Palladium-catalyzed oxidative C-H bond coupling of steered acetanilides and aldehydes: A facile access to ortho -acylacetanilides

Article abstract of DOI:10.1021/ol201201a

A palladium-catalyzed oxidative C-H bond functionalization/ortho-acylation of acetanilides using easily accessible aldehyde as the acyl source is described. In the presence of a Pd(TFA)₂ catalyst and tert-butylhydroperoxide at 90 °C in general, an array of ortho-acylacetanilides can be afforded in good yields.

Full text of DOI:10.1021/ol201201a

Supporting Information
Supporting Information
Palladium-Catalyzed Oxidative C-H Bond Coupling of Steered
Acetanilides and Aldehydes: A Facile Access to
ortho-Acylacetanilides
§
,†
†
§
*,§
*,†
Yinuo Wu, Baozhu Li, Fei Mao, Xingshu Li and Fuk Yee Kwong
§
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China;
†
State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
E-mail: lixsh@mail.sysu.edu.cn and bcfyk@inet.polyu.edu.hk
R2
R2
HN
O
O
O
NH
O
5
mol % Pd(TFA)2
H
R1
R3
TBHP, toluene
R1
R3
90 °C, 24 h
3
2 examples
up to 88% yield
Table of Contents
1
2
3
. Ge ne ra l c o nsid e ra tio ns........................................................................................2
. Pre p a ra tio n o f sub stitute d a c e ta nilid e sub stra te s ............................................3
. Ge ne ra l p ro c e d ure s fo r re a c tio n c o nd itio n sc re e ning s a nd c o up ling
re a c tio ns .................................................................................................................3
4
5
6
. Cha ra c te riza tio n d a ta o f c o up ling p ro d uc ts....................................................5
.
1H, 13C , NMR, a nd HRMS sp e c tra .......................................................................18
. Re fe re nc e s ...........................................................................................................94
S1

Supporting Information
1
. General considerations
Unless otherwise noted, all reagents were purchased from commercial suppliers
®
and used without purification. All the reactions were performed in Rotaflo
(
England) resealable screw-cap Schlenk flask (approx. 20 mL volume) in the presence
of Teflon coated magnetic stirrer bar (4 mm × 10 mm). N,N-Dimethylformamide
DMF) was distilled under calcium hydride under reduced pressure. Dioxane and
toluene were distilled from sodium under nitrogen. tert-Butanol was refluxing with
sodium and the distillate was stored under CaH and was distilled from calcium
hydride under nitrogen prior to use. The concentration of tert-butyl hydroperoxide
(
2
(TBHP) was determined by means of iodometric method which is generally used by
1
commercial supplier (http://www.aladdin-reagent.com/thir.asp?Rea_SubID=15038).
Note: The TBHP concentration we applied to this study was 70.6%. Thin layer
chromatography was performed on Merck precoated silica gel 60 F254 plates. Silica
1
gel (Merck, 70-230 and 230-400 mesh) was used for column chromatography.
H
NMR spectra were recorded on a Bruker (400 MHz) spectrometer. Spectra were
referenced internally to the residual proton resonance in CDCl (δ 7.26 ppm), or with
tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard. Chemical shifts (δ)
3
1
3
were reported as part per million (ppm) in δ scale downfield from TMS.
C NMR
spectra were referenced to CDCl (δ 77.0 ppm, the middle peak). Coupling
3
constants (J) were reported in Hertz (Hz). High-resolution mass spectra (HRMS)
were obtained on a Shimadzu LCMS-IT-TOF. MS spectra were recorded on an
Agilent LC–MS 6120 with ESI or APCI. The products described in GC yield were
accorded to the authentic samples/dodecane calibration standard from Agilent 6890N
GC-FID system. Compounds described in the literatures were characterized by
S2

Supporting Information
1
13
comparison of their H, and/or C NMR spectra to the previously reported data.
2
. Preparation of substituted acetanilide substrates
All the substituted acetanilides in Table 3 were prepared from their corresponding
2 2 2
precursors with Ac O in CH Cl according to the literature method without
2
modifications.
N-phenylbenzamide, N-phenylpivalamide and N-phenylisobutyramide were prepared
from phenylamine with their corresponding acyl chlorides in pyridine according to the
3
literature method without modifications.
3
. General procedures for reaction condition screenings and
coupling reactions
General procedures for screening: The acetanilide (0.135 g, 1.0 mmol) and the
metal complex (5 mol% or as indicated in Table 1) were loaded into a Schlenk tube
equipped with a Teflon-coated magnetic stir bar under air atmosphere. The solvent
(2.0 mL) was added into the tube. The solution was stirred for about 1 to 2 minutes
until the solid had been dissolved. 4-Chlorobenzaldehyde (2.0 mmol), TBHP (4.0
mmol) were loaded into the tube. The tube was stirred at room temperature for ~5
o
minutes and then placed into a preheated oil bath (40-120 C) for 24 hours. After
completion of reaction, the reaction tube was allowed to cool to room temperature.
Ethyl acetate (~10 mL), dodecane (114 μL, internal standard) and water (~3 ml) were
added. The organic layer was subjected to GC analysis. The GC yield obtained was
S3

Supporting Information
previously calibrated by authentic sample/dodecane calibration curve.
General procedure for C-H bond coupling of steered acetanilides and aldehydes:
Substituted acetanilide (1.0 mmol) and the Pd(TFA) (16.1 mg, 0.05 mmol) were
loaded into a Schlenk tube equipped with a Teflon-coated magnetic stir bar. Toluene
2.0 mL) was added into the tube. The solution was stirred for about 1 to 2 minutes
2
(
until the solid was dissolved. Substituted benzaldehyde (2.0 mmol), TBHP (4.0
mmol) were loaded into the tube. The tube was stirred at room temperature for ~5
o
minutes and then placed into a preheated oil bath at 90 C for 24 hours. After
completion of reaction as judged by GC analysis, the reaction tube was allowed to
2 3
cool to room temperature and quenched with saturated K CO and diluted with EtOAc.
The organic layer was separated and the aqueous layer was washed with EtOAc.
The filtrate was concentrated under reduced pressure. The crude products were
purified by flash column chromatography on silica gel (230-400 mesh) to afford the
desired oxidatively coupled product.
S4

Supporting Information
4
. Characterization data of coupling products
4
N-(2-(1-Naphthoyl)phenyl)acetamide (3ab)
Me
O
NH
O
1
Hexane: EtOAc (1:5); R
f
= 0. 4; H NMR (400 MHz, CDCl
3
) δ 11.49 (s, 1H), 8.69 (d,
J = 8.5 Hz, 1H), 7.91 (dd, J = 7.5, 1.5 Hz, 1H), 7.86 – 7.79 (m, 2H), 7.50 – 7.43 (m,
2
3
1
1
H), 7.43 – 7.38 (m, 3H), 7.32 (dd, J = 8.0, 1.5 Hz, 1H), 6.92 – 6.79 (m, 1H), 2.20 (s,
1
3
H);
3
C NMR (101 MHz, CDCl ) δ 202.16, 169.66, 141.54, 137.01, 135.39, 134.82,
33.63, 131.21, 130.63, 128.55, 127.41, 127.18, 126.62, 125.31, 124.43, 123.24,
+
22.19, 120.87, 25.56. ESI-MS [M+H] 290.1.
4
N-(2-(2-Naphthoyl)phenyl)acetamide (3ac)
Me
O
NH
O
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ10.79 (s, 1H), 8.66 (d, J
=
8.3 Hz, 1H), 8.18 (s, 1H), 7.94 (dd, J = 12.3, 8.7 Hz, 3H), 7.84 (dd, J = 8.5, 1.6 Hz,
1
3
1H), 7.68 – 7.54 (m, 4H), 7.15 – 7.07 (m, 1H), 2.24 (s, 3H);
C NMR (101 MHz,
CDCl
3
) δ199.38, 172.01, 140.29, 135.94, 135.23, 134.20, 133.49, 132.45, 131.84,
129.55, 128.64, 128.31, 127.83, 127.05, 126.77, 125.42, 122.28, 121.78, 25.25.
+
ESI-MS [M+H] 290.1.
S5

Supporting Information
5
N-(2-Benzoylphenyl)acetamide(3ad)
Me
O
NH
O
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ10.81 (s, 1H), 8.60 (d, J
=
8.2 Hz, 1H), 7.71 – 7.67 (m, 2H), 7.56 (dd, J = 15.8, 7.8 Hz, 3H), 7.48 (t, J = 7.6
1
3
3
Hz, 2H), 7.35 – 7.33 (m, 1H), 7.08 (s, 1H), 2.21 (s, 3H); C NMR (101 MHz, CDCl )
δ199.75, 169.44, 140.35, 134.28, 133.53, 132.57, 129.92, 128.36, 126.97, 122.18,
+
1
21.60, 25.23. ESI-MS [M+H] 240.1.
4
N-(2-(2-Methylbenzoyl)phenyl)acetamide (3ae)
Me
O
NH
O
Me
1
Hexane: EtOAc (1:5); R
8.5 Hz, 1H), 7.56 (dd, J = 11.4, 4.3 Hz, 1H), 7.39 (dd, J = 9.4, 2.6 Hz, 1H), 7.29 (d,
J = 7.7 Hz, 1H), 7.25 – 7.22 (m, 1H), 7.00 (t, J = 7.6 Hz, 1H), 2.29 (s, 3H), 2.28 (s,
f 3
=0.4; H NMR (400 MHz, CDCl ) δ11.56 (s, 1H), 8.75 (d, J
=
1
3
3H);
3
C NMR (101 MHz, CDCl ) δ202.92, 169.57, 141.54, 139.29, 135.90, 135.32,
134.52, 130.94, 130.25, 127.87, 125.38, 122.46, 122.17, 120.74, 25.55, 19.73.
+
ESI-MS [M+H] 254.1.
6
N-(2-(2-Methoxybenzoyl)phenyl)acetamide (3af)
Me
O
NH
O
OMe
1
f 3
Hexane: EtOAc (1:5); R =0. 4; H NMR (400 MHz, CDCl ) δ 11.61 (s, 1H), 8.75 (d, J
=
8.5 Hz, 1H), 7.58 – 7.53 (m, 1H), 7.52 – 7.44 (m, 2H), 7.32 – 7.28 (m, 1H), 7.06 (td,
S6

Supporting Information
J = 7.5, 0.7 Hz, 1H), 7.04 – 6.97 (m, 2H), 3.77 (d, J = 3.4 Hz, 3H), 2.26 (d, J = 15.3
13
Hz, 3H); C NMR (101 MHz, CDCl
3
) δ 200.62, 169.64, 156.81, 141.29, 135.09,
134.55, 131.99, 129.09, 128.50, 126.95, 122.58, 120.49, 120.47, 111.44, 55.64, 25.55.
+
ESI-MS [M+H] 270.1.
4
N-(2-(4-Methoxybenzoyl)phenyl)acetamide (3ag)
Me
O
NH
O
OMe
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ 10.44 (s, 1H), 8.47 (d, J
=
8.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.45 (dd, J = 10.1, 3.9 Hz, 2H), 7.01 (dd, J =
1
3
11.3, 3.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 2.11 (s, 3H);
C NMR
(
101 MHz, CDCl
3
) δ 197.89, 169.04, 163.45, 139.80, 133.51, 132.72, 132.61, 130.88,
+
1
24.27, 122.07, 121.72, 113.64, 55.52, 25.14. ESI-MS [M+H] 270.0.
N-(2-(3,5-Dimethoxybenzoyl)phenyl)acetamide (3ah)
Me
O
NH
O
OMe
OMe
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ10.69 (s, 1H), 8.53 (d, J
=
8.3 Hz, 1H), 7.58 – 7.38 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 2.2 Hz, 2H),
1
3
6
1
1
.60 (t, J = 2.2 Hz, 1H), 3.74 (s, 6H), 2.16 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ
99.40, 169.30, 160.55, 140.45, 140.38, 134.37, 133.51, 122.12, 121.54, 107.65,
+
04.81, 55.62, 25.26. HRMS: calcd. for C17
H
17 N O
4
Na : 322.1055, found 322.1051.
4
N-(2-(2-Fluorobenzoyl)phenyl)acetamide (3ai)
S7

Supporting Information
Me
NH
O
O
F
1
Hexane: EtOAc (1:5), R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ11.36 (s, 1H), 8.75 (d, J
=
8.5 Hz, 1H), 7.62 – 7.57 (m, 1H), 7.54 (dd, J = 6.7, 1.4 Hz, 1H), 7.52 – 7.48 (m,
1
7
1
1
2
H), 7.45 (d, J = 7.0 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.20 (d, J = 9.4 Hz, 1H), 7.09 –
1
3
.03 (m, 1H), 2.28 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ 197.09, 169.48,
58.4,141.32, 135.57, 134.16, 133.04 (d, JCF = 8.3 Hz), 130.19 (d, JCF = 2.3 Hz),
27.61 (d, JCF = 16.8 Hz), 124.28 (d, JCF = 3.5 Hz), 122.27, 120.79, 116.37 (d, JCF
=
1.4 Hz), 25.52. ESI-MS [M+H]+ 258.1.
4
N-(2-(4-Fluorobenzoyl)phenyl)acetamide (3aj)
Me
O
NH
O
F
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ10.65 (s, 1H), 8.61 (d, J
=
8.4 Hz, 1H), 7.82 – 7.74 (m, 2H), 7.64 – 7.49 (m, 2H), 7.19 (t, J = 8.6 Hz, 2H),
1
3
7.11 (s, 1H), 2.24 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ 197.81, 169.09, 166.53,
164.00, 140.06, 134.56 (d, JCF = 3.1 Hz), 132.90, 132.49 (d, JCF = 9.2 Hz), 127.57 (d,
J
CF = 155.5 Hz), 123.30, 121.88 (d, JCF = 43.1 Hz), 115.43 (d, JCF = 22.0 Hz), 25.07.
+
ESI-MS [M+H] 258.1.
4
N-(2-(2-Chlorobenzoyl)phenyl)acetamide (3ak)
S8

Supporting Information
Me
NH
O
O
Cl
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ11.56 (s, 1H), 8.86 –
8.74 (m, 1H), 7.60 (s, 1H), 7.51 – 7.45 (m, 2H), 7.38 (ddd, J = 5.5, 3.3, 1.7 Hz, 2H),
1
3
7
.33 (dd, J = 7.5, 1.3 Hz, 1H), 7.06 – 6.99 (m, 1H), 2.31 (s, 3H); C NMR (101 MHz,
CDCl
3
) δ 199.27, 169.65, 141.92, 138.74, 135.95, 134.60, 131.20, 130.94, 130.14,
+
1
28.65, 126.75, 122.28, 121.27, 120.64, 25.63. ESI-MS [M+H] 290.1.
4
N-(2-(4-Chlorobenzoyl)phenyl)acetamide (3al)
Me
O
NH
O
Cl
1
Hexane: EtOAc (1:5); R
f 3
=0.4; H NMR (400 MHz, CDCl ) δ10.70 (s, 1H), 8.62 (d, J
=
8.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.49 (dd, J = 13.5,
1
3
8
1
1
3
.1 Hz, 3H), 7.10 (t, J = 7.6 Hz, 1H), 2.23 (s, 3H); C NMR (101 MHz, CDCl ) δ
95.92, 168.10, 138.62, 137.81, 135.07, 133.14, 131.21, 130.29, 127.94, 126.01,
+
23.24, 122.25, 23.99. ESI-MS [M+H] 290.1.
4
N-(2-(2-Bromobenzoyl)phenyl)acetamide (3am)
Me
O
NH O
Br
1
Hexane: EtOAc (1:5); R
8.5 Hz, 1H), 7.65 (dd, J = 7.9, 0.9 Hz, 1H), 7.57 (dd, J = 11.4, 4.2 Hz, 1H), 7.39 –
S9
f 3
=0.4; H NMR (400 MHz, CDCl ) δ 11.54 (s, 1H), 8.80 (d, J
=

Supporting Information
1
3
7
.32 (m, 3H), 7.30 – 7.28 (m, 1H), 7.03 – 6.98 (m, 1H), 2.29 (s, 3H);
C NMR (101
MHz, CDCl
3
) δ199.88, 169.63, 142.03, 140.83, 135.94, 134.68, 133.23, 131.23,
+
1
28.56, 127.28, 122.27, 120.98, 120.64, 119.25, 25.62. ESI-MS [M+H] 318.0.
7
N-(2-(Cyclohexanecarbonyl)phenyl)acetamide (3an)
Me
O
NH
O
1
Hexane: EtOAc (1:5); R
8.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.7 Hz,
H), 3.34 (t, J = 11.2 Hz, 1H), 2.23 (s, 3H), 1.88 (d, J = 6.8 Hz, 4H), 1.46 (ddd, J =
f 3
=0.4; H NMR (400 MHz, CDCl ) δ11.76 (s, 1H), 8.73 (d, J
=
1
3
2
2
1
3
8.2, 20.3, 12.3 Hz, 4H), 1.32 – 1.20 (m, 2H);
3
C NMR (101 MHz, CDCl ) δ
08.62, 169.50, 141.41, 134.73, 130.49, 122.28, 121.09, 120.74, 46.67, 29.85, 25.89,
+
5.82, 25.58. ESI-MS [M+H] 246.1.
4
N-(2-iso-Butyrylphenyl)acetamide (3ao)
Me
O
NH
O
Me
Me
1
Hexane: EtOAc (1:5); R
f 3
=0.4; H NMR (400 MHz, CDCl ) δ 11.74 (s, 1H), 8.74 (dd,
J = 8.5, 0.8 Hz, 1H), 7.93 (dd, J = 8.1, 1.3 Hz, 1H), 7.64 – 7.47 (m, 1H), 7.18 – 7.03
1
3
(
m, 1H), 3.75 – 3.57 (m, 1H), 2.24 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H);
C NMR (101
MHz, CDCl
3
) δ209.28, 169.53, 141.45, 134.81, 130.55, 122.31, 121.11, 120.63, 36.26,
+
2
5.58, 19.52. ESI-MS [M+H] 206.1.
8
N-(2-Butyrylphenyl)acetamide (3ap)
S10

Supporting Information
Me
NH
O
O
Me
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ 11.76 (s, 1H), 8.73 (d, J
=
8.4 Hz, 1H), 7.92 (dd, J = 8.0, 1.3 Hz, 1H), 7.61 – 7.48 (m, 1H), 7.15 – 7.03 (m,
1H), 3.00 (t, J = 7.3 Hz, 2H), 2.24 (s, 3H), 1.76 (dd, J = 14.7, 7.4 Hz, 2H), 1.02 (t, J
1
3
=
7.4 Hz, 3H);
C NMR (101 MHz, CDCl
3
) δ205.11, 169.60, 140.95, 134.85,
+
1
30.74, 122.30, 121.57, 120.83, 41.88, 25.56, 17.98, 13.80. ESI-MS [M+H] 206.1.
N-(5-Chloro-2-(4-chlorobenzoyl)phenyl)acetamide (3bl)
Me
O
NH
O
Cl
Cl
1
Hexane: EtOAc (1:5); R
f 3
=0.4; H NMR (400 MHz, CDCl ) δ10.87 (s, 1H), 8.75 (d, J
=
2.0 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.50 – 7.44 (m, 3H), 7.07 (dd, J = 8.5, 2.0 Hz,
1
3
1
1
3
H), 2.24 (s, 3H); C NMR (101 MHz, CDCl ) δ197.62, 169.28, 141.63, 141.03,
39.23, 136.65, 134.29, 131.15, 128.83, 122.36, 121.42, 120.79, 25.31. HRMS:
+
calcd. for C15
H
11 N O
2
Cl
2
Na : 330.0065, found 330.0059.
9
N-(4-Chloro-2-(4-chlorobenzoyl)phenyl)acetamide (3cl)
Me
O
NH
O
Cl
Cl
1
f 3
Hexane: EtOAc (1:3); R =0.4; H NMR (400 MHz, CDCl ) δ10.52 (s, 1H), 8.60 (d, J
1
3
=
9.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.56 – 7.45 (m, 4H), 2.23 (s, 3H);
C
S11

Supporting Information
NMR (101 MHz, CDCl
3
) δ195.92, 167.80, 139.06, 137.79, 135.35, 133.14, 131.21,
+
1
30.29, 127.94, 126.30, 123.31, 122.25, 24.19. ESI-MS [M+H] 308.1.
10
N-(4-Bromo-2-(4-chlorobenzoyl)phenyl)acetamide (3dl)
Me
O
NH
O
Cl
Br
1
Hexane: EtOAc (1:3); R
f 3
=0.4; H NMR (400 MHz, CDCl ) δ10.52 (s, 1H), 8.54 (d, J
=
9.0 Hz, 1H), 7.69 – 7.63 (m, 3H), 7.61 (d, J = 2.3 Hz, 1H), 7.53 – 7.49 (m, 2H),
1
3
2
1
3
.22 (s, 3H);
C NMR (101 MHz, CDCl
3
) δ196.94, 169.13, 139.65, 139.29, 137.06,
+
36.08, 135.12, 131.32, 128.97, 124.68, 123.51, 114.68, 25.24. ESI-MS [M+H]
52.0.
N-(2-(4-Chlorobenzoyl)-6-methylphenyl)acetamide(3el)
Me
O
NH
O
Me
Cl
1
Hexane: EtOAc (1:3); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ 7.98 (s, 1H), 7.89 – 7.82
(
m, 2H), 7.44 – 7.37 (m, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.3, 1.1 Hz, 1H),
1
3
6.90 (dd, J = 7.7, 1.1 Hz, 1H), 3.84 (s, 3H), 2.03 (s, 3H);
C NMR (101 MHz,
CDCl
3
) δ193.87, 168.20, 151.78, 138.94, 135.41, 133.54, 131.76, 128.38, 124.91,
+
1
23.78, 120.92, 112.84, 55.93, 23.58. HRMS: calcd. for C16
H
14NO
2
ClNa :
310.0611, found 310.0605.
N-(2-(4-Chlorobenzoyl)-6-methoxyphenyl)acetamide(3fl)
S12

Supporting Information
Me
NH
O
O
MeO
Cl
Hexane: EtOAc (1:3), R
f
=0.4; 1H NMR (400 MHz, CDCl
3
)δ 8.73 (s, 1H), 7.71 (d, J =
8
2
1
2
.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.24 – 7.20 (m, 1H), 7.06 (d, J = 5.0 Hz, 2H),
1
3
.12 (s, 3H), 1.85 (s, 3H).
3
C NMR (101 MHz, CDCl ) δ 196.39, 168.96, 139.61,
35.52, 135.39, 134.02, 133.89, 131.94, 128.58, 127.34, 125.30, 77.46, 77.14, 76.82,
+
3.18, 18.47. HRMS: calcd. for C16
H
14NO
3
ClNa : 326.0560, found 326.0557.
N-(2-(4-Chlorobenzoyl)-5-methylphenyl)acetamide (3gl)
Me
O
NH
O
Me
Cl
1
Hexane: EtOAc (1:2); R
f
=0.3; H NMR (400 MHz, CDCl
3
) δ 10.90 (s, 1H), 8.49 (s,
1
8
1
1
3
H), 7.64 – 7.58 (m, 2H), 7.51 – 7.43 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 6.89 (dd, J =
13
.0, 0.8 Hz, 1H), 2.43 (s, 3H), 2.23 (s, 3H);
C NMR (101 MHz, DMSO) δ194.06,
68.08, 142.33, 137.12, 136.27, 131.21, 131.10, 130.12, 128.71, 128.19, 124.67,
+
23.50, 23.13, 21.04. HRMS: calcd. for C16
10.0613.
H14NO
2
ClNa : 310.0611, found
N-(2-(4-Chlorobenzoyl)-4-methylphenyl)acetamide (3hl)
Me
O
NH
O
Cl
Me
1
Hexane: EtOAc (1:3), R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ10.74 (s, 1H), 8.61 (d, J
S13

Supporting Information
=
8.4 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.31 (s, 1H), 7.09 (t,
1
3
J = 7.6 Hz, 1H), 2.46 (s, 3H), 2.23 (s, 3H); C NMR (101 MHz, DMSO) δ199.36,
1
1
3
69.22, 143.53, 140.19, 135.82, 133.97, 133.29, 130.23, 129.04, 123.68, 122.05,
+
21.58, 25.27, 21.67. HRMS: calcd. for C16
10.0619.
H14NO
2
ClNa : 310.0611, found
N-(2-(4-Chlorobenzoyl)-5-methoxyphenyl)acetamide (3il)
Me
O
NH
O
MeO
Cl
1
Hexane: EtOAc (1:3); R
f
=0.3; H NMR (400 MHz, CDCl
3
) δ 11.48 (s, 1H), 8.40 (d, J
=
2.6 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.51 – 7.44 (m, 3H), 6.59 (dd, J = 8.9, 2.6 Hz,
1
3
1
1
5
H), 3.92 (s, 3H), 2.27 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ 197.62, 169.66,
64.84, 143.91, 138.10, 137.75, 135.93, 130.78, 128.59, 115.21, 109.11, 104.88,
+
5.71, 25.57. HRMS: calcd. for C16
H
14NO
3
ClNa : 326.0560, found 326.0552.
N-(2-(4-Chlorobenzoyl)-4-methoxyphenyl)acetamide (3jl)
Me
O
NH O
Cl
OMe
1
Hexane: EtOAc (1:3); R
f 3
=0.3; H NMR (400 MHz, CDCl ) δ 10.20 (s, 1H), 8.46 (d, J
=
9.1 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 9.1,
1
3
3.0 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H), 3.77 (s, 3H), 2.20 (s, 3H);
C NMR (101
MHz, DMSO) δ193.21, 167.89, 155.79, 137.38, 135.64, 132.73, 131.27, 131.10,
+
128.22, 125.77, 117.13, 113.84, 55.42, 22.57. HRMS: calcd. for C16
H14NO
3
ClNa :
3
26.0560, found 326.0563.
S14

Supporting Information
N-(2-(4-Chlorobenzoyl)naphthalen-1-yl)acetamide (3kl)
Me
O
NH
O
Cl
1
Hexane: EtOAc (1:3); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ 8.91 (s, 1H), 7.95 (dd, J
=
17.6, 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 3H), 7.59 (dd, J = 18.0, 6.1 Hz, 2H), 7.53 (s,
1
3
2
1
1
3
H), 7.46 – 7.42 (m, 2H), 2.19 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ196.86,
69.80, 139.72, 135.35, 134.84, 131.92, 131.36, 130.38, 128.83, 128.65, 128.07,
+
27.77, 126.88, 125.70, 124.88, 124.18, 23.54. HRMS: calcd. for C19
46.0611, found 346.0603.
H14NO
2
ClNa :
(
2-Aminopyridin-3-yl)(4-chlorophenyl)methanone (3ll)
NH2
O
N
Cl
1
f 3
Hexane: EtOAc (1:5); R =0.4; H NMR (400 MHz, CDCl ) δ9.07 (s, 1H), 8.38 (d, J =
8.4 Hz, 1H), 8.19 (s, 1H), 7.91 – 7.84 (m, 2H), 7.81 – 7.70 (m, 1H), 7.45 (d, J = 8.6
1
3
Hz, 2H), 7.06 (dd, J = 6.9, 5.3 Hz, 1H); C NMR (101 MHz, CDCl
3
) δ 164.84,
151.49, 147.82, 138.58, 132.71, 129.07, 128.75 120.09, 114.38. HRMS: calcd. for
+
C
12 9 2
H N OClNa : 255.0301, found 255.0299.
Methyl 4-acetamido-3-(4-chlorobenzoyl)benzoate (3ml)
Me
O
NH O
Cl
COOMe
S15

Supporting Information
1
Hexane: EtOAc (1:5); R
f
=0.4; H NMR (400 MHz, CDCl
3
) δ 10.86 (s, 1H), 8.69 (d, J
=
9.4 Hz, 2H), 8.17 – 8.12 (m, 3H), 7.59 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H),
1
3
3
1
5
.81 (s, 2H), 2.19 (s, 3H);
3
C NMR (101 MHz, CDCl ) δ196.86, 168.40, 143.23,
38.54, 135.35, 134.41, 133.70, 130.31, 127.95, 127.65, 122.67, 121.09, 120.00,
+
1.30, 24.40. HRMS: calcd. for C17
H
14NO
4
ClNa : 354.0509, found 354.0502.
Ethyl 4-acetamido-3-(4-chlorobenzoyl)benzoate (3nl)
Me
O
NH O
Cl
COOEt
1
Hexane: EtOAc (1:5), R
f 3
=0.4; H NMR (400 MHz, CDCl ) δ10.93 (s, 1H), 8.76 (d, J
=
9.4 Hz, 1H), 8.23 (s, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (s,
1
3
1
H), 4.36 (d, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H);
C NMR (101
MHz, CDCl
3
) δ 196.85, 168.36, 143.13, 138.52, 135.36, 134.31, 133.69, 130.32,
127.91, 127.53, 123.05, 121.10, 119.93, 60.26, 24.38, 13.28. HRMS: calcd. for
+
C
18 4
H16NO ClNa : 368.0666, found 368.0658.
1
1
N-(2-(4-Chlorobenzoyl)phenyl)benzamide (5)
Ph
O
NH O
Cl
1
Hexane: EtOAc (1:5); R
8.4 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.57 – 7.52 (m, 5H),
.46 (d, J = 7.4 Hz, 1H), 7.36 (dd, J = 7.6, 1.2 Hz, 1H), 7.30 (d, J = 4.4 Hz, 1H), 7.26
f 3
=0.4; H NMR (400 MHz, CDCl ) δ11.83 (s, 1H), 8.68 (d, J
=
7
13
(
d, J = 7.3 Hz, 1H);
3
C NMR (101 MHz, CDCl ) δ 198.97, 190.95, 141.06, 138.99,
S16

Supporting Information
137.00, 134.87, 134.49, 133.70, 132.16, 130.92, 129.47, 128.88, 127.40, 122.86,
+
1
22.31, 121.64. ESI-MS [M+H] 336.1
N-(2-(4-Chlorobenzoyl)phenyl)isobutyramide (6)
iPr
O
NH O
Cl
1
Hexane: EtOAc (1:10); R
f
=0.3; H NMR (400 MHz, CDCl
3
) δ 10.87 (s, 1H), 8.69 (d,
J = 8.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.58 (s, 1H), 7.55 – 7.53 (m, 1H), 7.47 (d, J
1
3
=
8.5 Hz, 2H), 7.08 (s, 1H), 1.30 (s, 3H), 1.28 (s, 2H);
3
C NMR (101 MHz, CDCl )
δ198.54, 176.56, 140.93, 138.94, 137.03, 134.63, 133.39, 131.40, 128.99, 128.92,
+
1
21.98, 121.64, 37.09, 19.50. HRMS: calcd. for C17
24.0763.
H
16NO
2
ClNa : 324.0767, found
3
N-(2-(4-Chlorobenzoyl)phenyl)pivalamide (7)
tBu
O
NH O
Cl
Hexane: EtOAc (1:10); R
f
=0.3; NMR (400 MHz, CDCl
3
) δ 11.12 (s, 1H), 8.73 (s, 1H),
8
7
1
4
.71 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.48 (s, 1H),
1
3
3
.10 – 7.07 (m, 1H), 1.35 (s, 9H). C NMR (101 MHz, CDCl ) δ 198.50, 177.74,
41.19, 138.84, 137.09, 134.65, 133.51, 131.29, 128.90, 128.65, 121.92, 121.55,
+
0.18, 27.79. HRMS: calcd. for C18
H
18NO
2
ClNa : 338.0924, found 338.0918.
S17

Supporting Information
1
13
5
.
H and C NMR, and HRMS spectra
Me
O
NH
O
3ab
S18

Supporting Information
Me
NH
O
O
3ab
S19

Supporting Information
Me
NH
O
O
3ac
S20

Supporting Information
Me
NH
O
O
3ac
S21

Supporting Information
Me
NH
O
O
3
ad
S22

Supporting Information
Me
NH
O
O
3
ad
S23

Supporting Information
Me
NH
O
O
Me
3ae
S24

Supporting Information
Me
NH
O
O
Me
3ae
S25

Supporting Information
Me
NH
O
O
OMe
3af
S26

Supporting Information
Me
NH
O
O
OMe
3af
S27

Supporting Information
Me
NH
O
O
OMe
3ag
S28

Supporting Information
Me
NH
O
O
OMe
3ag
S29

Supporting Information
Me
NH
O
O
OMe
OMe
3
ah
S30