Reaction of chloroacetylenephosphonates with 5-thiotetrazoles

Article abstract of DOI:10.1016/j.tetlet.2013.07.032

1-Chloroacetylene-2-phosphonates react with 1-substituted 5-thio-1H-1,2,3,4-tetrazoles in anhydrous acetonitrile to form new fused heterocycles, 6-(dialkoxyphosphoryl)-3H-[1,3]thiazolo[3,2-d][1,2,3,4]tetrazol-7- ium chlorides, with a small quantity of Z-dialkyl (1,2-bis{[1-amino(methyl/ phenyl)-1H-tetrazol-5-yl]sulfanyl}ethenyl)phosphonates.

Full text of DOI:10.1016/j.tetlet.2013.07.032

Tetrahedron Letters 54 (2013) 5174–5177
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reaction of chloroacetylenephosphonates with 5-thiotetrazoles
z
⇑
Elena B. Erkhitueva , Albina V. Dogadina, Andrey V. Khramchikhin, Boris I. Ionin
St. Petersburg State Institute of Technology (Technical University), 26 Moscow Ave., St. Petersburg 190013, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Chloroacetylene-2-phosphonates react with 1-substituted 5-thio-1H-1,2,3,4-tetrazoles in anhydrous
acetonitrile to form new fused heterocycles, 6-(dialkoxyphosphoryl)-3H-[1,3]thiazolo[3,2-d][1,2,3,4]tet-
razol-7-ium chlorides, with a small quantity of Z-dialkyl (1,2-bis{[1-amino(methyl/phenyl)-1H-tetra-
zol-5-yl]sulfanyl}ethenyl)phosphonates.
Received 17 May 2013
Revised 25 June 2013
Accepted 5 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chloroacetylenephosphonates
Thiazolotetrazole
Heterocyclization
Phosphorylated thiazolotetrazoles
Zwitterions
15N NMR
[1,2-Bis(thiotetrazolyl)sulfanyl]
alkenephosphonates
Pharmaceutical chemistry has led to many drugs containing a
tetrazole ring as a structural fragment. Tetrazoles are not found
in nature, and there is scarce data on their biological activity. These
compounds are known to be resistant to metabolic processes. They
can be considered as isosteric analogs of various functional groups
in drugs. Thus, 5-substituted tetrazoles are nonclassical isosteres of
the carboxyl group and the thiazolidinedione ring, and 1,5-substi-
tuted tetrazoles can be used as isosteres of the cis-amide bond of
peptides. A class of cephalosporin antibiotics is known, which in-
cludes a 1-substituted 5-thiotetrazole fragment.1
Our previous work has shown the success of introducing a
5-substituted 3-thio-1,2,4-triazole (in the thione form) in
regioselective reactions with chloroacetylenephosphonates to give
phosphorylated heterocycles with fused rings of the thia-
zolotriazolium type.2
In this study, we have performed a similar reaction of chloro-
acetylenephosphonates3 with 1-substituted 5-thiotetrazoles.4 Ear-
lier, the thione structure of 5-substituted 3-thio-1,2,4-triazole was
clearly proven using 15N NMR spectroscopy: the spectrum showed
a doublet splitting for the signal due to the N-2 atom.2 We have ap-
plied the same strategy to reveal tautomeric forms of 5-substituted
thiotetrazoles. However, we failed to establish clearly the struc-
tures of the thiotetrazoles by 15N NMR spectroscopy, probably
because of the high acidity of the N-hydrogen atom. In the 15N
NMR spectra of the thiotetrazoles (recorded with and without pro-
ton decoupling) we observed only singlet signals. In the 1H NMR
spectra of the tetrazole, the ring proton appeared as a broad signal
due to proton exchange between two positions. Table 1 shows the
13C and 15N NMR spectral data of thiotetrazoles.
The reaction was carried out in anhydrous acetonitrile using an
equimolar ratio of the reactants, with stirring at 20–60 °C. Moni-
toring of the reaction progress was performed using 31P NMR spec-
troscopy. The reaction led to the complete disappearance of the
signal of the initial chloroacetylenephosphonate and resulted in
the preferential formation of the new cyclization products, 3-
substituted 6-dialkoxyphosphoryl-3H-thiazolo[3,2-d]tetrazol-7-
ium chlorides 1–9. However, it did not proceed chemoselectively:
new alkenephosphonates of linear structure, Z-dialkyl-(1,2-
bis{[1-amino(methyl/phenyl)-1H-tetrazol-5-yl]sulfanyl}eth-
enyl)phosphonates 10–12 were also obtained (see Scheme 1).5
The structures of the products were established on the basis of
1H, 13C, and 31P NMR spectra. For example, in the 1H NMR spectrum
of compound 3 upfield region there was a characteristic doublet
due to the vinyl proton of the thiazole fragment of the fused ring
at d 8.08 ppm (3JHP 11.0 Hz). The 13C NMR spectrum of compound
3 was characterized by the doublet signals of three carbon atoms
of the thiazole fragment: C-6 at 120.71 ppm (1JCP 216.3 Hz), C-5
at 137.39 ppm (2JCP 24.1 Hz), and C-8 at 150.07 ppm (3JCP < 1.0 Hz).
The chemical shifts of the phosphorus nuclei in chlorides 1–9 were
in the range of 3.1–8.8 ppm (see Table 2). Recrystallization of
⇑
Corresponding author.
E-mail address: serlxa@yandex.ru (E.B. Erkhitueva).
Deceased.
z
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.032

E. B. Erkhitueva et al. / Tetrahedron Letters 54 (2013) 5174–5177
5175
Table 1
NMR spectral data of 5-thiotetrazoles and 1-methyl-5-thiotetrazole sodium salta
R
N
1
5
S
N
2
HN
N
3
4
R
dC, ppm
dN, ppm
CH3
Ph
33.44 (CH3); 166.04 (C-5)
124.98 (m-CH); 129.81 (o-CH); 130.30 (p-CH); 134.27 (ipso-CH); 162.16 (C-5)
226.02 (N-1); 288.33 (N-4); 363.78 (N-2); 374.04 (N-3)
247.20 (N-1); 336.68 (N-4); 375.98 (N-2); 394.65 (N-3)
NH2
CH3 (Na salt)
156.08 (C-5)
32.99 (CH3); 168.11 (C-5)
77.23 (NH2); 246.27 (N-1); 312 (N-4); 377.03 (N-2); 387.07 (N-3)
224.16 (N-1); 320.92 (N-4); 363.68 (N-2); 385.55 (N-3)
a
Bruker avance 400, 100.61 MHz (13C), 40.54 MHz (15N), solvent DMSO-d6.
R1
N
RO OR
R1
N
Cl
S
Me
P
Me
N
Cl
S
MeCN
RT
N
+
O
N
N
S
R1
+
N
S
N
(RO)2P
Cl
R1
N
S
N
N
N
S
Δ
-MeCl
(RO)2P
O
N
N
MeO
O
N
N
N
N
HN N
P
O
N
(MeO)2P
O
N
N
O
N
1
1a
1-9, 93-95%
R=Me, R1=Me (1); R=Me, R1=Ph (2); R=Et, R1=Me (3);
10-12, 5-7%
Scheme 2. Synthesis of compound 1a.
R=Et, R1=Ph (4); R=Me, R1=NH2 (5); R=Et, R1=NH2 (6);
R=i-Pr, R1=Me (7); R=i-Pr, R1=Ph (8); R=i-Pr, R1=NH2 (9);
R=Me, R1=Me (10); R=Et, R1=Me (11); R=Et, R1=Ph (12)
due to the carbons of the alkene fragment appeared upfield: C-1,
dC 117.75 ppm (1JCP 196.1 Hz), C-2, dC 151.16 ppm (2JCP 23.1 Hz).
There were also singlet signals for the two carbon atoms of the
tetrazole fragment (C@N) at dC 149.11–149.94 ppm. The chemical
shifts of the phosphorus nuclei of compounds 10–12 were in the
range of 7.30–12.00 ppm.
X-ray diffraction data of isolated alkene 12 also confirmed the
formation of the phosphonate of a trisubstituted Z-alkene (Fig. 2).8
The same compound was obtained in high yield by an authentic
synthesis involving the reaction in anhydrous methanol catalyzed
by potassium tert-butoxide in a ratio of 1:2. The 31P NMR spectrum
Scheme 1. Synthesis of compounds 1–9.
chloride 1 from a mixture of MeOH and i-PrOH allowed the product
of dealkylation to be isolated, that is, zwitterionic monoester 1a,
that was consistent with published data (see Scheme 2).2
The 15N NMR spectrum of compound 1a contains singlet reso-
nances due to N-1 at dN 380.74, N-2 at dN 348.88 and N-3 at dN
216.65, and a doublet for N-7 at dN 268.28 (2JNP 5.6 Hz). More con-
vincing evidence was obtained from X-ray data. Figure 1 shows a
general view of representative zwitterion 1a.6
of the reaction mixture indicated the formation of
a small
The formation of the linear products 10–12 and their structures
were confirmed by an authentic synthesis, which was performed
using anhydrous methanol as the solvent, potassium tert-butoxide
as the catalyst, and the reactants in a ratio of 1:2. The yields of al-
kenes 10–12 in this synthesis were 80–85%.7
amount of the product with a cyclic structure, which points to the
occurrence of the thiotetrazole thionyl form, and related
thiolotetrazolylacetylenephosphonate.
These results suggest that the thiotetrazole thiol form reacts
with chloroacetylenephosphonates to produce compounds 10–12
with linear structure. A special feature of the reaction of chloroace-
tylenephosphonate with thiotetrazoles is the formation of com-
pounds 10–12 with thiotetrazole fragments at both carbon atoms
of the alkene system, in contrast to the published results,9 pointing
to the formation of substituted geminal alkenephosphonates under
similar reactions. The formation of vicinal substituted alkenes in
this case may be associated with a high mobility for the proton
in the tetrazole moiety, what causes elimination of HCl from the
The structures of trisubstituted alkenes 10–12 were confirmed
by NMR spectroscopy. In the 1H NMR spectrum the alkene proton
resonated upfield as a doublet in the range 8.50–8.99 ppm, with a
spin–spin coupling constant with the phosphorus nuclei (3JHP) of
13.5–16.0 Hz. The ratio of the integral intensities of the signals cor-
responded with the assumed structures of the compounds. The 13
C
NMR spectra also confirmed the structures of phosphorylated al-
kenes 10–12. In the 13C NMR spectrum of compound 11, signals
Table 2
NMR spectral data of compounds 1–9 and 1a
Compound
NMR spectral data: d, ppm (J, Hz)a
C-6 (1JCP
ESI-MS, m/z [M–Cl]b
C-5-H(3JHP
)
C-5 (2JCP
)
)
C-8 (3JCP
)
P
1
2
3
4
5
6
7
8
9
1a
8.09 (11.0)
8.19 (11.2)
8.08 (11.0)
8.30 (11.3)
8.29 (11.5)
8.29 (11.3)
8.08 (11.3)
8.29 (11.0)
8.30 (11.6)
8.25 (4.8)
138.37 (24.9)
136.31 (24.9)
137.39 (24.1)
136.43 (24.9)
137.57 (24.2)
136.69 (25.1)
136.52 (25.6)
135.72 (25.1)
135.93 (24.9)
132.19 (13.0)
119.25 (216.8)
120.64 (215.4)
120.71 (216.3)
121.14 (216.1)
119.11 (218.8)
120.54 (217.3)
121.86 (217.4)
122.44 (216.3)
121.66 (218.8)
131.15 (179.9)
149.78 (<1.0)
149.95 (<1.0)
150.07 (<1.0)
150.23 (<1.0)
150.74 (<1.0)
150.82 (<1.0)
150.27 (<1.0)
150.35 (<1.0)
150.89 (<1.0)
155.48 (8.0)
8.62
7.99
5.63
5.55
8.81
5.98
3.32
3.14
3.53
249.2070
311.2764
277.2561
339.3296
250.1950
278.2479
305.3132
367.3824
306.3010
256.9874[M+Na]
À7.09
a
Bruker avance 400, 400.13 MHz (1H), 100.61 MHz (13C), 161.98 MHz (31P), 40.54 MHz (15N), solvents CD3OD-d4 and CDCl3.
Bruker micrOTOF.
b

5176
E. B. Erkhitueva et al. / Tetrahedron Letters 54 (2013) 5174–5177
R
N
Cl
S
N
N
R
N
P
N
N
N
P
2S
Cl
N
H
R
N
R
N
Cl
S
MeOH
MeCN
RT
N
N
t
P
N
N
Cl
S
t-BuOK
P
R
N
N
H
N
H
N
N
S
H
P
R
N
N
H
A
-HCl
S
N
N
R
S
P
R
S
N
N
N
N
N
N N
N N
B
Scheme 3. A plausible reaction mechanism.
Due to the presence of the labile proton in the tetrazole moiety
of the intermediate sulfenyl chloride, in addition to the main path-
way involving attack of the N-4 atom on the phosphorus-substi-
tuted acetylene carbon atom, elimination of hydrogen chloride
occurs to form the product of chlorine substitution, followed by
addition of a second molecule of thiotetrazole to give the corre-
sponding phosphorylated 1,2-bis(thiotetrazolyl)-substituted al-
kene. However, the involvement of the thiotetrazole thiol forms
in this process cannot be completely denied. The formation of
fused cyclic compounds 1–9 is associated only with the thione
form of the thiotetrazole through the formation of a sulfenium
ion, which leads to the reverse polarization of the acetylene bond
compared to the initial chloroacetylenephosphonate.2
Figure 1. Crystal structure of zwitterion 1a (SHELXTL/ORTEP).
In conclusion, phosphorylated thiazolotetrazolium chlorides
1–9 have not been described previously in the literature. The struc-
tures of these substances suggest a potentially wide range of
biological activity. Nonphosphorylated analogs were obtained in
the 1970s through multi-stage syntheses as the salts, mainly as
the perchlorate or sulfite salts. The latter were found to be biolog-
ically active.10
Acknowledgments
This work was financially supported by the Ministry of Educa-
tion and Science of the Russian Federation within the framework
of the Federal Target Program, ‘‘Research and scientific-pedagogi-
cal personnel of innovative Russia’’ for 2009-2013 on the theme
‘‘Creating a new semi synthetic derivative and modifications of
existing polyene macrolide antibiotics in order to obtain high-
performance anti-fungal drugs’’ (State contract No. 2012-1.5-12-
000-1013-005).
Figure 2. Crystal structure of compound 12 (SHELXTL/ORTEP).
Supplementary data
intermediate sulfenic salt A to form an acetylenephosphonate-
containing thiotetrazole residue. Polarization of the acetylene bond
in the thiolotetrazole-acetylenephosphonate is probably almost
absent, as seen from the 13C NMR spectral data: both the acetylene
carbon atoms have almost the same chemical shifts.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.032. These data include MOL files and InChiKeys of the most
important compounds described in this article.
It should be noted that in the 1H, 13C, and 31P NMR spectra of the
reaction mixture, in addition to the signals of compounds 1–9 and
10–12, we detected signals related to the acetylenic structure B.
Product B was identified from the 13C NMR spectra, which
contained doublet signals due to C-1 at d 85.1–89.6 ppm (1JCP
288.8–292.2 Hz), and C-2 at d 82.1–84.2 ppm (2JCP 49.3–51.3 Hz).
References and notes
1. Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd. 2007, 1,
3–13.
2. (a) Erkhitueva, E. B.; Dogadina, A. V.; Khramchikhin, A. V.; Ionin, B. I.
Tetrahedron Lett. 2012, 53, 4304–4308; (b) Erkhitueva, E. B.; Dogadina, A. V.;
Khramchikhin, A. V.; Ionin, B. I. Russ. J. Gen. Chem. 2011, 81, 2377–2378. Zhur.
Obsch. Khim. 2011, 81, 1925–1926.
3. (a) Jonin, B. I.; Petrow, A. A. J. Gen. Chem. USSR (Engl. Transl.) 1965, 35, 1910.
Zh. Obsch. Khim. 1965. 35, p. 1917–1921.; (b) Pielichowski, J.; Popielarz, R.
Synthesis 1984, 5, 433–434.
4. 1-Phenyl-5-thiotetrazole and 1-methyl-5-thiotetrazole are commercially
available (Alfa Aesar). 1-Amino-5-thiotetrazole was synthesized as described
in: Wagatsuma, M.; Hatsuno, S.; Yamaguchi, T.; Ohshima, S. U.S. Patent
4,576,938, 1986.
1
The value of JCP coupling constant clearly shows the bonding be-
tween the phosphorus atom and the sp3-hybridized carbon atom.
For comparison, the related data in the 13C NMR spectrum of
the original chloroacetylenephosphonates are as follows: C-1,
d
58.3–59.7 ppm (1JCP 306.8–308.3 Hz), C-2, d 79.7–80.6 ppm
(2JCP 57.3–58.6 Hz).
According to the obtained results, we assume the following
mechanism for the reaction of chloroacetylenephosphonates with
1-substituted 5-thiotetrazoles (see Scheme 3).
5. Typical experimental procedure for the synthesis of compounds 1–9. To a solution
of 5 mmol of a dialkyl chloroacetylenephosphonate in 10 ml of anhydrous

E. B. Erkhitueva et al. / Tetrahedron Letters 54 (2013) 5174–5177
5177
MeCN was added 5 mmol of 1-amino(methyl/phenyl)-5-thiolo-1,2,3,4-
tetrazole under vigorous stirring at room temperature. The resulting
suspension was stirred vigorously at room temperature for 13–18 h. The
8. The X-ray crystal structure for compound 12 has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 932042. Formula: C20H21N8O3PS2. Crystal system triclinic, space group
p1. Unit cell parameters: a = 9.2740(9) Å, b = 10.0813(10) Å, c = 13.9866(13) Å,
obtained precipitate was filtered off (for compounds with
a methyl
substituent) and washed with Et2O to afford the thiazolotetrazolium salts 1–
9. Products with a phenyl substituent were clear solutions. The solvent was
removed under vacuum, and the viscous residue was recrystallized from
MeOH/i-PrOH (1:1) for compound 1a, and from EtOH/H2O (1:1) for other
compounds.
a
= 96.614(5)°,b = 109.330(5)°,
c
l
= 103.610(5)°. V = 1172.4(2) Å3; T = 296(2) K;
Z = 2;
q
calc = 1.463 Mg/m3;
= 0.336 mmÀ1 (for MoK
a, k = 0.71073 Å);
F(000) = 536; full-matrix least-squares on F2; data = 7022; parameters = 379;
restraints = 0; R(all) = 0.0460; wR(all) = 0.1138; GoF(all) = 1.011.
9. (a) Nakhmanovich, A. S.; Elokhina, V. N.; Karnaukhova, R. V.; Skvortsova, G. G.;
Kalikhman, I. D. Chem. Heterocycl. Compd. 1982, 18, 1154–1156. Khim.
Geterotsikl. Soed. 1982, 18, 1489–1491.; (b) Nakhmanovich, A. S.; Komarova,
T. N.; Mansurov, Yu. A. Bull. Acad. Sci. USSR 1984, 33, 1077–1078. Izv. Akad.
Nauk SSSR. 1984, 5, 1173–1175; (c) Garibina, V. A.; Leonov, A. A.; Dogadina, A.
V.; Ionin, B. I.; Petrov, A. A. J. Gen. Chem. USSR (Engl. Transl.) 1985, 55, 1994–
2006 (1771–1781).; (d) Garibina, V. A.; Leonov, A. A.; Dogadina, A. V.; Ionin, B.
I.; Petrov, A. A. J. Gen. Chem. USSR (Engl. Transl.) 1987, 57, 1481–1488 (1321–
1327).; (e) Stepanova, N. P.; Orlova, N. A.; Turbanova, E. S.; Petrov, A. A. J. Org.
Chem. USSR (Engl. Transl.) 1986, 22, 388–389. Zh. Org. Khim. 1986, 22, 439–
440.; (f) Tikhomirov, D. A.; Slyadevskaya, O. S.; Eremeev, A. V. Chem.
Heterocycl. Compd. 1991, 27, 966–969. Khim. Geterotsikl. Soed.1991, 9,
1205–1208.
6. The X-ray crystal structure for compound 1a has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 932040. Formula: C5H11N4O5PS. Crystal system orthorhombic, space
system P212121. Unit cell parameters: a = 6.89430(17) Å, b = 9.1278(3) Å,
c = 17.2139(5) Å,
a
= 90°, b = 90°,
c
= 90°. V = 1083.27(5) Å3; T = 100(2) K;
Z = 4;
q
calc = 1.657 Mg/m3;
l
= 4.253 mmÀ1 (for CuK
a,
k = 1.54184 Å);
F(000) = 560; full-matrix least-squares on F2; data = 2148; parameters = 163;
restraints = 2; R(all) = 0.0253; wR(all) = 0.0639; GoF(all) = 1.007.
7. Typical experimental procedure for the synthesis of compounds 10–12. To a
mixture of 2.5 mmol of a dialkyl chloroacetylenephosphonate in 10 ml of
anhydrous MeOH and a catalytic amount of KOtBu (0.3 mmol) was added
5 mmol of 1-amino(methyl/phenyl)-5-thiolo-1,2,3,4-tetrazole. The mixture
was stirred at room temperature for 1 h and then at 50–60 °C for 8–10 h. The
solvent was removed under vacuum and the viscous residue was recrystallized
from aqueous EtOH. The yields of alkenes 10–12 were 80–85%.
10. (a) Alper, H.; Stout, R. W. J. Heterocycl. Chem. 1973, 10, 5–10; (b) Askani, U.;
Neidlein, R.; Tauber, J. Pharmazie 1971, 26, 463–465; (c) Eldawy, M. A.;
Chaaban, I.; Mehanna, A. S. Egypt J. Pharm. Sci. 1978, 19, 185–200.