Rapid synthesis of benzodiazepines by ring expansion of aziridines with anthranilic acids by using a grinding technique

Article abstract of DOI:10.1055/s-0031-1289670

A grinding-induced, atom-economic, rapid, efficient, one-pot protocol was developed for the synthesis of pharmaceutically relevant benzo-1,4-diazepin-5- ones in excellent yields (72-91%) and high regioselectivities. The method involves a ring-opening-ring

Full text of DOI:10.1055/s-0031-1289670

PAPER
591
Rapid Synthesis of Benzodiazepines by Ring Expansion of Aziridines with
Anthranilic Acids by Using a Grinding Technique
S
ynthesis of Benzo
t
diazep
u
ines by a Gr
l
inding
Techni
K
que . Singh, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received 11 September 2011; revised 29 November 2011
cycles, those with two heteroatoms in the 1- and 4-
positions, especially benzodiazepines, are important scaf-
folds in medicinal chemistry, and many biologically ac-
tive compounds contain such cores.15 Benzodiazepines
Abstract: A grinding-induced, atom-economic, rapid, efficient,
one-pot protocol was developed for the synthesis of pharmaceuti-
cally relevant benzo-1,4-diazepin-5-ones in excellent yields (72–
91%) and high regioselectivities. The method involves a ring-
opening–ring-closure cascade of aziridines with anthranilic acids by are widely used as drugs of the central nervous system.
grinding the neat reactants at room temperature in the presence of
For example, diazepam, lorazepam, parazepam, and ox-
lithium bromide as a mild catalyst. Among the advantages of this
azepam are used as anxiolytics; flurazepam is a hypnotic;
protocol are its economic viability, the ability to recycle the cata-
clonazepan is an antiepileptic;15c triflubazam (A) and clo-
lyst, and the formation of water as the only byproduct.
bazam (B)16 are anxiolytic agents; anthramycin (C)17 is a
Key words: heterocycles, cyclizations, solid-phase synthesis, cas-
cade reactions, benzodiazepines
naturally occurring antitumor antibiotic, and other ana-
logues such as the pyrrolobenzodiazepine D18 display an-
tileishmanial activity (Figure 1). In addition, some
benzodiazepine derivatives are potent inhibitors of HIV-1
reverse transcriptase.19
The generation of complex molecular systems by cascade
reactions by following green chemistry protocols is an
area that is of current interest to organic chemists.1 In the
last decade, cascade reactions have become powerful
tools in organic chemistry, not only because they offer
significant potential to reduce byproduct formation, waste
production, energy costs, and materials consumption, to
mitigate hazards, and to use nonrenewable resources, but
also because they open the way to the development of new
methods for preparing previously unobtainable materi-
als.2 Recently, the initiation of solvent-free organic reac-
tions by grinding has attracted considerable interest, and
it has been found to provide several excellent methods for
performing aldol condensations,3 Grignard reactions,4
Reformatsky reactions,5 Dieckmann condensations,6
Knoevenagel condensations,7 reductions,8 and other or-
ganic reactions.9 Most of these reactions are carried out at
room temperature under neat conditions using only a pes-
tle and mortar.
Me
O
N
Me
O
N
Cl
F3C
N
N
O
O
Ph
Ph
B
A
CONH2
H
N
H
N
O
OH
NH
NH
C
D
In general, the chemistry of seven-membered heterocy-
cles has been far less extensively studied than that of five-
or six-membered heterocycles or that of inherently
strained small-ring heterocycles. The synthesis of hetero-
cycles with seven- to eleven-membered rings is difficult
for enthalpic and entropic reasons.10 In recent decades, the
synthesis of heterocycles with ring sizes in the range from
seven to eleven has received a great deal of attention be-
cause of the abundance of oxygen- and nitrogen-contain-
ing seven-membered and other medium-sized rings in
natural products,11 drug candidates,12 functional materi-
als,13 and catalysts.14 Among the seven-membered hetero-
Figure 1 Some medicinally important 1,4-benzodiazepine deriva-
tives
The widespread occurrence and medicinal applications of
benzodiazepines make these compounds attractive as tar-
gets for synthesis. Benzodiazepines are generally synthe-
sized by acid-catalyzed condensation of a benzene-1,2-
diamine with a ketone. This transformation is catalyzed
by many reagents including boron trifluoride etherate,20a
sodium borohydride,20b magnesium oxide–phosphoryl
trichloride,20c alumina–phosphorus pentoxide,20d acetic
acid (with microwave heating),20e diiodine,20f silver het-
eropolyphosphotungstate (Ag3PW12O40),20g indium(III)
bromide,20h bromo(dimethyl)sulfonium bromide,20i ceri-
um(IV) ammonium nitrate,20j silver nitrate,20k triflates,20l,m
SYNTHESIS 2012, 44, 591–599
x
x
.x
x
.2
0
1
2
Advanced online publication: 16.01.2012
DOI: 10.1055/s-0031-1289670; Art ID: N88611SS
© Georg Thieme Verlag Stuttgart · New York

592
A. K. Singh, L. D. S. Yadav
PAPER
palladium,20n or ionic liquids.20o Corral and co-workers ium bromide (Table 1, entries 2–4). Significantly lower
synthesized benzodiazepines by the addition of methyl yields of benzodiazepine 3a were obtained with the other
anthranilate to ethyl enimines with subsequent intramo- catalysts (Table 1, entries 1 and 5–10).
lecular cyclization of the resulting intermediates.21 How-
Table 1 Optimization of the Catalyst for the Synthesis of 2-Phenyl-
4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one (3a)
ever, most methodologies for the synthesis of
benzodiazepines have disadvantages such as long reaction
O
times, high temperatures, harsh reaction conditions, the
use of expensive reagents, or the use of toxic or hazardous
organic solvents. There is therefore a need to develop eco-
nomical and environmentally benign methods for the syn-
thesis of these compounds.
O
Ts
N
Ts
N
catalyst, neat
HO
H2N
+
r.t., grinding, 5 min
Ph
N
H
Ph
1a
2a
3a
In continuation of our ongoing efforts to develop new cy-
clization processes,22 we have devised an efficient, regi-
oselective, one-pot synthesis of pharmacologically
relevant benzo-1,4-diazepin-5-ones 3. Our protocol in-
volves ring expansion of an aziridine 1 with an anthranilic
acid 2 (Scheme 1).
Entry
1
Catalyst (mol%)
Yield (%)a
LiI (10)
60b
85
76
85
62
53
55
21
26
33
35
49
53
2
LiBr (10)
LiBr (5)
3
4
LiBr (15)
LiCl (10)
AlCl3 (10)
AlBr3 (10)
NaCl (10)
NaBr (10)
CuCl2 (10)
CuBr2 (10)
FeCl3 (10)
FeBr3 (10)
O
O
Ts
R1
Ts
N
R2
5
N
LiBr (10 mol%)
HO
+
6
neat, r.t.
grinding
R1
H2N
R2
N
H
7
2
3
1
8
Scheme 1 Ring expansion of aziridines to benzo-1,4-diazepin-5-
ones
9
10
11
12
13
We selected the N-tosylaziridine 1 and the anthranilic acid
2 as reactants on the basis of the disconnection approach
shown in Scheme 2.
O
R2
OH
a Isolated yield of purified product 3a.
O
R2
b N-(2-iodo-2-phenylethyl)-4-methylbenzenesulfonamide was also
Ts
R1
NH2
N
isolated in 24% yield.
O
HN
2
Ts
N
R2
N
H
No appreciable amount of product 3a was formed from
aziridine 1a and anthranilic acid 2a in the absence of lith-
ium bromide after grinding for five minutes at room tem-
perature, showing that lithium bromide is an effective
catalyst. For comparison, we also performed the reaction
in various solvents with lithium bromide as the catalyst,
but we obtained significantly lower yields of 3a in rela-
tively longer reaction times (13–19 hours; Table 2).
N
3
R1
Ts
R1
1
Scheme 2 Disconnection approach for the target compounds 3
Here, we report a lithium bromide-catalyzed reaction in-
volving regioselective cleavage of the aziridine ring in 1
by the amino group of the anthranilic acid 2, followed by
cyclization to afford the 1,2,3,4-tetrahydro-5H-1,4-ben-
zodiazepin-5-one 3 (Scheme 1). In general, the efficiency
of a synthetic process can be enhanced by increasing the
concentration of the reactants and by the use of a suitable
catalyst. To realize our idea, we initially examined the
synthesis of 2-phenyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-
benzodiazepin-5-one (3a) by the reaction of 2-phenyl-1-
tosylaziridine (1a) with 2-aminobenzoic acid (2a; anthra-
nilic acid) in the presence of several Lewis acid catalysts
that should efficiently catalyze both steps of the ring-
opening–ring-closing cascade of the aziridine with the an-
thranilic acid. The best results were obtained by using lith-
Of the solvents tested, dichloromethane was the best in
terms of the yield and reaction time (Table 2, entry 3).
Having optimized the reaction conditions, we then pro-
ceeded to examine the scope of our grinding method. A
wide range of benzo-1,4-diazepin-5-ones 3 were rapidly
synthesized in excellent yields and complete regioselec-
tivity (Table 3). The reaction therefore permits the intro-
duction of a considerable degree of molecular diversity
under mild reaction conditions. The regioselectivity of the
reaction was ascertained by recording the 1H NMR spec-
tra of the crude samples, and we found that the regio-
isomer 3 was formed exclusively. The regioselective
cleavage of the aziridine ring at the benzylic position is
Synthesis 2012, 44, 591–599
© Thieme Stuttgart · New York

PAPER
Synthesis of Benzodiazepines by a Grinding Technique
593
Table 2 Optimization of the Solvent for the Synthesis of 2-Phenyl-
4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one (3a)
results, we proposed the mechanism for the formation of
benzo-1,4-diazepin-5-ones 3 that is shown in Scheme 3.
Lithium bromide activates the aziridine ring by coordinat-
ing with the nitrogen atom, thereby facilitating regioselec-
tive nucleophilic ring cleavage by the amino group of
anthranilic acid 2 to form intermediate 4. Intramolecular
dehydrative cyclization of 4 affords the benzo-1,4-diaz-
epin-5-ones 3 and liberates lithium bromide to complete
the catalytic cycle (Scheme 3).
O
O
Ts
Ts
N
N
LiBr (10 mol%), solvent
stirring, r.t., 13–19 h
HO
+
H2N
Ph
N
H
Ph
1a
2a
3a
Entry
Solvent
Time (h)
15
Yield
(%)a
Table 3 Synthesis of 1,2,3,4-Tetrahydro-5H-1,4-benzodiazepin-5-
ones 3
1
2
3
4
5
6
THF
71
73
75
69
62
70
O
O
1,4-dioxane
CH2Cl2
EtOH
17
13
16
19
14
Ts
Ts
N
R2
N
LiBr, neat
HO
+
r.t., grinding, 5 min
R1
R2
H2N
N
H
R1
3
2
1
toluene
CHCl3
Entry Aziridine 1
R2
Product
Yield
(%)a,b
a Isolated yield of purified product 3a.
Ts
O
N
easily understandable. The regioselective ring opening of
the alkyl aziridines at the secondary position is in agree-
ment with reactivity–selectivity arguments reported in the
literature.23 Therefore, the amino group of the anthranilic
acid preferentially attacks the 2-alkyl-1-tosylaziridine at
the 2-position, which has a partial positive charge, rather
than at the 3-position.
Ts
1
H
85
N
Ph
N
H
Ph
3a
Ts
O
Ts
N
2
H
H
H
H
89
88
86
77
N
The important feature of this procedure is the compatibil-
ity of the reaction conditions with a broad range of func-
tional groups, including ether, nitro, and chloro groups.
Anthranilic acids 2 bearing an electron-withdrawing
group give slightly lower yields (Table 3, entries 6–10,
18, and 19) than those bearing electron-donating groups
(Table 3, entries 11–15). On the basis of our experimental
4-ClC6H4
N
4-ClC6H4
H
3b
Ts
O
Ts
N
N
3
4-MeOC6H4
N
4-MeOC6H4
H
O
3c
Ts
N
Ts
O
R2
Ts
N
N
Ts
N
H
4
N
R1
R1
4-MeC6H4
3
N
4-MeC6H4
1
H
LiBr
– H2O
3d
Ts
O
N
Ts
5
Li
Br
N
Ts
H2O
N
OLi
Ts
N
N
H
R1
••
R2
3e
N
Ts
R1
H
H2N
R1
O
R2
N
H
Ts
N
HO
6
5-Cl
82
N
R2
Cl
NH
Ts
Ph
O
N
2
Ph
H
OH
O
3f
4
Li
Br
Scheme 3 A plausible mechanism and catalytic cycle for ring ex-
pansion of aziridines
Synthesis 2012, 44, 591–599
© Thieme Stuttgart · New York

594
A. K. Singh, L. D. S. Yadav
PAPER
Table 3 Synthesis of 1,2,3,4-Tetrahydro-5H-1,4-benzodiazepin-5-
ones 3 (continued)
Table 3 Synthesis of 1,2,3,4-Tetrahydro-5H-1,4-benzodiazepin-5-
ones 3 (continued)
O
O
O
O
Ts
Ts
Ts
N
Ts
N
R2
R2
N
N
LiBr, neat
LiBr, neat
HO
HO
+
+
r.t., grinding, 5 min
r.t., grinding, 5 min
R1
R1
R2
R2
H2N
H2N
N
H
N
H
R1
R1
3
3
2
2
1
1
Entry Aziridine 1
R2
Product
Yield
(%)a,b
Entry Aziridine 1
R2
Product
Yield
(%)a,b
Ts
O
N
Ts
O
Ts
N
N
Ts
7
5-Cl
86
15
5-Me
78
N
Cl
4-ClC6H4
N
N
H
4-ClC6H4
H
3g
3o
Ts
Ts
O
O
Ts
Ts
N
N
8
5-Cl
84
87
76
84
88
87
91
16
H
85
81
N
N
Cl
4-O2NC6H4
4-MeOC6H4
N
N
4-MeOC6H4
4-O2NC6H4
H
H
3h
3p
Ts
Ts
O
O
Ts
Ts
N
N
N
9
5-Cl
17
H
N
Cl
4-MeC6H4
N
N
H
4-MeC6H4
H
3i
3q
Ts
N
Ts
O
O
N
Ts
Ts
10
5-Cl
N
18
5-NO2
5-NO2
77
72
N
Cl
NO2
N
H
Ph
N
Ph
H
3j
3r
Ts
Ts
O
O
N
Ts
N
Ts
11
5-Me
5-Me
5-Me
5-Me
N
19
N
Ph
N
NO2
Ph
N
H
H
3k
3s
Ts
O
a Isolated yield of purified product 3.
N
Ts
N
b All the products were solids and showed the expected IR, 1H NMR,
13C NMR, and EIMS spectra. Their C, H, and N analyses were within
0.36% of the expected values.
12
4-ClC6H4
N
H
4-ClC6H4
3l
In a pilot study of the one-pot enantioselective synthesis
of the benzo-1,4-diazepin-5-one (S)-3a (Scheme 4), a
mixture of aziridine (R)-1a (1 mmol), anthranilic acid 2a
(1 mmol), and lithium bromide (10 mol%) was ground in
a mortar with a pestle at room temperature for five min-
utes to give the (S)-benzo-1,4-diazepin-5-one (S)-3a in
87% yield with an enantiomeric excess (ee) of about 99%,
as determined by chiral HPLC using a chiral Eurocel col-
umn [250 × 4.6 mm, 5 ; l = 225 nm; i-PrOH–hexane
(10:90), 1 mL/min; tR = 6.4 min (minor), 7.6 min (ma-
jor)]; [a]D20 +94 (c 0.90, THF). This shows that the ring
opening of the optically active aziridine (R)-1a with an-
Ts
O
N
Ts
N
13
4-MeOC6H4
N
H
4-MeOC6H4
3m
Ts
O
N
Ts
14
N
4-MeC6H4
N
4-MeC6H4
H
3n
2
thranilic acid 2a proceeds by an SN -type pathway.
Synthesis 2012, 44, 591–599
© Thieme Stuttgart · New York

PAPER
Synthesis of Benzodiazepines by a Grinding Technique
595
MS (EI): m/z = 392 [M]+.
O
O
Ts
N
Ts
Anal. Calcd for C22H20N2O3S: C, 67.33; H, 5.14; N, 7.14. Found: C,
67.62; H, 5.50; N, 7.09.
N
LiBr, neat
HO
+
r.t., grinding, 5 min
(S)
Ph
H2N
(R)
Ph
N
H
2-(4-Chlorophenyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepin-5-one (3b)
Yellowish solid; yield: 379 mg (89%); mp 184–186 °C.
1a
2a
3a
ee >99%
Scheme 4 Enantioselective synthesis of (2S)-2-Phenyl-4-tosyl-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one [(S)-3a]
IR (KBr): 3326, 1702, 1603, 1326, 1158, 840 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H), 3.20 (dd, J = 12.2,
5.3 Hz, 1 H), 3.45 (dd, J = 12.2, 7.5 Hz, 1 H), 4.57 (dd, J = 7.5, 5.3
Hz, 1 H), 5.34 (br s, 1 H, NH, exchanges with D2O), 6.33 (dd,
J = 8.1, 1.0 Hz, 1 H, Harom), 6.65 (m, 1 H, Harom), 7.30 (d, J = 8.1 Hz,
2 H, Harom), 7.33–7.36 (m, 1 H, Harom), 7.65–7.70 (m, 2 H, Harom),
7.71 (d, J = 8.1 Hz, 2 H, Harom), 8.00 (dd, J = 8.2, 1.0 Hz, 1 H,
In summary, we have developed a simple and highly effi-
cient one-pot green protocol for the synthesis of pharma-
ceutically relevant benzo-1,4-diazepine derivatives by
means of a lithium bromide-catalyzed regioselective ring
expansion of an aziridine with an anthranilic acid. This
rapid synthesis is performed within five minutes at room
temperature under neat conditions by the application of
grinding. Moreover, the protocol has the advantages in
terms of sustainability, economic viability, recycling of
the catalyst, atom economy, high yield, and formation of
water as the sole byproduct, making it one of the most
convenient and efficient methods for the synthesis of this
class of compounds.
Harom), 8.10–8.17 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.9, 47.9, 62.5, 112.6, 115.8,
117.9, 127.7, 128.6, 128.7, 128.9, 130.0, 132.5, 133.4, 137.8, 141.8,
142.1, 147.9, 168.6.
MS (EI): m/z = 426 [M]+.
Anal. Calcd for C22H19ClN2O3S: C, 61.89; H, 4.49; N, 6.56. Found:
C, 62.17; H, 4.24; N, 6.69.
2-(4-Methoxyphenyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzo-
diazepin-5-one (3c)
Yellowish solid; yield: 371 mg (88%); mp 161–162 °C.
IR (KBr): 3328, 1705, 1598, 1328, 1159, 860 cm–1.
IR spectra in KBr were recorded on a Perkin-Elmer 993 IR spectro-
photometer. H NMR spectra were recorded on Bruker Avance II
1
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 3.21 (dd, J = 12.3,
5.2 Hz, 1 H), 3.46 (dd, J = 12.3, 7.7 Hz, 1 H), 3.85 (s, 3 H), 4.52 (dd,
J = 7.7, 5.2 Hz, 1 H), 5.34 (br s, 1 H, NH, exchanges with D2O),
6.30 (dd, J = 8.0, 1.2 Hz, 1 H, Harom), 6.61 (m, 1 H, Harom), 7.31 (d,
J = 8.2 Hz, 2 H, Harom), 7.35–7.37 (m, 1 H, Harom), 7.67–7.69 (m, 2
H, Harom), 7.71 (d, J = 8.2 Hz, 2 H, Harom), 7.94 (dd, J = 8.0, 1.2 Hz,
1 H, Harom), 8.01–8.03 (m, 2 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.6, 47.3, 55.6, 62.0, 112.1,
114.6, 115.4, 117.3, 127.1, 127.8, 128.3, 129.1, 133.2, 136.0, 137.9,
141.4, 147.5, 159.2, 168.0.
(400 MHz) Fourier-transform spectrometer in CDCl3 with TMS as
the internal reference. 13C NMR spectra were recorded on the same
instrument at 100 MHz in CDCl3 with TMS as internal reference.
Mass (EI) spectra were recorded on a JEOL D-300 mass spectrom-
eter. Elemental analyses were carried out in a Coleman automatic
carbon, hydrogen, and nitrogen analyzer. All chemicals were of re-
agent grade and were used as received without further purification.
Silica gel-G was used for TLC.
1,2,3,4-Tetrahydro-5H-1,4-benzodiazepin-5-one 3; General
Procedure
MS (EI): m/z = 422 [M]+.
Aziridine 1 (1 mmol), anthranilic acid 2 (1 mmol), and LiBr (10
mol%) were thoroughly ground with a pestle and mortar for 5 min
at r.t. When the reaction was complete [TLC, EtOAc–hexane (2:3)],
H2O (5 mL) was added and the mixture was extracted with EtOAc
(3 × 5 mL). The combined organic phase was dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The resulting crude
product was purified by column chromatography [silica gel,
EtOAc–hexane (1:3)]. After isolation of the product, the remaining
aqueous layer containing LiBr was washed with Et2O (2 × 5 mL) to
remove any organic impurities and dried under reduced pressure to
afford LiBr, which was reused in subsequent runs without further
purification and with no loss of efficiency.
Anal. Calcd for C23H22N2O4S: C, 65.38; H, 5.25; N, 6.63. Found: C,
65.07; H, 5.51; N, 6.41.
2-(4-Tolyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-
one (3d)
Yellowish solid; yield: 349 mg (86%); mp 154–155 °C.
IR (KBr): 3330, 1701, 1600, 1336, 1157, 855 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H), 2.36 (s, 3 H), 3.19
(dd, J = 12.0, 5.3 Hz, 1 H), 3.42 (dd, J = 12.0, 7.4 Hz, 1 H), 4.52
(dd, J = 7.4, 5.3 Hz, 1 H), 5.32 (br s, 1 H, NH, exchanges with D2O),
6.30 (dd, J = 8.0, 1.1 Hz, 1 H, Harom), 6.62 (m, 1 H, Harom), 7.10–7.36
(m, 5 H, Harom), 7.32 (d, J = 8.2 Hz, 2 H, Harom), 7.70 (d, J = 8.2 Hz,
2 H, Harom), 7.93 (dd, J = 8.0, 1.1 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.6, 24.9, 47.4, 62.5, 112.7,
115.2, 117.1, 126.8, 127.3, 128.2, 129.0, 129.4, 133.4, 136.2, 137.0,
140.7, 141.7, 147.5, 168.2.
2-Phenyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-
one (3a)
Yellowish solid; yield: 333 mg (85%); mp 175–177 °C.
IR (KBr): 3340, 1700, 1600, 1323, 1159, 810 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H), 3.22 (dd, J = 12.1,
5.4 Hz, 1 H), 3.46 (dd, J = 12.1, 7.6 Hz, 1 H), 4.55 (dd, J = 7.6, 5.4
Hz, 1 H), 5.36 (br s, 1 H, NH, exchanges with D2O), 6.32 (dd,
J = 8.3, 1.3 Hz, 1 H, Harom), 6.62 (m, 1 H, Harom), 7.16–7.31 (m, 6 H,
MS (EI): m/z = 406 [M]+.
Anal. Calcd for C23H22N2O3S: C, 67.96; H, 5.46; N, 6.89. Found: C,
67.80; H, 5.79; N, 6.61.
Harom), 7.33 (d, J = 8.2 Hz, 2 H, Harom), 7.71 (d, J = 8.2 Hz, 2 H,
Harom), 7.97 (dd, J = 8.3, 1.3 Hz, 1 H, Harom).
2-Methyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-
one (3e)
Yellowish solid; yield: 254 mg (77%); mp 93–94 °C.
IR (KBr): 3332, 1704, 1601, 1329, 1158, 850 cm–1.
13C NMR (100 MHz, CDCl3): d = 24.7, 47.8, 62.3, 112.6, 115.5,
117.8, 125.8, 127.1, 127.5, 128.5, 129.2, 129.9, 133.5, 137.3, 141.9,
143.0, 147.8, 168.4.
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1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.0 Hz, 3 H), 2.32 (s,
3 H), 3.00–3.32 (m, 1 H), 3.86 (dd, J = 12.3, 5.4 Hz, 1 H), 4.58 (dd,
J = 12.3, 7.8 Hz, 1 H), 5.30 (br s, 1 H, NH, exchanges with D2O),
6.31 (dd, J = 8.2, 0.9 Hz, 1 H, Harom), 6.60 (m, 1 H, Harom), 7.30 (d,
J = 8.1 Hz, 2 H, Harom), 7.34–7.36 (m, 1 H, Harom), 7.72 (d, J = 8.1
Hz, 2 H, Harom), 8.00 (dd, J = 8.2, 0.9 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 18.4, 24.8, 48.2, 52.3, 113.1,
115.8, 117.0, 127.5, 127.9, 129.1, 132.8, 136.6, 141.7, 147.8, 168.1.
MS (EI): m/z = 330 [M]+.
MS (EI): m/z = 456 [M]+.
Anal. Calcd for C23H21ClN2O4S: C, 60.46; H, 4.63; N, 6.13. Found:
C, 60.16; H, 4.81; N, 6.48.
7-Chloro-2-(4-tolyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepin-5-one (3i)
Yellowish solid; yield: 383 mg (87%); mp 159–161 °C.
IR (KBr): 3342, 1704, 1600, 1328, 1157, 834 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3 H), 2.36 (s, 3 H), 3.20
(dd, J = 12.2, 5.2 Hz, 1 H), 3.40 (dd, J = 12.2, 7.4 Hz, 1 H), 4.49
(dd, J = 7.4, 5.2 Hz, 1 H), 5.31 (br s, 1 H, NH, exchanges with D2O),
6.72 (d, J = 8.4 Hz, 1 H, Harom), 7.12–7.35 (m, 4 H, Harom), 7.32 (d,
J = 8.2 Hz, 2 H, Harom), 7.38 (dd, J = 8.4, 1.5 Hz, 1 H, Harom), 7.71
(d, J = 8.2 Hz, 2 H, Harom), 8.23 (d, J = 1.5 Hz, 1 H, Harom).
Anal. Calcd for C17H18N2O3S: C, 61.80; H, 5.49; N, 8.48. Found: C,
61.99; H, 5.80; N, 8.18.
7-Chloro-2-phenyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepin-5-one (3f)
Yellowish solid; yield: 349 mg (82%); mp 179–181 °C.
IR (KBr): 3345, 1705, 1603, 1323, 1160, 835 cm–1.
13C NMR (100 MHz, CDCl3): d = 24.5, 24.8, 47.3, 62.6, 114.8,
116.2, 122.8, 127.0, 127.5, 128.8, 129.2, 129.5, 133.6, 136.3, 137.9,
140.4, 141.8, 145.6, 168.3.
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H), 3.23 (dd, J = 12.3,
5.5 Hz, 1 H), 3.47 (dd, J = 12.3, 7.7 Hz, 1 H), 4.58 (dd, J = 7.7, 5.5
Hz, 1 H), 5.38 (br s, 1 H, NH, exchanges with D2O), 6.78 (d, J = 8.6
Hz, 1 H, Harom), 7.16–7.31 (m, 5 H, Harom), 7.35 (d, J = 8.3 Hz, 2 H,
Harom), 7.38 (dd, J = 8.6, 1.8 Hz, 1 H, Harom), 7.74 (d, J = 8.3 Hz, 2
H, Harom), 8.26 (d, J = 1.8 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.9, 47.9, 62.5, 115.3, 116.9,
123.1, 126.5, 127.3, 127.5, 128.3, 128.8, 129.6, 133.6, 137.4, 141.8,
143.9, 145.8, 168.4.
MS (EI): m/z = 440 [M]+.
Anal. Calcd for C23H21ClN2O3S: C, 62.65; H, 4.80; N, 6.35. Found:
C, 62.75; H, 4.58; N, 6.65.
7-Chloro-2-methyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepin-5-one (3j)
Yellowish solid; yield: 277 mg (76%); mp 100–101 °C.
IR (KBr): 3335, 1702, 1605, 1320, 1159, 838 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (d, J = 7.1 Hz, 3 H), 2.32 (s,
3 H), 3.08–3.36 (m, 1 H), 3.88 (dd, J = 12.4, 5.6 Hz, 1 H), 4.59 (dd,
J = 12.4, 7.9 Hz, 1 H), 5.33 (br s, 1 H, NH, exchanges with D2O),
6.74 (d, J = 8.6 Hz, 1 H, Harom), 7.34 (d, J = 8.2 Hz, 2 H, Harom), 7.40
(dd, J = 8.6, 1.6 Hz, 1 H, Harom), 7.73 (d, J = 8.2 Hz, 2 H, Harom),
8.22 (d, J = 1.6 Hz, 1 H, Harom).
MS (EI): m/z = 426 [M]+.
Anal. Calcd for C22H19ClN2O3S: C, 61.89; H, 4.49; N, 6.56. Found:
C, 61.63; H, 4.34; N, 6.88.
7-Chloro-2-(4-chlorophenyl)-4-tosyl-1,2,3,4-tetrahydro-5H-
1,4-benzodiazepin-5-one (3g)
Yellowish solid; yield: 396 mg (86%); mp 198–200 °C.
IR (KBr): 3342, 1703, 1598, 1332, 1156, 840 cm–1.
13C NMR (100 MHz, CDCl3): d = 18.4, 24.7, 48.4, 51.8, 115.4,
116.9, 123.1, 127.6, 128.9, 129.3, 133.2, 136.3, 141.9, 145.8, 168.3.
1H NMR (400 MHz, CDCl3): d = 2.36 (s, 3 H), 3.24 (dd, J = 12.3,
5.4 Hz, 1 H), 3.48 (dd, J = 12.3, 7.6 Hz, 1 H), 4.58 (dd, J = 7.6, 5.3
Hz, 1 H), 5.38 (br s, 1 H, NH, exchanges with D2O), 6.80 (d, J = 8.5
Hz, 1 H, Harom), 7.32 (d, J = 8.2 Hz, 2 H, Harom), 7.39 (dd, J = 8.5,
1.7 Hz, 1 H, Harom), 7.65–7.72 (m, 2 H, Harom), 7.73 (d, J = 8.2 Hz,
2 H, Harom), 8.12–8.19 (m, 2 H, Harom), 8.27 (d, J = 1.7 Hz, 1 H,
MS (EI): m/z = 364 [M]+.
Anal. Calcd for C17H17ClN2O3S: C, 55.96; H, 4.70; N, 7.68. Found:
C, 55.71; H, 4.99; N, 7.81.
7-Methyl-2-phenyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepin-5-one (3k)
Yellowish solid; yield: 341 mg (84%); mp 171–172 °C.
IR (KBr): 3343, 1702, 1595, 1319, 1157, 805 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.30 (s, 3 H), 2.32 (s, 3 H), 3.20
(dd, J = 12.1, 5.4 Hz, 1 H), 3.43 (dd, J = 12.1, 7.6 Hz, 1 H), 4.54
(dd, J = 7.6, 5.4 Hz, 1 H), 5.32 (br s, 1 H, NH, exchanges with D2O),
6.75 (d, J = 8.5 Hz, 1 H, Harom), 7.12–7.30 (m, 5 H, Harom), 7.32 (d,
J = 8.4 Hz, 2 H, Harom), 7.35 (dd, J = 8.5, 1.6 Hz, 1 H, Harom), 7.74
(d, J = 8.3 Hz, 2 H, Harom), 8.24 (d, J = 1.6 Hz, 1 H, Harom).
Harom).
13C NMR (100 MHz, CDCl3): d = 24.7, 48.1, 62.6, 114.7, 116.6,
122.9, 127.9, 128.5, 128.7, 128.9, 129.8, 132.9, 133.8, 137.9, 141.9,
142.2, 145.0, 168.7.
MS (EI): m/z = 460 [M]+.
Anal. Calcd for C22H18Cl2N2O3S: C, 57.27; H, 3.93; N, 6.07. Found:
C, 57.49; H, 3.65; N, 6.26.
7-Chloro-2-(4-methoxyphenyl)-4-tosyl-1,2,3,4-tetrahydro-5H-
1,4-benzodiazepin-5-one (3h)
Yellowish solid; yield: 383 mg (84%); mp 168–170 °C.
IR (KBr): 3338, 1703, 1602, 1326, 1158, 820 cm–1.
13C NMR (100 MHz, CDCl3): d = 24.2, 24.7, 47.6, 62.3, 112.5,
115.2, 126.6, 126.9, 127.2, 127.5, 128.7, 128.9, 129.6, 133.2, 137.7,
141.7, 143.2, 144.2, 168.1.
MS (EI): m/z = 406 [M]+.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 3.23 (dd, J = 12.5,
5.4 Hz, 1 H), 3.46 (dd, J = 12.5, 7.6 Hz, 1 H), 3.75 (s, 3 H), 4.50 (dd,
J = 7.6, 5.4 Hz, 1 H), 5.36 (br s, 1 H, NH, exchanges with D2O),
6.74 (d, J = 8.6 Hz, 1 H, Harom), 7.31 (d, J = 8.3 Hz, 2 H, Harom), 7.40
(dd, J = 8.6, 1.6 Hz, 1 H, Harom), 7.68–7.70 (m, 2 H, Harom), 7.72 (d,
J = 8.3 Hz, 2 H, Harom), 8.02–8.04 (m, 2 H, Harom), 8.28 (d, J = 1.6
Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.9, 47.5, 55.5, 62.0, 114.4,
115.1, 116.7, 123.1, 127.6, 128.1, 128.5, 129.2, 133.2, 135.9, 136.9,
141.5, 145.7, 158.9, 168.5.
Anal. Calcd for C23H22N2O3S: C, 67.96; H, 5.46; N, 6.89. Found: C,
67.64; H, 5.98; N, 6.63.
2-(4-Chlorophenyl)-7-methyl-4-tosyl-1,2,3,4-tetrahydro-5H-
1,4-benzodiazepin-5-one (3l)
Yellowish solid; yield: 387 mg (88%); mp 179–182 °C.
IR (KBr): 3345, 1700, 1600,1324, 1158, 824 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.30 (s, 3 H), 2.34 (s, 3 H), 3.23
(dd, J = 12.1, 5.2 Hz, 1 H), 3.46 (dd, J = 12.1, 7.6 Hz, 1 H), 4.58
Synthesis 2012, 44, 591–599
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Synthesis of Benzodiazepines by a Grinding Technique
597
(dd, J = 7.6, 5.2 Hz, 1 H), 5.33 (br s, 1 H, NH, exchanges with D2O),
6.78 (d, J = 8.3 Hz, 1 H, Harom), 7.31 (d, J = 8.3 Hz, 2 H, Harom), 7.38
(dd, J = 8.3, 1.7 Hz, 1 H, Harom), 7.61–7.70 (m, 2 H, Harom), 7.71 (d,
J = 8.3 Hz, 2 H, Harom), 8.09–8.16 (m, 2 H, Harom), 8.26 (d, J = 1.5
Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 23.7, 24.6, 47.8, 62.1, 113.1,
115.7, 126.6, 127.4, 128.3, 128.6, 128.9, 129.6, 132.7, 133.5, 137.2,
141.8, 142.1, 145.6, 168.3.
MS (EI): m/z = 344 [M]+.
Anal. Calcd for C18H20N2O3S: C, 62.77; H, 5.85; N, 8.13. Found: C,
62.85; H, 5.67; N, 8.37.
2-(4-nitrophenyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiaz-
epin-5-one (3p)
Yellowish solid; yield: 372 mg (85%); mp 215–217 °C.
IR (KBr): 3329, 1703, 1600, 1324, 1159, 826 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.30 (s, 3 H), 3.25 (dd, J = 12.1,
5.4 Hz, 1 H), 3.48 (dd, J = 12.1, 7.6 Hz, 1 H), 4.62 (dd, J = 7.6, 5.4
Hz, 1 H), 5.40 (br s, 1 H, NH, exchanges with D2O), 6.34 (dd,
J = 8.3, 1.0 Hz, 1 H, Harom), 6.67 (m, 1 H, Harom), 7.30 (d, J = 8.1 Hz,
2 H, Harom), 7.34–7.38 (m, 1 H, Harom), 7.66–7.68 (m, 2 H, Harom),
7.72 (d, J = 8.2 Hz, 2 H, Harom), 8.02 (dd, J = 8.2, 1.0 Hz, 1 H,
MS (EI): m/z = 440 [M]+.
Anal. Calcd for C23H21ClN2O3S: C, 62.65; H, 4.80; N, 6.35. Found:
C, 62.87; H, 4.92; N, 6.04.
2-(4-Methoxyphenyl)-7-methyl-4-tosyl-1,2,3,4-tetrahydro-5H-
1,4-benzodiazepin-5-one (3m)
Yellowish solid; yield: 379 mg (87%); mp 151–152 °C.
Harom), 8.15–8.19 (m, 2 H).
IR (KBr): 3342, 1705, 1598, 1326, 1159, 835 cm–1.
13C NMR (100 MHz, CDCl3): d = 25.3, 48.1, 62.6, 112.8, 115.9,
118.0, 121.3, 127.8, 128.1, 128.9, 129.6, 133.5, 136.9, 141.4, 141.8,
146.9, 149.7, 168.7.
1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3 H), 2.34 (s, 3 H), 3.22
(dd, J = 12.3, 5.1 Hz, 1 H), 3.44 (dd, J = 12.3, 7.3 Hz, 1 H), 3.73 (s,
3 H), 4.53 (dd, J = 7.3, 5.1 Hz, 1 H), 5.35 (br s, 1 H, NH, exchanges
with D2O), 6.74 (d, J = 8.5 Hz, 1 H, Harom), 7.30 (d, J = 8.1 Hz, 2 H,
Harom), 7.38 (dd, J = 8.5, 1.6 Hz, 1 H, Harom), 7.65–7.67 (m, 2 H,
MS (EI): m/z = 437 [M]+.
Anal. Calcd for C22H19N3O5S: C, 60.40; H, 4.38; N, 9.61. Found: C,
60.72; H, 4.11; N, 9.74.
Harom), 7.71 (d, J = 8.1 Hz, 2 H, Harom), 8.00–8.03 (m, 2 H, Harom),
8.25 (d, J = 1.4 Hz, 1 H, Harom).
2-Isopropyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-
5-one (3q)
Yellowish solid; yield: 290 mg (81%); mp 65–66 °C.
IR (KBr): 3331, 1702, 1600, 1326, 1158, 833 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12 (d, J = 6.7 Hz, 3 H), 1.25 (d,
J = 6.5 Hz, 3 H), 1.34–1.43 (m, 1 H), 2.32 (s, 3 H), 2.94–3.30 (m, 1
H), 3.84 (dd, J = 12.1, 5.5 Hz, 1 H), 4.52 (dd, J = 12.1, 7.6 Hz, 1 H),
5.28 (br s, 1 H, NH, exchanges with D2O), 6.30 (dd, J = 8.3, 0.9 Hz,
1 H, Harom), 6.60 (m, 1 H, Harom), 7.31 (d, J = 8.2 Hz, 2 H, Harom),
7.35–7.37 (m, 1 H, Harom), 7.70 (d, J = 8.2 Hz, 2 H, Harom), 8.02 (dd,
J = 8.3, 0.9 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 24.2, 24.7, 47.3, 55.3, 62.3,
113.2, 115.3, 115.6, 126.4, 127.3, 128.1, 128.9, 129.4, 132.8, 136.1,
137.2, 141.3, 144.8, 159.3, 168.4.
MS (EI): m/z = 436 [M]+.
Anal. Calcd for C24H24N2O4S: C, 66.03; H, 5.54; N, 6.42. Found: C,
65.94; H, 5.37; N, 6.78.
7-Methyl-2-(4-tolyl)-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzo-
diazepin-5-one(3n)
Yellowish solid; yield: 382 mg (91%); mp 145–146 °C.
IR (KBr): 3340, 1700, 1603, 1321, 1158, 810 cm–1.
13C NMR (100 MHz, CDCl3): d = 18.8, 19.6, 25.2, 31.6, 43.5, 61.9,
112.9, 115.9, 117.6, 127.2, 128.8, 129.6, 133.2, 136.9, 141.4, 147.9,
168.4.
1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3 H), 2.37 (s, 3 H), 2.72
(s, 3 H), 3.18 (dd, J = 12.1, 5.4 Hz, 1 H), 3.39 (dd, J = 12.1, 7.3 Hz,
1 H), 4.45 (dd, J = 7.3, 5.4 Hz, 1 H), 5.27 (br s, 1 H, NH, exchanges
with D2O), 6.70 (d, J = 8.3 Hz, 1 H, Harom), 7.10–7.32 (m, 4 H,
Harom), 7.30 (d, J = 8.1 Hz, 2 H, Harom), 7.35 (dd, J = 8.3, 1.3 Hz, 1
H, Harom), 7.70 (d, J = 8.1 Hz, 2 H, Harom), 8.20 (d, J = 1.3 Hz, 1 H,
Harom).
13C NMR (100 MHz, CDCl3): d = 24.4, 24.6, 24.8, 47.8, 62.6,
112.3, 115.6, 126.6, 126.9, 127.5, 128.5, 129.1, 129.3, 133.2, 136.5,
137.2, 140.8, 141.4, 144.9, 168.3.
MS (EI): m/z = 358 [M]+.
Anal. Calcd for C19H22N2O3S: C, 63.66; H, 6.19; N, 7.82. Found: C,
63.89; H, 6.36; N, 7.50.
7-Nitro-2-phenyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiaz-
epin-5-one (3r)
Yellowish solid; yield: 337 mg (77%); mp 224–226 °C.
IR (KBr): 3344, 1702, 1604, 1328, 1159, 845 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.36 (s, 3 H), 3.28 (dd, J = 12.5,
5.6 Hz, 1 H), 3.49 (dd, J = 12.5, 7.6 Hz, 1 H), 4.61 (dd, J = 7.6, 5.6
Hz, 1 H), 5.39 (br s, 1 H, NH, exchanges with D2O), 6.92 (d, J = 8.7
Hz, 1 H, Harom), 7.19–7.34 (m, 5 H, Harom), 7.36 (d, J = 8.4 Hz, 2 H,
MS (EI): m/z = 420 [M]+.
Anal. Calcd for C24H24N2O3S: C, 68.55; H, 5.75; N, 6.66. Found: C,
68.28; H, 6.04; N, 6.53.
2,7-Dimethyl-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-
5-one (3o)
H
H
arom), 7.76 (d, J = 8.4 Hz, 2 H, Harom), 8.13 (d, J = 1.9, 8.7 Hz, 1 H,
arom), 8.53 (dd, J = 1.9 Hz, 1 H, Harom).
Yellowish solid; yield: 268 mg (78%); mp 97–98 °C.
IR (KBr): 3339, 1703, 1604, 1322, 1159, 827 cm–1.
13C NMR (100 MHz, CDCl3): d = 24.8, 47.9, 62.7, 114.8, 117.1,
123.5, 125.9, 126.7, 127.4, 127.8, 128.8, 129.7, 137.3, 137.8, 141.9,
144.2, 153.8, 168.5.
1H NMR (400 MHz, CDCl3): d = 1.36 (d, J = 7.3 Hz, 3 H), 2.31 (s,
3 H), 2.36 (s, 3 H), 3.12–3.38 (m, 1 H), 3.89 (dd, J = 12.3, 5.4 Hz,
1 H), 4.61 (dd, J = 12.3, 8.0 Hz, 1 H), 5.35 (br s, 1 H, NH, exchang-
es with D2O), 6.73 (d, J = 8.5 Hz, 1 H, Harom), 7.32 (d, J = 8.1 Hz, 2
H, Harom), 7.42 (dd, J = 8.5, 1.5 Hz, 1 H, Harom), 7.70 (d, J = 8.1 Hz,
2 H, Harom), 8.23 (d, J = 1.5 Hz, 1 H, Harom).
13C NMR (100 MHz, CDCl3): d = 18.4, 24.2, 24.8, 48.3, 52.0,
112.8, 115.5, 126.8, 127.2, 127.6, 129.3, 132.7, 136.3, 141.3, 145.3,
168.0.
MS (EI): m/z = 437 [M]+.
Anal. Calcd for C22H19N3O5S: C, 60.40; H, 4.38; N, 9.61. Found: C,
60.28; H, 4.70; N, 9.79.
2-Methyl-7-nitro-4-tosyl-1,2,3,4-tetrahydro-5H-1,4-benzodiaz-
epin-5-one (3s)
Yellowish solid; yield: 270 mg (72%); mp 59–60 °C.
IR (KBr): 3338, 1701, 1602, 1325, 1158, 840 cm–1.
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A. K. Singh, L. D. S. Yadav
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1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7.3 Hz, 3 H), 2.33 (s,
3 H), 3.10–3.39 (m, 1 H), 3.89 (dd, J = 12.5, 5.8 Hz, 1 H), 4.61 (dd,
J = 12.5, 8.0 Hz, 1 H), 5.37 (br s, 1 H, NH, exchanges with D2O),
6.87 (d, J = 8.7 Hz, 1 H, Harom), 7.32 (d, J = 8.1 Hz, 2 H, Harom), 7.72
(d, J = 8.2 Hz, 2 H, Harom), 8.10 (dd, J = 8.7, 1.8 Hz, 1 H, Harom),
8.56 (d, J = 1.8 Hz, 1 H, Harom).
(6) Toda, F.; Suzuki, T.; Higa, S. J. Chem. Soc., Perkin Trans. 1
1998, 3521.
(7) Ren, Z.-J.; Cao, W.-G.; Tong, W.-Q. Synth. Commun. 2002,
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Engl. 1989, 28, 320.
(9) (a) Ren, Z.-J.; Cao, W.-G.; Ding, W.-Y.; Shi, W. Synth.
Commun. 2004, 34, 4395. (b) Ren, Z.; Cao, W.; Tong, W.;
Jin, Z. Synth. Commun. 2005, 35, 2509. (c) Schmeyers, T.;
Toda, F.; Boy, J.; Kaupp, G. J. Chem. Soc., Perkin Trans. 2
1998, 989. (d) Bose, A. K.; Pednekar, S.; Ganguly, S. N.;
Chakraborty, G.; Manhas, M. S. Tetrahedron Lett. 2004, 45,
8351. (e) Varughese, D. J.; Manhas, M. S.; Bose, A. K.
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13C NMR (100 MHz, CDCl3): d = 18.3, 24.9, 48.8, 52.9, 114.5,
116.5, 123.7, 125.5, 127.7, 129.5, 136.2, 137.4, 141.7, 153.5, 168.4.
MS (EI): m/z = 375 [M]+.
Anal. Calcd for C17H17N3O5S: C, 54.39; H, 4.56; N, 11.19. Found:
C, 54.16; H, 4.42; N, 11.47.
2-Phenyl-4-tosyl-1,2,3,4-Tetrahydro-2-phenyl-4-tosylben-
zo[e][tetrahydro-5H-1,4]-benzodiazepin-5-one (3a): Solution-
Phase Syntheses; General Procedure
A mixture of aziridine 1a (1 mmol), anthranilic acid 2a (1 mmol),
and LiBr (10 mol%) in the selected solvent (1 mL) was stirred at r.t.
for 13 h. When the reaction was complete [TLC, EtOAc–hexane
(2:3)], H2O (5 mL) was added and the mixture was extracted with
EtOAc (3 × 5 mL). The combined organic phase was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
resulting crude product was purified by column chromatography
[silica gel, EtOAc–hexane (1:3)] to give an analytically pure prod-
uct. After isolation of the product, the remaining aqueous layer con-
taining LiBr was washed with Et2O (2 × 5 mL) to remove any
organic impurity and dried under reduced pressure to afford LiBr,
which was reused in subsequent runs without further purification or
any loss of efficiency.
Acknowledgment
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding the microanalyses and spectra.
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