Hydrazones reaction with aldehydes

Azines, Aldehydes react with hydrazine to yield azines the reaction cannot usually be arrested at the hydrazone stage. This reaction may be illustrated by the preparation of bevzalazine from benzaldehyde ... 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

Cyclization of the hydrazone derivatives of 4-benzoyl[ 1,2,3]triazole 695 by reaction with one carbon inserting agent such as an orthoester, an aldehyde, a ketone, or a phosgene afforded triazolotriazine 696 or 697 (88JHC743). The newly created C—N bond displays particular sensitivity due to the electron-attracting effect of the triazole ring (Scheme 147). 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Aldehyde-containing macromolecules will react spontaneously with hydrazide compounds to form hydrazone linkages. The hydrazone bond is a form of Schiff base that is more stable than the Schiff base formed from the interaction of an aldehyde and an amine. The hydrazone, however, may be reduced and further stabilized by the same reductants utilized for reductive amination purposes (Chapter 3, Section 4.8). The addition of sodium cyanoborohydride to a hydrazide-aldehyde reaction drives the equilibrium toward formation of a stable covalent complex. Mallia (1992) found that adipic acid dihydrazide derivatization of periodate-oxidized dextran (containing multiple formyl functionalities) proceeds with much greater yield when sodium cyanoborohydride is present. 

Figure 1.110 The reaction of SANH with an amine-containing molecule results in an amide bond derivative that terminates in a protected hydrazine group. Reaction with an aldehyde-containing molecule results in release of the acetone-protecting group and formation of a stable hydrazone bond.

Derivatives of hydrazine, especially the hydrazide compounds formed from carboxylate groups, can react specifically with aldehyde or ketone functional groups in target molecules. Reaction with either group creates a hydrazone linkage (Reaction 44)—a type of Schiff base. This bond is relatively stable if it is formed with a ketone, but somewhat labile if the reaction is with an aldehyde group. However, the reaction rate of hydrazine derivatives with aldehydes typically is faster than the rate with ketones. Hydrazone formation with aldehydes, however, results in much more stable bonds than the easily reversible Schiff base interaction of an amine with an aldehyde. To further stabilize the bond between a hydrazide and an aldehyde, the hydrazone may be reacted with sodium cyanoborohydride to reduce the double bond and form a secure covalent linkage. 

Figure 9.32 Reaction of this BODIPY fluorophore with aldehyde groups creates hydrazone linkages.

Aldehyde particles are spontaneously reactive with hydrazine or hydrazide derivatives, forming hydrazone linkages upon Schiff base formation. Reactions with amine-containing molecules, such as proteins, can be done through a reductive amination process using sodium cyanoborohydride (Figure 14.21). 

In a fume hood, add 10 pi of 5M sodium cyanoborohydride (Sigma) per ml of reaction solution. Caution Cyanoborohydride is extremely toxic. All operations should be done with care in a fume hood. Also, avoid any contact with the reagent, as the 5M solution is prepared in IN NaOH. The addition of a reductant is necessary for stabilization of the Schiff bases formed between an amine-containing protein and the aldehydes on the antibody. For coupling to a hydrazide-activated protein, however, most protocols do not include a reduction step. Even so, hydrazone linkages may be further stabilized by cyanoborohydride reduction. The addition of a reductant during hydrazide/aldehyde reactions also increases the efficiency and yield of the reaction. 

Gyclocondensation of diazomalonaldehyde 336 with 4-fluoroaniline carried out in methanol-acetic acid provides l-(4-fluorophenyl)-l,2,3-triazole-l-carbaldehyde 337 in 78% yield. Oxidation with MnOz in the presence of sodium cyanide in methanol converts aldehyde 337 into methyl ester 338 with 79% yield. Hydrazide 339 (84% yield) is obtained in a reaction of ester 338 with hydrazine. Product 339 reacts with various aromatic aldehydes to give hydrazones possessing interesting antiplatelet activity (Scheme 53) <2003BMC2051>. 

Depending on the nature of the substrates, selectivity could be completely reversed between the two isomeric products. For example, switching R1 group between Buc and Ph gave high yields of the first and second product structures, respectively. The authors noted that the reaction did not proceed if the imine contained an ortho-MeO group at R2 or if the imine was replaced with an aldehyde, oxime, or hydrazone. The catalytic cycle is initiated by C-H activation of the imine, that is, the formation of a five-membered metallocycle alkyne insertion affords the intermediate drawn in Scheme 69. It is noteworthy that this is the first report of catalytic synthesis of indene derivatives via a C-H insertion mechanism (C-H activation, insertion, intramolecular addition). 

A frequently reported spectrophotometric technique for the determination of hydralazine is based on reactions with aromatic aldehydes to form hydrazones with absorption in the visible region. Luk yanchikova et al (5 +) used p-nitrobenzaldehyde Wesley-Hadzija and Abaffy (55) and Ruggieri (56) used p-dimethylaminobenzaldehyde Luk yanchi-kova (57,58) used cinnamaldehyde Schulert (33) used p-hydroxybenzaldehyde and Zak et al (59) used p-methoxy-benzaldehyde, after testing cinnamaldehyde, salicylaldehyde, 3, +,5-trimethoxybenzaldehyde, and 1-naphthaldehyde. 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

Most reactions with hydrazine are carried out with aldehydes and ketones in the presence of alkali. The reduction proper is preceded by formation of hydrazones that decompose in alkaline medium at elevated temperatures to nitrogen and compounds in which the carbonyl oxygen has been replaced by two hydrogens. The same results are obtained by alkaline-thermal decomposition of ready-made hydrazones of the carbonyl compounds. Both reactions are referred to as Wolff-Kizhner reduction [280]. 

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