First palladium-catalyzed direct regioselective C-5 (Het)arylation of mono- or disubstituted thiazolo[3,2-b][1,2,4]triazoles

Article abstract of DOI:10.1002/ejoc.201402193

An efficient and convenient method was developed for the formation of polysubstituted thiazolo[3,2-b][1,2,4]triazoles through C-5 (het)arylation. The direct C-H activation protocol giving access to di- and trisubstituted derivatives in excellent yields was optimized. The method is suitable for use with a wide range of (hetero)aryl bromides, and allows access to a collection of C-5,6 bis(het)aryl derivatives with full regioselectivity. The results are supported by a full description of all final compounds, and X-ray crystallographic data confirmed that the spectroscopic analyses were interpreted correctly. Copyright

Full text of DOI:10.1002/ejoc.201402193

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201402193
First Palladium-Catalyzed Direct Regioselective C-5 (Het)Arylation of Mono-
or Disubstituted Thiazolo[3,2-b][1,2,4]triazoles
Mikaël Le Meur,[a] Stéphane Bourg,[a] Stéphane Massip,[b] Mathieu Marchivie,[b]
Christian Jarry,[b] Gérald Guillaumet,*[a] and Sylvain Routier*[a]
Keywords: C–H activation / Regioselectivity / Nitrogen heterocycles / Sulfur heterocycles / Palladium
An efficient and convenient method was developed for the
formation of polysubstituted thiazolo[3,2-b][1,2,4]triazoles
cess to a collection of C-5,6 bis(het)aryl derivatives with full
regioselectivity. The results are supported by a full descrip-
through C-5 (het)arylation. The direct C–H activation proto- tion of all final compounds, and X-ray crystallographic data
col giving access to di- and trisubstituted derivatives in ex-
cellent yields was optimized. The method is suitable for use
with a wide range of (hetero)aryl bromides, and allows ac-
confirmed that the spectroscopic analyses were interpreted
correctly.
Introduction
Considerable effort has been devoted to developing new
methodologies that can be used to furnish molecular inno-
vation in newly built collections.
Lately, the fusion of two heterocycles containing five
atoms has attracted much attention. Systems containing
both nitrogen and sulfur atoms in the same cycle showed
remarkable properties and have proved to be suitable for
the development of functional organic materials as well as
pharmaceutically important molecules.[2]
Innovation in the design, synthesis, and production of
original molecules that have value as human therapeutic
agents remains one of the major objectives of organic and
medicinal chemistry programs. During the past decades, re-
search in heterocyclic chemistry has provided access to li-
braries based on the exploration of chemical space and the
creation of privileged and rare heterocyclic structures.[1]
Figure 1. Examples of thiazolo[3,2-b][1,2,4]triazoles with biological and medicinal activities.
[a] Institut de Chimie Organique et Analytique,
In connection with an ongoing project based on the devel-
Université d’Orléans, UMR CNRS 7311,
BP 6759, 45067 Orléans Cedex 2, France
E-mail: gerald.guillaumet@univ-orleans.fr
sylvain.routier@univ-orleans.fr
opment of efficient methodologies to generate original col-
lections of small nitrogen-containing heterocycles,[3] we
turned our attention to thiazolo[3,2-b][1,2,4]triazole. This
highly attractive unit has seldom been described, despite the
fact that some of its representatives have shown versatile
biological activities (Figure 1).[4–8] The thiazolo[3,2-b]-
[1,2,4]triazole core is found in structures possessing antimi-
http://www.icoa.fr/fr
[b] Université Bordeaux Segalen, CNRS FRE 3396,
Pharmacochimie,
146 Rue Léo Saignat, 33000 Bordeaux, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402193.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
Scheme 1. Optimization of the C–H arylation.
crobial I,[4] antibacterial II,[5] G-quadruplex stabilizing
III,[6] and anti-inflammatory IV[7,8] activities.
Results and Discussion
We considered that it would be of great interest to de-
Although a survey of the literature indicated that C-5
velop a versatile method based on the building of thi- arylation is efficient when using aryl iodides and copper
azolo[3,2-b][1,2,4]triazole derivatives that could take advan- catalysis,[10] in our hands, this copper-catalyzed reaction
tage of novel C–H arylation instead of the commonly used was unsuccessful using 2a (Table 1, entry 1) and 4-bromo-
but laborious method that only assembles intermediates anisole. In similar work to ours, the arylation of some C-2,6
possessing the desired substituents in advance.
disubstituted thiazolotriazoles under ligandless palladium
Transition-metal-catalyzed functionalization has always catalysis and microwave irradiation was reported.[11] How-
been an attractive alternative and a greener method than ever, the method, involving Cs2CO3 as base, appeared to be
other catalyzed reactions because it avoids the preliminary compatible only with activated bromobenzene derivatives
preparation of the requisite organometallic and/or halogen- and no mention was made of any selective reactions. In-
ated arenes.[9] As a result, the number of steps, the amount deed, under the conditions developed by Tian et al., start-
of waste, the amount of solvent, and the reaction time are ing from 2e and 4-bromoanisole, only starting material with
all usually reduced. We therefore developed a versatile strat- traces of the desired compound was recovered.
egy with which to assess the feasibility of C-5 (het)arylation
These two interesting reports prompted us to investigate
in the thiazolo[3,2-b][1,2,4]triazoles series. In particular, our an alternative sequence. We began our study with a reaction
method was designed to allow the construction of C-2,5,6 model involving 2a, which was obtained in 81% yield by
(V), and C-5,6 (VI) tri- and disubstituted collections from using commercially available 3-phenyl-1H-1,2,4-triazole-5-
C-2,6 and C-6 derivatives VII including quantitative re- thiol (1a) and 4-methoxyphenacyl bromide in a hydro-
gioselectivity in the latter case (Scheme 1).
chloric acid solution. As reported in Table 1, several condi-
Table 1. Optimization of direct Pd-catalyzed arylation.
Entry
Catalyst
Ligand
Base
Solvent
Yield [%][c]
[e]
1
2
3
4
5
6
7
8
9
Cu(acac)2
CuI
–
–
–
–
tBuOLi
tBuOLi
KOAc
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF/xylene
DMF
DMA
1,4-dioxane
DMA
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
–
–
–
[e]
[e]
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
32
57[d]
90
83
98
83
89
PCy3·HBF4
PCy3·HBF4
PCy3
PCy3
Xantphos
P(tBu)3·HBF4
10
[a] Reaction conditions A: (i) 4-methoxyphenacyl bromide, aq. HCl (37% w/w), EtOH, reflux, 15 h; (ii) satd. aq. Na2CO3, room temp.
[b] Reaction conditions B: sealed vial, 2a (0.33 mmol, 1.0 equiv.), 4-bromoanisole (1.5 equiv.), catalyst (10 mol-%), ligand (20 mol-%),
base (2.0 equiv.), solvent (2 mL), 130 °C, 15 h. [c] Yield of isolated product. [d] Addition of PivOH (30 mol-%) required. [e] Starting
material was fully recovered.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
C-5 (Het)Arylation of Substituted Thiazolo[3,2-b][1,2,4]triazoles
tions were tried before a suitable and near quantitative
method to obtain 3ab was achieved.
Thiazolotriazoles 2b–g were developed by following the
same procedure as that described for 2a. C–H arylation was
Some previously published copper and palladium condi- next carried out between various brominated (het)aryls and
tions were first evaluated, but no conversion was observed each prebuilt thiazolotriazole derivative (Table 2).
in our case.[12–14] A small amount of product was observed
Irrespective of the starting material used, i.e., C-2,6 or
using Pd(PPh3)4 and Cs2CO3 in dioxane, whereas a signifi- C-6 substituted derivatives 2a–g, the catalytic C–H (het)
cant increase in yield was observed by using Pd(OAc)2/PCy3 arylation smoothly afforded products 3aa–gh. Complete
or PtBu3·HBF4 as the catalytic system and K2CO3 as base. conversion as judged by TLC analysis was reached before
1
Dioxane proved to be better than DMA (entries 5 and 6) stopping the reaction, and H NMR analysis of the crude
as solvent. Switching the base to Cs2CO3 led to optimal material showed only one single product formed, without
conditions (entry 8), and full conversion and a near quanti- degradation. Steric enhancement (exemplified by C–H aryl-
tative yield were obtained. Further changes to solvent and ation from derivatives of type 2 and 2-methoxybromobenz-
carbonate source led to less efficient reactions. With half ene) did not affect the yield of the reactions. Substrates with
the amount of catalyst, compound 3ab was isolated in only either electron-donating (Me, OMe) or electron-with-
81% yield. Changing the heating mode to microwave irradi- drawing (CF3, CO2Me) groups on the bromo aryl groups
ation did not afford any benefit.
were broadly applicable for direct arylation. The only case
Table 2. C-5 C–H arylation leading to derivatives of type V and VI.
[a] Yield of isolated product. [b] Reaction performed at 160 °C. [c] Compounds 2b–g were prepared as described for 2a from the corre-
sponding 1,2,4-triazole-5-thiols of type 1 in yields of 76 (2b), 62 (2c), 61 (2d), 77 (2e), 58 (2f), and 71% (2g).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
in which we were unable to obtain full conversion, starting Table 3. Calculation of pKa for hydrogen atoms H-2 and H-5.
from substrate 2e and 4-bromoanisole, was compound 3ec.
In this case, no improvement was observed by increasing
the reaction time or the reaction temperature.
Activated as well as deactivated (het)aryl bromide deriva-
Entry
Product
R
H-2 pKa[a]
H-5 pKa[a]
tives can now be used in C-5 arylation without discrimi-
nation. Moreover, reactions with thiazolotriazoles free of
C-2 substituents lead to a fully regioselective C–H (het)aryl-
ation at C-5 (entries 3–7).
1
2
3
4
5
2c
2d
2e
2f
Ph
36.8
37
37.2
36.2
36.3
28.3
28.7
29.2
26.7
28.7
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
CH3
X-ray analysis of crystals of 3ee formally confirmed that
the spectroscopic analyses were interpreted correctly, par-
ticularly with respect to the regioselectivity of the C–H acti-
vation in C-5 vs. C-2. As clearly shown in Figure 2, the
three (het)aryl groups are not coplanar. Thiazolotriazole
forms a 72.4° angle with the pyrimidine in C-5 and a dihe-
dral angle of 23.9° with methoxybenzyl in C-6. Two hydro-
gen bonds were also identified. The first being an intramo-
lecular H bond between N-1 and the hydrogen of C-20,
whereas the second is an intermolecular H bond between
the N-1 and the hydrogen of C-2 from a homologous mole-
cule with the following symmetry code: x, 1/2 – y, 1/2 + z.
2g
[a] pKa predicted by using the B3LYP/6-31G** level of theory
within Jaguar.
poration experiments were carried out starting from 2c and
2g in the presence of Cs2CO3 (Scheme 2). Under these con-
ditions, the C-5 proton exchanged exclusively. Deuterated
derivatives were isolated in quantitative yields after one
hour of reaction in a sealed tube.
Scheme 2. Deuterium incorporation; each reaction was quantita-
tive.
Additionally, the kinetic isotope effect (KIE) with both
non-deuterated 2e and its deuterated analogue 2e-D was
determined with 5-bromopyrimidine to form 3ee
(Scheme 3). The kH/kD ratio for the C-H/C-D bond acti-
vations was found to be around 1, because the two reactions
reached completion in the same time. This indicates that
the palladium(II)-catalyzed C–H bond cleavage did not oc-
cur in the rate-determining step.[15] Consequently, several
mechanistic scenarios remain possible.[16]
Figure 2. ORTEP representation of 3ee.
To understand why (het)arylation takes place only in the
C-5 position (vs. C-2), pKa calculations were run using the
Jaguar software from Schrodinger (Table 3; for details see
the Supporting Information). A large pKa difference be-
tween the H-2 and H-5 hydrogen atoms was observed. The
pKa of H-2 was always around 36 and does not seem be
affected by the nature of the C-3 substituent. This acidity
Scheme 3. Determination of KIE of regioselective C–H arylation.
Conclusions
We have developed a novel and efficient direct C–H acti-
is higher (ca. 8 units) than that observed at the H-5 posi- vation protocol that gives access to di- and trisubstituted
tion, which confirms our experimental observations and the thiazolo[3,2-b][1,2,4]triazoles based on a palladium-metal
sensitivity to basic conditions.
catalyst. Excellent yields were obtained with a wide range
The large difference in acidity between the two hydrogen of (hetero)aryl halides with either electron-withdrawing or
atoms H-2 and H-5 prompted us to investigate the reaction electron-rich substituents. The method was used to generate
mechanism of the previously optimized Pd-catalyzed direct a collection of C-5,6 bis(het)aryl with full regioselectivity.
arylation reaction and its regioselectivity. Deuterium-incor- Further investigations involving the orchestration of such
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
C-5 (Het)Arylation of Substituted Thiazolo[3,2-b][1,2,4]triazoles
lowed to rise to room temperature. After full conversion, a satu-
rated solution of sodium carbonate was slowly added until pH 7.
The resulting solution was extracted with EtOAc (2ϫ 50 mL) and
the combined organic layers were washed with brine (20 mL), dried
with MgSO4, filtered, and concentrated under reduced pressure.
The resulting precipitate was washed with Et2O (2ϫ 10 mL) to
afford 2b (2.98 g, 76%) as a white solid. The product was fully
characterized without any further purification due to its high insol-
ubility; only a 135DEPT was furnished, m.p. 146–148 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.34 (d, J = 8.2 Hz, 2 H), 8.24 (d, J =
8.2 Hz, 2 H), 7.81 (d, J = 8.2 Hz, 2 H), 7.52–7.40 (m, 3 H), 7.23
(s, 1 H) ppm. 135 DEPT 13C NMR (101 MHz, CDCl3): δ = 129.9
(CHAr), 128.7 (2CHAr), 126.8 (2CHAr), 126.8 (2CHAr), 126.0 (q, J
palladium-catalyzed cross-coupling reactions with the ad-
ditional aim of preparing focused libraries of biologically
active compounds are in progress in our laboratory.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
DPX 250 MHz or 400 MHz instrument using CDCl3 or [D6]
DMSO; chemical shifts are reported in parts per million (δ scale)
and all coupling constant (J) values are in Hertz [Hz]. The follow-
ing abbreviations are used to explain the multiplicities: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doub-
let) and ddd (double double doublet). Melting points are uncor-
rected. IR absorption spectra were obtained with a Perkin–Elmer
Paragon 1000 PC and values are reported in cm–1. HRMS were
recorded with a Bruker maXis mass spectrometer. Monitoring of
the reactions was performed using silica gel TLC plates (silica
Merck 60 F254). Spots were visualized by UV light at 254 and
356 nm. Column chromatography was performed using silica gel
60 (0.063–0.200 mm, Merck). Reactions requiring anhydrous con-
ditions were performed under argon. All solvents were freshly dis-
tilled under argon prior to use. Chemicals were purchased from
Aldrich and Acros organics as commercial sources. Microwave irra-
diations were carried out in sealed 2–5 mL vessels placed in a
Biotage Initiator system using a standard absorbance level (300 W
maximum power). The temperatures were externally measured by
an IR probe that determined the temperature on the surface of the
vial and could be read directly from the instrument. The reaction
time was measured from when the reaction mixture reached the
stated temperature for temperature-controlled experiments. Pres-
sure was measured by a noninvasive sensor integrated into the cav-
ity lid.
= 3.9 Hz, CHAr), 109.5 (CHAr) ppm. IR (neat): ν = 3122, 1470,
˜
1443, 1323, 1167, 1069, 1017, 848, 707, 692 cm–1. HRMS (ESI): m/z
calcd. for C17H11F3N3S [M + H]+ 346.062029; found 346.062351.
6-Phenylthiazolo[3,2-b][1,2,4]triazole (2c): A mixture of 1H-1,2,4-
triazole-3-thiol (2.0 g, 19.80 mmol, 1.0 equiv.) and phenacyl brom-
ide (4.33 g, 21.78 mmol, 1.1 equiv.) in EtOH (200 mL) was heated
to reflux for 15 h. The solution was then cooled to room tempera-
ture and evaporated under reduced pressure. The solid was then
added to concentrated sulfuric acid solution (10 mL) at 0 °C and
stirred for 3 h at room temperature. After full conversion, a satu-
rated solution of sodium carbonate was slowly added until pH 7.
The resulting solution was extracted with EtOAc (2ϫ 50 mL) and
the combined organic layers were washed with brine (20 mL), dried
with MgSO4, filtered, and concentrated under reduced pressure.
The residue was then purified by flash chromatography (EtOAc/
petroleum ether, 1:3) to afford 2c (2.47 g, 62%) as a white solid,
m.p. 88–90 °C. 1H NMR (250 MHz, CDCl3): δ = 8.26 (d, J =
1.4 Hz, 1 H), 8.11 (d, J = 8.3 Hz, 2 H), 7.60–7.46 (m, 3 H), 7.16
(d, J = 1.4 Hz, 1 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 158.6
(Cq), 157.5 (CHAr), 134.6 (Cq), 131.3 (CHAr), 130.4 (2CHAr), 129.4
6-(4-Methoxyphenyl)-2-phenylthiazolo[3,2-b][1,2,4]triazole (2a): A
mixture of 5-phenyl-1H-1,2,4-triazole-3-thiol (1.0 g, 5.64 mmol,
1.0 equiv.), 4-methoxyphenacyl bromide (1.42 g, 6.21 mmol,
1.1 equiv.), EtOH (50 mL) and aqueous concentrated HCl solution
(37%, 2 mL) was heated at reflux for 15 h. The mixture was then
cooled to room temperature, and volatiles were evaporated under
reduced pressure. An aqueous saturated solution of sodium carb-
onate (20 mL) was added to the residue. After extraction with
CH2Cl2 (3ϫ 30 mL), the combined organic layers were washed
with brine (10 mL), dried with MgSO4, filtered, and evaporated
under reduced pressure. The resulting solid was washed with Et2O
(2ϫ 20 mL) to afford 2a (1.40 g, 81%), which was fully charac-
terized without any further purification, m.p. 134–136 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 6.9 Hz, 2 H), 8.14 (d,
J = 8.8 Hz, 2 H), 7.46 (m, 3 H), 7.07 (d, J = 8.8 Hz, 2 H), 6.96 (s,
1 H), 3.90 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.9
(Cq), 160.7 (Cq), 157.7 (Cq), 133.0 (Cq), 131.3 (Cq), 129.6 (CHAr),
128.6 (2CHAr), 128.2 (2CHAr), 126.8 (2CHAr), 120.7 (Cq), 114.4
(Cq), 128.1 (2CHAr), 109.9 (CHAr) ppm. IR (neat): ν = 3117, 1473,
˜
1447, 1402, 1237, 1189, 1172, 740, 689, 641 cm–1. HRMS (ESI):
m/z calcd. for C10H8N3S [M + H]+ 202.043345; found 202.043394.
6-(p-Tolyl)thiazolo[3,2-b][1,2,4]triazole (2d): A mixture of 1H-1,2,4-
triazole-3-thiol (2.0 g, 19.80 mmol, 1.0 equiv.), p-tolylphenacyl
bromide (4.64 g, 21.78 mmol, 1.1 equiv.), EtOH (200 mL), and con-
centrated HCl (37%, 8 mL) was heated to reflux for 72 h. The solu-
tion was then cooled to room temperature, and evaporated under
reduced pressure. A saturated solution of sodium carbonate was
slowly added until pH 7. The resulting solution was extracted with
EtOAc (2ϫ 50 mL) and the combined organic layers were washed
with brine (20 mL), dried with MgSO4, filtered, and concentrated
under reduced pressure. The residue was then purified by flash
chromatography (EtOAc/petroleum ether, 1:3) to afford 2d (2.6 g,
61 %) as a white solid, m.p. 98–100 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.23 (s, 1 H), 7.97 (d, J = 8.4 Hz, 2 H), 7.32 (d, J =
8.4 Hz, 2 H), 7.07 (s, 1 H), 2.42 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 157.1 (Cq), 156.0 (CHAr), 140.1 (Cq), 133.3 (Cq), 129.7
(2CHAr), 126.5 (2CHAr), 125.2 (Cq), 107.6 (CHAr), 21.5
(2CHAr), 105.6 (CHAr), 55.4 (CH ) ppm. IR (ATR Diamond): ν =
˜
3
3065, 1608, 1505, 1440, 1324, 1273, 1182, 1114, 813, 722 cm–1.
HRMS (ESI): m/z calcd. for C17H14N3OS [M + H]+ 308.085210;
found 308.085393.
(CH ) ppm. IR (neat): ν = 3109, 1475, 1248, 1180, 1018, 856, 821,
˜
3
732, 690, 644 cm–1. HRMS (ESI): m/z calcd. for C11H10N3S [M +
H]+ 216.058995; found 216.059289.
2-Phenyl-6-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole
(2b): A mixture of 5-phenyl-1H-1,2,4-triazole-3-thiol (2.0 g, 6-(4-Methoxyphenyl)thiazolo[3,2-b][1,2,4]triazole (2e): A mixture of
11.28 mmol, 1.0 equiv.) and 4-(trifluoromethyl)phenacyl bromide
(1.42 g, 12.41 mmol, 1.1 equiv.) in EtOH (50 mL) was heated to
reflux for 3 h. The resulting suspension was filtered and washed
successively with EtOH (2ϫ 10 mL) and Et2O (2ϫ 10 mL). The
resulting solid was then added to concentrated sulfuric acid solu-
tion (10 mL) at 0 °C and stirred for 1 h. The temperature was al-
1H-1,2,4-triazole-3-thiol (2.0 g, 19.80 mmol, 1.0 equiv.), 4-meth-
oxyphenacyl bromide (4.99 g, 21.78 mmol, 1.1 equiv.), EtOH
(200 mL), and concentrated HCl (37%, 8 mL) was heated to reflux
for 72 h. The mixture was then cooled to room temperature, and
evaporated under reduced pressure. A saturated solution of sodium
carbonate was slowly added until pH 7. The resulting solution was
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
extracted with EtOAc (2ϫ 50 mL) and the combined organic layers
were washed with brine (20 mL), dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was then purified
by flash chromatography (EtOAc/petroleum ether, 1:1) to afford 2c
(3.52 g, 77 %) as a white solid, m.p. 132–134 °C. 1H NMR
General Procedure A using thiazolo[3,2-b]triazole (2a, 100.0 mg,
0.325 mmol), palladium acetate (7.3 mg, 0.033 mmol), tricyclohex-
ylphosphine (18.2 mg, 0.065 mmol), cesium carbonate (212.7 mg,
0.651 mmol), and 2-bromoanisole (91.3 mg, 0.488 mmol). Standard
workup followed by flash chromatography (CH2Cl2) gave 3aa
(400 MHz, [D6]DMSO): δ = 8.42 (s, 1 H), 8.16 (d, J = 9.0 Hz, 2 (120 mg, 89 %) as a white solid, m.p. 150–152 °C. 1H NMR
H), 7.80 (s, 1 H), 7.12 (d, J = 9.0 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C
(400 MHz, CDCl3): δ = 8.22 (d, J = 6.7 Hz, 2 H), 7.63 (d, J =
NMR (101 MHz, [D6]DMSO): δ = 160.6 (Cq), 157.1 (Cq), 156.5 8.8 Hz, 2 H), 7.27–7.48 (m, 5 H), 6.96–6.88 (m, 4 H), 3.83 (s, 3 H),
(CHAr), 131.9 (Cq), 128.3 (2CHAr), 120.7 (Cq), 114.8 (2CHAr), 3.68 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.8 (Cq),
109.2 (CHAr), 55.8 (OCH ) ppm. IR (neat): ν = 3106, 1609, 1507,
160.2 (Cq), 157.3 (Cq), 156.2 (Cq), 132.4 (CHAr), 131.5 (Cq), 130.8
(CHAr), 130.5 (2CHAr), 129.4 (CHAr), 129.2 (Cq), 128.5 (2CHAr),
126.8 (2CHAr), 121.1 (Cq), 120.9 (CHAr, Cq), 120.2 (Cq), 113.9
(2CHAr), 111.5 (CHAr), 55.5 (OCH3), 55.3 (OCH3) ppm. IR (neat):
˜
3
1474, 1295, 1184, 1020, 831, 732, 691 cm–1. HRMS (ESI): m/z
calcd. for C11H10N3OS [M + H]+ 232.053909; found 232.054069.
6-[4-(Trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole (2f): A
mixture of 1H-1,2,4-triazole-3-thiol (2.0 g, 19.8 mmol, 1.0 equiv.)
and 4-(trifluoromethyl)phenacyl bromide (5.81 g, 21.78 mmol,
1.1 equiv.) in EtOH (200 mL) was hated to reflux for 15 h. The
solution was then cooled to room temperature, and evaporated un-
der reduced pressure. The solid was then added to concentrated
sulfuric acid solution at 0 °C and stirred for 3 h at room tempera-
ture. The temperature was allowed to rise to room temperature.
After full conversion, a saturated solution of sodium carbonate was
slowly added until pH 7. The resulting solution was extracted with
CH2Cl2 (2ϫ 50 mL) and the combined organic layers were washed
with brine (20 mL), dried with MgSO4, filtered, and concentrated
under reduced pressure. The residue was then purified by flash
chromatography (CH2Cl2) to afford 2d (3.09 g, 58%) as a white
ν = 2935, 1638, 1246, 1164, 1021, 806, 717, 695 cm–1. HRMS (ESI):
˜
m/z calcd. for C24H20N3O2S [M + H]+ 414.120774; found
414.127340.
5-(3-Methoxyphenyl)-6-(4-methoxyphenyl)-2-phenylthiazolo[3,2-b]-
[1,2,4]triazole (3ab): The reaction was carried out as described in
General Procedure A using thiazolo[3,2-b]triazole (2a, 100.0 mg,
0.325 mmol), palladium acetate (7.3 mg, 0.033 mmol), tricyclohex-
ylphosphine (18.2 mg, 0.065 mmol), cesium carbonate (212.7 mg,
0.651 mmol), and 3-bromoanisole (91.3 mg, 0.488 mmol). Standard
workup followed by flash chromatography (CH2Cl2/petroleum
ether, 3:1) gave 3ab (132 mg, 98 %) as a white solid, m.p. 182–
184 °C. 1H NMR (250 MHz, CDCl3): δ = 8.23 (d, J = 6.7 Hz, 2
H), 7.68 (d, J = 8.9 Hz, 2 H), 7.52–7.42 (m, 3 H), 7.23–7.29 (m, 1
H), 6.90–7.00 (m, 5 H), 3.90 (s, 3 H), 3.76 (s, 3 H) ppm. 13C NMR
(63 MHz, CDCl3): δ = 167.4 (Cq), 161.9 (Cq), 161.3 (Cq), 156.6
(Cq), 134.3 (Cq), 132.8 (2CHAr), 132.7 (Cq), 131.5 (CHAr), 131.0
(CHAr), 130.0 (2CHAr), 129.7 (Cq), 128.2 (2CHAr), 126.2 (Cq),
123.1 (CHAr), 121.5 (Cq), 116.1 (CHAr), 116.0 (CHAr), 115.6
1
solid, m.p. 106–108 °C. H NMR (400 MHz, CDCl3): δ = 8.26 (d,
J = 8.3 Hz, 2 H), 8.25 (s, 1 H), 7.78 (d, J = 8.3 Hz, 2 H), 7.27 (s,
1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.2 (Cq), 156.2
(CHAr), 131.7 (Cq), 131.6 (q, J = 32.6 Hz, Cq), 131.1 (d, J =
32.6 Hz, Cq), 126.8 (2CHAr), 126.0 (q, J = 3.8 Hz, 2CHAr), 123.8
(q, J = 272.4 Hz), 110.5 (CHAr) ppm. IR (neat): ν = 1470, 1319,
˜
(2CHAr), 56.8 (OCH ), 56.7 (OCH ) ppm. IR (neat): ν = 1602,
˜
3
3
1248, 1178, 1113, 1015, 849, 767, 704, 642 cm–1. HRMS (ESI): m/z
1511, 1468, 1439, 1292, 1233, 1177, 1026, 778 cm–1. HRMS (ESI):
m/z calcd. for C24H20N3O2S [M + H]+ 414.120774; found
414.127172.
calcd. for C11H7F3N3S [M + H]+ 270.030729; found 270.031073.
6-Methylthiazolo[3,2-b][1,2,4]triazole (2g): 3-Mercapto-1,2,4-tri-
azole (1b, 2.0 g, 19.80 mmol, 1.0 equiv.) was dissolved in EtOH
(50 mL) and chloroacetone (2.19 g, 23.8 mmol, 1.2 equiv.) was
added dropwise. The mixture was heated to reflux for 3 h. After
evaporation of solvent under reduced pressure, a saturated solution
of sodium carbonate was added to the mixture until pH 7. The
resulting solution was extracted with EtOAc (2ϫ 50 mL) and the
combined organic layers were washed with brine (20 mL), dried
with MgSO4, filtered, and concentrated under reduced pressure.
The obtained product 2g (1.95 g, 71%), which was obtained as a
white solid, was sufficiently pure to be fully characterized, m.p. 68–
70 °C. 1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H), 6.62 (s, 1
H), 2.55 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.3
(Cq), 156.1 (CHAr), 129.6 (Cq), 107.8 (CHAr), 12.5 (CH3) ppm. IR
5-(4-Methoxyphenyl)-6-(4-methoxyphenyl)-2-phenylthiazolo[3,2-b]-
[1,2,4]triazole (3ac): The reaction was carried out as described in
General Procedure A using thiazolo[3,2-b]triazole (2a, 100.0 mg,
0.325 mmol), palladium acetate (7.3 mg, 0.033 mmol), tricyclohex-
ylphosphine (18.2 mg, 0.065 mmol), cesium carbonate (212.7 mg,
0.651 mmol), and 4-bromoanisole (91.3 mg, 0.488 mmol). Standard
workup followed by flash chromatography (CH2Cl2) gave 3ac
(125 mg, 93 %) as a white solid, m.p. 198–200 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.20 (d, J = 6.6 Hz, 2 H), 7.64 (d, J =
8.9 Hz, 2 H), 7.48–7.39 (m, 3 H), 7.30 (d, J = 8.8 Hz, 2 H), 6.96
(d, J = 8.9 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 3.86 (s, 3 H), 3.83
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.8 (Cq), 160.4
(Cq), 160.0 (Cq), 155.0 (Cq), 131.3 (Cq), 131.2 (2CHAr), 130.6
(2CHAr), 129.5 (CHAr), 128.5 (2CHAr), 127.5 (Cq), 126.7 (2CHAr),
125.0 (Cq), 123.8 (Cq), 120.2 (Cq), 114.5 (2CHAr), 114.2 (2CHAr),
(neat): ν = 3077, 1472, 1407, 1351, 1241, 1172, 1138, 986, 810,
˜
783 cm–1. HRMS (ESI): m/z calcd. for C5H6N3S [M + H]+
140.027695; found 140.027864.
55.4 (OCH ), 55.3 (OCH ) ppm. IR (neat): ν = 2963, 1505, 1441,
˜
3
3
1294, 1267, 1174, 1023, 830, 786, 693 cm–1. HRMS (ESI): m/z
General Procedure A: A 2–5 mL vial containing a stirring bar was
loaded with the desired thiazolo[3,2-b][1,2,4]triazole synthon
(1.0 equiv.), (hetero)aryl bromide (1.5 equiv.), Cs2CO3 (2.0 equiv.),
PCy3 (20 mol-%), and Pd(OAc)2 (10 mol-%) in 1,4-dioxane (2 mL).
The tube was degassed for 10 min under argon, sealed, and then
heated at 130 °C for 15 h. The resulting mixture was cooled to
room temperature, 1,4-dioxane was removed under reduced pres-
sure, and the residue was purified by flash chromatography to af-
ford the desired product.
calcd. for C24H20N3O2S [M + H]+ 414.120774; found 414.127241.
6-(4-Methoxyphenyl)-2-phenyl-5-[4-(trifluoromethyl)phenyl]thiazolo-
[3,2-b][1,2,4]triazole (3ad): The reaction was carried out as de-
scribed in General Procedure A using thiazolo[3,2-b]triazole (2a,
100.0 mg, 0.325 mmol), palladium acetate (7.3 mg, 0.033 mmol),
tricyclohexylphosphine (18.2 mg, 0.065 mmol), cesium carbonate
(212.7 mg, 0.651 mmol), and 1-bromo-4-(trifluoromethyl)benzene
(109.8 mg, 0.488 mmol). Standard workup followed by flash
chromatography (CH2Cl2/petroleum ether, 3:1) gave 3ad (120 mg,
82 %) as a yellow solid, m.p. 204–206 °C. 1H NMR (250 MHz,
5-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-2-phenylthiazolo[3,2-b]-
[1,2,4]triazole (3aa): The reaction was carried out as described in
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
C-5 (Het)Arylation of Substituted Thiazolo[3,2-b][1,2,4]triazoles
CDCl3): δ = 8.21–8.18 (m, 2 H), 7.63–7.59 (m, 4 H), 7.51–7.51 (m, 1442, 1320, 1270, 1167, 1127, 1067, 1015, 844, 818, 696 cm–1
.
5 H), 6.98 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR HRMS (ESI): m/z calcd. for C24H14F6N3S [M + H]+ 490.080714;
(63 MHz, CDCl3): δ = 167.8 (Cq), 162.3 (Cq), 156.7 (Cq), 136.9 (d, found 490.080617.
J = 1.6 Hz, Cq), 132.8 (2CHAr), 132.5 (Cq), 132.0 (d, J = 32.8 Hz,
2-Phenyl-5-(pyrimidin-5-yl)-6-[4-(trifluoromethyl)phenyl]thiazolo-
Cq), 131.2 (CHAr), 130.9 (2CHAr), 130.8 (Cq), 130.0 (2CHAr), 128.2
[3,2-b][1,2,4]triazole (3bc): The reaction was carried out as de-
(2CHAr), 127.4 (q, J = 3.7 Hz, 2CHAr), 123.0 (Cq), 122.6 (q, J =
scribed in General Procedure A using thiazolo[3,2-b]triazole (2b,
227.4 Hz, Cq), 120.8 (Cq), 115.9 (2CHAr), 56.8 (OCH3) ppm. IR
100.0 mg, 0.290 mmol), palladium acetate (6.5 mg, 0.029 mmol),
(neat): ν = 1611, 1471, 1441, 1323, 1251, 1167, 1068, 841, 781,
˜
tricyclohexylphosphine (16.2 mg, 0.058 mmol), cesium carbonate
(188.7 mg, 0.580 mmol), and 5-bromopyrimidine (69.1 mg,
0.434 mmol). Standard workup followed by flash chromatography
(CH2Cl2/MeOH, 99.7:0.3) gave 3bc (115 mg, 94%) as a white solid,
695 cm–1. HRMS (ESI): m/z calcd. for C24H17F3N3OS [M + H]+
452.103894; found 452.104055.
6-(4-Methoxyphenyl)-2-phenyl-5-(pyrimidin-5-yl)thiazolo[3,2-b]-
[1,2,4]triazole (3ae): The reaction was carried out as described in
General Procedure A using thiazolo[3,2-b]triazole (2a, 100.0 mg,
0.325 mmol), palladium acetate (7.3 mg, 0.033 mmol), tricyclohex-
ylphosphine (18.2 mg, 0.065 mmol), cesium carbonate (212.7 mg,
0.651 mmol), and 5-bromopyrimidine (77.6 mg, 0.488 mmol). Stan-
dard workup followed by flash chromatography (CH2Cl2/petroleum
ether, 3:1) gave 3ae (110 mg, 88 %) as a white solid, m.p. 216–
1
m.p. 234–236 °C. H NMR (400 MHz, CDCl3): δ = 9.23 (s, 1 H),
8.74 (s, 2 H), 8.21–8.15 (m, 2 H), 7.79 (2d, J = 8.4 Hz, 4 H), 7.52–
7.41 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.1 (Cq),
158.7 (CHAr), 156.6 (2CHAr), 155.6 (Cq), 132.4 (q, J = 33.1 Hz,
Cq), 130.5 (Cq), 130.2 (2CHAr), 130.2 (CHAr), 130.1 (d, J = 1.4 Hz,
Cq), 129.2 (Cq), 128.7 (2CHAr), 126.9 (2CHAr), 126.4 (q, J =
3.6 Hz, 2CHAr), 126.2 (Cq), 123.5 (q, J = 272.6 Hz, Cq), 119.6
1
(C ) ppm. IR (neat): ν = 1444, 1320, 1270, 1185, 1108, 1066, 814,
˜
218 °C. H NMR (400 MHz, CDCl3): δ = 9.20 (s, 1 H), 8.76 (s, 2
q
716, 696, 628 cm–1. HRMS (ESI): m/z calcd. for C21H13F3N5S [M
H), 8.22 (m, 2 H), 7.61 (d, J = 8.3 Hz, 2 H), 7.53–7.44 (m, 3 H),
7.04 (d, J = 8.3 Hz, 2 H), 3.90 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 166.9 (Cq), 161.3 (Cq), 158.0 (CHAr), 156.4 (2CHAr),
155.4 (Cq), 131.3 (2CHAr), 130.8 (2Cq), 129.9 (CHAr), 128.6
(2CHAr), 127.1 (Cq), 126.9 (2CHAr), 118.5 (Cq), 116.8 (Cq), 114.9
+ H]+ 424.083828; found 424.083990.
5-(3-Methoxyphenyl)-6-phenyl-thiazolo[3,2-b][1,2,4]triazole (3ca):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2c, 100.0 mg, 0.497 mmol), palladium
acetate (11.2 mg, 0.050 mmol), tricyclohexylphosphine (27.9 mg,
0.100 mmol), cesium carbonate (323.8 mg, 0.994 mmol), and 3-bro-
moanisole (139.4 mg, 0.745 mmol). Standard workup followed by
flash chromatography (CH2Cl2) gave 3ca (140 mg, 92%) as a white
(2CHAr), 55.4 (OCH ) ppm. IR (neat): ν = 1511, 1466, 1443, 1418,
˜
3
1262, 1178, 1026, 810, 717, 695 cm–1. HRMS (ESI): m/z calcd. for
C21H16N5OS [M + H]+ 386.107008; found 386.107116.
5-(3-Methoxyphenyl)-2-phenyl-6-[4-(trifluoromethyl)phenyl]thiazolo-
[3,2-b][1,2,4]triazole (3ba): The reaction was carried out as de-
scribed in General Procedure A using thiazolo[3,2-b]triazole (2b,
100.0 mg, 0.290 mmol), palladium acetate (6.5 mg, 0.029 mmol),
tricyclohexylphosphine (16.2 mg, 0.058 mmol), cesium carbonate
(188.7 mg, 0.580 mmol), and 3-bromoanisole (81.2 mg,
0.434 mmol). Standard workup followed by flash chromatography
(CH2Cl2/petroleum ether, 1:1) gave 3ba (110 mg, 84%) as a white
solid. Due to high insolubility, only a 135DEPT was obtained, m.p.
224–226 °C. 1H NMR (250 MHz, CDCl3): δ = 8.25–8.15 (m, 2 H),
7.87 (d, J = 8.2 Hz, 2 H), 7.70 (d, J = 8.2 Hz, 2 H), 7.54–7.39 (m,
3 H), 7.30 (t, J = 8.0 Hz, 1 H), 6.98–6.86 (m, 3 H), 3.74 (s, 3
H) ppm. 135 DEPT 13C NMR (63 MHz, CDCl3): δ = 130.4
(CHAr), 130.2 (2CHAr), 129.8 (CHAr), 128.7 (2CHAr), 126.8
(2CHAr), 125.7 (q, J = 3.6 Hz, 2CHAr), 121.8 (CHAr), 115.1
1
solid. M.p 74–76 °C. H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1
H), 7.64–7.60 (m, 2 H), 7.42 (m, 3 H), 7.24 (t, J = 7.8 Hz, 1 H),
6.94 (d, J = 7.8 Hz, 1 H), 6.90–6.85 (m, 2 H), 3.67 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 159.8 (Cq), 155.2 (CHAr), 154.5
(Cq), 132.4 (Cq), 130.2 (CHAr), 129.8 (CHAr), 129.8 (2CHAr), 128.8
(2CHAr), 128.3 (Cq), 127.8 (Cq), 127.1 (Cq), 121.6 (CHAr), 115.0
(CHAr), 114.6 (CHAr), 55.2 (OCH ) ppm. IR (neat): ν = 1602, 1568,
˜
3
1406, 1354, 1288, 1153, 1050, 790, 706, 690 cm–1. HRMS (ESI): m/z
calcd. for C17H14N3OS [M + H]+ 308.085210; found 308.085585.
6-Phenyl-5-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole
(3cb): The reaction was carried out as described in General Pro-
cedure A using thiazolo[3,2-b]triazole (2c, 100.0 mg, 0.497 mmol),
palladium acetate (11.2 mg, 0.050 mmol), tricyclohexylphosphine
(27.9 mg, 0.100 mmol), cesium carbonate (323.8 mg, 0.994 mmol),
and 1-bromo-4-(trifluoromethyl)benzene (167.7 mg, 0.745 mmol).
Standard workup followed by flash chromatography (CH2Cl2/
MeOH, 99.5:0.5) gave 3cb (140 mg, 82%) as a yellow solid, m.p.
(CHAr), 114.9 (CHAr), 55.3 (OCH ) ppm. IR (neat): ν = 1596, 1472,
˜
3
1322, 1298, 1121, 1020, 849, 784, 715, 692 cm–1. HRMS (ESI): m/z
calcd. for C24H17F3N3OS [M + H]+ 452.103894; found 452.103943.
1
150–152 °C. H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.61–
2-Phenyl-5,6-bis[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]tri-
azole (3bb): The reaction was carried out as described in General
Procedure A using thiazolo[3,2-b]triazole (2b, 100.0 mg,
0.290 mmol), palladium acetate (6.5 mg, 0.029 mmol), tricyclohex-
ylphosphine (16.2 mg, 0.058 mmol), cesium carbonate (188.7 mg,
0.580 mmol), and 1-bromo-4-(trifluoromethyl)benzene (97.7 mg,
0.434 mmol). Standard workup followed by flash chromatography
(CH2Cl2/petroleum ether, 1:1) gave 3bb (130 mg, 92%) as a white
7.58 (m, 4 H), 7.48–7.42 (m, 5 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 155.6 (CHAr), 154.6 (Cq), 134.9 (d, J = 1.4 Hz, Cq),
130.9 (q, J = 32.9 Hz, Cq), 130.2 (CHAr), 129.8 (2CHAr), 129.5
(2CHAr), 129.4 (Cq), 129.1 (2CHAr), 127.2 (Cq), 126.1 (q, J =
3.8 Hz, 2CHAr), 125.3 (Cq), 123.7 (q, J = 272.3 Hz, Cq) ppm. IR
(neat): ν = 2923, 1473, 1323, 1163, 1019, 847, 768, 705, 693 cm–1.
˜
HRMS (ESI): m/z calcd. for C17H11F3N3S [M + H]+ 346.062029;
found 346.062233.
1
solid, m.p. 232–234 °C. H NMR (400 MHz, CDCl3): δ = 8.19 (d,
J = 8.0 Hz, 2 H), 7.82 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.2 Hz, 2 6-Phenyl-5-pyrimidin-5-yl-thiazolo[3,2-b][1,2,4]triazole (3cc): The
H), 7.65 (d, J = 8.0 Hz, 2 H), 7.51–7.46 (m, 5 H) ppm. 13C NMR
reaction was carried out as described in General Procedure A using
(101 MHz, CDCl3): δ = 166.6 (Cq), 155.4 (Cq), 134.5 (d, J = 1.7 Hz, thiazolo[3,2-b]triazole (2c, 100.0 mg, 0.497 mmol), palladium acet-
Cq), 131.9 (q, J = 32.9 Hz, Cq), 131.4 (q, J = 33.1 Hz, Cq), 130.8 ate (11.2 mg, 0.050 mmol), tricyclohexylphosphine (27.9 mg,
(d, J = 1.7 Hz, Cq), 130.7 (Cq), 130.3 (2CHAr), 130.0 (CHAr), 129.7 0.100 mmol), cesium carbonate (323.8 mg, 0.994 mmol), and 5-
(2CHAr), 128.7 (2CHAr), 127.8 (Cq), 126.8 (2CHAr), 126.3 (q, J = bromopyrimidine (118.5 mg, 0.745 mmol). Standard workup fol-
3.7 Hz, 2CHAr), 126.0 (q, J = 3.7 Hz, 2CHAr, Cq), 123.7 (q, J =
lowed by flash chromatography (EtOAc/petroleum ether, 3:1) gave
272.5 Hz, C ), 123.6 (q, J = 272.4 Hz, C ) ppm. IR (neat): ν =
3cc (125 mg, 90%) as a yellow solid, m.p. 170–172 °C. 1H NMR
˜
q
q
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
(250 MHz, CDCl3): δ = 9.17 (s, 1 H), 8.70 (s, 2 H), 8.19 (s, 1 H),
7.59–7.44 (m, 5 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 159.8
(CHAr), 157.9 (2CHAr), 157.4 (CHAr), 156.2 (Cq), 132.2 (Cq), 132.2
ylphosphine (24.2 mg, 0.086 mmol), cesium carbonate (281.8 mg,
0.865 mmol), and 2-bromoanisole (121.3 mg, 0.649 mmol). Stan-
dard workup followed by flash chromatography (CH2Cl2/MeOH,
(CHAr), 131.0 (2CHAr), 130.9 (2CHAr), 127.9 (Cq), 127.8 (Cq), 99.7:0.3) gave 3ea (116 mg, 80 %) as a yellow oil. 1H NMR
120.6 (C ) ppm. IR (neat): ν = 3090, 1549, 1475, 1416, 1360, 1171,
(400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.53 (d, J = 8.9 Hz, 2 H),
7.36 (td, J = 8.2, 1.7 Hz, 2 H), 7.24 (dd, J = 8.2, 1.7 Hz, 1 H),
6.94–6.87 (m, 4 H), 3.80 (s, 3 H), 3.67 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 160.2 (Cq), 157.3 (Cq), 155.5 (Cq), 155.0
(CHAr), 132.4 (CHAr), 130.9 (CHAr), 130.5 (2CHAr), 129.2 (Cq),
121.9 (Cq), 120.9 (Cq, CHAr), 120.0 (Cq), 114.0 (2CHAr), 111.5
˜
q
878, 759, 705, 630 cm–1. HRMS (ESI): m/z calcd. for C14H10N5S
[M + H]+ 280.065143; found 280.065371.
5-(3-Methoxyphenyl)-6-(p-tolyl)thiazolo[3,2-b][1,2,4]triazole (3da):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2d, 100.0 mg, 0.465 mmol), palladium
acetate (10.4 mg, 0.046 mmol), tricyclohexylphosphine (26.1 mg,
0.093 mmol), cesium carbonate (302.7 mg, 0.929 mmol), and 3-bro-
moanisole (130.3 mg, 0.697 mmol). Standard workup followed by
flash chromatography (CH2Cl2/MeOH, 99.5:0.5) gave 3da (143 mg,
96 %) as a yellow solid, m.p. 118–120 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.13 (s, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.23 (m, 3 H),
6.95–6.88 (m, 3 H), 3.69 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.8 (Cq), 155.2 (CHAr), 154.5 (Cq), 140.0
(Cq), 132.5 (Cq), 130.1 (CHAr), 129.6 (2CHAr), 129.6 (2CHAr),
128.5 (Cq), 126.5 (Cq), 124.8 (Cq), 121.6 (CHAr), 114.8 (CHAr),
(CHAr), 55.5 (OCH ), 55.3 (OCH ) ppm. IR (neat): ν = 2931, 1511,
˜
3
3
1488, 1358, 1290, 1167, 1023, 816, 752, 632 cm–1. HRMS (ESI): m/z
calcd. for C18H16N3O2S [M + H]+ 338.095774; found 338.095850.
5-(3-Methoxyphenyl)-6-(4-methoxyphenyl)thiazolo[3,2-b][1,2,4]tri-
azole (3eb): The reaction was carried out as described in General
Procedure A using thiazolo[3,2-b]triazole (2e, 100.0 mg,
0.432 mmol), palladium acetate (9.7 mg, 0.043 mmol), tricyclohex-
ylphosphine (24.2 mg, 0.086 mmol), cesium carbonate (281.8 mg,
0.865 mmol), and 3-bromoanisole (121.3 mg, 0.649 mmol). Stan-
dard workup followed by flash chromatography (CH2Cl2/petroleum
ether, 3:1) gave 3eb (127 mg, 87%) as a yellow solid, m.p. 124–
114.6 (CHAr), 55.2 (OCH ), 21.49 (CH ) ppm. IR (neat): ν = 3111,
˜
3
3
2917, 1469, 1414, 1236, 1164, 1042, 798, 766, 690 cm–1. HRMS
(ESI): m/z calcd. for C18H16N3OS [M + H]+ 322.100860; found
322.101096.
1
126 °C. H NMR (250 MHz, CDCl3): δ = 8.18 (s, 1 H), 7.60 (d, J
= 8.9 Hz, 2 H), 7.32–7.25 (m, 1 H), 7.03–6.89 (m, 5 H), 3.87 (s, 3
H), 3.74 (s, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 162.0 (Cq),
161.3 (Cq), 156.6 (CHAr), 155.8 (Cq), 134.1 (Cq), 132.6 (2CHAr),
131.6 (CHAr), 129.6 (Cq), 127.2 (Cq), 123.0 (CHAr), 121.4 (Cq),
116.1 (CHAr), 116.1 (CHAr), 115.7 (2CHAr), 56.8 (CH3), 56.7
6-(p-Tolyl)-5-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole
(3db): The reaction was carried out as described in General Pro-
cedure A using thiazolo[3,2-b]triazole (2d, 100.0 mg, 0.465 mmol),
palladium acetate (10.4 mg, 0.0465 mmol), tricyclohexylphosphine
(26.1 mg, 0.093 mmol), cesium carbonate (302.7 mg, 0.929 mmol),
and 1-bromo-4-(trifluoromethyl)benzene (156.8 mg, 0.697 mmol).
The mixture was heated at 160 °C. Standard workup followed by
flash chromatography (CH2Cl2/MeOH, 99.5:0.5) gave 3db (145 mg,
87 %) as a yellow solid, m.p. 146–148 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.17 (s, 1 H), 7.60 (d, J = 8.2 Hz, 2 H), 7.49 (d, J =
8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H),
2.41 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.5 (CHAr),
154.6 (Cq), 140.6 (Cq), 135.1 (d, J = 1.2 Hz, Cq), 130.8 (q, J =
33.0 Hz, Cq), 129.8 (2CHAr), 129.6 (2CHAr), 129.5 (2CHAr), 126.6
(Cq), 126.0 (q, J = 3.8 Hz, 2CHAr), 124.7 (Cq), 124.2 (Cq),123.7 (q,
(CH ) ppm. IR (neat): ν = 2951, 1595, 1406, 1357, 1290, 1164,
˜
3
1025, 857, 770, 689 cm– 1 . HRMS (ESI): m/z calcd. for
C18H16N3O2S [M + H]+ 338.095774; found 338.095774.
5-(4-Methoxyphenyl)-6-(4-methoxyphenyl)thiazolo[3,2-b][1,2,4]-
triazole (3ec): The reaction was carried out as described in General
Procedure A using thiazolo[3,2-b]triazole (2e, 100.0 mg,
0.432 mmol), palladium acetate (9.7 mg, 0.043 mmol), tricyclohex-
ylphosphine (24.2 mg, 0.086 mmol), cesium carbonate (281.8 mg,
0.865 mmol), and 4-bromoanisole (121.3 mg, 0.649 mmol). The
mixture was heated at 160 °C. Standard workup followed by flash
chromatography (CH2Cl2/MeOH, 99.5:0.5) gave 3cc (77 mg, 53%)
1
as a white solid, m.p. 138–140 °C. H NMR (400 MHz, CDCl3): δ
J = 272.3 Hz, C ), 21.5 (CH ) ppm. IR (neat): ν = 1616, 1469,
˜
q
3
= 8.14 (s, 1 H), 7.55 (d, J = 8.9 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2
H), 6.94 (d, J = 8.9 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3
H), 3.82 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.4
(Cq), 160.1 (Cq), 154.9 (CHAr), 154.2 (Cq), 131.1 (2CHAr), 130.6
(2CHAr), 127.4 (Cq), 126.0 (Cq), 123.6 (Cq), 120.1 (Cq), 114.5
(2CHAr), 114.3 (2CHAr), 55.4 (OCH3), 55.3 (OCH3) ppm. IR
1324, 1109, 1067, 1016, 883, 852, 781, 646 cm–1. HRMS (ESI): m/z
calcd. for C18H13F3N3S [M + H]+ 360.077680; found 360.077999.
6-(p-Tolyl)-5-pyrimidin-5-yl-thiazolo[3,2-b][1,2,4]triazole (3dc): The
reaction was carried out as described in General Procedure A using
thiazolo[3,2-b]triazole (2d, 100.0 mg, 0.465 mmol), palladium acet-
ate (10.4 mg, 0.0465 mmol), tricyclohexylphosphine (26.1 mg,
0.093 mmol), cesium carbonate (302.7 mg, 0.929 mmol), and 5-
bromopyrimidine (110.8 mg, 0.697 mmol). Standard workup fol-
lowed by flash chromatography (CH2Cl2/MeOH, 99:1) gave 3dc
(118 mg, 87 %) as a yellow solid, m.p. 198–200 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.20 (s, 1 H), 8.74 (s, 2 H), 8.22 (s, 1 H),
7.48 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 2.43 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.3 (CHAr), 156.4
(2CHAr), 156.0 (CHAr), 154.8 (Cq), 141.2 (Cq), 131.0 (Cq), 130.2
(2CHAr), 129.5 (2CHAr), 126.7 (Cq), 123.4 (Cq), 118.6 (Cq), 21.5
(neat): ν = 3062, 2933, 1518, 1442, 1295, 1166, 1024, 837, 766,
˜
648 cm–1. HRMS (ESI): m/z calcd. for C18H16N3O2S [M + H]+
338.095774; found 338.096112.
6-(4-Methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b]-
[1,2,4]triazole (3ed): The reaction was carried out as described in
General Procedure A using thiazolo[3,2-b]triazole (2e, 100.0 mg,
0.432 mmol), palladium acetate (9.7 mg, 0.043 mmol), tricyclohex-
ylphosphine (24.2 mg, 0.086 mmol), cesium carbonate (281.8 mg,
0.865 mmol), and 1-bromo-4-(trifluoromethyl)benzene (145.9 mg,
0.649 mmol). Standard workup followed by flash chromatography
(CH2Cl2/MeOH, 99.6:0.4) gave 3ed (144 mg, 89%) as a yellow so-
(CH ) ppm. IR (neat): ν = 3099, 1550, 1474, 1360, 1168, 911, 876,
˜
3
717, 658, 624 cm–1. HRMS (ESI): m/z calcd. for C15H12N5S [M +
1
lid, m.p. 132–134 °C. H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1
H]+ 294.080793; found 294.080990.
H), 7.59 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.48 (d, J
= 8.2 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 160.9 (Cq), 155.5 (CHAr), 154.5 (Cq),
135.2 (d, J = 1.6 Hz, Cq), 131.2 (2CHAr), 130.7 (q, J = 32.9 Hz,
Cq), 129.5 (2CHAr), 129.3 (Cq), 126.0 (q, J = 3.7 Hz, 2CHAr), 124.0
5-(2-Methoxyphenyl)-6-(4-methoxyphenyl)thiazolo[3,2-b][1,2,4]tri-
azole (3ea): The reaction was carried out as described in General
Procedure A using thiazolo[3,2-b]triazole (2e, 100.0 mg,
0.432 mmol), palladium acetate (9.7 mg, 0.043 mmol), tricyclohex-
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
C-5 (Het)Arylation of Substituted Thiazolo[3,2-b][1,2,4]triazoles
(Cq), 123.7 (q, J = 272.3 Hz, Cq), 119.3 (Cq), 114.6 (2CHAr), 55.4
(CH2Cl2) gave 3fc (115 mg, 89%) as a white solid. Due to high
1
(OCH ) ppm. IR (neat): ν = 1465, 1324, 1252, 1165, 1116, 1067, insolubility, only a 135 DEPT was obtained, m.p. 200–202 °C. H
˜
3
1026, 841, 804 cm–1. HRMS (ESI): m/z calcd. for C18H13F3N3OS
NMR (400 MHz, CDCl3): δ = 9.24 (s, 1 H), 8.74 (s, 2 H), 8.22 (s,
1 H), 7.75 (m, 4 H) ppm. 135 DEPT 13C NMR (101 MHz, CDCl3):
δ = 158.83 (CHAr), 156.58 (2CHAr), 156.09 (CHAr), 130.08
[M + H]+ 376.072594; found 376.072723.
6-(4-Methoxyphenyl)-5-pyrimidin-5-yl-thiazolo[3,2-b][1,2,4]triazole
(3ee): The reaction was carried out as described in General Pro-
cedure A using thiazolo[3,2-b]triazole (2e, 100.0 mg, 0.432 mmol),
palladium acetate (9.7 mg, 0.043 mmol), tricyclohexylphosphine
(24.2 mg, 0.086 mmol), cesium carbonate (281.8 mg, 0.865 mmol),
and 5-bromopyrimidine (103.1 mg, 0.649 mmol). Standard workup
followed by flash chromatography (CH2Cl2/MeOH, 98.8:1.2) gave
3ee (123 mg, 92%) as a white solid, m.p. 208–210 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.18 (s, 1 H), 8.73 (s, 2 H), 8.20 (s, 1 H),
7.52 (d, J = 8.8 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2 H), 3.86 (s, 3
(2CHAr), 126.46 (q, J = 3.8 Hz, 2CHAr) ppm. IR (neat): ν = 1550,
˜
1419, 1321, 1162, 1124, 1018, 881, 811, 724, 633 cm–1. HRMS
(ESI): m/z calcd. for C15H9F3N5S [M + H]+ 348.052527; found
348.052797.
5-(2-Methoxyphenyl)-6-methyl-thiazolo[3,2-b][1,2,4]triazole (3ga):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium
acetate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 2-bro-
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 161.3 (Cq), 158.2 moanisole (201.5 mg, 1.078 mmol). Standard workup followed by
(CHAr), 156.4 (2CHAr), 155.9 (CHAr), 154.7 (Cq), 131.1 (2CHAr), flash chromatography (CH2Cl2/MeOH, 99:1) gave 3ga (155 mg,
1
130.8 (Cq), 126.8 (Cq), 118.3 (Cq), 117.9 (Cq), 115.0 (2CHAr), 55.5
88%) as an orange oil. H NMR (400 MHz, CDCl3): δ = 8.07 (s,
1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 7.00–6.93
(m, 2 H), 3.79 (s, 3 H), 2.40 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 157.1 (Cq), 155.1 (Cq), 154.9 (CHAr), 132.0 (CHAr),
130.9 (CHAr), 126.4 (Cq), 121.3 (Cq), 120.8 (CHAr), 119.2 (Cq),
(CH ) ppm. IR (neat): ν = 3105, 1548, 1411, 1360, 1251, 1176,
˜
3
1025, 877, 701, 622 cm–1. HRMS (ESI): m/z calcd. for C15H12N5OS
[M + H]+ 310.075707; found 310.075723.
5-(3-Methoxyphenyl)-6-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b]-
[1,2,4]triazole (3fa): The reaction was carried out as described in
General Procedure A using thiazolo[3,2-b]triazole (2f, 100.0 mg,
0.371 mmol), palladium acetate (8.30 mg, 0.037 mmol), tricy-
clohexylphosphine (20.8 mg, 0.074 mmol), cesium carbonate
(242.0 mg, 0.743 mmol), and 3-bromoanisole (104.2 mg,
111.4 (CHAr), 55.5 (CH ), 11.81 (CH ) ppm. IR (neat): ν = 2929,
˜
3
3
1466, 1411, 1358, 1266, 1241, 1166, 1023, 752, 652 cm–1. HRMS
(ESI): m/z calcd. for C12H12N3OS [M + H]+ 246.069559; found
246.069815.
5-(3-Methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazole (3gb):
0.557 mmol). Standard workup followed by flash chromatography The reaction was carried out as described in General Procedure A
(CH2Cl2) gave 3fa (120 mg, 86 %) as a yellow solid, m.p. 112– using thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium
114 °C. H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 7.78 (d, J acetate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
= 8.2 Hz, 2 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.28 (t, J = 8.1 Hz, 1 H), 0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 3-bro-
6.94–6.86 (m, 3 H), 3.72 (s, 3 H) ppm. 13C NMR (101 MHz, moanisole (201.5 mg, 1.078 mmol). Standard workup followed by
1
CDCl3): δ = 160.0 (Cq), 155.3 (CHAr), 154.6 (Cq), 131.7 (Cq), 131.4
flash chromatography (CH2Cl2/MeOH, 99.5:0.5) gave 3gb (170 mg,
(q, J = 32.8 Hz, Cq), 131.3 (d, J = 1.0 Hz, Cq), 130.5 (CHAr), 130.0 96 %) as a yellow solid, m.p. 108–110 °C. 1H NMR (400 MHz,
(2CHAr), 128.9 (Cq), 126.7 (Cq), 125.7 (q, J = 3.8 Hz, 2CHAr), CDCl3): δ = 8.17 (s, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.08 (d, J =
123.7 (q, J = 272.4 Hz, Cq), 121.7 (CHAr), 115.2 (CHAr), 114.9 7.9 Hz, 1 H), 7.10–6.97 (m, 2 H), 3.88 (s, 3 H), 2.66 (s, 3 H) ppm.
(CHAr), 55.3 (OCH ) ppm. IR (neat): ν = 1596, 1465, 1325, 1245, 13C NMR (101 MHz, CDCl3): δ = 160.0 (Cq), 155.2 (CHAr), 154.3
˜
3
1163, 1038, 1022, 858, 775, 690 cm–1. HRMS (ESI): m/z calcd. for
(Cq), 132.4 (Cq), 130.2 (CHAr), 125.4 (Cq), 125.2 (Cq), 121.4
(CHAr), 114.9 (CHAr), 114.3 (CHAr), 55.4 (OCH3 ), 11.8
C18H13F3N3OS [M + H]+ 376.072594; found 376.072732.
(CH ) ppm. IR (neat): ν = 1602, 1571, 1467, 1359, 1240, 1129,
˜
3
5,6-Bis[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole (3fb):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2f, 100.0 mg, 0.371 mmol), palladium
acetate (8.30 mg, 0.037 mmol), tricyclohexylphosphine (20.8 mg,
0.074 mmol), cesium carbonate (242.0 mg, 0.743 mmol), and 1-
bromo-4-(trifluoromethyl)benzene (125.3 mg, 0.557 mmol). The
mixture was heated at 160 °C. Standard workup followed by flash
chromatography (CH2Cl2) gave 3fb (115 mg, 75%) as a white solid.
Due to high insolubility, only a 135 DEPT 13C was obtained, m.p.
1044, 876, 781, 694 cm–1. HRMS (ESI): m/z calcd. for C12H12N3OS
[M + H]+ 246.069559; found 264.069813.
5-(4-Methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazole (3gc):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium
acetate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 4-bro-
moanisole (201.5 mg, 1.078 mmol). Standard workup followed by
flash chromatography (CH2Cl2) gave 3gc (118 mg, 67%) as a yellow
1
160–162 °C. H NMR (250 MHz, CDCl3): δ = 8.22 (s, 1 H), 7.79
1
(d, J = 8.5 Hz, 2 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.2 Hz, 2
H), 7.52 (d, J = 8.2 Hz, 2 H) ppm. 135 DEPT 13C NMR (63 MHz,
CDCl3): δ = 155.7 (CHAr), 130.1 (2CHAr), 129.7 (2CHAr), 126.4
solid, m.p. 110–112 °C. H NMR (250 MHz, CDCl3): δ = 8.15 (s,
1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.02 (d, J = 8.7 Hz, 2 H), 3.88 (s,
3 H), 2.61 (s, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ = 161.5
(q, J = 3.7 Hz, 2CHAr), 126.1 (q, J = 3.7 Hz, 2CHAr) ppm. IR (Cq), 156.4 (CHAr), 155.5 (Cq), 131.8 (2CHAr), 126.9 (Cq), 125.8
(neat): ν = 1618, 1474, 1320, 1162, 1065, 1017, 882, 807, 703,
(Cq), 124.7 (Cq), 116.0 (2CHAr), 56.9 (OCH3), 13.0 (CH3) ppm. IR
˜
643 cm–1. HRMS (ESI): m/z calcd. for C18H10F6N3S [M + H]+
(neat): ν = 3094, 1601, 1509, 1408, 1361, 1247, 1140, 1032, 800,
˜
414.049414; found 414.049309.
700, 652 cm–1. HRMS (ESI): m/z calcd. for C12H12N3OS [M +
H]+ 246.069559; found 246.069875.
5-Pyrimidin-5-yl-6-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]-
triazole (3fc): The reaction was carried out as described in General
Procedure A using thiazolo[3,2-b]triazole (2f, 100.0 mg,
0.371 mmol), palladium acetate (8.30 mg, 0.037 mmol), tricy-
clohexylphosphine (20.8 mg, 0.074 mmol), cesium carbonate
(242.0 mg, 0.743 mmol), and 5-bromopyrimidine (88.6 mg,
6-Methyl-5-[4-(trifluoromethyl)phenyl]thiazolo[3,2-b][1,2,4]triazole
(3gd): The reaction was carried out as described in General Pro-
cedure A using thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol),
palladium acetate (16.1 mg, 0.072 mmol), tricyclohexylphosphine
(40.3 mg, 0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol),
0.557 mmol). Standard workup followed by flash chromatography and 1-bromo-4-(trifluoromethyl)benzene (242.5 mg, 1.078 mmol).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
The mixture was heated at 160 °C. Standard workup followed by
raphy (CH2Cl2/MeOH, 99:1) gave 3gh (194 mg, quant.) as a white
solid, m.p. 164–166 °C. H NMR (400 MHz, CDCl3): δ = 8.14 (d,
1
flash chromatography (CH2Cl2) gave 3gd (171 mg, 84%) as a yellow
1
solid, m.p. 132–134 °C. H NMR (400 MHz, CDCl3): δ = 8.16 (s, J = 8.2 Hz, 2 H), 8.12 (s, 1 H), 7.55 (d, J = 8.2 Hz, 2 H), 3.94 (s,
1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.61 (d, J = 8.2 Hz, 2 H), 2.66 (s,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.5 (CHAr), 154.5 (Cq), 155.4 (2Cq), 154.5 (Cq), 135.6 (Cq), 130.4 (2CHAr), 128.8
(Cq), 134.8 (d, J = 1.4 Hz, Cq), 130.9 (q, J = 32.9 Hz, Cq), 129.3 (2CHAr), 126.1 (Cq), 124.5 (Cq), 52.4 (OCH3), 11.9 (CH3) ppm. IR
3 H), 2.65 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.2
(2CHAr), 126.3 (Cq), 126.2 (q, J = 3.7 Hz, 2CHAr), 123.9 (Cq), (neat): ν = 3109, 1719, 1476, 1402, 1269, 1236, 1114, 850, 700,
˜
123.7 (q, J = 272.4 Hz, C ), 11.8 (CH ) ppm. IR (neat): ν = 2922,
693 cm–1. HRMS (ESI): m/z calcd. for C13H12N3O2S [M + H]+
274.064474; found 274.064676.
˜
q
3
1614, 1405, 1321, 1172, 1109, 1007, 835, 701, 652 cm–1. HRMS
(ESI): m/z calcd. for C12H9F3N3S [M + H]+ 284.046379; found
284.046540.
5-[2H]-6-Phenylthiazolo[3,2-b][1,2,4]triazole (3c-D): The reaction
was carried out as described in General Procedure A using thi-
azolo[3,2-b]triazole (2c, 100.0 mg, 0.497 mmol) and cesium carb-
onate (323.8 mg, 0.994 mmol) in a mixture of 1,4-dioxane/D2O
(4 mL, 1:1). Standard workup followed by flash chromatography
(dichloromethane) gave 3c-D (100 mg, quant.) as a white solid,
m.p. 90–92 °C. 1H NMR (250 MHz, CDCl3): δ = 8.22 (s, 1 H),
8.08–8.03 (m, 2 H), 7.54–7.41 (m, 3 H) ppm. 13C NMR (63 MHz,
CDCl3): δ = 158.4 (Cq), 157.4 (CHAr), 134.5 (Cq), 131.3 (CHAr),
130.4 (2CHAr), 129.3 (Cq), 128.0 (2CHAr), 109.7 (m, Cq) ppm. IR
6-Methyl-5-(pyrimidin-5-yl)thiazolo[3,2-b][1,2,4]triazole (3ge): The
reaction was carried out as described in General Procedure A using
thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium acet-
ate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 4-
bromopyrimidine (171.4 mg, 1.078 mmol). Standard workup fol-
lowed by flash chromatography (CH2Cl2/MeOH, 98.7:1.3) gave 3ge
(148 mg, 95 %) as a yellow solid, m.p. 224–226 °C. 1H NMR
(250 MHz, [D6]DMSO): δ = 9.25 (s, 1 H), 9.03 (s, 2 H), 8.32 (s, 1
H), 2.62 (s, 3 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 158.5
(CHAr), 156.8 (2CHAr), 156.1 (CHAr), 154.6 (Cq), 128.5 (Cq), 126.4
(neat): ν = 3113, 2920, 2303, 1406, 1351, 1240, 1185, 732, 653,
˜
612 cm–1. HRMS (ESI): m/z calcd. for C10H7N3SD [M + H]+
203.049621; found 203.050209.
(C ), 118.0 (C ), 11.7 (CH ) ppm. IR (neat): ν = 3105, 3031, 1478,
˜
5-[2H]-6-Methylthiazolo[3,2-b][1,2,4]triazole (3g-D): The reaction
was carried out as described in General Procedure A using thi-
azolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol) and cesium carb-
onate (468.2 mg, 1.437 mmol) in a mixture of 1,4-dioxane/D2O
(4 mL, 1:1). Standard workup followed by flash chromatography
(dichloromethane) gave 3g-D (100 mg, quant.) as a white solid,
m.p. 76–78 °C. 1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 1 H), 2.50
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.2 (Cq), 156.1
(CHAr), 129.5 (Cq), 107.9 (Cq), 127.6 (m, Cq), 14.4 (CH3) ppm. IR
q
q
3
1409, 1388, 1240, 1180, 906, 723, 651 cm–1. HRMS (ESI): m/z
calcd. for C9H8N5S [M + H]+ 218.049493; found 218.049799.
6-Methyl-5-(pyridin-4-yl)thiazolo[3,2-b][1,2,4]triazole (3gf): The re-
action was carried out as described in General Procedure A using
thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium acet-
ate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 4-
bromopyridine hydrochloride (209.6 mg, 1.078 mmol). The mixture
was heated at 160 °C. Standard workup followed by flash
chromatography (CH2Cl2/MeOH, 98:2) gave 3gf (126 mg, 81%) as
(neat): ν = 3113, 2920, 1472, 1406, 1351, 1240, 1162, 732, 637,
˜
612 cm–1. HRMS (ESI): m/z calcd. for C5H5N3SD [M + H]+
1
141.033971; found 141.034161.
a white solid, m.p. 146–148 °C. H NMR (400 MHz, CDCl3): δ =
8.74 (d, J = 6.1 Hz, 2 H), 8.18 (s, 1 H), 7.40 (d, J = 6.1 Hz, 2 H),
2.72 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.8 (CHAr),
154.5 (Cq), 150.7 (2CHAr), 139.1 (2Cq), 127.3 (Cq), 122.8 (2CHAr),
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR or 13C DEPT NMR spectra for all com-
pounds; pKa determination method.
12.1 (CH ) ppm. IR (neat): ν = 3097, 1600, 1476, 1408, 1362, 1240,
˜
3
1168, 1159, 817, 648 cm–1. HRMS (ESI): m/z calcd. for C10H9N4S
[M + H]+ 217.054244; found 217.054514.
Acknowledgments
6-Methyl-5-(p-tolyl)thiazolo[3,2-b][1,2,4]triazole (3gg): The reaction
was carried out as described in General Procedure A using thi-
azolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium acetate
(16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and 4-bro-
motoluene (184.3 mg, 1.078 mmol). Standard workup followed by
flash chromatography (CH2Cl2/petroleum ether, 3:1) gave 3gg
(125 mg, 76 %) as a white solid, m.p. 114–116 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.36 (d, J = 8.0 Hz, 2 H),
7.28 (d, J = 8.0 Hz, 2 H), 2.61 (s, 3 H), 2.41 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 155.1 (CHAr), 154.3 (Cq), 139.1 (Cq),
129.8 (2CHAr), 128.9 (2CHAr), 128.2 (Cq), 125.7 (Cq), 124.7 (Cq),
This research was supported by the French Medicinal Chemistry
Society (SCT) and by grants from the Institut de Recherches Serv-
ier. The authors also acknowledge the assistance of Mathieu Perrier
(ICOA) in the final development of this project.
[1] D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
103, 893–930.
[2] a) I. Khan, A. Ibrar, N. Abbas, Eur. J. Med. Chem. 2013, 63,
854–868; b) A. Locatelli, S. Cosconati, M. Micucci, A. Leoni,
L. Marinelli, A. Bedini, P. Ioan, S. M. Spampinato, E. Nov-
ellino, A. Chiarini, R. Budriesi, J. Med. Chem. 2013, 56, 3866–
3877; c) G. L. Huang, H. S. Sun, X. J. Qiu, C. Jin, C. Lin, Y. Z.
Shen, J. L. Jiang, L. Y. Wang, Org. Lett. 2011, 13, 5224–5227.
[3] a) S. Grosse, C. Pillard, F. Himbert, S. Massip, J.-M. Léger, C.
Jarry, P. Bernard, G. Guillaumet, Eur. J. Org. Chem. 2013,
4146–4155; b) S. Grosse, C. Pillard, S. Massip, J. M. Léger, C.
Jarry, S. Bourg, P. Bernard, G. Guillaumet, Chem. Eur. J. 2012,
18, 14943–14947; c) A. Tikad, M. Akssira, S. Massip, J. M.
Léger, C. Jarry, G. Guillaumet, S. Routier, Eur. J. Org. Chem.
2012, 4523–4532.
21.3 (CH ), 11.6 (CH ) ppm. IR (neat): ν = 2921, 1470, 1407, 1361,
˜
3
3
1235, 1170, 1139, 813, 653 cm–1. HRMS (ESI): m/z calcd. for
C12H12N3S [M + H]+ 230.074645; found 230.075020.
Methyl 4-(6-Methylthiazolo[3,2-b][1,2,4]triazol-5-yl)benzoate (3gh):
The reaction was carried out as described in General Procedure A
using thiazolo[3,2-b]triazole (2g, 100.0 mg, 0.718 mmol), palladium
acetate (16.1 mg, 0.072 mmol), tricyclohexylphosphine (40.3 mg,
0.144 mmol), cesium carbonate (468.2 mg, 1.437 mmol), and
methyl 4-bromobenzoate (231.7 mg, 1.078 mmol). The mixture was
heated at 160 °C. Standard workup followed by flash chromatog-
[4] a) M. S. Karthikeyan, Eur. J. Med. Chem. 2009, 44, 827–833; b)
H. A. H. El-Sherif, A. M. Mahmoud, A. A. O. Sarhan, Z. A.
Hozien, O. M. A. Habib, J. Sulfur Chem. 2006, 27, 65–85.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
C-5 (Het)Arylation of Substituted Thiazolo[3,2-b][1,2,4]triazoles
[5] S. F. Barbuceanu, G. L. Almajan, I. Saramet, C. Draghici, A. I.
Tarcomnicu, G. Bancescu, Eur. J. Med. Chem. 2009, 44, 4752–
4757.
[6] J. El Bakali, F. Klupsch, A. Guédin, B. Brassart, G. Fontaine,
A. Farce, P. Roussel, R. Houssin, J.-L. Bernier, P. Chavatte,
J. L. Mergny, J.-F. Riou, J.-P. Hénichart, Bioorg. Med. Chem.
Lett. 2009, 19, 3434–3438.
L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int.
Ed. 2009, 48, 9792–9826; Angew. Chem. 2009, 121, 9976.
Z. Xie, X. Zhu, Y. Guan, D. Zhu, H. Hu, C. Lin, Y. Pan, J.
Jiang, Org. Biomol. Chem. 2013, 11, 1390–1398.
S. H. Wang, W. J. Liu, H. Y. Zhan, H. Zang, Y. Liang, Y. Tian,
RSC Adv. 2014, 4, 1388–1392.
J. Roger, F. Pozgan, H. Doucet, J. Org. Chem. 2009, 74, 1179–
1186.
[10]
[11]
[12]
[13]
[7] B. Tozkoparan, S. P. Aytaç, S¸. Gürsoy, G. Aktay, Med. Chem.
Res. 2012, 21, 192–201.
˙
˙
H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404–
12405.
[8] A. Uzgören-Baran, B. Cahide Tel, D. Sarıgöl, E. I. Öztürk, I.
Kazkayası, G. Okay, M. Ertan, B. Tozkoparan, Eur. J. Med.
Chem. 2012, 57, 398–406.
[14] B. Liégault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
J. Org. Chem. 2009, 74, 1826–1834.
[15] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066–3072; Angew. Chem. 2012, 124, 3120.
[16] For reviews with mechanistic discussions on palladium(0)-cata-
lyzed, direct C–H coupling reactions of electron-rich and -de-
ficient heterocycles, see: a) D. Balcells, E. Clot, O. Eisenstein,
Chem. Rev. 2010, 110, 749–823; b) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173–1193; c) F. Bellina, S. Cauteric-
cio, R. Rossi, Curr. Org. Chem. 2008, 12, 774–790.
Received: March 4, 2014
[9] a) J. M. Joo, P. Guo, D. Sames, J. Org. Chem. 2013, 78, 738–
743; b) E. Van der Eycken, Chem. Eur. J. 2013, 19, 1158–1168;
c) S. W. Youn, D. Y.-K. Chen, Chem. Eur. J. 2012, 18, 9452–
9474; d) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glor-
ius, Angew. Chem. Int. Ed. 2012, 51,10236–10254; Angew.
Chem. 2012, 124, 10382; e) J. M. Joo, B. Barry Touré, D.
Sames, J. Org. Chem. 2010, 75, 4911–4920; f) B. Liégault, I.
Petrov, S. I. Gorelsky, K. Fagnou, J. Org. Chem. 2010, 75,
1047–1060; g) J. Roger, A. L. Gottumukkala, H. Doucet,
ChemCatChem 2010, 2, 20–40; h) L. Ackermann, R. Vicente,
A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9976–10011; i)
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O42193
/KAP1
Date: 05-05-14 16:21:55
Pages: 12
G. Guillaumet, S. Routier et al.
FULL PAPER
Heterocyclic Chemistry
M. Le Meur, S. Bourg, S. Massip,
M. Marchivie, C. Jarry, G. Guillaumet,*
S. Routier* ...................................... 1–12
First Palladium-Catalyzed Direct Regiose-
lective C-5 (Het)Arylation of Mono- or
Disubstituted Thiazolo[3,2-b][1,2,4]tri-
azoles
An efficient and convenient method has
been developed for the formation of poly-
substituted thiazolo[3,2-b][1,2,4]triazoles
through C-5 (het)arylation. The direct C–
H activation protocol giving access to di-
and trisubstituted derivatives in excellent
yields, and the method enables access to a
collection of C-5,6 bis(het)aryl derivatives
with full regioselectivity.
Keywords: C–H activation / Regioselectiv-
ity / Nitrogen heterocycles / Sulfur hetero-
cycles / Palladium
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0