Synthesis of tetrazolodiazepines by a five-centered four-component azide Ugi reaction. Scope and limitations

Article abstract of DOI:10.1007/s11172-012-0214-3

Tetrazolo[1,5-a][1,4]benzodiazepines were obtained by an efficient azide five-centered four-component Ugi reaction, which used ketones, sodium azide, ammonium chloride, and the corresponding isonitrile. Scope and limitations of this multi-component reaction were considered.

Full text of DOI:10.1007/s11172-012-0214-3

Russian Chemical Bulletin, International Edition, Vol. 61, No. 8, pp. 1609—1615, August, 2012
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Synthesis of tetrazolodiazepines by a fiveꢀcentered fourꢀcomponent
azide Ugi reaction. Scope and limitations
R. S. Borisov,a A. I. Polyakov,b L. A. Medvedeva,b N. I. Guranova,c and L. G. Voskressenskyc
aA. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences,
29 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 954 0222. Eꢀmail: borisov@ips.ac.ru
bN. N. Blokhin Russian Cancer Scientific Center, Russian Academy of Medical Sciences,
24 Kashirskoe shosse, 115478 Moscow, Russian Federation.
Fax: +7 (495) 324 2424. Eꢀmail: polyakov37@mail.ru
cPeoples´ Frendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (495) 955 0779. Eꢀmail: lvoskressensky@sci.pfu.edu.ru
Tetrazolo[1,5ꢀa][1,4]benzodiazepines were obtained by an efficient azide fiveꢀcentered
fourꢀcomponent Ugi reaction, which used ketones, sodium azide, ammonium chloride, and
the corresponding isonitrile. Scope and limitations of this multiꢀcomponent reaction were
considered.
Key words: azide, 1,4ꢀbenzodiazepines, Ugi reaction, tetrazolodiazepines, isonitriles.
1,4ꢀBenzodiazepines are a unique class of compounds
possessing significant tranquilizing,1 antitumor,2 muscle
relaxant,3 anticonvulsive,4 antiepileptic,5 and antitripanoꢀ
somic6 activity. Due to the high therapeutic index and low
toxicity, benzodiazepines have been widely used in mediꢀ
cine for more than 45 years. Many derivatives of this comꢀ
pounds are used either exclusively as sleeping drugs, or as
sleep inducers in addition to their sedative function.7 Exꢀ
ceptional pharmacological and clinical usefulness of these
compounds is pointed out in numerous reviews and monoꢀ
graphs devoted to the description of their properties.8 Tetꢀ
razolobenzodiazepines were confirmed to possess signifiꢀ
cant antiaggregation9 activity and to be cholecystokinin
antagonists.10 Among various approaches to the synthesis
of 1,4ꢀbenzodiazepine derivatives, a special attention is
deserved by the methods based on multiꢀcomponent reacꢀ
tions (MCR) with participation of isonitriles due to the
distinct advantage of the cost and efficiency of these methꢀ
ods.
The intermediately formed nitrilium ion reacted with
azide, giving substituted tetrazoles in good yields.11
Recently, we have described a new Ugi reaction with
participation of sodium azide for the synthesis of tetrazoloꢀ
[1,5ꢀa][1,4]benzodiazepines 1 resulting from a multiꢀcomꢀ
ponent reaction of methylisocyanobenzoate, sodium azide,
ammonium chloride, and various aliphatic ketones12
(Scheme 1).
Scheme 1
In the present work, we represented a multiꢀcompoꢀ
nent synthesis of tetrazolobenzodiazepine derivatives usꢀ
ing a fiveꢀcentered fourꢀcomponent Ugi reaction involvꢀ
ing sodium azide and studied the scope and limitations of
this method.
The Ugi reaction with participation of azides was deꢀ
scribed for the first time back in 1961 and was found to
include the step of the formation of a Schiff base from the
corresponding aldehyde or ketone and primary amine with
subsequent reaction of the imine obtained with isonitrile.
The starting isonitriles were obtained from commerꢀ
cially available methyl 2ꢀaminobenzoate, methyl 2ꢀamiꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1592—1598, August, 2012.
1066ꢀ5285/12/6108ꢀ1609 © 2012 Springer Science+Business Media, Inc.

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Borisov et al.
Scheme 3
noꢀ4ꢀbromobenzoate (2), dimethyl 2ꢀaminoterephthaꢀ
late (3), and methyl 3ꢀaminothiopheneꢀ2ꢀcarboxylate (4)
according to the standard procedure, including formylaꢀ
tion with subsequent dehydration (Scheme 2). Attempted
synthesis of isonitrile from methyl 2ꢀaminoꢀ4,5,6,7ꢀtetraꢀ
hydrobenzo[b]thiopheneꢀ3ꢀcarboxylate failed. According
to the LCMS and NMR data, a complicated mixture of
products was formed, probably, because of extremely low
stability of the target isonitrile.
Scheme 2
R = H (2, 68%), Br (3, 56%), CO2Me (4, 61%)
Because of instability of isonitriles 2—5 obtained (dark
oils with pungent odor) were used without additional puriꢀ
fication.
Product
Yield (%)
The model experiments showed that the use of crude
isonitriles had no significant effect on the yields of the
target products as compared to the use of commercially
available isonitriles12 (Scheme 3).
Present
work
40
Literature
data12
46
55
6
7
53
Later, we studied activities of various carbonyl comꢀ
pounds in this reaction. It was shown that this multiꢀ
component reaction was efficient in the case of aliphatic
ketones (below are given tetrazolobenzodiazepines 8—25
obtained by the MCR with participation of various aliꢀ
phatic ketones), whereas the use of 2ꢀacetylthiophene,
acetophenone and benzophenone did not lead to the forꢀ
mation of the target products. The latter only gave a hyꢀ
drolysis product of isonitrile, the corresponding Nꢀformylꢀ
methylanthranylate. We suppose that this fact can be exꢀ
plained by the low activity of the carbonyl carbon atom of
the aromatic ketones as compared to the aliphatic carbonꢀ
yl components, which facilitates hydrolysis. No formaꢀ
tion of the target products was observed either when acetꢀ
aldehyde, 2ꢀmethylpropanal, and 2,4ꢀdichlorobenzaldeꢀ
hyde were used instead of ketones.
Schiff base 26 in 46% yield. The latter reaction is an alterꢀ
native intermolecular reaction, in which the initially
formed aminotetrazole A reacts with the second molecule
The reaction of aliphatic aldehydes after 72 h of stirꢀ
ring leads to hydration of the isonitrile and is accompaꢀ
nied by significant resinification, probably, resulted from
the selfꢀcondensation of the aldehyde molecules. The use
of aromatic aldehyde allowed us to isolated an acyclic

Azide U5Cꢀ4CR approach to tetrazolodiazepines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1611
of 2,4ꢀdichlorobenzaldehyde, giving rise to the Schiff base
26 (Scheme 4).
Our studies also included the use of primary amines
instead of ammonium chloride. Both methylamine and
benzylamine hydrochlorides were easily involved in the
reaction, however, no formation of the expected tetrazoꢀ
lo[1,5ꢀa]benzodiazepines was observed: the only reaction
products were the corresponding aminotetrazoles 27 and
Scheme 4

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Borisov et al.
600 MHz) in CDCl3 and DMSOꢀd6, using residual signals of the
solvents as the reference. Mass spectra were recorded on Finniꢀ
gan MAT 95 XL GLCꢀMS spectrometer (EI, 70 eV). LCMS
spectra were obtained using a system including an Agilent 1100
Series liquid chromatograph, an Agilent Technologies LC/MSD
VL mass spectrometer (electro spray ionization, APCI), ELSD
Sedex 75.
28. The target derivatives of benzodiazepine 29 was obꢀ
tained from compound 28 through the Ugi postꢀcondenꢀ
sation upon the action of NaH in DMF (Scheme 5).
Scheme 5
The following reagents were purchased from commercial
companies and were used without additional purification: acetone,
adamantanone, tetrahydroꢀ2,2ꢀdimethylpyranꢀ4ꢀone, cyclohexꢀ
anone, 4ꢀmethylcyclohexanone, cyclopentanone, dihydroꢀ
thiopheneꢀ3(2H)ꢀone, NꢀBocꢀ, Nꢀmethylꢀ, Nꢀethylꢀ, Nꢀisoꢀ
propylꢀ, Nꢀbenzylpiperidinꢀ4ꢀone, ammonium chloride, methylꢀ
amine and benzylamine hydrochlorides, sodium azide.
Silufolꢀ254 plates were used for TLC, Fluka neutral alumina
of II degree of activity, 60 mesh was used for column chromatoꢀ
graphy.
Synthesis of isonitriles 2—5 (general procedure). A solution
of the corresponding amine (0.1 mmol) in ethyl formate (85 mL)
was refluxed for 7 h (TLC monitoring). The reaction mixture
was concentrated at reduced pressure and suspended in anhyꢀ
drous dichloromethane (250 mL). Freshly distilled triethylamine
(51 g, 0.5 mmol) was added and the mixture was cooled to –5 C,
followed by a dropwise addition of freshly distilled POCl3 (32 g,
0.21 mmol) so that to keep the temperature of the reaction mixꢀ
ture below 5 C. The mixture was vigorously stirred for 3 h
(LCMS monitoring) and poured on a finely crushed ice (300 g),
containing sodium carbonate (85 g). The emulsion obtained was
stirred for 1 h at 20 C, extracted with dichloromethane (3×75 mL).
The organic layer was concentrated in vacuo at 20 C (Attention!
No heating!). The isonitriles obtained were dark brown oils, which
were used in subsequent reactions without additional purificaꢀ
tion. (Caution! Good exhaust hood is required!).
Synthesis of tetrazolobenzodiazepines 6—25 (general proꢀ
cedure). A solution of ketone (1 mmol), sodium azide (78 mg,
1.2 mmol), ammonium chloride (64 mg, 1.2 mmol), and the
corresponding freshly prepared isonitrile (1 mmol) in a mixture
of water—methanol (1 : 3) (15 mL) was vigorously stirred for
24—45 h at room temperature. The reaction progress was moniꢀ
tored by TLC (SilufolꢀUVꢀ254, ethyl acetate—hexane, 1 : 3).
The indicated time corresponded to the time when the spot of
the isonitrile disappeared. The target product precipitated from
the reaction mixture, it was filtered off and dried in air (comꢀ
pounds 8, 11, 13, and 16 were additionally purified by recrystalꢀ
lization from ethyl acetate). The procedure was used for the
preparation of tetrazolobenzodiazepines 6—25.
tertꢀButyl 6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa]thieno[2,3ꢀf]ꢀ
[1,4]diazepineꢀ4ꢀspiroꢀ4´ꢀ(piperidinꢀ1´ꢀcarboxylate) (6). The
yield was 160 mg (40%), m.p. 241—242 C. The compound was
obtained from NꢀBocꢀpiperidinꢀ4ꢀone (200 mg) and methyl
3ꢀisocyanothiopheneꢀ2ꢀcarboxylate 5 (170 mg), NaN3, and
NH4Cl. The reaction required 30 h to reach completion. Specꢀ
tral characteristics correspond to the literature data.12
In conclusion, using a new multiꢀcomponent reaction
we studied an approach to the synthesis of tetrazolo[1,5ꢀa]ꢀ
[1,4]benzodiazepines. This reaction was shown to be effiꢀ
cient in the case when aliphatic ketones and ammonia
were used. The mild reaction conditions and easy isolaꢀ
tion of the products make this MCR very attractive. Aliꢀ
phatic aldehydes and aromatic ketones give no desired
products, whereas aromatic aldehydes and primary amines
can be used for the synthesis of acyclic compounds, which
can further be transformed to the benzodiazepine derivaꢀ
tives by the Ugi postꢀcondensation.
4ꢀEthyl 4ꢀmethylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzoꢀ
diazepinꢀ6ꢀone (7). The yield was 128 mg (53%), m.p. 135 C.
The compound was obtained from methyl ethyl ketone (72 mg,
0.1 mL), methyl 2ꢀisocyanobenzoate (160 mg), NaN3, and
NH4Cl. The reaction required 25 h to reach completion. Specꢀ
tral characteristics correspond to the literature data.12
Experimental
Elemental analysis was performed on a Carlo Erba 1106 inꢀ
1
strument. H and 13C NMR spectra were recorded on Brukerꢀ
8ꢀBromoꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepinꢀ6ꢀone (8). The yield was 120 mg (39%), m.p.
400 and JEOL JNMꢀECA600 spectrometers (1H, 400 and

Azide U5Cꢀ4CR approach to tetrazolodiazepines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1613
210 C. The compound was obtained from acetone (60 mg,
0.08 mL), methyl 5ꢀbromoꢀ2ꢀisocyanobenzoate (240 mg), NaN3,
and NH4Cl. The reaction required 24 h to reach completion.
Found (%): C, 42.81; H, 3.25; N, 22.65. C11H10BrN5O. Calcuꢀ
CH2ꢀPh); 7.25—7.32 (m, 5 H, C6H5); 7.72, 8.19 (both d, 1 H each,
thienyl, J = 5.3 Hz); 8.70 (br.s, 1 H, CONH). 13C NMR
(100 MHz, DMSOꢀd6), : 29.4, 32.1, 46.4, 57.6 (2 C), 61.5,
112.7, 123.4, 125.8, 127.8, 133.1 (2 C), 134.5 (2 C), 136.4, 141.5,
158.4, 160.1. MS, ESI MS: 367 [M + 1]+.
1
lated (%): C, 42.88; H, 3.27; N, 22.73. H NMR (400 MHz,
DMSOꢀd6), : 1.62 (s, 6 H, 2 Me); 7.92, 8.06 (both d, 1 H each,
C(9)H, C(10)H, J = 8.2 Hz); 8.16 (s, 1 H, C(7)H); 9.12 (br.s,
1 H, NH). 13C NMR (100 MHz, DMSOꢀd6), : 25.8 (2 C), 49.7,
122.1, 126.5, 129.8, 134.6, 136.5, 150.3, 156.8, 165.1. MS, EI MS:
1´ꢀIsopropylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa]thieno[2,3ꢀf][1,4]ꢀ
diazepineꢀ4ꢀspiroꢀ4´ꢀpiperidinꢀ6ꢀone (13). The yield was 137 mg
(43%), m.p. 210—213 C. The compound was obtained from
methyl 3ꢀisocyanothiopheneꢀ2ꢀcarboxylate (167 mg), Nꢀisoꢀ
propylpiperidinꢀ4ꢀone (140 mg, 0.15 mL), NaN3 and NH4Cl.
The reaction required 38 h to reach completion. Found (%):
C, 52.76; H, 5.64; N, 26.40. C14H18N6OS. Calculated (%):
M
+ = [M – N2] = 280.
tertꢀButyl 8ꢀbromoꢀ6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepineꢀ4ꢀspiroꢀ4´ꢀ(piperidinꢀ1´ꢀcarboxylate) (9). The
yield was 233 mg (52%), m.p. 255 C. The compound was obꢀ
tained from NꢀBocꢀpiperidinꢀ4ꢀone (200 mg), methyl 5ꢀbromoꢀ
2ꢀisocyanobenzoate (240 mg), NaN3, and NH4Cl. The reaction
required 45 h to reach completion. Found (%): C, 48.08; H, 4.62;
N, 18.67. C18H21BrN6O3. Calculated (%): C, 48.12; H, 4.71;
N, 18.70. 1H NMR (400 MHz, DMSOꢀd6), : 1.37 (s, 9 H,
(CH3)3); 1.91—2.10 (m, 4 H, (CH2)2); 3.30—3.52 (m, 4 H,
(CH2)2); 7.90, 8.08 (both d, 1 H each, C(9)H, C(10)H, J = 8.2 Hz);
8.12 (s, 1 H, C(7)H); 9.15 (br.s, 1 H, NH). 13C NMR (100 MHz,
DMSOꢀd6), : 27.6 (3 C), 34.2 (2 C), 45.9 (2 C), 50.1, 79.0,
121.7, 126.8, 128.3, 139.3 (2 C), 153.7, 156.7, 160.0, 166.3. MS,
EI MS: M+ = [M – N2] = 421.
8ꢀBromoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ4ꢀ
spiroꢀ2´ꢀtricyclo[3.3.1.13,7]decanꢀ6ꢀone (10). The yield was
312 mg (78%), m.p. 270 C. The compound was obtained from
adamantanꢀ2ꢀone (150 mg), methyl 5ꢀbromoꢀ2ꢀisocyanobenzoꢀ
ate (240 mg), NaN3, and NH4Cl. The reaction required 45 h to
reach completion. Found (%): C, 53.92; H, 4.51; N, 17.43.
C18H18BrN5O. Calculated (%): C, 54.01; H, 4.53; N, 17.50.
1H NMR (400 MHz, DMSOꢀd6), : 1.01 (m, 1 H, Ad); 1.40—2.20
(m, 10 H, Ad); 2.31—2.42 (m, 1 H, Ad); 2.61 (s, 1 H, Ad); 2.88
(m, 1 H, Ad); 7.92, 8.08 (both d, 1 H each, C(9)H, C(10)H,
J = 7.9 Hz); 8.13 (s, 1 H, C(7)H); 9.02 (br.s, 1 H, CONH).
13C NMR (100 MHz, DMSOꢀd6), : 25.6 (2 C), 30.7, 31.0, 32.1
(2 C), 32.6, 33.4, 38.2, 57.5, 123.2, 127.5, 131.2, 133.7, 134.1,
152.4, 157.5, 164.8. MS, EI MS: M+ = [M – N2] = 372.
4,5ꢀDihydrotetrazolo[1,5ꢀa]thieno[2,3ꢀf][1,4]diazepineꢀ4ꢀ
spiroꢀ2´ꢀtricyclo[3.3.1.13,7]decanꢀ6ꢀone (11). The yield was
65 mg (39%), m.p. 275 C. The compound was obtained from
adamantanꢀ2ꢀone (150 mg), methyl 3ꢀisocyanothiopheneꢀ2ꢀ
carboxylate (167 mg), NaN3, and NH4Cl. The reaction required
24 h to reach completion. Found (%): C, 58.68; H, 5.20; N, 21.37.
C16H17N5OS. Calculated (%): C, 58.70; H, 5.23; N, 21.39.
1H NMR (400 MHz, DMSOꢀd6), : 0.97 (m, 1 H, Ad); 1.55—1.94
(m, 10 H, Ad); 2.32 (m, 1 H, Ad); 2.68 (m, 1 H, Ad); 3.02 (m, 1 H,
Ad); 7.72, 8.18 (both d, 1 H each, thienyl, J = 4.9 Hz); 8.52
(br.s, 1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6), : 24.8
(2 C), 26.5, 29.8, 34.7 (2 C), 35.4 (2 C), 39.1 (overlaps with the
signal for DMSOꢀd6), 56.7, 117.3, 123.2, 126.1, 142.3, 157.4,
159.7. MS, ESI MS: 328 [M + 1]+.
1´ꢀBenzylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa]thieno[2,3ꢀf][1,4]ꢀ
diazepineꢀ4ꢀspiroꢀ4´ꢀpiperidinꢀ6ꢀone (12). The yield was 183 mg
(50%), m.p. 189—190 C. The compound was obtained from
methyl 3ꢀisocyanothiopheneꢀ2ꢀcarboxylate (167 mg), Nꢀbenzylꢀ
piperidinꢀ4ꢀone (190 mg, 0.18 mL), NaN3, and NH4Cl. The
reaction required 40 h to reach completion. Found (%): C, 58.91;
H, 4.84; N, 22.87. C18H18N6OS. Calculated (%): C, 59.00;
H, 4.95; N, 22.93. 1H NMR (400 MHz, DMSOꢀd6), : 2.03—2.25
(m, 4 H, (CH2)2); 3.30—3.48 (m, 4 H, (CH2)2); 3.51 (s, 2 H,
1
C, 52.81; H, 5.70; N, 26.39. H NMR (400 MHz, DMSOꢀd6),
: 0.94 (d, 6 H, (CH3)2, J = 6.2 Hz); 2.02—2.20 (m, 4 H, (CH2)2);
2.52—2.55 (m, 4 H, (CH2)2); 2.68 (m, 1 H, CH(CH3)2); 7.71,
8.18 (both d, 1 H each, H (thienyl), J = 5.3 Hz); 8.67 (br.s, 1 H,
CONH). 13C NMR (100 MHz, DMSOꢀd6), : 17.2 (2 C), 28.4,
31.2, 47.5 (2 C), 53.8, 54.8, 98.7, 117.3, 125.6, 136.5, 148.3,
154.6. MS, EI MS: M+ = [M – N2] = 290.
Methyl 6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazeꢀ
pineꢀ4ꢀspiroꢀ1´ꢀ(cyclopentane)ꢀ9ꢀcarboxylate (14). The yield was
132 mg (42%), m.p. 230 C (decomp.). The compound was obꢀ
tained from dimethyl 2ꢀisocyanoterephthalate (220 mg), cycloꢀ
pentanone (84 mg, 0.09 mL), NaN3, and NH4Cl. The reaction
required 25 h to reach completion. Found (%): C, 57.42; H, 4.81;
N, 22.37. C15H15N5O3. Calculated (%): C, 57.50; H, 4.83;
N, 22.35. 1H NMR (400 MHz, DMSOꢀd6), : 1.61—2.31 (m, 8 H,
(CH2)4); 3.93 (s, 3 H, CO2Me); 8.18 (s, 2 H, Harom); 8.39 (s, 1 H,
Harom); 9.26 (br.s, 1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6),
: 21.7 (2 C), 38.4, 40.1 (overlaps with the signals for DMSOꢀd6),
49.7, 51.6, 124.1, 125.4, 126.2, 131.8, 137.2, 144.5, 146.5, 167.9,
168.2. MS, EI MS: M+ = [M – N2] = 285.
Methyl 1´ꢀmethylꢀ6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepineꢀ4ꢀspiroꢀ4´ꢀ(piperidine)ꢀ9ꢀcarboxylate (15). The
yield was 215 mg (63%), m.p. 240—242 C. The compound was
obtained from dimethyl 2ꢀisocyanoterephthalate (220 mg),
Nꢀmethylpiperidinꢀ4ꢀone (113 mg, 0.12 mL), NaN3, and NH4Cl.
The reaction required 27 h to reach completion. Found (%):
C, 56.06; H, 5.26; N, 24.52. C16H18N6O3. Calculated (%):
1
C, 56.13; H, 5.30; N, 24.55. H NMR (400 MHz, DMSOꢀd6),
: 1.92—2.13 (m, 4 H, (CH2)2); 2.19 (s, 3 H, CH3—N); 3.23—3.55
(m, 4 H, (CH2)2); 3.94 (s, 3 H, CO2Me); 8.18 (s, 2 H, Harom);
8.41 (s, 1 H, Harom); 9.04 (br.s, 1 H, CONH). 13C NMR
(100 MHz, DMSOꢀd6), : 31.4, 32.6, 45.8, 47.3, 51.6 (2 C),
53.1, 122.6, 124.2, 126.9, 128.7, 136.5, 145.4, 148.1, 166.9, 170.1.
MS, ESI MS: 343 [M + 1]+.
Methyl 2´,2´ꢀdimethylꢀ6ꢀoxoꢀ4,5,3´,4´,5´,6´ꢀhexahydroꢀ
tetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ4ꢀspiroꢀ4´ꢀ(2Hꢀpyran)ꢀ9ꢀ
carboxylate (16). The yield was 136 mg (38%), m.p. 265 C. The
compound was obtained from dimethyl 2ꢀisocyanoterephthalate
(220 mg), 2,2ꢀdimethyltetrahydropyranꢀ4ꢀone (128 mg, 0.13 mL),
NaN3, and NH4Cl. The reaction required 28 h to reach compleꢀ
tion. Found (%): C, 57.08; H, 5.34; N, 19.58. C17H19N5O4.
Calculated (%): C, 57.14; H, 5.36; N, 19.60. 1H NMR (400 MHz,
DMSOꢀd6), : 0.87, 1.13 (both s, 3 H each, 2 CH3); 1.52—1.77
(m, 2 H, CH2); 2.05—2.18 (m, 1 H, CH2); 2.42—2.53 (m, 1 H,
CH2); 3.93 (s, 3 H, CO2Me); 3.95—4.08 (m, 2 H, CH2—O);
8.18 (m, 2 H, Harom); 8.42 (s, 1 H, Harom); 9.31 (s, 1 H, CONH).
13C NMR (100 MHz, DMSOꢀd6), : 27.1, 29.8, 33.4, 42.1, 48.6,
53.9, 60.2, 77.5, 124.8, 126.2, 128.3, 131.4, 137.2, 150.4, 152.6,
166.1, 169.7. MS, ESI MS: 358 [M + 1]+.

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Borisov et al.
Methyl 1´ꢀethylꢀ6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepineꢀ4ꢀspiroꢀ4´ꢀpiperidinꢀ9ꢀcarboxylate (17). The
yield was 192 mg (54%), m.p. 210 C. The compound was obꢀ
tained from dimethyl 2ꢀisocyanoterephthalate (220 mg), Nꢀethylꢀ
piperidinꢀ4ꢀone (127 mg, 0.130 mL), NaN3, and NH4Cl. The
reaction required 24 h to reach completion. Found (%): C, 57.22;
H, 5.65; N, 23.60. C17H20N6O3. Calculated (%): C, 57.29;
C, 61.15; H, 5.11; N, 27.41. C13H13N5O. Calculated (%):
C, 61.17; H, 5.13; N, 27.43. H NMR (400 MHz, DMSOꢀd6),
1
: 1.65—2.23 (m, 8 H, (CH2)4); 7.75, 7.89 (both t, 1 H each,
Harom, J = 7.2 Hz); 8.05, 8.10 (both d, 1 H each, Harom, J = 7.9 Hz);
9.08 (s, 1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6), : 21.7
(2 C), 36.5, 37.3, 51.4, 117.8, 122.6, 125.4, 132.7, 137.9, 143.8,
145.6, 164.5. MS, EI MS: M+ = [M – N2] = 227.
1
H, 5.66; N, 23.58. H NMR (600 MHz, DMSOꢀd6),, : 0.98
4´ꢀMethylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ
4ꢀspiroꢀ1´ꢀcyclohexanꢀ6ꢀone (22). The yield was 113 mg (40%),
m.p. 210—213 C. The compound was obtained from methyl
2ꢀisocyanobenzoate (160 mg), 4ꢀmethylcyclohexanone (112 mg,
0.12 mL), NaN3, and NH4Cl. The reaction required 36 h to
reach completion. Found (%): C, 63.55; H, 6.02; N, 24.67.
C15H17N5O. Calculated (%): C, 63.59; H, 6.05; N, 24.72. 1H NMR
(400 MHz, DMSOꢀd6), : 0.79 (d, 3 H, CH3, J = 6.2 Hz);
1.02—1.78 (m, 7 H, HAlk); 2.15—2.28 (m, 2 H, HAlk); 7.71 (m, 1 H,
Harom); 7.86 (m, 1 H, Harom); 7.95—8.09 (m, 2 H, Harom); 8.93
(s, 1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6), : 19.7,
23.4, 29.5 (2 C), 31.4, 33.7, 45.8, 122.6, 124.5, 126.3, 133.8,
136.7, 144.3, 148.6, 164.5. MS, EI MS: M+ = [M – N2] = 255.
1´ꢀIsopropylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazeꢀ
pineꢀ4ꢀspiroꢀ4´ꢀpiperidinꢀ6ꢀone (23). The yield was 165 mg
(53%), m.p. 238 C. The compound was obtained from methyl
2ꢀisocyanobenzoate (160 mg), Nꢀisopropylpiperidinꢀ4ꢀone
(140 mg, 0.15 mL), NaN3, and NH4Cl. The reaction required
26 h to reach completion. Found (%): C, 61.46; H, 6.43; N, 26.87.
C16H20N6O. Calculated (%): C, 61.52; H, 6.45; N, 26.90.
1H NMR (400 MHz, DMSOꢀd6), : 0.97 (d, 6 H, (CH3)2,
J = 6.2 Hz); 1.92—2.18 (m, 4 H, (CH2)2); 2.66 (m, 1 H, CH(CH3)2);
3.29—3.32 (m, 4 H, (CH2)2); 7.72 (m, 1 H, Harom); 7.86 (m, 1 H,
Harom); 7.95—8.07 (m, 2 H, Harom); 8.84 (br.s, 1 H, CONH).
13C NMR (100 MHz, DMSOꢀd6), : 19.7 (2 C), 29.8, 31.4, 42.8
(2 C), 48.5, 49.4, 118.6, 121.7, 124.6, 129.8, 132.5, 146.8, 147.3,
164.1. MS, EI MS: M+ = [M – N2] = 284.
1´ꢀBenzylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ
4ꢀspiroꢀ4´ꢀpiperidinꢀ6ꢀone (24). The yield was 260 mg (72%),
m.p. 213—214 C. The compound was obtained from methyl
2ꢀisocyanobenzoate (160 mg), Nꢀbenzylpiperidinꢀ4ꢀone (190 mg,
0.18 mL), NaN3, and NH4Cl. The reaction required 37 h to
reach completion. Found (%): C, 66.59; H, 5.55; N, 23.37.
C20H20N6O. Calculated (%): C, 66.65; H, 5.59; N, 23.32. 1H NMR
(400 MHz, DMSOꢀd6), : 1.95—2.18 (m, 4 H, (CH2)2);
2.41—2.49 (m, 4 H, (CH2)2); 3.44 (s, 2 H, CH2—Ph); 7.25
(m, 5 H, C6H5); 7.70 (m, 1 H, Harom); 7.84 (m, 1 H, Harom);
7.95—8.05 (m, 2 H, Harom); 8.92 (br.s, 1 H, CONH). 13C NMR
(100 MHz, DMSOꢀd6), : 28.7, 29.8, 48.1, 56.9 (2 C), 65.7,
117.3, 122.8, 124.6, 126.5, 130.7 (2 C), 132.5 (2 C), 135.4, 139.7,
141.9, 150.3, 151.6, 167.7. MS, EI MS: M+ = [M – N2] = 332.
4,5ꢀDihydrotetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ4ꢀspiroꢀ3´ꢀ
thiophenꢀ6ꢀone (25). The yield was 137 mg (50%), m.p. 240 C
(decomp.). The compound was obtained from methyl 2ꢀisoꢀ
cyanobenzoate (160 mg), dihydrothiophenꢀ3(2H)ꢀone (100 mg,
0.085 mL), NaN3, and NH4Cl. The reaction required 24 h to
reach completion. Found (%): C, 52.71; H, 3.98; N, 25.57.
C12H11N5OS. Calculated (%): C, 52.73; H, 4.06; N, 25.62.
1H NMR (400 MHz, DMSOꢀd6), : 2.52—2.75 (m, 2 H, CH2);
2.98—3.19 (m, 4 H, (CH2)2); 7.68 (m, 1 H, Harom); 7.83 (m, 1 H,
Harom); 7.93—8.08 (m, 2 H, Harom); 8.86 (br.s, 1 H, CONH).
13C NMR (100 MHz, DMSOꢀd6), : 28.7, 36.1, 47.8, 50.2, 119.3,
125.6, 127.8, 133.4, 136.8, 146.9, 153.4, 167.8. MS, EI MS:
M+ = [M – N2] = 245.
(t, 3 H, CH3—CH2, J = 7.2 Hz); 1.91—2.18 (m, 4 H, (CH2)2); 2.31
(q, 2 H, CH3—CH2); 2.39—2.53 (m, 4 H, (CH2)2); 3.94 (s, 3 H,
CO2Me); 8.18 (s, 2 H, Harom); 8.41 (s, 1 H, Harom); 9.09 (br.s,
1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6), : 14.8, 28.7,
31.4, 45.2, 49.7 (2 C), 50.4, 52.8, 123.6, 125.4, 126.9, 130.5,
134.9, 147.2, 149.7, 166.3, 169.8. MS, ESI MS: 357 [M + 1]+.
Methyl 1´ꢀisopropylꢀ6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa]ꢀ
[1,4]benzodiazepineꢀ4ꢀspiroꢀ4´ꢀpiperidineꢀ9ꢀcarboxylate (18).
The yield was 196 mg (53%), m.p. 265 C. The compound was
obtained from dimethyl 2ꢀisocyanoterephthalate (220 mg),
Nꢀisopropylpiperidinꢀ4ꢀone (140 mg, 0.15 mL), NaN3, and
NH4Cl. The reaction required 30 h to reach completion. Found (%):
C, 58.25; H, 5.93; N, 22.66. C18H22N6O3. Calculated (%):
1
C, 58.37; H, 5.99; N, 22.69. H NMR (400 MHz, DMSOꢀd6),
: 1.24 (d, 6 H, (CH3)2, J = 6.2 Hz); 2.32—2.61 (m, 5 H, (CH2)2 +
+ CH(CH3)2); 3.27—3.38 (m, 4 H, (CH2)2); 3.98 (s, 3 H,
CO2Me); 8.21 (s, 2 H, Harom); 8.42 (s, 1 H, Harom); 9.33 (br.s,
1 H, CONH). 13C NMR (100 MHz, DMSOꢀd6), : 20.1 (2 C),
33.4, 34.9, 48.5 (2 C), 49.2, 52.1, 54.6, 122.1, 124.8, 127.3, 131.6,
138.2, 151.7, 154.8, 166.4, 169.2. MS, ESI MS: 371 [M + 1]+.
Methyl 6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]benzodiazeꢀ
pineꢀ4ꢀspiroꢀ2´ꢀ(tricyclo[3.3.1.13,7]decane)ꢀ9ꢀcarboxylate (19).
The yield was 280 mg (74%), m.p. 165 C. The compound was
obtained from dimethylꢀ2ꢀisocyanoterephthalate (220 mg), adꢀ
amantanꢀ2ꢀone (150 mg), NaN3, and NH4Cl. The reaction
required 31 h to reach completion. Found (%): C, 63.27; H, 5.54;
N, 18.43. C20H21N5O3. Calculated (%): C, 63.31; H, 5.58;
N, 18.46. 1H NMR (400 MHz, DMSOꢀd6), : 1.40—2.20 (m, 14 H,
Ad); 3.90 (s, 3 H, CO2Me); 8.15, 8.25 (both d, 1 H each, Harom
,
J = 8.3 Hz); 8.38 (s, 1 H, Harom); 9.03 (br.s, 1 H, CONH).
13C NMR (100 MHz, DMSOꢀd6), : 26.8 (2 C), 28.4, 31.2, 32.8
(2 C), 34.6 (2 C), 39.9 (overlaps with the signals for DMSOꢀd6),
50.7, 58.1, 123.5, 126.1, 128.5, 133.4, 139.7, 152.1, 155.7, 167.1,
168.9. MS, ESI MS: 380 [M + 1]+.
Methyl 1´ꢀbenzylꢀ6ꢀoxoꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepineꢀ4ꢀspiroꢀ4´ꢀ(piperidine)ꢀ9ꢀcarboxylate (20). The
yield was 238 mg (57%), m.p. 154 C. The compound was obꢀ
tained from dimethyl 2ꢀisocyanoterephthalate (220 mg), Nꢀ
benzylpiperidinꢀ4ꢀone (190 mg, 0.18 mL), NaN3, and NH4Cl.
The reaction required 37 h to reach completion. Found (%):
C, 63.10; H, 5.28; N, 20.07. C22H22N6O3. Calculated (%):
1
C, 63.15; H, 5.30; N, 20.08. H NMR (400 MHz, DMSOꢀd6),
: 1.91—2.46 (m, 8 H, (CH2)4); 3.48 (s, 2 H, CH2—Ph); 3.96
(s, 3 H, CO2Me); 7.27 (m, 5 H, C6H5); 8.18 (m, 2 H, Harom);
8.40 (s, 1 H, Harom); 9.10 (s, 1 H, CONH). 13C NMR (100 MHz,
DMSOꢀd6), : 28.6, 31.1, 47.5, 50.6, 55.9 (2 C), 61.4, 123.6,
124.8, 127.3, 128.5, 129.8 (2 C), 131.2 (2 C), 132.4, 135.8, 137.4,
148.2, 150.5, 164.6, 166.7. MS, ESI MS: 419 [M + 1]+.
4,5ꢀDihydrotetrazolo[1,5ꢀa][1,4]benzodiazepineꢀ4ꢀspiroꢀ1´ꢀ
cyclopentanꢀ6ꢀone (21). The yield was 102 mg (40%), m.p. 250 C.
The compound was obtained from methyl 2ꢀisocyanobenzoate
(160 mg), cyclopentanone (84 mg, 0.09 mL), NaN3, and NH4Cl.
The reaction required 26 h to reach completion. Found (%):

Azide U5Cꢀ4CR approach to tetrazolodiazepines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1615
Methyl 2ꢀ{5ꢀ[(2,4ꢀdichlorophenyl)[(2,4ꢀdichlorophenyl)ꢀ
methylidene]amino}methyl]ꢀ1Hꢀtetrazoleꢀ1ꢀyl}benzoate (26).
A solution of 2,4ꢀdichlorobenzaldehyde (250 mg, 1.4 mmol),
freshly prepared isonitrile 2 (160 mg, 1 mmol), NaN3 (78 mg,
1.2 mmol), and NH4Cl (64 mg, 1.2 mmol) in a mixture of waꢀ
ter—methanol (1 : 3) (10 mL) was vigorously stirred for 10 h at
room temperature. A precipitate formed was filtered off and
purified by column chromatography (a 1.5×25ꢀcm column,
eluent ethyl acetate—hexane, 1 : 3) to obtain compound 26 (0.25 g,
46%) as a gray powder, m.p. 149—151 C. Found (%): C, 51.57;
H, 2.72; N, 13.12. C23H15Cl4N5O2. Calculated (%): C, 51.61;
H, 2.82; N, 13.09. 1H NMR (600 MHz, CDCl3), : 3.49 (s, 3 H,
CO2Me); 6.32 (s, 1 H, CHaliph); 7.12, 7.28 (both dd, 1 H each,
Harom, J = 8.2 Hz, J = 2.0 Hz); 7.21 (d, 1 H, Harom, J = 7.2 Hz);
7.33 (d, 1 H, Harom J = 2.0 Hz); 7.38—7.41 (m, 2 H, 2 CHarom);
7.57—7.65 (m, 2 H, 2 CHarom); 7.91 (d, 1 H, CHarom, J = 8.2 Hz);
8.12 (d, 1 H, Harom, J = 7.2 Hz); 8.61 (s, 1 H, N=CH). 13C NMR
(150.9 MHz, CDCl3), : 52.0, 54.8, 122.7 (2 C), 123.0, 126.7,
128.1, 129.6, 130.1, 130.2, 130.0, 130.8, 131.9, 132.4, 133.4,
134.6 (2 C), 136.5, 141.0, 155.3, 162.2, 164.6, 165.5. MS, EI MS:
1 : 10). The yield was 50 mg (52%), yellowish powder, m.p.
190 C (decomp.). Found (%): C, 67.67; H, 5.32; N, 21.81.
C18H17N5O. Calculated (%): C, 67.70; H, 5.37; N, 21.93.
1H NMR (400 MHz, CDCl3), : 1.73 (br.s, 6 H, 2 CH3); 5.00
(br.s, 2 H, CH2—Ph); 7.05 (d, 1 H, Harom, J = 7.7 Hz); 7.10—7.23
(m, 4 H, Harom); 7.56 (m, 1 H, Harom); 7.68 (m, 1 H, Harom);
7.93 (d, 1 H, Harom, J = 8.7 Hz); 8.19 (dd, 1 H, Harom, J = 8.7 Hz,
J = 1.3 Hz). 13C NMR (150.9 MHz, CDCl3), : 23.4, 24.3, 43.5,
58.3, 124.3, 124.6, 125.3, 128.7, 129.1 (2 C), 129.3 (2 C), 132.5,
135.7, 136.9, 137.6, 151.5, 166.2. MS, ESI MS: 320 [M + 1]+.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ00243ꢀa).
References
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M
+ = [M – N2] = 507.
Methyl 2ꢀ{5ꢀ[1ꢀ(methylamino)cyclohexyl]ꢀ1Hꢀtetrazoleꢀ1ꢀ
yl}benzoate (27). A solution of cyclohexanone (98 mg, 0.11 mL,
1 mmol), freshly prepared isonitrile 2 (160 mg, 1 mmol), NaN3
(78 mg, 1.2 mmol), and methylamine hydrochloride (82 mg,
1.2 mmol) in a mixture of water—methanol (1 : 3) (10 mL) was
vigorously stirred for 32 h at room temperature. A precipitate
formed was filtered off and purified by column chromatography
(a 1.5×25ꢀcm column, eluent ethyl acetate—hexane, 1 : 5)
to obtain compound 27 (0.14 g, 44%), colorless needles, m.p.
137—138 C. Spectral data are identical to those described earlier.12
Methyl 2ꢀ{5ꢀ[2ꢀ(benzylamino)propanꢀ2ꢀyl]ꢀ1Hꢀtetrazolꢀ1ꢀ
yl}benzoate (28). Colorless prisms, m.p. 151—152 C. The yield
was 0.16 g (48%). The compound was obtained according to the
procedure described for compound 7 from freshly prepared isoniꢀ
trile 2 (160 mg, 1 mmol), acetone (60 mg, 0.08 mL, 1 mmol),
BnNH2•HCl (0.17 g, 1.18 mmol), and NaN3 (78 mg, 1.2 mmol).
The reaction required 48 h to reach completion. Found (%):
C, 65.15; H, 6.00; N, 19.87. C19H21N5O2. Calculated (%):
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1
C, 64.94; H, 6.02; N, 19.93. H NMR (400 MHz, DMSOꢀd6),
: 1.43 (s, 6 H, 2 CH3); 2.33 (br.s, 1 H, NH); 3.55 (s, 2 H,
CH2—Ph); 3.95 (s, 3 H, CO2Me); 7.05—7.07 (m, 2 H, 2 Harom);
7.15—7.25 (m, 3 H, 3 Harom); 7.71—7.73 (m, 1 H, Harom);
7.78—7.81 (m, 2 H, 2 Harom); 8.08—8.10 (m, 1 H, Harom).
13C NMR (150 MHz, DMSOꢀd6), : 27.1 (2 C), 48.7, 52.7, 57.3,
121.3, 123.6, 127.4, 127.9, 129.5 (2 C), 130.7 (2 C), 132.6, 140.2,
141.7, 147.4, 153.1, 164.7. MS, ESI MS: 352 [M + 1]+.
5ꢀBenzylꢀ4,4ꢀdimethylꢀ4,5ꢀdihydrotetrazolo[1,5ꢀa][1,4]ꢀ
benzodiazepinꢀ6ꢀone (29). Sodium hydride (12 mg, 0.5 mmol)
was added in one portion to a solution of aminotetrazole 28
(100 mg, 0.3 mmol) in anhydrous DMF (5 mL). The reaction
mixture was stirred for 5 h at room temperature under argon, the
reaction progress was monitored by TLC (ethyl acetate—hexꢀ
ane, 1 : 3). Dimethylformamide was evaporated at reduced presꢀ
sure, the oily residue obtained was purified by column chromatoꢀ
graphy (a 1.5×25ꢀcm column, eluent ethyl acetate—hexane,
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12, 3894.
Received September 21, 2011;
in revised form April 2, 2012