Hydrogen bonding mediated enantioselective organocatalysis in brine: Significant rate acceleration and enhanced stereoselectivity in enantioselective Michael addition reactions of 1,3-dicarbonyls to β-nitroolefins

Article abstract of DOI:10.1039/c1cc13637b

Brine provides remarkable rate acceleration and a higher level of stereoselectivity over organic solvents, due to the hydrophobic hydration effect, in the enantioselective Michael addition reactions of 1,3-dicarbonyls to β-nitroolefins using chiral H-dono

Full text of DOI:10.1039/c1cc13637b

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COMMUNICATION
Hydrogen bonding mediated enantioselective organocatalysis in brine:
significant rate acceleration and enhanced stereoselectivity in
enantioselective Michael addition reactions of 1,3-dicarbonyls to
b-nitroolefinsw
a
a
a
a
ab
Han Yong Bae,z Surajit Some,z Joong Suk Oh, Yong Seop Lee and Choong Eui Song*
Received 19th June 2011, Accepted 14th July 2011
DOI: 10.1039/c1cc13637b
Brine provides remarkable rate acceleration and a higher level of
stereoselectivity over organic solvents, due to the hydrophobic
hydration effect, in the enantioselective Michael addition reac-
tions of 1,3-dicarbonyls to b-nitroolefins using chiral H-donors
as organocatalysts.
Nature uses water as a solvent for biosynthetic reactions to
sustain life. The ‘‘hydrophobic effect’’ is a key element in such
enzyme catalysis, in determining the structures of proteins and
Fig. 1 Screened cinchona-based organocatalysts.
transformations, we initially examined the asymmetric Michael
addition of 2,4-pentanedione (2) as a donor and b-nitrostyrene
(1a) as an acceptor using 2.0 mol% of the three types of H-bond
1
nucleic acids, and in the binding of antigens to antibodies.
Due to the green chemistry perspective and an increased
scientific effort to mimic nature, tremendous effort has been
applied recently toward developing enantioselective organo-
5
6
7
donor catalysts, QN-TU, QN-SA, and QN-SQA, in brine
or in CH Cl at room temperature (Table 1). Gratifyingly,
in all cases, brine provided remarkable rate acceleration and
a higher level of enantioselection over CH Cl , due to the
2
2
2
catalytic reactions in an aqueous environment. Chiral secondary
amines have been shown to be viable catalysts in an aqueous
environment for several C–C and C–heteroatom bond forming
2
2
8
hydrophobic hydration effect (entries 2, 4, 6 vs. entries 1, 3, 5).
Squaramide catalysts QN-SQA showed superior catalytic
3
processes, which proceed via iminium or enamine intermediates.
However, introducing water as a solvent into the H-bonding
4
mediated asymmetric catalysis still remains a challenge because
a
Table 1 Michael addition of b-nitrostyrene and 2,4 -pentanedione
water can interfere with organocatalysis due to its capacity for
disrupting hydrogen bonds and other polar interactions.
We report here the successful results of H-bonding mediated
enantioselective organocatalysis in an aqueous environment.
Enantioselective Michael addition using a bifunctional cinchona-
based squaramide organocatalyst was dramatically accelerated in
brine compared to the reaction in organic solvents due to the
hydrophobic hydration effect (Fig. 1). Remarkably, in most
cases, diastereo- and/or enantioselectivity also were enhanced
in brine. Catalyst loading at 0.5 mol% was sufficient to
complete most reactions within 10 min, affording the Michael
adduct in up to 499% yield and 499% ee.
b
Conv. (%) ee (%)
c
Entry Catalyst (mol%) Solvent
Time
13 h
1
2
3
4
5
6
7
8
9
1
1
QN-TU (2)
QN-TU (2)
QN-SA (2)
QN-SA (2)
QN-SQA (2)
QN-SQA (2)
CH
Brine
CH Cl
2
Cl
2
2
2
2
499
61
81
n.d.
61
o20 min 499
d
2
48 h
1 h
Trace
499
Brine
CH Cl
2
20 min 499
o3 min 499
499
499
499
499
Brine
To assess the effect of water on the reaction rate and on the
QN-SQA (0.5) CH
2
Cl
2 h
499
stereoselectivity for the H-bonding mediated asymmetric
QN-SQA (0.5) Brine
QN-SQA (0.5) LiClO
QN-SQA (0.5) NaCl in D
o10 min 499
d
4
in H
2
O 30 min o2
n.d.
0
1
2
O
2 h
499
499
98
a
Department of Chemistry, Sungkyunkwan University,
e
f
CN-SQA (0.5) Brine
o10 min 499
300 Cheoncheon, Jangan, Suwon, Gyeonggi, 440-746, Korea.
E-mail: s1673@skku.edu; Fax: +82 31-290-7075
Department of Energy Science, Sungkyunkwan University,
a
Reactions were carried out with 1a (0.5 mmol), 2 (2.0 equiv.), and
b
b
catalyst (2.0 mol%) in 1.5 mL of solvent. Determined by H NMR.
1
c
3
00 Cheoncheon, Jangan, Suwon, Gyeonggi, 440-746, Korea
w Electronic supplementary information (ESI) available. See DOI:
0.1039/c1cc13637b
Determined by HPLC analysis using
a
chiral AD-H column
see ESIw). Not determined. Using cinchonine squaramide catalyst.
f
d
e
(
1
Opposite enantiomer was obtained.
z These authors contributed equally to this work.
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9621–9623 9621

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a
activity and enantioselectivity (entries 5 and 6) than other
Table 3 Scope of Michael donors 4a–h
types of H-bond donors such as thiourea QN-TU and
9
sulfonamide QN-SA (entries 1–4). Catalyst loading at merely
0
.5 mol% of QN-SQA was sufficient to complete the reaction
within 10 minutes, affording the Michael adduct in up to 499%
yield and 499% ee (entry 8). Of note, the cinchonine-derived
catalyst CN-SQA gave the opposite enantiomer of 3a with the
same efficiency (entry 11). Evidence for the hydrophobic
hydration effect on rate acceleration was obtained using a
Yield
(%) dr
b
c
d
e
Entry Solvent Time
Product 5
ee (%)
salting-out agent such as LiClO
4
(entry 9). The rate was
, which is typically
dramatically slowed by the addition of LiClO
4
1
2
CH
Brine
2
Cl
2
12 h
o20 min
97
96
—
—
499
499
1
0
antihydrophobic. Moreover, a significant solvent isotope
effect also was observed, which provides additional support for
the hydrophobic hydration mechanism: the reaction slowed
1
1
noticeably when D O was used instead of water (entry 10).
2
f
f
3
4
CH
2
Cl
2
168 h
22 h
65
92
—
—
93
90
Next, the scope of the reaction with a range of b-nitroolefins
a–h as Michael acceptors was examined (Table 2). Excellent
Brine
1
enantioselectivities (98%–499% ee) were observed for a broad
range of aryl, heteroaryl and alkyl substituted b-nitroolefins.
Again, significant rate acceleration in brine was observed, which
also can be attributed to the hydrophobic hydration effect.
Next, we probed the scope of the reaction with a variety of
5
6
CH
2
Cl
2
1.5 h
94
95
1 : 1
1 : 1
499, 499
499, 499
Brine
o10 min
1
,3-dicarbonyl compounds 4a–h as Michael-donors (Table 3).
In all cases, rate acceleration and slightly increased diastereo-
and/or enantioselectivity were observed in brine compared to
7
8
CH
2
Cl
2
2
2
40 min
95
94
1.4 : 1 499, 499
1.5 : 1 499, 499
Brine
o10 min
a
Table 2 Scope of Michael acceptors 1a–h
9
1
CH
2
Cl
9 h
92
90
2.1 : 1 97, 94
4.9 : 1 98, 98
0
Brine
o10 min
g
g
1
1
1
2
CH
2
Cl
120 h
20 h
78
85
3.2 : 1 94, 72
7.3 : 1 97, 75
b
c
Entry
R
Solvent
Time
2 h
o10 min 98
Yield (%)
ee (%)
Brine
1
2
CH
2
Brine
Cl
2
97
499
499
1
14
3
CH Cl
Brine
2
2
1 h
o20 min
90
87
99 : 1
99 : 1
499, 68
499, 84
3
4
CH Cl
Brine
2
2
4 h 97
o10 min 92
98
98
5
6
CH Cl
Brine
2
2
2
2
2
2
3 h
91
99
98
15
CH
2
Cl
2
2 h
94
98
499 : 1 98, 72
499 : 1 99, 78
o20 min 91
1
6
Brine
o10 min
a
7
8
CH Cl
Brine
2
48 h
89
499
499
Reactions were carried out with 1a (0.5 mmol), 4a–h (2.0 equiv.), and
b
QN-SQA (0.5 mol%) in 1.5 mL of solvent. The configuration of the
o40 min 89
main diastereomer was determined by comparison of the HPLC
c
9
CH Cl
Brine
2
1 h
98
499
499
retention time with the literature data (see ESIw). Isolated yields.
d
f
1
e
1
0
o20 min 99
Determined by H NMR. Determined by chiral HPLC (see ESIw).
Reaction carried out with 5 mol% of QN-SQA. Reaction carried
g
out with 2 mol% of QN-SQA.
1
1
2
CH Cl
Brine
2
1 h
93
499
499
1
o20 min 96
1
2
those obtained in CH
2
Cl
2
.
Of note, more hydrophobic
1
3
4
CH
2
Cl
2 h
94
499
499
substrates seemed to display greater activities and stereo-
selectivities relative to less hydrophobic substrates, perhaps
as a result of enhanced aggregation between the organocatalysts
and the substrates in the aqueous environment (compare entries
1
Brine
o10 min 91
d
d
1
1
5
6
CH Cl
Brine
2
2
8 h
88
499
499
o10 min 90
4
, 6, 8, and 10).
a
Reactions were carried out with 1a–h (0.5 mmol), 2 (2.0 equiv.), and
Finally, to study a multigram-scale synthesis, b-nitrostyrene
1a) (7.5 g) and 2,4-pentanedione (2 equiv.) were vigorously
b
QN-SQA (0.5 mol%) in 1.5 mL of solvent. Isolated yields. Deter-
c
(
d
mined by chiral HPLC (see ESIw). Reaction carried out with 2 mol%
of QN-SQA.
stirred in the presence of QN-SQA (0.5 mol%) in brine
(
150 mL) at 25 1C. A solid white Michael product gradually
This journal is c The Royal Society of Chemistry 2011
9
622 Chem. Commun., 2011, 47, 9621–9623

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This work was supported by grants NRF-20090085824
(Basic Science Research Program, MEST), NRF-2010-0029698
(
Priority Research Centers Program, MEST), 2011-0001334
SRC program, MEST), R31-2008-10029 (WCU program,
(
MEST), B551179-10-03-00 (Cooperative R&D Program, Korea
Research Council Industrial Science and Technology), and the
Postdoctoral Research Program of Sungkyunkwan University
(
2010).
Notes and references
1
C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente and
S. Vera, Angew. Chem., Int. Ed., 2007, 46, 8431–8435.
(a) M. Raj and V. K. Singh, Chem. Commun., 2009, 6687–6703;
2
(
b) M. Gruttadauria, F. Giacalone and R. Noto, Adv. Synth.
Fig. 2 The scale-up reaction setup of 2,4-pentanedione with
b-nitrostyrene (1a) in the presence of QN-SQA in brine. (a) Reaction
mixture before mixing. (b) Reaction mixture after completion of the
reaction.
Catal., 2009, 351, 33–57; (c) N. Mase and C. F. Barbas, III, Org.
Biomol. Chem., 2010, 8, 4043–4050.
X. Yu and W. Wang, Org. Biomol. Chem., 2008, 6, 2037–2046.
M. Rueping and T. Theissmann, Chem. Sci., 2010, 1, 473–476.
S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
3
4
5
44, 6367–6370.
S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin and
C. E. Song, Angew. Chem., Int. Ed., 2008, 47, 7872–7875.
formed (Fig. 2). After 15 minutes, aqueous HCl solution
6
(
1 N, 10 mL) was added to quench the reaction. Filtration,
washing with water, and drying yielded the white solid product.
Neither extraction nor chromatography was needed to obtain
the product with excellent purity.
7 (a) J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem.
Soc., 2008, 130, 14416–14417; (b) H. Jiang, M. W. Paixao,
D. Monge and K. A. Jørgensen, J. Am. Chem. Soc., 2010, 132,
775–2783.
˜
2
In summary, we describe here the successful results of
H-bonding mediated enantioselective organocatalysis in an
aqueous environment. Enantioselective Michael addition of
8
Heterogeneity was crucial for observing large rate acceleration.
Thus, the reaction time can be strongly dependent on the efficiency
of mixing of the reaction mixture. Thus, we used several magnetic
stir bars for efficient mixing and grinding of the solid formed
during the reaction. More efficient mixing of the reaction mixture
would further shorten the reaction time.
Other solvents were also screened for the reaction using the catalyst
QN-SQA, but the conversion and enantioselectivity were found to
be significantly inferior in comparison to those obtained in brine;
e.g., DMSO (1 h for 99% conversion, racemic), MeOH (96 h for
99% conversion, 99% ee), see ESIw.
1
,3-dicarbonyl to nitroolefins using a bifunctional cinchona-
based squaramide organocatalyst in brine was dramatically
accelerated compared to that in organic solvents due to the
hydrophobic hydration effect; moreover, in most cases,
diastereo- and enantioselectivity also were enhanced in brine.
Merely 0.5 mol% catalyst loading was enough to complete
most reactions within a very short reaction time, affording the
Michael adduct in up to 499% yield and 499% ee.
Further studies focusing on the full scope of this catalytic
system in aqueous medium and related systems are currently
under investigation and will be reported in due course. Calcu-
lation studies for better understanding the role of water also
are currently under investigation in our laboratory.
9
1
0 R. Breslow, Acc. Chem. Res., 2004, 37, 471–478.
1
1 D O has a ca. 20% higher viscosity which may make mixing more
2
difficult, and is a better solvent for nonpolar solutes; this must
reduce the hydrophobic hydration effect; S. Narayan, J. Muldoon,
M. G. Finn, V. V. Fokin, H. C. Kolb and K. B. Sharpless, Angew.
Chem., Int. Ed., 2005, 44, 3275–3279.
1
2 The enhanced stereoselectivity might be explained by the difference
of hydrophobic character in the transition states for the each
stereomers.
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9621–9623 9623