Catalytic enantioselective addition of sodium bisulfite to chalcones

Article abstract of DOI:10.1002/anie.201102162

At last! The addition of bisulfite to olefins, discovered over a century ago, remains the most straightforward approach to aliphatic sulfonic acids. A catalytic enantioselective procedure has now been realized that employs a bifunctional aminothiourea catalyst (see picture). Sulfonic acids were obtained from chalcones in high yields and high enantioselectivity and in both configurations. Copyright

Full text of DOI:10.1002/anie.201102162

DOI: 10.1002/anie.201102162
Organocatalysis
Catalytic Enantioselective Addition of Sodium Bisulfite to Chalcones**
Maria Moccia, Francesco Fini, Michela Scagnetti, and Mauro F. A. Adamo*
Dedicated to Professor Alfredo Ricci on the occasion of his retirement
Herein we report the first example of the catalytic enantio-
selective addition of sodium bisulfite to a,b-unsaturated
alkenes 1a–q which was achieved by the selection of an
Sulfonic acids are among the strongest acids in organic
chemistry and are extensively employed as resolving agents.
Kellogg et al. reported a few enantiopure sulfonic acids 2,
obtained from chalcones, as resolving agents[5] by a “Dutch
Resolution” approach.[6] Several multistep syntheses of chiral
sulfonic acids have been reported.[7–11] However, the simple
addition of bisulfite to olefins, discovered over a century
ago,[12] remains the most straightforward access to aliphatic
sulfonic acids. This reaction employs reactants in large excess
and requires high temperature, which limits its synthetic
utility.[5,13] We have recently shown that 1) decreasing the
concentration of bisulfite and 2) employing organic base
catalysis can increase the rate of addition of bisulfite to
electrophilic alkenes.[14] Careful adjustment of these condi-
tions resulted in a mild protocol for the addition of bisulfite to
electrophilic alkenes.[14]
appropriate
aminothiourea
bifunctional
catalyst
(Scheme 1).[1–3]
Following the pioneering work carried out by the groups
of Sooꢀs, Connon, Deng, and Wang,[2] bifunctional catalysis
has matured to become a prominent area of organic syn-
thesis[3] and a key enabling technology for the planning of
cascade reactions.[4]
Scheme 1. Enantioselective addition of bisulfite to chalcones.
Table 1: Sulfonylation of 1a using bifunctional catalysts 3–9.
Scheme 2. Enantioselective addition of bisulfite to chalcone 1a medi-
ated by aminothiourea 3.
[*] Dr. M. Moccia,[+] Dr. F. Fini,[+] M. Scagnetti, Prof. M. F. A. Adamo
Centre for Synthesis and Chemical Biology (CSCB)
Department of Pharmaceutical and Medicinal Chemistry
Royal College of Surgeons in Ireland
Entry
Cat.
NaHSO3
t
[h]
Conv.
[%][a]
ee [%]
123 St. Stephen’s Green, Dublin 2 (Ireland)
Fax: (+353)1-402-2168
of 2a[b]
E-mail: madamo@rcsi.ie
Homepage: https://research1.rcsi.ie/pi/madamo/
[+] These authors contributed equally to this work.
1
2
3
4
5
6
7
8
3
3
4
5
6
7
8
9
4.8m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
0.48m (1.2 equiv)
72
18
21
>99
>99
>99
>99
>90
<20
>90
>90
40
70
60
38
0
0
0
0
96
[**] We acknowledge financial support from PRTLI cycle III (M.F.A.A.),
Enterprise-Ireland PC2008 341 (M.F.A.A., F.F.), IRCSET (M.S.), and
the EU M. Curie Scheme (M.M.). We acknowledge Prof. Kellogg and
Dr. Nieuwenhuijzen for data on the absolute stereochemistry of
compounds 2d and 2g; Kevin Conboy, Adam Coburn, and the mass
spectrometry facility of University College Dublin (UCD) for the
HRMS analysis of sulfonic acids 2a–q; and Dr. T. McCabe and the
crystallography facility of Trinity College Dublin (TCD) for the X-ray
analysis of sulfonic acid 2a.
120
120
120
120
[a] Conversion >99% evaluated by disappearance of 1a by thin-layer
chromatography (silica gel 60 F254) and then verified by 1H NMR analysis.
1
Incomplete conversions evaluated by H NMR analysis with an internal
standard. [b] Enantiomeric excess determined with the sulfonic acid
methyl ester generated by reaction of 2a with Me3SiCHN2 and analysis by
HPLC on a chiral stationary phase.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102162.
Angew. Chem. Int. Ed. 2011, 50, 6893 –6895
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6893

Communications
The catalysis displayed by organic bases[14] prompted us to
(0.48m) gave 2a in 70% ee (Table 1, entries 1 and 2).
Squaramide-based bifunctional catalysts 4 provided 2a in
lower but still significant enantioselectivity (Table 1, entry 3).
Bifunctional catalysts 5–9 gave compound 2a in low ee or as a
racemate (Table 1, entries 4–8). This study identified chin-
chona-based thiourea 3 as the best catalyst, and we retained it
in the next round of optimization involving variation of
solvent and temperature (Table 2). The reaction of 1a and
bisulfite was conducted in different solvents and at different
temperatures. This study identified methanol/toluene (3:1) as
the best solvent mixture and À28C as the optimal reaction
temperature (Table 2, entry 9) giving 2a in 95% ee with only
0.1 equivalent of catalyst 3.
The scope of the reaction was demonstrated by reacting
chalcones 1b–q under the optimized conditions. The results
collected (Table 3) point out the following facts: 1) Both
electron-withdrawing and electron-donating groups at R1 and
aryl groups at R2 are tolerated. 2) It was verified that at least
compound 2a could be obtained in a multigram (5–6 g)
preparative scale (Table 3, entry 1) without loss of yield or
enantioselectivity. 3) The use of the quasi-enantiomeric
catalyst 3’ allowed the preparation of compounds ent-2a,
explore the effect of enantiopure amines on the addition of
bisulfite to alkenes. Preliminary studies indicated that
1.0 equivalent of (À)-sparteine, (À)-ephedrine, (À)-diphenyl-
prolinol, or quinine promoted the addition of bisulfite to 1a,
giving sulfonic acid 2a in low enantioselectivity (9–30% ee).
Conversely, 1.0 equivalent of the bifunctional compound 3[2b]
gave 2a in 86% ee (Scheme 2).
Encouraged by this result, we undertook an in-depth
screening of the catalyst structure (Table 1) and the reaction
conditions (Table 2). It was confirmed that the concentration
of bisulfite strongly affects the reaction rate and catalyst
turnover, as was observed previously for triethylamine.[14]
Surprisingly, the concentration of bisulfite also has an effect
on the enantioselectivity of the reaction. Alkene 1a reacted
with 38% solution of bisulfite in water (4.8m) in the presence
of 0.2 equivalents of 3 to provide 2a in 40% ee. The same
reaction carried out using a more dilute solution of bisulfite
Table 2: Optimization of sulfonylation of 1a using bifunctional catalysts
3, 10, and 11.[a]
Table 3: Catalytic enantioselective sulfonylation of chalcones 2a–n.[a]
Entry
Cat.
(equiv)
Solvent mixture
T
[8C]
t
Conv.
[%][c]
ee [%]
[h][b]
of 2a[d]
1
2
3
4
5
6
7
8
9
10
3
(0.2)
3
(0.2)
3
(0.2)
3
(0.2)
3
(0.2)
10
(0.2)
11
(0.2)
3
CH3OH/CH3CN
1:1
CH3OH/CH2Cl2
1:1
CH3OH/Tol
1:1
CH3OH/Tol
3:1
CH3OH/Tol
1:3
CH3OH/Tol
3:1
CH3OH/Tol
3:1
CH3OH/Tol
3:1
20
20
18
18
18
2
>99
>99
>99
>99
<10
>99
>99
>99
>99
>99
70
82
95
93
n.d.
91
83
96
95
89
Entry Prod. 2 R1
R2
Yield [%] ee [%]
of 2[b] of 2[c]
20
1
2
3
4
5
6
2a
2b
2c
2d
2e
2 f
C6H5
C6H5
C6H5
4-ClC644
C6H5
C6H5
4-CH3OC6H4 97
97[d] (99) 96[d] (92)
20
93
4-NO2C6H4
C6H5
4-FC6H4
4-ClC6H4
C6H5
87
92
20
72
21
21
18
40
40
97 (95)
91
93 (97)
90
20
C6H5
95 (94)
95
92 (94)
91
7
8
9
2g
2h
2i
4-CH3OC6H4
4-FC6H4
C6H5
20
C6H5
96
92
3-ClC6H4
2,4-Cl2C6H3
3-CH3C6H4
CH3
96
98
À2
À2
À2
11
12
13
14
15
16
2l
C6H5
C6H5
C6H5
CH3
97
99
(0.2)
3
(0.1)
3
2m
2n
2o
2p
2q
96
93
CH3OH/Tol
3:1
CH3OH/Tol
3:1
97
83
C6H5
96
82
(CH3)2CHCH2 C6H5
C6H5 (CH3)3C
94
85
(0.05)
92
84
[a] Reactions were carried out in a test tube on a 0.1 mmol scale without
any precautions to exclude moisture and air. [b] Free sulfonic acids were
obtained by passing the crude reaction mixture through freshly activated
acidic ion-exchange resin. [c] Conversion evaluated by disappearance of
1a by thin-layer chromatography (silica gel 60 F254) and then verified by
1H NMR analysis. [d] Enantiomeric excess determined with the sulfonic
acid methyl ester generated by reaction of 2a with Me3SiCHN2 and
analysis by HPLC on a chiral stationary phase. n.d.=not determined.
[a] Reactions carried out in a test tube on 0.1 mmol scale without any
precautions to exclude moisture and air. [b] Free sulfonic acids were
obtained passing the reaction crude through freshly activated acidic ion
exchange resin. [c] Enantiomeric excess determined after methylation of
sulfonic acid 2a–q with TMSCHN2 and chiral stationary phase HPLC
carried out on sulfonic acid methyl ester. Results in brackets refer to the
opposite enantiomer, obtained using 3’ as the catalyst. [d] Reaction
performed on 20 mmol scale.
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Angew. Chem. Int. Ed. 2011, 50, 6893 –6895

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ent-2d, and ent-2 f with enantioselectivities comparable to
those obtained with catalyst 3 (Table 3, entries 1, 4, 6, values
in brackets). 4) Substrates 1n–q bearing an aliphatic group on
either R1 or R2 (Table 3, entries 13–16) reacted equally well,
providing the corresponding acids 2n–q in high 82–85% ee.
The present method significantly expands the range of
sulfonic acids that can be prepared. Only a few enantiopure
aromatic sulfonic acids, such as 2a, 2d, and 2g, can be
prepared by resolution;[5] the other aromatic sulfonic acids in
Table 3 and those bearing aliphatic groups, that is, 2n–q, can
be prepared only by the present methodology.
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In conclusion, we have reported the first protocol for the
enantioselective addition of bisulfite to a,b-unsaturated
ketones.[15] The reaction was catalyzed by the bifunctional
catalysts 3 and 3’ and afforded desired sulfonic acids 2a–q in
high yields and excellent enantioselectivity. The methodology
described afforded multigram quantities of sulfonic acids and
allowed the preparation of both enantiomers in high enantio-
selectivity. The sulfonic acids described herein could be
recrystallized to provide a single enantiomer.[16] These
materials will therefore be of interest to the synthetic
community as resolving agents, Brønsted acids, or chiral
building blocks.
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Received: March 28, 2011
Published online: June 9, 2011
Keywords: aminothiourea derivatives · chalcones ·
.
organocatalysis · sodium bisulfite · sulfonic acids
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[15] The asymmetric addition of bisulfite to a,b-unsaturated alkenes
is unprecedented. The group of Wang reported the addition of
thioacetic acid, a different thio nucleophile, to alkenes to
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[16] An HPLC trace of enantiopure (+)-2a is included in the
Supporting Information.
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