (or CBr4) in DMF under electrochemical reduction.96 The reaction of dihalocarbene X2C with DMF to form a Vilsmaier reagent (93) is proposed as the key process. The reaction of simple isocyanates (RNCO) with dimethoxycarbene normally gives hydantoin-type products. In the reaction with vinyhsocyanates such as (94), however, hydroindoles (95) are formed in good yields.97... 

Pyrazolo[3,4-fo]quinolines and pyrazolo[3,4-c]pyrazoles have been synthesized by microwave irradiation of j5-chlorovinylaldehydes and hydrazines in the presence of p-toluenesulfonic acid (PTSA) under solvent-free conditions (Scheme 8.30) [92] via hydrazone formation and sequential cyclization. 

Like the use of the imine as an ammonia surrogate, the hydrazone of benzophenone can be used as a hydrazine surrogate (Scheme 2.165). The coupling product 2.564 may be diverted directly into a Fischer indole synthesis via hydrazone exchange with an added ketone. This pathway gives an indole 2.565 with a free N-H. Alternatively, the available nitrogen atom may be alkylated or coupled a second time, and then diverted into a Fisher indole synthesis. In this way, indoles with no nitrogen substituent, or an A-alkylated indole 2.566 or an iV-arylated indole 2.567 can be formed. 

Arylketones or -aldehydes 9 bearing a leaving group in ortho-position react with hydrazine or monosubstituted hydrazines (via the (Z)-hydrazones 10) at elevated temperatures to give indazoles in an intramolecular SNAr process ... 

A number of reaction pathways have been proposed for the Fischer indolization reaction. The mechanism proposed by Robinson and Robinson in 1918, which was extended by Allen and Wilson in 1943 and interpreted in light of modem electronic theory by Carlin and Fischer in 1948 is now generally accepted. The mechanism consists of three stages (I) hydrazone-ene-hydrazine equilibrium (II) formation of the new C-C bond via a [3,3]-sigmatropic rearrangement (III) generation of the indole nucleus by loss of... 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Ethyl 3-dichloromethyl-2-quinoxalinecarboxylate 1,4-dioxide (281) with hydrazine gave pyridazino[4,5-h]quinoxalin-l(2//)-one (283, presumably via the intermediate hydrazone (282) (substrate, EtOH, H2NNH2 H2OJ, dropwise, 0°C 20°C, 24 h 60% note loss of A -oxide entities during the reactions) ... 

The deoxygenation of aldehydes and ketones to the corresponding hydrocarbons via the hydrazones is known as the Wolff-Kishner reduction.28 Various modifications of the original protocols have been suggested. One of the most useful is the Huang-Minlon modification, which substituted hydrazine hydrate as a safer and less expensive replacement of anhydrous hydrazine. In addition, diethylene glycol together with sodium hydroxide was used to increase the reaction... 

The enamine 141 can be cyclized to the [l,2,4]triazolopyridopyrimidine 142 upon treatment with sodium ethoxide (Scheme 40) <2002M1297>. This fused tricyclic system may also be obtained, like the pteridine analogue (cf. Scheme 38), from the reaction of hydrazonoyl halides and pyridopyrimidines such as 143, and also by treatment of the triazolopyrimidine 144 with dimethylformamide dimethylacetal (DMF-DMA) dimethylacetal and subsequent ring closure <2003MOL333, 2003HAC491> (Scheme 41). Another series of triazolopyridopyrimidines, for example, 146, can be prepared from a hydrazine-substituted pyridopyrimidine 145, in two ways either directly by reaction with an acid chloride, or via a derived hydrazone (Scheme 42) <1996MI585>. 

Treatment of carboxyaldehydes 252 with hydrazine hydrate in ethanolic KOH under refluxing conditions provides an easy entry to the novel imidazo[2,l-4][l,3]thiazole fused diazepinones 253 via lactone ring opening by intramolecular nucleophilic attack of the amino group of the intermediate hydrazone which could not be isolated (Equation 31) <2006TL2811>. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

Reaction of 2-isothiocyanato-/ra/w-cinnamaldehyde (110) with hydrazine gave the pyrazolo[l,5-c]quinazolines (111), presumably via the corresponding hydrazone and conjugate addition to the pyrazoline followed by cyclization [76JCS(P1)653]. 

---