Regio- and Diastereoselective Access to 4-Imidazolidinones via an Aza-Mannich Initiated Cyclization of Sulfamate-Derived Cyclic Imines with α-Halo Hydroxamates

Article abstract of DOI:10.1021/acs.joc.9b01128

An efficient regio- and diastereoselective cyclization of sulfamate-derived cyclic imines with unsubstituted or monosubstituted α-halo hydroxamates is developed under mild conditions. This reaction proceeds smoothly under transition-metal-free conditions via a domino aza-Mannich addition/intramolecular nucleophilic substitution sequence, providing a convenient route to access 2-monosubstituted and 2,5-disubstituted 4-imidazolidinones. Notably, the products were obtained with single trans-isomers in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.9b01128

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Article
Regio- and Diastereoselective Access to 4-Imidazolidinones
via an Aza-Mannich Initiated Cyclization of Sulfamate-
Derived Cyclic Imines with #-Halo Hydroxamates
Jing Zhou, Hong Zhang, Xue-Lian Chen, Ya-Li Qu, Qianqian Zhu, Chen-guo Feng, and Ya-Jing Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01128 • Publication Date (Web): 17 Jun 2019
Downloaded from http://pubs.acs.org on June 18, 2019
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Page 1 of 9
The Journal of Organic Chemistry
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Regio- and Diastereoselective Access to 4-Imidazolidinones via an Aza-
Mannich Initiated Cyclization of Sulfamate-Derived Cyclic Imines with
α-Halo Hydroxamates
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Jing Zhou,†,£ Hong Zhang,‡,£ Xue-Lian Chen,† Ya-Li Qu,† Qianqian Zhu,§ Chen-Guo Feng,ζ Ya-Jing
Chen*,†
†School of Pharmaceutical Sciences; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of
China; Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University, 100
Science Avenue, Zhengzhou, Henan 450001, P.R. China
‡Mineral Processing and Biometallurgy Institute, Rock and Mineral Testing Center of Henan Province, 28 Jinshui Road,
Zhengzhou, Henan 450012, P.R. China
§College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450001,
P.R. China
ζKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, P.R. China
O
O
S
R1
O
O
O
N
readily available starting materials
transition-metal free, mild conditions
high regio- and diastereoselectivity
domino aza-Mannich/SN
cyclization
2
S
O
R1
N
+
R2
( )
n
O
N
27 examples
up to 99% yield
R3O
OR3
X
O
N
n
n = 1, 2
H
R2
n = 1, 2
ABSTRACT: An efficient regio- and diastereoselective cyclization of sulfamate-derived cyclic imines with unsubstituted or
monosubstituted α-halo hydroxamates is developed under mild conditions. This reaction proceeds smoothly under transition-metal
free conditions via a domino aza-Mannich addition/intramolecular nucleophilic substitution sequence, providing a convenient route
to access 2-monosubstituted and 2,5-disubstituted 4-imidazolidinones. Notably, the products were obtained with single trans-
isomers in moderate to excellent yields.
Scheme 1. Previous Reports and Our Design
INTRODUCTION
Retrosynthetic analysis of 4-imidazolidinones:
4-Imidazolidinones are potential pharmaceuticals with
R2
N
X
R4
R2
N
R1
diverse biological activities,1,2 such as anticancer, antibiotic,
antithrombotic, antidiabetic and antiarrhythmic activities
(Figure 1). Traditional methods for synthesizing these
structure
R4
(1)
+
HN
R3
R1
N
O
R3
O
Different synthetic strategies:
previous work:
[3+2] cycloadditions via azaoxyallyl cations
Ar
Ar
Ar
N
N
N
or
N
Ar
O
S
Ar
R1
R2
O
O
HN
O
OH
R3
O
(a)
S
Ar
N
(2)
(3)
R1
O
OBn
N
N
N
O
N
N
N
N
O
O
N
R2
BnO
N
HN
O
R1
R2
OBn
H
HN
COOMe
N
O
O
H
O
O
X
O
S
O
S
N
O
Anticancer
Hetacillin
Antibiotic
Antithrombotic
R4
R4
N
(b)
R4
O
O
S
X
O
N
Cl
O
H
BnO
this work:
domino aza-Mannich/SN2 cyclization
O
N
N
BnO
N
N
N
O
O
N
O
S
O
N
N
N
F
O
F
F
OMe
O
Cl
motifs rely on time-consuming multistep synthesis from
glycine3 or ketone substrates4 in low yields. The development
of new procedures for general and efficient synthesis of such
key pharmaceutical scaffolds is of great importance.
Antidiabetic
Antiarrhythmic
Figure 1. Biologically active compounds containing the 4-
imidazolidinone scaffolds.
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Page 2 of 9
b
c
mg) in 2 mL of solvent. Isolated yield. Without 4Å MS. HFIP:
1,1,1,3,3,3-hexafluoroisopropanol.
[3+2] cyclizations of imines with α-halo amides are highly
efficient and atom-economical synthetic strategies for the
construction of 4-imidazolidinones (Scheme 1, eq 1). Among
them, α-halo hydroxamates are commonly used 3-atoms
sources due to their easy availability and high reactivity.
Previous methods using α-halo hydroxamates for synthesizing
4-imidazolidinones had used α-substituted substrates as the
materials and the reactions occurred via 1,3-dipole azaoxyallyl
cation species, in situ generated from α-substituted-α-halo
hydroxamates under basic reaction conditions5 (Scheme 1, eq
2). It was supposed that substituents are necessary to stabilize
the formed azaoxyallyl cation species6. Therefore, reactions
with unsubstituted α-halo hydroxamates will be rather
challenging.
1
2
3
4
5
6
7
8
With the optimized conditions in hand, we then explored the
scope and functional group tolerance for this novel process for
synthesizing 2-monosubstituted 4-imidazolidinones. As shown
in Scheme 2, the reactivity of various substituted imines 1 was
examined with unsubstituted α-bromohydroxamate 2a,
providing the desired products in moderate to good yields. The
electronic effect and the position of the substituents showed no
obvious influence on the reaction. For example, imines 1
substituted by either electron-withdrawing groups (F, Cl) (1b,
1c) or electron-donating groups (t-Bu, OMe) (1d, 1e) on the
ortho-position to the sulfonyl group all led to the desired
tricycle products in excellent yields (3ba-3ea). Moreover,
imine substrates substituted by halogen atoms on different
positions of phenyl ring were all successfully converted into
the expected products in excellent yields (3ba-3ca, 3fa-3ha,
3ma-3na). Substrate 1o with a naphthyl was compatible in this
reaction, affording the desired product 3oa in 65% yield. It
should be pointed out that the iminoether adducts 4 were not
detected from crude 1H-NMR analysis and GC-MS analysis in
the cyclization,6a,10 indicating the excellent regioselectivity of
N-atom in the cyclization. Furthermore, the structure of the
product 3ma was confirmed by a single-crystal X-ray analysis.
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On the other hand, sulfamate-derived cyclic imines have
been well studied and successfully employed to synthesize
diverse sulfamidate-derivatived compounds by cyclization
reactions,7 hydrogenations8 and 1,2-additions9. Especially,
they are highly reactive coupling partners in cyclization
reactions.
We envisioned that the formal [3+2] cycloadditions of
sulfamate-derived cyclic imines with unsubstituted α-halo
hydroxamates might occur via a different domino aza-
Mannich addition/intramolecular nucleophilic substitution
process (Scheme 1, eq 3).
Scheme 2. Substrate Scope for Iminesa,b
O
O
O
O
S
O
S
O
O
S
R
O
R
O
N
N
K2CO3, 4Å MS
CH3CN, rt, 24 h
O
Br
F
RESULTS AND DISCUSSION
R
+
OBn
N
H
N
O
N
O
BnO
N
OBn
O
We commenced our work by examining the reaction
between imine 1a and unsubstituted α-bromohydroxamate 2a
(Table 1). The reaction did not give the desired product by
using HFIP as the solvent in the presence of K2CO3 and 4Å
MS at room temperature (entry 1). Other solvents (CH2Cl2,
THF, CH3CN) were screened and CH3CN turned out to be the
best solvent, giving 3aa in 99% yield (entries 2-4).
Subsequently, different bases (Na2CO3, Cs2CO3, Et3N,
K2HPO4) were also tested and decreased yields were observed,
demonstrating that K2CO3 was the best reagent (entries 5-8).
Controlled experiment conducted in the absence of 4Å MS
provided a lower yield of 3aa (entry 9).
4
2a
3
1
t-Bu
Cl
OMe
O
S
O
O
S
O
O
O
O
O
O
O
S
O
O
S
N
O
S
O
N
N
N
N
N
N
N
N
N
BnO
3aa
BnO
BnO
BnO
BnO
O
O
O
O
O
3ba
3ca
3da, 85%
3ea
, 99%
, 95%
, 88%
, 96%
O
O
O
O
O
O
F
O
Cl
O
MeO
O
S O
O
S
N
O
S
N
O
S
N
O
S
N
O
N
N
N
N
N
N
F
BnO
BnO
BnO
3ia
BnO
3ja
, 57%
BnO
O
O
O
O
O
3ga
3ha
, 92%
, 92%
, 90%
3fa
, 85%
O
O
O
O
S
O
O
O
Table 1. Optimization of the Reaction Conditionsa
S
O
S
O
N
N
N
MeO
Br
N
N
N
O
O
BnO
3ka
BnO
3la
BnO
3ma
O
O
O
O
S
N
O
O
O
Base, 4Å MS
Solvent, rt
S
O
Br
OBn
, 83%
, 85%
, 87%
+
N
N
H
N
O
S
O
3ma
(X-ray diffraction)
O
BnO
O
O
2a
O
S
O
1a
3aa
N
N
Cl
N
N
Entry
Base
Solvent Temp.
Time
Yield
BnO
3na
BnO
O
O
(h)
24
24
24
24
24
24
24
24
24
(%)b
NR
20
3oa
, 65%
, 91%
aAll reactions were carried out with 1 (0.2 mmol), 2a (0.24 mmol),
K2CO3 (0.24 mmol), 4Å MS (100 mg) and CH3CN (2 mL) at rt
for 24 h. bIsolated yield.
1
2
3
4
5
6
7
8
9c
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
Et3N
HFIP
rt
rt
rt
rt
rt
rt
rt
rt
rt
CH2Cl2
THF
37
Inspired by these results, we next explored the scope for α-
halo hydroxamates 2. As summarized in Scheme 3,
unsubstituted α-bromohydroxamates
substituents (methyl, 2-naphthylmethylene, pentafluorobenzyl)
on oxygen atom, all produced the desired products 2-
monosubstituted 4-imidazolidinones (3ab-3ad) in moderate to
excellent yields. Unfortunately, the t-Bu substituted α-
bromohydroxamate 2e failed to give the desired product 3ae,
probably due to steric hindrance. When the α-
chlorohydroxamate 2f was applied to this formal [3+2]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
99
80
2
with different
69
51
K2HPO4
43
K2CO3
89
aUnless otherwise noted, all reactions were carried out with 1a
(0.2 mmol), 2a (0.24 mmol), base (0.24 mmol) and 4Å MS (100
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cycloaddition procedure, the expected product 3aa also could
be obtained in 46% yield.
changing the solvent from CH3CN to HFIP, the 5,5-dimethyl
adduct 3am could be obtained in 51% yield (Scheme 4, eq 1).
1
2
3
4
5
6
7
8
9
Moreover,
bromohydroxamate
the
cyclization
2a or
of
unsubstituted
monosubstituted
α-
α-
To our delight, N-Bn protected α-bromoacetamide 2g could
also react with 1a smoothly, providing the desired product 3ag
in 54% yield. This system does not require a strong base for
successful cyclization with α-bromoacetamide 2g,11 perhaps
owing to highly reactive sulfamate-derived cyclic imine 1a as
the coupling partner. The domino reaction was also efficient
when the N-(benzyloxy)-3-bromopropanamide 2h was used,
leading to the desired sulfamidate-fused tetrahydropyrimidin-
4-one 3ah in 70% yield. When using α-bromohydroxamate 2i
with an α-methyl group as the substrate, the 2,5-disubstituted
4-imidazolidinone 3ai was readily obtained in 95% yield,
purely as the trans isomer. Other 2,5-disubstituted 4-
imidazolidinones (3aj-3al) with different substituents (Et, n-Pr,
n-Bu) could be obtained in moderate to excellent yields (45%-
92%). The trans configuration of the 2,5-disubstituted-4-
imidazolidinone 3mi was confirmed by X-ray crystallographic
analysis.
bromohydroxamate 2i with 1a in HFIP does not occur at all.
The opposite reactivity trends of α-bromohydroxamates (2a, 2i
and 2m) observed in HFIP and CH3CN might be caused by
different reaction mechanisms. When using HFIP as the
solvent, the reaction might occur via azaoxyallyl cation
intermediate.5,6,10 While the reaction in CH3CN might occur
via a cascade aza-Mannich/intramole-cular SN2 pathway.6a,11,12
10
11
12
13
14
15
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In order to certify this plausible reaction mechanism, an
optically pure α-methyl-α-bromohydroxamate (R)-2i with 88%
ee was firstly synthesized.13 The reaction between (R)-2i and
1a occurred smoothly under standard conditions, generating
product 3ai in 95% yield with a slight loss in ee (81%)
(Scheme 4, eq 2). This result confirm that the reaction occur
via a cascade aza-Mannich/intramolecular SN2 pathway. If a
[3+2] cycloaddition via azaoxyallyl cation mechanism
operated, we would have seen a racemic product 3ai from (R)-
2i because the transient azaoxyallyl cation is achiral.
Meanwhile, a controlled experiment was conducted in the
absence of 1a under standard conditions (Scheme 4, eq 3). The
optical purity of substrate (R)-2i declined from 88% ee to 55%
ee, indicating the harmful effect of K2CO3 on the racemization
of (R)-2i.
Scheme 3. Substrate Scope for α-Halo Hydroxamatesa,b
O
O
S
N
O
O
S
O
O
R1
K2CO3, 4Å MS
CH3CN, rt, 24 h
O
OR2
X
+
N
H
N
n
n
N
R1
R2O
O
2
(±)3
1a
O
O
O
N
O
S
S
O
O
H
H
N
N
Br
N
N
Br
OMe
OBn
O
O
N
BnO
Scheme 4. Cyclization in HFIP or Using Chiral Substrate
MeO
3ab
O
O
, 70%
2b
2h
3ah
, 89%
O
O
R1 R2
S
N
O
O
S
O
H
O
O
K2CO3, 4Å MS
HFIP, rt, 24 h
O
O
R1
R2
N
S
(1)
+
Me
O
O
S
N
O
Br
OBn
H
N
H
N
N
N
N
O
Br
O
2-Nap
Br
OBn
Me
BnO
O
N
1a
O
O
, R1 = R2 = H
N
2a
2i
3aa,
3ai,
3am
no reaction
no reaction
, 51% yield
O
O
BnO
, R1 = Me; R2 = H
2-Nap
3ac
O
, R1 = R2 = Me
2c
2i
, 92%
O
(±)-3ai
, 95%
2m
O
O
O
S
O
S
N
O
Me
H
O
S
N
O
N
F
F
K2CO3, 4Å MS
CH3CN, rt, 24 h
O
O
H
N
S
Et
+
(2)
(3)
O
O
Me
N
F
H
N
Br
OBn
N
O
Br
O
N
N
O
Et
Br
OBn
F
F
O
O
BnO
1a
O
F
F
N
O
(R)-2i
, 88% ee
BnO
F
F
3ai
, 95% yield
81% ee
O
Me
Me
Br
H
H
K2CO3, 4Å MS
CH3CN, rt, 24 h
N
F
N
Br
OBn
OBn
(±)-3aj
2d
3ad
2j
, 92%
O
, 71%
O
O
O
O
O
(R)-2i
(R)-2i,
55% ee
, 88% ee
S
S
N
Pr
O
H
N
O
H
N
N
Br
Cl
OtBu
Pr
Br
Br
OBn
OBn
Scheme 5. Putative Aza-Mannich Addition/Intramolecular SN2
Reaction Pathway
O
N
N
O
tBuO
BnO
O
O
2e
3ae
2k
Bu
, trace
(±)-3ak
, 54%
O
Favored
O
S
O
O
O
S
O
O
O
S
S
O
O
O
H
N
O
N
H
H
N
R'
N
N
N
R
Br
OBn
Bu
R
H
S
SN
2
Re
O
S
R'
S
1
N
O
O
N
N
O
BnO
N
O
R
BnO
O
BnO
R'
O
O
A1
O
N
aza-Mannich
addition
BnO
trans-3
major product
2f
3aa
2l
, 46%
(±)-3al
, 45%
Br
N
O
O
R
O
O
N
H
R
-BH
H
BnO
B
S
N
Me Me
S
N
O
O
H
H
N
O
O
Br
H
N
O
Me
S
N
O
O
(R)-2
Br
Bn
Br
O
OBn
Si
SN
2
R'
Me
O
O2
N
R
N
R
OBn
S
S
BnO
Bn
O
N
O
O
N
BnO
O
2g
3ag
2m
3am
, not obtained
, 54%
H
A2
R'
3
cis-
minor product
Disfavored
O
O
Me
S
O
O
S
N
H
N
O
On the basis of previous reports6a,14 and the observed results,
we speculate that the reaction might occur through a cascade
aza-Mannich addition/intramolecular SN2 pathway. As
depicted in Scheme 5, under the promotion of base, the
deprotonation on the nitrogen atom of α-bromohydroxamates
2 and the concomitant aza-Mannich addition to imines 1 could
occur, generating intermediates A1 and A2. For the following
intramolecular SN2 substitution reaction, intermediate A1 is
the favored one and A2 is the disfavored one. So, the major
s.r.c
N
O
Me
Br
Br
OBn
+
N
Br
O
BnO
O
1m
2i
(±)-3mi
, 85%
aAll reactions were carried out with 1 (0.2 mmol), 2 (0.24 mmol),
K2CO3 (0.24 mmol), 4Å MS (100 mg) and CH3CN (2 mL) at rt
for 24 h. bIsolated yield.
When α,α-dimethyl α-bromohydroxamate 2m was used as
the starting material, the reaction failed to give the
corresponding product 3am under standard conditions. By
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19F NMR are reported in terms of chemical shift (δ, ppm). LCMS
samples were run on an Acquity UPLC I-Class PLUS system.
High-resolution mass spectra (HRMS) were recorded on a
Thermo Q-Exactive Spectrometer (ESI source).
configuration of generated 4-imidazolidinones 3 will be trans.
The diastereoselectivity could be attributed to the steric effect
between the benzene ring in imines 1 and the substituted group
R in α-bromohydroxamates 2.
1
2
3
4
5
6
7
8
9
General Procedure for Synthesis of Imines 1. Imines 1
were known compounds and synthesized according to reported
methods15. Anhydrous formic acid (40.0 mmol, 1.5 mL, 1 eq) was
added dropwise to neat chlorosulfonyl isocyanate (40.0 mmol, 3.5
Scheme 6. Gram Scale Synthesis of 3aa and Deprotections of
3aa
O
O
S
N
O
O
O
S
s.r.c.
O
o
Br
+
mL, 1 eq) at 0 C with rapid stirring. Vigorous gas evolution was
OBn
O
N
H
gram scale
(1)
(2)
N
N
observed during the addition process. The resulting viscous
suspension was stirred at room temperature until gas evolution
ceased (1-2 h). The resulting colorless solid was used in the
following step immediately. To a solution of aldehyde (15.0
BnO
1a
2a
O
3 mmol
3.6 mmol
3aa
, 97%, 1 g
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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O
O
S
O
S O
H2, MeOH
N
N
o
mmol) in DMA (100 mL) at 0 C was carefully added freshly
10% Pd/C, rt, 4 h
94%
N
N
BnO
HO
prepared ClSO2NH2 (4.6 g, 40.0 mmol) in small portions, and the
resulting solution was stirred for 18 h at room temperature. The
reaction was quenched carefully with ice-cold H2O (100 mL), and
the mixture was transferred to a separating funnel containing
CH2Cl2 (200 mL). The aqueous layer was separated and extracted
with CH2Cl2 (3 × 50 mL), and the combined organic layers were
washed with saturated NaHCO3 solution (100 mL), dried
(MgSO4), filtered through a short pad of silica using CH2Cl2 as
eluent and concentrated in vacuo. Imines 1 were isolated by flash
chromatography (PE/EtOAc) on silica gel.
O
O
3aa
5
O
O
O
O
S
O
S
O
SmI2, THF
(3)
N
N
rt, 12 h
98%
N
N
BnO
H
O
O
3aa
6
The synthesis utility of this protocol was further
demonstrated by performing the reaction on a gram scale
synthesis, which gave the desired product 3aa in 97% yield
(Scheme 6, eq 1). Furthermore, deprotections of the N-OBn of
3aa, generating N-OH and N-H 4-imidazolidinones in 94%
yield and 98% yield respectively, were also demonstrated on
3aa. (Scheme 6, eq 2 and eq 3).
benzo[e][1,2,3]oxathiazine 2,2-dioxide (1a). 1H NMR (400
MHz, CDCl3) δ 8.68 (s, 1H), 7.79-7.74 (m, 1H), 7.70-7.68 (m,
1H), 7.46-7.42 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H) ppm.
1
8-fluorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1b). H NMR
(400 MHz, CDCl3) δ 8.70 (d, J = 1.2 Hz, 1H), 7.59-7.54 (m, 1H),
7.51-7.48 (m, 1H),7.42-7.37 (m, 1H) ppm.
8-chlorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1c). H NMR
CONCLUSIONS
1
In conclusion, we have developed a newly regioselective
and diastereoselective cyclization between sulfamate-derived
cyclic imines and unsubstituted or monosubstituted α-
halohydroxamates via an aza-Mannich addition/intramolecular
nucleophilic substitution reaction. This reaction was
successfully performed under mild conditions with excellent
tolerance of a wide range of functional groups, which afforded
the single trans isomers in moderate to good yields.
Remarkably, the process does not require fluorinated solvents
or metals for successful cyclization, providing a practical route
to prepare 4-imidazolidinones. Detailed mechanistic insight
along with catalyzed asymmetric approach is currently
underway.
(400 MHz, CDCl3) δ 8.67 (s, 1H), 7.80 (dd, J = 8.4 Hz, J =1.6 Hz,
1H), 7.61 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H)
ppm.
8-(tert-butyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide (1d). 1H
NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.75 (dd, J = 8.0 Hz, J =
1.6 Hz, 1H), 7.52 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.36 (t, J = 7.8
Hz, 1H), 1.48 (s, 9H) ppm.
8-methoxybenzo[e][1,2,3]oxathiazine 2,2-dioxide (1e) 1H NMR
(400 MHz, CDCl3) δ 8.65 (s, 1H), 7.37-7.30 (m, 2H), 7.25-7.23
(m, 1H), 3.97 (s, 3H) ppm.
1
5-fluorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1f). H NMR
(400 MHz, CDCl3) δ 8.96 (s, 1H), 7.78-7.72 (m, 1H), 7.15-7.11
(m, 2H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 161.9 (d, J =
6.0 Hz), 161.1 (d, J = 261.9 Hz), 154.7 (d, J = 3.0 Hz), 139.0 (d, J
= 11.0 Hz), 114.6 (d, J = 4.0 Hz), 112.8 (d, J = 20.0 Hz), 105.9 (d,
J = 17.0 Hz) ppm.
EXPERIMENTAL SECTION
General Information. All reactions were performed in oven-
dried glassware with magnetic stirring. Unless otherwise stated,
all reagents were purchased from commercial suppliers and used
without further purification. All solvents were purified and dried
according to standard methods prior to use. Organic solutions
were concentrated under reduced pressure on a rotary evaporator
or an oil pump. Reactions were monitored through thin layer
chromatography (TLC) on silica gel-precoated glass plates.
Subsequent to elution, plates were visualized using UV radiation
at 254 nm and by staining with aqueous potassium permanganate
or ethanolic phosphomolybdic acid solution. Flash column
chromatography was performed using silica gel (300-400 mesh).
Nuclear Magnetic Resonance (NMR) spectras were acquired on a
1
7-fluorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1g). H NMR
(400 MHz, CDCl3) δ 8.63 (s, 1H), 7.74-7.70 (m, 1H), 7.17-7.12
(m, 1H), 7.04-7.02 (m,1H) ppm.
7-chlorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1h). H NMR
1
(400 MHz, CDCl3) δ 8.64 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.41
(dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H) ppm.
1
7-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide (1i). H NMR
(400 MHz, CDCl3) δ 8.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.22
(d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 2.51 (s, 3H) ppm.
7-methoxybenzo[e][1,2,3]oxathiazine 2,2-dioxide (1j). 1H
NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H),
6.90 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H),
3.94 (s, 3H) ppm.
1
Varian Mercury 400 operating at 400, 100 and 376 MHz for H,
1
6-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide (1k). H NMR
13C and 19F, respectively. Chemical shifts are reported in δ ppm
(400 MHz, CDCl3) δ 8.62 (s, 1H), 7.55 (dd, J = 8.8 Hz, J = 1.8
Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 2.45
(s, 3H) ppm.
referenced to an internal SiMe4 standard for 1H NMR,
1
chloroform-d (δ 77.16) for 13C NMR. Datas for H NMR are
recorded as follows: chemical shift (δ ppm), multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad),
coupling constant (Hz) and integration. Datas for 13C NMR and
6-methoxybenzo[e][1,2,3]oxathiazine 2,2-dioxide (1l). 1H
NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.30-7.27 (m, 1H), 7.23
(d, J = 9.2 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 3.88 (s, 3H) ppm.
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The Journal of Organic Chemistry
6-bromobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1m). 1H NMR
(400 MHz, CDCl3) δ 8.63 (s, 1H), 7.86-7.82 (m, 2H), 7.21 (d, J =
General Procedure for [3+2] Annulation Reaction. In a
10 mL test tube was sequentially added imine 1 (0.2 mmol, 1.0
eq), K2CO3 (0.24 mmol, 1.2 eq), α-halo hydroxamate 2 (0.24
mmol, 1.2 eq), 4Å MS (100 mg) and MeCN (2.0 mL). Then the
tube was sealed and stirred at room temperature. Once the imine 1
was completed consumption (24 h), the reaction mixture was
concentrated under reduced pressure and the resulting residue was
purified by flash column chromatography on silica gel to afford
the pure product 3. (hexane/EtOAc = 7/2 for 3aa, 3ea, 3ja, 3la,
3ma, 3ag, 3ah; hexane/EtOAc = 4/1 for 3ba, 3fa, 3ga, 3ka, 3ac;
hexane/EtOAc = 5/1 for 3ca, 3da, 3ha, 3ia, 3na, 3oa, 3ad, 3ai;
DCM/EtOAc = 100:1 for 3ab; petroleum ether/EtOAc = 6:1 for
3aj, 3mi; petroleum ether/EtOAc = 7:1 for 3am; petroleum
ether/EtOAc = 8:1 for 3ak, 3al).
1
2
3
4
5
6
7
8
8.8 Hz, 1H) ppm.
6-chlorobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1n). H NMR
1
(400 MHz, CDCl3) δ 8.64 (s, 1H), 7.72-7.67 (m, 2H), 7.29-7.26
(m, 1H) ppm.
naphtho[1,2-e][1,2,3]oxathiazine 3,3-dioxide (1o). 1H NMR
(400 MHz, CDCl3) δ 10.0 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.55
(d, J = 9.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.90-7.86 (m, 1H),
7.76-7.72 (m, 1H), 7.67 (d, J = 9.2 Hz, 1H) ppm.
General Procedure for Synthesis of α-Halo
9
Hydroxamates 2. α-Halo hydroxamates
2 were known
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14
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16
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compounds and synthesized according to reported methods16. To a
solution of O-substituted hydroxylamine hydrochloride (12.5
mmol, 1.0 eq) in dichloromethane (50 mL), triethylamine (1.75
mL, 12.5 mmol, 1.0 eq) was added. The reaction mixture was then
1-(benzyloxy)-1,10b-dihydrobenzo[e]imidazo[1,2-c][1,2,3]oxa-
thiazin-2(3H)-one 5,5-dioxide (3aa). This compound was
prepared via general procedure as light yellow granular powder
o
cooled to 0 C in an ice water bath. Next, 2-halo acyl bromide
o
1
(69 mg, 99% yield). m. p. 132-135 C. H NMR (400 MHz,
CDCl3) δ 7.58 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 7.48-7.42 (m,
6H), 7.28 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.09 (dd, J = 8.0 Hz, J
= 0.8 Hz, 1H), 5.80 (s, 1H), 5.16 (d, J = 10.8 Hz, 1H), 5.02 (d, J =
10.4 Hz, 1H), 4.07-4.00 (m, 2H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 162.7, 149.6, 133.8, 131.6, 130.0, 129.9, 129.2, 128.5,
126.5, 119.3, 117.8, 78.9, 73.2, 48.1 ppm; LRMS (ESI): m/z
347.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd. for
C16H15N2O5S [M+H]+: 347.0696, found: 347.0687.
1-(benzyloxy)-7-fluoro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ba). This compound
was prepared via general procedure as light yellow powder (69
mg, 95% yield). m. p. 121-124 oC. 1H NMR (400 MHz, CDCl3) δ
7.49-7.36 (m, 5H), 7.36-7.34 (m, 1H), 7.27-7.19 (m, 2H), 5.79 (s,
1H), 5.16 (d, J = 10.4 Hz, 1H), 5.05 (d, J = 10.4 Hz, 1H), 4.04 (s,
2H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 162.5, 151.1 (d, J =
252.3 Hz), 138.2 (d, J = 14.1 Hz), 133.6, 130.0, 129.9, 129.3,
126.4 (d, J = 6.8 Hz), 123.3(d, J = 4.2 Hz), 119.7, 118.6 (d, J =
17.4 Hz), 79.0, 73.1, 48.0 ppm; 19F NMR (376 MHz, CDCl3) δ -
130.7 ppm; LRMS (ESI): m/z 365.1 [M+H]+; HRMS (ESI): m/z
Exact mass calcd. for C16H14FN2O5S [M+H]+: 365.0602, found:
365.0608.
1-(benzyloxy)-7-chloro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ca). This compound
was prepared via general procedure as yellow powdery solid (67
mg, 88% yield). m. p. 167-170 oC. 1H NMR (400 MHz, CDCl3) δ
7.52-7.43 (m, 7H), 7.20 (t, J = 8.0 Hz, 1H), 5.77 (s, 1H), 5.16 (d,
J = 10.4 Hz, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.10-4.02 (m, 2H)
ppm; 13C{H} NMR (100 MHz, CDCl3) δ 162.5, 145.7, 133.6,
132.3, 130.0, 129.9, 129.3, 126.7, 126.5, 124.5, 119.6, 79.0, 73.2,
48.0 ppm; LRMS (ESI): m/z 381.1 [M+H]+; HRMS (ESI): m/z
Exact mass calcd. for C16H14ClN2O5S [M+H]+: 381.0306, found:
381.0308.
(12.5 mmol, 1.0 eq) was added dropwise to the reaction mixture.
The reaction was stirred at 0 ºC. After 4 h, the mixture was
allowed to warm to room temperature. The reaction was then
quenched with water. The resulting mixture was diluted with
CH2Cl2 and washed with 3x water, followed by brine. The organic
layers were dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The crude reaction mixture was
purified by silica gel chromatography (PE/EtOAc) to give α-halo
hydroxamates 2.
N-(benzyloxy)-2-bromoacetamide (2a). 1H NMR (400 MHz,
CDCl3) δ 8.69 (s, 1H), 7.42-7.38 (m, 5H), 4.95 (s, 2H), 3.80 (s,
2H) ppm.
2-bromo-N-methoxyacetamide (2b). 1H NMR (400 MHz,
CDCl3) δ 9.83 (s, 1H), 3.83-3.81 (m, 5H) ppm.
1
2-bromo-N-(naphthalen-2-ylmethoxy)acetamide (2c). H NMR
(400 MHz, CDCl3) δ 8.75 (s, 1H), 7.90-7.85 (m, 4H), 7.55-7.51
(m, 3H), 5.10 (s, 2H), 3.94-3.77 (m, 2H) ppm.
2-bromo-N-((perfluorophenyl)methoxy)acetamide (2d). 1H
NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 5.09 (s, 2H), 3.81 (s, 2H)
ppm.
1
2-bromo-N-(tert-butoxy)acetamide (2e). H NMR (400 MHz,
CDCl3) δ 8.59 (s, 1H), 3.85 (s, 2H), 1.30 (s, 9H) ppm.
N-(benzyloxy)-2-chloroacetamide (2f). 1H NMR (400 MHz,
CDCl3) δ 8.97 (s, 1H), 7.42-7.38 (m, 5H), 4.94 (s, 2H), 4.01 (s,
2H) ppm.
1
N-benzyl-2-bromoacetamide (2g) H NMR (400 MHz, CDCl3)
δ 7.39-7.29 (m, 5H), 6.75 (s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.94
(s, 2H) ppm.
N-(benzyloxy)-3-bromopropanamide (2h). 1H NMR (400 MHz,
CDCl3) δ 8.34 (s, 1H), 7.42-7.36 (m, 5H), 4.93-4.84 (m, 2H),
3.63-3.56 (m, 2H), 2.95-3.94 (m, 1H), 2.63-2.60 (m, 1H) ppm.
1
N-(benzyloxy)-2-bromopropanamide (2i). H NMR (400 MHz,
CDCl3) δ 8.30 (s, 1H), 7.41-7.38 (m, 5H), 4.94-4.84 (m, 2H),
1-(benzyloxy)-7-(tert-butyl)-1,10b-dihydrobenzo[e]imidazo[1,-
3.45-3.42 (m, 2H), 2.76-2.09 (m, 3H).
N-(benzyloxy)-2-bromobutanamide (2j). H NMR (400 MHz,
1
2-c][1,2,3]oxathiazin-2(3H)-one
5,5-dioxide
(3da).
This
compound was prepared via general procedure as pink solid
CDCl3) δ 8.65 (s, 1H), 7.42-7.38 (m, 5H), 4.97-4.91 (m, 2H),
4.15-4.12 (m, 1H), 2.14-1.99 (m, 2H), 1.01 (t, J = 3.0 Hz, 3H)
ppm.
o
1
powder (68 mg, 85% yield). m. p. 155-157 C. H NMR (400
MHz, CDCl3) δ 7.46 (dd, J = 6.0 Hz, J = 1.4 Hz, 1H), 7.45-7.38
(m, 5H), 7.37 (dd, J = 8.0 Hz, J = 3.0 Hz, 1H), 7.22 (t, J = 7.8 Hz,
1H), 5.80 (d, J = 1.6 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.80 (d, J
= 10.4 Hz, 1H), 4.20 (dd, J = 15.2 Hz, J = 1.6 Hz, 1H), 4.01 (d, J
= 14.8 Hz, 1H), 1.41 (s, 9H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 163.4, 149.3, 141.0, 133.7, 129.9, 129.8, 129.4, 129.1,
126.8, 126.0, 118.6, 78.9, 74.2, 48.5, 35.3, 30.1 ppm; LRMS
(ESI): m/z 403.2 [M+H]+; HRMS (ESI): m/z Exact mass calcd.
for C20H23N2O5S [M+H]+: 403.1317, found: 403.1318 .
1
N-(benzyloxy)-2-bromopentanamide (2k) H NMR (400 MHz,
CDCl3) δ 8.63 (s, 1H), 7.42-7.38 (m, 5H), 4.97-4.91 (m, 2H),
4.27-4.16 (m, 1H), 2.09-1.99 (m, 2H), 1.44-1.32 (m, 2H), 0.93-
0.88 (m, 3H) ppm.
1
N-(benzyloxy)-2-bromohexanamide (2l) H NMR (400 MHz,
CDCl3) δ 9.45 (s, 1H), 7.40-7.32 (m, 5H), 4.90 (s, 2H), 4.14-4.07
(m, 1H), 2.08-1.92 (m, 2H), 1.38-1.26 (m, 4H), 0.93-0.87 (m, 3H)
ppm.
N-(benzyloxy)-2-bromo-2-methylpropanamide (2m) 1H NMR
(400 MHz, CDCl3) δ 9.00 (s, 1H), 7.35-7.32 (m, 5H), 4.87-4.86
(m, 2H), 1.87-1.84 (m, 6H) ppm.
1-(benzyloxy)-7-methoxy-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ea). This compound
was prepared via general procedure as yellow powder (72 mg, 96%
yield). m. p. 147-150 oC. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44
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(m, 5H), 7.21 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.01 (d,
ppm; LRMS (ESI): m/z 377.1 [M+H]+; HRMS (ESI): m/z Exact
mass calcd. for C17H17N2O6S [M+H]+: 377.0802, found: 377.0791.
1-(benzyloxy)-9-methyl-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ka). This compound
was prepared via general procedure as light yellow powder (60
mg, 83% yield). m. p. 140-143 oC. 1H NMR (400 MHz, CDCl3) δ
7.48-7.44 (m, 5H), 7.34 (d, J = 1.2 Hz, 1H), 7.23 (dd, J = 8.4 Hz,
J = 1.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.76 (s, 1H), 5.18 (d, J
= 10.8 Hz, 1H), 4.98 (d, J = 10.8 Hz, 1H), 4.05 (dd, J = 14.8 Hz, J
1
2
3
4
5
6
7
8
J = 8.0 Hz, 1H), 5.80 (s, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.99 (d, J
= 10.4 Hz, 1H), 4.09-3.99 (m, 2H), 3.89 (s, 3H) ppm; 13C{H}
NMR (100 MHz, CDCl3) δ 162.7, 149.1, 139.2, 133.7, 129.91,
129.90, 129.2, 126.3, 119.2, 118.8, 114.0, 78.9, 73.4, 56.4, 48.1
ppm; LRMS (ESI): m/z 377.1 [M+H]+; HRMS (ESI): m/z Exact
mass calcd. for C17H17N2O6S [M+H]+: 377.0802, found: 377.0795.
1-(benzyloxy)-10-fluoro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3fa). This compound
was prepared via general procedure as light yellow solid (62 mg,
= 1.2 Hz,1H), 4.00 (d, J = 14.8 Hz, 1H), 2.34 (s, 3H) ppm; 13C{H}
NMR (100 MHz, CDCl3) δ 162.8, 147.5, 136.4, 133.8, 132.2,
129.91, 129.87, 129.2, 128.7, 119.0, 117.2, 78.9, 73.3, 48.1, 21.1
ppm; LRMS (ESI): m/z 361.1 [M+H]+; HRMS (ESI): m/z Exact
mass calcd. for C17H17N2O5S [M+H]+: 361.0853, found: 361.0857.
1-(benzyloxy)-9-methoxy-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3la). This compound
was prepared via general procedure as light yellow solid (64 mg,
o
1
85% yield). m. p. 146-150 C. H NMR (400 MHz, CDCl3) δ
7.47-7.43 (m, 3H), 7.41-7.39 (m, 3H), 7.06-7.02 (m, 1H), 6.96-
6.94 (m, 1H), 6.27 (d, J = 1.2 Hz, 1H), 5.15 (d, J = 10.0 Hz, 1H),
4.92 (d, J = 10.0 Hz, 1H), 4.22 (dd, J = 15.2 Hz, J = 2.0 Hz, 1H),
4.04 (d, J = 15.2 Hz, 1H) ppm; 13C{H} NMR (100 MHz, CDCl3)
δ 162.9, 161.1 (d, J = 252.4 Hz), 151.0 (d, J = 5.8 Hz), 133.4,
132.7 (d, J = 9.7 Hz), 130.1 (d, J = 1.0 Hz), 129.7, 128.9, 115.6 (d,
J = 3.6 Hz), 114.2 (d, J = 21.4 Hz), 107.8 (d, J = 19.0 Hz), 78.6,
70.8, 48.4 ppm; 19F NMR (376 MHz, CDCl3) δ -110.5 ppm;
LRMS (ESI): m/z 365.1 [M+H]+; HRMS (ESI): m/z Exact mass
calcd. for C16H14FN2O5S [M+H]+: 365.0602, found: 365.0606.
1-(benzyloxy)-8-fluoro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ga). This compound
was prepared via general procedure as yellow granular powder
9
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56
57
58
59
60
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1
85% yield). m. p. 140-143 C. H NMR (400 MHz, CDCl3) δ
7.49-7.43 (m, 5H), 7.03-7.01 (m, 2H), 6.94 (dd, J = 9.0 Hz, J =
3.0 Hz, 1H), 5.76 (s, 1H), 5.16 (d, J = 10.8 Hz, 1H), 5.04 (d, J =
10.8 Hz, 1H), 4.02 (s, 2H), 3.73 (s, 3H) ppm; 13C{H} NMR (100
MHz, CDCl3) δ 162.9, 157.3, 143.1, 133.8, 129.9, 129.8, 129.2,
120.2, 118.3, 117.2, 113.1, 79.0, 73.2, 55.9, 48.1 ppm; LRMS
(ESI): m/z 377.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd.
for C17H17N2O6S [M+H]+: 377.0802, found: 377.0798.
o
1
(67 mg, 92% yield). m. p. 176-180 C. H NMR (400 MHz,
CDCl3) δ 7.57-7.53 (m, 1H), 7.49-7.44 (m, 5H), 7.01-6.96 (m,
1H), 6.83 (dd, J = 8.6 Hz, J = 2.6 Hz, 1H), 5.74 (s, 1H), 5.15 (d, J
= 10.8 Hz, 1H), 5.05 (d, J = 10.8 Hz, 1H), 4.03 (s, 2H) ppm;
13C{H} NMR (100 MHz, CDCl3) δ 163.6 (d, J = 252.0 Hz), 162.6,
150.4 (d, J = 11.9 Hz), 133.7, 130.1 (d, J = 9.8 Hz), 130.0, 129.9,
129.3, 114.0 (d, J = 21.5 Hz), 113.8 (d, J = 4.0 Hz), 107.2 (d, J =
25.5 Hz), 79.0, 72.9, 48.0 ppm; 19F NMR (376 MHz, CDCl3) δ -
106.2 ppm; LRMS (ESI): m/z 365.1 [M+H]+; HRMS (ESI): m/z
Exact mass calcd. for C16H14FN2O5S [M+H]+: 365.0602, found:
365.0608.
1-(benzyloxy)-9-bromo-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ma). This compound
was prepared via general procedure as yellow powder (74 mg, 87%
yield). m. p. 140-143 oC. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J
= 2.0 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.51-7.45 (m, 5H), 6.98
(d, J = 8.8 Hz, 1H), 5.69 (s, 1H), 5.19 (d, J = 10.8 Hz, 1H), 5.03
(d, J = 10.8 Hz, 1H), 4.03-4.02 (m, 2H) ppm; 13C{H} NMR (100
MHz, CDCl3) δ 162.7, 148.6, 134.7, 133.6, 131.4, 130.1, 130.0,
129.3, 121.0, 119.6, 119.2, 79.2, 72.8, 48.0 ppm; LRMS (ESI):
m/z 425.0 [M+H]+. HRMS (ESI): m/z Exact mass calcd. for
C16H14BrN2O5S [M+H]+: 424.9801, found: 424.9808.
1-(benzyloxy)-9-chloro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3na). This compound
was prepared via general procedure as white powder (69 mg, 91%
yield). m. p. 146-150 oC. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J
= 2.4 Hz, 1H), 7.51-7.45 (m, 5H), 7.40 (dd, J = 8.8 Hz, J = 2.8 Hz,
1H), 7.04 (d, J = 8.8 Hz, 1H), 5.68 (s, 1H), 5.19 (d, J = 10.4 Hz,
1H), 5.04 (d, J = 10.8 Hz, 1H), 4.02 (s, 2H) ppm; 13C{H} NMR
(100 MHz, CDCl3) δ 162.6, 148.0, 133.6, 131.8, 131.7, 130.1,
130.0, 129.3, 128.5, 120.7, 119.2, 79.1, 72.9, 48.0 ppm; LRMS
(ESI): m/z 381.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd.
for C16H14ClN2O5S [M+H]+: 381.0306, found: 381.0308 .
1-(benzyloxy)-1,12c-dihydroimidazo[1,2-c]naphtho[1,2-e][1,-
2,3]oxathiazin-2(3H)-one 5,5-dioxide (3oa). This compound was
prepared via general procedure as white powder (51 mg, 65%
yield). m. p. 161-164 oC. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J
= 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.62-7.53 (m, 2H), 7.36-7.35 (m, 1H), 7.21-7.17 (m, 2H), 6.87-
6.86 (m, 3H), 5.00 (s, 1H), 4.85 (d, J = 9.2 Hz, 1H), 4.51 (dd, J =
15.6 Hz, J = 1.6 Hz, 1H), 4.12 (d, J = 15.6 Hz, 1H), 4.07 (d, J =
9.2 Hz, 1H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 164.7,
149.4, 133.3, 132.9, 129.8, 129.2, 129.0, 128.5, 128.4, 128.3,
128.2, 126.6, 123.5, 118.7, 113.0, 79.0, 72.6, 48.8 ppm; LRMS
(ESI): m/z 397.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd.
for C20H17N2O5S [M+H]+: 397.0853, found: 397.0859.
1-(benzyloxy)-8-chloro-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ha). This compound
was prepared via general procedure as light yellow solid (70 mg,
o
1
92% yield). m. p. 163-165 C. H NMR (400 MHz, CDCl3) δ
7.50-7.44 (m, 6H), 7.23 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 7.11 (d,
J = 2.0 Hz, 1H), 5.73 (s, 1H), 5.15 (d, J = 10.8 Hz, 1H), 5.06 (d, J
= 10.8 Hz, 1H), 4.03 (s, 2H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 162.6, 149.9, 137.3, 133.7, 130.1, 129.9, 129.5, 129.3,
126.8, 119.7, 116.2, 79.0, 72.9, 48.0 ppm; LRMS (ESI): m/z
381.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd. for
C16H14ClN2O5S [M+H]+: 381.0306, found : 381.0311.
1-(benzyloxy)-8-methyl-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ia). This compound
was prepared via general procedure as light yellow granular
o
1
powder (65 mg, 90% yield). m. p. 155-157 C. H NMR (400
MHz, CDCl3) δ 7.49-7.43 (m, 6H), 7.07 (dd, J = 8.0 Hz, J = 0.8
Hz, 1H), 6.90 (s, 1H), 5.77 (s, 1H), 5.15 (d, J = 10.8 Hz, 1H), 5.00
(d, J = 10.4 Hz, 1H), 4.04 (dd, J = 14.8 Hz, J = 1.2 Hz, 1H), 4.00
(d, J = 14.8 Hz, 1H), 2.37 (s, 3H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 162.8, 149.4, 142.6, 133.8, 129.90, 129.88, 129.2, 128.2,
127.3, 119.5, 114.7, 78.9, 73.2, 48.1, 21.3 ppm; LRMS (ESI): m/z
361.2 [M+H]+; HRMS (ESI): m/z Exact mass calcd. for
C17H17N2O5S [M+H]+: 361.0853, found: 361.0842.
1-(benzyloxy)-8-methoxy-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ja). This compound
was prepared via general procedure as dark yellow powder (43
mg, 57% yield). m. p. 196-198 oC. 1H NMR (400 MHz, CDCl3) δ
7.46-7.44 (m, 6H), 6.80 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.59 (d,
J = 2.0 Hz, 1H), 5.76 (s, 1H), 5.14 (d, J = 10.4 Hz, 1H), 5.01 (d, J
= 10.4 Hz, 1H), 4.7-3.99 (m, 2H), 3.81 (s, 3H) ppm; 13C{H}
NMR (100 MHz, CDCl3) δ 162.8, 161.9, 150.6, 133.8, 129.91,
129.90, 129.3, 129.2, 113.2, 109.5, 104.1, 78.9, 73.1, 55.9, 48.2
1-methoxy-1,10b-dihydrobenzo[e]imidazo[1,2-c][1,2,3]oxathia
zin-2(3H)-one5,5-dioxide (3ab). This compound was prepared via
1
general procedure as colorless oil (48 mg, 89% yield). H NMR
(400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.2 Hz,
1H), 7.32 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.25 (s,
1H), 4.09 (dd, J = 14.8 Hz, J = 1.2 Hz, 1H), 4.02 (d, J = 10.8 Hz,
1H), 3.92 (s, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 162.5,
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The Journal of Organic Chemistry
149.7, 131.7, 128.4, 126.6, 119.4, 118.1, 72.4, 64.2, 48.2 ppm;
1H), 7.49-7.41 (m, 6H), 7.29-7.25 (m, 1H), 7.08 (d, J = 8.4 Hz,
1H), 5.74 (d, J = 1.6 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 4.97 (d, J
= 10.8 Hz, 1H), 4.22-4.19 (m, 1H), 2.12-2.04 (m, 2H), 1.00 (t, J =
7.4 Hz, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 163.9,
148.6, 132.9, 130.5, 129.0, 128.9, 128.1, 127.8, 125.2, 118.2,
117.1, 77.8, 71.7, 59.2, 23.1, 6.7 ppm; LRMS (ESI): m/z 375.1
[M+H]+; HRMS (ESI): m/z Exact mass calcd. for C18H19N2O5S
[M+H]+: 375.1009, found: 375.1015.
1
2
3
4
5
6
7
8
LRMS (ESI): m/z 271.1 [M+H]+; HRMS (ESI): m/z Exact mass
calcd. for C10H11N2O5S [M+H]+: 271.0383, found: 271.0387.
1-(naphthalen-2-ylmethoxy)-1,10b-dihydrobenzo[e]imidazo[1,-
2-c]-[1,2,3]oxathiazin-2(3H)-one
5,5-dioxide
(3ac).
This
compound was prepared via general procedure as white solid (73
mg, 92% yield). m. p. 108-111 oC. 1H NMR (400 MHz, CDCl3) δ
7.93-7.87 (m, 4H), 7.61-7.53 (m, 4H), 7.43-7.39 (m, 1H), 7.26-
7.22 (m, 1H), 7.08-7.06 (m, 1H), 5.89 (s, 1H), 5.31 (d, J = 10.8
Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.08 (dd, J = 14.8 Hz, J = 1.6
Hz, 1H), 4.03 (d, J = 14.8 Hz, 1H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 162.9, 149.6, 133.8, 133.3, 131.6, 131.1, 129.7, 129.1,
128.6, 128.3, 128.0, 127.2, 126.9, 126.7, 126.4, 119.3, 117.8, 79.1,
73.3, 48.1 ppm; LRMS (ESI): m/z 397.1 [M+H]+; HRMS (ESI):
m/z Exact mass calcd. for C20H17N2O5S [M+H]+: 397.0853, found:
397.0850.
1-((perfluorophenyl)methoxy)-1,10b-dihydrobenzo[e]imidazo
[1,2-c][1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ad). This
compound was prepared via general procedure as colorless oil (62
mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H),
7.31-7.26 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.05 (s, 1H), 5.21-
5.15 (m, 2H), 4.18 (dd, J = 15.6 Hz, J = 1.6 Hz, 1H), 4.03 (d, J =
15.6 Hz, 1H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 164.6,
149.9, 147.4-144.9 (m, 2C), 143.9-141.4 (m, 1C), 138.8-136.4 (m,
2C), 131.9, 128.6, 126.6, 119.5, 117.8, 108.1-107.8 (m, 1C), 73.5,
64.5, 48.1 ppm; LRMS (ESI): m/z 437.0 [M+H]+; HRMS (ESI):
m/z Exact mass calcd. for C16H10F5N2O5S [M+H]+: 437.0225,
found: 437.0230.
1-benzyl-1,10b-dihydrobenzo[e]imidazo[1,2-c][1,2,3]oxathiazi
n-2(3H)-one 5,5-dioxide (3ag). This compound was prepared via
general procedure as white powder (36 mg, 54% yield). m. p. 173-
175 oC. 1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 3H), 7.39 (d,
J = 7.2 Hz, 1H), 7.32-7.30 (m, 2H), 7.28-7.26 (m, 2H), 7.14 (d, J
= 8.4 Hz, 1H), 6.01 (d, J = 0.4 Hz, 1H), 5.42 (d, J = 15.6 Hz, 1H),
4.25-4.12 (m, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 166.7,
149.8, 133.7, 131.3, 129.6, 128.8, 127.9, 127.7, 126.4, 120.0,
119.5, 73.9, 50.3, 44.7 ppm; LRMS (ESI): m/z 331.1 [M+H]+;
HRMS (ESI): m/z Exact mass calcd. for C16H15N2O4S [M+H]+:
331.0747, found: 331.0744.
1-(benzyloxy)-1,3,4,11b-tetrahydro-2H-benzo[e]pyrimido[1,2-c]
[1,2,3]oxathiazin-2-one 6,6-dioxide (3ah). This compound was
prepared via general procedure as colorless oil (50 mg, 70% yield).
1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.49-7.46
(m, 2H), 7.42-7.41 (m, 4H), 7.23 (d, J = 7.6 Hz, 1H), 7.04 (d, J =
8.0 Hz, 1H), 6.19 (s, 1H), 5.16-5.08 (m, 2H), 3.71-3.66 (m, 1H),
3.30-3.23 (m, 1H), 2.86-2.78 (m, 1H), 2.51-2.44 (m, 1H) ppm;
13C{H} NMR (100 MHz, CDCl3) δ 163.7, 149.1, 133.8, 131.3,
129.8, 129.5, 128.9, 128.0, 126.4, 118.8, 117.9, 77.3, 73.7, 41.8,
31.4 ppm; LRMS (ESI): m/z 361.1 [M+H]+; HRMS (ESI): m/z
Exact mass calcd. for C17H17N2O5S [M+H]+: 361.0853, found:
361.0859.
1-(benzyloxy)-3-propyl-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3ak). This compound
was prepared via general procedure as colorless oil (42 mg, 54%
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1
yield). H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.45-7.42 (m, 6H), 7.27 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.4 Hz,
1H), 5.75 (s, 1H), 5.12 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz,
1H), 4.21 (t, J = 5.6 Hz, 1H), 2.05-1.92 (m, 2H), 1.64-1.55 (m,
2H), 0.99 (t, J = 7.4 Hz, 3H) ppm; 13C{H} NMR (100 MHz,
CDCl3) δ 165.3, 149.7, 133.9, 131.5, 130.0, 129.9, 129.1, 128.8,
126.2, 119.2, 118.1, 78.7, 72.6, 59.5, 33.1, 16.9, 13.9 ppm; LRMS
(ESI): m/z 389.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd for
C19H21N2O5S [M+H]+: 389.1166, found: 389.1158.
1-(benzyloxy)-3-butyl-1,10b-dihydrobenzo[e]imidazo[1,2-c][1,-
2,3]oxathiazin-2(H)-one 5,5-dioxide (3al). This compound was
prepared via general procedure as colorless oil (36 mg, 45% yield).
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.46-7.42
(m, 6H), 7.27 (t, J = 13.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 5.73
(s, 1H), 5.13 (d, J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 4.22
(t, J = 5.6 Hz, 1H), 2.03-1.99 (m, 2H), 1.55-1.36 (m, 4H), 0.96 (t,
J = 7.2 Hz, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 165.2,
149.7, 133.9, 131.5, 130.0, 129.9, 129.1, 128.8, 126.2, 119.3,
118.1, 78.7, 72.7, 59.6, 30.8, 25.6, 22.6, 14.1 ppm; LRMS (ESI):
m/z 403.2 [M+H]+; HRMS (ESI): m/z Exact mass calcd. for
C20H23N2O5S [M+H]+: 403.1322, found: 403.1326.
1-(benzyloxy)-9-bromo-3-methyl-1,10b-dihydrobenzo[e]imida-
zo[1,2-c][1,2,3]oxathiazin-2(3H)-one 5,5-dioxide (3mi). This
compound was prepared via general procedure as white powder
(74 mg, 85% yield). m. p. 129-131 oC.1H NMR (400 MHz, CDCl3)
δ 7.70 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H),
7.49-7.45 (m, 5H), 6.96 (d, J = 8.8 Hz, 1H), 5.64 (d, J = 1.2 Hz,
1H), 5.21 (d, J = 10.4 Hz, 1H), 5.02 (d, J = 10.8 Hz, 1H), 4.11 (qd,
J = 6.8 Hz, J = 1.6 Hz, 1H), 1.63 (d, J = 6.4 Hz, 3H) ppm; 13C{H}
NMR (100 MHz, CDCl3) δ 165.3, 148.6, 134.5, 133.5, 131.4,
130.1 (3C), 129.3, 120.9, 119.9, 119.1, 78.8, 72.0, 55.7, 18.3 ppm;
LRMS (ESI): m/z 438.9 [M+H]+; HRMS (ESI): m/z Exact mass
calcd. for C17H16BrN2O5S [M+H]+: 438.9958, found: 438.9951.
General Procedure for Synthesis of 3am in HFIP. To a 10
mL test tube was sequentially added 1a (0.2 mmol, 1.0 eq),
K2CO3 (0.24 mmol, 1.2 eq), α-bromo hydroxamate 2m (0.24
mmol, 1.2 eq), 4Å MS (100 mg) and HFIP (2 mL). Then the tube
was sealed and stirred at room temperature. The reaction mixture
was concentrated under reduced pressure, the resulting residue
was purified by flash column chromatography (petroleum
ether/EtOAc = 7:1) on silica gel to afford the pure product 3am as
1-(benzyloxy)-3-methyl-1,10b-dihydrobenzo[e]imidazo[1,2-c]
[1,2,-3]oxathiazin-2(3H)-one 5,5-dioxide (3ai). This compound
was prepared via general procedure as white oil (68 mg, 95%
yield). 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.6 Hz, J = 1.2
Hz, 1H), 7.50-7.40 (m, 6H), 7.28-7.24 (m, 1H), 7.08 (d, J = 8.4
Hz, 1H), 5.74 (d, J = 1.6 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 5.02
(d, J = 10.8 Hz, 1H), 4.13 (qd, J = 6.7 Hz, J = 1.8 Hz, 1H), 1.64 (d,
J = 6.8 Hz, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 165.4,
149.5, 133.8, 131.5, 130.02, 129.99, 129.2, 128.5, 126.3, 119.2,
118.1, 78.6, 72.4, 55.7, 18.3 ppm; LRMS (ESI): m/z 361.1
[M+H]+; HRMS (ESI): m/z Exact mass calcd. for C17H17N2O5S
[M+H]+: 361.0853, found: 361.0856.
o
1
light yellow powder (38 mg, 51% yield). m. p. 116-119 C. H
NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H),
7.52-7.50 (m, 2H), 7.46-7.44 (m, 3H), 7.42-7.38 (m, 1H), 7.26-
7.21 (m, 1H), 7.03 (dd, J = 8.4 Hz, J = 0.6 Hz, 1H), 5.83 (s, 1H),
5.26 (d, J = 10.4 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 1.65 (s, 3H),
1.51 (s, 3H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 167.6,
149.8, 133.7, 131.3, 130.0, 129.9, 129.2, 127.6, 126.1, 119.1,
118.9, 78.3, 70.9, 63.7, 25.8, 21.6 ppm; LRMS (ESI): m/z 375.2
[M+H]+; HRMS (ESI): m/z Exact mass calcd. for C18H19N2O5S
[M+H]+: 375.1009, found: 375.1005.
General Procedure for Synthesis of 3aa on the Gram
Scale. To a 100 mL flask was sequentially added 1a (3.0 mmol,
1.0 eq), K2CO3 (3.6 mmol, 1.2 eq), α-bromo hydroxamate 2a (3.6
mmol, 1.2 eq), 4Å MS (1.5 g) and MeCN (30 mL). Then the flask
was sealed and stirred at room temperature. Once the imine 1a
1-(benzyloxy)-3-ethyl-1,10b-dihydrobenzo[e]imidazo[1,2-c][1,-
2,3] oxathiazin-2(3H)-one 5,5-dioxide (3aj). This compound was
prepared via general procedure as colorless oil (69 mg, 92% yield).
1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.8 Hz, J = 0.8 Hz,
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Page 8 of 9
was complete consumption (24 h), the reaction mixture was
Corresponding Author
1
2
3
4
5
6
7
8
concentrated under reduced pressure and the resulting residue was
purified by flash column chromatography (hexane/EtOAc = 7/2)
on silica gel to afford the pure product 3aa with 97% yield (1 g,
2.91 mmol).
* E-mail: chenyj@zzu.edu.cn
ORCID
General Procedure for Synthesis of 517. Compound 3aa
(0.2 mmol, 1.0 eq) was dissolved in MeOH (2 mL) and then 10%
Pd/C (6 mg) was added. The reaction mixture was stirred under
H2 atmosphere for 4 h at room temperature. After filtration
through a plug of Celite®, the filtrate was concentrated in vacuo
to yield the pure product 5 as a pale white powder (48 mg, 94%
Chen-Guo Feng: 0000-0001-9899-9489
Ya-Jing Chen: 0000-0002-1624-0741
Author Contributions
£ These authors contributed equally.
Notes
9
o
1
yield). Decomposition at 155 C. H NMR (400 MHz, CDCl3) δ
10.84 (s, 1H), 7.68 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.58-7.54 (m,
1H), 7.42-7.38 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 1.6
Hz, 1H), 4.26 (dd, J = 14.2 Hz, J = 1.4 Hz, 1H), 4.13 (d, J = 14.0
Hz, 1H) ppm; 13C{H} NMR (100 MHz, CDCl3) δ 161.4, 149.0,
131.3, 128.8, 126.2, 118.7, 118.4, 73.6, 47.9 ppm; LRMS (ESI):
m/z 257.1 [M+H]+; HRMS (ESI): m/z Exact mass calcd. for
C9H9N2O5S [M+H]+: 257.0227, found: 257.0224.
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We are grateful for financial support from the China Postdoctoral
Science Foundation (No. 2016M592301) and the Education
Department of Henan Province (No. 17A150021).
REFERENCES
General Procedure for Synthesis of 66a. To a 50 mL
Schlenk tube equipped with a magnetic stir bar was charged with
3aa (0.2 mmol) under Argon, anhydrous THF (2 mL) was added
at room temperature. Then SmI2 (6 mL, 0.1 M in THF) was added
to the stirring solution dropwise via syringe. After thin layer
chromatography analysis indicated complete reaction, the solution
was diluted with CH2Cl2 (20 mL) and quenched with a 10%
solution of Na2S2O3 (10 mL). The layers were separated and the
aqueous layer was extracted with CH2C12 (3 x 20 mL). The
combined organic layers were washed with brine and then dried
over sodium sulfate, filtered, and evaporated to dryness. The
crude product was purified by flash chromatography to yield the
pure product 6 as a white powder (47 mg, 98% yield). 1H NMR
(400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.51-7.46 (m, 2H), 7.42-
7.38 (m, 1H), 7.24-7.22 (m, 1H), 6.45 (s, 1H), 4.04 (dd, J = 14.4
Hz, J = 1.2 Hz, 1H), 3.95 (d, J = 14.0 Hz, 1H) ppm; 13C{H} NMR
(100 MHz, DMSO-d6) δ 168.0, 148.3, 130.7, 128.1, 126.5, 121.1,
118.5, 71.2, 48.6 ppm; LRMS (ESI): m/z 241.0 [M+H]+; HRMS
(ESI): m/z Exact mass calcd. for C9H9N2O4S [M+H]+: 241.0278,
found: 241.0283.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Copies of the NMR spectra for all new compounds and HPLC
chromatograms for 2i and 3ai (PDF)
X-ray crystallographic information for compound 3ma (CCDC
1905322) (CIF)
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Accession Codes
CCDC 1905322 (3ma) and 1905306 (3mi) contain the
supplementary crystallographic datas for this paper. These datas
can
be
obtained
free
of
or
charge
by
via
emailing
www.ccdc.cam.ac.uk/data_request/cif,
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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