Organocatalytic asymmetric aza-Michael addition of pyrazole to chalcone

Article abstract of DOI:10.1016/j.tetasy.2013.11.012

An efficient enantioselective aza-Michael addition of pyrazole to chalcone was established. In the presence of the primary amine derived from cinchona alkaloid and acidic additive, the reactions afforded 1,4-adducts in high yields (up to 98%) with 68-88%

Full text of DOI:10.1016/j.tetasy.2013.11.012

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic asymmetric aza-Michael addition of pyrazole
to chalcone
a
a
a,
Pengfei Li a,b, , Fang Fang , Ji Chen , Jun Wang
⇑
⇑
a Department of Chemistry, South University of Science and Technology of China, 1088 Tangchang Road, Nanshan District, Shenzhen, Guangdong 518055, PR China
b State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient enantioselective aza-Michael addition of pyrazole to chalcone was established. In the pres-
ence of the primary amine derived from cinchona alkaloid and acidic additive, the reactions afforded
1,4-adducts in high yields (up to 98%) with 68–88% ee.
Received 12 October 2013
Accepted 13 November 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
a catalyst. That is to say, the transformation would be less affected
by the background reaction between the nitrogen nucleophile and
The stereocontrolled construction of carbon–nitrogen bonds is
an important topic in modern organic synthesis, driven by the sig-
nificance of the biologically and synthetically interesting products
formed.1 Among a number of methods for this stereoselective
transformation, the Michael addition of nitrogen nucleophiles, also
known as aza-Michael addition, offers a straightforward C–N bond-
formation and has been successfully employed in the synthesis of
diversified bioactive natural products.2 In particular, organocata-
lytic asymmetric aza-Michael addition reactions have received
widespread attention because of the advantages of easy availability
and of carrying out asymmetric transformations in a metal-free
environment and under mild and non-inert reaction conditions.3
The search for new N-heterocyclic nucleophiles, as suitable
acceptors as well as more efficient catalyst systems for the synthe-
sis of compounds containing azole groups is of current interest.
Until now, various types of nitrogen nucleophiles have been ex-
plored in asymmetric aza-Michael addition such as N-protected
carbamates, triazoles, tetrazoles, benzotriazoles, imidazoles,
amines, imines, amides, indoles, tryptamines, hydrazones, ureas
etc.4 However, the organocatalytic enantioselective aza-Michael
additions of azole with impressive results are rarely reported.
Notably, poor yields (21% and 29%,5e 43%5g) with no more than
83% ee were obtained in the organocatalytic aza-Michael additions
of azole to chalcone even with a catalyst loading of 20 mol %.5
Recently, we have successfully developed catalyst-free aza-
chalcone and the asymmetric induction could be realized with a
suitable organocatalyst in the aza-Michael addition. Herein we
report an efficient organocatalytic asymmetric aza-Michael addi-
tion of pyrazole to chalcone in the presence of a primary amine
combined with an acidic additive (Scheme 1, Eq. 3).
Previous work
O
N
(1)
(2)
(3)
+
N
N
O
N
N
R1
CO2R2
N
H
R1
N
CO2R2
+
NO2
R3
N
H
NO2
O
R3
This work
Ar1
O
N
N
N
+
Ar2
N
H
Ar1
Ar2
Scheme 1. Aza-Michael addition of pyrazole.
2. Results and discussion
Initially we focused our attention on the primary amine8 and
thiourea9 catalytic aza-Michael additions between chalcone 1a
and pyrazole 2a, and the results are displayed in Table 1. The initial
results indicated that both primary amine I and thiourea II failed to
give asymmetric induction (Table 1, entries 1–3). A remarkable
enhancement was achieved when an acidic additive, 4-nitrobenzoic
acid A1, was introduced into the primary amine catalyzed reaction
system (Table 1, entry 4).10 Employing 3-hydroxy-2-naphthoic acid
A2 as an acidic additive resulted in a higher enantioselectivity
Michael addition of an azole to b,c-unsaturated a
-keto esters6
and nitroalkenes7 (Scheme 1, Eqs. 1 and 2). Moreover, it was found
that no reaction took place between pyrazole and chalcone without
⇑
Corresponding authors. Tel.: +86 755 88018319; fax: +86 755 88018304 (P.L.);
tel.: +86 755 88018317; fax: +86 755 88018304 (J.W.).
E-mail addresses: li.pf@sustc.edu.cn, flyli1980@gmail.com (P. Li), wang.j@sustc.
edu.cn (J. Wang).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.012
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2
P. Li et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
(Table 1, entry 5). When the reaction was carried out in Et2O as the
solvent, the combination of Ia and A2 furnished a 1,4-adduct in 85%
yield with 84% ee (Table 1, entry 6). Furthermore, good results could
be obtained when Ib was used as the chiral organocatalyst (Table 1,
entries 8 and 9). With these encouraging results in hand, further
optimization of the reaction conditions was carried out. After
careful screening of acidic additives, 1-hydroxy-2-naphthoic acid
A3, PhCO2H A4, N-Boc phenylglycine A5, and N-Boc glycine A6, it
was found that 1-hydroxy-2-naphthoic acid A3 afforded better
results (Table 1, entries 10–13). Investigation of the reaction
media indicated that ether was more suitable for the system
(Table 1, entries 14–19). Increasing or reducing the loading of A3
led to similar yields and slightly lower ee values (Table 1, entries
20 and 21). Doubling the loadings of Ib and A3 afforded 1,4-adduct
3aa in 80% isolated yield with 80% ee (Table 1, entry 22). If the
reaction was performed in Et2O, Ib with a loading of 10 mol %, it
enabled the formation of 3aa in 93% isolated yield with 76% ee
(Table 1, entry 23). Using 1,4-dioxane as the solvent furnished
3aa with 86% ee, the best enantioselectivity, and 62% isolated yield
(Table 1, entry 24).
Under the optimized reaction conditions, Ib/A3-catalyzed aza-
Michael additions between a series of chalcones 1 and pyrazole
2a were surveyed (Table 2). In the presence of Ib combined with
A3, 1,4-adducts 3aa–la were isolated in 50–96% yields with
68–84% ee. Increasing Et2O solvents ranging from 0.15 mL to
0.30 mL led to an increase of the asymmetric induction from 72%
to 77% (Table 2, entry 5). Replacing Et2O with 1,4-dioxane as the
reaction medium resulted in a higher enantioselectivity (Table 2,
entry 6). Various substituents, either electron-withdrawing
(Table 2, entries 2, 4–10, 14) or electron-donating groups (Table 2,
entries 1, 3, 11–13), could be introduced into both aromatic rings
of chalcone. 4-Methoxychalcone 1k was found to form 1,4-adduct
3ka with inferior results, 68% yield with 46% ee, in Et2O while
the ee value could be increased to 72% when the reaction was
performed in 1,4-dioxane (Table 2, entries 12 and 13).
Table 2
Substrate scope of the aza-Michael additiona
Ib (10 mol%)
A3 (20 mol%)
O
N
N
O
N
solvent,
+
N
H
RT
Table 1
Optimization of reaction conditionsa
R2
R1
1
2a
R1
3
R2
catalyst
acid
O
N
N
N
O
Entry
R1
R2
Solvent
t (h)
Yieldb (%)
eec (%)
+
N
H
Ph
Ph
solvent
1a
1
2
3
4
5
6
7
8
4-Me
3-Br
H
4-F
4-F
4-F
4-CF3
4-Br
3-NO2
4-Br
4-Me
4-MeO
4-MeO
H
H
H
Et2O (0.15 mL)
Et2O (0.15 mL)
Et2O (0.15 mL)
Et2O (0.15 mL)
Et2O
1,4-Dioxane
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
96
96
96
3ba, 93
3ca, 95
3da, 85
3ea, 96
3ea, 88
3ea, 68
3fa, 81
3ga, 89
3ha, 50
3ia, 51
3ja, 66
3ka, 68
3ka, 50
3la, 70
3ha, 40
3ja, 53
68
82
77
72
77
84
84
83
80
76
83
46
72
71
88
86
Ph
Ph
2a
3aa
catalyst:
R
3-MeO
H
H
H
H
H
H
3-Cl
4-MeO
H
H
3-Cl
H
96
112
112
96
96
96
96
96
112
112
112
90
H
N
H
N
NH
9
N
NH2
S
NH
Ar
10
11
12
13
14
15d
16d
Ia R = H
N
Ib R = OMe
II
Ar = 3,5-(CF3)-C6H3
1,4-Dioxane
Et2O
1,4-Dioxane
1,4-Dioxane
Entry
Cat.
Acid
Solvent
t (h)
Yieldb (%)
eec (%)
3-NO2
4-Me
1
2
3
4
Ia
Ib
II
—
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
24
24
24
24
24
42
20
20
48
20
20
20
20
20
20
20
20
20
20
20
20
48
96
112
12
14
12
43
48
85
80
69
90
83
37
75
51
52
73
49
0
0
0
4-MeO
90
a
Unless noted, the reaction was carried out with 1 (0.10 mmol), 2a (0.20 mmol),
Ia
Ia
Ia
Ia
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
Ib
A1
A2
A2
A2
A1
A2
A3
A4
A5
A6
A3
A3
A3
A3
A3
A3
A3
A3
A3
A3
A3
56
72
84
80
70
82
83
44
80
73
72
78
68
82
68
74
75
78
80
76
86
Ib (10 mol %), and A3 (20 mol %) in a solvent (0.30 mL) at room temperature for the
5
time given.
6
b
Isolated yield.
Determined by chiral HPLC.
Instead of Ib and A3, Ia (10 mol %) and A2 (20 mol %) were employed.
7d
c
8d
d
9
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d
20e
21f
22d
23
24
The Ia/A2-catalyzed aza-Michael additions of pyrazole to chal-
cone were also revisited. Higher asymmetric induction with med-
ium yields was obtained when the conjugate reactions were
catalyzed by the Ia/A2 system in 1,4-dioxane (Table 2, entries 15
and 16)
In addition to pyrazole 1a, we also expanded our catalytic sys-
tem to other azoles. Preliminary studies showed that up to 98%
yield with 72% ee could be obtained from the aza-Michael addition
of 3,5-dimethylpyrazole 2b to chalcone 1a when the Ib/A3
system was employed as the chiral catalyst in a solution of Et2O
(Scheme 2).
Et2O
Et2O
Et2O
1,4-dioxane
MeOCH2OMe
(MeOCH2)2
t-BuOMe
EtOAc
Toluene
Et2O
Et2O
79
51
79
85
82
Et2O
Et2O (0.15 mL)
1,4-Dioxane
80 (Isolated)
93 (Isolated)
62 (Isolated)
Ib
(10 mol%)
(20 mol%)
a
Unless noted, reaction was carried out: chalcone (0.10 mmol), pyrazole
O
A3
(0.2 mmol), catalyst (10 mol %), and acidic additive (20 mol %) in the solvent
(0.3 mL) were stirred at room temperature for the time given.
+
N
N
Et2O (0.15 mL),
RT, 96 h
Ph
Ph
N
O
N
H
b
HPLC yield.
c
Determined by chiral HPLC with Chiralpak AD-H.
Catalyst (20 mol %) and acid (40 mol %) were employed.
Catalyst (20 mol %) and acid (30 mol %) were employed.
Catalyst (20 mol %) and acid (60 mol %) were employed.
1a
Ph
Ph
2b
98% yield, 72% ee
d
3ab
e
f
Scheme 2. Aza-Michael addition of 3,5-dimethylpyrazole.
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P. Li et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
4.5. 1-(3-Methoxyphenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-
3. Conclusion
1-one 3da
Herein we have developed an organocatalytic aza-Michael addi-
tion of pyrazole to chalcone to afford products in 40–98% yields
with 68–88% ee. Compared with the reported results,5e,g higher
ee values and yields were obtained with this methodology. A wide
range of chalcones reacted smoothly with pyrazole to afford good
yields and ee values. These results represent the first systematic
and general report on the organocatalytic enantioselective
aza-Michael addition of pyrazole to chalcone. The development
of a new type of organocatalyst and further applications of these
reactions are currently under investigation.
1H NMR (400 MHz, CDCl3): d (ppm) 7.96 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 9.6, Hz, 2H), 7.33–7.24 (m, 5H), 6.91 (d, J = 8.8 Hz, 2H), 6.22
(s, 1H), 6.11 (dd, J = 5.4, 8.6 Hz, 1H), 4.42 (dd, J = 8.4, 17.2 Hz, 1H),
3.84 (s, 3H), 3.60 (dd, J = 5.2, 17.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 195.2, 163.8, 141.0, 139.4, 130.7, 129.9, 129.8,
128.9, 128.0, 126.8, 113.9, 105.6, 61.1, 55.6, 43.9. ½a D20
¼ þ66:5 (c
ꢀ
1.00, CHCl3) 77% ee. IR mmax: 3063, 3031, 2930, 1675, 1600, 1510,
1455, 1259, 1212, 1170, 1028, 835, 754, 694 cmꢁ1. HRMS: exact
mass calculated for [M+Na]+ (C19H18N2O2Na) requires m/z
329.1266, found m/z 329.1257.
4. Experimental
4.6. 3-(4-Fluorophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ea
4.1. General procedure for aza-Michael addition
1H NMR (400 MHz, CDCl3): d (ppm) 7.98-7.96 (m, 2H), 7.56
(t, J = 7.4 Hz, 1H), 7.52–7.48 (m, 2H), 7.44 (d, J = 7.8 Hz, 2H),
7.35–7.32 (m, 2H), 7.01 (t, J = 8.8 Hz, 2H), 6.23 (t, J = 2.0 Hz, 1H),
6.09 (dd, J = 5.6, 8.0 Hz, 1H), 4.43 (dd, J = 8.0, 17.6 Hz, 1H), 3.65
(dd, J = 5.6, 17.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm)
Unless noted otherwise, the reaction was carried out as
follows: to a solution of Et2O or 1,4-dioxane (0.3 mL) were added
chalcone 1 (0.1 mmol) and pyrazole 2 (0.2 mmol) in the presence
of catalyst Ib (10 mol %) combined with A3 (20 mol %). The reac-
tion mixture was stirred at room temperature for the time given.
Then the solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel to yield the
desired Michael adducts 3.
1
4
196.6, 162.5 (d, JCꢁF = 245.4 Hz), 139.6, 136.6 (d, JC–F = 3.3 Hz),
3
136.58, 133.6, 129.8, 128.8, 128.6 (d, JC–F = 8.1 Hz), 128.3, 115.8
(d, JC–F = 21.4 Hz), 105.8, 60.3, 44.4. ½a D20
ꢀ
¼ þ58:2 (c 1.00, CHCl3)
2
72% ee. IR mmax: 3117, 3063, 2914, 1685, 1597, 1510, 1449, 1396,
1224, 1045, 752, 689 cmꢁ1. HRMS: exact mass calculated for
[M+Na]+ (C18H15N2OFNa) requires m/z 317.1066, found m/z
317.1065.
4.2. 1,3-Diphenyl-3-(1H-pyrazol-1-yl)propan-1-one 3aa
1H NMR (400 MHz, CDCl3): d (ppm) 7.98 (d, J = 7.2 Hz, 2H),
7.58–7.50 (m, 3H), 7.46–7.43 (m, 2H), 7.34–7.26 (m, 5H), 6.24 (t,
J = 1.8 Hz, 1H), 6.12 (dd, J = 5.2, 8.4 Hz, 1H), 4.50 (dd, J = 4.6,
17.8 Hz, 1H), 3.64 (dd, J = 5.2, 18.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.7, 140.9, 139.4, 136.7, 133.5, 129.9, 128.9,
4.7. 3-(4-(Trifluoromethyl)phenyl)-1-phenyl-3-(1H-pyrazol-1-
yl) propan-1-one 3fa
1H NMR (400 MHz, CDCl3): d (ppm) 7.97 (d, J = 7.2 Hz, 2H),
7.60–7.51 (m, 5H), 7.47–7.43 (m, 4H), 6.26 (t, J = 2.0 Hz, 1H),
6.19–6.16 (m, 1H), 4.48 (dd, J = 8.0, 17.6 Hz, 1H), 3.68 (dd, J = 5.4,
17.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 196.3, 144.9,
128.7, 128.3, 128.1, 126.8, 105.7, 60.9, 44.3. ½a D20
¼ þ64:3 (c 1.00,
ꢀ
CHCl3) 76% ee. IR
mmax: 3063, 3031, 2914, 1684, 1556, 1508,
1449, 1261, 1207, 1043, 751, 689 cmꢁ1. HRMS: exact mass calcu-
lated for [M+Na]+ (C18H16N2ONa) requires m/z 299.1160, found
m/z 299.1161.
139.9, 136.5, 133.7, 130.0, 128.8, 128.3, 127.3, 125.9 (q, JC–F
=
3.6 Hz), 106.1, 60.5, 44.3. ½a D20
¼ þ60:2 (c 1.00, in CHCl3) 84% ee. IR
ꢀ
m
max: 3060, 2917, 1686, 1621, 1505, 1449, 1326, 1167, 1124,
4.3. 1-Phenyl-3-(1H-pyrazol-1-yl)-3-p-tolylpropan-1-one 3ba
1069, 753, 688 cmꢁ1. HRMS: exact mass calculated for [M+H]+
1H NMR (400 MHz, CDCl3): d (ppm) 7.98 (d, J = 7.2 Hz, 2H), 7.55
(t, J = 7.4 Hz, 1H), 7.50 (s, 1H), 7.47–7.42 (m, 3H), 7.24 (d, J = 8.0 Hz,
2H), 7.13 (d, J = 8.0 Hz, 2H), 6.22 (t, J = 2.0 Hz, 1H), 6.10–6.06 (m,
1H), 4.46 (dd, J = 8.4, 17.6 Hz, 1H), 3.64 (dd, J = 5.2, 17.6 Hz, 1H),
2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): d (ppm) 196.8, 139.3,
137.9, 137.8, 136.8, 133.4, 129.7, 129.6, 128.7, 128.3, 126.8,
(C19H16N2OF3) requires m/z 345.1215, found m/z 345.1199.
4.8. 3-(4-Bromophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ga
1H NMR (400 MHz, CDCl3): d (ppm) 7.96 (d, J = 7.2 Hz, 2H), 7.56
(t, J = 7.4 Hz, 1H), 7.51–7.48 (m, 2H), 7.46–7.44 (m, 4H), 7.22 (d,
J = 8.4 Hz, 2H), 6.24 (t, J = 2.0 Hz, 1H), 6.08–6.05 (m, 1H), 4.43
(dd, J = 8.0, 17.6 Hz, 1H), 3.64 (dd, J = 5.4, 17.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d (ppm) 196.4, 139.9, 139.7, 136.5, 133.6,
132.0, 129.9, 128.8, 128.6, 128.3, 122.1, 105.9, 60.4, 44.2.
105.6, 60.8, 44.3, 21.2. ½a D20
ꢀ
¼ þ34:2 (c 1.00, CHCl3) 68% ee. IR mmax
:
3060, 3022, 2920, 1686, 1596, 1513, 1448, 1283, 1204, 1043, 749,
688 cmꢁ1. HRMS: exact mass calculated for [M+H]+ (C19H19N2O)
requires m/z 291.1497, found m/z 291.1499.
½
a 2D0
ꢀ
¼ þ36:0 (c 1.00, CHCl3) 83% ee. IR
mmax: 3060, 2920, 1685,
4.4. 3-(3-Bromophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-
one 3ca
1596, 1488, 1448, 1396, 1207, 1011, 754, 689 cmꢁ1. HRMS: exact
mass calculated for [M+H]+ (C18H16N2OBr) requires m/z 355.0446,
found m/z 355.0445.
1H NMR (400 MHz, CDCl3): d (ppm) 7.98–7.96 (m, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.52–7.50 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H), 7.41 (d,
J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.25
(t, J = 2.0 Hz, 1H), 6.07 (dd, J = 5.2, 8.4 Hz, 1H), 4.47 (dd, J = 8.4,
17.6 Hz, 1H), 3.61 (dd, J = 5.2, 17.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.3, 143.1, 139.7, 136.5, 133.6, 131.3, 130.5,
4.9. 3-(3-Nitrophenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-1-one
3ha
1H NMR (400 MHz, CDCl3): d (ppm) 8.25 (s, 1H), 8.14 (d,
J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H),
7.59–7.55 (m, 3H), 7.51 (t, J = 8.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H),
6.27 (t, J = 2.0 Hz, 1H), 6.23-6.19 (m, 1H), 4.47 (dd, J = 7.8,
17.8 Hz, 1H), 3.74 (dd, J = 5.6, 18.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 196.0, 142.9, 140.2, 136.3, 133.8, 133.2, 130.1,
130.0, 128.8, 128.3, 125.5, 123.0, 106.0, 60.3, 44.2. ½a D20
¼ þ56:9
ꢀ
(c 1.00, CHCl3) 82% ee. IR
mmax: 3110, 3059, 2914, 1685, 1596,
1509, 1448, 1395, 1207, 1090, 756, 690 cmꢁ1. HRMS: exact mass
calculated for [M+H]+ (C18H16N2OBr) requires m/z 355.0446, found
m/z 355.0445.
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4
P. Li et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
129.9, 128.9, 128.3, 123.2, 122.1, 106.2, 60.2, 44.2. ½a D20
ꢀ
¼ þ27:9 (c
4.14. 3-(3,5-Dimethyl-1H-pyrazol-1-yl)-1,3-diphenylpropan-1-one
3ab
0.80, CHCl3) 80% ee. IR
m
max: 3079, 2914, 1684, 1597, 1529, 1448,
1351, 1210, 1092, 758, 688 cmꢁ1. HRMS: exact mass calculated
for [M+H]+ (C18H16N3O3) requires m/z 322.1192, found m/z
322.1180.
1H NMR (400 MHz, CDCl3): d (ppm) 8.01–7.99 (m, 2H), 7.57–
7.53 (m, 1H), 7.46–7.42 (m, 2H), 7.33–7.29 (m, 2H), 7.26–7.22
(m, 3H), 5.98 (dd, J = 4.8, 8.8 Hz, 1H), 5.78 (s, 1H), 4.58
(q, J = 8.8 Hz, 1H), 3.54 (dd, J = 4.6, 17.8 Hz, 1H), 2.26 (s, 3H), 2.19
(s, 3H). 13C NMR (100 MHz, CDCl3): d (ppm) 197.4, 147.2, 141.5,
139.7, 136.9, 133.3, 128.8, 128.6, 128.4, 127.6, 126.6, 105.4, 56.8,
4.10. 3-(4-Bromophenyl)-1-(3-chlorophenyl)-3-(1H-pyrazol-1-
yl) propan-1-one 3ia
1H NMR (400 MHz, CDCl3): d (ppm) 7.93 (t, J = 1.8 Hz, 1H), 7.85-
7.82 (m, 1H), 7.54–7.51 (m, 2H), 7.46 (d, J = 2.4 Hz, 2H), 7.44 (s,
1H), 7.41-7.37 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.24 (t, J = 2.2 Hz,
1H), 6.03 (dd, J = 5.4, 8.2 Hz, 1H), 4.43 (dd, J = 8.4, 17.6 Hz, 1H),
3.57 (dd, J = 5.4, 17.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): d
(ppm) 195.3, 139.7, 138.0, 135.2, 133.6, 132.1, 130.1, 129.9,
44.9, 13.8, 11.2. ½a D20
ꢀ
¼ þ124:4 (c 1.00, CHCl3, 72% ee). IR mmax
:
3062, 3025, 2917, 1685, 1555, 1449, 1361, 1206, 1024, 750,
690 cmꢁ1. HRMS: exact mass calculated for [M+H]+ (C20H21N2O)
requires m/z 305.1654, found m/z 305.1644.
Acknowledgment
128.6, 128.5, 126.4, 122.3, 106.1, 60.3, 44.3. ½a D20
¼ þ27:8 (c 1.00,
ꢀ
CHCl3) 76% ee. IR
m
max: 3066, 2961, 2923, 1690, 1603, 1488,
We gratefully thank the startup fund from South University of
Science and Technology of China (SUSTC) for financial support.
1394, 1280, 1207, 1074, 1011, 793, 679 cmꢁ1. HRMS: exact mass
calculated for [M+H]+ (C18H15N2OClBr) requires m/z 389.0056,
found m/z 389.0068.
References
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additions, see: Refs. [2c–f].
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4.11. 1-(4-Methoxyphenyl)-3-(1H-pyrazol-1-yl)-3-p-tolylpropan-
1-one 3ja
1H NMR (400 MHz, CDCl3): d (ppm) 7.96 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H),
7.13 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.21 (t, J = 2.0 Hz,
1H), 6.09–6.05 (m, 1H), 4.39 (dd, J = 8.4, 17.2 Hz, 1H), 3.85 (s,
3H), 3.60 (dd, J = 5.4, 17.4 Hz, 1H), 2.31 (s, 3H). 13C NMR
(100 MHz, CDCl3): d (ppm) 195.3, 163.8, 139.3, 137.9, 137.8,
130.6, 129.8, 129.7, 129.5, 126.8, 113.9, 105.5, 60.9, 55.6, 43.9,
21.2. ½a 2D0
ꢀ
¼ þ32:1 (c 1.00, CHCl3) 83% ee. IR
mmax: 3006, 2920,
2832, 1675, 1601, 1510, 1420, 1259, 1170, 1025, 809, 753 cmꢁ1
.
HRMS: exact mass calculated for [M+H]+ (C20H21N2O2) requires
m/z 321.1603, found m/z 321.1608.
4.12. 3-(4-Methoxyphenyl)-1-phenyl-3-(1H-pyrazol-1-yl)propan-
1-one 3ka
6. Wang, J.; Li, P.; Chan, S. H.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2012, 53,
2887.
7. Wu, Y.; Wang, J.; Li, P.; Kwong, F. Y. Synlett 2012, 788.
1H NMR (400 MHz, CDCl3): d (ppm) 7.97 (d, J = 7.2 Hz, 2H), 7.55
(t, J = 7.4 Hz, 1H), 7.50 (s, 1H), 7.47–7.42 (m, 3H), 7.29 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 8.4 Hz, 2H), 6.21 (t, J = 2.0 Hz, 1H), 6.07–6.04 (m,
1H), 4.43 (dd, J = 8.0, 17.6 Hz, 1H), 3.77 (s, 3H), 3.65 (dd, J = 5.6,
17.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 196.9, 159.5,
139.4, 136.8, 133.4, 132.9, 129.6, 128.7, 128.3, 128.2, 114.3,
8. For reviews, see: (a) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759; (b) Alba, A.
N.; Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432; (c)
Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229; (d) Jiang, L.; Chen, Y. C. Catal. Sci.
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Technol. 2013. http://dx.doi.org/10.1039/C3CY00739A. For the primary amine
catalytic Michael addition, see:; (h) Li, P.; Zhao, J.; Li, F.; Chan, A. S. C.; Kwong, F.
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Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (c) Miyabe, H.; Takemoto, Y. Bull.
Chem. Soc. Jpn. 2008, 81, 785; (d) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516;
(e) Connon, S. J. Chem. Commun. 2008, 2499; (f) Sohtome, Y.; Nagasawa, K.
Synlett 2010, 1; (g) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298; (h)
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Tsogoeva, S. B. Org. Biomol. Chem. 2013, 11, 7051; For the thiourea catalytic
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Chem. 2011, 9, 7997.
10. For the effects of an acidic additive on primary amine catalyzed reactions, see:
Refs. 8h,i (a) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.;
Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934; (b) Huang, H.; Jin,
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Huang, C. H.; Lin, W. W. Chem. Commun. 2012, 5590; (d) Paradisi, E.; Righi, P.;
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105.6, 60.6, 55.4, 44.4. ½a D20
ꢀ
¼ þ12:5 (c 1.00, CHCl3) 30% ee. IR mmax
:
2958, 2930, 2832, 1684, 1610, 1514, 1448, 1250, 1176, 1030,
748, 688 cmꢁ1
.
HRMS: exact mass calculated for [M+Na]+
(C19H18N2O2Na) requires m/z 329.1266, found m/z 329.1252.
4.13. 1-(3-Chlorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-
1-one 3la
1H NMR (400 MHz, CDCl3): d (ppm) 7.94 (t, J = 1.8 Hz, 1H), 7.86–
7.84 (m, 1H), 7.54–7.50 (m, 2H), 7.47 (d, J = 2.4 Hz, 1H), 7.40–7.34
(m, 2H), 7.32–7.28 (m, 4H), 6.24 (t, J = 2.0 Hz, 1H), 6.08 (dd, J = 5.0,
8.2 Hz, 1H), 4.48 (dd, J = 8.6, 17.8 Hz, 1H), 3.58 (dd, J = 5.2, 17.6 Hz,
1H). 13C NMR (100 MHz, CDCl3): d (ppm) 195.6, 140.7, 139.4, 138.2,
135.1, 133.4, 130.1, 129.9, 129.0, 128.5, 128.2, 126.8, 126.4, 105.9,
60.9, 44.4. ½a 2D0
ꢀ
¼ þ49:0 (c 1.00, CHCl3) 66% ee. IR
mmax: 3065, 3031,
2918, 1690, 1572, 1496, 1424, 1396, 1285, 1259, 1204, 1091,
1045, 753, 703 cmꢁ1. HRMS: exact mass calculated for [M+H]+
(C18H16N2OCl) requires m/z 311.0951, found m/z 311.0948.
Please cite this article in press as: Li, P.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.012