Copper-mediated C-H activation/C-S cross-coupling of heterocycles with thiols

Article abstract of DOI:10.1021/jo2017444

We report the synthesis of a series of aryl- or alkyl-substituted 2-mercaptobenzothiazoles by direct thiolation of benzothiazoles with aryl or alkyl thiols via copper-mediated aerobic C-H bond activation in the presence of stoichiometric CuI, 2,2′-bipyridine and Na₂CO₃. We also show that the approach can be extended to thiazole, benzimidazole, and indole substrates. In addition, we present detailed mechanistic investigations on the Cu(I)-mediated direct thiolation reactions. Both computational studies and experimental results reveal that the copper-thiolate complex [(L)Cu(SR)] (L: nitrogen-based bidentate ligand such as 2,2′-bipyridine; R: aryl or alkyl group) is the first reactive intermediate responsible for the observed organic transformation. Furthermore, our computational studies suggest a stepwise reaction mechanism based on a hydrogen atom abstraction pathway, which is more energetically feasible than many other possible pathways including β-hydride elimination, single electron transfer, hydrogen atom transfer, oxidative addition/reductive elimination, and σ-bond metathesis.

Full text of DOI:10.1021/jo2017444

Article
pubs.acs.org/joc
Copper-Mediated C−H Activation/C−S Cross-Coupling of
Heterocycles with Thiols
Sadananda Ranjit,† Richmond Lee,‡ Dodi Heryadi,‡ Chao Shen,⊥ Ji’En Wu,† Pengfei Zhang,⊥
Kuo-Wei Huang,*,‡ and Xiaogang Liu*,†,§
†Department of Chemistry, National University of Singapore, Singapore 117543
§Institute of Materials Research and Engineering, A*STAR, 3 Research Link, Singapore 117602
‡KAUST Catalysis Center and Division of Chemical and Life Sciences and Engineering, King Abdullah University of Science and
Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia
⊥College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
S
* Supporting Information
ABSTRACT: We report the synthesis of a series of aryl- or alkyl-
substituted 2-mercaptobenzothiazoles by direct thiolation of benzothiazoles
with aryl or alkyl thiols via copper-mediated aerobic C−H bond activation
in the presence of stoichiometric CuI, 2,2′-bipyridine and Na2CO3. We also
show that the approach can be extended to thiazole, benzimidazole, and
indole substrates. In addition, we present detailed mechanistic inves-
tigations on the Cu(I)-mediated direct thiolation reactions. Both
computational studies and experimental results reveal that the copper−
thiolate complex [(L)Cu(SR)] (L: nitrogen-based bidentate ligand such as
2,2′-bipyridine; R: aryl or alkyl group) is the first reactive intermediate
responsible for the observed organic transformation. Furthermore, our
computational studies suggest a stepwise reaction mechanism based on a
hydrogen atom abstraction pathway, which is more energetically feasible
than many other possible pathways including β-hydride elimination, single electron transfer, hydrogen atom transfer, oxidative
addition/reductive elimination, and σ-bond metathesis.
organohalide precursors and multistep procedures. Recently,
Fukuzawa and Daugulis have independently reported the direct
thiolation of benzoxazole and benzothiazole substrates with aryl
thiols or aryl disulfides.5 However, their methods have shown
limitation in reaction scope with access only to aryl thiols or
aryl disulfides, and the reaction mechanisms have not been
thoroughly investigated. Therefore, a general synthetic method
that allows direct thiolation of benzothiazole and its analogues
with alkyl or aryl thiols via C−H bond activation6 would be
highly desirable due to the simplified one-step procedure and
the elimination of halocarbon precursors.
As part of our longstanding interest in developing novel C−S
cross-coupling reactions, we recently developed a convenient
strategy for the synthesis of aryl-substituted benzothiazoles and
benzoxazoles through use of arylboronic acids by metal-
catalyzed direct arylation reactions.7 Herein, we report a new
route to 2-thio-substituted-1,3-benzothiazoles by direct C−H
bond functionalization with alky or aryl thiols in the presence of
copper. We also present mechanistic investigations that suggest
a stepwise reaction mechanism involving a hydrogen atom
abstraction pathway.
INTRODUCTION
■
The formation of C−S bonds, fundamental to the art of organic
synthesis, represents a key step to the synthesis of a broad
range of biologically important molecules and functional
materials.1 In particular, 2-thio-substituted-1,3-benzothiazoles
are essential building blocks found in a large number of
pharmaceutically active molecules. These molecules include
Cathepsin-D inhibitor (A), potent heat shock protein-90
inhibitor (B), avarol-3′-thiobenzothizole (C), 2-(thiocyanato-
methylthio)-1,3-benzothiazole (TCMBT; D), and dual antag-
onist for the human CCR1 and CCR3 receptors (E) (Figure
1).1 Additionally, 2-thio-substituted-1,3-benzothiazoles have
also been found in advanced materials used as corrosion
inhibitors, vulcanization catalysts in the rubber industry, as well
as reagents for metal-catalyzed cross-coupling reactions.2a−c
The most straightforward method for the synthesis of 2-
(arylthio)benzothiazoles involves either cross-coupling of
mercapto-benzothiazole with aryl halides (Scheme 1, route
a)2 or a nucleophilic attack of arylthiols by preformed 2-
halobenzothiazoles (Scheme 1, route b).3 Alternatively, the 2-
(arylthio)benzothiazole can be prepared through intramolecu-
lar S-arylation of a dithiocarbamate.4 Despite the promise of
these methods, there are significant limitations typically
associated with the need of mercapto-benzothiazole or
Received: August 23, 2011
Published: September 29, 2011
© 2011 American Chemical Society
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Table 1. Optimization of the C−S Coupling of
a
Benzothiazole with 4-Methoxythiophenol
additive
(equiv)
temp
conversion
b
entry
1
base
(°C)
solvent
(%)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NaOtBu
KOtBu
KOH
100
100
100
100
100
120
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
NMP
PEG
<3
<3
15
22
30
48
60
75
68
<3
<3
8
c
2
Cul (0.2)
Cul (0.2)
Cul (0.5)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
Cul (1.0)
CuBr (1.0)
CuCN (1.0)
CuCl (1.0)
CuCO3 (1.0)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
EG
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Figure 1. Molecular examples illustrating the incorporation of the 2-
thio-1,3-benzothiazole scaffold.
<5
<5
<1
10
54
Scheme 1. Classical routes for the synthesis of 2-
(arylthio)benzothiazoles
Cs2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
d
99 (95)
92
95
83
10
RESULTS AND DISCUSSION
■
1. Development of Direct Thiolation of Benzothia-
zole. The coupling of benzothiazole (1a) with electron-rich 4-
methoxythiophenol (2a) was chosen as a model system to
determine the optimum reaction conditions, and the selected
results are summarized in the Table 1. In the absence of a metal
salt or ligand, only trace amounts of desired products (3a) were
obtained after 24 h (Table 1, entries 1 and 2). However, to our
surprise, upon adding a combination of CuI (20 mol %) and
2,2′-bipyridine ligand (L-1) in the presence of K3PO4 in DMSO
at 100 °C, the desired product 3a was obtained in 15% yield
(Table 1, entry 3). The yield of 3a could be improved with an
increased amount of CuI/L-1 (Table 1, entries 4 and 5) or at
an increased reaction temperature (Table 1, entries 6 and 7).
Further experimentations revealed that this C−S cross-coupling
reaction was effective in a range of polar aprotic solvents such
as DMSO, DMF, and NMP (Table 1, entries 8 and 9). In stark
contrast, the coupling reaction proceeded less efficiently in
polar protic solvents (PEG, EG) or nonpolar solvent (dioxane).
In all cases studied, the conversion is less than 10% (Table 1,
entries 10−12). Notably, the reactions through use of strong
bases, including NaOtBu, KOtBu, KOH, and Cs2CO3, occurred
with low reaction conversions (Table 1, entries 13−16). The
reaction with K2CO3 or Na2CO3 as the base resulted in the
formation of 3a in 54 and 99% yield, respectively (Table 1,
entries 17 and 18). From subsequent examinations of various
copper sources (Table 1, entries 19−22), CuI was proven to be
the best (Table 1, entry 18).
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), solvent (3.0
b
c
mL), base (2.5 equiv), 140 °C, 24 h. GC analysis. The entry has
been done without the bipy ligand. Yield of the isolated product is in
parentheses. Bipy = 2,2′-bipyridine.
d
ligand (L7) that can stabilize the Cu(I) species in solutions are
well studied for C−S cross-coupling reactions.4a,8 In our
studies, the reaction with added L1 gave high reaction yields for
both aryl and alkyl thiol substrates. By comparison, 1,10-
phenanthroline (L2), N,N′′-dimethylethane-1,2-diamine (L3)
and N,N,N′,N′-tetramethylethane-1,2-diamine (L4) were much
less effective for the alkythiol substrate. In the case of using N1-
(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-dia-
mine (L5), ethane-1,2-diamine (L6), and pentane-2,4-dione
(L7), satisfactory results were not obtained for both aryl and
alky thiol substrates.
3. Scope of the Reaction. In a further set of experiments,
we examined the scope and generality of the approach for the
direct sulfurization of benzothiazole 1a with a series of alky and
aryl thiols (2b−o) under the optimum reaction conditions. Our
results showed that both alkyl and aryl thiols can be efficiently
converted to the corresponding cross-coupling products (Table
2). Importantly, good chemoselectivity was observed in the
coupling of 1a with 4-bromothiophenol (2m) or 4-
chlorothiophenol (2n). In both cases, the benzothiazole
underwent direct thiolation with the halogenated arylthiol
substrates to give the desired bromo- or chloro-substituted 2-
(arylthio)benzothiazoles (3m and 3n) in relatively high yield
(Table 2, entries 12 and 13). Functional group tolerance was
also tested in the reaction of benzothiazole and 4-amino-
thiolphenol (2o). We found that the amine substituent had no
marked effect on the reaction yield (Table 2, entry 14). The
GC/MS analysis of the reaction mixture revealed that no C−N
2. Ligand Influence on Direct Thiolation of Benzo-
thiazole. To investigate the ligand effect on the C−S cross-
coupling, a series of Cu(I)-mediated reactions between 1a and
arylthiol 2a or alkylthiol (1-octanethiol; 2e) in the presence of
different ligands were carried out under the standard reaction
conditions (see Figure 2). Nitrogen-based bidentate or
tridentate ligands (L1 to L6) and oxygen-based bidentate
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Table 2. CuI/Bipy-Mediated Direct Sulfurization of
a
Benzothiazole with Thiols
Figure 2. Effect of ligand on the cross-coupling of benzothiazoles with
thiols. Reaction condition: 1a (1.0 mmol), 2a (1.5 mmol), CuI/ligand
(1.0 equiv/1.0 equiv), and Na2CO3 (2.5 equiv) in DMF (3.0 mL) at
140 °C for 24 h.
coupling product is formed. Importantly, the amine-substituted
benzothiazole (3o) enables direct derivatization by reacting
with 3,5-dichloro-2-hydroxybenzoic acid in the presence of O-
(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-
fluorophosphate (HATU) to give the Cathepsin-D inhibitor
analogue (3p), demonstrating a potential utility of our
simplified strategy for accessing a broad range of biologically
important molecules (Scheme 2).
In addition to the benzothiazole substrate 1a, other
substituted heterocycles can react with arylthiols to furnish
the corresponding aryl sulfides. For example, under the
standard reaction conditions 1,3-thiazole is selectively mono-
thiolated at the 2 position by 4-methoxythiophenol 2a to
generate the cross-coupling product (3q) in 79% yield (Table
3). Similarly, 4,5-dimethylthiazole and 1-methylbenzimidazole
can be directly thiolated by 2a to afford the cross-coupling
thiazole and imidazole products (3r and 3s) in 86 and 96%
yields, respectively (Table 3). Interestingly, indole and its
methylated derivatives can be selectively monothiolated at the 3
position in good yields (3t−v) by reacting with phenylthiol (2i)
under the optimized reaction condition (Table 3). The
preferential electrophilic substitution of the indole substrate
at the 3 position is largely due to its more nucleophilic nature
than that at the 2 position.6e
a
Reaction conditions: 1a (1.0 mmol), 2b−o (1.5 mmol each), DMF
(3.0 mL), CuI (1.0 equiv), 2,2′-bipyridine (1.0 equiv), Na2CO3 (2.5
equiv), 140 °C, 24 h. Yields of the products are the average of at least
two experiments.
b
Scheme 2. Synthesis of Cathepsin-D Inhibitor Analogue
4. Mechanistic Considerations. 4.1. First Reactive
Intermediate. In an effort to gain a better understanding of
the reaction mechanism, we carried out density functional
theory (DFT) studies and concurrently conducted control
experiments to verify our hypothesis. The first active
intermediate formed may be either the C−H activated Cu-
benzothiazole complex (Ia)9−12 or the Cu-thiolate complex
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a
4.2. β-Hydride Elimination (BHE) versus Hydrogen Atom
Abstraction (HAA). Mechanistic scenarios into Cu-catalyzed
Ullmann-type coupling reactions have been proposed and
explored.13 Single electron transfer (SET), hydrogen atom
transfer (HAT), σ-bond metathesis, and oxidative addition/
reductive elimination (OA/RE) pathways were evaluated in
order to search for the most plausible pathway (Scheme 5).
The SET and HAT pathways were first ruled out due to
significantly increased energies of intermediates relative to I by
136.0 and 88.4 kcal/mol, respectively. The other two pathways
were also excluded as the OA/RE CuIII intermediate
optimization failed with the thiazolate breaking off and
nonconvergence for the σ-bond metathesis transition-state
structures. It was observed that the formation of the proposed
cuprous hydride species resulting from all above-mentioned
processes is unlikely (+39.5 kcal/mol relative to I), suggesting
that the preceding TS minima, even if located, would be of
considerably higher energy and unattainable under our reaction
conditions. Alternative pathways, independent of the Ullmann
type, were therefore proposed and examined (Scheme 6).
Starting from Cu-thiolate intermediate I, a benzothiazole-
coordinated intermediate II was proposed and located. The
phenylthiolate group was then found to migrate onto the
electrophilic sp2 carbon of the benzothiazole moiety to form
the Cu-mercaptobenzothiazole complex IV via transition state
TS-III. The occurrence of β-hydride elimination process from
IV via transition state TS-Vb to the CuI-hydrido intermediate
VIb and the product was ruled out due to the high overall
transition state energy of 57.5 kcal/mol (Figures 3 and 4).
These observations urged us to consider the involvement of
oxygen in these processes (Scheme 6).
Table 3. Scope of Heteroarene Coupling Partners
a
Reaction conditions: heterocycles (1.0 mmol), thiols (1.5 mmol),
DMF (3.0 mL), CuI (1.0 equiv), 2,2′-bipyridyl (1.0 equiv), Na2CO3
(2.5 equiv), 140 °C, 24 h. Yields of the products are the average of at
least two experiments.
(Ib) (Scheme 3). Results from our modeling suggested that the
formation of the Cu-thiolate complex Ib is thermodynamically
Scheme 3. Proposed Reaction Pathways
Reports on C−H bond activation/functionalization by CuII-
superoxo complexes in biological enzymes such as dopamine
hydroxylase and peptidylglycine α-hydroxylating monooxyge-
nases prompted us to construct models for probing the
reactivity of V(3), which is believed to form through dioxygen
binding to IV.14 The geometry of the optimized triplet state
intermediate V(3) shows a characteristic superoxo O−O bond
length of 1.26 Å and a Cu−O−O bond angle of 119.0° (Figure
4).15 The distance of 2.23 Å between the terminal O and the C-
2 hydrogen suggests that it is well positioned for the
subsequent hydrogen abstraction step. Through transition
state TS-VI(3), the hydroperoxo complex VII(3) is located but
at +18.0 kcal/mol relative to the singlet hydroperoxo complex
VII(1). By computing the potential energy surfaces of V for both
singlet and triplet states in the abstraction of the C-2 hydrogen,
it was observed that the two profiles intersect before TS-VI(3) at
the hypothetical point termed as the minimum-energy crossing
point (MECP) (Figure 3),16,17 which serves to rationalize the
transitioning of the triplet energy surface to the singlet energy
surface. Utilizing a code developed by Harvey and co-
workers,18 the MECP geometry and its corresponding energy
was estimated to be 2.0 kcal/mol lower than TS-VI(3) (Figure
4). It is portrayed that the bond length of the dioxygen
elongates as it reaches to abstract the hydrogen, beginning with
the O−O bond length of 1.26−1.33 Å of MECP and finally to
the hydroperoxo VII(1) O−O bond length of 1.49 Å.19
Complex VII(1) will dissociate to the desired product and the
CuI-hydroperoxo complex. We believe that the CuI-hydro-
peroxo complex will be subsequently oxidized to the CuII
species and no longer participate in the reaction.20
more favored than the Cu-benzothiazolate complex Ia by 19.8
kcal/mol (Figure 3). Further experimental evidence was
delineated from two parallel experiments. The reaction of
benzothiazole with CuI, 2,2′-bipyridine, and Na2CO3 dissolved
in deuterated dimethylformamide showed no formation of the
perceived C−H activated product Ia upon heating at 140 °C
1
for 4 h based on in situ H NMR analysis (Scheme 4, path A).
In sharp contrast, the second control experiment involving a
two-step procedure and the formation of a CuSPh complex
gave rise to the cross-coupling product, 3i, in 90% yield
(Scheme 4, path B). These data provide strong support that the
reaction between the benzothiazole and thiol substrates under
our standard reaction conditions may operate via the formation
of the Cu-thiolate complex intermediate.
To elucidate the critical role of molecular oxygen in
mediating the coupling reaction, we also conducted a series
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Figure 3. Schematic representation (energy versus reaction coordinate) of the Cu(I)-mediated C−S cross-coupling reaction. Inset: selected energies
of intermediates and the transition state compared with the energy of the optimized MECP structure. Relative energies are reported in kcal/mol.
Single-point energies in DMF on gas-phase optimized stationary points are styled italics and in parentheses.
The copper-mediated protocol is palladium free, tolerates a
variety of functional groups, and eliminates the need for an
organohalide species. Mechanistic investigations of this organic
transformation revealed that the generation of the first reactive
intermediate as a Cu-thiol complex occurs instead of the
generally accepted Cu-thiazole complex, as corroborated by
DFT calculations. We postulated that molecular oxygen
participates in the reaction by abstracting the hydrogen from
the C-2 carbon of the thiazole to form the Cu-hydroperoxo
compound. Further work is underway to expand the scope of
this direct C−S bond functionalization reaction.
Scheme 4. Control Experiments Supporting the Formation
of Thio-Substituted Benzothiazole via Path B
EXPERIMENTAL SECTION
General. Unless otherwise noted, all operations were performed
■
without taking precautions to exclude air and moisture, and all solvents
and chemicals were used as received. H NMR and 13C NMR spectra
1
of experiments by varying the concentration of oxygen. As
summarized in Table 4, the reaction between benzothiazole 1a
and 1-octanethiol (2e) conducted under N2 did not proceed
(entry 1). Intriguingly, the yield of coupling product 3e
increases with higher oxygen concentration and reaches 72% in
air (entries 2−4). However, the reaction yield decreased
significantly to 30% when the reaction was conducted under a
pure oxygen atmosphere. The suppressed production is likely
due to the facile formation of disulfide byproducts generated by
oxidation of 1-octanethiol at elevated oxygen concentrations.
were recorded on 300 and 75 MHz FT-NMR spectrometers as well as
500 and 125 MHz FT-NMR spectrometers and referenced to solvent
peaks. Coupling reactions of benzothiazole with 4-methoxybenzene-
thiol shown in Tables 1 and 4 were monitored by GCMS analysis.
Synthesis of the CuSPh Complex. The copper complex was
prepared according to a previously reported method.6t To an ice-cold
mixture of concd aq NH3 (25 mL) and water (100 mL) was added
CuSO4·5H2O (6.26 g, 25.1 mmol), forming a blue-colored solution.
Then, a solid form of NH2OH·HCl (3.89 g, 56.0 mmol) was added to
the resulting mixture and stirred overnight at 25 °C under a nitrogen
purge to produce a colorless solution of [Cu(NH3)2]+. A solution of
PhSH (2.84 g, 25.8 mmol) in 125 mL of ethanol was added dropwise,
resulting in formation of a pale yellow solid. The solid product was
collected via filtration, washed several times with water, ethanol, and
ether, and vacuum-dried. Yellowish solid; H NMR (500 MHz, D6-
DMSO): δ 7.51 (d, J = 10 Hz, 2H), 7.37 (t, J = 10 Hz, 2H), 7.28 (t, J =
5 Hz, 1H).
Copper(I)-Mediated C−S Cross-Coupling. Typical Procedure
for the Reaction of Benzothizole (1a) and 4-Methoxybenze-
nethiol (2a) (Table 1, Entry 18). To a solution of N,N-
dimethylformamide (DMF) (3.0 mL) charged with benzothizole
(1a, 0.5 mmol) and 4-methoxybenzenethiol (2a, 0.75 mmol) was
CONCLUSION
■
1
In summary, we have presented a general and highly efficient
method for C−S cross-coupling through direct functionaliza-
tion of a heterocyclic C−H bond with aryl or alky thiols in the
presence of a stoichiometric amount of copper(I) reagent. By
using this synthetic strategy, various substituted 2-mercapto-
benzothiazoles, imidazoles, and indoles were conveniently
synthesized in good yields under aerobic reaction conditions.
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a
Scheme 5. Plausible Ullmann-Type Reaction Pathways
a
Single electron transfer (SET), hydrogen atom transfer (HAT), σ-bond metathesis, and oxidative addition/reductive elimination (OA/RE). Relative
energies are reported in kcal/mol. Single-point energies in DMF on gas-phase optimized stationary points are styled italics and in parentheses.
Scheme 6. Proposed Reaction Mechanism
added CuI (95.2 mg, 0.5 mmol), 2,2′-bipyridyl (78 mg, 0.5 mmol), and
Na2CO3 (2.5 equiv). The resulting mixture was stirred at 140 °C and
monitored by TLC. Upon completion of the reaction (approximately
24 h), the mixture was cooled to room temperature and mixed with
water (15.0 mL). The product was then extracted with ethylacetate (3
× 15 mL). The organic layers were combined, dried over anhydrous
Na2SO4, concentrated under reduced pressure, and purified over a
column of silica gel (EtOAc/hexane as eluents) to give product 3a in
95% yield. The identity and purity of the products were confirmed by
spectroscopic analysis.
2-(4-Methoxyphenylthio)benzo[d]thiazole (3a).4b White
solid; 1H NMR (500 MHz, CDCl3) δ 7.86−7.85 (d, 1H), 7.68−
7.62 (m, 3H), 7.4−7.37 (t, 1H), 7.26−7.22 (t, 1H), 7.02−6.99 (d,
2H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.8, 161.7,
154.2, 137.5, 135.4, 126, 124, 121.8, 120.7, 120.2, 115.5, 55.4; HR
EIMS 273.0264 m/z (calcd for C14H11ONS2: 273.0282).
2-(Propylthio)benzo[d]thiazole (3b).4d Yellow liquid; 1H NMR
(300 MHz, CDCl3): δ 7.88−7.85 (d, 1H), 7.76−7.73 (d, 1H), 7.43−
7.38 (t, 1H), 7.31−7.26 (t, 1H), 3.35−3.31 (t, 2H), 1.92−1.80 (m,
2H), 1.11−1.06 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4,
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124.1, 121.4, 120.9, 33.6, 31.9, 29.63, 29.61, 29.5, 29.4, 29.3, 29.2, 29,
28.7, 22.6, 14.1; HR EIMS: 335.1741 m/z (calcd for C19H29NS2:
335.1741).
2-(Phenethylthio)benzo[d]thiazole (3g).4d Light yellow liquid;
1H NMR (500 MHz, CDCl3): δ 7.89−7.88 (d, 1H), 7.76−7.74 (d,
1H), 7.43−7.40 (t, 1H), 7.34−7.22 (m, 6H), 3.61−3.57 (t, 2H), 3.15−
3.12 (t, 2H); 13C NMR (125 MHz, CDCl3): δ 166.6, 153.3, 139.7,
135.3, 128.7, 128.6, 126.7, 126, 124.2, 121.5, 121, 35.6, 34.8; HR
EIMS: 271.0484 m/z (calcd for C15H13NS2: 271.0489).
2-(Cyclohexylthio)benzo[d]thiazole (3h). Yellow liquid; 1H
NMR (500 MHz, CDCl3): δ 7.88−7.87 (d, 1H), 7.75−7.74 (d,
1H), 7.42−7.39 (t, 1H), 7.30−7.27 (t, 1H), 3.93−3.87 (m, 1H), 2.22−
2.18 (m, 2H), 1.82−1.78 (m, 2H), 1.67−1.29 (m, 6H); 13C NMR
(125 MHz, CDCl3): δ 166.4, 153.4, 135.3, 125.9, 124.1, 121.6, 120.8,
47.3, 33.3, 25.8, 25.6; HR EIMS: 249.0636 m/z (calcd for C13H15NS2:
249.0646).
2-(Phenylthio)benzo[d]thiazole (3i).4b Light yellow liquid; H
1
NMR (300 MHz, CDCl3): δ 7.89−7.86 (d, 1H), 7.75−7.72 (d, 2H),
7.66−7.63 (d, 1H), 7.51−7.37 (m, 4H), 7.28−7.23 (t, 1H); 13C NMR
(75 MHz, CDCl3): δ 169.6, 153.9, 135.5, 135.3, 130.4, 129.94, 129.9,
126.1, 124.3, 121.9, 120.7; HR EIMS: 243.0157 m/z (calcd for
C13H9NS2: 243.0176).
Figure 4. Optimized geometries of selected transition states and
intermediates showing key bond lengths.
2-(p-Tolylthio)benzo[d]thiazole (3j).4b White solid; H NMR
1
(300 MHz, CDCl3): δ 7.87−7.84 (d, 1H), 7.63−7.6 (d, 3H), 7.4−7.35
(t, 1H), 7.29−7.21 (m, 3H), 2.42 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 170.7, 154, 141.1, 135.5, 135.4, 130.7, 126.2, 126, 124.1,
121.8, 120.7, 21.4; HR EIMS: 257.0314 m/z (calcd for C14H11NS2:
257.0333).
Table 4. Effect of Atmosphere on the Cross-Coupling
Reactions
a
2-(3,5-Dimethylphenylthio)benzo[d]thiazole (3k). Light yel-
low liquid; 1H NMR (500 MHz, CDCl3): δ 7.88−7.87 (d, 1H), 7.65−
7.64 (d, 1H), 7.41−7.38 (t, 1H), 7.35 (s, 2H), 7.27−7.24 (t, 1H), 7.13
(s, 1H), 2.35 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 170.5, 153.8,
139.7, 135.5, 132.9, 132.2, 129.2, 126.1, 124.2, 121.8, 120.7, 21.2; HR
EIMS: 271.0472 m/z (calcd for C15H13NS2: 271.0489).
2-(Naphthalen-2-ylthio)benzo[d]thiazole (3l). Brown solid;
1H NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 7.93−7.86 (m, 4H),
7.73−7.71 (dd, 1H), 7.62−7.55 (m, 3H), 7.41−7.38 (t, 1H), 7.27−
7.23 (t, 1H); 13C NMR (125 MHz, CDCl3): δ 169.7, 153.7, 135.5,
135.4, 133.8, 133.7, 131.1, 129.7, 128.1, 127.9, 127.7, 127, 126.2, 124.4,
121.9, 120.8; HR EIMS: 293.0315 m/z (calcd for C17H11NS2:
293.0333).
b
entry
O2/N2
0:100
conversion (%)
1
2
3
4
5
<1
5
∼(1:50)
∼(4:50)
air (21% O2)
100:0
15
72
30
a
Reaction conditions: 1a (1.0 mmol), 2e (1.5 mmol), DMF (3.0 mL),
CuI (1.0 equiv), 2,2′-bipyridine (1.0 equiv), Na2CO3 (2.5 equiv), 140
b
°C, 24 h. GC analysis.
2-(4-Bromophenylthio)benzo[d]thiazole (3m). Yellowish
white solid; 1H NMR (300 MHz, CDCl3): δ 7.9−7.87 (d, 1H),
7.7−7.67 (d, 1H), 7.63−7.57 (m, 4H), 7.45−7.39 (t, 1H), 7.32−7.26
(t, 1H); 13C NMR (125 MHz, CDCl3): δ 168.1, 153.7, 136.5, 135.5,
133.1, 129, 126.3, 125.1, 124.6, 122.1, 120.9; HR EIMS: 320.9265 m/z
(calcd for C13H8BrNS2: 320.9282).
153.2, 135.1, 126, 124.1, 121.4, 120.9, 35.5, 22.7, 13.4; HR EIMS:
209.0329 m/z (calcd for C10H11NS2: 209.0333).
2-(Butylthio)benzo[d]thiazole (3c). Yellow liquid; 1H NMR
(500 MHz, CDCl3): δ 7.87−7.86 (d, 1H), 7.75−7.74 (d, 1H), 7.42−
7.39 (t, 1H), 7.30−7.27 (t, 1H), 3.36−3.34 (t, 2H), 1.84−1.78 (m,
2H), 1.5−1.47 (m, 2H), 0.98−0.95 (t, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.4, 153.4, 135.1, 126, 124.1, 121.4, 120.9, 33.3, 31.2, 21.9,
13.6; HR EIMS: 223.0489 m/z (calcd for C11H13NS2: 223.0489).
2-(Hexylthio)benzo[d]thiazole (3d). Yellow liquid; 1H NMR
(300 MHz, CDCl3): δ 7.92−7.89 (d, 1H), 7.80−7.77 (d, 1H), 7.47−
7.42 (t, 1H), 7.35−7.30 (t, 1H), 3.41−3.36 (t, 2H), 1.91−1.81 (quint,
2H), 1.57−1.47 (quint, 2H), 1.41−1.29 (m, 4H), 0.96−0.91 (t, 3H);
13C NMR (125 MHz, CDCl3): δ 167.4, 153.4, 135.1, 126, 124.1, 121.4,
120.8, 33.6, 31.2, 29.1, 28.4, 22.4, 14; HR EIMS: 251.0791 m/z (calcd
for C13H17NS2: 251.0802).
2-(4-Chlorophenylthio)benzo[d]thiazole (3n). Yellow liquid;
1H NMR (300 MHz, CDCl3): δ 7.9−7.89 (d, 1H), 7.69−7.65 (m,
3H), 7.47−7.39 (m, 3H), 7.32−7.27 (t, 1H); 13C NMR (125 MHz,
CDCl3): δ 168.4, 153.7, 137, 136.4, 135.5, 130.1, 128.4, 126.3, 124.6,
122, 120.8; HR EIMS: 276.9780 m/z (calcd for C13H8ClNS2:
276.9787).
4-(Benzo[d]thiazol-2-ylthio)aniline (3o). Brown solid; 1H
NMR (500 MHz, CDCl3): δ 7.85−7.83 (d, 1H), 7.63−7.62 (d,
1H), 7.52−7.49 (d, 2H), 7.39−7.36 (t, 1H), 7.24−7.21 (t, 1H), 6.77−
6.74 (d, 2H); 13C NMR (125 MHz, CDCl3): δ 173.3, 154.3, 148.8,
137.6, 135.4, 126, 123.9, 121.6, 120.7, 116.8, 115.9; HR EIMS:
258.0274 m/z (calcd for C13H10N2S2: 258.0285).
2-(Octylthio)benzo[d]thiazole (3e). Yellow liquid; 1H NMR
(500 MHz, CDCl3): δ 7.87−7.85 (d, 1H), 7.75−7.74 (d, 1H), 7.42−
7.39 (t, 1H), 7.30−7.25 (t, 1H), 3.35−3.34 (t, 2H), 1.85−1.79 (quint,
2H), 1.5−1.45 (quint, 2H), 1.35−1.26 (m, 8H), 0.90−0.87 (t, 3H);
13C NMR (125 MHz, CDCl3): δ 167.4, 153.3, 135.1, 126, 124.1, 121.4,
120.8, 33.7, 31.7, 29.2, 29.1, 29, 28.7, 22.6, 14; HR EIMS: 279.1112 m/
z (calcd for C15H21NS2: 279.1115).
N-(4-(Benzo[d]thiazol-2-ylthio)phenyl)-3,5-dichloro-2-hy-
1
droxybenzamide (3p). Off-white solid; H NMR (500 MHz, [D6]
DMSO): δ 12.25 (br s, 1H), 10.86 (br s, 1H), 8.07 (s, 1H), 8.06−7.82
(m, 7H), 7.47−7.44 (t, 1H), 7.36−7.32 (t, 1H); 13C NMR (125 MHz,
[D6] DMSO): δ 169.5, 166.4, 154.1, 153.4, 140.1, 136.1, 134.7, 132.9,
126.6, 126.4, 124.4, 123.7, 122.6, 122.45, 122.4, 121.7, 121.3, 119.7;
HR EIMS: 445.9725 m/z (calcd for C20H12Cl2N2O2S2: 445.9717).
2-(4-Methoxyphenylthio)thiazole (3q). Yellow liquid; 1H
NMR (500 MHz, CDCl3): δ 7.65−7.64 (d, 1H), 7.62−7.59 (d,
2H), 7.14−7.13 (d, 1H), 6.97−6.94 (d, 2H), 3.85 (s, 3H); 13C NMR
2-(Dodecylthio)benzo[d]thiazole (3f).4e Yellow liquid; 1H
NMR (500 MHz, CDCl3): δ 7.87−7.86 (d, 1H), 7.75−7.74 (d,
1H), 7.42−7.39 (t, 1H), 7.30−7.27 (t, 1H), 3.36−3.33 (t, 2H), 1.85−
1.80 (quint, 2H), 1.50−1.45 (m, 2H), 1.35−1.26 (m, 16H), 0.89−0.87
(t, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4, 153.3, 135.1, 125.9,
9005
dx.doi.org/10.1021/jo2017444|J. Org. Chem. 2011, 76, 8999−9007

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Article
(125 MHz, CDCl3): δ 169, 161.2, 143.2, 136.7, 121.6, 119.3, 115.4,
55.4; HR EIMS: 223.0117 m/z (calcd for C10H9NOS2: 223.0120).
2-(4-Methoxyphenylthio)-4,5-dimethylthiazole (3r). Red
Enterprise (SPORE), the Science and Technology Plan of
Zhejiang Province (2011C24004), and the Singapore−MIT
alliance. X.L. is grateful to the National University of Singapore
for the Young Research Award (C-143-000-022). R.L., D.H.,
and K.-W.H. are grateful for funding from KAUST and
computing time from the NOOR computer cluster managed by
the KAUST supercomputing team.
1
liquid; H NMR (500 MHz, CDCl3): δ 7.57−7.54 (d, 2H), 6.93−
6.90 (d, 2H), 3.83 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 162.6, 160.9, 148.8, 136.2, 127.4, 122.5, 115.1, 55.3,
14.6, 11.2; HR EIMS: 251.0433 m/z (calcd for C12H13ONS2:
251.0439).
2-(4-Methoxyphenylthio)-1-methyl-1H-benzo[d]imidazole
1
(3s). Brown solid; H NMR (500 MHz, CDCl3): δ 7.71−7.69 (d,
REFERENCES
■
1H), 7.44−7.41 (d, 2H), 7.25−7.19 (m, 3H), 6.87−6.84 (d, 2H), 3.76
(s, 3H), 3.71 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 159.9, 149.6,
143, 136.5, 133.9, 122.7, 122.1, 121.1, 119.5, 115.1, 109, 55.3, 30.6;
HR EIMS: 270.0817 m/z (calcd for C15H14N2OS: 270.0827).
3-(Phenylthio)-1H-indole (3t). White solid; 1H NMR (300
MHz, CDCl3): δ 8.41 (br s, 1H), 7.64−7.61 (d, 1H), 7.49−7.43
(m, 2H), 7.3−7.03 (m, 7H); 13C NMR (125 MHz, CDCl3): δ 139.2,
136.5, 130.6, 129.1, 128.7, 126, 125.9, 124.8, 123, 120.9, 119.7, 111.5;
HR EIMS: 225.0607 m/z (calcd for C14H11NS: 225.0612).
5-Methyl-3-(phenylthio)-1H-indole (3u). White solid; 1H
NMR (300 MHz, CDCl3): δ 8.31 (br s, 1H), 7.44−7.43 (m, 2H),
7.34−7.31 (d, 1H), 7.26−7.04 (m, 6H), 2.43 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 139.5, 134.8, 130.8, 130.4, 129.4, 128.7, 125.7, 124.7,
124.6, 119.2, 111.2, 102.1, 21.4; HR EIMS: 239.0767 m/z (calcd for
C15H13NS: 239.0769).
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Computational Details. All DFT gas-phase calculations were
performed with the Gaussian 09 computational suite.21 Becke’s three-
parameter hybrid exchange functional and the nonlocal correlation
functional of Lee, Yang, and Parr (B3LYP) was applied for
optimizations of all compounds, and frequency analyses were done
to verify minimum structures showing positive eigenvalues of the
Hessian matrix or transition-state structures exhibiting only a single
negative eigenvalue.22 The LANL2DZ effective core potential of Hay
and Wadt was applied for I and Cu atoms,23 and the all-electron split-
valence Pople basis set 6-31+G(d,p) containing polarization functions
on both heavy atoms and hydrogens and diffuse functions on heavy
atoms was used.24 Single-point energies in DMF were computed at the
B3LYP/6-311+G(d,p) level of theory on the gas-phase optimized
structures with the default integral equation formalism variant
IEFPCM implemented in Gaussian 09.25,26 MECP was determined
and optimized with the code designed by Harvey and co-workers at
the same level of theory.18 This Fortan-based code together with shell
scripts extracts calculated Gaussian output energies and gradients of
two input structures with different spin states to generate an effective
gradient toward the MECP. All energies reported are a sum of
electronic energy with ZPE corrections except for the estimation of the
MECP energy.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Mechanistic studies and H NMR and 13C NMR spectra of all
compounds and details of DFT calculations. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chmlx@nus.edu.sg (X.L.); hkw@kaust.edu.sa (K.-
W.H.)
■
ACKNOWLEDGMENTS
This study was supported in part by the Ministry of Education
(MOE2010-T2-083), the Singapore−Peking−Oxford Research
■
9006
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