Synthesis of α-fluoro- And α,α-difluoro- benzenemethanesulfonamides: New inhibitors of carbonic anhydrase

Article abstract of DOI:10.1039/b417327a

Direct fluorination of arenemethanesulfonamide anions under mild conditions and in high yield has been accomplished using N-fluorobisbenzenesulfonimide, NFSi, on carbanions of N-tert-butyl- and N-bis-(4-methoxyphenyl-methyl)- benzenemethanesulfonamides giving novel α-fluoro- and α,α- difluoro-benzenemethanesulfonamides respectively: IC₅₀ and pK _a data show that α-halogenation enhances sulfonamide acidity incrementally and correlates well with increased carbonic anhydrase inhibition, while lipophilicity is also enhanced.

Full text of DOI:10.1039/b417327a

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C O M M U N I C A T I O N
Synthesis of a-fluoro- and a,a-difluoro-benzenemethanesulfonamides:
new inhibitors of carbonic anhydrase
G. Michael Blackburn*a and Hasan Tu¨rkmena,b
a University of Sheffield, Department of Chemistry, Sheffield, S3 7HF, ENGLAND.
E-mail: g.m.blackburn@shef.ac.uk; Fax: 01142229346; Tel: 01142229462
b University of Harran, Department of Chemistry, Sanlıurfa, TURKEY
Received 30th September 2004, Accepted 15th November 2004
First published as an Advance Article on the web 7th December 2004
Direct fluorination of arenemethanesulfonamide anions
under mild conditions and in high yield has been accom-
plished using N-fluorobisbenzenesulfonimide, NFSi, on
carbanions of N-tert-butyl- and N-bis-(4-methoxyphenyl-
methyl)-benzenemethanesulfonamides giving novel a-
fluoro- and a,a-difluoro-benzenemethanesulfonamides re-
spectively: IC50 and pKa data show that a-halogenation
enhances sulfonamide acidity incrementally and correlates
well with increased carbonic anhydrase inhibition, while
lipophilicity is also enhanced.
of base and NFSi, the difluoromethanesulfonamides (3a and
3b) were prepared directly in 40% isolated yield. Rather higher
yields of these products were obtained by re-fluorination of the
arenemonofluoromethanesulfonamides (2a and 2b) (Scheme 1).
Scheme 1 a) NaHMDS, 1.1 equiv., THF, −78 ◦C, 0.5 h; b) NFSi,
1.1 equiv., THF, −78 ◦C 6 h → rt; c) HCl aq.
a-Fluorination of alkanephosphonic acids was proposed as a
strategy for improving their performance as stable bioisosteres
for phosphate esters and anhydrides over 20 years ago.1 Since
then, a-fluoro- and a,a-difluoroalkanephosphonic acids have
been widely deployed as isosteric and isopolar mimics of
biological phosphates.2 Increasingly safe and effective routes
for their synthesis,3 especially the use of N-fluorobisbenzene-
sulfonimide,4 NFSi, have underpinned their wide application,
initially as nucleotide analogues5 and subsequently as peptidyl
phosphate surrogates.6 Such use of the CF2 group as an isosteric
and isopolar1 replacement for a bridging oxygen in phosphate
chemistry and biology has inspired its application to substitution
of the furanose ring-oxygen in nucleosides7 and, more recently,
in mimics of aryl sulfate esters, particularly of estrone 3-sulfate.8
However, the preparation and properties of a-fluoroarene-
methanesulfonamides has not been explored hitherto, though
the perfluoroalkanesulfonamides are well known,9 and currently
under investigation as environmental pollutants.10
Unfortunately, all attempts to remove the benzyl protecting
groups by various reduction procedures proved fruitless. Similar
problems have been reported previously.14 We therefore turned
to the use of the tert-butyl protecting group for the sulfon-
amide nitrogen. N-tert-Butyl-(benzenemethane)sulfonamide15
(4) was treated with n-butyllithium (2.2 equiv.) followed by
NFSi (2.2 equiv.) in THF at −78 ◦C to give N-tert-butyl-
(benzene-fluoromethane)-sulfonamide (5) in 68% yield after
flash chromatography. The tert-butyl group was readily removed
on stirring with trifluoroacetic acid, TFA, at rt for 2 h to
give benzenefluoro-methanesulfonamide (6) as a colourless
crystalline solid in 87% yield (Scheme 2). All efforts to introduce
a second fluorine either by repeated fluorination of (5) or by
using a large excess of base and FSi on the starting material (4)
were unsuccessful.
Broad-based studies in sulfonamide inhibition of carbonic
anhydrase, which have underpinned major developments in
glaucoma therapy,11 have linked increasing acidity of heteroare-
nesulfonamides and fluoroalkane-sulfonamides to their affinity
for carbonic anhydrase, where the anionic sulfonamide nitrogen
becomes a ligand for the catalytic zinc in the active site.12,13
Unfortunately, Maren’s discovery of the outstanding proper-
ties of trifluoromethanesulfonamide as a carbonic anhydrase
inhibitor has been compromised by its poor bioavailability.11 We
therefore decided to undertake a systematic investigation of the
effect of a-fluorination of arenealkane- and heteroarenealkane-
sulfonamides, seeking thereby to identify improved carbonic an-
hydrase inhibitors of enhanced acidity and greater lipophilicity.
Surprisingly, the chemical literature is almost devoid of any de-
scription of the preparation of arenefluoroalkane-sulfonamides.
After some experimental vicissitudes, we chose to focus on
electrophilic fluorination of arenealkanesulfonamides using
NFSi.4 We soon found that partial or total protection of the
sulfonamide nitrogen was required to achieve the necessary
ionisation of the sulfonamide a-CH2 group. Initial experiments
with N,N-bis-phenylmethyl-(benzenemethane)sulfonamide (1a)
and the corresponding 4-nitrobenzenemethanesulfonamide (1b)
using sodium hexamethyldisilazide (NaHMDS, 1.1 equiv.) and
NFSi (1.1 equiv.) in THF at −78 ◦C gave the respective
protected arenemonofluoromethanesulfonamides (2a and 2b) in
70% yield after flash chromatography. By using 2.2 equivalents
Scheme 2 a) BuLi, 2.2 equiv., THF, −78 ◦C → 0 ◦C → −78 ◦C, 1 h;
b) NFSi, 2.2 equiv, THF, −78 ◦C 10 h → rt; c) HCl aq., 0 ◦C; d) TFA,
rt, 2 h.
We therefore chose to employ the 4-methoxyphenyl-methyl
group to protect fully the sulfonamide. We prepared N-
bis-(4-methoxyphenylmethyl)-benzenemethanesulfonamide (7),
and established that it was easily converted into benzene-
methanesulfonamide (8) on stirring with TFA at rt. Treatment
of (7) with BuLi (1.1 equiv.) followed by TFSi (1.1 equiv.) at
−78 ◦C in THF gave N-bis-(4-methoxyphenylmethyl)-benzene-
fluoromethanesulfonamide (9) in 82% yield after crystallisa-
tion from ethanol. Benzenefluoromethanesulfonamide (6) was
obtained on stirring (9) with TFA overnight (41%) or by
oxidation of (9) with ceric ammonium nitrate (32%) in aque-
ous acetone. Stepwise, double fluorination of (8) with first
1.1 equiv. of base and NFSi followed by a second equivalent
of base and of NFSi led to N-bis-(4-methoxyphenylmethyl)-
benzene- difluoromethanesulfonamide (10) in 68% yield after
crystallisation from ethanol. Deprotection using TFA provided
benzenedifluoromethanesulfonamide (11) as white crystals from
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 5 – 2 2 6
2 2 5
©

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We thank the Turkish Council of Higher Education and
Sheffield University for financial support (to HT) and Dr.
Andrew J. Poss, Allied Chemicals, Buffalo, NY, for a generous
gift of NFSi.
Notes and references
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Scheme 3 a) TFA, rt, 2 h; b) BuLi, 1.1 equiv., THF, −78 ◦C, 0.5 h;
c) NFSi, 1.1 equiv., THF, −78 ◦C 45 min → rt; d) NaHCO3aq., rt; e)
TFA, 16 h, rt. (PMBn, p-methoxybenzyl).
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Fig. 1 Plot of log[IC50] against pKa for the seven sulfonamides listed
in Table 1. Linear regression analysis (KaleidagraphTM) gives slope of
+0.59, R = 0.945.
ether (27%). These results constitute the first rational syn-
theses of monofluoro- and difluoroarenemethanesulfonamides
(Scheme 3).16
The pKa values of these and other select sulfonamides
(Table 1) were determined by potentiometric titration at 37 ◦C in
water at ionic strength 0.1. Partition coefficients, Pether, were mea-
sured◦spectroscopically for the equilibrium ether : water (pH 7.2)
at 25 C; and IC50 values for inhibition of carbonic anhydrase
(Bovine type II, Boehringer Mannheim) were determined at 3 ◦C
and pH 7.2 by pH stat titration.17 These data clearly show first,
that a-fluorination of sulfonamides directly delivers increased
sulfonamide acidity (Table 1). Secondly, there is a direct linear
correlation between pKa and log(IC50) over four decades of
acidity showing that a-fluorination of alkanesulfonamides is
directly linked to both of these values (Fig. 1). Notably, di-
fluorination of (8) increases its CAI 11-fold. Thirdly, since both
benzenefluoromethanesulfonamide (6) and benzenedifluoro-
methane-sulfonamide (11) have good water solubility (in excess
of 30 g dm−3 at pH 7.2), while their hydrophobicity has increased
significantly relative to that of (8), it is evident that there is
excellent scope for the further deployment of the CF2 function to
generate improved sulfonamide inhibitors of carbonic anhydrase
with adequate water-solubility for topical use in glaucoma
therapy.
12 (a) U. F. Mansoor, X.-R. Zhang and G. M. Blackburn, in The
Carbonic Anhydrases: New Horizons, eds. W. R. Chegwidden,
N. D. Carter and Y. H. Edwards, Birkhauser Verlag, Basel, 2000, 437;
(b) C. T. Supuran, D. Vullo, G. Manole, A. Casini and A. Scozzafava,
Curr. Med. Chem.: Cardiovasc. Hematol. Agents, 2004, 2, 49.
13 However, we have found that within a family of structurally closely-
related acetazolamide derivatives, increased CA inhibition is linked
directly to elevated sulfonamide pKa; X.-R. Zhang, Ph.D. Thesis,
Sheffield University, 1995.
Table 1 Physical data for a range of alkane- and arenealkane-
sulfonamides
14 G. A. Epling and M. E. Walker, Tetrahedron Lett., 1982, 23, 3843.
15 J. C. Sheehan, U. Zoller and D. Ben-Ishai, J. Org. Chem., 1974, 39,
1817.
16 Parts of this work formed a poster presentation at IUPAC ISBOC-7,
Sheffield, June 2004. Since the submission of this MS, related work
has been described elsewhere:B. Hill, Y. Liu and S. D. Taylor, Org.
Lett., 2004, 6, 4285.
17 R. E. Forster, in The Carbonic Anhydrases: cellular physiology and
molecular genetics, eds. S. J. Dodgson, R. E. Tashian, G. Gross and
N. D. Carter, Plenum Press, NY, 1991, 79.
Compound
pKa
IC50/nM
Pether
CH3SO2NH2
10.8 0.15
10.5 0.10
9.1 0.1
8.80 0.05
7.70 0.05
6.50 0.10
6.30 0.05
650 40
630 25
390 20
220 10
—
PhCH2SO2NH2 (8)
CH2ClSO2NH2
PhCHFSO2NH2 (6)
PhCF2SO2NH2 (11)
C4F9SO2NH2
1.2 0.20
—
5.65 0.20
13.0 0.20
—
58
<2
<2
4
CF3SO2NH2
0.003
2 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 5 – 2 2 6