Copper-Catalyzed Synthesis of Thiadiazine-1-oxides in Reusable Aqueous Medium under External [Ag]/Ligand/Base-Free Conditions

Article abstract of DOI:10.1021/acs.joc.9b02828

We report herein a copper-catalyzed multicomponent reaction of simple NH-sulfoximine with readily available aldehyde and TMSN₃ in hot water and aerobic conditions. The reaction tolerated a broad range of functional groups under external [Ag]/li

Full text of DOI:10.1021/acs.joc.9b02828

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Article
Copper-Catalyzed Synthesis of Thiadiazine-1-oxides in Reusable
Aqueous Medium Under External [Ag]/Ligand/Base-Free Conditions
Cui Wu, Riting Huang, Ming Zhang, and Zhiyuan Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02828 • Publication Date (Web): 18 Dec 2019
Downloaded from pubs.acs.org on December 21, 2019
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Copper-Catalyzed Synthesis of Thiadiazine-1-oxides in
Reusable Aqueous Medium Under External [Ag]/Ligand/Base-
Free Conditions
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Cui Wu, Riting Huang, Ming Zhang, and Zhiyuan Chen*
Key Laboratory of Functional Small Organic Molecules, Ministry of Education, and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022 (P. R. China). E-mail: zchen@jxnu.edu.cn
O
S
O R2
R2
S
TMSN
Cu2O/TBAI/
R3 CHO
3
N
+
R1
R1
NH
H2O, 90 oC, air
R3
N
Br
40 examples, 35-95% yield.
Hot water as the solvent.
Resuable catalytic system
ABSTRACT: We report herein a copper-catalyzed multicomponent reaction of simple NH-sulfoximine with readily
available aldehyde and TMSN3 in hot water and aerobic conditions. The reaction tolerated a broad range of functional
groups under external [Ag]/ligand/base-free conditions, and can form three C-N bonds in a one-pot transformation,
thus represent an extremely cost-effective protocol to biologically active sulfoximine derivatives. This aqueous
catalytic system could be circularly utilized in consecutive runs of gram-scale preparations of thiadiazine-1-oxides
without extra addition of copper catalyst and PTA. Mechanistically, an "ortho-binding" effect in ortho-bromo NH-
sulfoximine was proposed to control the chemoselectivity, thus, the other free halides such as bromo- or iodo-atoms in
aldehydes 2 were compatible in the reaction.
INTRODUCTION
Biologically active sulfoximine derivatives have attracted noticeable attention recently due to the frequent
appearance of the structural motifs in pharmaceutical sciences.1 Fused heterocyclic benzothiadiazine 1‐oxides bearing
a benzene ‐ fused sulfoximine moiety are particularly relevant to potential medicinal applications (Figure 1).2 For
instance, the bicyclic thiadiazine-1-oxide A has been shown to exhibit blood pressure-lowering activity in animal
testing as an equipotent to the marketed drug Prazosin.3 NSC287474 possesses a potential reverse transcriptase
inhibitor with inhibition to HIV replication in lymphocytes.4 Tricyclic fused sulfoximine Gö4962 has displayed
significant characteristics as a partial benzodiazepine receptor agonist with excellent anxiolytic and anticonvulsive
activities. 5
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O
Me
O
S
Ph
S
N
MeO
MeO
O
S
Ph
Cl
N
N
N
N
O
N
.HCl
N
N
H
S
N
N
Me
O
A
NSC 287474
inhibition of HIV
replication in
lymphocytes
Go4962
anxiolytic and
anticonvulsive activity
an analog of a-adrenergic
receptor blocker Prazosin
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Figure 1. Selected bioactive thiadiazine-1-oxide derivatives.
In spite of the importance of these derivatives, the preparation methods of thiadiazine-1-oxides in organic synthesis
are amazingly limted and still need significant development, in efficient synthetic techniques for this structure. The
traditional pathways use nitroaryl thioethers or 2-thio-substituted anilines6 or N-protected sulfoxides7 as the starting
materials. Several preparation methods have reportedly utilized O-(mesitylenesulfonyl)hydroxylamine (MSH),
nBuLi/TsN3,8 or tert-butyl(2,4,6-trichlorobenzoyl)oxycarbamates (Scheme 1, eq. 1),9 as the key aminating reagents,
were reported for cyclic thiadiazine-1-oxide synthesis frameworks. Nevertheless, these methods generally require
multiple-step transformations and harsh reaction conditions. To account for these problems, we recently developed a
microwave assisted Cp*CoIII-catalyzed one-pot and one-step construction of diverse thiadiazine 1-oxides, starting from
NH-sulfoximines with 1,4,2-dioxazol-5-ones (Scheme 1, eq. 2).10 Recently, Dong and co-workers have also disclosed
a Cp*RhIII-catalyzed annulation reaction to build dihydrobenzo thiadiazine 1 ‐ oxide derivatives from NH ‐
sulfoximine and two components of benzyl azides (Scheme 1, eq. 3).11
Although these two methods maybe applicable for the preparation of the fused aza-heterocyclic sulfoximines,
several limitations still exist: (1) expensive transition-metal catalysts, Cp*M (M = Rh or Co) are needed; and
additionally, Ag salts or additional ligands should be added to activate the catalytic species; (2) almost all of the
amination reagents are not commercially available, and therefore they must be prepared in advance; (3) stoichiometric
excess of external bases or oxidants must be employed; and (4), organic halide solvents are also generally required.
These limitations create challenges in high cost and necessary considerations for environmental protection in order to
conduct a large-scale synthesis. To further investigate tandem cyclization transformations to polycyclic frameworks or
azaheterocyclic molecules,12 we have proposed a new strategy that would allow for the replacement of the expensive
Cp*M complexes with naturally abundant Cu salts as the catalyst. Additionally, if a readily available nitrogen source
and commercial aldehyde could be directly employed, a succinct and environment-friendly route to the class of
bicyclic sulfoximines could be developed.
Our previous findings revealed that the NH-benzoyl-substituted sulfoximine species, a key intermediate to deliver
the thiadiazine-1-oxides, could be generated through Cp*CoIII-catalyzed ortho-C−H amidation reaction.10 Therefore,
our current report will show an alternative facile synthesis of thiadiazine-1-oxides in an aqueouls solution. The starting
materials for the cascade reaction are from readily available azides as the N source and aldehydes as the coupling
reagent, thus to highly and efficiently generating diverse thiadiazine-1-oxides with excellent functional group tolerance
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under cost-effective copper catalyzed conditions (Scheme 1, eq. 4). It's interesting to note that this aqueous catalytic
system could be reused several times upon extraction of the final products when the reaction reaches completion,
without affecting the catalytic efficiency of the expected products.
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Scheme 1. Reported access to thiadiazine-1-oxides and our design.
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O
S
R
O
O
S
R
O
S
4 steps
R
Cp*RhIII
NHBoc
N
O
Ar
(1)
R'
NH
NH
N
NHBoc
Ar = 2,4,6-Cl3C6H2
O
O
O
Cp*Co(CO)I2
AgSbF6/PivOH
O
R
R
S
N
S
O
O
N
N
(2)
NH
tAmOH/CHCl3
MW, 110 oC
R'
R'
R
O
[Cp*RhCl2]2
AgNTf2
R
S
N3
S
S
N
2
NH
(3)
(4)
Ar
MesCOONa
DCE, 110 oC
N
Ar
R'
Bn
O
S
O
R
R
[Cu] / PTC (cat.)
TMSN3
N
NH
H2O as solvent
90 oC, open air
R' CHO
N
Br
This work: A resuable catalytic system.
Table 1. Optimization of the reaction conditions.a
[Cu] (5.0 mol%)
"N" (2.0 equiv)
O
S
O Me
S
CHO
Me
N
NH
additive (10 mol%)
solvent (1.0 mL)
80-100 oC, under air
Br
N
Ph
(1.0 equiv)
(1.2 equiv)
1a
2a
3aa
entry
[Cu]
CuI
"N"
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
additive
3aa /%
n.r.
10
1
2
3
4
5
6
7
8
NH3.H2O
-
-
-
-
-
-
-
-
CuI
NaN3
CuI
TMSN3
MsN3
29
CuI
trace
27
CuBr
CuCl
Cu2O
Cu
TMSN3
TMSN3
TMSN3
TMSN3
26
55
19
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Cu(OTf)2
-
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
NaN3
DMSO
DMSO
DMSO/H2O
H2O
-
22
0
10
11
12
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14
15
16
17
18
19
20
21
-
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
-
46b
65
56
60
81
72
87
60c
95d
89e
18
-
H2O
SDS
H2O
nBu4OAc
TritonX-100
TBAB
TBAI
TBAI
TBAI
TBAI
TBAI
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H2O
H2O
H2O
H2O
H2O
H2O
H2O
aReaction conditions: NH-sulfoximine 1a (0.30 mmol), benzaldehyde 2a (0.36 mmol) in 1.0 mL of solvent at 80 oC for
12-24 h, isolated yield. DMSO/H2O = 9 : 1 (v/v); c TBAI (1.0 equiv); d T = 90 C; e T = 100 C. SDS = sodium
b
o
o
dodecanesulfonate; TritonX-100 = polyethylene glycol mono-4-octylphenyl ether (n ≈ 10).
RESULTS AND DISCUSSION
We began the study by using 1-bromo-2-(S-methylsulfonimidoyl)benzene (1a) and benzaldehyde (2a) as the model
o
substrates in DMSO at 80 C (Table 1). NH-Sulfoximine 1a, which contained a methyl substitution at the S-linkage,
was selected as the starting material in this reaction because the S-alkyl substituted benzothiadiazine 1-oxides were
found to be difficult to generate in the previous Cp*M-catalyzed (M = Co, Rh) annulation reactions.10,11 To explore
reaction conditions that would be highly compatible with various functional groups, acidic or basic additives were
avoided in the subsequent optimizations. With CuI as the catalyst, different "N" sources were screened, such as
NH3.H2O, NaN3, azidotrimethylsilane (TMSN3), and methanesulfonyl azide (MsN3) were screened, which indicated
that the desired product 3aa could be generated in 29% yield when TMSN3 was utilized (entries 1-4). Subsequently,
the copper catalysts with varied oxidation states were evaluated. While even Cu powder worked to some extent (entry
8), Cu2O hold the most optimal results among the [Cu] catalyst examined (entries 5-9). A control experiment also
clearly indicated that no reaction occurred when in the absence of any metal catalyst species (entry 10). Water was
found to be unprofitable in the previous CuF2-mediated reductive amination reaction of aryl halides with azides,13
however, it was observed that the addition of water in no way harmful to this catalytic C-N bond formation reaction.
The expected product 3aa could be isolated in 46% yield when a mixture solvent of DMSO/H2O (9:1, v/v) was utilized
(entry 11). This result led us to employ pure water as the reaction medium, which then had an improved yield of 65%
(entry 12).14 The addition of phase-transfer catalyst (PTC) as an additive to this aqueous reaction also proved to be
useful. While a good yield was observed when 10 mol% of TritonX-100 was added, screening of different PTCs
showed that tetrabutylammonium iodide (TBAI) provided the best result at 87% (entries 13-17). In addition to the
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result, the reaction yield decreased when the stoichiometric amount of TBAI was added (entry 18). Furthermore, the
reaction time was shortened to about 12 h at reflux temperature, and an excellent yield of 95% was obtained when
heating the reaction was set at 90 oC (entries 19-20). However, under this aqueous medium using water as the solvent,
NaN3 was again not a good N source that can be used instead of TMSN3, because the yield of the desired product 3aa
was only 18% under the optimized conditions (entry 21). The aqueous and atmospheric conditions were found to be
optimal for this reaction, which suggests that this facile protocol be of probably utmost practical for industrial large-
scale applications.
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Once we completed optimization for the reaction conditions (Table 1, entry 19), we studied the scope for the Cu2O-
catalyzed protocol for the synthesis of thiadiazine-1-oxide 3. Initially, we chose NH-sulfoximine 1a as a model
substrate and commercially available aryl or alkyl aldehydes 2 to explore the feasibility and efficiency of the desired
transformation. As can be seen from Scheme 2, a wide range of aryl aldehydes 2 containing diversified functional
groups were well tolerated in the reactions, resulting in the expected bicyclic sulfoximine heterocycles 3aa-3av in
aqueous solution. The benzaldehyde 2, which bears strong electron-donating 4-MeO or 3-MeO, were tolerated to give
the desired products 3ab and 3ak in good yields. Aryl aldehydes 2 attached with electron-withdrawing halo-
substitutions, such as chloro (3ad and 3an), bromo (3ae and 3al), iodo (3af), fluoro (3ao), and trifluoromethyl (3ag)
groups, all were well tolerated without difficulty, regardless of their locations at the para-, meta- or ortho- position of
the phenyl moiety. In addition, the strong electron-withdrawing group, such as NO2 and CN, were also tolerated to
give the desired products 3ah and 3ai in acceptable yields. The steric effect of the ortho-substituted benzaldehydes
influenced the efficiency of the reaction dramatically, delivering compounds 3am and 3an in only serviceable yields.
Scheme 2. Reaction scope studies.a
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Cu2O (5.0 mol%)
TMSN3 (2.0 equiv)
TBAI (10 mol%)
O
S
O Me
Me
S
R3 CHO
+
N
NH
H2O (1.0 mL)
90 oC, under air
Br
N
R3
(1.0 equiv)
(1.2 equiv)
1a
2
3
O Me
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
(R = H), 95%
S
(R = 4-MeO), 91%
(R = 4-Me), 86%
(R = 4-Cl), 70%
(R = 4-Br), 79%
(R = 4-I), 82%
(R = 4-CF3), 62%
(R = 4-NO2), 63%
(R = 4-CN), 25%
(R = 4-CHO), 84%
(R = 3-MeO), 75%
(R = 3-Br), 74%
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N
F
N
O Me
Br
S
3ao
, 64%
N
O Me
N
S
R
N
N
(R = 2-NO2), 42%
(R = 2-Cl), 43%
HO
3ap
, 81%
Me
O Me
O Me
O Me
S
S
S
N
N
N
Cl
Me
N
N
N
HO
HO
3aq
, 70%
3ar
3as
, 71%
, 78%
O Me
O Me
O Me
S
S
S
N
N
N
S
O
N
N
N
3at
, 53%
3au
, 83%
3av
, 49%
O Me
O Me
S
O Me
S
N
S
N
N
N
N
N
3aw
3ax
, 80%
3ay
, 73%
, 64%
O Me
S
N
N
Cl
3az
, 35%
aReaction conditions: NH-sulfoximine 1a (0.30 mmol), aldehyde 2 (0.36 mmol, 1.3 equiv) and TBAI (10 mol%) in 1.0
mL of H2O at 90 oC under air conditions. Isolated yield.
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Interestingly, the terephthalaldehyde 2j which contained two formyl groups at the para positions of the phenyl ring
alsoreacted well to provide the CHO substituted product 3aj at a 84% yield. The existence of a free formyl substitition
in this compound 3aj indicated its capability to react with another NH-sulfoximine under similar conditions.
Furthermore, the tolerance of a free hydroxyl group in benzaldehyde 2 was then studied. The reactions occurred
smoothly with OH moiety in ortho- position to the formyl group, affording the expected products 3ap, 3aq, and 3ar
with good results. The heterocyclic 2-thenaldehyde and 2-furaldehyde also participated in the reaction to give the
cyclized products 3au and 3av in 83% and 49% yields, respectively.
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To our delight, modest to good yields were obtained for the reactions of alkyl or alkenyl aldehydes 2 with NH-
sulfoximine 1a in this reaction. For instance, the reactions of butyraldehyde 2w and cyclohexancarbaldehyde 2x with
1a proceeded nicely to produce the desired alkyl-substituted heterocyclic sulfoximine 3aw and 3ax in good yields. The
strained cyclopropanecarboxaldehyde 3y participated in the cyclization reaction, giving the cyclopropyl-substituted
sulfoximine heterocycle 3ay in 73% yield. Under the standard conditions, unsaturated 4-chlorocinnamaldehyde also
underwent the reaction to give the corresponding product 3az in synthetically useful yield.
Scheme 3. Reaction scope studies. a
Cu2O (5.0 mol%)
TMSN3 (2 equiv)
TBAI (10 mol%)
O
S
O R2
R2
S
R3 CHO
+
N
R1
R1
NH
H2O (0.33 M)
90 oC, under air
R3
N
Br
(1.0 equiv)
(1.2 equiv)
1
2
4
O Ph
O Ph
O Ph
S
S
N
N
S
N
N
N
N
Ph
Ph
OMe
I
4ba
, 90%
4bb
4bf
, 75%
, 75%
O Et
O Me
O Et
S
S
S
N
N
N
N
Cl
N
N
OMe
4ca
4cb
4da
, 82%
, 91%
, 74%
Me
O Me
O Me
O
S
S
S
N
N
N
Cl
N
PMP
Me
N
Ph
Me
N
PMP
4db
4ea
4eb
, 84%
, 73%
, 90%
O Me
S
N
O Me
O Me
S
S
N
MeO
I
N
Me
N
N
Ph
N
Ph
Me
4ga
4ef
4fa
, 70%
, 62%
, 0%
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aReaction conditions: NH-sulfoximine 1 (0.30 mmol), aldehyde 2 (0.36 mmol, 1.3 equiv) and TBAI (10 mol%) in 1.0
mL of H2O at 90 oC under air conditions. Isolated yield.
5
6
7
8
9
A series of structurally diverse NH-sulfoximines 1 with aldehydes 2 were further examined to investigate the
generality of the cyclization (Scheme 3). Diphenyl sulfoximine 1b reacted with free benzaldehyde 2a to give the
desired products 4aa in 90% yield. The tolerance of an iodo atom from 4-iodobenzaldehyde 2f could afford the halide-
substituted thiadiazine-1-oxide 4bf in 75% yield. Accordingly, the substitutions which attached to the S atom in NH-
sulfoximine 1 could be the ethyl group 2c, which produced the desired products 4ca and 4cb in 82% and 91% yields,
respectively. Moreover, a series of para-substituted substrates bearing either electron-withdrawing Cl or -donating Me
groups could all react smoothly, affording the desired products (4da–4ef) in good to excellent yields ranging from 62-
90%. And the synthetically versatile iodo group in compounds 4bf and 4ef indicated their further transformations
through transition-metal-catalyzed cross-coupling reactions could be easily achieved.
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Scheme 4. Synthesis of 1f.
[Cp*Rh(MeCN)3][SbF6]2
AcCl (1.2 equiv)
Py (3.0 equiv)
O
S
O
S
(5.0 mol%)
PivOH (1.1 equiv)
Me
Me
Me
Me
NH
NAc
DCM, r.t.
NBS (2.0 equiv)
DCE, 90 oC, 21h
1f_2
, 96%
1f_1
O
S
O
S
K2CO3 (5.0 equiv)
MeOH (5.0 mL)
Me
Me
Br
MeO
NAc
NH
Br
Br
1f_3
, 42%
1f
, 92%
In addition to these results, the 5-MeOCH2-substituted NH-sulfoximine 1f was synthesized according to the
protocol as illustrated in Scheme 4. The reaction of 1f with 2a was conducted under the standard conditions, the
expected product 5-MeOCH2-sustitution thiadiazine-1-oxide 4fa was isolated in 70% yield. However, a steric effect
was obtained for the reaction of 3-Me substituted sulfoximine 1g with benzaldehyde, the desired product 4ga could not
be obtained under the standard conditions.
The synthetic utility of this Cu2O-catalyzed synthesis of thiadiazine-1-oxides in H2O solution could be
demonstrated by sequential consecutive runs of gram-scale synthesis of the expected product 3aa Scheme 5). In the
first run of the procedure, the starting materials 1a (1.05 g, 4.5 mmol) and 2a (1.2 equiv), TMSN3 (2.0 equiv), Cu2O
o
(0.225 mmol) and TBAI (0.45 mmol) were mixed in 15 mL of H2O. The reaction was maintained at 90 C for 12 h.
Upon completion, the reaction was cooled to room temperature and the organic components were extracted with ethyl
acetate (EA) for several times; the upper organic layer was partitioned by a burette carefully each time. The combined
organic layer was concentrated and isolated to give product 3aa in 89% yield. The under layer aqueous phase was left
in the mother-flask for the second run, in which compounds 1a (4.5 mmol), 2a (1.2 equiv), and TMSN3 (2.0 equiv)
were added with 3.0 mL of H2O to the flask in this run, but without the addition of Cu2O and TBAI. The reaction was
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then heated at 90 C for another 12 h to reach completion. The yield of 3aa in the second run was 78% yield, which
indicated that the method could be applied for the consecutive synthesis of the desired products without any extra
addition of a copper catalyst and PTA. Unfortunately, a dramatic decrease in yield of 3aa was observed in the similar
third run, presumably due to the loss of the [Cu] and PTA during the extraction process.
3
4
5
6
7
8
9
Scheme 5. Gram-scale synthesis of 3aa in two consecutive runs.
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3aa
Cu2O (5.0 mol%)
TMSN3 (2 equiv)
TBAI (10 mol%)
1.03 g, 4.02 mmol
89% yield
1a,
2a,
1.05 g, 4.5
mmol.
572 mg,5.4
mmol.
combined organic layer
EA extraction
(3.0 mL x 5 times)
1st
workup
H2O (15 mL), 12 h
90 oC, sealed flask
Cu2O, TBAI, and
H2O (ca. 12 mL)
The 1st run.
aqueous layer for 2nd run
1a
, 1.05 g
2a
, 572 mg
TMSN3, 1.04 g
H2O (3.0 mL)
The 2nd run.
no extra [Cu]/PTC needed.
The 3rd run.
3aa
Reaction for 12 h
at 90 oC under air
3aa
0.54 g, 2.1 mmol
47% yield
0.897 g, 3.5 mmol
78% yield
2nd
workup
As mentioned above, the compound 3aj that contained a free formyl group (CHO) group indicated that this product
could be utilized as a starting material to react with NH-sulfoximine 1a or 1b under the standard conditions to give the
products 5, which contains two thiadiazine-1-oxide moieties in the molecule (Scheme 6, eq 1.). For the reaction of 1a
with 3aj, the expected product 5a could be isolated in 56% yield; however, in the reaction of 1b with 3aj, the desired
product 5b was isolated in 71% yield.
We have also tried the reaction of the other ortho-halide substituted NH-sulfoximine 1 with benzaldehyde 2a.
Good yield of 3aa was obtained for the reaction of aryl iodide 1h with 2a (Scheme 6, eq 2). However, only <10 yield
of 3aa was observed in the reaction of ortho-chloride substituted NH-sulfoximine with 2a.
Scheme 6. Extension reactions from 3aj and the reaction of ortho-iodide substituted NH-sulfoximine 1h.
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2
Me
O
3
4
5
6
7
8
9
S
Cu2O (5.0 mol%)
TMSN3 (2 equiv)
TBAI (10 mol%)
Me
O
N
(1)
R
O
S
N
S
N
NH
N
S
N
H2O (1 mL)
90 oC, under air
Br
N
CHO
(1.3 equiv)
(1.0 equiv)
1a
R
O
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3aj
5a
, R = Me, 56%
, R = Me
1b
5b
, R = Ph
, R = Ph, 71%
Cu2O (5.0 mol%)
TMSN3 (2.0 equiv)
TBAI (10 mol%)
O
S
O Me
S
N
CHO
Me
(2)
NH
H2O (1 mL)
90 oC, under air
I
N
Ph
(1.2 equiv)
(1.0 equiv)
1h
2a
3aa
, 71%
To further shed light on the reaction mechanism, several extention reactions were studied (Scheme 7). For the
Cu2O-catalyzed reaction of NH-sulfoximine 1a with TMSN3 without the addition of aldehyde, the ortho-amino
sulfoximine 6 was isolated in 51% yield under the standard conditions (eq. 1). This result indicated that a copper-
catalyzed C-Br amination reaction should be involved as a key step in the reaction sequence. This result was further
supported by the reactions of N-protected sulfoximine 7 or 9 with 4-methylbenzaldehyde 1c. In the reaction of NAc-
sulfoximine 7 with 1c, the cyclization product 3ac could be isolated in moderate yield while the putative imine side
product 8 could not be detected (eq. 2), due to the hydrolysis ability of the amide bond in compound 7. However,
when NMe-sulfoximine 9 was employed under the standard conditions, the amino-substituted intermediate 10 was
formed because N-Me bond was stable in aqueous condition, whilst 3ac cannot be detected (eq. 3).
Scheme 7. Control experiments.
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2
Cu2O (5.0 mol%)
3
4
5
6
7
8
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O Me
S
O
S
TMSN3 (2.0 equiv)
TBAI (10 mol%)
Me
NH
NH2
, 51%
NH
H2O (1 mL)
90 oC, under air
"standard conditions"
(1)
Br
(1.0 equiv)
1a
6
CHO
O
S
O Me
O Me
S
standard
Me
S
conditions
N
NAc (2)
NAc
Br
N
Tol
N Tol
Me
(1.0 equiv) (1.3 equiv)
7
1c
3ac
, 46%
8
, not found.
CHO
O Me
S
O
S
O Me
S
N
standard
Me
conditions
NMe
(3)
NMe
NH2
Br
N
Tol
Me
(1.0 equiv) (1.3 equiv)
9
1c
10
, 59%
3ac
, not found.
Scheme 8. Proposed mechanism.
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L
O
O
S
Me
O
S
O
S
Me
Me
Me
S
CuI OCu
-CuOH
TMSN3
H2O
- L
NH
CuI
Br
N
NH
N CuL
CuL
Br
Br
Br
L = H2O or PTC
1a
A
B
C
- N2
-TMSOH
O
S
NH
CuIII Br
N3
O Me
S
O Me
S
1/2 O2
Me
O Me
S
H2O
PhCHO
H2O
O2
Ph
2a
NH
N
NH
3aa
- H2O
- CuBr
CuIBr
N
H
E
N
H
F
NH2
TMS
D
6
Inspired by our current results and the previous reports on the copper-catalyzed cross-coupling reactions of aryl
bromide with azides,13,15 we proposed a possible mechanism for this reaction as outlined in Scheme 8. Initial
nucleophilic metallation reaction of substrate 1a with Cu2O could be expected to form a low-valent copper species A.
The ortho-C-Br bond in intermediate B could be selectively activated through "ortho-binding" effect, thus to efficiently
control the chemoselectivity of this reaction. Note that the other free halides, such as Br or I in aldehydes 2, could be
compatible in this reaction without difficulty. The next oxidative addition reaction with aryl bromide under the
assistance of H2O or PTC as a ligand to give the complex C. The subsequent oxidative addition of C with TMSN3 to
generate a copper-azide complex D, followed by a denitrogenative reductive elimination reaction with H2O to give
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5
complex E. Hydrolysis decomposition of E would give rise the ortho-amino sulfoximine intermediate 6 and regenerate
the active low valent copper species to complete the catalytic cycle. The final condensation reaction followed by
aromatization would deliver the observed product 3aa.
6
7
8
9
In summary, we have developed a copper-catalyzed multicomponent reaction of simple NH-sulfoximine
with aldehyde and TMSN3, to selectively produce diverse thiadiazine-1-oxides in good to excellent yields.
The readily available TMSN3 was found to be a suitable N source and common aldehydes were employed as
the annulation substrates, thus resulting in no external Ag salt, ligand, or base was required, and only hot
water was employed as the neat solvent under aerobic conditions. An "ortho-binding" effect in substrate 1 was
proposed in this reaction to control the chemoselectivity, thus, the other free bromo- or iodo-atoms in
aldehydes 2 were found to be well tolerated. This novel methodology represents an environmentally benign and
inexpensive avenue to deliver medicinally significant thiadiazine-1-oxides. In addition, this aqueous catalytic system
could be circularly utilized in consecutive runs of scaled-up preparations of the bicyclic heterocyclic sulfoximines.
Further applications of this facile and more sustainable method to synthesize useful heterocyclic sulfoximines are
currently underway.
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EXPERIMENTAL SECTION
General information. Unless otherwise noted, commercial reagents were purchased from the commercial
suppliers, and were used as received. Reactions were conducted under air. Analytical thin-layer chromatography (TLC)
was performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). Flash column chromatography was performed using silica gel (60-Å pore size, 32-63 µm, standard
grade). Organic solutions were concentrated on rotary evaporators at ~20 Torr (house vacuum) at 25-35 °C. Nuclear
magnetic resonance (NMR) spectra are recorded in parts per million (ppm) from internal standard tetramethylsilane
(TMS) on the δ scale. High resolution mass spectrometry (HRMS) spectra analysis was performed by electrospray
ionization (ESI-micrOTOF). Most of the starting NH-Sulfoximines 1, 7 and 9 were purchased from commercal source
in this project. Except for NH-Sulfoximine 1f, which was prepared in our lab following the literature method.16
General procedure for the preparation of NH-sulfoximine 1f.
To an ice-cold stirred solutuon of 1f_1 (960 mg, 5.68 mmol) and Py (1.34 g, 17 mmol) in 10 mL of
dichloromethane (DCM) was added acetyl chloride (531 mg, 6.82 mmol) dropwise at 0 oC. The resulting solution was
stirrred under N2 for 3 h. Upon completion, water (10 mL) was added to quench the reaction, and extracted with DCM
(5.0 mL x 3). The combined solvent was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue
was purified through column chromatography to give the desired product 1-methyl-3-(S-methylsulfonimidoyl)benzene
1f_2 (1.12 g, 96%) as a yellow oil.
N-(Methyl(oxo)(m-tolyl)-l6-sulfanylidene)acetamide 1f_2
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Yield 1.12 g, 96%; yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 2H), 7.47 (m, 2H), 3.35-3.29 (m, 3H), 2.46 (d, J
= 3.0 Hz, 3H), 2.21-2.11 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 180.3, 140.1, 138.6, 134.6, 129.5, 127.3, 124,
44.2, 26.8, 21.4. HRMS calcd. for C10H14NO2S (M+H)+: 212.0740, found: 212.0746.
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8
9
To a screw-capped test tube were added 1-methyl-3-(S-methylsulfonimidoyl)benzene 1f_2 (600 mg, 2.84 mmol),
NBS (1.01 g, 5.68 mmol),[Cp*Rh(MeCN)3][SbF6]2 (118 mg, 0.14 mmol), PivOH (332 mg, 3.12 mmol) and 1,2-DCE
o
(8.0 mL). The mixture was stirred at 90 C oil bath for 21 h. The reaction was monitored by TLC. The mixture was
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then cooled to room temperature, diluted with EtOAc (10 mL), and washed with saturated Na2S2O3 solution (20 mL).
The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash
chromatography on silica gel to give the desired product 1f_3 (417 mg, 42% yield) as a yellow solid.
N-((2-Bromo-5-(bromomethyl)phenyl)(methyl)(oxo)-l6-sulfanylidene)acetamide 1f_3
Yield 412 mg, 42%; yellow solid, mp: 154-155oC. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.0 Hz, 1H), 7.74 (d, J =
8.2 Hz, 1H), 7.52 (dd, J = 8.2, 2.1 Hz, 1H), 4.49 (m, 2H), 3.45 (s, 3H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 179.5, 139.0, 138.4, 136.2, 135.1, 132.1, 118.8, 41.6, 30.7, 26.2. HRMS calcd. for C10H12Br2NO2S (M+H)+:
367.8950, found: 367.8956.
To a stirred solution of NAc-Sulfoximine 1f_3 (210 mg, 0.57 mmol) and K2CO3 (395 mg, 2.86 mmol) were stirred
in MeOH (5.0 mL) at room temperature for 2 h. Upon the completion of the reaction as determined by TLC, the
solvent was removed in vacuo. The product was purified by flash chromatographyon silica gel to give the expect
product 1-bromo-4-(methoxymethyl)-2-(S-methylsulfonimidoyl)benzene 1f (146 mg, 92%) as a yellow oil.
(2-Bromo-5-(methoxymethyl)phenyl)(imino)(methyl)-l6-sulfanone 1f.
1
Yield 146 mg, 92%; yellow oil. H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.74 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H),
4.47 (s, 2H), 3.43 (d, J = 1.2 Hz, 3H), 3.32 (d, J = 1.2 Hz, 3H), 2.91 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
142.5, 139.1, 135.7, 132.8, 129.8, 119.4, 73.2, 58.6, 43.1. HRMS calcd. for C9H13BrNO2S (M+H)+: 277.9845, found:
277.9851.
General procedure for the preparation of thiadiazine-1-oxides 3 or 4.
To a vigorous stirred mixture of NH-Sulfoximine 1 (0.30 mmol), aldehyde 2 (0.36 mmol), Cu2O (0.015 mmol),
and TBAI (0.03 mmol) in H2O (1.0 mL) was added TMSN3 (0.60 mmol) under an air atmosphere. The reaction was
heated at 90 °C oil bath for about 12 h. Upon completion of the reaction as indicated by TLC, the reaction was allowed
to cool to room temperature, and diluted with water (2.0 mL) and saturated aqueous NaHCO3 (2.0 mL), then extracted
with ethyl acetate (3.0 mL×4). The combined organic layer was dried over Na2SO4, and concentrated to give the crude
product, which was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to afford the expected
thiadiazine-1-oxides 3 or 4, as a white solid.
1-Methyl-3-phenyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3aa)
Yield 73 mg, 95%; white solid, mp: 132-133 oC.
1H NMR (400 MHz, CDCl3) δ 8.39-8.37 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz,
1H), 7.46-7.44 (m, 3H), 7.38 (t, J = 7.4 Hz, 1H), 3.52 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 147.5, 137.4,
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135.0, 131.0, 128.9, 128.5, 128.2, 126.2, 123.5, 113.1, 47.1. HRMS calcd. for C14H13N2OS (M+H)+: 257.0743, found:
257.0741.
5
6
7
3-(4-Methoxyphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide(3ab)
Yield 78 mg, 91%; white solid, mp: 151-152 oC.
1H NMR (400 MHz, CDCl3) δ 8.35-8.33 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (d, J = 8.2 Hz,
1H), 7.36-7.32 (m, 1H), 6.96-6.93 (m, 2H), 3.85 (s, 3H), 3.51 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.2,
157.6, 147.9, 134.9, 130.3, 129.9, 128.7, 125.7, 123.5, 113.5, 112.8, 55.4, 47.1. HRMS calcd. for C15H14N2NaO2S
(M+Na)+: 309.0668, found: 309.0661.
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1-Methyl-3-(p-tolyl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ac)
Yield 70 mg, 86%; white solid, mp: 163-164oC.
1H NMR (400 MHz, CDCl3) δ 8.28-8.25 (m, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.74 -7.65 (m, 1H), 7.60 (d, J = 8.0 Hz,
1H), 7.37 (t, J = 7.2 Hz, 1H), 7.26-7.24 (m, 2H), 3.52 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.9,
147.6, 141.4, 134.9, 134.6, 128.9, 128.9, 128.5, 126.0, 123.5, 113.0, 47.1, 21.5. HRMS calcd. for C15H14N2NaOS
(M+Na)+: 293.0719, found: 293.0713.
3-(4-Chlorophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ad)
Yield 61 mg, 70%; white solid, mp: 176-177 oC.
1H NMR (400 MHz, CDCl3) δ 8.33-8.31 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 8.2
Hz, 1H), 7.42-7.40 (m, 3H), 3.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 156.8, 147.3, 137.2, 135.9, 135.1, 129.9,
128.9, 128.3, 126.4, 123.6, 113.0, 47.1. HRMS calcd. for C14H12ClN2OS (M+H)+: 291.0353, found: 291.0354.
3-(4-Bromophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ae)
Yield 79 mg, 79%; white solid, mp: 170-171oC.
1H NMR (400 MHz, CDCl3) δ 8.27-8.24 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.72 (m, 1H), 7.59 (m, 3H), 7.42 (t, J = 7.4
Hz, 1H), 3.55 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 156.9, 147.3, 136.3, 135.1, 131.3, 130.1, 128.9, 126.4,
125.8, 123.6, 113.1, 47.2. HRMS calcd. for C14H12BrN2OS (M+H)+: 334.9848, found: 334.9850.
3-(4-Iodophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3af)
Yield 94 mg, 82%; white solid, mp: 169-170 oC.
1H NMR (400 MHz, CDCl3) δ 8.12-8.09 (m, 2H), 7.80 (m, 3H), 7.71 (t, J = 7.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.43
(t, J = 7.6 Hz, 1H), 3.55 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.1, 147.3, 137.3, 136.9, 135.1, 130.2, 129.0,
126.4, 123.6, 113.1, 98.2, 47.2. HRMS calcd. for C14H12IN2OS (M+H)+: 382.9710, found: 382.9715.
1-Methyl-3-(4-(trifluoromethyl)phenyl)-1l4-benzo[e][1,2,4]thiadiazine1-oxide(3ag)
Yield 60 mg, 62%; white solid, mp: 153-154 oC.
1H NMR (400 MHz, CDCl3) δ 8.50-8.48 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.75-7.69 (m, 3H), 7.64 (d, J = 8.2 Hz, 1H),
7.45 (t, J = 7.5 Hz, 1H), 3.57 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 156.4, 147.1, 140.7, 135.1, 132.5, 129.1,
128.8, 126.8, 125.0, 124.1 (q, J = 270 Hz), 123.6, 113.2, 47.2. 19F NMR (376 MHz, CDCl3) δ: -62.67.HRMS calcd.
for C15H12F3N2OS (M+H)+: 325.0617, found: 325.0623.
1-Methyl-3-(4-nitrophenyl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ah)
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Yield 57 mg, 63%; yellow solid, mp: 193-194 oC.
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9
1H NMR (400 MHz, DMSO-d6) δ 8.52-8.50 (m, 2H), 8.36-8.33 (m, 2H), 8.28 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz,
1H), 7.63-7.58 (m, 2H), 3.98 (s, 3H). 13C{1H} NMR(100 MHz, DMSO-d6) δ 154.9, 149.3, 145.8, 143.6, 135.6, 129.5,
128.6, 127.8, 125.0, 124.0, 114.5, 45.7. HRMS calcd. for C14H11N3NaO3S (M+Na)+: 324.0413, found: 324.0410.
4-(1-Methyl-1-oxido-1l4-benzo[e][1,2,4]thiadiazin-3-yl)benzonitrile (3ai)
Yield 21 mg, 25%; yellow solid, mp: 191-192 oC.
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1H NMR (400 MHz, CDCl3) δ 8.42-8.40 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.69-7.65 (m, 3H), 7.56 (d, J = 8.4 Hz,
1H), 7.40 (t, J = 7.6 Hz, 1H), 3.51 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.8, 146.9, 141.5, 135.2, 131.9,
129.1, 129.0, 127.1, 123.6, 118.8, 114.1, 113.2, 47.1. HRMS calcd. for C15H11N3NaOS (M+Na)+: 304.0515, found:
304.0512.
4-(1-Methyl-1-oxido-1l4-benzo[e][1,2,4]thiadiazin-3-yl)benzaldehyde (3aj)
Yield 72 mg, 84%; yellow solid, mp: 196-197 oC.
1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.51-8.49 (m, 2H), 8.27 (d, J = 7.6 Hz, 1H), 8.05-8.03 (m, 2H), 7.83
(t, J = 7.4 Hz, 1H), 7.62-7.56 (m, 2H), 3.97 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 193.4, 155.7, 146.0,
142.9, 138.1, 135.5, 129.9, 129.0, 128.6, 127.5, 124.9, 114.5, 45.6. HRMS calcd. for C15H13N2O2S (M+H)+: 285.0692,
found: 285.0704.
3-(3-Methoxyphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ak)
Yield 64 mg, 75%; white solid, mp: 130-131oC.
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H),
7.62 (d, J = 8.2 Hz, 1H), 7.43-7.32 (m, 2H), 7.04-7.01 (m, 1H), 3.90 (s, 3H), 3.54 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 159.6, 157.7, 147.4, 138.9, 135.0, 129.1, 129.0, 126.2, 123.5, 121.1, 117.6, 113.1, 113.0, 55.5, 47.1. HRMS
calcd. for C15H14N2NaO2S (M+Na)+: 309.0668, found: 309.0664.
3-(3-Bromophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3al)
Yield 74 mg, 74%; yellow solid, mp: 152-153 oC.
1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H),
7.64-7.56 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 3.56 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
156.3, 147.1, 139.4, 135.1, 133.8, 131.5, 129.7, 129.0, 127.1, 126.6, 123.6, 122.4, 113.2, 47.1. HRMS calcd. for
C14H12BrN2OS (M+H)+: 334.9848, found: 334.9853.
1-Methyl-3-(2-nitrophenyl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3am)
Yield 40 mg, 42%; yellow solid, mp: 185-186 oC.
1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.0 Hz, 1H), 7.98-7.92 (m, 2H), 7.84-7.77 (m, 2H), 7.72 (t, J = 7.4 Hz,
1H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 155.8,
149.8, 145.7, 135.6, 132.8, 131.4, 131.0, 128.1, 127.7, 125.0, 124.3, 114.1, 45.6. HRMS calcd. for C14H11N3NaO3S
(M+Na)+: 324.0413, found: 324.0419.
3-(2-Chlorophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3an)
Yield 38 mg, 43%; yellow solid, mp: 133-134oC.
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1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.6 Hz, 1H), 7.76-7.66 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.51-7.39 (m,
2H), 7.38-7.29 (m, 2H), 3.57 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 146.8, 138.0, 135.2, 132.4, 130.43,
130.41, 130.3, 128.8, 127.0, 126.7, 123.5, 112.8, 47.0. HRMS calcd. for C14H11ClN2NaOS (M+Na)+: 313.0173, found:
313.0180.
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3-(4-Bromo-3-fluorophenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine1-oxide(3ao)
Yield 68 mg, 64%; yellow solid, mp: 173-174 oC.
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1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.4 Hz, 1H), 7.82 (d, J = 7.6 Hz,
1H), 7.72 (t, J = 7.8 Hz, 1H), 7.65-7.57 (m, 2H), 7.44 (t, J = 7.6 Hz, 1H), 3.56 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 158.9 (d, 1J = 245 Hz), 155.7, 147.0, 139.0, 135.2, 133.1, 129.0, 126.7, 125.1 (d, 3J= 4 Hz), 123.6, 116.3 (d,
2
2J = 25 Hz), 113.2, 112.1 (d, J = 21 Hz), 47.1. 19F NMR (376 MHz, CDCl3) δ: -107.62. HRMS calcd. for
C14H11BrFN2OS (M+H)+: 352.9754, found: 352.9763.
3-(2-Hydroxy-4-methylphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ap)
Yield 70 mg, 81%; yellow solid, mp: 174-175 oC.
1H NMR (400 MHz, DMSO-d6) δ 14.52 (br, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.56
(d, J = 7.8 Hz, 2H), 6.74 (s, 2H), 3.97 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7, 159.3,
144.4, 143.5, 135.9, 129.4, 127.2, 126.5, 125.2, 119.9, 118.0, 115.6, 114.7, 45.5, 21.7. HRMS calcd. for C15H15N2O2S
(M+H)+: 287.0849, found: 287.0850.
3-(5-Chloro-2-hydroxyphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3aq)
Yield 64 mg, 70%; yellow solid, mp: 149-150 oC.
1H NMR (400 MHz, DMSO) δ 14.65 (br, 1H), 8.29 (d, J = 7.4 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.85 (t, J = 7.6 Hz,
1H), 7.67-7.55 (m, 2H), 7.42 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.02 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 160.4, 158.0, 143.0, 136.0, 133.4, 128.3, 127.8, 126.6, 125.3, 122.3, 119.9, 119.2, 114.8, 45.5. HRMS
calcd. for C14H12ClN2O2S (M+H)+: 307.0303, found: 307.0308.
3-(2-Hydroxy-5-methylphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ar)
Yield 67 mg, 78%; yellow solid, mp: 185-186 oC.
1H NMR(400 MHz, DMSO-d6) δ 14.33 (br, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.61-
7.50 (m, 2H), 7.21 (dd, J = 8.3, 1.7 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 2.29 (s, 3H). 13C{1H} NMR (100
MHz, DMSO-d6) δ 159.6, 159.3, 143.5, 135.9, 134.7, 129.3, 127.4, 127.2, 126.6, 125.2, 117.7, 117.7, 114.7, 45.6,
20.6. HRMS calcd. for C15H14N2NaO2S (M+Na)+: 309.0668, found: 309.0669.
1-Methyl-3-(naphthalen-2-yl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3as)
Yield 65 mg, 71%; yellow solid, mp: 168-169 oC.
1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.50 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.90-7.85 (m, 2H), 7.80
(d, J = 8.0 Hz, 1H), 7.71-7.65 (m, 2H), 7.55-7.46 (m, 2H), 7.37 (t, J = 7.0 Hz, 1H), 3.54 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 157.8, 147.5, 135.0, 134.9, 134.7, 133.0, 129.3, 129.2, 129.0, 127.74, 127.69, 127.2, 126.3, 126.2,
125.3, 123.6, 113.1, 47.1. HRMS calcd. for C18H15N2OS (M+H)+: 307.0900, found: 307.0899.
1-Methyl-3-(naphthalen-1-yl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3at)
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Yield 49 mg, 53%; yellow solid, mp: 135-136 oC.
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1H NMR (400 MHz, DMSO-d6) δ 8.79-8.73 (m, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.07-7.93 (m, 3H), 7.84 (t, J = 7.8 Hz,
1H), 7.63-7.53 (m, 5H), 3.98 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.4, 146.2, 136.4, 135.4, 133.9, 130.9,
130.6, 128.8, 128.4, 128.3, 127.2, 126.9, 126.4, 126.3, 125.5, 124.8, 114.1, 45.4. HRMS calcd. for C18H15N2OS
(M+H)+: 307.0900, found: 307.0908.
1-Methyl-3-(thiophen-2-yl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3au)
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Yield 65 mg, 83%; white solid, mp: 151-152 oC.
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (d, J =
8.4 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.16-7.05 (m, 1H), 3.53 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 154.1, 147.3, 143.3, 135.0, 130.4, 129.9, 128.5, 127.8, 125.9, 123.6, 113.1, 47.1. HRMS calcd. for
C12H11N2OS2 (M+H)+: 263.0307, found: 263.0304.
3-(Furan-2-yl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3av)
Yield 36 mg, 49%; yellow solid, mp: 195-196 oC.
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.64-7.59 (m, 1H), 7.58-7.53 (m, 2H), 7.34-7.29 (m, 1H), 7.18
(d, J = 3.2 Hz, 1H), 6.46 (m, 1H), 3.48 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.3, 150.3, 147.0, 145.3, 135.1,
128.9, 126.2, 123.6, 114.8, 113.5, 112.0, 47.0. HRMS calcd. for C12H10N2NaO2S (M+Na)+: 269.0355, found:
269.0350.
1-Methyl-3-propyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3aw)
Yield 43 mg, 64%; yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 (t, J =
7.6 Hz, 1H), 3.38 (s, 3H), 2.54-2.42 (m, 2H), 1.73 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 165.1, 147.1, 134.9, 128.1, 125.9, 123.4, 112.6, 46.9, 42.7, 21.0, 13.8. HRMS calcd. for C11H15N2OS (M+H)+:
223.0900, found: 223.0907.
3-Cyclohexyl-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ax)
Yield 63 mg, 80%; yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.36 (t, J =
7.6 Hz, 1H), 3.45 (s, 3H), 2.56-2.44 (m, 1H), 1.96 (d, J = 12.8 Hz, 2H), 1.82 (d, J = 12.8 Hz, 2H), 1.64-1.56 (m, 2H),
1.45-1.20 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 168.5, 147.4, 134.8, 128.2, 125.8, 123.4, 112.8, 48.8, 46.9,
30.8, 30.7, 26.0, 25.9. HRMS calcd. for C14H19N2OS (M+H)+: 263.1213, found: 263.1219.
3-Cyclopropyl-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3ay)
Yield 48 mg, 73%; white solid, mp: 105-106 oC
1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (t, J =
7.6 Hz, 1H), 3.41 (s, 3H), 1.99-1.85 (m, 1H), 1.21-1.08 (m, 2H), 0.94-0.89 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3)
δ 166.1, 147.2, 134.9, 127.6, 125.3, 123.48, 112.9, 46.9, 19.2, 9.2, 8.4. HRMS calcd. for C11H13N2OS (M+H)+:
221.0743, found: 221.0741.
(E)-3-(4-Chlorostyryl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (3az)
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Yield 33 mg, 35%; yellow solid, mp: 183-184 oC.
1H NMR (400 MHz, CDCl3) δ 7.84-7.65 (m, 3H), 7.58-7.47 (m, 3H), 7.45-7.31 (m, 3H), 6.89 (d, J = 15.6 Hz, 1H),
3.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 147.2, 138.1, 135.1, 135.0, 134.4, 129.0, 128.9 128.5, 128.2,
126.4, 123.7, 113.7, 47.1. HRMS calcd. for C16H14ClN2OS (M+H)+: 317.0510, found: 317.0513.
1,3-Diphenylbenzo[e][1,2,4]thiadiazine 1-oxide (4ba)
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1H NMR (400 MHz, CDCl3) δ 8.45-8.43 (m, 2H), 7.89-7.87 (m, 2H), 7.68-7.59 (m, 3H), 7.57-7.53 (m, 2H), 7.46-7.43
(m, 4H), 7.25 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.1, 147.3, 140.8, 137.6, 134.4, 133.9, 131.0,
129.3, 128.7, 128.7, 128.6, 128.2, 126.3, 124.8, 113.8. HRMS calcd. for C19H15N2OS (M+H)+: 319.0900, found:
319.0904.
3-(4-Methoxyphenyl)-1-phenylbenzo[e][1,2,4]thiadiazine 1-oxide (4bb)
Yield 78 mg, 75%; white solid, 52-54 oC.
1H NMR (400 MHz, CDCl3) δ 8.41-8.38 (m, 2H), 7.89-7.87 (m, 2H), 7.65-7.60 (m 3H), 7.58-7.54 (m, 2H), 7.34 (d, J
= 8.0 Hz, 1H), 7.17-7.09 (m, 1H), 6.97-6.94 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
162.2, 157.8, 147.6, 141.0, 134.3, 133.7, 130.4, 130.2, 130.0, 128.6, 128.5, 125.8, 124.8, 113.6, 113.5, 55.4. HRMS
calcd. for C20H17N2O2S (M+H)+: 349.1005, found: 349.1006.
3-(4-Iodophenyl)-1-phenylbenzo[e][1,2,4]thiadiazine 1-oxide (4bf)
Yield 100 mg, 75%; yellow solid, mp: 175-176 oC.
1H NMR (400 MHz, CDCl3) δ 8.08-8.06 (m, 2H), 7.78-7.77(m, 2H), 7.70-7.67 (m, 2H), 7.56-7.50 (m, 3H), 7.49-7.45
(m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.20-7.13 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.2, 147.1, 140.6, 137.4,
137.2, 134.5, 134.0, 130.4, 129.4, 128.7, 128.6, 126.5, 124.9, 113.9, 98.2. HRMS calcd. for C19H14IN2OS (M+H)+:
444.9866, found: 444.9864.
1-Ethyl-3-phenyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4ca)
Yield 67 mg, 82%; viscid liquid.
1H NMR (400 MHz, CDCl3) δ 8.38-8.25 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.2
Hz, 1H), 7.43-7.33 (m, 3H), 7.27 (t, J = 7.4 Hz, 1H), 3.63-3.54 (m, 1H), 3.49-3.40 (m, 1H), 1.08 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 158.5, 148.7, 137.5, 135.0, 131.0, 128.8, 128.5, 128.2, 126.2, 123.7, 110.0, 52.6,
8.1. HRMS calcd. for C15H14N2NaOS (M+H)+: 293.0719, found: 293.0717.
1-Ethyl-3-(4-methoxyphenyl)-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4cb)
Yield 79 mg, 91%; white solid, mp: 120-121 oC.
1H NMR (400 MHz, CDCl3) δ 8.28-8.25 (m, 2H), 7.65-7.54 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H),
6.88-6.85 (m, 2H), 3.76 (s, 3H), 3.62-3.52 (m, 1H), 3.48-3.38 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 162.2, 158.2, 148.9, 134.9, 130.3, 130.0, 128.6, 125.7, 123.7, 113.5, 109.8, 55.4, 52.6, 8.1. HRMS
calcd. for C16H17N2O2S (M+H)+: 301.1005, found: 301.1006.
6-Chloro-1-methyl-3-phenyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4da)
Yield 64 mg, 74%; white solid, mp: 164-165 oC.
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1H NMR (400 MHz, CDCl3) δ 8.28-8.26 (m, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.45-7.32 (m, 3H), 7.25 (d, J
= 8.8 Hz, 1H), 3.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 148.8, 141.1, 136.9, 131.4, 128.7, 128.3, 128.2,
126.6, 124.9, 111.3, 47.2. HRMS calcd. for C14H12ClN2OS (M+H)+: 291.0353, found: 291.0353.
6-Chloro-3-(4-methoxyphenyl)-1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4db)
Yield 70 mg, 73%; white solid, mp : 143-144 oC.
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1H NMR (400 MHz, CDCl3) δ 8.27-8.19 (m, 2H), 7.65-7.59 (m, 1H), 7.50 (s, 1H), 7.24-7.17 (m, 1H), 6.91-6.82 (m,
2H), 3.78 (s, 3H), 3.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 158.6, 149.1, 141.0, 130.5, 129.4, 128.0,
126.1, 124.9, 113.5, 111.0, 55.4, 47.2. HRMS calcd. for C15H14ClN2O2S (M+H)+: 321.0459, found: 321.0461.
1,6-Dimethyl-3-phenyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4ea)
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1H NMR (400 MHz, CDCl3) δ 8.29-8.27 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.38-7.28 (m, 4H), 7.10 (d, J = 8.0 Hz,
1H), 3.40 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 147.5, 146.1, 137.5, 130.9, 128.5, 128.5,
128.1, 127.6, 123.4, 110.4, 47.2, 21.9. HRMS calcd. for C15H15N2OS (M+H)+: 271.0900, found: 271.0894.
3-(4-Methoxyphenyl)-1,6-dimethyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4eb)
Yield 76 mg, 84%; white solid, mp: 115-116 oC.
1H NMR (400 MHz, CDCl3) δ 8.33-8.31 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.95-
6.93 (m, 2H), 3.85 (s, 3H), 3.47 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 157.7, 147.8, 146.0,
130.2, 130.0, 128.3, 127.2, 123.4, 113.4, 110.2, 55.4, 47.2, 21.9. HRMS calcd. for C16H17N2O2S (M+H)+: 301.1005,
found: 301.1006.
3-(4-Iodophenyl)-1,6-dimethyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4ef)
Yield 74 mg, 62%; yellow solid, mp: 132-133 oC.
1H NMR (400 MHz, CDCl3) δ 8.09-8.07 (m, 2H), 7.78-7.76 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.22 (d, J
= 8.4 Hz, 1H), 3.50 (s, 3H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.1, 147.3, 146.2, 137.3, 137.1, 130.2,
128.5, 127.9, 123.4, 110.4, 98.1, 47.3, 21.9. HRMS calcd. for C15H14IN2OS (M+H)+: 396.9866, found: 396.9868.
7-(Methoxymethyl)-1-methyl-3-phenyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (4fa)
Yield 54.9 mg, 61%; white solid, mp: 143-144oC.
1H NMR (400 MHz, CDCl3) δ 8.30 (m, 2H), 7.73 (s, 1H), 7.56 (m, 2H), 7.42-7.34 (m, 3H), 4.45 (s, 2H), 3.48 (s, 3H),
3.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 146.9, 137.3, 136.9, 134.1, 131.0, 129.0, 128.5, 128.2, 121.9,
112.8, 73.5, 58.6, 47.1. HRMS calcd. for C16H17N2O2S(M+H)+: 301.1005, found: 301.1007.
Gram-scale synthesis of 3aa in two consecutive runs.
The 1st run: To a mixture of NH-Sulfoximine 1a (1.05 g, 4.50 mmol), benzaldehyde 2a (572 mg, 5.40 mmol),
Cu2O (0.225 mmol), and TBAI (0.45 mmol) in H2O (15.0 mL) was added TMSN3 (1.04 g, 9.0 mmol) in a round bottle
flask under air. The reaction was heated at 90 °C oil bath for 12 h. After completion of the reaction as monitored by
TLC, the reaction was allowed to cool to room temperature and extracted with ethyl acetate (10.0 mL × 4). The
combined organic layers was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which
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was further purified by column chromatography (silica; petroleum ether/ethyl acetate 5:1) to afford thiadiazine-1-oxide
3aa (1.03 g, 89%) as a white solid.
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The aqueous layer in the mother flask was collected for the 2nd run of the reaction, without additional Cu2O and
TBAI.
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The 2nd run: The aqueous layer in the mother flask was diluted with H2O (3.0 mL) to ca. 15 mL, then the
substrates NH-Sulfoximine 1a (1.05 g), benzaldehyde 2a (572 mg) and TMSN3 (1.04 g, 9.0 mmol) were added
subsequently. The reaction was heated at 90 °C oil bath for 12 h. After completion of the reaction as monitored by
TLC, the reaction was allowed to cool to room temperature and extracted with ethyl acetate (10.0 mL × 3). The
combined organic layers was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which
was further purified by column chromatography (silica; petroleum ether/ethyl acetate 5:1) to afford thiadiazine-1-oxide
3aa (0.897 g, 78%) as a white solid.
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General procedure for the reaction of 3aj to 5a and 5b.
To a mixture of aldehyde 3aj (0.39 mmol), and NH-Sulfoximine 1a or 1b (0.30 mmol), Cu2O (0.015 mmol), and
TBAI (0.03 mmol) in H2O (1.0 mL) was added TMSN3 (0.60 mmol) under an air atmosphere. After that, the tube was
sealed, and the reaction was heated at 90 °C oil bath for 12 h. After completion of the reaction as monitored by TLC,
the reaction was allowed to cool to room temperature, diluted with water (2 mL) and saturated KHCO3 aqueous
solution, extracted with ethyl acetate (3.0 mL×4). The combined organic layer was dried over Na2SO4, filtered and
concentrated to give the crude product, which was further purified by column chromatography (silica; petroleum
ether/ethyl acetate 5:1) to afford thiadiazine-1-oxides 5a or 5b.
3,3'-(1,4-Phenylene)bis(1-methyl-1l4-benzo[e][1,2,4]thiadiazine 1-oxide (5a)
Yield 73 mg, 56%; yellow solid, mp: 297-298 oC.
1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 4H), 8.27-8.25 (m, 2H), 7.84-7.80 (m, 2H), 7.62-7.60 (m, 2H), 7.57-
7.54(m, 2H), 3.96 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 156.3, 146.2, 139.9, 135.4, 128.4, 128.2, 127.1,
124.9, 114.5, 45.6. HRMS calcd. for C22H19N4O2S2 (M+H)+: 435.0944, found: 435.0947.
1-Methyl-3-(4-(1-oxido-1-phenyl-1l4-benzo[e][1,2,4]thiadiazin-3-yl)phenyl)-1l4-benzo[e][1,2,4]thiadiazine
1-
oxide (5b)
Yield 65 mg, 71%; yellow solid, mp: 144-145 oC.
1H NMR (400 MHz, DMSO-d6) δ 8.48-8.43 (m, 4H), 8.27 (d, J = 7.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.85-7.80 (m, 3H),
7.78-7.69 (m, 3H), 7.65-7.61 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 3.97 (s, 3H). 13C{1H} NMR
(100 MHz, DMSO-d6) δ 156.6, 156.3, 146.5, 146.2, 140.1, 139.8, 139.7, 135.6, 135.4, 135.1, 130.4, 129.1, 128.7,
128.5, 128.4, 127.8, 127.1, 125.5, 124.9, 114.5, 114.1, 45.6. HRMS calcd. for C27H21N4O2S2 (M+H)+: 497.1100, found:
497.1101.
General procedure for the reation of ortho-iodide NH-sulfoximine 1h with benzaldehyde 2a.
To a vigorous stirred mixture of NH-Sulfoximine 1h (84 mg, 0.30 mmol), aldehyde 2a (38 mg, 0.36 mmol), Cu2O
(0.015 mmol), and TBAI (0.03 mmol) in H2O (1.0 mL) was added TMSN3 (0.60 mmol) under an air atmosphere. The
reaction was heated at 90 °C oil bath for about 12 h. Upon completion of the reaction as indicated by TLC, the reaction
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was allowed to cool to room temperature, and diluted with water (2.0 mL) and saturated aqueous NaHCO3 (2.0 mL),
then extracted with ethyl acetate (3.0 mL × 3). The combined organic layer was dried over Na2SO4, and concentrated
to give the crude product, which was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to
afford the expected thiadiazine-1-oxide 3aa (55 mg, 0.21 mmol, 71%) as a white solid.
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General procedure for the synthesis of ortho-amino sulfoximine 6.
To a stirred mixture of NH-Sulfoximine 1a (0.30 mmol), Cu2O (0.015 mmol), and TBAI (0.03 mmol) in H2O (1.0
mL) was added TMSN3 (0.60 mmol) in a tube under an air atmosphere. The reaction tube was sealed and heated at 90
°C oil bath for 12 h. After completion of the reaction as monitored by TLC, the reaction was allowed to cool to room
temperature, diluted with water (2.0 mL) and saturated NaHCO3 aqueous solution, then extracted with ethyl acetate
(3.0 mL×4). The combined organic layer was dried over Na2SO4, the crude residue was purified by flash column
chromatography to yield 6 (26 mg, 51% yield) as a yellow oil.
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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.74 (d, J =
8.4 Hz, 1H), 5.36 (br, 2H), 3.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.3, 134.6, 129.6, 124.0, 117.7, 117.5,
43.0. HRMS calcd. for C7H11N2OS (M+H)+: 171.0587, found: 171.0589.
General procedure for the reaction of NAc-sulfoximine 7.
To a stirred mixture of NAc-Sulfoximine 7 (0.30 mmol), 4-methylbenzaldehyde 1c (0.39 mmol), Cu2O (0.015
mmol), and TBAI (0.03 mmol) in H2O (1.0 mL) was added TMSN3 (0.60 mmol) in a tube under an air atmosphere.
The reaction tube was sealed and heated at 90 °C oil bath for 12 h. After completion of the reaction as monitored by
TLC, the reaction was allowed to cool to room temperature, diluted with water (2.0 mL) and saturated KHCO3 aqueous
solution, then extracted with ethyl acetate (3.0 mL×4). The combined organic layer was dried over Na2SO4, the crude
residue was purified by flash column chromatography to yield 3ac (37 mg, 46% yield), as a white solid. Compound 8
was not detected in this reaction.
General procedure for the reaction of NMe-sulfoximine 9.
To a stirred mixture of NMe-Sulfoximine 9 (0.30 mmol), 4-methylbenzaldehyde 1c (0.39 mmol), Cu2O (0.015
mmol), and TBAI (0.03 mmol) in H2O (1.0 mL) was added TMSN3 (0.60 mmol) in a tube under an air atmosphere.
The reaction tube was sealed and heated at 90 °C oil bath for 12 h. After completion of the reaction as monitored by
TLC, the reaction was allowed to cool to room temperature, diluted with water (2.0 mL) and saturated KHCO3 aqueous
solution, then extracted with ethyl acetate (3.0 mL×4). The combined organic layer was dried over Na2SO4, the crude
residue was purified by flash column chromatography to yield 10 (33 mg, 59% yield), as a viscous solid. Compound
3ac was not detected in this reaction.
1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 1H), 7.29-7.26 (m, 1H), 6.76-6.66 (m, 2H), 5.24 (br, 2H), 3.00 (s, 3H),
2.62 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.5, 134.5, 131.3, 117.8, 117.1, 41.7. 29.6. HRMS calcd. for
C8H13N2OS (M+H)+: 185.0743, found: 185.0749.
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/ acs.joc-2019-02828c.
Copies of 1H and 13C NMR spectra (PDF).
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■ AUTHOR INFORMATION
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Corresponding Author
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*E-mail: zchen@jxnu.edu.cn
ORCID
Zhiyuan Chen: 0000-0002-5159-7287
■ ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (21672085, 21961015) and the Talented Youth Project of
Jiangxi Province (20171BCB23038) for financial support. Z.C was grateful for theopen project program of Polymer
Engineering Research Center, Jiangxi Science&Technology Normal University (KFGJ18014).
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