Synthesis of novel 1,4-benzodiazepine-3,5-dione derivatives: Reaction of 2-aminobenzamides under bargellini reaction conditions

Article abstract of DOI:10.1055/s-0032-1317297

In this paper, we report on a user-friendly synthesis of 1,4-benzodiazepine-3,5-dione derivatives via Bargellini-type reaction. The corresponding products were obtained using various 2-aminobenzamides under Bargellini reaction conditions, in good yields without unfavorable side reaction.

Full text of DOI:10.1055/s-0032-1317297

LETTER
▌2521
lSetyternthesis of Novel 1,4-Benzodiazepine-3,5-dione Derivatives: Reaction of
2-Aminobenzamides under Bargellini Reaction Conditions
1,4-Benzodiazepine-3,5-dione Derivatives
Mohammad Mahdavi,a Mehdi Asadi,b Mina Saeedi,a Zahra Rezaei,a Hooman Moghbel,b Alireza Foroumadi,a
Abbas Shafiee*a
a
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran 14176, Iran
Fax +98(21)66461178; E-mail: ashafiee@ams.ac.ir
b
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Received: 15.07.2012; Accepted after revision: 23.08.2012
process provides an easy and diverse strategy for the syn-
thesis of novel cyclic and acyclic compounds. Therefore,
it presents practical and useful protocols in drug discovery
processes and the total synthesis of natural products.
Abstract: In this paper, we report on a user-friendly synthesis of
1,4-benzodiazepine-3,5-dione derivatives via Bargellini-type reac-
tion. The corresponding products were obtained using various 2-
aminobenzamides under Bargellini reaction conditions, in good
yields without unfavorable side reaction.
As a part of our current research on the development of
novel synthetic routes toward new heterocycles particu-
larly bioactive compounds,7–11 we tried to outline an effi-
cient approach to benzodiazepine derivatives. They were
selected as our target compounds due to the effective bio-
logical properties and their use in wide range of medical
applications.12–14 Among various derivatives, 1,4-benzo-
diazepinediones have significant properties. They have
been reported as potent antagonists of the HDM2-p53 in-
teraction in vitro and in cell-based assays.15Also various
reports proved that they possess anticonvulsant, anxiolyt-
ic, and antitumor properties, and are effective cholecysto-
kinin receptor (CCK), opiate receptor, and also platelet
glycoprotein IIb-IIIa antagonists.16–18
Key words: Bargellini-type reaction, 1,4-benzodiazepine-3,5-di-
ones, 2-aminobenzamides, heterocycles, dichloro epoxide
The Bargellini reaction1 in which phenol is condensed
with acetone and chloroform in the presence of a strong
base to produce a sterically hindered α-phenoxy-isobutric
acid (1, Scheme 1), is a useful synthetic tool in organic
synthesis and various nucleophiles and ketones have been
employed in place of classic form.2–6 In this manner, it has
potentially been a constructive lead for the organic chem-
ists. Preparation of griseofulvin analogues by Korger,2
amino acids using sodium azide by Corey,3 Butcher’s re-
port in the synthesis of druglike molecules utilizing di-
verse nucleophilic aromatic amines and cyclic ketones,4
and Lai’s synthesis of morpholine and morpholinone
nitroxides5 illustrate the importance of this reaction com-
prehensively.
Despite the fact that frequent 1,4-benzodiazepine-2,5-di-
one derivatives have been synthesized and tested for the
bioactivity properties,15,19–21 only a few reports for the
synthesis of 1,4-benzodiazepine-3,5-diones are found in
the literature (2–5, Figure 1).22–24 One of the earliest syn-
thesis of 1,4-benzodiazepine-3,5-dione derivative was re-
ported by Gärtner22 through three steps from anthranilic
acid using CCl3CHO, PhNHNH2, and Ac2O (3, Figure 1).
Generally, in the Bargellini-type reaction dichloro epox-
ide intermediates are formed by the reaction of chloro-
form and ketones which are potentially active toward
regioselective nucleophilic attacks (Scheme 1).
O
Ph
N
O
R1
O
Ac
N
N
O
O
Cl
O
NaOH
CCl3
+
CHCl3
R2
N
Cl
N
H
R3
Cl
3
O
2
O
OH
PhOH
Cl
Cl
PhO
CO2H
Cl
O
O
PhO
R
1
N
NH
O
O
Scheme 1 Classic Bargellini reaction
N
N
H
R
5
4
However, studies of the Bargellini-type reactions are an
important issue in the field of organic synthesis since this
Figure 1 General structure of 1,4-benzo[e][1,4]diazepine-3,5-dione
derivatives 2; the first reported 1,4-benzodiazepine-3,5-dione 322 and
1H-1,4-benzodiazepine-3,5(2H,4H)-diones 4 and 523
SYNLETT 2012, 23, 2521–2525
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317297; Art ID: ST-2012-D0593-L
© Georg Thieme Verlag Stuttgart · New York

2522
M. Mahdavi et al.
LETTER
Recently, some 1H-1,4-benzodiazepine-3,5(2H,4H)-di- sodium hydroxide (60 mmol) at room temperature. After
ones (4 and 5, Figure 1), were prepared from N-carbamo- a few minutes as we expected 2,2-dichloro-3,3-dimethyl-
ylmethylanthranilic acids by Wiklund et al.23 It was oxirane was formed when a white emulsion was appeared.
discovered that for a successful synthesis, substituted At this step 2-amino-N-benzylbenzamide (2 mmol) was
starting materials with electron-withdrawing groups are added to the resulting mixture and the reaction continued
required.
at the same temperature. After three hours the correspond-
ing seven-membered heterocycle 11c (Table 1, entry 1)
was formed in a good yield (80%). The combination of all
analytical information confirmed the given structure
11c.25
O
O
R1
R1
O
N
R2
R3
N
Cl
+
H
O
Cl
R3
NH2
N
H
The six protons of two methyl groups show a chemical
shift of δ = 1.35 ppm. The existence of NCH2 protons is
R2
Scheme 2 Suggested retrosynthetic analysis of 1,4-benzodiazepine- elucidated by the signal at lower field (δ = 5.03 ppm).
3,5-diones
Nine aromatic protons are found at δ = 7.03–7.99 ppm.
The presence of a signal related to the NH group at δ =
6.80 ppm provides further evidence for the formation of a
benzodiazepine. Fifteen distinct resonances were ob-
served in 13C NMR spectroscopy. Signals at δ = 23.3, 48.5
and 56.5 confirmed the presence of methyl, methylene,
and quaternary aliphatic carbon, respectively. Ten aro-
matic carbons were observed between δ = 116.4 and 145.8
ppm. Two signals at δ = 167.6 and 176.4 ppm belong to
two amide carbonyl groups.
Therefore, there is a strong demand for the development
of new syntheses of these scaffolds and investigation of
their biological properties.
To obtain the 1,4-benzodiazepine-3,5-dione derivatives, a
retrosynthetic analysis to title compound was outlined in
Scheme 2. As can be seen in Scheme 2, a feasible strategy
in which compounds can be prepared by the reaction of
ambident nucleophiles and epoxides via the Bargellini re-
action is suggested.
As shown in Table 1, we then investigated reaction of var-
ious 2-aminobenzamides under the same condition as de-
scribed above.25 All the reactions were achieved
efficiently and no other side products were observed.
So we focused on this route and expanded the Bargellini
reaction using 2-aminobenzamides 10 as efficient bident
nucleophiles to report the successful synthesis of novel
1,4-benzodiazepine-3,5-dione derivatives 11 (Scheme 3).
We realized that compounds 10 react easily with dichloro
epoxide intermediates (generated by the reaction of chlo-
roform and acetone–ethyl methyl ketone in the presence
of NaOH) to produce the lead benzodiazepinediones 11.
In the next step we continued our investigation using ethyl
methyl ketone instead of acetone and followed the similar
reactions (Table 1, entries 2, 4, 6, 8, and 10). As reported
in Table 1, good results were obtained, and no remarkable
difference was observed in the yield, reaction time, and
reactivity. All products were stable and characterized by
IR, 1H NMR, and 13C NMR spectroscopy and mass spec-
trometry.22
It is worthwhile to mention that all 2-aminobenzamide de-
rivatives 10 were synthesized by a simple and green pro-
cedure. An equivalent amount of isatoic anhydride 9 and
amines 8 were reacted in water at room temperature for
two hours. After this time the precipitated products were
filtered and dried. The obtained 2-aminobenzamides were
completely pure and used for further reactions.
In summary, we have found that 2-aminobenzamides can
react as efficient nucleophiles in the Bargellini reaction to
prepare potentially bioactive 1,4-benzodiazepine-3,5-di-
one derivatives. This procedure, in which products are ob-
tained in good yields, can be an important alternative for
the synthesis of 1,4-benzodiazepine-3,5-diones.
Our experiments initiated by the reaction of chloroform
(60 mmol) and dried acetone (40 mmol) in the presence of
O
O
R2
O
O
R1
N
O
H2O
r.t.
Cl
Cl
NaOH
CHCl3
H
R2 NH2
+
R1
+
NH2
N
H
O
R1 = Me, Et
8
6
7
10
9
2–7 h
O
R2
N
O
N
H
R1
11
Scheme 3 Synthesis of 1,4-benzodiazepine-3,5-diones via Bargellini-type reaction
Synlett 2012, 23, 2521–2525
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,4-Benzodiazepine-3,5-dione Derivatives
2523
(5) (a) Lai, J. T. J. Org. Chem. 1980, 45, 754. (b) Lai, J. T.
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124.
Table 1 Synthesis of 1,4-Benzodiazepine-3,5-dione Derivatives 11
O
R2
O
N
R2
H
O
O
N
R1
Cl
Cl
NaOH
CHCl3
NH2
O
R1
10
2–7 h
N
H
R1
6
7
11
Entry R1
R2
Product Time (h) Yield (%)a
(9) Hamadi, H.; Khoobi, M.; Hossaini, Z.; Shafiee, A. Mol.
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K. L.; Gupta, V.; Lattanze, J.; Ramachandren, K.; Carver,
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765. (b) Cummings, M. D.; Schubert, C.; Parks, D. J.; Calvo,
R. R.; LaFrance, L. V.; Lattanze, J.; Milkiewicz, K. L.; Lu,
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(16) Horton, D. A.; Bourne, G. T. Chem. Rev. 2003, 103, 893.
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Labaudiniere, R. J. Org. Chem. 1998, 63, 8021.
(18) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61,
8935.
(19) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdacka,
C.; Hiller, W. Tetrahedron Lett. 2006, 47, 3423.
(20) Jadidi, K.; Ghahremanzadeh, R.; Asgari, D.; Eslami, P.;
Arvin-Nezhad, H. Monatsh. Chem. 2008, 139, 1229.
(21) Ciofi, L.; Trabocchi, A.; Lalli, C.; Menchi, G.; Guarna, A.
Org. Biomol. Chem. 2012, 10, 2780.
1
2
Me
H
H
11a
11b
2
2
85
85
Et
CH2
CH2
CH2
3
4
Me
11c
11d
3
3
80
75
Et
5
6
Me
11e
11f
3
3
82
75
Cl
CH2
Et
Cl
MeO
CH2
7
8
Me
Et
11g
11h
4
4
75
70
MeO
CH2
CH2
9
Me
Et
11i
11j
6
7
65
60
O
CH2
O
10
CH2CH2
(22) Gärtner, S. Justus Liebigs Ann. Chem. 1904, 332, 226.
(23) Wiklund, P.; Rogers-Evans, M.; Bergman, J. J. Org. Chem.
2004, 69, 6371.
11
Me
11k
4
70
OMe
MeO
a Isolated yields.
(24) Osman, A. N.; El-Gendy, A. A.; Omar, R. H.; Wagdy, L.;
Omar, A. H. Boll. Chim. Farm. 2002, 141, 8.
(25) Synthesis of 1,2-Dihydro-4H-benzo[e][1,4]diazepine-3,5-
dione Derivatives – General Procedure
Acknowledgment
A mixture of anhydrous acetone–ethyl methyl ketone (40
mmol, 3 mL) and CHCl3 (60 mmol, 4.6 mL) in the presence
of NaOH powder (60 mmol, 2.3 g) was stirred at r.t. for 10
min (in the case of ethylmethyl ketone it should be stirred for
15 min). After this time, 2-aminobenzamide derivatives (2
mmol) were added to the reaction mixture and it continued
for the corresponding time, as indicated in Table 1, at the
same temperature. Upon completion of reaction the solution
was extracted with CHCl3 (3 × 20 mL). The organic layer
was separated, dried (Na2SO4), and concentrated in vacuo to
yield the crude product which was purified by column
chromatography eluting with PE–EtOAc (6:1).
1,2-Dihydro-2,2-dimethyl-4H-benzo[e][1,4]diazepine-
3,5-dione (11a)
This research was supported by grants from the research council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
References and Notes
(1) Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329.
(2) Korger, G. Chem. Ber. 1963, 96, 10.
(3) Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906.
(4) Butcher, K. J.; Hurst, J. Tetrahedron Lett. 2009, 50, 2497.
Yield 0.17 g (85%); white crystals; mp 228–230 °C. IR
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2521–2525

2524
M. Mahdavi et al.
LETTER
IR (KBr): 3350 (NH) 1697 (C=O), 1623 (C=O) cm–1. 1H
(KBr): 3337 (NH), 1698 (C=O), 1636 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.48 (s, 6 H, CH3), 4.11 (s, 1 H, NH),
6.78 (d, J = 7.6 Hz, 1 H, H9), 7.02 (t, J = 7.6 Hz, 1 H, H7),
7.40 (td, J = 7.6, 1.4 Hz, 1 H, H8), 8.20 (dd, J = 7.6, 1.4 Hz,
1 H, H6), 8.11 (s, 1 H, NH). 13C NMR (125 MHz, CDCl3):
δ = 23.5, 56.5, 116.8, 118.6, 120.0, 131.8, 134.0, 146.8,
165.0, 173.6. Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92;
N, 13.72. Found: C, 64.80; H, 6.10; N, 13.55.
NMR (500 MHz, CDCl3): δ = 0.81 (t, J = 7.4 Hz, 3 H,
CH2CH3), 1.49 (s, 3 H, CH3), 1.80 (dq, J = 14.8, 7.4 Hz, 1 H,
CH2CH3), 1.87 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 4.50 (s,
1 H, NH), 5.19 (d, J = 15.7 Hz, 1 H, NCH2), 5.36 (d, J = 15.7
Hz, 1 H, NCH2), 6.77 (d, J = 8.0 Hz, 1 H, H9), 6.92 (t, J = 7.5
Hz, 1 H, H4′), 7.05 (t, J = 8.2 Hz, 1 H, H7), 7.12–7.18 (m, 2
H, H5′, H6′), 7.32–7.39 (m, 2 H, H8, H3′), 8.16 (d, J = 8.2 Hz,
1 H, H6). 13C NMR (125 MHz, CDCl3): δ = 7.5, 27.2, 47.2,
61.3, 119.1, 119.7, 126.6, 127.1, 127.8, 128.6, 129.0, 129.3,
132.8, 133.3, 134.2, 144.7, 167.5, 173.7. Anal. Calcd for
C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17. Found: C, 66.80;
H, 5.40; N, 7.95.
2-Ethyl-1,2-dihydro-2-methyl-4H-benzo[e][1,4]diazepine-
3,5-dione (11b)
Yield 0.18 g (85%); white crystals; mp 160–162 °C. IR
(KBr): 3359 (NH), 1698 (C=O), 1645 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.48 (s, 3 H, CH3), 1.75 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3),
1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 4.16 (s, 1 H, NH),
6.79 (d, J = 7.5 Hz, 1 H, H9), 7.00 (t, J = 7.5 Hz, 1 H, H7),
7.40 (dt, J = 7.5, 1.3 Hz, 1 H, H8), 8.19 (dd, J = 7.5, 1.3 Hz,
1 H, H6), 8.21 (s, 1 H, NH). 13C NMR (125 MHz, CDCl3):
δ = 7.5, 22.7, 27.9, 60.8, 120.3, 120.6, 133.1, 134.8, 145.5,
164.3, 173.8. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47;
N, 12.84. Found: C, 65.90; H, 6.55; N, 12.99.
4-(4-Methoxybenzyl)-1,2-dihydro-2,2-dimethyl-4H-
benzo[e][1,4]diazepine-3,5-dione (11g)
Yield 0.24 g (75%); white crystals; mp 120–122 °C. IR
(KBr): 3329 (NH), 1694 (C=O), 1609 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.43 (s, 6 H, CH3), 3.77 (s, 3 H,
OCH3), 4.42 (s, 1 H, NH), 5.12 (s, 2 H, NCH2), 6.70 (d,
J = 8.1 Hz, 1 H, H9), 6.82 (d, J = 8.5 Hz, 2 H, H3′, H5′), 6.91
(t, J = 7.6 Hz, 1 H, H7), 7.31–7.34 (m, 3 H, H8, H2′, H6′), 8.20
(dd, J = 7.6, 1.4 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3):
δ = 24.4, 48.7, 55.1, 57.7, 113.6, 114.1, 118.4, 118.8, 119.4,
129.4, 130.2, 133.4, 134.0, 144.5, 158.5, 167.8, 173.0. Anal.
Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C,
70.50; H, 6.44; N, 8.80.
4-Benzyl-1,2-dihydro-2,2-dimethyl-4H-benzo[e][1,4]-
diazepine-3,5-dione (11c)
Yield 0.23 g (80%); white crystals; mp 100–102 °C. IR
(KBr): 3335 (NH), 1698 (C=O), 1650 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.35 (s, 6 H, CH3), 5.03 (s, 2 H,
NCH2), 6.80 (s, 1 H, NH), 6.99–7.05 (m, 2 H, H9, H4′), 7.17–
7.19 (m, 3 H, H7, H2′, H6′), 7.27–7.37 (m, 3 H, H8, H3′, H5′),
7.98 (d, J = 7.2 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3):
δ = 23.3, 48.5, 56.5, 116.4, 117.9, 119.1, 126.7, 126.9,
128.2, 132.2, 133.9, 138.2, 145.8, 167.6, 176.4. Anal. Calcd
for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.30;
H, 6.40; N, 10.21.
4-(4-Methoxybenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-
benzo[e][1,4]diazepine-3,5-dione (11h)
Yield 0.24 g (70%); white crystals; mp 110–111 °C. IR
(KBr): 3320 (NH), 1698 (C=O), 1617 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.71 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.47 (s, 3 H, CH3), 1.67 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3),
1.76 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 3.76 (s, 3 H,
OCH3), 4.43 (s, 1 H, NH), 5.09 (d, J = 14.0 Hz, 1 H, NCH2),
5.15 (d, J = 14.0 Hz, 1 H, NCH2), 6.71 (d, J = 7.3 Hz, 1 H,
H9), 6.81 (d, J = 8.6 Hz, 2 H, H3′, H5′), 6.90 (t, J = 7.3 Hz, 1
H, H7), 7.32 (dt, J = 7.3, 1.5 Hz, 1 H, H8), 7.36 (d, J = 8.6 Hz,
2 H, H2′, H6′), 8.19 (dd, J = 7.3, 1.5 Hz, 1 H, H6). 13C NMR
(125 MHz, CDCl3): δ = 7.4, 23.1, 26.9, 48.7, 55.1, 60.9,
113.5, 118.3, 118.8, 119.3, 129.8, 130.2, 133.2, 134.0,
144.3, 158.5, 167.7, 173.1. MS: m/z (%) = 338 (76 [M+], 281
(20), 217 (20), 174 (59), 146 (52), 121 (100), 77 (25). Anal.
Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C,
71.15; H, 6.80; N, 8.35.
4-Benzyl-2-ethyl-1,2-dihydro-2-methyl-4H-benzo[e]-
[1,4]diazepine-3,5-dione (11d)
Yield 0.23 g (75%); white crystals; mp 134–136 °C. IR
(KBr): 3467 (NH), 1695 (C=O), 1641 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.78 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.46 (s, 3 H, CH3), 1.77–1.83 (m, 2 H, CH2CH3), 4.53 (s, 1
H, NH), 5.13 (d, J = 15.7 Hz, 1 H, NCH2), 5.31 (d, J = 15.7
Hz, 1 H, NCH2), 6.77 (d, J = 8.1 Hz, 1 H, H9), 6.89 (t, J = 7.5
Hz, 1 H, H7), 6.98–7.00 (m, 1 H, H4′), 7.06–7.11 (m, 2 H, H2′,
H6′), 7.29–7.39 (m, 3 H, H8, H3′, H5′), 8.11 (d, J = 7.5 Hz, 1
H, H6). 13C NMR (125 MHz, CDCl3): δ = 8.4, 20.3, 28.3,
47.1, 61.2, 118.1, 119.0, 119.6, 126.5, 126.8, 127.7, 129.2,
132.6, 133.2, 134.2, 134.9, 144.7, 167.5, 173.7. Anal. Calcd
for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.80;
H, 6.35; N, 9.30.
4-[(Furan-2-yl)-methyl]-1,2-dihydro-2,2-dimethyl-4H-
benzo[e][1,4]diazepine-3,5-dione (11i)
Yield 0.18 g (65%); white crystals; mp 103–105 °C. IR
(KBr): 3366 (NH), 1695 (C=O), 1625 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.45 (s, 6 H, CH3), 4.37 (s, 1 H, NH),
5.17 (s, 2 H, NCH2), 6.28–6.29 (m, 2 H, furan), 6.71 (dd,
J = 7.6, 0.9 Hz, 1 H, H9), 6.92 (dt, J = 7.6, 0.9 Hz, 1 H, H7),
7.30 (dd, J = 3.0, 1.0 Hz, 1 H, furan), 7.34 (dt, J = 7.6, 1.4
Hz, 1 H, H8), 8.21 (dd, J = 7.6, 1.4 Hz, 1 H, H6). 13C NMR
(125 MHz, CDCl3): δ = 24.5, 42.1, 57.8, 108.1, 110.2, 118.2,
118.9, 119.6, 133.5, 134.1, 141.6, 144.6, 151.4, 167.2,
173.2. MS: m/z (%) = 284 (35) [M+], 257 (15), 241 (20), 203
(20), 160 (100), 132 (90), 96 (71), 53 (28). Anal. Calcd for
C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.66; H,
5.86; N, 10.00.
4-(2-Chlorobenzyl)-1,2-dihydro-2,2-dimethyl-4H-
benzo[e][1,4]diazepine-3,5-dione (11e)
Yield 0.27 g (82%); yellow crystals; mp 130–132 °C. IR
(KBr): 3338 (NH), 1697 (C=O), 1622 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.51 (s, 6 H, CH3), 4.37 (s, 1 H, NH),
5.26 (s, 2 H, NCH2), 6.76 (dd, J = 8.2, 1.0 Hz, 1 H, H9), 6.95
(ddd, J = 8.2, 6.5, 1.1 Hz, 1 H, H4′), 7.05 (t, J = 7.0 Hz, 1 H,
H7), 7.14–7.17 (m, 2 H, H5′, H6′), 7.34 (dd, J = 6.5, 3.0 Hz, 1
H, H3′), 7.38 (ddd, J = 8.2, 7.0, 1.5 Hz, 1 H, H8), 8.20 (dd,
J = 7.0, 1.5 Hz, 1 H, H6). 13C NMR (125 MHz, CDCl3):
δ = 24.7, 47.3, 58.0, 118.4, 119.1, 119.9, 126.6, 127.0,
127.9, 129.4, 132.9, 133.5, 134.3, 135.1, 144.8, 167.6,
173.5. MS: m/z (%) = 330 (17) [M + 2]+, 328 (51) [M+], 300
(20), 203 (25), 160 (100). 132 (85), 92 (28), 65 (20). Anal.
Calcd for C18H17ClN2O2: C, 65.75; H, 5.21; N, 8.52. Found:
C, 65.90; H, 5.45; N, 8.40.
2-Ethyl-4-[(furan-2-yl)-methyl]-1,2-dihydro-2-methyl-
4H-benzo[e][1,4]diazepine-3,5-dione (11j)
Yield 0.18 g (60%); white crystals; mp 102–104 °C. IR
(KBr): 3336 (NH), 1697 (C=O), 1621 (C=O) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.73 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.49 (s, 3 H, CH3), 1.66 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3),
1.80 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 4.37 (s, 1 H, NH),
5.09 (d, J = 14.7 Hz, 1 H, NCH2), 5.23 (d, J = 14.7 Hz, 1 H,
4-(2-Chlorobenzyl)-2-ethyl-1,2-dihydro-2-methyl-4H-
benzo[e][1,4]diazepine-3,5-dione (11f)
Yield 0.26 g (75%); yellow crystals; mp 134–136 °C.
Synlett 2012, 23, 2521–2525
© Georg Thieme Verlag Stuttgart · New York

LETTER
NCH2), 6.28–6.31 (m, 2 H, furan), 6.72 (d, J = 8.0 Hz, 1 H,
1,4-Benzodiazepine-3,5-dione Derivatives
2525
(70%); white crystals; mp 125–127 °C. IR (KBr): 3367
(NH), 1687 (C=O), 1634 (C=O) cm–1. 1H NMR (500 MHz,
CDCl3): δ = 1.26 (s, 6 H, CH3), 2.88 (t, J = 7.8 Hz, 2 H,
NCH2CH2), 3.85 (s, 6 H, OCH3), 4.13 (t, J = 7.8 Hz, 2 H,
NCH2CH2), 4.45 (s, 1 H, NH), 6.72–6.80 (m, 4 H, H9, H2′,
H4′, H6′), 6.90 (t, J = 7.5 Hz, 1 H, H7), 7.32 (t, J = 7.5 Hz, 1
H, H8), 8.12 (d, J = 7.5 Hz, 1 H, H6). 13C NMR (125 MHz,
CDCl3): δ = 24.5, 34.9, 48.2, 55.7, 55.8, 57.8, 111.1, 112.1,
118.8, 119.5, 120.7, 132.4, 133.1, 134.0, 144.4, 147.4,
148.6, 168.1, 173.2. Anal. Calcd for C21H24N2O4: C, 68.46;
H, 6.57; N, 7.60. Found: C, 68.15; H, 6.30; N, 7.77.
H9), 6.91 (t, J = 7.7 Hz, 1 H, H7), 7.31–7.35 (m, 2 H, H8,
furan), 8.20 (d, J = 7.7 Hz, 1 H, H6). 13C NMR (125 MHz,
CDCl3): δ = 7.3, 23.2, 26.9, 42.1, 61.1, 108.5, 110.2, 118.1,
118.9, 119.5, 133.3, 134.1, 141.5, 144.4, 151.4, 167.1,
173.1. MS: m/z (%) = 298 (65) [M+], 271 (14), 241 (42), 217
(26), 174 (97), 146 (75), 81 (100), 53 (45). Anal. Calcd for
C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.25; H,
5.90; N, 9.15.
4-(3,5-Dimethoxyphenethyl)-1,2-dihydro-2,2-dimethyl-
4H-benzo[e][1,4]diazepine-3,5-dione (11k) Yield 0.26 g
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2521–2525

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