Chiral phosphine-phosphoramidite ligands for highly enantioselective hydrogenation of N-arylimines

Article abstract of DOI:10.1039/c4ra16062b

The asymmetric hydrogenation of N-arylimines with the chiral phosphine-phosphoramidite ligand, (S_c,S_a)-PEAPhos 2b, has been developed. The results revealed that the presence of the substituents on the 3,3′-positions of the binaphthyl backbone significantly improved the enantioselectivity. The utility of this methodology was demonstrated in the synthesis of the chiral fungicide (R)-metalaxyl. This journal is

Full text of DOI:10.1039/c4ra16062b

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PAPER
Chiral phosphine-phosphoramidite ligands for
highly enantioselective hydrogenation of N-
arylimines†
Cite this: RSC Adv., 2015, 5, 13702
ab
a
Qing Li,ab Chuan-Jin Hou,
Xiao-Ning Liu,ab De-Zhi Huang, Yan-Jun Liu,a
*
*
a
b
*
Rui-Feng Yang and Xiang-Ping Hu
Received 9th December 2014
Accepted 20th January 2015
The asymmetric hydrogenation of N-arylimines with the chiral phosphine-phosphoramidite ligand, (Sc,Sa)-
PEAPhos 2b, has been developed. The results revealed that the presence of the substituents on the 3,30-
positions of the binaphthyl backbone significantly improved the enantioselectivity. The utility of this
methodology was demonstrated in the synthesis of the chiral fungicide (R)-metalaxyl.
DOI: 10.1039/c4ra16062b
www.rsc.org/advances
harsh reaction conditions. Therefore, development of a new
catalyst system with high reactivity and enantioselectivity as
Introduction
well as broad substrate scope for asymmetric hydrogenation of
imines is still highly desirable.
Chiral amines are important synthetic intermediates in the
synthesis of many biologically active natural and unnatural
products. As a result, numerous methods are available for their
preparation. Among them, catalytic asymmetric hydrogenation
of imines has proven to be one of the most direct and conve-
nient routes to chiral amines and their derivatives, due to its
inherent efficiency and atom economy.1 Although great efforts
have been made during the past two decades, the development
of highly efficient catalytic asymmetric hydrogenation of imines
remains a challenging task, in contrast to the relative maturity
of catalytic asymmetric hydrogenation of olens and ketones,
probably due to the interconversion between E/Z isomers of
imines and the poisoning effect of the resulting amines on the
catalyst. In 1975, Scorrano and co-workers2 reported the rst
catalytic asymmetric hydrogenation of N-benzylimine with an
Rh-diphosphine catalyst. Since then, many highly enantiose-
lective chiral catalysts have been developed and a variety of
imine frameworks including cyclic and acyclic imines have been
efficiently hydrogenated in high enantioselectivities. Except for
the well-known iridium-Xyliphos catalyst3 applied to the
industrial production of chiral herbicide (S)-Metolachlor,
Buchwald's titanocene catalyst,4 Pfaltz's iridium-PHOX cata-
lyst,5 Zhang's iridium-f-Binaphane catalyst,6 Zhou's iridium-
SIPHOX catalyst7 also exhibited excellent results for asym-
metric hydrogenation of various imines. Despite these impres-
sive achievements,8 asymmetric hydrogenation of imines still
has challenges of low reactivity, narrow substrate scope and
Recently, we and other groups developed a series of
unsymmetrical hybrid chiral phosphine-phosphoramidite
ligands. These ligands have the advantages of easy accessi-
bility, modularity and stability toward air and moisture, which
can be exposed to air for several months without any changes in
their 1H or 31P NMR spectra and any loss in the catalytic activity
and enantioselectivity. Therefore, these ligands have been
found to display wide utility in asymmetric catalysis.9–15
However, there are few reports on the asymmetric hydrogena-
tion of imines with chiral phosphine-phosphoramidite ligands.
The only one example was reported by us recently,16 in which a
new H8-BINOL-derived phosphine-phosphoramidite ligand,
(Rc,Ra)-1, was found to be highly efficient in the enantioselective
hydrogenation of sterically hindered N-arylimines, a class of
challenging substrates. Further research disclosed that the
steric effect of substituents on the 3,30-postions of binaphthyl
backbone of the ligand showed a signicant inuence on the
enantioselectivity of the asymmetric hydrogenation of N-aryli-
mines. As a result, we report herein the asymmetric hydroge-
nation of N-arylimines with a 3,30-disubstituted binaphthyl
ligand, (Sc,Sa)-PEAPhos 2, in which high turnover numbers (up
to 50 000) and excellent enantioselectivity (up to 98% ee) were
obtained (Fig. 1).
Results and discussion
The chiral phosphine-phosphoramidite ligand (Sc,Sa)-PEAPhos
2a–c were synthesized from commercially available (S)-1-phenyl-
ethylamine as we have reported previously.10e,u With these
ligands in hand, we then examined their efficiency in the
iridium-catalyzed asymmetric hydrogenation of N-arylimines.
N-(1-Phenylethylidene)benzenamine 3a was selected as a model
aSchool of Light Industry and Chemical Engineering, Dalian Polytechnic University,
Dalian 116034, China. E-mail: houcj@dlpu.edu.cn; huangjj6688@163.com
bDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China. E-mail: xiangping@dicp.ac.cn
† Electronic supplementary information (ESI) available: Copies of NMR spectra
and HPLC for ee analysis. See DOI: 10.1039/c4ra16062b
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Table 2 Asymmetric hydrogenation of N-arylimines 3 to amines 4a
Entry
3 (R, Ar)
Yieldb (%)
eec (%)
Fig.
1 Chiral phosphine-phosphoramidite ligands, (Rc,Ra)-1 and
1
2
3
4
5
6
7
3a (R ¼ H, Ar ¼ C6H5)
99
99
98
98
98
95
95
95
95
92
98
99
93
92
94
93
97
93
95
62
72
78
83
85
(Sc,Sa)-PEAPhos 2.
3b (R ¼ H, Ar ¼ 4-CH3OC6H4)
3c (R ¼ H, Ar ¼ 4-ClC6H4)
3d (R ¼ H, Ar ¼ 4-NO2C6H4)
3e (R ¼ H, Ar ¼ 3-NO2C6H4)
3f (R ¼ H, Ar ¼ 3,4-ClC6H3)
3g (R ¼ 4-F, Ar ¼ C6H5)
substrate for the screening process and the result are summa-
rized in Table 1. The initial hydrogenation was carried out in the
presence of 1 mol% of catalyst prepared in situ from [Ir(COD)Cl]2
and 2.2 equiv. of chiral ligand with KI as an additive. To our
delight, (Sc,Sa)-PEAPhos 2a displayed a promising performance
in this reaction, affording N-(1-phenylethyl)benzenamine 4a in
full conversion with 80% ee (entry 1). Since the steric hindrance
of a chiral ligand normally affects the catalytic activity and
enantioselectivity, we then decided to investigate the ligands
2b–c with more sterically hindered substituents on the
3,30-postions of binaphthyl backbone. As expected, ligand 2b
with two methyl group on 3,30-postions provided an ee value of
93%, remarkably superior to that obtained with the parent
ligand 2a (entry 2). However, replacing methyl groups with more
sterically hindered phenyl groups on the 3,30-postions, the
enantioselectivity decreased signicantly (entry 3). The solvent
effect was next investigated with ligand 2b. It was found that all
of CH2Cl2, toluene and THF were suitable solvents for this
reaction, with CH2Cl2 being optimal in terms of conversion and
enantioselectivity (entries 4–7).
8d
9e
10f
11
12
3h (R ¼ H, Ar ¼ 2-CH3C6H4)
3i (R ¼ 2-CH3, Ar ¼ C6H5)
3j (R ¼ 2-CF3, Ar ¼ C6H5)
3k (R ¼ H, Ar ¼ 6-CH3O-2-naphthyl)
3l (R ¼ H, Ar ¼ thienyl)
a
Hydrogenation was carried out with 5.0 mol% of KI and 1.0 mol% of
Ir-catalyst in 2 mL CH2Cl2, 60 bar of H2, at rt for 24 h, unless otherwise
b
c
stated. Yields of isolated product. Enantiomeric excesses were
determined by chiral HPLC. d Using 2c as ligand. e Using 2a as ligand.
f
Using I2 as additive instead of KI.
(entries 1–7). The highest enantioselectivity (97% ee) was ach-
ieved in the hydrogenation of N-(1-(3-nitrophenyl)ethylidene)
benzene-amine 3e (entry 5). Notably, the hydrogenation
appeared to be sensitive to the steric property of the substitu-
ents on the aromatic ring. For substrates 3h–j having a
o-substituent on the phenyl ring, a dramatic decrease of enan-
tioselectivities (62–78% ee) was observed (entries 8–11).
Hydrogenation of 2-naphthyl substrate 3k also gave good ee-
value (entry 12). Meanwhile, a heteroaromatic derivative 3l
was also suitable for this hydrogenation (entry 13). These results
suggested that a variety of N-arylimines, which bear substituted
groups such as methoxy, nitro, uoro, chloro in the phenyl ring,
as well as naphthyl and heteroaromatic derivatives, all could be
hydrogenated to afford the corresponding chiral amines in
good to excellent enantioselectivities.
Under the optimal reaction conditions, a range of N-aryli-
mines were then investigated. As can be seen from Table 2, a
wide spectrum of N-arylimines with electron-donating and
-withdrawing substituents on the phenyl ring were hydroge-
nated with full conversions and excellent enantioselectivities
Table 1 Asymmetric hydrogenation of imine 3aa
Encouraged by these promising results, we then investigated
the hydrogenation of more challenging, sterically hindered
N-arylimines 5. The results are summarized in Table 3. The
additive was investigated because of its signicant inuence on
the asymmetric catalysis.17 It revealed that the use of I additives
could signicantly increase the enantioselectivity, which was in
Entry
Ligand
Solvent
Conv.b (%)
eec (%) accordance with the result reported before by us.16 I2 and KI
gave the similar results, while I2 was slightly superior to KI with
1
2
3
4
5
6
7
2a
2b
2c
2b
2b
2b
2b
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
>99
>99
>99
>99
>99
>99
>99
80
respect to enantioselectivity in the hydrogenation of sterically
hindered N-arylimines (entries 1 and 2). Under the optimized
93
29
90
90
86
62
condition, a variety of sterically hindered N-arylalkylarylimines
and N-aryldialkylimines could be hydrogenated in good to
excellent enantioselectivities. For N-arylarylalkylimines 5a–f,
the hydrogenation proceeded smoothly and afforded the cor-
responding sterically hindered chiral amines in excellent
enantioselectivities (94–98% ee) (entries 1–7). The electronic
AcOEt
MeOH
a
Hydrogenation was carried out with 5 mol% of KI and 1 mol% of Ir-
b
c
catalyst at rt for 24 h. Determined by GC. Determined by HPLC
using a chiral stationary phase.
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Table 3 Asymmetric hydrogenation of sterically hindered N-aryli-
mines 5a
gram scale and operated in air without loss of the enantiose-
lectivity and activity. The resulting product 6j can easily be
converted to herbicide (R)-metalaxyl 7,18 demonstrating the
potential utility of this method in the synthesis of chiral
pesticides.
Conclusions
Entry
Imine (R)
Yieldb (%)
eec (%)
In conclusion, we have demonstrated the asymmetric hydro-
genation
of
N-arylimines
with
chiral
phosphine-
1
5a: R ¼ C6H5
98
98
98
98
99
98
98
92
97
95
96
94
94
96
98
98
95
92
84
92
2d
3
5a: R ¼ C6H5
phosphoramidite ligand, (Sc,Sa)-PEAPhos 2b, in which high
turnover numbers (up to 50 000) and excellent enantiose-
lectivity (up to 98% ee) were achieved. The results revealed that
the presence of the substituents on the 3,30-positions of the
binaphthyl backbone signicantly improved the enantiose-
lectivity. The utility of this methodology was demonstrated by
the synthesis of chiral fungicide (R)-metalaxyl at a catalyst
loading of 0.002 mol%. Further applications of chiral
phosphine-phosphoramidite ligand in asymmetric catalysis are
in progress.
5b: R ¼ 4-CH3C6H4
5c: R ¼ 4-BrC6H4
5d: R ¼ 4-NO2C6H4
5e: R ¼ 3-NO2C6H4
5f: R ¼ 3-CH3OC6H4
5g: R ¼ 6-CH3O-2-naphthyl
5h: R ¼ i-Pr
4
5
6
7
8
9e
10
5i: R ¼ MeOCH2
a
Hydrogenation was carried out with 5.0 mol% of I2 and 1.0 mol% of Ir-
catalyst in 2 mL CH2Cl2, 60 bar of H2, at rt for 24 h, unless otherwise
b
c
stated. Yields of isolated product. Enantiomeric excesses were
d
determined by chiral HPLC or by chiral GC. Using KI as additive.
e
Hydrogenation was performed at 60 ꢀC under a H2 pressure of 70 bar.
Experimental section
General method
property of substituents on the phenyl ring showed no apparent
inuence on the enantioselectivity. For the hydrogenation of 2-
naphthyl substrate 5g, a slight decrease of enantioselectivity
(92% ee) was obtained (entry 8). It is noteworthy that the
hydrogenation of more challenging N-aryldialkylimines 5h and
5i were conducted smoothly with good enantioselectivities (84%
and 92% ee, respectively) (entries 9 and 10). These results
demonstrated the high efficiency of the present catalytic system
in the enantioselective hydrogenation of a broad scope of
sterically hindered N-arylimines.
All reactions were carried out under a nitrogen atmosphere.
Solvents were puried by standard procedure before use.
Commercial reagents were used without further purication. 1H
NMR spectra were recorded on a Bruker 400 MHz spectrometer.
Chemical shis for protons are reported in parts per million
(ppm) downeld from tetramethylsilane (TMS) and are refer-
enced to residual protium in the NMR solvent (CHCl3 ¼ d 7.26).
Enantiomeric ratios were determined by chiral HPLC with
n-hexane and i-PrOH as solvents.
To explore the synthetic utility of the current method, we
attempted this methodology as the key step in the enantiose-
lective synthesis of the chiral fungicide (R)-metalaxyl as shown
in Scheme 1. With the present catalytic system, hydrogenation
of imine 5j afforded the corresponding chiral amine 6j in 95%
ee with full conversion, even when the catalyst loading was
lowered to 0.002 mol% (S/C ¼ 50 000/1). It should be noted that
the asymmetric hydrogenation of 5j can be carried out on a
General procedure for the synthesis of phosphine-
phosphoramidite ligands 2a–2c
Chiral phosphine-phosphoramidite ligands were synthesized
according to literature.10e,u To a stirred solution of (Sa)-chlor-
ophosphite (1.0 mmol) in dried toluene (4.0 mL) at 0 ꢀC was
added a solution of (Sc)-DPPNHMe (1.0 mmol) and Et3N
(3.0 mmol) in dried toluene (4.0 mL) within 30 min. The
resulting mixture was stirred overnight at room temperature.
The precipitate was ltered, and the solid was washed with
toluene. The ltrate was collected, and concentrated under
reduced pressure to give the crude product which was further
puried by column chromatography.
1
(Sc,Sa)-PEAPhos 2a. H NMR (400 MHz, CDCl3) d 1.59–1.65
(m, 3H), 1.99 (d, J ¼ 3.1 Hz, 3H), 5.37–5.46 (m, 1H), 6.97–7.02
(m, 1H), 7.05 (d, J ¼ 8.8 Hz, 1H), 7.18–7.16 (m, 4H), 7.27–7.45
(m, 14H), 7.52 (d, J ¼ 8.7 Hz, 1H), 7.57–7.60 (m, 1H), 7.78 (d, J ¼
8.8 Hz, 1H), 7.85 (d, J ¼ 8.0 Hz, 1H), 7.90 (d, J ¼ 8.2 Hz, 1H), 7.96
(d, J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.6, 30.1, 56.7,
122.1, 124.5, 125.9, 127.0, 127.5, 128.2, 128.3, 128.4, 128.5,
128.6, 128.7, 129.2, 130.1, 130.6, 131.4, 132.7, 133.7, 133.9,
134.1, 134.5, 136.1, 136.7, 137.2, 147.4, 149.7, 150.7; 31P NMR
Scheme 1 Synthesis of chiral fungicide (R)-metalaxyl on gram scale.
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(162 MHz, CDCl3) d ꢁ18.5, 148.4; HRMS calcd for C41H33NO2P2:
N-(1-(4-Nitrophenyl)ethyl)benzenamine 4d. 98% yield. 93%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
633.1987, found: 633.1992.
1
PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 C): tr ¼ 25.7, 27.9
ꢀ
(Sc,Sa)-PEAPhos 2b. H NMR (400 MHz, CDCl3) d 1.56–1.64
min. 1H NMR (400 MHz, CDCl3): d 1.55 (d, J ¼ 8.0 Hz, 3H), 4.30
(br, 1H), 4.57 (q, J ¼ 8.0 Hz, 1H), 6.46 (d, J ¼ 8.0 Hz, 2H), 6.70 (t, J
¼ 8.0 Hz, 1H), 7.10 (t, J ¼ 8.0 Hz, 2H), 7.54 (d, J ¼ 8.0 Hz, 2H),
8.17 (d, J ¼ 8.0 Hz, 2H).
(m, 3H), 2.06 (d, J ¼ 2.2 Hz, 3H), 2.61 (s, 3H), 2.45 (s, 3H), 5.24–
5.35 (m, 1H), 6.91–6.97 (m, 1H), 7.10–7.20 (m, 4H), 7.23–7.39
(m, 14H), 7.63–7.66 (m, 1H), 7.68 (s, 1H), 7.75–7.82 (m, 3H); 13
C
NMR (100 MHz, CDCl3) d 17.9, 21.8, 29.4, 56.5, 122.0, 124.3,
124.9, 126.9, 127.1, 127.2, 127.5, 128.5, 128.6, 128.7, 128.9,
129.0, 129.3, 129.6, 130.4, 130.9, 131.2, 131.6, 133.8, 134.0,
136.2, 136.7, 137.2, 146.6, 146.9, 148.9, 150.1; 31P NMR (162
MHz, CDCl3) d ꢁ17.4, 144.7; HRMS calcd for C43H37NO2P2:
661.2300, found: 661.2310.
N-(1-(3-Nitrophenyl)ethyl)benzenamine 4e. 98% yield. 97%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
PrOH ¼ 85/15, 1.0 mL minꢁ1, 254 nm, 40 C): tr ¼ 18.4, 19.5
ꢀ
min. 1H NMR (400 MHz, CDCl3): d 1.56 (d, J ¼ 8.0 Hz, 3H), 4.26
(br, 1H), 4.58 (q, J ¼ 8.0 Hz, 1H), 6.49 (d, J ¼ 8.0 Hz, 2H), 6.69
(t, J ¼ 8.0 Hz, 1H), 7.11 (t, J ¼ 8.0 Hz, 2H), 7.49 (t, J ¼ 8.0 Hz, 1H),
7.73 (d, J ¼ 8.0 Hz, 1H), 8.09 (d, J ¼ 8.0 Hz, 1H), 8.25 (s, 1H).
N-(1-(3,4-Dichlorophenyl)ethyl)benzenamine 4f. 95% yield.
93% ee was determined by chiral HPLC (chiralcel OD-H, n-
hexane/i-PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 12.2,
1
(Sc,Sa)-PEAPhos 2c. H NMR (400 MHz, CDCl3) d 0.82–0.90
(m, 3H), 1.80 (s, 3H), 4.74–4.82 (m, 1H), 6.72–6.81 (m, 2H), 6.96–
7.03 (m, 2H), 7.04–7.09 (m, 2H), 7.11–7.17 (m, 2H), 7.19–7.35
(m, 12H), 7.35–7.44 (m, 6H), 7.69–7.77 (m, 4H), 7.86–7.95 (m,
3H), 7.99 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.7, 30.6, 57.1,
123.6, 124.9, 125.9, 126.8, 127.0, 127.1, 127.3, 127.5, 128.1,
128.2, 128.3, 128.4, 128.5, 128.6, 129.7, 130.0, 130.1, 130.4,
130.7, 131.1, 132.5, 133.6, 133.8, 134.0, 134.8, 135.3, 136.7,
137.3, 138.5, 147.3, 147.5, 147.8, 148.1; 31P NMR (162 MHz,
CDCl3) d ꢁ17.5, 148.2; HRMS calcd for C53H41NO2P2: 785.2613,
found: 785.2619.
1
14.3 min. H NMR (400 MHz, CDCl3): d 1.50 (s, 3H), 4.40–4.42
(m, 1H), 6.48 (d, J ¼ 8.0 Hz, 2H), 6.69 (s, 1H), 7.11–7.25 (m, 3H),
7.37 (d, J ¼ 8.0 Hz, 1H), 7.46 (s, 1H).
4-Fluoro-N-(1-phenylethyl)benzenamine 4g. 95% yield. 95%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
PrOH ¼ 99/1, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 12.3, 15.5 min.
1H NMR (400 MHz, CDCl3): d 1.49 (d, J ¼ 8.0 Hz, 3H), 3.97 (br,
1H), 4.40 (q, J ¼ 8.0 Hz, 1H), 6.40–6.43 (m, 2H), 6.78 (t, J ¼ 8.0
Hz, 2H), 7.19–7.24 (m, 1H), 7.28–7.35 (m, 4H).
General procedure for asymmetric hydrogenation
In a nitrogen-lled glovebox, a stainless steel autoclave was
charged with [Ir(COD)Cl]2 (0.0025 mmol), (Sc,Sa)-2b (0.0055
mmol) and KI or I2 (0.025 mmol) in 1.0 mL of a degassed
CH2Cl2. Aer stirring for 10 min at room temperature, a solu-
tion of the imine substrates 3 or 5 (0.5 mmol) in 1.0 mL of
CH2Cl2 was added to the reaction mixture, and then the
hydrogenation was performed at room temperature under an
H2 pressure of 60 bar for 24 hours. The solvent was then evap-
orated and the residue was puried by ash column chroma-
tography to give the corresponding hydrogenation product 4 or
6, which was analysed by chiral GC or chiral HPLC to determine
the enantiomeric excesses.
N-(1-Phenylethyl)benzenamine 4a. 99% yield. 93% ee was
determined by chiral HPLC (chiralcel OJ-H, n-hexane/i-PrOH ¼
97/3, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 20.9, 25.5 min. 1H NMR
(400 MHz CDCl3): d 1.49 (d, J ¼ 8.0 Hz, 3H), 4.02 (br, 1H), 4.46 (q,
J ¼ 8.0 Hz, 1H), 6.48–6.50 (m, 2H), 6.61–6.65 (m, 1H), 7.05–7.09
(m, 2H), 7.20–7.36 (m, 5H).
N-(1-(o-Tolyl)ethyl)benzenamine 4h. 95% yield. 62% ee was
determined by chiral HPLC (chiralcel OD-H, n-hexane/i-PrOH ¼
98/2, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 12.2, 13.5 min. 1H NMR
(400 MHz, CDCl3): d 1.49 (d, J ¼ 6.0 Hz, 3H), 2.42 (s, 3H), 4.67 (q,
J ¼ 6.0 Hz, 1H), 6.47 (d, J ¼ 7.2 Hz, 2H), 6.65 (d, J ¼ 7.7 Hz, 1H),
7.08 (t, J ¼ 7.7 Hz, 2H), 7.15 (s, 3H), 7.43 (s, 1H).
2-Methyl-N-(1-phenylethyl)benzenamine 4i. 95% yield. 72%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 5.1, 7.7 min.
1H NMR (400 MHz, CDCl3): d 1.55 (d, J ¼ 8.0 Hz, 3H), 2.22 (s,
3H), 3.85 (br, 1H), 4.53 (q, J ¼ 20.0 Hz, 1H), 6.36 (d, J ¼ 4.0 Hz,
1H), 6.59 (t, J ¼ 12.0 Hz, 1H), 6.95 (t, J ¼ 16.0 Hz, 1H), 7.04 (d, J ¼
8.0 Hz, 1H), 7.21 (t, J ¼ 16.0 Hz, 1H), 7.29–7.36 (m, 4H).
N-(1-Phenylethyl)-2-(triuoromethyl)aniline 4j. 92% yield.
78% ee was determined by chiral HPLC (chiralcel OD-H, n-
hexane/i-PrOH ¼ 99/1, 1.0 mL minꢁ1, 254 nm, 40 C): tr ¼ 4.5,
ꢀ
1
5.3 min. H NMR (400 MHz, CDCl3): d 1.57 (d, J ¼ 6.7 Hz, 3H),
4.57–4.59 (m, 1H), 4.73 (s, 1H), 6.49 (d, J ¼ 8.4 Hz, 1H), 6.66 (t, J
¼ 7.5 Hz, 1H), 7.18 (t, J ¼ 7.8 Hz, 1H), 7.25 (t, J ¼ 6.3 Hz, 1H),
7.11–7.41 (m, 4H), 7.44 (d, J ¼ 7.8 Hz, 1H).
N-(1-(4-Methoxyphenyl)ethyl)benzenamine 4b. 99% yield.
92% ee was determined by chiral HPLC (chiralcel OD-H, n-
hexane/i-PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 7.4,
N-(1-(6-Methoxynaphthalen-2-yl)ethyl)benzenamine 4k. 98%
yield. 83% ee was determined by chiral HPLC (chiralpak AD-H,
1
8.1 min. H NMR (400 MHz, CDCl3): d 1.54 (d, J ¼ 8.0 Hz, 3H),
n-hexane/i-PrOH ¼ 85/15, 0.5 mL minꢁ1, 254 nm, 40 C): tr ¼
ꢀ
3.82 (s, 3H), 4.09 (br, 1H), 4.50 (q, J ¼ 8.0 Hz, 1H), 6.56 (d, J ¼ 8.0
Hz, 2H), 6.70 (t, J ¼ 8.0 Hz, 1H), 6.90 (d, J ¼ 8.0 Hz, 2H), 7.15
(t, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H).
18.8, 19.7 min. 1H NMR (400 MHz, CDCl3): d 1.59 (d, J ¼ 8.0 Hz,
3H), 3.91 (s, 3H), 4.60–4.62 (m, 1H), 6.57–6.65 (m, 3H), 7.06–7.14
(m, 4H), 7.47 (d, J ¼ 8.0 Hz, 1H), 7.68–7.74 (m, 3H).
N-(1-(4-Cholrophenyl)ethyl)benzenamine 4c. 98% yield. 94%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 8.4, 9.8 min.
1H NMR (400 MHz, CDCl3): d 1.53 (d, J ¼ 8.0 Hz, 3H), 4.10 (br,
1H), 4.49 (q, J ¼ 8.0 Hz, 1H), 6.53 (d, J ¼ 8.0 Hz, 2H), 6.72 (t, J ¼
8.0 Hz, 1H), 7.15 (t, J ¼ 8.0 Hz, 2H), 7.33 (s, 4H).
N-(1-(Thiophen-2-yl)ethyl)benzenamine 4l. 99% yield. 85%
ee was determined by chiral HPLC (chiralcel OD-H, n-hexane/i-
PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 7.8, 8.3 min.
1H NMR (400 MHz, CDCl3): d 1.61–1.68 (m, 3H), 4.04 (br, 1H),
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4.81–4.89 (m, 1H), 6.64–6.74 (m, 3H), 6.98 (d, J ¼ 16.0 Hz, 2H), (m, 1H), 2.29 (s, 6H), 2.97 (br, 1H), 3.18–3.24 (m, 1H), 6.79 (t, J ¼
7.18 (s, 3H).
N-(1-Phenylethyl)-2,6-dimethylbenzenamine 6a. 98% yield.
7.6 Hz, 1H), 6.99 (d, J ¼ 7.6 Hz, 2H).
N-(1-Methoxypropan-2-yl)-2,6-dimethylbenzenamine 6i. 95%
96% ee was determined by chiral HPLC (chiralcel OJ-H, n- yield. 92% ee was determined by chiral GC (chiral b-DEX 120
hexane/i-PrOH ¼ 90/10, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼ 4.9, column, column temp.: 85 C, carrier gas: N2): tr ¼ 72.0, 73.7
ꢀ
1
5.4 min. H NMR (400 MHz, CDCl3): d 1.54 (d, J ¼ 8.0 Hz, 3H), min. 1H NMR (400 MHz, CDCl3): d 1.20 (d, J ¼ 6.0 Hz, 3H), 2.30
2.19 (s, 6H), 3.22 (br, 1H), 4.34 (q, J ¼ 6.8 Hz, 1H), 6.81 (t, J ¼ 8.0 (s, 6H), 3.35–3.80 (m, 7H), 6.82 (t, J ¼ 7.2 Hz, 1H), 6.99 (d, J ¼ 7.2
Hz, 1H), 6.97 (d, J ¼ 8.0 Hz, 2H), 7.25–7.27 (m, 1H), 7.31–7.32 Hz, 2H).
(m, 4H).
Methyl-2-(2,6-dimethylphenylamino)propanoate 6j. 96%
N-[1-(4-Methylphenyl)ethyl]-2,6-dimethylbenzenamine 6b. yield. 95% ee was determined by chiral HPLC (chiralcel OD-H,
98% yield. 94% ee was determined by chiral HPLC (chiralpak n-hexane/i-PrOH ¼ 99/1, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr ¼
1
AD-H, n-hexane/i-PrOH ¼ 99/1, 0.5 mL minꢁ1, 254 nm, 40 ꢀC): tr 7.6, 8.3 min. H NMR (400 MHz, CDCl3): d 1.38 (d, J ¼ 7.2 Hz,
1
¼ 14.5, 16.6 min. H NMR (400 MHz, CDCl3): d 1.48 (d, J ¼ 6.8 3H), 2.31 (s, 6H), 3.68 (s, 3H), 4.00 (q, J ¼ 7.2 Hz, 1H), 6.81 (t, J ¼
Hz, 3H), 2.18 (s, 6H), 2.32 (s, 3H), 3.19 (br, 1H), 4.30 (q, J ¼ 6.8 7.6 Hz, 1H), 6.97 (d, J ¼ 7.6 Hz, 2H).
Hz, 1H), 6.78 (t, J ¼ 7.6 Hz, 1H), 6.94 (d, J ¼ 7.6 Hz, 2H), 7.10 (d, J
¼ 8.0 Hz, 2H), 7.19 (d, J ¼ 8.0 Hz, 2H).
Synthesis of (R)-metalaxyl 7. To a stirred solution of 6j (20
mmol) in toluene was added NaHCO3 (24 mmol, 1.2 eq.) at 0 ꢀC.
6c. Methoxyacetyl chloride (24 mmol, 1.2 eq.) was then slowly
N-[1-(4-Bromophenyl)ethyl]-2,6-dimethylbenzenamine
98% yield. 96% ee was determined by chiral HPLC (chiralpak added and the mixture was stirred at room temperature for 1 h.
AD-H, n-hexane/i-PrOH ¼ 99.5/0.5, 0.3 mL minꢁ1, 254 nm, 40 The resulted mixture was washed with 5% Na2CO3 and water.
ꢀC): tr ¼ 9.0, 10.5 min. 1H NMR (400 MHz, CDCl3): d 1.51 (d, J ¼ The layer was separated and the organic phase was dried over
6.8 Hz, 3H), 2.18 (s, 6H), 3.17 (br, 1H), 4.29 (q, J ¼ 6.8 Hz, 1H), Na2SO4. It was ltered and concentrated under reduced pres-
6.81 (t, J ¼ 7.6 Hz, 1H), 6.97 (d, J ¼ 7.6 Hz, 2H), 7.18 (d, J ¼ 8.0 sure to give the crude product which was further puried by
Hz, 2H), 7.43 (d, J ¼ 8.0 Hz, 2H).
column chromatography.
N-[1-(4-Nitrophenyl)ethyl]-2,6-dimethylbenzenamine
6d.
(R)-Methyl-2-(N-(2,6-dimethylphenyl)-2-methoxyacetamido)
1
99% yield. 98% ee was determined by chiral HPLC (chiralpak propanoate 7. H NMR (400 MHz, DMSO-d6): d 0.89 (d, J ¼ 7.4
AD-H, n-hexane/i-PrOH ¼ 99/1, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr Hz, 3H), 2.13 (s, 3H), 2.38 (s, 3H), 3.17 (s, 3H), 3.35–3.53 (m, 2H),
¼ 5.6, 7.8 min. 1H NMR (400 MHz, CDCl3): d 1.57 (d, J ¼ 6.8 Hz, 3.68 (s, 3H), 4.40 (q, J ¼ 7.4 Hz, 1H), 7.17–7.28 (m, 3H).
3H), 2.16 (s, 6H), 3.13 (br, 1H), 4.40 (q, J ¼ 6.8 Hz, 1H), 6.81 (t, J
¼ 7.2 Hz, 1H), 6.96 (d, J ¼ 7.2 Hz, 2H), 7.45 (d, J ¼ 8.8 Hz, 2H),
Acknowledgements
8.15 (d, J ¼ 8.8 Hz, 2H).
N-[1-(3-Nitrophenyl)ethyl]-2,6-dimethylbenzenamine
6e. The authors are grateful for the nancial supports from the
98% yield. 98% ee was determined by chiral HPLC (chiralpak National Natural Science Foundation of China (21403022) and
AD-H, n-hexane/i-PrOH ¼ 99/1, 1.0 mL minꢁ1, 254 nm, 40 ꢀC): tr Program for Liaoning Excellent Talents in University
1
¼ 12.0, 12.4 min. H NMR (400 MHz, CDCl3): d 1.58 (d, J ¼ 6.8 (LJQ2013059).
Hz, 3H), 2.19 (s, 6H), 3.20 (br, 1H), 4.43 (q, J ¼ 6.8 Hz, 1H), 6.82
(t, J ¼ 7.6 Hz, 1H), 6.97 (d, J ¼ 7.6 Hz, 2H), 7.45 (t, J ¼ 7.6 Hz,
Notes and references
1H), 7.62 (d, J ¼ 7.6 Hz, 1H), 8.10 (d, J ¼ 7.6 Hz, 1H), 8.24 (s, 1H).
N-[1-(3-Methoxyphenyl)ethyl]-2,6-dimethylbenzenamine 6f.
98% yield. 95% ee was determined by chiral HPLC (chiralꢀpak
AD-H, n-hexane/i-PrOH ¼ 99/1, 0.5 mL minꢁ1, 254 nm, 40 C):
tr ¼ 19.2, 23.4 min. 1H NMR (400 MHz, CDCl3): d 1.50 (d, J ¼ 6.4
Hz, 3H), 2.18 (s, 6H), 3.21 (br, 1H), 3.75 (s, 3H), 4.29 (q, J ¼ 6.4
Hz, 1H), 6.76–6.80 (m, 2H), 6.80–6.83 (m, 1H), 6.89 (d, J ¼ 7.2
Hz, 1H), 6.95 (d, J ¼ 7.2 Hz, 2H), 7.20–7.25 (m, 1H).
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,
254 nm, 40 ꢀC): tr ¼ 16.3, 17.3 min. 1H NMR (400 MHz, CDCl3): d
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4.50 (q, J ¼ 6.8 Hz, 1H), 6.83 (t, J ¼ 7.6 Hz, 1H), 6.99 (d, J ¼ 7.6
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N-(3-Methylbutan-2-yl)-2,6-dimethylbenzenamine 6h. 97%
yield. 84% ee was determined by chiral GC (chiral b-DEX 120
ꢀ
column, column temp.: 100 C, carrier gas: N2): tr ¼ 27.9, 29.0
min. 1H NMR (400 MHz, CDCl3): d 0.97–1.05 (m, 9H), 1.76–1.84
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