α-Alkoxycarbonyl-α-hydroxy secondary amides from a carbamoylsilane and α-ketoesters

Article abstract of DOI:10.1016/j.tet.2017.08.035

The addition of N-methoxymethyl-N-organylcarbamoyl(trimethyl)silane to α-ketoesters in anhydrous toluene at 60 °C afforded α-alkoxycarbonyl-α-siloxy amides in high yields (75–96%). The methoxymethyl was used as an amino protecting group and could be easily converted into hydrogen atom by simple acid hydrolysis leading to α-alkoxycarbonyl-α- hydroxy secondary amides.

Full text of DOI:10.1016/j.tet.2017.08.035

Accepted Manuscript
α-Alkoxycarbonyl-α-hydroxy secondary amides from a carbamoylsilane and α-
ketoesters
Weidong Li, Yuling Han, Jianxin Chen
PII:
S0040-4020(17)30873-6
10.1016/j.tet.2017.08.035
TET 28929
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 June 2017
Revised Date: 16 August 2017
Accepted Date: 18 August 2017
Please cite this article as: Li W, Han Y, Chen J, α-Alkoxycarbonyl-α-hydroxy secondary amides from a
carbamoylsilane and α-ketoesters, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.035.
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α-Alkoxycarbonyl-α-hydroxy secondary
amides from a carbamoylsilane and α-
ketoesters
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Weidong Li, Yuling Han and Jianxin Chen
College of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, PR China

1
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Tetrahedron
journal homepage: www.elsevier.com
α-Alkoxycarbonyl-α-hydroxy secondary amides from a carbamoylsilane and α-
ketoesters
Weidong Li, Yuling Han and Jianxin Chen
College of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The addition of N-methoxymethyl-N-organylcarbamoyl(trimethyl)silane to α-ketoesters in
anhydrous toluene at 60˚C afforded α-alkoxycarbonyl-α-siloxy amides in high yields (75–96% ).
The methoxymethyl was used as an amino protecting group and could be easily converted into
hydrogen atom by simple acid hydrolysis leading to α-alkoxycarbonyl-α- hydroxy secondary
amides.
Available online
Keywords:
Ketoesters
2009 Elsevier Ltd. All rights reserved
.
Carbamoylsilanes
Amides
Addition
Synthetic methods
1. Introduction
towards the preparation of α-alkoxycarbonyl-α-hydroxy seconda-
ry amides by using a special carbamoylsilane. Therefore, carbam-
oylsilane containing an amino protecting group are expected to
solve this problem. Considering this, the N-methoxymethyl-N-
organylcarbamoyl(trimethyl)silane was selected as an amide sou-
rce to synthesize α-alkoxycarbonyl-α-hydroxy secondary amides,
wherein methoxymethyl was used as an amino protecting group.
The reaction proceeded smoothly, however, we previously found
that N-methoxymethyl-N-methylcarbamoyl(trimethyl)silane coul-
d not react with α-ketoamides.7 We here report on the successful
attempt in this regard.
α-Alkoxycarbonyl-α-hydroxy amides have attracted a great
deal of attentions, because their moieties are often found in
antibiotics1, and they serve as useful synthetic intermediates in
many natural products and pharmaceuticals such as olmesartan,
dihydroimidazoquinoline, vitamin B6, and thrombin-activatable
fibrinolysis inhibitor (TAFIa).2 They also are common structural
units in various functional group transformations as they
constitute an intriguing class of pronucleophiles providing
densely and differently functionalized chemical entities at the
tetrasubstituted carbon center.3 Due to their potential application,
a number of methods have been developed to synthesize the α-
alkoxycarbonyl-α-hydroxy amides.4 In recent years, the direct
oxidation of the α-alkoxycarbonyl amides with various oxidants
or molecular oxygen catalyzed by a transition-metal catalyst is a
2. Results and discussion
most frequently used method in organic synthesis.5 However
, the
use of organic oxidants or an oxygen atmosphere, the further
oxidation of α-alkoxycarbonyl-α-hydroxy amides under oxidative
reaction, the restricted scope of substrates, and the need to
Scheme 1 Synthesis of α-alkoxycarbonyl-α-siloxy amides 3
dispose toxic byproducts restrict their applications. We have
recently reported on a new addition reaction of the N,N-dimethyl-
carbamoyl(trimethyl)silane onto α-ketoesters leading to the form-
ation of α-alkoxycarbonyl-α-hydroxy amides.6 The key feature of
this reaction is the introduction of an aminocarbonyl group into
an organic substrate under mild conditions without the aid of a
catalyst. However, this approach only explored the formation of
Scheme 2 Synthesis of a-ketoesters 2
α-alkoxycarbonyl-α-hydroxy-N,N-dimethyl–substituted
amide
derivatives (tertiary amides), for efficient application within these
areas, synthesizing α-alkoxycarbonyl-α-hydroxy secondary amid-
es are required. We must meanwhile further develop this method
———
Starting a-ketoesters 2 were readily accessible in good yields
according to the procedures described in the literature8 from
the corresponding ethyl oxalyl chloride and aryl compounds
Corresponding author. E-mail address: jjxxcc2002@yahoo.com (J. Chen)

2
Tetrahedron
catalyzed by AlCl3 in dichloromethane at 40 °C (Scheme 2),
of α-alkoxycarbonyl-α-siloxy amides 3 were obtained, generally
ACCEPTED MANUSCRIPT
which were allowed to react with 1.2 equiv of carbamoylsilane 19
within a matter of a few hours at 60 °C (Scheme 1 and Table 1).
in toluene under anhydrous conditions, good to excellent yields
Table 1 α-alkoxycarbonyl-α-siloxy amides 3 from a-ketoesters 2 and carbamoylsilane 1.
Entry
a-Ketoester
Product
Timea (h)
Yield b,c (%)
1
24
81
2a
3a
2
3
28
42
81
79
2b
3b
2c
2d
2e
2f
3c
3d
3e
4
5
6
8
96
91
91
30
33
3f
7
20
10
77
95
2g
2h
2i
3g
3h
O
O
O
O
N
OSiMe3
8
O
O
O
12
16
96
92
O
O
N
OSiMe3
9
S
3i
10
2j
3j
aTo complete consumption of carbamoylsilane 1 in toluene at 60 ˚C.
bIsolated yield based on a-ketoesters.
c1:1.2 mol ratio of a-ketoesters and carbamoylsilane 1.

3
Table 2 Solvent effect on the addition of N-methoxymethyl-N-
methylcarbamoyl(trimethyl)silane to ethyl α-ketophenylacetate
α-hydroxy-N-methyl(4-chloro)phenylacetamide (4e) in 96%
yields.
ACCEPTED MANUSCRIPT
Entry
Solvent
Temp (ꢀ)
Timea (h) Yieldb,c (％)
1
2
3
4
acetonitrile
THF
toluene
benzene
60
60
60
60
30
28
24
26
46
60
81
75
aTo complete consumption of carbamoylsilane.
bIsolated yield based on ethyl α-ketophenylacetate.
c1:1.2 mol ratio of ethyl α-ketophenylacetate and carbamoylsilane.
Scheme 3 The formation of α-alkoxycarbonyl-α-hydroxyl secondary amides
4 by acid hydrolysis of 3
First, the addition of N-methoxymethyl-N-methylcarbamoyl
(trimethyl)silane to ethyl α-ketophenylacetate was chosen as a
model reaction to investigate the effects of solvents. When a
range of solvents were tested, the reaction proceeded smoothly in
tested solvents. As shown in Table 2, when the reaction was
carried out in toluene, the highest yields of product was achieved,
and the reaction time was short (Table 2, entry 3). Several other
tested solvents, including benzene, THF, and acetonitrile, gave
inferior results compared to toluene.
Table 3 The reaction of carbamoylsilanes 5 and 6 with a-ketoesters 2.
Next, we selected aliphatic α-ketoesters, such as ethyl pyruva-
te to react with 1.2 equiv of carbamoylsilane 1 in toluene at 60 ˚C.
It was found that no desired product was obtained, and carbamo-
ylsilane 1 was completely consumed. We speculate that the com-
petitive protonolysis of the carbamoylsilane 1 has occurred as the
ethyl pyruvate contained enolizable β-hydrogens, led to the des-
ilylative protonolysis of 1 into N-methoxymethyl-N-methylfor-
mamide, which had been found in reaction mixture.10 However,
ethyl pyruvate could react with N,N-dimethylcarbamoyl(trime-
thyl)silane smoothly.6 Similar phenomenon was previously obse-
rved when N-sulfonylimines with enolizable α-hydrogens were
reacted with carbamoylsilane.11
Entry Ketoester
Product
Timea (h) Yield b,c (%)
1
2
2a
2c
28
31
78
75
7a
7c
To explore the scope of the reaction between α-ketoesters and
carbamoylsilane 1, we tested the representative aryl or heteroaryl
α-ketoesters. Experimental results were summarized in Table 1.
For the aryl, heteroaryl and unsaturated aryl α-ketoesters, all of
the reactions gave good to excellent yields. A comparison of the
results obtained from 2a–2f indicates that the electronic proper-
ties of the substituents in the phenyl influenced both the reaction
time and the yields of products 3. Phenyl α-ketoesters bearing an
electron–donating group, such as a methoxy or methyl group,
gave slightly lower yields than those possessing electron–withdr-
awing group, such as a fluoro, chloro or bromo group. The α-
ketoesters 2a, 2b, and 2c afforded the addition products in good
yields (entries 1–3), while 2d, 2e and 2f gave higher yields
(entries 4–6). The reaction time of α-ketoesters 2d was shorter
than that of other α-ketoesters. This result may be from the strong
electron-withdrawing induction effect of fluoro. α-Ketoesters 2g
possessing two alkyl substituents on aromatic ring, and the meth-
yl being at the ortho-position of carbonyl, offered the slightly
lower yield of product 3g (entry 7). It was showed that the steric
environment is not an important factor. The α-ketoesters 2h and
2i containing an electron–rich heteroaryl group, the furyl and
thienyl, reacted with carbamoylsilane 1 to afford excellent yields
of desired addition products 3h and 3i (entries 8 and 9), and the
reaction time was short compared to most of aryl α-ketoesters.
β,γ-Unsaturated α-ketoester 2j was investigated to determine
whether 1,2- or 1,4-addition would occur in a conjugated system.
It was found that compound 3j corresponding to 1, 2-addition
product was exclusively obtained in higher yield (entry 10).
The α-alkoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
amides 3 can be easily hydrolyzed in a mixture of hydrochloric
acid and dichloromethane at room temperature, led to the α-
alkoxycarbonyl-α-hydroxy secondary amides 4 (Scheme 3). For
example, α-ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-met-
hyl amide 3e could be readily converted into α-ethoxycarbonyl-
3
2e
23
79
7e
8a
4
5
2a
2c
30
35
79
78
8c
8e
6
2e
26
80
aTo complete consumption of carbamoylsilane 1 in toluene at 60 ˚C.
bIsolated yield based on a-ketoesters.
c1:1.2 mol ratio of a-ketoesters and carbamoylsilanes.
To further explore the synthetic potential of developed proto-
col, carbamoylsilanes possessing different alkyls were selected as
amides source, such as N-methoxymethyl-N-propylcarbamoyl(tr-
imethyl)silane (5) and N-cyclohexyl-N-methoxymethylcarbamo-
yl(trimethyl)silane (6) to react with α-ketoesters 2a, 2c and 2e
which have different substituents in the phenyl under same
reaction conditions. The results are listed in Table 3. All carba-

4
Tetrahedron
ACCEPTED MANUSCRIPT
moylsilanes reacted smoothly to afford the corresponding α-
using tetramethylsilane (TMS) as an internal standard. Chemical
alkoxycarbonyl-α-siloxy-N-methoxymethyl amides in good
yields. Phenyl α-ketoesters bearing both an electron–withdrawing
and electron–donating group were tolerated. The total yields of
products are slightly lower than those of Table 1(3a, 3c, 3e).
A possible route to products 4 is presented in Scheme 4.
Carbamoylsilane 1 can rearrange to its nucleophilic carbene form
A.12 which attacked the α-carbonyl of α-ketoesters 2 to produce
an unstable intermediate B, followed by silyl group 1,4-migration
to give the α-alkoxycarbonyl-α-siloxy-N-methoxymethyl-N-me-
thyl amides 3. The latter can be easily hydrolyzed under the acid
condition to form α-alkoxycarbonyl-α-hydroxyl secondary
amides 4.
shifts are expressed in parts per million (ppm) and coupling
constants in Hertz (Hz). Infrared spectra were recorded as potas-
sium bromide (KBr) discs for solids or thin films on sodium
chloride plates for oils on an IMPACT–410 spectrophotometer.
Elemental analysis was performed on an EA–1108 analyzer.
Melting points were measured with a STUART SMP 10 melting
point apparatus and uncorrected. The monitoring of reaction and
checking of purity of the product were done using pre-coated
silica gel plates (Merck TLC Silica gel 60 F254). Column chroma-
tography was performed using silica gel 200. Visualization was
achieved by UV (254 nm) light detection and iodine staining.
4.2 General procedure for the preparation of a-ketoesters
2a–i8
To a 25 mL round bottom flask containing a stirring solution
of aromatic compounds (10 mmol) in dichloromethane (8 mL)
was added anhydrous AlCl3 (8 mmol), then added dropwise the
ethyl oxalyl chloride (7 mmol). After the mixture was vigor-
ously stirred at 40 for 6 h the reaction temperature was cooled
to room temperature in an ice bath, which was washed with
hydrochloric acid (10%, 5mL). The organic layer was separated,
dried over Na2SO4 and evaporated to afford the residue which
was purified by column chromatography to give pure a-ketoest-
ers.
14
1
4.2.1. Ethyl a-ketophenylacetate (2a).8a,
Pale yellow oil; H
NMR (600MHz, CDCl3) δH: 8.05–7.47 (m, 5H, Ar–H), 4.44 (q, J
= 7.2 Hz, 2H, CH2), 1.41 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(151MHz, CDCl3) δC: 186.5, 163.8, 134.9, 132.5, 130.1, 128.9,
62.4, 14.1.
Scheme 4 Proposed reaction mechanism
3. Conclusions
13
4.2.2. Ethyl a-keto-(4-methyl)phenylacetate (2b).8a, Brownish
1
oil; H NMR (600MHz, CDCl3) δH: 7.92–7.30 (m, 4H, Ar–H),
We have successfully developed a novel and highly efficient
procedure toward the α-alkoxycarbonyl-α-hydroxy secondary
amides by the addition of N-methoxymethyl-N-organylcarbam-
oyl(trimethyl)silane to α-ketoesters. The simple procedure allows
the preparation of a broad variety of α-alkoxycarbonyl-α-hydr-
oxy amides in one step, and in general provides good to excellent
yields of the products under mild reaction condition. This appr-
oach is an efficient synthesis method for secondary amides beca-
use of the acid hydrolysis of methoxymethyl of amides 3 was
easy at room temperature. This method can be applied to the
synthesis of complex compounds, which can introduce an
aminocarbonyl group into the molecule directly in the absence
of active hydrogen substrate, led to the formation of α-
hydroxy secondary amides. So the method provides a choice
for the synthesis of complex compounds. We anticipate that
our study may draw significant attention of chemists working on
the development of synthetic methodologies and will find
applications in organic and medicinal chemistry. Further
investigations to develop an asymmetric version of this reaction
are now in progress.
4.44 (q, J = 7.2 Hz, 2H, CH2), 2.43 (s, 3H, CH3), 1.42 (t, J = 7.2
Hz, 3H, CH3); 13C NMR (151MHz, CDCl3) δC: 186.1, 164.1,
146.3, 130.2, 130.1, 129.6, 62.3, 21.9, 14.1.
4.2.3. Ethyl a-keto-(4-methoxy)phenylacetate (2c).14 Reddish
1
brown oil; H NMR (600MHz, CDCl3) δH: 8.01–6.97 (m, 4H,
Ar–H), 4.44 (q, J = 7.2 Hz, 2H, CH2), 3.97 (s, 3H, CH3), 1.42 (t,
J = 7.2 Hz, 3H, CH3); 13C NMR (151MHz, CDCl3) δC: 184.9,
165.0, 164.2, 132.6, 125.5, 114.3, 62.2, 55.7, 14.1.
4.2.4. Ethyl a-keto-(4-fluoro)phenylacetate (2d).8a. 14 Pale yellow
1
oil; H NMR (600MHz, CDCl3) δH: 8.10 (d, J = 5.7 Hz, 2H, Ar–
H), 7.20 (m, J = 5.7 Hz, 4H, Ar–H), 4.47 (q, J = 7.2 Hz, 2H,
CH2), 1.45 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (151MHz, CDCl3)
δC: 184.6, 167.7, 163.4, 133.0, 129.0, 116.3, 62.5, 14.1.
13
4.2.5. Ethyl a-keto-(4-chloro)phenylacetate (2e).8a,
Reddish
1
brown oil; H NMR (600MHz, CDCl3) δH: 7.99–7.48 (m, 4H,
Ar–H), 4.46–4.44 (m, 2H, CH2), 1.44–1.42 (m, 3H, CH3); 13C
NMR (151MHz, CDCl3) δC: 184.9, 163.2, 141.6, 131.5, 130.9,
129.3, 62.6, 14.1.
4. Experimental section
4.1 General
4.2.6. Ethyl a-keto-(4-bromo)phenylacetate (2f).8a Pale yellow oil;
1H NMR (600MHz, CDCl3) δH: 8.12–7.64 (m, 4H, Ar–H), 4.45
(q, J = 7.2 Hz, 2H, CH2), 1.42 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(151MHz, CDCl3) δC: 185.2, 184.2, 163.2, 161.8, 132.3, 131.6,
131.5, 131.3, 131.2, 130.9, 130.7, 130.6, 62.6, 14.1.
Dry toluene and aromatic compounds were freshly distilled
from sodium and benzophenone as a moisture indicator under Ar
atmosphere before use. Dichloromethane was distilled from
phosphorous pentoxide. Carbamoylsilanes was prepared accord-
ing to our previous reported methods.9 1H (600 MHz) and 13C
(150.8 MHz) NMR spectra were recorded on Bruker (AV600)
NMR spectrometer. All spectra were recorded at room temper-
ature in deuterated chloroform (CDCl3) δ = 7.28 ppm for proton
NMR, δ = 77.16 ppm for carbon NMR) unless otherwise stated
4.2.7. Ethyl a-keto-(2-methyl-5-isopropyl)phenylacetate (2g).8a
1
Pale yellow oil; H NMR (600MHz, CDCl3) δH: 7.66–7.17 (m,
3H, Ar–H), 4.44 (q, J = 7.2 Hz, 2H, CH2), 2.96–2.94 (m, 1H,
CHMe2), 2.63 (s, 3H, CH3), 1.43 (t, J = 7.2 Hz, 3H, CH3), 1.29-

5
1.25 (m, 6H, 2CH3); 13C NMR (151MHz, CDCl3) δC: 188.4,
165.0, 155.5, 141.9, 133.0, 130.8, 128.8, 124.0, 62.1, 34.3, 29.0,
23.5, 21.8, 14.1.
(CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 171.2, 170.9, 170.3,
ACCEPTED MANUSCRIPT
170.0, 138.8, 138.7, 128.5, 128.2, 128.0, 127.8, 126.3, 126.0,
85.6, 85.5, 79.7, 79.1, 62.3, 56.4 54.6, 33.9, 32.0, 13.9, 1.9, 1.8;
Anal. Calcd for C17H27NO5Si: C, 57.76; H, 7.70; N, 3.96. Found:
C, 57.71; H, 7.69; N, 4.03.
4.2.8. Ethyl a-keto-(2)furylacetate (2h).8a Pale yellow oil; 1H
NMR (600MHz, CDCl3) δH: 7.78–7.74 (m, 2H, furyl–H), 6.65–
6.64 (m, 1H, furyl–H), 4.44 (q, J = 7.2 Hz, 2H, CH2), 1.44 (t, J =
7.2 Hz, 3H, CH3); 13C NMR (151MHz, CDCl3) δC: 171.1, 161.0,
149.8, 149.6, 124.8, 113.0, 62.8, 14.0.
4.4.2.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(4-methyl)phenylacetamide (3b). Yield=80.7%; yellowish liquid;
IR (KBr) νmax: 1746, 1659, 1448, 1394, 1252, 1141, 1028, 891,
847 cm–1; 1H NMR (600MHz, CDCl3) δH: 7.40–7.14 (m, 4H, Ar–
H), 4.80–4.47 (m, 2H, CH2), 4.27–4.16 (m, 2H, CH2), 3.33, 2.90
(ss, 3H, CH3), 2.73, 2.62 (ss, 3H, CH3), 2.35, 2.34 (ss, 3H, CH3),
1.26–1.22 (m, 3H, CH3), 0.25–0.23(m, 9H, (CH3)3Si); 13C NMR
(151MHz, CDCl3) δC: 171.3, 171.0, 170.4, 170.1, 137.9, 137.7,
135.8, 128.7, 128.5, 126.2, 126.0, 85.5, 79.7, 79.1, 62.2, 56.3,
54.6, 33.9, 31.9, 21.1, 13.9, 1.9, 1.8; Anal. Calcd for
C18H29NO5Si: C, 58.83; H, 7.95; N, 3.81. Found: C, 58.75; H,
8.06; N, 3.73.
1
4.2.9. Ethyl a-keto-(2)thienylacetate (2i).8a Pale yellow oil; H
NMR (600MHz, CDCl3) δH: 8.38–7.18 (m, 3H, thienyl–H), 4.46
(q, J = 7.2 Hz, 2H, CH2), 1.41 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(151MHz, CDCl3) δC: 176.5, 175.9, 161.6, 160.7, 139.5, 139.2,
138.9, 137.8, 137.5, 129.1, 128.8, 62.9, 14.0.
4.3 General procedure for the preparation of a-ketoesters 2j
8b
4.4.3.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
To a solution of benzaldehyde (0.2 mol) and pyruvic acid (0.2
mol) in methanol (15 mL) was cooled to 10 , and added
dropwise a solution of KOH (0.3 mol) in methanol (60 mL) at
(4-methoxy)phenylacetamide (3c). Yield=78.7%; yellowish liquid;
IR (KBr) νmax: 1744, 1657, 1511, 1463, 1394, 1251, 1030, 844
cm–1; H NMR (600MHz, CDCl3) δH: 7.43–6.86 (m, 4H, Ar–H),
1
15–20 . After the temperature increased to 35–40
the
4.80–4.47 (m, 2H, CH2), 4.26–4.17 (m, 2H, CH2), 3.80 (s, 3H,
CH3), 3.33, 2.92 (ss, 3H, CH3), 2.75, 2.65 (ss, 3H, CH3), 1.26–
1.23 (m, 3H, CH3), 0.25–0.23 (m, 9H, (CH3)3Si); 13C NMR
(151MHz, CDCl3) δC: 171.3, 171.0, 170.5, 170.2, 159.5, 159.3,
132.6, 130.3, 127.6, 127.3, 113.3, 113.1, 85.3, 85.3, 79.7, 79.1,
62.2, 56.3, 55.3, 55.2, 54.7, 33.9, 32.0, 14.0, 13.9, 1.9, 1.8; Anal.
Calcd for C18H29NO6Si: C, 56.37; H, 7.62; N, 3.65. Found: C,
56.45; H, 7.70; N, 3.50.
reaction mixture was stirred for 3 h, and maintained at 10 for
10 h. The solid precipitated out was filtered and washed with
methanol (75 mL) followed by diethyl ether (75 mL) to afford
potassium 4-phenyl-2-oxo-but-3-enoate.
To a solution of acetyl chloride (175 mmol) in ethanol (50 mL)
was cooled in an ice bath, and potassium 4-phenyl-2-oxo-but-3-
enoate (50 mmol) was added at 0 . The reaction was warmed to
room temperature and stirred for 2 h and then refluxed for 6 h.
The solvent was removed by evaporation. Water (20 mL) was
added to the crude product, which was then extracted with
CH2Cl2 (20 mL×2). The combined organic phase was washed
with sodium bicarbonate solution (10 mL×2) and then with
water (10 mL). After the organic layer was separated and dried
over MgSO4 the solvent was evaporated to afford the residue
which was purified by column chromatography to give a-
ketoester 2j in 80% yield.
4.4.4.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(4-fluoro)phenylacetamide (3d). Yield=96.0%; yellowish liquid;
IR (KBr) νmax: 1747, 1658, 1508, 1394, 1253, 1157, 1098, 1028,
891, 845 cm–1; 1H NMR (600MHz, CDCl3) δH: 7.51–7.03 (m, 4H,
Ar–H), 4.80–4.44 (m, 2H, CH2), 4.27–4.18 (m, 2H, CH2), 3.33,
2.92 (ss, 3H, CH3), 2.74, 2.66 (ss, 3H, CH3), 1.27–1.23 (m, 3H,
CH3), 0.25, 0.23 (ss, 9H, (CH3)3Si); 13C NMR (151MHz, CDCl3)
δC: 170.9, 170.7, 170.0, 169.7, 134.6, 128.2, 127.9, 115.0, 114.9,
114.8, 114.6, 85.1, 79.7, 79.2, 62.4, 56.4, 54.7, 33.9, 32.3, 13.8,
1.9, 1.8; Anal. Calcd for C17H26FNO5Si: C, 54.97; H, 7.05; N,
3.77. Found: C, 54.78; H, 7.08; N, 3.80.
a-Keto-4-phenyl-3-butenic acid ethylate (2j).8b, 15 Pale yellow oil;
1H NMR (600MHz, CDCl3) δH: 7.90 (d, J = 16.2 Hz, 1H, HC=),
7.67–744 (m, 5H, Ar–H), 7.40 (d, J = 16.2 Hz, 1H, HC=), 4.43 (q,
J = 7.2 Hz, 2H, CH2), 1.44 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(151MHz, CDCl3) δC: 182.9, 162.2, 148.5, 134.0, 131.8, 131.7,
129.3, 129.2, 129.1, 120.5, 62.6, 14.1.
4.4.5.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(4-chloro)phenylacetamide (3e). Yield=91.1%; yellowish liquid;
IR (KBr) νmax: 1748, 1660, 1490, 1396, 1252, 1093, 1028, 891,
846 cm–1; 1H NMR (600MHz, CDCl3) δH: 7.46–7.31 (m, 4H, Ar–
H), 4.79–4.44 (m, 2H, CH2), 4.26–4.17 (m, 2H, CH2), 3.32, 2.91
(ss, 3H, CH3), 2.73, 2.68 (ss, 3H, CH3), 1.25–1.22 (m, 3H, CH3),
0.25, 0.23(ss, 9H, (CH3)3Si); 13C NMR (151MHz, CDCl3) δC:
170.8, 170.5, 169.8, 169.6, 137.3, 134.1, 134.0, 128.2, 128.0,
127.8, 127.5, 85.2, 85.1, 79.7, 79.2, 62.5, 62.4, 56.4, 54.7, 33.9,
32.3, 13.9, 1.9, 1.8; Anal. Calcd for C17H26ClNO5Si: C, 52.63; H,
6.76; N, 3.61. Found: 52.69; H, 6.58; N, 3.67.
4.4 General procedure for the synthesis of α-ethoxycarbonyl
-α-siloxy-N-methoxymethyl amides 3, 7 and 8
A Schlenk tube fitted with a Teflon vacuum stopcock and
micro stirbar was flame heated under vacuum and refilled with
Ar. α-Ketoesters (1.0 mmol) and anhydrous toluene (1.5 mL)
were added at ice bath temperature. After 20 min, carbamoyl-
silane 1 (1.2 mmol) was added. The sealed reaction mixture was
stirred at 60 ℃until no carbamoylsilane 1 could be detected by
TLC. Volatiles were removed in vacuo to afford the crude
product which was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate combination) to give α-
alkoxycarbonyl-α-siloxy amides 3 (7 or 8).
4.4.6.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(4-bromo)phenylacetamide (3f). Yield=90.7%; yellowish liquid;
IR (KBr) νmax: 1748, 1658, 1487, 1394, 1251, 1027, 891, 847 cm–
1
1; H NMR (600MHz, CDCl3) δH: 7.50–7.35 (m, 4H, Ar–H),
4.81–4.44 (m, 2H, CH2), 4.28–4.16 (m, 2H, CH2), 3.33, 2.92 (ss,
3H, CH3), 2.73, 2.68 (ss, 3H, CH3), 1.26–1.23 (m, 3H, CH3), 0.25,
0.23 (ss, 9H, (CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 170.7,
170.5, 169.7, 169.5, 137.9, 131.2, 130.9, 128.1, 127.9, 122.3,
122.2, 85.3, 85.2, 79.7, 79.2, 62.5, 62.4, 56.4, 54.7, 33.9, 32.4,
13.9, 1.8, 1.7; Anal. Calcd for C17H26BrNO5Si: C, 47.22; H, 6.06;
N, 3.24. Found: C, 47.36; H, 6.01; N, 3.38.
4.4.1.
phenylacetamide (3a). Yield= 81.3%; yellowish liquid; IR (KBr)
νmax
1745, 1657, 1450, 1396, 1250, 1142, 1028, 892 cm–1; 1H NMR
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
:
(600MHz, CDCl3) δH: 7.54–7.31 (m, 5H, Ar–H), 4.82–4.45 (m,
2H, CH2), 4.28–4.18 (m, 2H, CH2), 3.35, 2.92 (ss, 3H, CH3), 2.73,
2.59 (ss, 3H, CH3), 1.27–1.23 (m, 3H, CH3) 0.26, 0.19(ss, 9H,

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.4.7. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
4.52 (m, 2H, NCH2O), 4.28–4.18 (m, 2H, CH2O), 3.83, (s, 3H,
(2-methyl-4-isopropyl)phenylacetamide (3g). Yield=76.8%;
yellowish liquid; IR (KBr) νmax: 1744, 1660, 1461, 1392, 1249,
1134, 1027, 892, 846 cm–1; 1H NMR (600MHz, CDCl3) δH: 7.22–
7.00 (m, 3H, Ar–H), 4.88–4.47 (m, 2H, CH2), 4.32–4.20 (m, 2H,
CH2), 3.43, 2.99 (ss, 3H, CH3), 2.88–2.86 (m, 4H, CH, CH3),
2.88–2.31 (m, 3H, CH3), 1.28–1.23 (m, 9H, CH3, (CH3)2C), 0.26–
0.18 (m, 9H, (CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 171.5,
171.1, 170.9, 170.8, 148.7, 148.6, 136.9, 136.4, 134.9, 134.6,
130.4, 130.2, 126.8, 123.4, 123.2, 86.5, 80.5, 79.5, 62.2, 56.9,
54.9, 34.8, 33.7, 33.6, 32.6, 23.9, 21.1, 14.0, 2.0, 1.9; Anal. Calcd
for C21H35NO5Si: C, 61.58; H, 8.61; N, 3.42. Found: C, 61.49; H,
8.76; N, 3.49.
CH3O), 3.42–3.22 (m, 2H, CH2N), 3.34, 2.71 (ss, 3H, CH3O),
1.66–1.60 (m, 2H, CH2), 1.30–1.25 (m, 3H, CH3), 0.91, 0.57 (tt, J
= 7.2 Hz, 3H, CH3), 0.26 (s, 9H, (CH3)3Si); 13C NMR (151MHz,
CDCl3) δC: 170.5, 170.4, 159.4, 131.1, 131.0, 127.7, 127.6, 113.2,
112.1, 85.4, 78.4, 76.5, 62.2, 56.6, 55.3, 54.8, 47.7, 46.6, 29.7,
20.8, 20.3, 14.0, 13.9, 11.5, 11.0, 2.0; Anal. Calcd for
C20H33NO6Si: C, 58.37; H, 8.08; N, 3.40. Found: C, 58.28; H,
7.86; N, 3.51.
4.4.13. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-propyl
(4-chloro)phenylacetamide (7e). Yield=79.1%; colourless liquid;
IR (KBr) νmax: 1744, 1657, 1482, 1245, 1090, 848 cm–1; 1H NMR
(600MHz, CDCl3) δH: 7.45–7.33 (m, 4H, Ar–H), 4.89–4.46 (m,
2H, NCH2O), 4.27–4.17 (m, 2H, CH2O), 3.43–3.17 (m, 2H,
CH2N), 3.33, 2.71 (ss, 3H, CH3O), 1.62–1.42 (m, 2H, CH2),
1.28–1.23 (m, 3H, CH3), 0.92, 0.56 (tt, J = 7.2 Hz, 3H, CH3),
0.25 (s, 9H, (CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 171.0,
170.0, 169.8, 169.7, 137.6, 137.5, 134.0, 129.3, 128.0, 127.9,
127.6, 85.6, 85.3, 78.4, 76.6, 62.4, 56.6, 54.7, 47.7, 47.0, 20.8,
20.4, 14.1, 13.9, 11.5, 11.0, 1.9; Anal. Calcd for C19H30ClNO5Si:
C, 54.86; H, 7.27; N, 3.37. Found: C, 54.72; H, 7.48; N, 3.49
4.4.8.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(2)furylacetamide (3h). Yield=95.0%; yellowish liquid; IR (KBr)
1
ν
max: 1751, 1671, 1448, 1395, 1251, 1161, 1028, 848 cm–1; H
NMR (600MHz, CDCl3) δH: 7.44–7.15 (m, 1H, furyl–H), 6.49–
6.38 (m, 2H, furyl–H), 4.94–4.67 (m, 2H, CH2), 4.34–4.24 (m,
2H, CH2), 3.31, 3.10 (ss, 3H, CH3), 2.97, 2.95 (ss, 3H, CH3),
1.32–1.28 (m, 3H, CH3), 0.10 (s, 9H, (CH3)3Si); 13C NMR
(151MHz, CDCl3) δC: 169.0, 168.9, 168.3, 150.7, 150.6, 142.3,
110.7, 109.4, 109.3, 81.2, 81.0, 79.9, 79.1, 62.5, 56.0, 54.9, 33.3,
33.1, 14.1, 14.0, 1.1; Anal. Calcd for C15H25NO6Si: C, 52.46; H,
7.34; N, 4.08. Found: C, 52.65; H, 7.40; N, 3.97.
4.4.14. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-cycloh-
exylphenylacetamide (8a). Yield= 79.3%; colourless liquid; IR
(KBr) νmax: 1749, 1647, 1448, 1245, 1148, 848 cm–1; H NMR
1
4.4.9.
α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
(600MHz, CDCl3) δH: 7.51–7.32 (m, 5H, Ar–H), 4.87–4.49 (m,
2H, NCH2O), 4.24–4.19 (m, 2H, CH2O), 3.97–3.82 (m, 1H,
CHN), 3.39, 2.59 (ss, 3H, CH3O), 1.90–0.52 (m, 13H,
cyclohexyl-H, CH3), 0.29, 0.25 (ss, 9H, (CH3)3Si); 13C NMR
(151MHz, CDCl3) δC: 171.7, 170.7, 170.3, 170.1, 139.1, 138.9,
128.0, 127.7, 126.4, 86.3, 86.2, 76.2, 73.7, 62.3, 62.2, 56.9, 56.3,
55.7, 54.3, 32.8, 31.1, 30.3, 29.9, 26.1, 26.0, 25.8, 25.3, 13.9,
13.4, 2.3, 1.9; Anal. Calcd for C22H35NO5Si: C, 62.67; H, 8.37; N,
3.32. Found: C, 62.56; H, 8.59; N, 3.23.
(2)thienylacetamide (3i). Yield=96.0%; yellowish liquid; IR
(KBr) νmax: 1748, 1661, 1446, 1396, 1252, 1149, 1103, 1027, 849
cm–1; 1H NMR (600MHz, CDCl3) δH: 7.30–6.95 (m, 3H, thienyl–
H), 4.89–4.73 (m, 2H, CH2), 4.28–4.22 (m, 2H, CH2), 3.31–2.91
(m, 3H, 2CH3), 1.26 (t, J = 7.2 Hz, 3H, CH3), 0.21–0.16 (m, 9H,
(CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 170.0, 169.7, 169.6,
169.4, 142.7, 142.5, 129.0, 128.2, 126.4, 126.3, 126.2, 83.1, 82.9,
79.8, 79.2, 62.5, 56.2, 54.7, 33.7, 32.8, 13.9, 1.6; Anal. Calcd for
C15H25NO5SSi: C, 50.11; H, 7.01; N, 3.90. Found: C, 50.05; H,
7.02; N, 4.18.
4.4.15. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-cycloh-
exyl(4-methoxy)phenylacetamide (8c). Yield=78.4%; colourless
liquid; IR (KBr) νmax: 1749, 1652, 1506, 1250, 1177, 828 cm–1;
1H NMR (600MHz, CDCl3) δH: 7.41–6.89 (m, 4H, Ar–H), 4.86–
4.55 (m, 2H, NCH2O), 4.25–4.20 (m, 2H, CH2O), 3.95–3.89 (m,
1H, CHN), 3.83 (s, 3H, CH3O), 3.37, 2.66 (ss, 3H, CH3O), 1.87–
0.64 (m, 13H, cyclohexyl-H, CH3), 0.27, 0.24 (ss, 9H, (CH3)3Si);
13C NMR (151MHz, CDCl3) δC: 171.8, 170.5. 170.4, 159.3,
131.3, 130.9, 127.7, 127.6, 113.1, 113.0, 85.9, 85.8, 76.2, 73.7,
62.2, 62.1, 56.8, 56.3, 55.7, 55.3, 54.4, 32.0, 31.2, 30.8, 30.0,
26.1, 25.9, 25.7, 25.3, 13.9, 2.2, 1.9; Anal. Calcd for
C23H37NO6Si: C, 61.17; H, 8.26; N, 3.10. Found: C, 61.29; H,
8.44; N, 3.31.
4.4.10. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-methyl
4-phenyl-3-butenylamide (3j). Yield=92.2%; yellowish liquid; IR
(KBr) νmax: 1749, 1665, 1448, 1396, 1251, 1182, 1099, 1028, 847
cm–1; H NMR (600MHz, CDCl3) δH: 7.45–7.17 (m, 5H, Ar–H),
1
6.85–6.81 (m, 1H, CH=), 6.74–6.70 (m, 1H, CH=), 5.01–4.67 (m,
2H, CH2), 4.34–4.28 (m, 2H, CH2), 3.34, 3.16 (ss, 3H, CH3), 3.08,
2.97 (ss, 3H, CH3), 1.31 (t, J = 6.6 Hz, 3H, CH3), 0.23 (s, 9H,
(CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 170.2, 168.8, 135.9,
131.8, 130.7, 129.0, 128.7, 128.3, 128.2, 127.9, 127.2, 126.9,
83.1, 82.6, 79.8, 79.1, 62.2, 56.1, 55.1, 33.4, 33.3, 14.2, 14.0, 1.9;
Anal. Calcd for C19H29NO5Si: C, 60.13; H, 7.70; N, 3.69. Found:
C, 60.26; H, 7.79; N, 3.53.
4.4.16. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-cycloh-
exyl(4-chloro)phenylacetamide (8e). Yield=80.1%; colourless
liquid; IR (KBr) νmax: 1743, 1649, 1488, 1267, 1095, 851 cm–1;
1H NMR (600MHz, CDCl3) δH: 7.45–7.32 (m, 4H, Ar–H), 4.84–
4.45 (m, 2H, NCH2O), 4.27–4.19 (m, 2H, CH2O), 3.97–3.78 (m,
2H, CH2N), 3.37, 2.66 (ss, 3H, CH3O), 1.82–0.59 (m, 13H,
cyclohexyl-H, CH3), 0.28, 0.25 (ss, 9H, (CH3)3Si); 13C NMR
(151MHz, CDCl3) δC: 171.3, 170.3, 169.9, 169.7, 137.7, 137.5,
133.9, 127.9, 127.8, 85.9, 85.8, 76.1, 73.7, 62.5, 62.4, 56.9, 56.3,
55.7, 54.3, 32.0, 31.2, 30.8, 30.0, 26.1, 26.0, 25.9, 25.6, 25.3,
13.9, 2.2, 1.9; Anal. Calcd for C22H34ClNO5Si: C, 57.94; H, 7.51;
N, 3.07. Found: C, 57.76; H, 7.73; N, 3.21.
4.4.11. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-propyl
phenylacetamide (7a). Yield= 78.3%; colourless liquid; IR (KBr)
νmax: 1749, 1647, 1443, 1250, 1143, 838 cm–1; 1H NMR (600MHz,
CDCl3) δH: 7.53–7.32 (m, 5H, Ar–H), 4.94–4.49 (m, 2H,
NCH2O), 4.27–4.18 (m, 2H, CH2O), 3.45–3.03 (m, 2H, CH2N),
3.36, 2.63 (ss, 3H, CH3O), 1.63–1.28 (m, 2H, CH2), 1.25 (t, J =
7.8 Hz, 3H, CH3), 0.92, 0.50 (tt, J = 7.2 Hz, 3H, CH3), 0.26 (s,
9H, (CH3)3Si); 13C NMR (151MHz, CDCl3) δC: 170.4, 170.1,
139.0, 138.9, 128.1, 127.8, 126.4, 85.7, 78.3, 76.6, 62.3, 56.6,
54.6, 47.7, 46.7, 20.7, 20.3, 13.9, 11.5, 11.0, 2.0; Anal. Calcd for
C19H31NO5Si: C, 59.81; H, 8.19; N, 3.67. Found: C, 60.01; H,
7.96; N, 3.55.
4.5 General procedure for acid hydrolysis of 3
4.4.12. α-Ethoxycarbonyl-α-siloxy-N-methoxymethyl-N-propyl
(4-methoxy)phenylacetamide (7c). Yield=75.4%; colourless
liquid; IR (KBr) νmax: 1739, 1647, 1511, 1255, 1032, 833 cm–1;
1H NMR (600MHz, CDCl3) δH: 7.42–6.88 (m, 4H, Ar–H), 4.93–
Hydrochloric acid (2 mL, 12 mol/L) was added dropwise to a
solution of 3 (50 mg) in dichloromethane (4 mL). After 12 hours’
stirring at room temperature, the organic layers was separated.

7
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The aqueous phase extracted with dichloromethane (3 × 2 mL).
The combined organic layers were dried over MgSO4 and evapor-
ated to afford α-ethoxycarbonyl-α-hydroxy-N-methyl amides 4.
ACCEPTED MANUSCRIPT
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amide 4e Yield = 96.2%; yellowish liquid; IR (KBr) νmax: 3397,
1
1668, 1535, 1489, 1408, 1255, 1092 cm–1; H NMR (600MHz,
CDCl3) δH: 7.70–7.33 (m, 4H, Ar–H), 7.13–7.12 (m, 1H, NH),
4.89 (s, 1H, OH), 4.33–4.32 (m, 2H, CH2), 2.84–2.83 (ss, 3H,
1
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CH3), 1.32 (t, J = 7.2 Hz, 3H, CH3); H NMR (600MHz, CDCl3)
δH: 171.0, 168.7, 136.0, 134.7, 128.4, 127.6, 79.1, 63.9, 26.7,
13.9; Anal. Calcd for C12H14ClNO4: C, 53.05; H, 5.19; N, 5.16.
Found: C, 53.12; H, 5.11; N, 5.13.
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Acknowledgments
This research was supported by Shanxi Province Foundation
for Returness (No. 0713), the Natural Science Foundation of
Shanxi Province (No. 2012011046–9) and Foundation of Shanxi
Normal University (No. WL2016CXCY–YJ–30), China.
7. Ma, F.; Liu, H.; Chen, J.-X. Tetrahedron Lett. 2016, 57, 5246–
5250.
References and notes
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