Synthesis of highly regioselective bifunctional tricyclic tetrazole-1 H -benzo[ b ][1,4]diazepins

Article abstract of DOI:10.1055/s-0033-1338953

A new approach for the synthesis of arrays of bifunctional tricyclic tetrazole-1H-benzo[b][1,4]diazepines has been investigated. It includes a sequential two-step isocyanide-based condensation reaction of diamines or 2-nitroanilines, ethyl 3-oxobutanoate or 2,2,6-trimethyl-4H-1,3-dioxin-4-one, isocyanides and trimethylsilyl azide in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338953

LETTER
▌1485
lSetyternthesis of Highly Regioselective Bifunctional Tricyclic Tetrazole-1H-
benzo[b][1,4]diazepins
Synthesis of Bifunctional Tricyclic Tetrazole-1H-benzo[b][1,4]diazepins
Ahmad Shaabani,*a Zeinab Hezarkhani,a Hamid Mofakham,a Seik Weng Ngb
a
Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
Fax +98(21)22431663; E-mail: a-shaabani@sbu.ac.ir
b
Department of Chemistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
Received: 18.03.2013; Accepted after revision: 24.04.2013
Cl
Abstract: A new approach for the synthesis of arrays of bifunction-
N
al tricyclic tetrazole-1H-benzo[b][1,4]diazepines has been investi-
gated. It includes sequential two-step isocyanide-based
OH
a
N
N
N
condensation reaction of diamines or 2-nitroanilines, ethyl 3-
oxobutanoate or 2,2,6-trimethyl-4H-1,3-dioxin-4-one, isocyanides
and trimethylsilyl azide in good yields.
N
NH
Key words: benzo[b][1,4]diazepin, tetrazole, multicomponent re-
action, isocyanide, regioselective
O
N
IV
N
N
N
N
N
N
N
Benzodiazepines are important biomolecules with a wide
array of biological and medicinal activities, and they are
one of the most prominent classes of privileged scaffolds.1
Indeed, several of these nitrogen-containing heterocycles
have been identified to have anxiolytic, anticonvulsant,
hypnotic, sedative, skeletal muscle relaxant, amnestic, di-
abetic nephropathy, or glomerulosclerosis properties. For
instance, diazepam (I), 2,3,4,5-tetrahydro-1H-1,5-benzo-
diazepines II, and peptide hormones III have a variety of
pharmaceutical proprieties (Figure 1).1–5
V
VI
Figure 2 Examples of medicinal tetrazole derivatives
Because of the above-mentioned properties of tetrazoles
and benzodiazepines, a variety of synthetic methods have
been reported.14
Recently, combinations of annulated heterocyclic struc-
tures have attracted attention. Strategies for preparing
suitably decorated compounds with a reduced number of
synthetic and purification steps are of special interest in
combinatorial chemistry,15 since they provide arrays of
molecules in an efficient manner.16 The tetrazole–diaze-
pin hybrid would appear to be a worthwhile target but lit-
erature surveys revealed no such interest. Recently,
however, some derivatives of this scaffold showed biolog-
ical activity.12,13
R5
R4
O
Me
O
N
N
R1
N
Cl
R3
N
H
R2
Ph
I
Multicomponent reactions (MCR) are very useful meth-
ods because of atom-economy of processes in which rela-
tively complex products can be obtained in a one-pot
reaction, in a convergent character, with operational sim-
plicity, and produce structural diversity.17 Within this ar-
ea, isocyanide-based multicomponent reactions (IMCR)
have provided a wealth of highly useful sequences for the
large libraries of organic molecules.18
II
O
Ph
O
O
N
N
Cl
O
NH
Ph
III
Figure 1 Examples of medicinal benzodiazepine derivatives
In view of our current interest in IMCR of diamines and
potential use of 1,4-benzodiazepines and tetrazoles,19 we
wish to report herein the possibility of the synthesis of a
new class of benzodiazepine-containing tetrazole moiety,
1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines
9a–h, via a two-step condensation reaction of o-phenyl-
enediamines 1 or 2-nitroanilines 7, ethyl 3-oxobutanoate
(2) or 2,2,6-trimethyl-4H-1,3-dioxin-4-one (3), an isocya-
nide 5 and trimethylsilyl azide (TMSN3, 6; Scheme 1).
1,5-Disubstituted tetrazole compounds show diverse
pharmacological activities;6–10 for example, losartan (IV),
angiotensin II antagonist,11 pentylenetetrazole (PTZ, V),12
and tetrazole VI (Figure 2).13
SYNLETT 2013, 24, 1485–1492
Advanced online publication: 06.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338953; Art ID: ST-2013-D0242-L
© Georg Thieme Verlag Stuttgart · New York

1486
A. Shaabani et al.
LETTER
R1
R2
NH2
O
H
N
R3 +N C–
5a–e
NH2
R1
R2
TMSN3
6
and
1a–c
MW, 10 min
+
o-xylene
MeOH, p-TsOH⋅H2O, r.t., 1 h
O
O
O
N
or
4a–c
route 1
O
O
OEt
O
H
N
2
R1
R2
R3
3
NO2
NH2
N
N
H
NH2
N
R3 +N C–
5a–e
route 2
R1
N
N
9a–h
40–70%
R1
NH
O
7a–b
+
1. MeOH, r.t., 48 h
NaH, THF
85 °C, 5 h
+
N
2. SnCl2⋅2H2O, reflux, 12h
O
O
TMSN3
6
OEt
N
N
R1, R2 = H, Me, NO2
3 = aliphatic, alicyclic, aromatic
N
OEt
R3
8a–d
2
R
Scheme 1 Synthesis of 1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines 9a–h
In a pilot experiment, o-phenylenediamine (1a) and ethyl tron-releasing groups. These results show that an electron-
3-oxobutanoate (2) or 2,2,6-trimethyl-4H-1,3-dioxin-4- withdrawing group activates the meta amine group and an
one (3) in o-xylene was irradiated by microwaves at electron-releasing group activates the para amine group.
136 °C for ten minutes and afforded 4a in 90% and 86% Electron-releasing groups at the para position, such as
yield, respectively.20 In continuation, benzo[b][1,4]diaze- CH3, activate the para amine group to give ben-
pine 4a, cyclohexyl isocyanide (5a), TMSN3 (6), and p- zo[b][1,4]diazepines 4b; while electron-withdrawing
toluenesulfonic acid were stirred in methanol for one hour groups, such as NO2, deactivate the para amine group,
at ambient temperature to provide 9a (Table 1).
and the reaction is initiated by the meta amine group to
give 4c as the favored product.19g
In view of this success, we explored the scope of the reac-
tion using various o-phenylenediamine derivatives and It is important to note that, in contrast to Bougrin and et al.
different isocyanides. Since ethyl 3-oxobutanoate 2 is a who reported the formation of 4b′ as the main product,20
commercially available and inexpensive compound, we our product is 4b. To confirm this, we provide the crystal
used it for the preparation of a library. As indicated in Ta- structure of 9b (Figure 3) to confirm that the electron-
ble 1, the reactions led to the formation of the correspond- releasing methyl group activates the para amine group
ing
1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4] and product 4b is selectively produced.
diazepine derivatives 9a–h in relatively good yields at
room temperature. All of the products 9a–h are novel
compounds with the structures being deduced from their
IR, mass, 1H NMR, and 13C NMR spectral data.
In order to investigate the scope and limitations of this re-
action, we decided to extend it to 2-nitroanilines 7 instead
of o-phenylenediamines 1 to lead to the synthesis of com-
pounds 8a–d (Table 2).
The synthetic route was highly regioselective due to the
regioselectivity of the first step (Scheme 2). The 1H NMR
and 13C NMR spectra obtained from products with elec-
tron-withdrawing or electron-releasing groups such as
NO2 and CH3 were consistent with the presence of only
one isomer. The selectivity may be explained as a result of
the electronic effect of the electron-withdrawing or elec-
In a pilot experiment, 2-nitroaniline and ethyl 3-oxobu-
tanoate were stirred in methanol at room temperature for
one hour, and then TMSN3 and cyclohexyl isocyanide
were added and the reaction mixture stirred for a further
48 hours at room temperature.21 In the second step, the re-
duction of the nitro group was carried out with
O
H
N
R1
R2
NH2
NH2
R1
R2
O
O
R1
R2
O
H2N
H2N
+
+
EtO
O
O
N
1b and 1c
2
4b–c
3
1b and 1c
R
1 = NO2 and R2 = Me
O
O
O
O
H
H
H
N
H
N
N
N
O2N
O2N
N
N
N
N
4b
4b'
4c
4c'
Scheme 2 Structure of benzo[b][1,4]diazepines 4b and 4c
Synlett 2013, 24, 1485–1492
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Bifunctional Tricyclic Tetrazole-1H-benzo[b][1,4]diazepins
1487
SnCl2·2H2O, and then the solvent was removed under vac- hydride as a 60% suspension in oil, was added and the
uum to give ethyl 3-[(2-aminophenyl)amino]-3-(1-cyclo- mixture heated at reflux for five hours to give 1H-tetrazol-
hexyl-1H-tetrazol-5-yl)butanoate (8a).22 Then, to a stirred 5-yl-4-methyl-1H-benzo[b][1,4]diazepine (9a).
solution of appropriate compound 8a in dry THF, sodium
Table 1 Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepine Derivatives 9a–h23
R1
NH2
O
H
N
O
R2
NH2
H
N
R3 +N C–
5a–e
TMSN3 R1
6
R1
R2
and
1a–c
MW, 10 min
R3
N
+
o-xylene
MeOH, p-TsOH⋅H2O, r.t., 1 h
O
R2
O
O
N
H
N
N
or
4a–c
N
O
O
N
OEt
9a–h
2
3
Entry
Diamine
Diketone source Product 1a
Yield
(%)c
Isocyanide
Product 2b
Yield
(%)c
O
O
O
H
N
OEt
O
O
H
N
NH2
NH2
2
3
N
+N C–
N
H
N
90
86
1
65
N
N
N
5a
1a
O
O
4a
9a
O
H
N
O
H
N
NH2
NH2
N
N
H
N
2
3
85
77
2
5a
65
N
N
N
1b
4b
9b
O
H
N
O2N
O
H
O2N
NH2
NH2
N
O2N
N
N
H
N
2
3
80
70
3
5a
66
N
N
N
1c
4c
9c
O
H
N
+N C –
N
N
H
N
4
1a
2
4a
90
70
N
N
5b
9d
© Georg Thieme Verlag Stuttgart · New York
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A. Shaabani et al.
LETTER
Table 1 Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepine Derivatives 9a–h23 (continued)
R1
R2
NH2
NH2
O
H
N
O
H
N
R3 +N C–
5a–e
TMSN3 R1
6
R1
R2
and
1a–c
MW, 10 min
R3
N
+
o-xylene
MeOH, p-TsOH⋅H2O, r.t., 1 h
O
R2
O
O
N
H
N
N
or
4a–c
N
O
O
N
OEt
9a–h
2
3
Entry
Diamine
Diketone source Product 1a
Yield
(%)c
Isocyanide
Product 2b
Yield
(%)c
O
H
N
N
N
H
N
+
N
C–
N
N
5
1a
2
4a
90
67
5c
9e
O
H
N
N
+
N
N
H
C –
N
N
N
6
1a
2
4a
90
70
5d
9f
O
H
N
N
N
H
N
+
N
C–
N
N
7
1a
2
4a
90
60
5e
9g
O
H
N
O2N
N
N
H
N
8
1c
2
4c
80
5b
66
N
N
9h
a Reaction conditions: diamines (1.00 mmol), ethyl 3-oxobutanoate (1.50 mmol), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.20 mmol), o-xylene
(2 mL), microwave irradiation, 10 min.
b Reaction conditions: 1,4-diazepines (0.50 mmol), isocyanide (0.50 mmol), TMSN3 (0.75 mmol), p-TsOH·H2O (0.05 g), MeOH (5.00 mL), 1 h.
c Isolated yield based on 0.5 mmol of 1,4-diazepine 4a, 4b, or 4c.
Synlett 2013, 24, 1485–1492
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Bifunctional Tricyclic Tetrazole-1H-benzo[b][1,4]diazepins
1489
Table 2 Synthesis of 1H-Tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepine Derivatives 9a,b,d,e
NO2
NH2
R1
R3 +N C–
NH2
O
H
N
5a–c
7a,b
R1
NH
O
1. MeOH, r.t., 48 h
NaH, THF, 85 °C, 5 h
OEt
R3
N
+
+
N
2. SnCl2⋅2H2O, reflux, 12 h
R1
O
O
TMSN3
6
N
H
N
N
N
N
N
N
OEt
R3
8a–d
9a,b,d,e
2
Entry
2-Nitroaniline
Isocyanide
Product 1a
Yield (%)c
Product 2b
Yield (%)c
NH2
NH
O
H
N
O
NO2
N
+
N
C–
N
N
H
N
OEt
1
N
67
45
N
N
NH2
N
N
5a
7a
9a
8a
NH2
NH
O
H
N
O
NO2
N
N
H
N
N
OEt
N
2
5a
70
46
N
N
NH2
N
N
7b
7a
9b
8b
NH2
O
H
N
NH
O
+
N
N
C–
N
H
N
N
OEt
3
63
40
N
N
N
N
N
5b
9d
8c
NH2
NH
O
H
N
O
N
N
H
N
N
OEt
+
N
N
C–
N
N
N
4
7a
64
40
N
5c
9e
8d
a Reaction conditions: 2-nitroanilines (1.00 mmol), ethyl 3-oxobutanoate (1.10 mmol), TMSN3 (1.50 mmol), isocyanide (1.50 mmol),
SnCl2·2H2O (5 mmol), MeOH (2 mL).
b Reaction conditions: NaH (2.5 mmol), THF (10 mL), 1 h.
c Isolated yield.
As shown in Table 2, we were able to extend this proce- 1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]diazepines
dure to a range of 2-nitroanilines and alkyl and alicyclic 9a,b,d,e.22b
isocyanides to obtain derivatives 8a–d. Reduction of
the nitro group of products 8a–d in dry THF gave
of products 9a,b,d,e were compared for both approaches,
As indicated in Table 3, times and yields for the formation
© Georg Thieme Verlag Stuttgart · New York
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1490
A. Shaabani et al.
LETTER
References and Notes
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Figure 3 ORTEP diagram of 9b
Table 3 Comparison of the Results of Two Approaches
Entry
Yield route 1 Yield route 2 Time route 1 Time route 2
(%)a,c
(%)b,c
(min)a
(h)b
9a
9b
9d
9e
65
65
70
67
45
46
40
40
70
70
70
70
65
65
65
65
(e) Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P. A.;
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a Reaction conditions: diamines (1.00 mmol), ethyl 3-oxobutanoate
(1.50 mmol), 1,4-diazepines (0.50 mmol), isocyanide (0.50 mmol),
TMSN3 (0.75 mmol), PTSA·H2O (0.05 g).
b Reaction conditions: 2-nitroanilines (1.00 mmol), ethyl 3-oxobu-
tanoate (1.10 mmol), TMSN3 (1.50 mmol), isocyanide (1.50 mmol),
SnCl2·2H2O (5 mmol).
c Isolated yield.
showing that the first approach is the best in in terms of
times and yields for the synthesis of 9a,b,d,e.
In summary, we have developed a straightforward proce-
dure for the regiocontrolled synthesis of a new class of
substituted 1H-tetrazol-5-yl-4-methyl-1H-benzo[b][1,4]-
diazepine derivatives using a two-step condensation reac-
tion of diamines or amines, ethyl 3-oxobutanoate or 2,2,6-
trimethyl-4H-1,3-dioxin-4-one, isocyanides and trimeth-
ylsilyl azide.21 This approach leads to high atom-econo-
my, regioselectivity, and combinatorial diversity.
(7) Nonoshita, K.; Ogino, Y.; Ishikawa, M.; Sakai, F.;
Nakashima, H.; Nagae, Y.; Tsukahara, D.; Arakawa, K.;
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Acknowledgment
(10) Miao, Z.; Sun, Y.; Nakajima, S.; Tang, D.; Wu, F.; Xu, G.;
Or, Y. S.; Wang, Z. US 2005153877, 2005; Chem. Abstr.
2005, 143, 153709
We gratefully acknowledge financial support from the Iran National
Science Foundation (INSF) and the Research Council of Shahid
Beheshti University.
Synlett 2013, 24, 1485–1492
© Georg Thieme Verlag Stuttgart · New York

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D. F.; Drewe, J. A.; Dillon, G. H. J. Pharmacol. Exp. Ther.
2001, 298, 986. (b) Jung, M. E.; Lal, H.; Gatch, M. B.
Neurosci. Biobehav. Rev. 2002, 26, 429.
(13) (a) Daya, S.; Kaye, P. T.; Mphahlele, M. J. Med. Sci. Res.
1996, 24, 137. (b) Ek, F.; Manner, S.; Wistrand, L.-G.; Frejd,
T. J. Org. Chem. 2004, 69, 1346.
(14) (a) Slusarchyk, W. A.; Vite, G.; Yan, N.; Manne, V.; Hunt,
J. T. J. Med. Chem. 1999, 42, 5241. (b) Borisov, R. S.;
Polyakov, A. I.; Medvedeva, L. A.; Khrustalev, V. N.;
Guranova, N. I.; Voskressensky, L. G. Org. Lett. 2010, 12,
3894. (c) Gunawan, S.; Ayaz, M.; De Moliner, F.; Frett, B.;
Kaiser, C.; Patrick, N.; Xu, Z.; Hulme, C. Tetrahedron 2012,
68, 5606.
reaction, as indicated by TLC (EtOAc–n-hexane, 3:1) after 1
h, the precipitate was filtered off and washed with H2O and
MeOH, and then crystallized from acetone to give products
9a–h.
General Procedure for the Synthesis of 1H-Tetrazol-5-yl-
4-methyl-1H-benzo[b][1,4]diazepines 9a,b,d,e
Ethyl 3-oxobutanoate (1.10 mmol) and 2-nitroanilines (1.00
mmol) were stirred in MeOH (2 mL) at r.t. for 1 h, and then
trimethylsilyl azide (1.50 mmol) and isocyanide (1.50
mmol) were added. The reaction mixture was stirred for 48
h at r.t. until the reaction was complete (indicated by TLC).19
To this solution was added SnCl2·2H2O (5 mmol), and the
resulting mixture stirred at reflux for 12 h. Then, the solvent
was removed under vacuum, and the crude product was
purified to give products 8a–d. To a stirred solution of
products 8a–d in dry THF (10 mL) was added NaH as a 60%
suspension in oil (0.121 g, 2.5 mmol), and the mixture was
heated to reflux for 5 h. On completion, the reaction mixture
was extracted with EtOAc (3 × 20 mL) and H2O (30 mL).
The organic layer was cooled, dried over Na2SO4, and the
solvent was removed under vacuum to give products
9a,b,d,e.20
(15) Terzidis, M. A.; Stephanidou-Stephanatou, J.; Tsoleridis, C.
A. J. Org. Chem. 2010, 75, 1948.
(16) Zarganes-Tzitzikas, T.; Terzidis, M. A.; Stephanidou-
Stephanatou, J.; Tsoleridis, C. A. Kostakis G. E. J. Org.
Chem. 2011, 76, 9008.
Analytical Data
4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-
1H-benzo[b][1,4]diazepin-2(3H)-one (9a)
(17) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(18) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Dömling, A. Chem. Rev.
2006, 106, 17.
Colorless crystals; mp >270 °C. IR (KBr): 3347, 3295, 3200,
3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526, 1449, 1376
cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.00–1.80 (13
H, m, 5 CH2 of cyclohexyl and CH3), 2.65 (1 H, ABq, J =
13.9 Hz, CH2), 2.79 (1 H, ABq, J = 13.9 Hz, CH2), 5.14 (1 H,
m, CH of cyclohexyl), 6.01 (1 H, s, NH), 6.80–6.97 (4 H, m,
HAr), 9.84 (1 H, br s, NHCO). 13C NMR (75.47 MHz,
DMSO-d6): δ = 25.1, 25.5, 25.6, 29.2, 33.4, 33.8, 47.1, 59.1,
61.2, 122.1, 122.2, 125.2, 129.9, 137.2, 157.9, 170.0. Anal.
Calcd for C17H22N6O: C, 62.56; H, 6.79; N, 25.75. Found: C,
62.52; H, 6.69; N, 25.70.
(19) (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org.
Chem. 2007, 72, 6309. (b) Shaabani, A.; Maleki, A.;
Mofakham, H.; Moghimi-Rad, J. J. Org. Chem. 2008, 73,
3925. (c) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi,
H. R. J. Comb. Chem. 2008, 10, 323. (d) Shaabani, A.;
Maleki, A.; Mofakham, H. J. Comb. Chem. 2008, 10, 595.
(e) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary,
A.; Khavasi, H. R. Org. Lett. 2008, 10, 2581. (f) Shaabani,
A.; Rezayan, A. H.; Sarvary, A.; Keshipour, S.; Ng, S. W.
Org. Lett. 2009, 11, 3342. (g) Shaabani, A.; Maleki, A.;
Hajishaabanha, F.; Mofakham, H.; Seyyedhamzeh, M.;
Mahyari, M.; Ng, S. W. J. Comb. Chem. 2010, 12, 186.
(h) Shaabani, A.; Mofakham, H.; Maleki, A.;
4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4,7-dimethyl-4,5-
dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9b)
Colorless crystals; mp 245–247 °C. IR (KBr): 3347, 3295,
3200, 3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526,
1449, 1376 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ =
1.00–1.80 (13 H, m, 5 CH2 of cyclohexyl and CH3), 2.20 (3
H, s, CH3), 2.55 (1 H, ABq, J = 14.2 Hz, CH2), 2.79 (1 H,
ABq, J = 13.9 Hz, CH2), 5.12 (1 H, m, CH of cyclohexyl),
5.89 (1 H, s, NH), 6.58 (1 H, ABq, J = 7.6 Hz, H-Ar), 6.76
(H, s, HAr), 6.93 (1 H, ABq, J = 7.7 Hz, HAr), 9.75 (1 H, br
s, NHCO).13C NMR (75.47 MHz, DMSO-d6): δ = 20.9, 25.1,
25.6, 28.3, 33.4, 33.8, 47.0, 59.1, 61.2, 122.4, 122.6, 127.5,
134.3, 137.1, 157.9, 169.9. Anal. Calcd for C18H24N6O: C,
63.51; H, 7.11; N, 24.69. Found: C, 63.41; H, 7.02; N, 24.60.
4-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methyl-8-nitro-4,5-
dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9c)
Red powder; mp 233–234 °C. IR (KBr): 3347, 3295, 3200,
3139, 3087, 2926, 2851, 1675, 1634, 1597, 1526, 1449, 1376
cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.00–1.80 (13
H, m, 5 CH2 of cyclohexyl and CH3), 3.12 (2 H, m, CH2),
4.71 (1 H, m, CH of cyclohexyl), 7.04 (1 H, s, NH), 7.70 (1
Hajishaabanha, F. J. Comb. Chem. 2010, 12, 630.
(i) Shaabani, A.; Mofakham, H.; Mousavifaraz, S. Synlett
2012, 23, 731.
(20) Bougrin, K.; Bennaoi, A. K. Tetousni S. F. Soufiaoui M.
Tetrahedron Lett. 1994, 35, 8373.
(21) Mayer, J.; Umkehrer, M.; Kalinski, C.; Ross, G.; Kolb, J.
Tetrahedron Lett. 2005, 46, 7393.
(22) (a) Baraldi, P. G.; Broceta, A. U.; de las Infantas, M. J. P.;
Mochun, J. J. D.; Espinosa, A.; Romagnoli, R. Tetrahedron
2002, 58, 7607. (b) Pathak, R.; Nag, S.; Batra, S. Synthesis
2006, 4205.
(23) General Procedure for the Synthesis of 1H-Tetrazol-5-yl-
4-methyl-1H-benzo[b][1,4]diazepines 9a–h
Diamines (1.00 mmol) and ethyl 3-oxobutanoate (1.50
mmol) or 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.20 mmol)
in o-xylene (2 mL) were activated by exposure to microwave
irradiation (700 W, multimode reactor) for 10 min. The
benzo[b][1,4]diazepines 4a–c were recrystallized by cooling
in o-xylene. The crystals were filtered and washed with Et2O
(2 × 5 mL) and then recrystallized from acetone to give
benzo[b][1,4]diazepines 4a–c.18 To a solution of 1,4-
diazepines 4a–c (0.50 mmol) and PTSA·H2O (0.05 g, 2.50
mol%) in MeOH (5.00 mL) was added isocyanide (0.50
mmol) and trimethylsilyl azide (0.75 mmol), and the
resulting mixture was stirred at r.t. After completion of the
H, s, HAr), 7.84 (2 H, m, HAr), 10.00 (1 H, br s, NHCO). 13
NMR (75.47 MHz, DMSO-d6): δ = 23.4, 24.7, 25.1, 29.8,
32.9, 33.9, 46.2, 58.2, 63.2, 115.3, 117.9, 120.5, 123.2,
C
134.3, 148.0, 158.4, 167.4. Anal. Calcd for C17H21N7O3: C,
54.98; H, 5.70; N, 26.40. Found: C, 54.90; H, 5.60; N, 26.35.
4-(1-tert-Butyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-
1H-benzo[b][1,4]diazepin-2(3H)-one (9d)
Colorless crystals; mp 246–247 °C. IR (KBr): 3348, 3289,
3196, 3128, 3075, 2970, 2917, 2870, 1674, 1648, 1600,
1523, 1467, 1374 cm–1. 1H NMR (300.13 MHz, DMSO-d6):
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1485–1492

1492
A. Shaabani et al.
LETTER
δ = 1.70 (9 H, m, 3 CH3), 1.80 (3 H, s, CH3), 2.61 (1 H, ABq,
J = 13.6 Hz, CH2), 3.21 (1 H, ABq, J = 13.9 Hz, CH2), 6.03
(1 H, br s, NH), 6.70–7.10 (4 H, m, HAr), 9.57 (1 H, br s,
NHCO). 13C NMR (75.47 MHz, DMSO-d6): δ = 31.0, 32.8,
49.0, 63.1, 64.3, 121.0, 121.6, 122.6, 125.2, 127.5, 131.2,
160.0, 170.1. Anal. Calcd for C15H20N6O: C, 59.98; H, 6.71;
N, 27.98. Found: C, 59.88; H, 6.65; N, 27.99.
4-Methyl-4-[1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-
5-yl]-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one
(9e)
White crystals; mp 263–265 °C. IR (KBr): 3357, 3310,
3196, 3075, 2962, 2891, 2860, 1672, 1603, 1507, 1393, 1319
cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ = 1.70 (12 H, br
s, 4 CH3), 2.25 (2 H, s, CH2), 2.64 (8 H, s, 2 CH3 and CH2),
5.73 (1 H, s, NH), 6.70–7.20 (4 H, m, HAr), 9.70 (1 H, br s,
NHCO). 13C NMR (75.47 MHz, DMSO-d6): δ = 28.1, 30.8,
31.6, 43.6, 45.8, 53.6, 63.0, 67.6, 121.9, 123.3, 125.1, 126.2,
128.9, 130.6, 161.9, 167.2. Anal. Calcd for C19H28N6O: C,
64.02; H, 7.92; N, 23.58. Found: C, 64.05; H, 7.85; N, 23.55.
4-(1-Benzyl-1H-tetrazol-5-yl)-4-methyl-4,5-dihydro-1H-
benzo[b][1,4]diazepin-2(3H)-one (9f)
Yellow powder; mp 192–194 °C. IR (KBr): 3354, 3285,
3212, 3028, 2965, 2854, 1681, 1635, 1517, 1450, 1374 cm–1.
1H NMR (300.13 MHz, DMSO-d6): δ = 1.75 (3 H, br s,
CH3), 2.91 (2 H, br s, CH2), 5.69 (1 H, ABq, J = 15.3 Hz,
CH2), 6.01 (1 H, ABq, J = 15.3 Hz, CH2), 6.88 (1 H, m, NH),
7.00–7.45 (9 H, m, HAr), 8.70 (1 H, br s, NHCO). 4.30 (2 H,
m, CH2), 5.13 (1 H, br s, NH), 6.66 (1 H, d, J = 7.95 Hz,
HAr), 6.76 (2 H, m, HAr), 7.27 (5 H, m, HAr), 8.45 (1 H, m,
NHCO), 9.47 (1 H, br s, NHCO). 13C NMR (75.47 MHz,
DMSO-d6): δ = 28.9, 46.5, 52.3, 62.0, 121.8, 122.4, 125.5,
128.0, 128.5, 128.6, 129.1, 130.5, 135.6, 137.4, 159.0,
170.1. Anal. Calcd for C18H18N6O: C, 64.66; H, 5.43; N,
25.13. Found: C, 64.60; H, 5.33; N, 25.10.
4-Methyl-4-[1-(2-methylbenzyl)-1H-tetrazol-5-yl]-4,5-
dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9g)
Yellow powder; mp 192–194 °C. IR (KBr): 3354, 3285,
3212, 3028, 2965, 2854, 1681, 1635, 1517, 1450, 1374 cm–1.
1H NMR (300.13 MHz, DMSO-d6): δ = 1.75 (3 H, s, CH3),
1.85 (3 H, s, CH3), 2.73 (2 H, br s, CH2), 6.44 (1 H, m, NH),
6.80–7.00 (4 H, m, HAr), 7.20–7.40 (4 H, m, HAr), 9.79 (1
H, br s, NHCO). 13C NMR (75.47 MHz, DMSO-d6): δ =
23.0, 29.8, 46.1, 58.9, 61.5, 121.9, 122.1, 122.4, 125.4,
126.9, 127.5, 128.5, 128.9, 129.0, 129.4, 137.6, 139.9,
158.6, 169.6. Anal. Calcd for C19H20N6O: C, 65.50; H, 5.79;
N, 24.12. Found: C, 65.50; H, 5.79; N, 24.12.
4-(1-tert-Butyl-1H-tetrazol-5-yl)-4-methyl-8-nitro-4,5-
dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (9h)
Red powder; mp 237–239 °C. IR (KBr): 3348, 3289, 3196,
3128, 3075, 2970, 2917, 2870, 1674, 1648, 1600, 1523,
1467, 1374 cm–1. 1H NMR (300.13 MHz, DMSO-d6): δ =
1.82 (9 H, m, 3 CH3), 2.31 (3 H, br s, CH3), 3.19 (2 H, s,
CH2), 4.37 (1 H, br s, NH), 7.65 (2 H, s, HAr), 8.47 (1 H, s,
HAr), 9.13 (1 H, br s, NHCO). 13C NMR (75.47 MHz,
DMSO-d6): δ = 30.7, 31.3, 44.8, 63.8, 64.8, 121.9, 123.9,
124.1, 126.2, 130.5, 148.5, 159.4, 170.4. Anal. Calcd for
C15H19N7O3: C, 52.17; H, 5.55; N, 28.39. Found: C, 52.11;
H, 5.48; N, 28.30.
Synlett 2013, 24, 1485–1492
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