Ru-catalyzed highly enantioselective hydrogenation of α-keto Weinreb amides

Article abstract of DOI:10.1007/s11426-012-4790-8

Asymmetric hydrogenation of α-keto Weinreb amides has been realized with [Ru((S)-Sunphos)(benzene)Cl]Cl as the catalyst and CeCl₃· 7H₂O as the additive. A series of enantiopure α-hydroxy Weinreb amides (up to 97% ee) have been obtained. Catalytic amount of CeCl ₃·7H₂O is essential for the high reactivity and enantioselectivity and the ratio of CeCl₃·7H₂O to [Ru((S)-Sunphos)(benzene)Cl]Cl plays an important role in the hydrogenation reaction.

Full text of DOI:10.1007/s11426-012-4790-8

SCIENCE CHINA
Chemistry
March 2013 Vol.56 No.3: 342–348
doi: 10.1007/s11426-012-4790-8
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
Ru-catalyzed highly enantioselective hydrogenation of α-keto
Weinreb amides
ZHAO MengMeng1, LI WanFang1, MA Xin1, FAN WeiZheng1, TAO XiaoMing1,
LI XiaoMing1, XIE XiaoMin1 & ZHANG ZhaoGuo1, 2*
1School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
2Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received September 2, 2012; accepted October 3, 2012; published online December 2, 2012
Asymmetric hydrogenation of α-keto Weinreb amides has been realized with [Ru((S)-Sunphos)(benzene)Cl]Cl as the catalyst
and CeCl3·7H2O as the additive. A series of enantiopure α-hydroxy Weinreb amides (up to 97% ee) have been obtained. Cata-
lytic amount of CeCl3·7H2O is essential for the high reactivity and enantioselectivity and the ratio of CeCl3·7H2O to
[Ru((S)-Sunphos)(benzene)Cl]Cl plays an important role in the hydrogenation reaction.
asymmetric hydrogenation, α-keto Weinreb amides, CeCl3·7H2O
1 Introduction
Weinreb amides [1] are important acylation reagents. They
can be easily converted to ketones through nucleophilic
addition with many organometallic reagents without the
hazard of over addition to form tertiary alcohols. Their ap-
plications in organic synthesis have been widely demon-
strated [2–7]. Enantiomerically pure α-hydroxy Weinreb
amides are key intermediates for many pharmaceuticals,
agrochemicals, and biologically relevant compounds be-
cause they provide useful precursors for α-hydroxy ketones
or aldehydes which usually obtained from benzoin conden-
sation [8, 9] or asymmetric hydrogenation of 1,2-diones
[10]. For example, natural products like Calyculin A [11],
Kurasoin A and B (Figure 1) [12] can be prepared from
several chiral α-hydroxy Weinreb amides which routinely
obtained from α-hydroxy acids, esters or acyl chlorides with
commercially available N,O-dimethylhydroxylamine hy-
drochloride [11, 12]. However, these synthetic routes suffer
from poor efficiency and enantioselectivity, and need over
Figure 1 Structures of Kurasoin A and Kurasoin B.
stoichiometric amount of activating agents. For example, to
obtain the α-hydroxy Weinreb amides, AlMe3 or 1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide hydrochloride is
usually employed to activate the acids. Accordingly, the
search for highly efficient and atom economic processes to
obtain such chiral moieties is of great significance. Obvi-
ously, the enantioselective hydrogenation of α-keto Weinreb
amides is the most straightforward method to provide these
important chiral blocks. However, only a few examples
*Corresponding author (email: zhaoguo@sjtu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
343
were reported on the enantioselective hydrogenation of
α-keto amides and the efficiency and substrate scope were
rather limited [13–15]. During our previous research, we
found that α-keto esters could be smoothly hydrogenated
catalyzed by [Ru((S)-Sunphos)(benzene)Cl]Cl in the pres-
ence of CeCl3·7H2O [16–18], here we report our recent
work on the asymmetric hydrogenation of a series of α-keto
Weinreb amides.
1H), 7.29 (dd, J = 16.8, 9.1 Hz, 2H), 3.64 (s, 3H), 3.33 (s,
3H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.9,
168.3, 141.0, 133.7, 132.5, 132.4, 131.7, 126.2, 62.1, 31.7,
21.6. HRMS calcd. for C11H14NO3 (M+H)+: 208.0974,
found: 208.0969.
N-methoxy-N-methyl-2-(2-methoxyphenyl)-2-oxoacetamide
(1c) [27]
Colorless oil; 5.4 g, 85% yield; 1H NMR (400 MHz, CDCl3)
δ 7.96 (dd, J = 7.8, 1.8 Hz, 1H), 7.56 (m, 1H), 7.08 (m, 1H),
6.98 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 3.29 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 189.4, 170.1, 160.6,
136.6, 136.2, 130.8, 130.3, 122.6, 121.2, 112.6, 61.6, 56.7,
32.3.
2 Experimental
2.1 General experimental section
Commercially available reagents were used without further
purification other than those detailed below. The solvents
used in catalyst preparation and hydrogenation reactions
were pretreated by the following procedures: Ethanol was
distilled over magnesium under nitrogen; THF was distilled
over sodium under nitrogen; CH2Cl2 was distilled over cal-
cium hydride. All reactions were carried out under an atmos-
phere of nitrogen using standard Schlenk techniques unless
otherwise noted. 1H and 13C NMR spectra were obtained on a
N-methoxy-N-methyl-2-oxo-2-(p-tolyl)acetamide (1d) [26]
1
White solid; M.p.: 111.1–112.3 °C; 4.9 g, 83% yield; H
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 2H), 7.30 (s,
2H), 3.64 (s, 3H), 3.35 (s, 3H), 2.43 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 190.8, 167.6, 146.0, 130.5, 129.7, 62.2,
31.5, 22.0.
1
N-Methoxy-N-methyl-2-(4-methoxyphenyl)-2-oxoacetamide
(1e) [26]
400 MHz NMR spectrometer. The chemical shifts for H
NMR were recorded in ppm downfield from tetrame-
thylsilane (TMS) with the solvent resonance as the internal
standard. The chemical shifts for 13C NMR were recorded in
ppm downfield using the central peak of CDCl3 as the inter-
nal standard. Coupling constants (J) are reported in Hz and
refer to apparent peak multiplications. Specific rotations were
operated at 25 °C (A = 589 nm). Flash column chromatog-
raphy was performed on silica gel (300–400 mesh).
White solid; M.p.: 41.5–43.4 °C; 5.7 g, 90% yield; 1H NMR
(400 MHz, CDCl3) δ 7.88 (d, J = 8.9 Hz, 2H), 6.97 (d, J =
8.9 Hz, 2H), 3.88 (s, 3H), 3.65 (s, 3H), 3.34 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 189.7, 167.8, 164.9, 132.5,
131.9, 126.0, 114.5, 62.2, 55.8, 31.5.
N-methoxy-N-methyl-2-oxo-2-(4-(trifluoromethyl)phenyl)ac
etamide (1f)
White solid; M.p.: 80.7–81.8 °C; 6.6 g, 89% yield; 1H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 2H), 7.77 (d, J =
8.2 Hz, 2H), 3.66 (s, 3H), 3.37 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 189.9, 166.6, 165.9, 159.8, 136.2, 135.9, 135.6,
135.3, 130.5, 129.8, 127.9, 127.6, 126.1, 124.9, 122.2,
119.5, 116.2, 95.8, 95.2, 62.3, 39.8, 36.1, 31.6. HRMS calcd.
for C11H11F3NO3 (M+H)+: 262.0691, found: 262.0677.
2.2 General procedure for the synthesis of 1
To N,N′-dimethoxy-N,N′-dimethyloxalamide (5.0 g, 28.4
mmol) in THF (40 mL) under N2 atmosphere was added
dropwise the corresponding Grignard reagent (42.5 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 MgSO4. Evaporation was carried out
under reduced pressure after filtration. The crude product
was purified by column chromatography.
N-methoxy-N-methyl-2-oxo-2-(4-(trifluoromethoxy)phenyl)-
acetamide (1g)
Yellow oil; 6.7 g, 85% yield; 1H NMR (400 MHz, CDCl3) δ
8.00–7.94 (m, 2H), 7.33 (dd, J = 8.8, 0.8 Hz, 2H), 3.67 (s,
3H), 3.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.4,
166.8, 153.6, 132.2, 131.5, 131.1, 124.2, 121.6, 120.7,
119.0, 62.1. HRMS calcd for C11H11F3NO4 (M+H)+:
278.0640, found: 278.0629.
N-methoxy-N-methyl-2-oxo-2-phenylacetamide (1a) [26]
1
White solid; M.p.: 56.1–57.2 °C; 19.7 g, 90% yield; H
NMR (400 MHz, CDCl3) δ 7.92 (d, J = 1.0 Hz, 1H), 7.90 (t,
J = 1.6 Hz, 1H), 7.67–7.61 (m, 1H), 7.54–7.48 (m, 2H),
3.64 (s, 3H), 3.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
191.1, 167.4, 134.8, 132.9, 129.5, 129.1, 62.2, 31.5.
N-methoxy-N-methyl-2-(naphthalen-2-yl)-2-oxoacetamide (1h)
1
White solid; M.p.: 101.2–102.3 °C; 6.1 g, 89% yield; H
NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.02–7.86 (m, 4H),
7.64 (m, 1H), 7.60–7.54 (m, 1H), 3.67 (s, 3H), 3.41 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 190.8, 167.2, 136.1, 132.4,
132.2, 130.0, 129.6, 129.1, 128.8, 127.8, 126.9, 123.3, 77.3,
N-methoxy-N-methyl-2-oxo-2-(o-tolyl)acetamide (1b)
White solid; M.p.: 80.5–81.8 °C; 5.1 g, 87% yield; 1H NMR
(400 MHz, CDCl3) δ 7.68 (d, J = 7.9 Hz, 1H), 7.56–7.41 (m,

344
Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
77.0, 76.6, 61.97, 31.3. HRMS calcd. for C14H14NO3
(M+H)+: 244.0974, found: 244.0957.
2.3 Typical procedure for the asymmetric hydrogena-
tion
To a 25 mL Schlenk tube were added [Ru(benzene)Cl2]2
(15.0 mg, 0.03 mmol) and (S)-SunPhos (45 mg, 0.066
mmol). The tube was vacuumed and purged with nitrogen
for three times before addition of freshly distilled and
freeze-and-thaw degassed Ethanol/CH2Cl2 (3 mL/3 mL).
The resulting mixture was heated at 50 °C for 1 h and then
cooled to room temperature. The solvent was then removed
under vacuum to give the catalyst as a yellow solid. The
catalyst was dissolved in degassed ethanol (24 mL) and then
the solution was equally divided into 12 vials which con-
tained 1 mmol of substrates and CeCl3·7H2O (12 eq.). Then
the vials were transferred into two 300 mL Parr 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 ee values were determined by HPLC after passing the
samples through a short pad of silica gel eluted with petro-
leum ether and ethyl acetate.
N-methoxy-N-methyl-2-oxo-2-(thiophen-2-yl)acetamide (1i)
[26]
1
Brown solid; M.p.: 59.2–61.0 °C; 3.1 g, 91% yield; H
NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 4.8, 1.2 Hz, 1H),
7.74 (dd, J = 3.8, 1.2 Hz, 1H), 7.18 (dd, J = 4.8, 4.0 Hz, 1H),
3.71 (s, 3H), 3.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
183.0, 166.3, 139.9, 136.4, 136.2, 128.8, 62.4, 31.7.
N-methoxy-N-methyl-2-oxopropanamide (1j) [28]
To pyruvate (5.0 g, 56.8 mmol) in CH3CN (150 mL) was
added N,O-dimethylhydroxylamine hydrochloride (8.3 g,
85.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide hydrochloride (14.1 g, 73.8 mmol). The mixture
was cooled to 0 °C using an ice bath, and Et3N (8.6 g, 85.1
mol) was added dropwise. After completing the addition of
Et3N, the reaction mixture was stirred at room temperature.
Upon complete consumption of starting material monitored
by TLC, the solvent was removed in vacuum. The aqueous
solution was extracted with CH2C12. The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, and concentrated in vacuum afforded 1g (10.2 g,
83% yield): light yellow oil; 1H NMR (400 MHz, CDCl3) δ
3.68 (s, 3H), 3.21 (s, 3H), 2.37 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 198.1, 167.8, 62.3, 31.4, 27.1.
2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (2a) [29]
1
Colorless oil; 146.8 mg, 75% yield; H NMR (400 MHz,
CDCl3) δ 7.39–7.28 (m, 5H), 5.35 (d, J = 6.1 Hz, 1H), 4.28
(d, J = 6.4 Hz, 1H), 3.21 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 70.7, 64.1, 25.2. [α]2D5 = +115.8 (c = 0.56, CHCl3)
for the (S)-isomer. Reference: [α]2D5 = –86.7 (c = 5.6, CHCl3)
for the (R)-isomer [30].
N-methoxy-N-methyl-2-oxo-4-phenylbutanamide (1k)
To 2-oxo-4-phenylbutanoic acid (6.0 g, 33.6 mmol) in
CH3CN (150 mL) was added N,O-dimethylhydroxylamine
hydrochloride (4.9 g, 50.5 mmol) and 1-ethyl-3-(3-dim-
ethylaminopropyl) carbodiimide hydrochloride (8.4 g, 43.8
mmol). The mixture was cooled to 0 °C using an ice bath,
and Et3N (5.1 g, 50.5 mol) was added dropwise. After com-
pleting addition of Et3N, the reaction mixture was stirred at
room temperature. Upon complete consumption of starting
material by TLC, the solvent was removed in vacuum. The
aqueous solution was extracted with CH2C12. The combined
organic layers were washed with brine, dried over anhy-
drous MgSO4, and concentrated in vacuum afforded 1k (6.3
2-Hydroxy-N-methoxy-N-methyl-2-(o-tolyl)acetamide (2b)
Light yellow solid; 130.7 mg, 62% yield; M.p.: 55.4–
1
57.2 °C; H NMR (400 MHz, CDCl3) δ 7.22–7.14 (m, 4H),
5.54 (d, J = 4.8 Hz, 1H), 4.16 (d, J = 5.6 Hz, 1H), 3.22 (s,
3H), 3.03 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 174.6, 138.0, 136.6, 130.9, 128.5, 127.7, 126.6, 69.2, 60.4,
33.0, 19.2. HRMS calcd. for C11H15NO3Na (M+Na)+:
232.0950, found: 232.0947. [α]2D5 = +123.3 (c = 1.05,
CH2Cl2).
2-Hydroxy-N-methoxy-2-(2-methoxyphenyl)-N-methylaceta-
1
g, 85% yield): colorless oil; H NMR (400 MHz, CDCl3) δ
mide (2c)
1
7.31–7.26 (m, 2H), 7.23–7.17 (m, 3H), 3.60 (s, 3H), 3.19 (s,
3H), 3.06–3.01 (m, 2H), 3.00–2.95 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 199.8, 168.0, 140.4, 128.6, 126.4, 62.3,
41.1, 31.6, 28.0. HRMS calcd. for C12H16NO3 (M+H)+:
222.1130, found: 222.1117.
White solid; 160.8 mg, 71% yield; M.p.: 65.8–67.6 °C; H
NMR (400 MHz, CDCl3) δ 7.30–7.24 (m, 1H), 7.19 (dd, J =
7.5, 1.7 Hz, 1H), 6.92 (dd, J = 15.3, 7.9 Hz, 2H), 5.68 (d, J
= 6.0 Hz, 1H), 4.16 (d, J = 5.6 Hz, 1H), 3.85 (s, 3H), 3.18 (s,
6H); 13C NMR (101 MHz, CDCl3) δ 174.4, 157.2, 129.8,
128.7, 128.3, 121.0, 111.3, 66.7, 60.7, 55.8, 33.0. HRMS
calcd. for C11H15NO4Na (M+Na)+: 248.0899, found:
248.0888. [α]2D5 = +114.4 (c = 1.60, CH2Cl2).
N-methoxy-N-methyl-2-oxo-3-phenylpropanamide (1l) [26]
Colorless oil; 3.8 g, 65% yield; 1H NMR (400 MHz, CDCl3)
δ 7.37–7.20 (m, 5H), 3.99 (s, 2H), 3.60 (s, 3H), 3.13 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 197.6, 131.9, 130.1, 128.8,
127.6, 127.1, 62.4, 46.5, 31.7.
2-Hydroxy-N-methoxy-N-methyl-2-(p-tolyl)acetamide (2d) [29]
Light yellow solid; 158.6 mg, 76% yield; M.p.:

Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
345
1
97.5–98.3 °C; H NMR (400 MHz, CDCl3) δ 7.23 (d, J =
NMR (101 MHz, CDCl3) δ 172.6, 142.8, 127.0, 126.2,
125.9, 66.5, 61.1, 32.9. HRMS calcd. for C8H11NO3SNa
(M+Na)+: 224.0357, found: 224.0355. [α]2D5 = +25.2 (c =
0.45, CH2Cl2).
8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 5.32–5.29 (m, 1H),
4.21 (d, J = 6.4 Hz, 1H), 3.22 (d, J = 14.5 Hz, 6H), 2.33 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 173.9, 138.3, 136.9,
129.5, 127.6, 71.5, 60.9, 32.8, 21.4. [α]2D5 = +76.4 (c = 1.05,
CH2Cl2).
2-Hydroxy-N-methoxy-N-methylpropanamide (2j) [31]
1
Colorless oil; 96.2 mg, 72% yield; H NMR (400 MHz,
2-Hydroxy-N-methoxy-N-methyl-2-(4-methoxyphenyl)aceta-
CDCl3) δ 4.54–4.42 (m, 1H), 3.71 (s, 3H), 3.34 (d, J = 7.9
Hz, 1H), 3.24 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H); 13C NMR
mide (2e)
Yellow solid; 136.5 mg, 61% yield; M.p.: 75.5–77.1 °C; 1H
NMR (400 MHz, CDCl3) δ 7.28–7.24 (m, 2H), 6.88 (t, J =
2.4 Hz, 2.8, 1H), 6.87 (t, J = 2.6 Hz, 2.4 Hz, 1H), 5.31 (s,
1H), 4.21 (s, 1H), 3.79 (s, 3H), 3.22 (d, J = 12.7 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 174.0, 159.7, 132.2, 128.9,
114.2, 71.2, 60.9, 55.4, 32.8. HRMS calcd. for
C11H15NO4Na (M+Na)+: 248.0899, found: 248.0893. [α]2D5
= +77.0 (c = 1.05, CH2Cl2).
(101 MHz, CDCl3) δ 175.8, 65.0, 61.4, 32.5, 21.0. [α]D25
–21.7 (c = 0.2, CH2Cl2).
=
2-Hydroxy-N-methoxy-N-methyl-4-phenylbutanamide (2k)
1
Colorless oil; 164.3 mg, 74% yield; H NMR (400 MHz,
CDCl3) δ 7.31–7.26 (m, 2H), 7.23–7.26 (m, 3H), 4.34–4.30
(m, 1H), 3.55 (s, 3H), 3.29 (d, J = 7.9 Hz, 1H), 3.20 (s, 3H),
2.89–2.70 (m, 2H), 2.10–2.02 (m, 1H), 1.85–1.76 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 175.2, 141.6, 128.8, 128.5,
126.1, 68.0, 61.3, 36.3, 32.6, 31.5. HRMS calcd. for
2-Hydroxy-N-methoxy-N-methyl-2-(4-(trifluoromethyl)phen
-yl)acetamide (2f)
C12H17NO3 (M+H)+: 224.1287, found: 224.1294. [α]2D5
+7.99 (c = 0.1, CH2Cl2).
=
1
White solid; 141.6mg, 54% yield; M.p.: 44.3–46.2 °C; H
NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.46 (d,
J = 8.1 Hz, 2H), 5.38 (d, J = 6.0 Hz, 1H), 4.43 (d, J = 6.5
Hz, 1H), 3.31 (s, 3H), 3.19 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.8, 143.7, 131.0, 130.7, 130.4, 130.1, 128.0,
126.2, 125.6, 71.1, 60.9, 32.8. HRMS calcd for
2-Hydroxy-N-methoxy-N-methyl-3-phenylpropanamide (2l)
[32]
1
Colorless oil; 198.7 mg, 95% yield; H NMR (400 MHz,
CDCl3) δ 7.27 (m, 5H), 4.62 (s, 1H), 3.72 (s, 3H), 3.31 (d, J
= 7.7 Hz, 1H), 3.24 (s, 3H), 3.07 (d, J = 13.6 Hz, 1H), 2.85
(dd, J = 13.6, 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
174.5, 137.5, 129.6, 128.5, 126.8, 69.9, 61.6, 41.2, 32.7.
[α]2D5 = –11.69 (c = 0.2, CH2Cl2) for the (S)-isomer. Refer-
ence: [α]2D5 = –70.90 (c = 0.97, CH2Cl2) for the (S)-isomer
[32].
C11H13F3NO3 (M+H)+: 264.0848, found: 264.0847. [α]2D5
+52.4 (c = 0.66, CH2Cl2).
=
2-Hydroxy-N-methoxy-N-methyl-2-(4-(trifluoromethoxy)phe
-nyl)acetamide (2g)
1
Yellow oil; 196.5 mg, 70% yield; H NMR (400 MHz,
CDCl3) δ 7.40–7.36 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.35
(d, J = 6.4 Hz, 1H), 4.30 (d, J = 6.4 Hz, 1H), 3.30 (s, 3H),
3.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 173.1, 149.2,
147.5, 138.5, 129.2, 128.2, 121.8, 121.2, 119.3, 70.8, 60.9,
32.8. HRMS calcd. for C11H12F3NO4Na (M+Na)+: 302.0616,
found: 302.0608. [α]2D5 = +53.7 (c = 2.1, CH2Cl2).
2-Hydroxy-N-methyl-2-phenylacetamide (3a) [33]
1
White solid; 44.9 mg, 23% yield; M.p.: 52.4–63.8 °C; H
NMR (400 MHz, CDCl3) δ 7.40–7.29 (m, 5H), 6.26 (s, 1H),
4.98 (d, J = 3.5 Hz, 1H), 3.88 (d, J = 3.5 Hz, 1H), 2.78 (d, J
= 5.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.7, 139.4,
128.7, 128.5, 126.8, 74.1, 26.2.
2-Hydroxy-N-methoxy-N-methyl-2-(naphthalen-2-yl)acetam
-ide (2h)
1
3 Results and discussion
Yellow solid; 144.1mg, 59% yield; M.p.: 86.3–86.9 °C; H
NMR (400 MHz, CDCl3) δ 7.87–7.80 (m, 4H), 7.56–7.45
(m, 3H), 5.53 (s, 1H), 4.42 (d, J = 5.1 Hz, 1H), 2.9 (s, 3H),
2.6 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 173.7, 137.2,
133.5, 133.4, 128.8, 128.3, 127.9, 127.1, 126.5, 125.2, 71.9,
60.9, 32.9. HRMS calcd. for C14H15NO3Na (M+Na)+:
268.0950, found: 268.0946. [α]2D5 = +99.7 (c = 1.2, CH2Cl2).
Initially,
N-methoxy-N-methyl-2-oxo-2-phenylacetamide
(1a) was employed as the model substrate to optimize hy-
drogenation conditions (Table 1). The compound 1a was
tested first in ethanol under 10 atm of H2 at 50 °C to provide
2a with 23.7% ee over 20 h (Table 1, entry 1). The results in
Table 1 showed that the stereoselective outcome of the hy-
drogenation was strongly dependent on the temperature and
hydrogen pressure. Increasing the hydrogen pressure from
10 to 20 atm, the reaction provided a lower ee (Table 1,
entry 2). Increasing the temperature from 50 to 70 °C re-
sulted in both higher reaction rate and better enantioselec-
tivity (Table 1, entry 3). However, a higher temperature of
2-Hydroxy-N-methoxy-N-methyl-2-(thiophen-2-yl)acetamid
e (2i)
1
Brown solid; 144.7mg, 72% yield; M.p.: 67.3–68.9 °C; H
NMR (400 MHz, CDCl3) δ 7.27–7.25 (m, 1H), 7.06–7.03
(m, 1H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 5.64 (d, J = 6.4 Hz,
1H), 4.20 (d, J = 6.8 Hz, 1H), 3.40 (s, 3H), 3.24 (s, 3H); 13C

346
Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
90 °C with 10 atm of hydrogen pressure gave the product at
the expense of both enantiomeric excess and conversion
(Table 1, entry 4). At a lower or higher hydrogen pressure,
such as 5 atm and 20 atm, the reaction provided lower ee
values (Table 1, entries 5, 6). It is reported that catalytic
amounts of additives play crucial roles in improving the
reactivity and/or enantioselectivity of many asymmetric
hydrogenation reactions [19–23] and it has been proved that
CeCl3·7H2O is useful for the hydrogenation of α-keto esters
[1618]. When CeCl3·7H2O (6 eq. relative to catalyst) was
added in this reaction under 10 atm of H2 at 70 °C, the ee
value of 2a improved slightly (entry 3 vs. 7, Table 1). Un-
expectedly, the trend of the effect of the hydrogen pressure
was found to be opposite to that obtained without additive.
The ee value dramatically increased to 94.7% when the hy-
drogen pressure was raised to 20 atm in the presence of
CeCl3·7H2O while decreased when the pressure went up to
30 atm (entry 8 vs. 9, Table 1). It was interesting that in-
creasing or decreasing the reaction temperature led to lower
conversion and poorer enantioselectivity (entries 10 and 11,
Table 1). Further investigation revealed that the catalyst was
unstable when the temperature was raised to 90 °C in the
presence of CeCl3·7H2O. It was reported that the magnesi-
um salts was able to chelate with the carbonyl and methoxy
of the Weinreb amides [24], we tested some other additives
such as MgCl2 (entry 12, Table 1) and ZnCl2 (entry 13, Ta-
ble 1). It showed that these two additives gave lower ee
values and conversions than CeCl3·7H2O. Notably, the
amount of additive also played an important role in the en-
antioselectivity. The ee of 2a increased from 94.7% to
97.3% when the amount of CeCl3·7H2O was increased from
6 eq. to 12 eq. relative to the catalyst (entry 14, Table 1).
However, the ee of 2a decreased when the amount of
CeCl3·7H2O was increased to 20 eq. relative to the catalyst
(entry 15, Table 1). The solvents also played important roles
in the asymmetric hydrogenation of many functionalized
ketones. EtOH was proved to be the best solvent in this hy-
drogenation reaction (entries 16–19, Table 1). MeOH could
also give a high ee but with low yield. Based on these re-
sults, the optimized reaction conditions were therefore set as
the following: EtOH as the solvent, 20 atm of H2, 12 eq. of
CeCl3·7H2O relative to [Ru((S)-Sunphos)(benzene)Cl]Cl as
the additive at 70 °C.
Having the optimized reaction conditions in hand, we
then extended the substrate scope to other Weinreb amides
(Table 2). Most aryl amides were hydrogenated in good to
excellent ee values. Substitution at ortho-position on phenyl
ring led to lower ee because of the steric effect. For example,
ee values of ortho-methyl 1b and methoxy 1c were 75.9%
and 73.6%, respectively (entries 2, 3, Table 2). The para-
substituted substrates gave moderate to good enantiomeric
excesses and the electronic nature of the para-substituent
did not show distinct influence on enantioselectivity (entries
4–7, Table 2). The naphthyl substituted substrate 1h also
Table 1 Optimization of the reaction conditionsa)
Entry
1
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
CH2Cl2
THF
Pressure (atm)
Temperature (°C)
Additive
none
Conversionb) (%)
42.5
ee c) (%)
23.7
15.1
54.9
29.8
11.5
15.6
67.3
94.7
91.9
80.8
49.3
31.5
9.9
97.3d)
62.5e)
89.0
20.5
66.1
77.6
10
20
10
10
5
50
50
70
90
70
70
70
70
70
50
90
70
70
70
70
70
70
70
70
2
none
67.3
3
none
56.8
4
none
23.4
5
none
51.3
6
20
10
20
30
20
20
20
20
20
20
20
20
20
20
none
68.6
7
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
MgCl2
64.4
8
95.0
9
100.0
92.6
10
11
12
13
14
15
16
17
18
19
51.9
37.5
ZnCl2
79.2
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
CeCl3·7H2O
100.0
77.2
96.1
86.1
20.4
76.5
a) All reaction were carried out with a substrate (1 mmol) concentration of 0.5 M for 20 h, substrate/catalyst/additive = 200/1/6; b) conversions of 2a
were determined by 1H NMR; c) ee values were determined by HPLC on a chiral OD-H column; d) catalyst/additive = 1/12; e) catalyst/additive = 1/20.

Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
Table 2 Asymmetric hydrogenation of α-keto Weinreb amidesa)
347
2
Entry
1
R
Yield (%) b)
ee (%) c)
97.3
75.9
73.6
89.1
97.1
88.8
92.9
91.9
91.2
46.6
49.3
13.1
1
2
1a
1b
1c
1d
1e
1f
C6H5
75
62
71
76
61
54
70
59
72
72
74
95
2-Me-C6H4
2-MeO-C6H4
4-Me-C6H4
4-MeO-C6H4
4-CF3-C6H4
4-CF3O-C6H4
2-naphthyl
2-thienyl
3
4
5
6
7
1g
1h
1i
8
9
10
11
12
1j
Me
1k
1l
PhCH2CH2
PhCH2
a) All reactions were carried out in EtOH with a substrate concentration of 0.5 M at 70 °C and 20 atm of H2 for 20 h. Substrate/[Ru((S)-Sunphos) (ben-
zene)Cl]Cl/additive: 200/1/12, 100% conversion; b) yields were determined by 1H NMR; c) the ee values were determined by HPLC.
This work was financially supported by the National Natural Science
Foundation of China (21172146).
gave high ee values. The hydrogenation of thienyl substi-
tuted substrate 1i (entry 9, Table 2) displayed well though
with a sulfur atom at meta-position. Unfortunately, the alkyl
substituted substrates 1j, 1k and the benzyl substituted sub-
strate 1l were hydrogenated in much lower ee.
1
2
Nahm S, Weinreb SM. N-methoxy-N-methylamides as effective
acylating agents. Tetrahedron Lett, 1981, 22(39): 3815–3818
Frye SV, Johnson MC, Valvano NL. Synthesis of
2-aminobenzophenones via rapid halogen-lithium exchange in the
presence of a 2-amino-N-methoxy-N-methylbenzamide. J Org Chem,
1991, 56(11): 3750–3752
Hlasta DJ, Court JJ. Tandem organometallic addition reactions to
N-methoxy-ureas and urethanes in the preparation of unsymmetrical
and symmetrical ketones. Tetrahedron Lett, 1989, 30(14): 1773–1776
Sibi MP, Sharma R, Paulson KL. N,N′-dimethoxy-N,N'-dimethyl-
It was also noticeable that the isolated yields of hydro-
genations were only 60–75%. 1H NMR analysis of the reac-
tion mixture showed that part of (15–30%) the N-methoxy
was removed during the hydrogenation reactions to generate
compound 3. In general, the removal of N-methoxy was
reported in the presence of lithium based organometallic
reagents [25]. To make sure whether the methoxy group of
Weinreb amide was removed before or after the hydrogena-
tion reaction, further investigation was conducted. When
product 2a was hydrogenated under the same conditions,
compound 3a was detected. Analysis of original reaction
products showed that the ee values of 2a and 3a were dif-
ferent (2a, 80.8% ee vs. 3a, 18.2% ee, Table 1, entry 10),
revealing that removal of the methoxy group after the hy-
drogenation reaction is not the only pathway, and the sub-
strates could also be demethoxylated under the reaction
conditions before hydrogenation.
3
4
5
6
ethanediamide:
A useful α-oxo-N-methoxy-N-methylamide and
1,2-diketone synthon. Tetrahedron Lett, 1992, 33(15): 1941–1944
Turner JA, Jacks WS. Acylation of ester enolates by
N-methoxy-N-methylamides: An effective synthesis of β-keto esters.
J Org Chem, 1989, 54(17): 4229–4231
Wolberg M, Hummel W, Müller M. Biocatalytic reduction of
β,δ-diketo esters: A highly stereoselective approach to all four
stereoisomers of a chlorinated β,δ-dihydroxy hexanoate. Chem Eur J,
2001, 7(21): 4562–4571
Murphy JA, Commeureuc AGJ, Snaddon TN, McGuire TM, Khan
TA, Hisler K, Dewis ML, Carling R. Direct conversion of
N-methoxy-N-methylamides (Weinreb amides) to ketones via a
nonclassical wittig reaction. Org Lett, 2005, 7(7): 1427–1429
Enders D, Niemeier O, Henseler A. Organocatalysis by
N-heterocyclic carbenes. Chem Rev, 2007, 107(12): 5606–5655
Baragwanath L, Rose CA, Zeitler K, Connon SJ. Highly
7
8
9
4 Conclusion
enantioselective benzoin condensation reactions involving
bifunctional protic pentafluorophenyl-substituted triazolium
precatalyst. J Org Chem, 2009, 74(23): 9214–9217
a
In conclusion, we have developed an efficient catalytic sys-
tem for the asymmetric hydrogenation of α-keto Weinreb
amides. CeCl3·7H2O as an additive was essential for the
high conversion and enantioselectivity. The hydrogenation
products provided valuable chiral blocks for the preparation
of chiral hydroxy ketones.
10 Busygin I, Nieminen V, Taskinen A, Sinkkonen J, Toukoniitty E,
Sillanpää R, Murzin DY, Leino R. A combined NMR, DFT, and
X-ray investigation of some cinchona alkaloid O-ethers. J Org Chem,
2008, 73(17): 6559–6569
11 Evans DA, Gage JR, Leighton JL. Total synthesis of (+)-calyculin A.
J Am Chem Soc, 1992, 114(24): 9434–9453
12 Andrus MB, Hicken EJ, Stephens JC, Bedke DK. Total synthesis of

348
Zhao MM, et al. Sci China Chem March (2013) Vol.56 No.3
the hydroxyketone kurasoin A using asymmetric phase-transfer
alkylation. J Org Chem, 2006, 71(22): 8651–8654
13 Pasquier C, Naili S, Pelinski L, Brocard J, Mortreux A, Agbossou F.
Synthesis and application in enantioselective hydroge nation of new
free and chromium complexed aminophosphine–phosphinite ligands.
Tetrahedron: Asymmetry, 1998, 9(2): 193–196
14 Carpentier JF, Mortreux A. Asymmetric hydrogenation of α-keto acid
derivatives by rhodium-amidophosphine-phosphinite catalysts.
Tetrahedron: Asymmetry, 1997, 8(7): 1083–1099
23 Xiao D, Zhang X. Highly enantioselective hydrogenation of acyclic
imines catalyzed by Ir–Binaphane complexes. Angew Chem Int Ed,
2001, 40(18): 3425–3428
24 Martin R, Pascual O, Romea P, Rovira R, Urpi F, Vilarrasa J. A
simple procedure for the preparation of enantiopure ethyl
α-hydroxyalkyl ketones. Tetrahedron Lett, 1997, 38: 1633–1636
25 Graham SL, Scholz TH. A new mode of reactivity of N-methoxy-
N-methylamides with strongly basic reagents. Tetrahedron Lett, 1990,
31(44): 6269–6272
15 Chiba T, Miyashita A, Nohira H, Takaya H. Bichep-Ru complexes,
highly efficient catalysts for asymmetric hydrogenation of carbonyl
compounds. Tetrahedron Lett, 1993, 34(14): 2351–2354
16 Sun Y, Wan X, Wang J, Meng Q, Zhang H, Jiang L, Zhang Z.
Ru-catalyzed asymmetric hydrogenation of α-ketoesters with
CeCl3·7H2O as additive. Org Lett, 2005, 7(24): 5425–5427
17 Meng Q, Sun Y, Ratovelomanana-Vidal V, Genêt JP, Zhang Z.
CeCl3·7H2O: An effective additive in Ru-catalyzed enantioselective
hydrogenation of aromatic α-ketoesters. J Org Chem, 2008, 73(10):
3842–3847
18 Meng Q, Zhu L, Zhang Z. Highly enantioselective sequential
hydrogenation of ethyl 2-oxo-4-arylbut-3-enoate to ethyl 2-hydroxy-
4-arylbutyrate. J Org Chem, 2008, 73(18): 7209–7212
19 Vogl EM, Gröger H, Shibasaki M. Towards perfect asymmetric
catalysis: Additives and cocatalysts. Angew Chem Int Ed, 1999,
38(11): 1570–1577
26 Sibi MP, Marvin M, Sharma R. -keto amides and 1,2-diketones
from N,N'-dimethoxy-N,N'-dimethylethanediamide. A synthetic and
mechanistic investigation. J Org Chem, 1995, 60(16): 5016-5023
27 Wang L, Xia XD, Guo W, Chen JR, Xiao WJ. Palladium- catalyzed
C-H acetoxylation of 2-methoxyimino-2-aryl-acetates and acetamides.
Org Bio Chem, 2011, 9(20): 6895–6898
28 Biju P. New methodology for the synthesis of , -difluoroketones.
Synth Commun, 2008, 38(12): 1940–1945
29 Chen CT, Kao JQ, Salunke SB, Lin YH. Enantioselective aerobic
oxidation of α-hydroxy-ketones catalyzed by oxidovanadium(V)
methoxides bearing chiral, N-salicylidene-tert-butylglycinates. Org
Lett, 2010, 13(1): 26–29
30 Barrow RA, Moore RE, Li LH, Tius MA. Synthesis of 1-aza-cryptop-
hycin 1, an unstable cryptophycin. An unusual skeletal rearrangement.
Tetrahedron, 2000, 56: 3339–3351
31 Arikan F, Li J, Menche D. Diastereodivergent aldol reactions of
β-alkoxy ethyl ketones: Modular access to (1,4)-syn and -anti
polypropionates. Org Lett, 2008, 10(16): 3521–3524
20 Ng Cheong Chan Y, Osborn JA. Iridium(iii) hydride complexes for
the catalytic enantioselective hydrogenation of imines. J Am Chem
Soc, 1990, 112(25): 9400–9401
32 Evans DA, Cee VJ, Siska SJ. Asymmetric induction in methyl ketone
aldol additions to α-alkoxy and α,β-bisalkoxy aldehydes: A model for
acyclic stereocontrol. J Am Chem Soc, 2006, 128(29): 9433–9441
33 Hoffman RV, Nayyar NK, Klinekole BW. Efficient conversion of
O-sulfonylated arylacetohydroxamic acids to 2-substituted secondary
amides. J Am Chem Soc, 1992, 114(15): 6262–6263
21 Togni A. Planar-chiral ferrocenes: Synthetic methods and
applications. Angew Chem Int Ed, 1996, 35(13-14): 1475–1477
22 Wang WB, Lu SM, Yang PY, Han XW, Zhou YG. Highly
enantioselective iridium-catalyzed hydrogenation of heteroaromatic
compounds, quinolines. J Am Chem Soc, 2003, 125(35): 10536–
10537