Direct amide formation from N-arylglycine ethyl esters and carboxylic acids catalysed by phenylboronic acid

Article abstract of DOI:10.3184/174751913X13729583884275

The phenylboronic acid-catalysed reaction of an N-arylglycine ethyl ester with various carboxylic acids, including N-acyl-N-phenylglycines, directly affords an amide or a dipeptide in 13-73% yields.

Full text of DOI:10.3184/174751913X13729583884275

460 RESEARCH PAPER
AUGUST, 460–463
JOURNAL OF CHEMICAL RESEARCH 2013
Direct amide formation from N-arylglycine ethyl esters and carboxylic
acids catalysed by phenylboronic acid
Wenhua Huang* and Wen-Bin Sha
Department of Chemistry, Tianjin University, 92 Weijin Road, Tianjin 300072, P. R. China
The phenylboronic acid-catalysed reaction of an N-arylglycine ethyl ester with various carboxylic acids, including
N-acyl-N-phenylglycines, directly affords an amide or a dipeptide in 13–73% yields.
Keywords: direct amide formation, N-arylglycine, phenylboronic acid, amino acid, dipeptide
Amide bonds are the main chemical bonds that link amino acid
building blocks together to give proteins which play a crucial
role virtually in all biological processes.1 Amide bond forma-
tion is one of the most commonly used reaction in synthesis of
drugs, as a survey showed that among all reactions employed
by medicinal chemists, about one in six was an amide
formation.2 Therefore, a vast number of methods3,4 have been
developed for the formation of amide bonds, but many of them
require stoichiometric reagents to activate carboxylic acids,
and thus are problematic in the context of atom-efficiency,
recyclability and functional group tolerance.5 Recently, boric
acid or an arylboronic acid was found to promote or even
catalyse the formation of an amide directly from a variety of
carboxylic acids and amines.6–16 To the best of our knowledge,
however, this method has not been tested in the amide forma-
tion of N-arylglycines, which are known17 to often suffer from
low conversion by using traditional methods. Herein, we report
direct amide formation catalysed d by phenylboronic acid from
an N-arylglycine ethyl ester 1a–j and carboxylic acids 2a–h
including N-acylglycines, as shown in Scheme 1.
volume of toluene by half slightly increased the yield of 3a to
40% (entry 4). To our delight, replacing toluene by xylene, the
yield of 3a increased to 73% (entry 5). Moreover, we found the
usage of PhB(OH)2 could be reduced to 10 mol % without
decreasing the yield of 3a (entry 6). Using mesitylene instead
of xylene or increasing the reaction time to 15 h also led to
almost the same yield of 3a (entries 7 and 8). When the usage
of PhB(OH)2 was reduced to 5 mol % the yield of 3a slightly
decreased to 66% (entry 9). In a control experiment, in the
absence of PhB(OH)2, just a trace of 3a was obtained and 1a
was recovered in 88% yield (entry 10), indicating a truly cata-
lytic role of PhB(OH)2 in direct amide formation. Based on the
above results, we balanced the yield of 3a against the usage
of PhB(OH)2, and reaction time and temperature, and finally
chose the following optimal reaction conditions to further
explore direct amide formation: 10 mol % PhB(OH)2, xylene,
and reflux for 10 h.
We then reacted a range of N-arylglycine ethyl esters 1a–j
with N-acetyl-N-phenylglycine 2a using the optimal reaction
conditions. As shown in Table 2, the reaction could tolerate
a variety of substituents, whether electron-withdrawing or
electron-donating or at different position, on the benzene ring
of the N-arylglycine ethyl ester to afford the corresponding
dipeptides 59–73% yields (entries 1–9), indicating that the
electron effect on the benzene ring was not obvious. However,
N-mesitylglycine ethyl ester 1j gave a low yield of 3j (entry
10), probably due to steric hindrance from two methyl groups
at the ortho positions of mesitylamine moiety.
Results and discussion
Initially we chose N-phenylglycine ethyl ester (1a) and N-
acetyl-N-phenylglycine (2a) as model compounds to explore
direct amide or peptide formation. The results are summarised
in Table 1. When a mixture of 1a (0.5 mmol), 2a (0.5 mmol),
and 25 mol % PhB(OH)2 in toluene (20 mL) was refluxed with
removal of water (4Å molecular sieves in a pressure equalising
dropping funnel) for 10 h, dipeptide 3a was obtained in 34%
yield after isolation by preparative TLC (entry 1). Using a
stoichiometric amount of PhB(OH)2 just slightly increased the
yield of 3a to 44% (entry 2). An attempt to employ the cheaper
B(OH)3 led to a lower yield (12%, entry 3). Reducing the
N-Phenylglycine ethyl ester 1a was then reacted with a vari-
ety of carboxylic acids 2b–h. N-Benzoyl-N-phenylglycine 2b
gave a slightly lower yield of 3k, whereas N-acetylglycine 2c
Table 1 Screening of reaction conditions for optimising
phenylboronic acid-catalysed amide formation using N-
phenylglycine ethyl ester 1a and N-acetyl-N-phenylglycine 2a
as modelsa
Entry
Catalyst/mol %
Solvent/mL
Yieldof 3a/%b
1
2
PhB(OH)2 (25)
PhB(OH)2 (100)
B(OH)3 (25)
PhB(OH)2 (25)
PhB(OH)2 (25)
PhB(OH)2 (10)
PhB(OH)2 (10)
PhB(OH)2 (10)
PhB(OH)2 (5)
-
Toluene (20)
Toluene (20)
Toluene (20)
Toluene (10)
Xylene (10)
Xylene (10)
Mesitylene (10)
Xylene (10)
Xylene (10)
Xylene (10)
34
44
12
40
73
72
73
74c
66
<1d
3
4
5
6
7
8
9
10
Scheme 1 Direct amide formation and structures of
N-arylglycine ethyl ester and carboxylic acids used.
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), PhB(OH)2,
solvent, and refluxed with removal of water for 10 h. b Isolated
yield by preparative TLC. c Refluxed for 15 h. d 1a was recovered
in 88% yield.
* Correspondent. E-mail: huangwh@tju.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2013 461
Table 2 Yields of amides or dipeptides 3a–q from the
phenylboronic acid-catalysed reaction of N-arylglycine ethyl
esters 1a–j with various carboxylic acids 2a–h (Scheme 1)a
NMR (CDCl3): δ 1.34 (t, J = 7.2 Hz, 3H, CH2CH3), 3.93 (s, 2H,
CH2COO), 4.27 (s, 1H, NH), 4.28 (q, J = 7.2 Hz, 2H, CH2CH3),
6.65 (d, J = 8.0 Hz, 2H, ArH), 6.80 (dd, J1 = 7.4 Hz, J2 = 7.4 Hz, 1H,
ArH), 7.24 (dd, J1 = 7.4 Hz, J2 = 8.0 Hz, 2H); 13C NMR (CDCl3):
δ 14.2, 45.9, 61.3, 113.0, 118.2, 129.3, 147.0, 171.2. The following
N-arylglycine ethyl ester was prepared according to the method A.
Ethyl 2-(p-tolylamino)acetate (1b): Colourless flakes (54%), m.p.
49–50 °C (lit.24 51 °C) (EtOH), IR: 3380 (NH), 1728 (C=O) cm−1; 1H
NMR (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H, CH2CH3), 2.28 (s, 3H,
ArCH3), 3.91 (d, J = 5.6 Hz, 2 H, CH2COO), 4.20 (brs, 1H, NH), 4.27
(q, J = 7.2 Hz, 2H, CH2CH3), 6.58 (d, J = 8.2 Hz, 2H, ArH), 7.04 (d,
J = 8.2 Hz, 2H, ArH); 13C NMR (CDCl3): δ 14.2, 20.4, 46.3, 61.3,
113.2, 127.4, 129.8, 144.9, 171.3.
Entry
1
2
3
Yield/%b of 3
1
2
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
72
71
67
65
70
59
73
71
69
19
54
35
22
69
58
13
29
3
4
5
Ethyl 2-((4-methoxyphenyl)amino)acetate (1c): Colourless gran-
6
ules (70%), m.p. 59–60 °C (lit.24 59 °C) (EtOH), IR: 3383 (NH), 1730
7
1g
1h
1i
1
(C=O) cm−1; H NMR (CDCl3): δ 1.31 (t, J = 7.2 Hz, 3H, CH2CH3),
8
3.77 (s, 3H, OCH3), 3.88 (s, 2 H, NCH2), 4.06 (brs, 1H, NH), 4.25
(q, J = 7.2 Hz, 2H, CH2CH3), 6.61 (d, J = 8.8 Hz, 2 H, ArH), 6.81
(d, J = 8.8 Hz, 2H, ArH); 13C NMR (CDCl3): 14.2, 46.9, 55.8, 61.2,
114.4, 114.9, 141.3, 152.6, 171.4.
9
10
11
12
13
14
15
16
17
1j
1a
1a
1a
1a
1a
1a
1a
Ethyl 2-((3-(methylthio)phenyl)amino)acetate (1d): White flakes
(73%), m.p. 57–58 °C (EtOH), IR: 3379 (NH), 1728 (C=O) cm−1; 1H
NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3 H, CH2CH3), 2.48 (s, 3 H,
SCH3), 3.91 (s, 2H, NCH2), 4.27 (q, J = 7.2 Hz, 2H, CH2CH3), 4.35
(brs, 1H, NH), 6.41 (dd, J1 = 1.8 Hz, J2 = 8.0 Hz, 1H, ArH), 6.52 (dd,
J1 = 1.6 Hz, J2 = 1.8 Hz, 1H, ArH), 6.67 (d, J1 = 1.6 Hz, J2 = 7.8 Hz,
1H, ArH), 7.13 (dd, J1 = 7.8 Hz, J2 = 8.0 Hz, 1H, ArH); 13C NMR
(CDCl3): δ 14.2, 15.7, 45.7, 61.4, 110.1, 110.8, 116.3, 129.6, 139.5,
147.4, 171.0; HRMS-ESI (positive) calcd for C11H15NNaO2S+
[M + Na]+: 248.0716; found: 248.0719.
2g
2h
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), PhB(OH)2
(0.05 mmol), xylene (10 mL), and refluxed with removal of
water for 10 h. b Isolated yield by preparative TLC.
Ethyl 2-((3-chlorophenyl)amino)acetate (1g): Colourless flakes
(82%), m.p. 114–115 °C (lit.25 113–114 °C) (EtOH), IR: 3380 (NH),
1725 (C=O) cm−1; 1H NMR (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H,
CH2CH3), 3.89 (d, J = 5.6 Hz, 2 H, CH2COO), 4.28 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.42 (brs, 1H, NH), 6.50 (dd, J1 = 1.8 Hz, J2 = 8.0 Hz, 1H,
ArH), 6.59 (dd, J1 = 1.5 Hz, J2 = 1.8 Hz, 1H, ArH), 6.73 (dd, J1 =
1.5 Hz, J2 = 8.0 Hz, 1H, ArH), 7.11 (dd, J1 = 8.0 Hz, J2 = 8.0 Hz,
1H, ArH); 13C NMR (CDCl3): δ 14.2, 45.5, 61.5, 111.3, 112.6, 118.0,
130.3, 135.1, 148.1, 170.7.
gave a low yield of 3l, indicating that a free NH of the glycine
moiety was unfavourable to direct amide formation (entries 11
and 12). While N-phthaloylglycine ethyl ester 2d gave only a
22% yield of 3m, N-phthaloyl-β-alanine ethyl ester 2e gave 3n
in 69% yield (entries 13 and 14). Phenylacetic acid 2f gave 3o
in 58% yield whereas benzoic acid 2g and cinnamic acid 2h
gave 3p and 3q in 13 and 29% yields, respectively (entries
15–17).
In summary, we have demonstrated that N-arylglycine ethyl
ester and carboxylic acids can undergo direct amide formation
in the presence of catalytic PhB(OH)2. When the carboxylic
acid was N-acyl-N-phenylglycine, a range of dipeptides could
be formed in reasonable yields. This direct amide formation
seems to be independent of the substituent on the benzene ring
of N-arylglycine ethyl ester but did depend on the structure of
the carboxylic acid.
Typical procedure for the synthesis of N-arylglycine ethyl ester
(method B)
A mixture of ClCH2COOEt (1.06 g, 8.62 mmol), NaI⋅2H2O (1.60 g,
8.62 mmol) in acetone (6 mL) was stirred at room temperature for 1 h.
The reaction mixture was filtered by suction, and then the filtrate was
evaporated to remove acetone. The obtained residue was dissolved
in DMF (2 mL), and added to a mixture of 4-chloroaniline (1.00 g,
7.84 mmol), K2CO3 (1.19 g, 8.62 mmol), and DMF (3 mL). The result-
ing mixture was stirred overnight under nitrogen, and then poured into
ice-water (50 mL). The white precipitates were collected after being
filtered by suction, and washed sequentially by water (10 mL × 3),
cold alcohol (1 mL × 3), and PE (3 mL × 3). Recrystallisation from
EtOH gave ethyl 2-((4-chlorophenyl)amino)acetate 1e (1.29 g, 77%).
Colourless flakes, m.p. 94–95 °C (lit.25 92.5–93.5 °C), IR: 3376 (NH),
1722 (C=O) cm−1; 1H NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3H,
CH2CH3), 3.88 (d, J = 5.2 Hz, 2H, CH2COO), 4.27 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.34 (brs, 1H, NH), 6.54 (d, J = 8.8 Hz, 2H, ArH), 7.16 (d,
J = 8.8 Hz, 2H, ArH); 13C NMR (CDCl3): δ 14.2, 45.8, 61.5, 114.1,
122.8, 129.2, 145.6, 170.9.
Experimental
NMR spectra were obtained on a MercuPlus 400 NMR spectrometer
(1H NMR at 400 MHz, 13C NMR at 100 MHz) in CDCl3 or DMSO-d6
using TMS as internal standard. IR spectra were obtained on a Thermo
Nicolet Avatar 360 IR spectrometer using KBr disks. High resolution
electrospray ionisation mass spectra (HRMS-ESI) were obtained on
an LCQ Advantage MAX (Finnigan) instrument. All melting points
were measured on a melting apparatus with microscope and hot stage
and are uncorrected. Compounds 1j,18 2a,19 2f,20 2b,21 and 2d22 and
were prepared according to the reported procedure. Phenylboronic
acid and other reagents were purchased from a local company and
used as received. All reactions were carried out under N2. PE =
petroleum ether (b.p. 60–90 °C).
The following N-arylglycine ethyl esters were prepared by method
B.
Ethyl 2-((2-chlorophenyl)amino)acetate (1f): Pale yellow oil (lit.25
b.p. 116 °C/1 mm Hg), isolated by preparative TLC (eluted with
PE/EtOAc (10/1, v/v), Rf = 0.52) in 21% yield, IR: 3408 (NH), 1742
1
(C=O) cm−1; H NMR (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H, CH2CH3),
Typical procedure for the synthesis of an N-arylglycine ethyl ester
(method A)
3.97 (s, 2H, CH2COO), 4.28 (q, J = 7.2 Hz, 2H, CH2CH3), 4.98 (s, 1H,
NH), 6.56 (d, J = 7.8 Hz, 1H, ArH), 6.71 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz,
1H, ArH), 7.16 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H, ArH), 7.30 (d, J =
7.8 Hz, 1H, ArH); 13C NMR (CDCl3): δ 14.2, 45.6, 61.5, 111.3, 118.1,
119.6, 127.8, 129.3, 143.0, 170.5.
K2CO3 (9.9 g, 0.071 mol) and ClCH2COOEt (8.3 g, 0.068 mol) were
added to a solution of aniline (6.0 g, 0.065 mol) in DMF (15 mL).
After this mixture had stirred for 30 min, NaI⋅2H2O (6.0 g, 0.032 mol)
was added. The resulting mixture was allowed to stir overnight under
nitrogen. Then the mixture was poured into ice-water (ca. 100 mL),
filtered by suction, and the precipitate washed sequentially with water
(15 mL × 3), cold ethanol (3 mL × 3), and PE (5 mL × 3), to afford
snow-white solids. Recrystallisation from EtOH/PE (9/1, v/v) gave
ethyl 2-(phenylamino)acetate (1a) (8.9 g, 76%). Colourless flakes,
Ethyl 2-((4-fluorophenyl)amino)acetate (1h): Colourless flakes
(75%s), m.p. 73–74 °C (lit.25 73–74 °C) (EtOH), IR: 3383 (NH), 1727
1
(C=O) cm−1; H NMR (CDCl3): δ 1.31 (t, J = 7.2 Hz, 3H, CH2CH3),
3.87 (d, J = 5.6 Hz, 2H, CH2COO), 4.21 (brs, 1H, NH), 4.26 (q,
J = 7.2 Hz, 2H, CH2CH3), 6.53–6.59 (m, 2H, ArH), 6.88–6.96 (m, 2H,
ArH); 13C NMR (CDCl3): δ 14.2, 46.4, 61.4, 113.9 (d, JF-C = 7.6 Hz),
1
m.p. 56–57 °C (lit.23 57 °C), IR: 3386 (NH), 1733 (C=O) cm−1; H

462 JOURNAL OF CHEMICAL RESEARCH 2013
115.8 (d, JF-C = 22.5 Hz), 143.5 (d, JF-C = 1.9 Hz), 156.2 (d, JF-C
234.2 Hz), 171.1.
=
cm−1; 1H NMR (CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H, CH2CH3), 1.82 (s,
3H, CH3C=O), 4.08 (s, 2H, AcNCH2), 4.11 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.30 (s, 2H, CH2COO), 7.23–7.27 (m, 1H, ArH), 7.26–7.36
(m, 8H, ArH); 13C NMR (CDCl3): δ 14.1, 22.0, 51.3, 51.7, 61.3, 127.9,
128.0, 129.5, 129.7, 130.1, 134.5, 140.1, 143.6, 168.3, 168.7, 170.6;
HRMS-ESI (positive) calcd for C20H21ClN2NaO4+ [M + Na]+:
411.1082; found: 411.1081; Eluent: PE/acetone (2/1, v/v), Rf = 0.44.
Ethyl 2-(N-(2-chlorophenyl)-2-(N-phenylacetamido)acetamido)-
acetate (3f): Pale yellow oil(59%), IR: 1751 (C=O), 1690 (C=O),
1662 (C=O) cm−1; 1H NMR (CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H,
OCH2CH3), 1.92 (s, 3H, CH3C=O), 3.70 (d, J = 17.4 Hz, 1H, one
proton of CH2COO), 3.99 (d, J = 16.4 Hz, 1H, one proton ofAcNCH2),
4.16–4.24 (m, 2H, CH2CH3), 4.26 (d, J = 16.4 Hz, 1H, another proton
of AcNCH2), 5.04 (d, J = 17.4 Hz, 1H, another proton of CH2COO),
7.32–7.42 (m, 7H, ArH), 7.49–7.53 (m, 1H, ArH), 7.70–7.74 (m,
1H, ArH); 13C NMR (CDCl3): δ 14.1, 22.1, 49.9, 51.4, 61.2, 127.9
(overlap, 2C), 128.2, 129.5, 130.3, 130.6, 131.6, 132.9, 138.4, 143.5,
168.4, 168.6, 170.6; HRMS-ESI (positive) calcd for C20H21ClN2NaO4+
[M + Na]+: 411.1082; found: 411.1079; Eluent: PE/acetone (2/1, v/v),
Rf = 0.37.
Ethyl 2-((4-bromophenyl)amino)acetate (1i): Colourless flakes
(69%), m.p. 95–96 °C (lit.25 94–95 °C) (EtOH), IR: 3376 (NH), 1721
1
(C=O) cm−1; H NMR (CDCl3): δ 1.32 (t, J = 7.2 Hz, 3H, CH2CH3),
3.87 (d, J = 5.6 Hz, 2H, NCH2), 4.26 (q, J = 7.2 Hz, 2H, CH2CH3),
4.36 (t, J = 5.6 Hz, 1H, NH), 6.50 (d, J = 8.8 Hz, 2H, ArH), 7.29 (d,
J = 8.8 Hz, 2H, ArH); 13C NMR (CDCl3): δ 14.2, 45.7, 61.5, 109.9,
114.5, 132.0, 146.0, 170.8.
3-(1,3-Dioxoisoindolin-2-yl)propanoic acid (2e): A mixture of
β-alanine (5.0 g, 0.056 mol), phthalic anhydride (8.7 g, 0.059 mol),
and DMF (20 mL) was refluxed under stirring for 3 h. The resulting
mixture was cooled to room temperature, poured into ice-water
(~100 mL), and then filtered by suction. The filter cake was sequen-
tially washed with water (15 mL × 3), alcohol (3 mL × 3), and ether
(10 mL × 2), and then dried in vacuo to give 2e (9.9 g, 80%) as a white
solid, m.p. 148–150 °C (lit.26 152 °C), IR: 1773 (C=O), 1699 (C=O)
cm−1; 1H NMR (DMSO-d6): δ 2.61 (t, J = 7.2 Hz, 2H, CH2COO), 3.79
(t, J = 7.2 Hz, 2H, NCH2), 7.82–7.89 (m, 4H, ArH), 12.40 (brs, 1 H,
COOH).
Ethyl 2-(N-(3-chlorophenyl)-2-(N-phenylacetamido)acetamido)-
Direct amide formation catalysed by PhB(OH)2; typical procedure
PhB(OH)2 (6 mg, 0.05 mmol), and xylene (10 mL) were added to a
round-bottom flask (100 mL), 1a (90 mg, 0.5 mmol), 2a (97 mg,
0.5 mmol). A pressure equalising dropping funnel, in which 4 Å
molecular sieves (6 g) were placed, was installed onto the flask. Then
a condenser was connected to the dropping funnel. After refluxing
under stirring for 10 h, the reaction mixture was cooled down to room
temperature, and evaporated to remove solvent. The resulting residue
was dissolved in EtOAc (20 mL), and then sequentially washed with
0.1 M NaOH (20 mL), water (20 mL), and brine (20 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was subjected to
preparative TLC (eluted with PE/acetone (2/1, v/v), Rf = 0.43) to
afford ethyl 2-(N-phenyl-2-(N-phenylacetamido)acetamido)acetate
3a (128 mg 72%) as a pale yellow oil, IR: 1751 (C=O), 1682 (C=O),
1658 (C=O) cm−1; 1H NMR (CDCl3): δ 1.24 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.89 (s, 3H, CH3C=O), 4.15 (s, 2H, AcNCH2), 4.17 (q,
J = 7.2 Hz, 2H, CH2CH3), 4.39 (s, 2H, CH2COO), 7.28–7.44 (m, 10H,
ArH); 13C NMR (CDCl3) δ 14.1, 22.1, 51.5, 51.8, 61.3, 127.9, 128.0,
128.3, 128.7, 129.5, 129.9, 141.7, 143.8, 168.4, 168.9, 170.7; HRMS-
ESI (positive) calcd for C20H22N2NaO4+ [M + Na]+: 377.1472; found:
377.1470.
Ethyl 2-(2-(N-phenylacetamido)-N-(p-toyl)acetamido)acetate (3b):
Yellow oil (71%), IR: 1748 (C=O), 1667 (C=O) cm−1; 1H NMR
(CDCl3): δ 1.19 (t, J = 7.2 Hz, 3H, CH2CH3), 1.84 (s, 3H, ArCH3), 2.31
(s, 3H, CH3C=O), 4.11 (q, J = 7.2 Hz, 2H, CH2CH3), 4.12 (s, 2H,
AcNCH2), 4.32 (s, 2H, CH2COO), 7.15 (d, J = 8.2 Hz, 2 H, ArH), 7.25
(d, J = 8.2 Hz, 2H, ArH), 7.27–7.29 (m, 1H, ArH), 7.29–7.35 (m, 4H,
ArH); 13C NMR(CDCl3): δ 14.1, 21.1, 22.1, 51.5, 51.8, 61.1, 127.861,
127.936, 127.947, 129.5, 130.5, 138.6, 139.0, 143.8, 168.5, 168.9,
170.6; HRMS-ESI (positive) calcd for C21H24N2NaO4+ [M + Na]+:
391.1628; found: 391.1624; Eluent: PE/acetone (2/1, v/v), Rf = 0.30.
Ethyl 2-(N-(4-methoxyphenyl)-2-(N-phenylacetamido)acetamido)-
acetate (3c): Light brown oil (67%), IR: 1746 (C=O), 1679 (C=O)
cm−1: 1H NMR (CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H, CH2CH3), 1.82 (s,
3H, CH3C=O), 3.73 (s, 3H, OCH3), 4.09 (s, 2H, AcNCH2), 4.10 (q,
J = 7.2 Hz, 2H, CH2CH3), 4.29 (s, 2H, CH2COO), 6.83 (d, J = 9.2 Hz,
2H, ArH), 7.22–7.31 (m, 7H, ArH); 13C NMR (CDCl3): δ 14.1, 22.1,
51.5, 51.7, 55.4, 61.1, 114.9, 127.8, 127.9, 129.3, 129.5, 134.2, 143.7,
159.5, 168.7, 168.9, 170.6; HRMS-ESI (positive) calcd for
C21H24N2NaO5+ [M + Na]+: 407.1577; found: 407.1580; Eluent: PE/
acetone (2/1, v/v), Rf = 0.26.
acetate (3g): Light yellow oil (73%), IR: 1749 (C=O), 1689 (C=O)
1
cm−1; H NMR (CDCl3): δ 1.19 (t, J = 7.2 Hz, 3H, CH2CH3), 1.83
(t, 3H, CH3C=O), 4.11 (s, 2H, AcNCH2), 4.12 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.30 (s, 2H, CH2COO), 7.23–7.34 (m, 8H, ArH), 7.40 (s,
1H, ArH); 13C NMR (CDCl3): δ 14.1, 22.0, 30.9, 51.3, 51.7, 61.3,
126.7, 127.9, 128.0, 128.5, 129.0, 129.5, 130.9, 135.2, 142.8, 143.6,
168.2, 168.6, 170.6; HRMS-ESI (positive) calcd for C20H21ClN2NaO4+
[M + Na]+: 411.1082; found: 411.1083; Eluent: PE/acetone (2/1, v/v),
Rf = 0.40.
Ethyl 2-(N-(4-fluorophenyl)-2-(N-phenylacetamido)acetamido)-
acetate (3h): Pale yellow oil (71%), IR: 1747 (C=O), 1667 (C=O)
cm−1; 1H NMR (CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H, CH2CH3), 1.82 (s,
3H, CH3C=O), 4.07 (s, 2H, AcNCH2), 4.11 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.30 (s, 2H, CH2COO), 6.99–7.05 (m, 2H, ArH), 7.23–7.28
(m, 1H, ArH), 7.28–7.34 (m, 4H, ArH), 7.36–7.40 (m, 2H, ArH): 13
C
NMR (CDCl3): δ 14.1, 22.0, 51.4, 51.7, 61.2, 116.7 (d, JF-C = 22.5 Hz),
127.9 (overlap, 2C), 129.5, 130.2 (d. JF-C = 8.7 Hz), 137.6 (d, JF-C
=
3.0 Hz), 143.7, 162.2 (d, JF-C = 247.5 Hz), 168.5, 168.8, 170.6; HRMS-
ESI (positive) calcd for C20H21FN2NaO4+ [M + Na]+: 395.1378; found:
395.1378; Eluent: PE/acetone (2/1, v/v), Rf = 0.39.
Ethyl 2-(N-(4-bromophenyl)-2-(N-phenylacetamido)acetamido)-
acetate (3i): Pale yellow oil (69%), IR: 1748 (C=O), 1665 (C=O) cm−1;
1H NMR (CDCl3): δ 1.18 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.82 (s, 3 H,
CH3CO), 4.08 (s, 2 H, AcNCH2), 4.11 (q, J = 7.2 Hz, 2 H, CH2CH3),
4.31 (s, 2 H, CH2COO), 7.22–7.34 (m, 7 H, ArH), 7.47 (d, J = 8.4 Hz,
2 H, ArH); 13C NMR (CDCl3): δ 14.1, 22.1, 51.3, 51.8, 61.3, 122.6,
127.9, 128.0, 129.5, 130.1, 133.1, 140.7, 143.6, 168.2, 168.7, 170.6;
HRMS-ESI (positive) calcd for C20H21BrN2NaO4+ [M + Na]+:
455.0577; found: 455.0579; Eluent: PE/acetone (2/1, v/v), Rf = 0.37.
Ethyl 2-(N-mesityl-2-(N-phenyacetamido)acetamido)acetate (3j):
1
Red-brown oil (19%), IR: 1751 (C=O), 1668 (C=O) cm−1; H NMR
(CDCl3): δ 1.25 (t, J = 7.2 Hz, 3H, CH2CH3), 1.89 (s, 3H, CH3C=O),
2.27 (s, 9H, 3 xArCH3), 4.00 (s, 2H, CH2COO), 4.14 (s, 2H,AcNCH2),
4.19 (q, J = 7.2 Hz, 2H, CH2CH3), 6.91 (s, 2H, ArH), 7.28–7.39
(m, 5H, ArH); 13C NMR (CDCl3): δ 14.1, 18.1, 20.9, 22.2, 51.46,
51.49, 61.1, 127.88, 127.92, 129.5, 130.0, 136.5, 137.0, 138.6, 143.8,
168.4, 168.9, 170.7; HRMS-ESI (positive) calcd for C23H28N2NaO4+
[M + Na]+: 419.1941; found: 419.1944; Eluent: PE/acetone (2/1, v/v),
Rf = 0.33.
Ethyl 2-(N-phenyl-2-(N-phenylbenzamido)acetamido)acetate (3k):
Pale yellow oil (54%), IR: 1749 (C=O), 1682 (C=O), 1651 (C=O)
1
cm−1; H NMR (CDCl3): δ 1.25 (t, J = 7.2 Hz, 3H, CH2CH3), 4.19
Ethyl 2-(N-(3-(methylthio)phenyl)-2-(N-phenylacetamido)acetam-
ido)acetate (3d): Light yellow oil (65%), IR: 1749 (C=O), 1676 (C=O)
cm−1; 1H NMR (CDCl3): δ 1.20 (t, J = 7.2 Hz, 3H, CH2CH3), 1.84 (s,
3H, CH3C=O), 2.42 (s, 3H, SCH3), 4.13 (q, J = 7.2 Hz, 2H, CH2CH3),
4.14 (s, 2H, AcNCH2), 4.31 (s, 2H, CH2COO), 7.12 (d, J = 8.0 Hz, 1H,
ArH), 7.17 (d, J = 8.0 Hz, 1H, ArH), 7.23–7.29 (m, 3H, ArH), 7.29–
7.35 (m, 4H); 13C NMR (CDCl3): δ 14.1, 15.3, 22.1, 51.4, 51.7, 61.3,
124.4, 125.2, 126.1, 127.9, 128.0, 130.0, 130.1, 141.1, 142.2, 143.7,
168.3, 168.8, 170.6; HRMS-ESI (positive) calcd for C21H24N2NaO4S+
[M + Na]+: 423.1349; found: 423.1350; Eluent: PE/acetone (2/1, v/v),
Rf = 0.34.
(q, J = 7.2 Hz, 2H, CH2CH3), 4.42 (s, 2H, CH2COO), 4.44 (s, 2H,
NCH2CON), 7.07–7.23 (m, 8H, ArH), 7.32–7.52 (m, 7H, ArH); 13C
NMR (CDCl3): δ 14.2, 51.5, 52.9, 61.3, 126.6, 127.2, 127.6, 128.3,
128.8, 128.9, 129.0, 129.7, 130.0, 135.4, 141.6, 144.3, 168.5, 169.0,
170.6; HRMS-ESI (positive) calcd for C25H24N2NaO4+ [M + Na]+:
439.1628; found: 439.1630; Eluent: PE/acetone (2/1, v/v), Rf = 0.48.
Ethyl 2-(2-benzamido-N-phenylacetamido)acetate (3l): White
solids (35%), m.p. 128–130 °C, IR: 3433 (NH), 1746 (C=O), 1677
(C=O), 1654 (C=O) cm−1; 1H NMR (CDCl3): δ 1.27 (t, J = 7.2 Hz, 3H,
CH2CH3), 4.02 (d, J = 4.0 Hz, 2H, NCH2CON), 4.21 (q, J = 7.2 Hz,
2H, CH2CH3), 4.40 (s, 2H, CH2COO), 7.24 (t, J = 4.0 Hz, 1 H, NH),
7.37–7.48 (m, 8H, ArH), 7.79 (d, J = 7.2 Hz, 2H, ArH); 13C NMR
Ethyl 2-(N-(4-chlorophenyl)-2-(N-phenylacetamido)acetamido)-
acetate (3e): Pale yellow oil (70%), IR: 1747 (C=O), 1685 (C=O)

JOURNAL OF CHEMICAL RESEARCH 2013 463
(CDCl3): δ 14.2, 42.5, 51.6, 61.5, 127.0, 128.0, 128.5, 129.3, 130.3,
131.5, 133.9, 140.6, 167.0, 168.7, 169.2; HRMS-ESI (positive) calcd
for C19H20N2NaO4+ [M + Na]+: 363.1315; found: 363.1316; Eluent:
PE/acetone (2/1, v/v), Rf = 0.23.
135.0, 142.4, 142.8, 166.4, 169.1; HRMS-ESI (positive) calcd
for C19H19NNaO3+ [M + Na]+: 332.1257; found: 332.1254; Eluent:
PE/acetone (2/1, v/v), Rf = 0.29.
Ethyl 2-(2-(1,3-dioxoisoindolin-2-yl)-N-phenylacetamido)acetate
(3m): Pale yellow solids (22%), m.p. 172–174 °C, IR: 1751 (C=O),
We thank the National Natural Science Foundation of China
(Grant No. 21272170) for their financial support of our
program.
1
1724 (C=O), 1678 (C=O) cm−1; H NMR (CDCl3): δ 1.28 (t, J =
7.2 Hz, 3H, CH2CH3), 4.21 (q, J = 7.2 Hz, 2H, CH2CH3), 4.27 (s, 2H,
CH2CON), 4.40 (s, 2H, CH2COO), 7.42–7.47 (m, 1H, ArH), 7.49–
7.54 (m, 2 H, ArH), 7.56–7.59 (m, 2H, ArH), 7.71–7.74 (m, 2H, ArH),
7.85–7.88 (m, 2 H, ArH); 13C NMR (CDCl3): δ 14.1, 39.7, 51.6, 61.4,
123.5, 128.3, 129.1, 130.2, 132.2, 134.0, 141.1, 166.4, 167.7, 168.5;
HRMS-ESI (positive) calcd for C20H18N2NaO5+ [M + Na]+: 389.1108;
found: 389.1110; Eluent: PE/acetone (2/1, v/v), Rf = 0.37.
Received 23 April 2013; accepted 26 May 2013
Paper 1301908 doi: 10.3184/174751913X13729583884275
Published online: 9 August 2013
References
Ethyl 2-(3-(1,3-dioxoisoindolin-2-yl)-N-phenylpropanamido)acetate
(3n): Pale yellow solids (69%), m.p. 115–116 °C, IR: 1769 (C=O),
1725 (C=O), 1665 (C=O) cm−1; 1H NMR (CDCl3): δ 1.28 (t, J = 7.2 Hz,
3H, CH2CH3), 2.56 (t, J = 7.6 Hz, 2H, CH2CON), 3.98 (t, J = 7.6 Hz,
2H, NCH2CH2), 4.20 (q, J = 7.2 Hz, 2H, CH2CH3), 4.37 (s, 2H,
CH2COO), 7.33–7.44 (m, 5H, ArH), 7.68–7.71 (m, 2H, ArH), 7.80–
7.83 (m, 2H, ArH); 13C NMR (CDCl3): 14.1, 32.4, 34.1, 51.1, 61.2,
123.1, 128.1, 128.5, 129.9, 132.0, 133.9, 142.2, 167.9, 168.9, 170.3;
HRMS-ESI (positive) calcd for C21H20N2NaO5+ [M + Na]+: 403.1264;
found: 403.1265; Eluent: PE/acetone (2/1, v/v), Rf = 0.45.
Ethyl 2-(N,2-diphenylacetamido)acetate (3o): Light yellow oil
(58%), IR: 1749 (C=O), 1671 (C=O) cm−1; 1H NMR (CDCl3): δ 1.26
(t, J = 7.2 Hz, 3H, CH2CH3), 3.54 (s, 2H, PhCH2), 4.20 (q, J = 7.2 Hz,
2H, CH2CH3), 4.38 (s, 2H, CH2COO), 7.08–7.10 (m, 2H, ArH),
7.17–7.27 (m, 3H, ArH), 7.28–7.32 (m, 2H, ArH), 7.34–7.42 (m, 3H,
ArH); 13C NMR (CDCl3): δ 14.2, 40.7, 51.6, 61.2, 126.6, 128.3,
128.37, 128.43, 129.1, 129.7, 135.1, 142.8, 169.1, 171.4; HRMS-ESI
(positive) calcd for C18H19NNaO3+ [M + Na]+: 320.1257; found:
320.1260; Eluent: PE/EtOAc (3/1, v/v), Rf = 0.23.
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Ethyl 2-(N-phenylbenzamido)acetate (3p): Pale yellow oil (13%),
1
IR: 1747 (C=O), 1653 (C=O) cm−1; H NMR (CDCl3): δ 1.31 (t,
J = 7.2 Hz, 3H, CH2CH3), 4.25 (q, J = 7.2 Hz, 2H, CH2CH3), 4.62 (s,
2H, CH2C=O), 7.14–7.29 (m, 8H, ArH), 7.36 (d, J = 7.6 Hz, 2H, ArH);
13C NMR (CDCl3): δ 14.2, 52.3, 61.4, 126.9, 127.5, 127.7, 128.8,
129.2 129.9, 135.1, 143.8, 169.1, 170.7. The spectra data are consis-
tent with those reported.27 Eluent: PE/EtOAc (3/1, v/v), Rf = 0.26.
Ethyl 2-(N-phenylcinnamamido)acetate (3q): Light yellow oil
1
(29%), IR: 1745 (C=O), 1657 (C=O), 1620 (C=C) cm−1; H NMR
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26 E. Guenin, M. Monteil, N. Bouchemal, T. Prange and M. Lecouvey, Eur. J.
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CH2CH3), 4.52 (s, 2H, CH2COO), 6.41 (d, J = 15.6 Hz, 1 H, ArCH=),
7.2807.35 (m, 5H, ArH), 7.38–7.42 (m, 3H, ArH), 7.44–7.49 (m, 2H,
ArH), 7.74 (d, J = 15.6 Hz, 1H, =CHC=O); 13C NMR (CDCl3): δ 14.2,
51.7, 61.3, 117.9, 128.0, 128.1(overlap, 2C), 128.7, 129.67, 129.71,
27 G. Belanger, M. April, E. Dauphin and S. Roy, J. Org. Chem., 2007, 72,
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