Synthesis of 1,4-benzodiazepine-2,5-dione derivatives

Article abstract of DOI:10.3987/COM-02-9525

A synthesis of a series of 1,4-benzodiazepine-2,5-dione derivatives with a carboxy group at the 3-position is realized in good yields by using methyl malonylchloride as a key reagent and intramolecular nucleophilic substitution as ring closure reaction.

Full text of DOI:10.3987/COM-02-9525

HETEROCYCLES, Vol. 57, No. 8, 2002, pp. 1501 - 1506, Received, 3rd June, 2002
SYNTHESIS OF 1,4-BENZODIAZEPINE-2,5-DIONE DERIVATIVES
Tong-Ing Ho,* Wen-Shiong Chen, Chi-Wei Hsu, Yeun-Min Tsai, and
Jim-Min Fang
Department of Chemistry, National Taiwan University, Roosevelt Road, Sec. 4,
Taipei, Taiwan, Republic of China
hall@ccms.ntu.edu.tw
Abstract-A synthesis of a series of 1,4-benzodiazepine-2,5-dione derivatives
with a carboxy group at the 3-position is realized in good yields by using methyl
malonylchloride as a key reagent and intramolecular nucleophilic substitution as
ring closure reaction.
1,4-Benzodiazepine-2,5-dione (BZD) and its derivatives whether it is natural1,2 or synthetic3,4,5 represent
one of the most important bioactive molecules. The BZD systems exhibit bioactivities such as
anticonvulsant,3 anxiolytic,4 antitumor1,5 pain releasing,6 platelet aggregation inhibiting7,8 and even
anti-AIDS activities.9
It was recently reported that10,11 the human receptor ETA subtype is selective to endothelin-1 (ET-1), a
21 amino acid peptide. ET-1 exhibits profound endogenous vasoconstriction and mitogenic activities.
Antagonism on the vasoconstrictor endothelin is a potential new approach to the treatment of a variety
of human diseases including ischemia, hypertension, congestive heart failure, pulmonary hypertension
and subarachnoid hemorrhage. In the process of searching for the non-peptide antagonists selective for
ETA and ETB receptors, it was found by Elliott12 that two phenyls on the indane derivative SB 209670
(Figure 1) are restricted dipeptide mimetic to Try-13 and Phe-14 of ET-1.
By molecular modeling, we have found that the N-phenyl and N-benzyl group of the BZD ring can be a
perfect match to the two phenyls of SB209670. Thus it is possible that compound (1) (Scheme 3) and its
derivatives may serve as alternative candidates for the non-peptide antagonists of ETA.
Many efforts have been devoted toward the synthesis of this bioactive BZD and its derivatives.9,13-15 For
example, Keating and Armstrong recently published3 a new synthetic method for BZD by using
rearrangement (Scheme 1). In a primary attempt (Scheme 2), the N-benzylisatoic anhydride (2) was
reacted with aniline to afford the amide (3). Then 3 was reacted with dimethyl chloromalonate to give 4.
However, cyclization to seven membered ring by intramolecular amide formation to 5 from 4 was not
successful.

Figure 1. Non-peptide antagonists, SB209670 and several synthesized BZD
derivatives.
O
O
N
CO2H
CO2Me
O
O
N
O
CO2H
O
OMe
O
11
SB 209670
MeO
O
MeO
O
Br
N
N
CO2Me
CO2Me
OMe
N
N
O
O
13
12
Scheme 1. Synthetic approach to BZD by using rearrangement.
H2N
O
Bu
O
(i)
(ii)
NH
I
(iii)
H
O
C
HN
O
NH2
O
O
NH2
H
N
(iv)
N
N
Bu
O
Bu
I
I
H
O
N
N
I
Bu
O
O
CN
I
O
(i) Bu-NH2 / MeOH (ii)
(iv) AcCl, MeOH
(iii)
H3N

A successful method to achieve the ring closure is shown in Scheme 3. Isatoic anhydride was reacted with
p-methoxyaniline in DMF to form amide (6) in 78% yield. The aniline part of the amide (6) was alkylated
with 3-methoxybenzyl chloride to afford 7 in 72% yield. The secondary amine part of 7 was acylated with
methyl malonylchloride to yield 8 (96%). In order to activate the methylene carbon of the malonamide (8),
a bromine atom is introduced to give 9. By using two equivalents of bulky base, sodium t-butoxide, the
ring closure occurred to afford the 1,4-benzodiazepine-2,5-dione (10) in 82% yield from compound (8)
without isolation of 9. The hydrolysis to the carboxylic acid (1) was achieved by lithium hydroxide in
90% yield.
In summary, a synthetic approach to a series of BZD derivatives has been described by using methyl
malonylchloride as a key reagent through the intramolecular nucleophilic substitution to achieve the
1,4-benzodiazepine-2,5-dione in good yield. The possible bioactivities are being determined.
ACKNOWLEDGEMENTS
We are grateful to the National Science Council of the Republic of China (Taiwan) for financial support.
The X-Ray diffraction work was carried out at NTU, we thank Dr. G. H. Lee and Professor S. M. Peng
for the measurement.
Scheme 2. Primary attempt to the BZD derivative (5).
O
N
OMe
OMe
NH
O
NH
N
O
O
(ii)
(i)
H
N
O
O
O
4
3
2
O
N
(iii)
CO2Me
O
O
N
o
C
(i) Aniline / DMF, 110 ; (ii)
/ THF, Et3N;
OMe
MeO
O
Cl
(iii) DMSO / reflux
5
SUPPORTING INFORMATIONS
13
1H and C NMR spectral data of compounds (1, 7, 8, 10)16 are available. The single crystal X-Ray
diffraction data are also included.

Scheme 3. Novel synthetic approach to a new BZD derivative (1).
OMe
OMe
OMe
O
O
O
(i)
(ii)
O
N
N
H
H
N
H
O
NH2
N
H
6 (78%)
7 (72%)
OMe
OMe
O
O
N
O
(iv)
(iii)
(v)
N
H
N
H
OMe
OMe
OMe
N
O
Br
O
O
MeO
MeO
9
8 (96%)
OMe
O
O
N
N
CO2H
CO2Me
OMe
(vi)
N
N
O
O
OMe
(90%)
1
10 (82%)
(i) p-Anisidine / DMF; (ii) 3-Methoxybenzyl chloride / THF; (iii) Methyl malonylchloride /
THF, 00C; (iv) PyHBr3 / THF, H+; (v) t-BuONa / DMF; (vi) LiOH, H2O, 00C
Figure 2. Perspective view of X-Ray crystal structure of 11.

REFERENCES AND NOTES
1. K. Kariyone, H. Yazawa, and M. Kohsaka, Chem. Pharm. Bull., 1971, 19, 2289.
2. S. M. Colegate, P. R. Dorling, C. R. Huxtable, T. J. Shaw, B. W. Skelton, P. Vogel, and A. H. White,
Aust. J. Chem., 1989, 42, 1249.
3. T. A. Keating and R. W. Armstrong, J. Am. Chem. Soc., 1996, 118, 2574.
4. W. B. Wright, H. J. Brabander, E. N. Granblatt, I. P. Day, and R. A. Hardy, J. Med. Chem., 1978, 21,
1087.
5. G. B. Jones, C. L. Davey, T. C. Jenkins, A. Kamal, G. G. Kneale, S. Neidle, G. D. Webster, and D. E.
Thurston, Anti-Cancer Drug Des., 1990, 5, 249.
6. P. M. Carabateas and L. S. Harris, J. Chem. Soc., 1965, 23, 6
7. R. S. McDowell, B. K. Blackburn, T. R. Gadek, L. R. McGee, T. Rawson, M. E. Reynolds, K. D.
Robarge, T. C. Somers, E. D. Thorsett, M. Tischer, R. R. Webb, and M. C. Venuti, J. Am. Chem. Soc.,
1994, 116, 5077.
8. R. R. Webb, P. L. Barker, M. Baier, M. E. Reynolds, K. D. Robarge, B. K. Blackburn, M. H. Tischler,
and K. J. Weese, Tetrahedron Lett., 1994, 35, 2113.
9. (a) N. S. Cho, K. Y. Song, and C. Parkanyi, J. Heterocycl. Chem., 1989, 26, 1807.(b) P. G. Baraldi, G.
Balboni, B. Cacciari, A. Guiotto, S. Manfredini, R. Romagnoli, G. Spalluto, D. E. Thurston, P. W.
Howard, N. Bianchi, C. Rutigliano, C. Mischiati, and R. Gambari, J. Med. Chem., 1999, 42, 5131.
10. M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Goto,
and T. Masaki, Nature, 1988, 332, 411.
11. M. Yanagisawa, Circulation., 1994, 89, 1320.
12. J. D. Elliott, M. A. Lago, R. D. Cousius, A. Gao, J. D. Leber, K. F. Erhard, P. Nambe, N. A.
Elshourkagy, C. Kumar, J. A. Lee, J. W. Bean, C. W. Debrosse, D. S. Eggleston, D. P. Brooks, G.
Feuerstein, R. R. Jr. Ruffolo, J. Weinstock, J. G. Gleason, C. E. Peishoff, and E. H Ohlstein, J. Med.
Chem., 1994, 37, 1553.
13. G. M. Karp, J. Org. Chem., 1995, 60, 5814.
14. C. G. Boojamra, K. M. Burow, and J. A. Ellman, J. Org. Chem., 1995, 60, 5742.
15. D. A. Goff and R. N. Zuckermann, J. Org. Chem., 1995, 60, 5744.
16. Spectral data for 11 (mp 148-150 °C (ethyl acetate)): IR(KBr) 3065, 3040, 2953, 1757, 1662, 1601,
1490, 1322, 784 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.87 (d, J = 1.5 Hz, 1H), 7.43 – 7.15 (m, 9H),
6.87 – 6.77 (m, 3H), 5.27(d, J = 15.8 Hz, 1H), 5.19 (s, 1H), 4.99 (d, J = 15.8 Hz, 1H), 3.74 (s, 3H),
13
3.40 (s, 3H); C NMR (CDCl3, 75 MHz) δ 165.1, 164.9, 158.9, 141.6, 137.5, 136.9, 131.5, 130.3,
128.7, 128.4, 128.0, 126.9, 125.5, 125.2, 120.5, 118.9, 117.6, 111.9, 110.9, 67.8, 54.1, 51.9, 50.8;
MS m/z (70 eV, EI) 430 (M+, 60), 278 (10), 146 (100), 221(90). HR-MS Calcd for C25H22N2O5
430.1528, found 430.1545.
1
Spectral data for 1 (white powder): IR (KBr) 3485, 1732, 1682, 1634 cm-1; H NMR (CDCl3, 300
MHz) δ 7.66 (d, J = 7.7 Hz , 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.30-7.19 (m,
4H), 7.02 (d, J = 8.7 Hz, 2H), 6.82-6.76 (m, 3H), 5.37 (s, 1H), 5.23 (d, J = 16.3 Hz, 1H,), 5.15 (d, J =

13
16.3 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 3H); C NMR (CDCl3) δ 167.0, 166.6, 165.8, 159.5, 158.1,
138.7, 138.2, 135.8, 132.6, 130.9, 129.6, 129.1, 127.5, 126.0, 122.0, 118.7, 114.3, 112.8, 111.7, 68.4,
55.4, 54.9, 49.9; FABMS: 417.1 (M+1).
Spectral data for 10 (mp 151-152 °C (ethyl acetate)): IR(KBr) 3005, 2955, 2836, 1756, 1676, 1511,
1
1458, 1245, 768 cm-1; H NMR (CDCl3, 300 MHz) δ 7.86 (dd, J = 7.3, 1.0 Hz, 1H), 7.42-7.15 (m,
6H), 6.94-6.77 (m, 5H), 5.26 (d, J = 15.9 Hz, 1H), 5.1 (s, 1H), 4.96 (d, J = 15.9 Hz, 1H), 3.80 (s, 3H),
13
3.74 (s, 3H), 3.39 (s, 3H); C NMR (CDCl3, 75 MHz ) δ 166.3, 166.1, 166.0, 159.9, 158.9, 138.0,
135.6, 132.5, 131.3, 129.8, 129.1, 127.5, 126.5, 121.4, 118.6, 114.6, 112.9, 111.9, 55.4, 69.2, 55.1,
52.9, 51.8 ,; MS (70 eV, EI) 260 (80), 401 (10), 254 (20), 146 (90), 121 (100); HR-MS Calcd for
C26H24N2O6 460.1634, found 460.1647.
Spectral data for 8 (mp 127-128 °C (ethyl acetate)): IR(KBr) 3298, 3061, 3001, 2952, 2836, 1741,
1
1656, 1600, 1537, 1411, 1321, 830 cm-1; H NMR (CDCl3, 300 MHz) δ 7.74-7.71 (m, 1H),
7.54-7.49 (m, 2H), 7.41-7.33 (m, 2H), 7.07-7.01 (m, 1H), 6.91-6.84 (m, 3H), 6.68-6.63 (m, 3H), 5.33
(d, J = 14.4 Hz, 1H), 4.39(d, J = 14.2 Hz, 1H), 3.78 (s, 3H), 3.66 (d, J = 15.3 Hz, 1H), 3.61 (s, 3H),
3.58 (s, 3H), 3.37(d, J = 15.9 Hz, 1H); 13C NMR (CDCl3) δ 168.7, 166.0, 164.5, 159.2, 156.2, 138.2,
137.4, 134.8, 130.9, 130.8, 129.9, 129.3, 128.9, 128.6, 121.7, 120.8, 114.0, 113.6, 112.9, 55.0, 54.6,
52.5, 52.0, 41.3; MS (70 eV, EI) 462 (M+, 10), 340 (10), 238 (10), 121 (100); HR-MS Calcd for
C26H26N2O6 462.1790, found 462.1804.
Spectral data for 7 (mp 125-126 °C (ethyl acetate)): IR(KBr) 3419, 3306, 3085, 3003, 2836, 1632,
1
1513, 1407, 1265, 820, 775 cm-1; H NMR (CDCl3, 200 MHz) δ 7.49-7.38 (m, 3H), 7.29-7.17 (m,
2H), 6.95–6.84(m, 4H), 6.78 (dd, J = 7.3, 1.8 Hz, 1H), 6.65-6.58 (m, 2H), 4.38 (d, J = 5.6 Hz, 2H),
3.78 (s, 3H), 3.75 (s, 3H); 13C NMR (CDCl3, 75 MHz ) δ 168, 159.8, 156.6, 149.5, 140.6, 133, 130.7,
129.5, 127.2, 122.6, 119.9, 119.3, 115.4, 115.2, 114.1, 112.7, 112.4, 55.4, 55.1, 47.1; MS (70 eV, EI)
362 (M+, 5), 240(30), 132 (10), 123(100). HR-MS Calcd for C22H22N2O3 362.1630, found 362.1634.
Spectral data for 6 (mp 120-121 °C (ethyl acetate)): IR(KBr) 3466, 3363, 3280, 1635, 1601, 1545,
1
1570, 1030, 834, 747 cm-1; H NMR (CDCl3, 200 MHz) δ 7.46-7.39 (m, 2H), 7.27-7.18 (m, 2H),
13
6.92-6.86 (m, 2H), 6.72-6.64 (m, 2H), 3.79 (s, 3H); C NMR (CDCl3, 75 MHz ) δ 167.5, 156.4,
148.6, 132.4, 130.7, 127.1, 112.6, 117.3, 116.6, 116.2, 114.0, 55.3; MS (70 eV, EI) 242 (M+, 50),
120 (100), 108 (20), 92 (40); HR-MS Calcd for C14H14N2O2 242.1053, found 242.1053.