Formation of an unusual product in the reaction of a 1,2,5-thiadiazolidine 1,1-dioxide-derived thioether with sulfuryl chloride

Article abstract of DOI:10.1002/jhet.136

(Chemical Equation Presented) The treatment of a 1,2,5-thiadiazolidine 1,1-dioxide-derived phenylthiomethyl ether with sulfuryl chloride yielded an unexpected dimeric product whose structure was determined using X-ray crystallography. A plausible mechanis

Full text of DOI:10.1002/jhet.136

July 2009
Formation of an Unusual Product in the Reaction of a
1,2,5-Thiadiazolidine 1,1-Dioxide-Derived Thioether with
Sulfuryl Chloride
669
Dengfeng Dou, Erach R. Talaty, Curtis E. Moore, John C. Bullinger,
David M. Eichhorn, and William C. Groutas*
Department of Chemistry, Wichita State University, Wichita, Kansas 67207
*E-mail: bill.groutas@wichita.edu
Received March 10, 2009
DOI 10.1002/jhet.136
Published online 9 July 2009 in Wiley InterScience (www.interscience.wiley.com).
The treatment of a 1,2,5-thiadiazolidine 1,1-dioxide-derived phenylthiomethyl ether with sulfuryl
chloride yielded an unexpected dimeric product whose structure was determined using X-ray crystallog-
raphy. A plausible mechanism for the formation of this product is proposed.
J. Heterocyclic Chem., 46, 669 (2009).
INTRODUCTION
Based on the successful development of (I), we rea-
soned that the replacement of the C¼¼O group by a CH2
group would generate a 1,2,5-thiadiazolidine 1,1-dioxide
(cyclosulfamide) and transform (I) into a new class of
noncovalent inhibitors (II) (Figure 1) [20]. Accordingly,
the appropriate substituted 1,2,5-thiadiazolidine 1,1-
dioxide-derived phenylthiomethyl ether intermediate was
synthesized and then treated with sulfuryl chloride to
obtain the N-chloromethyl derivative (Scheme 2). Sur-
prisingly, work up of the reaction mixture and subse-
quent purification of the product by flash chromatogra-
phy afforded a solid which did not exhibit the spectral
characteristics of the expected N-chloromethyl com-
pound. Instead, an interesting dimeric product (7) was
obtained, the structure of which and the mechanism
leading to it constitutes the subject of the present article.
Chronic obstructive pulmonary disease (COPD) is a
multifactorial inflammatory disorder characterized by al-
veolar wall destruction, enlargement of the air spaces,
and airflow obstruction due to chronic bronchitis and
emphysema [1–3]. The treatment of COPD is sympto-
matic [4,5], and there are no drugs capable of halting
the relentless progression of the disorder. Although the
pathogenesis of COPD is poorly understood, recent
ground-breaking studies indicate that the disorder
involves the close interplay of oxidative stress [6], alve-
olar septal cell apoptosis [7–9], extracellular matrix
destruction arising from a protease/antiprotease imbal-
ance [10,11], and chronic inflammation [12]. Proteases
implicated in COPD include serine (neutrophil elastase),
cysteine (cathepsin S), and metallo-(MMP-2, MMP-9,
and MMP-12) proteases [13]. Agents capable of modu-
lating the aberrant activity of these enzymes may be of
potential therapeutic value [14–16].
RESULTS AND DISCUSSION
We have previously described the design, synthesis,
and in vitro biochemical evaluation of a new and general
class of mechanism-based inhibitors of serine proteases
(structure (I), Figure 1) [17,18], and have recently demon-
strated that the time-dependent inactivation of these
enzymes by (I) proceeds through the initial formation of a
Michael acceptor (a sulfonyl imine), ultimately leading to
the formation of an inactive enzyme-inhibitor complex
(or complexes) [19]. A key step in the multistep synthesis
of (I) was the synthesis of a substituted N-chloromethyl
sulfohydantoin via a sulfuryl chloride-mediated cleavage
of a phenylthiomethyl ether (Scheme 1).
The structure of product (7) was established on the
basis of the following data: the molecular weight of the
compound was determined by ESI-MS to be 549, corre-
sponding to the molecular formula C27H40N4O4S2,
which was in agreement with the elementary analysis of
the product. The structure of (7) was established unam-
biguously via single crystal X-ray crystallography. An
ORTEP [21] view (Figure 2) and X-ray crystal structure
data (Table 1) are shown below [22].
A plausible mechanism depicting the formation of (7)
is outlined in Figure 3, line (a), whereby the initial for-
mation of a chlorosulfonium salt proceeds further along
C
V
2009 HeteroCorporation

670
D. Dou, E. R. Talaty, C. E. Moore, J. C. Bullinger, D. M. Eichhorn, and W. C. Groutas
Vol 46
Scheme 1
Figure 1. Design of noncovalent inhibitor (II).
two pathways: one leading to an iminium ion (A) [23],
and the other leading to a sulfur ylide (B), probably
favored by the high acidity of the methylene hydrogens
in the moiety -N(SO2N-)CH2SClPh. This ylide subse-
quently undergoes rearrangement to a-chlorosulfide (C)
in a process that is reminiscent of the Pummerer rear-
rangement [24,25]. When (C) dissociates into an ion
pair (both ions are stabilized by resonance), anion (D)
undergoes a Michael-type reaction with iminium ion (A)
to afford the unusual dimeric product (7). The equilib-
rium leading to (A) will likely be more favorable for
formation of (A) than (B), and hence more favorable for
(A) than for (C) and (D). However, capture of (D) by
(A) to produce (7) would shift the series of equilibria
from (B) to (C) and (D), ultimately leading to (7).
It now becomes clear why such a dimeric product is
not observed when the initial phenyl thiomethyl ether
bears a carbonyl group at position 3 of the 1,2,5-thiadia-
zolidine 1,1-dioxide ring, but merely affords the chloro-
methyl derivative upon treatment with sulfuryl chloride
(Figure 3, line (b)). The presence of a C¼¼O group adja-
cent to nitrogen located at position 2 diminishes its
nucleophilicity considerably (by virtue of being adjacent
to a C¼¼O group, as well as an SO2 group), rendering
path (a) in Figure 3 inoperative and blocking the forma-
tion of a dimer.
plausible mechanism leading to the formation of this
product is proposed.
EXPERIMENTAL
General. The 1H NMR spectra were recorded on a Varian
XL-300 or XL-400 NMR spectrometer. Melting points were
determined on a Mel-Temp apparatus and are uncorrected. IR
spectra were taken with a Nicolet FT-IR-Avatar 360 spectrom-
eter. MS spectra were recorded with VARIAN 1200L mass
spectrometer. Elemental analysis data were obtained from Co-
lumbia Analytical Services (Tucson, AZ). Reagents and sol-
vents were purchased from various chemical suppliers
(Aldrich, Acros rganics, TCI America, and Bachem). Silica gel
(230–450 mesh) used for flash chromatography was purchased
from Sorbent Technologies, Atlanta, GA. Thin layer chroma-
tography was performed using Analtech silica gel plates. The
TLC plates were visualized using iodine and/or UV light.
Methyl 2-(Benzylamino)-4-methylpentanoate (1). DL-Leu-
cine methyl ester hydrochloride (43.6 g; 240 mmol) was sus-
pended in 250 mL 1,2-dichloroethane, and then benzaldehyde
(30.8 g; 270 mmol) and acetic acid (19.2 g; 320 mmol) were
added, followed by sodium triacetoxyborohydride (71.2 g; 335
mmol). The reaction was stirred at RT overnight. The reaction
mixture was adjusted to pH 10 using 20% sodium hydroxide,
and then two layers were separated. The aqueous layer was
extracted with 2 ꢀ 100 mL diethyl ether and the organic
layers were combined and dried over anhydrous sodium
In summary, the structure of an unexpected dimeric
product formed in the reaction of a 1,2,5-thiadiazolidine
1,1-dioxide-derived phenylthiomethyl ether with sulfuryl
chloride was determined using X-ray crystallography. A
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Formation of an Unusual Product in the Reaction of a 1,2,5-Thiadiazolidine
1,1-Dioxide-Derived Thioether with Sulfuryl Chloride
671
gel/ethyl acetate/hexanes) to give compound 2 as a white solid
(31.0 g, 72.6% yield), mp 95–96ꢂC. ir (KBr pellet): 3355
1
(NH), 1740 (C¼¼O) cmꢁ1; H NMR (CDCl3): d 0.68 (dd, 6H,
2CH3, J ¼ 6.0, 94.5 Hz), 1.40–1.60 (m, 3H, CH & CH2), 1.50
(s, 9H, t-Butyl protons), 3.70 (s, 3H, OCH3), 4.65 (t, 1H,
alpha-H, J ¼ 7.5 Hz), 4.71 (dd, 2H, CH2, J ¼ 16.5, 122.1 Hz,
CH2), 7.25–7.45 (m, 5H, phenyl protons); ms: m/z 437
(MþþNa, 100%), 381 (Mþ-OCH3, 19%), 258 (Mþ-SO2NH-
BocþNa, 29%), 236 (Mþ-SO2NHBocþ1, 46%), 91 (PhCHþ2 ,
19%). Anal. Calcd. for C19H30N2O6S: C, 55.05; H, 7.29; N,
6.76. Found: C, 55.13; H, 7.03; N, 6.62.
tert-Butyl
N-Benzyl-N-(1-hydroxy-4-methylpentan-2-yl)
sulfamoylcarbamate (3). To a solution of compound 2 (27.21
g; 65.5 mmol) in 100 mL dry THF, a solution of 2M lithium
borohydride in THF (32.8 mL; 65.6 mmol) was added drop-
wise, followed by the dropwise addition of 197 mL absolute
ethanol. The reaction mixture was stirred at RT overnight. The
reaction mixture was cooled in an ice bath and neutralized to
pH 4 using 5% aqueous HCl solution, and then the solvent
was completely removed. Two hundred and fifty millilitres of
water was added and extracted with 3 ꢀ 300 mL ethyl acetate.
The combined organic extracts were dried over anhydrous so-
dium sulfate. Removal of the solvent yielded a crude product,
which was purified by flash chromatography (silica gel/ethyl
acetate/hexanes) to give compound 3 as a white solid (22.0 g,
86.7% yield), mp 107–109ꢂC. ir (KBr pellet): 3217 (OH),
Figure 2. ORTEP drawing of compound 7 showing the 30% thermal
ellipsoids. H atoms have been omitted for clarity.
sulfate. Removal of solvent yielded a crude product, which
was purified by flash chromatography (silica gel/ethyl acetate/
hexanes) to give compound 1 as a colorless oil (27.0 g, 48.6%
yield). ir (neat): 3333 (NH), 1735 (C¼¼O) cmꢁ1
;
1H NMR
(CDCl3): d 0.88 (dd, 6H, 2CH3, J ¼ 6.6, 19.8 Hz), 1.48 (t,
2H, CH2, J ¼ 7.5 Hz), 3.31 (t, 1H, alpha-H, J ¼ 7.5 Hz), 3.71
(dd, 2H, CH2, J ¼ 12.9, 60 Hz), 3.72 (s, 3H, OCH3), 7.20–
7.26 (mþ, 5H, phenyl protons); ms: m/z 258 (MþþNa, 27%),
236 (M þ1, 53%), 176 (Mþ-C(O)OCH3, 21%), 91 (phCHþ2 ,
100%). Anal. Calcd. for C14H21NO2: C, 71.46; H, 8.99; N,
5.95. Found: C, 71.19; H, 9.28; N, 5.94.
1
1733 (C¼¼O) cmꢁ1; H NMR (CDCl3): d 0.82 (dd, 6H, 2CH3,
J ¼ 6.3, 38.4 Hz), 1.05–1.35 (m, 2H, CH2), 1.48 (s, 9H, t-
Butyl protons), 1.56–1.65 (m, 1H, CH), 2.82 (t, 1H, OH, J ¼
5.4 Hz), 3.55–3.70 (m, 2H, CH2), 4.03–4.17 (m, 1H, CH),
4.50 (dd, 2H, CH2, J ¼ 15.9, 29.7 Hz), 7.18–7.45(m, 5H, phe-
nyl protons); ms: m/z 409 (MþþNa, 100%), 353 (Mþ-t-Bute-
neþNa, 12%), 230 (Mþ-SO2NHBocþNa, 35%), 91 (PhCHþ2 ,
9%). Anal. Calcd. for C18H30N2O5S: C, 55.94; H, 7.82; N,
7.25. Found: C, 56.11; H, 8.12; N, 7.18.
tert-Butyl 5-Benzyl-4-isobutyl-1,2,5-thiadiazolidine-2-car-
boxylate 1,1-dioxide (4). A solution of compound 3 (21.54 g;
55.7 mmol) in 170 mL dry THF was treated with triphenyl
phosphine (29.22 g; 111.4 mmol) and diethyl azodicarboxylate
(DEAD, 19.4 g; 111.4 mmol) with stirring at RT for 4 h. Re-
moval of the solvent left a crude product, which was purified
Methyl
2-(Benzyl(N-(tert-butoxycarbonyl)sulfamoyl)-
amino)-4-methylpentanoate (2). A solution of N-chlorosul-
fonyl isocyanate (14.9 g; 103 mmol) in 130 mL dry methylene
chloride cooled in an ice bath was added dropwise to a solu-
tion of t-butyl alcohol (7.72 g; 103 mmol) in 130 mL dry
methylene chloride with stirring. After 15 min stirring, the
resulting solution was added dropwise to a solution of com-
pound 1 (24.24 g; 103 mmol) and triethylamine (10.6 g; 103
mmol) in 130 mL dry methylene chloride under an ice bath.
The ice bath was removed after the addition and the reaction
stirred at RT for 6 h. The reaction mixture was washed
with150 mL brine and the organic layer was dried over anhy-
drous sodium sulfate. Removal of the solvent yielded a crude
product, which was purified by flash chromatography (silica
Table 1
Crystal data and structure refinement parameters for 7.
Empirical formula
Formula weight
Temperature
C
27H40N4O4S2
548.75
150 K
Crystal habit
Crystal color
H range for data collection
Needle
Colorless
2.04ꢂ to 26.00ꢂ
ꢁ50 ꢃ h ꢃ 50
ꢁ7 ꢃ k ꢃ 7
Diffractometer
Radiation
Bruker Kappa APEX II
˚
Mo Ka, 0.71073 A
Monoclinic
C2/c
Limiting indices
Crystal system
Space group
Unit cell dimensions
ꢁ34 ꢃ l ꢃ 34
Reflections collected/unique
Completeness to h ¼ 26.00ꢂ
Refinement method
Data/restraints/parameters
Refinement threshold
Data > threshold
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
50861/5705 [R(int) ¼ 0.4278]
99.8%
˚
˚
a ¼ 40.714(7) A
b ¼ 6.2300(9) A
Full-matrix least-squares on F2
5705/0/367
˚
c ¼ 27.774(4) A
b ¼ 124.547(9)ꢂ
I > 2r(I)
1681
3
˚
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
5802.5(16) A
8
1.256 Mg/m3
0.222 mmꢁ1
1.021
R1 ¼ 0.0896, wR2 ¼ 0.1829
R1 ¼ 0.3060, wR2 ¼ 0.3004
ꢁ3
˚
2352
0.43 ꢀ 0.06 ꢀ 0.05 mm3
Largest diff. peak and hole
0.491 and ꢁ0.400 e.A
Crystal size
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

672
D. Dou, E. R. Talaty, C. E. Moore, J. C. Bullinger, D. M. Eichhorn, and W. C. Groutas
Vol 46
Figure 3. Postulated mechanism for the formation of compound 7.
1
by flash chromatography (silica gel/ethyl acetate/hexanes) to
give compound 4 as a white solid (16.19 g, 79.ꢁ01% yield), mp
g, 84.0% yield). H NMR (CDCl3): d 0.75 (dd, 6H, 2CH3, J ¼
6.0, 20.7 Hz), 1.35–1.50 (m, 3H, CH & CH2), 2.95 (dd, 1H,
one proton of CH2, J ¼ 7.2, 9.0 Hz), 3.32–3.43 (m, 1H, CH),
3.65 (m, 1H), 3.65 (dd, 1H, one proton of CH2, J ¼ 7.2, 9.0
Hz), 4.38 (dd, 2H, CH2, J ¼ 7.8, 15.0 Hz), 4.45 (dd, 2H, CH2,
J ¼ 13.8, 156.9 Hz), 7.23–7.53 (m, 10H, phenyl protons); ms:
m/z 391 (Mþþ1, 78%), 281 (Mþ-PhSH, 100%). Anal. Calcd.
for C20H26N2O2S2: C, 61.50; H, 6.71; N, 7.17. Found: C,
61.34; H, 7.04; N, 7.16.
81–82ꢂC. ir (KBr pellet): 1721 (C¼¼O) cm
;
1H NMR
(CDCl3): d 0.79 (dd, 6H, 2CH3, J ¼ 6.3, 14.4 Hz), 1.35–1.60
(m, 3H, CH & CH2), 1.56 (s, 9H, t-Butyl protons), 3.40–3.51
(m, 2H, CH2), 3.80–3.88 (m, 1H, CH), 4.29 (dd, 2H, CH2, J ¼
15.3, 48.3 Hz), 7.30–7.41 (m, 5H, phenyl protons); ms: m/z
391 (MþþNa, 5%), 335 (Mþ-t-Butene þNa, 42%), 176 (Mþ-
CH2OH-SO2NHBoc, 35%), 91 (PhCHþ2 , 100%). Anal. Calcd.
for C18H28N2O4S: C, 58.67; H, 7.66; N, 7.60. Found: C,
58.85; H, 7.75; N, 7.53.
2,20-Methylenebis(5-benzyl-4-isobutyl-1,2,5-thiadi-azolidine)
1,1,10,10-tetraoxide (7). To a solution of compound 6 (1.18 g;
3.0 mmol) in 4 mL dry methylene chloride in an ice bath, a so-
lution of sulfuryl chloride (0.82 g; 6.0 mmol) in 2 mL dry
methylene chloride was added with stirring. The reaction was
allowed to warm to RT and stirred for 2 h. The solvent was
removed and the residue was purified by flash chromatography
(silica gel/ethyl acetate/hexanes) to give compound 7 as a white
2-Benzyl-3-isobutyl-1,2,5-thiadiazolidine 1,1-dioxide (5).
A solution of compound 4 (15.76 g; 42.8 mmol) in 40 mL dry
methylene chloride was treated with trifluoroacetic acid (140
mL) at RT for 3 h. Removal of the solvent left a crude prod-
uct, which was purified by flash chromatography (silica gel/
ethyl acetate/hexanes) to give compound 5 as a white solid
(10.5 g, 91.5% yield), mp 60–62ꢂC. ir (KBr pellet): 3225
1
solid (0.15 g, 18.2% yield), mp 127–128ꢂC. H NMR (CDCl3):
1
(NH) cmꢁ1; H NMR (CDCl3) d 0.80 (dd, 6H, 2CH3, J ¼ 6.3,
d 0.79 (dd, 12H, 4CH3, J ¼ 6.3, 24.0 Hz), 1.40–1.58 (m, 6H,
2CH & 2CH2), 3.25 (dd, 2H, two protons of 2CH2, J ¼ 6.3,
9.6 Hz), 3.38–3.48 (m, 2H, 2CH), 3.72 (dd, 2H, two protons of
2CH2, J ¼ 6.9, 9.6 Hz), 4.26 (dd, 4H, 2CH2, J ¼ 14.7, 62.1
Hz), 4.60 (s, 2H, bridge CH2), 7.25–7.41(m, 10H, phenyl pro-
tons); ms: m/z 549 (Mþþ1, 76%), 281 (Mþ-5, 100%), 91
(PhCHþ2 , 24%). Anal. Calcd. for C27H40N4O4S2: C, 59.09; H,
7.35; N, 10.21. Found: C, 59.02; H, 7.15; N, 10.17.
24.9 Hz), 1.38–1.58 (m, 3H, CH & CH2), 3.12–3.20 (m, 1H,
one proton of CH2), 3.40–3.50 (m, 1H, one proton of CH2),
3.50–3.60 (m, 1H, CH), 4.28(s, 1H, NH), 4.29 (dd, 2H, CH2, J
¼ 12.0, 45.6), 7.25-7.42 (m, 5H, phenyl protons); ms: m/z 291
(MþþNa, 100%), 91 (PhCHþ2 , 20%). Anal. Calcd. for
C13H20N2O2S: C, 58.18; H, 7.51; N, 10.44. Found: C, 58.09;
H, 7.42; N, 10.20.
2-Benzyl-3-isobutyl-5-[(phenylsulfanyl)methyl]-1,2,5-thia-
diazolidine 1,1-dioxide (6). A solution of compound 5 (0.97
g; 3.6 mmol) in 4 mL dry DMF was cooled in an ice bath,
and then sodium hydride (0.23 g; 60% w/w; 5.8 mmol) was
added with stirring. Ten minutes later, chloromethyl phenyl
sulfide (0.80 g; 5.0 mmol) was added. The reaction was
allowed to warm to room temperature and stirred for 2 h.
DMF was removed by oil pump under 40ꢂC. The residue was
dissolved in 30 mL ethyl acetate and washed with 2 ꢀ 20 mL
brine, and then the organic layer was dried over anhydrous so-
dium sulfate. Removal of the solvent left a crude product,
which was purified by flash chromatography (silica gel/ ethyl
acetate/ hexanes) to give compound 6 as a colorless oil (1.18
Acknowledgments. This work was generously supported by a
grant from the National Institutes of Health (HL 57788).
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Journal of Heterocyclic Chemistry
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July 2009
Formation of an Unusual Product in the Reaction of a 1,2,5-Thiadiazolidine
1,1-Dioxide-Derived Thioether with Sulfuryl Chloride
673
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Journal of Heterocyclic Chemistry
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