Superelectrophilic activation in superacid HF/SbF5 and synthesis of benzofused sultams

Article abstract of DOI:10.1021/ol9029287

(Figure Presented) The synthesis of benzofused sultams and/or fluorlnated sulfonamides, starting from N-allyllc sulfonamides, was performed In superacid HF/ SbF₅, through superelectrophilic activation. A dramatic effect of superacid composition on the selectivity of the reaction was shown and applied to the synthesis of cyclic 4-aminobenzenesulfonamides.

Full text of DOI:10.1021/ol9029287

ORGANIC
LETTERS
2010
Vol. 12, No. 4
868-871
Superelectrophilic Activation in Superacid
HF/SbF5 and Synthesis of Benzofused
Sultams
Fei Liu,† Agne`s Martin-Mingot,† Marie-Paule Jouannetaud,† Fabien Zunino,‡ and
Se´bastien Thibaudeau*,†
Laboratoire “Synthe`se et Re´actiVite´ des Substances Naturelles”, UMR 6514, 40,
aVenue du Recteur Pineau, F-86022, Poitiers Cedex, France, and @rtMolecule, 40,
aVenue du Recteur Pineau, F-86022 Poitiers Cedex, France
sebastien.thibaudeau@uniV-poitiers.fr
Received December 21, 2009
ABSTRACT
The synthesis of benzofused sultams and/or fluorinated sulfonamides, starting from N-allylic sulfonamides, was performed in superacid HF/
SbF5, through superelectrophilic activation. A dramatic effect of superacid composition on the selectivity of the reaction was shown and
applied to the synthesis of cyclic 4-aminobenzenesulfonamides.
The sulfonamides constitute an important class of drugs with
several types of pharmacological agents possessing antibac-
terial, diuretic, hypoglycemic, antithyroid, and antitumor
activity.1 High interest has also been directed to their cyclic
counterparts, the sultams, with the development of nonste-
roidal antiinflammatory agents2 (e.g., piroxicam), antiepi-
leptic agents3 (e.g., sulthiame), and antiglaucoma agents4
(e.g., brinzolamide). Recently, cyclic sulfonamides have been
shown to display a vast array of biological activities.5 At
the same time, drug candidates with one or more fluorines
have recently become common place.6 Thus, on the basis
of fluorine properties7 and of the development of sulfona-
mides as selective inhibitors of the zinc carbonic anhydrase,
broad-based studies linked increasing acidity of the het-
eroarene sulfonamides and fluoroalkane sulfonamides to their
affinity for carbonic anhydrases.8 Powerful methods have
been developed for sultam synthesis by cyclization protocols,
including Diels-Alder reactions,9a cycloadditions,9b and
transition-metal-catalyzed approaches such as copper-,9c
rhodium-,9d ruthenium-,9e and palladium-catalyzed cycliza-
tion.10 Other methods such as gold-catalyzed hydroamina-
† Laboratoire “Synthe`se et Re´activite´ des Substances Naturelles”.
‡ @rtMolecule.
(1) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr.
Med. Chem. 2003, 10, 925, and references cited therein.
(2) Rabasseda, T.; Hopkins, S. J. Drugs Today 1994, 30, 557.
(3) Tanimukai, H.; Inoui, M.; Hariguchi, S.; Kaneko, Z. Biochem.
Pharmacol. 1965, 14, 961.
(7) O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308, and references cited
therein.
(8) Blackburn, G. M.; Tu¨rkmen, A. Org. Biomol. Chem. 2005, 3, 225,
and references therein.
(9) (a) Rogatchov, V. O.; Bernsmann, H.; Schwab, P.; Fro¨hlich, R.;
Wibbeling, B.; Metz, P. Tetrahedron Lett. 2002, 43, 4753. (b) Chiacchio,
U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi, G.; Piperno, A.;
Privitera, T.; Romeo, G. Tetrahedron 2001, 57, 3425. (c) Dauban, P.;
Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707.
(d) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem.
2004, 69, 6377. (e) Jime´nez-Hopkins, M.; Hanson, P. R. Org. Lett. 2008,
10, 2223.
(4) Silver, L. H. Am. J. Ophtalmol. 1998, 126, 400.
(5) For recent examples please see: (a) Thiry, A.; Dogne´, J.-M.; Supuran,
C. T.; Masereel, B. Curr. Pharm. Des. 2008, 14, 661. (b) Supuran, C. T.
Curr. Pharm. Des. 2008, 14, 641.
(6) (a) Purser, S.; Moore, P. M.; Swallow, S.; Gouverneur, V. Chem.
Soc. ReV. 2008, 37, 320. (b) Be´gue´, J.-P.; Bonnet-Delpon, D. J. Fluorine
Chem. 2006, 127, 992. (c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(d) Morgenthaler, M.; Schweiser, E.; Hoffman-Roder, F.; Benini, F.; Martin,
R. E.; Jaeschke, G.; Wagner, B.; Fisher, H.; Bendels, S.; Zimmerili, D.;
Schneider, J.; Hiedrich, F.; Kansy, M.; Muller, K. Chem. Med. Chem. 2007,
2, 1100. (e) Hagmann, W. H. J. Med. Chem. 2008, 51, 4359.
(10) (a) Majumdar, K. C.; Mondal, S.; De, N. Synthesis 2009, 18, 3127,
and references therein. (b) Rayabarapu, D. K.; Zhou, A.; Jeon, K. O.;
Samarakoon, T.; Rolfe, A.; Siddiqui, H.; Hanson, P. R. Tetrahedron 2009,
65, 3180.
10.1021/ol9029287  2010 American Chemical Society
Published on Web 01/15/2010

tion,11 hydrogenation of N-sulfonylimines,12 or Friedel-Crafts
reactions13 are also used. However, in the recently reported
copper-catalyzed intramolecular carboamination, through an
oxidative cyclization process,14 no cyclization process start-
ing from simple N-allylic sulfonamides has been reported
to access benzofused sultams. We have recently reported the
first hydrofluorination of unsaturated amines in superacid.15
After polyprotonation and formation of a dicationic am-
monium-carbenium superelectrophile,16 fluorination led to
the corresponding ꢀ-fluoroamines. Interestingly, a competi-
tion between the fluoride ions of the media and the aromatic
sulfonamide was shown. Starting from N-tosyl-protected
allylic amine, the corresponding benzofused sultam was
formed in good yield. Owing to the ability to form
ammonium-carbenium dications, able to react either in an
intramolecular way with strongly deactivated aromatic ring
(sulfonamide) or with fluoride ions in an intermolecular way,
we conceived that superelectrophilic activation in superacid
HF/SbF5 might be used as a powerful synthetic method
toward either benzofused sultams or fluorinated sulfonamide
synthesis.
of the medium was lower,17 by decreasing SbF5 content, the
cyclization process decreased in favor of the hydrofluorina-
tion reaction (Table 1, entry 2). Moreover, when the acidity
of the medium increased, sultam 2a was formed in 64%
yield, and no traces of fluorinated products could be detected
in the crude reaction mixture (Table 1, entry 3).
It has to be noted that in all cases a deallylation process
also occurred to give p-chlorobenzenesulfonamide as a side
product of the reaction.18 To test whether a dilution effect
could influence the intramolecular cyclization, variation of
the substrate’s concentration was studied. As expected, higher
dilution afforded sultam in better yield, and by using 0.16
mol·L-1 concentration of substrate, sultam 2a could be
obtained in 67% yield (Table 1, entry 5). Thus, starting from
N-allylic sulfonamide, sultam or ꢀ-fluorinated product could
be selectively obtained in optimized conditions: Friedel-Crafts
intramolecular cyclization c ) 0.16 mol·L-1, % mol SbF5 )
13.6, -20 °C, 10 min (condition A); hydrofluorination c )
0.33 mol·L-1, % mol SbF5 ) 3.8, -20 °C, 10 min (condition
B). Taking into account the preliminary results, we postulated
the following mechanism (Scheme 1). Protonation of the
First, a study was performed to investigate whether the
variation of the reaction conditions could influence the
reaction course and could allow the selective formation of
the desired sultams or the fluorinated sulfonamides. Our
initial experiments showed that N-allylic-p-chlorobenzene-
sulfonamide 1a yielded sultam 2a and ꢀ-fluoro product 3a
after reaction in HF/SbF5 (Table 1, entry 1). When the acidity
Scheme 1. Reaction of 1a in Superacid HF/SbF5
sulfonamide function19 and the double bond of substrate 1a
in superacid gives the dication A, which undergoes fluorina-
tion and leads to ammonium B, the precursor of the
fluorinated product 3a after hydrolysis. To explain the
selective formation of sultam, a usual Friedel-Crafts type
process involving the superelectrophile A could be reason-
ably postulated. Then, we investigated whether the fluori-
nated derivative could be considered as an intermediate in
the cyclization process. Starting from fluoroderivative 3a,
after reaction in cyclization conditions, sultam 2a was formed
quantitatively, a result which confirmed our hypothesis.
However, to discuss the displacement of equilibrium (I)
toward ammonium-carbenium A in cylization condition, the
composition of the media has to be analyzed.
Table 1. Competition between Intramolecular Friedel-Crafts
and Hydrofluorination Reactions in Superacida
concentrationb
acidity
(% mol SbF5)
entry
(mol·L-1
)
products (yield)c
1
2
3
4
5
0.33
0.33
0.33
0.66
0.16
8.4
3.8
27
13.6
13.6
2a (55)
2a (13)
2a (64)
2a (49)
2a (67)
3a (17)
3a (71)
3a (0)
3a (0)
3a (0)
a 10 min reaction time at -20 °C. b Substrate concentration. c After
column chromatography.
Extensive reported studies of ionic composition in HF/
SbF5 solutions led to the accepted following conclusions.17
-
For SbF5 concentration lower than 10 mol %, SbF6 is
+
practically the only anionic species present, and H3F2 is
(11) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707.
(12) Yu, C.-B.; Wang, D.-W.; Zhou, Y.-G. J. Org. Chem. 2009, 74,
5633, and references cited therein.
(17) (a) Bonnet, B.; Mascherpa, G. Inorg. Chem. 1980, 19, 785. (b)
Mootz, D.; Bartmann, K. Angew. Chem., Int. Ed. Engl. 1988, 27, 391. (c)
Culmann, J.-C.; Sommer, J. J. Am. Chem. Soc. 1990, 112, 4057. (d)
Culmann, J.-C.; Fauconet, M.; Jost, R.; Sommer, J. New J. Chem. 1999,
23, 863. (e) Sommer, J.; Canivet, P.; Schwartz, S.; Rimmelin, P. New
J. Chem. 1981, 5, 45.
(13) Katritzky, A. R.; Wu, J.; Rachwal, S.; Rachwal, D.; Macomber,
W.; Smith, T. P. Org. Prep. Proced. Int. 1992, 24, 463.
(14) (a) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948.
(b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem.
2007, 72, 3896.
(18) To the best of our knowledge, no similar deallylation has been
encountered yet in superacid. However, Stamm reported a similar behavior
of N-allylsulfonamide in the presence of Lewis acid AlCl3, through in situ
enamide formation. Stamm, H.; Ornitschenko, A.; Buchholz, B.; Mall, T.
J. Org. Chem. 1989, 54, 193.
(15) Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud, M.-P.; Karam,
O.; Zunino, F. Chem. Commun. 2007, 3198.
(16) Olah, G. A.; Klumpp, D. in Superelectrophiles and their chemistry;
John Wiley and Sons: New York, 2008.
Org. Lett., Vol. 12, No. 4, 2010
869

the predominant cationic species. From 10 to 22 mol % SbF5
in HF, the anions are essentially SbF6- and Sb2F11- in slow
equilibrium, and only H3F2+ is observed. Taking into account
these conclusions, we can consider that the nucleophilicity
of the fluoride ion source strongly decreases by SbF5
concentration increase. Furthermore, it has now largely been
shown that increasing the amount of SbF5 increases the
acidity strength of the media. In cyclization conditions, the
fluorinated intermediate B, after protonation and HF elimina-
tion, could give A, which could be trapped by the more
nucleophilic species (aromatic ring) to give dication C,
precursor of the sultam after hydrolysis.
(Table 2, entries 1-3). However, ortho substitution seemed to
disfavor the cyclization (Table 2, entry 4). Deactivation of the
aromatic ring with electron mesomeric withdrawing groups led
only to the formation of fluorinated products, even in cyclization
conditions (Table 2, entries 13-18). As already observed in
superacid,17e methoxy and acetamido groups must be proto-
nated, changing the substituent from electron donor to a
strong attracting one (Table 2, entries 9-12). Surprisingly,
trifluoromethyl substitution did not completely deactivate the
aromatic ring toward substitution, and an equal amount of
sultam and fluorinated product was formed in cyclization
condition (Table 2, entry 5). The divergent synthetic character
of this method was well emphasized by halogen-substituted
substrate behavior. In almost all cases, reaction in cyclization
conditions led exclusively to sultams in good yields, whereas
using fluorination conditions fluorinated sulfonamides were
obtained (Table 2, entries 19-28). The obtained low yields
after reaction of substrate 1n confirmed the versatility of iodo
compounds in superacid.
Then, a variety of substrates with different aromatic patterns
were submitted to the reaction, to evaluate the scope of these
reactions and the influence of the nucleophilic character of the
aromatic ring on the selectivity of the reaction (Table 2). As
Table 2. Selective Sultam Synthesis and Hydrofluorinationa
We also examined the intramolecular Friedel-Crafts
reaction of various substituted sulfonamides, to evaluate if
this methodology could be applied toward the synthesis of
original sultam derivatives (Table 3). The ability to access
sterically hindered sultams was confirmed by the reaction
of sultams 4a and 4b (Table 3, entries 1, 2). When ortho
positions were already substituted with an electron-donating
group, seven-membered ring sultams could also be formed
(Table 3, entry 3). However, the reaction was not selective,
and the formation of a large amount of side products was
observed. Moreover, deactivated substrate 4d was found to
give only fluorinated products 5d and 5′d. As N-(2-
fluoropropyl)-saccharin derivative 5′d probably came from
base-catalyzed cyclization of 4d during a workup proce-
dure,20 hydrolysis time was increased, and fluorinated
saccharin derivative 5′d could be formed quantitatively
(Table 3, entries 4, 5).
entry
substrate
methodb
products (yield)c
2b (64)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
R1 ) Me
R2 ) H
R1 ) H
R2 ) Me
R1 ) CF3
R2 ) H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
b
2b (90)
2c (69)
2c (58)
2d (20)
3c (23)
3d (20)
3d (84)
3e (46)
3e (86)
3f (73)
3f (90)
3g (42)
3g (59)
3h (28)
3h (78)
3i (74)
3i (93)
3j (19)
3j (67)
R1 ) H
R2 ) CF3
R1 ) OMe
R2 ) H
R1 ) NHAc
R2 ) H
R1 ) COCH3
R2 ) H
R1 ) NO2
R2 ) H
R1 ) H
R2 ) CN
R1 ) F
R2 ) H
R1 ) Cl
R2 ) H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1g
1h
1i
In addition, sultam 5f could be formed in excellent yield
starting from methyl-substituted substrate (Table 3, entry 7).
Despite the stabilizing effect of the methyl substituent, the
formed dicationic intermediate still showed a superelectro-
philic character, to give the desired sultam. More notably,
the reaction was applied to the synthesis of a seven-
membered ring sultam 5g in good yield (Table 3, entry 8).
However, the cyclization of phenyl-substituted substrate 4h
was unsuccessful, and the reaction was not possible when
the double bond was too deactivated (Table 3, entries 9, 10).
We also found that 2H-1,2-benzothiazine 1,1-dioxide 5j
could be synthesized after cyclization and elimination in
superacid (Table 3, entry 11). The compatibility of the
superelectrophilic activation reaction with heteroaromatic
sulfonamide was confirmed by the formation of products 5e
and 5′e starting from thiophene substrate 4e. Original
electrophilic substitution on the 3-position of the thiophene
occurred,21 probably due to the stabilizing effect of the
formation of a six-membered ring product in this case (Table
3, entry 6).
1j
1k
1a
1l
2k (54)
2a (67)
2l (55)
3k (88)
3a (71)
R1 ) Br
R2 ) H
R1 ) H
R2 ) Cl
R1 ) I
R2 ) H
3l (42)
3m (16)d
3m (63)
1m
1n
2n (25)d
3n (39)d
a 10 min reaction time at -20 °C. Method A: c ) 0.16 mol·L-1, %
mol SbF5 ) 13.6. Method B: c ) 0.33 mol·L-1, % mol SbF5 ) 3.8 c After
column chromatography. d Side product formation.
expected, the inductive donating methyl group increased the
nucleophilic character of the aromatic ring, leading to the
exclusive formation of sultams, even in fluorination conditions
On the basis of these results, we show that superelectro-
philic activation in superacid could be a convenient method
870
Org. Lett., Vol. 12, No. 4, 2010

In addition to chemical libraries of sulfonamide compounds,
efforts have to be made to access rapidly and efficiently a
large variety of original cyclic sulfanilamide analogues. The
absence of cyclic product formation starting from substrate
1g (Table 2, entries 11, 12) led us to find an alternative
toward 4-aminobenzofused sultam. A three-step procedure
allowed the formation of 4-aminobenzofused sultam in
overall good yield (Scheme 2). Starting from N-allylic
Table 3. Reaction of Substituted Sulfonamides in Superacida
Scheme 2. 4-Aminobenzofused Sultam Synthesis
4-fluorobenzene sulfonamide 1k, superacid intramolecular
cyclization led to sultam 2k in 54% yield. N-Methylation
followed by a nucleophilic aromatic substitution of the
fluorine atom with morpholine or octylamine (secondary or
primary amine) yielded compounds 6k (88% yield) and 6′k
(74% yield).
In conclusion, superelectrophilic activation in superacid
has been demonstrated to be an efficient and divergent novel
method to access either benzofused sultams or fluorinated
sulfonamides, starting from easily accessible substrates. In
HF/SbF5, the reaction conditions were shown to be crucial
for the selective formation of novel original sultam synthesis.
A mechanism strongly based on the influence of the acidity
and, so, on the influence of the nucleophilic character of
fluoride ions source was postulated. We have also provided
evidence that this chemistry could be used as a real synthetic
tool, consistent with a multistep procedure. The ability to
use this strategy toward the divergent synthesis of potent
bioactive compounds was evaluated, and preliminary research
is now focused in this area.
a 10 min, - 20 °C, c ) 0.16 mol·L-1, % mol SbF5 ) 13.6. b After
column chromatography. c Molar ratio determined by 1H NMR. d Side
products formation. e Hydrolysis time: 24 h. f Complex mixture. g No
reaction.
Acknowledgment. We thank the region Poitou-Charentes
(grant to F.L.), the CNRS, and the University of Poitiers for
financial support and Ross Tudor for helpful discussions.
Supporting Information Available: Experimental pro-
cedure, product characterization, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
for the expeditious synthesis of original sultams. Then, we
focused on the ability to use this methodology to access
aminobenzene sulfonamides. Since the discovery of sulfa
drugs, the aminobenzene sulfonamide core became very
popular in medicinal chemistry research, which led recently
to the discovery of potent antiprotozoal lead compounds.22
OL9029287
(21) According to the 2-substituted thiophene electrophilic aromatic
substitution rules, a sulfonamido group acting as a electron-withdrawing
substituent should cause the substitution on the 4 and 5 positions: Katritzky,
A. R. Handbook of Heterocyclic Chemistry; Pergamon Press Ltd., 1985.
(22) (a) George, T. G.; Endeshaw, M. M.; Morgan, R. E.; Mahasenan,
K. V.; Delfin, D. A.; Mukherjee, M. S.; Yakovich, A. J.; Fotie, J.; Li, C.;
Werbovetz, K. A. Bioorg. Med. Chem. 2007, 15, 6071. (b) Krungkrai, J.;
Krungkrai, S. R.; Supuran, C. T. Bioorg. Med. Chem. Lett. 2008, 18, 5466,
and references cited therein.
(19) (a) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268. (b) Menger,
F. M.; Mandell, L. J. Am. Chem. Soc. 1967, 89, 4424. (c) Bagno, A.;
Bujnicki, B.; Bertrand, S.; Comuzzi, C.; Dorigo, F.; Janvier, P.; Scorrano,
G. Chem.sEur. J. 1999, 5, 523.
(20) Similar reaction has been reported on the N-alkyl sulfonamide
derivative: Robinson, R. I.; Fryatt, R.; Wilson, C.; Woddward, S. Eur. J.
Org. Chem. 2006, 4483.
Org. Lett., Vol. 12, No. 4, 2010
871