Synthesis of phenothiazines from cyclohexanones and 2-aminobenzenethiols under transition-metal-free conditions

Article abstract of DOI:10.1039/c3ra43989e

A convenient method for the synthesis of various substituted phenothiazines from cyclohexanones and 2-aminobenzenethiols using molecular oxygen as hydrogen acceptor in the absence of transition-metals is described. For the first time cyclohexanones were used as coupling partners for the construction of phenothiazines.

Full text of DOI:10.1039/c3ra43989e

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ARTICLE TYPE
Synthesis of phenothiazines from cyclohexanones and 2-
aminobenzenethiols under transition-metal-free conditions†
Yunfeng Liaoa, Pengcheng Jianga, Shanping Chena, Fuhong Xiaoa, Guo-Jun Deng*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A convenient method for the synthesis of various substituted phenothiazines from cyclohexanones and 2-aminobenzenethiols using
molecular oxygen as hydrogen acceptor in the absence of transition-metals is described. For the first time cyclohexanones were used as
coupling partners for construction of phenothiazines.
Phenothiazines are a class of important heterocycles and widely
10 used as common building blocks for the synthesis of
heterocycles.7 In 2008, Jørgensen et al. reported a protocol for the
synthesis of N-substituted phenothiazines via the palladium-
pharmaceuticals. Successful examples include the promazine 40 catalyzed three components coupling of bromothiophenols,
drugs, antitubercular agent, cholinesterase inhibitor, histamine H1
antagonist and multiple drug resistance reverting agent (Scheme
1).1 In addition, phenothiazine moieties have been found
15 frequently in other important molecules such as optoelectronic
primary amines and 1-bromo-2-iodobenzene derivatives.8 This
reaction assembled the N-substituted phenothiazines via
formation one C-S and two C-N bonds in one-pot. Ma et al.
developed the sequentially controlled CuI/proline-catalyzed
materials, antioxidants, polymerization inhibitors, industrial dyes 45 cascade C-S and C-N coupling of 2-bromothiophenols and 2-
and agrochemical compounds.2 Consequently, development of
iodoanilines for the synthesis of substituted phenothiazines.9
More recently, phenothiazines were synthesized by Cu-catalyzed
rearrangement of 2-aminobenzothiazoles in the presence of 1,2-
efficient methods for rapid construction of substituted
phenothiazines
20 Traditionally, phenothiazines were synthesized using the iodine-
catalyzed thionation reaction of diphenylamines with sulfur at 50 phenothiazine formation from aryl ortho-dihalides and 2-
has
stimulated
considerable
interest.
dibromobenzene.10 Zeng et al. developed
a CuI-catalyzed
high temperature.3 When meta-substituted diphenylamines are
used, the thionation at high temperature shows poor
regioselectivity and affords two regioisomers in a near 1:1 ratio
25 which are very
aminobenzenethiols in the absence of ligand.11 Apart from this,
Trivedi Amit R. et al reported a method of preparation of
phenothiazine from 2-aminobenzenethiols and substituted
phenols.12 In these excellent protocols which at least four reactive
55 centers existed in all coupling partners, the regioselectivity of the
coupling reactions was well controlled by using various efficient
transition-metal catalysts. Although transition-metals played very
important role in the selective carbon-heteroatom bond formation,
the preparation of these compounds under transition-metal-free
60 conditions is highly desirable especially for pharmaceutical
purposes due to the low threshold residual tolerance of metals.
Cyclohexanones are cheap, stable, readily available and easy to
handle. Recently, the Stahl group found that these compounds
can be dehydrogenated under palladium catalyzed reaction
65 conditions to selectively give the corresponding phenols or
cyclohexenones using molecular oxygen as hydrogen acceptor.13
We and others successfully used cyclohexanones as aryl sources
for C-N14 and C-O bond15 formation via palladium-catalyzed
dehydrogenation-tautomerization reactions. Carbazoles and 2-
70 Aminobenzothiazoles were prepared from cyclohexanones using
molecular oxygen as hydrogen acceptor without the aid of
transition-metals.16
S
N
S
N
S
N
R
O
OnBu
N
N
cholinesterase
inhibitor
Proethazin Tabs
(2006 sales: $127.4 million)
R = Cl, chlopromazine
R = CF3, triflupromazine
Scheme
1
Sampling of important drugs containing the
phenothiazine core.
difficult to separate because of the structural similarity. The
30 Smiles rearrangement provided an alternative approach to
overcome this drawback, but its four-step route increases the
synthetic difficulty and costs.4 Functionalization of unsubstituted
phenothiazine can provide a direct approach for preparation of
substituted phenothiazines although this method always suffers
35 from a lack of regioselectivity.5, 6
We envisaged that cyclohexanones might be similarly used as
aryl sources for construction of substituted phenothiazines with 2-
75 aminobenzenethiols (Scheme 2). The condensation of amino with
the carbonyl group in cyclohexanones will generate an imine
The transition-metal-catalyzed cross-coupling reactions have
proved to be very useful tools for constructing substituted
intermediate
a
which can be transformed into enamine
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intermediate
b
via tautomerization reaction.17 Subsequent
to give the desired products in good yields (entries 2-5). When 4-
phenylcyclohexanone (2f) was reacted with 1a, the desired
product 3f was obtained in 81% yield (entry 6). Ester functional
addition of thiol to enamine will afford a cyclized intermediate c.
The successive dehydrogenation of c will generate the final
50 Table 1 Optimization of the reaction conditionsa
O
S
SH
additives
O2
R1
R2
R1
+
O
R2
N
H
S
SH
NH2
additives
O2
3
+
N
H
NH2
dehydrogenation
condensation
1a
2a
3a
SH
N
SH
S
R1
R1
addition
R1
R2
Entry Additive 1 (mol %) Additive 2 (mol %) Solvent Yield (%)b
N
H
N
H
1
PhCl
26
R2
R2
a
c
b
2
3
DMSO (10)
A-1
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
35
43
5
Scheme 2 New strategy for the synthesis of phenothiazines from
(10)
cyclohexanones and 2-aminobenzenethiols.
4
5
6
7
A-2 (10)
A-3 (10)
A-4 (10)
41
39
37
product 3. Since only three reactive centers existed in both
coupling partners and the condensation reaction of amino group
A-1
trace
(10)
K2CO3 (10)
KBr (10)
KI (10)
10 with carbonyl group is very fast, the regioselectivity control for
this kind of transformation will be very simple. In the whole
process, no transition-metal is required and molecular oxygen can
be used as a green oxidant.
A-1 (10)
8
39
9
A-1 (10)
87
A-1
I2 (10)
10
11
12
13
14
15
16
17
(10)
PhCl
PhCl
PhCl
PhCl
PhCl
toluene
NMP
DMF
PhCl
37
64
73
79
69
9
To validate this hypothesis, we began our study by examining
15 the reaction of 2-aminobenzenethiol (1a) with cyclohexanone
(2a) in chlorobenzene by using molecular oxygen as oxidant at
140 oC. When 2-aminobenzenethiol reacted with 1.5 equiv of
cyclohexanone in the absence of any additives, the desired
product 3a was obtained in 26% yield as determined by GC and
20 1H NMR methods (Table 1, entry 1). Then various additives were
investigated under similar reaction conditions. The use of 10 mol
% DMSO could slightly improve the reaction yield to 35% (entry
2). Inspired by this, we tested various organic compounds
containing sulfone group and found that the use of benzyl aryl
25 sulfone is helpful for improving the reaction yield (entries 3-6).
Among them, benzyl phenyl sulfone (A-1) showed the best yield.
With A-1 as the organic additive, various inorganic chemicals
were also tested. K2CO3 completely inhibited the reaction and no
product was observed (entry 7). The use of salts containing
30 halogen benefited the reaction, and the desired product was
obtained in 87% yield when 10 mol % of potassium iodide (KI)
was employed (entry 9). Decreasing the amount of A-1 or KI
both decreased the reaction yield (entries 11-13). It is interesting
that use more KI also decreased the reaction yield (entry 14). The
35 replacement of chlorobenzene with other organic solvents all
decreased the reaction yield and no desired product was obtained
when DMF was used (entries 15-17). Much lower yield was
obtained when the reaction was carried out under an atmosphere
of air and no product was observed in argon (entries 18 and 19).
40 Temperature is another important factor for the reaction yield and
the reaction yield decreased to 65% when the temperature was
decreased to 120 oC (entry 20).
A-1 (5)
KI (10)
KI (10)
KI (5)
A-1
A-1
(10)
(10)
KI (20)
KI (10)
KI (10)
KI (10)
KI (10)
A-1 (10)
A-1
(10)
42
trace
30
A-1 (10)
A-1 (10)
18c
19d
A-1
(10)
KI (10)
KI (10)
PhCl
PhCl
trace
65
20e
A-1 (10)
a
1a
2a
(0.3 mmol), solvent (0.8 mL), 24 h,
Conditions:
(0.2 mmol),
140 oC, under oxygen unless otherwise noted. b GC yield based on
1a using dodecane as internal standard. c Under air. d Under argon.
e 120 oC.
F
OCH3
Ph
O
Ph
S
Ph
S
O
Ph
S
Ph
S
O
O
O
O
O
O
A-1
A-2
A-3
A-4
group could be well tolerated under the optimized reaction
conditions, and the corresponding product 3g was obtained in
55 72% yield (entry 7). Two isomers were obtained in a combination
yield of 70% (3h:3h’= 2:1) when 3-methylcyclohexanone (2h)
was used (entry 8). The position of the substituents on the
cyclohexanone ring profoundly affected the reaction yield. No
product was observed when 2-methylcyclohexanone (2i) was
60 used as the substrate due to the steric effect (entry 9).
Interestingly, the use of more reactive 3-methylcyclohex-2-enone
(2j) gave corresponding product with low yield, and the product
With the optimized reaction conditions established, a number
of substituted cyclohexanone derivatives were employed to react
45 with 1a (Table 2). The reactions with cyclohexanones bearing
electron-donating groups at the para position proceeded smoothly
2
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was isolated in 52% yield (entry 10).
Table Reaction of 2-aminobenzenethiol (1a) with various
cyclohexanonesa
25
2
Table
cyclohexanonesa
3
Reaction of various 2-aminobenzenethiols with
O
O
SH
S
S
SH
A-1
/ KI
O2, 140 o
A-1
/ KI
O2, 140 o
R1
+
R2
R1
R
R2
+
C
R
NH2
C
N
H
3
N
H
NH2
1
2
1a
2
3
Entry
Substrate
Substrate
Product
S
Yield (%)b
1
2
Entry Cyclohexanone
O
Product
S
Yield (%)b
SH
R1
R1
R
N
H
NH2
R
N
H
R1 = 5-CH3
1
1b
2a
3k
62
71(70)c
83
1
3a
3b
2a
R = H
R1 = 5-OCH3
R1 = 5-F
2
3
4
1c
1d
1e
2a
2a
2a
3l
58
76
75
2
3
4
2b
2c
2d
2e
R = 4-Me
R = 4-Et
3m
3n
3c
3d
3e
76
70
80
R1 = 5-Cl
R = 4-pentyl
R1 = 4-CH3
5
6
1f
2a
2a
3o
3p
65
60
5
R = 4-(tert-pentyl)
R1 = 4-CF3
1g
6
7
R = 4-pheny
3f
81
72
2f
1 = 4-F
7
8
9
1h
1i
2a
2a
2a
3q
3r
58
R
R = 4-CO2C2H5
3g
2g
R1 = 4-Cl
70
S
R1 = 3-CH3
1j
3s
trace
N
H
CH3
R1 = 5-Br
10
1K
2a
3a
55
3h
70
(3h:3h'=2:1)
+
Cl
S
R2
CH3
8
R = 3-Me
2h
Cl
SH
NH2
S
N
H
N
H
3h'
11
12
13
1e
1e
1e
2b
2c
2e
3t
(R2 = Me)
71
76
81
9
R = 2-Me
3i
3j
trace
52
2i
2j
3u
(R2 = Et)
O
10
3v
(R2 = tert-pentyl)
CH3
14
1e
2g
3w
(R2 = CO2Et)
85
a
1a
2
(0.2 mmol), (0.3 mmol), benzylsulfonyl)benzene
Conditions:
, 0.02 mmol), KI (0.02 mmol), PhCl (0.8 mL), 24 h, 140 oC, under
A-1
(
a
oxygen. b Isolated yield based on 1a. c Reaction was performed on a
Conditions: 1 (0.2 mmol), 2 (0.3 mmol), A-1 (benzylsulfonyl)benzene
(0.02 mmol), KI (0.02 mmol), PhCl (0.8 mL), 24 h, 140 oC, under oxygen.
b Isolated yield based on 1.
0.5 mmol scale.
5
To further explore the scope of the reaction, various 2-
aminobenzenethiols were employed to react with 2a under the
optimized conditions (Table 3). The reactions with 2-
aminobenzenethiols bearing electron-donating groups and
Conclusions
30
In summary, we have developed a novel approach for
10 electron-withdrawing substituents proceeded smoothly to give the
desired products in moderate to good yields. A series of
functional groups including methyl, methoxy, chloro and
trifluoromethyl were well tolerated under the optimal conditions
(entries 1-8). Interestingly, the reaction of 2-amino-5-
15 bromobenzenethiol (1k) with 2a also gave product 3a in 55%
yield (entry 10). In this reaction, the active bromide substitute
was hydrogenated under the reaction conditions. The position of
the methyl substituents on the phenyl ring of 2-
aminobenzenethiols affected the reaction yield significantly, and
20 the use of 2-amino-3-methylthiophenol (1j) only gave trace
amount of product (entry 9).The reaction of 1e with
cyclohexanones gave better reaction yields (entries 11-14). When
2e and 2g reacted with 1e, the desired product 3v and 3w were
obtained in 81% and 85% yields, respectively.
phenothiazine formation from 2-aminobenzenethiols and
cyclohexanones using molecular oxygen as hydrogen acceptor
under transition-metal-free conditions. The combination use of
benzyl phenyl sulfone and KI significantly improved the reaction
35 yields. For the first time cyclohexanones were used as efficient
coupling partners for phenothiazine synthesis. The condensation,
tautomerization, cyclization and dehydrogenation were realized in
one-pot. Functional groups such as alkyl, methoxy, fluoro, chloro,
trifluoromethyl and ester were all well tolerated under the
40 optimized reaction conditions. This method affords an alternative
route for the synthesis of phenothiazines in the absence of
transition-metal-catalyst. The scope, mechanism, and synthetic
applications of this reaction are under investigation.
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This work was supported by the National Natural Science
Foundation of China (21172185), the Hunan Provincial Natural
Science Foundation of China (11JJ1003, 12JJ7002), the New
Century Excellent Talents in University from Ministry of
Education of China (NCET-11-0974) and the Research Fund for
the Doctoral Program of Higher Education of China, Ministry of
Education of China (20124301110005).
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Notes and references
10 a Key Laboratory of Environmentally Friendly Chemistry and Application
of Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan 411105, China. Fax: (+86)0731-5829-2251; Tel: (+86)0731-
5829-8601; E-mail: gjdeng@xtu.edu.cn
b Key Laboratory of Molecular Recognition and Function, Institute of
15 Chemistry, Chinese Academy of Sciences, Beijing 100080, China.
† Electronic Supplementary Information (ESI) available: Experimental
section, spectra data and other information. See DOI: 10.1039/b000000x/
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Synthesis of phenothiazines from cyclohexanones and 2-aminobenzenethiols under
transition-metal-free conditions
Yunfeng Liao, Pengcheng Jiang, Shanping Chen, Fuhong Xiao, Guo-Jun Deng*