Heterocyclic pentafluorophenyl sulfonate esters as shelf stable alternatives to sulfonyl chlorides

Article abstract of DOI:10.1016/j.tet.2009.09.015

Heterocyclic pentafluorophenyl sulfonate esters are shelf stable alternatives to the often less stable sulfonyl chlorides. They are easily prepared from thiols and react readily with primary and secondary amines to produce sulfonamides in high yields.

Full text of DOI:10.1016/j.tet.2009.09.015

Tetrahedron 65 (2009) 9280–9284
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heterocyclic pentafluorophenyl sulfonate esters as shelf stable alternatives
to sulfonyl chlorides
,
Jan Bornholdt a, Karianne Wilhemsen Fjære a, Jakob Felding b, Jesper Langgaard Kristensen a
*
a Department of Medicinal Chemistry, University of Copenhagen, Faculty of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
b Leo-pharma A/S, Industriparken 55, 2750 Ballerup, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2009
Received in revised form 21 August 2009
Accepted 3 September 2009
Available online 9 September 2009
Heterocyclic pentafluorophenyl sulfonate esters are shelf stable alternatives to the often less stable
sulfonyl chlorides. They are easily prepared from thiols and react readily with primary and secondary
amines to produce sulfonamides in high yields.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
nature of the heterocycle, readily decomposes via extrusion of SO2
to give the corresponding heteroaryl chloride.4
The sulfonamide moiety has proven to be an important func-
tionality in the drug development process during the past decades.
Starting with the antibacterial sulfa drugs1 and later incorporated
into launched drugs with a variety of different pharmacological
effects, like Argatroban (Thrombin inhibitor), Udenafil (PDE5 in-
hibitor), Sumatriptan (5-HT agonist) and Tipranavir (HIV protease
inhibitor), see Figure 1. Furthermore, they are widely used in or-
ganic synthesis as nitrogen protecting groups.2
For this reason only a limited number of heterocyclic sulfonyl
chlorides are commercially available as compared to arylsulfonyl
chlorides. Thus, many heterocyclic sulfonyl chlorides have to be
used immediately once prepared to prevent decomposition.
Although this leads to the desired sulfonamides, it is inconvenient if
a series of compounds are to be prepared. In this context a shelf
stable reagent that can be used without any special precautions
would be a major advantage.
We were interested in preparing a series of heterocyclic sul-
fonamides, and were faced with the problems outlined above.
Herein, we wish to report that the corresponding pentafluo-
rophenyl sulfonate esters (PFP sulfonate esters) are excellent sur-
rogates for unstable heterocyclic sulfonyl chlorides. The PFP
sulfonate esters are readily prepared from the corresponding
thiols, and react with primary and secondary amines to give
sulfonamides.
O
O
N
H
N
N
O
O
OH
N
S
N
O
N
H
NH2
N
O
O
N
S
H2N
O
N
H
Udenafil
O
HN
Argatroban
O
O
H
N
O
N
S
O
S
O
N
H
OH
N
F
F
2. Results and discussion
N
H
F
Sumatriptan
Tipranavir
Heterocyclic sulfonyl chlorides have traditionally been prepared
via oxidation of the corresponding thiols with Cl2,5 although other
reagents have also been developed.6 Recently, Wright and Hall-
stro¨m described a very convenient procedure, where NaOCl was
used as the oxidant.7 They were confronted with the same prob-
lems of instability, and chose to react the sulfonyl chlorides directly
with amines. Subsequently, they sought to convert the sulfonyl
chlorides to a shelf stable entity that would react similarly. They
converted six different heterocyclic sulfonyl chlorides to the cor-
responding sulfonyl fluorides, as sulfonyl fluorides previously have
been reported to serve this purpose.8 However, the sulfonyl fluo-
rides proved to be quite difficult to handle, as they decomposed
Figure 1. Selected examples of sulfonamide based drugs.
Sulfonamides can be prepared from the corresponding sulfonyl
chlorides and amines, as this is a very efficient process in most
cases.3 However, some sulfonyl chlorides are difficult to prepare or
unstable. This is particularly the case with electron deficient het-
erocyclic sulfonyl chlorides, which, depending on the electronic
* Corresponding author. Tel.: þ45 35336487; fax: þ45 35336040.
E-mail address: jekr@farma.ku.dk (J.L. Kristensen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.015

J. Bornholdt et al. / Tetrahedron 65 (2009) 9280–9284
9281
upon attempted chromatography on silica or alumina. Further-
more, no details were given on how these sulfonyl fluorides may be
implemented in the synthesis of sulfonamides or other trans-
formations. Other surrogates for sulfonyl chlorides have been de-
veloped, e.g., Katritzky’s sulfonylbenzotriazoles, but they are not
very reactive and require heating at 80 ꢀC for extended periods of
time to react with amines.9
Recently, Caddick et al. have described the synthesis and ap-
plication of aryl PFP sulfonate esters (Ar-SO2OPFP).10 These esters
are much less reactive than the corresponding arylsulfonyl chlo-
rides, and as such also much more stable. Electron donating groups
on the aromatic ring decrease the reactivity of these reagents to-
ward amines, while electron withdrawing groups increase the re-
activity. We believed that this concept would be ideally suited to
electron deficient heterocyclic substrates. Heteroaryl PFP esters
(Het-SO2OPFP) would be expected to be more stable than the cor-
responding chlorides (Het-SO2Cl) while maintaining a reasonable
level of reactivity toward amines, therefore a good compromise
between reactivity and stability.
With the four different heteroaryl PFP sulfonate esters in hand
we examined their reaction with amines, see Table 1. Treatment of
3a–d with a slight excess of simple primary and secondary amines
in CH3CN at rt leads to full consumption of the Het-SO2OPFP within
1 h. Two different conditions can be used: either 3 equiv of the
amine (conditions A) or 1.1 equiv with 2 equiv of N,N-diisopropyl-
ethylamine (DIPEA) present to trap the pentafluorophenol pro-
duced (conditions B), see Experimental section for details. In all
cases the resulting sulfonamides were isolated in good to excellent
yields based on the pentafluorophenyl sulfonate esters, see Table 1.
Table 1
Reaction of Het-SO2OPFP with amines
A) 3 eq. amine
F
F
or
O
S
O
O
S
O
R1
R2
B) 1.1 eq. amine + 2 eq. DIPEA
Het
O
F
Het
N
CH3CN, rt, 1h.
F
F
Amine
Het-SO2OPFP Conditions
Product
Yield (%)
We adopted Wright and Hallstro¨m’s procedure with some mi-
nor improvements11 to prepare four different heterocyclic sulfonyl
chlorides 2a–d, which were directly converted to the correspond-
ing heterocyclic PFP esters 3a–d, see Scheme 1.
3a
3b
3c
3d
93
98
92
95
O
S
O
4a-d
Het
N
A
NH
3a
3b
3c
3d
95
93
93
94
O
S
O
5a-d
Het
N
F
F
F
F
A
NH
O
S
O
O
S
O
NaOCl / HCl
CH2Cl2 / H2O
PFPOH / NEt3
CH2Cl2
Het SH
Het
N
Cl
Het
O
F
3a
3b
3c
3d
91
92
90
92
O
S N
O
H
NH2
NH
1a-d
2a-d
3a-d
Het
Het
B
6a-d
N
N
N
S
3a
3b
3c
92
89
97
91
Het =
O
S
O
N
S
N
3b
N
B
3a
3c
3d
3d
7a-d
76 %
57 %
66 %
74 %
Isolated yield after recrystallisation on 30 mmol scale
Scheme 1. Synthesis of pentafluorophenyl sulfonate esters.
Finally, as the Het-SO2OPFP often would be used as a reagent, we
also performed a series of experiments with an amine as the lim-
iting factor. Tryptamine was reacted with 1.1 equiv of 3a–d in the
presence of 2 equiv DIPEA, which in all cases gave the corre-
sponding sulfonamides 8a–d in very good yields, see Scheme 2.
Pyridine-2-sulfonyl chloride (2a) is widely used to introduce the
pyridine sulfonyl moiety, both as a protecting group and as
a building block for medicinal chemistry programs.12 It is moder-
ately stable and can be stored for prolonged periods of time at low
temperature.13 We included this heterocyclic derivative in our
survey to investigate if the corresponding PFP sulfonate ester (3a)
would retain a reasonable level of reactivity, while at the same time
demonstrating a higher stability than 2a.
O
S
H
N
NH2
Het
1.1 eq. Het-SO2OPFP
2 eq. DIPEA
O
Starting from 2-mercaptopyridine (1a) the corresponding PFP
sulfonate ester (3a) was isolated in 76% yield after recrystallization
of the crude product, see Scheme 1. This material is very stable and
3a can be stored at rt without special precaution.14 Pyrimidine-2-
sulfonyl chloride (2b) is of much lower stability than 2a, and can
only be handled at low temperatures.15 Applying the same condi-
tions to 1b as described above provided 3b in 57% yield after
recrystallization.14 Vedejs et al. showed that 5-methyl-1,3,4-thia-
diazole-2-sulfonyl chloride (2c) (often abbreviated to ThsCl) and
benzo[d]thiazole-2-sulfonyl chloride (2d) (often abbreviated to
BtsCl) can be used to introduce the Ths- and Bts-group, re-
spectively.16 They are very useful nitrogen protecting groups, but
their use have been quite limited presumably due to the limited
stability of 2c and 2d17 and the fact that Cl2-gas was originally used
in their preparation. In our hands, 1c and 1d were converted to the
corresponding PFP sulfonate esters 3c and 3d in 66 and 74% yield
after recrystallization. 3c and 3d are both stable materials that can
be stored without any special precautions.14
N
H
CH3CN, rt.
8a-d
N
H
Tryptamine
N
N
S
N
S
N
Het =
N
8a
N
8b
8c
8d
Yield
93 %
97 %
96 %
92 %
Scheme 2. Synthesis of tryptamine derived sulfonamides.
In conclusion, our results validate that heterocyclic penta-
fluorophenyl sulfonate esters are a synthetically useful compromise
between reactivity and stability, and are ideally suited for the
synthesis of heterocyclic sulfonamides in parallel synthesis and in
general. Furthermore, the ease of preparation, high stability, and
reactivity of 3c and 3d might encourage chemists to reexamine the
utility of the Ths- and Bts-protecting groups in organic synthesis.

9282
J. Bornholdt et al. / Tetrahedron 65 (2009) 9280–9284
3. Experimental
30 mmol) gave 7.89 g of a light yellow solid, which was recrystal-
lized from EtOAc/n-heptane giving 5.93 g of 3b contaminated by
small amounts of Et3NH–OPFP salt. The product was dissolved in
EtOAc and filtered through a 3 cm plug of silica using EtOAc as el-
uent yielding 5.54 g (57%) of pure 3b as a white solid, mp 85.9–
86.7 ꢀC. A further recrystallization from EtOAc/n-heptane gave 3b
as white needles, mp 85.9–86.7 ꢀC. 1H NMR (300 MHz, CDCl3):
3.1. General
Flash chromatography was performed on silica gel (Merck Kie-
selgel 60, mesh 230–400). Melting points were measured on an
Optimelt automated melting point system using standard settings
and are uncorrected. 1H NMR and 13C NMR spectra were recorded
on a Bruker 300 DXP spectrometer. Chemical shifts (dH) are quoted
in parts per million (ppm), referenced to Me4Si and J values are
given hertz. Chemical shifts (dC) are quoted in parts per million
(ppm), referenced to the appropriate residual solvent peak
(77.16 ppm for CDCl3 and 39.52 ppm for DMSO-d). Chemical shifts
d
9.04 (d, J¼4.9, 2H), 7.72 (t, J¼4.9, 1H). 13C NMR (75 MHz, CDCl3):
d
162.2, 159.4, 125.2. Anal. Calcd for C10H3F5N2O3S: C 36.82; H 0.93;
N 8.59. Found: C 36.64; H 0.95; N 8.44.
3.2.3. Pentafluorophenyl 5-methyl-1,3,4-thiadiazole-2-sulfonate (3c).
Following the general procedure, the reaction of 2-mercapto-5-
methyl-1,3,4-thiadiazole (3.97 g, 30 mmol) gave 9.47 g pale yellow
solid, which was recrystallized from EtOAc/n-hexane yielding
7.66 g (73%) of 3c as white crystals, mp 61.7–62.2 ꢀC. 1H NMR
(dC) for the pentafluorophenol part of the heterocyclic penta-
fluorophenyl sulfonate esters (3a–d) are not reported due to C–F
couplings. The following compounds have previously been repor-
ted in the literature: 4a, 4d, 5a, 5d, 6a, 6b, 6d, 7a. NMR data of
known compounds 4d, 5d and 7a have been included here as they
do not appear in the literature. Copies of 1H and 13C NMR spectra of
all new compounds are available as Supplementary data.
(300 MHz, CDCl3): d d 172.6,
2.98 (s, 3H). 13C NMR (75 MHz, CDCl3):
161.8, 16.3. Anal. Calcd for C9H3F5N2O3S2: C 31.22; H 0.87; N 8.09.
Found: C 31.18; H 0.84; N 8.01.
3.2.4. Pentafluorophenyl benzothiazole-2-sulfonate (3d). Following
the general procedure, the reaction of 2-mercaptobenzothiazole
(5.02 g, 30 mmol) gave 9.66 g crude product, which was recrystal-
lized from EtOAc/n-heptane giving 7.50 g (66%) of 3d as off white
3.2. General procedure for the synthesis of heterocyclic
pentafluorophenyl sulfonate esters
The following procedure is adapted from Wright and Hall-
stro¨m.7 To a mechanical stirred mixture of 2 M HCl (76 mL) and
CH2Cl2 (100 mL) cooled to ꢁ5 ꢀC (internal temperature) was added
a cold (5 ꢀC) sodium hypochlorite (w10% solution, 1.55 M, 65 mL,
100 mmol, 3.3 equiv) at such a rate that the temperature was
maintained below 0 ꢀC. Thiol 1a–d (30 mmol) was added in small
portions while maintaining the internal temperature at ꢁ10 ꢀC to
ꢁ5 ꢀC. The mixture was stirred for 15–20 min at ꢁ10 ꢀC to ꢁ5 ꢀC
after the addition was complete. Excess chlorine was quenched by
adding cold (0 ꢀC) 1 M Na2SO3 or 1 M Na2S2O3 until the yellow
greenish color of the mixture disappeared and iodide paper
(KI/starch) no longer gave a fast coloration.18 The mixture was
then transferred to a separating funnel (pre-cooled either in the
freezer or with ice water) and the organic layer was rapidly
separated and collected in a clean flask cooled in a dry ice-
acetone bath. The aqueous phase was quickly extracted with
cold (ꢁ10 ꢀC) CH2Cl2 (40 mL). The organic extracts were com-
bined and dried over MgSO4 under N2 atmosphere cooled in
a dry ice-acetone bath. The mixture was filtered through a glass
fritted funnel into a cold (ꢁ30 ꢀC) stirred solution of penta-
fluorophenol (5.52 g, 30 mmol) and Et3N (4.40 mL, 31.5 mmol)
in 20 mL of CH2Cl2. The mixture was stirred for 1 h cooled in
a salt-ice bath. The reaction mixture was washed with water
(60 mL), 10% KH2PO4 (2ꢂ60 mL), saturated NaHCO3 (2ꢂ60 mL),
water (60 mL), and brine (60 mL). The organic fraction was
dried (MgSO4) and concentrated in vacuo.
crystals, mp 94.7–96.2 ꢀC. 1H NMR (300 MHz, CDCl3):
d
8.31–8.25
(m, 1H), 8.09–8.03 (m, 1H), 7.75–7.65 (m, 2H). 13C NMR (75 MHz,
CDCl3): 158.6, 152.2, 137.4, 129.3, 128.5, 126.3, 122.4. Anal. Calcd
d
for C13H4F5NO3S2: C 40.95; H 1.06; N, 3.67. Found: C 40.87; H 0.98;
N 3.47.
3.3. Synthesis of sulfonamides from PFP-sulfonates and
amines
3.3.1. General procedure A. The heterocyclic pentafluorophenyl
sulfonate ester (3a–d) (1 mmol) was dissolved in CH3CN (3 mL) and
the amine (3 mmol) was added. Stirring was continued at rt for 1 h
before the mixture was diluted with aqueous KH2PO4 (10%, 20 mL)
and extracted with CH2Cl2 (3ꢂ20 mL). The combined organic phase
was dried over MgSO4, and the solvent was removed in vacuo. Flash
chromatography (heptane/EtOAc) gave the pure sulfonamides.
3.3.2. General procedure B. The pentafluorophenyl sulfonate ester
(3a–d) (1 mmol) was dissolved in CH3CN (3 mL) and the amine
(1.1 mmol) and N,N-diisopropylethylamine (2 mmol) was added.
Stirring was continued at rt for 1 h before the mixture was diluted
with 10% KH2PO4 (aq) (20 mL) and extracted with CH2Cl2
(3ꢂ20 mL). The combined organic phase was dried over MgSO4,
and the solvent was removed in vacuo. Flash chromatography
(heptane/EtOAc) gave the pure sulfonamides.
3.3.3. General procedure C. Tryptamine (1 mmol) and the penta-
fluorophenyl sulfonate ester (3a–d) (1.1 mmol) were dissolved in
CH3CN (3 mL) and N,N-diisopropylethylamine (2 mmol) was added.
Stirring was continued at rt for 1 h before the mixture was diluted
with 10% KH2PO4 (aq) (20 mL) and extracted with CH2Cl2
(3ꢂ20 mL). The combined organic phase was dried over MgSO4,
and the solvent was removed in vacuo. Flash chromatography
(heptane/EtOAc) gave the pure sulfonamides.
3.2.1. Pentafluorophenyl pyridin-2-sulfonate (3a). Following the
general procedure with the following exception: the reaction mix-
ture was concentrated in vacuo, the residue was taken up in 200 mL
of Et2O, and worked up as described in the general procedure. The
reaction of 2-mercaptopyridine (3.33 g, 30 mmol) gave 9.25 g of
crude product. This was treated with activated carbon in EtOAc,
filtered through Celite, and recrystallized from EtOAc/n-hexane
giving 7.41 g (76%) of 3a as large off white crystals, mp 64.8–66.1 ꢀC.
1H NMR (300 MHz, CDCl3):
d
8.83–8.79 (m, 1H), 8.16–8.13 (m, 1H),
3.3.3.1. N,N-Diethyl-pyridine-2-sulfonamide
(4a). Following
8.06 (td, J¼7.8, 1.7, 1H), 7.70 (ddd, J¼7.5, 4.7, 1.2, 1H). 13C NMR
general procedure A: 3a and diethylamine gave 199 mg (93%) of 4a
as a clear colorless oil. 1H and 13C NMR are in full agreement with
previously reported values.19
(75 MHz, CDCl3):
d 153.4, 150.9, 138.8, 129.0, 124.1. Anal. Calcd for
C11H4F5NO3S: C 40.63; H 1.24; N 4.31. Found: C 40.41; H 1.10; N 4.13.
3.2.2. Pentafluorophenyl pyrimidine-2-sulfonate (3b). Following the
general procedure, the reaction of 2-mercaptopyrimidine (3.36 g,
3.3.3.2. N,N-Diethyl-pyrimidine-2-sulfonamide (4b). Following
general procedure A: 3b and diethylamine gave 210 mg (98%) of 4b

J. Bornholdt et al. / Tetrahedron 65 (2009) 9280–9284
9283
as a clear colorless oil. 1H NMR (300 MHz, CDCl3):
d
8.90 (d, J¼4.9,
128.3, 128.2, 48.2, 15.9. Anal. Calcd for C10H11N3O2S2: C 44.59; H
4.12; N, 15.60. Found: C 44.48; H 3.95; N 15.52.
2H), 7.49 (t, J¼4.9, 1H), 3.47 (q, J¼7.2, 4H), 1.19 (t, J¼7.2, 6H). 13C
NMR (75 MHz, CDCl3):
d 166.5, 158.5, 123.0, 43.3, 14.6. Anal. Calcd
for C8H13N3O2S: C 44.63; H 6.09; N, 19.52. Found: C 44.85; H 6.05; N
19.37.
3.3.3.12. N-Benzyl-benzo[d]thiazole-2-sulfonamide (6d). Follow-
ing general procedure B: 3d and benzylamine gave 280 mg (92%) of
6d as white crystals, mp 131.6–132.9 ꢀC (lit. 129–130 ꢀC).7 1H and
13C NMR are in full agreement with previously reported values.7
3.3.3.3. N,N-Diethyl-5-methyl-1,3,4-thiadiazole-2-sulfonamide
(4c). Following general procedure A: 3c and diethylamine gave
216 mg (92%) of 4c as white crystals, mp 47.6–48.8 ꢀC. 1H NMR
3.3.3.13. N-Benzyl-N-methyl-pyridine-2-sulfonamide (7a). Follo-
wing general procedure B: 3a and N-methyl-benzylamine gave
228 mg (92%) of 7a as white crystals, mp 52.9–53.9 ꢀC (lit. 50–
(300 MHz, CDCl3):
d
3.47 (q, J¼7.2, 4H), 2.85 (s, 3H), 1.25 (t, J¼7.2,
6H). 13C NMR (75 MHz, CDCl3):
d
169.2, 168.6, 43.7, 16.0, 14.5. Anal.
Calcd for C7H13N3O2S2: C 35.73; H 5.57; N, 17.86. Found: C 35.77; H
5.27; N 17.59.
52 ꢀC).23 1H NMR (300 MHz, CDCl3):
d 8.76–8.71 (m, 1H), 8.03–7.97
(m, 1H), 7.92 (td, J¼1.7, 7.7, 1H), 7.50 (ddd, J¼1.2, 4.7, 7.4, 1H), 7.39–
7.27 (m, 5H), 4.45 (s, 2H), 2.81 (s, 3H). 13C NMR (75 MHz, CDCl3):
3.3.3.4. N,N-Diethyl-benzo[d]thiazole-2-sulfonamide (4d). Follo-
wing general procedure A: 3d and diethylamine gave 258 mg (95%)
of 4d as white crystals, mp 72.5–73.4 ꢀC (lit.167–168 ꢀC).20 1H NMR
d
157.4, 150.1, 138.0, 136.1, 128.7, 128.4, 128.0, 126.6, 122.9, 55.1, 35.2.
3.3.3.14. N-Benzyl-N-methyl-pyrimidine-2-sulfonamide (7b). Foll-
(300 MHz, CDCl3):
d
8.18–8.14 (m, 1H), 7.99–7.94 (m, 1H), 7.62–7.50
owing general procedure B: 3b and N-methyl-benzylamine gave
(m, 2H), 3.49 (q, J¼7.2, 4H), 1.23 (t, J¼7.2, 6H). 13C NMR (75 MHz,
234 mg (89%) of 7b as white crystals, mp 119.2–120.1 ꢀC. 1H NMR
CDCl3):
d
166.5, 152.7, 136.4, 127.5, 127.4, 125.2, 122.2, 43.3, 14.4.
(300 MHz, CDCl3):
d
8.93 (d, J¼4.9, 2H), 7.52 (t, J¼4.9,1H), 7.41–7.27 (m,
165.9, 158.6,
5H), 4.53 (s, 2H), 2.92 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
3.3.3.5. 2-(Piperidin-1-ylsulfonyl)pyridine (5a). Following gen-
eral procedure A: 3a and piperidine gave 215 mg (95%) of 5a as
white crystals, mp 55.5–56.3 ꢀC (lit. 55.2 ꢀC).21 1H and 13C NMR are
in full agreement with previously reported values.21
135.8,128.8,128.5,128.0,123.3, 55.2, 35.4. Anal. Calcd for C12H13N3O2S:
C 54.74; H 4.98; N, 15.96. Found: C 54.59; H 4.73; N 15.78.
3.3.3.15. N-Benzyl-N,5-dimethyl-1,3,4-thiadiazole-2-sulfonamide
(7c). Following general procedure B: 3c and N-methyl-benzyl-
amine gave 275 mg (97%) of 7c as white crystals, mp 88.8–89.9 ꢀC.
3.3.3.6. 2-(Piperidin-1-ylsulfonyl)pyrimidine (5b). Following gen-
eral procedure A: 3b and piperidine gave 210 mg (93%) of 5b as
a clear colorless oil that solidified on standing in the fridge giving 5b
1H NMR (300 MHz, CDCl3):
d
7.41–7.29 (m, 5H), 4.52 (s, 2H), 2.93 (s,
3H), 2.88 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
169.4, 167.1, 135.0,
as white crystals, mp 28.0–28.8 ꢀC. 1H NMR (300 MHz, CDCl3):
d
8.92
(d, J¼4.9, 2H), 7.51 (t, J¼4.9, 1H), 3.46–3.40 (m, 4H), 1.71–1.62 (m,
4H), 1.61–1.51 (m, 2H). 13C NMR (75 MHz, CDCl3):
165.6, 158.5,
129.0, 128.6, 128.4, 55.1, 35.3, 16.0. Anal. Calcd for C11H13N3O2S2: C
46.62; H 4.62; N, 14.83. Found: C 46.57; H 4.45; N 14.71.
d
123.2, 47.6, 25.6, 23.7. Anal. Calcd for C9H13N3O2S: C 47.56; H 5.77; N,
18.49. Found: C 47.54; H 5.66; N 18.30.
3.3.3.16. N-Benzyl-N-methyl-benzo[d]thiazole-2-sulfonamide
(7d). Following general procedure B: 3d and N-methyl-benzyl-
amine gave 290 mg (91%) of 7d as white crystals, mp 95.9–96.6 ꢀC.
3.3.3.7. 2-Methyl-5-(piperidin-1-ylsulfonyl)-1,3,4-thiadiazole
(5c). Following general procedure A: 3c and piperidine gave
230 mg (93%) of 5c as white crystals, mp 98.7–99.9 ꢀC. 1H NMR
1H NMR (300 MHz, CDCl3):
d
8.24–8.19 (m, 1H), 8.01–7.97 (m, 1H),
7.66–7.54 (m, 2H), 7.39–7.27 (m, 5H), 4.49 (s. 2H), 2.90 (s, 3H). 13C
NMR (75 MHz, CDCl3): 164.6,152.7,136.4,135.3,128.9,128.6,128.3,
d
(300 MHz, CDCl3):
d
3.44–3.38 (m, 4H), 2.86 (s, 3H), 1.74–1.67 (m,
169.2, 166.9,
127.7, 127.5, 125.4, 122.3, 54.9, 35.2. Anal. Calcd for C15H14N3O2S2: C
56.58; H 4.43; N, 8.80. Found: C 56.49; H 4.28; N 8.65.
4H), 1.62–1.53 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
47.6, 25.3, 23.5, 16.0. Anal. Calcd for C8H13N3O2S2: C 38.85; H 5.30;
N, 16.99. Found: C 38.85; H 5.09; N 16.99.
3.3.3.17. N-(2-(1H-Indol-3-yl)ethyl)-pyridine-2-sulfonamide
(8a). Following general procedure C: 3a gave 281 mg (93%) of 8a as
3.3.3.8. 2-(Piperidin-1-ylsulfonyl)-benzo[d]thiazole (5d). Follo-
wing general procedure A: 3d and piperidine gave 265 mg (94%)
of 5d as white crystals, mp 121.4–122.6 ꢀC (lit. 112 ꢀC).22 1H NMR
white crystals, mp 95.6–96.4 ꢀC. 1H NMR (300 MHz, CDCl3):
d 8.52
(d, J¼4.6, 1H), 8.09 (s, 1H), 7.96–7.92 (m, 1H), 7.82 (td, J¼7.7, 1.7, 1H),
7.43 (d, J¼8.0, 1H), 7.38 (ddd, 7.6, 4.7, 1.1, 1H), 7.33 (d, J¼8.1, 1H),
7.21–7.13 (m, 1H), 7.09–7.02 (m, 1H), 7.01 (d, J¼2.3, 1H), 5.08 (t,
J¼5.9, 1H), 3.39 (q, J¼6.6, 2H), 2.95 (t, J¼6.7, 2H). 13C NMR (75 MHz,
(300 MHz, CDCl3):
d 8.21–8.18 (m, 1H), 8.00–7.95 (m, 1H), 7.64–
7.52 (m, 2H), 3.42–3.35 (m, 4H), 1.72–1.65 (m, 4H), 1.56–1.47 (m,
2H). 13C NMR (75 MHz, CDCl3):
125.3, 122.2, 47.6, 25.4, 23.6.
d
164.4, 152.8, 136.4, 127.6, 127.4,
CDCl3): d 157.4, 150.0, 138.0, 136.5, 127.1, 126.6, 122.8, 122.3, 122.2,
119.5, 118.6, 111.9, 111.5, 43.7, 25.9. Anal. Calcd for C15H15N3O2S: C
59.78; H 5.02; N, 13.94. Found: C 60.21; H 4.93; N 14.03.
3.3.3.9. N-Benzyl-pyridine-2-sulfonamide (6a). Following gen-
eral procedure B: 3a and benzylamine gave 226 mg (91%) of 6a as
white crystals, mp 102.9–103.7 ꢀC (lit. 102–103 ꢀC).7 1H and 13C
NMR are in full agreement with previously reported values.7
3.3.3.18. N-(2-(1H-Indol-3-yl)ethyl)-pyrimidine-2-sulfonamide
(8b). Following general procedure C: 3b gave 293 mg (97%) of 8b as
white crystals, mp 152.8–155.0 ꢀC. 1H NMR (300 MHz, DMSO):
d
10.80 (s,1H), 8.99 (d, J¼4.9, 2H), 8.17 (s,1H), 7.72 (t, J¼4.9,1H), 7.45
3.3.3.10. N-Benzyl-pyrimidine-2-sulfonamide
(6b). Following
(d, J¼7.7,1H), 7.32 (d, J¼8.0,1H), 7.15 (d, J¼2.3,1H), 7.09–7.03 (m,1H),
general procedure B: 3b and benzylamine gave 230 mg (92%) of 6b
as white crystals, mp 122.3–123.1 ꢀC (lit. 117–118 ꢀC).7 1H and 13C
NMR are in full agreement with previously reported values.7
7.00–6.94 (m, 1H), 3.37–3.28 (m, 2H), 2.92–2.83 (m, 2H). 13C NMR
(75 MHz, DMSO):
d 165.8, 158.8, 136.2, 127.0, 123.6, 122.9, 120.9,
118.3, 118.0, 111.4, 110.9, 44.1, 25.9. Anal. Calcd for C14H14N4O2S: C
55.61; H 4.67; N,18.53. Found: C 56.08; H 4.52; N 18.72. HRMS calcd
for C14H15N4O2S (MþHþ): 303.0916. Found 303.0892.
3.3.3.11. N-Benzyl-5-methyl-1,3,4-thiadiazole-2-sulfonamide
(6c). Following general procedure B: 3c and benzylamine gave
242 mg (90%) of 6c as white crystals, mp 103.3–104.4 ꢀC. 1H NMR
3.3.3.19. N-(2-(1H-Indol-3-yl)ethyl)-5-methyl-1,3,4-thiadiazole-
2-sulfonamide (8c). Following general procedure C: 3c gave 310 mg
(96%) of 8c as white crystals, mp 150.7–151.9 ꢀC. 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
7.33–7.27 (m, 5H), 6.15 (br s, 1H), 4.43 (s, 2H),
169.9, 168.6, 135.7, 128.9,
2.81 (s, 3H). 13C NMR (75 MHz, CDCl3):
d

9284
J. Bornholdt et al. / Tetrahedron 65 (2009) 9280–9284
5. Johnson, T. B. PNAS 1939, 25, 448.
DMSO-d):
d
10.83 (s, 1H), 8.88 (s, 1H), 7.46 (d, J¼7.8, 1H), 7.33 (d,
6. Prakash, G. K. S.; Mathew, T.; Panja, C.; Olah, G. A. J. Org. Chem. 2007, 72, 5847
and references cited therein.
7. Wright, S. W.; Hallstro¨m, K. N. J. Org. Chem. 2006, 71, 1080.
8. Brown, D. J.; Hoskins, J. A. J. Chem. Soc., Perkin Trans. 1 1971, 522.
9. Katritzky, A. R.; Rodriguez-Garcia, V.; Nair, S. K. J. Org. Chem. 2004, 69, 1849.
10. (a) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1025; (b)
Caddick, S.; Wilden, J. D.; Judd, D. B. Chem. Commun. 2005, 2727; (c) Caddick, S.;
Wilden, J. D.; Judd, D. B. Tetrahedron Lett. 2005, 46, 7637.
J¼8.0, 1H), 7.14 (d, J¼2.3, 1H), 7.10–7.03 (m, 1H), 7.01–6.94 (m, 1H),
3.32 (t, J¼7.5, 2H), 2.89 (t, J¼7.5, 2H), 2.79 (s, 3H). 13C NMR (75 MHz,
DMSO-d): d 170.0, 168.6, 136.2, 126.9, 123.1, 120.9, 118.3, 118.0, 111.4,
110.5, 43.8, 25.4,15.5. Anal. Calcd for C13H14N4O2S2: C 48.43; H 4.38;
N, 17.38. Found: C 48.76; H 4.21; N 17.51.
11. Adding NaOCl to a mixture of starting Het-SH in HCl/CH2Cl2 as suggested by
Wright and Hallstro¨m7 lead to a complex mixture when we attempted to
convert 1c to 3c. Adding 1c to the NaOCl/HCl/CH2Cl2 mixture suppressed the
formation of byproducts and was chosen as the standard procedure in this
study. Furthermore, the use of 2 M HCl instead of 1 M HCl helped preventing
the mixture from freezing out as well as reducing the total volume.
3.3.3.20. N-(2-(1H-Indol-3-yl)ethyl)-benzo[d]thiazole-2-sulfon-
amide (8d). Following general procedure C: 3d gave 328 mg (92%)
of 8d as white crystals, mp 104.2–105.6 ꢀC. 1H NMR (300 MHz,
CDCl3): d 8.11–8.07 (m,1H), 8.00 (s,1H), 7.94–7.89 (m,1H), 7.61–7.49
(m, 2H), 7.45 (d, J¼8.0, 1H), 7.32–7.28 (m, 1H), 7.17–7.11 (m, 1H),
´
12. Selected examples: Arrayas, R. G.; Cabrera, S.; Carretero, J. C. Org. Lett. 2005, 7,
7.04–6.99 (m, 2H), 5.19 (t, J¼5.9, 1H), 3.60 (q, J¼6.5, 2H), 3.01 (t,
219; (b) Bendale, P.; Olepu, S.; Suryadevara, P. K.; Bulbule, V.; Rivas, K.; Nallan,
L.; Smart, B.; Yokoyama, K.; Ankala, S.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.;
Williams, D. K.; Buckner, F. S.; Chakrabarti, D.; Verlinde, C. L. M. J.; Van Voorhis,
W. C.; Gelb, M. H. J. Med. Chem. 2007, 50, 4585; (c) Barrett, D. G.; Catalano, J. G.;
Deaton, D. N.; Long, S. T.; McFadyen, R. B.; Miller, A. B.; Miller, L. R.; Samano, V.;
Tavares, F. X.; Wells-Knecht, K. J.; Wright, L. L.; Zhou, H. Q. Bioorg. Med. Chem.
Lett. 2007, 17, 22.
J¼6.6, 3H). 13C NMR (75 MHz, CDCl3):
d 166.1, 152.4, 136.5, 127.7,
127.5,127.0,125.1,122.8,122.4,122.3, 119.7,118.5,111.41,111.38, 44.1,
25.8. One carbon signal is missing. Judging from a DEPT spectrum of
8d and the 13C integrals, the peak at 136.5 ppm most likely consists
of two coinciding signals. Furthermore, the tryptamine part in 8a–
8c and the benzo[d]thiazole-2-sulfonyl part in 4d, 5d, and 7d both
show 13C NMR signals in the vicinity of 136.5 ppm. Anal. Calcd for
C17H15N3O2S2: C 57.12; H 4.23; N 11.76. Found: C 56.64; H 4.01; 11.59.
HRMS calcd for C17H16N3O2S2 (MþHþ): 358.0684. Found 358.0671.
13. Hanessian, S.; Kagotani, M. Synthesis 1987, 4, 409.
14. Samples left on the shelf for months at rt did not change color or texture.
15. In order to estimate the stability of 2b the following experiment was per-
formed: Using CDCl3 instead of CH2Cl2 in the preparation of 2b from 1b (see
Experimental section for details) the solution of 2b thus obtained was allowed
to warm to rt immediately before an 1H spectrum was recorded. This showed
a w1:1 mixture of 2b and 2-chloropyrimidine. A second spectrum recorded
approximately 10 min later indicated that 2b had decomposed completely and
2-chloropyrimidine was the only detectable compound.
Supplementary data
16. (a) Vedejs, E.; Lin, S.; Klapars, A.; Wang, J. J. Am. Chem. Soc. 1996, 118, 9796; (b)
Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 66, 7358.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.09.015.
17. Vedejs reported that evolution of SO2 was apparent after several days or less at rt.
18. Omitting to quench excess chlorine resulted in highly colored byproducts and
lower yields. Na2S2O3 could also be used to quench excess chlorine, but a pre-
cipitate, probably originating from the instability of Na2S2O3 under acidic
conditions (it decomposes to S(s) and Na2SO4), sometimes formed, thereby
complicating the extraction process. Therefore Na2SO3 is the preferred reagent.
19. Cai, L.; Han, Y.; Ren, S.; Huang, L. Tetrahedron 2000, 56, 8253.
20. Takahashi, T.; Okada, J. Yakugaku Yzasshi 1954, 75, 277.
References and notes
1. Drews, J. Science 2000, 287, 1960.
2. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; Wiley: Hoboken, NJ, 2007; p 851–868.
3. Andersen, K. K. In Comprehensive Organic Chemistry; Jones, D. N., Ed.; Perga-
mon: Oxford, 1979; Vol. 3.
4. Roblin, R. O.; Clapp, J. W. J. Am. Chem. Soc. 1950, 72, 4890.
21. Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. J. Org. Chem. 1995, 60, 5969.
22. Stanovnik, B.; Tisler, M. Arch. Pharm. 1965, 298, 357.
23. Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.