Copper-Catalyzed C(sp3)-S Bond and C(sp2)-S Bond Cross-Coupling of 2-(2-Iodobenzoyl) Substituted or 2-(2-Iodobenzyl) Substituted 1,2,3,4-Tetrahydroisoquinolines with Potassium Sulfide: Synthesis of Isoquinoline-Fused 1,3-Benzothiazine Scaffolds

Article abstract of DOI:10.1021/acs.joc.6b02943

The sulfuration reaction of 2-(2-iodobenzoyl) substituted, or 2-(2-iodobenzyl) substituted 1,2,3,4-tetrahydroisoquinolines with potassium sulfide proceeded in the presence of copper catalysts to give tetrahydroisoquinoline-fused 1,3-benzothiazine scaffolds in moderate to appropriate yields. This protocol provided an efficient and simple strategy to construct the corresponding benzothiazine derivatives via formation of C(sp³)-S bond and C(sp²)-S bond, which the C-S bonds formed via different routes in this reaction (traditional cross-coupling reaction via the cleavage of C-I bond and oxidative cross-coupling reaction via C(sp³)-H bond functionalization).

Full text of DOI:10.1021/acs.joc.6b02943

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Note
Copper-Catalyzed C(sp3)–S Bond and C(sp2)–S Bond Cross-
Coupling of 2-(2-Iodobenzoyl) Substituted or 2-(2-Iodobenzyl)
Substituted 1,2,3,4-Tetrahydroisoquinolines with Potassium Sulfide:
Synthesis of Isoquinoline-Fused 1,3-Benzothiazine Scaffolds
Pan Dang, Zhilei Zheng, and Yun Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02943 • Publication Date (Web): 25 Jan 2017
Downloaded from http://pubs.acs.org on January 25, 2017
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CopperꢀCatalyzed C(sp3)–S Bond and C(sp2)–S Bond CrossꢀCoupling of 2ꢀ(2ꢀIodobenzoyl)
Substituted or 2ꢀ(2ꢀIodobenzyl) Substituted 1,2,3,4ꢀTetrahydroisoquinolines with Potassium
3
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Sulfide: Synthesis of IsoquinolineꢀFused 1,3ꢀBenzothiazine Scaffolds
Pan Dang, Zhilei Zheng, Yun Liang*
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National & Local Joint Engineering Laboratory for New Petroꢀchemical Materials and Fine Utilization
of Resources, Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research,
Ministry of Education, Key Laboratory of the Assembly and Application of Organic Functional
Molecules, Hunan Normal University, Changsha, Hunan 410081, China
Supporting Information Placeholder
ABSTRACT:
The sulfuration reaction of 2ꢀ(2ꢀiodobenzoyl) substituted, or 2ꢀ(2ꢀiodobenzyl) substituted
1,2,3,4ꢀtetrahydroisoquinolines with potassium sulfide proceeded in the presence of copper
catalysts to give tetrahydroisoquinolineꢀfused 1,3ꢀbenzothiazine scaffolds in moderate to
appropriate yields. This protocol provided an efficient and simple strategy to construct the
corresponding benzothiazine derivatives via formation of C(sp3)–S bond and C(sp2)–S bond,
which the C−S bonds formed via different routes in this reaction (traditional crossꢀcoupling
reaction via the cleavage of C−I bond and oxidative crossꢀcoupling reaction via C(sp3)−H bond
functionalization).
Development of straightforward and efficient methods for rapid construct to nitrogen and
sulfurꢀcontaining heterocyclic compounds is one of the central focuses in organic synthesis,1ꢀ3 as
well as applications in the pharmaceutical industry4 and materials science.5 1,3ꢀBenzothiazines6ꢀ9
and 1,2,3,4ꢀtetrahydroisoquinolines (THIQs)10ꢀ11, in particular, are the core structural motifs of
many
biologically
and
pharmaceutically
active
molecules.
Remarkably,
and
5,6ꢀdihydrobenzo[5,6][1,3]thiazino[2,3ꢀa]isoquinolinꢀ8(13aH)ꢀone
5,6,8,13aꢀtetrahydrobenzo[5,6][1,3]thiazino[2,3ꢀa]isoquinoline, which contain THIQ and
1,3ꢀbenzothiazine skeletons, are present as a key functional group in pharmacologically active
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compounds.12 They have been investigated as sedatives (e.g., A, Figure 1),13 cell growth inhibitors
(e.g., B, Figure 1).12aꢀb As a result, the design and development of a novel and straightforward
route for the generation of isoquinolineꢀfused 1,3ꢀbenzothiazines is particularly value.
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Figure 1. Examples of bioactive THIQꢀfused 1,3ꢀbenzothiazines
Conventional synthetic approaches for the construction of ringꢀfused 1,3ꢀthiazine scaffolds
focus on: (1) Direct imine acylation reaction of imines with thiosalicylic acid (Scheme 1, eq
1);13,14 (2) Redoxꢀneutral αꢀsulfenylation of secondary amine with thiosalicylaldehydes (Scheme 1,
eq 2).15 These reported routes are useful and interesting for the synthesis of ringꢀfused 1,3ꢀ
benzothiazines. However, the sulfuration reagents of functional thiols have unpleasant odors,
preparation difficulties and easy oxidation during their entire processes, which impede their
applications. Recently, our group discovered that inorganic metal sulfides as a good coupling
partner could be used to synthesize the fiveꢀmembers sulfurꢀcontaining heterocyclic
compounds,16ꢀ21 which are with the characteristics of low toxicity, low cost, readily available,
relatively stability and operationally simplicity. In continuation of our efforts on the synthesis of
sulfurꢀcontaining compounds using simple and lowꢀcost methods, we decided to explore the
synthesis of sixꢀmembers sulfurꢀcontaining heterocyclic compounds. We found that
2ꢀ(2ꢀiodobenzoyl) substituted, or 2ꢀ(2ꢀiodobenzyl) substituted THIQs could efficiently react with
potassium sulfide to obtain isoquinolineꢀfused 1,3ꢀbenzothiazines in the presence of copper
catalyst (Scheme 1, eq 3). Herein, we would introduced the details for constructing these
N,Sꢀheterocycles.
Scheme 1. Selected Approaches to Ring-fused 1,3-Benzothiazine
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Lombardino et al. (1961):
MeO
5
6
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8
N
O
MeO
MeO
HOOC
MeO
PhH
(1)
(2)
+
S
N
HS
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Seidel et al. (2014):
OHC
N
N
AcOH
+
NH
S
S
3A MS
PhMe, 60 oC
HS
This work:
Cu(OAc)2, TEMED
NMP, Air
N
Y
Y
+
K2S
(3)
I
Y = CH2 or C=O
The
initial
evaluation
was
carried
out
with
(3,4ꢀdihydroisoquinolinꢀ2(1H)ꢀyl)(2ꢀiodophenyl)methanone (1a) and K2S as the model substrates
to optimize the reaction conditions, and the results were summarized in Table 1. To our delight,
the desired product 2a was obtained in 70% yield by employing CuBr as catalyst and TEMED
(tetramethylethylenediamine) as ligand in NMP (Nꢀmethylꢀ2ꢀpyrrolidone) at 120 °C under air
atmosphere (entry 1). When the reaction was performed under oxygen atmosphere or nitrogen
atmosphere, the yields of product 2a are all decreased obviously (entries 2 and 3). Control
experiment revealed that the use of copper salt was imperative (entry 4). In order to achieving the
best result, a series of copper catalysts and nitrogenꢀligands are screened (entry 5, see the
supporting information for more details). Among the comparison of copper catalysts, monovalent
copper salt (CuCl, CuI, Cu2O) were inferior to bivalent copper salt (CuF2, CuCl2, CuBr2,
Cu(OAc)2, Cu(OTf)2), and Cu(OAc)2 showed the best catalytic efficiency. No ligand and the other
ligands
such
as
DMEDA
(N,N’ꢀdimethylethylenediamine),
Lꢀproline,
DMAP
(4ꢀdimethylaminopyridine) and 1,10ꢀphenanthroline all gave lower yields than TEMED.
Subsequently, several polar solvents (dimethylformamide, dimethyl sulfoxide, dimethylacetamide,
and acetonitrile) were evaluated as potential alternatives to NMP, but the desired product all gave
rise in lower yields (see the supporting information for more details). Finally, it is found that both
decreasing and increasing the temperature could not improve the yields (entries 6 and 7). In order
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to improve the yield, the other metal sulfides such as Na2S and Li2S were used to displace K2S.
Regrettably, they are not efficient sulfur reagents for the reaction, and no product 2a was obtained
under the identical conditions (entries 8 and 9). Thus, the use of 20 mol % of Cu(OAc)2 and 40
mol % of TEMED, in NMP at 120 o C for 24 h was found to be optimal reaction conditions (88%,
entry 5).
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Table 1. Optimization of Reaction Conditionsa
Entry Catalyst
M2S
Temp(oC)b Yield(%)
1
CuBr
CuBr
CuBr
––
K2S
K2S
K2S
K2S
120
120
120
120
120
100
140
120
120
70
2c
3d
4
37
58
NRe
5
Cu(OAc)2 K2S
Cu(OAc)2 K2S
Cu(OAc)2 K2S
Cu(OAc)2 Na2S
Cu(OAc)2 Li2S
88
6
41
7
58
8
trace
trace
9
a
Reaction conditions: 1a (0.3 mmol), M2S (0.9
mmol), Cu salt (20 mol %), TEMEDA (40 mol %),
NMP (2 mL ), under air atmosphere in sealed Schlenk
tube, at 120 oC for 24 h. b Temp: temperature. c Under
d
e
nitrogen atmosphere. Under oxygen atmosphere.
NR: no reaction.
With the optimal reaction conditions in hand, the scope of the substituents on the aromatic
ring of 2ꢀiodobenzoyl group was tested initially (Scheme 2, 2bꢀ2h). Both electronꢀdonating groups
(CH3 and OCH3) and electronꢀwithdrawing groups (F, Cl, and CF3) were tolerated, and could
smoothly transform into the desired isoquinolineꢀfused 1,3ꢀbenzothiazines under the optimized
conditions. For example, the N,Sꢀheterocycle 2b was afforded in 93% yield. Due to the biological
activity of bearing of methoxyl group on the isoquinolineꢀfused 1,3ꢀbenzothiazines, the methoxyl
group on the isoquinoline ring were evaluated (Scheme 2, 2iꢀ2k). Luckily, the desired products 2i
and 2k all were obtained in 85% yield. Importantly, the isoquinolineꢀfused 1,3ꢀbenzothiazine 2j
could be gained in 54% yield which has been investigated as sedatives. Finally, the reactivity of
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(2ꢀbromophenyl)(3,4ꢀdihydroisoquinolinꢀ2(1H)ꢀyl)methanone was investigated (Scheme 2, 2a).
Unfortunately, it could not efficiently react with K2S, and low yield of product 2a was afforded in
the standard reaction conditions.
Scheme 2. Synthesis of 5,6-Dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-onesa
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Cu(OAc)2
TEMED
N
O
N
O
R1
R1
+
K2S
I
NMP, Air
S
120 o
C
2
1
R2
R2
N
O
N
O
N
O
S
S
S
H3C
CH3
O
OCH3
2d 69%
2c 74%
2b 93%
N
O
N
S
O
N
S
S
OCH3
OCH3
Cl
F
2g 68%
2e 46%
2f 46%
H3CO
H3CO
H3CO
N
O
N
O
O
N
S
S
S
2i 85%
2j 54%
2h 53%
CF3
H3CO
O
N
N
S
O
H3CO
S
2a 18%b
2k 85% H3C
a Reaction conditions: 1 (0.3 mmol), K2S (0.9 mmol), Cu(OAc)2 (20
mol %), TEMED (40 mol %), NMP (2 mL ), under air atmosphere in
o
b
sealed Schlenk tube, at 120 C for 24 h. (2-bromophenyl)(3,4-
dihydroisoquinolin-2(1H)-yl)methanone was applied.
Encouraged
by
the
success
in
the
coupling
reaction
of
(3,4ꢀdihydroisoquinolinꢀ2(1H)ꢀyl)(2ꢀiodophenyl)methanones 1 with K2S, we next attempted to
examine the substrate scope to 2ꢀ(2ꢀiodobenzyl)ꢀTHIQs 3 (Scheme 3). However, it revealed that
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the reaction of 2ꢀ(2ꢀiodobenzyl)ꢀTHIQ 3a with potassium sulfide is sluggish under the standard
conditions. Fortunately, 3a was found to be a suitable substrate and achieved isoquinolineꢀfused
1,3ꢀbenzothiazines in 90% yield, when the reaction temperature was lowered to 80 oC.
Subsequently, the electronic effect of the substituents on the aromatic ring of isoquinoline was
investigated. We were pleased to find that the reactions of isoquinoline bearing both
electronꢀdonating groups and electronꢀwithdrawing groups worked well and afforded the
corresponding products in good yields (Scheme 3, 4b-4d). Among them, the products 4b and 4c
were both attained in 89% yields. To our delight, electronꢀwithdrawing group NO2 of isoquinoline
ring system gave compound 4d in 90% yield. Finally, a wide range of 2ꢀiodobenzylꢀsubstituted
THIQs were examined. It was observed that bearing either electronꢀdonating groups (CH3, OCH3)
or electronꢀwithdrawing groups (F, COOEt) on the phenyl ring of 3 proceeded smoothly, and
obtained the desired products 4 in 60−66% yields (Scheme 3, 4e-4h).
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Scheme 3. Synthesis of 5,6,8,13a-Tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolines a
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Cu(OAc)2
N
N
TEMED
R1
R1
+
K2S
I
S
NMP, Air
80 o
8
C
9
R2
R2
4
3
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H3CO
H3CO
N
N
N
H3CO
S
S
S
4a 90%
4c 89%
4b 89%
N
N
S
N
O2N
S
S
F
4d 90%
4e 62%
4f 66%
COOEt
N
N
S
S
H3C
4h 60%
4g 62%
OCH3
a Reaction conditions: 3 (0.3 mmol), K2S (0.9 mmol), Cu(OAc)2
(20 mol %), TEMED (40 mol %), NMP (2 mL), under air
atmosphere in sealed Schlenk tube, at 80 o C for 4 h.
Based on the reported literatures 1,22,23 and previous works, a plausible mechanism of this coupling
reaction was proposed in Scheme 4. First, intermediate
A
is formed from
(3,4ꢀdihydroisoquinolinꢀ2(1H)ꢀyl)(2ꢀiodophenyl)methanone 1a and K2S via the copperꢀcatalyzed
traditional coupling reaction. Subsequently, the intermediate A undergoes a copperꢀpromoted
singleꢀelectron transfer process to provide the iminium intermediate B, which can effectively
undergoes an intramolecular nucleophilic attack to give the desired crossꢀcoupling product 2a.
Scheme 4. Possible Reaction Mechanism
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Cu(OAc)2
N
O
+
N
O
TEMED
NMP,air
120oC
K2S
I
S
2a
1a
9
[Cu]
TEMEDA
CuILn
O2
K2S
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CuIILn
N
O
N
O
KS
KS
A
B
In conclusion, we have developed an efficient and straightforward method for the synthesis of
isoquinolineꢀfused 1,3ꢀbenzothiazines via copperꢀcatalyzed crossꢀcoupling of 2ꢀ(2ꢀiodobenzoyl)
substituted, or 2ꢀ(2ꢀiodobenzyl) substituted 1,2,3,4ꢀTHIQs with potassium sulfide. The main
features of this new methodology are: 1) This reaction provides an efficient protocol for the
construction C(sp3)ꢀS bond and C(sp2)ꢀS bond in a step; 2) The low cost, low toxicity, odorless,
and readily available potassium sulfide should be desired sulfuration reagent for the coupling
partner; 3) The isoquinolineꢀfused 1,3ꢀbenzothiazine derivatives have biologically and
pharmaceutically activity, which easily prepared using this synthetic strategy.
ꢀ
Experimental Section
General Information. NMR spectra of the products 2a-2k, 4a-4h were recorded using 500 MHz
NMR spectrometer. The chemical shifts were calibrated to TMS (1H NMR spectra) and CD(H)Cl3
(13C NMR spectra) as the internal reference (0.00 ppm for 1H NMR spectra and 77.00 ppm for 13
C
NMR spectra). Highꢀresolution mass spectra (HRMS) were recorded with an ESIꢀObitrap mass
spectrometer. Reactions were monitored by thinꢀlayer chromatography, and column
chromatography (petroleum ether/ethyl acetate) was performed on silica gel (200ꢀ300 mesh). All
reagents were used without further purification as received from commercial suppliers unless
otherwise noted. All solvents were dried and distilled prior to use according to the standard
protocols.
General Procedure for the Preparation of Starting Materials (1): A solution sodium nitrite
(703.8 mg, 10.2 mmol) in water (2 mL) was added slowly to a cold (0 oC) stirred solution of
substituted 2ꢀaminobenzoic acid (10 mmol) in water (25 mL) and concentrated hydrochloric acid
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(7.5 mL). On completion of the addition the solution was stirred for 5ꢀ10 min until complete
consumption of starting material was indicated by TLC. Then, a solution of the potassium iodide
(1693.2 mg, 10.2 mmol) in water (2.5 mL) was slowly added. The cooling bath was removed and
the mixture stirred for a further 30 min before carefully heating the suspension to 90 oC for 30 min.
The mixture was cooled to room temperature and the precipitated solid collected and washed with
water. The crude product was recrystallised from ethanol and water to afford the pure
substitutedꢀ2ꢀiodobenzoic acids.
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The substitutedꢀ2ꢀiodobenzoic acids (3 mmol), thionyl chloride (3.0 mL) and one drop of
N,Nꢀdimethylformamide were heated under reflux for 4 h. The mixture was cooled to room
temperature. The excess thionyl chloride was removed from the cooled reaction mixture and the
remaining acid chloride was dissolved in dichloromethane.
A solution oꢀIodoebenzoyl chlorides (3 mmol) in CH2Cl2 (3 mL) was added slowly to a cold
o
(0 C) stirred solution of isoquinoline (2.5 mmol) and triethylamine (0.84 mL, 6 mmol) in
dichloromethane (5 mL). The mixture was stirred until complete consumption of starting material
was indicated by TLC. The mixture was quenched with water and the organic layer extracted with
dichloromethane. The combined extracts were washed with brine, dried over Na2SO4,
concentrated under reduced pressure and purified by column chromatography to afford the pure
product 1.
Typical
experimental
procedure
for
the
synthesis
of
5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-ones (Scheme 2). The sealed
Schlenk tube was charged with (3,4ꢀdihydroisoquinolinꢀ2(1H)ꢀyl)(2ꢀiodophenyl)methanone
derivatives 1 (0.3 mmol), K2S (99 mg, 3 equiv, 0.9 mmol), Cu(OAc)2 (10.9 mg, 20 mol%, 0.06
mmol), TEMED (13.9 mg, 40 mol%, 0.12 mmol) and NMP (2 mL). Then the mixture was stirred
at 120 oC (oil bath temperature). After the reaction was finished, the reaction mixture was cooled
to room temperature, quenched by water and extracted with ethyl acetate. The combined organic
layer was washed with brine, and dried over Na2SO4, and concentrated in vacuum, and the
resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate)
to afford ringꢀfused 1,3ꢀbenzothiazine heterocycles 2.
Typical
experimental
procedure
for
the
synthesis
of
5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolines (Scheme 3). The sealed
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Schlenk tube was charged with 2ꢀ(2ꢀiodobenzyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline derivatives 3 (0.3
mmol), K2S (99 mg, 3equiv, 0.9 mmol), Cu(OAc)2 (10.9 mg, 20 mol%, 0.06 mmol), TEMED
(13.9 mg, 40 mol%, 0.12 mmol) and NMP (2 mL). Then the mixture was stirred at 80 oC for 4 h
(oil bath temperature). After the reaction was finished, the reaction mixture was cooled to room
temperature, quenched by water and extracted with ethyl acetate. The combined organic layer was
washed with brine, and dried over Na2SO4, and concentrated in vacuum, and the resulting residue
was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford
ringꢀfused 1,3ꢀbenzothiazine heterocycles 4.
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5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2a):14b white solid (70 mg,
1
88%); H NMR (CDCl3, 500 MHz) δ 2.92ꢀ2.96 (m, 1H), 3.11ꢀ3.22 (m, 2H), 4.78ꢀ4.81 (m, 1H),
6.22 (s, 1H), 7.24ꢀ7.26 (m, 1H), 7.29ꢀ7.34 (m, 4H), 7.38ꢀ7.42 (m, 2H), 8.19 (d, J = 8.0 Hz, 1H).
13C{H} NMR (CDCl3, 125 MHz) δ 29.4, 39.8, 60.5, 126.1, 126.8, 127.1, 127.5, 128.4, 128.7,
128.9, 130.6, 131.0, 131.7, 136.2, 137.6, 164.8.
12-methyl-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one
(2b):
pale
yellow solid (78 mg, 93%); mp: 79.9ꢀ81.3 oC; 1H NMR (CDCl3, 500 MHz) δ 2.33 (s, 3H), 2.94 (d,
J = 14.5 Hz, 1H), 3.11ꢀ3.22 (m, 2H), 4.77ꢀ4.80 (m, 1H), 6.13 (s, 1H), 7.20ꢀ7.31 (m, 5H), 7.41 (t, J
= 5.5 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ 19.8, 29.4, 39.7, 59.8,
125.3, 127.0, 127.6, 128.4, 128.6, 128.7, 128.9, 130.8, 132.8, 134.6, 136.3, 137.4, 165.1. HRMS
(ESI, m/z) calcd for [C17H15NOS]H+: 282.0947; found 282.0942.
11-methyl-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2c): pale yellow
1
oil (62 mg, 74%); H NMR (CDCl3, 500 MHz) δ 2.37 (s, 3H), 2.90ꢀ2.94 (m, 1H), 3.09ꢀ3.20 (m,
2H), 4.76ꢀ4.79 (m, 1H), 6.20 (s, 1H), 7.12 (t, J = 8.0 Hz, 2H), 7.23ꢀ7.25 (m, 1H), 7.28 (t, J = 4.5
Hz, 2H), 7.36ꢀ7.38 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ 21.3,
29.4, 39.7, 60.4, 126.3, 127.0, 127.1, 127.2, 127.5, 128.3, 128.6, 130.7, 130.9, 136.2, 137.4, 142.4,
164.8. HRMS (ESI, m/z) calcd for [C17H15NOS]H+: 282.0947; found 282.0943.
11-methoxy-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2d): pale
yellow solid (60 mg, 69%); mp: 142.3ꢀ143.8 oC; 1H NMR (CDCl3, 500 MHz) δ 2.90ꢀ2.93 (m, 1H),
3.08ꢀ3.19 (m, 2H), 3.84 (s, 3H), 4.74ꢀ4.77 (m, 1H), 6.23 (s, 1H), 6.79ꢀ6.84 (m, 2H), 7.23ꢀ7.25 (m,
1H), 7.29 (t, J = 4.5 Hz, 2H), 7.36ꢀ7.38 (m, 1H), 8.12 (d, J = 9.0 Hz, 1H). 13C{H} NMR (CDCl3,
125 MHz) δ 29.4, 39.6, 55.4, 60.5, 110.8, 112.8, 121.7, 127.0, 127.5, 128.3, 128.6, 130.6, 132.8,
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136.2, 139.4, 161.9, 164.7. HRMS (ESI, m/z) calcd for [C17H15NO2S]H+: 298.0896; found
298.0896.
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10,11-dimethoxy-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one
(2e):
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yellow oil (45 mg, 46%); H NMR (CDCl3, 500 MHz) δ 2.92ꢀ2.97 (m, 1H), 3.10ꢀ3.20 (m, 2H),
3.91 (s, 3H), 3.95 (s, 3H), 4.75ꢀ4.79 (m, 1H), 6.20 (s, 1H), 6.76 (s, 1H), 7.25 (t, J = 3.5 Hz, 1H),
7.30 (t, J = 5.0 Hz, 2H), 7.39 (t, J = 5.5 Hz, 1H), 7.69 (s, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ
29.4, 39.7, 56.0, 56.1, 60.8, 108.7, 112.9, 121.4, 127.0, 127.5, 128.3, 128.7, 130.3, 130.7, 136.2,
147.7, 151.9, 164.8. HRMS (ESI, m/z) calcd for [C18H17NO3S]H+: 328.1002; found 328.1001.
10-fluoro-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2f): yellow oil
(40 mg, 46%); 1H NMR (CDCl3, 500 MHz) δ 2.92ꢀ2.96 (m, 1H), 3.10ꢀ3.24 (m, 2H), 4.76ꢀ4.80 (m,
1H), 6.20 (s, 1H), 7.14 (td, J = 8.5 Hz, 2.5 Hz, 1H), 7.25ꢀ7.27 (m, 1H), 7.29ꢀ7.33 (m, 3H),
7.38ꢀ7.40 (m, 1H), 7.89 (dd, J = 9.5 Hz, 3.0 Hz, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ 29.4,
40.0, 60.7, 117.6 (d, J = 23.5 Hz), 119.3 (d, J = 22.6 Hz), 127.2, 127.6, 128.4 (d, J = 7.2 Hz),
128.5, 128.8, 130.3, 130.6 (d, J = 7.2 Hz), 132.7 (d, J = 3.2 Hz), 136.1, 161.2 (d, J = 244.7 Hz),
163.8. HRMS (ESI, m/z) calcd for [C16H12NOSF]H+: 286.0696; found 286.0697.
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10-chloro-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2g): yellow oil
(60 mg, 68%); 1H NMR (CDCl3, 500 MHz) δ 2.91ꢀ2.95 (m, 1H), 3.09ꢀ3.22 (m, 2H), 4.74ꢀ4.78 (m,
1H), 6.19 (s, 1H), 7.24ꢀ7.27 (m, 2H), 7.29ꢀ7.31 (m, 2H), 7.35ꢀ7.38 (m, 2H), 8.15 (d, J = 2.5 Hz,
1H). 13C{H} NMR (CDCl3, 125 MHz) δ 29.3, 39.9, 60.5, 127.2, 127.5, 128.0, 128.5, 128.7, 130.1,
130.2, 130.8, 131.7, 132.1, 135.9, 136.1, 163.6. HRMS (ESI, m/z) calcd for [C16H12ClNOS]H+:
302.0401; found 302.0399.
11-(trifluoromethyl)-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2h):
o
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pale yellow solid (53 mg, 53%); mp: 78.7ꢀ80.4 C; H NMR (CDCl3, 500 MHz) δ 2.94ꢀ2.99 (m,
1H), 3.12ꢀ3.25 (m, 2H), 4.77ꢀ4.81 (m, 1H), 6.25 (s, 1H), 7.26ꢀ7.29 (m, 1H), 7.32 (t, J = 4.0 Hz,
2H), 7.38ꢀ7.40 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H). 13C{H}
NMR (CDCl3, 125 MHz) δ 29.3, 40.0, 60.7, 122.7 (q, J = 3.5 Hz), 123.2 (q, J = 271.2 Hz ), 123.9
(q, J = 3.75 Hz), 127.3, 127.5, 128.7, 128.8, 129.9, 131.5, 131.6, 133.5 (q, J = 32.4 Hz), 136.1,
138.8, 163.7. HRMS (ESI, m/z) calcd for [C17H12NOSF3]H+: 336.0665; found 336.0660.
3-methoxy-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2i): yellow oil
(77 mg, 85%); 1H NMR (CDCl3, 500 MHz) δ 2.86ꢀ2.90 (m, 1H), 3.07ꢀ3.20 (m, 2H), 3.81 (s, 3H),
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4.74ꢀ4.78 (m, 1H), 6.16 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.5 Hz, 2.5 Hz, 1H),
7.28ꢀ7.31 (m, 3H), 7.38 (td, J = 7.5 Hz, 1.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H). 13C{H} NMR
(CDCl3, 125 MHz) δ 29.6, 39.7, 55.2, 60.3, 113.2, 113.3, 122.5, 125.9, 126.7, 128.7, 128.9, 130.9,
131.5, 137.6, 137.7, 159.3, 164.7. HRMS (ESI, m/z) calcd for [C17H15NO2S]H+: 298.0896; found
298.0896.
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2,3-dimethoxy-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one (2j):13 white
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solid (53 mg, 54%); H NMR (CDCl3, 500 MHz) δ 2.83ꢀ2.86 (m, 1H), 3.03ꢀ3.10 (m, 1H),
3.15ꢀ3.18 (m, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 4.74ꢀ4.78 (m, 1H), 6.15 (s, 1H), 6.72 (s, 1H), 6.86 (s,
1H), 7.29ꢀ7.33 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H). 13C{H} NMR (CDCl3,
125 MHz) δ 28.7, 39.7, 55.8, 55.9, 60.5, 109.9, 111.1, 122.0, 126.0, 126.7, 128.6, 128.9, 130.9,
131.6, 137.5, 148.1, 148.9, 164.8.
2,3-dimethoxy-12-methyl-5,6-dihydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinolin-8(13aH)-one
(2k): pale yellow solid (87 mg, 85%); mp: 142.1ꢀ143.3 oC; 1H NMR (CDCl3, 500 MHz) δ 2.34 (s,
3H), 2.84ꢀ2.87 (m, 1H), 3.04ꢀ3.10 (m, 1H), 3.15ꢀ3.21 (m, 1H), 3.89 (s, 3H), 3.91 (s, 3H),
4.73ꢀ4.77 (m, 1H), 6.06 (s, 1H), 6.73 (s, 1H), 6.88 (s, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.0
Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ 19.9, 28.8, 39.7, 55.9, 56.0,
59.8, 110.1, 111.1, 122.2, 125.3, 128.5, 128.7, 128.9, 132.8, 134.5, 137.4, 148.1, 149.0, 165.2.
HRMS (ESI, m/z) calcd for [C19H19NO3S]H+: 342.1158; found 342.1158.
5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4a):15 white solid (68 mg,
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90%); H NMR (CDCl3, 500 MHz) δ 2.84 (d, J = 12.0 Hz, 2H), 3.16ꢀ3.30 (m, 2H), 3.96 (d, J =
16.5 Hz, 1H), 4.55 (d, J = 17.0 Hz, 1H), 6.18 (s, 1H), 7.00ꢀ7.06 (m, 3H), 7.11 (td, J = 8.5 Hz, 2.0
Hz, 1H), 7.16ꢀ7.25 (m, 4H). 13C{H} NMR (CDCl3, 125 MHz) δ 28.7, 43.6, 57.7, 67.0, 124.1,
126.0, 126.2, 126.4, 126.5, 127.0, 127.8, 128.0, 129.2, 133.0, 134.7, 134.8.
2,3-dimethoxy-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4b):15 pale
yellow solid (84 mg, 89%); 1H NMR (CDCl3, 500 MHz) δ 2.81 (d, J = 7.5 Hz, 2H), 3.15 (d, J =
50.5 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.00 (s, 1H), 4.51 (s, 1H), 6.01 (s, 1H), 6.64 (s, 2H),
6.99ꢀ7.09 (m, 4H). 1H NMR (CDCl3, 500 MHz, ꢀ60 oC) δ 2.76 (d, J = 15.5 Hz, 1H), 2.83ꢀ2.86 (m,
1H), 3.07ꢀ3.20 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 3.98 (d, J = 16.5 Hz, 1H), 4.53 (d, J = 16.5 Hz,
1H), 6.14 (s, 1H), 6.65 (d, J = 21.5 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 7.04ꢀ7.09 (m, 2H), 7.13 (t, J
= 7.0 Hz, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ 28.4, 43.7, 55.8, 55.9, 57.8, 67.1, 108.9, 111.6,
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124.1, 125.2, 126.5, 126.6, 126.7, 126.9, 127.9, 134.9, 147.4, 148.6.
3-methoxy-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4c):15 pale yellow
solid (81 mg, 90%); 1H NMR (CDCl3, 500 MHz) δ 2.85 (s, 2H), 3.15 (s, 2H), 3.80 (s, 3H), 3.98 (s,
1H), 4.51 (s, 1H), 6.14 (s, 1H), 6.71 (s, 1H), 6.76 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 6.99ꢀ7.05 (m, 3H),
7.09ꢀ7.11 (m, 2H). 1H NMR (CDCl3, 500 MHz, ꢀ60 oC) δ 2.84 (d, J = 15.0 Hz, 2H), 3.19ꢀ3.26 (m,
2H), 3.82 (s, 3H), 4.00 (d, J = 17.0 Hz, 1H), 4.54 (d, J = 17.0 Hz, 1H), 6.17 (s, 1H), 6.74 (s, 1H),
6.80 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.06ꢀ7.16 (m, 4H). 13C{H} NMR (CDCl3,125
MHz) δ 28.9, 43.5, 55.1, 57.7, 66.8, 112.2, 113.8, 124.0, 126.4, 126.5, 126.8, 127.2, 127.3, 127.8,
134.5, 134.9, 158.9.
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2-nitro-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4d): pale yellow solid
o
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(80 mg, 90%); mp: 169.5ꢀ170.9 C; H NMR (CDCl3, 500 MHz) δ 2.86ꢀ2.96 (m, 2H), 3.20ꢀ3.32
(m, 2H), 3.96 (d, J = 16.5 Hz, 1H), 4.56 (d, J = 16.5 Hz, 1H), 6.18 (s, 1H), 7.02 (d, J = 8.0 Hz,
1H), 7.06 (s, 2H), 7.10ꢀ7.13 (m, 1H), 7.33 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.0 Hz,
1H). 13C{H} NMR (CDCl3, 125 MHz) δ 29.1, 43.0, 57.4, 66.0, 121.4, 122.7, 124.7, 125.9, 126.6,
127.2, 128.0, 130.2, 133.6, 136.2, 141.4, 146.2. HRMS (ESI) m/z calcd for [C16H15N2O2S]H+:
299.0849, found 299.0849.
10-fluoro-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4e): pale yellow
o
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solid (50 mg, 62%); mp: 138.5ꢀ139.8 C; H NMR (CDCl3, 500 MHz) δ 2.79ꢀ2.82 (m, 2H),
3.12ꢀ3.23 (m, 2H), 3.89 (d, J = 16.5 Hz, 1H), 4.48 (d, J = 17.0 Hz, 1H), 6.09 (s, 1H), 6.77ꢀ6.84 (m,
2H), 6.91ꢀ6.94 (m, 1H), 7.12ꢀ7.18 (m, 3H), 7.19ꢀ7.23 (m, 1H). 13C{H} NMR (CDCl3, 125 MHz) δ
28.7, 43.6, 57.6, 66.9, 114.5 (q, J = 21.5 Hz), 126.1, 126.2, 127.6, 127.7, 127.9, 128.0 (d, J = 5.75
Hz), 129.2, 129.5 (d, J = 2.8 Hz), 132.9, 134.5, 159.7 (d, J = 242.75 Hz). HRMS (ESI, m/z) calcd
for [C16H14NSF]H+: 272.0904; found 272.0905.
5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline-11-carboxylate Ethyl (4f):
white solid (64 mg, 66%); mp: 120.5ꢀ121.8 oC; 1H NMR (CDCl3, 500 MHz) δ 1.36 (t, J = 7.0 Hz,
3H), 2.79ꢀ2.81 (m, 2H), 3.16ꢀ3.19 (m, 2H), 3.97 (d, J = 17.0 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H),
4.52 (d, J = 16.5 Hz, 1H), 6.15 (s, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.13ꢀ7.24 (m, 4H), 7.65ꢀ7.76 (m,
2H). 13C{H} NMR (CDCl3, 125 MHz) δ 14.2, 28.7, 43.7, 57.6, 60.9, 67.2, 124.9, 126.1, 126.2,
127.7, 127.8, 127.9, 129.1, 129.2, 131.3, 132.9, 134.4, 135.5, 166.0. HRMS (ESI, m/z) calcd for
[C19H19NO2S]H+: 326.1209; found 326.1209.
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12-methyl-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4g): yellow solid
(50 mg, 62%); mp: 140.3ꢀ141.8 oC; 1H NMR (CDCl3, 500 MHz) δ 2.20 (d, J = 6.0 Hz, 3H), 2.82
(d, J = 15 Hz, 2H), 3.15ꢀ3.26 (m, 2H), 3.95 (d, J = 16.5 Hz, 1H), 4.54 (d, J = 16.5 Hz, 1H), 6.13 (s,
1H), 6.90ꢀ6.95 (m, 2H), 7.01 (t, J = 5.5 Hz, 1H), 7.17ꢀ7.23 (m, 4H). 13C{H} NMR (CDCl3, 125
MHz) δ 19.1, 28.7, 43.5, 58.1, 67.0, 123.0, 125.3, 125.9, 126.0, 126.2, 127.9, 128.2, 129.2, 133.1,
133.9, 134.2, 135.0. HRMS (ESI) m/z calcd for [C17H18NS]H+ 268.1155, found 268.1155.
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11-methoxy-5,6,8,13a-tetrahydrobenzo[5,6][1,3]thiazino[2,3-a]isoquinoline (4h):15
yellow
solid (50 mg, 60%); 1H NMR (CDCl3, 500 MHz) δ 2.81 (s, 2H), 3.20 (d, J = 19.5 Hz, 2H), 3.75 (s,
3H), 3.90 (d, J = 13.0 Hz, 1H), 4.48 (d, J = 15.0 Hz, 1H), 6.15 (s, 1H), 6.55 (d, J = 2.0 Hz, 1H),
6.60 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 7.14ꢀ7.24 (m, 4H). 13C{H} NMR
(CDCl3, 125 MHz) δ 28.7, 43.5, 55.2, 57.2, 67.1, 110.8, 110.9, 118.4, 126.0, 126.2, 127.8, 128.8,
129.2, 133.0, 134.7, 135.8, 158.2.
ꢀ
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: yliang@hunnu.edu.cn.
ORCID
Yun Liang: 0000ꢀ0002ꢀ2550ꢀ9220
Notes
The authors declare no competing financial interest.
ꢀ
ACKNOWLEDGMENTS
This work was supported by the Natural Science Foundation of China (21572051), Ministry of
Education of the People's Republic of China (213027A), Education Department of Hunan
Province (15A109) for financial support.
ꢀ
Supporting Information Available: Copies of 1H and 13C spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
ꢀ
REFERENCES
(1) (a) Liu, H.; Jiang, X. F. Chem.-Asian J. 2013, 8, 2546. (b) Partyka, D. V. Chem.
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