An efficient desulfitative C-C cross coupling of fused thiazolidine-2-thione with boronic acids and boronic acid pinacol esters: Formation of fused thiazoles

Article abstract of DOI:10.1039/c5ra17827d

An efficient Pd(0)-catalyzed Cu(i)-mediated desulfitative C-C cross-coupling of benzo-fused thiazolidine-2-thione with boronic acids under neutral Liebeskind-Srogl conditions is described. The desulfitative cross coupling of boronic acid pinacol esters has also been demonstrated with fused thiazolidine-2-thione under basic conditions to afford fused thiazoles with good to excellent yields.

Full text of DOI:10.1039/c5ra17827d

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An Efficient Desulfitative C-C Cross Coupling of Fused Thiazolidine-
2-thione with Boronic Acids and Boronic Acid Pinacol esters:
Formation of Fused Thiazoles †
Received 00th January 20xx,
Accepted 00th January 20xx
Kandasamy Rajaguru,a Arumugam Mariappan,a Ramachandran Manjusri,a
Shanmugam Muthusubramanian,a* and Nattamai Bhuvaneshb
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient Pd(0)-catalyzed Cu(I)-mediated desulfitative C-C cross-coupling of benzofused thiazolidine-2-thione with
boronic acids under neutral Liebeskind-Srogl condition is described. The desulfitative cross coupling of boronic acid pinacol
esters has also been demonstrated with fused thiazolidine-2-thione under basic condition to afford fused thiazoles with
good to excellent yields.
variety of protocols have been developed for the rapid
construction of benzfused or heteroaryl fused thiazoles from
prefunctionalized substrates.10 These highly functionalized
Introduction
The desulfitative cross-coupling reactions involving alkyl
thioethers, sulfones, and sulfonyls with organometallic
reagents have been largely employed toward the synthesis of
diverse molecules including important heterocyclic
compounds.1 In this connection, palladium metal catalyzed -
Cu(I) carboxylate mediated - Csp2-Csp2 cross coupling of
boronic acids and various thioorganic compounds have been
explored extensively under non-basic conditions for the
construction of diverse cyclic and acyclic motif.1,2 In this
Liebeskind-Srogl cross coupling reaction, the soft Cu(I)
carboxylate cofactor has high thiophilicity accelerating the
desulfitative C-C cross couplings selectively.1f,3 The non-basic
Liebeskind-Srogl cross coupling reaction has also gained
attention, making considerable progress.1g,2c,4,5 The
desulfitative cross-coupling of Sonogashira-Hagihara, Stille,
and Suzuki-Miyaura as well as Mizoroki-Heck couplings of
sulfonyl chlorides have been explored by Vogel and co-
workers.6 Because of their stability, low toxicity, easy handling,
and easy removal of degradable boron derived byproducts,
“green” boronic acids7 are much superior to boronic esters as
reactants.8 Currently, we are focusing on the development of
methods for the synthesis of some functionalized heterocyclic
compounds.9 In continuation, herein we report the Pd/Cu(I)
mediated desulfitative carbon-carbon cross coupling for the
synthesis of fused thiazole derivatives. Over the years, a
thiazoles are found in many pharmaceutical agents11 and in
some diversed materials with potent applications.12 The
synthesis of substituted benzothiazoles has been achieved
under Pd mediated Suzuki biaryl coupling of arylboronic acids
with 2-halobenzothiazoles,13 while direct coupling of aryl
bromides with benzothiazole14 is also been known. Direct C-H
arylation of heteroarenes via denitrogenative and desulfitative
mode of action has also been described.15,16 Gosmini and co-
workers17 have elaborated the Co(II)-catalyzed synthesis of
benzothiazole derivatives through coupling of aryl or
benzylzinc reagents and methylsulfanyl-N-heteroarenes. It is
pertinent to note that only very few reports are available
towards the construction of the heteroaryl fused thiazole and
that is the motive to undertake the present investigation.
The starting materials for the present study, fused
thiazolidine-2-thiones 1, have been prepared from cheap and
readily available 2-haloanilines and highly reactive potassium
ethyl xanthate.18 At first, the traditional Liebeskind-Srogl
coupling reaction of
1 with arylboronic acid 2 with an effective
thiophilic reagent - copper(I) thiophene-2-carboxylate (CuTC)
and various palladium sources in the presence of phosphine
ligands has been investigated (Scheme 1).
R
R
B(OH)2
or
BPin
H
N
S
N
S
S
R'
R'
R
S
O
S
X
X
(2)
1
3
Scheme 1. Plan for the synthesis of aryl thiazoles.
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Pd(MeCN)2Cl2 (10)/
L2 (10)
Results and Discussion
19
20
21
2/2
dioxane
dioxane
dioxane
8
18
8
100
100
100
53
----c
61
The screening experiments have been started using a
stoichiometric amount of 4-methoxyphenylboronic acid
Pd(dba)2 and PPh3 in the presence of a stoichiometric amount
of CuTC. The temperature range studied was 50-100 oC, and
the solvent tried was dioxane under a nitrogen atmosphere.
This resulted in fused thiazoles as the desired product, but the
conversion (22-42%) was not effective (Table 1, entries 1-3).
Satisfactory results were obtained with Pd2(dba)3. When the
combination of Pd(OAc)2 (10 mol%) - PPh3 (10 mol%) - RB(OH)2
1.5/2
1.5/2
Pd(OAc)2 (10 mol %)
Pd(PPh3)4 (10mol %)
a
L1=PPh3; L2=XPhos Experiments were performed in dioxane (5 mL) under N2
atm. b Isolated Yield. c No reaction.
Encouraged with this optimised condition, the substrate
scope of the reaction has been explored by coupling a range of
arylboronic acids and (E)-
in good yields and the derivatives synthesized are shown in
Table 2.
β-styrylboronic acids with 1 to obtain
3
o
(1.5 equiv) - CuTC (2 equiv) was tested at 100 C with dioxane
as the solvent, the reaction got completed in an hour under
nitrogen to get the best result (89%) (Table 1, entry 8).
Running the experiment with increased catalyst loading (20
mol%) or lowering the reaction temperature have not
increased the yield. The effective conversion has been
improved (64-89%, Table 1, entries 9-12) by the sacrificial
increment of CuTC as well as arylboronic acid. This can be
explained by the low thiophilicity of boron in the organoboron
compounds and relatively low nucleophilic reactivity
compared to CuTC.4c,19 The oxidation of Cu(I) cofactor has
been avoided under inert atmosphere, promoting the product
yield.1c,2a,20 Phosphine free conditions (Table 1, entry 20) or
extending the reaction time does not have any encouraging
result.
Table 2. Synthesis of aryl thiazolesa 3aa-3apa
Table 1. Optimization of the reaction Conditionsa
a Reaction conditions: In a reaction vessel thiazolidine-2-thione 1 (0.10 mmol), R-
B(OH)2 2 (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)2 (0.01 mmol, 10 mol %) and
PPh3 (0.01 mmol, 10 mol %) in dioxane (5 mL) heated at 100 ºC for 1-2 h under N2
atm.
2
Catalyst
(equvi)/
CuTC
(equvi)
(mol%)/ligand
(mol%)
Solvent
Time
(h)
Temp
(oC)
Yield
(%)
The homocoupling of boronic acids cannot be avoided
resulting in biaryls due to the efficiency of copper salt,21
though the conversion achieved is quite satisfactory. With
sterically hindering arylboronic acids or some functionalized
boronic acids or alkylboronic acids, the transformation was not
successful under the optimized condition. All the synthesized
compounds have been characterized by NMR studies and
further confirmed by single crystal X-ray analysis of 3ah22 as
shown in Figure 1.
Entry
3aab
1
2
3
4
5
6
1/1
1/1
Pd(dba)2 (10) /L1 (5)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
16
12
8
50
50
22
34
42
55
68
52
Pd(dba)2 (20)/ L1 (10)
Pd(dba)2 (10)/ XPhos
(10)
Pd2(dba)3. CHCl3
(10)/ L1(10)
Pd2(dba)3. CHCl3
(10)/ L1(10)
Pd2(dba)3. CHCl3
(10)/ L2 (10)
1/1
100
80
1.2/1
1.5/2
1.5/1
5
5
100
100
Having successfully effected the coupling with boronic acid,
we wanted to test the efficacy of this protocol with
organoboron pinacol esters. However, the neutral Liebeskind-
Srogl desulfitative coupling reaction conditions are apparently
not suitable in the case of organoboron pinacol esters, even
with 3-5 equivalent of CuTC in Pd(OAc)2/PPh3 system. The base
is essential for the cross-coupling with organoboron pinacol
esters. Earlier, Yu and Liebeskind8b have explored Pd(0)-
catalyzed, Cu(I) carboxylate-mediated cross-coupling of thiol
esters and B-alkyl-9-BBN under basic condition. We started
with oxygen bases such as Na2CO3, K2CO3, Cs2CO3 and K3PO4 to
accelerate the activation of organoboron pinacol ester in
dioxane at 100 oC under a nitrogen atmosphere, which
resulted in poor yield with undesired side products.
Fortunately, clean transformation has been achieved in the
3
7
8
1.5/2
1.5/2
PdCl2 (10)/ L2 (10)
dioxane
dioxane
8
1
100
100
22
89
Pd(OAc)2 (10)/ L1(10)
9
1.5/2
1.5/2
Pd(OAc)2 (10)/ L1(10)
Pd(OAc)2 (20)/ L1(10)
THF
1
1
100
100
72
65
10
dioxane
11
12
13
14
15
16
17
2/2
Pd(OAc)2 (10)/ L1 (5)
Pd(OAc)2 (10)/ L1 10)
Pd(OAc)2 (10)/ L1(10)
Pd(OAc)2 (5)/ L1 (10)
Pd(TFA)2 (10)/L1 (10)
Pd(TFA)2 (20)/L2 (10)
dioxane
dioxane
dioxane
THF
1
1
100
100
130
100
100
100
rt
64
82
2/3
1.5/2
1.5/2
1.2/1
1.5/2
1.5/2
1
32
1
52
dioxane
dioxane
dioxane
5
58
5
66
Pd(OAc)2 (10)/ L1(10)
Pd(MeCN)2Cl2 (10)/
L1 (10)
24
----c
18
1/2
dioxane
12
100
42
2 | J. Name., 2012, 00, 1-3
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presence of stoichiometric amount of KF with moderate yield,
though switching over to CsF (2.0 equiv) ended with the
desired product in moderate to excellent yield (Table 3).
Table 3. Optimization of the reaction Conditionsa
Figure 1. X-ray crystal structures of 3ah and 3aw. Thermal ellipsoids are shown at the
50% probability level.
Entry
2’
Pd(OAc)2
(mol %)/ PPh3
(mol %)
Base (equiv)
Time
(h)
Temp
(oC)
Yield
(%)
Based on the anticipated interaction between organosulfur
and organoboron (thiophilic/borophilic) in the presence of Cu
(equvi)
/CuTC
(equvi)
3ai[b
cofactors,1,2a,8b,23,24 the mechanism for the formation of
3
has
been illustrated in Scheme 2. The proposed mechanism for the
formation of by the boranepinacol ester strategy starts with
the Cu(I) thiolate species obtained by the thione-thiol
1
2
3
4
5
6
7
8
9
10
11
12
13
1.5/3
1.5/5
1.5/2
1.5/2
1.5/2
1.5/2
1.5/2
1.5/2
1.5/1
1.5/2
1.5/2
1.5/2
1.5/2
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/5
Pd(PPh3)4 (10)
Pd(OAc)2 (10)
Nil
Nil
18
18
18
12
8
8
5
2
8
100
100
100
100
100
100
100
100
100
rt
----c
----c
trace
12
28
42
3
Na2CO3 (1.0)
K2CO3 (1.0)
K3PO4 (2.0)
Cs2CO3(1.0)
KF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
5
tautomerization,25 which undergoes oxidative addition with
the Pd(0) catalyst and with an additional equivalent of CuTC
61
78
cofactor to form an intermediate
step, the fluoride accelerates the pinacolate deprotection from
2’ to yield with extrusion of and Cu2S. The subsequent
reductive elimination results in the cross-coupled product
6. In the transmetalation
34
24
2
4
----c
58
100
100
100
8
7
43
3.
24
----c
a
c
Experiments were performed in dioxane (5 mL) under N2 atm. b Isolated Yield.
No reaction.
O
S
H
N
O
CsF
No reaction occurred in the absence of the ligand. The
additional compounds added to the library of fused thiazole
analogues through this protocol are shown in Table 4. It can be
noted that under optimized condition, the coupling of
thiazolidine-2-thione with the heteroaryl organoboron pinacol
ester system seems to be more facile compared to arylboron
pinacol esters. Interestingly, homocoupling is not a problem
with boronic acid pinacolate ester.
N
S
S
LnPd(0)
S
S
N
S
X
Cs
1
R
X
5
CuTC
X
3
CuTC
S
L
L
S
L
L
O
Pd
Pd
N
O
Cu
N
R
CuTC
S
S
8
X
6
X
O
B
R
Table 4. Synthesis of aryl thiazoles 3aq-3bba
O
2'
CsF
CuTC; CsF
Pd(OAc)2:PPh3
H
O
O
N
N
S
R
B
+
Dioxane, 100 o
2-3 h
C
S
R
O
O
S
X
X
+
Cu2S
B
S
O
O
7
N
S
N
S
N
S
N
F
O
Scheme 2. Mechanism for the formation of fused thiazole 3
S
3ar; 74%
O
CF3
3aq; 71%
3at; 71%
3as; 63%
NO2
N
To support the proposed mechanism, some control
experiments have been performed (Scheme 3). In the first
experiment, a mixture of thiazolidine-2-thione and 4-methoxy
phenylboronic acid (2 equiv) (or boronic ester with CsF) was
heated under aerobic condition1g at 100 oC for 2 h in the
presence of Cu(II) acetate (1.5 equiv) and 1,10-phenanthroline
(2 equiv) in dioxane, which resulted in the carbon-sulfur cross-
coupled product 4a. This reaction is not proceeding under
nitrogen atmosphere indicating that the reaction may go via
disulfide formation. Under the optimized condition, Suzuki
N
S
N
S
N
N
O
Cl
S
S
N
N
N
N
N
3au; 69%
3av; 76%
3ax; 86%
3aw; 78%
CF3
O
N
S
N
N
N
S
N
O
N
S
S
3ay; 72%
3az; 81%
3ba; 69%
3bb; 56%
a Reaction conditions: In a reaction vessel thiazolidine-2-thione 1 (0.10 mmol) in
dioxane (5 mL), R-BPin 2’ (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)2 (0.01 mmol,
10 mol %), PPh3 (0.01 mmol, 10 mol %) and CsF (0.20 mmol) in dioxane (5 mL)
heated at 100 oC for 2-3 h under N2 atm.
The synthesized compounds were characterized by NMR active bromo substituted thiazolidine-2-thione and 4-methoxy
studies and further confirmed by single crystal X-ray analysis of phenylboronic acid (2 equiv), again yielded the anticipated
3aw26 as shown in Figure 1.
thiazole derivative without traces of the traditional Suzuki
coupled product (Table 2), while with boronic acid pinacol
esters, a complex mixture was observed with the bromo
substituted thiazolidine-2-thione system. Finally, the reaction
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of N-deuterium substituted aryl thiazolidine-2-thione and 4- petroleum ether (60–80 oC) and ethyl acetate as eluent.
methoxyphenylboronic acid under the same condition Elemental analyses were performed on a Perkin Elmer 2400
furnished the benzothiazole with no deuterium incorporation, Series II Elemental CHNS analyser. Mass spectra were recorded
proving no hydrogen exchange in the mechanism. From the in LCQ Fleet mass spectrometer, Thermo Fisher Instruments
above observations a chemoselective desulfitative couplings Limited, US. Electrospray ionisation mass spectrometry (ESI-
occurred at C=S and no case the C-S-C was affected to yield MS) analysis was performed in the positive ion and negative
fused hetero benzothiazoles.
ion mode on a liquid chromatography ion trap.
O
General procedure
OH
H
1,10-phenanthroline,
Cu(OAc)2, dioxane
N
B
A typical procedure for the synthesis of fused aryl
HO
HO
N
S
S
S
+
S
S
thiazoles 3: Neutral Condition: To a stirred solution of
O
O
air, 100 oC, 2h
4a; 78%
thiazolidine-2-thione
1 (0.10 mmol) in dioxane (5 mL), R-
OH
B
H
N
1,10-phenanthroline,
Cu(OAc)2, dioxane
B(OH)2 2 (0.15 mmol), CuTC (0.20 mmol), Pd(OAc)2 (0.01
+
No reaction
S
mmol, 10 mol%) and PPh3 (0.01 mmol, 10 mol%) were added
in a reaction vessel, and the reaction mixture heated at 100 oC
for 1 h under N2 atm. The completion of the reaction was
monitored by TLC. After cooling to room temperature, the
reaction mixture was filtered through Celite. Then, the filtrate
was washed with saturated solution of NH4Cl (3×10 mL) and
extracted with EtOAc (2×20 mL). The combined organic layers
were dried with anhydrous Na2SO4 and concentrated in vacuo.
The residue was then purified by column chromatography on
100 oC, 2h, N2
N
O
H
N
Cu(OAc)2, CsF
1,10-phenanthroline
O
B
N
S
+
S
S
O
S
dioxane,
air, 100 oC, 2h
O
N
4b; 67 %
H
N
Br
O
B
Optimized conditions
Optimized conditions
S
Complex mixture
O
+
S
O
N
Deutrium labelling experiments
D
OH
B
silica gel (hexanes/ethyl acetate 4.5:0.5) to yield arylthiazole
Basic condition: To a stirred solution of thiazolidine-2-
thione (0.10 mmol) in dioxane (5 mL), R-BPin 2’ (0.15 mmol),
3.
N
N
HO
S
+
O
S
S
O
1
3at; 78%
CuTC (0.20 mmol), Pd(OAc)2 (0.01 mmol, 10 mol%), PPh3 (0.01
mmol, 10 mol%) and CsF (0.20 mmol) were added in a reaction
vessel, and the reaction mixture heated at 100 oC for 2 h under
N2 atm. The completion of the reaction was monitored by TLC.
After cooling to room temperature, the reaction mixture was
filtered through Celite. Then, the filtrate was washed with
saturated solution of NH4Cl (3×10 mL) and extracted with
EtOAc (2×20 mL). The combined organic layers were dried with
anhydrous Na2SO4 and concentrated in vacuo. The residue was
then purified by column chromatography on silica gel
Scheme 3. Control Experiments
In addition, under the optimized condition the same
strategy has also been experimented with the controlled
amount of water and also performed under the normal
condition in the absence of CuTC as well but the desired
product was not achieved (Table S1 See ESI).
Conclusions
(hexanes/ethyl acetate 4.5:0.5) to yield aryl thiazole 3a
.
In summary, we have demonstrated
a Pd(0)/Cu(I)-
2-(4-Methoxyphenyl)thiazolo[5,4-b]pyridine
(3aa):
Isolated as white solid; mp: 120–123 oC; H NMR (300 MHz,
CDCl3) δ 8.53 (dd, J = 4.6, 1.2 Hz, 1H), 8.23 (dd, J = 8.2, 1.3 Hz,
1H), 8.05 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.2, 4.7 Hz, 1H), 7.02
(d, J = 8.8 Hz, 2H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
168.1, 162.2, 158.2, 147.2, 146.3, 129.2, 129.0, 125.9, 121.1,
114.3, 55.3. Anal. Calcd for C13H10N2OS: C, 64.44; H, 4.16; N,
11.56%. Found: C, 64.46; H, 4.11; N, 11.59%.
1
mediated desulfitative C-C cross-coupling of boronic acids with
fused thiazolidine-2-thione under neutral condition. We have
also performed desulfitative coupling under basic condition
with thiazolidine-2-thione and organoboron pinacol esters
ending in C-C bond formation. This strategy involves mild
reaction conditions towards the synthesis of diversely
substituted benzfused thiazoles in good to excellent yields.
2-(m-Tolyl)thiazolo[5,4-b]pyridine (3ab): Isolated as white
o
1
solid; mp: 84–86 C; H NMR (300 MHz, CDCl3) δ 8.56 (dd, J =
4.6, 1.4 Hz, 1H), 8.27 (dd, J = 8.2, 1.5 Hz, 1H), 7.94 – 7.82 (m,
2H), 7.45 – 7.32 (m, 3H), 2.45 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 168.7, 158.2, 147.0, 146.7, 138.8, 133.1, 132.2, 129.7, 128.8,
127.8, 124.7, 121.2, 21.2. Anal. Calcd for C13H10N2S: C, 69.00;
H, 4.45; N, 12.38%. Found: C, 69.04; H, 4.41; N, 12.33%.
Experimental Section
General Remarks: Nuclear Magnetic Resonance (1H and 13
C
NMR) spectra were recorded on a 300 MHz spectrometer in
CDCl3 using TMS as an internal standard. Chemical shifts are
reported in parts per million (δ), coupling constants (J values)
2-(3,5-Dichlorophenyl)thiazolo[5,4-b]pyridine
(3ac):
are reported in Hertz (Hz) and spin multiplicities are indicated
by the following symbols: s (singlet), d (doublet), t (triplet), m
(multiplet). 13C NMR spectra were routinely run with
broadband decoupling. Pre coated silica gel on aluminium
plates (Merck) were used for TLC analysis with a mixture of
Isolated as off–white solid; mp: 172–174 oC; 1H NMR (300
MHz, CDCl3) δ 8.65 – 8.60 (m, 1H), 8.31 (dd, J = 8.2, 1.4 Hz, 1H),
8.03 – 7.95 (m, 2H), 7.52 – 7.47 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 165.2, 163.9, 158.2, 147.7, 146.9, 135.9, 131.1, 130.5,
4 | J. Name., 2012, 00, 1-3
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125.7, 121.8. Anal. Calcd for C12H6Cl2N2S: C, 51.26; H, 2.15; N, 7.51 – 7.44 (m, 1H), 7.39 – 7.33 (m, 1H), 7.30 (d, J = 8.6 Hz, 2H),
2.52 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 154.0, 142.7,
134.7, 129.9, 127.6, 126.2, 125.8, 124.9, 122.9, 121.5, 14.9.
9.96%. Found: C, 51.31; H, 2.17; N, 9.92%.
2-(3-(Trifluoromethyl)phenyl)thiazolo[5,4-b]pyridine
(3ad): Isolated as white solid; mp: 101–103 oC;1H NMR (300 ESI-MS m/z calcd for C14H11NS2: [M+H]+ 257.03; Found: 258.12.
MHz, CDCl3) δ 8.62 (dd, J = 4.6, 1.3 Hz, 1H), 8.40 (s, 1H), 8.33
5-Nitro-2-(3-(trifluoromethyl)phenyl)benzo[d]thiazole
o
1
(dd, J = 8.2, 1.5 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.9 (3ak): Isolated as pale yellow solid; mp: 124–126 C; H NMR
Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.49 (dd, J = 8.2, 4.7 Hz, 1H). 13C (300 MHz, CDCl3) δ 8.92 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 8.32 –
NMR (75 MHz, CDCl3) δ 166.5, 158.2, 147.5, 146.9, 134.1, 8.26 (m, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H),
130.7, 130.3, 129.6, 127.8, 125.4, 124.1 (1JC-F = 272.2), 121.8, 7.68 (t, J = 7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 169.4,
121.6. Anal. Calcd for C13H7F3N2S: C, 55.71; H, 2.52; N, 10.00. 153.5, 146.9, 141.3, 133.1, 131.6 (2JC-F = 33.0), 130.7, 129.8,
Found: C, 55.76; H, 2.53; N, 10.04%.
128.2 (3JC-F = 3.7), 124.2 (3JC-F = 3.0), 123.5 (1JC-F = 271.5), 122.1,
2-(3-Bromophenyl)thiazolo[5,4-b]pyridine (3ae)27: Isolated 119.9, 118.6. Anal. Calcd for C14H7F3N2O2S: C, 51.85; H, 2.18; N,
1
as white solid; mp: 121–122 oC; H NMR (300 MHz, CDCl3) δ 8.64 %. Found: C, 51.88; H, 2.14; N, 8.69%.
8.60 (dd, J = 4.6, 1.3 Hz, 1H), 8.33 – 8.28 (m, 2H), 8.00 (ddd, J =
5-Bromo-2-(4-methoxyphenyl)-7-methylbenzo[d]thiazole
7.8, 1.6, 1.0 Hz, 1H), 7.66 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.47 (3al): Isolated as white solid; mp: 145–147 oC; 1H NMR (300
(dd, J = 8.2, 4.7 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.38 (s, 1H),
MHz, CDCl3) δ 166.6, 158.3, 147.3, 146.9, 135.1, 134.3, 130.5, 6.99 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.75 (s, 3H). 13C NMR (75
130.2, 130.1, 126.2, 123.2, 121.6.
MHz, CDCl3) δ 166.7, 161.9, 152.5, 136.1, 134.4, 129.9, 129.0,
2-(4-Fluoro-2-isopropoxyphenyl)thiazolo[5,4-b]pyridine
126.3, 121.3, 117.9, 114.3, 55.42, 18.20. ESI-MS m/z calcd for
(3af): Isolated as colorless solid; mp:119–120 C; H NMR (300 C15H12BrNOS: [M+H]+ 334.98; Found: 334.00. Anal. Calcd for
MHz, CDCl3) δ 8.54 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), C15H12BrNOS: C, 53.90; H, 3.62; N, 4.19%. Found: C, 53.94; H,
7.87 (dd, J = 11.8, 2.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.43 (dd, 3.64; N, 4.13%.
o
1
J = 8.2, 4.7 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 4.75 – 4.61 (m, 1H),
2-(4-Chlorophenyl)-6-methoxybenzo[d]thiazole
1
(3am):
1.43 (d, J = 6.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 166.7, Isolated as white solid; mp: 129–131 oC; H NMR (300 MHz,
158.1, 154.6 (1JC-F = 245.2), 151.3, 148.6 (3JC-F = 10.5), 146.5, CDCl3) δ 7.96 – 7.91 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.32 (d, J =
.
129.4, 126.1, 123.8 (4JC-F = 3.0), 121.2, 115.9 (2JC-F = 21.0), 2.5 Hz, 1H), 7.09 (dd, J = 9.0, 2.5 Hz, 1H), 3.87 (s, 3H) 13C NMR
114.9, 71.9, 21.7. Anal. Calcd for C15H13FN2OS: C, 62.48; H, (75 MHz, CDCl3) δ 163.9, 157.8, 148.5, 136.4, 132.3, 132.1,
4.54; N, 9.72%. Found: C, 62.50; H, 4.51; N, 9.77%.
129.1, 128.2, 123.7, 115.7, 104.0, 55.7. Anal. Calcd for
C14H10ClNOS: C, 60.98; H, 3.66; N, 5.08%. Found: C, 60.94; H,
2-(Benzo[b]thiophen-2-yl)thiazolo[4,5-c]quinoline (3ag)
Isolated as white solid; mp: 213–214 oC; 1H NMR (300 MHz, 3.69; N, 5.03%.
:
CDCl3) δ 9.54 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.01 (dd, J = 15.8,
(E)-2-(4-Chlorostyryl)thiazolo[5,4-b]pyridine
(3an):
7.7 Hz, 2H), 7.94 – 7.83 (m, 2H), 7.77 (t, J = 7.7 Hz, 1H), 7.68 (t, Isolated as white solid; mp: 172–174oC; 1H NMR (300 MHz,
J = 7.5 Hz, 1H), 7.60 – 7.50 (m, 1H), 7.45 – 7.42 (m, 1H). 13C CDCl3) δ 8.56 (d, J = 3.5 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.55 –
NMR (75 MHz, CDCl3) δ 161.9, 148.1, 145.9, 144.2, 140.9, 7.50 (m, 3H), 7.43 – 7.37 (m, 4H). 13C NMR (75 MHz, CDCl3)* δ
140.4, 139.3, 136.2, 130.5, 129.1, 127.7, 127.6, 126.5, 125.8, 167.2, 157.9, 147.2, 137.4, 135.7, 133.7, 129.7, 129.3*, 128.7,
125.1, 124.8, 124.7, 122.6
. ESI-MS m/z calcd for C18H10N2S2: 122.8, 121.5. Anal. Calcd for C14H9ClN2S: C, 61.65; H, 3.33; N,
[M+H]+ 318.03; found: 319.02. Anal. Calcd for: C18H10N2S2: C, 10.27%. Found: C, 61.68; H, 3.31; N, 10.23%. *Two carbons are
67.90; H, 3.17; N, 8.80%. Found: C, 67.95; H, 3.12; N, 8.84%.
merged.
(E)-2-(4-(Trifluoromethyl)styryl)benzo[d]thiazole
2-(Benzo[b]thiophen-3-yl)benzo[d]thiazole (3ah): Isolated
(3ao):
o
1
1
as off–white solid; mp: 79–81 C; H NMR (300 MHz, CDCl3) δ Isolated as white solid; mp: 161–163 oC; H NMR (300 MHz,
8.97 (dd, J = 4.9, 3.9 Hz, 1H), 8.17 – 8.12 (m, 1H), 8.10 (s, 1H), CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.67 (s,
7.91 (dd, J = 8.0, 0.7 Hz, 2H), 7.56 – 7.41 (m, 4H). 13C NMR (75 4H), 7.51 (d, J = 8.3 Hz, 2H), 7.50 – 7.38 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 162.1, 153.9, 140.4, 136.1, 134.1, 130.2, 129.9, MHz, CDCl3) δ 165.9, 153.7, 138.6, 135.5, 134.4, 130.7 (2JC-F
126.2, 125.3, 125.3, 125.1, 124.9, 123.3, 122.5, 121.2. ESI-MS 32.2), 127.3, 126.4, 125.8, 125.7 (3JC-F = 3.7), 124.3 (1JC-F
m/z calcd for C15H9NS2: [M+H]+ 267.02; Found: 268.11. Anal. 270.6), 123.1, 122.1, 121.5. Anal. Calcd for C16H10F3NS: C,
=
=
Calcd for C15H9NS2: C, 67.38; H, 3.39; N, 5.24%. Found: C, 62.94; H, 3.30; N, 4.59%. Found: C, 62.97; H, 3.35; N, 4.53%.
67.33; H, 3.37; N, 5.27%.
(E)-2-(2-([1,1'-Biphenyl]-4-yl)vinyl)benzo[d]thiazole (3ap):
2-(Naphthalen-1-yl)benzo[d]thiazole (3ai)28: Isolated as Isolated as white solid; mp: 192–193 oC; 1H NMR (300 MHz,
white solid; mp: 124–125oC; H NMR (300 MHz, CDCl3) δ 8.95 CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.64 (d,
1
(d, J = 8.3 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.02 – 7.92 (m, 4H), J = 10.5 Hz, 6H), 7.54 (s, 1H), 7.52 – 7.33 (m, 6H). 13C NMR (75
7.66 – 7.55 (m, 4H), 7.49 – 7.43 (m, 1H). 13C NMR (75 MHz, MHz, CDCl3) δ 166.9, 153.8, 141.9, 140.1, 137.0, 134.3, 134.2,
CDCl3) δ 167.4, 153.9, 135.2, 133.8, 130.8, 130.5, 130.4, 129.2, 128.8, 127.8, 127.6, 127.4, 126.9, 126.2, 125.2, 122.8, 121.9,
128.2, 127.4, 126.3, 126.0, 125.7, 125.0, 124.7, 123.3, 121.2
ESI-MS m/z calcd for C17H11NS: [M+H]+261.06; Found: 261.99.
.
121.4. ESI-MS m/z calcd for C21H15NS [M+H]+ 313.09; Found:
314.14. Anal. Calcd for C21H15NS: C, 80.48; H, 4.82; N, 4.47 %.
2-(4-(Methylthio)phenyl)benzo[d]thiazole (3aj)29: Isolated Found: C, 80.45; H, 4.88; N, 4.43%.
as white solid; mp: 142–144oC; 1H NMR (300 MHz, CDCl3) δ
o
8.06 – 8.02 (m, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.90 – 7.84 (m, 1H), mp: 110–111 C; H NMR (300 MHz, CDCl3) δ 8.04 – 7.99 (m,
2-Phenylbenzo[d]thiazole (3aq)29: Isolated as white solid;
1
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3H), 7.82 (d, J = 7.9 Hz, 1H), 7.45 – 7.37 (m, 4H), 7.33 – 7.27 (m, C11H9N3OS: C, 57.13; H, 3.92; N, 18.17%. Found: C, 57.17; H,
1H). 13C NMR (75 MHz, CDCl3) δ 167.8, 153.9, 134.9, 133.4, 3.95; N, 18.19%.
130.8, 128.8, 127.4, 126.1, 125.0, 123.0, 121.4.
2-(4-(Trifluoromethoxy)phenyl)thiazolo[5,4-c]quinoline
2-(4-Fluorophenyl)benzo[d]thiazole (3ar)28: Isolated as (3ay): Isolated as white solid; mp: 171–172 C; H NMR (300
white solid; mp:101–103 oC; 1H NMR (300 MHz, CDCl3) δ 8.10 – MHz, CDCl3) δ 9.55 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.20 (d, J =
8.04 (m, 3H), 7.89 (d, J = 7.9 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.41 – 8.7 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.69
7.35 (m, 1H), 7.21 – 7.14 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H). 13C NMR (75 MHz,
o
1
166.6, 165.9, 162.6 (1JC-F = 250.5), 153.9, 134.9, 129.3 (3JC-F
8.2), 126.3, 125.1, 123.1, 121.5, 116.0 (2JC-F = 21.7).
=
CDCl3)* δ 166.6, 153.1, 151.3, 148.5, 146.0, 144.2, 140.4,
131.4, 130.5, 129.1, 127.7, 124.8, 123.2 (1JC-F = 264.0), 121.3.
2-(3-(Trifluoromethoxy)phenyl)benzo[d]thiazole (3as)30: ESI-MS m/z calcd for C17H9F3N2OS: [M+H]+ 346.04; Found:
Isolated as off–white solid; mp: 100–102 oC; 1H NMR (300 346.95. Anal. Calcd for C17H9F3N2OS: C, 58.96; H, 2.62; N,
MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 6.6 Hz, 2H), 8.09%. Found: C, 58.98; H, 2.65; N, 8.04%. *one quartnary
7.92 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 11.6, 4.7 Hz, 2H), 7.42 (t, J carbon not picked up.
= 7.6 Hz, 1H), 7.35 (dd, J = 8.3, 1.0 Hz, 1H). 13C NMR (75 MHz,
3,5-Dimethyl-4-(thiazolo[5,4-c]quinolin-2-yl)isoxazole
CDCl3) δ 165.9, 153.9, 149.7, 141.6, 135.3, 130.3, 126.5, 125.7 (3az): Isolated as off–white solid; mp: 242–243 oC; 1H NMR
(1JC-F = 248.2), 125.4, 123.4, 122.9, 121.6, 119.3, 119.7. ESI-MS (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.03 (d,
m/z calcd for C14H8F3NOS [M+H]+ 295.03; Found: 295.02
J = 8.0 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H),
2-(4-Methoxyphenyl)benzo[d]thiazole (3at)31: Isolated as 2.87 (s, 3H), 2.69 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.1,
o
1
white solid; mp: 111–114 C; H NMR (300 MHz, CDCl3) δ 8.02 158.4, 158.1, 147.8, 145.9, 144.2, 139.2, 130.5, 128.9, 127.7,
(d, J = 8.8 Hz, 3H), 7.86 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 124.8, 123.1, 111.4, 13.4, 12.1. ESI-MS m/z calcd for
1H), 7.34 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H). C15H11N3OS: [M+H]+ 281.06; found: 282.03 Anal. Calcd for
13C NMR (75 MHz, CDCl3) δ 167.7, 161.7*, 154.1, 134.7, 128.9, C15H11N3OS: C, 64.04; H, 3.94; N, 14.94%. Found: C, 64.08; H,
126.0, 124.6, 122.7, 121.4, 114.2, 55.2. *Two quartnary 3.96; N, 14.99%.
carbons are merged.
(E)-2-(4-Methylstyryl)benzo[d]thiazole (3ba)32: Isolated as
2-(3-Nitrophenyl)benzo[d]thiazole (3au)28: Isolated as pale white solid; mp: 139–140 C; H NMR (300 MHz, CDCl3) δ 7.99
yellow solid; mp: 141–143 oC; 1H NMR (300 MHz, CDCl3) δ 8.92 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 – 7.67 (m, 1H),
(s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.11 (d, J 7.50 – 7.44 (m, 4H), 7.39 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.22
= 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 1H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
7.54 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H). 13C NMR (75 167.2, 153.8, 139.6, 137.6, 134.2, 129.6, 128.3, 127.3, 126.2,
MHz, CDCl3) δ 164.7, 153.8, 148.6, 135.1, 135.0, 132.9, 130.0, 125.1, 122.7, 121.4, 121.0, 21.4. ESI-MS m/z calcd for C16H13NS
126.7, 125.9, 125.0, 123.6, 122.1, 121.7. ESI-MS m/z calcd for [M+H]+ 251.08; Found: 252.09.
o
1
C13H8N2O2S: [M+H]+ 256.03; found 257.02.
(E)-2-Styrylbenzo[d]thiazole (3bb)28: Isolated as white
o
2-(4-Chlorophenyl)thiazolo[5,4-b]pyridine (3av): Isolated solid; mp 110–112 C; H NMR (300 MHz, CDCl3) δ 8.00 (d, J =
1
as white solid; mp: 157–158 oC; H NMR (300 MHz, CDCl3) δ 8.1 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 9.7, 3.1 Hz,
1
8.58 (dd, J = 4.6, 1.4 Hz, 1H), 8.27 (dd, J = 8.2, 1.5 Hz, 1H), 8.03 2H), 7.52 – 7.47 (m, 2H), 7.45 – 7.37 (m, 5H). 13C NMR (75
(d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.46 – 7.42 (m, 1H). MHz, CDCl3) δ 166.9, 153.8, 137.6, 135.3, 134.3, 129.4, 128.9,
13C NMR (75 MHz, CDCl3) δ 167.0, 158.3, 147.11, 147.06, 127.3, 126.2, 125.3, 122.9, 122.0, 121.4.
137.6, 131.8, 129.9, 129.3, 128.6, 121.5. Anal. Calcd for
C12H7ClN2S: C, 58.42; H, 2.86; N, 11.35%. Found: C, 58.46; H, Isolated as off–white solid; mp: 79–81 C; H NMR (300 MHz,
2.82; N, 11.39%. CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.60-7.69 (m, 3H), 7.43 – 7.36
2-((4-Methoxyphenyl)thio)benzo[d]thiazole
(4a)33:
o
1
2-(Pyridin-3-yl)thiazolo[5,4-b]pyridine (3aw): Isolated as (m, 1H), 7.28 – 7.22 (m, 1H), 7.01 (d, J = 8.9 Hz, 2H), 3.88 (s,
1
colorless solid; mp: 168–169 oC; H NMR (300 MHz, CDCl3) δ 3H). 13C NMR (75 MHz, CDCl3) δ 171.8, 161.5, 154.0, 137.4,
9.34 – 9.30 (m, 1H), 8.76 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (dd, J = 135.2, 125.9, 123.9, 121.5, 120.6, 119.9, 115.3, 55.3. ESI-MS
4.7, 1.5 Hz, 1H), 8.38 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 8.33 (dd, J = m/z calcd for C14H11NOS2[M+H]+ 273.03; Found; 274.06.
8.2, 1.5 Hz, 1H), 7.51 – 7.45 (m, 2H). 13C NMR (75 MHz, CDCl3)
4-(Benzo[d]thiazol-2-ylthio)-3,5-dimethylisoxazole (4b):
o
1
δ 165.1, 158.0, 151.9, 148.4, 147.4, 146.8, 134.5, 130.2, 129.3, Isolated as colorless solid; mp 102–104 C; H NMR (300 MHz,
123.7, 121.6. ESI-MS m/z calcd for C11H7N3S [M+H]+ 213.04; CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.29 (t,
Found: 214.00. Anal. Calcd for C11H7N3S: C, 61.95; H, 3.31; N, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 2.41 (s, 3H), 2.19 (s, 3H).
19.70%. Found: C, 61.91; H, 3.34; N, 19.73%.
13C NMR (75 MHz, CDCl3) δ 174.9, 167.8, 161.7, 154.1, 134.9,
3,5-Dimethyl-4-(thiazolo[5,4-b]pyridin-2-yl)isoxazole
126.2, 124.3, 121.7, 120.7, 102.5, 11.5, 9.9. ESI-MS m/z calcd
(3ax): Isolated as colorless solid; mp: 154–155 oC; 1H NMR (300 for C12H10N2OS2: [M+H]+ 262.02; Found: 262.98. Anal. Calcd for
MHz, CDCl3) δ 8.59 (d, J = 4.5 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), C12H10N2OS2: C, 54.94; H, 3.84; N, 10.68%. Found: C, 54.98; H,
7.47 (dd, J = 8.2, 4.7 Hz, 1H), 2.82 (s, 3H), 2.64 (s, 3H). 13C NMR 3.86; N, 10.65%.
(75 MHz, CDCl3) δ 170.2, 158.6, 158.5, 157.6, 146.9, 146.1,
129.8, 121.5, 111.7, 13.3, 12.1. ESI-MS m/z calcd for
C11H9N3OS: [M+H]+ 231.05; Found: 232.06.Anal. Calcd for
Acknowledgements
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Chen, C. C. Liao, H. S. Yu, Y. M. Tsai, S. M. Huang, F. Y. Tsai, H.
C. Shen, L. S. Chang, J. J. Wang, Bioorg. Med. Chem., 2010,
18, 6197; (h) K. Inamoto, C. Hasegawa, J. Kawasaki, K. Hiroya,
T. Doi, Adv. Synth. Catal., 2010, 352, 2643; (i) V. A. Kozlov, D.
V. Aleksanyan, Y. V. Nelyubina, K. A. Lyssenko, V. Petrovskii,
I. L. Odinets, A. A. Vasilev, I. L. Odinets, Organometallics,
2011, 30, 2920; (j) H. Wang, L. Wang, J. Shang, X. Li, H. Wang,
J. Gui, A. Lei, Chem. Commun., 2012, 48, 76; (k) Y. Cheng, J.
Yang, Y. Qu, P. Li, Org. Lett., 2012, 14, 98; (l) Y. Liao, H. Qi, S.
† The authors thank DST, New Delhi for assistance under the
IRHPA program for the NMR facility. K. R is gratefully
acknowledged for the award of a Junior Research Fellowship
and financial support from CSIR (Grant No. 02(0061)/12/EMR-
II), New Delhi.
Notes and references
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6004.
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1
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DOI: 10.1039/C5RA17827D
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DOI: 10.1039/C5RA17827D
An Efficient Desulfitative C-C Cross Coupling of Fused aryl Thiazolidine-2-thione with
Boronic acids and Boronic acid Pinacol esters: Formation of Fused aryl Thiazoles
Kandasamy Rajaguru,a Arumugam Mariappan,a Ramachandran Manjusri,a
Shanmugam Muthusubramanian,a* and Nattamai Bhuvaneshb
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai - 625 021, India
bX-ray Diffraction Laboratory, Department of Chemistry, Texas A & M University, College Station,
Texas 77842, USA.
E-mail: muthumanian2001@yahoo.com
In this study, an efficient Pd(0)-catalyzed Cu(I)-mediated desulfitative C-C cross-coupling of
benzfused thiazolidine-2-thione with boronic acids under neutral Liebeskind-Srogl condition
is described. The desulfitative cross coupling of boronic acid pinacol esters has also been
demonstrated with fused thiazolidine-2-thione under basic condition to afford fused
thiazoles with good to excellent yields.