A catalyst system, copper/ N -methoxy-1 H -pyrrole-2-carboxamide, for the synthesis of phenothiazines in poly(ethylene glycol)

Article abstract of DOI:10.1055/s-0034-1379045

A copper/N-methoxy-1H-pyrrole-2-carboxamide catalyst system has been established for the preparation of phenothiazines in good yields by two routes, starting from 2-iodoanilines and 2-bromobenzenethiol and from aryl ortho-dihalides and o-aminobenzenethiols, by conducting the reaction at 90 °C in poly(ethylene glycol)-100 (PEG-100). In addition, the catalyst system was useful for promoting direct arylation of various aryl amines, aliphatic amines, and aqueous ammonia. The simple experimental operation, low loading of catalyst system together with the use of green solvent, makes it attractive for the versatile syntheses of phenothiazines and various amines.

Full text of DOI:10.1055/s-0034-1379045

3356▌
PAPER
paper
A Catalyst System, Copper/N-Methoxy-1H-pyrrole-2-carboxamide, for the
Synthesis of Phenothiazines in Poly(ethylene glycol)
Copper-Catalyzed Syntheses of Phenothiazines in PEG
Manna Huang,a Jianying Hou,a Ruiqiao Yang,b Liting Zhang,a Xinhai Zhu,*a Yiqian Wan*a
a
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. of China
Fax +86(20)84113610; E-mail: ceswyq@mail.sysu.edu.cn
b
Hunan College for Preschool Education, Changde 415000, P. R. of China
Received: 01.07.2014; Accepted after revision: 06.08.2014
cyclization of diphenylamines with sulfur is substantially
Abstract: A copper/N-methoxy-1H-pyrrole-2-carboxamide cata-
improved by using iodine as catalyst; however, it suffers
lyst system has been established for the preparation of phenothi-
from certain disadvantages, including a high temperature
azines in good yields by two routes, starting from 2-iodoanilines
and 2-bromobenzenethiol and from aryl ortho-dihalides and o-ami-
requirement and difficulty in separating the regioiso-
nobenzenethiols, by conducting the reaction at 90 °C in poly(eth- mers.15 (3) There are also many other methods, such as cy-
clization with benzoquinones,16 cyclization of 2-
ylene glycol)-100 (PEG-100). In addition, the catalyst system was
useful for promoting direct arylation of various aryl amines, aliphat-
aminothiophenols with cyclohexane-1,3-diones,17 reduc-
ic amines, and aqueous ammonia. The simple experimental opera-
tive cyclization of 2-nitrodiphenyl sulfides with triethyl
tion, low loading of catalyst system together with the use of green
phosphite,18 and thermal cyclization of aryl azides with
solvent, makes it attractive for the versatile syntheses of phenothi-
azines and various amines.
1,2,3-benzothiadiazole.19 Moreover, the functionalization
of phenothiazine is also an important route to many phe-
Key words: copper, homogeneous catalysis, amination, green
chemistry, heterocycles
nothiazine’s derivatives, but it is often hindered by poor
regioselectivity.11,13,20
More recently, the application of transition-metal-cata-
lyzed reactions to synthesize phenothiazines has attracted
much attention. In 2008, Jorgensen21 reported a palladi-
um-catalyzed three-component approach to phenothi-
azines by way of formatting one C–S and two C–N bonds
with or without microwave irradiation. In 2010, Ma22 es-
tablished the first copper-catalyzed coupling protocol us-
ing L-proline as a ligand to obtain phenothiazine
derivatives from 2-iodoanilines and 2-bromobenzenethio-
ls, in which finely tuning the temperature and reaction
time of the C–S and C–N coupling, respectively, is cru-
cial. Thereafter, in 2012, Zeng23 reported a ligand-free
protocol with high loading of copper (i.e., up to 30 mol%)
as a catalyst to prepare the phenothiazines from aryl
ortho-dihalides and o-aminobenzenethiols. At the same
time, a simple one-pot method has been developed
through a copper-catalyzed rearrangement of 2-amino-
benzothiazoles.24 However, the necessity of high tempera-
ture and long periods of time might be problematic for
some types of substrates. Therefore, the development of
an efficient copper-catalyzed protocol to provide pheno-
thiazine and its derivatives in mild conditions and in a
shorter reaction time is highly desirable. Herein, we report
a novel catalyst system, copper/N-methoxy-1H-pyrrole-2-
carboxamide, with which, phenothiazines were prepared
from examples of both Ma’s22 and Zeng’s23 starting mate-
rials in good yields by direct carbon–heteroatom coupling
at 90 °C for 15 hours (Scheme 1).
Phenothiazine was first prepared by Bernthsenin in 1883
to elucidate the structure of Lauth’s violet and methylene
blue.1 Since then, the phenothiazine family has played an
important role in both human medicine and the materials
field. Phenothiazines represent the largest and oldest
group of antipsychotic compounds in clinical medicine. In
particular, they largely revolutionized the practice of psy-
chiatric medicine, a process that is now continuing with
the introduction of the newer atypical antipsychotics such
as risperidone and olanzapine.2 Chlorpromazine and
prochlorperazine can be viewed as the prototypes of the
many phenothiazines, and their congeners exert a signifi-
cant influence on many organ systems of the body at once
as cholinesterases inhibitors,3 histamine H1 antagonists,4
antitubercular agents,5 lipid peroxidation inhibitors,6 and
so on.5a,7 They have also been successfully employed in
the materials field as a high-affinity selective heparin sen-
sor,8 molecular wires,9 organic dyes,10 electrogenerated
chemiluminescence materials,11 a chemosensor for the se-
lective fluorescent detection of flavins,12 and for their oth-
er electronic properties.[13 Given the significance of
phenothiazines, many classical methods have been estab-
lished to construct their core moiety: (1) In the cyclization
of diphenyl sulfides, which is by far the most important
method, the central step involves a Smiles rearrangement;
however, many factors that govern the reaction, including
steric hindrance, electrophilicity, the acidity of the acyl-
amino group that attacks the aromatic nucleus and the na-
ture of the base, often reduce its applications.14 (2) The
As part of our ongoing research interest in copper-cata-
lyzed C–N coupling reactions, we envisioned that the li-
gand L0 (Figure 1), which was previously identified as a
high-performance ligand for a copper-catalyzed Ullmann-
type C–N coupling reaction in water,25 might also func-
tion in the synthesis of phenothiazines according to Ma’s
SYNTHESIS 2014, 46, 3356–3364
Advanced online publication: 10.09.2014
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DOI: 10.1055/s-0034-1379045; Art ID: ss-2014-f0413-op
© Georg Thieme Verlag Stuttgart · New York

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Copper-Catalyzed Syntheses of Phenothiazines in PEG
3357
SH
Br
I
SH
I
+
+
NH2
NH2
Br
CuI (10 mol%)
L-proline (20 mol%)
2-methoxyethanol
CuI (30 mol%)
DMSO
Zeng's protocol
S
90 °C, 48 h
110 °C, 72 h
120 °C, 48 h
N
H
Cu(OAc)2 (5 mol%)
L1 (5 mol%)
our protocol
SH
Br
I
SH
I
+
+
NH2
NH2
Br
Scheme 1 Different protocols of phenothiazine synthesis
strategy. However, the outcome was poor, affording ideal media for us to explore our catalyst system in more
mainly 2-[(2-bromophenyl)thio]aniline from 2-iodoani- detail.
line and 2-bromobenzenethiol together with trace of the
target compound. Increasing the quantity of the ligand and
As a starting point, L1 and its analogues (Figure 1) have
been synthesized and tested as ligands to establish a gen-
CuI afforded more of the desired compound but with in-
eral copper-catalyzed C–N coupling protocol. Fortunate-
crease of much more unidentified side-reactions. Consid-
ly, the target compound was obtained in 68% normalized
ering the different coordinative ability of O and N, we
GC yield from 4-bromoanisole and aniline in 2-meth-
tried to design a novel ligand L1 and its analogues using
oxyethanol with L1/Cu(OAc)2 as catalyst, which encour-
O instead of N-atom from L0 to alleviate the side-reac-
aged us to optimize the reaction conditions. The
optimized reaction condition consisting of Cu(OAc)2 (5
mol%)/L1 (5 mol%) and K3PO4 (150 mol%) with aniline
(300 mol%) in PEG-100 at 90 °C for 12 hours was devel-
oped. It should be noted that L1 was chosen to be an ulti-
mate ligand due to its commercial availability although
L5 assumed the similar ability to L1. Besides, low loading
tions and to develop a more effective method for the syn-
thesis of phenothiazine. It should be significant to test this
idea because only L4, as a ligand, showed some indication
for copper-catalyzed formation of highly substituted pyr-
azoles among these alkoxycarbamides to our knowl-
edge.26
of L1 demonstrated some advantages over those previous-
ly reported by us25,29 for copper-catalyzed C–N coupling.
H
H
H
N
N
N
Further, a variety of functionalized aryl halides were am-
inated using anilines (Scheme 2) or aliphatic amines
(Scheme 3). The N-arylation of anilines with most aryl
bromides, whether they are electron-rich, electron-
neutral, or electron-poor, provided the desired products in
good to excellent yields. It should be noted that even for
ortho- and meta-substituted aryl bromides (Scheme 2, 3d–f),
the reaction afforded the desired products in high yields
similar to the reactions para-substituted aryl bromides
(Scheme 2, 3a–c). These characteristics, especially the re-
duced steric ortho-effect, would accommodate itself to the
development of an efficient synthetic route to phenothi-
azines according to Ma’s22 or Zeng’s23 strategy.
N
H
OMe
OMe
N
H
N
N
H
H
O
O
O
L0
L1
L2
O
O
H
N
H
OMe
N
N
N
OMe
S
H
H
N
O
O
L3
L4
L5
Figure 1 Ligands used in the reaction
Moreover, poly(ethylene glycol)s (PEGs) are known to be
nontoxic, recyclable, thermally stable, and inexpensive
media for the use as phase-transfer catalysts (PTCs) and
co-solvent, especially, they have ever been applicable in
biomedical protocols.27 Many types of organic reactions,
such as substitution, oxidation, reduction, palladium- or
copper-catalyzed coupling, etc., have been successfully
performed in PEGs. Further work would no doubt contin-
ue using functional PEGs in polymer-supported syntheses
and in recyclable catalyst procedures.28 Hence, the benign
nature and potent catalytic ability of PEGs made it an
It was intriguing that the N-arylation of aqueous ammonia
directly to primary amine afforded only a 58% yield due
to the further arylation of the product under this experi-
mental condition. However, as illustrated in Scheme 4,
high yields of primary amines were otherwise readily pro-
vided under almost the same conditions, only using L2 in-
stead of L1.
With favorable results in hand, it was reasonable for us to
confront the syntheses of phenothiazines. As an applica-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3356–3364

3358
M. Huang et al.
PAPER
Cu(OAc)2•H2O (0.05 mmol)
Br
H
N
L1 (0.05 mmol)
Cu(OAc)2•H2O (0.05 mmol)
R1
NH2
Br
R2NH2
3 mmol
R2
L1 (0.05 mmol)
R1
HN
K3PO4 (1.5 mmol)
PEG-100 (2 g)
90 °C, 12 h
R
K3PO4 (1.5 mmol)
PEG-100 (2 g)
90 °C, 12 h
1 mmol
3 mmol
1 mmol
R
H
N
H
N
H
H
N
N
H
N
H
N
MeO
4a 84%
4b 78%
4c 80%
3a 78%, 80%a
3b 75%
3c 73%
H
H
N
H
N
N
H
N
H
N
H
N
O
O
N
Cl
OMe
4f 65%
4e 70%
4d 49%
O
H
H
N
H
N
N
3d 71%
3e 75%
3f 72%
H
N
H
N
MeO
O
H
N
4g 81%
4h 79%
4i 85%
O
H
N
H
N
F
H
N
3g 71%
3h 53%
3i 65%
N
H
Cl
4j 72%
4k 72%
4l 85%
H
N
N
H
N
H
N
H
N
N
Cl
3j 63%
3k 70%
MeO
O
4m 90%
4n 83%
4o 85%
Scheme 2 Products and isolated yields for amination of aryl bro-
H
N
H
N
H
N
mides with aniline. a 4-Iodoanisole was used.
N
Cl
tion of the optimized conditions to the protocol (Scheme
1), increasing the catalyst loading from 5 mol% to 10
mol% was rational because the reaction involved one C–
S and one C–N bond formation. More interestingly, the
replacement of the weak base (K3PO4) with a strong base
(KOH) increased the yield of phenothiazine from 65% to
74% (Table 1, entry 3, method A). Inspired by the result
of Zeng’s,23 the ligand-free protocol with CuI and
Cu(OAc)2 in PEG-100 was examined; however, only
trace of phenothiazine was detected by TLC. Therefore,
4r 75%
4p 75%
4q 84%
MeO
O
N
O
N
O
O
N
O
O
4s 74%
4t 71%
4u 62%
N
O
N
N
Cl
N
4v 59%
4w 65%
4x 65%
Scheme 3 Products and isolated yields for amination of aryl bro-
ligand L1 was proved to be necessary for copper-cata- mides with aliphatic amines
lyzed synthesis of phenothiazines in the green solvent,
PEG-100. Hence, proceeding from these typical exam-
Cu(OAc)2•H2O (0.05 mmol)
Br
ples, phenothiazines with electron-rich and electron-poor
substituents on the 3- or 4-position were obtained from
examples of both Ma’s22 and Zeng’s23 starting materials in
good yields at 90 °C for 15 hours (Table 1).
NH2
L2 (0.05 mmol)
+
NH3•H2O
R
R
K3PO4 (1.5 mmol)
PEG-100 (2 g)
90 °C, 12 h
1 mmol
5 mmol
NH2
In conclusion, we have established a copper/N-methoxy-
1H-pyrrole-2-carboxamide catalyst system that effective-
ly promoted the reactions of either 2-iodoanilines and 2-
bromobenzenethiol or aryl ortho-dihalides and o-amino-
benzenethiols to phenothiazines in PEG-100. Moreover,
the mild experimental conditions (90 °C, 15 h), the simple
experimental operation (tuning the temperature and the
reaction time stepwise is not necessary), and the low load-
ing of the catalyst system (10 mol%), especially using a
green solvent, PEG-100, make this approach useful for the
versatile synthesis of phenothiazines from various starting
materials. Furthermore, this protocol has also been con-
NH2
NH2
MeO
5a 80%, 58%a
5b 62%
5c 81%
NH2
NH2
NH2
N
O
Cl
5e 84%
5f 84%
5d 81%
Scheme 4 Products and isolated yields for amination of aryl bro-
mides with aqueous ammonia. a L1 was used.
Synthesis 2014, 46, 3356–3364
© Georg Thieme Verlag Stuttgart · New York

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Copper-Catalyzed Syntheses of Phenothiazines in PEG
3359
Table 1 Copper-Catalyzed Formation of Phenothiazinesa
compared with the previously reported data (see Supporting Infor-
1
mation). H NMR and 13C NMR spectra were recorded at r.t. on a
I
R1/R2/R3
I
Bruker Avance III 400 instrument or a Mercury-Plus 300 instru-
ment with TMS as an internal reference. LC/MS was run on a
LCMS-2010A. GC/MS was run on a Finnigan Voyager with an
electron impact (70 eV) mass selective detector and an innowax 30
m × 0.25 mm × 0.25 μm capillary a polar column. GC-MS method:
initial temperature: 50 °C, initial time: 3 min; ramp: 20 °C/min; fi-
nal temperature: 250 °C, final time: 2 min. EI mass spectra were re-
corded on the Thermo DSQ mass spectrometer. Elemental analyses
were carried out with a Vario EL series analyzer and have errors of
± 0.4% for CHN elements. Melting points were determined on a
WRS-1B digital melting point apparatus and are not corrected. IR
spectra were recorded on a Thermo 330 FT-IR spectrophotometer.
R1
NH2
R2
Br
Cu(OAc)2, L1
Cu(OAc)2, L1
+
+
HN
S
KOH, PEG-100
90 °C, 15 h
KOH, PEG-100
90 °C, 15 h
SH
Br
SH
NH2
R3
method A
method B
Entry
1
Product
Method
Yield (%)b
S
N-Methoxy-1H-pyrrole-2-carboxamide (L1)
[CAS Reg. No.: 890122-55-1]
A
B
46
74
N
H
To a 10 mL sealed vial equipped with a magnetic stir bar were add-
ed 2-(trichloroacetyl)pyrrole (1070 mg, 5 mmol), methoxyammoni-
um chloride (625 mg, 7.5 mmol), and Et3N (2.5 mL). The reaction
mixture was stirred in an oil bath preheated to 80 °C for 12 h. After
allowing the mixture to cool to r.t., it was concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel using EtOAc–PE (1:1) as eluent to afford L1; yield: 50 mg
(78%); yellow solid; mp 97–99 °C.
6a
S
2
3
4
5
A
73
N
H
6b
IR (KBr): 3217, 3152, 3003, 2938, 2804, 2737, 2677, 2491, 1599,
1528, 1469, 1443, 1403, 1344, 1279, 1204, 1189, 1150, 1096, 1040,
963, 933, 838, 752, 609, 571 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.63 (br s, 1 H, NH), 6.82–6.76
(m, 1 H, ArH), 6.72–6.67 (m, 1 H, ArH), 6.08–6.00 (m, 1 H, ArH),
3.69 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3 + DMSO-d6): δ = 160.8, 122.9, 122.4,
111.6, 109.5, 64.3.
MS (ESI+): m/z = 141 ([M + H] +).
S
A
B
74 (65)c
64
N
H
6c
S
A
B
58
55
Cl
N
H
6d
Cl
N-Methoxy-1H-indole-2-carboxamide (L2)
[CAS Reg. No.: 96680-12-5]
S
To a 100 mL round-bottomed flask equipped with a magnetic stir
bar were added indole-2-carboxylic acid (805 mg, 5 mmol), meth-
oxyammonium chloride (625 mg, 7.5 mmol), (dimethylaminopro-
pyl)carbodiimide hydrochloride (1440 mg, 7.5 mmol), 4-
dimethylaminopyridine (1830 mg, 15 mmol), and CH2Cl2 (50 mL).
The reaction mixture was stirred at r.t. overnight. After concentrat-
ing the mixture in vacuo, the residue was purified by flash column
chromatography on silica gel using CH2Cl2–MeOH (40:1) as eluent
to afford L2; yield: 776 mg (82%); white solid; mp 144–145 °C.
A
57
N
H
6e
a Reaction conditions: aniline (1 mmol) and 2-bromobenzenethiol
(1.2 mmol) (method A) or aryl halide (1 mmol) and 2-aminobenzen-
ethiol (1.2 mmol) (method B), Cu(OAc)2·H2O (10 mol%), L1 (10
mol%), KOH (4 mmol), PEG-100 (2 g), 90 °C, 15 h, under N2 atmo-
sphere.
IR (KBr): 3416, 3297, 3199, 2995, 2939, 2875, 1624, 1565, 1523,
1496, 1433, 1361, 1342, 1320, 1290, 1222, 1188, 1122, 1048, 980,
932, 855, 834, 777, 747, 735, 652, 543, 434 cm–1.
b Isolated yield.
c K3PO4 was used instead of KOH.
1H NMR (400 MHz, CDCl3): δ = 9.78 (br s, 1 H, NH), 7.65 (d, J =
8.0 Hz, 1 H, ArH), 7.45 (d, J = 8.3 Hz, 1 H, ArH), 7.33–7.28 (m, 1
H, ArH), 7.14 (t, J = 7.5 Hz, 1 H, ArH), 7.07 (s, 1 H, ArH), 3.92 (s,
3 H, OCH3).
13C NMR (101 MHz, CDCl3 + DMSO-d6): δ = 160.8, 136.7, 128.2,
127.4, 124.2, 121.9, 120.3, 112.2, 104.3, 64.4.
firmed to be efficient for the preparation of a variety of
amines from broad substrates, including a range of elec-
tron-rich, electron-neutral or electron-poor, and even
ortho-substituted aryl bromides, as well as various amines
including aryl amines, aliphatic amines, secondary
amines, and aqueous ammonia.
MS (ESI+): m/z = 213 ([M + Na]+).
N-Methoxy-1H-thiophene-2-carboxamide (L3)
[CAS Reg. No.: 103185-33-7]
All starting materials and reagents are commercially available and
used as received. Petroleum ether (PE) used refers to the fraction
boiling in the 60–90 °C range. Most reactions were carried out in a
preheated oil bath in vials (size: 10 mL) sealed with a septum. Flash
column chromatography was performed with silica gel (200–300
mesh). TLC was carried out with Merck silica gel GF254 plates. The
known products 3–5 were characterized by NMR and MS data and
To a 100 mL round-bottomed flask equipped with a magnetic stir
bar were added thiophene-2-carboxylic acid (720 mg, 5 mmol),
methoxyammonium chloride (625 mg, 7.5 mmol), (dimethylamino-
propyl)carbodiimide hydrochloride (1440 mg, 7.5 mmol), 4-dime-
thylaminopyridine (1830 mg, 15 mmol), and CH2Cl2 (50 mL). The
reaction mixture was stirred at r.t. overnight. After concentrating
the mixture in vacuo, the residue was purified by flash column chro-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3356–3364

3360
M. Huang et al.
PAPER
matography on silica gel using CH2Cl2–MeOH (40:1) as eluent to
afford L3; yield: 428 mg (50%); white solid; mp 60–61 °C.
purified by flash column chromatography on silica gel to afford the
desired product.
IR (KBr): 3210, 3108, 3054, 2975, 2933, 2896, 2811, 1628, 1533,
1502, 1436, 1417, 1352, 1310, 1249, 1143, 1080, 1060, 1014, 936,
827, 739, 715, 661, 605, 552 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.25 (br s, 1 H, NH), 7.72 (s, 1 H,
ArH), 7.56 (d, J = 4.9 Hz, 1 H, ArH), 7.12 (t, J = 4.2 Hz, 1 H, ArH),
3.88 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 161.5, 135.2, 131.0, 129.5, 127.8,
64.4.
MS (ESI+): m/z = 196 ([M + Na]+).
4-Methoxy-N-phenylaniline (3a)
[CAS Reg. No.: 1208-86-2]
According to GP A, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:20) as eluent to afford 3a; yield: 155 mg (78%); white
solid; mp 105–106 °C.
4-Methyl-N-phenylaniline (3b)
[CAS Reg. No.: 620-84-8]
According to GP A, 1-bromo-4-methylbenzene (171 mg, 1.0 mmol)
was treated with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:40) as eluent to afford 3b; yield: 137 mg (75%);
white solid; mp 87–88 °C.
N-Methoxypicolinamide (L4)
[CAS Reg. No.: 79081-08-6]
To a 100 mL round-bottomed flask equipped with a magnetic stir
bar were added picolinic acid (615 mg, 5 mmol), methoxyammoni-
um chloride (625 mg, 7.5 mmol), (dimethylaminopropyl)carbo-
diimide hydrochloride (1440 mg, 7.5 mmol), 4-dimethylamino-
pyridine (1830 mg, 15 mmol), and CH2Cl2 (50 mL). The reaction
mixture was stirred at r.t. overnight. After concentrating the mixture
in vacuo, the residue was purified by flash column chromatography
on silica gel using CH2Cl2–MeOH (50:1) as eluent to afford L4;
yield: 663 mg (87%); pale yellow solid; mp 35–36 °C.
4-Ethyl-N-phenylaniline (3c)
[CAS Reg. No.: 32804-22-1]
According to GP A, 1-bromo-4-ethylbenzene (185 mg, 1.0 mmol)
was treated with aniline (279 mg, 3.0 mmol) at 90 °C, 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:40) as eluent to afford 3c; yield: 143 mg (73%);
white solid; mp 86–87 °C.
IR (KBr): 3258, 2980, 2939, 2816, 1676, 1589, 1570, 1487, 1464,
1435, 1285, 1243, 1169, 1149, 1090, 1052, 1037, 998, 942, 891,
817, 751, 701, 621 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.44 (s, 1 H, NH), 8.51–8.41 (m,
1 H, ArH), 8.16–8.07 (m, 1 H, ArH), 7.84–7.76 (m, 1 H, ArH),
7.44–7.33 (m, 1 H, ArH), 3.86 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 161.9, 149.0, 148.2, 137.5, 126.7,
122.4, 64.6.
MS (ESI+): m/z = 153 ([M + H]+).
2-Methoxy-N-phenylaniline (3d)
[CAS Reg. No.: 1207-92-7]
According to GP A, 2-bromoanisole (87 mg, 1.0 mmol) was treated
with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The crude prod-
uct was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 3d; yield: 141 mg (71%); col-
orless oil.
3-Methoxy-N-phenylaniline (3e)
[CAS Reg. No.: 101-16-6]
N-(Benzyloxy)-1H-pyrrole-2-carboxamide (L5)
To a 10 mL sealed vial equipped with a magnetic stir bar were add-
ed 2-(trichloroacetyl)pyrrole (1070 mg, 5 mmol), benzylhydroxyl-
amine hydrochloride (1200 mg, 7.5 mmol), and Et3N (2.5 mL). The
reaction mixture was stirred in an oil bath preheated to 80 °C for 10
h. After allowing the mixture to cool to r.t., it was concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel using CH2Cl2–MeOH (50:1) as eluent to afford L5;
yield: 800 mg (74%); pale yellow solid; mp 102–104 °C.
According to GP A, 2-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 3e; yield: 149 mg (75%); col-
orless oil.
N-Phenylbenzo[d][1,3]dioxol-5-amine (3f)
[CAS Reg. No.: 222640-45-1]
IR (KBr): 3377, 3166, 2978, 1635, 1511, 1450, 1443, 1405, 1325,
1119, 1089, 1044, 1016, 964, 853, 828, 743, 695, 676, 593 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.81 (br s, 1 H, NH), 8.67 (s, 1 H,
ArH), 7.45–7.34 (m, 5 H, ArH), 6.98–6.93 (m, 1 H, ArH), 6.68 (s,
1 H, ArH), 6.26–6.19 (m, 1 H, ArH), 4.99 (s, 2 H, OCH2).
According to GP A, 5-bromobenzo[d][1,3]dioxole (201 mg, 1.0
mmol) was treated with aniline (279 mg, 3.0 mmol) at 90 °C for 12
h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:20) as eluent to afford 3f; yield: 153
mg (72%); colorless oil.
13C NMR (101 MHz, CDCl3 + DMSO-d6): δ = 160.7, 135.8, 129.2,
128.4, 128.3, 123.1, 122.1, 111.6, 109.3, 78.3.
Diphenylamine (3g)
[CAS Reg. No.: 122-39-4]
MS (EI, 70 eV): m/z (%) = 216 (6, [M+]), 94 (26, [C4H4CO+]), 91
(100, [C7H7 ]).
According to GP A, bromobenene (157 mg, 1.0 mmol) was treated
with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The crude prod-
uct was purified by column chromatography on silica gel using
EtOAC–PE (1:40) as eluent to afford 3g; yield: 120 mg (71%); pale
yellow solid.
+
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
66.70; H, 5.60; N, 12.95.
Amines 3a–k and 4a–x; General Procedure A (GP A)
1-[4-(Phenylamino)phenyl]ethanone (3h)
To a 10 mL sealed vial equipped with a magnetic stir bar were add-
ed Cu(OAc)2·H2O (10 mg, 0.05 mmol), L1 (7 mg, 0.05 mmol), aryl
bromide (1.0 mmol), amine (3.0 mmol), K3PO4 (318 mg, 1.5
mmol), and PEG-100 (2.0 g). The reaction mixture was stirred in an
oil bath preheated to 90 °C for 12 h. After allowing the mixture to
cool to r.t., it was extracted with EtOAc (3 × 25 mL) and the com-
bined organic phases were washed with H2O (20 mL), brine (70
mL), dried (Na2SO4), and concentrated in vacuo. The residue was
[CAS Reg. No.: 23600-83-1]
According to GP A, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with aniline (279 mg, 3.0 mmol) at 90 °C for 12
h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:5) as eluent to afford 3h; yield: 112
mg (53%); yellow solid; mp 112–114 °C.
4-Fluoro-N-phenylaniline (3i)
[CAS Reg. No.: 330-83-6]
Synthesis 2014, 46, 3356–3364
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Syntheses of Phenothiazines in PEG
3361
According to GP A, 1-bromo-4-fluorobenzene (185 mg, 1.0 mmol)
was treated with aniline (279 mg, 3.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:40) as eluent to afford 3i; yield: 122 mg (65%);
pale yellow solid; mp 36–37 °C.
using EtOAc–PE (1:10) as eluent to afford 4f; yield: 120 mg (65%);
white solid; mp 96–98 °C.
N-Butyl-4-methoxylaniline (4g)
[CAS Reg. No.: 61829-43-4]
According to GP A, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with butan-1-amine (219 mg, 3.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:20) as eluent to afford 4g; yield: 145 mg (81%);
colorless oil.
4-Chloro-N-phenylaniline (3j)
[CAS Reg. No.: 1205-71-6]
According to GP A, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with aniline (279 mg, 3.0 mmol) at 90 °C for 12
h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:40) as eluent to afford 3j; yield: 128
mg (63%); pale yellow solid; mp 64–65 °C.
N-Butyl-4-ethylaniline (4h)
According to GP A, 1-bromo-4-ethylbenzene (185 mg, 1.0 mmol)
was treated with butan-1-amine (219 mg, 3.0 mmol) at 90 °C for 12
h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:40) as eluent to afford 4h; yield: 140
mg (79%); colorless oil.
N-Phenylpyridin-2-amine (3k)
[CAS Reg. No.: 6631-37-4]
According to GP A, 2-bromopyridine (158 mg, 1.0 mmol) was
treated with aniline (279 mg, 3.0 mmol) at 90 for 12 h. The crude
product was purified by column chromatography on silica gel using
CH2Cl2 as eluent to afford 3k; yield: 120 mg (70%); white solid; mp
108–109 °C.
IR (KBr): 3413, 2960, 2929, 2869, 1867, 1618, 1581, 1520, 1479,
1409, 1376, 1317, 1263, 1183, 1143, 1085, 820, 531 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.02 (d, J = 8.5 Hz, 2 H, ArH),
6.59–6.53 (m, 2 H, ArH), 3.55 (br s, 1 H, NH), 3.15–3.05 (m, 2 H,
CH2), 2.55 (q, J = 7.6 Hz, 2 H, CH2), 1.66–1.54 (m, 2 H, CH2), 1.50–
1.36 (m, 2 H, CH2), 1.20 (t, J = 7.6 Hz, 3 H, CH3), 0.96 (t, J = 7.3
Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 148.0, 134.4, 129.9, 114.3, 45.4,
33.2, 29.3, 21.7, 17.4, 15.3.
N-Benzyl-4-methoxyaniline (4a)
[CAS Reg. No.: 17377-95-6]
According to GP A, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with benzylamine (321 mg, 3 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 4a; yield: 180 mg (84%); white
solid; mp 50–51 °C.
MS (ESI+): m/z = 178 ([M + H]+).
Anal. Calcd for C12H19N·0.05H2O: C, 80.89; H, 10.80; N, 7.86.
Found: C, 80.84; H, 10.61; N, 7.82.
N-Benzyl-4-ethylaniline (4b)
[CAS Reg. No.: 109240-32-6]
N-Butylaniline (4i)
[CAS Reg. No.: 1126-78-9]
According to GP A, 1-bromo-4-ethylbenzene (185 mg, 1.0 mmol)
was treated with benzylamine (321 mg, 3 mmol) at 90 °C for 12 h.
The crude product was purified by column chromatography on sili-
ca gel using EtOAc–PE (1:40) as eluent to afford 4b; yield: 165 mg
(78%); colorless oil.
According to GP A, bromobenene (157 mg, 1.0 mmol) was treated
with butan-1-amine (219 mg, 3.0 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 4i; yield: 126 mg (85%); col-
orless oil.
N-Benzylaniline (4c)
[CAS Reg. No.: 103-32-2]
1-[4-(Butylamino)phenyl]ethanone (4j)
[CAS Reg. No.: 99433-24-6]
According to GP A, bromobenzene (157 mg, 1.0 mmol) was treated
with benzylamine (321 mg, 3 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 4c; yield: 147 mg (80%); pale
yellow solid; mp 38–40 °C.
According to GP A, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with butan-1-amine (219 mg, 3.0 mmol) at 90 °C
for 12 h. The crude product was purified by column chromatogra-
phy on silica gel using EtOAc–PE (1:5) as eluent to afford 4j; yield:
137 mg (72%); yellow solid; mp 70–71 °C.
1-[4-(Benzylamino)phenyl]ethanone (4d)
[CAS Reg. No.: 59852-82-3]
N-Butyl-4-chloroaniline (4k)
[CAS Reg. No.: 5441-81-6]
According to GP A, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with benzylamine (321 mg, 3 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:5) as eluent to afford 4d; yield: 111
mg (49%); yellow solid; mp 88–90 °C.
According to GP A, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with butan-1-amine (219 mg, 3.0 mmol) at 90 °C
for 12 h. The crude product was purified by column chromatogra-
phy on silica gel using EtOAc–PE (1:20) as eluent to afford 4k;
yield: 132 mg (72%); colorless oil.
N-Benzyl-4-chloroaniline (4e)
[CAS Reg. No.: 2948-37-0]
N-Butylpyridin-2-amine (4l)
[CAS Reg. No.: 76293-30-6]
According to GP A, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with benzylamine (321 mg, 3 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:20) as eluent to afford 4e; yield: 151
mg (70%); pale yellow solid; mp 46–47 °C.
According to GP A, 2-bromopyridine (158 mg, 1.0 mmol) was
treated with butan-1-amine (219 mg, 3.0 mmol) at 90 °C for 12 h.
The crude product was purified by column chromatography on sili-
ca gel using CH2Cl2 as eluent to afford 4l; yield: 127 mg (85%); pale
yellow solid; mp 39–40 °C.
N-Benzylpyridin-2-amine (4f)
[CAS Reg. No.: 6935-27-9]
N-Cyclohexyl-4-methoxyaniline (4m)
[CAS Reg. No.: 780-02-9]
According to GP A, 2-bromopyridine (158 mg, 1.0 mmol) was
treated with benzylamine (321 mg, 3 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
According to GP A, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with cyclohexanamine (297 mg, 3.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3356–3364

3362
M. Huang et al.
PAPER
using EtOAc–PE (1:20) as eluent to afford 4m; yield: 185 mg
(90%); white solid; mp 41–42 °C.
According to GP A, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with morpholine (261 mg, 3 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:2) as eluent to afford 4v; yield: 121
mg (59%); white solid; mp 97–98 °C.
N-Cyclohexyl-4-ethylaniline (4n)
[CAS Reg. No.: 801192-87-0]
According to GP A, 1-bromo-4-ethylbenzene (185 mg, 1.0 mmol)
was treated with cyclohexanamine (297 mg, 3.0 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:40) as eluent to afford 4n; yield: 168
mg (83%); colorless oil.
4-(4-Chlorophenyl)morpholine (4w)
[CAS Reg. No.: 70291-67-7]
According to GP A, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with morpholine (261 mg, 3 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:10) as eluent to afford 4w; yield: 128
mg (65%); white solid; 74–76 °C.
N-Cyclohexylaniline (4o)
[CAS Reg. No.: 1821-36-9]
According to GP A, bromobenene (157 mg, 1.0 mmol) was treated
with cyclohexanamine (297 mg, 3.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:40) as eluent to afford 4o; yield: 148 mg (85%);
colorless oil.
4-(Pyridin-2-yl)morpholine (4x)
[CAS Reg. No.: 24255-25-2]
According to GP A, 2-bromopyridine (158 mg, 1.0 mmol) was
treated with morpholine (261 mg, 3 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using CH2Cl2–MeOH (100:1) as eluent to afford 4x; yield: 100 mg
(61%); colorless oil.
1-[4-(Cyclohexylamino)phenyl]ethanone (4p)
[CAS Reg. No.: 1056627-93-0]
According to GP A, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with cyclohexanamine (297 mg, 3.0 mmol) at 90
°C for 12 h. The crude product was purified by column chromatog-
raphy on silica gel using EtOAc–PE (1:5) as eluent to afford 4p;
yield: 162 mg (75%); yellow solid; mp 113–114 °C.
Anilines 5a–f; General Procedure B (GP B)
To a 10 mL sealed vial equipped with a magnetic stir bar were add-
ed Cu(OAc)2·H2O (10 mg, 0.05 mmol), N-methoxy-1H-indole-2-
carboxamide (9.5 mg, 0.05 mmol), aryl bromide (1.0 mmol), 28%
aq ammonia (0.4 mL, 5.0 mmol), K3PO4 (318 mg, 1.5 mmol), and
PEG-100 (2.0 g). The reaction mixture was stirred in an oil bath pre-
heated to 90 °C for 12 h. After allowing the mixture to cool to r.t.,
it was extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with H2O (20 mL) and brine (70 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel to afford the desired
product.
N-Cyclohexyl-4-chloroaniline (4q)
[CAS Reg. No.: 56506-61-7]
According to GP A, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with cyclohexanamine (297 mg, 3.0 mmol) at 90
°C for 12 h. The crude product was purified by column chromatog-
raphy on silica gel using EtOAc–PE (1:20) as eluent to afford 4q;
yield: 175 mg (84%); white solid; mp 43–44 °C.
4-Methoxyaniline (5a)
[CAS Reg. No.: 104-94-9]
N-Cyclohexylpyridin-2-amine (4r)
[CAS Reg. No.: 15513-16-3]
According to GP B, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with 28% aq ammonia (0.4 mL, 5.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using EtOAc–PE (1:5) as eluent to afford 5a; yield: 98 mg (80%);
white solid; mp 59–60 °C.
According to GP A, 2-bromopyridine (158 mg, 1.0 mmol) was
treated with cyclohexanamine (297 mg, 3.0 mmol) at 90 °C for 12
h. The crude product was purified by column chromatography on
silica gel using CH2Cl2 as eluent to afford 4r; yield: 128 mg (73%);
white solid; 106–107 °C.
p-Toluidine (5b)
[CAS Reg. No.: 106-49-0]
4-(4-Methoxyphenyl)morpholine (4s)
[CAS Reg. No.: 27347-14-4]
According to GP B, 1-bromo-4-methylbenzene (171 mg, 1.0 mmol)
was treated with 28% aq ammonia (0.4 mL, 5.0 mmol) at 90 °C for
12 h. The crude product was purified by column chromatography on
silica gel using CH2Cl2 as eluent to afford 5b; yield: 66 mg (62%);
white solid; mp 43–44 °C.
According to GP A, 4-bromoanisole (187 mg, 1.0 mmol) was treat-
ed with morpholine (261 mg, 3 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:10) as eluent to afford 4s; yield: 143 mg (74%); white
solid; mp 73–74 °C.
Aniline (5c)
[CAS Reg. No.: 62-53-3]
4-(4-Ethyphenyl)morpholine (4t)
[CAS Reg. No.: 1207717-24-5]
According to GP B, bromobenzene (157 mg, 1.0 mmol) was treated
with 28% aq ammonia (0.4 mL, 5.0 mmol) 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
CH2Cl2 as eluent to afford 5c; yield: 75 mg (81%); colorless oil.
According to GP A, 1-bromo-4-ethylbenzene (185 mg, 1.0 mmol)
was treated with morpholine (261 mg, 3 mmol) at 90 °C for 12 h.
The crude product was purified by column chromatography on sili-
ca gel using EtOAc–PE (1:10) as eluent to afford 4t; yield: 135 mg
(71%); white solid; mp 58–59 °C.
1-(4-Aminophenyl)ethanone (5d)
[CAS Reg. No.: 99-92-3]
4-Phenylmorpholine (4u)
[CAS Reg. No.: 92-53-5]
According to GP B, 1-(4-bromophenyl)ethanone (199 mg, 1.0
mmol) was treated with 28% aq ammonia (0.4 mL, 5.0 mmol) at 90
°C for 12 h. The crude product was purified by column chromatog-
raphy on silica gel using EtOAc–PE (1:2) as eluent to afford 5d;
yield: 109 mg (81%); white solid; mp 106–107 °C.
According to GP A, bromobenzene (157 mg, 1.0 mmol) was treated
with morpholine (261 mg, 3 mmol) at 90 °C for 12 h. The crude
product was purified by column chromatography on silica gel using
EtOAc–PE (1:40) as eluent to afford 4u; yield: 100 mg (62%); pale
yellow solid; mp 51–52 °C.
4-Chloroaniline (5e)
[CAS Reg. No.: 106-47-8]
1-(4-Morpholinophenyl)ethanone (4v)
[CAS Reg. No.: 39910-98-0]
Synthesis 2014, 46, 3356–3364
© Georg Thieme Verlag Stuttgart · New York

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Copper-Catalyzed Syntheses of Phenothiazines in PEG
3363
According to GP B, 1-bromo-4-chlorobenzene (191.5 mg, 1.0
mmol) was treated with 28% aq ammonia (0.4 mL, 5.0 mmol) at 90
°C for 12 h. The crude product was purified by column chromatog-
raphy on silica gel using EtOAc–PE (1:3) as eluent to afford 5e;
yield: 107 mg (84%); yellow solid; mp 70–71 °C.
IR (KBr): 3337, 2915, 1605, 1577, 1501, 1475, 1430, 1309, 1264,
1245, 1140, 1124, 1033, 925, 885, 807, 738, 715, 685, 645, 569,
547, 527, 499, 423 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.43 (s, 1 H, NH), 7.00–6.83
(m, 2 H, ArH), 6.79–6.53 (m, 5 H, ArH), 2.11 (s, 3 H, CH3).
Pyridin-3-amine (5f)
[CAS Reg. No.: 462-08-8]
13C NMR (101 MHz, DMSO-d6): δ = 143.0, 140.2, 131.3, 128.5,
128.0, 127.1, 126.8, 122.0, 117.0, 116.9, 114.9, 20.6.
MS (70 eV, EI+): m/z (%) = 213 (100, [M+]), 180 (68, [C13H10N+]).
According to GP B, 2-bromopyridine (158 mg, 1.0 mmol) was treat-
ed with 28% aq ammonia (0.4 mL, 5.0 mmol) at 90 °C for 12 h. The
crude product was purified by column chromatography on silica gel
using CH2Cl2–MeOH (20:1) as eluent to afford 5f; yield: 107 mg
(84%); yellow solid; 63–64 °C.
10H-Phenothiazine (6c)
[CAS Reg. No.: 92-84-2]
According to method A, 2-iodoaniline (219 mg, 1.0 mmol) was
treated with 2-bromobenzenethiol (227 mg, 1.2 mmol) at 90 °C for
15 h. The crude product was purified by column chromatography on
silica gel using EtOAc–PE (1:50) as eluent to afford 6c; yield: 148
mg (74%); white solid.
Phenothiazines 6a–e; General Procedure
Method A: To a 10 mL sealed vial equipped with a magnetic stir bar
were added Cu(OAc)2·H2O (20 mg, 0.1 mmol), L1 (14 mg, 0.1
mmol), aniline (1.0 mmol), 2-bromobenzenethiol (227 mg, 1.2
mmol), KOH (224 mg, 4.0 mmol), and PEG-100 (2.0 g). The reac-
tion mixture was stirred in an oil bath preheated to 90 °C for 15 h.
After allowing the mixture to cool to r.t., it was extracted with
EtOAc (3 × 40 mL). The combined organic layers were washed
with H2O (40 mL) and brine (80 mL), dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography on silica gel to afford the desired product.
According to method B, 1-bromo-2-iodobenzene (283 mg, 1.0
mmol) was treated with 2-aminobenzenethiol (150 mg, 1.2 mmol)
at 90 °C for 15 h. The crude product was purified by column chro-
matography on silica gel using EtOAc–PE (1:50) as eluent to afford
6c; yield: 127 mg (64%); white solid; mp 183–184 °C.
IR (KBr): 3340, 3051, 1596, 1570, 1472, 1442, 1306, 1282, 1262,
1243, 1153, 1119, 1078, 1033, 924, 884, 858, 847, 737, 715, 685,
656, 552, 531, 493, 426 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.61 (br s, 1 H, NH), 7.07–6.90
(m, 4 H, ArH), 6.82–6.66 (m, 4 H, ArH).
13C NMR (101 MHz, DMSO-d6): δ = 142.6, 128.0, 126.7, 122.2,
Method B: To a 10 mL sealed vial equipped with a magnetic stir bar
were added Cu(OAc)2·H2O (20 mg, 0.1 mmol), L1 (14 mg, 0.1
mmol), aryl halide (1.0 mmol), 2-aminobenzenethiol (1.2 mmol),
KOH (224 mg, 4.0 mmol), and PEG-100 (2.0 g). The reaction mix-
ture was stirred in an oil bath preheated to 90 °C for 15 h. After al-
lowing the mixture to cool to r.t., it was extracted with EtOAc (3 ×
40 mL). The combined organic layers were washed with H2O (40
mL) and brine (80 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel to afford the desired product.
116.8, 114.9.
MS (70 eV, EI+): m/z (%) = 199 (100, [M+]), 167 (38, [C12H9N+]).
2-Chloro-10H-phenothiazine (6d)
[CAS Reg. No.: 92-39-7]
According to method A, 5-chloro-2-iodoaniline (253 mg, 1.0 mmol)
was treated with 2-bromobenzenethiol (227 mg, 1.2 mmol) at 90 °C
for 15 h. The crude product was purified by column chromatogra-
phy on silica gel using EtOAc–PE (1:50) as eluent to afford 6d;
yield: 134 mg (58%); white solid.
2-Methyl-10H-phenothiazine (6a)
[CAS Reg. No.: 5828-51-3]
According to method A, 2-iodo-5-methylaniline (233 mg, 1.0
mmol) was treated with 2-bromobenzenethiol (227 mg, 1.2 mmol)
at 90 °C for 15 h. The crude product was purified by column chro-
matography on silica gel using EtOAc–PE (1:50) as eluent to afford
6a; yield: 97 mg (46%); white solid.
According to method B, 1-bromo-2-iodobenzene (283 mg, 1.0
mmol) was treated with 2-amino-4-chlorobenzenethiol (192 mg, 1.2
mmol) at 90 °C for 15 h. The crude product was purified by column
chromatography on silica gel using EtOAc–PE (1:50) as eluent to
afford 6d; yield: 129 mg (55%); white solid; mp 193–194 °C.
According to method B, 2-bromo-1-iodo-4-methylbenzene (297
mg, 1.0 mmol) was treated with 2-aminobenzenethiol (150 mg, 1.2
mmol) at 90 °C for 15 h. The crude product was purified by column
chromatography on silica gel using EtOAc–PE (1:50) as eluent to
afford 6a; yield: 157 mg (74%); white solid; mp 186–187 °C.
IR (KBr): 3334, 1593, 1567, 1467, 1429, 1369, 1302, 1274, 1241,
1154, 1122, 1094, 1031, 925, 850, 802, 745, 730, 673, 585, 552,
529, 478, 428 cm–1.
IR (KBr): 3336, 1592, 1567, 1470, 1431, 1377, 1311, 1281, 1258,
1176, 1151, 1123, 1033, 924, 862, 797, 739, 716, 677, 627, 581,
549, 531, 487, 427 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.47 (s, 1 H, NH), 6.99–6.91
(m, 1 H, ArH), 6.87 (dd, J = 7.6, 1.4 Hz, 1 H, ArH), 6.78–6.63 (m,
3 H, ArH), 6.56 (d, J = 7.7 Hz, 1 H, ArH), 6.49 (d, J = 0.7 Hz, 1 H,
ArH), 2.14 (s, 3 H, CH3).
1H NMR (300 MHz, DMSO-d6): δ = 8.73 (s, 1 H, NH), 7.04–6.83
(m, 3 H, ArH), 6.80–6.71 (m, 2 H, ArH), 6.70–6.61 (m, 2 H, ArH).
13C NMR (101 MHz, DMSO-d6): δ = 145.3, 142.9, 133.6, 129.6,
129.2, 128.1, 124.1, 123.0, 117.9, 117.4, 116.5, 115.6.
MS (70 eV, EI+): m/z (%) = 233 (75, [M+]), 235 (25, [M+]), 198
(100, [C12H8NS+]).
13C NMR (101 MHz, DMSO-d6): δ = 144.0, 143.8, 138.7, 129.2,
128.0, 127.8, 124.3, 123.4, 118.5, 116.9, 116.2, 114.8, 22.5.
3-Chloro-10H-phenothiazine (6e)
[CAS Reg. No.: 1207-99-4]
MS (70 eV, EI+): m/z (%) = 213 (100, [M+]), 180 (80, [C13H10N+]),
According to method A, 4-chloro-2-iodoaniline (253 mg, 1.0 mmol)
was treated with 2-bromobenzenethiol (227 mg, 1.2 mmol) at 90 °C
for 15 h. The crude product was purified by column chromatogra-
phy on silica gel using EtOAc–PE (1:50) as eluent to afford 6e;
yield: 132 mg (57%); white solid; mp 198–200 °C.
167 (32, [C12H9N+]).
3-Methyl-10H-phenothiazine (6b)
[CAS Reg. No.: 3939-47-7]
According to method A, 2-iodo-4-methylaniline (233 mg, 1.0
mmol) was treated with 2-bromobenzenethiol (227 mg, 1.2 mmol)
at 90 °C for 15 h. The crude product was purified by column chro-
matography on silica gel using EtOAc–PE (1:50) as eluent to afford
6b; yield: 155 mg (73%); white solid; mp 170–172 °C.
IR (KBr): 3336, 1594, 1469, 1427, 1375, 1307, 1293, 1272, 1241,
1152, 1124, 1103, 1031, 928, 880, 853, 813, 745, 712, 671, 632,
565, 545, 503, 464, 445 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3356–3364

3364
M. Huang et al.
PAPER
(9) Weiss, E. A.; Tauber, M. J.; Kelley, R. F.; Ahrens, M. J.;
1H NMR (300 MHz, DMSO-d6): δ = 8.70 (br s, 1 H, NH), 7.05–6.92
(m, 3 H, ArH), 6.89 (d, J = 7.5 Hz, 1 H, ArH), 6.74 (t, J = 7.3 Hz, 1
H, ArH), 6.64 (dd, J = 7.9, 4.1 Hz, 2 H, ArH).
Ratner, M. A.; Wasielewski, M. R. J. Am. Chem. Soc. 2005,
127, 11842.
(10) Jo, H. J.; Nam, J. E.; Kim, D.-H.; Kim, H.; Kang, J.-K. Dyes
Pigments 2014, 102, 285.
(11) Lai, R. Y.; Kong, X.; Jenekhe, S. A.; Bard, A. J. J. Am.
Chem. Soc. 2003, 125, 12631.
(12) Rhee, H.-W.; Choi, S. J.; Yoo, S. H.; Jang, Y. O.; Park, H.
H.; Pinto, R. M.; Cameselle, J. C.; Sandoval, F. J.; Roje, S.;
Han, K.; Chung, D. S.; Suh, J.; Hong, J.-I. J. Am. Chem. Soc.
2009, 131, 10107.
13C NMR (101 MHz, DMSO-d6): δ = 143.0, 142.5, 129.2, 128.6,
127.7, 126.8, 126.4, 123.4, 120.0, 117.0, 116.8, 116.0.
MS (70 eV, EI+): m/z (%) = 233 (100, [M+]), 235 (33, [M+]), 198
(78, [C12H8NS+]).
Acknowledgment
(13) Sailer, M.; Franz, A. W.; Muller, T. J. Chem. Eur. J. 2008,
14, 2602.
This work was supported financially by grants from the National
Natural Science Foundation of China (21272287) and Guangdong
Science Foundation (2012A080201007).
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Supporting Information for this article is available online
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10.1055/s-00000084.SunpfgIpi
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