An efficient method to prepare α-sulfonyl hydroxamic acid derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00835-8

α-Sulfonyl hydroxamic acid derivatives are biologically important molecules. An efficient protocol has been developed to make these molecules via a direct sulfonylation of enolates. Several piperidine containing α-sulfonyl hydroxamic acid compounds have been prepared by this procedure.

Full text of DOI:10.1016/S0040-4039(01)00835-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4605–4607
An efficient method to prepare a-sulfonyl hydroxamic acid
derivatives
Vincent P. Sandanayaka,* Arie Zask, Aranapakam M. Venkatesan and Jannie Baker
Chemical Sciences, Wyeth-Ayerst Research, Pearl River, NY 10965, USA
Received 8 May 2001; accepted 16 May 2001
Abstract—a-Sulfonyl hydroxamic acid derivatives are biologically important molecules. An efficient protocol has been developed
to make these molecules via a direct sulfonylation of enolates. Several piperidine containing a-sulfonyl hydroxamic acid
compounds have been prepared by this procedure. © 2001 Published by Elsevier Science Ltd.
a-Sulfonyl hydroxamic acid derivatives exhibit multiple
biological activities. In recent years, this class of com-
pounds has been reported as matrix metalloproteinase
(MMP) and TNF-a converting enzyme (TACE)
inhibitors,1 which are useful for the treatment of
rheumatoid and osteoarthritis, various cancers, multiple
sclerosis, and HIV infection. In addition, these com-
pounds act as IL-4 antagonists,2 renin inhibitors3 and
herbicides.4
we sought this method to be amenable to large-scale
synthesis of selected compounds. We considered the
direct addition of a sulfonyl group to the a-position of
an ester and subsequent conversion of the ester to a
hydroxamic acid, thus bypassing several steps that
would be otherwise necessary. One of the difficulties
associated with adding phenyl sulfonyl chlorides to an
ester enolate to form the corresponding a-sulfonyl
esters is the formation of a-chloro esters to a larger
extent.8 In this case, the sulfonyl functionality acts as
the leaving group and the positive chlorine emerges as
the dominant electrophile to furnish the undesired a-
chloro derivative. In contrast, following the initial
report by Hunig et al.8 in 1982, Kende and co-workers9
employed p-toluenesulfonyl fluoride as an effective
reagent for enolate sulfonylation, and they used the
resulting p-toluenesulfonyl group as the controlling or
activating element to eventually obtain sulfur-free com-
pounds. Surprisingly, this dual behavior of the sulfonyl
moiety10 has not been utilized as a rapid entry to
biologically important a-sulfonyl hydroxamates or
other sulfone containing derivatives. In this communi-
cation, we wish to report the development of an
efficient procedure to make piperidine containing a-sul-
fonyl hydroxamic acid derivatives utilizing the direct
enolate sulfonylation protocol.
The preparation of a-sulfonyl hydroxamates generally
involves an initial addition of a desired disulfide5 or a
sulfenyl chloride6 to an ester enolate to provide an
a-thioester. Subsequent oxidation of sulfur to sulfone
followed by conversion of ester to hydroxamate via the
corresponding carboxylic acid provides the required
a-sulfonyl hydroxamate. In an electronically inverse
fashion, a-thioesters have been prepared by alkylating
an appropriately substituted thiolate anion with an
a-halo acetic acid ester in which the sulfur containing
functionality now behaves as a nucleophile.7 In both
cases, the preparation of the requisite mercaptans or
disulfides often requires multiple steps that involve
sulfonyl chlorides or protected thiols as the intermedi-
ates, in addition to the oxidation step to convert
sulfides to sulfones.
In our MMP inhibitors program, we required an
efficient method to access various a-sulfonyl hydrox-
amic acid derivatives for SAR studies. Simultaneously,
Synthesis of the target molecules began by converting
appropriately functionalized sulfonyl chlorides into sul-
fonyl fluorides. Thus, sulfonyl chlorides 1 and 2 were
treated with a suspension of a solid KF–CaF2 mixture
in acetonitrile.11 Filtration of the resulting mixtures
after 5 h at room temperature and removal of the
* Corresponding author. Tel.: 845-732-2067; fax: 845-732-5561;
e-mail: sandanv@war.wyeth.com
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00835-8

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V. P. Sandanayaka et al. / Tetrahedron Letters 42 (2001) 4605–4607
solvent provided the desired fluorides 3 and 4† in 100
and 80% yields, respectively. 19F NMR clearly indicated
the presence of sulfonyl fluoride with a characteristic
peak at 66 ppm as the only peak in the spectrum. The
reaction was monitored by 13C NMR that distinguished
the ipso-carbon on the phenyl ring of sulfonyl fluoride
from that of sulfonyl chloride. The former shows a
doublet at 125 ppm (J=24.5 Hz) whereas the latter
gives a sharp peak at 136 ppm. Ester enolates prepared
by adding LDA to piperidines 6 and 7, were treated
with phenylsulfonyl fluorides to afford the correspond-
ing a-sulfonyl esters 8 and 9 in 85 and 60% yields, as
the exclusive products.12 a-Fluoro ester formation was
not detected in the reaction mixture. This reaction was
found to be a very facile process as shown in Scheme 1
and was carried out in multigram scale.
was also carried out effectively using benzyl bromide to
give the N-benzylated product 11 in 94% yield. These
esters were readily hydrolyzed with LiOH to give the
corresponding acids in excellent yields. Acids were
treated with either HOBT/EDC/NMM or (COCl)2/
DMF followed by NH2OH to furnish the correspond-
ing hydroxamic acids 12† and 13 in 53 and 91% yields,
respectively. Thus, starting from sulfonyl chlorides, var-
ious N-substituted piperidine containing a-sulfonyl
hydroxamic acids were obtained in 6 steps with good
overall yields (Scheme 2).
Alternatively, the same target compounds can be pre-
pared by changing the order of transformations after
the initial enolate sulfonylation process (Scheme 3).
Compound 8 was first hydrolyzed with LiOH to give
the corresponding acid in 98% yield. The acid was then
converted to hydroxamic acid 14 in 61% yield, under
the oxalyl chloride/hydroxyl amine coupling conditions.
Deprotection of the amine with 4N HCl provided the
free amine 15 in 95% yield as a HCl salt. At this point,
various R3-groups can be introduced selectively onto
piperidine nitrogen by employing known literature pro-
cedures. This was demonstrated by converting 15 into
16 in 75% yield using methyl 4-(bromomethyl)benzoate
Compounds 8 and 9 were converted into the free
amines by removing the Boc-group with 4N HCl in
dioxane. At this juncture, various groups can be intro-
duced onto piperidine nitrogen using standard chemical
transformations. For example, the free amine obtained
from compound 8 was treated with acetyl chloride in
the presence of Et3N to provide 10 in 80% yield.
Alkylation of the corresponding amine obtained from 9
a
R1O
SO2F
R1O
SO2Cl
O
X
O
S
O
3: R1 = Me
OR1
1: R1 = Me
2: R1 = 2-butynyl
R2O
4: R1 = 2-butynyl
c
Y
8: X = CH2; Y = NBoc;
R2 = Me; R1 = 2-butynyl
CO2H
Y
CO2R2
b
9: X = NBoc; Y = CH2;
R2 = Et; R1 = Me
X
X
Y
6: X = CH2; Y = NBoc; R2 = Me
7: X = NBoc; Y = CH2; R2 = Et
5: X = CH2; Y = NBoc
Scheme 1. (a) KF–CaF2, CH3CN; (b) K2CO3, MeI (95%); (c) LDA, THF, −78o C to rt.
O
X
O
X
O
O
O
O
S
OR1
S
OR1
a
b
R2O
HOHN
8, 9
Y
Y
12: X = CH2; Y = NCOCH3;
R1 = 2-butynyl
10: X = CH2; Y = NCOCH3;
R2 = Me; R1 = 2-butynyl
11: X = NCH2Ph; Y = CH2;
R2 = Et; R1 = Me
13: X = NCH2Ph; Y = CH2;
R1 = Me
Scheme 2. (a) i. 4N HCl in dioxane, CH2Cl2; ii. CH3COCl, Et3N (for 13) and PhCH2Br, Et3N (for 14); (b) i. LiOH, THF, MeOH,
H2O; ii. HOBT, EDC, NMM, 50% aq. NH2OH (for 15) and (COCl)2, DMF, NH2OH·HCl, Et3N (for 16).
† Compound 4: IR: 2925, 2242, 1596, 1579, 1406, 1261, 997 cm−1 1H NMR (300 MHz, CDCl3): l 1.87 (t, 3H, J=1.8 Hz), 4.76 (q, 2H, J=1.8
.
Hz), 7.14 (d, 2H, J=6.6 Hz), 7.95 (d, 2H, J=6.6 Hz). 13C NMR (75 MHz, CDCl3):l 3.6, 56.9, 72.4, 85.4, 115.8, 130.8, 163.3.
Compound 12: 1H NMR (300 MHz, CDCl3): l 1.64 (m, 1H), 1.85 (m, 3H), 1.99 (s, 3H), 2.31 (m, 4H), 2.83 (m, 1H), 3.88 (m, 1H), 4.41 (m,
1H), 4.88 (m, 2H), 7.16 (d, 2H, J=9.0 Hz), 7.66 (d, 2H, J=9.0 Hz), 9.20 (m, 1H), 11.00 (m, 1H). 13C NMR (75 MHz, CDCl3):l 3.5, 21.5, 36.1,
56.8, 70.2, 74.3, 84.7, 115.3, 126.7, 132.6, 162.3, 168.6; HRMS: m/z calcd for C18H22N2O6S 395.1271. Found 395.1271.

V. P. Sandanayaka et al. / Tetrahedron Letters 42 (2001) 4605–4607
4607
O
O
O
S
O
S
O
O
OCH2CCCH3
OCH2CCCH3
b
a
HOHN
HOHN
8
N
N
Boc
R3
14
15: R3 = H
16: R3 = CH2C6H4CO2CH3
Scheme 3. (a) i. LiOH, THF, MeOH, H2O (98%); ii. NH2OH.HCl, Et3N, DMF, (COCl)2 (61%); (b) i. 4N HCl in dioxane,
CH2Cl2; ii. CH3CO2C6H4CH2Br, Et3N.
Natchus, M. G.; Pikul, S. PCT Int. Appl. WO Patent
9,906,340, 1998.
2. Solomon, D. M.; Grace, M. J.; Fine, J. S.; Bober, L. A.;
Sherlock, M. H. US Patent 5,939,431, 1997.
3. Branca, Q.; Heitz, M. P.; Neidhart, W.; Stadler, H.;
Vieira, E.; Wostl, W. US Patent 5,393,875, 1995.
4. Maravetz, L. L.; Crawford, S. D.; Theodoridis, G. PCT
Int. Appl. WO Patent 9,828,280, 1997.
5. Yamanaka, E.; Narushima, M.; Inukai, K.; Sakai, S.
Chem. Pharm. Bull. 1986, 34, 77.
and Et3N. However, the selective acylation of nitrogen
using CH3COCl/Et3N conditions did not proceed well,
and led to a mixture of products. This alternative
procedure bears the potential to use as a combinatorial
route by attaching the hydroxyl amine moiety to a solid
phase linker.13
In summary, we have developed an efficient protocol
for the synthesis of biologically important piperidine
containing a-sulfonyl hydroxamic acid derivatives. This
method was employed to make a diverse array of MMP
and TACE inhibitors, which will be described together
with their biological data elsewhere. This methodology,
which utilizes direct enolate sulfonylation, should find
general application not only for a-sulfonyl hydroxam-
ates but also for other sulfone containing target
molecules.
6. Mach, R. H.; Kung, H. F.; Jungwiwattanaporn, P.; Guo,
Y.-Z Tetrahedron Lett. 1989, 30, 4069.
7. Stoit, A. R.; Pandit, U. K. Tetrahedron 1985, 41, 3345.
8. Hirsh, E.; Hunig, S.; Reibig, H.-U. Chem. Ber. 1982, 115,
399.
9. Kende, A. S.; Mendoza, J. S. J. Org. Chem. 1990, 55,
1125.
10. Trost, B. M.; Ghadiri, M. R. Bull. Chem. Soc. Jpn. 1988,
61, 107.
11. Ichihara, J.; Matsuo, T.; Hanafusa, T.; Ando, T. J.
Acknowledgements
Chem. Soc., Chem. Commun. 1986, 793.
12. Preparation of 8: To a solution of LDA (70 mmol) in
THF at −78°C, was added a solution of 6 (15.5 g, 64
mmol) in THF (300 mL) and the resulting mixture was
stirred for 0.5 h at that temperature. A solution of 4 (14.6
g, 64 mmol) in THF (150 mL) was then added, and the
resulting mixture was stirred for 5 h at rt, quenched with
saturated aqueous NH4Cl solution, and extracted with
EtOAc. The organic layer was washed with brine and
dried over anhyd. Na2SO4. The crude product was
purified by silica-gel chromatography to obtain 8 (24.5 g,
85%) as a white solid; IR: 2978, 2242, 1740, 1697, 1594,
1418, 1301, 1002, 908 cm−1.1H NMR (300 MHz, CDCl3):
l 1.44 (s, 9H), 1.87 (m, 3H), 1.98 (m, 2H), 2.32 (m, 2H),
2.62 (m, 2H), 3.74 (s, 3H), 4.17 (m, 2H), 4.74 (m, 2H),
7.09 (d, 2H, J=7.2 Hz), 7.71 (d, 2H, J=7.2 Hz). 13C
NMR (75 MHz, CDCl3): l 4.0, 28.2, 28.7, 53.5, 57.2,
72.9, 73.1, 80.5, 85.4, 115.3, 127.0, 132.6, 154.7, 162.9,
167.8; HRMS: calcd for C22H29NO7S (M+Na) 474.1557.
Found 474.1547.
We thank Drs. J. Skotnicki, J. Ellingboe and T. Man-
sour for their support of this work.
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