Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone containing pyridine

Article abstract of DOI:10.1016/j.tet.2016.11.063

A series of chiral thioureas derived from quinine were tested as catalysts in the enantioselective Michael additions of nitromethane to α,β-unsaturated ketones containing pyridine. The best results were obtained with the bifunctional catalyst prepared from 3,5-di(trifluoromethyl)-aniline under solvent-free conditions. This thiourea promoted the reaction with high enantioselectivities and chemical yields for aryl ketones. The origins of enantioselectivity were further investigated via experiment and computation. Meanwhile, the products from our reaction showed potent antibacterial activities against rice bacterial leaf blight, with the S-enantiomer performing much better than the R-enantiomer. Given the promising bioactivity of this class of molecules, our work is expected to offer important applications in developing future generations for drug design.

Full text of DOI:10.1016/j.tet.2016.11.063

Tetrahedron xxx (2016) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-free enantioselective conjugate addition and bioactivities of
nitromethane to Chalcone containing pyridine
,
Guoping Zhang a b, Chun Zhu a, Dengyue Liu a, Jianke Pan a, Jian Zhang a, Deyu Hu a,
,
*
Baoan Song a
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang, 550025, China
b Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral thioureas derived from quinine were tested as catalysts in the enantioselective Michael
Received 1 October 2016
Received in revised form
19 November 2016
Accepted 22 November 2016
Available online xxx
additions of nitromethane to
a,b-unsaturated ketones containing pyridine. The best results were ob-
tained with the bifunctional catalyst prepared from 3,5-di(trifluoromethyl)-aniline under solvent-free
conditions. This thiourea promoted the reaction with high enantioselectivities and chemical yields for
aryl ketones. The origins of enantioselectivity were further investigated via experiment and computation.
Meanwhile, the products from our reaction showed potent antibacterial activities against rice bacterial
leaf blight, with the S-enantiomer performing much better than the R-enantiomer. Given the promising
bioactivity of this class of molecules, our work is expected to offer important applications in developing
future generations for drug design.
Keywords:
Solvent-free
Asymmetric synthesis
© 2016 Published by Elsevier Ltd.
g-Nitroketones
Mechanism
Antibacterial activity
1. Introduction
aqueous-phase catalysis,21 and metal-catalysis,22 to synthesize
enantioselective compounds. However, highly selectivities are
Chalcone was one of the most useful molecular frameworks in
medicinal chemistry and its derivatives exhibited a broad spectrum
of biological activities.1 Especially 1,4-addition products of chalcone
were reported to possess promising biological activities such as
anticancer,2 antiplant-viral,3 antimicrobial,4 anti-HIV,5 and anti-
urease6 properties. The biological activity of 1,4-addition com-
pounds depends on their absolute configuration. Therefore, the
synthesis of enantiomerically pure 1,4-addition compounds has
received considerable attentions.7 At present, the enantioselective
addition of different nucleophiles to chalcone were obtained
successfully.8e12 Among them, the conjugate addition of nitro-
alkanes to chalcone (nitro-Michael reaction) has attracted enor-
mous attention because the nitro group can be converted to other
functional groups,13 such as pyrrolidines,14 lactones,15 carbo-
cycles,16 and amino acids.17
generally restricted to chalcone substrates without heterocyclic
moieties that are necessary for good bioactivities.23 In 2013, Blay
and co-workers24 first reported LaIII-pyBOX complexes-catalyzed
conjugate addition to chalcones containing pyridine to nitro-
alkanes, but only moderate yield and ee were obtained. In addition,
there are few studies in synthesizing highly enantiomerically pure
g
-nitroketones containing heterocycle that exhibit high biological
activities.
It is well known that there are pronounced advantages in
solvent-free synthetic approach include easy work-up procedures,
short reaction time, and simple apparatus requirements, which has
attracted considerable attention in recent years.25 Herein, we
report the efficient conjugate additions of nitromethane to chal-
cone containing pyridine via thiourea organic catalyst under
solvent-free conditions. The origins of enantioselectivity were
further investigated via experimental and computational studies.
Meanwhile, the antibacterial activities against rice bacterial leaf
blight of 1,4-addition chiral products were evaluated.
So far, there are many asymmetric approaches involving orga-
nocatalysis,18 heterogeneous catalysis,19 phase-transfer catalysis,20
* Corresponding author.
E-mail address: songbaoan22@yahoo.com (B. Song).
http://dx.doi.org/10.1016/j.tet.2016.11.063
0040-4020/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

2
G. Zhang et al. / Tetrahedron xxx (2016) 1e8
Table 1
2. Results and discussion
Optimization of reaction conditions for conjugate addition of nitromethane (2) with
trans-chalcone (1a).
Thiourea catalysts with the cinchona motif via hydrogen-
bonding interactions were successfully applied in different types
of Michael reactions.26 These findings prompted us to synthesize
bifunctional thiourea derivatives of quinine Q1~Q6 that are capable
of dual activation through two H bonding (Fig. 1) and apply them in
the conjugate addition of nitromethane (2) to 2-enoylpyridines (1a)
(Table 1). These catalysts were then studied for their ability to
mediate enantioselective 1,4-addition. Among them, Q1, Q3, and
Q4 turned out to be poor catalysts, and Q2 failed to accelerate this
transformation. However, catalysts Q5 and Q6 afforded promising
results (Table 1, entries 5, 6). The change trend in the catalytic ac-
tivity with the introduction of the different substituent on aromatic
ring, indicating that the electron withdrawing property contributed
to higher reactivity for 1,4-addition. In addition, quinine on the
catalyst is crucial for the reaction enantioselectivity. Next, the in-
fluence of solvents on the enantioselective 1,4-addition was studied
using the most efficient catalyst Q5 (Table 1, entry 7e10), toluene
performed better than alternative solvents (Table 1, entry 7). Most
notably, when the model reaction was performed in neat nitro-
methane, a nearly complete conversion was achieved (Table 1, en-
try 11). Almost no change in enantioselectivity and reactivity was
observed when the loading of Q5 was reduced from 20 mol% to
10 mol% (Table 1, entry 12); however, a little decrease of reactivity
and no significant loss of enantioselectivity were observed when a
catalyst load was reduced from 10 mol% to 5 mol% (Table 1, entry
13). Under this reaction condition, the chemical yield was not
improved when the reaction time was increased from 12 h to 24 h
(Table 1, entry 14). It should be noted that the other enantiomer of
the reaction could be obtained by using Q6 as the catalyst (Table 1,
entry 16). Based on the above results, the optimized reaction con-
ditions (entries 12,16) were used for the model reaction. In contrast
to the conventional process (Table 1, entry 15), solvent-free syn-
thetic approach reduced the reaction time dramatically, raised the
yield and simplified the post-treatment.
Entrya
Catalyst (mol%)
Solvent
Time (h)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Q1 (20)
Q2 (20)
Q3 (20)
Q4 (20)
Q5 (20)
Q6 (20)
Q5 (20)
Q5 (20)
Q5 (20)
Q5 (20)
Q5 (20)
Q5 (10)
Q5 (5)
xylene
xylene
xylene
xylene
xylene
xylene
toluene
THF
CH2Cl2
neat
neat
neat
neat
48
48
48
48
48
48
48
48
48
48
12
12
12
24
12
12
13
0
5
90
0
81
95
96
ꢀ95
95
93
92
98
98
97
95
95
94
ꢀ96
37
74
73
79
69
72
95
94
94
80
81
32
93
9
10
11
12
13
14
15
16
Q5 (5)
Q5 (10)
Q6 (10)
neat
toluene
neat
a
Reactions were carried out with 1a (0.2 mmol), 10 equiv of 2 (2 mmol) in capped
vials at R.T.
b
c
Isolated yields.
The ee was determined by chiral HPLC analysis.
Table 2
Enantioselective conjugate addition of nitromethane to a series of b-substituted 2-
enoylpyridines (3a~3m).
Yield (%)a
Ee (%)b
Under these optimized reaction conditions (Table 1, entry 12), a
series of enones were investigated in the asymmetric Michael
addition reaction. As illustrated in Table 2, consistently excellent
Entry
R
Product
1
2
3
4
5
6
7
8
Ph
2-FC6H4
3a (R)/(S)
3b (R)/(S)
3c (R)/(S)
3d (R)/(S)
3e (R)/(S)
3f (R)/(S)
3g (R)/(S)
3h (R)/(S)
3i (R)/(S)
3j (R)/(S)
3k (R)/(S)
3l (R)/(S)
3m (R)/(S)
93/94
95/97
96/97
96/98
91/93
92/94
93/92
94/93
93/92
92/91
83/85
76/79
81/82
96/97
96/98
94/95
96/97
95/96
95/97
97/98
96/97
96/97
98/99
95/96
98/99
96/97
enantioselectivity was observed for a broad range of enones.
substituted enones with various substituents afforded 1,4-adducts
with excellent enantioselectivities (Table 2, entries 1e11). -Het-
b-Aryl
2-CF3C6H4
2-BrC6H4
2-CH3C6H4
3-CH3OC6H4
3-BrC6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
2-furan
b
eroaromatic enones were also excellent substrates for the present
9
10
11
12
13
2-thienyl
a
Isolated yield after silica gel chromatography.
The ee was determined by chiral HPLC analysis; and absolute configuration of
b
the product 3a obtained using Q5 catalyst was determined by X-ray analysis of S
(CCDC:1457122) and the absolute configuration of all other product 3 were assigned
by analogy.
transformation (Table 2, entries 12e13).
b-Aryl and b-hetero-
aromatic enones underwent the Michael addition reaction
smoothly to give the corresponding products in high yields. By
comparison, enones with a para-substituted phenyl (Table 2, entry
9) or heteroaromatic (Table 2, entries 12e13) showed a slightly
reduced reactivity.
To understand the reaction mechanism, we applied both theo-
retical and experimental approaches to clarify how the catalyst
(Cat) activates the nucleophilic (Nu) and the electrophilic (EI)
groups. Via the experiments, the key factors for the enantioselective
Fig. 1. Thiourea-quinine organocatalysts (Q1eQ6).
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

G. Zhang et al. / Tetrahedron xxx (2016) 1e8
3
1,4-addition reaction were observed from the results summarized
in Table 3. The reaction using KOH as base to afford the racemic
product containing phenyl moiety in high yield (Table 3, entry 1),
however, in the same reaction condition, the reaction didn't afford
the racemic product containing pyridine (Table 3, entry 2). The
reaction afforded the product 3a in good yield (Table 3, entry 3)
only with strong base (NaH). The result implies that the substrate
with pyridine hinders Michael addition in alkaline condition. The
best enantioselectivity was obtained using thiourea-quinine (Q5)
catalyst (Table 3, entry 4 and entry 5); however, the reactivity of the
substrate with pyridine is higher than those with phenyl moiety.
The result shows that the nitrogen on pyridine is beneficial for the
reactivity via thiourea-quinine catalyst.
In short, the oxygen and nitrogen on chalone are key factors for
achieving the high enantioselectivity and reactivity; however, it is
not very important that nitromethane was activated by the nitro-
gen on quinine. Via the DFT calculations, the most stable CatꢀEi
complex (Fig. 2) are well consistent with our above experimental
results (Table 3). In addition, the most stable CatꢀNu complex
showed that hydrogen bonding was formed between the oxygen on
Nu and the NeH on thiourea together with the protonated quinine
amine. Based on the above results and the latest mechanism re-
ported by Wang and coworkers27 in 2012, a plausible mechanism
was proposed in Fig. 3. The oxygen and nitrogen on chalcone (1a)
activated by the NH on thiourea and nitromethane activated by
both the NH of thiourea and the nitrogen on quinine to form the
transition state, which undergoes the Michael reaction to afford the
product 3a.
Fig. 2. The most stable structures of Cat (a), CatꢀEI binary complex (b) and CatꢀNu
binary complex (c).
The antibacterial activities of chiral products from our reactions
against rice bacterial leaf blight were evaluated via the turbid meter
test. Bismerthiazol was used as the positive controls.28 The bioassay
results in vitro were shown in Table 4.
The result showed that (S)-compounds generally exhibited
higher antibacterial activity than the corresponding (R)-enan-
tiomer. Among them, some compounds exhibited higher antibac-
terial activities than controls. Especially, compounds (S)-3b and (S)-
Fig. 3. A plausible mechanism.
Table 4
Activities of chiral compounds against rice bacterial leaf blight.
3h possessed excellent activity at 100
Subsequently, compound (R)-3b and (R)-3h had slightly lower ac-
tivity (inhibition, 65% and 57% respectively) at 100 g/mL, which is
mg/mL (inhibition, 100%), and
Compd.
Inhibition (%)a
200 g/mL
Compd.
Inhibition (%)a
200 g/mL
m
m
100
0
65 3.2
38 2.8
43 1.8
0
m
g/mL
m
100
0
mg/mL
higher than that of Bismerthiazol (inhibition, 55%). Compounds (S)-
3c, (S)-3d, (S)-3k and (S)-3m showed good antibacterial activity,
which is higher than that of the control at 100 mg/mL. Subsequently,
their enantiomers displayed lower activity than the control.
Furthermore, two enantiomers of compounds 3a, 3e, 3f, 3i, 3j and
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(R)-3g
(R)-3h
(R)-3i
12 1.1
87 2.6
72 3.3
59 1.6
32 2.4
12 1.5
45 2.4
81 1.7
46 2.4
0
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
(S)-3i
(S)-3j
(S)-3k
(S)-3l
(S)-3m
23 2.1
100 2.4
82 2.2
79 2.9
52 1.7
42 2.3
60 2.1
100 1.4
76 2.1
25 1.4
81 1.6
17 2.5
98 1.8
100 1.8
58 1.9
59 3.8
23 2.5
16 1.9
46 2.6
100 1.9
51 1.6
0
0
26 2.8
57 2.6
22 2.1
0
33 2.4
0
Table 3
The key factors for the enantioselective addition of nitromethane to chalcone.
(R)-3j
(R)-3k
(R)-3l
63 1.5
0
68 2.1
74 1.7
68 2.3
0
75 2.1
(R)-3m
35 2.7
55 2.3
Controlb
a
Average of three replicates.
Bismerthiazol was used as the control.
b
3l showed poor antibacterial activity. In short, the above results
indicated that the phenyl substitution pattern markedly affected
the antibacterial activity of title compounds. Among them, com-
pounds with hydrogen bonding moieties (2-F, 2-CF3, 2-Br, 4-Cl, 4-
Br, 4-CH3O) at the 2 or 4 position of phenyl ring exhibited good
antibacterial activities. In contrast, compounds without hydrogen
bonding moieties (2-CH3 and 4-CH3) showed very low antibacterial
activities. In addition, compounds with the moieties (3-CH3O and
3-Br) at the 3 position of phenyl ring also show very low antibac-
terial activities. However, introduction of the thiophene
Entry
R
Cat. (equ)
Yield (%)c
Ee (%)d
1a
2a
3a
4b
5b
phenyl
KOH (1.0)
KOH (1.0)
NaH (1.0)
Q5 (0.1)
92
0
72
40
94
0
0
0
93
97
2-pyridine
2-pyridine
phenyl
2-pyridine
Q5 (0.1)
a
Reactions were carried out with 2a (0.2 mmol), 10 equiv of 1 (2 mmol) in THF
solvent at R.T.
b
c
Under solvent-free condition.
Isolated yield after silica gel chromatography.
Determined by HPLC using a Chiralpak IA column.
d
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
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4
G. Zhang et al. / Tetrahedron xxx (2016) 1e8
heterocycle at the position of phenyl ring, compound (S)-3m also
possessed good activity. In short, the S-configuration of title com-
pounds is the preferred antibacterial configuration. Among them,
compound (S)-3b and (S)-3h could offer considerable potential for
further development as chiral antibacterial agents. Meanwhile, the
1,4-addition chiral products would result in the synthesis of novel
Michael addition compounds and act as new lead compounds in
modern drug discovery.
(t, J ¼ 6.4 Hz, 1H), 6.29 (d, J ¼ 8.6 Hz, 1H), 5.89e5.71 (m, 1H), 4.97
(dd, J ¼ 27.3, 13.7 Hz, 2H), 3.99 (s, 3H), 3.57 (s, 1H), 3.40e3.31 (m,
1H), 3.24 (dd, J ¼ 13.5, 10.1 Hz, 1H), 2.81 (t, J ¼ 15.1 Hz, 1H), 2.73 (dd,
J ¼ 13.7, 2.9 Hz, 1H), 2.34 (s, 1H), 1.65 (d, J ¼ 30.6 Hz, 3H), 1.40 (t,
J ¼ 11.2 Hz, 1H), 0.88 (dd, J ¼ 13.3, 6.0 Hz, 1H); 13C NMR (126 MHz,
Methanol-d4)
d 180.85 (s), 158.24 (s), 146.92 (s), 143.78 (s), 141.14
(s), 138.57 (s), 129.82 (s), 128.80 (s), 128.68 (s), 125.10 (s), 123.81 (s),
122.40 (s), 120.00 (s), 113.70 (s), 102.89 (s), 60.08 (s), 55.20 (s), 55.13
(s), 41.34 (s), 39.38 (s), 27.50 (s), 27.26 (s), 25.53 (s).
3. Conclusion
Catalyst Q2: White solid, m.p. 148e150 ꢂC, yield 81%,
20
[
d
a
]
¼ ꢀ116.4ꢂ (c 0.39, CHCl3); 1H NMR (500 MHz, Methanol-d4)
D
In summary, we have developed a highly efficient and selective
catalytic method for the synthesis of the 1,4-addition products of
nitromethane to chalcones bearing pyridine by using thiourea
based quinine catalysts. The Michael products were obtained in
excellent enantioselectivities (up to 100% ee) and high yields. Via
experiments and DFT calculation, we know that the oxygen and
nitrogen on chalcone with pyridine was activated by the NH on
thiourea; and nitromethane was activated by both the NH of
thiourea and the nitrogen on quinine to form TS. This activation
model may provide further insight into the bifunctional thiourea
organocatalysts and their analogues. Meanwhile, the products from
our reaction showed potent antibacterial activities against rice
bacterial leaf blight, with the S-enantiomers showing superior
performance than the R-enantiomers accordingly. Given the
promising bioactivity of this class of molecules, our method is ex-
pected to offer important applications in developing future gener-
ations for drug design.
8.62 (d, J ¼ 4.6 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J ¼ 9.2 Hz, 1H), 7.67 (s,
2H), 7.59 (d, J ¼ 4.7 Hz, 1H), 7.39 (dd, J ¼ 9.2, 2.5 Hz, 1H), 6.18 (s, 1H),
5.80e5.73 (m, 1H), 5.03e4.94 (m, 2H), 3.95 (s, 3H), 3.56 (d,
J ¼ 34.5 Hz, 2H), 3.33 (t, J ¼ 12 Hz 1H), 2.88 (s, 2H), 2.40 (s, 1H),
1.75e1.65 (m, 3H), 1.44 (t, J ¼ 11.3 Hz, 1H), 0.97 (d, J ¼ 8.0 Hz, 1H);
13C NMR (126 MHz, Methanol-d4)
d 182.3 (s), 158.24 (s), 146.87 (s),
143.75 (s), 140.44 (s), 136.19 (s), 129.88 (s), 128.76 (s), 125.17 (s),
123.86 (s), 122.41 (s), 114.19 (s), 102.81 (s), 60.24 (s), 55.17 (s), 54.95
(s), 41.39 (s), 38.90 (s), 27.37 (s), 26.64 (s), 25.11 (s); 19F NMR
(471 MHz, Methanol-d4)
d
ꢀ64.07 (s).
Catalyst Q3: White solid, m.p. 133e134 ꢂC, yield 91%,
¼ ꢀ185.2ꢂ (c 0.61, CHCl3); 1H NMR (500 MHz, Methanol-d4)
20
[
d
a
]
D
8.59 (d, J ¼ 4.7 Hz, 1H), 8.02 (s, 1H), 7.90 (d, J ¼ 9.2 Hz, 1H), 7.47 (d,
J ¼ 4.7 Hz, 1H), 7.38 (dd, J ¼ 9.2, 2.7 Hz, 1H), 7.11 (d, J ¼ 8.4 Hz, 2H),
7.06 (d, J ¼ 8.3 Hz, 2H), 6.26 (s, 1H), 5.78e5.67 (m, 1H), 4.99e4.91
(m, 2H), 3.95 (s, 3H), 3.54 (s, 1H), 3.34 (dd, J ¼ 17.2, 10.2 Hz, 1H), 3.19
(dd, J ¼ 13.7, 10.2 Hz, 1H), 2.80e2.65 (m, 2H), 2.28 (s, 1H), 2.24 (s,
3H), 1.72e1.48 (m, 3H), 1.33 (dd, J ¼ 8.2, 5.0 Hz, 1H), 0.83 (dd,
4. Experimental section
J ¼ 13.0, 6.4 Hz, 1H); 13C NMR (126 MHz, Methanol-d4)
d 180.76 (s),
158.22 (s), 146.95 (s), 146.69 (s), 143.80 (s), 141.00 (s), 135.67 (s),
129.88 (s), 128.75 (s), 124.16 (s), 122.40 (s), 120.08 (s), 113.81 (s),
102.92 (s), 60.00 (s), 55.37 (s), 55.18 (s), 55.07 (s), 41.41 (s), 39.22 (s),
27.43 (s), 27.14 (s), 25.49 (s), 19.71 (s).
All reactions were carried out in oven dried glassware with
magnetic stirring. Unless otherwise stated, all reagents were pur-
chased from Aladdin Chemicals Co. (Aladdin, Shanghai, China) and
used without further purification. All solvents used in the reactions
were distilled from appropriate drying agents prior to use. Silica gel
GF254-coated glass plates (Branch Qingdao Haiyang Chemical Co.,
Qingdao, China) were used for thin layer chromatography under
detection at 254 nm. Silica gel 200e300 mesh (Branch Qingdao
Haiyang Chemical Co., Qingdao, China) was applied to column
chromatography. NMR spectra were recorded on a JEOL ECX-500
spectrometer (JEOL, Tokyo, Japan). Infrared (IR) spectra were
recorded on Bruker VECTOR 22 spectrometer (Bruker, Karlsruhe,
Germany) with KBr disks. HRMS data were measured on Thermo
Scientific Q Exactive (Thermo, Missouri, USA). HPLC analysis was
conducted by an Agilent Technologies 1200 Series system (Agilent,
Catalyst Q4: White solid, m.p. 145e147 ꢂC, yield 83%,
20
[a
]
¼ ꢀ137.5ꢂ (c 0.80, CHCl3); 1H NMR (500 MHz, Methanol-d4)
D
d
8.65 (d, J ¼ 4.7 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J ¼ 9.2 Hz, 1H), 7.62 (d,
J ¼ 8.5 Hz, 2H), 7.52 (dd, J ¼ 11.3, 6.7 Hz, 3H), 7.41 (dd, J ¼ 9.2, 2.7 Hz,
1H), 6.31 (d, J ¼ 9.9 Hz, 1H), 5.84e5.74 (m, 1H), 5.01e4.94 (m, 2H),
3.99 (s, 3H), 3.53 (s, 1H), 3.35 (dd, J ¼ 17.4, 10.2 Hz, 1H), 3.23 (dd,
J ¼ 13.7, 10.1 Hz, 1H), 2.81e2.71 (m, 2H), 2.31 (s, 1H), 1.67e1.55 (m,
3H),1.38 (dd, J ¼ 13.1, 10.2 Hz,1H), 0.83 (dd, J ¼ 13.5, 6.7 Hz,1H); 13
C
NMR (126 MHz, Methanol-d4)
d 180.82 (s), 158.25 (s), 146.99 (s),
146.62 (s), 143.72 (s), 142.86 (s), 141.06 (s), 129.89 (s), 128.81 (s),
125.47 (q, JCF ¼ 268.38 Hz), 125.37 (s), 124.37 (q, JCF ¼ 32.25 Hz),
122.45 (s), 120.01 (s), 113.83 (s), 109.92 (s), 60.11(s), 55.23 (s), 55.14
(s), 54.66 (s), 41.43 (s), 39.17 (s), 27.37 (s), 27.20 (s), 25.49 (s); 19F
California, USA) with a 250 mm ꢁ 4.6 mm i.d., 5
mm, Chiralpak IA
(Daicel) column. Optical rotation values were measured by a Wzz-
2s polarimeter (Shanghai Yue Feng Instrument and Meter Co.,
Shanghai, China).
NMR (471 MHz, Methanol-d4)
d
ꢀ63.22 (s);
Catalyst Q5: White solid, m.p.144e145 ꢂC, yield 87%,
¼ ꢀ107.3ꢂ (c 0.51, CHCl3); 1H NMR (500 MHz, Methanol-d4)
20
[
d
a
]
D
8.68 (d, J ¼ 4.6 Hz, 1H), 8.10 (s, 3H), 7.95 (d, J ¼ 9.2 Hz, 1H), 7.60 (s,
4.1. Procedure for synthesis
1H), 7.57 (d, J ¼ 4.7 Hz, 1H), 7.45 (dd, J ¼ 9.2, 2.5 Hz, 1H), 6.37 (d,
J ¼ 10.4 Hz, 1H), 5.94e5.79 (m, 1H), 5.07e4.95 (m, 2H), 4.03 (s, 3H),
3.61 (s, 1H), 3.42 (dd, J ¼ 17.5, 10.1 Hz, 1H), 2.90e2.76 (m, 2H), 2.38
(s, 1H), 1.77e1.61 (m, 3H), 1.47 (dd, J ¼ 13.0, 10.4 Hz, 1H), 0.87 (dd,
4.1.1. Procedure for synthesis of thiourea-quinine catalyst
According to the literature18c, to a solution of 9-aminoquinine
(2 mmol) in CH2Cl2 (10 mL) was slowly added to a solution of iso-
thiocyanate (2 mmol) in CH2Cl2 (5 mL). The mixture was stirred at
ambient temperature until reaction completion. The pure product
was obtained after purification by column chromatography on sil-
ica gel with EtOAc/CH3OH/Et3N (10:1:0.1) as eluant, affording the
catalyst (Q1~Q6).
J ¼ 12.8, 6.4 Hz, 1H); 13C NMR (126 MHz, Methanol-d4)
d 181.14 (s),
158.36 (s), 146.93 (s), 146.31 (s), 143.80 (s), 141.72 (s), 141.21 (s),
131.37 (q, JCF ¼ 33.4 Hz), 129.88 (s), 128.85 (s), 123.38 (q,
JCF ¼ 271.3 Hz), 122.51 (s), 122.29 (s), 119.85 (s), 116.48 (s), 113.71 (s),
102.80 (s), 60.15 (s), 55.39 (s), 55.19 (s), 41.54 (s), 39.40 (s), 27.45 (s),
27.28 (s), 25.65 (s); 19F NMR (471 MHz, Methanol-d4)
d
ꢀ64.39 (s).
Catalyst Q1: White solid, m.p. 132e133 ꢂC, yield 81%,
Catalyst Q6: White solid, m.p.126e128 ꢂC, yield 82%,
20
20
[
d
a
]
¼ ꢀ179.6ꢂ (c 0.54, CHCl3); 1H NMR (500 MHz, Methanol-d4)
[a
]
¼ þ152.0ꢂ (c 0.50, CHCl3); 1H NMR (500 MHz, Methanol-d4)
D
D
8.65 (d, J ¼ 4.7 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J ¼ 9.2 Hz, 1H), 7.52 (d,
d
8.64 (d, J ¼ 4.4 Hz,1H), 8.05 (d, J ¼ 33.9 Hz, 3H), 7.97e7.83 (m, 1H),
J ¼ 4.7 Hz, 1H), 7.43 (dd, J ¼ 9.2, 2.6 Hz, 1H), 7.34e7.26 (m, 4H), 7.13
7.61e7.47 (m, 2H), 7.40 (dd, J ¼ 9.1, 2.5 Hz, 1H), 6.36 (d, J ¼ 10.4 Hz,
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

G. Zhang et al. / Tetrahedron xxx (2016) 1e8
5
1H), 5.98e5.84 (m, 1H), 5.21e5.10 (m, 1H), 4.00 (s, 3H), 3.29 (s, 1H),
3.03e2.97 (m, 3H), 2.32 (s, 1H), 1.54 (d, J ¼ 40.4 Hz, 4H), 1.23e1.08
(m, 1H), 1.04e0.92 (m, 1H), 0.89 (t, J ¼ 6.9 Hz, 1H); 13C NMR
J ¼ 7.5 Hz, 1H), 7.27 (t, J ¼ 6.0 Hz, 2H), 2.44 (s, 3H); 13C NMR
(126 MHz, DMSO-d6)
d 189.13 (s), 153.90 (s), 149.73 (s), 141.68 (s),
138.73 (s), 133.79 (s), 131.47 (s), 131.13 (s), 128.20 (s), 127.13 (s),
123.05 (s), 122.21 (s), 19.90 (s).
(126 MHz, Methanol-d4) d181.30 (s), 158.31 (s), 146.93 (s), 143.79
(s), 141.72 (s), 140.40 (s), 131.36 (q, JCF ¼ 32.8 Hz), 129.84 (s), 124.45
(s), 122.66 (s), 122.32 (d, J ¼ 7.8 Hz), 116.49 (s), 113.96 (s), 102.64 (s),
60.15 (s), 55.14 (d, J ¼ 16.2 Hz), 48.84 (s), 38.83 (s), 27.32 (s), 26.00
4.1.2.6. (E)-3-(3-methoxyphenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1f). Yellow solid, m.p. 57e58 ꢂC, yield 87%; 1H NMR (500 MHz,
(s), 25.15 (s); 19F NMR (471 MHz, Methanol-d4)
d
ꢀ64.35 (s).
DMSO-d6)
d
8.80 (d, J ¼ 4.0 Hz, 1H), 8.25 (d, J ¼ 16.0 Hz, 1H), 8.10 (d,
J ¼ 8.0 Hz, 1H), 8.04 (t, J ¼ 7.0 Hz, 1H), 7.82 (d, J ¼ 16.0 Hz, 1H),
7.70e7.67 (m, 1H), 7.38e7.35 (m, 3H), 7.03 (d, J ¼ 7.0 Hz, 1H), 3.81 (s,
4.1.2. Procedure for synthesis of chalcones containing pyridine
Referring to the literature9b by a modified method, to a solution
of 2-acetyl pyridine (20 mmol) and aldehyde (20 mmol) in meth-
anol (60 mL) was added to KOH (20 mmol) and H2O (2 mL) at
ambient temperature. The resulting solution was stirred at room
temperature for 12 h. Then H2O (1000 mL) was added, filtered
under reduced the pressure, dried to obtain the crude product. The
crude product was purified by column chromatography over silica
gel with EtOAc/n-Hexane (1:10) as eluant, affording the chalcones
containing pyridine (1a~1m).
3H); 13C NMR (126 MHz, DMSO-d6)
d 189.29 (s), 160.20 (s), 153.93
(s), 149.73 (s), 144.61 (s), 138.30 (s), 136.53 (s), 130.65 (s), 128.20 (s),
123.06 (s), 121.63 (s), 117.48 (s), 114.06 (s).
4.1.2.7. (E)-3-(3-bromophenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1g). Yellow solid, m.p. 81e83 ꢂC, yield 78%; 1H NMR (500 MHz,
DMSO-d6)
d
8.77 (d, J ¼ 5.5 Hz, 1H), 8.24 (d, J ¼ 16.0 Hz, 1H),
8.08e7.98 (m, 3H), 7.80e7.75 (m, 2H), 7.68e7.64 (m, 1H), 7.61 (d,
J ¼ 9.0 Hz,1H), 7.38 (t, J ¼ 8.0 Hz,1H); 13C NMR (126 MHz, DMSO-d6)
d
189.18 (s), 153.78 (s), 149.73 (s), 142.73 (s), 138.30 (s), 137.64 (s),
4.1.2.1. (E)-3-Phenyl-1-(pyridin-2-yl)-prop-2-en-1-one
Yellow solid, m.p. 68e70 ꢂC, yield 72%; 1H NMR (500 MHz, DMSO-
d6)
8.78 (d, J ¼ 5.0 Hz, 1H), 8.24 (dd, J ¼ 16.5, 1.5 Hz, 1H), 8.08 (d,
(1a).
133.76 (s), 131.74 (s), 131.63 (s), 128.28 (s), 128.00 (s), 123.09 (s),
122.95 (s).
d
J ¼ 8.0 Hz, 1H), 8.03 (t, J ¼ 7.5 Hz, 1H), 7.83 (d, J ¼ 16.5 Hz, 1H), 7.79
4.1.2.8. (E)-3-(4-chlorophenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(t, J ¼ 2.5 Hz, 1H), 7.69 (t, J ¼ 6.0 Hz, 1H), 7.45 (t, J ¼ 2.5 Hz, 3H); 13
C
(1h). Yellow solid, m.p. 97e99 ꢂC, yield 89%; 1H NMR (500 MHz,
NMR (126 MHz, DMSO-d6)
d
189.18 (s), 153.94 (s), 149.66 (s), 144.49
DMSO-d6)
d
8.76 (d, J ¼ 4.5 Hz, 1H), 8.23 (d, J ¼ 16.5 Hz, 1H), 8.07 (d,
(s), 138.19 (s), 135.14 (s), 131.31 (s), 129.58 (s), 129.24 (s), 129.10 (s),
122.99 (s), 121.35 (s).
J ¼ 8.0 Hz, 1H), 8.02 (td, J ¼ 7.5, 2.0 Hz, 1H), 7.81 (d, J ¼ 8.0 Hz, 2H),
7.80 (d, J ¼ 16.5 Hz, 1H), 7.68e7.64 (m, 1H), 7.48 (d, J ¼ 8.0 Hz, 2H);
13C NMR (126 MHz, DMSO-d6)
d 189.14 (s), 153.79 (s), 149.72 (s),
4.1.2.2. (E)-3-(2-fluorophenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1b). Yellow solid, m.p. 76e78 ꢂC, yield 66%; 1H NMR (500 MHz,
143.07 (s), 138.32 (s), 135.83 (s), 134.06 (s), 130.98 (s), 129.65 (s),
128.26 (s), 123.06 (s), 122.01 (s).
DMSO-d6)
d
8.78 (d, J ¼ 4.0 Hz, 1H), 8.32 (d, J ¼ 16.5 Hz, 1H), 8.09 (d.
J ¼ 8.0 Hz, 1H), 8.03 (td, J ¼ 8.0, 1.5 Hz, 1H), 7.90 (td, J ¼ 8.0, 1.5 Hz,
1H), 7.87 (d, J ¼ 16.5 Hz, 1H), 7.69e7.66 (m, 1H), 7.52e7.48 (m, 1H),
7.31 (d, J ¼ 9.0 Hz, 1H), 7.28 (t, J ¼ 7.0 Hz, 1H); 13C NMR (126 MHz,
4.1.2.9. (E)-3-(4-methoxyphenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1i). Yellow solid, m.p. 81e83 ꢂC, yield 76%; 1H NMR (500 MHz,
DMSO-d6)
d
8.78 (d, J ¼ 4.0 Hz, 1H), 8.13 (d, J ¼ 16.0 Hz, 1H), 8.08 (d,
DMSO-d6)
d
189.14 (s), 161.65 (d, J ¼ 250.0 Hz), 153.65 (s), 149.74 (s),
J ¼ 7.5 Hz, 1H), 8.02 (td, J ¼ 7.5, 1.5 Hz, 1H), 7.81 (d, J ¼ 16.0 Hz, 1H),
7.76 (d, J ¼ 8.5 Hz, 2H), 7.66 (t, J ¼ 6.0 Hz, 1H), 7.00 (d, J ¼ 8.5 Hz,
138.29 (s), 136.38 (d, J ¼ 2.5 Hz), 133.26 (d, J ¼ 8.8 Hz), 130.45 (s),
128.30 (s), 125.68 (d, J ¼ 3.8 Hz), 123.78 (d, J ¼ 6.3 Hz), 123.12 (s),
122.82 (d, J ¼ 10.0 Hz), 116.75 (d, J ¼ 21.3 Hz); 19F NMR (471 MHz,
2H); 13C NMR (126 MHz, DMSO-d6)
d 189.01 (s), 162.07 (s), 154.19
(s), 149.63 (s), 144.58 (s), 138.19 (s), 131.23 (s), 127.96 (s), 127.77 (s),
122.91 (s), 118.77 (s), 115.11 (s), 55.90 (s).
DMSO-d6)
d
ꢀ114.85.
4.1.2.3. (E)-3-(2-trifluoromethylphenyl)-1-(pyridin-2-yl)-prop-2-en-
1-one (1c). Yellow solid, m.p. 67e68 ꢂC, yield 82%; 1H NMR
4.1.2.10. (E)-3-(4-bromophenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1j). Yellow solid, m.p. 101e102 ꢂC, yield 68%; 1H NMR (500 MHz,
(500 MHz, DMSO-d6)
d
8.77 (d, J ¼ 4.5 Hz, 1H), 8.26 (d, J ¼ 16.0 Hz,
DMSO-d6)
d
8.78 (dd, J ¼ 4.0, 1.0 Hz, 1H), 8.26 (d, J ¼ 16.0 Hz, 1H),
1H), 8.08 (d. J ¼ 7.5 Hz, 2H), 8.05e8.00 (m, 2H, AreH), 7.78 (d,
8.09 (d, J ¼ 8.0 Hz, 1H), 8.03 (td, J ¼ 7.5, 1.5 Hz, 1H), 7.80 (d,
J ¼ 8.0 Hz, 1H), 7.73 (t, J ¼ 7.5 Hz, 1H), 7.68e7.66 (m, 1H), 7.62 (t,
J ¼ 16.0 Hz, 1H), 7.76 (d, J ¼ 8.5 Hz, 2H), 7.70e7.66 (m, 1H), 7.64 (d,
J ¼ 7.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
d
188.87 (s), 153.45
J ¼ 8.0 Hz, 2H); 13C NMR (126 MHz, DMSO-d6)
d 189.17 (s), 153.79
(s), 149.72 (s), 138.35 (s), 138.29 (s), 133.61 (s), 133.34 (s), 131.08 (s),
128.86 (s), 128.38 (s), 128.12 (q, J ¼ 29.8 Hz), 126.72 (q, J ¼ 6.0 Hz),
125.55 (s), 124.63 (q, J ¼ 273.0 Hz), 123.19 (s); 19F NMR (471 MHz,
(s), 149.75 (s), 143.20 (s), 138.35 (s), 134.39 (s), 132.60 (s), 131.20 (s),
128.30 (s), 124.75 (s), 123.08 (s), 122.07 (s).
DMSO-d6)
d
ꢀ57.32.
4.1.2.11. (E)-3-(4-methylphenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
(1k). Yellow solid, m.p. 94e95 ꢂC, yield 71%; 1H NMR (500 MHz,
4.1.2.4. (E)-3-(2-bromophenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
DMSO-d6)
d
8.78 (dd, J ¼ 4.5, 1.5 Hz, 1H), 8.21 (d, J ¼ 16.0 Hz, 1H),
(1d). Yellow solid, m.p. 114e116 ꢂC, yield 63%; 1H NMR (500 MHz,
8.09 (d, J ¼ 7.5 Hz, 1H), 8.03 (td, J ¼ 7.0, 2.0 Hz, 1H), 7.81 (d,
J ¼ 16.0 Hz, 1H), 7.70e7.65 (m, 3H), 7.26 (d, J ¼ 8.0 Hz, 1H), 2.33 (s,
DMSO-d6)
d
8.77 (d, J ¼ 4.5 Hz, 1H), 8.23 (d, J ¼ 15.0 Hz, 1H),
8.10e7.96 (m, 4H), 7.72e7.66 (m, 2H), 7.45 (t, J ¼ 7.5 Hz, 1H), 7.45
3H); 13C NMR (126 MHz, DMSO-d6)
d 189.16 (s), 153.99 (s), 149.68
(td, J ¼ 7.5, 1.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
d
188.97 (s),
(s), 144.65 (s), 141.54 (s), 138.27 (s), 132.41 (s), 130.26 (s), 129.33 (s),
128.12 (s), 122.98 (s), 120.22 (s), 21.63 (s).
153.61 (s), 149.73 (s), 141.79 (s), 138.31 (s), 134.44 (s), 133.92 (s),
132.82 (s), 128.96 (s), 128.91 (s), 128.34 (s), 125.98 (s), 124.20 (s),
123.16 (s).
4.1.2.12. (E)-3-(furan-2-yl)-1-(pyridin-2-yl)-prop-2-en-1-one (1l).
Yellow solid, m.p. 48e50 ꢂC, yield 78%; 1H NMR (500 MHz, DMSO-
4.1.2.5. (E)-3-(2-methylphenyl)-1-(pyridin-2-yl)-prop-2-en-1-one
d6)
d
8.77 (s, 1H), 8.25e7.75 (m, 4H), 7.64 (d, J ¼ 18.5 Hz, 2H), 7.09 (s,
(1e). Yellow solid, m.p. 72e74 ꢂC, yield 76%; 1H NMR (500 MHz,
1H), 6.68 (s, 1H); 13C NMR (126 MHz, DMSO-d6)
d
188.73 (s), 153.81
DMSO-d6)
d
8.78 (d, J ¼ 5.0 Hz, 1H), 8.179 (d, J ¼ 16.0 Hz, 1H),
(s), 151.79 (s), 149.72 (s), 147.02 (s), 138.26 (s), 130.77 (s), 128.13 (s),
122.87 (s), 118.27 (s), 118.21 (s), 113.74 (s).
8.10e8.02 (m, 3H), 7.81 (d, J ¼ 7.5 Hz, 1H), 7.69e7.66 (m, 1H), 7.34 (t,
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

6
G. Zhang et al. / Tetrahedron xxx (2016) 1e8
4.1.2.13. (E)-3-(thiophen-2-yl)-1-(pyridin-2-yl)-prop-2-en-1-one
4.1.4.3. (S)-4-Nitro-3-(2-bromophenyl)-1-(pyridin-2-yl)-butan-1-
20
(1m). Yellow solid, m.p. 73e75 ꢂC, yield 67%; 1H NMR (500 MHz,
one (3d). White solid, m.p. 23e25 ꢂC, [
a
]
¼ þ30.8ꢂ (c 0.63,
D
DMSO-d6)
d
8.77 (d, J ¼ 4.5 Hz, 1H), 8.08e7.94 (m, 4H), 7.77 (d,
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.1 Hz, 1H),
J ¼ 5.0 Hz, 1H), 7.67e7.63 (m, 2H), 7.18 (t, J ¼ 4.5 Hz, 1H); 13C NMR
7.99e7.92 (m, 1H), 7.90 (d, J ¼ 7.8 Hz, 1H), 7.63 (ddd, J ¼ 7.4, 4.8,
1.4 Hz, 1H), 7.58 (dd, J ¼ 8.0, 1.3 Hz, 2H), 7.33 (td, J ¼ 7.6, 1.2 Hz, 1H),
7.19e7.10 (m, 1H), 5.00 (d, J ¼ 7.4 Hz, 2H), 4.62e4.57 (m, 1H), 3.72
(126 MHz, DMSO-d6)
d 188.55 (s), 153.76 (s), 149.69 (s), 140.59 (s),
138.23 (s), 137.30 (s), 134.26 (s), 131.03 (s), 129.42 (s), 128.13 (s),
122.89 (s), 119.64 (s).
(qd, J ¼ 18.4, 7.1 Hz, 2H); 13C NMR (126 MHz, DMSO-d6)
d 198.80 (s),
152.70 (s), 149.66 (s), 139.44 (s), 138.07 (s), 133.47 (s), 129.60 (s),
128.88 (s), 128.61 (s), 128.51 (s), 124.83 (s), 121.91 (s), 78.80 (s),
40.67 (s), 38.20 (s); IR (thin film, cmꢀ1): 3060 (s), 2916 (s), 1693 (s),
1583 (s), 1551 (s), 1472 (s), 1437 (s), 1377 (s), 1024 (s), 996 (s), 759
(s); HRMS (ES) m/z for C15H13BrN2O3 [MþH]þ cacld. 349.0182,
found. 349.0176; Elemental analysis for C15H13BrN2O3: calcd. C
51.60, H 3.75, N 8.02; found C 51.41, H 3.89, N 8.22; HPLC analysis:
4.1.3. Typical procedure for the preparation of racemic compounds
To the chalcone (0.2 mmol, 1) and the nitroalkane (2.0 mmol, 2)
in THF (2 mL) were added to NaH (0.4 mmol). Then the mixture was
stirred until completion. The products were isolated after filtration
and column chromatography.
4.1.4. General procedure for asymmetric synthesis of
containing pyridine
g
-nitroketones
IA, hexane: EtOH
¼
85%:15%, 1.0 mL/min, 20 ꢂC, 254 nm,
tR ¼ 17.644 min (major, S), 19.492 min (minor, R).
Chalcones containing pyridine (0.2 mmol, 1) and nitromethane
(2.0 mmol, 2) was added in capped vials containing the catalyst
(0.02 mmol, Q5). The resulting reaction mixture was stirred at room
temperature. After completion of the reaction as monitored by TLC,
the mixture was purified by column chromatography on silica gel
(EtOAc/hexane as eluant ¼ 2/1) affording the product (S)-3a~3m.
However, the products (R)-3a~3m were obtained using Q6 catalyst.
Enantiomeric excess of the product was determined by chiral sta-
tionary phase HPLC analysis using chiral IA column.
4.1.4.4. (S)-4-Nitro-3-(2-methylphenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3e). White solid, m.p. 76e77 ꢂC, [
a
]
¼ þ48.9ꢂ (c 0.35, CHCl3);
D
1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.7 Hz, 1H), 7.96 (td,
J ¼ 7.7, 1.7 Hz, 1H), 7.87 (d, J ¼ 7.8 Hz, 1H), 7.64 (ddd, J ¼ 7.5, 4.7,
1.2 Hz, 1H), 7.43 (d, J ¼ 7.7 Hz, 1H), 7.16e7.03 (m, 3H), 4.98 (dd,
J ¼ 13.1, 6.3 Hz,1H), 4.91 (dd, J ¼ 13.1, 9.2 Hz,1H), 4.40e4.31 (m,1H),
3.81 (dd, J ¼ 18.1, 8.1 Hz, 1H), 3.50 (dd, J ¼ 18.2, 6.1 Hz, 1H), 2.38 (s,
3H); 13C NMR (126 MHz, DMSO-d6)
d 199.32 (s), 152.82 (s), 149.69
(s), 139.00 (s), 138.15 (s), 136.72 (s), 130.85 (s), 128.52 (s), 127.33 (s),
126.80 (s), 126.58 (s), 121.90 (s), 79.88 (s), 41.51 (s), 34.43 (s), 19.67
(s); IR (thin film, cmꢀ1): 3055 (s), 3011 (s), 1699 (s), 1580 (s), 1550
(s), 1466 (s), 1437 (s), 1404 (s), 1376 (s), 1404 (s), 1376 (s), 1357 (s),
1276 (s), 1222 (s), 1043 (s), 995 (s), 775 (s); HRMS (ES) m/z for
4.1.4.1. (S)-4-Nitro-3-phenyl-1-(pyridin-2-yl)-butan-1-one
(3a).
20
White solid, m.p. 72e74 ꢂC, [
(500 MHz, DMSO-d6)
a]
¼ þ39.2ꢂ (c 0.51, CHCl3); 1H NMR
D
d
8.70 (ddd, J ¼ 4.7, 1.6, 0.9 Hz, 1H), 7.96 (td,
J ¼ 7.7, 1.7 Hz, 1H), 7.88 (dt, J ¼ 7.9, 1.1 Hz, 1H), 7.64 (ddd, J ¼ 7.5, 4.8,
1.3 Hz, 1H), 7.35 (dt, J ¼ 2.8, 1.8 Hz, 2H), 7.30e7.25 (m, 2H), 7.20
(ddd, J ¼ 7.3, 3.9, 1.3 Hz, 1H), 5.01 (dd, J ¼ 13.0, 5.8 Hz, 1H), 4.92 (dd,
J ¼ 13.0, 9.6 Hz, 1H), 4.10e4.02 (m, 1H), 3.80 (dd, J ¼ 18.3, 8.0 Hz,
1H), 3.55 (dd, J ¼ 18.3, 6.3 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
C
16H16N2O3 [MþH]þ cacld. 285.1234, found. 285.1228; Elemental
analysis for C16H16N2O3: calcd. C 67.59, H 5.67, N 9.85; found C
67.64, H 5.51, N 10.05; HPLC analysis: IA, hexane: EtOH ¼ 85%:15%,
1.0 mL/min, 20 ꢂC, 254 nm, tR ¼ 9.374 min (major, S), 11.577 min
(minor, R).
d
199.11 (s), 152.85 (s), 149.69 (s), 140.61 (s), 138.13 (s), 128.99 (s),
128.50 (s), 128.27 (s), 127.70 (s), 121.88 (s), 80.18 (s), 41.13 (s), 39.57
(s); IR (thin film, cmꢀ1): 3058 (s), 3030 (s), 2919 (s), 1699 (s), 1601
(s), 1582 (s), 1550 (s), 1495 (s), 1453 (s), 1436 (s), 1402 (s), 1387 (s),
1369 (s), 1349 (s), 1327 (s), 1299 (s), 1220 (s), 1200 (s), 996 (s), 977
(s), 776 (s), 763 (s); HRMS (ES) m/z for C15H14N2O3 [MþH]þ cacld.
271.1077, found. 271.1071; Elemental analysis for C15H14N2O3: calcd.
C 66.66, H 5.22, N 10.36; found C 66.50, H 4.95, N 10.41. HPLC
analysis: IA, hexane: EtOH ¼ 95%:5%, 1.0 mL/min, 20 ꢂC, 254 nm,
tR ¼ 23.263 min (major, S), 28.035 min (minor, R).
4.1.4.5. (S)-4-Nitro-3-(3-methoxyphenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3f). White solid, m.p. 113e115 ꢂC, [
a
]
¼ þ35.3ꢂ (c 0.51,
D
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.71 (d, J ¼ 3.9 Hz, 1H), 7.97
(td, J ¼ 7.7, 1.7 Hz, 1H), 7.89 (d, J ¼ 7.8 Hz, 1H), 7.65 (ddd, J ¼ 7.5, 4.8,
1.3 Hz, 1H), 7.18 (t, J ¼ 8.0 Hz, 1H), 6.93 (t, J ¼ 2.0 Hz, 1H), 6.90 (d,
J ¼ 7.7 Hz, 1H), 6.77 (ddd, J ¼ 8.3, 2.6, 0.8 Hz, 1H), 4.99 (dd, J ¼ 13.0,
5.9 Hz, 1H), 4.92 (dd, J ¼ 13.0, 9.4 Hz, 1H), 4.06e3.98 (m, 1H), 3.79
(dd, J ¼ 18.3, 7.9 Hz, 1H), 3.70 (s, 3H), 3.52 (dd, J ¼ 18.3, 6.4 Hz, 1H);
13C NMR (126 MHz, DMSO-d6)
d 199.13 (s), 159.75 (s), 152.87 (s),
4.1.4.2. (S)-4-Nitro-3-(2-fluorophenyl)-1-(pyridin-2-yl)-butan-1-one
149.71 (s), 142.19 (s), 138.16 (s), 130.03 (s), 128.52 (s), 121.91 (s),
120.47 (s), 114.14 (s), 112.86 (s), 80.05 (s), 55.48 (s), 41.06 (s), 39.55
(s); IR (thin film, cmꢀ1): 3040 (s), 3020 (s), 1693 (s), 1609 (s), 1581
(s), 1547 (s), 1489 (s), 1456 (s), 1437 (s), 1404 (s), 1363 (s), 1292 (s),
1275 (s), 1246 (s), 1219 (s), 1157 (s), 1048 (s), 995 (s), 868 (s), 791 (s),
777 (s); HRMS (ES) m/z for C16H16N2O4 [MþH]þ cacld. 301.1183,
found. 301.1175; Elemental analysis for C16H16N2O4: calcd. C 63.99,
H 5.37, N 9.33; found C 63.82, H 5.11, N 9.37; HPLC analysis: IA,
¼ þ26.3ꢂ (c 0.48, CHCl3); 1H
20
(3b). White solid, m.p. 76e77 ꢂC, [
a]
D
NMR (500 MHz, DMSO-d6)
d
8.71 (ddd, J ¼ 4.7, 1.7, 0.9 Hz, 1H), 7.97
(td, J ¼ 7.7, 1.7 Hz, 1H), 7.88 (dt, J ¼ 7.8, 1.1 Hz, 1H), 7.65 (ddd, J ¼ 7.5,
4.7, 1.2 Hz, 1H), 7.48 (td, J ¼ 7.6, 1.6 Hz, 1H), 7.31e7.21 (m, 1H),
7.18e7.05 (m, 2H), 5.01 (dd, J ¼ 13.1, 5.8 Hz, 1H), 4.92 (dd, J ¼ 13.1,
9.4 Hz, 1H), 4.41e4.29 (m, 1H), 3.78 (dd, J ¼ 18.3, 8.1 Hz, 1H), 3.63
(dd, J ¼ 18.3, 6.2 Hz,1H); 13C NMR (126 MHz, DMSO-d6)
d 198.85 (s),
161.78 (s), 159.83 (s), 152.75 (s), 149.70 (d, J ¼ 22.6 Hz), 138.12 (d,
J ¼ 3.5 Hz), 129.70 (d, J ¼ 23.9 Hz), 128.53 (d, J ¼ 66.5 Hz), 127.28 (d,
J ¼ 14.3 Hz), 125.12 (d, J ¼ 35.8 Hz), 121.89 (s), 116.01 (dd, J ¼ 36.9,
hexane: EtOH
tR ¼ 21.313 min (major, S), 24.080 min (minor, R).
¼
90%:10%, 1.0 mL/min, 20 ꢂC, 254 nm,
21.4 Hz), 79.17 (t, J ¼ 38.3 Hz), 40.44 (s), 32.85 (d, J ¼ 16.8 Hz); 19
F
4.1.4.6. (S)-4-Nitro-3-(3-bromophenyl)-1-(pyridin-2-yl)-butan-1-
20
NMR (487 MHz, DMSO-d6)
d
ꢀ117.36; IR (thin film, cmꢀ1): 3060 (s),
one (3g). White solid, m.p. 59e61 ꢂC, [
a]
¼ þ24.5ꢂ (c ¼ 0.49,
D
2991 (s), 2910 (s), 1691 (s), 1614 (s), 1580 (s), 1543 (s), 1490 (s), 1435
(s), 1384 (s), 1369 (s), 1330 (s), 1218 (s), 1106 (s), 1003 (s), 984 (s),
844 (s), 769 (s); HRMS (ES) m/z for C15H13FN2O3 [MþH]þ cacld.
289.0983, found. 289.0974; Elemental analysis for C15H13FN2O3:
calcd. C 62.50, H 4.55, N 9.72; found C 62.25, H 4.23, N 9.78; HPLC
analysis: IA, hexane: EtOH ¼ 95%:5%, 1.0 mL/min, 20 ꢂC, 254 nm,
tR ¼ 17.274 min (major, S), 18.969 min (minor, R).
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.0 Hz, 1H), 7.97
(td, J ¼ 7.7,1.7 Hz,1H), 7.89 (dt, J ¼ 7.9,1.1 Hz,1H), 7.69e7.61 (m, 2H),
7.42e7.35 (m, 2H), 7.24 (t, J ¼ 7.8 Hz, 1H), 5.03 (dd, J ¼ 13.2, 5.8 Hz,
1H), 4.96 (dd, J ¼ 13.2, 9.5 Hz, 1H), 4.07e4.01 (m, 1H), 3.80 (dd,
J ¼ 18.5, 8.1 Hz, 1H), 3.57 (dd, J ¼ 18.5, 6.1 Hz, 1H); 13C NMR
(126 MHz, DMSO-d6)
d 198.93 (s), 152.76 (s), 149.69 (s), 143.50 (s),
138.15 (s), 131.09 (s), 130.65 (s), 128.56 (s), 127.62 (s), 122.24 (s),
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

G. Zhang et al. / Tetrahedron xxx (2016) 1e8
7
121.89 (s), 79.74 (s), 40.98 (s), 39.22 (s); IR (thin film, cmꢀ1): 3061
(s), 3028 (s), 1697 (s), 1596 (s), 1580 (s), 1565 (s), 1546 (s), 1465 (s),
1435 (s), 1384 (s), 1363 (s), 1277 (s), 1221 (s), 1193 (s), 1066 (s), 995
(s), 792 (s), 773 (s); HRMS (ES) m/z for C15H13BrN2O3 [MþH]þ cacld.
349.0182, found. 349.0176; Elemental analysis for C15H13BrN2O3:
calcd. C 51.60, H 3.75, N 8.02; found C 51.68, H 3.57, N 8.21; HPLC
analysis: IA, hexane: EtOH ¼ 85%:15%, 1.0 mL/min, 20 ꢂC, 254 nm,
tR ¼ 23.449 min (major, S), 25.525 min (minor, R).
1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 3.9 Hz, 1H), 7.96 (td,
J ¼ 7.7, 1.8 Hz, 1H), 7.88 (dt, J ¼ 8.0, 1.0 Hz, 1H), 7.64 (ddd, J ¼ 7.5, 4.7,
1.3 Hz, 1H), 7.22 (d, J ¼ 8.0 Hz, 2H), 7.07 (d, J ¼ 7.8 Hz, 2H), 4.98 (dd,
J ¼ 12.9, 5.8 Hz, 1H), 4.88 (dd, J ¼ 12.9, 9.6 Hz, 1H), 4.05e3.98 (m,
1H), 3.77 (dd, J ¼ 18.2, 8.1 Hz,1H), 3.51 (dd, J ¼ 18.2, 6.2 Hz,1H), 2.21
(s, 3H); 13C NMR (126 MHz, DMSO-d6)
d 199.17 (s), 152.89 (s), 149.71
(s), 138.15 (s), 137.52 (s), 136.83 (s), 129.58 (s), 128.52 (s), 128.16 (s),
121.91 (s), 80.33 (s), 41.15 (s), 39.26 (s), 21.12 (s); IR (thin film,
cmꢀ1): 3058 (s), 1696 (s), 1582 (s), 1546 (s), 1520 (s), 1437 (s), 1376
(s), 1230 (s), 995 (s), 816 (s), 761 (s); HRMS (ES) m/z for C16H16N2O3
[MþH]þ cacld. 285.1234, found. 285.1227; Elemental analysis for
4.1.4.7. (S)-4-Nitro-3-(4-chlorophenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3h). White solid, m.p. 68e69 ꢂC, [
a]
¼ þ36.7ꢂ (c ¼ 0.45,
D
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.0 Hz, 1H), 7.96
C16H16N2O3: calcd. C 67.59, H 5.67, N 10.05; found C 67.54, H 5.54, N
(td, J ¼ 7.5, 1.5 Hz, 1H), 7.88 (dt, J ¼ 7.8, 1.1 Hz, 1H), 7.65 (ddd, J ¼ 7.5,
4.7, 1.3 Hz, 1H), 7.40 (d, J ¼ 8.6 Hz, 2H), 7.34 (d, J ¼ 8.6 Hz, 2H), 5.02
(dd, J ¼ 13.1, 5.7 Hz,1H), 4.93 (dd, J ¼ 13.1, 9.7 Hz,1H), 4.09e4.01 (m,
9.96; HPLC analysis: IA, n-Hexane: i-PrOH ¼ 90%:10%, 1.0 mL/min,
20 ꢂC, 254 nm, tR ¼ 27.825 min (major, S), 30.634 min (minor, R).
1H), 3.79 (dd, J ¼ 18.4, 8.2 Hz, 1H), 3.56 (dd, J ¼ 18.4, 6.1 Hz, 1H); 13
C
4.1.4.11. (S)-4-Nitro-3-(furan-2-yl)-1-(pyridin-2-yl)-butan-1-one
(3l). White solid, m.p. 60e62 ꢂC, [
¼ þ19.1ꢂ (c 0.37, CHCl3); 1H
20
NMR (126 MHz, DMSO-d6)
d
198.97 (s), 152.78 (s), 149.69 (s), 139.67
a
]
D
(s), 138.14 (s), 132.32 (s), 130.28 (s), 128.93 (s), 128.54 (s), 121.88 (s),
79.93 (s), 40.99 (s), 38.99 (s); IR (thin film, cmꢀ1): 3060 (s), 1699 (s),
1583 (s), 1546 (s), 1487 (s), 1438 (s), 1382 (s), 1367 (s), 1221 (s), 1091
(s), 1011 (s), 996 (s), 976 (s), 821 (s), 774 (s); HRMS (ES) m/z for
NMR (500 MHz, DMSO-d6)
d
8.73 (d, J ¼ 4.7 Hz, 1H), 8.00 (td, J ¼ 7.6,
1.7 Hz, 1H), 7.95 (d, J ¼ 7.8 Hz, 1H), 7.67 (ddd, J ¼ 7.4, 4.7, 1.3 Hz, 1H),
7.53 (d, J ¼ 1.8 Hz, 1H), 6.33 (dd, J ¼ 3.2, 1.9 Hz, 1H), 6.21 (d,
J ¼ 3.2 Hz, 1H), 4.95 (dd, J ¼ 13.1, 5.4 Hz, 1H), 4.86 (dd, J ¼ 13.1,
8.5 Hz, 1H), 4.23e4.16 (m, 1H), 3.80 (dd, J ¼ 18.3, 7.6 Hz, 1H), 3.55
C
15H13ClN2O3 [MþH]þ cacld. 305.0688, found. 305.0682; Elemental
analysis for C15H13ClN2O3: calcd. C 59.12, H 4.30, N 9.19; found C
58.93, H 4.11, N 9.32; HPLC analysis: IA, hexane: EtOH ¼ 85%:15%,
1.0 mL/min, 20 ꢂC, 254 nm, tR ¼ 21.187 min (major, S), 24.255 min
(minor, R).
(dd, J ¼ 18.3, 6.3 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
d 198.78 (s),
153.59 (s), 152.77 (s), 149.77 (s), 142.88 (s), 138.20(s), 128.61 (s),
122.00 (s), 111.02 (s), 107.00 (s), 78.36 (s), 38.77 (s), 33.22 (s); IR
(thin film, cmꢀ1): 3058 (s), 1702 (s), 1583 (s), 1553 (s), 1501 (s), 1437
(s), 1380 (s), 1290 (s), 1215 (s), 1186 (s), 1135 (s), 1071 (s), 1014 (s),
988 (s), 913 (s), 806 (s), 775 (s), 754 (s); HRMS (ES) m/z for
4.1.4.8. (S)-4-Nitro-3-(4-methoxyphenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3i). White solid, m.p. 68e69 ꢂC, [
a]
¼ þ35.5ꢂ (c 0.51, CHCl3);
C
13H12N2O4 [MþH]þ cacld. 261.0870, found. 261.0863; Elemental
D
1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.0 Hz, 1H), 7.96 (td,
analysis for C13H12N2O4: calcd. C 60.00, H 4.65, N 10.76; found C
J ¼ 7.7, 1.7 Hz, 1H), 7.88 (dt, J ¼ 7.9, 1.1 Hz, 1H), 7.64 (ddd, J ¼ 7.6, 4.8,
1.3 Hz, 1H), 7.26 (d, J ¼ 8.8 Hz, 2H), 6.82 (d, J ¼ 8.7 Hz, 2H), 4.97 (dd,
J ¼ 12.8, 5.8 Hz, 1H), 4.86 (dd, J ¼ 12.8, 9.7 Hz, 1H), 4.04e3.96 (m,
1H), 3.77 (dd, J ¼ 18.2, 8.1 Hz, 1H), 3.68 (s, 3H), 3.50 (dd, J ¼ 18.2,
60.20,
H
4.41,
N
10.91; HPLC analysis: IA, n-Hexane:
EtOH ¼ 85%:15%,1.0 mL/min, 20 ꢂC, 254 nm, tR ¼ 16.986 min (major,
S), 40.015 min (minor, R).
6.2 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
d
199.22 (s), 158.79 (s),
4.1.4.12. (S)-4-Nitro-3-(thiophene-2-yl)-1-(pyridin-2-yl)-butan-1-
20
152.89 (s), 149.71 (s), 138.15 (s), 132.32 (s), 129.35 (s), 128.50 (s),
121.89 (s), 114.34 (s), 80.45 (s), 55.46 (s), 41.22 (s), 38.92 (s); IR (thin
film, cmꢀ1): 3015 (s), 1691 (s), 1610 (s), 1580 (s), 1546 (s), 1516 (s),
1437 (s), 1396 (s), 1375 (s), 1249 (s), 1230 (s), 1181 (s), 1113 (s), 1024
(s), 995 (s), 827 (s), 780 (s), 762 (s); HRMS (ES) m/z for C16H16N2O4
[MþH]þ cacld. 301.1183, found. 301.1176; Elemental analysis for
one (3m). White solid, m.p. 61e63 ꢂC, [
a]
¼ þ30.7ꢂ (c 0.45,
D
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.72 (d, J ¼ 4.3 Hz, 1H), 7.99
(td, J ¼ 7.7, 1.7 Hz, 1H), 7.93 (d, J ¼ 7.8 Hz, 1H), 7.67 (ddd, J ¼ 7.4, 4.8,
1.3 Hz, 1H), 7.35 (dd, J ¼ 5.1, 1.1 Hz, 1H), 7.01 (d, J ¼ 3.4 Hz, 1H), 6.92
(dd, J ¼ 5.1, 3.5 Hz, 1H), 5.02 (dd, J ¼ 13.1, 5.4 Hz, 1H), 4.89 (dd,
J ¼ 13.1, 9.2 Hz, 1H), 4.40e4.34 (m, 1H), 3.86 (dd, J ¼ 18.3, 8.0 Hz,
1H), 3.59 (dd, J ¼ 18.3, 6.0 Hz, 1H); 13C NMR (126 MHz, DMSO-d6)
C
16H16N2O4: calcd. C 63.99, H 5.37, N 9.33; found C 64.14, H 5.23, N
9.54; HPLC analysis: IA, hexane: EtOH ¼ 85%:15%,1.0 mL/min, 20 ꢂC,
254 nm, tR ¼ 27.259 min (major, S), 37.695 min (minor, R).
d 198.75 (s), 152.78 (s), 149.77 (s), 143.25 (s), 138.21 (s), 128.63 (s),
127.50 (s), 125.83 (s), 125.32 (s), 122.00 (s), 80.71 (s), 41.89 (s), 34.73
(s); IR (thin film, cmꢀ1): 3056 (s), 1697 (s), 1582 (s), 1546 (s), 1438
(s), 1377 (s), 1226 (s), 1136 (s), 1003 (s), 994 (s), 853 (s), 841 (s), 763
(s); HRMS (ES) m/z for C13H12N2O3S [MþH]þ cacld. 277.0641, found.
277.0635; Elemental analysis for C13H12N2O3S: calcd. C 56.51, H
4.38, N 10.14; found C 56.54, H 4.18, N 10.36; HPLC analysis: IA, n-
4.1.4.9. (S)-4-Nitro-3-(4-bromophenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3j). White solid, m.p. 101e102 ꢂC, [
a
]
D
¼ þ32.3ꢂ (c 0.33,
CHCl3); 1H NMR (500 MHz, DMSO-d6)
d
8.70 (d, J ¼ 4.1 Hz, 1H), 7.97
(td, J ¼ 7.7, 1.7 Hz, 1H), 7.88 (d, J ¼ 7.8 Hz, 1H), 7.65 (ddd, J ¼ 7.5, 4.7,
1.2 Hz, 1H), 7.47 (d, J ¼ 8.4 Hz, 2H), 7.34 (d, J ¼ 8.5 Hz, 2H), 5.02 (dd,
J ¼ 13.1, 5.7 Hz,1H), 4.92 (dd, J ¼ 13.1, 9.6 Hz,1H), 4.10e3.98 (m, 1H),
3.79 (dd, J ¼ 18.4, 8.2 Hz,1H), 3.56 (dd, J ¼ 18.4, 6.0 Hz,1H); 13C NMR
Hexane: EtOH
tR ¼ 17.265 min (major, S), 26.148 min (minor, R).
¼
85%:15%, 1.0 mL/min, 20 ꢂC, 254 nm,
(126 MHz, DMSO-d6)
d
198.93 (s), 152.77 (s), 149.67 (s), 140.08 (s),
4.2. Biological assays
138.12 (s), 131.82 (s), 130.61 (s), 128.51 (s), 121.85 (s), 120.83 (s),
79.84 (s), 40.90 (s), 39.02 (s); IR (thin film, cmꢀ1): 3062 (s), 1698 (s),
1583 (s), 1546 (s), 1484 (s), 1437 (s), 1398 (s), 1383 (s), 1366 (s), 1302
(s),1286 (s),1221 (s),1008 (s), 997 (s), 976 (s), 821 (s), 774 (s); HRMS
The antibacterial activities against rice bacterial leaf blight of
chiral products from our reactions were evaluated via the turbid
meter test according to the reported method.29 The chiral com-
(ES) m/z for
C
15H13BrN2O3 [MþH]þ cacld. 349.0182, found.
pounds were dissolved in 150
containing Tween-20 (0.1%) to obtain final concentrations of 200
and 100 g/mL respectively. DMF in sterile distilled water served as
a blank control, whereas bismerthiazol served as a positive control.
Then, approximately 40 L NB containing rice bacterial leaf blight
mL of DMF and diluted with water
349.0176; Elemental analysis for C15H13BrN2O3: calcd. C 51.60, H
3.75, N 8.02; found C 51.52, H 3.58, N 8.20; HPLC analysis: IA,
m
hexane: EtOH
tR ¼ 24.386 min (major, S), 29.186 min (minor, R).
¼
85%:15%, 1.0 mL/min, 20 ꢂC, 254 nm,
m
was added to 4 mL NB (1.5 g of beef extract, 2.5 g of peptone, 0.5 g of
yeast powder, 5.0 g of glucose, and 500 mL of distilled water, pH 7.0
to 7.2) containing the test compounds or thiodiazole-copper (1 mL).
4.1.4.10. (S)-4-Nitro-3-(4-methylphenyl)-1-(pyridin-2-yl)-butan-1-
20
one (3k). White solid, m.p. 59e61 ꢂC, [
a]
¼ þ30.7ꢂ (c 0.45, CHCl3);
D
Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063

8
G. Zhang et al. / Tetrahedron xxx (2016) 1e8
(b) Molleti N, Rana NK, Singh VK. Org Lett. 2012;14:4322e4325.
10. (a) Zhao DP, Yuan Y, Chan ASC, Wang R. Chem Eur J. 2009;15:2738e2741;
(b) Zhao DP, Wang Y, Mao LJ, Wang R. Chem Eur J. 2009;15:10983e10987;
(c) Hatano M, Horibe T, Yamashita K, Ishihara K. Asian J Org Chem. 2013;2:
952e956;
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(e) Bera K, Namboothiri INN. Org Lett. 2012;14:980e983.
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(b) Bonollo S, Lanari D, Pizzo F, Vaccaro L. Org Lett. 2011;13:2150e2152;
(c) Rana NK, Singh VK. Org Lett. 2011;13:6520e6523.
The inoculated test tubes were incubated at 30
1
ꢂC with
continuous shaking at 180 rpm until OD600 of a blank control was
monitored to 0.6e0.8 with a spectrophotometer. Accordingly, the
relative inhibitory rate (%) of testing compounds was calculated as
follows: (ODcontrol e ODsample)/ODcontrol ꢁ 100; ODcontrol is the
corrected turbidity value of bacterial growth of a blank control),
and ODsample is the corrected turbidity value of bacterial growth of
testing compounds.
12. Tan B, Candeias NR, Barbas CF. Nat Chem. 2011;3:473e477.
13. Ono N. The Nitro Group in Organic Synthesis, Wiley Series in Organic Nitro
Chemistry. Germany: Wiley-VCH; 2001:30e69.
4.3. Computer calculation
14. (a) Halland N, Hazell RG, Jørgensen KA. J Org Chem. 2002;67:8331e8338;
~
€
(b) García-Mancheno O, Tangen P, Rohlmann R, Frohlich R, Aleman J. Chem Eur
J. 2011;17:984e992.
Structural optimizations and subsequent frequency calculations
for all systems were performed using the B3LYP30 hybrid functional
in combination with the all-electron 6-31G(d) basis set31 for all
atoms implemented in the Gaussian 09 package.32 Computational
data for optimized structures Cat, El, Nu, Cat-El and Cat-Nu at the
B3LYP/6-31G(d) level was shown in Table 1 in support information.
The binding energy of Cat-El is defined as ECat-Ei ¼ ECat-El-ECat-EEl;
15. (a) Sil D, Sharon A, Maulikb PR, Ram VJ. Tetrahedron Lett. 2004;45:6273e6276;
(b) Blay G, Hernandez-Olmos V, Pedro JR. Org Lett. 2010;12:3058e3061.
16. Ballini R, Barboni L, Bosica G, Fiorini D. Synthesis. 2002:2725e2728.
17. Zhus SL, Yu SY, Ma DW. Angew Chem Int Ed. 2008;47:545e554.
18. (a) Wang J, Li H, Zu L, Jiang W, Wang W. Adv Synth Catal. 2006;348:2047e2050;
(b) Kwiatkowski P, Dudzinski K, Lyzwa D. Org Lett. 2011;13:3624e3627;
ꢀ
(c) Vakulya B, Varga S, Csampai A, Soos T. Org Lett. 2005;7:1967e1969;
(d) Rabalakos C, Wulff WD. J Am Chem Soc. 2008;130:13524e13525;
(e) Manzano R, Andres JM, Alvarez R, Muruzabal MD, de Lera AR, Pedrosa R.
Chem Eur J. 2011;17:5931e5938;
(f) Gu XD, Dai YY, Guo TT, Franchino A, Dixon DJ, Ye JX. Org Lett. 2015;17:
1505e1508;
The binding energy of Cat¡Nu is defined as ECat-Nu ¼ ECat-Nu -ECat
ENu
-
.
Acknowledgments
(g) Varga S, Jakab G, Csampai A, Soos T. J Org Chem. 2015;80:8990e8996.
19. Choudary BM, Ranganath KVS, Pal U, Kantam ML, Sreedhar B. J Am Chem Soc.
2005;127:13167e13171.
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(b) Ooi T, Takada S, Doda K, Maruoka K. Angew Chem Int Ed. 2006;45:
7606e7608;
The authors gratefully acknowledge the National Natural Sci-
ence Foundation of China (Nos. 21132003, 21362004) and Collab-
orative Innovation Center for Natural Products and Biological Drugs
of Yunnan.
(c) Baschieri A, Bernardi L, Ricci A, Suresh S, Adamo MFA. Angew Chem Int Ed.
2009;48:9342e9345;
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Supplementary data
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Please cite this article in press as: Zhang G, et al., Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone
containing pyridine, Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.11.063