Superacid mediated reactions applied to 4-aminobenzofused sultams and fluorinated 4-aminobenzene sulfonamides synthesis

Article abstract of DOI:10.1016/j.tet.2010.06.095

A novel series of 4-aminobenzofused sultams was prepared using an efficient synthetic procedure based on superacid mediated reactions followed either by copper-catalyzed coupling or S_NAr reactions. The synthetic potential of the method toward the divergent synthesis of novel potent bioactive (fluorinated) aminobenzofused sultams and fluorinated 4-aminobenzene sulfonamides was shown, making it a new valuable process to synthesize a large diversity of compounds in bioactive 4-aminobenzene sulfonamide family.

Full text of DOI:10.1016/j.tet.2010.06.095

Tetrahedron 66 (2010) 7112e7118
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Superacid mediated reactions applied to 4-aminobenzofused sultams
and fluorinated 4-aminobenzene sulfonamides synthesis
*
Fei Liu, Neil Y. Musadji, Frédéric Lecornué, Marie-Paule Jouannetaud, Sébastien Thibaudeau
Université de Poitiers- UMR 6514-Laboratoire ‘Synthèse et Réactivité des Substances Naturelles’, 40, avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2010
Received in revised form 29 June 2010
Accepted 30 June 2010
Available online 6 July 2010
A novel series of 4-aminobenzofused sultams was prepared using an efficient synthetic procedure based
on superacid mediated reactions followed either by copper-catalyzed coupling or SNAr reactions. The
synthetic potential of the method toward the divergent synthesis of novel potent bioactive (fluorinated)
aminobenzofused sultams and fluorinated 4-aminobenzene sulfonamides was shown, making it a new
valuable process to synthesize a large diversity of compounds in bioactive 4-aminobenzene sulfonamide
family.
Keywords:
Superacid
Ó 2010 Elsevier Ltd. All rights reserved.
Superelectrophile
Copper-catalyzed
Sulfonamide
Fluorine
1. Introduction
Since the discovery of antibiotic and antibacterial properties of
sulfa drugs,1 sulfanilamide core became very popular in SAR studies
in medicinal chemistry research. The role of 4-aminobenzene sul-
fonamide substrates in matrix metalloprotease inhibition,2 carbonic
anhydrases inhibition,3 HIV protease inhibition4 or pyruvate kinase
isozyme activation5 has been largely proved. Sulfanilamides are
classically prepared from aniline derivatives, by chlorosulfonylation
method after N-acetylation.6 Even if this method has been largely
used, it requires four synthetic steps, due to the inevitable nitrogen
protection and deprotection,7 and harshness conditions (sulfony-
lation with concentrated sulfuric acid or oleum and chlorination
with phosphorus pentachloride). Surprisingly, in spite of the re-
cently reported very specific palladium-catalyzed transfer hydro-
genation of nitrobenzene sulfonamide,8 palladium-catalyzed
intramolecular cyclization,9 or Grignard-based sulfonamide syn-
thesis from 4-bromoaniline,10 no general route to 4-aminobenzene
sulfonamides has been reported. As a consequence, the diversity of
aminobenzene sulfonamide functionality in pharmaceutical re-
search is limited. Based on superelectrophilic activation11 in
superacid,12 we recently reported an extension of our work on un-
saturated nitrogen containing compounds behavior in HF/SbF5,13
toward the synthesis of benzofused sultams and fluorinated
benzenesulfonamides (Scheme 1).14
Scheme 1. Benzofused sultams and fluorinated benzenesulfonamides synthesis in
superacid HF/SbF5.
However, the synthesis of 4-aminobenzofused sultams from cor-
responding 4-aminosulfonamides (R¼NR1R2) could not be achieved
by using our methodology. To circumvent this problem, starting from
4-fluorosulfonamide (R¼F), we envisaged to use a sequential super-
acid/SNAr strategy. Herein we report, the extension of this work and
the development of alternative routes to novel 4-aminobenzofused
sultams and fluorinated 4-aminobenzene sulfonamides.
2. Results and discussion
Starting from N-allylic benzenesulfonamides A, substituted in
para position with an halogen atom, after either intramolecular
FriedeleCrafts type cyclization or hydrofluorination reaction in
superacid HF/SbF5, benzofused sultams B or fluorinated benzene-
sulfonamides C should be formed selectively. Then N-alkylation
followed by nucleophilic aromatic substitution should allow the
formation of a high diversity of 4-aminobenzofused sultams D and
fluorinated 4-aminobenzene sulfonamides E (Scheme 2).
* Corresponding author. Tel.: þ33 549454588; fax: þ33 549453501; e-mail
address: sebastien.thibaudeau@univ-poitiers.fr (S. Thibaudeau).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.095

F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
7113
Scheme 2. Synthesis of 4-aminobenzofused sultams and fluorinated 4-aminobenzene sulfonamides.
Whereas nucleophilic aromatic substitution on 4-nitro-
fluoroaromatics is a reaction of broad applicability, activation by
electron withdrawing groups other than nitro is less used. This is
mainly due to the decreased ability to stabilize the negative charge
in the intermediate anion during the SNAr process. By comparing
the sp-values of nitro group (1.27) versus SO2NMe2 (0.99),15 it is not
surprising that reports on replacement of fluorine (or halogen
atom) with nitrogen on 4-halogenobenzene sulfonamides are rare
despite the enormous biological potential of the sulfanilamide
derivatives.16 Thus, we examined carefully the SNAr reaction of the
proposed strategy (Table 1).
a large mixture of compounds, and only a small amount of desired
product could be obtained (Table 1, entry 3). As the acidity of the
sulfonamide proton could probably allow the formation of the
corresponding anion in the basic conditions, preventing substrate
from the nucleophilic aromatic substitution, corresponding
N-methyl sultam 2 was subjected to reaction in similar conditions
(Table 1, entry 4). Even if the reaction became selective, its rate was
found to be very slow. After 5 days of reaction, the desired product
6 could only be obtained in 16% yield. However, using neat condi-
tions, with an excess of morpholine (5 equiv), allowed the forma-
tion of product 5 in 54% yield (Table 1, entry 5). By increasing
reaction time, product 5 could be formed in 91% yield, and only 2
days of reaction were necessary to fully convert N-methyl analog 2
to product 6 (88% yield) in the same reaction conditions (Table 1,
entries 10e11). Similar conditions were also applied to bromo and
chloro derivatives. Not surprisingly, product 5 was formed in very
low yield starting from chloroderivative, and thus after prolonged
reaction time (30 days). The reaction did not occur with bromo
substituted substrate 4. This study confirmed the necessity to
perform N-alkylation of the sulfonamide function before per-
forming the SNAr reaction and allowed us to find optimized
conditions.
Then, starting from N-allyl-4-flurobenzene sulfonamide, by
using the proposed strategy, compounds of type D and E were
synthesized (Scheme 3). Selective superelectrophilic activated
intramolecular FriedeleCrafts type reaction gave the correspond-
ing sultam in 54% yield, which was subsequently N-methylated
with methyliodide to afford compound 2 in 95% yield. N-Alkylated
sultam 2 was subjected to the SNAr reaction with morpholine to
give the 4-aminobenzofused sultam 6 in 88% yield. The compati-
bility of the SNAr reaction with primary amines was also tested.
The reaction of sultam 2, in the presence of octylamine, gave
product 7 in 74% yield. Starting from the same substrate, by
modifying superacid reaction conditions, the hydrofluorination
reaction yielded corresponding fluorinated sulfonamide in 88%
yield. A subsequent N-methylation led to the formation of product
Table 1
Nucleophilic aromatic substitution of 4-halogenated benzofused sultams with
morpholinea
O
NH
N R1
SO2
N R1
SO2
X
O
N
Entry
X
R1
Substrate
Time
Product
Yieldb
1
2
3
4
F
F
F
F
H
H
H
Me
H
H
H
H
H
1
1
1
2
1
3
3
3
4
1
2
12 h
72 h
120 h
120 h
48 h
dc
dc
5
dc
dc
5%
6
16%
54%
dc
5d
6d
7d
8d
9d
10d
11d
F
5
Cl
Cl
Cl
Br
F
48 h
dc
120 h
30 days
124 h
120 h
48 h
5
7%
5
15%
dc
dc
H
Me
5
6
91%
88%
F
a
Reaction conditions: morpholine (1 equiv), K2CO3, DMSO, reflux.
Yields obtained after purification by flash-chromatography.
No reaction.
Morpholine (5 equiv), neat, 100 ꢁC.
b
c
d
Using morpholine as nucleophilic partner, and various sultams
as substrates, we evaluated the ability to perform the SNAr reaction.
First attempts, with fluorinated sultam 1 were unsuccessful (Table
1, entries 1 and 2). By increasing reaction time, the reaction led to
8. Then, fluorinated compound
8 was treated with either
Scheme 3. Reagents and conditions: (a) HF/SbF5 (mol %SbF5¼13.6), ꢀ20 ꢁC, 10 min, 54%; (b) CH3I (1 equiv), K2CO3, DMF, rt, 12 h, 95%; (c) morpholine (5 equiv), reflux, 48 h, 88%;
(d) octylamine (5 equiv), reflux, 72 h, 74%; (e) HF/SbF5 (mol %SbF5¼3.8), ꢀ20 ꢁC, 10 min, 88%; (f) CH3I (1 equiv), K2CO3, DMF, rt, 12 h, 95%; (g) morpholine (5 equiv), reflux, 48 h, 76%;
(h) octylamine (5 equiv), reflux, 48 h, 76%.

7114
F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
morpholine or octylamine, and gave, respectively, products 9 and
10 in good yields. However, despite the efficiency of this superacid-
based multistep divergent synthesis of 4-aminobenzene sulfon-
amides, the SNAr reaction is the critical step of this synthetic
method. The nucleophilic aromatic substitution with sensitive
amines could not be achieved by using these conditions, and using
a large excess of amine could be a limitation with more elaborated
amines. As a consequence, we explored the ability to find an al-
ternative to the SNAr step. Despite the high efficiency of the Pd-
catalyzed BuchwaldeHartwig reaction,17 the use of expensive
palladium and elaborate phosphine ligands would limit its appli-
cation to large scale production. Recently, the attractiveness of
cheap copper catalysts and the availability of copper ligands led to
the resurgence of interests in copper-catalyzed Ullman-type
reactions.18 However, to the best of our knowledge the examples of
perform the reaction (Table 2, entry 7). By increasing the amount of
the catalytic system, compound 6 was formed in 56% yield (Table 2,
entries 8 and 9). After decreasing the dilution and using 15 mol % of
CuI and 30 mol % of L-proline, optimized conditions were found
(Table 2, entries 10 and 11). It is noteworthy that the base modifi-
cation (K2CO3, Cs2CO3) had no positive effect on the reaction.
We next extended the scope of the reaction to various amine
derivatives (Table 3). We found that the reaction was applicable to
a broad range of derivatives. The coupling reactions were per-
formed well for the secondary amines (Table 3, entries 1e3). In
addition, primary amines were found to be compatible with the
reaction (Table 3, entries 4e6).
Table 3
CuI-Catalyzed coupling reaction of sultam with aminesa
aminobenzene sulfonamides synthesis via
a copper-catalyzed
N-arylation approach are relatively rare.19 In these cases, micro-
wave or high temperature conditions were needed to perform the
reaction and ortho sulfonamide substituent seemed to favor the
reaction.20 We therefore sought to investigate whether superacid
chemistry combined to copper-catalyzed Ullman-type N-arylation
could become an alternative to the previously described strategy.
The investigation was initiated by evaluating the coupling
reaction of 4-brominated sultam 11, product of FriedeleCrafts
intramolecular superacid reaction (Scheme 1, structure of type B
with R¼Br), with morpholine as a model reaction, to screen several
reaction parameters, such as temperature, ligand, solvent, and
catalyst amount (Table 2). First, a test reaction without copper-li-
gand system confirmed that classical SNAr reaction did not occur.
Entry
1
Amine
Product
Yieldb (%)
70
6
2
12
87
3
4
13
7
63
62c
5
6
14
15
71c
32c,d
Table 2
Optimization of the Ullmann-type couplinga
7
8
d
d
de
de
Entry
CuI (mol %)
Ligand (mol %)
Yieldb (%)
9
d
de
1
2
3
4
5
6
d
5
5
5
5
d
dc
dc
dc
12
1,10-Phenantroline (20)
2-Acetylcyclohexanone (20)
Dipivaloylmethane (20)
2-Phenylphenol (20)
N,N-Diethylsalicylamide (20)
10
16
75
22
5
dc
7d
8d
9d
10d
11d
5
L-Proline (10)
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (30)
35
51
0
10
10
10
15
56e
70e,f
70f
11
64f
a
Reaction conditions: substrate (0.34 mmol), CuI (x mol %), ligand (x0 mol %),
morpholine (3 equiv), K3PO4 (2 equiv), DMF (3 mL), 90 ꢁC, 24 h.
b
Yield obtained after purification.
No reaction.
DMSO was substituted to DMF.
Reaction time (72 h).
c
12
13
19
72c,f
65c
d
e
f
Solvent (0.2 mL).
20
21
Then, a series of ligands was screened. By using 5 mol % of CuI
and 20 mol % of ligand, it appeared that neither diamine ligands nor
diketone ones were efficient (Table 2, entries 2e4). The use of
2-phenylphenol allowed to convert substrate to sultam 6 in low
yield (Table 2, entry 5). However, increasing CuI and ligand amounts
did not improve the conversion, and thus even with higher tem-
perature and longer reaction time. Based on the recent reports of
Ma, showing the ability to use aminoacids as ideal promoters in the
CuI-catalyzed coupling reaction of aryl halides with amines,21 we
14
NH3 (aq)
81f
a
Reaction conditions: substrate (0.34 mmol), CuI (15 mol %),
amine (3 equiv), K3PO4 (2 equiv), DMSO (0.3 mL), 90 ꢁC, 24 h.
L-proline (30 mol %),
b
Yield obtained after purification.
Cs2CO3 was substituted to K3PO4.
Side products formation.
No reaction.
c
d
e
f
Reaction time: 72 h.
evaluated the catalytic activity of CuI/
attempt confirmed that this catalytic system could be efficient to
L
-proline system. The first
It is noteworthy that for primary amines, the use of Cs2CO3 was
preferred to K3PO4. As previously observed in Ullman-type

F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
7115
sultams. To the best of our knowledge, multistep synthesis in-
volving HF/SbF5 superacid chemistry at several stages has not been
previously done. This method should allow accessing rapidly
a large variety of diversely substituted cyclic or acyclic 4-amino-
benzene sulfonamides D, E or F where R1e3 could be functionalized
alkyl groups and Rf fluorinated alkyl groups. (Scheme 4).
As a model study, N-allyl-4-bromobenzene sulfonamide was used
as a starting material for the synthesis of 4-aminobenzofused sultams
D, fluorinated 4-aminobenzofused sultams E or fluorinated 4-ami-
nobenzene sulfonamides F (Scheme 5). A FriedeleCrafts superacid-
promoted intramolecular reaction afforded sultam 4 in 62% yield.
Aware of the necessity to protect nitrogen atom to perform the cop-
per-catalyzed amination,24 two strategies could be employed at this
stage. The first strategy combined a preliminary N-alkylation (for-
mation of product 11), followed by a copper-catalyzed Ullman-type
reaction and afforded 4-aminobenzofused sultam 6 in good yield.
Then, based on the recently reported deallylation process of
N-allylic sulfonamides in superacid HF/SbF5,14 we examined
a second strategy, with allylic protective group. Starting from the
Scheme 4. Targeted original 4-aminobenzene sulfonamides.
reactions, the choice of the base is dramatically important, but its
effect remains unclear and its choice remained empirical in our
case.22 Interestingly, in a synthetic point of view, allylamine was
found to be an excellent partner for the coupling reaction (Table 3,
entry 5). Despite strong efforts to catalyze the coupling of diamine
and a-aminoacids derivatives (screening of different ligands, ba-
ses, temperature conditions), the reaction of these substrates
remained unsuccessful (Table 3, entries 7e9). Intrigued by these
results, we explored the reaction efficiency with
g-aminoacids
derivatives. In these cases, the catalytic system was found to be
suitable for the formation of corresponding coupling products 16
and 18 (Table 3, entries 10 and 11). In basic conditions, 17 led
probably to the corresponding pyrrolidin-2-one 18 after intra-
molecular cyclization. The observed difference of reactivity,
depending on the distance between amino and carboxyl groups,
might be due to the ability of aminoacids derivatives to play the
role of competitive ligands.21 A similar behavior of amino-
piperidine could also be postulated. By using Cs2CO3 as a base, the
reaction also displayed a great tolerance to aminoalcohol sub-
strates (Table 3, entries 12 and 13). With aminoalcohol substrates,
a full chemoselectivity (N-arylation vs O-arylation) was observed,
probably due to the choice of the ligand.18b Based on the recently
reported elegant CuI-catalyzed amination reactions using aqueous
ammonia,23 we turned our attention to the formation of amino-
product 21. We were pleased to observe the full conversion of
substrate 11 after 3 days reaction, with the formation of desired
product 21 in 81% yield (Table 3, entry 14). With this novel route to
4-aminobenzofused sultam in hand, we tested this strategy in
a multistep superacid-based synthesis of novel functionalized
same substrate,
a FriedeleCrafts superacid-promoted intra-
molecular reaction afforded sultam 4, which was N-protected with
an allylic group (formation of product 22). Then Ullman-type re-
action gave in optimized conditions 4-aminobenzofused sultam 23
in 70% yield. At this stage an original deallylation reaction in HF/
SbF5 afforded product 5 (92% yield). A final N-alkylation gave
product 6 in good overall yield. The ability to introduce the N-alkyl
group at the last stage of the synthesis shows the high synthetic
potential of this strategy. Moreover, the excellent yield obtained
for the coupling reaction of morpholine with N-allylic substrate
should allow delivering efficiently a large variety of 4-amino-
benzofused sultams of type D. Interestingly, by a simple modifi-
cation of superacid conditions, we also proved that fluorinated 4-
aminobenzofused sultams of type F could easily be obtained with
this methodology. Starting from N-allylic compound 23, superacid
mediated hydrofluorination led to fluorinated product 24 in 69%
yield. The potent modifications of fluorinated alkyl group, by using
superacid reactions (hydrofluorination,13a,e bromofluorination,13f
hydroxylation,13a difluorination,13c.), strengthen the high
b
c
N Me
SO2
N Me
SO2
N H
SO2
Br
O
N
O
N
copper
11
6
catalyzed
5
superacid e
b
c
d
NH
N
N
Br
SO2
Br
SO2
22
O
N
SO2
23
copper
4
catalyzed
f
superacid
a
superacid
H
F
N
Br
SO2
N
24
O
N
SO2
superacid
g
H
F
F
F
Me
Me
h
b
N
N
N
9
Br
SO2
Br
SO2
O
N
SO2
copper
26
25
catalyzed
Scheme 5. Superacid/copper mediated multistep divergent synthesis of 4-aminobenzene sulfonamides. Reagents and conditions: (a) HF/SbF5 (mol % SbF5¼13.6), ꢀ20 ꢁC, 10 min,
62%. (b) CH3I, K2CO3, DMF, rt, 12 h, >95% (c) CuI, L-proline, morpholine, K3PO4, DMSO, 90 ꢁC, 24 h, 70%. (d) allylbromide, K2CO3, DMF, rt, 12 h, 83%. (e) HF/SbF5 (mol % SbF5¼27), 0 ꢁC,
10 min, 92%. (f) HF/SbF5 (mol % SbF5¼3.8), ꢀ20 ꢁC, 10 min, 69%. (g) HF/SbF5 (mol % SbF5¼3.8), ꢀ20 ꢁC, 10 min, 42%. (h) CuI, L-proline, morpholine, K3PO4, DMSO, 90 ꢁC, 24 h, 61%.

7116
F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
divergent character of this method and its potential toward orig-
inal fluorinated 4-aminobenzofused sultams synthesis. Encour-
aged by the recently reported Ullman-type reaction of
fluoroalcohols,25 which confirmed the compatibility of fluorinated
substrates with copper-catalyzed reaction, we tested the ability to
synthesize fluorinated 4-aminobenzene sulfonamide of type E by
using a similar strategy. Starting from the same substrate, super-
acid mediated hydrofluorination followed by N-alkylation yielded
fluorinated product 26 in good yield. As previously observed, the
coupling of fluorinated substrate was compatible with the CuI
catalytic system, yielded desired product 9 in 61% yield. Again,
a simple modification of superacid conditions should allow the
formation of a large variety of type E fluorinated novel products.
H2O, dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel.
4.2.1. Compound 6: 2,4-dimethyl-6-morpholin-4-yl-3,4-dihydro-2H-
benzo[1,2] thiazine 1,1-dioxide. Optimized procedure (48 h reaction
time) was followed; purification by flash column chromatography
(1/99,methanol/dichloromethane) gave 260 mg of the title com-
pound as a solid (88%). 1H NMR (400 MHz, CDCl3, ppm): 1.33 (d,
J¼6.8 Hz, 3H, CH3), 2.83 (s, 3H, NCH3), 3.20 (m, 5H, H-30, and H-4),
3.59 (m, 2H, H-3), 3.83 (m, 4H, H-20), 6.70 (s, 1H, H-5), 6.83 (d,
J¼8.8 Hz, 1H, H-7), 7.22 (d, J¼8.8 Hz, 1H, H-8). 13C NMR (100 MHz,
CDCl3, ppm): 19.3 (CH3), 28.2 (CH, C-4), 35.5 (NCH3), 48.1 (2CH2, C-
30), 55.5 (CH2, C-3), 66.6 (2CH2, C-20), 112.8 (CH, C-5), 113.5 (CH, C-
7), 125.2 (C-9), 126.2 (CH, C-8), 141.3 (C-6), 153.6 (C-10). MS (GCT,
CIþ): m/z (relative intensity %) 296 [M]þ (100). HRMS (ESI): calcd
for: (C14H20N2O3NaS) 319.10923, found 319.1090. Melting point
(ꢁC): 120e121.
3. Conclusion
In conclusion, a rapid and versatile novel method, based on se-
quential superacid/copper mediated reactions, for the synthesis of
diversified 4-aminobenzofused sultams is reported. This method
has been extended to a multistep strategy, offering a very attractive
alternative for the synthesis of a large variety of potent novel bio-
active(fluorinated) molecules in aminobenzene sulfonamide family.
Starting from the same substrate, a strong divergent characterof this
method was confirmed with the formation of diversely substituted
cyclic or acyclic fluorinated (or not) 4-aminobenzene sulfonamides.
Moreover, this is the first reported multistep sequence involving
superacid chemistry at different stages. This work emphasizes the
high potential of this original chemistry in organic synthesis.
4.3. General procedure for the CuI-catalyzed reactions of
sultams with amines
A mixture of sultam (0.34 mmol), amine (1 mmol), K3PO4
(0.68 mmol), CuI (0.05 mmol), and the appropriate ligand
(0.1 mmol) in 0.2 mL of DMSO was heated at 90 ꢁC. The cooled
mixture was partitioned between water and ethyl acetate. The or-
ganic layer was separated, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were washed with
H2O, dried over Mg2SO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel.
4. Experimental section
4.3.1. Compound 12: 2,4-dimethyl-6-piperidin-1-yl-3,4-dihydro-2H-
benzo[1,2] thiazine 1,1-dioxide. Optimized procedure (24 h reaction
time) was followed; purification by flash column chromatography
(100%, dichloromethane) gave 87 mg of the title compound as
a solid (87%). 1H NMR(400 MHz, CDCl3, ppm): 1.31 (d, J¼6.8 Hz, 3H,
CH3), 1.64 (m, 6H, H-30 et H-40), 2.82 (s, 3H, NCH3), 3.17 (m, 1H, H-4),
3.25 (m, 4H, H-20), 3.50 (dd, J¼14.4, 5.6 Hz, 1H, H-3), 3.63 (dd,
J¼14.4, 5.6 Hz, 1H, H-3), 6.68 (s, 1H, H-5), 6.81 (dd, J¼8.8, 2.4 Hz, 1H,
H-7), 7.22 (d, J¼9.2 Hz, 1H, H-8). 13C NMR (100 MHz, CDCl3, ppm):
19.2 (CH3), 24.2 (CH2, C-40), 25.3 (2CH2, C-30), 28.1 (CH, C-4), 35.4
(NCH3), 49.0 (2CH2, C-20), 55.5 (CH2, C-3), 112.9 (CH, C-5), 113.7 (CH,
C-7), 123.5 (C-9), 126.1 (CH, C-8), 141.1 (C-10), 153.9 (C-6). MS (GCT,
CIþ): m/z (relative intensity %) 294 [M]þ (100). HRMS (ESI): calcd
for: (C15H22N2O2NaS) 317.1300, found 317.1297. Melting point (ꢁC):
109e110.
4.1. General procedure for the superacid-promoted synthesis
of benzofused sultams
To a mixture of HF/SbF5 (6 mL, 4/2 M ratio) maintained at
ꢀ20 ꢁC, was added nitrogen derivative (1 mmol). The mixture was
magnetically stirred at the same temperature for reaction time. The
reaction mixture was then neutralized with water-ice/Na2CO3,
extracted with dichloromethane (ꢂ3). The combined organic pha-
ses were dried (MgSO4) and concentrated in vacuo. Products were
isolated by column chromatography over silica gel.
4.1.1. Compound 1: 6-fluoro-4-methyl-3,4-dihydro-2H benzo[1,2]
thiazine 1,1-dioxide. Optimized procedure (10 min reaction time)
was followed, starting from 215 mg of N-allyl-4-fluoroben-
zenesulfonamide (1 mmol). Purification by flash column chroma-
tography (70/29.5/0.5: dichloromethane/petroleum ether/NH3 aq)
afforded 117 mg of the title compound as a solid (54%). 1H NMR
(300 MHz, CDCl3, ppm): 1.28 (d, J¼7.1 Hz, 3H, CH3), 2.98 (m,1H, H-4),
3.37 (m,1H, H-3), 3.72 (m,1H, H-3), 5.38 (t, J¼7.0 Hz,1H, NH), 6.94 (m,
2H, H-5, and H-7), 7.64 (m, 1H, H-8). 13C NMR (75 MHz, CDCl3, ppm):
19.4 (s, CH3), 32.2 (s, CH, C-4), 48.4 (s, CH2, C-3),115.4 (d, 2JCeF¼22 Hz,
CH, C-7),115.8 (d, 2JCeF¼22 Hz, CH, C-5),128.1 (d, 3JCeF¼9 Hz, CH, C-8),
4.4. Synthesis of product 24
To a mixture of HF/SbF5 (6 mL, 4/2 M ratio) maintained at ꢀ20 ꢁC,
was added N-allyl-4-bromobenzene sulfonamide (1 mmol). The
mixture was magnetically stirred at the same temperature for re-
action time. The reaction mixture was then neutralized with water-
ice/Na2CO3, extracted with dichloromethane (ꢂ3). The combined
organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification by flash column chromatography over silica gel (70/30:
dichloromethane/petroleum ether) afforded 171 mg of product 4 as
a colorless oil (55%).
4
3
133.5 (d, JCeF¼3 Hz, C-9), 144.1 (d, JCeF¼8 Hz, C-10), 164.7 (d,
1JCeF¼252 Hz, C-6).19F {1H} NMR (282 MHz, CDCl3, ppm): ꢀ105.5. MS
(GCT, CIþ): m/z (relative intensity %) 215 [M]þ (65). HRMS (ESI): calcd
for:(C9H10NO2FS)215.04163, found215.0417. Meltingpoint(ꢁC):93.5.
4.2. General procedure for the SNAr reactions of sultams with
amines
4.4.1. Compound 4: 6-bromo-4-methyl-3,4-dihydro-2H-benzo[1,2]
thiazine 1,1-dioxide. 1H NMR (300 MHz, CDCl3, ppm): 1.27 (d,
J¼7.1 Hz, 3H, CH3), 2.95 (m, 1H, H-4), 3.36 (m, 1H, H-3), 3.72 (m, 1H,
H-3), 5.24 (t, J¼7.6 Hz, 1H, NH), 7.35 (m, 2H, H-5, and H-7), 7.46 (d,
J¼8.9 Hz, 1H, H-8). 13C NMR (75 MHz, CDCl3, ppm): 19.5 (CH3), 31.8
(CH, C-4), 48.3 (CH2, C-3), 125.9 (CH, C-7), 127.1 (C-6), 131.0 (CH, C-
8), 132.0 (CH, C-5), 136.3 (C-9), 142.8 (C-10). MS (GCT, CIþ): m/z
A mixture of sultam (1 mmol), amine (5 mmol), K2CO3 (2 mmol)
was heated at 100 ꢁC for the appropriate reaction time. The cooled
mixture was partitioned between water and ethyl acetate. The or-
ganic layer was separated, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were washed with

F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
7117
(relative intensity %) 275 [M]þ (10), 277 [M]þ (10). HRMS (ESI):
calcd for: (C9H10NO2SNaBr) 297.95133, found 297.9510.
neutralized with water-ice/Na2CO3, extracted with dichloro-
methane (ꢂ3). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. Products were isolated by column
chromatography purification (50/50: dichloromethane/petroleum
ether) to give 250 mg of compound 25 as a solid (42%).
To a suspension of K2CO3 (276 mg, 2 mmol) in DMF (5 mL) was
added dropwise substrate 4 (276 mg, 1 mmol). The mixture was
stirred for 15 min and allylbromide (0.094 ml, 1.1 mmol) was
added. The resulting mixture was stirred for 12 h under an N2 at-
mosphere at room temperature and then partitioned between
EtOAc (50 mL) and water (30 mL). The organic phase was separated
and dried, and then the solvent was removed in vacuo. 262 mg
(83%) of product 22 was isolated by column chromatography pu-
rification (dichloromethane). Then, a mixture of substrate 22
(0.34 mmol), morpholine (1 mmol), K3PO4 (0.68 mmol), CuI
4.5.1. Compound 25: 4-bromo-N-(2-fluoropropyl)-benzenesulfona-
mide. 1H NMR (300 MHz, CDCl3, ppm): 1.30 (dd, J¼23.8, 6.3 Hz, 3H,
H-30), 3.12 (m, 2H, H-10), 4.70 (dm, J¼48.9 Hz, 1H, H-20), 5.07 (m, 1H,
NH), 7.66 (d, J¼8.7 Hz, 2H, H-3), 7.73 (d, J¼8.7 Hz, 2H, H-2). 13C NMR
(75 MHz, CDCl3, ppm): 18.5 (d, J¼22 Hz, CH3, C-30), 48.5 (d, J¼21 Hz,
CH2, C-10), 89.5 (d, J¼167 Hz, CH, C-20), 128.2 (C-4), 128.9 (2CH, C-2),
132.9 (2CH, C-3), 139.3 (C-1). 19F {1H} NMR (282 MHz, CDCl3, ppm):
ꢀ180.4. MS (GCT, CIþ): m/z (relative intensity %) 222 [MꢀCH3CHF]þ
(12), 220 [MꢀCH3CHF]þ (18). HRMS (ESI): calcd for:
(C9H11NO2FSBrNa) 317.9576, found 317.9579. Melting point (ꢁC):
101e102.
(0.05 mmol), and L-proline (0.1 mmol) in 0.2 mL of DMSO was
heated at 90 ꢁC for 24 h. The cooled mixture was partitioned be-
tween water and ethyl acetate. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were washed with H2O, dried over MgSO4, and
concentrated in vacuo. Purification of the residual oil by flash col-
umn chromatography (100%, dichloromethane) gave 77 mg of
compound 23 as a colorless oil (70%).
To a suspension of K2CO3 (138 mg, 1 mmol) in DMF (2 mL) was
added dropwise 25 (148 mg, 0.5 mmol). The mixture was stirred for
15 min and CH3I (0.035 ml, 0.55 mmol) was added. The resulting
mixture was stirred for 8 h under an N2 atmosphere and then
partitioned between EtOAc (50 mL) and water (30 mL). The organic
phase was separated and dried, then the solvent was removed in
vacuo, and 154 mg of the desired compound 26 was obtained as
a solid (>95%). Then, a mixture of substrate 26 (0.34 mmol), mor-
pholine (1 mmol), K3PO4 (0.68 mmol), CuI (0.05 mmol), and
4.4.2. Compound 23: 2-allyl-4-methyl-6-morpholin-4-yl-3,4-dihy-
dro-2H-benzo[1,2] thiazine 1,1-dioxide. 1H NMR (400 MHz, CDCl3,
ppm): 1.29 (d, J¼7.2 Hz, 3H, CH3), 3.10 (m, 1H, H-4), 3.20 (t,
J¼4.8 Hz, 4H, H-30), 3.53 (m, 3H, H-3, and H-200), 3.80 (t, J¼4.8 Hz,
4H, H-20), 3.99 (dd, J¼14.4, 5.2 Hz, 1H, H-200), 5.25 (m, 2H, H-400),
5.80 (s, 1H, H-300), 6.68 (d, J¼2.0 Hz, 1H, H-5), 6.81 (dd, J¼8.8, 2.4 Hz,
1H, H-7), 7.63 (d, J¼8.8 Hz, 1H, H-8). 13C NMR (100 MHz, CDCl3,
ppm): 19.4 (CH3), 29.1 (CH, C-4), 47.9 (2CH2, C-30), 49.9 (CH2, C-30),
51.2 (CH2, C-3), 66.6 (2CH2, C-20), 112.9 (CH, C-5), 113.4 (CH, C-7),
119.5 (CH, C-400), 125.8 (CH, C-8), 126.4 (C-9), 132.9 (CH, C-300), 141.6
(C-6), 153.6 (C-10). MS (GCT, CIþ): m/z (relative intensity %) 345
[MþNa]þ (100). HRMS (ESI): calcd for: (C16H22N2O3NaS) 345.1248,
found 345.1248.
L
-proline (0.1 mmol) in 0.2 mL of DMSO was heated at 90 ꢁC for
24 h. The cooled mixture was partitioned between water and ethyl
acetate. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with H2O, dried over MgSO4, and concentrated in vacuo.
The residual oil was loaded on a silica gel column. Purification by
flash column chromatography (100%, dichloromethane) gave
66 mg of compound 9 as a solid (61%).
To a mixture of HF/SbF5 (3 mL, 7/1 M ratio) maintained at ꢀ20 ꢁC
for 10 min, was added substrate 23 (1 mmol). The mixture was
magnetically stirred at the same temperature for reaction time. The
reaction mixture was then neutralized with water-ice/Na2CO3,
extracted with dichloromethane (ꢂ3). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Products were iso-
lated by column chromatography purification (40/60, ethyl acetate/
petroleum ether) and 236 mg of the compound 24 was obtained as
a colorless oil (69%).
4.5.2. Compound 9: N-(2-fluoro-propyl)-N-methyl-4-morpholin-4-
yl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3, ppm): 1.35 (dd,
J¼23.6, 6.4 Hz, 3H, H-30), 2.79 (s, 3H, NCH3), 3.14 (m, 6H, H-10, and H-
200), 3.84 (t, J¼4.8 Hz, 4H, H-300), 4.83 (dm, J¼48.8 Hz, 1H, H-20), 6.89
(d, J¼9.2 Hz, 2H, H-3), 7.72 (d, J¼9.2 Hz, 2H, H-2). 13C NMR (100 MHz,
CDCl3, ppm): 18.4 (d, J¼22 Hz, CH3, C-30), 36.7 (d, J¼3 Hz, NCH3), 47.5
(s, 2CH2, C-200), 54.9 (d, J¼22 Hz, CH2, C-10), 66.5 (s, 2CH2, C-300), 90.3
(d, J¼168 Hz, CH, C-20), 113.8 (s, 2CH, C-3), 126.5 (s, C-1), 129.1 (s,
2CH, C-2), 153.8 (s, C-4). 19F {1H} NMR (282 MHz, CDCl3, ppm):
ꢀ179.7. MS (GCT, CIþ): m/z (relative intensity %) 339 [MþNa]þ (100),
317 [M]þ (65). HRMS (ESI): calcd for: (C14H21N2O3FNaS) 339.1154,
found 339.1156. Melting point (ꢁC): 103e104.
4.4.3. Compound 24: 2-(2-fluoro-propyl)-4-methyl-6-morpholin-4-yl-
3,4-dihydro-2H-benzo[1,2] thiazine 1,1-dioxide. 1H NMR (400 MHz,
CDCl3, ppm): 1.37 (m, 6H, CH3, and H-300), 3.12 (m, 1H, H-4), 3.23 (t,
J¼5.2 Hz, 4H, H-30), 3.57 (m, 4H, H-100, and H-3), 3.84 (t, J¼4.8 Hz,
4H, H-20), 4.90 (dm, J¼48.4 Hz, 1H, H-200), 6.70 (s, 1H, H-5), 6.82
(dd, J¼8.8, 2.0 Hz, 1H, H-7), 7.67 (d, J¼8.8 Hz, 1H, H-8). 13C NMR
(100 MHz, CDCl3, ppm): 18.0 and 18.6 (2d, J¼22 Hz, C-300), 19.1 and
19.3 (CH3), 29.1 and 29.6 (CH, C-4), 47.9 (s, 2CH2, C-30), 51.9 and
52.0 (2d, J¼21 Hz, CH2, C-100), 54.1 and 54.3 (CH2, C-3), 66.5 (s,
2CH2, C-20), 90.3 and 91.4 (2d, J¼168 Hz, CH, C-200), 112.9 (s, CH, C-
5), 113.3 (CH, C-7), 125.7 and 125.8 (CH, C-8), 126.3 and 126.6 (C-9),
141.6 and 141.7 (C-6), 153.6 (s, C-10). 19F {1H} NMR (282 MHz,
CDCl3, ppm): ꢀ179.4. MS (GCT, CIþ): m/z (relative intensity %) 365
[MþNa]þ (100). HRMS (ESI): calcd for: (C16H23N2O3FNaS) 365.1311,
found 365.1311.
Acknowledgements
We thank the region Poitou-Charentes (grant to F.L.), the CNRS,
and the University of Poitiers for financial support.
Supplementary data
Experimental procedures, products characterization and copies
of NMR spectra. Supplementary data associated with this article
can be found in online version at doi:10.1016/j.tet.2010.06.095.
4.5. Synthesis of product 9
References and notes
To a mixture of HF/SbF5 (3 mL, 7/1 M ratio) maintained at ꢀ20 ꢁC
for 10 min, was added N-allyl-4-bromobenzene sulfonamide
(2 mmol). The mixture was magnetically stirred at the same tem-
perature for reaction time. The reaction mixture was then
1. Antimicrobial Agents: Antibacterials and Antifungals; Bryskier, A., Ed.; ASM:
Washington, 2005.
2. Cheng, X.-C.; Wang, Q.; Fang, H.; Xu, W.-F. Curr. Med. Chem. 2008, 15, 368e373.
3. (a) Supuran, C. T. Nat. Rev. Drug. Discov. 2008, 7, 168e181; (b) Winum, J.-Y.; Rami,
M.; Scozzafava, A.; Montero, J.-L.; Supuran, C. Med. Res. Rev. 2008, 28, 445e463.

7118
F. Liu et al. / Tetrahedron 66 (2010) 7112e7118
4. Stranix, B. R.; Lavallée, J.-F.; Sévigny, G.; Yelle, J.; Perron, V.; LeBerre, N.; Herbart, D.;
15. Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165e195.
16. To the best of our knowledge reports on the replacement of fluorine with
nitrogen on fluorobenzene sulfonamides via SNAr reaction are scarse, please
see: (a) Badetti, E.; Moreno-Manas, M.; Pleixats, R.; Sebastian, R. M.; Serra,
A.; Soler, R.; Vallribera, A. Synlett 2005, 449e452; (b) Sheppard, G. S.; Wang,
J.; Kawai, M.; Fidanze, S. D.; BaMaung, N. Y.; Erickson, S. A.; Barnes, D. M.;
Tedrow, J. S.; Kolaczkowski, L.; Vasudevan, A.; Park, D. C.; Wang, G. T.;
Sanders, W. J.; Mantei, R. A.; Palazzo, F.; Tucker-Garcia, L.; Lou, P.; Zhang, Q.;
Park, C. H.; Kim, K. H.; Petros, A.; Olejniczak, E.; Nettesheim, D.; Hajduk, P.;
Henkin, J.; Lesniewski, R.; Davidsen, S. K.; Bell, R. L. J. Med. Chem. 2006, 49,
3832e3849.
Wu, J. J. Bioorg. Med. Chem. Lett. 2006, 16, 3459e3462 and references cited therein.
5. Boxer, M. B.; Jiang, J.-K.; Vander Heiden, M. G.; Shen, M.; Skoumbourdis, A. P.;
Southall, N.; Veith, H.; Leister, W.; Austin, C. P.; Park, H. W.; Inglese, J.; Cantley,
L. C.; Auld, D. S.; Thomas, C. J. J. Med. Chem. 2010, 53, 1048e1055.
6. Ilies, M. A.; Vullo, D.; Pastorek, J.; Scozzafava, A.; Ilies, M.; Caproiu, M. T.;
Pastorekova, S.; Supuran, C. T. J. Med. Chem. 2003, 46, 2187e2196.
7. (a) Lima, L. M.; Castro, P.; Machado, A. L.; Fraga, C. A. M.; Lugnier, C.; Gon-
çalves de Moraes, V. L.; Barreiro, E. J. Bioorg. Med. Chem. 2002, 10, 3067e3073;
(b) Jenkins, T. J.; Guan, B.; Dai, M.; Li, G.; Lightburn, T. E.; Huang, S.; Freeze, B.
S.; Burdi, D. F.; Jacutin-Porte, S.; Bennett, R.; Chen, W.; Minor, C.; Ghosh, S.;
Blackburn, C.; Gigstad, K. M.; Jones, M.; Kolbeck, R.; Yin, W.; Smith, S.; Car-
dillo, D.; Ocain, T. D.; Harriman, G. C. J. Med. Chem. 2007, 50, 566e584.
8. Gawin, R.; De Clercq, E.; Naesens, L.; Koszytkowska-Stawinska, M. Bioorg. Med.
Chem. 2008, 16, 8379e8389.
17. For recent reviews, please see: (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 6338e6361; (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046e2067; (c) Prim, D.; Campagne, J.-C.; Joseph, D.; Andrioletti, B. Tetrahedron
2002, 58, 2041e2075.
9. Majumdar, K. C.; Mondal, S.; De, N. Synthesis 2009, 18, 3127e3155.
10. Pandya, R.; Murashima, T.; Tedeshi, L.; Barrett, A. G. M. J. Org. Chem. 2003, 68,
8274e8276.
18. For recent reviews, please see: (a) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054e3131; (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2008, 47, 3096e3099.
11. Olah, G. A.; Klumpp, D. Superelectrophiles and their Chemistry; John Wiley: New-
York, NY, 2008.
12. Olah, G. A.; Prakash, G. K. S.; Mlnar, A.; Sommer, J. Superacid Chemistry, 2nd ed.;
Wiley Intersciences: New-York, NY, 2009.
19. (a) Lai, C.; Gum, R. J.; Daly, M.; Fry, E. H.; Hutchnins, C.; Abad-Zapatero, C.; von
Geldern, T. W. Bioorg. Med. Chem. Lett. 2006, 16, 1807e1810; (b) Kim, J.; Lee, S.
Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454e9457; (c) Rolfe, A.;
Hanson, P. R. Tetrahedron. Lett. 2009, 50, 6935e6937.
13. (a) Thibaudeau, S.; Martin-Mingot, A.; Jouannetaud, M.-P.; Karam, O.; Zunino, F.
Chem. Commun. 2007, 3198e3200; (b) Vardelle, E.; Gamba-Sanchez, D.; Martin-
Mingot, A.; Jouannetaud, M.-P.; Thibaudeau, S.; Marrot, J. Chem. Commun. 2008,
1473e1475; (c) Zunino, F.; Liu, F.; Berrier, C.; Martin-Mingot, A.; Thibaudeau, S.;
Jouannetaud, M.-P.; Jacquesy, J.-C.; Bachmann, C. J. Fluorine. Chem. 2008, 129,
775e780; (d) Vardelle, E.; Martin-Mingot, A.; Jouannetaud, M.-P.; Bachmann,
C.; Marrot, J.; Thibaudeau, S. J. Org. Chem. 2009, 74, 6025e6034; (e) Liu, F.;
Martin-Mingot, A.; Jouannetaud, M.-P.; Karam, O.; Thibaudeau, S. Org. Biomol.
Chem. 2009, 7, 4789e4797; (f) Moine, A.; Thibaudeau, S.; Martin, A.; Jouanne-
taud, M.-P.; Jacquesy, J.-C. Tetrahedron. Lett. 2002, 43, 4119e4122.
14. Liu, F.; Martin-Mingot, A.; Jouannetaud, M.-P.; Zunino, F.; Thibaudeau, S. Org.
Lett. 2010, 12, 868e871.
20. Similar ortho substituent effect of amido group on Ullman-type reaction has been
reported by Ma, et al. (a) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
16050e16051; (b) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45,1276e1279.
21. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164e5173 and references cited
therein.
22. Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew. Chem., Int. Ed.
2009, 48, 7398e7401.
23. Elmkaddem, M. K.; Fischmeister, C.; Thomas, C. M.; Renaud, J.-L. Chem. Com-
mun. 2010, 925e927 and references cited therein.
24. CuI catalyzed amination of substrate 4 failed whatever conditions used.
25. Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Eur. J. Org. Chem. 2009,
3513e3518.