Phosphine-Catalyzed [3+2] Annulation of β-Sulfonamido-Substituted Enones with Sulfamate-Derived Cyclic Imines

Article abstract of DOI:10.1021/acs.joc.8b02515

Phosphine-catalyzed [3+2] annulation of β-sulfonamido-substituted enones and sulfamate-derived cyclic imines has been developed, giving a series of imidazoline derivatives in moderate to excellent yields with good to excellent diastereoselectivities. A scale-up reaction worked well under mild reaction conditions. A possible mechanism was proposed on the basis of the results obtained.

Full text of DOI:10.1021/acs.joc.8b02515

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Article
Phosphine-Catalyzed [3+2] Annulation of #-Sulfonamido-
Substituted Enones with Sulfamate-Derived Cyclic Imines
Wangyu Shi, Leijie Zhou, Biming Mao, Qijun Wang, Chang Wang,
Cheng Zhang, Xuefeng Li, Yumei Xiao, and Hongchao Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02515 • Publication Date (Web): 24 Dec 2018
Downloaded from http://pubs.acs.org on December 24, 2018
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Phosphine-Catalyzed [3+2] Annulation of β-Sulfonamido-Substituted
Enones with Sulfamate-Derived Cyclic Imines
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Wangyu Shi, Leijie Zhou, Biming Mao, Qijun Wang, Chang Wang, Cheng Zhang, Xuefeng
Li, Yumei Xiao,* and Hongchao Guo*
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Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
Abstract: Phosphine-catalyzed [3+2] annulation of β-sulfonamido-substituted enones and
sulfamate-derived cyclic imines has been developed, giving a series of imidazoline derivatives
in moderate to excellent yields with good to excellent diastereoselectivities. A scale-up reaction
worked well under mild reaction conditions. A possible mechanism was proposed on the basis
of the results obtained.
Introduction
Imidazolines are important five-membered nitrogen-containing heterocycles which
have been proved to be a key structural units in numerous biologically active natural
products and artificial drugs.1 As shown in Figure 1, compound
Ⅰ exhibited powerful
cytotoxic against the human leukemia K562 and colon cancer SW1116 cell lines.2a,b
Compound
Compound
Ⅱ
showed potent H3 receptor antagonism and excellent selectivity.2c
have anti-colon cancer and anti-Leukemia effects.2d Besides, imidazoline
Ⅲ
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derivatives have been used as synthetic reagents such as chiral ligands and catalysts.3
Thus, synthesis of imidazoline derivatives is important and has attracted much attention.4
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Figure 1. Several Imidazoline Derivatives with Biological Activity.
Phosphine-catalyzed annulation reaction has been well developed for synthesis of
heterocyclic compounds in the past decades.5 Under phosphine catalysis, electron-
deficient allenoates, Morita–Baylis–Hillman carbonates, olefin, and alkynes generally
acted as phosphine accepter to produce phosphorus ylide for various annulation
reactions. Although phosphine catalysis has seen huge success, its development is in a
jam in most recent years due to its single activation mode. The search for new phosphine
acceptor exhibiting diverse reactivities especially exploring new activation modes
constitutes a major challenge in the area of phosphine catalysis.
β-sulfonamido-substituted enones have been proven as a kind of adaptable building
blocks for the construction of diverse nitrogen-containing heterocyclic compounds.
Under activation of amine catalysts, β-sulfonamido-substituted enones function as
nucleophilic reagents to react with electron-deficient olefin or imine for [3+2] annulation
reactions. In 2015, Du first reported a squaramide-catalyzed [3+2] annulation reaction
of β-sulfonamido-substituted enones and isatin-derived electron-deficient olefins for
synthesis of chiral spiropyrrolidine. Later, Du further extended the substrate scope of
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this reaction to include β-nitrostyrenes and unsaturated pyrazolone to prepare a variety
of chiral pyrrolidines.6 In 2018, Subhas Chandra Pan presented squaramide-catalyzed
[3+2] annulation of β-sulfonamido-substituted enones with N-sulfonylimines to give
chiral 2,4-disubstituted imidazolidines.7 Recently, our group developed Bu3P-catalyzed
[5+1] annulation of γ-sulfonamido-substituted enones and N-sulfonylimines, in which
γ-sulfonamido-substituted enones worked as a phosphine receptor (Scheme 1).8 Inspired
by this reaction, we herein report phosphine-catalyzed [3+2] annulation of β-
sulfonamido-substituted enones with sulfamate-derived cyclic imines for synthesis of
imidazoline derivatives (Scheme 1).
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Scheme 1. Phosphine-Catalyzed Annulation Reactions
RESULTS AND DISCUSSION
We initially implement our experiment with the reaction of β-sulfonamido-substituted
enone 1a with sulfamate-derived cyclic imines 2a as model reaction (Table 1). With the
use of CH2Cl2 (DCM) as the solvent, four tertiary phosphine catalysts were examined.
The weak nucleophilic Ph3P only resulted in trace product after 48 h (entry 1). To our
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delight, MePPh2 and Me2PPh promoted the [3+2] cycloaddition reaction to give the
product 3aa in 80% and 34% yield with good diastereoselectivity, respectively (entries
2, 3). Strangely, strong nucleophilic Bu3P did not show remarkable catalytic activities
(entry 4). Considering MePPh2 showed the good catalytic effect, we examined other two
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alkyldiaryl phosphines such as EtPPh2 and
catalytic activities. The cycloaddition product 3aa was obtained in 83% yield with 11:1
dr when EtPPh2 was used. In contrast, -PrPPh2 showed better catalytic capability,
n-PrPPh2, both which displayed excellent
n
giving the corresponding product 3aa in 91% yield with 9:1 dr. Several tertiary amines
such as DABCO, DMAP and DBU were tried in this reaction (entries 7–9). All of them
did not present good catalytic activity as phosphines did (entries 7–9 vs 5–6). With n-
PrPPh2 as a promising catalyst, we then evaluated several solvents and different
temperature. Other chlorinated solvents such as trichloromethane (CHCl3) and 1,2-
dichloroethane (DCE) gave similar catalytic results. Compared with DCM, DCE led to
a better diastereoselectivity (11:1) (entry 10 vs 6). Interestingly, lowering temperature
did not impact catalytic activity much, but remarkably worsened diastereoselectivity
(entries 12–13). Increasing the reaction temperature to 40 ℃ afforded lower yields of
the product, albeit with similar diastereoselectivity. According to the above results, the
optimal reaction conditions were determined to be with the use of n-PrPPh2 (20%) as the
catalyst and DCE (1 mL) as the solvent at room temperature (25 ℃). Under the
optimized conditions, asymmetric version of the reaction was also investigated.
Unfortunately, all available commercial chiral phosphines including acyclic, cyclic and
multifunctional chiral phosphine could only lead to racemic products.
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Table 1. Screening of the Reaction Conditions
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entry
1
catalyst
PPh3
solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
T/℃
25
25
25
25
25
25
25
25
25
25
25
0
t/h
48
1.5
1.5
48
1.5
1.5
24
24
24
1.5
1.5
5
yield (%)b
trace
80
drc
-
2
MePPh2
Me2PPh
Bu3P
10:1
6.5:1
-
3
34
4
trace
83
5
EtPPh2
11:1
9:1
6
n-PrPPh2
DMAP
DBU
91
7
65
>20:1
-
8
6
9
DABCO
n-PrPPh2
n-PrPPh2
n-PrPPh2
n-PrPPh2
n-PrPPh2
n-PrPPh2
55
14:1
11:1
7:1
10
11
12
13
14
15
89
CHCl3
DCM
DCE
87
92
8:1
0
5
91
8.5:1
10:1
8.5:1
DCM
DCE
40
40
1
69
1
66
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a Unless otherwise stated, all reactions were carried out with 1a (0.12 mmol), 2a (0.1 mmol),
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b
c
1
and catalyst (20 mol %) in 1 mL of solvent. Isolated yield. Determined by H NMR
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analysis.
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With the optimized reaction conditions in hand, we explored the scope of sulfamate-
derived cyclic imines (Table 2). A wide range of substituted cyclic imines (2a−2o) were
subjected to the optimized reaction conditions to furnish the corresponding imidazoline
derivatives with satisfactory yields and diastereoselectivities (Table 2). All halogen-
substituted products worked well to give the products in high yields with excellent
diastereoselectivities (14:1 dr to >20:1 dr, up to 94% yield, entries 2–7). However, some
cyclic imines having electron-donating groups such as 2h, 2m and 2n led to low yields
(37–46%). The relative configuration of the annulation products has been
unambiguously confirmed by X-ray crystallography of the product 3ao (CCDC
1868918) (Figure 2).9 Unfortunately, the sulfamate-derived ketamine 2p and acyclic N-
tosylaldimine 2q did not perform the reaction (entries 16–17). In our previous exploration,8
with the use of Bu3P as the catalyst, a [4+1] annulation of β-sulfonamido-substituted enones 1a
and N-tosylaldimine 2a occurred to give 2,5-dihydro-1H-pyrrole derivative in moderate yield.
Figure 2. X-Ray Crystallographic Diagram of the Product 3ao.
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Table 2. Substrate Scope of Sulfamate-Derived Cyclic Iminesa
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Entry
1
2
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
-
3
t/h
1.5
48
3
Yield (%)b drc
2a
2b
2c
2d
2e
2f
H
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
89
11:1
2
6-F
76
>20:1
17:1
14:1
>20:1
14:1
>20:1
8:1
3
7-F
73
4
8-F
3
94
5
7-Cl
8-Cl
7-Br
7-Me
8-Me
7-i-Pr
6-t-Bu
7-t-Bu
8-t-Bu
7-OMe
8-OMe
H
1.5
2
93
6
69
7
2g
2h
2i
48
48
1.5
48
1.5
48
48
48
1.5
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48
73
8d
9
46
80
6:1
10
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2j
3aj
3ak
3al
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12:1
12:1
14:1
4:1
2k
2l
72
86
2m
2n
2o
2p
3am
3an
3ao
3ap
3aq
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38
11:1
5:1
94
trace
trace
-
-
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a Unless otherwise stated, all reactions were carried out with 1a (0.12 mmol), 2 (0.1 mmol), and
n-PrPPh2 (20 mol%) in DCE (1 mL) at rt. b Isolated yield. c Determined by 1H NMR analysis. d
The reaction was performed at 40 ℃.
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As shown in Table 3, a broad scope of β-sulfonamido-substituted enones has been
established for phosphine-catalyzed [3+2] annulation reaction under the optimized
conditions. The enones bearing electron-withdrawing and -donating groups at the
benzene ring all performed annulation reaction well with the imine 2a to provide the
desired products (3ba
−
3ma) in moderate to excellent yields with good to excellent
12). 2-Chloro-substituted enone 1d and 2-OMe-
diastereoselectivities (entries 1
–
substituted enone 1k displayed a little lower reactivity to give the corresponding
products in 69% and 73% yield after 48 h, respectively (entry 3 and 10), indicating
certain influence of steric hindrance on reactivity of the substrates. Dichloro-substituted
enone was a viable substrate with high reactivity (entry 8). Of note, 4-phenyl substituted
enone 1m performed this annulation reaction to furnish the product 3ma in 95% yield
(entry 12). Delightedly, aliphatic enone 1n underwent the reaction to afford the expected
product 3na in 61% yield (entry 13). Other substituted enones with different protecting
groups were also examined (entries 14–16). Benzenesulfonyl-protected enone 1o worked well
to produce the desired product 3oa in 84% yield (entry 14). In contrast,
p
-nitrobenzenesulfonyl
protected enone (1p) and Boc
-substituted enone (1q) did not undergo this reaction
(entries 15–16).
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Table 3. Substrate Scope of β-Sulfonamido-Substituted Enonesa
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Entry
1
1
1b
1c
1d
1e
1f
R1
R2
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Bs
Ns
Boc
3
t/h
18
3
Yield (%)b
82
drc
13:1
>20:1
14:1
16:1
>20:1
>20:1
>20:1
16:1
8:1
2-FC6H4
3-FC6H4
2-ClC6H4
3-BrC6H4
4-BrC6H4
4-CNC6H4
4-CF3C6H4
3,4-Cl2C6H3
4-MeC6H4
2-OMeC6H4
3-OMeC6H4
4-PhC6H4
Me
3ba
3ca
3da
3ea
3fa
2
91
3
48
6
69
4
83
5
24
18
6
81
6
1g
1h
1i
3ga
3ha
3ia
80
7
90
8
3
93
9
1j
3ja
20
48
18
18
12
12
48
48
75
10
11
12
13
14
15
16
1k
1l
3ka
3la
73
10:1
10:1
16:1
14:1
10:1
-
87
1m
1n
1o
1p
1q
3ma
3na
3oa
3pa
3qa
95
61
C6H5
84
C6H5
trace
trace
C6H5
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a All reactions were performed with 1 (0.12 mmol), 2a (0.1 mmol), n-PrPPh2 (20 mol%) in
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7
DCE (1 mL) at rt. b Isolated yield. c Determined by 1H NMR analysis.
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To demonstrate the synthetic potential of the cycloaddition reaction, a scale-up
preparation of 3aa was performed (Scheme 2). The substituted enones 1a (757 mg, 2.4
mmol) reacted with cyclic imines 2a (366 mg, 2 mmol) under the standard condition to
give 3aa in 88% yield with 13:1 dr. In comparison with the reaction at 0.1 mmol of scale,
no significant loss at yield and diastereoselectivity was observed.
Scheme 2. The Scale-up Reaction
On the basis of the results obtained, a plausible mechanism was proposed. As shown in
Scheme 3, nucleophilic attack of phosphine to β-sulfonamido-substituted enone 1a leads to
β-phosphonium intermediate
A, which interconverts to the intermediate
B through proton
transfer. Subsequent nucleophilic addition of the intermediate
B
to cyclic imine 2a followed
by nucleophilic substitution gives the product 3aa with simultaneous regeneration of
phosphine catalyst. Treatment of sulfamate-derived cyclic imine 2a with n-PrPPh2 did not lead
to any changes that could be observed, therefore, the reaction of sulfamate-derived cyclic
imines with n-PrPPh2 giving phosphonium intermediate has been excluded. In the process of
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the intramolecular nucleophilic substitution, due to big hindrance between benzene ring and
benzoylmethyl group and that between sulfonyl group and benzoylmethyl group,
substitution reaction occurs from position far from benzoylmethyl group, thus resulting in
good diastereoselectivity.
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Scheme 3. A Plausible mechanism.
CONCLUSIONS
In summary, we have developed phosphine-catalyzed [3+2] annulation of β-
sulfonamido-substituted enones with sulfamate-derived cyclic imines. The reaction
proceeded smoothly under mild conditions to afford imidazoline derivatives in moderate
to excellent yields with good to excellent diastereoselectivities. It had a broad substrate
scope for both cyclic imines and substituted enones. In this reaction, β-sulfonamido-
substituted enones acting as phosphine acceptor was activated to achieve the annulation
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reaction, and displayed high potential as a new type of phosphine acceptor for phosphine
catalyzed reactions.
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EXPERIMENTAL SECTION
General Information. All reactions were performed under Ar atmospheres in glassware
with magnetic stirring. Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. All solvents were purified
and dried according to standard methods prior to use. Organic solutions were
concentrated under reduced pressure on a rotary evaporator or an oil pump. Reactions
were monitored through thin layer chromatography (TLC) on silica gel–precoated glass
plates. Chromatograms were visualized by fluorescence quenching with UV light at 254
nm. Flash column chromatography was performed using Qingdao Haiyang flash silica
gel (200-300 mesh). 1H and 13C NMR spectra were recorded in CDCl3 using a 300MHz,
400MHz or 600MHz NMR instrument (referenced internally to Me4Si). Chemical shifts
(δ, ppm) are relative to tetramethylsilane (TMS) with the resonance of the non-
deuterated solvent or TMS as the internal standard. 1H NMR data are reported as follows:
chemical shift, multiplicity (s = singlet; d = doublet; q = quartet; m = multiplet; br
=broad), coupling constant (Hz), and integral. Data for 13C NMR spectra are reported in
terms of chemical shift. Optical rotation was obtained on an Autopol V Plus polarimeter.
Accurate mass measurements were performed on an electrospray ionization (ESI)
apparatus using time-of-flight (TOF) mass spectrometry. HPLC analysis was performed
on Agilent 1100 series and Agilent 1260 series, UV detection monitored at 254 nm,
using a IA column with hexane and
collected using a Gemini E Rigak.
i-PrOH as solvents. X-ray crystallographic data were
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General Procedure for [3+2] Cycloaddition Reaction Catalyzed by
n
-PrPPh2. Under
(0.1 mmol,
(0.12 mmol, 1.2 equiv) was added
PrPPh2 (0.02 mmol, 0.2 equiv) and DCE (1 mL) at room temperature or 40 ℃. Then the
reaction solution was stirred for 1 48h and monitored by TLC. After the reaction was
complete, the mixture was directly purified by column chromatography on silica gel
CH2Cl2 or petroleum ether/EtOAc as the eluent) to furnish the corresponding product
3aa 3ao 3ba 3ma
an argon atmosphere, to a stirred solution of sulfamate-derived cyclic imine
1.0 equiv) and β-sulfonamido-substituted enones
2
1
n-
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–
(
–
,
–
.
General Procedure for the Scaled-up Annulation Reaction. An oven-dried 100 mL
of Schlenk tube was charged with sulfamate-derived cyclic imine 2a (0.36 g 2 mmol),
β-sulfonamido-substituted enones 1a (0.76 g, 2.4 mmol), n-PrPPh2 (0.2 equiv, 91 ul, 0.4
mmol), in 20 mL of DCE for 5 h under Ar atmosphere at 25 °C. Once the starting material was
completely consumed (monitored by TLC), the mixture was concentrated to dryness. The
residue was purified by flash column chromatography to afford the product 3aa (0.88 g, 88%
yield, 13:1 dr).
2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
phenylethan-1-one (3aa). 89% yield (44.4 mg), white solid, mp = 194 – 196 ℃. Eluent: CH2Cl2.
1H NMR (300 MHz, CDCl3) δ 7.86 – 7.78 (m, 2H), 7.73 – 7.57 (m, 4H), 7.53 – 7.39 (m, 3H),
7.38 – 7.29 (m, 3H), 7.04 (dd, J = 8.2, 1.3 Hz, 1H), 6.72 (s, 1H), 4.16 (ddt, J = 11.7, 7.9, 3.6
Hz, 1H), 3.83 (dd, J = 13.9, 8.5 Hz, 1H), 3.64 – 3.41 (m, 2H), 2.49 (s, 3H), 1.92 (dd, J = 18.5,
10.9 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.9, 149.8, 144.8, 135.2, 134.4, 133.5,
131.0, 130.0, 128.3, 128.3, 127.8, 127.6, 126.1, 117.9, 117.6, 77.0, 55.9, 50.7, 43.5, 21.3; IR
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(film) vmax 2922, 1674, 1597, 1450, 1407, 1358, 1204, 1164, 1088, 989, 886, 815, 760, 666,
631, 601, 570, 556, 542 cm-1; HRMS (ESI) calculated for C24H22N2O6S2Na+ [M+Na]+ 521.0811,
found 521.0815.
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2-(9-fluoro-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ab). 76% yield (39.1 mg), white solid, mp =
182 – 184 ℃. Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.77
(m, 2H), 7.72 – 7.66 (m, 2H), 7.66 – 7.58 (m, 1H), 7.52 – 7.41 (m, 2H), 7.41 – 7.28 (m, 3H),
7.19 – 7.09 (m, 1H), 7.04 (dd, J = 9.1, 4.4 Hz, 1H), 6.65 (s, 1H), 4.21 – 4.09 (m, 1H), 3.83 (dd,
J = 13.9, 8.5 Hz, 1H), 3.63 – 3.42 (m, 2H), 2.48 (s, 3H), 1.95 (dd, J = 18.5, 10.9 Hz, 1H);
13C{1H} NMR (75 MHz, CDCl3) δ 196.8, 159.5 (d, J = 246.8 Hz), 145.7 (d, J = 3.0 Hz), 145.0,
135.2, 134.2, 133.6, 130.1, 128.3, 127.8, 127.6, 119.7 (d, J = 8.3 Hz), 118.2 (d, J = 24.0 Hz),
114.9, 114.6, 56.0, 50.8, 43.4, 29.3, 21.3; IR (film) vmax 2926, 1683, 1597, 1487, 1410, 1362,
1256, 1208, 1166, 1089, 1001, 847, 817, 743, 688, 666, 627, 595, 550, 442 cm-1; HRMS (ESI)
calculated for C24H21FN2O6S2Na+ [M+Na]+ 539.0717, found 539.0708.
2-(8-fluoro-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ac). 73% yield (37.7 mg), white solid, mp =
189 – 191 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.77 (m, 2H), 7.72 – 7.58
(m, 4H), 7.47 (dd, J = 8.1, 7.0 Hz, 2H), 7.36 – 7.29 (m, 2H), 7.06 (ddd, J = 8.8, 7.8, 2.5 Hz,
1H), 6.79 (dd, J = 8.5, 2.5 Hz, 1H), 6.67 (s, 1H), 4.15 (ddt, J = 11.6, 8.5, 3.6 Hz, 1H), 3.83 (dd,
J = 13.9, 8.5 Hz, 1H), 3.64 – 3.41 (m, 2H), 2.48 (s, 3H), 1.92 (dd, J = 18.5, 10.9 Hz, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 197.4, 163.7 (d, J = 252.2 Hz), 151.0 (d, J = 12.1 Hz),
145.5, 135.7, 134.8, 134.2, 130.7, 130.6, 130.5, 128.9, 128.4, 128.2, 114.3 (d, J = 22.7 Hz),
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106.3 (d, J = 25.7 Hz), 56.6, 51.3, 44.0, 21.9; IR (film) vmax 2922, 1682, 1621, 1596, 1498,
1408, 1360, 1244, 1204, 1165, 1136, 1088, 988, 971, 857, 797, 665, 599, 580, 565, 536, 441
cm-1; HRMS (ESI) calculated for C24H21FN2O6S2Na+ [M+Na]+ 539.0717, found 539.0719.
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2-(7-fluoro-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ad). 94% yield (48.6 mg), white solid, mp =
169 – 171 ℃. Eluent: petroleum ether/EtOAc (5:1). 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.77
(m, 2H), 7.73 – 7.65 (m, 2H), 7.65 – 7.58 (m, 1H), 7.51 – 7.41 (m, 3H), 7.37 – 7.27 (m, 3H),
7.26 – 7.17 (m, 1H), 6.73 (s, 1H), 4.18 (ddt, J = 11.5, 10.3, 3.3 Hz, 1H), 3.83 (dd, J = 14.0, 8.4
Hz, 1H), 3.66 – 3.41 (m, 2H), 2.48 (s, 3H), 1.94 (dd, J = 18.5, 10.9 Hz, 1H); 13C{1H} NMR
(75 MHz, CDCl3) δ 196.7, 150.1 (d, J = 251.3 Hz), 145.0, 138.4 (d, J = 14.3 Hz), 135.2, 134.3,
133.6, 130.1, 128.3, 127.8, 127.6, 125.6 (d, J = 6.8 Hz), 123.0 (d, J = 4.5 Hz), 119.8, 117.8,
117.6, 76.9, 56.0, 50.7, 43.4, 21.3; IR (film) vmax 1682, 1596, 1477, 1410, 1358, 1305, 1272,
1208, 1180, 1161, 1119, 1089, 976, 866, 790, 772, 689, 666, 614, 591, 556, 542, 492, 448 cm-
1; HRMS (ESI) calculated for C24H21FN2O6S2Na+ [M+Na]+ 539.0717, found 539.0718.
2-(8-chloro-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ae). 93% yield (49.6 mg), white solid, mp =
185 – 187 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.83 – 7.77 (m, 2H), 7.71 – 7.66
(m, 2H), 7.65 – 7.58 (m, 2H), 7.46 (ddd, J = 8.1, 6.7, 1.2 Hz, 2H), 7.35 – 7.28 (m, 3H), 7.07 (d,
J = 2.0 Hz, 1H), 6.66 (s, 1H), 4.14 (ddt, J = 10.9, 8.5, 3.7 Hz, 1H), 3.82 (dd, J = 14.0, 8.5 Hz,
13
1H), 3.63 – 3.40 (m, 2H), 2.48 (s, 3H), 1.92 (dd, J = 18.5, 10.9 Hz, 1H); C{1H} NMR (75
MHz, CDCl3) δ 196.7, 150.1, 144.9, 136.4, 135.2, 134.3, 133.6, 130.1, 129.4, 128.3, 127.8,
127.6, 126.5, 118.2, 116.3, 56.0, 50.7, 43.4, 21.3; IR (film) vmax 2924, 2360, 1682, 1597, 1575,
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1480, 1449, 1405, 1359, 1205, 1178, 1164, 1122, 1088, 1000, 918, 814, 769, 670, 661, 640,
602, 571, 560, 545, 432 cm-1; HRMS (ESI) calculated for C24H21ClN2O6S2Na+ [M+Na]+
555.0422, found 555.0428.
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2-(7-chloro-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3af). 69% yield (31.5 mg), white solid, mp =
185 – 187 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.77 (m, 2H), 7.73 – 7.64
(m, 2H), 7.64 – 7.56 (m, 2H), 7.54 – 7.39 (m, 3H), 7.36 – 7.28 (m, 2H), 7.25 (d, J = 8.0 Hz,
1H), 6.71 (s, 1H), 4.24 – 4.12 (m, 1H), 3.83 (dd, J = 14.0, 8.5 Hz, 1H), 3.65 – 3.42 (m, 2H),
2.48 (s, 3H), 1.92 (dd, J = 18.5, 11.0 Hz, 1H);13C{1H} NMR (75 MHz, CDCl3) δ 196.7, 145.8,
145.0, 135.2, 134.2, 133.6, 131.6, 130.1, 128.3, 127.8, 127.6, 126.6, 125.9, 123.0, 119.6, 77.0,
56.1, 50.7, 43.4, 21.3; IR (film) vmax 2360, 1682, 1597, 1446, 1410, 1359, 1198, 1164, 1118,
1089, 993, 921, 855, 815, 782, 763, 666, 599, 581, 556, 542, 508, 473, 440 cm-1; HRMS (ESI)
calculated for C24H21ClN2O6S2Na+ [M+Na]+ 555.0422, found 555.0421.
2-(8-bromo-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ag). 73% yield (42.1 mg), white solid, m.p.
193 – 195 ℃. Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.76
(m, 2H), 7.72 – 7.64 (m, 2H), 7.63 – 7.58 (m, 1H), 7.54 (dd, J = 8.4, 0.8 Hz, 1H), 7.51 – 7.41
(m, 3H), 7.31 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 6.64 (s, 1H), 4.14 (ddt, J = 11.6,
7.3, 3.6 Hz, 1H), 3.82 (dd, J = 14.0, 8.5 Hz, 1H), 3.63 – 3.40 (m, 2H), 2.48 (s, 3H), 1.91 (dd, J
= 18.5, 10.9 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.7, 150.0, 144.9, 135.2, 134.2,
133.6, 130.1, 129.6, 129.4, 128.3, 127.8, 127.6, 124.0, 121.1, 116.8, 76.7, 56.0, 50.7, 43.4, 21.3;
IR (film) vmax 2921, 1684, 1596, 1474, 1414, 1399, 1352, 1204, 1165, 1120, 1089, 991, 897,
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810, 765, 687, 667, 637, 600, 569, 558, 542, 491cm-1; HRMS (ESI) calculated for
C24H21BrN2O6S2Na+ [M+Na]+ 600.9898, found 600.9890.
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2-(8-methyl-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
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c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ah). 46% yield (23.6 mg), white solid, mp =
210 – 212 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.75 (m, 2H), 7.72 – 7.66
(m, 2H), 7.64 – 7.57 (m, 1H), 7.52 – 7.39 (m, 3H), 7.35 – 7.28 (m, 2H), 7.18 – 7.08 (m, 1H),
6.85 (dd, J = 1.6, 0.8 Hz, 1H), 6.68 (s, 1H), 4.19 – 4.08 (m, 1H), 3.82 (dd, J = 13.9, 8.6 Hz,
1H), 3.62 – 3.41 (m, 2H), 2.48 (s, 3H), 2.39 (d, J = 0.9 Hz, 3H), 1.90 (dd, J = 18.5, 10.9 Hz,
1H); 13C{1H} NMR (75 MHz, CDCl3) δ 197.0 149.7, 144.7, 141.8, 135.3, 134.5, 133.5, 130.0,
128.3, 127.9, 127.8, 127.6, 127.0, 118.1, 114.4, 77.0, 55.8, 50.7, 43.5, 21.3, 20.8; IR (film) vmax
2921, 1669, 1596, 1449, 1406, 1356, 1196, 1164, 1087, 992, 948, 795, 665, 625, 603, 588, 570,
535 cm-1; HRMS (ESI) calculated for C25H24N2O6S2Na+ [M+Na]+ 535.0968, found 535.0974.
2-(7-methyl-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ai). 80% yield (41.1 mg), white solid, mp =
189 – 191 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.78 (m, 2H), 7.72 – 7.66
(m, 2H), 7.63 – 7.53 (m, 1H), 7.52 – 7.40 (m, 4H), 7.32 (d, J = 8.1 Hz, 2H), 7.20 (t, J = 7.6 Hz,
1H), 6.71 (s, 1H), 4.15 (ddt, J = 11.4, 7.3, 3.5 Hz, 1H), 3.82 (dd, J = 14.0, 8.5 Hz, 1H), 3.63 –
3.40 (m, 2H), 2.49 (d, J = 2.9 Hz, 3H), 2.30 (s, 3H), 1.94 (dd, J = 18.5, 10.9 Hz, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 197.0, 148.3, 144.7, 135.3, 134.5, 133.5, 132.3, 130.0, 128.3, 127.8,
127.6, 127.3, 125.7, 125.3, 117.3, 77.2, 55.9, 50.7, 43.5, 21.3, 15.0; IR (film) vmax 1682, 1597,
1449, 1404, 1358, 1203, 1156, 1087, 989, 910, 866, 796, 757, 689, 667, 612, 600, 584, 557,
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542, 442 cm-1; HRMS (ESI) calculated for C25H24N2O6S2Na+ [M+Na]+ 535.0968, found
535.0967.
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2-(8-isopropyl-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3aj). 71% yield (38.6 mg), white solid, mp =
192 – 194 ℃. Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.76
(m, 2H), 7.72 – 7.65 (m, 2H), 7.64 – 7.57 (m, 1H), 7.54 (dd, J = 8.1, 0.9 Hz, 1H), 7.51 – 7.40
(m, 2H), 7.35 – 7.28 (m, 2H), 7.18 (dd, J = 8.1, 1.7 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H), 6.68 (s,
1H), 4.14 (ddt, J = 10.7, 5.4, 3.6 Hz, 1H), 3.83 (dd, J = 13.8, 8.5 Hz, 1H), 3.61 – 3.42 (m, 2H),
2.93 (p, J = 6.9 Hz, 1H), 2.48 (s, 3H), 1.93 (dd, J = 18.6, 10.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 197.0, 152.8, 149.8, 144.7, 135.3, 134.5, 133.5, 130.0, 128.3,
128.0, 127.8, 127.6, 124.5, 115.5, 114.7, 77.0, 55.8, 50.7, 43.5, 33.5, 23.3, 23.2, 21.3; IR (film)
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v
max 2963, 1682, 1624, 1597, 1449, 1404, 1358, 1198, 1164, 1089, 992, 946, 881, 815, 791, 688,
666, 617, 600, 583, 567, 541, 484 cm-1; HRMS (ESI) calculated for C27H28N2O6S2Na+ [M+Na]+
563.1281, found 563.1281.
2-(9-(tert-butyl)-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ak). 72% yield (40.0 mg), white solid, mp =
192 – 194 ℃. Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.80
(m, 2H), 7.76 – 7.70 (m, 2H), 7.65 – 7.57 (m, 1H), 7.53 – 7.39 (m, 5H), 7.37 – 7.30 (m, 2H),
6.96 (d, J = 8.7 Hz, 1H), 6.68 (s, 1H), 4.18 (ddd, J = 14.3, 7.4, 3.3 Hz, 1H), 3.82 (dd, J = 13.9,
8.4 Hz, 1H), 3.69 – 3.47 (m, 2H), 2.49 (s, 3H), 2.14 (dd, J = 18.5, 10.9 Hz, 1H), 1.32 (s, 9H);
13C{1H} NMR (75 MHz, CDCl3) δ 197.0, 149.4, 147.6, 144.7, 135.3, 134.7, 133.5, 128.3, 128.1,
127.8, 127.6, 124.4, 117.5, 116.8, 55.9, 50.7, 43.5, 34.4, 30.9, 30.9, 21.3; IR (film) vmax 2964,
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1682, 1597, 1490, 1405, 1361, 1180, 1165, 1124, 1089, 1000, 930, 847, 815, 772, 688, 670,
659, 598, 573, 558, 540, 484 cm-1; HRMS (ESI) calculated for C28H30N2O6S2Na+ [M+Na]+
577.1437, found 577.1430.
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2-(8-(tert-butyl)-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3al). 86% yield (47.7 mg), white solid, mp =
186 – 188 ℃. Eluent: petroleum ether/EtOAc (5:1). 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.77
(m, 2H), 7.73 – 7.66 (m, 2H), 7.65 – 7.52 (m, 2H), 7.51 – 7.41 (m, 2H), 7.37 – 7.28 (m, 3H),
7.02 (d, J = 1.9 Hz, 1H), 6.68 (s, 1H), 4.15 (ddt, J = 11.8, 9.1, 3.6 Hz, 1H), 3.82 (dd, J = 13.9,
8.5 Hz, 1H), 3.61 – 3.43 (m, 2H), 2.48 (s, 3H), 1.96 (dd, J = 18.5, 10.9 Hz, 1H), 1.33 (s, 9H);
13C{1H} NMR (75 MHz, CDCl3) δ 197.0, 155.2, 149.6, 144.7, 135.3, 134.5, 133.5, 130.0, 128.3,
127.8, 127.7, 127.6, 123.4, 114.7, 114.4, 77.0, 55.8, 50.7, 43.5, 34.6, 30.7, 21.3; IR (film) vmax
2964, 1682, 1597, 1449, 1403, 1359, 1201, 1164, 1087, 1000, 938, 812, 771, 688, 665, 617,
600, 580, 564, 536, 496, 458 cm-1; HRMS (ESI) calculated for C28H30N2O6S2Na+ [M+Na]+
577.1437, found 577.1434.
2-(7-(tert-butyl)-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3am). 37% yield (20.5 mg), white solid, mp =
220 – 222 ℃. Eluent: petroleum ether/EtOAc (6:1). 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.78
(m, 2H), 7.69 (dq, J = 8.7, 1.8 Hz, 2H), 7.66 – 7.58 (m, 1H), 7.57 – 7.51 (m, 1H), 7.51 – 7.40
(m, 4H), 7.31 (d, J = 8.1 Hz, 2H), 6.71 (s, 1H), 4.21 – 4.11 (m, 1H), 3.87 (dd, J = 13.9, 8.5 Hz,
1H), 3.63 – 3.44 (m, 2H), 2.48 (s, 3H), 1.92 (dd, J = 18.6, 10.9 Hz, 1H), 1.41 (s, 9H); 13C{1H}
NMR (75 MHz, CDCl3) δ 197.1, 149.0, 144.7, 139.2, 135.3, 134.5, 133.5, 130.0, 128.5, 128.3,
127.8, 127.6, 126.2, 125.4, 77.2, 56.2, 50.7, 43.6, 34.6, 29.6, 21.3; IR (film) vmax 2962, 1682,
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1597, 1405, 1359, 1199, 1163, 1086, 1000, 911, 866, 813, 688, 666, 593, 559, 545, 477, 452
cm-1; HRMS (ESI) calculated for C28H30N2O6S2Na+ [M+Na]+ 577.1437, found 577.1438.
2-(8-methoxy-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
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c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3an). 38% yield (20.0 mg), white solid, mp =
185 – 187 ℃. Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.76
(m, 2H), 7.73 – 7.64 (m, 2H), 7.63 – 7.58 (m, 1H), 7.56 – 7.42 (m, 4H), 7.31 (d, J = 8.0 Hz,
2H), 6.87 (dd, J = 8.7, 2.5 Hz, 1H), 6.66 (s, 1H), 6.54 (d, J = 2.5 Hz, 1H), 4.14 (ddt, J = 11.7,
7.4, 3.6 Hz, 1H), 3.90 – 3.76 (m, 4H), 3.63 – 3.40 (m, 2H), 2.48 (s, 3H), 1.91 (dd, J = 18.5, 10.9
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.9, 161.3, 150.6, 144.7, 135.3, 134.5, 133.5,
130.0, 129.0, 128.3, 127.8, 127.6, 112.9, 109.1, 102.6, 76.9, 55.9, 55.4, 50.6, 43.5, 21.3; IR
(film) vmax 2360, 1683, 1624, 1506, 1405, 1358, 1248, 1202, 1166, 1097, 1001, 957, 796, 666,
616, 600, 582, 541 cm-1; HRMS (ESI) calculated for C25H24N2O7S2Na+ [M+Na]+ 551.0917,
found 551.0913.
2-(7-methoxy-5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3ao). 94% yield (49.6 mg), white solid, mp =
215 – 217 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.76 (m, 2H), 7.72 – 7.66
(m, 2H), 7.65 – 7.56 (m, 1H), 7.51 – 7.39 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 – 7.19 (m,
2H), 6.99 (dd, J = 7.1, 2.5 Hz, 1H), 6.71 (s, 1H), 4.17 (ddt, J = 11.4, 7.4, 3.6 Hz, 1H), 3.90 (s,
3H), 3.82 (dd, J = 13.8, 8.6 Hz, 1H), 3.63 – 3.41 (m, 1H), 2.48 (s, 3H), 1.92 (dd, J = 18.5, 10.9
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.9, 148.0, 140.6, 135.3, 134.5, 133.5, 130.0,
128.3, 127.8, 127.6, 127.6, 125.5, 119.0, 118.6, 113.0, 56.0, 55.9, 50.7, 43.5, 21.3; IR (film)
v
max 1682, 1597, 1481, 1457, 1405, 1358, 1321, 1276, 1204, 1161, 1120, 1083, 1000, 865, 792,
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667, 599, 542 cm-1; HRMS (ESI) calculated for C25H24N2O7S2Na+ [M+Na]+ 551.0917, found
551.0911.
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
(2-fluorophenyl)ethan-1-one (3ba). 82% yield (42.5 mg), white solid, mp = 183 – 185 ℃.
Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.77 (m, 2H), 7.68
– 7.51 (m, 5H), 7.43 (dddd, J = 8.1, 7.3, 1.8, 0.7 Hz, 1H), 7.38 – 7.28 (m, 3H), 7.04 (dd, J =
8.2, 1.2 Hz, 1H), 6.71 (s, 1H), 4.22 – 4.07 (m, 1H), 3.80 (dd, J = 13.9, 8.5 Hz, 1H), 3.64 – 3.38
(m, 2H), 2.49 (s, 3H), 1.93 (dd, J = 18.5, 10.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
194.8, 194.8, 161.8 (d, J = 254.3 Hz), 149.8, 145.2, 135.2 (d, J = 9.0 Hz), 134.1, 130.9, 130.1,
130.0, 129.9, 128.4, 127.6, 126.0, 124.3 (d, J = 3.0 Hz), 123.8, 123.6, 117.9, 117.6, 116.3 (d, J
= 23.3 Hz), 55.5, 55.5, 50.9, 48.4, 48.3, 21.3; IR (film) vmax 2922, 1679, 1609, 1481, 1453, 1405,
1357, 1202, 1165, 1089, 994, 889, 814, 762, 667, 630, 595, 571, 543 cm-1; HRMS (ESI)
calculated for C24H21FN2O6S2Na+ [M+Na]+ 539.0717, found 539.0727.
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
(3-fluorophenyl)ethan-1-one (3ca). 91% yield (47.1 mg), white solid, mp = 180 – 182 ℃.
Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.78 (m, 2H), 7.65
(ddd, J = 7.7, 1.8, 0.8 Hz, 1H), 7.50 – 7.39 (m, 3H), 7.38 – 7.27 (m, 5H), 7.04 (dd, J = 8.2, 1.2
Hz, 1H), 6.72 (s, 1H), 4.20 – 4.09 (m, 1H), 3.81 (dd, J = 14.0, 8.5 Hz, 1H), 3.60 – 3.36 (m, 2H),
2.50 (s, 3H), 1.90 (dd, J = 18.6, 10.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 195.69,
195.66, 162.41 (d, J = 247.5 Hz), 149.82, 144.95, 137.24 (d, J = 6.8 Hz), 134.4, 131.1, 130.1,
130.1, 130.0, 128.2, 127.8, 126.1, 123.4, 123.3, 120.6 (d, J = 26.3 Hz), 117.9, 117.5, 114.3 (d,
J = 25.0 Hz), 77.1, 55.7, 50.6, 43.6, 21.3; IR (film) vmax 1684, 1589, 1484, 1447, 1405, 1359,
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1306, 1246, 1207, 1163, 1088, 991, 888, 814, 761, 681, 666, 633, 589, 570, 557, 542, 478 cm-
1; HRMS (ESI) calculated for C24H21FN2O6S2Na+ [M+Na]+ 539.0717, found 539.0721.
1-(2-chlorophenyl)-2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)ethan-1-one (3da). 69% yield (37 mg), white solid, mp = 158 – 160 ℃.
Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.77 (m, 2H), 7.72
– 7.64 (m, 1H), 7.50 – 7.27 (m, 8H), 7.04 (dd, J = 8.2, 1.3 Hz, 1H), 6.70 (s, 1H), 4.18 – 4.08
(m, 1H), 3.83 (dd, J = 13.8, 8.5 Hz, 1H), 3.64 – 3.43 (m, 2H), 2.39 (s, 3H), 2.08 – 1.92 (m, 1H);
13C{1H} NMR (75 MHz, CDCl3) δ 199.1, 149.7, 144.9, 136.8, 134.2, 132.4, 131.2, 131.0, 130.6,
130.0, 129.1, 128.3, 127.7, 126.7, 126.1, 117.9, 117.6, 77.1, 55.6, 50.8, 47.5, 21.2; IR (film)
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v
max 1684, 1589, 1454, 1405, 1356, 1306, 1204, 1163, 1089, 989, 888, 826, 758, 666, 631, 594,
570, 556, 542, 483 cm-1; HRMS (ESI) calculated for C24H21ClN2O6S2Na+ [M+Na]+ 555.0422,
found 555.0419.
1-(3-bromophenyl)-2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)ethan-1-one (3ea). 83% yield (48.1 mg), white solid, mp = 188 –
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190 ℃. Eluent: petroleum ether/EtOAc (4:1). H NMR (300 MHz, CDCl3) δ 7.85 – 7.77 (m,
3H), 7.73 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.43 (tdd, J = 7.3, 1.8, 0.9 Hz,
1H), 7.39 – 7.29 (m, 4H), 7.04 (dd, J = 8.2, 1.2 Hz, 1H), 6.71 (s, 1H), 4.14 (ddt, J = 10.8, 8.5,
3.6 Hz, 1H), 3.81 (dd, J = 14.0, 8.5 Hz, 1H), 3.55 (dd, J = 14.0, 3.9 Hz, 1H), 3.47 – 3.36 (m,
1H), 2.52 (s, 3H), 1.92 (dd, J = 18.7, 10.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 195.6,
149.8, 145.0, 136.9, 136.4, 134.4, 131.0, 130.6, 130.0, 129.9, 128.2, 127.8, 126.1, 122.7, 117.9,
117.5, 77.0, 55.6, 50.7, 43.6, 21.5; IR (film) vmax 1684, 1454, 1406, 1358, 1203, 1165, 1089,
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995, 888, 815, 763, 667, 633, 584, 570, 556, 542 cm-1; HRMS (ESI) calculated for
C24H21BrN2O6S2Na+ [M+Na]+ 600.9898, found 600.9889.
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1-(4-bromophenyl)-2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)ethan-1-one (3fa). 81%yield (46.9 mg), white solid, mp = 211 –
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213 ℃. Eluent: petroleum ether/EtOAc (4:1). H NMR (300 MHz, CDCl3) δ 7.86 – 7.76 (m,
3H), 7.69 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.58 (dddd, J = 8.3, 7.1, 5.0, 1.9 Hz, 1H), 7.43 (dddd,
J = 8.2, 7.4, 1.8, 0.7 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.26 – 7.00 (m, 3H), 6.71 (s, 1H), 4.13 (ddt,
J = 11.6, 7.7, 3.6 Hz, 1H), 3.84 (dd, J = 13.8, 8.5 Hz, 1H), 3.54 (dd, J = 13.9, 4.0 Hz, 1H), 3.50
– 3.37 (m, 1H), 2.47 (s, 3H), 1.91 (ddd, J = 19.5, 10.9, 3.9 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3) δ 195.9, 149.8, 144.8, 134.4, 134.0, 131.7, 131.0, 130.0, 129.0, 128.8, 128.2, 127.8,
126.1, 117.9, 117.6, 77.0, 55.7, 50.7, 43.4, 21.4; IR (film) vmax 2918, 1672, 1585, 1483, 1453,
1407, 1348, 1309, 1205, 1165, 1089, 1072, 991, 907, 887, 814, 762, 668, 632, 595, 570, 555,
542, 496, 477, 462 cm-1; HRMS (ESI) calculated for C24H21BrN2O6S2Na+ [M+Na]+ 600.9898,
found 600.9866.
4-(2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-
yl)acetyl)benzonitrile (3ga). 80% yield (41.8 mg), white solid, mp = 205 – 207 ℃. Eluent:
petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.90 – 7.74 (m, 6H), 7.60 (dt, J =
7.5, 1.3 Hz, 1H), 7.48 – 7.39 (m, 1H), 7.37 – 7.29 (m, 3H), 7.05 (dd, J = 8.2, 1.2 Hz, 1H), 6.71
(s, 1H), 4.16 (ddt, J = 11.6, 7.5, 3.6 Hz, 1H), 3.80 (dd, J = 14.0, 8.5 Hz, 1H), 3.65 – 3.46 (m,
2H), 2.49 (s, 3H), 2.12 (dd, J = 18.7, 10.7 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 195.7,
149.8, 144.8, 138.0, 134.5, 132.2, 131.0, 130.0, 128.1, 128.0, 127.9, 126.1, 118.0, 117.5, 117.2,
116.9, 76.9, 55.6, 50.6, 43.7, 21.4; IR (film) vmax 2920, 1687, 1456, 1407, 1350, 1207, 1163,
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1087, 992, 908, 888, 814, 769, 666, 633, 599, 571, 542, 481 cm-1; HRMS (ESI) calculated for
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C25H22N3O6S2 [M+H]+ 524.0945, found 524.0939.
+
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
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(4-(trifluoromethyl)phenyl)ethan-1-one (3ha). 90% yield (51.0 mg), white solid, mp = 193 –
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195 ℃. Eluent: petroleum ether/EtOAc (4:1). H NMR (300 MHz, CDCl3) δ 7.87 – 7.79 (m,
4H), 7.73 (d, J = 8.4 Hz, 2H), 7.65 – 7.60 (m, 1H), 7.50 – 7.39 (m, 1H), 7.37 – 7.29 (m, 3H),
7.04 (dd, J = 8.2, 1.2 Hz, 1H), 6.72 (s, 1H), 4.16 (ddt, J = 10.6, 8.3, 3.6 Hz, 1H), 3.81 (dd, J =
13.9, 8.4 Hz, 1H), 3.64 – 3.47 (m, 2H), 2.48 (s, 3H), 2.05 (dd, J = 18.7, 10.8 Hz, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 196.0, 149.8, 144.8, 137.8, 134.5, 131.0, 130.0, 128.2, 128.0, 127.8,
126.1, 125.4 (q, J = 3.9Hz), 124.9, 121.3, 117.9, 117.5, 77.0, 55.7, 50.6, 43.7, 21.3; IR (film)
vmax 1686, 1454, 1407, 1359, 1323, 1205, 1163, 1127, 1109, 1089, 1065, 994, 889, 824, 758,
667, 634, 592, 570, 555, 542, 481 cm-1; HRMS (ESI) calculated for C25H21F3N2O6S2Na+
[M+Na]+ 589.0685, found 589.0688.
1-(3,4-dichlorophenyl)-2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)ethan-1-one (3ia). 93% yield (53.3 mg), white solid, mp = 203 –
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205 ℃. Eluent: petroleum ether/EtOAc (4:1). H NMR (300 MHz, CDCl3) δ 7.86 – 7.78 (m,
2H), 7.73 (t, J = 1.2 Hz, 1H), 7.64 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.55 (d, J = 1.2 Hz, 2H), 7.48
– 7.29 (m, 4H), 7.04 (dd, J = 8.2, 1.2 Hz, 1H), 6.71 (s, 1H), 4.13 (ddt, J = 10.6, 8.4, 3.6 Hz,
1H), 3.80 (dd, J = 13.9, 8.5 Hz, 1H), 3.62 – 3.33 (m, 2H), 2.52 (s, 3H), 1.94 (dd, J = 18.6, 10.8
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 194.7, 149.8, 145.0, 138.3, 134.7, 134.4, 133.1,
131.0, 130.5, 130.0, 129.5, 128.2, 127.9, 126.6, 126.1, 117.9, 117.5, 77.0, 55.6, 50.7, 43.5, 21.4;
IR (film) vmax 2923, 1684, 1584, 1454, 1405, 1357, 1307, 1202, 1164, 1118, 1089, 1031, 1019,
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993, 888, 814, 761, 666, 634, 608, 588, 570, 558, 542, 481, 434 cm-1; HRMS (ESI) calculated
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for C24H21Cl2N2O6S2 [M+H]+ 567.0213, found 567.0206.
+
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
(p-tolyl)ethan-1-one (3ja). 75% yield (38.6 mg), white solid, mp = 228 – 230 ℃. Eluent:
CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.77 (m, 2H), 7.71 – 7.63 (m, 1H), 7.61 – 7.54
(m, 2H), 7.43 (dddd, J = 8.1, 7.3, 1.8, 0.7 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.25 – 7.18 (m, 1H),
7.04 (dd, J = 8.2, 1.3 Hz, 1H), 6.71 (s, 1H), 4.20 – 4.09 (m, 1H), 3.82 (dd, J = 13.9, 8.5 Hz,
1H), 3.62 – 3.38 (m, 2H), 2.49 (s, 3H), 2.44 (s, 3H), 1.89 (dd, J = 18.4, 10.9 Hz, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 196.5, 149.8, 144.8, 144.5, 134.4, 132.8, 130.9, 130.0, 129.0, 128.3,
127.8, 127.7, 126.0, 117.9, 117.6, 77.1, 55.9, 50.8, 43.4, 29.3, 21.4, 21.3; IR (film) vmax 2917,
2360, 1683, 1541, 1507, 1457, 1407, 1361, 1205, 1167, 1089, 991, 887, 815, 668, 633, 600,
571, 543 cm-1; HRMS (ESI) calculated for C25H24N2O6S2Na+ [M+Na]+ 535.0968, found
535.0963.
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
(2-methoxyphenyl)ethan-1-one (3ka). 73% yield (38.5 mg), white solid, mp = 193 – 195 ℃.
Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.91 – 7.77 (m, 2H), 7.67
(ddd, J = 7.1, 5.0, 1.6 Hz, 2H), 7.58 – 7.49 (m, 1H), 7.47 – 7.36 (m, 1H), 7.34 – 7.22 (m, 3H),
7.11 – 6.90 (m, 3H), 6.65 (s, 1H), 4.13 (ddt, J = 11.5, 7.9, 4.0 Hz, 1H), 3.86 (s, 3H), 3.83 – 3.57
(m, 3H), 2.42 (s, 3H), 2.18 (dd, J = 18.9, 10.9 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
198.2, 158.8, 149.8, 144.5, 134.4, 134.2, 130.8, 130.0, 129.8, 128.4, 127.7, 126.0, 120.4, 117.8,
111.4, 76.9, 56.1, 55.2, 51.1, 48.7, 21.3; IR (film) vmax 1662, 1596, 1484, 1454, 1408, 1354,
1306, 1243, 1207, 1162, 1119, 1103, 1089, 1019, 993, 888, 826, 813, 759, 667, 631, 594, 570,
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557, 543 cm-1; HRMS (ESI) calculated for C25H24N2O7S2Na+ [M+Na]+ 551.0917, found
551.0909.
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2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-yl)-1-
(3-methoxyphenyl)ethan-1-one (3la). 87% yield (45.8 mg), white solid, mp = 164 – 166 ℃.
Eluent: petroleum ether/EtOAc (4:1). 1H NMR (300 MHz, CDCl3) δ 7.85 – 7.78 (m, 2H), 7.67
(ddd, J = 7.7, 1.8, 0.9 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.38 – 7.28 (m, 4H), 7.26 – 7.11 (m, 3H),
7.04 (dd, J = 8.2, 1.2 Hz, 1H), 6.71 (s, 1H), 4.20 – 4.09 (m, 1H), 3.86 (s, 3H), 3.83 – 3.75 (m,
1H), 3.61 – 3.39 (m, 2H), 2.49 (s, 3H), 1.90 (dd, J = 18.5, 11.0 Hz, 1H); 13C{1H} NMR (75
MHz, CDCl3) δ 196.8, 159.6, 149.8, 144.9, 136.6, 134.4, 130.9, 130.1, 129.3, 128.3, 127.8,
126.1, 120.2, 119.6, 117.9, 117.6, 112.2, 77.0, 55.9, 55.2, 50.7, 43.6, 21.3; IR (film) vmax 1676,
1582, 1402, 134, 1250, 1206, 1163, 1119, 1102, 1087, 1041, 988, 887, 864, 823, 815, 784, 762,
667, 635, 592, 570, 555, 542, 481, 446 cm-1; HRMS (ESI) calculated for C25H24N2O7S2Na+
[M+Na]+ 551.0917, found 551.0911.
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1-([1,1'-biphenyl]-4-yl)-2-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)ethan-1-one (3ma).95% yield (54.5 mg), white solid, mp = 195 –
1
197 ℃. Eluent: petroleum ether/EtOAc (4:1). H NMR (300 MHz, CDCl3) δ 7.87 – 7.73 (m,
4H), 7.72 – 7.61 (m, 5H), 7.55 – 7.40 (m, 4H), 7.33 (td, J = 7.6, 1.3 Hz, 3H), 7.05 (dd, J = 8.2,
1.2 Hz, 1H), 6.74 (s, 1H), 4.18 (ddt, J = 11.4, 7.4, 3.5 Hz, 1H), 3.84 (dd, J = 13.9, 8.5 Hz, 1H),
3.66 – 3.46 (m, 2H), 2.51 (s, 3H), 1.97 (dd, J = 18.4, 10.9 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3) δ 196.5, 149.8, 146.2, 144.8, 139.2, 134.4, 133.9, 131.0, 130.1, 128.7, 128.3, 128.2,
127.9, 126.9, 126.90, 126.1, 117.9, 117.6, 77.1, 55.9, 50.8, 43.5, 21.4; IR (film) vmax 1676, 1603,
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1453, 1404, 1358, 1206, 1165, 1089, 992, 888, 825, 762, 666, 632, 594, 570, 556, 542, 482 cm-
1; HRMS (ESI) calculated for C30H26N2O6S2Na+ [M+Na]+ 597.1124, found 597.1118.
1-(5,5-dioxido-1-tosyl-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazin-3-
yl)propan-2-one (3na). 61% yield (26.6 mg), white solid, mp = 166 – 168 ℃. Eluent: CH2Cl2.
1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H), 7.48 – 7.36
(m, 3H), 7.31 (dd, J = 7.6, 1.1 Hz, 1H), 7.01 (dd, J = 8.2, 0.9 Hz, 1H), 6.63 (s, 1H), 3.93 (ddd,
J = 14.8, 7.9, 3.8 Hz, 1H), 3.71 (dd, J = 13.6, 8.5 Hz, 1H), 3.46 (dd, J = 13.7, 4.2 Hz, 1H), 3.00
(dd, J = 18.9, 3.2 Hz, 1H), 2.52 (s, 3H), 1.99 (s, 3H), 1.74 – 1.55 (m, 1H); 13C{1H} NMR (75
MHz, CDCl3) δ 205.5, 149.7, 145.0, 134.3, 130.9, 129.9, 128.2, 127.8, 126.0, 117.9, 117.5,
76.8, 55.1, 50.8, 47.7, 29.4, 21.4; IR (film) vmax 1683, 1449, 1407, 1362, 1206, 1170, 1090,
1002, 909, 890, 827, 763, 721, 688, 651, 633, 614, 595, 571, 555 cm-1; HRMS (ESI) calculated
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for C23H20N2O6S2 [M+H]+ 485.0836, found 485.0834.
+
2-(5,5-dioxido-1-(phenylsulfonyl)-1,2,3,10b-tetrahydrobenzo[e]imidazo[1,2-
c][1,2,3]oxathiazin-3-yl)-1-phenylethan-1-one (3oa). 84% yield (40.7 mg), white solid, mp =
163 – 165 ℃. Eluent: CH2Cl2. 1H NMR (300 MHz, CDCl3) δ 7.98 – 7.91 (m, 1H), 7.76 – 7.67
(m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.57 (dd, J = 15.3, 7.4 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.33 (td,
J = 7.6, 1.1 Hz, 1H), 7.04 (dd, J = 8.2, 0.9 Hz, 1H), 6.72 (s, 1H), 4.15 (tt, J = 10.6, 3.3 Hz, 1H),
3.84 (dd, J = 13.8, 8.5 Hz, 1H), 3.55 (ddd, J = 21.5, 16.1, 3.5 Hz, 1H), 2.02 (dd, J = 18.4, 10.9
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.9, 149.8, 137.4, 135.2, 133.7, 133.6, 131.0,
129.5, 128.5, 128.4, 128.2, 127.8, 127.6, 127.5, 126.1, 117.9, 117.5, 77.0, 55.9, 50.9, 43.5; IR
(film) vmax 1457, 1406, 1362, 1275, 1266, 1209, 1168, 1001, 893, 815, 764, 750, 729, 701, 668,
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581, 571, 544, 439, 419, 414, 402; HRMS (ESI) calculated for C19H20N2O6S2 [M+H]+
+
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437.0836, found 437.0833.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:.
NMR data for all new compounds 1 and 3 (PDF)
X-ray crystal data for 3ao (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: hchguo@cau.edu.cn, xiaoyumei@cau.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work is supported by the Natural Science Foundation of China (Nos. 21572264,
21871293) and Chinese Universities Scientific Fund (Nos. 2018TC052, 2018TC055).
REFERENCES
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