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Supporting Information

Cobalt-catalyzed isocyanide insertion cyclization to dihydrobenzoimidazotriazins

Fereshteh Ahmadi, Peiman Mirzaei, Ayoob Bazgir*

Department of Chemistry, Shahid Beheshti University, General Campus, Tehran

1983963113, Iran.

E-mail: [email protected]

ContentsMaterials and Methods......................................................................................................S1

General procedure for synthesis of 3.................................................................................S2

Characterization data of all products.................................................................................S2-S6

Mechanism .......................................................................................................................S6

Reference...........................................................................................................................S71H and 13C NMR spectra of all products............................................................................S8-S27

Materials and Methods. Melting points were determined with a melting point Thermo

Scientific 9100 apparatus and are uncorrected. IR spectra were taken with a Bomem FT-IR MB

spectrometer. NMR spectra were recorded with 300 and 250 MHz Bruker DRX Avance

spectrometers. MS spectra were recorded with a Finnigan LCQ mass spectrometer in negative

ion mode.

All chemicals were purchased from Merck or Aldrich and were used without further purification.

General procedure for the synthesis of 1-(1H-benzo[d]imidazol-2-yl)guanidine (1a):

*Keywords: Isocyanide insertion, Cobalt-catalyzed isocyanide insertion, benzoimidazotriazine, Triazine.* Correspondence author: Fax +98-21-22431661; E-mail: [email protected] ;

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mailto:[email protected]

mailto:[email protected]%20;

The mixture of the appropriate o-phenylenediamine, (0.1 mol), cyanoguanidine (8.4 g, 0.1 mol)

and conc. hydrochloric acid (20 mL, 0.2 mol) in 200 mL of water was heated under reflux for 1

h. Then, the mixture cooled to 0 °C and 50 mL of 10% solution of potassium hydroxide was

added slowly. Precipitated 2-guanidinobenzimidazole 1a was filtered, washed with water, dried

and used in subsequent steps of the reactions without further purification [1].

General procedure for the synthesis of N4-(tert-butyl)benzo[4,5]imidazo[1,2-a]

[1,3,5]triazine-2,4(1H,3H)-diimine (3a):

A mixture of 1-(1H-benzo[d]imidazol-2-yl)guanidine 1a (0.5 mmol), t-buthyl isocyanide 2a

(0.75 mmol), Co(OAc)2.4H2O (0.05 mmol), K2CO3 (0.5 mmol) and K2S2O8 (0.5 mmol) in DMF

was stirred overnight at 80 ͦ C. After the completion of the reaction, the solvent was removed and

the residue was purified by column chromatography over silica gel using ethyl acetate/MeOH

(9:1) as eluent to give the desired product 3a.

N4-(tert-butyl)benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2,4-diamine

(3a). Cream powder (yield 64%); m.p. 248-250 ˚C. IR (KBr) (νmax /cm-1):

3429, 3151, 2965, 2906, 1633, 1546. MS (EI, 70 eV) m/z: 256 (M+).1H

NMR (300 MHz, DMSO-δ6) δH (ppm) 7.71 (1H, d, 3JHH = 9.0 Hz, H–Ar),

7.45 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.30 (1H, t, 3JHH = 9.0 Hz, H–Ar), 7.14 (1H, t, 3JHH = 9.0 Hz,

H–Ar), 7.01 (2H, s, NH2), 6.68 (1H, s, NH), 1.57 (9H, s, tBu). 13C NMR (75 MHz, DMSO-δ6): δC

(ppm) 162.2, 155.4, 151.4, 144.8, 126.4, 124.9, 119.3, 117.2, 113.6, 53.6, 28.8. Anal. Calcd for

C13H16N6: C, 60.92; H, 6.29; N, 32.79%. Found: C, 60.81; H, 6.35; N, 32.72.

N4-(tert-butyl)-7/8-methylbenzo[4,5]imidazo

[1,2-a][1,3,5]triazine-2,4-diamine (3b). Cream

powder (yield 54%); m.p. 238-240˚C. IR (KBr)

(νmax /cm-1): 3431, 3337, 3146, 1644, 1205, 1125.

MS (EI, 70 eV) m/z: 270 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 7.58 (1H, d, 3JHH = 6.0

Hz, H–Ar), 7.50 (1H, s, H–Ar), 7.34 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.26 (1H, s, H–Ar), 7.13 (1H,

d, 3JHH = 9.0 Hz, H–Ar), 7.08-6.90 (5H, m, NH2& H–Ar), 6.69 (1H, s, NH), 6.61 (1H, s, NH),

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2.45 (3H, s, CH3), 2.41 (3H, s, CH3), 1.57 (18H, s, tBu). 13C NMR (75 MHz, DMSO-δ6): δC

(ppm) 161.7, 161.5, 155.5, 151.4, 151.3, 145.0, 134.2, 128.4, 126.4, 126.0, 124.3, 120.3, 117.3,

116.8, 113.8, 113.0, 53.3, 28.7, 21.8, 21.7. Anal. Calcd for C14H18N6: C, 62.20; H, 6.71; N,

31.09%. Found: C, 62.03; H, 6.11; N, 30.96.

N4-(tert-butyl)-7,8-dimethylbenzo[4,5]imidazo[1,2-a][1,3,5]triazine-

2,4-diamine (3c). Cream powder (yield 57%); m.p. 286-288 ˚C. IR

(KBr) (νmax /cm-1): 3446, 3334, 3172, 1639, 1205, 1122. MS (EI, 70 eV)

m/z: 284 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 7.46 (1H, s,

H–Ar), 7.25 (1H, s, H–Ar), 6.84 (1H, bs, NH2), 6.52 (1H, s, NH), 2.35 (3H, s, CH3), 2.31 (3H, s,

CH3), 1.58 (9H, s, tBu). 13C NMR (75 MHz, DMSO-δ6): δC (ppm) 161.5, 154.8, 151.1, 133.5,

128.0, 124.3, 117.6, 113.8, 53.5, 28.7, 20.3, 20.2. Anal. Calcd for C15H20N6: C, 63.36; H, 7.09; N,

29.55%. Found: C, 63.29; H, 7.15; N, 29.64.

N4-(2,4,4-trimethylpentan-2-yl)benzo[4,5]imidazo[1,2-a]

[1,3,5]triazine-2,4-diamine (3d). Cream powder (yield 68%); m.p.

265-267 ˚C. IR (KBr) (νmax /cm-1): 3477, 3286, 3049, 1639, 1250, 1153.

MS (EI, 70 eV) m/z: 312 (M+). 1H NMR (300 MHz, DMSO-δ6) δH

(ppm) 7.79 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.47 (1H, d, 3JHH = 6.0 Hz, H–Ar), 7.31 (1H, t, 3JHH =

9.0 Hz, H–Ar), 7.16 (1H, t, 3JHH = 9.0 Hz, H–Ar), 7.05 (2H, bs, NH2), 6.45 (1H, s, NH), 2.10

(2H, s, CH2), 1.63 (6H, s, CH3), 0.99 (9H, s, CH- tBu). 13C NMR (75 MHz, DMSO-δ6): δC (ppm)

179.1, 161.6, 151.6, 145.0, 126.4, 125.2, 119.5, 117.4, 113.6, 57.2, 50.0, 31.9, 31.6, 29.7. Anal.

Calcd for C17H24N6: C, 65.36; H, 7.74; N, 26.90%. Found: C, 65.45; H, 7.65; N, 26.76.

7/8-methyl-N4-(2,4,4-trimethylpentan-2-

yl)benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2,4-

diamine (3e). Cream powder (yield 52%); m.p.

257-259 ˚C. IR (KBr) (νmax /cm-1): 3449, 3320,

3152, 1641, 1604, 1210, 1113. MS (EI, 70 eV)

m/z: 326 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 7.63 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.53

(1H, s, H–Ar), 7.34 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.27 (1H, s, H–Ar), 7.14 (1H, s, H–Ar), 6.98

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(4H, 2NH2), 6.41 (1H, s, NH), 6.31 (1H, s, NH), 2.45 (3H, s, CH3), 2.39 (3H, s, CH3), 2.06 (4H,

d, 2CH2), 1.60 (12H, d, 2CH3), 0.97 (9H, s, tBu), 0.95 (9H, s, tBu). 13C NMR (75 MHz, DMSO-

δ6): δC (ppm) 161.6, 161.5, 155.5, 155.0, 151.1, 150.9, 144.6, 142.1, 134.5, 128.9, 126.2, 126.2,

124.1, 120.8, 117.4, 116.9, 113.3, 112.6, 57.3, 57.2, 50.1, 49.9, 31.9, 31.6, 31.5, 29.7, 29.6, 21.7,

21.6. Anal. Calcd for C18H26N6: C, 66.23; H, 8.03; N, 25.74%. Found: C, 66.35; H, 8.11; N,

25.61.

7,8-dimethyl-N4-(2,4,4-trimethylpentan-2-yl)benzo[4,5]imidazo[1,2-

a][1,3,5]triazine-2,4-diamine (3f). Cream powder (yield 75%); m.p.

255-257 ˚C. IR (KBr) (νmax /cm-1): 3489, 3118, 2919, 1646, 1600. MS

(EI, 70 eV) m/z: 340 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm)

7.50 (1H, s, H–Ar), 7.25 (1H, s, H–Ar), 6.91 (2H, bs, NH2), 6.31 (1H, s, NH), 2.36 (3H, s, CH3),

2.30 (3H, s, CH3), 2.08 (2H, s, CH2),1.63 (6H, s, CH3), 0.99 (9H, s, CH- tBu). 13C NMR (75

MHz, DMSO-δ6): δC (ppm) 161.4, 155.0, 151.0, 143.2, 133.1, 127.5, 124.5, 118.0, 113.5, 57.2,

50.4, 31.9, 31.6, 29.6, 20.3, 20.3. Anal. Calcd for C19H28N6: C, 67.03; H, 8.29; N, 24.68%.

Found: C, 67.16; H, 8.21; N, 24.58.

7,8-dichloro-N4-cyclohexylbenzo[4,5]imidazo[1,2-a][1,3,5]triazine-

2,4-diamine (3g). Cream powder (yield 50%); m.p. 321-323 ˚C. IR

(KBr) (νmax /cm-1): 3474, 3394, 3214, 3109, 2852, 1636, 1262, 1096.

MS (EI, 70 eV)m/z: 350 (M+). 1H NMR (300 MHz, DMSO-δ6) δH

(ppm) 8.37 (1H, s, H–Ar), 7.64 (1H, s, H–Ar), 7.25 (NH2), 7.14 (1H, s, NH), 4.14 (1H, bs, CH-

cy), 2.03-1.52 (7H, m, CH-cy), 1.44-1.08 (3H, m, CH-cy). 13C NMR (75 MHz, DMSO-δ6): δC

(ppm) 162.6, 157.2, 150.9, 144.8, 127.4, 125.9, 121.1, 117.5, 114.7, 51.1, 31.9, 25.5. Anal. Calcd

for C15H16Cl2N6: C, 51.29; H, 4.59; N, 23.93%. Found: C, 20. 05; H, 4.50; N, 24.03.

7,8-dichloro-N4-(2,4,4-trimethylpentan-2-yl)benzo[4,5]imidazo[1,2-

a][1,3,5]triazine-2,4-diamine (3h). Cream powder (yield 53%); m.p.

273-275 ˚C. IR (KBr) (νmax /cm-1): 3436, 2972, 2919, 1633, 1606. MS

(EI, 70 eV) m/z: 380 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm)

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7.97 (1H, s, H–Ar), 7.65 (1H, s, H–Ar), 7.25 (2H, d, NH2), 6.79 (1H, s, NH), 2.07 (2H, s,

CH2),1.61 (6H, s, CH3), 0.99 (9H, s, CH- tBu). 13C NMR (75 MHz, DMSO-δ6): δC (ppm) 161.5,

156.7, 150.4, 144.3, 126.9, 125.4, 120.2, 117.1, 114.6, 57.2, 49.9, 31.5, 31.2, 28.9. Anal. Calcd

for C17H22Cl2N6: C, 53.55; H, 5.82; N, 22.04%. Found: C, 53.48; H, 5.76; N, 22.14.

N4-(2,6-dimethylphenyl)benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2,4-

diamine (3i). Cream powder (yield 51%); m.p. 273-275 ˚C. IR (KBr) (νmax

/ cm-1): 3480, 3314, 3060, 1636,1250,1153. MS (EI, 70 eV)m/z: 304 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 8.47 (1H, s, H–Ar), 7.55-7.16

(3H, m, H–Ar), 7.14-6.53 (4H, m, H–Ar & NH2), 2.08 (6H, s, 2CH3).

Because of low solubility, it is not possible to provide 13C-NMR spectra. Anal. Calcd for

C17H16N6: C, 67.09; H, 5.30; N, 27.61%. Found: C, 66.98; H, 5.38; N, 27.50.

Because of low solubility, it is not possible to provide 13C-NMR spectra for 6a-c.

N-(tert-butyl)-6-((4,5-dihydro-1H-imidazol-2-yl)amino)quinoxaline-

5-carboxamide (6a). Cream powder (yield 63%); m.p. 209-211 ˚C. IR

(KBr) (νmax /cm-1): 3212, 3052, 1684, 1042. MS (EI, 70 eV)m/z: 312

(M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 9.61 (1H, s, NH), 8.96

(1H, s, H–Ar), 8.84 (1H, s, H–Ar), 7.99 (1H, d, 3JHH = 9.0 Hz, H–Ar),

7.70 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.28 (1H, s, NH), 3.86 (2H, t, 3JHH = 9.0 Hz, CH2), 1.34 (9H, s,

tBu). Anal. Calcd for C16H20N6O: C, 61.52; H, 6.45; N, 26.90. Found: C, 61.45; H, 6.51; N,

26.97.

N-cyclohexyl-6-((4,5-dihydro-1H-imidazol-2-yl)amino)quinoxaline-5-

carboxamide (6b). Cream powder (yield 48%); m.p. 151-153 ˚C. IR

(KBr) (νmax /cm-1): 3203, 3049, 2849, 1681, 1040. MS (EI, 70 eV)m/z:

338 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 9.65 (1H, s, NH),

8.96 (1H, s, H–Ar), 8.85 (1H, s, H–Ar), 7.99 (1H, d, 3JHH = 9.0 Hz, H–

Ar), 7.70 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.30 (1H, s, NH), 3.88 (2H, t,

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CH2), 3.66 (1H, bs, CH-cy), 1.97-1.14 (10H, m, CH-cy). Anal. Calcd for C18H22N6O: C, 63.89;

H, 6.55; N, 24.83. Found: C, 63.75; H, 6.45; N, 24.71.

6-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(2,4,4-trimethylpentan-2-

yl)quinoxaline-5-carboxamide (6c). Cream powder (yield 66%); m.p.

159-161˚C. IR (KBr) (νmax /cm-1): 3209, 3055, 1681, 1042. MS (EI, 70

eV)m/z: 368 (M+). 1H NMR (300 MHz, DMSO-δ6) δH (ppm) 9.53 (1H, s,

NH), 8.96 (1H, s, H–Ar), 8.84 (1H, s, H–Ar), 7.98 (1H, d, 3JHH = 9.0 Hz,

H–Ar), 7.66 (1H, d, 3JHH = 9.0 Hz, H–Ar), 7.23 (1H, s, NH), 3.85 (2H, CH2), 1.74 (2H, s,

CH2),1.38 (6H, s, CH3), 0.97 (9H, s, tBu). Anal. Calcd for C20H28N6O: C, 65.19; H, 7.66; N,

22.81. Found: C, 65. 34; H, 7.58; N, 22.72.

Mechanism:On the basis of the literature reports [2, 3] and TEMPO trapping experiments, two possible ionic

pathways mechanism is suggested in Figure. In the Path A, cobalt acetate reacts with isocyanide

to form isocyanide coordinated cobalt(II) complex I. Then, under the basic condition, reaction of

imidazol guanidine 1 with I gave III. The other plausible pathway for the formation of III,

involves a direct reaction of the cobalt(II) acetate and 1 to give complex II. Then, isocyanide

insertion reaction resulted III (Figure2, path B). After the formation of III, two different

insertions into Co-complex III are possible to generate intermediate IV or V. Co(II) complex IV

can be easily oxidized to result cobalt(III)-complex VI or VII. The intermediates VI or VII

subsequently undergo reductive elimination to afford the desired product 3.

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In order to get more insight in to reaction mechanism we did the supplementary reactions. At the

first step we synthesized Cobalt-tBu isocyanide complex. Then, the reaction of Cobalt-tBu

isocyanide complex and 1-(1H-benzo[d]imidazol-2-yl)guanidine 1 was carried out in the same

reaction conditions. The reaction did not take place even after 48 h. At the second step, the

complex of Cobalt(II) 1-(1H-benzo[d]imidazol-2-yl)guanidine 1 was prepared. Then, tBu

isocyanide was added to this complex in the same reaction condition. The reaction was

successful and final product formed in 48% yield. So, Path B is more possible than Path A.

Reference: [1]. Dolzhenko, A. V.; Chui, W. K. J. Heterocyclic. Chem. 2006, 43, 95

[2] Shinde, A. H.; Arepally, S.; Baravkar, M. D.; Sharada, D. S. J. Org. Chem. 2017, 82, 331.

[3] Zhu, T. H.; Wang, S. Y.; Wei, T. Q.; Ji, S. J. Adv. Synth. Catal. 2015, 357, 823.

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