Among a large variety of nitrogen-containing heterocyclic compounds, heterocyclic containing hydrazine has received considerable attention because of their pharmacological properties and clinical applications [1-6]. Phthalazine derivatives were reported to possess anticonvulsant [7-10], cardiotonic [11], antitumor [12-16], antihypertensive [17-19], antithrombotic [20], a ntidiabetic [21,22], antimicrobial [23,24], antitry-panosomal [25], anti-inflammatory [26-32], cytotoxic [14], vasorelexant [19] and vascular endothelial growth factor receptor 11(VEGFR-2) inhibitory [33]. Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives [34-41]. These properties are more fully detailed in the supplementary material. The review comply published data on the synthesis of new phthalazine derivatives until 2013.

From hydrazine and hydrazine derivatives

Hydrazine and hydrazine derivatives are the most common reagents used for the synthesis of phthalazinone derivatives via their reactions with phthalic anhydride, phthalides, phthalimides etc.

Hydrazines with anhydrides: Several methods were reported for the preparation of phthalazinones derivatives. These methods mainly involve the reaction of phthalic anhydrides with hydrazine hydrate in the presence of acetic acid [42-44].

Phthalazinones 5,7-9 were synthesized from commercially available phthalic anhydride in 2-3 steps as depicted in (Scheme 1 and 2) [45-51].

Scheme 1: Synthesis of phthalazinone derivatives 2 and 5

Scheme 2: Synthesis of phthalazinone derivatives 7-9. Reagents and conditions: (a) CHCl₃, reflux, 5 h, 51%; (b) hydrazinehydrate, EtOH, addition at rt and then reflux, 90˚C, 2 h, 71%; (c) MeI, KOBut, DMF, 30 min, 80%; (d) LiOH, THF:MeOH:water (1:1:1), rt, 8–10 h, 81%.

Additionally, reaction of phthalic anhydride and aromatic hydrocarbons in the presence of anhydrous aluminum chloride under Friedel-Craft’s conditions afforded 2-aroylbenzoic acids 10 which treated with hydrazine hydrate and hydrazine derivatives to give the phthalazine (2H)-1-one 11,12 [52-57] (Scheme 3).

Scheme 3: Synthesis of phthalazin(2H)-1-one 11, 12

In 2006, Salvi et al. [58] reported that 2-[1-(4-oxo-3,4- dihydrophthalazin-1-yl)alkyl]-1H-isoindole-1,3-(2H)-diones 15 were obtained from fusion of phthalyl derivatives of amino acid 13 with phthalic anhydride in the presence of anhydrous sodium acetate followed by cyclization with hydrazine hydrate in n-butanol (Scheme 4).

Scheme 4: Synthesis of 2-[1-(4-oxo-3,4-dihydrophthalazin-1-yl)alkyl]-1H isoindole-1,3-(2H)-diones

Fifteen novel 1,4-disubstituted phthalazinylpiperazine derivatives were designed and synthesized using a convenient seven-step procedure starting from phthalic anhydride depicted in (Scheme 5). The cytotoxicities against A549, HT-29 and MDA-MB-231 cancer cell lines were tested [59]. An expeditious one-pot method has been developed for the synthesis of aryl, heteryl thiadiazinyl-phthalazin-1,4-diones via a multicomponent approach. Reaction of phenacyl bromides 22 with thiocarbohydrazide 23 and phthalic anhydride afforded corresponding aryl thiadiazinyl-phthalazine-1,4-diones 24 similarly, reaction of 3-(2-bromoacetyl) coumarins 25 with thiocarbohydrazide and phthalic anhydride afforded required heterylthiadiazinyl-phthalazine-1,4- diones 26 under the same reaction conditions in excellent yields [60] (Scheme 6).

Scheme 5: Synthesis of 1,4-disubstituted phthalazinylpiperazine derivatives 21

Scheme 6: One-pot Synthesis of thiadiazinyl-phthalazine-1,4-diones 24 and 26

Hydrazines with 2-acyl benzoic acids: Kirill et al. [31] reported the cyclization of 2-nitro-5-chloro phenylhydrazine27 with acyl benzoic acids 28 yielded 2-(2-nitro-5-chlorobenzene)-4-substituted phthalazin-1-ones 29 (Scheme 7).

Scheme 7: Synthesis of 4-substituted phthalazin-1-ones 29.

Lukacs and Simig [61] adopted a novel method for the synthesis of phthalazine derivatives 32 via the reaction of benzophenones30 with chromium (VI) oxide in a mixture of acetic anhydride and sulphuric acid followed by cyclization of the products with hydrazine hydrate in refluxing ethanol (Scheme 8).

Scheme 8: Synthesis of phthalazine derivatives 32

Hydrazine with 1,2-diester:The dimethylphthalate derivative 33 reacted with hydrazine to yield the desired phthalhydrazide34 which undergo chlorination with phosphorus oxychloride to give 35. Subsequent treatment with sodium methoxide afforded the methoxychloride 36 [62] (Scheme 9).

Scheme 9: Hydrazinolysis of dimethylphthalate derivative 33

Hydrazines with Phthalides: Chloroformylation of 3-methoxy benzoic acid 37 and subsequently radical bromination of 38 produced 39 in good yield. Treatment with triphenyl phosphine gave 40 and wittig olefination with 3,5-dichloro-4-pyridine carboxaldehyde 41 afforded the phthalide 42. Hydrazine cyclization of 42 resulted phthalazine derivative 43 [42] (Scheme 10).

Scheme 10: Synthesis of phthalazine derivative 43

Cockcroft et al. [12] synthesized the phthalazinone derivative 47 according the following (Scheme 11).

Scheme 11: Synthesis of phthalazinone derivative 47. Reagents and conditions (i) NaOMe/ MeOH/ reflux; (ii) NEt₃ / THF / reflux; (iii) N₂H₄.H₂O / reflux; (iv) a) aq. NaOH / THF; b) N₂H₄.H₂O / reflux

Hydrazines with phthalimide: Novel three-step method to prepare 4-substituted chlorophthalazines from phthalimide was reported [63] (Scheme 12).

Scheme 12: Synthesis of 4-substituted chlorophthalazines

Hydrazines with phthaloyl chloride: Recently [64] it was reported that the reaction of phthaloyl chloride 56 with N-methyl acetophenone hydrazones 57 leads to the formation of 2-ethenyl-3-methyl-2,3- dihydrophthalazine-1,4-diones 58 (Scheme 13).

Scheme 13: Synthesis of 2-ethenyl-3-methyl-2,3-dihydrophthalazine-1,4-diones 58

Hydrazines with 2-iodobenzyl bromide and diiodide: The systematic investigation of the cycloaminocarbonylation of bifunctional 2-iodobenzyl bromide and 1,2-diiodobenzene substrates towards tetrahydrophthalazin-one (tetrahydrophthalazindione) derivatives was described [65].

2-Iodobenzyl bromide 59 was reacted with hydrazine derivatives, such as methylhydrazine, phenylhydrazine, hydrazine, 1,2-dimethylhydrazine and 1,1-dimethyl hydrazine under atmospheric carbon monoxide pressure in DMF in the presence of palladium(0) catalysts generated in situ from palladium(II) acetate catalytic precursor and yielded the phthalazinones 60-64 (Scheme 14).

Scheme 14: Synthesis of phthalazinones 60-64.

1,2-Diiodobenzene 65 was reacted with hydrazines and gave the phthalazin-1,4-dione 66 together with side products (Scheme 15).

Scheme 15: Synthesis of phthalazin-1,4-dione 66.

Recently, practical synthesis of 2-substituted 1,2-dihydro phthalazines 69 that based on the reaction between 2-(bromomethyl) benzaldehyhdes and arylhydrazines under basic conditions and with FeCl₃ as the catalyst [66] (Scheme 16).

Scheme 16: Synthesis of 2-substituted 1,2-dihydro phthalazines 69

The reaction of 3,2-benzoxazin-4-ones with different nitrogen containing reagents, was successfully used in the preparation of different phthalazinone derivatives. For example, reaction of 1-aryl- 3,2-benzoxazin-4-ones 70 with hydrazine in refluxing ethanol yielded bis-phthalazinone 71.

Fusion of benzoxazin-4-one with ammonium acetate at 115°C gave 4-aryl-1(2H)-phthalazinone 72. The 4-aryl-2-(4-methylphenyl) phthalazinones 73 were obtained by reacting the benzoxazine-4-ones and p-toludine in refluxing ethanol [67]. In addition, Kassab [68] prepared 4-phenyl-1(2H) phthalazinone 72 by ammonolysis of 1-aryl- 3,2-benzoxazine-4-one with formamide (Scheme 17).

Scheme 17: Reaction of 1-aryl-3,2-benzoxazin-4-ones 82 with different nitrogen nucleophiles

Kassab et al. [69] used 3,1-benzoxazine-4-ones for the preparation of phthalazinone derivatives. Thus, the reaction of 3,1-benzoxazine- 4-one derivative 74 with thioglycolic acid in refluxing n-butanol yielded the 1-oxo-phthalazinyl thioglycolic acid derivative 75. In a similar manner [69] reaction of 74 with 2-amino pyridine in refluxing n-butanol gave 2-[2-(N-4-pyridyl-carboxamide) phenyl]-4-(4- bromophenyl) phthalazin-1-one 76 (Scheme 18).

Scheme 18: Synthesis of phthalazin-1-one 75, 76.

Inverse Diels-Alder reaction of tetrazine 77 with benzene cisdiol [70] 78 as a dienophile in CHCl₃ has been examined to give the addition product 81.

The adduct 81 was submitted to phenyl iodo-bis(trifluoroacetate) oxidation and yielded the fully aromatic compound 5-hydroxy phthalazine 82 was formed as the sole product in 62% yield. Furthermore, treatment of the adduct 81 with MnO₂and O₂ afforded phthalazine derivatives 83 and 84 (Scheme 19).

Scheme 19: Synthesis of phthalazine derivatives 83, 84

PyrazoloPhthalazines

Synthesis of highly functionalized 1H-pyrazolo[1,2-b]phthalazine- 1,2-dicarboxylates 87 via a one-pot isocyanide-based multi-component reactions (IMCRs) of various cyclic anhydrides, hydrazine hydrate, isocyanides 85 and dialkyl acetylene dicarboxylates 86 in EtOH/ acetone (1:1) at room temperature was reported [71,72] (Scheme 20).

Scheme 20: Synthesis of 1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates 87

One-pot four-component condensation reaction of phthalimide, hydrazine hydrate, aromatic aldehydes and malononitrile or ethyl cyanoacetate catalysed by Lewis acid NiCl₂.6H₂O was reported [73] to give 1H-pyrazolo[1,2-b] phthalazin-5,10-dione derivative 88 (Scheme 21).

Scheme 21: Synthesis of 1H-pyrazolo[1,2-b]phthalazin-5,10-dione derivative 88.

Treating pyrazolidindione 89 with 1,2-bis (bromomethyl) benzene 90 afforded the tricyclic 1H-pyrazolo[1,2-b] phthalazindione 91 [74] (Scheme 22).

Scheme 22: Synthesis of 1H-pyrazolo[1,2-b]phthalazindione 91

Pyrazolo[1,2-b]phthalazindione derivatives [75] were reported as anti-inflammatory, analgesic, antihypoxic and antipyretic agents [4]

There are only several literatures about the multi component synthesis for 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives, which were synthesized by a one pot three component reaction of phthalhydrazide, aromatic aldehydes and malononitrile or ethyl cyanoacetate catalyzed by PTSA [76], Et₃N [77] or [Bmim]OH [78].

Ghahremanzadeh et al. [76] synthesized 1H-pyrazolo [1,2-b] phthalazin-5,10-dione derivatives 92 via the simple condensation reaction of malononitrile or ethylcyanoacetate, phthalhydrazide and aldehydes in the presence of a catalytic amount of p-toluene sulphonic acid (PTSA) in ionic liquid 1-butyl-3-methyl imidazolium bromide as solvent at 100°C (Scheme 23).

Scheme 23: Synthesis of 1H-pyrazolo [1,2-b] phthalazin-5,10-dione derivatives 92

Recently, the synthesis of 2H-indazolo [2,1-b] phthalazintriones has been reported by Bazgir and co-workers using (PTSA) as catalyst [79].

A simple efficient and green practical approach to 1H-pyrazolo [1,2-b] phthalazine-5,10-diones 95 from phthalhydrazide, aldehydes and malononitrile/ethyl cyanoacetate has been developed that uses inexpensive and readily available InCl₃ as a catalyst in solvent free [80].

A schematic mechanism for the catalytic activity of InCl₃ in the synthesis of titled compounds 95 should be postulated as shown in (Scheme 24).

Scheme 24: A plausible mechanism for the synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-diones 95

The synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-dione derivatives 97 via condensation reaction of 2-chloro-3-formyl quinolines 96, malononitrile/ethyl cyanoacetate and 2,3-dihydro-1,4- phthalazinedione using a catalytic amount of piperidine in refluxing ethanol has been described. All the synthesized compounds were screened for their antibacterial activity against a panel of pathogenic strain of bacteria and fungi [81] (Scheme 25).

Scheme 25: Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 97.

A direct and efficient approach for the preparation of pyrazolo phthalazinyl spirooxindoles 99 has been developed through one-pot three-component reaction of easily available isatin, malononitrile or cyanoacetic ester, and phthalhydrazide catalyzed by nickel chloride in polyethylene glycol 600. Desired products were obtained in high to excellent yields using a simple workup procedure [82,83] (Scheme 26).

Scheme 26: Synthesis of pyrazolophthalazinyl spirooxindoles 99

Sonocatalysis synthesis of a novel class of spiroacenaphthylene- 1,1’-pyrazolo[1,2-b]phthalazines 101 via a facile, atom-economical and one pot three-component condensation reaction was investigated [84] (Scheme 27).

Scheme 27: Synthesis of spiroacenaphthylene-1,1’-pyrazolo[1,2-b]phthalazines 101

The1-{[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1H-pyrazolo[1,2-b] phthalazine-5,10-dione derivatives 104 were synthesized by a simple and efficient method, i.e., by the four-component, one-pot condensation reaction of phthalohydrazide, a (propargyloxy) benzaldehyde 102, an active methylene compound (malononitrile or ethyl cyanoacetate), and an azide103 in the presence of Cu(OAc)₂/sodium L-ascorbate as catalyst [85] (Scheme 28).

Scheme 28: Synthesis of 1-{[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1Hpyrazolo[1,2-b] phthalazine-5,10-dione derivatives 104

IndazoloPhthalazines

Shaterian et al. [86] reported an efficient method for the preparation of 2H-indazolo[2,1-b]phthalazine-triones derivatives 106 using silica sulfuric acid as recyclable solid acid catalyst under solvent-free conditions (Scheme 29).

Scheme 29: Synthesis of 2H-indazolo[2,1-b]phthalazine-triones derivatives 106.

A new green protocol has been developed for the synthesis of 2H-indazolo[1,2-b]phthalazine-triones 107 via one-pot, threecomponent condensation reaction of aromatic aldehydes with 1,3-dicarbonyl compounds and phthalhydrazide using reusable dodecylphosphonic acid (DPA) as heterogenous solid acid catalyst under solvent-free conditions. This protocol provides a novel and improved method for obtaining 2H-indazolo[1,2-b] phthalazinetriones in terms of good yields with little catalyst loading [87] (Scheme 30).

Scheme 30: Synthesis of 2H-indazolo[1,2-b] phthalazine-triones 107

1H-Imidazo Phthalazindiones

Kim et al. [14] reported a series of 1-substituted 2-methyl 1H-imidazo[4,5-g] phthalazine-4,9-dione derivatives 112 as depicted in (Scheme 31).

Scheme 31: Synthesis of 1H-imidazo[4,5-g] phthalazine-4,9-dione derivatives 112.

Yavari et al. [88] reported the synthesis of imidazophthalazines116 via nucleophilic substitution of chlorine atom with secondary alicyclic amines in the side benzene ring of phthalazine (Scheme 32).

Scheme 32: Synthesis of imidazo phthalazines 116.

[1,2,4] TriazoloPhthalazines

Lebsack et al. [75] synthesized [1,2,4]triazolo [3,4-a]phthalazine derivative 118 as follows: (Scheme 33).

Scheme 33: Synthesis of [1,2,4] triazolo [3,4-a]phthalazine derivative 118.

A general method is reported for the solid-phase synthesis of [1,2,4] triazolo [3,4-a] phthalazine 122 and tetrazolo [5,1-a] phthalazine derivatives 123 based on the cyclization of resin-bound chlorophthalazines with various hydrazides or sodium azide. The resin-bound chlorophthalazines produced by nucleophilic aromatic substitution reaction of dichloro-phthalazine with the secondary amines resins served as the key intermediate for subsequent triazolophthalazine resins and tetrazolophthalazine resins [40,89] (Scheme 34).

Scheme 34: Synthesis of [1,2,4] triazolo [3,4-a]phthalazine 122 and tetrazolo [5,1-a] phthalazine derivatives 123

4-(3,4-Dimethylphenyl)-1(2H)-phthalazinone 124 was used as key starting material for synthesis of fused [1,2,4] triazolophthalazines depending on the principles of lactam-lactim dynamic equilibrium phenomena [90,91] (Scheme 35).

Scheme 35: Synthesis of fused [1,2,4]triazolo phthalazines 127-129

Reaction with acetylinic compounds:

Ghahremanzadeh et al. [92] reported the reaction of phthalhydrazide and acetylene dicarboxylates in the presence of N-heterocycles to afford 130, 131 and 132 as follows: (Scheme 36).

Scheme 36: Reaction of phthalhydrazide with acetylene dicarboxylates.

Iwamoto et al. [93] reported that in the reaction of 1-substituted phthalazines with ynamines, there are three patterns of ring transformation giving naphthalene derivatives 133 through additioncyclization denitrogenation (type A), giving benzodiazocine derivatives 134 through addition-cyclization-ring expansion (type B) and giving pent substituted pyridine derivatives 135 through N-N bond cleavage of the pyridazine ring (type C) (Scheme 37).

Scheme 37: Reaction of phthalazines with ynamines.

A highly effected silver-catalysed formal inverse electron-demand Diel’s Alder (IEDDA) reaction of phthalazine 136 and siloxy alkynes 137 has been reported [94,95]. The reactions provided ready access to a wide range of siloxynaphthalenes 139 and anthracenes which are formed in good to high yields, under mild reaction conditions using low catalyst loadings (Scheme 38).

Scheme 38: Reaction of phthalazine 136 with siloxy alkynes 137.

A series of novel 3-(indolyl) prop-1-ynyl substituted phthalazines 142 were prepared via a concise pathway by palladium catalyzed cross coupling of appropriate halogens 140 and N-propargylindoles 141 [15,96] (Scheme 39).

Scheme 39: Synthesis of 3-(indolyl) prop-1-ynyl substituted phthalazines 142.

Reaction with Amines: (Nucleophilic substitution reactions)

The activity of halogen attached to either or both carbons of the azine ring was analogous to similar activity in 2-or 4-halogenoquinolines. In general the reaction of 1-halogeno or 1,4-dihalogeno phthalazines with ammonium derivatives (primary or secondary amines) [97] afforded 144.

Snaz et al. [98] showed the synthesis of mono and bi (alkyl amino) benzo [g] phthalazine derivatives 145 and 146 as follow: (Scheme 40).

Scheme 40: Synthesis of benzo[g] phthalazine derivatives 145 and 146.

It has been achieved [99] by the reaction of 1,4-dichlorobenzo[g] phthalazine with the corresponding poly amines a new series of mono and binuclear 1-alkylamino-4-chlorobenzo[g]phthalazine derivatives 147-149 containing flexible polyaminic chains. (Scheme 41)

Scheme 41: Synthesis of 1-alkylamino-4-chlorobenzo[g]phthalazine derivatives 147-149.

Piatnitski et al. [100] reported that, commercially available 1,4-dichlorophthalazine 150 was first reacted with an amine to give the mono substituted adduct 151 [101]. The remaining chloride was then coupled with boronic acid or boronic acid ester under Suzuki reaction conditions with microwave irradiation to give the desired final compound 152 (Scheme 42).

Scheme 42: Reaction of 1,4-dichlorophthalazine 150 with amine

Reaction with chalcones

Cyclocondensation of 1-aryl-3-ferrocenyl-2-propen-1-ones 153 with hetaryl hydrazine resulted in N-hetaryl-3-aryl-5-ferrocenyl pyrazolines155 [102] (Scheme 43).

Scheme 43: Synthesis of N-hetaryl-3-aryl-5-ferrocenyl pyrazolines 155.

Alkylation

Treatment of phthalazine or its alkyl derivatives with alkyl halides yields N-alkyl phthalazinium halides 156 and when treated with Ag₂O and KOH afforded the N-alkyl derivatives 157 and 158, respectively [103] (Scheme 44).

Scheme 44: Reaction of phthalazine with alkyl halides

A novel series of phthalazine derivatives bearing isoindol- 1,3-dione moiety were synthesized by treating 2-(4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl)isoindoline-1,3-dione 159 with various chemical alkylating reagents [104,105] (Scheme 45).

Scheme 45: Synthesis of novel phthalazine derivatives bearing isoindol-1,3-dione moiety

4-(3,4-Dimethylphenyl)-1(2H)-phthalazinone 124 was used as key starting material for synthesis a new series of 1,4-disubstituted phthalazines, and 2,4-disubstituted phthalazinones depending on the principles of lactam-lactim dynamic equilibrium phenomena [90,91] (Scheme 46).

Scheme 46: Synthesis of a new series of 1,4-disubstituted phthalazines, and 2,4-disubstituted phthalazinones.

Acylation

Acylation of 2-benzyl-2,3-dihydrophthalazine-1,4-dione 167 with 2-(bromomethyl)-benzoyl chloride 168 yielded 169 [106] (Scheme 47).

Scheme 47: Acylation of 2-benzyl-2,3-dihydrophthalazine-1,4-dione.

Reaction with galactopyranose and ribofuranose

Coupling of trimethylsilyl derivative of (2H) phthalazine-1-one 170 with 1,2,3,4,6-penta-O-acetyl-α-D-galactopyranose 171 in the presence of stannic chloride gave the respective glycosides, 2-(per-Oacetyl- D-glycosyloxy) phthalazines 172. Under the same conditions 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose 173 gave 1-(2,3,5-tri-Oacetyl- α-D-ribofuranosyloxy) phthalazine 174 [16] (Scheme 48).

Scheme 48: Coupling of trimethylsilyl derivative of (2H) phthalazine-1-one 170 with galactopyranose and ribofuranose.