Enantioselective Ruthenium(II)/Xyl-SunPhos/Daipen-Catalyzed hydrogenation of γ-Ketoamides

Article abstract of DOI:10.1021/jo5008916

A0series of γ-hydroxy amides were synthesized with high ena~tioselectivities (up to 99%) usyng asymmetric hydrogenation of the corresponding γ-ketoamides in the presence of Ru-Xyl-SunPhos-Daipen catalyst providing key building blocks for a variety of natu

Full text of DOI:10.1021/jo5008916

Article
pubs.acs.org/joc
Enantioselective Ruthenium(II)/Xyl-SunPhos/Daipen-Catalyzed
Hydrogenation of γ‑Ketoamides
Mengmeng Zhao,† Wanfang Li,† Xiaoming Li,† Kai Ren,† Xiaoming Tao,† Xiaomin Xie,† Tahar Ayad,§
Virginie Ratovelomanana-Vidal,*,§ and Zhaoguo Zhang*,†,‡
†School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
‡Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
§Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, PSL Research University, 75005 Paris, France
S
* Supporting Information
ABSTRACT: A series of γ-hydroxy amides were synthesized with
high enantioselectivities (up to 99%) using asymmetric hydro-
genation of the corresponding γ-ketoamides in the presence of Ru-
Xyl-SunPhos-Daipen catalyst providing key building blocks for a
variety of naturally occurring and biologically active compounds.
substrate scope, yielding either γ-lactones or a mixture of γ-
hydroxy carboxylates and γ-lactones. Consequently, using
asymmetric hydrogenation to synthesize γ-hydroxy acid
derivatives is still a challenging work.
INTRODUCTION
■
Enantiomerically pure γ-hydroxy acid derivatives are important
synthetic building blocks which can be easily transformed into a
series of natural, pharmaceutical, and agrochemical com-
pounds.1 Currently, a number of methods are available for
the synthesis of enantiomerically enriched γ-hydroxy acid
derivatives via enzymatic reduction,2 kinetic resolution,3
asymmetric hydrosilylation,4 hydroboration,5 and other meth-
ods.6 However, these synthetic routes suffered from either low
efficiency or poor enantioselectivity. Accordingly, the search for
effective and highly enantioselective approaches to access
enantiomerically pure γ-hydroxy acid derivatives is of
significance.
It is well established that hydrogenation of functionalized
ketones involves a chelating ring transition state.9d,11 The
seven-membered chelating ring transition state of γ-ketoesters
with ruthenium is considered less stable than those of the five-
membered ring transition state of α-ketoesters and a six-
membered transition state of β-ketoesters. In order to enhance
the reactivity of γ-functionalized ketones, we envisaged utilizing
the hydrogenation of γ-ketoamides, which have a stronger
coordination ability compared to esters and a lower tendency to
form γ-lactones as reported by Bruckner and ourselves.12
̈
Catalytic asymmetric hydrogenation of ketones is one of the
most practical and direct methods to prepare chiral alcohols
and has attracted much attention both in academia and
industry.7 Both functionalized and nonfunctionalized ketones
can be enantioselectively hydrogenated using efficient catalytic
systems, and many effective chiral diphosphines have been
developed for this important transformation.8 Although the
asymmetric hydrogenation of α- and β-ketoacid derivatives has
been studied,9 only a few approaches based on asymmetric
hydrogenation of γ-ketoacid derivatives have been reported so
far.1g,10 In 1990, Noyori and co-workers described the first
asymmetric hydrogenation of 4-oxo carboxylates catalyzed by
Ru(OCOCH3)2[(S)-BINAP] in the presence of HCl at 100
atm for 110 h affording a mixture of γ-hydroxy carboxylates and
γ-lactones.10a Later, Vinogradov and co-workers reported the
enantioselective hydrogenation of levulinates in the presence of
the Ru(II)-BINAP with 10 equiv of HCl to afford enantiomeri-
cally pure γ-lactone derivatives with 95% yield and 99% ee
under an H2 pressure of 60−70 atm.10e In 2008, a much simpler
catalytic system, RuCl3−BINAP-HCl, was used to achieve the
asymmetric hydrogenation of γ-ketoesters.10f However, most of
the hydrogenation methods employed high hydrogen pressure
and long reaction time and were only effective for a limited
Our groups have been involved in an ongoing program
toward the development of catalysts for asymmetric hydro-
genation of ketone derivatives and their applications in organic
synthesis including α- and β-keto acid derivatives, highly
functionalized ketones, and simple ketones.13 We report herein
the application of diphosphine−ruthenium−diamine catalyst
systems for the enantioselective synthesis of γ-hydroxy amides.
RESULTS AND DISCUSSION
■
First, γ-keto Weinreb amides were chosen as standard
substrates14 in order to enhance the coordination ability of
the C(O)NR1R2 amide moiety bearing methoxy and methyl
groups (R1= Me, R2 = OMe) and because the resulting γ-
hydroxy Weinreb amides could be easily converted to the
corresponding γ-hydroxy ketones through nucleophilic addition
using organometallic reagents, or reduced to chiral diols.
N-Methoxy-N-methyl-4-oxo-4-phenylbutanamide (1a) was
chosen as the model substrate, and [Ru(cymene)Cl2]2-(S)-
Sunphos was first set as the catalyst to investigate the
Received: April 22, 2014
Published: June 16, 2014
© 2014 American Chemical Society
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hydrogenation reaction. When the reaction was conducted in
alcohols, low conversions were observed because of the
formation of the Weinreb amine side product which probably
poisoned the catalyst as previously reported.12c Although THF
proved to be the solvent of choice for asymmetric hydro-
genation of β-keto Weinreb amides,12c low conversion and
poor enantioselectivity were obtained for the hydrogenation of
1a. Aprotic solvents with weak coordinating ability, such as
dichloromethane and 1,2-dichloroethane, were not efficient for
this transformation. Unlike Noyori’s work,10a no improvement
was seen when HCl was added.
Considering the weak chelating ability of γ-keto acid
derivatives to coordinate the Ru, we carried out the
hydrogenation reaction using RuCl2(diphosphine)(diamine)
bifunctional catalyst which was developed by Noyori and co-
workers and has been widely used in the hydrogenation of
nonfunctionalized ketones.15 Pleasingly, the hydrogenation of
1a gave complete conversion with 85% ee at a S/C = 100 under
10 atm of hydrogen pressure at 30 °C in i-PrOH in the
presence of t-C4H9OK by employing RuCl2[(S)-SunPhos][(S)-
Daipen] as catalyst (Table 1, entry 1). However, when methyl
4-oxo-4-phenylbutanoate was reduced under the same reaction
conditions, a mixture of products was obtained with 40%
conversion.
Figure 1. Structures of chiral bidentate ligands.
enantioselectivity, we tested the hydrogenation with ligands
L1−L3 (Table 1, entries 6−8). The best result was obtained
using Xyl-SunPhos (L2), which provided the corresponding
alcohol in full conversion and 99% ee (Table 1, entry 7). When
the more sterically hindered ligand L3 was used, the reaction
led to poor enantioselectivity and conversion, and a racemic
product was obtained with 53% conversion (Table 1, entry 8).
To verify whether the reaction involved a hydrogenation or
transfer hydrogenation process, we conducted the reaction
without H2. Under the same reaction conditions, the product
was obtained with 99% ee and 20% conversion (Table 1, entry
9). Apparently, the hydrogenation is much faster than transfer
hydrogenation in this transformation. Increasing the H2
pressure from 10 to 30 atm provided an equivalent reactivity
and enantioselectivity, and a higher hydrogen pressure of 50
atm resulted in equivalent enantiomeric excess and conversion
to 30 atm (Table 1, entry 11). It was interesting to observe that
increasing or decreasing the reaction temperature did not
obviously change the enantioselectivity but did slightly modify
the reaction rate (Table 1, entries 12 and 13).
Table 1. Asymmetric Hydrogenation of γ-Keto Weinreb
Amide Using Diphosphine−Ruthenium−Diamine Catalyst
a
b
c
entry
ligand
T (°C) P (atm) conv (%) ee (%)
1
2
3
4
5
6
7
(S)-SunPhos
30
30
30
30
30
30
30
30
30
30
30
10
50
10
10
10
10
10
10
10
10
100
100
73
85
93
83
87
82
−51
99
1
(S)-BINAP
(S)-SegPhos
(S)-SYNPHOS
96
(S)-C3-Tunephos
88
L1
L2
L3
L2
L2
L2
L2
L2
100
100
53
d
8
e
9
20
99
98
98
98
98
10
11
30
50
10
10
100
100
95
d
The optimized reaction conditions were therefore set as
follows: RuCl2[(S)-Xyl-SunPhos][(S)-Daipen] as the catalyst
in i-PrOH and t-C4H9OK as the base under 10 atm of H2 at 30
°C for 15 h.
12
13
100
a
Unless otherwise stated, all reactions were carried out with a substrate
(0.5 mmol) concentration of 0.25 M in i-PrOH at 30 °C for 15 h.
b
Under the optimized reaction conditions, a wide range of γ-
keto Weinreb amides were hydrogenated, and the results are
depicted in Table 2. The model substrate 1a was hydrogenated
to give a full conversion and 99% ee (Table 2, entry 1). To our
delight, substrates with electron-donating groups and electron-
withdrawing groups at the para position of the phenyl moiety
were hydrogenated in full conversions with good to excellent
enantioselectivities as high as 99%, and a wide tolerance of
functional groups was observed (Table 2, entries 2−7).
Substrates with a substituent at the meta position of the phenyl
ring did not show any negative effect on the reaction. As a
result, the hydrogenation of 1h afforded the corresponding
alcohol with complete conversion and 99% ee (Table 2, entry
8). However, the substrates possessing ortho substituents on the
aromatic ring showed a different behavior considering both
Substrate/catalyst/t-BuOK = 100/1/5. Determined by HPLC on a
c
d
chiral AD-H column. Determined by NMR analysis. Reaction time:
30 h. Without H2.
e
Optimizations of the reaction conditions were performed for
asymmetric hydrogenation of N-methoxy-N-methyl-4-oxo-4-
phenylbutanamide (1a) including ligands, reaction temper-
atures and hydrogen pressures (Table 1). Although good
enantioselectivities were obtained under the same reaction
conditions using several commercially available chiral bidentate
ligands, such as (S)-BINAP, (S)-SEGPhos, (S)-C3-TunePhos,
and (S)-SYNPHOS (Figure 1, Table 1, entries 1−5), (S)-
BINAP gave the highest ee value of 93% (Table 1, entry 2).
Because minor changes of chiral ligands in geometric, steric,
and electronic properties can lead to dramatic differences of
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a
Table 2. Asymmetric Hydrogenation of γ-Keto Weinreb
Amides
Table 3. Asymmetric Hydrogenation of γ-Ketoamides
a
b
c
entry
3
R1
R2
yield (%)
ee (%)
b
c
d
1
2
3
4
3a
3b
3c
3d
Me
Et
Me
Et
97
97
98
97
99
96
97
97
entry
1
R
conv (%)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
C6H5
100
100
100
100
100
100
100
100
100
45
92
92
92
91
92
91
91
91
90
40
90
92
91
89
72
99
98
99
98
99
99
99
99
97
70
97
98
98
5
−(CH2)4−
4-MeC6H4
4-OMeC6H4
4-CF3C6H4
4-FC6H4
−
CH2CH2OCH2C-
H2−
H
H
H
5
6
3e
3f
Ph
Cy
H
97
98
8
98
97
98
4-ClC6H4
4-BrC6H4
3-MeC6H4
2-MeC6H4
2-OMeC6H4
2,4-Me2C6H4
2-naphthyl
2-furyl
d
1g
1h
1i
7
3g
a
Unless otherwise stated, all reactions were carried out under 10 atm
e
9
of H2 for 15 h at 30 °C using 0.5 mmol of the substrate 3 in i-PrOH
(0.5 M) containing the [RuCl2(S)-Xyl-SunPhos(S)-Daipen] and t-
C4H9OK with 100% conversion. Substrate/catalyst/base = 100/1/5.
Isolated yield by column chromatography ee values were determined
by HPLC. 12% conversion.
e
10
1j
e
11
1k
1l
100
100
100
100
80
b
c
12
13
14
d
1m
1n
1o
Me
e
15
C6H5CH2
8
asymmetric hydrogenation of 3f with 97% ee and up to a
TON of 1000 instead of the low-yielding DIP-Cl or baker’s
yeast reduction of the γ-keto tert-butyl esters.1f However, when
the substrate 3g was hydrogenated, it gave a 98% ee with only
12% conversion and the hydrogenation reaction gave a
complicated mixture (Table 3, entry 7).
a
Unless otherwise stated, all reactions were carried out under 10 atm
of H2 for 15 h at 30 °C using 0.5 mmol of the substrate 1 in i-PrOH
(0.5 M) containing the [RuCl2(S)-Xyl-SunPhos(S)-Daipen] and t-
C4H9OK. Substrate/catalyst/base = 100/1/5. Determined by NMR
analysis. Isolated yield by column chromatography and trace of
b
c
d
lactone was obtained. Determined by HPLC on a ChiralPak column.
e
For 30 h.
CONCLUSION
■
In summary, we have successfully achieved a highly
enantioselective hydrogenation of a series of functionalized γ-
keto amides with excellent yields and enantioselectivities up to
99% using a Ru/diphosphine/diamine catalyst system. This
practical method has a broad substrate scope, and the
corresponding γ-hydroxy amides, obtained under mild reaction
conditions, provide valuable building blocks for the preparation
of pharmaceutically and biologically relevant compounds.
reactivity and enantioselectivity. For a noncoordinating o-Me-
substituted substrate 1i, the reactivity dropped dramatically
because of the steric effect but with an equivalent ee value
(Table 2, entry 9). For the o-OMe-substituted γ-keto Weinreb
amides (1j), the reaction afforded the desired product with
much lower conversion and enantioselectivity because of the
coordinating ability of the o-MeO group (Table 2, entry 10).
Although the reaction time was prolonged to 30 h, the
hydrogenation of 1j could not give a full conversion. The
substrate 1k with two methyl group on the ortho- and para-
position of the aryl gave results similar to those of 1i (Table 2,
entry 11). Asymmetric hydrogenation of substrates bearing
other aromatic rings, such as 1l and 1m, led to the
corresponding γ-hydroxy Weinreb amides with 98% and 98%
ee, respectively (Table 2, entries 12 and 13). It was noteworthy
that the alcohol resulting from hydrogenation of 1m was
obtained with higher yield and enantioselectivity (91% yield
and 98% ee) compared to that prepared by the transfer
hydrogenation process (87% yield and 91% ee). Compound
2m was an important intermediate to synthesize nakiterpios-
in.1g Unfortunately, the alkyl-substituted 1n and the benzyl-
substituted 1o were hydrogenated with much lower ee (Table
2, entries 14 and 15), and for the compound 1o, low
conversion was observed even when the hydrogenation was
conducted for 30 h.
EXPERIMENTAL SECTION
■
General Methods. Commercially available reagents were used
throughout without further purification beyond that detailed below:
DMF and i-PrOH used in catalyst preparation and hydrogenation were
distilled over calcium hydride. PE = petroleum ether, EA = ethyl
acetate. All reactions were carried out under an atmosphere of nitrogen
1
using standard Schlenk techniques unless otherwise noted. H NMR
and 13C NMR spectra were obtained on a 400 MHz NMR
spectrometer. The chemical shifts of 1H NMR were recorded in
ppm downfield from tetramethylsilane (TMS) with the solvent
resonance as the internal standard. The chemical shifts of 13C NMR
were recorded in ppm downfield using the central peak of CDCl3
(77.00 ppm) as the internal standard. Coupling constants (J) are
reported in hertz and refer to apparent peak multiplications. HRMS
were performed under ESI ionization technique on a Waters
Micromass Q-TOF Premier mass spectrometer. Flash column
chromatography was performed on silica gel (300−400 mesh). [α]D
values were recorded at the D line (589 nm) of a sodium lamp in a 0.5
dm cell at 25 °C.
Following the above reaction conditions, the scope of the
reaction was then extended to other γ-ketoamides, and
excellent enantioselectivities and yields were obtained for 3a−
f, with ee values ranging from 96% to 99% (Table 3).
Moreover, N-cyclohexyl-4-hydroxy-4-phenylbutanamide 4f,
which was used by Yang and co-workers for the syntheses of
a series of γ-aminoxy peptides, could be obtained by
Preparation of 1a−l,o.16,17 To N,N′-dimethoxy-N,N′-dimethyl-
succinamide (5.0 g, 24.5 mmol) in THF (40 mL) under N2
atmosphere was added dropwise the corresponding Grignard reagent
(26.9 mmol). Upon consumption of the starting material, the reaction
was quenched with 10% HCl, and THF was removed in vacuum. The
resulting aqueous solution was extracted with EtOAc. The combined
organic layers were washed with brine and dried over anhydrous
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MgSO4. Evaporation was carried out under reduced pressure after
filtration. The crude product was purified by column chromatography
(PE/EA = 2/1).
(d, J = 8.0 Hz, 1H), 7.09−7.01 (m, 2H), 3.76 (s, 3H), 3.23 (t, J = 6.6
Hz, 2H), 3.20 (s, 3H), 2.86 (t, J = 6.6 Hz, 2H), 2.48 (s, 3H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 202.0, 173.3, 141.7, 138.4,
134.6, 132.6, 129.1, 126.2, 61.1, 35.2, 32.2, 26.2, 21.4, 21.2; HRMS
calcd for C14H19NNaO3 (M + Na)+ 272.1263, found 272.1258.
N-Methoxy-N-methyl-4-(naphthalen-2-yl)-4-oxobutanamide
N-Methoxy-N-methyl-4-oxo-4-phenylbutanamide (1a):18 white
solid; 4.5 g, 83% yield; mp 58.9−59.4 °C; 1H NMR (400 MHz,
CDCl3) δ 8.03−7.96 (m, 2H), 7.58−7.51 (m, 1H), 7.48−7.42 (m,
2H), 3.77 (s, 3H), 3.33 (t, J = 6.8 Hz, 2H), 3.20 (s, 3H), 2.89 (t, J =
6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.8, 173.1, 136.6,
132.9, 128.4, 127.9, 61.1, 32.8, 32.1, 25.9.
1
(1l): white solid; 3.4 g, 51% yield; mp 83.7−85.4 °C; H NMR (400
MHz, CDCl3) δ 8.56 (s, 1H), 8.06 (dd, J = 8.8, 1.6 Hz, 1H), 7.97 (d, J
= 7.2 Hz, 1H), 7.89 (t, J = 8.4 Hz, 2H), 7.58 (m, 2H), 3.80 (s, 3H),
3.49 (t, J = 6.4 Hz, 2H), 3.23 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 198.7, 173.1, 135.4, 133.9, 132.4, 129.7,
129.4, 128.2, 127.6, 126.6, 123.7, 61.1, 32.9, 32.1, 26.0; HRMS calcd
for C16H17NNaO3 (M + Na)+ 294.1106, found 294.1104.
N-Methoxy-N-methyl-4-oxo-4-(p-tolyl)butanamide (1b):19 white
solid; 3.7 g, 65% yield; mp 64.2−65.3 °C; 1H NMR (400 MHz,
CDCl3) δ 7.95−7.86 (m, 2H), 7.28−7.26 (m, 1H), 7.25−7.23 (m,
1H), 3.78 (s, 3H), 3.32 (t, J = 6.8 Hz, 2H), 3.21 (s, 3H), 2.89 (t, J =
6.8 Hz, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.6,
173.3, 143.8, 134.2, 129.2, 128.1, 61.2, 32.8, 32.2, 26.0, 21.6.
N-Methoxy-N-methyl-4-oxo-4-(4-methoxyphenyl)butanamide
(1c):19 white solid; 3.5 g, 57% yield; mp 56.9−58.0 °C; 1H NMR (400
MHz, CDCl3) δ 8.00−7.95 (m, 2H), 6.94−6.88 (m, 2H), 3.85 (s, 3H),
3.76 (s, 3H), 3.28 (t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.87 (t, J = 6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 197.2, 173.2, 163.2, 130.1,
129.6, 113.4, 61.0, 55.2, 32.4, 32.0, 25.9.
N-Methoxy-N-methyl-4-oxo-5-phenylpentanamide (1o): light
1
yellow oil; 1.4 g, 24% yield; H NMR (400 MHz, CDCl3) δ 7.35−
7.29 (m, 2H), 7.27−7.20 (m, 3H), 3.77 (s, 2H), 3.70 (s, 3H), 3.16 (s,
3H), 2.78 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 207.0, 172.7, 134.0, 129.2, 128.4, 126.6, 60.9, 49.8,
35.8, 31.9, 25.7; HRMS calcd for C13H17NNaO3 (M + Na)+ 258.1106,
found 258.1104.
Preparation of 4-(Furan-2-yl)-N-methoxy-N-methyl-4-oxo-
butanamide (1m).1g,20 Succinic anhydride (10.0 g, 100.0 mmol)
was dissolved in CH2Cl2 (120 mL), and furan (13.6 g, 200.0 mmol)
was added to the mixture. Then, AlCl3 (13.3 g, 100.0 mmol) was
added in portions to the mixture at 0 °C. The mixture was warmed to
room temperature and stirred for 4 h. The mixture was poured into
HCl (2 M, 100 mL) to acidify to pH = 2 at 0 °C, and the layers were
partitioned. The aqueous layer was extracted with CH2Cl2 thoroughly,
and the organic layers were washed with water and saturated brine,
dried with Na2SO4, and concentrated in vacuo. After purification by
flash chromatography, the 4-(furan-2-yl)-4-oxobutanoic acid was
obtained. To a solution of 4-(furan-2-yl)-4-oxobutanoic acid (5.0 g,
29.7 mmol) in dry CH2Cl2 (100 mL) was added carbonyl diimidazole
(5.8 g, 35.7 mmol), and the mixture was stirred for 1 h under room
temperature. Then, N,O-dimethylhydroxylamine hydrochloride (3.5 g,
36.7 mmol) and NEt3 (6.0 g, 59.5 mmol) were added to the mixture.
After the mixture was stirred for overnight at 25 °C, water (100 mL)
was added, and the aqueous phase was extracted with CH2Cl2 (50 mL
× 3). The combined organic phases was washed with saturated brine
(50 mL × 1) and dried over Na2SO4. The crude product was purified
by column chromatography (PE/EA = 2/1) to give 1m as light yellow
oil (20% yield): 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 1.6, 0.8
Hz, 1H), 7.22 (dd, J = 3.6, 0.8 Hz, 1H), 6.52 (dd, J = 3.6, 1.6 Hz, 1H),
3.75 (s, 3H), 3.23−3.14 (m, 5H), 2.87 (t, J = 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 187.8, 172.7, 152.2, 146.1, 116.8, 111.9, 61.0,
32.4, 31.9, 25.5.
N-Methoxy-N-methyl-4-oxo-4-(4-(trifluoromethyl)phenyl)-
butanamide (1d):19 white solid; 6.0 g, 85% yield; mp 98.9−100.1 °C;
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 7.72 (d, J =
8.0 Hz, 2H), 3.78 (s, 3H), 3.33 (t, J = 6.4 Hz, 2H), 3.20 (s, 3H), 2.93
(t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.0, 172.8,
139.3, 134.1 (q, J = 33.0 Hz), 128.3, 125.5 (d, J = 3.2 Hz), 123.5 (q, J
= 270.8 Hz), 61.1, 33.0, 32.0, 26.0.
N-Methoxy-N-methyl-4-oxo-4-(4-fluorophenyl)butanamide (1e):
white solid; 4.7 g, 80% yield; mp 44.8−46.3 °C; 1H NMR (400 MHz,
CDCl3) δ 8.07−7.98 (m, 2H), 7.15−7.06 (m, 2H), 3.76 (s, 3H), 3.29
(t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.88 (t, J = 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 197.0, 172.8, 165.4 (d, J = 252.7 Hz), 132.9,
130.4 (d, J = 9.2 Hz), 115.2 (d, J = 21.7 Hz), 60.9, 32.5, 31.9, 25.8;
HRMS calcd for C12H14FNNaO3 (M + Na)+ 262.0855, found
262.0853.
N-Methoxy-N-methyl-4-oxo-4-(4-chlorophenyl)butanamide
(1f):19 white solid; 3.0 g, 48% yield; mp 63.9−65.3 °C; 1H NMR (400
MHz, CDCl3) δ 7.98−7.91 (m, 2H), 7.47−7.39 (m, 2H), 3.77 (s, 3H),
3.29 (t, J = 6.4 Hz, 2H), 3.20 (s, 3H), 2.90 (t, J = 6.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 197.6, 172.9, 139.3, 135.0, 129.4, 128.7,
61.1, 32.7, 32.1, 25.9.
N-Methoxy-N-methyl-4-oxo-4-(4-bromophenyl)butanamide
1
(1g): white solid; 2.1 g, 29% yield; mp 69.6−71.3 °C; H NMR (400
MHz, CDCl3) δ 7.91−7.82 (m, 2H), 7.63−7.55 (m, 2H), 3.76 (s, 3H),
3.28 (t, J = 6.6 Hz, 2H), 3.19 (s, 3H), 2.89 (t, J = 6.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 197.8, 172.9, 135.3, 131.7, 129.5, 128.0,
61.1, 32.7, 32.1, 25.9; HRMS calcd for C12H14BrNNaO3 (M + Na)+
322.0055, found 322.0049.
Typical Procedure for the Preparation of 1n, 3a−f.21 4-
Oxopentanoic acid (5 g, 43.1 mmol) was added to N,O-
dimethylhydroxylamine hydrochloride (5.0 g, 51.7 mmol) in CH2Cl2
(120 mL). To this mixture was added 1-ethyl-3-(3-(dimethylamino)-
propyl)carbodiimide (9.9 g, 51.7 mmol) in one batch at 0 °C, and then
Et3N (8.7 g, 86.1 mmol) was added dropwise over 10 min. The ice
bath was removed and the temperature maintained at room
temperature overnight. The mixture was poured into water (100
mL), and the aqueous phase was extracted with CH2Cl2 (50 mL × 3).
The combined organic phase was washed with saturated brine and
dried over Na2SO4. The crude product was purified by column
chromatography (PE/EA = 2/1) to give 1n. Similarly, compounds
(3a−f) were prepared from 4-oxo-4-phenylbutanoic acid, and the
corresponding amines and the products were purified by column
chromatography (PE/EA = 2/1).
N-Methoxy-N-methyl-4-oxo-4-(m-tolyl)butanamide (1h):19 white
solid; 3.8 g, 66% yield; mp 50.2−51.3 °C; 1H NMR (400 MHz,
CDCl3): δ 7.85−7.75 (m, 2H), 7.41−7.30 (m, 2H), 3.77 (s, 3H), 3.32
(t, J = 6.4 Hz, 2H), 3.20 (s, 3H), 2.89 (t, J = 6.4 Hz, 2H), 2.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 199.0, 173.1, 138.1, 136.6, 133.6,
128.4, 128.2, 125.1, 61.1, 32.9, 32.1, 26.0, 21.2.
N-Methoxy-N-methyl-4-oxo-4-(o-tolyl)butanamide (1i):19 color-
1
less oil; 3.3 g, 57% yield; H NMR (400 MHz, CDCl3) δ 7.75 (d, J =
8.0 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.4 Hz, 2H), 3.75 (s,
3H), 3.21 (t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.87 (t, J = 6.4 Hz, 2H),
2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 172.9, 137.5,
131.4, 130.8, 128.3, 125.3, 60.8, 35.3, 31.9, 26.0, 20.9.
N-Methoxy-N-methyl-4-oxo-4-(2-methoxyphenyl)butanamide
(1j): yellow oil; 2.9 g, 47% yield; 1H NMR (400 MHz, CDCl3) δ 7.75
(dd, J = 8.0, 1.8 Hz, 1H), 7.45 (m, 1H), 7.03−6.92 (m, 2H), 3.91 (s,
3H), 3.76 (s, 3H), 3.35 (t, J = 6.8 Hz, 2H), 3.20 (s, 3H), 2.85 (t, J =
6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 200.3, 173.2, 158.4,
133.2, 129.9, 127.3, 120.1, 111.2, 60.7, 55.1, 37.8, 31.7, 25.9; HRMS
calcd for C13H17NNaO4 (M + Na)+ 274.1055, found 274.1050.
N-Methoxy-N-methyl-4-(2,4-dimethylphenyl)-4-oxobutanamide
(1k): yellow oil; 3.6 g, 60% yield; 1H NMR (400 MHz, CDCl3) δ 7.71
N-Methoxy-N-methyl-4-oxopentanamide (1n):22 colorless oil; 3.7
1
g, 55% yield; H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.17 (s,
3H), 2.82−2.65 (m, 4H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 207.2, 172.8, 60.8, 37.1, 31.8, 29.7, 25.5.
N,N-Dimethyl-4-oxo-4-phenylbutanamide (3a):23 colorless oil;
4.1 g, 72% yield; 1H NMR (400 MHz, CDCl3) δ 8.02−7.99 (m, 2H),
7.55−7.48 (M, 1H), 7.47−7.41 (m, 2H), 3.34 (t, J = 6.6 Hz, 2H), 3.08
(s, 3H), 2.95 (s, 3H), 2.77 (t, J = 6.6 Hz, 2H); 13C NMR (100 MHz,
6167
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CDCl3) δ 198.8, 171.2, 136.4, 132.6, 128.1, 127.63, 36.6, 35.0, 33.2,
26.8.
4-Hydroxy-N-methoxy-N-methyl-4-phenylbutanamide (2a): col-
orless oil; 102.8 mg, 92% yield; 1H NMR (400 MHz, CDCl3) δ 7.40−
7.31 (m, 4H), 7.27−7.23 (m, 1H), 4.81−4.78 (m, 1H), 3.64 (s, 3H),
3.51 (b, 1H), 3.19 (s, 3H), 2.58 (t, J = 6.0 Hz, 2H), 2.14−2.03 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 174.7, 144.5, 128.1, 127.0,
125.6, 73.3, 61.0, 33.3, 32.0, 28.1; HPLC (Chiralcel AD-H column,
hexane/i-PrOH = 85/15, 0.8 mL/min, 210 nm) t1 = 14.2 min, t2 =
N,N-Diethyl-4-oxo-4-phenylbutanamide (3b):24 light yellow oil;
5.2 g, 79% yield; 1H NMR (400 MHz, CDCl3) δ 8.02−7.99 (m, 2H),
7.80−7.74 (m, 1H), 7.48−7.39 (m, 2H), 3.45−3.30 (m, 6H), 2.76 (t, J
= 6.6 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H)l 13C
NMR (100 MHz, CDCl3) δ 199.1, 170.5, 136.7, 132.8, 128.3, 127.8,
41.7, 40.1, 33.6, 26.9, 14.00, 12.9.
15.3 min; [α]25 = +23.8 (c 1.52, CH2Cl2); HRMS calcd for
D
1-Phenyl-4-(piperidin-1-yl)butane-1,4-dione (3c):25 white solid;
C12H17NNaO3 (M + Na)+ 246.1106, found 246.1100. The absolute
configuration of 2a was assigned as R on the basis of the optical
rotation of γ-phenyl-γ-butyrolactone 2a′.29,30
1
3.8 g, 56% yield; mp 49.8−52.1 °C; H NMR (400 MHz, CDCl3) δ
8.05−7.98 (m, 2H), 7.57−7.73 (m, 1H), 7.49−7.42 (m, 2H), 3.55 (t, J
= 5.6 Hz, 2H), 3.49 (t, J = 5.2 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 2.78
(t, J = 6.8 Hz, 2H), 1.69−1.58 (m, 4H), 1.56−1.51 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 199.1, 169.6, 136.6, 132.7, 128.3, 127.8, 46.2,
42.6, 33.4, 26.9, 26.1, 25.3, 24.3.
γ-Phenyl-γ-butyrolactone (2a′):29 colorless oil; 358.8 mg, 92%
1
yield; H NMR (400 MHz, CDCl3) δ 7.43−7.31 (m, 5H), 5.54−5.50
(m, 1H), 2.73−2.60 (m, 3H), 2.28−2.12 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 176.8, 139.2, 128.5, 128.2, 125.1, 81.1, 30.7, 28.8;
HPLC (Chiralcel OB-H column, hexane/i-PrOH = 65/35, 0.7 mL/
1-Morpholino-4-phenylbutane-1,4-dione (3d):26 white solid; 3.5
g, 50% yield; mp 85.4−86.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.03−
8.00 (m, 2H), 7.56−7.44 (m, 1H), 7.50−7.41 (m, 2H), 3.72 (t, J = 4.8
Hz, 2H), 3.68 (t, J = 4.6 Hz, 2H), 3.62 (t, J = 4.6 Hz, 2H), 3.58 (t, J =
4.8 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 198.9, 170.2, 136.6, 133.0, 128.4, 128.0,
66.7, 66.4, 45.69, 42.0, 33.4, 26.8.
min, 210 nm) t1 = 15.7 min, t2 = 20.7 min; [α]26 = +37.1 (c 0.5,
D
CHCl3) [lit. [α]26D = +30.0 (c 0.5, CHCl3), 97% ee for R enantiomer].
4-Hydroxy-N-methoxy-N-methyl-4-(p-tolyl)butanamide (2b): col-
1
orless oil; 108.6 mg, 91% yield; H NMR (400 MHz, CDCl3) δ 7.24
(s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 4.75−4.73 (m, 1H), 3.64 (s, 3H),
3.19 (s, 3H), 2.58 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.12−2.05 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 174.7, 141.5, 136.6, 128.8,
125.5, 73.2, 61.0, 33.2, 32.0, 28.1, 20.9; HPLC (Chiralcel OJ-H
column, hexane/i-PrOH = 88/12, 0.7 mL/min, 210 nm) t1 = 29.1 min,
N-Phenyl-4-oxo-4-phenylbutanamide (3e):25 white solid; 4.5 g,
63% yield; mp 150.4−151.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.04−
7.94 (m, 2H), 7.83 (s, 1H), 7.60−7.45 (m, 5H), 7.30 (t, J = 7.8 Hz,
2H), 7.08 (t, J = 7.4 Hz, 1H), 3.46 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.2
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 199.3, 170.4, 138.0, 136.3,
133.4, 128.9, 128.6, 128.1, 124.1, 119.7, 34.1, 31.4.
t2 = 30.1 min. [α]25 = +21.3 (c 1.20, CH2Cl2); HRMS calcd for
D
C13H19NNaO3 (M + Na)+ 260.1263, found 260.1260.
4-Hydroxy-N-methoxy-N-methyl-4-(4-methoxyphenyl)-
N-Cyclohexyl-4-oxo-4-phenylbutanamide (3f):27 white solid; 4.0
1
butanamide (2c): colorless oil; 116.1 mg, 92% yield; H NMR (400
1
g, 51% yield; mp 102.1−103.0 °C; H NMR (400 MHz, CDCl3) δ
MHz, CDCl3) δ 7.32−7.27 (m, 2H), 6.89−6.86 (m, 2H), 4.78−4.70
(m, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 3.27 (s, 1H), 3.19 (s, 3H), 2.59−
2.56 (m, 2H), 2.09−2.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
174.7, 158.7, 136.7, 126.9, 113.6, 73.1, 61.1, 55.1, 33.3, 32.1, 28.3;
HPLC (Chiralcel OB-H column, hexane/i-PrOH = 70/30, 1.0 mL/
8.00−7.97 (m, 2H), 7.58−7.54 (m, 1H), 7.49−7.42 (m, 2H), 5.61 (s,
1H), 3.79−3.70 (m, 1H), 3.36 (t, J = 6.6 Hz, 2H), 2.59 (t, J = 6.6 Hz,
2H), 1.96−1.85 (m, 2H), 1.76−1.65 (m, 2H), 1.62−1.57 (m, 1H),
1.40−1.29 (m, 2H), 1.22−1.08 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.2, 171.0, 136.6, 133.2, 128.6, 128.0, 48.2, 34.2, 33.1,
30.5, 25.5, 24.8.
min, 210 nm) t1 = 11.1 min, t2 = 16.0 min; [α]25 = +19.2 (c 1.03,
D
CH2Cl2); HRMS calcd for C13H19NNaO4 (M + Na)+ 276.1212, found
276.1211.
Preparation of 4-Oxo-4-phenylbutanamide (3g).1c,28 Methyl
4-oxo-4-phenylbutanoate (2.0 g, 10.4 mmol) was dissolved in MeOH
(30 mL). Then, ammonium hydroxide (25−28%, 30 mL) was added
to the mixture. The mixture was stirred for 12 h at 40 °C and
concentrated in vacuo. The aqueous phase was extracted with CH2Cl2
(20 mL × 3).The combined organic phases were washed with water
and saturated brine (20 mL × 1) and dried over Na2SO4. The crude
product was purified by column chromatography (PE/EA = 1/3) to
give 1m as a light yellow solid: 0.97 g, 53% yield; mp 123.2−124.1 °C;
1H NMR (400 MHz, CDCl3) δ 8.00−7.97 (m, 2H), 7.60−7.53 (m,
1H), 7.50−7.42 (m, 2H), 5.86 (s, 1H), 5.62 (s, 1H), 3.37 (t, J = 6.4
Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
199.0, 175.0, 136.3, 133.3, 128.6, 128.0, 33.8, 29.3.
4-Hydroxy-N-methoxy-N-methyl-4-(4-(trifluoromethyl)phenyl)-
butanamide (2d): white solid; 132.9 mg, 91% yield; mp 81.7−83.6
1
°C; H NMR (400 MHz, CDCl3) δ 7.59−7.47 (m, 2H), 4.87−4.85
(m, 1H), 4.17 (s, 1H), 3.65 (s, 3H), 3.20 (s, 3H), 2.60 (s, 2H), 2.16−
1.98 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 174.6, 148.8, 129.2 (q,
J = 32.0 Hz) 125.9, 125.1 (d, J = 3.4 Hz), 122.8, 72.8, 61.1, 33.2, 32.1,
28.1; HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15, 0.5
mL/min, 210 nm) t1 = 17.9 min, t2 = 19.2 min; [α]25D = +11.4 (c 0.91,
CH2Cl2); HRMS calcd for C13H16F3NNaO3 (M + Na)+ 314.0980,
found 314.0984.
4-(4-Fluorophenyl)-4-hydroxy-N-methoxy-N-methylbutanamide
(2e): colorless oil; 111.3 mg, 92% yield; 1H NMR (400 MHz, CDCl3)
δ 7.37−7.30 (m, 2H), 7.05−6.98 (m, 2H), 4.80−4.77 (m, 1H), 3.69 (s,
1H), 3.65 (s, 3H), 3.20 (s, 3H), 2.61−2.58 (m, 2H), 2.11−2.00 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 174.6, 161.7 (d, J = 243.1 Hz)
140.3, 127.2 (d, J = 7.9 Hz), 114.8 (d, J = 21.1 Hz), 72.7, 61.0, 33.4,
32.0, 28.01; HPLC (Chiralcel AD-H column, hexane/i-PrOH = 88/12,
0.7 mL/min, 210 nm) t1 = 53.3 min, t2 = 56.0 min; [α]25D = +21.6 (c
1.09, CH2Cl2); HRMS calcd for C12H16FNNaO3 (M + Na)+ 264.1012,
found 264.1009.
Typical Procedure for the Asymmetric Hydrogenation. To a
25 mL Schlenk tube were added [RuCl2 (cymene)]2 (6.0 mg, 0.01
mmol) and (S)-Xyl-SunPhos (17.2 mg, 0.022 mmol). The tube was
vacuumed and purged with nitrogen for three times before addition of
freshly distilled and freeze-and-thaw degassed DMF (3 mL). The
resulting mixture was heated at 100 °C for 10 min before it was cooled
to room temperature, and then (S)-Daipen (6.8 mg, 0.022 mmol) was
added under N2. The tube was vacuumed and purged with nitrogen for
three times before it was heated at 40 °C for 5 h. The solvent was
removed under vacuum to give the catalyst as a yellow solid. The
catalyst was dissolved in degassed i-PrOH (4 mL),and then the
solution was equally charged into four vials which contained 0.5 mmol
of substrates, t-BuOK (2.8 mg, 0.025 mmol), and 1 mL of i-PrOH.
The vials were then transferred into 300 mL autoclaves. The
autoclaves were purged three times with H2, and the required pressure
of H2 was set. The autoclaves were stirred under specified reaction
conditions. After being cooled to ambient temperature and careful
release of the hydrogen, the autoclaves were opened and the solvent
was evaporated. The reaction solution was purified by a silica gel
column to give the corresponding hydrogenation products, which was
then directly analyzed by HPLC to determine the enantiomeric excess.
4-(4-Chlorophenyl)-4-hydroxy-N-methoxy-N-methylbutanamide
1
(2f): colorless oil; 117.4 mg, 91% yield; H NMR (400 MHz, CDCl3)
δ 7.28 (s, 4H), 4.76−4.73 (m, 1H), 3.99 (s, 1H), 3.64 (s, 3H), 3.17 (s,
3H), 2.57−2.56 (m, 2H), 2.10−1.95 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 174.5, 143.1, 132.5, 128.2, 127.0, 72.5, 61.0, 33.22, 32.0,
28.0; HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15, 0.5
mL/min, 210 nm) t1 = 24.0 min, t2 = 25.7 min; [α]25D = +17.4 (c 2.40,
CH2Cl2); HRMS calcd for C12H16ClNNaO3 (M + Na)+ 280.0716,
found 280.0718.
4-(4-Bromophenyl)-4-hydroxy-N-methoxy-N-methylbutanamide
(2g): colorless oil; 137.0 mg, 91% yield; 1H NMR (400 MHz, CDCl3)
δ 7.47−7.41 (m, 2H), 7.26−7.20 (m, 2H), 4.76−4.73 (m, 1H), 3.97 (s,
1H), 3.64 (s, 3H), 3.18 (s, 3H), 2.58−2.57 (m, 2H), 2.11−1.95 (m,
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2H); 13C NMR (100 MHz, CDCl3) δ 174.5, 143.6, 131.1, 127.4,
120.6, 72.5, 61.0, 33.2, 32.0, 27.9; HPLC (Chiralcel AD-H column,
hexane/i-PrOH = 85/15, 0.5 mL/min, 210 nm) t1 = 26.2 min, t2 =
0 °C. The mixture was stirred at room temperature for 4 h and then
concentrated and flash column chromatographed to give the desired
product: yellow oil; 191.3 mg, 71% yield; 1H NMR (400 MHz,
CDCl3) δ 8.31−8.27 (m, 2H), 8.23−8.18 (m, 2H), 5.31−5.15 (m,
1H), 3.62 (s, 3H), 3.14 (s, 3H), 2.54 (t, J = 7.6 Hz, 2H), 2.16−2.01
(m, 2H), 1.41 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.3, 164.1, 150.3, 135.9, 130.6, 127.2, 123.8, 123.4, 72.5, 61.1, 32.0,
30.5, 27.8, 20.0; HPLC (Chiralcel OB-H column, hexane/i-PrOH =
80/20, 1.0 mL/min, 210 nm) t1 = 19.0 min, t2 = 27.1 min.
28.7 min; [α]25 = +16.2 (c 2.50, CH2Cl2); HRMS calcd for
D
C12H16BrNNaO3 (M + Na)+ 324.0211, found 324.0201.
4-Hydroxy-N-methoxy-N-methyl-4-(m-tolyl)butanamide (2h):
1
colorless oil; 108.3 mg, 91% yield; H NMR (400 MHz, CDCl3) δ
7.23−7.05 (m, 4H), 4.74−4.71 (m, 1H), 3.63 (s, 3H), 3.18 (s, 3H),
2.57 (s, 2H), 2.34 (s, 3H), 2.12−1.99 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 174.7, 144.4, 137.7, 128.0, 127.8, 126.3, 122.7, 73.32, 61.00,
33.3, 32.0, 28.2, 21.3; HPLC (Chiralcel AD-H column, hexane/i-
PrOH = 85/15, 0.5 mL/min, 210 nm) t1 = 19.7 min, t2 = 23.5 min;
4-Hydroxy-N-methoxy-N-methyl-5-phenylpentanamide (2o): col-
1
orless oil; 85.6 mg, 72% yield; H NMR (400 MHz, CDCl3) δ 7.33−
7.28 (m, 2H), 7.25−7.19 (m, 3H), 3.86 (s, 1H), 3.68 (s, 3H), 3.19 (s,
3H), 2.79−2.77 (m, 2H), 2.72−2.53 (m, 3H), 1.99−1.86 (m, 1H),
1.80−1.70 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 138.5, 129.4,
128.5, 126.4, 72.4, 61.2, 44.2, 40.1, 32.2, 30.9, 28.5; HPLC (Chiralcel
AD-H column, hexane/i-PrOH = 90/10, 0.5 mL/min, 210 nm) t1 =
26.6 min, t2 = 31.0 min. [α]25D = +0.7 (c 0.28, CH2Cl2); HRMS calcd
for C13H19NNaO3 (M + Na)+ 260.1263, found 260.1256.
[α]25 = +22.6 (c 1.60, CH2Cl2); HRMS calcd for C13H19NNaO3 (M
D
+ Na)+ 260.1263, found 260.1261.
4-Hydroxy-N-methoxy-N-methyl-4-(o-tolyl)butanamide (2i): col-
orless oil; 106.5 mg, 90% yield; 1H NMR (400 MHz, CDCl3) δ 7.53−
7.51 (m, 1H), 7.25−7.10 (m, 3H), 5.03−5.00 (m, 1H), 3.67 (s, 3H),
3.33 (s, 1H), 3.20 (s, 3H), 2.71−2.56 (m, 2H), 2.34 (s, 3H), 2.11−
1.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 174.8, 142.7, 134.1,
130.2, 126.8, 126.0, 125.1, 69.9, 61.1, 32.1, 31.9, 28.4, 18.9; HPLC
(Chiralcel AD-H column, hexane/i-PrOH = 90/10, 0.5 mL/min, 210
4-Hydroxy-N,N-dimethyl-4-phenylbutanamide (4a):27 colorless
1
oil; 101.0 mg, 97% yield; H NMR (400 MHz, CDCl3) δ 7.39−7.30
(m, 4H), 7.26−7.22 (m, 1H), 4.81−4.77 (m, 1H), 4.29 (d, J = 3.6 Hz,
1H), 2.97 (s, 3H), 2.96 (s, 3H), 2.46 (t, J = 6.4 Hz, 2H), 2.16−2.02
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.5, 144.7, 128.0, 126.8,
125.5, 73.1, 37.1, 35.3, 33.7, 29.5; HPLC (Chiralcel AD-H column,
hexane/i-PrOH = 85/15, 0.5 mL/min, 210 nm) t1 = 19.0 min, t2 =
nm) t1 = 30.6 min, t2 = 34.3 min; [α]25 = +41.7 (c 1.50, CH2Cl2);
D
HRMS calcd for C13H19NNaO3 (M + Na)+ 260.1263, found 260.1263.
4-Hydroxy-N-methoxy-N-methyl-4-(2-methoxyphenyl)-
1
butanamide (2j): colorless oil; 51.1 mg, 40% yield; H NMR (400
21.8 min; [α]25 = +27.6 (c 1.70, CH2Cl2).
MHz, CDCl3) δ 7.40−7.38 m, 1H), 7.25−7.19 (m, 1H), 6.97−6.85
(m, 2H), 4.96 (t, J = 6.0 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H), 3.19 (s,
3H), 2.72−2.53 (m, 2H), 2.12 (q, J = 6.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 175.0, 156.1, 132.2, 128.0, 126.7, 120.5, 110.2, 69.7,
61.0, 55.1, 32.1, 31.3, 28.5; HPLC (Chiralcel AD-H column, hexane/i-
PrOH = 85/15, 0.8 mL/min, 210 nm) t1 = 17.7 min, t2 = 20.2 min;
D
N,N-Diethyl-4-hydroxy-4-phenylbutanamide (4b): yellow oil;
114.3 mg, 97% yield; 1H NMR (400 MHz, CDCl3) δ 7.41−7.30
(m, 4H), 7.26−7.21 (m, 1H), 4.82−4.80 (m, 1H), 4.50 (s, 1H), 3.44−
3.34 (m, 2H), 3.27 (q, J = 7.2 Hz, 2H), 2.47 (t, J = 6.2 Hz, 2H), 2.19−
2.03 (m, 2H), 1.13 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 172.5, 144.7, 127.8, 126.6, 125.4, 72.9, 41.8, 40.1, 33.8, 29.3, 29.1,
13.7, 12.7; HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15,
0.8 mL/min, 210 nm) t1 = 10.9 min, t2 = 11.8 min; [α]25D = +30.0 (c
1.02, CH2Cl2); HRMS calcd for C14H21NNaO2 (M + Na)+ 258.1470,
found 258.1465.
[α]25 = +34.9 (c 1.34, CH2Cl2); HRMS calcd for C13H19NNaO4 (M
D
+ Na)+ 276.1212, found 276.1213.
4-Hydroxy-N-methoxy-N-methyl-4-(2,4-dimethylphenyl)-
1
butanamide (2k): colorless oil; 113.3 mg, 90% yield; H NMR (400
MHz, CDCl3) δ 7.37 (d, J = 7.6 Hz, 1H), 7.05−6.91 (m, 2H), 4.96−
4.93 (m, 1H), 3.65 (s, 3H), 3.31 (s, 1H), 3.18 (s, 3H), 2.70−2.55 (m,
2H), 2.29 (s, 6H), 2.07−1.92 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 174.7, 139.6, 136.2, 133.9, 130.8, 126.5, 125.0, 69.6, 61.0, 31.9, 28.3,
20.8, 18.7; HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15,
0.5 mL/min, 210 nm) t1 = 21.2 min, t2 = 23.2 min; [α]25D = +39.7 (c
1.60, CH2Cl2); HRMS calcd for C14H21NO3 (M + Na)+ 274.1419,
found 274.1409.
4-Hydroxy-4-phenyl-1-(piperidin-1-yl)butan-1-one (4c):27 color-
1
less oil; 121.3 mg, 98% yield; H NMR (400 MHz, CDCl3) δ 7.40−
7.31 (m, 4H), 7.27 (s, 1H), 7.27−7.22(m, 1H), 4.81−4.78 (m, 1H),
4.23 (s, 1H), 3.57 (t, J = 5.4 Hz, 2H), 3.36 (t, J = 5.4 Hz, 2H), 2.47 (t,
J = 6.4 Hz, 2H), 2.17−2.03 (m, 2H), 1.71−1.60 (m, 3H), 1.57−1.50
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.7, 144.8, 128.1, 126.9,
125.6, 73.4, 46.6, 42.8, 33.9, 29.6, 26.2, 25.4, 24.3; HPLC (Chiralcel
AD-H column, hexane/i-PrOH = 90/10, 0.5 mL/min, 210 nm) t1 =
4-Hydroxy-N-methoxy-N-methyl-4-(naphthalen-2-yl)-
34.4 min, t2 = 39.4 min; [α]25 = +20.3 (c 1.17, CH2Cl2).
1
butanamide (2l): colorless oil; 125.6 mg, 92% yield; H NMR (400
D
4-Hydroxy-1-morpholino-4-phenylbutan-1-one (4d):27 white
MHz, CDCl3) δ 7.86−7.79 (m, 4H), 7.53−7.41 (m, 3H), 4.99−4.98
(m, 1H), 3.73 (s, 1H), 3.62 (s, 3H), 3.20 (s, 3H), 2.62 (t, J = 5.2 Hz,
2H), 2.26−2.11 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 174.6,
141.9, 133.1, 132.6, 127.8, 127.7, 127.4, 125.8, 125.4, 124.2, 125.0,
73.2, 60.9, 33.1, 32.0, 28.0; HPLC (Chiralcel AD-H column, hexane/i-
PrOH = 85/15, 0.8 mL/min, 210 nm) t1 = 22.4 min, t2 = 23.9 min;
1
solid; 127.0 mg, 97% yield; mp 91.0−92.2 °C; H NMR (400 MHz,
CDCl3) δ 7.41−7.29 (m, 4H), 7.27−7.23 (m, 1H), 4.77 (dd, J = 7.6,
4.4 Hz, 1H), 3.66−3.59 (m, 6H), 3.41 (t, J = 4.8 Hz, 2H), 2.44 (t, J =
6.6 Hz, 2H), 2.16−2.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
171.9, 144.5, 128.1, 127.0, 125.5, 73.0, 66.5, 66.3, 45.7, 41.8, 33.8, 29.1;
HPLC (Chiralcel AD-H column, hexane/i-PrOH = 85/15, 0.8 mL/
[α]25 = +12.5 (c 1.80, CH2Cl2); HRMS calcd for C16H19NNaO3 (M
D
min, 210 nm) t1 = 18.2 min, t2 = 20.9 min; [α]25 = +21.8 (c 1.01,
+ Na)+ 296.1263, found 296.1262.
D
CH2Cl2).
4-Hydroxy-N-methoxy-N-methyl-4-(furan-2-yl)butanamide
(2m):1g colorless oil; 103.8 mg, 91% yield; 1H NMR (400 MHz,
CDCl3) δ 7.35−7.34 (m, 1H), 6.36−6.19 (m, 2H), 4.78−4.75 (m,
1H), 3.65 (s, 3H), 3.17 (s, 3H), 2.59 (t, J = 6.4 Hz, 2H), 2.21−2.12
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 174.3, 156.5, 141.4, 109.8,
109.6, 105.5, 66.8, 61.0, 31.9, 29.9, 27.7; HPLC (Chiralcel OB-H
column, hexane/i-PrOH = 80/20, 1.0 mL/min, 210 nm) t1 = 7.9 min,
N-Phenyl-4-hydroxy-4-phenylbutan-1-one (4e):26 white solid;
123.7 mg, 97% yield; mp 98.4−99.5 °C; 1H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 7.7 Hz, 3H), 7.40−7.28 (m, 6H), 7.11 (t, J = 7.4
Hz, 1H), 4.96−4.75 (m, 1H), 3.04 (br, 1H), 2.58−2.45 (m, 2H),
2.24−2.08 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.9, 144.1,
137.8, 128.9, 128.5, 127.5, 125.7, 124.3, 120.0, 73.5, 34.2, 33.9; HPLC
(Chiralcel AD-H column, hexane/i-PrOH = 90/10, 0.5 mL/min, 210
t2 = 11.6 min; [α]25 = +7.8 (c 2.30, CH2Cl2).
D
4-Hydroxy-N-methoxy-N-methylpentanamide (2n):31 colorless
nm) t1 = 33.9 min, t2 = 36.3 min; [α]25 = +18.7 (c 1.66, CH2Cl2).
D
N-Cyclohexyl-4-hydroxy-4-phenylbutanamide (4f):32 white solid;
127.7 mg, 98% yield; mp 83.5−85.2 °C; 1H NMR (400 MHz, CDCl3)
δ 7.39−7.30 (m, 4H), 7.27−7.23 (m, 1H), 5.56 (br, 1H), 4.78−4.65
(m, 1H), 4.12 (br, 1H), 3.80−3.70 (m, 1H), 2.30 (t, J = 6.6 Hz, 2H),
2.11−1.98 (m, 1H), 1.92−1.88 (m, 2H), 1.72−1.59 (m, 3H), 1.40−
1.30 (m, 2H), 1.19−1.04 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
172.7, 144.5, 128.2, 127.1, 125.6, 73.3, 48.3, 34.5, 33.0, 32.9, 25.3, 24.8;
HPLC (Chiralcel AD-H column, hexane/i-PrOH = 88/12, 0.7 mL/
1
oil; 71.9 mg, 89% yield; H NMR (400 MHz, CDCl3) δ 3.87−3.78
(m, 1H), 3.68 (s, 3H), 3.17 (s, 3H), 2.67−2.48 (m, 2H), 1.86−1.67
(m, 2H), 1.19 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
174.8, 67.3, 61.1, 33.3, 32.1, 28.3, 23.4. [α]25D = +0.2 (c 1.10, CH2Cl2).
5-(Methoxy(methyl)amino)-5-oxopentan-2-yl-4-nitrobenzoate
(2n′). To the hydroxyl product (0.14 g, 0.9 mmol) in CH2Cl2 (5 mL)
were added 4-nitrobenzoyl chloride (0.48 g, 2.7 mmol), pyridine (0.21
g, 2.7 mmol), and a catalytic amount of DMAP (0.01 g, 0.09 mmol) at
6169
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The Journal of Organic Chemistry
Article
min, 210 nm) t1 = 11.9 min, t2 = 13.1 min; [α]25 = +33.0 (c 0.90,
D. J.; de Vries, A. H. M.; de Vries, J. G. Chem. Soc. Rev. 2012, 41,
3340−3380.
D
CH2Cl2).
4-Hydroxy-4-phenylbutanamide (4g):1c white solid; 7.2 mg, 8%
(8) (a) Ohkuma, T.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 40.
1
yield; mp 82.7−83.5 °C; H NMR (400 MHz, CDCl3) δ 7.38−7.32
(b) Sandoval, C. A.; Muniz, K.; Ohkuma, T.; Noyori, R. Philos. Trans.
̃
(m, 4H), 7.29−7.26 (m, 1H), 5.58 (s, 1H), 5.42 (s, 1H), 4.83−4.79
(m, 1H), 3.22 (d, J = 3.6 Hz, 1H), 2.45−2.32 (m, 2H), 2.16−2.01 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 176.1, 144.3, 128.4, 127.4,
125.7, 73.5, 34.1, 32.0; HPLC (Chiralcel OB-H column, hexane/i-
PrOH = 80/20, 0.8 mL/min, 210 nm) t1 = 8.9 min, t2 = 12.0 min.
R. Soc. London, Ser. A 2005, 363, 901. (c) Kawano, H.; Ikariya, T.; Ishii,
Y.; Saburi, M.; Yoshikawa, S.; Uchida, Y.; Kumobayashi, H. J. Chem.
Soc., Perkin Trans. 1 1989, 1571. (d) Kitamura, M.; Tokunaga, M.;
Ohkuma, T.; Noyori, R. Tetrahedron Lett. 1991, 32, 4163. (e) Heiser,
B.; Broger, E. A.; Crameri, Y. Tetrahedron: Asymmetry 1991, 2, 51.
(f) Shao, L.-M.; Takeuchi, K.; Ikemoto, M.; Kawai, T.; Ogasawara, M.;
Takeuchi, H.; Kawano, H.; Saburi, M. J. Organomet. Chem. 1992, 435,
133. (g) Hoke, J. B.; Hollis, S.; Stern, E. W. J. Organomet. Chem. 1993,
ASSOCIATED CONTENT
* Supporting Information
■
S
455, 193. (h) Ratovelomanana-Vidal, V.; Cano De Andrade, M. C.;
̃
Details of the NMR and HPLC data. This material is available
free of charge via the Internet at http://pubs.acs.org.
̂
Pfister, X.; Guerreiro, P.; Lenoir, J. Y.; Genet, J.-P. Tetrahedron Lett.
1995, 36, 4801. (i) Ohta, T.; Tonomura, Y.; Nozaki, K.; Takaya, H.;
Mashima, K. Organometallics 1996, 15, 1521.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: virginie.vidal@chimie-paristech.fr.
*E-mail: zhaoguo@sjtu.edu.cn.
(9) (a) Mashima, K.; Kusano, K.-h.; Sato, N.; Matsumura, Y.-i.;
Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.;
Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064. (b) Laneman,
S. A.; Ager, D. J. Tetrahedron: Asymmetry 1997, 8, 3327. (c) Naota, T.;
Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2599. (d) Tang, W.-
J.; Zhang, X.-M. Chem. Rev. 2003, 103, 3029.
■
Notes
(10) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett.
1990, 31, 5509. (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521. (c) Yokozawa, T.;
Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H.; Saito, T.
Adv. Synth. Catal. 2001, 343, 264. (d) Benincori, T.; Rizzo, S.; Pilati,
T.; Ponti, A.; Pagliarini, E.; Ratti, S.; Giuseppe, C.; de Ferra, L.; Sada,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
for the financial support.
̀
M.; Sannicolo, F. Tetrahedron: Asymmetry 2004, 15, 2289. (e) Star-
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