Regiospecificity in the synthesis of diaryl sulfones

Article abstract of DOI:10.1021/jo026640x

The addition of arylsulfinic acids to 2-methyl-1,4-benzoquinone provides high yields of sulfones in a wide variety of solvents. The distribution of isomeric products obtained is strongly influenced by either (1) the acidity of aqueous solvents or (2) the water content of alcohol solvents. The distribution of isomeric products does not change in the various anhydrous, aprotic solvents examined.

Full text of DOI:10.1021/jo026640x

SCHEME 1
Regiosp ecificity in th e Syn th esis of Dia r yl
Su lfon es†
Daniel E. Allgeier, Sue Ann Herbert, Rory Nee,
Kenneth D. Schlecht, and K. Thomas Finley*
Department of Chemistry, State University of New York,
College at Brockport, 350 New Campus Drive,
Brockport, New York 14420-2972
SCHEME 2
kfinley@brockport.edu
Received October 31, 2002
Abstr a ct: The addition of arylsulfinic acids to 2-methyl-
1,4-benzoquinone provides high yields of sulfones in a wide
variety of solvents. The distribution of isomeric products
obtained is strongly influenced by either (1) the acidity of
aqueous solvents or (2) the water content of alcohol solvents.
The distribution of isomeric products does not change in the
various anhydrous, aprotic solvents examined.
the principal product in a similar reaction. Spinner et
al. used 4-(2-bromoethyl)benzenesulfinic acid to obtain
a 55% yield of compound 3 (Scheme 2).8 Since aqueous
ethanol was used in this instance, it seemed important
to examine the extent to which solvent and acidity can
shift the proportion of isomeric products.
Two other examples of the regiospecificity of nucleo-
philic sulfur addition to 2-methyl-1,4-benzoquinone have
been reported. Gates and his collaborators studied the
addition of 1-phenyl-5-mercaptotetrazole in methanol and
found the 2,5-adduct analogous to compound 1 to pre-
dominate in a 2 to 1 ratio. In this instance, a total yield
of only 38% was obtained.5 Lau and Kestner found that
thiourea adds to 2-methyl-1,4-benzoquinone in strongly
acidic solvents and produces an overall yield of 89% and
the 2,6-adduct corresponding to compound 2 in a 9 to 1
ratio.9
In 1992, Bruce and Lloyd-Williams repeated the ad-
dition shown in Scheme 1.10 Using a two-phase dichlo-
romethane/water system made strongly acidic with tri-
fluoroacetic acid, they found a 3 to 1 excess of compound
2. Their evidence demonstrates that the protonated
quinone is the reactive species and that selective proto-
nation of the two carbonyl groups explains the observed
product ratios.
The addition of benzenesulfinic acid to 2-methyl-1,4-
benzoquinone leads to two isomeric sulfones (Scheme 1):
The literature of quinone addition reactions has been
extensively reviewed and shows that the Michael adducts
from monosubstituted 1,4-benzoquinones, are not formed
in equal amounts.1 We wish to present appropriate
conditions for the preparation of each of these regioiso-
mers and analogous compounds.
In an earlier study of quinonoid electrochemistry,2 we
carried out this reaction in aqueous acetic acid as
described by Wanzlick,3 who had followed the original
method of Otto Hinsberg.4 No evidence was found for
compound 1, and since a good yield of compound 2 was
obtained, we did not pursue the subject further. The
NMR coupling constants of the hydroquinone ring pro-
tons, as described by Gates et al.,5 were used to establish
that the structure was sulfone 2. The ease with which
compound 2 was obtained was surprising since both
resonance theory6 and frontier molecular orbital theory7
predict 1 as the dominate isomer. Compound 1 is usually
referred to as the 2,5-adduct and has been reported as
The only aprotic solvent reported for the addition of
benzenesulfinic acid to a quinone is THF.11 This work
involved 1,2-benzoquinone and raises questions of re-
giospecificity related to the present study. In THF, the
only product found was 3-(phenylsulfonyl)-1,2-benzene-
diol. In water, the only product found was 4-(phenylsul-
fonyl)-1,2-benzenediol. We have not attempted to repeat
this chemistry, but we have studied the addition of
benzenesulfinic acid to 2-methyl-1,4-benzoquinone with
a select group of anhydrous aprotic solvents.
* To whom correspondence should be addressed. Phone: 585-395-
5588. Fax: 585-395-5805.
† Dedicated to Dr. B. Stuart Hurlbert, who by example taught the
beauty of research.
(1) Finley, K. T.; Tong, L. K. J . In The Chemistry of the Carbon-
Nitrogen Double Bond; Patai, S., Ed.; Interscience; London, 1970; pp
663-729. Finley, K. T. In The Chemistry of the Quinonoid Compounds;
Patai, S., Ed.; J ohn Wiley & Sons; New York, 1974; Part 2, pp 877-
1144. Finley, K. T. In The Chemistry of the Quinoid Compounds, Vol.
2; Patai, S., Rappoport, Z., Eds.; J ohn Wiley & Sons: Chichester,
England, 1988; Part 2, pp 537-717. Finley, K. T. Supplement E: The
Chemistry of Hydroxyl, Ether, and Peroxide Groups; Patai, S., Ed.; J ohn
Wiley & Sons: Chichester, England, 1993; pp 1027-1134.
(2) Brown, E. R.; Finley, K. T.; Reeves, R L. J . Org. Chem. 1971,
36, 2849.
A careful study of the influence of acidity and solvent
composition should provide a better understanding of this
reaction along with useful means of preparing the two
isomeric sulfones. We have examined the addition of
(3) Wanzlick, H. W. In Newer Methods of Preparative Organic
Chemistry; Foerst, W., Ed.; Academic Press: New York, 1968; Vol. 4,
pp 139-154.
(4) (a) Hinsberg, O. Ber. Dtsch. Chem. Ges. 1894, 27, 3259. (b)
Hinsberg, O. Ber. Dtsch. Chem. Ges. 1895, 28, 1315.
(5) Wilgus, H. S., III; Frauenglass, E.; J ones, E. T.; Porter, R. F.;
Gates, J . W., J r. J . Org. Chem. 1964, 29, 594.
(6) Thomson, R. H. J . Org. Chem. 1951, 16, 1082.
(7) Rozeboom, M. D.; Tegmo-Larsson, I.-M.; Houk, K. N. J . Org.
Chem. 1981, 46, 2338.
(8) Spinner, I. H.; Raper, W. D.; Metanomski, W. Can. J . Chem.
1963, 41, 483.
(9) Lau, P. T. S.; Gompf, T. E. J . Org. Chem. 1970, 35, 4103.
(10) Bruce, J . M.; Lloyd-Williams, P. J . Chem. Soc., Perkin Trans.
1 1992, 2877.
(11) Davies, R.; Pierpoint, W. S. Biochem. Soc. Trans. 1975, 3, 671.
10.1021/jo026640x CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003
4988
J . Org. Chem. 2003, 68, 4988-4990

TABLE 1. Ben zen esu lfin ic Acid a n d
2-Meth yl-1,4-ben zoqu in on e: P r od u ct Distr ibu tion a t
Va r iou s Acid ities
aqueous solution at pH 4.5, compound 1 was obtained in
60% yield. When the same reaction was carried out in
43% ethanol/water, compound 2 was obtained in 73%
yield. These results have been verified by replication as
previously indicated.
The optimum synthetic conditions are acetate buffer
(pH 4.5), which gave a 92% average yield in a 3:2 ratio
of compounds 1:2, and acetonitrile, which gave a 96%
average yield in a 1:6 ratio of compounds 1:2.
pHa
2,5-adduct (1) (%)
2,6-adduct (2) (%)
total yield (%)
1
20
41
60
39
80
59
40
61
85
90
92
91
2
4.5
5.5
a
Ambient temperature.
These results strongly suggest that the mechanistic
details of this chemistry are more complex and interest-
ing than previously appreciated.
TABLE 2. Ben zen esu lfin ic Acid a n d
2-Meth yl-1,4-ben zoqu in on e: P r od u ct Distr ibu tion in
Un bu ffer ed , Acid ic Solven t System s
On the basis of these findings, we re-examined the
work of Bruce and Lloyd-Williams. Our results, pre-
sented in Table 2, show excellent agreement with the
published values in overall yield and isomer distribution.
We attempted to reproduce the product distribution
reported by Spinner et al. for the reaction of 4-(2-bromo-
ethyl)benzenesulfinic acid and 2-methyl-1,4-benzoquino-
ne (Scheme 2).8 We improved the overall yield and the
yield of the 2,6-adduct (4) but failed to produce the excess
of 2,5-adduct (3) they reported. The greatest amount of
compound 3 we have obtained was produced using the
acetic acid/water solvent3. These results, along with
comparable results for benzenesulfinic acid, are pre-
sented in Table 5.
total
2,5-adduct (1) 2,6-adduct (2) yield
solventa
pH
(%)
(%)
(%)
CH2Cl2/H2O/F3CCO2H
HOAc/1 M HCl
HOAc/H2O
1
1
2.5
26
20
42
74
80
58
91b
84
86
Ambient temperature. Bruce and Lloyd-Williams:10 94%
total yield, 25% yield of 1, and 75% yield of 2.
a
b
TABLE 3. Ben zen esu lfin ic Acid a n d
2-Meth yl-1,4-ben zoqu in on e: P r od u ct Distr ibu tion in
Alcoh ol Wa ter Mixtu r es
total
2,5-adduct (1)
2,6-adduct (2)
yield
(%)
% ROHa
E TN
(%)
(%)
b
Bruce and Lloyd-Williams cite the study by Houk et
al.7 that shows when reaction takes place on the quinone
ring the 2,5-adduct (1) is favored. They argued that in
strongly acidic media, a methyl group introduces suf-
ficient steric hindrance to favor protonation of the 4-car-
bonyl group, which leads to the formation of the 2,6-
adduct (2). Carrying out the same reaction with 2-tert-
butyl-1,4-benzoquinone led to a 12 to 1 ratio of 2,6-adduct
to 2,5-adduct and makes the argument of the protonated
quinone as the reactive species very convincing.
Our results are consistent with the notion of selective
protonation in strongly acidic solution. We found that the
proportion of the 2,5-adduct is increased at acidities up
to pH 4.5, which suggests that the unprotonated quinone
plays an increasingly significant role. At higher acidities,
we observed the proportion of 2,5-adduct to decrease. If
this maximum is shown to be real, it may be related to
a change in rate-determining step from addition to
aromatization. Such a change was shown to occur at
exactly this pH by Ogata and his collaborators.14
The observations in aqueous ethanol are also instruc-
tive. The results found at 12.5% EtOH are identical to
those at pH 5.5. Furthermore the proportion of com-
pound 1 changes linearly with Reichardt’s Lewis acidity
parameter.12-13
12.5 (EtOH)
43 (EtOH)
99 (EtOH)
99 (MeOH)
0.96
0.85
0.66
0.76
40
27
10
9
60
73
90
91
90
82
81
80
a
b
Ambient temperature. Lewis acidity parameter.12,13
TABLE 4. Ben zen esu lfin ic Acid a n d
2-Meth yl-1,4-ben zoqu in on e: P r od u ct Distr ibu tion in
An h yd r ou s Ap r otic Solven ts
total
2,5-adduct (1) 2,6-adduct (2) yield
solventa
E TN
(%)
(%)
(%)
2,4-pentanedione 0.54
14
15
17
14
86
85
83
86
92
96
83
87
acetonitrile
acetone
tetrahydrofuran
0.46
0.36
0.18
a
Ambient temperature.
benzenesulfinic acid to 2-methyl-1,4-benzoquinone using
all of the solvent systems that have been reported for this
and similar Michael addition reactions.
Tables 1-4 report the total yield obtained as an
average of at least three individual runs. We also report
the relative yields of the two isomeric sulfones. The yields
of individual runs under each set of conditions agree to
within (4%.
The data in Tables 1-4 and the product ratios sum-
marized in Table 6 show that solvent and acidity can
markedly influence the product distribution obtained. In
five of the solvent systems studied, we obtained an aver-
age of 41 ( 1% yield of compound 1. In seven solvent
systems studied, an 84 ( 3% yield of compound 2 was
obtained. There are two additional experimental condi-
tions giving product distributions that are clearly differ-
ent from one another and from the other twelve. When
the reaction shown in Scheme 1 was carried out in
All of these findings suggest the importance of selective
hydrogen bonding and are consistent with selective
stabilization of nonidentical quinonoid species.
In conclusion, we offer optimal conditions for the
synthesis of the 2,5-adduct or the 2,6-adduct shown in
(12) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
2nd ed.; Verlag Chemie: Weinheim, Germany, 1988.
(13) Krygowski, T. M.; Wrona, P. K.; Zielkowska, U.; Reichardt, C.
Tetrahedron 1958, 41, 4519.
(14) (a) Ogata, Y.; Sawaki, Y.; Isono, M. Tetrahedron 1969, 25, 2715.
(b) Ogata, Y.; Sawaki, Y.; Isono, M. Tetrahedron 1970, 26, 731.
(15) Pickholz, S. J . Chem. Soc. 1946, 685.
(16) Walker, J . J . Chem. Soc. 1945, 630.
J . Org. Chem, Vol. 68, No. 12, 2003 4989

TABLE 5. Com p a r ison of Ar ylsu lfin ic Acid s Ad d ed to 2-Meth yl-1,4-ben zoqu in on e in Differ en t Solven t System s
4-(2-bromoethyl)benzenesulfinic acid
benzenesulfinic acid
solventa
2,5-adduct (4) (%)
2,6-adduct (5) (%)
total yield (%)
2,5-adduct (1) (%)
2,6-adduct (2) (%)
total yield (%)
HOAc/H2O3
EtOH/H2O8
49
35
51
65
95
87
42
27
58
73
86
82
a
Ambient temperature.
TABLE 6. Rea ction Con d ition s for Ben zen esu lfin ic Acid a n d 2-Meth yl-1,4-ben zoqu in on e
solventa
sulfinic acid
quinone
stirring time (h)
crude yield (%)b
1:2 ratio (%)c
reference
1 M HClO4 (100 mL)
1 M HOAc (15 mL)
HOAc/NaOAc 1:1d (40 mL)
HOAc/NaOAc 1:8 (20 mL)
MeOH or EtOH (4 mL)
30% EtOH/H2O (62 mL)
H2O (45 mL)
solid
1
85
90
92
91
83
82
90
87
86
84
87
20:80
41:59
60:40
39:61
10:90
27:73
40:60
43:57
42:58
20:80
14:86
14
14
14
14
5
1 M HOAc (15 mL)
1 M HOAc (40 mL)
HOAc/NaOAc 1:8 (20 mL)
MeOH or EtOH (4 mL)
EtOH (10 mL)
1
1
1
3
3
8
50% EtOH/H2O (15 mL)
H2O (25 mL)
1
15
16
3
9
5
1 M HCl H2O (6 and 4 mL)
H2O (15 mL)
1.25e
1.25f
0.5
3f
HOAc (15 mL)
2 M HCl (10 mL)
HOAc (12 mL)
THFg (5 mL)
THF (5 mL)
a
b
Volume in mL. Average of at least three determinations. c Relative areas ofNMR absorptions at δ 6.9 + 7.5 (1) and 6.9 + 7.0 (2).
Molar ratios ([AH]:[A-]). e Steam bath. f Ice bath. Also for acetone, acetonitrile, and 2,4-pentanedione.
d
g
mixture of two sulfones (3 and 4) as shown by TLC and NMR.
A representative total crude yield was 11 g, 87%. Recrystalli-
zation from aqueous ethanol yielded compound (3) 2-[[4′-(2-
bromoethyl)phenyl] sulfonyl]-5-methylhydroquinone, mp 119-
121 °C (lit.8 121-122 °C). Aqu eou s Acetic Acid .3 A solution of
2-methyl-1,4-benzoquinone (410 mg, 3.4 mmol) in 10 mL of
glacial acetic acid was added, in one portion, to a stirred
suspension of 4-(2-bromoethyl)benzenesulfinic acid (1.2 g, 4.8
mmol) in 10 mL of water. The quinone color disappeared along
with the sulfinic acid. After stirring for 0.5 h, the light tan solid
was suction filtered. After an additional 1 h of stirring, more
tan solid was filtered. The reaction mixture was diluted with
200 mL of ice-water, and a third crop was obtained. Each of
the three fractions was a mixture of compounds 3 and 4 as shown
by TLC and NMR. A representative total crude yield was 1.2 g,
91%. Recrystallization from aqueous ethanol yielded compound
4 2-[[4′-(2-bromoethyl)phenyl] sulfonyl]-6-methylhydroquinone
mp 145-146 °C (lit.8 146-147 °C).
Scheme 1. Complete resolution of mechanistic consider-
ations must await detailed kinetic studies in a variety
of solvents.
Exp er im en ta l Section
Gen er a l. NMR spectra (1H) were recorded in acetone-d6
solution using a 300 MHz spectrometer. Chemical shifts (δ) are
measured from the acetone absorption at 2.05 ppm. Yields of
the isomeric product (1/2 and 3/4) were determined from the
areas of the hydroquinone protons as described by Gates et al.5
Melting points are uncorrected. Thin-layer chromatography was
carried out on silica gel developed with ethyl acetate/hexane
(1:1 v/v). 2-Methyl-1,4-benzoquinone was recrystallized from
hexane or sublimed before use. Benzenesulfinic acid was used
immediately after acidifying its sodium salt. Table 6 presents
the experimental conditions under which each of the 14 different
solvent systems were studied.
Regiosp ecificity in th e Syn th esis of Dia r ylsu lfon es.
Com p ou n d 1: δH[300 MHz; (CD3)2CO] 7.96 (d, 2′-H and 6′-H),
7.60 (m, 3′-H, 4′ and 5′-H), 7.30 (s, 6-H), 6.75 (s, 3-H), and 2.15
(s, Me). The previously reported value of 7.14 for the m, 3′-H, 4′
and 5′-H is almost certainly a typographical error.10 Com p ou n d
2: δH[300 MHz; (CD3)2CO] 8.00 (d, 2′-H and 6′-H), 7.70 (m, 3′-
H, 4′ and 5′-H), 7.08 (d J 3.0 Hz, 5-H), 6.96 (d J 3.0 Hz, 3-H),
and 2.15 (s, Me). Com p ou n d 3: 1H NMR [300 MHz; (CD3)2CO]
7.90 (d, 2′-H and 6′-H), 7.50 (d, 3′-H and 5′-H), 7.28 (s, 6-H),
6.73 (s, 3-H), 3.71 (t, â-CH2), 3.25 (t, R-CH2), and 2.14 (s, Me).
Com p ou n d 4: 1H NMR [300 MHz; (CD3)2CO] 7.90 (m, 2′-H and
6′-H), 7.50 (m, 3′-H and 5′-H), 7.02 (d J 3.0 Hz, 5-H), 6.90 (d J
3.0 Hz, 3-H), 3.68 (t, â-CH2), 3.24 (t, R-CH2), and 2.11 (s, Me).
Ad d ition Rea ction : Sta n d a r d P r oced u r e. In a typical run,
benzenesulfinic acid (1.66 g, 10.1 mmol) was added to the solvent
being studied, followed by 1.0 g (8.2 mmol) of quinone. The
reaction was stirred, usually at room temperature, for various
times as reported for the specific solvent system employed (see
Table 6). No effort was made to exclude air from the reaction.
Except for the aprotic solvents, a precipitate formed shortly after
mixing. Successive crops of product were collected by suction
filtration and washed with hexane. NMR spectra for each crop
were taken, and thin-layer chromatography showed only the
presence of compounds 1 and 2.
P r od u ct Deter m in a tion . Samples chosen from the most
favorable runs were recrystallized from toluene to constant
melting points. Compound 1 (2-methyl-5-(phenylsulfonyl)hyd-
roquinone): mp 177.9-179.8 °C (lit.10 158-164 °C, sample
contaminated with 2). Compound 2 (2-methyl-6-(phenylsulfonyl)-
hydroquinone): mp 186.5-187.3 °C (lit.2 189-191 °C; lit.10 183-
186 °C).
Ad d it ion of 4-(2-Br om oet h yl)b en zen esu lfin ic Acid t o
2-Meth yl-1,4-ben zoqu in on e: Aqu eou s Eth a n ol.8 A solution
of 2-methyl-1,4-benzoquinone (1.2 g, 10 mmol) in 95% ethanol
(20 mL) was added dropwise to a stirred suspension of 4-(2-
bromoethyl)benzenesulfinic acid (3.0 g, 12 mmol) in 30%
aqueous ethanol (100 mL). As the quinone color faded, a solid
precipitate appeared and was filtrered under vacuum. The
filtrate was diluted with 300 mL of ice-water, and a second crop
was obtained. After the mixture was allowed to stand overnight,
a third crop was present. Each of the three fractions was a
Ack n ow led gm en t. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research (Grant PRF 6365B4) and to the Morris
Fellowship for Undergraduate Research. We are ap-
preciative of the helpful suggestions of our colleagues.
Professor Emory Morris rendered invaluable assistance
with the preparation of this article.
Su p p or tin g In for m a tion Ava ila ble: 1H spectra for com-
pounds 1-4. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026640X
4990 J . Org. Chem., Vol. 68, No. 12, 2003