Temperature-dependent annuloselectivity and stereochemistry in the reactions of methanesulfonyl sulfene with imines

Article abstract of DOI:10.1039/c6ob01259k

The annuloselectivity in the reactions of methanesulfonyl sulfene and imines varies with temperature. At a relatively higher temperature of 20 °C, the [2^s + 2ⁱ] annulation of different N-alkyl imines occurs exclusively, giving four-membered trans-β-sultams in up to 69% yields. At a lower temperature of -78 °C, the [2^s + 2ⁱ + 2ⁱ] annulation of N-methyl imines takes place specifically, delivering six-membered 1,2,4-thiadiazine 1,1-dioxides, 4-aza-δ-sultams, in up to 80% yields, with diverse configurations at the C3, C5, and C6 stereocenters. The trans-stereochemistry involved in the [2^s + 2ⁱ] annulations is attributed to the conrotatory ring closure of the thermodynamically stable 2,3-thiazabutadiene-type zwitterionic intermediates, while the diverse stereochemical outcomes in the [2^s + 2ⁱ + 2ⁱ] annulations are caused by the iminium isomerization in the stepwise nucleophilic [4 + 2] annulation between the same zwitterionic intermediates and a second molecule of N-methyl imines.

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Temperature-dependent annuloselectivity and
stereochemistry in the reactions of
Cite this: DOI: 10.1039/c6ob01259k
methanesulfonyl sulfene with imines†
Qiuyue Wu, Zhanhui Yang* and Jiaxi Xu*
The annuloselectivity in the reactions of methanesulfonyl sulfene and imines varies with temperature. At a
relatively higher temperature of 20 °C, the [2s + 2i] annulation of different N-alkyl imines occurs exclu-
sively, giving four-membered trans-β-sultams in up to 69% yields. At a lower temperature of −78 °C, the
[2s + 2i + 2i] annulation of N-methyl imines takes place specifically, delivering six-membered 1,2,4-thia-
diazine 1,1-dioxides, 4-aza-δ-sultams, in up to 80% yields, with diverse configurations at the C3, C5, and
C6 stereocenters. The trans-stereochemistry involved in the [2s + 2i] annulations is attributed to the con-
rotatory ring closure of the thermodynamically stable 2,3-thiazabutadiene-type zwitterionic intermedi-
ates, while the diverse stereochemical outcomes in the [2s + 2i + 2i] annulations are caused by the
iminium isomerization in the stepwise nucleophilic [4 + 2] annulation between the same zwitterionic
intermediates and a second molecule of N-methyl imines.
Received 9th June 2016,
Accepted 1st July 2016
DOI: 10.1039/c6ob01259k
www.rsc.org/obc
Introduction
The sulfa-Staudinger cycloadditions between sulfenes (or their
equivalents) and imines have been developed into an efficient
method to construct the β-sultam core structures,1–3 which
have witnessed wide applications in the synthetic4 and medic-
inal chemistry.5 However, the sulfa-Staudinger cycloadditions
between sulfene generated from sulfonyl chlorides 1 and
imines 2 or 3 proceed not only toward the [2s + 2i] annulations
to yield β-sultams 4, but also toward the [2s + 2i + 2i] annula-
tions to produce 1,2,4-thiadiazine 1,1-dioxides, 4-aza-δ-sultams
5 (Scheme 1a).2b,d,3b,6 The competitive relationship of these
two directions is referred to as annuloselectivity. Since the two
kinds of annuladducts display a wide spectrum of bioactiv-
ities,5,7 controlling the annuloselectivity becomes one of the
issues of concern in this field.
Scheme 1 Control of the annuloselectivity.
predict the annuloselective results based on the sulfene- and
imine-substituents. However, from a practical synthetic view-
point, controlling the annuloselectivity by external factors,
such as temperature, additives, solvents, etc., are meaningful
and useful.
Although the sulfa-Staudinger cycloaddition has received
much attention, the reactions between methanesulfonyl
sulfene (6) and imines 2 have not been well explored so far.3b
Herein, we present our studies on the temperature-dependent
annuloselectivity in the reactions of methanesulfonyl sulfene
(6), which could be generated either from the corresponding
methanesulfonylmethanesulfonyl chloride (1a) at room temp-
erature or by treating methanesulfonyl chloride (1b) at low
temperature (−78 °C) with strong bases, with imines 2
Very recently, we proposed the mechanisms of the [2s + 2i]
and [2s + 2i + 2i] annulations, and also found that the annulo-
selectivity was controlled by the sulfene- and imine-substitu-
ents, including the ring sizes of cyclic imines (Scheme 1a).2 In
other words, the annuloselectivity is governed by the innate
features of substrates. An empirical rule is also proposed to
State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing
100029, P. R. China. E-mail: zhyang@mail.buct.edu.cn, jxxu@mail.buct.edu.cn;
Fax: +86 10 64435565
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of products 7 and 8, NOE spectra of 8, and the 1H NMR spectra of
the crude reaction mixtures. See DOI: 10.1039/c6ob01259k
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(Scheme 1b), hoping to provide convenient methods to syn- 14% yields, respectively, as a mixture of (3,5)-cis-(5,6)-trans-
thesize trans-2-methanesulfonyl-β-sultams and 4-aza-6- and (3,5)-trans-(5,6)-cis-isomers (vide infra).
7
methanesulfonyl-δ-sultams 8 from the same substrates yet
under different conditions.
With the optimal conditions for the [2s + 2i] annulations, a
series of structurally diverse trans-2-methanesulfonyl-β-sultams
7 was easily synthesized, and the results are presented in
Table 2. All the crude reaction mixtures were examined using
1H NMR, and no [2s + 2i + 2i] annuladducts were observed,
indicating that the [2s + 2i] annulations occurred annulospeci-
fically. The N-methyl imines 2a–i reacted with sulfonyl chloride
1a to afford the corresponding [2s + 2i] annuladducts 7a–i in
moderate yields (21–69%). The C-substituents of imines did
not affect the [2s + 2i] annulations so much, with most of the
β-sultams obtained in 31–46% yields, except for 4-phenyl-
phenyl (7g) and the sterically large C-substituent 9-anthracenyl
(7j). 4-Phenylphenyl promoted the formation of the [2s + 2i]
annuladduct 7g with a relatively high 69% yield, while
9-anthracenyl prevented the [2s + 2i] annulation from forming
7j, presumably due to steric hindrance. The N-substituents of
imines did not affect the [2s + 2i] annulations obviously, either,
with most of the β-sultams obtained in 32–46% yields, except
for N-tert-butyl-β-sultam (7m) in low yield of 4%. By conduct-
ing the reactions with one equiv. of 1a and two equiv. of
Results and discussion
The [2s + 2i] annulation
With the model reaction between methanesulfonylmethane-
sulfonyl chloride (1a) and N-naphthalen-2-ylmethylene methyl-
amine (2a), the condition optimization was performed.
Generally, the sulfa-Staudinger cycloadditions were conducted
by mixing one equiv. of sulfonyl chloride 1a with two equiv. of
imine 2a without any other bases.2,3 With this procedure, the
solvent screening was conducted (Table 1, entries 1–7). The
results revealed that dichloromethane was the best choice,
with the product trans-sultam 7a obtained in a relatively high
42% yield (Table 1, entry 3). In these reactions, one equiv. of
imine 2a served as the base to generate the sulfene, and the
other took part in the cycloaddition. Further investigations on
other bases revealed that triethylamine gave the highest yield
of 51% (Table 1). Addition of bases affected not only the yield
of the [2s + 2i] annuladduct, but also the annuloselectivity. For
example, in the presence of N,N-dimethylaminopyridine
(DMAP) and 1,4-diazabicyclo[2.2.2]octane (DABCO), the [2s + 2i
+ 2i] annuladducts (8a and 9a) were also generated in 10% and
Table 2 [2s + 2i] Annulations at 20 °Ca,b
Table 1 Reaction condition optimization for the [2s + 2i] annulationa
Yieldb (%)
Entry
Solvent
Temp. (°C)
Base
7a
8a
1
2
3
4
5
6
7
8
THF
20
20
20
20
20
20
20
20
20
20
20
20
—
—
—
—
—
—
—
Et3N
2-ClPy
Py
DMAP
DABCO
8
30
42
11
26
6
Trace
51
43
22
19
15
0
0
0
0
0
0
0
0
0
CHCl3
CH2Cl2
DCE
MeCN
PhCH3
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
0
24c
21d
a All the reactions were performed on a 0.125 mmol scale based on 1a.
In entries 1–7, 1 equiv. of 1a and 2 equiv. of 2a were used. In entries
8–12, 1 equiv. of 1a, 1 equiv. of 2a, and 1 equiv. of base were used.
b Yields were calculated from the 1H NMR spectra of the crude reaction a The reactions were performed under the optimal conditions in
mixtures by analyzing the ratios of imines, aldehydes, 7a, 8a, and/or Table 1. b Isolated yields by column chromatography. c Yields were
9a. c As determined by the crude reaction mixture, 8a : 9a = 63 : 37. d As obtained by reacting 0.125 mmol of 1a with 0.25 mmol of 2e or 2n in
determined by the crude reaction mixture, 8a : 9a = 29 : 71.
THF.
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Table 3 Reaction condition optimization for the [2s
+ +
2i 2i]
imines in tetrahydrofuran, the yields of β-sultams 7e and 7m
were improved to 38% and 16%, respectively. Imines derived
from aliphatic aldehydes, for example, N-2-methylpropylidene
4-methylaniline (2o), also reacted with methanesulfonyl
sulfene (6) to give rise to the corresponding β-sultam 7o in low
yield (14%) due to unstable N-alkylidene imines. However,
imines prepared from aliphatic aldehydes and aliphatic
amines did not work well. For instance, the reaction of
methanesulfonyl sulfene (6) and the imine prepared from iso-
annulationa
Yieldb (%)
butanal and benzylamine generated
a complex mixture
because the prepared imine N-2-methylpropylidene benzyla-
mine could isomerize into N-benzylidene isobutanamine and
both these imines are unstable.
Entry
Solvent
Temp. (°C)
Base
7a
8a and 9a
1
2
3
4
5
CH2Cl2
CH2Cl2
THF
THF
THF
−78
−78
−78
−78
−78
DABCO
Et3N
DABCO
Et3N
0c
0
0
0
0
51d
10e
0
0
0
The [2s + 2i + 2i] annulation
DMAP
We envisioned that the [2s + 2i + 2i] annuloselectivity should
be enhanced when the reactions between methanesulfonyl
sulfene (6) and N-methyl imines were conducted at low temp-
erature, for example, −78 °C. As predicted, the reaction
between 1a and 2b at −78 °C yielded the [2s + 2i + 2i] annul-
adduct (3,5)-cis–(5,6)-trans-8c and (3,5)-trans–(5,6)-cis-9c in
15% total yield. As indicated by the 1H NMR analysis of the
crude reaction mixture, the ratio of 8c : 9c was 55 : 45, and the
[2s + 2i] annuladduct 7c was not observed (Scheme 2, eqn (1)).
It was reported that methanesulfonyl sulfene (6) could be
generated by treating methanesulfonyl chloride (1b) with tri-
ethylamine at −78 °C.8 Thus, preparation of the [2s + 2i + 2i]
annuladducts directly from methanesulfonyl chloride (1b) at
−78 °C is feasible. Preliminary work by Kobayashi and co-
workers disclosed that addition of methanesulfonyl chloride
(1b) into a mixture of triethylamine and imine 2b at −78 °C
failed to give the [2s + 2i] annuladduct 7c; instead, [2s + 2i + 2i]
annuladduct (3,5)-cis–(5,6)-trans-8c generated exclusively in
22% yield (Scheme 2, eqn (2)).3b It is of note that the stereo-
chemistry in the two reactions (Scheme 2) was not completely
the same, and a new diastereomer 9c was isolated in our
experiments. This indicates that the stereochemistry in the
[2s + 2i + 2i] annulations of linear imines was not as simple as
Kobayashi and co-workers reported.
a All the reactions were performed on a 0.5 mmol scale based on
methanesulfonyl sulfene (6); that is, 1 mmol of 1b, 1 mmol of base,
and 1.5 mmol of imine 2a were used. b Yields were calculated from the
1H NMR spectra of the crude reaction mixtures by analyzing the ratios
of imines, aldehydes, 7a, 8a, and/or 9a. c No product was observed by
the 1H NMR spectra of the crude reaction mixtures. d 8a : 9a = 29 : 71.
e 8a : 9a = 15 : 85.
reacting methanesulfonyl chloride (1b) with N-naphthalen-2-yl-
methylene methylamine (2a) at −78 °C. The results are sum-
marized in Table 3. When dichloromethane was used as the
solvent, strong bases DABCO and triethylamine promoted the
reactions toward the [2s + 2i + 2i] pathway, delivering 4-aza-
δ-sultams 8a and 9a in 51% and 10% total yields, respectively
(Table 3, entries 1 and 2). Further stereochemical studies by
NOE analyses showed that 8a exhibited a (3,5)-cis–(5,6)-trans-
configuration, while 9a exhibited (3,5)-trans–(5,6)-cis (for
detail, see Table 4, entry 1). The ratio of the two diastereomeric
products 8a : 9a was closely affected by the bases added. For
example, DABCO delivered 29 : 71 ratio, while triethylamine
15 : 85 ratio. In tetrahydrofuran solvent no [2s + 2i + 2i] annula-
tions were observed with any of the bases.
Studies on the [2s + 2i + 2i] annulations were performed, by
reacting different N-methyl imines 2a,c–h with methanesulf-
onyl chloride (1b) in the presence of DABCO in dichloro-
methane and tetrahydrofuran at −78 °C. The results are
presented in Table 4. The [2s + 2i + 2i] annulations gave struc-
turally diverse 4-aza-δ-sultams 8 and 9. The stereochemistry of
the C3 and C5 positions was determined by their NOE analy-
sis. As demonstrated by our previous work, an observed NOE
value between the protons at C3 and C5 positions indicated
the (3,5)-cis-configuration; otherwise, the (3,5)-trans-configur-
ation should be assigned. The stereochemistry of the C5 and
C6 was assigned on the basis of the coupling constants
between the protons at these positions. Generally, for the (5,6)-
cis-configuration, J = 0 − 5 Hz; for the (5,6)-trans-configuration,
J = 7–14 Hz.2b,d
With the above experimental results, the reaction condition
optimization for the [2s + 2i + 2i] annulation was conducted by
The C-aryl substituents of imines 2a,c–h affected not only
the yields, but also the stereochemistry, of the [2s + 2i + 2i]
annuladducts 4-aza-δ-sultams 8, 9 and 10. Taking the reactions
Scheme 2 Realization of the [2s + 2i + 2i] annulation from different
sulfene precursors.
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Table 4 [2s + 2i + 2i] Annulations at −78 °Ca,b,c
a The reactions were performed under the optimal conditions in Table 3, with DCM or THF as solvents. b Yields for the reactions in DCM were
obtained by column chromatography, while yields for reactions in THF were obtained by the 1H NMR spectra of the crude reaction mixtures by
analyzing the ratios of imines, aldehydes, [2s + 2i + 2i] annuladducts 8, 9, and/or 10. c The ratios of 8 : 9 were determined by the 1H NMR spectra
of the crude reaction mixtures.
in dichloromethane as examples, the reactions of imines 2a, erated, and the corresponding 8 : 9 ratios were 29 : 71, 53 : 47,
2c, 2d, 2e, and 2g afforded the corresponding 4-aza-δ-sultams 26 : 74, and 83 : 17 (Table 4, entries 1, 4, 6, and 7), respectively.
in 51%, 50%, 51%, 80%, and 48% total yields (Table 4, entries Contrastingly, the reactions of 2c, 2d, and 2f in dichloro-
1–4, 6), respectively, while the reactions of imines 2f and 2h methane stereospecifically gave rise to (3,5)-trans–(5,6)-cis-9c,
gave products in lower 14% and 15% total yields (Table 4, (3,5)-trans–(5,6)-trans-10d, and (3,5)-trans–(5,6)-cis-9f (Table 4,
entries 5 and 7), respectively. In the reactions of imines 2a, 2e, entries 2, 3, and 5), respectively.
2g, and 2h in dichloromethane, both (3,5)-cis–(5,6)-trans-pro-
The solvent effect was also an important factor in the
ducts (8a,e,g,h) and (3,5)-trans–(5,6)-cis-products (9a,e,g,h) gen- [2s + 2i + 2i] annulations. In most cases, higher yields of the
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mediates A are not stable, because of the large steric hindrance
between the methanesulfonyl group (MeSO2) and the R2
group. On one hand, A will isomerize fast into the thermo-
dynamically stable intermediates B by means of the CvN+
bond isomerization. On the other hand, the direct conrotation
of intermediates A was also drastically decreased by the repul-
sion between MeSO2 and R2, and the electron-withdrawing
methanesulfonyl group. As a result, in both [2s + 2i] and [2s +
2i + 2i] annulations, intermediates B act as the predominant
reactive intermediates to evolve toward the four-membered
β-sultams 7 and six-membered 4-aza-δ-sultams 8–10. In the
[2s + 2i] annulations at room temperature, only intermediates
Scheme 3 The [2s + 2i + 2i] annulations between 3,4-dihydroisoquino-
line and methanesulfonyl sulfene.
[2s + 2i + 2i] annuladducts were obtained in dichloromethane B undergo the conrotatory ring closure to form trans-β-sultams
than those in tetrahydrofuran (Table 4, entries 1, and 3–5). 7. This is the reason why most β-sultams (except for 7d) in
However, in the reactions of imines 2c and 2h, a converse Table 2 show an exclusive trans-configuration. The results also
solvent effect was observed, that is, the yields in tetrahydro- reveal that the energy barrier of the [2s + 2i] annulation is
furan were much higher than those in dichloromethane higher than that of the [2s + 2i + 2i] one because [2s + 2i] annu-
(Table 4, entries 2 and 7). In addition, the stereochemical lation requires a relatively higher temperature.
ratios in tetrahydrofuran also differed from those in dichloro-
methane, as shown by the different 8 : 9 ratios obtained in the conrotatory ring closure of intermediates B are affected by tem-
two solvents (Table 4, entries 2, 4, and 6).
perature.2c The lower the temperature, the slower the conrota-
Our previous mechanistic studies also pointed out that the
The [2s + 2i + 2i] annulation between sulfonyl chloride 1a tion. Thus, at −78 °C, the conrotation of intermediates B is
and cyclic imine 3,4-dihydroisoquinoline (11) was also significantly inhibited. This provided opportunities for inter-
observed, giving two stereochemically different products (3,5)- molecularly nucleophilic addition with another molecule of
cis–(5,6)-trans-12 and (3,5)-cis–(5,6)-cis-13 in 10% and 20% more strongly nucleophilic N-methyl imines9 to the iminium
yields (Scheme 3), respectively. The detailed mechanism of moiety in the corresponding intermediates B-1 (Scheme 5).
the stereochemistry has been rationalized in previous reports The direct nucleophilic addition of N-methyl imines to inter-
on the cyclic imine-participated sulfa-Staudinger cycloaddi- mediates B-1 from the bottom side generates intermediates C,
tions.2b,d
of which the further intramolecular nucleophilic addition
affords (3,5)-trans–(5,6)-trans-10, as represented by 10d in
Mechanistic rationalization
The temperature-controlled [2s + 2i] and [2s + 2i + 2i] annulo-
selectivity and the related stereochemistry can be explained
well.2 As shown in Scheme 4, the methanesulfonyl sulfene (6),
generated either by direct elimination of HCl from methane-
sulfonylmethanesulfonyl chloride (1a) under weakly or
strongly basic conditions or by the dimerization of sulfene
derived from methanesulfonyl chloride (1b) in the presence of
strong bases at −78 °C,8 is exo attacked by the nitrogen atom
in imines 2, giving rise to 2,3-thiazabutadiene-type zwitterionic
intermediates A. According to our previous theories,2a,c inter-
Scheme 4 Proposed mechanisms in the temperature-controlled
Scheme 5 Proposed stepwise mechanisms for the [2s 2i 2i]
+ +
annuloselectivity.
annulations.
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Table 4. Because the strongly electron-withdrawing ortho-nitro-
phenyl accelerates both direct intermolecular nucleophilic
addition (step a) and intramolecular nucleophilic addition
(step b), both CvN+ bonds in intermediates B-1 and C have no
opportunity to isomerize at low temperature (−78 °C).
The generation of cis-sultam cis-7d supports that the
Fig. 1 The intermediates in sulfa-Staudinger and Staudinger
cycloadditions.
iminium moiety in intermediate Bd/B-1d (where R1
=
2-O2NC6H4) shows more strong electrophilicity, favoring direct
conrotatory ring closure at a relatively higher temperature of
20 °C (Table 1, 7d)2c and intermolecularly nucleophilic attack
with a secondary imine molecule at a lower temperature of
−78 °C. In the case, isomerization of the iminium is
decreased. In addition, because intermediates C with a strong
electron-withdrawing R1 group are thermodynamically most
stable and favorable in the intramolecularly nucleophilic cycli-
zation, no isomerization of their CvN+ moieties can occur.
Thus, no (3,5)-cis–(5,6)-cis-products 14 could be observed.
In other cases (Scheme 5), N-methyl imines nucleophilically
attack thermodynamically CvN+-isomerized intermediates B-2
from their bottom side to yield intermediates D (step d), in
which the CvN+ would isomerize to form intermediates E
(step f). Both intermediates D and E undergo intramolecularly
nucleophilic addition to give rise to [2s + 2i + 2i] annuladducts
(3,5)-cis–(5,6)-trans-8, for examples, 8a, 8c, 8e, 8g, and 8h in
Table 4 (step e), and (3,5)-trans–(5,6)-cis-products 9, as rep-
resented by 9a, 9c, 9e, 9f, 9g, and 9h in Table 4 (step g),
respectively.
as depicted in Scheme 5, delivering stereochemically diverse
annuladducts. Contrastingly, in most [2k + 2i + 2i] annulations,
the Staudinger intermediates 16 follow a concerted hetero-
Diels–Alder cycloaddition mechanism, with an endo- or exo-
selectivity, to react with a second imine molecule, giving
stereochemically predictable annuladducts.12
Conclusions
The annuloselectivity in the reactions of methanesulfonyl
sulfene and imines varies with temperature. At a relatively
higher temperature of 20 °C with methanesulfonylmethane-
sulfonyl chloride as the sulfene precursor, the [2s + 2i] annula-
tion of different N-alkyl imines occur exclusively, giving four-
membered trans-β-sultams in up to 69% yields. At a lower
temperature of −78 °C with methanesulfonyl chloride as the
sulfene precursor, the [2s + 2i + 2i] annulations of N-methyl
imines take place specifically, delivering six-membered 4-aza-
δ-sultams in up to 80% yields, with diverse configurations at
the C3, C5, and C6 stereocenters. The trans-stereochemistry
involved in the [2s + 2i] annulations is attributed to the conro-
tatory ring closure of the thermodynamically 2,3-thiazabuta-
diene-type zwitterionic intermediates B. The diverse
stereochemistry in the [2s + 2i + 2i] annulations is explained
well by the stepwise [4 + 2] annulation between intermediates
B and N-methyl imines, with the inter/intramolecular nucleo-
philic additions and iminium isomerization as stereo-
determining steps. The current study provides convenient
methods to synthesize trans-β-sultams and 4-aza-δ-sultams
selectively from imines and methanesulfonyl chloride.
Similarly, N-methyl imines can also attack intermediates
B-1 and B-2 from their top side followed by the subsequent
processes, affording the enantiomers of the [2s + 2i + 2i] annul-
adducts generated from the bottom-side attack.
The stereochemical results in Table 4 indicated that not
only the intermolecularly nucleophilic addition of N-methyl
imines to B-1 (step a), and isomerization of B-1 to B-2 (step c),
but also the CvN+ isomerizations and intramolecular addition
inside intermediates D (step e and f) are in competition. The
competitions are sensitively affected by the steric hindrance or
electronic properties of the C-aryl substituents in the N-methyl
imines 2, and consequently give [2s + 2i + 2i] annuladducts in
different stereochemistry. The inter/intramolecular nucleo-
philic additions and CvN+ isomerizations are the stereo-
determining steps, deciding the C3, C5, and C6 stereo-
chemistry in different cases.
Experimental
Staudinger intermediates vs. sulfa-Staudinger intermediates
General information
In the Staudinger cycloadditions, similar [2k + 2i + 2i] annula- Tetrahydrofuran and toluene were refluxed over sodium with
tions between one ketene molecule and two imine molecules diphenyl ketone as an indicator, while acetonitrile, dichloro-
are also frequently observed.10 The key intermediates involved methane, and 1,2-dichloroethane were refluxed over calcium
are 2-aza-butadiene-type zwitterionic intermediates 16,11 struc- hydride. All the solvents were freshly distilled prior to use.
turally similar to the sulfa-Staudinger intermediates 15 Melting points were obtained on a Yanaco MP-500 melting
1
(Fig. 1). Even though both 15 and 16 can directly undergo con- point apparatus and are uncorrected. H and 13C NMR spectra
rotatory ring closure to form β-sultams and β-lactams, respect- were recorded on a Bruker 400 MHz or 600 MHz spectrometer
ively, the mechanisms of the corresponding [2s + 2i + 2i] and in CDCl3 with TMS as an internal standard and the chemical
[2k + 2i + 2i] annulations differ distinctly. In the [2s + 2i + 2i] shifts (δ) are reported in parts per million (ppm). The one-
annulations, the sulfa-Staudinger intermediates 15 react with dimensional selected NOE experiments were conducted on a
a second imine molecule followed by a stepwise mechanism, Bruker 600 MHz spectrometer. The IR spectra (KBr pellets,
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v [cm−1]) were obtained on a Nicolet 370 FTIR spectrometer. 2.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.4, 134.7, 130.9,
HRMS measurements were carried out on an Agilent LC/MS 129.6, 128.3, 125.9, 91.1, 54.4, 42.6, 32.1.
TOF mass spectrometer. TLC analyses were performed on
trans-Isomer: 1H NMR (400 MHz, CDCl3) δ 8.30–7.25 (m,
silica gel G plates, and the plates were visualized with UV light. 4H), 5.44 (d, J = 6.0 Hz, 1H), 5.16 (d, J = 6.1 Hz, 1H), 3.26 (s,
PE is the abbreviation for petroleum ether (60–90 °C), and EA 3H), 2.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.8, 134.4,
for ethyl acetate.
130.7, 128.4, 126.2, 125.1, 86.9, 50.2, 40.1, 31.2.
Sulfonyl chlorides 1a and 1b were used directly as commer-
IR (film) v cm−1 2930, 1528, 1497, 1342, 1193, 1166, 1144,
cially received. Imines 2a–o were prepared in quantitative 965. HRMS (ESI) calcd for C10H13N2O6S2 (M + H+) m/z
yields by refluxing the corresponding aldehydes (1 equiv.) and 321.0210, found 321.0207.
amines (1 equiv.) in dichloromethane for several hours with
MgSO4 (1.5 equiv.) as drying agents.2b,c
IR (film) v cm−1 2930, 1528, 1497, 1342, 1193, 1166, 1144,
965. HRMS (ESI) calcd for C10H13N2O6S2 (M + H+) m/z
321.0210, found 321.0207.
trans-2-Methyl-4-(methanesulfonyl)-3-(3-nitrophenyl)-1,2-
General procedure for the [2s + 2i] annulation
thiazetidine 1,1-dioxide (7e). White solid, mp 160–162 °C.
1
To a 10 mL reaction tube charged with a solution of an imine Yield: 9 mg, 21%. H NMR (400 MHz, CDCl3) 8.44 (dd, J = 1.8,
2 (0.125 mmol) and triethylamine (13 mg, 0.125 mmol) in dry 1.8 Hz, 1H), 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.91 (d, J = 7.7 Hz,
dichloromethane (1 mL) was added (methanesulfonyl)methane- 1H), 7.70 (dd, J = 8.0, 8.0 Hz, 1H), 5.23 (d, J = 5.6 Hz, 1H), 4.75
sulfonyl chloride (1a) (24 mg, 0.125 mmol). The tube was (d, J = 5.6 Hz, 1H), 3.28 (s, 3H), 2.90 (s, 3H). 13C NMR
quickly sealed, immersed into a 20 °C oil bath and stirred for (101 MHz, CDCl3) δ 149.0, 136.4, 132.9, 130.8, 124.8, 121.7,
6 h. After adding dichloromethane (5 mL), washing with brine 89.8, 52.3, 41.6, 31.5. ESI-HRMS: 321.0207. IR (film) v cm−1
(5 mL), drying over MgSO4, and concentrating at reduced 2921, 1348, 1181, 1143, 963. HRMS (ESI) calcd for
pressure, the residue was purified by column chromatography C10H13N2O6S2 (M + H+) m/z 321.0210, found 321.0207.
on silica gel with PE and EA (3 : 1, v/v) as the eluent to afford
β-sultam.
trans-2-Methyl-4-(methanesulfonyl)-3-(4-nitrophenyl)-1,2-
thiazetidine 1,1-dioxide (7f). White solid, mp 122–123 °C.
trans-2-Methyl-4-(methanesulfonyl)-3-(naphthalen-2-yl)-1,2- White solid. Rf = 0.2 (PE : EA = 3 : 1). Yield: 15 mg, 38%.
thiazetidine 1,1-dioxide (7a). White solid, mp 45–47 °C. Yield: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.74 (d,
1
21 mg, 51%. H NMR (400 MHz, CDCl3) δ 7.98–7.85 (m, 4H), J = 8.7 Hz, 2H), 5.20 (d, J = 5.5 Hz, 1H), 4.75 (d, J = 5.5 Hz, 1H),
7.65–7.44 (m, 3H), 5.31 (d, J = 5.4 Hz, 1H), 4.83 (d, J = 5.4 Hz, 3.28 (s, 3H), 2.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 148.8,
1H), 3.24 (s, 3H), 2.86 (s, 3H). 13C NMR (101 MHz, CDCl3) 141.0, 127.8, 124.7, 89.8, 52.2, 41.7, 31.5. IR (film) v cm−1
δ 133.9, 133.1, 130.9, 129.9, 128.2, 127.9, 127.3, 127.1, 127.1, 2919, 1523, 1348, 1181, 1143, 963. HRMS (ESI) calcd for
123.3, 90.1, 53.8, 41.6, 30.7. IR (film) v cm−1 2921, 1334, 1180, C10H13N2O6S2 (M + H+) m/z 321.0210, found 321.0205.
1142, 1123, 971. HRMS (ESI) calcd for C14H16NO4S2 (M + H+)
m/z 326.0515, found 326.0512.
trans-3-([1,1′-Biphenyl]-4-yl)-2-methyl-4-(methanesulfonyl)-
1,2-thiazetidine 1,1-dioxide (7g). White solid, mp 38–40 °C.
trans-2-Methyl-4-(methanesulfonyl)-3-(naphthalen-1-yl)-1,2- Yield: 30 mg, 69%. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J =
thiazetidine 1,1-dioxide (7b). White solid, mp 180–182 °C. 8.3 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.59–7.45 (m, 5H), 5.26 (d,
Yield: 13 mg, 33%. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = J = 5.4 Hz, 1H), 4.71 (d, J = 5.4 Hz, 1H), 3.24 (s, 3H), 2.85 (s,
8.5 Hz, 1H), 7.97–7.90 (m, 3H), 7.67–7.61 (m, 1H), 7.60–7.52 3H). 13C NMR (101 MHz, CDCl3) δ 143.0, 139.9, 132.5, 128.9,
(m, 2H), 5.46 (d, J = 5.5 Hz, 1H), 5.30 (d, J = 5.5 Hz, 1H), 3.18 128.2, 127.9, 127.4, 127.1, 90.1, 53.3, 41.5, 30.6. IR (film)
(s, 3H), 2.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 134.0, 130.8, v cm−1 2921, 1487, 1452, 1331, 1185, 1147, 962. HRMS (ESI)
130.6, 129.2, 129.0, 127.4, 126.6, 125.5, 124.8, 122.2, 90.3, 50.7, calcd for C16H18NO4S2 (M + H+) m/z 352.0672, found 352.0666.
42.1, 31.0. IR (film) v cm−1 2922, 1458, 1333, 1174, 1146, 960.
HRMS (ESI) calcd for C14H16NO4S2 (M + H+) m/z 326.0515, thiazetidine 1,1-dioxide (7h). Yellowish oil. Yield: 12 mg, 31%.
found 326.0515.
1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.7 Hz, 2H), 6.96 (d,
trans-3-(4-Methoxyphenyl)-2-methyl-4-(methanesulfonyl)-1,2-
trans-2-Methyl-4-(methanesulfonyl)-3-phenyl-1,2-thiazetidine J = 8.7 Hz, 2H), 5.18 (d, J = 5.3 Hz, 1H), 4.62 (d, J = 5.3 Hz, 1H),
1,1-dioxide (7c). Colorless oil. Yield: 17 mg, 46%. 1H NMR 3.83 (s, 3H), 3.22 (s, 3H), 2.78 (s, 3H). 13C NMR (101 MHz,
(400 MHz, CDCl3) δ 7.54–7.51 (m, 2H), 7.48–7.43 (m, 3H), 5.23 CDCl3) δ 160.9, 128.4, 125.3, 114.9, 90.2, 55.4, 53.3, 41.4, 30.3.
(d, J = 5.2 Hz, 1H), 4.66 (d, J = 5.2 Hz, 1H), 3.22 (s, 3H), 2.82 (s, IR (film) v cm−1 2921, 1330, 1171, 1147, 964. HRMS (ESI) calcd
3H). 13C NMR (400 MHz, CDCl3) δ 133.7, 129.9, 129.5, 126.9, for C11H16NO5S2 (M + H+) m/z 306.0464, found 306.0466.
90.0, 53.4, 41.5, 30.6. IR (film) v cm−1 2960, 1577, 1497, 1457,
1332, 1182, 1147, 1005, 963, 763, 727, 698. HRMS (ESI) calcd thiazetidine 1,1-dioxide (7i). Yellowish oil. Yield: 18 mg, 40%.
for C10H13NNaO4S2 (M + H+) m/z 298.0178, found 298.0177. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.5 Hz, 2H), 7.41 (d,
cis- and trans-2-Methyl-4-(methanesulfonyl)-3-(2-nitro- J = 8.4 Hz, 2H), 5.18 (d, J = 5.4 Hz, 1H), 4.62 (d, J = 5.4 Hz, 1H),
phenyl)-1,2-thiazetidine 1,1-dioxide (7d). Yellowish solid, 3.23 (s, 3H), 2.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 132.9,
mp 48–50 °C. Yield: 17 mg, 43%.
132.7, 128.5, 124.2, 89.9, 52.8, 41.5, 30.8. IR (film) v cm−1
trans-3-(4-Bromophenyl)-2-methyl-4-(methanesulfonyl)-1,2-
1
cis-Isomer: H NMR (400 MHz, CDCl3) δ 8.30–7.25 (m, 4H), 2920, 1329, 1147, 1120, 963. HRMS (ESI) calcd for
5.81 (d, J = 8.0 Hz, 1H), 5.30 (d, J = 8.0 Hz, 1H), 2.89 (s, 3H), C10H13BrNO4S2 (M + H+) m/z 353.9464, found 353.9460.
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trans-2-Cyclohexyl-4-(methanesulfonyl)-3-phenyl-1,2-thiazeti- at −78 °C for 6 h, and then was slowly warmed to room temp-
dine 1,1-dioxide (7k). White solid, mp 82–83 °C. Yield: 20 mg, erature. After adding dichloromethane (5 mL), washing with
46%. 1H NMR (400 MHz, CDCl3) δ 7.58–5.56 (m, 2H), brine (10 mL), drying over MgSO4, and concentrating at
7.46–7.38 (m, 3H), 5.07 (d, J = 5.0 Hz, 1H), 4.82 (d, J = 5.0 Hz, reduced pressure, the residue was purified by column chrom-
1H), 3.39–3.28 (m, 1H), 3.20 (s, 3H), 2.04–1.16 (m, 10H). atography on silica gel with PE and EA as the eluent to afford
13C NMR (101 MHz, CDCl3) δ 136.1, 129.6, 129.4, 126.7, 89.4, 4-aza-δ-sultam.
57.0, 50.2, 41.5, 31.6, 30.3, 25.2, 24.3, 24.0. IR (film) v cm−1
rel(3S,5S,6S)- and rel(3R,5S,6S)-2,4-Dimethyl-6-(methane-
2924, 1453, 1383, 1331, 1175, 1144, 962. HRMS (ESI) calcd for sulfonyl)-3,5-di(naphthalen-2-yl)-1,2,4-thiadiazinane 1,1-dioxide
C15H22NO4S2 (M + H+) m/z 344.0985, found 344.0984.
(8a and 9a). Inseparable mixtures. Colorless crystals, mp
trans-2-Benzyl-4-(methanesulfonyl)-3-phenyl-1,2-thiazetidine 105–110 °C. Total yield: 126 mg, 51%.
1,1-dioxide (7l). Yellowish solid, mp 107–108 °C. Yield: 20 mg,
rel(3S,5S,6S)-Isomer (8a). 1H NMR (400 MHz, CDCl3)
45%. 1H NMR (400 MHz, CDCl3) δ 7.47–7.44 (m, 2H), δ 8.06–7.44 (m, 14H), 5.38 (s, 1H), 4.91 (d, J = 8.3 Hz, 1H), 4.61
7.41–7.39 (m, 3H), 7.31–7.26 (m, 5H), 5.20 (d, J = 5.0 Hz, 1H), (d, J = 8.3 Hz, 1H), 2.89 (s, 3H), 2.87 (s, 3H), 1.89 (s, 3H).
4.69 (d, J = 5.0 Hz, 1H), 4.36 (d, J = 14.5 Hz, 1H), 4.25 (d, J = 13C NMR (101 MHz, CDCl3) δ 136.6, 133.7, 133.61, 133.4,
14.5 Hz, 1H), 3.19 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 134.0, 133.03, 132.84, 129.4, 129.1, 128.9, 128.8, 128.25, 128.15,
133.1, 129.8, 129.4, 128.9, 128.8, 128.5, 127.0, 89.9, 51.8, 49.0, 127.76, 127.72, 126.93, 126.8, 126.7, 126.6, 125.6, 125.2, 83.6,
41.3. IR (film) v cm−1 2920, 1496, 1457, 1332, 1178, 1148, 961. 79.2, 66.7, 43.9, 39.6, 32.9.
HRMS (ESI) calcd for C16H18NO4S2 (M + H+) m/z 352.0672,
found 352.0671.
rel(3R,5S,6S)-Isomer (9a). 1H NMR (400 MHz, CDCl3)
δ 8.06–7.44 (m, 14H), 5.25 (d, J = 1.9 Hz, 1H), 5.12 (d, J =
trans-2-(tert-Butyl)-4-(methanesulfonyl)-3-(2-nitrophenyl)-1,2- 2.0 Hz, 1H), 4.42 (s, 1H), 3.48 (s, 3H), 2.84 (s, 3H), 2.31 (s, 3H).
thiazetidine 1,1-dioxide (7m). White solid, mp 177–178 °C. 13C NMR (101 MHz, CDCl3) δ 133.9, 133.2, 133.01, 132.8,
Yield: 2 mg, 4%. 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 8.0, 132.6, 130.4, 129.3, 129.3, 129.0, 128.6, 128.3, 128.2, 128.0,
1.0 Hz, 1H), 8.00 (dd, J = 8.2, 0.9 Hz, 1H), 7.78 (dd, J = 7.7, 7.7 127.72, 127.68, 127.1, 127.0, 126.88, 126.5, 125.7, 84.9, 81.9,
Hz, 1H), 7.58 (ddd, J = 8.0, 8.0, 1.3 Hz, 1H), 5.91 (d, J = 5.1 Hz, 63.9, 40.2, 40.1, 31.9.
1H), 5.01 (d, J = 5.1 Hz, 1H), 3.26 (s, 3H), 1.32 (s, 9H). 13C NMR
IR and HRMS. IR (film) v cm−1 2928, 1318, 1165, 1141, 1020,
(101 MHz, CDCl3) δ 148.4, 134.3, 133.0, 130.4, 128.5, 125.4, 964. HRMS (ESI) calcd for C26H27N2O4S2 (M + H+) m/z
90.5, 58.8, 43.0, 40.7, 27.7. IR (film) v cm−1 2976, 2922, 1530, 495.1407, found 495.1400.
1334, 1171, 1149, 961. HRMS (ESI) calcd for C13H19N2O6S2
rel(3S,5S,6R)- and rel(3R,5S,6S)-Dimethyl-6-(methanesulfo-
nyl)-3,5-diphenyl-1,2,4-thiadiazinane 1,1-dioxide (8c and 9c).
(M + H+) m/z 363.0679, found 363.0673.
trans-2-Isopropyl-4-(methanesulfonyl)-3-(4-nitrophenyl)-1,2- Inseparable mixtures. Colorless crystals. Mp 140–144 °C. Yield:
thiazetidine 1,1-dioxide (7n). Colorless oil. Yield: 14 mg, 32%. 104 mg, 50%.
1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.79 (d,
rel(3S,5S,6R)-Isomer (8c). 1H NMR (400 MHz, CDCl3) δ 7.89
J = 8.7 Hz, 2H), 5.08 (d, J = 5.2 Hz, 1H), 4.90 (d, J = 5.2 Hz, 1H), (d, J = 7.2 Hz, 1H), 7.73–7.68 (m, 1H), 7.59 (d, J = 7.0 Hz, 2H),
3.68 (hept, J = 6.4 Hz, 1H), 3.25 (s, 3H), 1.34 (d, J = 6.4 Hz, 3H), 7.57–7.31 (m, 6H), 5.26 (s, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.36 (d,
1.14 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.7, J = 9.0 Hz, 1H), 2.83 (s, 3H), 2.81 (s, 3H), 1.85 (s, 3H). 13C NMR
143.3, 127.7, 124.7, 89.0, 50.4, 49.1, 41.7, 21.6, 20.4. IR (film) (101 MHz, CDCl3) δ 140.8, 139.1, 135.9, 129.6, 129.1, 128.8,
v cm−1 2925, 1526, 1348, 1185, 1145, 1111, 962. HRMS (ESI) 128.64, 128.62, 82.8, 79.0, 67.0, 44.0, 39.4, 32.4.
calcd for C12H17N2O6S2 (M
349.0525.
+
H+) m/z 349.0523, found
rel(3R,5S,6S)-Isomer (9c). 1H NMR (400 MHz, CDCl3)
δ 7.57–7.44 (m, 5H), 7.40–7.31 (m, 5H), 5.06 (d, J = 1.9 Hz, 1H),
trans-3-Isopropyl-4-(methanesulfonyl)-2-(4-methylphenyl)- 4.90 (d, J = 1.9 Hz, 1H), 4.22 (s, 1H), 3.42 (s, 3H), 2.78 (s, 3H),
1,2-thiazetidine 1,1-dioxide (7o). Yellowish oil. Yield: 11 mg, 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 135.4, 133.1, 129.6,
14%. 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 7.07 129.11, 129.10, 128.8, 128.64, 128.63, 84.8, 81.5, 63.9, 40.02,
(d, J = 8.4 Hz, 2H), 5.16 (d, J = 4.7 Hz, 1H), 4.32 (dd, J = 4.7, 39.97, 31.8.
4.7 Hz, 1H), 3.29 (s, 3H), 2.34 (s, 3H), 2.32–2.29 (m, 1H), 1.07
IR and HRMS. IR (film) v cm−1 2922, 1456, 1313, 1227, 1154,
(d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, 1135, 1116, 1000, 963. HRMS (ESI) calcd for C18H22N2NaO4S2
CDCl3) δ 136.4, 132.9, 130.4, 120.7, 84.2, 54.3, 41.4, 30.2, 20.9, (M + H+) m/z 417.0913, found 417.0907.
18.8, 16.7. IR (film) v cm−1 2922, 1655, 1514, 1328, 1220, 1047,
rel(3R,5S,6R)-2,4-Dimethyl-6-(methanesulfonyl)-3,5-bis-
966. HRMS (ESI) calcd for C13H20NO4S2 (M + H+) m/z (2-nitrophenyl)-1,2,4-thiadiazinane 1,1-dioxide (10d).
318.0828, found 318.0825.
Yellow oil. Yield: 124 mg, 51%. 1H NMR (400 MHz, CDCl3)
δ 8.23 (d, J = 7.9 Hz, 1H), 7.93 (dd, J = 8.0, 8.0 Hz, 2H), 7.80
(dd, J = 7.7, 7.7 Hz, 1H), 7.75 (dd, J = 7.6, 7.6 Hz, 1H), 7.65 (d,
General procedure for the [2s + 2i + 2i] annulations
To a 10 mL reaction tube were added N-methyl imine 2 J = 7.7 Hz, 1H), 7.60 (dd, J = 7.7, 7.7 Hz, 2H), 6.10 (d, J =
(1.5 mmol) and DABCO (112 mg, 1.0 mmol). Under a nitrogen 7.0 Hz, 1H), 5.88 (s, 1H), 5.02 (d, J = 7.0 Hz, 1H), 3.28 (s, 3H),
atmosphere at −78 °C, dry dichloromethane (4 mL) was added, 3.02 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.1,
followed by slow addition of methanesulfonyl chloride (1b) 149.5, 133.5, 132.8, 130.18, 130.06, 129.75, 129.69, 129.5,
(115 mg, 0.08 mL, 1 mmol). The resultant mixture was stirred 129.2, 125.6, 125.1, 79.8, 54.2, 42.6, 38.99, 38.92, 34.7.
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IR (film) v cm−1 2928, 1529, 1345, 1318, 1165, 1142, 967.
rel(3R,5R,6S)-Isomer (8h). 1H NMR (400 MHz, CDCl3)
HRMS (ESI) calcd for C18H21N4O8S2 (M + H+) m/z 485.0795, δ 7.49–7.39 (m, 4H), 6.96–6.89 (m, 4H), 5.21 (s, 1H), 4.69 (d, J =
found 485.0790.
9.2 Hz, 1H), 4.28 (d, J = 9.2 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H),
rel(3S,5S,6R)-2,4-Dimethyl-6-(methanesulfonyl)-3,5-bis(3-nitro- 2.82 (s, 3H), 2.80 (s, 3H), 1.83 (s, 3H). 13C NMR (101 MHz,
phenyl)-1,2,4-thiadiazinane 1,1-dioxide (8e). A trace amount was CDCl3) δ 82.0, 78.9, 66.8, 55.3, 55.2, 44.1, 39.1, 32.0 (only for
isolated as a yellow oil, therefore, only the 1H NMR is provided. aliphatic carbons).
1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.38 (s, 1H), 8.30 (d,
rel(3R,5S,6S)-Isomer (9h). 1H NMR (400 MHz, CDCl3)
J = 10.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.98 (t, J = 7.5 Hz, δ 7.49–7.39 (m, 4H), 6.96–6.89 (m, 4H), 5.00 (d, J = 1.9 Hz, 1H),
2H), 7.69 (dd, J = 7.9, 7.9 Hz, 1H), 7.63 (d, J = 8.0, 8.0 Hz, 1H), 4.81 (d, J = 1.9 Hz, 1H), 4.10 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H),
5.25 (s, 1H), 4.71 (d, J = 7.7 Hz, 1H), 4.61 (d, J = 7.7 Hz, 1H), 3.40 (s, 3H), 2.74 (s, 3H), 2.19 (s, 3H). 13C NMR (101 MHz,
3.23 (s, 3H), 2.85 (s, 3H), 1.88 (s, 3H).
CDCl3) δ 85.4, 81.2, 63.4, 55.5, 55.4, 42.0, 39.9, 31.5 (only for
rel(3R,5S,6S)-2,4-Dimethyl-6-(methanesulfonyl)-3,5-bis(3-nitro- aliphatic carbons).
phenyl)-1,2,4-thiadiazinane 1,1-dioxide (9e). Colorless crystals.
IR and HRMS. IR (film) v cm−1 2922, 1512, 1384, 1317, 1306,
Mp 110–120 °C. Yield: 99 mg, 41%, isolated from the reaction 1258, 1152, 1144, 974. HRMS (ESI) calcd for C20H26N2NaO6S2
in THF. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.39–8.31 (M + H+) m/z 477.1124, found 477.1114.
(m, 2H), 8.26 (dd, J = 8.2, 2.3 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H),
7.92 (d, J = 7.7 Hz, 1H), 7.82 (dd, J = 7.8, 7.8 Hz, 1H), 7.74 (dd,
J = 8.0, 8.0 Hz, 1H), 6.17 (d, J = 3.8 Hz, 1H), 5.21 (d, J = 3.8 Hz,
1H), 4.85 (s, 1H), 3.34 (s, 3H), 2.91 (s, 3H), 2.26 (s, 3H).
Acknowledgements
13C NMR (101 MHz, CDCl3) δ 147.9, 147.7, 138.6, 136.4, This work was supported by the National Basic Research
134.86, 134.81, 130.1, 129.9, 124.4, 123.9, 123.5, 123.2, 80.3, Program of China (No. 2013CB328905), the National Natural
79.7, 61.2, 39.7, 38.4, 33.4. IR (film) v cm−1 2927, 1530, 1349, Science Foundation of China (No. 21572017), and the BUCT
1315, 1229, 1154, 1139, 968. HRMS (ESI) calcd for Fund for Discipline Construction and Development (Project
C18H21N4O8S2 (M + H+) m/z 485.0795, found 485.0782.
rel(3R,5S,6S)-2,4-Dimethyl-6-(methanesulfonyl)-3,5-bis(4-nitro-
phenyl)-1,2,4-thiadiazinane 1,1-dioxide (9f). Colorless crystals.
Mp 197–199 °C. Yield: 34 mg, 14%. 1H NMR (400 MHz,
DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 2H), 8.29 (d, J = 8.5 Hz, 2H),
7.87 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 6.11 (d, J =
4.6 Hz, 1H), 5.17 (d, J = 4.6 Hz, 1H), 4.98 (s, 1H), 3.32 (s, 3H),
2.93 (s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.7,
147.4, 143.6, 140.7, 131.0, 129.5, 123.6, 123.4, 80.0, 61.1, 40.4,
38.4, 34.3, 31.5. IR (film) v cm−1 2922, 1314, 1144, 1035, 1006.
HRMS (ESI) calcd for C18H21N4O8S2 (M + H+) m/z 485.0795,
found 485.0796.
No. XK1533).
Notes and references
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1941.
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2844; (d) Z. H. Yang and J. X. Xu, RSC Adv., 2015, 5, 78396.
3 For selected reactions of sulfonyl chlorides with imines,
see: (a) O. Tsuge and S. Iwanami, Bull. Chem. Soc. Jpn.,
1970, 43, 3543; (b) T. Hiraoka and T. Kobayashi, Bull. Chem.
Soc. Jpn., 1975, 48, 480; (c) P. Loiseau, M. Bonnafous and
Y. Adam, Eur. J. Med. Chem., 1984, 19, 569;
(d) M. J. Szymonifka and J. V. Heck, Tetrahedron Lett., 1989,
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135; (f) E. Grunder-Klotz and J.-D. Ehrhardt, Tetrahedron
Lett., 1991, 32, 751; (g) M. F. Gordeev, E. M. Gordon and
D. V. Patel, J. Org. Chem., 1997, 62, 8177; (h) T. Iwama,
T. Kataoka, O. Muraoka and G. Tanabe, J. Org. Chem., 1998,
63, 8355; (i) T. Iwama, A. Takag and T. Kataoka, Chem.
Pharm. Bull., 1998, 46, 757; ( j) M. Zajac and R. Peters, Org.
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4 For reviews, see: (a) P. Hudhomme, Comprehensive Hetero-
cyclic Chemistry III, in Four-membered Rings with One Sulfur
and One Nitrogen Atom, Elsevier Ltd, 2008, vol. 2, pp.
729–759; (b) J. Chanet-Ray and R. Vessiere, Org. Prep.
Proced. Int., 1986, 18, 157. For selected examples, see:
(c) H. H. Otto and P. Schwenkkraus, Tetrahedron Lett., 1982,
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rel(3R,5R,6S)- and rel(3R,5S,6S)-3,5-Di([1,1′-biphenyl]-4-yl)-
2,4-dimethyl-6-(methanesulfonyl)-1,2,4-thiadiazinane
1,1-
dioxide (8g and 9g). Inseparable mixtures. White solid. Mp
158–160 °C. Yield: 131 mg, 48%.
rel(3R,5R,6S)-Isomer (8g). 1H NMR (400 MHz, CDCl3)
δ 7.78–7.36 (m, 18H), 5.34 (s, 1H), 4.86 (d, J = 8.8 Hz, 1H), 4.47
(d, J = 8.9 Hz, 2H), 2.92 (s, 3H), 2.90 (s, 4H), 1.97 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 82.8, 79.1, 66.7, 44.0, 39.5, 32.6
(only for aliphatic carbons).
rel(3R,5S,6S)-Isomer (9g). 1H NMR (400 MHz, CDCl3)
δ 7.78–7.36 (m, 18H), 5.14 (d, J = 1.8 Hz, 1H), 5.00 (d, J =
1.9 Hz, 1H), 4.37 (s, 1H), 3.47 (s, 3H), 2.97 (s, 3H), 2.36 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 84.7, 81.3, 63.7, 40.1, 38.9, 31.9
(only for aliphatic carbons).
IR and HRMS. IR (film) v cm−1 2922, 1486, 1367, 1317, 1167,
1141, 968. HRMS (ESI) calcd for C30H31N2O4S2 (M + H+) m/z
547.1720, found 547.1702.
rel(3R,5R,6S)- and rel(3R,5S,6S)-3,5-Bis(4-methoxyphenyl)-
2,4-dimethyl-6-(methanesulfonyl)-1,2,4-thiadiazinane
1,1-
dioxide (8h and 9h). Inseparable mixtures. Yellowish oil. Yield:
36 mg, 15%.
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