Access to a wide range of sultams by cyclodialkylation of α-substituted methanesulfonanilides

Article abstract of DOI:10.1002/ejoc.201200670

A wide range of five- and six-membered sultams bearing an α-ethoxycarbonyl-α-methyl substituent or an α-aryl group (17 examples) were synthesized by the cyclodialkylation of α-substituted methanesulfonanilides with α,ω-dihaloalkanes in the presence of K₂CO₃ or under phase-transfer catalysis (PTC) conditions. Upon treatment with K₂CO₃ in N,N-dimethylformamide (DMF) or NaH in dimethyl sulfoxide (DMSO), N-(2,3-dibromopropyl)-α- toluenesulfonanilides furnished different 1,3-diaryl-2-thia-3-azabicyclo[3.1.0] hexane 2,2-dioxides in good to excellent yields (51-88 %, 16 examples). The 4-methoxyphenyl (PMP) group was easily removed from the sultam nitrogen atom by treatment of the corresponding bicyclic sultams with cerium(IV) ammonium nitrate in acetonitrile (71-84 % yield, 6 examples). The intermolecular cyclodialkylation of α-substituted methanesulfonamides constitutes a simple and efficient route to five- and six-membered sultams with α-ethoxycarbonyl-α-methyl or α-aryl substitution. The intramolecular cyclodialkylation of N-(2,3-dibromopropyl)-α- toluenesulfanilides readily leads to bicyclic sultams bearing a cyclopropane ring. Copyright

Full text of DOI:10.1002/ejoc.201200670

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FULL PAPER
DOI: 10.1002/ejoc.201200670
Access to a Wide Range of Sultams by Cyclodialkylation of α-Substituted
Methanesulfonanilides
Valentin A. Rassadin,[a] Daria S. Grosheva,[a] Irina A. Arefeva,[a]
Aleksandr A. Tomashevskiy,[a] Victor V. Sokolov,*[a] and Armin de Meijere*[b]
Dedicated to Professor Heribert Offermanns on the occasion of his 75th birthday
Keywords: Synthetic methods / Heterocycles / Sulfonamides / Cyclodialkylation / Substituent effects
A wide range of five- and six-membered sultams bearing an
α-ethoxycarbonyl-α-methyl substituent or an α-aryl group (17
examples) were synthesized by the cyclodialkylation of α-
substituted methanesulfonanilides with α,ω-dihaloalkanes in
the presence of K2CO3 or under phase-transfer catalysis
(PTC) conditions. Upon treatment with K2CO3 in N,N-di-
methylformamide (DMF) or NaH in dimethyl sulfoxide
(DMSO), N-(2,3-dibromopropyl)-α-toluenesulfonanilides fur-
nished different 1,3-diaryl-2-thia-3-azabicyclo[3.1.0]hexane
2,2-dioxides in good to excellent yields (51–88%, 16 exam-
ples). The 4-methoxyphenyl (PMP) group was easily re-
moved from the sultam nitrogen atom by treatment of the
corresponding bicyclic sultams with cerium(IV) ammonium
nitrate in acetonitrile (71–84% yield, 6 examples).
access to a wide range of bicyclic sultams with a 1-meth-
oxycarbonyl-1-sulfonylcyclopropane moiety in good yields
(see Scheme 1, Type II).[9]
Introduction
The sulfonamide functional group stands out as one of
the most important pharmacophores and is therefore a con-
stituent in many commonly used therapeutic agents. Cyclic
sulfonamides (sultams) have also received significant atten-
tion because of their biological activities and medicinal
uses.[1] Up until now, sultams have been prepared by em-
ploying nucleophilic aromatic substitution,[2] ring-closing
metathesis,[3] the Diels–Alder reaction,[4] a Heck cycliza-
tion,[5] a radical cyclization,[6] and the reduction or alkyl-
ation of sulfonylimines.[7] As we have recently demon-
strated, the cyclodialkylation of α-(methoxycarbonyl)meth-
anesulfonanilides [see Scheme 1, Type I, EWG (electron-
withdrawing group) = CO2Me, R = H] by the treatment
with α,ω-dibromoalkanes provides a rather simple and ef-
ficient route to five-, six-, and seven-membered sultams
with the α-methoxycarbonyl group.[8] The analogous intra-
molecular cyclodialkylation of N-(ω–1,ω-dibromoalkyl)-
methoxycarbonylmethanesulfonanilides constitutes a facile
Scheme 1. Concept for inter- and intramolecular cyclodialkylation
of sulfonanilides.
Herein, we present a full account of our studies with re-
spect to the cyclodialkylations with α,ω-dibromides of a
variety of α-substituted methanesulfonanilides and their de-
rivatives along with the analogous intramolecular cyclodi-
alkylations. From the many potentially suitable acceptor
groups (EWG), such as alkoxycarbonyl, aryl, cyano, nitro,
or trifluoromethyl, we chose an alkoxycarbonyl (EWG =
CO2Et, R = Me) and an aryl (EWG = Ar, R = H) group,
as the corresponding starting sulfonyl chlorides 1 and 3–9
are most easily accessible.
[a] Department of Chemistry, Saint-Petersburg State University,
Universitetskii pr. 26, 198504 Saint-Petersburg, Russian
Federation
E-mail: vsokolo@mail.ru
Homepage: www.chem.spbu.ru
Results and Discussion
[b] Institut für Organische und Biomolekulare Chemie der
Georg-August-Universität Göttingen,
Sulfonamides 2a–2f can be easily prepared by the treat-
ment of sulfonyl chloride 1 with the respective anilines in
acetonitrile in the presence of pyridine (see Scheme 2,
Table 1). However, in the case of α-toluenesulfonyl chlorides
Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: ameijer1@gwdg.de
Homepage: www.adm.chemie.uni-goettingen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc201200670.
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V. V. Sokolov, A. de Meijere et al.
FULL PAPER
3–9, the procedure was not as straightforward. When Table 2. Preparation of monocyclic sultams 19a–19f and 20a–20e
(see Scheme 3).
sulfonamide 10h was prepared in pyridine, a small amount
of an unwanted byproduct was always formed. Therefore,
we searched for a simpler and more efficient route. Indeed,
treatment of the sulfonyl chlorides 3–9 with a wide range
of anilines in dichloromethane with N-methylmorpholine
(NMM) led to the respective sulfonamides 10–16 in good
yields.
Starting
material
R2
Product Yield [%] Product Yield [%]
2a
2b
2c
2d
2e
2f
Ph
19a
19b
19c
19d
19e
19f
75
63
86
76
72
68
20a
20b
20c
20d
20e
59
63
81
66
53
2-MeC6H4
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
2,6-Cl2C6H3
We observed no noticeable influence of the aryl substitu-
ents on the yields and reaction times. It is evident though
(see Table 2), that in the case of these α-(ethoxycarbonyl)-
ethanesulfonanilides, the cyclodialkylation reaction is less
sensitive to the electronic effects of substituents than in the
analogous reactions with α-(methoxycarbonyl)methanesul-
fonanilides.[8] To prepare the six-membered sultams, the
cyclodialkylation of sulfonamides 2a–2e was also performed
with 1-bromo-3-chloropropane (18). Overall, no difference
was observed between the five- and six-membered ring for-
mation.
The α-toluenesulfonamides did not react as cleanly. For
instance, under the same conditions employed above (DMF,
K2CO3), the reaction of the sulfonamide 10a with 1,2-di-
bromoethane (17) always produced byproduct 22a in sig-
nificant amounts, resulting from a second intermolecular
alkylation reaction (see Scheme 4).
Scheme 2. Synthesis of the starting sulfonamides 2a–2f and 10–16.
For details, see Table 1.
Table 1. Synthesis of the starting sulfonamides (see Scheme 2).
Starting material Product
R1
R2
Yield [%]
1
1
1
1
1
1
3
3
3
3
3
3
3
4
5
6
7
4
5
6
8
9
2a
2b
2c
2d
2e
–
–
–
–
–
–
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
58
61
52
78
55
64
57
57
43
72
72
59
74[a]
84
91
78
85
59
57
44
83
65
2-MeC6H4
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
2,6-Cl2C6H3
Ph
2-MeC6H4
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
4-BrC6H4
Ph
2f
10a
10b
10c
10d
10e
10g
10h
11a
12a
13a
14a
11d
12d
13d
15d
16d
Scheme 4. Cyclodialkylation and sidereaction of α-toluenesulf-
onanilide 10a in DMF in the presence of K2CO3.
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-MeO2CC6H4
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-NCC6H4
2,6-Cl2C6H3
Ph
Ph
Ph
Moreover, we observed that the alkylation reaction
stopped very soon after the addition of 1,2-dibromoethane,
probably because of a competing dehydrohalogenation pro-
cess. To avoid this difficulty, a two-phase system consisting
of toluene, aqueous NaOH, and tetrabutylammonium
bromide (TBAB) as a phase-transfer catalyst (PTC), pre-
viously used for the C-alkylation of tertiary sulfonamides,
was employed.[10] Under these conditions, the desired sul-
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
[a] This reaction was carried out in pure pyridine.
Using an excellent method for α-(methoxycarbonyl)- tams 21a, 21c, 21d, 21h, 23a, and 24a were obtained in
methanesulfonanilide derivatives,[8] we conducted the cyclo- moderate yields (see Scheme 5, Table 3).
dialkylation reaction of sulfonamides 2a–2f with 1,2-dibro-
These conditions, however, proved not to be optimal
moethane (17) in N,N-dimethylformamide (DMF) in the either. Subsequently, a simpler and more efficient protocol
presence of K2CO3. Upon heating at 70 °C for 14 h, the for the cyclodialkylation process was completed within
desired sultams were produced in good yields (see 30 min in the presence of a strong base such as dimsylsod-
Scheme 3, Table 2).
ium [generated by adding sodium hydride to dimethyl sulf-
Scheme 3. Cyclodialkylation of α-substituted ethanesulfonamides 2a–2f. For details, see Table 2.
2
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Access to Sultams by Cyclodialkylation
Scheme 5. Cyclodialkylation of α-toluenesulfonanilides under various conditions. For details, see Table 3.
Table 3. Synthesis of monocyclic diarylsultams 21a,c,d,h, 23a, and which in turn were obtained from the respective sulfonyl
24a (see Scheme 5).
chlorides 3 and 8 and N-allylaniline 25 (see Scheme 6). An
Starting material Product
R1
R2
Yield [%]
initial attempt to prepare 26a according to a previously
published procedure[9] gave at best low yields or none of the
desired product (see Scheme 6).
As an alternative approach, the easily available second-
ary α-toluenesulfonanilides 10–16 were alkylated with allyl
bromide in DMF in the presence of K2CO3 to give the N-
allyl-α-toluenesulfonanilides 26–32 in good to excellent
yields (see Scheme 6, Table 4). We observed no noticeable
influence of the aryl substituents in 10–16 on the yields and
reaction times.
A
B
10a
10c
10d
10h
13a
10a
21a
21c
21d
21h
23a
24a
Ph
Ph
Ph
Ph
2,6-Me2C6H3
4-MeOC6H4
4-BrC6H4
Ph
45
54
64
45
–
65
70
72
68
78
–
Ph
2-ClC6H4
Ph
Ph
24
oxide (DMSO)] in DMSO. However, significant excess
amounts of the alkylating agent and the base were required.
Although both of these methods furnished sultams in com-
parable yields, employing dimsylsodium was preferable, as
the reactions proceeded faster. The six-membered ring for-
mation was demonstrated by starting from sulfonamide 10a
using condition A with 1-bromo-3-chloropropane (18). This
transformation required a longer reaction time than that
with 1,2-dibromoethane (17) and also a slower addition of
the alkylating agent. Yet, the resulting sultam 24a was ob-
tained in only 24% yield.
Table 4. Synthesis of N-allyl-α-toluenesulfonamides (see Scheme 6).
Starting material Product
R1
R2
Yield [%]
10a
10b
10c
10d
10e
10g
11a
12a
13a
14a
11d
12d
13d
15d
16d
26a
26b
26c
26d
26e
26g
27a
28a
29a
30a
27d
28d
29d
31d
32d
Ph
Ph
Ph
Ph
Ph
Ph
96
72
65
71
75
55
84
91
78
85
56
58
77
89
95
2-MeC6H4
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
Ph
Ph
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-MeO2CC6H4
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-NCC6H4
2,6-Cl2C6H3
Ph
Ph
Ph
For the analogous intramolecular cyclodialkylations, N-
(2,3-dibromopropyl)sulfonamides 33 were prepared from
the corresponding N-allyl-α-toluenesulfonanilides 26–32,
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
The subsequent addition of bromine to the C–C double
bond proceeded smoothly to furnish the corresponding N-
(2,3-dibromopropyl)sulfonamide derivatives 33 in almost
quantitative yields. No impurities were detected by 1H
NMR spectroscopy, and therefore these compounds were
used in the next step without any additional purification
(see Scheme 7).
Scheme 6. Synthesis of N-allyl-α-toluenesulfonamides 26–32. For
details, see Table 4.
Scheme 7. Synthesis of N-(2,3-dibromopropyl)sulfonanilides 33 and their intramolecular cyclodialkylation reaction. For details, see
Table 5.
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FULL PAPER
Upon treatment with K2CO3 in DMF, the N-(2,3-dibro- the corresponding isomeric vinyl bromides, all arising from
mopropyl)sulfonamides 33 underwent an intramolecular dehydrobromination processes of 42.
cyclodialkylation reaction to yield the bicyclic sultams 34a
The recently discovered removal of the 4-methoxyphenyl
and 39a. However, under these conditions, the reactions (PMP) group from the N-atom of a sultam by treatment
proceeded very slowly, probably because of the low CH with an aqueous solution of ceric ammonium nitrate
acidity in sulfonamides 33. As the use of stronger bases (CAN) was tested on a few examples.[9] Indeed, upon treat-
should accelerate this process, the dibromopropylsulfon- ment with CAN in acetonitrile/water at 0 °C, the mono-
amides 33 were treated with dimsylsodium in DMSO. This cyclic sultams 19d and 20d as well as the bicyclic ones 34d,
indeed produced the desired bicyclic sultams 34–40 in excel- 35d, 36d, and 37d gave the nitrogen-deprotected sultams 45
lent yields within 30 min starting from all of the N-(2,3- and 46 as well as 47–50, respectively, within 1–2 h in yields
dibromopropyl)sulfonamide derivatives 33, regardless of ranging from 67–84% (see Scheme 9, Table 6).
the substituents on the aromatic ring (see Scheme 7,
Table 5). Thus, this method is considered to be general and
efficient for the syntheses of 1,3-diaryl-2-thia-3-azabicyclo-
[3.1.0]hexane derivatives of types 34–40.
Table 5. Synthesis of 1,3-diaryl-2-thia-3-azabicyclo[3.1.0]hexane de-
rivatives 34–40 in the presence of NaH (see Scheme 7).
Starting material Product
R1
R2
Yield [%]
26b
26c
26d
26e
26g
27a
28a
29a
30a
27d
28d
29d
31d
32d
34b
34c
34d
34e
34g
35a
36a
37a
38a
35d
36d
37d
39d
40d
Ph
Ph
Ph
Ph
Ph
2-MeC6H4
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
Ph
78
50
77
78
73
78
72
86
75
44
67
73
88
58
Scheme 9. Oxidative removal of the PMP group in monocyclic and
bicyclic sultams 19d, 20d, and 34d–37d. For details, see Table 6.
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-MeO2CC6H4
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-NCC6H4
2,6-Cl2C6H3
Table 6. Synthesis of the monocyclic (i.e., 45 and 46) and bicyclic
Ph
Ph
Ph
(i.e., 47–50) sultams with
Scheme 9).
a secondary nitrogen atom (see
Starting material
Product
R1
Yield [%]
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
19d
20d
34d
35d
36d
37d
45
46
47
48
49
50
–
–
Ph
84
76
80
67
74
71
2-MeC6H4
4-MeC6H4
2-ClC6H4
On the other hand, an attempted preparation of a 1,3-
diaryl-2-thia-3-azabicyclo[4.1.0]heptane derivative failed
(see Scheme 8). The N-(but-3-enyl)-α-toluenesulfonanilide
41 was prepared from sulfonanilide 13a and but-3-en-1-ol
by employing a Mitsunobu protocol.[11] Upon treatment of
41 with an excess amount of bromine, tribromide 42 was
produced in excellent yield. When treated with sodium hy-
Conclusions
The intermolecular cyclodialkylation of α-substituted
dride in DMSO, 42 gave a complex mixture of products methanesulfonamides constitutes a simple and efficient
containing alkynyl derivative 44 (7%) contaminated with route to five- and six-membered sultams with α-ethoxycarb-
Scheme 8. Attempt to prepare 1-(2-chlorophenyl)-3-(4-bromophenyl)-2-thia-3-azabicyclo[4.1.0]heptane 2,2-dioxide (43).
4
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Access to Sultams by Cyclodialkylation
C11H15NO4S (257.31): calcd. C 51.35, H 5.88, N 5.44; found C
51.25, H 5.64, N 5.32.
onyl-α-methyl or α-aryl substitution. The intramolecular
cyclodialkylation of N-(2,3-dibromopropyl)-α-toluenesulf-
onanilides readily leads to bicyclic sultams bearing a cyclo-
propane moiety annulated to a five-membered heterocycle.
1-(Ethoxycarbonyl)-N-(2-methylphenyl)ethanesulfonamide (2b): The
crude product was purified by flash chromatography (EtOAc/hex-
ane, 1:3; Rf = 0.24) followed by Kugelrohr distillation to give a
1
colorless solid (4.96 g, 61%); m.p 74–75 °C. H NMR (300 MHz,
CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.63 (d, J = 7.3 Hz,
3 H, CHCH3), 2.38 (s, 3 H, CCH3), 4.09 (q, J = 7.3 Hz, 1 H,
CHCH3), 4.20–4.28 (m, 2 H, OCH2), 6.58 (s, 1 H, NH), 7.09–7.23
(m, 3 H, Ar), 7.52–7.55 (m, 1 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.3 (CH3), 13.8 (CH3), 17.9 (CH3), 61.4 (CH), 62.4
(CH2), 122.4 (CH-Ar), 126.0 (CH-Ar), 126.9 (CH-Ar), 130.9 (C-
Ar), 131.1 (CH-Ar), 134.8 (C-Ar), 166.8 (CO) ppm. HRMS (ESI):
calcd. for C12H17NNaO4S [M + Na]+ 294.0776; found 294.0779.
C12H17NO4S (271.33): calcd. C 53.12, H 6.32, N 5.16; found C
53.00, H 6.40, N 5.20.
Experimental Section
General Remarks: The NMR spectroscopic data were recorded at
ambient temperature with a Bruker DPX 300 instrument at
300.13 MHz (1H NMR) and 75.47 MHz (13C NMR, DEPT 90 and
DEPT 135), a Varian Mercury VX 300 instrument at 300.05 MHz
(1H NMR), a Varian Unity 300 instrument at 300.15 MHz (1H
NMR) and 75.48 MHz [13C NMR and APT (attached proton
test)], a Varian VXR Inova 500 S instrument at 125.71 MHz (13C
NMR and APT), and
a Varian Inova 600 instrument at
599.74 MHz (1H NMR). The chemical shifts (δ) are given in ppm
relative to the resonances of the solvents (1H NMR: δ = 7.26 ppm
for CHCl3 and δ = 2.50 ppm for [D5]DMSO; 13C NMR: δ =
77.0 ppm for CDCl3 and δ = 39.5 ppm for [D6]DMSO). The cou-
pling constants (J) are given in Hz. The multiplicities of signals are
described by s = singlet, d = doublet, t = triplet, q = quadruplet,
and m = multiplet. The multiplicities of signals in the 13C NMR
spectra were determined by DEPT and APT techniques. The mass
spectra were recorded with a Finnigan MAT 95 (EI) and a Bruker
MicroTOF (ESI). All of the reagents were used as purchased with-
out further purification. The solvents were purified and dried prior
to use according to conventional methods. The chromatographic
separations were carried out with Macherey–Nagel silica gel 60 M
(230–400 mesh). Analytical TLC was performed with Macherey–
Nagel ready-to-use AluGram® Sil G/UV254 plates. Detection was
achieved by using a UV lamp or treating with a molybdatophos-
phoric acid solution (5% in EtOH). Melting points were deter-
mined by using capillary tubes with a Büchi 510 apparatus. The
elemental analyses were carried out with a Hewlett Packard
HP185B automatic CHN analyzer.
N-(2,6-Dimethylphenyl)-1-(ethoxycarbonyl)ethanesulfonamide (2c):
The crude product was purified by flash chromatography (EtOAc/
hexane, 1:3; Rf = 0.21) followed by recrystallization from EtOAc/
hexane to give a yellowish solid (4.46 g, 52%); m.p. 103–104 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.75 (d, J = 7.3 Hz, 3 H, CHCH3), 2.42 (s, 6 H, CCH3), 4.14 (q, J
= 7.3 Hz, 1 H, CHCH3), 4.32 (q, J = 7.2 Hz, 2 H, OCH2), 6.44 (s,
1 H, NH), 7.06–7.15 (m, 3 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.7 (CH3), 13.9 (CH3), 19.2 (2 C, CH3), 62.6 (CH2),
63.7 (CH), 127.8 (CH-Ar), 128.7 (2 C, CH-Ar), 132.5 (C-Ar), 137.4
(2 C, C-Ar), 167.7 (CO) ppm. HRMS (ESI): calcd. for
C13H19NNaO4S [M
+
Na]+ 308.0932; found 308.0930.
C13H19NO4S (285.36): calcd. C 54.72, H 6.71, N 4.91; found C
54.71, H 6.80, N 4.98.
General Procedure for the Synthesis of 1-Arylmethanesulfonanilides
10–16 (GP3): A solution of the respective sulfonyl chloride 3–9
(0.10 mol) in CH2Cl2 (100 mL) was slowly added dropwise to a
stirred solution of the respective aniline (0.11 mol) and N-methyl-
morpholine (11.1 g, 0.11 mol) in CH2Cl2 (100 mL) at 10–15 °C.
The mixture was warmed to 30 °C, stirred for 1 h, and then cooled
to room temperature. The reaction mixture was diluted with
CH2Cl2 (100 mL), and the resulting solution was successively
washed with water (100 mL), 10% HCl (2ϫ50 mL), water
(100 mL), and brine (50 mL) and then dried with Na2SO4. The
solvent was removed by distillation, and the crude product was
purified by recrystallization from EtOAc/hexane. The following
sulfonamides were prepared according to GP3.
General Procedure for the Synthesis of 1-(Ethoxycarbonyl)ethanesul-
fonanilides 2a–2f (GP2): A solution of ethyl 2-(chlorosulfonyl)pro-
pionate (1, 6.02 g, 30.0 mmol) in anhydrous MeCN (10 mL) was
slowly added to a stirred solution of the respective aniline
(33.0 mmol) and pyridine (2.84 g, 36.0 mmol) in anhydrous MeCN
(50 mL) at 10 °C. The reaction mixture was stirred at 30 °C for 1 h
and then concentrated under reduced pressure by using a rotary
evaporator. The residue was diluted with CH2Cl2 (200 mL), and
the resulting solution was washed with 5% HCl (3ϫ50 mL) and
brine (50 mL) and then dried with anhydrous MgSO4. The solvents
were removed by distillation, and the crude product was purified by
flash chromatography (EtOAc/hexane, 1:3) followed by Kugelrohr
distillation or recrystallization from EtOAc/hexane. The following
sulfonamides were prepared according to GP2 (for GP1, see Sup-
porting Information).
N,1-Diphenylmethanesulfonamide (10a): Colorless solid (14.1 g,
57%). M.p. 100–101 °C; ref.[12] m.p. 98–99 °C.
N-(2-Methylphenyl)-1-phenylmethanesulfonamide (10b): Colorless
solid (14.9 g, 57%). M.p. 82–83 °C; ref.[13] m.p. 83–84 °C.
N-(2,6-Dimethylphenyl)-1-phenylmethanesulfonamide (10c): Color-
less solid (11.8 g, 43%); m.p. 123–124 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.42 (s, 6 H, CH3), 4.44 (s, 2 H, CH2), 5.66 (br. s, 1
H, NH), 7.08–7.12 (m, 3 H, Ar), 7.38–7.41 (m, 3 H, Ar), 7.48–7.50
(m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4 (2 C,
CH3), 60.5 (CH2), 127.9 (CH-Ar), 128.78 (3 C, 2 CH-Ar, C-Ar),
128.82 (3 C, CH-Ar), 130.9 (2 C, CH-Ar), 133.0 (C-Ar), 137.2 (2
C, C-Ar) ppm. HRMS (ESI): calcd. for C15H17NNaO2S
[M + Na]+ 298.0878; found 298.0874. C15H17NO2S (275.37): calcd.
C 65.43, H 6.22, N 5.09; found C 65.32, H 6.16, N 5.09.
1-(Ethoxycarbonyl)-N-phenylethanesulfonamide (2a): The crude
product was purified by flash chromatography (EtOAc/hexane, 1:3;
Rf = 0.22) followed by Kugelrohr distillation to give a yellowish oil
(4.47 g, 58%). 1H NMR (300 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz,
3 H, CH2CH3), 1.58 (d, J = 7.3 Hz, 3 H, CHCH3), 4.00 (q, J =
7.3 Hz, 1 H, CHCH3), 4.24 (q, J = 7.2 Hz, 2 H, OCH2), 7.11 (br.
s, 1 H, NH), 7.17–7.22 (m, 1 H, Ar), 7.30–7.37 (m, 4 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.1 (CH3), 13.8 (CH3), 60.5
N-(4-Bromophenyl)-1-phenylmethanesulfonamide (10h): A solution
(CH), 62.5 (CH2), 121.4 (2 C, CH-Ar), 125.6 (CH-Ar), 129.4 (2 C, of α-toluenesulfonyl chloride (3, 0.50 g, 2.2 mmol) in MeCN
CH-Ar), 136.5 (C-Ar), 166.7 (CO) ppm. HRMS (ESI): calcd. for (7 mL) was added dropwise to a stirred mixture of 4-bromoaniline
C11H15NNaO4S [M
+
Na]+ 280.0619; found 280.0616.
(378 mg, 2.2 mmol) and NaOAc·3H2O (1.98 g, 2.4 mmol) in 50%
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 02-08-12 16:48:08
Pages: 11
V. V. Sokolov, A. de Meijere et al.
FULL PAPER
aqueous MeOH (8 mL). The reaction mixture was warmed to
60 °C, cooled to room temperature, and diluted 5-fold with cold
water. The resulting mixture was acidified to pH = 2 with concen-
trated HCl. The precipitate formed was removed by filtration and
recrystallized from EtOH to give a colorless solid (163 mg, 74%);
m.p. 141–143 °C. 1H NMR (300 MHz, CDCl3): δ = 4.33 (s, 2 H,
SO2CH2), 6.50 (br. s, 1 H, NH), 6.99–7.06 (m, 2 H, Ar), 7.24–7.30
(m, 2 H, Ar), 7.33–7.42 (m, 3 H, Ar), 7.44–7.50 (m, 2 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 57.6 (SO2CH2), 117.7 (C-Ar),
121.3 (2 C, CH-Ar), 128.1 (C-Ar), 128.9 (2 C, CH-Ar), 129.0 (CH-
Ar), 130.7 (2 C, CH-Ar), 132.5 (2 C, CH-Ar), 136.1 (C-Ar) ppm.
MS (EI): m/z (%) = 327 (22) [M(81Br)]+, 325 (21) [M(79Br)]+, 263
(37), 261 (36), 143 (2), 91 (100), 65 (20), 51 (4). C13H12BrNO2S
(326.21): calcd. C 47.87, H 3.71, N 4.29; found C 47.93, H 3.75, N
4.27.
320.0927. C14H19NO4S (297.37): calcd. C 56.55, H 6.44, N 4.71;
found C 56.35, H 6.41, N 4.51.
Ethyl 2-(2,6-Dimethylphenyl)-5-methylisothiazolidine-5-carboxylate
1,1-Dioxide (19c): The crude product was purified by flash
chromatography (EtOAc/hexane, 1:4; Rf = 0.21) followed by Kugel-
rohr distillation to give a yellowish oil (1.07 g, 86%). 1H NMR
(300 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.82
(s, 3 H, SO2CCH3), 2.35 (ddd, J = 5.6, 8.1, 13.5 Hz, 1 H, 4-H),
2.35 (s, 3 H, CCH3), 2.42 (s, 3 H, CCH3), 3.10 (ddd, J = 5.7, 8.2,
13.5 Hz, 1 H, 4Ј-H), 3.53 (td, J = 5.7, 8.1 Hz, 1 H, 3-H), 3.71 (td,
J = 5.6, 8.2 Hz, 1 H, 3Ј-H), 4.25–4.42 (m, 2 H, CH2CH3), 7.06–
7.18 (m, 3 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9
(CH2CH3), 18.3 (CCH3), 18.6 (CCH3), 19.3 (CCH3), 29.6 (C-4),
44.1 (C-3), 62.7 (OCH2), 64.3 (C-5), 128.95 (CH-Ar), 129.00 (CH-
Ar), 129.06 (CH-Ar), 132.1 (C-Ar), 140.1 (C-Ar), 140.5 (C-Ar),
167.9 (CO) ppm. HRMS (ESI): calcd. for C15H21NNaO4S [M +
Na]+ 334.1089; found 334.1084. C15H21NO4S (311.37): calcd. C
57.86, H 6.80, N 4.50; found C 57.90, H 6.72, N 4.56.
General Procedure for the Synthesis of Isothiazolidine 1,1-Dioxides
19a–19f (GP4): A solution of 1,2-dibromoethane (17, 902 mg,
4.8 mmol) in DMF (10 mL) was added dropwise over 5 h to a well-
stirred mixture of the respective sulfonamide 2a–2f (4.0 mmol),
K2CO3 (1.66 g, 12 mmol), and DMF (60 mL) at 70 °C. The mixture
was stirred at the same temperature for 7 h, and an additional
amount of 1,2-dibromoethane (376 mg, 2.0 mmol) was added in
one portion. The stirring was continued for 3 h. The solvent was
evaporated under reduced pressure, and the residue was treated
with CH2Cl2 (150 mL) and 10% HCl (50 mL). The organic phase
was separated and successively washed with 3% HCl (5ϫ80 mL),
water (50 mL), and brine (50 mL). The organic phase was dried
with Na2SO4, and the solvent was removed by distillation. The
crude product was purified by flash chromatography (EtOAc/hex-
ane, 1:4) followed by Kugelrohr distillation or recrystallization
from EtOAc/hexane. The following isothiazolidines were prepared
according to GP4.
General Procedure for the Synthesis of 2-Aryl-6-methyl-1,2-thiazin-
ane-6-carboxylate 1,1-Dioxides 20a–20e (GP5): A solution of 1-
bromo-3-chloropropane (18, 756 mg, 4.8 mmol) in DMF (10 mL)
was added within 5 h to a well-stirred mixture of the respective
sulfonamide 2a–2f (4.0 mmol), K2CO3 (1.66 g, 12 mmol), and
DMF (60 mL) at 70 °C. The mixture was stirred at the same tem-
perature for 9 h, and then an additional amount of 1-bromo-3-
chloropropane (18, 315 mg, 2.0 mmol) was added in one portion.
The stirring was continued for 3 h. The solvent was evaporated
under reduced pressure, and the residue was treated with CH2Cl2
(150 mL) and 10% HCl (50 mL). The organic phase was separated
and successively washed with 3% HCl (5ϫ80 mL), water (50 mL),
and brine (50 mL). The organic phase was then dried with Na2SO4,
and the solvent was removed by distillation. The crude product was
purified by flash chromatography (EtOAc/hexane, 1:4) followed by
Kugelrohr distillation. The following thiazinanes were prepared ac-
cording to GP5.
Ethyl 5-Methyl-2-phenylisothiazolidine-5-carboxylate 1,1-Dioxide
(19a): The crude product was purified by flash chromatography
(EtOAc/hexane, 1:4; Rf = 0.23) followed by Kugelrohr distillation
to give a colorless solid (0.85 g, 75%); m.p. 69–70 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.74
(s, 3 H, CCH3), 2.26 (ddd, J = 5.6, 7.7, 13.5 Hz, 1 H, 4-H), 3.02
(ddd, J = 6.1, 7.8, 13.5 Hz, 1 H, 4Ј-H), 3.63 (ddd, J = 6.1, 7.7,
8.7 Hz, 1 H, 3-H), 3.81 (ddd, J = 5.6, 7.8, 8.7 Hz, 1 H, 3Ј-H), 4.21–
4.36 (m, 2 H, CH2CH3), 7.11–7.16 (m, 1 H, Ar), 7.22–7.26 (m, 2
H, Ar), 7.30–7.36 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.9 (CH2CH3), 19.5 (CCH3), 29.1 (C-4), 43.6 (C-3), 62.8
(OCH2), 65.6 (C-5), 120.3 (2 C, CH-Ar), 124.9 (CH-Ar), 129.3 (2
C, CH-Ar), 137.7 (C-Ar), 167.3 (CO) ppm. HRMS (ESI): calcd.
Ethyl 6-Methyl-2-phenyl-1,2-thiazinane-6-carboxylate 1,1-Dioxide
1
(20a): Colorless oil (0.70 g, 59%); Rf = 0.23. H NMR (600 MHz,
CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.73 (s, 3 H,
CCH3), 1.89–1.95 (m, 1 H, 4-H), 2.03–2.09 (m, 1 H, 4Ј-H), 2.26
(ddd, J = 4.0, 7.9, 14.4 Hz, 1 H, 5-H), 2.65 (ddd, J = 4.0, 9.0,
14.4 Hz, 1 H, 5Ј-H), 3.76–3.84 (m, 2 H, 3-H and 3Ј-H), 4.18–4.25
(m, 2 H, CH2CH3), 7.20–7.23 (m, 1 H, Ar), 7.28–7.33 (m, 4 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7 (CH2CH3), 19.2
(CCH3), 21.3 (C-4), 34.2 (C-5), 52.8 (C-3), 62.1 (OCH2), 66.6 (C-
6), 126.1 (2 C, CH-Ar), 126.6 (CH-Ar), 128.7 (2 C, CH-Ar), 140.9
(C-Ar), 168.2 (CO) ppm. HRMS (ESI): calcd. for C14H19NNaO4S
[M + Na]+ 320.0932; found 320.0930. C14H19NO4S (297.37): calcd.
C 56.55, H 6.44, N 4.71; found C 56.63, H 6.52, N 4.87.
for C13H17NNaO4S [M
+
Na]+ 306.0776; found 306.0770.
C13H17NO4S (283.34): calcd. C 55.11, H 6.05, N 4.94; found C
55.21, H 6.15, N 4.88.
Ethyl 5-Methyl-2-(2-methylphenyl)isothiazolidine-5-carboxylate 1,1-
Dioxide (19b): The crude product was purified by flash chromatog-
raphy (EtOAc/hexane, 1:4; Rf = 0.26) followed by Kugelrohr distil-
lation to give a yellowish oil (0.75 g, 63%). 1H NMR (300 MHz,
CDCl3): δ = 1.31 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.77 (s, 3 H,
SO2CCH3), 2.25 (ddd, J = 5.8, 8.6, 13.5 Hz, 1 H, 4-H), 2.33 (s, 3
H, CCH3), 3.03 (ddd, J = 5.1, 8.6, 13.5 Hz, 1 H, 4Ј-H), 3.47 (td, J
= 5.1, 8.6 Hz, 1 H, 3-H), 3.66 (td, J = 5.8, 8.6 Hz, 1 H, 3Ј-H), 4.21–
4.38 (m, 2 H, CH2CH3), 7.16–7.24 (m, 3 H, Ar), 7.34–7.38 (m, 1
Ethyl
6-Methyl-2-(2-methylphenyl)-1,2-thiazinane-6-carboxylate
1
1,1-Dioxide (20b): Colorless oil (0.78 g, 63%); Rf = 0.21. H NMR
(300 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.32
(t, J = 7.2 Hz, 3 H, CH2CH3), 1.75 (s, 3 H, SO2CCH3), 1.87 (s, 3
H, SO2CCH3), 1.97–2.05 (m, 2 H), 2.22–2.33 (m, 7 H), 2.40 (s, 3
H, CCH3), 2.60–2.81 (m, 2 H), 3.37–3.55 (m, 2 H), 3.70–3.81 (m,
2 H), 4.20–4.37 (m, 4 H, CH2CH3), 7.15–7.26 (m, 6 H, Ar), 7.35–
7.40 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.75
(CH2CH3), 13.78 (CH2CH3), 18.1 (CCH3), 18.3 (CCH3), 19.3
H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH2CH3), (CCH3), 19.6 (CCH3), 21.2 (C-4), 21.8 (C-4), 33.6 (C-5), 34.6 (C-
17.7 (CCH3), 19.7 (CCH3), 29.5 (C-4), 45.9 (C-3), 62.6 (OCH2), 5), 53.6 (C-3), 62.0 (OCH2), 62.2 (OCH2), 66.5 (C-6), 67.1 (C-6),
64.5 (C-5), 126.9 (CH-Ar), 128.6 (CH-Ar), 128.7 (CH-Ar), 131.2
(CH-Ar), 134.9 (C-Ar), 138.8 (C-Ar), 167.8 (CO) ppm. HRMS
(ESI): calcd. for C14H19NNaO4S [M + Na]+ 320.0932; found
126.6 (CH-Ar), 126.7 (CH-Ar), 127.5 (CH-Ar), 127.6 (CH-Ar),
128.0 (CH-Ar), 128.1 (CH-Ar), 131.0 (CH-Ar), 131.1 (CH-Ar),
137.5 (C-Ar), 137.6 (C-Ar), 139.1 (C-Ar), 139.5 (C-Ar), 168.2 (CO),
6
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Eur. J. Org. Chem. 0000, 0–0

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Date: 02-08-12 16:48:08
Pages: 11
Access to Sultams by Cyclodialkylation
168.3 (CO) ppm. HRMS (ESI): calcd. for C15H21NNaO4S [M +
Na]+ 334.1089; found 334.1086. C15H21NO4S (311.40): calcd. C
57.86, H 6.80, N 4.50; found C 57.76, H 6.85, N 4.45.
δ = 25.6 (C-4), 45.8 (C-3), 55.5 (OCH3), 63.3 (C-5), 114.7 (2 C,
CH-Ar), 124.0 (2 C, CH-Ar), 129.0 (2 C, CH-Ar), 129.1 (2 C, CH-
Ar), 129.3 (CH-Ar), 130.4 (C-Ar), 130.9 (C-Ar), 157.7 (C-Ar) ppm.
MS (EI): m/z (%) = 303 (26) [M]+, 239 (32), 135 (100), 120 (57),
104 (22), 92 (17), 77 (18). C16H17NO3S (303.38): calcd. C 63.34, H
5.65, N 4.62; found C 63.20, H 5.64, N 4.59.
Ethyl 2-(2,6-Dimethylphenyl)-6-methyl-1,2-thiazinane-6-carboxylate
1
1,1-Dioxide (20c): Colorless oil (1.05 g, 81%); Rf = 0.28. H NMR
(600 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.86
(s, 3 H, SO2CCH3), 1.84–1.96 (m, 1 H, 4-H), 2.14–2.25 (m, 2 H,
4Ј-H and 5-H), 2.36 (s, 3 H, CCH3), 2.44 (s, 3 H, CCH3), 2.70–
2.74 (m, 1 H, 5Ј-H), 3.55–3.59 (m, 1 H, 3-H), 3.63–3.67 (m, 1 H,
3Ј-H), 4.21–4.30 (m, 2 H, CH2CH3), 7.00–7.07 (m, 3 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.7 (CH2CH3), 19.4 (CCH3),
20.0 (CCH3), 20.3 (CCH3), 22.0 (C-4), 34.2 (C-5), 52.2 (C-3), 62.1
(OCH2), 67.5 (C-6), 128.0 (CH-Ar), 129.0 (CH-Ar), 129.2 (CH-
Ar), 138.2 (C-Ar), 138.46 (C-Ar), 138.51 (C-Ar), 168.5 (CO) ppm.
HRMS (ESI): calcd. for C16H23NNaO4S [M + Na]+ 348.1245;
found 348.1243. C16H23NO4S (325.42): calcd. C 59.05, H 7.12, N
4.30; found C 59.12, H 7.26, N 4.35.
2-(4-Bromophenyl)-5-phenylisothiazolidine 1,1-Dioxide (21h): Color-
less solid (153 mg, 45%); m.p. 141–143 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.72–2.96 (m, 2 H, 4-H and 4Ј-H), 3.77–3.92 (m, 2 H,
3-H and 3Ј-H), 4.55 (dd, J = 7.3, 12.4 Hz, 1 H, 5-H), 7.16–6.21 (m,
2 H, Ar), 7.44–7.54 (m, 7 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.3 (C-4), 44.7 (C-3), 64.0 (C-5), 117.3 (C-Ar), 120.6
(2 C, CH-Ar), 129.0 (2 C, CH-Ar), 129.1 (2 C, CH-Ar), 129.5 (CH-
Ar), 129.8 (C-Ar), 132.3 (2 C, CH-Ar), 137.3 (C-Ar) ppm. MS (EI):
m/z (%) = 353 (16) [M(81Br)]+, 351 (16) [M(79Br)]+, 183 (100), 155
(23), 115 (19), 104 (79), 91 (51), 77 (64). C15H14BrNO2S (352.25):
calcd. C 51.15, H 4.01, N 3.98; found C 51.34, H 4.15, N 4.01.
General Procedure for the Synthesis of Isothiazolidine 1,1-Dioxides
21a–21h (GP6): A solution of the respective sulfonamide 10a–h
(1.0 mmol), 1,2-dibromoethane (17, 376 mg, 2.0 mmol), HMPA
(hexamethylphosphoramide, 0.25 mL, 1.8 mmol), and nBu4NBr
(32 mg, 0.1 mmol) in toluene (20 mL) was added within 30–60 min
to a vigorously stirred 50% aqueous solution of NaOH (3.2 g,
80 mmol) kept at 55–60 °C. Next, the reaction mixture was stirred
at the same temperature for 18 h and then cooled to ambient tem-
perature. The organic phase was separated, and the aqueous phase
was extracted with EtOAc (3ϫ10 mL). The combined organic
phases were successively washed with 5% HCl (3ϫ20 mL) and
water (3ϫ20 mL), dried with Na2SO4, and concentrated under re-
duced pressure. The crude product was purified by recrystallization
from hexane (to give 21a and 21c) or EtOH (to give 21d and 21h).
The following isothiazolidines were prepared according to GP6.
5-(2-Chlorophenyl)-2-phenylisothiazolidine 1,1-Dioxide (23a):
A
solution of sulfonamide 13a (1.69 g, 6.00 mmol) and 1,2-dibromo-
ethane (17, 11.3 g, 60 mmol) in anhydrous DMSO (20 mL) was
added in one portion to NaH (60% suspension in oil, 4.20 g,
120 mmol) in anhydrous DMSO (50 mL). The resulting mixture
was stirred at room temperature for 30 min. Then, water (100 mL)
was added in one portion, and the reaction mixture was acidified
to pH Յ 2 with 10% HCl. The resulting mixture was extracted
with CH2Cl2 (3ϫ40 mL). The combined organic phases were suc-
cessively washed with 2% HCl (5ϫ40 mL), water (50 mL), and
brine (30 mL) and then dried with MgSO4. The solvent was re-
moved under reduced pressure by using a rotary evaporator, and
the crude product was recrystallized from EtOAc/hexane to give a
colorless solid (1.44 g, 78%); m.p. 142–143 °C. 1H NMR
(600 MHz, CDCl3): δ = 2.69–2.80 (m, 2 H, 4-H and 4Ј-H), 3.79–
3.82 (m, 1 H, 3-H), 3.90 (td, J = 7.0, 9.0 Hz, 1 H, 3Ј-H), 5.24 (dd,
J = 7.6, 10.7 Hz, 1 H, 5-H), 7.14–7.17 (m, 1 H, Ar), 7.29–7.38 (m,
6 H, Ar), 7.46 (dd, J = 1.5, 7.9 Hz, 1 H, Ar), 7.66 (dd, J = 1.8,
7.7 Hz, 1 H, Ar) ppm. 13C NMR (300 MHz, CDCl3): δ = 26.0 (C-
4), 44.6 (C-3), 59.4 (C-5), 119.8 (2 C, CH-Ar), 124.7 (CH-Ar), 127.3
(CH-Ar), 129.0 (C-Ar), 129.3 (2 C, CH-Ar), 129.8 (CH-Ar), 129.9
(CH-Ar), 130.3 (CH-Ar), 135.4 (C-Ar), 137.8 (C-Ar) ppm. MS
(ESI): m/z = 330 [M(35Cl) + Na]+, 332 [M(37Cl) + Na]+.
2,5-Diphenylisothiazolidine 1,1-Dioxide (21a): Colorless solid
1
(0.143 g, 45%); m.p. 154–155 °C. H NMR (300 MHz, CDCl3): δ
= 2.70–2.97 (m, 2 H, 4-H and 4Ј-H), 3.78–3.98 (m, 2 H, 3-H and
3Ј-H), 4.59 (dd, J = 7.2, 12.0 Hz, 1 H, 5-H), 7.12–7.23 (m, 1 H,
Ar), 7.26–7.58 (m, 9 H, Ar) ppm. 13C NMR (300 MHz, CDCl3): δ
= 25.2 (C-4), 44.6 (C-3), 63.9 (C-5), 119.1 (2 C, CH-Ar), 124.3
(CH-Ar), 128.9 (2 C, CH-Ar), 129.1 (2 C, CH-Ar), 129.3 (2 C, CH-
Ar), 129.4 (CH-Ar), 130.1 (C-Ar), 138.1 (C-Ar) ppm. MS (EI): m/z
(%) = 273 (1) [M]+, 209 (6), 105 (100), 104 (67), 91 (6), 78 (22), 77
(54), 63 (9), 51 (32), 39 (17). C15H15NO2S (273.35): calcd. C 65.91,
H 5.53, N 5.12; found C 65.75, H 5.51, N 5.19.
2,6-Diphenyl-1,2-thiazinane 1,1-Dioxide (24a): A solution of sulfon-
amide 10a (180 mg, 0.70 mmol), 1-bromo-3-chloropropane (18,
157 mg, 1.4 mmol), HMPA (0.25 mL, 1.8 mmol), and nBu4NBr
(24 mg, 0.75 mmol) in toluene (20 mL) was added dropwise within
1 h to a vigorously stirred solution of NaOH (3.2 g, 80 mmol) in
water (3.2 mL) kept at 55–60 °C. The reaction mixture was stirred
at this temperature for 23 h. The organic phase was separated, and
the aqueous phase was extracted with EtOAc (3ϫ10 mL). The
combined organic phases were successively washed with 5% HCl
(3ϫ20 mL) and water (3ϫ20 mL), dried with Na2SO4, and con-
centrated under reduced pressure. The crude product was purified
by recrystallization from EtOH to give a colorless solid (274 mg,
24%); m.p. 121–123 °C. 1H NMR (300 MHz, CDCl3): δ = 1.99–
2.28 (m, 2 H), 2.36–2.45 (m, 1 H), 2.76–2.90 (m, 1 H), 3.61–3.68
(m, 1 H), 4.18 (td, J = 2.6, 12.6 Hz, 1 H, 3/3Ј-H), 4.33 (dd, J =
3.3, 12.5 Hz, 1 H, 6-H), 7.25–7.54 (m, 10 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.6 (C-4), 31.1 (C-5), 53.3 (C-3), 66.4 (C-
6), 126.6 (2 C, CH-Ar), 127.0 (CH-Ar), 128.6 (2 C, CH-Ar), 128.9
(CH-Ar), 129.0 (2 C, CH-Ar), 129.6 (2 C, CH-Ar), 132.0 (C-Ar),
2-(2,6-Dimethylphenyl)-5-phenylisothiazolidine 1,1-Dioxide (21c):
Colorless solid (205 mg, 54%); m.p. 172–173 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 2.48 (s, 3 H, CH3),
2.72–2.81 (m, 1 H, 4-H), 3.03 (tt, J = 8.7, 13.1 Hz, 1 H, 4Ј-H),
3.66–3.78 (m, 2 H, 3-H and 3Ј-H), 4.52 (dd, J = 6.5, 13.1 Hz, 1 H,
5-H), 7.07–7.23 (m, 3 H, Ar), 7.39–7.51 (m, 3 H, Ar), 7.54–7.64
(m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.57 (CH3),
18.64 (CH3), 25.5 (C-4), 45.1 (C-3), 62.2 (C-5), 128.81 (2 C, CH-
Ar), 128.88 (2 C, CH-Ar), 128.94 (CH-Ar), 129.16 (2 C, CH-Ar),
129.18 (CH-Ar), 130.3 (C-Ar), 133.1 (C-Ar), 139.7 (C-Ar), 140.5
(C-Ar) ppm. MS (EI): m/z (%) = 301 (32) [M]+, 237 (37), 133 (100),
132 (98), 117 (32), 104 (29), 91 (20), 77 (33). C17H19NO2S (301.40):
calcd. C 67.74, H 6.35, N 4.65; found C 67.66, H 6.34, N 4.77.
2-(4-Methoxyphenyl)-5-phenylisothiazolidine 1,1-Dioxide (21d):
Colorless solid (193 mg, 64%); m.p. 168–169 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.70–2.92 (m, 2 H, 4-H and 4Ј-H), 3.70–
3.93 (m, 2 H, 3-H and 3Ј-H), 3.82 (s, 3 H, OCH3), 4.54 (dd, J = 141.0 (C-Ar) ppm. MS (ESI): m/z = 288 [M + H]+. C16H17NO2S
8.0, 11.1 Hz, 1 H, 5-H), 6.90–6.98 (m, 2 H, Ar), 7.29–7.32 (m, 2 (287.38): calcd. C 66.87, H 5.96, N 4.87; found C 66.53, H 6.00, N
H, Ar), 7.40–7.58 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): 4.84.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20670
/KAP1
Date: 02-08-12 16:48:08
Pages: 11
V. V. Sokolov, A. de Meijere et al.
FULL PAPER
N-Allyl-N,1-diphenylmethanesulfonamide (26a): A solution of the α-
toluenesulfonyl chloride (3, 9.53 g, 50.0 mmol) in MeCN (20 mL)
was added dropwise within 2 h to a vigorously stirred solution of
N-allylaniline (6.66 g, 50.0 mmol) and pyridine (4.74 g, 60.0 mmol)
in MeCN (60 mL) kept at room temperature. The resulting solution
was stirred at 40 °C for 2 h and then cooled to room temperature.
Then, the MeCN was removed by distillation under reduced pres-
sure by using a rotary evaporator. The residue was diluted with
CH2Cl2 (100 mL), and the resulting solution was washed with 3%
HCl (3ϫ50 mL), water (50 mL), and brine (50 mL). The solution
was dried with Na2SO4, and the solvent was evaporated. The crude
product was recrystallized from EtOAc/hexane to give a yellow so-
CDCl3): δ = 2.41 (s, 6 H, CH3), 4.07 (d, J = 7.3 Hz, 2 H, NCH2),
4.41 (s, 2 H, SO2CH2), 5.04–5.11 (m, 2 H, CH=CH2), 5.84 (ddt, J
= 7.3, 10.2, 16.7 Hz, 1 H, CH=CH2), 7.09–7.18 (m, 3 H, Ar), 7.37–
7.40 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.5 (2
C, CH3), 54.3 (CH2), 60.4 (CH2), 119.7 (CH=CH2), 128.3 (CH),
128.6 (CH), 128.7 (2 C, CH-Ar), 128.8 (C-Ar), 128.9 (2 C, CH-
Ar), 130.8 (2 C, CH-Ar), 132.5 (CH), 137.4 (C-Ar), 138.6 (C-Ar)
ppm. MS (ESI): m/z = 316 [M + H]+. C18H21NO2S (315.43): calcd.
C 68.54, H 6.71, N 4.44; found C 68.66, H 6.84, N 4.63.
1,3-Diphenyl-2-thia-3-azabicyclo[3.1.0]hexane 2,2-Dioxide (34a): A
solution of bromine (3.36 g, 21.0 mmol) in CH2Cl2 (20 mL) was
slowly added to a stirred solution of sulfonamide 26a (5.75 g,
20.0 mmol) in CH2Cl2 (40 mL) kept at 0 °C. The resulting mixture
was stirred for an additional 10 min and then successively washed
with water (30 mL), 10% Na2SO3 (2ϫ30 mL), and brine (30 mL).
The mixture was then dried with anhydrous Na2SO4. The solvent
was removed under reduced pressure by using a rotary evaporator,
and the crude dibromide was used in the next step without any
additional purification. A solution of the crude dibromide in DMF
(50 mL) was added dropwise within 3 h to a suspension of K2CO3
(8.28 g, 60.0 mmol) in DMF (50 mL) kept at 50 °C, and the re-
sulting mixture was stirred at this temperature for an additional
36 h. Then, the DMF was removed under reduced pressure, and
CH2Cl2 (150 mL) and water (75 mL) were added to the residue.
The organic phase was separated and washed with 10% HCl
(3ϫ75 mL), water (50 mL), and brine (50 mL). The organic layer
was then dried with anhydrous MgSO4 and concentrated under re-
duced pressure by using a rotary evaporator. The crude product
was purified by recrystallization from EtOAc/hexane to give a col-
1
lid (7.46 g, 52%); m.p. 113–114 °C. H NMR (300 MHz, CDCl3):
δ = 4.06 (d, J = 6.5 Hz, 2 H, NCH2), 4.31 (s, 2 H, SO2CH2), 5.02–
5.08 (m, 2 H, CH=CH2), 5.67 (ddt, J = 6.5, 9.8, 17.4 Hz, 1 H,
CH=CH2), 7.25–7.50 (m, 10 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 54.4 (CH2), 57.6 (CH2), 118.7 (CH=CH2), 127.5 (CH-
Ar), 128.5 (2 C, CH-Ar), 128.7 (3 C, CH-Ar), 128.8 (C-Ar), 129.1
(2 C, CH-Ar), 130.8 (2 C, CH-Ar), 133.2 (CH-Ar), 139.1 (C-Ar)
ppm. HRMS (ESI): calcd. for C16H17NNaO2S [M
+
Na]+
310.0878; found 310.0872. C16H17NO2S (287.38): calcd. C 66.87,
H 5.96, N 4.87; found C 66.66, H 5.98, N 4.78.
N-Allyl-1-(4-cyanophenyl)-N-phenylmethanesulfonamide
(31a):
Compound 31a was prepared according to the procedure for 26a.
Colorless solid (6.86 g, 44%); m.p. 112–113 °C. 1H NMR
(300 MHz, CDCl3): δ = 4.16 (d, J = 5.8 Hz, 2 H, NCH2), 4.32 (s,
2 H, SO2CH2), 5.08–5.15 (m, 2 H, CH=CH2), 5.72 (ddt, J = 5.8,
9.5, 16.0 Hz, 1 H, CH=CH2), 7.25–7.44 (m, 5 H, Ar), 7.52–7.57
(m, 2 H, Ar), 7.67–7.71 (m, 2 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 54.5 (CH2), 57.1 (CH2), 112.7 (C-Ar), 118.2 (CN),
119.3 (CH=CH2), 128.0 (CH), 128.5 (2 C, CH-Ar), 129.4 (2 CH-
Ar), 131.6 (2 CH-Ar), 132.4 (2 C, CH-Ar), 132.6 (CH), 134.0 (C-
Ar), 138.7 (C-Ar) ppm. MS (ESI): m/z (%) = 335 [M + Na]+.
C17H16N2O2S (312.37): calcd. C 65.36, H 5.16, N 8.97; found C
65.16, H 4.83, N 8.85.
1
orless solid (4.16 g, 73%); m.p. 131–133 °C. H NMR (300 MHz,
CDCl3): δ = 1.56 (dd, J = 5.9, 7.9 Hz, 1 H, 6-H), 2.07 (t, J =
5.5 Hz, 1 H, 6Ј-H), 2.36 (ddd, J = 3.6, 4.9, 8.2 Hz, 1 H, 5-H), 3.78
(d, J = 9.4 Hz, 1 H, 4-H), 4.10 (dd, J = 3.6, 9.4 Hz, 1 H, 4Ј-H),
7.20–7.24 (m, 1 H, Ar), 7.34–7.42 (m, 7 H, Ar), 7.58–7.65 (m, 2 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.8 (C-6), 19.7 (C-5),
45.4 (C-1), 46.6 (C-4), 122.3 (2 C, CH-Ar), 125.7 (CH-Ar), 128.8
(2 C, CH-Ar), 129.39 (2 C, CH-Ar), 129.41 (CH-Ar), 129.7 (C-Ar),
131.3 (2 C, CH-Ar), 137.3 (C-Ar) ppm. MS (ESI): m/z = 286 [M
+ H]+. C16H15NO2S (285.36): calcd. C 67.34, H 5.30, N 4.91; found
C 67.36, H 5.14, N 5.03.
General Procedure for the Synthesis of N-Allyl-1-arylmethanesulfon-
anilides 26–32 (GP7):
A solution of allyl bromide (7.26 g,
60.0 mmol) in DMF (10 mL) was added dropwise within 1 h to
a vigorously stirred mixture of the respective sulfonamide 10–16
(50.0 mmol), K2CO3 (8.28 g, 60.0 mmol), and DMF (40 mL) kept
at 60 °C. The resulting mixture was stirred at this temperature for
an additional 2 h, and the DMF was removed under reduced pres-
sure by using a rotary evaporator. CH2Cl2 (100 mL) was added,
and the resulting mixture was acidified to pH Յ 2 with 15% HCl.
The organic phase was separated, successively washed with 3%
HCl (5ϫ50 mL), water (100 mL), and brine (50 mL), and then
dried with MgSO4. The solvent was evaporated, and the crude
product was recrystallized from EtOAc/hexane. The following sul-
fonamides were prepared according to GP7.
1-(4-Cyanophenyl)-3-phenyl-2-thia-3-azabicyclo[3.1.0]hexane
2,2-
Dioxide (39a): Compound 39a was prepared according to the pro-
1
cedure for 34a. Colorless solid (4.84 g, 78%); m.p. 119–120 °C. H
NMR (300 MHz, CDCl3): δ = 1.59 (t, J = 7.3 Hz, 1 H, 6-H), 2.14
(t, J = 5.5 Hz, 1 H, 6Ј-H), 2.39–2.45 (m, 1 H, 5-H), 3.80 (d, J =
9.5 Hz, 1 H, 4-H), 4.11 (dd, J = 3.3, 9.8 Hz, 1 H, 4Ј-H), 7.23–7.25
(m, 1 H, Ar), 7.36–7.43 (m, 4 H, Ar), 7.68–7.75 (m, 4 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.9 (C-6), 20.1 (C-5), 44.9 (C-
1), 46.6 (C-4), 113.1 (C-Ar), 118.1 (CN), 122.7 (2 C, CH-Ar), 126.2
(CH-Ar), 129.4 (2 C, CH-Ar), 131.9 (2 C, CH-Ar), 132.4 (2 C, CH-
Ar), 135.2 (C-Ar), 136.6 (C-Ar) ppm. MS (ESI): m/z = 311 [M +
H]+. C17H14N2O2S (310.37): calcd. C 65.79, H 4.55, N 9.03; found
C 65.98, H 4.26, N 9.01.
N-Allyl-N-(2-methylphenyl)-1-phenylmethanesulfonamide
(26b):
1
Colorless solid (10.8 g, 72%); m.p. 83–84 °C. H NMR (300 MHz,
CDCl3): δ = 2.37 (s, 3 H, CCH3), 4.05 (d, J = 6.5 Hz, 2 H, NCH2),
4.36 (s, 2 H, SO2CH2), 4.97–5.06 (m, 2 H, CH=CH2), 5.72 (ddt, J
= 6.5, 9.8, 17.4 Hz, 1 H, CH=CH2), 6.98 (d, J = 7.3 Hz, 1 H, Ar),
7.14–7.31 (m, 3 H, Ar), 7.39–7.52 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.7 (CH3), 54.9 (CH2), 58.1 (CH2), 119.5
(CH=CH2), 126.5 (CH), 128.5 (CH), 128.67 (CH), 128.75 (2 C,
CH-Ar), 128.84 (C-Ar), 129.2 (CH), 130.8 (2 C, CH-Ar), 131.5
(CH), 132.6 (CH), 137.9 (C-Ar), 139.7 (C-Ar) ppm. MS (ESI): m/z
= 324 [M + Na]+. C17H19NO2S (301.40): calcd. C 67.74, H 6.35,
N 4.65; found C 67.57, H 6.17, N 4.66.
General Procedure for the Preparation of Sultams 34–40 (GP8): A
solution of bromine (1.12 g, 7.0 mmol) in CH2Cl2 (10 mL) was
slowly added dropwise within 30 min to a stirred solution of the
respective sulfonamide 26–32 (6 mmol) in CH2Cl2 (30 mL) kept at
0 °C. The resulting mixture was stirred for an additional 10 min,
successively washed with water (30 mL), 10% Na2SO3 (2ϫ30 mL),
and brine (30 mL), and then dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure by using a rotary
evaporator, and the crude dibromide was used in the next step with-
N-Allyl-N-(2,6-dimethylphenyl)-1-phenylmethanesulfonamide (26c):
1
Colorless solid (10.2 g, 65%); m.p. 81–82 °C. H NMR (300 MHz,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20670
/KAP1
Date: 02-08-12 16:48:08
Pages: 11
Access to Sultams by Cyclodialkylation
out any additional purification. A solution of the respective dibro-
mide in anhydrous DMSO (20 mL) was added within 2 min to
NaH (60% suspension in oil, 2.40 g, 60.0 mmol) in anhydrous
DMSO (30 mL) at room temperature. The resulting mixture was
stirred at room temperature for 30 min. Then, the reaction mixture
was quenched with 15% HCl (100 mL), and the product was ex-
tracted from the mixture with CH2Cl2 (3ϫ40 mL). The combined
organic phases were successively washed with 2% HCl (5ϫ40 mL),
water (50 mL), and brine (30 mL) and then dried with MgSO4. The
solvent was removed by using a rotary evaporator, and the crude
product was recrystallized from EtOAc/hexane. The following
sulfonamides were prepared according to GP8.
stirred solution of sulfonamide 40 (10.08 g, 30.0 mmol) in CH2Cl2
(100 mL). The mixture was stirred for an additional 10 min and
then successively washed with water (30 mL), 10 % Na2SO3
(2ϫ30 mL), and brine (30 mL). The mixture was dried with anhy-
drous Na2SO4. The solvent was removed under reduced pressure
by using a rotary evaporator, and the crude dibromide was purified
by recrystallization from EtOAc/hexane to give a yellowish solid
1
(16.7 g, 97%); m.p. 103–104 °C. H NMR (300 MHz, CDCl3): δ =
1.79–1.89 (m, 1 H), 2.33–2.43 (m, 1 H), 3.51–3.58 (m, 1 H), 3.79–
3.90 (m, 3 H), 4.10–4.19 (m, 1 H), 4.56 (d, J = 14.0 Hz, 1 H,
SO2CHHЈ), 4.61 (d, J = 14.0 Hz, 1 H, SO2CHHЈ), 7.11–7.16 (m, 2
H, Ar), 7.23–7.36 (m, 2 H, Ar), 7.44–7.49 (m, 3 H, Ar), 7.54–7.57
(m, 1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 35.4 (CH2),
35.8 (CH2), 48.4 (CH), 49.1 (CH2), 53.8 (CH2), 121.8 (C-Ar), 126.6
(C-Ar), 127.3 (CH-Ar), 129.8 (2 C, CH-Ar), 129.9 (CH-Ar), 130.3
(CH-Ar), 132.5 (2 C, CH-Ar), 132.7 (CH-Ar), 134.9 (C-Ar), 137.7
(C-Ar) ppm. MS (ESI): m/z = 589 [M(35Cl, 79Br, 79Br, 79Br) +
NH4]+, 591 [(M + 2) + NH4]+, 593 [(M + 4) + NH4]+, 595 [(M +
6) + NH4]+, 597 [(M + 8) + NH4]+. C17H17Br3ClNO2S (574.55):
calcd. C 35.54, H 2.98, N 2.44; found C 35.70, H 2.73, N 2.52.
3-(2-Methylphenyl)-1-phenyl-2-thia-3-azabicyclo[3.1.0]hexane 2,2-
1
Dioxide (34b): Colorless solid (4.66 g, 78%); m.p. 119–120 °C. H
NMR (300 MHz, CDCl3): δ = 1.54 (dd, J = 5.9, 7.9 Hz, 1 H, 6-
H), 2.17 (t, J = 5.5 Hz, 1 H, 6Ј-H), 2.37–2.42 (m, 1 H, 5-H), 2.63
(s, 3 H, CH3), 3.83 (d, J = 9.4 Hz, 1 H, 4-H), 4.16 (dd, J = 3.6,
9.4 Hz, 1 H, 4Ј-H), 7.20–7.42 (m, 8 H, Ar), 7.50 (d, J = 7.4 Hz, 1
H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4 (C-6), 19.6
(CH3/C-5), 20.9 (C-5/CH3), 44.2 (C-1), 46.4 (C-4), 122.2 (2 C, CH-
Ar), 125.7 (CH-Ar), 126.2 (CH-Ar), 128.0 (C-Ar), 129.4 (2 C, CH-
Ar), 129.6 (CH-Ar), 130.9 (CH-Ar), 133.1 (CH-Ar), 137.4 (C-Ar),
140.9 (C-Ar) ppm. MS (ESI): m/z = 322 [M + Na]+. C17H17NO2S
(299.39): calcd. C 68.20, H 5.72, N 4.68; found C 68.31, H 5.53, N
4.74.
N-(4-Bromophenyl)-N-(but-3-ynyl)-1-(2-chlorophenyl)methanesulf-
onamide (44): NaH (60% dispersion in oil, 160 mg, 4.0 mmol) was
washed with anhydrous Et2O (3ϫ5 mL) and was then added to
anhydrous DMSO (30 mL). The resulting suspension was stirred at
60 °C until the solution became clear. To this solution was added
sulfonamide 41 (576 mg, 1 mmol) in DMSO (10 mL) dropwise at
room temperature, and the resulting mixture was stirred for 15 min.
The reaction was quenched with 15% HCl (50 mL), and the re-
sulting mixture was extracted with CH2Cl2 (3ϫ30 mL). The com-
bined organic phases were successively washed with 2 % HCl
(5ϫ20 mL), water (50 mL), and brine (30 mL) and then dried with
MgSO4. The solvent was removed under reduced pressure by using
a rotary evaporator, and the product was isolated by column
chromatography (EtOAc/hexane, 1:6; Rf = 0.15) to give a colorless
oil (28 mg, 7%). 1H NMR (300 MHz, CDCl3): δ = 2.00 (t, J =
2.6 Hz, 1 H, CϵCH), 2.37 (td, J = 2.6, 7.4 Hz, 2 H, NCH2CH2),
3.78 (t, J = 7.4 Hz, 2 H, NCH2), 4.60 (s, 2 H, SO2CH2), 7.12–7.17
(m, 2 H, Ar), 7.26 (td, J = 1.5, 7.4 Hz, 1 H, Ar), 7.33 (td, J = 1.9,
7.6 Hz, 1 H, Ar), 7.44–7.49 (m, 3 H, Ar), 7.66 (dd, J = 1.9, 7.4 Hz,
1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.2 (CH2), 50.2
(CH2), 54.4 (CH2), 70.7 (CϵCH), 80.2 (CϵCH), 122.0 (C-Ar),
126.8 (C-Ar), 127.3 (CH-Ar), 129.9 (CH-Ar), 130.26 (2 C, CH-Ar),
130.31 (CH-Ar), 132.5 (2 C, CH-Ar), 132.7 (CH-Ar), 135.0 (C-Ar),
137.7 (C-Ar) ppm.
3-(2,6-Dimethylphenyl)-1-phenyl-2-thia-3-azabicyclo[3.1.0]hexane
2,2-Dioxide (34c): Yellowish solid (3.13 g, 50%); m.p. 201–202 °C.
1H NMR (300 MHz, CDCl3): δ = 1.59 (dd, J = 5.9, 7.9 Hz, 1 H,
6-H), 2.23 (t, J = 5.6 Hz, 1 H, 6Ј-H), 2.37–2.45 (m, 1 H, 5-H), 2.43
(s, 3 H, CH3), 2.56 (s, 3 H, CCH3), 3.47 (d, J = 9.3 Hz, 1 H, 4-H),
4.27 (dd, J = 4.0, 9.3 Hz, 1 H, 4Ј-H), 7.07–7.18 (m, 3 H, Ar), 7.39–
7.43 (m, 3 H, Ar), 7.61–7.64 (m, 2 H, Ar) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 15.8 (C-6), 18.6 (CH3), 18.9 (CH3), 21.1
(C-5), 44.9 (C-1), 46.4 (C-4), 128.5 (2 C, CH-Ar), 128.77 (CH-Ar),
128.87 (CH-Ar), 128.89 (CH-Ar), 129.2 (CH-Ar), 131.0 (2 C, CH-
Ar), 131.3 (C-Ar), 131.8 (C-Ar), 140.2 (C-Ar), 140.3 (C-Ar) ppm.
MS (ESI): m/z = 314 [M + H]+. C18H19NO2S (313.41): calcd. C
68.98, H 6.11, N 4.47; found C 68.72, H 6.43, N 4.52.
N-(But-3-enyl)-1-(2-chlorophenyl)-N-phenylmethanesulfonamide
(41): Diethyl azodicarboxylate (DEAD, 13.1 g, 75.1 mmol) was
slowly added to a stirred solution of sulfonamide 13a (14.05 g,
50.0 mmol), but-3-en-1-ol (5.41 g, 75.0 mmol), and Ph3P (19.7 g,
75.0 mmol) in anhydrous THF (tetrahydrofuran, 100 mL) at room
temperature. The resulting solution was stirred at room tempera-
ture for an additional 24 h. The solvents were removed under re-
duced pressure by using a rotary evaporator, and the product was
isolated by column chromatography (EtOAc/hexane, 1:6; Rf = 0.54)
General Procedure for the Synthesis of Sultams 45–50 (GP9): A
solution of ceric ammonium nitrate (12.08 g, 22.05 mmol) in water
(80 mL) was added slowly to a stirred solution of the respective
sultam 19d, 20d, 34d–37d (7.0 mmol) in MeCN (100 mL) at 0 °C.
The resulting mixture was stirred for an additional 1 h and then
diluted with water (200 mL). The resulting mixture was extracted
with EtOAc (5ϫ50 mL). The combined organic phases were suc-
cessively washed with 10% Na2SO3 (100 mL), water (50 mL), and
brine (50 mL) and then dried with MgSO4. The solvents were re-
moved by distillation under reduced pressure by using a rotary
evaporator. The crude product was purified by recrystallization
from EtOAc/hexane (to give 47–50) or flash chromatography fol-
lowed by Kugelrohr distillation (to give 45–46). The following sul-
tams were prepared according to GP9.
1
to give a colorless solid (11.4 g, 68%); m.p. 103–104 °C. H NMR
(300 MHz, CDCl3): δ = 2.18–2.26 (m, 2 H, NCH2CH2), 3.69–3.74
(m, 2 H, NCH2), 4.56 (s, 2 H, SO2CH2), 4.98–5.06 (m, 2 H,
CH=CH2), 5.80 (ddt, J = 6.7, 10.5, 17.2 Hz, 1 H, CH=CH2), 7.21–
7.40 (m, 7 H, Ar), 7.45 (dd, J = 1.5, 7.8 Hz, 1 H, Ar), 7.56 (dd, J
= 1.9, 7.5 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 33.1
(CH2), 50.7 (CH2), 53.8 (CH2), 117.2 (CH=CH2), 127.1 (CH-Ar),
127.2 (C-Ar), 127.8 (CH-Ar), 128.7 (2 C, CH-Ar), 129.2 (2 C, CH-
Ar), 129.8 (CH), 130.0 (CH), 132.7 (CH), 134.3 (CH), 135.0 (C-
Ar), 138.8 (C-Ar) ppm. MS (ESI): m/z = 336 [M(35Cl) + H]+, 338
[M(37Cl) + H]+. C17H18ClNO2S (335.85): calcd. C 60.80, H 5.40,
N 4.17; found C 60.72, H 5.63, N 4.39.
Ethyl 5-Methylisothiazolidine-5-carboxylate 1,1-Dioxide (45): The
N-(4-Bromophenyl)-1-(2-chlorophenyl)-N-(3,4-dibromobutyl)-
methanesulfonamide (42): A solution of bromine (9.60 g,
60.0 mmol) in CH2Cl2 (30 mL) was slowly added at 0 °C to a colorless oil (1.22 g, 84%). H NMR (300 MHz, CDCl3): δ = 1.32
crude product was purified by flash chromatography (EtOAc/hex-
ane, 1:3; Rf = 0.15) followed by Kugelrohr distillation to give a
1
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V. V. Sokolov, A. de Meijere et al.
FULL PAPER
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(t, J = 7.1 Hz, 3 H, CH2CH3), 1.69 (s, 3 H, CCH3), 2.21 (ddd, J =
5.8, 8.4, 13.6 Hz, 1 H, 4-H), 2.93 (ddd, J = 5.5, 8.9, 13.6 Hz, 1 H,
4Ј-H), 3.24–3.35 (m, 1 H, 3-H), 3.39–3.50 (m, 1 H, 3Ј-H), 4.21–
4.36 (m, 2 H, CH2CH3), 4.53 (br. s, 1 H, NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.7 (CH2CH3), 18.6 (CCH3), 34.4 (C-4),
38.3 (C-3), 62.6 (OCH2), 64.4 (C-5), 168.3 (CO) ppm. HRMS
(ESI): calcd. for C7H13NNaO4S [M + Na]+ 230.0463; found
230.0463. C7H13NO4S (207.25): calcd. C 40.57, H 6.32, N 6.76;
found C 40.68, H 6.39, N 6.82.
Ethyl 6-Methyl-1,2-thiazinane-6-carboxylate 1,1-Dioxide (46): The
crude product was purified by flash chromatography (EtOAc/hex-
ane, 1:3; Rf = 0.18) to give a colorless solid (1.18 g, 76%); m.p. 73–
1
74 °C. H NMR (300 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.53–1.58 (m, 1 H, 4-H), 1.63 (s, 3 H, CCH3), 1.73–1.82
(m, 1 H, 4Ј-H), 2.14–2.21 (m, 2 H, 5-H and 5Ј-H), 3.33–3.38 (m, 1
H, 3-H), 3.41–3.48 (m, 1 H, 3Ј-H), 4.20–4.28 (m, 2 H, CH2CH3),
4.87 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9
(CH2CH3), 18.4 (CCH3), 21.4 (C-4), 35.0 (C-5), 45.5 (C-3), 62.3
(OCH2), 64.7 (C-6), 169.4 (CO) ppm. HRMS (ESI): calcd. for
C8H15NNaO4S [M + Na]+ 244.0619; found 244.0618. C8H15NO4S
(221.27): calcd. C 43.42, H 6.83, N 6.33; found C 43.21, H 6.96, N
6.38.
[5]
[6]
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, characterization data, and
1H and 13C NMR spectra of new compounds.
[7]
Acknowledgments
This work was supported by the Land Niedersachsen and by KA-
dem CustomChem. GmbH, Göttingen. V. A. R. is indebted to the
German Academic Exchange Service (DAAD) for a scholarship.
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Received: May 17, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 02-08-12 16:48:08
Pages: 11
Access to Sultams by Cyclodialkylation
New Sultams
V. A. Rassadin, D. S. Grosheva,
I. A. Arefeva, A. A. Tomashevskiy,
V. V. Sokolov,* A. de Meijere* ........ 1–11
Access to a Wide Range of Sultams by
Cyclodialkylation of α-Substituted Meth-
anesulfonanilides
The intermolecular cyclodialkylation of α-
substituted methanesulfonamides consti-
tutes a simple and efficient route to five-
and six-membered sultams with α-ethoxy-
carbonyl-α-methyl or α-aryl substitution.
The intramolecular cyclodialkylation of N-
(2,3-dibromopropyl)-α-toluenesulfanilides
readily leads to bicyclic sultams bearing a
cyclopropane ring.
Keywords: Synthetic methods / Hetero-
cycles / Sulfonamides / Cyclodialkylation /
Substituent effects
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