Transition-metal-free synthesis of phenothiazines from S-2-acetamidophenyl ethanethioate and ortho-dihaloarenes

Article abstract of DOI:10.1080/00397911.2017.1281959

An efficient cesium carbonate-mediated synthesis of phenothiazine derivatives from S-2-acetamidophenyl ethanethioates and ortho-dihaloarenes has been developed. This protocol affords an efficient approach for the construction of phenothiazine derivatives without the need of transition-metal catalyst or ligand. A plausible mechanism is proposed.

Full text of DOI:10.1080/00397911.2017.1281959

Transition Metal free Synthesis of Phenothiazines from S-2-acetamidophenyl
Ethanethioate and Ortho-Dihaloarenes
1
1
1
Yue Zhou , Qingle Zeng , Li Zhang
1
State Key Laboratory of Geohazard Prevention and Geoenvironment Protection
(Chengdu University of Technology), College of Materials, Chemistry & Chemical
Engineering, Chengdu University of Technology, Chengdu, Sichuan, P. R. China.
Coresponding to author: Qingle Zeng State Key Laboratory of Geohazard Prevention
and Geoenvironment Protection (Chengdu University of Technology), College of
Materials, Chemistry & Chemical Engineering, Chengdu University of Technology, 1#,
Dongsanlu, Erxianqiao, Chengdu 610059, Sichuan, P. R. China. E-mail:
qinglezeng@hotmail.com
Abstract
An efficient cesium carbonate-mediated synthesis of phenothiazine derivatives from
S-2-acetamidophenyl ethanethioates and ortho-dihaloarenes has been developed. This
protocol affords an efficient approach for the construction of phenothiazine derivatives
without the need of transition-metal catalyst or ligand. A plausible mechanism is
proposed.
Graphical Abstact
KEYWORDS: Phenothiazines; cesium carbonate; S-2-acetamidophenyl ethanethioates;
ortho-dihaloarenes; synthetic method
1

INTRODUCTION
Phenothiazines are extensively used in various fields, such as tricyclic antipycholic drugs,
1
rubber solidation agents. Thus synthesis of phenothiazines is becoming a hot research
spot in recent years. In traditional methods, phenothiazines are prepared via heating
2
3
diphenylamines and sulfur in high temperature, or via Smiles rearrangement. But the
two reactions afford low yields, and have narrow substrate scopes, that is, the former is
only suitable for some simple diphenylamines, and the latter are low atom economic and
uses ortho-nitroaryl halides as the complex substrates. Derivatization of phenothiazine
4
usually affords substituted phenothiazines with poor regioselectivity.
In 2008 Jørgensen and coworkers discovered the synthesis of N-substituted
phenothiazines via the palladium-catalyzed three component coupling of substituted
5
1
-bromo-2-iodobenzenes, primary amines and 2-bromobenzenethiol. Later Ma et al.
reported CuI/L-proline-catalyzed cascade C-S and C-N coupling of 2-iodoanilines and
6
2
-bromobenzenethiols. In 2012 our group disclosed a copper-catalyzed tandem C-S/C-N
coupling protocol, which avoids self-coupling reaction of the reactants via adopting
ortho-aminothiophenols as bi-nucleophiles and ortho-dihalobenzenes as bi-electrophiles.
More recently Zhang et al. developed a greener iron-catalyzed protocol to construct the
7
8
functionalized phenothiazines.
2

Transition metal free synthetic method is beneficial for product purification and
9
environment and becoming a research hotspot. In 2012 Alok et al. developed a transition
metal free synthetic protocol of phenothiazines via heating sulphur and the Schiff bases at
o
high temperature (260-280 C), which were prepared from cyclohexanone and
1
0
diphenylamines. In 2013 Deng and coworkers reported a new transition-metal-free
synthesis of phenothiazines from cyclohexanones and 2-aminobenzenethiols via in situ
1
1
condensation, addition and dehydrogenation. Very recently Zhang reported an
interesting transition-metal-free and ligand-free synthetic method of phenothiazines. They
found potassium carbonate promoted tandem C–S and C–N coupling reaction between
1
2
N-(2-iodophenyl)acetamides and 2-halo-benzenethiols.
9
In view of the promising development of transition-metal-free arylation, especially
Bolm’s transition-metal-free synthesis of N-substituted phenoxazines via the
intramolecular N-arylations and Zhang’s transition-metal-free and ligand-free synthesis
1
2
of phenothiazines, we envisioned that S-2-acetamidophenyl ethanethioate is possible to
react with ortho-dihaloarenes at higher reaction temperature (Scheme 1), which is
verified by our experiments.
1
3
As our on-going research on the cross coupling reactions, especially on our synthesis of
7
phenothiazines, we discovered a novel transition metal free and ligand-free cesium
3

carbonate-promoted synthesis of phenothiazines from S-2-acetamidophenyl ethanethioate
and ortho-dihaloarenes (Scheme 1).
RESULTS AND DISCUSSION
S-2-acetamidophenyl ethanethioates was facilely prepared via acetylation of
1
4
ortho-aminothiophenols.
With S-2-acetamidophenyl ethanethioates in hand, we tried a reaction of
o
S-2-acetamidophenyl ethanethioate and ortho-bromoiodobenzene in DMF at 130 C. To
our surprise, this reaction gave 81% yield (Table 1, entry 1).
This promising result encouraged us to further study this new type reaction. To improve
the reaction yield, the reaction conditions were examined (Table 1). Potassium carbonate
gave lower yield than that of Cs2CO3 (Entry 2 vs. 1). The strong non-nucleophilic base
sodium tert-butoxide afforded moderate yield (Entry 3), but KOH gave only 20% yield
(Entry 4). The reason should be that nucleophilic base KOH causes the reagent
S-2-acetamidophenyl ethanethioate saponification. The strong polar aprotic solvents
DMSO and DMA gave poorer results (Entries 5 to 6). It seems that the reaction
temperature highly influenced this reaction (Entries 7 to 9). Lower temperature of less
o
o
than 110 C resulted in little product (Entries 7 to 8), but high temperature of 150 C was
even not beneficial to this reaction (Entry 9). Shorter time afforded lower yield (Entries
4

1
0-11), but prolonging the reaction time under the conditions is not necessary (Entry 12).
After screening bases, solvents, temperature and reaction time, the original conditions
was still the best one (Entries 1-12).
With the optimized conditions in hand, we next explored S-2-acetamidophenyl
ethanethioate and various aryl dihalides (Table 2). The lower reactive reagent
1
1
-chloro-2-iodobenzene produced phenothiazine with lower yield (Entries 2 vs. 1).
,2-Diiodobenzene with higher activity achieved high yield up to 91% (Entry 3).
It is obvious that one additional electron-withdrawing group on aryl dihalides, such as
halo, trifluoromethyl, enhanced the reaction reactivity. Ortho-chloroiodobenzenes with an
additional CF3, Cl or Br group gave higher yields than ortho-chloroiodobenzene (Entries
4
-6 vs 2). Similarly, ortho-bromoiodobenzene with an additional Cl or F group afforded
better results (Entries 7-8 vs. 1). 1,4-Difluoro-2-iodobenzene with an ortho fluoro group
of lower activity also offered a good yield (Entry 9).
A complicated substrate 1,3-dibromo-2-iodo-5-fluorobenzene with multiple reaction
points gave lower yield (Entry 10). Although 2,3,5-triiodobenzoic acid afforded good
yield with 2.0 mmol and 3.0 mmol (Entry 11-12), perhaps due to saponification, methyl
3
-bromo-4-iodobenzonate gave much poorer yield (Entry 13). In order to avoid
saponification, fresh distilled DMF (dried over CaH ) was used to perform this reaction.
2
Actually the saponification during the reaction was effectively inhibited, and the yield
5

was increased to 65% (Entry 14). With the fresh distilled DMF at hand, the reaction of
S-2-acetamidophenyl ethanethioate and ortho-bromoiodobenzene was tried again. And
higher yield of 86% was obtained, as means this type reaction is not promoted by trace
water.
Dihalobenzene with an amino group 4-chloro-3-iodobenzenamine produced nothing
(Entry 16), because amidation, a by-reaction occurred between the amino group of
4
-chloro-3-iodobenzenamine and S-2-acetamidophenyl ethanethioate.
Substituted S-2-acetamidophenyl ethanethioates are also effective substrates for this
reaction. 4-Chloro-S-2-acetamidophenyl ethanethioate with a chloro substituent also gave
good yield (Entry 17).
These products are key intermediates of clinic tricyclic antidepressants, for example,
phenothiazine (Entries 1-3), 3-(trifluoromethyl)-10H-phenothiazine (Entry 4) and
2
-chloro-10H-phenothiazine (Entries 7-8) are the core structures of promethazine,
trifluoperazine, chlorpromazine, respectively.
About the mechanism of this reaction, it is not very clear now. Some preliminary
experiments were performed. This reaction cannot be carried out under acid condition or
under neutral condition. The common radical scavenger
6

2
,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 3.0 equiv.) reacted with
ortho-bromoiodobenzene, so much lower yield (18%) was obtained. Since the alkalic
condition is necessary for this reaction, it probably is a base-promoted reaction.
Lee reported synthesis of symmetrical and unsymmetrical aryl sulfides by Pd-catalyzed
1
5
couplings of aryl halides and thioacetates. For example, in the presence of palladium
catalyst and the base K3PO4, reaction of S-phenyl thioacetate and 4-tolyl bromide
1
5
afforded phenyl tolyl thioether. As means S-phenyl thioacetate will be turned into
potassium benzenethiolate, which is the really nucleophile to couple with bromobenzene.
With the same rule, acetyl group of N-acetylphenothiazine may be removed. A plausible
mechanism is proposed as shows in Scheme 2.
S-2-acetamidophenyl ethanethioate 1a is attacked by Cs2CO3, and turned into cesium
2
-acetamidobenzenethiolate 4, which attacks ortho-bromoiodobenzene via aromatic
nucleophilic reaction to give an intermediate 5. The intermediate 5 is deprotonated by
Cs CO to give cesium salt 6. An intramolecular aromatic nucleophilic substitution of
2
3
cesium salt 6 produces N-acetylphenothiazine 7. Due to strong alkalinity and the higher
temperature, acetyl group of N-acetylphenothiazine 7 is removed by Cs2CO3 to give
phenothiazine’s cesium salt 8, which grasps a proton from CsHCO3 or other proton
sources and produces phenothiazine 3a.
7

CONCLUSION
We discovered an efficient, transition metal free synthesis of phenothiazines via reaction
of S-2-acetamidophenyl ethanethioate and ortho-dihaloarenes. This new protocol is
simple, operation easy, ligand free and transition metal free. The products phenothiazines
may be used in drug synthesis and in fine chemical industries. A plausible mechanism is
proposed.
EXPERIMENTAL
Transition Metal Free Synthesis Of Phenothiazine From S-2-Acetamidophenyl
Ethanethioate
To an oven-dried 25 mL ground mouth test tube equipped with a stir bar was added
S-2-acetamidophenyl ethanethioate (0.5 mmol), 1-bromo-2-iodobenzene (0.6 mmol),
Cs2CO3 (2.0 mmol), DMF (3 mL). The test tube was sealed with a sleeve rubber stopper
o
and evacuated and refilled with argon for three cycles. The mixture was stirred 130 C for
1
0 hours. After cooling to room temperature, the reaction mixture was quenched with
water (20 mL), and extracted with ethyl acetate (20 mL) for three times. The combined
organic layer was dried with anhydrous MgSO4, and condensed in vacuum on a rotary
evaporator. The residual was purified on a silica gel chromatograph column by means of
gradient elution (eluent: petroleum ether / ethyl acetate) to give a white solid, mp
o
1
1
6
79-182 C. H NMR (400 MHz, DMSO-d ) δ 8.66 (s, 1H), 7.04 (td, J = 7.8, 1.5 Hz, 2H),
6
.97 (dd, J = 7.6, 1.3 Hz, 2H), 6.81 (td, J = 7.5, 1.2 Hz, 2H), 6.74 (dd, J = 7.9, 1.1 Hz,
8

1
3
2
H). C NMR (101 MHz, DMSO-d6) δ 142.57 (s), 128.03 (s), 126.72 (s), 122.25 (s),
116.78 (s), 114.89 (s).
FUNDING
We thank the National Natural Science Foundation of China (No. 21372034), the
Department of Science and Technology of Sichuan Province (No. 2016HH0074), the
Education Department of Sichuan Province (No. 16ZA0084) for financial support.
SUPPORTING INFORMATION
1
13
Full experimental detail, H and C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
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11

Table 1. Optimization of reaction conditions of S-2-acetamidophenyl ethanethioate and
-bromo-2-iodobenzene
1
Br
I
Conditions
S
O
+
NH
S
N
H
O
1
a
2a
3a
o
Entry Base
Cs2CO3 DMF
K2CO3 DMF
t-BuONa DMF
KOH DMF
Solvent Temp. ( C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
1
130
130
130
130
10
10
10
10
10
10
10
10
10
6
81
72
60
25
67
39
18
25
78
53
68
80
Cs2CO3 DMSO 130
Cs CO
DMA
130
90
2
3
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
110
150
130
130
130
0
1
1
8
1
2
12
Reaction conditions: S-2-acetamidophenyl ethanethioate (0.5 mmol),
-bromo-2-iodobenzene (0.6 mmol), base (2.0 mmol), solvent (3 mL), temperature, time,
argon.
1
12

Table 2. Evaluation of S-2-acetamidophenyl ethanethioate and various aryl dihalides
a
under catalyst-free conditions.
R
X
S
Cs CO , DMF
2
3
O
+
R'
R
R'
o
NH
S
130 C, 10 h
X'
N
H
O
1
2
3
Entry R
X
X
R
H
H
H
3
Yield (%)
1
2
3
4
5
6
7
8
9
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1-Br 2-I
1-Cl 2-I
3a 81
3a 54
3a 91
3b 65
3c 64
3d 70
3e 88
3f 82
3g 80
3h 65
1-I
1-Cl 2-I
2-Cl 3-I 1-Cl
2-I
4-CF3
1-I
1-I
1-I
2-Cl 4-Br
2-Br 4-Cl
2-Br 4-F
1-F 2-I 4-F
0
1-Br 2-I 3-Br, 5-F
11
2-I
2-I
3-I 5-I, 1-COOH 3i 73
3-I 5-I, 1-COOH 3i 75
c
1
1
1
1
2
3
4
5
3-Br 4-I
3-Br 4-I
1-Br 2-I
1-COOCH3
1-COOCH3
H
3j 42
3j 65
3a 86
d
d
13

1
6
7
H
4-Cl 3-I
1-NH2
H
--
0
1
4-Cl 1-Br 2-I
3c 81
a
Reaction conditions: S-2-acetamidophenyl ethanethioate (0.5 mmol),
-bromo-2-iodobenzene (0.6 mmol), Cs2CO3 (2.0 mmol), DMF (3 mL), 130 C, 10 h,
o
1
argon.
b
Isolated yield.
c
Cs2CO3 (3.0 mmol) was added.
d
Fresh distilled DMF (dried over CaH2) as solvent.
14

Scheme 1. Cesium carbonate-promoted synthesis of phenothiazines from
S-2-acetamidophenyl ethanethioate and ortho-dihaloarenes
15

Scheme 2. A plausible mechanism
16