A Novel Synthesis of N -Sulfonylformamidines from N Sulfonyl sulfonamides

Article abstract of DOI:10.1055/s-0036-1591936

N -Sulfonylformamidines were synthesized from N -sulfonylsulfonamides by reacting with p -toluenesulfonyl chloride (TsCl) and N, N - disubstituted formamides. In this reaction, it was expected that mixing TsCl with the N, N -disubstituted formamide would generate an iminium salt (Vilsmeier reagent). The reaction avoids the use of metal catalysts and hazardous reagents, and the desired N -sulfonylformamidines were obtained in 60% to quantitative yields.

Full text of DOI:10.1055/s-0036-1591936

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
Y. Jeong et al.
Paper
Synthesis
A Novel Synthesis of N-Sulfonylformamidines from N-Sulfonyl-
sulfonamides
Yuri Jeonga‡
R2
N
O
O
Cl
Jaeyoung Bana‡
Minkyung Lima
Hakjune Rhee*a,b
O
O
S
O
S
Et3N
R2
N
S
H
R1
N
R1
H
N
R2
S
R2
O
R1
25 °C
O
O
O
H
N-sulfonylsulfonamides
N-sulfonylformamidines
60% ~ quant
15 examples
a Department of Bionanotechnology, Hanyang University, 55
Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 15588,
South Korea
b Department of Applied Chemistry, Hanyang University, 55
Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 15588,
South Korea
hrhee@hanyang.ac.kr
‡ These authors contributed equally to this work
Received: 22.12.2017
Accepted after revision: 23.01.2018
Published online: 14.02.2018
Several synthetic methods to generate N-sulfonylforma-
midines from N-sulfonamides,4 azides,5 and isocyanates6
have previously been reported. In particular, direct conden-
sation of sulfonamide and formamide with Vilsmeier re-
agent by phosphoryl chloride,7 thionyl chloride,8 or oxalyl
chloride9 is the most straightforward and atom-economic
method for the synthesis of N-sulfonylformamidines. How-
ever, the reported methods require high temperatures, an-
hydrous conditions, corrosive reagents, and metal cata-
lysts,10 which are drawbacks to their utility. Polanc and co-
workers reported the transformation of N-acylsulfonamides
into N-sulfonylformamidines using oxalyl chloride.9 The re-
action can be performed in the presence of various func-
tional groups, and it is a very selective procedure for the
preparation of N-sulfonylformamidines. But this method
requires 2.5 equivalent of oxalyl chloride to complete the
reaction. We were interested in finding a better route for
the synthesis of N-sulfonylformamidines under mild reac-
tion conditions that would be more convenient and effi-
cient. It was inquisitive to find out whether N-sulfonylsul-
fonamides can be converted to N-sulfonylformamidines or
not. Here, we report a novel method for the synthesis of N-
sulfonylformamidines starting from N-sulfonylsulfon-
amides using p-toluenesulfonyl chloride (TsCl) and various
N,N-disubstituted formamides (Scheme 1). To date, there
has been no report on the synthesis of N-sulfonylformami-
dines from N-sulfonylsulfonamides.
DOI: 10.1055/s-0036-1591936; Art ID: ss-2017-f0831-op
Abstract N-Sulfonylformamidines were synthesized from N-sulfonyl-
sulfonamides by reacting with p-toluenesulfonyl chloride (TsCl) and
N,N-disubstituted formamides. In this reaction, it was expected that
mixing TsCl with the N,N-disubstituted formamide would generate an
iminium salt (Vilsmeier reagent). The reaction avoids the use of metal
catalysts and hazardous reagents, and the desired N-sulfonylformami-
dines were obtained in 60% to quantitative yields.
Key words N-sulfonylformamidine, N-sulfonylsulfonamide, sulfonamide,
sulfonyl chloride, Vilsmeier reagent
N-Sulfonylformamidines are widely used synthetic in-
termediates for medicinal compounds with immense bio-
logical importance. These compounds have emerged as bio-
active pharmacophores with antiresorptive, antitumor, and
antiproliferative properties.1 In addition, N-sulfonylforma-
midines, shown in Figure 1, are efficient inhibitors of gas-
tric acid incretion.2 Furthermore, N-sulfonylformamidines
have served as useful coordinating ligands.3
H2N
S
NH2
H
O
N
N
N
S
N
S
O
H2N
N
S
NH2
H
O
R2
N
N
S
O
N
O
S
H
N
Cl
O
O
O
Et3N
N
N
S
R2
O
S
S
S
R2
R1
R1
R1
H
N
R2
O
25 °C
O O
O
Br
H
Figure 1 Examples of compounds containing the N-sulfonylformamidine
N-sulfonylsulfonamides
N-sulfonylformamidines
moiety
Scheme 1 Synthesis of N-sulfonylformamidines from various substitut-
ed N-sulfonylsulfonamides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
Y. Jeong et al.
Paper
Synthesis
Prior to the N-sulfonylformamidine synthesis, we syn-
thesized various N-sulfonylsulfonamide derivatives from
sulfonamide and sulfonyl chloride. Interestingly, when
TsNH2 (1.0 equiv) was reacted with TsCl (1.2 equiv) and
base in DMF, N-sulfonylformamidine was obtained along
with N-sulfonylsulfonamide. It was anticipated that the use
of slightly excess TsCl participated in the formation of N-
sulfonylformamidine from N-sulfonylsulfonamide.
The reaction conditions were optimized with 4-methyl-
N-[(4-methylphenyl)sulfonyl]benzenesulfonamide (1a) and
TsCl as reagents to form the iminium salt in DMF (Table 1).
First, the reaction was optimized using NaH, triethylamine,
or without base and varying the amount of TsCl. The
amount of reagent was critical for reaction efficiency; thus,
the reactivity related to the amount of TsCl was tested. Un-
expectedly, it was confirmed that the reaction proceeded
with just 0.2 equivalent of TsCl (Table 1, entry 3). However,
to form sufficient iminium salt to complete the reaction, it
was necessary to use 0.5 equivalent of TsCl (entry 2). In the
absence of base, the desired product was obtained in 86%
yield, but when using a base, the product was obtained in
quantitative and 96% yield (entries 4, 5). Using either NaH
or triethylamine as base, the reaction gave similar results;
therefore, we chose the milder triethylamine base for the
synthesis of N-sulfonylformamidines. The reactivity was
excellent regardless of reaction temperature.
of the starting material by thin layer chromatography anal-
ysis. Furthermore, the reactivity of oxalyl chloride as anoth-
er reagent capable of forming the iminium salt was tested.
Oxalyl chloride is known to be a good reagent for making
iminium salts; however, when the sulfonylsulfonamide 1a
was reacted with oxalyl chloride (0.5 equiv) and Et3N in
DMF, the product was obtained in 64% yield. Under the op-
timized reaction conditions, we investigated the substrate
scope of the transformation with various N-sulfonylsulfon-
amides 1 and formamide derivatives 3 at 25 °C (Table 2).
The desired products 4 were obtained in 60% to quantita-
tive yield. In the cases of tert-butyl group and electron-
withdrawing groups, such as acetyl, nitro, and chloro sub-
stituents on the aromatic ring of the sulfonyl group (Table
2, entries 4–7), the yields were low at 25 °C. In these cases,
an increase to 1.5 equivalent of TsCl and to a temperature of
100 °C led to the desired products in 61% to quantitative
yields. N-Sulfonylformamidines with an aliphatic moiety
were also obtained in excellent yields except with a benzyl
substituent (Table 2, entries 9–11). Upon increasing the re-
action temperature to 100 °C, N-sulfonylformamidine 4k
was obtained in 77% yield (entry 11). We also tried the re-
action using various substituted formamides 3. Forma-
mides including N,N-diethylformamide, 1-pyrrolidinecar-
boxaldehyde, 1-piperidinecarboxaldehyde, and 4-morpho-
linecarboxaldehyde
gave
the
corresponding
N-
At either 60 °C or room temperature, the reaction gave
an excellent yield within 4 hours (Table 1, entries 5, 7). The
reaction time was determined based on the disappearance
sulfonylformamidines 4 in 66 to 97% yield (entries 12–15).
Table 1 Optimization Study for the Synthesis of N-Sulfonylformamidine 4aa
O
H
N
3a
H
N
O
O
O
S
O
S
N
S
S
Cl
N
O O
conditions
O
O
1a
2
4a
Entry
Base
TsCl (2) (equiv)
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
NaH
NaH
NaH
Et3N
Et3N
–
1.0
0.5
0.2
1.0
0.5
0.5
0.5
60
60
60
60
60
60
r.t.
4
4
4
4
4
4
4
quant
quant
62
quant
96
86
Et3N
97
a Reaction conditions: N-sulfonylsulfonamide 1a (1.68 mmol), base (2.10 mmol), DMF (3a; 3.0 mL).
b Isolated yield calculated from the equimolar amount of N-sulfonylsulfonamide.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Y. Jeong et al.
Paper
Synthesis
Table 2 Synthesis of Various N-Sulfonylformamidinesa
R2
R2
O
O
S
H
N
O
O
Et3N
O
S
R2
N
Cl
S
S
H
N
R2
R1
N
R1
R1
25 °C, 4 h
O
O O
O
3
4
1
2
Entry
1
R1
Formamide 3
Product 4
TsCl (2) (equiv)
Yield (%)b
O
S
O
N
H
N
0.5
97
90
N
O
1a
3a
4a
4b
4c
O
S
N
2
3
4
5
3a
3a
3a
3a
0.5
0.5
1.5
1.5
N
O
1b
1c
O
S
N
N
60
N
O
O
S
88c
61c
N
O
4d
1d
1e
O
S
O2N
N
N
O
NO2
4e
O
O
S
N
6
3a
1.5
76c
N
O
O
4f
1f
O
Cl
S
N
7
8
3a
3a
3a
3a
1.5
0.5
0.5
0.5
quantc
N
O
Cl
1g
4g
O
S
MeO
N
88
N
O
OMe
1h
1i
4h
O
S
N
Me
9
quant
84
N
O
4i
4j
O
S
N
10
N
N
O
1j
O
S
77c
N
O
11
3a
0.5
1k
4k
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Y. Jeong et al.
Paper
Synthesis
Table 2 (continued)
Entry
R1
Formamide 3
Product 4
TsCl (2) (equiv)
Yield (%)b
O
O
S
N
H
N
12
1a
0.5
82
97
90
N
O
4l
3b
O
O
O
S
N
N
H
N
N
13
14
1a
1a
0.5
0.5
N
O
4m
3c
O
S
H
N
O
4n
3d
O
O
S
N
H
N
15
1a
0.5
66
N
O
O
O
4o
3e
a Reaction conditions: N-sulfonylsulfonamide 1 (1.68 mmol), Et3N (2.10 mmol), N,N-disubstituted formamide 3 (3.0 mL), 25 °C.
b Isolated yield calculated from the equimolar amount of N-sulfonylsulfonamide.
c Reaction was carried out at 100 °C.
O
H
O
S
R
Based on the results, a plausible mechanism for the syn-
thesis of N-sulfonylformamidine is proposed, as shown in
Scheme 2. In situ iminium salt formed with TsCl (2) in DMF
(3a)11 reacts with N-sulfonylsulfonamide anion A to form
intermediate B. The counterion X– in B attacks the sulfonyl
group to release C, generating the desired product 4. Anoth-
er DMF reacts with C to form intermediate D, which can re-
act with N-sulfonylsulfonamide anion A to complete the re-
action cycle. Using 0.5 equivalent of TsCl, the reaction could
proceed to completion as suggested by this mechanism.
In summary, reactions were carried out under aerobic
conditions at room temperature using TsCl as a reagent to
form the iminium salt. In particular, the reactions were car-
ried out with 0.5 equivalent of TsCl and reached to comple-
tion in a short reaction time. In addition, a plausible mecha-
nism based on the optimized conditions is presented. Fur-
thermore, the reactions proceeded well with a variety of N-
sulfonylsulfonamides 1 and formamides 3. Yields of the re-
actions with various N-sulfonylsulfonamides 1 affected by
electronic or steric effects could be improved by controlling
the amount of TsCl and the reaction temperature. As a re-
sult, N-sulfonylsulfonamides 1 with electron-withdrawing
groups were obtained in yields ranging from 61 to quantita-
tive, while compounds with electron-donating groups were
obtained in yields ranging from 60–97%. In addition, reac-
tions with various substituted formamides proceeded in
yields ranging from 66–97%.
S
N
R
O
O
1
O
Et3N
O
S
Cl
H
N
O
HNEt3
O
2
3a
O
S
R
N
S
R
O
O
OTs
A
H
N
Cl
Vilsmeier Reagent (VR)
R
O
O
H
S
N
O
O
S
N
S
R
N
R
HNEt3
O
N
O
X
O
S
O
S
B
R
N
R
formamidines 4
X = Cl– or –OTs
O
O
A
O
S
O
R
X
R
S
O
N
O
C
O
H
X
O
D
H
N
Scheme 2 Plausible mechanism for the synthesis of N-sulfonylformamidines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Y. Jeong et al.
Paper
Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 147.9, 141.8, 128.1, 127.0, 28.5,
15.8.
HRMS (FAB): m/z [M + H]+ calcd for C16H19NO4S2 + H: 354.0834;
found: 354.0836.
Solvents such as anhydrous DMF and toluene in sure-seal bottles
were purchased from Sigma-Aldrich. All reagents including sulfon-
amides and sulfonyl chlorides were purchased from Sigma-Aldrich or
TCI and were used as received. Reaction progress was monitored by
TLC. The products N-sulfonylsulfonamides and N-sulfonylformami-
dines were characterized by 1H NMR, 13C NMR, and FT-IR spectrosco-
py. NMR spectra were obtained in CDCl3 or DMSO-d6 with a Bruker
400 MHz instrument (400 MHz for 1H NMR and 100 MHz for 13C
NMR). IR spectra were recorded on a Bruker Alpha FT-IR spectrome-
ter. Melting points were determined with a Sanyo Gallenkamp melt-
ing point apparatus. HRMS were obtained on a JMS 700 spectrometer
and were recorded in EI or FAB mode. N-Sulfonylsulfonamides were
purified by recrystallization (using hot CHCl3/hexane), and N-sulfo-
nylformamidine products were purified by silica gel flash column
chromatography.
4-tert-Butyl-N-[(4-tert-butylphenyl)sulfonyl]benzenesulfon-
amide (1d) CAS Reg. No. 1355251-10-3
White solid; yield: 1.28 g (28%); mp 207–208 °C.
IR (neat): 3168, 3970, 1593, 1362, 1164, 864, 624, 549 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.5 (br s, 1 H), 7.62 (d, J = 8.4 Hz, 4
H), 7.46 (d, J = 8.4 Hz, 4 H), 1.29 (s, 18 H).
13C NMR (100 MHz, DMSO-d6): δ = 154.7, 141.6, 126.7, 125.6, 35.2,
31.4.
HRMS (FAB): m/z [M + H]+ calcd for C20H27NO4S2 + H: 410.1460;
found: 410.1458.
N-Sulfonylsulfonamides 1; General Procedure
Method A (for 1a–h): A mixture of the appropriate arylsulfonyl chlo-
ride (11.2 mmol), the corresponding arylsulfonamide (12.3 mmol),
DMAP (0.274 g, 2.24 mmol), and Et3N (1.95 mL, 14.0 mmol) in tolu-
ene (0.5 M) was kept at 70 °C for 12 h (monitored by TLC). The reac-
tion was quenched with aq 2 M HCl (30 mL) to pH 1. The mixture was
extracted with EtOAc (3 × 20 mL) and the combined organic layers
were dried (anhydrous MgSO4). The solvent was evaporated, and the
crude product mixture was purified by recrystallization using hot
CHCl3/hexane to afford the desired product.
4-Nitro-N-[(4-nitrophenyl)sulfonyl]benzenesulfonamide (1e)14
CAS Reg. No. 4009-06-7
White solid; yield: 1.30 g (30%); mp 242–243 °C.
IR (neat): 3192, 1530, 1366, 1159, 874, 739 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.9 (br s, 1 H), 8.24 (d, J = 8.8 Hz, 4
H), 7.89 (d, J = 8.8 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 151.9, 148.7, 128.2, 124.0.
HRMS (EI): m/z [M]+ calcd for C12H9N3O8S2: 386.9831; found:
386.9828.
Method B (for 1i–k): The respective alkylsulfonamide (11.2 mmol)
and KOH (1.26 g, 22.4 mmol) were added to H2O (0.2 M), and the mix-
ture was cooled to 0 °C. The appropriate alkylsulfonyl chloride (12.3
mmol) was added dropwise, and the stirred solution was slowly
warmed to 60 °C and stirred for 12 h. The solution was then acidified
with HCl and kept at low temperature for 12 h to produce a white pre-
cipitate, which was collected by filtration. The product obtained was
pure enough for direct use in the next step.
4-Acetyl-N-[(4-acetylphenyl)sulfonyl]benzenesulfonamide (1f)
CAS Reg. No. 185117-45-7
Pale yellow solid; yield: 1.45 g (34%); mp 220–221 °C.
IR (neat): 3187, 2965, 1667, 1363, 1164, 868 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.28 (br s, 1 H), 7.92 (d, J = 8.8 Hz, 4
H), 7.74 (d, J = 8.8 Hz, 4 H), 2.59 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 198.0, 150.3, 138.2, 128.4, 126.9,
4-Methyl-N-[(4-methylphenyl)sulfonyl]benzenesulfonamide
(1a)12 CAS Reg. No. 3695-120-9
27.4.
White solid; yield: 1.53 g (42%); mp 171–172 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.4 (br s, 1 H), 7.56 (d, J = 8.0 Hz, 4
H), 7.23 (d, J = 8.0 Hz, 4 H), 2.34 (s, 6 H).
HRMS (FAB): m/z [M + H]+ calcd for C16H15NO6S2 + H: 382.0419;
found: 382.0417.
13C NMR (100 MHz, DMSO-d6): δ = 141.6, 140.9, 128.8, 126.5, 20.9.
4-Chloro-N-[(4-chlorophenyl)sulfonyl]benzenesulfonamide (1g)15
CAS Reg. No. 2725-55-5
N-(Phenylsulfonyl)benzenesulfonamide (1b)13 CAS Reg. No. 2618-
96-4
White solid; yield: 2.05 g (50%); mp 207–208 °C.
IR (neat): 3514, 1400, 1159, 880 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.74 (br s, 1 H), 7.63 (d, J = 8.4 Hz, 4
H), 7.43 (d, J = 8.4 Hz, 4 H).
13C NMR (100 Hz, DMSO-d6): δ = 144.8, 135.0, 128.2, 128.0.
.
White solid; yield: 0.699 g (21%); mp 270–271 °C.
IR (neat): 3072, 1360, 1153, 1082, 861, 755 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.44 (br s, 1 H), 7.68 (d, J = 7.2 Hz, 4
H), 7.46 (t, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.5, 131.2, 128.6, 126.7.
HRMS (EI): m/z [M]+ calcd for C12H9Cl2NO4S2: 364.9350; found:
364.9353.
HRMS (EI): m/z [M]+ calcd for C12H11NO4S2: 297.0129; found:
297.0131.
4-Methoxy-N-[(4-methoxyphenyl)sulfonyl]benzenesulfonamide
(1h) CAS Reg. No. 185117-44-6
4-Ethyl-N-[(4-ethylphenyl)sulfonyl]benzenesulfonamide (1c)
White solid; yield: 3.20 g (80%); mp 170–171 °C.
IR (neat): 3078, 1592, 1367, 1157, 824 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.06 (br s, 1 H), 7.58 (d, J = 8.8 Hz, 4
H), 6.95 (d, J = 8.8 Hz, 4 H), 3.81 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.2, 135.1, 129.1, 114.1, 56.0.
White solid; yield: 3.13 g (79%); mp 144–145 °C.
.
IR (neat): 3153, 2791, 1594, 1361, 1165, 833, 650, 538 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.13 (br s, 1 H), 7.57 (d, J = 8.0 Hz, 4
H), 7.24 (d, J = 8.0 Hz, 4 H), 2.49 (q, J = 7.6 Hz, 4 H), 1.18 (t, J = 7.6 Hz, 6
H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
Y. Jeong et al.
Paper
Synthesis
HRMS (EI): m/z [M]+ calcd for C14H15NO6S2: 357.0341; found:
N,N-Dimethyl-N′-(phenylsulfonyl)formimidamide (4b)17 CAS Reg.
357.0343.
No. 13707-43-2
White solid; yield: 0.321 g (90%); mp 189–190 °C; Rf = 0.45 (hex-
ane/EtOAc 1:1, v/v).
N-(Methylsulfonyl)methanesulfonamide (1i)16 CAS Reg. No. 5347-
82-0
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H), 7.90 (d, J = 8.0 Hz, 2 H),
White solid; yield: 1.75 g (90%); mp 152–153 °C.
7.54–7.44 (m, 3 H), 3.13 (s, 3 H), 3.02 (s, 3 H).
IR (neat): 3156, 3027, 1347, 1146, 946, 864 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 159.2, 142.4, 131.9, 128.7, 126.5, 41.5,
1H NMR (400 MHz, DMSO-d6): δ = 11.4 (br s, 1 H), 3.08 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 43.2.
35.6.
N,N-Dimethyl-N′-(4-ethylphenylsulfonyl)formimidamide (4c) CAS
Reg. No. 57603-97-1
HRMS (EI): m/z [M]+ calcd for C2H7NO4S2: 172.9816; found: 172.9818.
White solid; yield: 0.242 g (60%); mp 118–119 °C; Rf = 0.20 (hex-
ane/EtOAc 1:1, v/v).
N-(Isopropylsulfonyl)isopropanesulfonamide (1j) CAS Reg. No.
1416768-55-2
IR (neat): 2968, 2934, 1625, 1084, 846 cm–1
.
White solid; yield: 2.00 g (78%); mp 140–141 °C.
1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H),
7.28 (d, J = 8.4 Hz, 2 H), 3.12 (s, 3 H), 3.01 (s, 3 H), 2.69 (q, J = 7.6 Hz, 2
H), 1.24 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.1, 148.6, 139.7, 128.2, 126.6, 41.5,
35.5, 28.8, 15.3.
IR (neat): 3185, 2967, 1350, 1135, 843 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.35 (br s, 1 H), 3.48 (sept, J = 6.8
Hz, 2 H), 1.29 (d, J = 6.8 Hz, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 55.2, 16.4.
HRMS (FAB): m/z [M + H]+ calcd for C6H15NO4S2 + H: 230.0521; found:
230.0523.
HRMS (EI): m/z [M]+ calcd for C11H16N2O2S: 240.0932; found:
240.0934.
N-[(Phenylmethyl)sulfonyl]benzylsulfonamide (1k) CAS Reg. No.
856359-56-3
N,N-Dimethyl-N′-(4-tert-butylphenylsulfonyl)formimidamide(4d)
CAS Reg. No. 2089434-81-9
White solid; yield: 2.19 g (60%); mp 160–161 °C.
White solid; yield: 0.397 g (88%); mp 160–161 °C; Rf = 0.45 (hex-
ane/EtOAc 1:1, v/v).
IR (neat): 3095, 1356, 1134, 850 cm–1
.
IR (neat): 2960, 1629, 1297, 1152, 1107, 915, 830 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.38–7.27(m, 10 H), 6.14 (br s, 1 H),
1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.81 (d, J = 8.4 Hz, 2 H),
7.47 (d, J = 8.4 Hz, 2 H), 3.12 (s, 3 H), 3.02 (s, 3 H), 1.33 (s, 9 H).
4.36 (s, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 132.1, 131.4, 128.4, 127.9, 59.8.
13C NMR (100 MHz, CDCl3): δ = 159.2, 155.5, 139.4, 126.3, 125.7, 41.5,
HRMS (FAB): m/z [M + H]+ calcd for C14H15NO4S2 + H: 326.0521;
35.5, 35.0, 31.1.
found: 326.0519.
HRMS (EI): m/z [M]+ calcd for C13H20N2O2S: 268.1245; found:
N-Sulfonylformamidines 4; General Procedure
268.1243.
To a solution of N-sulfonylsulfonamide 1 (1.68 mmol) in N,N-disubsti-
tuted formamide 3 (3.0 mL) was added TsCl (2; 0.160 g, 0.840 mmol;
0.480 g, 2.52 mmol for products 4d–g) and Et3N (0.29 mL, 2.10
mmol). The mixture was stirred at r.t. (or heated to 100 °C in the cases
of 4d–g,k). After the starting material was consumed as indicated by
TLC, the reaction mixture was poured into H2O and extracted with
CH2Cl2. The combined organic phases were washed with H2O, dried
(anhydrous MgSO4), filtered, and concentrated under reduced pres-
sure. The crude product was purified, if necessary, by silica gel flash
column chromatography (hexane/EtOAc) to give the desired product
as a white solid (Table 2).
N,N-Dimethyl-N′-(4-nitrophenylsulfonyl)formimidamide (4e)4b
CAS Reg. No. 29912-59-2
White solid; yield: 0.264 g (61%); mp 186.5–187.5 °C; Rf = 0.20 (hex-
ane/EtOAc 1:1, v/v).
1H NMR (400 MHz, DMSO-d6): δ = 8.35 (d, J = 8.8 Hz, 2 H), 8.27 (s, 1
H), 8.03 (d, J = 8.8 Hz, 2 H), 3.17 (s, 3 H), 2.93 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 160.7, 149.6, 149.0, 128.0, 124.9,
41.6, 35.7.
N,N-Dimethyl-N′-(4-acetylphenylsulfonyl)formimidamide (4f)
N,N-Dimethyl-N′-tosylformimidamide (4a)4b CAS Reg. No. 25770-
White solid; yield: 0.325 g (76%); mp 154–155 °C; Rf = 0.20 (hex-
53-0
ane/EtOAc 1:1, v/v).
IR (neat): 2929, 1691, 1632, 1246, 1149, 907, 831 cm–1
.
White solid; yield: 0.369 g (97%); mp 136–137 °C; Rf = 0.15 (hex-
ane/EtOAc 1:1, v/v).
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.77 (d, J = 8.0 Hz, 2 H),
7.26 (d, J = 8.0 Hz, 2 H), 3.12 (s, 3 H), 3.01 (s, 3 H), 2.40 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H),
7.98 (d, J = 8.8 Hz, 2 H), 3.16 (s, 3 H), 3.04 (s, 3 H), 2.64 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 197.1, 159.4, 146.3, 139.4, 128.7,
13C NMR (100 MHz, CDCl3): δ = 159.1, 142.5, 139.6, 129.3, 126.5, 41.5,
126.8, 41.7, 35.7, 26.9.
35.5, 21.5.
HRMS (EI): m/z [M]+ calcd for C11H14N2O3S: 254.0725; found:
254.0723.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
Y. Jeong et al.
Paper
Synthesis
N,N-Dimethyl-N′-(4-chlorophenylsulfonyl)formimidamide (4g)4b
4-Methyl-N-(pyrrolidinomethylene)benzenesulfonamide (4m)4b
CAS Reg. No. 29619-30-5
CAS Reg. No. 57988-74-6
White solid; yield: 0.414 g (quant); mp 109–110 °C; Rf = 0.35 (hex-
White solid; yield: 0.411 g (97%); mp 139–140 °C; Rf = 0.20 (hex-
ane/EtOAc 1:1, v/v).
ane/EtOAc 1:1, v/v).
1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.82 (d, J = 8.4 Hz, 2 H),
7.43 (d, J = 8.4 Hz, 2 H), 3.15 (s, 3 H), 3.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.2, 141.0, 138.1, 129.0, 128.0, 41.6,
1H NMR (400 MHz, CDCl3): δ = 8.32 (s, 1 H), 7.78 (d, J = 8.4 Hz, 2 H),
7.25 (d, J = 8.4 Hz, 2 H), 3.60–3.57 (m, 2H), 3.48–3.45 (m, 2H), 2.40 (s,
3 H), 1.97–1.94 (m, 4 H).
35.6.
13C NMR (100 MHz, CDCl3): δ = 155.8, 142.4, 139.7, 129.3, 126.6, 50.0,
46.5, 25.0, 24.4, 21.5.
N,N-Dimethyl-N′-(4-methoxyphenylsulfonyl)formimidamide
(4h)4b CAS Reg. No. 1344029-97-5
4-Methyl-N-(piperidinomethylene)benzenesulfonamide (4n)4b
CAS Reg. No. 27049-60-1
White solid, yield: 0.358 g (88%); mp 152–153 °C; Rf = 0.20 (hex-
ane/EtOAc 1:1, v/v).
White solid; yield: 0.403 g (90%); mp 148–149 °C; Rf = 0.13 (hex-
ane/EtOAc 1:2, v/v).
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.82 (d, J = 8.8 Hz, 2 H),
6.94 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H), 3.12 (s, 3 H), 3.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 158.9, 134.4, 128.5, 113.9, 55.6,
1H NMR (400 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.77 (d, J = 8.4 Hz, 2 H),
7.26 (d, J = 8.4 Hz, 2 H), 3.61–3.58 (m, 2H), 3.42–3.40 (m, 2H), 2.40 (s,
3 H), 1.71–1.63 (m, 4 H), 1.61–1.56 (m, 2 H).
41.4, 35.5.
13C NMR (100 MHz, CDCl3): δ = 157.2, 142.4, 139.7, 129.3, 126.5, 51.9,
44.7, 26.4, 24.9, 24.0, 21.6.
N,N-Dimethyl-N′-(methylsulfonyl)formimidamide (4i) CAS Reg.
No. 52776-60-0
4-Methyl-N-(morpholinomethylene)benzenesulfonamide (4o)4b
CAS Reg. No. 15294-84-5
White solid; yield: 0.252 g (quant); mp 80–81 °C; Rf = 0.20 (hex-
ane/EtOAc 1:1, v/v).
White solid; yield: 0.298 g (66%); mp 169–170 °C; Rf = 0.30 (hex-
ane/EtOAc 1:2, v/v).
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1 H), 7.77 (d, J = 7.6 Hz, 2 H),
7.27 (d, J = 7.6 Hz, 2 H), 3.76–3.74 (m, 2H), 3.68–3.67 (m, 4 H), 3.50–
3.48 (m, 2H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.6, 142.7, 139.2, 129.4, 126.6, 66.8,
65.9, 50.3, 44.2, 21.5.
IR (neat): 2391, 1627, 1270, 1110, 964 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 1 H), 3.05 (s, 3 H), 2.94 (s, 3 H),
.
2.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.3, 42.0, 41.4, 35.4.
HRMS (EI): m/z [M]+ calcd for C4H10N2O2S: 150.0463; found:
150.0464.
N,N-Dimethyl-N′-(isopropylsulfonyl)formimidamide (4j)
Colorless oil; yield: 0.252 g (84%); Rf= 0.20 (hexane/EtOAc 1:2, v/v).
Funding Information
IR (neat): 2977, 2937, 1619, 1250, 1108, 902, 843 cm–1
.
This research was supported by the Basic Science Research Program
administered through the National Research Foundation of Korea
1H NMR (400 MHz, CDCl3): δ = 7.99 (s, 1 H), 3.11 (s, 1 H), 3.10 (sept, J =
6.8 Hz, 3 H), 3.03 (s, 3 H), 1.32 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 53.4, 41.3, 35.4, 16.7.
HRMS (EI): m/z [M]+ calcd for C6H14N2O2S: 178.0776; found:
178.0777.
(NRF),
funded
by
the
Ministry
of
Education
(2015R1D1A1A09058536) and by the Korean Ministry of Education
through the BK21-Plus project of the Hanyang University Graduate
Program.
)(
N,N-Dimethyl-N′-[(phenylmethyl)sulfonyl]formimidamide (4k)4b
CAS Reg. No. 90873-49-7
Acknowledgment
White solid, yield: 0.293 g (77%); mp 136–137 °C; Rf = 0.20 (hex-
ane/EtOAc 1:2, v/v).
We acknowledge the Daegu Center of KBSI for the HRMS data.
1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H), 7.37–7.32 (m, 5 H), 4.26
(s, 2 H), 2.99 (s, 3 H), 2.93 (s, 3 H).
Supporting Information
13C NMR (100 MHz, CDCl3): δ = 160.3, 130.9, 130.3, 128.4, 128.3, 59.7,
41.1, 35.3.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591936.
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p
p
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N,N-Diethyl-N′-tosylformimidamide (4l)4b CAS Reg. No. 29397-20-4
References
White solid; yield: 0.350 g (82%); mp 75–76 °C; Rf = 0.40 (hex-
ane/EtOAc 1:1, v/v).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H