Bicyclic sultams with a nitrogen at the bridgehead and a sulfur atom in the apex position: Facile preparation and conformational properties

Article abstract of DOI:10.1002/ejoc.201000345

A practical synthesis of bicyclic sultams with a pyramidal bridgehead nitrogen atom and a sulfur atom in the apex position has been elaborated. Compounds with 1-azathiabicyclo[2.2.1]heptane (12a), -bicyclo[3.2.1]octane (12b, 12d), and -bicyclo[3.3.1]nonane (13b) skeletons were obtained by direct twofold inter/intramolecular alkylation of corresponding monocyclic sultams 9 and 10 with α, ω-dihalides 11 in K₂CO₃/DMF in 56, 68, 52 and 52% yield, respectively. On the other hand, a 1-aza-9-thiabicyclo[4.2.1] nonane derivative (12c) could be prepared only by stepwise dialkylation in 24 % overall yield. Structural and conformational properties of four of the newly prepared bicyclic sultams in solution as well as in the solid state are discussed.

Full text of DOI:10.1002/ejoc.201000345

FULL PAPER
DOI: 10.1002/ejoc.201000345
Bicyclic Sultams with a Nitrogen at the Bridgehead and a Sulfur Atom in the
Apex Position: Facile Preparation and Conformational Properties
Valentin A. Rassadin,[a] Daria S. Grosheva,[a] Aleksandr A. Tomashevskiy,[a]
Viktor V. Sokolov,*[a] Dmitry S. Yufit,[b] Sergei I. Kozhushkov,[c] and Armin de Meijere*[c]
Keywords: Bridged sultams / Conformational analysis / Cyclization / Oxidative deprotection / Solid-state structures
A practical synthesis of bicyclic sultams with a pyramidal
bridgehead nitrogen atom and a sulfur atom in the apex posi-
K2CO3/DMF in 56, 68, 52 and 52% yield, respectively. On
the other hand, a 1-aza-9-thiabicyclo[4.2.1]nonane derivative
tion has been elaborated. Compounds with 1-azathiabicy- (12c) could be prepared only by stepwise dialkylation in 24%
clo[2.2.1]heptane (12a), -bicyclo[3.2.1]octane (12b, 12d),
and -bicyclo[3.3.1]nonane (13b) skeletons were obtained by
direct twofold inter/intramolecular alkylation of correspond-
ing monocyclic sultams 9 and 10 with α,ω-dihalides 11 in
overall yield. Structural and conformational properties of four
of the newly prepared bicyclic sultams in solution as well as
in the solid state are discussed.
Introduction
The sulfonamide functional group stands out as one of
the most important pharmacophores and thus is a constitu-
ent of many commonly used therapeutic agents. Cyclic
sulfonamides (sultams) have also received significant atten-
tion due to their biological activities and medicinal uses.[1]
For example, it has been shown recently that the rates of
hydrolytic ring opening of β-sultams are 102 to 103 fold
higher than those for the corresponding β-lactams[2] – com-
pounds, which inhibit serine transpeptidases by acylation
via ring opening.[3] While the acyclic sulfonamides can
easily be prepared by reaction of sulfonyl chlorides with
amines, the synthesis of their cyclic analogues (sultams) in
many cases appears to be a problem, which needs further Scheme 1. Known approaches to bicyclic sultams.[4–7]
development of convenient synthetic methods. No wonder
that only a few bridged sultams have been reported up to
Another known approach to bicyclic sultams of the type
now.[4–7] The first compounds of this type were synthesized
5 is based on an intramolecular Heck-type reaction
in 1999 applying a radical-initiated cyclization [Scheme 1,
[Scheme 1, Equation (2)].[7] Although this method provides
see Equation (1)].[6] However, this method has two major
such bicyclic sultams in good yields, it cannot be considered
disadvantages in that it does not provide access to azathia-
as being general, since it furnishes only benzannelated com-
bicyclo[2.2.1]heptanes (3, n = 2), and in other cases (n Ն
pounds of type 5. The third method, by which only the
3) always yields mixtures of 2 and 3, as simple reductive
single bicyclic sultam 8 with a pyramidal nitrogen at the
dehalogenation to furnish 2 competes with intramolecular
bridgehead and a sulfur atom at the apex position was pre-
cyclization.[4,6]
pared [Scheme 1, see Equation (3)],[5] relies on a ring-clos-
ing metathesis reaction (RCM) of the precursor 6, followed
by an intramolecular cycloalkylation in the seven-mem-
bered sultam 7.
Recently, our group has reported intermolecular alkyl-
ation reactions of secondary sulfonamides, containing an
additional nucleophilic center, with a wide range of alkylat-
ing agents.[8] As was found during that study, twofold inter/
intramolecular alkylation of such sulfonamides with α,ω-
[a] Department of Chemistry, Saint Petersburg State University,
Universitetskii pr. 26, 198504 Saint Petersburg, Russia
E-mail: vsokolo@mail.ru
[b] Department of Chemistry, University of Durham,
South Rd., Durham DH1 3LE, UK
[c] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: ameijer1@gwdg.de
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V. V. Sokolov and A. de Meijere
FULL PAPER
dibromides provides a rather simple and efficient route to
five-, six- and seven-membered sultams with an α-meth-
oxycarbonyl group. Analogous intramolecular cyclodialkyl-
ations occurring in N-(ω–1,ω-dibromoalkyl)(methoxy-
carbonyl)methanesulfanilides led to a wide range of bicyclic
sultams with 1-methoxycarbonyl-1-sulfonylcyclopropane
moieties in good yields.[9] Here we report our results con-
cerning sequential inter/intramolecular dialkylations of
sultams of type 9, 10 with a free NH group and an ad-
ditional nucleophilic center with different bifunctional
alkylating agents 11 (Scheme 2). The resulting bridged bi-
cyclic sultams 12 and 13 may constitute potential serine
protease inhibitors.
Scheme 3. Synthesis of 1-aza-7-thiabicyclo[2.2.1]heptane, 1-aza-8-
thiabicyclo[3.2.1]octane and 1-aza-9-thiabicyclo[3.3.1]nonane de-
rivatives 12, 13. For details see Table 1.
Scheme 2. Concept for a sequential inter/intramolecular dialkyl-
ation of sultams 9, 10.
Table 1. Synthesis of 1-aza-7-thiabicyclo[2.2.1]heptane, 1-aza-8-
thiabicyclo[3.2.1]octane and 1-aza-9-thiabicyclo[3.3.1]nonane de-
rivatives 12, 13 (see Scheme 3).
Results and Discussion
Starting materials
11
Product
n
m
Yield (%)
The monocyclic sultams methyl 1,2-thiazolidine-5-carbox-
ylate 1,1-dioxide (9) and methyl 1,2-thiazinane-6-carbox-
ylate 1,1-dioxide (10) were prepared in three steps from
methyl 2-(chlorosulfonyl)acetate and p-anisidine according
to previously published protocols.[8,9] Alkylation of com-
pound 9 with different α,ω-dihalides (11) was performed
under the conditions of White (K2CO3/DMF),[10] which
had turned out to be the most efficient ones for the inter-
molecular cyclodialkylation of the sulfonamides.[8] Thus,
treatment 9 with 1,2-dibromoethane (11a) led to methyl 1-
aza-7-thiabicyclo[2.2.1]heptane-4-carboxylate 7,7-dioxide
(12a) in 56% yield (Scheme 3, Table 1). Cyclodialkylations
of the six-membered sultam 10 required an excess of the
bifunctional alkylating agent and prolonged heating (see
Exp. Sect.). However, the corresponding bicyclic sultam 13a
was isolated in a similarly good yield (59%).
To test the scope and limitations of this method with
respect to the preparation of substituted azathiabicyclo-
[3.2.1]octane and azathiabicyclo[4.2.1]nonane skeletons, the
alkylations of 9 and 10 were carried out with 1-bromo-3-
chloropropane (11b), 1,4-dibromobutane (11c) and bis-
(chloromethyl) sulfide (11d). In the case of 11b and 11d,
the corresponding azathiabicyclooctanes 12b and 12d were
isolated in acceptable yields (Table 2). However, in the case
of 11c only the product 14c of a twofold intermolecular
nucleophilic substitution linking two molecules of 9 by a C4
chain was obtained in 53% yield (Scheme 3). This result
is due to the kinetically disfavored formation of a seven-
membered ring by intramolecular C-alkylation in the ini-
tially formed monoalkylation product.[11]
9
9
9
9
10
10
a
b
c
d
a
b
Br(CH2)2Br
Br(CH2)3Cl
Br(CH2)4Br
(ClCH2)2S
Br(CH2)2Br
Br(CH2)3Cl
12a
12b
14c
12d
13aϵ12b
13b
2
2
–
2
3
3
2
3
–
–
2
3
56
68
53
52
59
52
Table 2. Crystal and data collection parameters for compounds
12a–c, and 13b.
Compound
12a
C7H11NO4S C8H13NO4S C9H15NO4S C9H15NO4S
205.23 219.25 233.28 233.28
monoclinic orthorhombic orthorhombic monoclinic
12b
12c
13b
Formula
Molecular mass
Crystal system
Space group
a (Å)
b (Å)
c (Å)
β (°)
V (Å3)
Z
F(000)
D [g cm–3]
µ [mm–1]
Refl. collected
Refl. independent
Rint
R1 [IՆ2σ(I)]
wR2 (all data)
Number of parameters
refined
P21/n
P212121
Pna21
12.9261(3)
10.1607(2)
7.7015(2)
90.00
P21/n
6.4352(3)
7.1099(3)
6.3040(2)
16.2543(6)
10.0908(4)
99.51(2)
1019.78(6)
4
13.8165(6) 10.2973(5)
10.0096(5) 13.0695(6)
97.44(2)
882.47(7)
4
90.00
956.85(8)
4
1011.50(4)
4
432
464
496
496
1.545
0.349
9703
1.522
0.327
12011
2660
1.532
0.314
1.519
0.312
11193
2968
0.0475
0.0297
0.0663
12610
2943
0.0269
0.0311
0.0838
2557
0.0475
0.0299
0.0881
0.1038
0.0339
0.0807
162
179
196
196
GOOF
1.174
1.007
0.999
1.047
To circumvent this difficulty, the N-(p-methoxyphenyl)- trate (Scheme 4).[9] Subsequent treatment of the deprotected
protected monocyclic sultam 9-PMP was first C-alkylated 15-H with potassium carbonate in DMF gave the 1-aza-9-
with 1,4-dibromobutane (11c) and the resulting product 15- thiabicyclo[4.2.1]nonane derivative 12c in 56% yield (24%
PMP deprotected by oxidation with ceric ammonium ni- over three steps).
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Novel Bicyclic Sultams
Scheme 4. Synthesis of methyl 1-aza-9-thiabicyclo[4.2.1]nonane-6-carboxylate 9,9-dioxide (12c). PMP = 4-MeOC6H4.
The structures of the sultams 12a,b,c and 13b were une-
quivocally proved by X-ray crystallography (Figure 1).
Figure 2. Views of the molecules 12a–c and 13b along the N···Cquat
direction.
comes along with a different extent of interaction between
the carbonyl group and the sultam framework, causing the
bridgehead to carbonyl C–C bond in 12a to be significantly
shorter than the equivalent bonds in the three other com-
pounds [1.506(1) vs. 1.526–1.537Å]. Interestingly enough,
the other bond lengths are not affected. The ring strain en-
ergy decreases with the increase of bridge lengths in com-
pounds 12a–c, 13b, which can be easily derived from a com-
parison of the sums of bond angles at the nitrogen atoms
in these compounds. Indeed, these sums are equal to 310.2,
325.3, 341.6 and 340.0° in 12a–c, 13b, respectively, i.e. the
nitrogen atom in molecule 12a is the most pyramidalized
Figure 1. Molecular structures of methyl 1-aza-7-thiabicyclo[2.2.1]-
heptane-4-carboxylate 7,7-dioxide (12a), of methyl 1-aza-8-thia-
bicyclo[3.2.1]octane-5-carboxylate 8,8-dioxide (12b), of methyl 1-
aza-9-thiabicyclo[4.2.1]nonane-6-carboxylate 9,9-dioxide (12c) and
of methyl 1-aza-9-thiabicyclo[3.3.1]nonane-5-carboxylate 9,9-diox-
ide (13b) in the crystals.[12]
The Cambridge Crystallographic Database[13] contains one. Figure 2 also demonstrates the effect of the oligometh-
only thirteen structures of norbornane derivatives with a ylene spacer on the orientation of the methoxycarbonyl
substituent at the bridgehead carbon, the same number of group: in molecules 12a and 13b with symmetrical core
1-substituted bicyclo[3.3.1]nonanes (nine of which are part skeletons, the (SO2)C–C(OO) bonds are in the NSC plane,
of bulky triphenylene-based inclusion compounds[14]), and whereas in 12b and 12c they are bent significantly into the
only one 1-substituted bicyclo[3.2.1]octane derivative.[15] direction of the less bulky dimethylene bridges. The packing
Even fewer heterocyclic analogues with these skeletons have of molecules 12a–c, 13b can be described as a three-dimen-
been studied, so the synthesis and structural characteriza- sional network of various CH···O contacts. Short CH···N
tion of the sultams 12a–c and 13b provided an opportunity contacts are present only in the crystal of 12a. This proba-
to analyze the influence of ring size changes on the geome- bly reflects a higher basicity of the nitrogen atom in 12a
try of the skeleton and the orientation of the substituents. due to its more pyramidalized configuration (see above).
This effect is demonstrated in Figure 2, where the molecules
12a–c and 13b are viewed along the N···Cquat direction.
Molecules of heteroanalogues of bicyclo[3.3.1]nonane
are known to adopt chair-chair as well as chair-boat con-
Several features of the molecular geometries have to be formations in solution as well as in the solid state de-
noticed. The relative orientation of the methoxycarbonyl pending on their substitution pattern.[16] As expected, the
substituent is different in all four compounds: whereas in heterosubstituted bicyclo[3.3.1]nonane moiety in 13b
the molecule 12a the S–Cquat and C=O bonds are eclipsed, adopts a flattened chair-chair conformation in the solid
in the other three molecules these bonds are almost perpen- phase with torsional angles C8–C7–C6–C5 and N–C6–C7–
dicular to each other; the corresponding torsional angles S– C6 equal to –44.6 and 43.8°, respectively. An alternative
C–C–O are equal to –3.2, 88.8, 129.3 and 102.3° in 12a–c chair-boat conformer in this specific case should be ad-
and 13b, respectively. Such a difference in the orientation ditionally destabilized by van der Waals interactions be-
Eur. J. Org. Chem. 2010, 3481–3486
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V. V. Sokolov and A. de Meijere
FULL PAPER
nique. Assignment of signals for the bicyclic sultams 12, 13 were
performed on the basis of 2D NMR experiments (NOESY, HSQS,
gCOSY, TOCSY). Mass spectra were recorded with a Finnigan
MAT 95 spectrometer. TLC analyses were performed on precoated
sheets, 0.25 mm Sil G/UV254 (Macherey–Nagel). Silica gel grade
60 (230–400 mesh) (Merck) was used for column chromatography.
Melting points were determined with a Büchi 510 capillary melting
point apparatus, values are uncorrected. Elemental analyses of so-
lid compounds: Analytical Laboratory of the Department of Or-
ganic Chemistry, Chemical Faculty, Saint-Petersburg State Univer-
tween the SO2 moiety and the C-3 (C-7) methylene groups.
In the case of the sultam 12b, the six-membered fragment
also prefers a flattened chair conformation with torsional
angles C2–C3–C4–C5 and N–C2–C3–C4 equal to 48.9 and
–46.7°, respectively. It should be noted that the conforma-
tions of the six-membered fragments in sultams 12b and
13b are essentially the same.
1
In their H-NMR spectra, the sultams with a six-mem-
bered fragment exhibit a long-range spin-spin coupling be-
tween H-4Ј/H-6Ј (in sultam 12b) and H-2/H-4 (in sultam sity and Mikroanalytisches Laboratorium des Instituts für Anor-
12d) protons, with coupling constants of 4J = 1.2 and
ganische Chemie der Georg-August-Universität Göttingen.
2.8 Hz, respectively. Such couplings should be associated
with a W-type mutual arrangement of these hydrogen atoms
in solution. In the case of the sultam 12b, this phenomenon
undoubtedly indicates the chair conformation for the six-
membered ring moiety. In the case of 12d, however, no defi-
nite conclusion can be derived from this fact, as both, the
possible chair and boat conformers of the 2-aza-1,4-di-
thiane 1,1-dioxide moiety[16] should possess such a mutual
arrangement of protons. The conformations of sultams 12b,
13b can be unambiguously determined based on the differ-
ence in signal width for the two protons at the same carbon
atom. The corresponding values of these differences for H-
2 protons of sultams 12b and 13b are approximately the
same and equal to 10 Hz. This clearly indicates the chair
conformation of the 2-azathiane 1,1-dioxide fragments for
both of these compounds in their solutions.
Crystal Structure Analyses: Crystals suitable for X-ray diffractome-
try of compounds 12a–c, and 13b were obtained by slow evapora-
tion of their solutions in octane/EtOAc (12a, 12b), octane/CHCl3
(12c) and octane/CH2Cl2 (13b). The single-crystal X-ray data were
collected on a Bruker SMART-CCD 6000 diffractometer at
120.0(2) K using graphite-monochromated Mo-Kα radiation (λ =
0.71073 Å). All structures were solved by direct methods and re-
fined by full-matrix least-squares on F2 for all data. All non-hydro-
gen atoms were refined with anisotropic displacement parameters,
H-atoms were located on the difference map and refined iso-
tropically.[12] Crystal and data collection parameters are summa-
rized in Table 2.
General Procedure for the Dialkylation of the Sultams 9, 10 (GP1):
To a mixture of the respective sultam 9, 10 (3 mmol) and anhydrous
K2CO3 (1.38 g, 10 mmol) in DMF (100 mL), a solution of the re-
spective bifunctional alkylating agent 11 (3.2 mmol) in DMF
(20 mL) was added at 70 °C during 10 h, and the reaction mixture
was stirred at this temperature for an additional 12 h. [In the case
of sultam 10, an additional quantity of the bifunctional alkylating
agent (1 mmol) was added in one portion, and the reaction mixture
was stirred for an additional 10 h]. The reaction mixture was con-
centrated on a rotary evaporator, the residue taken up with CH2Cl2
Conclusions
The cyclodialkylation of N-unprotected sultams 9, 10
with an additional nucleophilic center appears to be a new (150 mL) and washed successively with water (2ϫ70 mL), 10% aq.
HCl solution (3ϫ75 mL), water (50 mL) and brine (50 mL). The
organic phase was dried (MgSO4) and concentrated under reduced
pressure. The crude product was purified by recrystallization from
EtOAc/hexane or by column chromatography to give the corre-
sponding bicyclic sultam 12, 13.
general and efficient method for the synthesis of bicyclic
sultams 12, 13 with a pyramidal nitrogen atom at the
bridgehead and a sulfur atom at the apex position. Varia-
tion of the starting materials 9, 10 and the bifunctional alk-
ylating agents 11 allows the preparation of a range of het-
erosubstituted bicyclo[n.m.1]alkanes 12, 13 with potential
biological activity. Further applications of the new synthetic
method towards this interesting family of heterocycles are
currently in progress.
Methyl 1-Aza-7-thiabicyclo[2.2.1]heptane-4-carboxylate 7,7-Dioxide
(12a): From 9 (537 mg, 3 mmol) and 11a (602 mg, 3.2 mmol), com-
pound 12a (344 mg, 56%) was obtained according to GP1 as a
slightly grey solid, m.p. 102–104 °C. IR (KBr): ν = 3022, 2981,
˜
1729, 1440, 1345, 1260, 1167, 1083, 1015, 926, 812, 759, 647 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.08–2.16 (m, 2 H), 2.81–2.96
(m, 4 H), 3.60–3.69 (m, 2 H), 3.88 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 30.6 (2 C, C-3, 5), 47.8 (2 C, C-2, 6),
52.6 (OCH3), 62.7 (C-4), 166.1 (CO) ppm. MS (EI, 70 eV): m/z
(%) = 205 (1) [M]+, 174 (16), 126 (60), 110 (12), 82 (100), 42 (80).
C7H11NO4S (205.2): calcd. C 40.97, H 5.40, N 6.82; found C 40.95,
H 5.41, N 6.96.
Experimental Section
General Aspects: Compounds 9, 9-PMP and 10 were prepared ac-
cording to previously published procedures.[8,9] All other chemicals
were used as commercially available. IR spectra were recorded with
a Bruker IFS 66 spectrometer as KBr pellets. 1H and 13C NMR
spectra were recorded at ambient temperature with a Bruker DPX
300 instrument at 300.13 (1H) and 75.54 (13C and DEPT) MHz,
Varian VXR Inova 500 S instrument at 125.71 (13C and APT) MHz
and Varian Inova 600 at 599.74 (1H) MHz. Chemical shifts (δ) are
given in ppm relative to resonances of solvents (1H: δ = 7.26 for
CHCl3 and δ = 2.50 for [D5]DMSO; 13C: δ = 77.0 for CDCl3 and
δ = 39.5 for [D6]DMSO). Coupling constants (J) are given in Hz.
Multiplicities of signals are described as follows: s = singlet, d =
doublet, t = triplet, m = multiplet. The multiplicities of signals in
13C NMR spectra were determined by the DEPT and APT tech-
Methyl 1-Aza-8-thiabicyclo[3.2.1]octane-5-carboxylate 8,8-Dioxide
(12b): From 9 (537 mg, 3 mmol) and 11b (504 mg, 3.2 mmol), com-
pound 12b (447 mg, 68%) was obtained according to GP1 as a
slightly grey solid, m.p. 104–105 °C. IR (KBr): ν = 2955, 1742,
˜
1440, 1339, 1288, 1254, 1156, 899, 851, 747, 657 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 1.64 (m, 1 H, H-3/3Ј), 1.82–1.91 (m, 1 H,
H-3Ј/3), 2.04 (ddt, J = 1.8, 6.0, 14.0 Hz, 1 H, H-4), 2.41 (ddd, J =
4.6, 10.7, 13.3 Hz, 1 H, H-6), 2.76 (ddt, J = 1.2, 5.4, 14.0 Hz, 1 H,
H-4Ј), 2.85–2.89 (m, 1 H, H-6Ј), 3.07 (ddd, J = 4.6, 10.7, 13.3 Hz,
1 H, H-7), 3.19 (ddd, J = 1.9, 5.9, 14.2 Hz, 1 H, H-2), 3.50 (dddd,
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Novel Bicyclic Sultams
J = 0.7, 4.8, 10.2, 13.3 Hz, 1 H, H-7Ј), 3.82 (s, 3 H, OCH3), 3.99 column chromatography to give 15-PMP (8.29 g, 56%) as a color-
(br. dt, J = 4.8, 14.2 Hz, 1 H, H-2Ј) ppm. 13C NMR (75 MHz, less solid, Rf = 0.26 (EtOAc/hexane, 1:2), m.p. 64–65 °C. IR (KBr):
CDCl3): δ = 17.5 (C-3), 30.0 (C-6), 32.9 (C-4), 43.9 (C-7), 53.5 ν = 3255, 2961, 2837, 1741, 1430, 1391, 1337, 1276, 1167, 1042,
˜
(OCH3), 54.0 (C-2), 64.6 (C-5), 167.6 (CO) ppm. MS (ESI): m/z = 925, 742, 707 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.31–1.45
220 [M + H]+, 242 [M + Na]+. C8H13NO4S (219.1): calcd. C 43.82,
H 5.98, N 6.39; found C 43.85, H 5.90, N 6.44.
(m, 1 H), 1.52–1.66 (m, 1 H), 1.53–2.00 (m, 3 H), 2.32 (ddd, J =
6.9, 8.0, 13.5 Hz, 1 H), 2.47 (dt, J = 4.4, 12.9 Hz, 1 H), 3.03 (ddd,
J = 4.8, 7.7, 13.4 Hz, 1 H), 3.45 (dt, J = 0.9, 6.4 Hz, 2 H), 3.57 (dt,
J = 4.7, 8.5 Hz, 1 H), 3.73–3.81 (m, 1 H), 3.81 (s, 3 H, OCH3),
3.89 (s, 3 H, OCH3), 6.88–6.93 (m, 2 H, H-Ar), 7.22–7.27 (m, 2 H,
H-Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.1 (CH2), 26.9
(CH2), 32.1 (CH2), 32.2 (CH2), 33.0 (CH2), 45.1 (CH2), 53.7
(OCH3), 53.7 (OCH3), 69.0 (SC), 114.7 (2 C, CH-Ar), 125.3 (2 C,
CH-Ar), 129.6 (C-Ar), 158.3 (C-Ar), 167.4 (CO) ppm. MS (ESI):
m/z = 419 [M(79Br)]+, 421 [M(81Br)]+, 442 [M(79Br) + Na]+, 444
[M(81Br) + Na]+, 458 [M(79Br) + K]+, 460 [M(81Br) + K]+, 861
[2M (79Br/79Br) + Na]+, 863 [2M (79Br/81Br) + Na]+, 865 [2M (81Br/
81Br) + Na]+, 877 [2M (79Br/79Br) + K]+, 879 [2M (79Br/81Br) +
K]+, 881 [2M (81Br/81Br) + K]+. C16H22BrNO5S (420.3): calcd. C
45.72, H 5.28, N 3.33; found C 45.74, H 5.31, N 3.14.
Dimethyl 2,2Ј-(Butane-1,4-diyl)bis(1,2-thiazolidine-5-carboxylate)
1,1,1Ј,1Ј-Tetraoxide (14c): From 9 (537 mg, 3 mmol) and 11c
(691 mg, 3.2 mmol), compound 14c (328 mg, 53%) was obtained
as a mixture of two diastereomers according to GP1 as a colorless
1
solid, m.p. 59–60 °C. H NMR (300 MHz, CDCl3): δ = 1.62–1.73
(m, 4 H), 2.43–2.58 (m, 2 H), 2.64–2.80 (m, 2 H), 3.06–3.16 (m, 4
H), 3.19–3.30 (m, 2 H), 3.33–3.40 (m, 2 H), 3.86 (s, 6 H, OCH3),
4.05–4.12 (m, 2 H), ppm. 13C NMR (75 MHz, CDCl3): δ = 22.49
(CH2), 22.52 (CH2), 24.97 (CH2), 25.01 (CH2), 45.04 (CH2), 45.10
(CH2), 45.27 (CH2), 45.35 (CH2), 53.64 (OCH3), 60.68 (CH),
165.61 (CO) ppm. MS (ESI): m/z = 413 [M + H]+, 435 [M +
Na]+, 451 [M + K]+, 847 [2M + Na]+, 863 [2M + K]+.
C14H24N2O8S2 (412.5): calcd. C 40.77, H 5.86, N 6.79; found C
40.77, H 5.84, N 6.76.
Methyl 5-(4-Bromobutyl)-1,2-thiazolidine-5-carboxylate 1,1-Dioxide
(15-H): To a stirred solution of methyl 5-(4-bromobutyl)-2-(4-meth-
oxyphenyl)-1,2-thiazolidine-5-carboxylate 1,1-dioxide (15-PMP)
(4.20 g, 10 mmol) in MeCN (100 mL), a solution of CAN (17.26 g,
31.5 mmol) in water (80 mL) was slowly added at 0 °C. The reac-
tion mixture was stirred for an additional 1 h, concentrated under
reduced pressure, to the residue was added water (100 mL), and
the mixture was extracted with EtOAc (5ϫ50 mL). The combined
organic phases were successively washed with aq. 10% Na2SO3
solution (3ϫ75 mL), water (50 mL), brine (50 mL), dried (MgSO4)
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography followed by recrystalli-
zation from EtOAc/hexane to afford 15-H (2.39 g, 76%) as a color-
Methyl 1-Aza-9-thiabicyclo[3.3.1]nonane-5-carboxylate 9,9-Dioxide
(13b): From 9 (579 mg, 3 mmol) and 11b (662 mg, 4.2 mmol), com-
pound 13b (363 mg, 52%) was obtained according to GP1 as a
colorless solid, m.p. 109–110 °C. IR (KBr): ν = 3438, 2964, 1738,
˜
1
1487, 1452, 1427, 1324, 1251, 1138, 927, 768, 720 cm–1. H NMR
(600 MHz, CDCl3): δ = 1.66 (br. dt, J = 6.8, 14.6 Hz, 2 H, H-3,
7), 2.15–2.25 (m, 2 H, H-3Ј,7Ј), 2.35 (ddt, J = 1.5, 6.8, 14.4 Hz, 2
H, H-4, 6), 2.87 (ddt, J = 2.3, 6.8, 14.2 Hz, 2 H, H-4Ј,6Ј), 3.33
(ddd, J = 1.3, 6.8, 14.8 Hz, 2 H, H-2, 8), 3.79 (s, 3 H, OCH3), 4.09
(br. dt, J = 5.9, 13.9 Hz, 2 H, H-2Ј,8Ј) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.1 (2 C, C-3, 7), 32.5 (2 C, C-4, 6), 52.0 (2 C, C-2,
8), 53.3 (OCH3), 62.6 (C-5), 169.2 (CO) ppm. MS (ESI): m/z = 256
[M + Na]+, 489 [2M + Na]+, 505 [2M + K]+. C9H15NO4S (233.3):
calcd. C 46.34, H 6.48, N 6.00, S 13.75; found C 46.00, H 6.53, N
5.88, S 13.74.
less solid, m.p. 69–70 °C. IR (KBr): ν = 3952, 2876, 2835, 1735,
˜
1513, 1311, 1234, 835, 809, 659 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.19–1.32 (m, 1 H), 1.38–1.52 (m, 1 H), 1.65 (dt, J =
4.4, 12.8 Hz, 1 H), 1.83–1.84 (m, 2 H), 2.13–2.24 (m, 2 H), 2.73–
2.82 (m, 1 H), 3.08–3.17 (m, 2 H), 3.48 (t, J = 6.6 Hz, 2 H), 3.77
(s, 3 H, OCH3), 7.11 (t, J = 6.8 Hz, 1 H, NH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 22.8 (CH2), 30.9 (CH2), 31.3 (CH2),
31.8 (CH2), 33.1 (CH2), 37.6 (CH2), 52.5 (OCH3), 67.8 (SC), 167.2
(CO) ppm. MS (ESI): m/z = 314 [M(79Br) + H]+, 316 [M(81Br) +
H]+, 336 [M(79Br) + Na]+, 338 [M(81Br) + Na]+, 352 [M(79Br) +
K]+, 354 [M(81Br) + K]+, 649 [2M (79Br/79Br) + Na]+, 651 [2M
(79Br/81Br) + Na]+, 653 [2M (81Br/81Br) + Na]+, 665 [2M (79Br/
79Br) + K]+, 667 [2M (79Br/81Br) + K]+, 669 [2M (81Br/81Br) +
K]+. C9H16BrNO4S (314.2): calcd. C 34.40, H 5.13, N 4.46; found
C 34.53, H 5.11, N 4.36.
Methyl 1-Aza-3,8-dithiabicyclo[3.2.1]octane-5-carboxylate 8,8-Di-
oxide (12d): From 9 (537 mg, 3 mmol) and 11e (419 mg, 3.2 mmol),
compound 12d (370 mg, 52%) was obtained according to GP1 as
a colorless solid, m.p. 94–96 °C. IR (KBr): ν = 3004, 2979, 1740,
˜
1
1343, 1269, 1231, 1156, 1087, 764, 726 cm–1. H NMR (600 MHz,
CDCl3): δ = 2.76 (ddd, J = 4.8, 10.7, 13.0 Hz, 1 H, H-6), 2.77 (dd,
J = 2.8, 14.0 Hz, 1 H, H-4), 2.88 (dddd, J = 0.8, 4.3, 9.9, 13.0 Hz,
1 H, H-6Ј), 3.36 (ddd, J = 4.3, 10.7, 12.6 Hz, 1 H, H-7), 3.47 (ddd,
J = 4.8, 9.9, 12.6 Hz, 1 H, H-7Ј), 3.83 (s, 3 H, OCH3), 3.96 (dd, J
= 2.8, 13.5 Hz, 1 H, H-2), 4.00 (br. d, J = 14.0 Hz, 1 H, H-4Ј), 5.29
(d, J = 13.5 Hz, 1 H, H-2Ј) ppm. 13C NMR (125 MHz, CDCl3): δ
= 30.4 (C-6), 36.7 (C-4), 43.7 (C-7), 53.8 (OCH3), 57.4 (C-2), 64.5
(C-5), 166.3 (CO) ppm. MS (ESI): m/z = 260 [M + Na]+, 276 [M
+ K]+, 497 [2M + Na]+, 513 [2M + K]+. C7H11NO4S2 (237.3):
calcd. C 35.43, H 4.67, N 5.90; found C 35.20, H 4.62, N 5.92.
Methyl 1-Aza-9-thiabicyclo[4.2.1]nonane-6-carboxylate 9,9-Dioxide
(12c): To a suspension of K2CO3 (690 mg, 5 mmol) in DMF
(100 mL), a solution of the (bromobutyl)sultam 15-H (471 mg,
1.5 mmol) in DMF (20 mL) was added at 70 °C over a period of
Methyl 5-(4-Bromobutyl)-2-(4-methoxyphenyl)-1,2-thiazolidine-5- 20 h. The reaction mixture was stirred at this temperature for an
carboxylate 1,1-Dioxide (15-PMP): To a mixture of 1,4-dibromo-
butane (11c) (75.6 g, 350 mmol), K2CO3 (6.9 g, 50 mmol) in DMF
(200 mL), a solution of methyl 2-(4-methoxyphenyl)-1,2-thiazolid-
ine-5-carboxylate 1,1-dioxide (9-PMP) (9.98 g, 35 mmol) in DMF
(50 mL) was added at 70 °C over a period of 5 h, and the reaction
mixture was stirred at this temperature for an additional 3 d. Then
the solvent was removed in vacuo, the residue was dissolved in
CH2Cl2 (250 mL) and the solution washed successively with water
(75 mL), 5% aq. HCl solution (5ϫ75 mL), water (50 mL) and
brine (50 mL). The organic phase was dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified by
additional 12 h and then concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (150 mL) and the solution washed
successively with water (75 mL), aq. 10% HCl solution
(3ϫ75 mL), water (50 mL) and brine (50 mL). The organic phase
was dried (MgSO4) and concentrated under reduced pressure. The
crude product was recrystallized from EtOAc/hexane/CH2Cl2 to
give 12c (196 mg, 56%) as a colorless solid, m.p. 114–115 °C. IR
(KBr): ν = 3472, 2953, 1744, 1430, 1325, 1264, 1212, 1138, 1079,
˜
1
700, 643 cm–1. H NMR (600 MHz, CDCl3): δ = 1.53–1.59 (m, 1
H, H-4), 1.77–1.85 (m, 2 H, H-3, H-5), 1.95–2.03 (m, 1 H, H-4Ј),
2.14–2.24 (m, 2 H, H-3Ј, H-7), 2.34 (ddd, J = 3.2, 11.3, 14.5 Hz, 1
Eur. J. Org. Chem. 2010, 3481–3486
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3485

V. V. Sokolov and A. de Meijere
FULL PAPER
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H, H-5Ј), 2.77 (ddd, J = 6.2, 10.0, 15.0 Hz, 1 H, H-2), 2.98–3.03
(m, 2 H, H-7Ј, H-8), 3.55 (ddd, J = 2.9, 6.6, 14.9 Hz, 1 H, H-2Ј),
3.65–3.70 (m, 1 H, H-8Ј), 3.82 (s, 3 H, OCH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.4 (C-4), 27.2 (C-3), 29.2 (C-7), 33.5 (C-
5), 46.9 (C-8), 51.0 (C-2), 53.4 (OCH3), 69.1 (C), 167.9 (CO) ppm.
MS (ESI): m/z = 234 [M + H]+, 256 [M + Na]+, 489 [2M + Na]+,
722 [3M + Na]+. C9H15NO4S (233.3): calcd. C 46.34, H 6.48, N
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Acknowledgments
This work was supported by the Land Niedersachsen and by KAd-
eMCustomChem GmbH, Göttingen.
[12] CCDC-769323 (for 12a), -769324 (for 12b), -769325 (for 12c),
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graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB21EZ, UK; Fax: +44-1223-336-033; or deposit@ccdc.cam.
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Eur. J. Org. Chem. 2010, 3481–3486