A four-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, 1,2-dibromoethane, and hydrazines

Article abstract of DOI:10.1039/c5ob01765c

A four-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, 1,2-dibromoethane, and hydrazines under metal-free conditions is described, providing a novel and efficient approach to 2-arylsulfonyl hydrazones. This transformation proceeds

Full text of DOI:10.1039/c5ob01765c

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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB01765C
Organic & Biomolecular Chemistry
A four-component reaction of aryldiazonium tetrafluoroborates,
sulfur dioxide, 1,2-dibromoethane, and hydrazines
Received 00th January 20xx,
Danqing Zheng,a Yunyan Kuang,a,* and Jie Wua,b,
*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A four-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, 1,2-dibromoethane, and hydrazines under
metal-free conditions is described, providing a novel and efficient approach to 2-arylsulfonyl hydrazones. This
transformation proceeds smoothly via insertion of sulfur dioxide under mild conditions with good functional group
tolerance.
sulfinate salts.11 However, early relevant studies were devoted
to the chemistry of diazenes, which was generated from the
decomposition of N',N'-disubstituted aminosulfonamides
Introduction
Over the past few years, considerable attention has been paid
to sulfone derivatives because of the importance of these
functional groups in pharmaceutical and agrochemical
molecules.1,2 Marketed drugs Bicalutamide3 and Eletriptan4, or
as the herbicides Mesotrione5 and Cafenstrole6, are some
examples featuring sulfone units. However, general methods
for sulfone preparation including oxidation of the
corresponding sulfides or sulfoxides and substitution reactions
of sulfonate salts, usually suffered from significant limitations
and drawbacks.7 For the oxidative method, the basic starting
material are foul smelling thiols and the substrate scope is
restricted due to the oxidizing condition. Sulfinate salts are
usually generated from the corresponding sulfonyl chlorides,
which themselves require procedures with harsh reaction
conditions.8,9 Moreover, the sulfinate method involving
alkylation of sulfinate salts demands inconvenient alcohols or
dipolar solvents.7b Thus, the development of efficient and
environmentally benign methods for the construction of
sulfone derivatives is of great importance.
under the action of base (Scheme 1, eq. a).11b-d Until 2013,
Willis and co-workers combined N',N'-disubstituted
aminosulfonamides with electrophilic coupling partners to
afford the corresponding sulfones in good to excellent yields
(Scheme 1, eq. b).8b This process could also be compressed to
a one-pot reaction via utilizing their previous reported
palladium-catalysed aminosulfonylation of aryl halides. Since
the hydrazine part dropped from N',N'-disubstituted
aminosulfonamide would result in hydrazone as the by-
product, this transformation had the disadvantage of low
atomic economy. Based on the above considerations and our
continuous interests in sulfur dioxide chemistry,12,13 we herein
report sulfinate salts and diazenes generated from the in situ
produced N',N'-disubstituted aminosulfonamides would react
Previous work
R1
N
a)
O2
S
base, heat
rearrangement
N
R2
tetrazenes, hydrazones
or hydrocarbons
R2N
N
H
-
-ArSO2
More recently, significant efforts have focused on the
utilization of unsubstituted sulfonylhydrazides as sulfonyl
precursor instead of sulfinate salts.10 Most of these
transformations are based on sulfonyl radicals and the
reaction conditions are mild and convenient. Noticeably, N-
aminosulfonamide derivatives such as N',N'-disubstituted
aminosulfonamides, which would expectably provide more
reaction possibility, have also been proven for the access of
early studies about diazenes
R1
b)
O2
S
N
base, heat
electrophiles
N
R2
sulfones
ArSO2
H
Sulfinate salts as intermediates for the synthesis of sulfones
This work
R
c)
O2
S
N2BF4
SO2 H2N NR'2
metal-free, rt
NR'2
N
R
H
a.Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn
one-pot
process
B
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
O2
S
R'2N
ArSO2
one-pot synthesis of 2-arylsulfonyl hydrazones
N
X
NR'2
X
N
R
† Dedicated to Prof. Xue-Long Hou on the occation of his 60th birthday.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Application of N',N'-disubstituted aminosulfonamides
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Organic & Biomolecular Chemistry
Page 2 of 6
Journal Name
12
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Br
8V0iew Article 6O5nline
with 1,2-dihaloethane, leading to 2-arylsulfonyl hydrazones
under metal-free conditions (Scheme 1, eq. c).
DOI: 10.1039/C5OB01765C
I
13
80
80
80
80
80
100
60
40
10
n.d.
67
14d
15e
16f
17g
18
Br
Br
Br
Br
Br
Br
Br
Br
68
Results and discussion
63
With an expectation to find optimal conditions, we began our
investigation for the generation of 2-arylsulfonyl hydrazones
by using N-aminosulfonamides as the starting materials. For
our initial experiments, N-morpholinobenzenesulfonamide 1a
was treated with 1,2-dichloroethane 2a using 2 equivalents of
Cs2CO3 as base in 1,4-dioxane at 80 °C. Gratifyingly, the desired
2-arylsulfonyl hydrazine 3a was produced in 32% yield (Table 1,
56
trace
66
19
20h
70
21
n.r.
a
Reaction conditions: N-aminosulfonamide (0.3 mmol), solvent (1.5
mL), base (2.0 equiv.), 1,2-dihaloethane (0.5 mL), 3h. b In the presence
entry
1).
The
structure
of
(E)-N-(2-
of Cs2CO3 (1.0 equiv.). In the presence of Cs2CO3 (3.0 equiv.). d 1,2-
c
(phenylsulfonyl)ethylidene)morpholin-4-amine
3a
was
e
f
dibromoethane (10 equiv.). 1,2-dibromoethane (5 equiv.). 1,2-
identified by X-ray diffraction analysis (see supporting
information). higher yield of 36% was obtained in
g
h
dibromoethane (2 equiv.). 1,2-dibromoethane (1.5 equiv.) 15h
(reaction time).
A
acetonitrile via further screening of solvents (Table 1, entries
2-5). The reaction was failed when NaHSO3, NaOAc or KF was
used as the base (Table 1, entries 6-8), while K3PO4 supplied a
lower yield (Table 1, entry 9). The yield was decreased to 24%
when the amount of Cs2CO3 was reduced to 1 equivalent, and
no improvement was observed when 3 equivalent of Cs2CO3
was employed (Table 1, entries 10-11). Pleasingly, when 1,2-
dibromoethane 2b was used as a replacement of 1,2-
dichloroethane, the corresponding product 3a was obtained in
65% yield (Table 1, entry 12). The reaction became complex
and no desired product was observed when 1,2-diiodoethane
2c was used (Table 1, entry 13). Screening of the amount of
1,2-dibromoethane revealed that the reaction worked
efficiently with the use of 5 equivalent of 1,2-dibromoethane
(Table 1, entries 14-17). A higher yield was obtained when the
reaction temperature was decreased to 40 °C (Table 1, entries
18-20). No reaction took place at the temperature of 10 °C
(Table 1, entry 21).
The reaction scope of N-aminosulfonamides
1 and
dihaloalkanes 2 was then explored under the above optimized
conditions. Various N-aminosulfonamides 1 reacted with 1,2-
dibromoethane 2b, giving rise to the desired products 3 in
moderate to good yields (Table 2). This transformation was
feasible for the N-aminosulfonamides with electron-
withdrawing or electron-donating groups attached on the
aromatic ring, leading to the corresponding products smoothly.
Moreover, the substrates with general functional groups
including ester, ether, halide and even nitro, proceeded well to
give the desired products 3. The N-aminosulfonamides bearing
ortho- or poly-substitutents worked efficiently as well. Other
N-aminosulfonamides generated from different hydrazides
such as piperidin-1-amine and 1-methyl-1-phenylhydrazine
could also be applied in this approach to produce the
corresponding products 3p and 3q. Unfortunately, other
dihaloalkanes
such
as
1,3-dibromopropane,
1,2-
dibromopropane and dibromomethane all failed in this
conversion (data not shown in Table 2). The sulofonylation
product bromomethylsulfonylbenzene was observed in 53%
yield when dibromomethane was used.8b
Table
1.
Initial
studies
for
the
reaction
of
N-
morpholinobenzenesulfonamide 1a with 1,2-dihaloethane 2a
O
O
O2
S
O2
S
N
N
Having established the synthesis of 2-arylsulfonyl
hydrazones using preformed N-aminosulfonamides, the one-
pot process involving the aminosulfonylation of aryldiazonium
tetrafluoroborates was then carried out. In the initial attempts
using phenyldiazonium tetrafluoroborate 4a and morpholin-4-
amine 5a, we found that the conversion of the N-
aminosulfonamide intermediate hardly went to completion.
This problem was probably resulted from the lower
concentration that the aminosulfonylation step required.
Therefore, When the reaction temperature was changed to
80 °C in the presence of 3.0 equivalent of Cs2CO3, the N-
aminosulfonamide intermediate transformed completely
leading to the desired product 3a in 55% yield. However, there
was no further improvement of the yield through our efforts.
As expected, various aryldiazonium tetrafluoroborates and
hydrazines were feasible for this four-component reaction,
delivering the corresponding 2-arylsulfonyl hydrazones in
moderate yields (Table 3).
N
N
sovent, base
temp.
X
+
H
X
2
3a
1a
Entry
Solvent
Base
X
Temp.
(oC)
Yield (%)
1
1,4-dioxane
CH3CN
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaHSO3
NaOAc
KF
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
80
80
80
80
80
80
80
80
80
80
80
32
2
36
3
20
4
Toluene
EtOH
24
5
16
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
n.d.
n.d.
n.d.
32
7
8
9
K3PO4
10b
11c
Cs2CO3
Cs2CO3
24
36
2 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
N2BF4
View ARrt2icle Online
DOI: 10.1039/C5OB01765C
Br
2b
Br
O2
S
R1
Cs2CO3
N
Table 2. Generation of 2-arylsulfonyl hydrazones through the reaction of N-
aminosulfonamides 1 with dihaloalkanes 2a,b
4
R2
N
R3
N
R3
+
CH3CN R1
NH2
5
3
"SO2"
R2
N
R2
N
O2
S
O2
S
R3
Cs2CO3
CH3CN, 40 o
N
R3
N
Br
O
R1
O
O2
+
O
H
R1
Br
O
O2
S
O2
C
S
N
N
N
S
N
N
N
2b
1
3
O
O
O
O
3a, 55% yield
3b, 53% yield
3c, 45% yield
O2
S
O2
S
O2
N
N
S
N
N
N
N
O
O
O
O2
S
O2
S
O2
S
O
N
N
N
3a, 70% yield
3c, 69% yield
N
3b, 70% yield
N
N
tBu
O
O
EtO2C
O2
S
O2
S
Cl
O2
S
N
N
N
3e, 46% yield
3h, 56% yield
3d, 48% yield
N
N
N
Cl
tBu
Br
3d, 61% yield
3e, 76% yield
3f, 66% yield
O
O2
S
O2
S
O2
S
N
N
N
N
N
N
O
O
O
O2
O2
O2
S
N
N
S
N
S
N
N
N
3q, 51% yield
3p, 36% yield
3o, 45% yield
O2N
O
F
EtOOC
O
3g, 67% yield
3i, 45% yield
3h, 80% yield
Reaction conditions: DABCO.(SO2)2 (0.18 mmol) and 5 (0.3 mmol) in
a
O
O2
S
O2
S
O2
S
CH3CN (2.0 mL), followed by dropwise addition of 4 (0.33 mmol) in
N
N
N
N
N
N
CH3CN (1.0 mL) under N2 protection in 10 minutes, then 1,2-
b
Cl
dibromoethane 2b (5 equiv.), Cs2CO3 (3 equiv.), 80 °C, 5h. Isolated
Cl
3j, 62% yield
3l, 54% yield
3k, 55% yield
yield based on hydrazine 5.
O
O
O2
S
O2
S
O
O2
S
N
N
N
N
N
On the basis of the above experimental results and the
previous reports,8b,11,12c a possible mechanism was proposed in
Scheme 3. We reasoned that the radical aminosulfonylation
N
OMe
COOMe
3o, 60% yield
3m, 53% yield
3n, 71% yield
process
of
aryldiazonium
tetrafluoroborates
with
DABCO.(SO2)2 and hydrazines would deliver the N-
aminosulfonamide 1. Next, the base promoted decomposition
of N-aminosulfonamide 1 would occur to produce diazene 8
and sulfinate salt 9. The substitution reaction between
sulfinate salt 9 and 1,2-dibromoethane 2b would generate the
sulofonylation intermediate 10, followed by an elimination
process producing the vinylsulfone 11. Then the diazene 8
would react with vinylsulfone 11 via Michael addition to bring
out the intermediate 12. Further isomerization of intermediate
12 would afford the desired product 3 (Scheme 3).
O2
S
O2
S
N
N
N
N
3q, 75% yield
3p, 56% yield
a
Reaction conditions: N-aminosulfonamide
1 (0.3 mmol), 1,2-
dibromoethane 2b (5 equiv.), Cs2CO3 (2 equiv.), CH3CN (1.5 mL), 40 oC,
15h. b Isolated yield based on N-aminosulfonamide 1.
Preliminary mechanistic investigation was carried out to
understand the mechanism of the combination of N-
aminosulfonamide and 1,2-dibromoethane. The combination
procedure took place smoothly to afford 2-arylsulfonyl
hydrazone 3a when 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was introduced to the standard reaction as the
additive, suggesting this transformation was not a radical
process (Scheme 2, eq. a). Inspired by the limited scope of
dihaloalkanes, we suspected that vinylsulfone might be an
intermediate in the transfomation. Thus, we added
vinylsulfonylbenzene 6 to the reaction of 1,2-dibromoethane
2b and 4-methoxy-N-morpholinobenzenesulfonamide 1c. Both
types of 2-arylsulfonyl hydrazone were observed and 1-
methoxy-4-(vinylsulfonyl)benzene was generated in 15% yield,
which indicated that vinylsulfone was most likely the key
intermediate in this process (Scheme 2, eq. b).
(a)
O
O
O2
S
O2
S
N
N
TEMPO (2.0 equiv)
Cs2CO3, CH3CN
Br
N
N
+
Br
O
H
40 !
C
1a
3a, 68% yield
2b
(b)
O
O
O2
S
N
O2
S
N
N
N
O
3c, 19% yield
H
Cs2CO3, CH3CN
O
Br
+
O2
S
1c, 0.2 mmol
Br
40 !
C
N
N
O2
S
2b
3a, 20% yield
O2
S
6, 0.2 mmol
O
7, 15% yield
Scheme 2. Investigation of the mechanism
Table 3. Synthesis of 2-arylsulfonyl hydrazones via a four-component
reaction a,b
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Organic & Biomolecular Chemistry
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Journal Name
R2
N
mixture was directly purified by flash column chVrioewmAartticolegOranlpinhe
(EtOAc/n-hexane, 1:1) to give the desired product 3.
O2
S
O2
S
1,2-dibromoethane
SN2
SO2
DOI: 10.1039/C5OB01765C
R1
N
R3
R1
R1
Br
H
10
9
1
General experimental procedure for the one-pot synthesis of
2-arylsulfonyl hydrazones
R2
base
elimination
N
N
R3
8
Aryldiazonium tetrafluoroborate 4 (0.30 mmol) in CH3CN
(1.0 mL) was added dropwisely to a solution of DABCO•(SO2)2
(0.18 mmol) and hydrazine 5 (0.36 mmol) in CH3CN (2.0 mL)
under N2 in 10 minutes. The mixture was stirred at room
temperature for another 10 minutes. Then 1,2-dibromoethane
2b (5 equiv.) and Cs2CO3 (3 equiv.) were added to the above
mixture. The mixture was stirred at 80 °C for 5h. After
completion of reaction as indicated by TLC, the mixture was
directly purified by flash column chromatograph (EtOAc/n-
hexane, 1:1) to give the desired product 3.
base
R2
H
R2
N
O2
O2
O2
S
S
S
N
R1
Michael
addition
R1
N
R3
R1
N
R3
11
3
12
Scheme 3. A possible mechanism for the generation of 2-arylsulfonyl
hydrazones
Conclusions
In conclusion, we have developed a novel and efficient
approach to 2-arylsulfonyl hydrazones via a four-component
reaction of aryldiazonium tetrafluoroborates, sulfur dioxide,
1,2-dibromoethane and hydrazines. The key sulfonyl motif is
introduced via a radical aminosulfonylation process, delivering
a N-aminosulfonamide intermediate. The diazene and sulfinate
salt decomposed from the N-aminosulfonamide intermediate
would be bridged by 1,2-dibromoethane, leading to the
corresponding 2-arylsulfonyl hydrazones. This transformation
takes place smoothly under mild conditions and tolerates a
broad range of functional groups. We believe that the versatile
reactive groups in the structure of 2-arylsulfonyl hydrazones
will make this method attractive for further applications.
(E)-N-(2-(Phenylsulfonyl)ethylidene)morpholin-4-amine (3a):
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 2H), 7.66 (t, J =
7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 5.6 Hz, 1H), 4.02
(d, J = 6.0 Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H);
13C NMR (100 MHz, CDCl3) δ 138.4, 133.8, 129.0, 128.4, 124.2,
66.0, 60.1, 51.2; HRMS (ESI) calcd for C12H17N2O3S: 269.0954
(M + H+), found: 269.0964.
(E)-N-(2-Tosylethylidene)morpholin-4-amine (3b): 1H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz,
2H), 6.74 (t, J = 5.6 Hz, 1H), 3.99 (d, J = 5.6 Hz, 2H), 3.76 (t, J =
4.8 Hz, 4H), 2.91 (t, J = 4.8 Hz, 4H), 2.44 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.8, 135.6, 129.6, 128.4, 124.6, 66.0, 60.1,
51.2, 21.6; HRMS (ESI) calcd for C13H19N2O3S: 283.1111 (M +
H+), found: 283.1115.
Experimental Section
General experimental methods
(E)-N-(2-(4-Methoxyphenylsulfonyl)ethylidene)morpholin-4-
amine (3c): 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H),
7.00 (d, J = 8.8 Hz, 2H), 6.75 (t, J = 5.6 Hz, 1H), 3.99 (d, J = 5.6
Hz, 2H), 3.88 (s, 3H), 3.77 (t, J = 4.8 Hz, 4H), 2.93 (t, J = 4.8 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 163.8, 130.5, 130.0, 124.8,
114.2, 66.0, 60.3, 55.6, 51.3; HRMS (ESI) calcd for C13H19N2O4S:
299.1060 (M + H+), found: 299.1051.
Unless otherwise stated, all commercial reagents were
used as received. All solvents were dried and distilled
according to standard procedures. Flash column
chromatography was performed using silica gel (60-Å pore size,
32–63μm,
standard
grade).
Analytical
thin–layer
(E)-N-(2-(4-Chlorophenylsulfonyl)ethylidene)morpholin-4-
amine (3d): 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H),
7.54 (d, J = 8.4 Hz, 2H), 6.74 (t, J = 5.6 Hz, 1H), 4.01 (d, J = 5.6
Hz, 2H), 3.79 (t, J = 4.8 Hz, 4H), 2.93 (t, J = 4.8 Hz, 4H); 13C NMR
(100 MHz, CDCl3) δ 140.5, 136.9, 129.9, 129.3, 123.7, 66.0,
60.1, 51.2; HRMS (ESI) calcd for C12H16ClN2O3S: 303.0565 (M +
H+), found: 303.0557.
chromatography was performed using glass plates pre-coated
with 0.25 mm 230–400 mesh silica gel impregnated with a
fluorescent indicator (254 nm). Thin layer chromatography
plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrated on rotary evaporators at ~20 Torr
at 25–35°C. Nuclear magnetic resonance (NMR) spectra are
recorded in parts per million from internal tetramethylsilane
on the δ scale. 1H and 13C NMR spectra were recorded in CDCl3
on a Bruker DRX-400 spectrometer operating at 400 MHz and
100 MHz, respectively. All chemical shift values are quoted in
ppm and coupling constants quoted in Hz. High resolution
mass spectrometry (HRMS) spectra were obtained on a
micrOTOF II Instrument.
(E)-N-(2-(4-tert-Butylphenylsulfonyl)ethylidene)morpholin-4-
amine (3e): 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 2H),
7.56 (d, J = 8.4 Hz, 2H), 6.76 (t, J = 5.6 Hz, 1H), 4.01 (d, J = 5.6
Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.91 (t, J = 4.8 Hz, 4H), 1.34 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 157.7, 135.4, 128.3, 126.0,
124.6, 66.0, 60.1, 51.2, 35.2, 31.0; HRMS (ESI) calcd for
C16H25N2O3S: 325.1580 (M + H+), found: 325.1584.
General experimental procedure for the reaction of N-
aminosulfonamides 1 with 1,2-dibromoethane 2b
(E)-N-(2-(4-Bromophenylsulfonyl)ethylidene)morpholin-4-
amine (3f): 1H NMR (400 MHz, CDCl3) δ 7.68-7.75 (m, 4H), 6.73
(t, J = 5.6 Hz, 1H), 4.02 (d, J = 6.0 Hz, 2H), 3.78 (t, J = 4.8 Hz, 4H),
2.93 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ137.4,
Dihaloalkane 2 (5 equiv.) and Cs2CO3 (0.6 mmol, 2.0 equiv.)
were added to a solution of N-aminosulfonamide 1 (0.3mmol)
in CH3CN (2.0 mL). The mixture was stirred at 40 °C for 10-15
hours. After completion of reaction as indicated by TLC, the
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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133.0, 132.3, 130.0, 123.7, 66.0, 60.0, 51.2; HRMS (ESI) calcd (E)-N-(2-(3-Methoxyphenylsulfonyl)ethylidene)mVoierwphAroticllienO-4nl-ine
for C12H16BrN2O3S: 347.0060 (M + H+), found: 347.0067.
1
amine (3n): H NMR (400 MHz, CDCl3)DδOI:71.04.410-379.4/C85O(mB0,1726H5C),
7.35 (s, 1H), 7.15-7.18 (m, 1H), 6.75 (t, J = 5.6 Hz, 1H), 4.02 (d, J
= 5.6 Hz, 2H), 3.87 (s, 3H), 3.77 (t, J = 4.8 Hz, 4H), 2.93 (t, J = 4.8
Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 159.8, 139.6, 130.1, 124.2,
120.5, 120.3, 112.7, 66.0, 60.0, 55.6, 51.2; HRMS (ESI) calcd for
C13H19N2O4S: 299.1060 (M + H+), found: 299.1062.
(E)-N-(2-(4-Fluorophenylsulfonyl)ethylidene)morpholin-4-
amine (3g): H NMR (400 MHz, CDCl3) δ 7.86-7.89 (m, 2H),
7.22-7.27(m, 2H), 6.74 (t, J = 5.6 Hz, 1H), 4.02 (d, J = 5.6 Hz, 2H),
3.78 (t, J = 4.8 Hz, 4H), 2.92 (t, J = 4.8 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 165.8 (d, JF = 255.2 Hz), 134.4, 131.3 (d, JF = 9.5
1
Hz), 123.9 , 116.3 (d, JF = 22.6 Hz), 66.0, 60.1, 51.2; HRMS (ESI) (E)-N-(2-(Mesitylsulfonyl)ethylidene)morpholin-4-amine (3o):
calcd for C12H16FN2O3S: 278.0860 (M + H+), found: 278.0864.
1H NMR (400 MHz, CDCl3) δ 6.95 (s, 2H), 6.77 (t, J = 5.6 Hz, 1H),
4.02 (d, J = 5.6 Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz,
4H), 2.64 (s, 6H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
143.3, 140.1, 132.6, 132.0, 124.2, 66.0, 60.0, 51.1, 23.0, 20.9;
HRMS (ESI) calcd for C15H23N2O3S: 311.1424 (M + H+), found:
311.1423.
(E)-Ethyl 4-(2-(Morpholinoimino)ethylsulfonyl)benzoate (3h):
1H NMR (400 MHz, CDCl3) δ8.21 (d, J = 8.4 Hz, 2H), 7.93 (d, J =
8.8 Hz, 2H),6.73 (t, J = 5.6 Hz, 1H), 4.42 (m, 2H), 4.05 (d, J = 5.6
Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H), 1.42 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 142.1, 135.2,
130.0, 128.5, 123.5, 65.9, 61.8, 59.9, 51.2, 14.1; HRMS (ESI) (E)-N-(2-(Phenylsulfonyl)ethylidene)piperidin-1-amine (3p):
calcd for C12H16FN2O3S: 341.1166 (M + H+), found: 341.1162.
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.65 (t, J =
7.6 Hz, 1H), 7.56 (t, J = 7.2 Hz, 2H), 6.66 (t, J = 5.6 Hz, 1H), 4.03
(d, J = 5.6 Hz, 2H), 2.91 (t, J = 5.6 Hz, 4H),1.58-1.66 (m, 4H),
1.46-1.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ138.6, 133.6,
128.9, 128.4, 122.0, 60.4, 51.5, 24.6, 23.7; HRMS (ESI) calcd for
C13H19N2O2S: 267.1162(M + H+), found: 267.1167.
(E)-N-(2-(4-Nitrophenylsulfonyl)ethylidene)morpholin-4-
1
amine (3i): H NMR (400 MHz, CDCl3) δ8.42 (d, J = 8.0 Hz, 2H),
8.06 (d, J = 8.0 Hz, 2H),6.74 (t, J = 5.6 Hz, 1H), 4.09 (d, J = 6.0 Hz,
2H), 3.78 (t, J = 4.8 Hz, 4H), 2.92 (t, J = 4.8 Hz, 4H); 13C NMR
(100 MHz, CDCl3) δ144.0, 130.0, 129.3, 124.1, 122.6, 65.9, 59.8,
51.1; HRMS (ESI) calcd for C12H16N3O5S: 314.0805 (M + H+), (E)-1-Methyl-1-phenyl-2-(2-
(phenylsulfonyl)ethylidene)hydrazine (3q): 1H NMR (400 MHz,
found: 314.0797.
CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (t,
J = 8.0 Hz, 2H), 7.22 (t, J = 8.0Hz, 2H), 6.90-6.95 (m, 3H), 6.65 (t,
J = 5.6 Hz, 1H), 4.17 (d, J = 5.6 Hz, 2H), 3.25 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 147.0, 138.6, 133.6, 129.0, 128.8, 128.4,
121.3, 119.6, 115.6, 60.2, 33.7; HRMS (ESI) calcd for
C15H17N2O2S: 289.1005(M + H+), found: 289.1011.
(E)-N-(2-(o-Tolylsulfonyl)ethylidene)morpholin-4-amine (3j):
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.52 (t, J =
7.6 Hz, 1H), 7.33-7.37 (m, 2H), 6.71 (t, J = 5.6 Hz, 1H), 4.07 (d, J
= 6.0 Hz, 2H), 3.74 (t, J = 4.8 Hz, 4H), 2.85 (t, J = 4.8 Hz, 4H),
2.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ138.3, 136.7, 133.7,
132.5, 130.5, 126.2, 124.3, 65.9, 59.3, 51.2, 20.4; HRMS (ESI)
calcd for C13H19N2O3S: 283.1111 (M + H+), found: 283.1113.
1
1-Methoxy-4-(vinylsulfonyl)benzene (7): H NMR (400 MHz,
CDCl3) δ 7.82-7.85 (m, 2H), 7.01-7.04 (m, 2H), 6.65 (m, 1H),
6.40 (d, J = 16.4Hz, 1H), 5.98 (d, J = 10.0Hz, 1H), 3.89 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 139.0, 136.9, 130.1, 126.4, 114.5,
55.6; HRMS (ESI) calcd for C9H11O3S: 199.0423(M + H+), found:
199.0429.
(E)-N-(2-(2-Chlorophenylsulfonyl)ethylidene)morpholin-4-
amine (3k): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H),
7.55-7.60 (m, 2H), 7.43-7.48 (m, 1H), 6.69 (t, J = 5.6 Hz, 1H),
4.34 (d, J = 6.0 Hz, 2H), 3.73 (t, J = 4.8 Hz, 4H), 2.84 (t, J = 4.8 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 134.7, 133.1, 132.0, 131.7,
127.0, 123.6, 65.9, 58.0, 51.1; HRMS (ESI) calcd for
C12H16ClN2O3S: 303.0565 (M + H+), found: 303.0561.
Acknowledgements
(E)-N-(2-(3-Chlorophenylsulfonyl)ethylidene)morpholin-4-
amine (3l): 1H NMR (400 MHz, CDCl3) δ 7.83 (t, J = 2.0 Hz, 1H),
7.75 (d, J = 8.0 Hz, 1H), 7.61-7.64 (m, 1H), 7.51 (t, J = 8.0Hz, 1H),
6.73 (t, J = 5.6 Hz, 1H), 4.03 (d, J = 6.0 Hz, 2H), 3.78 (t, J = 4.8 Hz,
4H), 2.93 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 140.0,
135.2, 133.9, 130.3, 128.6, 126.5, 123.4, 66.0, 60.0, 51.2;
HRMS (ESI) calcd for C12H16ClN2O3S: 303.0565 (M + H+), found:
303.0564.
Financial support from National Natural Science Foundation of
China (No. 21372046) and the Science
& Technology
Commission of Shanghai Municipality (No. 12JC1403800) is
gratefully acknowledged.
Notes and references
1
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(E)-Methyl
3-(2-(Morpholinoimino)ethylsulfonyl)benzoate
(3m): 1H NMR (400 MHz, CDCl3) δ 8.50 (t, J = 1.6 Hz, 1H), 8.30-
8.33 (m, 1H), 8.03-8.06 (m, 1H), 7.66 (t, J = 8.0Hz, 1H), 6.75 (t, J
= 5.6 Hz, 1H), 4.04 (d, J = 5.6 Hz, 2H), 3.97 (s, 3H), 3.76 (t, J =
4.8 Hz, 4H), 2.90 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3)
δ165.1, 138.9, 134.6, 132.4, 131.2, 129.7, 129.3, 123.6, 66.0,
60.0, 52.6, 51.1; HRMS (ESI) calcd for C14H19N2O5S: 327.1009
(M + H+), found: 327.1019.
2
For
a
list
of
topdrugs
by
year,
see:
http://cbc.arizona.edu/njardarson/group/top-
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