Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2-Dioxides Catalyzed by Cinchona Alkaloid-based Primary Amines

Article abstract of DOI:10.1002/asia.201601149

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2-dioxides could be successfully carried out utilizing a combination of cinchona alkaloid-derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89–97 % ee and with various aryl methyl ketones in 85–98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.

Full text of DOI:10.1002/asia.201601149

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Accepted Article
Title: Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Ben-
zo[e][1,2,3]oxathiazine 2,2-Dioxides Catalyzed by Cinchona Alkaloid-based
Primary Amines
Authors: Xiao-Yu Cui; Hui-Xin Duan; Yongna Zhang; You-Qing Wang
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Chemistry - An Asian Journal
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Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic
Imines Benzo[e][1,2,3]oxathiazine 2,2-Dioxides Catalyzed by
Cinchona Alkaloid-based Primary Amines
Xiao-Yu Cui, Hui-Xin Duan, Yongna Zhang,* and You-Qing Wang*[a]
Dedication ((optional))
Abstract: Aryl ketones represent problematic substrates for
asymmetric Mannich reactions due to a large steric hindrance
exhibited by this compound species. A highly enantioselective direct
Mannich reaction of aryl methyl ketones with cyclic imines
benzo[e][1,2,3]oxathiazine 2,2-dioxides could be successfully carried
out, utilizing a combination of cinchona alkaloid derived primary
amines with TFA, for the primary amines feature a superior catalytic
efficacy over secondary amines with a variety of sterically hindered
carbonyl compounds as substrates. The reaction proceeded well
with various cyclic imines in 89-97% ee, and with various aryl methyl
ketones in 85-98% ee. Moreover, aryl carbonyl of a Mannich product
could be transformed to ketoxime, further undergoing a Beckmann
rearrangement to produce an amide compound while maintaining
enantioselectivity.
ketones in the asymmetric Mannich reaction via Brønsted acid
catalysis was realized by Gong[5] and Rueping[6]. Unfortunately,
the substrate scope was narrow (no more than two
acetophenone derivatives could be used as Mannich donors)
and the corresponding enantioselectivities were modest (34-86%
ee).[5-6] Using Brønsted base catalysis, an enolate-mediated
three-component Mannich reaction of unfunctionalized aryl
ketones was reported by Zhao and co-works.[7] Wang & Loh et al.
demonstrated a highly enantioselective Mannich reaction of N-
sulfonyl cyclic ketimines with ketones using amino
sulfonohydrazides as organocatalysts. Here, only one example
of acetophenone as a donor provided a moderate ee (80%).[8]
More recently, our group reported the highly enantioselective
direct Mannich reaction of acetophenone derivatives with seven-
membered imines catalyzed by (S)-azetidine-2-carboxylic acid.[9]
Although this reaction proceeds via an enamine-based
organocatalysis, four-membered (S)-azetidine-2-carboxylic acid
was chosen as a catalyst rather than the most common five-
membered (S)-proline. This resulted in a reasonable reactivity
so as to loss a few ee values. Furthermore, aryl β-ketoacids
have been successfully employed as enolate equivalents
instead of aryl methyl ketone donors through decarboxylative
Mannich reactions.[10] Aryl methyl ketones, such as
acetophenone, are simple, cheap, and easily accessible
chemicals widely used in organic synthesis. In this regard, the
direct extension to acetophenone derivatives in asymmetric
Mannich reactions would be of particular interest.[11-12]
Introduction
Mannich reactions are particularly useful techniques in organic
chemistry for the synthesis of β-amino carbonyl derivatives, via
formation of new carbon-carbon bonds.[1] Corresponding
asymmetric Mannich-type reactions have been the subject of
extensive investigations over the past decades, and a number of
highly enantioselective catalytic methodologies have been
reported.[2] Within this area, in the last ten years, organocatalysis
has played a crucial role in the development of asymmetric
Mannich reactions. Particularly the activation of carbonyl
nucleophiles using chiral secondary amine derivatives has been
an area of research that has attracted significant attention.[2c,2d]
Considering for depending on the formation of highly reactive
enamine intermediates, efficient Mannich donors mainly consist
of alkyl aldehydes or ketones.[2-3] In sharp contrast, aryl ketones,
e.g. acetophenone and tetralone derivatives, represent
challenging substrates that have been explored to a much lesser
extent. The presence of α-aryl functionalities in the carbonyl
compounds results in twisted and less reactive enamines
intermediates due to low orbital overlap between the enamine
double bond and the nitrogen lone pair as a consequence of
bigger steric hindrance (Scheme 1).[4] Applications of aryl methyl
Scheme 1. Secondary and primary amine catalysis through enamine
intermediate in Mannich reactions of aryl methyl ketones.
[a]
X.-Y. Cui, H.-X. Duan, Y. Dr. Zhang, Prof. Dr. Y.-Q. Wang
Key Laboratory of Polyoxometalate Chemistry of Henan Province,
Key Laboratory of Natural Medicine and Immuno-Engineering of
Henan Province, College of Chemistry and Chemical Engineering
Henan University
Widening the scope of either the acceptors or the donors
employable in the asymmetric Mannich addition is a crucial
feature to gain access to the diversity of products and reaction
types. Compared with the most extensively studied acyclic imine
Kaifeng, Henan 475004, P. R. China
E-mail: zhangyongna@henu.edu.cn; wyouqing@hotmail.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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acceptors, cyclic imines have been rarely explored for
enantioselective Mannich reactions.[2] A variety of reports can be
found in the literature describing a few highly enantioselective
Mannich reactions of cyclic imines in organocatalysis to
construct N-heterocycles with β-carbonyl groups.[9,10c,10d,10e,13-14]
The catalytic asymmetric addition to cyclic sulfonyl imines 1 has
been shown to be an efficient method for the synthesis of chiral
benzo-fused cyclic sulfamidate heterocycles,[15] which can
undergo a nucleophilic displacement to convert optically active
amines.[16] Moreover, our group reported the highly
enantioselective direct Mannich reaction of alkyl ketones with
cyclic sulfonyl imines 1 using a cinchona alkaloid derived
primary amine as an organocatalyst.[14b] Primary amines as
catalysts generally feature a small steric hindrance compared to
secondary amines.[17] Therefore, we anticipate that the use of
sterically less-hindered primary amines may result in a higher
observed activity for Mannich additions of less flexible aryl
methyl ketones (Scheme 1). In an effort to continue the studies
on Mannich reactions of cyclic imines,[9,14] we hereby report
highly enantioselective Mannich reactions of cyclic sulfonyl
imines 1 with aryl methyl ketones catalyzed by combining a
cinchona alkaloid derived primary amine with TFA.
Temp.
(oC)
Time
(h)
Yield
(%)[b]
ee
Entry
Catalyst
Solvent
(%)[c]
1
2
C1
C2
C3
C4
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
25
25
25
25
10
40
40
40
40
40
40
40
40
40
40
96
96
96
96
96
96
96
96
96
96
96
96
19
96
24
51
64
39
57
66
83
52
69
0
94
96
3
-84[d]
-91[d]
98
4
5
Results and Discussion
6
98
Cinchona-based primary amine catalysts have been
successfully developed for the functionalization of carbonyl
compounds in asymmetric reactions.[17b,17c,17e] Therefore, for the
investigation of catalysts, we focused our studies on the primary
amines C1-4 that are, easily derived from natural cinchona
alkaloids. The Mannich reactions were optimized using six-
membered cyclic imine 1a and acetophenone 2a as the model
substrates, and results were listed in Table 1. First, the catalytic
effects of four cinchona alkaloid derived primary amines C1-4
were examined (entries 1-4). All primary amine catalysts were
effective in promoting the Mannich reactions, with quinine-
derived primary amine C2 demonstrating the best
enantioselectivity (entry 2). Next, we investigated the effect of
reaction temperature on the reaction outcome. When the
7
87
8
CHCl3
90
9
THF
-
10
11
12
13
14
15
CH3CN
MeOH
19
31
48
94
92
98
45
57
Benzene
o-xylene
m-xylene
p-xylene
94
95
96
97
o
temperature was decreased to 10 C, the ee was found to be
slightly improved while retaining reactivity (entry 5). Interestingly,
increasing the temperature to 40 C resulted in an improved 83%
[a] Unless otherwise noted, reactions were conducted with imine 1a (0.1
mmol), acetophenone 2a (0.5 mmol), primary amine C1-4 (0.01 mmol, 10
mol%) and TFA (0.02 mmol, 20 mol%) in 1.0 mL of solvent. [b] Isolated
yield. [c] Determined by HPLC using a chiral column. [d] The minus ee
value indicates that the opposite enantiomer was obtained as the major
form.
o
yield and 98% ee (entry 6). The subsequent screening different
solvent demonstrated that the reaction worked well in aromatic
solvents (entries 12-15). More specifically, p-xylene furnished
the best results compared to other solvents tested, and the
reaction time could be shortened significantly, with full
conversion achieved after 24 hours (entry 15). Upon comparing
the optical rotation of the Mannich product 3aa, we found that
the compound exhibits an opposite sign than what has been
reported in the literature, indicating that enantiomers are
obtained.[10d] Therefore, the absolute configuration of compound
3aa could be assigned (S-configuration).
Various cyclic imines 1 were tested with acetophenone 2a as
precursor for this Mannich reaction under optimized reaction
conditions (Table 1, entry 15) and the results can be found
summarized in Table 2. The corresponding Mannich products 3
were obtained in excellent yields and high enantioselectivities
using different substituted cyclic imines
1 bearing either
electron-donating or electron-withdrawing substituents on the
phenyl ring (entries 1-7). Additionally, cyclic imines 1i-l, bearing
two substituent groups on the phenyl ring, were also found to be
suitable for this Mannich reaction, affording slightly lower
Table 1. Optimization of reaction conditions.[a]
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enantioselectivities (89-93% ee) than those of the non-
substituented cyclic imines (entries 8-11). Moreover, a cyclic
imine 1l bearing two tert-butyl groups on the phenyl ring acting
as a strong steric hindrance of the substrate, proved to be
suitable for this reaction type to afford good yield and high
enantioselectivities (93% ee), even though an increased reaction
time was required to complete the sequence (entry 11). When a
cyclic imine 1m bearing a diethylamino group was used, the
reaction failed to proceed (entry 12).
and shorter reaction times than electron-withdrawing
substituents (entries 1-4). Furthermore, the relative reactivity of
the aryl methyl ketones decreased in the order: Br>Cl>F. This
order is the exact opposite of the electronegativity of halogen
atoms. The ortho-substituted aryl methyl ketone 2i resulted in a
relatively lower yield and enantioselectivity than the para- or
meta- substituted species, likely due to the effect of steric
repulsion (entry 8 vs 6 or 7). Aryl methyl ketones bearing two
substituents on the phenyl ring were also applicable to this
Mannich reaction. As expected, ketone 2k bearing ortho-chlorine
on the phenyl group resulted in a lower activity (entries 9-10).
Using the 2-naphthyl-derived ketone 2l resulted in a quantitative
yield with high ee values (entry 11). Noteworthy, several
heteroaryl methyl ketones 2m, 2n, 2o and 2p were also found to
be suitable and the desired Mannich reaction products 3am, 3an
and 3ap were obtained in high yields and with high
enantioselectivities (entries 12-13 and 15). However the
Table 2. Substrate scope of cyclic imines for asymmetric Mannich
reaction.[a]
corresponding product 3ao bearing
a S-heteroatom was
obtained in only moderate yield but with high enantioselectivity
(entry 14).
Entry
1
X (1)
Time (h)
40
3
Yield (%)[b]
ee (%)[c]
93
6-OMe (1b)
7-OMe (1c)
8-OMe (1d)
6-Me (1e)
6-F (1f)
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
-
99
90
99
98
97
99
99
99
99
87
92
0
Table 3. Substrate scope of aryl methyl ketones for asymmetric Mannich
reaction.[a]
2
63
93
3
22
94
4
22
94
5
24
95
6
6-Cl (1g)
20
94
Entry
1
Ar (2)
Time (h)
96
3
Yield (%)[b]
ee (%)[c]
95
7
6-Br (1h)
17
94
p-Br-C6H4 (2b)
p-Cl-C6H4 (2c)
p-F-C6H4 (2d)
p-NO2-C6H4 (2e)
p-MeO-C6H4 (2f)
p-Me-C6H4 (2g)
m-Me-C6H4 (2h)
o-Me-C6H4 (2i)
3,4-Me2-C6H4 (2j)
2,4-Cl2-C6H4 (2k)
2-naphthyl (2l)
2-pyridinyl (2m)
2-furanyl (2n)
3ab
3ac
3ad
3ae
3af
86
71
56
66
88
99
99
35
96
32
99
92
92
51
90
8
6,8-Cl2 (1i)
6,8-Br2 (1j)
6-Cl, 8-Br (1k)
6,8-tBu2 (1l)
6-NEt2 (1m)
17
91
2
96
96
9
25
89
3
96
94
10
11
12
23
91
4
96
90
66
93
5
18
93
96
-
6
40
3ag
3ah
3ai
92
[a] Reaction conditions: imine 1 (0.15 mmol), acetophenone 2a (0.75
mmol), C2 (0.015 mmol, 10 mol%) and TFA (0.03 mmol, 20 mol%) in p-
xylene (1.5 mL) at 40°C. [b] Isolated yield. [c] Determined by HPLC using a
chiral column.
7
40
96
8
96
88
9
16
3aj
96
Next, various aryl methyl ketones were examined for this
asymmetric Mannich reaction by using imine 1a as an electron-
acceptor. As listed in Table 3, much various aryl methyl ketones,
e.g. with both electron-withdrawing and electron-donating
substituents in different positions on the phenyl rings or
heteroaryl groups bearing various N-, O-, S-heteroatoms, were
found to be well tolerated, and the corresponding Mannich
products could be produced with high enantioselectivities.
Furthermore, we found that the electronic nature of the
substituents affected on the reactivity. For example, the
substituted electron-donating aryl methyl ketones in the para-
position on the phenyl ring (entries 5-6) afforded better yields
10
11
12
13
14
15
96
3ak
3al
85
48
95
20
3am
3an
3ao
3ap
94
36
95
2-thienyl (2o)
108
36
93
3-thienyl (2p)
98
[a] Reaction conditions: imine 1 (0.15 mmol), acetophenone 2a (0.75
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mmol), C2 (0.015 mmol, 10 mol%) and TFA (0.03 mmol, 20 mol%) in p-
xylene (1.5 mL) at 40°C. [b] Isolated yield. [c] Determined by HPLC using a
chiral column.
The further transformation of the obtained, highly enantio-rich
Mannich products 3 was studied, and an example can be found
illustrated in Scheme 3. The carbonyl group of compound 3aa
could be easily transformed into the corresponding ketoxime in
the presence of hydroxylamine hydrochloride and potassium
acetate. The AlCl3 catalyzed Beckmann rearrangement[19] of
A proposed transition state for the enantioselective Mannich
addition to give S adducts 3 as the major enantiomer is shown in
Figure 1. Both sulfone oxygen atoms of imines 1 can form two
hydrogen bonds with organocatalyst to creat a good chiral
environment.[3c] Nucleophilic carbon of enamines formed from
aryl methyl ketones and primary amine attacks the imines 1 from
the Si-face. The predominant production of S adducts 3 is
reasonably explained by this transition-state model.
ketoxime
4 provided the amide 5 in 94% yield. The
enantioselectivity of amide 5 was determined to be 98% ee as
judged by chiral HPLC. This finding indicates that the optical
purity can indeed be completely retained throughout the entire
process.
Conclusions
In conclusion, we have successfully developed a highly
enantioselective Mannich reaction of aryl methyl ketones with
cyclic sulfonyl imine benzo[e][1,2,3]oxathiazine 2,2-dioxides.
The combination of cinchona alkaloid derived primary amine
with TFA was found to be the most efficient organocatalyst for
this Mannich addition. A range of different aryl methyl ketones
bearing moieties with different electronic properties and steric
hindrance characteristics could be successfully employed in this
highly enantioselective reaction types..
Figure 1. Proposed transition state and observed S adducts 3.
Experimental Section
To evaluate the overall practicability of the present synthetic
method, this Mannich reaction was also performed on a gram
scale (Scheme 2). The Mannich product 3aa was obtained in
91% yield with 98% ee after flash column chromatographic
purification. The reaction on this larger scale proceeded
smoothly, without any detrimental effects on enantioselectivity.
Compared with the decarboxylative Mannich reaction of β ‑
ketoacid to obtain Mannich product 3aa,[10d] this direct Mannich
reaction of aryl methyl ketones can be carried out with: easily
obtained acetophenone used as a substrate[18] and the reaction
proceeds with higher operational simplicity and with higher ee
values.
General methods
1H NMR, and 13C NMR spectra were recorded on Bruker DRX-400/300
spectrometers. Chemical shifts were recorded in ppm (δ), and the
residual solvent peak was used as an internal reference: proton
(chloroform δ 7.26, DMSO δ 2.50, acetone δ 2.05), carbon (chloroform δ
77.0, DMSO δ 39.5). Flash column chromatography was performed on
silica gel (200-300 mesh). TLC analysis was performed using glass-
backed plates coated with 0.2 mm silica. After elution, plate was
visualized under at 254 nm UV illumination. The following abbreviations
were used for elution solvents: PE = petroleum ether, EA = ethyl acetate.
All commercially available compounds were used as provided without
further purification. The solvents were distilled from appropriate drying
agents prior to use, unless otherwise noted. Cyclic imines 1 were
prepared according to our published papers.[14b,15d]
Typical procedure and data of asymmetric Mannich reaction (Table
1, 2 and 3)
To the mixture of quinine-NH2 C2 (0.015 mmol, 10 mol%) and cyclic
imine 1 (0.15 mmol) in p-xylene (1.45 mL) was added the solution of TFA
(0.03 mmol, 20 mol%) in p-xylene (0.05 mL). After the reaction mixture
was heated to 40°C, acetophenone (0.75 mmol) was added. This
reaction mixture was stirred in showed reaction time. Direct purification
reaction mixture by column chromatography on a silica gel gave the
desired Mannich products. The enantiomeric excess was determined by
HPLC. Racemic Mannich products were obtained with the combination of
10 mol% benzyl amine and 20 mol% TFA.
Scheme 2. Mannich reaction of cyclic imine 1a with acetophenone 2a at a
gram scale.
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Scheme 3. Transformation of Mannich product 3aa.
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
CDCl3) δ 7.99-7.97 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.10 (d, J = 8.5 Hz, 1H), 6.96-6.93 (m, 2H), 5.77 (d, J = 7.9 Hz, 1H),
5.37 (td, J = 7.7, 3.5 Hz, 1H), 4.27 (dd, J = 18.2, 7.5 Hz, 1H), 3.40 (dd, J
= 18.2, 3.6 Hz, 1H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.7,
149.0, 136.1, 135.2, 134.1, 130.2, 128.9, 128.2, 126.2, 121.1, 118.8,
53.6, 42.1, 20.8; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 11.1 min (major, S), t2 = 22.1 min (minor).
phenylethan-1-one (3aa):[10d] White solid; m.p. 127.1-128.0 °C; Rf = 0.35
(CH2Cl2); 97% ee, [α]25D = 48.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.98-7.96 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H),
7.33-7.28 (m, 1H), 7.15 (d, J = 4.2 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 5.91
(s, 1H), 5.42 (dd, J = 7.3, 3.7 Hz, 1H), 4.28 (dd, J = 18.2, 7.3 Hz, 1H),
3.41 (dd, J = 18.2, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 197.8,
151.3, 136.2, 134.2, 129.6, 128.9, 128.3, 126.0, 125.5, 121.7, 119.2,
53.7, 41.8; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 8.6 min (major, S), t2 = 16.7 min (minor).
(S)-2-(6-fluoro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
phenylethan-1-one (3fa):[10d] White solid; m.p. 86.2-87.1 °C; Rf = 0.17
(CH2Cl2); 95% ee, [α]25D = 53.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.98-7.95 (m, 2H), 7.66-7.60 (m, 1H), 7.50 (t, J = 7.40 Hz, 2H), 7.04-
7.00 (m, 2H), 6.89-6.86 (m, 1H), 5.94 (d, J = 8.3 Hz, 1H), 5.38 (td, J = 7.5,
3.9 Hz, 1H), 4.23 (dd, J = 18.3, 7.1 Hz, 1H), 3.43 (dd, J = 18.3, 3.9 Hz,
(S)-2-(6-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-
1-phenylethan-1-one (3ba):[10d] White solid; m.p. 114.3-115.1 °C; Rf =
0.22 (CH2Cl2); 93% ee, [α]25 = -4.4 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
1
CDCl3) δ 7.99-7.96 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz,
2H), 7.10 (dd, J = 8.1, 1.1 Hz, 1H), 6.94-6.91 (m, 2H)), 5.87 (d, J = 7.9
Hz, 1H), 5.38 (td, J = 7.8, 3.6 Hz, 1H), 4.26 (dd, J = 18.2, 7.7 Hz, 1H),
3.38 (dd, J = 18.2, 3.7 Hz, 1H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
197.8, 149.0, 136.1, 135.2, 134.1, 130.2, 128.8, 128.2, 126.3, 121.1
118.8, 53.6, 42.1, 20.8; HPLC (Chiralcel IC column, hexane/iPrOH =
70/30, 0.8 mL/min, 254 nm): t1 = 9.6 min (major, S), t2 = 17.9 min (minor).
1H); 13C NMR (75 MHz, CDCl3) δ 197.4, 159.3 (d, JF-C = 244.2 Hz),
147.0 (d, 4JF-C = 2.7 Hz), 135.9, 134.3, 128.9, 128.2, 123.2 (d, 3JF-C = 7.0
2
Hz), 120.7 (d, 3JF-C = 8.4 Hz), 116.6 (d, 2JF-C = 23.5 Hz), 112.7 (d, JF-C
=
4
24.8 Hz), 53.4 (d, JF-C = 1.6 Hz), 41.7; HPLC (Chiralcel IC column,
hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1 = 7.6 min (major, S), t2 =
13.2 min (minor).
(S)-2-(6-chloro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
phenylethan-1-one (3ga):[10d] White solid; m.p. 102.9-103.5 °C; Rf = 0.33
(CH2Cl2); 94% ee, [α]25D = -8.9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.98-7.95 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H),
7.29-7.26 (m, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.95
(d, J = 8.3 Hz, 1H), 5.38 (td, J = 7.7, 3.8 Hz, 1H), 4.25 (dd, J = 18.3, 7.2
Hz, 1H), 3.43 (dd, J = 18.3, 3.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
197.3, 149.7, 135.9, 134.3, 130.7, 129.7, 128.9, 128.2, 125.9, 123.2,
120.5, 53.3, 41.7; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 7.1 min (major, S), t2 = 12.0 min(minor).
(S)-2-(7-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-
1-phenylethan-1-one (3ca): White solid; m.p. 144.0-144.5 °C; Rf = 0.15
(CH2Cl2); 93% ee, [α]25D = 50.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.96 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 8.09 Hz,
2H), 7.03 (d, J = 8.7 Hz, 1H), 6.69 (dd, J = 8.7, 2.6 Hz, 1H), 6.56 (d, J =
2.5 Hz, 1H), 5.94 (d, J = 8.0 Hz, 1H), 5.34 (td, J = 7.5, 3.8 Hz, 1H), 4.22
(dd, J = 18.1, 7.3 Hz, 1H), 3.78 (s, 3H), 3.36 (dd, J = 18.1, 3.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 198.0, 160.3, 151.9, 136.2, 134.1, 128.9,
128.2, 126.5, 113.2, 112.3, 103.8, 55.6, 53.3, 41.7; HRMS (ESI): m/z
calculated for C16H15NNaO5S [M+Na]+ 356.0569, found: 356.0542; HPLC
(Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1
11.9 min (major, S), t2 = 23.9min (minor).
=
(S)-2-(6-bromo-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
phenylethan-1-one (3ha):[10d] White solid; m.p. 103.1-104.0 °C; Rf = 0.26
(CH2Cl2); 94% ee, [α]25 = -26.8 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
(S)-2-(8-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-
CDCl3) δ 7.99-7.96 (m, 2H), 7.67-7.62 (m, 1H), 7.54-7.49 (m, 2H), 7.43
(dd, J = 8.7, 2.2 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H),
5.85 (d, J = 8.3 Hz, 1H), 5.38 (td, J = 7.6, 3.8 Hz, 1H), 4.25 (dd, J = 18.3,
7.1 Hz, 1H), 3.44 (dd, J = 18.3, 3.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
197.4, 150.2, 135.8, 134.3, 132.5, 128.9, 128.2, 123.6, 120.8, 118.1,
53.1, 42.0; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 7.3 min (major, S), t2 = 12.7 min (minor).
1-phenylethan-1-one (3da): White solid; m.p. 174.5-175.5 °C; Rf = 0.20
(PE/EA, 3:1); 94% ee, [α]25 = 38.2 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.98-7.95 (m, 2H), 7.65-7.60 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H),
7.07 (t, J = 8.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H),
5.85 (d, J = 7.9 Hz, 1H), 5.40 (td, J = 7.6, 3.6 Hz, 1H), 4.28 (dd, J = 18.2,
7.2 Hz, 1H), 3.89 (s, 3H), 3.40 (dd, J = 18.2, 3.7 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 197.7, 149.0, 136.1, 134.1, 128.9, 125.1, 122.6, 116.9,
111.9, 56.2, 53.8, 41.6; HRMS (ESI): m/z calculated for C16H15NNaO5S
[M+Na]+ 356.0569, found: 356.0540; HPLC (Chiralcel IC column,
hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1 = 16.4 min (major, S), t2
= 43.6 min (minor).
(S)-2-(6,8-dichloro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-
1-phenylethan-1-one (3ia): White solid; m.p. 111.8-112.3 °C; Rf = 0.28
(CH2Cl2); 91% ee, [α]25D = 40.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.97-7.94 (m, 2H), 7.67-7.62 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.39 (d, J
= 2.3 Hz, 1H), 7.06-7.05 (m, 1H), 6.12 (d, J = 8.3 Hz, 1H), 5.39 (td, J =
7.4, 3.8 Hz, 1H), 4.25 (dd, J = 18.4, 7.0 Hz, 1H), 3.44 (dd, J = 18.4, 3.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.2, 145.9, 135.7, 134.4, 130.3,
130.1, 129.0, 128.2, 125.0, 124.6, 124.3, 53.4, 41.7; HRMS (ESI): m/z
(S)-2-(6-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
phenylethan-1-one (3ea):[10d] White solid; m.p. 112.5-113.5 °C; Rf = 0.45
(PE/EA, 3:1); 94% ee, [α]25 = 4.3 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
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calculated for C15H11Cl2NNaO4S [M+Na]+ 393.9684, found: 393.9679;
HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm):
t1 = 6.0 min (major, S), t2 = 10.3 min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(4-
fluorophenyl)ethan-1-one (3ad):[10d] White solid; m.p. 104.5-105.3 °C; Rf
1
= 0.51 (PE/EA, 3:1); 95% ee, [α]25 = 28.9 (c 1.0, CHCl3); H NMR (300
D
MHz, CDCl3) δ 8.02-7.98 (m, 2H), 7.31-7.29 (m, 1H), 7.19-7.13 (m, 4H),
7.05 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 5.43-5.41 (m, 1H), 4.26 (dd, J =
18.1, 7.6 Hz, 1H), 3.36 (dd, J = 18.1, 3.2 Hz, 1H); 13C NMR (75 MHz,
(S)-2-(6,8-dibromo-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-
yl)-1-phenylethan-1-one (3ja): White solid; m.p. 165.4-166.1 °C; Rf = 0.41
(CH2Cl2); 89% ee, [α]25D = 46.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 7.4 Hz, 2H), 7.55-7.48 (m, 2H),
7.37 (t, J = 7.6 Hz, 2H), 7.11 (s, 1H), 5.97 (dd, J = 17.2, 9.0 Hz, 1H), 5.26
(d, J = 2.8 Hz, 1H), 4.12 (dd, J = 18.4, 7.1 Hz, 1H), 3.30 (dd, J = 18.4, 3.6
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.2, 147.3, 135.7, 134.4, 128.9,
128.3, 128.0, 125.0, 117.9, 113.8, 53.3, 41.9; HRMS (ESI): m/z
calculated for C15H11Br2NNaO4S [M+Na]+ 483.8653, found: 483.8629;
HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm):
t1 = 6.3 min (major, S), t2 = 11.1 min (minor).
1
4
CDCl3) δ 196.1, 166.3 (d, JF-C = 255.2 Hz), 151.1, 132.6 (d, JF-C = 3.0
3
2
Hz), 131.0 (d, JF-C = 9.5 Hz), 129.6, 125.7 (d, JF-C = 37.7 Hz), 121.4,
119.1, 116.01 (d, 2JF-C = 21.9 Hz), 53.6, 42.0; HPLC (Chiralcel IC column,
hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1 = 7.8 min (major, S), t2 =
14.7min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(4-
nitrophenyl)ethan-1-one (3ae): White solid; m.p. 117.6-118.3 °C; Rf =
0.41 (PE/EA, 3:1); 90% ee, [α]25 = 10.8 (c 1.0, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 8.36-8.33 (m, 2H), 8.15 (d, J = 8.9 Hz, 2H), 7.38-7.33 (m,
1H), 7.23-7.16 (m, 2H), 7.09 (d, J = 8.7 Hz, 1H), 5.57 (d, J = 7.8 Hz, 1H),
5.47 (td, J = 7.7, 3.4 Hz, 1H), 4.38 (dd, J = 18.2, 8.2 Hz, 1H), 3.39 (dd, J
= 18.2, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 196.2, 151.0, 150.8,
140.4, 129.9, 129.4, 126.2, 125.7, 124.1, 121.0, 119.2, 53.4, 43.3; HRMS
(ESI): m/z calculated for C15H13NNaO4S [M+Na]+ 371.0314, found:
371.0314; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 19.5 min (major, S), t2 = 32.6 min (minor).
(S)-2-(8-bromo-6-chloro-2,2-dioxido-3,4-
dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-phenylethan-1-one (3ka): White
solid; m.p. 140.1-141.0 °C; Rf = 0.40 (CH2Cl2); 91% ee, [α]25 = 43.9 (c
D
1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 2H), 7.68-7.61
(m, 1H), 7.57-7.50 (m, 3H), 7.09 (dd, J = 2.2, 0.7 Hz, 1H), 5.96-5.91(m,
1H), 5.40-5.34 (m, 1H), 4.25 (dd, J = 18.5, 6.7 Hz, 1H), 3.46 (dd, J = 18.4,
3.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.2, 146.8, 135.6, 134.4,
132.9, 130.7, 129.0, 128.2, 125.1, 124.6, 113.5, 53.4, 41.8; HRMS (ESI):
m/z calculated for C15H11BrClNNaO4S [M+Na]+ 437.9178, found:
439.9181; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 6.2 min (major, S), t2 = 10.7 min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(4-
methoxyphenyl)ethan-1-one (3af):[10d] White solid; m.p. 144.5-145.3 °C;
Rf = 0.37 (PE/EA, 3:1); 93% ee, [α]25 = 86.4 (c 1.0, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 7.94 (d, J = 8.7 Hz, 2H), 7.32-7.26 (m, 1H), 7.15-
7.10 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.09 (d, J
= 7.7 Hz, 1H), 5.41-5.35 (m, 1H), 4.22 (dd, J = 17.9, 7.2 Hz, 1H), 3.88 (s,
3H), 3.34 (dd, J = 17.9, 3.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 196.2,
164.3, 151.2, 130.7, 129.5, 129.2, 125.9, 125.4, 121.7, 119.0, 114.0,
55.6, 53.8, 41.1; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 14.3 min (major, S), t2 = 27.1min (minor).
(S)-2-(6,8-di-tert-butyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-
4-yl)-1-phenylethan-1-one (3la): White solid; m.p. 127.9-128.3 °C; Rf =
0.40 (PE/EA, 5:1); 93% ee, [α]25 = -7.4 (c 1.0, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6
Hz, 2H), 7.34 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 5.81 (d, J = 7.4
Hz, 1H), 5.41 (td, J = 7.8, 3.6 Hz, 1H), 4.30 (dd, J = 17.9, 8.2 Hz, 1H),
3.34 (dd, J = 17.9, 3.7 Hz, 1H), 1.43 (s, 9H), 1.24 (s, 9H) 13C NMR (75
MHz, CDCl3) δ 198.1, 148.1, 147.6, 139.4, 136.3, 134.0, 128.8, 128.2,
124.3, 121.9, 120.9, 54.0, 42.8, 35.1, 34.6, 31.3, 30.0; HRMS (ESI): m/z
calculated for C23H29NNaO4S [M+Na]+ 439.1749, found: 439.1739; HPLC
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(p-
tolyl)ethan-1-one (3ag):[10d] White solid; m.p. 140.1-141.0 °C; Rf = 0.57
(PE/EA, 3:1); 92% ee, [α]25 = 54.9 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
(Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1
5.9 min (major, S), t2 = 7.7 min (minor).
=
CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.28-7.26 (m, 3H), 7.14-7.10 (m, 2H),
7.02 (d, J = 8.2 Hz, 1H), 5.41-5.37 (m, 2H), 4.23 (dd, J = 18.1, 7.3 Hz,
1H), 3.36 (dd, J = 18.0, 3.5 Hz, 1H), 2.41 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 197.4, 151.1, 145.2, 133.6, 129.5, 129.5, 128.3, 126.0 125.4,
121.6, 119.0, 53.6, 41.6, 21.7; HPLC (Chiralcel IC column, hexane/iPrOH
= 70/30, 0.8 mL/min, 254 nm): t1 = 10.7 min (major, S), t2 = 22.2min
(minor).
(S)-1-(4-bromophenyl)-2-(2,2-dioxido-3,4-
dihydrobenzo[e][1,2,3]oxathiazin-4-yl)ethan-1-one (3ab):[10d] White solid;
m.p. 140.4-141.2 °C; Rf = 0.54 (PE/EA, 3:1); 95% ee, [α]25D = 30.2 (c 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.62 (d, J
= 8.1 Hz, 2H), 7.34-7.29 (m, 1H), 7.19-7.14 (m, 2H), 7.03 (d, J = 8.2 Hz,
1H), 5.90-5.88 (m, 1H), 5.42 (td, J = 7.8, 3.4 Hz, 1H), 4.25 (dd, J = 18.1,
7.8 Hz, 1H), 3.34 (dd, J = 18.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
196.8, 151.0, 134.8, 132.2, 129.7, 129.6, 129.5, 126.1, 125.5, 121.3,
119.1, 53.5, 42.2; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 7.9 min (major, S), t2 = 15.3min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(m-
tolyl)ethan-1-one (3ah):[10d] White solid; m.p. 135.8-136.5 °C; Rf = 0.56
(PE/EA, 3:1); 97% ee, [α]25 = 53.8 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.77-7.76 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.39-7.35 (m, 1H),
7.33-7.28 (m, 1H), 7.15 (dd, J = 10.5, 2.5 Hz, 1H), 7.04 (d, J = 8.2 Hz,
1H), 5.98 (d, J = 8.2 Hz, 1H), 5.41 (td, J = 7.7, 3.7 Hz, 1H), 4.27 (dd, J =
18.2, 7.3 Hz, 1H), 3.40 (dd, J = 18.2, 3.7 Hz, 1H), 2.41 (s, 1H);13C NMR
(100 MHz, CDCl3) δ 197.9, 151.2, 138.8, 136.1, 134.9, 129.5, 128.73,
128.70, 125.9, 125.44, 125.42, 121.6, 119.0, 53.6, 41.8, 21.3; HPLC
(S)-1-(4-chlorophenyl)-2-(2,2-dioxido-3,4-
dihydrobenzo[e][1,2,3]oxathiazin-4-yl)ethan-1-one (3ac):[10d] White solid;
m.p. 117.6-118.5 °C; Rf = 0.57 (PE/EA, 3:1); 96% ee, [α]25D = 27.4 (c 1.0,
1
(Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1
9.9 min (major, S), t2 = 19.4 min (minor).
=
CHCl3); H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.45 (d, J
= 8.2 Hz, 2H), 7.34-7.29 (m, 1H), 7.19-7.15 (m, 2H), 7.04 (d, J = 8.2 Hz,
1H), 5.88 (d, J = 7.9 Hz, 1H), 5.42 (td, J = 7.8, 3.5 Hz, 1H), 4.26 (dd, J =
18.1, 7.8 Hz, 1H), 3.34 (dd, J = 18.1, 3.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 196.5, 151.1, 140.7, 134.4, 129.6, 129.2, 126.0, 125.5, 121.3,
119.1, 53.5, 42.1; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 8.0 min (major, S), t2 = 15.6min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(o-
tolyl)ethan-1-one (3ai):[10d] White solid; m.p. 149.9-150.6 °C; Rf = 0.58
(PE/EA, 3:1); 88% ee, [α]25 = 20.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.72 (d, J = 7.7 Hz, 1H), 7.43 (td, J = 7.5, 1.0 Hz, 1H), 7.34-7.30
(m, 2H), 7.27 (s, 1H), 7.17-7.12 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 5.94 (d,
J = 8.3 Hz, 1H), 5.36 (td, J = 7.8, 3.6 Hz, 1H), 4.18 (dd, J = 18.0, 7.3 Hz,
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1H), 3.38 (dd, J = 18.0, 3.7 Hz, 1H), 2.43 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 201.3, 151.3, 139.0, 136.6, 132.4, 132.3, 129.6, 128.9, 126.0,
125.8, 125.4, 121.5, 119.1, 54.0, 43.9, 21.4; HPLC (Chiralcel IC column,
hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1 = 8.4 min (major, S), t2 =
12.6 min (minor).
HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm):
t1 = 15.2min (major, S), t2 = 37.2 min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(thiophen-
2-yl)ethan-1-one (3ao): White solid; m.p. 161.9-162.6 °C; Rf = 0.22
(CH2Cl2); 93% ee, [α]25 = -12.4 (c 1.0, CH3OH); 1H NMR (300 MHz,
D
(S)-1-(3,4-dimethylphenyl)-2-(2,2-dioxido-3,4-
DMSO-d6) δ 8.75 (s, 1H), 8.07-7.99 (m, 2H), 7.52 (d, J = 6.5 Hz, 1H),
7.39 (t, J = 7.0 Hz, 1H), 7.28-7.26 (m, 2H), 7.12 (d, J = 7.9 Hz, 1H), 5.27
(d, J = 8.5 Hz, 1H), 3.94 (dd, J = 16.4, 10.4 Hz, 1H), 3.59-3.54 (m, 1H);
13C NMR (75 MHz, DMSO-d6) δ 189.4, 150.8, 143.5, 135.6, 134.0, 129.5,
129.0, 127.5, 125.3, 122.0, 118.3, 52.7, 43.1; HRMS (ESI): m/z
calculated for C13H11NNaO4S2 [M+Na]+ 332.0027, found: 332.0018;
HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm):
t1 = 11.4 min (major, S), t2 = 40.9 min (minor).
dihydrobenzo[e][1,2,3]oxathiazin-4-yl)ethan-1-one (3aj): White solid; m.p.
124.5-125.2 °C; Rf = 0.28 (PE/EA, 5:1); 96% ee, [α]25 = 93.0 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.73-7.70 (m, 2H), 7.32-7.28 (m,
1H), 7.24 (d, J = 7.8 Hz, 1H), 7.14-7.11 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H),
6.02 (d, J = 8.3 Hz, 1H), 5.38 (td, J = 7.7, 3.7 Hz, 1H), 4.24 (dd, J = 18.1,
7.1 Hz, 1H), 3.38 (dd, J = 18.1, 3.7 Hz, 1H), 2.32 (d, J = 6.5 Hz, 6H); 13
C
NMR (100 MHz, CDCl3) δ 197.6, 151.2, 144.0, 137.3, 134.0, 130.1,
129.5, 129.5, 126.0, 125.8, 125.4, 121.7, 119.0, 53.7, 41.3, 20.1, 19.8;
HRMS (ESI): m/z calculated for C17H18Br2NO4S [M+H]+ 332.0957, found:
332.0958; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 12.3 min (major, S), t2 = 24.6 min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(thiophen-
3-yl)ethan-1-one (3ap): White solid; m.p. 138.8-139.6 °C; Rf = 0.33
(PE/EA, 3:1); 98% ee, [α]25D = -17.1 (c 1.0, CH3OH); 1H NMR (300 MHz,
DMSO-d6) δ 8.71 (s, 1H), 8.57 (s, 1H), 7.66 (d, J = 0.5 Hz, 1H), 7.57-7.50
(m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 7.0 Hz, 1H), 7.11 (d, J = 7.6
Hz, 1H), 5.27 (d, J = 9.6 Hz, 1H), 3.88 (dd, J = 17.3, 10.3 Hz, 1H), 3.55
(dd, J = 16.8, 0.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 190.6, 150.8,
141.6, 134.5, 129.4, 127.7, 127.4, 126.5, 125.2, 122.2, 118.3, 52.5, 43.8;
HRMS (ESI): m/z calculated for C13H12NO4S2 [M+H]+ 310.0208, found:
310.0199; HPLC (Chiralcel IC column, hexane/iPrOH = 70/30, 0.8
mL/min, 254 nm): t1 = 9.7 min (major, S), t2 = 17.3 min (minor).
(S)-1-(2,4-dichlorophenyl)-2-(2,2-dioxido-3,4-
dihydrobenzo[e][1,2,3]oxathiazin-4-yl)ethan-1-one (3ak): White solid; m.p.
113.9-114.5 °C; Rf = 0.47 (PE/EA, 3:1); 86% ee, [α]25 = 7.5 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51-7.47 (m, 2H), 7.35-7.31 (m,
2H), 7.19-7.13 (m, 2H), 7.07-7.05 (m, 1H), 5.65 (d, J = 8.1 Hz, 1H), 5.38
(td, J = 8.0, 3.6 Hz, 1H), 4.20 (dd, J = 18.2, 8.0 Hz, 1H), 3.45 (dd, J =
18.2, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 199.0, 151.2, 138.7,
136.0, 132.5, 130.80, 130.77, 129.8, 127.7, 126.0, 125.5, 120.9, 119.2,
53.8, 46.2; HRMS (ESI): m/z calculated for C15H11Cl2NNaO4S [M+Na]+
393.9684, found: 393.9676; HPLC (Chiralcel IC column, hexane/iPrOH =
70/30, 0.8 mL/min, 254 nm): t1 = 7.9 min (major, S), t2 = 16.4 min (minor).
Transformation of Mannich product 3aa (Scheme 3)
(S,E)-4-(2-(hydroxyimino)-2-phenylethyl)-3,4-
dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (4):
A mixture of 3aa
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-
(242.6 mg, 0.8 mmol), hydroxylamine hydrochloride (194.6 mg, 2.8 mmol)
and KOAc (196.3 mg, 2.0 mmol) in 80% aqueous EtOH (15 mL) was
heated gently to reflux for 3 hours. After the reaction mixture was cooled
to room temperature, the solvent was removed in vacuo and the residue
was purified by column chromatography to provide yellow solid (233.5
(naphthalen-2-yl)ethan-1-one (3al):[10d] White solid; m.p. 132.3-133.0 °C;
Rf = 0.51 (PE/EA, 3:1); 95% ee, [α]25 = 66.6 (c 1.0, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 8.41 (s, 1H), 7.89 (t, J = 8.8 Hz, 2H), 7.82-7.77 (m,
2H), 7.57-7.46 (m, 2H), 7.24-7.17 (m, 1H), 7.12-7.03 (m, 2H), 6.96 (d, J =
8.2 Hz, 1H), 5.94 (d, J = 5.8 Hz, 1H), 5.39 (d, J = 2.3 Hz, 1H), 4.34 (dd, J
= 18.1, 7.4 Hz, 1H), 3.43 (dd, J = 18.1, 3.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 197.7, 151.1, 135.9, 133.4, 132.3, 130.4, 129.7, 129.5, 129.0,
128.7, 127.8, 127.0, 126.1, 125.4, 123.4, 121.6, 119.0, 53.7, 42.0; HPLC
mg, 92% yield); m.p. 169.3-170.1 °C; Rf = 0.42 (PE/EA, 3:1); [α]25
=
D
66.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.38 (br, 1H), 7.64-7.60
(m, 2H), 7.40-7.35 (m, 3H), 7.31-7.28 (m, 2H), 7.2-7.12 (m, 1H), 7.01-
6.99 (m, 1H), 5.57 (s, 1H), 5.24-5.07 (m, 1H), 3.65 (dd, J = 13.7, 10.9 Hz,
1H), 3.43 (dd, J = 13.8, 4.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 156.6,
150.8, 134.6, 130.0, 129.7, 128.9, 126.7, 126.5, 125.4, 121.6, 119.0,
55.1, 32.0; HRMS (ESI): m/z calculated for C15H14N2NaO4S [M+Na]+
341.0572, found: 341.0565.
(Chiralcel IC column, hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1
11.6 min (major, S), t2 = 21.9 min (minor).
=
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(pyridin-2-
yl)ethan-1-one (3am): White solid; m.p. 73.7-74.2 °C; Rf = 0.35 (CH2Cl2);
1
94% ee, [α]25 = -25.4 (c 1.0, CH3OH); H NMR (400 MHz, DMSO-d6) δ
D
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-N-
8.75-8.69 (m, 2H), 8.06 (d, J = 3.5 Hz, 2H), 7.74-7.68 (m, 1H), 7.48 (d, J
= 7.6 Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H), 7.25 (dd, J = 10.8, 4.3 Hz, 1H),
7.16-7.08 (m, 1H), 5.34 (dd, J = 8.8, 4.0 Hz, 1H), 4.17 (dd, J = 18.3, 9.8
Hz, 1H), 3.81 (dd, J = 18.3, 3.7 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 197.4, 152.3, 150.8, 149.3, 137.7, 129.4, 128.1, 127.2, 125.2, 122.5,
121.5, 118.2, 52.1, 42.5; HRMS (ESI): m/z calculated for C14H13N2O4S
[M+H]+ 305.0596, found: 305.0595; HPLC (Chiralcel IC column,
hexane/iPrOH = 70/30, 0.8 mL/min, 254 nm): t1 = 22.1 min (major, S), t2
= 35.7 min (minor).
phenylacetamide (5): To a solution of ketoxime 4 (130.5 mg, 0.41 mmol)
in dry MeCN (2 mL) under N2, AlCl3 (5.5 mg, 0.041 mmol) was added.
Then the reaction mixture was heated to reflux for 1.5 hours. After
completion of the reaction (TLC), it was quenched with H2O (10 mL),
extracted with ethyl acetate, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resulting crude product was
purified by column chromatography to give the corresponding amide 5 as
a white solid (122.6 mg, 94% yield); m.p. 194.2-195.2 °C; Rf = 0.31
1
(PE/EA, 3:1); 97% ee, [α]25 = -26.8 (c 1.0, CHCl3); H NMR (300 MHz,
D
DMSO-d6) δ 10.11 (s, 1H), 8.75 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.47-
7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.22 (m, 1H), 7.14-7.05 (m, 2H),
5.22 (s, 1H), 3.21-3.07 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.6,
150.7, 138.9, 129.4, 128.7, 127.1, 125.2, 123.3, 122.3, 119.1, 118.3,
53.2, 41.5; HRMS (ESI): m/z calculated for C15H14N2NaO4S [M+Na]+
341.0572, found: 341.0561; HPLC (Chiralcel IC column, hexane/iPrOH =
70/30, 0.8 mL/min, 254 nm): t1 = 6.7 min (major, S), t2 = 8.3 min (minor).
(S)-2-(2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-(furan-2-
yl)ethan-1-one (3an):[10d] White solid; m.p. 184.5-185.3 °C; Rf = 0.26
(CH2Cl2); 95% ee, [α]25 = 51.8 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
Acetone-d6) δ 7.88 (d, J = 1.1 Hz, 1H), 7.51-7.38 (m, 4H), 7.27 (td, J =
7.6, 1.1 Hz, 1H), 7.08 (dd, J = 8.2, 0.9 Hz, 1H), 6.71 (dd, J = 3.6, 1.7 Hz,
1H), 5.48 (dd, J = 9.6, 3.8 Hz, 1H), 4.04 (dd, J = 17.3, 9.6 Hz, 1H), 3.44
(dd, J = 17.3, 3.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 184.5, 151.7,
150.8, 148.3, 129.5, 127.4, 125.3, 122.0, 119.5, 118.3, 112.7, 52.3, 42.5;
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Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (No. U1404211). We thank
Professor Fangrui Zhong (HUST, China) for helpful discussion
about the nature of benzoylacetic acid.
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The asymmetric Mannich reaction of
various aryl methyl ketones
(acetophenone derivatives) with
different substituted cyclic imines
benzo[e][1,2,3]oxathiazine 2,2-
dioxides using alkaloid derived
primary amine as an organocatalyst,
providing benzo-fused cyclic
sulfamidate N-heterocycles with 85-
98% ee.
X.-Y. Cui, H.-X. Duan, Y. Zhang,* Y.-Q.
Wang*
Page No. – Page No.
Asymmetric Mannich Reaction of Aryl
Methyl Ketones with Cyclic Imines
Benzo[e][1,2,3]oxathiazine 2,2-
Dioxides Catalyzed by Cinchona
Alkaloid-based Primary Amines
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Author(s), Corresponding Author(s)*
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Title
Text for Table of Contents
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