Regioselective thiolation of arenes and heteroarenes: C-H functionalization strategy for C-S bond formation

Article abstract of DOI:10.1021/jo501793q

A facile transition-metal-free oxidative cross-dehydrogenative coupling reaction involving selective formation of a C-S bond leading to the synthesis of arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthiobenzothiazoles has been described. This highly regioselective C-H functionalization reaction with electron-rich aromatic systems including heteroaromatics is achieved by reversing the reactivity of sulfur in the presence of a suitable oxidant and strong acid. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501793q

Article
pubs.acs.org/joc
Regioselective Thiolation of Arenes and Heteroarenes: C−H
Functionalization Strategy for C−S Bond Formation
Begur Vasanthkumar Varun and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S
* Supporting Information
ABSTRACT: A facile transition-metal-free oxidative cross-dehydrogenative coupling reaction involving selective formation of a
C−S bond leading to the synthesis of arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthiobenzothiazoles has been
described. This highly regioselective C−H functionalization reaction with electron-rich aromatic systems including
heteroaromatics is achieved by reversing the reactivity of sulfur in the presence of a suitable oxidant and strong acid.
bond is a relatively less explored area, because thiols and sulfur
compounds are known to undergo oxidation during trans-
formations and often poison the metal catalysts by binding to
them irreversibly.10 Therefore, CDC reactions to generate C−S
bonds in the absence of both thiols and metal catalysts would be a
practically viable and useful strategy. In continuation of our
investigation on C−H functionalization,11 we conceptualized a
strategy by using thiones as masked thiols to form C−S bonds by
employing a suitable oxidant and reaction conditions. Benzox-
azole-2-thione 1a exists in equilibrium with its thiol form in the
presence of a strong acid (Scheme 1), in which the sulfur atom
behaves as a good nucleophile.12 We anticipated that it may be
possible to reverse the reactivity of sulfur in the presence of an
additive/oxidant and couple it with a suitable nucleophile/
pronucleophile.
INTRODUCTION
■
The sulfur-containing organic compounds are of great
significance in chemistry and biology.1 Thioethers of benzazoles
(benzoxazoles and benzothiazoles) have been important targets
due to their biological activities.2 They are extensively useful as
anticancer agents, enzyme inhibitors, antagonizing agents,
antituburculosis agents, and fungicides (Figure 1).3 Particularly,
the 3,4,5-trimethoxyphenyl thioether of benzoxazole shows anti-
breast-cancer activity.3j Generally, thioethers of benzothiazoles
are synthesized using 2-mercaptobenzothiazoles in reactions
with aryl halides,4a−e aryl boronic acids,4f or alcohols.4g,h It is also
well-known that direct C−H thiolation of benzazoles can be
carried out with thiols5a−c and disulfides5d,e using metal catalysts
such as Cu or Rh. Similarly, disulfides can also be cleaved and
coupled with electron-rich arenes under suitable conditions.5f,g
Furthermore, catechols are known to undergo oxidation to their
corresponding quinones under electrochemical conditions,6 and
these quinones are coupled with 2-mercaptobenzoxazoles to give
catechol thioethers, which exhibit antibacterial and antioxidant
properties6 (Scheme 1). 2-Thio-substituted benzothiazoles are
also synthesized by a domino reaction using copper catalysts.7
C−H functionalization is one of the thrust areas which is
rapidly developing as it offers an efficient, economical, and
environmentally benign strategy for functionalization of
unfunctionalized organic molecules.8 Although the C−H
functionalization strategy is attractive, it is challenging to achieve
selective functionalization as C−H bonds are ubiquitous and
activation of inert C−H bonds is a demanding task.9 However,
the C−H bond functionalization strategy using CDC (cross-
dehydrogenative coupling) reactions for the formation of a C−S
RESULTS AND DISCUSSION
■
To test the above hypothesis, we began our investigation using 5-
methylbenz[d]oxazole-2(3H)-thione (1a) and anisole (2a) in
the presence of a variety of oxidants as well as strong acids.
Reactions of 1a and 2a at room temperature (with TFA) as well
as at 60 °C (with TFA, MeSO3H, PTSA, or HClO4) in CH3CN
were not successful (entries 1−5, Table 1). However, the
reaction of 1a with 2a in the presence of K2S2O8 and TfOH in
CH3CN at higher temperatures (60 and 80 °C) furnished the
product 3a in good yields (2 h, 76% and 74%, respectively, entries
6 and 7). A reaction of 1a and 2a at room temperature in CH3CN
Received: August 4, 2014
© XXXX American Chemical Society
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Figure 1. Examples of pharmaceutically active azole derivatives.
Scheme 1
a
Table 1. Screening Studies
a
b
Reaction conditions: 1a (0.25 mmol). nd = not detected. In entries 1−3 and 5, starting material was observed (TLC). 1H NMR conversion. Values
c
in parentheses are isolated yields. Starting material decomposed.
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a
Table 2. Thiolation of Anisole and Its Derivatives
a
b
c
d
Reaction conditions unless otherwise noted: 1 (0.25 mmol), 2 (1 mmol). Reaction conditions: 1 (0.5 mmol), 2 (2 mmol). For 4 h. A 2 equiv
amount of 1,2,3-trimethoxybenzene was used.
or under solvent-free conditions required a longer reaction time
(12 h) and furnished 3a as a major product along with minor
amounts of 3aa and 3bb (entries 8 and 9). Further studies
(entries 10−14) indicated that 3 equiv of K2S2O8, 5 equiv of
TfOH, and 4 equiv of 2a in CH3CN at 60 °C for 2 h are optimal
reaction conditions to obtain 3a as the sole product in good yield
(86%, entry 14, Table 1). Although (NH4)2S2O8 (2 equiv) was a
useful oxidant, it furnished 3a as a major product along with the
oxidized product 3bb (12%, entry 15, Table 1). Further
screening studies to find a suitable oxidant revealed that the
utility of oxone (2 equiv) resulted in the formation of 3a and 3bb
in 42% and 58% yields, respectively (entry 16), whereas m-CPBA
C
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a
Table 3. Optimization of the Reaction Conditions for the Reaction of 1a with Phenol
a
Reaction conditions: 1a (0.5 mmol), solvent (3 mL).
a
Table 4. CDC Reaction of Phenols with Benz[d]oxazole-2(3H)-thiones
a
b
Reaction conditions unless otherwise noted: 1 (0.25 mmol), 4 (2 mmol). Reaction conditions: 1b (0.5 mmol), 4e (2 mmol).
and H2O2 were not helpful in promoting the reaction (entries 17
and 18). In the solvent screening studies it was found that the
starting material 1a decomposed when DMF was used as the
solvent, whereas a similar reaction in DCE formed a mixture of
3a, 3aa, and 3bb in 83%, 7%, and 10% yields, respectively (entries
19 and 20). The reaction in the absence of oxidant under solvent-
free conditions did not yield the expected product 3a and
furnished 3aa in 42% isolated yield (entry 21, Table 1; see the
Supporting Information for the mechanism, SI-Scheme 1).
To find the scope and limitation of the reaction, a variety of
substituted thiones were treated with anisole derivatives (Table
2). Anisole (2a) underwent a facile reaction with thiones 1a, 1b,
1c, and 1d to furnish the thiolated products 3a, 3b, 3c, and 3d in
good yields (86%, 54%, 63%, and 48%, respectively).
Furthermore, 2b reacted well with 1a, 1b, 1c, and 1d to afford
the products 3e, 3f, 3g, and 3h in 89%, 87%, 82%, and 83% yields,
respectively. Similarly, 2c reacted with 1b to furnish the coupled
product 3i in excellent yield (95%). 3,4,5-Trimethoxyphenyl
thioether derivatives are a commonly found scaffold in anticancer
13
compounds.3l, In light of this information, 1,2,3-trimethox-
ybenzene (2d; 2 equiv) was subjected to a coupling reaction with
thiones 1b, 1c, and 1d to obtain the products 3j and 3k in good
yields (85% and 90%, respectively). As trimethoxybenzene is a
highly electron rich system, the reaction proceeded well with 2
D
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equiv of trimethoxybenzene. Furthermore, 1b reacted well with
2e and 2f to afford the products 3l and 3m (37% and 90% yields,
respectively). Under the optimal reaction conditions, 2g
underwent a facile reaction with 1a and 1e to form 3n and 3o
in 95% yield. Naphth[2,3-d]oxazole-2(3H)-thione (1f) was
coupled with 2b to form the corresponding thionated product 3p
in 52% yield. Under the optimal reaction conditions, thione 1g
was found to be less reactive. Reaction of 1g with 2a and 1,2-
dimethoxybenzene (2b) as well as 2d furnished the products 3q,
3r, and 3s (0%, 28%, and 52% yields, respectively). Interestingly,
thioanisole (2h) also underwent a facile reaction with 1a to afford
the product 3t in 79% yield.
Table 5. Optimization of the Reaction Conditions for
Reaction of 1a with Thiophene
a
The reactions of anisole derivatives with a variety of thiones
prompted us to examine the reactions of phenol derivatives
under similar reaction conditions (Table 3). As can be seen from
the quick screening studies, the reaction conditions required are
almost similar to those adopted for anisole. It was observed that
decreasing the amount of phenol or K2S2O8 led to the formation
of 5-methylbenzoxazol-2-one as a byproduct (entries 1 and 2,
Table 3). It was found that the reactions furnishes 5a in major
amounts by using 3−4 equiv of phenol and 3 equiv of K2S2O8
(62% and 68% yields, respectively, entries 3 and 4, Table 3).
Hence, the optimal reaction conditions for reaction of 1a with
phenol (4a) to obtain 5a in good yield (68%, entry 4, Table 3)
are 4 equiv of 4a, 3 equiv of K2S2O8, and 5 equiv of TfOH in
CH3CN at 60 °C for 2 h.
Under the optimized reaction conditions, phenol (4a)
underwent a CDC reaction with thiones 1a and 1c to afford 5a
and 5b in moderate to excellent yields (68% and 84%,
respectively, Table 4), whereas 2,6-dimethylphenol (4b) reacted
well with thiones 1b and 1c to form 5c and 5d in good yields
(89% and 78%, respectively). 3,5-Dimethylphenol (4c) was
found to react well with 1a to afford 5e in 72% yield. Similarly,
the coupling reaction of 2,6-di-tert-butylphenol (4d) with
thiones 1b and 1e resulted in the formation of the products 5f
and 5g in good yields (82% and 77%, respectively). To expand
the scope of this CDC reaction, catechol (4e) was reacted with
1a and 1b to obtain the products 5i and 5j in good yields (72%
and 62%, respectively).
The regioselective CDC reaction of thione derivatives with
anisole and phenol to form C−S bonds has encouraged us to
explore further possibilities. It is known that thiophene-
containing thioethers are potential lipoxygenase inhibitors,14
and it is also well-known that thiophene is a relatively less reactive
aromatic heterocycle. In this direction, preliminary screening
studies of 1a with thiophene (6a) revealed that the reaction is
facile and proceeds well at room temperature. As can be seen in
Table 5, either increasing the temperature or extending the
reaction time was not helpful in furnishing 7a in good yields
(entries 1−4, Table 5). Finally, a good yield of 7a was furnished
by performing the reaction of thiophene (10 equiv) with 1a using
K2S2O8 (3 equiv) and TfOH (5 equiv) in CH3CN at rt (entry 5,
75%, Table 5). However, the reactions under solvent-free
conditions or in DCE were not helpful (entries 6 and 7, Table 5).
Under the optimized conditions, the reaction of 1a and 1b
with excess thiophene (6a) in the presence of K2S2O8 (3 equiv)
and TfOH (5 equiv) in CH3CN at rt furnished the compounds
7a and 7b (75% and 52% yields, respectively, Table 6). Similarly,
2-methylthiophene (6b) and 2,5-dimethylthiophene (6c) at 60
°C underwent thiolation with 1b and 1a to furnish the products
7c, 7d, and 7e (72%, 80%, and 74%, respectively, Table 6). The
coupling reaction of benzo[b]thiophene (6d; 4 equiv) with 1a
and 1b at room temperature proceeded well to furnish 7f and 7g
a
Reaction conditions: 1a (0.5 mmol), solvent (3 mL).
in 72% and 73% yields, respectively. Similarly, 1f underwent a
similar coupling reaction with 6d under the optimal reaction
conditions to form the product 7h in low yield (23%). As can be
seen in the molecular structure diagrams (Table 6, see
Supporting Information for ORTEP diagram of 7a and 7g),
the thiolation of thiophene derivatives has taken place at the C-2
position (7a−7d). However, a similar reaction of benzothio-
phene led to C−S bond formation at C-3 (7f−7h).
The regioselective reaction of thione with anisole, phenol, and
thiophene led us to perform the reaction of thiones with 1,4-
dimethoxybenzene or 1,3,5-trimethoxybenzene. Hence, 1a was
reacted with 1,4-dimethoxybenzene (8a) at 60 °C for 10 h to
obtain the corresponding thionated product 2-((2,5-
dimethoxyphenyl)thio)-5-methylbenz[d]oxazole (9) in 38%
yield (Scheme 2). The thiolation of 1,3,5-trimethoxybenzene
(8b; 2 equiv) with 1a and 1d afforded the monosubstituted
products 2-((2,4,6-trimethoxyphenyl)thio)-5-methylbenz[d]-
oxazole (10a) and 6-nitro-2-((2,4,6-trimethoxyphenyl)thio)-
benz[d]oxazole (10b) in good yields (80% and 81%,
respectively).
It was interesting to observe that a similar reaction of
benzothiazole-2-thione (1g; 0.5 equiv) with 8b (1 equiv) under
reaction conditions similar to those adopted for 5-methylbenz-
[d]oxazole-2(3H)-thione (1a) resulted in the formation of a
mixture of mono- and dithionated products 11a and 11b in 66%
yield in a 1:1 ratio. Further efforts to obtain di- and trithionated
products using excess 1g (2 or 4 equiv) resulted in the formation
of dithionated product 11b in 25% and 27% yields, respectively
(Scheme 3).
Our attempts to react alkyl-substituted aromatic systems such
as toluene or xylene under the optimal reaction conditions were
not successful. However, the reaction of 5-methylbenzoxazole-2-
thione (1a) with excess mesitylene at 60 °C resulted in the
formation of the corresponding thiolated product 13 in 71%
yield (Scheme 4).
To find the selectivity in the reaction of 5-methylbenzoxazole-
2-thione (1a) with anisole (2a), phenol (4a), thioanisole (2h),
and 2-methoxyphenol (14) under the optimal reaction
conditions, the reactions in Scheme 5 were performed. As can
be seen in the reaction of 1a with anisole and thioanisole, anisole
was found to react preferentially over thioanisole. Similarly,
phenol was found to react preferentially over anisole. These
experiments suggest that the reaction is highly regio- and
chemoselective and the order of chemoselectivity is as follows:
phenol > anisole > thioanisole. The structure of 15 was
confirmed by X-ray crystallography.
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a
Table 6. CDC Reaction of Thiophene with Benz[d]oxazole-2(3H)-thiones
a
b
c
Reaction conditions unless otherwise noted: 1 (0.5 mmol), 6 (5 mmol). At 60 °C for 2 h. Reaction conditions: 1b (0.25 mmol), 6b (2.5 mmol).
d
e
At rt for 12 h using 6d (2 mmol). Reaction conditions: 1 (0.25 mmol), 6d (1 mmol).
Scheme 2. Reaction of Thione with Trimethoxybenzene and Dimethoxybenzene
a
b
Reaction conditions unless otherwise noted: 1 (0.25 mmol), K2S2O8 (3 equiv), CH3CN (3 mL). Isolated yields in parentheses. 1a (0.5 mmol) was
c
used. For 4 h.
Scheme 3. Thiolation of 1,3,5-Trimethoxybenzene (8b) with Benzothiazole-2-thione (1g)
a
b
Reaction conditions: 8b (1 mmol), 1g (0.5 mmol), K2S2O8 (3 equiv), TfOH (5 equiv), CH3CN (3 mL). Reaction conditions: 8b (0.25 mmol), 1g
(0.5 or 1 mmol), K2S2O8 (3 equiv), TfOH (5 equiv), CH3CN (3 mL).
were performed. On the basis of the screening studies (Table 1),
the tautomerization of benz[d]oxazole-2-thione is critical for the
thiolation to proceed. On the basis of the literature precedence
and to ensure the equilibrium of benz[d]oxazole-2-thione in
acidic media, the 1H NMR sepctrum of 5-methylbenz[d]oxazole-
2-thione (1a) in either TFA or TfOH in CD3CN was recorded. It
Scheme 4. Thiolation of Mesitylene (12) with 5-
Methylbenzoxazole-2-thione (1a)
1
is clearly observed that the H NMR spectrum of 1a in thione
form (Figure 2, entry 1) shows a singlet for the CH3 group at δ
2.39 (Figure 3, spectrum i) and that of the thiol form of 1a
(Figure 2, 1aa) appears at δ 2.56 (Figure 3, spectrum iv). As can
be seen from Figures 2 and 3, the thione 1a exclusively exists in
Mechanistic Considerations. To follow the reaction
pathway of the thiolation reaction, the following experiments
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Scheme 5. Chemoselective Reactions of Phenol, Anisole, Thioanisole, and 2-Methoxyphenol with 1a
reaction of thiophenol with anisole under the optimal reaction
conditions did not yield the expected thiolated product. Further
studies are under way to substantiate this observation.
CONCLUSION
■
In conclusion, we have described an unprecedented CDC
reaction for the formation of a C−S bond by utilizing thione as a
masked thiol. The method, although limited to electron-rich
partners, nonetheless provides an elegant and new avenue for
synthesizing thioethers, despite the propensity of thiols to easily
undergo oxidation. This strategy provides a rare opportunity to
use thione in the CDC reaction to form C−S bonds to obtain
arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthio-
benzothiazoles, which are pharmaceitically valuable compounds.
This highly regioselective CDC reaction is unique as it requires
the reversal of the reactivity of sulfur to form the C−S bonds.
Figure 2. Tautomerism of 1a.
thiol form in 5 equiv of TfOH (Figure 2, entry 4), whereas in
TFA or in a lower amount of TfOH (3 equiv) the equilibrium
shifts toward the thione form (Figure 2, entries 2 and 3,
respectively). This observation is in good agreement with the
optimization study, which indicates that the reaction does not
proceed with other acids (entries 1−5, Table 1) and the reaction
furnishes a lower yield with fewer equivalents of TfOH (entries
10 and 11). These preliminary NMR studies indicate that the
thiol form exists exclusively when 5 equiv of TfOH is used.
Further investigation in this direction revealed that the
protonation of nitrogen in benzothiazole or benzoxazole is
important and needs a very strong acid. The reaction of disulfide
16 with 1,3,5-trimethoxybenzene (8b) in TfOH (10 equiv) in the
absence of oxidizing agent K2S2O8 furnished the corresponding
thiolated product 11a and benzothiazole-2-thione (1g) along
with monosulfide 17 in a considerable amount (27%, Scheme 6;
also see the Supporting Information, SI-Scheme 2).
Additionally, the reaction of 5-methylbenzoxazole-2-thione
(1a) with anisole (2a) under standard conditions in the presence
of radical inhibitor BHT (3 equiv) did not furnish the product 3a,
indicating that the reaction proceeds through the corresponding
thioradical. Similarly, the reaction of 1a with 2a under optimal
conditions in the presence of TEMPO resulted in a decrease of
the yield of the expected product 3a to 60%.15 A tentative
mechanism has been proposed on the basis of the above studies
(Scheme 7). The benzazole-2-thio radical that has been
generated by the reaction of benzazole with K2S2O8 forms either
the corresponding disulfide or a benzazole persulfate adduct in
which the nitrogen is protonated (intermediates 1 and 2, Scheme
7). These intermediates further react with the electron-rich
aromatic system to furnish the products. However, a similar
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out using distilled
solvents. Reactions were monitored by using precoated silica TLC
plates. Mass spectra were recorded in EI and ESI (TOF) modes. NMR
spectra were recorded at 400 MHz. Column chromatography was
carried out with 100−200 mesh silica gel. Unless otherwise noted,
materials obtained from commercial suppliers were used without further
purification.
Typical Procedure for the Preparation of Benz[d]oxazole-
2(3H)-thione Derivatives Using 5-Methylbenz[d]oxazole-2(3H)-
thione (1a) as an Example.16 To a well-stirred, ice-cold solution of 2-
amino-4-methylphenol (6.15 g, 0.05 mol) and KOH or K2CO3 (0.075
mmol) in an ethanol−water mixture (1:0.5, 30 mL) was added CS2
(0.075 mol, 5.7 g, 4.5 mL) dropwise. After complete addition of CS2, the
reaction mixture was allowed to attain room temperature followed by
heating at 80 °C for 8 h. The reaction mixture was then cooled to room
temperature, water was added (50 mL), the mixture was acidified with 2
N HCl, and the solid precipitated was filtered. The crude product was
purified on a silica gel (100−200 mesh) column (EtOAc/hexane, 30:70)
to give 1a (90%, 7.4 g).
Typical Procedure for the Preparation of Naphth[1,2-
d]oxazole-2(1H)-thione (1f). To a well-stirred, ice-cold solution of
1-amino-2-naphthol hydrochloride salt (1 g, 5.1 mmol), K2CO3 (1.05 g,
5.6 mmol), and triethylamine (772 mg, 5.6 mmol) in an ethanol−water
mixture (1:0.5, 30 mL) was added CS2 (581 mg, 7.66 mmol, 0.46 mL)
dropwise. After complete addition of CS2, the reaction mixture was
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Figure 3. 1H NMR experiments: (i) 1a (4.5 mg) in CD3CN (0.5 mL); (ii) 1a (1 equiv) in TFA (5 equiv) and CD3CN (0.45 mL); (iii) 1a (41.25 mg) in
TfOH (3 equiv) and CD3CN (0.94 mL); (iv) 1a (20.5 mg) in TfOH (5 equiv) and CD3CN (0.45 mL).
a
Scheme 6. Reaction of Disulfide with Trimethoxybenzene
a
Reaction conditions: 15 (1.0 mmol), 8b (4.0 mmol).
allowed to attain room temperature followed by heating at 80 °C for 8 h.
The reaction mixture was then cooled to room temperature, water awas
dded (50 mL), the mixture was acidified with 2 N HCl, and the solid
precipitated was filtered. The crude product was purified on a silica gel
(100−200 mesh) column (EtOAc/hexane, 30:70) to give 1f (70%, 1.4
g).
Typical Procedure for the Reaction of Anisole or Phenol with
5-Methylbenz[d]oxazole-2(3H)-thione To Give 3a−3t and 5a−5i
Using 3a as an Example. To a well-stirred, ice-cold solution of 1a
(41.25 mg, 0.25 mmol), anisole17 (108 mg, 1 mmol), and K2S2O8 (202.5
mg, 0.75 mmol) in CH3CN (3 mL) was added TfOH (187.6 mg, 1.25
mmol, 0.11 mL) dropwise over 3 min. The reaction mixture was allowed
to attain room temperature followed by heating at 60 °C for 2 h. The
reaction was monitored by TLC. Upon completion of the reaction, the
reaction mixture was cooled to room temperature, water was added (50
mL), and the crude compound was extracted with DCM (20 mL × 3),
dried over Na2SO4, and purified on a silica gel column (EtOAc/
petroleum ether, 5:95) to obtain 3a (59 mg, 86%).
and stirring was continued for 12 h. The reaction was monitored by
TLC. Upon completion of the reaction, the reaction mixture was cooled
to room temperature, water was added (50 mL), and the crude
compound was extracted with DCM (20 mL × 3), dried over Na2SO4,
and purified on a silica gel column (EtOAc/petroleum ether, 3:97) to
obtain 7a (92 mg, 75%).
Note: For 2-methylthiophene (6b) and 2,5-dimethylthiophene (6c)
the reactions were carried out at 60 °C for 2 h.
Synthesis of Reference Compound 5-Methylbenz[d]oxazol-
2(3H)-one (3bb).19 To a stirred ice-cold solution of 2-amino-4-
methylphenol (10 mmol, 1.23 g) in dioxane (20 mL) was added ethyl
chloroformate (10 mmol, 1.08 g) dropwise over 4−5 min. After
complete addition of ethyl chloroformate, the reaction mixture was
allowed to attain room temperature and stirred 4 h. The reaction was
monitored by TLC. After complete conversion of starting material, the
solvent was evaporated, and 20 mL of ethanol and 10 mL of 2 N HCl
were added to the crude compound followed by reflux at 80 °C for 4 h.
The solvent was evaporated. A 20 mL volume of water was added to the
crude compound, and the crude compound was extracted with EtOAc
(20 mL × 3), dried over Na2SO4, and purified on a silica gel (100−200
mesh) column (EtOAc/hexane, 30:70) to give 3bb in 60% yield (0.894
g).
Typical Procedure for the Reaction of Thiophene with 5-
Methylbenz[d]oxazole-2(3H)-thione To Give 7a−7h Using 7a as
an Example. To a well-stirred, ice-cold solution of 1a (82.5 mg, 0.5
mmol), thiophene18 (6a; 420 mg, 5 mmol), and K2S2O8 (405 mg, 1.5
mmol) in CH3CN (3 mL) was added TfOH (375 mg, 2.5 mmol)
dropwise. The reaction mixture was allowed to attain room temperature,
1H NMR Experimental Procedure. (i) The 1H NMR spectrum of
1a (4.5 mg) in CD3CN (0.5 mL) was recorded. (ii) To a mixture of 1a
H
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Scheme 7. Proposed Mechanism
(21 mg, 0.125 mmol, 1 equiv) in CD3CN (0.45 mL) was added TFA
(0.05 mL, 0.625 mmol, 5 equiv), and 0.1 mL of this heterogeneous
solution was diluted to 0.5 mL using CD3CN. The 1H NMR spectrum
was recorded. (iii) To a mixture of 1a (41.25 mg, 0.250 mmol, 1 equiv)
in CD3CN (0.94 mL) was added TfOH (0.066 mL, 0.748 mmol, 3
equiv), and the solution turned homogeneous. The 1H NMR spectrum
was recorded. (iv) To a mixture of 1a (20.5 mg, 0.125 mmol, 1 equiv) in
CD3CN (0.45 mL) was added TfOH (0.05 mL, 0.625 mmol, 5 equiv),
129.3, 123.5, 111.2, 110.3. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd
for C7H4ClONNaS 207.9600, found 207.9600.
6-Nitrobenz[d]oxazole-2(3H)-thione (1d). 1d was prepared as
described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
3:97 to 5:95). White solid. Yield: 85% (8.33 mg). mp 235−237 °C (lit.23
234−235 °C). Rf (20% EtOAc/hexane): 0.4. IR (KBr, cm−1): 3045,
2929, 1613, 1536, 1518, 1478, 1410, 1377, 1347. 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 14.45−14.37 (br, m, 1H), 8.39 (d, J = 1.5 Hz, 1H),
8.20 (dd, J1 = 8.7 Hz, J2 = 1.6 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H). 13C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 181.9, 147.5, 143.4, 137.2, 121.7,
110.1, 106.0. MS (m/z): 196 (M+).
1
and the solution turned homogeneous. The H NMR spectrum was
recorded.
1H NMR data for 1a in CD3CN (400 MHz, CD3CN): δ (ppm) 10.96
(br s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.07−7.05 (m, 2H), 2.38 (s, 3H).
1H NMR data for 1a (21 mg, 1 equiv) and TFA (71.25 mg (0.05 mL),
5 equiv) in CD3CN (0.45 mL) (400 MHz, CD3CN): δ (ppm) 10.96 (br
s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.07−7.05 (m, 2H), 2.39 (s, 3H).
Characterization Data: Precursors 1a−1f. 5-Methylbenz[d]-
oxazole-2(3H)-thione (1a).20 1a was prepared as described in the
typical experimental procedure. The crude product was purified on a
silica gel (100−200 mesh) column (EtOAc/hexane, 30:70). White solid.
Yield: 90% (7.4 g). Mp: 224−226 °C (lit.20 220−223 °C). Rf (10%
EtOAc/hexane): 0.4. IR (KBr, cm−1): 2924, 2854, 1622, 1460, 1468. 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 13.76 (br s, 1H), 7.36 (d, J = 8.7
Hz, 1H), 7.06−7.04 (m, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 180.2, 146.3, 134.8, 131.2, 124.3, 110.5, 109.5, 20.8.
HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C8H7NNaOS 188.0146,
found 188.0147.
6-Methylbenz[d]oxazole-2(3H)-thione (1e).24 1e was prepared as
described in the typical experimental procedure. The crude product was
purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
30:70). White solid. Yield: 90% (7.4 g). Mp: 212−213 °C. Rf (10%
EtOAc/hexane): 0.3. IR (KBr, cm−1): 1628, 1500, 1425, 1218, 1156,
1099. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 13.76 (br s, 1H), 7.31
(s, 1H), 7.09 (s, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-
d6): δ (ppm) 179.7, 148.3, 133.7, 128.8, 125.7, 110.2, 109.9, 20.8. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C8H7NNaOS 188.0146, found
188.0142.
Naphth[1,2-d]oxazole-2(1H)-thione (1f). 1f was prepared as
described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
3:97 to 5:95). White solid. Yield: 70% (1.4 g). Mp: 238−241 °C (lit.25
248 °C). Rf (10% EtOAc/hexane): 0.5. IR (KBr, cm−1): 2923, 2854,
1508, 1490, 1458. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 14.60 (br
s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.9
Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5
Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 179.5, 145.2,
130.5, 128.8, 127.4, 126.1, 125.8, 124.5, 121.2, 118.8, 110.4. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C11H7NNaOS 224.0146, found
224.0148.
Characterization Data: Products. 2-((4-Methoxyphenyl)thio)-5-
methylbenz[d]oxazole (3a). 3a was prepared as described in the typical
experimental procedure. Colorless liquid. Yield: 86% (58 mg). Rf (5%
EtOAc/hexane): 0.25. IR (neat, cm−1): 1593, 1492, 1480, 1251, 1146,
842. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.62 (d, J = 8.7 Hz, 2H),
7.36 (s, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.97 (d, J
= 8.7 Hz, 2H), 3.84 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 164.1, 161.1, 150.1, 142.2, 136.6, 134.0, 125.0, 118.9,
117.2, 115.2, 109.2, 55.3, 21.4. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C15H14NO2S 272.0745, found 272.0745.
Benz[d]oxazole-2(3H)-thione (1b).21 1b was prepared as described
in the typical experimental procedure. The crude product was purified
on a silica gel (100−200 mesh) column (EtOAc/hexane, 30:70). White
solid. Yield: 90% (6.75 g). Mp: 195−197 °C (lit.21 191 °C). Rf (10%
EtOAc/hexane): 0.4. IR (KBr, cm−1): 1616, 1507, 1447, 1420, 1131. 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 13.9 (br s, 1H), 7.50 (d, J = 7.6
Hz, 1H), 7.31−7.23 (m, 3H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
(ppm) 180.1, 148.1, 131.2, 125.2, 123.8, 110.5, 110.1. HRMS (ESI-
TOF) (m/z): [M + Na]+ calcd for C7H5NNaOS 173.9990, found
173.9994.
5-Chlorobenz[d]oxazole-2(3H)-thione (1c).20 1c was prepared as
described in the typical experimental procedure. The crude product was
purified on a silica gel (100−200 mesh) column (EtOAc/hexane, 3:97
to 5:95). White solid. Yield: 85% (7.82 g). Mp: 270−272 °C (lit.22 268
°C). Rf (10% EtOAc/hexane): 0.2. IR (KBr, cm−1): 3098, 3061, 1607,
1
1513, 1455, 1462, 1422, 1264. H NMR (400 MHz, DMSO-d6): δ
(ppm) 14.01 (br s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.06−7.04(m, 2H).
13C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 180.7, 146.9, 132.5,
I
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2-((4-Methoxyphenyl)thio)benz[d]oxazole (3b).5d 3b was prepared
as described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
3:97 to 5:95). Colorless solid. Yield: 54% (69 mg). Mp: 48−50 °C. Rf
(10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1590, 1494, 1453, 1249. 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.63 (2H, d, J = 8.9 Hz), 7.57 (1H,
d, J = 6.3 Hz), 7.40−7.38 (1H, m), 7.26−7.21 (2H, m), 6.97 (2H, d, J =
8.8 Hz), 3.84 (3H, s). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
164.4, 161.2, 151.8, 142.0, 136.7, 124.2, 124.0, 118.9, 116.9, 115.3, 109.9,
55.4. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C14H12NO2S
258.0559, found 258.0585.
5-Chloro-2-((4-methoxyphenyl)thio)benz[d]oxazole (3c). 3c was
prepared as described in the typical experimental procedure. Colorless
liquid. Yield: 63% (46 mg). Rf (20% EtOAc/hexane): 0.4. IR (KBr,
cm−1): 1679, 1521, 1250, 1129,1019. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.62 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.6
Hz, 1H), 7.18 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H),
3.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 166.2, 161.3,
150.4, 143.1, 136.8, 129.7, 124.1, 118.8, 116.4, 115.3, 110.5, 55.4. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C14H10ClNNaO2S 314.0018,
found 314.0020.
2-((4-Methoxyphenyl)thio)-6-nitrobenz[d]oxazole (3d). 3d was
prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90). Brown solid. Yield: 48% (36 mg). Mp: 120−
122 °C. Rf (10% EtOAc/hexane): 0.2. IR (KBr, cm−1): 1597, 1494,
1338, 1299, 1255, 1133. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.31 (d,
J = 2.0 Hz, 1H), 8.23 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.65−7.61 (m,
3H), 7.02 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 170.7, 161.6, 150.9, 147.3, 144.1, 137.0, 120.7, 118.4,
115.5, 115.4, 106.3, 55.4. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C14H11N2O4S 303.0440, found 303.0444.
(EtOAc/hexane, 10:90 to 15:85). White solid. Yield: 83% (69 mg). Mp:
136−138 °C. Rf (20% EtOAc/hexane): 0.5. IR (KBr, cm−1): 1506, 1347,
1262, 1233, 1135. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.31 (d, J = 1.8
Hz, 1H), 8.23 (dd, J1 = 6.8 Hz, J2 = 1.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H),
7.32 (dd, J1 = 6.4 Hz, J2 = 1.8 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.98 (d, J
= 8.4 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 170.6, 151.3, 150.9, 149.6, 147.3, 144.1, 128.8, 120.7,
118.4, 117.8, 115.4, 111.8, 106.4, 56.1, 56.0. HRMS (ESI-TOF) (m/z):
[M + Na]+ calcd for C15H12N2NaO5S 355.0365, found 355.0367.
2-((2,4-Dimethoxyphenyl)thio)benz[d]oxazole (3i). 3i was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 5:95 to 10:90). Faint yellow solid. Yield: 95% (137 mg). Mp:
88−90 °C. Rf (10% EtOAc/hexane): 0.3. IR (KBr, cm−1): 1600, 1470,
1452, 1306, 1286, 1209. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60−
7.56 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.25−7.17 (m, 2H), 6.58−6.56
(m, 2H), 3.85 (s, 3H), 3.80 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ (ppm) 164.2, 163.3, 160.9, 151.8, 142.2, 137.8, 124.1, 123.7, 118.8,
109.8, 105.64, 105.60, 99.6, 56.0, 55.5. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C15H13NNaO3S 310.0514, found 310.0517.
2-((2,3,4-Trimethoxyphenyl)thio)benz[d]oxazole (3j). 3j was pre-
pared as described in the typical experimental procedure. Yellow liquid.
Yield: 85% (79 mg). Rf (10% EtOAc/hexane): 0.3. IR (KBr, cm−1):
1557, 1408, 1295, 1237, 1223. 1H NMR (400 MHz, CDCl3): δ (ppm)
7.58 (d, J = 7.3 Hz, 1H), 7.42−7.39 (m, 2H), 7.26−7.20 (m, 2H), 6.75
(d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 164.0, 156.2, 154.7, 151.8, 143.0,
142.1, 131.0, 124.2, 123.9, 118.8, 112.0, 109.9, 107.8, 61.3, 60.1, 56.4.
HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C16H15NNaO4S
340.0619, found 340.0620.
5-Chloro-2-((2,3,4-trimethoxyphenyl)thio)benz[d]oxazole (3k). 3k
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90). White solid. Yield: 90% (85 mg). Mp: 68.5−
69.5 °C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1578, 1482,
1451, 1297, 1143, 1039. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.54 (d,
J = 1.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.18
(dd, J1 = 8.7 Hz, J2 = 1.9 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H),
3.90 (s, 3H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
165.9, 156.4, 154.7, 150.4, 143.2, 143.0, 131.0, 129.7, 124.0, 118.8, 111.3,
110.5, 107.8, 61.3, 60.9, 56.0. HRMS (ESI-TOF) (m/z): [M + Na]+
calcd for C16H14ClNNaO4S 374.0230, found 374.0229.
2-(Benzo[d][1,3]dioxol-5-ylthio)benz[d]oxazole (3l). 3l was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 10:90 to 15:85). White solid. Yield: 37% (50 mg). Mp: 83−85
°C. Rf (20% EtOAc/hexane): 0.25. IR (KBr, cm−1): 1612, 1480, 1243,
930. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 (d, J = 7.2 Hz, 1H),
7.40 (d, J = 7.68 Hz, 1H), 7.27−7.20 (3H, m), 7.15 (s, 1H), 6.86 (d, J =
8.0 Hz, 1H), 6.04 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
164.0, 151.8, 149.6, 148.4, 141.9, 129.5, 124.3, 124.1, 118.9, 118.2, 115.0,
109.9, 109.2, 101.8. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C14H9NNaO3S 294.0201, found 294.0204.
2-((3,4-Dimethoxyphenyl)thio)-5-methylbenz[d]oxazole (3e). 3e
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 5:95 to 10:90). White solid. Yield: 89% (67 mg). Mp:
111.5−112.5 °C. Rf (10% EtOAc/hexane): 0.25. IR (KBr, cm−1): 1583,
1
1508, 1497, 1480, 1466, 1263, 1231. H NMR (400 MHz, CDCl3): δ
(ppm) 7.30 (s, 1H), 7.28−2.26 (m, 2H), 7.18 (1H, s), 7.03 (d, J = 8.2
Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.4 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 163.9, 150.7, 150.1, 149.4,
142.2, 134.1, 128.3, 125.1, 119.0, 117.6, 117.3, 111.7, 109.3, 56.0, 55.9,
21.4. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C16H15NNaO3S
324.0670, found 324.0695.
2-((3,4-Dimethoxyphenyl)thio)benz[d]oxazole (3f). 3f was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 5:95 to 10:90). White solid. Yield: 87% (125 mg). Mp: 86−88
°C. Rf (10% EtOAc/hexane): 0.3. IR (KBr, cm−1): 1583, 1497, 1262,
1229, 1129. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 (d, J = 7.0 Hz,
1H), 7.42−7.40 (m, 1H), 7.31 (dd, J1 = 8.2 Hz, J2 = 1.5 Hz, 1H), 7.28−
7.22 (m, 2H), 7.19 (d, J = 1.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.93 (s,
3H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 164.2,
151.8, 150.8, 149.4, 142.0, 128.4, 124.3, 124.1, 118.9, 117.7, 117.1, 111.7,
109.9, 56.0, 55.9. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C15H13NNaO3S 310.0514, found 310.0512.
5-Chloro-2-((3,4-dimethoxyphenyl)thio)benz[d]oxazole (3g). 3g
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 5:95 to 10:90). White solid. Yield: 82%. Mp: 112−114
°C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1588, 1509, 1496,
1252, 1261, 1239. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.55 (d, J = 1.8
Hz, 1H), 7.32−7.28 (m, 2H), 7.21−7.17 (m, 2H), 6.94 (d, J = 8.5 Hz,
1H), 3.94 (s, 3H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 166.1, 151.0, 150.4, 149.5, 143.1, 129.8, 128.5, 124.2, 118.9,
117.7, 116.5, 111.8, 110.5, 56.1, 55.9. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C15H12ClNNaO3S 344.0124, found 344.0126.
2-((4-Methoxy-2,6-dimethylphenyl)thio)benz[d]oxazole (3m). 3m
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 3:97 to 5:95). Yellow solid. Yield: 90% (65 mg). Mp:
62−64 °C. Rf (5% EtOAc/hexane): 0.5. IR (KBr, cm−1): 1638, 1125,
1093, 1030. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.57−7.55 (m, 1H),
7.39−7.37 (m, 1H), 7.24−7.20 (m, 2H), 6.77 (s, 2H), 3.82 (s, 3H), 2.49
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 163.8, 160.9,
151.8, 145.4, 142.2, 124.1, 123.7, 124.1, 118.7, 116.5, 114.2, 109.8, 55.1,
22.2. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C16H15NNaO2S
308.0721, found 308.0724.
2-((4-Methoxy-2,3-dimethylphenyl)thio)-5-methylbenz[d]oxazole
(3n). 3n was prepared as described in the typical experimental
procedure. The crude product was purified on a silica gel (100−200
mesh) column (EtOAc/hexane, 3:97). faint yellow solid. Yield: 95% (71
mg). Mp: 120−123 °C. Rf (5% EtOAc/hexane): 0.4. IR (KBr, cm−1):
1575, 1498, 1262, 1139, 1095. 1H NMR (400 MHz, CDCl3): δ (ppm)
2-((3,4-Dimethoxyphenyl)thio)-6-nitrobenz[d]oxazole (3h). 3h
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
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The Journal of Organic Chemistry
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7.57 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.00 (d, J
= 8.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 2.40
(s, 3H), 2.2 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 164.4,
159.4, 150.1, 142.39, 142.36, 135.0, 133.9, 127.0, 124.7, 118.8, 117.0,
109.2, 108.5, 55.5, 21.6, 18.0, 12.7. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C17H17NNaO2S 322.0878, found 322.0883.
7.04−7.02 (m, 2H), 2.74 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 165.6, 150.2, 142.1, 134.0, 124.7, 118.3, 109.2,
21.4, 14.5. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C9H10NOS180.0483, found 180.0482.
Reference Compound 5-Methylbenz[d]oxazol-2(3H)-one (3bb).27
White solid. Yield: 60% (8.94 g). Mp: 129−131 °C (lit.28 130−131 °C).
Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 2926, 1791, 1737, 1459,
1498. 1H NMR (400 MHz, CDCl3): δ (ppm) 9.82 (br s, 1H), 7.08 (d, J
= 8.1 Hz, 1H), 6.94−6.90 (m, 2H), 2.37 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 156.6, 141.9, 134.2, 129.4, 123.1, 110.7, 109.6,
21.4. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C8H7NNaO2
172.0372, found 172.0374.
2-((4-Methoxy-2,3-dimethylphenyl)thio)-6-methylbenz[d]oxazole
(3o). 3o was prepared as described in the typical experimental
procedure. The crude product was purified on a silica gel (100−200
mesh) column (EtOAc/hexane, 3:97). Faint yellow solid. Yield: 95%
(71 mg). Mp: 110−112 °C. Rf (5% EtOAc/hexane): 0.4. IR (KBr,
cm−1):1576, 1508, 1262, 1210, 1087. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.56 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.19 (s, 1H),
7.04 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 3.85 (m, 3H), 2.43 (s,
3H), 2.42 (s, 3H), 2.2 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 163.7, 159.3, 152.1, 142.3, 139.9, 134.9, 134.1, 127.0, 125.2,
118.2, 117.0, 110.2, 108.5, 55.5, 21.6, 18.0, 12.7. HRMS (ESI-TOF) (m/
z): [M + Na]+ calcd for C17H17NNaO2S 322.0878, found 322.0877.
2-((3,4-Dimethoxyphenyl)thio)naphth[2,3-d]oxazole (3p). 3p was
prepared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 10:90). Orange solid. Yield: 52% (84 mg). Mp: 93−95 °C. Rf
(20% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1582, 1506, 1496, 1377,
1259, 1230, 1130, 1003, 1011. 1H NMR (400 MHz, CDCl3): δ (ppm)
8.43 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.9 Hz,
1H), 7.63−7.49 (m, 3H), 7.34 (dd, J1 = 8.3 Hz, J2 = 1.8 Hz, 1H), 7.26 (s,
1H), 6.93 (d, J = 8.4 Hz, 1H), 3.93−3.90 (m, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 161.7, 150.6, 149.4, 149.3, 137.5, 131.0, 128.4,
127.9, 126.9, 125.7, 125.4, 125.2, 122.1,118.1, 117.4, 111.7, 110.4, 56.1,
56.0. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C19H15NNaO3S
(M+ + Na): 360.0669, found 360.0670.
2-((3,4-Dimethoxyphenyl)thio)benzo[d]thiazole (3r). 3r was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 10:90 to 15:85). White solid. Yield: 28% (42 mg). Mp: 101−102
°C. Rf (20% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1582, 1502, 1426,
1255, 1235, 1135. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.86 (d, J = 8.2
Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.41−7.33 (m, 2H), 7.27−7.21 (m,
2H), 6.95 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 171.6, 154.0, 151.2, 149.7, 135.3, 129.1,
126.0, 124.1, 121.7, 120.7, 120.2, 118.1, 111.8, 56.0, 55.9. HRMS (ESI-
TOF) (m/z): [M + Na]+ calcd for C15H13NNaO2S2 326.0285, found
326.0282.
4-((5-Methylbenz[d]oxazol-2-yl)thio)phenol (5a). 5a was prepared
as described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
5:95 to 15:85). White solid. Yield: 68% (44 mg). Mp: 185−186 °C. Rf
(20% EtOAc/hexane): 0.4. IR (KBr, cm−1): 3233, 1588, 1491, 1460,
1
1230, 1153, 1091. H NMR (400 MHz, CDCl3): δ (ppm) 9.30 (br s,
1H), 7.42 (d, J = 8.2 Hz, 2H), 7.36−7.34 (m, 2H), 7.08 (d, J = 8.2 Hz,
1H), 6.68 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 167.6, 159.6, 150.0, 140.8, 137.2, 134.7, 125.4, 117.83,
117.80, 114.0, 109.55, 21.3. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd
for C14H12NNaO2S 258.0589, found 258.0590.
4-((5-Chlorobenz[d]oxazol-2-yl)thio)phenol (5b). 5b was prepared
as described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
5:95 to 15:85). Brown crystalline solid. Yield: 84% (58 mg). Mp: 190−
192 °C. Rf (20% EtOAc/hexane): 0.4. IR (KBr, cm−1): 3437, 1618,
1460, 1286. 1H NMR (400 MHz, DMSO): δ (ppm) 10.16 (br s, 1H),
7.69 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.33−7.31
(m, 1H), 6.90 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO): δ
(ppm) 165.9, 159.7, 150.1, 142.7, 137.1, 128.9, 124.3, 118.3, 116.9,
113.3, 115.5. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C13H8NNaO2SCl 299.9862, found 299.9863.
4-(Benz[d]oxazol-2-ylthio)-2,6-dimethylphenol (5c). 5c was pre-
pared as described in the typical experimental procedure. Pale yellow
solid. The crude product was purified on a silica gel (100−200 mesh)
column (EtOAc/hexane, 5:95 to 10:90). Yield: 89% (60 mg). Mp: 210−
212 °C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 3413, 1649,
1507, 1452, 2452, 1320, 1257, 1204. 1H NMR (400 MHz, DMSO): δ
(ppm) 8.93 (s, 1H), 7.61−7.57 (m, 2H), 7.30−7.28 (m, 4H), 2.19 (s,
6H). 13C{1H} NMR (100 MHz, DMSO): δ (ppm) 163.9, 155.6, 151.2,
141.4, 135.2, 126.0, 124.6, 124.4, 118.5, 113.6, 110.3, 16.4. HRMS (ESI-
TOF) (m/z): [M + Na]+ calcd for C15H13NNaO2S 294.0565, found
294.0563.
4-((5-Chlorobenz[d]oxazol-2-yl)thio)-2,6-dimethylphenol (5d). 5d
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90). Cream-colored solid. Yield: 79% (60 mg). Mp:
216−218 °C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 3448, 1648,
1475, 1253, 1133. 1H NMR (400 MHz, DMSO): δ (ppm) 8.95 (br s,
1H), 7.69 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.32−7.30 (m, 3H), 2.18 (s,
6H). 13C{1H} NMR (100 MHz, DMSO): δ (ppm) 166.1, 155.8, 150.0,
142.7, 135.3, 128.8, 126.0, 124.2, 118.2, 113.0, 111.5, 16.4. HRMS (ESI-
TOF) (m/z): [M + Na]+ calcd for C15H12ClNNaO2S 328.0175, found
328.0175.
2-((2,3,4-Trimethoxyphenyl)thio)benzo[d]thiazole (3s). 3s was
prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90). White solid. Yield: 52% (43 mg). Mp: 108−
110 °C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1455, 1424,
1294, 1088, 1004. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.85 (d, J = 8.2
Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.39 (dd, J1=
J2= 7.7 Hz, 1H), 7.25 (dd, J1 = J17= 0.9 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H),
3.94 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 171.3, 156.7, 155.2, 154.1, 143.2, 135.4, 132.3, 126.0,
124.0, 121.7, 120.7, 114.8, 107.9, 61.7, 61.0, 56.1. HRMS (ESI-TOF)
(m/z): [M + Na]+ calcd for C16H15NNaO3S 356.0391, found 356.0415.
5-Methyl-2-((4-(methylthio)phenyl)thio)benz[d]oxazole (3t). 3t
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 3:97 to 5:95). White solid. Yield: 79% (57 mg). Mp:
69−70 °C. Rf (5% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1645, 1507,
1253,1147. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 (d, J = 8.3 Hz,
2H), 7.38 (s, 1H), 7.29−7.26 (m, 3H), 7.04 (d, J = 8.2 Hz, 1H), 2.51 (s,
3H), 2.42 (s, 3H) 3.83 (3H, s). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 163.3, 150.1, 142.1, 141.7, 134.9, 134.2, 126.8, 125.2, 122.6,
119.0, 109.3, 21.4, 15.2. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C15H13NNaOS2 310.0336, found 310.0336.
3,5-Dimethyl-4-((5-methylbenz[d]oxazol-2-yl)thio)phenol (5e). 5e
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90). White solid. Yield: 72% (52 mg). Mp: 248−
250 °C. Rf (20% EtOAc/hexane): 0.3. IR (KBr, cm−1): 3473, 3123,
2922, 1590, 1463, 1313, 1257, 1152, 1105, 1023. 1H NMR (400 MHz,
DMSO): δ (ppm) 10.07 (br, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H),
7.04 (d, J = 8.2 Hz, 1H), 6.67 (s, 2H), 2.32 (s, 3H), 2.29 (s, 6H).
13C{1H} NMR (100 MHz, DMSO): δ (ppm) 163.6, 159.5, 149.9, 145.3,
141.9, 134.5, 125.5, 118.6, 116.1, 114.3, 109.9, 21.9, 21.2. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C16H16NO2S 286.0902, found
286.0902.
5-Methyl-2-(methylthio)benz[d]oxazole (3aa, Table 1, Entry 21).26
Yellow liquid. Yield: 42% (19 mg). White semisolid. Rf (10% EtOAc/
hexane): 0.4. IR (KBr, cm−1): 1499, 1477, 1255, 1153. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.3855 (d, J = 0.6 Hz, 1H), 7.30−7.26 (m, 1H),
4-(Benz[d]oxazol-2-ylthio)-2,6-di-tert-butylphenol (5f). 5f was
prepared as described in the typical experimental procedure. The
K
dx.doi.org/10.1021/jo501793q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 5:95). Faint yellow solid. Yield: 82% (71 mg). Mp: 96−
98 °C. Rf (10% EtOAc/hexane): 0.6. IR (KBr, cm−1): 3448, 1615, 1451,
1223. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 (d, J = 7.4 Hz, 1H),
7.50 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.25−7.20 (m, 2H), 5.50 (br s,
1H), 1.45 (s, 18H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 164.5,
155.6, 151.8, 142.2, 137.2, 132.0, 124.2, 123.9, 118.9, 116.0, 109.9, 34.5,
30.1. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C21H26NO2S
356.1684, found 356.1684.
2,6-Di-tert-butyl-4-((6-methylbenz[d]oxazol-2-yl)thio)phenol
(5g). 5g was prepared as described in the typical experimental
procedure. The crude product was purified on a silica gel (100−200
mesh) column (EtOAc/hexane, 2:98). Yellow solid. Yield: 77% (71
mg). Mp: 146−148 °C. Rf (5% EtOAc/hexane): 0.8. IR (KBr, cm−1):
3432, 1641, 1504, 1260, 1213. 1H NMR (400 MHz, CDCl3): δ (ppm)
7.49 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.21 (s, 1H), 7.06 (d, J = 8.0 Hz,
1H), 5.48 (br, 1H), 2.43 (s, 3H), 1.45 (s, 18H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 163.3, 155.5, 152.1, 139.9, 137.1, 134.3, 131.9,
125.3, 118.2, 116.3, 110.2, 34.5, 30.1, 21.6. HRMS (ESI-TOF) (m/z):
[M + Na]+ calcd for C22H27NNaO2S 392.1660, found 392.1660.
4-((5-Methylbenz[d]oxazol-2-yl)thio)benzene-1,2-diol (5h). 5h
was prepared as described in the typical experimental procedure.
White solid. Yield: 72% (49 mg). Mp: 208−210 °C. Rf (30% EtOAc/
hexane): 0.4. IR (KBr, cm−1): 3507, 3468, 1596, 1507, 1492, 1479, 1281,
1257. 1H NMR (400 MHz, DMSO): δ (ppm) 9.61(br s, 1H), 9.47 (br s,
1H), 7.47 (d, J = 8.3 Hz, 1H), 7.39 (s, 1H), 7.10−7.06 (m, 2H), 6.99 (dd,
J1 = 8.2 Hz, J2 = 2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 2.37 (s, 3H).
13C{1H} NMR (100 MHz, DMSO): δ (ppm) 163.6, 149.5, 148.0, 146.2,
(EtOAc/hexane, 3:97 to 5:95). Dark brown liquid. Yield: 72% (94 mg).
Rf (5% EtOAc/hexane): 0.5. IR (neat, cm−1): 1781, 1498, 1479, 1256,
1145, 1100. 1H NMR (400 MHz, CDCl3): δ (ppm) 740 (s, 1H), 7.29−
7.26 (m, 2H), 7.04 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 2.54 (s,
3H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 163.1,
150.1, 148.1, 142.0, 138.1, 134.1, 126.4, 125.2, 119.6, 119.0, 109.4, 21.4,
15.8. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C13H11NNaOS2
284.0182, found 284.0180.
2-((5-Methylthiophene-2-yl)thio)benz[d]oxazole (7d). 7d was
prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 3:97 to 5:95). Dark brown liquid. Yield: 80% (50 mg).
Rf (5% EtOAc/hexane): 0.45. IR (neat, cm−1): 1783, 1498, 1451, 1238,
1127. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.61 (dd, J1 = 6.7 Hz, J2 =
2.0 Hz, 1H), 7.41 (dd, J1 = 6.8 Hz, J2 = 2.0 Hz, 1H), 7.27−7.20 (m, 3H),
6.79 (d, J = 2.7 Hz, 1H), 2.53 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 163.3, 151.9, 148.3, 141.9, 138.2, 126.4, 124.3, 124.2,
119.5, 119.1, 110.0, 15.9. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C12H9NNaOS2 (M+ + Na): 270.0023, found 270.0023.
2-((2,5-Dimethylthiophene-3-yl)thio)-5-methylbenz[d]oxazole
(7e). 7e was prepared as described in the typical experimental procedure.
The crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 3:97 to 5:95). Dark brown liquid. Yield: 74% (102 mg).
Rf (5% EtOAc/hexane): 0.6. IR (KBr, cm−1): 1503, 1479, 1255, 1144,
1100. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.4 (s, 1H), 7.27 (d, J = 8.3
Hz, 1H), 7.02 (dd, J1 = 8.3 Hz, J2 = 1.1 Hz, 1H), 6.78 (d, J = 0.9 Hz, 1H),
2.48 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 163.1, 150.1, 143.6, 142.2, 136.6, 134.0, 129.8, 124.9,
118.9, 116.8, 109.3, 21.4, 15.3, 14.2. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C14H13NNaOS2 298.0336, found 298.0340.
141.6, 134.0, 126.8, 125.3, 122.0, 118.4, 116.6, 113.8, 109.7, 20.9. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C14H11NNaO3S 296.0357,
found 296.0358.
2-(Benzo[b]thiophene-3-ylthio)-5-methylbenz[d]oxazole (7f). 7f
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 3:97). Yellow solid. Yield: 72% (54 mg). Mp: 96−98
°C. Rf (5% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1503, 1477, 1252,
1143, 1099. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.0 (s, 1H), 7.92−
7.86 (m, 2H), 7.43−7.41 (m, 2H), 7.35 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H),
7.01 (d, J = 8.2 Hz, 1H), 2.40 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 161.9, 150.1, 142.1, 139.6, 138.8, 134.8, 134.3, 125.3,
125.2, 125.1, 122.9, 122.7, 119.0, 117.2, 109.4, 21.4. HRMS (ESI-TOF)
(m/z): [M + Na]+ calcd for C16H11NNaOS2 320.0180, found 320.0179.
2-(Benzo[b]thiophene-3-ylthio)benz[d]oxazole (7g). 7g was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 3:97 to 5:95). yellow solid. Yield: 61% (87 mg). Mp: 128−129
°C. Rf (5% EtOAc/hexane): 0.5. IR (KBr, cm−1): 1633, 1502, 1453,
1238, 1127. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.01 (s, 1H), 7.93−
7.87 (m, 2H), 7.56 (d, J = 7.2 Hz, 1H) 7.43−7.40 (m, 2H), 7.33 (d, J =
7.8 Hz, 1H), 7.24−7.18 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 162.1, 151.8, 141.9, 139.6, 138.8, 135.0, 125.2, 125.1, 124.4,
124.2, 123.0, 122.7, 119.0, 117.0, 110.0. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C15H9NNaO2S2 306.0025, found 306.0023.
2-(Benzo[b]thiophene-3-ylthio)naphth[2,3-d]oxazole (7h). 7h was
prepared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 3:97 to 5:95). Cream-colored solid. Yield: 23% (19 mg). Mp:
137−139 °C. Rf (5% EtOAc/hexane): 0.5. IR (KBr, cm−1): 1636, 1457,
1383, 1374, 1142. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.41 (d, J = 8.2
Hz, 1H), 8.05 (s, 1H), 7.96−7.98 (m, 3H), 7.67 (d, J = 8.9 Hz, 1H), 7.60
(dd, J1 = J2 = 7.3 Hz, 1H), 7.52−7.47 (m, 2H), 7.45−7.42 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 159.9, 149.3, 139.6, 138.9,
4-(Benz[d]oxazol-2-ylthio)benzene-1,2-diol (5i).6a 5i was prepared
as described in the typical experimental procedure. The crude product
was purified on a silica gel (100−200 mesh) column (EtOAc/hexane,
30:70). Cream-colored solid. Yield: 62% (80 mg). Mp: 158−160 °C
(lit.6a 155−157 °C). Rf (30% EtOAc/hexane): 0.25. IR (KBr, cm−1):
3537, 3450, 2924, 1597, 1508, 1497, 1454, 1334,1280, 1239, 1132, 1113.
1H NMR (400 MHz, DMSO): δ (ppm) 9.57 (br s, 1H), 9.48 (br s, 1H),
7.62−7.59 (m, 2H), 7.31−7.30 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 7.01
(dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 1H), 6.87−6.86 (d, J = 8.2 Hz, 1H).
13C{1H} NMR (100 MHz, DMSO): δ(ppm) 163.7, 151.3, 148.0, 146.2,
141.4, 126.8, 124.6, 124.4, 122.1, 118.5, 116.6, 113.7, 110.2. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C13H9NNaO3S 282.0201,
found 282.0198.
5-Methyl-2-(thiophene-2-ylthio)benz[d]oxazole (7a). 7a was pre-
pared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 3:97 to 5:95). Colorless crystalline solid. Yield: 75% (92 mg).
Mp: 85−87 °C. Rf (5% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1637,
1491, 1254, 1146. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60 (dd, J1
=5.3 Hz, J2 =0.8 Hz, 1H), 7.48−7.47 (m, 1H), 7.39 (s, 1H), 7.28 (d, J =
8.4 Hz, 1H), 7.13 (dd, J1 =5.3 Hz, J2 =3.7 Hz, 1H), 7.04 (d, J = 8.2 Hz,
1H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 162.6,
150.2, 142.0, 137.7, 134.3, 133.0, 128.0, 125.4, 123.2, 119.2, 109.4, 21.4.
HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C12H9NNaOS2
270.0023, found 270.0035.
2-(Thiophene-2-ylthio)benz[d]oxazole (7b). 7b was prepared as
described in the typical experimental procedure. The crude product was
purified on a silica gel (100−200 mesh) column (EtOAc/hexane, 3:97
to 5:95). Colorless solid. Yield: 52% (60 mg). Mp: 85−87 °C. Rf (5%
EtOAc/hexane): 0.4. IR (KBr, cm−1): 1638, 1460, 1375. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.63−7.60 (m, 2H), 7.49−7.48 (m, 1H), 7.22
(dd, J1 = 6.6 Hz, J2 = 1.9 Hz, 1H), 7.28−7.24 (m, 2H), 7.16−7.14 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 162.8, 151.9, 141.9,
137.8, 133.1, 128.1, 124.45, 124.38, 123.0, 119.2, 110.1. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C11H8NOS2234.0047, found
234.0048.
137.4, 134.5, 131.0, 128.4, 127.0, 125.7, 125.4, 125.3, 125.2, 125.1, 122.9,
122.8, 122.1, 117.7, 110.4. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd
for C19H11NNaOS2 356.0180, found 356.0182.
2-((2,5-Dimethoxyphenyl)thio)-5-methylbenz[d]oxazole (9). 9 was
prepared as described in the typical experimental procedure. The crude
product was purified on a silica gel (100−200 mesh) column (EtOAc/
hexane, 5:95 to 10:90). White solid. Yield: 38% (57 mg). Mp: 116−118
°C. Rf (10% EtOAc/hexane): 0.4. IR (KBr, cm−1): 1499, 1480, 1278,
1224, 1142. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.39 (s, 1H), 7.26
5-Methyl-2-((5-methylthiophene-2-yl)thio)benz[d]oxazole (7c).
7c was prepared as described in the typical experimental procedure.
The crude product was purified on a silica gel (100−200 mesh) column
L
dx.doi.org/10.1021/jo501793q | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(d, J = 8.0 Hz, 1H), 7.23 (d, J = 2.9 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H),
6.98 (dd, J1 = 9.0 Hz, J2 = 2.9 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 162.7, 153.6, 153.4, 150.1, 142.3, 134.0, 125.1, 120.5, 119.0,
116.9, 116.3, 112.8, 109.3, 56.7, 55.8, 21.4. HRMS (ESI-TOF) (m/z):
[M + Na]+ calcd for C16H15NNaO3S 324.0670, found 324.0670.
5-Methyl-2-((2,4,6-trimethoxyphenyl)thio)benz[d]oxazole (10a).
10a was prepared as described in the typical experimental procedure.
The crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 20:80). White solid. Yield: 80% (66 mg). Mp: 164−
166 °C. Rf (20% EtOAc/hexane): 0.5. IR (KBr, cm−1): 1600, 1583,
1493, 1234, 1148, 1126. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34 (s,
1H), 7.22 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.98 (s, 2H), 3.87
(s, 3H), 3.81 (s, 6H), 2.4 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 164.3, 163.6, 162.0, 150.1, 142.6, 133.6, 124.3, 118.6, 109.1, 94.1,
91.4, 56.3, 55.4, 21.4. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C17H17NNaO4S 354.0776, found 354.0776.
6-Nitro-2-((2,4,6-trimethoxyphenyl)thio)benz[d]oxazole (10b).
10b was prepared as described in the typical experimental procedure.
The crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 20:80). Faint yellow solid. Yield: 81% (73 mg). Mp:
164−166 °C. Rf (20% EtOAc/hexane): 0.2. IR (KBr, cm−1): 1594, 1489,
1339, 1232, 1113. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (d, J = 1.9
Hz, 1H), 8.20 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H),
6.24 (s, 2H), 3.89 (s, 3H), 3.84 (s, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 170.8, 164.3, 162.0, 150.8, 147.9, 143.8, 120.5, 117.9,
106.1, 92.3, 91.4, 56.3, 55.5. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd
for C16H14N2NaO6S 385.0470, found 385.0469.
7.16 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz,
1H), 3.78 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, DMSO): δ
(ppm) 163.6, 149.5, 149.0, 148.3, 141.7, 134.0, 128.7, 125.2, 118.7,
118.4, 116.4, 114.0, 109.7, 55.8, 20.9. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C15H13NNaO3S 310.0514, found 310.0524.
Bis(benzo[d]thiazol-2-yl)sulfane (17).29 White solid. Yield: 27% (81
mg). Mp: 101−102 °C (lit.28 103−104 °C). Rf (10% EtOAc/hexane):
0.5. IR (KBr, cm−1): 2364, 1636, 1410, 1237, 1010, 991, 754. 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.04 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 7.8
Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 159.9, 152.8, 136.5, 126.6, 125.6, 122.9,
121.2. MS (m/z): 300 (M+).
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C spectra and spectral data for all compounds, plausible
mechanisms for the formation of 3aa and 16, ORTEP diagrams
and crystallographic data for 7a, 7g, and 15, and CIF data for 7a,
7g, and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: prabhu@orgchem.iisc.ernet.in. Phone: +91-80-
22932887. Fax: +91-80-23600529.
■
Notes
2-((2,4,6-Trimethoxyphenyl)thio)benzo[d]thiazole (11a).5e 11a
was prepared as described in the typical experimental procedure. The
crude product was purified on a silica gel (100−200 mesh) column
(EtOAc/hexane, 10:90 to 15:85). White solid. Yield: 33% (55 mg). Mp:
120−122 °C (lit.5e 88−89 °C). Rf (20% EtOAc/hexane): 0.3. IR (KBr,
cm−1): 1597, 1581, 1454, 1426, 1230,1123. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.83 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.6 Hz, 1H),
7.35 (dd, J1 = J2 = 7.5 Hz, 1H), 7.20 (dd, J1 = J2 = 7.5 Hz, 1H), 6.23 (s,
2H), 3.90 (s, 3H), 3.84 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 172.8, 164.3, 162.5, 154.6, 135.3, 125.7, 123.5, 121.4, 120.5, 97.2,
91.1, 56.3, 55.5. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C16H15NNaO3S2 356.0391, found356.0391.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. P. Balaram on the occasion of his
65th birthday. Financial support from IISc CSIR, New Delhi
(Grant 01(2415)/10/EMR-II), and RL Fine Chem is gratefully
acknowledged. We thank Prof. T. N. Guru Row, Mr. M. S. Pavan,
and Mr. A. Hosamani for their help with the X-ray crystal
structure determination and Dr. A. R. Ramesha for useful
discussion. B.V.V. thanks CSIR for a senior fellowship.
2,2′-((2,4,6-Trimethoxy-1,3-phenylene)bis(sulfanediyl))bis(benzo-
[d]thiazole) (11b). 11b was prepared as described in the typical
experimental procedure. The crude product was purified on a silica gel
(100−200 mesh) column (EtOAc/hexane, 20:80). White solid. Yield:
33% (41 mg). Mp: 178−180 °C. Rf (20% EtOAc/hexane): 0.2. IR (KBr,
cm−1): 1575, 1422, 1376, 1217, 1119. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.92 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.43 (dd, J1 = J2
= 7.5 Hz, 2H), 7.31 (dd, J1 = J2 = 7.5 Hz, 2H), 6.94 (s, 1H), 3.99 (s, 6H),
3.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 170.2, 165.7,
165.0, 153.8, 134.7, 126.4, 124.2, 121.7, 121.2, 103.6, 94.5, 63.1, 57.3.
HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H18N2 NaO3S4
521.0092, found 521.0098.
2-(Mesitylthio)-5-methylbenz[d]oxazole (13). 13 was prepared as
described in the typical experimental procedure. The crude product was
purified on a silica gel (100−200 mesh) column (eluent hexane).
Colorless crystalline solid. Yield: 71% (50 mg). Mp: 117−119 °C. Rf
(3% EtOAc/hexane): 0.3. IR (KBr, cm−1): 1565, 1496, 1477, 1255,
1143, 1100. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.35 (s, 1H), 7.25
(d, J = 10.3 Hz, 1H), 7.04 (s, 2H), 7.01 (d, J = 8.4 Hz, 1H), 2.46 (s, 6H),
2.40 (s, 3H), 2.33 (s, 3H). 13C{1H} (100 MHz, CDCl3): δ (ppm) 163.4,
150.1, 143.5, 142.3, 140.6, 134.0, 129.6, 124.7, 122.4, 118.8, 109.2, 21.9,
21.4, 21.2.. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for
C17H17NNaOS 306.0929, found 306.0931.
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