One-Pot Synthesis of Pyrrolo[3,2,1-kl]phenothiazines through Copper-Catalyzed Tandem Coupling/Double Cyclization Reaction

Article abstract of DOI:10.1021/acs.joc.5b01745

A novel and efficient synthesis of pyrrolo[3,2,1-kl]phenothiazines has been developed through a Cu(I)-catalyzed tandem C-S coupling/double cyclization process. Using 2-alkynyl-6-iodoanilines and o-bromobenzenethiols as the starting materials, a wide range

Full text of DOI:10.1021/acs.joc.5b01745

Note
pubs.acs.org/joc
One-Pot Synthesis of Pyrrolo[3,2,1-kl]phenothiazines through
Copper-Catalyzed Tandem Coupling/Double Cyclization Reaction
Jiaming Tang, Bingqing Xu, Xi Mao, Hongyan Yang, Xiaoxia Wang, and Xin Lv*
Department of Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People’s Republic of
China
S
* Supporting Information
ABSTRACT: A novel and efficient synthesis of pyrrolo[3,2,1-
kl]phenothiazines has been developed through a Cu(I)-
catalyzed tandem C−S coupling/double cyclization process.
Using 2-alkynyl-6-iodoanilines and o-bromobenzenethiols as
the starting materials, a wide range of pyrrolo[3,2,1-kl]pheno-
thiazine derivatives were facilely and efficiently generated in
one pot under Cu(I) catalysis.
eteroaryl-fused heterocyclic scaffolds can be found in
numerous useful natural products, synthetic drugs, and
scope.4−9 Therefore, developing convenient and efficient
approaches to a diverse range of substituted pyrrolo[3,2,1-
kl]phenothiazines is highly desirable.
Catalytic domino transformation is a convenient and
powerful method for constructing molecular complexity in a
single operation.10 And Cu-mediated domino reactions with
intramolecular hydroamination11 as the key step(s) have also
been intensely investigated.12 On the other hand, Cu-catalyzed
one-pot transformations involving cross-coupling processes are
efficient and facile strategies for the one-step assembly of
structurally diversified molecules.13 As shown in Scheme 1, Ma
H
functional materials.1 The existence of the polycyclic indole2
and phenothiazine moieties3 in many biologically active
molecules and promising functional materials has stimulated
the exploitation of their synthetic routes. Pyrrolo[3,2,1-
kl]phenothiazines, which incorporate both indole and pheno-
thiazine moieties, have aroused considerable interest in the
fields of medicinal chemistry and material science. For instance,
as shown in Figure 1, some pyrrolo[3,2,1-kl]phenothiazines (A)
Scheme 1. Some Related Reports on Cu-Mediated One-Pot
Approaches to Phenothiazine Derivatives
Figure 1. Several useful pyrrolophenothiazine derivatives.
display anti-inflammatory activity.4 They also demonstrate
activities as potent antiarthritis and antibronchitis agents.5 It
was claimed that heteroaromatic phenothiazines (B) might be a
neuroleptic drug option.6 Several pyrrolophenothiazines (C)
can be used for the treatment of chronic diabetic disease.7
Certain polycyclic phenothiazines (D) play important roles in
the field of organic electroluminescent devices.8
Although these polycyclic heteroarenes are important,
efficient synthetic approaches to substituted pyrrolo[3,2,1-
kl]phenothiazines have rarely been documented. And pre-
viously referred routes might have some limitations such as
tedious procedures, low efficiency, and/or narrow application
et al. first discovered the Cu-catalyzed domino synthesis of
phenothiazines via the C−S/C−N coupling of o-iodoanilines
with o-bromothiophenols (eq 1).14b Then the Zeng group
developed a one-pot approach to phenothiazines through Cu-
catalyzed C−S/C−N coupling of aryl o-dihalides and o-
aminobenzenethiols (eq 2).14a Although great progress has
been achieved, most reports focus on the use of the substrates
Received: July 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01745
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
bearing one or two functional groups at an aryl ring. And there
are very limited examples on the Cu-mediated one-pot
assembly of polycyclic heteroarenes with the substrates bearing
more than three functional groups at the same aryl ring.15
Moreover, the use of multifunctionalized substrates in one-pot
transformations would modularly produce interesting moieties
that exist in numerous useful compounds. One of the greatest
challenges for achieving these transformations is the compat-
ibility of different functional groups in the same catalytic
system.
Table 1. Optimization of the Reaction Conditions
We are particularly interested in finding new one-pot
transformations for the facile synthesis of various cyclic
molecules under Cu catalysis.16 Herein we report the
development of a Cu-catalyzed synthesis of pyrrolo[3,2,1-
kl]phenothiazines from 2,6-difunctionalized anilines and o-
bromobenzenethiols through a one-pot multibond forming
process. As depicted in Scheme 1, although the starting
materials seem partially similar to those of the previous reports
on the domino synthesis of tricyclic phenothiazines,14 our
method is quite different from theirs with regard to the
following factors: (1) the products are tetracyclic pyrrolo-
phenothiazines instead of tricyclic phenothiazines; (2) it
involves a probable C−S coupling/double cyclization pathway;
and (3) it presents a new strategy on applying multi-
functionalized substrates to the generation of polycyclic
heteroaromatics in one pot under Cu catalysis (eq 3).
We commenced our investigation with the reaction between
2-iodo-6-alkynylaniline 1a17 and o-bromobenzenethiol 2a.
Initially, treatment of substrate 1a with 2a, CuI (10 mol %),
L-proline (20 mol %), and Cs2CO3 (2 equiv) in DMSO at 100
°C delivered only a 19% yield of the target product 3a, in
company with a 63% yield of the C−S coupling product 4a
(Table 1, entry 1). Increasing the temperature to 130 °C gave a
moderate yield (entry 2). This tandem transformation also
seemed to be sensitive to heating method. When the mixture
was heated at 80 °C for 24 h and then stirred at 130 °C, 3a was
exclusively generated in 68% yield (entry 3). And a 76% yield
was obtained when the mixture was stirred at 90 and 130 °C for
24 h respectively (entry 4). Switching the base to K2CO3 gave a
deteriorated result (entry 5), whereas the use of K3PO4 led to a
slightly better result (entry 6). A screen of different solvents
identified DMSO as the best medium (entry 6 vs entries 7 and
8). A series of ligands were then studied (entries 6 and 9−12).
When N,N-dimethylglycine (DMG) was used as the ligand, the
yield increased to 82% (entry 9). Other ligands were inferior to
DMG. A moderate yield of 3a was produced in the absence of
any ligand (entry 13). Then different Cu sources were tested,
and CuI showed the best efficiency (entries 6 and 14−16). We
also found that the time for stirring at 90 °C could be reduced
to 18 h (entry 17), while further shortening this process caused
a decline in the yield (entry 18). The structure of product 3a
was further determined by single-crystal X-ray analysis that
unambiguously presented the construction of the tetracyclic
pyrrolo[3,2,1-kl]phenothiazine moiety (see the Supporting
Information, Figure S1).
T1/T2
t1/t2
yield
b
entry [Cu]
base
L
(°C/°C)
(h/h)
(%)
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
−
L2
L2
L2
L2
L2
110/−
130/−
80/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
90/130
48/−
48/−
19 (63)
62 (15)
68
2
3
24/24
24/24
24/24
24/24
24/24
24/36
24/24
24/24
24/24
24/24
24/36
24/24
24/24
18/24
12/24
4
76
5
11 (52)
78
6
c
7
65
d
8
61
9
82
11
12
13
14
15
16
17
18
trace
76
52
71
61
trace
82
78
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Cu source (0.1
mmol), ligand (0.2 mmol), base (2.0 mmol), in DMSO (3 mL), under
N2, at T1 °C for t1 h and then at T2 °C for t2 h. Isolated yield of 3a.
The isolated yield of 4a was given in the parentheses if it was
separable. DMF was used as the solvent. Ethylene glycol
monomethyl ether was used as the solvent.
b
c
d
strong electron-donating group (such as MeO) at the aryl ring
of the alkyne were less effective than the others (entries 3 and
4). Interestingly, the substrate with a heteroaryl ring at its
alkynyl chain gave an excellent yield (entry 5). Different
substituents (including Me, i-Pr, Cl, F, and CF3) at the phenyl
ring of the aniline were also studied (entries 1 and 8−12). The
reactions of the electron-poor anilines furnished relatively lower
yields than those of the electron-rich ones (entries 9−12 vs
entries 1 and 8). Next, different substituted o-bromobenzene-
thiols were also studied. It was found that the reactions with o-
bromobenzenethiols bearing either an electron-donating (Me)
or electron-withdrawing group (Cl) proceeded smoothly,
affording the expected products in moderate to good yields
(entries 13−21).
In order to gain insight into the pathway, some control
experiments were carried out (Scheme 2). After 2-iodo-6-
alkylnylaniline 1a reacted with o-bromobenzenethiol 2a at 90
°C for 18 h, the C−S coupling product 4a was exclusively
isolated in 86% yield (eq 4). On further investigation we found
that when the temperature was raised up to 110 °C for 8 h, a
71% yield of 4a was obtained, accompanied by a small amount
of 3a (eq 5). In this case, neither the intermediate 5a derived
from the C−S coupling/cyclization process nor the C−S/C−N
coupling product 6a was isolated. We supposed that the
intramolecular cyclization proceeded very fast under these
conditions; thus, it was unfeasible to capture the intermedi-
With the optimized conditions in hand, we subsequently
studied the substrate scope of the one-pot method (Table 2).
First, a broad range of 2-iodo-6-alkynylanilines were surveyed
(entries 1−12). A variety of substituted 2-iodo-6-alkynylanilines
successfully afforded desired products 3. Both aromatic (entries
1−5) and aliphatic substituents (entries 6 and 7) at the alkynyl
terminal position were well tolerated under the conditions. The
substrates bearing an electron-withdrawing (such as F) or a
B
DOI: 10.1021/acs.joc.5b01745
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The Journal of Organic Chemistry
Note
ate(s) of the second step. With this possibility considered, a
nonhalogenated thiophenol 2d was used. And the reaction
efficiently gave 7-phenylthio indole 5b (eq 6), indicating that
C−S coupling/cyclization/C−N coupling process was a
possible pathway. However, the C−S coupling/C−N cou-
pling/cyclization process might also be involved, since the
intermediate such as 6a could not be excluded under these
conditions.14b
Table 2. Copper-Catalyzed One-Pot Synthesis of
Pyrrolo[3,2,1-kl]phenothiazines
a
Based on the above experiments and related literatures,14b,18
a plausible pathway is depicted in Scheme 3. Under the catalysis
Scheme 3. Proposed Pathways for the One-Pot Synthesis of
Pyrrolo[3,2,1-kl]phenothiazine
of Cu(I), 2-iodo-6-alkylnylaniline 1 reacted with o-bromo-
benzenethiol 2 to furnish the C−S coupling intermediate 4.
Then intermediate 4 may undergo two probable pathways: (a)
a 5-endo-dig cyclization provided the 7-phenylthio indole-type
intermediate 5, and subsequent intramolecular C−N coupling
of 5 delivered pyrrolo[3,2,1-kl]phenothiazine 3; (b) the
formation of 1-phenylethynyl phenothiazine-type intermediate
6 via an intramolecular C−N coupling, followed by the
cyclization to afford product 3.
In conclusion, a novel Cu(I)-catalyzed C−S coupling/double
cyclization reaction has been developed for the synthesis of
pyrrolo[3,2,1-kl]phenothiazines. Using the reactions of 2-
alkynyl-6-iodoanilines and o-bromobenzenethiols, a wide
range of the desired pyrrolo-fused phenothiazines could be
efficiently synthesized. Moreover, the method provides a good
example in applying the multifunctionalized substrates to the
a
Reaction conditions: 2-iodo-6-alkylnylaniline 1 (1.0 mmol), 2-
bromobenzenethiol 2 (1.5 mmol), CuI (0.1 mmol), DMG (0.2
mmol), K3PO4 (2.0 mmol), in DMSO (3 mL), under N2, at 90 °C for
18 h and then at 130 °C for 24 h. Isolated yield of product 3.
b
Scheme 2. Several Control Experiments Aiming at Probing the Probable Pathway
C
DOI: 10.1021/acs.joc.5b01745
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The Journal of Organic Chemistry
Note
839, 752 cm−1; HRMS (ESI) calcd for C21H16NS+ [M + H]+:
314.0998; found: 314.1010.
Important Crystal Data for 3a. C21H15NS, M = 357.47,
direct and modular generation of polycyclic heteroaromatics in
one pot under Cu catalysis.
monoclinic, space group P1, a = 11.7583(8) Å, b = 12.9661(8) Å, c
̅
EXPERIMENTAL SECTION
= 13.8658(9) Å. V = 1821.5(2) Å3, Z = 4, T = 293(2) K, 54 551
reflections collected, 8139 independent reflections. Final R = 0.2071,
wR = 0.3915, GoF = 1.267 for 8139 reflections with I > 2σ(I) and 469
parameters. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. CCDC-
1056785.
■
General Information. All one-pot reactions were carried out in an
oven-dried Schlenk tube equipped with a magnetic stir bar under a
nitrogen atmosphere. DMF and DMSO were distilled from CaH2;
EGME was dried over Na2SO4 before being distilled. 2-Alkynyl-6-
iodoanilines 1 were produced from the Sonogashira reactions between
corresponding 2,6-diiodoanilines and terminal alkynes.19 o-Bromo-
benzenethiols 2 were synthesized according to the known literatures.20
All other reagents were gained from commercial sources and used
without further purification, if not stated otherwise. All melting points
are uncorrected. The NMR spectra were recorded in CDCl3 on a 400
or 600 MHz instrument with TMS as the internal standard. Recorded
shifts were reported in parts per million (δ) downfield from TMS.
Data are shown as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J),
and integration. TLC was carried out with 0.2 mm thick silica gel
plates (GF254). Visualization was accomplished by UV light. The
chromatographic columns were hand packed with silica gel 60 (200−
300 mesh). Infrared spectra were recorded with an IR spectrometer
and are reported in reciprocal centimeter (cm−1). The unknown key
products were additionally confirmed by HRMS. HRMS analyses were
carried out using a TOF-MS instrument with an ESI source.
4-Methyl-1-(p-tolyl)pyrrolo[3,2,1-kl]phenothiazine (3b). Yellow
oil (131 mg, 80% yield); Rf = 0.60 (petroleum/DCM 10:1); 1H
NMR (600 MHz, CDCl3) δ 7.62−7.60 (m, 2H), 7.49−7.46 (m, 2H),
7.45−7.42 (m, 1H), 7.07−7.04 (m, 2H), 6.75−6.72 (m, 2H), 6.59 (s,
1H), 6.48 (s, 1H), 2.40 (s, 3H), 1.97 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 140.3, 136.7, 136.3, 136.0, 133.8, 133.6, 128.7 (2 × CH),
128.4 (2 × CH), 128.0, 127.7, 127.4, 124.8, 120.2, 119.1, 118.8, 117.8,
117.2, 109.0, 21.5, 21.1; IR (film) vmax 3055, 2912, 1590, 1459, 1323,
1215, 1144, 841, 755 cm−1; HRMS (ESI) calcd for C22H18NS+ [M +
H]+: 328.1154; found: 328.1161.
1-(4-Fluorophenyl)-4-methylpyrrolo[3,2,1-kl]phenothiazine (3c).
Yellow oil; (114 mg, 69% yield); Rf = 0.70 (petroleum/EtOAc
10:1); 1H NMR (600 MHz, CDCl3) δ 7.59−7.54 (m, 2H), 7.19−7.15
(m, 3H), 7.04 (s, 1H), 6.92 (td, J = 7.6, 1.1 Hz, 1H), 6.86−6.82 (m,
1H), 6.73 (s, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.55 (s, 1H), 2.39 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 162.7 (d, JC−F = 246.7 Hz), 139.2,
General Procedure for the Synthesis of 2-Alkynyl-6-Iodoani-
lines 1. An oven-dried two-necked flask was charged with a magnetic
136.3, 136.2, 133.9, 130.02, 129.97 (2 × CH), 129.8, 128.2, 127.4,
126.9, 124.2, 122.9, 119.0 (d, J = 2.2 Hz), 117.5, 117.3, 115.9 (d, JC−F
= 21.6 Hz) (2 × CH), 109.3, 21.5; IR (film) vmax 3069, 2923, 1590,
1461, 1322, 1218, 1156, 836, 749 cm−1; HRMS (ESI) calcd for
C21H15FNS+ [M + H]+: 332.0904; found: 332.0898.
1-(4-Methoxyphenyl)-4-methylpyrrolo[3,2,1-kl]phenothiazine
(3d). Yellow oil; (100 mg, 58% yield); Rf = 0.55 (petroleum/EtOAc
10:1); 1H NMR (600 MHz, CDCl3) δ 7.52 (dd, J = 8.6, 1.2 Hz, 2H),
7.17 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 7.00 (dd, J = 8.6, 1.2 Hz, 2H),
6.90 (t, J = 7.6 Hz, 1H), 6.83 (t, J = 7.8 Hz, 1H), 6.74−6.69 (m, 2H),
6.51 (d, J = 1.2 Hz, 1H), 3.90 (d, J = 1.2 Hz, 3H), 2.38 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 159.6, 140.3, 136.5, 136.1, 133.7, 129.6 (2
× CH), 128.0, 127.5, 126.8, 126.2, 124.1, 122.8, 119.0, 118.6, 117.3,
117.1, 114.2 (2 × CH), 108.3, 55.4 (CH3O), 21.5; IR (film) vmax 3063,
2927, 1589, 1455, 1226, 835, 754 cm−1; HRMS (ESI) m/z: calcd for
C22H18ONS+ [M + H]+: 344.1104; found: 344.1109.
stir bar, 4-substituted 2,6-diiodoaniline (5 mmol), Pd(PPh3)2Cl2 (175
mg, 0.25 mmol, 5 mol %), and CuI (95 mg, 0.5 mmol, 10 mol %). The
flask was evacuated and backfilled with nitrogen (three times). Under a
positive pressure of nitrogen, a solution of terminal alkyne (5 mmol)
in TEA (20 mL) was added via syringe. The mixture was stirred at rt
for 15 h and then stirred at 50 °C for about 5 h (monitored by TLC).
After being cooled to rt, the mixture was diluted with 60 mL of EtOAc.
The mixture was washed with brine (10 mL × 3). Then the organic
phase was dried over Na2SO4 and concentrated. The residue was
purified by column chromatography on silica gel using petroleum/
EtOAc (10:1, v/v) as eluent to afford substrate 1.
General Procedure for the Copper-Catalyzed One-Pot
Synthesis of Pyrrolo[3,2,1-kl]phenothiazines 3. An oven-dried
Schlenk tube was charged with a magnetic stir bar, 2-alkynyl-6-
iodoanilines 1 (0.5 mmol), CuI (0.05 mmol, 10 mol %), DMG (0.1
mmol, 20 mol %), and K3PO4 (2.0 mmol, 4.0 equiv). The tube was
capped and then evacuated and backfilled with nitrogen (three times).
Under a positive pressure of nitrogen, a solution of o-bromobenzene-
thiol 2 (0.5 mmol, 1 equiv) in DMSO (2.0 mL) was added via syringe.
The mixture was stirred at 90 °C for about 18 h. Then it was stirred at
130 °C for 24 h (monitored by TLC). After being cooled to rt, the
mixture was diluted with 30 mL of EtOAc. The mixture was washed
with brine (10 mL × 3). Then the organic phase was dried over
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel using petroleum/EtOAc (12:1−8:1, v:v)
as eluent to give product 3.
4-Methyl-1-(quinolin-2-yl)pyrrolo[3,2,1-kl]phenothiazine (3e).
Orange solid (170 mg, 93% yield); Rf = 0.65 (petroleum/EtOAc
1
5:1); mp 179−181 °C; H NMR (600 MHz, CDCl3) δ 9.16 (s, 1H),
8.32 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz,
1H), 7.77−7.81 (m, 1H), 7.64−7.60 (m, 1H), 7.20 (dd, J = 7.8, 1.4
Hz, 1H), 7.08 (s, 1H), 6.91 (td, J = 7.6, 1.1 Hz, 1H), 6.81−6.75 (m,
2H), 6.74 (s, 1H), 6.65 (dd, J = 8.3, 0.9 Hz, 1H), 2.40 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 150.0, 147.4, 136.8, 136.6, 136.0, 134.1,
134.0, 129.9, 129.5, 128.4, 128.1, 127.7, 127.42, 127.41, 127.2, 126.9,
124.5, 123.0, 119.6, 118.9, 117.7, 117.5, 110.9, 21.5; IR (KBr) vmax
3057, 2915, 1617, 1576, 1446, 1304, 1254, 1155, 1019, 815, 746 cm−1;
HRMS (ESI) m/z: calcd for C24H17N2S+ [M + H]+: 365.1107; found:
365.1115.
1-Cyclopropyl-4-methylpyrrolo[3,2,1-kl]phenothiazine (3f). Yel-
1
low oil (111 mg, 80% yield); Rf = 0.50 (petroleum/EtOAc 10:1); H
NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 7.06−7.10 (m,
2H), 6.96−6.90 (m, 1H), 6.83 (s, 1H), 6.50 (s, 1H), 6.16 (s, 1H), 2.32
(s, 3H), 2.20−2.16 (m, 1H), 1.19−1.15 (m, 2H), 1.01−0.97 (m, 2H);
13C NMR (150 MHz, CDCl3) δ 142.1, 136.6, 132.94, 132.92, 127.6,
127.0, 126.7, 124.1, 122.3, 117.0, 116.4, 116.3, 104.4, 100.0, 21.4, 12.2
(cyclopropyl-CH), 9.6 (2 × cyclopropyl-CH2); IR (film) vmax 3065,
3012, 2920, 1589, 1467, 1331, 1283, 1220, 1161, 831, 744 cm−1;
HRMS (ESI) m/z: calcd for C18H16NS+ [M + H]+: 278.0998; found:
278.1013.
4-Methyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3a). Yellow
solid (128 mg, 82% yield); Rf = 0.60 (petroleum/DCM 10:1); mp
1
112−114 °C; H NMR (400 MHz, CDCl3) δ 7.62−7.60 (m, 2H),
7.49−7.40 (m, 3H), 7.19 (dd, J = 7.7, 1.5 Hz, 1H), 7.05 (s, 1H), 6.91
(td, J = 7.5, 1.2 Hz, 1H), 6.85−6.80 (m, 1H), 6.74 (s, 1H), 6.69 (dd, J
= 8.3, 1.1 Hz, 1H), 6.59 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 140.4, 136.4, 136.3, 133.8, 133.7, 128.8 (2 × CH), 128.3 (2
× CH), 128.1, 128.0, 127.5, 126.8, 124.1, 122.8, 119.2, 118.9, 117.5,
117.3, 109.3, 21.5; IR (KBr) vmax 3054, 1589, 1460, 1326, 1217, 1141,
1-Butyl-4-methylpyrrolo[3,2,1-kl]phenothiazine (3g). Yellow oil
1
(122 mg, 83% yield); Rf = 0.50 (petroleum/EtOAc 10:1); H NMR
(600 MHz, CDCl3) δ 7.42−7.39 (m, 1H), 7.11−7.06 (m, 2H), 6.93
(td, J = 7.7, 1.1 Hz, 1H), 6.86 (s, 1H), 6.51 (s, 1H), 6.27 (s, 1H),
D
DOI: 10.1021/acs.joc.5b01745
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The Journal of Organic Chemistry
Note
3.09−3.05 (m, 2H), 2.32 (s, 3H), 1.81−1.76 (m, 2H), 1.51−1.47 (m,
2H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 141.0,
136.6, 133.6, 133.0, 128.8, 127.9, 127.1, 126.9, 124.1, 122.7, 117.0,
116.5, 116.2, 105.8, 31.1, 30.9, 22.6, 21.4, 14.0; IR (film) vmax 3054,
2926, 2860, 1590, 1465, 1328, 1217, 1164, 834, 741 cm−1; HRMS
(ESI) m/z: calcd for C19H20NS+ [M + H]+: 294.1311; found:
294.1315.
4-Isopropyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3h). Yellow
oil (130 mg, 76% yield); Rf = 0.60 (petroleum/DCM 10:1); 1H NMR
(600 MHz, CDCl3) δ 7.64−7.58 (m, 2H), 7.49−7.45 (m, 2H), 7.44−
7.40 (m, 1H), 7.20 (dd, J = 7.7, 1.4 Hz, 1H), 7.13 (s, 1H), 6.92 (td, J =
7.6, 1.1 Hz, 1H), 6.85−6.79 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.63 (s,
1H), 2.98−2.94 (m, 1H), 1.33−1.32 (m, 6H); 13C NMR (150 MHz,
CDCl3) δ 145.4, 140.5, 136.7, 136.4, 133.8, 128.8 (2 × CH), 128.3 (2
× CH), 128.11, 128.09, 127.4, 126.8, 124.1, 122.8, 119.2, 117.5, 116.7,
114.8, 109.6, 34.4, 24.5 (2 × CH3); IR (film) vmax 3053, 2912, 1590,
1459, 1342, 1142, 751 cm−1; HRMS (ESI) m/z: calcd for C23H20NS+
[M + H]+: 342.1311; found: 342.1320.
140.3, 136.7, 136.3, 136.0, 133.8, 133.6, 128.7 (2 × CH), 128.4 (2 ×
CH), 128.1, 127.7, 127.4, 124.8, 120.1, 119.1, 118.8, 117.7, 117.1,
108.9, 21.5, 21.0; IR (film) vmax 3054, 2923, 1599, 1460, 1308, 1287,
1175, 841, 761 cm−1; HRMS (ESI) m/z: calcd for C22H18NS+ [M +
H]+: 328.1154; found: 328.1162.
9-Chloro-4-methyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3n).
Yellow oil (128 mg, 74% yield); Rf = 0.60 (petroleum/DCM 10:1);
1H NMR (600 MHz, CDCl3) δ 7.59−7.57 (m, 2H), 7.51−7.48 (m,
2H), 7.47−7.44 (m, 1H), 7.07−7.04 (m, 2H), 6.88 (dd, J = 8.3, 2.1
Hz, 1H), 6.71 (s, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.59 (s, 1H), 2.39 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 140.3, 137.3, 136.0, 134.2,
133.0, 132.4, 129.0 (2 × CH), 128.51, 128.50, 128.3 (2 × CH), 127.6,
124.0, 121.3, 119.2, 119.1, 117.6, 117.0, 109.7, 21.5; IR (film) vmax
3052, 2915, 1564, 1459, 1326, 1223, 752, 638 cm−1; HRMS (ESI) m/
z: calcd for C21H15ClNS+ [M + H]+: 348.0608 (35Cl); found: 348.0615
(35Cl).
4,9-Dimethyl-1-(p-tolyl)pyrrolo[3,2,1-kl]phenothiazine (3o). Yel-
low solid (138 mg, 81% yield); Rf = 0.60 (petroleum/DCM 10:1); mp
127−130 °C. 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.0 Hz, 2H),
7.27 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.73
(d, J = 7.7 Hz, 1H), 6.71 (s, 1H), 6.54 (d, J = 5.6 Hz, 2H), 2.47 (s,
3H), 2.39 (s, 3H), 1.98 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
140.5, 138.0, 136.7, 136.22, 136.15, 133.6, 130.9, 129.4 (2 × CH),
128.3 (2 × CH), 127.7, 127.5, 124.8, 120.1, 119.1, 118.6, 117.7, 117.1,
108.6, 21.5, 21.4, 21.1; IR (KBr) vmax 3049, 2910, 1590, 1458, 1322,
1138, 746 cm−1; HRMS (ESI) m/z: calcd for C23H20NS+ [M + H]+:
342.1311; found: 342.1318.
1-(4-Fluorophenyl)-4,9-dimethylpyrrolo[3,2,1-kl]phenothiazine
(3p). Yellow oil (125 mg, 72% yield); Rf = 0.60 (petroleum/DCM
10:1); 1H NMR (600 MHz, CDCl3) δ 7.59−7.55 (m, 2H), 7.17−7.15
(m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.74 (d, J = 7.8 Hz,
1H), 6.72 (s, 1H), 6.54 (s, 1H), 6.44 (s, 1H), 2.38 (s, 3H), 1.99 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 162.6 (d, JC−F = 248.3 Hz)
(CF), 139.1, 136.8, 136.3, 135.9, 133.7, 130.06 (d, JC−F = 8.1 Hz) (2 ×
CH), 129.9 (d, JC−F = 3.4 Hz), 127.8, 127.3, 124.9, 120.0, 119.2, 118.9,
117.8, 117.1, 115.8 (d, JC−F = 21.6 Hz) (2 × CH), 109.0, 21.5, 21.1; IR
(film) vmax 3055, 2921, 1604, 1460, 1317, 1221, 1155, 832, 802 cm−1;
HRMS (ESI) m/z: calcd for C22H17FNS+ [M + H]+: 346.1060; found:
346.1066.
4-Chloro-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3i). Yellow
solid (100 mg, 60% yield); Rf = 0.70 (petroleum/EtOAc 10:1); mp
1
56−58 °C; H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 6.8 Hz, 2H),
7.50−7.45 (m, 3H), 7.21−7.20 (m, 1H), 7.17−7.16 (m, 1H), 6.94 (t, J
= 7.5 Hz, 1H), 6.86−6.81 (m, 2H), 6.69 (d, J = 8.3 Hz, 1H), 6.57 (s,
1H); 13C NMR (150 MHz, CDCl3) δ 141.2, 136.2, 135.6, 133.1,
129.3, 128.9 (2 × CH), 128.5, 128.4 (2 × CH), 128.1, 127.7, 127.1,
124.6, 122.1, 119.6, 119.4, 117.3, 116.9, 108.8; IR (KBr) vmax 3050,
1590, 1566, 1479, 1453, 1359, 1191, 1078, 748, 636 cm−1; HRMS
(ESI) m/z: calcd for C20H13ClNS+ [M + H]+: 334.0452 (35Cl); found:
334.0453 (35Cl).
4-Chloro-1-(4-fluorophenyl)pyrrolo[3,2,1-kl]phenothiazine (3j).
Yellow oil (125 mg, 71% yield); Rf = 0.60 (petroleum/EtOAc 10:1);
1H NMR (600 MHz, CDCl3) δ 7.56 (dd, J = 8.6, 5.4 Hz, 2H), 7.47−
7.46 (m, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.20−7.16 (m, 2H), 6.96 (t, J =
7.5 Hz, 1H), 6.88−6.83 (m, 2H), 6.65 (d, J = 8.1 Hz, 1H), 6.55 (s,
1H); 13C NMR (150 MHz, CDCl3) δ 162.9 (d, JC−F = 247.8 Hz)
(CF), 140.1, 136.1, 135.5, 130.1 (d, JC−F = 8.2 Hz) (2 × CH), 129.4,
129.3, 128.2, 127.7, 127.2, 124.7, 122.3, 119.7, 119.2, 117.4, 116.9,
116.1 (d, JC−F = 21.8 Hz) (2 × CH), 108.7; IR (film) vmax 3066, 1587,
1480, 1453, 1336, 1224, 1157, 1075, 837, 755, 603 cm−1; HRMS (ESI)
m/z: calcd for C20H12ClFNS+ [M + H]+: 352.0358 (35Cl); found:
352.0366 (35Cl).
1-(4-Methoxyphenyl)-4,9-dimethylpyrrolo[3,2,1-kl]phenothiazine
(3q). Yellow solid (98 mg, 55% yield); Rf = 0.55 (petroleum/EtOAc
1
4-Fluoro-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3k). Yellow oil
10:1); mp 161−163 °C; H NMR (600 MHz, CDCl3) δ 7.52 (d, J =
1
(92 mg, 58% yield); Rf = 0.70 (petroleum/EtOAc 10:1); H NMR
8.7 Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.02−7.00 (m, 2 H), 6.99 (s,
1H), 6.73 (d, J = 7.8 Hz, 1H), 6.70 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H),
3.91 (s, 3H), 2.38 (s, 3H), 2.00 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 159.6, 140.2, 136.7, 136.1 (d, J = 11.9 Hz), 133.6, 133.0, 129.6 (2 ×
CH), 127.7, 127.5, 126.3, 124.8, 120.0, 119.1, 118.5, 117.6, 117.0,
114.1 (2 × CH), 108.1, 55.4 (CH3O), 21.5, 21.2; IR (KBr) vmax 3069,
2929, 1588, 1453, 1336, 1224, 1157, 833, 751 cm−1; HRMS (ESI) m/
z: calcd for C23H20NOS+ [M + H]+: 358.1260; found: 358.1253.
4-Isopropyl-9-methyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine
(3r). Yellow oil (135 mg, 76% yield); Rf = 0.60 (petroleum/DCM
10:1); 1H NMR (600 MHz, CDCl3) δ 7.62−7.59 (m, 2H), 7.49−7.46
(m, 2H), 7.44−7.42 (m, 1H), 7.12 (s, 1H), 7.07 (d, J = 7.9 Hz, 1H),
6.80 (s, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 6.47
(s, 1H), 2.97−2.93 (m, 1H), 1.97 (s, 3H), 1.32−1.31 (m, 6H); 13C
NMR (150 MHz, CDCl3) δ 145.2, 140.4, 136.7, 136.6, 136.0, 133.8,
128.7 (2 × CH), 128.4 (2 × CH), 128.1, 127.7, 127.3, 124.8, 120.2,
119.1, 117.8, 116.6, 114.6, 109.2, 34.4, 24.5 (2 × CH3), 21.1; IR (film)
vmax 3069, 2968, 1590, 1464, 1261, 1092, 1023, 796, 750 cm−1; HRMS
(ESI) m/z: calcd for C24H22NS+ [M + H]+: 356.1467; found:
356.1458.
(600 MHz, CDCl3) δ 7.60−7.59 (m, 2H), 7.49−7.43 (m, 3H), 7.17
(dd, J = 7.7, 1.4 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.91−6.88 (m, 1H),
6.86−6.82 (m, 1H), 6.69 (dd, J = 8.3, 1.0 Hz, 1H), 6.66 (dd, J = 9.0,
2.2 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
160.5 (d, JC−F = 237.9 Hz) (CF), 141.5, 135.8, 134.3, 133.3, 128.9 (2
× CH), 128.5, 128.4 (2 × CH), 128.0, 127.2 (d, J = 11.0 Hz), 127.1,
124.5, 122.0, 119.5, 119.4, 109.3 (d, JC−F = 4.3 Hz), 106.0 (d, JC−F
=
29.4 Hz), 102.4 (d, JC−F = 24.4 Hz); IR (film) vmax 3049, 1589, 1478,
1461, 1347, 1166, 1072, 749 cm−1; HRMS (ESI) m/z: calcd for
C20H13FNS+ [M + H]+: 318.0747; found: 318.0741.
Phenyl-4-(trifluoromethyl)pyrrolo[3,2,1-kl]phenothiazine (3l).
Yellow oil (123 mg, 67% yield); Rf = 0.60 (petroleum/EtOAc 10:1);
1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 6.8 Hz, 2H), 7.55 (s, 1H),
7.51−7.46 (m, 3H), 7.19 (d, J = 6.9 Hz, 1H), 7.08 (s, 1H), 6.97 (t, J =
7.4 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.72 (s, 1H), 6.70 (d, J = 8.4 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 141.7, 139.1, 135.6, 134.2 (d,
JC−F = 361.6 Hz) (CF3), 129.0 (2 × CH), 128.8, 128.7, 128.4 (2 ×
CH), 128.2, 127.7, 127.2, 126.3, 125.0, 122.3, 119.5, 119.4, 115.3 (d,
JC−F = 4.3 Hz), 113.9 (d, JC−F = 3.5 Hz), 109.5; IR (film) vmax 3062,
1575, 1447, 1351, 1268, 1113, 1069, 875, 753 cm−1; HRMS (ESI) m/
z: calcd for C21H13F3NS+ [M + H]+: 368.0715; found: 368.0697.
4,9-Dimethyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3m). Yel-
9-Chloro-4-isopropyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine
(3s). Yellow oil (141 mg, 75% yield); Rf = 0.60 (petroleum/DCM
1
10:1); H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.0 Hz, 2H), 7.51
1
(t, J = 7.2 Hz, 2H), 7.49−7.45 (m, 1H), 7.14 (s, 1H), 7.07 (d, J = 8.3
Hz, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 1H), 6.81 (s, 1H), 6.66−6.61 (m,
2H), 2.99−2.94 (m, 1H), 1.33 (d, J = 6.9 Hz, 6H); 13C NMR (150
MHz, CDCl3) δ 145.8, 140.5, 137.3, 136.3, 133.0, 132.4, 129.0 (2 ×
CH), 128.53, 128.52, 128.3 (2 × CH), 127.6, 124.0, 121.3, 119.2,
low oil (131 mg, 80% yield); Rf = 0.55 (petroleum/DCM 10:1); H
NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.8
Hz, 2H), 7.17 (dd, J = 7.8, 1.5 Hz, 1H), 7.03 (s, 1H), 6.91 (td, J = 7.5,
1.2 Hz, 1H), 6.82 (td, J = 7.5, 1.2 Hz, 1H), 6.74−6.69 (m, 2H), 6.55
(s, 1H), 2.46 (s, 3H), 2.38 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
E
DOI: 10.1021/acs.joc.5b01745
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
117.1, 116.9, 115.0, 110.0, 34.4, 24.5 (2 × CH3); IR (film) vmax 3055,
2938, 1588, 1457, 1340, 1161, 748, 641 cm−1; HRMS (ESI) m/z: calcd
for C23H19ClNS+ [M + H]+: 376.0921 (35Cl); found: 376.0940 (35Cl).
4-Chloro-9-methyl-1-phenylpyrrolo[3,2,1-kl]phenothiazine (3t).
Yellow oil (107 mg, 62% yield); Rf = 0.60 (petroleum/DCM 10:1);
1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 2H), 7.50−7.45
(m, 3H), 7.20 (d, J = 1.4 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (d, J
= 1.4 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.57 (s, 1H), 6.47 (s, 1H),
1.96 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 141.2, 137.1, 136.1,
135.3, 133.2, 129.2, 128.8 (2 × CH), 128.5, 128.4 (2 × CH), 127.7,
127.6, 125.3, 120.4, 119.9, 118.5, 117.2, 116.7, 108.4, 21.1; IR (film)
vmax 3052, 2915, 1652, 1564, 1459, 1326, 1223, 752, 635 cm−1; HRMS
(ESI) m/z: calcd for C21H15ClNS+ [M + H]+: 348.0608 (35Cl); found:
348.0617 (35Cl).
9-Methyl-1-phenyl-4-(trifluoromethyl)pyrrolo[3,2,1-kl]pheno-
thiazine (3u). Yellow oil (114 mg, 60% yield); Rf = 0.60 (petroleum/
EtOAc 10:1); 1H NMR (600 MHz, CDCl3) δ 7.60 (dd, J = 7.8, 1.5 Hz,
2H), 7.54 (s, 1H), 7.51−7.47 (m, 3H), 7.08−7.03 (m, 2H), 6.78 (d, J
= 7.4 Hz, 1H), 6.70 (s, 1H), 6.49 (s, 1H), 1.97 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 141.6, 139.0, 137.2, 134.0 (d, JC−F = 299.6 Hz)
(CF3), 128.9 (2 × CH), 128.8, 128.5 (2 × CH), 128.4, 127.8, 126.34,
126.28, 125.6, 121.3, 120.5, 119.7, 118.6, 115.1 (d, J = 4.4 Hz), 113.7
(d, J = 3.6 Hz), 109.2, 21.1; IR (film) vmax 3053, 2920, 1601, 1468,
1338, 1268, 1152, 1117, 804, 765, 694 cm−1; HRMS (ESI) m/z: calcd
for C22H15F3NS+ [M + H]+: 382.0872; found: 382.0857.
REFERENCES
■
(1) For selected reviews on some useful heteroaromatic-fused
heterocyles, see: (a) Dsouza, R. N.; Pischel, U.; Nau, W. M. Chem.
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(b) Tanaka, M.; Sagawa, S.; Hoshi, J.-I.; Shimoma, F.; Yasue, K.;
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Kim, D.; Kang, M.-S.; Song, K.; Kang, S. O.; Ko, J. Tetrahedron 2009,
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(3) For selected references on the applications of phenothiazines in
medicinal chemistry and photoelectric science, see: (a) Matralis, A. N.;
Kourounakis, A. P. J. Med. Chem. 2014, 57, 2568. (b) Yang, C.-J.;
Chang, Y. J.; Watanabe, M.; Hon, Y.-S.; Chow, T. J. J. Mater. Chem.
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3148.
2-((2-Bromophenyl)thio)-4-methyl-6-(phenylethynyl)aniline (4a).
Yellow vicious oil (170 mg, 86% yield); 1H NMR (600 MHz, CDCl3)
δ 7.58−7.52 (m, 3H), 7.41−7.36 (m, 4H), 7.33 (s, 1H), 7.19−7.13 (m,
1H), 7.05−7.00 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.85 (s, 2H), 2.29
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 148.1, 138.8, 137.6, 135.0,
132.9, 131.51 (2 × CH), 131.50, 128.5 (2 × CH), 127.9, 127.3,
126.42, 126.39, 123.0, 120.8, 112.8, 108.6, 95.2 (C, alkynyl), 85.7 (C,
alkynyl), 20.1; IR (film) vmax 3478, 3376, 3069, 2917, 2197, 1574,
1446, 1232, 750, 691, 579 cm−1; HRMS (ESI) m/z: calcd for
C21H17BrNS+ [M + H]+: 396.0239 (81Br); found: 396.0246 (81Br).
5-Methyl-2-phenyl-7-(phenylthio)-1H-indole (5b). Yellow vicious
oil (124 mg, 79% yield); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H),
7.61 (d, J = 7.4 Hz, 2H), 7.52 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.38−
7.31 (m, 2H), 7.30−7.25 (m, 2H), 7.24−7.15 (m, 3H), 6.84 (d, J = 2.0
Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.4, 136.96,
136.95, 132.0, 130.8, 130.5, 130.0, 129.2 (2 × CH), 129.0 (2 × CH),
127.9, 127.2 (2 × CH), 125.8, 125.2 (2 × CH), 122.0, 112.7, 100.1,
21.4; IR (film) vmax 3471, 3058, 2959, 1603, 1582, 1452, 1238, 1076,
1024, 737, 689 cm−1; HRMS (ESI) m/z: calcd for C21H18NS+ [M +
H]+: 316.1154; found: 316.1165.
(4) (a) Isakson, P. C.; Anderson, G. D.; Gregory, S. A. US patent
6136839; Chem. Abstr. 2000, 133, 321880. (b) Isakson, P. C.;
Anderson, G. D.; Gregory, S. A. World patent 9641626; Chem. Abstr.
1997, 126, 166479. (c) Mylari, B. L.; Carty, T. J.; Moore, P. F.;
Zembrowski, W. J. J. Med. Chem. 1990, 33, 2019.
(5) Mylari, B. L.; McManus, J. M.; Lombardino, J. G. European
patent 0332364, Chem. Abstr.: 1990, 112, 118796.
(6) Earl, R. A.; Myers, M. J. World patent 9409009. Chem. Abstr.
1994, 121, 108835.
(7) Irikura, T.; Takagi, K.; Fujimori, S.; Hirata, Y. US patent
4593092; Chem. Abstr. 1986, 105, 114900.
(8) Hikime, M.; Miura, N.; Ono, K.; Sekine, N.; Hakoi, Y. Japanese
patent 2012248663, Chem. Abstr.: 2012, 158, 91908.
(9) Steps from special polycyclic substrates such as phenothiazines:
(a) Silva, G. A.; Costa, L. M. M.; Brito, F. C. F.; Miranda, A. L. P.;
Barreiro, E. J.; Fraga, C. A. M. Bioorg. Med. Chem. 2004, 12, 3149.
(b) Hollins, R. A.; Pinto, A. C. J. Heterocycl. Chem. 1978, 15, 711.
(c) Boekelheide, V.; Hollins, R. A. J. Org. Chem. 1971, 36, 2437
Generally, only relevant unsubstituted or monosubstituted pyrrolo-
phenothiazines were synthesized under strong acidic/basic conditions..
(10) For selected reports on domino reactions, see: (a) Pellissier, H.
Chem. Rev. 2013, 113, 442. (b) Tietze, L. F.; Brasche, G.; Gericke, K.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2006. For some representative reports on catalytic domino
synthesis of related heterocycles: (c) Synthesis of indoles via various
Pd-catalyzed domino reactions: Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873. (d) Synthesis of indoles via Pd-catalyzed annulation
of o-haloanilines with internal alkynes: Larock, R.; Yum, E.; Refvik, M.
J. Org. Chem. 1998, 63, 7652. (e) Synthesis of phenothiazines through
Pd-catalyzed multicomponent reactions of aryl o-dihalides, primary
amines, and o-bromobenzenethiols: Dahl, T.; Tornøe, C. W.; Bang-
Andersen, B.; Nielsen, P.; Jorgensen, M. Angew. Chem., Int. Ed. 2008,
47, 1726. (f) Synthesis of phenothiazines via Fe-catalyzed reactions
between aryl o-dihalides and N-acyl o-aminobenzenethiols: Hu, W.;
Zhang, S. J. Org. Chem. 2015, 80, 6128.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01745.
Copies of 1H NMR and 13C NMR spectra for the
products and key intermediates, and X-ray crystal
structure of product 3a (PDF)
Crystallographic data of 3a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
(11) Two important reviews on the application of intramolecular
hydroaminations: (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo,
F.; Tada, M. Chem. Rev. 2008, 108, 3795. (b) Alonso, F.; Beletskaya, I.
P.; Yus, M. Chem. Rev. 2004, 104, 3079.
*E-mail: lvxin@zjnu.cn.
Notes
The authors declare no competing financial interest.
(12) Some selected recent examples on copper-catalyzed domino
reaction with intramolecular hydroamination as the key step(s):
(a) Cacchi, S.; Fabrizi, G.; Iazzetti, A.; Molinaro, C.; Verdiglione, R.;
Goggiamani, A. Adv. Synth. Catal. 2015, 357, 1053. (b) Kumar, A.;
Kumar, M.; Maurya, S.; Khanna, R. S. J. Org. Chem. 2014, 79, 6905.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC, Grant No. 21202152) for financial support.
F
DOI: 10.1021/acs.joc.5b01745
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(c) Xing, Y.; Cheng, B.; Wang, J.; Lu, P.; Wang, Y. Org. Lett. 2014, 16,
4814. (d) Naresh, G.; Kant, R.; Narender, T. Org. Lett. 2014, 16, 4528.
(13) For important reviews, see: (a) Liu, Y.; Wan, J. Chem. - Asian J.
2012, 7, 1488. (b) Liu, Y.; Wan, J. Org. Biomol. Chem. 2011, 9, 6873.
(14) (a) Dai, C.; Sun, X.; Tu, X.; Wu, L.; Zhan, D.; Zeng, Q. Chem.
Commun. 2012, 48, 5367. (b) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y.
Angew. Chem., Int. Ed. 2010, 49, 1291.
(15) The reports on the Cu-mediated one-pot synthesis of
heterocycles with the substrates bearing three or more functional
groups at an aryl ring: (a) Okano, K.; Mitsuhashi, N.; Tokuyama, H.
Chem. Commun. 2010, 46, 2641. (b) Suzuki, Y.; Ohta, Y.; Oishi, S.;
Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 4246. (c) Lu, B.; Wang, B.;
Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337. (d) Jia, W.; Wang, R.;
Song, D.; Ball, S. J.; McLean, A. B.; Wang, S. Chem. - Eur. J. 2005, 11,
832. Note that in most cases (excepting ref 13a), only symmetric
multifunctionalized substrates were utilized. Reference 13a reported an
interesting Cu-catalyzed double amination of the unsymmetric
multifunctionalized substrates in the total synthesis of PDE-II.
(16) (a) Gao, J.; Shao, Y.; Zhu, J. Y.; Zhu, J. Q.; Mao, H.; Wang, X.;
Lv, X. J. Org. Chem. 2014, 79, 9000. (b) Yuan, G.; Liu, H. Q.; Gao, J.;
Xu, H.; Jiang, L.; Wang, X.; Lv, X. RSC Adv. 2014, 4, 21904. (c) Yuan,
G.; Liu, H.; Gao, J.; Yang, K.; Niu, Q.; Mao, H.; Wang, X.; Lv, X. J.
Org. Chem. 2014, 79, 1749. (d) Niu, Q.; Mao, H.; Yuan, G.; Gao, J.;
Liu, H.; Tu, Y.; Wang, X.; Lv, X. Adv. Synth. Catal. 2013, 355, 1185.
(17) The substrates 1 can be readily and efficiently synthesized from
the Sonogashira reactions of the corresponding diiodoanilines with
terminal alkynes. For details, see the Experimental Section.
(18) It was reported that unmodified o-alkynylanilines could
smoothly undergo cyclization to afford the 1H-indoles facilitated by
copper/base in strong polar solvents: (a) Koradin, C.; Dohle, W.;
Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
(b) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488−2490.
(19) Capelli, L.; Manini, P.; Pezzella, A.; d'Ischia, M. Org. Biomol.
Chem. 2010, 8, 4243.
(20) Xiao, W.; Alper, H. J. Org. Chem. 1999, 64, 9646.
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DOI: 10.1021/acs.joc.5b01745
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