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Synthesis 2009(10): 1663-1666  
DOI: 10.1055/s-0028-1088055
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Hypervalent Iodine Mediated Oxidation of 1,2-Diaminobenzimidazole and Its Schiff Bases: Efficient Synthesis of 3-Amino-1,2,4-benzotriazine and 2-Aryl-1,2,4-triazolo[1,5-a]benzimidazoles

Ashok Kumar, Mahavir Parshad, Rakesh K. Gupta, Devinder Kumar*
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar 125001, Haryana, India
Fax: +91(01662)276240; e-Mail: dk_ic@yahoo.com;

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Publication History

Received 6 January 2009
Publication Date:
20 April 2009 (online)

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Abstract

Hypervalent iodine mediated oxidation of 1,2-diaminobenzimidazole and its Schiff bases is described. The reaction produces 3-amino-1,2,4-benzotriazine and 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles efficiently.

Key words

hypervalent iodine reagents - 1,2-diaminobenzimidazole - 1,2,4-benzotriazine - 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles

Hypervalent iodine compounds have gained much significance in view of their versatile applications and diverse chemical behavior in organic synthesis. [¹] In the recent past, there has been much research in the field of nitrogen heterocycles. 1,2-Diaminobenzimidazole and its derivatives are biologically important molecules and reactions with these molecules have generated a wide variety of heterocycles. [²] 1,2-Diaminobenzimidazoles have been shown to be potential antimalarial agents [³] as well as selective inhibitors of nitric oxide synthase. [4]

3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ), one of the most promising prodrugs, is currently in phase II and III clinical trials. [5] A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives that has recently been synthesized even show more hypotoxic-cytotoxic activity than TPZ itself. [6] Recently, [7-(2,6-dichlorophenyl)-5-methylbenzo[1,2,4]triazi-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine, which is a potent orally active Src inhibitor with desirable pK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth. [7] Similarly, triazolo[1,5-a]benzimidazoles, derived from 1,2-diaminobenzimidazole, have been found to possess antifungal, anti-inflammatory and analgesic [8] as well as anti-histamine effects. [9] Bearing in mind the biological importance of 1,2,4-benzotriazines and 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles, it was thought to be of interest to provide an efficient synthesis of these molecules by the oxidation of 1,2-diaminobenzimidazole and its Schiff bases utilizing hypervalent iodine reagents.

Oxidation of 1,2-Diaminobenzimidazole with Hypervalent Iodine Reagents

1,2-Diaminobenzimidazole (1), which was needed in the present study, was prepared from 2-aminobenzimidazole and hydroxylamine-O-sulphonic acid. 1,2-Diaminobenzimidazole (1), on stirring with iodobenzene diacetate [PhI(OAc)2] or polymer-supported iodobenzene diacetate (PSIBD) at 25 ˚C, efficiently afforded 3-amino-1,2,4-benzotriazine (3) exclusively in 80% yield via ring expansion of the imidazole nucleus (Scheme  [¹] ). The most probable mechanism for the ring expansion is best rationalized via the intermediacy of nitrene 2, generated by the initial attack of the 1-amino nitrogen on the electron-deficient iodine(III) reagent. The nitrene, so generated, inserts into the C-N bond to furnish 3. The benzotriazine was purified by column chromatography over silica gel (60-120 mesh) using hexane-ethyl acetate (4:1) as eluent.

Scheme 1

The structure of the benzotriazine was established by physical and spectroscopic techniques. The IR spectrum of the 3-amino-1,2,4-benzotriazine displays two broad absorptions at 3280 cm-¹ and 3148 cm-¹, due to the NH2 group, in addition to other bands. In the ¹H NMR spectrum, the NH2 protons appear at δ = 5.60 ppm as a broad singlet, the H-6 and H-7 protons resonate at δ = 7.78 and 7.50 ppm, respectively, the H-5 proton appears as doublet at δ = 7.62 ppm (J = 8.4 Hz), while the H-8 proton resonates as doublet of doublets at δ = 8.31 ppm (J = 8.4, 1.2 Hz).

Oxidation of 1,2-diaminobenzimidazole with either PhI(OAc)2 or PSIBD is a simple and efficient method of preparing 3-amino-1,2,4-benzotriazine (3) and illustrates the versatility of hypervalent iodine reagents in the oxidation of N-amino compounds. Furthermore, the obtained 3-amino-1,2,4-benzotriazine can be employed as a precursor for synthesizing 3-amino-1,2,4-benzotriazine-1,4-oxides (TPZ). [6] This method offers many advantages over similar oxidation reactions with 1,2-diaminobenzimidazoles using lead(IV) acetate [¹0] or manganese dioxide, [¹¹] to afford 3-amino-1,2,4-benzotriazines.

Oxidation of 2-Amino- N ¹ -(arylideneamino)benzimidazoles with Hypervalent Iodine Reagents

2-Amino-1-(arylideneamino)benzimidazoles (Schiff bases, 4) were obtained regioselectively from 1 and aryl­aldehydes in ethanol, in 76-81% yield (Scheme  [²] ). The regioselective formation of 4 may be attributed to the greater nucleophilicity of the 1-amino nitrogen as compared to the 2-amino nitrogen. The structure of Schiff bases was established by physical and spectroscopic techniques (IR, ¹H and ¹³C NMR and HRMS). The IR spectrum of the Schiff bases displayed two broad absorption bands at 3445±15 cm-¹ and 3050±20 cm-¹, corresponding to the NH2 group, in addition to other bands. In the ¹H NMR spectrum of 4b, the methoxy protons resonate at δ = 3.88 ppm, while the NH2 protons appeared as a broad singlet. The methine proton was found as singlet at δ = 8.88 ppm, in addition to other signals (see experimental). As expected, the molecular ion of 4b was found at m/z = 266.1171 (71%) in the HRMS. The characteristic fragmentation involves cleavage of the N-N bond to produce the 2-aminobenzimidazole radical cation [m/z = 132.0568 (100%)] as the base peak.

Scheme 2

Oxidation of 4 with either PhI(OAc)2 or PSIBD in dichloromethane at 25 ˚C resulted in the formation of 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles (5) in 48-57% yield, along with minor amounts (18-25%) of 3-amino-1,2,4-benzotriazine (3). The formation of 4 may be explained by the intramolecular participation of the 1-amino group, while 3 is probably formed due to partial cleavage of the Schiff base to generate the 1,2-diaminobenzimidazole (1), which is then available for further oxidation. The products were separated by column chromatography over silica gel (60-120 mesh) using hexane-ethyl acetate as eluent.

The structure of 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles (5) was established using physical and spectroscopic techniques (IR, NMR, HRMS). In particular, the IR spectrum of 5a showed absorption bands at 3038 cm-¹ due to N-H stretching and at 1679 cm-¹ and 1589 cm-¹ due to C=N stretching, in addition to other bands. The structure of 5a was established through NMR (¹H, ¹³C) and 2D NMR. The HRMS and fragmentation pattern of 5b was in complete agreement with the structure.

A plausible mechanistic pathway for the formation of 5 involves initial electrophilic attack of either PhI(OAc)2 or PSIBD on the C=N bond of 4, with simultaneous intramolecular nucleophilic participation of the 2-amino group, resulting in cyclic adduct 6. Reductive elimination of the iodobenzene or iodopolystyrene, in addition to acetic acid­, furnished 5 (Scheme  [³] ).

Scheme 3

Although 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles (5) may exist in three tautomeric forms (1H, 3H and 4H), NMR data revealed that it exists mostly in the 4H form (Figure  [¹] ). This observation has found support from a similar study that established the position of the tautomeric equilibrium by means of a number of physicochemical methods in conjunction with quantum-mechanical calculations and alkylation data. [¹²] The relative amount of the 4H tautomer in the equilibrium mixture was two to three orders of magnitude greater than the amount of 3H tautomer, while no evidence for the existence of the 1H form was found.

Figure 1

A number of reports describe the synthesis of 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles (5), for example, pyrolysis of 1-(2-benzimidazolyl)-5-1H-tetrazoles [¹³] and from the reaction of 1,2-diaminobenzimidazole with carboxylic anhydrides [¹4] [¹5] or formamides. [¹6] However, although compound 5 could not be obtained by the cyclization of 4 using copper(II) acetate monohydrate, [¹0] 2-methylamino-1-arylidenebenzimidazoles were converted into the corresponding triazolo[1,5-a]benzimidazoles on refluxing in nitrobenzene (20-30% yield), along with trace amounts of 2-methylaminobenzimidazole and aryl nitriles. [¹7] Biologically active 1-acyl-2-alkylthio-1,2,4-triazolo[2,3-a]benzimidazoles were also synthesized by the reaction of 1,2-diaminobenzimidazole with carbon disulfide in dimethyl formamide, followed by reaction with one equivalent of alkyl halide to give the corresponding 2-alkylthio-1,2,4-triazolo[2,3-a]benzimidazole and acylation with various acyl halides. [8] In the present study the reaction has been generalized and involves simple and efficient experimental techniques that result in good yields of pure product.

In conclusion, we have found that hypervalent iodine mediated oxidative reaction of 1,2-diaminobenzimidazole (1) led to the efficient synthesis of 3-amino-1,2,4-benzo­triazines (3), whereas 2-amino-1-(arylideneamino)benzimidazoles (Schiff bases, 4) produced 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles (5) in 48-57% yield. All the reactions were also carried out using 2% cross-linked polystyrene-supported (diacetoxyiodo)benzene (PSDIB). It was found that the reactivity, reaction time and yields of both approaches were comparable. However, the advantage of using PSDIB was that iodopolystyrene generated during the reaction could be filtered off and recycled to PSDIB for further use.

Melting points were determined in open capillaries and are uncorrected. FTIR spectra were obtained in KBr on either Shimadzu FTIR 8210 PC or Perkin-Elmer Spectrum RX1 instruments and are reported in cm-¹. ¹H and ¹³C NMR spectra were determined on a Bruker Avance II NMR spectrometer operating at 400 MHz and 100 MHz, respectively, in CDCl3 or CDCl3 + DMSO-d 6 and are expressed in ppm with respect to TMS. 2D-NMR spectra were scanned on a Bruker Avance II NMR spectrometer. Elemental analysis was carried out on a Perkin-Elmer 2400 instrument. HRMS were recorded on a VG 70 EB mass spectrometer and accurate mass measurements were made on a PE-Biosystems Mariner ESI-TOF mass spectrometer. All solvents were dried using standard procedures.

Oxidation of 1,2-Diaminobenzimidazole (1) to 3-Amino-1,2,4-benzotriazine (3) Using Iodobenzene Diacetate

Iodobenzene diacetate (708 mg, 2.2 mmol) was added to a suspension of 1,2-diaminobenzimidazole (1; 296 mg, 2 mmol) in CH2Cl2 (10 mL), and the resulting mixture was stirred at 25 ˚C for 40 min (TLC indicated the reaction was complete). Excess solvent was removed under reduced pressure at low temperature and the crude, gummy mass was purified by percolating through a short column of silica gel (60-120 mesh; hexane-EtOAc, 4:1) to afford the yellowish benzotriazine.

Yield: 80%; mp 206-207 ˚C (Lit. [¹0] 206 ˚C).

IR (KBr): 3235, 3090, 1665, 1545, 1201, 987, 764 cm-¹.

¹H NMR (CDCl3): δ = 5.60 (br s, 2 H, NH2), 7.50 (dd, J = 1.2, 7.6 Hz, 1 H, H-7), 7.62 (d, J = 8.4 Hz, 1 H, H-5), 7.78 (dd, J = 1.4, 7.7 Hz, 1 H, H-6), 8.31 (dd, J = 1.2, 8.4 Hz, 1 H, H-8).

Synthesis of Schiff Bases of 1,2-Diaminobenzimidazole; General Procedure

Appropriate aromatic aldehyde (10 mmol) was added to a solution of 1,2-diaminobenzimidazole (1; 1.48 g, 10 mmol) in anhydrous EtOH (20 mL) containing 3-4 drops of glacial AcOH. The resulting solution was refluxed for 10-12 h on a heating mantle. The solid obtained on cooling was collected at suction, washed with H2O (3 × 10 mL) and recrystallized form aq EtOH to afford the pure Schiff bases.

2-Amino- N ¹ -(4-methylbenzylideneamino)benzimidazole (4a)

Yield: 79%; mp 231-232 ˚C.

IR (KBr): 3441, 3079, 1659, 1611, 1551, 1491, 1439, 1412, 1354, 1302, 1265, 1139, 865, 729 cm-¹.

¹H NMR (CDCl3 + DMSO-d 6): δ = 2.42 (s, 3 H, CH3), 5.96 (br s, 2 H, NH2), 7.05 (dt, J = 1.4, 7.6 Hz, 1 H, 6-H), 7.13 (dt, J = 0.7, 7.7 Hz, 1 H, H-5), 7.29 (d, J = 7.9 Hz, 2 H, H-3′, H-5′), 7.37 (d, J = 7.5 Hz, 1 H, H-4), 7.60 (d, J = 7.8 Hz, 1 H, H-7), 7.79 (d, J = 8.0 Hz, 2 H, H-2′, H-6′), 8.89 (s, 1 H, N=CH).

¹³C NMR (CDCl3 + DMSO-d 6): δ = 21.02 (CH3), 109.3, 116.3, 119.3, 122.0, 127.0, 129.0, 130.4, 140.8, 141.2, 147.8, 153.2.

HRMS: m/z (%) calcd for C15H14N4: 250.1218; found: 250.1215 (59), 249.1141 (19), 133.0630 (26), 132.0565 (100), 105.0442 (38), 90.0342 (14).

2-Amino- N ¹ -(4-methoxybenzylideneamino)benzimidazole (4b)

Yield: 76%; mp 213-214 ˚C.

IR (KBr): 3437, 3024, 1660, 1606, 1552, 1514, 1481, 1452, 1417, 1359, 1303, 1255, 1168, 1028, 829, 719 cm-¹.

¹H NMR (CDCl3 + DMSO-d 6): δ = 3.88 (s, 3 H, OCH3), 5.86 (br s, 2 H, NH2), 7.00 (d, J = 8.0 Hz, 2 H, H-3′, H-5′), 7.05 (dt, J = 0.8, 7.6 Hz, 1 H, H-6), 7.13 (dt, J = 0.9, 7.6 Hz, 1 H, H-5), 7.37 (d, J = 7.5 Hz, 1 H, H-4), 7.59 (d, J = 7.8 Hz, 1 H, H-7), 7.83 (d, J = 8.8 Hz, 2 H, H-2′, H-6′), 8.88 (s, 1 H, N=CH).

¹³C NMR (CDCl3 + DMSO-d 6): δ = 54.8 (OCH3), 109.1, 113.7, 116.3, 119.2, 121.8, 125.6, 128.7, 129.0, 141.2, 148.0, 153.0, 161.3.

HRMS: m/z (%) calcd for C15H14N4O: 266.1167; found: 266.1171 (71), 265.1090 (18), 133.0629 (51), 132.0568 (100), 105.0461 (40), 90.0344 (23).

2-Amino- N ¹ -(4-chlorobenzylideneamino)benzimidazole (4c)

Yield: 81%; mp 210-211 ˚C.

IR (KBr): 3452, 3091, 1653, 1601, 1593, 1538, 1449, 1375, 1281, 1068, 1011, 819, 742 cm-¹.

¹H NMR (CDCl3 + DMSO-d 6): δ = 6.02 (br s, 2 H, NH2), 7.06 (t, J = 7.0, 7.4 Hz, 1 H, H-6), 7.15 (t, J = 7.2, 7.6 Hz, 1 H, H-5), 7.38 (d, J = 8.1 Hz, 1 H, H-4), 7.45 (d, J = 8.4 Hz, 2 H, H-3, H-5), 7.61 (d, J = 7.8 Hz, 1 H, H-7), 7.85 (d, J = 7.8 Hz, 2 H, H-2′, H-6′), 8.98 (s, 1 H, N=CH).

¹³C NMR (CDCl3 + DMSO-d 6): δ = 109.5, 116.3, 119.5, 122.4, 128.2, 128.5, 128.8, 131.8, 136.0, 141.1, 145.8, 153.1.

HRMS: m/z (%) calcd for C14H11ClN4: 272.0642, 270.0672; found: 272.0633 (13), 270.0662 (35), 133.0623 (23), 132.0569 (100), 105.0395 (38), 90.0345 (23).

2-Amino- N ¹ -(4-bromobenzylideneamino)benzimidazole (4d)

Yield: 80%; mp 224-225 ˚C.

IR (KBr): 3460, 3068, 1656, 1612, 1589, 1550, 1454, 1365, 1299, 1278, 1247, 1066, 1008, 817, 734 cm-¹.

¹H NMR (CDCl3 + DMSO-d 6): δ = 5.99 (br s, 2 H, NH2), 7.06 (t, J = 7.3, 8.0 Hz, 1 H, H-6), 7.15 (t, J = 7.2, 8.0 Hz, 1 H, H-5), 7.37 (d, J = 7.6 Hz, 1 H, H-4), 7.60-7.64 (m, 3 H, H-3′, H-5′, H-7), 7.80 (d, J = 8.4 Hz, 2 H, H-2, H-6), 8.89 (s, 1 H, N=CH).

¹³C NMR (CDCl3 + DMSO-d 6): δ = 109.5, 116.4, 119.4, 122.3, 124.4, 128.4, 128.9, 131.4, 132.2, 141.4, 145.6, 153.2.

HRMS: m/z (%) calcd for C14H11BrN4: 316.0146, 314.0167; found: 316.0148 (21), 314.0178 (22), 133.0611 (23), 132.0551 (100), 105.0442 (38), 90.0357 (22).

Oxidation of Schiff Bases to Triazolo[1,5- a ]benzimidazoles (5) and 3-Amino-1,2,4-benzotriazine (3); General Procedure

Iodobenzene diacetate (1.42 g, 4.2 mmol) was added to a suspension of the appropriate Schiff base (4 mmol) in CH2Cl2 (15 mL), whereupon the Schiff base started to dissolve and the reaction mixture became dark-brown. The reaction was stirred for 1 h at 25 ˚C, then excess solvent was removed under reduced pressure. The gummy mass, so obtained, was adsorbed on silica gel (60-120 mesh) and purified by chromatography (silica gel; hexane-EtOAc, 9:1→95:5) to isolate first 3-amino-1,2,4-benzotriazine (3) followed by triazolo[1,5-a]benzimidazoles (5).

2-(Methylphenyl)-1,2,4-triazolo[1,5- a ]benzimidazole (5a)

Yield: 56%; mp 116-117 ˚C (Lit. [¹³] 330-331 ˚C).

IR (KBr): 3314, 2927, 1606, 1560, 1504, 1448, 1394, 1328, 1236, 1103, 1010, 835, 763 cm-¹.

¹H NMR (CDCl3): δ = 2.47 (s, 3 H, CH3), 7.39 (d, J = 8.0 Hz, 2 H, H-3′, H-5′), 7.78-7.82 (m, 1 H, H-7), 7.92-7.96 (m, 1 H, H-6), 8.07 (d, J = 8.2 Hz, 1 H, H-5), 8.51 (dd, J = 0.7, 8.4 Hz, 1 H, H-8), 8.65 (d, J = 8.2 Hz, 2 H, H-2, H-6).

¹³C NMR (CDCl3): δ = 21.68 (CH3), 128.7, 129.1, 129.3, 129.6, 129.8, 129.9, 132.9, 135.4, 141.1, 141.9, 146.4, 159.9.

HRMS: m/z (%) calcd for C15H12N4: 248.1062; found: 248.1079 (100) [M+].

2-(Methoxyphenyl)-1,2,4-triazolo[1,5- a ]benzimidazole (5b)

Yield: 48%; mp 133-134 ˚C (Lit. 320-322 ˚C, [¹³] 168-170 ˚C¹8).

IR (KBr): 3398, 3023, 2890, 1584, 1501, 1388, 1285, 1225, 1091, 845, 735 cm-¹.

¹H NMR (CDCl3): δ = 3.92 (s, 3 H, OCH3), 7.09 (d, J = 8.9 Hz, 2 H, H-3, H-5), 7.76-7.78 (m, 1 H, H-7), 7.93 (dt, J = 1.2, 8.4 Hz, 1 H, H-6), 8.04 (d, J = 8.4 Hz, 1 H, H-5), 8.49 (d, J = 8.3 Hz, 1 H, H-5), 8.73 (d, J = 8.8 Hz, 2 H, H-2′, H-6′).

¹³C NMR (CDCl3): δ = 55.5 (OCH3), 114.4, 128.3, 129.0, 129.6, 130.5, 135.4, 141.4, 141.2, 146.2, 159.7, 162.5.

HRMS: m/z (%) calcd for C14H12N4O: 264.1011; found: 264.1003 (23) [M+], 237.0924 (76), 209.0843 (100), 166.0655 (36), 103.0422 (22), 90.0347 (33).

2-(Chlorophenyl)-1,2,4-triazolo[1,5- a ]benzimidazole (5c)

Yield: 55%; mp 142-143 ˚C (Lit. [¹³] 339-340 ˚C).

IR (KBr): 3442, 3038, 2852, 1667, 1589, 1498, 1390, 1240, 1089, 1006, 836, 764 cm-¹.

¹H NMR (CDCl3): δ = 7.56 (d, J = 8.6 Hz, 2 H, H-3′, H-5′), 7.86-7.89 (m, 1 H, H-7), 7.99 (t, J = 6.9, 7.8 Hz, 1 H, H-6), 8.09 (d, J = 8.4 Hz, 1 H, H-5), 8.54 (d, J = 8.3 Hz, 1 H, H-8), 8.72 (d, J = 8.6 Hz, 2 H, H-2′, H-6′).

¹³C NMR (CDCl3): δ = 129.1, 129.3, 129.7, 130.1, 130.5, 134.1, 135.8, 137.9, 141.0, 146.5, 159.0. HRMS: m/z (%) calcd for C14H9N4Cl: 268.0516; found: 268.0471 (100) [M+].

2-(Bromophenyl)-1,2,4-triazolo[1,5- a ]benzimidazole (5d)

Yield: 57%; mp 138-139 ˚C.

IR (KBr): 3401, 2927, 1585, 1488, 1466, 1388, 1325, 1278, 1165, 1066, 1002, 763, 725 cm-¹.

¹H NMR (CDCl3): δ = 7.70 (d, J = 8.6 Hz, 2 H, H-3′, H-5′), 7.86 (t, J = 1.2, 6.8 Hz, 1 H, H-7), 7.96-7.98 (m, 1 H, H-6), 8.08 (d, J = 8.5 Hz, 1 H, H-5), 8.54 (d, J = 8.44 Hz, 1 H, H-8), 8.64 (dd, J = 2.1, 9.28 Hz, 2 H, H-2′, H-6′).

¹³C NMR (CDCl3): δ = 126.5, 129.1, 129.6, 130.3, 130.5, 132.2, 134.5, 135.8, 141.0, 146.5, 159.0.

HRMS: m/z (%) calcd for C14H9N4Br: 312.0011; found: 312.0003 (100) [M+].

Acknowledgment

The authors are thankful to the University Grants Commission, New Delhi for financial support to Mr. Ashok Kumar (SRF). We also appreciate Mr. Avtar Singh of Panjab University, Chandigarh for recording NMR spectra efficiently. The mass spectrometry facility, University of California, USA is highly acknowledged for HRMS data.

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Scheme 1

Scheme 2

Scheme 3

Figure 1