Access to Phenothiazine Derivatives via Iodide-Mediated Oxidative Three-Component Annulation Reaction

Article abstract of DOI:10.1021/acs.joc.0c00562

Herein, a new iodide-mediated three-component annulation reaction of secondary anilines, cyclohexanones, and elemental sulfur is demonstrated, which allows access to various phenothiazines with the merits of formation of multiple chemical bonds in one single operation, high step and atom efficiency, readily available feedstocks and catalyst system, and good substrate and functional group compatibility. The developed chemistry capable of constructing novel phenothiazines with structural diversity offers a significant basis for further applications.

Full text of DOI:10.1021/acs.joc.0c00562

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Article
Access to Phenothiazine Derivatives via Iodide-Mediated
Oxida-tive Three-Component Annulation Reaction
Qinghua Chen, Rong Xie, Huanhuan Jia, Jialu Sun, Guangpeng Lu, Huanfeng Jiang, and Min Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00562 • Publication Date (Web): 23 Mar 2020
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Page 1 of 9
The Journal of Organic Chemistry
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Access to Phenothiazine Derivatives via Iodide-Mediated Oxidative
Three-Component Annulation Reaction
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Qinghua Chen, Rong Xie, Huanhuan Jia, Jialu Sun, Guangpeng Lu, Huanfeng Jiang and Min Zhang*
ABSTRACT: Herein, a new iodide-mediated three-
component annulation reaction of secondary anilines,
R
R2
NaI, DMSO
N
p-Nitrobenzoic acid
R1
+
S8
+
R1
cyclohexanones and elemental sulfur is demonstrated,
which allows access to various phenothiazines with the
merits of formation of multiple chemical bonds in one
single operation, high step and atom efficiency, readily
available feedstocks and catalyst system, good substrate
and functional group compability. The developed
R
N
PhCl, O2 balloon
O
S
R2
H
 Readily available feedstocks
 Metal free catalyst system
 Multiple bonds formation in one operation
 Good functional compability
 High regio- and chemoselectivity
 Valuable products
chemistry capable of constructing novel phenothiazines with structural diversity offers a significant basis for further applications.
■ INTRODUCTION
requisite coupling reactants, the use of transition metal catalysts
and less environmentally benign halogenated substrates, and
low step and atom-efficiency. To overcome these issues, the
Deng group has developed a four-component approach via a
key iodide-mediated sulfuration of two β-sites of enamines,
arising from the condensation of amines and two molecules of
cyclohexanones (eq 3).8 However, such a method is more
applicable for access to symmetrical phenothiazines. In this
context, the development of new and transition metal-free
shortcuts, enabling access to both symmetrical and
unsymmetrical phenothiazines, especially for those of structural
novel ones, would be highly desirable, as it would offer the
potential for the discovery of functional products with original
physical and chemical properties.
Phenothiazines constitute
a class of highly important
heterocyclic compounds. With the observation of diverse
biological and therapeutic activities, such compounds have
been extensively employed for the development of biomedical
products, such as antitubercular and multiple drug resistance
(MDR) reverting agents (Figure 1, compound A),
cholinesterase inhibitors, and antihistaminics.1 To date, more
than 100 phenothiazine derivatives (e.g., marketing drug B:
Chlorpromazine) have been utilized for the treatment of
psychotic diseases.2 Due to the high electron-donating
capability and the nonplanar butterfly conformation inhibiting
molecular aggregation, phenothiazines are promising materials
utilized as light-emitting diodes, photovoltaic cells and
photosensitisers.3 Recently, such compounds have been
successfully developed as cathode materials of flow batteries
(compound C) and polymerization inhibitors and mediators in
hair dye (compound D)4.
Scheme 1. The Previous Work and Our New Observation
Ma et al
S
I
HS
R1
R1
+
Cat: [Cu], ligand, base
R2
R2
(1)
N
R
NHR
Br
alternative methods
X
S
S
S
S
S
HS
R1
R2
R1
(2)
R2
Cat: [Cu] or [Fe], base
+
N
Cl
N
N
N
N
Y
RHN
R
(X, Y = halogens)
N
Deng's work
R1NH2
N
S
S
D
N
C
A
B
Ph
R2
KI, DMSO, PhCl
S8, O2, 150 oC, 14 h
R2
+
R2
R2
Figure 1. Representative examples
(3)
N
R1
2
2
R
N
R1
O
Due to the extensive functions, considerable attention has
been directed toward the construction of phenothiazines over
the past decades. In 2008, an early example via palladium-
catalyzed three-component coupling of bromothiophenols,
primary amines and 1-bromo-2-iodobenzene was reported by
the Jørgensen group.5 After that, several approaches have also
been elegantly developed. For instance, Ma et al reported a
protocol via copper-catalyzed cascade C–S and C–N bond
formations of ortho-halogenated anilines with ortho-
halogenated thiols (Scheme 1, eq 1).6 Alternatively, the cross-
coupling of 1,2-dihalogenated (hetero)arenes and ortho-
aminobenzenethiols (or its surrogates) offers useful ways to
achieve the related end (eq 2).7 Despite the significant utility,
these transformations generally suffer from one or more
limitations such as the need for pre-installation steps to access
The new observation
S
N
KI, DMSO, PhCl
S8, O2, 150 oC, 14 h
(4)
+
3aa
3aa
p-Nitrobenzoic acid (0 eq.):
p-Nitrobenzoic acid (0.5 eq.):
, 0%
, 8%
O
N
3aa
1a
2a
H
■ RESULTS AND DISCUSSION
To form an efficient reaction system, we chose the synthesis of
phenothiazine 3aa from THQ 1a, 4-methylcyclohexanone 2a
and S8 as a model system to evaluate different reaction
parameters. At first, the reaction charged with a O2 balloon, 4.0
equivalents of DMSO and 0.5 equivalent of p-nitrobenzoic acid
was performed in chlorobenzene at 150 oC for 16 h, and several
iodide catalysts were tested (Table 1, entries 1-3). The results
showed that the use of NaI was the best choice. Then, we
examined several acidic additives, but they were inferior to p-
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nitrobenzoic acid, and the use of base failed to afford any
Page 2 of 9
With the optimal (standard) conditions in hand (Table 1,
entry 13), we then examined the generality of the developed
synthetic protocol. First, various tetrahydroquinolines (1) in
combination with 4-methylcyclohexanone 2a were tested. As
shown in Scheme 2, all the reactions proceeded smoothly and
1
2
3
4
5
6
7
8
product (entries 4-8). The absence of DMSO had a detrimental
influence on the yield (entry 9). Further, replacing S8 with K2S
or Na2S2O3 (entry 10), or the use of other polar solvents (entry
11) was unable to yield product 3aa, and increase of S8 loading
could not improve the yield (entry 12). Gratifyingly, prolonging
the reaction time to 18 h resulted in an optimal yield (entry 13).
furnished
the
desired
2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazines in moderate to good yields upon isolation
(3aa-3ja). Various functional groups on the benzene ring of
THQs 1 (–Me, –OMe, –F, –Cl, –Br, –CO2Me) were well
tolerated in the transformation, which would offer the potential
for molecular complexity via further chemical transformations.
Moreover, these functionalities affected the reaction to some
extent. In general, THQs having an electron-donating or weak
electron-withdrawing group (3ba-3ha) afforded desirable
yields, whereas THQs containing an strong electron-
withdrawing substituent gave no product (e.g. –NO2 and –CF3)
or low (–CO2Me, 3ja: 30%) product yield. This phenonmenon
reveals that the presence of a relatively electron-rich THQ is
essential for the present annulation reaction. Upon GC-MS
analysis, the low yield of 5-MeO-substitutited THQ is assigned
to partial decomposition of such a THQ during the reaction
(3ia). In addition to THQs, other secondary anilines, inculding
benzocyclic amines (3ka-3la), N-alkylanilines (3ma-3pa) and
diarylamines (3qa) were also amenable to the transformation,
affording the desired products in moderate yields.
Table 1. Optimization of the Reaction Conditionsa
Yield% of 3aab
Additive
Entry Cat.
S source
9
I2
p-Nitrobenzoic acid
S8
S8
S8
S8
S8
S8
S8
S8
S8
13
28
71
61
22
<5
12
0
1
10
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12
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NIS p-Nitrobenzoic acid
2
NaI
NaI
NaI
NaI
-
p-Nitrobenzoic acid
Benzoic acid
p-TSA
3
4
5
L-proline
6
HI
7
NaI
NaI
NaI
NaI
NaI
K2CO3
8
p-Nitrobenzoic acid
53c
0
9
p-Nitrobenzoic acid K2S or Na2S2O3
10
11
12
13
p-Nitrobenzoic acid
p-Nitrobenzoic acid
S8
S8
S8
0d
68e
82f
Scheme 3. Variation of THQs and Secondary Anilines
NaI p-Nitrobenzoic acid
R2
S
R2
aReaction conditions: unless otherwise stated, all the reactions charged with
an O2 balloon were performed with 1a (0.25 mmol), 2a (0.30 mmol), S8 (0.5
eq), catalyst (20 mol %), additive (0.5 eq), DMSO (4.0 eq), solvent (2.0
mL) at 150 oC for 16 h. bGC yield using n-hexadecane as an internal
standard. cWithout DMSO. dUse of DMF, DMSO, NMP as the solvents. eS8
(2 eq). f18 h.
NaI (20 mol %), DMSO (4 eq)
p-Nitrobenzoic acid (0.5 eq)
R1
R1
S8 (0.5 eq)
+
+
N
PhCl, O2, 150 oC, 18 h
O
3
N
1
2
(1.2 eq.)
H
n-pr
S
S
N
Et
S
N
N
3ab
, 56%
3ac
, 77%
n-pentyl
3ad
, 77%
S
S
S
N
t-Bu
Ph
Scheme 2. Variation of THQs
S
N
N
NaI (20 mol %), DMSO (4 eq)
R1
R1
p-Nitrobenzoic acid (0.5 eq)
+
3ae, 70%
3af, 67%
S
8 (0.5 eq)
+
3ag, 34%
R
N
R
PhCl, O2, 150 oC, 18 h
N
O
H
N
H
S
N
CO2Et
S
N
S
t-Bu
2a
3
(1.2 eq.)
1
O
S
N
S
N
N
S
N
3ai
3ah
, 21%
, 53%
3de
, 81%
n-pentyl
n-pr
Cl
S
N
3aa
, 72%
S
3ba
, 72%
3ca
, 50%
MeO
S
N
F
Cl
S
S
N
3ff
, 42%
3hd
, 66%
N
N
3da
, 65%
3fa
3ia
, 66%
3ea
, 80%
S
S
N
Ph
N
S
N
MeO
S
N
Br
S
MeO
N
N
S
, 50%
3bb
, 55%
3qb
, 33%
3rb
3ha
3ka
3ga
, 53%
, 74%
S
, 32%
S
MeO2C
S
Subsequently, we turned our attention to the variation of both
THQs and cyclohexanones (2b-2i, see Scheme S1 in SI for
structures). Gratifyingly, all the substrates underwent efficient
three-component annulation reaction and afforded the desired
products in moderate to high yields (Scheme 3). Different
substituents on cyclohexanones 2 were well tolerated (alkyl, –
Ph, –CO2Et, –NHCOMe), and the phenyl and amino groups led
to relatively low product yields due to the occurrence of partial
dehydroaromatization of such cyclohexanones. Noteworthy, 4'-
N
N
N
S
O
3ja
, 30%
3la
, 60%
, 46%
n-Bu
N
N
N
S
S
S
, 41%
MeO
a
a
a
3na
, 54%
3oa
3ma
, 55%
Ph
NC
N
N
propyl-[1,1’-bi(cyclohexan)]-4-one 2d,
a key component
S
S
a
3qa
, 45%
3pa
, 46%
frequently employed for the preparation of liquid crystal
materials,12 also smoothly reacted with elemental sulphur and
aUsing I2 (20 mol %) instead of NaI
2
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The Journal of Organic Chemistry
THQs (1a and 1h), affording the desired products (3ad and
Although the mechanistic details are not fully elucidated at
the current stage, a plausible reaction pathway is depicted in
Scheme 6 on the basis of the above findings. At first, the
oxidation of NaI with DMSO and O2 generates molecular I2.
Moreover, the single electron transfer from I- to S8 would
generate I2 and trisulphur radical ion S3.-.16 The I2-mediated α-
iodination17 of 4-methylcyclohexanone 2a (see A) followed by
nucleophilic substitution by S3.- forms sulfur radical B.18 Then,
the radical addition of B to the C8-site of THQ 1a under the
assistance of H-bonding and I2-induced single electron
oxidation of the coupling adduct C gives intermediate D.
Finally, the intramolecular dehydrative cyclization followed by
I2-mediated dehydroaromatization of E gives rise to the desired
product 3aa.
1
2
3
4
5
6
7
8
3hd) in good yields. In addition, it is important to note that 10-
phenyl-10H-phenothiazine (3qb), a photocatalyst extensively
employed for radical polymerization13 and radical
dehalogenations14, could be prepared in one single operation
with our developed approach. Such a transition metal-free
streamline synthesis is far superior to the conventional
approach via ruthenium-catalyzed cross-coupling of
phenothiazine and anhydrous chlorobenzene with excess t-
BuONa.13
To show the practicality of the developed synthetic protocol,
a gram-scale synthesis of ring-fused phenothiazine 3aa was
achieved under the standard conditions by scaling up reactants
1a and 2a to 10 mmol and 12 mmol, respectively (Scheme 4, eq
1). Moreover, in consideration that the introduction of sulfonyl
group into organic molecules would significantly change their
electron distribution and result in some interesting properties
including new bioacitvities,15 we herein could efficiently
convert compound 3aa to its sulfonyl counterpart in CH2Cl2 by
using m-chloroperbenzoic acid (m-CPBA) as an oxidant at
room temperature (eq 2).
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Scheme 6. Plausible Reaction Pathway
I2
2 I- + S8
1/4 S8
DMSO, O2
2 I-
I2
+
2S3
+
I
S3
O
S3
- I-
I2
S
N
H
- I-, H+
O
O
A
B
N
O
- 1/4 S8
H
C
Scheme 4. Gram-Scale Synthesis
I2
S
N
I- + H+
O2, DMSO
I2
I- + H+
S
S
S
standard conditions
+
S8
+
O2, DMSO
N
(1)
(2)
- H2O
O
N
N
H
N
O
E
3aa
D
H
2a
(12 mmol)
1a
(10 mmol)
3aa
, 50 % (1.27 g)
■ CONCLUSIONS
O
O
S
N
S
N
In summary, we have developed a new iodide-mediated three-
component annulation reaction. Various secondary anilines,
including tetrahydroquinolines, benzocyclic amines, N-
alkylanilines and diarylamines, were efficiently transformed in
combination with cyclohexanones and elemental sulfur into the
phenothiazine derivatives. The synthetic protocol features
formation of multiple chemical bonds in one single operation,
high step and atom efficiency, readily available feedstocks and
catalyst system, good substrate and functional group
compability, which offers a practical platform for access to
various phenothiazines. Due to the significant importance of
phenothiazines in medicinal and biological chemistry,
functional materials, and photocatalysis, the developed method
capable of constructing novel phenothiazines with structural
diversity offers a significant basis for further discovery of new
applications.
m-CPBA
CH2Cl2, r.t.
3aa
3aa'
, 61 %
In an effort to gain mechanistic insights into the reaction, we
conducted several control experiments. Subjection of 1-
(cyclohex-1-en-1-yl)-1,2,3,4-tetrahydroquinoline 3ab-1 or 1-
phenyl-1,2,3,4-tetrahydroquinoline 3ab-2 with sulfur or with
additional aniline 1a and cyclohexanone 2b under the standard
conditions failed to yield the annulation product 3ab (Scheme
5, eq 1), indicating that compounds 3ab-1 and 3ab-2 serving as
the reaction intermediates can be rule out. Interruption of the
model reaction after 3 h generated 3aa and a cyclization
compound 3aa-1 in 21% and 6% yields, respectively (eq 2), and
compound 3aa-1 was consumed up after prolonging the
reaction time to 18 h, indicating that compound 3aa-1 is a key
reaction intermediate. Further, the addition of excess TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) to the model reaction
completely suppressed the product formation, and TEMPO
trapping a thiol group was observed by GC-MS analysis (eq 3),
which suggests that the reaction involves sulfur radicals.
■ EXPERIMENTAL SECTION
General information. All the obtained products were
characterized by melting points (m.p.), 1H-NMR,13C-NMR and
infrared spectra (IR). MS analyses were performed on an
Agilent 5975 GC-MS instrument (EI). High-resolution mass
spectra (HRMS) were recorded using electrospray ionization
(ESI) and time-of-flight (TOF) mass analysis. Melting points
were measured on an Electrothemal SGW-X4 microscopy
digital melting point apparatus and are uncorrected; IR spectra
were recorded on a FTLA2000 spectrometer; 1H-NMR and 13C-
NMR spectra were obtained on Bruker-400/500 and referenced
to 7.26 ppm for chloroform solvent with TMS as internal
standard (0 ppm) or 2.50 ppm for DMSO-d6. Chemical shifts
were reported in parts per million (ppm, δ) downfield from
tetramethylsilane. Proton coupling patterns are described as
singlet (s), doublet (d), triplet (t), multiplet (m); TLC was
performed using commercially prepared 100-400 mesh silica
Scheme 5. Control Experiments
S
standard
conditions
(1)
+
S8
or
N
N
N
3ab-1
3ab
, 0%
S
3ab-2
S
standard
conditions
+
+
S8
O
+
N
N
3 h
(2)
(3)
N
+
2a
1a
1a
H
3aa
, 21 %
3aa-1
, 6%
standard conditions
TEMPO (3.0 eq)
2a
3aa
, 0%
+
S8
+
N
O
HS
detected
3
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Page 4 of 9
gel plates (GF254), and visualization was effected at 254 nm;
20.0; IR (KBr): 3016, 2927, 2851, 1640, 1495, 1447, 1352,
1321, 1259, 1208, 1119, 925, 870, 797, 564, 512 cm-1; HRMS
(ESI) m/z: [M]+ Calcd for C17H17NS 267.1082; Found
267.1071.
1
2
3
4
5
6
7
8
Unless otherwise stated, all the reagents were purchased from
commercial sources, used without further purification.
Substrates preparation. All the utilized 1,2,3,4-
tetrahydroquinolines are known compounds, which were
purchased from commercial sources or prepared via the
literature procedures.19 Cyclohexanones, N-alkylanilines, and
diarylamines were all purchased form Energy Chemic, J&K
Chemic, TCI, Fluka, Acros, Bidepharm, SCRC.
Typical procedure for the synthesis of 3aa. The mixture of
1,2,3,4-tetrahydroquinoline 1a (33.2 mg, 0.25 mmol), 4-
methylcyclohexanone 2a (33.6 mg, 0.30 mmol), S8 (32.0 mg,
0.125 mmol), NaI (7.5 mg, 0.05 mmol), p-Nitrobenzoic acid
(20.9 mg, 0.125 mmol), and DMSO (78.0 mg, 1.00 mmol) in
PhCl (2.0 mL) was stirred in a 50 mL Schleck tube at 150 °C in
an oil bath for 18 h under O2 atmosphere (using an O2 balloon).
After cooling down to room temperature, the resulting mixture
was concentrated by removing the solvent under vacuum, and
the residue was purified by preparative TLC on silica gel eluting
with petroleum ether, 3aa was afforded as a light yellow liquid
(45.5 mg, 72% yield).
3,9-dimethyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine
(3da): Brownish liquid, PE as the eluent, 43.5 mg, 65% yield;
1H NMR (400 MHz, CDCl3): δ 6.98 (d, J = 7.3 Hz, 2H), 6.95
(s, 2H), 6.87 – 6.76 (m, 2H), 3.75 – 3.64 (m, 2H), 2.94 (h, J =
6.8 Hz, 1H), 2.27 (s, 3H), 2.24 – 2.17 (m, 1H), 1.96 – 1.88 (m,
1H), 1.34 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ 142.3, 141.1, 131.9, 129.7, 127.8, 127.5, 126.6,
125.3, 121.9, 121.6, 119.8, 112.7, 43.5, 31.0, 29.0, 21.4, 20.3;
IR (KBr): 2955, 2921, 2860, 1496, 1469, 1434, 1313, 1247,
1190, 801, 773, 735, 553 cm-1; HRMS (ESI) m/z: [M]+ Calcd
for C17H17NS 267.1082; Found 267.1072.
9
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5-fluoro-9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3ea): Light yellow liquid, PE as the eluent,
53.9 mg, 80% yield; 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J
= 8.3 Hz, 1H), 6.94 (s, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.70 (d, J
= 7.9 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 3.66 (t, J = 5.2 Hz, 2H),
2.75 (t, J = 5.9 Hz, 2H), 2.27 (s, 3H), 2.17 – 2.11 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3): δ 157.9 (d, J = 242.4 Hz),
142.4, 137.8 (d, J = 3.0 Hz), 131.9, 128.1, 127.6, 126.0 (d, J =
8.1 Hz) , 122.1 (d, J = 8.1 Hz), 121.0, 113.86 (d, J = 22.2 Hz),
112.6, 111.9 (d, J = 24.2 Hz), 46.7, 28.3, 21.5, 20.2; 19F NMR
(376 MHz, CDCl3): δ –123.9; IR (KBr): 2940, 2852, 1451,
1314, 1259, 1112, 858, 793, 735, 492cm-1; HRMS (ESI) m/z:
[M]+ Calcd for C16H14FNS 271.0830; Found 271.0822.
Gram-scale synthesis of 3aa. The mixture of 1,2,3,4-
tetrahydroquinoline 1a (1.33 g, 10 mmol), 4-
methylcyclohexanone 2a (1.35 g, 12 mmol), S8 (1.28 g, 5
mmol), NaI (0.30 g, 2 mmol), p-Nitrobenzoic acid (0.84 g, 5
mmol), and DMSO (3.1 g, 40 mmol) in PhCl (80 mL) was
stirred in a 350 mL Schleck tube at 150 °C in an oil bath for 18
h under O2 atmosphere (using an O2 balloon). After cooling
down to room temperature, the resulting mixture was
concentrated by removing the solvent under vacuum, and the
residue was purified by preparative TLC on silica gel eluting
with petroleum ether, 3aa was afforded as a light yellow liquid
(1.27 g, 50% yield).
5-chloro-9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3fa): Light yellow liquid, PE as the eluent,
47.1 mg, 66% yield; 1H NMR (500 MHz, CDCl3): δ 6.83 (d, J
= 8.3 Hz, 1H), 6.81 – 6.76 (m, 2H), 6.70 (d, J = 2.1 Hz, 1H),
6.61 (d, J = 8.3 Hz, 1H), 3.51 – 3.47 (m, 2H), 2.59 (t, J = 6.1
Hz, 2H), 2.14 (s, 3H), 2.00 (p, J = 6.0 Hz, 2H); 13C{1H} NMR
(126 MHz, CDCl3): δ 141.9, 140.3, 132.1, 128.1, 127.6, 127.2,
126.1, 125.9, 124.6, 121.9, 120.9, 112.7, 46.8, 28.1, 21.6, 20.3;
IR (KBr): 2927, 2855, 1561, 1495, 1466, 1318, 1256, 1186,
1090, 1026, 858, 799, 637, 526 cm-1; HRMS (ESI) m/z: [M]+
Calcd for C16H14ClNS 287.0535; Found 287.0524.
Analytic data of the obtained compounds. 9-methyl-2,3-
dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3aa): Light yellow
liquid, PE as the eluent, 45.5 mg, 72% yield; 1H NMR (500
MHz, CDCl3): δ 6.90 (d, J = 5.7 Hz, 3H), 6.82 (d, J = 7.4 Hz,
1H), 6.74 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.65 –
3.54 (m, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.22 (s, 3H), 2.11 (p, J =
5.8 Hz, 2H);13C{1H} NMR (126 MHz, CDCl3): δ 142.3, 141.5,
131.8, 127.8, 127.8, 127.6, 125.3, 124.9, 121.7, 121.5, 120.0,
112.6, 47.0, 28.2, 21.8, 20.3; IR (KBr): 3018, 2928, 2956, 1496,
1443, 1315, 1256, 1187, 800, 764, 730, 604, 553 cm-1; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H16NS 254.0998; Found
254.0996.
4-bromo-9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3ga): Light yellow liquid, PE as the eluent,
44.2 mg, 53% yield; 1H NMR (500 MHz, CDCl3): δ 6.95 (dd, J
= 8.1, 3.2 Hz, 1H), 6.90 – 6.80 (m, 2H), 6.69 (dd, J = 8.1, 3.1
Hz, 1H), 6.65 (dd, J = 8.6, 3.3 Hz, 1H), 3.63 – 3.50 (m, 2H),
2.69 (q, J = 6.1 Hz, 2H), 2.14 (d, J = 3.0 Hz, 3H), 2.00 (q, J =
4.7, 4.0 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 143.8,
142.1, 132.3, 128.0, 127.7, 125.8, 125.5, 124.6, 123.9, 122.3,
120.2, 113.1, 46.4, 28.9, 21.4, 20.3; IR (KBr): 2922, 2854,
1552, 1438, 1412, 1255, 1163, 1026, 796, 490 cm-1; HRMS
(ESI) m/z: [M]+ Calcd for C16H14BrNS 331.0030; Found
331.0019.
5,9-dimethyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine
(3ba): Light yellow liquid, PE as the eluent, 47.9 mg, 72%
yield;1H NMR (400 MHz, CDCl3): δ 6.95 (s, 2H), 6.78 (s, 1H),
6.74 (d, J = 8.7 Hz, 1H), 6.69 (s, 1H), 3.67 – 3.62 (m, 2H), 2.74
(t, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.22 (s, 3H), 2.15 (p, J = 6.0
Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 142.5, 139.0,
131.4, 131.0, 128.4, 127.8, 127.5, 125.7, 124.7, 121.5, 119.9,
112.4, 46.9, 28.2, 21. 9, 20.3, 20.2; IR (KBr): 3015, 2923, 2852,
1497, 1460, 1319, 1257, 1189, 854, 800, 731, 564 cm-1; HRMS
(ESI) m/z: [M]+ Calcd for C17H17NS 267.1082; Found
267.1073.
5-methoxy-9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3ha):Light yellow liquid, PE as the eluent,
52.4 mg, 74% yield; 1H NMR (400 MHz, CDCl3): δ 6.96 (d, J
= 5.9 Hz, 2H), 6.74 (d, J = 8.7 Hz, 1H), 6.58 (s, 1H), 6.47 (s,
1H), 3.76 (s, 3H), 3.67 – 3.62 (m, 2H), 2.75 (t, J = 5.3 Hz, 2H),
2.27 (s, 3H), 2.14 (p, J = 6.0 Hz, 2H);13C{1H} NMR (101 MHz,
CDCl3): δ 154.6, 142.8, 135.3, 131.3, 127.9, 127.6, 125.9,
121.5, 121.2, 113.3, 112.3, 110.6, 55.6, 46.8, 28.5, 21.8, 20.3;
IR (KBr): 2934, 2836, 1602, 1497, 1463, 1430, 1309, 1248,
1135, 1045, 801, 721, 556 cm-1; HRMS (ESI) m/z: [M]+ Calcd
for C17H17NOS 283.1031; Found 283.1021.
6,9-dimethyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine
(3ca): Light yellow liquid, PE as the eluent, 33.5 mg, 50%
yield; 1H NMR (400 MHz, CDCl3): δ 7.00 (s, 1H), 6.96 (d, J =
8.3, 1H), 6.81 – 6.70 (m, 3H), 3.71 – 3.66 (m, 2H), 2.76 (t, J =
5.5 Hz, 2H), 2.34 (s, 3H), 2.16 – 2.10 (m, 2H); 13C{1H} NMR
(101 MHz, CDCl3): δ 142.7, 141.4, 133.3, 131.6, 127.9, 127.8,
127.1, 123.0, 122.6, 121.8, 120.5, 112.5, 47.1, 28.1, 21.7, 20.3,
4-methoxy-9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
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kl]phenothiazine (3ia): Light yellow liquid, PE as the eluent,
cm-1; HRMS (ESI) m/z: [M]+ Calcd for C15H15NOS 257.0874;
22.5 mg, 32% yield; 1H NMR (400 MHz, CDCl3): δ 6.97 (s,
1H), 6.95 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.78 (d,
J = 8.2 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.71 –
3.65 (m, 2H), 2.71 (t, J = 6.2 Hz, 2H), 2.27 (s, 3H), 2.15 – 2.08
(m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 156.7, 142.9,
142.5, 131.6, 127.7, 127.6, 124.5, 122.7, 114.3, 112.8, 112.0,
103.7, 55.6, 46.4, 21.5, 21.0, 20.2; IR (KBr): 2929, 2838, 1579,
1495, 1464, 1426, 1333, 1253, 1196, 1125, 1091, 1065, 1031,
873, 795, 624, 554 cm-1; HRMS (ESI) m/z: [M]+ Calcd for
C17H17NOS 283.1031; Found 283.1023.
Found 257.0865.
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7
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10-butyl-3-methyl-10H-phenothiazine (3oa): Light yellow
liquid, PE as the eluent, 27.6 mg, 41% yield, m.p: 134-136 °C;
1H NMR (400 MHz, CDCl3) ： δ 7.19 – 7.15 (m, 2H), 7.03 –
6.95 (m, 2H), 6.93 (dd, J = 7.4, 1.2 Hz, 1H), 6.88 (d, J = 8.3 Hz,
1H), 6.79 (d, J = 8.1 Hz, 1H), 3.95 – 3.81 (m, 2H), 2.28 (s, 3H),
1.86 – 1.77 (m, 2H), 1.49 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 145.7, 142.8,
131.9, 127.9, 127.7, 127.4, 127.1, 124.8, 124.8, 122.0, 115.2,
47.0, 29.1, 20.3, 20.2, 13.9; IR (KBr): 2955, 2924, 2868, 1575,
1494, 1463, 1282, 1241, 1218, 1134, 1039, 806, 744 cm-1;
HRMS (ESI) m/z: [M + H]+ Calcd for C17H20NS 270.1310;
Found 270.1307.
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9-methyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine-5-
carboxylate (3ja): Yellow liquid, PE/EtOAc (10:1) as the
eluent, 23.4 mg, 30% yield;1H NMR (400 MHz, CDCl3): δ 7.56
(s, 1H), 7.54 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.75
(d, J = 8.2 Hz, 1H), 3.87 (s, 3H), 3.70 – 3.62 (m, 2H), 2.77 (t, J
= 5.8 Hz, 2H), 2.25 (s, 3H), 2.17 (p, J = 5.9 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3): δ 166.6, 145.6, 140.9, 132.9, 129.5,
128.8, 127.6, 126.7, 123.9, 122.8, 121.2, 119.3, 113.1, 51.9,
47.1, 28.1, 21.6, 20.2; IR (KBr): 2945, 2857, 1711, 1594, 1498,
1429, 1322, 1271, 1225, 1188, 1097, 995, 899, 802, 764, 636,
554, 452 cm-1; HRMS (ESI) m/z: [M]+ Calcd for C18H17NO2S
311.0980; Found 311.0967.
3-(3-methyl-10H-phenothiazin-10-yl)propanenitrile
(3pa):
Brownish solid, PE/CH2Cl2 (2:3) as the eluent, 30.6 mg, 46%
yield, m.p: 99-100 °C; 1H NMR (400 MHz, CDCl3): δ 7.25 –
7.17 (m, 2H), 7.07 – 6.96 (m, 3H), 6.85 (d, J = 8.2 Hz, 1H), 6.75
(d, J = 8.1 Hz, 1H), 4.29 – 4.18 (m, 2H), 2.87 – 2.80 (m, 2H),
2.29 (s, 3H);13C{1H} NMR (101 MHz, CDCl3): δ 144.2, 141.3,
133.2, 128.4, 128.0, 127.9, 127.5, 126.2, 126.0, 123.2, 117.6,
115.2, 115.2, 43.5, 20.4, 16.5; IR (KBr): 2921, 2248, 1601,
1578, 1493, 1463, 1333, 1252, 1198, 1108, 1037, 807, 748, 616,
547cm-1; HRMS (ESI) m/z: [M]+ Calcd for C16H14N2S
266.0878; Found 266.0868.
9-methyl-1,2-dihydro-[1,4]oxazino[2,3,4-kl]phenothiazine
(3ka):Green liquid, PE as the eluent, 38.4 mg, 60% yield; 1H
NMR (400 MHz, CDCl3): δ 6.96 (d, J = 6.0 Hz, 2H), 6.83 –
6.78 (m, 1H), 6.72 (d, J = 7.8 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H),
4.40 (t, J = 4.5 Hz, 2H), 3.77 (t, J = 4.4 Hz, 2H), 2.27 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 144.8, 140.5, 132.2, 130.8,
128.0, 127.9, 122.5, 120.6, 120.1, 120.0, 115.8, 112.1, 64.0,
45.1, 20.3; IR (KBr): 2921, 2868, 1581, 1496, 1459, 1319,
1260, 1110, 1060, 976, 897, 800, 770, 720, 532, 492, 453 cm-1;
HRMS (ESI) m/z: [M]+ Calcd for C15H13NOS 255.0718; Found
255.0708.
3-methyl-10-phenyl-10H-phenothiazine (3qa): Yellow solid,
1
PE as the eluent, 32.7 mg, 45% yield, m.p: 108-109 °C; H
NMR (500 MHz, CDCl3): δ 7.48 (t, J = 7.6 Hz, 2H), 7.35 (t, J
= 7.4 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.3 Hz, 1H),
6.76 (s, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H),
6.55 (d, J = 8.3 Hz, 1H), 6.12 (d, J = 8.1 Hz, 1H), 6.02 (d, J =
8.3 Hz, 1H), 2.09 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
144.4, 141.8, 141.3, 132.1, 130.7, 130.6, 127.9, 127.4, 127.2,
126.8, 126.8, 122.3, 120.4, 120.3, 116.2, 116.1, 20.2; IR (KBr):
3059, 2920, 2855, 1584, 1493, 1465, 1305, 1250, 1039, 933,
806, 745, 578 cm-1; HRMS (ESI) m/z: [M]+ Calcd for C19H15NS
289.0925; Found 289.0916.
9-methyl-1,2-dihydro-[1,4]thiazino[2,3,4-kl]phenothiazine
(3la): Light yellow liquid, PE as the eluent, 31.1 mg, 46% yield
；1H NMR (400 MHz, CDCl3): δ 7.01 (d, J = 2.0 Hz, 1H), 7.00
(d, J = 1.5 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 6.94 (dd, J = 7.6,
1.5 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H),
4.20 – 4.13 (m, 2H), 3.26 – 3.17 (m, 2H), 2.29 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 143.4, 138.8, 132.5, 128.0, 126.1,
125.6, 124.0, 123.8, 122.6, 121.4, 112.3, 47.2, 25.2, 20.4; IR
(KBr): 3122, 2920, 1733, 1488, 1422, 1244, 1194, 1094, 1045,
801, 762, 605, 491 cm-1; HRMS (ESI) m/z: [M]+ Calcd for
C15H13NS2 271.0489; Found 271.0480.
3,10-dimethyl-10H-phenothiazine (3ma): Known product,20
light yellow solid, PE as the eluent, 31.3 mg, 55% yield, m.p:
145-146 °C; 1H NMR (400 MHz, CDCl3): δ 7.20 (t, J = 8.3 Hz,
2H), 7.00 (d, J = 8.9 Hz, 2H), 6.95 (t, J = 7.5 Hz, 1H), 6.83 (d,
J = 8.0 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.38 (s, 3H), 2.29 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 146.1, 143.4, 132.0,
127.9, 127.7, 127.4, 127.2, 123.4, 123.2, 122.2, 113.9, 35.3,
20.4; IR (KBr): 3054, 2915, 2818, 1603, 1571, 1496, 1459,
1327, 1256, 1137, 1036, 837, 810, 753, 490 cm-1; MS (EI), m/z:
227.1 [M]+.
2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3ab): Known
product,21 light yellow liquid, PE as the eluent, 33.6 mg, 56%
yield; 1H NMR (400 MHz, CDCl3): δ 7.20 – 7.10 (m, 2H), 6.95
(t, J = 7.6 Hz, 2H), 6.91 – 6.80 (m, 3H), 3.76 – 3.66 (m, 2H),
2.79 (t, J = 6.0 Hz, 2H), 2.18 (p, J = 5.9 Hz, 2H);13C{1H} NMR
(101 MHz, CDCl3): δ 144.7, 141.3, 127.9, 127.4, 127.0, 125.3,
125.1, 122.3, 121.9, 121.8, 120.2, 112.8, 47.0, 28.2, 21.8; IR
(KBr): 3060, 2930, 2857, 1655, 1579, 1438, 1316, 1184, 1103,
740, 603, 490 cm-1: MS (EI, m/z): 239.1 [M]+.
9-ethyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3ac):
Brownish liquid, PE as the eluent, 51.3 mg, 77% yield;1H NMR
(400 MHz, CDCl3): δ 7.00 (d, J = 6.6 Hz, 2H), 6.97 (d, J = 8.0
Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.81 (dd, J = 8.2, 5.3 Hz, 2H),
3.71 – 3.65 (m, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.58 (q, J = 7.6
Hz, 2H), 2.22 – 2.13 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 142.5, 141.5, 138.4, 127.8, 126.7,
126.5, 125.3, 125.2, 124.9, 121.7, 121.6, 120.1, 112.7, 47.0,
28.2, 27.8, 21.8, 15.7; IR (KBr): 2960, 2929, 2863, 1600, 1495,
1447, 1314, 1256, 1187, 1111, 878, 808, 746, 605, 568 cm-1.
HRMS (ESI) m/z: [M]+ Calcd for C17H17NS 267.1082; Found
267.1073.
3-methoxy-7,10-dimethyl-10H-phenothiazine (3na): Brownish
solid, PE as the eluent, 34.5 mg, 54% yield, m.p: 105-106 °C;
1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 8.6 Hz, 2H), 6.80 (s,
1H), 6.74 (s, 2H), 6.72 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 3.34
(s, 3H), 2.28 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) ：δ
155.2, 143.9, 139.8, 131.6, 128.0, 127.7, 124.7, 122.8, 114.3,
113.6, 112.9, 112.6, 55.8, 35.3, 20.3; IR (KBr): 2952, 2827,
1591, 1502, 1470, 1262, 1225, 1152, 1037, 811, 741, 595, 491
9-(4-propylcyclohexyl)-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3ad):Yellow solid, PE as the eluent, 70.1 mg,
77% yield, m.p: 134-135 °C; 1H NMR (400 MHz, CDCl3): δ
7.01 (d, J = 7.4 Hz, 2H), 6.96 (d, J = 7.4 Hz, 1H), 6.87 (d, J =
7.3 Hz, 1H), 6.80 (d, J = 7.9 Hz, 2H), 3.74 – 3.66 (m, 2H), 2.77
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(t, J = 5.9 Hz, 2H), 2.40 (t, J = 12.2 Hz, 1H), 2.17 (q, J = 5.8
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NMR (101 MHz, DMSO-d6): δ 168.4, 141.2, 139.9, 134.8,
128.5, 125.6, 125.3, 122.0, 121.1, 118.8, 118.6, 117.7, 113.7,
46.9, 27.9, 24.4, 21.7; IR (KBr): 3008, 2927, 2849, 1764, 1651,
1581, 1525, 1443, 1309, 1264, 1248, 1183, 1013, 872, 802, 762,
606, 480, 451 cm-1; HRMS (ESI) m/z: [M]+ Calcd for
C17H16N2OS 296.0983; Found 296.0975.
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Hz, 2H), 1.88 (d, J = 11.2 Hz, 4H), 1.44 – 1.38 (m, 4H), 1.27 –
1.22 (m, 2H), 1.19 – 0.84 (m, 6H); 13C{1H} NMR (101 MHz,
CDCl3): δ 142.6, 142.1, 141.5, 127.8, 125.7, 125.4, 125.3,
124.9, 121.6, 121.6, 120.1, 112.6, 47.0, 43.6, 40.0, 37.0, 34.4,
33.6, 28.2, 21.8, 20.08, 14.5; IR (KBr): 2974, 2919, 1494, 1446,
1383, 1314, 1259, 1187, 1088, 1049, 881, 803, 759, 735, 434
cm-1; HRMS (ESI) m/z: [M]+ Calcd for C24H29NS 363.2020;
Found 363.2008.
9-(tert-butyl)-3-methyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3de): Light yellow liquid, PE as the eluent,
62.3 mg, 81% yield; 1H NMR (400 MHz, CDCl3) : δ 7.20 (d, J
= 11.4 Hz, 2H), 6.99 (d, J = 7.4 Hz, 2H), 6.85 (t, J = 7.8 Hz,
2H), 3.71 (q, J = 10.9, 10.1 Hz, 2H), 2.94 (q, J = 6.6 Hz, 1H),
2.22 (dd, J = 10.5, 6.7 Hz, 1H), 1.99 – 1.88 (m, 1H), 1.33 (s,
12H); 13C{1H} NMR (101 MHz, CDCl3): δ 145.5, 142.2, 141.1,
129.8, 126.7, 125.3, 124.2, 124.1, 121.7, 121.5, 119.8, 112.5,
43.4, 34.1, 31.4, 31.0, 29.0, 21.5; IR (KBr): 3058, 2958, 1601,
1497, 1470, 1436, 1322, 1271, 1192, 1085, 880, 850, 774, 735,
619, 587, 444 cm-1; HRMS (ESI) m/z: [M]+ Calcd for C20H23NS
309.1551; Found 309.1542.
9-(tert-butyl)-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine
(3ae): White solid, PE as the eluent, 51.9 mg, 70% yield, m.p:
97-98 °C; 1H NMR (500 MHz, CDCl3): δ 7.03 (d, J = 8.8 Hz,
2H), 6.82 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.66 (dd,
J = 13.9, 7.8 Hz, 2H), 3.53 (s, 2H), 2.62 (t, J = 6.0 Hz, 2H), 2.06
– 1.97 (m, 2H), 1.18 (s, 9H);13C{1H} NMR (126 MHz, CDCl3):
δ 145.4, 142.2, 141.4, 127.8, 125.3, 124.9, 124.2, 121.6, 121.3,
120.1, 112.4, 47.0, 34.1, 31.4, 28.2, 21.8; IR (KBr): 3053, 2955,
2863, 1497, 1446, 1262, 1187, 1112, 878, 806, 763, 602 cm-1;
HRMS (ESI) m/z: [M]+ Calcd for C19H21NS 295.1395 Found
295.1386.
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5-methoxy-9-(4-propylcyclohexyl)-2,3-dihydro-1H-
pyrido[3,2,1-kl] phenothiazine (3hd): Yellow solid, PE as the
eluent, 65.1 mg, 66% yield, m.p: 138-139 °C; 1H NMR (400
MHz, CDCl3): δ 7.00 (d, J = 7.3 Hz, 2H), 6.78 (d, J = 8.5 Hz,
1H), 6.59 (d, J = 2.8 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 3.75 (s,
3H), 3.65 (s, 2H), 2.75 (t, J = 5.7 Hz, 2H), 2.39 (t, J = 12.4 Hz,
1H), 2.14 (p, J = 5.7 Hz, 2H), 1.87 (d, J = 11.2 Hz, 4H), 1.43 –
1.36 (m, 4H), 1.27 – 1.20 (m, 2H), 1.19 – 0.83 (m, 6H); 13C{1H}
NMR (101 MHz, CDCl3): δ 154.6, 143.1, 141.7, 135.2, 125.9,
125.7, 125.4, 121.6, 121.1, 113.3, 112.3, 110.6, 55.6, 46.8, 43.6,
39.8, 37.0, 34.4, 33.6, 28.5, 21.8, 20.1, 14.5; IR (KBr): 2995,
2949, 2919, 2847, 1600, 1496, 1462, 1434, 1309, 1253, 1210,
1136, 1047, 829, 804, 729, 677, 603, 559, 475 cm-1; HRMS
(ESI) m/z: [M]+ Calcd for C25H31NOS 393.2126; Found
393.2114.
9-pentyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3af):
Light yellow liquid, PE as the eluent, 51.9 mg, 67% yield; 1H
NMR (500 MHz, CDCl3): δ 6.82 (s, 3H), 6.74 (d, J = 7.4 Hz,
1H), 6.70 – 6.61 (m, 2H), 3.63 – 3.45 (m, 2H), 2.63 (t, J = 6.0
Hz, 2H), 2.39 (t, J = 7.6 Hz, 2H), 2.07 – 1.98 (m, 2H), 1.47 (p,
J = 7.5 Hz, 2H), 1.22 (td, J = 16.5, 15.4, 6.5 Hz, 4H), 0.80 (t, J
= 6.8 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 141.4,
140.5, 135.9, 126.7, 126.2, 125.9, 124.2, 123.8, 120.6, 120.5,
119.0, 111.5, 45.9, 33.7, 30.3, 30.1, 27.2, 21.5, 20.7, 13.0; IR
(KBr): 3053, 2925, 2853, 1589, 1467, 1439, 1307, 1257, 1094,
1019, 805, 740, 700 cm-1; HRMS (ESI) m/z: [M]+ Calcd for
C20H23NS 309.1551; Found 309.1541.
9-phenyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3ag):
Light yellow liquid, PE as the eluent, 26.5 mg, 34% yield; 1H
NMR (500 MHz, CDCl3): δ 7.41 (d, J = 7.4 Hz, 2H), 7.28 (t, J
= 7.1 Hz, 2H), 7.22 (d, J = 6.8 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H),
6.82 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 6.66 (t, J =
7.3 Hz, 1H), 3.52 (s, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.00 (p, J =
5.9 Hz, 2H);13C{1H} NMR (126 MHz, CDCl3): δ 143.9, 141.0,
140.0, 135.3, 128.8, 128.0, 127.0, 126.4, 126.0, 125.4, 125.4,
125.2, 122.3, 122.0, 119.8, 113.0, 47.1, 28.2, 21.8; IR (KBr):
3058, 3029, 2932, 2860, 1596, 1447, 1324, 1265, 1187, 1044,
808, 762, 730, 696, 569, 512 cm-1; HRMS (ESI) m/z: [M]+
Calcd for C21H17NS 315.1082; Found 315.1070.
5-chloro-9-pentyl-2,3-dihydro-1H-pyrido[3,2,1-
kl]phenothiazine (3ff): Light yellow liquid, PE as the eluent,
36.3 mg, 42% yield; 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J
= 8.3 Hz, 1H), 6.95 – 6.89 (m, 2H), 6.84 (s, 1H), 6.77 (d, J =
8.3 Hz, 1H), 3.68 – 3.61 (m, 2H), 2.73 (t, J = 5.9 Hz, 2H), 2.52
(t, J = 7.7 Hz, 2H), 2.14 (p, J = 5.6 Hz, 2H), 1.58 (q, J = 7.3 Hz,
2H), 1.34 (td, J = 13.6, 13.2, 5.8 Hz, 4H), 0.92 (t, J = 6.7 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 142.1, 140.3, 137.4,
127.5, 127.2, 127.0, 126.1, 126.0, 124.6, 121.9, 120.8, 112.7,
46.8, 34.8, 31.4, 31.1, 28.1, 22.6, 21.6, 14.1; IR (KBr): 3019,
2951, 2926, 2854, 1600, 1495, 1448, 1318, 1257, 1186, 1091,
857, 802, 645, 558, 456 cm-1; HRMS (ESI) m/z: [M]+ Calcd for
C20H22ClNS 343.1161; Found 343.1151.
ethyl
2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine-9
carboxylate (3ah) Yellow liquid, PE/CH2Cl2 (1:5) as the eluent,
41.2 mg, 53% yield; 1H NMR (500 MHz, CDCl3): δ 7.79 (dd, J
= 8.6, 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 7.4,
1.7 Hz, 1H), 6.84 (dd, J = 7.4, 1.6 Hz, 1H), 6.79 (dd, J = 14.0,
8.0 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.71 – 3.60 (m, 2H), 2.73
(t, J = 6.1 Hz, 2H), 2.12 (p, J = 5.9 Hz, 2H), 1.37 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3): δ 166.0, 148.3, 140.0,
129.5, 128.1, 128.0, 125.5, 125.4, 124.1, 122.7, 121.4, 119.6,
111.9, 60.7, 47.3, 28.1, 21.7, 14.4; IR (KBr): 3059, 2974, 2935,
1708, 1578, 1444, 1395, 1264, 1118, 1023, 900, 763, 575 cm-1;
HRMS (ESI) m/z: [M]+ Calcd for C18H17NO2S 311.0980;
Found 311.0970.
5-methyl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine (3bb):
Red liquid, PE as the eluent, 34.8 mg, 55% yield;1H NMR (500
MHz, CDCl3): δ 7.16 – 7.04 (m, 2H), 6.86 (t, J = 7.4 Hz, 1H),
6.80 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.66 (s, 1H), 3.62 (q, J =
5.3, 3.9 Hz, 2H), 2.70 (t, J = 6.2 Hz, 2H), 2.18 (s, 3H), 2.11 (t,
J = 5.8 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 144.9,
138.8, 131.4, 128.5, 127.3, 127.0, 125.7, 124.9, 122.0, 121.7,
120.0, 112.5, 46.9, 28.1, 21.9, 20.2; IR (KBr): 3057, 3009,
2932, 2850, 1578, 1457, 1322, 1261, 1190, 1043, 851, 744, 561,
454 cm-1; HRMS (ESI) m/z: [M]+ Calcd. for C16H15NS
253.0925; Found 253.0918.
N-(2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazin-9-
10-phenyl-10H-phenothiazine (3qb): Known product,13 Yellow
solid, PE as the eluent, 22.7 mg, 33% yield, m.p: 89-91 °C; 1H
NMR (400 MHz, CDCl3): δ 7.63 (t, J = 7.5 Hz, 2H), 7.51 (t, J
= 7.4 Hz, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.05 (d, J = 7.2 Hz, 2H),
6.86 (p, J = 7.2 Hz, 4H), 6.24 (d, J = 7.8 Hz, 2H);13C{1H} NMR
(101 MHz, CDCl3): δ 144.3, 141.0, 130.9, 130.8, 128.2, 126.8,
yl)acetamide (3ai): Light yellow solid, PE/EtOAc (1:1) as the
eluent, 15.6 mg, 21% yield, m.p: 236-237 °C; 1H NMR (400
MHz, DMSO-d6): δ 9.85 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.90
(d, J = 7.6 Hz, 3H), 6.78 (t, J = 7.5 Hz, 1H), 3.64 – 3.54 (m,
2H), 2.71 (t, J = 5.6 Hz, 2H), 2.05 – 2.02 (m, 5H); 13C{1H}
6
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The Journal of Organic Chemistry
126.7, 122.5, 120.2, 116.1; IR (KBr): 3059, 2922, 1585, 1489,
Min Zhang – Key Lab of Functional Molecular Engineering of
Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Wushan
Rd-381, Guangzhou 510641, P.R. China; Orcid.org/0000-
0002-7023-8781; E-mail: minzhang@scut.edu.cn
1460, 1442, 1302, 1255, 1125, 1042, 741, 705, 629 cm-1; MS
(EI, m/z): 275.1 [M]+.
1
2
3
4
5
6
7
8
3-methyl-10-(p-tolyl)-10H-phenothiazine (3rb): Light yellow
solid, PE as the eluent, 38.1 mg, 50% yield, m.p: 106-107 °C;
1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.7 Hz, 2H), 7.30
(d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.4 Hz, 1H), 6.90 – 6.77 (m,
3H), 6.67 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 6.15 (d,
J = 8.3 Hz, 1H), 2.51 (s, 3H), 2.22 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3): δ 144.6, 142.1, 138.4, 138.0, 131.9, 131.4,
130.8, 129.9, 127.3, 127.1, 126.8, 126.7, 124.5, 122.0, 119.8,
119.8, 115.8, 115.7, 21.3, 20.2; IR (KBr): 3027, 2919, 2860,
1576, 1505, 1465, 1305, 1249, 1129, 808, 743, 571 cm-1;
HRMS (ESI) m/z: [M]+ Calcd for C20H17NS 303.1082; Found
303.1072.
Authors
Qinghua Chen
– Key Lab of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Wushan Rd-381, Guangzhou 510641, P.R. China
Rong Xie – Key Lab of Functional Molecular Engineering of
Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Wushan
Rd-381, Guangzhou 510641, P.R. China
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Huanhuan Jia
– Key Lab of Functional Molecular
Synthesis
of
1-(cyclohex-1-en-1-yl)-1,2,3,4-
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Wushan Rd-381, Guangzhou 510641, P.R. China
Jialu Sun – Key Lab of Functional Molecular Engineering of
Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Wushan
Rd-381, Guangzhou 510641, P.R. China
Guangpeng Lu – Key Lab of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Wushan Rd-381, Guangzhou 510641, P.R. China
Huanfeng Jiang – Key Lab of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Wushan Rd-381, Guangzhou 510641, P.R. China;
Orcid.org/0000-0002-4355-0294
tetrahydroquinoline (3ab-1): The mixture of 1,2,3,4-
tetrahydroquinoline 1a (1.33 g, 10 mmol), cyclohexanone 2b
(4.90 g, 50 mmol), p-TSA (0.17 g, 1 mmol), anhydrous Na2SO4
(1.0 g) and PhMe (20 mL) was stirred in a 100 mL Schleck tube
at 120 °C in an oil bath for 12 h. After cooling down to room
temperature, the resulting mixture was concentrated by
removing the solvent under vacuum, and the residue was
purified by preparative TLC on silica gel eluting with petroleum
ether, 3ab-1 was afforded as a light yellow liquid (14.6 mg). 1H
NMR (500 MHz, CDCl3) δ 6.77 (d, J = 7.3 Hz, 1H), 6.70 (d, J
= 7.3 Hz, 1H), 6.49 (t, J = 7.4 Hz, 1H), 5.63 (s, 1H), 4.12 (s,
1H), 3.22 (t, J = 5.4 Hz, 2H), 2.71 (t, J = 6.2 Hz, 2H), 2.10 (d,
J = 21.7 Hz, 4H), 1.88 – 1.82 (m, 2H), 1.70 – 1.64 (m, 2H), 1.64
– 1.58 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 141.3,
136.5, 129.5, 127.9, 126.7, 126.1, 121.1, 116.0, 42.1, 29.5, 27.4,
25.5, 23.2, 22.2, 22.2; IR (KBr): 2923, 2832, 1547, 1488, 1327,
1290, 1088, 973, 697. 680 cm-1. HRMS (ESI) m/z: [M + H]+
Calcd for C15H20N 214.1590; Found 214.1593.
Notes
The authors declare no competing financial interest.
Synthesis
of
9-methyl-2,3-dihydro-1H-pyrido[3,2,1-
ACKNOWLEDGMENT
kl]phenothiazine 7,7-dioxide (3aa’): The mixture of 3aa (25.3
mg, 0.1 mmol), m-CPBA (51.8mg, 0.3 mmol) and CH2Cl2 (2
ml) was stirred in a 50 mL Schleck tube at room temperature
overnight. The resulting mixture was concentrated by removing
the solvent under vacuum, and the residue was purified by
preparative TLC on silica gel eluting with PE/CH2Cl2 (1:3), 3aa’
was afforded as a White solid (17.4 mg, 61% yield), m.p: 184-
185 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 6.0 Hz, 2H),
7.45 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.28 (d, J =
8.7 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 4.10 – 3.92 (m, 2H), 3.05
– 2.92 (m, 2H), 2.45 (s, 3H), 2.30 (q, J = 5.6 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3): δ 138.8, 137.6, 134.2, 132.5, 131.8,
126.6, 123.0, 122.2, 121.5, 120.7, 114.3, 47.6, 28.1, 21.5, 20.5.
IR (KBr): 3030, 2938, 2252, 1594, 1574, 1472, 1446, 1330,
1237, 1215, 1135, 1021, 913, 629, 586 cm-1. HRMS (ESI) m/z:
[M + H]+ Calcd for C16H16NO2S 286.0896; Found 286.0894.
We thank the National Key Research and Development
Program of China (2016YFA0602900), National Natural
Science Foundation of China (21971071), Guangdong Province
Science Foundation (2017B090903003), and the foundation of
the Department of Education of Guangdong Province
(2017KZDXM085) for financial support.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.XXX.
1H and 13NMR spectra for the products (PDF)
AUTHOR INFORMATION
Corresponding Author
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