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W. Liu et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 10.91 (s, 1 H), 7.94 (d, J = 8.0 Hz,
1 H), 7.23 (d, J = 7.6 Hz, 2 H), 7.14 (t, J = 7.6 Hz, 1 H), 2.60 (s, 3
H), 2.38 (s, 3 H).
Cl
Cl
O
H
H
N
N
Pd(OAc)2
CuCl2
O
O
O
13C NMR (100 MHz, CDCl3): δ = 199.9, 161.9, 143.4, 133.6, 130.8,
2a
1a
129.5, 126.8, 126.4, 122.7, 26.3, 17.9.
CuCl2 Pd(OAc)2
MS (EI): m/z (%) = 133.1 (100).
Cl
O
H
N
Anal. Calcd for C11H11Cl2NO2: C, 50.79; H, 4.26; N, 5.38. Found:
C, 50.91; H, 4.15; N, 5.44.
ClPd
HN
O
O
O
Pd
Cl
3
6
Cu(II)
2,2-Dichloro-3-oxo-N-(p-tolyl)butanamide (2c)
Yield: 171.8 mg (66%); pale yellow crystals; mp 44.6–45.8 °C.
Pd(II)
Pd(0)
IR (KBr): 2952, 2821, 1712, 1611, 1501, 1454, 1377, 1055, 733
cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.89 (s, 1 H), 7.46 (d, J = 8.4 Hz,
2 H), 7.18 (d, J = 8.4 Hz, 2 H), 2.50 (s, 3 H), 2.34 (s, 3 H).
Cl
Cl
H
N
PdCl
O
H
N
H
N
O
O
O
O
Pd
Cl
O
5
1k
4
13C NMR (100 MHz, CDCl3): δ = 200.1, 161.5, 143.5, 136.1, 129.7,
121.3, 26.3, 21.0.
Scheme 4 Proposed mechanism
MS (EI): m/z (%) = 133.2 (100).
Anal. Calcd for C11H11Cl2NO2: C, 50.79; H, 4.26; N, 5.38. Found:
C, 50.58; H, 4.17; N, 5.55.
In summary, we have described a directed methylene C–
H dichlorination reaction of acyclic β-dicarbonyl com-
pounds in the presence of palladium(II) acetate as the cat-
alyst and copper(II) chloride as the additive. In
comparison to the literature methods, this procedure is
highly regioselective as it only chlorinates the activated
methylene group of N-aryl acetoacetamides. Further stud-
ies on the application this method to other more valuable
compounds and detailed investigations of the reaction
mechanism are in progress.
2,2-Dichloro-N-(4-chlorophenyl)-3-oxobutanamide (2d)40
Yield: 204.1 mg (73%); pale yellow crystals; mp 62.0–64.0 °C.
1H NMR (400 MHz, CDCl3): δ = 11.00 (s, 1 H), 7.53 (d, J = 8.4 Hz,
2 H), 7.33 (d, J = 8.4 Hz, 2 H), 2.56 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.8, 162.3, 143.8, 134.2, 131.9,
129.3, 122.5, 26.3.
2,2-Dichloro-N-(4-methoxyphenyl)-3-oxobutanamide (2e)
Yield: 209.5 mg (76%); pale yellow crystals; mp 124.2–125.4 °C.
IR (KBr): 2884, 1735, 1668, 1455, 1380, 1088, 751 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.83 (s, 1 H), 7.49 (d, J = 8.8 Hz,
2 H), 6.89 (d, J = 8.4 Hz, 2 H), 3.79 (s, 3 H), 2.55 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.2, 162.4, 153.5, 142.9, 128.8,
122.9, 114.7, 55.6, 26.3.
All reactions were carried out at room temperature over eight hours
in a Schlenk tube equipped with a magnetic stir bar. Solvents and
reagents were purchased from Aldrich Chemicals or J & K Scientif-
ic Ltd, and were used as received. Petroleum ether (PE) refers to the
fraction boiling in the 60–90 °C range. Thin-layer chromatography
was performed using Qingdao-Haiyang 600 mesh silica gel plates
(GF254), and samples were made visual with short-wavelength UV
light (254 nm). Melting points are uncorrected. IR spectra were ob-
tained using a Bruker Vector 22 spectrophotometer. 1H NMR (400
MHz) and 13C NMR (100 MHz) were recorded in CDCl3. GC–MS
was performed using Agilent 6890N/5973 instrumentation in elec-
tron ionization (EI) mode. Elemental analysis was performed using
a Vario EL cube CHNOS elemental analyzer.
MS (EI): m/z (%) = 149.2 (100).
Anal. Calcd for C11H11Cl2NO3: C, 47.85; H, 4.02; N, 5.07. Found:
C, 47.96; H, 4.18; N, 5.14.
2,2-Dichloro-N-(2-methoxyphenyl)-3-oxobutanamide (2f)
Yield: 174.0 mg (63%); pale yellow crystals; mp 127.0–128.1 °C.
IR (KBr): 2973, 1713, 1692, 1545, 1417, 1380, 1089, 881 cm–1.
1H NMR (400 MHz, CDCl3): δ = 11.37 (s, 1 H), 8.15 (d, J = 8.0 Hz,
1 H), 7.15 (t, J = 8.4 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.93 (d,
J = 8.4 Hz, 1 H), 3.92 (s, 3 H), 2.55 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 199.8, 161.0, 152.0, 126.5, 121.5,
121.3, 118.3, 110.8, 100.2, 56.3, 27.0.
2,2-Dichloro-3-oxo-N-phenylbutanamide (2a);39 Typical Proce-
dure
To a Schlenk tube were added successively 3-oxo-N-phenylbutan-
amide (1a) (177 mg, 1.0 mmol), CuCl2 (670 mg, 5.0 mmol),
Pd(OAc)2 (0.012 mg, 0.05 mmol) and CH2Cl2 (3.0 mL), and the re-
sulting soln stirred for 8 h at r.t. The mixture was then subjected to
purification by preparative thin-layer chromatography (PE–EtOAc,
2:1) to afford product 2a.
MS (EI): m/z (%) = 149.1 (100).
Anal. Calcd for C11H11Cl2NO3: C, 47.85; H, 4.02; N, 5.07. Found:
C, 47.81; H, 4.11; N, 5.22.
Yield: 175.0 mg (71%); pale yellow crystals; mp 45.0–47.0 °C.
1H NMR (400 MHz, CDCl3): δ = 10.95 (s, 1 H), 7.57 (d, J = 7.6 Hz,
2 H), 7.39 (t, J = 8.0 Hz, 2 H), 7.22 (t, J = 7.6 Hz, 1 H), 2.56 (s, 3 H).
2,2-Dichloro-N-(4-ethoxyphenyl)-3-oxobutanamide (2g)
Yield: 212.2 mg (73%); yellow crystals; mp 114.6–116.0 °C.
IR (KBr): 2925, 1722, 1684, 1601, 1512, 1455, 1380, 1045, 718
cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.82 (s, 1 H), 7.47 (d, J = 8.8 Hz,
2 H), 6.87 (d, J = 8.8 Hz, 2 H), 4.01 (q, J = 6.8 Hz, 2 H), 2.51 (s, 3
H), 1.39 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 200.4, 155.8, 142.1, 131.5, 129.2,
126.2, 121.3, 26.5.
2,2-Dichloro-3-oxo-N-(o-tolyl)butanamide (2b)
Yield: 176.4 mg (68%); pale yellow crystals; mp 47.4–48.3 °C.
13C NMR (100 MHz, CDCl3): δ = 200.1, 161.5, 157.1, 143.6, 128.5,
122.8, 114.9, 63.7, 26.3, 14.7.
IR (KBr): 2973, 2885, 1726, 1684, 1454, 1380, 1049, 881, 669
cm–1.
MS (EI): m/z (%) = 135.1 (100).
Synthesis 2013, 45, 2600–2604
© Georg Thieme Verlag Stuttgart · New York