Synthesis of thiazolo[3,2-d][1,2,4] triazines through palladium-catalyzed heteroannulation of acetylenic compounds

Article abstract of DOI:10.1002/jhet.5570440328

(Chemical Equation Presented) The reaction of 6-methyl-5-(prop-2-ynylthio)- 5,6-dihydro-1,2,4-triazin-3(4H)-one 1 with various iodobenzenes 2 in the presence of palladium catalyst leads to the formation of substituted triazolotriazines.

Full text of DOI:10.1002/jhet.5570440328

May-Jun 2007
693
Synthesis of Thiazolo[3,2-d][1,2,4] Triazines through Palladium-
catalyzed Heteroannulation of acetylenic Compounds
Majid M. Heravia,b,* , Ali Kivanlooa, Mohammad Rahimizadeha, Mehdi Bakavolia
and Mitra Ghassemzadehc
aDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
bDepartment of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
cChemistry & Chemical Engineering Research Center of Iran, P.O.Box 14335-186, Tehran, Iran
*Corresponding author: email:mmh113@yahoo.com
Received February 14, 2006
Y
X
I
H
N
Y
S
I, II, III
O
O
S
N
N
+
CH CN
3
N
N
Me
Me
N
X
1
3a-f
2a-f
I: (Ph P) PdCl
2
3
2
II: CuI
III:
Et N
3
The reaction of 6-methyl-5-(prop-2-ynylthio)-5,6-dihydro-1,2,4-triazin-3(4H)-one 1 with various
iodobenzenes 2 in the presence of palladium catalyst leads to the formation of substituted triazolotriazines.
J. Heterocyclic Chem., 44, 693 (2007).
yields of product mixture. When copper(I) iodide was
used alone no reaction took place. Triethyl amine was
found to be the base of choice. Use of this base gives
cleaner products and better yields.
INTRODUCTION
The bicyclic compounds from 1,2,4-triazine have both
fundamental and applied interest. Its synthesis needs
conventional heterocyclization strategies and isomeric
systems have proven pharmacological value [1-2]. The
chemistry of thiazolotriazine has been well documented [3].
There has been considerable interest in transition metal
mediated cycloaddition reaction of alkynes in organic
synthesis [4] especially those involving palladium [5].
Palladium catalyzed cyclization reactions of 3-(prop-2-
ynylthio)1,2,4-triazines to thiazolo-1,2,4-triazinones have
reported by Mizutani et al. [6]. We have used this strategy
Scheme 1
Y
X
I
H
N
Y
S
I, II, III
O
O
S
N
N
+
CH CN
3
N
N
Me
Me
N
X
1
for the synthesis of
a novel heterocyclic system,
3a-f
2a-f
I: (Ph P) PdCl
2
thiazolo[3,2-d][1,2,4] triazine [7]. In continuation of our
studies [7] on the palladium catalyzed reactions of
acetylenic substrates, we are interested in developing a
general synthesis of thiazolo[3,2-d][1,2,4] triazines using
palladium-copper catalysis [8].
3
2
II: CuI
III:
Et N
3
The reaction was carried out by stirring a mixture of
acetylenic compound 1 and aryl iodide 2a-f in the presence
of palladium catalyst, copper(I) iodide and triethylamine in
acetonitrile. The results are shown in table 1.
RESULTS AND DISCUSSION
In this communication we wish to report that when 6-
methyl-5-(prop-2-ynylthio)-5,6-dihydro-1,2,4-triazin-3(4H)-one
(1) [7] is treated with an aryl halide in triethylamine in the
presence of bis(triphenylphosphine)palladium (II) chlor-
ide and coprous iodide, 3-benzyl substituted thiazolo[3,2-
d]-1,2,4-triazinones are obtained in high yields (Scheme
1, Table 1).
Although bis(triphenylphosphine) palladium(II) chlor-
ide is the catalyst of choice, it seems however that
copper(I) iodide is an essential co-catalyst. Reactions
carried out with [(PPh3)2PdCl2] alone led to very poor
Table 1
Reaction of 1 with 2a-f Catalyzed by Pd
Entry
ArI
Mp (°C)
Yield (%)
X
Y
3a
3b
3c
3d
3e
3f
NO2
NO2
H
CN
Cl
H
Cl
NO2
H
CN
H
232
224
227
230
222
181
82
95
84
78
87
43
H

694
M. M. Heravi, A. Kivanloo, M. Rahimizadeh, M. Bakavoli and M. Ghassemzadeh
Vol 44
When iodo benzene was used as an aryl halide (2; X,
via a six membered intermediate palladacycle and
subsequent reductive elemination. The last step obviously
involves the isomerization and aromatization catalyzed by
triethylamine. To make sure that the reaction is Pd
catalyzed this reaction was coducted only with catalytic
amounts of CuI. In this case very small amounts of
product was detected on tlc along with large amounts of
starting materials.
Y=H), in the same reaction condition, the condensed
product 4 was isolated. The subsequent reflux in a
mixture of triethylamine in DMF gave 3f (X, Y=H,
Scheme 1).
H
In conclusion, we have developed
a successful
S
O
N
palladium catalyzed reaction for the synthesis 3-aryl
substituted thiazolo[3,2-d]triazinone from readily
available starting materials. This method is carried out
under mild condition free from any toxic reagent.
N
Me
N
4
It is worthwhile to mention that when p-iodotoluene
(X=CH3, Y=H, 2g) was used as an aryl iodide, the
cyclization occurred without the participation of aryl iodide
to afford 8-methyl-3-methylene-2,3-dihydro-5H-[1,3]-
thiazolo[3,2-d][1,2,4]triazin-5-one (5) (Scheme 2). This
compound has been already synthesized and reported [7].
EXPERIMENTAL
Melting points are uncorrected and were obtained by a Kofler
Heizbank Reichart type 7841 melting point apparatus. IR spectra
were obtained on a 4300 Shimadzu spectrometer. The HNMR
spectra were recorded on a Bruker AC 100, unless otherwise
stated using TMS as standard reference. Mass spectra scanned
on a Varian CH-7 instrument at 70 eV.
1
Scheme 2
Synthesis of 8-methyl-3-substituted-5H-[1,3]thiazolo[3,2-d]-
[1,2,4]triazine-ones (3). A typical reaction condition. A
mixture of aryl iodide 2a-f (0.75 mmol), [(PPh3)2PdCl2] (0.0175
g, 0.025 mmol) and triethylamine (0.2 mL, 0.275 mmol) was
stirred in acetonitrile (6 mL) under argon atmosphere for 3 min
at ambient temperature. 6-Methyl-5-(prop-2-ynylthio)-5,6-
dihydro-1,2,4-triazin-3(4H)-one 1 (0.231 g, 1.275 mmol) was
then added and the reaction mixture was then stirred for 12 hrs
at room temperature. The solid was collected by filtration,
washed with water and crystallized from ethanol to afford the
product 3a-f (Table 1).
I
H
Y
I, II, III
O
N
S
S
O
N
+
CH CN
3
N
N
Me
N
N
Me
X
1
2g
5
I: (PPh ) PdCl
3 2
II: CuI
III: Et N
X = CH3, Y = H
2
3
8-Methyl-3(4-nitrobenzyl)-5H-[1,3]thiazolo[3,2-d][1,2,4]-
triazin-5-one (3a). This compound was obtained as a creamy
powder in 82% yield., mp 232 °C, HNMR, ꢀ(CDCl3), 2.42 (s,
3H, CH3), 4.25 (s, 2H, CH2), 6.46 (s, 1H, CH), 7.5 (d, 2H, J=
8Hz), 8.25 (d, 2H, J= 8Hz), IR, ꢁ(KBr disc): 3060, 1632, 1482,
1374 cm-1; MS, M+, m/e 302(7), 300(10), 299(52), 251(100),
211(80), 188(92), 180(60), 157(70), 143(89), 113(43), 101(87).
Anal. Calcd. for C13H10N4SO3 (302.13) calcd.: C, 51.64; H, 3.33;
N, 18.53%. Found: C, 51.68; H, 3.29; N, 18.49%.
Mechanistically, the formation of 3-benzyl substituted
thiazolo[3,2-d][1,2,4]triazin-5-one could be explained as
shown in Scheme 3.
This thiazolotriazine synthesis presumably proceeds via
oxidative addition of the mercaptoalkyne into aryl
palladium bond nitrogen displacement of the palladium in
the resulting phenylpalladium intermediate quite possibly
1
3-(2-Chloro-4-nitrobenzyl)-8-methyl-5H-[1,3]thiazolo[3,2-d]-
[1,2,4]triazin-5-one (3b). This compound was obtained as a
creamy powder in 95% yield, mp 224°C, 1HNMR, ꢀ(d6-DMSO),
2.23 (s, 3H, CH3), 4.36 (s, 2H, CH2), 7.03 (s, 1H, CH), 7.65 (d,
1H, J= 8.5Hz), 8.10-8.2 (dd, 1H, J1= 8.5Hz, J2= 2Hz), 8.32 (d,
1H, J= 2Hz); IR, ꢁ(KBr disc): 3068, 1633, 1475, 1345, 897 cm-1;
MS, M+, m/e 337(5), 335(12), 334(16), 257(100), 209(30),
84(53). Anal. Calcd. for C13H9ClN4SO3 (336.75) calcd.: C,
46.36; H, 2.69; N, 16.63%. Found: C, 46.19; H, 2.60; N,
16.51%.
Scheme
3
Ar
H
N
H
N
O
S
O
S
Songogashira coupling
+ ArI
N
N
[(PPh3)2PdCl2]
Et2N, CuI, DMF
N
Me
N
Me
Pd (II)
8-Methyl-3-(2-nitrobenzyl)-5H-[1,3]thiazolo[3,2-d][1,2,4]-
triazin-5-one (3c). This compound was obtained as a creamy
powder in 84% yield, mp 227 °C, 1HNMR, ꢀ(d6-DMSO), 2.36 (s,
3H, CH3), 4.51 (s, 2H, CH2), 6.69 (s, 1H, CH), 7.47-7.77 (m,
3H, ArH), 8.05 (d, 1H, J= 7Hz); IR, ꢁ(KBr disc): 3075, 1637,
1482, 1338, 792 cm-1; MS, M+, m/e 302(11), 301(49), 298(68),
237(84), 225(40), 222(66), 181(33), 155(48), 84(90), 44(100),
ArH2C
ArHC
ArHC
O
Et3N
(Et3HN)+
O
N
N
N
S
O
N
N
S
N
N
N
N
Me
Me
Me

May-Jun 2007
Synthesis of Thiazolo[3,2-d][1,2,4] Triazines
695
through Palladium-catalyzed Heteroannulation
28(98. Anal. Calcd. for C13H10N4SO3 (302.13) calcd.: C, 51.64;
H, 3.33; N, 18.53%. Found: C, 51.68; H, 3.29; N, 18.49%.
3-[4-Cyanobenzyl]-8-methyl-5H-[1,3]thiazolo[3,2-d][1,2,4]-
triazin-5-one (3d). This compound was obtained as a creamy
powder in 78% yield.mp 230 °C,1HNMR, ꢀ(CDCl3), 2.41 (s, 3H,
CH3), 4.19 (s, 2H, CH2), 6.40 (s, 1H, CH), 7.42 (d, 2H, J= 8Hz),
7.68 (d, 2H, J= 8Hz), IR, ꢁ(KBr disc): 3072, 2230, 1630, 1471
cm-1; MS, M+, m/e 282(10), 280(19), 237(92), 234(96), 207(42),
171(98), 167(99), 127(100). Anal. Calcd. for C14H10N4SO
(282.32) calcd.: C, 59.56; H, 3.57; N, 19.84%. Found: C, 60.00;
H, 3.53; N, 19.90%.
201(57), 85(100), 76(62). Anal. Calcd. for C13H11N3SO (257.31)
calcd.: C, 60.68; H, 4.30; N, 16.33%. Found: C, 60.59; H, 4.25;
N, 16.29%.
REFRENCES
[1] M. F. G. Stevenes, J. A .Heckman. R. Stone, G. U. Baig, E.
Luny and C. Newton, J. Med. Chem., 27, 196-204 (1984); L. Ibrahim, S.
G. Farid and G. K. Mohamed, Pharmazie, 41, 812-816 (1986).
[2] V. Issartel, P. Coudert, C. Rubat, S. Nhamias and J.
Cauquelet, J. Pharmacy and Pharmacology, 50, 576-82 (1998) and
references cited therein, M. M. Heravi, K. Aghapoor and M. A.
Nooshabadi, Synth. Commun., 28, 233-37 (1998)M. M. Heravi, K.
Aghapoor and M. A. Nooshabadi, and M. M. Mojtahedi, Monatsh.
Chem., 128, 1143 -47(1997), M. M. Heravi, N. Montazeri, M.
Rahimizadeh, M. Bakavoli and M. Ghassemzadeh, J. Chem. Res., 10,
464-65 (2000).
3-[4-Chloro-2-cyanobenzyl]-8-methyl-thiazolo[3,2-d][1,2,4]-
triazin-5-one (3e). This compound was obtained as a creamy
powder in 87% yield, mp 222 °C,1HNMR, ꢀ(d6-DMSO), 2. 23
(s, 3H, CH3), 4.32 (s, 2H, CH2), 7.1 (s, 1H, CH), 7.53 (d, 1H, J=
8Hz), 7.67(dd, 1H, J1= 8Hz, J2= 2.5Hz), 8.07 (s, 1H, J= 2.5Hz),
IR, ꢁ(KBr disc): 3049, 2226, 1630, 1482, 876 cm-1; MS, M+2,
m/e 315(60), 313(94), 263(98), 234(51), 212(60), 148(98),
103(66), 83(98), 67(100). Anal. Calcd. for C14H9N4SO (316.74)
calcd.: C, 53.08; H, 2.86; N, 17.68%. Found: C, 53.00; H, 2.90;
N, 17.59%.
[3] N. E. Schare, Chem. Rev., 88, 1081-1102 (1988) and
references cited therein.
[4] S. Cacchi, G. Fabrizi and L. Maro, J. Org. Chem., 62, 5327-
32 (1997); R. C. Larock, E. K. Yum and M. D. Refnik., J. Org. Chem.,
63, 7652-62 (1998); S. Cacchi, J. Organomet., 576, 42-64 (1999); N.
Sato and S. Fukuya, J. Chem. Soc., Perkin Trans I, 1, 89-95 (2000); F.
L. Qing, W. Z. Gao and J. Ying, J. Org. Chem., 65, 2003-2006 (2000);
B. Nandi and N. G. Kundu., Org. Lett., 2, 235-238 (2000); C.
Choudhury, G. Chaudhari, S. Guha, A. K. Mukherjee and N. G. Kundu.,
J. Org. Chem., 63, 1863-71 (1988); N. G. Kundu and B. Nandi, J. Org.
Chem., 66, 4563-75 (2001).
[5] M. Mizutani, Y. Sanemitsu, Y. Tamaru and Z. I.Yoshida,
Tetrahedron Lett., 26, 1237-40 (1985) and references cited therein.
[6] M. M. Heravi and M. Bakavoli, J. Chem. Res., 480-81 (1995)
and references cited therein.
[7] J. M. Nuss, B. H. Levine, R. A. Rennels and M. M. Heravi ,
Tetrahedron Lett., 32, 5243-46 (1991); J. M. Nuss, M. M. Murphy, R. A.
Rennels and M. M. Heravi, Tetrahedron Lett., 34, 3079-82 (1993); M.
M. Heravi, K. Aghapoor, M. A. Nooshabadi and M. M. Mojtahedi,
Monatsh. Chem., 128, 1143-47 (1997); M. M. Heravi, Y. Sh.
Beheshtiha, H. A. Oskooiee and M. Salarkia, Indian J. Chem., 37, 694-
96 (1998). M. M. Heravi, A. Keivanloo, M. Rahimizadeh, M. Bakavoli
and M. Ghassemzadeh, Tetrahedron Lett., 45, 5747-49 (2004); Heravi
M. M., Kivanloo A., Rahimzadeh M., Bakavoli M., Ghassemzadeh and
M., Neumüller B., Tetrahedron Lett., 46, 1607-1610 (2005)
3-(Benzyl)-8-methyl-5H-[1,3]thiazolo[3,2-d][1,2,4]triazin-
5-one (3f). This compound was obtained as a creamy powder in
43% yield.mp 181-183 °C, 1HNMR, ꢀ(CDCl3), 2.43 (s, 3H, CH3),
4.14 (s, 2H, CH2), 6.24 (s, 1H, CH), 7.26-7.35 (m, 5H, ArH); IR,
ꢁ(KBr disc): 3100, 1646, 1487, 1373, 1260 cm-1; MS, M+, m/e
257(9), 254(51), 215(78), 181(82), 165(100), 127(50), 86(49);
elemental analyses for C13H11N3SO (257.31) calcd.: C, 60.68; H,
4.30; N, 16.33%. Found: C, 60.59; H, 4.25; N, 16.29%.
6-Methyl-5[(3-phenyl-2-propynyl)sulfanyl]-1,2,4-triazin-
3(4H)-one(4). To a solution of sodium methoxide(0.02 mol), 6-
methyl[1,2,4]triazine-3- one-5- thione (0.01 mol) in methanole
(50ml), propargyl bromide (.015 mol) was gradually added on
stirring which was continued for 4 hours at room temperature.
The volume reduced to half under vacuo and acetic acid(2ml)
was added. The residue was filtered off and recrystalized from
1
ethanole as creamy powder. Mp 181°C; yield 58%; HNMR,
ꢀ(d6-DMSO), 2.13 (s, 3H, CH3), 4.27 (s, 2H, CH2), 7.38 (s, 5H,
ArH), 13.83 (s broad, 1H, NH), IR, ꢁ(KBr disc): 3675, 3089,
1635, 1476, 1347 cm-1; MS, M+, m/z 257(30), 254(41), 213(43),
[8] Sonogashira K., J. Organomet. Chem., 653, 46 -49(2003).