Equilibria of the 5-Substituted-1,2-acylated Tetrazoles and Imidoyl Azides

Article abstract of DOI:10.1021/jo000267g

Equilibrium of acylated-5-alkyloxy (aryloxy) tetrazoles and acylated-imidoyl azides was measured by ¹H NMR and/or IR spectroscopy. In nonpolar solvents the relatively weakly electron-withdrawing acyl group (CO₂CH₃) favored

Full text of DOI:10.1021/jo000267g

7284
J . Org. Chem. 2000, 65, 7284-7290
Equ ilibr ia of th e 5-Su bstitu ted -1,2-a cyla ted Tetr a zoles a n d
Im id oyl Azid es†
Hossein A. Dabbagh*,‡ and Walter Lwowski*,§
College of Chemistry, Isfahan University of Technology, Isfahan, 8415 Islamic Republic of Iran, Iran, and
Department of Chemistry, New Mexico State University, Las Cruces, New Mexico, 88003-0001
dabbagh@cc.iut.ac.ir
Received February 26, 2000
Equilibrium of acylated-5-alkyloxy (aryloxy) tetrazoles and acylated-imidoyl azides was measured
by 1H NMR and/or IR spectroscopy. In nonpolar solvents the relatively weakly electron-withdrawing
acyl group (CO2CH3) favored acylation at the 2-position of the 5-substituted tetrazoles. Moderately
electron-withdrawing groups (CO2CH2CCl3, CO2CCl3) move the equilibrium to the side of 1-acyl-
5-substituted tetrazole. Strong electron-withdrawing groups (CN, SO2CH3, SO2CF3) favored the
formation of the azide. The rate of isomerization of tetrazoles and the azide increases at higher
concentrations and polarity of the solvent. In solid phase or in the nonpolar solvent (diethyl ether),
only one of the three isomers is present, its structure depending on the nature of the substituents
at the 1 or 2 positions of tetrazoles.
Sch em e 1
In tr od u ction
Increasing attention has been paid over the past two
decades to the chemistry of tetrazoles and tetrazole
derivatives. The major area of interest has been the
application of tetrazoles in pharmacological compounds
with antihypertensive, antiallergenic, antibiotic, and
other pharmaceutical activities. Another research area
of interest is the isomerization of tetrazoles.1-16
† Based in part on the thesis of H. A. Dabbagh, New Mexico State
University, 1985.
‡ Isfahan University of Technology.
Tetrazoles, substituted at the 5-position, are known to
exist as equilibrium mixtures of their 1H- and 2H-
tautomers.1 In a review, Buttler2 discussed the rapid
equilibrium of 1H- and 2H-5-substituted tetrazoles. In
the present work, 15N NMR spectra of 5-methoxytetrazole
indicate only two signals (rapid equilibrium) at -19.0
ppm and at -126.0 ppm (relative to liquid ammonia)
corresponding to NdN and N-H, respectively.
It has been reported that the acylation of 5-substituted
tetrazole always gives the 2-acyl derivative T3.17,18
Accordingly, the reaction of cyanogen bromide with
aryloxytetrazoles T4 was reported to produce 5-aryl-
oxy-2-cyanotetrazole T5, Scheme 1.19
§ New Mexico State University.
(1) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Ress, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K.,
1996; Vol. 4, p 621.
(2) Butler, R. N. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Boutton, A. J ., Eds.; Academic Press: New York, 1977; Vol. 21.
(3) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; J . Wiley and Sons: New York, 1984; p 559.
(4) Singh, H.; Chawla, A. S.; Kapoor, U. K.; Paul, D.; Malhotra, R.
K. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.;
Elsevier: North-Holland, 1980; Vol. 17, p 151.
(5) Cubero, E.; Orozco, M.; Luque, F. J . Org. Chem. 1998, 63, 2354.
(6) Cubero, G.; Orozco, M.; Luque, F. J . Am. Chem. Soc. 1998, 120,
4723.
(7) Dabbagh, H. A.; Ghaelee, S. J . Org. Chem. 1996, 61, 3439.
(8) Kamiya, N. J .; Shiro, Y.; Iwatee, T.; Iizuka, T.; Iwasaki, H. J .
Am. Chem. Soc. 1991, 113, 1826.
Subba Rao and Lwowski reported that reactions of
5-methoxy- or 5-ethoxytetrazoles with cyanogen bromide
or methane sulfonyl chloride gave imidoyl azides, aparent-
ly by ring opening of 1-acylated-5-substituted terazoles,
followed by spontaneous ring opening to the correspond-
ing imidoyl azides, Scheme 2.20,21 Obviously, the “2-
acylation rule” (acylation taking place exclusively at
2-position) does not hold in this case. The nearly quan-
(9) Katritzky, A. R.; J ozwiak, A. R.; J ozwiak, A. R.; J ozwiak, A.; Lue,
P.; Yannakopoulou, K.; Palenik, G. J .; Zhang, Z. Y. Tetrahedron 1990,
46, 633.
(10) Katritzky, A. R.; Yannakopoulou, K.; Anders, E.; Stevens, J .;
Szafran, M. J . Org. Chem. 1990, 55, 5683.
(11) (a) Hall, J . H.; Parcell, W. L. Inorg. Chem. 1990, 29, 3806. (b)
Temple, C., J r.; Montgomory, J . A. J . Org. Chem. 1965, 30, 826. (c).
Temple, C., J r.; Mckee, R. L.; Montgomory, J . A. J . Org. Chem. 1965,
30, 829. (d) Bruke, L. A.; Elguero, J .; Leroy, G.; Sana, M. J . Am. Chem.
Soc. 1976, 98, 1685. (e) Denisov, A. Y.; Krivopalov, V. P.; Mamatyuk,
V. I.; Mamaev, V. P. Magn. Reson. Chem. 1988, 26, 42. (f) Markgraf,
J . H.; Bachmann, W. T.; Hollis, D. P. J . Org. Chem. 1965, 30, 3472.
(g) Tisler, M. Synthesis 1973, 123. (h) Sasaki, T.; Kanematsu, M.;
Murata, M. Tetrahedron 1971, 27, 5121. (i) Temple, C.; Montgemory,
J . A. J . Org. Chem. 1965, 30, 826. (j) Temple, C.; Montgemory, J . A. J .
Am. Chem. Soc. 1964, 86, 2946. (k) Temple, C.; McKee, J . A.;
Montgemory, J . A. J . Org. Chem. 1965, 30, 829.
(15) Elguero, J .; Claramunt, R. M.; Summers, A. J . Adv. Heterocycl.
Chem. 1978, 22, 183.
(16) Konnecke, A.; Lippmann, E.; Klein, P. Tetrahedron Lett. 1976,
533.
(17) Herbst, R. M. J . Org. Chem. 1961, 26, 2372.
(18) Ginberg, F. J . Org. Chem. 1967, 32, 3686.
(19) Martin, D.; Weise, A. Chem. Ber. 1966, 99, 317.
(20) Subba Rao.; Lwowski, W. J . Heterocycl. Chem. 1980, 17, 187.
(21) Subba Rao.; Lwowski, W. Tertrahedron Lett. 1980, 21, 727.
(12) Dabbagh, H. A.; Lwowski, W. J . Org. Chem. 1989, 54, 3952.
(13) Zabrocki, J .; Smith, G. D.; Dunbar, J . B.; J r.; Iijima, H.;
Marshall, G. R. J . Am. Chem. Soc. 1988, 110, 5875.
(14) Yu, K. L.; J ohnson, R. L. J . Org. Chem. 1987, 52, 2051.
10.1021/jo000267g CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/11/2000

5-R-1,2-Acylated Tetrazole-Imidoyl Azide Equilibria
J . Org. Chem., Vol. 65, No. 22, 2000 7285
Sch em e 2
Sch em e 6
Sch em e 7
Sch em e 3
Sch em e 4
Sch em e 8
Sch em e 5
been studied by ab initio calculations using the STO-3G
basis set.11d The authors predicted that the transition
state resembled strongly the azide rather than the
tetrazole and that cyclization should be accelerated in
polar solvents. Their theoretical results are in reasonable
agreement with available experimental ones, Scheme 7.
Denisov and co-workers used 13C-1H coupling con-
stants for the investigation of azide-tetrazole tautom-
erism of 2,4- and 4,6-diazidopyrimidines in chloroform-d
and DMSO-d6.11e They demonstrated that the position of
equilibrium depends on the polarity of the solvent,
Scheme 8. Markgraf and Bachmann used proton NMR
to study the tautomeric equilibrium of a 5-substituted
tetrazole.11f
Some aspects of azido-tetrazolo isomerization were
reviewed by Tisˇler.11g The effects of substitution, solvent,
and temperature on tetazole-azide isomerization on
several substituted pyridines and diazines are presented
in Table 1.11h-k
To this date, there is no evidence indicating that
1H-tetrazole gives 1-alkyl or 1-acyltetrazole upon alkyl-
ation or acylation or that 2H-tetrazole gives only 2-alkyl
or 2-acyltetrazole, rather either tetrazole might give,
at some rate, either alkyl (acyl) tetrazole. In principle,
the alkyl (acyl) tetrazoles could interconvert k7 h k8,
Scheme 9.
titative yields of imidoyl azide A7 show that either the
1-acyl compound T6 was the major primary product or
any 2-acyltetrazole formed was converted to the 1-isomer
and then removed from the system by ring opening.
Theoretical study of azido-tetrazole isomerzation, the
effect of solvent and substitution, and the mechanism of
isomerzation have been investigated by self-consistent
reaction field (SCRF) and Monte Carlo-Free Energy
Perturbation (MC-FEP) techniques in three different
solvents (carbon tetrachloride, chloroform, and water).5,6
The results show that the azido form of thiazole[3,2-d]-
tetrazole is clearly disfavored as the solvent polarity
increases. The effect of substitution is also consistent with
the experimental available data, with electron-withdraw-
ing groups shown to favor the azido isomer while the
opposite effect is observed for electron-donating substit-
uents, Scheme 3.
Katritzky et al.9,10 recently reported that tetrazoles T8
h T9 undergo fast N-1 to N-2 substituent isomerization,
Scheme 4.
Purcell and Hall investigated the novel linkage isomer-
ization of 5-substituted tetrazole complexes and explored
the effect of the electronic and steric factors on the
mechanism of the interconversion of the isomerizing
ligand. They concluded that the relief of steric hindrance
as a major driving force for the isomerzation is consistent
with the experimental observations, Scheme 5.11a
The azidoazomethine-tetrazole equilibrium for
pyrimidine derivatives has been examined by means
of infrared and proton magnetic resonance spectro-
scopy.11b,c The authors concluded that an electron-releas-
ing group on the pyrimidine ring would destabilized the
tetrazole, Scheme 6.
The question raised here was whether 5-substituted
tetrazole acylated at one position is in equilibrium with
the substituted tetrazole acylated at two positions? Is
1-acylated-5-substituted tetrazole in equilibrium with its
opening form, the imidoyl azide? What is the effect of
solvent polarity, concentration, and electronic effect of
substituent on the rate of achieving equilibrium? A major
problem could arise if these tautomers which have
different physical and chemical properties equilibrate
during the course of the reaction. Three species rather
than one might participate in the reaction! To gain more
insight into the isomerization of the tetrazoles (and to
find the factors that control the rate of their intercon-
versions), several tetrazoles (depicted in Scheme 10) are
synthesized and their isomerization is investigated in
The potential energy hypersurface for the isomeriza-
tion of aziodoazomethine-tetrazole isomerization has

7286 J . Org. Chem., Vol. 65, No. 22, 2000
Dabbagh and Lwowski
Ta ble 1. Effect of Solven t P ola r ity a n d Tem p er a tu r e on th e Equ ilibr iu m of Azid otetr a zoles
Sch em e 9
Sch em e 10
detail (in three solvents: tetrahydrofuran, chloroform,
and diethyl ether) at room temperature.
Resu lts
Rea ction s of 5-Meth oxytetr a zoles (1TA h 1TB)
w it h (a ) Met h yl Ch lor ofor m a t e. Tetrazoles (1TA
h
1TB), methyl chloroformate, anhydrous peroxide free
tetrahydrofurn (THF), and triethylamine in an ice bath
produced a liquid mixture of 1- and 2-methoxycarbonyl-
5-methoxytetrazoles 4 h 5. The proton NMR analysis of
the reaction mixture, 5 min after the addition of the base
was completed, showed approximately 80% of tetazole 5
in the mixture. The ratio of 5/4, several hours after the
addition of the base was completed, was equal to 0.70,
corresponding to 59% 4 in the solution. This clear liquid
mixture of 4 h 5 in diethyl ether at 0 °C or by cooling
alone at -25 °C gave pure white crystals of 4 in 83% total
yield. When pure 4 was dissolved in chloroform, the same
ratio (5/4 = 0.70) of the equilibrium mixture of 4 h 5 was
produced at room temperature, Figure 1a, Tables 2-5,
Scheme 10.
spectrum of the mixture showed strong carbonyl and
azide bands, Scheme 10, Tables 2-5.
(c) Tr iflu or om eth a n esu lfon yl Ch lor id e (TF MSC).
Tetrazoles 1, TF MSC, anhydrous peroxide free tetrahy-
drofurn, and triethylamine in an ice bath produced a
viscous liquid. This liquid when passed over a silica gel
column and crystallized in ethyl ether gave 50% of pure
white crystals of methoxy-N-trifluoromethanesulfonyl-
1
(b) 2,2,2-Tr ich lor oeth yl Ch lor ofor m a te (TCC). Tet-
razoles 1, TCC, chloroformate, anhydrous peroxide free
THF, and triethylamine produced in an ice bath a liquid
mixture of 1- and 2-(2,2,2-trichloroethoxycarbonyl)-5-
(methoxy)tetrazoles and methoxy-N-2,2,2-trichloroethox-
carbimidoyl azide (12). H NMR analysis of the reaction
mixture did not indicate any possible equilibration of
10 h 11 h 12; however, the TLC and 13C NMR of 12 in
chloroform showed only compound 12. The IR (KBr)
spectrum of 12 showed an azide band, Scheme 10, Tables
2-5.
1
ycarbonylcarbimidoyl azide (7 h 8 h 9). The H NMR
analysis of the reaction mixture, 5 min after the addition
of the base was completed, showed approximately 17%
of azide 9 in the mixture. This liquid mixture of 7 h 8 h
9 did not yield a single compound in either diethyl ether
at 0 °C or by cooling alone at -25 °C. The IR (KBr)
Rea ction s of 5-Eth oxytetr a zoles (2TA h 2TB) w ith
Meth yl Ch lor ofor m a te. Reactions of tetrazoles 2 with
methyl chloroformate in anhydrous peroxide free THF
in an ice bath produced a liquid mixture of 1- and
2-methoxycarbonyl-5-ethoxytetrazoles (13 h 14). 1H NMR

5-R-1,2-Acylated Tetrazole-Imidoyl Azide Equilibria
J . Org. Chem., Vol. 65, No. 22, 2000 7287
F igu r e 1. (a) Time dependence of equilibria of 2-methoxycarbonyl-5-methoxy tetrazole (4) in a dilute (2), 0.28 M (b), and 1.27
M (9) chloroform solutions of 24 at room temperature. (b) Comparison of time dependence of equilibria of tetrazoles 5/4 (2),
tetrazoles 14/13 (9), and tetrazoles 17/16 (b) in chloroform solutions of 24 at room temperature. (c) Time dependence of equilibria
1
of azide 21 as measured by H NMR (b) or by IR (9) in chloroformsolutions of 24 at room temperature. (d) Time dependence of
the equilibria of 1-tetrazole 23 and azide 24 in chloroform at room temperature.
Ta ble 2. Effect of Su bstitu tion or Solven t on th e
Equ ilibr iu m of Acyla ted 5-Su bstitu ted Tetr a zoles a t
Room Tem p er a tu r ea
Rea ction s of 5-(2,6-Dim eth ylp h en oxy)tetr a zoles
(3TA h 3TB) w ith (a ) Meth yl Ch lor ofor m a te. Reac-
tions of tetrazoles 3 with methyl chloroformate, anhy-
drous peroxide free THF, and triethylamine in an ice bath
produced a liquid mixture of 1- and 2-methoxycarbonyl-
5-(2,6-dimethylphenoxy)tetrazoles (16 h 17). 1H NMR
analysis of the reaction mixture 5 min after the addition
of the base was completed showed approximately 37% of
tetrazole 16 in the mixture. The ratio of 17/16 (measured
several hours after the addition of the base was com-
substituents
Y (acyl)
CO2CH3
relative %b
Z
2-tetrazole 1-tetrazole
azide
CH3O
CH3Oc
CH3O
CH3Oc
62 (4)
100 (4)
46 (7)
38 (5)
0 (5)
37 (8)
0 (11)
37.5 (14)
0 (14)
37 (17)
30 (20)
100 (20)
70 (23)
0 (23)
0 (6)
0 (6)
17 (9)
100 (12)
(15)
0 (15)
0 (18)
47 (21)
0 (21)
28.5 (24)
100 (24)
CO2CH3
CO2CH2CCl3
SO2CF3
0 (10)
CH3CH2O CO2CH3
62.5 (13)
100 (13)
63 (16)
2 (19)
0 (19)
1.5 (22)
0 (22)
CH3CH2Oc CO2CH3
1
ArOd
ArOd
ArOc,d
ArOd
ArOc,d
CO2CH3
pleted by H NMR) was equal to 0.60, corresponding to
CO2CH2CCl3
CO2CH2CCl3
CO2CCl3
63% 16 and 37% 17 in the solution. This clear liquid
mixture of 16 h 17 in diethyl ether at 0 °C or by cooling
alone at -25 °C gave pure white crystals of 16 in 94%
total yield. Pure 16, when dissolved in chloroform,
produced the same equilibrium mixture of (17/16 = 0.60)
at room temperature, Scheme 10, Tables 2-5, Figure 1b.
CO2CCl3
a
b
The solvent is CDCl3 unless otherwise stated. Calculated by
1H NMR, compound number is given in parnetheses. c The solvent
d
is diethyl ether. Ar ) 2,6-dimethylphenyl.
(b) 2,2,2-Tr ich lor oeth yl Ch lor ofor m a te (TCC). Tet-
razoles 3, TCC, anhydrous peroxide free THF, and
triethylamine in an ice bath produced a liquid mixture
of 1- and 2-(2,2,2-trichloroethoxycarbonyl)-5-(2,6-dimeth-
ylphenoxy)tetrazoles and 2,6-dimethylphenoxy-N-2,2,2-
trichloroethoxycarbonylimidoyl azide (19 h 20 h 21). 1H
NMR analysis of the reaction mixture 5 min after the
addition of the base was completed showed approximately
47% of azide 21 in the mixture. This clear liquid mixture
of 19 h 20 h 21 in ethyl ether at 0 °C or by cooling alone
at -25 °C gave pure white crystals of 20 in 78% total
yield. Pure 20, when dissolved in chloroform, produced
the same equilibrium mixture of (19 h 20 h 21) at room
analysis of the reaction mixture, 5 min after the addition
of the base was completed, showed approximately 65%
of 1-substituted tetrazole 14 in the mixture. The ratio of
14/13 (measured several hours after the addition of the
base was completed by 1H NMR) was equal to 0.60,
corresponding to 37.5% 14 in the solution. This clear
liquid mixture of 13 h 14 gave pure white crystals of 13
in high yield either in diethyl ether solvent at 0 °C or by
cooling alone at -25 °C . Pure 13, when dissolved in
chloroform, produced the same equilibrium mixture of
(14/13 = 0.60) at room temperature, Scheme 10, Tables
2-5, Figure 1b.

7288 J . Org. Chem., Vol. 65, No. 22, 2000
Dabbagh and Lwowski
Ta ble 3. P r ep a r a tion a n d Ch a r a cter iza tion of 1- a n d 2-Z-Tetr a zoles a n d Im id oyl Azid esa
calcd
H
found
H
compd no.
yield,%
mp, °C
C
N
C
N
M.F.
solventb
4
12
13
16
20
24
83
50
74
94
78
56
56-57
51-52
30.39
15.52
34.89
53.23
39.42
37.58
3.82
1.30
4.68
4.68
3.03
2.58
35.43
24.13
32.55
22.57
15.32
15.94
30.66
15.81
NA
53.36
39.83
NA
3.60
1.23
NA
5.07
3.27
NA
35.56
24.16
NA
22.84
15.63
NA
C4H6N4O3
C3H3N4O3F3S
C5H8N4O3
c
c
d
d
d
d
49-50
98-99
C
C
11H12N4O3
12H11N4O3Cl3
99-100
105-107e
C11H9N4O3Cl3
a
d
Compound 13 and 24 were unstable; they decomposed during purification. bCrystallization solvent. c Ethyl ether-n-hexane. Ethyl
ether-chloroform. e Decomposition temperature.
Ta ble 4. 1H NMR, IR, a n d Ma ss Sp ectr om etr y of 1- a n d 2-Alk oxyca r bon yl-Z-tetr a zoles a n d Im id oyl Azid es
1H NMR (δ ppm)a
IR
compd no.
Z
ring
Y
KBr
1800
1800
1790
CHCl3
1800
mass (m/z)
158
4
5
7
8
9
12
13
14
16
17
19
20
21
23
24
4.31 (s)
4.23 (s)
4.22 (s)
4.14 (s)
4.18 (s)
5.10 (s)
4.79 (s)
5.20 (s)
158
4.0 (s)
1810
4.30 (s)
4.08 (s)
1.25 (t),4.70 (q)
1.20 (t),4.50 (q)
2.19 (s)
2.19 (s)
2.18 (s)
2.20 (s)
2.20 (s)
1750, 2155
2160, 2200
1800
1800
1810
4.10 (s)
4.20 (s)
4.15 (s)
4.19 (s)
4.17 (s)
4.15 (s)
4.75 (s)
7.04-7.08
7.04-7.08
7.07-7.10
7.07-7.10
7.13
1810
1750
1750
1805,2150
364, 366, 368
364, 366, 368
364, 366, 368
M-133 ) 218
M-133 ) 218
1800
2.18 (s)
2.23 (s)
7.08
7.08
1765
2160
a
The solvent was CDCl3 unless otherwise stated.
Ta ble 5. 13C NMR a n d 15N NMR of 1- a n d 2-Alk oxyca r bon yl-Z-tetr a zoles a n d Im id oyl Azid esa
13C NMR (δ ppm)a,b
15C NMR (δ ppm)c
compd no.
Z
ring
Y
N1
N2
N3
N4
1
4
5
12
13
14
16
17
19
-126
-102
-160
-19
-122
+10
-19
-126
-63
62.0
60.0
163.
57.0 (CH3), 163.60 (CO)
57.70 (CH3), 173.50 (CO)
118.8 (CF3) (q, J ) 319 Hz)
55.9 (CH3O), 146.1 (CO)
56.6 (CH3O), 145.9 (CO)
+9.0
173.50
160.09
161.4
-19
-94
59.6 (CH3)
14.3 (CH3), 71.2 (CH2O)
14.3(CH3), 68.5 (CH2O)
171.5
-103
-162
-119
+8.6
+8
-19
-61.5
-92.6
16.0 (CH3)
16.1 (CH3)
16.2 (CH3)
15.9 (CH3)
16.2 (CH3)
127, 129, 129.4, 144.3
150.9
126.7, 129.3, 129.9
144.2, 150.6,
127.4, 129.3
130.1, 148.9
126.53, 129.1, 129.2
129.9,147.9
127.5,129.2, 129.3
130.0, 148.9
76.4 (CCl3), 93 (CH2O)
156.8 (CO)
77.0 (CCl3), 94.6 (CH2O)
160.2 (CO)
77.6 (CCl3), 92.9 (CH2O)
150.4 (CO)
77.3 (CCl3), 170.4 (CO)
20
21
23
24
76.9 (CCl3), 150.7 (CO)
25
26
-112
-183
-116
+3
+3
-16
-83
-93
a
The solvent is CDCl3 unless otherwise stated. b 1H NMR decoupled. c The solvent is CH3NO2, Cr(acac)3.
temperature. An IR of this solution showed two carbonyl
bands and one azide band. An IR (KBr) spectrum of 20
showed only a strong carbonyl band but no azide band,
Figure 1c, Scheme 10, Tables 2-5.
(c) Tr ich lor om eth yl Ch lor ofor m a te (TCM). Tet-
razoles 3, TCM, anhydrous peroxide free tetrahydrofurn,
and triethylamine in an ice bath produced a liquid
mixture of 1-trichloromethoxycarbonyl-5-(2,6-dimethyl-
phenoxy)tetrazoles and 2,6-dimethylphenoxy-N-trichlo-
romethoxycarbonylimidoyl azide (23 h 24). 1H NMR
analysis of the reaction mixture 5 min after the addition
of the base was completed (in anhydrous peroxide free
tetrahydrofuran) showed approximately 34% of azide 24
in the mixture (24/23 = 0.51). This clear liquid mixture

5-R-1,2-Acylated Tetrazole-Imidoyl Azide Equilibria
J . Org. Chem., Vol. 65, No. 22, 2000 7289
Sch em e 11
23 h 24 in ethyl ether at 0 °C or by cooling alone at -25
°C gave pure white crystals of 24 in 56% total yield. Pure
24, when dissolved in chloroform, produced the same
equilibrium mixture (24/23 = 0.40) at room temperature,
Figure 1d. The amount of time required to achieve
equilibrium in anhydrous peroxide free tetrahydrofuran
and chloroform is =5 and =50 min, respectively. An IR
(KBr) spectrum of 24 showed strong carbonyl and azide
bands, Scheme 10, Tables 2-5.
Discu ssion
The relative percentages of each tautomer for the
systems in this study are given in Table 2. It is shown
that in all systems under investigation 1- and 2-acyltet-
razoles and, in certain cases, the imidoyl azides may be
safely assumed to be in equilibrium. The position of
equilibria and the rate of equilibration depend on the
electron-withdrawing nature of Y. The more electron-
withdrawing Y is, the stronger the shift of the equilib-
rium will be toward the azide. The reverse of this
electronic effect would shift the equilibrium toward the
2-acyltetrazole.
spectrum, and 13C NMR spectrum of the reaction mixture
of 1-and 2-methoxycarbonyl-5-ethoxytetrazoles 13 h 14
and 1- and 2-methoxycarbonyl-5-(2,6-dimethylphenoxy)-
tetrazoles (16 h 17) showed equilibrium patterns similar
to that of tetrazoles 4 h 5, Scheme 10, Figure 1, Tables
2-5.
1
The H NMR spectra of the reaction mixture of 1- and
2-methoxycarbonyl-5-methoxy tetrazoles just after the
addition of the base was completed (in anhydrous per-
oxide free THF) indicated that 1-tetrazole 5 is formed
and then isomerizes to the more stable 2-tetrazole 4 at
room temperature at a rate depending on solvent and
concentration, Figure 1a. For an approximately 10%
solution of 4 in CDCl3, equilibrium was established
within 1 h, while it took over 48 h to achieve equilibrium
in a saturated CDCl3 solution. Crystallization of the
equilibrium mixture of tetrazoles 4 h 5 (a clear liquid)
in a proper solvent (diethyl ether) allowed us to isolate
the (most stable) 2-tetrazole 4. Equilibrium is reestab-
lished when the pure form of crystal 4 is dissolved in
more polar solvents (THF or CDCl3), Table 2, Figure 1.
The infrared spectra of the equilibrium mixture of 4 in
CDCl3 did not show any azide band; however, the
intensity of the carbonyl band corresponding to 1-tetra-
zole 5 decreased with an increase in the intensity of the
carbonyl band of 2-teratzole 4. The 15N NMR spectrum
of the mixture 4 h 5 showed eight signals, each assigned
by comparing its chemical shift with that of 15N NMR
signals of 5-methoxytetrazoles (1TA h 1TB) and other
known tetrazoles (25, 26). The sp3 nitrogens produce the
most upfield signals. The N-3 signals (sp2) always ap-
peared downfield (near the CH3NO2 signals). The signals
produced by N-4 are found somewhat upfield from that
of N-3. The position of the N-1 and N-2 signals depends
on which one is the sp3 nitrogen (which gives the most
upfield peaks), Table 5. The 13C NMR spectrum of pure
4 in CDCl3 (in the first several minutes) showed only four
signals (similar in their chemical shifts to other 2-acy-
lated tetrazoles, Table 5). After equilibrium was achieved
(860 min), four new sets of signals appeared with a ratio
of 5/4 = 0.70. The mass spectra fragmentation pattern
of the equilibrium mixture of 4 h 5 showed fragments
corresponding to both tetrazoles [m/e ) 158 (4%), 130
(2%), 100 (2%), 99 (3%), 87 (3%), 71 (3%), 59 (100%), 44
(13%), 43 (24%), 31 (8)]. The mass spectra fragmentation
pattern of solid 4 showed fragments corresponding only
to 2-tetrazoles 4 [m/e ) 158 (4%), 130 (2%), 99 (3%), 87
(3%), 59 (100%), 44 (13%), 43 (24%)]. The 1H NMR
spectra, mass spectra fragmentation pattern, 15N NMR
The thermal decomposition of the equilibrium mixture
of 16 h 17 in the presence of cyclohexene produced
nitrogen and a mixture consisting of 39% of 2-(2,6-
dimethylphenoxy)-4-methyl-1,3,4-oxadiazole-5-one 16AA
and 61% of an approximately 50:50 mixture of 3-(2,6-
dimethylphenoxy)-5-methoxy-1,2,4-oxadiazole 17A and
3-(2,6-dimethylphenoxy)-4-methyl-1,2,4-oxadiazole-5-
one 17AA (all attempts to separate 17A from 17AA
failed), see Scheme 11. This suggests that (a) intramo-
lecular cyclization is favored over intermolecular cycload-
dition with cyclohexene and (b) equilibration is rapid at
a high temperature (acetonitrile reflux) and favors the
formation of 2-tetrazole 16. The ratio of the oxadiazoles
(17A + 17AA/16AA = 0.640) is similar to the ratio of
the parent tetrazoles (17/16 = 0.60).
Equ ilibr ia of Tetr a zoles w ith Im id oyl Azid es. The
next step was to investigate the isomerization of tetra-
zoles with the imidoyl azides. This was accomplished by
increasing the electron-withdrawing availability of the
acyl group.
Reaction of tetrazoles 3TA h 3TB with 2,2,2-trichloro-
ethyl chloroformate in anhydrous peroxide free THF
produced an equilibrium mixture of 1- and 2-(2,2,2-
trichloroethoxycarbonyl)-5-(2,6-dimethylphenoxy)tetra-
zoles and 2,6-dimethylphenoxy-N-2,2,2-trichloroethoxy-
carbonylcarbimidoyl azide (19 h 20 h 21). In this case,
1-tetrazole is first formed and then equilibrated to a
mixture of tetrazoles and azide. The equilibrium shifted
to the side of the most stable isomer (in this case the
1-tetrazole 20) when the mixture of tetrazoles and azide
19 h 20 h 21 was dissolved in diethyl ether. In other
words, 1-tetrazole (the least soluble in ether solution) is
favored in the crystalline form. Equilibrium is reestab-
lished after 50 min when the pure form of 20 is dissolved
in more polar solvents (chloroform or THF). The rate of
disappearance of tetrazole 20 to an equilibrium mixture
1
was followed by both infrared and H NMR spectroscopy
in CDCl3. Within experimental error, both methods
showed similar results, Table 2, Figure 1c, Scheme 10.
Reaction of tetrazoles 3TA h 3TB with trichloromethyl
chloroformate produced an equilibrium mixture of 1- and

7290 J . Org. Chem., Vol. 65, No. 22, 2000
Dabbagh and Lwowski
through silica gel or an aluminum oxide column; (f) the proton
NMR, IR spectrum, and TLC of each fraction was studied in
detail. The proton NMR, 13C NMR, 15N NMR, mass analysis,
IR, melting points, and elemental analyses are listed in Tables
3-5.
2-(trichloromethoxycarbonyl)-5-(2,6-dimethylphenoxy)tet-
razoles and 2,6-dimethylphenoxy-N-trichloromethoxy-
carbonylcarbimidoyl azide (22 h 23 h 24). Again, 1-sub-
stituted tetrazole is formed first and then equilibrates
to a mixture of tetrazoles and azide. Surprisingly, in this
case the equilibrium favored the 1-tetrazole 23 (in
contrast to compounds 19 h 20 h 21 which at equilibri-
um favored the azide 21 in chloroform). At this time,
there is no explanation for this behavior. The equilibrium
favored the side of the most stable isomer (the azide 24)
when the mixture of tetrazoles and azide (22 h 23 h 24)
was dissolved in diethyl ether. In this case, azide is
favored in the crystalline form. Equilibrium is reestab-
lished (24/23 = 0.40) when the pure form of azide 24 is
dissolved in chloroform, Table 2, Figure 1d, Scheme 10.
Reaction of tetrazoles 1TA h 1TB with trifluoromethane-
sulfonyl chloride produced pure white crystals of meth-
oxy-N-trifluoromethanesulfonylcarbimidoyl azide (12).
Equ ilibr iu m Stu d ies. The following experimental proce-
dures were performed in order to investigate the equilibrium
(isomerization-tautomerzation) of 5-substituted acylated tet-
razoles and imidoyl azides. (a) 1H NMR analysis: The 1H NMR
spectra of the reaction mixture, just after the addition of the
base was completed, indicate which tetrazole is first acylated
at the one position. Time dependence of equilibria (the rate to
achieve equilibrium) of the most stable isomer and the
reversibility and the position of the equilibrium were measured
by 1H NMR; the chemical shift for each isomer is listed in Table
4.(b) Crystallization: When the equilibrium mixture of tetra-
zoles-imidoyl azides was dissolved in a proper solvent (diethyl
ether), the least soluble or most prevalent isomer (tetrazole
or azide) was crystallized in pure form. Generally the equi-
librium is reestablished when pure crystals of the most stable
isomer are dissolved in a proper solvent (polar solvents, CDCl3,
THF, DMSO, CH3CN, etc.). (c) IR analysis: The infrared
spectra of the equilibrium mixture showed two carbonyl bands
in the region of 1700-1800 cm-1 for tetrazoles and an azide
band near 2200 cm-1. (d) 15N NMR analysis: The 15N NMR
spectrum of each tetrazole showed four signals, each assigned
by comparing its chemical shift with 15N NMR signals of
5-methoxytetrazoles (1TA and 1TB) or with 1- or 2-methyl-5-
aryloxytetrazole 26 or 25, Table 5. (e) 13C NMR analysis: The
13C NMR chemical shift spectrum of each substituted tetrazole
is compared with that of unsubstituted tetrazole and/or a
known tetrazole, Table 5. (f) Mass spectra analysis: The mass
spectra fragmentation pattern shows different fragments
corresponding to each tetrazole, Table 4. (g) Thermal decom-
position: The thermal decomposition of the equilibrium mix-
ture of tetrazoles is expected to produce nitrogen and nitrene
and/or nitrilimines. These reactive intermediates might be
either trapped intermolecularly by cyclohexene or cyclized to
isomeric oxadiazoles, Scheme 11.
1
The H NMR or IR analysis of the reaction mixture in
several solvents did not indicate any isomers of 10 h 11
h 12, Tables 2-5, Scheme 10.
Con clu sion
Acylated-5-alkyloxy (aryloxy) tetrazoles and acylated-
imidoyl azides do coexist as an equilibrium mixture. The
rate of equilibration depends on the electronic nature of
the substituents, the concentration, and the polarity of
the solvent. In nonpolar solvents, the less electron-
withdrawing acyl group favored acylation at the 2-posi-
tion of the 5-substituted tetrazole. Moderately electrons-
withdrawing groups favor an equilibrium on the side of
1-acyl-5-substituted tetrazoles. Strongly electron-with-
drawing groups favor the formation of the azide. The rate
of isomerization of tetrazoles and the azide increases at
higher concentrations and polarities of the solvent. The
rate of equilibrium is less sensitive to the substituents
at the 5-position of the tetrazoles. In solid phase or the
in less-polar solvent (diethyl ether), one of the three
isomers is formed depending on the nature of the sub-
stituents at the 1- or 2-positions of tetrazoles.
Tet r a zoles. 5-Methoxytetrazole, 5-ethoxytetrazole, and
5-(2,6-dimethylphenoxy)tetrazole were prepared as described
earlier.7,12,20,21
Typ ica l Th er m a l Rea ction s. A solution (3.1 g, 0.0124 mol)
of 16 and cyclohexene (10.2 g, 0.124 mol) in 50 mL of CH3CN
was heated to reflux for 6 days. At the end of thermolysis
(confirmed by TLC analysis), excess cyclohexene and CH3CN
were removed under reduced pressure to give a viscous brown
residue. Distillation of the residue by Kugelrohr at 106 ( 2
°C (1.5 mm) gave 0.53 g (39% yield) of a clear liquid, 2-(2,6-
Exp er im en ta l Section
Gen er a l. Elemental analysis was performed by Micanal
Organic Microanalysis, Tucson, AZ. Solvents and all the
chemicals used were reagent grade and were purchased from
J .T. Baker Chemical Co., Mallinkcrodt Inc., Burdick and
J ackson Labratories Inc., or Aldrich Chemical Co. All the
chemicals were purified properly and stored in the dark under
dry conditions prior to use.
The following experimental procedures were carried out at
room temperature: (a) 1H NMR spectra (in CDCl3) of each
reaction were studied 5 min after the addition of the base (in
an ice bath) was completed in anhydrous peroxide free THF
and after the completion of the reaction at room temperature;
(b) excess solvent (anhydrous peroxide free THF) or reactants
were removed under reduced pressure (excess solid reactants
were washed out with a suitable solvent); (c) the proton NMR,
IR spectrum, and TLC of the residues were analyzed; the liquid
residues were either distilled (under reduced pressure) or
passed through silica gel or aluminum oxide and eluted with
an appropriate solvent; (e) the solid residues (viscous liquids)
were either crystallized from a suitable solvent or passed
1
dimethylphenoxy)-4-methyl-1,3,4-oxadiazol-5-one (16AA). H
NMR (δ ppm, CDCl3) 2.20 (s, 6H), 3.50 (s, 3H0, 7.10 (s, 3H).
13C NMR (δ ppm, CDCl3, 1H-decl.) 16.18, 40.10, 126.28, 124.05,
130.23, 150.88, 168.80, 171.20. IR (neat), 1800 cm-1 (s). Mass
spectrum (70 eV) m/e M+ 220. Anal. Calcd for C11H12N2O3: C,
59.99; H, 5.49; N, 12.72. Found: C, 60.34; H, 5.26; N, 12.32.
The remaining residue from Kugelrohr distillation was passed
through a short column of aluminum oxide using chloroform
as the eluting solvent to give a white solid (mp 94-99 °C)
mixture in a 1:1 ratio of 3-(2,6-dimethylphenoxy)-4-N-methyl-
1,2,4-oxazole (17AA) and 3-(2,6-dimethylphenoxy)-5-methoxy-
1
1,2,4-oxadiazole (17A). H NMR (δ ppm, CDCl3) 1.19 (s, 6H),
2.21 (s, 6H), 3.34 (s, 3H), 4.00 (s, 3H) 7.12 (s, 6H). 13C NMR (δ
ppm, CDCl3, 1H-decl.) 15.94, 16.06, 27.38, 32.03, 124.5, 126.95,
127.30, 129.33, 129.35, 129.6, 148.28, 150.7, 157.47, 159.55,
160.26. IR (KBr) 1805 (s), 1790 (s). Mass spectrum (70 eV) m/e
M+ 220. Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N,
12.72. Found: C, 59.84; H, 5.47; N, 12.68.
J O000267G