Titanium-Promoted Acylation of Sulfonamides to N -Acylsulfonamide PPAR Antagonists

Article abstract of DOI:10.1080/00397911.2015.1092552

The direct acylation of sulfonamides by esters represents an attractive strategy in organic chemistry, being an interesting alternative to classical approaches to N-acylsulfonamides. Here is described a simple and effective method to obtain N-acylsulfonam

Full text of DOI:10.1080/00397911.2015.1092552

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Titanium-Promoted Acylation of Sulfonamides to
N-Acylsulfonamide PPARα Antagonists
Alessandra Ammazzalorso, Maria Luisa Tricca, Isabella Bruno, Barbara
De Filippis, Mauro Di Matteo, Marialuigia Fantacuzzi, Letizia Giampietro,
Cristina Maccallini, Adriano Mollica & Rosa Amoroso
To cite this article: Alessandra Ammazzalorso, Maria Luisa Tricca, Isabella Bruno,
Barbara De Filippis, Mauro Di Matteo, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina
Maccallini, Adriano Mollica & Rosa Amoroso (2015): Titanium-Promoted Acylation of
Sulfonamides to N-Acylsulfonamide PPARα Antagonists, Synthetic Communications, DOI:
10.1080/00397911.2015.1092552
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Date: 04 November 2015, At: 02:17

Titanium-Promoted Acylation of Sulfonamides to N-Acylsulfonamide PPARα
Antagonists
Alessandra Ammazzalorso1, Maria Luisa Tricca1, Isabella Bruno1, Barbara De Filippis1,
Mauro Di Matteo1, Marialuigia Fantacuzzi1, Letizia Giampietro1, Cristina Maccallini1,
Adriano Mollica1, Rosa Amoroso1
1Dipartimento di Farmacia, Università G. d’Annunzio, 66100 Chieti, Italy
Corresponding Author to A. Ammazzalorso & R. Amoroso: Dipartimento di Farmacia,
Università G. d’Annunzio, via dei Vestini 31, 66100 Chieti, Italy.
E-mail: aammazzalorso@unich.it (A. Ammazzalorso) Email: ramoroso@unich.it (Rosa
Amoroso)
Abstract
The direct acylation of sulfonamides by esters represents an attractive strategy in organic
chemistry, being an interesting alternative to classical approaches to N-acylsulfonamides.
Here is described a simple and effective method to obtain N-acylsulfonamides of
pharmaceutical interest, in a reaction promoted by titanium(IV) chloride. This strategy
was successfully applied to the synthesis of a Peroxisome Proliferator-Activated Receptor
α antagonist with a benzenesulfonimide moiety, ensuring an excellent yield of product.
The reaction was further studied exploring the behaviour of different α-bromoesters and
esters, and the effects of para-substitution in the benzenesulfonamide moiety.
1

KEYWORDS: PPAR antagonists, N-acylsulfonamides, Lewis acids, titanium
tetrachloride, α-bromoesters
INTRODUCTION
Since the discovery in 1990s of Peroxisome Proliferator-Activated Receptors (PPARs), a
large amount of work has been developed in the effort to clarify the biological role of
three PPAR subtypes and their involvement in physiological and pathological
conditions.[1-2] PPARα is highly expressed in metabolically active tissues and it is mainly
implicated in lipid and lipoprotein metabolism;[3-4]
insulin sensitivity and glucose homeostasis, in addition to anti-inflammatory properties.[5-
6]
.
[7] Potent
and selective agonists, dual and pan-agonists were described and their important actions
on lipid and glucose homeostasis were demonstrated.[8-10] In a parallel way, also PPAR
inverse agonists and antagonists received great attention, because a reduced activation of
these receptors ensured beneficial effects in energetic balance and glycemic control.[11-13]
In recent years a number of PPAR antagonists has been described and their promising
antitumoral effects have attracted research attention.[14] Blocking PPARα is emerging as a
new interesting strategy to interfere with energetic metabolism of organisms, so
potentially favourable in different cancer types, where metabolic pathways appear
deregulated.[15-17] Also PPARγ and PPARδ antagonists could favourably interfere with
survival and differentiation of cancer cells, determining apoptosis or arrest of cell
growth.[18-19] In previous works we reported the identification of new N-acylsulfonamide
PPARα antagonists, found to inhibit the nuclear receptor in low micromolar range.[20-21]
2

These compounds were developed starting from benzothiazole carboxylic acids, PPARα
agonists at micromolar concentrations (Figure 1).[22]
The switch from a carboxylic acid to a sulfonimide moiety has been described as a
chemical strategy to obtain PPARα antagonists, based on the hypothesis of the folding of
helix 12, a substructure of ligand binding domain (LBD), responsible for the
transcriptional activation of PPARs.[23] Sulfonimide group is often used in medicinal
chemistry to replace carboxylic acid, being a bioisostere endowed with a comparable
acidity (pKa 4-5); its chemical and enzymatic stability to hydrolysis makes it amenable to
being used as enzymatic inhibitor.[24-25] In the literature different synthetic approaches to
N-acylsulfonamides have been described: in addition to coupling agents (carbodiimides,
carbonyldiimidazole),[26-30] acylation of sulfonamides by acyl chlorides or anhydrides in
basic or acidic conditions has been widely realized, also in the presence of catalysts.[31-36]
Alternatively, N-acylbenzotriazoles were used as acylating agents in basic conditions.[37]
Recently, the use of Lewis acid as catalyst in the preparation of sulfonimides has been
described: a panel of Lewis acids were screened by using anhydrides or esters as
acylating agents. [38-39] For the synthesis of our sulfonimide PPARα antagonists, we
applied a classical synthetic route, by a direct coupling of carboxylic acids and
sulfonamides in the presence of EDC as condensing agent.
In an attempt to explore a new synthetic route to N-acylsulfonamides, we decided to
attempt a new strategy using esters as acylating agents; to this end, a recent work by Fu et
al proposes the acylation of sulfonamides by esters in the presence of titanium chloride as
3

a promoter of the reaction. [40] This titanium-mediated strategy has been applied to a
panel of esters, but in literature there are no examples of application to α-bromoesters,
versatile and useful building blocks in medicinal chemistry. We decided to explore the
applicability of this method to our compounds, starting from α-bromoesters,
intermediates in our synthetic scheme (Figure 2).
To our knowledge, there are no previous examples of the transformation of α-
bromoesters in α-bromosulfonimides; data from literature report the synthesis of α-
bromosulfonimides by reacting sulfonamides with α-bromoacyl halides. [41-42]
In this paper we report the study of the applicability of titanium-mediated acylation of
sulfonamides to our recently developed PPARα antagonists.
RESULTS AND DISCUSSION
Among the PPARα antagonists previously synthesized, we selected the isopropyl and
phenyl derivatives (1 and 2, respectively) (Figure 3) as targets to tune up the new
synthetic route. We chose the isopropyl derivative as an example of compound bearing an
aliphatic substituent, endowed with a steric hindrance, and the phenyl derivative, that was
the most promising compound due its biological profile. [20]
For the synthesis of the isopropyl derivative 1, ethyl 2-bromo-3-methylbutanoate was
reacted with benzenesulfonamides 3a-e to obtain α-bromosulfonimide intermediates 4a-e.
The reactions were carried out in toluene or 1,1,2,2-tetrachloroethane (TCE) at 115 °C, in
4

a sealed tube, with a fixed TiCl4 amount of 1.5 equivalents, found to be the best
conditions in previous experiments (data not shown). Intermediate 4a was reacted with 2-
mercapto-5-chlorobenzothiazole, in basic conditions, to obtain target compound 1 in
good yields (88%) (Scheme 1). In Table 1 data obtained for the synthesis of 4a-e
intermediates are reported.
Testing the ability of TiCl4 in promoting the acylation of benzenesulfonamide, we
observed a nearly quantitative yield of product in toluene at 115 °C for a time of reaction
of 8 h (entry 1), whereas the yield drastically decreased by only changing the solvent
(entry 2). When the same reaction was applied to a group of p-substituted
benzenesulfonamides, we observed a general decrease of yields with respect to the
unsubstituted derivatives. The reaction of p-toluensulfonamide in toluene afforded the
product at 54-57% (entries 3-4), for reaction times of 8 and 24 h, respectively. By using
TCE as solvent, a strong dependence on time of reaction was observed: yields of 31, 72,
and 17% were obtained, respectively, after 8, 24, and 70 h of reaction (entries 5-7). The
p-methoxy and p-chloro derivatives gave corresponding products with very similar yields
(59 and 60%, entries 8-9); in this series, the best substitution was the p-nitro, with a
recovery of product of 82% (entry 10), but changing the solvent the yield strongly
decreased (37%, entry 11). These results clearly demonstrate the possibility to apply this
strategy to our selected -bromoester, with good to moderate yields depending on
experimental conditions and differently substituted benzenesulfonamides. This procedure
allowed us to strongly improve the way to prepare 1, with a simplified synthetic route and
excellent yield of reaction.
5

By comparison, the direct coupling of proper carboxylic acid and benzenesulfonamide by
EDC fournished 4a in 69% yield.
With these good results, we tried to apply the same synthetic strategy to phenyl derivative
2, starting from ethyl α-bromophenylacetate (Scheme 2, Table 2). The classical synthesis
with EDC gave desired product in 30% yield.
Unfortunately, the N-acylation of benzenesulfonamides by ethyl α-bromophenylacetate
did not afford the desired products, in the different experimental conditions tested (entries
1-10). The variation of solvent, temperature, reaction time and p-substitution of
benzenesulfonamide had no effect in the outcome of the reactions: crude materials clearly
-bromoester. From
these results it is evident that the substituent in α position to the bromoester strongly
influences the reaction: whereas the isopropylic substituent allows the N-acylation of the
substrate, the aromatic ring negatively affects the reaction.
In an attempt to clarify this result we applied the same synthetic strategy to the ethyl
phenylacetate. Our aim was to verify if the presence of an aromatic ring in Cα to the ester
could disallow the reaction, or if the failure has to be ascribed to the contemporary
presence, in the starting, of a bromine atom and a phenyl ring on Cα. Results obtained in
the reaction between ethyl phenylacetate and benzenesulfonamides 2a-e (Scheme 3) are
shown in Table 3.
6

Both solvents tested, toluene and TCE, allowed the transformation of ethyl phenylacetate
in the corresponding benzenesulfonimide 5a, at 115 °C; for a reaction time of 8 h in
toluene, 72% yield was obtained (entry 1). The yield decreased by prolonging time of
reaction (66% and 17% for 24 h and 70 h, respectively, entries 2 and 4). TCE allowed the
transformation, with yields of 64 and 26%, for 24 and 70 h, respectively (entries 3 and 5).
Testing p-substituted benzenesulfonamides, an overall decrease in yields was observed.
The p-toluensulfonamide was reacted in different experimental conditions, producing
moderate yields of product in TCE (45%, entry 9). The p-methoxy and p-
chlorobenzenesulfonamides gave low yields (entries 11-12), whereas p-
nitrobenzenesulfonamide afforded 43% of product (entry 13). These experiments show
the titanium mediated approach as a valuable alternative in the synthesis of N-
acylsulfonamides starting from proper esters and -bromoesters.
In conclusion, the titanium-promoted acylation of sulfonamides by esters was studied and
its applicability was tested to obtain sulfonimide PPARα antagonists. The reactions gave
good yields of product with ethyl 2-bromo-3-methylbutanoate; the possibility to use α-
bromoesters as acylating agents opens interesting views for organic and medicinal
chemistry. This method was extended to p-substituted benzenesulfonamides, providing
desired sulfonimides in moderate to good yields.
The study of titanium-mediated acylation of sulfonamides was further extended including
ethyl α-bromophenylacetate and ethyl phenylacetate. Results of our experiments showed
7

no conversion in sulfonimides for the first α-bromoester, and yields of products good to
moderate for ethyl phenylacetate.
EXPERIMENTAL
All the solvents and commercial reagents were used as received from Aldrich or Fluka.
Reactions were monitored employing precoated silica gel 60 F254 plates (Merck). NMR
spectra were run at 300 MHz on a Varian instrument with TMS as internal standard;
chemical shifts ( ) are reported in ppm and coupling constants, J, are expressed in Hertz
(Hz). Melting points were determined on a Büchi B-540 apparatus and are uncorrected.
Infrared spectra were recorded on a FT-IR 1600 Perkin-Elmer spectrometer.
Microanalyses were carried out with an Eurovector Euro EA 3000 model analyser and
the analytical results were within 0.4% of the theoretical values.
General Procedure For Direct N-Acylation Of Benzenesulfonamides
Benzenesulfonamide (1.2 mmol), ethyl α-bromophenylacetate or ethyl phenylacetate
(2.4 mmol), and toluene (4 mL) were combined in a sealed tube equipped with a stir bar.
The mixture was stirred at 50 °C for 10 min, then TiCl4 (1.8 mmol) was added and the
reaction mixture was heated to 115 °C. After a variable period of time the mixture was
diluted with H2O (10 mL) to remove the excess of TiCl4, filtered and extracted with
AcOEt (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4
and the solvent was evaporated in vacuo. Crude compounds were purified by flash
column chromatography (silica gel; cyclohexane / AcOEt 8:2).
8

ACKNOWLEDGEMENTS
This study was supported by Università G. d’Annunzio of Chieti (Italy) local grants.
SUPPLEMENTAL MATERIAL
Full experimental detail, 1H and 13C NMR spectra for this article can be accessed on the
publisher’s website.
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12

Table 1. N-acylation of benzenesulfonamides 3a-e by ethyl 2-bromo-3-methylbutanoate a
Entry
R
Solvent
toluene
TCE
Time (h)
Yield % b
98 (4a)
23 (4a)
54 (4b)
57 (4b)
31 (4b)
72 (4b)
17 (4b)
59 (4c)
60 (4d)
82 (4e)
37 (4e)
1
H
8
2
H
8
3
CH3
CH3
CH3
CH3
CH3
OCH3
Cl
toluene
toluene
TCE
8
4
24
8
5
6
TCE
24
70
24
24
24
24
7
TCE
8
toluene
toluene
toluene
TCE
9
10
11
NO2
NO2
a Reaction conditions: ester (2.4 mmol), benzenesulfonamide (1.2 mmol), TiCl4 (1.8
mmol), solvent (4 mL). Reactions were carried out in a sealed tube. b Isolated yield
obtained after chromatographic purification.
13

Table 2. Experimental conditions tested to N-acylation of benzenesulfonamides 3a-e by
ethyl -bromophenylacetate.a
Entry
R
Solvent
Temperature
(°C)
115
Time (h)
1
H
toluene
TCE
24
24
70
36
20
24
70
24
24
24
2
H
115
3
H
TCE
145
4
CH3
CH3
CH3
CH3
OCH3
Cl
toluene
TCE
115
5
110
6
TCE
115
7
TCE
130
8
toluene
toluene
toluene
115
9
115
10
NO2
115
a Reaction conditions: ester (2.4 mmol), benzenesulfonamide (1.2 mmol), TiCl4 (1.8
mmol), solvent (4 mL). Reactions were carried out in a sealed tube.
14

Table 3. N-acylation of benzenesulfonamides 3a-e by ethyl phenylacetate.a
Entry
R
Solvent
toluene
toluene
TCE
Time (h)
Yield %b
72 (5a)
66 (5a)
64 (5a)
17 (5a)
26 (5a)
18 (5b)
35 (5b)
23 (5b)
45 (5b)
19 (5b)
21 (5c)
22 (5d)
43 (5e)
1
H
8
2
H
24
24
70
70
8
3
H
4
H
toluene
TCE
5
H
6
CH3
CH3
CH3
CH3
CH3
OCH3
Cl
toluene
TCE
7
8
8
toluene
TCE
24
24
70
24
24
24
9
10
11
12
13
TCE
toluene
toluene
toluene
NO2
a Reaction conditions: ester (2.4 mmol), benzenesulfonamide (1.2 mmol), TiCl4 (1.8
b
mmol), solvent (4 mL). Reactions were carried out in sealed tube. Isolated yield
obtained after chromatographic purification.
15

Scheme 1. Synthetic route to compound 1 via α-bromosulfonimide intermediates 4a-e.
16

Scheme 2. Synthetic route to compound 2 via -bromosulfonimide intermediates.
17

Scheme 3. Synthetic route to sulfonimides 5a-e
18

Figure 1. From carboxylic PPAR agonists to sulfonimide PPARα antagonists.
19

Figure 2. Classical and titanium-mediated synthetic approach to the synthesis of
sulfonimide PPAR antagonists.
20

Figure 3. Target compounds 1 and 2.
21