Catalyst- and Additive-Free Chemoselective Transfer Hydrogenation of α-Keto Amides to α-Hydroxy Amides by Sodium Formate

Article abstract of DOI:10.1002/ejoc.201901073

A catalyst- and additive-free chemoselective transfer hydrogenation of α-keto amides to α-hydroxy amides is easily achieved by using sodium formate as a hydrogen source. The utility of this method is demonstrated by gram-scale synthesis and transformation of the resultant α-hydroxy amides into polysubstituted acetamides and 2-arylindole derivatives. Control experiments suggest that the NH group of α-keto amides is crucial for the chemoselective reduction through the formation of hydrogen bonds.

Full text of DOI:10.1002/ejoc.201901073

A Journal of
Accepted Article
Title: Catalyst- and Additive-free Chemoselective Transfer
Hydrogenation of α-Keto Amides to α-Hydroxy Amides by Sodium
Formate
Authors: Feiyue Hao, Zhenyu Gu, Guyue Liu, Wubing Yao, Huajiang
Jiang, and Jiashou Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901073
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901073
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
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Catalyst- and Additive-free Chemoselective Transfer
Hydrogenation of α-Keto Amides to α-Hydroxy Amides by Sodium
Formate
Feiyue Hao,[a] Zhenyu Gu,[a] Guyue Liu,[a] Wubing Yao,[a] Huajiang Jiang,[a] and Jiashou Wu*,[a]
Abstract:
A
catalyst- and additive-free chemoselective transfer
additives covering tetrabutylammonium fluoride (TBAF),16
K3PO4,17 and Cs2CO3,18 are still needed and can not be recycled.
hydrogenation of α-keto amides to α-hydroxy amides is easily
achieved by using sodium formate as a hydrogen source. The utility Therefore, from the practical and economical viewpoint, the
of this method is demonstrated by gram-scale synthesis and development of a catalyst- and additive-free chemoselective
transformation of the resultant α-hydroxy amides into polysubstituted reduction of α-keto amides is of great interest.
acetamides and 2-arylindole derivatives. Control experiments
suggest that the NH group of α-keto amides is crucial for the
chemoselective reduction via the formation of hydrogen bonding.
Introduction
α-Hydroxy amides are important structural motifs in a large
number of biologically active compounds exhibiting a wide
spectrum of pharmacological properties, such as antibiotic,1
anticonvulsant,2 antituberculosis,3 and γ-secretase inhibitory
activities.4 Besides, α-hydroxy amides also serve as valuable
Scheme 1. Chemoselective reduction of α-keto amides
synthetic intermediates in organic synthesis owing to their
versatile transformations into
compounds with structural
alkoxy/aryl/amino amides,5-8 1,2-aminoalcohols,9 and other
structurally complex molecules.10 Hence, the development of
efficient methods for the preparation of α-hydroxy amides has
attracted considerable attention among organic chemists.11
a
variety of functionalized
diversity, including α-
Formate derivatives are regarded as an important class of
hydrogen storage today, because of their decomposition into H2
and CO2 with high efficiency.19 The hydrogenation of unsaturated
functional groups using formate derivatives as a hydrogen
source has been extensively investigated, among which
transition metal-catalyzed transfer hydrogenation of the ketone
functionality is a subject of current interest.20 Unexpectedly,
there is no report on metal-free hydrogenation of the ketone
functionality by formates, even though this protocol avoids the
use of costly metal catalysts and ligands, and is more
environmentally benign. As part of our continuing interest in the
development of metal-free transformations, herein for the first
time we demonstrate a facile and efficient chemoselective
transfer hydrogenation of the ketone group of α-keto amides by
employing sodium formate as a hydrogen donor without using
any catalyst or additive.
Among preparative methods for α-hydroxy amides, the
chemoselective reduction of α-keto amides is the most efficient
approach from a practical viewpoint, as it requires only simple
experimental manipulations (Scheme 1). Conventional methods
for chemoselective hydrogenation of the ketone group of α-keto
amides into a hydroxy group involve the use of reducing agents
such as H2, hydrosilanes, NaBH4 or isopropanol, along with a
metal catalyst including iridium,12 nickel,9 palladium,13 ceria
nanosphere14 or zirconium-based metal-organic framework.15
However, these methods suffer from their own limitations, such
as the use of a high loading of reducing agents and the
employment of expensive noble metals together with inert
atmosphere and essential ligands. Despite metal-free
chemoselective reduction of α-keto amides employing different
hydrosilanes as hydrogen sources has also been developed,
Results and Discussion
To evaluate the potential for chemoselective transfer
hydrogenation of α-keto amides, initially, 2-oxo-2-phenyl-N-(p-
tolyl)acetamide 1a was chosen as the model substrate to react
with HCOONa·2H2O in DMF at 100 ℃ for 10 h, affording α-
hydroxy amide 2a in 44% yield, along with the recovery of 1a in
54% yield (Table 1, entry 1). Next, different solvents were
screened, and the best result was obtained in the reaction using
DMSO as the solvent (entries 2–8). A better transformation of 1a
was observed in the case of prolonged reaction time (entry 9).
[a]
School of Pharmaceutical and Materials Engineering,
Taizhou University,
Jiaojiang 318000,
Zhejiang Province,
China
Email:jsw79@tzc.edu.cn
Homepage:http://www.yyhg.tzc.edu.cn/info/1093/3295.htm
Characterization data including copies of 1H and 13C NMR spectra.
This material is available free of charge via the internet at
https://doi.org/10.1002/ejoc.201901073R1.
Compared to
a higher loading of HCOONa·2H2O, higher
temperature was found to be more effective for this reaction,
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
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giving 2a in 93% yield (entries 10 and 11). Moreover, HCOONa,
HCOOLi·H2O, and HCOONH4 were also screened, affording 2a
in a comparable yield, respectively (entries 12–14). However,
the employment of HCOOK led to a low yield, which might be
due to the stronger basicity that facilitated the deprotonation of
NH group to cause the tautomerization between α-keto amide
and iminone, leading to the low electrophilicity of the ketone
group (entry 15).15 Indeed, the reaction involving HCOOH did
not proceed at all (entry 16). Overall, reaction conditions utilized
in entry 11 were determined to be optimal.
CF3 and CN, were well tolerated in this protocol, the substrate
with a NO2 group produced a complex mixture, which might be
caused by the potential reduction of the NO2 group into other
functionalities under the current reaction conditions (entries 11–
13).19a As expected, the replacement of phenyl group with
naphthyl group did not cause any influence on the yield (entry
14). Furthermore, the substrate with an aliphatic amide moiety
was investigated as well. While the secondary amide 1o–q with
a benzyl, butyl or cyclohexyl group afforded the target product
efficiently, the tertiary amide 1r with double ethyl groups did not
show any conversion, implying that NH group might play an
important role in the reduction process (entries 15–18).
Table 1. Optimization of reaction conditions
Table 2. Investigation on the amide moiety of α-keto amides
Entry
Solv.
HCOOM
Temp.
( ℃)
Time
(h)
Yielda
Entry
1
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Yielda
93
96
85
89
91
84
91
92
90
94
88
92
c.m.b
89
90
88
87
0
1
2
DMF
HCOONa·2H2O
HCOONa·2H2O
100
100
6
6
44
70
4-MeC6H4
2-MeC6H4
4-t-BuC6H4
4-MeOC6H4
3-MeOC6H4
4-(Me)2NC6H4
C6H4
a
b
c
d
e
f
DMSO
2
1,4-
dioxane
3
HCOONa·2H2O
100
6
11
3
4
MeCN
i-PrOH
H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa·2H2O
HCOONa
100
100
100
100
100
100
100
120
120
120
120
120
120
6
trace
0
4
5
6
5
6
6
0
6
7
toluene
DCE
6
0
7
g
h
i
8
6
0
8
4-ClC6H4
3-ClC6H4
4-FC6H4
4-NCC6H4
4-F3CC6H4
3-O2NC6H4
1-naphthyl
benzyl
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
12
12
12
12
12
12
12
12
78
83
93
82
80
78
15
0
9
10b
11
12
13
14
15
16
10
11
12
13
14
15
16
17
18
j
k
l
HCOOLi·H2O
HCOONH4
m
n
o
p
q
r
HCOOK
HCOOH
Bu
aIsolated yield. b1.5 Equiv. of HCOONa·2H2O was used.
cyclohexyl
Et
With the optimized reaction conditions in hand, we started to
explore the scope of the substrates. We firstly screened a wide
array of α-keto amides with different functional groups on the
benzene ring attached to the amide moiety (Table 2). As
depicted, α-keto amides 1a–j bearing electron-donating Me, t-Bu,
MeO, and (Me)2N groups or weakly electron-withdrawing halo
groups successfully gave the corresponding α-hydroxy amides
2a–j in good to excellent yields, regardless of their positions
(entries 1–10). Although strongly electron-withdrawing groups,
aIsolated yield. bComplex mixture.
Next, the scope of this protocol was expanded to other α-keto
amides with diverse functional groups on the aromatic ring
attached to the keto moiety (Table 3). As described, both
electron-donating and electron-withdrawing groups showed
good tolerance with this reaction, affording the corresponding
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
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products 2s–w in high yields, respectively (entries 1–5). In
addition, the α-keto amide with naphthyl or thienyl group was
also usable as the substrate to afford the desired product in an
excellent yield (entries 6 and 7). Furthermore, this protocol was
compatible with the methyl-substituted α-keto amide as well,
which afforded α-hydroxypropionamide 2z in 75% yield (entry 8).
produce the corresponding products (eq. b and c). Although the
highly reactive benzaldehyde 5 could be easily reduced by
metal-catalyzed transfer hydrogenation using HCOONa as a
hydrogen donor,21 it did not yield even a trace amount of the
reduced product under the current reaction conditions (eq. d).
Table 4. Chemoselective hydrogenation of the keto group of α-keto amides in
the presence of other unsaturated groups
Table 3. Study on the ketone moiety of α-keto amides
Entry
R3
Yielda
89
1
2
3
4
5
6
7
8
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
2-naphthyl
2-thienyl
Me
s
t
90
Overall, the result of the above control experiments indicates
that NH group is crucial for the reduction of the ketone group of
α-keto amides, which was further verified by the smooth
hydrogenation of the CHO group having a TsNH group at the
adjacent position on the benzene ring (eq. e). Furthermore, the
reaction in the absence of HCOONa did not occur, which
unambiguously showed that the H atom at the α-position of α-
hydroxy amides comes from HCOONa (eq. f).
u
v
w
x
y
z
87
88
86
83
93
75
aIsolated yield.
To examine the chemoselectivity of the developed method, we
further extended the scope of this transfer hydrogenation to the
simple ketone, and the α-keto amides containing additional
unsaturated groups. When α-keto amide 1A or 1B having an
isolated keto or amide group on the benzene ring was subjected
to this transformation, α-ketone group was selectively reduced
with no effect on the isolated keto or amide group (Table 4). In
these chemoselective reductions, the ketone group of α-keto
amides should be more electrophilic and active than the isolated
ketone or amide group because of the electron-withdrawing
effect of the adjacent carbonyl group. Additionally, the NH group
of α-keto amide might also facilitate the chemoselective
reduction of the ketone group. Furthermore, the reduction only
took place on the α-keto amide moiety despite of the introduction
of an unsaturated alkynyl group into the substrate.
Unfortunately, the reaction using β-keto amide as the substrate
did not occur even at higher temperature with longer time, which
might be caused by the low reactivity of the ketone group due to
the poor eletrophilicity and the keto-enol tautomerism under
basic conditions.
In order to elucidate the mechanism of this transformation,
several control experiments were carried out (Scheme 2). The
addition of TEMPO had a slight influence on the transformation,
suggesting that radical intermediates were not involved in this
process (eq. a). Piperidyl substituted α-ketone amide 1D and α-
ketone ester 3, in both of which NH group was absent, failed to
Scheme 2. Control experiments
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Based on the abovementioned results, a plausible mechanism of
this transformation is illustrated in Scheme 3. The ketone group
of α-keto amide 1 should be activated by the neighbouring
carbonyl and NH group through the electron-withdrawing and
intramolecular hydrogen bonding effect,22 respectively. Then, the
H2O-mediated intermolecular hydrogen bonding with NH group
and formate anion promotes the reduction of the α-ketone group
through a ring transition state that decreases the activation
energy.23 Next, the hydride from formate attacks the electrophilic
ketone carbon atom followed by the protonation with H2O to
afford the target α-hydroxy amide 2.14
Scheme 4. Scalability and synthetic utility of this protocol
Experimental Section
Scheme 3. A plausible mechanism for transfer hydrogenation
General information
The melting points were determined on Buchi M-565 Automated Melting
Point System, and are uncorrected. The 1H NMR spectra were measured
on a Bruker Ascend-400 at 400 MHz with tetramethylsilane as an internal
standard. The 13C NMR spectra were measured on a Bruker Ascend-400
at 100 MHz, and assignments of 13C NMR spectra were performed by
DEPT experiments. The high-resolution mass spectra were measured on
SYNAPT-G2-Si. The IR spectra were recorded on a JASCO FT/IR-4200
spectrometer. All the reagents and solvents were commercially available
and used as received.
Finally, to illustrate the scalability and synthetic utility of the
developed protocol, the chemoselective reduction of α-keto
amide 1u was conducted in a gram-scale, and the yield was not
influenced in comparison with the reaction in a milligram-scale,
which implied that this protocol could be further developed for
large-scale production (Scheme 4, a). Next, the conversion of
the resulting α-hydroxy amides into other useful synthetic
building blocks was investigated. As shown, treatment of α-
hydroxy amide 2a with benzyl bromide in the presence of
sodium hydride afforded novel polysubstituted acetamide 9 in a
good yield (Scheme 4, b). In addition, the intramolecular
cyclization of α-hydroxy amide 2a into 2-arylated indole 10 in the
presence of polyphosphoric acid was achieved, providing a new
and useful access to 2-arylindole derivatives (Scheme 4, c).24
General procedure for preparation of α-keto amides 1
Oxalyl chloride (6.4 mmol) was added dropwise to a mixture of
benzoyl formic acid (5.0 mmol) and a drop of DMF in CH2Cl2 (20 mL),
and the reaction mixture was stirred at room temperature for 2 h. Then, a
mixture of amine (7.2 mmol) and Et3N (14.4 mmol) in CH2Cl2 (10 mL)
was added dropwise, and the resultant mixture was stirred at room
temperature for further 4 h. Next, water (30 mL) was added to the
reaction mixture, and the organic layer was separated. After
concentration under reduced pressure, the obtained residue was purified
through silica gel cloumn chromatography (eluted with petroleum
ether/ethyl acetate = 5/1) to afford α-keto amides 1.
Conclusions
In conclusion, an operationally simple and metal-free
chemoselective transfer hydrogenation of α-keto amides to α-
hydroxy amides was developed by using sodium formate as a
hydrogen source. The synthetic utility was demonstrated by
gram-scale synthesis and transformation of the obtained α-
hydroxy amides into other useful compounds. Several control
experiments revealed that the NH group of α-keto amides is
crucial for the chemoselective reduction via the formation of
hydrogen bonding. Further investigations on the application of
this protocol for synthesizing structurally diverse compounds are
currently in progress in our group.
General procedure for synthesis of α-hydroxy amides 2
To a solution of α-keto amide 1 (0.21 mmol) in DMSO (2 mL), was added
HCOONa·2H2O (0.25 mmol), and the resultant mixture was stirred at
120 ℃ for 12 h. Then, the mixture was cooled to the room temperature,
and water (5 mL) was added. The obtained mixture was extracted with
CH2Cl2 (5 mL × 2 ) and dried over Na2SO4. After concentration under
reduced pressure, the residue was subjected to column chromatography
on silica gel to isolate 2 (eluted with petroleum ether/ethyl acetate = 3/1).
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2-hydroxy-2-phenyl-N-(p-tolyl)acetamide (2a)17
7.32 (t, J = 7.6 Hz, 2H), 7.36−7.42 (m, 3H), 7.48 (d, J = 7.6 Hz, 2H), 7.52
(d, J = 7.6 Hz, 2H), 8.14 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 74.7
(CH), 119.8 (CH), 124.7 (CH), 126.9 (CH), 128.9 (CH), 129.0 (CH), 129.1
(CH), 137.1 (C), 139.0 (C), 169.9 (CO).
White solid (46.7 mg, 0.19 mmol, 93%). 1H NMR (CDCl3, 400 MHz) δ
2.31 (s, 3H), 3.43 (d, J = 3.2 Hz, 1H), 5.18 (d, J = 3.2 Hz, 1H), 7.12 (d, J
= 8.4 Hz, 2H), 7.34−7.43 (m, 5H), 7.48 (d, J = 8.0 Hz, 2H), 8.00 (br s, 1H);
13C NMR (CDCl3, 100 MHz) δ 20.9 (CH3), 74.7 (CH), 119.8 (CH), 126.9
(CH), 128.9 (CH), 129.0 (CH), 129.5 (CH), 134.4 (C), 134.5 (C), 139.0
(C), 169.7 (CO).
N-(4-chlorophenyl)-2-hydroxy-2-phenylacetamide (2h)17
White solid (50.1 mg, 0.19 mmol, 92%). 1H NMR (DMSO-d6, 400 MHz)
δ 5.11 (d, J = 4.8 Hz, 1H), 6.49 (d, J = 4.8 Hz, 1H), 7.29 (t, J = 7.2 Hz,
1H), 7.34-7.38 (m, 4H), 7.51 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H),
10.1 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 74.5 (CH), 121.8 (CH),
127.0 (CH), 127.6 (C), 128.1 (CH), 128.6 (CH), 128.9 (CH), 138.0 (C),
141.1 (C), 171.9 (CO).
2-hydroxy-2-phenyl-N-(o-tolyl)acetamide (2b)13
White solid (48.2 mg, 0.20 mmol, 96%). 1H NMR (CDCl3, 400 MHz) δ
2.12 (s, 3H), 3.80 (br s, 1H), 5.16 (s, 1H), 7.05 (t, J = 7.2 Hz, 1H),
7.14−7.20 (m, 2H), 7.33−7.42 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.86 (d, J
= 8.4 Hz, 1H), 8.02 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.4 (CH3),
74.7 (CH), 122.1 (CH), 125.3 (CH), 126.8 (CH), 126.9 (CH), 128.5 (C),
128.9 (CH), 129.0 (CH), 130.5 (CH), 134.9 (C), 139.2 (C), 170.1 (CO).
N-(3-chlorophenyl)-2-hydroxy-2-phenylacetamide (2i)18
White solid (48.9 mg, 0.19 mmol, 90%). 1H NMR (DMSO-d6, 400 MHz)
δ 5.12 (d, J = 4.4 Hz, 1H), 6.51 (d, J = 4.4 Hz, 1H), 7.11 (d, J = 8.0 Hz,
1H), 7.28-7.38 (m, 4H), 7.52 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H),
7.92 (s, 1H), 10.1 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 74.5 (CH),
118.6 (CH), 119.6 (CH), 123.7 (CH), 127.0 (CH), 128.2 (CH), 128.6 (CH),
130.7 (CH), 133.4 (C), 140.5 (C), 141.0 (C), 172.1 (CO).
N-[4-(tert-butyl)phenyl]-2-hydroxy-2-phenylacetamide (2c)
White solid (49.4 mg, 0.18 mmol, 84%). Mp 129.1−130.2 °C; 1H NMR
(CDCl3, 400 MHz) δ 1.29 (s, 9H), 3.42 (d, J = 3.2 Hz, 1H), 5.18 (d, J = 3.2
Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.35-7.49 (m, 7H), 8.01 (br s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 31.3 (CH3), 34.4 (C), 74.7 (CH), 119.5 (CH),
125.9 (CH), 126.9 (CH), 128.9 (CH), 129.0 (CH), 134.4 (C), 139.1 (C),
147.8 (C), 169.7 (CO); IR (ATR/cm-1) ν 3313, 3206, 2962, 2904, 2867,
1655; HRMS (ESI/TOF) Calcd for C18H21NO2Na [(M+Na)+]: 306.1470,
found306.1474.
N-(4-fluorophenyl)-2-hydroxy-2-phenylacetamide (2j)25
White solid (48.0 mg, 0.20 mmol, 94%). 1H NMR (CDCl3, 400 MHz) δ
3.34 (d, J = 3.2 Hz, 1H), 5.20 (d, J = 3.2 Hz, 1H), 7.01 (t, J = 8.4 Hz, 2H),
7.35−7.43 (m, 3H), 7.48−7.51 (m, 4H), 8.17 (br s, 1H); 13C NMR (CDCl3,
2
3
100 MHz) δ 74.7 (CH), 115.7 (d, JCF = 22.0 Hz, CH), 121.6 (d, JCF = 8.0
2-hydroxy-N-(4-methoxyphenyl)-2-phenylacetamide (2d)17
Hz, CH), 126.9 (CH), 129.0 (CH), 129.1 (CH), 133.1 (C), 138.9 (C), 159.6
1
(d, JCF = 243.0 Hz, CF), 169.8 (CO).
White solid (47.6 mg, 0.19 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ
3.52 (d, J = 3.2 Hz, 1H), 3.78 (s, 3H), 5.16 (d, J = 3.2 Hz, 1H), 6.84 (d, J
= 8.8 Hz, 2H), 7.34−7.48 (m, 5H), 7.47 (dd, J = 1.6 Hz, 8.0 Hz, 2H), 8.03
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 55.5 (CH3), 74.7 (CH), 114.2
(CH), 121.6 (CH), 126.9 (CH), 128.9 (CH), 129.0 (CH), 130.2 (C), 139.1
(C), 156.7 (C), 169.7 (CO).
N-(4-cyanophenyl)-2-hydroxy-2-phenylacetamide (2k)17
White solid (46.1 mg, 0.18 mmol, 88%). 1H NMR (CDCl3, 400 MHz) δ
3.49 (d, J = 3.6 Hz, 1H), 5.21 (d, J = 3.6 Hz, 1H), 7.35−7.42 (m, 3H), 7.46
(d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 8.65
(br s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ 74.6 (CH), 105.8 (C), 119.5
(C), 120.2 (CH), 127.0 (CH), 128.2 (CH), 128.7 (CH), 133.6 (CH), 140.8
(C), 143.3 (C), 172.6 (CO).
2-hydroxy-N-(3-methoxyphenyl)-2-phenylacetamide (2e)13
White solid (48.9 mg, 0.20 mmol, 91%). 1H NMR (CDCl3, 400 MHz) δ
3.35 (br s, 1H), 5.20 (s, 1H), 6.68 (dd, J = 2.0, 8.4 Hz, 1H), 6.98 (dd, J =
1.2, 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 1.2, 2.0 Hz, 1H),
7.37−7.43 (m, 3H), 7.48 (d, J = 7.6 Hz, 2H), 8.15 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 55.3 (CH3), 74.8 (CH), 105.3 (CH), 110.7 (CH),
111.8 (CH), 126.9 (CH), 128.9 (CH), 129.0 (CH), 129.7 (CH), 138.3 (C),
138.9 (C), 160.3 (C), 169.8 (CO).
2-hydroxy-2-phenyl-N-[4-(trifluoromethyl)phenyl]acetamide (2l)17
White solid (56.5 mg, 0.19 mmol, 92%). 1H NMR (DMSO-d6, 400 MHz)
δ 5.15 (d, J = 4.4 Hz, 1H), 6.54 (d, J = 4.4 Hz, 1H), 7.30 (t, J = 7.2 Hz,
1H), 7.37 (t, J = 7.2 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 8.4 Hz,
2H), 7.95 (d, J = 8.4 Hz, 2H), 10.32 (br s, 1H); 13C NMR (DMSO-d6, 100
2
MHz) δ 74.5 (CH), 120.1 (CH), 124.0 (q, JCF = 31.8 Hz, C), 124.8 (q, J =
3
N-[4-(dimethylamino)phenyl]-2-hydroxy-2-phenylacetamide (2f)
269.8 Hz, CF3), 126.3 (q, JCF = 3.5 Hz, CH), 127.0 (CH), 128.2 (CH),
128.6 (CH), 141.0 (C), 142.6 (C), 172.4 (CO).
White solid (47.2 mg, 0.18 mmol, 84%). Mp 173.3−174.2 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.91 (s, 6H), 3.65 (br s, 1H), 5.14 (s, 1H), 6.69 (d, J
= 8.4 Hz, 2H), 7.33−7.41 (m, 5H), 7.45−7.48 (m, 2H), 7.88 (br s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 41.0 (CH3), 74.6 (CH), 96.2 (C), 113.1 (C),
116.4 (C), 121.5 (CH), 127.0 (CH), 128.8 (CH), 129.0 (CH), 139.3 (CH),
169.6 (CO); IR (ATR/cm-1) ν 3309, 3218, 2797, 1656; HRMS (ESI/TOF)
Calcd for C16H17N2O2 [(M-H)-]: 269.1290, found 269.1290.
2-hydroxy-N-(naphthalen-1-yl)-2-phenylacetamide (2n)17
White solid (51.3 mg, 0.185 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ
3.95 (d, J = 3.2 Hz, 1H), 5.23 (d, J = 3.2 Hz, 1H), 7.33−7.52 (m, 8H),
7.62−7.64 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.82−7.85 (m, 1H), 7.94 (d, J
= 7.6 Hz, 1H), 8.73 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 74.9 (CH),
119.9 (CH), 120.2 (CH), 125.7 (CH), 125.9 (CH), 126.0 (CH), 126.4 (CH),
126.7 (C), 126.9 (CH), 128.8 (CH), 128.9 (CH), 129.0 (CH), 131.4 (C),
134.0 (C), 139.2 (C), 170.7 (CO).
2-hydroxy-N,2-diphenylacetamide (2g)17
White solid (42.9 mg, 0.19 mmol, 91%). 1H NMR (CDCl3, 400 MHz) δ
3.46 (d, J = 2.8 Hz, 1H), 5.18 (d, J = 2.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H),
N-benzyl-2-hydroxy-2-phenylacetamide (2o)16
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
FULL PAPER
White solid (45.2 mg, 0.19 mmol, 90%). 1H NMR (CDCl3, 400 MHz) δ
3.64 (s, 1H), 4.41 (dd, J = 5.6, 15.2 Hz, 1H), 4.46 (dd, J = 5.6, 15.2 Hz,
1H), 5.06 (s, 1H), 6.49 (br s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.24−7.42 (m,
8H); 13C NMR (CDCl3, 100 MHz) δ 43.5 (CH2), 74.3 (CH), 126.7 (CH),
127.5 (CH), 127.6 (CH), 128.7 (CH), 128.8 (CH), 128.9 (CH), 137.7 (C),
139.4 (C), 172.1 (CO).
318.0130, found 318.0131.
2-(2-bromophenyl)-2-hydroxy-N-(p-tolyl)acetamide (2w)
White solid (57.0 mg, 0.18 mmol, 86%). Mp 150.3−152.4 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.31 (s, 3H), 4.07 (d, J = 4.4 Hz, 1H), 5.63 (d, J = 4.4
Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.21 (ddd, J = 1.6, 7.6, 8.0 Hz, 1H),
7.35 (ddd, J = 0.8, 7.6, 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.49 (dd, J =
1.6, 8.0 Hz, 2H), 7.60 (dd, J = 0.8, 8.0 Hz, 1H), 8.06 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 20.9 (CH3), 72.7 (CH), 119.9 (CH), 122.9 (C), 128.3
(CH), 128.9 (CH), 129.6 (CH), 130.3 (CH), 133.1 (CH), 134.4 (C), 134.6
(C), 138.7(C), 169.2 (CO); IR (ATR/cm-1) ν 3346, 3143, 1655; HRMS
(ESI/TOF) Calcd for C15H13NO2Br [(M-H)-]: 318.0130, found 318.0131.
N-butyl-2-hydroxy-2-phenylacetamide (2p)18
White solid (42.3 mg, 0.18 mmol, 88%). 1H NMR (CDCl3, 400 MHz) δ
0.88 (t, J = 7.2 Hz, 3H), 1.28 (tq, J = 7.2, 7.6 Hz, 2H), 1.45 (tt, J = 7.2, 7.6
Hz, 2H), 3.19-3.31 (m, 2H), 3.75 (br s, 1H), 4.99 (s, 1H), 6.12 (br s, 1H),
7.31-7.41 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 13.7 (CH3), 19.9 (CH2),
31.5 (CH2), 39.4 (CH2), 74.1 (CH), 126.9 (CH), 128.6 (CH), 128.9 (CH),
139.6 (C), 172.0 (CO).
2-hydroxy-2-(naphthalen-2-yl)-N-(p-tolyl)acetamide (2x)
N-cyclohexyl-2-hydroxy-2-phenylacetamide (2q)13
White solid (50.4 mg, 0.17 mmol, 83%). Mp 209.2−209.9 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 2.23 (s, 3H), 5.27 (s, 1H), 6.56 (br s, 1H), 7.09 (d,
J = 8.4 Hz, 2H), 7.49-7.54 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.67 (dd, J =
1.6, 8.8 Hz, 1H), 7.89-7.93 (m, 3H), 8.01 (s, 1H), 9.90 (br s, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 20.9 (CH3), 74.6 (CH), 120.2 (CH), 125.2
(CH), 125.7 (CH), 126.4 (CH), 126.7 (CH), 128.0 (CH), 128.1 (CH), 128.3
(CH), 129.4 (CH), 132.9 (C), 133.0 (C), 133.1 (C), 136.5 (C), 138.9 (C),
171.3 (CO); IR (ATR/cm-1) ν 3275, 2919, 2851,1648; HRMS (ESI/TOF)
Calcd for C19H16 NO2 [(M-H)-]: 290.1181, found 290.1182.
White solid (42.3 mg, 0.18 mmol, 87%). 1H NMR (CDCl3, 400 MHz) δ
1.02-1.18 (m, 3H), 1.25-1.38 (m, 2H), 1.56-1.69 (m, 3H), 1.81-1.87 (m,
2H), 3.69-3.77 (m, 1H), 3.87 (br s, 1H), 4.95 (s, 1H), 6.09 (br s, 1H),
7.30-7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 24.6 (CH2), 24.7 (CH2),
25.4 (CH2), 32.8 (CH2), 48.4 (CH2), 74.1 (CH), 126.9 (CH), 128.5 (CH),
128.8 (CH), 139.7 (C), 171.2 (CO).
2-hydroxy-N,2-di(p-tolyl)acetamide (2s)14
2-hydroxy-2-(thiophen-2-yl)-N-(p-tolyl)acetamide (2y)
White solid (47.4 mg, 0.19 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ
2.30 (s, 3H), 2.35 (s, 3H), 3.43 (d, J = 1.6 Hz, 1H), 5.12 (d, J = 1.6 Hz,
1H), 7.11 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.39 (d, J = 8.4 Hz, 2H), 8.00 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 20.9 (CH3), 21.2 (CH3), 74.5 (CH), 119.8 (CH), 126.9 (CH), 129.5 (CH),
129.7 (CH), 134.3 (C), 134.6 (C), 136.1 (C), 138.8 (C), 170.0 (CO).
White solid (47.8 mg, 0.19 mmol, 93%). Mp 169.9−171.5 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.32 (s, 3H), 3.66 (d, J = 3.6 Hz, 1H), 5.46 (d, J = 3.6
Hz, 1H), 7.02 (dd, J = 3.6, 4.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.20 (d, J
= 3.6 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 8.08 (br
s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.9 (CH3), 70.6 (CH), 119.9 (CH),
126.3 (CH), 126.5 (CH), 127.1 (CH), 129.6 (CH), 134.3 (C), 134.6 (C),
141.9 (C), 168.6 (CO); IR (ATR/cm-1) ν 3310, 3146, 2921, 2841, 1670;
HRMS (ESI/TOF) Calcd for C13H13NO2NaS [(M+Na)+]: 270.0565, found
270.0567.
2-hydroxy-2-(4-methoxyphenyl)-N-(p-tolyl)acetamide (2t)14
White solid (50.7 mg, 0.19 mmol, 90%). 1H NMR (CDCl3, 400 MHz) δ
2.30 (s, 3H), 3.44 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 5.10 (d, J = 2.8 Hz,
1H), 6.91 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 7.2 Hz,
2H), 7.39 (d, J = 7.2 Hz, 2H), 8.03 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 20.9 (CH3), 55.4 (CH3), 74.2 (CH), 114.4 (CH), 119.8 (CH), 128.4 (CH),
129.5 (CH), 131.2 (C), 134.3 (C), 134.6 (C), 160.0 (C), 170.1 (CO).
2-hydroxy-N-(p-tolyl)propanamide (2z)25
Colorless oil (27.9 mg, 0.16 mmol, 75%). 1H NMR (CDCl3, 400 MHz) δ
2.29 (s, 3H), 3.94 (br s, 1H), 4.28 (q, J = 6.4 Hz, 1H), 7.09 (d, J = 8.0 Hz,
2H), 7.39 (d, J = 8.0 Hz, 2H), 8.55 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 20.9 (CH3), 21.1 (CH3), 68.7 (CH), 120.0 (CH), 129.5 (CH), 134.3 (C),
134.5 (C), 173.0 (CO).
2-(4-chlorophenyl)-2-hydroxy-N-(p-tolyl)acetamide (2u)
White solid (50.0 mg, 0.18 mmol, 87%). Mp 160.2−162.1 °C; 1H NMR
(CDCl3, 400 MHz) δ 2.31 (s, 3H), 3.67 (br s, 1H), 5.12 (s, 1H), 7.11 (d, J
= 8.0 Hz, 2H), 7.33−7.41 (m, 6H), 8.17 (br s, 1H); 13C NMR (CDCl3, 100
MHz) δ 20.9 (CH3), 73.9 (CH), 119.8 (CH), 128.2 (CH), 129.1 (CH), 129.6
(CH), 134.3 (C), 134.6 (C), 134.7 (C), 137.5 (C), 169.3 (CO); IR
N-(4-acetylphenyl)-2-hydroxy-2-phenylacetamide (2A)9
White solid (50.8 mg, 0.19 mmol, 91%). 1H NMR (DMSO-d6, 400 MHz)
δ 2.52 (s, 3H), 5.15 (d, J = 4.8 Hz, 1H), 6.52 (d, J = 4.8 Hz, 1H), 7.30 (t, J
= 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.86 (d, J
= 8.8 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 10.32 (br s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 26.9 (CH3), 74.5 (CH), 119.5 (CH), 127.0 (CH),
128.2 (CH), 128.6 (CH), 129.8 (CH), 132.4 (C), 141.0 (C), 143.4 (C),
172.3 (CO), 197.1 (CO).
(ATR/cm-1)
ν 3288, 3043, 1670, 1636; HRMS (ESI/TOF) Calcd for
C15H14NO2NaCl [(M+Na)+]: 298.0611, found 298.0614.
2-(4-bromophenyl)-2-hydroxy-N-(p-tolyl)acetamide (2v)
White solid (58.4 mg, 0.18 mmol, 88%). Mp 162.9−163.8 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 2.24 (s, 3H), 5.09 (d, J = 4.8 Hz, 1H), 6.52 (d, J =
4.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.56 (d, J =
8.4 Hz, 4H, overlap), 9.86 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
20.9 (CH3), 73.7 (CH), 120.2 (CH), 121.2 (C), 129.2 (CH), 129.4 (CH),
131.4 (CH), 133.0 (C), 136.4 (C), 140.8 (C), 170.9 (CO); IR (ATR/cm-1) ν
3346, 3143, 1655; HRMS (ESI/TOF) Calcd for C15H13NO2Br [(M-H)-]:
4-(2-hydroxy-2-phenylacetamido)-N-methylbenzamide (2B)
White solid (52.7 mg, 0.19 mmol, 89%). Mp 203.9−205.1 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 2.76 (d, J = 4.0 Hz, 3H), 5.13 (s, 1H), 6.52 (br s,
1H), 7.29 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.52 (d, J = 7.6 Hz,
2H), 7.52 (s, 4H, overlap), 8.32 (d, J = 4.0 Hz, 1H), 10.14 (br s, 1H); 13C
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
FULL PAPER
NMR (DMSO-d6, 100 MHz) δ 26.7 (CH3), 74.5 (CH), 119.4 (CH), 127.0
(CH), 128.1 (CH), 128.2 (CH), 128.6 (CH), 129.8 (C), 141.1 (C), 141.4
(C), 166.5 (CO), 172.0 (CO); IR (ATR/cm-1) ν 3377, 3277, 1655, 1650;
HRMS (ESI/TOF) Calcd for C16H15N2O3 [(M-H)-]: 283.1083, found
283.1082.
CH2Cl2 (5 mL × 2) and dried over Na2SO4. After concentration under
reduced pressure, the residue was subjected to column chromatography
on silica gel to isolate 10 (eluted with petroleum ether/ethyl acetate =
30/1) as a white solid (29.3 mg, 0.14 mmol, 69%).
1H NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 6.67 (d, J = 1.2 Hz, 1H),
6.94 (dd, J = 1.2, 8.0 Hz, 1H), 7.17-7.25 (m, 2H), 7.33-7.37 (m, 3H), 7.55-
7.58 (m, 2H), 8.17 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.6 (CH3),
99.6 (CH), 110.7 (CH), 120.4 (CH), 124.1 (CH), 125.2 (CH), 127.7 (CH),
129.1 (CH), 129.5 (C), 129.6 (C), 132.6 (C), 135.3 (C), 138.1 (C).
2-hydroxy-2-phenyl-N-[2-(phenylethynyl)phenyl]acetamide (2C)
White solid (59.8 mg, 0.18 mmol, 88%). Mp 134.7−135.1 °C; 1H NMR
(CDCl3, 400 MHz) δ 3.84 (d, J = 3.2 Hz, 1H), 5.16 (d, J = 3.2 Hz, 1H),
7.06 (t, J = 8.4 Hz, 1H), 7.25-7.32 (m, 4H), 7.35-7.37 (m, 3H), 7.44-7.49
(m, 3H), 7.52-7.55 (m, 2H), 8.39 (d, J = 8.4 Hz, 1H), 9.29 (br s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 75.0 (CH), 84.0 (C), 96.7 (C), 112.6 (C), 119.1
(CH), 122.4 (C), 123.9 (CH), 126.9 (CH), 128.5 (CH), 128.8 (CH), 128.9
(CH), 129.0 (CH), 129.7 (CH), 131.5 (CH), 131.6 (CH), 138.2 (C), 138.9
Acknowledgments
We are grateful for financial support of the Chemical
Engineering & Technology of Zhejiang Province First-Class
Discipline (Taizhou University).
(C), 170.3 (CO); IR (ATR/cm-1)
(ESI/TOF) Calcd for C22 H16NO2 [(M-H)-]: 326.1181, found 326.1181.
ν 3331, 3219, 2250, 1650; HRMS
Synthesis
of
N-[2-(hydroxymethyl)phenyl]-4-
Keywords: α-keto amides
• α-hydroxy amides • transfer
methylbenzenesulfonamide 826
hydrogenation • sodium formate • hydrogen bonding
To
a solution of N-(2-formylphenyl)-4-methylbenzenesulfonamide 7
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(57.5 mg, 0.21 mmol) in DMSO (2 mL), was added HCOONa·2H2O (26.1
mg, 0.25 mmol), and the resultant mixture was stirred at 120 ℃ for 24 h.
Then, the mixture was cooled to the room temperature, and water (5 mL)
was added. The obtained mixture was extracted with CH2Cl2 (5 mL × 2)
and dried over Na2SO4. After concentration under reduced pressure, the
residue was subjected to column chromatography on silica gel to isolate
8 (eluted with petroleum ether/ethyl acetate = 3/1) as a white solid (40.5
mg, 0.15 mmol, 70%).
1H NMR (CDCl3, 400 MHz) δ 2.19 (br s, 1H), 2.38 (s, 3H), 4.39 (s, 2H),
7.06-7.10 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.23-7.28 (m, 1H), 7.43 (d, J
= 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.90 (br s, 1H); 13C NMR (CDCl3,
100 MHz) δ 21.6 (CH3), 63.9 (CH2), 123.5 (CH), 125.4 (CH), 127.1 (CH),
129.3 (CH), 129.1 (CH), 129.6 (CH), 131.7 (C), 136.4 (C), 136.9 (C),
143.8 (C).
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Synthesis of polysubstituted acetamide 9
H. Shang, F. Y. Hao, L. Pan, H. Chen, M. S. Cheng, HETEROCYCLES
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To a solution of 2a (50.0 mg, 0.21 mmol) and benzyl bromide (71.0 mg,
0.42 mmol) in CH2Cl2 (2 mL), was added NaH (60% dispersion in mineral
oil, 41.5 mg, 1.05 mmol), and the resultant mixture was stirred at room
temperature for 12 h. Then, water (2 mL) was added to the reaction
mixture, and the organic layer was separated. After concentration under
reduced pressure, the obtained residue was purified through silica gel
cloumn chromatography (eluted with petroleum ether/ethyl acetate = 5/1)
to afford polysubstituted acetamide 9 as a colorless oil (39.2 mg, 0.10
mmol, 90%).
1H NMR (CDCl3, 400 MHz) δ 2.24 (s, 3H), 4.33 (d, J = 11.6 Hz, 1H),
4.42 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.4 Hz,
1H), 4.74 (s, 1H), 4.87 (d, J = 14.4 Hz, 1H), 6.41 (d, J = 7.6 Hz, 2H), 6.85
(d, J = 7.6 Hz, 2H), 7.04-7.22 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ
21.1 (CH3), 53.4 (CH2), 70.6 (CH2), 77.3 (CH), 127.3 (CH), 127.7 (CH),
128.1 (CH), 128.3 (3CH, overlap), 128.4 (CH), 128.5 (CH), 128.6 (CH),
128.9 (CH), 129.8 (CH), 136.6 (C), 137.2 (C), 137.7 (C), 138.0 (C), 138.2
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(C), 169.9 (CO); IR (ATR/cm-1)
(ESI/TOF) Calcd for C29H28NO2 [(M+H)+]: 422.2120, found 422.2123.
ν 3051, 2928, 2876, 1646; HRMS
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Synthesis of 5-methyl-2-phenyl-1H-indole 1024
A solution of 2a (50.0 mg, 0.21 mmol) in PPA (1 mL) was heated at
180 ℃ for 10 h. Then, the mixture was cooled to the room temperature,
and water (2 mL) was added. The obtained mixture was extracted with
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201901073
European Journal of Organic Chemistry
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Practicality and Chemoselectivity
Feiyue Hao, Zhenyu Gu, Guyue Liu,
Wubing Yao, Huajiang Jiang, and
Jiashou Wu*
A
catalyst-
and
additive-free
transfer
chemoselective
hydrogenation of α-keto amides to α-
hydroxy amides is easily achieved by
using sodium formate as a hydrogen
source. Control experiments suggest
that the NH group of α-keto amides is
Page No. – Page No.
Catalyst- and Additive-free
Chemoselective Transfer
Hydrogenation of α-Keto Amides to α-
Hydroxy Amides by Sodium Formate
crucial
for
thechemoselective
reduction via the formation of
hydrogen bonding.
This article is protected by copyright. All rights reserved.