Dynamic covalent chemistry of disulfides offers a highly efficient synthesis of diverse benzofused nitrogen-sulfur heterocycles in one pot

Article abstract of DOI:10.1021/cc100042v

The thiol-disulfide dynamic interchange reaction mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was extensively studied. By this synthetic method sulfides can be prepared successfully within seconds in high yields at room temperature from stable and readily available disulfides and an alkylating agent. The method was further demonstrated to efficiently produce benzofused nitrogen-sulfur heterocycles with high skeletal diversity in a one-pot process.

Full text of DOI:10.1021/cc100042v

J. Comb. Chem. 2010, 12, 531–540
531
Dynamic Covalent Chemistry of Disulfides Offers a Highly Efficient
Synthesis of Diverse Benzofused Nitrogen-Sulfur Heterocycles in
One Pot
Ning Zhu, Fa Zhang, and Gang Liu*
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2
Nanwei Road, Xuanwu District, Beijing 100050, China
ReceiVed March 13, 2010
The thiol-disulfide dynamic interchange reaction mediated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
was extensively studied. By this synthetic method sulfides can be prepared successfully within seconds in
high yields at room temperature from stable and readily available disulfides and an alkylating agent. The
method was further demonstrated to efficiently produce benzofused nitrogen-sulfur heterocycles with high
skeletal diversity in a one-pot process.
Introduction
Herein, we disclose a new and highly efficient synthesis
of benzofused nitrogen-sulfur heterocycles involving a
tandem or a multistep process in a one-pot reaction, which
first involves a thiol-disulfide interchange reaction initiated
by DBU in situ to form sulfides and then a cyclization
reaction.
Sulfur-containing organic compounds are widely present
in natural products and drugs.1 Benzofused nitrogen-sulfur
heterocycles, such as zopolrestat,2 diltiazem,3 and quetiapine4
for clinical treatments of diabetes, hypertension, and schizo-
phrenia and depressive episodes, respectively, (Figure 1),
comprise an important class of compounds. Sulfides are
usually obtained by the reactions of a thiolate or thiol with
an organic halide or a Michael acceptor. However, most
thiols or thiophenols are readily oxidized to their corre-
sponding disulfide.5 The disulfide bond can be broken and a
carbon-sulfur bond formed by reducing reagents,6 transition
metal reagents or catalysts,5,7 strong bases (e.g., NaH),8 and
thiolates.9 However, these methods all possess one or more
of the following disadvantages, including prolonged reaction
time, harsh reaction conditions, or the requirement for costly,
air-sensitive, and toxic substances. Thus, new methods using
more stable and simply prepared disulfides to synthesize
sulfides or sulfur heterocycles are very attractive.
Result and Discussion
We began our study with the reactions of aromatic
disulfides 1 and alkyl halides 2, using different bases.
Without ethanethiol (EtSH), the reaction of disulfide 1a with
2a in the presence of DBU8b did not afford any product at
room temperature (r.t.; Table 1, entry 1). However, the
reaction did produce the target product in low yield at 100
°C for 15 h (Table 1, entry 2). The reaction conditions were
optimized by using several organic bases or other reagents.
Much to our delight, when EtSH was added to the reaction
solution, the anticipated product was obtained immediately
at room temperature (Table 1, entries 3-5). Other organic
bases such as DABCO, triethylamine (TEA), and DMAP
were investigated in the presence of EtSH (Table 1, entries
6-8). The most favorable conditions were determined to be
2.0 equivalents (equiv) of DBU and 2.0 equiv of EtSH in
tetrahydrofuran (THF; Table 1, entry 3), which afforded a
quantitative yield of sulfide 3a as determined by LC-MS
analysis, within a very short reaction time. However, when
less than 2.0 equiv of either DBU or EtSH were used, the
yield of 3a was reduced greatly (entries 4-5). When other
weaker bases such as DMAP, DABCO, or TEA were used,
the yield of 3a decreased (Table 1, entries 6-8). The reaction
efficacy was further demonstrated by the reaction of 1a with
the Michael acceptor 4a to afford sulfide 5a. It is evident
from Table 2 that a low loading of DBU from 3 to 0.05
equiv is still effective, although the reactivity was decreased
(entries 2-4). Taking into account the reaction time and
yield, 0.5 equiv of DBU to 1a was selected as the best
reaction conditions for the Michael addition reactions. The
use of DBU alone (Table 2, entry 1) or TEA and EtSH (Table
Reversible thiol-disulfide interconversion has been studied
previously10 and has numerous applications for screening
disulfide-based catalysis,11 assembly of stable ꢀ-sheet pep-
tides,12 molecular recognition through a host-guest com-
munication,13 producing covalent cages14 and the synthesis
of polyrotaxane networks.15 We hypothesized that the thiol-
disulfide interchange could selectively provide various thi-
olates in situ in the presence of a suitable base and that these
could react further to directly generate sulfides and sulfur-
containing heterocycles. Although the thiol-disulfide inter-
change reaction to give thiols which can be alkylated to give
sulfides is well-known,16 to the best of our knowledge, no
reports on the formation of sulfur-carbon bonds through
the thiol-disulfide interchange reactions in a single one-pot
sequence exist.
* To whom correspondence should be addressed. Phone: +86-10-
63167165. Fax: +86-10-63165246. E-mail: gliu@imm.ac.cn.
10.1021/cc100042v  2010 American Chemical Society
Published on Web 05/28/2010

532 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhu et al.
Figure 1. Bioactive Benzofused Sulfur Heterocycles.
Table 1. Nucleophilic Substitution Reactions Carried out under Basic Conditionsa
entry
EtSH
base
time [min]
yield [%]b
1
2
3
4
5
6
7
8
0
0
DBU (5 equiv)
DBU (5 equiv)
DBU (2 equiv)
DBU (1eq)
DBU (2 equiv)
DMAP (3 equiv)
DABCO (5 equiv)
TEA (5 equiv)
300
900
1
1
1
300
300
60
0
43c
94d
53d
56d
49
2 equiv
2 equiv
1 equiv
3 equiv
3 equiv
3 equiv
52
85
a 1a (0.1 mmol) and 2a (0.3 mmol) in 4 mL THF or MeOH at r.t. b Yield of Isolated product. c Reaction at 100 °C. d 0.2 mmol 2a was used.
Table 2. Michael Addition Reactions Carried out under Basic Conditions
entry
EtSH
base
time [min]
isolated yield [%]
1
2
3
4
5
0
DBU (5 equiv)
DBU (3 equiv)
DBU (0.5 equiv)
DBU (0.05 equiv)
TEA (5 equiv)
300
1
1
180
300
0
92
91
72
0
3 equiv
3 equiv
3 equiv
3 equiv
2, entry 5) did not produce the target product 5a. We could
conclude from the above reaction conditions that both DBU
and EtSH were very important to the alkylation reaction and
Michael addition reaction. Many organic solvents, such as
THF, 1,4-dioxane, MeOH, DCM, and toluene, could be used
in this reaction.
Using the optimal reaction conditions, a wide range of
organic halides or Michael acceptors with various structures
were investigated further. As is evident from Table 3, the
reaction of R-halo esters and allylic bromides with 1a readily
afford the corresponding sulfides in high yields (entries 1,
2, 4). However, the yield of the product was reduced and
stronger reaction condition needed to be used when the less
reactive reagent R-bromo acetal was used (entry 5). Because
of the steric effect and weaker reactivity of the reagent
t-BuBr, the target product could not be obtained at all under
conditions afforded product in only low yield and methyl
tiglate (entry 14) did not give the desired product because
of weaker electrophilicity caused by a combination of steric
and electronic effects. The ꢀ-bromo ester (entry 3) reacted
well under standard conditions, but it is not clear if this is a
direct alkylation or a base induced elimination-addition
process.
The scope of this method was also demonstrated after
extensively screening various aryl disulfides (Table 4). Most
of the aryl disulfides with either electron-withdrawing or
electron-donating groups gave quantitative reaction yields,
as determined by LC-MS analysis, and isolated yields were
also high (entries 1-8). Several functional groups, such as
nitro, keto, and amido groups, are well-tolerated under these
reaction conditions. These functional groups would allow
additional transformations to give more complex sulfides or
sulfur heterocycles. Disulfides also reacted with an R-halo
ketone or benzoyl chloride to give sulfides or S-p-tolyl
thiobenzoate, respectively, in very high yields (entries 9-10).
To elucidate the mechanism of the sulfide formation, the
the
con-
ditions examined (entry 6). Furthermore, the Michael adducts
of 1a were also efficiently obtained in good yields using a
variety of R,ꢀ-unsaturated reagents (entries 7-12). However,
the reactions with either R- or ꢀ-methyl substituted acrylates
proceeded more slowly (entries 11-12). The reaction of 1a
with methyl cinnamate (entry 13) under the stronger reaction
1
thiol-disulfide interchange process was monitored by H
NMR spectroscopy (Figure 2). The chemical shifts of TEA
and EtSH did not change in a solution containing TEA and

Synthesis of Benzofused Nitrogen-Sulfur Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 533
Table 3. Organic Halides or Michael Acceptors that Were Reacted with Disulfide 1a in the Presence of DBU/EtSH
a Reaction conditions: 1a/2/DBU/EtSH in molar ratio 1/3/3/3. b Reaction conditions: 1a/2 or 4/DBU/EtSH in molar ratio 1/3/3 or 0.5/5, at 80 °C,
assisted by Microwave. c Reaction conditions: 1a/4/DBU/EtSH in molar ratio 1/3/0.5/3. d Reaction conditions: 1a/4/DBU/EtSH in molar ratio 1/3/0.5/5.
EtSH (Figure 2 b, 2c). However, upon mixing of DBU and
EtSH, the S-H proton signal disappeared and other proton
signals were unaltered, which suggested that DBU could
cause the thiol proton to be deuterated quickly (Figure 2
thiol-disulfide dynamic exchange process occurred (Scheme
1). Considerable changes in the chemical shifts of protons
2, 6, 9, and 11 of DBU (the chemical shifts of DBU were
assigned by 2D NMR in the Supporting Information) were
observed, and DBU was demonstrated to be cationic
(DBU · H+) in the thiol-disulfide interchange solution (Figure
2i). The aryl thiolate produced in situ by DBU reacted with
organic halides very fast, and almost no byproduct (3m)
(Scheme 1 and Table 1, entry 3) was produced. When TEA
or another weaker base was used, a high concentration of
the corresponding aryl thiolate was not produced, meaning
that formation of 3a was slow, and the byproduct (3m in
Scheme 1) was produced in higher amounts, leading to
1
a-d). The HNMR spectra (Figure 2, a-d) showed that
neither TEA nor DBU could convert EtSH to a great amount
of the corresponding EtS-, and hence the ethanethiol reacted
with R-bromo ester (2a) only very slowly to afford the
byproduct of ethyl 2-(ethylthio)butanoate 3m (Scheme 1).
Furthermore, no change was detected in the presence of EtSH
along with 1a (Figure 2e). However, the new proton signals
of 1f and diethyl disulfide were clearly observed when DBU
or TEA was added (Figure 2 f-i), which indicated that a

534 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhu et al.
Table 4. Various Disulfides 1 Reacted with Organic Halides or Michael Acceptors
a Reaction conditions: 1a/2/DBU/EtSH in molar ratio 1/3/3/3. b Reaction conditions: 1a/4/DBU/EtSH in molar ratio 1/3/0.5/3.
reduced yields of the target product (Table 1, entries 6-8).
The Michael adducts could be obtained using a catalytic
amount of DBU, and the proposed mechanism is given in
Scheme 2.
7-14). The disulfides 1 reacted with R,ꢀ-unsaturated esters
to yield the corresponding sulfides, which afforded the target
compounds 10 and 11 in a one-pot reaction that involved an
additional two-step reaction, involving hydrolysis with LiOH
and cyclization with 1-ethyl-3-(3-dimethylaminopropyl) car-
bodiimide hydrochloride (EDC · HCl) (Scheme 4, Table 5,
entries 15-18). Furthermore, the compounds of scaffolds
12 and 13 were obtained in a three-step, one-pot reaction,
involving sulfide formation from the reaction of disulfide 1
with an R,ꢀ-unsaturated ketone or aldehyde or R-halo ketone,
cyclization to a Schiff base and reduction with NaBH3CN
(Scheme 4, Table 5, entries 19-22). Accordingly, a good
variety of benzofused nitrogen-sulfur heterocycles with
skeletal diversity could be prepared by this synthetic method.
Having achieved a better understanding of the best
conditions for synthesis of various sulfides, we expanded the
method to prepare benzofused nitrogen-sulfur heterocycles
in a one-pot process. Sulfur heterocycles (6, 7, 8) were
obtained in good yields after the addition of DBU to a
mixture of 1 and EtSH, and ethyl 2-chloro-3-oxobutanoate
or isothiocyanate or CS2 at room temperature, respectively,
in a three-step tandem reaction involving aryl thiolate
formation, nucleophilic addition (or nucleophilic substitution)
and cyclization (Scheme 3, Table 5, entries 1-6). When 1
was reacted with R-halo esters in the presence of DBU and
EtSH the sulfide intermediate formed immediately and was
directly converted to 9 in a one-pot reaction under microwave
conditions at 110 °C in 10 min (Scheme 4, Table 5, entries
Conclusion
In summary, we have reported an extensive study to
establish a new and very efficient single-pot method to

Synthesis of Benzofused Nitrogen-Sulfur Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 535
Figure 2. Dynamic Reversible Interchange of Disulfide 1a and EtSH in the Presence of DBU or TEA as Determined by 1H NMR Spectroscopy
(300 MHz, C5D5N, 24 °C).
Scheme 1. Proposed Mechanism of Sulfide Formation Mediated by DBU/EtSH
prepare diverse sulfides in high yields, via an in situ thiol-
disulfide interchange reaction mediated by DBU. The
methodology produced sulfides within seconds at room
temperature from stable and readily available disulfides and
a variety of alkylating agents. Our approach eliminates the
requirements for hydride-based reducing agents or costly
transition metal reagents or catalysts. We demonstrated the
successful use of this synthetic method to efficiently prepare
benzofused nitrogen-sulfur heterocycles with good skeletal
diversity in a one-pot process.
Experimental Section
General Procedure for the Synthesis of Sulfides 3. To a
magnetically stirred solution of 1.0 equiv (0.1 mmol) of
disulfide 1 in 4 mL of THF, 3.0 equiv of EtSH (0.3 mmol)
and 3.0 equiv of DBU (0.3 mmol) were added, followed by

536 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhu et al.
Scheme 2. Proposed Mechanism of Michael Addition Catalyzed by DBU
Scheme 3. Highly Efficient Synthesis of Benzofused
Nitrogen-Sulfur Heterocycles in a Tandem Process
yields after purification by column chromatography through
a silica gel column.
Methyl 3-[2,4-Diamino-5-(3,5-dimethylphenoxy)phenyl-
thio]propanoate, 5a. Isolated as a colorless oil (63 mg, 91%),
1
(eluent: petroleum ether/ethyl acetate, 1/1, v/v); H NMR
(300 MHz, DMSO-d6) δ 2.18 (s, 6H), 2.45 (t, J ) 7.2, 2H),
2.72 (t, J ) 7.1, 2H), 3.54 (s, 3H), 4.86 (s, 2H), 5.06 (s,
2H), 6.14 (s, 1H), 6.45 (s, 2H), 6.61 (s, 1H), 6.67 (s, 1H).
13C NMR (101 MHz, DMSO-d6) δ 20.9, 29.5, 33.5, 51.3,
100.0, 100.2, 113.2, 123.1, 129.2, 132.2, 138.7, 143.0, 148.1,
158.7, 171.9. HRMS (ESI) Calcd. for C18H23N2O3S [M +
H]+: 347.1429, Found: 347.1431.
Synthesis of 6a by a Three-Step Tandem Reaction. To a
magnetically stirred solution of 1.0 equiv (51.8 mg, 0.1
mmol) of disulfide 1a in 4 mL of THF, 3.0 equiv of EtSH
(0.3 mmol) and 2.2 equiv of ethyl 2-chloro-3-oxobutanoate
(0.22 mmol) were added. Upon addition of 3.0 equiv of DBU
(0.3 mmol) to the mixture solution at room temperature,
disulfide 1a was completely consumed within 1 min as
determined by LC-MS or TLC. The reaction solution was
evaporated under vacuum to dryness. Purification of the
residue by column chromatography through a silica gel
column eluting with petroleum ether and ethyl acetate (2:1,
v:v) gave the compound 6a as yellow solid, mp 134-135
°C (46 mg, 62%).
Ethyl 6-Amino-7-(3,5-dimethylphenoxy)-3-methyl-4H-
benzo[b][1,4]thiazine-2-carboxylate, 6a. 1H NMR (300 MHz,
DMSO-d6) δ 1.15 (t, J ) 6.9, 3H), 2.20 (s, 9H), 4.01 (q, J
) 6.9, 2H), 4.85 (s, 2H), 6.18 (s, 1H), 6.26 (s, 1H), 6.46 (s,
2H), 6.64 (s, 1H), 8.59 (s, 1H). 13C NMR (75 MHz, DMSO-
d6) δ 14.6, 20.2, 21.3, 60.0, 86.4, 103.2, 104.7, 114.0, 118.7,
124.1, 136.9, 138.2, 139.3, 139.9, 153.6, 158.0, 163.9. HRMS
(ESI) Calcd. for C20H22N2O3S [M]+: 370.1351, Found:
370.1359.
3.0 equiv of an organic halide 2 (R-halo esters, R-halo ketone,
benzoyl chloride or allylic bromide) (0.30 mmol) at room
temperature. The reaction mixture immediately produced a
white solid upon addition of the alkyl halides, and disulfide
1 was completely consumed within 1 min as determined by
LC-MS or TLC. Sulfides 3 could be isolated in excellent
yield after purification by column chromatography through
a silica gel column.
Ethyl 2-[2,4-Diamino-5-(3,5-dimethylphenoxy)phenyl-
thio]butanoate, 3a. Isolated as a yellow oil (70 mg, 94%),
1
(eluent: petroleum ether/ethyl acetate, 2/1, v/v); H NMR
(300 MHz, DMSO-d6) δ 0.88 (t, J ) 7.3, 3H), 1.07 (t, J )
7.1, 3H), 1.52-1.79 (m, 2H), 2.19 (s, 6H), 3.26-3.34 (m,
1H), 3.96 (q, J ) 7.1, 2H), 4.93 (s, 2H), 5.05 (s, 2H), 6.11
(s, 1H), 6.46 (s, 2H), 6.61 (s, 2H). 13C NMR (75 MHz,
DMSO-d6) δ 11.7, 13.9, 20.9, 24.1, 51.5, 60.3, 98.5, 99.9,
113.3, 123.2, 129.7, 132.3, 138.6, 143.5, 148.7, 158.6, 171.5.
HRMS (ESI) Calcd. for C20H27N2O3S [M + H]+: 375.1742,
Found: 375.1742.
Synthesis of 7 or 8 by a Three-Step Tandem Reaction.
To a magnetically stirred solution of 1.0 equiv (0.1 mmol)
of disulfide 1 in 4 mL of THF, 3.0 equiv of EtSH (0.3 mmol)
and 3.0 equiv of isothiocyanate (0.3 mmol) or CS2 (0.3
mmol) were added, followed by 3.0 equiv of DBU (0.3
mmol). The mixture was allowed to stir for an additional 30
min (isothiocyanate) or 2 h (CS2) at room temperature and
disulfide 1 was completely consumed as determined by LC-
MS or TLC. After acidification with acetic acid (40 µL),
the reaction solution was stirred for 10 min then evaporated
under vacuum to dryness. The residue was purified by
General Procedure for the Synthesis of Sulfides 5. To a
magnetically stirred solution of 1.0 equiv (0.1 mmol) of
disulfide 1 in 4 mL of THF, 3.0 equiv of EtSH (0.3 mmol)
and 0.5 equiv of DBU (0.05 mmol) were added, followed
by 2.2 equiv of Michael acceptors such as propiolates, R,ꢀ-
unsaturated ester, ketone, and nitrile (0.22 mmol) at room
temperature. The reaction mixture immediately turned color-
less upon addition of a Michael acceptor 4, and disulfide 1
was completely consumed within 1 min as determined by
LC-MS or TLC. Sulfides 5 could be achieved in excellent

Synthesis of Benzofused Nitrogen-Sulfur Heterocycles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 537
column chromatography through a silica gel column gave
the compounds 7 or 8.
by 2.2 equiv of ethyl 3-phenylpropiolate or an R,ꢀ-unsatur-
ated ester (0.22 mmol) at room temperature. The disulfide 1
was completely consumed within 1 min as determined by
LC-MS or TLC. Then 6.0 equiv of LiOH · H2O (0.6 mmol)
in 2 mL of water was added directly to the stirred reaction
solutions. The reaction mixture was continuously stirred for
30 min at room temperature (for R,ꢀ-unsaturated ester) or
irradiated in a Microwave for 10 min at 90 °C (for ethyl
3-phenylpropiolate). After the hydrolysis of the ester by
LiOH was complete as determined by LC-MS, the pH value
of the reaction solution was adjusted to 7.0 with 2 N HCl.
Then 4.0 equiv of EDC · HCl (0.4 mmol) was directly added
to the reaction solution, and the mixture was allowed to react
for an additional 30 to 60 min at 50 °C until the reaction
was complete, as monitored by LC-MS or TLC. The mixture
was concentrated under vacuum to remove THF and was
extracted with DCM (3 × 50 mL). The organic phase was
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatog-
raphy to give the products 10 or 11.
7-Amino-8-(3,5-dimethylphenoxy)-2,3-dihydrobenzo[b][1,4]-
thiazepin-4(5H)-one, 10a. Isolated as a white solid, mp
274-275 °C (47 mg, 75%), (eluent: dichloromethane/
methanol, 25/1, v/v); 1H NMR (300 MHz, DMSO-d6) δ 2.23
(s, 6H), 2.40 (t, J ) 6.8, 2H), 3.22 (t, J ) 6.9, 2H), 5.32 (s,
2H), 6.54 (s, 3H), 6.71 (s, 1H), 6.82 (s, 1H), 9.56 (s, 1H).
13C NMR (101 MHz, DMSO-d6) δ 20.9, 33.5, 34.2, 109.6,
110.0, 114.7, 124.3, 125.5, 138.9, 139.0, 139.5, 141.9, 157.2,
172.5. HRMS (ESI) Calcd. for C17H19N2O2S [M + H]+:
315.1167, Found: 315.1166.
[2-(4-Methoxyphenylamino)benzo[d]thiazol-5-yl](phe-
nyl) Methanone, 7b. Isolated as a white solid, mp 207-208
°C (67 mg, 93%), (eluent: dichloromethane/methanol, 100/
1, v/v); 1H NMR (300 MHz, DMSO-d6) δ 3.73 (s, 3H), 6.95
(d, J ) 9.1, 2H), 7.51 (dd, J ) 8.2, 1.6, 1H), 7.57 (t, J )
7.4, 2H), 7.63-7.73 (m, 3H), 7.73-7.80 (m, 3H), 7.96 (d,
J ) 8.1, 1H), 10.46 (s, 1H). 13C NMR (101 MHz, DMSO-
d6) δ 55.2, 114.2, 119.7, 119.9, 121.2, 123.1, 128.5, 129.5,
132.37, 133.6, 134.8, 135.3, 137.5, 152.2, 154.9, 163.1,
195.5. HRMS (ESI) Calcd. for C21H17N2O2S [M + H]+:
361.1011, Found: 361.1017.
5-Amino-6-morpholinobenzo[d]thiazole-2-thiol, 8b. Iso-
lated as a yellow solid, mp 274-275 °C (48 mg, 90%),
1
(eluent: petroleum ether/ethyl acetate, 4/1, v/v); H NMR
(300 MHz, DMSO-d6) δ 2.76 (t, J ) 4.2, 4H), 3.74 (t, J )
4.2, 4H), 5.23 (s, 2H), 6.69 (s, 1H), 7.20 (s, 1H), 13.31 (s,
1H). 13C NMR (75 MHz, DMSO-d6) δ 51.2, 66.5, 97.0,
112.4, 115.7, 136.5, 138.4, 142.9, 188.7. HRMS (ESI) Calcd.
for C11H14N3OS2 [M + H]+: 268.0578, Found: 268.0580.
Synthesis of 9 in a One-Pot Reaction. To a magnetically
stirred solution of 1.0 equiv (0.1 mmol) of disulfide 1 in 4
mL of THF, 3.0 equiv of EtSH (0.3 mmol) and 3.0 equiv of
DBU (0.3 mmol) were added, followed by 2.2 equiv of an
R-halo ester (0.22 mmol) at room temperature. After disulfide
1 was completely consumed as determined by LC-MS or
TLC (within 1 min), 200 µL AcOH was added directly to
the reaction mixture. Then the mixture solution was irradiated
in a Microwave oven at 110 °C for 10 min. After the solvent
was evaporated under vacuum to dryness, the residue was
purified by column chromatography through a silica gel
column gave the desired products 9 in excellent yields.
6-Amino-7-(3,5-dimethylphenoxy)-2-ethyl-2H-benzo[b][1,4]-
thiazin-3(4H)-one, 9a. Isolated as a white solid, mp 212-213
°C (63 mg, 96%), (eluent: petroleum ether/ethyl acetate, 1/1,
(Z)-7-amino-8-(3,5-dimethylphenoxy)-2-phenylbenzo[b][1,4]-
thiazepin-4(5H)-one, 11a. Isolated as a light yellow solid,
mp 207-208 °C (30.5 mg, 39%), (eluent: petroleum ether/
1
ethyl acetate, 2/1, v/v); H NMR (300 MHz, DMSO-d6) δ
2.21 (s, 6H), 5.37 (s, 2H), 6.47 (d, J ) 1.2, 1H), 6.52 (s,
2H), 6.63 (s, 1H), 6.69 (s, 1H), 6.94 (s, 1H), 7.34-7.49 (m,
3H), 7.62-7.80 (m, 2H), 10.32 (s, 1H). 13C NMR (101 MHz,
DMSO-d6) δ 20.9, 108.6, 112.4, 114.4, 123.6, 124.2, 125.1,
127.3, 128.8, 129.9, 137.4, 138.6 139.0, 142.4, 149.5, 157.3,
167.6. HRMS (ESI) Calcd. for C23H21N2O2S [M + H]+:
389.1324, Found: 389.1323.
1
v/v); H NMR (300 MHz, DMSO-d6) δ 0.93 (t, J ) 7.3,
3H), 1.34-1.57 (m, 1H), 1.65-1.88 (m, 1H), 2.20 (s, 6H),
3.28 (dd, J ) 8.5, 6.1, 1H), 5.00 (s, 2H), 6.44 (s, 1H), 6.48
(s, 2H), 6.67 (s, 2H), 10.32 (s, 1H). 13C NMR (126 MHz,
DMSO-d6) δ 11.2, 20.9, 22.2, 43.5, 102.7, 103.7, 114.1,
119.6, 123.9, 134.2, 137.4, 138.9, 140.0, 157.6, 167.1. HRMS
(ESI) Calcd. for C18H21N2O2S [M + H]+: 329.1324, Found:
329.1329.
Synthesis of 12 or 13 in a One-Pot Reaction. To a
magnetically stirred solution of 1.0 equiv (0.1 mmol) of
disulfide 1 in 4 mL of THF, 3.0 equiv of EtSH (0.3 mmol)
and 3.0 equiv of DBU (0.3 mmol, for R-halo ketone) or 0.5
equiv of DBU (0.05 mmol, for R,ꢀ-unsaturated ketone or
aldehyde) were added, followed by 2.2 equiv of an R-halo
ketone, R,ꢀ-unsaturated ketone or aldehyde (0.22 mmol) at
room temperature. The disulfide 1 was completely converted
into the unstable intermediate within 1 min as determined
by LC-MS or TLC. After acidification with 6.0 equiv of
acetic acid (0.6 mmol), 6.0 equiv of NaBH3CN (0.6 mmol)
and 2 mL of MeOH were added directly to the stirred
reaction solutions. The reaction mixture was continuously
stirred for an additional 30 min at room temperature, and
the unstable intermediates were completely converted into
the stable target product 12 or 13 as monitored by LC-MS
or TLC. After being quenched with saturated NaHCO3 (0.5
mL), the reaction mixture was extracted with DCM (3 × 50
6-Benzoyl-2-ethyl-2H-benzo[b][1,4]thiazin-3(4H)-one, 9g.
Isolated as a white solid, mp 124-125 °C (53 mg, 89%),
1
(eluent: petroleum ether/ethyl acetate, 3/1, v/v); H NMR
(300 MHz, DMSO-d6) δ 0.98 (t, J ) 7.4, 3H), 1.42-1.66
(m, 1H), 1.70-1.93 (m, 1H), 3.57 (dd, J ) 8.4, 6.2, 1H),
7.33 (dd, J ) 8.0, 1.8, 1H), 7.41 (d, J ) 1.7, 1H), 7.52 (d,
J ) 8.0, 1H), 7.54-7.62 (m, 2H), 7.64-7.77 (m, 3H), 10.74
(s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 11.1, 23.1, 42.7,
117.5, 123.7, 124.2, 127.8, 128.5, 129.5, 132.6, 135.2, 136.9,
137.0, 166.3,194.6. HRMS (ESI) Calcd. for C17H16NO2S [M
+ H]+: 298.0902, Found: 298.0907.
Synthesis of 10 or 11 in a One-Pot Reaction. To a
magnetically stirred solution of 1.0 equiv (0.1 mmol) of
disulfide 1 in 4 mL of THF, 3.0 equiv of EtSH (0.3 mmol)
and 0.5 equiv of DBU (0.05 mmol) were added, followed

538 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhu et al.
Table 5. Detailed Nitrogen-Sulfur Heterocycles Synthesized by This Method

Synthesis of Benzofused Nitrogen-Sulfur Heterocycles
Table 5. Continued
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 539
mL). The organic phase was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to give the
products 12 or 13.
127.2, 128.2, 129.8, 139.8, 140.9, 144.2. HRMS (ESI) Calcd.
for C18H22N3OS [M + H]+: 328.1484, Found: 328.1484.
7-(3,5-Dimethylphenoxy)-3-(4-methoxyphenyl)-3,4-dihy-
dro-2H-benzo[b][1,4]thiazin-6-amine, 12b. Isolated as a
colorless oil (52 mg, 66%), (eluent: petroleum ether/ethyl
7-Morpholino-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thi-
azin-6-amine, 12a. Isolated as a white solid, mp 217-218
°C (50 mg, 77%), (eluent: dichloromethane/methanol, 100/
1
acetate, 3/1, v/v); H NMR (300 MHz, DMSO-d6) δ 2.20
1
(s, 6H), 2.91 (d, J ) 5.4, 2H), 3.74 (s, 3H), 4.46 (s, 2H),
4.54 (t, J ) 4.9, 1H), 6.03 (s, 1H), 6.15 (s, 1H), 6.36 (s,
1H), 6.46 (s, 2H), 6.61 (s, 1H), 6.91 (d, J ) 8.7, 2H), 7.29
(d, J ) 8.6, 2H). 13C NMR (101 MHz, DMSO-d6) δ 21.0,
32.2, 54.3, 55.1, 100.0, 102.0, 113.4, 113.6, 119.3, 123.2,
1, v/v); H NMR (300 MHz, DMSO-d6) δ 2.58-2.75 (m,
4H), 2.82-3.04 (m, 2H), 3.61-3.77 (m, 4H), 4.50-4.68 (m,
3H), 5.99 (s, 1H), 6.08 (s, 1H), 6.45 (s, 1H), 7.28 (dt, J )
8.6, 4.2, 1H), 7.35 (d, J ) 4.2, 4H). 13C NMR (101 MHz,
DMSO-d6) δ 32.2, 51.8, 54.7, 66.8, 99.6, 101.1, 118.2, 126.7,

540 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Zhu et al.
Scheme 4. Highly Efficient Synthesis of Benzofused
Nitrogen-Sulfur Heterocycles in a Multistep Process in One
Pota
References and Notes
(1) (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717–1760. (b)
Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152–
161.
(2) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.;
Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Singleton, D. H.
J. Med. Chem. 1991, 34, 108–122.
(3) Claas, S. A.; Glasser, S. P. Expert Opin. Pharmacother. 2005,
6, 765–776.
(4) Becker, P. M.; Sattar, M. Curr. Treat. Options Neurol. 2009,
11, 349–357.
(5) Ranu, B. C.; Mandal, T. Synth. Commun. 2007, 37, 1517–
1523.
(6) (a) Zhong, W.; Chen, X.; Zhang, Y. Synth. Commun. 2000,
30, 4451–4460. (b) Zhong, W.; Zhang, Y. Tetrahedron Lett.
2001, 42, 3125–3127. (c) Lee, C. L.; Lam, Y.; Lee, S. Y.
Tetrahedron Lett. 2001, 42, 109–111. (d) Lee, C. L.; Chan,
K. P.; Lam, Y.; Lee, S. Y. Tetrahedron Lett. 2001, 42, 1167–
1169. (e) Hutchinson, I.; Chua, M.-S.; Browne, H. L.; Trapani,
V.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G.
J. Med. Chem. 2001, 44, 1446–1455. (f) Ajiki, K.; Hirano,
M.; Tanaka, K. Org. Lett. 2005, 7, 4193–4195. (g) Mortimer,
C. G.; Wells, G.; Crochard, J.-P.; Stone, E. L.; Bradshaw,
T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem.
2006, 49, 179–185. (h) Tang, R.-Y.; Zhong, P.; Lin, Q.-L. J.
Fluorine Chem. 2006, 127, 948–953. (i) Tang, R.-Y.; Zhong,
P.; Lin, Q.-L. Synthesis 2007, 85–91. (j) Dmitrenko, O.;
Thorpe, C.; Bach, R. D. J. Org. Chem. 2007, 72, 8298–8307.
(7) (a) Chowdhury, S.; Roy, S. Tetrahedron Lett. 1997, 38, 2149–
2152. (b) Prabhu, K. R.; Sivanand, P. S.; Chandrasekaran, S.
Angew. Chem., Int. Ed. 2000, 39, 4316–4319. (c) Ranu, B. C.;
Mandal, T. J. Org. Chem. 2004, 69, 5793–5795. (d) Ranu,
B. C.; Mandal, T. Synlett 2004, 1239–1242. (e) Taniguchi,
N. J. Org. Chem. 2004, 69, 6904–6906. (f) Taniguchi, N.;
Onami, T. J. Org. Chem. 2004, 69, 915–920. (g) Kumar, S.;
Engman, L. J. Org. Chem. 2006, 71, 5400–5403. (h) Ranu,
B. C.; Chattopadhyay, K.; Banerjee, S. J. Org. Chem. 2006,
71, 423–425. (i) Taniguchi, N. J. Org. Chem. 2006, 71, 7874–
7876. (j) Taniguchi, N. J. Org. Chem. 2007, 72, 1241–1245.
(k) Go´mez-Ben´ıtez, V.; Baldovino-Pantaleo´n, O.; Herrera-
a Reagents and conditions: (a) (i) R-halo ester, 1 min; (ii) AcOH, MW,
10 min; (b) (i) R,ꢀ-unsaturated ester, 1 min; (ii) LiOH, THF/H2O, r.t., 30
min; (iii) HCl (aq.), EDC · HCl, r.t., 3 h; (c) (i) ethyl 3-phenylpropiolate, 1
min; (ii) LiOH, THF/H2O, MW, 10 min; (iii) HCl (aq.), EDC · HCl, r.t.,
3 h; (d) (i) R-halo ketone, 1 min; (ii) NaBH3CN, AcOH, MeOH/THF, r.t.,
20 min; (e) (i) R,ꢀ-unsaturated ketone or aldehyde, 1 min; (ii) NaBH3CN,
AcOH, MeOH/THF, r.t., 20 min.
127.9, 133.3, 135.8, 138.6, 138.7, 140.6, 158.6. HRMS (ESI)
Calcd. for C23H25N2O2S [M + H]+: 393.1637, Found:
393.1639.
8-(3,5-Dimethylphenoxy)-4-ethyl-2,3,4,5-tetrahydrobenzo-
[b][1,4]thiazepin-7-amine, 13a. Isolated as a white solid, mp
137-138 °C (60 mg, 92%), (eluent: petroleum ether/ethyl
acetate, 2/1, v/v); 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t,
J ) 7.3, 3H), 1.37-1.56 (m, 2H), 1.56-1.75 (m, 1H),
1.88-2.12 (m, 1H), 2.19 (s, 6H), 2.39-2.47 (m, 1H),
2.80-3.07 (m, 2H), 4.60 (s, 1H), 4.71 (s, 2H), 6.35 (s,
1H), 6.45 (s, 2H), 6.58 (s, 1H), 6.63 (s, 1H). 13C NMR (101
MHz, DMSO-d6) δ 11.0, 21.0, 28.4, 30.4, 38.1, 57.9, 107.2,
110.2, 113.8, 123.5, 123.8, 134.9, 138.7, 140.0, 148.7, 158.1.
HRMS (ESI) Calcd. for C19H25N2OS [M + H]+: 329.1688,
Found: 329.1691.
´
Alvarez, C.; Toscano, R. A.; Morales-Morales, D. Tetrahedron
Lett. 2006, 47, 5059–5062.
(8) (a) Jacobsen, N.; Kolind-Andersen, H. Synthesis 1990, 911–
914. (b) Kaye, P. T.; Nocanda, X. W. Synthesis 2001, 2389–
2392.
2-Ethyl-8-morpholino-2,3,4,5-tetrahydrobenzo[b][1,4]thi-
azepin-7-amine, 13b. Isolated as a white crystal, mp 182-183
°C (38 mg, 66%), (eluent: dichloromethane/methanol, 100/
(9) Weinstein, A. H.; Pierson, R. M.; Wargotz, B.; Yen, T. F. J.
Org. Chem. 1958, 23, 363–372.
(10) Shaked, Z.; Szajewski, R. P.; Whitesides, G. M. Biochemistry
1980, 19, 4156–4166.
(11) Brisig, B.; Sanders, J. K. M.; Otto, S. Angew. Chem., Int. Ed.
2003, 42, 1270–1273.
(12) Krishnan-Ghosh, Y.; Balasubramanian, S. Angew. Chem., Int.
Ed. 2003, 42, 2171–2173.
(13) (a) Ramstro¨m, O.; Lehn, J. M. ChemBioChem 2000, 1, 41–
48. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Science
2002, 297, 590–593. (c) Kieran, A. L.; Bond, A. D.;
Belenguer, A. M.; Sanders, J. K. M. Chem. Commun. 2003,
2674–2675. (d) Corbett, P. T.; Tong, L. H.; Sanders, J. K. M.;
Otto, S. J. Am. Chem. Soc. 2005, 127, 8902–8903.
(14) West, K. R.; Bake, K. D.; Otto, S. Org. Lett. 2005, 7, 2615–
2618.
(15) Bilig, T.; Oku, T.; Furusho, Y.; Koyama, Y.; Asai, S.; Takata,
T. Macromolecules 2008, 41, 8496–8503.
(16) Liang, C.-F.; Yan, M.-C.; Chang, T.-C.; Lin, C.-C. J. Am.
Chem. Soc. 2009, 131, 3138–3139.
1
1, v/v); H NMR (300 MHz, DMSO-d6) δ 0.97 (t, J ) 7.3,
3H), 1.49 (p, J ) 7.1, 2H), 1.64 (m, 1H), 1.93-2.18 (m,
1H), 2.55-2.84 (m, 6H), 3.28 (m, 1H), 3.69 (s, 4H), 4.79
(s, 2H), 5.11 (s, 1H), 6.16 (s, 1H), 6.74 (s, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 11.9, 27.5, 45.3, 46.9, 51.6, 66.7,
105.1, 108.0, 124.1, 131.1, 142.6, 150.7. HRMS (ESI) Calcd.
for C15H24N3OS [M + H]+: 294.1640, Found: 294.1643.
Acknowledgment. The authors thank the National Natural
Science Foundation of China (No. 90713045) for their
financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
CC100042V