Synthesis of six-membered cyclic sulfonimidamides

Article abstract of DOI:10.1055/s-0033-1339760

A general synthetic route to six-membered cyclic N-aryl- and N-alkyl-substituted sulfonimidamides via an intramolecular ring closure of suitably functionalised acyclic sulfonimidamides is described. The structure of this new ring system was confirmed by v

Full text of DOI:10.1055/s-0033-1339760

3018▌
PAPER
paper
Synthesis of Six-Membered Cyclic Sulfonimidamides
Synthesis of Six-Membered Cyclic Sulfonimidamides
Indira Sen,a Daniel P. Kloer,b Roger G. Hall,c Sitaram Pal*a
a
Syngenta Biosciences Pvt. Ltd., Santa Monica Works, Corlim, Ilhas, Goa 403110, India
Fax +91(832)2490525; E-mail: sitaram.pal@syngenta.com
b
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
E-mail: daniel.kloer@syngenta.com
c
Syngenta Crop Protection Münchwilen AG, Schaffhauserstrasse, 4332 Stein / AG, Switzerland
E-mail: roger_g.hall@syngenta.com
Received: 07.06.2013; Accepted after revision: 16.08.2013
thionylanilines 6,12 which were conveniently prepared
from the reaction of anilines with thionyl chloride as
shown in Scheme 213 (Table 1). For the synthesis of N-al-
kyl derivatives a different strategy was used to prepare
Abstract: A general synthetic route to six-membered cyclic N-aryl-
and N-alkyl-substituted sulfonimidamides via an intramolecular
ring closure of suitably functionalised acyclic sulfonimidamides is
described. The structure of this new ring system was confirmed by
various analytical methods and in one example by X-ray structural sulfinamides 2. Sulfinamides 2l–m were prepared from
phenylsulfonyl chloride by the method,14 which involves
analysis.
in situ reduction of the sulfonyl chloride to sulfinyl chlo-
ride and coupling with amines 1 (Scheme 3).
Key words: sulfonimidamide, heterocycles, cyclisation, sulfur, in-
tramolecular
H
O
N
R1
S
Sulfonimidamides are derivatives of sulfonic acid and an-
alogues of sulfonamides. They are known since early
1960 when the first report was published by Levchenko et
al.1 Although known for sometime, the attention given to
sulfonimidamides has been modest until recently; early
reports described the preparation2 and exploration of the
chemistry of such systems.3 Most of the recent reports de-
scribe the use of sulfonimidamides as reagents in organic
synthesis such as a source of nitrogen for metal-catalysed
nitrene transfer reactions,4 aziridination of olefins,5 as chi-
ral organocatalysts,6 or as ligands for transition metal-ca-
talysed asymmetric synthesis.7 There are also reports
which describe the use of sulfonimidamides as potential
pharmaceutical8 or as potential crop protecting agents.9
Constraining this functionality within a ring system via
the N–S–N system has received little attention with only
two reports of five-membered ring systems being pub-
lished.10,11 The most recent publication11 has prompted us
to report our own research into such ring systems, and we
now describe our investigations into six-membered cyclic
sulfonimidamides 5.
R2
H
N
R2
N
R1
S
R1 NH2
O
1
O
2
O
3
H
N
O
R2
R1
S
O
R2
S
R1
O
N
N
N
O
HO
5
4
Scheme 1 General scheme for the synthesis of cyclic sulfonimidam-
ides
O
R1
S
R1MgX
7
NH2
NSO
NH
SOCl2
THF
0 °C to r.t.
2 h
toluene
reflux
2–3 h
R2
R2
R2
1
2a–k
6
Our strategy focused on the construction of the ring sys-
tem by an intramolecular ring closure, via nitrogen, of
suitably functionalised acyclic sulfonimidamides. The lat-
ter could be obtained from the reaction of sulfonimidoyl
chlorides (prepared in situ) with a β-amino ester (Scheme
1). We were keen to prepare such rings containing the am-
ide functionality, as this would hopefully enable further
derivatisation of these rings.
Scheme 2 Synthesis of N-aryl sulfinamides (Table 1)
O
O
Cl
S
R
S
Ph3P, Et3N
N
R
O
H
+
H2N
CH2Cl2, 0 °C
2 h
1
8
2l: R = t-Bu, 71%
2m: R = i-Pr, 58%
The synthesis of intermediate N-aryl sulfinamides 2a–k
was achieved by the addition of a Grignard reagent 7 to N-
Scheme 3 Synthesis of N-alkyl sulfinamides
The synthesis of cyclic sulfonimidamides 5 is shown in
Scheme 4 (Table 2). Oxidative chlorination using tert-bu-
tyl hypochlorite (t-BuOCl) of sulfinamides 2 generates
SYNTHESIS 2013, 45, 3018–3028
Advanced online publication: 10.09.2013
DOI: 10.1055/s-0033-1339760; Art ID: SS-2013-T0397-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Synthesis of Six-Membered Cyclic Sulfonimidamides
3019
the sulfonimidoyl chlorides, which are further treated
without isolation with β-alanine ethyl ester HCl salt in the
presence of base to give the sulfonimidamides 3 in 35–
66% yields.15 Attempted cyclisation of sulfonimidamides
3 under a variety of conditions16 failed to give 5. We next
turned our attention to obtain the cyclic sulfonimidamides
5 via the corresponding acids 4; these compounds were
prepared by basic hydrolysis of esters 3 in good to excel-
lent yields (Table 2). The cyclisation of acids 4 was then
investigated. Treatment of 4a with Mukaiyama’s reagent
indeed led to the formation of the six-membered ring 5a;
however, separation of 5a from the by-product proved te-
dious. We were then pleased to find that when acids 4
were subjected to intramolecular cyclisation using 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI) and 1-hydroxybenzotriazole hydrate (HOBt),
the cyclised products 5 were formed and could be readily
isolated by chromatography (Table 2). The yields in the fi-
nal cyclisation step illustrate the impact of steric effects,
that is, when R1 = tert-butyl, it was not possible to isolate
any cyclised product; however, with R1 = isopropyl, the
cyclisation proceeded in 55% yield.
Table 1 Substrate Scope for N-Aryl Sulfinamides 2a–k
Entry
R1
R2
Yield of 2 (%)a
1
2
Et
H
2a, 83
2b, 88
2c, 80
2d, 95
2e, 95
2f, 82
2g, 86
2h, 75
2i, 53
2j, 95
2k, 80
Et
4-Br
4-Me
4-OMe
2-Me
2,6-Me2
H
3
Et
4
Et
5
Et
6
Et
7
c-C3H5
CH(Me)Et
CH(Me)Et
i-Pr
8
4-F
9
2-OMe
H
10
11
Bn
H
a Isolated yields by CombiFlash chromatography over two steps.
t-BuOCl, CCl4, 1.5 h
H
O
H
O
O
N
R1
S
N
EDCI, HOBt
Et3N, CH2Cl2
O
R2
N
R1
R2
LiOH•H2O
S
O
R2
R2
R1
O
S
N
NH2•HCl
THF–H2O
O
S
N
N
O
O
NH
r.t., 3–4 h
r.t., 12 h
Et3N, CCl4
0 °C to r.t., 12 h
R1
2
O
5
HO
4
3
Scheme 4 Synthesis and cyclisation of sulfonimidamides (Table 2)
Table 2 Substrate Scope for Alkyl and Aryl Sulfonimidamides
Entry
R1
R2
Yield of 3 (%)a
Yield of 4 (%)b
Yield of 5 (%)a
5 Mp (°C)
1
2
Ph
Et
3a, 55
3b, 56
3c, 35
3d, 35
3e, 35
3f, 57
3g, 58
3h, 60
3i, 66
3j, 40
3k, 46
3l, 66
3m, 56
4a, 85
4b, 90
4c, 92
4d, 90
4e, 90
4f, 70
4g, 85
4h, 85
4i, 90
4j, 72
4k, 84
4l, 70
4m, 90
5a, 76
5b, 65
5c, 60
5d, 60
5e, 55
5f, 45
5g, 60
5h, 55
5i, 50
5j, 71
5k, 70
5l, 0
103–105
114–116
88–90
80–82
oil
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
2,6-Me2C6H3
Ph
Et
3
Et
4
Et
5
Et
6
Et
oil
7
c-C3H5
CH(Me)Et
CH(Me)Et
i-Pr
126–128
167–169
oil
8
4-FC6H4
2-MeOC6H4
Ph
9
10
11
12
13
144–146
184–186
–
Ph
Bn
t-Bu
Ph
i-Pr
Ph
5m, 55
81–83
a Isolated yields by CombiFlash chromatography.
b Isolated yields by acid-base workup.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3018–3028

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I. Sen et al.
PAPER
The synthesis of these ring systems using a substituted β-
amino ester was also investigated. Reaction of sulfin-
amide 2c with t-BuOCl gave the sulfonimidoyl chloride,
which was treated with racemic ethyl 3-aminobutyrate.
After hydrolysis and ring closure as described above, a 1:1
mixture of diastereomers 5n and 5o (Figure 1) was ob-
tained, which could be readily separated by chromatogra-
phy. The absolute configurations of these structures have
not been assigned.
Table 3 Comparison of Bond Lengths and Angles Around the Sulfur
in 5j
CSDa
5j
Bond length S1–N3
1.67 ± 0.04 Å
1.54 ± 0.04 Å
117.0 ± 4.4°
1.705 Å
1.510 Å
116.96°
Bond length S1=N14
Bond angle S1=N14–C13
a The median values from 6 structures in the Cambridge Structure Da-
tabase containing the acyclic N–S=N fragment is provided for com-
parison.
O
O
S
S
N
N
N
N
molecules 5j revealed a nonplanar geometry of the hetero-
cyclic ring. Currently, we are exploring the chemistry of
such ring systems, and in addition investigating the syn-
thesis of five- and seven-membered ring systems.
O
O
Figure 1 Products 5n and 5o
The geometry of the six-membered ring was confirmed by
X-ray structure analysis of 5j. This showed the ring to
have an envelope shape, with five atoms (C12, C10, N3,
S1, and N14) co-planar, and one atom C13 significantly
out of the plane (Figure 2). The phenyl ring is perpendic-
ular to the plane of the ring. Bond distances for the S=N
and S–N bonds are in agreement with values observed in
similar compounds reported in the Cambridge Crystallo-
graphic Database (Table 3).
All the chemical reagents were purchased and used as received, un-
less otherwise indicated. Grignard reagent used was EtMgBr (3.40
1
M solution in Et2O, Aldrich), unless otherwise noted. H and 13C
NMR spectra were recorded on a Bruker Avance II-400 spectrome-
ter and all chemical shift values refer to δTMS = 0.00 or CDCl3 δΗ =
7.26; δC, 77.1. The HRMS analyses were performed on an Agilent
QTOF 6520 mass spectrometer and LCMS on THERMO MSQ
PLUS mass spectrometer. IR spectra were recorded on Shimadzu
DRS Prestige 21 spectrophotometer. Column chromatographic pu-
rifications were performed on a CombiFlash Rf (Teledyne Isco)
with silica gel using the indicated mobile phase.
N-Phenylethanesulfinamide (2a);17a Typical Procedure
Method A: To a stirred solution of aniline (1a; 2.00 g, 21.5 mmol)
in anhydrous toluene (10 mL) at r.t. was added a solution of SOCl2
(3.29 g, 2.00 mL, 27.9 mmol) in anhydrous toluene (10 mL). This
suspension was refluxed for 2–3 h under N2 atmosphere, whereupon
a clear solution was observed. All the volatiles were removed by re-
ducing under pressure to afford the crude N-thionylaniline 6a,
which was dissolved in anhydrous THF (10 mL). To this solution
was added at 0 °C commercial EtMgBr solution in Et2O (9.47 mL,
32.2 mmol, 3.40 M) under N2 atmosphere. The reaction mixture was
stirred at 0 °C for 1 h, and then at r.t. for 1 h, under N2 atmosphere.
The mixture was quenched by sat. aq NH4Cl (50 mL) and extracted
with EtOAc (3 × 100 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude product was purified by CombiFlash chromatography (silica
gel, n-hexane–EtOAc, 4:1) to afford the desired sulfinamide 2a;
yield: 3.00 g (83%); sticky yellow solid.
IR (KBr): 3153, 1598, 1490, 1411, 1232, 1060, 1022, 885, 750, 696,
516 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H, CH3),
2.87–2.99 (m, 2 H, SCH2), 6.50 (br s, 1 H, NH), 6.90–7.00 (m, 3 H,
ArH), 7.17–7.22 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.7, 49.4, 117.8, 120.2, 122.9,
129.5, 141.4.
Figure 2 Crystal structure of 5j ORTEP-style diagram with non-hy-
ESI-MS: m/z = 170.06 [M + H]+.
drogen atoms shown at 50% probability, atom numbering is arbitrary
N-(4-Bromophenyl)ethanesulfinamide (2b)
From 4-bromoaniline (3.67 g, 21.5 mmol); yield: 4.60 g (88%); yel-
low solid; mp 65–68 °C.
IR (KBr): 3136, 1589, 1489, 1381, 1298, 1176, 1116, 821 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.6 Hz, 3 H, CH3),
2.92–2.94 (m, 2 H, SCH2), 6.86–6.90 (m, 2 H, ArH), 7.05 (br s, 1 H,
NH), 7.30–7.34 (m, 2 H, ArH).
In summary, we have developed a general and straightfor-
ward route to access six membered cyclic sulfonimidam-
ides. The structures of these molecules have been fully
characterised; X-ray crystallographic data of one of the
Synthesis 2013, 45, 3018–3028
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Synthesis of Six-Membered Cyclic Sulfonimidamides
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13C NMR (100 MHz, CDCl3): δ = 7.6, 49.5, 115.5, 119.7, 132.3,
140.6.
ESI-MS: m/z = 245.87, 247.87 ([ M – H]+ for 79Br and 81Br).
N-(4-Fluorophenyl)butane-2-sulfinamide (2h)
From 4-fluoroaniline (2.38 g, 21.5 mmol) and Me2CHCH2MgCl
(16.1 mL, 32.2 mmol, 2.00 M in THF); yield: 3.50 g (75%); white
solid; mp 78–80 °C.
N-(p-Tolyl)ethanesulfinamide (2c)17b
From p-toluidine (2.30 g, 21.5 mmol); yield: 3.20 g (80%); white
solid; mp 65–68 °C.
IR (KBr): 3454, 1645, 1511, 1216, 1080, 1047, 895, 821, 759 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.02–1.04 (m, 3 H, CH3), 1.07–
1.09 (m, 3 H, CH3), 2.10–2.16 (m, 1 H, SCH), 2.78–2.91 (m, 2 H,
CH2), 6.89–6.99 (m, 4 H, ArH), 7.00 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): δ = 21.8, 22.3, 24.6, 64.6, 115.9,
116.1, 120.5, 137.2, 157.9, 160.3.
IR (KBr): 3134, 2933, 1612, 1514, 1284, 1236, 1055, 896, 808, 671,
522 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H, CH3), 2.28
(s, 2 H, ArCH3), 2.88–3.04 (m, 2 H, SCH2), 6.54 (br s, 1 H, NH),
6.92–6.97 (m, 2 H, ArH), 7.04–7.06 (m, 2 H, ArH).
ESI-MS: m/z = 216.08 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 7.5, 20.6, 49.4, 119.1, 129.8,
132.9, 138.4.
ESI-MS: m/z = 183.89 [M + H]+.
N-(2-Methoxyphenyl)butane-2-sulfinamide (2i)
From o-anisidine (2.64 g, 21.5 mmol) and Me2CHCH2MgCl (16.1
mL, 32.2 mmol, 2.00 M in THF); yield: 2.60 g (53%); yellow solid;
mp 78–80 °C.
IR (KBr): 3772, 1596, 1495, 1250, 1048, 882, 742, 562 cm–1.
N-(4-Methoxyphenyl)ethanesulfinamide (2d)
From p-anisidine (2.64 g, 21.5 mmol); yield: 4.10 g (95%); yellow
solid; mp 77–79 °C.
1H NMR (400 MHz, CDCl3): δ = 1.02–1.04 (m, 6 H, 2 × CH3),
2.08–2.15 (m, 1 H, SCH), 2.73–2.84 (m, 2 H, CH2), 3.75 (s, 3 H,
OCH3), 6.36 (br s, 1 H, NH), 6.76–6.79 (m, 1 H, ArH), 6.81–6.92
(m, 2 H, ArH), 7.16–7.19 (dd, J = 1.6, 8.0 Hz, 1 H, ArH).
IR (KBr): 3122, 1508, 1456, 1303, 1240, 1110, 1035, 898, 823, 684
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.6 Hz, 3 H, CH3),
2.84–3.01 (m, 2 H, SCH2), 3.75 (s, 3 H, OCH3), 6.54 (br s, 1 H, NH),
6.71–6.81 (m, 2 H, ArH), 6.98–7.02 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.6, 49.3, 55.5, 114.6, 121.9,
133.8, 156.4.
13C NMR (100 MHz, CDCl3): δ = 21.9, 22.5, 24.5, 55.7, 65.3, 110.9,
117.0, 121.2, 123.0, 130.7, 148.7.
ESI-MS: m/z = 227.81 [M + H]+.
N-Phenylpropane-2-sulfinamide (2j)17c
From aniline (2.00 g, 21.5 mmol) and Me2CHMgCl (16.1 mL, 32.2
mmol, 2.00 M in THF); yield: 3.73 g (95%); white solid; mp 65–
67 °C.
ESI-MS: m/z = 200.06 [M + H]+.
N-(o-Tolyl)ethanesulfinamide (2e)
From o-toluidine (2.30 g, 21.5 mmol); yield: 3.80 g (95%); yellow
oil.
IR (film): 3184, 1495, 1242, 1064, 1030, 891, 748 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.2 Hz, 3 H, CH3), 2.24
(s, 3 H, ArCH3), 2.99–3.02 (m, 2 H, SCH2), 6.18 (br s, 1 H, NH),
6.98–7.00 (m, 1 H, ArH), 7.14–7.16 (m, 2 H, ArH), 7.25–7.26 (m,
1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.5, 17.8, 49.8, 119.5, 123.9,
127.0, 128.3, 130.9, 139.3.
IR (KBr): 3169, 1598, 1498, 1475, 1402, 1280, 1226, 1049, 873,
754, 696, 509 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.35 (m, 6 H, 2 × CH3), 2.96–3.03
(m, 1 H, SCH), 5.90 (br s, 1 H, NH), 7.00–7.04 (m, 3 H, ArH), 7.24–
7.28 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 15.8, 16.2, 54.4, 117.9, 122.5,
129.0, 142.1.
ESI-MS: m/z = 184.06 [M + H]+.
N,1-Diphenylmethanesulfinamide (2k)17d
From aniline (915 mg, 9.84 mmol) and BnMgCl (7.38 mL, 14.7
mmol, 2.00 M in THF); yield: 1.82 g (80%); white solid; mp 138–
140 °C.
ESI-MS: m/z = 184.20 [M + H]+.
N-(2,6-Dimethylphenyl)ethanesulfinamide (2f)
From 2,6-dimethylaniline (2.60 g, 21.5 mmol); yield: 3.50 g (82%);
white solid; mp 68–70 °C.
IR (KBr): 3180, 1478, 1401, 1197, 1042, 880, 780, 636 cm–1.
IR (KBr): 3219, 3059, 1598, 1496, 1444, 1419, 1157, 1055, 985,
746, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.80–3.85 (dd, J = 7.2, 13.2 Hz, 1
H, SCH2), 4.16–4.20 (dd, J = 5.2, 13.2 Hz, 1 H, SCH2), 4.26 (br s,
1 H, NH), 7.18–7.26 (m, 3 H, ArH), 7.40–7.47 (m, 3 H, ArH), 7.69–
7.72 (dd, J = 1.6, 8.0 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 44.7, 126.0, 127.7, 128.3, 128.7,
128.9, 131.0, 137.7, 144.0.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H, CH3), 2.26
(s, 6 H, 2 × ArCH3), 2.89–2.97 (m, 2 H, SCH2), 5.40 (br s, 1 H, NH),
6.89–6.98 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.5, 17.6, 19.1, 50.6, 126.0, 128.4,
126.0, 128.4, 128.8, 133.6, 137.3, 137.5.
ESI-MS: m/z = 198.13 [M + H]+.
ESI-MS: m/z = 232.07 [M + H]+.
N-Phenylcyclopropanesulfinamide (2g)
N-tert-Butylbenzenesulfinamide (2l);14a Typical Procedure
Method B: To a stirred solution of benzenesulfonyl chloride (5.00 g,
28.4 mmol) and Et3N (5.73 g, 7.86 mL, 56.8 mmol) in CH2Cl2 (75
mL) at 0 °C under N2 atmosphere was added a solution of Ph3P
(7.44 g, 28.4 mmol) and tert-butylamine (2.07 g, 2.98 mL, 28.4
mmol) in CH2Cl2 (75 mL) using a syringe pump over a period of 1
h. The reaction mixture was stirred under N2 atmosphere for 1 h and
monitored by TLC (eluent: hexane–EtOAc, 3:2). After completion,
the reaction mixture was concentrated under reduced pressure. The
crude product was purified by CombiFlash chromatography (silica
gel, n-hexane–EtOAc, 4:1) to afford the desired sulfinamide 2l;
yield: 4.00 g (71%); white solid; mp 55–58 °C.
From aniline (2.00 g, 21.5 mmol) and cyclopropylmagnesium bro-
mide (64.4 mL, 32.2 mmol, 0.50 M in THF); yield: 3.40 g (86%);
white solid; mp 84–86 °C.
IR (KBr): 3153, 1598, 1498, 1400, 1232, 1064, 889, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88–0.94, 1.33–1.36 (m, 4 H, 2 ×
cyclopropyl CH2), 2.34–2.38 (m, 1 H, SCH), 5.99 (br s, 1 H, NH),
7.02–7.08 (m, 3 H, ArH), 7.26–7.30 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 0.0, 4.5, 32.2, 119.8, 124.4, 130.6,
142.0.
ESI-MS: m/z = 182.15 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3018–3028

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I. Sen et al.
PAPER
IR (KBr): 3178, 2972, 1473, 1444, 1234, 1082, 1047, 744, 686
cm–1.
IR (film): 3336, 2981, 2939, 1732, 1506, 1309, 1186, 1055, 786
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.41 [s, 9 H, C(CH3)3], 3.85 (br s,
1 H, NH), 7.46–7.48 (m, 3 H, ArH), 7.68–7.70 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 31.1, 54.3, 125.6, 128.7, 130.9,
146.6.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3 H, CH3), 1.41
(t, J = 7.2 Hz, 3 H, CH3), 2.21 (s, 3 H, ArCH3), 2.41–2.45 (m, 2 H,
CH2), 3.19–3.23 (m, 2 H, CH2), 3.30–3.36 (m, 2 H, CH2), 4.06–4.10
(m, 2 H, CO2CH2), 6.94–6.97 (m, 4 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.5, 13.1, 40.4, 40.6, 45.6, 48.9,
59.6, 122.0, 122.2, 128.5, 130.3, 140.1, 170.3.
ESI-MS: m/z = 198.45 [M + H]+.
N-Isopropylbenzenesulfinamide (2m)14b
From benzenesulfonyl chloride (4.97 g, 28.2 mmol) and isopropyl-
amine (1.66 g, 2.30 mL, 28.2 mmol); yield: 3.00 g (58%); yellow
oil.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O3S: 299.1420; found:
299.1423.
Ethyl 3-{[Ethyl(4-methoxyanilino)oxo-1λ6-sulfanylidene]ami-
no}propanoate (3d)
From 2d (915 mg, 4.60 mmol); yield: 500 mg (35%); yellow oil.
IR (film): 3273, 2982, 1729, 1505, 1313, 1237, 1053, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3 H, CH3), 1.40
(t, J = 6.2 Hz, 3 H, CH3), 2.40–2.44 (m, 2 H, SCH2), 3.16–3.23 (m,
2 H, NCH2), 3.29–3.32 (m, 2 H, COCH2), 3.47 (s, 3 H, OCH3),
4.05–4.11 (m, 2 H, CO2CH2), 6.75–6.77 (m, 2 H, ArH), 7.01–7.03
(m, 2 H, ArH).
IR (film): 3202, 2968, 1444, 1244, 1086, 1051, 874, 751, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (d, J = 6.4 Hz, 3 H, CH3), 1.28
(d, J = 6.4 Hz, 3 H, CH3), 3.55–3.64 (m, 1 H, SCH), 3.88 (br s, 1 H,
NH), 7.45–7.50 (m, 3 H, ArH), 7.68–7.84 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 24.5, 24.8, 46.2, 125.7, 128.7,
130.7, 145.3.
ESI-MS: m/z = 183.9 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 8.2, 14.2, 34.8, 39.3, 48.8, 55.4,
60.9, 114.3, 124.5, 136.6, 155.1, 172.1.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O4S: 315.1372; found:
315.1367.
Ethyl 3-[(Anilineethyloxo-1λ6-sulfanylidene)amino]propanoate
(3a); Typical Procedure
To a stirred solution of the sulfinamide 2a (2.00 g, 11.8 mmol) in
CCl4 (20 mL) cooled to 0 °C in an round-bottomed flask covered
with aluminum foil was added dropwise tert-butyl hypochlorite17e
(1.91 g, 17.7 mmol) in CCl4 (5 mL) and the reaction mixture was
stirred for 1.5 h at 0 °C under N2 atmosphere. The mixture was then
concentrated under reduced pressure, maintaining an atmosphere of
N2 and the residue dissolved in CCl4 (25 mL). To this solution was
added β-alanine ethyl ester hydrochloride (4.51 g, 29.5 mmol), Et3N
(8.36 g, 11.4 mL, 82.8 mmol) in CCl4 (20 mL) at 10–15 °C. The
mixture was stirred at r.t. for 12 h under N2 atmosphere, diluted with
H2O (50 mL), and extracted with EtOAc (3 × 70 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude product was purified by Combi-
Flash chromatography (silica gel, n-hexane–EtOAc, 7:3) to afford
the desired product 3a; yield: 1.85 g (55%); yellow oil.
Ethyl 3-{[Ethyl(2-methylanilino)oxo-1λ6-sulfanylidene]ami-
no}propanoate (3e)
From 2e (3.00 g, 16.3 mmol); yield: 1.70 g (35%); yellow oil.
IR (film): 3286, 2980, 1732, 1489, 1311, 1188, 1056, 759 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.6 Hz, 3 H, CH3), 1.44
(t, J = 7.6 Hz, 3 H, CH3), 2.25 (s, 3 H, ArCH3), 2.42–2.46 (m, 2 H,
NCH2), 3.20–3.25 (m, 2 H, SCH2), 3.28–3.33 (m, 2 H, COCH2),
4.06–4.12 (m, 2 H, CO2CH2), 4.65 (br s, 1 H, NH), 6.85–6.89 (m, 1
H, ArH), 7.01–7.05 (m, 1 H, ArH), 7.10–7.12 (m, 1 H, ArH), 7.21–
7.23 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 8.7, 14.1, 18.4, 34.7, 39.3, 49.5,
60.9, 122.0, 122.3, 126.2, 130.3, 132.2, 142.2, 172.2.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O3S: 299.1423; found:
IR (film): 3271, 2981, 2939, 1732, 1595, 1489, 1305, 1186, 1055,
912, 758, 731, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H, CH3), 1.42
(t, J = 7.2 Hz, 3 H, CH3), 2.40–2.45 (m, 2 H, NCH2), 3.20–3.24 (m,
2 H, SCH2), 3.31–3.34 (m, 2 H, COCH2), 4.07–4.11 (m, 2 H,
CO2CH2), 6.93–6.97 (m, 1 H, ArH), 7.09–7.11 (m, 2 H, ArH), 7.18–
7.25 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.2, 13.1, 33.6, 38.2, 48.1, 59.9,
121.0, 122.4, 128.0, 142.7, 171.1.
299.1419.
Ethyl 3-{[(2,6-Dimethylanilino)ethyloxo-1λ6-sulfanylidene]ami-
no}propanoate (3f)
From 2f (1.61 g, 8.21 mmol); yield: 1.46 g (57%); yellow oil.
IR (film): 2980, 1729, 1471, 1301, 1203, 1184, 1104s, 1058, 767
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3 H, CH3), 1.49
(t, J = 7.2 Hz, 3 H, CH3), 2.33 (s, 6 H, 2 × ArCH3), 2.38–2.41 (m, 2
H, NCH2), 3.24–3.30 (m, 4 H, SCH2, COCH2), 4.02–4.14 (m, 2 H,
CO2CH2), 4.58 (br s, 1 H, NH), 6.82–6.86 (m, 1 H, ArH), 6.96–6.99
(m, 2 H, ArH).
HRMS (EI): m/z [M + H]+ calcd for C13H20N2O3S: 285.1267; found:
285.1261.
Ethyl 3-{[(4-Bromoanilino)ethyloxo-1λ6-sulfanylidene]ami-
no}propanoate (3b)
From 2b (1.57 g, 6.40 mmol); yield: 1.30 g (56%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 9.2, 14.2, 19.6, 35.0, 39.5, 49.8,
IR (film): 3273, 2980, 1732, 1485, 1305, 1188, 1053, 831 cm–1.
60.8, 123.0, 128.1, 133.7, 139.7, 172.4.
HRMS (EI): m/z [M + H]+ calcd for C15H24N2O3S: 313.1580; found:
313.1577.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.6 Hz, 3 H, CH3), 1.40
(t, J = 7.6 Hz, 3 H, CH3), 2.38–2.45 (m, 2 H, NCH2), 3.20–3.29 (m,
2 H, SCH2), 3.30–3.35 (m, 2 H, COCH2), 4.06–4.14 (m, 2 H,
CO2CH2), 6.95–6.99 (m, 2 H, ArH), 7.25–7.30 (m, 2 H, ArH),
Ethyl 3-[(Anilinocyclopropyloxo-1λ6-sulfanylidene)amino]pro-
panoate (3g)
From 2g (1.31 g, 7.22 mmol); yield: 1.24 g (58%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 7.2, 13.1, 33.6, 38.2, 48.1, 60.5,
IR (film): 3280, 1732, 1489, 1271, 1188, 1049, 891 cm–1.
113.6, 124.1, 130.8, 142.1, 171.0.
HRMS (EI): m/z [M + H]+ calcd for C13H19BrN2O3S: 363.0373;
found: 363.0369.
1H NMR (400 MHz, CDCl3): δ = 0.96–1.09, 1.22–1.35 (m, 4 H, 2 ×
cyclopropyl CH2), 1.22 (t, J = 7.2 Hz, 3 H, CH3), 2.42–2.47 (m, 2
H, NCH2), 2.60–2.64 (m, 1 H, SCH), 3.34–3.37 (m, 2 H, COCH2),
4.06–4.12 (m, 2 H, CO2CH2), 4.80 (br s, 1 H, NH), 6.91–6.96 (m, 1
H, ArH), 7.08–7.12 (m, 2 H, ArH), 7.17–7.21 (m, 2 H, ArH).
Ethyl 3-{[Ethyl(4-methylanilino)oxo-1λ6-sulfanylidene]ami-
no}propanoate (3c)
From 2c (1.75 g, 9.56 mmol); yield: 1.00 g (35%); yellow oil.
Synthesis 2013, 45, 3018–3028
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Six-Membered Cyclic Sulfonimidamides
3023
13C NMR (100 MHz, CDCl3): δ = 4.9, 6.4, 14.1, 32.4, 34.7, 39.2,
60.9, 121.9, 123.5, 128.9, 143.7, 172.1.
HRMS (EI): m/z [M + H]+ calcd for C14H20N2O3S: 297.1267; found:
297.1269.
Ethyl 3-{[(tert-Butylamino)oxophenyl-1λ6-sulfanylidene]ami-
no}propanoate (3l)
From 2l (3.80 g, 19.4 mmol); yield: 4.00 g (66%); yellow oil.
IR (film): 3284, 2972, 1730, 1445, 1287, 1139, 1091, 755, 690, 605
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3 H, CH3), 1.29
(s, 9 H, C (CH3)3), 2.46–2.54 (m, 2 H, NCH2), 3.16–3.22 (m, 1 H,
COCH2), 3.36–3.40 (m, 1 H, COCH2), 4.10–4.17 (m, 2 H,
CO2CH2), 7.40–7.46 (m, 3 H, ArH), 7.87–7.89 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 14.2, 31.5, 35.6, 38.7, 54.4, 60.6,
127.0, 128.6, 131.4, 143.6, 173.2.
HRMS (EI): m/z [M + H]+ calcd for C15H24N2O3S: 313.1580; found:
313.1582.
Ethyl 3-{[(4-Fluoroanilino)oxo-sec-butyl-1λ6-sulfanyli-
dene]amino}propanoate (3h)
From 2h (1.50 g, 7.07 mmol); yield: 1.40 g (60%); yellow oil.
IR (film): 3286, 2963, 1733, 1501, 1304, 1213, 1046, 837, 723
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.15 (m, 6 H, 2 × CH3), 1.23 (t,
J = 7.2 Hz, 3 H, CH3), 2.35–2.43 (m, 3 H, CH2, SCH), 2.92–2.98
(m, 1 H, COCH2), 3.11–3.17 (m, 1 H, COCH2), 3.28–3.32 (m, 2 H,
NCH2), 4.05–4.11 (m, 2 H, CO2CH2), 4.75 (br s, 1 H, NH), 6.85–
6.90 (m, 2 H, ArH), 7.01–7.04 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 13.0, 21.4, 21.6, 24.0, 33.6, 38.4,
59.9, 61.4, 114.3, 114.5, 123.6, 123.7, 138.8, 156.2, 158.6, 171.0.
Ethyl 3-{[(Isopropylamino)oxophenyl-1λ6-sulfanylidene]ami-
no}propanoate (3m)
From 2m (3.30 g, 17.9 mmol); yield: 3.00 g (56%); yellow oil.
IR (film): 3272, 2975, 1728, 1446, 1259, 1139, 755, 690 cm–1.
HRMS (EI): m/z [M + H]+ calcd for C15H23FN2O3S: 331.1486;
1H NMR (400 MHz, CDCl3): δ = 1.00 (d, J = 6.4 Hz, 3 H, CH3), 1.10
(d, J = 6.4 Hz, 3 H, CH3), 1.22 (t, J = 7.2 Hz, 3 H, CH3), 2.49–2.54
(m, 2 H, CH2), 3.23–3.26 (m, 1 H, CH2), 3.36–3.38 (m, 1 H, CH2),
3.47–3.50 (m, 1 H, NCH), 4.06–4.13 (m, 2 H, CO2CH2), 7.40–7.47
(m, 3 H, ArH), 7.86–7.88 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 12.2, 24.8, 25.0, 36.1, 38.3, 45.6,
60.5, 126.9, 128.8, 131.9, 141.5, 173.0.
found: 331.1481.
Ethyl 3-{[(2-Methoxyanilino)oxo-sec-butyl-1λ6-sulfanyli-
dene]amino}propanoate (3i)
From 2i (1.30 g, 5.76 mmol); yield: 1.30 g (66%); yellow solid; mp
60–62 °C.
IR (KBr): 3066, 1728, 1585, 1494, 1286, 1222, 1174, 1024, 765,
628, 524 cm–1.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O3S: 299.1424; found:
299.1424.
1H NMR (400 MHz, CDCl3): δ = 1.12–1.14 (m, 6 H, 2 × CH3), 1.21
(t, J = 7.2 Hz, 3 H, CH3), 2.38–2.43 (m, 3 H, CH2, SCH), 3.05–3.19
(m, 2 H, COCH2), 3.30–3.36 (m, 2 H, NCH2), 3.83 (s, 3 H, OCH3),
4.06–4.11 (m, 2 H, CO2CH2), 6.83–6.88 (m, 2 H, ArH), 6.97–7.01
(m, 1 H, ArH), 7.21–7.23 (dd, J = 1.6, 7.6 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 12.5, 20.9, 23.6, 33.7, 37.2, 54.1,
59.0, 60.6, 109.6, 119.5, 122.1, 124.1, 129.6, 151.2, 170.5
Ethyl 3-{[Ethyl(4-methylanilino)oxo-1λ6-sulfanylidene]ami-
no}butanoate (3n)
From 2c (1.67 g, 9.16 mmol); yield: 1.00 g (35%); yellow oil.
IR (film): 3336, 2980, 1734, 1506, 1301, 1188, 1055, 786 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.18–1.21 (m, 6 H, 2 × CH3), 1.32
(t, J = 6.4 Hz, 3 H, CH3), 2.19 (s, 3 H, ArCH3), 2.26–2.27 (m, 1 H,
COCH2), 2.38–2.40 (m, 1 H, COCH2), 3.08–3.18 (m, 2 H, SCH2),
3.73–3.81 (m, 1 H, NCH), 3.97–4.08 (m, 2 H, CO2CH2), 6.90 (s, 4
H, ArH),
HRMS (EI): m/z [M + H]+ calcd for C16H26N2O4S: 343.1686; found:
343.1679.
Ethyl 3-[(Anilinoisopropyloxo-1λ6-sulfanylidene)amino]pro-
panoate (3j)
From 2j (1.70 g, 9.23 mmol); yield: 1.10 g (40%); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 7.3, 13.1, 19.7, 33.7, 38.2, 48.0,
60.0, 122.3, 128.5, 130.3, 139.9, 171.1.
HRMS (EI): m/z [M + H]+ calcd for C18H22N2O3S: 313.1579; found:
IR (film): 3257, 2981, 2937, 2252, 1728, 1597, 1489, 1307, 1269,
1201, 1045, 910, 732, 495 cm–1.
313.1581.
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 3 H, CH3),
1.42–1.47 (m, 6 H, 2 × CH3), 2.38–2.43 (m, 2 H, NCH2), 3.31–3.35
(m, 3 H, COCH2, SCH), 4.03–4.09 (m, 2 H, CO2CH2), 6.91–6.95
(m, 1 H, ArH), 7.09–7.11 (m, 2 H, ArH), 7.17–7.25 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 13.0, 15.5, 15.8, 33.9, 38.5, 54.3,
59.8, 120.9, 122.5, 127.9, 142.9, 171.1.
3-[(Anilinoethyloxo-1λ6-sulfanylidene)amino]propanoic Acid
(4a); Typical Procedure
To a stirred solution of sulfonimidamide ester 3a (1.50 g, 5.28
mmol) in THF (8 mL) was added a solution of LiOH (664 mg, 15.8
mmol) in H2O (3 mL) at r.t. The reaction mixture was refluxed for
3–4 h, with monitoring by TLC (eluent: hexane–EtOAc, 1:9) until
completion. The mixture was concentrated under reduced pressure
to remove THF, diluted with H2O (10 mL), and extracted with
EtOAc (50 mL) (this organic layer was discarded to remove impu-
rities). The aqueous layer was then acidified with aq 10% HCl and
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated under reduced pres-
sure to afford the desired product 4a; yield: 1.10 g (85%); yellow
oil.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O3S: 299.1423; found:
299.1418.
Ethyl 3-[(Anilinobenzyloxo-1λ6-sulfanylidene)amino]propano-
ate (3k)
From 2k (1.45 g, 6.28 mmol), yield: 1.00 g (46%); yellow oil.
IR (film): 3282, 2981, 1730, 1595, 1489, 1301, 1271, 1184, 1051,
786 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.2 Hz, 3 H, CH3),
2.17–2.22 (m, 2 H, NCH2), 3.01–3.04 (m, 2 H, COCH2), 3.92–3.96
(m, 2 H, CO2CH2), 4.30–4.39 (m, 2 H, SCH2), 6.83–6.87 (m, 1 H,
ArH), 6.99–7.12 (m, 2 H, ArH), 7.08–7.13 (m, 2 H, ArH), 7.27–7.31
(m, 3 H, ArH), 7.34–7.39 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 13.0, 29.8, 33.7, 59.7, 121.0,
122.4, 127.2, 127.8, 128.2, 128.3, 130.2, 142.9, 170.9.
IR (film): 3271, 2533, 1714, 1593, 1489, 1286, 1265, 1184, 1051,
912, 806 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.6 Hz, 3 H, CH3),
2.46–2.58 (m, 2 H, NCH2), 3.22–3.27 (m, 2 H, SCH2), 3.38–3.42
(m, 2 H, COCH2), 6.63 (br s, 2 H, NH), 6.98–7.02 (m, 1 H, ArH),
7.10–7.13 (m, 2 H, ArH), 7.21–7.25 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 8.1, 34.8, 38.2, 47.8, 122.9, 123.6,
129.2, 142.6, 175.9.
HRMS (EI): m/z [M + H]+ calcd for C18H22N2O3S: 347.1423; found:
347.1417.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3018–3028

3024
I. Sen et al.
PAPER
HRMS (EI): m/z [M + H]+ calcd for C11H16N2O3S: 257.0954; found:
257.0955.
CH2), 3.73–3.76 (m, 2 H, CH2), 6.59 (br s, 1 H, NH), 6.93–7.01 (m,
3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 9.2, 21.9, 37.6, 41.2, 48.0, 125.3,
127.6, 134.6, 134.9, 174.2.
HRMS (EI): m/z [M + H]+ calcd for C13H20N2O3S: 285.1267; found:
285.1262.
3-{[(4-Bromoanilino)ethyloxo-1λ6- sulfanylidene]amino}propa-
noic Acid (4b)
From 3b (1.20 g, 3.32 mmol); yield: 1.00 g (90%); yellow oil.
IR (film): 3234, 3018, 1712, 1485, 1280, 1215, 1051 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.6 Hz, 3 H, CH3),
2.44–2.60 (m, 2 H, NCH2), 3.20–3.25 (m, 2 H, SCH2), 3.30–3.40
(m, 2 H, COCH2), 6.88 (br s, 1 H, NH), 7.12–7.14 (m, 2 H, ArH),
7.37–7.39 (m, 2 H, ArH),
13C NMR (100 MHz, CDCl3): δ = 7.0, 33.5, 35.1, 47.3, 114.3, 124.1,
131.0, 141.3, 175.4.
3-[(Anilinocyclopropyloxo-1λ6-sulfanylidene)amino]propanoic
Acid (4g)
From 3g (1.04 g, 3.51 mmol); yield: 800 mg (85%); yellow oil.
IR (film): 3018, 2358, 1714, 1489, 1288, 1215, 1049, 891 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.00–1.02, 1.24–1.27 (m, 4 H, 2 ×
cyclopropyl CH2), 2.50–2.70 (m, 3 H, CH2, SCH), 3.39–3.46 (m, 2
H, CH2), 6.58 (br s, 1 H, NH), 6.90–7.04 (m, 1 H, ArH), 7.11–7.15
(m, 2 H, ArH), 7.20–7.26 (m, 2 H, ArH).
HRMS (EI): m/z [M + H]+ calcd for C11H15BrN2O3S: 335.0060;
found: 335.0053.
13C NMR (100 MHz, CDCl3): δ = 4.9, 6.3, 31.7, 34.5, 38.3, 123.1,
124.0, 129.1, 142.0, 175.8.
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O3S: 269.0955; found:
269.0950.
3-{[Ethyl(4-methylanilino)oxo-1λ6-sulfanylidene]amino}propa-
noic Acid (4c)
From 3c (900 mg, 3.02 mmol); yield: 750 mg (92%); yellow oil.
IR (film): 3224, 3001, 1715, 1475, 1285, 1212, 1042, 742 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.6 Hz, 3 H, CH3), 2.21
(s, 3 H, ArCH3), 2.44–2.55 (m, 2 H, NCH2), 3.26–3.27 (m, 2 H,
SCH2), 3.29–3.38 (m, 2 H, COCH2), 6.10 (br s, 1 H, NH), 7.01 (s, 4
H, ArH).
3-{[(4-Fluoroanilino)oxo-sec-butyl-1λ6-sulfanylidene]ami-
no}propanoic Acid (4h)
From 3h (835 mg, 2.53 mmol); yield: 650 mg (85%); yellow oil.
IR (film): 3528, 2965, 1716, 1501, 1307, 1214, 1090, 1043, 837
cm–1.
13C NMR (100 MHz, CDCl3): δ = 6.9, 19.7, 28.6, 33.7, 37.0, 46.7,
122.7, 128.9, 132.5, 136.9, 174.5.
HRMS (EI): m/z [M + H]+ calcd for C12H18N2O3S: 271.1111; found:
271.1108.
1H NMR (400 MHz, CDCl3): δ = 1.11–1.19 (m, 6 H, 2 × CH3),
2.31–2.39 (m, 1 H, SCH), 2.43–2.59 (m, 2 H, CH2), 2.99–3.04 (dd,
J = 6.4, 14.0 Hz, 1 H, CH2), 3.14–3.19 (dd, J = 6.0, 14.0 Hz, 1 H,
CH2), 3.32–3.40 (m, 2 H, CH2), 6.88–6.92 (m, 2 H, ArH), 7.02–7.07
(m, 2 H, ArH), 7.77 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): δ = 20.0, 21.4, 24.0, 33.5, 37.3, 59.4,
114.5, 114.8, 123.8, 123.9, 137.4, 156.7, 159.1, 170.3.
3-{[Ethyl(4-methoxyanilino)oxo-1λ6-sulfanylidene]amino}pro-
panoic Acid (4d)
From 3d (500 mg, 1.59 mmol); yield: 410 mg (90%); yellow oil.
IR (film): 3447, 2934, 1717, 1506, 1254, 1212, 1033, 836 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.6 Hz, 3 H, CH3),
2.50–2.61 (m, 2 H, CH2), 3.45–3.47 (m, 2 H, CH2), 3.57–3.59 (m, 2
H, CH2), 3.77 (s, 3 H, OCH3), 6.80–6.82 (m, 2 H, ArH), 7.20–7.26
(m, 2 H, ArH), 7.40 (br s, 1 H, NH).
HRMS (EI): m/z [M + H]+ calcd for C13H19FN2O3S: 303.1173;
found: 303.1170.
3-{[(2-Methoxyanilino)oxo-sec-butyl-1λ6-sulfanylidene]ami-
no}propanoic Acid (4i)
From 3i (1.28 g, 3.75 mmol); yield: 1.06 g (90%); solid; mp 83–
85 °C.
13C NMR (100 MHz, CDCl3): δ = 14.2, 35.4, 48.0, 55.5, 60.4, 114.7,
126.2, 128.8, 129.6, 130.9, 157.6, 175.3.
IR (KBr): 3259, 2953, 1712, 1494, 1240, 1217, 1029, 827, 748
cm–1.
HRMS (EI): m/z [M + H]+ calcd for C12H18N2O4S: 287.1060; found:
287.1056.
1H NMR (400 MHz, CDCl3): δ = 1.02–1.06 (m, 6 H, 2 × CH3),
2.28–2.33 (m, 1 H, SCH), 2.40–2.43 (m, 2 H, CH2), 3.03–3.05 (m,
1 H, CH2), 3.08–3.14 (m, 1 H, CH2), 3.27–3.35 (m, 2 H, CH2), 3.73
(s, 3 H, OCH3), 6.40 (br s, 1 H, NH), 6.77–6.80 (m, 2 H, ArH), 6.92–
6.94 (m, 1 H, ArH), 7.17–7.19 (m, 1 H, ArH).
3-{[Ethyl(2-methylanilino)oxo-1λ6-sulfanylidene]amino}propa-
noic Acid (4e)
From 3e (795 mg, 2.67 mmol); yield: 650 mg (90%); yellow oil.
IR (film): 3269, 2939, 1712, 1489, 1286, 1215, 1056, 758 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.42 (t, J = 7.6 Hz, 3 H, CH3), 2.25
(s, 3 H, ArCH3), 2.46–2.54 (m, 2 H, NCH2), 3.20–3.25 (m, 2 H,
SCH2), 3.33–3.37 (m, 2 H, COCH2), 6.57 (br s, 1 H, NH), 6.89–6.93
(m, 1 H, ArH), 7.04–7.07 (m, 1 H, ArH), 7.12–7.14 (m, 1 H, ArH),
7.21–7.23 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 7.4, 17.3, 33.6, 37.5, 47.7, 121.7,
122.0, 125.3, 129.5, 131.6, 140.2, 175.3.
13C NMR (100 MHz, CDCl3): δ = 19.7, 21.4, 21.5, 24.3, 34.0, 37.2,
54.6, 60.6, 110.3, 120.1, 123.0, 123.8, 129.4, 151.4, 175.1.
HRMS (EI): m/z [M + H]+ calcd for C14H22N2O4S: 315.1373; found:
315.1373.
3-[(Anilinoisopropyloxo-1λ6-sulfanylidene)amino]propanoic
Acid (4j)
From 3j (814 mg, 2.73 mmol); yield: 530 mg (72%); yellow oil.
HRMS (EI): m/z [M + H]+ calcd for C12H18N2O3S: 271.1111; found:
271.1108.
IR (film): 3248, 2956, 1710, 1488, 1220, 1203, 1032, 837, 735
cm–1.
3-{[(2,6-Dimethylanilino)ethyloxo-1λ6-sulfanylidene]ami-
no}propanoic Acid (4f)
From 3f (100 mg, 0.32 mmol); yield: 64 mg (70%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.38 (d, J = 6.8 Hz, 3 H, CH3), 1.44
(d, J = 6.8 Hz, 3 H, CH3), 2.39–2.56 (m, 2 H, CH2), 3.40–3.43 (m,
2 H, CH2), 3.46–3.51 (m, 1 H, SCH), 6.97–7.01 (m, 1 H, ArH),
7.11–7.13 (m, 2 H, ArH), 7.20–7.25 (m, 2 H, ArH), 7.30 (br s, 1 H,
NH).
IR (film): 3200, 2933, 1711, 1473, 1281, 1203, 1103, 1053, 773
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.6 Hz, 3 H, CH3), 2.35
(s, 6 H, 2 × ArCH3), 2.51–2.60 (m, 2 H, CH2), 3.36–3.43 (m, 2 H,
13C NMR (100 MHz, CDCl3): δ = 16.4, 16.6, 35.0, 38.7, 54.8, 122.8,
123.5, 129.1, 142.6, 176.0.
Synthesis 2013, 45, 3018–3028
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Six-Membered Cyclic Sulfonimidamides
3025
HRMS (EI): m/z [M + H]+ calcd for C12H18N2O3S: 271.1111; found:
271.1108.
and extracted with CH2Cl2 (3 × 50 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude product was purified by CombiFlash chroma-
tography (silica gel, n-hexane–EtOAc, 7:3) to afford the desired
product 5a; yield: 700 mg (76%); white solid; mp 103–105 °C.
3-[(Anilinobenzyloxo-1λ6-sulfanylidene)amino]propanoic Acid
(4k)
From 3k (906 mg, 2.62 mmol); yield: 700 mg (84%); yellow oil.
IR (KBr): 2997, 2870, 1697, 1485, 1303, 1134, 1022, 829, 759, 698,
524 cm–1.
IR (film): 3205, 2975, 1710, 1460, 1350, 1250, 1140, 978, 805, 740,
602 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.04 (s, 2 H, SCH2), 2.89–3.05 (m,
2 H, NCH2), 4.15–4.32 (m, 2 H, COCH2), 5.70 (br s, 1 H, NH),
6.82–6.99 (m, 3 H, ArH), 7.03–7.08 (m, 2 H, ArH), 7.14–7.15 (m,
2 H, ArH), 7.20–7.25 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 28.6, 36.0, 57.7, 127.3, 127.4,
128.0, 128.6, 130.2, 143.4, 177.5.
HRMS (EI): m/z [M + H]+ calcd for C16H18N2O3S: 319.1111; found:
319.1112.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
2.69–2.87 (m, 2 H, NCH2), 3.03–3.25 (m, 2 H, SCH2), 3.49–3.57
(ddd, J = 3.4, 5.6, 13.1 Hz, 1 H, COCH2), 3.82–3.92 (m, 1 H,
COCH2), 7.27–7.35 (m, 2 H, 2 × o-CHArN), 7.39–7.51 (m, 3 H, 2 ×
m-CHArN, p-CHArN).
13C NMR (100 MHz, CDCl3): δ = 9.0, 34.9, 38.7, 46.9, 129.5, 129.6,
129.8, 133.5, 170.7.
HRMS (EI): m/z [M + H]+ calcd for C11H14N2O2S: 239.0850; found:
239.0854.
3-{[(tert-Butylamino)oxophenyl-1λ6-sulfanylidene]amino}pro-
panoic Acid (4l)
2-(4-Bromophenyl)-1-ethyl-1-oxo-1λ6-thia-2,6-diazacyclohex-6-
en-3-one (5b)
From 4b (815 mg, 2.44 mmol); yield: 500 mg (65%); white solid;
mp 114–116 °C.
From 3l (1.88 g, 6.03 mmol); yield: 1.20 g (70%); yellow oil.
IR (film): 3209, 2971, 1707, 1468, 1365, 1245, 1139, 981, 869, 811,
755, 598 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.23 [s, 9 H, C(CH3)3], 2.36–2.54
(m, 2 H, NCH2), 3.01–3.08 (m, 1 H, COCH2), 3.21–3.27 (m, 1 H,
COCH2), 7.26 (br s, 1 H, NH), 7.46–7.54 (m, 3 H, ArH), 7.92–7.94
(m, 2 H, ArH).
IR (KBr): 2974, 2947, 2854, 1701, 1485, 1307, 1130, 1022, 829,
736, 659, 555, 520 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.2 Hz, 3 H, CH3),
2.69–2.86 (m, 2 H, NCH2), 2.99–3.25 (m, 2 H, SCH2), 3.48–3.58
(m, 1 H, COCH2), 3.82–3.89 (ddd, J = 4.3, 10.5, 13.1 Hz, 1 H,
COCH2), 7.17–7.24 (m, 2 H, 2 × o-CHArN), 7.54–7.64 (m, 2 H, 2 ×
m-CHArN).
13C NMR (100 MHz, CDCl3): δ = 31.4, 35.3, 37.5, 45.8, 55.4, 127.8,
129.0, 132.1, 142.4, 176.2.
HRMS (EI): m/z [M + H]+ calcd for C13H20N2O3S: 285.1267; found:
13C NMR (100 MHz, CDCl3): δ = 8.9, 34.8, 38.6, 47.0, 123.7, 131.3,
285.1262.
132.6, 132.9, 170.5.
HRMS (EI): m/z [M + H]+ calcd for C11H13BrN2O2S: 316.9955;
found: 316.9486.
3-{[(Isopropylamino)oxophenyl-1λ6-sulfanylidene]amino}pro-
panoic Acid (4m)
From 3m (2.50 g, 8.40 mmol); yield: 2.04 g (90%); yellow oil.
1-Ethyl-1-oxo-2-(p-tolyl)-1λ6-thia-2,6-diazacyclohex-6-en-3-one
IR (film): 3258, 2972, 1716, 1446, 1253, 1134, 755, 689, 559 cm–1.
(5c)
From 4c (713 mg, 2.64 mmol); yield: 400 mg (60%); white solid;
1H NMR (400 MHz, CDCl3): δ = 0.92 (d, J = 6.4 Hz, 3 H, CH3), 1.18
(d, J = 6.4 Hz, 3 H, CH3), 2.43–2.44 (m, 1 H, CH2), 2.55–2.58 (m,
1 H, CH2), 3.08–3.10 (m, 1 H, NCH), 3.22–3.27 (m, 2 H, CH2),
7.49–7.68 (m, 3 H, ArH), 7.68 (br s, 1 H, NH), 7.89–7.90 (m, 2 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 24.0, 25.7, 35.5, 37.1, 45.7, 128.3,
129.2, 132.5, 139.3, 176.7.
mp 88–90 °C.
IR (KBr): 2974, 2873, 1701, 1508, 1300, 1141, 1018, 833, 725, 671,
609, 528 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.32 (t, J = 7.2 Hz, 3 H, CH3), 2.32
(s, 3 H, ArCH3), 2.62–2.79 (m, 2 H, NCH2), 2.96–3.18 (m, 2 H,
SCH2), 3.41–3.49 (m, 1 H, COCH2), 3.75–3.82 (ddd, J = 4.3, 10.5,
13.1 Hz, 1 H, COCH2), 7.10–7.15 (m, 2 H, 2 × o-CHArN), 7.18–7.23
(m, 2 H, 2 × m-CHArN).
13C NMR (100 MHz, CDCl3): δ = 8.9, 21.2, 35.0, 38.7, 46.8, 129.4,
130.4, 130.7, 139.7, 170.9.
HRMS (EI): m/z [M + H]+ calcd for C12H18N2O3S: 271.1111; found:
271.1109.
3-{[Ethyl(4-methylanilino)oxo-1λ6-sulfanylidene]amino}buta-
noic Acid (4n)
From 3n (1.04 g, 3.33 mmol); yield: 900 mg (95%); yellow oil.
IR (film): 3363, 2978, 1714, 1506, 1286, 1053 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3 H, CH3),
1.30–1.35 (m, 3 H, CH3), 2.20 (s, 3 H, ArCH3), 2.4–2.60 (m, 1 H,
CH2), 2.41–2.50 (m, 1 H, CH2), 3.14–3.39 (m, 2 H, CH2), 3.85–3.95
(m, 1 H, NCH), 7.01–7.05 (m, 4 H, ArH).
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O2S: 253.1005; found:
253.0983.
1-Ethyl-2-(4-methoxyphenyl)-1-oxo-1λ6-thia-2,6-diazacyclo-
hex-6-en-3-one (5d)
From 4d (177 mg, 0.62 mmol); yield: 100 mg (60%); white solid;
mp 80–82 °C.
IR (KBr): 2951, 2854, 1701, 1512, 1303, 1261, 1018, 822, 732, 667,
574 cm–1.
13C NMR (100 MHz, CDCl3): δ = 7.0, 20.1, 21.0, 40.3, 45.8, 47.9,
122.6, 128.8, 132.7, 137.0, 173.6.
HRMS (EI): m/z [M + H]+ calcd for C13H20N2O3S: 285.1267; found:
285.1269.
1H NMR (400 MHz, CDCl3): δ = 1.38 (t, J = 7.2 Hz, 3 H, CH3),
2.70–2.85 (m, 2 H, NCH2), 3.02–3.24 (m, 2 H, SCH2), 3.46–3.64
(m, 1 H, COCH2), 3.81 (s, 3 H, OCH3), 3.73–3.92 (m, 1 H, COCH2),
6.90–7.02 (m, 2 H, 2 × o-CHArN), 7.14–7.30 (m, 2 H, 2 × m-
CHArN).
1-Ethyl-1-oxo-2-phenyl-1λ6-thia-2,6-diazacyclohex-6-en-3-one
(5a);18 Typical Procedure
To a stirred solution of 4a (990 mg, 3.90 mmol) in CH2Cl2 (10 mL)
was added Et3N (985 mg, 1.35 mL, 9.76 mmol) at r.t. To this mix-
ture was then added EDCI (1.11 g, 5.85 mmol) and HOBt (895 mg,
5.85 mmol). The reaction mixture was stirred for 12 h at r.t. under
N2 atmosphere. The reaction mass was diluted with H2O (10 mL)
13C NMR (100 MHz, CDCl3): δ = 8.8, 34.9, 38.5, 46.6, 55.4, 114.9,
125.4, 130.7, 160.1, 170.9.
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O3S: 269.0955; found:
269.0910.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3018–3028

3026
I. Sen et al.
PAPER
1-Ethyl-2-(o-tolyl)-1-oxo-1λ6-thia-2,6-diazacyclohex-6-en-3-one
(5e)
IR (film): 2979, 1696, 1591, 1498, 1293, 1113, 1019, 875, 763, 676,
568 cm–1.
From 4e (600 mg, 2.23 mmol); yield: 310 mg (55%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 0.99 (d, J = 6.8 Hz, 3 H, CH3), 1.03
(d, J = 6.8 Hz, 3 H, CH3), 2.22–2.28 (m, 1 H, SCH), 2.76–2.79 (m,
2 H, NCH2), 2.85–2.91 (dd, J = 7.2, 14.0 Hz, 1 H, CH2), 3.10–3.19
(m, 1 H, CH2), 3.50–3.53 (td, J = 5.3, 13.1 Hz, 1 H, COCH2), 3.79–
3.84 (m, 1 H, COCH2), 3.85 (s, 3 H, OCH3), 7.00–7.06 (m, 2 H,
ArH), 7.37–7.44 (m, 2 H, ArH); rotamers were observed in 1H NMR
spectrum.
13C NMR (100 MHz, CDCl3): δ = 21.2, 21.8, 23.6, 33.5, 38.2, 54.7,
58.9, 110.9, 119.7, 120.5, 120.8, 130.1, 131.0, 154.5, 168.2.
HRMS (EI): m/z [M + H]+ calcd for C14H20N2O3S: 297.1267; found:
297.0782.
IR (film): 2970, 1697, 1489, 1303, 1012, 783, 758 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.42 (t, J = 7.2 Hz, 3 H, CH3), 2.23
(s, 3 H, ArCH3), 2.70–2.75 (m, 2 H, NCH2), 3.20–3.24 (m, 2 H,
SCH2), 3.44–3.48 (m, 1 H, COCH2), 3.76–3.79 (m, 1 H, COCH2),
7.02–7.04 (m, 1 H, ArH), 7.18–7.20 (m, 1 H, ArH), 7.26–7.29 (m,
2 H, ArH); rotamers were observed in 1H NMR spectrum.
13C NMR (100 MHz, CDCl3): δ = 9.1, 11.7, 35.0, 38.5, 47.4, 127.0,
128.8, 129.9, 132.1, 132.8, 138.7, 170.9.
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O2S: 253.1005; found:
253.1005.
1-Isopropyl-1-oxo-2-phenyl-1λ6-thia-2,6-diazacyclohex-6-en-3-
2-(2,6-Dimethylphenyl)-1-ethyl-1-oxo-1λ6-thia-2,6-diazacyclo-
hex-6-en-3-one (5f)
one (5j)
From 4j (450 mg, 1.67 mmol); yield: 300 mg (71%); white solid;
mp 144–146 °C.
From 4f (1.10 g, 3.84 mmol); yield: 460 mg (45%); yellow oil.
IR (film): 2976, 1696, 1473, 1290, 1136, 999 855, 831, 725, 663
cm–1.
IR (KBr): 2981, 2854, 1705, 1323, 1300, 1122, 1014, 825, 698, 555
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.2 Hz, 3 H, CH3), 2.23
(s, 3 H, ArCH3), 2.13 (s, 3 H, ArCH3), 2.80–2.85 (m, 2 H, NCH2),
3.13–3.28 (m, 2 H, SCH2), 3.53–3.57 (td, J = 4.7, 13.1 Hz, 1 H,
COCH2), 3.80–3.89 (m, 1 H, COCH2), 7.12–7.19 (m, 2 H, 2 × m-
CHArN), 7.19–7.28 (m, 1 H, p-CHArN).
13C NMR (100 MHz, CDCl3): δ = 8.3, 18.5, 19.2, 35.0, 38.8, 48.1,
128.8, 129.4, 129.6, 131.7, 136.9, 139.0, 170.4.
1H NMR (400 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 6 H, 2 × CH3),
2.63–2.76 (m, 2 H, NCH2), 3.11–3.18 (sept, J = 6.8 Hz, 1 H, SCH),
3.44–3.49 (ddd, J = 2.6, 5.6, 12.9 Hz, 1 H, COCH2), 3.76–3.84 (m,
1 H, COCH2), 7.24–7.27 (m, 2 H, 2 × o-CHArN), 7.34–7.45 (m, 3 H,
2 × m-CHArN, p-CHArN).
13C NMR (100 MHz, CDCl3): δ = 14.3, 17.0, 34.0, 37.2, 52.4, 128.3,
128.5, 128.7, 132.6, 170.1.
HRMS (EI): m/z [M + H]+ calcd for C13H18N2O2S: 267.1162; found:
267.1151.
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O2S: 253.1005; found:
253.0958.
1-Cyclopropyl-1-oxo-2-phenyl-1λ6-thia-2,6-diazacyclohex-6-
en-3-one (5g)
From 4g (800 mg, 3.00 mmol); yield: 450 mg (60%); white solid;
mp 126–128 °C.
1-Benzyl-1-oxo-2-phenyl-1λ6-thia-2,6-diazacyclohex-6-en-3-one
(5k)
From 4k (400 mg, 1.28 mmol); yield: 270 mg (70%); white solid;
mp 184–186 °C.
IR (KBr): 3523, 2873, 1697, 1300, 1122, 1022, 877, 833, 543 cm–1.
IR (KBr): 2868, 1707, 1490, 1305, 1240, 1022, 962, 866, 696, 601,
534 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.85–0.95 (m, 2 H, cyclopropyl
CH2), 1.03–1.20 (m, 2 H, cyclopropyl CH2), 2.40–2.50 (tt, J = 4.8,
7.6 Hz, 1 H, SCH), 2.68–2.86 (m, 2 H, NCH2), 3.50–3.56 (ddd, J =
3.1, 5.6, 13.0 Hz, 1 H, COCH2), 3.84–3.90 (ddd, J = 4.1, 10.9, 13.0
Hz, 1 H, COCH2), 7.30–7.37 (m, 2 H, 2 × o-CHArN), 7.41–7.49 (m,
3 H, 2 × m-CHArN, p-CHArN).
13C NMR (100 MHz, CDCl3): δ = 6.1, 7.6, 30.6, 34.7, 38.8, 129.4,
130.3, 133.7, 170.5.
HRMS (EI): m/z [M + H]+ calcd for C12H14N2O2S: 251.0850; found:
251.0761.
1H NMR (400 MHz, CDCl3): δ = 2.34–2.38 (ddd, J = 5.4, 10.0, 17.0
Hz, 1 H, NCH2), 2.58–2.64 (m, 1 H, NCH2), 3.37–3.47 (ddd, J = 5.1,
9.7, 13.0 Hz, 1 H, COCH2), 3.70–3.76 (ddd, J = 3.8, 9.7, 13.2 Hz, 1
H, COCH2), 4.36 (s, 2 H, SCH2), 7.36–7.45 (m, 7 H, 2 × o-CHArN,
2 × o-CHArCH2, 2 × m-CHArCH2, p-CHArCH2), 7.45–7.56 (m, 3 H,
2 × m-CHArN, p-CHArN).
13C NMR (100 MHz, CDCl3): δ = 34.6, 39.4, 58.8, 127.8, 128.8,
129.3, 129.5, 129.6, 130.2, 131.1, 131.5, 133.3, 170.7.
HRMS (EI): m/z [M + H]+ calcd for C16H16N2O2S: 301.1005; found:
301.0990.
2-(4-Fluorophenyl)-1-oxo-1-sec-butyl-1λ6-thia-2,6-diazacyclo-
hex-6-en-3-one (5h)
From 4h (675 mg, 2.24 mmol); yield: 350 mg (55%); white solid;
mp 167–169 °C.
2-Isopropyl-1-oxo-1-phenyl-1λ6-thia-2,6-diazacyclohex-6-en-3-
one (5m)
From 4m (820 mg, 3.03 mmol); yield: 420 mg (55%); white solid;
IR (KBr): 2954, 1709, 1507, 1306, 1220, 1139, 1021, 955, 875, 800,
662, 573 cm–1.
mp 81–83 °C.
IR (KBr): 2992, 1681, 1472, 1295, 1218, 1136, 1021, 990, 825, 754,
670, 582 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (d, J = 4.3 Hz, 3 H, CH3), 1.08
(d, J = 4.3 Hz, 3 H, CH3), 2.24–2.34 (m, 1 H, SCH), 2.72–2.85 (m,
2 H, NCH2), 2.94–3.06 (m, 2 H, CH2), 3.49–3.55 (m, 1 H, COCH2),
3.81–3.84 (ddd, J = 4.8, 9.5, 13.1 Hz, 1 H, COCH2), 7.14–7.17 (m,
2 H, 2 × o-CHArN), 7.25–7.33 (m, 2 H, 2 × m-CHArN).
13C NMR (100 MHz, CDCl3): δ = 22.2, 22.6, 25.2, 34.9, 38.8, 60.0,
116.6, 116.8, 129.3, 131.9, 161.6, 164.1, 170.5.
1H NMR (400 MHz, CDCl3): δ = 0.98 (d, J = 6.8 Hz, 3 H, CH3), 1.42
(d, J = 6.8 Hz, 3 H, CH3), 2.62–2.67 (m, 1 H, NCH2), 2.78–2.87 (m,
1 H, NCH2), 3.50–3.56 (ddd, J = 2.3, 6.1, 12.9 Hz, 1 H, COCH2),
3.78–3.85 (dt, J = 3.1, 12.6 Hz, 1 H, COCH2), 3.93–3.96 [sept, J =
6.9 Hz, 1 H, NCH(CH3)2], 7.54–7.58 (m, 2 H, 2 × m-CHArS), 7.64–
7.70 (m, 1 H, p-CHArS), 8.00–8.04 (m, 2 H, 2 × o-CHArS).
HRMS (EI): m/z [M + H]+ calcd for C13H17FN2O2S: 285.1068;
found: 285.096.
13C NMR (100 MHz, CDCl3): δ = 19.3, 20.1, 36.2, 38.9, 50.9, 129.2,
129.3, 133.9, 137.7, 170.3.
2-(2-Methoxyphenyl)-1-oxo-1-sec-butyl-1λ6-thia-2,6-diazacy-
clohex-6-en-3-one (5i)
From 4i (995 mg, 3.17 mmol); yield: 470 mg (50%); yellow oil.
HRMS (EI): m/z [M + H]+ calcd for C12H16N2O2S: 253.1005; found:
253.1008.
Synthesis 2013, 45, 3018–3028
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Six-Membered Cyclic Sulfonimidamides
3027
1-Ethyl-5-methyl-1-oxo-2-(p-tolyl)-1λ6-thia-2,6-diazacyclohex-
6-en-3-one (5n + 5o)
(g) Worch, C.; Atodiresei, I.; Raabe, G.; Bolm, C. Chem.
Eur. J. 2010, 16, 677. (h) Mancheño, O. G.; Bolm, C.
Beilstein J. Org. Chem. 2007, 3, No. 25. (i) Pennington, R.
L.; Shab, X.; King, S. B. Bioorg. Med. Chem. Lett. 2005, 15,
2331. (j) Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.;
Gustavsson, S.; Nilsson, L. I.; Minidis, A.; Holenz, J.;
Rotticci, D.; Lundkvist, J.; Arvidsson, P. I. Chem. Med.
Chem. 2012, 7, 396. (k) Levchenko, E. S.; Markovskii, L.
N.; Shermolovich, Y. G. Russ. J. Org. Chem. 2000, 36, 143.
(3) (a) Johnson, C. R.; Lavergne, O. M. J. Org. Chem. 1993, 58,
1922. (b) Azzaro, S.; Fensterbank, L.; Lacôte, E.; Malacria,
M. Synlett 2008, 2253. (c) Azzaro, S.; Murr, M. D. E.;
Fensterbank, L.; Lacôte, E.; Malacria, M. Synlett 2011, 849.
(d) Maldonado, M. F.; Sehgelmeble, F.; Bjarnemark, F.;
Svensson, M.; Åhman, J.; Arvidsson, P. I. Tetrahedron
2012, 68, 7456. (e) Worch, C.; Bolm, C. Synthesis 2008,
739. (f) Borhade, S. R.; Sandstorm, A.; Arvidsson, P. I. Org.
Lett. 2013, 15, 1056.
(4) (a) Leca, D.; Toussaint, A.; Mareau, C.; Fensterbank, L.;
Lacôte, E.; Malacria, M. Org. Lett. 2004, 6, 3573.
(b) Rashatasakhon, P.; Harmata, M. Chemtracts: Org.
Chem. 2006, 19, 143.
(5) (a) Di Chenna, P. H.; Robert-Peillard, F.; Dauban, P.; Dodd,
R. H. Org. Lett. 2004, 6, 4503. (b) Robert-Peillard, F.; Di
Pablo, C.; Liang, H. C.; Lescot, C.; Collet, F.; Dodd, R. H.;
Dauban, P. Tetrahedron: Asymmetry 2010, 21, 1447.
(c) Liang, C.; Robert-Peillard, F.; Fruit, C.; Mueller, P.;
Dodd, R. H.; Dauban, P. Angew. Chem. Int. Ed. 2006, 45,
4641. (d) Lescot, C.; Darses, B.; Collet, F.; Retailleau, P.;
Dauban, P. J. Org. Chem. 2012, 77, 7232.
From 4n (850 mg, 3.00 mmol).
Column fraction 1: Yield: 240 mg (30%); white solid; mp 82–
84 °C.
IR (KBr): 2970, 2927, 1697, 1508, 1307, 1114, 1018, 825, 744, 532
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.30 (d, J = 6.4 Hz, 3 H, CH3), 1.33
(t, J = 7.6 Hz, 3 H, CH3), 2.30 (s, 3 H, ArCH3), 2.33–2.40 (dd, 1 H,
J = 12.0, 16.8 Hz, COCH2), 2.63–2.68 (dd, J = 2.6, 16.9 Hz, 1 H,
COCH2), 2.93–3.18 (m, 2 H, SCH2), 3.97–4.08 (m, 1 H, NCH),
7.08–7.14 (m, 2 H, 2 × o-CHArN), 7.17–7.23 (m, 2 H, 2 × m-
CHArN).
13C NMR (100 MHz, CDCl3): δ = 9.3, 21.2, 23.6, 42.7, 45.1, 46.9,
129.4, 130.3, 130.9, 139.6, 170.7.
HRMS (EI): m/z [M + H]+ calcd for C13H18N2O2S: 267.1162; found:
267.0915.
Column fraction 2: Yield: 240 mg (30%); white solid; mp 114–
116 °C.
IR (KBr): 2954, 2905, 1701, 1512, 1307, 1269, 1118, 1010, 837,
694, 570, 543 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.3 Hz, 3 H, CH3), 1.39
(d, J = 6.5 Hz, 3 H, CH3), 2.3 (s, 3 H, ArCH3), 2.51–2.57 (dd, J =
7.2, 16.8 Hz, 1 H, COCH2), 2.74–2.80 (dd, J = 4.3, 16.8 Hz, 1 H,
COCH2), 3.02–3.08 (dq, J = 2.3, 7.3 Hz, 2 H, SCH2), 3.75–3.79 (m,
1 H, NCH), 7.11–7.13 (m, 2 H, 2 × o-CHArN), 7.19–7.21 (m, 2 H, 2
× m-CHArN).
13C NMR (100 MHz, CDCl3): δ = 8.1, 21.2, 23.7, 41.4, 46.5, 48.3,
129.6, 130.4, 139.8, 170.1.
HRMS (EI): m/z [M + H]+ calcd for C13H18N2O2S: 267.1162; found:
267.0834.
(6) Worch, C.; Bolm, C. Synlett 2009, 2425.
(7) (a) Steurer, M.; Bolm, C. J. Org. Chem. 2010, 75, 3301.
(b) Lescot, C.; Darses, B.; Collet, F.; Retailleau, P.; Dauban,
P. J. Org. Chem. 2012, 77, 7232. (c) Patureau, F. W.; Worch,
C.; Siegler, M. A.; Spek, A. L.; Bolm, C.; Reek, J. N. H. Adv.
Synth. Catal. 2012, 354, 59.
Acknowledgment
(8) (a) Kleemann, H. W.; Brendel, J.; Schwark, J. R.; Weichert,
A.; Lang, H. J.; Albus, U.; Scholz, W. Hoechst AG,
Frankfurt am Main, Germany Patent EP 0771788 A2, 1997;
Chem. Abstr. 1997, 127, 17500 (b) Kleemann, H. W.; Lang,
H. J.; Schwark, J. R.; Weichert, A.; Scholz, W.; Albus, U.
Hoechst AG, Frankfurt am Main, Germany Patent US
6057322 A, 2000; Chem. Abstr. 2000, 132, 293573
(9) (a) Paulini, R.; Breuninger, D.; von Deyn, W.; Bastiaans, H.
M. M.; Beyer, C.; Anspaugh, D. D.; Oloumi-Sadeghi, H.
BASF SE, Ludwigshafen, Germany PCT Int. Appl
WO2009156336 A1, 2009; Chem. Abstr. 2009, 152, 97451
(b) Paulini, R.; von Deyn, W.; Bastiaans, H. M. M.; Beyer,
C. BASF SE, Ludwigshafen, Germany PCT Int. Appl
WO2011069955 A1, 2011; Chem. Abstr. 2011, 155, 93714
(c) Gnamm, C.; Jeanguenat, A.; Dutton, A. C.; Grimm, C.;
Kloer, D. P.; Crossthwaite, A. J. Bioorg. Med. Chem. Lett.
2012, 22, 3800.
This work has been completed as a part of the Ph.D. thesis (I. Sen)
affiliated to the University of Mangalore with guidance from Dr.
Sitaram Pal at Syngenta Goa Research & Technology Centre.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI: 10.4125/pd0050th. mPiDrayramPtirDayra4t0.215p/d00P50hri
m
t.yarDaZataehnl101
C
hemyrsti
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3018–3028

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I. Sen et al.
PAPER
(15) Other chlorinating agents like N-chlorobenzotriazole also
gave similar results, but the separation of product 3 from
benzotriazole was tedious.
(16) (a) Treatment of sulfonimidamide 3h or 3m with NaOEt in
EtOH under reflux conditions led only to hydrolysis of ester
functionality to give 4h or 4m (see ref. 11). (b) Using
t-BuOK in refluxing toluene resulted in only 3 being
recovered. (c) Under acidic conditions using PTSA in
refluxing toluene, 3 was again recovered, with minor
cleavage of the R1NH-moiety being also observed.
(17) (a) Corey, E. J.; Durst, T. J. Am. Chem. Soc. 1968, 90, 5548.
(b) Bowlus, S. B.; Katzenellenbogen, J. A. Synth. Commun.
1974, 4, 137. (c) Ruano, J. L. G.; Parra, A.; Yuste, F.;
Mastranzo, V. M. Synthesis 2008, 311. (d) Uchino, M.;
Sekiya, M. Chem. Pharm. Bull. 1980, 28, 126. (e) Mintz, M.
J.; Walling, C. Org. Synth. Coll. Vol. 5; Wiley: New York,
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(18) The assignments of the aromatic H’s in substituents R1 for
compounds 5 has been made in analogy to the HMBC
experiment of 5j (see Supporting Information).
Synthesis 2013, 45, 3018–3028
© Georg Thieme Verlag Stuttgart · New York