Lewis acids promoted 3 + 2 cycloaddition of oxaziridines and cyclic allylic alcohols through carbonyl imine intermediates

Article abstract of DOI:10.1021/acs.joc.9b00246

Syntheses of isoxazolidines through the carbonyl imine intermediates are currently limited to monosubstituted olefin substrates. Herein, we reported syntheses of novel bicyclic isoxazolidine-containing compounds through 1,3-dipolar cycloaddition reactions

Full text of DOI:10.1021/acs.joc.9b00246

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Article
Lewis Acids Promoted 3+2 Cycloaddition of Oxaziridines and
Cyclic Allylic Alcohols through Carbonyl Imine Intermediates
Erbao Zhao, Feilong Zhou, and Yujun Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00246 • Publication Date (Web): 14 Mar 2019
Downloaded from http://pubs.acs.org on March 14, 2019
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Lewis Acids Promoted 3+2 Cycloaddition of Oxaziridines
and Cyclic Allylic Alcohols through Carbonyl Imine
Intermediates
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Erbao Zhao,a,b,† Feilong Zhou,b,† Yujun Zhao b,c*
a
Nano Science and Technology Institute, University of Science and Technology of
China, Suzhou, Jiangsu 215123, China
b
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China
c
School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu, China,
224007
†
Equal contribution
KEYWORDS: Isoxazolidine, 3+2 Cycloaddition, Carbonyl imine, Oxaziridine,
Allylic alcohol, Allylic cation, Oxocarbenium.
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ABSTRACT:
Syntheses of isoxazolidines through the carbonyl imine intermediates are currently
limited to mono-substituted olefin substrates. Herein, we reported syntheses of novel
bicyclic isoxazolidine-containing compounds through 1,3-dipolar cycloaddition
reactions using cyclic allylic alcohols as substrates, which are challenging in previous
reports. Generally, the reaction yields range from good to high and the reaction
substrates tolerate various functional groups including the cyclopropyl and amine
groups. Mechanistic studies suggest that an allylic cation and a carbonyl imine
intermediates are involved and responsible for the observed stereochemistry and
diastereoselectivity.
0
1
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0
HO R3
R2
O N
R2
SnCl4
O N
R1
R1
R2
O
R1
N
o
H
-78 C
R3
3
5 examples
Up to 99% yield
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INTRODUCTION
Isoxazolidines are unique five-membered heteocycles featuring a labile N-O bond in a
saturated oxazole ring.1-2 Several methods have been reported for the synthesis of
isoxazolidine-containing compounds and most of them are based on 1,3-dipolar
cycloaddition reactions of oxaziridines/nitrones with olefines or cyclization of
hydroxylamines.2-13 Recently, Yoon's group reported a practical method for
preparation of isoxazolidines from the oxaziridines and olefines (Scheme 1, equation
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
),14 via a challenging and less-well studied carbonyl imines intermediates.10, 15-16
1
Previous Work:
Ns
Ns
R
O N
Ph
Lewis Acid
N O
Ns
O
O
Ph
(1)
(2)
N
R
Ph
H
(I)
HO R3
This Work:
R2
R2
O N
O N
Lewis Acid
R1
R2
R1
N
R1
H
R3
(II)
Scheme 1: Proposed synthesis of bicyclic isoxazolidines (2) in comparison with
Yoon's methods (1).
Although computational studies suggested that the carbonyl imines, formed through
the C-N cleavage of N-sulfonyl oxaziridines, are significantly higher in energy than
the isomeric nitrones formed through C-O cleavage,17-18 yet the 1,3-dipolar
cycloaddition reaction involving the carbonyl imine intermediates proceeded
smoothly. Generally, the reaction yields and diastereoselectivity for such a
transformation are high for terminal mono-substituted olefins. However, the reported
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reaction yields for disubstituted olefines is low (ca. 20%) in Partridge et. al.’s study.14
Although this issue is minor, it may limit the applications of synthesizing more
versatile 1,2-isoxazolidine-containing compounds from multiple substituted olefin
substrates. Further improvement of the synthetic method is warranted. In view of the
biological activities of several classes of isoxazolidine-containing compounds2, 19-22
including natural alkaloids (-)-Flueggine A, (+)-Virosaine B, and Zetekitoxin AB,23-26
we are interested in developing a practical method to synthesize versatile
isoxazolidine-containing compounds. In this paper, we report our studies of a reaction
between N-sulfonyl oxaziridines ("Davis oxaziridines") and cyclic allylic alcohols
0
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(Scheme 1, equation 2), which affords novel isoxazolidine-containing bicyclic
compounds in good to high yields in a single step.
RESULTS AND DISCUSSION
We firstly screened suitable reaction conditions for the oxaziridine 1a and the
allylic alcohol 2a (Table 1). In the presence of 0.1 equiv. of TiCl , we obtained a
4
mixture 3a and 4a with a 47% yield at room temperature (Table 1, entry 1). The
o
reaction yield decreased either at -78 C (entry 2) or in the presence of 1.0 equiv. of
TiCl (entry 3). We also screened additional Lewis acids suitable for this
4
transformation (entries 4-7) and found SnCl that gave a 99% yield of 3a and 4a with
4
a ratio of 44:56. Structures of 3a/4a have been determined by X-ray crystallography
studies (Supporting Information). Additionally, a less amount of SnCl (entry 8), the
4
absence of molecular sieve (entry 9), or a shorter reaction time (entry 10) were all
detrimental to the reaction yields. In summary, the best reaction condition for this
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transformation is to use a stoichiometric amount of SnCl in the presence of molecular
4
o
sieve 4Å, toluene as the solvent, and an optimal reaction temperature at -78 C.
Table 1: Screening of reaction conditions
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ts
N
O
Ts
N
O
H
H
H
H
Cl
Ts
N
OH
Acids
Ph
Ph
O
Toluene
Ph
1a (1.0 eq)
2a (1.5 eq)
3a Cl
4a Cl
T( C) Time Yield 3a:4ab
o
Entry
Acid
MS
4Å
Eq.
0.1
(h)
(%)a
Ratioc
1
TiCl4
Yes
rt
12
47
62:38
2
3
4
5
6
7
8
9
TiCl4
TiCl4
Yes
Yes
0.1
1.0
0.1
1.0
1.0
1.0
0.1
1.0
1.0
-78
rt
12
12
12
12
12
12
12
12
2
<5
26
0
100:0
38:62
---
Cu(TFA)2 No
rt
BF
∙OEt
No
-78
rt
61
69
99
29
91
87
39:61
39:61
44:56
45:55
41:59
44:56
3
2
InBr3
SnCl4
SnCl4
SnCl4
SnCl4
No
Yes
Yes
No
-78
-78
-78
-78
1
0
Yes
a
Isolated yield; b The structures of 3a and 4a have been confirmed by X-ray
crystallography studies c Ratio of isomers determined by H NMR of the crude
1
products.
It is worth noting that the reaction between 1a and cyclohexene or other simple
olefines did not proceed under the best reaction conditions (Scheme 2 and SI Scheme
S1), suggesting that simple disubstituted olefines are inactive substrates for this
transformation.
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5
5
5
5
5
5
6
SnCl 1.0 eq.
4
Ts
N
O
4
Å MS
No reaction
o
Ph
1
Toluene, -78 C,12 h
a (1.0 eq.)
excess
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
9
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0
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9
0
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2
3
4
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8
9
0
Scheme 2: Control reaction of 1a and cyclohexene
Table 2: Substrate scope of substituted phenylsulfonyl-1,2-oxaziridines
R
R
O
H
O
H
S
S
N
O
O
N
SnCl 1.0 eq.
4
Cl
O
O
O
N
4Å MS
O
S
O
OH
H
H
Ph
Ph
Ph
R
-
78 C, Toluene
1
a-1j (1.0 eq.)
2a (1.5 eq.)
3a-3j
4a-4j
Cl
Cl
Yield(%)a
3+4
3:4
ratiob
Entry
1
R
Reactant Product
Me
1a
1b
3a+4a
3b+4b
99
44:56
36:64
Me
2
3
80
Me
1c
3c+4c
39
39:61
4
5
6
7
8
9
1d
1e
1f
3d+4d
3e+4e
3f+4f
90
91
69
46
30
37:63
40:60
43:57
39:61
40:60
MeO
MeO2C
F
1g
1h
3g+4g
3h+4h
Cl
Br
1i
1j
3i+4i
3j+4j
35
25
49:51
53:47
1
0
Me-
a
b
1
Isolated yield; Ratio of isomers determined by H NMR of the crude products
After identifying the optimized reaction conditions, we explored the substrate scope
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of 1,2-oxaziridines (Table 2). We found that N-aryl sulfonyl 1,2-oxaziridines 1a-1i
(
entries 1-9) are generally better substrates than N-methanesulfonyl 1,2-oxaziridine 1j
entry 10). The 3-phenyl-1,2-oxaziridine 1d (entry 4) and its phenyl substituted
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
analogues 1a, 1b, and 1e (entries 1, 2, 4, and 5) afforded the desired products 3a/4a,
b/4b, 3d/4d, and 3e/4e giving 99%, 80%, 90%, and 91% yields respectively. 1f
(entry 6) with a p-CO Me substituted phenyl group also furnished the desired product
3
2
3
f/4f in a 69% yield. However, 1c, 1g, 1h, and 1i (entries 3, and 7-9) only gave the
corresponding products in 30-50% yields. In addition, two isomers were obtained for
all aforementioned reactions and the isomer ratios were low at around 40:60 to 50:50.
We next explored the substrate scope of N-toluenesulfonyl-1,2-oxaziridines with
different substituents on the 3-phenyl group (Table 3). The alklyl (1k, 1l, 1m) and
halogen (1n, 1p, 1q) substituted phenyl groups were tolerated and the desired product
yields of 3k/4k, 3l/4l, and 3n/4n-3q/4q were >70% in all cases with 4k, 4l, and
4n-4p as the major isomers (entries 1-6). When 1m was used as the substrate, a
region-isomer 3x was also obtained as a single isomer in a 31% yield.27-28
Unfortunately, para-electron-withdrawing group substitutions on the 3-aryl group
were detrimental for this transformation with no products isolated (SI Scheme S2).
Table 3: Substrate scope of substituted toluenesulfonyl-1,2-oxaziridines
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ts
N
O
Ts
H
H
H
H
N
SnCl 1.0 eq.
4
Cl
O
O
N
4Å MS
OH
R
R
R
Ts
o
-
78 C, Toluene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
l-1q (1.0 eq.)
2a (1.5 eq.)
3k-3q
4k-4q
Cl
Cl
Yield(%)
3:4
Produc
a
ratiob
44:56
34:66
37:63
37:63
43:57
58:42
Entry
R
Reactant
t
3
+4
Me
1
2
1k
1l
3k+4k
80
86
57
76
70
78
Me
3l+4l
3m+4m
3n+4n
3p+4p
3q+4q
3c
4
1m
1n
1p
Me
F
5
Cl
Br
6
1q
H
H
O
Ts
N
Me
3x
Cl
a
b
1
c
Isolated yield; Ratio of isomers determined by H NMR of the crude products; Isomer
3
x was isolated in 31% yield, its structure was determined by X-ray crystallography studies.
In order to explore the substrate compatibility of the allylic alcohols, we tested the
reaction of 1a with a small library of cyclic allylic alcohols 2b-2n and the results are
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summarized in Table 4. In general, the R group of 2 tolerates various functional
groups including aromatic and aliphatic groups. When the R groups were phenyl,
halogen substituted phenyl, alkly substituted phenyl, CF -substituted phenyl, and
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-Ts-substituted phenyl (entries 1-3, 5-8), the desired products 5b/6b-5d/6d and
5
f/6f-5i/6i were obtained in good to high yields. When meta position of phenyl was an
isopropyl group (entry 9), a moderate yield of 5j/6j was obtained likely because of the
steric repulsion of the isopropyl group.
Table 4: Substrate scope of allylic alcohols
Ts
Ts
SnCl 1.0 eq.
H
H
H
H
4
OH
R
N
N
O
N
4 Å MS
O
O
Ph
Ts
o
-
78 C, Toluene
Ph
Ph
R
R
1a (1.0 eq.)
2b-2n (1.5 eq.)
5b-5n
6b-6n
Yield(%)a
5:6
ratiob
Entry
R
Reactant Product
5
+6(%)
1
2b
5b+6b
92
48:52
F
2
3
4
5
2c
2d
2e
2f
5c+6c
5d+6d
5e+6e
5f+6f
99
93
37
84
38:62
43:57
68:32
50:50
Br
Me
Me
Me
6
7
8
2g
2h
2i
5g+6g
5h+6h
5i+6i
73
67
62
37:63
28:72
47:53
F3C
N
Ts
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9
2j
5j+6j
45
22:78
10
2k
2l
---
0
---
MeO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
2
5l+6l
94
83
94
61:39
29:71
63:37
Ph
Me
Et
2m
2n
5m+6m
5n+6n
13
a
b
1
Isolated yield; Ratio of isomers determined by H NMR of the crude products;
Unfortunately, we only obtained 5e/6e with a 37% yield and 5e was the major
isomer. No product was found when 2k was used (entry 10). When the R were
aliphatic groups (entries 11-13), the desired cyclization products 5l/6l-5n/6n were
obtained in high yields. Again, two isomers were obtained in all these cases and the
diastereoselectivity was poor.
We also tried 3-alkyl groups substituted 1,2-oxaziridines as the reaction substrates
and most of these efforts were futile (SI Scheme S2), which suggested the aromatic
aryl groups may function as cation stabilization groups for this transformation. It is
well known that the cyclopropyl group can stabilize a carbenium cation, we therefore
study whether the 3-cyclopropyl substituted 1,2-oxaziridine 7 is a suitable substrate,
and the results are summarized in Table 5. Interestingly, all cyclic allylic alcohols
reacted with 7 smoothly and the anticipated products 10a/11a, 10c/11c, 10d/11d,
1
0h/11h, and 10l/11l - 10n/11n were obtained, while additional compounds 8/9 were
also observed in all cases. To simplify the data analysis, the crude reaction products
were treated with AgSF to facilitate the removal of Cl atoms. Upon treatment of the
6
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silver salt, the anticipated cyclization products were isolated with good to high yields
(
Entries 1-7). Again, moderate isomer ratios of 10/11 were obtained, ranging from
9:31 to 21:79. The relative stereochemistry of the cyclization product 11a was
further confirmed by X-ray crystallography studies. It is noteworthy to point out that
-cyclopropyl-1,2-oxaziridine type substrate was found inactive in previous reports,14
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
which suggests that a distinct reaction mechanism is probably involved.
Table 5: Reaction with 3-cyclopropyl substituted 1,2-oxaziridine 7
Ts
Ts
H
H
N
N
O
Cl
R
O
Cl
R
H
H
9
1
0a, 10c, 10d,
SnCl 1.0 eq.
4
Ts
N
O
10h, 10l-10n
4
Å MS
8
AgSbF6
OH
R
Ts
Ts
o
H
H
11a, 11c, 11d,
11h, 11l-11n
-
78 C, Toluene
N
N
O
O
7 (1.0 eq.)
2a, 2c, 2d
2h, 2l-2n (1.5 eq.)
H
H
R
R
1
1
0a, 10c, 10d, 11a, 11c, 11d,
0h, 10l-10n 11h, 11l-11n
Yield(%)a
10+11
10:11
ratiob
Entry
R
Reactant Products
c
1
2
3
2a
2c
2d
10a +11a
10c+11c
10d+11d
99
99
99
65:35
65:35
69:31
Cl
Br
4
2h
10h+11h
72
21:79
F3C
5
6
7
2l
2m
2n
10l+11l
10m+11m
10n+11n
80
63
81
33:67
59:41
66:34
Ph
Et
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
b
1
c
Isolated yield; Ratio of isomers determined by H NMR of the crude products;
The structure of 11a has been confirmed by X-ray crystallography studies
To investigate the reaction mechanism, we synthesized 12a-12e to react with 1a
(Table 6).
Table 6: Model reactions to probe reaction mechanism
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SnCl 1.0 eq.
Ts
Ts
Y
4
H
H
4
Å MS
N
N
O
O
O
N
Z
Ph
Ts
Toluene, -78 °C
X
H
H
Ph
Ph
R
R
1
2a-12e
2a, 2d, 2m
1.5 eq.)
1
a (1.0 eq.)
3a/5d/5m
4a/6d/6m
(
Isomer
ratiob
Entry Reactant Reactant Product Yield(%)a
1
2
2m
12a
12b
2a
83
80
42
99
75
63
93
99
29:71
24:76
43:57
44:56
39:61
30:70
43:57
42:58
HO
5m+6m
OH
3
Cl
4c
5c
6c
7
HO Ar
Ar
12c
12d
2d
3a+4a
OH
Cl
Ar
HO Ph
Ph
5
d+6d
8
12e
OH
a
b
1
Isolated yield; Ratio of isomers determined by H NMR of the crude products for
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c
3a:4a, 5d:6d, and 5m:6m; Ar is a 4-Cl phenyl group.
Interestingly, three different substrates 2m, 12a, and 12b (entries 1-3) gave the
same products 5m/6m in 83%, 80%, and 42% yields respectively with no significant
differences of isomer ratios. Similarly, substrates 2a, 12c, and 12d (entries 4-6) gave
the same products 3a/4a in 99%, 75%, and 63% yields respectively with no
significant differences of isomer ratios. The same trend was also observed for
substrates 2d and 12e (entries 7-8).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Because the same products were obtained from different reaction substrates, we
hypothesized that common intermediates were involved for all of these
transformations. It has been previously demonstrated that an allylic cation could be
generated from allylic alcohols and allylic chlorides in the presence of acids,29-33 we
therefore postulate that allylic cationic intermediates are involved in our reactions.
Based on our data, we proposed the following reaction mechanism for such a
transformation (Scheme 3).
R
R
R
R
R
HO
SnCl4
HO
H
R1
H
2
14
+
Cl Sn
4
+
N
N
R1
O
R'
O
R'
O
N
O
SnCln
R'
N
R1
O
R'
N
R1
R'
13
R1
15
16
16'
R
H+
R
-
H
H
H
H
R = Ar, cyclopropyl
1
N
N
R1
R'
O
1
R1
O
17
R'
8
Scheme 3: Proposed reaction mechanism
In the presence of SnCl , oxaziridine 13 opens up and generates a carbonyl imine
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
intermediate 15, which is in line with the observed arrangement of N-O-C sequences
in the final products. The N atom of the carbonyl imine intermediate 15 attacks the
allylic cation 14, in situ formation from the allylic alcohol 2, from a less hindered site
furnishing the intermediates 16 and 16'. Subsequently, the olefine electron flows into
the oxocarbenium of 16 and 16' furnishing a stabilized carbenium 17. The
oxocarbenium of 16 and 16' approach the olefine from the same side of the N group,
which leads to the cis stereochemistry of the fused ring system. However, the benzylic
stereogenic center of 17 epimizes because both E/Z oxocarbenium can be possible
active electrophiles. Finally, elimination of a proton from 17 yields the desired final
products 18 as a mixture of two isomers where R is one of aryl groups. When R is a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
cyclopropyl group, similar reaction mechanism is observed except that 17 is likely to
be quenched by Cl anions. Subsequent elimination is facilitated by treatment of
AgSbF and 18 is obtained as a mixture of two isomers. Our data shown that the
6
3-phenyl and 3-cyclopropyl groups (not 3-cyclohexyl nor 3-methyl group) substituted
oxaziridines are the only reactive substrates. These experimental observations are
consistent with the proposed reaction mechanism, which indicates that a carbocation
stabilization group is required for such a transformation.
CONCLUSIONS
In conclusion, we have reported a novel 1,3-dipolar cycloaddition reactions of the
oxaziridines and the cyclic allylic alcohols, which are challenging substrates with low
reactivities in precedent reports. In our reaction conditions, the yields range from
good to high and the activities of the substrates decorated with various functional
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groups are robust. Mechanistic studies suggested that an allylic cation and a carbonyl
imine intermediates are involved and responsible for the observed stereochemistry
and diastereoselectivity. We consider that our practical method may be applied to
obtain diverse bicyclic compounds embedded with isoxazolidine moieties, which are
of potential interests for future studies.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General Methods. Unless otherwise stated, reagents were purchased from
commercial suppliers and used as received without further purification:
2-Cyclohexen-1-one (Energy), dichloromethane (J&K, Super Dry, with molecular
.
sieves), SnCl (Energy), BF OEt (Aladdin), TiCl (Aladdin), AgSbF (TCI), AgBF
4
3
2
4
6
4
1
(Energy). Proton nuclear magnetic resonance ( H NMR) and carbon nuclear magnetic
1
3
resonance ( C NMR) spectroscopy were performed on Bruker Advance NMR 400
1
and 500, Chemical shifts of H NMR spectra are reported as δ in units of parts per
million (ppm) downfield from SiMe (δ= 0.0) and relative to the signal of CDCl (δ =
4
3
7
.26, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q
(quartet); dd (doublet of doublets); dt (doublet of triplets); and m (multiplets). The
number of protons for a given resonance is indicated by nH. Coupling constants are
13
reported as J values in Hz. Carbon nuclear magnetic resonance spectra ( C NMR) are
reported as proton-decoupled carbon data and δ in units of parts per million (ppm)
downfield from SiMe (δ = 0.0) and relative to the signal of CDCl (δ = 77.23,
4
3
1
9
triplet). Fluorine nuclear magnetic resonance spectra ( F NMR) are reported as δ in
units of parts per million (ppm) downfield from CFCl (δ = 0) and relative to the
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
signal of PhCF (δ = -63.72). Low resolution mass spectrum analysis was performed
3
on The LTQ linear ion trap mass spectrometer (Finnigan) and Thermo DFS (Thermo
Fisher Scientific). High-resolution mass spectral analysis (HRMS) was performed on
UHPLC-QTOF (Agilent Corporation) and Thermo DFS (Thermo Fisher Scientific).
Melting points (mp) were measured on DSC Q2000 (V24.11 Build 124). Known
1,2-oxaziridines34-35 and allylic alcohols29 were prepared according to literature
procedures.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of 1, 2-Oxaziridines
A round-bottom flask equipped with a magnetic stirring bar was charged with
TsNH (17.15 mmol, 1.0 equiv.), aldehyde (18.87 mmol, 1.1 equiv.), and toluene. To
2
3
6
this mixture, BF ·OEt (0.28 mmol, 0.016 equiv.) was added. The mixture was
3
2
o
allowed to heat to 120 C and stirred for overnight. The resulting mixture was
concentrated in vacuo. The crude was used directly for the next m-CPBA oxidation.
In a second 100 ml round-bottom flask equipped with a magnetic stirring bar was
o
charged with m-CPBA (3.76 mmol, 1.1 equiv.) and dichloromethane at 0 C followed
3
4
by addition of KOH (11.98 mmol, 3.5 equiv.). After 10 min, the crude material from
o
the first step (3.42 mmol, 1.0 equiv.) was added as a dichloromethane solution at 0 C.
The mixture was allowed to warm up to room temperature and stirred for 15 min. The
mixture was filtered and concentrated in vacuo. The residual crude materials were
purified by flash column chromatography to yield the desired products.
3
-Phenyl-2-(m-tolylsulfonyl)-1, 2-oxaziridine (1b): a white solid (0.18 g, 20%
1
yield). H NMR (400 MHz, CDCl ): δ 7.89 (d, J = 1.6 Hz, 2H), 7.63 – 7.39 (m, 7H),
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3
1
5.51 (s, 1H), 2.51 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 139.8, 135.9, 134.5,
3
1
31.4, 130.5, 129.6, 129.2, 128.8, 128.3, 126.5, 76.3, 21.3. HRMS (ESI): m/z
32
+
+
calculated for C H NO S [M+H] : 276.0689, Found [M+H] : 276.0689.
1
4
14
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3-Phenyl-2-(o-tolylsulfonyl)-1, 2-oxaziridine (1c): a yellow solid obtained (0.74 g,
1
4
1% yield). H NMR (400 MHz, CDCl ): δ 8.32 – 7.99 (m, 1H), 7.61 (dd, J = 7.6, 1.4
3
1
3
1
Hz, 1H), 7.55 – 7.38 (m, 7H), 5.57 (s, 1H), 2.87 (s, 3H). C{ H} NMR (100 MHz,
CDCl ): δ 140.3, 135.0, 133.4, 133.0, 131.4, 131.1, 130.7, 128.8, 128.3, 126.5, 75.7,
3
32
+
2
1.0. HRMS (ESI): m/z calculated for C H NO S [M+H] : 276.0689, Found
14 14 3
+
[M+H] : 276.0688.
Methyl 4-((3-phenyl-1, 2-oxaziridin-2-yl)sulfonyl)benzoate (1f): a yellow solid
1
obtained (0.63 g, 57% yield). H NMR (400 MHz, CDCl ): δ 8.21 (d, J = 8.37 Hz,
3
13
1
2
H), 8.06 (d, j = 8.37 Hz, 2H), 7.4 - 7.33 (m, 5H), 5.46 (s, 1H), 3.92 (s, 3H). C{ H}
NMR (100 MHz, CDCl ): δ 164.3, 137.6, 135.0, 130.5, 129.4, 129.2, 128.3, 128.0,
3
1
27.8, 127.3, 126.9, 125.5, 124.9, 75.3, 51.8. HRMS (EI): m/z calculated for
3
2
C H NO S: 319.0509, Found: 319.0508.
1
5
13
5
2
-((4-Fluorophenyl)sulfonyl)-3-phenyl-1, 2-oxaziridine (1g) : a white solid
1
obtained (730 mg, 68% yield). H NMR (400 MHz, CDCl ): δ 8.08 (m, 2H), 7.55 –
3
1
3
1
7
1
1
.37 (m, 4H), 7.38 – 7.28 (m, 2H), 5.50 (s, 1H). C{ H} NMR (125 MHz, CDCl ): δ
3
66.7 (d, JC-F = 257 Hz), 132.3 (d, JC-F = 10 Hz), 131.5, 130.7 (d, JC-F = 3 Hz), 130.2,
28.7, 128.8, 128.3, 116.9 (d, JC-F = 22 Hz), 76.5. HRMS (EI): m/z calculated for
32
C H NO F S: 279.0360, Found: 279.0363.
1
3
10
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2
2
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2
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2'-Isopropyl-3, 4-dihydro-[1, 1'-biphenyl]-1(2H)-ol (2j): To a solution of the
corresponding 1-bromo-2-isopropylbenzene (5.7 mmol, 1.0 equiv.) in anhydrous THF
o
at -40 C, n-buthyllithium (6.8 mmol, 1.2 equiv. 1.6 M in hexane) was added. The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction mixture was stirred for 30 min before 2-Cyclohexen-1-one (1.0 g, 8.5 mmol,
o
1
.5 equiv.) was added via a syringe. The reaction mixture was allowed to stir at -40 C
for overnight before quenching with saturated aqueous solution of NH Cl. The
4
aqueous layer was extracted with ethyl acetate (3 × 50 ml), and the combined organic
layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The residual crude material was purified by flash column
1
chromatography to give the final product as yellow oil (1.94 g, 75 % yield). H NMR
(400 MHz, CDCl ): δ 7.60 (dd, J = 7.9, 1.5 Hz, 1H), 7.35 (dd, J = 7.8, 1.5 Hz, 1H),
3
7
.29 – 7.23 (m, 1H), 7.14 (ddd, J = 7.9, 7.1, 1.5 Hz, 1H), 5.99 (ddd, J = 9.9, 4.6, 2.9
Hz, 1H), 5.91 – 5.85 (m, 1H), 2.22 – 2.07 (m, 2H), 2.07 – 1.94 (m, 2H), 1.85 (m, 2H),
1
3
1
1.65 (m, 1H), 1.30 – 1.13 (m, 6H). C{ H} NMR (125 MHz, CDCl ): δ 147.1, 143.3,
3
1
33.7, 129.4, 127.4, 126.4, 125.1, 72.6, 37.7, 28.7, 27.0, 24.8, 24.7, 19.3. HRMS
(EI): m/z calculated for C H O: 216.1509, Found: 216.1511.
1
5
20
General procedures for reactions between the oxaziridines and the allylic
alcohols
To a dry round-bottom flask equipped with a magnetic stirring bar, the oxaziridine
(0.2 mmol, 1.0 equiv.), 4Å MS (87 mg), the allylic alcohol (0.3 mmol, 1.5 equiv.),
o
and anhydrous toluene (5 mL) were added. The solution was cooled to -78 C
followed by addition of SnCl (0.2 mmol, 1.0 equiv. 1.0 M solution in CH Cl ) via a
4
2
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syringe. The reaction mixture was allowed to proceed at -78 C for another 12 h
before filtration and concentration in vacuo. The residual crude material was purified
by flash column chromatography. In each case, the cyclization compounds were
obtained as two pairs of enantiomers, and the name of only one enantiomer of each
pair was shown as follows.
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(
3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro
benzo[c]isoxazole (3a) / (3S, 3aS, 7aR)-4-(4-Chlorophenyl)-3-phenyl-1-tosyl-1, 3,
3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (4a) : White solid (3a + 4a = 92 mg, 99 %
1
yield). 3a: H NMR (400 MHz, CDCl ): δ 7.92 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1
3
Hz, 2H), 6.97 (m, 5H), 6.79 (d, J = 7.3 Hz, 2H), 6.72 – 6.60 (m, 2H), 5.90 (s, 1H),
5
1
.65 (d, J = 9.5 Hz, 1H), 4.83 (m, 1H), 4.23 (m, 1H), 2.43 (s, 4H), 2.33 – 2.20 (m,
13
1
H), 2.13 (m, 1H), 1.96 (m, 1H). C{ H} NMR (100 MHz, CDCl ): δ 145.1, 139.8,
3
135.4, 134.3, 133.0, 132.2, 129.7, 129.3, 128.8, 128.1, 127.8, 127.8, 127.4, 126.9,
6.4, 76.7, 58.6, 47.5, 25.7, 23.1, 21.8. HRMS (EI): m/z calculated for
8
3
5
32
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C H O N Cl S: 465.1160, Found: 465.1161, mp: 161.5 C.
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1
4
a: H NMR (400 MHz, CDCl ): δ 7.92 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.1 Hz,
3
2H), 7.23 – 6.99 (m, 5H), 6.99 – 6.78 (m, 2H), 6.83 – 6.61 (m, 2H), 6.04 (s, 1H), 4.72
(
d, J = 9.9 Hz, 1H), 4.61 (m, 1H), 3.65 (t, J = 8.6 Hz,1H), 2.44 (m, 5H), 2.23 – 2.07
m,1H), 2.07 – 1.85 (m, 1H). 13C{ H} NMR (100 MHz, CDCl ): δ 145.2, 137.9,
1
(
3
1
5
36.7, 134.1, 132.5, 132.2, 129.7, 128.3, 128.1, 128.0, 127.7, 127.7, 127.6, 89.0, 59.7,
35 32
1.2, 25.3, 24.2, 21.8. HRMS (EI): m/z calculated for C H O N Cl S: 465.1160,
2
6
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o
Found: 465.1161, mp: 184.8 C.
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(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(m-tolylsulfonyl)-1, 3, 3a, 6, 7,
7
a-hexahydrobenzo [c]isoxazole (3b) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-
3
-phenyl-1-(m- tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4b) :
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6
7
8
9
0
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2
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7
8
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0
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1
White solid (3b + 4b = 74 mg, 80% yield). 3b: H NMR (400 MHz, CDCl ): δ 7.89 –
3
7
.80 (m, 2H), 7.51 – 7.38 (m, 2H), 7.09 – 6.91 (m, 5H), 6.83 – 6.77 (m, 2H), 6.75 –
6.69 (m, 2H), 5.95 – 5.87 (m, 1H), 5.66 (d, J = 9.5 Hz, 1H), 4.58 (m, 1H), 4.24 (t, J =
1
8
.7 Hz, 1H), 2.43 (m, 5H), 2.20 – 2.08 (m, 1H), 2.00 (m, 1H). 13C{ H} NMR (125
MHz, CDCl ): δ 139.9, 136.2, 135.5, 135.0, 134.5, 132.5, 129.6, 129.1, 128.9, 128.3,
3
128.0, 127.6, 127.1, 126.6, 86.6, 58.7, 47.6, 29.9, 26.9, 23.2. HRMS (EI): m/z
3
5
32
calculated for C H O N Cl S: 465.1160, Found: 465.1164.
2
6
24
3
1
4
b: H NMR (400 MHz, CDCl ): δ 7.89 – 7.80 (m, 2H), 7.51 – 7.38 (m, 2H), 7.17
3
–
7.09 (m, 1H), 7.09 – 6.91 (m, 4H), 6.90 – 6.83 (m, 2H), 6.75 – 6.69 (m, 2H), 6.04
(m, 1H), 4.86 (m, 1H), 4.73 (d, J = 9.8 Hz, 1H), 3.56 (t, J = 8.6 Hz, 1H), 2.43 (m,
1
3
1
5
1
1
H), 2.20 – 2.08 (m, 1H), 2.00 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 139.5,
3
38.1, 136.7, 135.1, 135.0, 134.2, 132.7, 130.2, 129.0, 128.5, 128.1, 127.9, 127.9,
27.7, 127.0, 89.2, 60.0, 53.6, 51.2, 25.6, 24.3, 21.5. HRMS (EI): m/z calculated for
35 32
C H O N Cl S: 465.1160, Found: 465.1164.
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(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(o-tolylsulfonyl)-1, 3, 3a, 6, 7,
7
3
a-hexahydrobenzo [c]isoxazole (3c) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-
-phenyl-1-(o-tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4c):
1
White solid (3c + 4c = 36 mg, 39 % yield). 3c: H NMR (400 MHz, CDCl ): δ 7.49 (t,
3
J = 7.5 Hz, 2H), 7.42 – 7.20 (m, 2H), 7.13 - 6.90 (m, 5H), 6.90 – 6.73 (m, 2H), 6.69
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(d, J = 8.2 Hz, 2H), 5.92 (d, J = 4.3 Hz, 1H), 5.78 (d, J = 9.6 Hz, 1H), 4.94 (m, 1H),
4
1
.34 (t, J = 8.9 Hz, 1H), 2.74 (s, 3H), 2.56 – 2.21 (m, 2H), 2.16 (m, 1H), 1.97 (m,
13
1
H). C{ H} NMR (125 MHz, CDCl ): δ 139.9, 139.7, 135.4, 134.7, 134.4, 133.9,
3
1
1
1
1
1
1
1
1
1
1
2
2
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132.3, 131.8, 131.5, 128.6, 128.3, 128.3, 128.0, 127.9, 127.5, 126.3, 85.8, 56.8, 46.5,
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2
5.8, 23.2, 20.8. HRMS (EI): m/z calculated for C H O N Cl S: 465.1160, Found:
26 24 3
465.1157.
1
4
c: H NMR (400 MHz, CDCl ): δ 8.10 (m, 1H), 7.42 – 7.20 (m, 1H), 7.13 (m, 2H),
3
7.09 – 6.90 (m, 3H), 6.90 – 6.73 (m, 2H), 6.69 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2
Hz, 2H), 6.04 (d, J = 4.1 Hz, 1H), 4.87 – 4.77 (m, 1H), 4.74 (d, J = 10.2 Hz, 1H), 3.81
(t, J = 8.7 Hz, 1H), 2.74 (s, 3H), 2.56 – 2.21 (m, 2H), 2.16 (m,1H), 1.97 (m, 1H).
1
3
1
C{ H} NMR (125 MHz, CDCl ): δ 139.8, 138.0, 136.8, 134.3, 134.2, 124.1, 132.8,
3
1
32.6, 128.2, 127.9, 127.8, 127.7, 127.1, 126.3, 89.7, 59.0, 51.5, 25.3, 24.7, 20.9.
3
5
32
HRMS (EI): m/z calculated for C H O N Cl S: 465.1160, Found: 465.1157.
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(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(phenylsulfonyl)-1, 3, 3a, 6, 7,
7
a-hexahydrobenzo [c]isoxazole (3d) (3S, 3aS, 7aR)-4-(4-Chloro
/
phenyl)-3-phenyl-1-(phenylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole
1
(4d) : White solid (3d + 4d = 80 mg, 90 % yield). 3d: H NMR (400 MHz, CDCl ): δ
3
8
5
9
2
.13 – 7.94 (m, 2H), 7.74 – 7.61 (m, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.13 – 6.89 (m,
H), 6.87 – 6.74 (m, 2H), 6.74 – 6.58 (m, 2H), 5.92 (t, J = 4.3 Hz, 1H), 5.65 (d, J =
.4 Hz, 1H), 4.94 – 4.76 (m, 1H), 4.23 (s, 1H), 2.38 (d, J = 5.1 Hz, 1H), 2.27 (m 1H),
13
1
.13 (m, 1H), 2.05 – 1.90 (m, 1H). C{ H} NMR (100 MHz, CDCl ): δ 137.9, 136.5,
3
135.3, 134.1, 132.6, 129.7, 129.2, 129.0, 128.4, 128.1, 128.1, 127.8, 127.7, 127.6,
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126.9, 89.0, 59.8, 51.4, 31.9, 29.7, 29.4, 25.4, 24.2, 22.7, 14.1. HRMS (EI): m/z
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32
calculated for C H O N Cl S: 451.1003, Found: 451.1004.
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3
1
0
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4d: H NMR (400 MHz, CDCl ): δ 8.05 (d, J = 7.3, 1.4 Hz, 2H), 7.78 – 7.61 (m,
3
1
2
H), 7.56 (t, J = 8.4, 7.1 Hz, 2H), 7.13 (m, 1H), 7.08 – 6.99 (m, 4H), 6.90 – 6.83 (m,
H), 6.77 – 6.69 (m, 2H), 6.04 (dd, J = 5.0, 3.3 Hz, 1H), 4.73 (d, J = 9.8 Hz, 1H), 4.61
(ddd, J = 11.7, 7.2, 4.8 Hz, 1H), 3.60 (t, J = 8.6 Hz, 1H), 2.56 – 2.24 (m, 2H), 2.14
13
1
(
m, 1H), 1.99 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 136.6, 135.5, 134.3,
3
133.2, 133.0, 132.9, 131.5, 128.6, 128.2, 128.0, 128.0, 127.8, 127.4, 127.1, 127.0,
1
2
4
26.9, 126.7, 126.7, 126.5, 126.4, 125.9, 88.0, 85.4, 58.7, 57.6, 50.1, 46.5, 24.7, 24.6,
3
5
32
4.4, 23.1. HRMS (EI): m/z calculated for C H O N Cl S: 451.1003, Found:
2
5
22
3
51.1002.
(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-methoxyphenyl)sulfonyl)-3-phenyl-1, 3,
a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3e) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-
3
1
-((4-methoxyphenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo
1
[
c]isoxazole (4e) : White solid (3e + 4e = 87 mg, 91 % yield ). 3e: H NMR (400
MHz, CDCl ): δ 7.96 (d, J = 8.8 Hz, 2H), 7.08 – 6.90 (m, 2H), 6.90 – 6.83 (m, 5H),
3
6.80 (d, J = 7.3 Hz, 2H), 6.70 – 6.62 (d, J = 8.58 Hz, 2H), 5.96 – 5.85 (m, 1H), 5.64
(d, J = 9.4 Hz, 1H), 4.81 (ddd, J = 10.6, 7.8, 4.8 Hz, 1H), 4.23 (t, J = 8.8 Hz, 1H),
13
1
3
.86 (d, J = 2.0 Hz, 3H), 2.50 – 2.18 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H). C{ H}
NMR (125 MHz, CDCl ): δ 164.2, 138.1, 136.9, 134.3, 132.7, 131.6, 128.4, 128.2,
3
1
28.1, 127.9, 127.5, 126.7, 114.4, 89.1, 59.9, 55.9, 51.3, 25.5, 24.3. HRMS (EI): m/z
3
5
32
calculated for C H O N Cl S: 481.1109, Found: 481.1105.
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4e: H NMR (400 MHz, CDCl ): δ 7.96 (d, J = 8.8 Hz, 2H), 7.17 – 7.08 (m, 1H),
3
7
8
.08 – 6.90 (m, 2H), 6.90 – 6.83 (m, 4H), 6.80 (d, J = 7.3 Hz, 2H), 6.77 – 6.71 (d, J =
.58 Hz, 2H), 6.03 (t, J = 4.1 Hz, 1H), 4.71 (d, J = 9.8 Hz, 1H), 4.58 (ddd, J = 11.7,
1
1
1
1
1
1
1
1
1
1
2
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2
2
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2
2
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2
2
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5
6
0
1
2
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7
8
9
0
1
2
3
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6
7
8
9
0
1
2
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6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
7.2, 4.8 Hz, 1H), 3.86 (d, J = 2.0 Hz, 3H), 3.64 (t, J = 8.7 Hz, 1H), 2.50 – 2.18 (m,
1
3
1
1
H), 2.11 (m, 1H), 1.98 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 164.2, 140.0,
3
135.6, 134.5, 132.4, 132.0, 129.0, 128.3, 128.0, 127.9, 127.7, 127.6, 127.1, 114.5,
3
5
32
8
4
6.5, 58.8, 55.9, 47.6, 26.0, 23.2. HRMS (EI): m/z calculated for C H O N Cl S:
26 24 4
81.1109, Found: 481.1105.
Methyl-4-(((3S, 3aR, 7aS)-4-(4-chlorophenyl)-3-phenyl-3a, 6, 7, 7a-
tetrahydrobenzo[c]isoxazol- 1(3H)-yl)sulfonyl)benzoate (3f) / Methyl-4-(((3S,
3
7
aS,
7aR)-4-(4-chlorophenyl)-3-phenyl-3a,
6,
7,
a-tetrahydrobenzo[c]isoxazol-1(3H)- yl)sulfonyl)benzoate (4f): White solid (3f +
1
4f = 70 mg, 69 % yield). 3f: H NMR (400 MHz, CDCl ): δ 8.18 (d, J = 8.2 Hz, 2H),
3
8
8
.10 (d, J = 8.2 Hz, 2H), 7.10 – 6.86 (m, 5H), 6.80 (d, J = 7.6 Hz, 2H), 6.67 (d, J =
.2 Hz, 2H), 5.93 (d, J = 4.3 Hz, 1H), 5.69 (d, J = 9.3 Hz, 1H), 4.89 (m, 1H), 4.26 (t, J
=
8.8 Hz, 1H), 3.95 (s, 3H), 2.58 – 2.35 (m, 1H), 2.35 – 2.21 (m, 1H), 2.12 (m, 1H),
13
1
2
.03 – 1.85 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 165.7, 140.2, 139.9, 135.2,
3
135.0, 134.4, 132.4, 130.3, 129.4, 129.0, 128.2, 128.1, 128.1, 127.7, 127.1, 86.7, 58.7,
3
5
32
5
5
3.6, 52.9, 47.7, 25.9, 23.1. HRMS (EI): m/z calculated for C H O N Cl S:
27 24 5
09.1058, Found: 509.1056.
1
4
f: H NMR (400 MHz, CDCl ): δ 8.20 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz,
3
2H), 7.14 (td, J = 5.9, 5.4, 2.6 Hz, 1H), 7.10 – 7.01 (m, 4H), 6.93 – 6.82 (m, 2H), 6.81
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– 6.68 (m, 2H), 6.05 (t, J = 4.2 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.64 (m, 1H), 3.96
(s, 3H), 3.65 (t, J = 8.6 Hz, 1H), 2.44 (m, 1H), 2.24 – 2.05 (m, 1H), 2.00 (m, 1H).
13
1
C{ H} NMR (125 MHz, CDCl ): δ 165.7, 139.5, 138.0, 136.5, 135.1, 134.2, 132.8,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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4
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7
8
9
0
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6
7
8
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0
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3
4
5
6
7
8
9
0
130.2, 129.8, 128.7, 128.4, 128.2, 128.0, 127.8, 127.2, 89.3, 59.9, 52.9, 51.4, 25.5,
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5
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2
4.3. HRMS (EI): m/z calculated for C H O N Cl S: 509.1058, Found: 509.1056.
27 24 5
(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-fluorophenyl)sulfonyl)-3-phenyl-1, 3,
3
a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3g) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-
1-((4-fluorophenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]
1
isoxazole (4g): White solid (3g + 4g = 43 mg, 46 % yield ). 3g: H NMR (400 MHz,
CDCl ): δ 8.05 (dd, J = 8.6, 5.1 Hz, 2H), 7.21 (td, J = 8.6, 2.7 Hz, 2H), 7.14 (h, J =
3
4
6
.2 Hz, 1H), 7.07 (d, J = 4.4 Hz, 3H), 7.01 – 6.92 (m, 1H), 6.81 (d, J = 7.6 Hz, 2H),
.68 (d, J = 8.5 Hz, 2H), 5.93 (d, J = 4.3 Hz, 1H), 5.70 (d, J = 9.5 Hz, 1H), 4.96 –
4.80 (m, 1H), 4.28 (t, J = 8.8 Hz, 1H), 2.58 – 2.21 (m, 2H), 2.13 (m, 1H), 2.10 – 1.88
1
3
1
(
m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 166.3 (d, J = 255 Hz), 140.0, 136.8,
3 C-F
1
34.6, 132.5, 132.4 (d, JC-F = 10 Hz), 132.3 (d, JC-F = 3 Hz), 129.1, 128.5, 128.4, 128.3,
1
9
1
27.8, 127.2, 116.7 (d, JC-F = 23 Hz), 86.8, 58.8, 47.8, 26.0, 23.2. F NMR (471 MHz,
35
32
CDCl ): δ -103.0. HRMS (EI): m/z calculated for C H O N ClF S: 469.0909,
3
25 21
3
Found: 469.0909.
1
4
g: H NMR (400 MHz, CDCl ): δ 8.05 (dd, J = 8.6, 5.1 Hz, 2H), 7.21 (td, J = 8.6,
3
2.7 Hz, 2H), 7.14 (h, J = 4.2 Hz, 1H), 7.07 (d, J = 4.4 Hz, 3H), 7.01 – 6.92 (m, 1H),
6.87 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 6.05 (t, J = 3.9 Hz, 1H), 4.74 (d, J =
9.9 Hz, 1H), 4.63 (m, 1H), 3.68 (t, J = 8.6 Hz, 1H), 2.58 – 2.21 (m, 2H), 2.13 (m, 1H),
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2.10 – 1.88 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 166.4 (d, J = 255 Hz),
3
C-F
1
1
38.1, 136.8, 134.3, 132.9, 132.7 (d, JC-F = 10 Hz), 131.6 (d, JC-F = 3 Hz), 128.5, 128.7,
28.2, 128.0, 127.7, 127.8, 116.6 (d, JC-F = 23 Hz), 89.4, 60.0, 52.5, 25.5, 24.4. 19F
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (471 MHz, CDCl ): δ -102.8. HRMS (EI): m/z calculated for
3
3
5
32
C H O N ClF S: 469.0909, Found: 469.0909.
2
5
21
3
(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-chlorophenyl)sulfonyl)-3-phenyl-1, 3,
a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3h) / (3S, 3aS, 7aR)-4-(4-Chloro
phenyl)-1-((4-chlorophenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7,
3
7a-hexahydrobenzo[c] isoxazole (4h) : White solid (3h + 4h = 30 mg, 30 % yield ).
1
3
h: H NMR (400 MHz, CDCl ): δ 8.02 – 7.91 (m, 2H), 7.55 – 7.46 (m, 2H), 7.10 –
3
6.90 (m, 5H), 6.84 – 6.77 (m, 2H), 6.74 – 6.61 (m, 2H), 5.92 (m, 1H), 5.69 (d, J = 9.4
Hz, 1H), 4.86 (m, 1H), 4.26 (t, J = 8.8 Hz, 1H), 2.54 – 2.33 (m, 1H), 2.33 – 2.18 (m,
13
1
1
H), 2.12 (m, 1H), 2.05 – 1.87 (m, 1H). C{ H} NMR (100 MHz, CDCl ): δ 140.7,
3
139.7, 135.1, 134.8, 134.3, 132.3, 130.6, 129.4, 128.8, 128.1, 127.9, 127.5, 126.9,
3
5
32
8
6.5, 58.5, 47.5, 25.8, 22.9. HRMS (EI): m/z calculated for C H O N Cl S:
25 21 3 2
485.0614, Found: 485.0616.
1
4
h: H NMR (400 MHz, CDCl ): δ 7.96 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz,
3
2H), 7.21 – 7.01 (m, 5H), 6.88 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 8.1 Hz, 2H), 6.05 (t, J
4.0 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.63 (p, J = 5.3 Hz, 1H), 3.68 (t, J = 8.6 Hz,
=
1
3
1
1
H), 2.62 – 2.29 (m, 2H), 2.23 – 2.06 (m, 1H), 1.98 (m, 1H). C{ H} NMR (100
MHz, CDCl ): δ 140.9, 137.8, 136.5, 134.0, 133.9, 132.6, 131.0, 129.3, 128.5, 128.2,
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1
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2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
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4
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5
5
5
5
5
5
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6
128.0, 127.8, 127.7, 127.6, 89.2, 59.7, 51.2, 25.3, 24.1. HRMS (EI): m/z calculated for
3
5
32
C H O N Cl S: 485.0614, Found: 485.0616.
2
5
21
3
2
(3S, 3aR, 7aS)-1-((4-Bromophenyl)sulfonyl)-4-(4-chlorophenyl)-3-phenyl-1, 3,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3i) / (3S, 3aS, 7aR)-1-((4-bromophenyl)
sulfonyl)-4-(4-chlorophenyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]
1
isoxazole (4i): White solid (3i + 4i = 37 mg, 35 % yield). 3i: H NMR (500 MHz,
CDCl ): δ 7.81 (dq, J = 9.1, 2.2 Hz, 2H), 7.64 – 7.58 (m, 2H), 7.13 - 6.93 (m, 5H),
3
6
.83 – 6.76 (d, J = 8.5 Hz, 2H), 6.70 – 6.63 (d, J = 8.5 Hz, 2H), 5.85 (ddd, J = 5.1, 3.4,
1.4 Hz, 1H), 5.62 (d, J = 9.4 Hz, 1H), 4.79 (ddd, J = 10.6, 7.8, 4.8 Hz, 1H), 4.18 (t, J
1
3
1
=
8.7 Hz, 1H), 2.45 – 2.13 (m, 2H), 2.05 (m, 1H), 1.91 (m, 1H). C{ H} NMR (125
MHz, CDCl ): δ 139.9, 135.5, 135.4, 134.4, 132.5, 132.4, 130.8, 129.5, 129.0, 128.2,
3
1
28.1, 127.7, 127.1, 86.7, 88.7, 47.7, 29.9, 25.9, 23.1. HRMS (EI): m/z calculated for
79
35 32
C H O N Br Cl S: 529.0109, Found: 529.0096.
2
5
21
3
1
4i: H NMR (500 MHz, CDCl ): δ 7.81 (dq, J = 9.1, 2.2 Hz, 2H), 7.64 – 7.58 (m,
3
2
H), 7.13 – 7.03 (m, 1H), 7.03 – 6.93 (m, 4H), 6.93 – 6.84 (m, 2H), 6.76 – 6.70 (m,
2H), 5.97 (dd, J = 5.3, 3.0 Hz, 1H), 4.66 (d, J = 9.8 Hz, 1H), 4.55 (ddd, J = 11.6, 7.2,
.7 Hz, 1H), 3.61 (t, J = 8.6 Hz, 1H), 2.45 – 2.13 (m, 2H), 2.05 (m, 1H), 1.91 (m, 1H).
4
13
1
C{ H} NMR (125 MHz, CDCl ): δ 138.0, 136.6, 134.6, 134.2, 133.8, 132.5, 131.2,
3
129.6, 128.7, 128.3, 128.2, 127.8, 127.7, 89.3, 59.9, 51.5, 29.9, 25.4, 24.3. HRMS
7
9
35 32
(
EI): m/z calculated for C H O N Br Cl S: 529.0109, Found: 529.0096.
25 21 3
(3R, 3aS, 7aR)-4-(4-Chlorophenyl)-1-(methylsulfonyl)-3-phenyl-1, 3, 3a, 6, 7,
a-hexahydrobenzo[c]isoxazole (3j) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-1-(methyl
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sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4j): White solid
1
(
3j + 4j = 20 mg, 25 % yield). 3j: H NMR (400 MHz, CDCl ): δ 7.26 – 7.19 (m, 2H),
3
7
.19 – 7.10 (m, 1H), 7.08 – 6.97 (m, 2H), 6.96 – 6.85 (m, 2H), 6.73 – 6.66 (m, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5.94 (dd, J = 5.7, 3.4 Hz, 1H), 5.81 (d, J = 9.6 Hz, 1H), 4.80 (ddd, J = 10.8, 7.9, 5.0
Hz, 1H), 4.28 (t, J = 8.9 Hz, 1H), 3.22 (s, 3H), 2.53 – 2.35 (m, 1H), 2.36 – 2.21 (m,
1
3
1
1H), 2.12 (m, 1H), 1.95 (m, 1H). C{ H} NMR (125 MHz, CDCl ): δ 137.9, 136.8,
3
1
2
34.2, 132.8, 128.7, 128.4, 128.2, 128.1, 127.9, 127.1, 90.1, 58.4, 51.5, 37.8, 25.1,
35 32
4.7. HRMS (EI): m/z calculated for C H O N Cl S: 389.0847, Found: 389.0846.
2
0
20
3
1
4j: H NMR (400 MHz, CDCl ): δ 7.19 – 7.10 (m, 2H), 7.08 – 6.97 (m, 3H), 6.96 –
3
6
.85 (m, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.05 (d, J = 4.9 Hz, 1H), 4.87 (d, J = 10.4 Hz,
1H), 4.74 – 4.65 (m, 1H), 3.85 – 3.73 (m, 1H), 3.22 (s, 1.6H), 3.18 (s, 1.4H), 2.53 –
1
3
1
2
.35 (m, 1H), 2.36 – 2.21 (m, 1H), 2.12 (m, 1H), 1.95 (m, 1H). C{ H} NMR (125
MHz, CDCl ): δ 139.9, 135.4, 134.6, 133.4, 128.7, 128.4, 128.1, 127.9, 127.7, 127.1,
3
3
5
32
86.9, 57.2, 47.6, 38.2, 25.8, 23.2. HRMS (EI): m/z calculated for C H O N Cl S:
2
0
20
3
3
89.0847, Found: 389.0846.
(3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(o-tolyl)-1-tosyl-1, 3, 3a, 6, 7,
a-hexahydrobenzo[c]isoxazole (3k) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-
7
3
-(o-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4k): White solid
1
(3k + 4k = 74 mg, 80 % yield). 3k: H NMR (400 MHz, CDCl ): δ 7.96 – 7.84 (m,
3
2
H), 7.34 (dd, J = 8.1, 4.1 Hz, 2H), 7.19 – 7.07 (m, 1H), 7.06 – 6.82 (m, 2H), 6.81 –
6.71 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.60 – 6.49 (m, 2H), 5.93 (t, J = 4.6 Hz, 1H),
5
.46 (d, J = 7.6 Hz, 1H), 4.98 – 4.83 (m, 1H), 4.06 (t, J = 7.7 Hz, 1H), 2.44 (m, 5H),
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
6
1
3
1
2.18 (m, 1H), 2.09 – 1.92 (m, 1H), 1.76 (d, J = 17.7 Hz, 3H).
C{ H} NMR (125
MHz, CDCl ): δ 145.2, 137.5, 135.4, 134.9, 133.3, 133.2, 132.8, 131.9, 129.9, 129.6,
3
1
28.0, 127.6, 127.1, 127.0, 126.6, 90.1, 58.4, 51.5, 37.8, 25.1, 24.7. HRMS (EI): m/z
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5
32
calculated for C H O N Cl S: 479.1316, Found: 479.1314.
2
7
26
3
1
4
k: H NMR (400 MHz, CDCl ): δ 7.96 – 7.84 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H),
3
7.34 (dd, J = 8.1, 4.1 Hz, 2H), 7.19 – 7.07 (m, 1H), 7.06 – 6.82 (m, 3H), 6.81 – 6.71
m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.11 (t, J = 4.2 Hz, 0.57H), 5.09 (d, J = 9.7 Hz,
.57H), 4.54 (ddd, J = 11.7, 7.4, 4.8 Hz, 0.57H), 3.62 (t, J = 8.6 Hz, 0.57H). 2.44 (m,
(
0
1
3
1
5H), 2.18 (m, 1H), 2.09 – 1.92 (m, 1H), 1.76 (d, J = 17.7 Hz, 3H). C{ H} NMR (125
MHz, CDCl ): δ 145.3, 140.3, 136.5, 134.6, 133.8, 133.2, 132.2, 130.0, 129.9, 129.8,
3
129.4, 128.3, 127.7, 127.4, 127.0, 126.4, 83.6, 60.1, 51.1, 25.9, 24.5, 24.3, 21.9, 19.3.
3
5
32
HRMS (EI): m/z calculated for C H O N Cl S: 479.1316, Found: 479.1314.
2
7
26
3
(
3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(m-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa
hydrobenzo[c] isoxazole (3l) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-3-(m- tolyl)-1-
tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4l): White solid (3l + 4l = 80
1
mg, 86 % yield). 3l: H NMR (400 MHz, CDCl ): δ 8.00 – 7.82 (m, 2H), 7.34 (t, J =
3
8
.5 Hz, 2H), 7.05 – 6.78 (m, 4H), 6.78 – 6.59 (m, 3H), 6.45 (s, 1H), 5.91 (d, J = 4.5
Hz, 1H), 5.58 (d, J = 9.3 Hz, 1H), 4.81 (ddd, J = 10.3, 7.6, 4.6 Hz, 1H), 4.18 (t, J = 8.7
1
3
1
Hz, 1H), 2.55 – 2.31 (m, 4H), 2.31 – 2.18 (m, 1H), 2.18 – 1.73 (m, 5H). C{ H}
NMR (125 MHz, CDCl ): δ 145.3, 138.2, 137.7, 136.8, 134.5, 132.7, 132.3, 129.8,
3
129.4, 129.0, 128.7, 128.3, 128.1, 127.9, 127.6, 124.4, 88.9, 59.9, 51.5, 25.7, 24.2,
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21.9, 21.2. HRMS (EI): m/z calculated for C H O N Cl S: 479.1316, Found:
2
7
26
3
4
79.1316.
1
4
l: H NMR (400 MHz, CDCl ):δ 8.00 – 7.82 (m, 2H), 7.34 (t, J = 8.5 Hz, 2H),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.05 – 6.78 (m, 4H), 6.78 – 6.59 (m, 3H), 6.54 (s, 1H), 6.03 (t, J = 4.0 Hz, 1H), 4.66
d, J = 9.7 Hz, 1H), 4.54 (ddd, J = 11.8, 7.4, 4.9 Hz, 1H), 3.52 (t, J = 8.9 Hz, 1H), 2.55
(
1
3
1
– 2.31 (m, 4H), 2.31 – 2.18 (m, 1H), 2.18 – 1.73 (m, 5H). C{ H} NMR (125 MHz,
CDCl ): δ 145.2, 140.1, 137.1, 135.4, 134.5, 133.4, 133.4, 129.9, 129.4, 128.9, 128.5,
3
1
27.9, 127.2, 127.8, 124.8, 86.4, 58.9, 47.7, 26.0, 23.1, 21.9, 21.2. HRMS (EI): m/z
3
5
32
calculated for C H O N Cl S: 479.1316, Found: 479.1316.
2
7
26
3
(
3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(p-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa
hydrobenzo[c]isoxazole (3m) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)- 3-(p-tolyl)-
1
-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4m): White solid (3m + 4m
1
=
55 mg, 57 % yield). 3m: H NMR (400 MHz, CDCl ): δ 7.91 (d, J = 7.9 Hz, 2H),
3
7.33 (dd, J = 8.2, 3.9 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.86 (m, 3H), 6.79 – 6.59 (m,
H), 5.91 (d, J = 4.3 Hz, 1H), 5.58 (d, J = 9.3 Hz, 1H), 4.80 (m, 1H), 4.15 (t, J = 8.6
4
1
3
1
Hz, 1H), 2.43 (m,5H), 2.21 (m, 3H), 2.09 (m, 1H), 2.05 – 1.88 (m, 1H). C{ H}
NMR (125 MHz, CDCl ): δ 145.3, 138.4, 138.1, 134.4, 133.3, 132.6, 132.2, 129.8,
3
1
29.4, 128.2, 128.0, 127.8, 127.1, 88.9, 58.9, 47.6, 25.5, 24.2, 21.9, 21.2. HRMS (EI):
3
5
32
m/z calculated for C H O N Cl S: 479.1316, Found: 479.1314.
2
7
26
3
1
4
m: H NMR (400 MHz, CDCl ): δ 7.91 (d, J = 7.9 Hz, 2H), 7.33 (dd, J = 8.2, 3.9
3
Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.86 (m, 3H), 6.79 – 6.59 (m, 4H), 6.02 (t, J = 4.0
Hz, 1H), 4.68 (d, J = 9.7 Hz, 1H), 4.55 (m, 1H), 3.57 (t, J = 8.6 Hz, 1H), 2.43 (m,5H),
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