Novel sulfonamide derivatives as inhibitors of histone deacetylase

Article abstract of DOI:10.1002/hlca.200590129

Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC ₅₀ values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure - activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m11.1, also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies.

Full text of DOI:10.1002/hlca.200590129

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Helvetica Chimica Acta Vol. 88 (2005)
Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase
by Paul W. Finn, Morwena Bandara, Chris Butcher, Angela Finn, Ruth Hollinshead, Nagma Khan,
Norman Law, Sreenivasa Murthy, Rosario Romero, and Clare Watkins
TopoTarget UK Ltd., 87A Milton Park, Abingdon, Oxfordshire, United Kingdom, OX14 4RY
and Victor Andrianov, Rasma M. Bokaldere, Klara Dikovska, Vija Gailite, Einars Loza, Irina Piskunova,
Igor Starchenkov, Maxim Vorona, and Ivars Kalvinsh*
Latvian Institute of Organic Synthesis, Aizkraules 21, Riga, LV-1006, Latvia
(tel.: ‡ 371-753233; fax: ‡ 371-7550338; e-mail: kalvins@osi.lv)
Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday
Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of
cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit
human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC50 values in the low
nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell
culture. Extensive characterization of the structure activity relationships of this series identified key
requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on
the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality
also influenced the HDAC inhibitory activity. One of these compounds, m11.1, also designated PXD101, has
entered clinical trials for solid tumors and haematological malignancies.
1. Introduction.
DNA in eukaryotic cells is tightly complexed with histone
proteins to form chromatin. Histones are small proteins which are rich in basic amino
acids. They are positively charged at physiological pH and contact the negatively
charged phosphate groups of DNA. There are five main classes of histones: H1, H2A,
H2B, H3, and H4. The amino acid sequences show remarkable conservation between
species, with H1 varying somewhat, and in some cases being replaced by another
histone, e.g., H5. Four pairs of each of H2A, H2B, H3, and H4 together form a disk-
shaped octomeric protein core, around which DNA (ca. 140 base pairs) is wound to
form a nucleosome. Individual nucleosomes are connected by short stretches of linker
DNA associated with another histone molecule (e.g., H1, or in certain cases, H5) to
form a structure resembling a beaded string, which is itself arranged in a helical stack,
known as a solenoid. Within minutes of its synthesis, new DNA becomes associated
with histones in nucleosomal structures.
Histones undergo a variety of post-translational modifications: in particular
methylation, acetylation, or phosphorylation. These modifications predominantly
occur in the N-terminal sequences of histones which extend from the nucleosomal core,
and affect chromatin structure and gene expression [1].
Acetylation and deacetylation of histones is associated with transcriptional events
leading to cell proliferation and/or differentiation, and the correlation between the
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
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acetylation status of histones and the transcription of genes has been known for over 30
years [2]. The enzymes that catalyze and regulate the acetylation state of histones are
the histone acetyltransferases (HATs) and deacetylases (HDACs). They have been
identified in many organisms and have been implicated in the regulation of numerous
genes, confirming the link between acetylation and transcription [3]. In general,
histone acetylation correlates with transcriptional activation, whereas histone deacet-
ylation is associated with gene repression. HDACs function as part of large multi-
protein complexes, which are tethered to the promoter and repress transcription. Well-
characterized transcriptional repressors such as Mad [4], pRb [5], nuclear receptors
[6], and YY1 [7] associate with HDAC complexes to exert their repressor function.
Interestingly, the regulation of the function of transcription factors is also mediated
through acetylation. Further background on histone deacetylation can be found in
recent reviews [8][9].
The study of inhibitors of histone deacetylases also indicates that these enzymes
play an important role in cell proliferation and differentiation. The natural product
inhibitor trichostatin A (TSA; 1) [10] (see Figure) causes cell-cycle arrest at both the
G1 and G2 phases of the cell cycle [11], reverts the transformed phenotype of different
cell lines, and induces differentiation of Friend leukaemia cells and others [12]. TSA
and the synthetic suberoylanilide hydroxamic acid (SAHA ˆ N-hydroxy-N'-phenyl-
octanediamide; 2) have been reported to inhibit cell growth, induce terminal
differentiation, and prevent the formation of tumors in mice [13][14]. Other synthetic
HDAC inhibitors such as LAQ-824 (3) have also been reported as possessing antitumor
activity in animal models [15]. Whilst many of the small-molecule HDAC inhibitors
reported are hydroxamic acids (ˆ N-hydroxyamides), other chemical classes have been
reported, such as MS-275 (4), an example of the benzamide-class of inhibitor [16].
Figure. Natural product and synthetic inhibitors of histone deacetylase (HDAC)
Cell-cycle arrest by TSA correlates with increased expression of gelsolin [17], an
actin-regulatory protein that is down-regulated in malignant breast cancer [18]. Similar
effects on cell cycle and differentiation have been observed with a number of

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Helvetica Chimica Acta Vol. 88 (2005)
deacetylase inhibitors [19]. Trichostatin A has also been reported to be useful in the
treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis [20].
The modulation of HDAC enzyme activity, therefore, represents a novel approach
for intervening in cell-cycle regulation, with potential therapeutic application in cancer
and other proliferative diseases [21].
The classical pharmacophoric description of small-molecule HDAC inhibitors
consists of three linearly connected groups, AÀBÀC. A represents an aryl group which
provides potency and selectivity; B is a predominantly hydrophobic linking group, and
C represents a moiety which interacts with the catalytic Zn-atom at the HDAC active
site. This general arrangement can be clearly seen in compounds 1 3.
We decided to base our design on the structures of hydroxamic acid containing
inhibitors of histone-deacetylase known at the initiation of this work, particularly TSA.
We designed templates which we believed would contain the appropriate motifs to
provide potent enzyme inhibition whilst simultaneously being compatible with drug
development. In this work, we describe the design, characterization, and structure
activity relationships of one of these templates, a series of novel sulfonamide
derivatives, as histone-deacetylase inhibitors. One of these, PXD101, compound
m11.1, is currently under clinical investigation in cancer against both solid tumors and
haematological disease.
2. Syntheses.
The general synthetic strategies shown in Schemes 1 9 were
employed for the preparation of sulfonamide derivatives as HDAC inhibitors. One of
the structural features that emerged as of most interest was the direction of attachment
of the linking sulfonamide moiety. When present in the structure in such a way that the
N-atom of the sulfonamide is nearer to the hydroxamic acid moiety, we designate this as
the −forward× sulfonamide direction. When the linkage is in the opposite direction, we
designate it as −reverse×.
The −reverse× arylsulfonamides (NHSO2 linkage direction) 11 with ortho or meta
substitutions were prepared by sulfonylation of benzaldehyde (5) with oleum followed
by coupling of the obtained 3-formyl derivative m6 with methyl(dimethoxyphos-
phinyl)acetate to give an intermediate m7 (Scheme 1). Similarly, commercial o6 was
converted to o7. Sulfonyl chlorides m,o8 were obtained by reacting m,o7 with excess of
SOCl2. Compounds m10.1 m10.52 and o10.1 o10.3 were prepared by coupling
appropriately substituted aromatic amines with appropriate m,o8 followed by basic
hydrolysis. The desired −reverse× sulfonamides m11.1 m11.52 and o11.1 o11.3 were
obtained via the corresponding acid chlorides by treating compounds 10 with oxalyl
chloride followed by excess of hydroxylamine.
The −reverse× sulfonamides 15 with para substitution were prepared from cinnamic
acid (12) by chlorosulfonylation to yield the para derivative 13 (Scheme 2).
Sulfonamides 14.1 14.7 were obtained by condensing 13 with appropriately sub-
stituted aromatic amines. The desired hydroxamic acids 15.1 15.7 were obtained via
acid chlorides as in Scheme 1.
The −forward× sulfonamides (SO2NH linkage direction) 20 were prepared from
nitro-substituted cinnamyl esters m,p16 by reaction with SnCl2 and then with
substituted aromatic sulfonyl chlorides in dioxane (Scheme 3). Subsequent ester
hydrolysis gave compounds m19.1 m19.6 and p19.2 p19.4. The corresponding

Helvetica Chimica Acta Vol. 88 (2005)
1633
Scheme 1
R'a)
m11.1 Ph
R''a)
R'a)
R''a)
H
H
H
H
H
H
H
H
H
H
H
H
m11.29 PhCH2
m11.30 (1,3-benzodioxol-5-yl)CH2
m11.31 (pyridin-3-yl)CH2
H
H
H
H
H
H
H
H
H
H
H
H
g
m11.2 4-MeÀC6H4
m11.3 4-BrÀC6H4
m11.4 4-ClÀC6H4
)
m11.32 (3,4,5-trimethoxyphenyl)CH2
m11.33 (naphthalen-2-yl)CH2
m11.34 (3,5-dimethoxyphenyl)CH2
m11.35 (furan-2-yl)CH2
m11.36 PhCH2CH2
m11.37 (3,4-dimethoxyphenyl)CH2CH2
m11.38 PhCH2CH2CH2
m11.39 PhOCH2CH2
m11.5 2-MeOÀC6H4
m11.6 3-MeOÀC6H4
m11.7 3-BrÀC6H4
m11.8 4-CF3OÀC6H4
m11.9 2-FÀC6H4
m11.10 3-FÀC6H4
m11.11 4-CHF2OÀC6H4
m11.12 2,6-difluorophenyl
m11.40 PhCH2CH2CH2CH2
m11.41 Ph2CH
m11.13 2-methoxy-5-(trifluoromethyl)phenyl H
H
m11.14 4-CF3ÀC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
m11.42 PhCH2CH(Ph)
m11.43 PhCH2CH(Et)
m11.44 PhCH(OH)CH2
m11.45 Ph2CHCH2CH2
m11.46 Ph
m11.47 Ph
m11.48 PhCH2
m11.49 (pyridin-3-yl)CH2
H
H
H
H
m11.15 3-CF3SÀC6H4
m11.16 4-CF3SÀC6H4
m11.17 2,6-dimethylphenyl
m11.18 3,5-difluorophenyl
m11.19 3,5-bis(trifluoromethyl)phenyl
m11.20 4-MeOÀC6H4
Me
Me2CHCH2
(pyridin-3-yl)CH2
(1,3-benzodioxol-5-yl)CH2
g
m11.21 3,4-dimethoxyphenyl
m11.22 naphthalen-1-yl
)
m11.50 (3,4-dimethoxyphenyl)CH2CH2 4-MeOÀC6H4CH2
m11.23 naphthalen-2-yl
m11.51 PhCH2CH2CH2
m11.52 PhCH2CH2CH2
o11.1 Ph
(3,4-dimethoxyphenyl)CH2CH2
PhCH2CH2CH2
H
H
m11.24 [1,1'-biphenyl]-2-ylb)
m11.25 [1,1'-biphenyl]-4-ylc)
m11.26 1H-benzimidazol-6-yld)
m11.27 9-ethyl-9H-carbazol-3-yle)
m11.28 adamantan-1-ylf)
o11.2 naphthalen-2-yl
o11.3 Ph
Me
a) The same substituents R' and R'' are applicable to the corresponding intermediates.
b
c
d
e
f
g
)
)
)
)
)
)
a) Oleum; 51%. b) (MeO)2P(O)CH2COOMe, K2CO3, H2O. c) SOCl2, cat. DMF, benzene. d) R'R''NH,
dioxane, aq. NaHCO3 soln. e) aq. NaOH soln., MeOH. f) 1. (COCl)2, CH2Cl2, cat. DMF; 2. NH2OH ¥ HCl, THF,
aq. NaHCO3 soln.

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Helvetica Chimica Acta Vol. 88 (2005)
Scheme 2
Ra)
Ra)
Ra)
15.1
15.2
15.3
Ph
15.4
15.5
[1,1'-biphenyl]-4-ylb)
naphthalen-2-yl
15.6
15.7
9-ethyl-9H-carbazol-3-ylc)
PhCH2
4-BrÀC6H4
4-ClÀC6H4
a) The same substituent Ris applicable to the corresponding intermediates. b) See Footnote c in Scheme 1.
c) See Footnote e in Scheme 1.
a) HSO3Cl; 34%. b) R NH, CH2Cl2, pyridine. c) 1. (COCl)2, CH2Cl2, cat. DMF; 2. NH2OH ¥ HCl, THF, aq.
2
NaHCO3 soln.
Scheme 3
Ra)
Ra)
Ra)
m20.1
m20.2
m20.3
m20.4
Ph
m20.5
m20.6
p20.1
PhCH2
p20.2
p20.3
p20.4
[1,1'-biphenyl]-4-ylb)
3,4-dimethoxyphenyl
(E)-PhCHˆCH
4-MeÀC6H4
(E)-PhCHˆCH
3,4-dimethoxyphenyl
[1,1'-biphenyl]-4-ylb)
Ph
a) The same substituent Ris applicable to the corresponding intermediates. b) See Footnote c in Scheme 1.
a) SnCl2, EtOH, 808. b) R SOCl, dioxane, aq. NaHCO3 soln. c) aq. NaOH soln., MeOH. d) 1. (COCl)2, CH2Cl2,
2
cat. DMF; 2. NH2OH ¥ HCl, THF, aq. NaHCO3 soln. e) NH2OH ¥ HCl, MeOH, THF, H2O, KOH.

Helvetica Chimica Acta Vol. 88 (2005)
1635
sulfonamides 20 were obtained by treating compounds 19 with oxalyl chloride followed
by hydroxylamine, except for p20.1, which was directly prepared from ester p18.1 with
hydroxylamine in the presence of base.
The alkyne analogues m,p27 of −reverse× sulfonamides were prepared from
appropriately substituted halobenzenesulfonyl chlorides m,p21 by condensation with
aniline (! m,p22) and subsequent Pd/Cu-catalyzed coupling with propargyl alcohol
(ˆ prop-2-yn-1-ol) to yield m,p23 (Scheme 4). The primary alcohols m,p23 were
oxidized to aldehydes m,p24 by a Dess Martin periodinane protocol. Unsaturated
esters m,p25 were prepared by treating m,p24 with methyl(dimethoxyphosphinyl)
acetate. The hydroxamic acids m,p27 were obtained by hydrolysis of m,p25 and
subsequent treatment of the acids m,p26 with oxalyl chloride followed by hydroxyl-
amine.
Scheme 4
a) PhNH2, MeCN, Na2CO3. b) HCꢀCCH2OH, [Pd(Ph3P)4], CuI, Et3N, benzene, reflux. c) Dess Martin
protocol, CH2Cl2. d) (MeO)2P(O)CH2COOMe, NaH, THF. e) aq. NaOH soln., MeOH. f) 1. (COCl)2, CH2Cl2,
cat. DMF; 2. NH2OH ¥ HCl, THF, aq. NaHCO3 soln.
The −forward× sulfonamides 30 containing an aliphatic linkage between the
sulfonamide and hydroxamic acid fragments were synthesized from methyl 6-amino-
hexanoate (28) by condensation with the appropriate sulfonyl chloride (!29) and the
sodium methoxide/hydroxylamine procedure (! hydroxamic acids 30.1 30.4;
Scheme 5). The COOH-containing intermediate 29.4 was converted to the arylamide
intermediate 29.4a before conversion to the hydroxamic acid 30.4.
The −reversed× sulfonamides containing an aliphatic linkage between the sulfon-
amide and hydroxamic acid fragments were synthesized from appropriate w-
bromocarboxylates 31 via the sodium sulfonates 32 which were treated with PCl5
followed by the appropriate aromatic amine (Scheme 6). The obtained esters 33.1
33.6 were converted to the hydroxamic acids 34.1 34.6 by the sodium methoxide/
hydroxylamine procedure.

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Helvetica Chimica Acta Vol. 88 (2005)
Scheme 5
Ra)
Ra)
Ra)
30.1
30.2
Ph
30.3
(E)-PhCHˆCH
30.4
3-{[(4-methylphenyl)amino]carbonyl}phenylb)
MeSO2ÀC6H4
b
a) The same substituent Ris applicable to the corresponding intermediates, except for 29.4.
)
a) R SOCl, MeCN, Na2CO3. b) NH2OH ¥ HCl, MeONa, MeOH. c) 1. (COCl)2, CH2Cl2, cat. DMF; 2. 4-
2
methylaniline, MeCN.
Scheme 6
Ara)
Ra)
na)
Ara)
Ra)
na)
34.1
34.2
34.3
Ph
Ph
H
H
H
5
4
4
34.4
34.5
34.6
Ph
Ph
Ph
H
H
Me
6
7
7
naphthalen-2-yl
a) The same substituents Ar and R, and the same n are applicable to the corresponding intermediates.
a) Na2SO3, EtOH, H2O. b) 1. PCl5; 2. ArNH2 or PhNHMe, benzene. c) NH2OH ¥ HCl, MeONa, MeOH.
To investigate the structure activity relationship (SAR) of the cinnamoyl moiety
of the inhibitors, saturated analogues of some of the −reversed× sulfonamido-sub-
stituted hydroxamic acids were prepared. The appropriate starting material was

Helvetica Chimica Acta Vol. 88 (2005)
1637
hydrogenated over Pd-catalyst to give the corresponding saturated analogues 35.1
35.6 (Scheme 7).
Scheme 7
Ra)
Ra)
Ra)
35.1
35.2
Ph
35.3
35.4
2-MeOÀC6H4
4-MeOÀC6H4
35.5
35.6
[1,1'-biphenyl]-4-ylb)
PhCH2CH2CH2
4-MeÀC6H4
a) The same substituent Ris applicable to the corresponding m11. b) See Footnote c in Scheme 1.
To further investigate the SARof this part of the molecule, compounds 40 with
−forward× sulfonamide and oxymethyl fragments were prepared from appropriate
nitrophenols m,p36 by O-alkylation with ethyl bromoacetate (! m,p37) and reduction
to anilines m,p38 (Scheme 8). The anilines m,p38, were treated with appropriate
aromatic sulfonyl chlorides followed by hydroxylamine in the presence of base to afford
hydroxamic acids m40.1, m40.2, and p40.
Also −reversed× sulfonamide derivatives 45 and 48 with extended and shortened
arylalkyl linker parts were synthesized (Scheme 9). Thus, sodium 3-formylbenzenesul-
Scheme 8
Ara)
Ph
Ara)
Ph
Ara)
p40
m40.1
m40.2
naphthalen-1-yl
a)
The same substituent Ar is applicable to the corresponding intermediates.
a) BrCH2COOEt, K2CO3, MeCN. b) H2, 10% Pd/C, MeOH. c) ArSO2Cl, NaHCO3, acetone, H2O. d) NH2OH ¥
HCl, MeOH, THF, H2O, KOH.

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Helvetica Chimica Acta Vol. 88 (2005)
Scheme 9
a) 1. SOCl2, cat. DMF, benzene; 2. PhNH2, aq. NaHCO3 soln.; 58%. b) [Ph3P(CH2)3COOMe]I, NaH, THF;
31%. c) aq. NaOH soln., MeOH. d) H2, 5% Pd/C, MeOH. e) 1. (COCl)2, CH2Cl2, cat. DMF; 2. NH2OH ¥ HCl,
THF, aq. NaHCO3 soln.; 66%. f) NH2OH ¥ HCl, MeONa, MeOH. g) CrO3, H2SO4, acetone; 98%. h) MeOH,
HCl; 84%.
fonate m6 was condensed with aniline (!41) and treated with ylide to give (Z)/(E)-
ester 42. The mixture (Z)/(E)-42 was separated into the isomers (Z)- and (E)-42 by
HPLC, and each was separately treated with hydroxylamine in the presence of base to
give the (Z)- and (E)-isomers 45.1 and 45.2, respectively. The hydroxamic acid with a

Helvetica Chimica Acta Vol. 88 (2005)
1639
saturated side chain 45.3 was obtained from 42 by ester hydrolysis (!43), hydro-
genation (!44), and the oxalyl chloride/hydroxylamine procedure. Alternatively,
aldehyde 41 was oxidized to acid 46. After esterification (!47), treatment with
hydroxylamine in the presence of base gave hydroxamic acid 48.
3. Biological Activity.
3.1. Preamble. Compounds described in Sect. 2 were
profiled by using partially purified HDAC enzyme obtained from HeLa cell lysates.
The HDAC inhibitory activity, measured as IC50 [nm] are shown in Tables 1 6,
together with the antiproliferative activity of the compounds. In the vast majority of
cases, enzyme activity was determined with a fluorometric assay format. In a few cases,
a radiometric assay format was used these are indicated by values in italics in the
Tables. Extensive comparative studies showed that these assays yield equivalent results.
Analysis of this data enables a number of observations and conclusions to be drawn
from the SARs of this arylsulfonamido-substituted hydroxamic acid series of HDAC
inhibitors.
3.2. Direction of Sulfonamide Bond. Table 1 summarizes the data indicating that
compounds having a −reverse× sulfonamide functionality (NHSO2) in the meta position,
i.e., m11.1, m11.2, m11.21, m11.25, and m11.29 show a small but consistently better
HDAC-inhibitory activity compared to their counterparts with a −forward× sulfonamide
functionality (SO2NH2) in the meta position, i.e., m20.1, m20.2, m20.3, m20.4, and
m20.5. At least in the one case examined, this is also the case when there is an
intervening methylene between the aryl group and the sulfonamide moiety (m11.29 vs.
m20.5). There is no obvious equivalent trend when the substitution across the central
aromatic ring is para although the number of compounds available for this comparison
is relatively small (last four entries in Table 1).
Table 1. Direction of Sulfonamide Bond (n.t. ˆ not tested)
Inhibitor Sulfon-
amide
Position of Enzyme WST1 Inhibitor Sulfon-
Position of Enzyme
attachment IC50 [nm]
WST1
[mm]
attachment IC50 [nm] [mm]
amide
direction
direction
m11.1
m20.1
m11.2
m20.2
m11.21
m20.3
m11.25
NHSO2 meta
28
188
18
123
23
137
54
1.27 m20.4
SO2NH meta
NHSO2 meta
SO2NH meta
NHSO2 para
SO2NH para
NHSO2 para
SO2NH para
106
34
3.35
3.79
SO2NH meta
NHSO2 meta
SO2NH meta
NHSO2 meta
SO2NH meta
NHSO2 meta
8.85 m11.29
1.64 m20.5
4.10 15.1
2.90 p20.1
16.75 15.4
1.41 p20.2
23%@1000 n.t.
29
59
66
30
1.13
3.75
1.40
1.58
3.3. Position of Substitution. Both meta- and para-substitution patterns across the
central aromatic ring lead to highly potent compounds (Table 2). Either pattern leads
to approximately equal activity, but a slight preference may be discernable for greater
activity with the para-substitution pattern in the case of the −forward× sulfonamides, and
equal or slightly greater activity for the −reverse× sulfonamides when substituted meta.
Although the differences are small, it is interesting to observe that for the −reverse×
sulfonamides, meta substitution seems to be preferred when substituted with bulky
aromatic groups, but that in both cases where substitution is with a simple halo-
substituted aromatic group, the para compounds are more potent (m11.3 vs. 15.2 and

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Helvetica Chimica Acta Vol. 88 (2005)
Table 2. Position of Substitution
Inhibitor Sulfon-
amide
Position of Enzyme WST1 Inhibitor Sulfon-
Position of Enzyme WST1
attachment IC50 [nm] [mm]
attachment IC50 [nm] [mm]
amide
direction
direction
m11.1
15.1
NHSO2
NHSO2
SO2NH
SO2NH
SO2NH
SO2NH
NHSO2
NHSO2
SO2NH
SO2NH
NHSO2
NHSO2
NHSO2
meta
para
meta
para
meta
para
meta
para
meta
para
meta
para
meta
28
29
188
59
137
21
54
66
106
30
34
97
1.27
1.13
8.85 15.2
3.75 m11.4
16.75 15.3
3.52 m11.27
1.41
1.40
3.35 p20.4
1.58 o11.1
15.5
m11.3
NHSO2
NHSO2
NHSO2
para
meta
para
44
54
16
42
27
36
163
96
203
inact.
inact.
inact.
0.38
2.01
3.40
2.33
1.71
0.90
2.35
5.98
1.35
m20.1
p20.1
m20.3
p20.3
m11.25
15.4
m20.4
p20.2
m11.29
15.7
NHSO2- meta
NHSO2
NHSO2
NHSO2
SO2NH
SO2NH
NHSO2
NHSO2
NHSO2
para
meta
para
meta
para
ortho
ortho
ortho
15.6
m20.6
106.00
78.00
89.00
3.79 o11.2
5.45 o11.3
1.42
m11.23
42
m11.4 vs. 15.3). The ortho-substitution invariably leads to inactive compounds (o11.1
o11.3).
3.4. Influence of the Aromatic Head Group. HDAC-Inhibitory activity is also
modulated by the substitution patterns and size of the aromatic head group R'
(Table 3). In general, substitution of the aromatic ring with small groups leads to
compounds of approximately equal potency, irrespective of the electronic properties of
the group or its position of attachment, especially when this substitution is meta or para.
There is a suggestion that ortho substitution is somewhat disfavored, as indicated by the
weaker activity of compounds m11.24, m11.12, m11.13, m11.5, and m11.17. Compound
m11.9, where the ortho substitutent is the small F-atom, retains activity. Some clear
SARtrends are shown among various bulky head groups tried. In the light of the ortho-
substitution findings just noted, it is perhaps surprising that there is only a twofold
potency difference between the naphthalen-1-yl and naphthalen-2-yl derivatives
m11.22 and m11.23, respectively. However, consistent with this SAR, the more-extended
[1,1'-biphenyl]-4-yl derivative m11.25 is more potent than the [1,1'-biphenyl]-2-yl
analog m11.24. Planar bicyclic or tricyclic substituents R' such as the 1H-benzimidazol-
6-yl (m11.26), and 9-ethyl-9H-carbazol-3-yl group (m11.27) produced good activity,
which was not preserved with the nonplanar adamantan-1-yl derivative m11.28.
3.5. Influence of the Alkyl Spacer Group. A homologous series of compounds was
created by inserting a straight alkyl chain of increasing length in R' between the Ph
groups and the sulfonamide moiety. This does not affect the activity of the compounds,
except for a very modest decrease in activity for the longer homologues, despite adding
considerable incremental rotational freedom to the molecules (Table 4 ; see m11.1,
m11.29, m11.36, m11.38, and m11.40). Presumably, the entropic penalty on binding is
compensated by an equivalent gain in enthalpy of binding. The incorporation of
heteroatoms into the linking group is also allowed without loss of activity (see m11.39).
Some aromatic systems other than Ph are also tolerated in R' when there is a methylene
or ethylene spacer (see m11.30 and m11.34), but not universally (see m11.31, m11.32,
and m11.33). The weak activity of the naphthalen-2-yl derivative m11.33 in particular
contrasts with its potent activity when directly attached (see m11.23 in Table 3).

Helvetica Chimica Acta Vol. 88 (2005)
1641
Table 3. Influence of Aryl Group (n.t. ˆ not tested)
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
m11.1
m11.2
m11.3
m11.4
m11.5
m11.6
m11.7
m11.8
m11.9
m11.10
m11.11
m11.12
m11.13
m11.14
28
18
54
42
81
22
31
16
32
20
10
92
74
41
1.27
1.64
2.01
2.33
1.63
4.07
1.59
1.87
2.60
2.00
1.22
12.51
3.55
8.53
m11.15
m11.16
m11.17
m11.18
m11.19
m11.20
m11.21
m11.22
m11.23
m11.24
m11.25
m11.26
m11.27
m11.28
34
76
113
18
13
13
23
71
42
311
54
6.27
15.60
4.33
5.10
11.78
0.48
2.90
0.76
1.42
5.06
1.41
n.t.
9
36
120
0.90
0.68
Introducing additional aryl substituents into the linking chain of R' is poorly tolerated
(see m11.41, m11-42, and m11.45), but small alkyl or OH substituents can be introduced
to good effect (see m11.43 and m11.44). Few compounds with a −forward× sulfonamide
were synthesized, but it is interesting to observe that a single methylene linker yields an
inactive compound, whereas an ethenyl linker provides an inhibitor with modest
activity (but only when substituted in the meta position; see m20.5, m20.6, and p20.4).
Table 4. Influence of Alkyl Spacer (n.t. ˆ not tested)
Inhibitor
Enzyme FDL IC50 [nm]
WST1 [mm]
Inhibitor
Enzyme FDL IC50 [nm]
WST1 [mm]
m11.1
28
34
27
58
76
32
36
163
389
640
25
1.27
3.79
1.88
3.50
4.80
1.47
9.67
3.79
86.50
9.67
3.37
m11.35
m11.37
m11.41
m11.42
m11.43
m11.44
m11.45
m20.5
89
122
268
182
50
39
408
23%@1000
96
4.14
9.55
5.69
5.96
1.85
2.20
6.60
n.t.
m11.29
m11.36
m11.38
m11.40
m11.39
m11.30
m11.31
m11.32
m11.33
m11.34
m20.6
p20.4
5.98
1.35
203
3.6. Substitution of the Sulfonamide Moiety. Compounds in which the sulfonamide
N-atom was substituted (R''=H) are shown in Table 5. Substitution of the amide
proton at the −reverse× sulfonamide functionality with an alkyl group decreased the
HDAC inhibitory activity (see m11.46 and m11.47). Similarly, arylalkyl substitution
yields compounds with reduced activity (see m11.48 m11.52).
Table 5. Influence of Sulfonamide Substitution
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
m11.46
m11.47
m11.48
m11.49
476
510
174
164
7.29
17.93
3.54
m11.50
m11.51
m11.52
368
434
566
1.35
3.07
6.03
6.60

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Helvetica Chimica Acta Vol. 88 (2005)
3.7. Compounds Not Based on Cinnamic Acid. Saturation of the CˆC bond of the
cinnamic acid moiety leads to compounds with significantly reduced enzyme-inhibition
activity and weak antiproliferative activity (see 35.1 35.6, Table 6) when compared to
their cinnamic acid counterparts. Extending the length of the alkyl linker, either
unsaturated or saturated, yields compounds with a similar profile (see 45.1 45.3).
Complete removal of the CˆC bond yields a completely inactive compound (see 48).
Replacing one of the C-atoms with an O-atom is also not tolerated (see m40.2, m40.1,
and p40).
Table 6. Compounds Not Based on Cinnamic Acid (n.t. ˆ not tested)
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
Inhibitor
Enzyme IC50 [nm]
WST1 [mm]
35.1
35.2
35.3
35.4
35.6
35.5
45.1
45.2
45.3
48
346
207
616
122
165
148
20%@100
29%@100
135
inact.
inact.
inact.
136
21.45
17.60
70%@90
3.24
13.95
29.45
n.t.
49
47
14
45
1.10
0.78
5.70
16.73
72.00
4.20
2.85
6.82
96.20
n.t.
m27
p27
30.1
30.2
30.3
30.4
34.1
34.2
34.3
34.4
34.5
34.6
795
892
142
69
246
2030
145
379
181
565
n.t.
11.90
inact.
31.30
39.80
11.65
m40.2
m40.1
p40
18.35
10.67
n.t.
Other unsaturated systems are also compatible with good activity, e.g., in
compounds structurally related to oxamflatin (49) [22] (see m27 and p27). There is
an interesting contrast between the sulfonamide-containing HDAC inhibitors reported
here and the compounds reported in the scientific and patent literature which employ a
carboxamide linking group, such as SAHA (2). These molecules typically employ a
straight-chain saturated alkyl group between the hydroxamic acid and carboxamide
linkage, yielding highly potent enzyme inhibitors. However, this SARdoes not
translate when a sulfonamide linkage is used, as compounds of this type are generally
weak inhibitors (see 30.1 30.3 and 34.1 34.5). As with the carboxamides, short chains
give inactive compounds, but the inhibitors remain weak even as the length of the chain
increases. Moderately potent compounds can be obtained, however, by appropriate
manipulation of the group on the distal side of the sulfonamide from the hydroxamic

Helvetica Chimica Acta Vol. 88 (2005)
1643
acid (see 30.4). In common with the cinnamic acid series, methylation of the
sulfonamide N-atom yields a less active compound, 34.6.
3.8. Antiproliferative Activity. There is no very strong correlation between enzyme
inhibition and antiproliferative activity as measured by the WST-1 assay. This is
perhaps not surprising given the quite large structural diversity of the inhibitors. The
concomitant differences in polarity, hydrophobicity, and other factors that affect
cellular uptake and stability will impact on this correlation. Another possibly
confounding factor is the existence of multiple enzyme isoforms (see below).
Nonetheless chemical series that generally make weak inhibitors of the enzyme tend
also to be poor antiproliferatives, such as the alkyl-linker class and when the cinammic
acid CˆC bond is saturated. In fact, all compounds which are inactive in the
biochemical assay, or have inhibitory activity that is weak (close to mm), are also weak
antiproliferatives. Analyzing the set of compounds for which numerical data is
available in both assays gives a rank correlation coefficient of ca. 0.6, which is quite
reasonable given the considerations outlined above. It is also interesting to note that
compounds which have good cellular activity relative to their enzyme-inhibitory
potency tend to be more hydrophobic than the average (see m11.28, m11.50, p20.4, and
15.5), and that those where the translation is less good often have halogen or other
heteroatom substitution (see m11.18, m11.19, m11.30, and 15.2).
The most-potent antiproliferative compounds are from the cinnamic acid series, and
with the aryl group directly connected to the sulfonamide. Planar aromatic groups, such
as phenyl, naphthalenyl, and carbazolyl groups have the best activity.
4. Conclusion.
An extensive survey of the SARs of a novel sulfonamide-
containing class of histone-deacetylase inhibitors was performed. This has identified
sulfonamides based on cinnamic acid as a template for the generation of potent HDAC
inhibitors, with enzyme inhibition in the low nanomolar range. Appropriately aryl-
substituted compounds with low micromolar or submicromolar antiproliferative
activity were also obtained. These molecules are also active in both syngeneic (data
to be presented elsewhere) and xenograft animal models of cancer [23]. Based in part
on the data presented here, a molecule, m11.1, also designated PXD101, was selected
for clinical investigation and is currently in phase-I and phase-II trials for cancer.
The area of HDAC inhibitors remains one with great potential for drug discovery. A
growing number of histone-deacetylase-family members have been identified [24], and
may be drug targets. The first deacetylase, HDAC1, was identified in 1996 [25].
Subsequently, two other nuclear mammalian deacetylases were found, HDAC2 and
HDAC3 [26 30]. To date, eleven human HDACs have been cloned, falling into two
distinct classes, with HDACs 1 3 and 8 belonging to class I, and HDACs 4 7 and 9 11
to class II. In the work reported here, a HeLa cell extract was used as source of histone-
deacetylase activity. This source of enzyme, therefore, represents a mixture of at least
some of these isoforms. A continuing focus of our own work, and that of others, is the
elucidation of the role of the different HDAC family members in disease and the
identification of family-member-specific inhibitors as pharmacological tools and
potential therapeutic compounds with exciting opportunities in cancer and other areas
of high unmet medical need.

1644
Helvetica Chimica Acta Vol. 88 (2005)
Experimental Part
1. Biology. 1.1. Histone Deacetylase Assays. Candidate compounds were assessed for their ability to inhibit
deacetylase activity (biochemical assays) and to inhibit cell proliferation (cell-based antiproliferation assays), as
described below.
1.2. Primary Assay 1 (P.A.1): Deacetylase Activity. Radiometric Assay. Briefly, this assay relies on the
release of radioactive acetate from a radioactively labelled histone fragment by the action of HDAC enzyme.
Test compounds, which inhibit HDAC, reduce the yield of radioactive acetate. Signal (e.g., scintillation counts)
measured in the presence and absence of a test compound provide an indication of that compound×s ability to
inhibit HDAC activity. Decreased activity indicates increased inhibition by the test compound.
The histone fragment was an N-terminal sequence from histone H4, and it was labelled with radioactively
labelled acetyl groups by using tritiated acetylcoenzyme A (Ac-CoA) in conjunction with an enzyme which is
the histone acetyltransferase domain of the transcriptional coactivator p300. Peptide H4 (ˆthe N-terminal 20
amino acids of histone H4, synthesized by conventional methods; 0.33 mg) was incubated with His6-tagged p300
histone acetyltransferase domain (amino acids 1195 1673, expressed in E. coli strain BLR(DE3)pLysS
(Novagen, Cat. No. 69451-3) and 3H-acetyl-CoA (10 ml of 3.95 Ci/mmol; from Amersham) in a total volume of
300 ml of HAT buffer (50 mm Tris ¥ HCl (pH 8), 5% glycerol, 50 mm KCl, 0.1 mm ethylenediaminetetraacetic
acid (edta), 1 mm dithiothreitol (DTT), and 1 mm 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). The
mixture was incubated at 308 for 45 min after which the His-p300 was removed by using nickel/trinitriloacetic
acid agarose (Qiagen, Cat No. 30210). The acetylated peptide was then separated from free Ac-CoA by size-
exclusion chromatography (Sephadex G-15 (Sigma G-15-120), dist. H2O).
After purification of the radiolabelled histone fragment, it was incubated with a source of HDAC (an
extract of HeLa cells), and any released acetate was extracted into an org. phase and quantitatively determined
by scintillation counting. By including a test compound with the source of HDAC, that compound×s ability to
inhibit the HDAC was determined.
Assay Method: A source of HDAC (e.g., 2 ml of crude HeLa extract; in elution buffer, as above) was
incubated with 3 ml of radioactively labelled peptide along with appropriate dilutions of candidate compounds
(1.5 ml) in a total volume of 150 ml of buffer (20 mm Tris ¥ HCl (pH 7.4), 10% glycerol). The reaction was carried
out at 378 for 1 h, after which the reaction was stopped by adding 20 ml of 1m HCl/0.4m NaOAc. Then, 750 ml of
AcOEt was added, the samples were vortexed and, after centrifugation (14000 r.p.m., 5 min), 600 ml from the
upper phase were transferred to a vial containing 3 ml of scintillation liquid (UltimaGold, Packard, Cat. No.
6013329). Radioactivity was measured with a Tri-Carb-2100TR liquid scintillation analyzer (Packard).
Percent activity (% activity) for each test compound was calculated as % activity ˆ {(SC À B)/(S8 À B)} ¥
100, wherein SC denotes the signal measured in the presence of enzyme and the compound being tested, S8
denotes the signal measured in the presence of enzyme but in the absence of the compound being tested, and B
denotes the background signal measured in the absence of both enzyme and compound being tested. The IC50
corresponds to the concentration which achieves 50% activity.
1.3. Primary Assay 2 (P.A.2): Deacetylase Activity: Fluorescent Assay. Alternatively, the activity of the
compounds as HDAC inhibitors was determined with a commercially available fluorescent assay kit: (Fluor de
LysTM, BioMol Research Labs, Inc., Plymouth Meeting, USA). HeLa Extract was incubated for 1 h at 378 in
assay buffer (25 mm HEPES, 137 mm NaCl, 2.7 mm KCl, 1 mm MgCl2, pH 8.0) with 15 mm acetylated substrate
in the presence of test compound (HDAC inhibitor). The extent of deacetylation was determined by the
addition of 50 ml of a 1-in-500 dilution of developer and measurement of the fluorescence (excitation 355 nm,
emission 460 nm), according to the instructions provided with the kit. The IC50 corresponds to the concentration
which achieves 50% activity. IC50 values were calculated with the software package Prism 3.0 (GraphPad
Software Inc., San Diego, CA), setting the top value at 100 and the bottom value at 0.
Extensive comparative studies showed that P.A.1 and P.A.2, discussed above, yield equivalent results.
Primary-assay results reported herein are a) exclusively from P.A.1, b) exclusively from P.A.2, or c) from both
P.A.1 and 2.
1.4. HeLa Cell Extracts. HeLa cells (ATCC Ref. No. CCL-2) were cultured in DMEM containing 10% FCS,
100 U/ml of penicillin and 100 mg/ml of streptomycin. Subconfluent cells were harvested by trypsinization and
washed twice in ice-cold PBS. The cells were resuspended in 2 volumes of buffer (60 mm Tris ¥ HCl (pH 7.4),
30% glycerol, 450 mm NaCl) and lysed by three freeze and thaw cycles (dry ice/ À 308). Cell debris was removed
by centrifugation at 20817 g and the supernatant aliquoted and stored at À 808.
1.5. Secondary Assay: Cell Proliferation. Compounds with HDAC-inhibition activity, as determined by the
primary assay, were subsequently evaluated using secondary cell-based assays. HeLa Cells were cultured,

Helvetica Chimica Acta Vol. 88 (2005)
1645
exposed to candidate compounds, and incubated for a time, and the number of viable cells was then assessed by
using the cell proliferation reagent WST-1 from Boehringer Mannheim (Cat. No. 1644807), described below.
Cells were plated in 96-well plates at 3 10 ¥ 103 cells/well in 100 ml of culture medium. The following day,
different concentrations of candidate compounds were added and the cells incubated at 378 for 48 h.
Subsequently, 10 ml/well of WST-1 reagent was added, and the cells were reincubated for 1 h. After the
incubation time, absorbance was measured.
WST-1 is a tetrazolium salt which is cleaved to a formazan dye by cellular enzymes. An expansion in the
number of viable cells results in an increase in the overall activity of mitochondrial dehydrogenases in the
sample. This augmentation in the enzyme activity leads to an increase in the amount of formazan dye formed,
which directly correlates to the number of metabolically active cells in the culture. The formazan dye produced
is quantified by a scanning multiwell spectrophotometer by measuring the absorbance of the dye soln. at 450 nm
wavelength (reference wavelength 690 nm).
Percent activity (% activity) in reducing the number of viable cells was calculated for each test compound
as: % activity ˆ {(SC À B)/(S8 À B)} ¥ 100, wherein SC denotes the signal measured in the presence of the
compound being tested, S8 the signal measured in the absence of the compound being tested, and B the
background signal measured in blank wells containing medium only. The IC50 corresponds to the concentration
which achieves 50% activity. IC50 Values were calculated with the software package Prism 3.0 (GraphPad
Software Inc., San Diego, CA), setting the top value at 100 and the bottom value at 0.
Measurement of cell viability in the presence of increasing concentration of test compound at different time
points was used to assess both cytotoxicity and the effect of the compound on cell proliferation.
2. Syntheses. General. All the solvents were purified before use by routine techniques. The reaction products
were isolated by evaporating the solvent (vacuum rotary evaporator). Column chromatography (CC): silica gel
0.035 0.070 mm (Acros). Anal. HPLC (reversed phase): Varian ProStar HPLC system equipped with a
»
spectrophotometer; check of the purity of synthesized compounds. M.p.: Boetius or Fisher micro melting point
apparatus; uncorrected. NMRSpectra: Varian WH-90/DS- or Mercury-200 spectrometers; at r.t.; d in ppm, J in
Hz. Elemental analyses: Carlo-Erba EA-1108 instrument.
Sodium 3-Formylbenzenesulfonate (m6). While maintaining the temp. at 308, 5 (2.00 g, 18.84 mmol) was
added slowly to oleum (5 ml). The resultant soln. was stirred at 408 for 10 h and at r.t. overnight. The mixture
was poured into ice and extracted with AcOEt. The aq. phase was treated with CaCO3 until the evolution of CO2
ceased (pH ca. 6 7), and the precipitated CaSO4 was filtered off and washed with H2O. The filtrate was treated
with solid Na2CO3 until the pH of the medium increased to 8, obtained CaCO3 was filtered off, and the soln. was
evaporated. The residue was washed with MeOH, the washings were evaporated, and the obtained solid was
1
dried in a desiccator (P2O5): m6 (2.00 g, 51%). H-NMR(D O, 90 MHz): 7.56 8.40 (m, 4 H); 10.04 (s, 1 H).
2
Sodium 3-[(1E)-3-Methoxy-3-oxoprop-1-enyl]benzenesulfonate (m7).
A mixture of m6 (1.00 g,
4.80 mmol), K2CO3 (1.32 g, 9.56 mmol), methyl (dimethoxyphosphinyl) acetate (1.05 g, 5.77 mmol) and H2O
(2 ml) was stirred at r.t. for 30 min. Precipitated solid was filtered off and washed with MeOH. The filtrate was
1
evaporated and dried: m7 (0.70 g, 55%). White solid. H-NMR((D 6)DMSO, 90 MHz): 3.68 (s, 3 H); 6.51 (d,
J ˆ 16.0, 1 H); 7.30 7.88 (m, 5 H).
Methyl (2E)-3-[3-(Chlorosulfonyl)phenyl]prop-2-enoate (m8). To m7 (13.1 g, 49.5 mmol) in benzene
(150 ml), SOCl2 (10.6 ml, 146.1 mmol) and DMF (0.2 ml, 2.6 mmol) were added, and the resultant suspension
was stirred under reflux until all the solid dissolved (ca. 4 5 H). The mixture was evaporated, the residue
dissolved in benzene (100 ml), the soln. filtered, the filtrate evaporated, the residue dissolved in benzene
(50 ml), and the soln. again evaporated. This procedure was repeated once more, and the obtained material was
dried over P2O5 in vacuo: m8 (10.6 g, 82%). White solid. 1H-NMR(CDCl 3, 90 MHz): 3.82 (s, 3 H); 6.57 (d, J ˆ
16.1, 1 H); 7.66 (t, J ˆ 7.5, 1 H); 7.70 (d, J ˆ 16.1, 1 H); 7.85 (dt, J ˆ 1.5, 7.5, 1 H); 8.03 (dt, J ˆ 1.5, 7.5, 1 H); 8.16 (t,
J ˆ 1.5, 1 H).
Methyl (2E)-3-{3-[(Phenylamino)sulfonyl]phenyl}prop-2-enoate (m9.1). A soln. of m8 (1.00 g, 3.83 mmol)
in dioxane (12 ml) was added to a mixture of benzenamine (0.38 ml, 3.43 mmol) in dioxane (5 ml) and NaHCO3
(0.64 g, 7.66 mmol) in H2O (7.5 ml). The resultant mixture was stirred at r.t. for 1 h (TLC control), evaporated,
and supplemented with H2O (25 ml). The mixture was stirred at r.t. for 1 h, the precipitate filtered, washed with
H2O, and dried: 0.89 g (74%) of m9.1. 1H-NMR(CDCl 3, 90 MHz): 3.72 (s, 3 H); 6.34 (d, J ˆ 16.0, 1 H); 6.68 (br.
s, 1 H); 6.92 7.89 (m, 10 H).
(2E)-3-{3-[(Phenylamino)sulfonyl]phenyl}prop-2-enoic Acid (m10.1). m9.1 (4.10 g, 12.9 mmol) was
dissolved in MeOH (50 ml), 1m NaOH (38.75 ml, 38.75 mmol) was added, and the soln. was stirred at r.t.
overnight (TLC control). The mixture was partitioned between AcOEt and H2O. The aq. layer was acidified
with 2m HCl and stirred for 30 min. The precipitated solid was filtered, washed with H2O, and dried in the

1646
Helvetica Chimica Acta Vol. 88 (2005)
1
desiccator (P2O5): m10.1 (3.32 g, 85%). White solid. H-NMR((D 6)DMSO, 90 MHz): 6.53 (d, J ˆ 16.0, 1 H);
6.87 7.34 (m, 5 H); 7.52 (t, J ˆ 7.6, 1 H); 7.56 (d, J ˆ 16.0, 1 H); 7.73 (d, J ˆ 8, 1 H); 7.89 (d, J ˆ 8, 1 H); 7.96 (s,
1 H); 10.23 (br. s, 1 H); 12.53 (br. s, 1 H).
(2E)-N-Hydroxy-3-{3-[(phenylamino)sulfonyl]phenyl}prop-2-enamide (m11.1). To a suspension of m10.1
(2.88 g, 9.49 mmol) in CH2Cl2 (35 ml), oxalyl chloride (2.7 ml, 30.84 mmol) and 1 drop of DMF were added. The
mixture was stirred at reflux for 1 h and then evaporated and the residue dried in vacuo and dissolved in THF
(30 ml). In another vessel, to a suspension of hydroxylamine hydrochloride (3.36 g, 48.69 mmol) in THF
(55 ml), a sat. NaHCO3 soln. (38 ml) was added, and the resultant mixture was stirred at r.t. for 10 min. The
contents of both vessels were combined and stirred at r.t. for 1 h. The mixture was partitioned between AcOEt
and 2m HCl. The org. phase was washed successively with H2O and sat. NaCl soln. and evaporated, and the
residue crystallized from AcOEt: m11.1 (2.57 g, 85%). White crystals. M.p. 1728. 1H-NMR((D 6)DMSO,
90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 7.18 8.05 (m, 10 H); 9.16 (br. s, 1 H); 10.34 (s, 1 H); 10.85 (br. s, 1 H). Anal.
calc. for C15H14N2O4S (318.35): C 56.59, H 4.43, N 8.80; found: C 56.55, H 4.41, N 8.66.
3-[(Aminosulfonyl)phenyl]-N-hydroxypropenamides m11.2 m11.52 and o11.1 o11.3 were obtained as
described for m11.1.
(2E)-N-Hydroxy-3-{3-{[(4-methylphenyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.2): M.p. 2008.
1H-NMR((D 6)DMSO, 90 MHz): 2.16 (s, 3 H); 6.47 (d, J ˆ 16.0, 1 H); 6.98 (s, 4 H); 7.29 7.98 (m, 5 H); 9.09
(br. s, 1 H); 10.09 (s, 1 H); 10.76 (br. s, 1 H). Anal. calc. for C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43; found:
C 57.61, H 4.93, N 8.16.
(2E)-3-{3-{[(4-Bromophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.3): M.p. 2048.
1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 7.05 (d, J ˆ 9.0, 2 H); 7.34 7.98 (m, 7 H); 9.09 (br. s,
1 H); 10.47 (s, 1 H); (br. s, 1 H). Anal. calc. for C15H13BrN2O4S (397.25): C 45.35, H 3.30, N 7.05; found: C 45.73,
H 3.33, N 6.81.
(2E)-3-{3-{[(4-Chlorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.4): M.p. 1988.
1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 6.98 8.05 (m, 9 H); 9.16 (br. s, 1 H); 10.49 (s, 1 H);
10.85 (s, 1 H). Anal. calc. for C15H13ClN2O4S (352.80): C 51.07, H 3.71, N 7.94, S 9.09; found: C 50.96, H 3.62, N
7.76, S 9.00.
(2E)-N-Hydroxy-3-{3-{[(2-methoxyphenyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.5): M.p. 1818.
1H-NMR((D 6)DMSO, 90 MHz): 3.45 (s, 3 H); 6.49 (d, J ˆ 16.0, 1 H); 6.76 7.96 (m, 9 H); 9.09 (br. s, 1 H);
9.54 (s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C16H16N2O5S (348.38): C 55.16, H 4.63, N 8.04; found: C 55.14, H
4.52, N 7.99.
(2E)-N-Hydroxy-3-{3-{[(3-methoxyphenyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.6): M.p. 1378.
1H-NMR((D 6)DMSO, 90 MHz): 3.65 (s, 3 H); 6.38 6.78 (m, 4 H); 6.98 7.27 (m, 1 H); 7.34 8.03 (m, 5 H);
9.14 (br. s, 1 H); 10.30 (s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C16H16N2O5S ¥ 0.2 H2O (351.98): C 54.60, H 4.70,
N 7.96; found: C 54.61, H 4.58, N 7.96.
(2E)-3-{3-{[(3-Bromophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.7): M.p. 135.5
136.58. 1H-NMR((D 6)DMSO, 200 MHz): 6.53 (d, J ˆ 15.6, 1 H); 7.07 7.28 (m, 4 H); 7.48 (d, J ˆ 15.6, 1 H);
7.60 (t, J ˆ 7.6, 1 H); 7.72 (d, J ˆ 7.6, 1 H); 7.81 (d, J ˆ 7.6, 1 H); 7.94 (s, 1 H); 9.15 (br. s, 1 H); 10.60 (br. s, 1 H);
10.84 (br. s, 1 H). Anal. calc. for C15H13BrN2O4S (397.25): C 45.35, H 3.30, N 7.05; found: C 45.38, H 3.03, N 6.96.
(2E)-N-Hydroxy-3-{3-{{[4-(trifluoromethoxy)phenyl]amino}sulfonyl}phenyl}prop-2-enamide (m11.8):
M.p. 1318. 1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 7.03 8.05 (m, 9 H); 8.98 (br. s, 1 H);
10.54 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C16H13F3N2O5S (402.35): C 47.76, H 3.26, N 6.96; found: C
47.68, H 3.15, N 6.91.
(2E)-3-{3-{[(2-Fluorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.9): M.p. 102 1038.
1H-NMR((D 6)DMSO, 90 MHz): 6.44 (d, J ˆ 16.0, 1 H); 6.96 7.24 (m, 4 H); 7.43 (d, J ˆ 16.0, 1 H); 7.49 7.91
(m, 4 H); 9.04 (br. s, 1 H); 10.13 (br. s, 1 H); 10.73 (br. s, 1 H). Anal. calc. for C15H13N2O4FS ¥ 0.9 EtOH (377.80):
C 53.41, H 4.91, N 7.41; found: C 53.79, H 4.62, N 7.13.
(2E)-3-{3-{[(3-Fluorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.10): M.p. 130
1
1338. H-NMR((D 6)DMSO, 200 MHz): 6.52 (d, J ˆ 15.8, 1 H); 6.75 6.97 (m, 4 H); 7.17 7.32 (m, 1 H); 7.47
(d, J ˆ 15.8, 1 H); 7.58 (t, J ˆ 7.8, 1 H); 7.67 7.85 (m, 2 H); 7.94 (s, 1 H); 9.19 (br. s, 1 H); 10.89 (br. s, 1 H). Anal.
calc. for C15H13N2O4FS ¥ 0.65 EtOH (366.28): C 53.45, H 4.65, N 7.65, S 8.75; found: C 53.54, H 4.32, N 7.37, S
8.50.
(2E)-3-{3-{{[4-(Difluoromethoxy]phenyl]amino}sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.11):
M.p. 91 938. 1H-NMR((D 6)DMSO, 90 MHz): 6.47 (d, J ˆ 16.0, 1 H); 6.96 (s, 4 H); 7.31 7.93 (m, 6 H). Anal.
calc. for C16H14N2O5F2S ¥ 0.3 H2O ¥ 0.5 EtOH (412.79): C 49.46, H 4.30, N 6.79, S 7.77; found: C 49.46, H 3.95, N
6.65, S 7.39.

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(2E)-3-{3-{[(2,6-Difluorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.12): M.p. 79
1
828. H-NMR((D 6)DMSO, 90 MHz): 6.47 (d, J ˆ 16.0, 1 H); 6.89 7.89 (m, 8 H); 9.07 (br. s, 1 H); 10.02 (br.
s, 1 H); 10.73 (br. s, 1 H). Anal. calc. for C15H12N2O4F2S ¥ 1.2 EtOH (409.61): C 51.02, H 4.72, N 6.84, S 7.83;
found: C 50.84, H 4.60, N 6.78, S 7.76.
(2E)-N-Hydroxy-3-{3-{{[2-methoxy-5-(trifluoromethyl)phenyl]amino}sulfonyl}phenyl}prop-2-enamide
(m11.13): M.p. 2078 (dec.). 1H-NMR((D 6)DMSO, 90 MHz): 3.57 (s, 3 H); 6.52 (d, J ˆ 15.8, 1 H); 7.12 (d, J ˆ 8.4,
1 H); 7.36 8.09 (m, 7 H); 9.11 (br. s, 1 H); (s, 1 H); 10.82 (s, 1 H). Anal. calc. for C17H15F3N2O5S (416.38): C
49.04, H 3.63, N 6.78; found: C 49.39, H 3.41, N 6.66.
(2E)-N-Hydroxy-3-{3-{{[4-(trifluoromethyl)phenyl]amino}sulfonyl}phenyl}prop-2-enamide (m11.14): M.p.
184 1858. 1H-NMR((D 6)DMSO, 200 MHz): 6.53 (d, J ˆ 15.9, 1 H); 7.30 (d, J ˆ 8.4, 2 H); 7.49 (d, J ˆ 15.9, 1 H);
7.61 (t, J ˆ 7.4, 1 H); 7.62 (d, J ˆ 8.4, 2 H); 7.78 (d, J ˆ 8.4, 1 H); 7.82 (d, J ˆ 8.2, 1 H); 8.00 (s, 1 H); 9.17 (s, 1 H);
10.86 (s, 1 H); 10.97 (br. s, 1 H). Anal. calc. for C16H13F3N2O4S (386.35): C 49.74, H 3.39, N 7.25, S 8.30; found: C
49.78, H 3.47, N 7.05, S 8.34.
(2E)-N-Hydroxy-3-{3-{{{3-[(trifluoromethyl)thio]phenyl}amino}sulfonyl}phenyl}prop-2-enamide
(m11.15): M.p. 139 1408. 1H-NMR((D 6)DMSO, 90 MHz): 6.51 (d, J ˆ 15.8, 1 H); 7.26 7.53 (m, 5 H); 7.58 (t,
J ˆ 7.7, 1 H); 7.71 (d, J ˆ 8.0, 1 H); 7.80 (d, J ˆ 7.6, 1 H); 7.91 (s, 1 H); 9.14 (s, 1 H); 10.70 (s, 1 H); 10.84 (s, 1 H).
Anal. calc. for C16H13F3N2O4S2 (418.42): C 45.93, H 3.13, N 6.70, S 15.33; found: C 46.04, H 3.02, N 6.74, S 15.31.
(2E)-N-Hydroxy-3-{3-{{{4-[(trifluoromethyl)thio]phenyl}amino}sulfonyl}phenyl}prop-2-enamide
(m11.16): M.p. 1518 (dec.). 1H-NMR((D 6)DMSO, 200 MHz): 6.53 (d, J ˆ 15.7, 1 H); 7.24 (d, J ˆ 8.6, 2 H); 7.49
(d, J ˆ 15.7, 1 H); 7.59 (d, J ˆ 8.6, 2 H); 7.63 (d, J ˆ 7.8, 1 H); 7.78 (d, J ˆ 8.0, 1 H); 7.80 (t, J ˆ 7.9, 1 H); 7.99 (s,
1 H); 9.16 (s, 1 H); 10.85 (s, 1 H); 10.91 (s, 1 H). Anal. calc. for C16H13F3N2O4S2 (418.42): C 45.93, H 3.13, N 6.70;
found: C 45.99, H 2.96, N 6.61.
(2E)-3-{3-{[(2,6-Dimethylphenyl)amino]sulfonyl}pheny}-N-hydroxyprop-2-enamide (m11.17): M.p. 163
1658. 1H-NMR((D 6)DMSO, 90 MHz): 1.96 (s, 6 H); 6.56 (d, J ˆ 16.0, 1 H); 7.07 (m, 3 H); 7.56 (d, J ˆ 16.0,
1 H);7.69 7.98 (m, 4 H); (br. s, 2 H); 10.76 (br. s, 1 H). Anal. calc. for C17H18N2O4S ¥ 1.4 H2O, (371.62): C 54.94,
H 5.64, N 7.54; found: C 54.96, H 5.20, N 7.58.
(2E)-3-{3-{[(3,5-Difluorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.18): M.p. 1358.
1H-NMR((D 6)DMSO, 200 MHz): 6.54 (d, J ˆ 15.7, 1 H); 6.69 6.82 (m, 2 H); 6.90 (tt, J ˆ 2.1, 9.4, 1 H); 7.52 (d,
J ˆ 15.7, 1 H); 7.61 (t, J ˆ 7.9, 1 H); 7.78 (d, J ˆ 7.9, 1 H); 7.84 (d, J ˆ 7.9, 1 H); 7.99 (s, 1 H); 9.16 (s, 1 H); 10.86 (s,
2 H). Anal. calc. for C15H12F2N2O4S (354.33): C 50.85, H 3.41, N 7.91; found: C 50.71, H 3.22, N 7.99.
(2E)-3-{3-{{[3,5-Bis(trifluoromethyl)phenyl]amino}sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.19):
Foam. 1H-NMR((D 6)DMSO, 200 MHz): 6.54 (d, J ˆ 15.8, 1 H); 7.48 (d, J ˆ 15.8, 1 H); 7.63 (t, J ˆ 7.7, 1 H); 7.65
(s, 3 H); 7.73 7.81 (m, 2 H); 7.84 (d, J ˆ 7.6, 1 H); 7.98 (s, 1 H); 9.14 (br. s, 1 H); (s, 1 H). Anal. calc. for
C17H12F6N2O4S (454.35): C 44.96, H 2.63, N 6.17; found: C 44.94, H 2.66, N 6.17.
(2E)-N-Hydroxy-3-{3-{[(4-methoxyphenyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.20): M.p. 1868.
1H-NMR((D 6)DMSO, 90 MHz): 3.67 (s, 3 H); 6.49 (d, J ˆ 16.0, 1 H); 6.72 8.03 (m, 9 H); 9.14 (br. s, 1 H); 9.91
(s, 1 H); 10.85 (br. s, 1 H). Anal. calc. for C16H16N2O5S (348.38): C 55.16, H 4.63, N 8.04, S 9.20; found: C 55.07, H
4.60, N 7.94, S 9.01.
(2E)-3-{3-{[(3,4-Dimethoxyphenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.21): M.p.
1918. 1H-NMR((D 6)DMSO, 90 MHz): 3.60 (s, 3 H); 3.65 (s, 3 H); 6.34 6.87 (m, 4 H); 7.32 8.03 (m, 5 H);
9.09 (br. s, 1 H); 9.92 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C17H18N2O6S (378.41): C 53.96, H 4.79, N 7.40;
found: C 53.84, H 4.78, N 7.25.
(2E)-N-Hydroxy-3-{3-[(naphthalen-1-ylamino)sulfonyl]phenyl}prop-2-enamide (m11.22): M.p. 1808.
1H-NMR((D 6)DMSO, 90 MHz): 6.45 (d, J ˆ 16.0, 1 H); 7.14 (dd, J ˆ 1.4, 7.0, 1 H); 7.31 8.14 (m, 11 H); 9.09
(br. s, 1 H); 10.27 (s, 1 H); (br. s, 1 H). Anal. calc. for C19H16N2O4S (368.41): C 61.94, H 4.38, N 7.60; found: C
61.18, H 4.32, N 7.54.
(2E)-N-Hydroxy-3-{3-[(naphthalen-2-ylamino)sulfonyl]phenyl}prop-2-enamide (m11.23): M.p. 1648.
1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 7.16 7.89 (m, 12 H); 7.98 (br. s, 1 H); (s, 1 H); 10.76
(br. s, 1 H). Anal. calc. for C19H16N2O4S (368.41): C 61.94, H 4.38, N 7.60; found: C 61.44, H 4.39, N 7.48.
(2E)-3-{3-[([1,1'-Biphenyl]-2-ylamino)sulfonyl]phenyl}-N-hydroxyprop-2-enamide (m11.24): Foam.
1H-NMR((D 6)DMSO, 90 MHz): 6.43 (d, J ˆ 16.0, 1 H); 6.94 7.85 (m, 14 H); 9.07 (br. s, 1 H); 9.58 (br. s,
1 H); 10.78 (br. s, 1 H). Anal. calc. for C21H18N2O4S ¥ 0.5 H2O (403.45): C 62.52, H 4.75, N 6.94; found: C 62.58, H
4.66, N 6.65.
(2E)-3-{3-[([1,1'-Biphenyl]-4-ylamino)sulfonyl]phenyl}-N-hydroxyprop-2-enamide (m11.25): M.p. 1888.
1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 7.07 8.07 (m, 14 H); 9.09 (br. s, 1 H); 10.35 (br. s, 1 H);

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Helvetica Chimica Acta Vol. 88 (2005)
10.80 (br. s, 1 H). Anal. calc. for C21H18N2O4S ¥ 0.2 H2O (398.05): C 63.37, H 4.66, N 7.04; found: C 63.42, H 4.57,
N 6.95.
(2E)-3-{3-[(1H-Benzimidazol-6-ylamino)sulfonyl]phenyl}-N-hydroxyprop-2-enamide (m11.26): M.p. 1978
(dec.). 1H-NMR((D 6)DMSO, 90 MHz): 6.49 (d, J ˆ 16.0, 1 H); 6.94 (dd, J ˆ 2.0, 8.8, 1 H); 7.22 8.07 (m, 7 H);
8.13 (s, 1 H); 9.11 (br. s, 1 H); 10.12 (s, 1 H); 10.80 (s, 1 H); 12.34 (br. s, 1 H). Anal. calc. for C16H14N4O4S ¥
0.2 AcOEt ¥ 0.4 H2O (383.20): C 52.66, H 4.31, N 14.62, S 8.37; found: C 52.50, H 3.82, N 14.57, S 8.45.
(2E)-3-{3-{[(9-Ethyl-9H-carbazol-3-yl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.27): M.p.
130 1338. 1H-NMR((D )DMSO, 90 MHz): 1.20 (t, J ˆ 6.6, 3 H); 4.34 (q, J ˆ 6.6, 2 H); 6.42 (d, J ˆ 16.0, 1 H);
6
6.93 8.07 (m, 13 H); 9.07 (br. s, 1 H); 10.3 (br. s, 1 H). Anal. calc. for C23H21N3O4S ¥ 0.8 H2O ¥ 0.4 EtOH
(468.34): C 60.91, H 5.11, N 9.27, S 7.07; found: C 61.01, H 5.15, N 8.75, S 6.65.
(2E)-N-Hydroxy-3-{3-[(tricyclo[3.3.1.1.3,7]dec-1-ylamino)sulfonyl]phenyl}prop-2-enamide (m11.28): M.p.
1798. 1H-NMR((D 6)DMSO, 90 MHz): 1.32 2.05 (m, 15 H); 6.52 (d, J ˆ 16.0, 1 H); 7.29 7.87 (m, 5 H); 7.98 (br.
s, 1 H); 9.09 (s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C19H24N2O4S (376.48): C 60.62, H 6.43, N 7.44; found: C
60.71, H 6.39, N 7.24.
(2E)-3-{3-[(Benzylamino)sulfonyl]phenyl}-N-hydroxyprop-2-enamide (m11.29): M.p. 1798. 1H-NMR
((D6)DMSO, 90 MHz): 4.02 (d, J ˆ 6.4, 2 H); 6.53 (d, J ˆ 16.0, 1 H); 7.25 (s, 5 H); 7.39 8.03 (m, 5 H); 8.20
(t, J ˆ 6.4, 1 H); 9.12 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43,
S 9.60; found: C 57.59, H 4.82, N 8.14, S 9.65.
(2E)-3-{3-{[(1,3-Benzodioxol-5-ylmethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.30):
M.p. 1638. 1H-NMR((D 6)DMSO, 90 MHz): 3.92 (d, J ˆ 6.4, 2 H); 5.92 (s, 2 H); 6.49 (d, J ˆ 16.0, 1 H); 6.67
(s, 3 H); 7.34 7.89 (m, 5 H); 8.12 (t, J ˆ 6.4, 1 H); 9.07 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C17H16N2O6S
(376.39): C 54.25, H 4.28, N 7.44; found: C 54.19, H 4.20, N 7.33.
(2E)-N-Hydroxy-3-{3-{[(pyridin-3-ylmethyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.31): M.p. 1918.
1H-NMR((D 6)DMSO, 90 MHz): 4.05 (d, J ˆ 6.4, 2 H); 6.56 (d, J ˆ 16.0, 1 H); 7.16 8.05 (m, 7 H); 8.16 8.49
(m, 3 H); 9.12 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C15H15N3O4S (333.37): C 54.04, H 4.54, N 12.60;
found: C 53.72, H 4.33, N 12.41.
(2E)-N-Hydroxy-3-{3-{[(3,4,5-trimethoxybenzyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.32): Foam.
1H-NMR((D 6)DMSO, 90 MHz): 3.54 (s, 3 H); 3.65 (s, 6 H); 3.98 (m, 2 H); 6.46 (s, 2 H); 6.56 (d, J ˆ 15.0, 1 H);
7.32 7.98 (m, 5 H); 8.18 (br. t, J ˆ 5.5, 1 H); 9.12 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C19H22N2O7S ¥
0.5 H2O (431.46): C 52.89, H 5.37, N 6.49; found: C 53.13, H 5.31, N 6.02.
(2E)-N-Hydroxy-3-{3-{[(naphthalen-1-ylmethyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.33): M.p.
1
1778. H-NMR((D 6)DMSO, 90 MHz): 4.45 (d, J ˆ 6.0, 2 H); 6.58 (d, J ˆ 16.0, 1 H);7.29 8.38 (m, 13 H); 9.12
(br. s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C20H18N2O4S (382.44): C 62.54, H 4.70, N 7.21; found: C 62.81, H
4.74, N 7.32.
(2E)-3-{3-{[(3,5-Dimethoxybenzyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.34): M.p.
1
1148. H-NMR((D 6)DMSO, 200 MHz): 3.64 (s, 6 H); 3.98 (d, J ˆ 5.0, 2 H); 6.28 (t, J ˆ 2.2, 1 H); 6.35 (d, J ˆ
2.2, 2 H); 6.53 (d, J ˆ 15.8, 1 H); 7.47 (d, J ˆ 15.8, 1 H); 7.57 (t, J ˆ 7.9, 1 H); 7.70 7.80 (m, 2 H); 7.88 (s, 1 H);
8.15 8.26 (m, 1 H); 9.13 (br. s, 1 H); 10.81 (br. s, 1 H). Anal. calc. for C18H20N2O6S (392.43): C 55.09, H 5.14, N
7.14; found: C 55.12, H 5.05, N 7.09.
(2E)-3-{3-{[(2-Furan-2-ylmethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.35): M.p. 1658.
1H-NMR((D 6)DMSO, 90 MHz): 4.03 (d, J ˆ 6.4, 2 H); 6.23 (m, 2 H); 6.54 (d, J ˆ 16.0, 1 H); 7.38 8.05 (m,
6 H); 8.20 (t, J ˆ 6.4, 1 H); 9.09 (br. s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C14H14N2O5S (322.34): C 52.17, H
4.38, N 8.69; found: C 51.87, H 4.39, N 8.41.
(2E)-N-Hydroxy-3-{3-{[(2-phenylethyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.36): M.p. 1148.
1H-NMR((D 6)DMSO, 90 MHz): 2.67 (m, 2 H); 3.00 (m, 2 H); 6.55 (d, J ˆ 16.0, 1 H); 7.00 8.05 (m, 11 H);
9.12 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C17H18N2O4S (346.41): C 58.94, H 5.24, N 8.09, S 9.26; found: C
58.81, H 5.16, N 8.00, S 9.05.
(2E)-3-{3-{{[2-(Dimethoxyphenyl)ethyl]amino}sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.37):
Foam. 1H-NMR((D 6)DMSO, 90 MHz): 2.58 (t, J ˆ 7.0, 2 H, overlapped with DMSO); 2.85 3.16 (m, 2 H);
3.67 (s, 6 H); 6.38 6.94 (m, 4 H); 7.38 8.05 (m, 6 H); 9.16 (br. s, 1 H); 10.76 (br. s, 1 H). Anal. calc. for
C19H22N2O6S ¥ H2O (424.47): C 53.76, H 5.70, N 6.60; found: C 53.75, H 5.24, N 6.45.
(2E)-N-Hydroxy-3-{3-{[(3-phenylpropyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.38): M.p. 1488.
1H-NMR((D 6)DMSO, 90 MHz): 1.40 1.83 (m, 2 H); 2.27 2.94 (m, 4 H, overlapped with DMSO); 6.56 (d,
J ˆ 15.6, 1 H); 6.98 7.38 (m, 5 H); 7.38 8.09 (m, 6 H); 9.16 (br. s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for
C18H20N2O4S (360.44): C 59.98, H 5.59, N 7.77; found: C 59.73, H 5.55, N 7.63.

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(2E)-N-Hydroxy-3-{3-{[(2-phenoxyethyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.39): M.p. 1518.
1H-NMR((D 6)DMSO, 90 MHz): 3.00 3.54 (m, 2 H, overlapped with H2O); 3.94 (t, J ˆ 7.0, 2 H); 6.59 (d,
J ˆ 16.0, 1 H); 6.74 7.05 (m, 3 H); 7.12 8.12 (m, 8 H); 9.09 (br. s, 1 H); 10.76 (br. s, 1 H). Anal. calc. for
C17H18N2O5S (362.41): C 56.34, H 5.01, N 7.73; found: C 56.04, H 4.96, N 7.54.
(2E)-N-Hydroxy-3-{3-{[(4-phenylbutyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.40): M.p. 1038.
1H-NMR((D 6)DMSO, 90 MHz): 1.16 1.83 (m, 4 H); 2.27 3.58 (m, 4 H, overlapped with DMSO); 6.56 (d,
J ˆ 15.6, 1 H); 6.94 7.40 (m, 5 H); 7.41 8.12 (m, 6 H); 9.16 (s, 1 H); 10.83 (s, 1 H). Anal. calc. for C19H22N2O4S
(374.46): C 60.94, H 5.92, N 7.48; found: C 60.76, H 5.86, N 7.41.
(2E)-3-{3-{[(Diphenylmethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.41): M.p. 1808.
1H-NMR((D 6)DMSO, 90 MHz): 5.60 (d, J ˆ 9.0, 1 H); 6.43 (d, J ˆ 16.0, 1 H); 6.98 7.83 (m, 15 H); 8.85 (d,
J ˆ 9.0, 1 H); 9.14 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C22H20N2O4S (408.48): C 64.69, H 4.94, N 6.86;
found: C 64.60, H 4.94, N 6.77.
(2E)-3-{3-{[(1,2-Diphenylethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.42): M.p. 1508.
1H-NMR((D 6)DMSO, 90 MHz): 2.83 (d, J ˆ 9.0, 2 H); 4.47 (q, J ˆ 9.0, 1 H); 6.38 (d, J ˆ 16.0, 1 H); 6.92
7.65 (m, 15 H); 8.38 (d, J ˆ 9.0, 1 H); 9.12 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C23H22N2O4S (422.51): C
65.39, H 5.25, N 6.63; found: C 64.97, H 5.14, N 6.57.
(2E)-3-{3-{[(1-Benzylpropyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.43): M.p. 129
1308. 1H-NMR((D 6)DMSO, 200 MHz): 0.67 (t, J ˆ 7.3, 3 H); 1.09 1.45 (m, 2 H); 2.40 2.66 (m, 2 H,
overlapped with DMSO); 3.14 3.41 (m, 1 H, overlapped with H2O); 6.55 (d, J ˆ 15.8, 1 H); 6.97 7.23 (m, 5 H);
7.48 (d, J ˆ 15.8, 1 H); 7.53 (t, J ˆ 7.6, 1 H); 7.63 7.80 (m, 3 H); 7.86 (s, 1 H); 9.15 (s, 1 H); 10.84 (s, 1 H). Anal.
calc. for C19H22N2O4S (374.46): C 60.94, H 5.92, N 7.48; found: C 60.88, H 5.92, N 7.39.
(2E)-N-Hydroxy-3-{3-{[(2-hydroxy-2-phenylethyl)amino]sulfonyl}phenyl}prop-2-enamide (m11.44):
1
Foam. H-NMR((D 6)DMSO, 200 MHz): 2.77 2.98 (m, 2 H); 4.49 4.61 (m, 1 H); 5.52 (d, J ˆ 4.4, 1 H); 6.56
(d, J ˆ 15.8, 1 H); 7.17 7.36 (m, 5 H); 7.51 (d, J ˆ 15.8, 1 H); 7.59 (t, J ˆ 8.0, 1 H); 7.70 7.84 (m, 3 H); 7.95 (s,
1 H); 9.14 (br. s, 1 H); 10.82 (br. s, 1 H). Anal. calc. for C17H18N2O5S ¥ 0.5 H2O (371.41): C 54.98, H 5.16, N 7.54;
found: C 54.90, H 4.91, N 7.18.
(2E)-3-{3-{[(3,3-Diphenylpropyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.45): M.p. 1698.
1H-NMR((D 6)DMSO, 200 MHz): 2.11 (q, J ˆ 7.3, 2 H); 2.65 (q, J ˆ 6.5, 2 H); 3.97 (t, J ˆ 7.8, 1 H); 6.55 (d, J ˆ
16.0, 1 H); 7.07 7.29 (m, 10 H); 7.51 (d, J ˆ 16.0, 1 H); 7.60 (t, J ˆ 7.6, 1 H); 7.70 (d, J ˆ 7.6, 1 H); 7.75 (t, J ˆ 5.6,
1 H); 7.80 (d, J ˆ 7.6, 1 H); 7.88 (s, 1 H); 9.14 (s, 1 H); 10.02 (s, 1 H). Anal. calc. for C24H24N2O4S (436.53): C
66.04, H 5.54, N 6.42; found: C 66.11, H 5.47, N 6.40.
(2E)-N-Hydroxy-3-{3-{[methyl(phenyl)amino]sulfony}phenyl}prop-2-enamide (m11.46): M.p. 1528.
1H-NMR((D 6)DMSO, 90 MHz): 3.16 (s, 3 H); 6.47 (d, J ˆ 16.0, 1 H); 7.03 7.96 (m, 10 H); 9.09 (br. s, 1 H);
10.78 (br. s, 1 H). Anal. calc. for C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43; found: C 57.82, H 4.83, N 8.35.
(2E)-N-Hydroxy-3-{3-{[(2-methylpropyl)phenylamino]sulfonyl}phenyl}prop-2-enamide (m11.47): M.p.
154 1558. 1H-NMR((D 6)DMSO, 200 MHz): 0.85 (d, J ˆ 6.6, 6 H); 1.43 (m, 1 H); 3.37 (d, J ˆ 6.6, 2 H,
overlapped with H2O); 6.49 (d, J ˆ 16.0, 1 H); 7.02 7.13 (m, 2 H); 7.27 7.42 (m, 3 H); 7.48 (d, J ˆ 7.6, 1 H); 7.51
(d, J ˆ 16.0, 1 H); 7.60 (t, J ˆ 7.8, 1 H); 7.67 (s, 1 H); 7.86 (d, J ˆ 7.6, 1 H); 9.15 (br. s, 1 H); 10.81 (s, 1 H). Anal.
calc. for C19H22N2O4S (374.46): C 60.94, H 5.92, N 7.48, S 8.56; found: C 60.91, H 5.83, N 7.35, S 8.54.
(2E)-3-{3-{[Benzyl(pyridin-3-ylmethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.48): M.p.
1468. 1H-NMR((D 6)DMSO, 90 MHz): 4.38 (s, 4 H); 6.60 (d, J ˆ 16.0, 1 H); 7.00 7.38 (m, 6 H); 7.39 8.09 (m,
6 H); 8.20 8.54 (m, 2 H); 9.16 (br. s, 1 H); 10.80 (br. s, 1 H). Anal. calc. for C22H21N3O4S (423.49): C 62.40, H
5.00, N 9.92; found: C 62.29, H 4.95, N 9.76.
(2E)-3-{3-{[(1,3-Benzodioxol-5-ylmethyl)(pyridin-3-ylmethyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-
enamide (m11.49): M.p. 858. 1H-NMR((D 6)DMSO, 200 MHz): 4.23 (s, 2 H); 4.37 (s, 2 H); 5.93 (s, 2 H); 6.54
6.68 (m, 3 H); 6.72 (d, J ˆ 8.4, 1 H); 7.22 (dd, J ˆ 4.7, 7.7, 1 H); 7.48 (dt, J ˆ 1.7, 7.7, 1 H); 7.54 (d, J ˆ 16.0, 1 H);
7.65 (t, J ˆ 7.8, 1 H); 7.80 7.93 (m, 2 H); 7.99 (s, 1 H); 8.27 (d, J ˆ 1.8, 1 H); 8.36 (dd, J ˆ 1.2, 4.7, 1 H); 9.15 (br. s,
1 H);10.81 (br. s, 1 H). Anal. calc. for C23H21N3O6S ¥ 0.5 H2O ¥ 0.25 Et2O (495.03): C 58.23, H 4.99, N 8.49; found:
C 58.28, H 4.95, N 8.13.
(2E)-3-{3-{{[2-(3,4-Dimethoxyphenyl)ethyl](4-methoxybenzyl)amino}sulfonyl}phenyl}-N-hydroxyprop-2-
1
enamide (m11.50): M.p. 1148. H-NMR((D 6)DMSO, 90 MHz): 2.23 2.69 (m, 2 H, overlapped with DMSO);
2.98 3.45 (m, 2 H, overlapped with H2O); 3.60 (s, 6 H); 3.76 (s, 3 H); 4.27 (s, 2 H); 6.42 7.09 (m, 6 H); 7.15
7.43 (m, 2 H); 7.45 8.09 (m, 5 H); 9.09 (br. s, 1 H); 10.72 (br. s, 1 H). Anal. calc. for C27H30N2O7S (526.61): C
61.58, H 5.74, N 5.32; found: C 61.36, H 5.66, N 5.27.
(2E)-3-{3-{{[2-(3,4-Dimethoxyphenyl)ethyl](3-phenylpropyl)amino}sulfonyl}phenyl}-N-hydroxyprop-2-
enamide (m11.51): M.p. 478. 1H-NMR((D 6)DMSO, 200 MHz): 1.58 1.87 (m, 2 H); 2.42 2.59 (m, 2 H,

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Helvetica Chimica Acta Vol. 88 (2005)
overlapped with DMSO); 2.59 2.81 (m, 2 H); 2.97 3.24 (m, 2 H); 3.24 3.47 (m, 2 H, overlapped with H2O);
3.70 (s, 6 H); 6.49 6.91 (m, 4 H); 7.04 7.37 (m, 5 H); 7.46 8.03 (m, 5 H); 9.16 (br. s, 1 H); 10.76 (br. s, 1 H).
Anal. calc. for C28H32N2O6S ¥ 0.3 H2O (530.04): C 63.45, H 6.20, N 5.29; found: C 63.45, H 6.30, N 5.14.
(2E)-3-{3-{[Bis(3-phenylpropyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (m11.52): M.p. 1178.
1H-NMR((D 6)DMSO, 200 MHz): 1.62 1.81 (m, 4 H); 2.43 2.61 (m, 4 H, overlapped with DMSO); 3.13 (t,
J ˆ 7.3, 4 H); 6.58 (d, J ˆ 16.2, 1 H); 7.08 7.32 (m, 10 H); 7.47 7.75 (m, 3 H); 7.80 7.90 (m, 2 H); 9.44 (br. s,
1 H); 10.38 (br. s, 1 H). Anal. calc. for C27H30N2O4S (478.62): C 67.76, H 6.32, N 5.85; found: C 67.54, H 6.30, N
5.88.
(2E)-N-Hydroxy-3-{2-[(phenylamino)sulfonyl]phenyl}prop-2-enamide (o11.1): M.p. 205 206.58.
1H-NMR((D 6)DMSO, 90 MHz): 6.37 (d, J ˆ 16.0, 1 H); 6.99 8.04 (m, 10 H); 8.23 (d, J ˆ 16.0, 1 H); 10.55
(s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C15H14N2O4S ¥ 0.1 MeCN ¥ 0.3 H2O (327.86): C 55.63, H 4.58, N 8.97;
found: C 55.63, H 4.36, N 9.07.
(2E)-N-Hydroxy-3-{2-[(naphthalen-1-ylamino)sulfonyl]phenyl}prop-2-enamide (o11.2): M.p. 186 1878.
1H-NMR((D 6)DMSO, 90 MHz): 6.29 (d, J ˆ 15.0, 1 H); 7.17 8.16 (m, 11 H); 8.36 (d, J ˆ 15.0, 1 H); 9.14 (br. s,
1 H); 10.57 (s, 1 H); 10.83 (s, 1 H). Anal. calc. for C19H16N2O4S ¥ 0.5 H2O (377.41): C 60.47, H 4.54, N 7.42; found:
C 60.46, H 4.35, N 7.69.
(2E)-N-Hydroxy-3-{2-{[methyl(phenyl)amino]sulfonyl}phenyl}prop-2-enamide (o11.3): M.p. 144.5
145.58. 1H-NMR((D 6)DMSO, 90 MHz): 3.16 (s, 3 H); 6.32 (d, J ˆ 16.0, 1 H); 7.00 7.86 (m, 9 H); 8.09 (d,
J ˆ 16.0, 1 H); 9.12 (br. s, 1 H); 10.80 (s, 1 H). Anal. calc. for C16H16N2O4S ¥ 0.8 H2O (346.79): C 55.42, H 5.12, N
8.08; found: C 55.17, H 4.65, N 8.05.
(2E)-3-[4-(Chlorosulfonyl)phenyl]prop-2-enoic Acid (13). To neat chlorosulfonic acid (50.1 g, 0.43 mol) at
13 168, cinnamic acid (12, 7.9 g, 0.054 mmol) was added in portions. The mixture was stirred at 10 128 for 26 h,
at r.t. for 2 h, and at 468 for 1 h. The dark, viscous syrup was poured onto ice and the precipitate filtered, washed
with H2O, and dried in vacuo (P2O5) to afford a white solid (6.06 g). The solid was crystallized from dioxane: 13
1
(4.5 g, 34%). White crystals. M.p. 2198. H-NMR((D 6)DMSO, 200 MHz): 6.53 (d, J ˆ 16.0, 1 H); 7.57 (d, J ˆ
16.0, 1 H); 7.60 (d, J ˆ 8.5, 2 H); 7.64 (d, J ˆ 8.5, 2 H); 9.53 (br. s, 1 H and H2O).
(2E)-3-{4-[(Phenylamino)sulfonyl]phenyl}prop-2-enoic Acid (14). To a mixture of benzenamine (0.35 g,
3.75 mmol) and pyridine (1 ml), a soln. of 13 (0.45 g, 1.82 mmol) in CH2Cl2 (3 ml) was added, and the resultant
soln. was stirred at 408 for 1 h. The mixture was evaporated and the residue partitioned between AcOEt and 6m
HCl. The org. layer was washed successively with H2O, sat. NaCl soln., dried (Na2SO4), and evaporated: 14.1
(0.30 g, 54%). 1H-NMR((D 6)DMSO, 90 MHz): 6.60 (d, J ˆ 16.0, 1 H); 6.93 7.43 (m, 5 H); 7.60 (d, J ˆ 16.0,
1 H); 7.79 (d, J ˆ 8.0, 2 H); 7.87 (d, J ˆ 8.0, 2 H); 10.35 (s, 1 H).
(2E)-N-Hydroxy-3-{4-[(phenylamino)sulfonyl]phenyl}prop-2-enamide (15.1). As described for m11.1,
with 14; washing with Et2O: 39% of 15.1. White crystals. M.p. 176 177.58. 1H-NMR((D 6)DMSO, 90 MHz): 6.54
(d, J ˆ 16.0, 1 H); 6.96 7.32 (m, 5 H); 7.47 (d, J ˆ 16.0, 1 H); 7.76 (s, 4 H); 9.14 (br. s, 1 H); (br. s, 1 H); (s, 1 H).
Anal. calc. for C15H14N2O4S (318.35): C 56.59, H 4.43, N 8.80; found: 55.82, H 4.38, N 9.01.
3-[4-(Aminosulfonyl)phenyl]-N-hydroxypropenamides 15.2 15.7 were obtained as described for 15.1.
(2E)-3-{4-{[(4-Bromophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (15.2): M.p. 219 220.58.
1H-NMR((D 6)DMSO, 90 MHz): 6.54 (d, J ˆ 16.0, 1 H); 7.05 (d, J ˆ 8.0, 2 H); 7.43 (d, J ˆ 8.0, 2 H); 7.49 (d, J ˆ
16.0, 1 H); 7.63 7.87 (m, 4 H); 9.11 (br. s, 1 H); 10.45 (s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C15H13BrN2O4S
(397.25): C 45.35, H 3.30, N 7.05; found: C 45.44, H 3.28, N 7.05.
(2E)-3-{4-{[(4-Chlorophenyl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (15.3): M.p. 201 2028.
1H-NMR((D 6)DMSO, 90 MHz): 6.52 (d, J ˆ 16.0, 1 H); 7.08 (d, J ˆ 8.0, 2 H); 7.29 (d, J ˆ 8.0, 2 H); 7.45 (d, J ˆ
16.0, 1 H); 7.63 7.89 (m, 5 H); 10.43 (br. s, 1 H); 10.83 (br. s, 1 H). Anal. calc. for C15H13ClN2O4S (352.80): C
51.07, H 3.71, N 7.94; found: C 51.14, H 3.70, N 7.86.
(2E)-N-Hydroxy-3-{4-[([1,1'-biphenyl]-4-ylamino)sulfonyl]phenyl}prop-2-enamide (15.4): M.p. 211
211.58. 1H-NMR((D 6)DMSO, 90 MHz): 6.53 (d, J ˆ 16.0, 1 H); 7.19 (d, J ˆ 8.0, 2 H); 7.32 7.69 (m, 8 H);
7.72 7.92 (m, 4 H); 9.09 (br. s, 1 H); 10.45 (s, 1 H); 10.85 (br. s, 1 H). Anal. calc. for C21H18N2O4S (394.45): C
63.94, H 4.60, N 7.10; found: C 63.51, H 4.37, N 7.11.
(2E)-N-Hydroxy-3-{4-[(naphthalen-2-ylamino)sulfonyl]phenyl}prop-2-enamide (15.5): M.p. 198.5 199.58.
1H-NMR((D 6)DMSO, 90 MHz): 6.54 (d, J ˆ 16.0, 1 H); 7.16 (dd, J ˆ 2.0, 8.0, 1 H); 7.29 8.12 (m, 11 H); 9.11
(br. s, 1 H); 10.07 (s, 1 H); 10.87 (s, 1 H). Anal. calc. for C19H16N2O4S ¥ 0.3 H2O (373.81): C 61.05, H 4.48, N 7.49;
found: C 60.96, H 4.28, N 7.56.
(2E)-3-{4-{[(9-Ethyl-9 H-carbazol-3-yl)amino]sulfonyl}phenyl}-N-hydroxyprop-2-enamide (15.6): M.p.
198.5 199.58. 1H-NMR((D 6)DMSO, 90 MHz): 1.26 (t, J ˆ 6.9, 3 H); 4.39 (q, J ˆ 6.9, 2 H); 6.50 (d, J ˆ 15.8,
1 H); 7.07 7.20 (m, 2 H); 7.38 7.49 (m, 3 H); 7.57 (d, J ˆ 8.2, 1 H); 7.62 (d, J ˆ 8.8, 2 H); 7.67 (d, J ˆ 8.8, 2 H);

Helvetica Chimica Acta Vol. 88 (2005)
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7.83 (d, J ˆ 2.0, 1 H); 8.04 (d, J ˆ 7.6, 1 H); 9.13 (br. s, 1 H); 10.11 (br. s, 1 H); 10.83 (s, 1 H). Anal. calc. for
C23H21N3O4S (435.51): C 63.43, H 4.86, N 9.65; found: C 62.99, H 4.73, N 9,59.
(2E)-3-{4-[(Benzylamino)sulfonyl]phenyl}-N-hydroxyprop-2-enamide (15.7): M.p. 190 191.58. 1H-NMR
((D6)DMSO, 90 MHz): 3.99 (d, J ˆ 6.2, 2 H); 6.57 (d, J ˆ 16.2, 1 H); 7.20 7.30 (m, 5 H); 7.51 (d, J ˆ 16.2, 1 H);
7.73 (d, J ˆ 8.6, 2 H); 7.80 (d, J ˆ 8.8, 2 H); 8.21 (t, J ˆ 6.2, 1 H); 9.15 (br. s, 1 H); 10.88 (s, 1 H). Anal. calc. for
C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43; found: C 57.38, H 4.74, N 8.25.
Methyl (2E)-3-(3-Aminophenyl)prop-2-enoate (m17). A mixture of m16 (10.0 g, 48 mmol) and SnCl2 ¥
2 H2O (54 g, 240 mmol) in anh. EtOH (200 ml) was heated at 808 for 1 h. The mixture was allowed to cool to r.t.,
then the solvent was partially evaporated (up to ca. 1³2 volume). The residue was poured in ice-water, neutralized
(pH ca. 7) with sat. Na2CO3 soln., and the resulting mixture extracted with AcOEt. The org. extract was washed
with sat. NaCl soln. and dried (Na2SO4). The soln. was filtered through a small amount of SiO2 and evaporated:
m17 (8.5 g, 99%). 1H-NMR(CDCl 3, 90 MHz): 3.69 (br. s, 2 H); 3.79 (s, 3 H); 6.39 (d, J ˆ 16.0, 1 H); 6.61 7.03
(m, 3 H); 7.18 (t, J ˆ 7.6, 1 H); 7.62 (d, J ˆ 16.0, 1 H).
Methyl (2E)-3-{3-{{[(1E)-2-phenylethenyl]sulfonyl}amino}phenyl}prop-2-enoate (m18.6). A soln. of (1E)-
2-phenylethenesulfonyl chloride (0.59 g, 2.82 mmol) in dioxane (3 ml) was added to a mixture of m17 (0.50 g,
2.82 mmol) in dioxane (12 ml) and NaHCO3 (0.36 g, 4.28 mmol) in H2O (8 ml), and the resultant soln. was
stirred at r.t. until completion of the reaction (TLC). The mixture was evaporated and the residue partitioned
between AcOEt and 2m HCl. The org. phase was washed successively with H2O, sat. NaCl soln., dried (Na2SO4),
and evaporated and the residue purified by CC (SiO2, CHCl3/AcOEt 50 :1): 0.68 g (70%) of m18.6. White solid.
1H-NMR(CDCl 3, 90 MHz): 3.78 (s, 3 H); 6.39 (d, J ˆ 16.0, 1 H); 6.77 (d, J ˆ 15.8, 1 H); 6.78 (s, 1 H); 7.17 7.48
(m, 9 H); 7.49 (d, J ˆ 15.8, 1 H); 7.58 (d, J ˆ 16.0, 1 H).
(2E)-3-{3-{{[(1E)-2-Phenylethenyl]sulfonyl}amino}phenyl}prop-2-enoic Acid (m19.6). As described for
1
m10.1, with m18.6: 90% of m19.1. White solid. H-NMR((D 6)DMSO, 90 MHz): 6.41 (d, J ˆ 16.0, 1 H); 7.12
7.51 (m, 9 H); 7.55 7.81 (m, 3 H); 10.16 (br. s, 1 H); (br. s, 1 H).
(2E)-N-Hydroxy-3-{3-{{[(1E)-2-phenylethenyl]sulfonyl}amino}phenyl}prop-2-enamide (m20.6). As de-
scribed for m11.1, with m19.1; crystallization from AcOEt: 42% of m20.6. White crystals. M.p. 1718.
1H-NMR((D 6)DMSO, 90 MHz): 6.38 (d, J ˆ 16.0, 1 H); 7.07 7.80 (m, 12 H); 9.03 (br. s, 1 H); 10.16 (s, 1 H);
10.76 (br. s, 1 H). Anal. calc. for C17H16N2O4S (344.39): C 59.29, H 4.68, N 8.13; found: C 59.13, H 4.70, N 7.92.
(2E)-N-Hydroxy-3-{4-[(phenylsulfonyl)amino]phenyl}prop-2-enamide (p20.1). As described for p40, with
p18.1: 31% of p20.1. M.p. 189 1918. 1H-NMR((D )DMSO, 200 MHz): 6.30 (d, J ˆ 15.8, 1 H); 7.12 (d, J ˆ 8.5,
6
2 H); 7.32 (d, J ˆ 15.8, 1 H); 7.45 (d, J ˆ 8.5, 2 H); 7.48 7.86 (m, 6 H); 9.01 (s, 1 H); 10.56 (s, 1 H); 10.72 (s, 1 H).
Anal. calc. for C15H14N2O4S (318.35): C 56.59, H 4.43, N 8.80, S 10.07; found: C 56.03, H 4.24, N 8.66, S 10.02.
3-{[(R)sulfonylamino]phenyl}-N-hydroxypropenamides m20.1 m20.5 and p20.2 p20.4 were obtained as
described for m20.6.
(2E)-N-Hydroxy-3-{3-[(phenylsulfonyl)amino]phenyl}prop-2-enamide (m20.1): M.p. 1728. 1H-NMR
((D6)DMSO, 90 MHz): 6.35 (d, J ˆ 16.0, 1 H); 6.96 7.92 (m, 10 H); 9.03 (br. s, 1 H); 10.38 (s, 1 H); 10.78
(br. s, 1 H). Anal. calc. for C15H14N2O4S(318.35): C 56.59, H 4.43, N 8.80; found: C 56.48, H 4.57, N 8.45.
(2E)-N-Hydroxy-3-{3-{[(4-methylphenyl)sulfonyl]amino}phenyl}prop-2-enamide (m20.2): M.p. 1478.
1H-NMR((D 6)DMSO, 90 MHz): 2.32 (s, 3 H); 6.36 (d, J ˆ 16.0, 1 H); 6.94 7.76 (m, 9 H); 9.03 (br. s, 1 H);
10.32 (s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C16H16N2O4S (332.38): C 57.82, H 4.85, N 8.43; found: C 57.73, H
4.86, N 8.36.
(2E)-3-{3-{[(3,4-Dimethoxyphenyl)sulfonyl]amino}phenyl}-N-hydroxyprop-2-enamide (m20.3): M.p. 1588.
1H-NMR((D 6)DMSO, 90 MHz): 3.72 (s, 3 H); 3.80 (s, 3 H); 6.36 (d, J ˆ 16.0, 1 H); 6.89 7.52 (m, 8 H); 9.03 (br.
s, 1 H); 10.16 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C17H18N2O6S (378.41): C 53.96, H 4.79, N 7.40; found:
C 53.74, H 4.71, N 7.35.
(2E)-3-{3-[([1,1'-Biphenyl]-4-ylsulfonyl)amino]phenyl}-N-hydroxyprop-2-enamide (m20.4): M.p. 1158.
1H-NMR((D 6)DMSO, 90 MHz): 6.38 (d, J ˆ 16.0, 1 H); 6.98 7.65 (m, 10 H); 7.87 (s, 4 H); 9.03 (br. s, 1 H);
10.45 (br. s, 1 H); 10.78 (br. s, 1 H). Anal. calc. for C21H18N2O4S containing 1.3% of inorganic impurities
(394.45): C 63.11, H 4.54, N 7.01; found: C 63.16, H 4.53, N 6.93.
(2E)-3-{4-[([1,1'-Biphenyl]-4-ylsulfonyl)amino]phenyl}-N-hydroxyprop-2-enamide (p20.2): M.p. 190
1
191.58. H-NMR((D )DMSO, 90 MHz): 6.29 (d, J ˆ 16.0, 1 H); 7.16 (d, J ˆ 8.0, 2 H); 7.24 7.78 (m, 8 H); 7.86
6
(m, 4 H); 8.94 (br. s, 1 H); 10.57 (s, 1 H); 10.66 (br. s, 1 H). Anal. calc. for C21H18N2O4S (394.45): C 63.94, H 4.60,
N 7.10; found: C 63.64, H 4.45, N 7.00.
(2E)-3-{4-{[(3,4-Dimethoxyphenyl)sulfonyl]amino}phenyl}-N-hydroxyprop-2-enamide (p20.3): M.p.
178.5 1798. 1H-NMR((D 6)DMSO, 90 MHz): 3.72 (s, 3 H); 3.78 (s, 3 H); 6.32 (d, J ˆ 16.0, 1 H); 7.00 7.65

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Helvetica Chimica Acta Vol. 88 (2005)
(m, 8 H); 8.98 (br. s, 1 H); 10.32 (br. s, 1 H); 10.69 (s, 1 H). Anal. calc. for C17H18N2O6S (378.41): C 53.96, H 4.79,
N 7.40; found: C 53.58, H 4.56, N 7.62.
(2E)-N-Hydroxy-3-{4-{{[(1E)-2-phenylethenyl]sulfonyl}amino}phenyl}prop-2-enamide (p20.4): 1H-NMR
((D6)DMSO, 200 MHz): 6.33 (d, J ˆ 15.8, 1 H); 7.21 (d, J ˆ 8.4, 1 H); 7.25 (s, 1 H); 7.33 (s, 1 H); 7.37 7.45 (m,
3 H); 7.49 (d, J ˆ 8.6, 1 H); 7.53 (d, J ˆ 15.8, 1 H); 7.66 7.76 (m, 2 H); 9.02 (s, 1 H); 10.36 (s, 1 H); 10.72 (s, 1 H).
Anal. calc. for C17H16N2O4S (344.39): C 59.23, H 4.56, N 8.26, S 9.25; found: C 59.29, H 4.68, N 8.13, S 9.31.
3-Bromo-N-phenylbenzenesulfonamide (m22). At r.t., 3-bromobenzenesulfonyl chloride (m21; 1.0 g,
3.9 mmol) was added to a mixture of benzenamine (0.47 g, 5.1 mmol) in MeCN (10 ml) and Na2CO3 (1.3 g,
12.3 mmol) in H2O (10 ml). The mixture was stirred at r.t. for 1 h and extracted with AcOEt (30 ml). The
extract was dried (Na2SO4) and evaporated: m22 (1.15 g, 94%). Oil which solidified upon standing. M.p. 98
1008. 1H-NMR((D 6)DMSO, 90 MHz): 6.94 7.48 (m, 5 H); 7.50 7.96 (m, 4 H); 10.36 (s, 1 H).
3-(3-Hydroxyprop-1-ynyl)-N-phenylbenzenesulfonamide (m23). A mixture of m22 (1.0 g, 3.2 mmol),
benzene (2.4 ml), [Pd(PPh3)4] (0.4 g, 0.34 mmol), CuI (0.032 g, 0.16 mmol), Et3N (2.4 ml, 17.2 mmol), and
prop-2-yn-1-ol (1.0 ml, 17.2 mmol) was refluxed under Ar for 30 min. The mixture was diluted with 5% HCl soln.
(50 ml) and extracted with AcOEt (50 ml). The extract was washed successively with 5% NaHCO3 soln. and
H2O, dried (Na2SO4), and evaporated, and the residue purified by CC (SiO2, AcOEt/hexane 1:1): m23 (0.59 g,
64%). Oil. 1H-NMR((D 6)DMSO, 90 MHz): 4.29 (d, J ˆ 6.0, 2 H); 5.36 (t, J ˆ 6.0, 1 H); 6.94 7.32 (m, 5 H);
7.35 7.91 (m, 4 H); 10.32 (s, 1 H).
3-(3-Oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (m24). m23 (0.55 g, 1.9 mmol) was dissolved in a soln.
of Dess Martin reagent in CH2Cl2 (0.157 g/ml, 8.2 ml), and the mixture was stirred at r.t. for 30 min. The
mixture was partitioned between H2O (50 ml) and Et2O (50 ml) and the org. phase washed with 5% Na2CO3
soln. and H2O, dried (Na2SO4), and evaporated: m24 (0.47 g, 72%). Oil. 1H-NMR((D 6)DMSO, 90 MHz):
6.96 7.41 (m, 5 H); 7.54 8.07 (m, 4 H); 9.45 (s, 1 H); 10.41 (s, 1 H).
Methyl (2E)-5-{3-[(Phenylamino)sulfonyl]phenyl}pent-2-en-4-ynoate (m25). To a soln. of methyl (di-
methoxyphosphinyl)acetate (0.81 g, 4.5 mmol) in dry THF (20 ml) under Ar at r.t., NaH (0.12 g, 5.0 mmol) was
added. The mixture was stirred at r.t. for 1 h, and a soln. of m24 (0.44 g, 1.5 mmol) in dry THF (20 ml) was added
dropwise at 15 208. The mixture was stirred at r.t. for 1 h and quenched with 3% HCl soln. (20 ml). The product
was extracted with AcOEt (50 ml), the extract washed with 5% NaHCO3 soln. and H2O, dried (Na2SO4), and
evaporated, and the residue purified by CC (SiO2, AcOEt/hexane 1:2): m25 (0.39 g, 74%). White solid. M.p.
1
134 1368. H-NMR((D 6)DMSO, 90 MHz): 3.73 (s, 3 H); 6.49 (d, J ˆ 15.5, 1 H); 7.03 (d, J ˆ 15.5, 1 H); 7.01
7.38 (m, 5 H); 7.41 7.89 (m, 4 H, C6H4); 10.34 (s, 1 H).
(2E)-5-{3-[(Phenylamino)sulfonyl]phenyl}pent-2-en-4-ynoic Acid (m26). As for m10.1, with m25: 95% of
m26. White crystals. M.p. 188 1908. 1H-NMR((D )DMSO, 90 MHz): 6.36 (d, J ˆ 15.8, 1 H); 6.92 (d, J ˆ 15.8,
6
1 H); 7.01 7.36 (m, 5 H); 7.38 7.89 (m, 4 H); 10.32 (s, 1 H).
(2E)-N-Hydroxy-5-{3-[(phenylamino)sulfonyl]phenyl}pent-2-en-4-ynamide (m27). To a soln. of m26
(0.25 g 0.77 mmol) in CH2Cl2 (5 ml), oxalyl chloride (0.42 g 3.1 mmol) was added. The mixture was stirred at
r.t. for 1 h and then evaporated. The residue was dissolved in MeCN (5 ml), and the obtained soln. was added to
a mixture of NH2OH ¥ HCl (0.3 g, 4.3 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in H2O (8 ml). The resulting
mixture was stirred for 10 min and then extracted with AcOEt (30 ml). The org. phase was extracted with 10%
Na2CO3 soln. and the aq. phase acidified with 3% HCl soln. The precipitate was filtered and dried: m27 (0.12 g,
(46%). M.p 88 908. Rf (MeCN/H2O 10 :1) 0.5. 1H-NMR((D 6)DMSO, 90 MHz): 6.41 (d, J ˆ 15.8, 1 H); 6.82 (d,
J ˆ 15.8, 1 H); 6.92 7.41 (m, 5 H); 7.47 8.01 (m, 4 H); 8.94 11.21 (br. s, 3 H). Anal. calc. for C17H14N2O4S ¥
0.4 H2O (349.57): C 58.58, H 4.27, N 8.01; found: C 58.12, H 4.03, N 7.80.
(2E)-N-Hydroxy-5-{4-[(phenylamino)sulfonyl]phenyl}pent-2-en-4-ynamide (p27). As described for m27.
M.p. 161 1638. 1H NMR((D 6)(DMSO, HMDSO (hexamethyldisiloxane)) 6.38 (d, J ˆ 16.0, 1 H); 6.78 (d, J ˆ
16.0, 1 H); 6.89 7.43 (m, 5 H); 7.67 (d, J ˆ 9.0, 2 H); 7.78 (d, J ˆ 9.0, 2 H); 10.05 (br. s, 3 H). Anal. calc. for
C17H14N2O4S ¥ 0.4 H2O (349.57): C 58.86, H 4.21, N 8.08; found: C 58.36, H 3.93, N 7.82.
Methyl 6-[(Phenylsulfonyl)amino]hexanoate (29.1). To a mixture of methyl 6-aminohexanoate hydro-
chloride (28; 1.82 g, 10 mmol) in MeCN (10 ml) and Na2CO3 (2.6 g, 24.6 mmol) in H2O (10 ml), benzenesulfonyl
chloride (0.88 g, 5.0 mmol) was added. The mixture was stirred at r.t. for 6 h and then extracted with AcOEt
(30 ml), the extract dried (Na2SO4) and evaporated, and the residue purified by CC (SiO2, hexane/AcOEt 2 :1):
29.1 (1.28 g, 90%). Oil. 1H-NMR((D 6)DMSO, 90 MHz): 0.90 1.63 (m, 6 H); 2.21 (t, J ˆ 7.0, 2 H); 2.71 (q, J ˆ
6.0, 2 H); 3.58 (s, 3 H); 7.40 7.72 (m, 3 H); 7.72 7.89 (m, 2 H).
N-Hydroxy-6-[(phenylsulfonyl)amino]hexanamide (30.1). A soln. of MeONa (6 mmol) in MeOH (5 ml)
was added to a soln. of NH2OH ¥ HCl (0.28 g, 4 mmol) in MeOH (8 ml). The mixture was stirred at r.t. for
10 min, and the precipitate was filtered off. Then 29.1 (0.36 g, 1 mmol) was added to the filtrate, and the mixture

Helvetica Chimica Acta Vol. 88 (2005)
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was heated to the complete dissolving. The resultant mixture was stirred for 4 h at r.t. and evaporated. The
residue was dissolved in H2O (10 ml) and acidified with 3% HCl soln. The precipitate was filtered off and
crystallized from MeOH: 30.1 (0.19 g, 52%). White crystals. M.p. 80 828. 1H-NMR((D 6)DMSO, 90 MHz):
0.98 1.58 (m, 6 H); 1.87 (t, J ˆ 7.5, 2 H); 2.69 (q, J ˆ 6.0, 2 H); 7.38 7.69 (m, 4 H); 7.69 7.87 (m, 2 H); 8.58 (s,
1 H); 10.27 (s, 1 H). Anal. calc. for C12H18N2O4S (286.35): C 50.33, H 6.34, N 9.78; found: C 50.48, H 6.25, N 9.69.
N-Hydroxy-6-{{[4-(methylsulfonyl)phenyl]sulfonyl}amino}hexanamide (30.2). As described for 30.1. M.p.
161 1638. 1H-NMR((D )DMSO, 90 MHz): 1.01 1.61 (m, 6 H); 1.72 1.98 (m, 2 H); 2.49 (s, 3 H, overlapped
6
with DMSO); 2.63 2.91 (m, 2 H); 7.85 (t, J ˆ 6.0, 1 H), 7.85 (d, J ˆ 8.6, 2 H); 8.15 (d, J ˆ 8.6, 2 H); 8.59 (br. s,
1 H); 10.27 (s, 1 H). Anal. calc. for C13H20N2O6S2 (364.44): C 42.84, H 5.53, N 7.69; found: C 42.85, H 5.43, N 7.58.
N-Hydroxy-6-{{[(1E)-2-phenylethenyl]sulfonyl}amino}hexanamide (30.3). As described for 30.1. M.p.
107 1098. 1H-NMR((D 6)DMSO, 90 MHz): 0.98 1.66 (m, 6 H); 1.91 (t, J ˆ 6.5, 2 H); 2.86 (t, J ˆ 6.5, 2 H); 7.13
(d, J ˆ 16.0, 1 H); 7.36 (d, J ˆ 16.0, 1 H); 7.36 7.87 (m, 5 H); 8.38 9.43 (br. s, 3 H). Anal. calc. for C14H20N2O4S
(312.39): C 53.83, H 6.45, N 8.97; found: C 53.30, H 6.32, N 8.53.
3-{[(6-Methoxy-6-oxohexyl)amino]sulfonyl}benzenecarboxylic Acid (29.4). As described for 29.1, with 3-
(chlorosulfonyl)benzenecarboxylic acid: 82% of 29.4. White solid. 1H-NMR((D 6)DMSO, 90 MHz): 0.94 1.65
(m, 6 H); 2.21 (t, J ˆ 7.0, 2 H); 2.74 (q, J ˆ 6.0, 2 H); 3.67 (s, 3 H); 7.61 7.94 (m, 2 H); 7.94 8.14 (m, 1 H); 8.14
8.29 (m, 1 H); 8.29-8.45 (m, 1 H).
Methyl 6-{{{3-{[(Methylphenyl)amino]carbonyl}phenyl}sulfonyl}amino}hexanoate (29.4a). To a suspen-
sion of 29.4 (0.33 g, 1.0 mmol) in CH2Cl2 (10 ml), oxalyl chloride (0.36 g, 3.0 mmol) and 1 drop of DMF were
added. The mixture was stirred at r.t. for 1 h and evaporated. The residue was dissolved in MeCN (8 ml) and the
obtained soln. added to 4-methylbenzenamine (0.32 g, 3.0 mmol) in MeCN (8 ml). The mixture was stirred at
r.t. for 1.5 h, poured into AcOEt (50 ml), washed successively with H2O (20 ml), 5% HCl soln. (30 ml), H2O
(20 ml), and dried (Na2SO4). After evaporation the residue was dried in vacuo: 29.4a (0.327 g, 78%). Oil.
1H-NMR((D 6)DMSO, 90 MHz): 0.98 1.63 (m, 6 H); 2.22 (t, J ˆ 7.0, 2 H); 2.27 (s, 3 H); 2.72 (q, J ˆ 6.0, 2 H);
3.67 (s, 3 H); 7.18 (d, J ˆ 8.5, 2 H); 7.51 7.83 (m, 2 H); 7.64 (d, J ˆ 8.5, 2 H); 7.83 8.07 (m, 1 H); 8.07 8.34 (m,
2 H); 10.41 (s, 1 H).
3-{{[6-(Hydroxyamino)-6-oxohexyl]amino}sulfonyl}-N-(4-methylphenyl)benzenecarboxamide (30.4). As
described for 30.1; crystallization from MeCN: 54% of 30.4. M.p. 137 1388. 1H-NMR((D 6)DMSO, 90 MHz):
1.02 1.61 (m, 6 H); 1.87 (t, J ˆ 6.6, 2 H); 2.29 (s, 3 H); 2.61 2.89 (m, 2 H); 7.16 (d, J ˆ 8.5, 2 H); 7.65 (d, J ˆ 8.5,
2 H); 7.72 8.29 (m, 4 H); 8.32 (br. s, 1 H); 8.61 (br. s, 1 H); 10.27 (br. s, 1 H); 10.38 (br. s, 1 H). Anal. calc. for
C20H25N3O5S (419.50): C 57.26, H 6.01, N 10.02; found: C 57.22, H 5.88, N 9.92.
Sodium 6-Ethoxy-6-oxohexane-1-sulfonate (32, n ˆ 5). To a soln. of ethyl 6-bromohexanoate (31; 2.48 g,
11.0 mmol) in EtOH (6 ml), a soln. of Na2SO3 (2.16 g, 20.6 mmol) in H2O (9 ml) was added, and the mixture was
refluxed for 1 h. After evaporation, the obtained solid was extracted with boiling EtOH in a Soxhlet extraction
apparatus for 15 20 h. The extract was evaporated and the residue crystallized from EtOH/Et2O (1:10): 32
(n ˆ 5) (2.71 g, 99%). White crystals. 1H-NMR((D 6)DMSO, 90 MHz): 1.05 1.78 (m, 6 H); 1.17 (t, J ˆ 7.2, 3 H);
2.26 (t, J ˆ 7.5, 2 H); 2.26 (t, J ˆ 7.5, 2 H); 4.05 (q, J ˆ 7.2, 2 H).
Ethyl 6-[(Phenylamino)sulfonyl]hexanoate (33.1). 32 (n ˆ 5; 1.68 g, 6.8 mmol) was mixed with PCl5, and
the mixture was carefully pestled in a mortar. After the reaction came to the end (cease of the foaming), the
mixture was extracted with dry benzene (50 ml). The extract was evaporated and the residue dried in vacuo and
dissolved in benzene (10 ml). To this soln., benzenamine (1.648 g, 17.7 mmol) was added. The mixture was
stirred at r.t. for 24 h, and partitioned between AcOEt and 1m HCl. The org. phase was washed with H2O and sat.
NaCl soln., dried (Na2SO4), and evaporated, and the crude product purified by CC (SiO2, petroleum ether/t-
BuOMe 3 :2): 0.927 g (45%) of 33.1. Oil. 1H-NMR((D 6)DMSO, 90 MHz): 1.03 1.81 (m, 6 H); 1.15 (t, J ˆ 7.1,
3 H); 2.23 (t, J ˆ 6.8, 2 H); 3.07 (t, J ˆ 7.6, 2 H); 4.04 (q, J ˆ 7.1, 2 H); 7.00 7.47 (m, 5 H); 9.76 (s, 1 H).
N-Hydroxy-6-[(phenylamino)sulfonyl]hexanamide (34.1). To a mixture of 33.1 (0.45 g, 1.5 mmol) and
NH2OH ¥ HCl (0.43 g, 6.2 mmol) in MeOH (5 ml), 3.43m MeONa (2.62 ml, 9.0 mmol) in MeOH was added, and
the mixture was stirred at r.t. for 40 min. The mixture was poured into sat. NaH2PO4 soln. (15 ml) and extracted
with AcOEt. The extract was washed with H2O and sat. NaCl soln., dried (Na2SO4), and evaporated and the
residue washed with Et2O and crystallized from AcOEt: 34.1 (0.30 g, 69%). White crystals. M.p. 97 988.
1H-NMR((D 6)DMSO, 90 MHz): 1.02 1.78 (m, 6 H); 1.90 (br. t, J ˆ 6.4, 2 H); 3.06 (t, J ˆ 7.0, 2 H); 6.94 7.60
(m, 5 H); 8.66 (br. s, 1 H); 9.76 (br. s, 1 H); 10.36 (br. s, 1 H). Anal. calc. for C12H18N2O4S (286.35): C 50.33, H
6.34, N 9.78, S 11.20; found: C 50.10, H 6.22, N 9.83, S 11.10.
w-(Aminosulfonyl)-N-hydroxyalkanamides 34.2 34.6 were obtained as described for 34.1.
N-Hydroxy-5-[(phenylamino)sulfonyl]pentanamide (34.2): M.p. 128 1298. 1H-NMR((D 6)DMSO,
90 MHz): 1.37 1.78 (m, 4 H); 1.92 (t, J ˆ 5.9, 2 H); 3.07 (t, J ˆ 7.0, 2 H); 6.97 7.47 (m, 5 H); 8.69 (s, 1 H);

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Helvetica Chimica Acta Vol. 88 (2005)
9.78 (s, 1 H); 10.33 (s, 1 H). Anal. calc. for C11H16N2O4S (272.33): C 48.52, H 5.92, N 10.29, S 11.77; found: C
48.57, H 5.92, N 10.21, S 11.65.
N-Hydroxy-5-[(naphthalen-2-ylamino)sulfonyl]pentanamide (34.3): M.p. 163 1648. 1H-NMR
((D6)DMSO, 90 MHz): 1.39 1.78 (m, 4 H); 1.93 (t, J ˆ 6.4, 2 H); 3.16 (m, 2 H, overlapped with H2O); 7.30
7.61 (m, 3 H); 7.67 (d, J ˆ 2.0, 1 H); 7.76 7.99 (m, 3 H); 8.67 (br. s, 1 H); 10.00 (br. s, 1 H); 10.31 (br. s, 1 H).
Anal. calc. for C15H18N2O4S (322.39): C 55.89, H 5.63, N 8.69, S 9.95; found: C 55.83, H 5.52, N 8.68, S 9.95.
N-Hydroxy-5-[(phenylamino)sulfonyl]heptanamide (34.4): M.p. 94 958. 1H-NMR((D 6)DMSO,
200 MHz): 1.07 1.51 (m, 6 H); 1.53 1.73 (m, 2 H); 1.89 (t, J ˆ 7.2, 2 H); 3.04 (t, J ˆ 7.6, 2 H); 7.03 7.40 (m,
5 H); 8.67 (s, 1 H); 9.78 (s, 1 H); 10.33 (s, 1 H). Anal. calc. for C13H20N2O4S (300.38): C 51.98, H 6.71, N 9.33, S
10.67; found: C 51.83, H 6.64, N 9.23, S 10.65.
N-Hydroxy-8-[(phenylamino)sulfonyl]octanamide (34.5): M.p. 87 888. 1H-NMR((D 6)DMSO, 200 MHz):
1.08 1.51 (m, 8 H); 1.52 1.73 (m, 2 H); 1.90 (t, J ˆ 7.2, 2 H); 3.05 (t, J ˆ 7.6, 2 H); 7.02 7.39 (m, 5 H); 8.66 (s,
1 H); 9.74 (s, 1 H); 10.32 (s, 1 H). Anal. calc. for C14H22N2O4S (314.41): C 53.48, H 7.05, N 8.91, S 10.20; found: C
53.23, H 7.05, N 8.82, S 10.25.
N-Hydroxy-8-{[methyl(phenyl)amino]sulfonyl}octanamide (34.6): M.p. 65.5 66.58. 1H-NMR
((D6)DMSO, 200 MHz): 1.06 1.72 (m, 10 H); 1.91 (t, J ˆ 7.2, 2 H); 3.09 (t, J ˆ 7.6, 2 H); 3.25 (s, 3 H); 7.21
7.50 (m, 5 H); 8.64 (s, 1 H); 10.31 (s, 1 H). Anal. calc. for C15H24N2O4S (328.43): C 54.86, H 7.37, N 8.53, S 9.76;
found: C 54.68, H 7.30, N 8.55, S 9.70.
N-Hydroxy-3-{3-[(phenylamino)sulfonyl]phenyl}propanamide (35.1). A mixture of m11.1 (0.200 g,
0.63 mmol) and 10% Pd/C (170 mg) in MeOH (5 ml) was hydrogenated at r.t. for 4 h. The catalyst was filtered
off, the solvent evaporated, and the residue crystallized from Et2O: 35.1 (0.110 g, 55%). White crystals. M.p. 628.
1H-NMR((D 6)DMSO, 90 MHz): 2.19 (t, J ˆ 7.5, 2 H); 2.82 (t, J ˆ 7.5, 2 H); 6.88 7.27 (m, 5 H); 7.28 7.66 (m,
5 H); 10.18 (s, 1 H); 10.36 (s, 1 H). Anal. calc. for C15H16N2O4S ¥ 0.5 Et2O (357.42): C 57.13, H 5.92, N 7.84; found:
C 57.03, H 5.94, N 7.70.
3-[3-(Aminosulfonyl)phenyl]propanamides 35.2 35.6 were obtained as described for 35.1.
N-Hydroxy-3-{3-{[4-(methylphenyl)amino]sulfonyl}phenyl}propanamide (35.2): M.p. 1708. 1H-NMR
((D6)DMSO, 200 MHz): 2.18 (s, 3 H); 2.23 (t, J ˆ 7.7, 2 H); 2.84 (t, J ˆ 7.7, 2 H); 6.95 (d, J ˆ 8.6, 2 H); 7.02 (d,
J ˆ 8.6, 2 H); 7.36 7.56 (m, 3 H); 7.58 (s, 1 H); 8.75 (s, 1 H); 9.98 (br. s, 1 H); 10.40 (s, 1 H). Anal. calc. for
C16H18N2O4S (334.40): C 57.47, H 5.43, N 8.38; found: C 57.39, H 5.40, N 8.17.
N-Hydroxy-3-{3-{[(2-methoxyphenyl)amino]sulfonyl}phenyl}propanamide (35.3): M.p. 1298. 1H-NMR
((D6)DMSO, 200 MHz): 2.23 (t, J ˆ 7.9, 2 H); 2.85 (t, J ˆ 7.9, 2 H); 3.49 (s, 3 H); 6.86 (dt, J ˆ 1.3, 8.2, 1 H);
6.89 (d, J ˆ 8.2, 1 H); 7.11 (dt, J ˆ 1.6, 8.0, 1 H); 7.19 (dd, J ˆ 1.6, 8.0, 1 H); 7.35 7.57 (m, 4 H); 8.75 (s, 1 H); 9.41
(s, 1 H); 10.41 (s, 1 H). Anal. calc. for C16H18N2O5S (350.40): C 54.85, H 5.18, N 7.99; found: C 54.93, H 5.14, N
7.95.
N-Hydroxy-3-{3-{[(4-methoxyphenyl)amino]sulfonyl}phenyl}propanamide (35.4): M.p. 1298. 1H-NMR
((D6)DMSO, 200 MHz): 2.23 (t, J ˆ 7.6, 2 H); 2.84 (t, J ˆ 7.6, 2 H); 3.66 (s, 3 H); 6.79 (d, J ˆ 9.0, 2 H); 6.95
(d, J ˆ 9.0, 2 H); 7.38 7.61 (m, 4 H); 8.75 (s, 1 H); 9.85 (s, 1 H); 10.39 (s, 1 H). Anal. calc. for C16H18N2O5S
(350.40): C 54.85, H 5.18, N 7.99; found: C 54.64, H 5.01, N 7.85.
3-{3-[([1,1'-Biphenyl]-4-ylamino)sulfonyl]phenyl}-N-hydroxypropanamide (35.5): M.p. 1088. 1H-NMR
((D6)DMSO, 200 MHz): 2.25 (t, J ˆ 7.6, 2 H); 2.86 (t, J ˆ 7.6, 2 H); 7.18 (d, J ˆ 8.5, 2 H); 7.31 (t, J ˆ 7.3, 1 H);
7.35 7.49 (m, 4 H); 7.50 7.65 (m, 3 H); 7.54 (d, J ˆ 8.5, 2 H); 7.67 (s, 1 H); 8.75 (s, 1 H); 10.39 (s, 2 H). Anal.
calc. for C21H20N2O4S ¥ 0.3 AcOEt (422.89): C 63.05, H 5.34, N 6.62; found: C 63.05, H 5.25, N 6.56.
N-Hydroxy-3-{3-{[(3-phenylpropyl)amino]sulfonyl}phenyl}propanamide (35.6): Foam. 1H-NMR
((D6)DMSO, 200 MHz): 1.64 (quint., J ˆ 7.3, 2 H); 2.29 (t, J ˆ 7.6, 2 H); 2.46 2.60 (m, 2 H, overlapped with
DMSO); 2.75 (q, J ˆ 6.3, 2 H); 2.90 (t, J ˆ 7.6, 2 H); 7.06 7.32 (m, 5 H); 7.43 7.53 (m, 2 H); 7.54 7.68 (m, 3 H);
8.76 (s, 1 H); 10.41 (s, 1 H). Rf (CH2Cl2/MeOH 20:1) 0.53. Anal. calc. for C18H22N2O4S ¥ 0.15 H2O (365.15): C
59.21, H 6.16, N 7.67; found: C 59.22, H 6.05, N 7.45.
Ethyl 2-(4-Nitrophenoxy)acetate (p37). To a mixture of 4-nitrophenol (p36; 4.17 g, 30.0 mmol) and K2CO3
(4.25 g, 30.8 mmo) in MeCN (35 ml), ethyl 2-bromoacetate (l, 31.5 mmol) was added, and the resulting
suspension was stirred at 608 for 3.5 h. The mixture was evaporated and the residue successively washed with
H2O, dried, and washed with petroleum ether/AcOEt 4 :1: p37 (6.2 g, 91%). 1H-NMR((D 6)DMSO, 90 MHz):
1.20 (t, J ˆ 7.0, 3 H); 4.16 (q, J ˆ 7.0, 2 H); 4.94 (s, 2 H); 7.12 (d, J ˆ 9.0, 2 H); 8.16 (d, J ˆ 9.0, 2 H).
Ethyl 2-(4-Aminophenoxy)acetate (p38). A mixture of p37 (6.2 g, 27.5 mmol) and 10% Pd/C (2.0 g) in
MeOH (120 ml) was hydrogenated at r.t. for 2.5 h. The catalyst was filtered off and the solvent evaporated: p38
(4.9 g, 91%). Colored crystals, darkening in air. 1H-NMR((D )DMSO, 90 MHz): 1.16 (t, J ˆ 7.0, 3 H); 4.10 (q,
6
J ˆ 7.0, 2 H); 4.95 (s, 2 H); 5.08 (br. s, 2 H); 6.61 (d, J ˆ 9.0, 2 H); 6.71 (d, J ˆ 9.0, 2 H).

Helvetica Chimica Acta Vol. 88 (2005)
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Ethyl 2-{4-[(Phenylsulfonyl)amino]phenoxy}acetate (p39). To combined solns. of p38 (4.9 g, 25 mmol) in
acetone (40 ml) and NaHCO3 (2.1 g, 25 mmol) in H2O (30 ml), benzenesulfonyl chloride (3.2 ml, 25 mmol) was
added, and the mixture was stirred at r.t. for 2 h. The acetone was evaporated, and the precipitated crystals were
1
filtered and washed with H2O and Et2O: p39 (7.55 g, 90%). H-NMR((D 6)DMSO, 200 MHz): 1.20 (t, J ˆ 7.2,
2 H); 4.14 (q, J ˆ 7.2, 2 H); 4.68 (s, 2 H); 6.82 (d, J ˆ 9.0, 2 H); 6.98 (d, J ˆ 9.0, 2 H); 7.49 7.64 (m, 3 H); 7.64
7.75 (m, 2 H); 9.98 (s, 1 H).
N-Hydroxy-2-{4-[(phenylsulfonyl)amino]phenoxy}acetamide (p40). To
a mixture of p39 (7.55 g,
22.5 mmol) and NH2OH ¥ HCl (4.7 g, 67.5 mmol) in THF (32 ml) and MeOH (3 ml) at 108, a soln. of KOH
(6.3 g, 112.5 mmol) in MeOH (32 ml) and H2O (6.5 ml) was added over 5 min. The mixture was stirred at r.t. for
2 h and supplemented with H2O (35 ml). The pH of the medium was brought to 7 by 3m HCl (ca. 20 ml), the
mixture extracted with AcOEt (2 Â 75 ml), the extract dried (Na2SO4) and evaporated, and the oily residue
converted to crystals by treating with petroleum ether/AcOEt 4 :1 (80 ml) followed by washing with Et2O: p40
(6.0 g, 83%). M.p. 1478 (dec.). 1H-NMR((D 6)DMSO, 200 MHz): 4.36 (s, 2 H); 6.81 (d, J ˆ 9.1, 2 H); 6.97 (d, J ˆ
9.1, 2 H); 7.46 7.64 (m, 3 H); 7.65 7.73 (m, 2 H); 8.96 (br. s, 1 H); 9.97 (br. s, 1 H); 10.76 (br. s, 1 H). Anal. calc.
for C14H14N2O5S (322.34): C 52.17, H 4.38, N 8.69; found: C 52.24, H 4.27, N 8.42.
N-Hydroxy-2-{3-[(phenylsulfonyl)amino]phenoxy}acetamide (m40.1). As described for p40. M.p. 148
1508. 1H-NMR((D 6)DMSO, 200 MHz): 4.35 (s, 2 H); 6.58 (dd, J ˆ 2.1, 8.1, 1 H); 6.68 (dd, J ˆ 1.6, 8.1, 1 H); 6.74
(t, J ˆ 2.0, 1 H); 7.11 (t, J ˆ 8.1, 1 H); 7.48 7.65 (m, 3 H); 7.74 7.82 (m, 2 H); 8.96 (s, 1 H); 10.35 (br. s, 1 H);
10.83 (s, 1 H). Anal. calc. for C14H14N2O5S (322.34): C 52.17, H 4.38, N 8.69; found: C 51.93, H 4.31, N 8.14.
N-Hydroxy-2-{3-[(naphthalen-1-ylsulfonyl)amino]phenoxy}acetamide (m40.2). As described for p40.
1
Foam. H-NMR((D 6)DMSO, 200 MHz): 4.29 (s, 2 H); 6.48 (dd, J ˆ 1.8, 8.2, 1 H); 6.61 (dd, J ˆ 1.2, 8.0, 1 H);
6.67 (t, J ˆ 1.6, 1 H); 7.03 (t, J ˆ 8.1, 1 H); 7.63 (t, J ˆ 7.7, 1 H); 7.65 (t, J ˆ 7.4, 1 H); 7.74 (dt, J ˆ 1.2, 7.6, 1 H); 8.06
(d, J ˆ 8.0, 1 H); 8.20 (d, J ˆ 7.6, 1 H); 8.24 (d, J ˆ 7.6, 1 H); 8.72 (d, J ˆ 8.4, 1 H); 8.93 (br. s, 1 H); 10.78 (br. s,
2 H). Anal. calc. for C18H16N2O5S ¥ 0.5 H2O ¥ 0.3 AcOEt (407.83): C 56.55, H 4.79, N 6.87; found: C 56.87, H 4.61,
N 6.57.
3-Formyl-N-phenylbenzenesulfonamide (41). To m6 (6.3 g, 30.3 mmol), benzene (25 ml), SOCl2 (6.5 ml,
89.6 mmol), and DMF (0.1 ml, 1.3 mmol) were added, and the resultant suspension was stirred under reflux for
4 h. The mixture was evaporated, the residue dried in vacuo and dissolved in dioxane (5 ml), and the soln. added
to a mixture of benzenamine (4.5 ml, 47.3 mmol) and NaHCO3 (4.8 g, 57.2 mmol) in H2O (20 ml). The mixture
was stirred at r.t. for 24 h and supplemented with AcOEt. The aq. phase was separated, the pH of the medium
brought to 4 by 2m HCl and extracted with AcOEt. The combined org. solns. were washed with 2m HCl and sat.
NaCl soln., dried (Na2SO4), and evaporated, and the oily residue was treated with CH2Cl2/AcOEt 50 :1 to give
white crystals. The crystals were filtered off. The filtrate was evaporated and the residue purified by CC (SiO2,
CH2Cl2/AcOEt 50 :1). The obtained product from CC was combined with the crystals: 41 (4.58 g, 58%).
1H-NMR((D 6)DMSO, 90 MHz): 6.91 7.39 (m, 5 H); 7.78 (t, J ˆ 7.6, 1 H); 8.03 (dt, J ˆ 1.7, 7.8, 1 H); 8.14 (dt, J ˆ
1.7, 7.5, 1 H); 8.25 (t, J ˆ 1.7, 1 H); 10.06 (s, 1 H); 10.44 (br. s, 1 H).
Methyl (4Z)- and (4E)-5-{3-[(Phenylamino)sulfonyl]phenyl}pent-4-enoate (Z)- and (E)-42, resp. To a
mixture of 41 (0.192 g, 0.73 mmol) and [Ph3P(CH2)3COOMe]I (1.09 g, 2.2 mmol) in THF (5 ml), a 60%
suspension of NaH in mineral oil (0.088 g, 2.2 mmol) was added, and the resulting mixture was stirred at r.t. for
3 h. The mixture was poured into sat. NaH2PO4 soln. and extracted with AcOEt. The extract was washed with
sat. NaCl soln., dried (Na2SO4), and evaporated and the crude product purified by CC (SiO2, petroleum ether/t-
BuOMe 2 :3: 42 (0.079 g, 31%). The mixture 42 was separated by prep. HPLC (hexane/AcOEt 3 :1): (Z)-42
(0.0293 g, 12%) and (E)-42 (0.0181 g, 7%).
1
Data of (Z)-42: H-NMR((D 6)DMSO, 90 MHz): 2.33 2.57 (m, 4 H); 3.68 (s, 3 H); 5.51 5.89 (m, 1 H);
6.40 (d, J ˆ 11.6, 1 H); 6.83 (br. s, 1 H); 6.96 7.29 (m, 5 H); 7.30 7.50 (m, 2 H); 7.52 7.82 (m, 2 H).
Data of (E)-42: 1H-NMR((D 6)DMSO, 90 MHz): 2.30 2.61 ((m, 4 H); 3.69 (s, 3 H); 5.97 6.39 (m, 1 H);
6.39 (d, J ˆ 16.0, 1 H); 6.51 (br. s, 1 H); 6.92 7.48 (m, 7 H); 7.56 (dt, J ˆ 1.6, 7.4, 1 H); 7.71 ((t, J ˆ 1.5, 1 H).
(4Z)-N-Hydroxy-5-{3-[(phenylamino)sulfonyl]phenyl}pent-4-enamide (45.1). As described for 30.1, with
(Z)-42. CC (SiO2, CHCl3/MeOH 9 :1) gave 41% of 45.1. Foam. 1H-NMR((D 6)DMSO, 200 MHz): 2.07 (t, J ˆ
7.2, 2 H); 2.40 (q, J ˆ 7.1, 2 H); 5.67 (dt, J ˆ 7.0, 11.8, 1 H); 6.42 (d, J ˆ 11.8, 1 H); 6.96 7.14 (m, 3 H); 7.17 7.29
(m, 2 H); 7.47 7.67 (m, 4 H); 8.76 (s, 1 H); 10.30 (br. s, 1 H); 10.43 (s, 1 H). Anal. calc. for C17H18N2O4S ¥
0.2 AcOEt (364.02): C 58.73, H 5.43, N 7.70, S 8.81; found: C 58.64, H 5.43, N 7.54, S 8.86.
(4E)-N-Hydroxy-5-{3-[(phenylamino)sulfonyl]phenyl}pent-4-enamide (45.2). As described for 30.1, with
(E)-42. CC (SiO2, CHCl3/MeOH 9 :1) gave 46% of 45.2. Foam. 1H-NMR((D 6)DMSO, 200 MHz): 2.12 (t, J ˆ
7.3, 2 H); 2.41 (q, J ˆ 6.9, 2 H); 6.30 (dt, J ˆ 6.3, 15.9, 1 H); 6.45 (d, J ˆ 15.9, 1 H); 6.96 7.13 (m, 3 H); 7.16 7.28
(m, 2 H); 7.45 (t, J ˆ 7.6, 1 H); 7.52 7.63 (m, 2 H); 7.72 (s, 1 H); 8.73 (d, J ˆ 1.6, 1 H); 10.25 (br. s, 1 H); 10.43 1(s,

1656
Helvetica Chimica Acta Vol. 88 (2005)
1 H). Anal. calc. for C17H18N2O4S ¥ 0.1 AcOEt (355.21): C 58.84, H 5.33, N 7.89, S 9.03; found: C 58.47, H 5.31, N
7.57, S 9.00.
5-{3-[(Phenylamino)sulfonyl]phenyl}pentanoic Acid (44). A crude mixture 42 was hydrolyzed to 43 as
described for m10.1 and hydrogenated as described for 35.1:44. 1H-NMR(CDCl 3, 90 MHz): 1.41 1.86 (m,
4 H); 2.34 (t, J ˆ 6.5, 2 H); 2.61 (t, J ˆ 6.5, 2 H); 6.82 (br. s, 1 H); 6.94 7.74 (m, 9 H).
N-Hydroxy-5-{3-[(phenylamino)sulfonyl]phenyl}pentanamide (45.3). As described for m11.1, with 44. CC
1
(SiO2, CH2Cl2/MeOH 9 :1) gave 66% of 45.3. Foam. H-NMR((D 6)DMSO, 200 MHz): 1.33 1.60 (m, 4 H);
1.94 (t, J ˆ 6.5, 2 H); 2.59 (t, J ˆ 6.8, 2 H); 7.01 (t, J ˆ 7.4, 1 H); 7.07 (d, J ˆ 7.8, 2 H); 7.22 (d, J ˆ 7.8, 2 H); 7.37
7.49 (m, 2 H); 7.50 7.61 (m, 2 H); 8.67 (s, 1 H); 10.19 (br. s, 1 H); 10.34 (s, 1 H). Anal. calc. for C17H20N2O4S ¥
0.15 AcOEt (361.63): C 58,46, H 5.91, N 7.75, S 8.87; found: C 58.56, H 5.91, N 7.77, S 8.81.
3-[(Phenylamino)sulfonyl]benzenecarboxylic Acid (46). To a soln. of 41 (0.100 g, 0.38 mmol) in acetone
(2 ml) at 28, 2.64m Jones reagent (0.16 ml, 0.42 mmol) was added, and the mixture was stirred at 2 48 for 1.5 h.
Then, i-PrOH (2 ml) was added and the mixture stirred for 0.5 h and poured into sat. NaCl soln. The mixture was
extracted with AcOEt, the extract washed with sat. NaCl soln., dried (Na2SO4), and evaporated, and the residue
dried in vacuo: 46 (0.104 g, 98%). White solid. 1H-NMR((D 6)DMSO, 90 MHz): 6.86 7.39 (m, 5 H); 7.65 (t, J ˆ
7.8, 1 H); 7.92 (d, J ˆ 7.8, 1 H); 8.11 (d, J ˆ 7.8, 1 H); 8.27 (s, 1 H); 10.34 (br. s, 1 H).
Methyl 3-[(Phenylamino)sulfonyl]benzenecarboxylate (47). To a soln. of 46 (0.133 g, 0.48 mmol) in MeOH
(2 ml) was added a soln. of AcCl (0.102 ml, 1.44 mmol) and MeOH (1 ml), prepared beforehand. The resulting
mixture was stirred at r.t. for 24 h and at 658 for 1 h. After evaporation, the crude product was purified by CC
(SiO2, petroleum ether/AcOEt 2 :1): 47 (0.118 g, 84%). White solid. 1H-NMR(CDCl 3, 90 MHz): 3.97 (s, 3 H);
6.54 (br. s, 1 H); 6.97 7.36 (m, 5 H); 7.53 (t, J ˆ 7.8, 1 H); 7.94 (dt, J ˆ 1.5, 8.0, 1 H); 8.23 (dt, J ˆ 1.5, 7.6, 1 H);
8.50 (t, J ˆ 1.5, 1 H).
N-Hydroxy-3-[(phenylamino)sulfonyl]benzamide (48). As described for 34.1, with 47. CC (SiO2, CHCl3/
MeOH 5 :1) gave 30% of 48. White crystals. M.p. 158 1598. 1H-NMR((D 6)DMSO, 200 MHz): 6.97 7.13 (m,
3 H); 7.22 (t, J ˆ 7.7, 2 H); 7.61 (t, J ˆ 7.8, 1 H); 7.85 (d, J ˆ 7.8, 1 H); 7.92 (d, J ˆ 7.8, 1 H); 8.18 (s, 1 H); 9.20 (s,
1 H); 10.39 (br. s, 1 H); 11.40 (br. s, 1 H). Anal. calc. for C13H12N2O4S (292.32): C 53.42, H 4.14, N 9.58, S 10.97;
found: C 53.45, H 4.01, N 9.56, S 10.92.
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Received February 28, 2005