Triflic acid–catalyzed rearrangement of unalkylated benzene sulfonanilides

Article abstract of DOI:10.1080/00397911.2016.1178776

ABSTRACT: Previous work has demonstrated that alkylated benzene sulfonanilides undergo sulfuric acid (98%)–catalyzed rearrangement to alkylamino diaryl sulfones. Similar treatment of their unalkylated analogs typically leads only to hydrolysis. Surprisingly, when the unalkylated benzene sulfonanilides react with triflic acid, rearrangement to sulfones does occur.

Full text of DOI:10.1080/00397911.2016.1178776

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
Triflic Acid-Catalyzed Rearrangement of
Unalkylated Benzene Sulfonanilides
Rebecca Newcomer, James McKee & Murray Zanger
To cite this article: Rebecca Newcomer, James McKee & Murray Zanger (2016): Triflic Acid-
Catalyzed Rearrangement of Unalkylated Benzene Sulfonanilides, Synthetic Communications,
DOI: 10.1080/00397911.2016.1178776
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Date: 27 April 2016, At: 16:27

Triflic Acid-Catalyzed Rearrangement of Unalkylated Benzene Sulfonanilides
Rebecca Newcomer, James McKee, Murray Zanger
1Department of Chemistry & Biochemistry, University of the Sciences, Philadelphia PA,
Philadelphia, PA
Corresponding Author: Murray Zanger. E-mail: m.zanger@usciences.edu
Abstract
Previous work has demonstrated that alkylated benzene sulfonanilides undergo sulfuric
acid (98%) catalyzed rearrangement to alkylamino diaryl sulfones. Similar treatment of
their unalkylated analogues typically leads only to hydrolysis. Surprisingly, when the
unalkylated benzene sulfonanilides react with triflic acid, rearrangement to sulfones does
occur.
KEYWORDS: Triflic Acid, Rearrangement, Unalkylated Benzenesulfonanilides, Diaryl
Sulfones
INTRODUCTION
Trifluoromethanesulfonic acid[1] (Triflic acid, TfOH) ranks as one of the strongest
organic acids. This superacid and its conjugate base have extreme thermal stability and
resistance to oxidation/reduction reactions. The triflate anion is a very weak nucleophile
and does not readily form triflates. In short, Triflic acid functions almost exclusively as
an acid catalyst unlike other acids such as sulfuric or perchloric. In addition it is miscible
with water and is easy to remove from reaction mixtures.
1

The acid-catalyzed rearrangement of N-alkylated benzene sulfonanilides to
aminodiarylsulfones has been extensively investigated in this laboratory[2-6]. These
sulfones are of interest because they exhibit a broad range of pharmacological
activity against HIV, tuberculosis and bacterial infections[19]. Initially, concentrated
sulfuric acid (98%) was the reagent of choice but several compounds were found to
hydrolyze instead of rearranging. Polyphosphoric acid (PPA) and triflic acid (TfOH)
proved successful in some cases where sulfuric acid failed[5]. Although no definitive
mechanism fully explained these results, the presence of small amounts of water in
concentrated sulfuric acid, and the greater sensitivity of some compounds to this water,
provide some rationalization for hydrolysis in these cases. Both PPA and TfOH are water
free. For this work triflic acid was purchased in multiple small batches so fresh,
unhydrolyzed acid was used for this study.
Unlike their N-alkylated derivatives, unalkylated benzene sulfonanilides when treated
with concentrated sulfuric acid routinely undergo hydrolysis[3] although they can be
rearranged by a Fries reaction[7a] and via anionic catalysis[7b]. Attempts were made to
rearrange these compounds using PPA and TfOH[6]. A number of unalkylated benzene
sulfonanilides were prepared and treated with either PPA or TfOH. PPA led to hydrolysis
while TfOH gave rearranged products (Scheme 1.). The products for the unalkylated
compounds lacking a nitro group yielded only para amino sulfones while the alkylated
sulfonanilides formed mainly ortho products.
2

Nine known unalkylated benzene sulfonanilides[8-14] , Table 1, were prepared. Several
compounds contained nitro and methyl-groups at the 2- and 4-positions on the sulfonic
acid portion of the molecule and methyl and chloro-groups at the 2- and 4-positions on
the aniline moiety. All were subjected to treatment with TfOH resulting in the formation
twelve sulfones (seven new; 12, 14, 16, 17, 19, 20, 21 ), Table 1[9,15-16]. Interestingly, the
four compounds containing a nitro-group rearranged with extensive decomposition
giving products which were difficult to purify and with very poor yields (<10%). By
comparison the N-alkylated analogues with nitro-groups rearranged cleanly.
RESULTS AND DISCUSSION
The Schotten-Baumann reaction was initially used to synthesize some of the
sulfonanilides9-14], using either pyridine or sodium hydroxide as the base (Proc. A).
Several compounds [8], were synthesized using acetic acid and anhydrous sodium acetate
(Proc. B). Ultimately the preferred synthetic method for the sulfonanilides, especially
those containing nitro-groups was using aqueous or dilute methanol solutions of sodium
acetate[17] as the base (Proc. C). This method gave high yields and very clean products.
Rearrangement of the sulfonanilides was done in TfOH, which proved to be more
effective than either sulfuric acid or PPA. Use of sulfuric acid or PPA led to hydrolysis of
the sulfonanilide. Details about the percent yield and structures of the synthesized
sulfonanilides and sulfones are listed in Table I. Type I represents the general structure of
the sulfonanilides whereas Type II and Type III depict the o-amino- and p-amino-product
sulfones respectively.
3

Sulfonanilides, such as (3), (4), (7) and (8), on which there was an electron withdrawing
group (NO2) did rearrange to sulfones but with extensive decomposition. Product
purification required prep-scale TLC from ether and gave yields below 10%. As a
synthetic scheme for the preparation of these nitrosulfones alternate methods would be
preferable. In addition, unlike the analogues which did not contain a nitro group, nitrated
compounds where possible also gave some ortho-products.
To summarize:
Unalkylated sulfonanilides generally rearranged to p-aminosulfones. o-amino-sulfones
were also produced when a nitro-group was present (on the sulfonic acid portion of the
molecule) or when the para-position was blocked. The rearrangement was catalyzed by
TfOH while concentrated sulfuric acid or PPA led to hydrolysis.
Alkylated sulfonanilides rearranged to o-aminosulfones but gave some p-aminosulfones
when a nitro-group was present (on the sulfonic acid portion of the molecule) or when the
ortho-position was blocked. The rearrangement was catalyzed by conc. sulfuric acid,
PPA and TfOH.
EXPERIMENTAL
Most chemicals were purchased from Sigma-Aldrich Chemical Co. and were used
without further purification. Trifluoromethanesulfonic Acid (Triflic Acid) was purchased
from TCI America. Melting points were obtained using a Mel-Temp II Laboratory
Device. 1H and 13C NMR spectra were obtained in d6-acetone, d1-chloroform and d6-
dimethyl sulfoxide on a Bruker 400 MHz Nuclear Magnetic Resonance Spectrometer. An
4

Orbitrap Exactive mass spectrometer was used to obtain all mass spectra. All infrared
spectra were obtained on a Perkin-Elmer FT-IR Spectrophotometer.
Synthesis Of Sulfonamides
Procedure A
In a beaker equipped with a magnetic stir bar, an acid chloride and amine are added. 10%
NaOH is added in portions and the reaction mixture is stirred for an hour at room
temperature. The mixture was confirmed to be basic at the end of the reaction. The
mixture is then acidified to pH 2 with 10% HCl and the solid is collected by vacuum
filtration. After filtration, the solid is washed with water (4 x 20 mL), decolorized with
Norit and recrystallized from 60% ethanol.
Procedure B
The aniline is added to a beaker containing acetic acid and heated to 118ºC. The sulfonyl
halide (10% molar excess) is gradually added to the beaker causing the mixture to boil
along with the formation of a precipitate. One equivalent of anhydrous sodium acetate is
added at five to ten minute intervals in decreasing amounts; ½, ¼, ⅛, ⅛. A 25% molar
excess is achieved after a final addition of ¼ molar quantity. The mixture was stirred for
15 additional minutes before adding a minimal amount of water to dissolve any
precipitates. The mixture was cooled, and vacuum filtered. The product was then washed
with 60% acetic acid, dil. HCl and water. The product was recrystallized from 60%
alcohol.
5

Procedure C
In this scheme the sodium acetate was dissolved in water followed by the addition of the
sulfonyl chloride and aniline. The stirred mixture is then heated to 80-85oC. until there is
evidence of a reaction and stirring is continued until the dark gummy solid is converted to
a finely divided solid. The solid is recovered via vacuum filtration and recrystallized from
60% ethanol.
Following are representative examples of syntheses using Procedures A, B and C.
Sample Procedure For The Synthesis Of N-Phenylbenzenesulfonamide (1)
Procedure A, as described above, was performed using benzene sulfonyl chloride (10.1
mL, 0.079 mol) and aniline (7.1 mL, 0.078 mol). Sodium hydroxide (10%) was added in
small portions with stirring until the mixture tested basic. The pale yellow reaction
mixture was gravity filtered and then the crude product was recrystallized (65% ethanol)
to yield 8.1 g of beige pebbles, N-phenyl-benzenesulfonamide (1). Yield: 44%, mp 112-
113ºC (lit. 110-112ºC); IR: 3234 cm-1 (NH), 1159 cm-1 (SO2); 1H (400 MHz, Acetone-d6)
δ 8.88 (s, 1H), 7.83 (d, 2H), 7.61 (t, 1H), 7.53 (d, 2H), 7.24 (d, 4H), 7.14 (m, 1H); 13C
NMR (101 MHz, acetone-d6) 140.04, 137.86, 132.74, 128.99, 128.82, 127.02, 124.65,
120.98. M.W.calcd. 233.05 m/z ASAP (+ mode) 234.06 (C12H11NO2S)
Sample Procedure For The Synthesis Of 4-Methyl-N-Phenylbenzenesulfonamide (2)
Procedure B was performed using aniline (8.8 mL, 0.0966 mol) and p-toluenesulfonyl
chloride (23 g, 0.1206 mol) and 60 mL of glacial acetic acid. The aniline was dissolved in
6

the acetic acid and heated with stirring to 100ºC. The tosyl chloride was added in several
portions as the acetic acid reached the boiling point. The sodium acetate was added in
several batches; 3.7 g., 1.8 g., 1.0 g., 1.0 g. at 5-10 minute intervals. A final 1.8 g. of
acetate was added and the heating was continued for 15 minutes. The mixture was poured
over ice and vacuum filtered. The product was recrystallized from 60% ethanol, forming
white crystals (16.8 g) (2). Yield: 70%, mp 111-112ºC (lit 104-105 ºC); IR: 3258 cm-1
(NH brd. str.), 1160 cm-1 (SO2, med); 1H (400 MHz, DMSO-d6), δ 10.23 (s, 1H), 7.65 (d,
2H), 7.33 (d, 2H), 7.21 (t, 2H), 7.10 (d, 2H), 7.0 (t, 1H) 2.29 (s, 3H), 13C M.W.calcd.
247.07 m/z ASAP (+ mode) 248.07 (C13H13NO2S)
Sample Procedure For The Synthesis Of 4-Nitro-N-Phenylbenzenesulfonamide (4)
Procedure C was performed using 4-nitrobenzensulfonyl chloride (3 g, 0.0135 mol) and
aniline (1.28 mL, 0.014 mol) and sodium acetate (anhyd.) (1.64 g, 0.02 mol). The acetate
was dissolved in 18 mL of water and the other reactants were added, stirred with a
magnetic stirrer and gradually heated to about 85ºC. A dark, viscous solid formed
initially but continued heating and stirring converted the product to a pale yellow, finely
divided solid. The solid was collected by gravity filtration, washed with water and
recrystallized in 65% ethanol forming 3.1 g of white crystalline flakes (4). Yield: 82%,
mp 169-170ºC (lit. 168ºC); IR: 3278 cm-1 (NH, str), 1524 cm-1 (NO2, str.), 1161 cm-1
(SO2, str.); 1H (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.37 (d, 2H), 7.99 (d, 2H), 7.26 (t,
2H), 7.08 (t, 3H), M.W.calcd. 278.04 m/z ASAP (+mode) 279.04 (C12H10N2O4S)
Rearrangement Reactions: Syntheses Of R-(Sulfonyl)Benzenes
7

In a clean test tube TfOH was combined with a benzenesulfonanilide. The test tube was
loosely corked and placed in a 108ºC oven for an hour. Following the hour’s span, the
test tube was removed from the oven and the contents were poured over ice, resulting in
formation of a solid. The solid was vacuum filtered and washed with water (4 x 20mL).
In a beaker equipped with a magnetic stir bar, the solid was combined with saturated
sodium bicarbonate solution and stirred for a half hour. The filtered solid was decolorized
with Norit and recrystallized from ethanol/water. In cases where isomers were formed,
the partially purified product was applied to prep-scale silica-gel plates, 20 x 20 cm (2000
μ), and developed using ethyl ether.
The nitro-substituted amides were treated as above but heated to 80-85 ºC for 30-40
minutes.
Sample Procedure For The Synthesis Of 4-[(2-Nitrophenyl)Sulfonyl]Aniline (12)
And Of 2-[(2-Nitrophenyl)Sulfonyl]-Aniline (20). Rearrangement Of (3)
The rearrangement procedure as described above was performed using TfOH (8 mL, 0.09
mol) and 2-nitro-N-phenylbenzene-sulfonamide (3) (2.0 g, 0.0072 mol). The crude
product weighed 1.1 g but gave two bands on TLC analysis. Prep scale TLC (from ethyl
ether) yielded two products; For (12), the purified product weighed 0.20 g Yield 10%, mp
133-135 oC ; IR: 3481, 3383 cm-1 (NH2), 1540 cm-1 (o-NO2), 1151 cm-1 (SO2); 1H (400
MHz, acetone-d6) δ 8.50 (d, 1H), 8.32 (d, 1H), 8.15, (t, 1H), 7.86 (t, 1H), 7.34 (d, 2H),
6.68 (d, 2H), 5.33 (s, 2H); 13C NMR (101 MHz, acetone-d6) 151.79, 144.87, 135.22,
131.27, 130.70, 128.62, 125.95, 125.29, 119.97, 113.74. M.W.calcd. 278.04 m/z ASAP
8

(+mode) 279.04 (C12H11N2O4S). For (20), the purified product weighed 0.096 g Yield ,
<10%, mp 125-127 oC; IR: 3482, 3384 cm-1 (NH2), 1539 cm-1 (o-NO2), 1142 cm-1 (SO2);
1H (400 MHz, acetone-d6) δ 8.28 (d, 1H), 7.92 (m, 3H), 7.71 (d, 1H), 7.40 (t, 1H), 6.94
(d, 1H), 6.81 (t, 1H), 5.94 (s, 2H); 13C NMR (101 MHz, acetone-d6) 148.04, 135.64,
134.93, 133.74, 132.17, 130.69, 130.41, 124.62, 119.51, 117.75, 117.69, 116.34.
M.W.calcd. 278.04 m/z ASAP (+mode) 279.04 (C12H11N2O4S).
Attempted Rearrangement of an unalkylated benzene sulfonanilide with Sulfuric
Acid
In a test tube, N-phenylbenzenesulfonamide (1) (4.0 g, 0.016 mol) was mixed
with 12 ml of concentrated sulfuric acid. The mixture gradually colored and when
complete solution occurred it was heated on a steam bath for 45 minutes. The tube was
cooled and the contents were poured over an ice-water mixture. No products separated
out. The hydrolysis products were water soluble.
Supporting information: Seven novel sulfones were prepared; 12, 14, 16, 17, 19,
20, & 21. Full experimental detail, 1H and 13C NMR spectra, IR and MS spectra. This
material can be found via the “Supplemental Experimental Information” section of the
article’s webpage.
REFERENCES
9

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(DHPA) Sulfonamides and Subsequent Acid-Catalyzed Rearrangement to Diaryl
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Hellwinkel, D., Possibilities and Limits of the Anionically Induced Sulfonamide-amino
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Sulfone Derivatives, Tetrahedron; 2003, 59(39), 7651
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Benzothiadiazine Dioxides ; J. Org Chem. 1951, 16, 815
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[11] Snyder, H. R.; A Method for the Rapid Cleavage of Sulfonamides; J. Am. Chem.
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Tetrahedron: A symmetry; 2009, 20(13), 1500
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Derivatives ; J. Chem. Soc., 1946, 729
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Pseudohalogens Justus Liebigs Annalen der Chemie; 1955, 597, 20
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Alkylsulfonyl Derivatives of Primary Aromatic Amines into Amino Sulfones; Zhyurnal
Organicheskoi Khimii, 1965, 1(9) 1667
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Meijere, A., Eur. J. Org Chem., 2009, 2635
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D. Exploring QSAR. Chem. Rev. 1971, 71(6), 525
11

Table 1. Sulfonamide Reactants
R4
R2
O
S
NH
R3
O
R1
#
R1
H
R2
H
R3 R4
Formula
Yield(%)
1
H H
C12H11NO2S
C13H13NO2S
C12H10N2O4S
C12H10N2O4S
C14H15NO2S
C14H15NO2S
C13H12N2O4S
C13H12N2O4S
44
70
40
82
92
41
85
2
3
4
5
6
7
8
9
H
H
H CH3
NO2 H
H NO2
H CH3
H CH3
NO2 H
NO2 H
H CH3
H
H
H
H
CH3
H
H
CH3
CH3
H
H
CH3
H
52
Cl
C13H12ClNO2S 52
12

Table 2. Product Sulfones
R3
O
O
R3
O
O
S
H2N
S
R1
R1
R4
R4
H2N
R2
Type II
Type I
#
Type R1
R2
H
H
H
H
R3 R4
Formula
Yield(%)
59
10
11
12
13
14
I
I
I
I
I
H
H
H
H
C12H11NO2S
C13H13NO2S
CH3
H
H
47
H
NO2 C12H10N2O4S
10
NO2
H
H
H
H
C12H10N2O4S
C14H15NO2S
C14H15NO2S
<10
36
CH3 CH3
H
15 II
CH3
H
H
CH3
54
16 II
H
CH3 NO2 C13H12N2O4S
<10
<10
17 II
H
CH3
H
H
Cl
H
H
H
NO2 C13H12N2O4S
18 II
CH3
NO2
H
H
H
C13H12ClNO2S 64
C12H10N2O4S <10
19. II*
20. II**
H
H
NO2 C12H10N2O4S
NO2 C13H12N2O4S
<10
<10
21 II*** H
CH3
*ortho isomer of 13
**ortho isomer of 12
***ortho isomer of 17
13

Scheme 1. Acid-catalyzed reactions of sulf onanilides
14