Synthesis and properties of hydrazones bearing amide, thioamide and amidine functions

This review provides detailed methods for the synthesis, structures and chemical properties of hydrazones bearing carboxamide, thioamide and amidine functions. The main accent was put on the cyclization reactions leading to pyrazoles, thiazoles, 1,2,3-triazoles, 1,2,3-thiadiazoles, 1,2,4- triazines and other heterocyclic compounds. In addition, we have reviewed methods for the synthesis of substrates for pericyclic reactions from the hydrazones.


Introduction
Hydrazones and their derivatives constitute a versatile class of compounds in organic chemistry. These compounds have interesting biological properties, such as anti-inflammatory, analgesic, anticonvulsant, antituberculous, antitumor, anti-HIV and antimicrobial activity. 1 Hydrazones are important compounds for drug design, as possible ligands for metal complexes, organocatalysis and also for the syntheses of heterocyclic compounds. 2 The ease of preparation, increased hydrolytic stability relative to imines, and tendency toward crystallinity are all desirable characteristics of hydrazones. Due to these positive traits, hydrazones have been under study for a long time, but much of their basic chemistry remains unexplored. Hydrazones contain two connected nitrogen atoms of different nature and a C-N double bond that is conjugated with a lone electron pair of the terminal nitrogen atom. These structural fragments are mainly responsible for the physical and chemical properties of hydrazones ( Figure  1). Both nitrogen atoms of the hydrazone group are nucleophilic, although the amino type nitrogen is more reactive. The carbon atom of hydrazone group has both electrophilic and nucleophilic character. 3 Due to the capability to react with electropilic and nucleophilic reagents, hydrazones are widely used in organic synthesis, especially for the preparation of heterocyclic compounds. It is worth mentioning the synthesis of indoles 3 according to the Fischer reaction, 3a the synthesis of 4-thiazolidin-4-ones 4, 1a the synthesis of azetidines 5 4 by [2+2] cycloaddition and different syntheses of various five-membered heterocyclic compounds 6 by 1,3-dipolar cycloaddition of azomethine imines 5 that are formed by a 1,2-H-shift as depicted in the Scheme 1.

Scheme 1
The introduction of functional groups in the hydrazone molecules expands the scope of use of the latter in organic synthesis. Moreover, the combination of the hydrazono group with other functional groups leads to compounds with unique physical and chemical properties. Hydrazones containing a halo atom in α-or β-positions have been explored for many years as ways to generate nitrile imines 6 and 1,2-diaza-1,3-butadienes 7 that are active intermediates in cycloaddition chemistry. The amidrazones and thiosemicarbazones are well documented because of their biological activity and use in the synthesis of heterocyclic compounds. 3a,8 Synthetic approaches and chemical reactivity of the hydrazones substituted with ester and cyano groups were first reported in 1894 but new findings were continuously added, some only recently. 9 We are reporting here a review on the synthesis, spectral and chemical properties of hydrazones of type 7 containing amide, thioamide and amidine groups ( Figure 2). The structure 8 represents a special case where these groups are incorporated into a ring.  N X R 5 = Ph N X X = CH 2 , (CH 2 ) 2 , OCH 2

Scheme 2
The use of the benzyl protecting group allowed the authors 11f,g to obtain the bis-hydrazones 15 and 16. The first stage of the method is the condensation of the dihydrazines 12, where two nitrogen atoms are protected by benzyl groups, with two equivalents of methyl benzoylformate 13. Then bis(hydrazonoester) 14 was transformed into the bis(hydrazonoamide) 15 by the action of dimethylaluminium dimethylamide formed in situ by addition of dimethylamine to trimethylaluminium (Scheme 3). The benzyl groups were removed by hydrogenolysis at the last step.

Scheme 3
It is interesting to note that the reaction of N-methyl-α-chloroacetoacetamide 17 with ethyl carbazate in ethanol affords N-acylhydrazones 18 as the only product. The expected substitution of chlorine atom was not observed (Scheme 4)

Scheme 4
Since indole derivatives exhibit interesting biological properties, a series of hydrazones 20 bearing an amide group incorporated into an indole moiety were prepared by reactions of isatines 19 with hydrazines 9 (R 2 =H). 13 Compounds 20 (R 1 =4-SO 2 NH 2 C 6 H 4 ) represent a novel class of CDK2 (cyclin-dependent kinase 2) inhibitor (Scheme 5). Members of this series of inhibitors cause an arrest of the cell cycle and exhibit a selective killing effect on several tumor cell lines. 13a Hydrazones of angular isatines were synthesized to check their antiviral activity. 13b Compounds 20 with an acylhydrazono group prepared by this reaction exhibited the inhibition of cannabinoid receptors 2. 13c

Scheme 6
To improve this protocol, microwave-assisted organic synthesis was used. Under these conditions, a full conversion of the starting imines 21 into the desired 2-hydrazono-2Hchromenes 22 took place in a reduced (2 h to 2 min) reaction time. 14

Coupling of diazonium salts with active methylene compounds
The coupling of diazonium compounds with active methylene compounds is one of the oldest methods for the synthesis of arylhydrazones. 3, 10,15 In a typical reaction between compounds 23, containing two electron-withdrawing groups, with aryl(hetaryl)diazonium chloride 24 an unstable azo intermediate 25 is considered to form, which spontaneously tautomerizes into the hydrazone 26 (Scheme 7). The reaction is usually carried out in a cold aqueous solution buffered with sodium acetate, but the pH of the medium can be lowered for strongly activated methylene compounds.

Scheme 9
A series of arylhydrazonothioacetanilides 32 were prepared by the Japp-Klingemann reaction, which is an azo coupling accompanied by the elimination of one of the two electronwithdrawing groups such as COOH, COMe, CONH 2 and COOEt (Scheme 10

Scheme 10
The use of Japp-Klingemann reaction is also a convenient method for the synthesis of hydrazonoacetamides 34 bearing halogen atom (Scheme 11). 16g,20

Scheme 11
Isatine hydrazones 36 were prepared either by condensation of isatine with hydrazines 9 or by the alternative process of azo coupling of aryldiazonium salts 24 with indole-2-one 35 (Scheme 12). 21 The combination of two methods allowed to prepare a library of hydrazones 36 where R includes aryl, alkyl, carbamoyl and thiocarbamoyl moieties.

Scheme 14
These compounds are not stable and partial decomposition during the preparation takes place. To prepare these compounds one should keep the pH of medium well within the narrow interval of 4-5. 23a-c It is worth noting that the synthetic method for hydrazones by the azo coupling reaction is more suitable to prepare compounds bearing carbamoyl, thiocarbamoyl and amidine groups than the alternative method based on the reaction of carbonyl compounds with hydrazines.

Synthesis of hydrazones by modification of the substituents
Hydrazono-amides 42, 43 can be prepared by reaction of hydrazono-esters with amines or by hydrolysis of a cyano group of hydrazonomalononitriles (Scheme 15). 16l, 24 The reaction in sulfuric acid accompanied by sulfonation to give final compounds 43. These reactions are not widely used in organic synthesis because of the availability of hydrazono-amides by other methods.

Scheme 18
3-Hydrazonopyrazole-2-thione 52 was prepared by both thionation of amide 38 with Lawesson's reagent and by a two step synthesis via chlorination of 38 with phosphorus pentachloride followed by substitution of chlorine to the thione function by reaction with sodium sulfide (

Scheme 19
There are only few examples of the synthesis of 2-arylhydrazonoacetamidines 40 by reaction of aryldiazonium salts with malonamidines known (Scheme 14). The alternative route for the synthesis of this type of hydrazones is the reaction of 2-arylhydrazonomalononitriles 41 with amines 53 (Scheme 20). 24

Scheme 20
This method has been applied successfully to prepare amidines 54a,b,c derived from biologically relevant product moieties, such as tryptamine, cytisine and piperazine. 27 Addition of two molecules of glycine to malononitrile 41 took place under high temperature to form bis-amidine 55 that readily cyclized to bis-imidazolinone 56 in boiling glacial acetic acid (Scheme 21

Scheme 24
Indeed, reactions of carbonyl compounds with hydrazines, coupling of diazonium salts with malonamides, malonthioamides and malonamidines and elaboration of preformed hydrazones constitute an arsenal of synthetic methods to hydrazones containing amide, thioamide and amidine groups.

Structure of hydrazonoamides -thioamides and -amidines
The hydrazono-amide, -thioamide, and -amidine molecules contain a π-system of two double bonds and an NH-fragment that provides the basis for the azo-hydrazone tautomerism and Z,Estereoisomerism. The lone electron pairs of the heteroatoms and the NH-bonds can form hydrogen bonds and may stabilize both tautomer forms and stereoisomers. This section contain data on the azo-hydrazone tautomerism, the Z,E stereoisomerism and the hydrogen bonds.
The azo-hydrazone tautomerism has been investigated by numerous workers with a view to prove the existence of an equilibrium, to investigate the influence of substituents, solvents, temperature and to gain an understanding on the (non)existence of this thermodynamic equilibrium. 33 These investigations have been conducted by a combination of spectroscopic (IR, UV, NMR 1 H, 13 C, 15 N) and computational methods and they have shown the existence of most compounds in the form of hydrazones rather than azo compounds (Scheme 25). 3,9,11b,13a,16i, 16m,21,22a

Hydrazono-amides
The study of the fine structure of hydrazones by various spectral methods and by single crystal X-ray diffraction analysis has focused in major part on 2-hydrazonoacetamides. This is explained by the wide availability of many derivatives of this series and with their importance as pigments and biologically active compounds. 28,33 The absorption pattern in the UV region for hydrazono-amides substituted by keto-, cyano-, amino groups and by chlorine was in each case characterized by the presence of three bands. The first one is located in the range of 390-350 nm; the second band is located in the 290-250 nm region and the third one is below 240 nm. 16g-i,m,28a The introduction of electron-acceptor substituents to arylhydrazonoyl fragment was shown to lead to a bathochromic shift of the first band. 16m UV spectra of azo compounds are characterized by an intensive wave maximum at 270-280 nm. In contrast to azo compounds, a weak absorption band (or no band) for hydrazones is located at 284 to 295 nm and a strong absorption band is observed at 390-320 nm, which distinguishes these two types of compounds. 34 It is worth noting that this absorption is shifted to higher wavelength in the case of the E-isomer in comparison with the Z-isomer, possibly due to the different hydrogen bonding in both isomers. 28c Indeed the data of UV spectra are rather in accordance with the hydrazone than with the azo structure.

Scheme 26
The presence of a С=N bond in the molecules affects the position of the CN stretching, shifting it to 2220 см -1 . A shift of the CO bond stretching to lower wavenumber has been observed in the IR spectra of hydrazones 28, 34 due to both conjugation with C=N bond and formation of a hydrogen bond with the carbonyl group. 16h The 1 Н, 13 С and 15 N NMR spectroscopic techniques and an X-ray diffraction of single crystals are much more informative tools for the study of the fine structure of hydrazono-amides including information on Z,E-isomerism and hydrogen bonding.
The presence of a signal in the 1 Н NMR spectra in the region of 8-15 ppm gives evidence of the presence of an ArNH fragment and confirms the hydrazone structure. Furthermore, the downfield shift of this signal is characteristic for the formation of an intramolecular hydrogen bond of the NH proton. The amide proton (-NH-C=O) is found back as a singlet at δ 10.98-11.16, and the hydrazone proton (>C=N-NH) shows a singlet at δ 13. 90-14.32. 3,33b The strongest hydrogen bonds are presented in the amides of 2-hydrazonoacetoacetic acid 28 (X=O, R 4 =Ac). For this type of compounds, one can propose keto-hydrazone and azo-enol tautomer forms. The X-ray analysis of azo-pigment Maize 1 (28c) allows to rule out the azo-enol form 28c from consideration for crystalline state (Scheme 27 The signals of the NHN=C proton of hydrazonoyl chlorides 34 (X=Cl, R 1 =Ar, NR 2 R 3 =NHAr) in the 1 Н NMR spectra are upfield shifted in comparison with ketone hydrazones 63 and are slightly down shifted in comparison with arylhydrazone of acetone 64 (Scheme 28). 28a

Scheme 28
Similar to the trends seen in the 1 Н NMR spectra, the signal of iminyl carbon of hydrazonoyl chlorides 34 in the 13 C NMR spectra is upfield shifted for more than 25 ppm in comparison with acetone N-phenylhydrazones 64 and for 15 ppm in comparison with 2arylhydrazonoacetoacetates 63 (Scheme 28). 3, 35 The data of single crystal X-ray diffraction of of arylhydrazonoyl chloride 34 show the coplanarity of the amide and the hydrazono fragments with a deviation from planarity of only 7-9 о (Scheme 29). Two intramolecular hydrogen bonds N-H-Cl and N-H-N are present in the molecule as shown in Scheme 29. Both compounds, as shown by X-ray analysis, are Zconfigured. 28a

Scheme 29
NMR spectra of amidrazones of type 60 (Scheme 22) are rather complex and often contain sets of signals for protons of various isomers. The introduction of an amino group leads to the possibility of formation of new hydrogen bonds, that can stabilize stereoisomers with various positions of carbonyl and С=N bonds of the hydrazono group. Crude products of different reaction mixtures were investigated by 1 H NMR spectroscopy. It could be observed that the mixture contained variable amounts of E-isomers but always less than 50%. NOE experiments with compound 60a (R 1 =Ph, R 2 =Ph, NR 3 R 4 =NMe 2 ) revealed that it exists as a mixture of Z-and E-isomers (Scheme 30) where the Z-isomer is the major product. 28c

Scheme 30
In some cases, Z-and E-isomers of hydrazones 60 could be separated from the crude products by fractional crystallization or column chromatography. X-ray diffraction analysis of the hydrazones 60b,c confirmed that these compounds are Z-configured (Scheme 31). 28c

Scheme 31
Unfortunately, all efforts to get crystals of E-isomers 60a resulted in the isolation of crystals of an E/Z-isomer mixture in ratio 1:1 (Scheme 32 Similar to Z-60b,c, that is stabilized by two intramolecular hydrogen bonds (Scheme 31), E-60a has also two hydrogen bonds one of them is between the carbonyl oxygen atom and the NH of the hydrazono group and another one between the NH of the amide fragment and the oxygen atom of the carbonyl group of the Z/E-isomer 60a as shown in Scheme 32. The formation of two intramolecular hydrogen bonds is confirmed by the shift of signals for the amide NH proton and of the carbon signal the C=N-NHAr group of Z-60 that is upfield shifted in comparison with the E-isomer. On the contrary the proton signal of the hydrazono group is downfield shifted (Scheme 33

Scheme 33
Ab initio calculations, carried out at the RHF/6-31G* level 28c demonstrated that the Zisomers of compounds 60 containing either dimethylamino or morpholino groups at position 2 are thermodynamically more stable than the E-isomers. The energy differences between the Zand E-isomers range between 1.411 kcal/mol.
On the other hand, F. Krauth et al. 28d calculated the energy of Z-, and E-isomers for hydrazones 60 bearing a piperidine ring at position 2 by the B3LYP/6-31G(d) method and confirmed the higher stability of E-isomer for compounds 60d,e and equal stability for the isomers of 60f (Scheme 34).

Scheme 34
It is worth noting that intra-and intermolecular hydrogen bond interactions, which are identified in solid state of compounds 60 (Scheme 30-33), may not be present in polar solvents. All compounds were found to form E/Z-equilibrium in solution. 28

Hydrazono-thioamides
The fine structure of hydrazono-thioamides has been studied to a lesser extent as hydrazonoamides. As the rule, authors publish limited data sufficient to identify the common structure and purity of prepared compounds.
The study of the NMR spectra of thioamides 45 shows that the NH proton signals and the carbon signals of the С=N-NH fragment are downfield shifted in comparison with amide 11 as shown in Scheme 35. Single crystal X-ray diffraction analysis of compound 45a has shown that hydrazono-thioamides of this type mainly exist in the Z-isomeric form. 11b

Scheme 36
In the case of the presence of groups bearing heteroatoms with lone electron pair at position 4, an alternative hydrogen bond with the linker NH can be formed allowing the formation of the E(trans)-conformation. 13a 1 H NMR spectra of equilibrated samples 20c (R 1 =OPh) and 20d (R 1 = CONH 2 ) correspond to a mixture of Z-and E-isomers. For example, the 4-phenoxy derivate 20c was observed as 5 : 2 Z : E mixture after 10 days of equilibration (Scheme 37), and 20d was found as 1 :

Scheme 37
In principle, hydrazono-pyrazoles 38(X=O) and 52(X=S) (Schemes 13,19) can exist in four isomeric froms A-D (Scheme 38). 22a,d,36 As shown by NMR spectroscopy in solution and X-ray structural determinations in the solid state, the tautomer A represents the energy preferred isomeric forms for most compounds 38,52.

Scheme 38
To study the tautomerism of these compounds, 4-hydrazono-1H-pyrazol-5(4H)-ones 38 (X=O) labeled with 15 N in the NHR 1 fragment were synthesized and their 1 H NMR spectra were carefully studied. 22a In chloroform solution at 38 and 60 °C, the unlabeled material 38 a,b (X=O, R 1 =R 2 =Ph, R 3 =Me (a), X=NHPh, R 1 =R 2 =Ph, R 3 =Me (b)) gave a broad singlet at 13.5 ppm, whereas the compound labeled by 15 N showed a doublet at 13.5 ppm, indicative of a proton attached to 15 N. Since the value of the spin-spin coupling constant is quite large (J = 96 Hz), and since the area of the 15 N proton peaks relative to the aromatic protons was in good ratio, these compounds must exist entirely in the hydrazono form under these conditions. The presence of one 15 N-induced doublet in the 1 H NMR spectrum of 38a,b indicates that only one geometric isomer of the hydrazono form exists in this solvent, while the far-downfield position of the NH peak suggests that the proton is involved in strong intramolecular hydrogen bonds.

ISSN 1551-7012
determination support the formation of arylazopyrazolones as their hydrazone tautomers both in solution and the solid state.

Scheme 39
For the imino derivatives 38 (X=NR) the equilibrium is shifted to the amino-azo form B. 22d

Scheme 40
There are no NH proton signals in the 1 H NMR spectra of compounds 54 that would correspond to the hydrazono group. The signals of the amino groups of the amidine fragment are shown as a broad four proton singlet for compounds 54 (R 1 =R 2 =H) at 6.65 -7.18 ppm; as a one proton singlet and a two proton singlet for compounds 54 (R 1 =H, R 2 =Me, Cy) at 7. 15 -7.42 ppm; and as a two proton singlet for compounds 54 (NR 1 R 2 =NAlk 2 ) at 6.58-6.97 ppm. IR spectra of compounds 54 show a few broad bands between 3200-3450 cm -1 confirming the presence of amino groups. X-Ray diffraction analysis of single crystal for 54 (NR 1 R 2 =piperidin-1-yl, Ar=4-MeOC 6 H 4 ) show the existence of compounds 54 in the E,E-arylazo tautomeric form C with planarity of double bonds C=C and N=N bonds. It is worth noting the presence of the hydrogen bond of the amidine hydrogen with the nitrogen atom of the azo group as shown in Scheme 40.
Indeed, of hydrazonoamide, -thioamide and -amidine molecules contain hydrogen bonds that take part in stabilization of various isomeric forms. In contrast to hydrazonoamides andthioamides that exist in the hydrazono form, hydrazonoamidines exist preferably in the arylazo tautomeric form both in solution and in the solid state.

Chemical properties of hydrazono-amides, -thioamides and -amidines
Hydrazones exhibit a varied reactivity, taking part in reactions with nucleophiles, electrophiles and other chemical reagents. Being ambident nucleophiles, hydrazones react with electrophilic reagents with participation of either the nitrogen atom (compounds 65,66), 3a,10 or the carbon atom of the azomethine group (compounds 67). 3a

Reactions with nucleophiles
Hydrazones of aldehydes and ketones are prone to form the addition products to the C=N bond, rather than to form the products of substitution. In contrast, in the case of the presence of good leaving groups at the carbon atom, the substitution reactions occur smoothly to give compounds with new substituents. 6 The nucleophilic reagents that can be used in these reactions are alkali hydroxides, alkoxides, azides, ammonia, amines and hydrazines. Thus, substitution reaction of halogen by amines is used to prepare amidrazones 60 (Scheme 22).
The introduction of amide and thioamide groups to the molecules of hydrazones drastically expands the scope of these reactions. Most of such reactions are used to prepare new derivatives of hydrazones bearing amide, thioamide and amidine groups. Thus, 2-hydrazonoacetamides 11, isatine hydrazones 36, 49, and hydrazonopyrazolones 38 react with Lawesson's reagent to form the substitution products of the oxygen atom by sulfur, namely the thioamides 45-47,50,52 . The cyano group of hydrazonomalononitriles 41 is capable of adding hydrogen sulfide to give 2-hydrazonothioacetamide 44 (Scheme 16). Primary and secondary amines can also react with hydrazonomalononitriles 41 to form hydrazono-amidines 54 (Scheme 20).

Reactions with electrophiles
The introducing of amide, thioamide and amidine groups to molecules of hydrazones of aldehydes and ketones gives new centers that are capable of reacting with electropilic reagents. Alternative reactions can take place to give products of substitution at both hydrazono and new groups. Alkylation of arylhydrazones 28 (X=O) is directed to NH of hydrazono group to afford disubstituted hydrazones 75. This reaction can be recommended as the methods of choice to prepare disubstituted hydrazones of type 75 (Scheme 45). 16l,t,37

Scheme 44
Reactions of 2-аlkylhydrazono-2-phenylethanethioamides 45 with less polarizable electrophiles take place at the nitrogen atom of the thioamide function to give N-acyl (orsulfonyl)

Scheme 48
Indeed, the examples of the study of alkylation and acylation reactions of hydrazono-amides and thioamides are sometimes contradictive and not numerous enough to make conclusions on the general reactivity of these compounds in reactions of electrophilic substitution. They are not studied at all for hydrazono-amidines. More information on the matter can be found in part 4.4.

Oxidation and reduction
Oxidative substitution of hydrazono group by oxygen occurs when hydrazones 28 (X=O) were reacted with ozone at low temperature to form 1,2-dicarbonyl compounds 84 (Scheme 49

Scheme 49
Reduction of 2-phenylhydrazonoacetamidine 40a with zinc dust in acidic medium led to the cleavage of the hydrazono N-N bond to form 2,3-diamino-3-iminopropanamide 85 in good yield (Scheme 50). 23a

Use of hydrazono-amides, -thioamides and -amidines in the synthesis of heterocyclic compounds
The hydrazono-amide, -thioamide and -amidine molecules contain a number of nucleophilic and electrophilic centers. Therefore, one can envisage that these compounds will react with bifunctional chemical reagents to form cyclic systems. Depending on the nature of the reagents, and the reactivity of the nucleophilic and electrophilic centers of the hydrazones, different interactive combinations can be realized to afford a large variety of heterocyclic compounds (Figure 3). Heterocyclization reactions of compounds 7 are the result of the reactions (i) with bifunctional reagents bearing two electrophilic groups, (ii) with bifunctional reagents having one electrophilic and one nucleophilic group; (iii) by cycloaddition reactions; (iv) intramolecular condensation and (v) reactions with oxidation reagents.

Reactions with derivatives of formic acid, ketones, carbon disulfide and thiophosgene.
This part summarizes the literature on the reactions of bielectrophilic reagents providing one atom (carbon) to the newly formed heterocycle. Reactions of arylhydrazonoacetamides 28 (X=O, NR 2 R 3 =NH 2 ) with orthoesters 88 were shown to afford 1,2,4-triazinones 90 in high to moderate yields. A systematic study of the reaction conditions with variation of the solvent, temperature and catalyst led to a method of choice involving the use of dry boiling meta-xylene while azeotropically removing the ethanol formed (Scheme 52

Scheme 52
The reaction mechanism involves the formation of a double and a single C-N bond accompanied by the elimination of three molecules of ethanol. 2,5-Dihydro-1,2,4-triazines 90 are not stable in the presence of water and transform to acyl amides 91 presumably by addition of a molecule of water to the C=N bond of the 1,2,4-triazine ring, followed by cleavage of the C-N bond and formation of an acyl group. This process is accelerated by addition of acids.

Scheme 53
The formation of the product 89 (R 2 =Alk) confirms that the reaction mechanism of hydrazono-amides 28 (X=O, NR 2 R 3 =NH 2 , R 4 =CN) with orthoethers takes place via triazines 89 (R 2 =H) (Scheme 52). Tetrahydrotriazinones 89 (R 2 =Alk) are crystalline substances which are quite stable to acids and bases at room temperature but when boiled in ethanol with an equimolar amount of sulfuric acid they decompose to the starting hydrazones 28 (X=O).
In contrast to the reaction of derivatives 28 (X=O, NR 2 R 3 =NH 2 , R 4 =CN) with orthoesters 88 (Scheme 52), the reactions of compounds 28 (X=O, NR 2 R 3 =NHAlk, R 4 =CN) with triethyl orthoacetate 88b and orthopropionate 88c and the reaction of hydrazones 28 (X=O, NR 2 R 3 =NHPh, NHCy) with all types of orthoesters 88 leads to N-ethylhydrazones 93 (Scheme 54). Their formation was explained by the decrease in reactivity of the amide NH group of hydrazone 28 (X=O, NR 2 R 3 =NHCy, NHPh, R 4 =CN) by introducing of a bulkier aryl or cyclohexyl substituent that hinder cyclization of the intermediates. 16s Migration of the ethyl group to the N-atom of the hydrazone fragment and elimination of ethyl formate then occurs.

Scheme 54
Reactions of 2-arylhydrazonothioacetamides 28 (X=S) with ethyl orthoformate 88a, irrespective of the substituents, take place with participation of the nitrogen atoms of both the thioamide and hydrazono group to afford 1-aryl-1,4-dihydro-1,2,4-triazine-4-thiones 94 rather than thiazines 95 or triazine-4-ones 96 (Scheme 55). 17b The observed selective formation of product 96 in the reaction of thioamide 28 (X=S, NR 2 R 3 =NH 2 , R 4 =CONH 2 ) is indicative of the higher reactivity of the thioamide nitrogen in comparison to its sulfur atom; and also shows that the hydrazono NH group is more reactive than the carboxamide NH.  -2,5-dihydro-[1,2,4]triazines 94 similar to the corresponding 5-oxo-[1,2,4]triazines 90 are capable of transforming to formylthioamides 97 after heating at reflux in organic solvents in the presence trace of water. It is worth noting that compounds 94 are slightly more stable than their oxygen analogs 90.

Scheme 58
Reaction of amidrazones 60 with alkyl ketones 104 under acidic catalysis includes attack of the latter at the NH functions of the hydrazono and amino groups of compounds 60 to afford 4,5dihydro-1H-1,2,4-triazoles 105 (Scheme 59

Scheme 60
Reaction of hydrazones of type 40 with formamide takes place with participation of the amidine and C(X)NH 2 groups to give 5-phenylazopyrimidine 110. It is worth noting that the hydrazono group of compounds 40 does not take part in the cyclization process (Scheme 61

Scheme 61
Cyclocondensation of arylhydrazonoacetamides 28 (X=O) with carbon disulfide in pyridine at reflux temperature furnished the 1,2,4-triazinone derivative 112 in good yield. The formation of compound 112 is assumed to proceed via initial attack of the secondary amino group of hydrazone 28 (X=O) to the thiocarbonyl group of the carbon disulfide followed by intramolecular cyclisation accompanied by elimination of hydrogen sulfide (Scheme 62). 16u

Scheme 64
It is worth noting that the reaction of hydrazones 28 (X=O) with chloroacetyl chloride occurs on the nitrogen atom of the hydrazono group, similarly to the reaction with other acylating reagents.

Scheme 65
A plausible mechanism for the Thorpe reaction is proposed in Scheme 65. The initial HBr removal from α-bromo ketone or ester and α-arylhydrazononitriles 28 (X=O) resulting in intermediate 118 followed by the intramolecular nucleophilic addition of CH onto the nitrile group, gave imines 120 that could tautomerize to the aromatic enamines (4-amino-1-aryl-3,5substituted-1H-pyrazoles 121) . The yield of the reaction increased under microwave (Method D) and ultrasound (Method C) irradiation. 16w In contrast to 28 (X=O) the alkylation of unsubstituted thioamides 28 (X=S, NR 2 R 3 =NH 2 ) with bielectrophiles 122 is directed to the sulfur atom, generating thioimidates 123. Subsequent cyclization of the latter leads to thiazoles 124 (Scheme 66). 17b-e,42

Scheme 66
However, the introduction of a phenyl group at the nitrogen atom of the thiocarbamoyl radical leads to the formation of thiazol-2(3H)-ylidenes 126 and 4,5-dihydrothiophenes 127 or their mixture via both Hantsch (A) and Thorpe-Ziegler (B) pathways, respectively (Scheme 67 The formation of the thiophene ring in the reaction of N-phenylthioacetamides 28 (X=S, NR 2 R 3 =NHPh) with halo ketones 122 (R 6 =H) can be explained by the decrease of the nucleophilicity of the thioamide nitrogen atom and the higher acidity of the SCH 2 group of compounds with electron-withdrawing substituents that enhance the Thorpe-Ziegler reaction leading to thiophenes 127.
The arylhydrazone group does not participate directly in the reaction, but affects the direction of the cyclization since it is a "transmitter" of the electronic effects from rather distant parts of the molecule to the reaction site.
The reaction of arylhydrazonocyanothioacetamides 28 (X=S, NR 1 R 2 =Cy) containing an Ncyclohexyl fragment with chloroacetone, phenacyl bromide, ethyl chloroacetate, and chloroacetonitrile was studied and it was shown that such a substituent with a large steric effect in the thioamide group alters the direction of intramolecular cyclization of the thioimidate intermediate (Scheme 68). 17f,g Rather than the expected Hantsch reaction, which usually leads to the formation of thiazol-2(3H)-ylidenes 129 under these conditions, the only products were 3amino-4-arylhydrazono-4,5-dihydrothiophenes 130.

Reactions with of acetylene carboxylic esters.
Reactions of acetylenecarboxylic esters with compounds with a number of nucleophilic centers are of interest to organic chemists as convenient methods for the synthesis of various heterocyclic compounds. 43 Various directions for this reaction can take place, resulting in the formation of regio-and stereoisomers.

Scheme 69
The formation of a six-membered ring occurs in the reaction of 4-arylhydrazonopyrazole-5thiones 52 with of acetylene carboxylic esters 132 in methanol in the presence of triethylamine to afford thiazino-pyrazoles 134 as exclusive products. The hydrazono group does not take part in the formation of the bonds of the new ring, but enhances the formation of the final product, providing a hydrogen atom to the nitrogen-2 atom of the first ring (Scheme 70

Scheme 70
The reactions shown in the schemes 69 and 70 prove that the diene systems (C=N + C=S bonds) of compounds 28 (X=S) and 52 are not reactive, although the close structural analogs of 28, 2-cyanothioacrylamides readily react with DMAD, methyl propiolate, and N-phenyl maleimides via a 4+2 cycloaddition pathway to give thiopyrans, irrespective of the electronic or spatial effects of the substituents in the thioamide group and in position 3 of the 1-thiabuta-1,3diene system. 44

Reactions with reagents containing both electrophilic and nucleophilic functions.
Hydrazones can react with isothiocyanates to form compounds with a thiocarbamoyl group. In the case of presence of the cyano group at position 2 of the hydrazone, the highly electrophilic carbon atom of the intermediate thiosemicarbazone 135 undergoes cyclisation to 4,5-dihydro-ISSN 1551-7012 1,2,4-triazine-3(2H)-thiones 136. 45 Indeed, both nucleophilic and electrophilic centers of hydrazones 28 take part in the process of heterocyclization (Scheme 71

Scheme 71
Reaction of hydrazono-amidine 54 with phenylisothiocyanate begins with the attack of the latter to the NH of the amidine group, followed by the reaction of the cyano group with the thiocarbamoyl fragment to form 5-arylazo-4-imino-1,4-dihydropyrimidin-2-thiones 137. The hydrazono group does not take part in the reaction, other than of providing a hydrogen atom to the new ring (Scheme 72

Scheme 76
Active methylene compounds such as malononitrile and ethyl cyanoacetate 147 react with 2acetyl-2-hydrazonoacetamide 28 (X=O) in ethanol in the presence of a catalytic amount of piperidine to generate a hydrazone of type 148. 48 The latter, via interaction of the hydrazono group with cyano-or ester functions, affords 6-imino-and 6-oxo-pyridazines 149, respectively (Scheme 77).

Scheme 78
It is worth noting that highly electrophilic cyano-and keto groups located at position 4 often take part in a step of the heterocyclization process of hydrazones as shown in the Schemes 64,

Scheme 82
We have expanded this method, involving a large series of starting thioamido-hydrazones 28 (X=S) and using a number of oxidation reagents. The scope and limitations of the reaction were also determined. 25b In all cases, the oxidation of arylhydrazonothioacetamides with bromine in acetic acid afforded 5-imino-2,5-dihydro-1,2,3-thiadiazole salts 158 as the major products (Scheme 83). This process is characterized by good yields, with exception for the starting materials with a strong electron-acceptor substituent on the aromatic ring (CF 3 , NO 2 ). The oxidation of 4nitrophenylhydrazonothioacetamide 28 (X=S, R 1 =4-NO 2 C 6 H 4 ) with NCS afforded 1,2,4thiadiazoles 159 as the only cyclic product (Scheme 83).

Scheme 86
The successful synthesis of heterocycles 162 demonstrated that the oxidative cyclization of hydrazonothiocarbonyl compounds can be used for the synthesis of 1,2,3-thiadiazoles fused with other heterocyclic rings.

Scheme 89
It should be noted that in all cases the involvement of the primary rather than the secondary amino group in the oxidative cyclization process is observed. The scale of the present investigation shows that this reaction is a general method for the synthesis of a large variety 2aryl-2H-1,2,3-triazole-5-amines. Furthermore, this allowed to prepare compounds 165a and 165b with natural product moieties, e.g. tryptamine and the alkaloid cytisine.

Hydrazono-thioamides for the synthesis of substrates for pericyclic transformations
Due to the presence of electron lone pairs, the π-conjugated system and the mobility of some of their protons, arylhydrazones are often used as starting materials in the synthesis of active substrates for cycloaddition reactions. 6, 7 Gil et al. have found that reaction of arylhydrazonothioacetamides with acid chlorides or mesyl chloride in the presence of sodium hydride took place at the nitrogen atom of the thioamide group to form disubstituted thioamides 79 (Scheme 90). 11c In most cases compounds 79 are not isolated and undergo intramolecular cyclisation to give 6-acylamino-3,6-dihydro-2H-1,3,4-thiadiazines 167. This reaction passes probably through the zwitterionic form A which isomerizes to a tautomer B via 1,5-sigmatropic shift of hydrogen atom. In the latter the thiolate adds to the iminium carbon atom to form the final product (Scheme 90).

Scheme 90
We have found that 1,2-diazadienes 77, bearing an S,N-acetal group, that were obtained by the reaction of arylhydrazonoacetothioamides 28 (X=S) with haloalkanes (Scheme 43) take part in various pericyclic transformations. 26 It has been shown that on standing in CHCl 3 , benzene, acetone and acetonitrile at room or high temperature compounds 77 were gradually transformed into fused 1,2,4-triazines 168 as the main products in moderate yields. 26a (Scheme 91).

Scheme 91
Two mechanistic possibilities for the transformation of 3-allyl-and 3-prop-1-ynylsulfanyl-2arylazo-3-cycloalkylaminoacrylonitriles 77 to fused 1,2,4-triazines 168 were discussed. The first one can be described in analogy to cyclizations relying on the so called "tert-amino-effect" as compounds 77 contain both tert-amino function and a conjugated system. 51 An alternative mechanism depicted in Scheme 92 involves the elimination of R 5 H (propene in the case of allylthioimidates 77) to afford intermediate A, containing a conjugated hetero-hexatriene system. The latter undergoes a 6π-electrocyclic reaction to furnish the final product.

Scheme 92
The presence of allyl(propargyl)thio group along with active α-protons makes the compounds 77 well suited for the pericyclic group transfer reactions leading to final products 168 by elimination of propene(propyne) via intermediate A. It is worth noting that the formation of propene as the principal gas-phase product of the reaction for 77 (R 5 =Allyl) was confirmed by a GC-MS experiment.
Interestingly, another type of pericyclic reaction occurred when 3-alkylsulfanyl-3pyrrolidin-1-yl-2-arylazo-acrylonitrile 77 was treated with compounds that bear active triple and double bonds. 26b,c Thus, the reaction of compound 77 with DMAD is accomplished with elimination of alkylthiols to give the product of [3+2] addition, bicyclic pyrrole 170. Reactions with dimethyl maleate take place in a similar way to give the mixture of isomeric pyrrolizines 171. Compounds 173 containing three nonaromatic rings were prepared by treatment of N,Sthioacetals 77 with maleimides 172 in similar conditions (Scheme 93).

Scheme 93
The formation of these compounds was explained by a 1,3-dipolar cycloaddition of an in situ generated azomethine ylides. Experimental and theoretical investigation of the mechanisms of these reactions by DFT calculations allowed one to conclude that although the azo group is not included into the cyclic products it affects the mechanism of the generation of the azomethine ylides. The first step is a 1,6-hydrogen shift occurring in compounds 77 yielding the intermediate A (Scheme 94). The process depends on the type of the structural fragments on the sulfur and at the aromatic ring.

Conclusions
The introduction of amide, thioamide and amidine groups containing nucleophilic and electrophilic centers, electron lone pairs, mobile bonds C-heteroatom leads to new structural features and novel chemical reactions of hydrazones. The presence of several nucleophilic centers causes the hydrazones to react with various bielectrophilic reagents affording a variety of heterocyclic compounds. The presence of electrophilic centers leads to an increase of the possibilities for heterocyclizations. Both factors are the background to the use of functionalized hydrazones in the synthesis of heterocyclic compounds and for the preparations of substrates for the pericyclic reaction.