Catalyzed double Michael addition of anilines to vinyl sulfone

Article abstract of DOI:10.1016/S0040-4039(03)00702-0

Substituted anilines and vinyl sulfone undergo a facile double Michael addition to form substituted phenylthiomorpholine dioxide, catalyzed with AlCl₃ or H₃PO₄. Scope and conditions were explored.

Full text of DOI:10.1016/S0040-4039(03)00702-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3459–3462
Catalyzed double Michael addition of anilines to vinyl sulfone
Jiong Jack Chen,* Cuong V. Lu and Rebecca N. Brockman†
Early Process Research and Development, Pharmacia Corporation, Kalamazoo, MI 49001, USA
Received 16 December 2002; revised 12 March 2003; accepted 13 March 2003
Abstract—Substituted anilines and vinyl sulfone undergo a facile double Michael addition to form substituted phenylthiomorpho-
line dioxide, catalyzed with AlCl3 or H3PO4. Scope and conditions were explored. © 2003 Elsevier Science Ltd. All rights reserved.
In the preparation of an active pharmaceutical interme-
diate, we needed a large quantity of compound 3. Since
2,6-difluoroaniline (1) and vinyl sulfone (2) are both
readily available, we sought to prepare compound 3
using these two starting materials, based on a literature
procedure reported by Ford-Moore1 and later in a
patent by Straley and Fisher.2 Under the neat condi-
tions reported by Ford-Moore, the reaction between
aniline and vinyl sulfone produced 56% of the desired
double-Michael addition product, 4-phenylthiomorpho-
line 1,1-dioxide.3 However, applying Ford-Moore’s
conditions to the reaction between 2,6-difluoroaniline
(1) and vinyl sulfone (2) only resulted in mostly starting
materials and some uncyclized mono-Michael adduct
(4) after extensive heating. The double Michael addi-
tion did not proceed, presumably because 2,6-
placement of the resulting alkyl chloride rather than a
Michael addition? To test this hypothesis, 2,6-
difluoroaniline was heated with bis(2-chloroethyl)-
sulfone under neat conditions. This reaction gave no
conversion, thus disproving this hypothesis. Interest-
ingly, when AlCl3 was added, the reaction produced
trace amounts of desired product (3) along with some
vinyl sulfone. It was postulated that initially AlCl3
catalyzed the formation of vinyl sulfone from bis(2-
chloroethyl)sulfone. Subsequently, the vinyl sulfone
underwent a catalyzed double Michael addition to gen-
erate the desired product. This observation further sup-
ported that the reaction proceeds via the Michael
addition mechanism (Scheme 1).
Various Lewis acids (i.e. FeCl3, BiCl3, ZnCl2, and
SnCl2) were then screened, and some were found to
effect the double Michael addition. However, only
AlCl3 gave a complete conversion within an adequate
timeframe (i.e. less than 24 h). By screening the various
reaction conditions using AlCl3, we defined some key
parameters. The reaction proceeds well within an ade-
quate timeframe at 90–110°C at a concentration
between 0.5–1.0 M. By using the optimized conditions
(i.e. AlCl3 in chlorobenzene or toluene at 1 M concen-
tration at 110°C for 24 h) a yield of 68% was obtained
upon work-up. The low recovery was most likely the
result of a Lewis-acid promoted polymerization of vinyl
sulfone.
difluoroaniline is
a
poor Michael donor (two
electron-withdrawing fluorine atoms). Interestingly,
when 1 equivalent of AlCl3 was added to the toluene
solution of starting materials, the reaction proceeded
smoothly to give desired compound 3. To our knowl-
edge, the use of a Lewis acid to activate vinyl sulfone as
a Michael acceptor is unprecedented.4 With this new
finding, we decided to explore the mechanism and
define the scope of this interesting reaction.
When a strong base, KOtBu, was added to the mixture
of 2,6-difluoroaniline (1) and vinyl sulfone (2), the vinyl
sulfone (2) polymerized instantaneously with a strong
exotherm. Thus, the activation of the Michael donor
does not facilitate this reaction. As the chloride ion in
AlCl3 may add to the double bond in vinyl sulfone, is it
possible that the reaction mechanism involved the dis-
To minimize the competing side reactions and to sim-
plify the work-up, zeolites and protic acids were also
screened as the catalysts. Fourteen common zeolites
were first tried, none of them gave >5% of conversion
based on GLC. The use of triflic acid was more promis-
ing. The reaction under neat conditions provided
mostly product within 40 h. However, the work-up was
problematic because the reaction mixture solidified
Keywords: Michael addition; vinyl sulfone; thiomorpholine; catalysis.
* Corresponding author. Tel.: 1-269-833-9044; fax: 1-269-833-9282;
e-mail: jiong.j.chen@pharmacia.com
† Currently a graduate student at University of California, Berkerley.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00702-0

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J. J. Chen et al. / Tetrahedron Letters 44 (2003) 3459–3462
Scheme 1.
upon cooling. If the reaction using triflic acid was
conducted in organic solvents, the reaction time
required for completion was beyond three days.
Weaker methanesulfonic acid and 98% sulfuric acid
were tried under the neat conditions, but no conver-
sion was observed at all. To our surprise, heating the
starting materials in neat phosphoric acid at 140°C
provided a complete conversion in less than 24 h
along with some black residues. More surprisingly,
the common 85% phosphoric acid proceeded cleaner
and faster than neat phosphoric acid at the same
temperature. Under these conditions, the work-up and
the yield were significantly improved. Upon comple-
tion, the reaction was simply cooled and poured into
water, stirred, and the product was then filtered to
provide an 89% isolated yield.
tion was complete in 1 h with a 92% yield of com-
pound 9. Under the phosphoric acid conditions, the
reaction was complete after 5 h and provided an 84%
yield. 2,4-Dimethoxyaniline (10), an activated aniline,
was expected to yield similar results as compound 8.
Interestingly, a major impurity was identified as the
4-demethoxy analog of compound 11. This impurity
was formed even without any catalyst. Under the
phosphoric acid conditions, only 25% isolated yield of
the desired product 11 was obtained. For the deacti-
vated system such as 4-nitroaniline (12), the reaction
provided no conversion without catalyst. Under AlCl3
conditions, the reaction also gave no conversion due
to the formation of an insoluble aniline–aluminum
complex. After work-up, only starting material was
obtained. For the phosphoric acid conditions, the
reaction was complete after 17 h and provided a 76%
yield of 13. For the 2,3,5,6-tetrafluroaniline (14), the
reaction gave no conversion in the absence of a cata-
lyst. With AlCl3 as the catalyst, the reaction gave
only a 65% conversion by GLC after 24 h of heating.
Attempts to work-up the reaction were unsuccessful
due to emulsion and gelling. Under the phosphoric
acid conditions, the reaction provided compound 16
in a 66% yield.
With optimized conditions found for AlCl3 (Method
A)5 and 85% phosphoric acid (Method B),6 we were
interested in the generality of this reaction toward
other substrates. Various anilines were employed to
study the scope of this reaction (Table 1).
For the ‘neutral’ aniline (6), the reaction under the
AlCl3 conditions provided a quantitative conversion
after only 45 min of heating at 110°C. After work-up,
a 73% isolated yield was obtained. Under the phos-
phoric acid conditions, an improved 78% isolated
yield was obtained. These unoptimized yields were
significantly improved from the 56% yield reported by
Ford-Moore.1,3 2,4-Dimethylaniline (8) should give
better results since it is a better Michael donor. With
no catalyst in toluene, the reaction provided a 90%
conversion, 63% desired product, and 3% bis-Michael
adduct in 24 h based on GLC. With AlCl3, the reac-
Using AlCl3 and phosphoric acid as catalysts, synthe-
ses of various substituted 4-phenylthiomorpholine 1,1-
dioxide were demonstrated to provide good to
excellent yields. The scope of this reaction appears to
be wide ranging to include both activated and de-acti-
vated anilines.8 This new finding should provide
organic chemists with another synthetic tool, for the
formation of thiomorpholine dioxides.

J. J. Chen et al. / Tetrahedron Letters 44 (2003) 3459–3462
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Table 1.
(1.8 kg). The column was eluted with methylene chloride
(16 L) until clear. The methylene chloride solution was
concentrated to give 387 g of compound 3 as light brown
solids (68% yield).
References
1. Ford-Moore, A. H. J. Chem. Soc. 1949, 2433–2440.
2. Straley, J. M.; Fisher, J. G. US Patent No: 3,585,182.
3. Using 1:1 ratio of aniline and vinyl sulfone, Ford-Moore
obtained 56% yield of desired 4-phenylthiomorpholine,
1,1-dioxide and 10% yield of 2,2%-dianilinodiethyl sulfone.
Using 2:1 ratio, 76% yield of the desired product was
obtained. However, for our purpose, neither starting mate-
rial was cheap, thus 2:1 ratio was not an option. Plus,
purification became more challenging if excess aniline was
used.
6. Method B typical procedure: 2,6-Difluoroaniline (1) (6.5
mL, 60 mmol) and vinyl sulfone (2) (6.0 mL, 60 mmol)
were charged to 30 mL of 85% H3PO4 at room tempera-
ture. The mixture was heated to 140°C for 16 h. The
resulting suspension was cooled to ꢀ70°C and poured
into 100 mL of water. After cooling to room temperature,
the mixture was filtered. The beige solids were washed with
water and dried to give 13.2 g (89%) of compound 3.
7. Analytical data for previously unknown compounds 3, 4,
5, 9, 11, 13, and 15.
4. Using Lewis acids to catalyze sulfone for other transfor-
mations are known, such as Friedel–Crafts reaction: Trost,
B. M.; Matsuoka, R. T. Synlett 1992, 27–30.
4 - (2,6 - Difluorophenyl)thiomorpholine 1,1 - dioxide (3):
1H NMR (DMSO-d6) l 7.10 (m, 3H), 3.51 (m, 4H), 3.21
(m, 4H). HRMS calcd for [M+1]: 248.0557. Found:
248.0552. Anal. calcd for C10H11F2NO2S: C, 48.58; H,
4.48; N, 5.66. Found: C, 48.80; H, 4.37; N, 5.36.
(2-Ethenesulfonyl-ethyl)-2,6-difluorophenylamine (4): This
compound was isolated in a non-catalyzed reaction. It
co-elutes with vinyl sulfone. Thus, a pure sample was not
obtained. However, 1H NMR spectrum of the mixture
indicated additional vinyl peaks. If this mixture was
treated with Lewis acid, compound 3 was formed based on
GLC.
5. Method A typical procedure: Aluminum chloride (310 g,
2.3 mol) was added to chlorobenzene (2.5 L, toluene works
also) to give a cloudy green suspension. Vinyl sulfone (2)
(230 mL, 2.3 mol) was added via funnel. 2,6-difluoroani-
line (1) (250 mL, 2.3mol) was added via funnel. The light
brown solution was heated to 110°C. Upon completion at
24 h, the heat was removed and the black solution was
cooled to 70°C. The reaction mixture was quenched into
methylene chloride (4 L) and ice water (5 L). The aqueous
phase was extracted with methylene chloride (4×2 L). The
combined organic layers were concentrated and added
branched octane (3 L), and then cooled to 0°C for 30 min.
The solids were filtered and washed with branched octane
(2×500 mL). The crude black solids were dissolved into
methylene chloride (3 L) and then loaded onto a SiO2 plug
N-(2-{[2-(2,6-Difluoroanilino)ethyl]sulfonyl}ethyl)-2,6-di-
fluoroaniline (5): This compound was isolated in a run
without catalyst. NMRs were obtained. However, collec-
tion of other data was not possible in our hands due to its

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J. J. Chen et al. / Tetrahedron Letters 44 (2003) 3459–3462
partial conversion to compound 4. 1H NMR (CDCl3) l
HRMS calcd for [M]: 256.0518. Found: 256.0514. Anal.
calcd for C10H12N2O4S: C, 46.87; H, 4.72; N, 10.93; S,
12.51. Found: C, 47.67; H, 4.37; N, 10.74.
6.87–6.67 (m, 6H), 3.85 (m, 4H), 3.32 (m, 4H). 13C NMR
(CDCl3) l 155.1, 151.9, 124.3 (t, JC–F=11.6 Hz), 118.8 (d,
J
C–F=8.7 Hz), 54.5, 40.0.
4-(2,3,5,6-Tetrafluorophenyl)thiomorpholine
(15):
1,1-dioxide
4 - (2,4 - Dimethylphenyl)thiomorpholine 1,1 - dioxide (9):
1H NMR (CDCl3): l 7.02 (s, 1H), 6.96 (m, 2H), 3.38 (m,
4H), 3.19 (m, 4H), 2.28 (s, 3H), 2.27 (s, 3H). 13C NMR
(CDCl3): l 148.1, 134.8, 132.9, 132.4, 127.8, 120.6, 53.0,
51.1, 21.1, 18.0. HRMS calcd for [M+1]: 240.1058. Found:
240.1054. Anal. calcd for C12H17NO2S: C, 60.22; H, 7.16;
N, 5.85; S, 13.40. Found: C, 59.76; H, 7.13; N, 5.78.
4 - (2,4 - Dimethoxyphenyl)thiomorpholine 1,1 - dioxide (11):
1H NMR (CDCl3): l 7.00 (m, 1H), 6.51 (m, 1H), 6.45 (m,
1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.54 (m, 4H), 3.24 (m, 4H).
13C NMR (CDCl3): l 154.1, 121.6, 104.1, 100.4, 56.0, 55.9,
52.6, 50.4. Anal. calcd for C12H17NO4S: C, 53.12; H, 6.32;
N, 5.16; S, 11.82. Found: C, 52.95; H, 6.37; N, 5.10.
4 - (4 - Nitrophenyl)thiomorpholine 1,1 - dioxide (13):
1H NMR (DMSO-d6): l 8.9 (d, 2H, J=9.3 Hz), 7.16 (d,
2H, J=9.3 Hz), 4.02 (m, 4H), 3.18 (m, 4H). 13C NMR
(DMSO-d6): l 152.7, 138.2, 126.1. 113.8, 50.7, 45.8.
1H NMR (CDCl3): l 6.83 (m, 1H), 3.74 (m, 4H), 3.35 (m,
4H). HRMS calcd for [M+1]: 284.0368. Found: 284.0923.
Anal. calcd for C10H9F4NO2S: C, 42.40; H, 3.20; N, 4.95;
S, 11.32; F, 26.83. Found: C, 41.88; H, 3.21; N, 4.69.
8. Several monovinyl sulfones, such as phenyl vinyl sulfone
and methyl vinyl sulfone, have been tried under the same
conditions. The Michael addition did proceed under cata-
lyzed conditions. However, some Michael addition
product continued to the second Michael addition to give
a bis-adduct (an adduct derived from one aniline and two
monovinyl sulfone). A mixture of products was formed,
thus, makes this extended application less useful. Further-
more, the reaction mixture was very obnoxious, suggesting
the decomposition of monovinyl sulfones under Lewis acid
conditions.