Synthesis of chiral α-amino anilides via a DMEDA-promoted selective C─N coupling reaction of aryl halides and α-aminoamides

Article abstract of DOI:10.1016/j.tet.2018.03.003

A DMEDA-promoted and copper-catalyzed approach has been designed for the coupling of aryl halides and chiral α-aminoamides to afford a range of functionalized chiral α-amino anilides. This method has a higher yield and better reproducibility than those under ligand-free conditions. Of the two amino groups in the same molecule, only the amide NH₂ is observed to react, showing high regioselectivity. In addition, no racemization occurs, and the ee can reach 99%. For certain hydroxyl-containing substrates, such as L-tyrosine amide and L-threonine amide, addition of a phase transfer catalyst (15-Crown-5) is necessary for such a transformation.

Full text of DOI:10.1016/j.tet.2018.03.003

Accepted Manuscript
Synthesis of chiral α-amino anilides via a DMEDA-promoted selective C─N coupling
reaction of aryl halides and α-aminoamides
Xiangting Min, Xiaoyu Li, Yu Wang, Yawen Dong, Jingjing Tang, Jing Wang, Jianhui
Liu
PII:
S0040-4020(18)30246-1
10.1016/j.tet.2018.03.003
TET 29343
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 December 2017
Revised Date: 27 February 2018
Accepted Date: 2 March 2018
Please cite this article as: Min X, Li X, Wang Y, Dong Y, Tang J, Wang J, Liu J, Synthesis of chiral
α-amino anilides via a DMEDA-promoted selective C─N coupling reaction of aryl halides and α-
aminoamides, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.003.
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Synthesis of chiral α-amino anilides via a
DMEDA-promoted selective C─N coupling
reaction of aryl halides and α-aminoamides
Leave this area blank for abstract info.
Xiangting Min a, Xiaoyu Li b, Yu Wang a, Yawen Dong c, Jingjing Tang c, Jing Wang c, Jianhui Liu a, c
*
aSchool of Petroleum and Chemical Engineering, Dalian University of Technology, Panjin Campus, Panjin,
Liaoning Province, 124221, P. R. China
bDalian Dechang Pharmaceutical Co., Distribution Branch of Medicine, Hutan Rd. No 11, Zhongshan District,
Dalian, Liaoning Province, P. R. China
cState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning Province, 116024,
P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of chiral α-amino anilides via a DMEDA-promoted selective C─N coupling
reaction of aryl halides and α-aminoamides
Xiangting Mina , Xiaoyu Lib, Yu Wanga, Yawen Dongc, Jingjing Tangc, Jing Wangc, Jianhui Liua,c,
aSchool of Petroleum and Chemical Engineering, Dalian University of Technology, Panjin Campus, Panjin, Liaoning Province, 124221, P. R. China
bDalian Dechang Pharmaceutical Co., Distribution Branch of Medicine, Hutan Rd. No 11, Zhongshan District, Dalian, Liaoning Province, P. R. China
cState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning Province, 116024, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A DMEDA-promoted and copper-catalyzed approach has been designed for the coupling of aryl
halides and chiral α-aminoamides to afford a range of functionalized chiral α-amino anilides.
This method has a higher yield and better reproducibility than those under ligand-free
conditions. Of the two amino groups in the same molecule, only the amide NH2 is observed to
react, showing high regioselectivity. In addition, no racemization occurs, and the ee can reach
99%. For certain hydroxyl-containing substrates, such as L-tyrosine amide and L-threonine
amide, addition of a phase transfer catalyst (15-Crown-5) is necessary for such a transformation.
Available online
Keywords:
Selective cross-coupling
α-Aminoamides
Copper-catalyst
2009 Elsevier Ltd. All rights reserved
1. Introduction
Chiral α-amino anilides are useful synthetic intermediates and
have a wide range of applications, especially in the field of
medicine, such as tocainide, an antiarrhythmic agent;7a
amoxicillin, a broad-spectrum antibiotic;7b histone deacetylases
for treating cancer and other disorders;7c pH-controlled, light-
activated reagents for cancer therapy;7d and antimalarial agents.7e
In addition, the proposed anilides can be used as ligands and
catalysts in organic synthesis.8 Since two amino groups exist on
the same chiral α-aminoamide moiety, the key to this reaction is
to control the selectivity of C─N coupling at the desired amino
group.8 The previous synthesis of chiral amino anilides involved
protection and deprotection of the amino group of the primary
amine, and these extra steps made the procedure cumbersome.9
Since its discovery, the Goldberg reaction (or the modified
Ullmann reaction) has evolved as a powerful tool for the
formation of Csp2─N single bonds.1 The N-arylation of amides
by aryl halides via the C─N coupling reaction offers an
alternative approach to the synthesis of N-arylamides.2 Compared
to the Pd-catalyzed Buchwald-Hartwig C─N coupling reaction,
Cu-catalyzed Goldberg C─N coupling is more practical since
competitive coupling to aliphatic NH2 rather than the amide NH2
is often observed in the Pd-catalyzed Buchwald-Hartwig
coupling reaction.2c However, the copper-catalyzed C─N
coupling reaction is sensitive to external conditions, and different
parameters will yield different coupling results.2b,3 In addition,
the typical copper-catalyzed Goldberg reaction requires a high
temperature, a stoichiometric amount of copper powder, and a
long reaction time, and these requirements limit the application
of such reactions.4 Many efforts have been made to overcome
these limitations, including the addition of ligands, such as β-
diketone,4 diamine,5a salicylamide,5b ethylene glycol,5c L-
proline,5d and 1,10-phenanthroline,5e to the reaction system, as
well as the use of other transition metals, such as manganese,6a
a
manganese/copper bimetallic catalyst,6b and Ni(acac)2.6c However,
more efforts are needed to selectively achieve the carbon-
nitrogen coupling of aryl halides and α-aminoamides bearing
sensitive groups, including hydroxyl, amino, and amide groups.
Scheme 1. Yields of the DMEDA-promoted and ligand-free methods.
In this investigation of the preparation of (S)-2-amino-N-2-
diphenyl acetamide (3a), a key intermediate in our synthesis of
Jianhui Liu. e-mail: liujh@dlut.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
epinastine, from iodobenzene (1a) and L-phenylglycinamide (2a)
in the presence of CuI and K2CO3 at 110 °C, we determined that
this ligand-free method afforded only a 30% isolated yield
(scheme 1, a).8 Repeated trials were completed, strictly following
the conditions reported; however, the highest yield was still no
more than 30%, which was far less than the 90% yield recorded
in the literature. Since this yield was far lower than expected and
could not meet the requirements of this study, we needed to
develop a high-yield method for the preparation of chiral amino
anilides. Herein, we report a copper-catalyzed, DMEDA-
promoted approach for the synthesis of chiral α-amino anilides.
of the base. In most cases, the choice of base has an important
effect on the reaction rate, and the reaction can be well conducted
if the rate for deprotonating and coupling can be properly
matched.10a Cs2CO3 was the optimal choice of base after
screening Cs2CO3, K3PO4, KOtBu, NaOH and K2CO3 (Table 1,
entries 9-12 and entry 1). In addition to the ligand and base used,
the nature of the solvent was investigated. An increase in the
desired product was obtained in toluene and xylene, and a
decrease was observed in DMF, DMSO, DMA and DMF/toluene
(Table 1, entries 13-17 and entry 9). Various Cu catalysts were
screened, and CuCl provided the best results among CuBr, CuCl,
CuCl2, Cu(acac)2, and CuO (Table 1, entries 18-23 and entry 9).
The temperature also significantly influenced the yield. At room
temperature, the reaction yield was 60%. Increasing the reaction
temperature to 50 °C substantially improved the yield to 90%. No
further improvements were observed when the temperature was
increased to 70 °C (Table 1, entries 24-26). The reaction time
was typically 18 hours, and altering the reaction time did not
increase the product formation (Table 1, entries 27-28). Thus, 1a
(1.2 eq.) and 2a (1 eq.) as the reactants, CuCl (10 mol%) as the
catalyst, DMEDA (1 eq.) as the ligand and toluene (4 mL) as the
solvent, a temperature of 50 °C, and a duration of 18 hours were
defined as the optimized reaction conditions for further studies
(Table 1, entry 25).
2. Results and discussion
We initially examined the reaction of iodobenzene (1a) with
L-phenylglycinamide (2a), which were used as the model
substrates for the optimization of the selective cross-coupling
conditions, and the results are shown in Table 1. Amide 3a was
formed in only 30% yield in the absence of ligands after all
attempts to follow the literature procedure (Table 1, entry1).8 We
found that DMEDA (1 eq.) effectively catalyzed the reaction
between 1a and 2a to give the desired 3a in a yield of 75%
(Table 1, entries 1-2). However, decreasing its loading to 0.5 and
0.2 eq. led to reduced yields of 66% and 34%, respectively,
which indicated the positive effects of the nitrogen ligands on the
cross-coupling reaction (Table 1, entries 3-4). When the reaction
was undertaken using other nitrogen-containing ligands, namely,
After establishing the feasibility of the reaction between
iodobenzene (1a) and L-phenylglycinamide (2a), we explore the
scope of the process with respect to ArX. In this case, 2a was
taken as the standard chiral α-aminoamide under the optimized
conditions mentioned above to react with aryl halides bearing
1,10-phenanthroline,
2,2'-bipyridine,
4,7-diphenyl-1,10-
phenanthroline, and 1,10-phenanthroline-5,6-dione, poor yields
that ranged from trace to 43% were obtained (Table 1, entries 5-
8). We then turned our attention to an examination of the effects
Table 1
Optimization of the reaction conditions.a
Entry
Ligand (eq.)
Base
Catalyst
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
3
─
K2CO3
K2CO3
K2CO3
CuI
CuI
CuI
toluene
toluene
toluene
110
110
110
24
18
18
30
75
66
DMEDA (1.0)
DMEDA (0.5)
4
DMEDA (0.2)
K2CO3
CuI
toluene
110
18
34
5
6
7
8
1,10 -phen (0.5)
bipy (0.5)
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
─
CuCl2
CuBr
CuCl
Cu(acac)2
CuO
CuCl
CuCl
CuCl
CuCl
CuCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
DMSO
DMA
DMF/ toluene 1/1
o-xyle
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
70
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
12
24
43
38
13
Trace
80
74
23
Trace
44
27
55
62
79
NR
68
82
87
72
85
4,7-diph-1,10-phen (0.5)
1,10-phen-5,6-dione (0.5)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
DMEDA (1.0)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
KOtBu
NaOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
86
90
60
86
50
r.t.
50
50
90
a Unless otherwise specified, the reactions were conducted with 1a (1.0 eq.), 2a (1.2 mmol), cat. (10 mol %), solvent (4.0 mL), base (2.0
eq.), ligand (X eq.) in a sealed reaction tube under N2.
b Yield of isolated product.

3
Table 3
diverse substituents on different positions of the phenyl ring. The
first eight substrates employed aryl iodides, which reacted with
ACCEPTED MANUSCRIPT
Substrate scope for various chiral α-aminoamides 2 and aryl halides
1a.a
1a to give 3a-3h in good to excellent yields. In addition to
iodobenzene, as mentioned previously (Table 2, entry 1), the
reaction tolerated a range of substituents on the phenyl ring,
including electron-donating Me and OMe (Table 2, entries 2-3)
and electron-withdrawing CO2Me, CF3 and Cl (Table 2, entries
4-6), except for p-NO2Ph, which decreased the yield of 3g to
60% (Table 2, entry 7). In all these cases, good to excellent
isolated yields of 83-92% were obtained. Entry 8 demonstrates
that fused rings such as naphthyl groups were also good
substrates, furnishing 3h in a yield of 91%. The reaction of
pyridine iodide bearing a 2-pyridyl group gave the corresponding
coupling product in a yield of 85% (Table 2, entry 9).
Bromoarenes and chloroarene such as PhBr (1j), 3-
bromopyridine (1k) and PhCl (1l) were also compatible with the
reaction, and the corresponding products, 3a, 3i and 3a, were
afforded in 50%, 55% and 40% yields, respectively (Table 2,
entries 10-12). In some cases, a higher temperature was
unfavorable for the conversion, and many by-products were
produced from reactions of 4-NO2-C6H4I (1g), 4-MeO-C6H4I (1c),
3-iodopyridine (1i) and 3-bromopyridine (1k) at 110 °C,
resulting in difficult product isolation. Therefore, a lower
temperature is essential for the DMEDA-promoted cross-
coupling reaction.
Entry
1c
Chiral α-Aminoamides
Product
Yield %b
88
90
2a
3a
(-)-3a
3j
2d
3
(+)-2a
2b
88
4
60
2c
3k
5
82 (92)e
84 (96)e
75
2d
2e
3l
Table 2
Substrate scope for various aryl halides 1 and L-phenylglycinamide
2a.a
6
3m
3n
7d
Entry
1
ArX
Product
3a
Yield %b
90
2f
PhI (1a)
2
2-Me-C6H4I (1b)
4-MeO-C6H4I (1c)
2-I-C6H4COOCH3 (1d)
2-I-C6H4CF3 (1e)
3-Cl-C6H4I (1f)
4-NO2-C6H4I (1g)
1-I-naphthalene (1h)
3-I-pyridine (1i)
PhBr (1j)
3b
3c
91
8
75
3
92
(±)-2f
(±)-3n
3o
4
3d
3e
83
5
92
9g
10
11 g
20 (74)f
Trace (67)f
Trace (54)f
6
3f
89
2g
7
3g
60
8
3h
3i
91
9
85
2h
2i
3p
3q
10
11
12
3a
50
3-Br-pyridine (1k)
PhCl (1l)
3i
55
3a
40
a Unless otherwise specified, the reaction was conducted with 1a (1.0
mmol), 2 (1.2 mmol), CuCl (0.1 mmol), DMEDA (1.0 mmol),
Cs2CO3 (2.0 mmol), and toluene (4.0 mL) at 50 °C for 18 h under N2.
b Yield of isolated product.
a Unless otherwise specified, the reaction was conducted with 1 (1.0
mmol), 2a (1.2 mmol), CuCl (0.1 mmol), DMEDA (1.0 mmol),
Cs2CO3 (2.0 mmol), and toluene (4.0 mL) at 50 °C 18 h under N2.
b Yield of isolated product.
c 2a with 82.6% optical purity
d 99% enantiomeric excess (ee) was obtained (Chiral HPLC trace is
given in the Supporting Information).
The scope of the chiral α-aminoamides was investigated under
the same reaction conditions as those summarized in Table 3.
Various α-aminoamide derivatives (2a-2g) were tolerated in the
coupling reaction, and most of them gave the corresponding N-
aryl aminoamide (chiral α-amino anilides) in good to excellent
yields. For instance, phenylglycinamide 2a (with 82.6% optical
purity)11 and L-phenylglycinamide ((+)-2a) as a pure enantiomer
gave good yields (Table 3, entries 1-2). Other aminoamides, D-
phenylalaninamide (2b), L-alaninamide (2c), L-valinamide (2d)
and L-leucinamide (2e), with different chain lengths provided the
e This reaction was conducted at 110 °C.
f Increase in the reaction temperature to 110 °C while adding a phase
transfer catalyst, 15-Crown-5 (0.2 mmol).
g Cs2CO3 (3.0 mmol) was used.
desired products 3j-m in 60-88% yields (Table 3, entries 3-6). At
a higher temperature of 110 °C, the yields of 3l and 3m increased
to 92% and 96%, compared to 82% and 84% at 50 °C,
respectively (Table 3, entries 5-6). Both L-prolinamide (2f) and

4
Tetrahedron
ACCEPTED MANUSCRIPT
D/L-phenylalaninamide ((±)-2f), which contain a saturated five-
membered ring, gave a slightly lower yield (75%) (Table 3,
entries 7-8). The reactant L-tryptophanamide (2g), which bears
an indolyl moiety, proved to be less effective (yield of only 20%),
but if the temperature was increased to 110 °C and a phase
transfer catalyst such as tetrabutyl ammonium bromide (TBAB)
or 15-Crown-5 was used, good yields of up to 70% and 74%
respectively were observed (Table 3, entry 9). As recorded in the
literature, the reaction of L-tyrosinamide (2h) and L-
threoninamide (2i), which bear an additional hydroxyl group,
cannot occur using the method developed by Zeng.8 In contrast,
these two substrates were good candidates for the reaction
developed in the present study. At first, trace products were
detected under these conditions. Further modification at 110 °C
using 15-Crown-5 as a phase transfer catalyst led to much
improved yields of 67% for L-tyrosinamide and 54% for L-
threoninamide (Table 3, entries 10-11). Notably, the
corresponding yields were only 14% and 10%, respectively,
without the use of a phase transfer catalyst. The phase transfer
catalyst plays a critical role in the reaction of α-aminoamides
containing a hydroxy group.
regioselectivity make this method an attractive complement to
the existing ligand-free C─N coupling reactions.
Scheme 3. Proposed catalytic pathway to produce 3
4. Experimental section
4.1. General
To verify whether racemization occurred during the C─N
cross coupling, the ee of products 3a and 3n was analyzed by
chiral HPLC (Table 3, entry 2 and entry 7). The ee values of (-)-
3a and 3n were 99% with a high level of stereoselectivity (the
optical purity of the raw material is 98%), which means that no
All reactions were carried out in a Schlenk-type tube (25 mL)
under a nitrogen atmosphere, unless otherwise indicated. An oil
bath was used as a heating source. All reagents were purchased
from commercial sources and used without further treatment, but
the solvents used in the reaction were subjected to anhydrous
anaerobic treatment before use. NMR spectra were recorded on a
racemization occurred during coupling. We obtained
a
satisfactory optical purity without reducing the yield.8 Finally, to
illustrate the synthetic potential of this method, we performed a
gram-scale synthesis of the chiral amino acid anilide 3a and
obtained an overall yield of 89 % upon isolation (Scheme 2).
1
Bruker Avance II 400 NMR spectrometer (400 MHz for H; 100
MHz for 13C). CDCl3 and d6-DMSO were used as the NMR
solvent. Chemical shifts are reported in parts per million. Data
were reported as follows: chemical shift, multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant
(hertz, Hz), and integration. High-resolution mass spectrometry
(HRMS) spectra were recorded on a quadrupole analyzer using
an ESI source (Agilent Technologies G6224A). TLC was
performed using commercially prepared 100-400-mesh silica gel
GF254 (Qingdao Haiyang Chemical Co., Ltd.) plates, and
visualization was achieved at 254 nm.
Scheme 2. Gram-scale synthesis of the chiral amino acid anilide 3a.
Based on previous related works and the above
results,3b,4,8,10b,10c a proposed catalytic pathway for the formation
of 3 is outlined in Scheme 3. The copper complex A is initially
formed by the reaction of CuCl and DMEDA. Then the ligand
exchange with the amino amide 2 would afford the Cu(III)
complex B, which could undergo oxidative addition to give the
Cu(III) complex C. The reductive elimination of C would deliver
the coupling product and regenerate complex A. A lower
transition-state energy for the ligand exchange to Cu(I)-amide
complexes than for the ligand exchange to Cu(I)-aliphatic amine
complexes might make the formation of intermediate B easier;
therefore, the coupling reaction could proceed smoothly. 12
4.2.1 General Procedure for the chiral α-amino anilides (3a-3n)
A 25-mL Schlenk-type tube equipped with a magnetic stir bar
was charged with a chiral amino acid amide or its hydrochloride
(1.2 mmol), Cs2CO3 (2.0 mmol; 3.0 mmol was used when an
amino acid amide hydrochloride was used), and CuCl (0.1 mmol)
before sealing. A syringe was used under a nitrogen atmosphere
to add aryl halide (1.0 mmol), DMEDA (1.0 mmol) and toluene
(4.0 mL). If aryl halides were solid at room temperature, they
were added with CuCl and Cs2CO3 at the same time. The tube
was placed into an oil bath pot preheated to 50 °C and stirred at a
steady temperature for 18 h. The reaction mixture was then
cooled to room temperature, quenched with water, and extracted
with ethyl acetate (20 mL) three times. The organic layers were
combined, dried over anhydrous Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with a solution of
dichloromethane and ethyl alcohol (80/1 to 10/1) to afford the
chiral α-amino anilides.
3. Conclusion
In summary, a DMEDA-promoted and copper-catalyzed
approach has been designed for the synthesis of chiral α-amino
anilides from aryl halides and chiral α-aminoamides. This
process produced a useful N-aryl-substituted amide in good to
excellent yields via a C─N cross-coupling reaction, with a much
broader substrate scope compared to previous methods. The
result from the addition of DMEDA was significantly better than
that without using any ligands, which was confirmed by the
reactivity of substrates L-tryptophanamide (2g), L-tyrosine amide
(2h) and L-threonine amide (2i). Two chiral α-amino anilides
with high ee were obtained with retention at the chiral carbon
atom. The mild reaction conditions and the high level of
4.2.2 General procedure for Chiral α-Amino Acid Anilides (3o-
3q)
A 25-mL of Schlenk-type tube equipped with a magnetic stir bar
was charged with a chiral amino acid amide or its hydrochloride

5
ACCEPTED MANUSCRIPT
(1.2 mmol), Cs2CO3 (2.0 mmol; 3.0 mmol used when amino acid
amide hydrochloride was used), and CuCl (0.1 mmol) before
sealing. A syringe was used under a nitrogen atmosphere to add
aryl halide (1.0 mmol), DMEDA (1.0 mmol), toluene (4.0 mL)
and 15-Crown-5 (0.2 mmol). The tube was put into an oil bath
pot preheated at 110 °C and was stirred at a steady temperature
for 18 h. The reaction mixture was then cooled to room
temperature, quenched with water, and extracted with ethyl
acetate (20 mL) three times. The organic layers were combined,
dried over anhydrous Na2SO4, and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
Yellow solid, 270 mg, yield: 92%. 1H NMR (400 MHz,
CDCl3): δ 10.08 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 7.8
Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.1 Hz, 2H), 7.25-
7.15 (m, 3H), 7.03 (t, J = 7.6 Hz, 1H), 4.49 (s, 1H), 1.87 (s, 2H).
13C NMR (100 MHz, CDCl3): δ 171.5, 140.2, 135.3, 132.7, 128.8,
128.1, 126.7, 125.8 (q, J = 5.4 Hz), 125.4, 123.7, 122.7, 119.2 (d,
J = 29.8 Hz), 60.2. HRMS (ESI) m/z: Calcd for C15H14F3N2O ([M
+ H]+) 295.1058, found 295.1050.
4.3.6 (S)-2-amino-N-(3-chlorophenyl)-2-phenylacetamide (3f)13b
silica gel column chromatography with
a
solution of
White solid, 231 mg, yield: 89%. 1H NMR (400 MHz, CDCl3):
δ 9.41 (s, 1H), 7.64 (s, 1H), 7.41-7.32 (m, 3H), 7.30-7.12 (m, 3H),
7.19-7.11 (m, 1H), 6.99 (d, J = 7.9 Hz, 1H), 4.56 (s, 1H), 1.77 (s,
2H). 13C NMR (100 MHz, CDCl3): δ 171.1, 140.3, 138.8, 134.7,
123.0, 129.0, 128.3, 126.8, 124.2, 119.6, 117.4, 60.3.
dichloromethane and ethyl alcohol (80/1 to 10/1) to afford the
chiral α-amino anilides.
4.3.1 (S)-2-amino-N,2-diphenylacetamide (3a)8
White solid, 203 mg, yield: 90%, 99% ee (HPLC, Diacel
Chiralcel OD-H column, 70:30 hexanes/2-propanol, 0.8 mL/min,
254 nm; (S)-2-amino-N,3-diphenylpropanamide, rt = 10.482 min;
(R)-2-amino-N,3-diphenyl-propanamide, rt = 11.570 min). 1H
NMR (400 MHz, CDCl3): δ 9.29 (s, 1H), 7.52 (d, J = 7.8 Hz,
2H), 7.37 (d, J = 7.1 Hz, 2H), 7.33-7.20 (m, 5H), 7.02 (t, J = 7.4
Hz, 1H), 4.57 (s, 1H), 1.75 (s, 2H). 13C NMR (100 MHz, DMSO-
d6): δ 172.3, 142.3, 138.8, 128.7, 128.1, 127.1, 126.7, 123.3,
119.2, 59.6.
4.3.7 (S)-2-amino-N-(4-nitrophenyl)-2-phenylacetamide (3g)13b
Yellow solid, 162 mg, yield: 60%. 1H NMR (400 MHz,
CDCl3): δ 9.94 (s, 1H), 8.21 (d, J = 9.1 Hz, 2H), 7.78 (d, J = 9.1
Hz, 2H), 7.46-7.29 (m, 5H), 4.69 (s, 1H), 1.97 (s, 2H). 13C NMR
(100 MHz, CDCl3): δ 171.8, 143.4, 143.3, 139.9, 129.0, 128.3,
126.7, 124.9, 118.9, 60.2.
4.3.8 (S)-2-amino-N-(naphthalen-1-yl)-2-phenylacetamide (3h)14a
4.3.2 (S)-2-amino-N-(2-methylphenyl)-2-phenylacetamide (3b)13a
White solid, 251 mg, yield: 91%. 1H NMR (400 MHz, CDCl3):
White solid, 218 mg, yield: 91%. 1H NMR (400 MHz, CDCl3):
δ 9.45 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H),
7.40-7.28 (m, 3H), 7.24-7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H),
4.61 (s, 1H), 2.26 (s, 3H), 2.05 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 170.9, 140.6, 135.6, 130.1, 128.7, 127.84, 127.80,
126.7, 126.5, 124.3, 121.1, 60.2, 17.4.
δ
9.99 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.72-7.62 (m, 2H), 7.45
(d, J = 8.2 Hz, 1H), 7.34-7.20 (m, 5H), 7.08-7.19 (m, 3H), 4.45 (d,
J = 4.2 Hz, 1H), 1.90 (s, 2H). 13C NMR (100 MHz, CDCl3): δ
171.4, 140.6, 133.8, 132.1, 128.7, 128.5, 127.9, 126.7, 126.1,
126.0, 125.7, 125.6, 124.8, 120.1, 118.4, 60.3.
4.3.9 (S)-2-amino-2-phenyl-N-(pyridin-3-yl)acetamide (3i)
White solid, 193 mg, yield: 85%. 1H NMR (400 MHz,
DMSO-d6): δ 8.80 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 4.7, 1.3 Hz,
1H), 8.08 (ddd, J = 8.3, 2.5, 1.5 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H),
7.38-7.30 (m, 4H), 7.29-7.22 (m, 1H), 4.57 (s, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 173.0, 144.3, 141.9, 140.9, 135.5, 128.2,
127.2, 126.8, 126.1, 123.6, 59.7. HRMS (ESI) m/z: Calcd for
C13H14N3O ([M + H]+) 228.1137, found 228.1130.
4.3.3 (S)-2-amino-N-(4-methoxyphenyl)-2-phenylacetamide (3c)
13b
White solid, 235 mg, yield: 92%. 1H NMR (400 MHz, CDCl3):
δ 9.25 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H),
7.36 (t, J = 7.2 Hz, 2H), 7.32-7.27 (m, 1H), 6.85 (d, J = 8.9 Hz,
2H), 4.71 (s, 1H), 3.78 (s, 3H), 2.01 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 170.6, 156.3, 140.7, 130.9, 128.9, 128.1, 126.9, 121.1,
114.1, 55.5, 29.7.
4.3.10 (R)-2-amino-N,3-diphenylpropanamide (3j)8
White solid, 211 mg, yield: 88%. 1H NMR (400 MHz, CDCl3):
δ 9.33 (s, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.23 (s, 4H), 7.19 (s, 3H),
7.01 (t, J = 7.4 Hz, 1H), 3.81 (s, 1H), 3.29 (dd, J = 13.7, 3.8 Hz,
1H), 2.80 (dd, J = 13.7, 8.9 Hz, 1H), 2.28 (s, 2H). 13C NMR (100
MHz, CDCl3): δ 172.0, 137.6, 137.5, 129.3, 129.0, 128.8, 127.0,
124.2, 119.5, 56.8, 40.6.
4.3.4 (S)-2-amino-N-(2-methoxycarbonylphenyl)-2-
penylacetamide (3d)
White solid, 236 mg, yield: 83%. 1H NMR (400 MHz, CDCl3):
δ 12.10 (s, 1H), 8.74 (d, J = 7.4 Hz, 1H), 8.03 (d, J = 6.5 Hz, 1H),
7.67-7.44 (m, 3H), 7.45-7.29 (m, 3H), 7.07 (s, 1H), 4.71 (s, 1H),
3.95 (s, 3H), 1.97 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 172.5,
168.2, 141.0, 140.9, 134.5, 130.9, 128.9, 128.1, 127.0, 122.7,
120.5, 115.8, 61.5, 52.4. HRMS (ESI) m/z: Calcd for C16H17N2O3
([M + H]+) 285.1239, found 285.1239.
4.3.11 (S)-2-amino-N-phenylpropanamide (3k)8
1
White solid, 98 mg, yield: 60%. H NMR (400 MHz, CDCl3):
δ 9.38 (s, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H),
7.02 (t, J = 7.0 Hz, 1H), 3.55 (d, J = 6.7 Hz, 1H), 1.64 (s, 2H),
4.3.5
(S)-2-amino-N-(2-trifluoromethylphenyl)-2-
phenylacetamide (3e)

6
Tetrahedron
ACCEPTED MANUSCRIPT
1.36 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.7,
137.8, 129.0, 124.0, 119.4, 51.2, 21.6.
1H), 3.55 (s, 3H), 1.13 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 138.6, 128.7, 123.3, 119.1, 69.5, 67.3, 20.8. HRMS
(ESI) m/z: Calcd for C10H15N2O2 ([M + H]+) 195.1134, found
195.1127.
4.3. 12 (S)-2-amino-3-methyl-N-phenylbutanamide (3l)8
White solid, 157 mg, yield: 82% (92% when temperature is
110 oC). 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 7.52 (d, J =
7.7 Hz, 2H), 7.23 (t, J = 7.9 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H),
3.27 (d, J = 3.5 Hz, 1H), 2.24-2.41 (m, 1H), 1.54 (s, 2H), 0.94 (d,
J = 7.0 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 172.6, 137.7, 128.8, 123.9, 119.4, 60.3, 30.7, 19.7,
16.0.
Acknowledgments
This work was supported financially by the State Key
Laboratory of Fine Chemicals (Panjin) (Grant No. JH2014009)
project and the Fundamental Research Funds for the Central
Universities
Appendix A. Supplementary data
4.3. 13 (S)-2-amino-4-methyl-N-phenylpentanamide (3m)8
White solid, 173 mg, yield: 84% (96% when temperature is
110 oC). 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.50 (d, J =
7.6 Hz, 2H), 7.21 (t, J = 7.9 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H),
3.38 (m, 1H), 1.74-1.63 (m, 2H), 1.60 (s, 2H), 1.37-1.23 (m, 1H),
0.86 (dd, J = 12.1, 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
173.7, 138.0, 128.7, 123.8, 119.3, 53.8, 43.7, 24.8, 23.2, 21.2.
References
1. a) Goldberg, I. Eur. J. Inorg. Chem. 1906, 39, 1691-1692;
b) Lange, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J. M.;
Verveer, P. C.; Kruse, C. G.; Feenstra, R. W. Tetrahedron Lett. 2002, 43,
1101-1104;
c) Sherborne, G. J.; Adomeit, S.; Menzel, R.; Rabeah, J.; Brückner, A.;
Fielding, M. R.; Willans, C. E.; Nguyen, B. N. Chem. Sci. 2017, 8, 7203-
7210;
d) Jiang, L. Molecules. 2014, 19, 13448-13460;
e) Klapars, A. ; Antilla, J. C. ; Huang, X. ; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727–7729.
2. a) Ma, D.; Cai, Q. Accounts. Chem. Res. 2008, 41, 1450-1460;
b) Güell, I.; Ribas, X. Eur. J. Org. Chem. 2014, 2014, 3188-3195;
c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
3. a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13-31;
b) Zhang, Y.; Yang, X.; Yao, Q.; Ma, D. Org. Lett. 2012, 14, 3056-3059.
4. Sharma, K. K.; Sharma, S.; Kudwal, A.; Jain, R. Org. Biomol. Chem.
2015, 13, 4637-4641.
4.3. 14 (S)-N-phenylpyrrolidine-2-carboxamide (3n)8
White solid, 142 mg, yield: 75%, 99% ee (HPLC, Diacel
Chiralcel OD-H column, 70:30 hexanes/2-propanol, 0.8 mL/min,
254 nm; (R)-N-phenylpyrrolidine-2-carboxamide, rt = 6.489 min;
(S)-N-phenylpyrrolidine-2-carboxamide, rt = 7.245 min). 1H
NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 7.64 (d, J = 7.9 Hz,
2H), 7.29 (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 3.68 (s,
1H), 3.09 (s, 1H), 2.89 (s, 2H), 2.13-1.96 (m, 1H), 1.87-1.72 (m
1H), 1.71-1.56 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ
5. a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684-11688;
173.3, 138.5, 128.6, 123.2, 119.0, 60.8, 46.7, 30.4, 25.9
.
b) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581-584;
c) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796;
d) Yong, F.-F.; Teo, Y.-C. Tetrahedron Lett. 2010, 51, 3910-3912;
e) Goodbrand, H. B.; Hu, N.-X. J. Am. Chem. Soc. 1999, 64, 670-674.
6. a) Yong, F.-F.; Teo, Y.-C. Tetrahedron Lett. 2010, 51, 3910-3912;
b) Teo, Y.-C.; Yong, F.-F.; Ithnin, I. K.; Yio, S.-H. T.; Lin, Z. Eur. J. Org.
Chem. 2013, 2013, 515-524;
c) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008, 73,
1429-1434.
7. a) Hyun, M.-H.; Min, H.-J.; Cho, Y.-J. Bull. Korean Chem. Soc. 2003, 24,
911-915;
4.3.15
(S)-2-amino-3-(1H-indol-2-yl)-N-phenylpropanamide
(3o)8
White solid, 206 mg, yield: 74%. 1H NMR (400 MHz, CDCl3):
δ 9.34 (s, 1H), 8.06 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.52 (d, J =
7.7 Hz, 2H), 7.35-7.21 (m, 3H), 7.14 (t, J = 7.3 Hz, 1H), 7.09-
6.97 (m, 3H), 3.78 (d, J = 6.2 Hz, 1H), 3.41 (d, J = 14.4 Hz, 1H),
3.01-2.92 (m, 1H), 1.57 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
δ 173.7, 138.8, 136.1, 128.6, 127.4, 123.7, 123.1, 120.8, 119.2,
118.5, 118.2, 111.3, 110.5, 56.2, 30.9.
b) Liu, Z.; Lu, W.; Qian, L.; Zhang, X.; Zeng, P.; Pan, J. J. Control.
Release. 2005, 102, 135-144;
c) Zhang, Y.; Feng, J.; Liu, C.; Fang, H.; Xu, W. Bioorg. Med. Chem.
2011, 19, 4437-4444;
d) Yang, W.-Y.; Breiner, B.; Kovalenko, S. V.; Ben, C.; Singh, M.;
LeGrand, S. N.; Sang, Q.-X. A.; Strouse, G. F.; Copland, J. A.; Alabugin, I.
V. J. Am. Chem. Soc. 2009, 131, 11458-11470;
e) Heinrich, S.; Altenkamper, M.; Bechem, B.; Perruchon, J.; Ortmann, R.;
Dahse, H. M.; Wang, Y.; Lanzer, M.; Schlitzer, M. Eur. J. Med. Chem.
2011, 46, 1331-1342.
8. Dong, J.; Wang, Y.; Xiang, Q.; Lv, X.; Weng, W.; Zeng, Q. Adv. Synth.
Catal. 2013, 355, 692-696.
9. a) Escorihuela, J.; Burguete, M. I.; Luis, S. V. Tetrahedron Lett. 2008, 49,
6885-6888;
4.3.16 (S)-2-amino-3-(4-hydroxyphenyl)-N-phenylpropanamide
(3p)14b
White solid, 171 mg, yield: 67%. 1H NMR (400 MHz,
DMSO-d6): δ 9.79 (s, 1H), 9.19 (s, 1H), 7.59 (d, J = 7.9 Hz, 2H),
7.29 (t, J = 7.5 Hz, 2H), 7.03 (t, J = 7.7 Hz, 3H), 6.66 (d, J = 8.0
Hz, 2H), 3.50 (t, J = 6.4 Hz, 1H), 2.89 (dd, J = 13.3, 5.3 Hz, 1H),
2.62 (dd, J = 13.4, 7.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6):
b) Maekawa, K.; Kubo, K.; Igarashi, T.; Sakurai, T. Tetrahedron. 2005, 61,
11211-11224;
δ
173.4, 155.7, 138.8, 130.1, 128.6, 128.3, 123.2, 119.2,
114.9, 57.1
.
c) Schallenberg, E. E.; Calvin, M. J. Am. Chem. Soc.1955, 77, 2779-2783;
d) IKOTA, N. Chem. and Pharm. Bull. 1990, 38, 1601-1608.
10. a) Pan, Y. Friend of Chemical Industry 2007, 3, 44-45;
b) Eric R. Strieter; Donna G. Blackmond, a.; Stephen L. Buchwald. J. Am.
Chem. Soc. 2005, 127, 4120-4121;
4.3. 17 (S)-2-amino-3-hydroxy-N-phenylbutanamide (3q)
White solid, 105 mg, yield: 54%. 1H NMR (400 MHz,
DMSO-d6): δ 10.06 (br, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.31 (t, J =
7.9 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 4.81 (br, 1H), 4.01-3.90 (m,
c) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421-7428.

7
11. This example was used for finding out the peak position of (+)-3a and
ACCEPTED MANUSCRIPT
(-)-3a.
12. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Artis Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 34, 6653-6655.
13. a) Ouyang, L.; Liu, B.; Zhang, F.; Fu, L.; Wei, Y. CN Patent 106748892
A; 2017;
b) Li, J.; Li, X.; Wang, X.; Hou, J.; Zang, J.; Gao, S.; Xu, W.; Zhang, Y.
Chem. Biol. Drug. Des. 2016, 88, 574-584.
14. a) Zhang, L.; Wang, X.; Li, X.; Zhang, L.; Xu, W. J. Enzyme. Inhib.
Med.
Chem. 2014, 29, 582-589;
b) Murakami, S.; Yamamoto, K. I.; Shinmori, H.; Takeuchi, T. Chem.
Lett. 2008, 37, 1028-1029.