Synthesis of α-fluorosulfonamides by electrophilic fluorination

Article abstract of DOI:10.1021/ol048249z

(Chemical Equation Presented) α-Fluorosulfonamides were prepared by electrophilic fluorination of tertiary sulfonamides using N- fluorobenzenesulfonimide as fluorinating agent and utilizing the dimethoxybenzyl group (DMB) as a new sulfonamide protecting g

Full text of DOI:10.1021/ol048249z

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4285-4288
Synthesis of
Electrophilic Fluorination
r-Fluorosulfonamides by
Bryan Hill, Yong Liu, and Scott D. Taylor*
Department of Chemistry, UniVersity of Waterloo, 200 UniVersity AVenue West,
Waterloo, Ontario, Canada N2L 3G1
s5taylor@sciborg.uwaterloo.ca
Received August 31, 2004
ABSTRACT
r
-Fluorosulfonamides were prepared by electrophilic fluorination of tertiary sulfonamides using N-fluorobenzenesulfonimide as fluorinating
agent and utilizing the dimethoxybenzyl group (DMB) as a new sulfonamide protecting group. Removal of the DMB group with TFA/CH2Cl2
gave primary and secondary -fluorosulfonamides.
r
The sulfonamide moiety is one of the most important
pharmacophores in medicinal chemistry, and numerous
bioactive agents bear this functionality.1 Included in this class
of compounds are R-fluorosulfonamides which have been
shown to have herbicidal and antiinflammatory activity, some
of which are used commercially.2a-d The introduction of
fluorines R to the sulfonamide results in a linear acidity
increase of 1.47 pKa units per fluorine as well as a significant
increase in lipophilicity.3 Both of these features can have a
significant impact on biological activity.2a-c Biological
studies on R-fluorinated sulfonamides have focused mainly
on fluoromethane sulfonamides (F3CSO2NRR or HF2CSO2-
NRR). R-Alkyl or R-aryl R-fluorosulfonamides, of general
structure 1, have received less attention possibly due to a
lack of a facile method for their preparation.
sulfonamides, such as compound 2, to test as reversible
inhibitors of the enzyme estrone sulfatase (ES) and as probes
to test mechanisms proposed for the irreversible inhibition
of this therapeutically significant enzyme by sulfamates, such
as compound 3.4 Here we report that compound 2, as well
as other primary, secondary, and tertiary sulfonamides of
type 1, can be prepared by electrophilic fluorination of
R-carbanions of protected sulfonamides.
We previously reported that R,R-difluorosulfonates can be
prepared by electrophilic fluorination of R-carbanions of
sulfonate esters using N-fluorobenzene sulfonamide.5a-c
Therefore, we envisioned preparing R,R-difluorosulfon-
amides by electrophilic fluorination of R-carbanions of
sulfonamides. We initiated our studies on model tertiary
sulfonamides 7 and 8 in which the sulfonamide was protected
with the benzyl or p-methoxybenzyl (PMB) groups, two
(2) (a) Moore, G. G. I.; Harrington, J. K. J. Med. Chem. 1975, 18, 386-
391. (b) Trepka, R. D.; Harrington, J. K.; McConville, J. W.; McGurran,
K. T.; Mendel, A.; Pauly, D. R.; Robertson, J. E.; Waddington, J. T. J.
Agric. Food Chem. 1974, 22, 1111-1119. (c) Trepka, R. D.; Harrington,
J. K.; Robertson, J. E.; Waddington, J. T. J. Agric. Food Chem. 1970, 18,
1176-1177. (d) Harrington, J. K.; Robertson, J. E.; Kvam, D. C.; Hamilton,
R. R.; McGurran, K. T.; Trancik, R. J.; Swingle, K. F.; Moore, G. G. I.;
Gerster, J. F. J. Med. Chem. 1970, 22, 137.
(3) Trepka, R. D.; Harrington, J. K.; Belisle, J. W. J. Org. Chem. 1974,
39, 1094-1098.
(4) Compound 3 and other aryl sulfamates are potent irreversible
inhibitors of ES. For a discussion on the mechanism of inhibition of ES by
sulfamates, see: Ahmed, S.; Owen, C. P.; James, K.; Patel, C. K.; Sampson,
L. J. Steroid Biochem. Mol. Biol. 2002, 80, 429-440.
Our interest in the synthesis of R-fluorosulfonamides
stemmed from our desire to prepare benzylic R,R-difluoro-
(1) Bowman, W. C.; Rand, M. J. Textbook of Pharmacology, 2nd ed.;
Blackwell: London, 1979; Chapter 34.
10.1021/ol048249z CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/13/2004

Scheme 1
Table 1. Synthesis and Deprotection of Benzylic
R,R-difluorosulfonamides 25-34
% yield
25-34
% yield
35-41
substratea
15 (R1 ) 4-BrPh, R2 ) R3) DMB)
16 (R1 ) 4-IPh, R2, R3 ) DMB)
17 (R1 4-NO2Ph, R2 ) R3 ) DMB)
84 (25) 92 (35, R3 ) H)
86 (26) 86 (36, R3 ) H)
65 (27) 91 (37, R3 ) H)
18 (R1 ) 4-MePh, R2 ) R3 ) DMB) 76 (28) 56 (38, R3 ) H)
19 (R1 ) 3-BrPh, R2 ) R3 ) DMB) 92 (29) 82 (39, R3 ) H)
20 (R1 ) Ph, R2 ) DMB, R3 ) Me) 65 (30) 90 (40, R3 ) Me)
21 (R1 ) Ph, R2 ) DMB, R3 ) Ph)
22 (R1 ) Ph, R2 ) R3 ) Me)
23 (R1 ) Ph, R2 ) TBS, R3 ) Me)
24 (R1 ) Ph, R2 ) TBS, R3 ) Ph)
75 (31) 96 (41, R3 ) Ph)
69 (32) nab
67 (33) 87 (40, R3 ) Me)c
24 (34)d 58 (41, R3 ) Ph)e
moieties that have been used to protect sulfonamides.6
Compounds 7 and 8 were prepared in yields of 86 and 70%
by reacting benzylsulfonyl chloride with 1.2 equiv of the
secondary amines 4 and 5 in the presence of 1.2 equiv of
Et3N and cat. DMAP in THF (Scheme 1). The one-step
fluorination procedure that we developed for the fluorination
of sulfonates5a was used for the fluorination of 7 and 8. Thus,
2.2 equiv of NaHMDS was added to a solution of the
sulfonamide containing 2.5 equiv of N-fluorobenzenesulfon-
imide (NFSi) in THF at -78 °C, stirred for 2 h, followed
by warming to rt. This gave the desired difluorinated
compounds 10 and 11 in 76 and 72% yields, respectively.
However, conditions that are typically used to remove benzyl
protecting groups from sulfonamides (Pd(OH)2, 45 psi H2
in MeOH6b) failed with 10 with only 4% of the desired
product 13 being formed after 2 days. The PMB group is
typically removed using 50% TFA/CH2Cl2 in about 12 h at
room temperature.6a However, even after being subjected to
80% TFA/CH2Cl2 for 15 h, only 30% of 11 was converted
into 13. Due to the difficulties in removing these groups,
we decided to examine the 2,4-dimethoxybenzyl moiety
(DMB) as a sulfonamide protecting group. Although never
before used for sulfonamide protection, we anticipated that
the DMB group would be more readily removed than the
benzyl and PMB groups. Thus, reaction of benzylsulfonyl
chloride with bis-2,4-dimethoxybenzylamine, 6,7 in the
presence of DMAP in THF gave sulfonamide 9 in 78% yield.
Fluorination of 9 gave fluorosulfonamide 12 in 81% yield.
In this case, deprotection of 12 was readily achieved in 4-5
h using 30% TFA/CH2Cl2 at 0 °C to give 13 in an excellent
yield of 90%. Therefore, the DMB group was used for all
subsequent studies.
a Sulfonamides 15-21 were prepared by reacting the sulfonyl chlorides
with secondary amines 6, N,N-methyl-2,4-dimethoxybenzylamine, or N,N-
phenyl-2,4-dimethoxybenzylamine in the presence of DMAP and or Et3N
in THF. Sulfonamides 23 and 24 were prepared by reacting N-methyl- or
N-phenylbenzylsulfonamide with KH and 18-C-6 followed by the addition
of TBDMSCl. See the Supporting Information for details. b na ) not
applicable. c Deprotection achieved using 1 N HCl/THF d Loss of the TBS
group occurred during fluorination. e Formed during fluorination reaction.
procedure but with n-BuLi or LDA yielded mainly mono-
fluorinated product 14 in 39 and 59% yield, respectively.
LiHMDS gave 69% 12 and 12% 14 while NaHMDS and
KHMDS gave exclusively difluoro product in yields of 81
and 90%, respectively. The yield increases with the size of
the cation. This may be due to the larger cations being less
strongly bound to the anion.
Using the above procedure, a variety of tertiary benzylic
sulfonamides bearing the DMB group (Table 1, 15-21) were
fluorinated in good to excellent yield as did the N,N-
dimethylsulfonamide 22. We also examined the TBS group
as a protecting group using N-TBS-N-methyl- and N-TBS-
N-phenylsulfonamides 23 and 24 as model substrates. In the
case of 24, the TBDMS group was partially removed during
the fluorination reaction yielding 24% and 58% of both
protected, 34, and deprotected, 41, products, respectively.
However, the TBS group in methyl derivative 23 was
retained during the fluorination reaction and gave the desired
product 33 in a 67% yield. Deprotection of DMB-protected
compounds 25-31 using 30% TFA/CH2Cl2 proceeded
smoothly in most cases giving primary (35-39) or secondary
(40 and 41) sulfonamides in good to excellent yields, the
exception being the 4-Me derivative (38) which gave the
desired product in 56%. The TBS group from 33 was
removed in 87% yield using 1 N HCl in THF.
The fluorination reaction was found to be dependent upon
the base and cation. Fluorination of 9 using the above
(5) (a) Leung, C.; Lee, J.; Meyer, N.; Jia, C.; Grzyb, J.; Liu, S.; Hum
G.; Taylor, S. D. Bioorg. Med. Chem. 2002, 10, 2309-2323. (b) Liu, S.;
Dockendorf, C.; Taylor, S. D. Org. Lett. 2001, 3, 1571-1574. (c) Kotoris,
C.; Chen, M.-J.; Taylor, S. D. J. Org. Chem. 1998, 63, 8052-8057.
(6) (a) Morris, J.; Wishka, D. G. J. Org. Chem. 1991, 56, 3549-3556.
(b) Burlingham, B. T.; Widlanski, T. S. J. Am. Chem. Soc. 2001, 123, 2937-
2945.
Dianions of secondary sulfonamides have been R-alkylated
in good yield by subjecting the sulfonamides to 2 equiv of
n-BuLi at -78 °C, warming to 0 °C for 1 h followed by the
addition of 1 equiv of an electrophile at - 78 °C.8 However,
electrophilic fluorination of secondary sulfonamides 42 and
(7) Katrizky, A. R.; Zhao, X.; Hitchings, G. J. Synthesis 1991, 703-
708.
4286
Org. Lett., Vol. 6, No. 23, 2004

Scheme 2
Scheme 4
43 under these conditions (2.2 equiv of n-BuLi, 2.5 equiv
of NFSi) gave only monofluorinated products 44 and 45 and
in low yield (Scheme 2).9 In the case of the methyl derivative
we were also able to isolate compound 46 which resulted
from the attack of the amide anion on the sulfur of NFSi
and partly account for the low yields of these reactions.
Addition of HMPA or employing other bases, even in
considerable excess, did not result in an increase in the yield
of any fluorinated products. Therefore, the most effective
route to R-fluoro secondary sulfonamides appears to be
protection of the secondary sulfonamides followed by
fluorination and deprotection (e.g., compounds 40 and 41,
Table 1).
respectively (Scheme 3). This approach to difluorination is
similar to that taken by Differding, who also found it
necessary to purify and then fluorinate the monofluoro
products during the synthesis of R,R-difluoroalkyl phospho-
nates using NFSi.10
We also examined the fluorination of nonbenzylic tertiary
sulfonamides using ethyl, propyl and isopropyl derivatives
47-49 as model substrates (Scheme 3). Fluorination of
Electrophilic fluorination of cyclic sulfonamides (sultams)
was examined using compounds 59 and 60 as model systems,
which were prepared using a procedure recently described
by Lee et al. (Scheme 4).11 For the nonbenzylic sultam 59,
electrophilic fluorination using the conditions described
above for the monofluorination of alkyl sulfonamides gave
compound 61 in just 18% yield, as well as trace amounts of
the difluoro compound 62. A byproduct was also isolated in
10% yield, which was identified as compound 63 and
resulted from the reaction of the carbanion with the sulfur
of NFSi.12 Using 1.2 equiv of LDA as base, we were able
to obtain monofluoro product 61 in a 25% yield; however,
the amount of byproduct 63 increased also to 14%. Fluorina-
tion of the benzylic cyclic sulfonamide 60 using 2.0 equiv
of NaHMDS, 2.2 equiv of NFSi, in THF at -78 °C to rt,
proceeded smoothly giving the monofluoro product 64 in a
90% yield as a mixture of diastereomers (ratio: 1:1.7).
Deprotection using our usual conditions gave sultam 65 in
a low 22% yield. However, by using 10% TFA and adding
the cation scavenger, iPr3SiH, the yield of 65 was increased
to 77%.
Scheme 3
ethylsulfonamide 47 employing the one-step procedure using
NaHMDS, KHMDS, or n-BuLi was unsuccessful. However,
when the reaction was performed in the presence of 1.2 equiv
of n-BuLi, 2.5 equiv of NFSi, and 5 equiv of HMPA, the
monofluorinated product 50 could be obtained in a respect-
able 60% yield (Scheme 3). Applying these conditions to
n-propylsulfonamide 48, the monofluorinated product 51 was
obtained in 69% yield. However, under these conditions, the
isopropyl compound 52 was obtained in only a 14% yield.
Nevertheless, the yield of 52 could be improved to 41% by
adding 2.2 equiv of t-BuOK. Fluorination of the purified
monofluoro species 50 and 51 using the same procedure gave
the difluoro products 53 and 54 in 33% and 50% yields,
(9) Under these conditions, except using MeI as electrophile, we could
readily R-methylate secondary sulfonamides in 60-70% yields.
(10) Differding, E.; Duthaler, R. O.; Kreiger, A.; Ruegg, G. M.; Schmit,
C. Synlett 1991, 395-396.
(11) Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett. 2003, 5,
4175-4177.
(12) A comparison of the 19F NMR of compound 63 with the 19F NMR’s
obtained from the crude reaction mixtures from the fluorination of
compounds 47 and 48 suggested that similar byproducts were formed during
the fluorination of 47 and 48. However, we were unable to isolate these
byproducts in pure form to confirm this. These results may account for the
lower yields obtained with the alkyl derivatives compared to the benzylic
derivatives.
(8) For example see: Thompson, M. E. J. Org. Chem. 1984, 49, 1700-
1703.
Org. Lett., Vol. 6, No. 23, 2004
4287

by keeping the reaction at - 78 °C. Warming to room
temperature resulted in a decrease in yield due to an increase
in unidentified byproducts. Finally, deprotection of 69 using
TFA/CH2Cl2 gave 2 in a 69% yield.13
Scheme 5
In summary, a variety of R-fluorosulfonamides have been
prepared by electrophilic fluorination of R-carbanions of
sulfonamides using NFSi as fluorinating agent. Benzylic
sulfonamides are generally fluorinated in higher yields than
nonbenzylic sulfonamides. To our knowledge, this is the first
report describing the electrophilic fluorination of sulfon-
amides. We expect that this procedure will be very useful
for the preparation of new fluorinated sulfonamides with
useful biological properties. Also of note is the first use of
the DMB group as a protecting group for sulfonamides. This
group is stable to base and nucleophiles yet is readily
removed under very mild conditions. We expect that the
DMB group will find widespread use as a protecting group
for sulfonamides in general.
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council (NSERC)
of Canada. We also thank Merck-Frosst Canada & Co. for
financial support and the Government of Ontario for a
Premiere’s Research Excellence Award to S.D.T.
Finally, compound 2 was prepared according to Scheme
5. 4,7-Dimethylchromen-2-one was selectively brominated
at the 7-methyl group to give 66 in 89% yield using NBS.
Conversion of bromide to the sulfonate 67 was achieved in
76% yield using sodium sulfite. Treatment of 67 with SOCl2/
cat. DMF and reaction of the resulting sulfonyl chloride with
amine 6 gave sulfonamide 68 in a 62% yield. Subjecting 68
to 2.5 equiv of NaHMDS and NFSi at - 78 °C gave difluoro
compounds 69. Unlike our previous fluorination of benzylic
sulfonamides, the best yield for the fluorination was achieved
Supporting Information Available: Preparation proce-
dures and characterization data for 2 and 7-69. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048249Z
(13) Inhibition studies with compound 2 and ES will be reported
elsewhere.
4288
Org. Lett., Vol. 6, No. 23, 2004