Synthesis and reactivity of 2,3-dihydro-1H-2,3-benzodiazepine-1,4(5H)-dione

Article abstract of DOI:10.1055/s-2007-990893

Based on an orthogonal protective group strategy dealing with N-protected hydrazine, we established for the first time a highly efficient synthetic pathway leading to 2,3-benzodiazepine-1,4-dione. Moreover, the versatile reactivities exhibited by this 2,3

Full text of DOI:10.1055/s-2007-990893

PAPER
3791
Synthesis and Reactivity of 2,3-Dihydro-1H-2,3-benzodiazepine-1,4(5H)-dione
2
, 3-Dihydro-1
r
H
-2,3-be
é
nzodiazepi
d
ne-1,4(5
H
)
-d
é
ione ric J.-J. Bihel,* Malik Hellal, Jean-Jacques Bourguignon
Institut Gilbert Laustriat, UMR 7175 CNRS, Département Pharmacochimie de la Communication Cellulaire,
Faculté de pharmacie, Université Strasbourg I, 74 route du rhin, BP60024, 67400 Illkirch Graffenstaden, France
Fax +33(3)90244310; E-mail: frederic.bihel@pharma.u-strasbg.fr
Received 14 May 2007; revised 20 September 2007
ported by Whitmore and Cooney, but only the compound
Abstract: Based on an orthogonal protective group strategy dealing
with N-protected hydrazine, we established for the first time a high-
ly efficient synthetic pathway leading to 2,3-benzodiazepine-1,4-di-
one. Moreover, the versatile reactivities exhibited by this 2,3-
3 was obtained in 71% yield (Scheme 1). The most elec-
trophilic carbonyl carbon at the 3-position of the 1H-iso-
chromene-1,3(4H)-dione undergoes a first nucleophilic
benzodiazepine-1,4-dione were evaluated towards both benzylation attack by hydrazine affording a hydrazide intermediate,
and amination reactions.
which exhibits both amine and amide functions as possi-
ble nucleophilic groups for cyclocondensation. Surpris-
ingly, the observed cyclization involved the amide
nitrogen, which is less nucleophilic than the amino group,
leading to the 6- membered ring 3.4 As an alternative path-
way, we synthesized the 3-methoxyisocoumarine 2, in
which the only electrophilic carbonyl carbon is at the po-
sition 1. However, the reaction with hydrazine led again to
the six-membered ring 3, as previously observed
(Scheme 1).
Key words: benzodiazepine, hydrazine, amides, aminations, bicy-
clic compounds
During the course of our investigations dealing with py-
ridazine-3,6-dione and phthalazine-1,4-dione scaffolds,
extensive work has been done focusing on the regio- and
chemoselective functionalization of the amide functions
to provide either amidines through nucleophilic substitu-
tion or iminoaryl groups through palladium-catalyzed re-
actions.1 Most of the synthesized compounds, derived
from the six-membered azine ring, were found pharmaco-
logically active on various targets (receptors or enzymes)
involved in pathologies such as Alzheimer’s disease or
pain.2 In our quest of new bioactive compounds, we fo-
cused our research on design, synthesis, and functional-
ization of the 2,3-benzodiazepine (2,3-BZD) scaffold, as
a seven-membered-ring homologue of the 2,3-phthalazine
scaffold, and consequently report here a new convenient
route to the 2,3-BZD-1,4-dione (I) (Figure 1). Moreover,
the reactivity of this new scaffold toward both amination
and benzylation reactions was examined.
O
COOH
O
COOR
O
R = H
(i)
86%
1: R = Me
71% (iv)
96%
(ii)
O
O
O
N
NH2
O
(iii)
52%
OMe
2
3
O
NH
NH
Scheme 1 Reagents and conditions: (i) MeOH, H2SO4, D; (ii)
TFAA, CH2Cl2, 0 °C; (iii) NH2NH2·H2O, MeOH, r.t.; (iv)
NH2NH2·H2O, EtOH, D.
O
I
It appeared that the amine function did not trigger the ex-
pected seven-membered-ring cyclization, which may be
explained by the syn-position of the amine function to-
ward the oxygen atom of the amide function. Consequent-
ly, it seemed critical to use a substituted hydrazine in
order to modify the spatial position of the amine group to-
ward the amide function. In agreement with this hypothe-
sis, the synthesis of 2,3-dimethyl-2,3-BZD-1,4-dione was
reported by Rosen et al., who used the 1,2-dimethylhydra-
zine to perform the cyclization.4 However, the main limi-
tation of this procedure was the impossibility to remove
the alkyl groups of the resulting 2,3-dimethyl-2,3-BZD-
1,4-dione. So, we chose to develop an orthogonal protec-
tive group strategy in which the first amine function of hy-
Figure 1 2,3-Dihydro-1H-benzodiazepine-1,4(5H)-dione (I)
A unique example of the 2,3-BZD-1,4-dione (I) synthesis
was reported in 1944, when Whitmore and Cooney
claimed that the reaction of homophthalic anhydride with
hydrazine hydrate in boiling ethanol led to the 2,3-BZD-
1,4-dione (I).3 However, this result was later disproved by
several reports in which, using the same experimental
conditions, only the N-aminoisoquinoline-1,3-dione (3)
was isolated.4 We also tried to reproduce the procedure re-
SYNTHESIS 2007, No. 24, pp 3791–3796
x
x.
x
x
.
2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990893; Art ID: T08307SS
© Georg Thieme Verlag Stuttgart · New York

3792
F. J.-J. Bihel et al.
PAPER
COOH
COOH
COOH
COOMe
drazine was protected by a Boc group, whereas the second
amine function was protected either by a nosyl moiety (4)
or by a benzyl group (6) (Scheme 2).5 Both benzyl and
nosyl protections afford a satisfactory nucleophilic char-
acter of the protected amine allowing the coupling reac-
tion with the carboxylic acid derivative 1,6 to obtain the
compounds 7a and 7b in 63 and 85% yield, respectively
(Scheme 3). A trifluoroacetic acid treatment led to the
cleavage of the Boc group which was followed by a spon-
taneous cyclization step to provide the 2,3-BZD-1,4-di-
ones 8a and 8b in 88% and 92% yield, respectively. The
cleavage of the benzyl moiety was performed by hydro-
genolysis using palladium chloride as catalyst.7 However,
the deprotection remained incomplete after a reaction
time of 24 hours and the expected 2,3-BZD-1,4-dione (I)
was obtained in a poor 26% yield. On the contrary, the
cleavage of the nosyl moiety was easily performed in mild
conditions by treatment of 8b with thiophenol under basic
conditions,8 leading to the unsubstituted 2,3-BZD-1,4-di-
one (I) in 76% yield.
(i)
84%
1
(ii)
O
O
R
NH
O
(iii)
R
N
N
HN
Boc
COOMe
8a: R = Bn, 88%
8b: R = Ns, 92%
7a: R = Bn, 63%
7b: R = Ns, 85%
(vi)
26%
(vii)
76%
I: R = H
Scheme 3 Reagents and conditions: (i) MeOH, H2SO4 (cat.), D; (ii)
4 or 6, HBTU, DIPEA, DMF, r.t., 12 h; (iii) TFA, CH2Cl2, 1 h, r.t.;
(iv) H2 (60 psi), PdCl2, AcOH, EtOAc, r.t., 12 h; (v) PhSH, Cs2CO3,
DMF, r.t., 3 h.
and 3-benzyl 9) were both isolated in 22% yield, whereas
the 2,3-dibenzylated compound 10 was isolated in 56%
yield (Table 1). The same results were obtained with
K2CO3 in DMF. However, no benzylation was detected
under Mitsunobu conditions. Considering the fact that 8a
and 9 were obtained in the same yield, we can assume that
both amide groups of 2,3-BZD-1,4-dione (I) exhibit an
equal nucleophilicity toward this benzylation reaction, de-
spite the difference between benzamide and phenylaceta-
mide moieties. Moreover, the dibenzylated compound 10
was obtained in the highest yield (56%), highlighting the
fact that as soon as one of the amide functions was benzy-
lated, the nucleophilicity of the second one was increased.
Consequently, it appears very difficult to regioselectively
alkylate a single amide group of compound I. Among the
alternatives, an initial alkylation of Boc-hydrazine would
lead to the corresponding 2-alkyl-2,3-BZD-1,4-dione,
while the alkylation of the compound 8b, followed by
nosyl deprotection, would provide the corresponding 3-
alkyl-2,3-BZD-1,4-dione.
Boc
Boc
(i)
HN NH
H2N NH
80%
O2N
S
O
O
78%
(ii)
N
4
Boc
NH
Boc
HN NH
(iii)
87%
5
6
Scheme 2 Reagents and conditions: (i) NsCl, K2CO3, r.t., 1 h; (ii)
PhCHO, THF, r.t., 1 h; (iii) H2 (60 psi), Pd/C, MeOH, 2 h.
We next focused our study on the reactivity of this 2,3-
BZD-1,4-dione (I) towards the benzylation of the amide
function and its conversion into an amidine. A standard
benzylation using benzyl bromide was performed in the
presence of NaH in DMF, leading to a mixture of three
compounds: monobenzylated derivatives (2-benzyl 8a
Table 1 Benzylation of the 2,3-Benzodiazepine-1,4-dione (I)
O
O
O
O
Bn
NH
O
Bn
NH
NH
N
NH
N
N
Bn
N Bn
O
O
O
8a
9
10
I
Benzylating reagent
Equiv
Conditions
T (°C)
Time (h)
Products
8a
9
10
56
89
53
BnBr
1
2
1
1
NaH, DMF
0
1
1
22
22
a
a
BnBr
NaH, DMF
0
–
–
BnBr
K2CO3, DMF
DIAD, Ph3P, DMF
r.t.
r.t.
24
24
24
20
a
a
a
BnOH
–
–
–
a Not detected.
Synthesis 2007, No. 24, 3791–3796 © Thieme Stuttgart · New York

PAPER
2,3-Dihydro-1H-2,3-benzodiazepine-1,4(5H)-dione
3793
The cyclic amidine represents an important functional
group in medicinal chemistry and can be found in many
FDA-approved drugs (i.e., clozapine). The most common
and convergent strategies for amidine synthesis are based
on substitution by an amine of an activated amide inter-
mediate such as imidoyl chloride or O-triflated imidate.9
Unfortunately, our initial attempts to activate the amide
functions of 2,3-BZD-1,4-dione (I) failed. Indeed, along
with the fact there is a putative competition between both
amides, the main problem was the lack of solubility of the
compound I, especially in solvents such as THF, MeCN,
or pyridine which are commonly used in this field. Several
attempts under acidic conditions (POCl3) failed, most of
them led to degradation. Even the milder procedure using
N,N-dimethyl-p-toluidine base in order to stabilize the im-
idoyl chloride, was performed without success. Under ba-
sic conditions, a multivariate screening analysis of the
following variables was performed: solvent (THF, pyri-
dine, MeCN, DMF), temperature, and nature of the elec-
trophile (Tf2O, TosCl, anhydride, etc.), but in most of the
cases, the solubility was an issue.10 In order to bypass this
parameter, we applied the multivariate screening analysis
on the 2-benzyl-2,3-BZD-1,4-dione (8a), in which the
amide at the 1-position is protected by a benzyl moiety. In
most of the cases, no reaction was observed. However, un-
der tosylation conditions (TsCl, NaH, DMF), the corre-
sponding N-tosylated compound 11 was obtained in 67%
yield, while no O-tosylation was detected (Scheme 4).
This lack of reactivity of the carbonyl groups appeared to
be the same as for the benzylation reactions, in which no
O-benzylated compound was obtained.
Table 2 Amination of the 2,3-Benzodiazepine-1,4-dione (I)
O
O
NH
NH
NH
TiCl4, anisole, amine
N
microwave
(30 min, 100 °C)
O
R
12a–e
I
Amine (RH)
Equiv
30
Product
Yield (%)
53
12a
NH2
NH2
30
30
10
12b
12c
12d
49
50
53
N
O
NH
NH
10
12e
51
Me
N
NH
detected at the 1-position. The phenylacetamide moiety
appeared to be much more reactive toward this TiCl4-
mediated amination than the benzamide moiety.
In conclusion, we have shown that an orthogonal protec-
tive group strategy applied to hydrazine moiety allowed
the synthesis of 2,3-BZD-1,4-dione (I) for the first time in
a very efficient manner. We next compared the reactivity
of both amide functions exhibited by the 2,3-BZD-1,4-di-
one (I). We were able to demonstrate that both nitrogen
atoms show an equal nucleophilicity under N-substitution
conditions, whereas the phenylacetamide moiety was
more reactive than benzamide moiety under TiCl4-medi-
ated amination. This differential reactivity led to a regio-
selective conversion of the carbonyl at the 4-position of I
yielding the corresponding amidines 12a–e. Considering
the strong interest in drug design of benzodiazepinones in
general, we may assume that these efficient syntheses
could be used to develop new libraries of 2,3-benzodiaze-
pinone derivatives.
O
O
Bn
NH
O
Bn
N
N
(i)
N
Ts
67%
O
11
8a
Scheme 4 Reagents and conditions: (i) TsCl, NaH, THF, 0 °C, 1 h.
We recently published an efficient microwave-assisted
cyclic amidine synthesis using TiCl4.11 This conversion of
an amide into the corresponding amidine involves a two-
step one-pot reaction. At first, the amide function interacts
with the activated titanium complex to form an imidotita-
nium adduct, which can be displaced by an amine moiety
All anhydrous reactions were carried avoiding moisture by standard
procedures under argon. Commercially available reagents were
to yield the corresponding amidine.12 The microwave- used as received. The solvents were dried by distillation over the ap-
propriate drying agents. Reactions were monitored by TLC inspec-
tion on silica gel GF254 plates. Column chromatography was
assisted amination of I was performed in the presence of
1.2 equivalents of TiCl4 along with 10 equivalents of a pri-
generally performed on silica gel (200–300 mesh). All solvent ra-
mary amine (2-piperidin-1-ylethylamine, cyclohexyl-
tios are given as v/v. 1H, 13C NMR spectra, and NOE experiments
were recorded on a Bruker DPX 200 MHz or a Bruker Avance 300
amine) or 30 equivalents of a secondary amine (N-
methylpiperazine, piperidine, morpholine) at 100 °C for
30 minutes (Table 2). A regioselective amination was ob-
served leading to the amidines 12a–e. The amination site
at the 4-position was fully characterized by nuclear Over-
hauser effect (NOE) contact between the methylene group
at the 5-position and the protons assignable to methylenes
at the a-position of the amine moiety. No amination was
spectrometer. The chemical shifts (d) are reported in ppm and cou-
pling constants (J) in Hz. High-resolution mass spectra (HRMS)
and mass spectra (MS) were obtained from a MALDI-TOF and an
Agilent 1200SL mass spectrometer, respectively. Melting Points
were measured on a Büchi Melting-Point B-540 apparatus. All the
microwave reactions were performed with a self-tunable micro-
wave synthesizer (Biotage Initiator EXP microwave apparatus).
Synthesis 2007, No. 24, 3791–3796 © Thieme Stuttgart · New York

3794
F. J.-J. Bihel et al.
PAPER
The instrument continuously adjusted the wattage automatically to
maintain the desired temperature.
on silica gel (40% EtOAc in heptane) afforded 7a as a colorless oil
(1.29 g, 63%).
1H NMR (DMSO-d6, 300 MHz, 130 °C): d = 8.76 (s, 1 H, NH),
7.39–7.31 (m, 9 H, Ar), 4.71 (s, 2 H, CH2CO2Me), 3.71 (s, 2 H,
CH2Ph), 3.62 (s, 3 H, OCH3), 1.27 (s, 9 H, t-C4H9).
13C NMR (DMSO-d6, 75 MHz, 25 °C): d = 173.0, 172.9, 154.1,
136.8, 136.2, 130.7, 130.4, 129.5, 128.6, 127.8, 127.2, 125.7, 81.3,
52.4, 51.1, 37.9, 28.3.
3-Methoxyisocoumarine (2)13
To a solution of 2-(2-methoxy-2-oxoethyl)benzoic acid (1; 200 mg,
1.03 mmol) in degassed anhyd CH2Cl2 (5 mL) at 0 °C was added
dropwise a solution of trifluoroacetic anhydride (175 mL, 1.24
mmol) in CH2Cl2 (1 mL). The mixture was stirred for 1 h at 0 °C and
concentrated in vacuo. The residue was partitioned between EtOAc
(20 mL) and H2O (20 mL). The organic layer was washed with H2O
(2 × 20 mL), aq sat. NaHCO3 (20 mL), and brine (2 × 20 mL), dried
(Na2SO4), and evaporated in vacuo to yield 2 as a colorless solid
(175 mg, 96%).
ESI-HRMS: m/z calcd for C22H26N2O5Na [M + Na]+: 421.1739;
found: 421.1730.
{2-[N-tert-Butoxycarbonyl-N¢-(4-nitrobenzenesulfonyl)hy-
drazinocarbonyl)]phenyl}acetic Acid Methyl Ester (7b)
Purification by chromatography on silica gel (40% EtOAc in hep-
tane) afforded 7b as a yellow oil (2.12 g, 85%).
1H NMR (CDCl3, 200 MHz): d = 8.16 (d, J = 7.8 Hz, 1 H, Ar), 7.59
(ddd, J = 1.0, 7.3, 7.8 Hz, 1 H, Ar), 7.31–7.26 (m, 2 H, Ar), 5.54 (s,
1 H, H-4), 3.90 (s, 3 H, OCH3).
1H NMR (CDCl3, 300 MHz): d = 8.49 (d, J = 9.1 Hz, 2 H, Ar), 8.40
(d, J = 9.1 Hz, 2 H, Ar), 7.75 (s, 1 H, NH), 7.38–7.32 (m, 3 H), 7.22
(d, J = 7.5 Hz, 1 H, Ar), 3.92 (s, 2 H, CH2), 3.70 (s, 3 H, OCH3),
1.42 (s, 9 H, t-C4H9).
13C NMR (CDCl3, 75 MHz): d = 161.5, 160.1, 140.2, 135.4, 130.0,
125.8, 125.0, 117.7, 79.2, 56.4.
MS (ES+): m/z = 177 [M + H]+.
13C NMR (DMSO-d6, 75 MHz): d = 172.5, 170.7, 153.4, 150.6,
143.2, 133.5, 130.9, 130.7, 130.5, 126.7, 125.4, 123.4, 82.6, 52.3,
37.4, 27.7.
ESI-HRMS: m/z calcd for C21H23N3O9SNa [M + Na]+: 516.1053;
found: 516.1077.
2-Aminoisoquinoline-1,3(2H,4H)-dione (3)4
To a solution of hydrazine hydrate (153 mg, 149 mL, 1.08 mmol) in
EtOH (5 mL) was added homophthalic anhydride (500 mg, 1.08
mmol) and the mixture was refluxed for 6 h. The precipitate was
collected and washed with cold EtOH (20 mL). Recrystallization
from hot EtOH yielded 3 as a white powder (385 mg, 71%); mp 146
°C (Lit.4 mp 147–148 °C).
1H NMR (DMSO-d6, 200 MHz): d = 8.04 (d, J = 7.6 Hz, 1 H, Ar),
7.66 (dd, J = 7.6, 7.6 Hz, 1 H, Ar), 7.48 (dd, J = 7.6, 7.6 Hz, 1 H,
Ar), 7.39 (d, J = 7.6 Hz, 1 H, Ar), 5.53 (s, 2 H, NH2), 4.21 (s, 2 H,
H-4).
Cleavage of Boc Protected 7a,b and Cyclization to 8a,b; General
Procedure
To a solution of 7a or 7b (3.26 mmol) in anhyd CH2Cl2 (10 mL) was
added trifluoroacetic acid (10 mL). The mixture was stirred for 1 h
at r.t. and concentrated in vacuo. Et2O (5 mL) was added and soni-
cation of the resulting solution for 60 s afforded a white solid which
was filtered and dried at reduced pressure to yield 8a or 8b as white
powders.
13C NMR (DMSO-d6, 75 MHz): d = 167.4, 162.5, 135.5, 134.1,
128.5, 128.4, 128.1, 125.4, 36.7.
MS (ES+): m/z = 177 [M + H]+.
2-Benzyl-2,3-dihydro-5H-2,3-benzodiazepine-1,4-dione (8a)
Yield: 764 mg (88%); mp 143 °C.
1-Boc-2-(4-nitrobenzenesulfonyl)hydrazine (4)
To a solution of tert-butyl carbazate (3.96 g, 0.30 mol) in anhyd
DMF (20 mL) were added K2CO3 (4.42 g, 0.32 mol) and 4-nitroben-
zenesulfonyl chloride (5.98 g, 0.27 mol). The mixture was stirred
for 1 h at r.t. and concentrated in vacuo. The residue was partitioned
between EtOAc (40 mL) and aq 1 N HCl (40 mL). The organic layer
was washed with aq 1 N HCl (2 × 20 mL), aq sat. NaHCO3 (2 × 20
mL), and brine (2 × 20 mL), dried (Na2SO4), and evaporated in vac-
uo to yield 4 as a yellow powder (7.61 g, 80%); mp 141 °C.
1H NMR (CDCl3, 300 MHz): d = 8.17 (br s, 1 H, NH), 7.92 (dd,
J = 1.5, 6.8 Hz, 1 H, Ar), 7.49–7.42 (m, 2 H, Ar), 7.38–7.31 (m, 5
H, Ar), 7.20 (dd, J = 1.5, 6.8 Hz, 1 H, Ar), 4.96 (dd, J = 14.0, 127
Hz, 2 H, CH2Ph), 3.48 (dd, J = 13.0, 169 Hz, 2 H, CH2CO).
13C NMR (CDCl3, 75 MHz): d = 175.8, 169.0, 136.3, 135.4, 132.9,
130.8, 129.4, 128.9, 128.7, 128.6, 52.7, 41.0.
ESI-HRMS: m/z calcd for C16H14N2O2Na [M + Na]+: 289.0953;
1H NMR (CDCl3, 200 MHz): d = 8.33 (d, J = 9.1 Hz, 2 H, Ar), 8.11
(d, J = 9.1 Hz, 2 H, Ar), 6.73 (s, 1 H, NH), 6.65 (s, 1 H, NH), 1.22
(s, 9 H, t-C4H9).
13C NMR (CDCl3, 75 MHz): d = 154.7, 151.0, 143.2, 130.4, 83.5,
28.2.
ESI-HRMS: m/z calcd for C11H14N3O6S [M – H]–: 316.0608; found:
316.0610.
found: 289.0939.
2-(4-Nitrobenzenesulfonyl)-2,3-dihydro-5H-2,3-benzodi-
azepine-1,4-dione (8b)
Yield: 1.08 g (92%); mp 241 °C.
1H NMR (DMSO-d6, 300 MHz): d = 10.87 (s, 1 H, NH), 8.53 (d,
J = 9.0 Hz, 2 H, Ar), 8.44 (d, J = 9.0 Hz, 2 H, Ar), 7.81 (dd, J = 1.5,
7.5 Hz, 1 H, Ar), 7.66 (ddd, J = 1.5, 7.5, 7.5 Hz, 1 H, Ar), 7.50 (m,
2 H, Ar), 3.87 (dd, J = 13.0, 225 Hz, 2 H, CH2).
13C NMR (CDCl3, 75 MHz): d = 175.7, 167.5, 151.8, 143.8, 137.4,
135.3, 131.7, 131.2, 130.6, 130.2, 129.4, 125.5, 41.0.
ESI-HRMS: m/z calcd for C15H10N3O6S[M – H]–: 360.0290; found:
360.0294.
Hydrazides 7a,b; General Procedure
To a solution of 1 (1.00 g, 5.15 mmol) in anhyd DMF (20 mL) were
added HBTU (2.15 g, 5.67 mmol) and Et3N (1.40 mL, 10.31 mmol).
The mixture was stirred for 10 min at r.t. and 4 or 6 (5.67 mmol) was
added. The mixture was stirred overnight at r.t. and concentrated in
vacuo. The residue was partitioned between EtOAc (40 mL) and aq
1 N HCl (40 mL). The organic layer was washed with aq 1 N HCl
(2 × 20 mL), aq sat. NaHCO3 (2 × 20 mL), and brine (2 × 20 mL),
dried (Na2SO4), and evaporated in vacuo.
2,3-Dihydro-5H-2,3-benzodiazepine-1,4-dione (I)
By Cleavage of the Nosyl Group: To a solution of 8b (1.00 g, 2.77
mmol) in anhyd DMF (5 mL) were added Cs2CO3 (2.70 g, 8.31
mmol) and thiophenol (311 mL, 3.05 mmol). The mixture was
stirred for 3 h at r.t., and concentrated in vacuo. The resulting crude
product was dissolved in a solution of 5% MeOH in CH2Cl2, filtered
[2-(N-Benzyl-N¢-tert-butoxycarbonylhydrazinocarbonyl)phe-
nyl]acetic Acid Methyl Ester (7a) Purification by chromatography
Synthesis 2007, No. 24, 3791–3796 © Thieme Stuttgart · New York

PAPER
2,3-Dihydro-1H-2,3-benzodiazepine-1,4(5H)-dione
3795
and purified by chromatography on silica gel (5% MeOH in CH2Cl2
ESI-HRMS: m/z calcd for C16H14N2O2Na [M + Na]+: 289.0953;
+ 1% AcOH) to yield I as a white powder (370 mg, 76%).
found: 289.0945.
By Cleavage of the Benzyl Group: To a solution of 8a (40 mg, 0.15
mmol) in EtOAc (4 mL) and AcOH (1 mL) was added PdCl2 (3.00
mg, 10% mol). The mixture was hydrogenated at r.t. at 60 psi. After
24 h, the mixture was filtered and evaporated in vacuo. The result-
ing crude product was dissolved in EtOAc (10 mL) and washed with
brine (2 × 5 mL), dried (Na2SO4), and evaporated in vacuo. Purifi-
cation was performed by chromatography on silica gel (5% MeOH
in CH2Cl2 + 1% AcOH) to yield I as a white powder (7 mg, 26%);
mp 185 °C.
1H NMR (DMSO-d6, 300 MHz): d = 10.19 (s, 1 H, NH), 9.78 (s, 1
H, NH), 7.72 (dd, J = 1.6, 7.5 Hz, 1 H, Ar), 7.53 (ddd, J = 1.6, 7.5,
7.5 Hz, 1 H, Ar), 7.43 (ddd, J = 1.3, 7.5, 7.5 Hz, 1 H, Ar), 7.37 (d,
J = 7.5 Hz, 1 H, Ar), 3.66 (dd, J = 13.0, 242 Hz, 2 H, CH2).
2,3-Dibenzyl-2,3-dihydro-5H-2,3-benzodiazepine-1,4-dione
(10)
Mp 119 °C.
1H NMR (CDCl3, 300 MHz): d = 7.36–7.25 (m, 6 H, Ar), 7.19–7.13
(m, 3 H, Ar), 7.02–6.94 (m, 3 H, Ar), 6.71 (d, J = 7.2 Hz, 2 H, Ar),
4.87 (dd, J = 14.0, 392 Hz, 2 H, CH2Ph), 4.65 (dd, J = 14.0, 374 Hz,
2 H, CH2Ph), 3.30 (dd, J = 13.0, 156 Hz, 2 H, CH2CO).
13C NMR (CDCl3, 75 MHz): d = 173.4, 170.0, 136.0, 14.9, 134.2,
132.5, 131.7, 129.9, 129.7, 129.5, 129.4, 128.9, 128.6, 128.4, 128.2,
128.1, 49.4, 48.8, 41.3.
ESI-HRMS: m/z calcd for C23H20N2O2Na [M + Na]+: 379.1422;
found: 379.1408.
13C NMR (DMSO-d6, 75 MHz): d = 173.5, 169.1, 136.6, 132.1,
131.8, 129.4, 128.4, 127.6, 40.8.
ESI-HRMS: m/z calcd for C9H8N2O2SNa [M + Na]+: 199.0483,
2-Benzyl-3-(p-toluenesulfonyl)-2,3-dihydro-5H-benzodi-
azepine-1,4-dione (11)
To a solution of 8a (400 mg, 1.5 mmol) in anhyd THF (20 mL) was
added NaH (60% suspension in mineral oil; 78 mg, 1.95 mmol) at
0 °C and the mixture was stirred for 30 min at 0 °C. Then, tosyl
chloride (342 mg, 1.80 mmol) was quickly added and the mixture
was stirred for 1 h and concentrated in vacuo. The residue was par-
titioned between EtOAc (20 mL) and H2O (20 mL). The organic
layer was washed with brine (2 × 20 mL), dried (Na2SO4), and
evaporated in vacuo. Purification by chromatography on silica gel
(10% to 50% EtOAc in heptane) afforded 8 as a colorless oil, which
was dissolved in Et2O and sonicated to yield 11 as a white powder
(420 mg, 67%); mp 155 °C.
found: 199.0490.
Benzylation of 2,3-Dihydro-5H-2,3-benzodiazepine-1,4-dione
(I)
Method A: To a solution of I (20.0 mg, 0.11 mmol) in anhyd DMF
(1 mL) at 0 °C was added a dispersion of NaH (60%, 3.00 mg, 0.08
mmol) and the mixture was stirred for 10 min at 0 °C. Then, benzyl
bromide (20.0 mg, 14.0 mL, 0.08 mmol) was quickly added and the
mixture was stirred for 1 h at r.t., and concentrated in vacuo. The
residue was partitioned between EtOAc (20 mL) and H2O (20 mL).
The organic layer was washed with brine (2 × 20 mL), dried
(Na2SO4), and evaporated in vacuo. Purification by chromatogra-
phy on silica gel (25% to 50% EtOAc in heptane) afforded the com-
pounds 8a, 9, and 10 in 22% (4.0 mg), 22% (4.0 mg), and 56% (8.0
mg) yield, respectively.
1H NMR (CDCl3, 300 MHz): d = 7.79 (dd, J = 1.5, 7.3 Hz, 1 H),
7.35 (m, 9 H), 7.00 (d, J = 8.3 Hz, 2 H), 6.84 (d, J = 7.3 Hz, 1 H),
5.16 (dd, J = 14.0, 305 Hz, 2 H), 3.20 (dd, J = 13.0, 122 Hz, 2 H),
2.30 (s, 3 H).
Method B: To a solution of I (19.0 mg, 0.11 mmol) in anhyd DMF
(2 mL) at 0 °C was added K2CO3 (55.00 mg, 0.28 mmol) and the
mixture was stirred for 10 min at 0 °C. Then, benzyl bromide (11.0
mL, 0.09 mmol) was quickly added and the mixture was stirred for
1 h at r.t., and concentrated in vacuo. The residue was partitioned
between EtOAc (20 mL) and H2O (20 mL). The organic layer was
washed with brine (2 × 20 mL), dried (Na2SO4), and evaporated in
vacuo. Purification by chromatography on silica gel (25% to 50%
EtOAc in heptane) afforded the compounds 8a, 9, and 10 in 24%
(6.0 mg), 20% (5.0 mg), and 53% (9.0 mg) yield, respectively.
13C NMR (CDCl3, 75 MHz): d = 171.4, 169.1, 146.2, 135.3, 133.2,
132.9, 132.5, 131.3, 130.7, 130.5, 130.2, 130.1, 129.8, 129.6, 129.5,
129.2, 129.1, 128.9, 54.1, 42.3, 22.0.
ESI-HRMS: m/z calcd for C9H8N2O2SNa [M + Na]+: 443.1041;
found: 443.1039.
Amination of 2,3-Dihydro-5H-2,3-benzodiazepine-1,4-dione
(I); General Procedure
To a 1 M solution of TiCl4 in CH2Cl2 (250 mL, 0.25 mmol) was add-
ed anisole (700 mL) under argon and the mixture was stirred for 15
min. Then, amine (10 equiv for a primary amine, 30 equiv for a sec-
ondary amine) and I (38.2 mg, 0.21 mmol) were added and the mix-
ture was irradiated under microwave at 100 °C for 30 min and was
partitioned between EtOAc (20 mL) and aq sat. NaHCO3 (20 mL).
The organic layer was washed with aq sat. NaHCO3 (2 × 20 mL),
and brine (2 × 20 mL), dried (Na2SO4), and evaporated in vacuo.
Purification by chromatography on silica gel (5% MeOH in CH2Cl2
+ 1% AcOH) afforded the expected amidine.
Method C: To a solution of I (20.0 mg, 0.11 mmol) in anhyd DMF
(2 mL) at 0 °C was added a dispersion of NaH (60%, 9.0 mg, 0.0.22
mmol) and the mixture was stirred for 10 min at 0 °C. Then, benzyl
bromide (28.0 mL, 0.22 mmol) was quickly added and the mixture
was stirred for 1 h at r.t., and concentrated in vacuo. The residue was
partitioned between EtOAc (20 mL) and H2O (20 mL). The organic
layer was washed with brine (2 × 20 mL), dried (Na2SO4), and
evaporated in vacuo. Purification by chromatography on silica gel
(25% to 50% EtOAc in heptane) afforded the compound 10 in 89%
(36.0 mg) yield.
4-(4-Methylpiperazin-1-yl)-2,5-dihydro-1H-2,3-benzodiazepin-
1-one (12a)
Yield: 28.0 mg (53%).
3-Benzyl-2,3-dihydro-5H-2,3-benzodiazepine-1,4-dione (9)
Mp 162 °C.
1H NMR (CDCl3, 300 MHz): d = 8.39 (s, 1 H, NH), 8.00 (dd,
J = 1.5, 7.6 Hz, 1 H, Ar), 7.48–7.41 (m, 2 H, Ar), 7.17 (d, J = 7.6
Hz, 1 H), 3.73 (s, 2 H, CH2C=N), 3.38 (t, J = 4.9 Hz, 4 H, 2 ×
CH2N), 2.41 (t, J = 4.9 Hz, 4 H, 2 × CH2N), 2.28 (s, 3 H, CH3).
13C NMR (CDCl3, 75 MHz): d = 169.3, 162.9, 136.9, 132.9, 132.5,
131.1, 128.1, 127.0, 54.8, 46.5, 46.4, 33.7.
1H NMR (CDCl3, 300 MHz): d = 7.70 (s, 1 H, NH), 7.65 (dd,
J = 1.3, 7.8 Hz, 1 H, Ar), 7.53 (ddd, J = 1.3, 7.5, 7.8 Hz, 1 H, Ar),
7.38 (dd, J = 7.5, 7.5 Hz, 1 H, Ar), 7.33 (d, J = 7.5 Hz, 1 H, Ar),
7.31–7.24 (m, 3 H, Ar), 7.10 (dd, J = 1.6, 7.5 Hz, 2 H, Ar), 4.72 (dd,
J = 14.0, 37 Hz, 2 H, CH2Ph), 3.90 (dd, J = 13.0, 209 Hz, 2 H,
CH2CO).
ESI-HRMS: m/z calcd for C14H19N4O [M + H]+: 259.1559; found:
259.1548.
13C NMR (CDCl3, 75 MHz): d = 175.0, 173.4, 139.2, 137.2, 136.6,
133.7, 133.2, 132.4, 132.2, 131.9, 131.5, 55.6, 45.3.
Synthesis 2007, No. 24, 3791–3796 © Thieme Stuttgart · New York

3796
F. J.-J. Bihel et al.
PAPER
4-(Piperidin-1-yl)-2,5-dihydro-1H-2,3-benzodiazepin-1-one
(12b)
ESI-HRMS: m/z calcd for C15H20N3O [M + H]+: 258.1601; found
258.1608.
Yield: 27.0 mg (49%).
1H NMR (CDCl3, 300 MHz): d = 8.30 (br s, 1 H, NH), 8.07 (dd,
J = 1.2, 7.6 Hz, 1 H), 7.53 (dd, J = 1.7, 7.3 Hz, 1 H, Ar), 7.42 (dd,
J = 1.2, 7.3 Hz, 1 H, Ar), 7.22 (d, J = 7.6 Hz, 1 H, Ar), 3.42–3.19
(m, 6 H, 3 × CH2), 2.53–2.39 (m, 4 H, 2 × CH2), 1.61–1.54 (m, 2 H,
CH2).
13C NMR (CDCl3, 75 MHz): d = 168.1, 163.2, 140.5, 133.3, 131.6,
129.0, 128.4, 58.6, 55.2, 48.6, 30.1, 26.1.
Acknowledgment
We thank C. Antheaume for NOE analysis. The authors also thank
Biotage AB for providing the initiator EXP microwave synthesis
system and Armen Instrument for providing the flash liquid chro-
matography apparatus Spot.
ESI-HRMS: m/z calcd for C14H18N3O [M + H]+: 244.1444; found:
244.1441.
References
(1) Bourguignon, J. J.; Oumouch, S.; Schmitt, M. Curr. Org.
Chem. 2006, 10, 277.
4-(Morpholin-1-yl)-2,5-dihydro-1H-2,3-benzodiazepin-1-one
(2) (a) Watterson, D. M.; Mirzoeva, S.; Guo, L.; Whyte, A.;
Bourguignon, J. J.; Hilbert, M.; Haiech, J.; Van Eldik, L. J.
Neurochem. Int. 2001, 39, 459. (b) Mirzoeva, S.; Sawkar,
A.; Zasadzki, M.; Guo, L.; Velentza, A. V.; Dunlap, V.;
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J.; Watterson, D. M. J. Med. Chem. 2002, 45, 563.
(c) Contreras, J. M.; Rival, Y. M.; Chayer, S.; Bourguignon,
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(d) Cesari, C.; Biancalani, N.; Vergelli, C.; Dal Piaz, V.;
Graziano, A.; Biagini, P.; Ghelardini, C.; Galeotti, N.;
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(3) Whitmore, W. F.; Cooney, R. C. J. Am. Chem. Soc. 1944, 66,
1237.
(12c)
Yield: 25.0 mg (50%).
1H NMR (CDCl3, 300 MHz): d = 8.52 (br s, 1 H, NH), 8.01 (dd,
J = 1.6, 7.6 Hz, 1 H, Ar), 7.50 (dd, J = 1.6, 7.5 Hz, 1 H, Ar), 7.41
(dd, J = 1.2, 7.8 Hz, 1 H, Ar), 7.16 (d, J = 7.5 Hz, 1 H, Ar), 3.72 (s,
2 H, CH2C=N), 3.71 (t, J = 4.7 Hz, 4 H, 2 × CH2), 3.33 (t, J = 4.7
Hz, 4 H, 2 × CH2).
13C NMR (CDCl3, 75 MHz): d = 167.7, 161.5, 135.3, 131.5, 129.7,
126.7, 125.5, 65.6, 45.6, 32.1.
ESI-HRMS: m/z calcd for C13H16N3O2 [M + H]+: 246.1237; found:
246.1235.
(4) (a) Rosen, G.; Popp, F. D. J. Heterocycl. Chem. 1969, 6, 9.
(b) Flammang, M. Ph.D. Thesis; Louis Pasteur University:
Strasbourg (France), 1974.
(5) Loser, R.; Schilling, K.; Dimmig, E.; Gutschow, M. J. Med.
Chem. 2005, 48, 7688.
(6) Sabitha, G.; Srividya, R.; Yadav, J. S. Tetrahedron 1999, 55,
4015.
(7) (a) Keck, G. E.; Boden, E.; Sonnewald, U. Tetrahedron Lett.
1981, 22, 2615. (b) Zhang, H. J.; Padwa, A. Org. Lett. 2006,
8, 247.
4-[(2-Piperidin-1-ylethyl)amino]-2,5-dihydro-1H-2,3-benzodi-
azepin-1-one (12d)
Yield: 32.0 mg (53%).
1H NMR (DMSO-d6, 300 MHz): d = 9.92 (s, 1 H, NHCO), 7.72 (d,
J = 7.5 Hz, 1 H, Ar), 7.50 (dd, J = 7.5, 7.5 Hz, 1 H, Ar), 7.37 (dd,
J = 7.5, 7.5 Hz, 1 H, Ar), 7.23 (d, J = 7.5 Hz, 1 H, Ar), 6.93 (br s, 1
H, NHCH2), 3.55 (s, 2 H, CH2C=N), 3.21 (m, 2 H, CH2NH), 2.67
(m, 4 H, 2 × CH2N), 1.43 (m, 8 H, 4 × CH2).
13C NMR (CDCl3, 75 MHz): d = 169.3, 161.2, 137.4, 132.9, 132.2,
130.6, 128.0, 127.9, 56.5, 54.4, 38.0, 37.5, 24.5, 23.5.
ESI-HRMS: m/z calcd for C16H23N4O [M + H]+: 287.1872; found:
287.1885.
(8) Fukuyama, T.; Cheung, M.; Jow, C. K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(9) (a) Raboisson, P.; Baurand, A.; Cazenave, J. P.; Gachet, C.;
Schultz, D.; Spiess, B.; Bourguignon, J. J. J. Org. Chem.
2002, 67, 8063. (b) McCluskey, A.; Keller, P. A.; Morgan,
J.; Garner, J. Org. Biomol. Chem. 2003, 1, 3353.
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2005, 3, 1694.
(10) Bischofberger, N. Tetrahedron Lett. 1987, 28, 2821.
(11) Hellal, M.; Bihel, F.; Mongeot, A.; Bourguignon, J. J. Org.
Biomol. Chem. 2006, 4, 3142.
4-Cyclohexylamino-2,5-dihydro-1H-benzodiazepin-1-one (12e)
Yield: 28.0 mg (51%).
1H NMR (CDCl3, 300 MHz): d = 8.32 (br s, 1 H, NHCO), 8.01 (dd,
J = 1.7, 7.3 Hz, 1 H), 7.52 (dd, J = 1.5, 7.6 Hz, 1 H, Ar), 7.42 (dd,
J = 1.2, 7.3 Hz, 1 H, Ar), 7.17 (d, J = 7.6 Hz, 1 H, Ar), 4.39 (br s, 1
H, NH), 3.55 (s, 2 H, CH2C=N), 3.50–3.40 (m, 1 H, CH), 2.04–1.90
(m, 2 H, CH2), 1.77–1.56 (m, 4 H, 2 × CH2), 1.37–1.21 (m, 2 H,
CH2), 1.20–1.04 (m, 2 H, CH2).
(12) Kissounko, D. A.; Guzei, I. A.; Gellman, S. H.; Stahl, S. S.
Organometallics 2005, 24, 520.
(13) Spangler, R. J.; Kim, J. H.; Cava, M. P. J. Org. Chem. 1977,
42, 1697.
13C NMR (CDCl3, 75 MHz): d = 169.4, 160.1, 137.3, 132.8, 132.3,
130.9, 128.2, 127.4, 50.7, 39.0, 33.2, 26.1, 25.2.
Synthesis 2007, No. 24, 3791–3796 © Thieme Stuttgart · New York