Highly regioselective heterocyclization reactions of 1H-1,2,4-triazole-3- thiols with chloroacetylenephosphonates

Article abstract of DOI:10.1016/j.tetlet.2012.05.157

1-Chloroacetylene-2-phosphonates react with 1H-1,2,4-triazole-3-thiols in anhydrous acetonitrile with high regioselectivity to form the fused heterocycles, 6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ylium chlorides 1-5. A significant difference from the previously known reactions of binucleophiles with haloacetylenes is the involvement of both acetylenic carbon atoms in the heterocycle formation. A reaction mechanism is hypothesized that assumes the formation of a sulfenium cation at the acetylene C-1 atom followed by attack of the C-2 atom by the ring N-2 atom. Compounds 1-5 easily lose one alkyl group from the dialkoxyphosphoryl fragment to form zwitterions (e.g., 6-8) which further can be transformed into inner salts 9 and 10 when heated with concentrated hydrochloric acid.

Full text of DOI:10.1016/j.tetlet.2012.05.157

Tetrahedron Letters 53 (2012) 4304–4308
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Tetrahedron Letters
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Highly regioselective heterocyclization reactions
of 1H-1,2,4-triazole-3-thiols with chloroacetylenephosphonates
⇑
Elena B. Erkhitueva , Albina V. Dogadina, Andrey V. Khramchikhin, Boris I. Ionin
St. Petersburg State Institute of Technology (Technical University), 26 Moscovskii prospect, 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 1H-1,2,4-triazole-3-thiols in anhydrous acetonitrile with
high regioselectivity to form the fused heterocycles, 6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-
b][1,2,4]triazol-7-ylium chlorides 1–5. A significant difference from the previously known reactions of
binucleophiles with haloacetylenes is the involvement of both acetylenic carbon atoms in the heterocycle
formation. A reaction mechanism is hypothesized that assumes the formation of a sulfenium cation at the
acetylene C-1 atom followed by attack of the C-2 atom by the ring N-2 atom. Compounds 1–5 easily lose
one alkyl group from the dialkoxyphosphoryl fragment to form zwitterions (e.g., 6–8) which further can
be transformed into inner salts 9 and 10 when heated with concentrated hydrochloric acid.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 26 March 2012
Revised 17 May 2012
Accepted 31 May 2012
Available online 12 June 2012
Keywords:
Chloroacetylenephosphonates
Binucleophiles
Thiazolotriazole
Thione-thiol tautomerism
Heterocyclization
Phosphorylated thiazolotriazoles
Zwitterions
15N NMR spectroscopy
Five-membered heterocycles with two or three heteroatoms,
such as imidazoles, thiazoles, triazoles and others, are key struc-
tural units in many pharmaceutical preparations.1 The usual course
of the synthesis of such compounds consists of the reaction of
binucleophiles (diamines, diols and thioloamines containing nucle-
ophilic sites at the vicinal position) with carbonyl and carboxyl
compounds. Such structures have increasingly been created by
using 1-haloacetylenes. The reactivity of the latter is sufficiently
high when the second acetylenic carbon atom is connected to an
electron-withdrawing activating fragment such as a carbonyl, car-
boxyl or phosphoryl group.2 Less active 1-haloacetylenes contain-
ing an electron-donor group at the 2-position react with
binucleophiles in the presence of a catalyst.3 The haloacetylenes
show advantages over carbonyl (carboxyl) containing reagents as
they do not release water, which may affect the reaction course.
The reactions of haloacetylenes with binucleophiles usually
proceed regioselectively with attack by both nucleophilic sites on
the acetylenic carbon atom C-1 connected to the halogen. For
example, reactions of 1-chloroacetylene-2-phosphonates with
ortho-phenylenediamine, ortho-aminophenol, 1,2-alkanediols and
vicinal hydroxyalkylamines afford 2-(dialkoxyphosphorylmethyl)-
substituted benzimidazoles, benzoxazoles, 1,3-oxolanes and 4,5-
dihydrooxazoles, respectively.2 A similar trend in the reactions
with binucleophiles is known for
haloacetylenes.4
a
number of other
In continuation of our studies on the reactions of chloroace-
tylenephosphonates with mono- and binucleophiles, we utilized
these highly reactive compounds in condensations with heterocy-
clic binucleophiles with the aim of obtaining phosphorylated five-
membered condensed heterocycles. As heterocyclic binucleophiles,
we used readily accessible 5-substituted 4-amino-1H-1,2,4-tria-
zole-3-thiols produced by the reaction of carboxylic acids and their
derivatives with thiocarbazide.5
To our best knowledge, there is only one publication4 concern-
ing the reaction of 4-aminotriazoles with haloacetylenes. The prod-
ucts were fused heterocyclic systems comprising sulfur and NH2
groups as the nucleophilic sites and one haloacetylene carbon
atom C-1 (Scheme 1).
However, we recently encountered an unexpected course of the
reaction of dimethyl 1-chloroacetylene-2-phosphonate with 4-ami-
no-5-methyl-1H-1,2,4-triazole-3-thiol. The reaction proceeded
readily under mild conditions with high selectivity to afford 3-ami-
no-6-(dimethoxyphosphoryl)-2-methyl-3H-thiazolo[3,2-b][1,2,4]
triazol-7-ylium chloride (1) as a result of involvement of bothcarbon
atoms of the haloacetylenic compound in formation of a condensed
thiazolotriazolium ring6 (Scheme 2).
The reaction was conducted by stirring equivalent amounts of
the reagents for 3–5 h in anhydrous acetonitrile at room tempera-
ture. It is noteworthy that the amino group at position 4 was not
involved in the reaction, while the condensed thiazole ring was
⇑
Corresponding author.
E-mail address: serlxa@yandex.ru (E.B. Erkhitueva).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.157

E. B. Erkhitueva et al. / Tetrahedron Letters 53 (2012) 4304–4308
4305
H
H
HS
N
S
N
R
O
R
O
N
N
R
O
N
N
C
H
N
Br
S
N
N
Br
N
H
Ph
H2N
Ph
Ph
H2N
Br
R = Ph, 2-thienyl
Scheme 1. Reaction of the 4-amino-3-mercapto-5-phenyl-1,2,4-triazole with 1-bromo-2-acyl acetylenes.
R1
N4
R1
NH2
O
Cl
N
S
N4
3
NH2
Me
O
N
3
5
5
HS
+
Me
S
N
HS
R
R
(MeO)2P
Cl
(MeO)2P
N
HN
N
1
N
N
1
N
N
2
2
A
B
1
R1=Me, NH2
Scheme 2. Synthesis of compound 1.
Scheme 3. Tautomeric forms of 1H-1,2,4-triazole-3-thiols.
formed through the nitrogen atom N-2 of the triazole ring resulting
in a quaternary salt. The structure of compound 1 was proved by
1H, 13C and 31P NMR spectroscopy and an XRD study (Fig. 1).
To identify the causes of the unusual reaction course, we ex-
plored in more detail the structure of the parent 3-thiol-1,2,4-tria-
zole, expanded the range of compounds studied and applied a
variety of reaction conditions.
5 (Scheme 4) with the same core structure, that is 2,3-substituted
6-(dialkoxyphosphoryl)-2-methyl-3H-thiazolo[3,2-b][1,2,4]tria-
zol-7-ylium chlorides.
Chlorides 1–5 (see Table 2) were crystalline substances melting
at 200–250 °C with decomposition, and were poorly soluble in or-
ganic solvents, and readily soluble in water, dimethyl sulfoxide,
methanol and ethanol.7
The 1H-1,2,4-triazole-3-thiols contain several nucleophilic sites
and can exist in two tautomeric forms: thiol A and thione B
(Scheme 3).
The structure of the previously synthesized6 salt 1 was proved
by an X-ray diffraction study8 (Fig. 1). The structures of compounds
2–5 follow from the similarities of their NMR and mass spectral
characteristics to those of compound 1 (see Table 4).
Using 15N NMR spectroscopy (see Table 1), we found that the
original triazoles existed almost exclusively as the thione isomers
B. The spectra of 4-aminotriazoles contain three signals due to
the 15N nuclei of the triazole ring and a signal for the amine nitro-
gen nucleus. The accuracy of the assignment of the signals was
In the 1H NMR spectra of compounds 1–5 the sole proton C-5-H
on the thiazolotriazolium ring resonated at a low field at ꢀ8.5 ppm
as a doublet due to spin–spin coupling with the phosphorus nu-
cleus, JHP 8.0 Hz. The HCO protons in the R2 group of the
(R2O)2P(O) fragment resonated as typical multiplets split by the
1
confirmed by recording the spectra with no 15NÀ H decoupling:
the signals of the N-1, N-4 nuclei remained as singlets, whilst the
signal for N-2 was split into a doublet, and that of the amine nitro-
gen was a triplet. These spectral data correspond to the thione
structure.
3
phosphorus nucleus with the coupling constant JHP ꢀ12 Hz. The
integral intensities of the signals corresponded to the proposed
structures. In the 13C NMR spectra the signal of the C-6 carbon
atom linked directly to the phosphorus atom was a doublet of
We found that regardless of the substituents at C-5 of the thi-
onotriazole, as well as when the substituent R1 at C-4 was a methyl
instead of an amino group, the reaction in anhydrous acetonitrile,6
in all cases, resulted in the formation of condensed heterocycles 1–
1
low intensity at 125 ppm with a spin–spin coupling constant, JCP
215–219 Hz, typical of phosphonates with an sp2-hybridized car-
bon atom. The signal due to the C-5 carbon of greater intensity
was shifted slightly downfield and split into a doublet, 131–
2
132 ppm, JCP 14–18 Hz. The assignment of this signal was con-
firmed by recording the 13C NMR spectrum of compound 1 without
proton decoupling: the signal was further split into a doublet with
a coupling constant, 1JCH 204.2 Hz, while the signal at 125 ppm was
2
split with a small constant, JCH 9.0 Hz.
Prolonged exposure of compounds 1–5 to water, or heating in a
polar solvent at a temperature of 50–70 °C, resulted in cleavage of
one alkyl group of the dialkoxyphosphoryl fragment with forma-
tion of a phosphonate monoanion and release of an alkyl halide,
to form the corresponding monophosphonates of zwitterionic
structure (see Table 3). Cleavage of the methyl group occurred
readily, resulting in a low yield of compound 1 and the failure to
isolate diesters corresponding to the zwitterions 7 and 10. Heating
zwitterions 6–8 with hydrochloric acid resulted in removal of the
second alkyl group on the phosphoryl fragment to form zwitterions
of acid structure (internal salts). The zwitterions 6–8 were crystal-
line substances melting at temperatures above 200 °C with decom-
position.7 Zwitterions 9 and 10 were crystalline substances melting
with decomposition at temperatures above 200 °C, and were read-
ily soluble in water, and poorly soluble in organic solvents includ-
ing alcohols.9
The structures of zwitterions 710 and 911 were proved by X-ray
diffraction studies (Figs. 2 and 3, respectively). The structures of
Figure 1. Crystal structure of compound 1 (SHELXTL/ORTEP).

4306
E. B. Erkhitueva et al. / Tetrahedron Letters 53 (2012) 4304–4308
Table 1
15N NMR spectral data of 1,2,4-triazole derivatives
R
R1
15N chemical shifts (ppm) and spin–spin coupling constants (1JNH, Hz)
N1
N2
N4
NH2
R1
Me
NH2
265.42 s
197.32 d
(108.2)
188.89 s
66.62 t
(70.1)
Et
Pr
NH2
NH2
NH2
265.30
265.90
197.54
197.33
255 d
(107.8)
204.94
192.28 d
(107.0)
286.92
187.54
187.04
189.55 s
66.22
66.20
69.00 t
(70.0)
—
45.80 t
(69.0)
67.69
4
N
3
5
S
2-MeOC6H4
270.68 d
(2JNH 7.7)
278.48
232.03 d
(2JNH 12.5)
292.41
R
H
NH2
CH3
H
168.58
157.28 d
(101.3)
184.93
HN
2
N
1
CH3 (S–K salt)
NH2
R1
3N
R1
R1
N
Cl
Cl
N 4
4
..
8
3
2
5
S
S
R
MeCN
RT, 4-15 h
S
R
5
N
N
H
HN
N
N N
H
7
1
2
1
6
O
(OR2)
2
P
O
O
P(OR2)2
O
P
OR2
Scheme 4. Synthesis of compounds 1–5, compounds 6–8.
Table 2
2,3-Substituted
chlorides
6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ylium
Product
R
R1
R2
Time (h) Yield (%)
1
2
3
4
5
Me NH2 Me
Me NH2 Et
Me NH2 i-Pr 12–15
4–5
10–12
2–5a
67
R1
N3
Cl
57
4
8
39a
24a
2
H
H
Me
Me
Et
1–1.5
S
R
i-Pr 1–1.5
N7
5
N
1
6
P(OR2 )2
O
a
Low yield obtained due to conversion into zwitterions.
Figure 2. Crystal structure of zwitterion 7 (SHELXTL/ORTEP).
Table 3
Examples of zwitterions 6–10
Product
R
R1
R2
Time
(h)
Yield
(%)
R1
6
7
Me
2-
MeOC6H4
H
Pr
NH2 Me 4–5
NH2 Me 6–8
72a
48a
N3
S4
52a
48b
50b
8
2
8
9
10
Me
Me 6–8
R
NH2
NH2
H
H
16
16
5
N7
O
OR2
N1
2-
MeOC6H4
6
P
O
a
Yield obtained by heating in ethanol or water.
Yield obtained by heating in concentrated hydrochloric acid.
b
Figure 3. Crystal structure of zwitterion 9 (SHELXTL/ORTEP).
zwitterions 6, 8 and 10 follow from the similarities of their NMR
characteristics to those of compounds 1, 7 and 9 (see Table 4).
The main peaks in the ESI-MS spectra of compounds 6–9 corre-
spond to the protonated molecules.
The obtained results allowed us to hypothesize that the reaction
in an aprotic medium involves formation of a sulfenium cation
with cleavage of chloride. The positively charged sulfur polarizes
the triple bond oppositely to that which occurred in the original
1-chloroacetylene-2-phosphonate, which leads to almost simulta-
neous attack by the second nucleophilic site, the N-2 nitrogen
atom, on the acetylene carbon atom C-2, with proton transfer to
C-1. The reaction is completed by redistribution of electron density
leading to neutral sulfur and positively charged N-7 atoms.
We observed that in contrast to previous results, the same reac-
tions of thiolotriazoles with chloroacetylenephosphonates, but car-
ried out in anhydrous acetonitrile in the presence of potassium

E. B. Erkhitueva et al. / Tetrahedron Letters 53 (2012) 4304–4308
4307
Table 4
NMR spectral parameters and mass ions in the ESI-MS spectra of compounds 1–10
Compound
NMR spectral parameters: d, ppm (J, Hz)a
C-5 (2JCP C-6 (1JCP
ESI-MS, m/z
C-5-H (3JHP
)
C-2
)
)
C-8 (3JCP
)
P
1
2
3
4
5
6
7
8
9
8.53 (5.6)
8.43 (8.0)
8.36 (8.0)
8.03 (8.0)
8.49 (8.0)
7.93 (8.0)
7.99 (4.0)
7.97 (4.0)
7.45 (8.0)
7.92 (8.0)
161.39
160.92
160.91
150.35
150.38
160.15
158.78
149.71
162.51
158.64
132.28 (21.8)
131.66 (18.1)
131.26 (18.1)
133.15 (17.1)
132.77 (18.1)
125.84 (15.0)
125.67 (14.1)
127.41 (15.1)
125.04 (16.0)
124.61 (15.1)
123.72 (215.2)
124.27 (217.3)
125.24 (218.3)
124.27 (219.3)
125.31 (219.3)
130.43 (187.1)
131.57 (184.8)
130.30 (187.1)
130.84 (193.1)
132.68 (188.1)
155.83 (11.0)
154.98 (12.0)
154.98 (11.0)
154.48 (12.0)
154.55 (11.0)
154.57 (10.0)
154.92 (10.0)
154.06 (9.0)
154.11 (9.0)
154.69 (9.0)
2.68
262.73 [M-Cl]+b
À0.90
À3.90
À1.02
À4.02
À3.92
À4.07
À3.97
À7.81
À6.37
291.0698 [M-Cl]+c
319.2907 [M-Cl]+c
276.0580 [M-Cl]+c
304.0894 [M-Cl]+c
249.0226 [M+H]+c
363.0314 [M+Na]+c
234.0124 [M+H]+c
263.0415 [M+H]+c
326.75 [M]+b
10
a
b
c
Bruker Avance 400, 400.13 MHz (1H), 100.61 MHz (13C), 161.98 MHz (31P), 40.54 MHz (15N), solvents D2O and DMSO-d6.
TSQ Quantum Access MAX.
Bruker micrOTOF.
2001, 424–428; (c) Yu, H.-X.; Ma, J.-F.; Xu, G.-H.; Li, S.-L.; Yang, J.; Liu, Y.-Y.;
Cheng, Y.-X. J. Organomet. Chem. 2006, 691, 3531–3539; (d) Smicius, R.;
Burbuliene, M. M.; Jakubkiene, V.; Udrenaite, E.; Vainilavicius, P. J. Heterocycl.
Chem. 2007, 44, 279–284; (e) Aytac, S. P.; Tozkoparan, B.; Kaynak, F. B.; Aktay,
G.; Goektas, O.; Uenuevar, S. Eur. J. Med. Chem. 2009, 44, 4528–4538; (f) Kaynak,
F. B.; Aytac, S. P.; Tozkoparan, B. Struct. Chem. 2010, 21, 795–802.
carbonate, or in a protic solvent (methanol or acetonitrile-metha-
nol mixture), or using potassium triazolothiolate, resulted in diffi-
cult to separate mixtures that included, in addition to the
thiazolotriazolium derivatives, compounds containing, by NMR
spectroscopy, PCH@ and PCH2 groups, as well as other substances.
Obviously, in these cases, parallel reactions proceed with attack of
both nucleophilic sites on the haloacetylenic carbon atom. In the
presence of a proton-donor (solvent) or a base (potassium thio-
late), the sulfenium cation was not formed or was rapidly con-
verted into a sulfide group, which exhibited an electron-donor
effect causing a change in the reaction regioselectivity.
6. Erkhitueva, E. B.; Dogadina, A. V.; Khramchikhin, A. V.; Ionin, B. I. Russ. J. Gen.
Chem. 2011, 81, 2377–2378. Zh. Obsch. Khim. 2011, 81, 1925–1926.
7. Typical experimental procedure for the synthesis of compounds 1–5 and 6–8. To a
solution of 5 mmol of
anhydrous MeCN under vigorous stirring at room temperature was added
5 mmol of 4-amino(methyl)-3-thiolo-5-alkyl(aryl)-1,2,4-triazole. The
a dialkyl chloroacetylenephosphonate in 10 ml of
suspension was stirred vigorously at room temperature for 3–15 h. The
resulting precipitate was filtered and washed with Et2O to afford the
thiazolotriazolium salt 1–5 (see Table 2). The solvent was removed from the
filtrate under vacuum, and the viscous crystalline residue was recrystallized
from a mixture of MeOH–2-propanol (1:1). The resulting crystals were the
corresponding zwitterions 6–8 (see Table 3). The zwitterions with ethoxy- and
isopropoxyphosphoryl groups (not considered in this Letter) can be obtained
from the corresponding thiazolotriazolium salts by heating in EtOH or H2O for
2–3 h at 70–80 °C. 3-Amino-6-(dimethoxyphosphoryl)-2-methyl-3H-thiazolo[3,2-
b][1,2,4]triazol-7-ylium chloride (1). IR (KBr, cmÀ1): 567, 617, 702, 760, 818, 845,
968, 1049, 1192, 1238, 1269, 1373, 1404, 1524, 1558, 1651, 2951, 3013, 3121.
1H NMR (400.13 MHz, D2O): d 2.72 (s, 3H, CH3), 3.94 (d, 3JHP 11.6 Hz, 6H, OCH3),
Acknowledgements
The authors would like to thank Valentin I. Zakharov PhD (SPb-
STI; the Department of Organic Chemistry; Laboratory NMR) for
NMR spectral analyses and Konstantin Lysenko (INEOS, Laboratory
for X-Ray Diffraction Studies) for XRD data.
3
8.53 (d, JHP 5.6 Hz, 1H, H-ring). 13C NMR (100.61 MHz, D2O): d 10.10 (s, CH3),
55.55 (d, 2JCP 6.0 Hz, OCH3), 123.72 (d, 1JCP 215.2 Hz, C6), 132.28 (d, 2JCP 21.8 Hz,
Supplementary data
3
C5), 155.83 (d, JCP 11.0 Hz, C8), 161.39 (s, C2). 31P NMR (161.98 MHz, D2O): d
2.68. ESI-MS: calcd for C7H12ClN4O3PS: 298.6869; found: 262.73 (M-Cl)+. 3-
Amino-6-(diethoxyphosphoryl)-2-methyl-3H-thiazolo[3,2-b][1,2,4]triazol-7-ylium
chloride (2). IR (KBr, cmÀ1): 542.9, 580, 761, 970, 1004, 1089, 1066, 1239, 1264,
1298, 1398, 1442, 1558, 1634, 2938, 2990, 3095, 3186. 1H NMR (400.13 MHz,
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.05.157.
3
3
D2O): d 1.30 (t, JHH 8.0 Hz, 6H, OCH2CH33), 2.67 (s, 3H, CH3), 4.29 (dq, JHH
8.0 Hz, JHP 12.0 Hz, 4H, OCH2), 8.43 (d, JHP3 8.0 Hz, 1H, H-ring). 13C NMR
3
(100.61 MHz, D2O): d 9.83 (s, CH3), 15.51 (d, JCP 6.0 Hz, OCH2CH3), 66.33 (d,
References and notes
2JCP 6.0 Hz, OCH2), 124.27 (d, JCP 217.3 Hz, C6), 131.66 (d, JCP 18.1 Hz, C5),
154.98 (d, 3JCP 12.0 Hz, C8), 160.92 (s, C2). 31P NMR (161.98 MHz, D2O): d À0.90.
ESI-MS: calcd for C9H16ClN4O3PS: 326.7401; found: 291.0698 (M-Cl)+. 3-
Methyl-6-(diethoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ylium chloride
(4). IR (KBr, cmÀ1): 557, 574, 795, 936, 984, 1016, 1043, 1069, 1164, 1253,
1269, 1299, 1454, 1567, 1835, 2910, 2995, 3116. 1H NMR (400.13 MHz, D2O): d
1
2
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3
3
3
1.32 (t, JHH 8.0 Hz, 6H, CH3), 4.10 (s, 3H, NCH3), 4.32 (dq, JHH 8.0 Hz, JHP
12.0 Hz, 4H, OCH2), 8.03 (d, JHP 8.0 Hz, 1H, H-ring), 9.07 (s, 1H, N@CH). 13C
3
3
NMR (100.61 MHz, D2O): d 15.53 (d, JCP 6.0 Hz, OCH2CH3), 34.72 (s, NCH3),
66.45 (d, 2JCP 6.0 Hz, OCH2), 124.27 (d, 1JCP 219.3 Hz, C6), 133.15 (d, 2JCP 17.1 Hz,
C5), 150.35 (s, C2), 154.48 (d, JCP 12.0 Hz, C8). 31P NMR (161.98 MHz, D2O): d
3
À1.02. ESI-MS: calcd for C9H15ClN3O3PS: 311.7254; found: 276.0580 (M-Cl)+.
Methyl
3-amino-2-methyl-3H-thiazolo[3,2-b][1,2,4]triazol-7-ylium-6-
phosphonate (6). IR (KBr, cmÀ1): 548, 555, 586, 762, 962, 1044, 1099, 1106,
1182, 1251, 1651, 1670, 3107, 3259, 3378, 3401. 1H NMR (400.13 MHz, D2O): d
3
3
2.63 (s, 3H, CH3), 3.52 (d, JHP 12.0 Hz, 3H, OCH3), 7.93 (d, JHP 8.0 Hz, 1H, H-
ring). 13C NMR (100.61 MHz, D2O): d 9.77 (s, CH3), 52.91 (d, 2JCP 6.0 Hz, OCH3),
125.84 (d, 2JCP 15.0 Hz, C5), 130.43 (d, 1JCP 187.1 Hz, C6), 154.57 (d, 3JCP 10.0 Hz,
C8), 160.15 (s, C2). 15N NMR (40.54 MHz, D2O): d 66.06 (s, NH2), 173.43 (s, N3),
232.84 (d, 2JNP 6.6 Hz, N7), 269.09 (s, N1). 31P NMR (161.98 MHz, D2O): d À3.92.
ESI-MS: calcd for C6H9N4O3PS: 248.1994; found: 249.0226 (M+H)+.
3. (a) Fan, X.; He, Y.; Zhang, X.; Guo, S.; Wang, Y. Tetrahedron 2011, 67, 6369–
6374; (b) Zhang, M.-T.; Irebo, T.; Johansson, O.; Hammarstroem, L. J. Am. Chem.
Soc. 2011, 133, 13224–13227; (c) Shen, W.; Kohn, T.; Fu, Z.; Jiao, X. Y.; Lai, S.;
Schmitt, M. Tetrahedron Lett. 2008, 49, 7284–7286.
4. Glotova, T. E.; Nakhmanovich, A. S.; Sigalov, M. V. J. Org. Chem. USSR (Engl.
Transl.) 1988, 24, 1941–1945. Zh. Org. Khim. 1988, 24, 2151–2156.
8. The X-ray crystal structure for compound
1 has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 848044. Formula: C7H12ClN4O3PS. Crystal system monoclinic, space
group P2(1)/c. Unit cell parameters: a = 15.3837(11) Å, b = 6.0034(4) Å,
c = 14.5397(10) Å,
T = 100(2) K; Z = 4;
a
= 90°, b = 110.5360(10)°,
c
= 90°. V = 1257.47(15) Å3;
q
calc = 1.578 Mg/m3; = 0.599 mmÀ1 (for MoK
l a,
5. (a) Beyer, H.; Kroege, C.-F. Liebigs Ann. Chem. 1960, 637, 135–145; (b)
Cartwright, D. D. J.; Clark, B. A. J.; McNab, H. J. Chem. Soc., Perkin Trans. 1
k = 0.71073 Å); F(000) = 616; full-matrix least-squares on F2; data = 3710;
parameters = 157; restraints = 0; wR(all) = 0.0837; GoF(all) = 1.034.

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E. B. Erkhitueva et al. / Tetrahedron Letters 53 (2012) 4304–4308
9. Typical procedure for obtaining zwitterions 9 and 10. A solution of 2.5 mmol of
compound 6–8 in 5–10 ml of concentrated HCl was heated at a temperature of
80–90 °C for 16 h. The solvent was removed under vacuum and the residue was
recrystallized from a mixture of EtOH–H2O (2:1) (see Table 3). 3-Amino-2-(o-
methoxyphenyl)-6-phosphono-3H-thiazolo[3,2-b][1,2,4]triazolo-7-ylium (internal
salt) (10). IR (KBr, cmÀ1): 558, 694, 744, 762, 968, 1010, 1056, 1170, 1257, 1286,
1302, 1350, 1493, 1573, 1609, 2974, 3152. 1H NMR (400.13 MHz, D2O): d 3.86
10. The X-ray crystal structure for compound 10 has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 867704. Formula: C12H13N4O4PS. Crystal system orthorhombic, space
group Pbca. Unit cell parameters: a = 8.5974(5) Å, b = 13.6503(8) Å,
c = 23.7719(14) Å,
Z = 8;
calc = 1.620 Mg/m3;
F(000) = 1408; full-matrix
a
= 90°, b = 90°,
= 0.372 mmÀ1 (for MoK
least-squares on
F2;
c
= 90°. V = 2789.8(3) Å3; T = 100(2) K;
q
l
a
,
k = 0.71073 Å);
data = 3701;
3
3
(s, 3H, OCH3), 7.14 (t, JHH 8.0 Hz, m-CH, 1H), 7.22 (d, JHH 8.0 Hz, m-CH, 1H),
parameters = 219; restraints = 8; wR(all) = 0.0826; GoF(all) = 1.150.
11. The X-ray crystal structure for compound has been deposited at the
7.54 (dd, 3JHH 8.0 Hz, 4JHH 1.5 Hz, o-CH, 1H), 7.58 (dt, 3JHH 8.0 Hz, 4JHH 1.5 Hz, p-
9
3
CH, 1H), 7.92 (d, JHP 8.0 Hz, 1H, H-ring). 13C NMR (100.61 MHz, D2O): d 56.13
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 867702. Formula: C7H11N4O3PS. Crystal system orthorhombic, space
group Pbca. Unit cell parameters: a = 12.5994(9) Å, b = 8.8703(6) Å,
2
(s, OCH3), 110.56 (s, ipso-C), 112.33 (s, m-C), 121.33 (s, m-C), 124.61 (d, JCP
15.1 Hz, C5), 132.00 (s, o-C), 132.68 (d, 1JCP 188.1 Hz, C6), 135.11 (s, p-C), 154.69
(d, 3JCP 9.0 Hz, C8), 157.57 (s, ipso-C), 158.64 (s, C2). 15N NMR (40.54 MHz, D2O):
c = 19.2231(14) Å,
Z = 8;
calc = 1.621 Mg/m3;
F(000) = 1088; full-matrix
a
= 90°, b = 90°,
= 0.449 mmÀ1 (for MoK
least-squares on
F2;
c
= 90°. V = 2148.4(3) Å3; T = 100(2) K;
2
d 68.39 (s, NH2), 173.91 (s, N3), 234.54 (d, JNP 6.4 Hz, N7), 272.16 (s, N1). 31P
q
l
a,
k = 0.71073 Å);
data = 2594;
NMR (161.98 MHz, D2O): d À6.37. ESI-MS: calcd for C11H11N4O4PS: 326.2682;
found: 326.75 (M)+.
parameters = 149; restraints = 0; wR(all) = 0.1107; GoF(all) = 1.085.