Chemistry of carbofunctionally substituted hydrazones

Synthetic approaches and chemical reactivity of title compounds since 1894 to date are reported. Emphasis is placed on pinpointing old literature reports that need reinspection in light of modern techniques and recent advances in utilizing the title compounds as precursors to polyfunctional heteroaromatics.


Introduction
2][3] Nitrogen lone pair resonance (cf.Scheme 1) renders hydrazone carbon atom electron rich and nucleophilicity of this carbon atom although have been noted in old literature 4 has now been recognized and utilized extensively in synthesis.Despite their theoretical and practical importance to our knowledge, no trial to review reported chemical reactivities, structural studies and synthetic approaches to those molecules has ever been made.In the following article we review the chemistry of this class of compounds.Arylhydrazono azoles, azines and their condensed derivatives if having an α-functional group on ring nitrogen (e.g. 3 and or 4) are not considered in this review as plenty of these derivatives have been extensively utilized as dyes and their chemistry is reviewed in specialized dye chemistry texts 3 .The chemistry of hydrazonyl halide X or Y = halogen and of hydrazononitriles X or Y = CN have been surveyed recently and will not be included here.

Condensation of functionalized aldehydes and ketones with hydrazines
This is a most logical route provided the required α-functional aldehyde and / or ketone is easily obtainable.As functionally substituted aldehydes are generally difficult to obtain and store this route however has only relatively limited application for the synthesis of monofunctionally substituted hydrazone [5][6][7][8][9][10][11] Condensing glyoxal 5a and substituted glyoxal 5b,c with substituted hydrazines leads to formation of mono or bis hydrazones 6 or 7 depending on molar ratio and applied reaction conditions [5][6][7][8][9][10][11] It has been reported that 5b reacts with phenylhydrazine to yield initially 8 which then rearranges into the thermodynamically stable 6; R = CH 3 (cf.Scheme 2).The mechanism of this rearrangement however had to be classified although reversibility of initial condensation reaction might be visional and that 8 is the kinetic product.

Coupling active methylenes with aromatic and heteroaromatic diazonium salts
This is the most generally utilized route to 1.The coupling reaction is generally conducted at room temperature and in protic organic solvent in presence of a base.Sodium acetate is most commonly used but coupling in presence of sodium hydroxide or in pyridine solutions has been reported.Acetylacetone 9a, benzoylacetone 9b, diphenylpentanedione 9c and other 1,3-diketones including cyclic ketones (e.g.10a,b) have been coupled with aromatic diazonium salts in ethanolic sodium acetate to yield corresponding coupling products 11a-c [12][13][14][15][16][17][18][19][20] and 12a,b 21,22

Scheme 6
The methylene group in
Thus, it was assumed by Bamberger et al. 137 that (Z)-phenylglyoxal-2-nitrophenylhydrazones could be distinguished from the (E)-isomer by its relatively lower melting point, as in (E) recently H-bonding decrease tendency for association through intramolecular hydrogen bonding greater stability in certain solvents like benzene, deeper shade of colour and ease of crystallization. 137ome authors believed that phenylhydrazones having a strong internal hydrogen bonding has a lower carbonyl band frequency in IR. 138 This finding was utilized to differentiate between the (Z) and (E) forms of pyruvamide phenylhydrazone. 139The (E) form showed the carbonyl band at higher frequency than that of the (Z) form.On the other hand, IR studies 140 of phenylglyoxalarylhydrazones indicate that the isomeric (Z) and (E) forms of these compounds can be easily distinguished by the position of the carbonyl as well as the NH stretching bands.Tanner 141 found that the carbonyl frequencies of both the (Z) and (E) forms of phenylglyoxal-2nitrophenylhydrazone were almost the same (1641 and 1640 cm -1 , respectively) and that there was only a little difference in the NH stretching frequencies of these isomers (3128 and 3166, respectively).
The NMR of the hydrazone NH of α-oxophenylhydrazones appears at δ 12-14 ppm.Studies of the isomeric forms in different solvents indicate that the equilibrium shifts in favor of (E) form in solvents that favor hydrogen bonding formation.
The structure of phenyhydrazones of four α-dicarbonyl compounds were determined from the IR and NMR spectra of the 14 N and 15 N isotopes.The compounds exist only in the phenyhydrazone tautomeric form and, except for the phenyhydrazones of phenylglyoxal in solution, primarily as the geometric isomer with the NHC 6 H 5 group oriented away from the carbonyl.The effect of solvent on the composition of the geometric isomerism equilibria was discussed. 142El-Ashry et al. 143 concluded that these compounds exist mainly in chelated hydrogen bonded form.
In the light of recent x-ray crystallography by Elnagdi et al. 144-15-46 that arylhydrazono-3oxoalkene nitriles exists in (E) form to make up for stereo electronic requirements previous conclusions about structure of arylhydrazo-ketones and ketoester should be rechecked (cf.structures 62-65).
It can thus be concluded that the observed low field NH signal in 1 H-NMR is in fact due to extensive delocalization of nitrogen atom lone pair rendering hydrazone carbon atom electron rich.In support of this view 1 H-NMR of phenylazomalononitrile showed NH signal at δ 13.0 ppm.Here hydrogen bonding is not possible.The most significant reactivity is the nucleophilicity of hydrazone carbon atom.This was noted since more than hundred years.Thus reactions like Mannich reaction, coupling reaction and halogenation have took place readily at such carbon.Recently Michael type addition was also described.Hydrazone nitrogen atom however remains the main site for attack by acylating and alkylating agents.It seemed that hard nucleophiles attack preferentially nitrogen atom, while soft ones attack preferentially at carbon atom.
The functional substituents retain their established reactivity pattern although generally become more electrophilic.Also multidentate reagents in several cases afford rings involving hydrazone moiety.In addition a variety of intramolecular cyclizations leading to cinnolines have been reported.In the following we will survey reported chemical reactivity pattern.

Reaction with carbon electrophiles
The reaction of α-ketohydrazones with Mannich reagents have been reported in the last century (c.f.formation of 67 from 66 is Scheme 15).Mustafa et al. 147 have shown that 68 undergo Mannich reaction at hydrazone carbon atom to yield intermediates 69 that readily undergo Japp-Klingemann cleavage yielding 70 in good yields.This reaction has recently been adopted to aromatic aldehydes. 147

Scheme 16
Glyoxaldiphenylhydrazone 71 also react with Mannich bases to yield either 72 or 73 depending on nature of utilized aldehyde (cf.][154] Aromatic aldehydes also react with 74 to yield 75.In absence of urea the reaction does not proceed.Naphthoquinone 76 reacts with 74 to yield either 77 or 78 depending on applied reaction conditions.Cinnamonitriles 79 also reacted with 74 to yield dihydropyridazines 80 (cf.Scheme 17). 155NH  In contrast to reported reactivity at carbon in this reaction, treatment of 16b,d with alkylhalides affords N-alkyl derivatives 82a,b [157][158][159] The reaction of 16b,d with chloroacetone, chloroacetonitrile or ethyl chloroacetate affords aminopyrazoles 84, most likely, via intermediacy of non isolable acyclic 83. 160

Scheme 19
The reaction of 3-(2-phenylhydrazono)pentane-2,4-dione 11a with diazomethane afforded pyrazole 87 in addition to 85 and 86. 161,162Although reaction sequence looks logical, this result should be checked again and reaction product should be characterized spectroscopically.
ARKAT USA, Inc.The azadiene 91 reacts with 16a to yield the pyrazole 93.Initial formation of adduct 92 is postulated. 167It should be mentioned however that in absence of conversing spectral evidence supporting these structures reported conclusions seems highly unlikely.For example 97 can also cyclized to 1,2,4-triazine formation of N-N bonds or N-S bonds as well as highly strained non aromatic heterocycles seems in light of modern knowledge least likely.

Reactions with halogen electrophiles
Halogenation occurs either at hydrazone carbon or at aryl or alkyl moieties depending on the nature of substituents on hydrazone moiety.Normally in acetic acid and in presence of sodium acetate halogenation occurs at hydrazone carbon and is followed by Japp-Klingemann cleavage of one of the functional groups attached to hydrazone carbon.If the hydrazone aryl moiety carry a strong electron attracting substituent (e.g.nitro function) initial halogenation occur at alkyl moieties in the molecule when they do exist.4][175] Bromine in acetic acid affords mono bromination products 109.If bromination is conducted in acetic acid in the presence of sodium acetate bromination at hydrazone carbon followed by Japp-Klingmann cleavage yielding 110 occurs.][178][179][180]

Scheme 27
It has been reported that if the arylhydrazone moiety is not substituted it can also participate in these reactions.For example chlorination of 16a with iodine chloride gives product of attack at both hydrazone carbon and phenyl moiety yielding 111. 181Bromination of 16a gives 112.Utility of excess of bromine is believed to yield 113. 182 Again spectroscopic evidence or X-ray crystallography is needed to support or revise these structures.Deviations from the general pattern have been reported.It seems that as a result of the fact that good part of these investigations has been made before development of appropriate spectroscopic methods for structural elucidation led in several cases in concluding structures with no solid evidence.For example chlorination of 16 (Ar= C 6 H 4 NO 2 -p) has been claimed to yield 114. 183 In other report chlorination in acetic acid in presence of sodium acetate gave 115.We believe that concluded structure need to be reinvestigated. 173

Scheme 30
Benzoylacetonitrile, cyclohexanone, cyanoacetamide and malononitrile were also condensed with arylazo derivatives to yield pyridazinones. 192 The benzotriazolyl derivative 117 and the hydrazonopyruvate also condense with ethyl cyanoacetate to yield 118 and 119, respectively. 186ondensation of 16 with 2-aminoprop-1-ene-1,1,3-tricarbonitrile 30 gives 122 via 120 and 121. 193,194Although this work has been published recently, the luck of convincing spectral evidence to support these conclusions seems quite strange as several alternate structures looks also possible.

Scheme 32
The arylhydrazonals 41 also reacted with ethyl cyanoacetate yielding pyridazinones 123.Wittigs reagents condense also with 41 to yield the corresponding pyridazinones 124 in good to excellent yields. 195,196 carbon Mitsunobu reaction of 41; X = CHAr (or better a Baylis-Hillman like reaction) has been reported.Thus reacting 41; X = COAr with dimethyl acetylene dicarboxylate and triphenylphosphine in methylene chloride gives the pyridazinedicarboxylates 125.It is believed that this reaction proceeds via sequence shown in Scheme 35.197,198 ARKAT USA, Inc. Phenols condense with 16 to yield chromene derivatives.For example condensation of 16a with resorcinol affords 128, salicylaldehyde gives 129. 35 Recently, however, Elnagdi et al. 208 have reported that reaction of 144 with hydrazines affords the stable hydrazones 145.These could be cyclized only under drastic conditions into pyrazoles 146 [209][210][211] .It can thus be suggested that this is beyond the stability of these hydrazones.Hydroxylamine hydrochloride reacts with 144 in basic media to yield isoxazolones 148.212,213 However, again only oximes 147 were produced from reaction of 144 with hydroxylamine.The latter either cyclised into 1,2,3-triazoles 150 214,215 or were converted into nitriles 149 216  The reaction of hydroxylamine hydrochloride with 16b,d derivatives give amidoximes 151 that are converted into isoxazoles 152 upon reflux in ethanolic sodium ethoxide or treated with concentrated sulfuric acid.On the other hand when the reaction is conducted in ethanolic sodium ethoxide, isomeric 5-aminoisoxazoles 153 were produced. The depdence of the products on the applied reaction conditions is attributed to extra activation of cyano function in protic media.217 ARKAT USA, Inc.

Reduction
Reduction of arylhydrazone 16 at dropping mercury electrode proceeds in two successive 2e processes.Initially reductive cleavage of N-N bond occurs.This is followed by 2e reduction of C=NH yielding pi-functionally substituted amines.Again we believe that these results need to be rechecked as functional amines are unstable compounds and although may be formed in solution isolated products should be carefully identified by modern tools.The arylhydrazone moiety in 16 is reduced by sodium dithionate into aromatic amine and an α-amino ester.While in potassium borohydride (10%) reduction of carbonyl group was occurred (cf.Scheme 52). 230 Scheme 2 Scheme 4 Scheme 5 whose configuration have not yet been defined with certainty although structures have been assumed (
100has been recently observed that 42 couples with aromatic diazonium salt to yield arylglyoxal-2-arylhydrazones 45.Formation of intermediate iminium ion 43 is believed to hydrolyze to 44 that undergo a Japp-Klingemann cleavage to 45 (cf.Scheme 9).100 Thus carbon disulphide reacts with 16 to yield 95 via intermediate 94. similarly phenylisothiocyanate affords 97, most likely via intermediate 96.The reaction of 16 with chlorosulfonylisothiocyanate affords at 0-5 °C the chlorosulphonyl derivative 98 that is readily cyclized into 99 by aqueous KOH in presence of thiophenol.At 105-110 °C however enol form of 16 affords 101 via intermediacy of 100.