A notable conversion of a thiolacetate to its corresponding sulfonyl chloride

Article abstract of DOI:10.1016/j.tetlet.2012.03.111

A direct conversion of a thiolacetate to its corresponding sulfonyl chloride in the presence of acid and base sensitive functional groups is described.

Full text of DOI:10.1016/j.tetlet.2012.03.111

Tetrahedron Letters 53 (2012) 3203–3205
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A notable conversion of a thiolacetate to its corresponding sulfonyl chloride
⇑
Yuhua Huang , Frank Bennett, Vishal Verma, F. George Njoroge, Malcolm MacCoss
Merck Research Laboratories, 126 East Lincoln Ave., Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct conversion of a thiolacetate to its corresponding sulfonyl chloride in the presence of acid and
base sensitive functional groups is described.
Received 28 October 2011
Revised 23 March 2012
Accepted 26 March 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sulfonamide
Sulfonyl chloride
Thiolacetate
The sulfonamide functionality has a well established history in
the development of pharmaceuticals, first introduced into antimi-
crobials (sulfa drugs, e.g. Prontosil). This functionality was then ex-
panded into other classes of drugs such as diuretics (e.g.
Furosemide), drugs used to treat inflammatory bowel disease
(e.g. Sulsalazine), anticonvulsants (e.g. Sultiame), the PDE5 inhibi-
tor, Viagra, and a key component of the blockbuster COX-2 inhibi-
tor, Celebrex (Celecoxib).
The primary method of forming a sulfonamide involves treating
a sulfonyl chloride with an amine or ammonia. In turn, most com-
monly, sulfonyl chlorides are prepared from the oxidative chlorina-
tion of thiols. Unfortunately, many of these processes are
conducted under harsh conditions sometimes requiring excessive
amounts of reagents.
As part of a medicinal chemistry program we required an effi-
cient preparation of sulfonyl chloride (1; Fig. 1) to prepare a series
of sulfonamides. We reasoned that this critical intermediate could
be obtained from thiol 2.
As can be seen in Figure 1, the desired oxidation would have to
be carried out in the presence of acid (isopropylidene protection of
1,2-diol) and base (phthalimide protection of amine) sensitive
functionality. Requiring controlled conditions we were attracted
to the potassium nitrate–sulfuryl chloride system, developed by
Park et al.1 a process that has not gone unnoticed by fellow work-
ers within the Merck organization. For example, workers in Eng-
land while developing a series of potential Alzheimer’s agents
displaced iodide (3; Scheme 1) with potassium O-ethylxanthate,
which was subsequently hydrolyzed to thiol 4 in quantitative
yield, prior to oxidation to sulfonyl chloride 5.2
Chemists at Merck Frosst in Canada relying on the weak S–Si
bond, converted a range of aromatic (e.g. Scheme 2) and aliphatic
triisopropylsilanylsulfanyls directly to the corresponding sulfonyl
chlorides.3 For obvious reasons we were particularly interested in
the direct conversion of phthalimide 6 to sulfonyl chloride 7, which
was treated in crude form with amine 8 to give the desired sulfon-
amide 9, albeit in a modest 31% isolated yield.
With the aforementioned examples in mind, from the commer-
cially available triol 10, the thiolacetate 14 was prepared in 3 steps
(Scheme 3). Initially, the amino functionality is protected as
phthalimide 12, followed by conversion of the 1,2-diol to the iso-
propylidine 13, in an overall 70% isolated yield. Transformation
of the primary alcohol to the thioester 14 was achieved under
Mitsonobu conditions in the presence of thioacetic ester, in excel-
lent yield.
Prior to conversion to the mercaptan we decided to try the
KNO3-sulfuryl chloride oxidations on the thioester (Scheme 4).
Eliminating this step from the reaction sequence avoids both the
potential hydrolytic partial opening of the phthalimide functional-
ity and dimerization (to the symmetrical disulfide) on exposure to
O
O
N
Cl
N
S
HS
O
O
O
O
O
O
O
O
⇑
2
Corresponding author. Tel.: +1 732 594 3278; fax: +1 908 740 7152.
1
E-mail
addresses:
yuhua.huang@spcorp.com,
yuhua.huang@merck.com
(Y. Huang).
Figure 1. Prospective preparation of sulfonyl chloride 1 from thiol 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.111

3204
Y. Huang et al. / Tetrahedron Letters 53 (2012) 3203–3205
F
F
O
O
O
N
O
O
O
O
N
Cl
i
S
S
I
S
S
O
iii
O
O
i, ii
O
F
F
O
O
O
Cl
Cl
O
ii
14
1
SH
3
4
O
F
N
R2R1N
S
O
O
O
O
O
O
O
S
F
Cl
15
Scheme 4. Reagents and conditions: (i) KNO3–SO2Cl2 (2.5 equiv), CH3CN, À20 °C,
(ii) R1R2NH (2 equiv), CH2Cl2, 0 °C.
SO2Cl
5
Scheme 1. Reagents and conditions: (i) KSCOSEt, DMF, 25 °C, (ii) NaOH, MeOH–
H2O, 25 °C, 100% from 3, (iii) KNO3–SO2Cl2 (2.5 equiv), CH3CN, 0 °C, 42%.
Table 1
Preparation of sulfonamides from thiolacetate as shown in Scheme 4
Entry
Amine
Yield (%)
O
O
1
2
3
4
5
6
7
8
Morpholine
Piperidine
96
93
100
90
62
92
i
Bn
N
Bn N
Cyclohexanamine
Benzylamine
4-Aminopyridine
Dimethylamine
N-Phenylpiperazine
Aniline
SSiMe
SO2Cl
O
O
6
7
92
88
O
Ph
ii
N
Bn
N
N
S
HN
O
O
O
N
8
Ph
other entries). Even the weakly nucleophilic aniline (entry 8) gen-
erated the desired product in 88% isolated yield from the starting
thioester 14.
9
Scheme 2. Reagents and conditions: (i) KNO3–SO2Cl2 (2.5 equiv), CH3CN, 0 °C, (ii)
excess 8, 31% from 6.
In summary, the commercially available ‘carbasugar 10’ was
transformed, efficiently, into thiolester 14. When exposed to the
KNO3-sulfurylchloride oxidation system, the thioester 134 was
cleanly converted to the sulfonyl chloride 1, a previously unre-
ported reaction. With no further purification, the isolated crude
sulfonyl chloride 1 was subsequently transformed into sulfona-
mides (Table 1) in good to excellent yield over 2 steps. This inex-
pensive process appears very practical and applicable to a wide
range of substrates including those containing acid and/or base
sensitive functionality.
adventitious oxygen. We were extremely pleased to observe that a
smooth transformation to the sulfonyl chloride took place at
À20 °C in less than 0.5 h.4 The crude product was deemed suffi-
ciently pure that we decided to conduct the next transformation,
conversion to sulfonamides, prior to purification.5
A selection of the results is shown in Table 1. The overall yields
range from good (entry 5) with 4-aminopyridine to excellent (all
References and notes
O
1. Park, Y. J.; Shin, H. H.; Kim, Y. H Chem. Lett. 1992, 21(8), 1483.
2. Churcher I.; Harrison, T.; Kerrad, S.; Oakley, P. J.; Shaw, D. E.; Teall, M. R.;
Williams, S. World. Patent 031137/A1, 2004.
NH2·HCl
N
HO
HO
3. Gareau, Y.; Pellicelli, J.; Laliberte, S.; Gavreau, D. Tetrahedron Lett. 2003, 44, 7821.
4. Sulfuryl chloride (1.06 ml, 13.3 mmol) was added dropwise to a mixture of
thioacetate (14; 2 g, 5.33 mmol) and KNO3 (1.34 g, 13.3 mmol) in anhydrous
acetonitrile (60 ml) at À20 °C to À30 °C under nitrogen atmosphere. After 0.5 h
saturated aqueous NaHCO3 was added to the reaction mixture and stirring was
continued for a further 30 min. The organics were extracted with CH2Cl2 (Â2).
The combined organic layers were dried, and concentrated under reduced
pressure to give the crude sulfonyl chloride (1; 1.60 g, 75% yield), which was
used in the next step without purification. 1H NMR (400 MHz, DMSO), 7.87–7.83
(m, 4H), 4.92–4.90 (dd, J = 4 & 7 Hz, 1H), 4.43–4.38 (m, 2H), 2.85 (dd, J = 3.5 &
13.5 Hz, 1H), 2.57–2.49 (m, 1H), 2.40–2.35 (m, 1H), 2.33–2.25 (m, 1H), 2.05 (q,
J = 12.5 Hz), 1.44 (s, 3H), 1.20 (s, 3H). 13C NMR (125 MHz, DMSO), 167.6, 134.4,
131.3, 122.98, 112.1, 83.5, 80.98, 54.5, 54.3, 41.0, 39.9, 39.7, 39.6, 39.4, 39.2,
39.1, 38.8, 34.3, 27.5, 25.2.
i
O
HO
OH
10
HO OH
12
O
O
iii
O
ii
N
N
HO
S
O
O
O
O
O
O
5. The crude sulfonyl chloride (1; 100 mg, 0.25 mmol) obtained from procedure
above (100 mg, 0.25 mmol) in CH2Cl2 (5 ml) was cooled in ice bath under N2
atmosphere and benzylamine was added (47 mg, 0.5 mmol). After1 h, LCMS
indicated the reaction was complete. The reaction mixture was poured into 1 N
HCl in ethyl acetate. The organic layer was separated, dried, and concentrated to
obtain 106 mg of desired product (90% yield). 1H NMR (400 MHz, CDCl3), 7.32
14
13
Scheme 3. Reagents and conditions: (i) Phthalic anhydride, Hunigs base, 150 °C, (ii)
2,2-dimethoxypropane, MsOH, acetone 25 °C, 70% from 10, (iii) thiolacetic acid,
DIAD, THF, 0 °C, 94%.

Y. Huang et al. / Tetrahedron Letters 53 (2012) 3203–3205
3205
(m, 1H), 7.26 (m, 1 H), 4.23 (s, 1H), 4.20 (m, 2H), 3.39 (d, 1H), 3.27 (2H), 3.19 (q,
J = 7.1 Hz, 1H), 2.98 (q, J = 7.1 Hz, 1H), 2.38 (m 1H), 2.29 (q, 1H), 1.42 (m, 3H),
1.33 (m, 1H), 1.23 (s, 3H). 13C NMR (125 MHz, CDCl3), 137.99, 133.2, 129.3,
128.6, 128.4, 126.4, 113.5, 87.7, 84.97, 78.3, 78.0, 77.8, 57.6, 56.3, 49.7, 49.5,
49.3, 49.2, 48.98, 48.8, 48.6, 47.4, 40.7, 38.96, 27.4, 25.1. LC-MS (ESI): calcd for
C
24H26N2O6S 470.5, found [M+H]+ 471.2.