Chemistry of halonitroethenes, part 2: Trichloronitroethene as a building block for the novel synthesis of 5-chloro(nitro)methyl-substituted 1-aryltetrazoles

Article abstract of DOI:10.1055/s-0031-1289716

Conversion of 1,1,2-trichloro-2-nitroethene with an excess of 1H-benzotriazole, followed by transamination of the resulting 1,1-bis(benzotriazol-1-yl)-2-chloro-2-nitroethene with different aniline derivatives provides the corresponding 1-(arylimino)-1-(be

Full text of DOI:10.1055/s-0031-1289716

PAPER
885
Chemistry of Halonitroethenes, Part 2: Trichloronitroethene as a Building
Block for the Novel Synthesis of 5-Chloro(nitro)methyl-Substituted
1-Aryltetrazoles
N
ovel Synthesis
o
i
1-Ar
y
k
l-5-[chloro(n
t
itro)me
o
thyl]tetrazol
r
es A. Zapol’skii,a Xuena Yang,a Jan C. Namyslo,a Mimoza Gjikaj,b Dieter E. Kaufmann*a
a
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstraße 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722834; E-mail: dieter.kaufmann@tu-clausthal.de
Institute of Inorganic and Analytical Chemistry, Clausthal University of Technology, Paul-Ernst-Straße 4, 38678 Clausthal-Zellerfeld,
Germany
b
Received 24 November 2011; revised 23 January 2012
with twofold N-substitution only, the introduction of ben-
zotriazolyl groups giving 2 allows subsequent stepwise
substitution.
Abstract: Conversion of 1,1,2-trichloro-2-nitroethene with an ex-
cess of 1H-benzotriazole, followed by transamination of the result-
ing 1,1-bis(benzotriazol-1-yl)-2-chloro-2-nitroethene with different
aniline derivatives provides the corresponding 1-(arylimino)-1-
(benzotriazolyl)ethanes. Upon cycloaddition with sodium azide,
these amidines enable the formation of hitherto unknown 1-aryltet-
razoles bearing a chloro(nitro)methyl group in the 5-position. The
structure of a 4-fluorophenyl derivative was proven by single-crys-
tal X-ray diffraction analysis. Starting from arenediamines, this re-
action affords bistetrazoles. In addition, the tetrazoles are
interesting starting materials for further conversions of the side
chain.
Mechanistically, the 1,1-bis(1H-benzotriazol-1-yl)-2-
chloro-2-nitroethene (2) is formed by a twofold SNVin
reaction via addition of the nucleophile and subsequent
elimination of hydrochloric acid, which is subsequently
trapped by another equivalent of benzotriazole. In detail,
TCNiE 1 reacts with benzotriazole to give the quaternary
ammonium salt A which then loses hydrochloric acid to
give monoazole B. After this, a second nucleophilic attack
is easier due to the strong push–pull activation at this car-
bon atom. Hence, further addition–elimination affords C
and bisazole 2, thereafter. Attempts to isolate intermediate
B upon reaction of 1 with at most two equivalents of ben-
zotriazole were unsuccessful and resulted in incomplete
conversion of starting material 1, but formation of bisben-
zotriazole 2, only. The position of the triazole proton in
intermediate C is directly related to the assumed regio-
selectivity of the initial nucleophilic attack of Bzt-H.
However, subsequent tautomerization to N2 or N3 due to
better charge stabilization is conceivable. Electrophile 2 is
attacked by the subset arylamine to give the triamino-
ethane intermediate D. Finally, enamine E is formed from
D upon loss of benzotriazole. The sequence ends with the
tautomerization of E, which finally provides the imines 3–
11 (Scheme 1).
Key words: nitro compounds, nucleophilic substitution, amidines,
arenes, heterocycles, tetrazoles
Halonitroalkenes are widely applicable building blocks
for the straightforward synthesis of various four-, five-,
and six-membered heterocycles with exceptional substitu-
tion patterns.1 In a series of papers we have already shown
a multitude of synthetic applications of one of the key
compounds, 2-nitroperchlorobuta-1,3-diene,2 and we con-
tinue to investigate its entire synthetic potential. In the
present paper, we will apply the second key compound of
our research, 1,1,2-trichloro-2-nitroethene (TCNiE, 1), as
starting material. This perchlorovinylogue of nitryl chlo-
ride, which includes a characteristic and highly reactive
moiety of many polychloro(nitro)alkenes, is able to fur-
nish [chloro(nitro)methyl]arylimines as well as 1-aryltet-
razoles. Fortunately, TCNiE (1) now is easily accessible
on 100-gram scale and with high purity by means of an
electrophilic nitration of the inexpensive industrial sol-
vent trichloroethene with nitric acid.2f,3
The exclusive formation of structure 2 is well-defined by
its 13C and 15N NMR spectra. The 1H NMR spectrum of 2
reveals both benzotriazole substituents to be non-equiva-
lent. Thus, two sets of aromatic proton signals are dis-
played. We assume that the observed difference is due to
intramolecular stabilization of enamine 2 as zwitterionic
structures 2¢ or 2¢¢, respectively, are conceivably formed.
In both cases, a hydrogen bridge causes the formation of
a relatively rigid eight-membered ring (Scheme 2).
The reaction of 1 with four equivalents of 1H-benzotria-
zole directly provided 1,1-diamino-2-chloro-2-nitroethene
2 in 83% yield, which is itself prone to further nucleo-
philic attack.4 Supported by the excellent leaving group
quality of the benzotriazolyl substituent, the transamina-
tion of 2 with a variety of electronically varying aryl-
amines led to the N-monoarylated acetamidines 3–11 in
up to 93% yield (Table 1). While primary amines attack 1
The N-arylacetamidines 3–11 are obtained as single iso-
mers. In detail, the E-configuration was confirmed by nu-
clear Overhauser effect (NOE) spectroscopy as the proton
of the CH(NO2)Cl group gave a strong response to the
ortho-protons of the aryl substituent.
SYNTHESIS 2012, 44, 885–894
Advanced online publication: 17.02.2012
DOI: 10.1055/s-0031-1289716; Art ID: T110211SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
2
Considering the interesting substitution pattern of 3–11, it
is worthy of note that the presence of a CH(NO2)Cl moi-
ety, in comparison to a simple methyl group, almost half

886
V. A. Zapol’skii et al.
PAPER
Table 1 Synthesis of N-Monoarylated Acetamidines 3–11, Leading to Tetrazoles 12–20
N
N
Cl
Cl
Cl
Bzt
N
Bzt
Cl
Bzt
Cl
BztH (4 equiv)
(83%)
H2NAr (1 equiv)
NaN3
Ar
NO2
3–11
Cl
N
N
MeOH
NO2
NO2
NO2
Ar
1
2
12–20
Bzt = benzotriazol-1-yl
Ar
Entry
Product 3–11
Yield (%)
Product 12–20
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
3
4
80
85
93
80
74
87
68
86
89
12
13
14
15
16
17
18
19
20
81
87
84
88
93
75
87
94
77
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
5
6
7
4-MeC6H4
4-O2NC6H4
8
9
3,4-(MeO)2C6H3
3,4-Cl2C6H3
10
11
N
N
HN
N
HN
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
N
BztH
Cl
H
N
– BztH⋅HCl
NO2
Cl
NO2
N
NO2
N
A
1
B
N
N
N
N
N
N
N
N
HN
BztH
– BztH⋅HCl
ArNH2
N
N
N
Cl
NO2
Cl
Cl
NO2
C
2
N
N
N
N
Bzt
Bzt
NHAr
NO2
N
NAr
N
Cl
Ar
N
– BztH
H2
NO2
Cl
Cl
3–11
NO2
E
D
Scheme 1 Assumed mechanism for the formation of 2 and 3–11
N
N
N
N
N
N
H
N
N
N
N
N
N
N
N
H
N
Cl
O
Cl
O
Cl
O
N
N
N
N
N
N
O
O
H
O
2'
2
2''
Scheme 2 Non-equivalence of the benzotriazole substituents in 2 supported by hydrogen bridges
Synthesis 2012, 44, 885–894
© Thieme Stuttgart · New York

PAPER
Novel Synthesis of 1-Aryl-5-[chloro(nitro)methyl]tetrazoles
887
a century ago was found to increase greatly the antifungal in the literature. Among these, the antimicrobial
activity.5 However, from a chemical viewpoint, we be- activity11a of 1-aryl-5-(haloalkyl)tetrazoles, their efficien-
came interested in the synthetic potential of these highly cy as tachykinin receptor11b and P2X receptor antago-
functionalized azomethines. Thus, reaction of 3–11 with nists,11c as well as their applicability as serotonin
one equivalent of sodium azide in methanol under mild transporter inhibitors11d is found in the literature. On ac-
conditions gave tetrazoles 12–20 in good yields of up to count of such prominent examples, the biological testing
94% (Table 1).
of compounds 12–20, as first representatives of 1-aryl-5-
[halo(nitro)methyl]tetrazoles, is under way.
Again, the distinct leaving group character of the benzo-
triazole supports nucleophilic substitution at the already The expected high chemical reactivity of these derivatives
activated imine carbon. Thus, upon attack of an azide an- prompted us to employ the CHCl(NO2) group as donor in
ion, the intermediate F is then stabilized by elimination of Michael-type additions. Even though, in the present case
benzotriazole. The resulting azidoimine G consecutively the additional chloro substituent (in comparison to the
undergoes an intramolecular 1,3-dipolar cycloaddition parent compound nitromethane on its application, e.g., in
that provides the tetrazoles 12–20 (Scheme 3).
the classical Henry reaction) should facilitate deprotona-
tion, we examined both reported conditions, the transfor-
mation in the presence of a base and without such a
catalyst. In detail, without any base, there was no reaction
at all, applying ethyl acrylate, cyclohex-2-enone, acrylo-
nitrile, or methyl vinyl ketone, respectively. However, on
addition of sodium ethoxide, sodium hydroxide, sodium
hydride, sodium carbonate, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU), or piperidine elimination of the chlo-
ro(nitro)methyl fragment occurred. Consequentially, for
example, upon treatment with base the 5-unsubstituted 1-
aryltetrazoles 21 and 22 were isolated from these reaction
mixtures, albeit in moderate yields. In a similar manner,
treatment of tetrazole 14 with 90% sulfuric acid for five
hours at 105 °C led to complete Nef-type hydrolysis of the
chloro(nitro)methyl group with subsequent decarboxyl-
ation of the intermediate carboxylic acid. Thus, the known
1-(4-chlorophenyl)-1H-tetrazole (22)12 was obtained in
77% yield (Scheme 4). It should be mentioned that, alter-
natively, 1-substituted tetrazoles are accessible via three-
component condensation of an amine, trimethyl orthofor-
mate, and sodium azide in the presence of a catalytic
amount of indium triflate under solvent-free conditions.13
intramolecular
N
N
N
1,3-dipolar
N
N
cycloaddition
N
N3
H
N
N
Cl
3–11
N
N
12–20
N
Cl
– BztH
NO2
Ar
NO2
Ar
F
G
Scheme 3 Assumed mechanism for the formation of 12–20
NMR spectra alone are not capable of proving the pres-
ence of a tetrazole ring. Instead, an IR spectrum should
give an unambiguous result, to assure that the cycloaddi-
tion of the primary substitution product has indeed taken
place. In our case, the characteristic azide band6a at ca.
2100 cm–1 was not present, whereas the strong tetrazole
vibration at ca. 1600 cm–1 was observed (accompanied by
the weaker band6b at 1900 cm–1). Moreover, tetrazole 13
was effectually subjected to X-ray crystal structure analy-
sis (Figure 1).7,8 This synthetic pathway to chloro(ni-
tro)methyl-substituted tetrazoles is novel, short, and
efficient. An interesting alternative synthesis of the tetra-
zole ring was recently published. This procedure compris-
es the bromination of an appropriate isocyanide followed
by reaction with sodium azide.9 Strategies and prospects
in the functionalization of tetrazoles have been reviewed
recently.10
N
N
N
N
N
N
Cl
N
N
N
N
N
H2SO4–H2O
9:1
N
NO2
base
X = Cl
(77%)
X
Cl
X
21 X = F (43%)
22 X = Cl (45%)
13, 14
22
Zn, AcOH, H2O
D2O
X = F
X = F
(59%)
Ac2O
X = F
(30%)
NH
OAc
N
N
N
N
N
Cl
N
HN
N
F
D
NO2
N
NH2
Figure 1 ORTEP plot from X-ray analysis of tetrazole 137,8
The bioisosteric similarity of the tetrazole ring and the
carboxy group offers increased stability against metabo-
lism, a fact that is very useful in drug design. Some appli-
cations as pharmaceutically potent compounds are found
F
F
23
24
25
Scheme 4 Synthetic applications of tetrazoles 13 and 14
© Thieme Stuttgart · New York
Synthesis 2012, 44, 885–894

888
V. A. Zapol’skii et al.
PAPER
tive, affording the main product 23 in only 30% yield, it is
worthy of note. To the best of our knowledge, such anhy-
drides are very rare in the literature: a current literature
search revealed only three papers that note H2N-C(=NH)-
OAc.14 An assumed mechanistic cascade that describes
the formation of 23 is depicted in Scheme 5.
N
N
N
N
N
N
OAc
Cl
AcO
Cl
N
N
N
N
Ac2O
130 °C
OAc
Cl
NO2
N
N
NO2
–
Ar
NO2
Ar
Ar
Ac
13
H
I
Ar = 4-F-C6H4
A plausible start of the sequence from 13 to 23 could be a
nucleophilic attack of the acetoxy group at C5 in the tetra-
zole 13. The resulting intermediate H then eliminates 1-
chloro-1-nitroacetone to give 5-acetoxytetrazole I. Subse-
quent isomerization of tetrazole I into the open-chain imi-
no azide J, followed by hydrolysis, affords amidine K,
and finally, K tautomerizes to anhydride 23. As suggested
above, the acidic proton within the chloro(nitro)methyl
unit of tetrazoles 12–20 is prone to H/D exchange on re-
action with deuterium oxide, furnishing 24. The simple
treatment of 13 with zinc dust in aqueous acetic acid, does
not harm the tetrazole ring, but both the C–Cl and the nitro
group are reduced, so that the aminomethyl derivative 25
is afforded in 59% yield (Scheme 4). This kind of reduc-
tion employing an –CH(Hal)NO2 group to synthesize a
CH2NH2 fragment is previously unknown.
HN
OAc
HN
Ar
H2N
N
N
N
N
OAc
H2O
OAc
N
Ar
Ar
23
K
J
Scheme 5 Assumed mechanistic cascade, e.g., for the formation of
23
A quite interesting molecule, derived from tetrazole 13 re-
sulted from its reaction with acetic anhydride: upon open-
ing of the hetero ring, 1-chloro-1-nitroacetone was
extruded resulting in an acetic carbamimidic anhydride
23. Although, this reaction appeared to be quite unselec-
NH2
H2N
Bzt
NO2
Cl
NO2
Cl
N
N
N
N
N
NaN3, MeOH
MeOH, r.t
r.t., 24 h
(33%)
48 h
(65%)
N
Cl
N
Cl
N
N
N
Bzt
NO2
NO2
26
29
NH2
Bzt
N
N
N
NO2
Cl
Cl
NO2
N
H2N
N
Bzt
Bzt
Cl
NaN3, DMF
MeOH, r.t.
2
30
72 h
(56%)
r.t., 48 h
(80%)
NO2
NO2
Cl
O2N
N
N
2
Cl
N
Bzt
N
N
27
Bzt
N
N
NO2
Cl
NO2
N
N
N
Cl
H2N
NH2
NaN3, DMF
MeOH, r.t.
r.t., 24 h
(90%)
24 h
(46%)
NO2
Cl
O2N
N
N
Cl
N
Bzt
28
N
N
31
Scheme 6 Synthesis of bistetrazoles 29–31
Synthesis 2012, 44, 885–894
© Thieme Stuttgart · New York

PAPER
Novel Synthesis of 1-Aryl-5-[chloro(nitro)methyl]tetrazoles
1,1-Bis(1H-benzotriazol-1-yl)-2-chloro-2-nitroethene (2)
889
At the end of our investigations, we turned again to trans-
formations of the aforementioned nitroethene 2 to check
the limits to the feasibility of our methodology. Thus, re-
acting 0.5 equivalents of an aromatic N,N-bisnucleophile
(in our cases benzene-1,3-diamine, benzene-1,4-diamine,
or benzidine) in methanol at room temperature gave the
corresponding bisamidines 26–28 in moderate yields (46–
65%). In analogy to the above discussed structural assign-
ment of the E-configured (arylimino)ethanes 3–11, com-
pounds 26–28 have E,E-configuration. Furthermore, the
reaction of bisimines 26–28 with two equivalents of sodi-
um azide (MeOH or DMF as solvent, at r.t., 1–2 d) gave
the bistetrazoles 29–31. Thereby, the reaction of the meta-
substituted benzene derivative 26 occurred unselective
(with only 33% yield of tetrazole 29), whereas the para-
disubstituted compound 27 as well as the biphenyl 28 af-
forded the bistetrazoles 30 and 31 in good yields (80% and
90%, respectively) (Scheme 6).
To a soln of nitroethene 1 (30.00 g, 0.17 mol) in THF (200 mL) was
added 1H-benzotriazole (80.00 g, 0.68 mol) at r.t. The resulting
mixture was stirred at r.t. for 2 d and was then kept at reflux temper-
ature for 2 h. After cooling, the solvent was removed in vacuo, the
residue was stirred with H2O (150 mL) for 10 min, concd HCl was
added (30 mL), and the mixture was stirred for an additional 30 min.
The yellow precipitate that formed was filtered off and washed suc-
cessively with H2O (2 × 100 mL) and MeOH (75 mL), and dried in
air to give pure 2 (47.84 g, 83%) as a yellow solid; mp 140–141 °C.
IR (KBr): 3101, 3069, 1622, 1538, 1491, 1460, 1432, 1361, 1331,
1313, 1289, 1188, 1157, 1057, 1020, 992, 934, 868, 843, 767, 746,
656, 443, 434 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.24–8.20 (m, 1 H), 8.18–8.14 (m,
1 H), 7.58–7.52 (m, 2 H), 7.48–7.40 (m, 2 H), 7.06–7.04 (m, 1 H),
6.71–6.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 146.0 (Cq), 145.8 (Cq), 131.6
(CNO2), 131.5 (Cq), 131.3 (Cq), 130.6 (CH), 130.5 (CH), 128.9
(C1), 126.2 (CH), 126.0 (CH), 121.3 (CH), 121.2 (CH), 110.1 (CH),
109.1 (CH).
Especially, the symmetrical compounds 30 and 31 may
serve as valuable precursors, for example, in the synthesis
of MOFs or paracyclophanes. Finally, it seems interesting
to mention that all these tetrazoles show uncritical behav-
ior on heating; for example, upon determination of their
melting points, no explosion has yet occurred.
15N NMR (60.83 MHz, CDCl3): d = –156.6 (N1), –155.2 (N1¢),
–18.8 (NO2), –17.5 (N3¢), –16.5 (N3), 0.6 (N2), 2.0 (N2¢).
MS (DCP, 70 eV): m/z (%) = 341 (2) [M]+, 313 (15) [M – N2]+, 267
(3) [M – N2 – NO2]+, 239 (20) [M – 2 N2 – NO2]+, 205 (25), 93 (100)
[CClNO2]+.
HRMS (EI): m/z [M]+ calcd for C14H8ClN7O2: 341.0428; found:
341.0431.
In conclusion, we have found a novel, unusual one-pot
method for the synthesis of a series of thermally stable, 5-
[chloro(nitro)methyl]-substituted 1-aryltetrazoles by in-
tramolecular 1,3-dipolar cycloaddition of substituted
acetamidines with sodium azide. The tetrazoles are inter-
esting precursors for successive conversions on the side
chain. They are potentially biologically active com-
pounds, which will be tested in various assays.
1-(Arylimino)-1-(1H-benzotriazol-1-yl)-2-chloro-2-nitro-
ethanes 3–11; Typical Procedure I
A soln of the appropriate aniline derivative (10.1 mmol) in MeOH
(10 mL) was added dropwise to a suspension of nitroethene 2 (3.42
g, 10.0 mmol) in MeOH (30 mL) at 0–5 °C over 15 min. The result-
ing mixture was kept at the same temperature for an additional 1 h
and was then stirred at r.t. for 5–24 h. After addition of cold H2O
(150 mL, 0 °C) and concd HCl (6 mL), the mixture was stirred for
1 h, the resulting precipitate was filtered off, washed with H2O
(2 × 30 mL), and air-dried.
Melting points were determined with a Büchi apparatus 520 and are
uncorrected. TLC was performed on Merck TLC-plates (aluminum-
based) silica gel 60 F 254. FTIR spectra were obtained with a Bruk-
er Vector 22 FT-IR in the range of 400–4000 cm–1 (2.5% pellets in
KBr). Mass spectra were obtained on a Hewlett Packard MS 5989B
spectrometer, usually in direct mode with electron impact (70 eV).
In the case of chlorinated and brominated compounds, all peak val-
ues of molecular ions as well as fragments refer to the isotopes 35Cl
and 79Br. The elemental composition was confirmed by HRMS (EI,
70 eV; VG Autospec). 1H NMR (600 MHz), 13C NMR (150 MHz):
Avance III 600 MHz FT-NMR spectrometer (Bruker, Rhein-
1-(1H-Benzotriazol-1-yl)-2-chloro-2-nitro-1-(phenylimi-
no)ethane (3)
Following typical procedure I (r.t., 20 h) gave 3 as a yellow solid;
yield: 2.52 g (80%); mp 109–110 °C.
IR (KBr): 2917, 1672, 1583, 1486, 1451, 1413, 1350, 1074, 1042,
922, 878, 827, 780, 766, 745, 696, 573, 550, 429 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (d, J = 8.0 Hz, 1 H), 8.18 (d,
J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.45–7.60 (m, 3 H), 7.32
(t, J = 8.0 Hz, 1 H, HPh), 7.11 (d, J = 8.0 Hz, 2 H, o-HPh), 6.96 (s, 1
H, CHCl).
13C NMR (100 MHz, CDCl3): d = 146.2 (C1), 144.5 (Cq), 143.3
(Cq), 131.2 (Cq), 130.3 (CH), 130.0 (2 CH, m-CPh), 126.4 (CH),
126.3 (CH), 120.5 (CH), 119.7 (2 CH, o-CPh), 114.9 (CH), 79.5
(C2).
MS (DCP, 70 eV): m/z (%) = 315 (25) [M]+, 241 (7) [M – N2 –
NO2]+, 221 (6) [M – CHClNO2]+, 205 (100) [M – NO2 – HCl – N2]+,
151 (85) [M – Bzt – NO2]+.
1
stetten); H NMR (400 MHz), 13C NMR (100 MHz): Avance 400
FT-NMR spectrometer (also Bruker). In most cases, peak assign-
ments were accomplished using the results of 1H,13C-HSQC and
-HMBC NMR experiments. 14N and 15N NMR spectra were mea-
sured at their appropriate resonance frequency on the aforemen-
tioned spectrometers; 15N measurements were performed as 1H,15N
1
HMBC NMR experiments (inverse detection). H and 13C NMR
spectra were referenced to the residual solvent peak: CDCl3,
d = 7.26 (1H), d = 77.0 (13C); DMSO-d6, d = 2.50 (1H), 39.7 (13C);
acetone-d6, d = 2.09 (1H), 29.8 (13C). 14N and 15N NMR spectra
were referenced to MeNO2 (d = 0.0). Purifications were carried out
by column chromatography on silica gel 60 (Merck); petroleum
ether (PE) had bp 60–70 °C. 1,1,2-Trichloro-2-nitroethene (1) was
synthesized from trichloroethene according to the literature
procedure2f in 33% yield with respect to trichloroethene conversion,
bp 56–57 °C/25 mbar, nD20 = 1.5189.
HRMS (EI): m/z [M]+ calcd for C14H10ClN5O2: 315.0523; found:
315.0521.
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(4-fluorophenyl)imino]-2-
nitroethane (4)
Following typical procedure I (r.t., 8 h) gave 4 as a white solid;
yield: 2.83 g (85%); mp 126–127 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 885–894

890
V. A. Zapol’skii et al.
PAPER
IR (KBr): 3073, 2972, 1665, 1581, 1349, 1291, 1266, 1155, 1125,
1083, 1039, 941, 922, 884, 838, 795, 701, 643, 614, 480 cm–1.
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(4-iodophenyl)imino]-2-
nitroethane (7)
Following typical procedure I (r.t., 1 d) gave 7 as a yellow solid;
yield: 3.26 g (74%); mp 119–120 °C.
1H NMR (400 MHz, CDCl3): d = 8.39 (d, J = 8.2 Hz, 1 H), 8.17 (d,
J = 8.2 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H),
7.12–7.28 (m, 2 H), 7.03–7.11 (m, 2 H), 7.01 (s, 1 H, CHCl).
IR (KBr): 3443, 2966, 1667, 1581, 1487, 1479, 1408, 1347, 1324,
1293, 1069, 1040, 1008, 921, 883, 785, 769, 746, 727, 496, 426
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.37 (d, J = 8.0 Hz, 1 H), 8.18 (d,
J = 8.0 Hz, 1 H), 7.81 (d, J = 8.5 Hz, 2 H), 7.69 (t, J = 8.0 Hz, 1 H),
7.56 (t, J = 8.0 Hz, 1 H), 6.95 (s, 1 H, CHCl), 6.87 (d, J = 8.5 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 146.2 (C1), 144.1 (Cq), 143.6
(Cq), 139.0 (2 CH, m-CPh), 131.0 (Cq), 130.4 (CH), 126.6 (CH),
121.7 (2 CH, o-CPh), 120.6 (CH), 114.8 (CH), 90.6 (CI), 79.5 (C2).
MS (DCP, 70 eV): m/z (%) = 441 (20) [M]+, 331 (5) [M – NO2 – N2
– HCl]+, 277 (36)[M – Bzt – NO2]+, 229 (7) [M – Bzt –
CH(NO2)Cl]+, 205 (100) [M – NO2 – N2 – I – Cl]+.
13C NMR (100 MHz, CDCl3): d = 161.4 (d, 1JC,F = 246.5 Hz, CF),
4
146.2 (C1), 143.8 (Cq), 140.5 (d, JC,F = 3.1 Hz, Cq,Ph), 131.0 (Cq),
3
130.4 (CH), 126.5 (CH), 121.5 (2 CH, d, JC,F = 8.1 Hz, o-CPh),
2
120.5 (CH), 117.0 (2 CH, d, JC,F = 22.6 Hz, m-CPh), 114.8 (CH),
79.4 (C2).
MS (DCP, 70 eV): m/z (%) = 333 (26) [M]+, 259 (10) [M – NO2 –
N2]+, 239 (10) [M – NO2CHCl]+, 223 (100) [M – NO2 – HCl – N2]+,
169 (80) [M – Bzt – NO2]+.
HRMS (EI): m/z [M]+ calcd for C14H9ClFN5O2: 333.0429; found:
333.0431.
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(4-chlorophenyl)imino]-
2-nitroethane (5)
Following typical procedure I (r.t., 6 h) gave 5 as a white solid;
yield: 3.25 g (93%); mp 133–134 °C.
HRMS (EI): m/z [M]+ calcd for C14H9ClIN5O2: 440.9490; found:
440.9493.
IR (KBr): 3424, 2951, 1666, 1580, 1486, 1449, 1402, 1349, 1292,
1076, 1039, 1010, 889, 883, 786, 771, 754, 725 cm–1.
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(4-methylphenyl)imino]-
2-nitroethane (8)
Following typical procedure I (–10 °C, 1 h, r.t., 6 h) gave 8 as a
yellowish solid; yield: 2.86 g (87%); mp 85–86 °C.
1H NMR (400 MHz, CDCl3): d = 8.37 (d, J = 8.0 Hz, 1 H), 8.17 (d,
J = 8.0 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H),
7.47 (d, J = 8.7 Hz, 2 H), 7.06 (d, J = 8.7 Hz, 2 H), 6.98 (s, 1 H,
CHCl).
IR (KBr): 3440, 2960, 1662, 1583, 1504, 1487, 1404, 1348, 1292,
1016, 921, 883, 821, 791, 773, 748, 705, 486 cm–1.
13C NMR (100 MHz, CDCl3): d = 146.2 (Cq), 143.6 (C1), 143.0
(Cq), 132.0 (CCl), 131.0 (Cq), 130.4 (CH), 130.2 (2 CH, m-CPh),
126.5 (CH), 121.2 (2 CH, o-CPh), 120.6 (CH), 114.8 (CH), 79.5
(C2).
1H NMR (400 MHz, CDCl3): d = 8.41 (d, J = 8.1 Hz, 1 H), 8.16 (d,
J = 8.1 Hz, 1 H), 7.67 (t, J = 8.1 Hz, 1 H), 7.54 (t, J = 8.1 Hz, 1 H),
7.30 (d, J = 8.0 Hz, 2 H), 7.02 (s, 1 H, CHCl), 7.00 (d, J = 8.0 Hz, 2
H), 2.41 (s, 3 H, Me).
MS (DCP, 70 eV): m/z (%) = 349 (24) [M]+, 275 (8) [M – NO2 –
N2]+, 239 (98) [M – NO2 – N2 – HCl]+, 205 (100) [M – NO2 – N2 –
2 Cl]+, 185 (65) [M – Bzt – NO2]+.
HRMS (EI): m/z [M]+ calcd for C14H9Cl2N5O2: 349.0130; found:
349.0130.
13C NMR (100 MHz, CDCl3): d = 146.1 (C1), 143.3 (Cq), 142.1
(Cq), 136.3 (Cq-Me), 131.1 (Cq), 130.6 (2 CH, m-CPh), 130.2 (CH),
126.6 (CH), 120.4 (CH), 119.6 (2 CH, o-CPh), 114.9 (CH), 79.4
(C2).
MS (DCP, 70 eV): m/z (%) = 329 (17) [M]+ (17), 235 (5) [M –
CH(NO2)Cl]+, 219 (77) [M – NO2 – N2 – HCl]+, 205 (20) [M – NO2
– N2 – Me – Cl]+, 165 (100) [M – Bzt – NO2]+.
1-(1H-Benzotriazol-1-yl)-1-[(4-bromophenyl)imino]-2-chloro-
2-nitroethane (6)
Following typical procedure I (r.t., 1 d) gave 6 as a white solid;
yield: 3.14 g (80%); mp 137–138 °C.
HRMS (EI): m/z [M]+ calcd for C15H12ClN5O2: 329.0679; found:
329.0681.
IR (KBr): 3442, 2945, 1666, 1578, 1483, 1450, 1408, 1398, 1369,
1073, 1038, 1009, 883, 829, 785, 771, 753, 724, 701 cm–1.
1-(1H-Benzotriazol-1-yl)-2-chloro-2-nitro-1-[(4-nitrophe-
nyl)imino]ethane (9)
Following typical procedure I (r.t., 1 h, reflux, 10 h) gave 9 as a
yellow solid; yield: 2.45 g (68%); mp 141–142 °C.
1H NMR (400 MHz, CDCl3): d = 8.36 (d, J = 8.0 Hz, 1 H), 8.17 (d,
J = 8.0 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.7 Hz, 2 H),
7.56 (t, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.97 (s, 1 H,
CHCl).
IR (KBr): 3102, 2966, 1670, 1588, 1511, 1487, 1418, 1343, 1110,
1061, 1035, 920, 890, 859, 775, 753, 717, 693, 666 cm–1.
13C NMR (100 MHz, CDCl3): d = 146.2 (Cq), 143.7 (Cq), 143.4
(Cq), 133.1 (2 CH, m-CPh), 131.0 (Cq), 130.4 (CH), 126.5 (CH),
121.5 (2 CH, o-CPh), 120.5 (CH), 119.7 (CBr), 114.8 (CH), 79.5
(C2).
1H NMR (400 MHz, CDCl3): d = 8.38 (d, J = 9.1 Hz, 2 H, m-HPh),
8.35 (d, J = 8.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.73 (t, J = 8.0
Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.25 (d, J = 9.1 Hz, 2 H), 6.96 (s,
1 H, CHCl).
15N NMR (60.83 MHz, CDCl3): d = –10.7 (NO2), –77.1 (NAr), –
13C NMR (100 MHz, CDCl3): d = 149.7 (Cq), 146.4 (Cq), 145.7
(Cq), 143.8 (Cq), 130.9 (Cq), 130.8 (CH), 126.9 (CH), 125.8 (2 CH),
120.8 (CH), 120.5 (2 CH), 114.7 (CH), 80.0 (C2).
1
141.2 (N1Bzt); N2Bzt and N3Bzt were not detected applying H,15N-
HMBC that was optimized on 8 Hz long-range N,H-coupling.
MS (DCP, 70 eV): m/z (%) = 393 (35) [M]+, 299 (2) [M –
NO2CHCl]+, 282 (8) [M – HNO2 – N2 – HCl]+, 238 (14) [M – Ph-
Br]+, 229 (65) [M – Bzt – NO2]+, 205 (100) [M – NO2 – N2 – Br –
Cl]+.
MS (DCP, 70 eV): m/z (%) = 360 (7) [M]+, 266 (6) [M –
CH(NO2)Cl]+, 250 (10) [M – NO2 – N2 – HCl]+, 205 (100) [M – 2
NO2 – N2 – Cl]+, 196 (85) [M – Bzt – NO2]+.
HRMS (EI): m/z [M]+ calcd for C14H9ClN6O4: 360.0374; found:
360.0371.
HRMS (EI): m/z [M]+ calcd for C14H9BrClN5O2: 392.9628; found:
392.9630.
Synthesis 2012, 44, 885–894
© Thieme Stuttgart · New York

PAPER
Novel Synthesis of 1-Aryl-5-[chloro(nitro)methyl]tetrazoles
891
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(3,4-dimethoxyphe-
nyl)imino]-2-nitroethane (10)
13C NMR (100 MHz, CDCl3): d = 148.0 (C5), 134.5 (Cq), 131.2
(CH), 129.4 (2 CH), 124.5 (2 CH), 78.7 (CHCl).
Following typical procedure I (–10 °C, 1 h, r.t., 6 h) gave 10 as a yel-
lowish solid; yield: 3.23 g (86%); mp 135–137 °C.
MS (DCP, 70 eV): m/z (%) = 239 (8) [M]+, 165 (100) [M – NO2 –
N2]+, 151 (20) [M – NO2 – N3]+, 129 (95) [M – HCl – NO2 – N2]+.
IR (KBr): 3443, 2951, 1652, 1578, 1514, 1403, 1353, 1293, 1265,
1233, 1208, 1136, 1070, 1040, 943, 777, 755, 560 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.42 (d, J = 8.2 Hz, 1 H), 8.17 (d,
J = 8.2 Hz, 1 H), 7.69 (t, J = 8.2 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H),
7.13 (s, 1 H, CHCl), 6.97 (d, J = 8.3 Hz, 1 H), 6.79–6.57 (m, 2 H),
3.93 (s, 6 H, 2 Me).
HRMS (EI): m/z [M]+ calcd for C8H6ClN5O2: 239.0211; found:
239.0210.
5-[Chloro(nitro)methyl]-1-(4-fluorophenyl)-1H-tetrazole (13)
Following typical procedure II (r.t., 1 d) gave 13 as a white solid;
yield: 2.24 g (87%); mp 80–81 °C.
13C NMR (100 MHz, CDCl3): d = 150.2 (CO), 147.6 (CO), 146.1
(Cq), 143.4 (C1), 137.9 (Cq), 131.1 (Cq), 130.2 (CH), 126.4 (CH),
120.4 (CH), 114.9 (CH), 111.9 (CH), 111.0 (CH), 104.6 (CH), 79.5
(C2), 56.2 (Me), 56.0 (Me).
MS (DCP, 70 eV): m/z (%) = 375 (90) [M]+, 301 (20) [M – NO2 –
N2]+, 281 (8) [M – CH(Cl)NO2]+, 265 (62) [M – NO2 – HCl – N2]+,
211 (100) [M – Bzt – NO2]+.
IR (KBr): 3087, 2960, 2923, 1915, 1584, 1518, 1347, 1229, 1157,
876, 846, 760, 701, 618, 571, 528, 431 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45 (dd, J = 9.6, 4.4 Hz, 2 H),
7.27 (dd, J = 9.6, 6.8 Hz, 2 H), 7.10 (s, 1 H, CHCl).
1
13C NMR (100 MHz, CDCl3): d = 164.6 (d, JC,F = 219 Hz, CF),
2
149.2 (C5), 128.2 (Cq), 128.1 (d, JC,F = 22 Hz, 2 CH), 117.8 (d,
3JC,F = 8 Hz, 2 CH), 79.8 (CHCl).
HRMS (EI): m/z [M]+ calcd for C16H14ClN5O4: 375.0734; found:
375.0732.
19F NMR (564.89 MHz, CDCl3): d = –106.4 (sept.).
15N NMR (60.83 MHz, CDCl3): d = –11.8 (NO2), –44.0 (N4),
–136.5 (N1); N2 and N3 were not detected applying 1H,15N-HMBC
that was optimized on 8 Hz long-range N,H-coupling.
1-(1H-Benzotriazol-1-yl)-2-chloro-1-[(3,4-dichlorophenyl)imi-
no]-2-nitroethane (11)
Following typical procedure I (r.t., 2 h, 35–40 °C, 5 h) gave 11 as a
yellowish solid; yield: 3.41 g (89%); mp 124–126 °C.
MS (DCP, 70 eV): m/z (%) = 257 (27) [M]+, 211 (12) [M – NO2]+,
183 (100) [M – NO2 – N2]+, 148 (48) [M – Cl – NO2 – N2]+.
HRMS (EI): m/z [M]+ calcd for C8H5ClFN5O2: 257.0116; found:
257.0118.
IR (KBr): 3089, 2965, 1670, 1588, 1487, 1450, 1415, 1383, 1344,
1325, 1295, 1125, 1067, 1039, 896, 825, 790, 752, 570 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.2 Hz, 1 H), 8.19 (d,
J = 8.2 Hz, 1 H), 7.70 (t, J = 8.2 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H),
7.55 (d, J = 8.5 Hz, 1 H, H5Ph), 7.24 (d, J = 2.4 Hz, 1 H, H2Ph), 6.97
(s, 1 H, CHCl), 6.95 (dd, J = 2.4, 8.5 Hz, 1 H, H6Ph).
13C NMR (100 MHz, CDCl3): d = 146.2 (Cq), 144.3 (C1), 143.7
(Cq), 134.2 (CCl), 131.7 (C5Ph), 130.9 (CCl), 130.6 (CH), 130.3
(Cq), 126.7 (CH), 121.9 (C2Ph), 120.7 (CH), 119.2 (C6Ph), 114.7
(CH), 79.5 (C2).
MS (DCP, 70 eV): m/z (%) = 383 (52) [M]+, 336 (5) [M – NO2]+,
308 (18) [M – HNO2 – N2]+, 289 (6) [M – CH(Cl)NO2]+, 272 (62)
[M – HNO2 – HCl – N2]+, 239 (100) [M – NO2 – 2 Cl – N2]+, 219
(60) [M – Bzt – NO2]+.
X-ray data are given in the literature section.7
5-[Chloro(nitro)methyl]-1-(4-chlorophenyl)-1H-tetrazole (14)
Following typical procedure II (r.t., 1 d) gave 14 as a white solid;
yield: 2.29 g (84%); mp 80–81 °C.
IR (KBr): 3090, 2961, 1923, 1672, 1580, 1493, 1344, 1218, 1094,
1012, 873, 838, 803, 760, 700, 573, 528 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.63 (d, J = 8.0 Hz, 2 H), 7.46 (d,
J = 8.0 Hz, 2 H), 7.13 (s, 1 H, CHCl).
13C NMR (100 MHz, CDCl3): d = 148.8 (C5), 138.6 (Cq), 130.7 (2
CH), 130.6 (=C–Cl), 127.1 (2 CH), 79.6 (CHCl).
MS (DCP, 70 eV): m/z (%) = 273 (8) [M]+, 227 (7) [M – NO2]+, 199
HRMS (EI): m/z [M]+ calcd for C14H8Cl3N5O2: 382.9744; found:
382.9732.
(65) [M – NO2 – N2]+, 163 (20) [M – HCl – NO2 – N2]+.
HRMS (EI): m/z [M]+ calcd for C8H5Cl2N5O2: 272.9820; found:
272.9818.
1-Aryl-5-[chloro(nitro)methyl]-1H-tetrazole 12–20; Typical
Procedure II
1-(4-Bromophenyl)-5-[chloro(nitro)methyl]-1H-tetrazole (15)
Following typical procedure II (r.t., 2 d) gave 15 as a yellowish sol-
id; yield: 2.79 (88%); mp 75–76 °C.
To a suspension of acetamidine 3 (3.15 g, 10.0 mmol) in MeOH (30
mL) was added NaN3 (0.70 g, 10.1 mmol) at 0 to –5 °C within 5 min
in small portions. The resulting mixture was stirred at this tempera-
ture for 1 h, then at r.t. for 4–48 h. After completion of the reaction,
the mixture was poured into cold (0 °C) concd HCl (10 mL) in H2O
(100 mL) soln and stirred for 2 h. Usually, a precipitate formed,
which was filtered off, washed with H2O (2 × 30 mL), and air dried.
When precipitation failed, the product was extracted from the acidic
H2O with CHCl3 (3 × 30 mL). The combined organic phases were
then washed with H2O (50 mL), dried (anhyd CaCl2), and evaporat-
ed to dryness. The initially obtained oil crystallized within several
hours.
IR (KBr): 3425, 2958, 1920, 1580, 1489, 1401, 1384, 1342, 1274,
1218, 1121, 1101, 1069, 1009, 985, 937, 873, 834, 698, 520 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 8.7 Hz, 2 H), 7.38 (d,
J = 8.7 Hz, 2 H), 7.15 (s, 1 H, CHCl).
13C NMR (100 MHz, CDCl3): d = 148.7 (C5), 133.6 (2 CH), 131.1
(Cq-N), 127.1 (2 CH), 126.6 (CBr), 79.6 (CHCl).
MS (DCP, 70 eV): m/z (%) = 317 (3) [M]+, 245 (18) [M – N2 –
NO2]+, 231 (5) [M – NO2 – N3]+, 209 (8) [M – HCl – NO2 – N3]+,
155 (100) [PhBr]+.
HRMS (EI): m/z [M]+ calcd for C8H5BrClN5O2: 316.9315; found:
316.9313.
5-[Chloro(nitro)methyl]-1-phenyl-1H-tetrazole (12)
Following typical procedure II (r.t., 1 d) gave 12 as a white solid;
yield: 1.94 g (81%); mp 56–57 °C.
5-[Chloro(nitro)methyl]-1-(4-iodophenyl)-1H-tetrazole (16)
IR (KBr): 3069, 2967, 1917, 1589, 1494, 1456, 1345, 1088, 878,
819, 765, 717, 691, 614, 545 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.61–7.53 (m, 3 H), 7.44–7.40 (m,
2 H), 7.12 (s, 1 H, CHCl).
Following typical procedure II (r.t., 1 d) gave 16 as a yellow solid;
yield: 3.39 g (93%); mp 86–87 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 885–894

892
V. A. Zapol’skii et al.
PAPER
5-[Chloro(nitro)methyl]-1-(3,4-dichlorophenyl)-1H-tetrazole
IR (KBr): 3093, 2968, 1908, 1592, 1487, 1400, 1344, 1060, 1008,
1069, 887, 827, 734, 540 cm–1.
(20)
Following typical procedure II (r.t., 8 h) gave 20 as a yellow solid;
yield: 2.36 g (77%); mp 66–68 °C.
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 8.7 Hz, 2 H), 7.25 (d,
J = 8.7 Hz, 2 H), 7.13 (s, 1 H, CHCl).
IR (KBr): 3097, 2970, 2113, 1655, 1590, 1478, 1390, 1344, 1247,
1136, 1087, 1037, 880, 823, 734, 698, 602 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72 (d, J = 8.5 Hz, 1 H), 7.66 (d,
J = 2.3 Hz, 1 H), 7.38 (dd, J = 8.5, 2.3 Hz, 1 H), 7.21 (s, 1 H, CHCl).
13C NMR (100 MHz, CDCl3): d = 148.7 (C5), 137.1 (Cq-N), 134.8
(CCl), 132.0 (CH), 131.1 (CH), 127.7 (CH), 124.8 (CH), 79.6
(CHCl).
MS (DCP, 70 eV): m/z (%) = 307 (4) [M]+, 261 (1) [M – NO2]+, 233
(19) [M – NO2 – N2]+, 219 (6) [M+ – NO2 – N3]+, 197 (25) [M – NO2
– HCl – N2]+, 146 (100) [C6H3Cl2]+.
13C NMR (100 MHz, CDCl3): d = 148.6 (C5), 140.0 (2 CH), 131.9
(Cq-N), 127.2 (2 CH), 98.7 (CI), 79.8 (CHCl).
MS (DCP, 70 eV): m/z (%) = 365 (13) [M]+, 291 (12) [M – N2 –
HNO2]+, 277 (5) [M – HNO2 – N3]+, 203 (53) [PhI]+, 164 (93) [M+
– I – HNO2 – N2], 76 (100).
HRMS (EI): m/z [M+] calcd for C8H5ClIN5O2: 364.9177; found:
364.9179.
5-[Chloro(nitro)methyl]-1-(4-methylphenyl)-1H-tetrazole (17)
Following typical procedure II (r.t., 2 d) gave 17 as a yellow solid;
yield: 1.40 g (75%); mp 51–52 °C.
HRMS (EI): m/z [M]+ calcd for C8H4Cl3N5O2: 306.9431; found:
IR (KBr): 2967, 2927, 1912, 1588, 1518, 1454, 1345, 1180, 1111,
1085, 1016, 994, 879, 821, 759, 699, 617, 545 cm–1.
306.9427.
1-(4-Fluorophenyl)-1H-tetrazole (21); Typical Procedure III
At r.t. [chloro(nitro)methyl]tetrazole 13 (0.50 g, 1.94 mmol) was
treated with pyridine (5 mL) overnight with stirring. Subsequently,
the mixture was cooled to 0 °C and cold H2O was added (50 mL).
After 10 min, the mixture was neutralized with 10% HCl and the or-
ganic layer was extracted with CHCl3 (3 × 50 mL). The combined
organic phases were washed with H2O (2 × 100 mL) and then dried
(anhyd CaCl2). The crude product was purified by column chroma-
tography (PE–EtOAc, gradually 10:1 to 1:1) to give 21 (0.14 g,
43%) as a yellow oil that solidified after several hours; mp 91–92
°C.
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 8.4 Hz, 2 H), 7.36 (d,
J = 8.4 Hz, 2 H), 7.09 (s, 1 H, CHCl), 2.53 (s, 3 H, Me).
13C NMR (100 MHz, CDCl3): d = 149.2 (C5), 143.0 (C-Me), 131.3
(2 CH), 129.5 (Cq-N), 125.7 (2 CH), 79.8 (CHCl), 21.6 (Me).
MS (DCP, 70 eV): m/z (%) = 253 (7) [M]+, 179 (58) [M – N2 –
HNO2]+, 165 (7) [M – NO2 – N3]+, 143 (30) [M – HCl – HNO2 –
N2]+, 91 (100) [PhMe]+.
HRMS (EI): m/z [M]+ calcd for C9H8ClN5O2: 253.0367; found:
253.0368.
IR (KBr): 3129, 3093, 1884, 1604, 1515, 1237, 1206, 1184, 1160,
1097, 1003, 961, 888, 836, 613, 530, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.00 (s, 1 H), 7.72 (dd, J = 9.1, 4.5
Hz, 2 H), 7.29 (dd, J = 9.1, 7.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.1 (d, 1JC,F = 251.3 Hz, C–F),
140.6 (C5), 130.0 (d, 4JC,F = 3.1 Hz), 123.5 (d, 3JC,F = 8.9 Hz), 117.3
(d, 2JC,F = 23.5 Hz).
5-[Chloro(nitro)methyl]-1-(4-nitrophenyl)-1H-tetrazole (18)
Following typical procedure II (reflux, 4 h) gave 18 as a yellowish
solid; yield: 2.47 g (87%); mp 75–76 °C.
IR (KBr): 3424, 3121, 2974, 1934, 1597, 1531, 1494, 1347, 1314,
1089, 1013, 879, 857, 818, 751, 715, 689 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.52 (d, J = 8.1 Hz, 2 H), 7.77 (d,
J = 8.1 Hz, 2 H), 7.27 (s, 1 H, CHCl).
13C NMR (100 MHz, CDCl3): d = 149.5 (C5), 148.6 (Cq-NO2),
137.1 (Cq-N), 126.9 (2 CH), 125.7 (2 CH), 79.6 (CHCl).
MS (DCP, 70 eV): m/z (%) = 284 (1) [M]+, 210 (30) [M – N2 –
NO2]+, 196 (21) [M – NO2 – N3]+, 164 (100) [M – 2 NO2 – N2]+, 122
(65) [PhNO2]+.
HRMS (EI): m/z [M + H]+ calcd for C8H6ClN6O4: 285.0139; found:
285.0135.
MS (DCP, 70 eV): m/z (%) = 164 (3) [M+], 136 (77) [M+ – N2], 109
(100) [M+ – CHN3], 95 (30) [PhF].
HRMS (EI): m/z [M+] calcd for C7H5FN4: 164.0498; found:
164.0497.
1-(4-Chlorophenyl)-1H-tetrazole (22)
Following typical procedure III using 14 (0.50 g, 1.82 mmol) gave,
with no purification as it precipitated in high purity, 22 (0.148 g,
45%) as a yellow solid; mp 152–153 °C (Lit.15 154–156 °C).
5-[Chloro(nitro)methyl]-1-(3,4-dimethoxyphenyl)-1H-tetra-
zole (19)
Typical procedure II (r.t., 1 d) gave 19 as a white solid; yield: 2.81
IR (KBr): 3124, 1902, 1647, 1505, 1463, 1387, 1212, 1092, 1000,
884, 828, 660, 530, 518, 508 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.01 (s, 1 H), 7.69 (d, J = 8.8 Hz,
2 H), 7.58 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 140.4 (C5), 136.1 (Cq), 132.2
(CCl), 130.4 (2 CH), 122.4 (2 CH).
g (94%); mp 116–117 °C.
IR (KBr): 3443, 3002, 2984, 1855, 1604, 1588, 1524, 1468, 1456,
1347, 1286, 1264, 1231, 1187, 1137, 1086, 1016, 859, 848, 814,
769, 759, 639 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.10 (s, 1 H, CHCl), 7.06–7.00
(m, 2 H), 6.95 (d, J = 2.2 Hz, 1 H), 3.97 (s, 3 H, Me), 3.91 (s, 3 H,
Me).
13C NMR (100 MHz, CDCl3): d = 151.8 (C–O), 150.1 (C–O), 149.1
(C5), 124.7 (Cq-N), 118.3 (CH), 111.4 (CH), 108.9 (CH), 79.7
(CHCl), 56.4 (Me), 56.3 (Me).
MS (DCP, 70 eV): m/z (%) = 299 (52) [M]+, 225 (73) [M – N2 –
NO2]+, 211 (12) [M – NO2 – N3]+, 190 (40) [M – Cl – NO2 – N2]+,
151 (100) [NPh(OMe)2]+, 137 (70) [Ph(OMe)2]+.
MS (DCP, 70 eV): m/z (%) = 180 (4) [M+], 152 (92) [M+ – N2], 125
(100) [M+ – CHN3], 111 (17) [PhCl].
HRMS (EI): m/z [M+] calcd for C7H5ClN4: 180.0203; found:
180.0204.
1-(4-Chlorophenyl)-1H-tetrazole (22) by Acidic Hydrolysis with
Sulfuric Acid
At 0 °C, [chloro(nitro)methyl]tetrazole 14 (0.50 g, 1.82 mmol) was
added dropwise to 90% H2SO4 (5 mL) with vigorous stirring. After
10 min the mixture was heated to 100–105 °C for 5 h. Then, the
mixture was cooled to 0 °C and poured onto ice/H2O (50 mL). The
HRMS (EI): m/z [M]+ calcd for C10H10ClN5O4: 299.0421; found:
299.0419.
Synthesis 2012, 44, 885–894
© Thieme Stuttgart · New York

PAPER
Novel Synthesis of 1-Aryl-5-[chloro(nitro)methyl]tetrazoles
893
resulting precipitate was filtered off, washed with H2O (2 × 10 mL)
and finally air dried, affording 22 (0.253 g, 77%).
1H NMR (400 MHz, CDCl3): d = 8.39 (d, J = 8.0 Hz, 2 H), 8.18 (d,
J = 8.2 Hz, 2 H), 7.77–7.66 (m, 2 H), 7.64–7.52 (m, 3 H), 7.16 (s, 2
H, CHCl), 7.04 (d, J = 8.0 Hz, 2 H), 6.86 (s, 1 H).
Acetic N-(4-Fluorophenyl)carbamidic Anhydride (23)
Tetrazole 13 (0.50 g, 1.94 mmol) was added to Ac2O (2 mL) and the
mixture was heated at reflux for 1 h and then allowed to stand over-
night at r.t. without stirring. The resulting precipitate was filtered
off, washed with H2O (3 × 50 mL) and air dried. The acetylated de-
rivative 23 was obtained as a yellow solid; yield: 0.114 g (30%); mp
208–209 °C.
13C NMR (100 MHz, CDCl3): d = 146.3 (Cq), 145.8 (Cq), 143.9
(NCN), 131.7 (CH), 131.6 (CH), 130.9 (Cq), 130.5 (CH), 126.6
(CH), 120.6 (CH), 117.3 (CH), 117.2 (CH), 114.8 (CH), 111.3
(CH), 79.8 (CHCl).
MS (DCP, 70 eV): m/z (%) = 552 (3) [M+], 333 (12), 284 (28), 205
(40), 73 (100).
HRMS (EI): m/z [M]+ calcd for C22H14Cl2N10O4: 552.0577; found:
552.1079.
IR (KBr): 3417, 3237, 3132, 2991, 1717, 1692, 1615, 1570, 1511,
1372, 1266, 1212, 1165, 837, 805, 752, 692, 505 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.69 (s, 1 NH), 10.49 (s, 1
NH), 7.53 (dd, J = 9.4, 5.6 Hz, 2 H), 7.17 (dd, J = 9.4, 8.8 Hz, 2 H),
2.10 (s, 3 H, Me).
N,N¢-Bis[(1E)-1-(1H-benzotriazol-1-yl)-2-chloro-2-nitro-
ethylidene]benzene-1,4-diamine (27)
Following typical procedure I in analogy to 26 using 2 (2.00 g, 6.0
mmol) and p-phenylenediamine (0.38 g, 3.5 mmol) gave 27 (1.08 g,
56%) as a yellow solid; mp 196–197 °C.
13C NMR (100 MHz, DMSO-d6): d = 173.3 (C=O), 158.6 (d,
3
1JC,F = 217.0 Hz), 151.2 (C=NH), 134.1 (Cq), 121.9 (d, JC,F = 8.2
Hz), 115.8 (d, 2JC,F = 22.5 Hz), 23.9 (CH3).
IR (KBr): 3420, 2977, 1667, 1585, 1486, 1451, 1405, 1346, 1294,
1068, 1034, 922, 888, 780, 751, 7134 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.40–8.24 (m, 4 H), 7.83 (s, 2
H, CHCl), 7.78 (s, 4 H, Ph), 7.70–7.55 (m, 4 H).
MS (DCP, 70 eV): m/z (%) = 196 (30) [M+], 137 (72) [M+ – OAc],
111 (37) [FC6H4NH+], 43 (100) [CH3CO+].
HRMS (EI): m/z [M+] calcd for C9H9FN2O2: 196.0648; found:
196.0649.
13C NMR (100 MHz, DMSO-d6): d = 145.0 (Cq), 144.8 (Cq), 144.6
(Cq), 130.9 (Cq), 130.0 (CH), 125.6 (CH), 125.5 (CH), 120.2 (CH),
115.1 (CH), 80.2 (CHCl).
MS (DCP, 70 eV): m/z (%) = 552 (2) [M+], 333 (17), 284 (6), 205
(37), 119 (100) [BztH].
HRMS (EI): m/z [M]+ calcd for C22H14Cl2N10O4: 552.0577; found:
552.0568.
5-[Chloro(nitro)(2H)methyl]-1-(4-fluorophenyl)-1H-tetrazole
(24)
A soln of tetrazole 13 (5 mg, 0.0194 mmol) in CDCl3 (1.5 mL) was
treated with D2O (2 drops). After 1 h, the mixture was dried over 4
Å molecular sieves, transferred into an NMR tube, and subjected to
proton measurement.
1H NMR (400 MHz, CDCl3): d = 7.50 (dd, J = 9.5, 4.6 Hz, 2 H),
7.32 (dd, J = 9.5, 7.0 Hz, 2 H).
(E,E)-N,N¢-Bis[1-(1H-benzotriazol-1-yl)-2-chloro-2-nitro-
ethylidene]biphenyl-4,4¢-diamine (28)
Following typical procedure I in analogy to 26 using 2 (2.00 g, 6.0
mmol) and benzidine (0.65 g, 3.5 mmol) gave 28 (1.01 g, 46%) as
a yellow solid; mp 168–170 °C.
1-[1-(4-Fluorophenyl)-1H-tetrazol-5-yl]methanamine (25)
A soln of tetrazole 13 (0.08 g, 0.31 mmol) in 50% AcOH (2 mL)
was reduced using Zn dust (490 mg, 7.5 mmol) at 0 °C. Then, with-
out the cooling bath, the mixture was stirred for 2 h at r.t. After re-
moval of the zinc salt, the supernatant liquid was neutralized with
sat. NaHCO3. The mixture was extracted with EtOAc (2 × 50 mL),
washed with brine (30 mL), dried (anhyd CaCl2), and the solvent
was evaporated to give 25 as a yellow solid; yield: 0.035 g (59%);
mp 70–71 °C.
IR (KBr): 3425, 2928, 1660, 1584, 1487, 1451, 1411, 1349, 1294,
1066, 1039, 1003, 884, 856, 769, 750, 711 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.45 (d, J = 8.0 Hz, 2 H), 8.34
(d, J = 8.0 Hz, 2 H), 8.09 (s, 2 H, CHCl), 7.98 (d, J = 8.0 Hz, 4 H,
Ph), 7.85–7.65 (m, 6 H), 7.32 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 145.3, 143.3, 137.2, 131.2,
130.6, 128.0 (CH), 127.7 (CH), 126.8 (CH), 121.1 (CH), 120.2
(CH), 114.6 (CH), 80.7 (CHCl).
MS (DCP, 70 eV): m/z (%) = 628 (2) [M+], 409 (12), 322 (45), 268
(25), 120 (100).
HRMS (EI): m/z [M + H]+ calcd for C28H19Cl2N10O4: 629.0968;
found: 629.0955.
IR (KBr): 3400, 3330, 1601, 1505, 1465, 1260, 1223, 1155, 1117,
1096, 1012, 845, 610, 567 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.62 (dd, J = 9.3, 4.5 Hz, 2 H),
7.30 (dd, J = 9.3, 7.5 Hz, 2 H), 4.16 (s, 2 H, CH2), 1.83 (br s, 2 H,
NH2).
13C NMR (100 MHz, CDCl3): d = 163.3 (d, 1JC,F = 251.8 Hz), 155.4
4
3
(C5), 129.8 (d, JC,F = 3.4 Hz), 126.7 (d, JC,F = 8.9 Hz), 117.1 (d,
2JC,F = 23.3 Hz), 35.6 (CH2).
1,3-Bis{5-[chloro(nitro)methyl]-1H-tetrazol-1-yl}benzene (29)
Following typical procedure II using 26 (1.30 g, 2.3 mmol) and
NaN3 (0.38 g, 5.2 mmol) at r.t. for 1 d gave spectroscopically pure
29 (0.30 g, 33%) as a black solid; mp 126–127 °C.
MS (DCP, 70 eV): m/z (%) = 193 (8) [M+], 177 (20) [M+ – NH2],
149 (100) [M+ – NH2 – N2].
HRMS (EI): m/z [M + H]+ calcd for C8H9FN5: 194.0842; found:
194.0840.
IR (KBr): 3426, 2971, 1594, 1479, 1347, 1121, 1085, 886, 800, 687
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.61 (s, 1 H), 8.31 (s, 1 H),
8.15 (s, 2 H, CHCl), 8.18–8.05 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 150.0 (NCqN), 133.0 (NCq),
132.2 (CH), 129.5 (CH), 123.5 (CH), 80.9 (CHCl).
MS (DCP, 70 eV): m/z (%) = 400 (8) [M+], 312 (6) [M+ – N3 –
NO2], 266 (20) [M+ – N3 – 2 NO2], 238 (45) [M+ – CClHNO2 –
CN4], 190 (52), 164 (75), 90 (100).
N,N¢-Bis[(1E)-1-(1H-benzotriazol-1-yl)-2-chloro-2-nitro-
ethylidene]benzene-1,3-diamine (26)
Following typical procedure I (–10 °C, 3 h, r.t., 1 d) using 2 (3.00 g,
9.0 mmol) and m-phenylenediamine (0.48 g, 4.5 mmol). The pre-
cipitate that resulted from the workup procedure was purified by
column chromatography (CHCl3–PE, 3:1) affording 26 (1.62 g,
65%) as a yellow solid; mp 109–110 °C.
IR (KBr): 3452, 2962, 1665, 1587, 1487, 1451, 1411, 1347, 1294,
1207, 1065, 1038, 922, 889, 790, 769, 749, 697, 494 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 885–894

894
V. A. Zapol’skii et al.
PAPER
HRMS (EI): m/z [M + H]+ calcd for C10H7Cl2N10O4: 401.0029;
(3) Scribner, R. M. J. Org. Chem. 1965, 30, 3657.
found: 401.0087.
(4) (a) Katritzky, A. R.; Belyakov, S. A. Aldrichimica Acta
1998, 35. (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko,
O. V. Chem. Rev. 1998, 98, 409. (c) Katritzky, A. R.;
Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.; Steel, P.
J. J. Org. Chem. 2005, 70, 9211. (d) Katritzky, A. R.; Cai,
C.; Suzuki, K.; Singh, S. K. J. Org. Chem. 2004, 69, 811.
(5) Clark, N. G.; Hams, A. F.; Leggetter, B. E. Nature 1963,
200, 171.
1,4-Bis{5-[chloro(nitro)methyl]-1H-tetrazol-1-yl}benzene (30)
Following typical procedure II using 27 (1.20 g, 2.2 mmol) and
NaN3 (0.31 g, 4.8 mmol) at r.t. for 2 d gave 30 (0.70 g, 80%) as a
yellow solid; mp 149–150 °C.
IR (KBr): 3083, 2995, 1920, 1655, 1585, 1522, 1349, 1237, 1107,
1084, 1048, 1017, 986, 875, 848, 818, 760, 697, 572 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.51 (s, 2 H, CHCl), 8.14 (s, 4
H).
13C NMR (100 MHz, DMSO-d6): d = 149.6 (NCqN), 134.5 (NCq),
128.1 (CH), 80.6 (CHCl).
MS (DCP, 70 eV): m/z (%) = 400 (2) [M+], 266 (10) [M+ – N3 – 2
NO2], 238 (12) [M+ – CClHNO2 – CN4]. 190 (28), 164 (37), 97
(100).
(6) (a) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(b) Gunn, S. J.; Baker, A.; Bertram, R. D.; Warriner, S. L.
Synlett 2007, 2643.
(7) X-ray crystal structure analysis for C8H5ClFN5O2,
M = 257.62 g mol–1: A suitable single crystal of the title
compound was selected under a polarization microscope and
mounted in a glass capillary (d = 0.3 mm). The crystal
structure was determined by X-ray diffraction analysis using
graphite monochromated MoKa radiation (0.71073 Å)
[T = 223(2) K], whereas the scattering intensities were
collected with a single crystal diffractometer (STOE IPDS
II). The crystal structure was solved by Direct Methods
using SHELXS-978 and refined using alternating cycles of
least squares refinements against F2 (SHELXL-978). All
non-H atoms were located in Difference Fourier maps and
were refined with anisotropic displacement parameters. The
H positions were determined by a final Difference Fourier
Synthesis. C8H5ClFN5O2 crystallized in the orthorhombic
space group Pna21 (No. 33), lattice parameters a = 13.458(4)
Å, b = 6.058(2) Å, c = 25.281(9) Å, b = 103.88(3)°,
V = 2061.1(1) Å3, Z = 8, dcalc = 1.660 g cm–3, F(000) = 1040
using 3597 independent reflections and 348 parameters.
R1 = 0.0605, wR2 = 0.1023 [I > 2s(I)], goodness of fit on
F2 = 1.085, residual electron density = 0.672 and –0.424
e Å–3. Further details of the crystal structure investigations
have been deposited with the Cambridge Crystallographic
Data Center, CCDC 826045. Copies of this information may
be obtained free of charge from The Director, CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [Fax:
+44 (1223)336 033; e-mail: fileserv@ccdc.ac.uk or
http://www.ccdc.cam.ac.uk].
HRMS (EI): m/z [M]+ calcd for C10H6Cl2N10O4: 399.9951; found:
399.9954.
4,4¢-Bis{5-[chloro(nitro)methyl]-1H-tetrazol-1-yl}biphenyl (31)
Following typical procedure II using 28 (1.30 g, 2.1 mmol) and
NaN3 (0.30 g, 4.6 mmol) at r.t. for 1 d gave 31 (0.90 g, 90%) as a
white solid; mp 175–176 °C.
IR (KBr): 2964, 1918, 1626, 1590, 1507, 1346, 1086, 1009, 996,
829, 758, 716, 690, 551 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.48 (s, 2 H, CHCl), 8.16 (d,
J = 8.0 Hz, 4 H), 7.91 (d, J = 8.0 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 149.7 (NCqN), 141.3 (Cq),
132.1 (NCq), 128.8 (CH), 126.7 (CH), 80.6 (CHCl).
MS (DCP, 70 eV): m/z (%) = 476 (1) [M+], 429 (1) [M+ – HNO2],
402 (1) [M+ – N2 – NO2], 166 (100).
HRMS (EI): m/z [M]+ calcd for C16H10Cl2N10O4: 476.0264; found:
476.0031.
Acknowledgment
(8) Sheldrick, G. M. SHELXS 97 and SHELXL 97, Program for
the Solution and Refinement of Crystal Structures;
University of Göttingen: Germany, 1997.
We thank Dr. G. Dräger, University of Hannover, Germany, for
high resolution mass spectra.
(9) El Kaim, L.; Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261.
(10) Koldobskii, G. I. Russ. J. Org. Chem. 2006, 42, 469.
(11) (a) Schuren, F. H. J.; Thijssen, H. M. W. M.; Montijn, R. C.
EP 1,769,796, 2007. (b) Caldwell, C. G.; Chiang, Y.; Dorn,
C.; Finke, P.; Hale, J.; Maccoss, M.; Mills, S.; Robichaud, A.
US 5,877,191, 1999. (c) Chen, L.; Dillon, M. P.; Feng, L.;
Hawley, R. C.; Yang, M. WO 2009,077,371, 2009.
(d) Denhart, D. J.; Degnan, A. P.; Tora, G. O.; Han, Y.;
Ramkumar, R.; Ditta, J. L.; Gillman, K. W. WO
2007,121,389, 2007.
(12) Su, W. Eur. J. Org. Chem. 2006, 12, 2723.
(13) Kundu, D.; Majee, A.; Hajra, A. Tetrahedron Lett. 2009, 50,
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(14) (a) Mueller, B.; Sauter, H.; Wingert, H.; Koenig, H.; Roehl,
F.; Ammermann, E.; Lorenz, G. EP 579,071, 1994.
(b) Neunhoeffer, H.; Metz, H.-J. Liebigs Ann. Chem. 1983,
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Hoeffken, H. W.; Pfeiffer, T.; Koser, S.; Mack, H. US
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Synthesis 2012, 44, 885–894
© Thieme Stuttgart · New York