Efficient ligand-free, palladium-catalyzed amidocarbonylation in ionic liquids: Facile synthesis of N-acyl-α-arylglycines

Article abstract of DOI:10.1080/00397910802369588

A ligand-free, palladium-catalyzed amidocarbonylation reaction of aromatic aldehyde, acetamide, and CO in ionic liquids [C4mim]PF6, [C6mim]PF6, [C8mim]PF6, and [C6mim]BF4 as solvents is developed. The yields decreased in the order [C6mim]PF6 > [C8mim]PF6 > [C4mim]PF6 > [C6mim]BF4, and substrate concentration affected the catalytic activity of amidocarbonylation. The excellent yield with up to 98% in amidocarbonylation of benzaldehyde was obtained using 15 mol% LiBr · H2O and 6 mol% H2SO4 at 80°C. This reaction could proceed smoothly, resulting in several functionalized ortho-, meta-, and para-substituted N-acyl-α-phenylglycines in moderate to good yields, and o-tolualdehyde and m-tolualdehyde as substrates were amidocarbonylated for the first time in [C6mim]PF6. A significant dependence of product yield on both substituent position and electronic effect of aromatic aldehyde was observed. The ligand-free synthetic method and convenient separation of the products highlighted the versatility of this newly developed methodology. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802369588

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Efficient Ligand-Free,
Palladium-Catalyzed
Amidocarbonylation in Ionic
Liquids: Facile Synthesis of N-
Acyl-α-arylglycines
Qing-Lu Zhao a b , Min Yang a & Lai-Lai Wang a
a State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Lanzhou Institute of Chemical
Physics , Chinese Academy of Sciences , Lanzhou ,
China
b Graduate University of Chinese Academy of
Sciences , Beijing , China
Published online: 07 Nov 2008.
To cite this article: Qing-Lu Zhao , Min Yang & Lai-Lai Wang (2008) Efficient Ligand-
Free, Palladium-Catalyzed Amidocarbonylation in Ionic Liquids: Facile Synthesis
of N-Acyl-α-arylglycines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:24, 4460-4473, DOI:
10.1080/00397910802369588
To link to this article: http://dx.doi.org/10.1080/00397910802369588
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Synthetic Communications1, 38: 4460–4473, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369588
Efficient Ligand-Free, Palladium-Catalyzed
Amidocarbonylation in Ionic Liquids: Facile
Synthesis of N-Acyl-a-arylglycines
Qing-Lu Zhao,1,2 Min Yang,1 and Lai-Lai Wang1
1State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, China
2Graduate University of Chinese Academy of Sciences, Beijing, China
Abstract: A ligand-free, palladium-catalyzed amidocarbonylation reaction of
aromatic aldehyde, acetamide, and CO in ionic liquids [C4mim]PF6, [C6mim]PF6,
[C8mim]PF6, and [C6mim]BF4 as solvents is developed. The yields decreased in
the order [C6mim]PF6 > [C8mim]PF6 > [C4mim]PF6 > [C6mim]BF4, and substrate
concentration affected the catalytic activity of amidocarbonylation. The excellent
yield with up to 98% in amidocarbonylation of benzaldehyde was obtained using
15 mol% LiBr ꢀ H2O and 6 mol% H2SO4 at 80 ꢁC. This reaction could proceed
smoothly, resulting in several functionalized ortho-, meta-, and para-substituted
N-acyl-a-phenylglycines in moderate to good yields, and o-tolualdehyde and m-
tolualdehyde as substrates were amidocarbonylated for the first time in
[C6mim]PF6. A significant dependence of product yield on both substituent posi-
tion and electronic effect of aromatic aldehyde was observed. The ligand-free syn-
thetic method and convenient separation of the products highlighted the
versatility of this newly developed methodology.
Keywords: Amidocarbonylation, aromatic aldehyde, ionic liquids, N-acyl-a-aryl-
glycine, palladium
Received April 19, 2008.
Address correspondence to Lai-Lai Wang, State Key Laboratory for Oxo
Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, China. E-mail: wll@lzb.ac.cn
4460

Amidocarbonylation Reaction in Ionic Liquids
4461
Scheme 1. Amidocarbonylation of aldehydes, amides, and CO.
INTRODUCTION
Transition-metal-catalyzed amidocarbonylation of aldehyde, amide, and
carbon monoxide is an efficient multicomponent reaction for the synth-
esis of N-acyl-a-amino acids (Scheme 1),[1–7] which are versatile pharma-
ceuticals, herbicides, anionic sarcosinate tensides, simple dipeptides such
as the sweetener aspartame, important starting materials in peptide
synthesis, and intermediates for the production of biologically active
agents.[8] Traditionally, cobalt,[1] palladium,[2–5] rhodium, iridium, ruthe-
nium,[6] and platinum[7] catalysts have been applied in this amidocarbo-
nyltion reaction. Recently, palladium has emerged as a preferable
catalyst for this reaction because of its higher catalytic activity under rela-
tively mild conditions. Ligand triphenylphosphine and high-boiling-point
organic solvent N-methylpyrrolidone (NMP, bp 202 ꢁC) are generally
used in this homogeneous palladium-catalyzed amidocarbonylation reac-
tion, which complicate the separation of the products.[2–4] In addition,
some aldehydes such as indole aldehydes, carbohydratealdehydes, iodo-
and bromo-substituted aldehydes, and a few arylacetaldehydes as sub-
strates are not amenable to this amidocarbonylation reaction, and up
to 35 mol% of bromide salts as cocatalyst are generally used.[2]
Ionic liquids (ILs), potential green solvents, have successfully
replaced the conventional organic solvents in numerous organic and cat-
alytic reactions, such as Friedel–Crafts reaction,[9] Heck reaction,[10]
Diels–Alder reaction,[11] allylation,[12] olefin dimerization and oligomeri-
zation,[13] hydrogenation,[14] Mannich reaction,[15] and hydroformyla-
tion.[16] Moreover, they could simplify product separation and enhance
reaction efficiency. Jiang et al. described the amidocarbonylation reac-
tion catalyzed by palladium–phosphine complex in halide anion ILs.
However, merely moderate yield (up to 53%) was obtained when aro-
matic aldehydes were employed as reaction substrates, and hydrophilic
halide anion ILs as solvents complicate the manipulation of reaction.[5b]
Our aim was to develop environmentally friendly catalytic systems for
amidocarbonylation, and the use of ILs [C4mim]PF6, [C6mim]PF6,
[C8mim]PF6, and [C6mim]BF4 as solvents for related endeavors remains

4462
Q.-L. Zhao, M. Yang, and L.-L. Wang
unexplored. Herein, we report our initial studies on phosphine-free,
palladium-catalyzed amidocarbonylation of aromatic aldehydes in ionic
liquids [C4mim]PF6, [C6mim]PF6, [C8mim]PF6, and [C6mim]BF4 as sol-
vents, leading to various N-acyl-a-arylglycines in moderate to excellent
yields with a decreased amount of co-catalyst LiBr ꢀ H2O (15 mol%).
RESULTS AND DISCUSSION
An initial investigation of amidocarbonylation was carried out using ben-
zaldehyde (1a) and acetamide (2) as probe substrates to optimize reaction
conditions, and the results are summarized in Table 1. By using PdBr2 as
catalytic precursor and LiBr ꢀ H2O and H2SO4 as cocatalysts, the reaction
could generate product N-acetyl-a-phenylglycine (3a) with yield of 71%
Table 1. Palladium-catalyzed amidocarbonylation of benzaldehyde and aceta-
mide in ionic liquidsa
Substrate
concentration Temperature Yield
LiBr H2SO4
Entry Catalyst (mol%) (mol%) Solventb
(mol ꢀ Lꢂ1
)
(ꢁC)
(%)c
1
2
3
4d
5
6
7
8
9
10
11
12
13
PdBr2
Pd(OAc)2
PdCl2
15
15
15
6
6
6
6
6
6
6
6
6
6
3
6
6
[C4mim]PF6
[C4mim]PF6
[C4mim]PF6
[C6mim]PF6
[C6mim]PF6
[C8mim]PF6
[C6mim]BF4
[C6mim]PF6
[C6mim]PF6
[C6mim]PF6
[C6mim]PF6
[C6mim]PF6
[C6mim]PF6
3.1
3.1
3.1
3.1
3.1
3.1
3.1
2.3
1.8
2.3
2.3
2.3
2.3
80
80
80
80
80
80
80
80
80
80
80
60
100
71
58
67
11
93
76
49
98
61
48
64
23
57
PdBr2=PPh3 15
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
15
15
15
15
15
10
15
15
15
aReaction conditions: 1a (30 mmol), 2 (25 mmol), Pd catalytic precursor
(0.5 mol%), CO (5 MPa of initial pressure), 12 h.
bAbbreviations: [C4mim] denotes 1-n-butyl-3-methylimidazolium, [C6mim] denotes
1-n-hexyl-3-methylimidazolium, and [C8mim] denotes 1-n-octyl-3-methyl imidazolium.
cYield of isolated product.
d0.5 mol% PdBr2 and 1 mol% PPh3 were used.

Amidocarbonylation Reaction in Ionic Liquids
4463
in [C4mim]PF6 medium (Table 1, entry 1). The result indicated that ami-
docarbonyltion could be readily carried out in [C4mim]PF6. It has been
known that the amidocarbonylation of benzaldehyde and acetamide
under ligand-free condition in ILs [C4mim]PF6 were not presented by
Jiang et al.[5b] Encouraged by our result, we then tested effect of other
reaction parameters on reactivity under IL media. Evaluation of palla-
dium salts, such as PdBr2, Pd(OAc)2, and PdCl2, showed that PdBr2
was the most efficient catalyst precursor (Table 1, entries 1–3).
It should be noted that the reaction efficiency was affected by
both cationic scaffold and anionic counterpart of ILs. With application
of [C6mim]PF6, [C8mim]PF6, and [C6mim]BF4 as media, the yields
decreased in the order [C6mim]PF6 > [C8mim]PF6 > [C6mim]BF4 (Table 1,
entries 5–7). Thus, for the imidazolium-based ILs, hydrophobic
[C4mim]PF6, [C6mim]PF6, and [C8mim]PF6 were more suitable for this
reaction than hydrophilic [C6mim]BF4. Similar anion effect of ILs med-
iun on reaction efficiency has also been known for the carbonylation of
aryl halides[17] and copolymerization of styrene and carbon monoxide.[18]
The optimum concentration of substrate was 2.3 mol Lꢂ1 (Table 1, entries
5, 8, and 9). The experimental results showed that substrate concentra-
tion had an impact on the catalytic performance of amidocarbonylation.
Similar results were observed for Beckmann rearrangement of ketoximes
in ionic liquids.[19]
LiBr ꢀ H2O and H2SO4 as cocatalysts have an enhancing effect on this
reaction. A variation in the amounts of both cocatalysts resulted in sub-
stantial change of the yield. The best result was obtained with 15 mol%
LiBr ꢀ H2O and 6 mol% H2SO4 (Table 1, entries 8, 10, and 11). Finally,
it was important to note that ideal reaction temperature appeared to be
at 80 ꢁC (Table 1, entries 8, 12, and 13). Considering the almost stoichio-
metric yield of up to 98%, the effect of other reaction conditions on the
reactivity was not further investigated. So far, to our knowledge, it was
the highest yield achieved in amidocarbonylation of benzaldehyde
(Table 1, entry 8).
Under the optimal reaction conditions, amidocarbonylation of
some aromatic aldehydes (1b–i) were carried out. As shown in Table 2,
several functionalized ortho-, meta-, and para-substituted N-acetyl-a-
tolylglycines and N-acetyl-a-methoxyphenylglycines (3b–g) were pre-
pared with moderate to good yields in [C6mim]PF6 medium. A significant
dependence of product yield on both substituent position and electronic
effect of aromatic systems was observed, in which m-substituted benzal-
dehydes gave higher yield than o- or p-substituted ones (Table 2,
entries 1–6). However, by employing o-chlorobenzaldehyde (1h) and
p-chlorobenzaldehyde (1i) as reaction substrate, much lower yields
were afforded (Table 2, entries 7 and 8). These results clearly indicate that

4464
Q.-L. Zhao, M. Yang, and L.-L. Wang
Table 2. Palladium-catalyzed amidocarbonylation of aromatic aldehydes and
a
acetamide in [C6mim]PF6
Yield
(%)b
Entry
1
Aldehyde
Product
60
2
83
3
80
50
4c
5c
60
6c
52
(Continued )

Amidocarbonylation Reaction in Ionic Liquids
4465
Table 2. Continued
Yield
(%)b
Entry
7
Aldehyde
Product
14
8
26
aUnless otherwise noted, the reactions were performed with 1 (30 mmol), 2
(25 mmol), PdBr2 (0.5 mol%), H2SO4 (6 mol%), and LiBr ꢀ H2O (15 mol%) in
11 mL [C6mim]PF6 under CO (5 MPa of initial pressure) at 80 ꢁC for 12 h.
bYield of isolated product.
cThe reaction required 12 mol% H2SO4.
benzaldehydes bearing electon-donating substituents react more readily
than those with electron-withdrawing groups. This possibly indicates that
a better stabilization of an intermediate benzylic cation (III, scheme 2)
bearing an electron-donating substituent was very important when func-
tionalized aromatic aldehydes (1b–i) were used as substrates. It was
shown that o-tolualdehyde (1b) and m-tolualdehyde (1c) as reaction
substrates were first amidocarbonylated by this method. To the best of
our knowledge, the amidocarbonylation reaction of 1b or 1c in organic
solvents has not been reported.
The mechanism for palladium-catalyzed amidocarbonylation of aro-
matic aldehyde in NMP as solvent had been proposed.[2,3] Reaction of
aldehyde with amide generated N-(a-hydroxyalkyl)amide (I), then
nucleophilic substitution of lithium bromide to I gave intermediate
N-(a-bromoalkyl)amide (II) in the presence of cocatalysts H2SO4. Oxida-
tive addition of II to palladium is followed by CO insertion and hydro-
lysis to yield the product N-acyl-a-arylglycine (Scheme 2). Interestingly,
several results with LiBr ꢀ H2O and H2SO4 as cocatalysts have promoting
effects on the reaction; PdBr2 performs the best catalysis among the used
catalytic precursors, and benzaldehydes with electron-donating substitu-
ents react more efficiently than those bearing electron-withdrawing groups.
These are consistent with those in which NMP is solvent. However, it could
not be understood why triphenylphosphine as additional ligand had so

4466
Q.-L. Zhao, M. Yang, and L.-L. Wang
Scheme 2. Proposed mechanism for the Pd-catalyzed amidocarbonylation.
much detrimental effect on this reaction in ILs. Further investigation on the
question and the reuse of ILs is currently under way in our group.
It is worth pointing out that the separation process of these products
turned out to be more convenient using [C6mim]PF6 than NMP and
Jiang’s procedure.[2,5] [C6mim]PF6 is insoluble in water[20]; thus, to treat
the produced liquid mixture with aqueous NaOH could produce two
phases of liquids. The aqueous phase containing sodium N-acyl-
a-arylglycinate was adjusted to pH ¼ 2 with 85% phosphoric acid, and
the product N-acyl-a-arylglycine could be easily precipitated.
In conclusion, we have developed a palladium-catalyzed amidocar-
bonylation reaction of aromatic aldehyde, acetamide, and CO under
ligand-free and IL media. In the absence of any phosphine ligand, the
reaction could proceed smoothly with only 15 mol% of LiBr ꢀ H2O as
co catalyst. Several functionalized N-acyl-a-arylglycines were synthe-
sized by this preparative route to extend the scope of reaction
substrates, and up to 98% yield of N-acetyl-a-phenylglycine was
obtained in [C6mim]PF6 as solvent, which was the best result achieved
in amidocarbonylation of benzaldehyde to date. We believe the ligand-
free synthetic method and convenient separation process based on ILs
are attractive for many organic chemists working in this and related
areas.

Amidocarbonylation Reaction in Ionic Liquids
EXPERIMENTAL
4467
1H NMR and 13C NMR spectra were recorded in DMSO-d6 solution on
400 and 100 MHz, respectively, using Bruker AM 400 spectrometer with
tetramethylsilane (TMS, d ¼ 0.00) as internal standard. Proton chemical
shifts (d) and coupling constants (J) were given in parts per million
(ppm) and in hertz, respectively. Spin multiplicities were given as s (sing-
let), d (doublet), t (triplet), and m (multiplet) as well as b (broad). IR
spectra were taken with Bruker IFS 120 HR FT-IR spectrometer. MS
spectra were obtained on Waters ZQ 4000. All the melting points were
determined on an X-4 Electrothermal digital melting-point apparatus
and are uncorrected. The ILs used herein were prepared according to
the reported procedures.[20] All other reagents were commercially
available.
Typical Experimental Procedure
In a 200-mL stainless steel reactor with a magnet-driven propeller stir-
rer, 30 mmol aromatic aldehyde, 25 mmol acetamide, 0.5 mol% PdBr2,
15 mol% LiBr ꢀ H2O, 6 mol% H2SO4, and 11 mL ILs were allowed to
react at 50 bar of initial CO pressure and 80 ꢁC for 12 h. At the end
of this period, the residue gas was released, and 20 mL of dichloro-
methane was added to the reactor. Treatment of the mixture with
30 mL of aqueous 1.5 mol Lꢂ1 NaOH formed two phases of liquid.
The aqueous phase was extracted with dichloromethane (30 mL ꢃ 3)
and then adjusted to pH ¼ 2 with 85% phosphoric acid. The white pre-
cipitate was filtered off, washed by distilled water, and dried in vacuo.
The products were recrystallized from water=methanol mixtures
(v=v, 1=1) and characterized by 1H NMR, 13C NMR, IR, and mass
spectroscopy.
Data
N-Acetyl-a-phenylglycine (3a)[5b]
White solid (4.75 g, 98% yield); mp 199–201 ꢁC. IR (KBr): 3343, 1716,
1601, 1544 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 8.61 (d,
J ¼ 7.6 Hz, 1H), 7.34 (m, 5H), 5.30 (d, J ¼ 7.6 Hz, 1H), 1.88 (s, 1H).
13C NMR (100 MHz, DMSO-d6): d ¼ 172.1, 169.1, 137.2, 128.5, 128.0,
127.7, 56.3, 22.3. ESI-MS: m=z (%) ¼ 191.9 (85) [M–H], 147.8 (100)
[M–COOH].

4468
Q.-L. Zhao, M. Yang, and L.-L. Wang
N-Acetyl-a-(2-tolyl)glycine (3b)
White solid (3.1 g, 80% yield); mp 196–197 ꢁC. IR (KBr): 3363, 1740,
1608, 1546 cmꢂ1. 1H NMR (400 MHz, DMSO-d6): d ¼ 8.57 (d, J ¼ 7.2 Hz,
Hz, 1H), 7.19 (m, 4H), 5.25 (d, J ¼ 7.6 Hz, 1H), 2.29 (s, 3H), 1.88 (s, 3H).
13C NMR (100 MHz, DMSO-d6): d ¼ 172.1, 169.2, 137.7, 137.1, 128.6,
128.5, 128.3, 124.8, 56.3, 22.3, 21.0. ESI-MS: m=z (%) ¼ 206.1 (97)
[M–H], 162.1 (100) [M–COOH], 163.1 (12) [M–H–CH3CO].
N-Acetyl-a-(3-tolyl)glycine (3c)
White solid (4.3 g, 83% yield); mp 202–203 ꢁC. IR (KBr): 3361, 3335,
1
1704, 1617, 1544 cmꢂ1. H NMR (400 MHz, DMSO-d6): d ¼ 12.80 (s,
1H), 8.54 (d, J ¼ 7.6 Hz, 1H), 7.22 (m, 4H), 5.52 (d, J ¼ 7.6 Hz, 1H),
2.33 (s, 3H), 1.86 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d ¼ 172.4,
169.1, 136.3, 136.0, 130.4, 127.9, 127.1, 126.2, 52.8, 22.2, 19.0. ESI-MS:
m=z (%) ¼ 206.1 (62) [M–H], 162.1 (100) [M–COOH], 163.1 (12)
[M–H–CH3CO].
N-Acetyl-a-(4-tolyl)glycine (3d)[2b]
White solid (4.2 g, 81% yield); mp 226–228 ꢁC. IR (KBr): 3339, 1717,
1546, 1601 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 12.6 (s, 1H),
8.47 (d, J ¼ 7.60 Hz, 1H), 7.26 (d, J ¼ 8.0 Hz, 2H), 7.16 (d, J ¼ 7.6 Hz,
2H), 5.25 (d, J ¼ 7.2 Hz, 1H), 2.28 (s, 3H), 1.87 (s, 3H). 13C NMR
(100 MHz, DMSO-d6): d ¼ 172.5, 168.9, 136.9, 134.9, 128.9, 127.5, 56.3,
22.3, 20.7. ESI–MS: m=z (%) ¼ 413.4 (22) [2M–H], 205.8 (100) [M–H],
161.7 (17) [M–COOH].
N-Acetyl-a-(2-methoxyphenyl)glycine (3e)[21]
White solid (2.8 g, 50% yield); mp 165–167 ꢁC. IR (KBr): 3358, 1740,
1
1604, 1531 cmꢂ1. H NMR (400 MHz, DMSO-d6): d ¼ 12.54 (bs, 1H),
8.35 (d, J ¼ 8.0 Hz, 1H), 7.30 (m, 2H), 7.01 (d, J ¼ 8.4 Hz, 1H), 6.93
(dd, J ¼ 7.6, 7.6 Hz, 1H), 5.63 (d, J ¼ 7.6 Hz, 1H), 3.77 (s, 3H), 1.85 (s,
3H). 13C NMR (100 MHz, DMSO-d6): d ¼ 172.3, 169.1, 156.7, 129.3,
128.6, 125.6, 120.4, 111.3, 55.6, 50.3, 22.3. ESI-MS: m=z (%) ¼ 222.2
(70) [M–H], 178.1 (100) [M–COOH], 179.1 (19) [M–H–CH3CO], 163.0
(18) [M–H–CH3CONH].

Amidocarbonylation Reaction in Ionic Liquids
4469
N-Acetyl-a-(3-methoxyphenyl)glycine (3f)[2g]
White solid (3.4 g, 60% yield); mp 146–147 ꢁC. IR (KBr): 3343, 1718,
1610, 1587, 1540 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 8.58 (d,
J ¼ 7.6 Hz, 1H), 7.27 (dd, J ¼ 8.4, 8.0 Hz, 1H), 6.92 (m, 3H), 5.28 (d,
J ¼ 7.6 Hz, 1H), 3.73 (s, 3H), 1.88 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): d ¼ 172.0, 169.1, 159.3, 138.7, 129.6, 119.9, 113.4, 113.3,
56.2, 55.1, 22.3. ESI-MS: m=z (%) ¼ 222.2 (58) [M–H], 178.1 (100)
[M–COOH], 179.1 (19) [M–H–CH3CO].
N-Acetyl-a-(4-methoxyphenyl)glycine (3g)[2b]
White solid (2.9g, 52% yield); mp 210–212 ꢁC. IR (KBr): 3340, 1717,
1612, 1547, 1516cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 12.7 (s,
1H), 8.52 (d, J ¼ 7.6 Hz, 1H), 7.29 (d, J ¼ 8.4 Hz, 2H), 6.92 (d, J ¼ 8.8 Hz,
Hz, 2H), 5.22 (d, J ¼ 7.60 Hz, 1H), 3.73 (s, 3H), 1.86 (s, 3H). 13C NMR
(100 MHz, DMSO-d6): d ¼ 172.3, 169.0, 160.0, 129.1, 129.0, 113.9, 55.6,
55.2, 22.3. ESI-MS: m=z (%) ¼ 445.4 (12) [2M–H], 219.9 (100) [M–H],
177.8 (27) [M–COOH], 178.8 (10) [M–H–CH3CO].
N-Acetyl-a-(2-chlorophenyl)glycine (3h)[2b,22]
White solid (0.8 g, 14% yield); mp 164–165 ꢁC. IR (KBr): 3360, 1717,
1610, 1537 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 13.01 (s, 1H),
8.68 (d, J ¼ 8.0 Hz, 1H), 7.40 (m, 4H), 5.76 (d, J ¼ 7.6 Hz, 1H), 1.88
(s, 3H). 13C NMR (100 MHz, DMSO-d6): d ¼ 171.4, 169.1, 135.4,
133.0, 129.7, 129.5, 129.1, 127.5, 53.1, 22.2. ESI-MS: m=z
(%) ¼ 226.2 (18) [M–H], 182.0 (90) [M–COOH], 184.0 (28) [M(37Cl)–
COOH].
N-Acetyl-a-(4-chlorophenyl)glycine (3i)[2b]
White solid (1.5 g, 26% yield); mp 196–198 ꢁC. IR (KBr): 3339, 1717,
1546, 1601 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 13.0 (s, 1H),
8.67 (d, J ¼ 7.6 Hz, 1H), 7.41 (m, 4H), 5.33 (d, J ¼ 7.60 Hz, 1H),
1.88 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d ¼ 171.7, 169.1,
136.4, 132.6, 129.5, 128.5, 55.5, 22.3. ESI-MS: m=z (%) ¼ 453.3 (25)
[2M–H], 225.9 (100) [M–H], 181.8 (96) [M–COOH], 183.7 (32)
[M(37Cl)–COOH].

4470
Q.-L. Zhao, M. Yang, and L.-L. Wang
ACKNOWLEDGMENTS
We are grateful for the financial support of this work by the National
Natural Science Foundation of China (Nos. 20343005, 20473107,
20673130, and 20773147).
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