o-Nitroaniline derivatives. Part 10. 5- and 6-Amino-1H-benzimidazole 3-oxides

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 691 o-Nitroaniline Derivatives. Part ?Om15-and 6-Amino-IH-benzimidazole 3-Oxides Michael D.McFarlane, David J. Moody, and David M.Smith* Department of Chemistry, University of St. Andrews, Purdie Building, St. Andrews, Fife KY 16 9ST Cyclisation of N-(4- or 5-acylamino-2-nitropheny1)glycineesters in basic media gives alkyl 5-or 6-acylaminobenzimidazole-2-carboxylate N-oxides, e.g. (I1a) or (I1b). Acid hydrolysis of the latter, followed by reaction with ammonia, gives the title compounds (1b) and (1c), in acceptable yield. The corresponding react ion sequence with 4-acy lami no-N-cya nomet hyl-o-nitroaniIines also gives (1b); where the acyl group is methylsulphonyl, however, the final product is 5-methanesulphon-amidobenzimidazole N-oxide (9).Compound (I b) is also obtainable from ethyl 5-nitrobenzimid- azole-2-carboxylate N-oxide by reduction followed by hydrolysis. Attempts to cyclise N-(0-nitropheny1)glycine derivatives containing a free amino group at the 5- position are unsuccessful. This failure is attributed to mesomeric deactivation of the nitro group by the amino lone pair. In Part 9' we have described a general synthetic route to ONHZ (CHZO),. KCN benzimidazole N-oxides which are unsubstituted both at the _____.c ONHCHZCNother nitrogen and at C-2, and we now consider the application RNH NO;! ZnCL2,~cOt-l RNH NO2 of this method to the synthesis of benzimidazole N-oxides with an amino substituent in the carbocyclic ring, viz. (la-d). These hitherto unknown compounds are of potential biological EtOH K;!CO3interest in view of their structural resemblance to the natural ipurines: thus (la)and (Id) are obviously related to adenine (2), and (lb) and (lc) possess some of the functionality of guanine 7 H.(6)0-L the case of the acetamido compound (6a), the hydrolysis product is the dihydrochloride (7) of the 5-amino N-oxide (la), and the free N-oxide is obtained by reaction of the dihydrochloride with ammonia (cJ Part 9'). The amino- protecting groups in (6b) and (6c), however, are more resistant to hydrolysis; thus the hydrolysis of (6b) gives, via n the monohydrochloride @a), 5-methanesulphonamidobenz-imidazole N-oxide (9a), and the corresponding hydrolysis of the cyanocarbamate (6c) gives a mixture of the dihydrochloride (7) and the monohydrochloride (8b), and thence the N-oxides (lb) and (9b).(ii) From 4-JEuor0-3-nitroaniline.Although the amino group in this (commercially available) amine deactivates the fluorine towards nucleophilic displacement, the N-acetyl derivative (10) (3).The N-oxides (1a-d) are also of chemical interest in their reacts cleanly with glycine ethyl ester to give the ester (lla). own right, since they may be expected to react as This, like the corresponding nitrile (5a),is cyclised in base to the multifunctional nucleophiles. In this paper we describe the benzimidazole oxide (12a), and the latter hydrolysed to the syntheses and characteristics of the 5- and 6-amino compounds dihydrochloride (7) and thence to the amino N-oxide (lb).(lb) and (lc). (iii) From 5-nitrobenzimidazole N-oxide. The most obvious route to (lb), viz. the catalytic hydrogenation of 5-nitrobenz- 5-Amino-1H-benzimidazole 3-Oxide (1b).-(i) From 2-nitro-p-imidazole N-oxide,' presents practical difficulties because of phenylenediarnine. Monoacylation of 2-nitro-p-phenylene-the low solubility of the nitro compound in the usual diamine occurs selectively at the 4-amino gr~up,~,~ and the solvents. However, catalytic hydrogenation of the nitro ester acetyl-, methylsulphonyl-, and ethoxycarbonyl protected (13) proceeds smoothly, and gives the amino ester (14) diamines (4) are then cyanomethylated at the other amino which, although itself not easily purified, is hydrolysable to group by Dimroth and Aurich's method4 (cj the preceding the dihydrochloride (7)and thence to (lb).paper '). Cyclisation of the resulting cyanomethyl compounds (5) in ethanolic potassium carbonate ' gives the 5-acylamino- 6-Amino-1H-benzimiduzole 3-oxide (lc).-3-Fluoro-4-nitro- 2-cyanobenzimidazole oxides (6) in good yield, and the latter aniline,' unlike the 4-fluoro-3-nitro isomer, reacts readily with are then hydrolysed in concentrated hydrochloric acid. In glycine ethyl ester giving N-(5-amino-2-nitrophenyl)glycine J. CHEM. SOC. PERKIN TRANS. I 1988 H ethyl ester (15).Surprisingly, this ester is not cyclised at all in the -NH3 presence of base, but merely undergoes hydrolysis to the (lb, OH(7) H20 H I OH (8) NH31H20 0-(8a),(9a) R = S02Me ; (8b) ,( 9b) : R = C02Et AcNH 0:0, I 0-(13) R =NO2 (14) R =NH2 6. 3 ( 111 1 H I 0-(lb) or (lc) corresponding carboxylic acid.However, the monoacetyl derivative of (15), viz. (llb), is readily cyclised in base to the benzimidazole oxide (12b), and hydrolysis of the latter, as described for its isomer (12a),leads to the parent N-oxide (lc). I U I OH (15) (16) As befits such polar compounds, the N-oxides (lb) and (lc) are appreciably soluble in polar media, and crystallise from water in hydrated form. Presumably as a consequence of the extensive hydrogen bonding, there is no distinct NH stretching absorption in the i.r. spectra; however, the mass spectra show prominent ions for M”, (A4-16)+, and (A4-29)’ (i.e. loss of 0 and CH0),6 and the ‘H n.m.r.spectra show the characteristic lowfield singlet corresponding to 2-H. The failure of the glycine ester (15) to undergo cyclisation is evidently due to the presence of the primary amino group. The effect of ring substituents on intramolecular condensations involving nitro groups has not been widely or systematically studied: although, for example, we are accumulating evidence that the presence of a second nitro group in the ring may facilitate base-catalysed condensation in certain cases, it is by no means clear, from isolated examples here and there in the literature,’ to what extent this represents a general trend. The effect of a powerful electron-donor on these condensations is even less well documented. Seventy-five years ago, Fries and Roth * reported as ‘merkwiirdig’ (noteworthy, or remarkable) the fact that the aminodinitrodiphenylhydrazine(17a) failed to RNH NHNHPh NHa:$NPh 02 N ON O, 02 N (17a) R = H (18) (17b) R = AC undergo cyclisation in base, whereas the corresponding aceta- mido compound (17b) was readily cyclised to the benzotriazole (18);no explanation was offered for this difference in reactivity, and we are unaware of any other recorded examples in the more recent literature.In the case of the ester (15), as in Fries and Roth’s experiment, we believe that the mesomeric effect of thep- amino group reduces the electrophilicity of the nitro group to such an extent that it is unreactive towards attack by the adjacent nucleophile.The inhibiting effect of a 5-amino substituent on the cyclisation of an N-(o4trophenyl)glycine derivative is ob- served even when an additional nitro group is present. Thus, for example, N-(5-amino- and 5-dimet hylamino-2,4-dinitrophenyl)-glycine ethyl esters (19a) and (19b) are recovered largely unchanged from treatment with strong base, and attempts to cyclise diaminodinitrobenzene derivatives such as (20) and (21) in basic media have similarly proved unsuccessful, substantial quantities of starting materials being recovered in each case. RzNoNHCH2CO2Et 02N NO2 (19a) R =H (20)R = C02Et (19b) R=Me (21) R = CN J. CHEM. SOC. PERKIN TRANS. I 1988 Experimental1.r.spectra were recorded for Nujol mulls, and 'H n.m.r. spectra were recorded at 80 MHz for solutions in [2H6]-dimethyl sulphoxide. 4-Amino-3-nitroacetanilide (4a).-Acetic anhydride (10.2 g, 0.1 mol) was added, with stirring, to a solution of 2-nitro-p-phenylenediamine (1 5.3 g, 0.1 ml) in acetic acid (1 50 mol) and the mixture set aside overnight.The crystalline product was filtered off, washed with water, and recrystallised from aqueous ethanol. The amide (4a) (1 1.6 g, 59%) had m.p. 187-189 "C (decomp.) (lit.,, 189 "C); v,,,. 3 430 (amide NH), 3 280-3 360 (multiplet; NH,), 1 660 (CO), and 1 510 and 1 335 cm-' (NO,); 6,2.02 (3 H, S, Me), 7.00 (1 H, d, 5-H), 7.29 (2 H, br s, NH,), 7.53 (1 H, dd, 6-H), 8.37 (1 H, d, 2-H), and 9.87 (1 H, br s, NHAc); J2,6 2.2 Hz and J5,69 Hz.N-(4-Amino-3-nitrophenyl)methanesulphonamide (4b).-Methanesulphonyl chloride (11.5 g, 0.1 mol) was added gradually over 3 min to a solution of 2-nitro-p-phenyl-enediamine (1 5.3 g) in pyridine (70 ml). The temperature of the mixture rose to ca. 70 "C; the solution was set aside for 10 min, and then heated under reflux for a further 15 min. The pyridine was evaporated under reduced pressure, and water added to the residue; the sulphonamide (4b) was filtered off, and recrystal- lised from ethanol (with charcoal); yield 14.6 g (63%), m.p. 166- 168 "C (lit.,3 168-171 "C); v,,,. 3 480, 3 365, 3 240 (NH and 693 (Found: C, 40.1; H, 3.7; N, 20.6. C9HloN,04S requires C, 40.0 H, 3.7; N, 20.7%); v,,,. 3 370 and 3 270 (2 x NH), 2 250 w (CN), 1 525 and 1 335 (NO,), 1 310 and 1 140 cm-' (SO,); 6,3.05 (3 H, s, Me),4.65 (2 H, d, CH,), 7.35 (1 H, d, 6-H), 7.75 (1 H, dd, 5- H), 8.20 (1 H, d, 3-H), 8.37 (1 H, br t, NHCH,), and 9.5-10.0 (1 H, br, NHMs); J3,52.8 Hz, J5,69.2 Hz, and JCH2,NH 6 Hz.N-Cyanomethyl-4-ethoxycarbonylamino-2-nitroaniline(5). This compound, m.p. 194-195°C (from acetic acid), was similarly prepared (8 h reaction time) from the carbamate (4c) (8.0 g) in 70% yield (Found: C. 50.1; H, 4.5; N, 21.2. C, ,H ,2N404 requires C, 50.0 H, 4.6; N, 2 1.2%); v,,,, 3 400 and 3 355 (2 x NH), 2 230vw (CN), 1 710 (CO), and 1 510 and 1 335 cm-' (NO,); 6, 1.30 (3 H, t, Me), 4.25 (2 H, q, CH,Me), 4.65 (2 H, d, CHZNH), 7.30 (1 H, d, 6-H), 7.90 (1 H, dd, 5-H), 8.30 (1 H, br t, NHCH,), 8.65 (1 H, d, 3-H), and 9.85 (1 H, s, NHCOZEt); J3,5 2.6 Hz, J5,6 9.8 Hz, JCH2,NH 6 Hz, and JMe,CH27 HZ.5-Acetamido-2-cyano- 1 H-benzimidazole 3-Oxide (6a).-4-Acetamido-N-cyanomethyl-2-nitroaniline(5a) (7.0 g, 0.03 mol) was dissolved, as far as possible, in hot ethanol (320 ml). Potassium carbonate (4.1 g, 30 mmol) was added carefully, and the mixture heated under reflux for 45 min. Evaporation of the solvent under reduced pressure gave a solid which was dissolved as far as possible in water (300 ml). The solution was filtered, and the filtrate acidified (conc. HCl) with cooling and stirring. The colourless product was filtered off, washed with water, and NH,), 1 515 and 1 345 (NO,), and 1 310 and 1 140 cm-I (SO,); recrystallised from aqueous ethanol.The N-oxide (6a) (4.6 g, 6,3.00(3H,~,Me),7.20(1H,d,5-H),7.50(1H,dd,6-H),7.55(271%) had m.p. 233-234 "C (Found: C, 55.55; H, 3.7; N, 26.0. H,s, NH,), 8.03 (1 H, d, 2-H),9.60(1 H,s,NHMs);J,,, 2Hzand J5.6 9 HZ. Ethyl N-(4-Amino-3-nitrophenyl)carbamate(4c).-Pyridine (16.0 g, 0.2 mol) was added to a solution of 2-nitro-p-phenylenediamine (15.3 g) in acetonitrile (100 ml) and the mixture cooled to ca. 5 "C. Ethyl chloroformate (10.8 g, 0.1 mol) was added dropwise, with cooling and stirring, over ca.30 min, and the mixture was allowed to warm to room temperature over a further 1 h. The solvent was evaporated under reduced pressure, the oily residue added to ice-water with vigorous stirring, and the solid product filtered off, washed with water, and recrystallised (twice) from aqueous ethanol (with charcoal), to give the carbamate (4c) (16.6 g, 7473, m.p.129-130 "C(lit.,, 129-132 "C);v,,,. 3 320 (br, NH and NH,), 1 680 (CO), and 1 540 and 1 340 cm-' (NO,); 6, 1.28 (3 H, t, Me), 4.25 (2 H, q, CH,), 7.1 1 (1 H, d, 5-H), 7.40 (2 H, br s, NH,), 7.65 (1 H, dd, 6- H), 8.40 (1 H, d, 2-H), and 9.70 (1 H, s, NHC0,Et); J2.6 2.2 Hz, J5,69.2 Hz, and JCH,-CH2 7 Hz. 4-A cetamido-N- cyanome thyl- 2-nitroan iline (5a).-To 4-amino-3-nitroacetanilide (4a) (15 g, 74 mmol) were added, successively, paraformaldehyde (7.41 g, 0.247 mol CH,O), potassium cyanide (15.34 g, 0.236 mol), zinc chloride (39.3 g, 0.29 mol), and acetic acid (400 ml) containing concentrated sulphuric acid (1 5 drops).The vigorously stirred mixture was heated to 50 "C over ca. 30 min, and kept at this temperature for 6 h. It was then added to crushed ice; the solid product was filtered off and washed well with water. The nitrile (5a) (14.4 g, 80%) had m.p. 228-229 "C (from acetic acid) (Found: C, 51.3; H, 4.3; N, 24.0. Cl,Hl,N403 requires C, 51.3; H, 4.3; N, 23.9:d); vmax.3 390 and 3 350 (2 x NH), 2 245w (CN), 1 680 (CO), and 1 510 and 1 335 cm-' (NO,); 6, 2.07 (3 H, s, Me), 4.60 (2 H, d, CH,), 7.30 (1 H, d, 6-H), 7.95 (1 H, dd, 5-H), 8.30 (1 H, br t, NHCH,), and 8.70 (1 H, d, 3-H); J3,52.8 Hz, J5.6 9.2 Hz, and JCHJW 6 Hz. N-C~unomethyl-4-methanesulphonamido-2-nitroaniline(5b). This compound, m.p.169-170 "C (from ethanol), was similarly obtained (yield 82%) from the sulphonamide (4b) (21.2 g) C,,H,N,O, requires C, 55.6; H, 3.7; N, 25.9%); v,,,. 3 320 (NHAc), 2 600br (NH/OH), 2 230 (CN), and 1 630 cm-' (CO); 6,2.17(3H,s,Me),7.53(1 H,dd,6-H),7.91 (1 H,d,7-H),8.48(1 H, d, 4-H), 10.40 (1-H, s, NHAc), and 13.0-13.5 (1 H, br s, NH/OH); J4.6 2.0 HZ and J6,7 9.0 HZ. 2-Cyano-5-methanesulphonamido-1H-benzimiduzole3-oxide (6b). This compound, m.p. 223-224 "C (decomp.) (from aqueous ethanol), was similarly obtained (reaction time, 1 h; yield, 92%) from the sulphonamidonitrile (5b) (1 1.4 g) (Found: C, 42.8; H, 3.0; N, 22.3. C,H,N,O,S requires C,42.85; H, 3.2; N, 22.2%); vmax.3 300br (NH), 2 235 (CN), and 1 320 and 1 145 cm-' (SO,);6,3.15 (3 H, S, Me), 7.45 (1 H, dd, 6-H), 7.65 (1 H, d, 4-H), 7.95 (1 H, d, 7-H), 10.35 (1 H, s, NHMs); J4.62.0 Hz and J6.7 9.2 HZ.1 H- benzimidazole 3-oxide2-Cyano-5-ethoxycarbonylumino-(6c).This compound, m.p. 2 15-2 16 "C (decomp.) (from aqueous ethanol) was similarly obtained (reaction time, 1.5 h; yield, 84%) by cyclisation of the cyanocarbamate (5)(8.3 g) (Found: C, 53.8; H, 4.0; N, 22.7. C,,H,,N,O, requires C, 53.7; H, 4.1; N, 22.75%.) v,,,. 3 220 (NH-CO,Et), 3 050br (NH/OH), 2 220 (CN), and 1680 cm-' (CO); 6 1.30 (3 H, t, Me), 4.30 (2 H, q, CH,), 7.53 (1 H, dd, 6-H), 7.85 (1 H, d, 7-H), 8.12 (1 H, d, 4-H), 10.07 (1 H, s, NH-CO,Et), 12.7-13.5 (1 H, br s, NH/OH); J4,6 2.0 Hz, J6,79.2 Hz, and JMe,CH27.0 Hz. N-(4-Acetamido-2-nitropheny1)glycineEthyl Ester (1 la).--4- Fluoro-3-nitroacetanilide (lo), m.p.140-141 "C (from aqueous ethanol, with charcoal; lit.,' 139 "C) was prepared in 89% yield by reaction of 4-fluoro-3-nitroaniline (15 g) with acetic an- hydride (30 g) at 25 "C, and addition of the mixture to ice-water after 45 min. A suspension of the amide (10) (12.5 g, 63 mmol), glycine ethyl ester hydrochloride (9.7 g, 70 mmol), and sodium hydrogen carbonate (10.6 g, 0.126 mol) in dimethyl sulphoxide (40 ml) was stirred for 6 h at 60-65 "C; the mixture was then poured very slowly, with vigorous stirring, into ice-water (500 ml), and the red precipitate filtered off. Recrystallisation from ethanol gave the ester (lla) (8.83 g, 50%)as orange needles, m.p.164-165°C (Found: C, 51.5; H, 5.3; N, 14.9. Cl,H15N,0, requires C, 51.2; H, 5.4; N, 14.9%); v,,,, 3 380 (NH), 1 725 and 1 685 (CO), and 1 525 and 1 320 cm-' (NO,); 6, 1.23 (3 H, t, MeCH,), 2.03 (3 H, s, MeCO), 4.16 (2 H, q, CH,Me),* 4.20 (2 H, d, CH,NH),* 6.88 (1 H, d, 6-H), 7.63 (1 H, dd, 5-H), 8.21 (1 H, br t, NHCH,), 8.44 (1 H, d, 3-H), 10.05 (1 H, s, NHAc); J3,52 Hz, J5,6 9 Hz, JMeCH2 7 Hz, and JCH~,NH5 Hz. N-(5-Amino-2-nitrophenyl)glycine Ethyl Ester (15).-3-Fluoro-4-nitroaniline 'J (3.4 g, 22 mmol), glycine ethyl ester hydrochloride (4.2 g, 30 mmol), and sodium hydrogen carbonate (3.7 g, 44 mmol) were stirred in dimethyl sulphoxide (15 ml) for 4 h at 90-1 00"C. The orange suspension was cooled and added to ice-water (200 ml), and the precipitate filtered off and recrystallised from aqueous ethanol to give the ester (15) (4.43 g, 85%), m.p.123-127 "C (Found: C, 50.2; H, 5.5; N, 17.8. CloH13N304 requires C, 50.2; H, 5.5; N, 17.6%); v,,,. 3 580, 3 460,3 330, and 3 220 (NH), 1 730 (CO), and 1 560 and 1 310 cm-' (NO,); 6, 1.25 (3 H, t, Me), 4.09 (2 H, d, CH,NH), 4.20 (2 H, q, CH,Me), 5.69 (1 H, d, 6-H), 6.04 (1 H, dd,4-H), 6.53 (2 H, br s, NH,), 7.81 (1 H, d, 3-H), and 8.60 (1 H, t, NHCH,); J3,49 Hz, J4,6 2 Hz, JCHzMe 7 Hz, and JCH2,NH5 Hz. N-(5-Amino-2-nitrophenyl)glycine.(a) The foregoing ester (15) (0.24 g, 1.0 mmol), potassium carbonate (0.16 g, 1.1 mmol), and ethanol (15 ml) were heated together under reflux for 1 h. The yellow precipitate was filtered off and dissolved in water; acidification (HCI) gave the free acid (0.13 g, 62%).(b)lo 3-Fluoro-4-nitroaniline (0.75 g, 4.8 mmol), glycine (0.38 g. 5.1 mmol), sodium hydrogen carbonate (4.0 g), ethanol (30 ml), and water (10 ml) were heated together under reflux for 3 h. The solution was then concentrated under reduced pressure to cu. 10 ml, and acidified (HCI) to precipitate the acid (0.40 g, 40%).N-( 5-Amino-2-nitrophenyl)glycine had m.p. 2 10-2 14 "C (from aqueous ethanol) (Found: C, 45.6; H, 4.35; N, 19.6. C,H,N30, requires C, 45.5; H, 4.3; N, 19.9%); v,,,. 3 480 and 3 380 (NH), 1 725 (CO), and 1 555 and ca. 1 300 cm-' (NO,); 6, 4.00 (2 H, d, CH,), 5.70 (1 H, d, 6-H), 6.03 (1 H, dd, 4-H), 6.55 (2 H, br s, NH,), 7.84 (1 H, d, 3-H), 8.59 (1 H, br t, NHCH,); J3,49 Hz, J4,62 Hz, and JCH2NH 5 Hz. N-(5-Acetamido-2-nitropheny1)glycine ethyl ester (1 1b).This compound, m.p. 210-212 "C (from ethanol), was prepared by acetylation of the 5-amino analogue (15) (4 g) with acetic anhydride (8 g) at 100 "C for 30 min; it was isolated by adding the reaction mixture to ice-water (150 ml); yield, 3.89 g (83%) (Found: C, 51.4; H, 5.3; N, 14.9. Cl,HlSN305 requires C, 51.2; H, 5.4; N, 14.9%); v,,,, 3 360, 3 340, 3 310sh (NH), 1 745 and 1 695 (CO), and 1 550 and 1 320 cm-' (NO,); 6,1.25 (3 H, t, Me-CH,), 2.1 1 (3 H, s, MeCO), 4.1 5 (2 H, d, CH,NH),* 4.19 (2 H, q, CH,Me),* 6.86 (1 H, dd, 4-H), 7.29 (1 H, d, 6-H), 8.06 (1 H, d, 3- H), 8.49 (1 H, br t, NHCH,), and 10.28 (1 H, s, NHAc); J3,49 Hz, J4.6 2 Hz, JCH2,NH 6 Hz, and JCH~M~7 Hz.Ethyl 5-Acetamido- 1 H-benzimidazole-2-carboxylate3-Oxide ( 12a).-N-(4-Acetamido-2-ni tropheny1)glycine ethyl ester (1 1a) (8 g, 28 mmol), potassium carbonate (3.93 g, 28 mmol), and ethanol (300 ml) were heated together under reflux for 2 h (a precipitate was formed). The solvent was evaporated under reduced pressure, and the residue partitioned between water and dichloromethane; the aqueous layer was acidified (HCI) and the N-oxide (12a) filtered off. It had m.p. 133-134 OC (from aqueous ethanol); the yield was 4.84 g (61%) (Found: C, 51.2; H, 5.3; N, 15.0. C,,H,,N304-H,0 requires C, 51.2; H, 5.4; N, 14.904);v,,,. 3 360 (NHAc), 3 300br (H,O?), 2 650br (NH/OH), and 1 720 and 1 655 cm-' (CO); 6,1.35 (3 H, t, MeCH,), 2.10 (3 H, s, MeCO), 4.39 (2 H, q, CH,), 7.26 (1 H, dd, 6-H), 7.64 (1 H, d, J.CHEM. SOC. PERKIN TRANS. I 1988 7-H),8.15 (1 H, d, 4-H), 10.15 (1 H, s, NHAc), and 12.05 (1 H, br S, NH/OH); J4.6 2 Hz, J6.7 9 Hz, and JCH3CH27 Hz. Ethyl 6-acetamido-1H-benzimidazole-2-carboxylate3-oxide (12b). This compound, m.p. 198-200 OC (from dimethyl- formamide-water), was similarly obtained from the 5-acetamido analogue (Ilb) (3.5 g, 12 mmol) and potassium carbonate (1.72 g, 12 mmol) in ethanol (100 ml); yield 2.34 g (67%) (Found: C, 51.2; H, 5.3; N, 15.3. Cl2Hl3N3O,~H2O requires C, 51.2; H, 5.4; N, 14.9%); v,,,, 3 110-3 280br (NHAc, NH/OH), and 1 705 and 1660 cm-' (CO); 6, 1.36 (3 H, t, MeCH,), 2.08 (3 H, s, MeCO), 4.40 (2 H, q, CH,), 7.35-7.5 (2 H, m) tand 7.9-8.1 ( 1 H, m, ArH),? 10.01 (1 H, s, NHAc), and 12.13 (1 H, br s, NH/OH).Ethyl 5-Amino- 1 H-benzimidazole-2-carboxylate 3-Oxide (14).-A solution of ethyl 5-nitro-1H-benzimidazole-2-carb-oxylate 3-oxide (13)' (1.0 g) in ethanol (250 ml) was hydrogenated in presence of 5% palladium-charcoal (0.3 g). When the uptake of hydrogen was complete (15-20 min), the catalyst was filtered off and the filtrate concentrated under reduced pressure. The buff residue was recrystallised from ethyl acetate to give the amino ester (14) (0.55 g, 63%), m.p. 156-159 "C (Found: C, 54.8; H, 5.1; N, 18.5. CloH,,N303 requires C, 54.3; H, 5.0; N, 19.0%); vmax.3 485 and 3 370 (NH,), 2 600br (NH/OH), and 1 700 cm-' (CO); 6, 1.35 (3 H, t, Me), 4.38 (2 H, q, CH,), 6.60 (1 H, d, 4-H), 6.72 (1 H, dd, 6-H), and 7.42 (1 H, d, 7-H); J4,62 Hz, J6,,9 Hz, and JMeCH2 7.5 Hz; m/z 221 (M", 9573, 205 (32%), 175 (5579, 160 (40%), 159 (69%), 133 (4573, 132 (91%), 131 (loo%), etc. Although a completely pure sample was not obtained, the amino ester appeared to darken on storage, and so was used immediately without further purification. 5-Amino-1 H-benzimidazole 3-Oxide Dihydrochloride (7).-(a) From the acetamido-ester (12a).The ester (12a) (3 g, 10 mmol) and concentrated hydrochloric acid (25 ml) were heated together under reflux for 1.5 h. The colourless dihydrochloride (7) (1.86 g, 74%) crystallised from the cooled solution. (b) From the acetamido nitrile (6a). The nitrile (2 g, 9 mmol) was similarly hydrolysed to give compound (7) (1.45 g, 71%).(c) From the amino ester (14). The crude amino ester (0.2 g) and concentrated hydrochloric acid (10 ml) were heated together under reflux for 1 h. Cooling gave compound (7) (0.090 g), and concentration of the mother-liquor gave a further crop (0.070 g; total yield 80%). The dihydrochloride (7) had m.p. 238 "C (decomp.) (from conc. HCl) (Found: C, 37.5; H, 4.1; N, 18.9. C,H7N30*2HCI requires C, 37.9; H, 4.1; N, 18.9%);v,,,. 2 600 (v br; NH and OH); 6H7.5 1 (1 H, dd, 6-H), 7.79 (1 H, d, 4-H), 7.94 (1 H, d, 7-H), 9.90 (1 H, s, 2-H), and 10.63 (5 H, br s, kH3, AH, OH); J4,6 2 Hz and J6.-,8.5 Hz. 5-Amino- 1 H-benzimidazole 3-Oxide (1 b).-The dihydro-chloride (7) (1.4 g, 6 mmol) was dissolved in aqueous ammonia (d0.88; 10 ml) and the solution was immediately evaporated to dryness under reduced pressure.The residue was washed with a little water, filtered off, and recrystallised from water to give the colourless N-oxide (lb) (0.6 g, 5773, m.p. 97-98 "C (Found: C, 50.0; H, 5.5; N, 25.5. C,H,N,O-H,O requires C, 50.3; H, 5.4; N, 25.1%);v,,,. 3 430sh, 3 310, 3 320sh, 3 140, and 3 080 cm-' (all broad); 6, 5.65 (br s, NH, + H,O), 6.45-6.63 (2 H, m),? 7.15-7.33 (1 H, m),? and 8.00 (1 H, s, 2-H); m/z 149 (M", 60%), 133 (loo%), 132 (87%), 120 (2073, 106 (20%), and 105 (67%), eCc. 5-Me thanesulph onam ido- 1 H-benzimidazoIe 3- Oxide (9a).-The sulphonamido nitrile (6b) (2 g) was hydrolysed with * Overlapping signals.t Not first-order spectrum. J. CHEM. SOC. PERKIN TRANS. I 1988 concentrated hydrochloric acid as described above for com- pound (12a). No crystalline product was obtained on cooling the solution; the acid was distilled off under reduced pressure and the residue washed with warm ethanol (30 ml). The hydrochloride (8a) (1.18 g, 57%) showedv,,,. 3 l00br (NHMs), 2 625br (NH/OH), and 1 320 and 1 140 cm-' (SO,); 6, 3.10 (3 H, s, Me), 7.48 (1 H, dd, 6-H), 7.69 (1 H, d, 4-H), 7.86 (1 H, d, 7-H), 9.82 (1 H, s, 2-H), and 10.32 (1 H, s, NHMs). A sample recrystallised from a large volume of ethanol had m.p. 211-212°C (Found: C, 36.5; H, 3.8; N, 15.95. C8H,N30,S*HC1 requires C, 36.4; H, 3.8; N, 15.9%). Reaction of the hydro- chloride with ammonia, as described in the preceding para- graph, gave the sulphonamido N-oxide (9a), m.p.220-222 "C (from ethanol) (Found: C, 42.6; H, 3.9; N, 18.6. C8H,N,03S requires C,42.3; H, 4.0; N, 18.5%);v,,,. 3 215 (NHMs),and 1 320 to dryness under reduced pressure, and the residue washed with ice-cold water (20 ml). The buff N-oxide (lc) (0.86 g, 68%) had m.p. 185 "C (decomp.) (from water) (Found: C, 45.7; H, 5.9; N, 22.8. C7H7N30*2H,0requires C, 45.4; H, 6.0; N, 22.7%); v,,,. 3 360,3 160br, and 3 080 cm-'; 6,4.8 (br s, NH,, H,O), 6.63- 6.85(2H,m),*7.15-7.35(1 H,m),*and8.20(1 H,s,2-H);m/z 149 (M+',67%), 133 (loo%), 132 (4779, 121 (13%), 120 (13%), 106 (20%), and 105 (3379, etc. 13-Dichloro-2,4-dinitrobenzene.-This compound, m.p.99-101 "C (from ethanol; lit.," 103-104 "C), was prepared in 59% yield by nitration of m-dichlorobenzene.' ' N-(5-Amino-2,4-dinitrophenyl)glycineEthyl Ester (19a).-Aqueous ammonia (d 0.88; 200 ml) was added to 1,5-dichloro- and 1 145 cm-' (SO,); 6, 2.95 (3 H, s, Me), 7.09 (1 H, dd, 6-H), 2,4-dinitrobenzene (30 g) in ethanol (300 ml), and the mixture 7.39(1 H,d,4-H),7.59(1 H,d,7-H),8.31(1H,~,2-H),9.70(1H,heated under reflux for 3 h. The yellow crystalline product was S, NHMs), 11.88 (1 H, br S, NH/OH); J4,62 HZand J6,79 Hz. Hydrolisisof' the Cyano Carbamate (6c).-Compound (6c) (5.0 g) and concentrated hydrochloric acid (50 ml) were heated together under reflux for 2.5 h. 5-Ethoxycarbonylamino-1H-benzimida;ole 3-oxide hydrochloride (8b) crystallised from the cooled solution.Recrystallised from ethanol, it had m.p. 210-21 1 "C (decomp.); yield 2.20 g (42%) (Found: C, 46.8; H. 4.7; N, 16.2. CloHl ,N,O,-HCl requires C, 46.6; H, 4.7; N, 16.3%); v,,,. 3 280, 3 200, 3 130 (NH), 2 600br (&H, OH), and 1 720 cm-' (CO);6, 1.29 (3 H, t, Me), 4.19 (2 H, 9, CH,), 7.58 (1 H, dd, 6-H), 7.78 (1 H, d, 7-H), 8.11 (1 H, d, 4-H), 9.83 (1 H, S, 2-H), 10.13 (1 H, S, NHCO,Et), and 12.78 (2 H, br S, NH/OH); J4,62 Hz, J6,79 Hz, and JMeCH2 7 Hz. The reaction mother-liquor was concentrated under reduced pressure to cu. 10 ml, and cooled in ice. 5-Amino-1H-benzimidazole 3-oxide dihydrochloride (7) (1.57 g, 35%) crystallised out and was identified by comparison with an authentic sample.Increasing the reaction time to 7 h increased the product ratio (7):(8b)but some decomposition also occurred and the products were therefore less easily isolated. A black tarry residue was also obtained. 5-Etho.xycarbonylarn ino-1 H- benzimidazole 3-Oxide (9b).-The hydrochloride (8b)(1 g) was dissolved in aqueous ammonia (d 0.88; 10 ml), the solution was concentrated under reduced pressure until precipitation commenced, and the mixture was then cooled in ice and the product filtered off and washed with a little water. The N-oxide (9b) (0.44 g, 51%) had m.p. 205 "C (decomp.) (from ethanol) (Found: C, 54.3; H, 5.0; N, 18.8. C,oHl,N,O, requires C, 54.3; H, 5.0; N, 19.0%) v,,,, 3 310 (NH), 2 300 br (NH/OH), and 1 700 cm-' (CO); 6, 1.28 (3 H, t, Me), 4.18 (2 H, q, CH,), 7.22 (1 H, dd, 6-H), 7.54 (1 H, d, 7-H), 7.86 (1-H, d, 4-H), 8.28 (1 H, s, 2-H), and 9.71 (1 H, s, NHC0,Et); J4.6 2 Hz, J6,, 8.5 Hz, and JMeCHz 7 Hz.6-Amino-1 H-benzimidazole 3-Oxide (lc).-The acetamido ester (12b) (4.3 g, 15 mmol) and concentrated hydrochloric acid (70 ml) were heated together under reflux for 3 h. The solution was evaporated to dryness under reduced pressure to give the dihydrochloride(16) (1.93 g, 5773, m.p. 255 "C (decomp.) (from hydrochloric acid, with charcoal) (Found: C, 37.8; H, 4.4; N, 19.2. C,H,N30-2HCl requires C, 37.9; H, 4.1; N, 18.9%); v,,,. 2 580 cm-' (v br); 6, 7.6-7.75 (1 H, m),* 7.9-8.13 (2 H, m),* 9.3 (br s. NH, OH, &H3), and 9.96 (1 H, s, 2-H). The dihydrochloride (1.5 g) was added in small portions to aqueous ammonia (d0.88; 15 ml) at &5 "C; the solution was evaporated * Not first-order spectrum.filtered off,washed with water and a little cold ethanol, and recrystallised from ethanol to give 5-chloro-2,4-dinitroaniline (19 g, 69%),m.p. 172-174 "C (lit.,8 178 "C). To a warm (60 "C) solution of this amine (10 g, 46 mmol) in dimethyl sulphoxide (40 ml) were added, with stirring, sodium hydrogen carbonate (7.7 g, 92 mmol) and glycine ethyl ester hydrochloride (6.5 g, 46 mmol). Stirring was continued while the mixture was heated to 100-1 10 "C over 20 min, and kept at this temperature until effervescence ceased (a further 20 min). When cooled, the mixture set solid; water was added, and the product filtered off, washed with water, and recrystallised from acetic acid.The ester (19a) had m.p. 179-180 "C; yield 8.8 g (67%) (Found: C, 42.6; H, 4.3; N, 19.8. C ,H 2N406requires C, 42.3; H, 4.3; N, 19.7%); v,,,. 3 460 and 3 330 (NH), 1 735 (CO), and 1 510 and 1 315 cm-' (NO,); 6,1.25 (3 H, t, Me), 4.20 (2 H, d, CH,NH),t 4.26 (2 H, q, CH,Me),f 6.10 (1 H, s, 6-H), 7.90 (2 H, br s, NH,), 8.60 (1 H, t, NH-CH,), and 9.08 (1 H, s, 3-H); JMeCH27 Hz and JCH2NH 6 Hz. N-(5-N,N-Dimethylamino-2,4-dinitrophenyl)glycine ethyl ester (19b). This compound was similarly obtained. 5-Chloro- N,N-dimethyl-2,4-dinitroaniline,m.p. 1 19-123 "C (from etha- nol; lit.,', 129 "C) was prepared in 850/ ield from 1,5-dichloro- 2,4-dinitrobenzene and dimethy lami;: and was converted into the ester (19b) in 42% yield by reaction with sodium hydrogen carbonate and glycine ethyl ester hydrochloride in dimethyl sulphoxide, initially for 30 min at 80 "C followed by 10 min at 95 "C.The ester (19b)had m.p. 190-191 "C (from acetic acid) (Found: C, 46.1; H, 5.0; N, 17.8. Cl2H1,N4O6 requires C, 46.15; H, 5.2; N, 17.8%); vmax,3 340 (NH), 1 730 (CO),and 1 5 10 and 1 335 cm-' (NO,); 6, 1.24 (3 H, t, MeCH,), 2.93 (6 H, s, Me,N), 4.22 (2 H, q, CH,Me),t 4.32 (2 H, d, CH,NH),t 5.92 (1 H, s, 6-H), and 8.66 (1 H, s, 3-H and 1 H, br t, NH): $ JMeCH2 7 Hz and JCH2,NH 5 Hz. N,N-( 4,6- Din itro-1,3-phenylene) bisgly cine Diethy 1 Ester (20).-To a solution of 1,5-dichloro-2,4-dinitrobenzene(9 g, 39 mmol) in dimethyl sulphoxide (45 ml) were added sodium hydrogen carbonate (13.1 g, 0.156 mol) and glycine ethyl ester hydrochloride (10.9 g, 78 mmol).The mixture was stirred and heated at 60°C until effervescence had almost ceased (ca. 35 min); it was then heated to 90°C and maintained at this temperature until no more carbon dioxide was evolved (a further 20 min). The mixture was then cooled, diluted with water, and filtered. The solid product was recrystallised from acetic acid to give the diester (20) (10.7 g, 76%) as bright yellow needles, m.p. 190-191 "C (Found: C, 45.5; H, 4.8; N, 15.1. Cl4Hl8N4O8requires C, 45.4; H, 4.9; N, 15.104); v,,,. 3 350 t Overlapping signals. 1Coincident chemical shifts. (NH), 1 715 (CO), and 1 535 and 1 350 cm-' (NO,); 6 1.28 (6 H, t, 2 x Me), 4.22 (4 H, q, 2 x CH,Me),* 4.30 (4 H, d, 2 x CH,NH),* 5.74 (1 H, s, 2-H), 8.67 (2 H, br t, 2 x NH), and 8.98 (1 H, S, 5-H); JMeCHZ 7 HZ and JCHz,NH5 Hz.N,N'-Biscyanomethyl-4,6-dinitrobenzene-1,3-diamine (21)-Sodium carbonate (5.7 g, 68 mmol) and powdered aminoaceto- nitrile hydrochloride (3.15 g, 34 mmol) were added to a solution of 1,5-dichloro-2,4-dinitrobenzene(4.0 g, 17 mmol) in dimethyl sulphoxide (20 ml). The mixture was stirred and heated at 80-90°C until effervescence ceased (ca. 40 min) and was then poured into ice-water (200 ml). The solid product was filtered off, washed with ethanol, and recrystallised from dimethyl- formamide-acetic acid (1 :1) to give the dinitriZe (21) (2.70 g, 58%), m.p.274-276°C (Found: C, 43.6; H, 2.9; N, 30.5. C,,H,N,O, requires C, 43.5;H, 2.9;N, 30.4%); v,,,. 3 340 (NH), 2 240w (CN), and 1 530 and 1 320 cm-' (NO,); 6,4.80 (4 H, d, 2 x CH,), 6.30 (1 H, s, 2-H), 9.00 (2 H, t, 2 x NH), and 9.18 (1 H, s, 5-H); JCHz,NH Hz. Attempted Cyclisations of Compounds (19)-(21).-(a) (19a) With sodium ethoxide. The ester (19a) (3 g, 10.5 mmol) in dimethylformamide (10ml) was added slowly, with stirring, to a solution of sodium ethoxide (from sodium, 0.25 g, 10.8 mmol) in ethanol (200 ml). Precipitation of a yellow solid began almost immediately; when addition of the ester was complete, the mixture was stirred for 30 min, and the solid (2.1 g) filtered off and washed with ethanol. It was dissolved in water, and the solution acidified (HCl) to give only the starting ester (1.7 g), identical with an authentic sample.(b) (19b) With sodium ethoxide. The dimethylamino ester (19b) (1 g, 2.8 mmol) in dimethylformamide (50 ml) and ethanol (25 ml) was treated dropwise, over 10 min, with sodium ethoxide solution [from sodium (0.074 g, 3.2 mmol) and ethanol (10ml)]. The mixture was set aside overnight, then diluted with water (400 ml) and filtered; the filtrate was acidified (HCl), giving unchanged starting material (0.80 g). (c) (20) With sodium ethoxide. The ethoxide solution [from sodium (0.23 g) and ethanol (10 ml)] was added dropwise over 10 min to a stirred solution of the diester (20) (3.52 g, 9.5 mmol) in dimethylformamide (50 ml) at 5--10°C. The dark red * Overlapping signals.J. CHEM. SOC. PERKIN TRANS. I 1988 solution was stirred at this temperature for 15min after which it was evaporated under reduced pressure at 60 "C and the residue dissolved in water. Acidification (HCl) gave the starting diester (20) (2.0 g), identical with an authentic sample. (d) (21) With sodium hydride. Sodium hydride (50% dispersion in oil; 0.36 g, 7.5 mmol) in dry dimethyl sulphoxide (5 ml) was added dropwise, with stirring and cooling, to the dinitrile (21) (1.0g, 3.6 mmol) in the same solvent (10ml) so that the temperature was maintained at 20-25 "C. When addition was complete (10 min) the dark red solution was kept at room temperature for a further 45 min and then added to ice-water (100 ml). The sticky black precipitate was filtered off, washed with water and ethanol, and recrystallised from aqueous dimethylformamide, to give the starting dinitrile (21) (0.27 g) as' the only isolated product. Acknowledgements We thank Mr. I. W. Harvey for preparative and other technical help; Mrs. S. Smith for microanalyses; Mrs. M. Smith for n.m.r. spectra; Mr. C. Millar for mass spectra; and the S.E.R.C. and the University authorities, respectively, for Research Studentships to M. D. M. and D. J. M. References 1 Part 9, I. W. Harvey, M. D. McFarlane, D. J. Moody, and D. M. Smith, J. Chem. SOC.,Perkin Trans. I, preceding paper. 2 C. Bulow and E. Mann, Ber., 1897, 30,977. 3 S. Rajappa and R. Sreenivasan, Indian J. Chem., 1980, 19B, 533. 4 K. Dimroth and H. G. Aurich, Chem. Ber., 1965,98, 3902. 5 H. H. Hodgson and D. E. Nicholson, J. Chem. SOC.,1941, 766. 6 cf:D. Johnston, J. Machin, and D. M. Smith, J. Chem. Res., 1978, (S), 366. 7 For a review of nitro group condensations, see P. N. Preston and G. Tennant, Chem. Rev., 1972,72, 627. 8 K. Fries and E. Roth, Liebigs Ann. Chem., 1912, 389, 318. 9 J. J. Blanksma, W. J. van der Broek, and D. Hoegen, Red. Trau. Chim. Pays-Bas, 1946,6S, 329. 10 cf: R. S. Goudie and P. N. Preston, J. Chem. SOC.C, 1971, 1139. 11 J. H. Boyer, R. S. Buriks, and U. Toggweiler,J.Am. Chem. Soc., 1960, 82, 2213. 12 W. Borsche, Ber., 1917, 50, 1339. Received 23rd February 1987; Paper 71333