Syntheses of 5-(3-arylsydnon-4-yl)tetrazole derivatives

Article abstract of DOI:10.1002/jccs.200200056

3-Arylsydnone-4-carbohydroximic acid chlorides (1) could react with sodium azide to produce the corresponding 3-arylsydnone-4-carbazidoximes (2), but not 1-hydroxytetrazoles 3. Treatment of 3-arylsydnone-4-carbazidoximes (2) with acid chlorides such as ac

Full text of DOI:10.1002/jccs.200200056

Journal of the Chinese Chemical Society, 2002, 49, 361-368
361
Syntheses of 5-(3-Arylsydnon-4-yl)tetrazole Derivatives
Mei-Hsiu Shiha,b
(
), Mei-Jin Leea (
) and Mou-Yung Yeha* (
)
aDepartment of Chemistry, National Cheng Kung University, Tainan, Taiwan 701, R.O.C.
bDepartment of Chemical Engineering, Southern Taiwan University of Technology,
Tainan, Taiwan 710, R.O.C.
3-Arylsydnone-4-carbohydroximic acid chlorides (1) could react with sodium azide to produce the corre-
sponding 3-arylsydnone-4-carbazidoximes (2), but not 1-hydroxytetrazoles 3. Treatment of 3-arylsydnone-
4-carbazidoximes (2) with acid chlorides such as acetyl chloride (4a), propionyl chloride (4b) and benzoyl
chloride (4c) in the presence of excess triethylamine generated the derivatives of the azidoximes 5. To obtain
the desired tetrazoles, the azidoximes 2 should first cyclize directly with acetyl chloride (4a) or propionyl
chloride (4b) to afford the acetyl or propionyl derivatives 6. The cyclized tetrazole derivatives 6 underwent
deacylation upon heating in ethanol to give 1-hydroxy-5-(3-arylsydnon-4-yl)tetrazoles (3).
INTRODUCTION
Numerous sydnone compounds have been found to
and we used them as starting materials to prepare 4-hetero-
cyclic sydnones.23-28 To obtain 4-tetrazole substituted syd-
nones, carbohydroximic acid chlorides 1a-1d were first
treated with sodium azide in aqueous methanol solution
(Scheme I). The reaction solutions were stirred at 0 °C for 1-2
h to give products 2a-2d. Following recrystallization, the
yields of the reactions ranged from 66-74%.
possess unique pharmacological activities.1-9 Meanwhile,
various substituted tetrazoles also have biological properties
and behavior. Such heterocyclic compounds have been exten-
sively applied in many fields. For example, 5-(2-anilino-
phenyl)tetrazoles have exhibited antiinflammatory activ-
ity;10 5-aminotetrazoles have been applied as plant growth
regulators to increase tomato yields and accelerate ripen-
ing;11 and 1-alkyl-5-aminotetrazoles and 1-aryl-5-dialkyl-
amino-methyltetrazoles have been identified as central ner-
vous stimulants.12 Furthermore, many reports have empha-
sized the biological and pharmacological activities of tetra-
zoles.13-18 The most common routes for synthesizing tetra-
zoles are the conversion of nitriles to 5-substituted tetrazoles
by reaction with azide ion,18-20 or the treatment of carbohy-
droximic acid chlorides with sodium azide to obtain the cor-
responding azidoximes which then rearrange themselves or
cyclize to tetrazole derivatives by other reagents.21,22 The au-
thors have already studied numerous aspects of 3-aryl-
sydnone-4-carbohydroximic acid chlorides (1),23-28 and thus
this work focuses on the syntheses of 4-tetrazole substituted
sydnones through the reaction of starting materials 1 and so-
dium azide. The corresponding 3-arylsydnone-4-carbazidox-
imes (2) were obtained first and then cyclized with acid chlo-
rides to produce the desired products.
Scheme I
N3
OH
Ar
N
N
Cl
OH
N
Ar
N
O
N
O
N
MeOH/H2O
2
NaN3
+
o C
N
0
O
O
N
N
1
Ar
N
N
OH
N
O
O
3
1a, 2a : Ar = C6H5
1c, 2c : Ar = p-CH3OC6H4
1b, 2b : Ar = p-CH3C6H4
1d, 2d : Ar = p-CH3CH2OC6H4
The reported infrared spectra of an azido group pos-
sesses a characteristic absorption band at 4.67 , while a large
number of tetrazoles show no such band in this region.29,30
The experimental results herein reveal that the characteristic
IR frequencies 2160-2090 cm-1 ( N3) agree with the azidox-
imes structures of these new compounds 2. Meanwhile, the
1H NMR spectra taken at room temperature in acetone-d6 re-
vealed a sharp signal from the OH proton in the 11-12 ppm
region, further indicating that these compounds exist as
RESULTS AND DISCUSSION
Our previous studies found 3-arylsydnone-4-carbohy-
droximic acid chlorides (1) to be stable at room temperature,

362 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Shih et al.
open-chain azidoximes and do not isomerize to 1-hydroxy-
tetrazoles 3 (Scheme I).
Scheme II
Many published reports30-35 indicate that the azidoazo-
methine-tetrazole equilibrium was influenced by the elec-
tronic properties of R, R substituents. The azido group of the
azidoxime structure originally had a linear form (A). Mean-
while, the -electron in azomethine double bond delocaliza-
tion to the azido group could make the three nitrogens bend
away from the linear arrangement, and the end-nitrogen of
the azido group comes within bonding distance as resonance
form (B) to cyclize to afford the tetrazole form (C). The na-
ture of groups R, R could determine whether a given com-
pound exists in the azido form (A) or the tetrazole form (C).
The tetrazole tautomer is stabilized by electron-donating
groups or low electronegative atoms, while the azido tauto-
mer is stabilized by electron-withdrawing groups or more
electronegative atoms. Since the electron-donating groups of
R, R can stabilize the bent resonance form (B), the cycliza-
tion becomes easy.
N3
O
N3
Ar
Ar
O
N
C
N
OH
Et3N
N
O
R
N
+
R
Cl
N
N
O
O
O
O
4a~4c
4b : R = C2H5
5aa~5dc
4c : R = C6H5
2a~2d
4a : R = CH3
treatment of 3-arylsydnone-4-carbazidoximes (2) with acid
catalyst would obtain not only the rearranged 1-hydroxy-5-
(3-arylsydnon-4-yl)tetrazoles (3) but also 3-arylsydnone-4-
carbonitriles. Meanwhile, compounds 3 are too soluble in or-
ganic solvent to isolate them in pure form from the mixture by
recrystallization. Consequently, it is difficult to obtain the
tetrazoles directly from the azidoximes, and another route for
synthesizing the desired tetrazoles needs to be developed.
Numerous tests found that mixing 3-arylsydnone-4-
carbazidoximes (2a-2d) with acetyl or propionyl chlorides
(4a-4b) in a benzene solution at room temperature and then
stirring for 24-36 hours obtained high yields of 1-acetoxy-
5-(3-arylsydnon-4-yl)tetrazoles (6aa-6da) or 1-propion-
oxy-5-(3-arylsydnon-4-yl)tetrazoles (6ab-6db). Such series
of 1-acyloxytetrazoles are very stable at room temperature
and easy to isolate in pure form. These compounds could be
recrystallized from benzene and, then, undergo deacylation
by being heated in ethanol at 50-60 C to produce good yields
of the deacylated products 1-hydroxy-5-(3-arylsydnon-4-
yl)tetrazoles (3) (Scheme III, Table 2). The IR spectrum of
6aa-6db showed no absorption bands in the 2200-1900 cm-1
region, suggesting that cyclization to the tetrazole ring oc-
curred during the reaction.21 The deacylated products 3a-3d
revealed no IR characteristic absorption bands in the region
for the azido group, a strong and very broad band 3000-2200
cm-1 of OH was found.
R
N
R'
R'
R'
-
R
R
+
N
N
N
N
N
+
N
N
N
N
N
-
N
(C)
(B)
(A)
Herein, the reason that the linear azidoximes 2 could
not directly rearrange into 1-hydroxytetrazoles 3 might be
owing to the strong electronegativity of the hydroxy group.
Numerous azidoximes have been isolated in pure forms, and
the stability of such compounds varies widely. The synthe-
sized 3-arylsydnone-4-carbazidoximes 2 could be recrys-
tallized from ethanol. However, when stored at room temper-
ature for several days, compounds 2 decomposed slightly to
3-arylsydnone-4-carbonitriles accompanied with red nitrous
oxide gas, a process that has been described in detail,36,37 and
thus compounds 2 should be stored in cool conditions.
By the Schotten-Baumann method, 3-arylsydnone-4-
carbazidoximes (2a-2d) could react with carboxylic acid
chlorides (4a-4c) in the presence of an excess of triethyl-
amine to obtain linear products, namely O-substituted-3-
arylsydnone-4-carbazidoximes (5aa-5dc), shown in Scheme
II and Table 1. The structures of compounds 5 were also con-
firmed by the presence of strong N3 bands in the 2200-2100
cm-1 region.
Among these new products, the colorless crystal 6aa
obtained was analytically pure and suitable for X-ray struc-
Table 1. The Yields of Azidoximes Derivatives (5aa-5dc)
Starting
Material
Acid
Chloride
Product Yield
2a (Ar C6H5)
2a (Ar C6H5)
2a (Ar C6H5)
2b (Ar p-CH3C6H4)
2c (Ar p-CH3OC6H4)
2d (Ar p-C2H5OC6H4)
4a (R CH3)
4b (R C2H5)
4c (R C6H5)
4c (R C6H5)
4c (R C6H5)
4c (R C6H5)
5aa
5ab
5ac
5bc
5cc
5dc
45
51
87
91
92
89
By the aid of an acid catalyst, the azidoximes would re-
arrange themselves into tetrazoles. But the acid catalyst
would simutaneously enhance the decomposition of azidox-
imes which splits off nitrogen and hyponitrous acid with the
quantitative formation of corresponding nitriles.36,37 The
Recrystallization yield

Syntheses of 5-(3-Arylsydnon-4-yl)tetrazole Derivatives
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 363
Table 2. The Yields of 4-Tetrazole Substituted Sydnones (6aa-6db, 3a-3d)
Starting
Material
Reagent
Product
Yield*
%
2a (Ar C6H5)
2b (Ar p-CH3C6H4)
2c (Ar p-CH3OC6H4)
2d (Ar p-C2H5OC6H4)
2a (Ar C6H5)
4a (R CH3)
4a (R CH3)
4a (R CH3)
4a (R CH3)
4b (R C2H5)
4b (R C2H5)
4b (R C2H5)
4b (R C2H5)
EtOH
6aa
6ba
6ca
6da
6ab
6bb
6cb
6db
3a
76
67
55
63
54
50
61
65
89
85
80
84
2b (Ar p-CH3C6H4)
2c (Ar p-CH3OC6H4)
2d (Ar p-C2H5OC6H4)
6aa (Ar C6H5, R = CH3)
6ba (Ar p-CH3C6H4, R = CH3)
6ca (Ar p-CH3OC6H4 , R = CH3)
6da (Ar p-C2H5OC6H4 , R = CH3)
EtOH
EtOH
EtOH
3b
3c
3d
Recrystallization yield
protonation of the C-bonded azido N atom bearing the high-
est negative charge, as shown in Scheme IV. In the mecha-
nism, the -electron of azomethine double bond can be shifted
towards the protonated N atom, and the lone pair of terminal
N atoms can form a new bond with the azomethine N atom.
The electron-withdrawing CO group acts to reduce the elec-
tron density on the azomethine N atom, and thus assists in
cyclisation. On the other hand, both the acetoxy and pro-
pionoxy groups can inhibit the decomposition, thus creating
very pure and stable compounds 6.
Scheme III
N
N
N
N3
OH
O
Ar
Ar
N
N
O
N
O
R
N
+
N
Cl
N
R
O
O
O
O
(2a~2d)
(4a~4b)
(6aa~6db)
N
N
N
Ar
N
4a
4b
: R = CH3
: R = C2H5
EtOH
N
OH
0 C
50~60
N
Table 3. Crystal Data of Compound 6aa
O
O
(3a~3d)
Diffractometer
Rigaku AFC7S
Formula
C11H8N6O4
288.22
orthorhombic
Pbca ( 61)
34.708(8)
10.753(2)
6.734(2)
2513(3)
8
1.523
1184.00
1.13
0.42 0.48 0.54
298
-2
ture determination. Fig. 1 shows the molecular structure of
1-acetoxy-5-(3-phenylsydnon-4-yl)tetrazole (6aa), while
Tables 3-6 summarize details of the crystal data.
Formula weight
Crystal system
Space group
a/Å
The above results support the conjecture that cyclisa-
tion of O-acylazidoximes to tetrazoles can be initiated by
b/Å
c/Å
V/Å3
Z
Dcalc (g cm-3)
F000
(Mo, K ), cm-1
Crystal size (mm)
Temperature (K)
Scan type
2
max, deg
52.0
Reflections measured
No. observations [I 3.00 (I)]
No. variables
2892
1597
190
Residuals: R; Rw
GoF
0.055; 0.070
1.99
Fig. 1. Molecular structure of 1-acetoxy-5-(3-phenyl-
sydnon-4-yl)tetrazole (6aa).

364 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Table 4. Selected Bond Distances Å for Compound 6aa
Shih et al.
Scheme IV
N
O
O(1)-N(2)
O(2)-C(2)
O(3)-C(10)
N(1)-N(2)
N(1)-C(3)
N(3)-C(9)
N(5)-N(6)
C(1)-C(2)
C(3)-C(4)
C(4)-C(5)
C(6)-C(7)
C(10)-C(11)
1.365(3)
1.204(3)
1.439(4)
1.290(3)
1.450(3)
1.323(3)
1.330(3)
1.410(4)
1.368(4)
1.385(4)
1.372(5)
1.467(4)
O(1)-C(2)
O(3)-N(6)
O(4)-C(10)
N(1)-C(1)
N(3)-N(4)
N(4)-N(5)
N(6)-C(9)
C(1)-C(9)
C(3)-C(8)
C(5)-C(6)
C(7)-C(8)
1.416(4)
1.368(3)
1.179(4)
1.360(3)
1.364(3)
1.293(3)
1.341(3)
1.441(4)
1.375(4)
1.372(5)
1.378(4)
+
N
-
N
O
N3
Ar
Ar
O
N
N
OH
_
HCl
N
O
R
N
+
Cl
R
N
N
O
O
O
N
+
N
+
N
N
..
N
H
H
N
O
O
H+
N
Ar
Ar
N
N
O
R
N
O
R
N
N
O
N
O
O
O
Table 5. Selected Bond Angles/deg for Compound 6aa
..
N(2)-O(1)-C(2)
N(2)-N(1)-C(1)
C(1)-N(1)-C(3)
N(4)-N(3)-C(9)
N(4)-N(5)-N(6)
O(3)-N(6)-C(9)
N(1)-C(1)-C(2)
C(2)-C(1)-C(9)
O(1)-C(2)-C(1)
N(1)-C(3)-C(4)
C(4)-C(3)-C(8)
C(4)-C(5)-C(6)
C(6)-C(7)-C(8)
N(3)-C(9)-N(6)
N(6)-C(9)-C(1)
110.7(2)
114.5(2)
127.8(2)
106.1(2)
105.2(2)
129.1(2)
105.9(2)
130.2(2)
103.4(2)
119.6(3)
122.5(3)
120.6(3)
120.5(3)
106.5(2)
126.1(2)
N(6)-O(3)-C(10)
N(2)-N(1)-C(3)
O(1)-N(2)-N(1)
N(3)-N(4)-N(5)
O(3)-N(6)-N(5)
N(5)-N(6)-C(9)
N(1)-C(1)-C(9)
O(1)-C(2)-O(2)
O(2)-C(2)-C(1)
N(1)-C(3)-C(8)
C(3)-C(4)-C(5)
C(5)-C(6)-C(7)
C(3)-C(8)-C(7)
N(3)-C(9)-C(1)
O(3)-C(10)-O(4)
112.2(2)
117.7(2)
105.5(2)
111.2(2)
119.9(2)
110.9(2)
123.6(2)
119.6(3)
137.0(3)
117.9(2)
118.1(3)
120.1(3)
118.3(3)
127.3(2)
120.3(3)
:
+
N
N
N
-
+
N
H
N
+
O
H
O
Ar
N
Ar
N
N
O
R
N
O
N
R
N
N
O
O
O
O
N
O
N
O
_
H+
Ar
N
N
O
R
N
O
O(3)-C(10)-C(11) 107.5(3)
O(4)-C(10)-C(11) 132.2(3)
CONCLUSION
Table 6. Atomic Coordinates for Compound 6aa
In summary, products obtained from the reaction of
3-arylsydnone-4-carbohydroximic acid chlorides (1) with so-
dium azide exist as open-chain 3-arylsydnone-4-carbazidox-
imes (2) and do not isomerise to 1-hydroxytetrazoles 3. This
study has described an adequate synthetic method for prepar-
ing 1-hydroxy-5-(3-arylsydnon-4-yl)tetrazoles (3) through
the deacylation of 1-acyloxy-5-(3-arylsydnon-4-yl)tetra-
zoles (6) which are stable at room temperature and good pre-
cursors. The treatment of 4-carbazidoximes 2 with acetyl or
propionyl chlorides in benzene solvent led to high yields of
the appropriate precursors 1-acyloxytetrazoles 6 being ob-
tained.
Atom
x
y
z
O(1)
O(2)
O(3)
O(4)
N(1)
N(2)
N(3)
N(4)
N(5)
N(6)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
0.93370(6)
0.96114(6)
0.93007(6)
0.92857(7)
0.87706(6)
0.89865(7)
0.83750(6)
0.83268(7)
0.86547(7)
0.89183(6)
0.89475(7)
0.93277(8)
0.83777(7)
0.81242(9)
0.77484(9)
0.76389(8)
0.79015(9)
0.82765(8)
0.87513(7)
0.94715(9)
0.98753(9)
0.1866(2)
0.0650(2)
-0.1715(2)
-0.0556(2)
0.1150(2)
0.2003(2)
-0.0638(2)
-0.1662(2)
-0.2140(2)
-0.1425(2)
0.0431(2)
0.0883(3)
0.1056(3)
0.2003(3)
0.1867(4)
0.0825(4)
-0.0100(3)
0.0008(3)
-0.0504(2)
-0.1182(3)
-0.1581(3)
0.1036(3)
-0.1324(4)
-0.2573(3)
-0.5399(4)
0.1170(3)
0.1928(4)
-0.1605(4)
-0.2775(4)
-0.3271(4)
-0.2404(3)
-0.0217(4)
-0.0364(5)
0.1886(4)
0.1528(4)
0.2184(5)
0.3214(5)
0.3587(5)
0.2935(5)
-0.1341(4)
-0.4326(5)
-0.4390(6)
EXPERIMENTAL SECTION
All melting points were determined on a Yanaco MP-J3
micromelting point apparatus and were uncorrected. IR spec-
tra were recorded on a Hitachi 270-30 Infrared Spectro-

Syntheses of 5-(3-Arylsydnon-4-yl)tetrazole Derivatives
photometer. Mass spectra were measured on a VG 70-250S
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 365
3-(4 -Methoxyphenyl)sydnone-4-carbazidoxime (2c)
White crystals from EtOH; yield 69%; mp 141-142 C;
IR (KBr) 3322 ( O-H), 2152, 2122, 2098 ( N3), 1755 (
C=O) cm-1; 1H NMR (acetone-d6), 3.94 (s, 3H), 7.22 (d, J =
9.1 Hz, 2H), 7.72 (d, J = 9.1 Hz, 2H), 11.13 (s, 1H); EIMS (20
eV) m/z (%): 276 (M+, 3), 218 (M+-NO-CO, 62), 159 (M+-
1
GC/MS/MS spectrometer. H NMR spectra were run on a
Bruker AMX-200 NMR spectrometer, using TMS as internal
standard. Elemental analyses were taken with a Heraeus
CHN-O-Rapid Analyzer. X-ray spectra were performed on a
Rigaku AFC7S diffractometer.
+
NO-CO-N3-OH, 100); 107 (CH3OC6H4 , 48); Anal. Calcd for
Starting Materials
C10H8N6O4: C, 43.49; H, 2.92; N, 30.43. Found: C, 43.46; H,
3.00; N, 30.45.
3-Phenylsydnone-4-carbohydroximic acid chloride
(1a), 3-(4 -methylphenyl)sydnone-4-carbohydroximic acid
chloride (1b), 3-(4 -methoxyphenyl)sydnone-4-cabohydrox-
imic acid chloride (1c) and 3-(4 -ethoxyphenyl)sydnone-4-
carbohydroximic acid chloride (1d) were prepared according
to the literature.23
3-(4 -Ethoxyphenyl)sydnone-4-carbazidoxime (2d)
White crystals from benzene; yield 73%; mp 139-140
C; IR (KBr) 3304 ( O-H), 2146, 2122, 2092 ( N3), 1752 (
C=O) cm-1; 1H NMR (acetone-d6), 1.37 (t, J = 6.9 Hz, 3H),
4.14 (q, J = 6.9 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 7.71 (d, J =
9.1 Hz, 2H), 11.15 (s, 1H); EIMS (20 eV) m/z (%): 290 (M+,
3), 232 (M+-NO-CO, 77), 173 (M+-NO-CO-N3-OH, 100);
Reaction of 3-arylsydnone-4-carbohydroximic acid chlo-
rides (1a-1d) with sodium azide
+
Typical procedure: To an ice cooled solution of sodium
azide (71.5 mg, 1.1 mmol) in methanol (4 mL) with distilled
water (1 mL), 3-phenylsydnone-4-carbohydroximic acid
chloride (239.5 mg, 1 mmol) was slowly added over 0.5 h.
After the addition was completed, stirring was continued at 0
C for an additional 2 h. The precipitating solid was collected
by filtration, washed with ethanol (95%) and a practically
pure solid (228.5 mg) was obtained. The solid could be
recrystallized from ethanol to afford 3-phenylsydnone-4-
carbazidoxime (2a) as white crystal (183.5 mg, 74%). The
chemical and physical spectral characteristics of these prod-
ucts (2a-2d) are given below.
121 (C2H5OC6H4 , 68); Anal. Calcd for C11H10N6O4: C,
45.52; H, 3.47; N, 28.96. Found: C, 45.51; H,3.51; N, 28.80.
Acylation of 3-arylsydnone-4-carbazidoximes(2a-2d) in
the presence of base
General procedure: To an ice cooled solution of 3-
phenylsydnone-4-carbazidoxime (2a, 123 mg, 0.5 mmol) in
benzene (5 mL), triethylamine (81 mg, 0.8 mmol) was added.
The mixed base solution was stirred at 0 C, and acetyl chlo-
ride (47 mg, 0.6 mmol) was added dropwise. A white solid
was produced, and the reaction mixture was kept stirring at 0
C for an additional 20 minutes. Then the reaction mixture
was concentrated and the obtained solid was washed with
cooling water and collected by filtration. The solid could be
recrystallized from ethyl acetate/n-hexane to afford O-acetyl-
3-phenylsydnone-4-carbazidoxime (5aa) as white crystal (65
mg, 45%). The chemical and physical spectral characteristics
of these products (5aa-5dc) are given below.
3-Phenylsydnone-4-carbazidoxime (2a)
White crystals from EtOH; yield 74%; mp 147-148 C;
IR (KBr) 3324 ( O-H), 2152, 2128, 2092 ( N3), 1755 (
C=O) cm-1; 1H NMR (acetone-d6), 7.78-8.02 (m, 5H), 11.11
(s, 1H); EIMS (20 eV) m/z (%): 246 (M+, 3), 188 (M+-NO-
CO, 88), 129 (M+-NO-CO-N3-OH, 100). Anal. Calcd for
C9H6N6O3: C, 43.91; H, 2.46; N, 34.14. Found: C, 43.94; H,
2.48; N, 34.13.
O-Acetyl-3-phenylsydnone-4-carbazidoxime (5aa)
mp 90-91 C; IR (KBr) 2174, 2152, 2128 ( N3), 1799
( C=O), 1767 ( C=O) cm-1; 1H NMR (acetone-d6), 1.92 (s,
3H), 7.60-7.87 (m, 5H); EIMS (20 eV) m/z (%): 288 (M+, 2),
3-(4 -Methylphenyl)sydnone-4-carbazidoxime (2b)
Pale yellow crystals from benzene; yield 66%; mp
135-136 C; IR (KBr) 3310 ( O-H), 2152, 2122, 2098 ( N3),
1755 ( C=O) cm-1; H NMR (acetone-d6), 2.49 (s, 3H),
+
230 (M+-NO-CO, 14), 188 (M+-NO-CO-N3, 28), 77 (C6H5 ,
100); Anal. Calcd for C11H8N6O4: C, 45.84; H, 2.80; N, 29.16.
Found: C, 46.06; H, 2.90; N, 28.98.
1
7.52 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 11.11 (s,
1H); EIMS (20 eV) m/z (%): 260 (M+, 2), 202 (M+-NO-CO,
O-Propionyl-3-phenylsydnone-4-carbazidoxime (5ab)
mp 101-102 C; IR (KBr) 2200, 2146 ( N3), 1780 (
C=O), 1767 ( C=O) cm-1; 1H NMR (acetone-d6), 0.95 (t, J
= 7.4 Hz, 3H), 2.24 (q, J = 7.4 Hz, 2H), 7.06-7.87 (m, 5H);
+
62), 143 (M+-NO-CO-N3-OH, 88); 91 (CH3C6H4 , 100);
Anal. Calcd for C10H8N6O3: C, 46.16; H, 3.10; N, 32.30.
Found: C, 46.24; H, 3.12; N, 32.32.

366 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Shih et al.
+
EIMS (20 eV) m/z (%): 244 (M+-NO-CO, 4), 77 (C6H5 , 98),
57 (C2H5 CO+, 98); Anal. Calcd for C12H10N6O4: C, 47.69; H,
3.33; N, 27.80. Found: C, 47.80; H, 3.38; N, 27.59.
utes. The reaction mixture was kept stirring at room tempera-
ture for about 24-36 h until the reaction was completed. The
resulting yellow clear solution was concentrated and filtered.
The obtained white solid was recrystallized from benzene to
afford 1-acetoxy-5-(3-phenylsydnon-4-yl)tetrazole (6aa,
108.8 mg, 76%) as colorless crystals. The chemical and phys-
ical spectral characteristics of tetrazole derivatives 6aa-6db
are given below.
O-Benzoyl-3-phenylsydnone-4-carbazidoxime (5ac)
mp 103-104 C; IR (KBr) 2185, 2146 ( N3), 1779 (
C=O), 1767 ( C=O) cm-1; 1H NMR (acetone-d6), 7.80-8.21
(m, 10H); EIMS (20 eV) m/z (%): 250 (M+-NO-CO-N3, 4),
105 (C6H5CO+, 100); Anal. Calcd for C16H10N6O4: C, 54.86;
H, 2.88; N, 23.99. Found: C, 54.79; H, 2.93; N, 23.85.
1-Acetoxy-5-(3-phenylsydnon-4-yl)tetrazole (6aa)
mp 151-152 C; IR (KBr) 1839 ( C=O), 1773 ( C=O)
1
O-Benzoyl-3-(4 -methylphenyl)sydnone-4-carbazidoxime
(5bc)
cm-1; H NMR (acetone-d6), 2.54 (s, 3H), 7.81-8.01 (m,
5H); EIMS (20 eV) m/z (%): 288 (M+, 1), 188 (M+-NO-CO-
N 3, 100); Anal. Calcd for C11H8N6O4: C, 45.84; H, 2.80; N,
29.16. Found: C, 45.85; H, 2.87; N, 29.12.
mp 127-128 C; IR (KBr) 2187, 2145 ( N3), 1779 (
C=O) cm-1; 1H NMR (acetone-d6), 2.46 (s, 3H), 7.50 (d, J =
8.7 Hz, 2H), 7.61-7.71 (m, 3H), 7.75 (d, J = 8.7 Hz, 2H),
7.96-8.08 (m, 2H); EIMS (20 eV) m/z (%): 306 (M+-NO-CO,
1-Acetoxy-5-[3-(4 -methylphenyl)sydnon-4-yl]tetrazole
(6ba)
+
2), 264 (M+-NO-CO-N3, 4), 105 (C6H5 CO ,100); Anal.
Calcd for C17H12N6O4: C, 56.05; H, 3.32; N, 23.07. Found: C,
56.16; H, 3.37; N, 23.12.
mp 162-163 C; IR (KBr) 1839 ( C=O), 1773 ( C=O)
cm-1; 1H NMR (acetone-d6), 2.50 (s, 3H), 2.53 (s, 3H), 7.51
(d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H); EIMS (20 eV)
m/z (%): 302 (M+, 1), 202 (M+-NO-CO-N3, 100); Anal. Calcd
for C12H10N6O4: C, 47.69; H, 3.33; N, 27.80. Found: C, 47.82;
H, 3.39; N, 27.82.
O-Benzoyl-3-(4 -methoxyphenyl)sydnone-4-carbazidoxime
(5cc)
mp 130-131 C; IR (KBr) 2174, 2140 ( N3), 1780 (
C=O) cm-1; 1H NMR (acetone-d6), 3.91 (s, 3H), 7.19 (d, J =
9.1 Hz, 2H), 7.51-8.02 (m, 7H); EIMS (20 eV) m/z (%): 322
(M+-NO-CO, 2), 280 (M+-NO-CO-N3, 4), 105 (C6H5 CO+,
100); Anal. Calcd for C17H12N6O5: C, 53.69; H, 3.18; N,
22.10. Found: C, 53.65; H, 3.24; N, 21.97.
1-Acetoxy-5-[3-(4 -methoxyphenyl)sydnon-4-yl]tetrazole
(6ca)
mp 148-149 C; IR (KBr) 1838 ( C=O), 1774 ( C=O)
cm-1; 1H NMR (acetone-d6), 2.54 (s, 3H), 3.96 (s, 3H), 7.22
(d, J = 9.0 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H); EIMS (20 eV)
m/z (%): 318 (M+, 2), 288 (M+-NO, 33), 260 (M+-NO-CO,
100), 218 (M+-NO-CO-N3, 97), 159 (M+-NO-CO-N3-
CH3COO, 76); Anal. Calcd for C12H10N6O5: C, 45.29; H,
3.17; N, 26.41. Found: C, 45.03; H, 3.21; N, 26.65.
O-Benzoyl-3-(4 -ethoxyphenyl)sydnone-4-carbazidoxime
(5dc)
mp 129-130 C; IR (KBr) 2180, 2145 ( N3), 1756 (
C=O) cm-1; 1H NMR (acetone-d6), 1.40 (t, J = 7.1 Hz, 3H),
4.17 (q, J = 7.1 Hz, 2H), 7.17 (d, J = 9.1 Hz, 2H), 7.35-7.71
(m, 3H), 7.84 (d, J = 9.1 Hz, 2H), 8.00 (d, J = 6.3 Hz, 2H),
EIMS (20 eV) m/z (%): 336 (M+-NO-CO, 12), 294 (M+-NO-
CO-N3, 1), 105 (C6H5CO+, 100); Anal. Calcd for C18H14N6O5:
C, 54.82; H, 3.58; N, 21.31. Found: C, 54.82; H, 3.60; N,
21.34.
1-Acetoxy-5-[3-(4 -ethoxyphenyl)sydnon-4-yl]tetrazole
(6da)
mp 131-132 C; IR (KBr) 1836 ( C=O), 1776 ( C=O)
cm-1; 1H NMR (acetone-d6), 1.43 (t, J = 6.9 Hz, 3H), 2.53 (s,
3H), 4.21 (q, J = 6.9 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 7.75 (d,
J = 9.1 Hz, 2H); EIMS (20 eV) m/z (%): 332 (M+, 1), 274
(M+-NO-CO, 95), 232 (M+-NO-CO-N3, 83), 43 (CH3CO+,
100); Anal. Calcd for C13H12N6O5: C, 46.99; H, 3.64; N,
25.29. Found: C, 47.08; H, 3.69; N, 25.20.
Syntheses of 1-Acyloxy-5-(3-arylsydnon-4-yl)tetrazoles
(6aa-6db)
The method of synthesis of 1-acetoxy-5-(3-phenyl-
sydnon-4-yl)tetrazole (6aa) described below was used as a
general procedure for the syntheses of tetrazole derivatives
6aa-6db. To a solution of acetyl chloride (117.8 mg, 1.5
mmol) in benzene (5 mL), 3-phenylsydnone-4-carbazidox-
ime (123 mg, 0.5 mmol) was gradually added over 20 min-
1-Propionoxy-5-(3-phenylsydnon-4-yl)tetrazole (6ab)
mp 135-136 C; IR (KBr) 1840 ( C=O), 1778 ( C=O)
cm-1; 1H NMR (acetone-d6), 1.29 (t, J = 7.4 Hz, 3H), 2.88(q,
J = 7.4 Hz, 2H), 7.71-7.87 (m, 5H); EIMS (20 eV) m/z (%):

Syntheses of 5-(3-Arylsydnon-4-yl)tetrazole Derivatives
J. Chin. Chem. Soc., Vol. 49, No. 3, 2002 367
+
302 (M+, 4), 244 (M+-NO-CO, 7), 77 (C6H5 , 27), 57
1-Hydroxy-5-(3-phenylsydnon-4-yl)tetrazole (3a)
(CH3CH2CO+, 100); Anal. Calcd for C12H10N6O4: C, 47.69;
H, 3.33; N, 27.80. Found: C, 47.52; H, 3.32; N, 27.79.
mp 187-188 C; IR (KBr) 3000-2200 ( O-H), 1776 (
1
C=O) cm-1; H NMR (DMSO-d6), 5.15 (s, 1H), 7.65-7.75
(m, 5H); EIMS (20 eV) m/z (%): 246 (M+, 3), 188 (M+-NO-
+
1-Propionoxy-5-[3-(4 -methylphenyl)sydnon-4-yl]tetrazole
(6bb)
CO, 98); 77 (C6H5 , 100); Anal. Calcd for C9H6N6O3: C,
43.91; H, 2.46; N, 34.14. Found: C, 43.98; H, 2.57; N, 34.04.
mp 149-150 C; IR (KBr) 1850 ( C=O), 1772 ( C=O)
cm-1; 1H NMR (acetone-d6), 1.29 (t, J = 7.4 Hz, 3H), 2.49 (s,
3H), 2.87 (q, J = 7.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.70 (d,
J = 8.4 Hz, 2H); EIMS (20 eV) m/z (%): 316 (M+, 2), 258
1-Hydroxy-5-[3-(4 -methylphenyl)sydnon-4-yl]tetrazole
(3b)
mp 157-158 C; IR (KBr) 3000-2200 ( O-H), 1747 (
C=O) cm-1; 1H NMR (DMSO-d6), 2.40 (s, 3H), 5.19 (s, 1H),
7.43 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H); EIMS (20
eV) m/z (%): 260 (M+, 3), 202 (M+-NO-CO, 79); 91
+
(M+-NO-CO, 6), 91 (CH3C6H4 , 23), 57 (CH3CH2CO+, 100);
Anal. Calcd for C13H12N6O4: C, 49.37; H, 3.82; N, 26.57.
Found; C, 49.23; H, 3.85; N, 26.59.
+
(CH3C6H4 , 100); Anal. Calcd for C10H8N6O3: C, 46.16; H,
1-Propionoxy-5-[3-(4 -methoxyphenyl)sydnon-4-yl]tetrazole
(6cb)
3.10; N, 32.30. Found: C, 46.17; H, 3.15; N, 32.36.
mp 164-165 C; IR (KBr) 1838 ( C=O), 1778 ( C=O)
cm-1; 1H NMR (acetone-d6), 1.29 (t, J = 7.4 Hz, 3H), 2.87 (q,
J = 7.4 Hz, 2H), 3.94 (s, 3H, CH3O), 7.20 (d, J = 9.1 Hz, 2H),
7.76 (d, J = 9.1 Hz, 2H); EIMS (20 eV) m/z (%): 332 (M+, 3),
302 (M+-NO, 10), 274 (M+-NO-CO, 22), 57 (CH3CH2CO+,
100); Anal. Calcd for C13H12N6O5: C, 46.99; H, 3.64; N,
25.29. Found: C, 46.89; H, 3.61; N, 25.38.
1-Hydroxy-5-[3-(4 -methoxyphenyl)sydnon-4-yl]tetrazole
(3c)
mp 156-158 C; IR (KBr) 3000-2200 ( O-H), 1730 (
C=O) cm-1; 1H NMR (DMSO-d6), 3.91 (s, 3H), 5.15 (s, 1H),
7.16 (d, J = 9.1 Hz, 2H), 7.71 (d, J = 9.1 Hz, 2H); EIMS (20
eV) m/z (%): 276 (M+, 5), 218 (M+-NO-CO, 100), 159 (M+-
+
NO-CO-N3-OH, 76), 107 (CH3OC6H4 , 36); Anal. Calcd for
C10H8N6O4: C, 43.49; H, 2.92; N, 30.43. Found: C, 43.42; H,
2.94; N, 30.30.
1-Propionoxy-5-[3-(4 -ethoxyphenyl)sydnon-4-yl]tetrazole
(6db)
mp 111-112 C; IR (KBr) 1845 ( C=O), 1778 ( C=O)
cm-1; 1H NMR (acetone-d6), 1.29 (t, J = 7.4 Hz, 3H), 1.42 (t,
J = 6.9 Hz, 3H), 2.87 (q, J = 7.4 Hz, 2H), 4.20 (q, J = 6.9 Hz,
2H), 7.18 (d, J = 9.3 Hz, 2H); 7.73 (d, J = 9.3 Hz, 2H); EIMS
(20 eV) m/z (%): 346 (M+, 1), 316 (M+-NO, 5), 288 (M+-NO-
CO, 17), 57 (CH3CH2CO+, 100); Anal. Calcd for C14H14N6O5:
C, 48.56; H, 4.07; N, 24.27. Found: C, 48.51; H, 4.09; N,
24.26.
1-Hydroxy-5-[3-(4 -ethoxyphenyl)sydnon-4-yl]tetrazole
(3d)
mp 187-188 C; IR (KBr) 3000-2100 ( O-H), 1756 (
C=O) cm-1; 1H NMR (DMSO-d6), 1.34 (t, J = 7.1 Hz, 3H),
4.11 (q, J = 7.1 Hz, 2H), 5.10 (s, 1H), 7.17 (d, J = 9.1 Hz, 2H),
7.62 (d, J = 9.1 Hz, 2H); EIMS (20 eV) m/z (%): 290 (M+, 1),
232 (M+-NO-CO, 71), 45 (C2H5O+, 100); Anal. Calcd for
C11H10N6O4: C, 45.52; H, 3.47; N, 28.96. Found: C, 45.51; H,
3.51; N, 28.79.
Converting 1-Acetoxy-5-(3-arylsydnon-4-yl)tetrazoles
(6aa-6da) into the corresponding 1-hydroxy-5-(3-
arylsydnon-4-yl)tetrazoles (3a-3d)
Crystallography
Crystal data for compound 6aa are summarized in Ta-
ble 3. Selected bond distances and bond angles are listed in
Table 4 and Table 5, respectively. Atomic coordinates are
given in Table 6.
Typical procedure: 1-Acetoxy-5-(3-phenylsydnon-4-
yl)tetrazole (6aa, 144 mg, 0.5 mmol) was dissolved in hot
ethanol and then evaporated to nearly dry. To the above resi-
due, n-hexane was added to get the desired solid. The precipi-
tating solid was collected by filtration and washed with
n-hexane. The solid could be recrystallized from dichloro-
methane/n-hexane to afford 109 mg (89%) of 1-hydroxy-5-
(3-phenylsydnon-4-yl)tetrazole (3a) as white crystalline.
The chemical and physical spectral characteristics of tetra-
zoles 3a-3d are given below.
ACKNOWLEDGMENT
Financial support of this work by the National Science
Council of the Republic of China and Southern Taiwan Uni-
versity of Technology is highly appreciated.

368 J. Chin. Chem. Soc., Vol. 49, No. 3, 2002
Shih et al.
Purchase, C. F.; Roth, B. D.; White, A. D.; Anderson, M.;
Mueller, S. B.; Bocan, T.; Bousley, R.; Hamelehle, K. L.;
Homan, R.; Lee, P.; Krause, B. R.; Reindel, J. F.; Stanfield,
R. L.; Turluck, D. J. of Med. Chem. 1996, 39, 2354.
16. Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J. F.;
White, H. L. J. of Med. Chem. 1996, 39, 1857.
17. O’ Brien, P. M.; Sliskovic, D. R.; Bernabei, A.; Hurley, T.;
Anderson, M. K.; Bousley, R. F.; Krause, B. R.; Stanfield, R.
L. Bioorg. & Med. Chem. Lett. 1995, 5, 295.
18. O’ Brien, P. M.; Sliskovic, D. R.; Anderson, M. K.; Bousley,
R. F.; Krause, B. R.; Stanfield, R. L. Bioorg. & Med. Chem.
Lett.1995, 5, 289.
Received December 14, 2001.
Key Words
Sydnones; Nitrile oxides; Carbohydroximic acid
chlorides; Azidoximes; Tetrazoles;
3-Arylsydnone-4-carbazidoximies;
1-Acyloxy-5-(3-arylsydnon-4-yl)trazoles;
1-Hydroxy-5-(3-arylsydnon-4-yl)tetrazoles.
REFERENCES
19. Carpenter, W. R. J. Org. Chem. 1962, 27, 2085.
20. Smith, P. A. S.; Clegg, J. M.; Hall, J. H. J. Org. Chem. 1958,
23, 524.
21. Plenkiewicz, J. Tetrahedron Lett. 1975, 341.
22. Plenkiewicz, J. Tetrahedron 1978, 34, 2961.
23. Chu, W. C.; Chan, F. F.; Yeh, M. Y. Hua-Hzueh 1988, 46,
181.
24. Yeh, M. Y.; Chu, W. C. J. Chin. Chem. Soc. 1988, 35, 451.
25. Shih, M. H.; Yeh, M. Y. J. Chin. Chem. Soc. 1990, 37, 71.
26. Shih, M. H.; Yeh, M. Y. J. Chin. Chem. Soc. 1992, 39, 163.
27. Shih, M. H. J. Technology 1994, 9, 459.
28. Shih, M. H.; Lu, L. H.; Yeh, M. Y. J. Chin. Chem. Soc. 2001,
48, 883.
1. Stewart, F. H. C. Chem. Rev. 1964, 64, 129.
2. Ohta, M.; Kato, H. Non-Benzenoid Aromatics, I; Academic
Press: New York, 1969; pp 117-171.
3. Greco, C. V.; Tobias, J.; Kier, L. B. J. Heterocycl. Chem.
1967, 4, 160.
4. Kier, L. B.; Roche, E. B. J. Pharm. Sci. 1967, 56, 149.
5. Greco, C. V.; Nyberg, W. H.; Cheng, C. C. J. Med. Pharm.
Chem. 1962, 5, 861.
6. Imashiro, Y.; Masuda, K. Japan Patent 1969, 6932411;
Chem. Abstr. 1970, 72, 111482q.
7. Saito, Y.; Kamitani, T. Japan Patent 1970, 7021710; Chem.
Abstr. 1970, 73, 87926k.
29. Eloy, F. J. Org. Chem. 1961, 26, 952.
30. Reynolds, G. A.; VanAllan, J. A.; Tinker, J. F. J. Org. Chem.
1959, 24, 1205.
31. Boyer, J. H.; Miller, E. J. Jr. J. Am. Chem. Soc. 1959, 81,
4671.
32. Boyer, J. H.; Hyde, H. W. J. Org. Chem. 1960, 25, 458.
33. Temple, C. Jr.; Kussner, C. L.; Montgomery, J. A. J. Org.
Chem. 1966, 31, 2210.
8. Masuda, K.; Okutani, T. Japan Patent 1970, 7020903;
Chem. Abstr. 1970, 74, 87928n.
9. Satyanarayana, K.; Rao, M. N. A. J. Pharm. Sci. 1995, 84, 2,
263.
10. Juby, P. F.; Hudyma, T. W.; Brown, M. J. Med. Chem. 1968,
11, 111.
11. Mashtanov, S. M. Nauka Bor’be Urozhai 1970, 32; Chem.
Abstr. 1971, 74, 139862d.
34. Temple, C. Jr.; Montgomery, J. A. J. Am. Chem. Soc. 1964,
86, 2946.
12. Herbst, R. M.; Roberts, C. W.; Givens, H. T. F.; Harvill, E. K.
J. Org. Chem. 1952, 17, 262.
35. Chang, M. S.; Matuszko, A. J. J. Org. Chem. 1963, 28, 2260.
36. Grundmann, C.; Frommeld, H. D. J. Org. Chem. 1966, 31,
157.
37. Buchholz, J. R.; Powell, R. E. J. Am. Chem. Soc. 1965, 87,
2350.
13. Bond, A.; Lodge, D.; Hicks, C. A.; Ward. M. A.; O’ Neill, M.
J. Eur. J. Pharmacol. 1999, 380, 91.
14. Nagamatsu, T.; Hayashi, K.; Oka, T.; Suzuki, Y. Eur. J.
Pharmacol. 1999, 374, 93.
15. O’Brien, P. M.; Sliskovic, D. R.; Picard, J. A.; Lee, H. T.;