Palladium-catalyzed direct and regioselective C-5 desulfitative arylation of thiazolo[3,2- b ]-1,2,4-triazoles with sodium sulfinates

Article abstract of DOI:10.1055/s-0033-1340320

An efficient Pd(OAc)₂-catalyzed direct arylation of thi?azolo[3,2-b]-1,2,4-triazoles with sodium sulfinates has been developed. The reaction shows high regioselectivity, good reaction efficiency and excellent functional group compatibility. This approach provides a useful protocol for the preparation of functionalized thiazolo[3,2-b]-1,2,4-triazole derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340320

586▌
LETTER
letter
Palladium-Catalyzed Direct and Regioselective C-5 Desulfitative Arylation of
Thiazolo[3,2-b]-1,2,4-triazoles with Sodium Sulfinates
Desulfitative C–H Arylation of Thiazolo[3,2-b]-1,2,4-triazoles
Shaohua Wang, Wenjie Liu,* Juan Lin, Yi Jiang, Qi Zhang, Yue Zhong
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. of China
Fax +86(760)88207939; E-mail: wjliu1113@126.com
Received: 13.10.2013; Accepted after revision: 06.11.2013
occurred under mild conditions. The exploration of this
Abstract: An efficient Pd(OAc)2-catalyzed direct arylation of thi-
method for direct C–H arylation of heteroarenes would af-
azolo[3,2-b]-1,2,4-triazoles with sodium sulfinates has been devel-
ford a facile and effective synthetic route to aryl–hetero-
aryl units.
oped. The reaction shows high regioselectivity, good reaction
efficiency and excellent functional group compatibility. This ap-
proach provides a useful protocol for the preparation of functional-
ized thiazolo[3,2-b]-1,2,4-triazole derivatives.
Table 1 Optimization of the Reaction Conditionsa
Key words: desulfitative arylation, C–H activation, thiazolo[3,2-
b]-1,2,4-triazoles, sodium arylsulfinates
N
N
N
cat. Pd
oxidant
N
N
+
SO2Na
Ph
N
S
S
1a
2a
3a
The biaryl motif with aryl–heteroaryl bonds represents a
predominant core structure found in many biologically ac-
tive compounds, natural products, medicinal chemistry
and functional materials.1 Transition-metal-catalyzed di-
rect arylation of C–H bonds has emerged as a powerful
and straightforward synthetic method for rapid construc-
tion of aryl–heteroaryl bonds.2 Over the past several
years, various arylating reagents have been applied for
this type of reaction, including aryl halides,3 arylsilanes,4
aryl boronic acid,5 aryltrifluoroborates,6 diaryl iodonium
salts,7 and aromatic carboxylic acid.8 Despite these suc-
cesses, there has been an increasing interest in exploring
new reliable alternative arylating reagents and expanding
the substrate scopes.
Entry Cat.
Oxidant
Solvent
Yield
(%)b
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuCl2
CuBr2
dioxane–diglyme (1:1) 60
dioxane–diglyme (1:1) 46
3
Cu(OAc)2 dioxane–diglyme (1:1) 78
4
FeCl3
Ag2O
AgOAc
K2S2O8
TBHP
BQ
dioxane–diglyme (1:1) trace
dioxane–diglyme (1:1) trace
dioxane–diglyme (1:1) trace
dioxane–diglyme (1:1) n.r.
dioxane–diglyme (1:1) n.r.
dioxane–diglyme (1:1) n.r.
5
6
7
8
Compounds ArSO2X (X = Cl, H, NHNH2, Na) have been
successfully used as the aryl sources in the direct arylation
of various arene C–H bonds.9 However, the arylsulfonyl
chlorides and arylsufinic acids are moisture-sensitive, and
arylsulfonyl hydrazides are relatively expensive. Com-
pared to the above compounds, arylsulfinic acid sodium
salts are much more stable, easy to handle, and commer-
cially available. Thus, arylsulfinic acid sodium salts are
ideal aryl sources for C–C bond forming reaction via re-
leasing SO2 under relatively mild conditions. In 1992,
Sato and Okoshi reported a Pd-catalyzed desulfitative bi-
aryl synthesis with sodium sulfinates and aromatic bro-
mides under harsh conditions.10 Since then, sulfinic salts
have rarely been used as an aryl source via desulfitative
reactions, whereas they were generally used as sulfonyl-
ation reagents.11 Recently, there have been several reports
9
10
11
12
13
14
15
16
17
O2
dioxane–diglyme (1:1)
8
–
dioxane–diglyme (1:1) n.r.
Cu(OAc)2 dioxane–diglyme (1:2) 83
Cu(OAc)2 dioxane–diglyme (1:3) 79
Cu(OAc)2 dioxane
Cu(OAc)2 diglyme
Cu(OAc)2 NMP
Cu(OAc)2 DMF
53
37
42
30
18c Pd(OAc)2
Cu(OAc)2 dioxane–diglyme (1:2) 56
Cu(OAc)2 dioxane–diglyme (1:2) 70
Cu(OAc)2 dioxane–diglyme (1:2) n.r.
Cu(OAc)2 dioxane–diglyme (1:2) 63
Cu(OAc)2 dioxane–diglyme (1:2) 75
Cu(OAc)2 dioxane–diglyme (1:2) 46
on the desulfitative reactions of sodium arylsulfinates 19d Pd(OAc)2
with olefins,12 aldehydes,13 nitriles,14 CuCN,15 and direct
20
–
C–H arylation with heterocyclic compounds.9i–l The de-
sulfitative reactions were not sensitive to moisture and 21
PdCl2
22
Pd(OH)2
Pd(PPh3)4
SYNLETT 2014, 25, 0586–0590
23
Advanced online publication: 06.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

DOI: 10.1055/s-0033-1340320; Art ID: ST-2013-W0963-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Desulfitative C–H Arylation of Thiazolo[3,2-b]-1,2,4-triazoles
587
Table 1 Optimization of the Reaction Conditionsa (continued)
compounds containing thiazolo[3,2-b]-1,2,4-triazole ring
as an activator of cephalosporins.20 Herein, we describe
the first palladium-catalyzed desulfitative arylation of thi-
azolo[3,2-b]-1,2,4-triazoles with aromatic sodium sul-
finates via C–H bond activation.
N
N
N
N
cat. Pd
oxidant
N
N
+
SO2Na
Ph
S
S
1a
2a
3a
Here we began this study by choosing 6-methylthiazolo-
[3,2-b]-1,2,4-triazole (1a) and sodium benzenesulfinate
(2a) as model substrates to optimize the reaction condi-
tions (Table 1). The effects of different oxidants, solvents,
and palladium sources were systematically examined. The
desired desulfitative arylation product 3a was obtained in
60% yield by using 5 mol% of Pd(OAc)2 as catalyst, and
two equivalents of CuCl2 as an oxidant in dioxane–di-
glyme at 120 °C (entry 1). It is particularly noteworthy
that only C-5 arylated product 3a was found. Among other
oxidants tested, CuBr2 was less effective (entry 2), and
Cu(OAc)2 displayed the highest reactivity (entry 3). The
replacement of Cu(OAc)2 by FeCl3, Ag2O, AgOAc, and
K2S2O8 was ineffective (entries 4–7). Organic oxidants,
such as tert-butyl hydroperoxide (TBHP) and benzoqui-
none (BQ) were also not suited to this kind of transforma-
tion (entries 8 and 9). Using pure oxygen as oxidant, the
product 3a was detected in 8% yield, and the reaction did
not occur in the absence of oxidant (entries 10 and 11).
Entry Cat.
Oxidant
Solvent
Yield
(%)b
24
25
Pd(TFA)2
Cu(OAc)2 dioxane–diglyme (1:2) 40
Pd(MeCN)2Cl2 Cu(OAc)2 dioxane–diglyme (1:2) 66
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (5
mol%), oxidant (2 equiv) in mixed solvent (1 mL) at 120 °C for 24 h.
b GC yield.
c Amount of Cu(OAc)2 used was 1.0 equiv.
d Amount of Cu(OAc)2 used was 3.0 equiv.
Molecules containing thiazolo[3,2-b]-1,2,4-triazole ring
play an important role in a wide range of natural products
and drugs.16 In particular, thiazolo[3,2-b]-1,2,4-triazole
derivatives with a biaryl motif show excellent biological
and pharmaceutical activities, such as anti-inflammato-
ry,17 antimicrobial,18 and antibacterial.19 Shibahara et al.
described the synthesis and characterization of several
R1
R1
N
N
N
a
N
+
NaO2S
N
S
R2
N
S
R2
1a,b
2
3
N
N
N
N
N
N
N
N
N
N
N
S
S
N
S
S
3a, 79%, 85%b
3b, 73%
3c, 76%
3d, 80%
N
N
N
N
N
N
N
S
N
N
N
F
Cl
S
S
S
N
N
F
Cl
3e, 71%
3f, 78%
3g, 77%
3h, 81%
Ph
Ph
N
N
N
N
N
N
N
N
N
Br
CF3
S
N
S
S
S
N
N
3k, 82%, 86%b
3l, 75%
3j, 79%
3i, 79%
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
S
N
N
S
F
S
N
S
F
3m, 78%
3n, 83%
3o, 76%
3p, 80%
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
CF3
Cl
Br
S
N
S
S
S
N
N
Cl
3q, 79%
3r, 80%
3s, 81%
3t, 78%
Scheme 1 A regioselective C-5 arylation of thiazolo[3,2-b]-1,2,4-triazoles with different sodium arylsulfinates. The yields are of the isolated
products. Reagents and conditions: (a) 1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (2 equiv), 1,4-dioxane–diglyme (1:2, 1 mL),
120 °C for 24 h. (b) CuCl (10 mol%) as additive.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 586–590

588
S. Wang et al.
LETTER
The solvent also had a significant impact on the reaction tuted sodium arylsulfinate selectively underwent the de-
yield. The yield increased to 83% in a mixture of dioxane sulfitative C–H arylation.
and diglyme (1:2), but slightly decreased with the increas-
Additionally, the thiazolo[3,2-b]-1,2,4-triazoles bearing
ing proportion of diglyme (entries 12 and 13). Moderate
various groups at 2- and 6-positions were investigated and
yields were obtained when the reaction was tested in pure
the results are shown in Scheme 2. As can be seen from
dioxane, diglyme, NMP and DMF (entries 14–17). An at-
Scheme 2, the tandem reactions of thiazolo[3,2-b]-1,2,4-
triazoles 1c–g with sodium benzenesulfinate or sodium
p-tolylsulfinate generated the corresponding products 4a–
i in good yields.
tempt to lower or increase the amount of Cu(OAc)2 to one
equivalent or three equivalents resulted in a low consump-
tion of the reagent 1a (entries 18 and 19). Other palladium
salts were also investigated and moderate to good yield
were obtained when PdCl2, Pd(OH)2, Pd(PPh3)4,
Pd(TFA)2, and Pd(MeCN)2Cl2 were used instead of
Pd(OAc)2 (entries 21–25). The Pd catalyst was essential
and product 3a was not detected in the absence of the Pd
It is well known that Cu(I) salts have been widely used as
catalyst or activator in direct C-arylation of N-hetero-
arenes.3e,21 As shown in Table 1, Cu(OAc)2 was the best
choice as compared to the other oxidants for fulfilling the
catalytic cycle, suggesting that a catalytic amount of Cu(I)
salt formed from Cu(OAc)2 could promote the C–H bond
activation of N-heteroarenes. As expected, an addition of
source (entry 20). It was clearly demonstrated that the best
yield of product 3a (83%, entry 12) was obtained in the
presence of Pd(OAc)2 (5 mol%) in combination with two
CuCl (10 mol%) improved the yields of the desired prod-
equivalents of Cu(OAc)2 as oxidant in dioxane–diglyme
ucts, hinting that copper salt is not only the oxidant but
(1:2) at 120 °C for 24 hours.
also the co-catalyst during the catalytic cycle (Scheme 1,
products 3a and 3k).
With the optimized conditions in hand, we explored the
scope of this process with different sodium arylsulfinate
On the basis of the above results, a plausible mechanism
compounds (Scheme 1). Sodium arylsulfinates with dif-
of this transformation has been proposed and is shown in
ferent functional groups including methyl, fluoro, chloro,
Scheme 3. Take arylation of substrate 1a as an example.
bromo, and trifluoromethyl were tolerated and the desired
First, the Pd(II) catalyst reacts with 6-methylthiazolo[3,2-
products were obtained in moderate to good yields. Nota-
b]-1,2,4-triazole (1a) at the C-5 position to form an Ar–
bly, the groups on the para- or meta-position of benzene
Pd(II)–X intermediate I (X = OAc), which is subsequently
rings also reacted with 1a or 1b smoothly. Meanwhile,
displaced by sulfinic acid to form intermediate II. Next,
yields of the desired products (3b, 3e, 3l and 3o) were
this Ar–Pd(II)–SO2Ar species II undergoes desulfination
to generate the key aryl–palladium intermediate III, fol-
slightly affected by an ortho-position effect. It is known
that aryl bromides can be used as the coupling partners in
lowed by reductive elimination to produce the desired
the Pd(OAc)2-catalyzed direct C–H arylation with a wide
product 3a. Pd(0) could be reoxidized by Cu(OAc)2 to re-
alize the catalytic cycle.
range of heteroarenes. But it was found that bromo-substi-
R1
R1
N
N
N
N
N
a
N
R3
+
R3
NaO2S
S
S
R2
R2
1c–g
2
4
N
N
N
N
N
N
N
S
N
S
S
N
4a, 78%
4b, 81%
4c, 80%
N
N
N
N
S
N
S
N
4d, 82%
4e, 80%
N
N
N
N
Cl
S
N
S
N
4f, 82%
4g, 75%
Ph
N
N
N
N
N
N
Cl
S
S
4h, 78%
4i, 83%
Scheme 2 The scope of thiazolo[3,2-b]-1,2,4-triazoles in the reaction. The yields are of the isolated products. Reagents and conditions: (a) 1
(0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (5 mol%), Cu(OAc)2 (2 equiv), 1,4-dioxane–diglyme (1:2, 1 mL), 120 °C for 24 h.
Synlett 2014, 25, 586–590
© Georg Thieme Verlag Stuttgart · New York

LETTER
Desulfitative C–H Arylation of Thiazolo[3,2-b]-1,2,4-triazoles
589
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N
N
S
N
N
CuX2
1a
Ar
PdX2
S
N
HX
Pd(0)
3a
N
N
N
N
N
PdII
X
PdIIAr
S
I
N
S
III
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–
ArSO2
N
N
N
PdII SO2Ar
S
II
Scheme 3 Proposed reaction mechanism
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In conclusion, we have developed an efficient palladium-
catalyzed regioselective desulfitative arylation of thiazo-
lo[3,2-b]-1,2,4-triazoles at C-5 position using sodium ar-
ylsulfinates.22 Various thiazolo[3,2-b]-1,2,4-triazoles and
sodium arylsulfinates can be tolerated in this reaction to
afford the desired products in good yields. Further studies
to expand the substrate scope and detail the reaction
mechanism are currently underway.
Acknowledgment
The work was financially supported by the Foundation for Distin-
guished Young Talents in Higher Education of Guangdong
(2012LYM_0086), the Natural Science Foundation of Guangdong
Province (S2013040012962) and the National Natural Science
Foundation of China (21302023, 21373061).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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Synlett 2014, 25, 586–590

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(22) General Procedure for the Synthesis of 3 and 4: A
reaction vessel was charged with thiazolo[3,2-b]-1,2,4-
triazoles 1 (0.5 mmol), sodium arylsulfinates 2 (1 mmol),
Pd(OAc)2 (5 mol%), Cu(OAc)2 (2 equiv), and dioxane–
diglyme (1:2; 1 mL). The mixture was stirred at 120 °C and
monitored by TLC. After the completion of the reaction, the
mixture was poured into H2O (10 mL), and extracted with
EtOAc (3 × 10 mL). The combined extract was dried with
anhyd MgSO4. The solvent was removed and the crude
product was separated by column chromatography (eluted
with petroleum ether–EtOAc) to give the desired products 3
and 4.
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6-Methyl-5-o-tolylthiazolo[3,2-b]-1,2,4-triazole(3b): The
product was isolated as a colorless oil in 73% yield (84 mg).
1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 7.28–7.36 (m,
4 H), 2.37 (s, 3 H), 2.29 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 155.2, 138.2, 131.5, 130.6, 129.8, 129.4, 126.1,
126.0, 123.9, 20.0, 11.2. ESI–MS: m/z (%) = 230 (100) [M +
H]+. Anal. Calcd for C12H11N3S: C, 62.86; H, 4.84; N, 18.33.
Found: C, 62.81; H, 4.80; N, 18.28.
2,6-Dimethyl-5-phenylthiazolo[3,2-b]-1,2,4-triazole (4a):
The product was isolated as a white solid in 78% yield (90
mg); mp 72–73 °C. 1H NMR (400 MHz, CDCl3): δ = 7.40–
7.48 (m, 5 H), 2.60 (s, 3 H), 2.57 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 165.3, 155.3, 131.3, 129.1, 129.0, 128.8,
124.9, 124.0, 14.9, 11.7. ESI–MS: m/z (%) = 230 (100) [M +
H]+. Anal. Calcd for C12H11N3S: C, 62.86; H, 4.84; N, 18.33.
Found: C, 62.82; H, 4.81; N, 18.27.
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Kokai Tokkyo Koh JP1992339952, 1994.
Synlett 2014, 25, 586–590
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