Synthesis of isomeric fluoronitrobenzene-sulfonyl chlorides

Article abstract of DOI:10.1016/j.tet.2010.06.036

The synthesis of five hitherto unknown isomeric fluoronitrobenzenesulfonyl chlorides is described. The compounds are prepared from difluoronitrobenzenes by a two-step procedure. In the first step the starting compounds undergo a regioselective reaction with phenylmethanethiol giving rise to the corresponding thioethers. The oxidative cleavage of the latter with chlorine results in the sulfonyl chlorides in good yields. One example of a threefold sequential functionalization of 2-fluoro-6-nitrobenzenesulfonyl chloride showing the synthetic utility of the title compounds is provided.

Full text of DOI:10.1016/j.tet.2010.06.036

Tetrahedron 66 (2010) 5982e5986
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of isomeric fluoronitrobenzene-sulfonyl chlorides
,
b
,
a
a,b
Sergey Zhersh a, Oleg Lukin a , Vitaly Matvienko , Andrey Tolmachev
*
a Enamine Ltd., A. Matrosova St. 23, 01103 Kiev, Ukraine
b National Taras Shevchenko University, ChemBioCenter, Volodymyrska St. 62, 01033 Kiev, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of five hitherto unknown isomeric fluoronitrobenzenesulfonyl chlorides is described. The
compounds are prepared from difluoronitrobenzenes by a two-step procedure. In the first step the
starting compounds undergo a regioselective reaction with phenylmethanethiol giving rise to the cor-
responding thioethers. The oxidative cleavage of the latter with chlorine results in the sulfonyl chlorides
Received 15 March 2010
Received in revised form 24 May 2010
Accepted 14 June 2010
Available online 18 June 2010
in good yields. One example of
benzenesulfonyl chloride showing the synthetic utility of the title compounds is provided.
Ó 2010 Elsevier Ltd. All rights reserved.
a threefold sequential functionalization of 2-fluoro-6-nitro-
Keywords:
Sulfonyl chlorides
Isomers
Aromatic substitution
Chemoselectivity
Organofluorine compounds
1. Introduction
NO2
NO2
NO2
NO2
The synthesis of functional organic compounds for different
applications largely relies on laborious approaches involving an
extensive usage of protecting groups. Nowadays inventive chemo-
selective routes to the construction of complex molecules are be-
coming a better alternative because they shorten the length of
multistep syntheses by excluding protecting groups and, as a con-
sequence, lead to increased overall yields of the target compounds.1
It is also of importance for both high-throughput chemistry and
fragment-based drug design to have building blocks capable of
consecutive linking of two or more fragments in chemically and
stereochemically predefined manners.2 In this context fluoroni-
trobenzenesulfonyl chlorides shown in Figure 1 are attractive
building blocks. They contain three selectively addressable func-
tional groups, which could be employed in a variety of synthetic
transformations involving acylation, arylation, and nitro-group
reduction with options for follow up chemistry. Despite the ap-
parent synthetic potential of the fluoronitrobenzenesulfonyl chlo-
rides their chemistry has been little explored. Up to the present the
synthesis of only five (compounds 1,3 2,3 3,4 6,5 and 95) out of ten
possible isomers depicted in Figure 1 was described. Moreover,
there are only a few reports showing the synthetic utility of the
known fluoronitrobenzene-sulfonyl chlorides. For example, step-
wise derivatizations of compound 3 were successfully used in the
F
F
F ClO2S
F
SO2Cl
ClO2S
SO2Cl
1
2
3
4
NO2
NO2
NO2
SO2Cl
SO2Cl
SO2Cl
F
F
F
5
6
7
NO2
NO2
NO2
F
SO2Cl
F
SO2Cl
SO2Cl
F
8
9
10
* Corresponding author. Tel.: þ380 44 5373218; fax: þ380 44 5373253; e-mail
address: oleg.lukin@univ.kiev.ua (O. Lukin).
Figure 1. Constitutional isomers of fluoronitrobenzene-sulfonyl chloride.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.036

S. Zhersh et al. / Tetrahedron 66 (2010) 5982e5986
5983
synthesis of biologically active compounds modulating protein/
protein interactions,6 lead compounds for potentiators of cancer
chemotherapy,7 and inhibitors of nuclear enzymes.8 Compound 9
was shown to be a handy building block in the synthesis of drug-
like substances9 and some functionalized organofluorine species.10
Many more ways to use the fluoronitrobenzenesulfonyl chlorides
can be envisaged.
For example, since these are isomers they can be used for the
preparation of isosteric sets of biologically potent compounds.
Synthesis of new functional branched macromolecular assemblies,
such as dendrimers and hyperbranched polymers is another per-
spective to use these compounds. For example, the fluoroni-
trobenzenesulfonyl chlorides can be employed as core units for
attaching dendrons of up to three different types or, alternatively,
they can be used as branching units in repetitive steps of reduction
and sulfonylation in divergent synthesis of functionalized den-
drimers (for structural examples see Ref. 11). Therefore, having the
complete set of isomers (Fig. 1) available on a multi-gram scale
would stimulate progress in medicinal chemistry and materials
science. Given this synthetic potential it is of importance to de-
velop methods for the preparation of new isomeric fluoroni-
trobenzenesulfonyl chlorides. It is also advantageous to simplify
the synthesis of the existing isomers.
nucleophilic displacement of one fluorine in a resin-bound 4,5-
difluoro-2-nitrobenzamide with an S-nucleophile was described.
The ability of the nitro-group to selectively activate one out of the
two CareF bonds in the aromatic ring prompted us to investigate
nucleophilic displacement of the fluorine in readily available
difluoronitrobenzenes. As illustrated in Scheme 1, the treatment of
a difluoronitrobenzene with an equimolar amount of phenyl-
methanethiol in the presence of potassium carbonate leads to a clean
regioselective substitution of one fluorine. Only in the case of com-
Ph
Ph
NO2
NO2
NO2
S
20%
S
F
F
ClO2S
F
ii
i
+
NO2
51%
93%
Ph
11
4
S
F
80%
12
Ph
NO2
NO2
NO2
In this contribution we described the synthesis of five hitherto
unknown isomeric fluoronitrobenzenesulfonyl chlorides and an
optimized route to one previously reported structure. We also
disclose one example of sequential transformations of the three
functional groups demonstrating the synthetic utility of the title
compounds.
F
S
F
SO2Cl
F
i
99%
ii
58%
Ph
F
13
14
5
NO2
NO2
NO2
F
SO2Cl
S
2. Results and discussion
i
ii
90%
F
57%
F
F
The synthesis of the five new isomeric fluoronitrobenzenesulfonyl
chlorides is summarized in Scheme 1. The rationale for the selected
synthetic strategy was as follows. First, the starting benzene de-
rivatives must be readily accessible on a multi-gram scale. Second, to
minimize number of synthetic steps the starting compounds should
bear two functional groups, which are present in the product while
the third group should be introduced in a most straightforward way.
We considered several options to approach the target compounds: (i)
electrophilic reactions including the sulfochlorination of nitro-
fluorobenzenes, and the nitration of fluorobenzenesulfonyl chlorides,
(ii) nucleophilic reactions, such as displacements of nitro- and fluoro-
groups in fluorodinitrobenzenes and difluoronitrobenzenes, re-
spectively. From structural considerations of the target species in
Scheme 1 the sulfochlorination with chlorosulfonic acid was dis-
carded from the list because the nitro-group would prevent the
electrophilic attack attherequired positions. Although thenitration is
a more aggressive electrophilic process it seemed of little use for the
preparation of the new isomeric fluoronitrosulfonyl chlorides on ac-
count of an unfovarable meta-location of fluorine with regard to the
nitro-group in compounds 5, 7, 8, and 10. A nitration of m-fluoroni-
trobenzenesulfonyl chloride 21 (Scheme 2) gave rise to the known
5-fluoro-2-nitrobenzenesulfonyl chloride 65 while no traces of com-
pound 4 were isolated. Notably, the nitration of 21 showninScheme 2
simplifies considerably the published five-step synthesis of 6. Anal-
ysis of the literature shows that the nucleophilic aromatic displace-
ment of the nitro-group with S-, N-, and F-nucleophiles occurs only in
highly activated substances, such as trinitrobenzene and its
derivatives.12 Nucleophilic displacement of the fluorine also requires
the presence of strong electron withdrawing groups in the aromatic
ring. The widely used 1-fluoro-2,4-dinitrobenzene (Sanger reagent)13
reacts with many nucleophiles in the presence of a base under very
mild conditions. A simultaneous presence of nitro- and sulfo-groups
inthe fluoroaromatic ringisalsoknownto activate the CareF bond.6,14
Our attention was drawn by a recent report14 in which a selective
15
16
7
NO2
NO2
NO2
i
ii
99%
67%
F
F
F
F
S
SO2Cl
Ph
17
18
8
NO2
20%
Ph
Ph
S
NO2
NO2
S
i
ii
51%
+
NO2
95%
F
SO2Cl
F
F
80%
Ph
19
10
F
S
20
Scheme 1. Synthesis of new isomeric fluoronitrobenzenesulfonyl chlorides. Reagents
and conditions: (i) phenylmethanethiol, K2CO3, DMF; (ii) Cl2, H2O, 5 ꢀC.
NO2
SO2Cl
SO2Cl
HNO3 / H2SO4
50%
F
F
21
6
Scheme 2. A simplified route to fluoronitrosulfonyl chloride 6.

5984
S. Zhersh et al. / Tetrahedron 66 (2010) 5982e5986
pounds 11 and 19 partial disubstitution took place. The latter obser-
vation can be explained by the fact that introduction of one thioether
unit into 11 and 19 increases electron density in ortho- and para-po-
sitions while meta-located CF groups remain largely unaffected.
Consequently, intermediates 12 and 20 compete to some degree with
their parent difluoronitrobenzenes in the nucleophilic substitution of
fluorine.
4. Experimental details
4.1. General
1H, 13C, and 19F NMR spectra were recorded on Bruker Avance
DRX 500 spectrometer with TMS as an internal standard. Melting
points were measured with a Büchi melting point apparatus. HPLC-
MS analyses were done on an Agilent 1100 LCMSD SL instrument
(chemical ionization (CI)). IR spectra were recorded on a Per-
kineElmer Spectrum BX II FT-IR spectrometer. Difluoroni-
trobenzenes 11, 15, 17, and 19 were purchased from commercial
sources. 2,3-Difluoronitrobenzene 13 was prepared from commer-
cially available 2,3-difluoroaniline by the published procedure.16
However, as will be shown below the latter mixtures can be
used in the following synthetic step without purification. The
obtained fluoronitrophenylbenzylthioether intermediates can un-
dergo oxidative cleavage with chlorine resulting in the corre-
sponding sulfonyl chlorides. However, the use of glacial acetic acid
as solvent in the available experimental procedure15 was not suit-
able for our purpose on account of the poor solubility of the
obtained thioethers. We have found that saturating a rigorously
stirred emulsion consisting of equal volumes of water and
a dichloromethane solution of a thioether with chlorine readily
gives the desired sulfonyl chloride. The latter is isolated by ex-
traction. Although, thioethers 12 and 20 used for the preparation of
sulfonyl chlorides 4 and 10, respectively, were contaminated by 20%
with the disubstituted byproducts, the raw sulfonyl chlorides were
successfully purified by distillation in vacuum. The compounds can
be additionally purified by recrystallization from hexane. The
structure and the high purity of the new isomeric fluoroni-
trobenzenesulfonyl chlorides were confirmed by means of 1H, 13C,
and 19F NMR, LC/MS, and elemental analysis.
To illustrate the synthetic utility of the new compounds
a threefold sequential chemoselective functional group trans-
formation of compound 5 was undertaken. As shown in Scheme 3,
in the first step the chlorosulfo-group of 5 readily reacts with
aqueous ammonia giving rise to the corresponding sulfonamide 22.
The latter undergoes substitution of the fluorine by the reaction
with pyrrolidine in refluxed ethanol producing aminosulfonamide
23. Finally, the nitro-group of the compound 23 is reduced yielding
4.1.1. 3-Fluoro-2-nitrobenzenesulfonyl chloride (4). To a solution of
1,3-difluoro-2-nitrobenzene 11 (30 g, 189 mM) in DMF (200 mL) po-
tassium carbonate (27.6 g, 200 mM) was added. Then to the stirred
mixture phenylmethanethiol (23.4 g, 189 mM) was added dropwise.
During the addition the temperature of the reaction mixture was kept
below 20 ꢀC. Upon the addition the reaction mixture was allowed to
stir for 2 h at room temperature. Then the mixture was filtered and
the filtrate was evaporated to give red oil in a yield of 46 g (93%). The
1H NMR analysis of the crude product revealed that the target thio-
ether 12 was contaminated by ca. 20% of the disubstituted byproduct.
This mixture was dissolved in 200 mL of dichloromethane. To the
solution deionized water (200 mL) was added. The chlorine was
bubbled slowly into the stirred reaction mixture. The reaction course
was monitored by TLC. The organic layer of the resulting mixture was
separated andwashed with a saturated water solution of Na2S2O3. The
organic layer was dried over MgSO4 and evaporated in vacuum to give
a viscous residue. The residue was subjected to a vacuum distillation
giving rise to 21 g (51%) of 4 that crystallized upon standing. Yellowish
crystals; mp 51e52 ꢀC; 1H NMR (500 MHz, CDCl3)
AreHpara), 7.83e7.87 (m, 1H, AreHmeta), 8.03 (d, 1H, JH,H¼7.5 Hz,
d 7.77 (m, 1H,
3
aniline 24 that can undergo
transformations.
a
SO2
22
variety of further synthetic
AreHortho); 13C NMR (125 MHz, CDCl3)
d 124.9 (s, CHeCeS), 125.0
(s, CHeCHeCeS), 125.1 (d, 2JC,F¼4 Hz, CHeCeF), 132.9 (d, 2JC,F¼8 Hz,
CeN), 136.0 (C-S), 153.8 (d, JC,F¼263 Hz, C-F); 19F NMR (376 MHz,
1
CDCl3)
d
ꢁ120.23; IR: 3106 (CH), 1549 (NO2), 1266, 1179 (SO2) cmꢁ1
;
H2N
SO2
H2N
elemental analysis: calcd for C6H3ClFNO4S: C, 30.08; H,1.26; Cl,14.80;
N, 5.85; S, 13.38. Found: C, 30.18; H, 1.20; Cl, 14.66; N, 5.67; S, 13.53.
SO2Cl
O2N
F
O2N
F
O2N
N
i
ii
4.1.2. 2-Fluoro-6-nitrobenzenesulfonyl chloride (5). The reaction
conditions for the first step are identical with those used for the
preparation of 4. 30.4 g (190 mM) of 1,2-difluoro-3-nitrobenzene 13,
200 mL of DMF, 27.6 g (200 mM) of potassium carbonate, and 23.6 g
(190 mM) of phenylmethanethiol were used in the reaction. The yield
of the target 2-(benzylsulfanyl)-1-fluoro-3-nitrobenzene 14 was
50.6 g (99%). No traces of a disubstitution product were detected by
80%
93%
5
23
H2N
SO2
H2N
N
iii
23
NMR and LC/MS. Brownish oil;1HNMR (500 MHz, CDCl3)
d4.17 (s, 2H,
81%
PheCH2), 7.21e7.28 (m, 6H, AreH), 7.32e7.37 (m, 1H, AreH), 7.49 (d,
24
3JH,H¼7.5 Hz,1H, AreHortho-NO2,); 13C NMR (125 MHz, CDCl3)
d 39.5 (d,
Scheme 3. Reagents and conditions: (i) aqueous ammonia, dioxane, room tempera-
ture; (ii) pyrrolidine, ethanol, reflux; (iii) iron powder, ammonium chloride, ethanol/
water, reflux.
2
2
4JC,F¼8 Hz, CH2), 118.5 (d, JC,F¼23 Hz, C-S), 119.5 (d, JC,F¼25 Hz,
CHeCeF),120.7 (d, 4JC,F¼4 Hz, CHeCeN),127.6,128.6,129.0,129.4 (d,
3JC,F¼9 Hz, CHeCHeCeF),136.4 (s, CeN),162.8 (d,1JC,F¼250 Hz, CeF);
19F NMR (376 MHz, CDCl3)
d
ꢁ102.48; MS (EI): m/z (%)¼263.0 (100)
3. Conclusions
[M]þ. To a solution of 14 (50 g,190 mM) in dichloromethane (200 mL)
deionized water (200 mL) was added. The chlorine was bubbled
slowly into the stirred reaction mixture. The reaction course was
monitored by TLC. The organic layer of the mixturewas separated and
washed with a saturated water solution of Na2S2O3. Upon drying over
MgSO4 the solvent was removed under reduced pressure. The viscous
colorless residue crystallized upon standing. The crude product was
transferred into a glass filter, washed with ethanol (25 mL), and dried
in vacuum. Yield 27 g (58%); colorless crystals, mp 91 ꢀC; 1H NMR
To conclude, we have developed a convenient synthetic pro-
cedure for a multi-gram scale preparation of six isomeric fluo-
ronitrobenzene-sulfonyl chlorides of which five have not been
described before. We have also shown that the three functional
groups in these compounds can be addressed consecutively with
no need for protecting groups exemplifying their synthetic poten-
tial for many applications. Presently our attention is focused on the
preparation of other halonitrobenzenesulfonyl chlorides that could
be employed in a metal-mediated cross-coupling chemistry.
(500 MHz, CDCl3)
d
7.52 (d, 1H, 3JH,H¼7.5 Hz, AreHortho-NO2), 7.60 (d,
1H, 3JH,H¼7.5 Hz, AreHmeta-NO2), 7.92e7.96 (m, 1H, AreHpara-NO2); 13
C

S. Zhersh et al. / Tetrahedron 66 (2010) 5982e5986
5985
NMR (125 MHz, CDCl3)
d
119.8 (d, 4JC,F¼4 Hz, CHeCeN), 121.3 (d, 2JC,
3.68; N, 5.15; S, 12.29. Compound 18 ((50.4 g, 192 mM)) was sus-
pended in formic acid (400 mL). The chlorinewas bubbled slowly into
the stirred suspension. The reaction course was monitored by TLC
taking small portions of the reaction mixture into water and
extracting with chloroform. Then the reaction mixture was poured
into 2 L of deionized water and extracted with chloroform. The or-
ganic layer was separated, washed with water, and saturated water
solutions of Na2S2O3 and Na2CO3. Upon drying over MgSO4 the
chloroform was removed under reduced pressure and the crude
product distilled at 2 mm (bp 145e152 ꢀC). The liquid product crys-
tallized upon standing affording 24.4 g (67%) of 8 as a yellow crys-
¼23 Hz, CeS), 124.2 (d, 2JC,F¼15 Hz, CHeCeF), 138.2 (d, 3JC,F¼10 Hz,
F
CHeCHeC-F), 148.53 (s, CeN), 159.1 (d, 1JC,F¼269 Hz, CeF); 19F NMR
(376 MHz, CDCl3)
d
ꢁ101.38; elemental analysis: calcd for
C6H3ClFNO4S: C, 30.08; H, 1.26; Cl, 14.80; N, 5.85; S, 13.38. Found: C,
30.33; H, 1.14; Cl, 14.61; N, 6.07; S, 13.41.
4.1.3. 5-Fluoro-2-nitrobenzenesulfonyl chloride (6). A stirred mix-
ture of a concentrated nitric acid (13 mL,
trated sulfuric acid (26 mL,
r
¼1.5 g/mL) and a concen-
r
¼1.83 g/mL) was cooled on an ice bath
below 5 ꢀC. Then to the stirred mixture 3-fluorobenzenesulfonyl
chloride (9.75 g, 50 mM) was carefully added over a 30 min period
keeping the temperature of the reaction mixture below 5 ꢀC. Upon
theaddition thereaction mixturewasallowed tostirfor 2 h at 0e5 ꢀC
and then for 4 h at room temperature. The reaction mixture was
carefully poured onto ice (ca. 200 g) and extracted with diethyl ether
(3ꢂ100 mL). The joined organic layers were washed with water and
dried over Na2SO4. Then the solvent was removed under reduced
pressure and the crude product was recrystallized from hexane to
give 6 g (50%) of 6. The analytical data of 6 are in full agreement with
talline solid. Mp 70 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.23e8.29 (m, 3H,
AreH); 13C NMR (125 MHz, CDCl3)
d
114.2 (d, 2JC,F¼26 Hz, CHeCeF),
119.8 (s, CHeCeN), 133.4 (d, 3JC,F¼5 Hz), 130.8 (s, CHeCeS), 136.6 (d,
3
2JC,F¼13 Hz, CeS), 152.7 (d, JC,F¼9 Hz, CeN), 158.6 (d, 1JC,F¼267 Hz,
CeF); 19F NMR (376 MHz, CDCl3)
for C6H3ClFNO4S: C, 30.08; H,1.26; Cl,14.80; N, 5.85; S 13.38. Found C,
29.87; H, 1.40; Cl, 14.70; N, 5.61; S, 13.33.
d
ꢁ102.49; elementalanalysis:Calcd
4.1.6. 3-Fluoro-5-nitrobenzenesulfonyl chloride (10). The conditions
of the reaction of 1,3-difluoro-5-nitrobenzene 19 with phenyl-
methanethiol are analogous to those used to prepare 4, 7, and 8.
51 g of 19, 300 mL of DMF, 69.5 g of potassium carbonate, and
39.8 g of phenylmethanethiol were used in the reaction. The crude
product was isolated in the form of yellow oil. According to its 1H
and 19F NMR spectra it contained ca. 20% of a disubstituted
byproduct. The crude product was used in the next step without
purification. The crude 20 (166 g, 630 mM) was dissolved in
methylene chloride (200 mL). To the solution deionized water
(200 mL) was added. The chlorine was bubbled slowly into the
stirred reaction mixture. The reaction course was monitored by
TLC. The organic layer of the mixture was separated and washed
with a saturated water solution of Na2S2O3. Upon drying over
MgSO4 the solvent was removed under reduced pressure and the
residue was distilled at 2 mm. A fraction with bp 136e138 ꢀC was
collected in a yield of 76 g (51%). Yellow oil crystallized upon
the published ones.5 19F NMR (376 MHz, CDCl3)
d
ꢁ102.74 ppm.
4.1.4. 4-Fluoro-2-nitrobenzenesulfonyl chloride (7). The reaction
conditions for the first step are identical with those used for the
preparation of 4. 5 g (31 mM) of 1,4-difluoro-2-nitrobenzene 15,
50 mL of DMF, 8 g (58 mM) of potassium carbonate, and 3.9 g (31 mM)
of phenylmethanethiol were used in the reaction. The yield of the 1-
(benzylsulfanyl)-4-fluoro-2-nitrobenzene 16 was 7.4 g (90%). No
traces of a disubstitution product were detected by NMR and LC/MS.
Yellowish crystalline solid; mp 104 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
4.37 (s, 2H, PheCH2), 7.29e7.43 (m, 5H, AreH), 7.67e7.68 (m, 1H,
AreH), 7.77e7.79 (m, 1H, AreH), 8.08 (d, 3JC,F¼5 Hz,1H,AreHortho-NO2);
13C NMR (125 MHz, CDCl3)
d
36.9 (CH2), 113.4 (d, JC,F¼27 Hz,
2
CHeCeN), 122.3 (d, 2JC,F¼22 Hz, CHeCeF), 128.0, 129.1 (s, CeS), 129.7,
130.6 (d, 3JC,F¼6 Hz, CHeCeS), 132.2, 136.1, 145.7 (d, 3JC,F¼9 Hz, CeN),
159.3 (d, 1JC,F¼246 Hz, CeF); 19F NMR (376 MHz, DMSO-d6)
ꢁ102.69;
d
elemental analysis: calcd for C13H10FNO2S: C, 59.30; H, 3.83; N, 5.32; S,
12.18. Found: C, 59.32; H, 3.75; N, 5.19; S, 12.34. Compound 16 (59.5 g)
was dissolved in dichloromethane (500 mL). Deionized water
(300 mL) was added to the solution. The chlorine was bubbled slowly
into the stirred reaction mixture. The reaction course was monitored
by TLC. The organic layer of the mixture was separated and washed
with a saturated water solution of Na2S2O3. Upon drying over MgSO4
the solvent was removed under reduced pressure and the residue was
distilled at2 mm collecting the fractionwith bp 150e155 ꢀC.Theliquid
product obtained in a yield of 31 g (57%) crystallized upon standing.
standing. Mp 46 ꢀC; 1H NMR (500 MHz, CDCl3)
8.35e8.36 (m, 1H), 8.7 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
8.12e8.14 (m,1H),
117.9
(d, JC,F¼27 Hz, FeCeCHeCeN), 118.2 (d, JC,F¼6 Hz, NeCHeCeS),
d
2
4
2
3
120.3 (d, JC,F¼26 Hz, FeCeCHeCeS), 146.4 (d, JC,F¼7 Hz, CeS),
3
1
149.5 (d, JC,F¼5 Hz, CeN), 162.2 (d, JC,F¼260 Hz, CeF); 19F NMR
(376 MHz, CDCl3)
d
ꢁ102.93; IR: 3104, 3092 (CH), 1546 (NO2),
1254, 1172 (SO2) cmꢁ1; elemental analysis: calcd for C6H3ClFNO4S:
C, 30.08; H, 1.26; Cl, 14.80; N, 5.85; S, 13.38. Found: C, 30.12; H,
1.16; Cl, 14.68; N, 5.63; S, 13.57.
Yellow crystals; mp 45e47 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.57e7.65
4.1.7. 2-Fluoro-6-nitrobenzenesulfonamide (22). 2-Fluoro-6-nitro-
benzenesulfonyl chloride (5) (10 g, 42 mM) was dissolved in di-
oxane (50 mL). Concentrated aqueous ammonia solution (20 mL)
was added dropwise to the stirred solution of 5 at 0 ꢀC. The re-
action mixture was allowed to stir for 2 h slowly reaching room
temperature. Then the solvent was removed under reduced
pressure and the solid residue was triturated with deionized
water (50 mL) and filtered affording upon drying 8.5 g (93%) of 22.
Colorless crystalline solid; mp 164 ꢀC; 1H NMR (500 MHz, CDCl3)
(m, 2H, AreH), 8.32 (m, 1H, AreH); 13C NMR (125 MHz, CDCl3)
d
113.8 (d, 2JC,F¼28 Hz, CHeCeN),120.1 (d, 2JC,F¼22 Hz, CHeCeF),132.1
(d, 4JC,F¼4 Hz, CeS),133.4 (d, 3JC,F¼10 Hz, CHeCeS),143.8 (CeN),166.0
(d, 1JC,F¼266 Hz, CeF); 19F NMR (376 MHz, CDCl3)
ꢁ95.99; elemental
d
analysis: calcd for C6H3ClFNO4S: C, 30.08; H, 1.26; Cl, 14.80; N, 5.85; S,
13.38. Found: C, 30.18; H, 1.20; Cl, 14.66; N, 5.67; S, 13.53.
4.1.5. 2-Fluoro-4-nitrobenzenesulfonyl chloride (8). The conditions
of the reaction of 1,2-difluoro-4-nitrobenzene 17 with phenyl-
methanethiol are analogous to those used to prepare 4 and 7. 30.5 g
(191 mM) of 17, 200 mL of DMF, 55.2 g (400 mM) of potassium car-
bonate, and 23.8 g (191 mM) of phenylmethanethiol were used in the
reaction to yield 50.4 g (99%) of 18. No traces of a disubstitution
product were detected by NMR and LC/MS. Yellowish crystalline
d
7.72e7.75 (m, 2H, AreH), 7.84e7.88 (m, 1H, AreH), 8.29 (s, 2H,
NH2); 13C NMR (125 MHz, CDCl3):
d
119.9 (d, 4JC,F¼4 Hz, CHeCeN),
120.7 (d, 2JC,F¼23 Hz, CHeCeF), 124.5 (d, 3JC,F¼8 Hz, CHeCHeCeF),
2
1
136.6 (d, JC,F¼10 Hz, C-S), 148.8 (s, C-N), 158.5 (d, JC,F¼257 Hz,
CeF); elemental analysis: calcd for C6H5FN2O4S: C, 32.73; H, 2.29;
N, 12.72; S, 14.56. Found: C, 32.58; H, 2.20; N, 12.54; S, 14.74.
solid; mp 126 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 4.46 (s, 2H,
3
PheCH2), 7.28 (t, JH,H¼7.5 Hz, 1H, AreH), 7.33e7.36 (m, 3H, AreH),
4.1.8. 2-Nitro-6-pyrrolidin-1-ylbenzenesulfonamide (23). Compound
22 (6.7 g, 30 mM) and pyrrolidine (5 g, 70 mM) were dissolved in
ethanol (50 mL). The mixture was refluxed for 5 h and then the sol-
vent was removed under reduced pressure. Theresiduewas triturated
7.46 (d, 3JH,H¼7.5 Hz, 2H), 7.69e7.72 (m, 1H), 8.04e8.08 (m, 1H); 19
F
NMR (376 MHz, CDCl3)
d
ꢁ110.29; elemental analysis: Calcd for
C13H10FNO2S: C, 59.30; H, 3.83; N, 5.32; S, 12.18. Found: C, 59.06; H,

5986
S. Zhersh et al. / Tetrahedron 66 (2010) 5982e5986
with water (50 mL) and the precipitated reddish crystalline solid was
References and notes
filtered and dried in vacuum. Yield 6.6 g (80%); mp 152 ꢀC; 1H NMR
1. (a) Hoffmann, R. W. Synthesis 2006, 3531e3541; (b) Young, I. S.; Baran, P. S. Nat.
Chem. 2009, 1, 193e205.
2. Chung, S.; Parker, J. B.; Bianchet, M.; Amzel, L. M.; Stivers, J. T. Nat. Chem. Biol.
2009, 5, 407e413.
3. Courtin, A. Helv. Chim. Acta 1983, 66, 68e75.
(500 MHz, CDCl3)
d 1.91 (m, 4H, NCH2eCH2), 3.41 (m, 4H, NeCH2),
7.21e7.23 (m, 2H), 7.26e7.43 (br 2H, NH2), 7.47 (t,3JH,H¼7 Hz, AreH);
13C NMR (125 MHz, CDCl3):
150.8, 152.6; elemental analysis: calcd for C10H13N3O4S: C, 44.27; H,
4.83; N, 15.49; S, 11.82. Found: C, 44.05; H, 4.88; N, 15.25; S, 11.82.
d 25.6, 53.4, 114.5, 122.7, 123.5, 132.2,
4. Dehn, J.W., Jr.; Gancher, E.; Resniek, P.; Kuhenfuss, H.J. Patent Fr. 1,412,060, 1965.
Chem. Abstr. 1996, 65, 7326d.
5. Courtin, A. Helv. Chim. Acta 1982, 65, 546e550.
6. Hu, X.; Sun, J.; Wang, H.-G.; Manetsch, R. J. Am. Chem. Soc. 2008, 130,
13820e13821.
4.1.9. 2-Amino-6-pyrrolidin-1-ylbenzenesulfonamide (24). To
a
solution of compound 23 (0.5 g, 1.8 mmol) in 95% ethanol (20 mL)
iron powder (0.5 g, 9 mmol) and ammonium chloride (0.5 g,
9 mmol) were added. The reaction mixture was stirred for 1 h at
reflux. The stirred mixture was allowed to cool down to room
temperature and then sodium carbonate (2 g) and activated char-
coal (2 g) were added. Upon filtration the solvent was removed
under reduced pressure and the crude product was crystallized
from ethanol/water affording 0.35 g (81%) of the target amine. Mp
7. (a) Wendt, M. D.; Shen, W.; Kunzer, A.; McClellan, W. J.; Bruncko, M.; Oost, T. K.;
Ding, H.; Joseph, M. K.; Zhang, H.; Nimmer, P. M.; Ng, S.-C.; Shoemaker, A. R.;
Petros, A. M.; Oleksijew, A.; Marsh, K.; Bauch, J.; Oltersdorf, T.; Belli, B. A.;
Martineau, D.; Fesik, S. W.; Rosenberg, S. H.; Elmore, S. W. J. Med. Chem. 2006,
49, 1165e1181; (b) Silvestri, R.; Artico, M.; De Martino, G.; Novellino, E.; Greco,
G.; Lavecchia, A.; Massa, S.; Loi, A. G.; Doratiottod, S.; La Collad, P. Bioorg. Med.
Chem. 2000, 8, 2305e2309.
8. Pescatore, G.; Kinzel, O.; Attenni, B.; Cecchetti, O.; Fiore, F.; Fonsi, M.; Rowley,
M.; Schultz-Fademrecht, C.; Serafini, S.; Steinkühler, C.; Jones, P. Bioorg. Med.
Chem. Lett. 2008, 5528e5532.
146 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 1.87 (br s, 4 H, NCH2eCH2),
9. Xie, Y.; Gong, G.; Liu, Y.; Deng, S.; Rinderspacher, A.; Branden, L.; Landry, D. W.
Tetrahedron Lett. 2008, 49, 2320e2323.
10. Sipyagin, A. M.; Bateman, C. P.; Tan, Y.-T.; Thrasher, J. S. J. Fluorine Chem. 2001,
112, 287e295.
3.35 (br s, 4H, NeCH2), 6.20 (s, 2H, AreNH2) 6.63 (m, 2H, AreH),
7.05 (s. 2H, SeNH2), 7.16 (br s,1H, AreH); 13C NMR (125 MHz, CDCl3)
d
24.6, 54.9, 111.3, 114.9, 122.3, 132.8, 147.6, 151.6; elemental anal-
11. (a) Lukin, O.; Gramlich, V.; Kandre, R.; Zhun, I.; Felder, T.; Schalley, C. A.;
Dolgonos, G. J. Am. Chem. Soc. 2006, 128, 8964e8974; (b) Lukin, O.;
Schubert, D.; Müller, C.; Corda, M.; Kandre, R. J. Org. Chem. 2008, 73,
3562e3565.
ysis: calcd for C10H15N3O2S: C, 49.77; H, 6.27; N, 17.41; S, 13.29.
Found: C, 49.65; H, 6.51; N, 17.29; S, 13.43.
12. Zlotin, S. G.; Kislitsin, P. G.; Kucherov, F. A.; Gakh, A. A. Heterocycles 2006, 68,
1109e1121.
13. Sanger, F. Biochem. J. 1945, 39, 507e515.
Supplementary data
14. Grimstrup, M.; Zaragoza, F. Eur. J. Org. Chem. 2006, 3233e3246.
15. Baker, R. H.; Dodson, R. M.; Riegel, B. J. Am. Chem. Soc. 1946, 68, 2636e2639.
16. Suzuki, H.; Kawakami, T. Synthesis 1997, 855e857.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.036.