Synthesis of α-Hydroxycarboxylic Acid Anilides via Copper-Catalyzed C-N Coupling of α-Hydroxyamides with Aryl Halides

Article abstract of DOI:10.1055/s-0035-1560473

The synthesis of highly important α-hydroxycarboxylic acid anilides via copper-catalyzed chemoselective C-N coupling reactions of α-hydroxyamides and aryl halides is described. This highly selective N-arylation process demonstrates wide substrate scope, c

Full text of DOI:10.1055/s-0035-1560473

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3751–3757
paper
3751
Z. Li et al.
Paper
Synthesis
Synthesis of α-Hydroxycarboxylic Acid Anilides via Copper-Cata-
lyzed C–N Coupling of α-Hydroxyamides with Aryl Halides
Zhijie Li
OH
OH
H
X
Quan Wen
N
NH2
CuI, K2CO3, DMEDA
toluene, 110 °C, 24 h
R
Lihong Zhou
Xingmei Deng
Qingle Zeng*
+
R
O
O
R
R
Institute of Green Catalysis and Synthesis, College of Materials
and Chemistry & Chemical Engineering, Chengdu University of
Technology, Chengdu 610059, P. R. of China
qinglezeng@hotmail.com
qlzeng@cdut.edu.cn
Received: 21.06.2015
Accepted after revision: 18.08.2015
Published online: 09.09.2015
There are three mainly synthetic methods for the prepa-
ration of highly valuable α-hydroxycarboxylic acid anilides
currently available: (1) the transformation of α-hydroxy-
carboxylic acids into acyl chlorides using halogenating re-
agents, followed by condensation of the resulting acyl ha-
lides with anilines;14 (2) the condensation of α-hydroxycar-
boxylic acids and anilines with the assistance of
condensation reagents;15 (3) titanium tetrachloride (TiCl4)
mediated additions of isocyanides to aldehydes.16
DOI: 10.1055/s-0035-1560473; Art ID: ss-2015-h0391-op
Abstract The synthesis of highly important α-hydroxycarboxylic acid
anilides via copper-catalyzed chemoselective C–N coupling reactions of
α-hydroxyamides and aryl halides is described. This highly selective N-
arylation process demonstrates wide substrate scope, cost savings and
easy operation. In addition, the chirality of L-3-phenyllactamide is pre-
served during the reaction.
It should be noted that lactic acid anilides and mandelic
acid anilides can be synthesized using other methods. For
example, the condensation of mandelic acid and N-tosyl-
anilines,17 the copper-catalyzed transamidation of man-
delamide and anilines,18 the nickel–N,N,N′,N′-tetramethyl-
ethylenediamine (Ni–TMEDA) catalyzed reduction of 2-oxo-
N-2-diphenylacetamide,19 and the coupling of (±)-lact-
amide and iodobenzene to afford the corresponding race-
mic lactic acid anilide.20
Chemoselective carbon–heteroatom cross-coupling re-
actions of hydrazides,21 amino alcohols,22 o-aminobenz-
amides,23 aminophenols,24 phenols and aliphatic alcohols,25
2-aminobenzimidazoles,26 and α-aminoamides27 have been
successfully developed. Hence it is worthwhile to further
study chemoselective C–N cross-coupling reactions of α-
hydroxyamides, which have two types of nucleophilic
group: acylamino and hydroxy.
Key words α-hydroxycarboxylic acid anilides, copper, cross-coupling,
α-hydroxyamides, catalysis, chemoselectivity
α-Hydroxycarboxylic acid anilides are used widely in
medicine and agriculture (Figure 1). So far as lactic acid an-
ilides are concerned, both naproanilide1 and clomeprop2
exhibit highly selective herbicidal activities in rice fields.
Iopamidol3 and ioglucomide4 are non-ionic iodinated con-
trast agents, commonly used in radiology, whilst p-lacto-
phenetide has analgesic and antipyretic activity.5 Bicalut-
amide is an oral non-steroidal anti-androgen used in the
treatment of prostate cancer,6 and hirsutism7 and hydroxy-
flutamide are other examples of commonly used anti-
androgen agents.8
In addition, many further examples of bioactive 3-aryl-
lactic acid anilides have been discovered. Diltiazem, which
is marketed as a single 2S,3S-diastereomer, has emerged as
one of the most important calcium channel blockers in clin-
ical use.9 Other bioactive compounds belonging to this class
of anilides are used as anticancer agents,10 coagulation fac-
tor IXa inhibitors,11 and as inhibitors of factor Xa for pre-
venting or treating coagulation disorders.12 Finally,
BMS961, a mandelic acid anilide derivative, is a selective
agonist of RARγ, a transcriptional regulator.13
In continuation of our studies on coupling reactions,27,28
and in view of the importance of α-hydroxycarboxylic acid
anilides and the practicality of Ullmann-type C–N coupling
reactions,29 we have investigated chemoselective C–N
cross-coupling reactions of α-hydroxyamides for the syn-
thesis of α-hydroxycarboxylic acid anilides, and our results
are reported herein.
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Table 1 Optimization of the Reaction Conditions for the Coupling of
Mandelamide and p-Bromotoluenea
the reasons probably being due to the similar acidities of
the acylamino and hydroxy groups in mandelamide,30,31
and enolization.32
Next, an Ullmann-type coupling reaction was adopted
for the desired transformation. Under common Ullmann-
type reaction conditions, the target product, 2-hydroxy-2-
phenyl-N-(p-tolyl)acetamide, was obtained in 73% yield
(Table 1, entry 2). Furthermore, unwanted o-phenylation
products were not detected.
OH
OH
H
Br
N
NH2
+
O
O
3a
2a
1a
Entry Solvent
Catalyst
Ligand
Base
Yield (%)b
Examination of different solvents demonstrated that
weakly polar non-protic solvents were more suitable for
the coupling reaction (Table 1, entries 2–5), with toluene
giving the highest yield among those tested (Table 1, entry
5). Copper sources such as copper(I) bromide (CuBr) and
copper(I) chloride (CuCl) (Table 1, entries 6 and 7), and oth-
er ligands including N,N,N′,N′-tetramethylethylenediamine
(TMEDA), phenanthroline, L-proline and 1,1′-bi-2-naphthol
(BINOL) (Table 1, entries 8–11) all gave poorer results. In
contrast to C–N coupling reactions of α-aminoamides,29 the
use of a copper catalyst (CuI) without a ligand gave a mod-
erate yield of the desired product (Table 1, entry 12).
Weak bases such as cesium carbonate (Cs2CO3) and po-
tassium phosphate (K3PO4) gave lower yields compared to
potassium carbonate (K2CO3) (Table 1, entries 13 and 14 vs
5), whilst strong bases including potassium hydroxide
(KOH) and potassium tert-butoxide (t-BuOK) resulted in
only trace amounts of the desired product (Table 1, entries
15 and 16). Shortening the reaction time to 15 hours result-
ed in a lower yield (Table 1, entry 17), and doubling the re-
action time gave only a marginal increase in the amount of
product (Table 1, entry 18). Tuning the temperature (Table
1, entries 19 and 20) and manipulating the ratio of man-
delamide and p-bromotoluene (Table 1, entries 5 vs 21 and
22) were not beneficial to the reaction outcome.
With optimized reaction conditions in hand, we next
performed reactions between various aryl halides and
mandelamide (Table 2). The position of the substituents on
the aromatic ring of the aryl bromide had an obvious influ-
ence on the results (Table 2, entries 2 and 3). The use of m-
bromotoluene resulted in a lower yield than that obtained
with p-bromotoluene (Table 2, entries 2 vs 1); o-bromotol-
uene was the poorest substrate among the methyl-substi-
tuted aryl bromides examined (Table 2, entry 3). The cou-
pling reaction with bromobenzene also gave a poorer result
(72% yield) (Table 2, entries 4 vs 1), whilst chlorobenzene
afforded a substantially lower 18% yield (Table 2, entries 5
vs 4). In contrast, iodobenzene proved to be a better sub-
strate (Table 2, entry 6).
1c
2
3
4
5
6
7
8
9
toluene
DMF
Pd2(dba)3
CuI
JohnPhos
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
TMEDA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
73
58
87
88
53
58
80
70
26
40
53
81
67
trace
trace
60
89
58
64
86
78
DMSO
CuI
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CuI
CuI
CuBr
CuCl
CuI
CuI
phenanthroline K2CO3
10
CuI
L-proline
BINOL
K2CO3
K2CO3
K2CO3
11
CuI
12
CuI
–
13
CuI
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
Cs2CO3
K3PO4
KOH
14
CuI
15
CuI
16
CuI
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
17d
18e
19f
20g
21h
22i
CuI
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: mandelamide (1.2 mmol), p-bromotoluene (1.0
mmol), CuI (0.05 mmol), K2CO3 (2.0 mmol), DMEDA (0.1 mmol), toluene
(5 mL), 110 °C, 24 h (unless otherwise noted).
b Yield of isolated product.
c An intractable reaction mixture was obtained.
d Reaction time was 15 h.
e Reaction time was 48 h.
f Reaction run at 90 °C.
g Reaction run at 120 °C.
h Mandelamide (1.0 mmol) and p-bromotoluene (1.0 mmol) were used.
i Mandelamide (1.0 mmol) and p-bromotoluene (1.2 mmol) were used.
DL-mandelamide and p-bromotoluene were chosen as
model substrates in order to investigate the coupling reac-
tion (Table 1). Initially, the cross-coupling of these sub-
strates was performed using tris(dibenzylideneacetone)di-
palladium(0) [Pd2(dba)3] as the catalyst and 2-(di-tert-bu-
tylphosphino)biphenyl (JohnPhos) as the ligand, however,
the reaction mixture proved intractable and no product
was isolated (Table 1, entry 1). Other palladium catalytic
systems were examined, which were equally unsuccessful,
From the above-described results, it appears that sub-
strates with weak electron-donating groups promote this
coupling reaction. Both the m- and p-isomers of bromo-
and iodotoluenes offered better yields than those obtained
from bromo- and iodobenzene, respectively (Table 2, en-
tries 1 and 2 vs 4, and entries 7 and 8 vs 6). However, it
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Synthesis
Table 2 Reactions of Mandelamide and Different Aryl Halidesa
OH
OH
H
X
NH2
N
CuI, K2CO3, DMEDA
toluene, 110 °C, 24 h
R
+
R
O
O
1a
2
3
Entry
ArX
Product
Yield (%)b
1
2
4-MeC6H4Br (2a)
3-MeC6H4Br (2b)
2-MeC6H4Br (2c)
PhBr (2d)
3a
3b
3c
3d
3d
3d
3b
3a
3e
3f
88
82
60
72
18
79
84
90
81
trace
42
3
4
5
PhCl (2e)
6
PhI (2f)
7
3-MeC6H4I (2g)
4-MeC6H4I (2h)
4-MeOC6H4I (2i)
4-O2NC6H4Br (2j)
2-ClC6H4I (2k)
8
9
10
11
3g
a Reaction conditions: mandelamide (1.2 mmol), aryl halide (1.0 mmol), CuI (0.05 mmol), K2CO3 (2.0 mmol), DMEDA (0.1 mmol), toluene (5 mL), 110 °C, 24 h.
b Yield of isolated product.
should be noted that an aryl halide with a strong electron-
donating group such as methoxy gave a slightly lower yield
than those with a weak example (Table 2, entry 9).
In general, electron-withdrawing groups on aryl halides
favor copper-catalyzed C–N cross-coupling reactions.22
However, 1-bromo-4-nitrobenzene gave only a trace of
product in this coupling reaction (Table 2, entry 10). o-
Chloroiodobenzene also gave the corresponding N-arylated
product, but in a lower yield (Table 2, entry 11) due to steric
hindrance and the poorer reactivity of the ortho-chloro
substituent.
In the next step, the reactions of various α-hydroxy-
amides with iodobenzene were examined (Table 3). Except
for p-bromomandelamide, which gave a moderate yield, all
the mandelamides afforded the target products in good to
high yields (Table 3, entries 1–8). Interestingly, a mandel-
amide with an ortho-substituent also gave a good yield of
the expected product (Table 3, entries 4 vs 3). This is proba-
bly due to the fact that the substituent is placed far enough
away from the reaction site and thus the effect of its steric
hindrance is marginal.
It should also be mentioned that p-bromomandelamide
gave a lower yield, probably because the highly active bro-
mo group of this substrate resulted in a self-coupling reac-
tion (Table 3, entry 6). The product of the coupling of lact-
amide and iodobenzene (Table 3, entry 7) is the core struc-
ture of three drugs, namely naproanilide, clomeprop and p-
lactophenetide. The coupling of DL-3-phenyllactamide with
iodobenzene afforded the target product in a very high
yield of 97% (Table 3, entry 8).
In view of the satisfying reaction result of DL-3-phenyl-
lactamide (see Table 3, entry 8), both the L- and DL-isomers
were examined in reactions with three different aryl io-
dides (Table 4). The L-isomer gave yields similar to those
obtained with the DL-isomer (Table 4, entries 1–6). Delight-
fully, all the L-3-phenyllactic acid anilides were formed
with extremely high enantioselectivities (Table 4, entries 2,
4 and 6), and no obvious racemization occurred under the
reaction conditions.
The analgesic and antipyretic agent (R)-p-lactophe-
netide (3q)5 was easily prepared in 87% yield using our re-
ported method (Scheme 1).
H
Br
CuI, K2CO3, DMEDA
toluene, 110 °C, 24 h
N
H2N
OH
+
OH
O
EtO
O
EtO
3q, 87% yield
Scheme 1 Synthesis of (R)-p-lactophenetide (3q)
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Synthesis
O
O
O
HO
HN
HN
OEt
O
Cl
O
HN
Cl
p-lactophenetide
naproanilide
OH
clomeprop
HO
O
F
HN
O
O
O
O
I
I
S
OH
OH
OMe
NC
F3C
NH
O
OH
H
N
Me2N
N
HN
S
O
I
O
O
OH
bicalutamide
iopamidol
diltiazem
O
O
O
NH2
O
OH
HO
P
O
HN
O
HN
N
H
O
O
O
OH
F
S
NH2
OH
N
O
BMS961
US4963539 A1
US6638980 B1
Figure 1 Some representative α-hydroxycarboxylic acid anilides
Table 3 Reactions of Different α-Hydroxyamides with Iodobenzenea
Table 4 Reactions of DL- and L-3-Phenyllactamide with Different Aryl
Iodidesa
OH
OH
H
I
N
OH
CuI, K2CO3
DMEDA
OH
CuI, K2CO3, DMEDA
toluene, 110 °C, 24 h
NH2
R
H
+
R
N
NH2
ArIH
+
O
Ar
toluene, 110 °C
24 h
O
O
O
2f
1
3
1h
2
3
Entry
R
Product
Yield (%)b
Entry Isomer (1h) Ar
Product
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph (1a)
3d
3h
3i
76
84
93
87
78
58
74
97
1
2
3
4
5
6
DL
L
Ph (2f)
DL-3n
L-3n
97
96
92
95
97
94
–
4-BnOC6H4 (1b)
4-ClC6H4 (1c)
2-ClC6H4 (1d)
3-ClC6H4 (1e)
4-BrC6H4 (1f)
Me (1g)
Ph (2f)
99
–
DL
L
4-MeC6H4 (2h)
4-MeC6H4 (2h)
4-MeOC6H4 (2i)
4-MeOC6H4 (2i)
DL-3o
L-3o
3j
93
–
3k
3l
DL
L
DL-3p
L-3p
95
3m
3n
a Reaction conditions: DL- or L-3-phenyllactamide (1.2 mmol), aryl halide
(1.0 mmol), CuI (0.05 mmol), K2CO3 (2.0 mmol), DMEDA (0.1 mmol), tolu-
ene (5 mL), 110 °C, 24 h.
PhCH2 (1h)
a Reaction conditions: α-hydroxyamide (1.2 mmol), iodobenzene (1.0
mmol), CuI (0.05 mmol), K2CO3 (2.0 mmol), DMEDA (0.1 mmol), toluene
(5 mL), 110 °C, 24 h.
b Yield of isolated product.
c Enantiomeric excess determined by chiral HPLC.
b Yield of isolated product.
In conclusion, the synthesis of valuable α-hydroxycar-
boxylic acid anilides via the chemoselective copper(I) io-
dide catalyzed C–N cross-coupling of α-hydroxyamides
with aryl halides has been studied. All the α-hydroxyam-
ides gave only α-hydroxycarboxylic acid anilides without
any of the corresponding O-arylated products being detect-
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Synthesis
ed, thereby verifying that the selectivity of the N-arylation
of α-hydroxyamides is excellent. Moreover, the configura-
tion of the chiral 3-phenyllactamide substrate is main-
tained during the coupling reaction.
N-Phenyl-p-benzyloxymandelamide (3h)
Yield: 0.2798 g (84%); pale yellow solid; mp 110–113 °C.
IR (KBr): 3275, 1637, 1595, 1533, 1446, 1246, 1174, 1067, 1008, 754,
696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.58 (t, J = 8.0 Hz, 2 H),
7.45–7.36 (m, 6 H), 7.35–7.31 (m, 3 H), 7.15 (d, J = 4.0 Hz, 1 H), 7.01
(q, J = 8.0 Hz, 2 H), 5.14 (d, J = 4.0 Hz, 1 H), 5.08 (s, 2 H), 3.37 (d, J = 4.0
Hz, 1 H).
13C NMR (101 MHz, acetone-d6): δ = 170.81 (s), 158.63 (s), 138.70 (s),
137.49 (s), 133.08 (s), 128.64 (s), 128.39 (s), 127.94 (s), 127.71 (s),
127.50 (s), 123.59 (s), 119.39 (d, J = 9.0 Hz), 114.54 (d, J = 15.0 Hz),
73.97 (s), 69.48 (s).
All reactions were carried out under an argon atmosphere. All glass-
ware was dried in an electric oven at 120 °C. All chemicals were pur-
chased from Alfa Aesar, Shanghai Aladdin Reagent Co., Ltd, and
Chengdu Changzheng Chemical Co., and were used as received. Petro-
leum ether (PE) refers to the fraction boiling in the 60–90 °C range.
Products were characterized by IR, 1H NMR and 13C NMR spectrosco-
py and by HRMS, unless otherwise mentioned. Compounds 3a,19 3c,33
3d,18 3e,34 3g,33 3i,35 3k,36 3l,37 DL-3n,16a L-3n,38 DL-3p39 and 3q40 have
been described in the literature. Melting points were determined us-
ing a Shanghai Jingke SGW X-4 microscope melting point apparatus.
Optical rotations were recorded on a Rudolph Research Analytical Au-
topol IV auto rotation instrument (Na D line, cell length = 10 cm,
λ = 589 nm). IR spectra were recorded on a Bruker Tensor-27 infrared
spectrometer. NMR spectra were recorded on a Bruker Avance 300
MHz spectrometer or a Bruker Avance III 400 MHz spectrometer. 1H
NMR chemical shifts (δ) are reported in parts per million (ppm), and
were measured relative to the signals for residual chloroform (7.26
ppm), DMSO (2.50 ppm) or acetone (2.05 ppm) in the deuterated sol-
vent, unless otherwise stated. 13C NMR spectra are reported in ppm
relative to deuterated chloroform (77.2 ppm), DMSO (39.5 ppm) or
acetone (206.7 ppm for C=O), unless otherwise stated, and were ob-
tained with 1H decoupling. High-resolution mass spectra were re-
corded on a Shimadzu LCMS-IT-TOF instrument. Chiral HPLC analyses
were performed by liquid chromatography on a Shimadzu LC-10ATVP
with a Daicel Chiralcel OD-H chiral column (4.6 mm × 250 mm × 5
μm).
HRMS (ESI-TOF): m/z [M – H]+ calcd for C21H18NO3: 332.1292; found:
332.1279.
N-Phenyl-o-chloromandelamide (3j)
Yield: 0.2271 g (87%); pale yellow solid; mp 147–149 °C.
IR (KBr): 3308, 1659, 1600, 1546, 1445, 1070, 755, 696 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.02 (s, 1 H), 7.73 (d, J = 10.4 Hz, 2
H), 7.58 (t, J = 12.0 Hz, 1 H), 7.46–7.43 (m, 1 H), 7.36–7.28 (m, 4 H),
7.09 (d, J = 9.6 Hz, 1 H), 6.65 (d, J = 6.8 Hz, 1 H), 5.48 (d, J = 6.8 Hz, 1
H).
13C NMR (101 MHz, DMSO-d6): δ = 170.47 (s), 139.16 (s), 138.95 (s),
133.04 (s), 130.05–129.41 (m), 129.08 (s), 127.65 (s), 124.10 (s),
120.24 (s), 71.60 (s).
HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11ClNO2: 260.0484;
found: 260.0487.
(R)-N-Phenyllactamide (3m)
Yield: 0.1221 g (74%); white solid; mp 45–48 °C; [α]D12 +9.6 (c 0.68,
acetone).
N-p-Tolylmandelamide (3a); Typical Procedure
IR (KBr): 3294, 1656, 1601, 1538, 1496, 1445, 1321, 1123, 1076, 1042,
To an oven-dried test tube possessing a ground joint neck and con-
taining a magnetic stir bar was added mandelamide (1.2 mmol), p-
bromotoluene (1 mmol), CuI (0.05 mmol), K2CO3 (2 mmol), DMEDA
(0.1 mmol) and toluene (5 mL). The test tube was sealed with a rub-
ber sleeve stopper and then evacuated and refilled with argon (three
cycles). The test tube was placed in an oil bath preheated to 110 °C for
24 h. After cooling, the reaction mixture was quenched with H2O (5
mL) and extracted with EtOAc (3 × 20 mL). The combined organic lay-
er was dried over anhydrous MgSO4, filtered and the filtrate concen-
trated under vacuum. The residue was purified by silica gel column
chromatography (mixed solvent of PE–EtOAc, 5:1 to 2:1) to give N-p-
tolylmandelamide (3a) (0.2122 mg, 88%) as a white solid.
756, 694 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.54 (t, J = 8.0 Hz, 2 H),
7.34–7.29 (m, 2 H), 7.15 (t, J = 12.0 Hz, 1 H), 4.33 (q, J = 12.0 Hz, 1 H),
4.19 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 173.36 (s), 137.02 (s), 129.06 (s),
124.75 (s), 120.03 (s), 68.70 (s), 21.08 (d, J = 9.7 Hz).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H11NO2Na: 188.0682;
found: 188.0657.
N-p-Tolyl-DL-3-phenyllactamide (DL-3o)
Yield: 0.2346 g (92%); white solid; mp 128–130 °C.
IR (KBr): 3323, 1652, 1596, 1549, 1104, 1075, 821, 726, 698 cm–1
.
N-m-Tolylmandelamide (3b)
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H), 7.39 (d, J = 8.0 Hz, 2 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.28–7.25 (m, 3 H), 7.12 (d, J = 8.0 Hz, 2 H),
4.40 (t, J = 8.0 Hz, 1 H), 3.34 (dd, J = 4.0, 4.0 Hz, 1 H), 2.99–2.93 (m, 1
H), 2.64 (d, J = 4.0 Hz, 1 H), 2.30 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.38 (s), 136.65 (s), 134.53 (s),
134.23 (s), 129.55 (d, J = 3.4 Hz), 128.92 (s), 127.20 (s), 119.88 (s),
40.88 (s), 20.91 (s).
Yield: 0.1976 g (82%); white solid; mp 166–169 °C.
IR (KBr): 3307, 3210, 1652, 1613, 1564, 1494, 1304, 1071, 777, 771,
693 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.82 (s, 1 H), 7.53–7.46 (m, 4 H),
7.37 (t, J = 16.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 16.0 Hz, 1
H), 6.87 (d, J = 8.0 Hz, 1 H), 6.42 (d, J = 4.0 Hz, 1 H), 5.09 (d, J = 4.0 Hz,
1 H), 2.25 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 171.53 (s), 141.34 (s), 138.89 (s),
138.26 (s), 128.93 (s), 128.55 (s), 128.06 (s), 127.01 (s), 124.67 (s),
120.61 (s), 117.28 (s), 74.41 (s), 21.64 (s).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H17NO2Na: 278.1151;
found: 278.1107.
HPLC (Chiracel OD-H): tR = 45.70 min (S form), 54.04 min (R form) (n-
hexane–propan-2-ol, 8:2).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H15NO2Na: 264.0995;
found: 264.0983.
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N-p-Tolyl-L-3-phenyllactamide (L-3o)
Yield: 0.2423 g (95%); white solid; mp 143–145 °C; [α]D12 –60.5
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(c 0.43, acetone).
IR (KBr): 3323, 1652, 1596, 1549, 1104, 1075, 821, 726, 698 cm–1
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7.35 (d, J = 8.0 Hz, 2 H), 7.28–7.25 (m, 3 H), 7.12 (d, J = 8.0 Hz, 2 H),
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13C NMR (101 MHz, CDCl3): δ = 170.38 (s), 136.65 (s), 134.53 (s),
134.23 (s), 129.55 (d, J = 3.4 Hz), 128.92 (s), 127.20 (s), 119.88 (s),
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HPLC (Chiracel OD-H): 93% ee (S form) (n-hexane–propan-2-ol, 8:2).
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N-p-Methoxyphenyl-L-3-phenyllactamide (L-3p)
Yield: 0.2547 g (94%); white solid; mp 126–128 °C; [α]D12 –52.0
(c 0.40, acetone).
IR (KBr): 3300, 1652, 1550, 1510, 1247, 1110, 1033, 836, 736, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.39 (t, J = 8.0 Hz, 2 H),
7.31–7.29 (m, 2 H), 7.26–7.23 (m, 3 H), 6.84–6.82 (m, 2 H), 4.38 (t,
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(m, 1 H), 2.67 (d, J = 8.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 170.32 (s), 156.56 (s), 136.68 (s),
130.22 (s), 129.57 (s), 128.90 (s), 127.19 (s), 121.60 (s), 114.17 (s),
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101;
found: 294.1057.
HPLC (Chiracel OD-H): 95% ee (S form), (n-hexane–propan-2-ol, 7:3).
N-p-Ethoxyphenyl-L-lactamide [(R)-p-lactophenetide] (3q)
Yield: 0.1818 g (87%); white solid; mp 101–105 °C; [α]D12 +15.5
(c 0.68, acetone).
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IR (KBr): 3274, 2979, 1648, 1553, 1510, 1246, 1114, 1043, 837, 786,
680, 521 cm–1
.
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6.82 (m, 2 H), 4.33–4.30 (m, 1 H), 4.02–3.96 (m, 2 H), 3.42 (d, J = 4.0
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
21372034) and the Cultivating Program for Excellent Innovation
Teams of Chengdu University of Technology (No. HY0084) for finan-
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Supporting Information
Supporting information for this article is available online at
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3751–3757