One pot regioselective synthesis of a small library of dibenzo[ b, f ][1,4]thiazepin-11(10 H)-ones via smiles rearrangement

Article abstract of DOI:10.1021/co300139s

A facile and efficient method has been developed for the synthesis of a small library of dibenzo[b,f][1,4]thiazepin-11(10H)-ones via Smiles rearrangement. Compounds were obtained in excellent isolated yields (70%-92%) under metal-free conditions. More specifically, this transition metal-free process relates to an environmentally friendly, economical, and efficient method for preparing benzoic-fused seven-membered lactams.

Full text of DOI:10.1021/co300139s

Research Article
pubs.acs.org/acscombsci
One Pot Regioselective Synthesis of a Small Library of
Dibenzo[b,f][1,4]thiazepin-11(10H)‑ones via Smiles Rearrangement
Yongmei Zhao, Qiaoling Dai, Zhi Chen, Qihui Zhang, Yongcheng Bai, and Chen Ma*
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P R China
S
* Supporting Information
ABSTRACT: A facile and efficient method has been developed for the synthesis
of a small library of dibenzo[b,f ][1,4]thiazepin-11(10H)-ones via Smiles
rearrangement. Compounds were obtained in excellent isolated yields (70%−
92%) under metal-free conditions. More specifically, this transition metal-free
process relates to an environmentally friendly, economical, and efficient method
for preparing benzoic-fused seven-membered lactams.
KEYWORDS: metal-free process, benzoic-fused seven-membered lactams, Smiles rearrangement
the demand for substrates which are not readily or commercially
available, and inefficiency of the transformations restrain the
wider utilization. Therefore, a new and more effective method
involving mild, environmentally benign, atom-economical, and
metal-free conditions is still highly needed for the combinato-
rial synthesis of a diversified, small-molecules library to fill the
demands for dibenzo[b,f ][1,4]thiazepin-11(10H)-ones.
We have been studying the development of economical syntheses
of heterocyclic systems.23 Herein, we describe a one pot synthesis
of dibenzo[b,f ][1,4] thiazepin-11(10H)-ones via Smiles rearrange-
ment and without metal catalysts or microwave−assistance.
The benzoazepine-2-ones were obtained by the reaction of
halobenzenethiol or 3-chloro-5-(trifluoromethyl)pyridine-2-thiol
with N-substituted nitrobenzamide (Scheme 1).
INTRODUCTION
■
The development of heterocyclic scaffolds is a fast emerging
subject in medicinal chemistry. Among these, benzo-fused sul-
furated seven-membered lactams are endowed with a large
spectrum of biological activities with a wide range of interesting,
physiological activities. For example, they were reported as potential
Ca-channel blockers,1 NMDA glycine-site antagonists,2 antico-
agulants,3 inhibitors of proteases,4,5 antihypertensive agents,6−8
and antitumor agents.9 6-(4-Methylpiperazin-1-yl)benzo[f]pyrido-
[2,3-b][1,4]thiazepine has good affinity to D1, D2 and cho-
linergic receptors.10 Additionally, dibenzo[b,f][1,4]thiazepin-
11(10H)-ones and some of their analogues were useful for
AIDS prevention and treatment.11−14 Moreover, they were also
used as an intermediate compound for the preparation of quetia-
pine.15−17 Additionally, some 3,4-dibenzo[b,f][1,4]thiazepin-
11(10H)-ones have recently been described with anti-TBC
activity18 Because of this, there still remains a need for new
benzoazepine-2-one derivatives which exhibit physiological and
pharmaceutical activities.
Scheme 1. Synthesis of Benzoic-Fused Seven-Membered
Lactams
RESULTS AND DISCUSSION
■
Optimized reaction conditions were found by systematically
investigating the reaction parameters using 2,3-dichlorobenze-
nethiol and N-benzyl-2-chloro-5-nitro benzamide (Table 1).
First, testing different bases like Cs2CO3, KOH, NaH, BuOK,
Et3N in dimethylformamide (DMF) at 150 °C proved that
KOH was the most suitable base. Then we probed into the
Many methods have been used to synthesize benzoazepine-2-
ones, such as multistep cyclization processes,19 denitrocycliza-
tion by intramolecular substitution of the nitro group,20
photoisomerization via homolytic cleavage of the S−N
bond,21 and click-cyclization via microwave assistance.22
However, there are still some potential limitations including
Received: November 21, 2012
Revised: January 7, 2013
Published: January 14, 2013
© 2013 American Chemical Society
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ACS Combinatorial Science
Research Article
a
Table 1. Optimization of the Reaction Conditions
Table 2. Synthesis of Dibenzo[b,f ][1,4]thiazepin-11(10H)-
ones 3
b
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
Cs2CO3
KOH
BuOK
NaH
DMF
7
43
85
70
65
0
DMF
5
DMF
5
DMF
5
Et3N
DMF
8
KOH
KOH
KOH
CH3CN
DMSO
NMP
8
30
65
0
5
10
a
Reaction conditions: N-benzyl-2-chloro-5-nitrobenzamide 1c (0.6
mmol), 2,3-dichlorobenzenethiol 2b (0.5 mmol), and base (1.5 mmol)
in solvent (15.0 mL) under N2 at 150 °C (entries 1−5, 7−8)/80 °C
b
(entries 5 and 6). Isolated yield.
influence of different solvents on the reaction. DMF was found
to be superior to CH3CN, DMSO, and NMP.
The optimized reaction conditions were used to explore the
scope and limitations for synthesizing dibenzo[b,f ][1,4]thiazepin-
11(10H)-ones (Tables 2, 3 and 4). The desired dibenzo[b,f ]-
[1,4]thiazepin-11(10H)-ones were obtained in 70% to 92%
yield (Tables 2 and 3). Besides, we used DMSO as solvent
when R2 was aryl (Table 2, entries 5−10) because of its better
solubilizing power for the N-aryl compounds. Varying R2
from aryl to alkyl afforded no significant differences in yield
(Table 2) with this solvent change. We also found that neither
the N-aryl substrates with an electron-donating group (Table 2,
entries 8−10) nor substrates with an electron-withdrawing
group (Table 2, entries 5−7) affected the experimental results.
According to the experimental results, when the N-substituent
of 1 was isopropyl or cyclohexyl, the reaction did not afford
the expected product in spite of trying higher temperature
and reaction times. We believe steric hindrance is respon-
sible for the results. Additionally, from Table 3, it is
interesting to note that neither the variation of halogen type
nor the variation of the halogens’ position did interfere with
the outcome of the reaction. Besides, a short series of
Scheme 2. Plausible Reaction Mechanism
a
Reaction conditions: 2,3-dichlorobenzenethiol 2b (0.5 mmol),
N-substituted nitrobenzamide 1a and analogues 1b−1j (0.6 mmol)
and KOH (1.5 mmol) in DMF (15.0 mL, 1a−1d)/DMSO (15.0 mL,
b
1e−1j) under N2 at 150 °C for 4 h. Isolated yield.
pyridobenthiazepine derivatives were also obtained with high
yields (Table 4).
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Research Article
Table 3. Synthesis of Dibenzo[b,f ][1,4]thiazepin-11(10H)-
Table 4. Synthesis of Benzo[1,4]thiazin-3(4H)-ones 6
ones 4
a
Reaction conditions: N-benzyl-2-chloro-5-nitrobenzamide 1c (0.6
mmol), halogenous benzenethiol 2a and analogues 2c−2e (0.5 mmol)
and KOH (1.5 mmol) in DMF (15.0 mL) under N2 at 150 °C for 4 h.
b
Isolated yield.
Additionally, the molecular structure of the representative
product 3c was determined by X-ray crystallography analysis
(Figure 1). Thus, a plausible mechanism was presented in
a
Reaction conditions: 3-chloro-5-(trifluoromethyl)pyridine-2-thiol 5
(0.5 mmol), N-substituted nitrobenzamide analogues 1b−1d and 1f,
1h, 1i, 1k (0.6 mmol) and KOH (1.5 mmol) in DMF (15.0 mL,
1b−1d) / DMSO (15.0 mL, 1f, 1h, 1i, 1j) under NRR2 RRat 150 °C
b
for 4 h. Isolated yield.
Moreover, we recently did a theoretical study of this S−N
type Smiles rearrangement process to rationalize the exper-
imental observations.23a By performing quantum chemistry
calculations, we show the molecular mechanism for the S−N
type Smiles rearrangement. And the theoretical results show
that the Smiles rearrangement pathway is energetically more
favorable than the direct nucleophilic substitution pathway.
Figure 1. X-ray structure of compound 3c.
Scheme 2, on the basis of our results combined with the
reported papers.22 The reaction of 1c with 2b yielded
compound 7. Compound 7 could proceed via two paths (I
and II). Path II could afford the direct intramolecular
nucleophilic substitution product 9. By contrast, path I could
lead to the compound 3c via Smiles rearrangement. We only
obtained compound 3c. Imido nitrogen in compound 8
underwent intramolecular nucleophilic attack on the carbonium
ion 10. Migration of the spiro-sulfur, proceeding through the
“Meisenheimer Complex” 10, with intramolecular nucleophilic
displacement of chlorine anion by a sulfur anion of compound
11 yielded the desired cyclic product 3c (Scheme 2).
CONCLUSION
■
We have developed an operationally simple and economic
synthesis of a great number of benzo-fused sulfurated seven-
membered lactams in high yields. This metal-free method
accords with the developing of the current organic synthesis
trend toward cleaner and greener chemical processes because of
the pressing environmental and energy problems. Therefore,
this transition metal-free process has potential applications in
the synthesis of biologically and medicinally relevant com-
pounds.
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Research Article
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EXPERIMENTAL PROCEDURES
■
General Experimental Procedures for the Synthesis of
TTdibenzo[b,f ][1,4]thiazepin-11(10H)-ones or benzo[b]-
pyrido[2,3-f ][1,4]thiazepin-11(10H)-ones. A 25 mL Schlenk
tube equipped with a magnetic stirring bar was charged with
halogenous benzenethiol (2a−2e) or 3-chloro-5-(trifluoro-
methyl)pyridine-2-thiol (5) (0.5 mmol, 1.0 equiv), N-substituted
nitrobenzamides (1a−1j) (0.6 mmol, 1.2 equiv), KOH (84 mg,
1.5 mmol, 3.0 equiv), and then 15 mL of DMF or DMSO was
added via syringe at room temperature, and the mixture was
prestirred for about 15 min. Then the reaction was stirred at
150 °C. After the reaction was completed, the mixture was
diluted with brine (40 mL) and extracted with ethyl acetate
twice (2 × 30 mL). The combined organic layers were dried
over MgSO4, and the solvent was removed in vacuo to afford a
residue. The crude product was then purified by column
chromatography on silica gel to give the pure product.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Representative experimental procedures, copies of H NMR
and 13C NMR spectra of all compounds and X-ray data of 3c in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: HTHTTchenma@sdu.edu.cnTT.
Funding
We are grateful to the National Natural Science Foundation of
China (No. 21172131) for financial support of this research.
Notes
The authors declare no competing financial interest.
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