Asymmetric henry reaction of 2-acylpyridine N-oxides catalyzed by a Ni-aminophenol sulfonamide complex: An unexpected mononuclear catalyst

Article abstract of DOI:10.3390/molecules24081471

The asymmetric Henry reaction of 2-acylpyridine N-oxide remains a challenge as N-oxides generally act as competitive catalyst inhibitors or displace activating ligands. A novel variable yield (up to 99%) asymmetric Henry reaction of 2-acypyridine N-oxides

Full text of DOI:10.3390/molecules24081471

molecules
Article
Asymmetric Henry Reaction of 2-Acylpyridine
N-Oxides Catalyzed by a Ni-Aminophenol
Sulfonamide Complex: An Unexpected
Mononuclear Catalyst
Mouxiong Liu †, Dongdong Gui †, Ping Deng and Hui Zhou *
School of Pharmaceutical Science, Chongqing Medical University, Chongqing 400016, China;
mouxiongliu@163.com (M.L.); g420646114@163.com (D.G.); 100865@cqmu.edu.cn (P.D.)
* Correspondence: hzhou@cqmu.edu.cn
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Rafael Chinchilla
Received: 4 April 2019; Accepted: 12 April 2019; Published: 14 April 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The asymmetric Henry reaction of 2-acylpyridine N-oxide remains a challenge as N-oxides
generally act as competitive catalyst inhibitors or displace activating ligands. A novel variable yield
(up to 99%) asymmetric Henry reaction of 2-acypyridine N-oxides catalyzed by a Ni-aminophenol
sulfonamide complex with good to excellent enantioselectivity (up to 99%) has been developed.
Mechanistic studies suggest that the unique properties of the electron-pairs of N-oxides for
complexation with Ni makes the unexpected mononuclear complex, rather than the previously
reported dinuclear complex, the active species.
Keywords: asymmetric catalysis; Henry reaction; ketones; N-oxides; aminophenol sulfonamide
1. Introduction
The asymmetric construction of chiral quaternary stereocenters represents a considerable challenge
in modern organic synthesis [1–6]. The Henry (nitroaldol) reaction [7–13] of ketones has become one
of the most important and versatile reactions for the construction of quaternary carbons containing
hydroxyl and nitro groups. In recent years, considerable effort has been devoted to the development of
efficient chiral catalysts for asymmetric Henry reactions of reactive ketones, such as trifluoromethyl
ketones (for selected examples, see ref [14
–
18]),
α
-keto esters (for selected examples, see [19
–24]), α-keto
amides (for selected examples, see [25 26]),
,
α
-keto-phosphonates [27 28], and glyoxal hydrates [29].
,
Although Matsunaga and Shibasaki reported the kinetic resolution of racemic derivatives [30], the
asymmetric catalytic version of simple ketones has experienced little progress. At the same time,
interest in pyridine derivatives has increased dramatically with the discovery of many bioactive
compounds [31
the Henry reactions to 2-acylpyridine N-oxides, which provided a convenient way for synthesizing
-amino tert-alcohols substructure bearing a quaternary stereocenter bonded to a 2-pyridyl moiety [40].
–33] and ligands containing pyridine rings [34–39]. Pedro and Blay first extended
β
The asymmetric Henry reaction of 2-acylpyridine N-oxide remains a challenge as N-oxides generally
act as competitive catalyst inhibitors or displace activating ligands (For examples of related asymmetric
Henry reaction using N-oxides as ligands, see ref [22,41–43]). We recently reported an asymmetric
Henry reaction of 2-acylpyridine N-oxides catalyzed by a pre-prepared Ni-PyBisulidine complex, and
the corresponding results are not satisfactory [23]. Herein, we describe a Ni-aminophenol sulfonamide
complex for the asymmetric Henry reaction of 2-acylpyridine N-oxides.
Molecules 2019, 24, 1471; doi:10.3390/molecules24081471
www.mdpi.com/journal/molecules

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2. Results and Discussion
2.1. Catalytic Asymmetric Henry Reaction
In the preliminary study, the complexes prepared in situ from L1 (Figure 1) and different metal salts
in a 1/2 molar ratio (for examples in asymmetric bimetallic catalysis based on aminophenol sulfonamide
ligands, see [44–46]) were used to catalyze the asymmetric Henry reaction of 2-acylpyridine N-oxide
and nitromethane, and Ni(OAc)2 gave the best results (see the supplementary materials for details).
However, in the subsequent molar ratio investigation of metal/ligand, it was found that 1/1 gave better
enantioselectivity than 2/1 (Table 1, entry 1 vs. entry 3).
L1: Ar = 4-Me-C6H4
L2: Ar = 4-NO2-C6H4
L3: Ar = 4-MeO-C6H4
L4: Ar = 4-tBu-C6H4
L5: Ar = Ph
L6: Ar = 2,4,6-Me-C6H2
L7: Ar = 1-naphthyl
L8: Ar = 2-naphthyl
OH HN
HN
Ph
Ph
Ph
Ph
NH
OH HN
HN
Ph
Ph
OH HN
HN
Ph
Ph
Ph
Ph
NH
O
HN
Ph
Ph
NH
S
O
S
O
O
O
O
S
O
NHTs
TsHN
Ar
O
S
O
Ar
Ar
Ar
L9: Ar = 4-NO2-C6H4 L10: Ar = 4-NO2-C6H4
L11
Figure 1. Structures of ligands.
Table 1. Effect of the metal/ligand ratio and the ligand structure in the asymmetric Henry reaction a.
x mol% Ni(OAc)2
y mol% ligand
20 mol% i-Pr2NEt
O
N
O
O
N
OH
NO2
+
CH3NO2
THF, 0 ℃
1a
2a
Yield (%) b
Entry
Ni(OAc)2 (x)
Ligand (y)
x/y
ee (%) c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
15
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
L1 (10)
L1 (10)
L1 (10)
L1 (11)
L1 (12)
L1 (15)
L1 (20)
L2 (11)
L3 (11)
L4 (11)
L5 (11)
L6 (11)
L7 (11)
L8 (11)
L9 (11)
L10 (11)
L11 (11)
2/1
1.5/1
1/1
1/1.1
1/1.2
1/1.5
1/2
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
94
98
81
86
79
72
73
99
90
91
89
50
82
92
88
69
98
76
81
81
85
83
84
83
91
83
76
89
4 d
76
92
7
5 d
15
a
Reactions were carried out with 2-acylpyridine N-oxides (0.2 mmol) with i-Pr2NEt (20 mol%) in a mixture of THF
(0.8 mL) and CH3NO2 (0.2 mL) for 20 h. b Isolated yield. c Determined by chiral HPLC. d The absolute configuration
of the major product was inverse compared with the others by the analysis of HPLC.
The ratio was investigated intensively with the results summarized in Table 1 (entries 1–7). It was
found that increased metal ratio could increase the reactivity (Table 1, entries 1 and 2 vs. 3–7) and
excess ligands provided higher ee (Table 1, entries 4–7 vs. 1–3). The best ratio of metal/ligand was 1/1.1

Molecules 2019, 24, 1471
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with 86% yield and 85% ee. We speculate that the excess metal could increase the amount of Ni/N-oxide
complexes and Ni2/L1 complexes [45], both of which are higher active species with lower selectivity.
At the ratio of 1/1.1, a 1/1 coordination complex of Ni/L1 could be generated to the greatest extent.
After the screening of benzenesulfonyl moiety, L2 was found to be the most promising ligand (Table 1,
entries 8–14; Figure 1). The corresponding results of L9-L11 (Table 1, entries 15–17; Figure 1) showed
both of the phenolic hydroxyl group and sulphonamide group played a key role in achieving high ee.
Next, different bases were examined, with the results shown in Table 2. The tertiary and secondary
amines investigated showed excellent activity, except for N-methylmorpholine. The substituent size
at the nitrogen atoms plays a key role in the selectivity and N,N-dicyclohexyl-methylamine gave the
best results (Table 2, entry 2). On the other hand, the addition order of 2-acylpyridine N-oxide and
nitromethane had an effect on the enantioselectivity and the addition of 2-acylpyridine N-oxide first
was conducive to high ee (Table 2, entries 2 vs. 8).
Table 2. Further optimization of the reaction a.
Ni(OAc)2/L2
(1:1.1, 10 mol%)
O
N
O
O
N
OH
NO2
+
CH3NO2
20 mol% base
THF, 0 ℃
1a
2a
Yield (%) b
Entry
Base
ee (%) c
1
2
3
4
5
iPr2NEt
Cyhex2NMe d
Et3N
99
99
99
87
99
99
99
99
91
94
89
86
81
88
88
83
NMM e
iPr2NH
6
Bu2NH
Cyhex2NH f
7
8 g
Cyhex2NMe d
a Reactions were carried out with 2-acylpyridine N-oxides (0.2 mmol) with base (20 mol%) in a mixture of THF (0.8 mL)
b
c
and CH3NO2 (0.2 mL) for 15–20 h. Isolated yield. Determined by chiral HPLC. d N,N-Dicyclohexylmethylamine.
e
f
g
N-methylmorpholine. Dicyclohexylamine. Different reaction operation: the order of addition of nitromethane
and 2-acylpyridine N-oxide was reversed. In the standard operation, 2-acylpyridine N-oxide was added to the
complex prepared in situ for 10 min before the addition of nitromethane. For the detailed standard operation, see
the experimental section.
With the optimized reaction conditions in hand (for more detailed results of optimization studies,
such as solvents effect, substrate concentration and the amount of nitromethane, see the supplementary
materials), the substrate scope was explored. The results are summarized in Table 3. The presence
of 4- and 5-substituents (Me or Cl) on the pyridine ring did not affect the high activity and excellent
selectivity (Table 3, entries 2, 3 and 5). The substituent of 5-Br provided an unexpectedly low yield
with a good ee (Table 3, entry 6). The 6-position substituent on the pyridine ring greatly impairs the
ee (Table 3, entry 4). The reaction between 3-methyl substituted substrate and CH3NO2 did not take
place. This catalytic system is still effective for ethyl and propyl ketones (Table 3, entrys 7 and 8). The
aromatic ketone afforded product 2i in good ee, albeit with moderate yield (Table 3, entry 9).

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Table 3. Substrate scope for the asymmetric Henry reaction a.
Ni(OAc)2/L2
(1:1.1, 10 mol%)
R2
O
N
O
O
N
OH
NO2
R2
+
CH3NO2
20 mol% Cyhex2NMe
THF, 0 ℃
R1
R1
1
2
Yield (%) b
Entry
R1
R2
Product
Time (h)
ee (%) c
1
2
3
4
5
6
7
8
9
H
Me
Me
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
15
15
15
24
17
72
42
42
72
99
99
99
99
99
26
86
67
48
94
99
97
17
92
84
92
69
79
4-Me
5-Me
6-Me
4-Cl
5-Br
H
H
H
Bu
4-ClC6H4
a Reactions were carried out with 2-acylpyridine N-oxides (0.2 mmol) withN,N-dicyclohexyl-methylamine (20 mol%)
c
in a mixture of THF (0.8 mL) and CH3NO2 (0.2 mL). b Isolated yield. Determined by chiral HPLC.
2.2. Mechanistic Studies of Ni-Aminophenol Sulfonamide Complex
The control experiments (Table 1, entries 1–7) indicated that the mononuclear system is important
for high stereoselectivity and the addition of 2-acylpyridine N-oxide first was conducive to high ee
(Table 2, 2 and 8). To gain some insight into the mechanism, the ESI-MS studies of the mixture of
Ni(OAc)2/L2 (1:1.1) and 1a were carried out (Figure 2, for more details, see supplementary materials).
The spectrum displayed ions at m/z 1179, 1316, 1453, 1590, which corresponded to C1
This confirms the unique properties of the electron-pairs of N-oxides for complexation with Lewis
acids [47 49]. In addition, there was a linear relationship between the enantiomeric excess of the
-C4 (Figure 3).
–
Ni(OAc)2-L2 (1:1.1) catalyst and product 2a (Figure 4). These results suggested that the active species
in the present reaction would be a monomeric NiOAc-L2 catalyst. The proposed working model was
illustrated in Figure 5 to rationalize the asymmetric induction. The keto functionality is coordinated to
Ni in the more Lewis acidic equatorial position for maximal activation [50
generated by the base is positioned by the hydrogen bonding.
,
51], whereas the nitronate
X0318-C 55 (1.128) Cm (51:60-39:48)
1589.73
1: Scan ES+
9.12e5
1587.70
1590.75
535.40
1569.71
553.39
1313.56
927.57
1315.45
1591.70
1452.59
1316.58
1592.73
1593.76
928.55
929.57
1317.45
1318.52
554.46
571.39
1176.49
1179.46
1594.90
1595.86
930.59
931.63
1180.53
572.38
600
738.56
916.38
1620.81
1836.76
1800
0
m/z
800
1000
1200
1400
1600
2000
Figure 2. ESI-MS of Ni(OAc)2/L2/1a = 0.1/0.11/1.

Molecules 2019, 24, 1471
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Ph
S
Ph
Ph
S
NH
O
NH
NH
O
NH
Ph
Ph
Ph
Ph
AcO Ni
Ph
AcO Ni
NH
O
NH
O
O
NH
O
O
O
N
NH
S
O
S
O
N
O
O
O
O
O
O
N
O2N
NO2
O2N
C2
NO2
C1
Calcd. For C58H55N7NiO13S2
Calcd. For C65H62N8NiO15S2
[ML2 - H + NiOAc + M1a]+: 1179.26;
Found: 1179.46
[ML2 - H + NiOAc + 2M1a]+: 1316.31;
Found: 1316.58
Ph
Ph
Ph
Ph
N
O
Ph
Ph
S
Ph
NH
O
HN
NH
O
NH
N
N
Ph
O
O
O
O
O
O
O
NH
HN
Ni OAc
NH
Ni OAc
S
S
HN
O
O
O
O
O
O
S
O
N
O
O
N
O
O
O
O
O
O2N
NO2
O2N
N
N
NO2
C4
C3
Calcd. For C79H76N10NiO19S2
Calcd. For C72H69N9NiO17S2
[ML2 - H + NiOAc + 4M1a]+: 1590.41;
Found: 1590.75
[ML2 - H + NiOAc + 3M1a]+: 1453.36;
Found: 1453.58
Figure 3. The speculated structures of Ni/L2/1a according to the ESI-MS analysis.
Figure 4. Linear relationship between ee of L2 and ee of product 2a.
OAc
O
N
Ni
O
*
O
N
N
ArO2S
H
N
O-
-O
N+
Figure 5. The proposed working model.
3. Experimental Section
3.1. General Information
Commercial reagents were used as purchased. NMR spectra (600 MHz, Bruker, Karlsruhe,
Germany) were recorded in the deuterated solvents as stated, using residual non-deuterated solvent
signals as the internal standard. High resolution mass spectra were recorded with a Bruker Solari

Molecules 2019, 24, 1471
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XFT-ICR-MS system. The enantiomeric excess (ee) was determined by HPLC analysis (LC-16, Shimadzu,
Suzhou, China) using the corresponding commercial chiral column as stated in the experimental
procedures at 23 ◦C with UV detector. Optical rotations were measured on a commercial polarimeter
T
(Autopol I, Rudolph, Hackettstown, NJ, USA) and are reported as follows: [
solvent). The absolute configuration of 2a 2d 2f
α
]
(c = g/100 mL,
D
–
,
,
2g and 2i were assigned by comparison with the
sign of optical rotation value found in the literature. The absolute configuration of 2e and 2h was
determined by analogy.
3.2. General Procedure for Catalytic Asymmetric Reaction
The mixture of Ni(OAc)2 4H2O (0.02 mmol, 10 mol%) and L2 (0.022 mmol, 11 mol%) was stirred
·
in THF (0.5 mL) at 35 ◦C for 1 h. Then 2-acylpyridine N-oxide (0.2 mmol) and the base (0.04 mmol,
20 mol%) were added. The mixture was cooled to 0 ◦C. After stirring for 10 min at 0 ◦C, CH3NO2
(0.2 mL) and THF (0.3 mL) were added. The mixture was further stirred at 0 ◦C for the time indicated
in Table 3. The resulting solution was purified by column chromatography (EtOH/AcOEt or petroleum
ether/AcOEt) on silica gel to afford the products.
1-Methyl-2-nitro-1-(1-oxido-2-pyridinyl) ethanol (2a), brown oil, 99% yield, 94% ee; 1H-NMR (CDCl3)
δ
8.26 (d, 1H, J = 6.4), 7.45–7.42 (m, 2H), 7.37–7.35 (m, 1H), 5.35 (d, 1H, J = 11.1), 4.82 (d, 1H, J = 11.2), 1.79
(s, 3H). [α]2D0 = +57 (c 0.9, MeOH) [lit. [40] [α]2D0 = +48 (c 0.9, MeOH) in 86% ee]; HPLC (CHIRALPAK
AD-H column, Daicel, Osaka, Japan, hexane/2-propanol = 75/25, flow 1.0 mL/min, detection at 254 nm)
tr = 8.7 min (major) and tr = 20.7 min (minor).
1-Methyl-2-nitro-1-(4-methyl-1-oxido-2-pyridinyl) ethanol (2b), brown solid, 99% yield, 99% ee; 1H-NMR
(CDCl3)
δ 8.26 (s, 1H), 8.16 (d, 1H, J = 6.6), 7.20 (s, 1H), 7.17 (d, 1H, J = 6.7), 5.47 (d, 1H, J = 11.0), 4.73
(d, 1H, J = 10.9), 2.42 (s, 3H), 1.81 (s, 3H). [α]2D0 = +156 (c 0.4, MeOH) [lit. [40] [α]2D0 = +41 (c 0.9, MeOH)
in 84% ee]; HPLC (CHIRALPAK AD-H column, hexane/2-propanol = 80/20, flow 1.0 mL/min, detection
at 254 nm) tr = 8.2 min (major) and tr = 32.8 min (minor).
1-Methyl-2-nitro-1-(5-methyl-1-oxido-2-pyridinyl) ethanol (2c), brown solid, 99% yield, 97% ee; 1H-NMR
(CDCl3) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.30–7.29 (m, 1H), 7.26–7.25 (m, 1H), 5.43 (d, 1H, J = 10.9), 4.73 (d,
1H, J = 10.9), 2.37 (s, 3H), 1.80 (s, 3H). [α]D20 = +181 (c 0.4, MeOH) in 97% ee [ lit. [40] [α]2D0 = +60 (c 0.6,
MeOH) in 81% ee]; HPLC (CHIRALPAK AD-H column, hexane/2-propanol = 75/25, flow 1.0 mL/min,
detection at 254 nm) tr = 12.4 min (major) and tr = 18.3 min (minor).
1-Methyl-2-nitro-1-(6-methyl-1-oxido-2-pyridinyl) ethanol (2d), brown solid, 99% yield, 17% ee; 1H-NMR
(CDCl3) δ 8.30 (s, 1H), 7.37–7.29 (m, 3H), 5.47 (d, 1H, J = 10.9), 4.73 (d, 1H, J = 11.0), 2.58 (s, 3H), 1.80
(s, 3H). [α]2D0 = +21 (c 0.4, MeOH) in 17% ee [ lit. [40] [α]2D0 = +109 (c 0.9, MeOH) in 55% ee]; HPLC
(CHIRALPAK AD-H column, hexane/2-propanol = 80/20, flow 1.0 mL/min, detection at 254 nm) tr =
7.7 min (major) and tr = 11.1 min (minor).
1-Methyl-2-nitro-1-(4-chlorine -1-oxido-2-pyridinyl) ethanol (2e), brown solid, 99% yield, 92% ee; 1H-NMR
(CDCl3) δ 8.20 (d, 1H, J = 6.9), 7.45 (d, 1H, J = 2.9), 7.41 (s, 1H), 7.36 (dd, 1H, J1 = 6.9, J2 = 2.8), 5.40 (d,
1H, J = 11.5), 4.85 (d, 1H, J = 11.5), 1.80 (s, 3H). 13C-NMR (150 MHz, CDCl3)
δ 150.6, 141.1, 134.9, 126.0,
125.4, 80.0, 72.4, 23.0. HRMS (ESI): m/z Calcd [C8H10ClN2O4]+ [M + H]+: 233.0324 (Cl35), 235.0300
(Cl37), Found 233.0323, 235.0290. [α]2D0 = +52 (c 0.5, MeOH); HPLC (CHIRALPAK AD-H column,
hexane/2-propanol = 75/25, flow 1.0 mL/min, detection at 254 nm) tr = 6.0 min (major) and tr = 14.2 min
(minor).
1-Methyl-2-nitro-1-(5-bromo-1-oxido-2-pyridinyl) ethanol (2f), brown solid, 26% yield, 84% ee; 1H-NMR
(CDCl3)
δ 8.42 (d, 1H, J = 1.9), 7.57 (dd, 1H, J1 = 8.6, J2 = 1.8), 7.32 (d, 1H, J = 8.6), 5.39 (d, 1H, J = 11.4),
4.80 (d, 1H, J = 11.3), 1.79 (s, 3H). [α]2D0 = +48 (c 0.3, MeOH) [lit. [40] [α]2D0 = +74 (c 0.9, MeOH) in 89%
ee]; HPLC (CHIRALPAK AD-H column, hexane/2-propanol = 80/20, flow 1.0 mL/min, detection at 254
nm) tr = 9.5 min (major) and tr = 10.7 min (minor).

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1-Nitromethyl-1-(1-oxido-2-pyridinyl)propan-1-ol (2g), brown solid, 86% yield, 92% ee; 1H-NMR (CDCl3)
8.29 (d, 1H, J = 6.4), 7.46–7.44 (m, 2H), 7.38–7.36 (m, 1H), 5.31 (d, 1H, J = 11.4), 4.97 (d, 1H, J = 11.4),
2.28–2.22 (m, 1H), 2.12–2.05 (m, 1H), 1.09 (t, 3H, J = 7.4). [α]2D0 = +64 (c 0.4, MeOH) [lit. [40] [α]2D0
δ
=
+63 (c 1.2, MeOH) in 81% ee]; HPLC (CHIRALPAK AD-H column, hexane/2-propanol = 80/20, flow
1.0 mL/min, detection at 254 nm) tr = 12.6 min (major) and tr = 31.9 min (minor).
Nitromethyl-1-(1-oxido-2-pyridinyl) but-1-ol (2h), brown solid, 67% yield, 69% ee; 1H-NMR (CDCl3)
δ
8.28 (d, 1H, J = 6.5), 7.47–7.43 (m, 2H, J = 12.3), 7.37–7.35 (m, 1H), 5.28 (d, 1H, J = 11.5), 5.02 (d, 1H,
J = 11.4), 2.20–2.15 (m, 1H), 2.03–1.98 (m, 1H), 1.65–1.59 (m, 1H), 1.46–1.41 (m, 1H), 1.0 (t, 3H, J =
7.4).13C-NMR (150 MHz, CDCl3)
δ 148.2, 139.7, 126.9, 124.6, 124.5, 78.2, 73.8, 36.2, 15.1, 13.2. HRMS
(ESI): m/z calcd for C10H14N2NaO4+ [M + Na]+: 249.0846, found 249.0840. [α]2D0 = +67 (c 0.3, MeOH);
HPLC (CHIRALPAK IA column, hexane/2-propanol = 85/15, flow 0.8 mL/min, detection at 254 nm) tr
= 16.2 min (major) and tr = 19.2 min (minor).
1-(4-Chlorophenyl)-2-nitro-1-(1-oxido-2-pyridinyl)ethanol (2i), brown solid, 48% yield, 79% ee; 1H-NMR
(CDCl3)
δ 8.22 (d, 1H, J = 6.3), 7.55 (dd, 1H, J1 = 8.1, J2 = 1.8), 7.46 (t, 1H, J = 7.7), 7.43–7.41 (m, 2H),
7.39–7.36 (m, 3H), 5.44 (d, 1H, J = 12.7), 5.12 (d, 1H, J = 12.7). [α]2D0 = +50 (c 0.2, MeOH) [lit. [40] [α]2D0
=
+55 (c 0.7, MeOH) in 90% ee]; HPLC (CHIRALPAK AD-H column, hexane/2-propanol = 80/20, flow
1 mL/min, detection at 254 nm) tr = 13.4 min (major) and tr = 17.9 min (minor).
4. Conclusions
We have developed a new mononuclear Ni-aminophenol sulphonamide complex for the
asymmetric Henry reaction of 2-acylpyridine N-oxides. The simple experimental protocol affords
various optically active pyridine-containing β-nitro tert-alcohols in variable yield (up to 99%) with good
to excellent enantioselectivity (up to 99%). Mechanistic studies suggested that the unique properties of
the electron-pairs of N-oxides for complexation with Ni makes the unexpected mononuclear complex,
rather than the previously reported dinuclear complex, the active species.
Supplementary Materials: The following are available online: NMR spectra of L11
, 2a–2i; HPLC of 2a–2i; ESI-MS
analysis of Ni(OAc)2/L2 (1:1.1) and 1a; more detailed results of optimization studies.
Author Contributions: H.Z. outlined the research strategy and idea. M.L. and D.G. performed the experiments;
H.Z. and P.D. drafted and revised the manuscript. All authors read and approved the final manuscript.
Funding: This study was supported by the National Nature Science Foundation of China (21672031), Fundamental
and Advanced Research Projects of Chongqing City (cstc2017jcyjAX0352).
Acknowledgments: We are grateful for the generous financial support by the National Nature Science Foundation
of China (21672031), Fundamental and Advanced Research Projects of Chongqing City (cstc2017jcyjAX0352).
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: All data generated and/or compound samples analyzed during this study are included in
this article and are available from the corresponding author on reasonable request.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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