On water direct Pd-catalysed C-H arylation of thiazolo[5,4-d]pyrimidine derivatives

Article abstract of DOI:10.1039/c2gc35399g

A novel protocol for the direct arylation of thiazolo[5,4-d]pyrimidine derivatives with aryl iodides is reported. The reactions were catalysed by a combination of Pd(PPh₃)₄ and Ag₂CO₃ (acting as the oxidant and the base as well), using exclusively water as the solvent and furnishing the desired products in good to excellent yields at only 60 °C. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc35399g

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PAPER
“On water” direct Pd-catalysed C–H arylation of thiazolo[5,4-d]pyrimidine
derivatives†
Ye-Xiang Su, Ya-Hui Deng, Ting-Ting Ma, Yu-Yan Li* and Li-Ping Sun*
Received 19th March 2012, Accepted 26th April 2012
DOI: 10.1039/c2gc35399g
A novel protocol for the direct arylation of thiazolo[5,4-d]pyrimidine derivatives with aryl iodides is
reported. The reactions were catalysed by a combination of Pd(PPh3)4 and Ag2CO3 (acting as the oxidant
and the base as well), using exclusively water as the solvent and furnishing the desired products in good
to excellent yields at only 60 °C.
is one of the few that can proceed at temperatures below
Introduction
100 °C.6 Therefore, it is a representative “on-water” reaction
termed by Sharpless and co-workers.7 Conducting the reaction
2-Arylsubstituted thiazolo[5,4-d]pyrimidine derivatives are
found to be the main motif of some pharmacologically relevant
compounds such as Tie-2 inhibitors,1a phosphatidylinositide
3-kinases (PI3K) inhibitors,1b immunosuppressive agents,1c XOD
inhibitor,1d human erythrocyte membrane phosphatidylinositol
4-kinase inhibitors1e and E. coli and S. aureus SecA inhibitors.1f
Therefore, the synthesis of thiazolo[5,4-d]pyrimidine derivatives
is a major concern in medicinal chemistry. Childress and McKee
have achieved its synthesis by effective cyclization of benzoic
anhydride with 5-amino-6-mercaptopyrimidine.2 2-Arylsubsti-
tuted thiazolo[5,4-d]pyrimidine derivatives can also be obtained
through dehydrocyclization of 4-amino-5-arylamidopyrimidines
with polyphosphoric acid or ring closure of benzoylamino-
pyrimidines with phosphorus pentasulfide.3 These procedures
require some toxic reagents and harsh conditions which have
limited their applications. The direct construction of C–C bonds
between 2-halo(bromine or chlorine) substituted thiazolo[5,4-d]-
pyrimidine with phenylboronic acid or tributylphenylstannane
catalyzed by palladium was also achieved.1f Although the advan-
tages of the reactions include: (i) the easy realization of regios-
electivity; (ii) the access to nearly all structural motifs due to
thorough research of this area, they still suffer from the appli-
cation of stoichiometric organometallic reagents together with
troubles concerned with their preparations, stability and func-
tional group compatibility.4
on-water can be substantially benefits, such as safety because of
its high heat capacity; the ease of operation and post-treatment
due to the insolubility of both reaction substrates and products;
most significantly it can greatly increase reaction rate and selec-
tivity.8 It should be pointed out that rate acceleration is not
relevant to the amount of water used; it should just be enough
to keep a clear phase separation.9 The on-water procedure was first
applied by Greaney and co-workers, viable to the direct arylation
of several heteroarenes at temperature as low as 50 °C.6a
Results and discussion
On the outset of our study, we tried to exam the direct coupling
reaction between 7-chloro-2-methylthiazolo[5,4-d]pyrimidine 1
and iodobenzene 2a in the presence of Pd(dppf)Cl2, with
Ag2CO3 and PPh3 as base and ligand respectively, in water.
Although 7-chloro-2-methylthiazolo[5,4-d]pyrimidine is nearly
consumed, the yield was only 14%. After repeating several
times, the results were still almost the same. Taking the hypothe-
tical effect that Ag+ may coordinate with chlorine in 7-chloro-2-
methylthiazolo[5,4-d]pyrimidine
and
7-chloro-5-methyl-2-
phenylthiazolo[5,4-d]pyrimidine into consideration and with
the expectation of higher yields, we substituted the substrate
with 5-methyl-N-phenylthiazolo[5,4-d]pyrimidin-7-amine
3
We report here a method for the coupling of thiazolo[5,4-d]-
pyrimidine derivatives and aryl iodides with tetrakis(triphenyl-
phosphine)palladium(0) as catalyst, in the presence of silver
carbonate in water. This method is representative of atom-
economy.5 Our procedure is one of the examples that uses water
as a reaction medium rather than traditional organic solvents and
(Scheme 1). Unfortunately, no reaction was detected between the
substituted substrate and iodobenzene. According to the obser-
vation that none of substrate and desired product can be detected
except iodobenzene, we speculated that the interaction between
Ag+ and the NH fragment may be responsible for this phenom-
enon. As we have noticed that free-NH10 or NH2 are tolerated
11
in the direct arylation between heteroarenes and aryl halides cata-
lyzed by palladium, we can eliminate the effect of palladium.
Besides, we are also aware of the fact that Ag+ can crystallize
with secondary amine and the formed complex has good solubi-
lity in polar solvents.12 Compared with its counterpart, demethy-
lated indole required a much longer reaction time, higher
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing 210009, P.R. China. E-mail: chslp@cpu.edu.cn;
Fax: +(86)2583271351; Tel: +(86)2583271445
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35399g
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1979–1981 | 1979

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temperature and offered a lower yield in the direct arylation cata-
lyzed by palladium and silver salt.13
Then, in order to continue our study, we used another sub-
strate, 4-(5-methylthiazolo[5,4-d]pyrimidin-7-yl)morpholine 6,
which can be obtained by the reaction between 1 and morpholine
in ethanol at room temperature. The coupling reaction can be
effectively carried out with 5 mmol% palladium-catalyst, in the
presence of 10 mmol% PPh3, using Ag2CO3 as the silver source
and base, in water at 60 °C. Pd(dppf)Cl2 and Pd(PPh3)4 can give
the desired products in good yield (Table 1, entries 1, 3).
However, the coupling with Pd(OAc)2 as catalyst just offered a
yield of 30% (Table 1, entry 2). From the angle of yield and
cost, Pd(PPh3)4 is the favorable catalyst. Then, Ag2CO3 was
replaced by Cs2CO3 or K3PO4. Unfortunately, the yields were
trace or 8% respectively (Table 1, entries 4–5). Compared with
entry 3, the yield of coupling was almost the same when PPh3
was removed (Table 1, entry 6). Excellent yield was achieved
when the amount of iodobenzene was increased to 2 equiv
(Table 1, entry 7). Finally, the yield was drastically decreased
after water was changed to acetonitrile (Table 1, entry 8). The
good premixing of substrates and the catalytic system is vital to
the success of the arylation reaction. It is an easy task for solid
aryl halides, while enough attention should be paid to the liquid
aryl halides. Solid components should be added first; then the
Scheme 2 Pd-catalyzed C–H arylation between 6 and aryl iodides.
liquid aryl halides, thus preventing them from adhering to the
inner surface of microwave tube; last deionized water was
injected. It should also be noted that the stirring bar may be
strapped by the mixture which may induce incompletion of the
reaction.
With this optimal catalytic system, the direct coupling
reactions between 4-(5-methylthiazolo[5,4-d]pyrimidin-7-yl)-
morpholine 6 and several other aryl iodides were explored
(Scheme 2). Aryl iodides bearing electron-donating functional-
ities offered the products in moderate to excellent yields (7b,
7f). Unfortunately, para-iodoaniline failed to give any coupling
product although it contains a strong electron-rich functionality
(7g). The slightly electron-withdrawing groups furnished the
desired products in good yields similar to that of electron-rich
aryl iodides (7c, 7e). However, this product can offer a platform
for further elaboration as it contains chlorine (7c). Chlorine will
not be a source of side reactions, because no reaction was
detected between 4-(5-methylthiazolo[5,4-d]pyrimidin-7-yl)-
morpholine and chlorobenzene under this very catalytic system.
The strong electron-withdrawing group, –CF3, drastically
decreased the yield, it offered the expected product 7d in 39%
yield.
Scheme 1 The direct arylation of 1 or 3 and iodobenzene.
Table 1 Conditions screening for 4-(5-methylithiazolo[5,4-d]-
pyrimidin-7-yl) morpholine 6 and iodobenzenea
It is also remarkable that the reaction between iodobenzene
and more rigid 5-methyl-7-phenylthiazolo[5,4-d]pyrimidine 8a
proceeded efficiently under similar conditions, only requiring an
extended reaction time of 48 h (Scheme 3, 9a). Compared with
4-(5-methylthiazolo[5,4-d]-pyrimidin-7-yl)morpholine, the rigid-
ity may be responsible for the longer reaction time. However,
Cat.
Entry (equiv)
Base
(equiv)
Solvent
(ml)
Ligand
(equiv)
Yieldb
(%)
7-(4-methoxyphenyl)-5-methylthiazolo[5,4-d]pyrimidine
8b
offered a higher yield than 5-methyl-7-phenylthiazolo[5,4-d]-
pyrimidine, which may be due to the effect of the OCH3 group,
in which the oxygen may promote the combination of catalyst
and substrate (9i). The electron-rich substitutes still contributed
to the higher yields (9b, 9f, 9j, 9n), while 4-iodoaniline gave no
coupling product (9j, 9o). Considering all the results of the reac-
tions involving substrates bearing NH or NH2 groups, we may
conclude that this established catalytic system is not viable for
them. Fortunately, the coupling reaction between 5-methyl-7-
phenylthiazolo[5,4-d]pyrimidine derivatives with 2-iodothiophene
is viable, although reaction times had to be prolonged to 72 h
and the expected products were obtained in 34% and 35% yields
1
Pd(dppf)
Cl2
Ag2CO3
H2O
PPh3
59
2
3
4
5
Pd(OAc)2 Ag2CO3
Pd(PPh3)4 Ag2CO3
Pd(PPh3)4 Cs2CO3
Pd(PPh3)4 K3PO4
Pd(PPh3)4 Ag2CO3
Pd(PPh3)4 Ag2CO3
Pd(PPh3)4 Ag2CO3
H2O
H2O
H2O
H2O
H2O
H2O
CH3CN
PPh3
PPh3
PPh3
PPh3
30
68
Trace
8
66
94
26
6
7c
8c
a Reaction conditions:
1 (0.1 mmol) and 2 (0.12 mmol), base
(0.2 mmol), PPh3 (0.01 mmol), catalyst (0.005 mmol), solvent (1 ml),
60 °C. b Isolated yield. c 2 (0.2 mmol). dppf
=
1,1′-bis-
(diphenylphosphino)ferrocene.
1980 | Green Chem., 2012, 14, 1979–1981
This journal is © The Royal Society of Chemistry 2012

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pyrimidin-7-amine, 5-methyl-7-phenylthiazolo[5,4-d]pyrimidine,
7-(4-methoxyphenyl)-5-methylthiazolo[5,4-d]pyrimidine were
synthesized according to the literature procedure.14
Acknowledgements
We are grateful to the funds supported by the National Natural
Science Foundation of China (no. 20872181, no. 21172265) and
in part sponsored by Qing Lan Project in Jiangsu Province.
Notes and references
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Scheme 3 Pd-catalyzed C–H arylation between 8 and aryl iodides.a
respectively (9p, 9h). The aryl iodides containing electron-with-
drawing functionalities can give good to excellent yields (9c, 9e,
9k, 9m). Even the reagents bearing strong electron-withdrawing
CF3 groups can still furnish products in 65% and 89% yields
respectively (9d, 9l).
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Conclusion
In conclusion, we have developed an effective and relatively
inexpensive palladium catalytic system for the direct arylation of
thiazolo[5,4-d]pyrimidine derivatives with aryl iodides using
water as reaction medium. Furthermore, the reaction temperature
is much lower than that of commonly reported in the literature in
the direct arylation of heteroarenes catalyzed by transition
metals. Further elaboration may be expected to enlarge the scope
of functional group tolerance of this procedure.
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Experimental
General
1H and 13C NMR are recorded on 300 MHz spectrometers at
25 °C unless otherwise stated and are calibrated to residual
solvent peaks (CDCl3 7.26, DMSO-d6 2.5, 3.3 ppm). The data is
reported as chemical shift (ppm), and then the interpretation
of the peak with relevant coupling constants reported in Hertz.
Pd(PPh3)4 was stored in a refrigerator. Reactions were performed
in a 10 ml microwave tube. 5-Methyl-N-phenylthiazolo[5,4-d]-
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1979–1981 | 1981