Functionality of amidines and amidrazones

The review summarizes literature dealing with the synthesis of amidines and amidrazones including some of their physical and chemical properties along with their applications in heterocycles synthesis


Introduction
The amidino group in 1a, which contains an amino nitrogen atom with a free electron pair conjugated with the π-electrons of the C=N double bond, is the bis-nitrogen analogue of carboxylic acids and esters 2. 1 It combines the properties of an azomethine-like C=N double bond with an amide like C-N single bond with a partial double bond character as indicated by the resonance form 1b. 2 Amidines are strong bases (pKa ranges from 5-12).The protonation occurs on the imino nitrogen 4,5 leading to symmetrical amidinium ion 3 which is stabilized by resonance as in the isoelectronic carboxylate anion 4.
In a strong acidic media, the dication 5 is formed, which has a localized carbon-nitrogen double bond, whereas in a strong alkaline solution the anion 6 can be formed. 6 Numerous methods have been reported for the preparation of amidines. 9The most common methods of amidine synthesis are from amides, nitriles and/or thioamides.

Amidines from amides or carboxylic acids
Amides can be converted to imidoyl chlorides using phosphorous pentachloride.The forming imidoyl chlorides can react with primary or secondary amines to yield amidines (Scheme 1). 10 This method is generally poor for preparing unsubstituted amidines from primary amides, but it is an excellent general method for preparing di-and tri-substituted amidines.Other reagents such as phosphorous oxychloride or thionyl chloride can be employed in the synthesis of imidoyl chlorides but usually lower yields are obtained.

Scheme 2
Direct synthesis of amidines from carboxylic acids and amines can be performed via intermediate amides using polyphosphoric acid trimethylsilyl ester (PPSE), generated in situ from the reaction of phosphorus pentoxide with hexamethyldisiloxane as a condensing agent (Scheme 3). 12

Amidines from nitriles
Nitriles are activated to the intermediate salts in the presence of ethanol and hydrogen chloride under anhydrous conditions.The separated salts are then reacted with amines to generate the amidines shown in Scheme 4. 13,14 This method can be also considered as the most widely used procedure for the preparation of unsubstituted amidines.The direct synthesis of amidines from nitriles and amines can only be achieved if nitriles are substituted by electron-withdrawing groups. 15Unreactive nitriles have been used to prepare amidines in the presence of Lewis acids such as AlCl 3 or ZnCl 2 at elevated temperatures of 150-200 °C. 16Previously, it was shown that alkylchloroaluminum amides are useful reagents for the conversion of nitriles to amidines under milder conditions. 16It was found that 17 addition of alkylchloroaluminum amides, generated conveniently from trimethyl aluminum and ammonium chlorides, to nitriles in warm toluene efficiently afforded the desired amidines in reasonable yields after hydrolysis of aluminum species as shown in Schemes 5 and 6. + Moss 18 demonstrated that reaction of methylchloroaluminum amide with sterically hindered nitriles 7-10 produced the corresponding amidines (Scheme 6).

Scheme 6
A general preparation of amidines from unactivated nitriles has been reported. 19toichiometric copper(I) chloride induced addition of various amines to nitriles provided amidines in excellent yields (Scheme 7).Scheme 8 illustrates the catalytic use of Ln(III) ions in the addition of primary amines to unactivated nitriles to give intermediate mono-substituted amidines, which can react with another primary amine to yield di-substituted amidines. 20

R'NH
Substituted benzonitriles were converted into intermediate benzamidoximes, which are then successfully reduced to benzamidines, via palladium-catalyzed hydrogenolysis in acetic acid/acetic anhydride mixture (Scheme 9). 21Acetic anhydride was found to be a necessary acylating agent in providing useful reaction rates in the hydrogenolysis step.

Scheme 9
Iron pentacarbonyl was employed to the conversion of amidoximes into amidines via reductive cleavage of the N-O bond (Scheme 10). 22midates were prepared from nitriles in the presence of thiophenol and HBr (Scheme 11). 23henylthioimidates were readily converted to amidine salts in the presence of various amines.Previously, it was shown that addition of primary amines to ethylthioimidates under acidic conditions provided amidines (Scheme 12).

Scheme 12
Schäfer used N-acetylcysteine 11 to transform nitriles to thioimido intermediates 12, which reacted with ammonia to give amidine salts 13 (Scheme 13). 25The amidines are then isolated as their acetate salts via ion exchange.

Scheme 13
An efficient synthesis of amidinoformic acids 18 has been published using benzyl cyanoformate (14) as a synthon.Compound 14 was converted to the thioamide 15 in the presence of hydrogen sulfide (Scheme 14). 26

Cyclic Amidines
Cyclic optically active amidines are strongly basic compounds which can serve as chiral reagents for NMR analysis of enantiomeric mixture of weakly acid compounds, or as ligands in catalysts for enantioselective synthesis.Enantiopure C 2 -chiral amidines 22 were synthesized from diamines 19 and ∆ 2 -oxazolinium salts 20 or imidic ester salts 21 (Scheme 15). 27n interesting synthesis of cyclic amidine 24 from diamines 23 using trimethylorthoformate and formic acid at 100 ºC was also reported (Scheme 16).Similarly, amidines 30, derivatives of D-glucose were prepared from the reaction of thiolactam 29 as part of a study of inhibiting glycosidases (Scheme 19). 31A one-flask synthesis of 2-diethylamino-3-oxo-3H-indole (32) was prepared by the action of oxygen copper-catalyzed oxidation on 1H-indole (31)

Scheme 20
Bis-nitriles react with ethylenediamine and dry hydrogen sulfide in refluxing ethanol to afford cyclic diamidines 33 (Scheme 21). 33Mechanistically, the addition of hydrogen sulfide to the cyano groups of bis-nitriles afforded the corresponding bis-thioamides as shown in Scheme

Miscellaneous Amidines
The reaction of compound 35 with alcohols under Mitsunobu conditions gave amidines 36, which after hydrogenolysis afforded free amidines as noted in Scheme 22. Another synthetic approach to substituted amidines was established during the reactions of 35 with amines to give 37 followed by hydrogenolysis (Scheme 22).

Synthesis of amidrazones and amidoximes
The use of ammonia or amines in excess at high temperatures can displace one of the nitrogens of the amidino group (Scheme 24).

Scheme 24
Similar equilibria are also established with certain derivatives of ammonia such as hydrazines and hydroxylamines, e.g., phenylhydrazine hydrochloride heated with amidines yields amidrazones (Scheme 25).

Synthesis of heterocyclic derivatives
Cyclization is the most important reaction of amidines leading to various heterocyclic compounds containing the -N=C-N= group.

Scheme 28
The reaction of diphenylketene 42 with disubstituted amidines was attempted.Most of the formed β-lactams were very sensitive to moisture which led to their decomposition. 44Addition of 42 to a disubstituted amidine led only to an amide 45 (Scheme 29). 44

Amidrazones
Amidrazones are weak monoacid bases characterized by the structural formula 74, where R, R', R'', R''' and R'''' can be any of a wide variety of atomic or organic moieties.A particularly wellknown example of this class of compounds is aminoguanidine 75.The nomenclature applied to compounds of type 74 has been somewhat confusing, and sometimes the name hydrazidine [68][69][70] has also been used.Besides this, the name hydrazidine has been applied to compounds of type 76 which are also termed as hydrazide-hydrazones or dihydroformazans.These names cover, respectively, amidrazones of the types 77 and 78 (R' ≠ H) which are incapable of tautomerism.It is intended to adhere to the name amidrazone for all compounds of type 74 and furthermore to employ the nomenclature introduced by Rapoport and Bonner 71 as it is the least ambiguous.Amidrazone is named after the acid theoretically obtained from it by hydrolysis. 71Hence, CH 3 C(=NNH 2 )NH 2 is acetamidrazone, In addition, in compounds containing N substituents, the nitrogen atoms are numbered 71 as shown in formula 79 which is therefore named N 1 -phenyl-N 1 ,N Related compounds having the structure of 81 were initially termed dihydrazidines, but have become known as amide-azines. 72Again difficulty arises with these compounds when their structures preclude tautomerism (e.g., compound 82, R = C 6 H 5 ; R' = CH 3 ), and it may well be more convenient to consider compounds 81 and 82 as N,N'-diamidines.Formula 81 thus represents N 1 ,N 1 '-dimethyl-N 2 ,N 2 '-diphenyl-N 1 ,N 1 '-diformamidine.Otherwise, these compounds might be described as 1,2-seco-4,5-dihydro-syn-tetrazines 82 or diazabutadienes 81.

General properties
3][74] In the free state, amidrazones tend to be either liquids or low-melting solids, and unsubstituted amidrazones show strong reducing properties akin to hydrazine itself. 75Indeed these amidrazones are almost unknown in the free state, the perfluoroalkyl compounds being almost unique in having been successfully characterized. 76Thus amidrazones in general tend to be unstable in alkaline solution undergoing hydrolysis but are much more stable in acid; 77,78

Scheme 44
The enhanced stability of the ion over that of the free base can be seen in the light of resonance theory which has been applied to the closely related amidines. 79The free amidrazones can be looked on as mesomeric, but the charge separation in structure 83b suggests that it does not contribute greatly to the resonance hybrid (83a ↔ 83b).Amidrazones are divided into two classes: those able to exhibit tautomerism between N 2 and N 3 and those unable to exhibit this phenomenon.Although amidines of the type 87 have been reported to have been isolated in two distinct forms (87a and 87b), presumably due to the presence of the sulfonyl groups, 80 no substantiated claims for the isolation of any two tautomers of an amidrazone are known; the earlier claims of von Pechmann 39 have been proved false.

Spectral properties.
The IR spectra for perfluoroalkylamidrazones showed three mediumstrong bands in the 3500-3100 cm -1 region due to NH 2 and NH stretch.Two other strong bands in the 1700-1600 cm -1 region were assigned to C=N stretch (1690 cm -1 ) and NH 2 deformation (1655 cm -1 ).A weak band due to NH deformation was also noticed around 1690 cm -1 .The N 1 ,N 1 -dialkyl compounds also gave two bands in the region 3550-3380 cm -1 as well as the 1670 and 1655 cm -1 bands.N 3 -Arylamidrazones of the type ArC(=NNH 2 )NHAr have also been found to exhibit bands at 3427 and 3300 cm -1 , indicating interaction between the NH 2 and NH vibrations. 81RC 6 H 4 CH(OH)C(NH 2 )=NHNHC 6 H 5 X + -88 Optical rotatory dispersion measurements on the compounds 88 (R = H or CH 2 O, X = Cl) gave plain curves down to 285 mµ at which point light absorption proved too great for further examination.82 However, the (+)-amidrazone (-)-mandelate (88, R = CH 2 O; X = C 6 H 5 CH(OH)COO) exhibited a Cotton effect curve of high amplitude (+ 4260 peak 283 mµ; -7390 trough, 263 mµ), due probably to the presence of the various aromatic chromophores.82 The optically active amidrazone 88 (R = H) and its hydrochloride have been prepared by interaction of phenylhydrazine with ethyl (-) mandelimidate hydrochloride.83 N 1 -Phenylmethoxymandelamidrazone has been resolved by means of the mandelic acids.

From imidoyl halides with hydrazines or acid hydrazides.
This process is base on the reaction of an imidoyl halide with a substituted hydrazine. 91This reaction can give rise to two products if suitably chosen monosubstituted hydrazines are used.These products are the N 1 ,N 3and the N 2 ,N 5.2.7 From amides and thioamides 5.2.7.1 Amides.Amides provide a feasible starting point to the synthesis of amidrazones, either directly or via the imidoyl halide.A typical example of a direct synthesis is the condensation of an N,N-disubstituted amide with a substituted hydrazine in the presence of phosphorus oxychloride (Scheme 53).

Scheme 55
Sn/ HCl Scheme 55 5.2.9 Reduction of formazans and tetrazolium salts.The stepwise hydrogenation of tetrazolium salts and formazans has been studied (Scheme 56). 99,100The successful methods of reduction are (a) hydrogenation using 5% palladium on barium sulfate, (b) Raney nickel in methanol and (c) the use of sodium dithionite.The reduction process follows the sequence as outlined in Scheme 56. 99,100N Scheme 56 5.2.10 From heterocyclic systems.In addition to the tetrazolium salts, various heterocyclic systems have been used to prepare amidrazones through interaction with hydrazines, although the heterocyclic precursors themselves are not always easily formed.Thus the reaction of 1,3,4oxathiazoline 3-dioxide in dioxane solution with hydrazine gives good yields of amidrazones (Scheme 57). 101N

Industrial and Medicinal Applications of Amidrazones
A process has been described for obtaining thermally stable polymers containing amidrazones and/or 1,2,4-triazoles from, e.g., isophthalaldehyde and hexafluoroglutaramidrazone. 142A further patent describes the use of amidrazones, e.g., from heptafluorobutyronitrile and hydrazine, as intermediates in the synthesis of 2-perfluoroalkyl-5-aryl-1,3,4-triazoles which are useful as heattransfer media. 143,144Amidrazones and triazoles of the anthraquinone series have been described and used in the production of vat dyes; these include compounds of the types 129 and 130 in which R, R', and R'' are all aromatic groups of which at least one is an anthraquinone residue.Aminoguanidine is an important precursor for many useful compounds, 149 among them the plant growth regulator, 3-amino-1,2,4-triazole. 150 Amidrazones derived from nicotinic and isonicotinic acids among others have been tested for their pharmacological activity. 151,152yridine-4-carboxamidrazone is reported to be about half as effective as isoniazid in its tuberculostatic properties but only about one-half to one-third as toxic.Moreover, the isonicotinamidrazone-rifamycin-O reaction product has been found to be very active against gram positive microorganisms. 153,154Pteridine amidrazone or their aldehyde or ketone condensation products have been the subject of several patents as compounds that have diuretic and natiuretic properties. 155

33 34 Scheme 21
21. Addition of ethylenediamine to the bis-thioamides afforded the intermediate 34 after expulsion of ammonia.Finally, intramolecular cyclization of intermediate 34 provided 33 after elimination of hydrogen sulfide (Scheme 21). 38,39 42t in practice this reaction is not useful, since amidines like 40b are generally obtained from iminoethers (Scheme 26).42

5.2.1 Interaction of nitriles with hydrazines 5.2.1.1 Hydrazine. Nucleophilic
78tack of hydrazine on a cyanamide can lead to amidrazone (Scheme 45).84Herbicides of the general formula (CH 3 ) 2 NN=C(NH 2 )-C(NH 2 )=NNH 2 have been synthesized in a two step processes.78Thefirst step involves the reaction of the cyanogen with dimethylhydrazine in hexane at 5 ºC (Scheme 47).The second contains treatment of the resultant cyanoformamidrazone at higher temperatures with hydrazine in isopropyl alcohol (Scheme 47).

Scheme 47 Scheme 47 5.2.2 Interaction of nitriles with hydrazines
86A modification of the general procedure consists in the introduction of sodium into the reaction.Thus methylphenylhydrazine and benzonitrile in benzene were condensed in the presence of sodium to produce N 1 -methylphenylbenzamidrazone (Scheme 48).86

Scheme 48 Scheme 48 5.2.3 From imidates and their salts 5.2.3.1 Monosubstituted hydrazines.
Imidate salts react smoothly in alcohol at room temperatures with monosubstituted hydrazines.The products are mainly N 1 -substituted amidrazones, but in some cases formazans; such as, dihydroformazan, may form in these reactions.When two parts of hydrazine to one part of imidate are employed, the corresponding formazans are obtained in good yield (Scheme 49).

Reactions of amidrazones 5.3.1 Reaction with Grignard reagents.
104 formyl group of N1-formylformamidrazones (e.g.92) reacts with phenylmagnesium bromide to afford benzaldehyde and a small amount of benzhydrol.N 3 ,N 3 -Dimethyl-N 1 -phenyl-formamidrazone was found to give only a trace of benzaldehyde on treatment with the Grignard reagent (Scheme 59).104

.3 Condensation of amidrazones with aldehydes or ketones 5.3.3.1 Unsubstituted amidrazones. p
106luamidrazone gave compound 93 on treatment with benzaldehyde.Aminoguanidine reacts in similar reaction with aldehydes (Scheme 61).106Bladin 107 obtained two products from the action of excess benzaldehyde with an alcoholic solution of N 1 -phenylcyanoformamidrazone, namely a Schiff base 94 and a triazole 95 (Scheme 62).