HETEROCYCLES

Review | Regular issue | Vol. 83, No. 12, 2011, pp. 2689-2730
Received, 4th July, 2011, Accepted, 25th August, 2011, Published online, 30th August, 2011.
DOI: 10.3987/REV-11-713

■ Synthetic Utilities of o-Phenylenediamines: Synthetic Approaches for Benzimidazoles, Quinoxalines and Benzo[1,5]diazepines

Magdy Ahmed Ibrahim*

Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11711, Egypt

Abstract

This review represents the methods developed for the synthesis of benzimidazoles, quinoxalines and benzo[1,5]diazepines from the condensation of o-phenylenediamines with a variety of electrophilic reagents.

CONTENTS
1. INTRODUCTION
2. SYNTHETIC APPROACHES FOR BENZIMIDAZOLE DERIVATIVES
3. SYNTHETIC APPROACHES FOR QUINOXALINE DERIVATIVES
4. SYNTHETIC APPROACHES FOR BENZO[1,5]DIAZEPINE DERIVATIVES
5. REFERENCES

1. INTRODUCTION
Heterocycles make up an exceedingly important class of compounds due to their expansive range of applications. They are predominant among all types of pharmaceuticals, agrochemicals and veterinary products.1–8 This comes as no surprise, since the most potent natural compounds and alkaloids are heterocyles. Nitrogen heterocycles in particular exhibit diverse biological and pharmacological activities9–11 due in part to the similarities with many natural and synthetic molecules with known biological significance.12 o-Phenylenediamines are good starting materials for the synthesis of a variety of heterocyclic rings especially benzimidazoles, quinoxalines and 1,5-benzodiazepines. The present review concerted on the utilities of o-phenylenediamines in the synthesis of benzimidazoles, quinoxalines and 1,5-benzodiazepines via chemical reactions with bifunctional electrophiles.

2. SYNTHETIC APPROACHES FOR BENZIMIDAZOLE DERIVATIVES
Benzimidazole nucleus is a constituent of several natural and non-natural products such as Vitamin B12,13 marine alkaloid kealiiquinone,14 benzimidazole nucleosides.15 Some of their derivatives are marketed as anti-fungal agents such as Carbendazim16 and anti-helmintic agents such as Mebendazole and Thiabendazole.17 Benzimidazole has been an important pharmacophore and privileged structure in medicinal chemistry, encompassing a plethora of useful biological activities such as antimicrobial,18–20 anticancer21–23 and anti HIV.24–26 Benzimidazoles are fundamental structural units not only in the pharmaceutical industry but also in several other fields such as agricultural, electronic, and polymer chemistry.27–30
Condensation reactions of o-phenylenediamines with mono electrophilic reagents represent one of the most important routes for the synthesis of benzimidazole derivatives. Carboxylic acids are the most important, thus, 1H-benzimidazole derivatives 2 were synthesized via condensation reactions of o-phenylenediamine 1 with carboxylic acid derivatives in the presence of 4.5N HCl or polyphosphoric acid (PPA). Methylation of compound 2 (R=Ph) gave the corresponding N-methylbenzimidazole 3.31-37

Also, fusion of 4-(1-adamantyl)-1,2-diaminobenzene dihydrochloride 4 with a variety carboxylic acids yielded the corresponding 5-(1-adamantyl)benzimidazoles 5.38

Condensation of 1 with anthranilic acid in PPA at 250 °C gave 2-(o-aminophenyl)benzimidazole 6.39,40 Ten new 2-o-arylideneaminophenylbenzimidazoles 7 were prepared via the condensation of 6 with various aryl aldehydes. 6-Arylbenzimidazo[1,2-c]quinazolines 8 as antimicrobial agents were obtained through oxidative cyclization of compounds 7.40

Condensation of o-phenylenediamine 1 with cinnamic acid derivatives 9 in boiling ethylene glycol gave 2-styrylbenzimidazole 10 in 91-99% yields.41

Likewise, condensation of 1 with α-hydroxycinnamic acids 11 in boiling water afforded 1-(1H-benzimidazol-2-yl)-2-(hydroxyphenyl)ethane derivatives 12.41

Heating o-phenylenediamines 1 with 1-bromo-2-naphthoic acid 13 in PPA gave 2-(1-bromo-2-naphthyl)-1H-benzimidazoles 14 which underwent N-allylation using allyl bromide in sodium hydride/THF to give 1-allyl-2-(1-bromo-2-naphthyl)benzimidazoles 15. Bu3SnH mediated cyclization of 15 in refluxing toluene afforded compounds 16.42

Condensation of o-phenylenediamine 1 with o-acylbenzoic acids 17 in refluxing toluene using catalytic amount of p-toluenesulfonic acid (p-TsOH) led to the formation of isoindolobenzimidazoles 18 in reasonable yields. Similar, condensation of 1 with aroylcyclohexane-2-carboxylic acids 19 gave hexahydroisoindolobenzimidazoles 20.43,44

Substituted 5H-benzimidazo[l,2-b]isoquinolin-11-ones 22 were synthesized in good yields (53-83%) by refluxing the appropriate o-phenylenediamines 1 with α-(o-carboxyphenyl)acetonitriles 21 in n-amyl alcohol.45

Reaction of 1 with lactic acid gave 2-(α-hydroxyethyl)benzimidazole 23. Compound 23 on oxidation with acid dichromate yielded 2-acetylbenzimidazole 24 which underwent N-methylation with dimethylsulfate in acetonitrile/potassium carbonate/triethylbenzyl ammonium chloride (as a phase-transfer catalyst), yielding the corresponding N-methylated compound 25. Bromination of 25 in acetic acid gave monobromoacetyl derivative 26 and its dibromo derivative 27.46

2,1,3-Benzothiadiazole-4,5-diamine 28 was condensed with various substituted coumarin-8-carboxaldehyde 29 and chromone-3-carboxaldehyde 30 in the presence of mercaptoacetic acid, in benzene under reflux, to give the corresponding coumarinylbenzothiadiazoles 31 and chromenylbenzothiadiazoles 32, respectively.47

On the other hand, aliphatic and aromatic aldehydes were good precursors for the formation of benzimidazole heterocycles. Thus, condensation of o-phenylenediamines 1 with aromatic aldehydes, in the presence of potassium ferrocyanide (acted as an oxidant in different solvents) or strongly acidic conditions gave 2-aryl-1H-benzimidazoles 2 in good yields.48,49

Also, it was reported that condensation of o-phenylenediamine 1 with some aromatic aldehydes in aqueous ethanol gave 2-aryl-1-arylmethyl-1H-benzimidazoles 33 in 37-95% yields not the other expected products 2.50,51

The catalytic effect of trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxolane in the presence of HCl has been explored in one-pot condensation reaction of 1 with a variety of aldehydes into their corresponding 2-aryl-1-arylmethylimidazoles 2. The reactions were conducted under mild conditions in MeCN at room temperature to afford the products in excellent yield.52

Compound 1 reacted with an equimolar amount of anthracene-9-carbaldehyde 34 to give N-(9-anthrylmethyl)benzene-1,2-diamine 35. Reactions of 35 with a series of substituted salicylaldehydes afforded N-(9-anthrylmethyl)-N′-arylmethylidenebenzene-1,2-diamines 36 which underwent oxidation with atmospheric oxygen to the corresponding benzimidazole derivatives 37.53

Reaction of 1 with bis-(3-benzoylquinoxaline) derivatives 38 in acetic acid under reflux gave bis-(benzimdizaolyl) derivatives 39.54

Condensation of 1 and phthaloyldicarboxaldehyde 40 in the presence of potassium cyanide and sodium hydrogen sulfite gave 2-(2-aminoaryl)-1-cyanoisoindoles 41. Diazotization of the latter compound gave isoindolo[2,1-c]benzo[1,2,4]triazines 42.55

Direct and efficient syntheses of the benzimidazo[2,1-a]isoquinolines 43 have been achieved with 2-bromoarylaldehydes, terminal alkynes and o-phenylenediamines 1 in the presence of palladium acetate as a catalyst under microwave irradiation process.56

Condensation of 1 with 2-(2-phenylethynyl)benzaldehyde 44 in refluxing nitrobenzene resulted in an oxidative cyclization to give 6-phenylbenzimidazo[2,1-a]isoquinoline 47 via intermediates 45 and 46.57

Cyclic anhydrides on treatment with o-phenylenediamines under different reaction conditions also afforded benzimidazole derivatives. Thus, 11H-isoindolo[2,1-a]benzimidazol-11-one derivatives 48 were mostly prepared from the condensation reaction of 1 and aromatic anhydrides on the surface of silica gel impregnated with ZnCl2 under solvent free microwave irradiation conditions or at 140-150 °C.58,59

Benzimidazolo[1,2-a]pyrrolidin-2-one derivative 50 was prepared from the reaction of 1 with E-fulgide 49 in boiling toluene.60

Similarly, isoindolobenzimidazolone 52 was prepared from heating phthalic anhydride with the pyridylphenylenediamine derivative 51 in boiling acetic anhydride.61

Refluxing isochroman-1,3-dione 53 with o-phenylenediamine 1 in glacial acetic acid gave 11H-benzimidazo[1,2-a]isoquinolin-11-one 54.62 Also, treatment of 1 with 1,8-naphthoic anhydride derivatives 55 gave the pentacyclic fused system; 7H-benzimidazo[2,1-a]benzo[d,e]isoquinolin-7-ones 56.63,64

Likewise, 2-N-ethylamino-5-methylbenzimidazo[1,2-a]quinoline 58 was formed in 18% yield when 7-diethylamino-4-methylcoumarin 57 reacted with compound 1 in the presence of PPA at 240 °C.65

The hydroxyisoindolobenzimidazole derivatives 61 and 62 were synthesized from condensation of 1 and 1,2-di(triflouroacetyl)benzene 59 and 3-benzylidenephthalide 60, respectively.66,67

Reaction of 1 with benzoxazinone 63 in boiling dioxane gave benzimidazole derivative 64, while, in the absence of solvents at 160 °C in an oil bath benzimidazo[1,2-c]quinazoline derivative 65 was obtained.68

Reaction of 1 with 3,4-diamino-2,5-dicarbethoxythieno[2.3-b]thiophene 66 in PPA gave 3,4-diamino-2,5-dihetarylthieno[2,3-b]thiophenes 67.69

Reaction of 1 with methyl cyanocarbamate 68 in acidic medium gave methyl 2-benzimidazolylcarbamate 69.70

Reaction of 1 with (3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)propanedinitrile 70 in ethanol at 20 °C gave 4-chloro-5-cyano-1,2,6-thiadiazino[3’,4’:5,4]pyrrolo[1,2-a]benzimidazole 71 via loss of HCl and NH3 molecules.71

Reaction of 1 with 2,5-bis(bromomethyl)benzene-1,4-dinitrile 72 in boiling DMF led to the formation of polycyclic skeleton 73.72

Cyclocondensation of 1 with hexachloroacetone 74 in ethylene glycol at 40–50 °C led to substituted bis-benzimidazoles 75.73

Reaction of o-phenylenediamine 1 with acid chloride 76 gave a mixture of monosubstituted derivative 77 and N,N’-disubstituted derivative 78. Treatment of both 77 and 78 with POCl3 yielded the same benzimidazole derivative 79.74

Chlorocyclohepta[b]pyrroles 80 reacted with o-phenylenediamine 1 to give 2-(2-aminoanilino)cyclohepta[b]pyrroles 81 in good yields. Treatment of 81 with PPA or p-TsOH in n-butanol afforded cycloheptapyrrolobenzimidazoles 82 in good yields.75

1H-Benzimidazole-2-thiols 83 were prepared by refluxing ethanol–water solution of sodium hydroxide, carbon disulfide and 4-(un)substituted-1,2-diaminobenzenes. The reaction between chloroacetic acid and 83 (R=H) in the presence of sodium hydroxide led to (benzimidazol-2-ylthio)acetic acids 84. 1,3-Thiazolo[3,2-a]benzimidazol-3(2H)-ones 85 were obtained by heating 84 and acetic anhydride in pyridine medium at 100 °C.76

In a similar manner for the synthesis of benzimidazoles, reaction of o-phenylenediamine 1 with phosphonyl dichloride in dry toluene in the presence of triethylamine gave the corresponding 2-(2-chloroethyl/allyl/benzyl)-2,3-dihydro-5-benzoyl-1H-1,3,2-benzodiazaphosphole-2-oxide 86.77 Also, treatment of 1 with 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent) afforded 1,3-dihydro-1,3,2-benzodiazaphosphole-2-sulfide-2-p-alkoxy(phenoxy)phenyl 87.78

3. SYNTHETIC APPROACHES FOR QUINOXALINE DERIVATIVES
Quinoxaline derivatives are the subject of considerable interest from both academic and industrial perspective.79-85 Quinoxalines possessing broad spectrum of biological activities including antiviral, antibacterial, anti-inflammatory, askinase inhibitors, anticancer, antitumor, antidepressant, antimycobacterial, cadiotonic and anthelmintic agents.86-95 Also, quinoxalines have been reported for their applications in dyes,96 pharmaceuticals97 and have also been used as building blocks for the synthesis of organic semiconductors.98,99 Moreover, quinoxaline ring is a part of various antibiotics such as Echinomycin, Levomycin and Actinoleutin100,101 that are known to inhibit growth of gram positive bacteria and are active aganist various transplantable tumors.102
A variety of synthetic strategies have been developed for the preparation of quinoxaline derivatives. One of the most common methods is the double condensation between aryl-1,2-diamines with 1,2-dicarbonyl compounds in refluxing ethanol or acetic acid for 2-12 h, to produce quinoxalines in 34-85% yields.103 From the synthesis standpoint, this traditional process generally requires high reaction temperature, strong acidic media, and mostly long reaction time.
A number of methods have been developed to improve the reaction conditions and yields. Thus, clay-catalyzed condensation of o-phenylenediamine 1 with 1,2-diketones 88 gave 2,3-disubstituted quinoxaline 89. In the presence of catalytic amounts NH4Cl104 or cerium trichloride105 the yield was improved in a very short time. Moreover, under microwave irradiation, quinoxaline derivatives 89 were obtained in 71-98% yields.106-108 Also, reaction of 1 with 1,2-diketones 88 in DMSO in the presence of iodine as a catalyst gave quinoxaline derivatives 89 in 85-95% yields.109

2,3-Disubstituted quinoxalines 89 (68-93% yields) were also prepared from reaction of 1 with benzil 88 at room temperature in the presence of different catalysts such as oxalic acid, ZnCl2, Mn(OAc)2, CoCl2, Ni(OAc)2 or silica bonded S-sulfonic acid (SBSSA).110,111 Similarly, dibenzo[a,c]phenazine derivatives 90 and acenaphtho[1,2-b]quinoxaline derivatives 91 were efficiently prepared from condensation of 1 with phenanthrene-9,10-dione and acenaphene-1,2-dione in the presence of SBSSA.111

Diaminopyrrolobenzimidazole 92 underwent condensation reaction with phenanthrene-9,10-dione in AcOH at reflux to give hepta-fused-heterocyclic system 93.112

Condensation of O,O-dimethyl derivative of diaminoquinazirin 94 with glyoxal or diacetyl in THF gave naphtha[2,3-g]quinoxaline-6,11-dione derivatives 95.113

Microwave-assisted reaction of o-phenylenediamine 1 with α-hydroxy ketones (acyloins such as benzoin) 96 in the presence of MnO2,114 acidic alumina,115 or Clay,116 as a catalyst gave 2,3-disubstituted-quinoxaline 89. The reaction was supposed to be carried out via a tandom oxidation process of acyloin to the corresponding 1,2-dicarbonyl compounds.

It was found that, in symmetrical diamines the product will be same irrespective of which amine participates first in the reaction as reported above. In case of unsymmetrical diamines, the substituents influence initial participation of a particular amino group in the reaction, resulting in region-specific products. The electron withdrawing/donating nature of substituents in diamine influenced the nucleophilicity of the amine group. Thus, reaction of 3-nitro-5-trifluoromethyl-1,2-phenylenediamine 97 with 1,2-diketones 88 gave quinoxaline derivatives 89 in 82-88% yields using MW and 66-75% yields under thermal conditions. It is presumed that the amino group meta to CF3 and NO2 groups participates initially in the Schiff base formation, while the other amino group could not participates initially because it is ortho to nitro and para to CF3 group which are considered to be powerful electron withdrawing groups and may reduce the nucleophilicity of amine. Hence the formation of other region isomer to compound 98 was not seen.117

Condensation of 4-benzoyl-1,2-phenylenediamine 99 with pyruvic acid in acetic acid at room temperature gave a mixture of 3-methylquinoxalinone 100 and the corresponding isomer 101. 6-Benzoyl-3-substituted-styryl-2(1H)-quinoxalinones 102 were obtained via fusion of 101 with aromatic aldehydes in the presence of piperidine at 160 ºC.118

1,2-Dihydro-3-substitutedquinoxalin-2-ones 104 were prepared by condensation of α-ketocarboxylic acids or corresponding esters 103 with diamine 1.119-131

Instead of α-ketocarboxylic acids or α-ketoesters, it is possible to use great variety of functional derivatives (e.g. oxalomonoimidic acid diethylester) to react with o-phenylenediamine 1 to produce 3-aminoquinoxalin-2-one 105 which on acetylation gave 3-acetylamino analogs 106.132-134

Also, treatment of 1 with coumarandione 107 yielded 3-(2-hydroxyphenyl)quinoxalin-2-ones 108.135

Haloesters are also very good starting compounds when reacted with o-phenylenediamine 1 to produce tetrahydroquinoxalines 109 which on dehydrogenation by hydrogen peroxide gave compounds 110.136

3-(2-Acetylaminophenyl)-1,2-dihydroquinoxaline-2-ones 112 were prepared by the reaction of N-acetylisatin 111 with 1,2-diamines 1 in acetic acid under reflux. The corresponding amino derivative 113 was then prepared by alkaline hydrolysis of 112. Boiling amino derivative 113 in acetic acid or phosphorus oxychloride furnished the fused system; indolo[2,3-b]quinoxalines 114. The diazotization of compound 114 afforded solution of the corresponding diazonium salts 115, which under thermal decomposition yielded [1]benzofuro[2,3-b]quinoxalines 116. Compounds 116 were split in alkaline medium into the 3-(2-hydroxyphenyl)-1,2-dihydroquinoxalin-2-ones 117. During decomposition of 115 with the presence of iodide ions, 3-(2-iodophenyl)-1,2-dihydroquinoxalines 118 were obtained.137-140

Coupling of diazonium salts 115 with 6,7-disubstituted-3-methyl-1,2-dihydroquinoxalin-2-ones, ethyl cyanoacetate and malononitrile gave the corresponding hydrazones 119-121. Hydrazones 121 were cyclized with hydrazine hydrate to the corresponding pyrazole derivatives 122.140

Instead of α-keto-carboxylic acids or α-ketoesters, it is possible to use great variety of functional derivatives including ureides and lactams (e.g. alloxane 123) to produce quinoxalines 124.141,142

Condensation of 1 with polyfluoroacyl pyruvates 125 resulted in the formation of 3-(2-oxofluoroalkylidene)-1,2,3,4-tetrahydroquinoxalin-2-ones 126 in 50-85% isolated yields. The same products 126 were obtained from chelates 127 and diamine 1.143

Reaction of 1 with 2-thienoylpyruvate 128 gave 2-chloro-3-(2’-thienoylmethyl)quinoxaline 130 via treatment of 2-hydroxy-3-(2’-thienoylmethyl)quinoxaline 129 with phosphorus oxychloride.144

Treatment of 2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)acetic acid esters 131 with o-phenylenediamine 1 gave the corresponding 3-(2-oxo-2,3-dihydro-1H-indol-3-yl)-3,4-dihydroquinoxaline-2(1H)-ones 132.145

Condensation of 5-fluoro-4-moephilino- and 5-fluoro-4-(4-methylpiperazino)-1,2-phenylenediamines 133 with 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine 134 gave a region-isomeric mixture of 8-fluoro-3-phenyl-1-phenyliminothiazolo[3,4-а]quinoxalin-4(5H)-ones 135 and 7-fluoro-3-phenyl-1-phenylimino-thiazolo[3,4-а]quinoxalin-(5H)-ones 136. Herein again, the use of unsymmetrically substituted 1,2-phenylenediamines resulted in the formation of a mixture of two isomeric thiazoloquinoxalones 135 and 136 in a ratio 2:3.146

Reaction of 1 with 1-(1-alkyl/aralkyl-1H-benzimidazol-2-yl)ethanone 137 in ethanol containing iodine gave 2-(1-methyl-1H-benzimidazole-2-yl)quinoxaline 138.147

Literature survey reveals that quinoxaline having coumarine constituent possesses antibacterial activity.148 o-Phenylenediamines 1 on reaction with various substituted 4-hydroxycoumarin 139 in ethanol under reflux afforded 2,9,10-trisubstituted-6-oxo-7,12-dihydrochromeno[3,4-b]quinoxalines 140 in 70-80% yields.149

2,3-Dihydroxy-6,7-dichloroquinoxaline 141 was synthesized in good yield by condensation of corresponding diamine 1 with oxalic acid in refluxing 4M hydrochloric acid.150 Chlorination of 141 gave 2,3,6,7-tetrachloroquinoxaline 142, which on subsequent reaction with sodium hydrogen sulfide gave of 2,3-dimercapto-6,7-dichloroquinoxaline 143 in quantitative yield.151 Partial ammonolysis of compound 143, using alcoholic ammonia, yielded 2-amino-3-mercapto-6,7-dichloroquinoxaline 144 in 70% yield. Acetylation of 144 using acetic anhydride under reflux afforded 2-methyl-6,7-dichlorothiazolo[4,5-b]quinoxaline 145 in 71% yield.152

Ethyl quinoxalin-3(4H)-on-2-ylacetate 147 was synthesized by reaction of 1 with sodium salt of diethyl oxalacetate 146 (prepared from diethyl oxalate and ethyl acetate in benzene in the presence of sodium) in acetic acid. Condensation of 147 with dialkylaminobenzaldehydes afforded the styryl disperse dyes 148 in 70-80% yields.153

Commercially available 2,3-diaminonaphthalene 149 was reacted with diethyl oxalate to give annulated quinoxalinedione 150 which under treatment with phosphorus oxychloride under reflux afforded dichloro derivative 151. Compound 151 was then reacted with propargylamine to give amino-chloro derivative 152, which was cyclized under acidic conditions to provide 1-methyl-4-chlorobenzimidazoquinaxoline 153. Compound 153 then served as a key intermediate to generate 4-amino-substituted analogues 154.154

Reaction of 1 with 3-benzoyl-2,3-dibromopropionic acid 155, in ethanol containing triethylamine, afforded 3-phenyl-2-carboxymethylene-1,2-dihydroquinoxalines 156.155

Condensation of 1 with 3,6,6-trichloro-2-hydroxy-2-cyclohexen-1-one 158, prepared by electrochemical reduction of 3,3,6,6-tetrachloro-1,2-cyclohexanedione 157, gave the corresponding intermediates 159 in high yields. Compounds 159 were converted into the corresponding 1-chlorophenazines 160 by simple treatment with 2,6-lutidine. Also, condensation of 1 with 157 gave the corresponding tetrachloro derivatives 161.156

Treatment of diaminocarbazole derivative 162 with ethyl bromopyruvate in N-methylpyrrolidine (NMP) containing triethylamine gave the fused system 163 in 29% yield.157

The reaction of o-phenylenediamine 1 with 4-bromo-3-sulfolanone 164, in the presence of dichloro-dicyanobenzoquinone (DDQ), yielded 1,3-dihydrothieno[3,4-b]quinoxaline-2,2-dioxide 165. Compound 165 was also prepared from the reaction of 3,4-dibromosulfolane 166 with o-phenylenediamine 1, followed by the dehydrogenation of tetrahydroquinoxaline intermediate 167.158,159

Diethyl dihydrothieno[3,4-b]quinoxaline-1,3-dicarboxylate 169 was obtained in 15% yield by the reaction of diester 168 and o-phenylenediamine 1 in acetic acid.160

Moreover, 2-benzoyl-3-phenylthieno[2,3-b]quinoxaline 171 was prepared via the condensation of thiophene-2,3-dione derivative 170 with o-phenylenediamine 1.161

Similarly, condensation of 1 with cyclic diketosulfone derivative 172 yielded 1,3-diphenyl-1,3-dihydrothieno[3,4-b]quinoxaline derivative 173.162

Condensation of benzothiophene-2,3-diones 174 with compound 1 has been reported to give the corresponding benzothiopheno[2,3-b]quinoxalines 175.163

Reaction of 1,4-dibromo-2,3-butanedione 176 with o-phenylenediamine 1 gave 2,3-di(bromomethyl)quinoxalines 177. Compounds 177 were converted into the corresponding dihydrothienoquinoxalines 178 by treatment with anhydrous sodium sulfide. Oxidation of 178 afforded compound 179 which on dehydrogenation gave thieno[3,4-b]quinoxalines 180.164,165

Reaction of 1 with 1,2-dibromophenylethane derivatives 181 and 182 gave tetrahydroquinoxaline derivatives 183 and 184, respectively.166

Reaction of pyruvic acids 185 and 186 with o-phenylenediamine 1 gave dihydroquinoxaline derivatives 187 and 188, respectively.166

Reaction of o-phenylenediamine 1 with epoxides 189 and chlorocyanohydrins 190 gave 2-alkoxycarbonyl-3-aryl-3,4-dihydroqouinoxalines 191 and 192, respectively.167

Reactions of o-phenylenediamine 1 with ethyl ethoxymethylidene-2,4-dioxo-4-pentafluoro-phenylbutanoate 193 gave 3-[2-(2-aminophenylamino)-1-pentafluorobenzoylethenyl]-1,2-dihydro-quinoxalin-2-one 194. The reaction was accompanied by condensation at the α-oxoester to form quinoxaline moiety and the second molecule of o-phenylenediamine 1 underwent replacement to the ethoxy group leading to product 194.168 Reaction of 1 with dialkylacetylene dicarboxylate 195 gave 3,4-dihydro-3-(alkoxycarbonylmethylene)quinoxalin-2(1H)-one 196.169

4. SYNTHETIC APPROACHES FOR BENZO[1,5]DIAZEPINE DERIVATIVES
Benzodiazepines and its derivatives constitute an important class of heterocyclic compounds which possess a wide range of therapeutic and pharmacological properties. Derivatives of benzodiazepines are widely used as anticonvulsant, antianxiety, analgesic, sedative, antidepressive, and hypnotic agents.170 In the last decade, the area of biological interest of 1,5-benzodiazepines has been extended to several diseases such as cancer, viral infection and cardiovascular disorders.171
The most common route to benzodiazepines is the condensation reactions between o-phenylenediamines and 1,3-bifunctional electrophiles. Thus, 1,5-benzodiazepines 197 were prepared via treatment of o-phenylenediamine 1 with ethyl acetoacetate and ethyl benzoylacetate.172,173

Similarly, heating 1 with acetyl/benzoyl acetone gave 1,5-benzodiazepines 198 in 69-92% yields.173

Also, treatment of 1 with 3-(l-adamantyl)-3-oxoethyl propionate 199, in boiling xylene, led to 4-adamantyl-1,5-benzodiazepin-2-one 200. Thionation the latter compound using phosphorus pentasulfide in boiling pyridine gave the corresponding thione derivative 201.174

2,4,6-Trichloro-1,3,5-triazine (TCT) efficiently catalyzed the condensation reactions between o-phenylenediamine 1 and various enolizable ketones to afford 1,5-benzodiazepines 202 in good to excellent yields. This method achieves cheap catalyst and easy workup.175

Likewise, bis-benzodiazepine 204 was prepared in moderate yield from the reaction of bis-diamine 203 with acetone in the presence of TCT.175

Also, 2,3-dihydro-1H-1,5-benzodiazepines 202 were synthesized in excellent yields (79-94%) via condensation of 1 with ketones having a hydrogen at α-position, using RuCl3·xH2O, ytterbium trichloride, sulfamic acid or p-nitrobenzoic acid as a catalyst.176-179

o-Phenylenediamine 1 on reaction with 2-benzylidene-3-oxoalkanoates 205 yielded benzodiazepines 206 together with benzimidazole 2.180

A convenient, solvent free and green approach for novel 1,5-benzodiazepines was achieved from the irradiation of ethyl acetoacetate and aromatic aldehydes for a sufficient interval of time followed by addition of o-phenylinediamine 1, which condenses with the intermediate and afforded the desired product 207 in 86-97% yields.181

Treatment of 1 with 3-[2-oxo-2-aryl(hetaryl)ethylidene]-1H-indol-2-ones 208 gave 1,3-dihydrospiro[1,5-benzodiazepine-2,3'-indole]-2'(1'H)-one 209 together with 3-[2-(2-aminophenylimino)-2-arylethylidene]-2,3-dihydro-1H-indol-2-ones 210.182

Reaction of o-phenylenediamine 1 with chalcones 211, in ethanol under strongly acidic conditions or DMSO containing fused sodium acetate, gave 2-(2-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)- phenols 212.183

1,5-Benzodiazepines 214 were synthesized in excellent yields by treating 1 with 1H-2-oxo-4-hydroxy-quinolin-3-yl-3-aryl-2-propenones 213 using catalytic amount of mesoporous zeolite MCM-41.184

Reaction of 1 with enaminone 215 gave 4-(3-O-benzyl-1,2-O-isopropylidene-α-d-xylotetrafuranos-4-yl)-1H-benzo[b][1,5]diazepine-3-carbonitrile 216.185

Condensation of 1 with ethyl 3-(5-chloro-1,3-diphenylpyrazole-4-methylidene)-2-cyanoacrylate 217 in boiling ethanol containing catalytic amount of piperidine afforded pyrazolo[3,4-b][1,5]-benzodiazepine derivative 220 via the non isolable intermediates 218 and 219.186

The reaction of 3-(isobutoxymethylene)pentane-2,4-dione derivatives 221 with various benzene-1,2-diamines gave 2,5-dihydro-2-trifluoroacetyl-2-trifluoromethyl-1H-benzo[b][1,5]diazepines 222 in moderate to high yields under very mild conditions.187

Methyl crotonic acid did not undergo any reaction with diamine 1 using 1:1 molar ratios of the reactants in 4N HCl under reflux. However, when the amount of methyl crotonic acid was doubled in the same experiment, the reaction occurred after thirteen hours of reflux and gave two pure crystalline products which were identified as 5-chloro-2-(1-isobutenyl)benzimidazole 223 and 7-chloro-4,4-dimethyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one 224.188

Reaction of 1 and methacrylic acid gave 2-(2'-propenyl)benzimidazole 225 and 3-methyl-1,2,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one 226.188

Reaction of 1 with 3-cyanochromone 227 gave (2-amino-1H-benzo[b][1,5]diazepin-3-yl)(2-hydroxyphenyl)methanone 229 via the non isolable intermediate 2-[(2-aminophenylimino)methyl]-3-hydroxy-3-(2-hydroxyphenyl) acrylonitrile 228.189

2,4,4-Trimethyl-3H-5-hydro-1,5-benzodiazepine 230 was obtained in 86% yield from the reaction of o-phenylenediamine 1 with acrylic acid at room temperature in the presence of acetonedicarboxylic acid (or acetone) as a catalyst.190

Reaction of 1 with methyl isothiocyanate gave N-(2-aminophenyl)-N’-methyl thiourea 231 which reacted with aromatic aldehydes in acetic acid to give 3-N-methyl-4-(substituted phenyl)-1,3,5-benzotriazepine-2-thiols 232 with 62-85% yield.191

Reaction of 2-acetyl-2-oxopropylidene S,S-acetal 233 with o-phenylenediamine 1, in 1:1 or 1:2 molar ratios in refluxing acetonitrile gave benzdiazepene 234, as well as benzodiazepino[5,6-e]benzodiazepine derivatives 235, respectively.192

Reaction of 1 with tetronic acid 236 or pyrone 177 led to binucleophilic enaminone intermediates 238 and 239, respectively. Under diazotization reaction, these two enaminones cyclized rapidly with good yields to generate benzotriazoles 240. On the other hand, when enaminones 238 and 239 were allowed to react with carbon disulfide in dimethylsulfoxide in the presence of a catalytic amount of pyridine gave novel condensed benzobenzodiazepin-2-thiones 241 fused to dihydropyrone or tetronic acid moieties.193

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