Ligand-Controlled Chemoselective One-Pot Synthesis of Dibenzothiazepinones and Dibenzoxazepinones via Twice Copper-Catalyzed Cross-Coupling

Article abstract of DOI:10.1055/s-0036-1558959

A highly efficient and generally applicable protocol, starting from 2-bromobenzamides and 2-bromo(thio)phenols via twice copper-catalyzed couplings to afford dibenzothiazepines and dibenzoxazepinones has been developed. High levels of yield and chemoselectivity are achieved in a single-pot reaction by using an appropriate ligand. Moreover, this facile methodology allows rapid access to a variety of bio-active compounds and known psychotropic drug, which should broaden its application in organic synthesis.

Full text of DOI:10.1055/s-0036-1558959

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–H
letter
A
Y. Chen et al.
Letter
Synlett
Ligand-Controlled Chemoselective One-Pot Synthesis of Dibenzo-
thiazepinones and Dibenzoxazepinones via Twice Copper-Cata-
lyzed Cross-Coupling
Yanyu Chena
O
R1
CONHR1
Br
Qiujun Penga
Rong Zhanga
Jian Hua
Yijun Zhoub
Lanting Xu*b
Xianhua Pan*b
CuI, ligand, Cs2CO3
DMF, 80 or 100 °C, 24 h
N
R2
R2
+
Br
YH
then 120 °C, 48 h
Y
R
1 = alkyl, aryl,
naphthyl, pyridinyl, H
Ligand:
N,N-dimethylglycine
2,2,6,6-tetramethylheptane-3,5-dione
33 examples
Yield: 68–93%
Yield: 82–93%
Y = S
Y = O
a School of Perfume and Aroma Technology, Shanghai
Institute of Technology, 100 Haiquan Road, Shanghai
201418, P. R. of China
b Shanghai Research Institute of Fragrance and Flavor
Industry, 480 Nanning Road, Shanghai 200232,
P. R. of China
Ligand-controlled highly chemoselective
One-pot reaction
Broad substrate scope
xulanting@sit.edu.cn
Received: 23.12.2016
Accepted after revision: 04.02.2017
Published online: 27.02.2017
ammonia insertion, respectively, to afford dibenzodiaze-
pines and dibenzoxazepines. Almost at the same time,
Garattini reported the copper-catalyzed cross-coupling re-
action to synthesize dibenzothiazepinone derivatives from
2-mercaptobenzoic acid and 1-bromo-4-methoxy-2-nitro-
benzene.3 After that, more and more groups have focused
on developing efficient methods for assembling dibenzothi-
azepine and dibenzoxazepinone derivatives through one-
pot strategy.12 However, none of the strategies could be ap-
plied in the synthesis of dibenzoxazepines and dibenzothi-
azepinones simultaneously.
DOI: 10.1055/s-0036-1558959; Art ID: st-2016-w0866-l
Abstract A highly efficient and generally applicable protocol, starting
from 2-bromobenzamides and 2-bromo(thio)phenols via twice copper-
catalyzed couplings to afford dibenzothiazepines and dibenzoxazepino-
nes has been developed. High levels of yield and chemoselectivity are
achieved in a single-pot reaction by using an appropriate ligand. More-
over, this facile methodology allows rapid access to a variety of bio-
active compounds and known psychotropic drug, which should broad-
en its application in organic synthesis.
Copper-promoted carbon–heteroatom bond formations
are widely used in construction of heterocyclic com-
pounds.13,14 During our studies of the amino acid promoted
copper catalyst reaction, we have completed an efficient
and facile approach to assemble substituted quinazolinones
from N-substituted o-bromobenzamides and amides.13g
The relatively mild coupling conditions (80 °C) used here
are remarkable and may result from the ortho-substitution
effect displayed by N-alkyl and N-aryl aminocarbonyl
groups.15 Thus, we envisioned that, under the influence of
an ortho-substituent effect, copper-catalyzed C–O or C–S
coupling between 2-bromobenzamides and 2-bro-
mo(thio)phenols should proceeded smoothly, the resulting
diaryl (thio)ethers would undergo an intramolecular Gold-
berg reaction to give dibenzothiazepines and dibenzoxaze-
pinones in a one-pot process (Scheme 1, path A).
Initially, we used K2CO3 as base and 20 mol% trans-4-hy-
droxy-L-proline (Figure 2, L1) as ligand with 10 mol% CuI for
the coupling of 2-bromothiophenol (9a) and N-phenyl-2-
bromobenzamide (8a) in DMF at 100 °C. After 12 h, the re-
action provided 51% yield for the corresponding diaryl thio-
ether 10a (Table 1, entry 1). The replacement of trans-4-hy-
droxy-L-proline by 1,10-phenanthroline (L2) or L-proline
Key words copper-Catalyzed, dibenzothiazepinone, dibenzoxazepino-
ne, chemoselectivity, ligands, one-pot
Dibenzo(thi/x)azepinone derivatives are a highly valu-
able class of heterocyclic compounds with remarkable bio-
logical and pharmacological activities,1 including cannabi-
noid receptor antagonist (1),2 histone deacetylase inhibitor
(4),3 MshC inhibitor (2),4 HIV-1 reverse transcriptase inhibi-
tor (5).5 Additionally, some therapeutic agents containing
this key structure, such as quetiapine fumarate (3),6
Sintamil (6),7 loxapine (7),8 have been patented as psycho-
tropic drug on the market for the treatment of schizophre-
nia and depression disease (Figure 1).
Although these tricyclic heterocycles can be synthesized
by conventional methods9 via tandem carbon–heteroatom
bond formation, reduction of nitro to amino group and de-
hydrative condensation under acidic conditions, the syn-
thetic scope was extremely restricted because of the re-
quirement of harsh reaction conditions, limited range of
suitable substrates, and the moderate yields of products.
Recently, Alper10 and Buchwald11 independently reported
novel approaches starting from functionalized diaryl ether
substrates via palladium-catalyzed carbon monoxide and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

B
Y. Chen et al.
Letter
Synlett
HO
O
S
O
O
O
N
O
N
O
N
O
NH
N
N
S
N
H
Cl
N
N
1
S
3
2
N
N
O
R
O
O2N
N
N
O
O
CONHOH
R
5
O
N
X
N
6
5
R = H
S
N
N
F
4
N
Cl
R =
X = C or N
5
O
7
Figure 1 Biologically and pharmacologically active dibenzothiazepine and dibenzoxazepinone derivatives
(L3) led to increased yields. When N,N-dimethylglycine (L4)
was employed, the yield was up to 85% (Table 1, entries 2–
4). Cs2CO3 as base gave the best yield (97%) of product in
comparison with bases such as K2CO3 and K3PO4 (Table 1,
entries 4–6). We attempted to heat the foregoing reaction
mixture to 120 °C so as to realize the following intramolec-
ular Goldberg reaction. To our delight, after 36 hours, the
desired dibenzothiazepinone product 11a was obtained in
95% yield (Table 1, entry 7).
Using the above-mentioned optimized conditions, we
investigated the C–O bond formation of 2-bromophenol
(12a) and N-phenyl-2-bromobenzamide (8a) followed by
intramolecular cyclization. However, the reaction gave the
self-coupling compound as the predominant product 14
along with a small amount of C–O coupling and the corre-
sponding cyclized products 13a (Table 2, entry 1). The for-
mation of undesired self-coupling product can be rational-
Br
CONHPh
YH
Y = O, S
O
Ph
Path A:
Ullmann reaction
Y
N
intramolecular
Goldberg reaction
Br
Y
O
N
Ph
CuL*
O
Br
Ph
Path B:
intermolecular
Goldberg reaction
N
H
N
Ph
CONHPh
Br
O
Br
Scheme 1 Copper-catalyzed intramolecular and intermolecular Goldberg reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

C
Y. Chen et al.
Letter
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HO
O
O
O
Et
N
COOH
O
N
H
OH
COOH
N
H
N
N
HCl
L1
L2
L3
L4
L5
O
O
H
N
OH
N
N
N
N
H
NH2
OH
O
L6
L7
L8
L9
L10
Figure 2 Ligand toolbox
ized mechanistically by copper-catalyzed intermolecular
Goldberg reaction of N-phenyl-2-bromobenzamide
(Scheme 1, path B).
Thereby a new round of ligand screening was conducted
to improve chemoselectivity (Table 2).16 The use of ethyl 2-
oxocyclohexanecarboxylate (L5) and quinolin-8-ol (L6) as
ligand gave mixed products of 13a and 14 (Table 2, entries 2
and 3). Picolinic acid (L7) could give the corresponding di-
aryl ether as sole product, but the following intramolecular
Goldberg reaction did not occur even if the reaction tem-
perature was elevated to 140 °C (Table 2, entry 4). The best
result was observed by using 2,2,6,6-tetramethylheptane-
3,5-dione (L8) as ligand (Table 2, entry 5). After reacted at
80 °C for 12 hours and then 120 °C for 36 hours, the reac-
tion of 2-bromophenol with 2-bromo-N-phenylbenzamide
furnished the expected dibenzoxazepinone 13a with up to
92% yield. These results clearly demonstrated that the
choice of ligand could avoid the intermolecular Goldberg
Table 1 Optimization of the Reaction between 2-Bromothiophenol
and N-Phenyl-2-bromobenzamidea
Table 2 Optimization of the Reaction between 2-Bromophenol and N-
Phenyl-2-bromobenzamidea
CONHPh
CONHPh
Br
O
N
Ph
CONHPh
N
Br
H
O
O
Ph
Ph
8a
Ph
1. CuI, ligand,
base
CuI, ligand
base, DMF
Br
120 °C
Br
8a
N
N
S
+
+
+
O
SH
2. 120 °C, 36 h
Br
S
O
Br
10a
11a
13a
14
OH
12a
9a
Ligand
Entry
Ligand
Base
Solvent
Yield (%)b
Entry
Base
Temp (°C)
Yield (%)b
13a
14a
10a
11a
1
L4
Cs2CO3
DMF
DMF
DMF
DMF
DMF
22
60
32
10
1
2
3
4
5
6
7c
L1
L2
L3
L4
L4
L4
L4
K2CO3
100
100
100
100
100
100
120
51
60
80
85
90
97
n.d.d
2
L5
L6
L7
L8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
40
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
n.d.d
n.d.d
n.d.d
n.d.d
n.d.d
95
3
73
4c
5d
n.d.e
92
n.d.e
n.d.e
a Reaction conditions: 8a (0.25 mmol), 12a (0.375 mmol), CuI (0.025
mmol), ligand (0.050 mmol), base (0.50 mmol), solvent (1.0 mL), 100 °C,
12 h; then 120 °C, 36 h.
n.d.
b Isolated yield.
a Reaction conditions: 8a (0.25 mmol), 9a (0.375 mmol), CuI (0.025
mmol), ligand (0.050 mmol), base (0.50 mmol), solvent (1.0 mL), 100 °C,
c The reaction was conducted with L7 and only afforded O-arylated product
instead of the desired intramolecular cyclization product dibenzoxazepino-
ne.
12 h.
b Isolated yield.
d 80 °C, 12 h, then 120 °C, 36 h.
c 100 °C, 12 h; then 120 °C, 36 h.
d n.d. = not detected.
e n.d. = not detected.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

D
Y. Chen et al.
Letter
Synlett
reaction and have remarkable influence on both chemose-
lectivity and conversion.
Entry
8
Y
Yield (%)b
O
After the optimized reaction conditions were estab-
lished, we set out to explore the substrate scope of this
method. The results were shown in Table 3. The benzamide
derivatives 8a–m possessing a variety of N-substitutents,
including aromatic, heterocyclic, cyclic, and acyclic substit-
uents even with functional groups, were readily derived from
2-bromobenzonic acid. Reactions of the prepared 2-bromo-
benzamides with 2-bromothiophenol under conditions A
or with 2-bromophenol under conditions B resulted in the
corresponding N-substituted dibenzothiazepines and
dibenzoxazepinones with 73–95% yields (Table 3, entries 1–
19). For the comparison, reaction of 2-bromobenzamide 8n
and 2-bromothiophenol was also conducted and afforded
corresponding N-unsubstituted dibenzothiazepinone in the
yield of 85% (Table 3, entry 20). These results indicate that
variation on N-substituent has less effect on the yields of fi-
nal products.
Me
5
6
S
O
89
93
N
H
Br
O
8d
8e
8f
N
H
7
8
O
S
87
85
Br
O
n-Hexyl
N
H
Br
O
9
10
S
O
93
85
N
H
Table 3 Synthesis of Dibenzothiazepinones and Dibenzoxazepinones
via a CuI-Catalyzed One-Pot Coupling–Cyclization Process from 2-Bro-
mobenzamidesa
Br
O
8g
CONHR2
11
12
S
O
82
86
N
H
R1
O
R2
Br
O
X
8h
8i
N
8
condtions A or B
R1
+
Y
Br
Bn
13
14
S
O
90
84
N
H
Y = S, 11
Y = O, 13
YH
Y = S, 9
Y = O, 12
Br
O
O
Entry
8
Y
Yield (%)b
N
H
15
S
91
O
Br
O
Ph
8j
1
2
S
O
95
92
N
H
O
Br
O
N
8a
16
17
S
O
87
85
N
H
OMe
Br
O
8k
8l
3
4
N
H
O
87
85
Br
O
8b
8c
N
H
5COOMe
18
19
S
78
73
Br
O
N
H
S
Br
N
N
H
O
Br
8m
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

E
Y. Chen et al.
Letter
Synlett
Table 3 (continued)
employed in the methodology, thus enabled the synthesis
of dibenzoxazepinone from a wide range of readily avail-
able starting materials (Table 3, entries 26, 27). It is notable
that several bioactive compounds could be efficiently pre-
pared by this one-pot process. For example, hydroxylami-
nolysis of 8l could form the core unites for a class of histone
deacetylase inhibitors 4 which possesses potent antiprolif-
erative and differentiating activities and are regarded as
promising antitumor agents 3. The N-alkyl dibenzoxazepi-
none, derived from 13e, represent novel non-nucleoside in-
hibitors of HIV-1 reverse transcriptase 5b.
Entry
8
Y
Yield (%)b
O
NH2
20c
S
S
85
Br
8n
O
MeO
Ph
N
H
21
89
Br
In 2012, Snieckus described a protocol for the construc-
tion of dibenzoxazepinones.17 It was observed that an un-
usual Smiles rearrangement occurred before final ring-clos-
ing process. Regardless a notable achievement, the investi-
gation scope was limited to the reaction of substituted 2-
bromophenols and 2-iodobenzamides. Thus we became in-
terested in determining whether the rearrangement would
take place in the reaction between 2-bromothiophenols
and 2-bromobenzamides.
8o
O
PhHNOC
8p
Ph
22
23
S
O
80
82
N
H
Br
O
O2N
Ph
N
H
24
S
68
74
75
80
The model reaction of 2-bromo-4-chlorothiophenol
(9b) and N-phenyl-2-bromobenzamide (8a) was conducted
under the optimized conditions (Table 4). 2,2,6,6-Te-
tramethylheptane-3,5-dione (L8) gave sole Goldberg prod-
uct 11u in 87% yield (Table 4, entry 1), and the structure
was further confirmed by an X-ray crystallographic analysis
(see Supporting Information). However, N,N-dimethylgly-
cine hydrochloride (L4) provided a mixture of both Gold-
berg and rearrangement products (Table 4, entry 2). These
results indicate that ligands were marginally effective on
tuning selectivity of the coupling–annulation process.
Consequently, parallel reactions with a series of ligands
were carried out according to the same procedures as be-
fore. Reaction in the absence of ligand needs higher reac-
tion temperature and prolonged time to realize the final cy-
clization and afford 8-chloro-N-phenylbenzothiazepinone
(11u) in 83% yield (Table 4, entry 3). Diketone ligands (L8,
L5) manifested great catalytic activity to realize the final
ring-closing step at 120 °C with excellent yields (Table 4,
entries 1, 4). N-Substituted α-amino acid (L2) or equiva-
lents (L6, L7) were also effective to provide dibenzothiaze-
pinone 11u as predominant product along with a small
amount of rearrangement compound 15u (Table 4, entries
2, 5, 6). L-Proline (L3) and analogue (L1) possessing N–H
moiety gave almost trisected mixture of dibenzoxazepino-
ne 11u, 15u and intermediate 10u (Table 4, entries 7, 8). Di-
amine ligands (L2, L9, and L10) exhibited reversed selectiv-
ity but weakened reactivity compared to that of diketones
(Table 4, entries 9–11). These results clearly demonstrate
that the choice of ligands have remarkable influence on
Smiles rearrangement chemical processes. Furthermore, a
survey of bases conducted under the same conditions sug-
gested that the reaction proceeded more efficiently in the
presence of Cs2CO3 than KOt-Bu and K3PO4 (Table 4, entries
12, 13).
Br
8q
O
Ph
N
H
25
S
F
8r
Br
O
N
26d
O
O
H
N
Cl
O
8s
8t
N
H
27c
Cl
a Reaction conditions for Y = S: 2-bromobenzamide (0.25 mmol), 2-bromo-
thiophenol (0.375 mmol), CuI (0.025 mmol), N,N-dimethylglycine hydro-
chloride (0.050 mmol), Cs2CO3 (0.50 mmol), DMF (1.0 mL), 100 °C, 12 h;
then 120 °C, 36 h; Reaction conditions for Y = O: 2-bromobenzamide (0.25
mmol), 2-bromophenol (0.375 mmol), CuI (0.025 mmol), 2,2,6,6-te-
tramethylheptane-3,5-dione (0.050 mmol), Cs2CO3 (0.50 mmol), DMF (1.0
mL), 80 °C, 12 h; then 120 °C, 36 h.
b Isolated yield.
c 100 °C, 12 h; then 140 °C, 36 h.
d 100 °C, 12 h; then 120 °C, 48 h.
Next, the effect of electronic property on the 2-bromo-
benzoxyl moiety was investigated. Substrates with elec-
tron-donating groups gave higher yield than with electron-
withdrawing groups (Table 3, entries 21–25). It was noted
that the reaction showed a regioselectivity to the bromo
position other than the fluor position where the nucleop-
hilc substitution on aromatic rings occurs commonly. Addi-
tionally, aromatic chlorides as substrate were successfully
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

F
Y. Chen et al.
Letter
Synlett
Next, 2-Bromothiophenols with different substituents
were checked under the standard experimental conditions.
From the results listed in Table 5, we can ascribe the reac-
tion selectivity to the electronic nature of thiophenol sub-
strates. For example, the presence of halogen and methyl
group in thiophenol at C4 position provided single Gold-
berg product (Table 5, entries 1–3). When a strong elec-
tron-withdrawing group such as trifloromethyl group was
presented at C4 position, the reaction afforded the rear-
rangement product (Table 5, entry 4). 5-Chloro-2-bromo-
thiophenol gave a mixture of two dibenzoxazepinone prod-
ucts (Table 5, entry 5). Coupling reaction of 5-methyl-2-
bromothiophenol and N-phenyl-2-bromobenzamide pro-
ceeded smoothly, but the following cyclization could not be
realized under current conditions unless the temperature
increased to 140 °C.
In summary, we have developed a highly efficient and
generally applicable one-pot protocol for the construction
of dibenzothiazepines and dibenzoxazepinones and their
structural analogues via copper-catalyzed tandem C–
S(O)/C–N coupling reactions. It was also found that ligands
have remarkable influence on both chemoselectivity and
conversion. Moreover, this facile methodology allows rapid
access to a variety of bioactive compounds and known psy-
chotropic drug, which should broaden its application in or-
ganic synthesis.
Acknowledgment
This work was supported by the Collaborative and Innovation Pro-
gram for Education and Research (1021ZK162001). The authors
would like to thank the Perfume, Aroma and Cosmetic Service Center,
Table 4 Ligand Screening in the CuI-Catalyzed Reaction of 2-Bromo-4-chlorothiophenol and N-Phenyl-2-bromobenzamidea
Ph
NH
O
Br
S
SH
O
Br
Cl
10u
N
CuI, ligand
DMF, base
+
coupling
H
O
Ph
O
Ph
Br
N
Cl
N
8a
9b
+
S
Cl
S
Cl
11u
15u
coupling–cyclization
rearrangement cyclization
Entry
Ligand
Base
Yield (%)b
10u
11u
15u
1
2
L8
L4
–
Cs2CO3
0
0
87
81
83
91
72
85
30
27
23
11
26
0
0
15
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOt-Bu
K3PO4
3c
4
0
L5
L6
L7
L3
L1
L2
L9
L10
L10
L10
0
0
5
0
18
0
6
0
7
28
35
27
54
19
91
88
32
27
44
31
50
0
8
9
10
11
12
13
0
0
a Reaction conditions A: 8a (0.25 mmol), 9b (0.375 mmol), CuI (0.025 mmol), ligand (0.050 mmol), base (0.50 mmol), DMF (1.0 mL), 100 °C, 12 h; then 120 °C,
36 h.
b Isolated yield.
c 100 °C, 12 h; then 140 °C, 48 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

G
Y. Chen et al.
Letter
Synlett
Table 5 The Effect of Substituents on Smiles Rearrangement in the
Primary Data
Synthesis of Dibenzothiazepinonesa
for this article are available online at http://www.thieme-con-
nect.com/products/ejournals/journal/10.1055/s-00000083 and
O
can be cited using the following DOI: 10.4125/pd0088th. PmriaryDatPmriaryDat104.1
2
5
p/
d
0
0
8
8
Pthm.riary
D
atZ
a
heln
1
0
1
C
h
e
msytri
N
H
O
O
Br
Ph
Ph
8a
CuI (10 mol%)
L5 (20 mol%)
References
N
N
R
+
+
(1) (a) Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M. J.;
Breslin, H. J.; Raeymaeckers, A.; Van Gelder, J.; Woestenborghs,
R.; Heykants, J. Nature (London, U.K.) 1990, 343, 470.
(b) Hargrave, K. D.; Proudfoot, J. R.; Grozinger, K. G.; Cullen, E.;
Kapadia, S. R.; Patel, U. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, J. J.
Med. Chem. 1991, 34, 2231. (c) Inoue, H.; Konda, M.; Hashiyama,
T.; Otsuka, H.; Takahashi, K.; Gaino, M.; Date, T.; Aoe, K.; Takeda,
M. J. Med. Chem. 1991, 34, 675. (d) Das, J.; Floyd, D. M.; Kimball,
S. D.; Duff, K. J.; Lago, M. W.; Krapcho, J.; White, R. E.; Ridgewell,
R. E.; Obermeier, M. T. J. Med. Chem. 1992, 35, 2610.
(e) Goldstein, J. M.; Arvanitis, L. A. CNS Drug Rev. 1995, 1, 50.
(f) Murakami, Y.; Hara, H.; Okada, T.; Hashizume, H.; Kii, M.;
Ishihara, Y.; Ishikawa, M.; Shimamura, M.; Mihara, S.; Kato, G.;
Hanasaki, K.; Hagishita, S.; Fujimoto, M. J. Med. Chem. 1999, 42,
2621. (g) Levy, O.; Erez, M.; Varon, D.; Keinan, E. Bioorg. Med.
Chem. Lett. 2001, 11, 2921. (h) Storck, P.; Aubertin, A. M.;
Grierson, D. S. Tetrahedron Lett. 2005, 46, 2919. (i) Vilar, S.;
Santana, L.; Uriarte, E. J. Med. Chem. 2006, 49, 1118. (j) Al-Tel, T.
H.; Al-Qawasmeh, R. A.; Schmidt, M. F.; Al-Aboudi, A.; Rao, S. N.;
Sabri, S. S.; Voelter, W. J. Med. Chem. 2009, 52, 6484.
DMF, Cs2CO3
S
S
SH
R
Br
11
15
coupling–cyclization rearrangement–cyclization
R
9
Entry
9
Yield (%)b
11
15
SH
Br
1
2
3
87
0
Cl
9b
SH
Br
84
87
0
0
0
Br
9c
SH
(2) (a) Burstein, E. S.; Gardell, L. R. WO 2008118141, 2008.
(b) Pettersson, H.; Bülow, A.; Ek, F.; Jensen, J.; Ottesen, L. K.;
Fejzic, A.; Ma, J. N.; Del Tredici, A. L.; Currier, E. A.; Gardell, L. R.
J. Med. Chem. 2009, 52, 1975.
(3) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.;
Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao,
M.; Garattini, E. ACS Med. Chem. Lett. 2010, 1, 411.
Br
9d
SH
Br
4
78
38
0
F3C
9e
(4) Newton, G. L.; Buchmeier, N.; La Clair, J. J.; Fahey, R. C. Bioorg.
Med. Chem. 2011, 19, 3956.
Cl
SH
(5) (a) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.; Grozinger, K.;
Skoog, M.; Wu, J. C.; Shih, C. K.; Eckner, K.; Hattox, S.; Adams, J.
Science 1990, 250, 1411. (b) Klunder, J. M.; Hargrave, K. D.;
West, M.; Cullen, E.; Pal, K.; Behnke, M. L.; Kapadia, S. R.;
McNeil, D. W.; Wu, J. C.; Chow, G. C. J. Med. Chem. 1992, 35,
1887. (c) Li, R.; Farmer, P.; Wang, J.; Boyd, R.; Cameron, T.;
Quilliam, M.; Walter, J.; Howlett, S. Drug Des. Discovery 1995,
12, 337.
(6) (a) Kumar, K. V.; Kanhaiya, L.; Suhail, A.; David, L. WO
2006113425, 2006. (b) Thase, M. E.; Macfadden, W.; Weisler, R.
H.; Chang, W.; Paulsson, B.; Khan, A.; Calabrese, J. R. J. Clin. Psy-
chopharmacol. 2006, 26, 600.
(7) (a) David, J.; Grewal, R. Indian J. Exp. Biol. 1974, 12, 225.
(b) Nagarajan, K. Indian J. Chem. 1974, 12, 270. (c) Nagarajan, K.;
David, J.; Kulkarni, Y.; Hendi, S.; Shenoy, S.; Upadhyaya, P. Eur. J.
Med. Chem. 1986, 21, 21.
(8) (a) Jann, M. W. Pharmacotherapy 1991, 11, 179. (b) Liao, Y.;
Venhuis, B. J.; Rodenhuis, N.; Timmerman, W.; Wikström, H. J.
Med. Chem. 1999, 42, 2235.
5
56
76
Br
9f
SH
6c
Br
9g
a Reaction conditions: 2-bromobenzamide (0.25 mmol), 2-bromothiophe-
nol (0.375 mmol), CuI (0.025 mmol), N,N-dimethylglycine (0.050 mmol),
Cs2CO3 (0.50 mmol), DMF (1.0 mL), 100 °C, 12 h; then 120 °C, 36 h.
b Isolated yield.
c100 °C, 12 h; then 140 °C, 36 h.
Shanghai for their scientific and technical support. The author is also
grateful to Prof. Dawei Ma’s guidance and helpful advice.
(9) (a) Allen, R. C.; Reitano, P. A.; Urbach, H. J. Med. Chem. 1978, 21,
838. (b) Konstantinova, A.; Gerasimova, T.; Kozlova, M.;
Petrenko, N. Chem. Heterocycl. Compd. 1989, 25, 451. (c) Samet,
A. V.; Marshalkin, V. N.; Kislyi, K. A.; Chernysheva, N. B.;
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1558959.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

H
Y. Chen et al.
Letter
Synlett
Strelenko, Y. A.; Semenov, V. V. J. Org. Chem. 2005, 70, 9371.
(d) Samet, A.; Kislyi, K.; Marshalkin, V.; Semenov, V. Russ. Chem.
Bull. 2006, 55, 549.
R.; Rodríguez Rivero, M.; Buchwald, S. L. Angew. Chem. Int. Ed.
2006, 45, 7079. (j) Bao, W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett.
2008, 10, 3899. (k) Coste, A.; Toumi, M.; Wright, K.;
Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett.
2008, 10, 3841. (l) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem.
2009, 121, 354.
(10) (a) Lu, S. M.; Alper, H. J. Am. Chem. Soc. 2005, 127, 14776.
(b) Yang, Q.; Cao, H.; Robertson, A.; Alper, H. J. Org. Chem. 2010,
75, 6297.
(11) Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133,
14228.
(14) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(c) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48,
6954. (d) Sperotto, E.; Van Klink, G. P. M.; Van Koten, G.; De
Vries, J. G. Dalton Trans. 2010, 39, 10338. (e) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(15) (a) Cai, Q.; Zou, B.; Ma, D. Angew. Chem. Int. Ed. 2006, 45, 1276.
(b) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
(c) Cai, Q.; Zhang, H.; Zou, B.; Xie, X.; Zhu, W.; He, G.; Wang, J.;
Pan, X.; Chen, Y.; Yuan, Q.; Jiang, Y.; Ma, D. Pure Appl. Chem.
2009, 81, 227.
(16) (a) Jiang, Y.; Xu, L.; Zhou, C.; Ma, D. Cu-Catalyzed Ullmann-Type
C-Heteroatom Bond Formation: The Key Role of Dinucleating
Ancillary Ligands, In RSC Catalysis Series; RCS: Cambridge, 2013,
1. (b) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
17423.
(12) (a) Yang, B.; Tan, X.; Guo, R.; Chen, S.; Zhang, Z.; Chu, X.; Xie, C.;
Zhang, D.; Ma, C. J. Org. Chem. 2014, 79, 8040. (b) Zhou, Y.; Zhu,
J.; Li, B.; Zhang, Y.; Feng, J.; Hall, A.; Shi, J.; Zhu, W. Org. Lett.
2016, 18, 380. (c) Yang, X.; Shan, G.; Rao, Y. Org. Lett. 2013, 15,
2334. (d) Zhao, Y.; Dai, Q.; Chen, Z.; Zhang, Q.; Bai, Y.; Ma, C. Acs
Comb. Sci. 2013, 15, 130. (e) Shen, C.; Neumann, H.; Wu, X. F.
Green Chem. 2015, 17, 2994. (f) Zhang, Z.; Dai, Z.; Ma, X.; Liu, Y.;
Ma, X.; Li, W.; Ma, C. Org. Chem. Front. 2016, 3, 799.
(13) (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem. Int. Ed. 2007, 46, 2598.
(b) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291. (c) Wang,
B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761.
(d) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew.
Chem. 2009, 121, 4286. (e) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y.
Angew. Chem. 2010, 122, 1313. (f) Ma, D.; Lu, X.; Shi, L.; Zhang,
H.; Jiang, Y.; Liu, X. Angew. Chem. Int. Ed. 2011, 50, 1118. (g) Xu,
L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150. (h) Xu, L.; Peng, Y.;
Pan, Q.; Jiang, Y.; Ma, D. J. Org. Chem. 2013, 78, 3400. (i) Martín,
(17) Kitching, M. O.; Hurst, T. E.; Snieckus, P. V. Angew. Chem. Int. Ed.
2012, 124, 2979.
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