Construction of thiazines and oxathianes: Via [3 + 3] annulation of N -tosylaziridinedicarboxylates and oxiranes with 1,4-dithiane-2,5-diol: Application towards the synthesis of bioactive molecules

Article abstract of DOI:10.1039/c7ob00941k

Lewis acid catalyzed [3 + 3] annulation of N-tosylaziridinedicarboxylates and oxiranes with in situ generated mercaptoaldehyde for the synthesis of functionalized thiazine and oxathiane derivatives has been developed. Additionally, this method facilitates the derivatization of thiazines by detosylation and Krapcho monodecarboxylation.

Full text of DOI:10.1039/c7ob00941k

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ARTICLE
Construction of Thiazines and Oxathianes via [3+3] Annulation of
N-Tosylaziridinedicarboxylates and Oxiranes with 1,4-dithiane-
2,5-diol: Application Towards the Synthesis of Bioactive Molecules
Received 00th January 20xx,
Accepted 00th January 20xx
Rohit Kumar Varshnaya and Prabal Banerjee*
DOI: 10.1039/x0xx00000x
Lewis acid catalyzed [3+3] annulation of N-tosylaziridinedicarboxylates and oxiranes with in situ generated
mercaptoaldehyde for the synthesis of functionalized thiazine and oxathiane derivatives has been developed. Additionally,
this method facilitate the derivatization of thiazine by detosylation and Krapcho monodecarboxylation.
www.rsc.org/
significant attention. In this context, we envisioned exploring
the one step synthesis of thiazine and oxathiane from aziridine
and oxiranes with 1,4-dithiane 2,5-diol.
Introduction,
There are numerous bioactive molecules whose skeleton
include six membered ring containing two heteroatoms.1 Out
of these heteroatom containing six-membered rings, thiazines
and oxathianes are of particular importance, as these scaffolds
are core structural motifs of many natural products and
bioactive heterocycles. 1,3-Thiazine derivatives possess various
Aziridines are multifaceted synthetic intermediate for the
synthesis of nitrogen containing biologically active compounds.
The chemistry of aziridine plays an important role due to its
high reactivity of the C-N bond for nucleophilic opening of the
heterocyclic ring.5 The selective C-C heterolysis of aziridine has
been less explored due to its relative high energy barrier.6 In
presence of Lewis acid, N-tosylarylaziridinyl dicarboxylate
favor the C-C bond cleavage, which can undergo formal
cycloaddition reactions with various dipolarophiles.7 Similarly,
the donor acceptor oxiranes (D-A Oxirane) has also emerged as
versatile tool for the synthesis of numerous biologically active
compounds for contemporary interest. The chemistry of
oxiranes favors the C-O bond cleavage, but for the C-C bond
cleavage harsh conditions are required. Herein, we report
Lewis acid catalyzed chemoselective C-C bond cleavage of
oxiranes, which are entrapped by dipolarophiles bearing C-X
(X = O and C ) multiple bonds.8
biological
activities
viz.
cholecystokinin
antagonist,
antimycobacterial, antimalarial, antifungal and antithyroid
activity.2 On the other hand, oxathiane derivative constitutes
the cyclic core structure of MIF (macrophage migration
inhibitory factor) inhibitor.3
O
O
HO
O
S
H
N
H
N
O
S
O
S
S
HO
N
N
NH2
O
O
O
HO
O
OH
TZ-1
Br
MIF inhibitor
Metathiazinan 4-one
(Antifungal agent)
Cephalosporin C
(Antibiotic)
1,4-Dithiane 2,5-diol has been employed an efficient substrate
for the synthesis of thiazine and oxathine via catalytic [3+3]
Fig. 1 Biologically active compounds containing thiazine, oxathiane and their
derivative
A: Previous work
EtO2C CO2Et
R3
OH
AlCl3
In addition, 1,3-thiazines are being transformed into useful
structures which are important constituents of biologically
active compounds. These structure constitute the cyclic core
structure of antibiotic cephalosporin C and TZ-1. TZ-1 exhibits
antimycobacterial and antitubular activity.4 Consequently,
efficient construction of these scaffolds has received
R2 = OEt
R3 =Benzoyl group
Srinivasan et al.10
CO2Me
R1
S
CO2Me
OH
R3
MeO2C
MeO2C
Ph
S
S
OH
OH
Sc(OTf)3
R2 = OMe
COR2
COR2
Zhang et al.11
R1
HO
Ph
S
S
trans
cis
COR2
COR2
OH
R1
chiral N, N-dioxide/ Sc(OTf)3
Feng et al.12
S
R2 = Aryl
B: This work
S
S
OH
CO2Et
Ar
X
MgI2
X
CO2Et
CO2Et
CO2Et
DCM, rt
S
HO
Ar
OH
X= O, N-Ts
Scheme 1 Annulation of strained ring with 1,4-dithiane 2,5-diol
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annulation. There are numerous reports in the literature for No further improvement in yield was achieved with higher
the synthesis of thiazines and oxathines, but synthesis increment of MgI2 (40 mol%). The use of MgBr2 gave excellent
employing [3+3] cycloaddition of heteroatom containing yield of 3a at 80 ℃. Indium containing Lewis Acid, InCl3 and InI3
strained ring is not yet reported in literature.9
gave desired product in moderate to excellent yield
Srinivasan and coworkers reported one pot synthesis of respectively (Table 1 entry 5 and 14). Other commercial
tetrasubstitutedthiophene via [3+3] annulation of trans-2- available Lewis acids, such as Zn(OTf)2, FeCl2, Cu(OTf)2 failed to
aroyl-3-arylcyclopropane-1,1-dicarboxylates
and catalyze the titled transformation (Table 1, entry 8-9 and 13).
mercaptoaldehyde in presence of catalytic amount of AlCl3.10 In case of Sn(OTf)2,Yb(OTf)3, AgOTf, Mg(OTf)2 and MgCl2, trace
Zhang et.al in their seminal work, reported Sc(OTf)3 catalyzed amount of 3a was observed (Table 1, entry 6-7 and 10-12).
[3+3] annulation of cyclopropane 1,1-diester with
Table 2 Effect of solventa
mercatoaldehyde (Scheme 1B).11 Feng et.al report a highly
diastereo- and enatioselective [3+3] annulation of cyclopropyl
ketone with mercaptoaldehyde catalyzed by a chiral N,N’-
dioxide/scandium(III) complex.12 Recently, our group explored
the possibility of cycloaddition reaction of strained ring with
Entry
MgI2
Solvent
Time
Isolated
other 2π component and another strained ring in presence of
MgI2.13 Encouraged by these results, we became interested in
assessing the reactivity of N-tosylaziridinedicarboxylate and
oxirane with 1,4-dithiane 2,5-diol (Scheme 1)
[mol%]
Yieldc [%]
1
2
3
4
5
6
20
20
20
20
20
20
DCMb
DCEb
20 min.
1h
86
82
CHCl3
8h
76
Results and discussion,
THFb
1h
c.m.d
c.m.d
46
We initiated the present investigation with donor-acceptor
CH3CN
Toluene
1h 30 min
12h
aziridines (D-A aziridines) 1a (1 equiv.) and 1,4-dithiane 2,5-
diol
reaction between 1a and
examined, MgI2 was found to be most effective (Table 1). mmol,
2
to afford substituted thiazine. In order to optimize the
aReaction was carried out in inert atmosphere 1a (0.21 mmol, 1 equiv), 2 (0.21
equiv), Lewis Acid (0.043 mmol, 0.2 equiv) and
bDCM=
Dichloromethane. DCE= dichloroethane. THF= tetrahydrofuran. cIsolated yield
after flash column chromatography, dc.m. = complex mixture.
2
to give 3a, various Lewis acid were
1
When 10 mol% MgI2 was used the yield of the reaction was
70%. Gratifyingly, we got the desired product in 86% yield by
increasing the MgI2 loading up to 20 mol% (Table 1, entry 2).
A brief screening of solvents revealed that chlorinated solvents
like DCM, chloroform and DCE gave good to excellent yield of
desired product 3a ( Table 2 entry 1,2 and 3). In case of CH3CN
and THF, the annulated product was not detected. (Table 2,
entry 4 and 5). However, when toluene was chosen as reaction
medium, moderate yield of the product was observed after
12h.
Table 1 Optimization of reaction condition between 1a and 2aa
Entry
Lewis acid
LA
[mol%]
10
T[°C]
Solvent
Isolated
Yieldb [%]
70
With the optimized reaction condition, the scope of the
transformation assessed with various D-A Aziridines and 1,4-
dithiane 2,5-diol. To our delight, D-A aziridines bearing
electron withdrawing substituents gave excellent yield of the
1
2
MgI2
MgI2
25
25
25
80
25
25
25
25
25
25
25
25
25
25
DCM
DCM
DCM
DCE
20
86
3
MgI2
40
74
4
MgBr2
InCl3
20
80
desired product in short time (Table 3, 3a-3d). p-Bromophenyl
5
20
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
60
substituted D-A aziridine shows higher yield of annulated
product 3e (78%) than o-bromophenyl substituted cycloadduct
3f (74%). It may be due to the steric hindrance of o-bromo
group. Less activated phenyl and napthyl substituted aziridines
also produces substituted thiazine in good yield (Table 3 entry
3g and 3h). As expected, we obtained the desired products
with p-methyl and p-isopropyl phenyl substituted D-A
aziridines in good yield (Table 3 entry 3i and 3j). The aziridines
substituted with strong electron-donating groups, such as
methoxy, hydroxyl and dimethylamino leads to highly unstable
substrates which could not be used for further the formation
of cycloadduct. On the other hand, alkyl substituents, like
cyclohexyl and isopropyl bearing aziridines gave complex
6
Sn(OTf)2
Yb(OTf)3
Zn(OTf)2
FeCl2
20
15
7
20
18
8
20
n.r.c
n.r.c
12
9
20
10
11
12
13
14
AgOTf
Mg(OTf)2
MgCl2
Cu(OTf)2
InI3
20
20
24
20
14
n.r.c
20
20
76
aReaction was carried out in inert atmosphere 1a (0.21 mmol, 1 equiv), 2 (0.21
mmol, 1 equiv), Lewis Acid (0.04 mmol, 0.2 equiv) and DCM, bIsolated yield after
flash column chromatography, cn.r = no reaction.
mixture. Different ester group containing aziridines (1k and 1l
)
2 | J. Name., 2012, 00, 1-3
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Table 3 Scope of the methodologya
reaction at room temperature using DCM as solvent (Table 4).
Usually electron releasing D-A oxiranes performed better than
electron withdrawing aryl substituted oxirane (Table 4, entry
5b, 5c and 5d) which can be attributed to the destabilization of
developed positive charge on adjacent C-atom of the dipole by
electron deficient aryl moiety during the course of the
reaction. In addition, phenyl substituted oxirane gave desired
product in excellent yield of 80% (Table 4, entry 5a). The
geometry of 5a was determined by using NOESY studies.
O2N
NC
Ts
Ts
N
N
CO2Et
CO2Et
CO2Et
CO2Et
S
S
OH
OH
3a, 86%
20 min.
3b, 84%
15 min.
Cl
Br
F
Ts
N
Ts
N
Ts
CO2Et
CO2Et
CO2Et
CO2Et
N
CO2Et
CO2Et
S
S
S
OH
OH
OH
3d, 80%
20 min.
3c, 81%
20 min.
Fig. 2 NOESY correlation of compound 5a
3e, 78%
15 min.
Ts
Ts
N
The plausible mechanism for both cycloaddition reactions is
outlined in scheme 2. Initially Lewis acid coordinated with
Ts
N
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
S
Br
S
S
OH
OH
malonyl ester of strained ring
1, which result in C-C bond
OH
3f, 74%
25 min.
3g, 70%
15 min.
3h, 74%
30 min.
cleavage to form complex A. The mercaptoaldehyde
B
which in
O2N
Ts
N
Ts
N
Ts
N
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
S
S
S
OH
OH
OH
3k, 87%
10 min.
3i, 74%
20 min.
3j, 72%
25 min.
O2N
Ts
N
CO2iPr
CO2iPr
S
OH
3l, 83%
10 min.
aUnless otherwise specified all reaction were carried out in DCM at rt with 1
equiv of 1 and 1 equiv of 2 in presence of Lewis acid (20 mol%).
Were used to check the effect of the size of the ester group in
the transformation, annulated product was formed in
excellent yield in all the cases (Table 3, entry 3k and 3l).
Structure of 3b was confirmed by single crystal X-ray analysis
(see also the supporting information).14
Scheme 2 Plausible mechanism
situ generated from
SN2 fashion to give
2
C
attack on aryl substituted C-atom of A in
which undergoes 120° rotation to bring
To test the reactivity of different D-A oxiranes with 1,4-
dithiane 2,5-diol, we carried out Lewis acid (MgI2) catalyzed
the malonate anion closer to the aldehyde group to form
intermediate . The malonyl ester anion undergo nucleophilic
addition on aldehyde group to give the cycloadduct
D
E
.
Table 4 Scope of annulation reaction between 4 and 2a
To check the potential of substituted thiazine 3a for further
synthetic application, we performed the detosylation reaction.
In the presence of NaH at room temperature 3a easily gave
substituted imine
hydroxyl group of 3a could be protected to give compound
quantitative yield. Krapcho monodecarboxylation
accompanied by elimination of the acetoxy group gave the
monoester . These structure is a scaffold of biologically active
natural product and drug (Scheme 3).
6
in excellent yield (80%). Moreover, the
7
in
8
aUnless otherwise specified all reaction were carried out in DCM at rt with
1 equiv of 4 and 1 equiv of 2 in presence of lewis acid (20 mol%).
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N-(4-fluorobenzylidene)-4-methylbenzenesulfonamide (0.50 g,
1.83 mmol), 2-bromomalonate (0.59 g, 1.98 mmol), NaH (0.04
g, 1.98 mmol), dry CH3CN (16 mL), Reaction time = 10 min., 1c
(0.67 g, Yield: 86%), Colorless oil. 1H NMR (400 MHz): δ 7.95 (d,
J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.21-7.28 (m, 2 H),
6.91-6.99 (m, 2 H), 4.85 (s, 1 H), 4.35-4.43 (m, 2H), 3.98 (q, J =
7.2 Hz, 2 H), 2.45 (s, 3 H), 1.37 (t, J = 7.2 Hz, 3 H), 0.93 (t, J =
7.20 Hz, 3H).
Diethyl 3-(4-chlorophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1d):
Scheme 3 Synthetic transformation of cycloadduct
N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide (0.50 g,
1.70 mmol), 2-bromomalonate (0.44 g, 1.87 mmol), NaH (0.04
g, 1.87 mmol), dry CH3CN (17 mL), Reaction time = 15 min., 1d
(0.62 g, Yield: 80%), Colorless oil. 1H NMR (400 MHz): δ 7.94 (d,
J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),
7.19 (d, J = 8.4 Hz, 2H), 4.83 (s, 1H), 4.32-4.42 (m, 2H), 3.94-
4.11 (m, 2H), 2.45 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.2
Hz, 3H).
Experimental
General information
All reactions were carried out under inert atmosphere using
oven dried glassware. All solvents and reagents were obtained
from commercial sources and were purified using standard
procedure prior to use. The developed chromatogram was
analyzed by UV lamp (254 nm), or p-anisaldehyde solution.
Products were purified by flash chromatography on silica gel
(mesh size 230-400). The 1H and 13C-NMR spectra were
Diethyl 3-(4-bromophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1e):
N-(4-bromobenzylidene)-4-methylbenzenesulfonamide (0.50
g, 1.47 mmol), 2-bromomalonate (0.48 g, 1.62 mmol), NaH
(0.03 g, 1.62 mmol), dry CH3CN (16 mL), Reaction time = 12
1
min., 1e (0.64 g, Yield: 88%), Colorless oil. H NMR (400 MHz):
recorded in CDCl3. Chemical shifts of H and 13C-NMR spectra
1
δ 7.94 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.36 (d, J =
8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 4.82 (s, 1 H), 4.30-4.50 (m,
2 H), 3.90-4.01 (m, 2 H), 2.45 (s, 3 H), 1.37 (t, J = 7.2 Hz, 3 H),
0.95 (t, J = 7.2 Hz, 3 H).
are expressed in parts per million (ppm). All coupling constants
are given in absolute values and are expressed in Hz. The
description of the signals include: s = singlet, d = doublet, dd =
doublet of doublet, t = triplet, dt = doublet of triplet, q =
quartet, pent = pentet, br = broad and m = multiplet.
General procedure for synthesis of N-tosyl aziridine-2,2-
dicarboxylate):
Diethyl 3-(2-bromophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1f):
N-(2-bromobenzylidene)-4-methylbenzenesulfonamide (0.50
g, 1.47 mmol), 2-bromomalonate (0.48 g, 1.62 mmol), NaH
(0.03 g, 1.62 mmol), dry CH3CN (16 mL), Reaction time = 17
min., 1f (0.63 g, Yield: 87%), Colourless oil. 1H NMR (400 MHz):
δ 7.98 (d, J = 8.0 Hz, 2 H), 7.50-7.53 (m, 1 H), 7.38 (d, J = 8.0 Hz,
2 H), 7.13-7.19 (m, 2 H), 7.06-7.11 (m, 1 H), 5.01 (s, 1 H), 4.41
(q, J = 6.8 Hz, 2 H), 3.86-3.98 (m, 2 H), 2.46 (s, 3 H), 1.38 (t, J =
7.2 Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3 H).
Aziridines were prepared according to the literature.15
Diethyl 3-(4-nitrophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1a):
4-methyl-N-(4-nitrobenzylidene)benzenesulfonamide (0.50 g,
1.64 mmol), 2-bromomalonate (0.43 g, 1.80 mmol), NaH (0.04
g, 1.80 mmol), dry CH3CN (16 mL), Reaction time = 17 min., 1a
(0.63 g, Yield: 84%), Colorless oil. 1H NMR (400 MHz): δ 8.14 (d,
J = 7.6 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H),
7.38 (d, J = 7.6 Hz, 2H), 4.92 (s, 1H), 4.35-4.47 (m, 2H), 3.90-
4.04 (m, 2H), 2.47 (s, 3H), 1.38 (t, J = 6.6 Hz, 3H), 0.95 (t, J = 6.6
Hz, 3H).
Diethyl 3-phenyl-1-tosylaziridine-2,2-dicarboxylate (1g):
N-benzylidene-4-methylbenzenesulfonamide (0.50 g, 1.92
mmol), 2-bromomalonate (0.50 g, 2.11 mmol), NaH (0.05 g,
2.11 mmol), dry CH3CN (19 mL), Reaction time = 12 min., 1g
(0.67 g, Yield: 83%), Colorless oil. 1H NMR (400 MHz): δ 7.96 (d,
J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.20-7.27 (m, 5H), 4.89
(s, 1H), 4.36-4.42 (m, 2H), 3.86-4.00 (m, 2H), 2.43 (s, 3H), 1.36
(t, J = 7.0 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H).
Diethyl 3-(4-cyanophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1b):
N-(4-cyanobenzylidene)-4-methylbenzenesulfonamide (0.50 g,
1.75 mmol), 2-bromomalonate (0.57 g, 1.93 mmol), NaH (0.04
g, 1.93 mmol), dry CH3CN (16 mL), Reaction time = 14 min., 1b
(0.70 g, Yield: 90%), Colorless oil. 1H NMR (400 MHz): 7.94 (d, J
= 8.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.31-7.41 (m, 4 H), 4.89
(s, 1 H), 4.34-4.45 (m, 2 H), 3.90-3.99 (m, 2H), 2.46 (s, 3 H),
1.37 (t, J = 7.0 Hz, 3 H), 0.92 (t, J = 7.0 Hz, 3 H).
Diethyl 3-(naphthalen-1-yl)-1-tosylaziridine-2,2-dicarboxylate
(1h):
4-methyl-N-(naphthalen-1-ylmethylene)benzenesulfonamide
(0.50 g, 1.61 mmol), 2-bromomalonate (0.43 g, 1.77 mmol),
NaH (0.04 g, 1.77 mmol), dry CH3CN (16 mL), Reaction time =
10 min., 1h (0.61 g, Yield: 82%), Colorless oil. 1H NMR (400
MHz): δ 8.24 (d, J = 8.0 Hz, 1H), 8.03 ( d, J = 8.4 Hz, 2H), 7.83 (d,
J = 8.0 Hz, 1H), 7.74-7.78 (m, 1H), 7.55-7.60 (m, 1H), 7.48-7.52
(m, 1 H), 7.39 (d, J = 8.0 Hz, 2H), 7.28-7.33 (m, 2H), 5.30 (s, 1H),
Diethyl 3-(4-fluorophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1c):
4 | J. Name., 2012, 00, 1-3
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4.48 (q, J = 7.2 Hz, 2H), 3.70 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), Diethyl 3-(4-nitrophenyl)oxirane-2,2-dicarboxylate (4c):
1H NMR (400 MHz);δ 8.20 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz,
2H), 4.65 (s, 1H), 4.32 (q, J = 7.32 Hz, 2H), 4.04 (q, J = 7.2 Hz,
1.42 (t, J = 7.2 Hz, 3H), 0.45 (t, J = 7.2 Hz, 3H).
Diethyl 3-(p-tolyl)-1-tosylaziridine-2,2-dicarboxylate (1i):
4-methyl-N-(4-methylbenzylidene)benzenesulfonamide (0.50 2Н), 1.33 (t, J = 7.2 Hz, 3Н), 1.02 (t, J = 7.2 Hz, 3Н).
g, 1.82 mmol), 2-bromomalonate (0.47 g, 2.0 mmol), NaH (0.05 Diethyl 3-(p-tolyl)oxirane-2,2-dicarboxylate (4d):
mg, 2.0 mmol), dry CH3CN (18 mL), Reaction time = 10 min., 1i 1H NMR (400 MHz): δ 7.22 (d, J = 7.6 Hz, 2 H), 7.14 (d, J = 7.6
(0.6 g, Yield: 77%), Colorless oil. 1H NMR (400 MHz): δ 7.95 (d, J Hz, 2 H), 4.53 (s, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 4.06 (q, J = 7.2
= 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), Hz, 2 H), 2.33 (s, 3 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.02 (t, J = 7.2 Hz,
7.05 (d, J = 8.0 Hz, 2H), 4.85 (s, 1 H), 4.32-4.44 (m, 2H), 3.97 (q, 3 H).
J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.28 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H), Representative procedure for Cycloaddition reaction of N-
0.93 (t, J = 7.0 Hz, 3H).
tosyl aziridine-2,2-dicarboxylate and 2,5-dihydroxy-1,4-
Diethyl
3-(4-isopropylphenyl)-1-tosylaziridine-2,2- dithiane.
dicarboxylate (1j):
To a round bottom flask equipped with a magnetic stir bar was
added with N-tosylaziridine-2,2-dicarboxylate (1 equiv.) and
2,5-dihydroxy-1,4-dithiane and MgI2 (0.2 equiv.) under
nitrogen atmosphere. DCM was added as a solvent to the
reaction mixture and stirred at room temperature until
completion of the reaction (as monitored by TLC). Reaction
mixture was passed through small pad of celite and solvent
was evaporated in rotary evaporator. Crude mixture was
further purified by flash column chromatography on silica gel
with EtOAc/Hexane as eluent.
N-(4-isopropylbenzylidene)-4-methylbenzenesulfonamide
(0.50 g, 1.65 mmol), 2-bromomalonate (0.43 g, 1.81 mmol),
NaH (0.04 g, 1.81 mmol), dry CH3CN (16 mL), Reaction time =
10 min., 1j (0.6 g, Yield: 79%),Colorless oil, 1H NMR (400 MHz):
δ 7.96 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.6
Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 4.87 (s, 1H), 4.36-4.43 (m, 2H),
4.07-4.17 (m, 1H), 3.89-4.01 (m, 2H), 2.44 (s, 3H), 1.36 (t, J =
6.8 Hz, 3H), 1.17 (d, J = 6.4 Hz, 6H), 0.84 (t, J = 6.8 Hz, 3H).
Dimethyl 3-(4-nitrophenyl)-1-tosylaziridine-2,2-dicarboxylate (1k):
4-methyl-N-(4-nitrobenzylidene)benzenesulfonamide (0.50 g, Scope of N-tosyl aziridine-2,2-dicarboxylate and 2,5-
1.64 mmol), 2-bromomalonate (0.37 g, 1.80 mmol), NaH (0.04 dihydroxy-1,4-dithiane
g, 1.80 mmol), dry CH3CN (12 mL), Reaction time = 12 min., 1k
(2S,5S)-diethyl
5-hydroxy-2-(4-nitrophenyl)-3-tosyl-1,3-
(0.63 g, Yield: 84%), yellow solid, 1H NMR (400 MHz): δ 8.14 (d,
J = 8.73 Hz, 2H), 7.94 (d, J = 8.47 Hz, 2H) 7.44 (d, J = 8.73 Hz,
2H), 7.38 (d, J = 8.28 Hz, 2H), 4.91 (s, 1H), 3.95 (s, 3H), 3.51 (s,
3H), 2.47 (s, 3H).
thiazinane-4,4-dicarboxylate (3a)
Reaction Time: 20 min., 1a (0.10 g, 0.21 mmol),
2 (0.03 g, 0.21
mmol), yellow viscous liquid, 0.10 g, Yield: 86%, Rf-value: 0.42
(EtOAc/Hexane) 4:10 (v/v).
3a: 1H NMR (400 MHz): δ 7.86 (d, J = 8.90 Hz, 2H), 7.61 (d, J =
8.57 Hz, 2H), 7.44 (d, J = 8.57 Hz, 2H), 7.07 (d, J = 8.36 Hz, 2H),
diisopropyl 3-(4-nitrophenyl)-1-tosylaziridine-2,2-dicarboxylate
(1l):
4-methyl-N-(4-nitrobenzylidene)benzenesulfonamide (0.50 g, 6.12 (s, 1H), 4.51-4.43 (m, 4H), 4.32 (m, 2H), 2.90 (m, 1H), 2.57
1.64 mmol), 2-bromomalonate (0.48 g, 1.80 mmol), NaH (0.04 (m, 1H), 2.29 (s, 3H), 1.47 (t, J = 7.38 Hz, 3H), 1.42 (t, J = 7.27
g, 1.80 mmol), dry CH3CN (12 mL), Reaction time = 16 min., 1l Hz, 3H). 13C NMR (100 MHz): δ 170.8, 168.1, 147.1, 146.7,
1
(0.69 g, Yield: 86%), white solid, H NMR (400 MHz): δ 8.13 (d, 144.6, 136.3, 129.3, 128.4, 127.6, 122.9, 73.8, 71.8, 63.3, 58.2,
J = 8.83 Hz, 2H), 7.96 (d, J = 8.36 Hz, 2H), 7.42 ( d, J = 8.91 Hz, 28.0, 21.5, 13.8. IR (neat)νmax 3739, 3676, 3617, 3414, 2924,
2H), 7.37 (d, J = 8.51 Hz, 2H0, 5.27- 5.23 (m, J = 6.46, 6.38 Hz, 2855, 2312, 1740, 1705, 1604, 1523, 1457, 1343, 1263, 1159,
1H), 4.90 (s, 1H), 4.82-4.77 ( m, J = 5.95, 6.48 Hz, 1H), 2.46 (s, 1100, 1028, 896, 858, 811, 703, 663 cm-1. HRMS (ESI) Calcd for
1H), 1.36 ( q, J = 6.31, 7.38 Hz, 6H), 1.07 (d, J = 6.26 Hz, 3H), C23H26N2O9S2Na [M+Na] 561.0977 found 561.0967.
0.76 ( d, J = 6.42 Hz, 3H).
2.2 General procedure for synthesis of Oxirane:16
(2S,5S)-diethyl
2-(4-cyanophenyl)-5-hydroxy-3-tosyl-1,3-
thiazinane-4,4-dicarboxylate (3b)
Reaction Time: 15 min., 1b (0.10 g, 0.22 mmol),
2 (0.03 g, 0.22
A solution of the alkene (5 mmol) in CH3CN (3 mL) is added to
neutral alumina (4.5 g). Then 2N aqueous NaOCl solution
(commercial beach 5 mL) is added slowly at room temperature
under stirring. When the reaction is complete, the epoxide is
extracted with CH2Cl2 (2 x 25 mL), the solvent removed and the
product is purified by silica gel chromatography to afford
oxiranes (yield 48-96 %).
mmol), white solid m.p. 136
℃, 0.09 g, Yield: 84%, Rf-value:
0.64 (EtOAc/Hexane) 4:10 (v/v).
3b: 1H NMR (400 MHz): δ 7.59 (d, J = 8.41 Hz, 2H), 7.39 (d, J =
8.47 Hz, 2H), 7.29 (d, J = 8.63 Hz, 2H), 7.07 (d, J = 8.31 Hz, 2H),
6.08 (s, 1H), 4.51-4.41 (m, 4H), 4.31 (m, J = 9.66, 2.44 Hz, 2H),
2.89 (m, 1H), 2.55 (m, 1H), 2.32 (s, 3H), 1.46 (t, J = 7.44 Hz, 3H),
1.41 (t, J = 7.11 Hz, 3H). 13C NMR (100 MHz): δ 170.8, 168.1,
145.2, 144.5, 136.4, 131.5, 129.2, 128.4, 127.4, 118.4, 110.0,
73.8, 63.3, 58.4, 28.0, 21.5, 13.8. IR (neat)νmax 3740, 3679,
3618, 3533, 2976, 2926, 2380, 2313, 2218, 1733, 1602, 1506,
1457, 1403, 1351, 1302, 1248, 1194, 1157, 1085, 1033, 971,
896, 843, 822, 757, 707, 660 cm-1. HRMS (ESI) Calcd for
C24H26N2O7S2Na [M+Na] 541.1079 found 541.1066.
Diethyl 3-phenyloxirane-2,2-dicarboxylate (4a):
1H NMR (400 MHz): δ 7.32 (s, 5Н), 4.57 (s, 1H), 4.32 (q, J = 7.0
Hz, 2Н), 4.02 (q, J = 7.0 Hz, 2Н), 1.33 (t, J = 7.0 Hz, 3Н), 0.97 (t, J
= 7.0 Hz, 3Н).
Diethyl 3-(4-chlorophenyl)oxirane-2,2-dicarboxylate (4b):
1H NMR (400 MHz): δ 7.32 (d, J = 8.5 Hz, 2Н), 7.29 (d, J = 8.5
Hz, 2Н), 4.53 (s, 1H), 4.32 (q, J = 7.0 Hz, 2Н), 4.06 (q, J = 7.0 Hz,
2Н), 1.32 (t, J = 7.0 Hz, 3Н), 1.03 (t, J = 7.0 Hz, 3Н).
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DOI: 10.1039/C7OB00941K
ARTICLE
Journal Name
(2S,5S)-diethyl
2-(4-fluorophenyl)-5-hydroxy-3-tosyl-1,3- 71.8, 63.3, 59.0, 28.2, 21.4, 13.8. IR (neat)νmax 3739, 3673,
thiazinane-4,4-dicarboxylate (3c)
3613, 2973, 2925, 2377, 2311, 1734, 1651, 1518, 1462, 1379,
(0.03 g, 0.22 1262, 1158, 1093, 1033, 954, 811 cm-1. HRMS (ESI) Calcd for
Reaction Time: 20 min., 1c (0.10 g, 0.22 mmol),
2
mmol), white viscous liquid, 0.08 g, Yield: 76%, Rf-value: 0.45 C23H26BrNO7S2Na [M+Na] 596.0388 found 596.0196.
(EtOAc/Hexane) 4:10 (v/v)
(2S,5S)-diethyl 5-hydroxy-2-phenyl-3-tosyl-1,3-thiazinane-4,4-
3c: 1H NMR (400 MHz): δ 7.62 (d, J =8.12 Hz, 2H), 7.24 (m, 2H), dicarboxylate (3g)
7.08 (d, J = 8.37 Hz, 2H), 6.68 (t, J = 8.61 Hz, 2H), 6.06 (s, 1H), Reaction Time: 15 min., 1g (0.10 g, 0.23 mmol),
2 (0.03 g, 0.23
4.50-4.40 (m, 4H), 4.38-4.28 (m, 2H), 2.92 (dd, J = 7.46, 4.96 mmol), white viscous liquid, 0.08 g, Yield: 70%, Rf-value: 0.56
Hz, 1H), 2.56 (dd, J = 7.91, 4.93 Hz, 2H), 2.32 (s, 3H), 1.46 (t, J (EtOAc/Hexane) 2:10 (v/v).
=7.01 Hz, 3H), 1.41 (t, J = 7.43 Hz, 3H). 13C NMR (100 MHz): δ 3g: 1H NMR (400 MHz): δ 7.61 (d, J = 8.48 Hz, 2H), 7.24 (d, J =
176.0, 171.0, 160.5, 144.1, 136.7, 135.0, 129.2, 128.6, 128.4, 6.70 Hz, 2H), 7.02 (m, 5H), 6.10 (s, 1H), 4.50-4.44 (m, 4H), 4.43-
114.6, 73.8, 63.2, 58.6, 28.1, 21.5, 13.9. IR (neat)νmax 3475, 4.41 (m, 1H), 4.29 (d, J = 11.90 Hz, 1H), 2.92 (dd, J = 8.20, 5.47
2923, 2856, 1744, 1711, 1600, 1504, 1455, 1344, 1257, 1227, Hz, 1H), 2.53 (dd, J = 8.34, 5.19 Hz, 1H), 2.29 (s, 3H), 1.46 (t, J =
1156, 1095, 1032, 883, 844, 761, 709, 660 cm-1. HRMS (ESI) 7.11 Hz, 3H), 1.41 (t, J = 7.11 Hz, 3H). 13C NMR (100 MHz): δ
Calcd for C23H26FNO7S2Na [M+Na] 534.1032 found 534.1022.
171.1, 168.3, 143.9, 139.2, 136.8, 129.1, 128.5, 127.7, 127.2,
(2S,5S)-diethyl 2-(4-chlorophenyl)-5-hydroxy-3-tosyl-1,3- 126.7, 73.9, 72.0, 63.1, 59.2, 28.1, 21.5, 13.9. IR (neat)νmax
thiazinane-4,4-dicarboxylate (3d)
3740, 3478, 2980, 2929, 1745, 1710, 1597, 1445, 1345, 1255,
(0.03 g, 0.22 1157, 1095, 1032, 896, 813, 774, 728, 660 cm-1. HRMS (ESI)
Reaction Time: 20 min., 1d (0.10 g, 0.22 mmol),
2
mmol), white viscous liquid, 0.09 g, Yield: 80%, Rf-value: 0.48 Calcd for C23H27NO7S2Na [M+Na] 516.1127 found 516.1117.
(EtOAc/Hexane) 4:10 (v/v).
(2S,5S)-diethyl
5-hydroxy-2-(naphthalen-2-yl)-3-tosyl-1,3-
3d: 1H NMR (400 MHz): δ 7.61 (d, J = 8.34 Hz, 2H), 7.19 (d, J = thiazinane-4,4-dicarboxylate (3h)
8.60 Hz, 2H), 7.08 (d, J = 8.34 Hz, 2H), 6.97 (d, J = 8.75 Hz, 2H), Reaction Time: 30 min., 1h (0.10 g, 0.21 mmol),
2 (0.03 g, 0.21
6.04 (s, 1H), 4.49-4.41 (m, 4H), 4.37-4.28 (m, 2H), 2.92 (q, J = mmol), white viscous liquid, 0.08 g, Yield: 74%, Rf-value: 0.46
7.66, 5.08 Hz, 1H), 2.55 (q, J = 7.55, 4.82 Hz, 1H), 2.32 (s, 3H), (EtOAc/Hexane) 2:10 (v/v).
1.45 (t, J = 7.10 Hz, 3H), 1.41 (t, J = 7.10 Hz, 3H). 13C NMR (100 3h: 1H NMR (400 MHz): δ 8.04, (d, J = 8.59 Hz, 1H), 7.78 (d, J =
MHz): δ 170.9, 168.2, 144.2, 137.9, 136.5, 133.0, 129.2, 128.4, 8.01 Hz, 1H), 7.51 (m, J = 7.10. 10.03, 8.99 Hz, 3H), 7.37 (d, J =
128.1, 127.8, 73.8, 63.2, 58.5, 28.0, 21.5, 13.8. IR (neat)νmax 8.27 Hz, 1H), 6.83 (t, J = 8.20 Hz, 1H), 6.76 (d, J = 7.88 Hz, 1H),
3740, 3476, 2925, 1743, 1595, 1484, 1452, 1346, 1257, 1158, 4.83 (m, J = 7.68, 4.49, 3.51 Hz, 1H), 4.60 (s, 1H), 4.57-4.47 (m,
1093, 1031, 895, 813, 719, 659 cm-1. HRMS (ESI) Calcd for 4H), 2.93 (dd, J = 8.59, 4.82 Hz, 1H), 2.49 (dd, J = 6.97, 6.12 Hz,
C23H26ClNO7S2Na [M+Na] 550.0737 found 550.0725.
1H), 2.16 (s, 3H), 1.54 (t, J = 7.36 Hz, 3H), 1.44 (t, J = 7.16 Hz,
(2S,5S)-diethyl
2-(4-bromophenyl)-5-hydroxy-3-tosyl-1,3- 3H). 13C NMR (100 MHz): δ 171.9, 168.5, 143.6, 136.8, 133.9,
thiazinane-4,4-dicarboxylate (3e)
132.7, 129.3, 129.1, 128.7, 128.1, 126.1, 125.6, 125.0, 124.2,
Reaction Time: 15 min., 1e (0.10 g, 0.20 mmol),
2
(0.03 g, 0.20 123.4, 74.6, 63.3, 56.8, 28.8, 21.4, 13.9. IR (neat)νmax 3741,
mmol), white solid m.p. 71
(EtOAc/Hexane) 2:10 (v/v).
℃
, 0.09 g, Yield: 82%, Rf-value: 0.74 3677, 3618, 3417, 2974, 2925, 2856, 2380, 2312, 1834, 1742,
1705, 1651, 1525, 1461, 1345, 1262, 1159, 1101, 1035, 896,
3e: 1H NMR (400 MHz): δ 7.60 (d, J = 8.70 Hz, 2H), 7.12 (s, 4H), 860, 808, 718, 662 cm-1. HRMS (ESI) Calcd for C27H29NO7S2Na
7.08 (d, J = 7.67 Hz, 2H), 6.01 (s, 1H), 4.50-4.40 (m, 4H), 4.38- [M+Na] 566.1283 found 566.1272.
4.28 (m, 2H), 2.92 (dd, J = 7.59, 5.37 Hz, 1H), 2.55 (dd, J = 7.59, (2S,5S)-diethyl 5-hydroxy-2-(p-tolyl)-3-tosyl-1,3-thiazinane-
5.06 Hz, 1H), 2.33 (s, 3H), 1.46 (t, J =7.19 Hz, 3H), 1.41 (t, J = 4,4-dicarboxylate (3i)
7.11 Hz, 3H). 13C NMR (100 MHz): δ 170.9, 168.2, 144.2, 138.5, Reaction Time: 20 min., 1i (0.10 g, 0.23 mmol),
2 (0.03 g, 0.23
136.5, 130.8, 129.2, 128.4, 121.2, 73.8, 71.9, 63.2, 58.6, 28.0, mmol), white viscous liquid, 0.08 g, Yield: 74%, Rf-value: 0.48
21.5, 13.8. IR (neat)νmax 3740, 3677, 3617, 2975, 2926, 2380, (EtOAc/Hexane) 2:10 (v/v).
2312, 1742, 1481, 1348, 1258, 1159, 1096, 1035, 893, 816, 3i: 1H NMR(400 MHz): δ 7.62 (d, J = 8.39 Hz, 2H), 7.13 (d, J =
703, 660 cm-1. HRMS (ESI) Calcd for C23H26BrNO7S2Na [M+Na] 7.70 Hz, 2H), 7.06 (d, J = 8.21 Hz, 2H), 6.80 (d, J = 8.14 Hz, 2H),
596.0388 found 596.0196.
6.05 (s, 1H), 4.48-4.40 (m, 5H), 4.27 (d, J = 11.79 Hz, 1H), 2.92
(2S,5S)-diethyl 2-(2-bromophenyl)-5-hydroxy-3-tosyl-1,3- (dd, J = 7.92, 4.84 Hz, 1H), 2.54 (dd, J = 8.10, 4.55 Hz, 1H), 2.30
thiazinane-4,4-dicarboxylate (3f)
(s, 3H), 2.20 (s, 3H), 1.45 (t, J = 7.34 Hz, 3H), 1.41 (t, J = 5.28 Hz,
(0.03 g, 0.20 3H). 13C NMR (100 MHz): δ 171.1, 168.4, 143.8, 136.9, 136.8,
Reaction Time: 25 min., 1j (0.10 g, 0.20 mmol),
2
mmol), white solid m.p. 145
℃
, 0.08 g, Yield: 78%, Rf-value: 136.1, 129.1, 128.5, 128.4, 126.3, 73.8, 63.1, 59.2, 28.1, 21.5,
21.0, 13.9. IR (neat)νmax 3740, 3478, 2978, 2928, 1746, 1711,
0.74 (EtOAc/Hexane) 2:10 (v/v).
3f: 1H NMR (400 MHz): δ 7.48 (d, J = 8.21 Hz, 1H), 7.40 (d, J = 1600, 1450, 1346, 1258, 1159, 1097, 1034, 896, 854, 814, 775,
7.92 Hz, 1H), 7.07 (d, J = 7.99 Hz, 1H), 6.88 (m, 3H), 6.73 (t, J = 702, 662 cm-1. HRMS (ESI) Calcd for C24H29NO7S2Na [M+Na]
7.77 Hz, 1H), 6.30 (s, 1H), 4.68 (m, 1H), 4.61 (d, J = 1.84 Hz, 530.1218 found 530.1274.
1H), 4.54-4.43 (m, 4H), 2.98 (dd, J = 7.85, 5.06 Hz, 1H), 2.52 (2S,5S)-diethyl 5-hydroxy-2-(4-isopropylphenyl)-3-tosyl-1,3-
(dd, J = 6.89, 6.38 Hz, 1H), 2.20 (s, 3H), 1.50 (t, J = 7.11 Hz, 3H), thiazinane-4,4-dicarboxylate (3j)
1.42 (t, J = 7.11 Hz, 3H) 13C NMR (100 MHz): δ 171.5, 168.3,
143.8, 137.0, 136.6, 133.4, 128.9, 128.1, 126.6, 122.3, 75.1,
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00941K
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ARTICLE
Reaction Time: 25 min., 1j (0.10 g, 0.21 mmol),
mmol), white viscous liquid, 0.08 g, Yield: 72%, Rf-value: 0.48 138.9, 129.4, 128.1, 127.9, 79.4, 62.2, 61.5, 51.9, 37.8, 14.1,
(EtOAc/Hexane) 2:10 (v/v). 13.9. IR (neat)νmax 3493, 2979, 1720, 1452, 1376, 1257, 1193,
2
(0.03 g, 0.21 0.78 (t, J = 7.23 Hz, 3H). 13C NMR (100 MHz): δ 168.4, 168.0,
3j: 1H NMR (400 MHz): δ 7.58 (d, J = 8.58 Hz, 2H), 7.11 (d, J = 1084, 1023, 860, 810, 742, 696 cm-1. HRMS (ESI) Calcd for
7.12 Hz, 2H), 7.01 (d, J = 7.95 Hz, 2H), 6.82 (d, J = 8.58 Hz, 2H), C16H20O6SNa [M+Na] 363.0878 found 363.0768.
6.06 (s, 1H), 4.53-4.41 (m, 5H), 4.30 (d, J = 11.72 Hz, 1H), 2.97 (2S,5S)-diethyl 2-(4-chlorophenyl)-5-hydroxy-1,3-oxathiane-
(dd, J = 7.74, 4.82 Hz, 1H), 2.75 (m, 1H), 2.53 (dd, J = 7.58, 4.82 6,6-dicarboxylate (5b)
Hz, 1H), 2.27 (s, 3H), 1.46 (t, J = 7.11 Hz, 3H), 1.41 (t, J = 7.26 Reaction Time: 6h, 4b (0.10 g, 0.33 mmol), 2 (0.05 g, 0.33
Hz, 3H), 1.13 (d, J = 6.90 Hz, 6H). 13C NMR (100 MHz): δ 168.3, mmol), yellow viscous liquid, 0.10 g, Yield: 82%, Rf-value: 0.61
147.9, 143.6, 136.9, 136.3, 129.0, 128.4, 126.7, 125.7, 74.0, (EtOAc/Hexane) 2:10 (v/v).
63.1, 59.1, 33.6, 28.2, 24.1, 23.9, 21.5, 13.9. IR (neat)νmax 3369, 5b: 1H NMR (400 MHz): δ 7.47 (d, J = 8.61 Hz, 2H), 7.24 (d, J =
3018, 2923, 2852, 1793, 1605, 1526, 1384, 1262, 1217, 1157, 8.61 Hz, 2H), 5.32 (s, 1H), 5.00 (m, 1H), 4.33-4.22 (m, 2H), 3.87
1123, 1093, 1029, 857, 771, 668, 579 cm-1. HRMS (ESI) Calcd (m, 2H), 3.54 (dd, J = 7.35, 8.78 Hz, 1H), 2.98 (dd, J = 4.43, 6.93
for C26H33NO7S2Na [M+Na] 558.1596 found 558.1581.
Hz, 1H), 2.77 (d, J = 7.88 Hz, 1H), 1.27 (t, J = 7.46 Hz, 3H), 0.851
(2S,5S)-dimethyl
5-hydroxy-2-(4-nitrophenyl)-3-tosyl-1,3- (t, J = 7.06 Hz, 3H). 13C NMR (100 MHz): δ 168.1, 167.6, 137.2,
thiazinane-4,4-dicarboxylate (3k)
133.7, 131.9, 130.8, 128.1, 127.9, 79.5, 62.3, 61.6, 51.2, 38.1,
14.1, 13.4. IR(neat)νmax 3435, 2923, 2852, 1728, 1617, 1525,
1490, 1456, 1386, 1260, 1197, 1158, 1092, 858, 827, 773, 691,
575 cm-1. HRMS (ESI) Calcd forC16H19ClO6SNa [M+Na] 397.0489
found 397.0489 Molecular formula.
Reaction Time: 15 min., 1k (0.10 g, 0.23 mmol),
2 (0.03 g, 0.23
mmol), white solid m.p. 152
℃, 0.10 g, Yield: 87%, Rf -value:
0.20 (EtOAc/Hexane) 4:10 (v/v).
1
3j: H NMR (400 MHz): δ 7.85 (d, J = 8.65 Hz, 2H), 7.58 (d, J = 8.54
Hz, 2H), 7.41 (d, J = 8.43 Hz, 2H), 7.06 (d, J = 8.32 Hz, 2H), 6.09 ( s,
1H), 4.33-4.24 ( m, 2H), 3.97 (d, J = 3.28 Hz, 6H), 2.88-2.86 (q, J =
7.12 , 5.58 Hz, 1H), 2.55-2.51 (q, J = 7.34, 5.36 Hz, 1H), 2.28 (s, 3H).
13C NMR (100 MHz): δ 171.6, 168.5, 146.9, 144.8, 136.1, 129.4,
128.4, 127.6, 123.0, 74.6, 71.7, 58.3, 54.0, 28.0, 21.5. IR (neat)νmax
3483, 2958, 2933, 2852, 1745, 1712, 1521, 1342, 1309, 1278, 1263,
1228, 1188, 1163, 1116, 1091, 1047, 1031, 958, 891, 860, 808, 773,
671, 655, 570, 559, 543, 478, 459cm-1.HRMS (ESI) Calcd for
C21H22N2O9S2Na [M+Na] 533.0664 found 533.0670.
(2S,5S)-diethyl
5-hydroxy-2-(4-nitrophenyl)-1,3-oxathiane-
6,6-dicarboxylate (5c)
Reaction Time: 5h, 4c (0.10 g, 0.32 mmol),
2 (0.04 g, 0.32
mmol), yellow viscous liquid, 0.09 g, Yield: 74%, Rf-value: 0.56
(EtOAc/Hexane) 2:10 (v/v).
5c: 1H NMR (400 MHz):δ 8.13 (d, J = 8.79 Hz, 2H), 7.71 (d, J =
8.77 Hz, 2H), 5.45 (s, 1H), 5.03 (q, J = 3.94, 3.61 Hz 1H), 4.33-
4.24 (m, J = 3.88, 3.56, 3.56, 7.18, 9.27 Hz, 2H), 3.93-3.86 (m,
2H), 3.51 (dd, J = 7.08, 3.87 Hz, 1H), 3.03 (dd, J = 3.62, 7.58 Hz,
1H), 2.72 (d, J = 7.25 Hz, 1H), 1.27 (t, J = 7.08 Hz, 3H), 0.826 (t, J
= 7.25 Hz, 3H). 13C NMR (100 MHz): δ 167.8, 167.2, 146.2,
130.6, 123.1, 79.8, 62.5, 61.7, 51.4, 38.7, 14.1, 13.5. IR
2 (0.03 g, 0.20 (neat)νmax 3391, 3018, 2924, 2399, 1605, 1525, 1384, 1263,
(2S,5S)-diisopropyl
5-hydroxy-2-(4-nitrophenyl)-3-tosyl-1,3-
thiazinane-4,4-dicarboxylate (3l)
Reaction Time: 20 min., 1l (0.10 g, 0.20 mmol),
mmol), white solid m.p. 149℃
0.76 (EtOAc/Hexane) 2:10 (v/v).
, 0.94 g, Yield: 83%, Rf-value: 1216, 1026, 928, 770, 669 cm-1. HRMS (ESI) Calcd for
C16H20NO8SNa [M+Na] 386.091 found 386.0864.
1
3l: H NMR (400 MHz): δ 7.84 (d, J = 8.75 Hz, 2H), 7.62 (d, J = 8.41 (2S,5S)-diethyl
Hz, 2H), 7.43 ( d, J = 8.86 Hz, 2H), 7.05 (d, J = 8.19 Hz, 2H), 6.11 (s, dicarboxylate (5d)
5-hydroxy-2-(p-tolyl)-1,3-oxathiane-6,6-
1H), 5.33-5.26 ( m, 2H), 4.36-4.28 ( m, 2H), 2.91-2.88 (q, J = 8.08, Reaction Time: 30 min., 4d (0.10 g, 0.35 mmol),
2
(0.05 g, 0.21
5.27 Hz, 1H), 2.59-2.56 (q, J = 7.52, 5.27 Hz, 1H), 2.27 (S, 3H), 1.47- mmol), white viscous liquid, 0.09 g, Yield: 76%, Rf-value: 0.54
1.37 (m, 12H). 13C NMR (100 MHz): δ 170.1, 167.7, 147.3, 146.7, (EtOAc/Hexane) 2:10 (v/v).
144.5, 136.5, 129.3, 128.4, 127.6, 122.9, m73.7, 71.9, 71.6, 71.2, 5d: 1H NMR (400 MHz): δ 7.31 (d, J = 8.29 Hz, 2H), 7.04 (d, J =
58.1, 28.0, 21.5. IR (neat) νmax 3452, 2980, 2914, 1743, 1712, 1597, 8.04 Hz, 2H), 5.25 (s, 1H), 5.01 (m, 1H), 4.33-4.19 (m, 2H), 3.83-
1517, 1429, 1348, 1278, 1259, 1165, 1101, 1089, 1031, 893, 862, 3.69 (m, 2H), 3.50 (m, 1H), 2.93 (dd, J = 5.29, 5.53 Hz, 1H), 2.88
813, 754, 574, 542 cm-1. HRMS (ESI) Calcd for C25H30N2O9S2Na (d, J = 7.58 Hz, 1H), 2.27 (s, 3H), 1.25 (t, J = 7.44 Hz, 3H), 0.79
[M+Na] 589.1290 found 589.1293.
(t, J = 7.08 Hz, 3H). 13C NMR (100 MHz): δ 168.4, 168.0, 137.6,
135.8, 130.3, 129.2, 128.7, 128.5, 79.1, 62.2, 61.5, 51.6, 37.4,
29.7, 21.1, 14.1, 13.3. IR (neat)νmax 3682, 3434, 3019, 2926,
2854, 2400, 2371, 2341, 1723, 1606, 1522, 1385, 1262, 1215,
1123, 1156, 1094, 928, 850,768, 669, 626 cm-1. HRMS (ESI)
Calcd for C17H22O6SNa [M+Na] 377.1035 found 377.1029.
Scope of Oxirane 2,2-dicarboxylate and 2,5-dihydroxy-1,4-
dithiane.
(2S,5S)-diethyl
5-hydroxy-2-phenyl-1,3-oxathiane-6,6-
dicarboxylate (5a)
Reaction Time: 30 min., 4a (0.10 g, 0.37 mmol),
2
(0.05 g, 0.21
Diethyl
5-hydroxy-2-(4-nitrophenyl)-5,6-dihydro-4H-1,3-
mmol), white viscous liquid, 0.10 g, Yield: 78%, Rf-value: 0.70
(EtOAc/Hexane) 2:10 (v/v).
5a: 1H NMR (400 MHz): δ 7.46 (dd, J = 1.72, 6.66 Hz, 2H), 7.24-
7.19 (m, 2H), 5.32 (s, 1H), 5.04 (dd, J = 4.93, 6.13 Hz, 1H), 4.35-
4.21 (m, 2H), 3.81-3.76 (m, 2H), 3.48 (m, 1H), 2.97 (dd, J = 5.00,
6.06 Hz, 1H), 2.92 (d, J = 7.40 Hz, 1H), 1.27 (t, J = 7.05 Hz, 3H),
thiazine-4,4-dicarboxylate (6)
Under argon atmosphere NaH (0.01 g, 0.47 mmol) filled in
single necked round bottom flask then add THF (4 mL). The
solution of 3a (0.18 g, 0.31 mmol) in THF (4 mL) was added
dropwise to the stirred solution at 0 °C then the reaction was
allow to stir at room temperature for 30 min. After completion
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of the reaction (monitored by TLC), the reaction was quenched 2.88 (m, J = 5.10, 4.96, 6.64 Hz, 2H), 2.49 (s, 3H), 1.42 (t, J =
with cold water. The organic solution was extracted with 6.98 Hz, 3H). 13C NMR (100 MHz): δ 165.1, 147.7, 145.1, 144.4,
diethyl ether (3 times) and dried with anhydrous Na2SO4. The 133.9, 131.1, 129.9, 128.7, 128.3, 123.8, 123.6, 62.2, 59.0,
solution was concentrated in under reduced pressure. The 21.8, 14.8. IR (neat)νmax 2981, 2929, 2854, 1735, 1678, 1595,
crude mixture was further purified by silica gel column 1521, 1479, 1367, 1346, 1276, 1217, 1188, 1165, 1109, 1089,
chromatography.
1037, 1012, 983, 937, 900, 862, 848, 813, 734, 717, 673, 578,
Reaction Time: 30 min., yellow viscous liquid, 0.05 g, Yield: 543 cm-1. HRMS (ESI) Calcd for C2H20N2O6S2Na [M+Na]
80%, Rf-value: 0.51 (EtOAc/Hexane) 2:10 (v/v).
471.0660 found 471.0654.
1H NMR (400 MHz): δ 8.22 (d, J = 8.78 Hz, 2H), 8.02 (d, J = 8.96
Hz, 2H), 4.63 (m, 1H), 4.39-4.27 (m, 2H), 3.69 (d, J = 5.07 Hz,
1H), 3.32 (dd, J = 3.35, 9.23 Hz, 1H), 3.27 (dd, J = 6.34, 7.06 Hz,
1H), 1.33 (t, J = 7.15 Hz, 3H), 1.29 (t, J = 5.16 Hz, 3H). 13C NMR
(100 MHz): δ 169.1, 167.7, 161.3, 149.5, 143.6, 128.1, 123.7,
63.0, 61.5, 29.2, 14.1. IR (neat)νmax 3682, 3370, 3020, 2400,
2341, 1727, 1600, 1525, 1385, 1215, 1156, 1124, 1030, 929,
850, 757, 669, 627 cm-1. HRMS (ESI) Calcd for C16H18N2O7SNa
[M+Na] 405.0732 found 405.0723.
Conclusions
In conclusion, we have developed an efficient protocol for the
synthesis of two heteroatom containing substituted 1,3–
thiazine and 1,3–oxathiane through [3+3] cycloaddition of N-
tosylaziridinedicarboxylate and oxirane with 1,4-dithiane 2,5-
diol. Additionally, we also demonstrated the chemical
conversion of substituted 1,3-thiazine in to various structure
which have immense biological application like cephalosporin
and TZ-1.
(2S,5S)-diethyl
5-acetoxy-2-(4-nitrophenyl)-3-tosyl-1,3-
thiazinane-4,4-dicarboxylate (7)
Under an argon atmosphere, 3a, (0.10 g, 0.18 mmol), pyridine
(0.02 g, 0.27 mmol), and DMAP (2 mg) were added to CH2Cl2 (7
mL) at 0 °C. Then a solution of Ac2O (0.03 ml, 0.03 mmol) in
CH2Cl2 (1.0 mL) was added with vigorous stirring. The reaction
mixture was gradually warmed to room temperature, and
stirred for 12 h. Then the reaction was quenched with
saturated aqueous NaHCO3 (2 mL), and the mixture was
extracted with ethyl acetate (3 X 20 mL). The organic layer was
dried with Na2SO4, and concentrated in vacuo. The residue was
Acknowledgements
R.K.V. thanks to the UGC, New Delhi, India for a research
fellowship. PB acknowledges the DST-India for financial
support. We also thankful to Dr. C. M. Nagaraja, Department
of Chemistry, IIT Ropar for solving the single crystal X-ray
structure mentioned in this paper.
purified by silica gel column chromatography to give 7. Yellow
viscous liquid, 0.05 g, Yield: 55%, Rf-value: 0.48
(EtOAc/Hexane) 2:10 (v/v).
Notes and references
1H NMR (400 MHz): δ 7.92 (m, 2H), 7.68 (d, J = 8.35 Hz, 2H),
7.61 (d, J = 8.35 Hz, 2H), 7.11 (d, J = 8.06, 2H), 6.14 (s, 1H), 5.62
(q, J = 7.34, 8.20 Hz, 1H), 4.44-4.38 (m, 2H), 4.32-4.24 (m, 2H),
3.00-2.89 (m, 2H), 2.33 (s, 3H), 2.04 (s, 3H), 1.39 (t, J = 7.19 Hz,
3H), 1.36 (t, J = 4.03 Hz, 3H). 13C NMR (100 MHz): δ 169.0,
167.5, 166.6, 147.1, 145.9, 144.6, 136.7, 129.3, 128.6, 128.3,
123.0, 71.7, 63.1, 59.0, 21.5, 20.7, 13.9. IR (neat)νmax 2985,
2929, 2337, 1757, 1737, 1597, 1514, 1469, 1438, 1344, 1278,
1261, 1238, 1219, 1190, 1165, 1111, 1080, 1039, 1012, 941,
902, 846, 813, 775, 756, 734, 675, 655, 596, 574, 542, 464 cm-
1. HRMS (ESI) Calcd for C25H28N2O10S2Na [M+Na] 603.1083
found 603.1075.
1
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(dd, J =3.02,1.81 Hz, 1H), 6.09 (s, 1H), 4.45-4.30 (m, 2H), 3.01-
8 | J. Name., 2012, 00, 1-3
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