Facile and efficient synthesis of 1,4-benzodiazepines from 1,4-naphthoquinones

Article abstract of DOI:10.3987/COM-08-S(N)63

Concise intramolecular cyclization reaction of 2,3-diamino-1,4-dihydro-naphthalenediones 4 and 7 in anhydrous K₂CO₃/Et₃N and EtOH yielded novel 1,4-benzodiazepines 5 and 6 fused with 1,4-naphthoquinone nucleus.

Full text of DOI:10.3987/COM-08-S(N)63

HETEROCYCLES, Vol. 76, No. 2, 2008
1007
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1007 - 1010. © The Japan Institute of Heterocyclic Chemistry
Received, 26th March, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)63
FACILE AND EFFICIENT SYNTHESIS OF 1,4-BENZODIAZEPINES
FROM 1,4-NAPHTHOQUINONES
Vishnu K. Tandon* and Hardesh K. Maurya
Department of Chemistry, University of Lucknow, Lucknow – 226 007, India
E. mail: vishnutandon@yahoo.co.in
Dedicated to Professor Dr. Ryoji Noyori on occasion of his 70th birthday.
Abstract — Concise intramolecular cyclization reaction of 2,3-diamino-1,4-
dihydro-naphthalenediones 4 and 7 in anhydrous K2CO3 /Et3N and EtOH yielded
novel 1,4-benzodiazepines 5 and 6 fused with 1,4-naphthoquinone nucleus.
The quinone group forms the basis of biological and pharmacological activity of a number of clinical and
experimental drugs that are associated with anticancer, antiviral, antifungal and antibacterial studies.1-5
The synthesis of quinones condensed with seven-membered heterocycles are rarely reported.6 However,
the synthesis of azepines condensed with naphthoquinone nucleus of Lapachol has been recently
described.7
In our medicinal chemistry program geared towards synthesis of a seven membered ring with two
nitrogen atoms fused to 1,4-naphthoquinone ring, we required a robust approach to a diverse set of title
heterocycles 5 and 6. Herein we report a high-yielding concise synthesis of 12-aryl and alkyl derivatives
of 13-amino-12H-5,12-diazabenzo[4,5]cyclohepta[1,2-b]naphthalene-6,11-diones 5 and 6.
12-Aryl derivatives of 13-amino-12H-5,12-diazabenzo[4,5]cyclohepta[1,2-b]naphthalene-6,11-diones 5
were synthesized in one-pot by condensing 2,3-dichloro-1,4-naphthoquinone 1 and monosubstituted 2-
aminobenzonitrile derivatives 2 in refluxing ethanol in the presence of potassium carbonate (Scheme 1).
When the reaction was carried out in other bases such as NaHCO3 and DBU, only intermediates 2-[3-(2-
cynophenylamino)-1,4-dioxo-1,4-dihydronaphthalen-2-yl]aminobenzonitriles 4 were isolated and 5 were
not detected.
In order to synthesize 12-alkyl derivatives of 13-amino-12H-5,12-diazabenzo[4,5]cyclohepta[1,2-b]-
naphthalene-6,11-dione 6, the reaction of 2,3-dichloro-1,4-naphthoquinone 1 was carried out with
o
monosubstituted 2-aminobenzonitrile derivatives 2 at 50 C in ethanol in the presence of potassium

1008
HETEROCYCLES, Vol. 76, No. 2, 2008
carbonate to yield a mixture of monosubstituted 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
yl)aminobenzonitriles 3 and disubstituted 2-[3-(2-cynophenylamino)-1,4-dioxo-1,4-dihydronaphthalen-2-
yl]aminobenzonitriles 4. 2-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)aminobenzonitriles 3 on
further reaction with alkyl and aryl amines in refluxing ethanol in the presence of Et3N resulted in the
formation of 6 (Scheme 1). A variety of functionalized aliphatic and aromatic amines participated in this
reaction to give 1,4-benzodiazepines 6(a-f) in good to excellent yields.
1
1
R
R
1
O
O
O
R
O
H
N
R
Cl H N
2
NH
NH
R
K CO / EtOH
2
3
+
+
o
NC
50 C
CN
CN
Cl
NC
R
Cl
O
O
1
70%
R=R =H
1
2
1
R
3
2
o
R -NH
2
K CO 80-90 C
2
3
1
R=R =H
R
Et N / EtOH
3
20%
EtOH
o
1
4
80-90 C
R
O
R
1
N
N
1
2
O
R
6a. R=R =H; R =Me
6b. R=R =H; R =i-Pr
1
2
N
N
1
R
5a. R=R =H
5b. R=Cl; R =H
1
2
6c. R=R =H; R =t-Bu
6d. R=R =H; R =Bn
1
NH
CN
2
1
2
O
1
5c. R= R =Cl
5d. R=Me; R =H
1
1
2
R
NH
6e. R=R =H; R =Ph
2
2
1
O
R
1
2
6f. R=R =H; R =2-(3,4-dimethoylphenyl)ethyl
6(a-f)
5(a-d)
R
Scheme1
The formation of 1,4-benzodiazepines 5 and 6 proceeds by intramolecular cyclization of 2,3-diamino-
1,4-naphthoquinones 7 and 4 respectively in presence of K2CO3/Et3N. The plausible mechanism of
formation of 5 and 6 is depicted in Scheme 2.
O
H
O
O
O
H
N
N
..
N
..
NH
C
N
R/Ar
C N
N
NH
O
NH2
O
R/Ar
R/Ar
5(a-d) / 6(a-f)
7
Scheme 2
In summary, a general and concise practical method of synthesizing 1,4-benzodiazepines fused with 1,4-
naphthoquinone nucleus from 2,3-dichloro-1,4-naphthoquinone has been developed. This method
tolerates a variety of alkyl/aryl amines and gives 12,13- disubstituted1,4-benzodiazepines 5 and 6 in good
to excellent yields.

HETEROCYCLES, Vol. 76, No. 2, 2008
1009
Table-1: Physical spectral and micro analytical data of 3-6 8,9
Entry
3
Yield Mp
Spectra
70
20
85
233 IR (KBr):554, 680, 734, 836, 879, 1002, 1158, 1229, 1274, 1380, 1478, 1539, 1591, 1679, 2364, 3450, cm-1; 1H NMR (300 MHz, CDCl3): δ 1.25
(bs, 1H, NH), 7.07-8.22 (m, 8H, Ar-H); 13CNMR(CDCl3): 99.64, 113.26, 117.12, 118.28, 119.40, 128.82, 130.12, 131.12, 133.80, 134.24,
136.61, 151.72, 152.24, 178.33, 179.12; MS: M+(M++1): 309; Anal. Calcd (C17H9ClN2O2): C, 66.14; H, 2.94; N, 9.07 Found: C, 65.85; H, 2.70;
N, 8.94
4
258 IR (KBr): 505, 617, 645, 716, 761, 793, 851, 912, 1016, 1095, 1135, 1241, 1287, 1332, 1383, 1469, 1509, 1598, 1677, 2222, 2366, 3265, 3416
cm-1; H NMR (300 MHz, CDCl3 +DMSO-D6): δ 1.25 (bs, 2H, 2NH), 7.02-8.24 (m, 12H, Ar-H); 13CNMR(CDCl3): 99.08, 118.52, 119.02,
1
119.82, 120.85, 126.92, 131.88, 135.42, 134.82, 137.02, 151.22, 181.76; MS: M+ (M++1): 391; Anal. Calcd (C24H14N4O2):C, 73.84; H, 3.61; N,
14.35 Found: C, 74.02; H, 3.82; N, 14.60
IR (KBr): 491, 531, 602, 670, 719, 757, 858, 984, 1006, 1038, 1071, 1105, 1203, 1252, 1274, 1302, 1350, 1384, 1460, 1507, 1601, 1655, 2363,
5a
150
2926, 3390, 3451 cm-1; H NMR (300 MHz, CDCl3): δ 1.25 (bs, 2H, NH2), 6.99-8.12 (m, 12H, Ar-H); 13CNMR(CDCl3): 68.90, 90.04, 105.04,
1
116.71, 123.28, 123.51, 126.44, 130.17, 131.79, 132.22, 132.58, 132.65, 133.20, 134.53, 140.80, 142.07, 156.02, 180.21, 182.20; MS:
M+(M++1): 391; Anal. Calcd (C24H14N4O2): C, 73.84; H, 3.61; N, 14.35 Found: C, 73.64; H, 3.72; N, 14.52.
IR (KBr): 490, 532, 604, 675, 740, 753, 855, 982, 1008, 1038, 1072, 1106, 1205, 1250, 1276, 1304, 1352, 1388, 1463, 1504, 1607, 1654, 2359,
5b
5c
5d
6a
81
51
83
90
171-
172
2930, 3385, 3460 cm-1; H NMR (300 MHz, CDCl3): δ 1.26 (bs, 2H, NH2), 6.95-8.12 (m, 10H, Ar-H); Anal. Calcd (C24H12Cl2N4O2): C, 62.76;
1
H, 2.63; N, 12.20 Found: C, 62.90; H, 2.80; N, 12.42.
IR (KBr): 495, 533, 605, 674, 742, 754, 858, 985, 1012, 1042, 1073, 1110, 1208, 1254, 1280, 1305, 1354, 1388, 1466, 1512, 1610, 1655, 2363,
2942, 3392, 3462 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.25 (bs, 2H, NH2), 6.98-8.15 (m, 8H, Ar-H); Anal. Calcd (C24H10Cl4N4O2): C, 54.58; H,
1.99; N, 10.69 Found: C, 54.72; H, 2.20; N, 10.82.
198-
199
IR (KBr): 490, 530, 608, 670, 720, 758, 859, 985, 1006, 1036, 1072, 1106, 1204, 1252, 1275, 1304, 1352, 1386, 1462, 1509, 1602, 1656, 2362,
2920, 2932, 3392, 3452 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.25 (bs, 2H, NH2), 2.32 (s, 3H, CH3), 238 (s, 3H, CH3), 6.90-8.15 (m, 10H, Ar-H);
Anal. Calcd (C26H18N4O2): C, 74.63; H, 4.34; N, 13.39 Found: C, 74.84; H, 4.42; N, 13.52.
158-
160
IR (KBr):546, 610,678, 720,816, 869, 965, 1025, 1072, 1124, 1262, 1299, 1337, 1415, 1457, 1520, 1599, 1681, 2942, 3334, 3452 cm-1; 1H NMR
(300 MHz, CDCl3): 1.25 (bs, 2H, NH2) 3.47 (m, 3H, NCH3), 6.49-8.15(m, 8H, Ar-H); 13CNMR(CDCl3): 35.05, 68.92, 105.22, 116.71, 123.52,
126.54, 131.80, 132.58, 133.22, 134.53, 135.88, 140,38, 156.02, 180.40, 182.02; MS: M+(M++1): 304; Anal. Calcd (C18H13N3O2): C, 71.28; H,
4.32; N, 13.85 Found: C, 71.52; H, 4.50; N, 13.98.
90
IR (KBr): 492, 549, 628, 670, 702, 754, 893, 931, 996, 1067, 1121, 1158, 1227, 1252, 1290, 1352, 1460, 1513, 1603, 1672, 2978, 3022, 3224,
3318 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.00 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.25 (bs, 2H, NH2) 3.55 (m, 1H, isopropyl-H), 6.47-8.11(m, 8H,
Ar-H); MS: M+(M++1): 332; Anal. Calcd (C20H17N3O2): C, 72.49; H, 5.13; N, 12.68 Found: C, 72.32; H, 5.02; N, 12.82.
IR (KBr): 488, 552, 635, 678, 704, 762, 894, 932, 996, 1068, 1125, 1167, 1256, 1292, 1360, 1462, 1514, 1605, 1680, 2854, 2972, 3010, 3264 cm-
1; 1H NMR (300 MHz, CDCl3): 1.25 (bs, 2H, NH2) 1.56 (s, 9H, C(CH3)3), 6.99-8.12(m, 8H, Ar-H); Anal. Calcd (C21H19N3O2): C, 73.03; H, 5.54;
6b
6c
6d
6e
6f
70
68
82
80
55
158
136
oil
N, 12.17 Found: C, 73.28; H, 5.70; N, 12.38
1
IR (Neat): 495, 607, 701, 753, 971, 1027, 1073, 1162, 1289, 1337, 1454, 1499, 1607, 1670, 2857, 2925, 3050, 3064 3347, 3465 cm-1; H NMR
(300 MHz, CDCl3): 1.25 (bs, 2H, NH2) 4.21 (s, 2H, NCH2), 6.60-8.23(m, 13H, Ar-H); Anal. Calcd (C24H17N3O2): C, 75.97; H, 4.52; N, 11.08
Found: C, 76.22; H, 4.78; N, 11.26.
IR (KBr): 473, 498, 583, 663, 724, 756, 797, 858, 905, 971, 1019, 1041, 1084, 1157, 1202, 1263, 1313, 1385, 1474, 1603, 1675, 2932, 2983,
3072, 3372, 3471 cm-1; 1H NMR (300 MHz, CDCl3): 1.25 (bs, 2H, NH2) 6.72-8.05(m, 13H, Ar-H); Anal. Calcd (C23H15N3O2): C, 75.60; H, 4.14;
N, 11.50 Found: C, 75.82; H, 4.30; N, 11.72.
60-
62
IR (KBr):487, 675, 769, 972, 1029, 1081, 1219, 1370, 1461, 1508, 1617, 1657, 2854, 2923, 3370, 3427 cm-1; 1H NMR (300 MHz, CDCl3): 1.25
(bs, 2H, NH2), 2.64 (t, 2H,CH2), 3.31 (t, 2H, CH2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3) 6.46-8.09(m, 11H, Ar-H); Anal. Calcd (C27H23N3O4):
C, 71.51; H, 5.11; N, 9.27 Found: C, 71.72; H, 5.32; N, 9.48.
178

1010
HETEROCYCLES, Vol. 76, No. 2, 2008
ACKNOWLEDGEMENTS
H. K. M. acknowledges UGC, New Delhi, India for Senior Research Fellowship.
REFERENCES AND NOTES
1. I. Gomez-Monterrey, G. Santelli, P. Campiglia, D. Califano, F. Falasconi, C. Pisano, L. Vesci,
T. Lama, P. Grieco, and E. Novellino, J. Med. Chem., 2005, 48, 1152.
2. H. Seradj, W. Cai, N. O. Erasga, D. V. Chenault, K. A. Knuckles, J. R. Ragains, and M.
Behforouz, Org. Lett., 2004, 6, 473.
3. V. K. Tandon, H. K. Maurya, D. B. Yadav, A. Tripathi, M. Kumar, and P. K. Shukla, Bioorg.
Med. Chem. Lett., 2006, 16, 5883.
4. C. K. Ryu, J. Y. Shim, M. J. Chae, I. H. Choi, J. Y. Han, O. J. Jung, J. Y. Lee, and S. H. Jeong,
Eur. J. Med. Chem., 2005, 40, 438.
5. C. K. Ryu, J. Y. Han, O. J. Jung, S. K. Lee, J. Y. Lee, and S. H. Jeong, Bioorg. Med. Chem.
Lett., 2005, 15, 679.
6. J. A. Valderrama, H. Pessoa-Mohana, and R. Tapia, J. Heteroycl. Chem., 1992, 29, 1177.
7. C. A. Camara, A. C. Pinto, M. D. Vargas, and J. Zukerman-Schpector, Tetrahedron, 2002, 58,
6135.
8. General procedure (5): To a solution of 2,3-dichloro-1,4-naphthoquinone 1 (1 g, 4.40 mmol) in
abs. EtOH (100 mL), 2-aminobenzonitriles 2 (1.4 g, 8.80 mmol) was added followed by
anhydrous K2CO3 (871 mg, 8.80 mmol). The reaction mixture was vigorously stirred at 80-90
0C for 15 h. The reaction mixture was then distilled and dried in vacuo. The residue was
chromatographed on SiO2 (0-20% EtOAc in hexane).
9. General procedure (3 and 4): To a solution of 2,3-dichloro-1,4-napthoquinone 1 (1 g, 4.40
mmol) in abs. EtOH (100 mL), 2-aminobenzonitrile 2 (0.52 g, 4.40 mmol) was added followed
by anhydrous K2CO3 (435 mg, 4.40 mmol). The reaction mixture was vigorously stirred at 50
oC for 24 h. The reaction mixture was distilled and dried in vacuo. The mixture of 3 and 4 was
separated by column chromatography (SiO2) using EtOAc in hexane (0-35%);
General Procedure (6): To a solution of 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
yl)aminobenzonitrile 3 (308 mg, 1 mmol) in abs. EtOH (90 mL), isopropylamine (71 mg, 1.2
mmol) and triethylamine (121 mg, 1.2 mmol) were added. The mixture was stirred first at rt for
o
0.5 h and then at 80-90 C for 10-38 h. The reaction mixture was distilled and dried in vacuo
and purified by flash column chromatography (SiO2) using EtOAc in hexane (0-15%).