New route for the synthesis of N-alkyl-2-(phenylsulfonyl)anilines

Article abstract of DOI:10.1007/s10593-016-1933-4

[Figure not available: see fulltext.] The main objective of this work was to study the rearrangement reactions of 1-alkyl-2-[(phenylsulfonyl)methyl]pyridinium iodides in the presence of various nucleophiles, leading to N-alkyl-2-(phenylsulfonyl)aniline derivatives. The best results were achieved with alkylammonium sulfites, leading to pyridine ring opening followed by recyclization to give diphenyl sulfone derivatives in up to 78% yields.

Full text of DOI:10.1007/s10593-016-1933-4

DOI 10.1007/s10593-016-1933-4
Chemistry of Heterocyclic Compounds 2016, 52(8), 570–573
New route for the synthesis of N-alkyl-2-(phenylsulfonyl)anilines
Aisha Hossan1*
1 Department of Chemistry, Faculty of Science for Girls, King Khalid University,
Abha, Saudi Arabia; е-mail: aishahossan2012@yahoo.com
Submitted April 4, 2016
Accepted after revision June 5, 2016
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(8), 570–573
The main objective of this work was to study the rearrangement reactions of 1-alkyl-2-[(phenylsulfonyl)methyl]pyridinium iodides in the
presence of various nucleophiles, leading to N-alkyl-2-(phenylsulfonyl)aniline derivatives. The best results were achieved with
alkylammonium sulfites, leading to pyridine ring opening followed by recyclization to give diphenyl sulfone derivatives in up to 78%
yields.
Keywords: alkylammonium sulfites, diaryl sulfones, 2-[(phenylsulfonyl)methyl]pyridine, pyridinium salts, sodium benzenesulfinate.
Sulfones have been proven as valuable synthons for the
synthesis of a wide variety of biologically active hetero-
cyclic systems.1–5 In addition, Fadda and coworkers6–15
have studied the recyclization of pyridinium salts to anili-
nes in the presence of aqueous alkali, alkylamines, or
alkylammonium sulfite. The nature and position of substi-
tuents in the pyridine ring have considerable effects on
these types of reactions.
The aforementioned pyridine ring recyclization includes
reactions involving the sp3-carbon attached to position 2 of
the pyridine ring and suggests that the recyclization could
also involve more remote reactive groups.
The recyclization of pyridinium salts into anilines
appears to be a fundamental type of pyridine ring transfor-
mation into benzene ring. In the present study, we report
the effects of sulfonyl moiety as well as that of various
amines on the recyclization of pyridinium salts. Thus,
2-[(phenylsulfonyl)methyl]pyridine (3) was selected as a
key precursor for the synthesis of some hitherto unreported
2-(phenylsulfonyl)aniline derivatives with an expected
broad spectrum of biological effects.
The reaction of 2-(chloromethyl)pyridine hydrochloride
(1) with sodium benzenesulfinate (2) in refluxing ethanol
furnished exclusively the corresponding 2-[(phenylsufonyl)-
methyl]pyridine (3) in excellent yield (Scheme 1). The
identity of compound 3 was confirmed by elemental
analysis, the mass spectrum with a molecular ion peak with
m/z 233 ([M]+, 50%), and 1H NMR spectrum which
revealed a singlet signal at 5.00 ppm due to CH2 protons.
Compound 3 was further used as a versatile reagent for
the construction of several diaryl sulfone derivatives.
Scheme 1
It was expected that the activation of 2-CH2 group by
the electron-withdrawing phenylsulfonyl substituent in the
salt 4a would facilitate the formation of the intermediate A,
a key step in the reaction that occurs in the presence of
NaOH. The treatment of the salt 4a with aqueous sodium
hydroxide solution ultimately led to N-methyl-2-(phenyl-
sulfonyl)aniline (5) in 4% yield (Scheme 2), confirmed by
mass spectrum featuring the molecular ion peak with
m/z 247 ([M]+, 60%) and 1H NMR spectrum which showed
singlet signals at 2.64 and 6.72 ppm for CH3 and NH
protons, respectively. However, when the same reaction
was carried out in the presence of aqueous methylamine, it
proceeded with the formation of a mixture containing
compound 5 in a better yield (12%), as well as 2-(phenyl-
sulfonyl)phenol (6) in 3% yield, and pyridine base 3 in 40%
yield, resulting from parallel process of dealkylation by
virtue of direct attack of the nucleophile on the N–Me bond
(SN2 mechanism). Since it has been reported that 2-picoli-
nium salts do not undergo enamine rearrangement in
aqueous ethanolic solutions of alkali or alkyl amines,16 the
formation of compound 5 in the present study indicates that
the phenylsulfonyl group activates the 2-methylene group
towards the rearrangement (Scheme 3).
On the other hand, in the presence of methylammonium
sulfite as a recyclization reagent, the iodide 4a underwent
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0009-3122/16/52(8)-0570©2016 Springer Science+Business Media New York

Chemistry of Heterocyclic Compounds 2016, 52(8), 570–573
Scheme 2
Scheme 3
Scheme 4
Scheme 5
rearrangement to N-methyl-2-(phenylsulfonyl)aniline (5) in
a good yield (78%). The formation of compound 5 by the
pathway shown in Scheme 3 was in line with a number of
previously reported cases. 6–15,17,18,19
In the present study, the action of methylammonium
sulfite on 1-ethyl-2-(phenylsulfonylmethyl)pyridinium
iodide (4b) led to the formation of a mixture of N-methyl-
2-(phenylsulfonyl)aniline (5) (64%), 2-(phenylsulfonyl)-
phenol (6) (15%), and compound 3 (10%) (Scheme 4).
These results were in a good agreement with previously
reported work.10,11
and 1H NMR spectrum showing a singlet signal at
10.13 ppm, assigned to the OH proton.
Based on the evidence that treatment of N-alkyl-
pyridinium salts with aqueous ammonia18 or ammonium
sulfite19,20 leads to dealkylation only, it seemed of interest
to study the action of ammonium sulfite on compound 4a
(Scheme 3). In this case, recyclization was found to occur
without the exchange of methylamino fragment by amino
function, and the reaction products were identified as
compounds 3 (50%), 5 (4%), and 6 (10%). The high yield
of compound 3 may be attributed to its simultaneous
formation via two pathways, one involving the N-dealkyla-
tion of pyridinium iodide 4a by direct nucleophilic attack
of the reagent at the N-methyl group, and the other
(evidently the principal pathway) by opening of the
pyridine ring, exchange of the methyl amine fragment for
an amine fragment in the open structure, and subsequent
ring formation giving the products shown in Scheme 3.
Based on the evidence that 2-picoline undergoes recycli-
zation to N-methylaniline when treated with aqueous
methylammonium sulfite,17,20 the recyclization of unquater-
nized 2-[(phenylsulfonyl)methyl]pyridine (3) was studied.
Thus, we found that the action of aqueous methylammo-
nium sulfite on unquaternized 2-[(phenylsulfonyl)methyl]-
pyridine (3) led to opening of the pyridine ring with
exchange of the amine fragment for a methylamine
fragment and the formation of the pyridinium salt recycli-
zation product, i.e., N-methyl-2-(phenylsulfonyl)aniline (5),
although it was obtained in a very low yield (8%, Scheme 5).
However, the bulk of compound 3 was recovered
unchanged. These results were in a good agreement with
previously reported work.10 There is no evidence for the
formation of 2-(phenylsulfonyl)aniline as a product of
recyclization reaction by spectroscopic data. All attempts to
obtain the latter compound by treatment of compound 3
with aqueous ammonium sulfite failed.
On the other hand, the reaction of ethylammonium sulfite
with the N-methylpyridinium iodide 4a gave compound 5
as the main product (40%) instead of N-ethyl-2-(phenyl-
1
sulfonyl)aniline (7), which could not be detected in H NMR
spectrum (Scheme 3). However, GC-MS data of the mixture
indicated that compound 7 was formed in a very poor yield.
This shows that the substitution of methylamino group by
ethylamino group occurs with great difficulty (Scheme 3).
The treatment of pyridinium iodide 4a with dimethyl-
ammonium sulfite gave compounds 5 (6%) and 3 (50%),
indicating that the secondary amine (dimethylamine) was
not involved in the reamination reaction (Scheme 3). Thus,
it was concluded that this type of reactions depends on the
steric bulk of the attacking nucleophile.
When the nucleophile was less bulky, such as methyl-
ammonium sulfite, the reamination reaction was found to
be facile. However, in the case of a bulkier nucleophile,
such as ethylammonium sulfite, the increased steric hindrance
greatly decreased the yield of the reamination product 7.
The bulky dimethylamino group in dimethylammonium
sulfite prevented the exchange reaction, and therefore no
2-(dimethylamino)diphenyl sulfone was obtained. However,
the high basicity of dimethylamine gave compound 6 in a
considerable yield, which confirmed by mass spectrum
showing a molecular ion peak with m/z 234 ([M]+, 50%)
571

Chemistry of Heterocyclic Compounds 2016, 52(8), 570–573
The structures of all the compounds obtained were
(50). Found, %: C 41.52; H 3.60; N 3.64. C13H14INO2S.
1
proved by a combination of spectral methods (IR, H and
Calculated, %: C 41.61; H 3.76; N 3.73.
13C NMR spectroscopy), mass spectrometric analysis, and
by comparison with literature data.
1-Ethyl-2-[(phenylsulfonyl)methyl]pyridinium iodide
(4b). Yield 82%, mp 156°C. IR spectrum, ν, cm–1: 1310
1
Thus, heterocyclic sulfones have proven to be valuable
synthons for the synthesis of a wide variety of potentially
biologically active diaryl sulfones. We have reported here
for the first time the synthesis of diaryl sulfones by using
nucleophile-induced rearrangement of pyridinium salts
bearing (phenylsulfonyl)methyl moieties, as these com-
pounds are not always readily accessible by previously
known methods.
(SO2). H NMR spectrum, δ, ppm (J, Hz): 1.57 (3H, t,
J = 8.0, CH3); 4.67 (2H, s, CH2); 4.80 (2H, q, J = 8.0,
CH2); 7.60–8.50 (9H, m, H Ar). 13C NMR spectrum,
δ, ppm: 17.1; 56.1; 64.0; 125.4; 126.4; 128.3 (2C); 129.7
(2C); 133.7; 137.6; 145.6; 146.3; 151.3. Mass spectrum, m/z
(Irel, %): 262 [M]+ (40). Found, %: C 43.10; H 4.01; N 3.50.
C14H16INO2S. Calculated, %: C 43.20; H 4.14; N 3.60.
Ring opening and recyclization of pyridinium salts
4a,b. Method I. Compound 4a (3.74 g, 0.010 mol) was
treated with 25% aqueous sodium hydroxide (10 ml) and
ethanol (1 ml) to obtain a homogeneous solution, then
heated for 3 h under nitrogen atmosphere, cooled, and
extracted twice with ether. The ethereal extract was dried
over anhydrous magnesium sulfate and chromatographed
on a silica gel column (100/160 µm), eluting with benzene.
Removal of solvent from the collected fractions under
reduced pressure gave compound 5 as oil.
Experimental
IR spectra were recorded for thin films on KBr disk on a
Mattson 5000 FTIR spectrometer at the Faculty of Science,
Mansoura University, Egypt. 1H and 13C NMR spectra were
acquired on a Bruker WPSY spectrometer (200 and 50 MHz,
respectively) for DMSO-d6 solutions with TMS as internal
standard. The mass spectra were recorded with EI
ionization (70 eV) on a Varian MAT 311 instrument at the
Micro Analytical Center, Faculty of Science, Cairo
University. Elemental analyses were carried out on a
Heraeus MIKRO-K flask type Schöniger combustion
apparatus at the Faculty of Science, Cairo University.
Melting points were determined on a Gallenkamp digital
melting point apparatus and were not corrected. The
homogeneity of the products was checked by TLC with
benzene as eluent. All alkylammonium sulfite reagents
were prepared according to a previously reported method.7
Synthesis of 2-[(phenylsulfonyl)methyl]pyridine (3).
A mixture of compound 1 (1.64 g, 0.010 mol) and sodium
benzenesulfinate 2 (2.46 g, 0.015 mol) in absolute ethanol
(30 ml) was refluxed for 6 h. The reaction mixture was left
to cool at room temperature and poured into cold water.
The solid product that precipitated was filtered off, washed
thoroughly with water, dried, and recrystallized from
absolute ethanol. Yield 78%, white crystals, mp 110–112°C
Method II. Aqueous methylamine (35%, 22.24 g, 0.71 mol)
was added to compound 4a (7.48 g, 0.020 mol). The
mixture was heated in a pressure tube in silicone oil bath at
150°C for 8 h. The product was extracted with ether, dried
over anhydrous magnesium sulfate, and chromatographed
on silica gel (100/160 µm). Elution with benzene gave
compounds 5, 3 and 6.
Method III: Reaction of pyridinium iodide 4a with methyl-
ammonium sulfite. Aqueous methylammonium sulfite (35%,
25 ml) was added to pyridinium iodide 4a (7.48 g, 0.02 mol),
and the reaction mixture was heated in a pressure tube in
silicone oil bath at 150°C for 10–15 h. The product was
extracted with ether, dried over anhydrous magnesium
sulfate and chromatographed on silica gel (100/160 µm) using
benzene as eluent. The benzene eluate was evaporated
under reduced pressure to give N-methyl-2-(phenyl-
sulfonyl)aniline (5) along with the dealkylation product 3.
Method IV. An aqueous solution of methylammonium
sulfite (35%, 30 ml) was added to the pyridinium iodide 4b
(7.78 g, 0.020 mol), and the mixture was heated in pressure
tube at 150°C for 20–30 h. The product was extracted with
ether, dried over anhydrous MgSO4 and separated by
chromatography on a silica gel (100/160 μm) column using
benzene as eluent to give compound 5.
1
(mp 111–112°C21,22). IR spectrum, ν, cm–1: 1310 (SO2). H
NMR spectrum, δ, ppm: 5.00 (2H, s, CH2); 7.26–8.23 (9H,
m, H Ar). 13C NMR spectrum, δ, ppm: 66.2; 120.9; 124.1;
128.3 (2C); 129.7 (2C); 133.7; 136.2; 137.6; 148.6; 158.6.
Mass spectrum, m/z (Irel, %): 233 [M]+ (50). Found, %:
C 61.65; H 4.63; N 5.85. C12H11NO2S. Calculated, %:
C 61.78; H 4.75; N 6.00.
Synthesis of 2-[(phenylsulfonyl)methyl]pyridinium
iodides 4a,b (General method). A mixture of compound 3
(2.33 g, 0.01 mol) and methyl iodide (2.84 g, 0.02 mol) or
ethyl iodide (3.12 g, 0.02 mol) was allowed to stand at
room temperature for one day in pressure tube. The yellow
crystals that formed were recrystallized from ethanol–ether,
3:1, to give compounds 4a and 4b, respectively.
N-Methyl-2-(phenylsulfonyl)aniline 5. Yield 4%
(method I), 12% (method II), 78% (method III), 64%
(method IV). Rf 0.65. IR spectrum, ν, cm–1: 3450 (NH),
1310 (SO2). 1H NMR spectrum, δ, ppm: 2.64 (3H, s, CH3); 6.72
(1H, s, NH); 6.84–7.97 (9H, m, H Ar). 13C NMR spectrum,
δ, ppm: 29.6; 112.4; 117.2; 118.1; 122.0; 124.1; 124.7;
128.3 (2C); 129.7 (2C); 133.7; 141.4. Mass spectrum, m/z
(Irel, %): 247 [M]+ (60). Found, %: C 63.01; H 5.22; N 5.45.
C13H13NO2S. Calculated, %: C 63.14; H 5.30; N 5.66. The
spectral data for compound 5 matched the literature.24
2-[(Phenylsulfonyl)methyl]pyridine (3). Yield 40%
(method II), 10% (method IV), mp 110–112°C (mp 111–
1-Methyl-2-[(phenylsulfonyl)methyl]pyridinium iodide
(4a). Yield 90%, mp 135°C. IR spectrum, ν, cm–1: 1310
1
(SO2). H NMR spectrum, δ, ppm: 4.39 (3H, s, N–CH3);
4.67 (2H, s, CH2); 7.67–8.69 (9H, m, H Ar), in agreement
with the literature.23 13C NMR spectrum, δ, ppm: 40.6;
63.7; 125.4; 126.4; 128.3 (2C); 129.7 (2C); 133.7; 137.6;
145.6; 146.3; 151.3. Mass spectrum, m/z (Irel, %): 247 [M]+
1
112°C21,22), Rf 0.55. Identical spectral data (IR, H NMR,
and mass spectra) with that obtained above.
572

Chemistry of Heterocyclic Compounds 2016, 52(8), 570–573
2-(Phenylsulfonyl)phenol (6).25–27 Yield 3% (method II),
7. Fadda, A. A.; Kost, A. N.; Sagitullin, R. S. Org. Prep. Proc.
15% (method IV), mp 52°C. Rf 0.58. IR spectrum, ν, cm–1:
Int. 1981, 13, 203.
1
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3455 (OH), 1300 (SO2). H NMR spectrum, δ, ppm: 6.98–
7.97 (9H, m, H Ar); 10.13 (1H, s, OH). 13C NMR
spectrum, δ, ppm: 115.7; 122.3; 128.3 (2C); 129.7 (3C);
130.3; 133.7; 141.4; 149.0; 153.1. Mass spectrum, m/z (Irel, %):
234 [M]+ (50). Found, %: C 61.40; H 4.15. C12H10O3S. Calcu-
lated, %: C 61.52; H 4.30.
Ring opening and recyclization of pyridine derivative 3.
Aqueous 35% methylammonium sulfite (25 ml) was added
to 2-[(phenylsulfonyl)methyl]pyridine (3) (2.33 g, 0.01 mol),
and the reaction mixture heated in a pressure tube for 60 h at
150°C. The resultant product was extracted with ether,
dried (MgSO4), and chromatographed on a silica gel
(100/160 μm) column using benzene–ethyl acetate, 4:1, as
eluent to give compound 5 (yield 8%) with identical IR,
1H NMR, and mass spectral characteristics to those
described above.
The author is deeply thankful to Dr. Ahmed A. Fadda,
Professor of Organic Chemistry, Faculty of Science,
Mansoura University, for suggesting the research topic,
continuous guidance, practical help, and valuable
discussions.
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