PhI(OAc)2-promoted umpolung acetoxylation of enamides for the synthesis of α-acetoxy ketones

Article abstract of DOI:10.1007/s11426-016-0478-3

Umpolung is a fundamental concept in organic chemistry, which provides an alternative strategy for the synthesis of target compounds which were not easily accessible by conventional methods. Herein, a mild and efficient PhI(OAc)₂-promoted umpolung acetoxylation reactions of enamides was developed for the synthesis of α-acetoxy ketones. The reaction tolerates a wide range of functional groups and affords α-acetoxy ketones in good to excellent yields. PhI(OAc)₂ serves as a source of acetoxy in the reaction.

Full text of DOI:10.1007/s11426-016-0478-3

SCIENCE CHINA
Chemistry
doi: 10.1007/s11426-016-0478-3
• ARTICLES •
PhI(OAc)2-promoted umpolung acetoxylation of enamides for the
synthesis of α-acetoxy ketones
Ming Chen1, Wei Zhang1, Zhi-Hui Ren1, Wen-Yun Gao2, Yao-Yu Wang1 & Zheng-Hui Guan1*
1Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials
Science, Northwest University, Xi’an 710127, China
2College of Life Sciences/National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an 710069, China
Received November 16, 2016; accepted December 15, 2016; published online February 21, 2017
Umpolung is a fundamental concept in organic chemistry, which provides an alternative strategy for the synthesis of target
compounds which were not easily accessible by conventional methods. Herein, a mild and efficient PhI(OAc)2-promoted
umpolung acetoxylation reactions of enamides was developed for the synthesis of α-acetoxy ketones. The reaction tolerates a
wide range of functional groups and affords α-acetoxy ketones in good to excellent yields. PhI(OAc)2 serves as a source of
acetoxy in the reaction.
umpolung, enamides, acetoxylation, hypervalent iodine reagents, α-acetoxy ketones
Citation:
Chen M, Zhang W, Ren ZH, Gao WY, Wang YY, Guan ZH. PhI(OAc)2-promoted umpolung acetoxylation of enamides for the synthesis of α-acetoxy
ketones. Sci China Chem, doi: 10.1007/s11426-016-0478-3
1 Introduction
route to afford the desirable products that are hardly syn-
thesized using regular approaches [20–26]. Hypervalent
iodine reagents due to their high electrophilicity have been
used to achieve umpolung of electronegative compounds,
such as enolates and ketones [27–32]. Recently, Wirth and
co-workers [33] have developed pioneering research on the
hypervalent iodine reagents promoted functionalizatons of
silyl enol ethers through umpolung strategy (Scheme 2(a)).
Enamides are nitrogen analogs of silyl enol ethers. The
Cβ-position is a nucleophilic center and is prone to elec-
trophilic attack [34]. With this idea in mind and our interest
in the enamides transformations [35–39], we hypothesized
that hypervalent iodine reagents promoted transformation of
enamides may be achieved through an umpolung process.
The Cβ-position of enamides react with PhI(OAc)2 to give
intermediate A. Then, intramolecular nucleophilic displace-
ment by acetoxy affords intermediate B with release of
iodobenzene to achieve umpolung [9,30]. Hydrolysis of
intermediate B in the presence of H2O affords α-acetoxy
α-Acetoxy ketones represent an important class of interme-
diates in organic synthesis [1–4], medicinal industries, and
biological system (Scheme 1) [5–8]. Accordingly, various
methods such as oxidation of enolates, ketones, and termi-
nal alkynes [9–15], acetylation of α-bromo and α-hydroxyl
ketones [6,16], and copper-catalyzed insertion of O–H bond
of carboxylic acids into α-diazo ketones [17] have been de-
veloped for the formation of α-acetoxy ketones. Despite this
progress, most of these reactions require expensive and toxic
heavy metals oxidants [18,19], which would hamper their ap-
plications in synthetic organic chemistry. Therefore, devel-
opment of novel and environmentally friendly strategies to-
wards α-acetoxy ketones is still highly desirable.
Umpolung or polarity inversion provides an alternative
*Corresponding author (email: guanzhh@nwu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2017
chem.scichina.com link.springer.com

Chen et al. Sci China Chem
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Scheme 1 α-Acetoxy ketones as precursors for molecules of medicinal and biological importance.
iodine oxidant under neutral conditions. Herein, we report a
facile and efficient PhI(OAc)2-promoted umpolung acetoxy-
lation reaction of enamides for the synthesis of α-acetoxy ke-
tones under mild conditions (Scheme 2(c)).
2 Experimental
2.1 Typical procedure for umpolung acetoxylation of
enamides
A 10-mL round flask was charged with PhI(OAc)2 (0.24
mmol, 77.3 mg) and enamides 1 (0.2 mmol, 1.0 equiv.) in
CH2Cl2/H2O (2.0 mL, v/v=1:1). The flask was heated to
50 °C under vigorous stirring. Upon completion (detected
by thin layer chromatography (TLC)) of the reaction, the
reaction mixture was cooled down to room temperature. It
was quenched with H2O (5 mL) and extracted with EtOAc
(2×10 mL). The combined organic layers were dried over an-
hydrous Na2SO4 and then evaporated in vacuo. The residue
was purified by column chromatography on silica gel with
hexane/ethyl acetate (v/v=6:1) as the eluent to afford the
corresponding product 2.
2.2 Characterization data of α-acetoxy ketones
2-Oxo-2-phenylethyl acetate (2a). Yield: 77% (27.4 mg),
colourless liquid. 1H NMR (CDCl3, 400 MHz) δ 7.92 (d,
J=8.0 Hz, 2 H), 7.61 (t, J=7.2 Hz, 1 H), 7.49 (t, J=7.6 Hz, 2
H), 5.35 (s, 2 H), 2.23(s, 3 H); 13C NMR (CDCl3, 100 MHz) δ
192.1, 170.4, 134.1, 133.9, 128.8, 127.7, 66.0, 20.5. HRMS
Calcd. (ESI) m/z for C10H10NaO3: [M+Na]+ 201.0522, found:
201.0527.
Scheme 2 Umpolung strategy for constructing of α-acetoxy ketones.
ketone (Scheme 2(b)). However, till date the umpolung re-
actions of enamides have been much less developed [40,41].
To achieve this conception, two main challenges that needed
to be addressed were as follows: (1) the enamides easily de-
composes under acidic conditions [42–47]; (2) the enamides
would be oxidized to give imides in the presence of strong ox-
idant [48,49]. A practical solution is to use mild hypervalent
2-Oxo-2-p-tolylethyl acetate (2b). Yield: 69% (26.4 mg),
colourless liquid. 1H NMR (CDCl3, 400 MHz) δ 7.82 (d,
J=8.4 Hz, 2 H), 7.29 (d, J=8 Hz, 2 H), 5.33 (s, 2 H), 2.42
(s, 3 H), 2.24 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.7,
170.5, 144.9, 131.6, 129.5, 127.8, 65.9, 21.7, 20.6. HRMS
Calcd. (ESI) m/z for C11H12NaO3: [M+Na]+ 215.0679, found:
215.0672.

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Chen et al. Sci China Chem
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2-Oxo-2-o-tolylethyl acetate (2c). Yield: 75% (28.8 mg),
found: 231.0624.
colourless liquid. 1H NMR (CDCl3, 400 MHz) δ 7.61 (d,
J=7.6 Hz, 1 H), 7.42 (t, J=7.2 Hz, 1 H), 7.29 (d, J=7.6 Hz,
2 H), 5.18 (s, 2 H), 2.52 (s, 3 H), 2.21 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 195.7, 170.4, 139.0, 134.3, 132.2, 132.1,
128.0, 125.7, 67.2, 21.1, 20.5. HRMS Calcd. (ESI) m/z for
C11H12NaO3: [M+Na]+ 215.0679, found: 215.0671.
2-(3-Methoxyphenyl)-2-oxoethyl acetate (2j). Yield: 81%
(33.7 mg), colourless liquid; H NMR (CDCl3, 400 MHz)
1
δ 7.48–7.44 (m, 2 H), 7.39 (t, J=8 Hz,1 H), 7.16–7.13 (m,
1 H), 5.32 (s, 2 H), 3.85 (s, 3 H), 2.23 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 192.0, 170.4, 159.9, 135.4, 129.8, 120.3,
120.1, 112.0, 66.0, 55.4, 20.5. HRMS Calcd. (ESI) m/z for
C11H12NaO4: [M+Na]+ 231.0628, found: 231.0629.
2-(3,4-Dimethylphenyl)-2-oxoethyl acetate (2d). Yield:
1
94% (38.7 mg), white solid, m.p. 74–75 °C. H NMR
2-(3,4-Dimethoxyphenyl)-2-oxoethyl acetate (2k). Yield:
85% (40.5 mg), colourless liquid. 1H NMR (CDCl3, 400
MHz) δ 7.53–7.48 (m, 2 H), 6.90 (d, J=8.4 Hz, 1 H), 5.31
(s, 2 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 2.23 (s, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 190.6, 170.4, 153.8, 149.2, 127.2, 122.1,
110.1, 109.8, 65.6, 56.0, 55.9, 20.5. HRMS Calcd. (ESI) m/z
for C12H14NaO5: [M+Na]+ 261.0733, found: 261.0727.
2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl acetate (2l).
(CDCl3, 400 MHz) δ 7.68 (s, 1 H), 7.64 (d, J=7.6 Hz, 1 H),
7.23 (d, J=8.0 Hz, 1 H), 5.31 (s, 2 H), 2.31 (s, 3 H), 2.31 (s,
3 H), 2.22 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.9,
170.4, 143.5, 137.2, 129.9, 128.8, 125.3, 65.9, 20.5, 20.0,
19.7. HRMS Calcd. (ESI) m/z for C12H14NaO3: [M+Na]+
229.0835, found: 229.0835.
2-(2,5-Dimethylphenyl)-2-oxoethyl acetate (2e). Yield:
90% (37.1 mg), colourless liquid. 1H NMR (CDCl3, 400
MHz) δ 7.40 (s, 1 H), 7.23 (d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz,
1 H), 5.18 (s, 2 H), 2.46 (s, 3 H), 2.36 (s, 3 H), 2.21 (s, 3 H);
13C NMR (CDCl3, 100 MHz) δ 195.7, 170.4, 135.8, 135.3,
134.2, 132.9, 132.1, 128.5, 67.2, 20.8, 20.6, 20.5. HRMS
Calcd. (ESI) m/z for C12H14NaO3: [M+Na]+ 229.0835, found:
229.0835.
1
Yield: 76% (33.7 mg), yellow solid, m.p. 80–81 °C. H
NMR (CDCl3, 400 MHz) δ 7.49 (dd, J1=1.6 Hz, J2=8 Hz, 1
H), 7.39 (d, J=1.6 Hz, 1 H), 6.86 (d, J=8.4 Hz, 1 H), 6.06 (s, 2
H), 5.26 (s, 2 H), 2.22 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 190.1, 170.4, 152.3, 148.3, 128.8, 123.9, 108.1, 107.5,
101.9, 65.7, 20.5. HRMS Calcd. (ESI) m/z for C11H10NaO5:
[M+Na]+ 245.0420, found: 245.0415.
2-(2,4-Dimethylphenyl)-2-oxoethyl acetate (2f). Yield:
96% (39.6 mg), colourless liquid. 1H NMR (CDCl3, 400
MHz) δ 7.54 (d, J=8 Hz, 1 H), 7.09–7.07 (m, 2 H), 5.19
(s, 2 H), 2.50 (s, 3 H), 2.36 (s, 3 H), 2.21 (s, 3 H); 13C
NMR (CDCl3, 100 MHz) δ 194.7, 170.4, 143.0, 139.6,
133.1, 131.2, 128.4, 126.3, 67.0, 21.4, 21.3, 20.5. HRMS
Calcd. (ESI) m/z for C12H14NaO3: [M+Na]+ 229.0835, found:
229.0832.
2-Oxo-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl acetate
(2g). Yield: 89% (41.1 mg), colourless liquid. 1H NMR
(CDCl3, 400 MHz) δ 7.62–7.60 (m, 2 H), 7.15 (d, J=8.4
Hz, 1 H), 5.30 (s, 2 H), 2.80 (t, J=6.4 Hz, 4 H), 2.22 (s,
3 H), 1.83–1.79 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ
191.9, 170.4, 144.1, 137.7, 131.6, 129.5, 128.6, 124.7, 65.9,
29.6, 29.3, 22.8, 22.6, 20.5. HRMS Calcd. (ESI) m/z for
C14H16NaO3: [M+Na]+ 255.0992, found: 255.0982.
2-(Biphenyl-4-yl)-2-oxoethyl acetate (2h). Yield: 80%
(40.6 mg), white solid, m.p. 108–109 °C. 1H NMR (CDCl3,
400 MHz) δ 7.98 (d, J=8.4 Hz, 2 H ), 7.69 (d, J=8.4 Hz, 2
H), 7.61 (d, J=7.2 Hz, 2 H), 7.47 (t, J=7.2 Hz, 2 H), 7.41 (d,
J=7.2 Hz, 1 H), 5.36 (s, 2 H), 2.24 (s, 3 H); 13C NMR (CDCl3,
100 MHz) δ 191.7, 170.4, 146.5, 139.5, 132.8, 128.9, 128.4,
128.3, 127.4, 127.2, 66.0, 20.5. HRMS Calcd. (ESI) m/z for
C16H14NaO3: [M+Na]+ 277.0835, found: 277.0829.
2-(4-Acetamidophenyl)-2-oxoethyl acetate (2m). Yield:
43% (20.2 mg), yellow liquid. 1H NMR (DMSO-d6, 400
MHz) δ 10.34 (s, 1 H), 7.92 (d, J=8.8 Hz, 2 H), 7.73 (d,
J=8.8 Hz, 2 H), 5.40 (s, 2 H), 2.14 (s, 3 H), 2.09 (s, 3 H); 13C
NMR (DMSO-d6, 100 MHz) δ 191.2, 169.9, 169.1, 144.3,
129.1, 128.4, 118.3, 66.2, 24.2, 20.4. HRMS Calcd. (ESI)
m/z for C12H13NNaO4: [M+Na]+ 258.0737, found: 258.0730.
2-(4-(tert-Butoxycarbonylamino)phenyl)-2-oxoethyl ac-
etate (2n). Yield: 64% (37.5 mg), white solid, m.p. 126–127
1
°C. H NMR (CDCl3, 400 MHz) δ 7.85 (d, J=8.8 Hz, 2 H),
7.49 (d, J=8.8 Hz, 2 H), 7.02 (s, 1 H), 5.30 (s, 2 H), 2.22 (s,
3 H), 1.52 (s, 9 H); 13C NMR (CDCl3, 100 MHz) δ 190.7,
170.5, 152.1, 143.7, 129.2, 128.5, 117.5, 81.3, 65.8, 28.2,
20.6. HRMS Calcd. (ESI) m/z for C15H19NNaO5: [M+Na]+
316.1155, found: 316.1153.
2-(4-Fluorophenyl)-2-oxoethyl acetate (2o). Yield: 76%
1
(29.8 mg), colourless liquid. H NMR (CDCl3, 400 MHz) δ
7.97–7.93 (m, 2 H), 7.16 (t, J=8.4 Hz, 2 H), 5.30 (s, 2 H), 2.23
(s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 190.6, 170.4, 166.1
(d, JCF=254.5 Hz ), 130.6 (d, JCF=3.1 Hz ), 130.4 (d, JCF=9.4
Hz ), 116.1 (d, JCF=21.9 Hz ), 65.8, 20.5. HRMS Calcd. (ESI)
m/z for C10H9FNaO3: [M+Na]+ 219.0428, found: 219.0421.
2-(4-Chlorophenyl)-2-oxoethyl acetate (2p). Yield: 83%
1
(35.2 mg), colourless liquid. H NMR (CDCl3, 400 MHz) δ
2-(4-Methoxyphenyl)-2-oxoethyl acetate (2i). Yield: 77%
(32.0 mg), colourless liquid. H NMR (CDCl3, 400 MHz) δ
7.90 (d, J=8.8 Hz, 2 H), 6.95 (d, J=8.8 Hz, 2 H), 5.30 (s, 2
H), 3.87 (s, 3 H), 2.23 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 190.6, 170.5, 164.0, 130.0, 127.1, 114.0, 65.7, 55.5, 20.6.
HRMS Calcd. (ESI) m/z for C11H12NaO4: [M+Na]+ 231.0628,
7.87 (d, J=6.8 Hz, 2 H), 7.47 (d, J=6.8 Hz, 2 H), 5.31 (s, 2
H), 2.24 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.0, 170.4,
140.4, 132.4, 129.2, 129.1, 65.8, 20.5. HRMS Calcd. (ESI)
m/z for C10H9ClNaO3: [M+Na]+ 235.0132, found: 235.0135.
2-(2-Chlorophenyl)-2-oxoethyl acetate (2q). Yield: 95%
1
1
(40.3 mg), colourless liquid. H NMR (CDCl3, 400 MHz) δ

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7.62 (d, J=7.2 Hz, 1 H), 7.45–7.42 (m, 2 H), 7.38–7.34 (m, 1
H), 5.20 (s, 2 H), 2.18 (s, 3 H); 13C NMR (CDCl3, 100 MHz):
δ 195.2, 170.3, 135.7, 132.8, 131.5, 130.5, 129.9, 127.1, 68.2,
20.4. HRMS Calcd. (ESI) m/z for C10H9ClNaO3 [M+Na]+
235.0132, found: 235.0133.
Hz, 1 H), 2.19 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 200.6,
170.4, 150.3, 135.8, 134.4, 128.1, 126.6, 124.4, 74.0, 33.3,
20.7. HRMS Calcd. (ESI) m/z for C11H10NaO3: [M+Na]+
213.0522, found: 213.0516.
1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl acetate (2y).
1
2-(4-Bromophenyl)-2-oxoethyl acetate (2r). Yield: 95%
Yield: 63% (25.7 mg), colourless liquid. H NMR (CDCl3,
1
(48.6 mg), white solid, m.p. 81–82 °C. H NMR (CDCl3,
400 MHz) δ 8.03 (d, J=8 Hz, 1 H), 7.51 (t, J =7.6 Hz, 1 H),
7.33 (t, J=7.6 Hz, 1 H), 7.27 (d, J=2 Hz, 1 H), 5.57–5.53 (m,
1 H), 3.26–3.11 (m, 1 H), 3.10–3.06 (m, 1 H), 2.40–2.37 (m,
1 H), 2.31–2.26 (m, 1 H), 2.23 (s, 3 H); 13C NMR (CDCl3,
100 MHz) δ 193.0, 170.2, 143.0, 133.9, 131.5, 128.6, 127.8,
126.9, 74.5, 29.1, 27.9, 20.8. HRMS Calcd. (ESI) m/z for
C12H12NaO3: [M+Na]+ 227.0679, found: 227.0679.
400 MHz) δ 7.77 (d, J=8.8 Hz, 2 H), 7.62 (d, J=8.4 Hz, 2 H),
5.28 (s, 2 H), 2.22 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ
191.2, 170.3, 132.8, 132.1, 129.2, 129.1, 65.8, 20.5. HRMS
Calcd. (ESI) m/z for C10H9BrNaO3: [M+Na]+ 278.9627,
found: 278.9624.
2-(4-Iodophenyl)-2-oxoethyl acetate (2s). Yield: 70%
(42.6 mg), white solid, m.p. 116–117 °C. 1H NMR (CDCl3,
400 MHz) δ 7.85 (d, J=8.4 Hz, 2 H), 7.62 (d, J=8.4 Hz, 2 H),
5.28 (s, 2 H), 2.22 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ
191.6, 170.3, 138.1, 133.3, 129.0, 102.0, 65.7, 20.5. HRMS
Calcd. (ESI) m/z for C10H9INaO3: [M+Na]+ 326.9489, found:
326.9484.
Ethyl 2-acetoxy-3-oxo-3-phenylpropanoate (2aa). Yield:
1
6% (3.0 mg), colourless liquid. H NMR (CDCl3, 400 MHz)
δ 8.02–8.00 (m, 2 H), 7.64 (t, J=7.2 Hz, 1 H), 7.51 (d, J=8.0
Hz, 2 H), 6.33 (s, 1 H), 4.28–4.23 (m, 2 H), 2.24 (s, 3 H), 1.22
(t, J=7.2 Hz, 3 H). HRMS Calcd. (ESI) m/z for C13H14NaO5:
[M+Na]+ 273.0733, found: 273.0729.
2-Oxo-2-(4-(trifluoromethyl)phenyl)ethyl acetate (2t).
Yield: 73% (35.9 mg), white solid, m.p. 69–71 °C. 1H NMR
(CDCl3, 400 MHz) δ 8.03 (d, J=8 Hz, 2 H), 7.76 (d, J=8.4
Hz, 2 H), 5.34 (s, 2 H), 2.24 (s, 3 H); 13C NMR (CDCl3, 100
2-Oxo-2-phenylethyl 4-methylbenzenesulfonate (4).
Yield: 63% (36.5 mg), white solid, m.p. 71–72 °C. 1H NMR
(CDCl3, 400 MHz) δ 7.86–7.82 (m, 4 H), 7.61 (t, J=7.6 Hz,
1 H), 7.47 (t, J=8.0 Hz, 2 H), 7.34 (d, J=8.4 Hz, 2 H ), 5.27
(s, 2 H), 2.44 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 190.2,
145.3, 134.2, 133.6, 132.5, 129.9, 128.9, 128.1, 127.9, 69.9,
21.6. HRMS Calcd. (ESI) m/z for C15H14SNaO4: [M+Na]+
313.0505, found: 313.0512.
MHz) δ 191.5, 170.3, 136.8, 135.1 (d, JCF =32.6 Hz), 128.1,
3
125.9 (d, JCF =3.5 Hz), 124.7, 122.0, 66.0, 20.4. HRMS
Calcd. (ESI3) m/z for C11H9F3NaO3: [M+Na]+ 269.0396,
found: 269.0396.
2-(Acetylimino)-2-phenylethyl acetate (B). Yield: 12%
(5.3 mg), colourless liquid. 1H NMR (CDCl3, 400 MHz) δ
7.75 (d, J=7.6 Hz, 2 H), 7.52 (t, J=8.0 Hz, 1 H), 7.45 (t, J=7.6
Hz, 2 H), 5.26 (s, 2 H), 2.28 (s, 3 H), 2.14 (s, 3 H). HRMS
Calcd. (ESI) m/z for C12H13NNaO3: [M+Na]+ 242.0788,
found: 242.0784.
2-(4-Nitrophenyl)-2-oxoethyl acetate (2u). Yield: 85%
(37.9 mg), yellow liquid. H NMR (CDCl3, 400 MHz) δ 8.35
1
(d, J=8.8 Hz, 2 H), 8.09 (d, J=8.8 Hz, 2 H), 5.35 (s, 2 H),
2.24 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 191.1, 170.2,
150.7, 138.6, 128.9, 124.0, 66.0, 20.4. HRMS Calcd. (ESI)
m/z for C10H9NNaO5: [M+Na]+ 246.0373, found: 246.0370.
2-(Naphthalen-2-yl)-2-oxoethyl acetate (2v). Yield: 88%
1
(40.1 mg), brown solid, m.p. 76–77 °C. H NMR (CDCl3,
3 Results and discussion
400 MHz) δ 8.39 (s, 1 H), 7.96–7.92 (m, 2 H), 7.90–7.85 (m,
2 H), 7.62–7.59 (m, 1 H), 7.57–7.55 (m, 1 H), 5.46 (s, 2 H),
2.25 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 192.0, 170.4,
135.8, 132.3, 131.4, 129.5, 129.4, 128.8, 128.8, 127.8, 127.0,
123.2, 66.0, 20.5. HRMS Calcd. (ESI) m/z for C14H12NaO3:
[M+Na]+ 251.0679, found: 251.0675.
1-Oxo-1-phenylpropan-2-yl acetate (2w). Yield: 40%
(15.4 mg), colourless liquid. 1H NMR (CDCl3, 400 MHz)
δ 7.95 (d, J=7.2 Hz, 2 H), 7.60 (t, J=7.6 Hz, 1 H), 7.49 (t,
J=8.0 Hz, 2 H), 6.00–5.95 (m, 1 H), 2.15 (s, 3 H), 1.52 (d,
J=7.2 Hz, 3 H). HRMS Calcd. (ESI) m/z for C11H12NaO3:
[M+Na]+ 215.0679, found: 215.0670.
1-Oxo-2,3-dihydro-1H-inden-2-yl acetate (2x). Yield:
79% (30.0 mg), colourless liquid. 1H NMR (CDCl3, 400
MHz) δ 7.79 (d, J=8 Hz, 1 H), 7.65 (t, J=7.6 Hz, 1 H),
7.47–7.40 (m, 2 H), 5.43 (dd, J1=4.8 Hz, J2=8 Hz, 1 H), 3.66
(dd, J1=8 Hz, J2=16.8 Hz, 1 H), 3.05 (dd, J1=4.8 Hz, J2=17.2
We initiated the investigation by using N-(1-phenylvinyl)-ac-
etamide as substrate in the presence of (diacetoxy)iodoben-
zene at 50 °C in CH2Cl2 solvent, and the product α-acetoxy
ketones 2a was obtained only in 10% yield along with imides
byproducts [48,49]. Encouraged by this preliminary result,
we tried to optimize the reaction conditions (Table 1). Firstly,
different solvents, such as dimethyl sulfoxide (DMSO) and
CH3CN were screened. However, improvement in the yield
was not observed (entries 2 and 3). The reaction mechanism
indicates that the presence of H2O is important for promoting
this reaction. Indeed, the yield of 2a was improved to 34%
when the 10 equiv. of H2O was added in CH2Cl2 (entry 4).
Further optimization of the reaction conditions showed that
the reaction was most productive when a mixed solvent of
CH2Cl2/H2O (1:1) was used (entry 5). Slightly lower yield
(70%) was obtained when H2O was employed as the solvent

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Chen et al. Sci China Chem
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Table 1 Optimization of reaction conditions a)
Entry
1
Oxidant
Additive
Solvent
CH2Cl2
Yield of 2a (%)
PhI(OAc)2
10
0
2
PhI(OAc)2
DMSO
3
PhI(OAc)2
CH3CN
5
b)
4
PhI(OAc)2
H2O
CH2Cl2
34
5
PhI(OAc)2
CH2Cl2/H2O
H2O
77
70
58
0
6
PhI(OAc)2
7
DMP
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
8
1-Acetoxy-1,2-benziodoxole-3(1H)-one
c)
9
PhIO
Koser’s reagent
m-CPBA
HOAc
HOAc
51
c),d)
10
11
12
13
14
0
e)
HOAc, PhI
18
f)
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
22
g)
53
h)
40
a) Reaction conditions: 1a (0.2 mol, 1.0 equiv.), hypervalent iodine reagents (0.24 mmol, 1.2 equiv.), solvent (2 mL), CH2Cl2/H2O (1:1, 2 mL), T=50 °C,
isolated yield; b) H2O (10 equiv.) was added; c) HOAc (2.4 equiv.) was added; d) the 2-oxo-2-phenylethyl 4-methylbenzenesulfonate 4 was formed in 63%
yield; e) PhI (10 mol%), AcOH (5.0 equiv.) and m-CPBA (2.0 equiv.); f) PhI(OAc)2 (0.5 equiv.) was used; g) 30 °C; h) 70 °C; DMP=Dess-Martin periodinane.
(entry 6). Moreover, we also observed that other hyper-
valent iodine reagents, such as Dess-Martin periodinane
and 1-acetoxy-1,2-benziodoxole-3(1H)-one were inferior
to PhI(OAc)2 (entries 7 and 8). It should be noted that the
α-acetoxy ketone 2a was obtained in 51% yield using PhIO
combined with 2.4 equiv. of HOAc as the oxidant (entry 9).
When Koser’s reagent/AcOH was used as the oxidant, the
2-oxo-2-phenylethyl 4-methylbenzenesulfonate 4 instead of
α-acetoxy ketone 2a was obtained in 63% yield (entry 10).
Furthermore, when in-situ generated PhI(OAc)2 (PhI, AcOH
and m-CPBA) [9] was employed as the umpolung reagent,
only 18% yield of the desired product 2a was obtained (entry
11). The yield was decreased to 22% when 0.5 equiv. of
PhI(OAc)2 was used (entry 12). Finally, we have varied
the reaction temperature, it was found that the conversion
was decreased at 30 °C (entry 13). However, the yield was
decreased when the reaction was conducted at 70 °C, due to
the byproducts (imides and acetophenone) were prominent.
(entry 14).
Having established the optimized reaction conditions,
we have surveyed the scope of various enamides toward
umpolung acetoxylation reaction as summarised in Table 2.
The reaction displayed good functional-group tolerance and
proved to be a general method for the synthesis of α-acetoxy
ketones. A variety of para-, meta-, and ortho-substituents
on the aromatic ring of the enamides furnished the desired
products in good to excellent yields. Notably, the reac-
tion was successfully performed on a gram scale affording
α-acetoxy ketone 2a in 74% yield (entry 1). Enamides with
methyl, alkyl, and phenyl on the aromatic ring afforded the
corresponding products in 69%–96% yields (entries 2–8).
Enamides with strong electron-donating groups such as
methoxy, dimethoxy, [1,3]dioxole, and amino substituted
enamides were converted into desired products in good to
high yields (entries 9–14). Notably, aryl enamides with
fluoro, chloro, and sensitive functional groups such as bromo
and iodo, provided the best results with up to 95% yield
of the α-acetoxy ketones (entries 15–19). The strong elec-
tron-withdrawing groups, such as trifuoromethyl and nitro
were well tolerated to produce the corresponding products in
high yields (entries 20 and 21). This reaction also afforded
88% yield for β-naphthyl-substituted enamide 1v (entry
22). Interestingly, β-substituted enamides such as 1w, 1x
and 1y, also underwent the reaction smoothly to give the
corresponding products 2w, 2x and 2y in 40%, 79% and 63%
yield, respectively (entries 23–25). However, only a trace of
the desired α-acetoxy ketone 2z was observed when aliphatic
enamide such as N-cyclohexenylacetamide 1z was used as
the substrate (entry 26).
Furthermore, N-unsubstitued enamines and enol carbonates
were investigated for further extending the substrate scope
(Scheme 3). However, the desired ethyl 2-acetoxy-3-oxo-3-
phenylpropanoate 2aa was obtained in only 6% yield, with
52% recovery of the enamine 1aa (Scheme 3(a)). No reac-
tion occurred when enol carbonate 1ab was employed as the
substrate (Scheme 3(b)).
To gain insight into the reaction mechanism, the control
experiments were performed (Scheme 4). Firstly, when N-(1-

Chen et al. Sci China Chem
() Vol. No.
6
a)
Table 2 Reaction of enamides with PhI(OAc)2
a) Reaction conditions: 1 (0.2 mol), PhI(OAc)2 (0.24 mmol, 1.2 equiv.), CH2Cl2/H2O (1:1, 2 mL), T=50 °C; b) isolated yield; c) 1a (10.0 mmol), PhI(OAc)2
(12.0 mmol, 1.2 equiv.) CH2Cl2/H2O (1:1, 20 mL), T=50 °C.

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Chen et al. Sci China Chem
() Vol. No.
4 Conclusions
In summary, we have developed an efficient umpolung ace-
toxylation of enamides for the synthesis of α-acetoxy ketones.
PhI(OAc)2 was used as environmentally benign and inexpen-
sive reagent for umpolung of enamides. The reaction dis-
played good functional-group tolerance and furnished the de-
sired products in good to excellent yields under mild reaction
conditions. The control experiments demonstrated that the
acetoxy group in products came from PhI(OAc)2.
Scheme 3 Reaction of enamino esters, and enol carbonates with PhI(OAc)2
(color online).
Acknowledgments This work was supported by the National Natural Sci-
ence Foundation of China (21622203, 21472147, 21272183), and the Fund
of Northwest University (334100036).
Conflict of interest
The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online
athttp://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
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