New efficient synthesis of 1,4-benzodiazepin-5-ones by catalytic aza-Wittig reaction

Article abstract of DOI:10.1055/s-0034-1378874

1,4-Benzodiazepin-5-ones were synthesized in 71-89% yields from 2-isocyanato-N-(2-oxoalkyl)benzamides via a new catalytic intramolecular aza-Wittig reaction. Starting from easily accessible phthalic anhydride and α-arylamino ketones, the corresponding 2-{[(2-oxoalkyl)amino]carbonyl}benzoic acids underwent sequential formation of the acid azide and Curtis rearrangement to give 2-isocyanato-N-(2-oxoalkyl)benzamides that were reacted directly to give the final 2,4-diaryl-3,4-dihydro-5H-1,4-benzodiazepin-5-ones and 4-aryl-2-tert-butyl-3,4-dihydro-5H-1,4-benzodiazepin-5-ones.

Full text of DOI:10.1055/s-0034-1378874

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3522–3528
paper
3522
L. Wang et al.
Paper
Synthesis
New Efficient Synthesis of 1,4-Benzodiazepin-5-ones by Catalytic
Aza-Wittig Reaction
Long Wang
O
R1
O
R1
1. ClCOOEt, Et3N
2. NaN3
Ru-Qing Qin
Hong-Ye Yan
Ming-Wu Ding*
N
R2
N
3.
N
O
COOH
R2
(5 mol%)
Key Laboratory of Pesticide & Chemical Biology of Ministry of
Education, Central China Normal University, Wuhan 430079,
P. R. of China
P
Ph
O
16 examples
71–89%
mwding@mail.ccnu.edu.cn
Received: 24.04.2015
Accepted after revision: 03.07.2015
Published online: 13.08.2015
Wittig reactions by using stoichiometric phosphine as reac-
tant.10 Therefore, there is an unmet need for the develop-
ment of a practical, general, and efficient pathway toward
1,4-benzodiazepin-5-ones starting from easily accessible
materials.
DOI: 10.1055/s-0034-1378874; Art ID: ss-2015-h0262-op
Abstract 1,4-Benzodiazepin-5-ones were synthesized in 71–89%
yields from 2-isocyanato-N-(2-oxoalkyl)benzamides via a new catalytic
intramolecular aza-Wittig reaction. Starting from easily accessible
phthalic anhydride and α-arylamino ketones, the corresponding 2-{[(2-
oxoalkyl)amino]carbonyl}benzoic acids underwent sequential forma-
tion of the acid azide and Curtis rearrangement to give 2-isocyanato-N-
(2-oxoalkyl)benzamides that were reacted directly to give the final 2,4-
diaryl-3,4-dihydro-5H-1,4-benzodiazepin-5-ones and 4-aryl-2-tert-bu-
tyl-3,4-dihydro-5H-1,4-benzodiazepin-5-ones.
The aza-Wittig reaction of an iminophosphorane with a
carbonyl compound provides an excellent method for the
construction of the C=N bond under mild and neutral reac-
tion conditions.12 The intramolecular aza-Wittig reaction
has become an efficient tool in the construction of various
N-heterocycles through intramolecular cyclization with a
wide variety of carbonyl groups.13 However, the aza-Wittig
reaction produces stoichiometric triphenylphosphine oxide
as a byproduct, which results in low atom efficiency of the
reaction, and, in some cases, the separation of the product
from the byproduct triphenylphosphine oxide is problem-
atic. In 2008, Marsden reported firstly a catalytic aza-Wittig
reaction using carbonyl isocyanate derivatives that cyclize
to produce benzoxazoles and phenanthridines, under catal-
ysis by commercially available phospholene oxide.14 In con-
trast to the conventional aza-Wittig reaction, the catalytic
aza-Wittig process shows high atom efficiency (solely re-
leasing CO2 as a byproduct) by utilizing a catalytic amount
of an organophosphorus reagent. However, despite the im-
mense importance of this reaction there remains only one
reported example. The catalytic Wittig and aza-Wittig reac-
tion may also be carried out using a catalytic amount of
phosphine in the presence of stoichiometric reductant, usu-
ally a suitable silane.15,16 Recently, we have been interested
in the synthesis of various heterocycles via the aza-Wittig
reaction17 or catalytic aza-Wittig reaction.16b Herein we
wish to report a new efficient synthesis of 1,4-benzodiaze-
pin-5-ones by the catalytic aza-Wittig reaction, starting
from easily accessible phthalic anhydride and α-arylamino
ketones.
Key words 1,4-benzodiazepin-5-one, catalytic aza-Wittig reaction,
Curtius reaction, acyl azide, isocyanate
Benzodiazepines are an important and widely used
structural motif in many drugs and biologically active com-
pounds, especially for the treatment of anxiety and sleep
disorders.1 A large number of derivatives of these heterocy-
cles have also been found to show other biological activity.
For example, some 1,4-benzodiazepin-5-ones were recent-
ly reported to exhibit significant anticancer,2 HIV-1 reverse
transcriptase inhibitive,3 histone deacetylase inhibitive,4
and vitamin D receptor transactivation inhibitive activity.5
In addition, 1,4-benzodiazepin-5-one rings are also found
as building blocks in some natural products such as anthra-
mycin, chicamycin, and DC-81, which are produced from
various Streptomyces bacteria.6 Although much effort has
been directed toward the construction of 1,4-benzodiaze-
pines,7 only few efficient synthesis methods for 1,4-benzo-
diazepin-5-ones have been developed over the past few de-
cades.8–11 For example, some 1,4-benzodiazepin-5-one de-
rivatives were prepared either by intramolecular azide or
nitrilimine cycloadditions,8 or by palladium-catalyzed ami-
nation of N-allylanthranilamides.9 Other 1,4-benzodiaze-
pin-5-ones were also obtained from intramolecular aza-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3522–3528

3523
L. Wang et al.
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Synthesis
The required carbonyl acid derivatives 2 were easily ob-
tained according to standard protocols (Scheme 1).18 At first
various α-arylamino ketones 1 were obtained by the alkyla-
tion of primary amines with α-bromo ketones in methanol
according to the literature report.19 Only such compounds 1
where R1 is an aryl group and R2 is an aryl or tert-butyl
group can be prepared. We attempt to prepare compounds
1 with other alkyl groups than tert-butyl on the R2 position,
or with R1 group different from aryl groups, however, all at-
tempts failed probably due to the limitations of the method.
Only compounds 1 which precipitate directly from the sol-
vent may be prepared, otherwise a complex mixture result-
ed. The obtained α-arylamino ketones 1 reacted further
with phthalic anhydride at room temperature to provide
carbonyl acid derivatives 2 in good yields.
The reaction was unsuccessful when the catalyst was
changed to triphenylphosphine oxide, probably due to its
low reactivity.
O
R1
O
R1
ClCOOEt
Et3N
R2
N
60–70 °C
R2
N
NaN3
O
CON3
O
COOH
3
2
P
O
R1
R2
O
Ph
O
R1
N
(A, 5 mol%)
R2
O
N
toluene
reflux
R1NH2
N
NCO
O
O
NaHCO3
71–89%
R1HN
Br
R2
R2
5
4
MeOH, r.t.
52–86%
Scheme 2 Preparation of 1,4-benzodiazepin-5-ones 5
Table 1 Preparation of 1,4-Benzodiazepin-5-ones 5
1
O
O
O
R1
Entry
Product
R1
4-MeC6H4
R2
Ph
Yielda (%)
R2
N
O
1
2
5a
5b
5c
5d
5e
5f
89
87
75
71
72
82
81
87
83
81
82
79
76
82
78
72
CH2Cl2, r.t.
O
COOH
Ph
Ph
74–91%
3
4-ClC6H4
2-MeC6H4
3-ClC6H4
Ph
Ph
2
4
Ph
Scheme 1 Preparation of acid derivatives 2
5
Ph
6
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
Ph
The next objective was transforming carbonyl acid 2 by
Curtius reaction into carbonyl isocyanate intermediate 4,
which was then used to prepare the 1,4-benzodiazepin-5-
one via catalytic aza-Wittig reaction. When carbonyl acid 2
was treated with ethyl chloroformate/triethylamine fol-
lowed by sodium azide in tetrahydrofuran, the acyl azide 3
was produced. The azide 3 was then transformed into car-
bonyl isocyanate intermediate 4 by heating in toluene. Fur-
ther heating the isocyanate 4 in toluene with a catalytic
amount of phospholene oxide A afforded a single product,
which was isolated and verified to be 1,4-benzodiazepin-5-
one 5 (Scheme 2). All the reactions were carried out
smoothly to give the corresponding 1,4-benzodiazepin-5-
ones 5 in toluene at reflux temperature, and satisfactory
yields were obtained with various substituents on the reac-
tants (Table 1). As the R2 group is an aromatic substituent,
good yields were obtained whenever the substituent on the
phenyl ring is an electron-withdrawing (entries 8–11) or
electron-donating group (entries 6 and 7). It is noteworthy
that good yields were obtained even when R2 is a sterically
hindered tert-butyl group (entries 15 and 16). The R1 group
has no obvious effects on the reaction yield regardless of
the substituents (Cl, F, Me, OMe, OEt) on the benzene ring.
7
5g
5h
5i
4-MeC6H4
Ph
8
9
4-MeC6H4
4-ClC6H4
Ph
10
11
12
13
14
15
16
5j
5k
5l
4-EtOC6H4
4-FC6H4
4-MeOC6H4
4-MeC6H4
Ph
5m
5n
5o
5p
Ph
Ph
t-Bu
t-Bu
a Isolated yields based on acids 2.
A possible mechanism for the catalytic aza-Wittig trans-
formation of 4 to 5 is proposed (Scheme 3). It presumably
involves (i) a metathesis reaction of isocyanate 4 with phos-
pholene oxide A to give the iminophosphorane 6 and car-
bon dioxide;20 (ii) intramolecular aza-Wittig reaction of
iminophosphorane 6 through the carbonyl group to pro-
duce 1,4-benzodiazepin-5-one 5 and phospholene oxide A,
which enters a new catalytic cycle.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3522–3528

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L. Wang et al.
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Synthesis
O
R1
R2
CH3
N
P
O
Ph
O
ClCOOEt
Et3N
O
N
P
N
(5 mol%)
O
Ph
toluene
reflux
NaN3
N
CO2
R1
O
R1
R2
N
N
O
O
6
COOH
R2
N
N
2a
5a
(5.61 g, 86%)
(20 mmol)
O
NCO
5
(cat.)
Scheme 5 Preparation of 5a on a larger scale
P
4
Ph
O
A
tion. Owning to the high atom efficiency, the mild reaction
conditions, the good yields, and the easily available starting
materials, we think that this new approach has potential in
the preparation of various 1,4-benzodiazepin-5-ones that
are of considerable interest as potential biologically active
compounds or pharmaceuticals.
Scheme 3 Possible mechanism for formation of 5
As a comparison, the cyclization reaction of isocyanate
4 under the conventional hydrolysis/dehydration condi-
tion21 was further investigated (Scheme 4). When the isocy-
anate 4k or 4o was treated with formic acid/4-(dimethyl-
amino)pyridine instead of phospholene oxide A, a mixture
of amine 7k or 7o and 1,4-benzodiazepin-5-one 5k or 5o
resulted and the 1,4-benzodiazepin-5-ones 5k or 5o were
only obtained as minor products (28–33%), which implies
the advantage of the above catalytic aza-Wittig reaction in
the preparation of the cyclic compounds.
Melting points were determined using a X-4 model apparatus and are
uncorrected. MS were measured on a Finnigan Trace MS spectrome-
ter. NMR were recorded in CDCl3 or DMSO-d6 on a Varian Mercury
600 or 400 spectrometer and resonances relative to TMS. Elemental
analyses were taken on a Vario EL III elementary analysis instrument.
To evaluate the applicability of the above catalytic aza-
Wittig reaction on a larger scale, we successfully prepared
5a on a gram scale in a satisfactory 86% yield, and the cata-
lyst was recovered in 95% yield (Scheme 5).
In conclusion, we have developed an efficient synthesis
of 1,4-benzodiazepin-5-ones via catalytic aza-Wittig reac-
3,4-Dihydro-5H-1,4-benzodiazepin-5-ones 5a–p; General Proce-
dure
To a solution of carboxylic acid 218 (1 mmol) in anhyd THF (10 mL) at
–10 °C was added dropwise Et3N (0.11 g, 1.1 mmol), followed by the
addition of ethyl chloroformate (0.12 g, 1.1 mmol) over 30 min; the
mixture was stirred at –10 °C for 1 h. Then a solution of NaN3 (0.072
g, 1.1 mmol) in water (1 mL) was added dropwise and the mixture
Br
Br
O
O
O
N
HCOOH
N
N
+
Ph
O
Ph
NCO
O
DMAP
N
NH2
Br
7k, 51%
5k, 33%
4k
O
O
N
O
HCOOH
DMAP
N
+
N
N
NCO
O
NH2
O
7o, 52%
5o, 28%
4o
Scheme 4 Cyclization reaction of isocyanate 4 under conventional hydrolysis/dehydration conditions
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3522–3528

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L. Wang et al.
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Synthesis
was stirred at –10 °C for 3 h. The mixture was extracted with CH2Cl2
(3 × 10 mL). The organic layers were combined, washed with brine,
and dried (anhyd Na2SO4). The solvent was removed under reduced
pressure to give crude acyl azide 3. The crude product 3 was dissolved
in toluene (10 mL) and the mixture was heated to 60–70 °C for 0.5 h
to form isocyanate intermediate 4. Then 3-methyl-1-phenyl-2-phos-
pholene 1-oxide (A, 0.01 g, 0.05 mmol) was added and the mixture
was stirred at 110 °C. When the reaction was complete (4–12 h), the
solvent was removed under reduced pressure and the residue was pu-
rified by flash chromatography (silica gel, Et2O–petroleum ether, 1:4)
to give 3,4-dihydro-5H-1,4-benzodiazepin-5-ones 5a–p.
IR (KBr): 1637, 1596, 1452, 1406, 1219 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.14 (d, J = 7.8 Hz, 1 H, HAr), 7.77 (d, J =
7.2 Hz, 2 H, HAr), 7.62–7.14 (m, 10 H, HAr), 4.49–4.36 (m, 2 H, CH2),
2.08 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 166.6, 165.0, 146.5, 141.3, 136.2,
135.5, 131.7, 131.3, 131.1, 130.8, 128.7, 128.2, 127.5, 127.2, 127.0,
126.8, 126.1, 47.8, 18.0.
MS: m/z (%) = 326 (M+, 58), 309 (13), 221 (17), 179 (100), 118 (23),
105 (26).
Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 81.14;
H, 5.41; N, 8.57.
2-Phenyl-4-(p-tolyl)-3,4-dihydro-5H-1,4-benzodiazepin-5-one
(5a)
4-(3-Chlorophenyl)-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
White solid; yield: 0.29 g (89%); mp 228–230 °C.
5-one (5e)
IR (KBr): 2914, 1649, 1592, 1450, 1341, 1200 cm–1
.
White solid: yield: 0.25 g (72%); mp 118–120 °C.
IR (KBr): 3066, 1640, 1590, 1401, 1340, 1201 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 1 H, HAr), 7.80 (d, J =
.
1H NMR (600 MHz, CDCl3): δ = 8.12 (d, J = 7.8 Hz, 1 H, HAr), 7.81 (d, J =
7.8 Hz, 2 H, HAr), 7.61–7.14 (m, 10 H, HAr), 4.51 (s, 2 H, CH2), 2.38 (s, 3
H, CH3).
7.2 Hz, 2 H, HAr), 7.62–7.14 (m, 10 H, HAr), 4.50 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.3, 165.0, 146.5, 139.6, 137.3,
136.2, 131.7, 131.3, 130.9, 130.1, 128.8, 127.7, 127.4, 126.8, 126.4,
126.1, 48.0, 21.1.
13C NMR (100 MHz, CDCl3): δ = 167.1, 164.7, 146.5, 143.0, 135.9,
134.8, 132.0, 131.5, 130.8, 130.3, 128.9, 127.7, 127.6, 126.9, 126.8,
126.2, 124.8, 47.6.
MS: m/z (%) = 326 (M+, 52), 179 (100), 119 (43), 105 (17).
MS: m/z (%) = 346 (M+, 28), 207 (8), 179 (100), 103 (12), 76 (13).
Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 81.09;
H, 5.37; N, 8.72.
Anal. Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C,
72.81; H, 4.32; N, 8.27.
2,4-Diphenyl-3,4-dihydro-5H-1,4-benzodiazepin-5-one (5b)
2-(4-Methoxyphenyl)-4-phenyl-3,4-dihydro-5H-1,4-benzodiaze-
White solid: yield: 0.27 g (87%); mp 174–176 °C.
pin-5-one (5f)
IR (KBr): 2918, 1652, 1592, 1405, 1342, 1202 cm–1
.
White solid: yield: 0.28 g (82%); mp 148–150 °C.
IR (KBr): 1646, 1591, 1454, 1259, 1178 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 7.2 Hz, 1 H, HAr), 7.78 (d, J =
1H NMR (600 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1 H, HAr), 7.76 (d, J =
9.0 Hz, 2 H, HAr), 7.58 (t, J = 7.8 Hz, 1 H, HAr), 7.45–7.28 (m, 5 H, HAr),
7.27 (d, J = 7.2 Hz, 2 H, HAr), 6.89 (d, J = 8.4 Hz, 2 H, HAr), 4.49 (s, 2 H,
CH2), 3.83 (s, 3 H, OCH3).
6.6 Hz, 2 H, HAr), 7.60–7.25 (m, 11 H, HAr), 4.51 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.2, 165.0, 146.5, 142.1, 136.1,
131.8, 131.3, 130.8, 129.4, 128.8, 127.7, 127.4, 127.3, 126.8, 126.6,
126.1, 47.9.
13C NMR (100 MHz, CDCl3): δ = 167.3, 164.1, 162.2, 146.8, 142.1,
131.7, 130.8, 129.7, 129.5, 129.4, 128.6, 127.4, 127.2, 126.7, 126.6,
125.7, 114.1, 55.3, 47.6.
MS: m/z (%) = 312 (M+, 45), 179 (100), 105 (41).
Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.97;
H, 5.07; N, 9.04.
MS: m/z (%) = 342 (M+, 73), 237 (23), 209 (100), 166 (17), 118 (17).
4-(4-Chlorophenyl)-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
5-one (5c)
Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.41;
H, 5.13; N, 8.22.
White solid: yield: 0.26 g (75%); mp 240–242 °C.
2-(4-Methoxyphenyl)-4-(p-tolyl)-3,4-dihydro-5H-1,4-benzodiaze-
pin-5-one (5g)
IR (KBr): 2916, 1653, 1591, 1451, 1342, 1219 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1 H, HAr), 7.81 (d, J =
7.8 Hz, 2 H, HAr), 7.61 (t, J = 7.2 Hz, 1 H, HAr), 7.55–7.32 (m, 7 H, HAr),
7.81 (d, J = 9.0 Hz, 2 H, HAr), 4.51 (s, 2 H, CH2).
White solid: yield: 0.29 g (81%); mp 147–149 °C.
IR (KBr): 1646, 1598, 1510, 1386, 1252, 1181 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1 H, HAr), 7.78 (d, J =
8.4 Hz, 2 H, HAr), 7.59–7.32 (m, 3 H, HAr), 7.20 (d, J = 7.8 Hz, 2 H, HAr),
7.13 (d, J = 7.8 Hz, 2 H, HAr), 6.90 (d, J = 8.4 Hz, 2 H, HAr), 4.46 (s, 2 H,
CH2), 3.84 (s, 3 H, OCH3), 2.37 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.3, 164.1, 162.1, 146.8, 139.6,
137.2, 131.6, 130.7, 130.0, 129.5, 128.6, 127.3, 126.7, 126.3, 125.6,
114.1, 55.3, 47.7, 21.1.
13C NMR (100 MHz, CDCl3): δ = 167.2, 164.7, 146.5, 140.5, 135.9,
133.0, 132.0, 131.5, 130.8, 129.6, 128.9, 127.9, 127.6, 126.9, 126.3,
47.7.
MS: m/z (%) = 346 (M+, 36), 206 (6), 179 (100), 139 (18).
Anal. Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C,
72.98; H, 4.27; N, 8.24.
MS: m/z (%) = 356 (M+, 62), 237 (26), 209 (100), 166 (17), 119 (18).
2-Phenyl-4-(o-tolyl)-3,4-dihydro-5H-1,4-benzodiazepin-5-one
(5d)
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.58;
H, 5.49; N, 7.96.
White solid: yield: 0.23 g (71%); mp 113–115 °C.
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Synthesis
2-(4-Chlorophenyl)-4-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
4-(4-Ethoxyphenyl)-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
5-one (5h)
5-one (5l)
White solid: yield: 0.30 g (87%); mp 183–185 °C.
White solid: yield: 0.28 g (79%); mp 168–170 °C.
IR (KBr): 3062, 1637, 1586, 1417, 1353, 1088 cm–1
.
IR (KBr): 2978, 1648, 1510, 1449, 1246, 1048 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 1 H, HAr), 7.72 (d, J =
8.0 Hz, 2 H, HAr), 7.60 (t, J = 7.6 Hz, 1 H, HAr), 7.45–7.32 (m, 7 H, HAr),
7.24 (d, J = 7.6 Hz, 2 H, HAr), 4.48 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.0, 163.7, 146.2, 141.9, 137.5,
134.4, 131.8, 130.8, 129.5, 129.0, 128.9, 127.5, 127.2, 126.7, 126.4,
126.3, 47.6.
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 7.8 Hz, 1 H, HAr), 7.81 (d, J =
7.2 Hz, 2 H, HAr), 7.60 (t, J = 7.2 Hz, 1 H, HAr), 7.49–7.35 (m, 5 H, HAr),
7.16 (d, J = 8.4 Hz, 2 H, HAr), 6.91 (d, J = 8.4 Hz, 2 H, HAr), 4.83 (s, 2 H,
CH2), 4.05 (q, J = 7.2 Hz, 2 H, OCH2), 1.43 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.3, 165.0, 157.8, 146.4, 136.1,
134.9, 131.6, 131.2, 130.7, 128.7, 127.7, 127.6, 127.3, 126.7, 126.0,
115.1, 63.6, 48.1, 14.7.
MS: m/z (%) = 346 (M+, 71), 213 (100), 178 (49), 151 (18), 105 (88).
MS: m/z (%) = 356 (M+, 97), 209 (9), 179 (100), 149 (65), 135 (33).
Anal. Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C,
72.96; H, 4.32; N, 8.23.
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.64;
H, 5.45; N, 8.01.
2-(4-Chlorophenyl)-4-(p-tolyl)-3,4-dihydro-5H-1,4-benzodiaze-
pin-5-one (5i)
4-(4-Fluorophenyl)-2-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
5-one (5m)
White solid: yield: 0.30 g (83%); mp 153–154 °C.
White solid: yield: 0.25 g (76%); mp 191–193 °C.
IR (KBr): 1652, 1510, 1387, 1218, 1089 cm–1
.
IR (KBr): 1650, 1508, 1401, 1213, 1154 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.0 Hz, 1 H, HAr), 7.74 (d, J =
8.4 Hz, 2 H, HAr), 7.60 (t, J = 7.6 Hz, 1 H, HAr), 7.45–7.37 (m, 4 H, HAr),
7.21 (d, J = 8.0 Hz, 2 H, HAr), 7.13 (d, J = 8.0 Hz, 2 H, HAr), 4.47 (s, 2 H,
CH2), 2.38 (s, 3 H, CH3).
1H NMR (600 MHz, CDCl3): δ = 8.10 (d, J = 7.8 Hz, 1 H, HAr), 7.81 (d, J =
7.8 Hz, 2 H, HAr), 7.62 (t, J = 7.2 Hz, 1 H, HAr), 7.51–7.23 (m, 7 H, HAr),
7.10 (t, J = 7.8 Hz, 2 H, HAr), 4.51 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.2, 163.8, 146.2, 139.4, 137.6,
137.5, 134.5, 131.8, 130.9, 130.1, 129.0, 128.9, 127.3, 126.8, 126.3,
126.2, 47.8, 21.1.
13C NMR (100 MHz, CDCl3): δ = 167.2, 164.7, 162.3, 159.9, 146.4,
137.9, 135.8, 131.7, 131.3, 130.6, 128.7, 128.3, 128.2, 127.5, 126.8,
126.7, 126.0, 116.3, 116.0, 47.7.
MS: m/z (%) = 360 (M+, 67), 213 (96), 178 (46), 119 (100).
MS: m/z (%) = 330 (M+, 47), 209 (6), 179 (100), 152 (7), 123 (15).
Anal. Calcd for C22H17ClN2O: C, 73.23; H, 4.75; N, 7.76. Found: C,
73.35; H, 4.48; N, 7.91.
Anal. Calcd for C21H15FN2O: C, 76.35; H, 4.58; N, 8.48. Found: C, 76.61;
H, 4.29; N, 8.43.
2,4-Bis(4-chlorophenyl)-3,4-dihydro-5H-1,4-benzodiazepin-5-one
4-(4-Methoxyphenyl)-2-phenyl-3,4-dihydro-5H-1,4-benzodiaze-
(5j)
pin-5-one (5n)
White solid: yield: 0.31 g (81%); mp 157–159 °C.
White solid: yield: 0.28 g (82%); mp 159–161 °C.
IR (KBr): 3062, 1647, 1589, 1490, 1392, 1091 cm–1
.
IR (KBr): 1645, 1511, 1448, 1252, 1025 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 7.6 Hz, 1 H, HAr), 7.74 (d, J =
8.4 Hz, 2 H, HAr), 7.61 (t, J = 7.6 Hz, 1 H, HAr), 7.45–7.37 (m, 6 H, HAr),
7.19 (d, J = 8.4 Hz, 2 H, HAr), 4.47 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.1, 163.4, 146.2, 140.3, 137.8,
134.2, 133.1, 132.0, 130.8, 129.6, 129.1, 128.8, 127.8, 126.9, 126.8,
126.4, 47.4.
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 7.8 Hz, 1 H, HAr), 7.81 (d, J =
7.2 Hz, 2 H, HAr), 7.60 (t, J = 7.2 Hz, 1 H, HAr), 7.49–7.35 (m, 5 H, HAr),
7.18 (d, J = 7.2 Hz, 2 H, HAr), 6.92 (d, J = 6.6 Hz, 2 H, HAr), 4.49 (s, 2 H,
CH2), 3.83 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.3, 165.0, 158.4, 146.4, 136.1,
135.0, 131.6, 131.2, 130.7, 128.7, 127.7, 127.6, 127.3, 126.7, 126.0,
114.6, 55.4, 48.1.
MS: m/z (%) = 380 (M+, 34), 243 (15), 213 (100), 178 (46).
MS: m/z (%) = 342 (M+, 94), 209 (10), 179 (100), 152 (11), 135 (52),
121 (35).
Anal. Calcd for C21H14Cl2N2O: C, 66.16; H, 3.70; N, 7.35. Found: C,
66.44; H, 3.48; N, 7.43.
Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.14;
H, 5.10; N, 8.39.
2-(4-Bromophenyl)-4-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-
5-one (5k)
2-tert-Butyl-4-(p-tolyl)-3,4-dihydro-5H-1,4-benzodiazepin-5-one
(5o)
White solid: yield: 0.32 g (82%); mp 184–186 °C.
IR (KBr): 3060, 1638, 1581, 1447, 1230, 1005 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 7.8 Hz, 1 H, HAr), 7.66–7.25
(m, 12 H, HAr), 4.49 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.1, 163.8, 146.2, 141.9, 134.9,
132.0, 131.9, 130.8, 129.5, 129.1, 127.6, 127.2, 126.8, 126.5, 126.4,
126.2, 47.6.
.
White solid: yield: 0.24 g (78%); mp 159–161 °C.
IR (KBr): 2962, 1638, 1451, 1342, 1120 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.87 (d, J = 7.2 Hz, 1 H, HAr), 7.60 (t,
J = 7.2 Hz, 1 H, HAr), 7.35 (t, J = 7.2 Hz, 1 H, HAr), 7.28–7.22 (m, 5 H,
HAr), 4.14 (br, 2 H, CH2), 2.33 (s, 3 H, CH3), 1.04 (s, 9 H, 3 CH3).
13C NMR (100 MHz, DMSO-d6): δ = 177.7, 166.1, 145.9, 139.5, 135.8,
131.7, 130.3, 129.2, 127.0, 126.5, 126.3, 125.6, 46.4, 39.0, 27.0, 20.6.
MS: m/z (%) = 390 (M+, 54), 259 (91), 178 (45), 105 (100).
Anal. Calcd for C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C,
64.51; H, 3.69; N, 7.29.
MS: m/z (%) = 307 (M+ + 1, 40), 272 (21), 256 (22), 211 (41), 144 (100).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3522–3528

3527
L. Wang et al.
Paper
Synthesis
Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C, 78.62;
H, 7.17; N, 9.28.
lowed by the addition of ethyl chloroformate (2.39 g, 22 mmol) over
30 min; the mixture was stirred at –10 °C for 1 h. Then a solution of
NaN3 (1.43 g, 22 mmol) in water (10 mL) was added dropwise and the
mixture was stirred at –10 °C for 3 h. The mixture was extracted with
CH2Cl2 (3 × 100 mL). The organic layers were combined, washed with
brine, and dried (anhyd Na2SO4). The solvent was removed under re-
duced pressure to give crude acyl azide 3a. The crude product 3a was
dissolved in toluene (100 mL) and the mixture was heated to 60–70
°C for 0.5 h to form isocyanate intermediate 4a. Then 3-methyl-1-
phenyl-2-phospholene 1-oxide (A, 0.192 g, 1 mmol) was added and
the mixture was stirred at 110 °C. When the reaction was complete (6
h), the solvent was removed under reduced pressure and the residue
was purified by flash chromatography (silica gel, Et2O–petroleum
ether, 1:4) to give 3,4-dihydro-5H-1,4-benzodiazepin-5-one 5a (5.61
g, 86%) along with the phosphine catalyst A (0.182 g, 95% recovery).
2-tert-Butyl-4-phenyl-3,4-dihydro-5H-1,4-benzodiazepin-5-one
(5p)
White solid: yield: 0.21 g (72%); mp 140–142 °C.
IR (KBr): 2964, 1641, 1449, 1348, 1200 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.87 (d, J = 7.8 Hz, 1 H, HAr), 7.61 (t,
J = 7.2 Hz, 1 H, HAr), 7.45–7.28 (m, 7 H, HAr), 4.16 (br, 2 H, CH2), 1.04 (s,
9 H, 3 CH3).
13C NMR (100 MHz, DMSO-d6): δ = 177.7, 166.1, 145.9, 141.9, 131.8,
130.3, 128.7, 127.0, 126.6, 126.5, 126.4, 125.6, 46.4, 39.0, 26.9.
MS: m/z (%) = 292 (M+, 100), 235 (27), 187 (62), 159 (59), 144 (46),
103 (63).
Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 78.21;
H, 6.74; N, 9.47.
Acknowledgment
We gratefully acknowledge financial support of this work by the Na-
tional Natural Science Foundation of China (No. 21172085).
Conventional Hydrolysis/Dehydration of Isocyanates 4k and 4o
To the isocyanate 4k or 4o prepared as above in toluene, was added
formic acid (0.092 g, 2 mmol) and DMAP (0.037 g, 0.3 mmol). The
mixture was stirred at 110 °C for 12 h. The solvent was removed un-
der reduced pressure and the residue was purified by flash chroma-
tography (silica gel, Et2O–petroleum ether, 1:4) to give 3,4-dihydro-
5H-1,4-benzodiazepin-5-one 5k (0.13 g, 33%) or 5o (0.086 g, 28%) and
amine 7.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378874.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
2-Amino-N-(2-(4-bromophenyl)-2-oxoethyl)-N-phenylbenzamide
(7k)
References
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White solid: yield: 0.21 g (51%); mp 150–152 °C.
IR (KBr): 3350, 1705, 1639, 1584, 1511, 1374, 1219 cm–1
.
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White solid: yield: 0.17 g (52%); mp 206–208 °C.
IR (KBr): 3365, 2969, 1718, 1634, 1511, 1291 cm–1
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3522–3528