Superacid synthesized tertiary benzenesulfonamides and benzofuzed sultams act as selective hCA IX inhibitors: Toward understanding a new mode of inhibition by tertiary sulfonamides

Article abstract of DOI:10.1039/c3ob41538d

A series of tertiary (fluorinated) benzenesulfonamides was synthesized in superacid HF-SbF₅. To circumvent the problem of the in situ iminium ion formation, proved by low temperature NMR experiments, a tandem superacid catalysed cross-coupling

Full text of DOI:10.1039/c3ob41538d

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Superacid synthesized tertiary benzenesulfonamides
and benzofuzed sultams act as selective hCA IX
inhibitors: toward understanding a new mode of
inhibition by tertiary sulfonamides†
Cite this: Org. Biomol. Chem., 2013, 11,
7540
Benoît Métayer,a Agnès Martin-Mingot,a Daniella Vullo,b Claudiu. T. Supuran*b and
Sébastien Thibaudeau*a
A series of tertiary (fluorinated) benzenesulfonamides was synthesized in superacid HF–SbF5. To circum-
vent the problem of the in situ iminium ion formation, proved by low temperature NMR experiments, a
tandem superacid catalysed cross-coupling reaction was employed to synthesize the benzofuzed sultams
analogues. These tertiary benzenesulfonamides were tested as inhibitors of human carbonic anhydrases
(hCAs, EC 4.2.1.1). These compounds did not inhibit the widespread off target hCA II isoform and
showed strong selectivity toward tumor-associated carbonic anhydrase isoform IX. A dramatic effect of
the electronic and structural shape of the inhibitors on selectivity was demonstrated, confirming the
non-zinc-bonding mode of inhibition of this class of sulfonamides. This work allowed identifying a
highly selective hCA IX inhibitor lead in this series.
Received 26th July 2013,
Accepted 16th September 2013
DOI: 10.1039/c3ob41538d
www.rsc.org/obc
of inhibitors.4,5 In their deprotonated forms, sulfonamides
bind to the Zn2+ ion of the active site, disrupting the catalytic
Introduction
Carbonic anhydrases (CAs, EC 4.2.1.1) are metallo-enzymes process.2 However, the inhibition of the cytosolic highly cataly-
that catalyse the reversible hydration of carbon dioxide to tically active isoform CA II is known to be responsible for most
bicarbonate and proton.1 Sixteen different α-carbonic anhy- of the side effects of the sulfonamide-based CA inhibitors. The
drase isoforms have been isolated and characterized in cytosolic hCA II, abundant in many tissues/organs, has a
mammals, and many of them are well established therapeutic strong physiological relevance, going from pH homeostasis,
targets to treat a wide range of disorders. Their inhibition or secretion of electrolytes, transport of anions and others, and
activation can be used to treat disorders along with glaucoma, its inhibition can induce dramatic consequences.6,7 The other
obesity, osteoporosis, cancer, etc.2 Recently, transmembrane cytosolic isoform, hCA I, is widespread in the blood and gas-
isoforms IX (hCA IX) and XII (hCA XII) have been shown to be trointestinal tract, but its physiologic role is poorly under-
over-expressed in many tumors, and associated with cancer stood.3,7 As a consequence, there is a clear need to design
progression and response to therapy,3 making them very specific CA inhibitors for the tumor associated isoforms hCA
attractive anticancer drug targets.4 The primary benzenesulfo- IX and XII, which should present lower affinity for the main
namides constitute the most common and best characterized off-target isoform hCA II.8 Therefore, in order to be more selec-
class of α-carbonic anhydrases inhibitors.5 Crystallographic tive toward the different isoforms, much effort was dedicated
studies of many sulfonamides adducts with several CA in the last few years to the development of new hCA inhibitors,
isozymes largely show the anchoring properties of this type with poor affinity for the CA zinc binding site.3 This led to the
discovery of new chemotypes that selectively inhibit hCA IX
isoform (for example coumarins, thiocoumarines,9 and more
recently sulfocoumarins10). In due course, our work focused
aSuperacid group in “Organic Synthesis” team – Université de Poitiers,
on the use of superelectrophilic activation11 in superacid12
CNRS UMR 7285 IC2MP; 4, avenue Michel Brunet F-86022 Poitiers Cedex, France.
HF–SbF5,13 and new benzenesulfonamides were prepared and
E-mail: sebastien.thibaudeau@univ-poitiers.fr; Fax: (+) 33-549453501;
evaluated as hCA IX selective inhibitors.14 The identification of
Tel: (+) 33-549454588
bUniversità degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188,
halogenated tertiary substituted benzenesulfonamides as
Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy
selective nanomolar tumor-associated isoforms inhibitors
led us to envisage that this high level of inhibition could
†Electronic supplementary information (ESI) available: Experimental procedures
and spectral data. See DOI: 10.1039/c3ob41538d
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Scheme 1 Tertiary benzenesulfonamide inhibition data.
come from a “non-classical” inhibition mechanism.15 These
compounds showed strong selectivity toward tumor-associated
hCA IX isoform, without inhibiting the widespread off target
hCA II. This never reported inhibition profile of tertiary benzene-
sulfonamides which cannot act as zinc binding inhibitor
(strong steric impairment and no deprotonated form) strongly
intrigued us. In addition, a strong influence of both aliphatic
and aromatic modifications on CA inhibition selectivity could
be attributed to a new “non-zinc binding” mode of inhibition
(Scheme 1).
Scheme 2 Synthesis of N-allylic and fluorinated tertiary benzenesulfonamides
A focus on the depicted inhibition data clearly demon-
strated that a small modification of the electronic distribution
on the arylamino group strongly impacted the inhibition
selectivity. In addition, the influence of the β-fluorinated alkyl
core could not be predicted, but strongly modified the inhi-
bition profile of the tested inhibitors. As a consequence, these
new tertiary (fluorinated) benzenesulfonamides may interact
strongly with the lipophilic/hydrophilic enzymes pocket16 and
could be considered as valuable leads for the quest of new
hCA IX non-zinc binding selective inhibitors. Therefore, the
evaluation of other tertiary substituted benzenesulfonamides
can represent a valuable approach to generate new selective
hCA IX tumor-associated inhibitors.
In this article, using compounds A–D as leads, the super-
acid catalyzed synthesis of new tertiary benzenesulfonamides
is depicted. A mechanistic investigation allowed us to under-
stand the original behaviour of arylated benzenesulfonamides
in superacid and to synthesize the fluorinated analogues. In
addition, a series of sterically crowded benzofuzed sultams
has been synthesized by combining superacid chemistry and
copper catalyzed coupling reactions. A systematic evaluation of
their inhibition profile toward hCA I, II, IX and XII isoforms
led to the identification of a highly hCA IX selective inhibitor.
(overall yields).
68%, 73% and 78% overall yields, respectively. To evaluate a
potent steric effect of the aromatic sulfonamido group, using
either mesyl chloride or 2,4,6-triisopropylbenzenesulfonyl
chloride, analogues 3d and 3e were also synthesized (64% and
86% overall yield). Using a similar procedure with 4-bromo-
butene as an alkylating agent, the homoallylic product 5 could
also be synthesized in 99% overall yield. The observed strong
effect of the modification of the electronic density of the
amino substituted aromatic ring on the selectivity of the inhi-
bition (Scheme 1) let us envisage evaluating a similar effect by
modifying the electronic density on the benzenesulfonamide
ring. Starting from 4-methylaniline, allylated products 3f–3h
and β-fluorinated tertiary benzenesulfonamides 4f–4h were
synthesized in overall good yields after a sulfonylation/
allylation/superacid catalysed hydrofluorination process
(Scheme 2).13
Then, to impact the conformational mobility of the tested
N-arylated tertiary benzenesulfonamides, N-arylated benzo-
fuzed sultams were targeted. Using a two step procedure
recently reported by our group,17 the targeted benzofuzed
sultams 6 could have been obtained by a cyclization reaction
through the superacid catalyzed formation of super-
electrophilic ammonium–carbenium dicationic intermediates
(Scheme 3).
Chemistry
To investigate the hypothesis that these tertiary substituted
Unfortunately, irrespective of the conditions used, no cycli-
benzenesulfonamides type inhibitors may interact in the half zation product of type 6 could be obtained and only deallylated
hydrophilic/half hydrophobic pocket of the enzymes, the product of type 7, besides a large amount of non-characterized
impact of both electronic and steric shapes of the tertiary ben- side products, was obtained. However, starting from the sec-
zenesulfonamides on the selectivity and efficiency of the inhi- ondary sulfonamide analogue 8, the cyclization process
bition had to be evaluated. Using a classical sulfonylation– occurred in 90% yield.17 The dramatic effect of the aromatic
allylation procedure, allylic tertiary benzenesulfonamides 3 substituent on the cyclization process let us envisage a strong
were prepared (Scheme 2). After tosylation of the appropriate difference of behaviour between NH free benzenesulfonamide
aromatic amine and allylation, indane derivative 3a, fluorene and N-arylated one for the Friedel–Crafts cyclization process in
derivative 3b and anthracene derivative 3c were prepared in superacid HF–SbF5.
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Scheme 5 Postulated mechanism for N-allylic tertiary benzenesulfonamide
behaviour in superacid HF–SbF5.
These data encouraged us to postulate the following mecha-
nism to explain the difficulty in accessing cyclised products
under a superacid activation process (Scheme 5).
Scheme 3 Friedel–Crafts cyclization process in superacid.
Starting from the allylated substrates of type 3, after double
protonation, the formation of the superelectrophilic intermedi-
ates of type G occurs, allowing their fluorination and the for-
mation of ion H precursors of the fluorinated products. To
favour a cyclization process, the composition of the super-
acidic media has to be modified, as already shown in our pre-
vious studies.13,17 The displacement of the equilibrium (III)
toward the formation of the ammonium–carbenium ion G is
needed to allow any cyclization process. Extensive reported
studies of ionic composition in HF–SbF5 solutions18 led to the
following largely accepted conclusions. For SbF5 concentration
Scheme 4 Low-temperature study of tertiary benzenesulfonamide 3i behav-
iour in superacid HF–SbF5.
−
lower than 10 mol%, SbF6 is practically the only anionic
+
species present, and H3F2 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 con-
sider that the nucleophilicity of fluoride ion source strongly
decreases by SbF5 concentration increase, and it has now
largely been shown that increasing the amount of SbF5
increases the acidity strength of the media. Using a HF–SbF5
mixture (SbF5 mol% = 21.6) the equilibrium (III) must be dis-
placed toward the formation of the dication G. However, and
thus probably due to steric constraints, the aromatic rings
cannot play the role of the nucleophile and no cyclization
occurs. Then, due to repulsive effects, equilibrium (II) must be
Fig. 1 13C NMR of ion E in superacid HF–SbF5 at −40 °C.
To evaluate this hypothesis, derivative 3i was dissolved in displaced in favor of the formation of the more stable inter-
1
HF–SbF5 (mol% SbF5 = 21.6) and studied by H, 13C NMR and mediate F. Then, considering the low basicity of the sulfona-
DEPT experiments at −20 °C (Scheme 4 and Fig. 1).
mide function, the concomitant formation of the C-protonated
No clear 1H NMR spectrum could be obtained from sub- intermediate I through the equilibriums (I) and (IV) can occur.
strate 3i, however the low-temperature 13C NMR spectra and The formation of the more stable iminium ion E after iso-
DEPT spectra are consistent with that of iminium ion E. For merization can be postulated. This intermediate being
instance, in the 13C NMR spectrum, the observed resonance highly stabilized through nitrogen electron lone pair back-
signal at 181.0 ppm confirmed the presence of a Csp2- donation, in the reaction condition used, this species must
iminium carbon atom. In addition, the eight signals (four qua- be the major stable intermediate in solution. The formation
ternary carbons and four CH carbons) observed between of the deallylated product 7 after hydrolysis seems to reinforce
155.6 ppm and 116.4 ppm confirmed that both aromatic rings this hypothesis.
remained in their non-protonated forms. Interestingly, besides
Although the synthesis of the targeted N-arylated benzo-
the two CH3 signals observed at 19.8 ppm and 4.8 ppm, fuzed sultams could not be achieved through this direct
respectively, which can be attributed to the methyl groups of process, a strategy based on a tandem superacid catalyzed
the tosyl and of the aliphatic chain, the CH2 signal observed at Friedel–Crafts cyclization/copper catalyzed cross-coupling19
28.0 ppm proved the protonation and isomerisation of the reaction allowed the synthesis of compounds 6a–6c
olefin.
(Scheme 6).
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action of benzenesulfonamide inhibitors, similar to what was
recently reported on non-zinc-binding inhibitors such as (thio)-
coumarin derivatives.9 The strongest effect of the benzene-
sulfonamide modification can be noted for the substrate 3e.
Derivative 3e can be considered as an excellent selective lead
for the future quest for a tertiary benzenesulfonamide selective
hCA IX inhibitor. Even if compound 3e inhibits hCA IX at a
low nanomolar level, the absence of inhibition of the other
tested isoforms is really encouraging. This result reinforces the
hypothesis of a strong impact of the conformational behaviour
Scheme 6 Synthesis of N-arylated benzofuzed sultams.
Biological evaluations
These new tertiary benzenesulfonamides were then evaluated of the molecule on the inhibition profile for these new non-
as hCA inhibitors against hCA I, hCA II, hCA IX and hCA XII zinc-binding type inhibitors. The presence of the isopropyl
and compared to the previously reported compounds A–D groups in the ortho positions of this compound must strongly
(Table 1). The following SAR should be noted from data of alter the rotational freedom of the molecule, with a dramatic
Table 1. First, all the tested tertiary substituted benzenesulfo- consequence on its inhibitory profile. In addition, the strong
namides were found to be ineffective as hCA II inhibitors. Con- impact of these isopropyl groups might be attributed to the
sidering that the inhibition of the cytosolic hCA II, which is modification of the lipophilic/hydrophilic balance of the
widespread in many tissues/organs, showing a strong physio- compound, with consequences on its interaction within the
logical relevance, is the cause of most of the side-effects of the enzyme.
sulfonamide based inhibitors, the absence of inhibition of
hCA II confirms the strong potential of this series for further
exploration. Exceptionally, whereas they do not inhibit the
highly catalytically active hCA II, compounds 3a–3h, 4f–4h and
Conclusions
5 inhibited the tumor associated transmembrane isoform A series of tertiary (fluorinated) benzenesulfonamides was
hCA IX at the nanomolar level (KIs of 24.9–451 nM). When synthesized in superacid. Due to iminium ion formation,
these tertiary benzenesulfonamides act as hCA I, IX and XII proved by performing low-temperature in situ NMR experi-
inhibitors, the benzofused sultams 6a–6c did not act as carbo- ments, accessing the targeted N-arylated benzofused sultams
nic anhydrase inhibitors. These results confirm that the con- was impossible. As an alternative, a strategy based on a
formational behaviour of the proposed new class of tertiary tandem superacid catalysed cross-coupling reaction was
benzenesulfonamide inhibitors is essential for their inhibition employed to synthesize the desired substrates. These new ter-
profile. A locked conformation in the case of the benzofuzed tiary benzenesulfonamides were explored as inhibitors of
sultams might prohibit the molecules from adopting the physiologically/pathologically relevant carbonic anhydrase iso-
required conformation to act as inhibitors. The already zymes, with the aim of confirming a new mode of CA inhi-
observed impact of the aromatic aniline modification on the bition for sulfonamides type inhibitors. Almost all the tested
efficiency of the inhibition (comparison of inhibition pro- compounds in this series were shown to be highly selective
perties of compounds A and C), was confirmed by analysing tumor associated carbonic anhydrases inhibitors, without
the inhibition data obtained for substrates 3a–3c. For these inhibiting the off target widespread isoform hCA II. The strong
substrates, the modification of the aromatic ring strongly impact of aromatic modification reinforced the hypothesis of a
decreased the inhibition efficiency for both cytosolic and new mode of inhibition for these benzenesulfonamide non-
transmembrane isoforms (Table 1, entries 5–7). Then, the zinc-binding inhibitors, with an interesting anti-cancer
evaluation of the inhibition properties of 4-methylaniline pharmacological profile. This work allowed identifying a never
derivatives allows further advancement in the quest for selec- yet reported benzenesulfonamide highly selective hCA IX
tive hCA IX inhibitors. By replacing the tosyl group with mesyl inhibitor, making this compound a new lead for further
or other substituents in the para position of the aromatic sul- investigations.
fonamides, the level of inhibition for hCA IX was maintained
or improved, whereas the inhibition of hCA I was slightly less
favoured and hCA XII inhibition level strongly decreased (com-
pounds 3d, 3f–h). A similar impact of the aromatic benzenesul-
fonamide modification on the hCA XII inhibition was also
Experimental section
General method
observed for the β-fluorinated analogues 4f–h. It is also inter-
CA inhibition assay. An Applied Photophysics stopped-flow
esting to note that the modification of the allylic moiety with a instrument was used for assaying the CA catalysed CO2
homoallylic one seems also to strongly impact the hCA XII hydration activity.20 Phenol red (at a concentration of 0.2 mM)
inhibition (comparison of substrates A and 5 inhibition was used as an indicator, working at the absorbance
profile). The strong effect of the aromatic sulfonamide substi- maximum of 557 nm, with 20 mM Hepes (pH 7.5) as a buffer,
tution on the inhibition profile of these compounds, especially and 20 mM Na2SO4 (for maintaining constant the ionic
on hCA XII, reinforced our earlier hypothesis of a new mode of strength), following the initial rates of the CA-catalyzed CO2
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Table 1 hCA inhibition data of tertiary benzenesulfonamides
Ki a (nM)
Selectivityb,c
Entry
1
Substrate
hCA I
75.1
hCA II
hCA IX
70.1
hCA XII
17.7
I/IX
1.1
I/XII
4.2
II/IX
II/XII
d
e
e
A
/
/
/
d
e
e
2
3
4
5
B
73.1
238
9.8
/
9.3
8.3
33.6
82.5
7.8
28
2.2
/
/
d
e
e
C
/
2.8
/
/
d
e
e
D
3a
/
86.1
145
3511
450
0.1
2.6
0.003
0.8
/
/
d
e
e
378
/
/
/
d
e
e
6
7
3b
3c
431
615
/
218
371
683
2.0
1.7
0.6
0.1
/
/
d
e
e
/
5420
/
/
d
e
e
8
9
3d
3e
123
/
85.2
451
3247
1.4
0.04
/
/
d
d
d
e
e
e
e
/
/
/
/
/
/
/
d
e
e
10
11
12
13
14
3f
3g
3h
5
154
98
/
76.5
61.1
42.7
49.5
35.8
2768
3241
2569
2458
1463
2.0
1.6
1.8
0.9
1.5
0.06
0.03
0.03
0.02
0.04
/
/
d
e
e
/
/
/
d
e
e
76.1
47.6
55.1
/
/
/
d
e
e
/
/
/
d
e
e
4f
/
/
/
d
e
e
15
16
4g
4h
68.3
87.6
/
24.9
70.6
1239
1356
2.7
1.2
0.05
0.06
/
/
d
e
e
/
/
/
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Table 1 (Contd.)
Ki a (nM)
Selectivityb,c
Entry
17
Substrate
hCA I
hCA II
hCA IX
hCA XII
I/IX
I/XII
II/IX
II/XII
d
d
d
d
e
e
e
e
e
e
6a
/
/
/
/
/
/
/
/
/
/
d
d
d
d
e
e
e
18
19
6b
6c
/
/
/
/
/
/
/
d
d
d
d
e
e
e
/
/
/
/
/
/
/
a Errors in the range of 5% of the reported data from 3 different assays. b Selectivity ratio between hCA I (hCA II) and IX. c Selectivity ratio
between hCA I (hCA II) and XII. d Not active >1000 nM. e Not determined >1000.
hydration reaction for a period of 10–100 s. The CO2 concen-
trations ranged from 1.7 to 17 mM for the determination of
the kinetic parameters and inhibition constants. For each
inhibitor, at least six traces of the initial 5–10% of the reaction
have been used for determining the initial velocity. The un-
catalyzed rates were determined in the same manner and sub-
tracted from the total observed rates. Stock solutions of
inhibitor (0.1 mM) were prepared in distilled-deionized water
and dilutions up to 0.01 nM were done thereafter with the
assay buffer. Inhibitor and enzyme solutions were preincu-
bated together for 15 min–6 h at room temperature (15 min) or
4 °C (6 h) prior to the assay, in order to allow for the formation
of the E-I complex. The inhibition constants were obtained by
non-linear least-squares methods using PRISM 3, as reported
earlier,21 and represent the mean from at least three different
determinations. All CA isoforms were recombinant ones
obtained in-house as reported earlier.22,23
Synthesis. The authors draw the reader’s attention to the
dangerous features of superacidic chemistry. Handling of
hydrogen fluoride and antimony pentafluoride must be done
by experienced chemists with all the necessary safety arrange-
ments in place. Reactions performed in superacid were carried
out in a sealed Teflon® flask with a magnetic stirrer. No
further precautions have to be taken to prevent the mixture
from moisture (test reaction worked out in anhydrous con-
ditions leads to the same results as expected).
General synthetic procedures for the synthesis of carbonic anhy-
drase inhibitors. Procedure A: optimized procedure for the
N-sulfonylation of amine.
Into a round bottom flask cooled to 0 °C, amine derivative
(1 eq.), sulfonylchloride derivative (1.2 eq.) and dichloro-
methane were introduced. The mixture was stirred under nitro-
gen atmosphere. Pyridine (3 eq.) was slowly added. The
mixture was magnetically stirred at room temperature for an
additional 48 hours. The reaction mixture was then neutralized
with water–sodium carbonate solution (100 mL) extracted with
dichloromethane (×3). The combined organic layers were
washed with hydrochloric acid 2 M (×4), dried over magnesium
sulphate, filtered and concentrated in vacuo. Products were iso-
lated by column chromatography over silica gel.
Procedure B: optimized procedure for the N-allylation of
N-arylbenzenesulfonamides.
Into a round bottom flask at room temperature, N-arylben-
zenesulfonamide derivative (1 eq.), acetonitrile (60 mL) and
potassium carbonate (10 eq.) were introduced. Allyl bromide (3
eq.) was slowly added. The mixture was magnetically stirred
under nitrogen atmosphere at 80 °C for 16 hours. The reaction
mixture was then concentrated in vacuo, washed with water
(×1), dried over magnesium sulphate, filtered and concentrated
in vacuo. Products were isolated by column chromatography
over silica gel.
Procedure C: optimized procedure for the hydrofluorination
reaction in superacid media.
Yields refer to isolated pure products.
1H, 13C and 19F NMR were recorded on a 400 MHz Bruker
Advance DPX spectrometer using CDCl3 as a solvent. COSY
1H–1H and 1H–13C experiments were used to confirm the NMR
peaks assignments. Melting points were determined in a capil-
lary tube with a device Büchi melting point B-545 and were
uncorrected.
Mass Spectra (MS) were performed with coupled gas chrom-
atography (electronic impact). All separations were done under
flash-chromatography conditions on silica gel (15–40 μm).
To a mixture of hydrofluoric acid and antimony pentafluor-
ide (8 mL, 3.8 mol% antimony pentafluoride) maintained at
−65 °C, was added N-allyl-N-arylbenzenesulfonamide derivative.
The mixture was magnetically stirred at the same temperature
for 10 minutes. The reaction mixture was then neutralized with
water-ice-sodium carbonate solution, extracted with dichloro-
methane (×3). The combined organic phases were dried over
magnesium sulphate, filtered and concentrated in vacuo. Pro-
ducts were isolated by column chromatography over silica gel.
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Procedure D: optimized procedure for the cyclization reac- Jtrans = 17.1 Hz, H3″), 5.07–5.03 (dm, 1 H, Jcis = 10.2 Hz, H3″),
tion in superacid media. 4.13 (dm, 2 H, J = 6.3 Hz, H1″), 3.86 (s, 2 H, H7), 2.44 (s, 3 H,
To a mixture of hydrofluoric acid and antimony pentafluor- H4′). 13C NMR (CDCl3, 100 MHz, ppm) δ: 144.0 (Car), 143.7
ide (6 mL, 12.2 mol% antimony pentafluoride) maintained at (Car), 143.5 (Car), 141.5 (Car), 140.9 (Car), 137.7 (Car), 135.6
−20 °C, was added N-allylbenzenesulfonamide derivative. The (Car), 133.1 (CH, C2″), 129.5 (CH, C3′), 127.9 (CH, C2′), 127.2
mixture was magnetically stirred at the same temperature (CH, C2 and C12), 127.0 (CH, C11), 126.4 (CH, C6), 125.2 (CH,
for 10 minutes. The reaction mixture was then neutralized C13), 120.2 (CH, C10), 119.3 (CH, C3), 118.9 (CH2, C3″), 55.9
with water-ice-sodium carbonate solution, and extracted with (CH2, C1″), 37.0 (CH2, C7), 21.7 (CH3, C5′). HRMS (MALDI/TOF,
dichloromethane (×3). The combined organic phases were ES+, CH3CN): m/z calc for C23H21NO2S [M + Na]+: 398.1191, m/z
dried over magnesium sulphate, filtered and concentrated found: 398.1190.
in vacuo. Products were isolated by column chromatography
Compound 3c. N-Allyl-N-(2-anthracene)-4-methylbenzene-
over silica gel.
sulfonamide. This compound was obtained from anthracen-
Procedure E: optimized procedure for the CuI-catalyzed 2-amine (193 mg, 1 mmol) following the general procedures A
sulfonamide N-arylation. then B. The reaction crude was purified over silica gel with the
A sealed tube is charged with sultam (1 eq.), aryl iodide eluent petroleum ether–ethyl acetate: 90/10, thereby obtaining
derivative (1.5 eq.), CuI (0.05 eq.) and Cs2CO3 (2 eq.). The tube compound 3c (301 mg, 78% for two steps). Aspect: Brown
is evacuated and backfilled with nitrogen. Then DMF (0.5 mL) viscous oil. 1H NMR (CDCl3, 400 MHz, ppm) δ: 8.40 (s, 1 H,
is added. The reaction mixture is stirred under 130 °C for 24 h. H10), 8.32 (s, 1 H, H7), 8.02–7.95 (m, 2 H, H11 and H14 or H12
The resulting mixture is cooled to room temperature. The and H13), 7.92 (d, 1 H, J = 9.2 Hz, H3), 7.65 (d, 1 H, J = 1.5 Hz,
residue is filtered through a 3 cm pad of Celite® with dichloro- H6), 7.52 (d, 2 H, J = 8.3 Hz, H2′), 7.50–7.45 (m, 2 H, H11 and
methane, dried over magnesium sulphate, filtered and H14 or H12 and H13), 7.24 (d, 2 H, J = 8.0 Hz, H3′), 7.16 (dd,
concentrated in vacuo. Products were isolated by column 1 H, J = 9.0 Hz, J = 2.1 Hz, H2), 5.81 (ddt, 1 H, Jtrans = 17.1 Hz,
chromatography over silica gel.
Jcis = 10.2 Hz, J = 6.3 Hz, H2″), 5.15–5.09 (dm, 1 H, Jtrans =
Compound 3a. N-Allyl-N-(5-indane)-4-methylbenzenesulfona- 17.1 Hz, H3″), 5.06–5.02 (dm, 1 H, Jcis = 10.2 Hz, H3″), 4.31 (dt,
mide. This compound was obtained from 2,3-dihydro-1H- 2 H, J = 6.3 Hz, J = 1.3 Hz, H1″), 2.43 (s, 3 H, H5′). 13C NMR
indan-5-amine (133 mg, 1.0 mmol) following the general pro- (CDCl3, 100 MHz, ppm) δ: 143.7 (Car), 136.1 (Car), 135.6 (Car′),
cedures A then B. The reaction crude was purified over silica 132.9 (CH, C2″), 132.2 (Car), 132.0 (Car), 131.3 (Car), 130.6 (Car),
gel with the eluent petroleum ether–ethyl acetate: 90/10, 129.6 (CH, C3′), 129.2 (CH, C3), 128.3 (CH), 128.2 (CH), 127.9
thereby obtaining compound 3a (224 mg, 68% for two steps). (CH, C2′), 127.7 (CH, C6), 126.7 (CH, C7), 126.4 (CH, C2), 126.2
Aspect: Brown viscous oil. 1H NMR (CDCl3, 400 MHz, ppm) (CH, C10), 125.9 (CH), 125.9 (CH), 119.1 (CH2, C3″), 53.6 (CH2,
δ: 7.52 (d, 2 H, J = 8.3 Hz, H2′), 7.25 (d, 2 H, J = 7.9 Hz, H3′), C1″), 21.7 (CH3, C5′). HRMS (MALDI/TOF, ES+, CH3CN): m/z
7.09 (d, 1 H, J = 8.0 Hz, H3), 6.95 (sbroad, 1 H, H6), 6.70 (dd, calc for C24H21NO2S [M + Na]+: 410.1191, m/z found: 410.1186.
1 H, J = 8.0 Hz, J = 2.0 Hz, H2), 5.74 (ddt, 1 H, Jtrans = 17.1 Hz,
Compound 3d. N-Allyl-N-(4-methylphenyl)methylsulfona-
Jcis = 10.2 Hz, J = 6.2 Hz, H2″), 5.11–5.01 (m, 2 H, H3″), 4.13 (dt, mide. This compound was obtained from 4-methylaniline
2 H, J = 6.2 Hz, J = 1.3 Hz, H1″), 2.89–2.83 (m, 4 H, H7 and H9), (214 mg, 2 mmol) following the general procedures A and then
2.43 (s, 3 H, H5′), 2.07 (p, 2 H, J = 7.5 Hz, H8). 13C NMR B. The reaction crude was purified over silica gel with the
(CDCl3, 100 MHz, ppm) δ: 145.2 (Car), 144.2 (Car), 143.4 (Car), eluent petroleum ether–ethyl acetate: 80/20, thereby obtaining
137.3 (Car), 135.9 (Car), 133.2 (CH, C2″), 129.5 (CH, C3′), 127.9 compound 3d (287 mg, 64% for two steps). Aspect: pale yellow
(CH, C2′), 126.4 (CH, C2), 125.5 (CH, C6), 124.5 (CH, C3), 118.6 oil. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.22 (d, 2 H, J = 8.6 Hz,
(CH2, C3″), 54.0 (CH2, C1″), 32.9 (CH2, C7 or C9), 32.6 (CH2, H2 or H3), 7.18 (d, 2 H, J = 8.6 Hz, H2 or H3), 5.83 (ddt, 1 H,
C7 or C9), 25.6 (CH2, C8), 21.7 (CH3, C5′). HRMS (MALDI/TOF, Jtrans = 16.9 Hz, Jcis = 10.2 Hz, J = 6.4 Hz, H2″), 5.20–5.11 (m,
ES+, CH3CN): m/z calc for C19H21NO2S [M + Na]+: 350.1191, m/z 2 H, H3″), 4.26 (dbroad, 2 H, J = 6.3 Hz, H1″), 2.90 (s, 3 H, H1′),
found: 350.1189.
2.35 (s, 3 H, H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 138.3
Compound 3b. N-Allyl-N-(2-fluorene)-4-methylbenzenesulfo- (Car), 136.7 (Car), 133.1 (CH, C2″), 130.2 (CH), 128.6 (CH), 119.1
namide. This compound was obtained from 9H-fluoren- (CH2, C3″), 53.9 (CH2, C1″), 38.1 (CH3, C1′), 21.2 (CH3, C5). This
3-amine (181 mg, 1.0 mmol) following the general procedures compound has already been described.24
A then B. The reaction crude was purified over silica gel with
Compound 3e. N-Allyl-N-(4-methylphenyl)-2,4,6-triisopropyl-
the eluent petroleum ether–ethyl acetate: 90/10, thereby benzenesulfonamide. This compound was obtained from
obtaining compound 3b (275 mg, 73% for two steps). Aspect: 4-methylaniline (429 mg, 4 mmol) following the general pro-
1
Brown viscous oil. H NMR (CDCl3, 400 MHz, ppm) δ: 7.75 (d, cedures A and then B. The reaction crude was purified over
1 H, J = 7.4 Hz, H10), 7.66 (d, 1 H, J = 8.1 Hz, H3), 7.54 (d, 1 H, silica gel with the eluent petroleum ether–ethyl acetate: 97/3,
J = 8.3 Hz, H13), 7.52 (d, 2 H, J = 8.3 Hz, H2′), 7.37 (td, 1 H, J = thereby obtaining compound 3e (1.427 g, 86% for two steps).
7.4 Hz, J = 0.8 Hz, H11), 7.31 (td, 1 H, J = 7.4 Hz, J = 1.3 Hz, Aspect: white powder. Mp: 68.3–69.5 °C. 1H NMR (CDCl3,
H12), 7.31 (d, 1 H, J = 1.2 Hz, H6), 7.26 (d, 2H, J = 7.9 Hz, H3′), 400 MHz, ppm) δ: 7.09–7.03 (m, 6 H, H2 and H3 and H3′), 5.78
6.95 (dd, 1 H, J = 8.0 Hz, J = 1.3 Hz, H2), 5.74 (ddt, 1 H, Jtrans
=
(ddt, 1 H, J = 17.5 Hz, J = 9.7 Hz, J = 6.6 Hz, H2″), 5.07–5.01 (m,
17.0 Hz, Jcis = 10.3 Hz, J = 6.3 Hz, H2″), 5.13–5.07 (dm, 1 H, 2 H, H3″), 4.26 (dbroad, 2 H, J = 6.6 Hz, H1″), 3.93 (hept, 2 H,
7546 | Org. Biomol. Chem., 2013, 11, 7540–7549
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J = 6.8 Hz, H5′), 2.88 (hept, 1 H, J = 6.9 Hz, H7′), 2.29 (s, 3 H, 7.09 (d, 2 H, J = 8.5 Hz, H3), 6.89 (d, 2 H, J = 8.3 Hz, H2), 5.74
H5), 1.23 (d, 6 H, J = 6.9 Hz, H8′), 1.13 (d, 12 H, J = 6.8 Hz, H6′). (ddt, 1 H, J = 17.1 Hz, J = 10.2 Hz, J = 6.3 Hz, H2″), 5.11–5.05
13C NMR (CDCl3, 100 MHz, ppm) δ: 153.1 (C, C4′), 151.5 (m, 2 H, H3″), 4.18 (dt, 2 H, J = 6.3 Hz, J = 1.3 Hz, H1″), 2.65
(C, C2′), 138.1 (Car), 136.3 (Car), 133.4 (CH, C2″), 132.0 (Car), (s, 3 H, H6′), 2.33 (s, 3 H, H5). 13C NMR (CDCl3, 100 MHz,
130.2 (CH), 129.9 (CH), 123.8 (CH), 119.0 (CH2, C3″), 53.2 (CH2, ppm) δ: 197.1 (C, C5′), 142.7 (Car), 140.0 (Car), 138.4 (Car), 136.0
C1″), 34.2 (CH, C7′), 29.6 (CH, C5′), 24.9 (CH3, C6′), 23.7 (CH3, (Car), 132.7 (CH, C2″), 129.9 (CH, C3), 128.8 (CH), 128.8 (CH),
C8′), 21.2 (CH3, C5). HRMS (MALDI/TOF, ES+, CH3CN): m/z calc 128.1 (CH, C2′), 119.3 (CH2, C3″), 54.1 (CH2, C1″), 27.0
for C25H35NO2S [M + Na]+: 436.2286, m/z found: 436.2288.
(CH3, C6′), 21.3 (CH3, C5). HRMS (MALDI/TOF, ES+, CH3CN):
Compound 3f. N-Allyl-4-fluoro-N-(4-methylphenyl)benzene- m/z calc for C18H19NO3S [M + Na]+: 352.0983, m/z found:
sulfonamide. This compound was obtained from 4-methylani- 352.0982.
line (214 mg, 2 mmol) following the general procedures A then
Compound 4f. 4-Fluoro-N-(2-fluoropropyl)-N-(4-methyl-
B. The reaction crude was purified over silica gel with the phenyl)-benzenesulfonamide. This compound was obtained
eluent petroleum ether–ethyl acetate: 97/3, thereby obtaining from N-allyl-4-fluoro-N-(4-methylphenyl)benzenesulfonamide
compound 3f (436 mg, 87% for two steps). Aspect: white 3f (80 mg, 0.26 mmol) following the general procedure C. The
powder. Mp: 65.9–66.4 °C. 1H NMR (CDCl3, 400 MHz, ppm) reaction crude was purified over silica gel with the eluent pet-
δ: 7.65–7.59 (m, 2 H, H2′), 7.17–7.10 (m, 2 H, H3′), 7.09 (d, 2 H, roleum ether–ethyl acetate: 94/6, thereby obtaining compound
J = 8.0 Hz, H3), 6.90 (d, 2 H, J = 8.3 Hz, H2), 5.73 (ddt, 1 H, J = 4f (37 mg, 43%). Aspect: pale yellow solid. Mp: 100.7–101.2 °C.
17.1 Hz, J = 10.2 Hz, J = 6.3 Hz, H2″), 5.11–5.05 (dm, 1 H, J = 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.64–7.58 (m, 2 H, H2′),
17.1 Hz, H3″), 5.08–5.04 (dm, 1 H, J = 10.1 Hz, H3″), 4.15 (dt, 7.16–7.10 (m, 4 H, H3 and H3′), 6.93 (d, 2 H, J = 8.3 Hz, H2),
2 H, J = 6.3 Hz, J = 1.3 Hz, H1″), 2.33 (s, 3 H, H5). 13C NMR 4.81–4.60 (dm, 1 H, J = 48.6 Hz, H2″), 3.79 (td, 1 H, J = 14.0 Hz,
(CDCl3, 100 MHz, ppm) δ: 165.2 (d, J = 254.5 Hz, C, C4′), 138.2 J = 7.2 Hz, H1″), 3.60 (ddd, 1 H, J = 23.4 Hz, J = 14.3 Hz, J =
(Car), 136.2 (Car), 134.8 (d, J = 3.0 Hz, C, C1′), 132.8 (CH, C2″), 4.3 Hz, H1″), 2.34 (s, 3 H, H5), 1.34 (dd, 3 H, J = 23.7 Hz, J =
130.5 (d, J = 9.1 Hz, CH, C2′), 129.8 (CH), 128.8 (CH), 119.1 6.3 Hz, H3″). 13C NMR (CDCl3, 100 MHz, ppm) δ: 165.3 (d, J =
(CH2, C3″), 116.1 (d, J = 22.4 Hz, CH, C3′), 53.9 (CH2, C1″), 21.3 254.8 Hz, C, C4′), 138.6 (Car), 136.9 (Car), 134.7 (d, J = 3.3 Hz, C,
(CH3, C5). 19F {1H} NMR (CDCl3, 376 MHz, ppm) δ: −105.4 C1′), 130.5 (d, J = 9.4 Hz, CH, C2′), 130.1 (CH, C3), 128.9 (CH,
(F4′). HRMS (MALDI/TOF, ES+, CH3CN): m/z calc for C2), 116.1 (d, J = 22.5 Hz, CH, C3′), 88.6 (d, J = 170.8 Hz, CH,
C16H16NO2FS [M + Na]+: 328.0784, m/z found: 328.0785.
C2″), 56.2 (d, J = 24.9 Hz, CH2, C1″), 21.2 (CH3, C5), 18.6 (d, J =
Compound 3g. N-Allyl-4-trifluoromethyl-N-(4-methylphenyl)- 21.7 Hz, CH3, C3″). 19F {1H} NMR (CDCl3, 376 MHz, ppm) δ:
benzenesulfonamide. This compound was obtained from −105.1 (F5′), −178.2 (F4″). HRMS (MALDI/TOF, ES+, CH3CN):
4-methylaniline (214 mg, 2 mmol) following the general pro- m/z calc for C16H17NO2F2S [M + Na]+: 348.0846, m/z found:
cedures A then B. The reaction crude was purified over silica 348.0844.
gel with the eluent petroleum ether–ethyl acetate: 95/5, thereby
Compound 4g. 4-Trifluoromethyl-N-(2-fluoropropyl)-N-
obtaining compound 3g (691 mg, 97% for two steps). Partial (4-methylphenyl)benzenesulfonamide. This compound was
desulfonylation occurred on silica gel. Aspect: white solid. Mp: obtained from N-allyl-4-trifluoromethyl-N-(4-methylphenyl)-
70.5–71.0 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.76–7.71 (m, benzenesulfonamide 3g (86 mg, 0.242 mmol) following the
4 H, H2′ and H3′), 7.11 (d, 2 H, J = 8.6 Hz, H3), 6.90 (d, 2 H, J = general procedure C. The reaction crude was purified over
8.3 Hz, H2), 5.74 (ddt, 1 H, J = 17.0 Hz, J = 10.2 Hz, J = 6.3 Hz, silica gel with the eluent petroleum ether–ethyl acetate: 94/6,
H2″), 5.12–5.06 (m, 2 H, H3″), 4.18 (ddd, 2 H, J = 6.3 Hz, J = thereby obtaining compound 4g (41 mg, 48%). Aspect: pale
1.3 Hz, J = 1.3 Hz, H1″), 2.34 (s, 3 H, H5). 13C NMR (CDCl3, yellow solid. Mp: 102.5–103.6 °C. 1H NMR (CDCl3, 400 MHz,
100 MHz, ppm) δ: 142.4 (C, C1′), 138.5 (Car), 135.9 (Car), 132.6 ppm) δ: 7.76–7.70 (m, 4 H, H2′ and H3′), 7.13 (d, 2 H, J = 8.0 Hz,
(CH, C2″), 130.0 (CH, C3), 128.8 (CH, C2), 128.3 (CH, C2′), 126.9 H3), 6.94 (d, 2 H, J = 8.3 Hz, H2), 4.71 (dm, 1 H, J = 48.7 Hz,
(q, J = 3.7 Hz, CH, C3′), 119.4 (CH2, C3″), 54.1 (CH2, C1″), 21.3 H2″), 3.83 (td, 1 H, J = 14.0 Hz, J = 7.4 Hz, H1″), 3.61 (ddd,
(CH3, C5). Due to partial desulfonylation in deuterated sol- 1 H, J = 24.3 Hz, J = 14.3 Hz, J = 4.1 Hz, H1″), 2.35 (s, 3 H, H5),
vents, long time carbon NMR acquisition could not have been 1.34 (dd, 3 H, J = 23.6 Hz, J = 6.3 Hz, H3″). 13C NMR (CDCl3,
performed, and so the CF3 group carbon peak did not appear 100 MHz, ppm) δ: 142.3 (Car), 138.9 (Car), 136.5 (Car), 134.5 (q,
in the spectrum. 19F {1H} NMR (CDCl3, 376 MHz, ppm) J = 33.0 Hz, C, C4′), 130.2 (CH, C3), 128.9 (CH, C2), 128.3 (CH,
δ: −63.0 (F5′). HRMS (MALDI/TOF, ES+, CH3CN): m/z calc for C2′), 126.1 (q, J = 3.6 Hz, CH, C3′), 123.4 (q, J = 272.9 Hz, C5′),
C17H16NO2F3S [M + Na]+: 378.0752, m/z found: 378.0751.
88.4 (d, J = 171.1 Hz, CH, C2″), 56.3 (d, J = 24.5 Hz, CH2, C1″),
Compound 3h. 4-Acetyl-N-allyl-N-(4-methylphenyl)benzene- 21.2 (CH3, C5), 18.5 (d, J = 21.8 Hz, CH3, C3″). 19F {1H}
sulfonamide. This compound was obtained from 4-methylani- NMR (CDCl3, 376 MHz, ppm) δ: −63.0 (F6′), −178.3 (F4″).
line (214 mg, 2 mmol) following the general procedures A then HRMS (MALDI/TOF, ES+, CH3CN): m/z calc for C17H17NO2F4S
B. The reaction crude was purified over silica gel with the [M + Na]+: 398.0814, m/z found: 398.0811.
eluent petroleum ether–ethyl acetate: 80/20, thereby obtaining
Compound 4h. 4-Acetyl-N-(2-fluoropropyl)-N-(4-methyl-
compound 3h (535 mg, 81% for two steps). Aspect: white phenyl)benzenesulfonamide. This compound was obtained
1
powder. Mp: 100.3–101.1 °C. H NMR (CDCl3, 400 MHz, ppm) from 4-acetyl-N-allyl-N-(4-methylphenyl)benzenesulfonamide
δ: 8.02 (s, 2 H, J = 8.7 Hz, H3′), 7.71 (d, 2 H, J = 8.7 Hz, H2′), 3h (107 mg, 0.33 mmol) following the general procedure C.
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The reaction crude was purified over silica gel with the eluent
Compound 6b. 2-(4-Fluorophenyl)-4,6-dimethyl-3,4-dihydro-
petroleum ether–ethyl acetate: 88/12, thereby obtaining com- 2H-1,2-benzothiazine-1,1-dioxide.
This
compound
was
pound 4h (34 mg, 30%). Aspect: pale yellow solid. Mp: obtained from allylamine (18.9 mg, 0.33 mmol) following the
131.9–132.6 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ: 8.01 (d, general procedures A then D then E. The reaction crude was
2 H, J = 8.7 Hz, H3′), 7.69 (d, 2 H, J = 8.6 Hz, H2′), 7.11 (d, 2 H, purified over silica gel with the eluent petroleum ether–ethyl
J = 8.0 Hz, H3), 6.92 (d, 2 H, J = 8.3 Hz, H2), 4.70 (dm, 1 H, J = acetate: 85/15, thereby obtaining compound 6b (13 mg, 13%
48.7 Hz, H2″), 3.81 (dt, 1 H, J = 14.1 Hz, J = 7.3 Hz, H1″), 3.61 for 3 steps). Aspect: colorless viscous oil. 1H NMR (CDCl3,
(ddd, 1 H, J = 24.0 Hz, J = 14.3 Hz, J = 4.1 Hz, H1″), 2.64 (s, 3 H, 400 MHz, ppm) δ: 7.76 (d, 1 H, J = 8.0 Hz, H8′), 7.30–7.26 (m,
H6′), 2.33 (s, 3 H, H5), 1.33 (dd, 3 H, J = 23.6 Hz, J = 6.3 Hz, 2 H, H2), 7.22 (dbroad, 1 H, J = 8.1 Hz, H7′), 7.18 (sbroad, 1 H,
H3″). 13C NMR (CDCl3, 100 MHz, ppm) δ: 197.0 (C, C5′), 142.6 H5′), 7.04 (t, 2 H, J = 8.5 Hz, H3), 4.11 (dd, 1 H, J = 13.7 Hz, J =
(Car), 140.1 (Car), 138.7 (Car), 136.5 (Car), 130.1 (CH, C3), 128.9 5.3 Hz, H3′), 3.83 (dd, 1 H, J = 13.6 Hz, J = 7.9 Hz, H3′), 3.33
(CH, C2 or C3′), 128.7 (CH, C2 or C3′), 128.1 (CH, C2′), 88.5 (d, (sextbroad, 1 H, J = 6.7 Hz, H4′), 2.43 (s, 3 H, H12′), 1.43 (d, 3 H,
J = 171.1 Hz, CH, C2″), 56.3 (d, J = 24.7 Hz, CH2, C1″), 27.0 J = 6.9 Hz, H11′). 13C NMR (CDCl3, 100 MHz, ppm) δ: 161.9 (d,
(CH3, C6′), 21.2 (CH3, C5), 18.5 (d, J = 21.8 Hz, CH3, C3″). J = 247.5 Hz, C, C4), 143.2 (Car), 140.0 (Car), 136.4 (d, J = 3.0 Hz,
19F {1H} NMR (CDCl3, 376 MHz, ppm) δ: −178.3 Hz (F2″). C, C1), 134.7 (Car), 129.3 (d, J = 8.6 Hz, CH, C2), 128.9 (CH, C5′),
HRMS (MALDI/TOF, ES+, CH3CN): m/z calc for C18H20NO3FS 128.3 (CH, C7′), 124.2 (CH, C8′), 116.3 (d, J = 22.7 Hz, CH, C3),
[M + Na]+: 372.1046, m/z found: 372.1046.
57.1 (CH2, C3′), 31.9 (CH3, C4′), 21.8 (CH3, C12′), 19.5 (CH3,
Compound 5. N-Homoallyl-4-methyl-N-(4-methylphenyl)- C11′). 19F {1H} NMR (CDCl3, 376 MHz, ppm) δ: −113.8 (F4).
benzenesulfonamide. This compound was obtained from HRMS (TOF, ES+, CH3CN): m/z calc for C16H16NO2FS [M + Na]+:
4-methyl-N-(4-methylphenyl)benzenesulfonamide (1.05 g, 4 mmol) 328.0784, m/z found: 328.0784.
following the general procedure B. The reaction crude was fil-
Compound 6c. 4,6-Dimethyl-2-[4-(trifluoromethyl)phenyl]-
tered over silica gel with the eluent ethyl acetate, thereby 3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide. This compound
obtaining compound 5 (1.26 g, 99%). Aspect: brown viscous was obtained from allylamine (19.2 mg, 0.34 mmol) following
oil. 1H NMR (CDCl3, 400 MHz, ppm) δ: 7.48 (d, 2 H, J = 8.3 Hz, the general procedures A then D then E. The reaction crude
H2′), 7.24 (d, 2 H, J = 7.9 Hz, H3′), 7.10 (d, 2 H, J = 8.0 Hz, H3), was purified over silica gel with the eluent petroleum ether–
6.91 (d, 2 H, J = 8.3 Hz, H2), 5.73 (ddt, 1 H, J = 16.8 Hz, ethyl acetate: 85/15, thereby obtaining compound 6c (20 mg,
J = 10.6 Hz, J = 6.7 Hz, H3″), 5.04–4.97 (m, 2 H, H4″), 3.56 17% for 3 steps). Aspect: colorless viscous oil. 1H NMR (CDCl3,
(t, 2 H, J = 7.3 Hz, H1″), 2.42 (s, 3 H, H5′), 2.34 (s, 3 H, H5), 400 MHz, ppm) δ: 7.76 (d, 1 H, J = 8.0 Hz, H8′), 7.61 (d, 2 H, J =
2.21–2.14 (m, 2 H, H2″). 13C NMR (CDCl3, 100 MHz, ppm) 8.2 Hz, H3), 7.42 (d, 2 H, J = 8.3 Hz, H2), 7.23 (dbroad, 1 H, J =
δ: 143.0 (Car), 137.5 (Car), 136.0 (Car), 135.1 (Car), 134.3 (CH, 8.0 Hz, H7′), 7.18 (sbroad, 1 H, H5′), 4.18 (dd, 1 H, J = 13.8 Hz,
C3″), 129.3 (CH, C3), 129.1 (CH, C3′), 128.4 (CH, C2), 127.3 (CH, J = 5.3 Hz, H3′), 3.94 (dd, 1 H, J = 13.8 Hz, J = 8.0 Hz, H3′),
C2′), 116.6 (CH2, C4″), 49.7 (CH2, C1″), 32.3 (CH2, C2″), 21.1 3.40–3.29 (m, 1 H, H4′), 2.43 (s, 3 H, H12′), 1.44 (d, 3 H, J = 6.9
(CH3, C5′), 20.7 (CH3, C5). HRMS (MALDI/TOF, ES+, CH3CN): Hz, H11′). 13C NMR (CDCl3, 100 MHz, ppm) δ: 143.9 (C, C1),
m/z calc for C18H21NO2S [M + Na]+: 338.1191, m/z found: 143.5 (Car), 139.9 (Car), 134.5 (Car), 129.2 (q, J = 32.9 Hz, C, C4),
338.1189.
128.9 (CH, C5′), 128.4 (CH, C7′), 126.7 (CH, C2), 126.5 (CH, C3),
Compound 6a. Ethyl 4-(4,6-dimethyl-1,1-dioxido-3,4-dihydro- 124.2 (CH, C8′), 123.9 (q, J = 272.0 Hz, C, C5), 56.6 (CH2, C3′),
2H-1,2-benzothiazin-2-yl)benzoate. This compound was 31.8 (CH, C4′), 21.8 (CH3, C12′), 19.6 (CH3, C11′). 19F {1H} NMR
obtained from allylamine (57.1 mg, 1 mmol) following the (CDCl3, 376 MHz, ppm) δ: −62.5 (F5). HRMS (MALDI/TOF, ES+,
general procedures A then D then E. The reaction crude was CH3CN): m/z calc for C17H16NO2F3S [M + Na]+: 378.0752, m/z
purified over silica gel with the eluent petroleum ether–ethyl found: 378.0753.
acetate: 85/15, thereby obtaining compound 6a (178 mg, 50%
1
for 3 steps). Aspect: white solid. Mp: 157.8–159.1 °C. H NMR
(CDCl3, 400 MHz, ppm) δ: 8.01 (d, 2 H, J = 8.6 Hz, H3), 7.74
(d, 1 H, J = 8.0 Hz, H8′), 7.36 (d, 2 H, J = 8.7 Hz, H2), 7.20
Acknowledgements
(dbroad, 1 H, J = 8.1 Hz, H7′), 7.17 (sbroad, 1 H, H5′), 4.35 (q, 2 H, This work was generously supported by the CNRS, the
J = 7.1 Hz, H6), 4.17 (dd, 1 H, J = 13.9 Hz, J = 5.5 Hz, H3′), 3.94 University of Poitiers, the French National Research Agency
(dd, 1 H, J = 13.9 Hz, J = 8.1 Hz, H3′), 3.35 (sextbroad, 1 H, J = (VINFLUSUP project: ANR JCJC SIMI 7 no ANR-11-JS07-003-01)
7.0 Hz, H4′), 2.41 (s, 3 H, H12′), 1.42 (d, 3 H, J = 7.0 Hz, H11′), and by an FP7 EU grant (METOXIA).
1.37 (t, 3 H, J = 7.1 Hz, H7).
13C NMR (CDCl3, 100 MHz, ppm) δ: 165.9 (C, C5), 144.7
(Car), 143.4 (Car), 139.9 (Car), 134.5 (Car), 130.7 (CH, C3), 128.8
(Car or CH, C5′), 128.8 (Car or CH, C5′), 128.3 (CH, C7′), 125.9
Notes and references
(CH, C2), 124.1 (CH, C8′), 61.2 (CH2, C6), 56.4 (CH2, C3′), 31.7
(CH, C4′), 21.7 (CH3, C12′), 19.5 (CH3, C11′), 14.4 (CH3, C7).
HRMS (MALDI/TOF, ES+, CH3CN): m/z calc for C19H21NO4S
[M + H]+: 360.1270, m/z found: 360.1276.
1 (a) V. M. Krishnamurthy, G. K. Kaufman, A. R. Urbach,
I. Gitlin, K. L. Gudiksen, D. B. Weibel and G. M. Whitesides,
Chem. Rev., 2008, 108, 946; (b) C. T. Supuran, in Drug
Design of Zinc-Enzyme Inhibitors: Functional, Structural, and
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Disease Applications, ed. C. T. Supuran and J. Y. Winum, 13 (a) S. Thibaudeau, A. Martin-Mingot, M.-P. Jouannetaud,
Wiley, Hoboken (NJ), 2009, pp. 15–38; (c) J. F. Domsic,
B. S. Avvaru, C. U. Kim, S. M. Gruner, M. Agbandje-
McKenna, D. N. Silverman and R. J. McKenna, J. Biol.
Chem., 2008, 283, 30766.
2 (a) C. T. Supuran, Nat. Rev. Drug Discovery, 2008, 7, 168;
(b) J. Y. Winum, M. Rami, A. Scozzafava, J. L. Montero and
C. T. Supuran, Med. Res. Rev., 2008, 28, 445; (c) C. T. Supuran,
A. Scozzafava and A. Casini, Med. Res. Rev., 2003, 23, 146.
3 V. Alterio, A. Di Fiore, K. D’Ambrosio, C. T. Supuran and
G. De Simone, Chem. Rev., 2012, 112, 4421.
O. Karam and F. Zunino, Chem. Commun., 2007, 3198;
(b) E. Vardelle, D. Gamba-Sanchez, A. Martin-Mingot,
M. P. Jouannetaud, S. Thibaudeau and J. Marrot, Chem.
Commun., 2008, 1473; (c) F. Liu, A. Martin-Mingot,
M. P. Jouannetaud, C. Bachmann, G. Frapper, F. Zunino
and S. Thibaudeau, J. Org. Chem., 2011, 76, 1460;
(d) G. Compain, K. Jouvin, A. Martin-Mingot, G. Evano,
J. Marrot and S. Thibaudeau, Chem. Commun., 2012, 48,
5196; (e) G. Compain, A. Martin-Mingot, G. Frapper,
C. Bachmann, M. P. Jouannetaud and S. Thibaudeau,
Chem. Commun., 2012, 48, 5877; (f) G. Compain,
C. Bonneau, A. Martin-Mingot and S. Thibaudeau, J. Org.
Chem., 2013, 78, 4463.
4 (a) V. Alterio, M. Hilvo, A. Di Fiore, C. T. Supuran, P. Pan,
S. Parkkila, A. Scaloni, J. Pastorek, S. Pastorekova,
C. Pedone, A. Scozzafava, S. M. Monti and G. De Simone,
Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 16233; (b) A. Di Fiore, 14 G. Compain, A. Martin-Mingot, A. Maresca, S. Thibaudeau
E. Truppo, C. T. Supuran, V. Alterio, N. Dathan, F. Bootorabi, and C. T. Supuran, Bioorg. Med. Chem., 2012, 21, 1555.
S. Parkkila, S. M. Monti and G. De Simone, Bioorg. Med. 15 B. Métayer, A. Mingot, D. Vullo, C. T. Supuran and
Chem. Lett., 2010, 20, 5023. S. Thibaudeau, Chem. Commun., 2013, 49, 6015.
5 V. Alterio, A. Di Fiore, K. D’Ambrosio, C. T. Supuran and 16 G. De Simone, V. Alterio and C. T. Supuran, Expert Opin.
G. De Simone, in Drug Design of Zinc-Enzyme Inhibitors: Drug Discovery, 2013, 8, 793.
Functional, Structural, and Disease Applications, ed. 17 F. Liu, A. Martin-Mingot, M.-P. Jouannetaud, F. Zunino and
C. T. Supuran and J. Y. Winum, Wiley, Hoboken (NJ), 2009,
pp. 73–138.
S. Thibaudeau, Org. Lett., 2010, 12, 868.
18 (a) B. Bonnet and G. Mascherpa, Inorg. Chem., 1980, 19,
785; (b) D. Mootz and K. Bartmann, Angew. Chem., Int. Ed.
Engl., 1988, 27, 391; (c) J.-C. Culmann and J. Sommer,
J. Am. Chem. Soc., 1990, 112, 4057; (d) J.-C. Culmann,
M. Fauconet, R. Jost and J. Sommer, New J. Chem., 1999,
23, 863; (e) J. Sommer, P. Canivet, S. Schwartz and
P. Rimmelin, New J. Chem., 1981, 5, 45.
6 (a) A. Di Fiore, S. M. Monti, M. Hilvo, S. Parkkila,
V. Romano, A. Scaloni, C. Pedone, A. Scozzafava,
C. T. Supuran and G. De Simone, Proteins, 2009, 74, 164;
(b) J. Y. Winum, C. Temperini, K. El Cheikh, A. Innocenti,
D. Vullo, S. Ciattini, J. L. Montero, A. Scozzafava and
C. T. Supuran, J. Med. Chem., 2006, 49, 7024; (c) A. Innocenti,
A. Casini, M. C. Alcaro, A. M. Papini, A. Scozzafava and 19 W. Deng, L. Liu, C. Zhang, M. Liu and Q.-X. Guo, Tetra-
C. T. Supuran, J. Med. Chem., 2004, 47, 5224; (d) F. Carta, hedron Lett., 2005, 46, 7295.
C. T. Supuran and A. Scozzafava, Expert Opin. Ther. Pat., 20 R. G. Khalifah, J. Biol. Chem., 1971, 246, 2561.
2012, 22, 79.
21 (a) A. Maresca, C. Temperini, H. Vu, N. B. Pham,
S. A. Poulsen, A. Scozzafava, R. J. Quinn and C. T. Supuran,
J. Am. Chem. Soc., 2009, 131, 3057; (b) A. Maresca,
C. Temperini, L. Pochet, B. Masereel, A. Scozzafava and
C. T. Supuran, J. Med. Chem., 2010, 53, 335.
7 C. T. Supuran, Bioorg. Med. Chem. Lett., 2010, 20, 3467.
8 D. Neri and C. T. Supuran, Nat. Rev. Drug Discovery, 2011,
10, 767 and references cited therein.
9 (a) A. Maresca, C. Temperini, H. Vu, N. B. Pham,
S. A. Poulsen, A. Scozzafava, R. J. Quinn and C. T. Supuran, 22 F. Carta, C. Temperini, A. Innocenti, A. Scozzafava, K. Kaila
J. Am. Chem. Soc., 2009, 131, 3057; (b) A. Maresca, and C. T. Supuran, J. Med. Chem., 2010, 53, 5511.
C. Temperini, L. Pochet, B. Masereel, A. Scozzafava and 23 (a) A. Di Fiore, E. Truppo, C. T. Supuran, V. Alterio,
C. T. Supuran, J. Med. Chem., 2010, 53, 335; (c) F. Carta,
A. Maresca, A. Scozzafava and C. T. Supuran, Bioorg. Med.
Chem., 2012, 20, 2266.
N. Dathan, F. Bootorabi, S. Parkkila, S. M. Monti and
G. De Simone, Bioorg. Med. Chem. Lett., 2010, 20, 5023;
(b) M. Hilvo, L. Baranauskiene, A. M. Salzano, A. Scaloni,
D. Matulis, A. Innocenti, A. Scozzafava, S. M. Monti, A. Di
Fiore, G. Simone, M. Lindfors, J. Janis, J. Valjakka,
S. Pastorekova, J. Pastorek, M. S. Kulomaa, H. R. Nordlund,
C. T. Supuran and S. Parkkila, J. Biol. Chem., 2008, 283,
27799.
10 K. Tars, D. Vullo, A. Kazaks, J. Leitans, A. Lends,
A. Grandane, R. Zalubovskis, A. Scozzafava and
C. T. Supuran, J. Med. Chem., 2013, 56, 293.
11 G. A. Olah and D. Klumpp, in Superelectrophiles and their
chemistry, John Wiley and Sons, New York, 2008.
12 G. A. Olah, G. K. S. Prakash, A. Molnar and J. Sommer, 24 S. Inada, S. Hirabayashi, K. Taguchi and M. Okazaki,
Superacids, Wiley, New-York, 2nd edn, 2009.
Nippon Kagaku Kaishi, 1978, 1, 86.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 7540–7549 | 7549