Asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors: Highly efficient catalysts for enantio- and diastereoselective nitro-Mannich reaction of amidosulfones

Article abstract of DOI:10.1021/ol503264n

Bifunctional asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors have rarely been explored. The first quaternary ammonium type of these catalysts derived from cinchona alkaloids were readily prepared and found to be highly efficie

Full text of DOI:10.1021/ol503264n

Letter
pubs.acs.org/OrgLett
Asymmetric Phase-Transfer Catalysts Bearing Multiple Hydrogen-
Bonding Donors: Highly Efficient Catalysts for Enantio- and
Diastereoselective Nitro-Mannich Reaction of Amidosulfones
Bin Wang, Yuxin Liu, Cong Sun, Zhonglin Wei, Jungang Cao, Dapeng Liang, Yingjie Lin,*
and Haifeng Duan*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
S
* Supporting Information
ABSTRACT: Bifunctional asymmetric phase-transfer catalysts bearing
multiple hydrogen-bonding donors have rarely been explored. The first
quaternary ammonium type of these catalysts derived from cinchona
alkaloids were readily prepared and found to be highly efficient catalysts for
asymmetric nitro-Mannich reactions of amidosulfones. Compared with
previous reports, very broad substrate generality was observed, and both
enantiomers of the products were achieved in high enantio- and
diastereoselectivity (90−99% ee, 13:1 to 99:1 dr).
The catalytic asymmetric nitro-Mannich (or aza-Henry)
n recent years, the multiple hydrogen-bonding strategy,
1
Ifrequently used in supramolecular chemistry, has attracted reaction is one of the most useful and attractive C−C bond
forming reactions.6,7,2f In terms of stability, generality, and
increasing attention from organic chemists. Compared with
practicality of substrates, nitro-Mannich reactions of amidosul-
fones8,4i−k,9 are more fascinating than N-acyl imines, but existing
catalytic systems with a sufficiently broad substrate scope are
rare,9d and are highly efficient either for aromatic series4j or the
aliphatic series.9a,b Moreover, when cinchona alkaloids were
employed as the chiral source, the corresponding pseudoenan-
tiomeric catalysts often give enantiomeric products in signifi-
cantly lower enantioselectivity.4i,9d
catalysts containing single and double H-bonding donors,
catalysts bearing multiple H-bonding donors have great potential
to ehance their catalytic activity and give a better level of
enantiocontrol. Based on this strategy, some kinds of chiral
organocatalysts have been raised.2 In contrast, bifunctional
asymmetric phase-transfer (APT) catalysts3,4 bearing multiple
H-bonding donors are rare. In fact, only two examples can be
found in the literature (Figure 1).5
We envision that the disadvantages described above will be
tackled when the multiple hydrogen-bonding strategy is used in
bifuctional APT catalysis. Therefore, bifunctional chiral
ammonium catalysts bearing multiple H-bonding donors were
synthesized in our laboratory (Scheme 1). To the best of our
knowledge, these are the first quaternary ammonium type
bifunctional APT catalysts bearing multiple H-bonding donors.
Herein, we wish to report the synthesis of these new catalysts and
their catalytic performance in the nitro-Mannich reaction.
Starting from known 9-amino-9-deoxyepiquinine,10 the
catalysts can be readily prepared through three steps in two
pots as outlined in Scheme 1. 9-Amino-9-deoxyepiquinine was
transformed with N,N′-carbonyldiimidazole to the correspond-
ing carbamoylimidazole 1,11 without isolation; treatment of 1
with various β-aminoalcohols gave rise to ureas 2 bearing
multiple H-bonding donors under basic conditions. Subsequent
quaternization afforded catalysts 3a−g. Apparently, the H-bond
donor can be finely tuned and the pseudoenantiomeric catalysts
can also be prepared easily.
Figure 1. Bifunctional APT catalysts bearing multiple H-bonding
donors reported in the literature.
Received: November 10, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503264n | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
including the L-phenylglycinol moiety gave the best result (entry
6, 95% yield, 94% ee). In terms of reactivity and enantioselectvity,
3f showed significant improvement over the previous report
which just used a urea unit as H-bonding donors (59% yield, 80%
ee) under the same conditions.4i These results also indicate that
matching the chirality is important and the absolute config-
urations of products are mainly determined by 9-amino-9-
deoxyepicinchona alkaloid moieties (entry 1 vs 2, 3 vs 4, 5 vs 6).
By replacing the moiety L-phenylglycinol with L-phenylalaninol,
the enantioselectivity decreased slightly (entry 7, 91% ee). The
ensuing investigation of solvent effect indicated that this reaction
gave a slightly higher level of enantiocontrol in CH2Cl2 and
CHCl3, but the yields dropped significantly (entries 8 and 9).
Finally mixed solvent optimization was performed, and a mixture
of toluene and CHCl3 (9:1) was chosen as the best solvent
(entries 10 and 11). It is worth noting that high enantioselectivity
was still achieved although the yield was dropped when the
catalyst loading was reduced to 2.5 and 1 mol % (95% and 92%
ee, entries 12 and 13).
Scheme 1. Synthesis of the Catalysts
The scope of this reaction was further explored under optimal
conditions with a series of amidosulfones and nitroalkanes
(Table 2). In all cases, high to excellent yields (70−99%) and
excellent ee values (90−97% ee) were obtained. Aromatic
aldehyde derived substrates having either electron-rich or -poor
groups were well tolerated (entries 1−11), and the position of
the substituents seemed to have limited influence (entry 4 vs 10,
3 vs 9 and 11). Poly- and heteroaromatic substrates also proved
effective (entries 12−14). Moreover, the aliphatic amidosulfones
also participated well (entries 15−17). Finally, we investigated
the generality of the reaction with other nitroalkanes. Pleasingly,
nitroethane 6b and nitropropane 6c showed the same reactivity
as nitromethane 6a, and high yields (95%, 99%) and excellent
enantio-/diasteroselectivities (96% ee, 15:1 dr; 96% ee, 21:1 dr)
were obtained respectively (entries 18 and 19). Larger
nitroalkanes tend to give better stereocontrol (entry 18 vs 19).
Notably, cyclohexyl aminosulfones 5o and nitroethane 6b yield
the expected product 7t with excellent stereocontrol (97% ee,
99:1 dr); after column chromatography, a pure anti-diastereomer
was achieved.
With catalysts 3a−g in hand, we first investigated the reaction
between amidosulfone 5a and nitromethane 6a in the presence
of 5 equiv of KOH at −20 °C in toluene (Table 1). Initially,
catalysts 3a−3f were tested (entries 1−6); from Table 1, it can be
seen that, in all cases, high yields were obtained. Catalyst 3f
a
Table 1. Optimization of Reaction Conditions
Facile access to both enantiomers of products in high
enantiopurity respectively is of great importance in asymmetric
catalysis, especially regarding the direct or indirect application of
this product in medical chemistry research. As cinchona alkaloids
exist as pseudoenantiomers, one cinchona salt usually gives the
enantiomeric product in slightly to drastically lower enantiose-
lectivity than the corresponding pseudoenantiomeric one.4f,i,9d
To the best of our knowledge, nitro-Mannich reactions using
cinchona alkaloid-derived catalysts, giving both enantiomers of
the products in high enantiopurity (≥90% ee), have never been
reported so far. So we are eager to know whether this multiple H-
bonding strategy can mitigate this negative effect; thus, catalyst 4
derived from quinidine and D-phenylglycinol was prepared and
the catalytic efficiency of catalyst 4 was tested. A broad substrate
scope was also observed, and high yields (81−99%) and excellent
enantio-/ diastereoselectivities (90−99% ee, 13:1−25:1 dr) were
obtained (Table 3). In most cases, a slightly higher enantiomeric
purity was obtained than catalyst 3f (entries 1−3, 5−7, 10−12).
Notably, cyclohexyl aminosulfones 5o reacted with nitomethane
6a and nitroethane 6b yielding the expected products 8j and 8o
with excellent stereocontrol (95% ee; 96% ee, 25:1 dr; entries 10
and 15) compared with previous reports (84% ee; 95% ee, 9:1
dr).4i
b
c
entry
cat.
x (%)
solvent
toluene
yield (%)
ee (%)
1
3a
3b
3c
3d
3e
3f
5
93
92
93
95
95
95
93
70
80
93
90
75
70
57
65
68
88
59
94
91
95
96
95
95
95
92
2
5
toluene
3
5
toluene
4
5
toluene
5
5
toluene
6
5
toluene
7
3g
3f
5
toluene
8
5
CH2Cl2
9
3f
5
CHCl3
10
11
12
13
3f
5
Tol/CHCl3 (9:1)
Tol/CHCl3 (7:3)
Tol/CHCl3 (9:1)
Tol/CHCl3 (9:1)
3f
5
3f
2.5
1
3f
a
Reactions were conducted at 0.15 mmol scale in 1.5 mL of solvent.
Yield of isolated product. Determined by HPLC using a chiral
b
c
stationary phase.
B
dx.doi.org/10.1021/ol503264n | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substrate Scope of Nitro-Mannich Reaction Using Catalyst 3f
b
d
c
entry
5
R1
6
R2
7
yield (%)
dr
ee (%)
1
5a
5b
5c
5d
5e
5f
Ph
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
Me
7a
7b
7c
7d
7e
7f
93
95
87
89
85
70
98
98
90
93
88
99
75
99
90
99
81
95
99
95
95
93
90
96
95
90
97
91
92
95
91
93
95
90
93
91
91
96
96
97
2
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
p-CF3C6H4
o-FC6H4
3
4
5
6
7
5g
5h
5i
7g
7h
7i
8
9
o-MeOC6H4
m-ClC6H4
m-MeOC6H4
α-naphthyl
β-naphthyl
2-furyl
10
11
12
13
5j
7j
5k
5l
7k
7l
5m
5n
5o
5p
5q
5a
5a
5o
7m
7n
7o
7p
7q
7r
7s
7t
e
14
15
16
17
cyclohexyl
phenyl ethyl
isobutyl
e
18
Ph
15:1
21:1
99:1
e
19
Ph
ef
,
20
cyclohexyl
a
b
Unless otherwise noted, all reactions were conducted at 0.15 mmol scale in 1.5 mL of toluene/CHCl3 (9:1). Yield of isolated product.
c
d
e
1
Determined by HPLC using a chiral stationary phase. Determined by chiral HPLC analysis or H NMR. CHCl3 was used as solvent instead of
f
toluene/CHCl3. Pure anti diastereomer was obtained after column chromatography.
a
Table 3. Substrate Scope of Nitro-Mannich Reaction Using Catalyst 4
b
d
c
entry
5
R1
6
R2
8
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5f
Ph
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6b
H
8a
8b
8c
8d
8e
8f
93
99
81
87
94
99
95
98
99
93
99
95
95
99
96
99
91
96
95
93
97
92
90
95
95
95
95
95
96
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NO2C6H4
o-FC6H4
m-MeOC6H4
α-naphthyl
2-furyl
H
H
H
H
5h
5k
5l
H
H
8g
8h
8i
H
e
9
5n
5o
5p
5q
5a
5a
5o
H
10
11
12
cyclohexyl
phenyl ethyl
isobutyl
H
8j
H
8k
8l
H
e
13
Ph
Me
Et
Me
8m
8n
8o
13:1
16:1
25:1
e
14
Ph
ef
,
15
cyclohexyl
85
a
b
c
Unless otherwise noted, all reactions were conducted at 0.1 mmol scale in 1.0 mL of toluene/CHCl3 (9:1). Yield of isolated product. Determined
d
e
by HPLC using a chiral stationary phase. Determined by chiral HPLC analysis or 1H NMR. CHCl3 was used as solvent instead of toluene/CHCl3.
f
Pure anti diastereomer was obtained after column chromatography.
In order to assess the role of the multiple H-bonding donors
played in the reaction and gain insight into the cooperative
catalysis of the catalyst.12 Two control experiments were carried
out as shown in Scheme 2. Using methylated 3f (3h) as the
catalyst under the optimized conditions, the reaction became a
little sluggish and the enantioselectivity of the product was
significantly decreased (83% yield, 62% ee). When we employed
catalyst 2f which lacks the quaternary ammonium center
C
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compared with 3f, the reaction became sluggish (75% yield), and
a nearly racemic product was obtained (only 7% ee). These
results support cooperative catalysis of the bifunctional catalysts
and indicate that the hydroxy on the phenylalaninol moiety plays
a significant role in this nitro-Mannich reaction.
In summary, we have developed a new class of bifunctional
phase-transfer catalysts bearing multiple H-bonding donors
derived from cinchona alkaloids and various β-aminoalcohols,
which has been successfully applied to the nitro-Mannich
reactions of amidosulfones, with a very broad substrate scope;
both enantiomers of the products can be obtained in excellent
enantio-/diastereoselectivity (90−99% ee, 13:1−99:1 dr). Since
reports about the synthesis and application of phase-transfer
catalysts bearing multiple H-bonding donors are rare, we believe
that this work will encourage development in this area. Further
efforts to investigate the mechanism and apply these catalysts to
other useful asymmetric transformations are underway in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
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Detailed experimental procedures including complete character-
izations (1H NMR and 13C NMR spectra, spectral data, and
HRMS).This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: linyj@jlu.edu.cn.
*E-mail: duanhf@jlu.edu.cn.
Notes
(8) Yin, B.; Zhang, Y.; Xu, L.-W. Synthesis 2010, 3583−3595.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the financial support from the National Natural
Science Foundation of China (No. 51373067).
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dx.doi.org/10.1021/ol503264n | Org. Lett. XXXX, XXX, XXX−XXX