New synthetic methodology for construction of the 1,3,4,5-tetrahydro-2 H -1,3-benzodiazepin-2-one skeleton

Article abstract of DOI:10.1055/s-0029-1218673

We hereby report a new synthetic methodology for construction of the 1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one skeleton. 2-(2-Carboxyethyl) benzoic acid was converted into the corresponding bis(acyl azide). Curtius rearrangement of the diazide followed by reaction with alcohols provided diurethane derivatives. Ring-closure reaction of the diurethanes with base resulted in formation of the 1,3-benzodiazepin-2-one skeleton. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218673

PAPER
1365
New Synthetic Methodology for Construction of the 1,3,4,5-Tetrahydro-2H-
1,3-benzodiazepin-2-one Skeleton
S
ynthesis of 1,3,4
a
,5-Tetrahy
g
dro-2
H
-1,3-b
a
enzodiazep
t
in-2-o
a
ne y Dengiz,a Sevil Özcan,a,b Ertan Şahin,c Metin Balci*a
a
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Fax +90(312)2103200; E-mail: mbalci@metu.edu.tr
b
c
Department of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
Department of Chemistry, Atatürk University, 25240 Erzurum, Turkey
E-mail: ertan@atauni.edu.tr
Received 13 December 2009
lowed by Michael addition of tert-butyl 4-amino-
piperidine-1-carboxylate to the resulting activated vinyl
compound, hydrogenation and cyclic urea formation.
Abstract: We hereby report a new synthetic methodology for con-
struction of the 1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one
skeleton. 2-(2-Carboxyethyl)benzoic acid was converted into the
corresponding bis(acyl azide). Curtius rearrangement of the diazide
followed by reaction with alcohols provided diurethane derivatives.
Ring-closure reaction of the diurethanes with base resulted in for-
mation of the 1,3-benzodiazepin-2-one skeleton.
By targeting the synthesis of nitrogen-containing com-
pounds of biological interest with parent skeleton 2, we
wish to report here a novel route for formation of the 1,3-
benzodiazepin-2-one skeleton 2 based upon the double
Curtius rearrangement of the diazide derived from 2-(2-
carboxyethyl)benzoic acid (bishomophthalic acid, 6) fol-
lowed by cyclization.
Key words: acyl azide, isocyanate, Curtius rearrangement, ure-
thanes, benzodiazepinone
2-(2-Carboxyethyl)benzoic acid (6) can serve as a build-
ing block for 1,3-benzodiazepin-2-one 2. The starting ma-
terial 6 has been synthesized starting from b-naphthol
(Scheme 1). b-Naphthol (4) was first oxidized to o-car-
boxycinnamic acid (5) by reaction with peroxyacetic acid.
Diacid 5 was then reacted with Raney nickel in basic
aqueous solution to give the desired acid 6, as described
in the literature.6
Since the initial discovery of the sedative and tranquiliz-
ing effects of diazepam (1) (Figure 1), benzodiazepines
have been extensively investigated.1 Further extensive in-
vestigations of this class of seven-membered N-heterocy-
cles have also led to the development of a number of
pharmacologically active agents directed against other
diseases such as cancer, HIV and cardiac arrhythmia.2
Relatively little work, however, has been done on the syn-
thesis of the 1,3-benzodiazepin-2-one 2. Some derivatives
of 2, such as 3 substituted at the nitrogen atom with a pip-
eridine ring or other substituents, are CGRP (calcitonin
gene-related peptide) receptor antagonists for the treat-
ment of migraine.3 Therefore, a great attention has been
directed towards the synthesis of 3 and its derivatives in
recent years.
For the synthesis of bis(acyl azide) 8, 2-(2-carboxyeth-
yl)benzoic acid (6) was treated with oxalyl chloride in the
presence of N,N-dimethylformamide in dichloromethane,
followed by addition of a solution of sodium azide in a
mixture of acetone and water (Scheme 1).
After the successful synthesis of bis(acyl azide) 8, we
turned our attention to the Curtius rearrangement. Our
plan for the construction of the desired heterocyclic ring
system involved an intramolecular cyclization reaction of
the diisocyanate 9, which can be generated by the Curtius
reaction.7 Thus, bis(acyl azide) 8 was allowed to reflux in
benzene for one hour to effect the transformation of the
acyl azide functionalities to the corresponding isocyanate
groups (Scheme 2). Treatment of the resulting diisocyan-
ate 9 with aniline in dichloromethane at room temperature
for 12 hours gave the expected diurea 10 in 69% yield.
Me
N
O
O
H
N
O
H
N
N
NH
NH
N
Cl
Ph
1
2
3
Figure 1
The most general synthetic approach to 1,3-benzodiaz-
epin-2-one 2 yet reported involves the reaction of o-ami-
noalkyl-substituted aromatic amines and selenium in the
presence of N-methylpyrrolidone.4 More recently, Han
and co-workers5 succeeded in the synthesis of 3 and its de-
rivatives by Stille reaction of o-halonitrobenzenes fol-
As a result of this, we redirected our efforts to the ring-
closure reaction of 10, already bearing the necessary func-
tionalities, as shown in Scheme 2. All efforts with various
bases, such as pyridine, potassium carbonate and cesium
carbonate, did not reveal the formation of the ring-closure
product 11; however, treatment of diurea 10 with lithium
diisopropylamide under reflux for one week afforded
N,N¢-diphenylurea8 (12) as the isolable product in 47%
yield (based on the consumed starting material). The spec-
troscopic data of 12 was in complete agreement with those
SYNTHESIS 2010, No. 8, pp 1365–1370
x
x
.
x
x
.2
0
1
0
Advanced online publication: 11.02.2010
DOI: 10.1055/s-0029-1218673; Art ID: P16809SS
© Georg Thieme Verlag Stuttgart · New York

1366
C. Dengiz et al.
PAPER
COOH
COOH
COOH
OH
40% AcOOH
AcOH
Raney nickel
NaOH, H2O
heat
COOH
4
5
6
(COCl)2
DMF, CH2Cl2
r.t., 96%
CON3
CON3
COCl
COCl
NaN3
acetone, H2O
79%
8
7
Scheme 1 Synthesis of the key compound, bis(acyl azide) 8
of 12 obtained by the reaction of phenyl isocyanate (13)
with aniline (Scheme 2).
N
C O
CON3
CON3
benzene
After the failure of the ring-closure reaction of 10, we de-
cided to increase the reactivity of the carbonyl groups in
10. For that purpose, bis(acyl azide) 8 was reacted with
methanol and tert-butyl alcohol at the reflux temperature
of the alcohol to give the corresponding diurethane deriv-
atives 14a and 14b, respectively. Reaction of 14a and 14b
with various bases, such as sodium hydride, potassium
carbonate and triethylamine, did not result in the forma-
tion of any trace of the ring-closure products; however,
when 14a and 14b were reacted with lithium hexamethyl-
disilazide for 30–60 minutes, the 1,3-benzodiazepinone
derivatives 16a and 16b were obtained in 44% and 52%
yield, respectively. Prolonged reaction time resulted in a
decreased amount of the desired product.
N
C O
reflux, 1 h
72%
9
8
PhNH2
r.t., 69%
H
O
N
H
N
O
NH
O
X base
O
N
HN
10
LDA
NH
N
H
11
reflux, 7 d
47%
Spectroscopic data allowed the assignment of the struc-
tures 16a and 16b. In order to confirm the structure and
elucidate the structural impact of the substituents on the
benzodiazepinone scaffold, we conducted single crystal
X-ray analysis studies on the product 16a (Figure 2).
O
PhNH2
r.t.
N
C
O
N
N
H
H
The compound crystallizes in the triclinic space group P1,
with two molecules in the unit cell (Figure 3). The diaze-
pinone ring adopts a slightly distorted boat conformation.
12
13
Scheme 2 Synthesis of diurea 10 and its reaction with lithium diiso-
propylamide
O
OR
NH
H
N
CON3
ROH
O
O
+
HN
CON3
reflux, 6–12 h
OR
14a (86%)
14b (65%)
8
15
a R = Me
b R = t-Bu
LiHMDS
THF, reflux
H
H
O
O
N
N
O
TFA
NH
N
CH2Cl2, r.t.
91% (from 16b)
OR
2
16a (44%)
16b (52%)
Scheme 3 Synthesis of diurethanes 14a and 14b, and their ring-closure reactions
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Synthesis of the 1,3,4,5-Tetrahydro-2H-1,3-benzodiazepin-2-one Skeleton
1367
The unsymmetrical distortion arises from the torsional
strains between the substituted units. The C=O bond
lengths are within the expected range [1.201(4)–1.225(4)
Å]. Furthermore, the compound exists as a dimer, exhib-
iting intermolecular N–H···O hydrogen bonding [N2–
H···O3i = 2.899(2) Å; N2–H···O3i = 175°; symmetry code
(i); 1-x,-y,1-z].
In the reaction of diurethane 14a or 14b with base, a mix-
ture of two regioisomers 16 and 17 is expected as a result
of the attack of the amide functionalities to the two carbo-
nyl groups (Figure 4). Because of the increased acidity of
the NH attached directly to the benzene ring, one would
expect 17 as the sole or major product. Surprisingly, the
isomers 16a and 16b were formed as sole products. We
assume that the abstraction of the more acidic NH proton
in 14 is hindered by the bulky base which is used, or the
nucleophilicity of the amide functionality conjugated with
the benzene ring may also be reduced due to the conjuga-
tion.
Figure 2 Single crystal X-ray diffraction analysis of 16a; the
ORTEP drawing depicts thermal ellipsoids at a 40% probability level
OR
O
H
O
O
N
N
O
N
NH
OR
16
17
Figure 4
Hydrolysis of the half ester 16b with trifluoroacetic acid
in dichloromethane at room temperature gave the 1,3-ben-
zodiazepin-2-one 2 in high yield (Scheme 3). The spectro-
scopic data of 2 was fully in accordance with the proposed
structure.4 Furthermore, we reacted diurethane 14a with
lithium diisopropylamide in tetrahydrofuran; two prod-
ucts were formed and, after chromatographic separation,
were identified as the cyclization products 2 and 16a
(Scheme 4). For further derivatization of 1,3-benzodiaz-
epin-2-one 2, reaction with sodium hydride in tetrahydro-
furan followed by quenching with acetic anhydride
Figure 3 Unit cell along the a-axis (data for 16a); dashed lines in-
dicate intermolecular hydrogen bonding
O
OMe
NH
H
O
H
O
N
N
O
LDA
O
NH
N
+
HN
reflux, 30 min
OMe
OMe
14a
2
16a
1. NaH, THF
2. Ac2O, r.t., 30 min
1. NaH, THF
2. ClCO2Et, r.t., 30 min
83%
70%
OEt
O
O
N
O
O
O
N
O
N
N
OEt
18
19
Scheme 4 Reaction of diurethane 14a with lithium diisopropylamide, and derivatization of 2
Synthesis 2010, No. 8, 1365–1370 © Thieme Stuttgart · New York

1368
C. Dengiz et al.
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reduced pressure to give the diisocyanate 9 as a colorless oil which
was directly used for the next step without further purification;
yield: 0.33 g (72%).
provided the diacetyl derivative 18. Similarly, the diester
derivative 19 was obtained by reaction of the initially
formed salt with ethyl chloroformate.
IR (KBr): 2968 (w), 2274 (s), 2146 (m), 1713 (m), 1513 (m), 1226
(m), 756 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.18–7.13 (m, 2 H, H-4 and H-5),
7.10 (br dd, J = 7.3, 1.4 Hz, H-3 or H-6), 7.06 (br dd, J = 7.9, 1.2
Hz, H-3 or H-6), 3.46 (t, J = 6.8 Hz, 2 H, H-2¢), 2.87 (t, J = 6.8 Hz,
2 H, H-1¢).
In summary, the present investigation has resulted in the
preparation of 1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-
2-one (2) and its derivatives by application of a new syn-
thetic methodology, where two Curtius rearrangements
are involved as the key step. This methodology should be
a suitable synthetic method for the introduction of further
substituents at the aromatic ring, as well as the seven-
membered ring. Further research in this field is in
progress.
13C NMR (100 MHz, CDCl3): d = 134.4, 133.7, 132.6, 130.3, 128.3,
128.0, 127.3, 124.3, 44.7, 35.8.
N-(2-{2-[(Anilinocarbonyl)amino]ethyl}phenyl)-N¢-phenylurea
(10)
A soln of PhNH2 (1.2 g, 12.9 mmol) in benzene (5 mL) was added
dropwise to a stirred soln of diisocyanate 9 (1.0 g, 5.32 mmol) in an-
hyd CH2Cl2 (50 mL) at r.t. and the mixture was stirred for 12 h. The
formed diurea 10 was collected by filtration and washed with
CH2Cl2 (5–10 mL) to give a colorless powder; yield: 1.36 g (69%);
mp 207–208.5 °C.
Melting points were determined on a Thomas Hoover capillary
melting point apparatus. IR spectra were recorded on a Perkin
Elmer 980 spectrometer. 1H and 13C NMR spectra were recorded on
a Bruker Avance instrument at 400 and 100 MHz, respectively. Ap-
parent splitting is given in all cases. Mass spectra were recorded on
an Agilent Technologies 5975C mass spectrometer operating at an
ionization potential of 70 eV. Column chromatography was per-
formed on Merck silica gel (60 mesh). TLC was carried out on Mer-
ck 0.2 mm silica gel 60 F254 analytical aluminum plates.
IR (KBr): 3347 (s), 3218 (m), 3043 (m), 1648 (s), 1620 (s), 1565 (s),
1317 (s), 1179 (s), 893 (w), 709 (s), 691 (s) cm–1.
1H NMR (400 MHz, acetone-d6): d = 8.84 (s, NH), 8.63 (s, NH),
8.33 (s, NH), 7.87 (dd, J = 7.5, 1.2 Hz, 1 H), 7.46 (br d, J = 7.6 Hz,
2 H), 7.40 (br d, J = 7.6 Hz, 2 H), 7.28 (br t, J = 7.6 Hz, 2 H), 7.23
(br t, J = 7.5 Hz, 2 H), 7.21–7.18 (m, 2 H), 7.01 (dt, J = 7.4, 1.1 Hz,
1 H), 6.98 (br t, J = 7.4 Hz, 1 H), 6.92 (br t, J = 7.3 Hz, 1 H), 6.35
(t, J = 5.6 Hz, NH), 3.38–3.26 (m, 2 H), 2.79 (t, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, acetone-d6): d = 155.8, 152.8, 140.2, 139.8,
137.4, 129.5, 129.2, 128.8, 128.6, 126.7, 122.9, 121.74, 121.69,
121.3, 118.1, 117.9, 39.1, 31.7.
1-Chloro-3-[2-(chlorocarbonyl)phenyl]propan-1-one (7)
To a suspension of 2-(2-carboxyethyl)benzoic acid (6; 1.0 g, 5.15
mmol) in CH2Cl2 (50 mL), oxalyl chloride (1.77 mL, 20.6 mmol)
was added quickly at r.t. This was followed by the addition of DMF
(2 drops) as catalyst, and the reaction mixture was stirred for 4 h at
r.t. The reaction was completed after all the starting material had
dissolved in the CH2Cl2. The reaction mixture was concentrated un-
der reduced pressure to afford dichloride 7 as a colorless oil; yield:
1.14 g (96%).
Anal. Calcd for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96. Found: C,
70.22; H, 5.88; N, 15.03.
IR (KBr): 2922 (w), 1797 (s), 1771 (s), 1451 (w), 1275 (m), 1188
(s), 750 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.24 (d, J = 8.0 Hz, H-6¢), 7.59 (t,
J = 7.2 Hz, H-5¢), 7.43 (t, J = 7.7 Hz, H-4¢), 7.37 (d, J = 7.7 Hz, H-
3¢), 3.27–3.19 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 172.8, 168.1, 141.4, 134.9, 134.5,
132.2, 131.7, 127.8, 47.5, 30.0.
N,N¢-Diphenylurea (12); Reaction of Diurea 10 with Lithium
Diisopropylamide
LDA soln was prepared by the addition of 1.6 M n-BuLi in hexane
(3.67 mL, 5.9 mmol) to a soln of freshly distilled i-Pr2NH (0.83 mL,
5.9 mmol) in THF (5 mL) at –78 °C, followed by stirring for 30 min.
Diurea 10 (0.5 g, 1.34 mmol) was added to the solution. The mixture
was refluxed for 7 d. The reaction was monitored by TLC. After
completion of the reaction, aq NH4Cl soln (20 mL) was added, the
mixture was extracted with EtOAc (3 × 50 mL) and the extracts
were dried (MgSO4). Removal of EtOAc gave a mixture (0.35 g).
Chromatography of this mixture over silica gel (EtOAc–hexane,
1:2) gave N,N¢-diphenylurea8 (12); yield: 99 mg (35%; 47% based
on the consumed starting material); as the second fraction, unreact-
ed starting material 10 was isolated (130 mg, 0.35 mmol).
1-Azido-3-[2-(azidocarbonyl)phenyl]propan-1-one (8)
To a soln of dichloride 7 (1.14 g, 4.93 mmol) in acetone (10 mL) at
0 °C, a soln of NaN3 (1.28 g, 19.7 mmol) in H2O (5 mL) was added.
Precipitation of inorganic salt was immediately observed. After
completion of the addition, the resulting mixture was stirred for 1 h
and H2O (25 mL) was added. The mixture was extracted with
EtOAc (3 × 75 mL). The organic extracts were dried (MgSO4). Af-
ter removal of the solvent under reduced pressure, bis(acyl azide) 8
was obtained as a colorless oil which was directly used for the next
step without further purification; yield: 0.948 g (79%).
1H NMR (400 MHz, DMSO-d6): d = 8.72 (s, 2 H, NH), 7.50 (br d,
J = 7.6 Hz, 4 H), 7.32 (br t, J = 7.6 Hz, 4 H), 7.00 (br t, J = 7.6 Hz,
2 H).
13C NMR (100 MHz, DMSO-d6): d = 152.5, 139.7, 128.7, 121.8,
118.2.
IR (KBr): 2979 (w), 2275 (s), 2137 (s), 1715 (s), 1692 (s), 1229 (s),
1082 (m), 913 (m), 748 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.88 (dd, J = 7.8, 1.2 Hz, H-6¢),
7.43 (dt, J = 7.5, 1.4 Hz, H-4¢), 7.25–7.21 (m, 2 H, H-3¢ and H-5¢),
3.23 (t, J = 7.6 Hz, 2 H, H-2), 2.63 (t, J = 7.6 Hz, 2 H, H-1).
13C NMR (100 MHz, CDCl3): d = 180.3, 173.7, 143.5, 134.4, 132.3,
132.0, 129.6, 127.5, 38.5, 30.2.
Methyl2-{2-[(Methoxycarbonyl)amino]ethyl}phenylcarbamate
(14a)
Bis(acyl azide) 8 (2.87 g, 11.75 mmol) was dissolved in MeOH
(150 mL) and the mixture was refluxed for 6 h. The reaction was
monitored by TLC. After completion of the reaction, the solvent
was removed under reduced pressure. Chromatography of the resi-
due on silica gel (50 g; EtOAc–CH2Cl2, 1:3) afforded the known
3,4-dihydroquinolin-2(1H)-one9 (15) as the first fraction; yield:
0.092 g (5.4%). The second fraction was identified as diurethane
14a; yield: 2.55 g (86%); colorless crystals (EtOAc); mp 82–84 °C.
1-Isocyanato-2-(2-isocyanatoethyl)benzene (9)
Bis(acyl azide) 8 (0.59 g, 2.4 mmol) was dissolved in anhyd ben-
zene (50 mL) and the mixture was refluxed for 1 h. After comple-
tion of the reaction, the reaction mixture was concentrated under
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Synthesis of the 1,3,4,5-Tetrahydro-2H-1,3-benzodiazepin-2-one Skeleton
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IR (KBr): 3324 (s), 3015 (m), 2953 (m), 1704 (s), 1533 (s), 1242 (s),
1068 (s), 757 (s) cm–1.
IR (KBr): 3243 (m), 3162 (m), 3003 (w), 2989 (w), 2901 (w), 1702
(s), 1156 (m), 759 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79 (br s, 1 H), 7.42 (br s, 1 H,
NH), 7.18 (t, J = 7.7 Hz, 1 H), 7.06 (d, J = 7.3 Hz, 1 H), 6.99 (t,
J = 7.3 Hz, 1 H), 4.98 (br s, 1 H, NH), 3.72 (s, 3 H, OCH3), 3.64 (s,
3 H, OCH3), 3.23 (dt, J = 7.4, 6.2 Hz, 2 H, H-2¢), 2.75 (t, J = 7.2 Hz,
2 H).
13C NMR (100 MHz, CDCl3): d = 157.8, 155.1, 136.1, 129.9,
129.2, 127.6, 124.5, 122.6, 52.5, 52.3, 41.3, 31.8.
1H NMR (400 MHz, CDCl3): d = 8.49 (br s, 1 H, NH), 7.19 (br d,
J = 7.3 Hz, 1 H, H-9), 7.17 (br d, J = 7.0 Hz, 1 H, H-6), 7.08–7.03
(m, 2 H, H-7 and H-8), 3.98 (t, J = 6.0 Hz, 2 H, H-4), 3.09 (t, J = 6.0
Hz, 2 H, H-5), 1.51 [s, 9 H, OC(CH3)3].
13C NMR (100 MHz, CDCl3): d = 156.2, 152.5, 136.4, 130.7, 128.1,
127.3, 124.2, 121.3, 82.4, 45.3, 32.3, 28.1.
Anal. Calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
63.89; H, 6.92; N, 10.70.
Anal. Calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10. Found: C,
57.43; H, 6.43; N, 11.12.
1,3,4,5-Tetrahydro-2H-1,3-benzodiazepin-2-one (2)
tert-Butyl 2-{2-[(tert-Butoxycarbonyl)amino]ethyl}phenylcar-
bamate (14b)
1,3-Benzodiazepine-3-carboxylate 16b (80 mg, 0.3 mmol) was dis-
solved in CH2Cl2 (10 mL). TFA (235 mg, 2 mmol) was added drop-
wise at 0 °C and the mixture was stirred for 1 h at r.t. After
completion of the reaction, H2O (20 mL) was added and the result-
ing mixture was extracted with EtOAc (3 × 25 mL). The combined
organic layers were washed with H2O (25 mL) and dried (MgSO4).
Removal of the solvent gave the crude product 2 [yield: 45 mg
(91%)] which was crystallized (EtOAc–n-hexane) to give colorless
crystals; mp 170–172 °C (Lit.4b 170.5–171 °C, Lit.4c 169–171 °C).
Bis(acyl azide) 8 (2.37 g, 9.7 mmol) was dissolved in t-BuOH (200
mL) and the mixture was refluxed for 12 h. The reaction was mon-
itored by TLC. After completion of the reaction, the solvent was re-
moved under reduced pressure. Chromatography of the residue on
silica gel (50 g; EtOAc–n-hexane, 1:3) afforded diurethane 14b;
yield: 2.12 g (65%); colorless crystals (EtOH–n-hexane); mp 90–
92 °C.
IR (KBr): 3333 (s), 2979 (m), 2934 (m), 1690 (s), 1520 (s), 1166 (s),
744 (s) cm–1.
1H NMR (400 MHz, CD3OD): d = 7.00 (br t, J = 7.4 Hz, 1 H, H-8),
6.94 (br d, J = 7.5 Hz, 1 H, H-9), 6.85 (br d, J = 8.0 Hz, 1 H, H-6),
6.80 (br t, J = 7.5 Hz, 1 H, H-7), 4.75 (br s, 2 H, NH), 3.26–3.24 (m,
2 H, H-4), 2.89–2.87 (m, 2 H, H-5).
13C NMR (100 MHz, CD3OD): d = 159.2, 138.4, 130.5, 130.2,
127.8, 123.0, 119.7, 43.2, 35.3.
1H NMR (400 MHz, CDCl3): d = 7.78 (br d, J = 7.4 Hz, 1 H, H-6),
7.43 (br s, 1 H, NH), 7.14 (dt, J = 7.2, 1.6 Hz, 1 H, H-5), 7.01 (br d,
J = 6.7 Hz, 1 H, H-3), 6.93 (br t, J = 7.3 Hz, 1 H, H-4), 4.80 (br s, 1
H, NH), 3.16 (dt, J = 7.8, 6.5 Hz, 2 H, H-2¢), 2.70 (t, J = 7.8 Hz, 2
H), 1.45 [s, 9 H, OC(CH3)3], 1.39 [s, 9 H, OC(CH3)3].
Reaction of Methyl 2-{2-[(Methoxycarbonyl)amino]ethyl}phe-
nylcarbamate (14a) with Lithium Diisopropylamide
13C NMR (100 MHz, CDCl3): d = 156.7, 153.8, 136.8, 129.7, 128.7,
127.4, 123.7, 122.2, 80.0, 79.7, 41.1, 32.1, 28.4, 28.0.
LDA soln was prepared by the dropwise addition of 1.6 M n-BuLi
in hexane (6.25 mL, 10 mmol) to a soln of i-Pr2NH (1.0 g, 9.9
mmol) in THF (5 mL) at –78 °C, followed by stirring for 30 min.
Then, diurethane 14a (1.0 g, 3.96 mmol) in THF (5 mL) was added
at –78 °C. The resulting solution was stirred for 30 min at –78 °C
and an additional 30 min at the reflux temperature. The resulting re-
action mixture was quenched with sat. aq NH4Cl soln (25 mL), the
mixture was extracted with EtOAc (3 × 50 mL) and the extracts
were dried (MgSO4). The solvent was removed under reduced pres-
sure and the residue was chromatographed on silica gel (EtOAc–
CH2Cl2, 1:3) which afforded three compounds in the following or-
der: unreacted starting material 14a (185 mg, 0.73 mmol), 16a
[yield: 105 mg (15% based on the consumed starting material)] and
2 [yield: 225 mg (43% based on the consumed starting material)].
Anal. Calcd for C18H28N2O4: C, 64.26; H, 8.39; N, 8.33. Found: C,
64.01; H, 8.25; N, 8.62.
Methyl 2-Oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepine-3-
carboxylate (16a)
Diurethane 14a (500 mg, 1.98 mmol) was dissolved in THF (25
mL) under N2 atmosphere and reacted with LiHMDS as described
for the reaction of 14b below. After reaction workup, the residue
was chromatographed on silica gel (EtOAc–CH2Cl2, 1:1) to give
16a as colorless crystals (EtOAc–n-hexane); yield: 176 mg (44%);
mp 145–147 °C. Prolonged reaction time resulted in decreased
yield of the product; the hydrolysis product was formed.
IR (KBr): 3245 (m), 2956 (w), 2916 (w), 1700 (s), 1403 (m), 1309
(m), 1219 (m), 772 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.21 (br s, 1 H, NH), 7.15–7.11
(m, 2 H), 7.02 (dt, J = 7.4, 1.3 Hz, 1 H, H-7), 6.82 (br dd, J = 7.9,
1.4 Hz, 1 H, H-6), 3.95 (t, J = 6.1 Hz, 2 H, H-4), 3.73 (s, 3 H,
OCH3), 3.03 (t, J = 6.1 Hz, 2 H, H-5).
1,3-Diacetyl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one
(18)
1,3-Benzodiazepin-2-one 2 (120 mg, 0.74 mmol) was dissolved in
THF (10 mL) and the solution was cooled to 0 °C. NaH (60%; 150
mg, 3.75 mmol) was added and the reaction mixture was allowed to
warm to r.t. and was stirred for 30 min. Then, Ac2O (500 mg, 4.9
mmol) was added and the mixture was stirred for an additional 30
min at r.t. After completion of the reaction, excess NaH was
quenched by the dropwise addition of H2O. The aqueous phase was
extracted with EtOAc (3 × 50 mL). The combined organic layers
were washed with H2O (2 × 25 mL), dried (MgSO4) and the solvent
was evaporated to give the crude diacetyl derivative 18. Chroma-
tography of the residue over a short silica gel column (EtOAc–
CH2Cl2, 1:1) gave pure 18 as a colorless oil; yield: 127 mg (70%).
1H NMR (400 MHz, CDCl3): d = 7.24–7.17 (m, 4 H), 4.01 (br s, 2
H, H-4), 3.00 (t, J = 6.8 Hz, 2 H, H-5), 2.34 (s, 3 H, CH3), 2.24 (s,
3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 170.3, 168.5, 154.7, 132.9, 130.8,
128.2, 127.02, 126.97, 125.4, 42.0, 27.8, 23.2, 22.3.
13C NMR (100 MHz, CDCl3): d = 155.5, 154.4, 135.8, 130.7, 128.6,
127.6, 124.9, 121.2, 53.8, 46.5, 31.6.
Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
59.62; H, 5.49; N, 12.70.
tert-Butyl 2-Oxo-1,2,4,5-tetrahydro-3H-1,3-benzodiazepine-3-
carboxylate (16b)
Diurethane 14b (1.14 g, 3.4 mmol) was dissolved in THF (25 mL)
under N2 atmosphere. A soln of 1 M LiHMDS in THF (5.1 mL, 5.1
mmol) was added dropwise and the resulting mixture was refluxed
for 1 h. After completion of the reaction, aq NH4Cl soln (25 mL)
was added, the mixture was extracted with EtOAc (3 × 50 mL) and
the extracts were dried (MgSO4). After evaporation of the solvent,
the residue was crystallized (EtOAc–n-hexane) to give 16b as col-
orless crystals; yield: 462 mg (52%); mp 177–179 °C.
Synthesis 2010, No. 8, 1365–1370 © Thieme Stuttgart · New York

1370
C. Dengiz et al.
PAPER
MS: m/z (%) = 246 (6) [M+], 204 (100) [MH+ – COCH3], 161 (38)
[MH+ – 2 × COCH3], 106 (50), 72 (87).
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Diethyl 2-Oxo-4,5-dihydro-1H-1,3-benzodiazepine-1,3(2H)-di-
carboxylate (19)
1,3-Benzodiazepin-2-one 2 (120 mg, 0.74 mmol) was carboxylated
by adding NaH as described above, then adding ethyl chloroformate
(540 mg, 5 mmol). Chromatography of the residue over a short sil-
ica gel column (EtOAc–CH2Cl2, 1:1) gave pure diester derivative
19; yield: 188 mg (83%); mp 62–64 °C.
IR (KBr): 2984 (w), 1791 (s), 1728 (s), 1370 (m), 1220 (s), 773 (s)
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.34–7.15 (m, 4 H), 4.23 (q,
J = 7.0 Hz, 2 H, OCH2), 4.13 (q, J = 7.0 Hz, 2 H, OCH2), 3.97 (t,
J = 6.5 Hz, 2 H, H-4), 3.03 (t, J = 6.5 Hz, 2 H, H-5), 1.23 (t, J = 7.0
Hz, 3 H, CH3), 1.18 (t, J = 6.5 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 153.7, 152.9, 152.2, 135.2, 132.5,
129.7, 128.6, 128.5, 127.2, 63.5, 63.4, 46.1, 30.0, 14.23, 14.16.
MS: m/z (%) = 306 (15) [M+], 234 (12) [MH+ – COOEt], 188 (38),
162 (10), 146 (25), 132 (100), 118 (72), 102 (50), 77 (25).
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Anal. Calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15. Found: C,
58.51; H, 6.12; N, 9.16.
Single Crystal X-ray Analysis of Compound 16a
Full crystallographic parameters (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre
under reference number CCDC 749741. These data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgment
The authors are indebted to TUBITAK (Scientific and Technologi-
cal Research Council of Turkey, Grant Number 108-M168), the De-
partment of Chemistry at Middle East Technical University, and
TUBA (Turkish Academy of Sciences) for their financial support of
this work.
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Synthesis 2010, No. 8, 1365–1370 © Thieme Stuttgart · New York