Facile synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine and related amide derivatives

Article abstract of DOI:10.3184/174751917X15064232103128

An efficient one-pot synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine was performed using 4-bromoaniline as the starting material. A novel and widely applicable amidation procedure was then employed, whereby 1-(4-bromophenyl)-1H-tetrazol-5-amine was acylated with different acyl chlorides in the presence of lithium bis(trimethylsilyl)amide as catalyst, for the high-yield synthesis of [1-(4-bromophenyl)-1H-tetrazol-5-yl]amide derivatives.

Full text of DOI:10.3184/174751917X15064232103128

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 OCTOBER, 581–585
RESEARCH PAPER 581
Facile synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine and related amide
derivatives
Hao Yanga, Yifan Ouyanga, Yutong Suna, Zhe Wanga, Xuanli Zhua, Xiaoli Tana, Hao Wanga,b and
Wei Hongc*
aSchool of Pharmacy, Ningxia Medical University, Yinchuan 750004, P.R. China
bKey Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, P.R. China
cSchool of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, P.R. China
An efficient one-pot synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine was performed using 4-bromoaniline as the starting material. A
novel and widely applicable amidation procedure was then employed, whereby 1-(4-bromophenyl)-1H-tetrazol-5-amine was acylated with
different acyl chlorides in the presence of lithium bis(trimethylsilyl)amide as catalyst, for the high-yield synthesis of [1-(4-bromophenyl)-
1H-tetrazol-5-yl]amide derivatives.
Keywords: aminotetrazole, acyl chloride, amidation, lithium bis(trimethylsilyl)amide
Introduction
membrane effectively. Thus, introducing the amide structure at
the 5-amino position of the tetrazole could increase the value
of log P, which would be expected to enhance the activity
of small molecules (Fig. 1c).29 However, only the reaction of
highly reactive acyl chlorides with 5-aminotetrazole has so far
been reported;30 reactions with less active acyl chlorides, such
as benzyl chloroformate have not yet been described.
Herewereportaone-potsyntheticmethodfor1-(4-bromophenyl)-
1H-tetrazol-5-amine, in good yield over three steps. Moreover,
we have explored methods for amidation of aminotetrazole with
active or relatively inactive acyl chlorides. In the presence of
lithium bis(trimethylsilyl)amide, all of the acyl chlorides with high
reactivity or low reactivity reacted with 1-(4-bromophenyl)-1H-
tetrazol-5-amine to produce amide derivatives with satisfactory
yields.
Tetrazoles are increasingly popular heterocycles1 being
used in various applications, such as for propellants2,3 and
explosives.4 The compounds are also used in high-energy-
density materials (HEDM),5–6 in photography as stabilising
agents7 and as carboxylate bio-isosteres.8–16 Tetrazoles also play
key roles in improving the biological activity of compounds
and in pharmacokinetics, and are widely used in drug design
and development in medicinal chemistry. Among the various
tetrazole compounds, many 5-aminotetrazole derivatives
have high biological activities, as in anti-allergy,17 anti-virus,18
anti-inflammatory,19 anti-tumour (Fig. 1a)20 and anti-HIV21
preparations (Fig. 1b). As yet, 5-aminotetrazoles have not been
found to occur in natural products. Therefore, the synthesis of
5-aminotetrazole compounds is currently a very active research
field.
Results and discussion
Although several methods for the synthesis of
5-aminotetrazoles have been reported, the methods suffer from
several drawbacks. For example, hydrazoic acid is a highly
toxic reagent;22 cyanogen bromide on contact with water or
water vapour will emit toxic, flammable, corrosive hydrogen
bromide and hydrogen cyanide;23–25 use of heavy metal salts
(Hg or Pb) may have serious environmental impacts;26 and Zr is
an expensive reagent.27 Moreover, the tandem procedure, with
thiocyanogen as starting material and using ammonia, sodium
azide, iodine and triethylamine, results in the production of
5-aminotetrazole in quite low yield (only 10%).28 So far, a mild,
simple, high-yielding and environmentally friendly synthetic
method has not been reported.
The synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine 4
was obtained through a one-pot reaction with 4-bromoaniline
serving as the starting material (Scheme 1). The process
involved first the reaction of 4-bromoaniline 1 (1 equiv.)
with 1,4-diazabicyclo[2.2.2]-octane (DABCO;
3 equiv,)
in carbon disulfide/acetone (5:1), followed by reaction
with triphosgene (0.34 equiv.) to give the isothiocyanate 2.
Subsequent treatment with 25% aqueous ammonia (10 equiv.)
in tetrahydrofuran (THF) generated the intermediate thiourea
3; finally, intermediate 3 and sodium azide (3 equiv.) were
cyclised in the presence of triethylamine (3 equiv.) and iodine
(1.2 equiv.) in N,N-dimethylformamide (DMF) to produce
1-(4-bromophenyl)-1H-tetrazol-5-amine 4. The overall yield for
the three steps (Scheme 1) was 79%. Initially, tetrazole 4 was
prepared according to Patel’s method,28 in which isothiocyanate
In general, for a drug to be effective, it should be sufficiently
lipophilic in nature. In short, increasing the fat water partition
coefficient (log P) could help the drug to pass through the cell
Fig. 1 Some biologically important 5-aminotetrazoles.
* Correspondent. E-mail: hongwei136@hotmail.com

582 JOURNAL OF CHEMICAL RESEARCH 2017
Scheme 1 Synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine.
Table 1 Optimisation of reaction conditions for the amidation of
1-(4-bromophenyl)-1H-tetrazol-5-amine 4 and benzyl chloroformatea
is similar to the guanidine structure, the electron cloud density
on the amino group is relatively low and the amidation reaction
is less likely to proceed. With a view to optimising the reaction
conditions, the amidation of 4 with benzyl chloroformate as
model reaction was studied, and the results are summarised
in Table 1. It was found that with iodine as Lewis acid and
4-dimethylaminopyridine (DMAP) as catalyst to activate the
benzyl chloroformate, and with triethylamine and pyridine as
base to activate the amino group on 4, compound 6 was not
generated (Table 1, entries 1–4). On further experimentation, it
was noted that tetrazole 4 had reacted with benzyl chloroformate
in the presence of aqueous NaOH solution in acetone to
generate compound 6 in low yield (30%, Table 1, entry 5).
Moreover, use of a longer reaction time did not improve the
reaction yield. Presumably the amidation of 5-aminotetrazole 4
needed a stronger base to activate the amino group, so lithium
bis(trimethylsilyl)amide was used at room temperature for
5 hours; these conditions resulted in a much improved yield
(65%, Table 1, entry 6). Extending the reaction time and
increasing the temperature were next studied as a means to
improve the yield. For example, extending the reaction time to
12 hours at room temperature improved the yield to 75% (Table
1, entries 7 and 8). Also, increasing the temperature to 50 °C
for 5 hours gave a high yield of 82% (Table, entry 9). Further
increases in either reaction time or temperature gave no further
improvements in reaction yields (Table, entry 10). Therefore,
the optimised reaction conditions selected for the amidation
of 5-aminotetrazole were the use of lithium bis(trimethylsilyl)
amide as base catalyst in THF at 50 °C for 5 hours.
As shown in Scheme 2, the proposed mechanism for amidation
of 1-(4-bromophenyl)-1H-tetrazol-5-amine 4 with benzyl
chloroformate is that first the base lithium bis(trimethylsilyl)
amide abstracts the proton from the amino group on compound
4 to generate the anion 7, thereby increasing the nucleophilic
character of the amino group; the anion then attacks benzyl
chloroformate to give compound 6.
Subsequently, we explored the application of the above
conditions to the amidation reaction of 1-(4-bromophenyl)-1H-
tetrazol-5-amine 4 with various types of acyl chlorides 5a–l.
As shown in Table 2, the reactions proceeded efficiently in
the presence of lithium bis(trimethylsilyl)amide to afford the
Temp.
(°C)
Time
(h)
Yieldb
(%)
Entry Catalyst
Solvent
CH2Cl2
1
I2
50
50
50
50
50
rt
0
5
5
2
DMAP
Et3N
Py
DMF
0
3
CH2Cl2
5
0
CH2Cl2
5
0
4
5
6
7
8
9
10
48
5
30
65
75
75
82
82
NaOH
Acetone/H2O
(Me3Si)2NLi THF
(Me3Si)2NLi THF
(Me3Si)2NLi THF
(Me3Si)2NLi THF
(Me3Si)2NLi THF
rt
8
rt
12
5
50
80
48
aAll reactions were carried out using 1-(4-bromophenyl)-1H-tetrazol-5-amine (1.0 mmol),
benzyl chloroformate (1.8 mmol) and (Me3Si)2NLi (1.3 mmol).
bIsolated yield based on 1-(4-bromophenyl)-1H-tetrazol-5-amine.
2 was reacted with aqueous ammonia to generate thiourea 3
in situ, and this was then reacted directly with sodium azide,
iodine and triethylamine. However, the yield of tetrazole
4 was quite low (only 10%) for the following reasons: (1)
isothiocyanate 2 was difficult to dissolve in aqueous ammonia;
and (2) aqueous ammonia could not be removed completely by
rotary evaporation, which affected the subsequent cyclisation
reaction. Therefore, the reaction conditions were altered:
isothiocyanate 2 was reacted with aqueous ammonia in THF
to increase solubility; thiourea 3 was isolated by removal of the
aqueous ammonia and used without further purification. The
final step of the one-pot procedure resulted in a new synthetic
route for 1-(4-bromophenyl)-1H-tetrazol-5-amine 4 with good
yields being obtained.
corresponding
(1-(4-bromophenyl)-1H-tetrazol-5-yl)amides
6a–l (Table 2, entries 1–12) in good yields (61–93%). It can be
observed that the process is tolerant of all types of substituents
in the acyl chloride, i.e. aliphatic groups, in compounds 5a–c,
aryl substituents, in compounds 5d–f, the heteroaroyl chloride
5g and benzyloxy groups, from compounds 5h–l. In addition,
it can be seen that the electron-withdrawing and electron-
donating groups did affect to some extent the product yields. For
example, on testing aliphatic acid chlorides 5a–c in the reaction
with 4, it was found that acryloyl chloride 5c gave a higher yield
Next, we investigated the reaction conditions for amidation of
5-aminotetrazole. Because the amino group of 5-aminotetrazole

JOURNAL OF CHEMICAL RESEARCH 2017 583
Scheme 2 Amidation of 1-(4-bromophenyl)-1H-tetrazol-5-amine 4 and benzyl chloroformate.
Table
2
(Me3Si)2NLi-catalysed synthesis of N-(1-(4-
(92%) than either acetyl chloride 5a or cyclopropanecarbonyl
chloride 5b. When different substituted acyl chlorides, such as
arylacetyl chlorides 5d–f, were treated with 4, 4-fluorobenzoyl
chloride 5d gave a high yield (93%). Moreover, when benzyl
chloroformate 5h, which is considered an unactivated acyl
chloride compared with aliphatic acyl chlorides, aroyl and
heteroaroyl chlorides, was treated with 4, the yield of compound
6h was less than for compounds 6a–g. Given the electron-
donating and electron-withdrawing substituents on the aromatic
ring in 5i–l, it is clear that the use of 3-trifluoromethylbenzyl
chloroformate 5k or 4-trifluoromethylbenzyl chloroformate 5l
generated higher yields than 4-methoxybenzyl chloroformate
5i or 3,4,5-trimethoxybenzyl chloroformate 5j. All of the
structures of the products 6a–l were analysed and characterised
using infrared (IR), 1H and 13C NMR and high resolution mass
spectrometry (HRMS).
bromophenyl)-1H-tetrazol-5-yl)amide derivatives 6a–la
Entry
1
R
Products Time (h) Yieldb (%)
CH3 (5a)
6a
5
91
6b
5
89
2
3
5b
5c
Conclusion
6c
6d
5
5
92
93
In summary, a concise and efficient synthetic procedure has
been developed for 1-(4-bromophenyl)-1H-tetrazol-5-amine
4 that includes a novel approach to amidation of compound 4
with different acyl chlorides to generate [1-(4-bromophenyl)-
1H-tetrazol-5-yl]amide derivatives. 4-Bromoaniline served as
the starting material in the one-pot reaction, with compound
4 being prepared in good yield in three steps and avoiding the
use of toxic, harmful reagents and heavy-metal salts. Moreover,
[1-(4-bromophenyl)-1H-tetrazol-5-yl]amide derivatives were
synthesised in the presence of lithium bis(trimethylsilyl)
amide, which proved suitable for the reaction of various
amino-substituted tetrazoles with highly reactive and relatively
unreactive acyl chlorides. The advantages of this protocol
include a wide range of applications, good yields and easy
work-up to large-scale industrial production.
F
4
5
6
5d
5e
5
5
90
86
6e
6f
O
5f
S
5
5
91
82
7
8
6g
6h
5g
O
5h
Experimental
O
5
8
72
61
9
6i
6j
All chemicals were purchased from commercial sources and used as
supplied, unless stated otherwise. Dry THF was distilled over sodium
benzophenone. Thin-layer chromatography (TLC) was carried out
using silica gel 60 pre-coated aluminium plates (0.20 mm thickness)
from Macherey-Nagel, with visualisation by ultraviolet (UV) light
(254 nm). Flash chromatography was performed on silica gel (particle
size 40–63 μm). All melting points were determined using a WRS-1
B Digital Melting-point apparatus and are uncorrected. IR spectra
were recorded on a Bruker Tensor 27 spectrometer in potassium
bromide (KBr) pellets. Nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker Avance III 400 spectrometer in dimethyl
sulfoxide (DMSO-d6). Mass spectra were recorded on a Thermo TSQ
Quantum Access Max. HRMS spectra were obtained on an Agilent
6545 Quadrupole Time-of-Flight (Q-TOF) Liquid Chromatography-
Mass Spectrometer (LC/MS). The method of ionisation was
electrospray ionisation (ESI).
OCH3
5i
5j
OCH3
O
10
OCH3
OCH3
O
5
5
85
11
12
6k
6l
CF3
5k
O
84
CF3
Synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine (4)
5l
aAll reactions were carried out using 1-(4-bromophenyl)-1H-tetrazol-5-amine (1.0 mmol),
acid chloride (1.8 mmol) and (Me3Si)2NLi (1.3 mmol) at 50 °C with THF as solvent.
bIsolated yield based on 1-(4-bromophenyl)-1H-tetrazol-5-amine.
4-Bromoaniline 1 (4.01 g, 23.3 mmol) and DABCO (7.84 g, 69.9 mmol)
were dissolved in acetone (20 mL), followed by addition of CS2
(100 mL) to the stirred reaction solution. The solution was then allowed

584 JOURNAL OF CHEMICAL RESEARCH 2017
to react at room temperature, with the mixture then being stirred at
room temperature for 2 h. After completion of the reaction, monitored
by TLC, filtration gave a yellow solid, which was washed with
acetone and dried in vacuo at 70 °C for 7 h. Thereafter, the resulting
salt was dissolved in CHCl3 (30 mL) in an ice bath (0–5 °C), and then
a solution of triphosgene (2.31 g, 7.77 mmol) in CHCl3 (10 mL) was
added dropwise to the reaction solution over a period of 30 minutes.
The reaction mixture was stirred for 4 h and monitored by TLC. At
the end of the reaction, the solid was filtered off and the filtrate was
concentrated in vacuo to give intermediate 2.
Intermediate 2 was dissolved in THF (20 mL) and 25% aqueous
ammonia (7.1 mL) was added. The mixture was stirred at room
temperature for 50 min and monitored by TLC. The reaction was
terminated and the solvent was removed under reduced pressure to give
a yellow solid 3.
828, 793; 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H, NH), 7.87–7.74
(m, 2H, ArH), 7.63–7.53 (m, 2H, ArH), 6.43 (dd, J = 17.1, 10.3 Hz, 1H,
CH), 6.24 (dd, J = 17.1, 1.6 Hz, 1H, CH2), 5.88 (dd, J = 10.3, 1.6 Hz, 1H,
CH2); 13C NMR (100 MHz, DMSO-d6) δ 164.1, 149.62, 133.7, 133.2,
130.8, 129.6, 126.2, 123.5, 39.6. MS (ESI) m/z: 296.0 (M+, 100); HRMS
(ESI) m/z [M+H]+: Calcd for C10H9BrN5O: 293.9990; found: 295.9958.
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]-4-fluorobenzamide
(6d): Pale yellow solid (198.5 mg, 93%); m.p. 184.1–186.1 °C; IR
(KBr) νmax/cm−1: 3279, 1676, 1602, 1540, 1502, 1404, 1308, 1259,
1226, 1155, 1087, 1070, 1008, 911, 856, 836, 762; 1H NMR (400 MHz,
DMSO-d6) δ 11.86 (s, 1H, NH), 8.00 (qd, J = 7.3, 6.5, 3.6 Hz, 2H, ArH),
7.85–7.74 (m, 2H, ArH), 7.64 (d, J = 8.3 Hz, 2H, ArH), 7.39 (t, J = 8.6
Hz, 2H, ArH); 13C NMR (100 MHz, DMSO-d6) δ 165.4, 164.1, 150.1,
133.8, 133.3, 131.7, 131.6, 128.7, 125.8, 123.5, 116.4, 116.2, 116.0; MS
(ESI) m/z: 362.0 (M+, 100); HRMS (ESI) m/z [M+H]+: Calcd for
C14H10BrFN5O: 362.0053; found: 362.0035.
Intermediate 3 was dissolved in DMF (20 mL) and NaN3 (4.54 g,
69.9 mmol), I2 (7.11 g, 28.0 mmol) and Et3N (7.07 g, 69.9 mmol) were
added sequentially. After completion of the reaction, monitored by
TLC, the reaction was quenched by addition of 5% Na2S2O3 solution
(20 mL) to remove excess I2. The reaction solution was extracted
three times with ethyl acetate (EtOAc, 3 × 25 mL), and the combined
organic layers were washed with saturated NaCl solution, dried with
Na2SO4, filtered and concentrated. The residue was purified by column
chromatography on silica gel using EtOAc/petroleum ether (v/v, 1:1) as
eluent to give compound 4 as: Pale yellow solid (4.42 g, 78.8%); m.p.
240.6–240.8 °C (lit.27 m.p. 239–240 °C); IR (KBr) νmax/cm−1: 3336,
3142, 1650, 1589, 1574, 1493, 1451, 1403, 1323, 1143, 1108, 1068, 1007,
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]-4-methylbenzamide (6e):
Light red solid (309.6 mg, 90%); m.p. 187.6–189.0 °C; IR (KBr) νmax
/
cm−1: 3166, 1698, 1609, 1591, 1550, 1501, 1403, 1294, 1259, 1184,
1
1073, 1004, 842, 742; H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H,
NH), 7.92–7.74 (m, 4H, ArH), 7.66 (d, J = 8.3 Hz, 2H, ArH), 7.29 (dd,
J = 31.5, 8.0 Hz, 2H, ArH), 2.36 (d, J = 12.5 Hz, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ 166.7, 143.7, 141.5, 133.2, 129.8, 129.6 (d,
J = 4.3 Hz), 129.2, 128.8, 128.0, 125.7, 21.6. MS (ESI) m/z: 358.0 (M+,
100); HRMS (ESI) m/z [M+H]+: Calcd for C15H13BrN5O: 358.0303;
found: 358.0290.
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]-4-methoxybenzamide
(6f): Light red solid (209.1 mg, 86%); m.p. 178.6–179.8 °C; IR (KBr)
1
836, 817; H NMR (400 MHz, DMSO-d6) δ 7.84–7.77 (m, 2H, ArH),
ν
max/cm−1: 3183, 2932, 1697, 1609, 1560, 1508, 1253, 1175, 1073, 1029,
7.58–7.50 (m, 2H, ArH), 6.95 (s, 2H, NH2); 13C NMR (100 MHz,
DMSO-d6) δ 155.38, 133.23, 133.14, 126.74, 122.69; MS (ESI) m/z:
240.0 (M+, 100); HRMS (ESI) m/z [M+H]+: Calcd for C7H7BrN5:
239.9885; found: 239.9878.
1
1010, 843, 760, 601; H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H),
7.96–7.84 (m, 2H, ArH), 7.83–7.73 (m, 2H, ArH), 7.67–7.59 (m, 2H,
ArH), 7.11–6.96 (m, 2H, ArH), 3.84 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 165.9, 163.5, 133.9, 133.2, 130.9, 125.7, 123.4, 114.4, 56.0;
MS (ESI) m/z: 376.0 (M+, 100); HRMS (ESI) m/z [M+H]+: Calcd for
C15H13BrN5O: 374.0253; found: 376.0219.
Synthesis
of
N-(1-(4-bromophenyl)-1H-tetrazol-5-yl)amide
derivatives (6a–l); general procedure
1-(4-Bromophenyl)-1H-tetrazol-5-amine 4 (1.67 mmol) was dissolved
in dry THF (20 mL) and lithium bis(trimethylsilyl)amide 1.0 M
solution in THF (2.51 mmol, 2.51 mL) was added to the solution. After
stirring at room temperature for 15 min, the substituted acyl chloride
(3.34 mmol) was added. The reaction mixture was then allowed to
reach 50 °C. The course of the reaction was monitored by TLC and
on completion was quenched by addition of saturated NH4Cl solution
(10 mL). The reaction mixture was extracted three times with EtOAc
(3 × 25 mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated. The residue was purified by column
chromatography on silica gel using EtOAc/petroleum ether (v/v, 1:1) as
eluent to give (6a–l) in good yields.
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]thiophene-2-carboxamide
(6g): Light red solid (245.4 mg, 91%); m.p. 180.0–181.3 °C; IR (KBr)
ν
max/cm−1 : 3172, 3094, 1678, 1556, 1420, 1313, 1264, 1069, 1010, 888,
1
861, 825, 731; H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H, NH),
7.99 (d, J = 3.8 Hz, 1H, ArH), 7.92 (d, J = 5.0 Hz, 1H, ArH), 7.84–7.77
(m, 2H, ArH), 7.68 (d, J = 8.5 Hz, 2H, CH), 7.24 (dd, J = 5.0, 3.8 Hz,
1H, CH); 13C NMR (100 MHz, DMSO-d6) δ 163.3, 161.5, 134.0,
133.2, 132.0, 131.4, 129.1, 128.9, 128.3, 125.6, 123.1; MS (ESI) m/z:
350.0 (M+, 100); HRMS (ESI) m/z [M+H]+: Calcd for C12H9BrN5OS:
349.9711; found: 349.9672.
Benzyl N-[1-(4-bromophenyl)-1H-tetrazol-5-yl]carbamate (6h):
Light red solid (301.0 mg, 82%); m.p. 157.2–159.9 °C; IR (KBr) νmax
/
cm−1: 3418, 3330, 3270, 3087, 1739, 1689, 1589, 1578, 1486, 1446, 1404,
1343, 1316, 1231, 1142, 1070, 838, 753, 733, 698; 1H NMR (400 MHz,
DMSO-d6) δ 11.11 (s, 1H, NH), 7.85–7.76 (m, 2H, ArH), 7.61–7.52 (m,
2H, ArH), 7.36 (dt, J = 4.6, 2.4 Hz, 3H, ArH), 7.27–7.23 (m, 2H, ArH),
5.07 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 152.9, 149.8,
136.1, 133.2, 128.9, 128.8, 128.7, 128.4, 128.2 (d, J = 1.5 Hz), 126.5,
123.7, 67.6; MS (ESI) m/z: 376.0 (M+, 100); HRMS (ESI) m/z [M+H]+:
Calcd for C15H13BrN5O2: 374.0253; found: 376.0217.
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]acetamide
(6a):
Pale
yellow solid (203.3 mg, 91%); m.p. 165.2–167.2 °C; IR (KBr) νmax
/
cm−1: 3178, 3029, 2926, 1726, 1565, 1492, 1233, 1011, 825; H NMR
(400 MHz, DMSO-d6) δ 11.22 (s, 1H, NH), 7.83–7.78 (m, 2H, ArH),
7.59–7.54 (m, 2H, ArH), 2.04 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 169.7, 149.6, 133.7, 133.1, 126.2, 123.5, 23.2; MS
(ESI) m/z: 282.0 (M+, 100); HRMS (ESI) m/z [M+H]+: Calcd for
C9H9BrN5O: 281.9990; found: 281.9979.
1
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]cyclopropanecarboxamide
(6b): Yellow solid (304.5 mg, 89%); m.p. 193.7–195.9 °C; IR (KBr)
4-Methoxybenzyl
N-[1-(4-bromophenyl)-1H-tetrazol-5-yl]
carbamate (6i): Yellow solid (189.3 mg, 72%); m.p. 144.6–147.1 °C; IR
(KBr) νmax/cm−1: 2930, 1737, 1598, 1578, 1487, 1317, 1268, 1230, 1175,
1142, 1072, 1033, 840, 807; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s,
1H, ArH), 7.82–7.78 (m, 2H, ArH), 7.57–7.53 (m, 2H, ArH), 7.19 (d,
J = 8.6 Hz, 2H, ArH), 6.91 (dd, J = 8.6, 1.9 Hz, 2H, ArH), 4.99 (s, 2H,
CH2), 3.77 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ 159.8,
153.0, 149.8, 133.3, 133.2, 130.5, 128.4, 128.0, 126.5, 123.7, 114.2, 67.5,
55.6; MS (ESI) m/z: 426.0 (M+, 100); HRMS (ESI) m/z [M+Na]+:
Calcd for C16H14BrN5NaO3: 426.0178; found: 426.0156.
ν
max/cm−1: 3017, 1704, 1538, 1484, 1414, 1390, 1161, 1101, 1066, 1008,
1
945, 833, 817, 736; H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H,
NH), 7.89–7.75 (m, 2H, ArH), 7.60–7.49 (m, 2H, ArH), 1.88 (tt, J = 7.8,
4.5 Hz, 1H, CH), 0.85 (dt, J = 7.7, 3.4 Hz, 2H, CH2), 0.68 (dt, J = 4.4,
3.2 Hz, 2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 173.0, 149.5,
133.8, 133.0, 126.1, 123.4, 14.3, 8.7; MS (ESI) m/z: 308.0 (M+, 100);
HRMS (ESI) m/z [M+H]+: Calcd for C11H11BrN5O: 308.0147; found:
308.0132.
N-[1-(4-Bromophenyl)-1H-tetrazol-5-yl]acrylamide (6c): Light red
solid (207.0 mg, 92%); m.p. 159.4–160.0 °C; IR (KBr) νmax/cm−1: 3205,
2946, 1708, 1595, 1490, 1413, 1320, 1195, 1110, 1069, 1011, 976, 938,
3,4,5-Trimethoxybenzyl
carbamate (6j): Yellow solid (178.5 mg, 61%); m.p. 164.1–166.7 °C;
IR (KBr) νmax/cm−1: 2927, 1744, 1594, 1492, 1461, 1421, 1334, 1307,
N-[1-(4-bromophenyl)-1H-tetrazol-5-yl]

JOURNAL OF CHEMICAL RESEARCH 2017 585
1
2
3
B.S. Jursic and B.W. LeBlanc, J. Heterocycl. Chem., 1998, 35, 405.
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1236, 1126, 1069, 1008, 827; H NMR (400 MHz, DMSO-d6) δ 11.08
(s, 1H, NH), 7.80–7.75 (m, 2H, ArH), 7.71–7.63 (m, 2H, ArH), 6.68
(s, 2H, ArH), 4.98 (s, 2H, CH2), 3.76 (d, J = 4.6 Hz, 6H, OCH3), 3.65
(d, J = 4.1 Hz, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ 153.3,
133.0, 132.0, 129.2, 126.1, 105.9, 71.6, 60.5, 56.3; MS (ESI) m/z: 486.0
(M+, 100); HRMS (ESI) m/z [M+Na]+: Calcd for C18H18BrN5NaO5:
486.0389; found: 486.0361.
3-(Trifluoromethyl)benzyl N-[1-(4-bromophenyl)-1H-tetrazol-5-yl]
carbamate (6k): Yellow solid (563.3 mg, 85%); m.p. 124.0–129.5 °C;
IR (KBr) νmax/cm−1: 3201, 1743, 1594, 1576, 1530, 1491, 1418, 1331,
1311, 1225, 1165, 1074, 839, 802, 703; 1H NMR (400 MHz, DMSO-d6)
δ 11.14 (s, 1H, NH), 7.78–7.72 (m, 2H, ArH), 7.68 (td, J = 6.6, 6.0, 2.4
Hz, 4H, ArH), 7.64–7.56 (m, 2H, ArH), 5.14 (s, 2H, CH2); 13C NMR
(100 MHz, DMSO-d6) δ 133.9, 132.9, 132.2, 129.9, 125.8, 125.0, 124.7,
66.2; MS (ESI) m/z: 442.0 (M+, 100); HRMS (ESI) m/z [M+H]+:
Calcd for C16H12BrF3N5O2: 442.0126; found: 442.0111.
4
5
6
7
8
9
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4-(Trifluoromethyl)benzyl N-[1-(4-bromophenyl)-1H-tetrazol-5-yl]
carbamate (6l): Yellow solid (386.1 mg, 84%); m.p. 122.6–129.4 °C;
IR (KBr) νmax/cm−1: 3219, 1735, 1601, 1579, 1520, 1418, 1330, 1244,
1168, 1125, 1068, 1017, 816, 765, 637; 1H NMR (400 MHz, DMSO-d6)
δ 11.22 (s, 1H, NH), 7.83–7.77 (m, 2H, ArH), 7.74 (d, J = 8.1 Hz, 2H,
ArH), 7.61–7.56 (m, 2H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH), 5.18 (s,
2H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 152.9, 149.8, 147.9, 141.0,
133.2 (d, J = 4.8 Hz), 128.5, 127.2, 126.5, 125.7 (d, J = 3.9 Hz), 125.4 (d,
J = 3.7 Hz), 123.7, 66.6; MS (ESI) m/z: 442.0 (M+, 100); HRMS (ESI)
m/z [M+H]+: Calcd for C16H12BrF3N5O2: 442.0126; found: 442.0107.
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Acknowledgement
This study was supported by the National Natural Science
Foundation of China (Nos. 81460538, 81660588 and 81773582).
The first authors, Hao Yang and Yifan Ouyang have contributed
equally to this paper.
25 A.F. Brigas, W. Clegg, C.J. Dillon, C.F.C. Fonseca and R.A.W. Johnstone,
J. Chem. Soc. Perkin Trans. 2, 2001, 1315.
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2013, 144, 1569.
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Received 1 May 2017; accepted 20 September 2017
Paper 1704736
https://doi.org/10.3184/174751917X15064232103128
Published online: 11 October 2017
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