Regioselective synthesis of 6-benzylthiazolo[3,2-b]1,2,4-triazoles during Sonogashira coupling

Article abstract of DOI:10.1016/j.tetlet.2005.01.091

The reaction of 3-mercaptopropargyl-1,2,4-triazoles with various iodobenzenes catalyzed by Pd-Cu leads to the regioselective formation of 6-benzylthiazolo[3,2-b]1,2,4-triazoles 4. The structure of 4d was confirmed by X-ray analysis.

Full text of DOI:10.1016/j.tetlet.2005.01.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1607–1610
Regioselective synthesis of 6-benzylthiazolo-
[3,2-b]1,2,4-triazoles during Sonogashira coupling
Majid M. Heravi,a,* Ali Kivanloo,b Mohammad Rahimzadeh,b Mehdi Bakavoli,b
Mitra Ghassemzadehc and Bernhard Neumullerd
¨
aDepartment of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran 1993891167, Iran
bDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 1331418, Iran
cChemistry & Chemical Engineering Research Center of Iran, Tehran 14335186, Iran
dFachbereich Chemie der Universita¨t, Marburg 35043, Germany
Received 29 September 2004; revised 9 January 2005; accepted 19 January 2005
Available online 1 February 2005
Abstract—The reaction of 3-mercaptopropargyl-1,2,4-triazoles with various iodobenzenes catalyzed by Pd–Cu leads to the regio-
selective formation of 6-benzylthiazolo[3,2-b]1,2,4-triazoles 4. The structure of 4d was confirmed by X-ray analysis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
3-Mercapto-1,2,4-triazoles 1 (R = CH3 and Ph)8 were
reacted with propargyl bromide in refluxing ethanol to
yield the corresponding 3-propargylmercapto-1,2,4-
triazoles 2.8 When 2 (R = Ph) was treated with 4-nitro-
1-iodobenzene 3d and triethylamine in the presence of
bis(triphenylphosphine)palladium chloride and copper
iodide, a single compound was obtained as detected by
The azole antifungals appear to offer scope for provid-
ing truly effective drugs.1 Imidazole antifungals such as
clotrimazole, miconazole and ketoconazole show good
activity, but are only of limited value for systemic
administration.2 Triazole derivatives possess a broad
spectrum of antifungal activity and reduced toxicity
compared with the imidazole antifungals.2
1
TLC. The H NMR spectrum of the product showed
one aromatic proton at d 6.52ppm, characteristic of a
fused thiazole ring, as well as benzylic protons at d
6.52ppm. The mass spectrum showed an M + at m/z 336.
Although several methods have been reported for the
synthesis of thiazolo[3,2-b]1,2,4-triazoles,3 those which
use 3-mercapto-1,2,4-triazoles 1 as the starting materials
have the disadvantage of also giving regioisomeric thiaz-
olo[2,3-c]1,2,4-triazoles.4
Mechanistically, either thiazolo-1,2,4-triazines 4d or 5d
were possible products as illustrated in Scheme 1. Prob-
ably a two-step process had occured: a standard Sono-
gashira coupling9 followed by
a Pd(II)-catalyzed
Pd-catalyzed annulation has been utilized successfully
for the synthesis of carboxylic5 and heterocyclic com-
pounds.6 In continuation of our recent studies7 on Pd-
catalyzed reactions of acetylenes leading to heterocyclic
compounds of biological significance, we became
interested in developing a regioselective synthesis of
substituted thiazolo-1,2,4-triazoles.
intermolecular cyclization of either nitrogen 2or nitro-
gen 4 onto the triple bond followed by base-induced
aromatization.10
However, other mechanisms for this reaction are also
plausible, for example, cyclization via initial generation
of the exocyclic olefin followed by an intermolecular
Heck reaction, which would provide a facile pathway
for migration of the double bond into the endocyclic po-
sition11 or alternatively a 5-exo dig. cyclization may be
simply triggered by the formation an Ar–Pd(II) species
followed by reduction, elimination–isomerization. This
type of cyclization has been observed for acetylenic
lactams.12
Keywords: Sonogashira coupling; Thiazoles; Triazoles; Pd-catalyzed
reaction; Thiazolotriazoles.
*
Corresponding author. Tel.: +98 21 804 13 47; fax: +98 21 804 78
61; e-mail: mmh1331@yahoo.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.091

1608
M. M. Heravi et al. / Tetrahedron Letters 46 (2005) 1607–1610
H
S
N
N
EtOH
N
N
HC C CH2 Br
+
R
N
H
2
S CH2
C
CH
R
N
H
(R = CH3, Ph)
(R = CH , Ph)
1
3
I
N
N
Y
N
N
Sonogashira coupling
+
R
N
H
S CH2
C
C
Ar
[(PPh3)2PdCl2]
Et3N, CuI, DMF
R
N
H
S CH2
C
CH
X
2
Pd(II)
3a-e
7
N
CH2Ar
6
1
N
N
N
or
5
2
R
ArCH2
N
S
R
N
S
4
3
4a-h
5
Scheme 1.
The spectral data were not much helpful in deciding in
favor of either product 4d or 5d. The product, however,
crystallized as colorless needles suitable for X-ray crys-
tallography and was identified as 6-(4-nitrobenzyl)-2-
phenylthiazolo[3,2-b]1,2,4-triazole 4d. The molecule
crystallized in the triclinic space group P-1 with four
molecules in the unit cell. The crystallographic data of
4d are listed in Table 1 and the selected bond lengths
and bond angles are given in Table 2. Figure 1 shows
a perspective view of the structure of 4d. The thiaz-
olo[3,2-b]1,2,4-triazole ring system is planar and has a
geometry similar to that reported for another compound
with a similar ring system.3b
The dihedral angles between the Ôbest planesÕ of the com-
pound are 72ꢁ for A and B (A: S1 N1 N2N3 C1 C2C3
C4 and B: C32C33 C34 C35 C36 C37) and 3 ꢁ for A and
D (D: C41 C42C43 C44 C45 C46) and 2 ꢁ for B and C
(C: N4 O1 O2).
To establish the generality of the synthesis, several aryl
iodides 3a–e were reacted with 2 (R = CH3 and Ph) by
this method to afford compounds 4a–h in good to high
yields (Table 3). The presence of electron-withdrawing
groups such as –NO2, –Cl and –CN on the aryl iodide
seems to be essential. When PhI was used as the aryl
halide, a complicated mixture was obtained.
Table 1. Crystallographic data for 4d
Formula
Formula
mass (g/mol)
Crystal size
(mm)
C
336.37
17H12N4O2S
qcalc (g/cm3)
Temperature (K)
1.499
193
0.52 · 0.4 · 0.14 l (cmꢀ1
)
2
.4The reactions must be carried out under an argon atmos-
phere and the mixture of DMF and triethylamine must
be degassed prior to use. Bis(triphenylphosphine) palla-
dium chloride and triethylamine were found to be the
catalyst and base of choice.
a (pm)
b (pm)
751.5(1)
1076.2(1)
1093.0(1)
61.23(1)
87.11(1)
74.92(1)
745.3(1)
2hmax (ꢁ)
52.62
h
k
l
ꢀ9 ! 9
ꢀ13 ! 13
ꢀ13 ! 13
c (pm)
a (ꢁ)
b (ꢁ)
Measured reflections 10,844
Copper iodide was found to be an essential cocatalyst.
Reactions carried out just with either copper(I) iodide
c (ꢁ)
Unique reflections
Data with
2993
2602
V (pm3106)
Fo > 4r(Fo)
Parameter
Space group P-1
Z
265
Table 2. Selected bond lengths (pm) and bond angles (ꢁ) of 4d
4
R1[Fo > 4r(Fo)]
wR2 (all data)
Max residual
0.0488
0.1342a
0.58
S1–C1
S1–C2
C2–C3
N1–C1
N1–C3
N1–N2
C4–N2
172.2(2)
174.5(2)
134.5(2)
135.2(2)
139.6(2)
136.1(2)
133.7(2)
N3–C4
N3–C1
C3–C31
C4–C41
C35–N4
N4–O1
N4–O2
137.2(2)
131.9(2)
149.4(2)
147.1(2)
146.5(2)
122.6(2)
122.6(2)
13
Programs
used
SHELXS-97
14
SHELXL
Electron density
(e/pm3 · 106)
15
ORTEP
16
PLATON-98
Crystallographic data (excluding structure factors) for the crystal
structure has been deposited at the Cambridge Crystallographic Data
Centre, CCDC-257521. Copies of the data can be obtained on appli-
cation to CCDC, 12Union Road, Cambridge CB21EZ, UK (Fax.:
int. code +44 1223/336 033; e-mail: deposit@ccdc.cam.ac.uk).
a w = 1/[r2(Fo) + (0.01047 · P)2 + (0.02P)];
C1–S1–C289.67(8)
S1–C2–C3
C2–C3–N1
C4–N3–C1
101.5(1)
114.0(1)
109.5(1)
116.4(2)
101.1(1)
116.1(2)
N3–C1–S1
N3–C1–N1
138.2(1)
111.2(2)
120.0(2)
112.1(2)
118.2(1)
C3–N1–N2
N1–N2–C4
N2–C4–N3
N1–C3–C31
C3–C31–C32
C35–N4–O2
P ¼ fMaxðF 2o; 0Þ þ 2 ꢁ F 2c ꢂ=3.

M. M. Heravi et al. / Tetrahedron Letters 46 (2005) 1607–1610
1609
274. Anal. Calcd for C12H10N4O2S: C, 52.54; H, 3.67;
N, 20.42. Found: C, 51.98; H, 3.64; N, 20.50.
2.3. Selected data for 4b
1
Yield: 54%, mp: 112–114 ꢁC, H NMR, d (CDCl3) 2.53
(s, 3H, CH3), 4.26 (s, 2H, CH2), 6.45 (s, 1H, CH of thi-
azole), 7.46 (d, J = 8.0 Hz, 2H, ArH), 7.66 (d, J = 8.1,
2H, ArH). IR m (KBr disc) 2269 cmꢀ1, MS m/z 254.
Anal. Calcd for C13H10N4S: C, 61.39; H, 3.96; N,
22.03. Found: C, 61.42; H, 3.86; N, 21.99.
Figure 1. Perspective view of the crystal structure of 4d (thermal
ellipsoids at 50% probability).
2.4. Selected data for 4c
1
Yield: 48%, mp: 116–117 ꢁC, H NMR, d (CDCl3) 2.52
(s, 3H, CH3), 4.57 (s, 2H, CH2), 6.49 (s, 1H, CH of thi-
azole), 7.46–7.60 (m, 3H, ArH), 8.05 (d, J = 8.3, 1H,
ArH). IR m (KBr disc) 1520, 1350 cmꢀ1, MS m/z 274.
Anal. Calcd for C12H10N4O2S: C, 52.54; H, 3.67; N,
20.42. Found: C, 52.14; H, 3.58; N, 20.70.
Table 3. Melting points and yields of the prepared 6-benzylthiaz-
olo[3,2-b]1,2,4-triazoles
Product 1,2,4-Triazole R
ArI
Mp (ꢁC) Yielda (%)
X
Y
4a
4b
4c
4d
4e
4f
CH3
CH3
CH3
Ph
NO2
CN
H
H
H
128–129 57
112–114 54
2.5. Selected data for 4d
NO2 116–117 48
168 81
1
Yield: 81%, mp: 168 ꢁC, H NMR, d (CDCl3) 4.36 (s,
NO2
NO2 Cl
H
2H, CH2), 6.52(s, 1H, CH of thiazole), 7.42–7.61 (m,
5H, ArH), 8.11–8.26 (m, 4H, ArH). IR m (KBr disc)
1516, 1347 cmꢀ1, MS m/z 336, UV (CDCl3) kmax
264.4 nm. Anal. Calcd for C17H12N4O2S: C, 60.70; H,
3.59; N, 16.65. Found: C, 60.57; H, 3.47; N, 16.49.
Ph
Ph
165–166 65
NO2 184 78
H
Cl
4g
4h
Ph
Ph
CN
H
126–127 62
156
CN
68
a Yields refer to isolated products.
2.6. Selected data for 4e
or Pd(II) chloride as the catalyst led to very poor yields
of products.
1
Yield: 65%, mp: 165–166 ꢁC, H NMR, d (CDCl3) 4.48
(s, 2H, CH2), 6.62(s, 1H, CH of thiazole), 7.42–7.48 (m,
3H, ArH), 7.72(d, J = 8.1 Hz, 1H, ArH), 8.06–8.31 (m,
4H, ArH). IR m (KBr disc) 1518, 1352cm ꢀ1, MS m/z
370, UV (CHCl3) kmax 263.2 nm. Anal. Calcd for
C17H11ClN4O2S: C, 55.06; H, 2.98; N, 15.10. Found:
C, 55.00;H, 3.01; N, 15.02.
In summary, we have developed an efficient and extre-
mely useful method for the regioselective synthesis of
6-substituted benzylthiazolo[3,2-b]1,2,4-triazoles.
2. Experimental
2.1. General procedure for the preparation of 6-substi-
tuted thiazolo[3,2-b]1,2,4-triazoles
2.7. Selected data for 4f
1
Yield: 78%, mp: 184 ꢁC, H NMR, d (CDCl3) 4.67 (s,
A mixture of the aryl iodide (0.75 mmol), (PPh3)2PdCl2
(0.025 mmol), CuI (0.055 mmol) and triethylamine
(2mmol) was stirred in DMF (5 mL) in a round-
bottomed flask under an argon atmosphere at ambient
temperature. The appropriate 3-propargyl mercapto-
1,2,4-triazole (2, R = CH3, Ph) was then added and the
mixture was stirred at room temperature for 24 h.
Upon completion of the reaction, water (5 mL) was
added and the mixture was extracted with CHCl3. The
chloroform layer was separated and concentrated and
the crude product was subjected to column chromato-
graphy using CHCl3–MeOH, 98/2% as eluent to afford
the product (Table 3).
2H, CH2), 6.62(s, 1H, CH of thiazole), 7.44–7.67 (m,
6H, ArH), 7.14–8.19 (m, 3H, ArH). IR m (KBr disc)
1515, 1345 cmꢀ1, MS m/z 336, UV (CHCl3) kmax
261 nm. Anal. Calcd for C17H12N4O2S: C, 60.70; H,
3.59; N, 16.65. Found: C, 60.65; H, 3.53; N, 16.55.
2.8. Selected data for 4g
Yield: 62%, mp.: 126–127 ꢁC, 1H NMR, d (CDCl3) 4.45
(s, 2H, CH2), 6.78 (s, 1H, CH of thiazole), 7.26–7.73 (m,
6H, ArH), 8.11–8.21 (m, 2H, ArH). IR m (KBr disc)
2226 cmꢀ1, MS m/z 350 (M+), UV (CHCl3) kmax
258.4 nm. Anal. Calcd for C18H11ClN4S: C, 61.62; H,
3.16; N, 15.96. Found: C, 61.55; H, 3.14; N, 16.00.
2.2. Selected data for 4a
2.9. Selected data for 4h
1
Yield: 57%, mp: 128–129 ꢁC, H NMR, d (CDCl3) 2.53
(s, 3H, CH3), 4.31 (s, 2H, CH2), 6.50 (s, 1H, CH of thi-
azole), 7.52(d, J = 7.8 Hz, 2H, ArH), 8.22 (d, J = 8.6,
2H, ArH). IR m (KBr disc) 1517, 1344 cmꢀ1, MS m/z
Yield: 68%, mp: 156 ꢁC, 1H NMR, d (d6-DMSO) 4.35 (s,
2H, CH2), 7.02(s, 1H, CH of thiazole), 7.37–7.64 (m,
6H, ArH), 8.01–8.10 (m, 3H, ArH). IR m (KBr disc)

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M. M. Heravi et al. / Tetrahedron Letters 46 (2005) 1607–1610
2221 cmꢀ1, MS m/z 316, UV (CHCl3) kmax 285 nm.
Anal. Calcd for C18H12N4S: C, 68.33; H, 3.82; N,
17.70. Found: C, 68.00; H, 3.79; N, 16.98.
Sanemitsu, Y.; Tamaru, Y.; Yoshida, Z.-I. Tetrahedron
Lett. 1985, 26, 1237; (f) Zeni, G.; Larock, R. C. Chem.
Rev. 2004, 104, 2285.
7. (a) Heravi, M. M.; Bakavoli, M. J. Chem. Res. 1995, 480;
(b) Heravi, M. M.; Aghapoor, K.; Nooshabadi, M. A.;
Mojtahedi, M. M. Monatsh. Chem. 1997, 128, 1143; (c)
Heravi, M. M.; Kivanloo, A.; Rahimizadeh, M.; Bakavoli,
M.; Ghassemzadeh, M. Phosphorus, Sulfur and Silicon
2002, 177, 2491; (d) Heravi, M. M.; Kivanloo, A.;
Rahimizadeh, M.; Bakavoli, M.; Ghassemzadeh, M.
Tetrahedron Lett. 2004, 45, 5747.
References and notes
1. Erol, D. D.; Calis, U.; Demirdamar, R.; Yully, N.; Ertan,
M. J. Pharm. Sci. 1995, 84, 462–465.
2. Odds, F. C.; Abbott, A. B. J. Antimicrob. Chemother.
1984, 14, 105–114, and references cited therein.
3. (a) Dale, D. J.; Cartwright, B. A.; Clark, A. J.; Mc Naib,
H. J. Chem. Soc., Perkin Trans. 1 2001, 424–428; (b)
Katritzky, A. R.; Pastor, A.; Varonkov, M.; Steel, P. J.
Org. Lett. 2000, 2, 424–431, and references cited therein.
4. (a) Potts, K. T.; Hussain, S. J. Org. Chem. 1971, 36, 10; (b)
Kochhar, M. M.; Williams, A. J. Med. Chem. 1972, 15,
332; (c) Kiran, J.; Handa, R. N. Indian J. Chem., Sect B
1982, 21B, 732.
8. Heravi, M. M.; Tajbakhsh, M. J. Chem. Res. 1998,
488.
9. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46, and
references cited therein.
10. Bates, D. K.; Xia, M. D.; Aho, M.; Mueller, H.;
Raghavan, R. R. Heterocycles 1999, 51, 475.
11. Yin, L. X.; Liebscher, E. Synthesis 2004, 14, 1329.
12. Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.; Kooijman,
H.; Spek, A. L.; Hiemstra, H. J. Organomet. Chem. 2001,
624, 244.
5. Ma, S.; Negishi, E. I. J. Am. Chem. Soc. 1995, 117, 6345,
and references cited therein.
6. (a) Luo, F. T.; Schreuder, I.; Wang, R. T. J. Org. Chem.
1992, 57, 2213; (b) Spencer, J.; Pfeffer, M.; Decian, A.;
Fischer, T. J. Org. Chem. 1995, 60, 1005; (c) Chawdhury,
C.; Chaudhari, G.; Guha, S.; Mukhiryee, A. K.; Kundu,
N. G. J. Org. Chem. 1998, 63, 1863; (d) Kundu, N. G.;
Nandi, B. J. Org. Chem. 2001, 66, 4563; (e) Mizutani, M.;
13. Sheldrick G. M., SHELXS-97, Universita¨t Go¨ttingen
1997.
14. Sheldrick G. M., SHELXL-97, Go¨ttingen 1997.
15. Johnson, C. K. ORTEP, ORNL-3794; Oak Ridge
National Laboratory: Tennessee, 1965.
16. Spek A. L., PLATON-98, Utrecht 1998.