Enantioselective Hydrogenation of Diarylmethanimines for Synthesis of Chiral Diarylmethylamines

Article abstract of DOI:10.1021/acs.joc.6b01273

An enantioselective hydrogenation of N-substituted diarylmethanimines under mild conditions has been first realized by using an iridium catalyst with a chiral f-spiroPhos ligand. This method provides an efficient access to the asymmetric synthesis of a variety of chiral diarylmethylamines and their derivatives with excellent enantioselectivities (up to 99.4% ee) and high turnover numbers (TON up to 4000).

Full text of DOI:10.1021/acs.joc.6b01273

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Article
Enantioselective Hydrogenation of Diarylmethanimines
for Synthesis of Chiral Diarylmethylamines
Duanyang Kong, Meina Li, Guofu Zi, Guohua Hou, and Yong He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01273 • Publication Date (Web): 13 Jul 2016
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Enantioselective Hydrogenation of Diarylmethanimines for Synthesis
of Chiral Diarylmethylamines
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Duanyang Kong, Meina Li, Guofu Zi, Guohua Hou* and Yong He*
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University,
Beijing 100875, China
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Email: ghhou@bnu.edu.cn; heyong@bnu.edu.cn
ABSTRACT: An enantioselective hydrogenation of N-substituted diarylmethanimines under mild
conditions has been first realized by using an iridium catalyst with a chiral f-spiroPhos ligand.
This method provides an efficient access to the asymmetric synthesis of a variety of chiral
diarylmethylamines and their derivatives with excellent enantioselectivities (up to 99.4% ee) and
high turnover numbers (TON up to 4,000).
INTRODUCTION
Chiral diarylmethylamines are extremely important building blocks and are widely present in a
broad range of natural products, pharmaceuticals and biologically active compounds (Figure 1).1
As a consequence, the synthesis of chiral diarylmethylamines has attracted considerable attention
from chemists and several approaches including resolution of racemates, asymmetric additions of
organometallic reagents to imines and enantioselective transfer hydrogenation have been
developed.2-5
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Figure 1. Structures of Biologically Active Compounds Containing Diarylmethylamine Moiety.
Although a number of chiral transition-metal catalysts, organocatalysts and biocatalysts have
been developed and exhibited high enantioselectivties in asymmetric hydrogenation of aryl alkyl
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imines and reductive amination of carbonyl compounds,6c, 7 surprisingly, up to now there is no
efficient catalyst for asymmetric hydrogenation of diarylmethanimines. The following obstacles
have possibly thwarted attempts involving their use as substrates in asymmetric hydrogenations: 1)
The interconversion of Z/E isomers of imines results in a diminished enantioselectivity; 2) the
instability and strong coordination of both substrates and products to the catalyst leads to
deactivation and hindered hydrogenation; 3) For most of chiral catalysts, it is very difficult to
distinguish between two sterically similar aryl groups at a stereogenic center. Zhang and
co-workers reported the asymmetric hydrogenation of benzophenone N-H iminium salts catalyzed
by an iridium complex carrying a monodentate phosphoramidite ligand.8 Despite protecting group
free and high enantioselecitvities in the hydrogenation of ortho-substituted substrates, low
efficiency was observed and very high catalyst loading (5 mol%, TON = 20) were required to
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achieve full conversions and good enantioselectivities. Furthermore, for the substrates without or
with a smaller ortho-substituent (such as 2-F), this catalyst system was inefficient giving poor
enantioselectivities. As one of the most efficient and straightforward approaches to chiral
diarylmethylamines, the asymmetric hydrogenation of diarylmethanimines regardless of with or
without N-protecting group, still remains a great challenge. Consequently, to develop novel high
efficient catalysts for the asymmetric hydrogenation of this kind of substrates is highly desirable
and of significant importance in asymmetric synthesis.
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Recently, we demonstrated that the chiral ferrocenyl ligand, f-spiroPhos, containing a
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1,1′-spirobiindane scaffold
was an efficient ligand for Rh/Ir-catalyzed asymmetric
hydrogenation.10 These encouraging results promoted us to tackle the asymmetric hydrogenation
of this class of challenging diarylmethanimines. We herein report the asymmetric hydrogenation
of these substrates catalyzed by an iridium/f-spiroPhos complex with excellent enantioselectivities
(up to 99.4% ee) and high turnover numbers (TON of up to 4,000), which represents the best
result for this kind of substrates to date (Scheme 1).
Scheme 1. Asymmetric Hydrogenation of Diarylmethanimines.
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RESULTS AND DISCUSSION
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Our initial investigation began with the hydrogenation of 2-methylbenzophenone imine 1a as
o
the model substrate under 80 atm of H2 in CH2Cl2 at 40 C with various iridium catalysts
generated in situ from 0.5 mol% [Ir(COD)Cl]2 and a series of 2.2 mol% phosphorus ligands. The
evaluation of chiral ligands indicated that f-spiroPhos was most promising one achieving an
enantioselectivity of 96% ee (Table 1, entry 7). Diphosphonite ligand 1 and (S,S)-f-Binaphane also
gave moderate to good enantioselectivities (75% ee and 91% ee, respectively) with full
conversions (entries 5–6), while (S,R)-DuanPhos and (R)-JosiPhos-1 only exhibited poor activities
and enantioselectivities (entries 3–4). In addition to CH2Cl2, 1,4-dioxane was also suitable and
afforded increased enantioselectivity (98% ee, entry 13). Although comparable enantioselectivities
were achieved in THF and DME solvents, incomplete conversions were obtained (entries 10–11).
Lower H2 pressure (30 atm H2) led to a slight decrease of conversion but with maintained
o
enantioselectivity (entry 13). To our delight, increasing the reaction temperature to 60 C resulted
in complete conversion under 30 atm H2 pressure with a much shorter reaction time (12 hours)
without any erosion of enantioselectivity (entry 14).
Table 1. Ir-Catalyzed Asymmetric Hydrogenation of 1a, Optimizing Reaction conditions a
entry
ligand
solvent
CH2Cl2
CH2Cl2
conv. (%)b
ee. (%)c
ND
1
2
(S)-Monophos
(S)-Binap
<5
60
85
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3
(S,R)-DuanPhos
(R)-JosiPhos-1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeOH
THF
11
10
ND
91
75
96
42
65
97
97
98
98
98
4
<5
5
(S,S)-f-Binaphane
Ligand 1
>99
>99
>99
25
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(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
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31
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13d
14e
58
DME
72
dioxane
dioxane
dioxane
>99
97
>99
a
Unless otherwise mentioned, all reactions were carried out with
a
[Ir(COD)Cl]2/ligand/substrate ratio of 0.5 : 1.1 : 100, 80 atm H2, 40 oC, 24 h. b Determined by 1H
NMR. c Determined by HPLC analysis using a chiral stationary phase. d 30 atm H2, 40 oC, 24 h. e
30 atm H2, 60 oC, 12 h.
Encouraged by the promising result obtained in the hydrogenation of substrate 1a, a variety of
diarylmethanimines were prepared and hydrogenated using the Ir/f-spiroPhos catalyst under
optimized reaction conditions (Table 2, 1a–1x). The hydrogenation appears to be sensitive to the
steric difference of two aromatic rings. Substrates containing a methyl, fluoro, chloro or bromo
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substituent at the ortho position of the aromatic ring gave excellent enantioselectivities (94%–98%
ee), regardless of the steric and electronic properties of the substituents at the meta or para
position of the second aromatic ring. Even for substrates with a coordinating 2-methoxy (1e) or
smaller 2-F substituent (1n–1o), excellent enantioselectivities with full conversions were observed.
1-Naphthyl substituted imine (1t) was also smoothly hydrogenated furnishing the desired product
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t
in high enantioselectivity, 95% ee. Changing the ester moiety to CH2CO2Et and CH2CO2 Bu had
no obvious effect on the enantioselectivities and conversions providing the corresponding
products 2u and 2v with similar ee values and full conversions. Notably, substrates without an
N-ester group, 1w and 1x were also successfully hydrogenated to the corresponding products 2w
and 2x with even higher enantioselectivities, 99.4% ee and 99% ee, respectively, which means that
the ester group is not required in order to achieve high reactivity and enantioselectivity in this
hydrogenation. Considering the easy C-H imine activation by Ir complexes reported by Pfaltz and
Xiao,11 we envisioned that there was an effect of C-H imine activation in this hydrongenation,
which was helpful for the discrimination between two aryl groups and the excellent
enantioselectivities. But the results of deuteration reactions indicated that C-H imine activation by
Ir complexes was not observed (see Experimental Section and ESI).
Table 2. Ir-Catalyzed Asymmetric Hydrogenation of Various Diarylmethanimines 1 a
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a
Unless otherwise mentioned, all reactions were carried out with
a
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[Ir(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of 0.5 : 1.1 : 100, dioxane, 30 atm H2, 60 oC, 12 h.
The enantioselectivity was determined by HPLC analysis using a chiral stationary phase. b 80 atm
H2, 60 oC, 12 h. c 30 atm H2, 60 oC, 24 h. d 80 atm H2, 80 oC, 36 h. e 30 atm H2, rt, 24 h. f 30 atm H2,
rt, 36 h.
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Despite excellent results obtained in the hydrogenation of ortho-substituted imines, poor
enantioselectivities were observed for substrates without an ortho-substituent,12 which was
possibly attributed to the persence of Z/E isomers of substrates. In the synthesis of the substrates
bearing a meta or para substituent, we found that these substrates were obtained as a mixture of
Z/E isomers and the ratio was not changed during the hydrogenation. Although we attempted to
isolate any isomer of them, we still got the mixture with a maintained ratio. These results revealed
that the quick interconversion of Z/E imine isomers led to the difficulty of isolation. Fortunately,
however, the introduction of ortho substituents in imine substrates could prevent the isomerization
and this class of ortho substituted imines could be prepared as a single isomer. Therefore, the
desired products with excellent ee values could be obtained by the enantioselective hydrogenation
of the corresponding 2-Cl or 2-Br substrates subsequently followed by dehalogenation of the
hydrogenation products. For example, the substrate 1i containing a 2-Cl substituent was
hydrogenated to produce 2i with 97% ee which was then dehalogenated catalyzed by Pd/C in the
presence of K2CO3 affording the desired 3-Me product 3a with remained enantioselectivity. In this
way, meta- and para-substituted diarylmethylamines 3b – 3e could be readily provided with high
yields and excellent enantioselectivities, up to 98% ee.
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More remarkably, the hydrogenation could be accomplished on a gram scale with much lower
catalyst loading. Using 0.025 mol% of the Ir-(R,R)-f-spiroPhos catalyst, the hydrogenation of the
substrates 1a was successfully carried out affording the desired product quantitatively without any
erosion of the enantioselectivity. These results indicated that this catalyst is exceptionally efficient
for the asymmetric hydrogenation of these diarylmethanimines and shows very high turnover
numbers (TON) approaching 4,000, to the best of our knowledge, which represents the highest
turnover numbers for this class of substrates so far (Scheme 2).
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Scheme 2. Asymmetric Hydrogenation of 1a under Lower Catalyst Loading.
Finally, this method could be used for synthesis of chiral diarylmethylamines and some
important pharmaceuticals (Scheme 3), such as the histamine H1-receptor antagonist
Levocetirizine.3a,13 The hydrogenation product 3e was treatment with ICH2COOC2H5 affording the
compound 4 which could be readily converted to Levocetirizine.14 The free chiral
diarylmethylamines 5 could also be obtained with maintained enantioselectivities by removal of
N-substituted ester group.15
Scheme 3. Asymmetric Synthesis of Levocetirizine and Diarylmethylamines.
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CONCLUSIONS
In conclusion, an enantioselective hydrogenation of N-substituted diarylmethanimines under
mild conditions has been first realized by using an iridium catalyst with a chiral f-spiroPhos ligand.
The reaction provides an efficient access to the asymmetric synthesis of a variety of chiral
diarylmethylamines with excellent enantioselectivities (up to 99.4% ee) and high turnover
numbers (up to 4,000).
EXPERIMENTAL SECTION
General Information: All the air or moisture sensitive reactions and manipulations were
performed by using standard Schlenk techniques and in a nitrogen-filled glovebox. DME, THF,
dioxane and toluene were distilled from sodium benzophenone ketyl. CH2Cl2 was distilled from
1
calcium hydride. Anhydrous MeOH was distilled from magnesium. H NMR spectra were
recorded on 400 MHz spectrometers. 13C NMR (proton-decoupled) spectra were obtained at 100
MHz. CDC13 was the solvent used for the NMR analysis, with TMS as the internal standard.
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Chemical shifts were reported upfield to TMS (0.00 ppm) for H NMR. Data is represented as
follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, dd = double of doublets,
t = triplet, q = quartet, m = multiplet) and coupling constants (J) in Hertz (Hz). Optical rotation
was determined using a polarimeter. HRMS were recorded on a mass spectrometer with APCI or
ESI.
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Preparation and Analytical Data of Substrates 1: A 50 mL round bottom flask was charged
with benzophenone imine (5.0 mmol), glycine ester hydrochloride (6.0 mmol) and CH2Cl2 (10.0
mL). The milky white mixture was stirred at rt-40 oC under an argon atmosphere until no starting
material was detected by TLC. The white insoluble substance was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified via flash chromatography
(PE/EA/CH2Cl2 = 10/1/1 to 20/1/1) to afford 1 as light yellow oil.16
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(E)-Methyl 2-((phenyl(o-tolyl)methylene)amino)acetate (1a): 1.24 g, Yield: 93%; H NMR
(CDCl3, 400 MHz) δ: 7.56 (d, J = 7.7 Hz, 2H), 7.33-7.11 (m, 6H), 6.94 (d, J = 7.5 Hz, 1H), 4.00 (s,
2H), 3.62 (s, 3H), 1.97 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.6, 171.7, 138.9, 136.4,
135.5, 131.2, 131.1, 129.4, 128.9, 128.8, 127.7, 126.7, 55.9, 52.6, 19.8. TOF-HRMS Calcd. for
C17H18NO2 [M+H+]: 268.1332, found 268.1333.
(E)-Methyl 2-(((3-methoxyphenyl)(o-tolyl)methylene)amino)acetate (1b): 1.37 g, Yield: 92%;
1H NMR (CDCl3, 400 MHz) δ: 7.21-7.19 (m, 2H), 7.17 (s, 1H), 7.15-7.07 (m, 2H), 6.96 (d, J =
7.8 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.83-6.80 (m, 1H), 3.94 (d, J = 2.0 Hz, 2H), 3.68 (s, 3H),
3.60 (s, 3H), 1.93 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.5, 171.7, 160.2, 140.5, 136.5,
135.5, 131.1, 129.8, 129.4, 127.8, 126.7, 121.8, 117.3, 113.3, 56.0, 55.9, 52.6, 19.8. TOF-HRMS
Calcd. for C18H20NO3 [M+H+]: 298.1437, found 298.1439.
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(E)-Methyl 2-((m-tolyl(o-tolyl)methylene)amino)acetate (1c): 1.27 g, Yield: 90%; H NMR
(CDCl3, 400 MHz) δ: 7.55 (s, 1H), 7.27-7.19 (m, 6H), 6.96 (d, J = 7.7 Hz, 1H), 4.06-3.97 (m, 2H),
3.67 (s, 3H), 2.27 (s, 3H), 2.00 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.8, 171.7, 138.9,
138.5, 136.6, 135.5, 132.0, 131.0, 129.3, 128.8, 128.7, 127.7, 126.7, 126.4, 55.9, 52.5, 21.9, 19.8.
TOF-HRMS Calcd. for C18H20NO2 [M+H+]: 282.1488, found 282.1487.
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(E)-Methyl 2-((o-tolyl(p-tolyl)methylene)amino)acetate (1d): 1.23 g, Yield: 88%; H NMR
(CDCl3, 400 MHz) δ: 7.46 (d, J = 7.8 Hz, 2H), 7.26-7.19 (m, 3H), 7.05 (d, J = 16.1 Hz, 2H), 6.94
(d, J = 7.2 Hz, 1H), 3.99 (s, 2H), 3.65 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 171.8, 171.2, 140.8, 136.0, 135.7, 134.9, 130.4, 129.0, 128.7, 128.1, 127.1, 126.1,
55.2, 51.9,21.4, 19.2. TOF-HRMS Calcd. for C18H20NO2 [M+H+]: 282.1488, found 282.1487.
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(E)-Methyl 2-(((4-fluorophenyl)(o-tolyl)methylene)amino)acetate (1e): 1.27 g, Yield: 89%; H
NMR (CDCl3, 400 MHz) δ: 7.53-7.49 (m, 2H), 7.21-7.12 (m, 3H), 6.89-6.85 (m, 3H), 3.92 (s, 2H),
3.59 (s, 3H), 1.92 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.4 (d, J = 26.0 Hz), 164.9 (d,
1JC-F = 249.0 Hz), 136.1, 135.4, 135.2 (d, J = 3.0 Hz), 131.1, 130.8 (d, J = 8.0 Hz), 129.5, 127.6,
126.8, 115.9, 115.6, 55.8, 52.5, 19.7. TOF-HRMS Calcd. for C17H17NO2F [M+H+]: 286.1237,
found 286.1238.
(E)-Methyl 2-(((2-methoxyphenyl)(phenyl)methylene)amino)acetate (1f): 1.30 g, Yield: 92%;
1H NMR (CDCl3, 400 MHz) δ: 7.69 (d, J = 7.4 Hz, 2H), 7.39-7.33 (m, 4H), 7.04-7.00 (m, 3H),
4.25-4.04 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.1, 169.4,
156.6, 139.6, 131.0, 130.9, 129.5, 128.9, 128.6, 125.2, 121.4, 111.5, 56.2, 56.0, 52.5. TOF-HRMS
Calcd. for C17H18NO3 [M+H+]: 284.1281, found 284.1282.
(E)-Methyl 2-(((2-chlorophenyl)(phenyl)methylene)amino)acetate (1g): 1.32 g, Yield: 92%; 1H
NMR (CDCl3, 400 MHz) δ: 7.58 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.34-7.27 (m, 5H),
7.08 (d, J = 7.1 Hz, 1H), 4.21-3.92 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz)
δ:171.4, 169.0, 138.3, 135.6, 132.1, 131.2, 130.8, 130.4, 129.5, 128.8, 128.7, 127.7, 55.8, 52.5.
TOF-HRMS Calcd. for C16H15NO2Cl [M+H+]: 288.0785, found 288.0785.
(E)-Methyl 2-(((2-chlorophenyl)(3-methoxyphenyl)methylene)amino)acetate (1h): 1.41 g,
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Yield: 89%; H NMR (CDCl3, 400 MHz) δ: 7.43-7.41 (m, 1H), 7.35-7.27 (m, 3H), 7.19-7.15 (m,
1H), 7.09-7.07 (m, 1H), 7.03-7.01 (m, 1H), 6.91-6.88 (m, 1H), 4.21-3.90 (m, 2H), 3.75 (s, 3H),
3.67 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.4, 168.9, 160.1, 139.8, 135.7, 132.2, 130.8,
130.4, 129.7, 129.5, 127.7, 121.7, 117.5, 113.2, 55.9, 52.6. TOF-HRMS Calcd. for C17H17NO3Cl
[M+H+]: 318.0891, found 318.0889.
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(E)-Methyl 2-(((2-chlorophenyl)(m-tolyl)methylene)amino)acetate (1i): 1.31 g, Yield: 87%; 1H
NMR (CDCl3, 400 MHz) δ: 7.54 (s, 1H), 7.44-7.41 (m, 1H), 7.33-7.29 (m, 2H), 7.22 (s, 1H),
7.16-7.14 (m, 2H), 7.08-7.06 (m, 1H), 4.20-3.90 (m, 2H), 3.68 (s, 3H), 2.28 (s, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 171.4, 169.3, 138.6, 138.3, 135.8, 132.2, 130.8, 130.4, 129.6, 128.9, 128.7,
127.7, 126.3, 55.9, 52.6, 21.9. TOF-HRMS Calcd. for C17H17NO2Cl [M+H+]: 302.0942, found
302.0940.
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(E)-Methyl 2-(((2-chlorophenyl)(p-tolyl)methylene)amino)acetate (1j): 1.33 g, Yield: 88%; H
NMR (CDCl3, 400 MHz) δ: 7.48-7.41 (m, 3H), 7.33-7.29 (m, 2H), 7.09-7.06 (m, 3H), 4.19-3.89
(m, 2H), 3.67 (s, 3H), 3.29 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.6, 168.9, 141.7, 135.9,
135.7, 132.2, 130.7, 130.4, 129.6, 129.5, 128.7, 127.7, 55.8, 52.6, 22.0. TOF-HRMS Calcd. for
C17H17NO2Cl [M+H+]: 302.0942, found 302.0940.
(E)-Methyl 2-(((2-chlorophenyl)(4-fluorophenyl)methylene)amino)acetate (1k): 1.31 g, Yield:
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86%; H NMR (CDCl3, 400 MHz) δ: 7.60-7.56 (m, 2H), 7.44-7.42 (m, 1H), 7.35-7.31 (m, 2H),
7.08-7.06 (m, 1H), 6.98-6.93 (m, 2H), 4.18-3.89 (m, 2H), 3.67 (s, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 171.4, 167.9, 165.1 (d, 1JC-F = 250.0 Hz), 135.4, 134.6 (d, J = 3.0 Hz), 132.1, 130.9 (d, J
= 13.0 Hz), 130.7 (d, J = 24.0 Hz), 129.5, 127.9, 116.0, 115.8, 55.8, 52.7. TOF-HRMS Calcd. for
C16H14NO2FCl [M+H+]: 306.0691, found 306.0694.
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(E)-Methyl 2-(((2-chlorophenyl)(4-chlorophenyl)methylene)amino)acetate (1l): 1.48 g, Yield:
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92%; H NMR (CDCl3, 400 MHz) δ: 7.53-7.50 (m, 2H), 7.45-7.42 (m, 1H), 7.37-7.29 (m, 2H),
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7.26-7.23 (m, 2H), 7.08-7.05 (m, 1H), 4.18-3.90 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 171.2, 167.9, 137.5, 136.8, 135.2, 132.1, 131.0, 130.6, 130.0, 129.4, 129.1, 127.9, 55.9,
52.6. TOF-HRMS Calcd. for C16H14NO2Cl2 [M+H+]: 322.0396, found 322.0394.
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(E)-Methyl 2-(((2-bromophenyl)(phenyl)methylene)amino)acetate (1m): 1.41 g, Yield: 85%;
1H NMR (CDCl3, 400 MHz) δ: 7.62-7.57 (m, 3H), 7.38-7.33 (m, 2H), 7.30-7.23 (m, 3H),
7.08-7.05 (m, 1H), 4.20-3.90 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.4,
170.1, 138.1, 137.9, 133.6, 131.3, 130.9, 129.6, 128.9, 128.8, 128.3, 121.4, 55.8, 52.6.
TOF-HRMS Calcd. for C16H15NO2Br [M+H+]: 332.0280, found 332.0280.
(E)-Methyl 2-(((2-bromophenyl)(3-fluorophenyl)methylene)amino)acetate (1n): 1.52 g, Yield:
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87%; H NMR (CDCl3, 400 MHz) δ: 7.63-7.60 (m, 1H), 7.39-7.35 (m, 2H), 7.29-7.21 (m, 3H),
7.08-7.02 (m, 2H), 4.20-3.90 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.2,
169.0, 163.4 (d, 1JC-F = 243.0 Hz), 140.5 (d, J = 7.0 Hz), 137.4, 133.8, 131.2, 130.3 (d, J = 8.0 Hz),
129.6, 128.5, 124.7 (d, J = 3.0 Hz), 121.3, 118.3 (d, J = 22.0 Hz), 115.5 (d, J = 23.0 Hz), 55.9,
52.7. TOF-HRMS Calcd. for C16H14NO2FBr [M+H+]: 350.0186, found 350.0185.
(E)-Methyl 2-(((2-bromophenyl)(4-fluorophenyl)methylene)amino)acetate (1o): 1.45 g, Yield:
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83%; H NMR (CDCl3, 400 MHz) δ: 7.62-7.56 (m, 3H), 7.38-7.34 (m, 1H), 7.28-7.25 (m, 1H),
7.07-7.05 (m, 1H), 6.98-6.94 (m, 2H), 4.18-3.88 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100
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MHz) δ: 171.4, 167.5 (d, JC-F = 260.0 Hz), 163.8, 137.6, 134.3 (d, J = 3.0 Hz), 133.7, 131.1,
130.9 (d, J = 8.0 Hz), 129.5, 128.4, 121.3, 115.9 (d, J = 21.0 Hz), 55.8, 52.6. TOF-HRMS Calcd.
for C16H14NO2FBr [M+H+]: 350.0186, found 350.0185.
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(E)-Methyl 2-(((2-bromophenyl)(4-chlorophenyl)methylene)amino)acetate (1p): 1.54 g, Yield:
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84%; H NMR (CDCl3, 400 MHz) δ: 7.60-7.57 (m, 3H), 7.46-7.42 (m, 1H), 7.36-7.13 (m, 3H),
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7.11-7.10 (m, 1H), 4.26-3.96 (m, 2H), 3.75 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.3,
168.9, 137.5, 137.3, 136.5, 133.7, 130.1, 129.5, 129.1, 128.4, 121.2, 55.8, 52.6. TOF-HRMS
Calcd. for C16H14NO2ClBr [M+H+]: 365.9890, found 365.9889.
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(E)-Methyl 2-(((2-fluorophenyl)(phenyl)methylene)amino)acetate (1q): 1.16 g, Yield: 86%; 1H
NMR (CDCl3, 400 MHz) δ: 7.53 (d, J = 7.4 Hz, 2H), 7.33-7.20 (m, 4H), 7.13-7.00 (m, 3H),
4.13-4.00 (m, 2H), 3.61 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.4, 166.8 (d, 1JC-F = 250.0
Hz), 139.0, 131.8, 131.3, 130.1, 128.9, 128.8, 125.1, 123.9, 123.7, 116.8 (d, J = 21.0 Hz), 56.3,
52.6. TOF-HRMS Calcd. for C16H15NO2F [M+H+]: 272.1081, found 272.1082.
(E)-Methyl 2-(((2-fluorophenyl)(m-tolyl)methylene)amino)acetate (1r): 1.23 g, Yield: 86%; 1H
NMR (CDCl3, 400 MHz) δ: 7.56 (s, 1H), 7.42-7.40 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.09 (m, 5H),
4.23-4.08 (m, 2H), 3.71 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 171.4, 167.0, 159.3 (d, 1JC-F
= 250.0 Hz), 138.8 (d, J = 44.0 Hz), 132.1, 131.7 (d, J = 7.0 Hz), 130.1 (d, J = 4.0 Hz), 129.0,
128.6, 126.4, 125.0 (d, J = 3.0 Hz), 123.9 (d, J = 18.0 Hz), 116.7, 116.5, 56.3, 52.6, 21.9.
TOF-HRMS Calcd. for C17H17NO2F [M+H+]: 286.1237, found 286.1238.
(E)-Methyl 2-(((2-fluorophenyl)(4-fluorophenyl)methylene)amino)acetate (1s): 1.18 g, Yield:
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82%; H NMR (CDCl3, 400 MHz) δ: 7.62-7.56 (m, 2H), 7.42-7.37 (m, 1H), 7.21-7.04 (m, 3H),
6.96 (d, J = 8.7 Hz, 2H), 4.18-4.00 (m, 2H), 3.68 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ:
171.4, 165.9, 165.0 (d, 1JC-F = 247.0 Hz), 159.7 (d, 1JC-F = 247.0 Hz), 135.3 (d, J = 3.0 Hz), 131.9
(d, J = 8.0 Hz), 131.0 (d, J = 8.0 Hz), 130.1 (d, J = 4.0 Hz), 125.2 (d, J = 4.0 Hz), 123.5 (d, J =
19.0 Hz), 116.8 (d, J = 21.0 Hz), 115.8 (d, J = 22.0 Hz), 56.3, 52.7. TOF-HRMS Calcd. for
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C16H14NO2F2 [M+H+]: 290.0987, found 290.0988.
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(E)-Methyl 2-((naphthalen-1-yl(phenyl)methylene)amino)acetate (1t): 1.35 g, Yield: 89%; H
NMR (CDCl3, 400 MHz) δ: 7.94 (t, J = 6.8 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.58-7.50 (m, 3H),
7.43-7.38 (m, 2H), 7.37-7.29 (m, 3H), 4.11-4.00 (m, 2H), 3.70 (s, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 171.2, 171.1, 139.0, 134.1, 133.4, 130.7, 130.1, 129.0, 128.6, 128.4, 128.2, 127.1, 126.6,
125.4, 125.3, 125.1, 55.5, 52.0. TOF-HRMS Calcd. for C20H18NO2 [M+H+]: 304.1332, found
304.1330.
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(E)-Ethyl 2-((phenyl(o-tolyl)methylene)amino)acetate (1u): 1.27 g, Yield: 90%; H NMR
(CDCl3, 400 MHz) δ: 7.60-7.58 (m, 2H), 7.32-7.19 (m, 6H), 6.97 (d, J = 7.7 Hz, 1H), 4.15-4.10
(m, 2H), 4.01-4.00 (m, 2H), 2.00 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 172.4, 171.2, 139.0, 136.5, 135.5, 131.1, 131.0, 129.3, 128.8, 128.7, 127.8, 126.7, 61.4,
56.1, 19.8, 14.7. TOF-HRMS Calcd. for C18H20NO2 [M+H+]: 282.1488, found 282.1487.
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(E)-tert-Butyl 2-((phenyl(o-tolyl)methylene)amino)acetate (1v): 1.42 g, Yield: 92%; H NMR
(CDCl3, 400 MHz) δ: 7.59-7.57 (m, 2H), 7.31-7.19 (m, 6H), 6.97 (d, J = 7.6 Hz, 1H), 3.97-3.87
(m, 2H), 2.00 (s, 3H), 1.38 (s, 9H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.0, 170.3, 139.1, 136.7,
135.5, 131.0, 130.9, 129.2, 128.8, 128.7, 127.9, 126.6, 81.6, 56.7, 28.6, 27.4, 19.8. TOF-HRMS
Calcd. for C20H24NO2 [M+H+]: 310.1801, found 310.1803.
(E)-N-(Phenyl(o-tolyl)methylene)methanamine (1w): 0.91 g, Yield: 87%; 1H NMR (CDCl3, 400
MHz) δ: 7.46-7.44 (m, 2H), 7.23-7.14 (m, 6H), 7.14-6.88 (m, 1H), 3.03 (s, 3H), 1.95 (s, 3H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 169.7, 138.9, 136.4, 134.9, 130.1, 129.8, 128.2, 128.1, 127.5,
127.1, 125.8, 40.9, 19.1. TOF-HRMS Calcd. for C15H16N [M+H+]: 210.1277, found 210.1280.
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MHz) δ: 7.47-7.44 (m, 2H), 7.23-7.12 (m, 6H), 6.90-6.89 (m, 1H), 3.21-3.11 (m, 2H), 1.95 (s, 3H),
1.13-1.09 (m, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 167.7, 139.2, 137.0, 135.0, 130.2, 129.9,
128.3, 128.2, 127.8, 127.4, 125.9, 48.2, 19.4, 16.0. TOF-HRMS Calcd. for C16H18N [M+H+]:
224.1433, found 224.1435.
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General Procedure of Hydrogenation and Analytical Data of Products 2: A stock solution
was made by mixing [Ir(COD)Cl]2 with (R,R)-f-spiroPhos in a 1:1.1 molar ratio of
Ir/(R,R)-f-spiroPhos in dioxane at room temperature for 20 min in a nitrogen-filled glovebox. An
aliquot of the catalyst solution (1.0 mL, 0.001 mmol) was transferred by syringe into the vials
charged with different substrates (0.1 mmol for each) in dioxane (2.0 mL). The vials were then
placed into a steel autoclave. The inert atmosphere was replaced by H2 and the reaction mixture
o
was stirred under H2 (30 atm) at 60 C. The hydrogen gas was released slowly and carefully. The
solution was concentrated and passed through a short column of silica gel to remove the metal
complex affording the products as light yellow oil. The ee values of all products were determined
by HPLC analysis on a chiral stationary phase.
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(S)-Methyl 2-((phenyl(o-tolyl)methyl)amino)acetate (2a): 26.6 mg, Yield: 99%; 98% ee; [α]D
= +20.6 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex =
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10:90, 1.0 mL/min, 254 nm; tA = 6.8 min (major), tB = 7.4 min (minor). H NMR (CDCl3, 400
MHz) δ: 7.56 (d, J = 7.6 Hz, 1H), 7.27-7.01 (m, 8H), 5.00 (s, 1H), 3.63 (s, 3H), 3.32 (t, J = 18.2
Hz, 2H), 2.19 (s, 3H), 2.03 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.7, 142.9, 141.2, 136.5,
131.1, 129.0, 128.6, 127.7, 127.5, 127.2, 126.8, 62.8, 52.3, 49.5, 20.1. TOF-HRMS Calcd. for
C17H20NO2 [M+H+]: 270.1488, found 270.1490.
(+)-Methyl 2-(((3-methoxyphenyl)(o-tolyl)methyl)amino)acetate (2b): 29.0 mg, Yield: 97%; 94%
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ee; [α]D20 = +19.6 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 8.7 min (minor), tB = 9.8 min (major). H NMR (CDCl3,
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400 MHz) δ: 7.61 (d, J = 7.6 Hz, 1H), 7.25-7.11 (m, 4H), 6.95-6.92 (m, 2H), 6.77-6.75 (m, 1H),
5.06 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.45-3.35 (m, 2H), 2.30 (s, 3H), 2.13 (s, 1H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 173.6, 160.3, 144.6, 141.2, 136.5, 131.1, 130.0, 127.5, 127.2,
126.8, 121.0, 114.3, 113.0, 62.7, 55.7, 52.3, 49.5, 20.1. TOF-HRMS Calcd. for C18H22NO3
[M+H+]: 300.1594, found 300.1595.
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(+)-Methyl 2-((m-tolyl(o-tolyl)methyl)amino)acetate (2c): 27.5 mg, Yield: 98%; 96% ee; [α]D
= +23.5 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex = 5:95,
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1.0 mL/min, 254 nm; tA = 7.3 min (minor), tB = 7.8 min (major). H NMR (CDCl3, 400 MHz) δ:
7.58 (d, J = 7.7 Hz, 1H), 7.18-7.06 (m, 6H), 6.97 (d, J = 7.2 Hz, 1H), 5.00 (s, 1H), 3.66 (s, 3H),
3.34 (q, J = 17.6, 21.6 Hz, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 2.08 (s, 1H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 173.6, 142.8, 141.2, 138.6, 136.5, 131.1, 129.2, 128.8, 128.5, 127.4, 127.1, 126.7, 125.6,
62.7, 52.3, 49.5, 22.0, 20.1. TOF-HRMS Calcd. for C18H22NO2 [M+H+]: 284.1645, found
284.1644.
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(+)-Methyl 2-((o-tolyl(p-tolyl)methyl)amino)acetate (2d): 28.0 mg, Yield: 99%; 97% ee; [α]D
= +20.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex =
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10:90, 1.0 mL/min, 254 nm; tA = 5.7 min (minor), tB = 6.5 min (major). H NMR (CDCl3, 400
MHz) δ: 7.58 (d, J = 7.7 Hz, 1H), 7.19-7.15 (m, 3H), 7.07-7.02 (m, 4H), 4.97 (s, 1H), 3.65 (s, 3H),
3.32 (q, J = 17.6, 22.1 Hz, 2H), 2.00 (s, 3H), 1.98 (m, 3H), 1.96 (s, 1H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 173.7, 141.4, 139.9, 137.3, 136.5, 131.1, 129.7, 128.5, 127.4, 127.0, 126.8, 62.5,
52.3, 49.5, 21.7, 20.1. TOF-HRMS Calcd. for C18H22NO2 [M+H+]: 284.1645, found 284.1644.
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(+)-Methyl 2-(((4-fluorophenyl)(o-tolyl)methyl)amino)acetate (2e): 28.2 mg, Yield: 98%; 96%
ee; [α]D20 = +18.0 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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400 MHz) δ: 7.62 (d, J = 8.6 Hz, 1H), 7.33-7.09 (m, 6H), 7.00-6.95 (m, 1H), 5.07 (s, 1H), 3.72 (s,
3H), 3.43-3.33 (m, 2H), 2.26 (s, 3H), 2.10 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.6,
162.5 (d, 1JC-F = 244.0 Hz), 141.2 (d, J = 41.0 Hz), 139.9, 138.7 (d, J = 3.0 Hz), 136.4 (d, J = 2.0
Hz), 131.2 (d, J = 13.0 Hz), 130.2 (d, J = 8.0 Hz), 127.5 (d, J = 24.0 Hz), 127.0 (d, J = 6.0 Hz),
126.8 (d, J = 12.0 Hz), 115.8 (d, J = 21.0 Hz), 62.3 (d, J = 45.0 Hz), 52.3 (d, J = 6.0 Hz), 49.5, (d,
J = 11.0 Hz), 20.1 (d, J = 6.0 Hz). TOF-HRMS Calcd. for C17H19NO2F [M+H+]: 288.1394, found
288.1396.
(-)-Methyl 2-(((2-methoxyphenyl)(phenyl)methyl)amino)acetate (2f): 27.4 mg, Yield: 96%; 95%
ee; [α]D20 = -16.4 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 7.3 min (minor), tB = 8.3 min (major). H NMR (CDCl3,
400 MHz) δ: 7.50-7.40 (m, 3H), 7.31-7.19 (m, 4H), 6.97-6.93 (m, 1H), 6.85-6.81 (m, 1H), 5.25 (s,
1H), 3.78 (m, 3H), 3.71(m, 3H), 3.40 (m, 2H), 2.23 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ:
173.5, 157.5, 143.5, 131.7, 128.8, 128.2, 127.4, 121.3, 111.1, 60.1, 55.9, 52.3, 49.7. TOF-HRMS
Calcd. for C17H20NO3 [M+H+]: 286.1437, found 286.1440.
(-)-Methyl 2-(((2-chlorophenyl)(phenyl)methyl)amino)acetate (2g): 28.1 mg, Yield: 97%; 97%
ee; [α]D20 = -25.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.3 min (minor), tB = 7.1 min (major). H NMR (CDCl3,
400 MHz) δ: 7.68-7.66 (m, 1H), 7.40-7.38 (m, 2H), 7.29-7.12 (m, 6H), 5.32 (s, 1H), 3.68 (s, 3H),
3.34 (q, J = 17.4, 39.9 Hz, 2H), 2.17 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3, 142.4,
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140.7, 134.2, 129.1, 129.0, 128.9, 128.4, 128.0, 127.7, 62.7, 52.4, 49.5. TOF-HRMS Calcd. for
C16H17NO2Cl [M+H+]: 290.0942, found 290.0944.
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(-)-Methyl 2-(((2-chlorophenyl)(3-methoxyphenyl)methyl)amino)acetate (2h): 30.7 mg, Yield:
96%; 95% ee; [α]D20 = -22.4 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 8.3 min (minor), tB = 9.2 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.69-7.67 (m, 1H), 7.32-7.14 (m, 4H), 7.03-6.99 (m, 2H), 6.78-6.75 (m, 1H),
5.34 (s, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.38 (q, J = 17.4, 20.5 Hz, 2H), 2.20 (s, 1H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 173.3, 160.3, 144.0, 140.7, 134.2, 130.2, 130.0, 129.1, 128.9, 127.7, 120.7,
114.0, 113.2, 62.5, 55.7, 52.4, 49.5. TOF-HRMS Calcd. for C17H19NO3Cl [M+H+]: 320.1047,
found 320.1049.
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(-)-Methyl 2-(((2-chlorophenyl)(m-tolyl)methyl)amino)acetate (2i): 29.5 mg, Yield: 97%; 97%
ee; [α]D20 = -18.2 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 7.9 min (minor), tB = 8.4 min (major). H NMR (CDCl3,
400 MHz) δ: 7.65-7.63 (m, 1H), 7.26-7.10 (m, 6H), 6.98 (t, J = 7.0 Hz, 1H), 5.26 (s, 1H), 3.66 (s,
3H), 3.31 (q, J = 17.4, 21.9 Hz, 2H), 2.25 (s, 3H), 2.13 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz)
δ: 173.4, 142.3, 140.8, 138.7, 134.2, 130.3, 129.2, 129.0, 128.9, 128.8, 128.7, 127.7, 125.4, 62.6,
52.4, 49.6, 22.1. TOF-HRMS Calcd. for C17H19NO2Cl [M+H+]: 304.1098, found 304.1100.
(-)-Methyl 2-(((2-chlorophenyl)(p-tolyl)methyl)amino)acetate (2j): 29.8 mg, Yield: 98%; 96%
ee; [α]D20 = -25.9 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 5.6 min (minor), tB = 6.5 min (major). H NMR (CDCl3,
400 MHz) δ: 7.74-7.72 (m, 1H), 7.33-7.26 (m, 4H), 7.19-7.11 (m, 3H), 5.34 (s, 1H), 3.39 (q, J =
17.4, 22.6 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3, 140.9,
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139.3, 137.6, 134.1, 130.2, 129.7, 129.0, 128.7, 128.2, 127.7, 62.4, 52.4, 49.5, 21.6. TOF-HRMS
Calcd. for C17H19NO2Cl [M+H+]: 304.1098, found 304.1100.
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(-)-Methyl 2-(((2-chlorophenyl)(4-fluorophenyl)methyl)amino)acetate (2k): 30.1 mg, Yield:
98%; 97% ee; [α]D20 = -19.6 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.2 min (minor), tB = 7.3 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.70-7.68 (m, 1H), 7.40-7.15 (m, 5H), 7.00-6.95 (m, 2H), 5.33 (s, 1H), 3.72
(s, 3H), 3.35 (q, J = 17.4, 23.8 Hz, 2H), 2.17 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3,
162.6 (d, 1JC-F = 244.0 Hz), 140.5, 138.2, 138.1, 134.1, 130.4, 130.0 (d, J = 8.0 Hz), 129.0 (d, J =
15.0 Hz), 127.8, 115.9 (d, J = 22.0 Hz), 62.0, 52.5, 49.4. TOF-HRMS Calcd. for C16H16NO2FCl
[M+H+]: 308.0848, found 308.0848.
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(-)-Methyl 2-(((2-chlorophenyl)(4-chlorophenyl)methyl)amino)acetate (2l): 31.4 mg, Yield:
97%; 97% ee; [α]D20 = -28.2 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.7 min (minor), tB = 8.2 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.67-7.65 (m, 1H), 7.37-7.25 (m, 6H), 7.20-7.17 (m, 1H), 5.32 (s, 1H), 3.72
(s, 3H), 3.35 (q, J = 17.4, 22.4 Hz, 2H), 2.13 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.2,
140.9, 140.3, 134.1, 133.7, 130.4, 129.8, 129.2, 129.1, 128.9, 127.8, 62.0, 52.5, 49.4. TOF-HRMS
Calcd. for C16H16NO2Cl2 [M+H+]: 324.0552, found 324.0551.
(-)-Methyl 2-(((2-bromophenyl)(phenyl)methyl)amino)acetate (2m): 32.8 mg, Yield: 98%; 96%
ee; [α]D20 = -14.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.7 min (minor), tB = 7.5 min (major). H NMR (CDCl3,
400 MHz) δ: 7.63-7.60 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.27-7.22 (m,
3H), 7.19-7.16 (m, 1H), 7.05-7.00 (m, 1H), 5.27 (s, 1H), 3.66 (s, 3H), 3.31 (q, J = 17.4, 22.4 Hz,
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2H), 2.15 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3, 142.3, 142.2, 133.6, 129.6, 129.2,
129.0, 128.4, 128.3, 128.0, 124.8, 65.0, 52.4, 49.5. TOF-HRMS Calcd. for C16H17NO2Br [M+H+]:
334.0437, found 334.0437.
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(-)-Methyl 2-(((2-bromophenyl)(3-fluorophenyl)methyl)amino)acetate (2n): 33.8 mg, Yield:
96%; 94% ee; [α]D20 = -20.5 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.5 min (minor), tB = 7.8 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.51-7.49 (m, 1H), 7.40-7.38 (m, 1H), 7.21-6.95 (m, 5H), 6.81-6.77 (m, 1H),
5.21 (s, 1H), 3.59 (s, 3H), 3.22 (q, J = 17.4, 21.6 Hz, 2H), 2.07 (s, 1H). 13C{1H}NMR (CDCl3, 100
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MHz) δ: 173.2, 163.5 (d, JC-F = 244.0 Hz), 145.1, 145.0, 141.6, 133.6, 130.5 (d, J = 8.0 Hz),
129.5, 128.5, 124.7, 124.0 (d, J = 3.0 Hz), 115.2 (d, J = 22.0 Hz), 114.9 (d, J = 21.0 Hz), 64.4 (d, J
= 1.0 Hz), 52.5, 49.4. TOF-HRMS Calcd. for C16H16NO2FBr [M+H+]: 352.0342, found 352.0342.
(-)-Methyl 2-(((2-bromophenyl)(4-fluorophenyl)methyl)amino)acetate (2o): 34.2 mg, Yield:
97%; 98% ee; [α]D20 = -22.4 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.1 min (minor), tB = 7.0 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.68-7.65 (m, 1H), 7.52-7.30 (m, 4H), 7.12-7.08 (m, 1H), 7.00-6.96 (m, 2H),
5.30 (s, 1H), 3.72 (s, 3H), 3.35 (q, J = 17.4, 24.8 Hz, 2H), 2.13 (s, 1H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 173.2, 162.6 (d, 1JC-F = 244.0 Hz), 141.9, 138.1, 133.6, 130.1 (d, J = 8.0 Hz), 129.3 (d, J
= 6.0 Hz), 128.4, 124.7, 116.0, 115.8 (d, J = 21.0 Hz), 64.4, 52.4, 49.4. TOF-HRMS Calcd. for
C16H16NO2FBr [M+H+]: 352.0342, found 352.0342.
(-)-Methyl 2-(((2-bromophenyl)(4-chlorophenyl)methyl)amino)acetate (2p): 36.1 mg, Yield:
98%; 96% ee; [α]D20 = -21.9 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.7 min (minor), tB = 7.9 min (major). 1H NMR
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(CDCl3, 400 MHz) δ: 7.67-7.65 (m, 1H), 7.52-7.50 (m, 1H), 7.40-7.25 (m, 5H), 7.12-7.07 (m, 1H),
5.32 (s, 1H), 3.72 (s, 3H), 3.37-3.35 (m, 2H), 2.19 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ:
173.1, 141.7, 140.8, 133.7, 133.6, 129.8, 129.4, 129.3, 129.2, 128.4, 124.6, 64.3, 52.4, 49.3.
TOF-HRMS Calcd. for C16H16NO2ClBr [M+H+]: 368.0047, found 368.0046.
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(+)-Methyl 2-(((2-fluorophenyl)(phenyl)methyl)amino)acetate (2q): 27.0 mg, Yield: 99%; 94%
ee; [α]D20 = +12.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 5:95, 1.0 mL/min, 254 nm; tA = 8.0 min (minor), tB = 8.5 min (major). H NMR (CDCl3,
400 MHz) δ: 7.59-7.55 (m, 1H), 7.39 (d, J = 7.4 Hz, 2H), 7.29-7.09 (m, 5H), 6.97-6.92 (m, 1H),
5.20 (s, 1H), 3.68 (m, 3H), 3.36 (s, 2H), 2.18 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3,
161.1 (d, 1JC-F = 244.0 Hz), 142.7, 130.8, 130.6, 129.2, 129.1, 128.6 (d, J = 4.0 Hz), 128.0, 124.9
(d, J = 4.0 Hz), 116.0 (d, J = 22.0 Hz), 59.4 (d, J = 3.0 Hz), 52.4, 49.5. TOF-HRMS Calcd. for
C16H17NO2F [M+H+]: 274.1237, found 274.1238.
(+)-Methyl 2-(((2-fluorophenyl)(m-tolyl)methyl)amino)acetate (2r): 28.4 mg, Yield: 99%; 94%
ee; [α]D20 = +10.4 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 8.4 min (minor), tB = 9.0 min (major). H NMR (CDCl3,
400 MHz) δ: 7.61 (t, J = 6.8 Hz, 1H), 7.24-6.96 (m, 7H), 5.20 (s, 1H), 3.72 (s, 3H), 3.40 (s, 2H),
2.32 (s, 3H), 2.19 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.3, 161.1 (d, 1JC-F = 244.0 Hz),
142.6, 138.7, 130.8 (d, J = 7.0 Hz), 129.1 (d, J = 8.0 Hz), 128.9, 128.7, 128.6 (d, J = 4.0 Hz),
125.0, 124.9 (d, J = 3.0 Hz), 116.1, 115.9, 59.3 (d, J = 2.0 Hz), 52.4, 49.4, 30.3, 22.0. TOF-HRMS
Calcd. for C17H19NO2F [M+H+]: 288.1394, found 288.1396.
(+)-Methyl 2-(((2-fluorophenyl)(4-fluorophenyl)methyl)amino)acetate (2s): 28.5 mg, Yield:
98%; 94% ee; [α]D20 = +14.6 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60
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mm), ipa : hex = 10:90, 1.0 mL/min, 254 nm; tA = 5.7 min (minor), tB = 6.1 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.60-7.56 (m, 1H), 7.41-7.37 (m, 2H), 7.22-7.11 (m, 2H), 7.00-6.96 (m, 3H),
5.21 (s, 1H), 3.72 (s, 3H), 3.37 (s, 2H), 2.15 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 173.2,
162.6 (d, 1JC-F = 244.0 Hz), 161.0 (d, 1JC-F = 245.0 Hz), 138.4 (d, J = 3.0 Hz), 130.6 (d, J = 12.0
Hz), 129.6 (d, J = 8.0 Hz), 129.3, (d, J = 8.0 Hz), 128.4 (d, J = 4.0 Hz), 125.0, (d, J = 4.0 Hz),
115.9 (d, J = 14.0 Hz), 58.7 (d, J = 3.0 Hz), 52.4, 49.3, 30.2. TOF-HRMS Calcd. for C16H16NO2F2
[M+H+]: 292.1143, found 292.1145.
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(-)-Methyl 2-((naphthalen-1-yl(phenyl)methyl)amino)acetate (2t): 29.9 mg, Yield: 98%; 95%
ee; [α]D20 = -23.5 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
hex = 10:90, 1.0 mL/min, 254 nm; tA = 9.1 min (major), tB = 15.7 min (minor). 1H NMR (CDCl3,
400 MHz) δ: 8.17 (d, J = 7.7 Hz, 1H), 7.87-7.78 (m, 3H), 7.53-7.45 (m, 5H), 7.33-7.21 (m, 3H),
5.71 (s, 1H), 3.73 (s, 3H), 3.50 (q, J = 17.6, 27.8 Hz, 2H), 2.27 (s, 1H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 173.7, 143.1, 138.4, 134.5, 131.9, 129.4, 129.1, 128.5, 128.4, 127.9, 126.6, 126.1, 126.0,
125.2, 124.0, 62.6, 52.4, 49.6. TOF-HRMS Calcd. for C20H20NO2 [M+H+]: 306.1488, found
306.1487.
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(+)-Ethyl 2-((phenyl(o-tolyl)methyl)amino)acetate (2u): 28.0 mg, Yield: 98%; 97% ee; [α]D
=
+23.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex = 10:90,
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1.0 mL/min, 254 nm; tA = 6.4 min (minor), tB = 6.8 min (major). H NMR (CDCl3, 400 MHz) δ:
7.66 (d, J = 7.6 Hz, 1H), 7.37-7.11 (m, 8H), 5.10 (s, 1H), 4.19 (q, J = 7.1, 30.8 Hz, 2H), 3.39 (q, J
= 17.5, 22.0 Hz, 2H), 2.28 (s, 3H), 2.11 (s, 1H), 1.27 (t, J = 7.5 Hz, 3H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 173.2, 142.9, 141.2, 136.5, 131.1, 129.0, 128.6, 127.7, 127.4, 127.2, 126.7, 62.8,
61.3, 49.7, 20.1, 14.8. TOF-HRMS Calcd. for C18H22NO2 [M+H+]: 284.1645, found 284.1644.
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(+)-tert-Butyl 2-((phenyl(o-tolyl)methyl)amino)acetate (2v): 30.5 mg, Yield: 98%; 97% ee;
[α]D20 = +20.5 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60 mm), ipa : hex
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= 3:97, 1.0 mL/min, 254 nm; tA = 5.3 min (minor), tB = 5.9 min (major). H NMR (CDCl3, 400
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MHz) δ: 7.68 (d, J = 7.7 Hz, 1H), 7.37-7.10 (m, 8H), 5.08 (s, 1H), 3.28 (q, J = 17.4, 25.5 Hz, 2H),
2.28 (s, 3H), 2.14 (s, 1H), 1.47 (s, 9H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.5, 143.1, 141.4,
136.5, 131.1, 129.0, 128.6, 127.6, 127.4, 127.2, 126.8, 81.7, 62.8, 50.6, 28.7, 20.1. TOF-HRMS
Calcd. for C20H26NO2 [M+H+]: 312.1958, found 312.1957.
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(+)-N-Methyl-1-phenyl-1-(o-tolyl)methanamine (2w): 20.7 mg, Yield: 98%; 99.4% ee; [α]D
=
+16.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60 mm), ipa : hex = 10:90,
1.0 mL/min, 254 nm; tA = 9.0 min (major), tB = 10.4 min (minor). 1H NMR (CDCl3, 400 MHz) δ:
7.60-7.58 (m, 1H), 7.34-7.11 (m, 8H), 4.88 (s, 1H), 2.43 (s, 3H), 2.30 (s, 3H), 1.56 (s, 1H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 143.0, 141.4, 135.8, 130.5, 128.4, 128.0, 127.0, 126.7, 126.3,
126.2, 65.3, 35.3, 19.6. TOF-HRMS Calcd. for C15H18N [M+H+]: 212.1433, found 212.1435. The
analytical data are in accordance with those reported in the literature.17
(+)-N-(Phenyl(o-tolyl)methyl)ethanamine (2x): 22.1 mg, Yield: 98%; 99 % ee; [α]D20 = +14.0 (c
= 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60 mm), ipa : hex = 5:95, 1.0
1
mL/min, 254 nm; tA = 9.4 min (major), tB = 13.6 min (minor). H NMR (CDCl3, 400 MHz) δ:
7.54-7.53 (m, 1H), 7.29-7.06 (m, 8H), 4.96 (s, 1H), 2.61-2.56 (m, 2H), 2.24 (s, 3H), 1.35 (s, 1H),
1.10-1.07 (m, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 143.9, 142.3, 136.3, 131.0, 128.9, 128.5,
127.4, 127.2, 127.0, 126.7, 63.9, 43.3, 20.2, 16.1. TOF-HRMS Calcd. for C16H20N [M+H+]:
226.1590, found 226.1589.
Procedure for the synthesis of compound 3: A 25 mL round bottom flask was charged with
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compound 2 (0.5 mmol), MeOH (5 mL), K2CO3 (0.5 mmol or 1.0 mmol) and 10% Pd/C (10 mg).
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material was detected by TLC. The catalyst was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified via flash chromatography to afford 3 as yellow oil.18
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(-)-Methyl 2-((phenyl(m-tolyl)methyl)amino)acetate (3a): 127 mg, Yield: 95%; 97% ee; [α]D
= -23.5 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex =
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10:90, 1.0 mL/min, 254 nm; tA = 6.4 min (major), tB = 6.9 min (minor). H NMR (CDCl3, 400
MHz) δ: 7.30-6.90 (m, 9H), 4.72 (s, 1H), 3.59 (s, 3H), 3.27 (s, 2H), 2.19 (s, 3H), 2.11 (s, 1H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 173.0, 143.3, 143.1, 138.2, 128.6, 128.5, 128.0, 127.4, 127.2,
124.4, 66.6, 51.8, 48.9, 21.5. TOF-HRMS Calcd. for C17H20NO2 [M+H+]: 270.1488, found
270.1490.
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(+)-Methyl 2-((phenyl(p-tolyl)methyl)amino)acetate (3b): 128 mg, Yield: 96%; 96% ee; [α]D
= -18.0 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex = 3:97,
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1.0 mL/min, 254 nm; tA = 8.0 min (minor), tB = 9.2 min (major). H NMR (CDCl3, 400 MHz) δ:
7.28-6.97 (m, 9H), 4.71 (s, 1H), 3.58 (s, 3H), 3.25 (s, 2H), 2.17 (s, 3H), 2.07 (s, 1H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 173.1, 143.4, 140.3, 136.9, 129.3, 128.6, 127.3, 127.2, 127.1,
66.3, 51.8, 48.9, 21.1. TOF-HRMS Calcd. for C17H20NO2 [M+H+]: 270.1488, found 270.1490.
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(-)-Methyl 2-(((3-fluorophenyl)(phenyl)methyl)amino)acetate (3c): 128 mg, Yield: 94%; [α]D
= -15.2 (c = 0.5, CH2Cl2); 94% ee; HPLC condition: Lux 5u Amylose-2 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.5 min (minor), tB = 6.7 min (major). H NMR (CDCl3,
400 MHz) δ: 7.26-7.01 (m, 8H), 6.79-6.74 (m, 1H), 4.74 (s, 1H), 3.58 (s, 3H), 3.25-3.21 (m, 2H),
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2.07 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.9, 163.1 (d, 1JC-F = 244.0 Hz), 145.9 (d, J =
7.0 Hz), 142.7, 130.0 (d, J = 8.0 Hz), 128.7, 127.5, 127.3, 123.0, 122.9, 114.1 (d, J = 26.0 Hz),
66.1, 51.9, 48.7. TOF-HRMS Calcd. for C16H17NO2F [M+H+]: 274.1237, found 274.1238.
(-)-Methyl 2-(((4-fluorophenyl)(phenyl)methyl)amino)acetate (3d): 131 mg, Yield: 96%; 98%
ee; [α]D20 = -18.7 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
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hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.8 min (minor), tB = 7.2 min (major). H NMR (CDCl3,
400 MHz) δ: 7.39-7.20 (m, 7H), 7.00-6.95 (m, 2H), 4.86 (s, 1H), 3.71 (s, 3H), 3.36 (s, 2H).
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13C{1H}NMR (CDCl3, 100 MHz) δ: 173.0, 161.9 (d, JC-F = 244.0 Hz), 143.0, 139.0 (d, J = 3.0
Hz), 129.0 (d, J = 8.0 Hz), 128.7, 127.4 (d, J = 15.0 Hz), 115.5, 115.3, 65.8, 51.9, 48.8.
TOF-HRMS Calcd. for C16H17NO2F [M+H+]: 274.1237, found 274.1238.
(-)-Methyl 2-(((4-chlorophenyl)(phenyl)methyl)amino)acetate (3e): 138 mg, Yield: 96%; 96%
ee; [α]D20 = -20.3 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa :
1
hex = 10:90, 1.0 mL/min, 254 nm; tA = 6.9 min (minor), tB = 8.2 min (major). H NMR (CDCl3,
400 MHz) δ: 7.26-7.10 (m, 9H), 4.74 (s, 1H), 3.58 (s, 3H), 3.24 (s, 2H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 173.5, 143.3, 142.3, 133.5, 129.3, 129.2, 129.1, 128.0, 127.8, 66.4, 52.4, 49.3.
TOF-HRMS Calcd. for C16H15NO2Cl [M+H+]: 288.0785, found 288.0785.
Procedure for the synthesis of compound 4: A mixture of 3e (1.0 mmol), ICH2CO2C2H5 (1.1
mmol), and K2CO3 (1.0 mmol) in DMF (5.0 mL) was heated at 80-90 °C. The mixture was stirred
until no starting material was detected by TLC and then concentrated in vacuo. The residue was
extracted with EtOAc, washed with brine, dried over NaSO4 and concentrated in vacuo.
Purification by flash column chromatography on silica gel afforded 4 (316 mg) as yellow oil.14
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Yield: 84%; 95% ee; [α]D = -17.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u C-1 (250 × 4.60
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mm), ipa : hex = 20:80, 1.0 mL/min, 254 nm; tA = 5.9 min (minor), tB = 6.8 min (major). 1H NMR
(CDCl3, 400 MHz) δ: 7.28-7.04 (m, 9H), 5.20 (s, 1H), 3.99-3.94 (m, 2H), 3.50 (s, 3H), 3.41-3.38
(m, 4H),1.09-1.05 (m, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 172.4, 171.9, 142.1, 141.5, 133.5,
129.9, 129.4, 129.3, 128.6, 128.1, 60.9, 52.5, 52.4, 52.0, 14.7. TOF-HRMS Calcd. for
C20H23NO4Cl [M+H+]: 376.1310, found 376.1313.
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Procedure for the synthesis of compound 5: A solution of 2a or 3e (0.18 mmol) in dry THF (5.0
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mL) was added to a solution of LiAlH4 (1.05 mmol) in dry THF (10 mL) at 0 C under nitrogen.
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The mixture was stirred at 0 C until complete formation of the corresponding aminoalcohol was
observed by TLC. The reaction mixture was decomposed by the careful dropwise addition of
water (2.0 mL) and the product extracted with ethyl acetate. The combined organic layers were
dried over Na2SO4, concentrated and purified by column chromatography to give the
corresponding aminoalcohol.19 Lead acetate (0.148 mmol) was added to a solution of the
corresponding aminoalcohol (0.124 mmol), CH2Cl2 (0.5 mL), and MeOH (0.5 mL) at 0 °C. The
mixture was stirred at 0 °C for 30 min. Hydroxylamine hydrochloride (1.24 mmol) was added and
the mixture was stirred at 0 °C for 30 min before concentration in vacuo. The residue was
suspended in CH2Cl2 followed by filtration of the precipitate. The filtrate was extracted with 1 N
HCl. The combined aqueous layers were washed with Et2O, treated with 20% NaOH until pH 14
and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4,
concentrated and purified by column chromatography to afford 5 as yellow oil.15a
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(+)-Phenyl(o-tolyl)methanamine (5a): 21 mg, Yield: 87%; 97% ee; [α]D = +10.8 (c = 0.5,
CHCl3); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex = 10:90, 1.0 mL/min,
254 nm; tA = 5.8 min (minor), tB = 6.3 min (major). 1H NMR (CDCl3, 400 MHz) δ: 7.44-7.42 (m,
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1H), 7.19-7.00 (m, 8H), 5.26 (s, 1H), 2.14 (s, 3H), 1.66 (s, 2H). The analytical data are in
accordance with those reported in the literature.20
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(-)-(4-Chlorophenyl)(phenyl)methanamine (5b): 24 mg, Yield: 89%; 95% ee; [α]D20 = -6.9 (c =
0.5, EtOH); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60 mm), ipa : hex = 10:90, 1.0 mL/min,
254 nm; tA = 6.6 min (minor), tB = 7.8 min (major). 1H NMR (CDCl3, 400 MHz) δ: 7.37-7.21 (m,
9H) , 5.17 (s, 1H), 1.76 (s, 2H). The analytical data are in accordance with those reported in the
literature.21
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Experiments of Deuteration Reactions: A 50 mL round bottom flask was charged with
benzophenone imine (5.0 mmol) which was synthesized by d5-PhBr and 2-methylbenzonitrile,
glycine ester hydrochloride (6.0 mmol) and CH2Cl2 (10.0 mL). The milky white mixture was
stirred at rt-40 oC under an argon atmosphere until no starting material was detected by TLC. The
white insoluble substance was filtered and the filtrate was concentrated under reduced pressure.
The residue was purified via flash chromatography to provide the deuterium-labeling substrate.
The procedure of hydrogenation of this deuterium-labeling substrate was carried out under the
optimized reaction conditions according to the hydrogenation of substrates 1.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Grant No. 21272026, 21172022,
21472013), the Ministry of Education of China (the Fundamental Research Funds for the Central
Universities, Specialized Research Fund for the Doctoral Program of Higher Education of China
(20130003120012)), and Beijing Municipal Commission of Education for generous financial
support.
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