A two-step synthesis of 1H-tetrazolyl-1H-1,4-benzonitriles and 1H-tetrazolyl-benzo[b ][1,4]diazepines

Article abstract of DOI:10.1055/s-0031-1290603

A two-step synthetic protocol for the title heteroannulated diazepines has been developed. The approach includes a pseudo five-component isocyanide-based condensation reaction between diamines, ketones, isocyanides and trimethylsilyl azide and proceeds in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290603

LETTER
731
A Two-Step Synthesis of 1H-Tetrazolyl-1H-1,4-benzonitriles and
1H-Tetrazolyl-benzo[b][1,4]diazepines
S
ynthesis of 1,4-D
h
iazepines mad Shaabani,* Hamid Mofakham,* Sajjad Mousavifaraz
Department of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
Fax +98(21)29903247; E-mail: a-shaabani@cc.sbu.ac.ir
Received 10 December 2011
properties of drugs.9 1,5-Disubstituted tetrazoles have a
wide range of applications in the drug industry.10 Gluco-
kinase activators,11 NAD(P)H oxidase inhibitors,12 anti-
migraine agents,13 and hepatitis C virus serine protease
NS3 inhibitors are some of the uses of 1,5-disubstituted
tetrazole containing compounds.14 Losartan IV, angio-
tensin II antagonist,15 pentylenetetrazole (PTZ) V,16 and
tetrazole VI also show some biological activities
(Figure 2).17
Abstract: A two-step synthetic protocol for the title heteroannulat-
ed diazepines has been developed. The approach includes a pseudo
five-component isocyanide-based condensation reaction between
diamines, ketones, isocyanides and trimethylsilyl azide and pro-
ceeds in good yields.
Key words: diazepine, tetrazole, multicomponent reactions, iso-
cyanide
The benzodiazepine moiety appears as an important struc-
tural component in both biological and medicinal com-
pounds.1 For instance, benzodiazepine compounds I, II,
and III have a variety of pharmaceutical proprieties in-
cluding anxiolytic, anticonvulsant, hypnotic, sedative,
skeletal muscle relaxant, amnestic, diabetic nephropathy
or glomerulosclerosis and peptide hormones properties
(Figure 1).1–5 Because of these properties of benzodiaz-
epines, a variety of synthetic methods have been devel-
oped by different research groups.6
Cl
N
OH
N
N
N
N
NH
N
N
N
N
IV
V
R5
O
N
R4
Me
N
N
N
O
O
N
N
R1
VI
N
Cl
R3
N
H
Figure 2 Examples of medicinal tetrazole derivatives
R2
Ph
I
II
A general and efficient method to protected tetrazoles is
required in medicinal chemistry. The cyanoethyl group
can be used to protect tetrazoles and mild conditions allow
for subsequent deprotection (aqueous hydroxide, r.t.).
General and efficient methods for the synthesis of tetra-
zole compounds involve the conversion of a secondary
amide A into the corresponding imidoyl chloride B fol-
lowed by treatment with sodium azide (Scheme 1,
X = Na)18a,b or hydrazoic acid (Scheme 1, X = H)18c,d to
afford the desired tetrazole C. In recent years, the employ-
ment of trimethylsilyl azide in conjunction with imidoyl
chlorides has been reported for the synthesis of N-alkyl
and N-aryl tetrazoles.19
O
Ph
O
O
N
N
Cl
O
NH
Ph
III
Figure 1 Examples of medicinal benzodiazepine derivatives
Tetrazole compounds also show diverse biological activi-
ties.7 This moiety is a bioisostere of carboxylic acid that
does not show acidic properties.8 Introducing a tetrazole
group instead of a carboxylic moiety can reduce the toxic
R
R
R
N
R
PCl5
XN3
N
R
NH
R
N
N
O
Cl
N
SYNLETT 2012, 23, 731–736
x
x.
x
x.
2
0
1
2
A
B
C
Advanced online publication: 28.02.2012
Scheme 1 Tetrazole synthesis via imidoyl chlorides
DOI: 10.1055/s-0031-1290603; Art ID: D76011ST
© Georg Thieme Verlag Stuttgart · New York

732
A. Shaabani et al.
LETTER
progress of the reaction was monitored by TLC. After 4 h,
isocyanides and water were added to the reaction mixture
and stirring was continued for 12 h. After completion of
the reaction, an aqueous workup afforded compounds 8a–
g.20a The use of phosphorus pentachloride, trimethylsilyl
azide and pyridine as a catalyst successively under reflux
conditions provided 6a–g in good yields (Figure 3). The
structures of compounds 6a–g were deduced from their
IR, mass, 1H NMR, and 13C NMR spectral data.
N
N
N
N
N
N
N
N
H
N
H
N
NC
NC
NC
NC
N
N
H
H
6a 65%
6b 70%
N
N
N
To investigate the scope and limitations of this reaction,
we decided to extend it to aromatic 1,2-diamines 2 instead
of 2,3-diaminomaleonitrile 1 and synthesize compounds
9a–f and subsequently 7a–f in good yields (Scheme 3).20d
As indicated in Figure 4, the reaction proceeded efficient-
ly and led to the regioselective formation of 1H-tetrazolyl-
benzo[b][1,4]diazepine derivatives 7a–f in good yields.
N
N
N
N
N
H
N
H
N
NC
NC
NC
NC
N
H
N
H
6c 67%
6d 70%
A possible mechanism for the formation of products 6a–g
and 7a–f is shown in Scheme 4. It is conceivable that the
initial event is the formation of diimine 10 from conden-
sation between diamines and ketones.21,22 Then, an in-
tramolecular imine–enamine cyclization of 11 affords
seven-membered ring 12.23 On the basis of the well-estab-
lished chemistry of the reaction of isocyanides with im-
ines,21 intermediate 13 could be produced by nucleophilic
attack of isocyanide 4 to iminium 12 followed by nucleo-
philic attack of a water molecule on the nitrilium moiety
and production of compound 14. Subsequent, tautomer-
ization of intermediate 14 produces compounds 8a–g and
9a–f. Intermediate 15 can be produced by reaction of
amide 8a–g and 9a–f and PCl5. Nucleophilic attack of
N
N
N
N
N
N
N
N
H
N
H
N
NC
NC
NC
NC
N
H
N
H
6e 60%
6f 65%
N
N
N
N
H
N
NC
NC
N
N
N
N
N
N
N
N
N
H
H
H
N
N
O2N
6g 66%
N
H
N
H
Figure 3 Structures of 1H-tetrazolyl-1H-1,4-diazepine-2,3-dicar-
bonitrile derivatives
7b 60%
7a 65%
In view of our current interest in isocyanide-based multi-
component reaction (IMCR) of diamines20 and the poten-
tial use of 1,4-benzodiazepines and tetrazoles, we wished
to investigate the possibility of synthesizing a new class of
tetrazole-containing diazepine compounds 1H-tetrazolyl-
1H-1,4-diazepine-2,3-dicarbonitriles 6a–g and 1H-tetra-
zolyl-benzo[b][1,4]diazepines 7a–f with regiochemical
control, through a condensation reaction between 2,3-di-
aminomaleonitrile 1 or o-phenylenediamines 2, ketones 3,
isocyanides 4 and TMSN3 (5) via a two-step route
(Scheme 2). To the best of our knowledge, this is the first
report of the synthesis of 1H-tetrazol-1H-1,4-diazepine-
2,3-dicarbonitrile and 1H-tetrazolyl-benzo[b][1,4]diaz-
epine derivatives using a two-step IMCR strategy, and
this new reaction opens an important field to the use of
MCR strategies in heterocyclic synthesis.
N
N
N
N
N
N
N
N
O
H
N
H
N
O2N
Ph
N
H
N
H
7c 70%
7d 68%
N
N
N
N
N
N
N
N
O
H
H
N
N
Ph
N
H
N
H
7e 65%
7f 67%
In a pilot experiment, 2,3-diaminomaleonitrile and ke-
tones were stirred in methanol at ambient temperature
with a catalytic amount of p-toluenesulfonic acid. The
Figure 4 Structures of 1H-tetrazolyl-benzo[b][1,4]diazepine deri-
vatives
Synlett 2012, 23, 731–736
© Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Diazepines
733
R3
HN
N
N
N
O
N
R3
H
N
H
N
R1
R2
R1
O
NH2
NH2
iii, iv
i, ii
R2
R3
N
C
2
R2
+
+
R1
R1
R2
N
H
N
H
R1
R2
1 or 2
3
4
6a–g or 7a–f
8a–g or 9a–f
R1, R2, R3 = aliphatic, alicyclic, aromatic
60–70%
Scheme 2 Synthesis of 1H-tetrazolyl-1H-1,4-diazepine-2,3-dicarbonitriles 6a–g and 1H-tetrazolyl-benzo[b][1,4]diazepines 7a–f. Reagents
and conditions: (i) 1 (or 2) + 3, MeOH, TsOH·H2O, r.t., 4 h; (ii) 4, H2O, r.t., 12 h; (iii) CH2Cl2, pyridine, PCl5, reflux, 6 h; (iv) 5, r.t. 24 h.
R3
N
N
HN
N
O
N
R3
H
N
H
N
R1
R2
R1
X
X
O
X
X
NH2
NH2
X
X
i, ii
iii, iv
R2
R3
N
C
2
R2
+
+
R1
N
H
R1
R2
N
H
R1
R2
2
3
4
9a–f
7a–f
60–70%
R1, R2, R3 = aliphatic, alicyclic, aromatic
X = H, Me, NO2, COPh
Scheme 3 Synthesis of 1H-tetrazolyl-benzo[b][1,4]diazepines 7a–f. Reagents and conditions: (i) 2 + 3, MeOH, TsOH·H2O, r.t., 4 h; (ii) 4,
H2O, r.t., 12 h; (iii) CH2Cl2, pyridine, PCl5, reflux, 6 h; (iv) 5, r.t. 24 h.
azide ion 5 on the imidoyl chloride 15 and production of In summary, we have developed a straightforward proce-
compound 16. Finally, a [3+2] intramolecular cycloaddi- dure for the synthesis of a new class of substituted 1H-
tion reaction between the C=N and N3 group of interme- tetrazolyl-1H-1,4-diazepine-2,3-dicarbonitrile and 1H-
diate 16 takes place to produce 1H-tetrazolyl-1H-1,4- tetrazolyl-benzo[b][1,4]diazepine derivatives with regio-
diazepine-2,3-dicarbonitriles 6a–g or 1H-tetrazolyl-ben- chemical control, using a two-step protocol centered on
zo[b][1,4]diazepines 7a–f.24
condensation reactions between o-phenylenediamines or
H
OH
R1
R2
R1
H
N
R2
R1
R1
N
N
NH2
NH2
R2
R1
C
N
R3
R1
R1
R2
R1
R2
3
N
N
N
H
R2
R2
R2
1 or 2
10
11
OH
12
R3
N
R3
R3
R3
N
N
OH
R1
R2
R1
Cl
R1
R2
NH
H
N
H
N
H
N
H
N
O
R2
R1
R2
H2O
PCl5
R1
R2
N
H
R1
R2
R1
R2
N
H
N
H
N
H
R1
R2
15
13
14
8a–g or 9a–f
R3
R3
N
N
N
N3
R1
H
N
H
N
N
R1
R2
N
TMSN3
R2
R1
R2
N
H
N
H
R1
R2
16
6a–g or 7a–f
Scheme 4 Possible mechanism for the formation of products 6a–g and 7a–f
© Thieme Stuttgart · New York
Synlett 2012, 23, 731–736

734
A. Shaabani et al.
LETTER
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pharmaceutically important 1H-tetrazolyl-1H-1,4-diaz-
epine-2,3-dicarbonitrile
and
1H-tetrazolyl-ben-
zo[b][1,4]diazepine derivatives, especially, spirocyclic
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Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
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Synlett 2012, 23, 731–736
© Thieme Stuttgart · New York

LETTER
3925. (c) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi,
Synthesis of 1,4-Diazepines
735
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4,5,6,7-tetrahydro-1H-1,4-diazepine-2,3-dicarbonitrile
(6a): Colorless crystals; mp 229–231 °C. IR (KBr): 3350,
3135, 3078, 2940, 2865, 2213, 1656, 1625, 1478, 1390 cm–
1. 1H NMR (300.13 MHz, DMSO-d6): d = 1.00–2.10 (m,
20 H, 5 × CH2 of c-Hex, 3 × CH3 and 1 H CH), 2.79 (ABq,
J = 14.2 Hz, 1 H, CH2), 4.75 (m, 1 H, CH of c-Hex), 5.75 (s,
1 H, NH), 6.78 (s, 1 H, NH). 13C NMR (75.47 MHz, DMSO-
d6): d = 25.0, 25.3, 30.5, 31.6, 31.8, 33.9, 34.2, 46.5, 54.8,
56.8, 58.1, 106.0, 109.7, 116.3, 116.8, 158.8. MS: m/z = 340
(20) [M]+, 258 (15), 189 (55), 173 (20), 153 (20), 133 (100),
111 (15), 83 (20), 56 (65). Anal. Calcd for C17H24N8: C,
59.98; H, 7.11; N, 32.92. Found: C, 59.92; H, 7.00; N, 32.82.
9a-(1-Cyclohexyl-1H-tetrazol-5-yl)-1,4,5a,6,7,8,9,9a-
octahydrospiro[benzo[e][1,4]diazepine-5,1¢-
cyclohexane]-2,3-dicarbonitrile (6b): Colorless crystals;
mp >300 °C. IR (KBr): 3345, 3135, 2983, 2935, 2857, 2225,
2206, 1622, 1495, 1454, 1404, 1297 cm–1. 1H NMR (300.13
MHz, DMSO-d6): d = 1.00–2.10 (m, 28 H, 14 × CH2 of c-
Hex), 2.64 (m, 1 H, CH), 4.69 (m, 1 H, CH of c-Hex), 4.80
(s, 1 H, NH), 6.85 (s, 1 H, NH). 13C NMR (75.47 MHz,
DMSO-d6): d = 19.0, 20.9, 21.6, 25.0, 25.4, 30.5, 34.2, 34.8,
37.4, 46.2, 49.0, 56.5, 57.9, 59.8, 61.2, 106.1, 110.0, 116.1,
116.5, 161.1. Anal. Calcd for C23H32N8: C, 65.69; H, 7.67;
N, 26.64. Found: C, 65.60; H, 7.60; N, 26.55.
Hajishaabanha, F. J. Comb. Chem. 2010, 12, 630.
(21) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Dömling, A. Chem. Rev.
2006, 106, 17.
(22) (a) Horiguchi, E.; Shirai, K.; Jaung, J.; Furusyo, M.; Takagi,
K.; Matsuoka, M. Dyes Pigm. 2001, 50, 99. (b) Shirai, K.;
Matsuoka, M.; Fukunishi, K. Dyes Pigm. 2000, 47, 107.
(c) Handa, M.; Farida, A.; Thompson, L.; Hayashibara, C.;
Sugimori, T.; Hiromitsu, I.; Kasuga, K. Mol. Cryst. Liq.
Cryst. Sci. Technol., Sect. A 2000, 342, 75.
(23) (a) Begland, R. W.; Hartter, D. R.; Jones, F. N.; Sam, D. J.;
Shepperd, W. A.; Webster, O. W.; Weigert, F. J. J. Org.
Chem. 1974, 39, 2341. (b) Ohtsuka, Y. J. Org. Chem. 1976,
41, 629. (c) Ohtsuka, Y.; Tohma, E. J. Org. Chem. 1979, 44,
4871. (d) Mague, J. T.; Eduok, E. E. J. Chem. Crystallogr.
2000, 30, 311.
(24) (a) Jin, T.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett.
2004, 45, 9435. (b) Kennedy, L. J. Tetrahedron Lett. 2010,
51, 2010.
4¢,7-di-tert-Butyl-9a-(1-cyclohexyl-1H-tetrazol-5-yl)-
1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[e][1,4]-
diazepine-5,1¢-cyclohexane]-2,3-dicarbonitrile (6c):
Colorless crystals; mp >300 °C. IR (KBr): 3358, 3128, 3072,
2941, 2867, 2217, 1657, 1620, 1473, 1398, 1294 cm–1. 1H
NMR (300.13 MHz, DMSO-d6): d = 0.76 (s, 9 H, 4 × CH3),
0.85 (s, 9 H, 4 × CH3), 1.10–2.70 (m, 27 H, 12 × CH2 of c-
Hex and 3 × CH), 4.56 (s, 1 H, NH), 4.67 (m, 1 H, CH of c-
Hex), 6.71 (s, 1 H, NH). Anal. Calcd for C31H48N8: C, 69.89;
H, 9.08; N, 21.03. Found: C, 69.79; H, 9.01; N, 21.00.
9a-(1-Cyclohexyl-1H-tetrazol-5-yl)-4¢,7-diphenyl-
1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[e][1,4]-
diazepine-5,1¢-cyclohexane]-2,3-dicarbonitrile (6d):
Brown powder; mp >300 °C. IR (KBr): 3419, 3351, 3090,
3021, 2938, 2862, 1619, 1495, 1453, 1398 cm–1. 1H NMR
(300.13 MHz, DMSO-d6): d = 1.00–2.20 (m, 24 H, 12 × CH2
of c-Hex), 2.43 (m, 1 H, CH), 2.64 (m, 1 H, CH), 3.10 (m,
1 H, CH), 4.79 (m, 1 H, CH of c-Hex), 5.02 (s, 1 H, NH),
7.03 (s, 1 H, NH), 7.00–7.15 (m, 3 H, ArH), 7.15–7.30 (m,
3 H, ArH), 7.32 (m, 4H, ArH). 13C NMR (75.47 MHz,
DMSO-d6): d = 25.1, 25.4, 28.1, 28.5, 29.2, 30.4, 33.4, 34.2,
34.9, 42.7, 43.0, 46.4, 58.1, 59.2, 106.2, 110.3, 116.1, 116.5,
126.3, 126.6, 127.0, 127.2, 128.7, 128.9, 146.8, 147.3,
161.1. MS: m/z = 421 (10) [M+ – 151], 309 (30), 227 (35),
184 (15), 145 (35), 117 (45), 91 (100), 55 (23). Anal. Calcd
for C35H40N8: C, 73.40; H, 7.04; N, 19.56. Found: C, 73.33;
H, 7.00; N, 19.46.
(25) Melting points were measured with an Electrothermal 9200
apparatus. Mass spectra were recorded with a Finnigan-
MAT 8430 mass spectrometer operating at an ionization
potential of 70 eV. IR spectra were recorded with a
Shimadzu IR-470 spectrometer. 1H NMR spectra were
recorded with a Bruker DRX-300 Avance spectrometer at
300.13 MHz; chemical shifts (d) are reported in units of parts
per million(ppm). 1H NMR spectra are reported in the order:
multiplicity, approximate coupling constant (J value) in
hertz (Hz), and integration. 13C NMR spectra were recorded
at 75.47 MHz; chemical shifts (d) are reported in ppm.
Elemental analyses were performed with an Elementar
Analysensysteme GmbH VarioEL. All the products are new
compounds, which were characterized by IR, 1H and 13
NMR spectra and Mass spectral data.
C
Synthesis of 1H-tetrazolyl-1H-1,4-diazepine-2,3-
dicarbonitriles 6a–g and 1H-tetrazolyl-benzo[b]-
[1,4]diazepines 7a–f; General Procedure: A solution of
the diamine (1.00 mmol) and ketone (2.20 mmol) in the
presence of p-TsOH·H2O (0.095 g, 5 mol%) was stirred for
4 h in MeOH (5 mL) at ambient temperature. After
completion of the reaction, as indicated by TLC (EtOAc–n-
hexane, 3:1), the isocyanide (1.00 mmol) and H2O (0.50 mL)
were added to the reaction mixture. The resulting mixture
was stirred for 12 h at ambient temperature. After
4¢,7-di-tert-Butyl-9a-(1-tert-butyl-1H-tetrazol-5-yl)-
1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[e][1,4]-
completion of the reaction, as indicated by TLC (EtOAc–n-
hexane, 4:1), the product was filtered off, washed further
with H2O, and then crystallized from acetone to give the 1,4-
diazepine derivative.
To a solution of the 1,4-diazepine (0.50 mmol) and pyridine
(3.00 mmol) in CH2Cl2 (5.00 mL) was added PCl5 (0.75
mmol) and the resulting mixture was heated to reflux. After
6 h the reaction mixture was cooled to ambient temperature
and TMSN3 (2.00 mmol) was added and stirred for 24 h at
ambient temperature. After completion of the reaction, as
indicated by TLC (EtOAc–n-hexane, 4:1), the product was
filtered off, washed further with H2O and MeOH, and then
crystallized from acetone to give 6a–g and 7a–f.
diazepine-5,1¢-cyclohexane]-2,3-dicarbonitrile (6e):
Colorless crystals; mp 170–171 °C. IR (KBr): 3340, 3089,
2935, 2856, 2215, 1570, 1545, 1450 cm–1. 1H NMR (300.13
MHz, DMSO-d6): d = 0.80–2.40 (m, 43 H, 7 × CH2 of c-
Hex, 9 × CH3 and 2 × CH), 3.03 (m, 1 H, CH), 4.70 (s, 1 H,
NH), 6.67 (s, 1 H, NH). 13C NMR (75.47 MHz, DMSO-d6):
d = 21.8, 22.1, 22.8, 26.1, 27.5, 27.8, 31.5, 32.5, 32.8, 33.0,
33.7, 46.9, 57.3, 60.6, 65.1, 104.1, 105.8, 110.6, 115.3,
163.4. Anal. Calcd for C29H46N8: C, 68.74; H, 9.15; N,
22.11. Found: C, 68.62; H, 9.05; N, 22.07.
© Thieme Stuttgart · New York
Synlett 2012, 23, 731–736

736
A. Shaabani et al.
LETTER
2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-
9a-(1-tert-Butyl-1H-tetrazol-5-yl)-4¢,7-diphenyl-
1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[e][1,4]-
yl)(phenyl)methanone (7c): Yellow powder; mp 293–
295 °C. IR (KBr): 3349, 3084, 3040, 2970, 2935, 2850,
1631, 1570, 1492, 1402, 1342, 1301 cm–1. 1H NMR (300.13
MHz, DMSO-d6): d = 1.28 (br s, 3 H, CH3), 1.32 (br s, 3 H,
CH3), 1.44 (br s, 3 H, CH3), 1.00–2.00 (m, 11 H, 5 × CH2 of
c-Hex and 1 × CH), 3.08 (ABq, J = 13.5 Hz, 1 H, CH2), 4.69
(m, 1 H, CH of c-Hex), 5.16 (br s, 1 H, NH), 6.30 (br s, 1 H,
NH), 6.47 (ABq, J = 8.1 Hz, 1 H, ArH), 6.83 (ABq, J = 7.5
Hz, 1 H, ArH), 7.41 (s, 1 H, ArH), 7.45–7.60 (m, 5 H, ArH).
13C NMR (75.47 MHz, DMSO-d6): d = 24.9, 25.0, 25.1,
31.2, 32.4, 33.1, 33.4, 34.5, 49.9, 53.5, 55.8, 57.6, 118.1,
119.2, 123.9, 127.7, 128.6, 129.2, 131.6, 135.1, 139.3,
141.8, 160.0, 194.2. Anal. Calcd for C26H32N6O: C, 70.24;
H, 7.26; N, 18.90. Found: C, 70.15; H, 7.20; N, 18.81.
4a¢-(1-Cyclohexyl-1H-tetrazol-5-yl)-7¢-nitro-
1¢,2¢,3¢,4¢,4a¢,5¢,10¢,11a¢-octahydrospiro[cyclohexane-
1,11¢-dibenzo[b,e][1,4]diazepine] (7d): Red powder; mp
>300 °C. IR (KBr): 3394, 3368, 3065, 2932, 2857, 1594,
1524, 1493, 1467, 1327, 1272 cm–1. 1H NMR (300.13 MHz,
DMSO-d6): d = 1.00–2.10 (m, 28 H, 14 × CH2 of c-Hex),
2.86 (m, 1 H, CH), 4.55 (m, 1 H, CH of c-Hex), 5.08 (br s,
1 H, NH), 6.39 (br s, 1 H, NH), 6.65 (ABq, J = 8.7 Hz, 1H,
ArH), 7.37 (ABq, J = 6.6 Hz, 1 H, ArH), 7.72 (br s, 1 H,
ArH). 13C NMR (75.47 MHz, DMSO-d6): d = 21.2, 21.3,
21.5, 24.8, 24.9, 25.2, 25.4, 25.8, 31.1, 34.7, 49.0, 57.8, 58.4,
58.7, 59.4, 111.0, 115.6, 118.4, 137.6, 140.2, 141.8, 162.3.
Anal. Calcd for C25H35N7O2: C, 64.49; H, 7.58; N, 21.06.
Found: C, 64.39; H, 7.48; N, 21.01.
{4a¢-(1-Cyclohexyl-1H-tetrazol-5-yl)-1¢,2¢,3¢,4¢,4a¢,5¢,10¢,11a¢-
octahydrospiro[cyclohexane-1,11¢-dibenzo[b,e][1,4]-
diazepine]-7¢-yl}(phenyl)methanone(7e): Yellowpowder;
mp >300 °C. IR (KBr): 3381, 3354, 2926, 2856, 1625, 1575,
1500, 1445, 1398, 1336 cm–1. 1H NMR (300.13 MHz,
DMSO-d6): d = 1.00–2.10 (m, 28 H, 14 × CH2 of c-Hex),
2.86 (m, 1 H, CH), 4.59 (m, 2 H, CH of c-Hex and NH), 6.13
(br s, 1 H, NH), 6.60 (ABq, J = 7.7 Hz, 1 H, ArH), 6.83 (ABq,
J = 8.1 Hz, 1 H, ArH), 7.38 (s, 1 H, ArH), 7.50–7.60 (m,
5 H, ArH). 13C NMR (75.47 MHz, DMSO-d6): d = 21.4,
21.5, 25.0, 25.3, 25.5, 25.9, 32.0, 32.9, 34.8, 37.8, 49.6, 57.6,
58.4, 58.9, 117.7, 119.7, 122.8, 128.7, 129.3, 131.7, 137.7,
139.2, 139.4, 162.7, 194.3. Anal. Calcd for C32H40N6O: C,
73.25; H, 7.68; N, 16.02. Found: C, 73.14; H, 7.58; N, 15.93.
2-(1-Cyclohexyl-1H-tetrazol-5-yl)-2,4,4,7-tetramethyl-
2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (7f):White
powder; mp 202–204 °C. IR (KBr): 3381, 3306, 2928, 2862,
1600, 1525, 1478, 1451, 1398, 1309 cm–1. 1H NMR (300.13
MHz, DMSO-d6): d = 1.00–2.10 (m, 23 H, 5 × CH2 of c-
Hex, 4 × CH3 and 1 × CH), 2.78 (ABq, J = 14.1 Hz, 1 H,
CH2), 4.96 (m, 1 H, CH of c-Hex), 5.69 (br s, 1 H, NH), 6.37
(br s, 1 H, ArH), 6.38 (ABq, J = 7.7 Hz, 1 H, ArH), 6.56 (br
s, 1 H, NH), 6.62 (ABq, J = 7.7 Hz, 1 H, ArH). 13C NMR
(75.47 MHz, DMSO-d6): d = 20.6, 20.8, 25.1, 25.4, 31.5,
31.6, 31.8, 32.0, 32.3, 32.9, 34.3, 51.6, 53.1, 55.8, 57.9,
117.7, 121.2, 121.4, 127.8, 134.4, 135.3, 160.1. MS: m/z =
354 (80) [M]+, 203 (80), 187 (100), 147 (80), 55 (23). Anal.
Calcd for C20H30N6: C, 67.76; H, 8.53; N, 23.71. Found: C,
67.69; H, 8.45; N, 23.61.
diazepine-5,1¢-cyclohexane]-2,3-dicarbonitrile (6f).
Brown powder; mp >300 °C. IR (KBr): 3406, 3236, 3160,
3040, 3021, 2926, 2850, 2219, 2194, 1634, 1544, 1443,
1366, 1316 cm–1. 1H NMR (300.13 MHz, DMSO-d6): d =
1.00–2.20 (m, 23 H, 7 × CH2 of c-Hex and 3 × CH3), 2.40
(m, 1 H, CH), 2.64 (m, 1 H, CH), 3.30 (m, 1 H, CH), 4.92 (s,
1 H, NH), 6.92 (s, 1 H, NH), 7.16 (m, 3 H, ArH), 7.18 (m,
3 H, ArH), 7.32 (m, 4 H, ArH). 13C NMR (75.47 MHz,
DMSO-d6): d = 27.9, 28.6, 29.3, 30.8, 31.6, 33.4, 37.7, 42.9,
43.1, 48.8, 60.7, 61.2, 65.2, 105.8, 111.6, 116.6, 117.0,
126.3, 126.6, 127.1, 127.2, 128.6, 128.8, 146.9, 147.4,
163.5. Anal. Calcd for C33H38N8: C, 72.50; H, 7.01; N,
20.50. Found: C, 72.42; H, 6.91; N, 20.41.
9a-(1-(2,4,4-Trimethylpentan-2-yl)-1H-tetrazol-5-yl)-
1,4,5a,6,7,8,9,9a-octahydrospiro[benzo[e][1,4]-
diazepine-5,1¢-cyclohexane]-2,3-dicarbonitrile (6g):
Colorless crystals; mp 167–169 °C. IR (KBr): 3406, 3282,
3128, 3021, 2946, 2850, 2215, 2200, 1618, 1529, 1454,
1304 cm–1. 1H NMR (300.13 MHz, DMSO-d6): d = 1.00–
2.10 (m, 35 H, 9 × CH2 of c-Hex, 1 × CH2 and 5 × CH3),
2.94 (m, 1 H, CH), 4.69 (s, 1 H, NH), 6.70 (s, 1 H, NH). 13
C
NMR (75.47 MHz, DMSO-d6): d = 20.6, 20.7, 21.1, 21.6,
24.7, 25.4, 25.5, 25.6, 31.1, 31.2, 31.5, 48.8, 61.0, 61.8, 65.1,
105.7, 107.1, 111.2, 116.5, 163.4. Anal. Calcd for C25H38N8:
C, 66.63; H, 8.50; N, 24.87. Found: C, 66.58; H, 8.41; N,
24.77.
2-(1-Cyclohexyl-1H-tetrazol-5-yl)-2,4,4-trimethyl-
2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (7a):
Colorless crystals; mp 241–242 °C. IR (KBr): 3383, 2924,
2861, 1600, 1508, 1478, 1450, 1302, 1259 cm–1. 1H NMR
(300.13 MHz, DMSO-d6): d = 1.00–2.00 (m, 20 H, 5 × CH2
of c-Hex, 3 × CH3 and 1 × CH), 2.80 (ABq, J = 13.8 Hz, 1 H,
CH2), 3.99 (br s, 1 H, NH), 4.96 (t, J = 10.9 Hz, 1 H, CH of
c-Hex), 5.88 (br s, 1 H, NH), 6.40–6.50 (m, 2 H, ArH), 6.57
(dd, J = 6.8, 7.4 Hz, 1 H, ArH), 6.73 (ABq, J = 7.6 Hz, 1 H,
ArH). 13C NMR (75.47 MHz, DMSO-d6): d = 25.0, 25.4,
31.6, 32.0, 32.5, 32.9, 34.3, 51.5, 53.2, 55.8, 57.9, 117.3,
119.2, 120.7, 120.9, 135.2, 136.9, 160.1. MS: m/z = 440 (75)
[M]+, 189 (80), 173 (100), 133 (80), 90 (10), 55 (15). Anal.
Calcd for C19H28N6: C, 67.03; H, 8.29; N, 24.68. Found: C,
69.90; H, 8.22; N, 24.60.
4-(1-Cyclohexyl-1H-tetrazol-5-yl)-2,2,4-trimethyl-7-
nitro-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine(7b):
Red powder; mp 196–198 °C. IR (KBr): 3400, 3374, 2928,
2859, 1644, 1594, 1530, 1461, 1404, 1309 cm–1. 1H NMR
(300.13 MHz, DMSO-d6): d = 1.00–2.10 (m, 20 H, 5 × CH2
of c-Hex, 3 × CH3 and 1 × CH), 3.09 (ABq, J = 13.2 Hz, 1 H,
CH2), 4.67 (m, 1 H, CH of c-Hex), 5.75 (br s, 1 H, NH), 6.50
(br s, 2 H, ArH and ABq, J = 9.3 Hz, ArH), 6.38 (ABq,
J = 7.7 Hz, 1 H, ArH), 7.76 (br s, 1 H, NH). 13C NMR (75.47
MHz, DMSO-d6): d = 24.7, 24.9, 25.2, 31.0, 32.5, 33.0, 33.6,
34.4, 49.2, 53.8, 55.8, 57.7, 112.9, 116.8, 117.9, 134.7,
138.9, 144.2, 159.6. MS: m/z = 385 (50) [M]+, 234 (65), 218
(100), 177 (50), 132 (45), 83 (10), 55 (35). Anal. Calcd for
C19H27N7O2: C, 59.20; H, 7.06; N, 25.44. Found: C, 59.07;
H, 7.01; N, 25.34.
(4-(1-Cyclohexyl-1H-tetrazol-5-yl)-2,2,4-trimethyl-
Synlett 2012, 23, 731–736
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