Acid-catalyzed intramolecular cyclization of N-(4,4-diethoxybutyl)sulfonamides as a novel approach to the 1-sulfonyl-2-arylpyrrolidines

Article abstract of DOI:10.1080/00397911.2016.1249288

Herein we report our studies on the acid-catalyzed cyclisation of N-(4,4-diethoxybutyl)sulfonamides at the presence of polyatomic phenols as an efficient one-pot approach to the synthesis of 1-sulfonyl-2-arylpyrrolidines from the acyclic precursors.

Full text of DOI:10.1080/00397911.2016.1249288

Acid-catalyzed intramolecular cyclisation of N-(4,4-diethoxybutyl)sulfonamides as a
novel approach to the 1-sulfonyl-2-arylpyrrolidines
Almir S. Gazizov1, Andrey V. Smolobochkin1, Ekaterina A. Anikina2, Julia К.
Voronina1, Alexander R. Burilov1, Michail A. Pudovik1
1A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center,
Russian Academy of Sciences, Kazan, Russian Federation, 2Kazan National Research
Technological University, Kazan, Russian Federation
Corresponding author, Almir S. Gazizov, Email: agazizov@iopc.ru
Abstract
Herein we report our studies on the acid-catalyzed cyclisation of N-(4,4-
diethoxybutyl)sulfonamides at the presence of polyatomic phenols as an efficient one-pot
approach to the synthesis of 1-sulfonyl-2-arylpyrrolidines from the acyclic precursors.
Graphical Abstract:
KEYWORDS: acetal, cyclisation, resorcinol, pyrrolidine, sulfonamide
1

INTRODUCTION
Pyrrolidine derivatives containing sulfonamide group and aromatic moiety exhibit wide
range of biological activity. 1-Sulfonyl-2-arylpyrrolidines are suggested for the treatment
of thromboembolic[1,2] and neurodegenerative disorders, such as Huntington,
Parkinson[3,4] and Alzheimer[5] deseases. There is also evidence of the ability of these
compounds to inhibit matrix metalloproteinase 2 (MMP2).[6]
The most widely used approach to the synthesis of these compounds is an intramolecular
cyclisation of aryl substituted alkenes and alkynes containing sulfonamide group. A
cyclisation of but-3-ene-1-amines,[7–16] but-3-yne-1-amines,[17] pent-4-ene-1-amines,[18–20]
hexa-4,5-dien-1-amines[21,22] can be given as an example (Scheme 1).
The other methods include oxidative cyclisation of sulfonamides,[23–27] carbonylation of
N-tosylpentenamine derivatives,[28,29] reaction of sulfonamides with cyclopropanes[30–32]
and [3+2] cycloaddition of N-tosyl-4-aminobutanal with alkenes.[33] In general, these
reactions require usage of metal catalysts, such as palladium salts,[10,11,14,15,28]
rhodium[13,29] and gold[30–32] complexes; hypervalent iodine compounds are also used.[23–
26] The most obvious way of the synthesis of 1-sulfonyl-2-arylpyrrolidines is a reaction of
2-arylpyrrolidines with sulfonyl chlorides,[4,6,34] which is, however, used only
occasionally.
The common disadvantages of abovementioned methods are harsh reaction conditions,
usage of expensive catalysts and reagents. The need in preliminary synthesis of
2

appropriately substituted starting compounds is also limits these approaches. Thus, the
development of novel, effective method of synthesis of 1-sulphonyl-2-arylpyrrolidines is
of great interest.
DISCUSSION
Earlier, we have developed approach to the synthesis of 2-arylpyrrolidine-1-
carboxamides based on trifluoroacetic acid-catalyzed intramolecular cyclisation of (4,4-
diethoxybutyl)ureas at the presence of various phenols. Reaction proceeds in mild
conditions and leads to the target compounds with good to high yields (Scheme 2).[35–38]
Since amide and sulfonamide groups are isosteric and possess similar electronic
characteristics, we supposed that N-(4,4-diethoxybutyl)sulfonamides are also able to
undergo intramolecular cyclisation in acidic media giving rise to 1-sulfonylpyrrolidines.
This hypothesis was further supported by some papers describing formation of
heterocyclic products in the reaction of 4,4-diethoxybutane-1-amine with arylsulfonyl
chlorides.[39–41]
We attempted to synthesize starting N-(4,4-diethoxybutyl)-4-methylbenzenesulfonamide
1a according to the previously described procedure[41] via the reaction of 4,4-
diethoxybutane-1-amine with tosyl chloride at the presence of triethylamine.
Surprisingly, the reaction product appeared to be not the target sulfonamide 1a, but 2-
ethoxypyrrolidine 2a (Scheme 3), which was obtained with 58% yield. Further studies
have shown that the result of this reaction depends on the order of mixing the reactants.
3

The slow addition of tosyl chloride to the solution of triethylamine and 4,4-
diethoxybutane-1-amine leads to the formation of 2-ethoxypyrrolidine 2a. When the
order of mixing the reactants is reversed, i.e. 4,4-diethoxybutane-1-amine is added to the
solution of tosyl chloride and triethylamine, the sulfonamide 1a became a sole product.
We assume that in this case the first stage of the reaction is the formation of
sulfonamidinium salt[42] which subsequently undergoes nucleophilic substitution with
elimination of triethylamine. Thus, we have found reaction conditions allowing selective
preparation of either 2-ethoxypyrrolidine 2a or its acyclic precursor 1a. The
arylsulfonamides 1b,c and 2-ethoxy-1-(phenylsulfonyl)pyrrolidine 2b were obtained in
similar way.
These results were of a considerable interest both for the synthesis of key N-(4,4-
diethoxybutyl)sulfonamides as well as intramolecular cyclization of these compounds.
Therefore, we further studied the interaction of 4,4-diethoxybutan-1-amine with sulfonyl
chlorides having alkyl substituent at sulfur atom. The product of the reaction of 4,4-
diethoxybutan-1-amine with ethanesulfonyl chloride was found to be the N-(4,4-
diethoxybutyl)methanesulfonylamide 1d regardless of its conditions. It should be noted
that the formation of the corresponding 2-ethoxy-1-methanesulfonilpirrolidines 2d was
detected by NMR spectroscopy. However, this compound easily undergo ring opening
during reaction workup and we failed to isolate it. The mechanism of this ring opening
probably similar to the mechanism described by us previously[36] for the pyrrolidine-1-
carboxamides. Reaction of 4,4-diethoxybutan-1-amine with methanesulfonyl chloride
proceeds similarly and leads to the formation of sulfonamide 1e (Scheme 4).
4

Thus, we succeeded in the synthesis of starting N-(4,4-diethoxybutyl)sulphonamides
having both aromatic and aliphatic substituent at sulfur atom. Moreover, results obtained
during these studies suggest their easy cyclisation in acidic media with pyrrolidine core
formation.
With this in hand, we started to study the reactions of N-(4,4-
diethoxybutyl)sulphonamides with phenols. N-(4,4-Diethoxybutyl)-4-
methylbenzenesulfonamide 1a was taken as a model compound. Interaction of
sulphonamide 1a with resorcinol, 2-methylresorcinol and pyrogallol in chloroform at the
presence of trifluoroacetic acid led to the formation of pyrrolidine derivatives 3а, 4а and
5а (Scheme 5). All of these compounds were isolated as a mixtures of diastereomers,
diastereomeric ratio was determined by 1H NMR spectroscopy (Table 1, № 1-3).
Interestingly, carrying out these reactions in benzene allowed us to isolate pyrrolidines 4а
and 5а as a single diastereomers (Table 1, №5,6). In case of compound 3a the
diastereomeric ratio was also improved significantly (Table 1, №4). However, reasons of
such a significant effect of a solvent on a diastereomeric ratio are not clear enough at the
moment.
Encouraged with these results, we examined the interaction of resorcinol, 2-
methylresorcinol and pyrogallol with acetals 1c-e in benzene (Scheme 6). Data obtained
are summarized in Table 2.
5

Reaction of alkylsulfonamides 1d,e with resorcinol, 2-methylresorcinol and pyrogallol
led to the corresponding pyrrolidine derivatives 3-5 (Table 2, №10-15). The compounds
4d,e were present in reaction mixture according to NMR data, however, we were not able
to isolate them due to the gummy tar formation during reaction workup. All of the
compound were obtained as single diastereomers. The arylsulfonamide 1c reacted with
phenols to form corresponding pyrrolidines 3c-5c, but the reaction diastereoselectivity
decreased significantly in this case (Table 2, №7-9).
We also were lucky enough to grow crystals of the compounds 3e, 4а and 5а,e suitable
for X-ray analysis. X-ray investigations of compounds 4a, 5e, 3e and 5a revealed that all
of them are crystal solvates with DMSO with different ratios (1 : 1 in 4a and 5e, 1 : 2 in
3e and 1 : 3 in 5a). The bond lengths, valence and torsion angles in molecules the studied
compounds have values that are within standard for each type of chemical bond.
Molecule of compound 3e in crystal is in special position on the screw axe and have R,R-
configuration. Molecules 4a, 5e, and 5a are in the general position and have R,S-
configuration.
According to the literature data, 2-alkoxypyrrolidines are able to react with various
nucleophiles, such as organosilicon compounds,[40,43–45] trialkylphosphites,[46]
isocyanides[47] and trialkylbenzenes[48] at the presence of Lewis acids. In view of these
data, we examined the interaction of 2-ethoxypyrrolidines 2 with phenols at the presence
of trifluoroacetic acid (Scheme 7). The results are given in Table 3.
6

Expectedly, the reaction led to the formation of pyrrolidine derivatives 3-5. Just as in the
case of N-(4,4-diethoxybutyl)sulfonamides 1, using chloroform as the solvent led to the
formation of diastereomeric mixtures. Carrying out the same reactions in benzene
allowed us to obtain target pyrrolidine derivatives 3b-5b as a single diastereomers (Table
3, № 4-6).
Based on literature data, we proposed the following mechanism for these reactions
(Scheme 8). The key step of the reaction is the elimination of ethanol molecule from the
2-ethoxypyrrolidine 2 leading to the formation of intermediate iminium ion A. Further
reaction of this ion with aromatic nucleophile leads to the formation of target 2-
arylpyrrolidines. In principle, these reactions can be considered as a variant of Mannich
reaction, in which an N,O-acetal is used as an equivalent of carbonyl compound.[49,50]
In conclusion, we have developed a novel approach to the synthesis of 1-sulfonyl-2-
arylpyrrolidines based on acid-catalyzed reaction of N-(4,4-diethoxybutyl)sulfonamides
with phenols. The proposed approach benefits from simple one-step procedure, does not
require the use of expensive reagents and catalysts and leads to the target compounds in
good to high yields.
EXPERIMENTAL
Synthesis Of 1-Sulfonyl-2-Arylpyrrolidines, General Procedure A
To a solution of N-(4,4-diethoxybutyl)sulfonamide 1 (1.59 mmol) in chloroform (10 ml)
appropriate phenol (0.80 mmol) and trifluoroacetic acid (1.59 mmol) were added.
7

Reaction mixture was stirred at room temperature for 12 h. Solvent was removed, the
residue was washed with diethyl ether (10 ml) and dried in vacuum (r.t., 0.01 torr, 12 h).
Synthesis Of 1-Sulfonyl-2-Arylpyrrolidines, General Procedure B
To a solution of N-(4,4-diethoxybutyl)sulfonamide 1 (1.59 mmol) in benzene (10 ml)
appropriate phenol (0.80 mmol) and trifluoroacetic acid (1.59 mmol) were added.
Reaction mixture was stirred at room temperature for 12 h. Solvent was removed, the
residue was washed with diethyl ether (10 ml) and dried in vacuum (r.t., 0.01 torr, 12 h).
Synthesis Of 1-Sulfonyl-2-Arylpyrrolidines, General Procedure C
To a solution of 2-ethoxypyrrolidine 2 (1.86 mmol) in chloroform (10 ml) appropriate
phenol (0.93 mmol) and trifluoroacetic acid (1.86 mmol) were added. Reaction mixture
was stirred at room temperature for 12 h. Solvent was removed, the residue was washed
with diethyl ether (10 ml) and dried in vacuum (r.t., 0.01 torr, 12 h).
Synthesis Of 1-Sulfonyl-2-Arylpyrrolidines, General Procedure D
To a solution of 2-ethoxypyrrolidine 2 (1.86 mmol) in benzene (10 ml) appropriate
phenol (0.93 mmol) and trifluoroacetic acid (1.86 mmol) were added. Reaction mixture
was stirred at room temperature for 12 h. Solvent was removed, the residue was washed
with diethyl ether (10 ml) and dried in vacuum (r.t., 0.01 torr, 12 h).
8

SUPPORTING INFORMATION
Full experimental procedures, characterization data and copies of NMR spectra for all
synthesized compounds. This material can be found via the ‘‘Supplementary Content’’
section of this article’s webpage. Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC 1479990- 1479993. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
ACKNOWLEDGMENT
This work was supported by the Russian Scientific Foundation (grant no. № 16-13-
10023).
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Table 1. Influence of solvent on diastereomeric ratio of pyrrolidines 3a-5a.
Yield,b
№ Cmpd R
Solvent drа
%
1
2
3
4
5
6
H
CHCl3 40 : 60 47
3a
4a
5а
3a
4a
5а
Me CHCl3 89 : 11 63
OH CHCl3 34 : 66 80
H
C6H6
87 : 13 33
<95 : 5 77
<95 : 5 48
Me C6H6
OH C6H6
аAccording to 1H NMR data
bIsolated yield
13

Table 2. Synthesis of pyrrolidines 3-5.
№
7
Compound R1
R2
drа
Yield,b %
H
p-AcNH-C6H4
50 : 50
34 : 66
14 : 86
<95 : 5
–
33
28
28
73
0c
3c
4c
5c
3d
4d
5d
3e
4e
5e
8
Me
OH
H
p-AcNH-C6H4
9
p-AcNH-C6H4
10
11
12
13
14
15
Et
Me
OH
H
Et
Et
<95 : 5
<95 : 5
–
42
46
0c
Me
Me
Me
Me
OH
<95 : 5
61
аAccording to 1H NMR data
bIsolated yield
cCompound was not isolated from byproducts
14

Table 3. Reaction of 2-ethoxypyrrolidines 2 with phenols.
№
1
Compound
R1
R2
Solvent
CHCl3
CHCl3
CHCl3
C6H6
drа
Yield,b %
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
Ph
H
50 : 50
42 : 58
50 : 50
<95 : 5
<95 : 5
<95 : 5
80
93
64
23
56
32
3a
4a
5а
3b
4b
5b
2
Me
OH
H
3
4
5
Ph
Me
OH
C6H6
6
Ph
C6H6
аAccording to 1H NMR data
bIsolated yield
15

Scheme 1. The most widely used approaches to the 1-sulfonylpyrrolidines
16

Scheme 2. Synthesis of 2-arylpyrrolidine-1-carboxamides.
17

Scheme 3. Synthesis of arylsulfonamides 1a,c and 2-ethoxypyrrolidines 2.
18

Scheme 4. Synthesis of alkylsulfonamides 1d,e.
19

Scheme 5. Reaction of sulfonamide 1a with phenols.
20

Scheme 6. Reaction of phenols with sulfonamides 1c-e.
21

Scheme 7. Reaction of 2-ethoxypyrrolidines 2 with phenols.
22

Scheme 8. Proposed mechanism for the 2-arylpyrrolidines formation.
23

Figure 1. Molecular structure of R,R-3e and R,S-5e in studied crystals. H-atoms are
omitted for clarity.
24