Palladium-catalyzed oxidative C-H/C-H cross-couplings of thiazolo[5,4-d]pyrimidine with aromatic (hetero)cycles

Article abstract of DOI:10.1016/j.tet.2014.03.103

A novel Pd(II)-catalyzed dehydrogenative cross-coupling reaction of thiazolo[5,4-d]pyrimidine with unactivated (hetero)arenes via C-H bond activation was achieved. This protocol provides a straightforward and operationally simple method for the synthesis of 2-arylsubstituted thiazolo[5,4-d]pyrimidines of interest in pharmaceutical sciences.

Full text of DOI:10.1016/j.tet.2014.03.103

Tetrahedron 70 (2014) 3730e3734
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Tetrahedron
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Palladium-catalyzed oxidative CeH/CeH cross-couplings of thiazolo
[5,4-d]pyrimidine with aromatic (hetero)cycles
,
,
,b,
Sheng-Wei Yang a b, Ye-Xiang Su a b, Li-Ping Sun a
*
a Jiangsu Key Laboratory of Drug Design & Optimization, China Pharmaceutical University, Nanjing 210009, PR China
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Pd(II)-catalyzed dehydrogenative cross-coupling reaction of thiazolo[5,4-d]pyrimidine with
unactivated (hetero)arenes via CeH bond activation was achieved. This protocol provides a straightfor-
ward and operationally simple method for the synthesis of 2-arylsubstituted thiazolo[5,4-d]pyrimidines
of interest in pharmaceutical sciences.
Received 25 January 2014
Received in revised form 19 March 2014
Accepted 31 March 2014
Available online 13 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Palladium-catalyzed
Cross-coupling
Thiazolo[5,4-d]pyrimidine
CeH activation
1. Introduction
phosphatidylinositol 4-kinase inhibitors.15 By using the classic
synthesis methods of heterocyclic chemistry, C-2 arylated thiazolo
Classical transition-metal-catalyzed methods for the direct C-
arylation, such as Kumada, Negishi, Stille, Suzuki, and Hiya-
maeDenmark reactions, require functionalized groups in at least
one of the two coupling partners prior to cross-coupling.1 Recently,
the direct functionalization of CeH bonds of organic compounds has
emerged as a powerful and ideal method for carbonecarbon (CeC)
bond formation.2 During the last few decades, much effort has been
made towards reliable transition-metal-catalyzed intermolecular
oxidative CeH cross-coupling reactions.3 In this context, direct CeH/
CeH cross-coupling between two unfunctional groups provides an
alternative and potentially more efficient synthetic methodology.
Generally, although CeH oxidative cross-coupling between two
unactivated (hetero)arenes are most challenging, they still represent
significant progress toward the stated goals of Green Chemistry. To
date, intermolecular CeH oxidative cross-coupling of many motifs
with (hetero)arenes has been developed, including indoles,4 ben-
zofurans,5 benzazoles,6 benzoxazoles,7 xanthines,8 pyridin-N-ox-
ides,9 anilides,10 perfluoroarenes.11
[5,4-d]pyrimidines can only be achieved by cyclization of benzoic
anhydride with 5-amino-6-mercaptopyrimidine,16 dehydrocycli-
zation of 4-amino-5-arylamido-pyrimidines with polyphosphoric
acid or ring closure of benzoyl aminopyrimidines with phosphorus
pentasulfide.17 As these procedures require some toxic reagents
and harsh conditions, their applications are always limited. Thus,
the development of new synthetic methodologies for the synthesis
of this motif is of major importance.
As a continuing effort of our work in the construction of het-
erocycles by transition-metal-catalyzed cross-coupling reactions,18
we herein disclose a novel Pd-catalyzed CeH oxidative cross-
couplings of thiazolo[5,4-d]pyrimidine with aromatic (hetero)cy-
cles for the synthesis of C-2 arylated thiazolopyrimidines.
2. Results and discussion
In our investigation of the direct coupling reaction between 4-
(5-methylthiazolo[5,4-d]pyrimidin-7-yl)morpholine (1a) and ben-
zene (2a), a twofold CeH functionalization occurs between 1a and
benzene to form 4-(5-methyl-2-phenyl-thiazolo[5,4-d]pyrimidin-
7-yl)morpholine (3a) in the presence of Pd(OAc)2(Table 1, entry 1).
So we focused on the cross-coupling of 1a and benzene with
Pd(OAc)2 as a catalyst and screened several parameters including
oxidant, additive and solvent. On the outset of our study, the direct
coupling reaction between 1a and 2a was performed in the pres-
ence of 20 mol % of Pd(OAc)2 in DMF at 120 ꢀC, with Cu(OAc)2 and
2-Arylsubstituted thiazolo[5,4-d]pyrimidines have been ex-
plored as an array of pharmacologically active compounds, such as
Tie-2 inhibitors,12 phosphatidylinositide 3-kinases (PI3K) in-
hibitors,13 immunosuppressive agents14 and human membrane
* Corresponding author. Tel.: þ86 2583271445; fax: þ86 2583271351; e-mail
address: chslp@cpu.edu.cn (L.-P. Sun).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.103

S.-W. Yang et al. / Tetrahedron 70 (2014) 3730e3734
3731
Table 1
Table 2
Pd-catalyzed CeH oxidative cross-coupling reaction of 4-(5-methylthiazolo[5,4-d]
Pd-catalyzed C-2 or C-5 arylation of 1a with heteroarenesa
pyrimidin-7-yl)morpholine (1a) with benzene (2a)a
Entry
Catalyst (mol %)
Oxidant
Additive
Solvent
Yield (%)c
1
2
3
4
5
6
7
8
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(20)
Pd(OAc)2(10)
Pd(OAc)2(40)
PdCl2(20)
d
d
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
<10
24
30
45
18
46
42
64
60
75
62
77
69
56
80
Cu(OAc)2
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
PivOH
PivOH
PivOH
Pyridine
PivOH
PivOH
PivOH
9
PivOHþTBAB
PivOHþTBAI
PivOHþTBAI
PivOHþTBAI
PivOHþTBAI
PivOHþTBAI
PivOHþTBAI
10
11
12
13
14
15
Pd(dppf)Cl2b(20)
Pd(PPh3)2Cl2(20)
a
Reaction conditions: entry 1e6: 1a (0.1 mmol), 2a (1 mmol), catalyst
(0.02 mmol), oxidant (0.3 mmol), additive (0.6 mmol), Solvent: 2 mL dry DMF, in
a sealed tube, 120 ꢀC, 20 h, unless otherwise indicated. Entry 7e12: 1a (0.1 mmol),
catalyst (0.02 mmol), oxidant (0.3 mmol), additive: PivOH(0.6 mmol),
with N-methylimidazole (2h) furnished 3h in excellent yield at
86%. Heteroarenes bearing electron-donating functionalities of-
fered the products in moderate to excellent yields, and the slightly
electron-withdrawing groups furnished the desired products in
good yields inferior to that of electron-rich groups. However,
a poor result was obtained when heteroarenes bearing a strong
electron-withdrawing group, eAc. The reaction between 1a and
pyrrole (2j) failed to give any coupling product. This result cohered
with our previous study that the Agþ can crystallize with the NH
fragment and lead to this phenomenon.18 Interestingly, all the
substituted heteroarenes, which have at least two sites for CeH
activation, reacted with 1a selectively at C-2 or C-5 positions to
give the desire product. This phenomenon was especially evident
in the coupling of 1a with 3-methylthiophene (2d). Two different
products, which have similar amount were obtained in the re-
action. The regioselectivity of the cross-couplings may be gov-
erned by the CeH acidity at C-2 and C-5 positions of the aromatic
heterocycles.6,20
To further ascertain the scope of this methodology, a variety of
substituted arenes were also investigated. To our surprise, with this
optimal catalytic system, coupling reactions between 1a and
substituted arenes (toluene, chlorobenzene, anisole, N,N-dimethy-
laniline, 1,4-dimethylbenzene) afforded 3a as the major product,
even no benzene was provided. According to the previous reports
that olefins and some simple arenes could be arylated by triphe-
nylphosphine in the presence of palladium through C(sp2)eP/
C(sp2)eH bond cleavage.21 Our experiment revealed that the
Pd(PPh3)2Cl2 could also directly coupled with 4-(5-methylthiazolo
[5,4-d]pyrimidin-7-yl)morpholine (1a). Based on the results that
Pd(PPh3)2Cl2 catalyzed double CeH activation between thiazolo
[5,4-d]pyrimidine and heteroarenes can afford the desire product,
we concluded that the priority of coupling with thiazolo[5,4-d]
pyrimidine was heteroarenes>PdCl2(PPh3)2 or PPh3>>substituted
arenes.
TBAI(0.02 mmol), Solvent: 2 mL dry benzene, in a sealed tube, 120 ꢀC, 20 h.
b
Dppf¼1,10-bis-(diphenylphosphino)ferrocene,
TBAB¼tetrabutyl-ammonium
bromide, TBAI¼tetrabutylammonium iodide.
c
All the yield was isolated yield.
PivOH as oxidant and additive, respectively. The yield was only 24%
(Table 1, entry 2). When replacing Cu(OAc)2 with AgOAc, the yield
of 3a can be improved to 30% (Table 1, entry 3). In comparison,
Ag2CO3 give a higher yield of 45% (Table 1, entry 4). In consideration
of yield, Ag2CO3 is the favorable oxidant. Then PivOH was replaced
by pyridine, the yield was decreased to only 18% (Table 1, entry 5).
Other bases, including Cs2CO3, K3PO4, also gave a lower yield at
trace or 10%, respectively. When PivOH was replaced by AcOH and
TFA, the yield of coupling was only 31% and 20%. In addition, we
noticed that when DMF was replaced with other solvent, such as
DMSO and dioxane, the yields of 3a were almost the same (Table 1,
entry 4, 6, 7). Remarkably, a moderate yield was achieved when 2a
was used as solvent (Table 1, entry 8). Gong, Li, and co-workers
reported that added TBAB helps to mediate and stabilize the
Ag2CO3 oxidant.19 Therefore we used TBAB or TBAI as another ad-
ditive. The yield of the 3a could be increased to 75% by adding TBAI
to the reaction system and TBAB was inferior to TBAI (Table 1, entry
9, 10). Reduce the amount of catalyst gave a lower yield and an
increase in the catalyst loading to 40 mol % made no significant
difference to the yield(Table 1, entry 11, 12). In addition, we noticed
that the cross-coupling reaction of 1a and 2a was not restricted to
using Pd(OAc)2 as a catalyst, so other Pd complexes, including
PdCl2, PdCl2(dppf) and Pd(PPh3)2Cl2 were used as well (Table 1,
entry 13e15). Finally, the best yield of 3a (80%) was obtained when
the reaction was performed with 20 mol % of Pd(PPh3)2Cl2, 3 equiv
of Ag2CO3, 6 equiv of PivOH and 20 mol % TBAI in dry benzene (2a)
(Table 1, entry 15).
Next, we examined direct CeH activation of 1a with substituted
arenes to form 3meq under the reaction conditions of entry 10 in
Table 1 (Table 3). Most substituted arenes were well tolerated un-
der this condition. The arylated thiazolo[5,4-d]pyrimidine (3meq)
could be obtained with yields ranging from 25% to 60 %. As ex-
pected, good yields were generally obtained with electron-rich
arenes (3o, 3p). Electron-poor motifs afforded slightly lower
yields (3m).
With this optimal catalytic system, different substituted het-
eroarenes, including thiophene, thiazole, imidazole, pyrazole, and
pyrrole, were explored as coupling partners for 1a to test the
versatility of this direct oxidative CeH/CeH cross-coupling
methodology (Table 2). Compared with other heteroarenes, im-
idazole offered a higher yield. Thiazole, pyrazole, thiophene,
pyrrol could also offer a moderate yield. The cross-coupling of 1a

3732
S.-W. Yang et al. / Tetrahedron 70 (2014) 3730e3734
Table 3
(EtOAc-PE, 1/4) to give 3a. Yield: 25 mg, 80%, white solid; Spectral
data of 3a are reported previously.18c
Pd-catalyzed CeH cross-coupling reaction of 1a with substituted arenes
4.2.2. 4-(5-Methyl-2-(thiophen-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)
morpholine (3b). Yield: 15.9 mg (50%) white solid. Mp 195e196 ꢀC.
1H NMR (300 MHz, CDCl3)
d
7.53 (d, J¼3.12 Hz, 1H), 7.45 (d,
J¼4.83 Hz,1H), 7.10 (t, J¼4.08 Hz,1H), 4.38 (s, 4H), 3.85 (t, J¼4.47 Hz,
4H), 2.57 (s, 3H). 13C NMR (75 MHz, CDCl3)
166.3, 163.1, 154.0,
153.1, 137.5, 130.8, 128.8, 128.0, 126.9, 67.1, 46.3, 25.8. FTIR (KBr,
d
cmꢁ1
) n 3133, 1637, 1565, 1544, 1400, 1114, 692. HRMS (ESI-TOF) m/
z: [MþH]þ Calcd for C14H14N4OS2 319.0682; found 319.0672.
4.2.3. 4-(2-(5-Chlorothiophen-2-yl)-5-methylthiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3c). Yield: 20.1 mg (57%) white solid. Mp
189e190 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.31 (d, J¼4.02 Hz, 1H),
6.94 (d, J¼4.02 Hz, 1H), 4.37 (s, 4H), 3.87 (t, J¼4.95 Hz, 4H), 2.58 (s,
3H). 13C NMR (75 MHz, CDCl3)
166.0, 163.4, 153.9, 152.8, 135.9,
d
134.1, 128.7, 127.2, 127.0, 67.1, 46.3, 25.8. FTIR (KBr, cmꢁ1
) n 3124,
1637, 1561, 1400, 1138, 1116, 999. HRMS (ESI-TOF) m/z: [MþH]þ
Calcd for C14H13ClN4OS2 353.0292; found: 353.0274.
4.2.4. 4-(5-Methyl-2-(3-methylthiophen-2-yl)thiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3d-1). Yield: 9.3 mg (28%) white solid. Mp
139e140 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.35 (d, J¼5.07 Hz, 1H),
3. Conclusions
6.96 (d, J¼5.07 Hz, 1H), 4.40 (s, 4H), 4.10 (t, J¼4.82 Hz, 4H), 3.26 (s,
3H), 2.57 (s, 3H). HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
In conclusion, we have developed a straightforward and prac-
tical method for direct Pd-catalyzed oxidative cross-coupling of
thiazolo[5,4-d]pyrimidine with aromatic (hetero) cycles via two-
fold CeH functionalization. This catalyzed system is notable for its
synthetic simplicity and inexpensive palladium catalytic system.
Furthermore, the arylation of thiazolo[5,4-d]pyrimidine is not re-
stricted to benzene itself but can also be conducted with other
substituted heteroarenes. The most important is that this synthetic
protocol provides a concise access to afford 2-arylsubstituted
thiazolo[5,4-d]pyrimidine derivatives, which are meaningful to
pharmaceutical art.
C15H16N4OS2 333.0838; found 333.0824.
4.2.5. 4-(5-Methyl-2-(4-methylthiophen-2-yl)thiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3d-2). Yield: 11.6 mg (35%) white solid. Mp
141e143 ꢀC.1H NMR (300 MHz, CDCl3)
d 7.38 (s,1H), 7.06 (s,1H), 4.40
(s, 4H), 4.10 (t, J¼4.82 Hz, 4H), 2.59 (s, 3H), 2.25 (s, 3H). HRMS (ESI-
TOF) m/z: [MþH]þ Calcd for C15H16N4OS2 333.0838; found 333.0824.
4.2.6. 4-(5-Methyl-2-(2-methylthiazol-5-yl)thiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3f). Yield: 23.4 mg (70%) white solid. Mp
215e216 ꢀC. 1H NMR (300 MHz, CDCl3)
d 8.07 (s, 1H), 4.38 (s, 4H),
3.87 (t, J¼4.95 Hz, 4H), 2.79 (s, 3H), 2.60 (s, 3H). 13C NMR (75 MHz,
4. Experimental section
4.1. General methods
CDCl3)
d 166.0, 163.5, 154.0, 150.8, 143.5, 132.8, 130.8, 128.8, 67.0,
46.3, 27.7, 25.8. FTIR (KBr, cmꢁ1
) n 3125, 1664, 1565, 1400, 1264,
1121, 1070. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C14H15N5OS2
334.0791; found 334.0780.
A variety of chemical reagents were commercially purchased
and used without further purification. Analytical TLC was carried
out on pre-coated plates and visualized with UV. 1H and 13C NMR
spectra were collected on BRUKER AV-300 (300 MHz) spectrome-
4.2.7. 4-(2-(Benzo[d]thiazol-2-yl)-5-methylthiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3g). Yield: 27.7 mg (75%) white solid. Mp
254e255 ꢀC. 1H NMR (300 MHz, CDCl3)
d
8.14 (dd, J¼0.57, 7.86 Hz,
ter. Chemical shifts were reported in d (parts per million), relative to
1H), 7.95 (dd, J¼0.75, 6.45 Hz, 1H), 7.49e7.57 (m, 2H), 4.46 (s, 4H),
the internal standard of TMS. The signals observed were described
as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). The
number of protons (n) for a given resonance was indicated as nH.
Coupling constants are reported as J value in Hertz. 13C NMR is
3.91 (t, J¼4.71 Hz, 4H), 2.62 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
164.4, 161.4, 154.4, 153.5, 135.3, 133.2, 129.3126.8, 126.5, 124.1,
123.9, 121.788, 67.1, 46.3, 26.0. FTIR (KBr, cmꢁ1
) n 3123, 3003, 1562,
1535, 1400, 1121, 997, 753. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
reported as
signal of chloroform-d (
d
(ppm) in downfield from TMS and relative to the
77.00, triplet). Mass spectrometry was
C
17H15N5OS2 370.0791; found 370.0786.
d
obtained using a Q-tof high resolution mass spectrometer.
4.2.8. 4-(5-Methyl-2-(1-methyl-1H-imidazol-5-yl)thiazolo[5,4-d]
pyrimidin-7-yl)morpholine(3h). Yield: 27.3 mg (86%) white solid.
4.2. General procedure and characterization data of all
compounds
Mp 202e203 ꢀC. 1H NMR (300 MHz, CDCl3)
d 7.19 (s, 1H), 7.06 (s,
1H), 4.40 (s, 4H), 4.09 (s, 3H), 3.87 (t, J¼4.68 Hz, 3H), 2.61 (s, 3H). 13
C
NMR (75 MHz, CDCl3) d 165.9, 163.5, 154.3, 152.4, 140.2, 129.7, 129.1,
4.2.1. 4-(5-Methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl) morpho-
line (3a). To a solution of 1a (24 mg, 0.1 mmol) in anhydrous
benzene (2.0 mL) was added Ag2CO3 (82 mg, 0.3 mmol), TBAI
(15 mg, 0.04 mmol), PivOH (61 mg, 0.6 mmol), and Pd(PPh3)2Cl2
(14 mg, 0.02 mmol) in a sealed tube. The reaction mixture was
stirred at 120 ꢀC for 20 h, during, which the reaction was monitored
by means of TLC. Then the mixture was concentrated in vacuo, and
the residue was subjected to column chromatography over silica gel
125.1, 67.0, 46.2, 35.5, 25.8. FTIR (KBr, cmꢁ1
) n 3124, 1663, 1571,
1400, 1139, 1068, 953. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
C14H16N6OS 317.1179; found 317.1155.
4.2.9. 4-(2-(1,2-Dimethyl-1H-imidazol-5-yl)-5-methylthiazolo[5,4-
d]pyrimidin-7-yl)morpholine (3i). Yield: 28.6 mg (81%) white solid.
Mp 190e191 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.48 (s, 1H), 7.28 (s,
1H), 4.54 (t, J¼4.5 Hz, 4H), 3.92 (s, 3H), 3.84 (t, J¼4.74 Hz, 4H), 2.57

S.-W. Yang et al. / Tetrahedron 70 (2014) 3730e3734
3733
(s, 3H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3)
150.7, 149.3, 132.1, 130.8, 128.6, 66.9, 46.2, 32.7, 29.6, 25.7. FTIR (KBr,
d
165.0, 163.0, 153.9,
206e207 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.90 (d, J¼8.85 Hz, 2H),
6.98 (d, J¼8.85 Hz, 2H), 4.42 (s, 4H), 3.84e3.88 (m, 7H), 2.58 (s, 3H).
cmꢁ1
)
n
3124,1654, 1637, 1560,1400,1139, 1068. HRMS (ESI-TOF) m/
13C NMR (75 MHz, CDCl3, ppm)
146.5, 128.5, 126.3, 114.3, 67.1, 55.5, 46.3, 25.8. FTIR (KBr, cmꢁ1
) n
d 166.0, 162.7, 161.9, 160.1, 154.1,
z: [MþH]þ Calcd for C15H18N6OS 331.1336; found 331.1312.
3119, 1605, 1559, 1400, 1259, 1069, 996. HRMS (ESI-TOF) m/z:
4.2.10. 4-(5-Methyl-2-(1-methyl-1H-pyrrol-2-yl)thiazolo[5,4-d]pyr-
imidin-7-yl)morpholine (3k). Yield: 19.3 mg (61%) white solid. Mp
[MþH]þ Calcd for C17H18N4O2S 343.1223; found 343.1241.
154e155 ꢀC. 1H NMR (300 MHz, CDCl3)
d
6.80 (t, J¼2.3ꢀHz, 1H), 6.76
4.3.5. 4-(2-(2,5-Dimethylphenyl)-5-methylthiazolo[5,4-d]pyrimidin-
(dd, J¼1.71, 3.93 Hz, 1H), 6.20 (dd, J¼1.29, 3.93 Hz, 1H), 4.37 (t,
7-yl)morpholine (3q). Yield: 14.3 mg (42%) white solid. Mp
J¼4.83 Hz, 4H), 4.00 (s, 3H), 3.85 (t, J¼4.77 Hz, 4H), 2.58 (s, 3H). 13
C
215e216 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.52 (s, 1H), 7.22 (s, 1H),
7.21 (s, 1H), 4.45 (s, 4H), 3.86 (t, J¼4.08 Hz, 4H), 2.63 (s, 3H), 2.62 (s,
3H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
165.1, 163.5,
153.9, 150.8, 143.5, 142.1, 141.7, 132.1, 130.9, 128.8, 128.7, 67.0, 46.3,
NMR (75 MHz, CDCl3) d 165.2, 162.5, 153.9, 152.9, 129.1, 128.1, 126.2,
114.8, 108.9, 67.1, 46.3, 37.0, 25.8. FTIR (KBr, cmꢁ1
)
n
3123, 3007,
d
1637, 1570, 1400, 1119, 1068, 955. HRMS (ESI-TOF) m/z: [MþH]þ
Calcd for C15H17N5OS 316.1227; found 316.1215.
25.8, 19.5, 19.1. FTIR (KBr, cmꢁ1
) n 3215, 1637, 1559, 1400, 1119, 1069.
HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C18H20N4OS 341.1431;
4.2.11. 4-(5-Methyl-2-(1-methyl-1H-pyrrol-2-yl)thiazolo[5,4-d]pyr-
found 341.1452.
imidin-7-yl)morpholine (3l). Yield: 22.1 mg (70%) white solid. Mp
222e223 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.52 (d, J¼3.6ꢀHz,1H), 6.73
Acknowledgements
(d, J¼3.6 Hz, 1H), 4.39 (s, 4H), 4.24 (s, 3H), 3.85 (t, J¼4.65 Hz, 4H),
2.58 (s, 3H). 13C NMR (75 MHz, CDCl3)
138.6, 134.9, 128.9, 109.0, 67.0, 46.3, 39.7, 25.9. FTIR (KBr, cmꢁ1
d 166.0, 163.7, 154.6, 149.8,
We are grateful to the funds supported by the National Natural
Science Foundation (No. 21172265 and No. 20872181), Qing Lan
Project in Jiangsu Province and Graduate Education Innovation
Project in Jiangsu Province (CXZZ13_0322).
)
n
3125, 2919, 1655, 1576, 1400, 1069, 954. HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C14H16N6OS 317.1179; found 317.1144.
4.3. General procedure of 3meq
Supplementary data
4.3.1. 4-(5-Methyl-2-p-tolylthiazolo[5,4-d]pyrimidin-7-yl)morpho-
line (3m-1) and 4-(5-methyl-2-m-tolylthiazolo[5,4-d]pyrimidin-7-yl)
morpholine (3m-2). To a solution of 1a (24 mg, 0.1 mmol) in an-
hydrous toluene (2.0 mL) was added Ag2CO3 (82 mg, 0.3 mmol),
TBAI (15 mg, 0.04 mmol), PivOH (61 mg, 0.6 mmol), and Pd(OAc)2
(8 mg, 0.02 mmol) in a sealed tube. The reaction mixture was
stirred at 120 ꢀC for 20 h, during, which the reaction was monitored
by means of TLC. Then the mixture was concentrated in vacuo, and
the residue was subjected to column chromatography over silica gel
(EtOAc-PE, 1/4) to give 3m. Yield: 12.5 mg (40%).
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.103.
References and notes
1. (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359e1470; (b) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol.
1e2; (c) Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651e2710; (d) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174e238; (e) Ackermann, L.
Chem. Commun. (Camb) 2010, 4866e4877; (f) Basolo, L.; Beccalli, E. M.; Borsini,
E.; Broggini, G. Tetrahedron 2009, 65, 3486e3491.
2. (a) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008,
73, 5022e5028; (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792e9826; (c) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew.
Chem., Int. Ed. 2009, 48, 5094e5115; (d) Yamaguchi, J.; Yamaguchi, A. D.; Itami,
K. Angew. Chem., Int. Ed. 2012, 51, 8960e9009; (e) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215e1292.
3. (a) de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512e1513; (b) Mandal,
D.; Yamaguchi, A. D.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2011, 133,
19660e19663; (c) Meng, G.; Niu, H. Y.; Qu, G. R.; Fossey, J. S.; Li, J. P.; Guo, H.
M. Chem. Commun. (Camb) 2012, 48, 9601e9603; (d) Potavathri, S.; Pereira,
K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010,
132, 14676e14681; (e) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 12072e12073; (f) Stuart, D. R.; Fagnou, K. Science 2007, 316,
1172e1175; (g) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 14047e14049.
3m-1: White solid. 1H NMR (300 MHz, CDCl3)
d 7.85 (d,
J¼8.16ꢀHz, 2H), 7.36 (d, J¼7.48 Hz, 2H), 4.46 (s, 4H), 3.89 (t,
J¼4.47 Hz, 4H), 2.62 (s, 3H), 2.43 (s, 3H). HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C17H18N4OS 327.1274; found 327.1228.
3m-2: White solid. 1H NMR (300 MHz, CDCl3)
d 7.75 (m, 2H),
7.03 (t, J¼4.26ꢀHz, 2H), 4.46 (s, 4H), 3.89 (t, J¼4.47 Hz, 4H), 2.62 (s,
3H), 2.46 (s, 3H). HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
C
17H18N4OS 327.1274; found 327.1228.
4.3.2. 4-(2-(3-Chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)
morpholine (3n-1) and 4-(2-(2-chlorophenyl)-5-methylthiazolo[5,4-
d]pyrimidin-7-yl) morpholine (3n-2). Yield: 8.7 mg (25%).
3n-1: White solid. 1H NMR (300 MHz, CDCl3)
d 7.82e8.02 (m,
4H), 4.45 (s, 4H), 3.89 (t, J¼4.5 Hz, 4H), 2.62 (s, 3H). HRMS (ESI-TOF)
4. Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050e8057.
5. Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9,
3137e3139.
6. Han, W.; Mayer, P.; Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 2178e2182.
7. Wu, G.; Zhou, J.; Zhang, M.; Hu, P.; Su, W. Chem. Commun. (Camb) 2012, 48,
8964e8966.
8. (a) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett. 2011, 13,
1378e1381; (b) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J.
Am. Chem. Soc. 2010, 132, 1822e1824.
m/z: [MþH]þ Calcd for C16H15ClN4OS 347.0728; found 347.0707. 3n-
2: White solid. 1H NMR (300 MHz, CDCl3)
d 7.27e7.55 (m, 4H), 4.45
(s, 4H), 3.89 (t, J¼4.5 Hz, 4H), 2.61 (s, 3H). HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C16H15ClN4OS 347.0728; found 347.0707.
4.3.3. N,N-Dimethyl-4-(5-methyl-7-morpholinothiazolo[5,4-d]pyr-
9. Gosselin, F.; Savage, S. J.; Blaquiere, N.; Staben, S. T. Org. Lett. 2012, 14, 862e865.
10. Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207e2210.
11. He, C. Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850e12852.
12. Luke, R. W.; Ballard, P.; Buttar, D.; Campbell, L.; Curwen, J.; Emery, S. C.; Griffen,
A. M.; Hassall, L.; Hayter, B. R.; Jones, C. D.; McCoull, W.; Mellor, M.; Swain, M.
L.; Tucker, J. A. Bioorg. Med. Chem. Lett. 2009, 19, 6670e6674.
13. Giordanetto, F.; Kull, B.; Dellsen, A. Bioorg. Med. Chem. Lett. 2011, 21, 829e835.
14. Jang, M. Y.; Lin, Y.; De Jonghe, S.; Gao, L. J.; Vanderhoydonck, B.; Froeyen, M.;
Rozenski, J.; Herman, J.; Louat, T.; Van Belle, K.; Waer, M.; Herdewijn, P. J. Med.
Chem. 2011, 54, 655e668.
imidin-2-yl) aniline (3o). Yield: 14.2 mg (45%). White solid. Mp
198e199 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.84 (d, J¼8.97 Hz, 2H),
6.74 (d, J¼9.0 Hz, 2H), 4.45 (s, 4H), 3.89 (t, J¼4.77 Hz, 4H), 3.07 (m,
6H), 2.61 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
168.8, 163.5,
154.0, 150.8, 142.1, 141.7, 132.8, 130.8, 128.7, 67.0, 41.2, 27.7. FTIR
d
(KBr, cmꢁ1
) n 3123, 1611, 1400, 1119, 1068, 951. HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C18H21N5OS 356.1540; found 356.1526.
15. Young, R. C.; Jones, M.; Milliner, K. J.; Rana, K. K.; Ward, J. G. J. Med. Chem. 1990,
33, 2073e2080.
16. Childress, S. J.; Mckee, R. L. J. Am. Chem. Soc. 1951, 73, 3862e3864.
4.3.4. 4-(2-(4-Methoxyphenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-
yl)morpholine (3p).18c Yield: 20.6 mg (60%). White solid. Mp

3734
S.-W. Yang et al. / Tetrahedron 70 (2014) 3730e3734
17. (a) Chinoporos, E.; Fu, S. C. J.; Terzian, H. J. Org. Chem. 1965, 30, 1916e1920; (b)
Hitchings, G. H.; Falco, E. A. J. Am. Chem. Soc. 1950, 72, 3203e3205; (c) Hurst, D.
T.; Atcha, S.; Marshall, K. L. Aust. J. Chem. 1991, 44, 129e134.
18. (a) Zhong, Q. F.; Sun, L. P. Tetrahedron 2010, 66, 5107e5111; (b) Xu, D.; Sun, L. P.;
You, Q. D. Tetrahedron 2012, 68, 4248e4251; (c) Su, Y. X.; Deng, Y. H.; Ma, T. T.;
Li, Y. Y.; Sun, L. P. Green. Chem. 2012, 14, 1979e1981.
20. Shen, K.; Fu, Y.; Li, J. N.; Liu, L.; Guo, Q. X. Tetrahedron 2007, 63, 1568e1576.
21. (a) Kikukawa, K.; Yamane, T.; Tkagi, M.; Matsuda, T. J. Chem. Soc., Chem. Com-
mun. 1972, 695e696; (b) Yamano, T.; Kikukawa, K.; Takagi, T.; Matsuda, M.
Tetrahedron 1973, 29, 955e962; (c) Ryabov, A. D.; Yatsimirsky, A. K. J. Mol. Catal.
1978, 4, 449e452; (d) Li, Z. Y.; Zhou, H. P.; Xu, J. Y.; Wu, X. M.; Yao, H. Q. Tet-
rahedron 2013, 69, 3281e3286.
19. Gong, X.; Song, G.; Zhang, H.; Li, X. Org. Lett. 2011, 13, 1766e1799.