Pd-catalyzed C-H lactonization for expedient synthesis of biaryl lactones and total synthesis of cannabinol

Article abstract of DOI:10.1021/ol400877q

A practical Pd(II)/Pd(IV)-catalyzed carboxyl-directed C-H activation/C-O cyclization to construct biaryl lactones has been developed. The synthetic utility of this new reaction was demonstrated in an atom-economical and operationally convenient total synthesis of the natural product cannabinol from commercially available starting materials, with the newly developed method used for two key steps.

Full text of DOI:10.1021/ol400877q

Supporting Information
For
Pd-Catalyzed C–H Lactonization for Expedient Synthesis of Biaryl
Lactones and Total Synthesis of Cannabinol
Yan Li, Yan-Jun Ding, Jian-Yong Wang, Yi-Ming Su and Xi-Sheng Wang*
Department of Chemistry, University of Science and Technology of China, 96
Jinzhai Road, Hefei, Anhui 230026, China
Tabel of Contents
General Information
S2
S3
S3
S3
S4
S4
S5
S5
S6
S6
S7
S7
S8
S8
Tables of the Optimization of Reaction Conditions
Solvent Screening without Ligand
Oxidant Screening without Ligand
Base Screening without Ligand
Ligand Screening
Solvent Screening
Base Screening
Ligand Screening
Temperature Screening
Amount of Reagents Screening
Oxidant Screening
Experimental Procedures
General Procedure for Preparation of diarylcarboxylic acid
General Procedure of Pd(OAc)
Discussion of Mechanism
References
2
-Catalyzed C-H Activation/C-O Cyclization S14
S25
S26
S28
1
13
H and C NMR Spectra
S1

General Information:
Solvents were obtained from Sinopharm and used directly without further
1
purification. NMR spectra were recorded on Bruker-400 (400 MHz for H; 100 MHz
for 13C) instruments internally referenced to SiMe
spectra were recorded on P-SIMS-Gly of Bruker Daltonics Inc. using ESI-TOF
electrospray ionization-time of flight). Iodobenzene diacetate and N-acetyl amino
signal. High resolution mass
4
(
acid were obtained from Darui Finechamical and used as received. Potassium acetate
was purchased from Sinopharm and used as received. Palladium acetate was
purchased from Strem.
S2

Table 1. Solvent Screening without Liganda,b
1a
2a
t
n
a
1a
b
Table 2. Oxidant Screening without Liganda,b
S3

Table 3. Base Screening without Liganda,b
Table 4. Ligand Screening Ia,b
S4

Table 5. Solvent Screening with Liganda,b
Table 6. Base Screening with Ligand a,b
2
2
3
3
2
3
2
3
2
3
2
3
2
2
3
4
2
2
4
3
3
4
2
2
a
2
2
b
S5

Table 7. Ligand Screening IIa,b
Table 8. Temperature Screening with Ligand a,b
O
Pd(OAc) (10 mol%)
KOAc (2.0 equiv.)
O
OH
H
PhI(OAc) (1.5 equiv.)
O
Ac-Leu-OH (0.3 equiv.)
t-BuOH, T, 24h
entry
1
Temperature(°C)
yield (%)
19
entry
Temperature(°C)
yield (%)
40
50
7
8
100
110
120
130
140
67
67
70
69
65
2
3
41
74
60
70
80
90
9
4
5
6
77
80
78
10
11
a
Unless otherwise noted, the reaction conditions were as follows:
(0.2 mmol), Pd(OAc) (0.02
mmol, 10 mol%), PhI(OAc) (0.3 mmol, 1.5 equiv.), KOAc (0.4 mmol, 2.0 equiv.), Ac-Leu-OH (0.06
mmol, 0.3 equiv.), t-BuOH (2 mL), Temperature, 24 h. b Isolated yield.
S6

Table 9. Amount of Reagents Screeninga,b
Table 10. Oxidant Screening with Ligand a,b
O
Pd(OAc) (5 mol%)
KOAc (2.0 equiv.)
O
OH
H
Oxidant (2.0 equiv.)
Ac-Gly-OH (0.15 equiv.)
BuOH (4 mL), 80 °C, 12h
O
entry
1
Oxidant
yield (%)
entry
Oxidant
yield (%)
BPO
Cu(OAc)
BQ
40
0
13
14
15
16
17
18
19
20
21
NCS
NBS
0
2
3
0
0
NIS
0
4
5
AgOAc
0
0
NFSI
trace
Ag CO
Ag O
NFTPT
DDQ
0
0
0
0
0
6
7
0
CAN
15
CuCl
8
9
K S O
3
0
V O
( -BuO)
(NH ) S O
t
1
0
1
BzOO Bu
trace
9
22
23
TEMPO
FeCl
0
0
1
PhI(TFA)
Oxone
12
trace
24
Ce(SO )
trace
a
Unless otherwise noted, the reaction conditions were as follows:
(0.2 mmol), Pd(OAc) (0.02
mmol, 5 mol%), PhI(OAc) (0.4 mmol, 2.0 equiv.), KOAc (0.4 mmol, 2.0 equiv.), Ac-Leu-OH (0.06
mmol, 0.15 equiv.), -BuOH (4 mL), 80 °C, 12 h.
S7

Preparation of Substrates
Substrate 1a was purchased from Accela ChemBio Co. Ltd. and used as received.
1
2
1
3
2
1
1
2
2
4
4
Substrates 1b , 1c , 1g , 1h , 1j , 1p , 1q ,1s , 1t , 1v , 1w were synthesized through
the known methods. The other diarylcarboxylic acids were prepared via Suzuki cross
coupling.
General procedure of synthesis of diarylcarboxylic acid (1d-1f, 1k-1n, 1r, 1u,
1
ab)2
Methyl 2-iodobenzoate (2.5 mL, 17 mmol) was added to arylboronic acid (22 mmol)
and Na CO (3.6 g, 34 mmol) dissolved in THF (68 mL) and water (34 mL) mixed
solvents. The reaction mixture was degassed three times and charged with Argon,
2
3
after which PdCl
2
(PPh
3
2
) (8 mol%, 1 g, 1.4 mmol) was added. The reaction mixture
o
was heated to 60 C overnight. The resulting reaction mixture was cooled to room
temperature and added to water, the product was extracted with dichloromethane three
times. The combined organic phases were dried with Na
2
SO and the solvent was
4
evaporated via vacuo. The product was purified by column chromatography to give a
colourless liquid. The methyl 2-arylbenzoate was dissolved in a solution of 3.4 g
o
NaOH in 50 mL H
2
O and 50 mL MeOH and stirred at 50 C for 6 h. MeOH was
removed under vacuum and the reation mixture was diluted with H
with Et O. The aqueous phase was acidified with 3N HCl, then extracted with Et
three times. The combined organic phase was washed with H O and brine, dried over
Na SO , filtered and the filtration was evaporated under reduced pressure to give the
desired product as a solid.
-(4-fluoro)phenylbenzoic acid (1d):
2
O, and washed
2
2
O
2
2
4
2
1H NMR (400 MHz, CDCl
3
) δ 8.06 – 7.92 (m, 1H), 7.56 (td, J = 7.6, 1.2 Hz,
CO H
2
1
H), 7.43 (td, J = 7.7, 1.1 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.31 – 7.26 (m,
13
2
3
H), 7.12 – 7.02 (m, 2H). C NMR (101 MHz, CDCl ) δ 173.5, 162.5 (d, J =
F
1
d
2
46.3 Hz), 142.7, 137.2 (d, J = 3.3 Hz), 132.4, 131.4, 131.0, 130.2 (d, J = 8.`
S8

Hz), 129.3, 127.5, 115.1 (d, J = 21.5 Hz). HRMS (EI-TOF) calcd. for C13
H
9
O
F (M+):
2
2
2
16.0587, found: 216.0580.
-(4-chloro)phenylbenzoic acid (1e):
1H NMR (400 MHz, CDCl
) δ 7.91 (dd, J = 7.8, 1.2 Hz, 1H),
3
CO H
2
7.50 (td, J = 7.6, 1.4 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.31
–
7.27 (m, 2H), 7.25 (dd, J = 7.7, 1.0 Hz, 1H), 7.21 – 7.15 (m,
Cl
1
e
13
2
H). C NMR (101 MHz, CDCl
3
) δ 172.9, 142.5, 139.7, 133.7,
1
32.5, 131.3, 131.1, 130.0, 129.1, 128.4, 127.7. HRMS (ESI) calcd. for C13
H
8
2
O Cl
-
(
[M-H] ) 2132.0207, found 231.0213.
2
-(4-bromo)phenylbenzoic acid (1f):
1H NMR (400 MHz, CDCl
.50 (td, J = 7.6, 1.4 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.38 (td, J =
.6, 1.3 Hz, 1H), 7.26 (dd, J = 7.7, 0.9 Hz, 1H), 7.16 – 7.10 (m,
3
) δ 7.91 (dd, J = 7.8, 1.1 Hz, 1H),
CO H
2
7
7
4
Br
1
3
1f
H). C NMR (101 MHz, CDCl ) δ 171.4, 142.5, 140.2, 132.4,
3
1
31.3, 131.2, 1311, 130.3, 129.0, 127.8, 121.9. HRMS (ESI) calcd. for C13
H
8
2
O Br
-
(
[M-H] ) 274.9702, found 274.9705.
2
-(3-methoxy)phenylbenzoic acid (1k):
1H NMR (400 MHz, CDCl
) δ 7.85 (dd, J = 7.8, 1.1 Hz, 1H), 7.47
3
CO H
2
(
td, J = 7.6, 1.4 Hz, 1H), 7.34 (td, J = 7.6, 1.3 Hz, 1H), 7.30 (dd, J =
.7, 0.9 Hz, 1H), 7.24 – 7.18 (m, 1H), 6.88 – 6.76 (m, 3H), 3.74 (s,
7
1
3
OMe 3H). C NMR (101 MHz, CDCl
3
) δ 173.3, 159.4, 143.2, 142.5,
1
k
132.1, 131.2, 130.7, 129.6, 129.2, 127.4, 121.2, 114.3, 113.2, 55.4.
-
HRMS (ESI) calcd. for C14
H
11
O ([M-H] ) 2227.0703, found 227.0707.
3
2
-(3-fluoro)phenylbenzoic acid (1l):
1H NMR (400 MHz, CDCl
td, J = 7.6, 1.3 Hz, 1H), 7.38 (td, J = 7.7, 1.2 Hz, 1H), 7.35 – 7.21
) δ 7.90 (dd, J = 7.8, 1.3 Hz, 1H), 7.50
3
CO H
2
(
1
3
(
m, 2H), 7.06 – 6.93 (m, 3H). C NMR (101 MHz, CDCl
3
) δ 172.9,
F
162.6 (d, J = 245.7 Hz), 143.4 (d, J = 8.0 Hz), 142.4 (d, J = 2.0 Hz),
1l
132.4, 131.2, 131.0, 129.6 (d, J = 8.4 Hz), 129.3, 127.8, 124.5 (d, J
S9

=
2.9 Hz), 115.7 (d, J = 22.1 Hz), 114.4 (d, J = 21.0 Hz). HRMS (ESI) calcd. for
-
C
13
H
8
O
2
F ([M-H] ) 215.0503, found 215.0509.
2
-(3-chloro)phenylbenzoic acid (1m):
1H NMR (400 MHz, CDCl
) δ 7.91 (dd, J = 7.8, 1.1 Hz, 1H), 7.50
3
CO H
2
(
(
td, J = 7.6, 1.4 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.29 – 7.20
1
3
m, 4H), 7.12 (dt, J = 6.8, 1.7 Hz, 1H). C NMR (101 MHz, CDCl )
3
Cl
δ 172.8, 143.1, 142.3, 134.0, 132.5, 131.3, 131.1, 129.3, 129.1, 128.6,
27.9, 127.6, 127.0. HRMS (ESI) calcd. for C13
Cl ([M-H]-)
1m
1
H
8
O
2
2
2
31.0207, found 231.0213.
-(3-trifluoromethyl)phenylbenzoic acid (1n):
1H NMR (400 MHz, CDCl
.48 (m, 3H), 7.44 – 7.35 (m, 3H), 7.27 (dd, J = 7.6, 1.1 Hz, 1H).
13C NMR (101 MHz, CDCl
) δ 172.9, 142.4, 142.0, 132.7, 132.0 (d,
J = 1.1 Hz), 131.4, 131.3, 130.5 (q, J = 32.3 Hz), 129.0, 128.5,
) δ 7.94 (dd, J = 7.8, 1.2 Hz, 1H), 7.57 –
3
CO H
2
7
3
CF3
1
n
1
28.1, 125.5 (q, J = 3.8 Hz), 124.3 (d, J = 272.4 Hz), 124.2 (q, J =
-
3
2
.8 Hz). HRMS (ESI) calcd. for C14
-(2-fluoro)phenylbenzoic acid (1r):
1H NMR (400 MHz, CDCl
H
8
O
2
F
3
([M-H] ) 265.0471, found 265.0472.
3
) δ 7.98 (dd, J = 7.8, 1.1 Hz, 1H), 7.53
CO H
2
(
(
td, J = 7.6, 1.4 Hz, 1H), 7.39 (td, J = 7.7, 1.3 Hz, 1H), 7.31 – 7.19
m, 3H), 7.11 (td, J = 7.5, 1.2 Hz, 1H), 6.99 (ddd, J = 9.2, 8.2, 1.0 Hz,
F
1
r
13
1
H). C NMR (101 MHz, CDCl
3
) δ 172.3, 159.6 (d, J = 245.8 Hz),
1
8
37.3, 132.7, 131.8, 131.0, 130.5 (d, J = 3.4 Hz), 129.8 (d, J = 0.6 Hz), 129.5 (d, J =
.2 Hz), 129.0 (d, J = 15.9 Hz), 128.1, 124.1 (d, J = 3.6 Hz), 115.3 (d, J = 22.3 Hz).
-
HRMS (ESI) calcd. for C13
H
8
O
2
F ([M-H] ) 215.0503, found 215.0509.
2
-(thiophen-2-yl)benzoic acid (1u):
1H NMR (400 MHz, CDCl
) δ 7.82 (dd, J = 7.8, 1.0 Hz, 1H), 7.44
3
CO H
2
(
dtd, J = 8.9, 7.7, 1.3 Hz, 2H), 7.35 (ddd, J = 7.4, 7.2, 1.6 Hz, 1H),
7
.28 (dd, J = 5.0, 1.3 Hz, 1H), 7.00 (ddd, J = 8.5, 4.3, 2.4 Hz, 2H).
S
1u
13C NMR (101 MHz, CDCl
) δ 173.1, 141.7, 135.3, 132.0, 131.9,
3
S10

1
2
2
30.6, 130.3, 127.9, 127.4, 126.9, 126.2. HRMS (ESI) calcd. for C11
03.0161, found 203.0157.
H
7
O
S ([M-H]-)
2
-(o-tolyl)-3-methylbenzoic acid (1ab):
1H NMR (400 MHz, CDCl
) δ 7.84 (d, J = 7.7 Hz, 1H), 7.45 (d, J =
3
CO H
2
7
.5 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.28 – 7.15 (m, 3H), 6.95 (d, J
=
7.3 Hz, 1H), 1.97 (s, 3H), 1.96 (s, 3H). 13C NMR (100 MHz,
) δ 171.7, 142.5, 139.7, 137.7, 135.7, 134.3, 129.8, 129.5,
1ab
CDCl
3
1
28.4, 128.2, 127.4, 127.2, 125.7, 20.4, 19.8. HRMS (EI-TOF) calcd. for C15
H
14
O
2
+
(
M ): 226.0994, found: 224.0988.
General procedure of synthesis of diarylcarboxylic acid (1i, 1o)5
To a solution of 2-iodobenzoic acid (2.48 g, 10 mmol), K CO (2.76 g, 20 mmol),
2
3
TBAI (369 mg, 1 mmol) in THF (60 mL) was added PMBCl (1.63 mL, 12 mmol).
The mixture was heated to reflux for 6 h. After cooling to room temperature, filtered
off the insolubles, the filtrate was diluted with water, and extracted with
dichloromethane for 3 times, the combined organic extracts was washed with Na
sat.) and brine, dried over Na SO . The product was purified by column
chromatography after removed the solvent. p-methoxybenzyl 2-iodobenzoate was
added to arylboronic acid (12 mmol) and Na CO (1.8 g, 17 mmol) dissolved in THF
34 mL) and water (17 mL) mixed solvents. The reaction mixture was degassed three
2
S
2
O
3
(
2
4
2
3
(
times and charged with Argon, after which PdCl
2
(PPh
3
2
) (8 mol%, 0.5 g, 0.7 mmol)
o
was added. The reaction mixture was heated to 60 C overnight. The resulting reaction
mixture was cooled to room temperature and added to water, the product was
extracted with dichloromethane three times. The combined organic phases were dried
with Na
column chromatography to give a colourless liquid. The p-methoxybenzyl
-arylbenzoate was dissolved in 35 mL dichloromethane, and trifluoroacetic acid (2.8
2
SO
4
and the solvent was evaporated via vacuo. The product was purified by
2
mL, 35 mmol) was added and the solution was stirred at room temperature for 1 h
after which time the reaction mixture was evaporated to dryness. The residue was
purified by column chromatography.
S11

2
-(4-ethoxycabonyl)phenylbenzoic acid (1i):
1H NMR (400 MHz, CDCl
J = 7.8, 1.1 Hz, 1H), 7.57 (td, J = 7.6, 1.4 Hz, 1H), 7.45 (td, J
7.7, 1.3 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.34 (dd, J = 7.7, 0.9
Hz, 1H), 4.39 (q, J = 7.1 Hz, 1H), 1.40 (t, J = 7.1 Hz, 1H).
13C NMR (101 MHz, CDCl
) δ 172.8, 166.7, 146.0, 142.8, 132.4, 131.2, 131.1, 129.5,
29.4, 129.2 (2C), 128.7, 127.9, 61.1, 14.5. HRMS (EI-TOF) calcd. for C16
(M+):
3
) δ 8.13 – 8.02 (m, 2H), 7.99 (dd,
CO H
2
=
CO Et
2
1i
3
1
2
2
H
4
O
4
70.0892, found: 270.0896.
-(3-methoxycarbonyl)phenylbenzoic acid (1o):
1H NMR (400 MHz, CDCl
) δ 8.06 – 7.96 (m, 3H), 7.58 (td, J =
CO H
3
2
7
1
1
.6, 1.3 Hz, 1H), 7.52 – 7.40 (m, 3H), 7.35 (dd, J = 7.6, 0.7 Hz,
1
3
H), 3.90 (s, 1H). C NMR (101 MHz, CDCl ) δ 172.6, 167.2,
3
CO Me
2
42.8, 141.6, 133.3, 132.5, 131.4, 131.2, 130.1, 129.6, 129.1,
1
o
+
1
28.6, 128.1, 127.8, 52.3. HRMS (EI-TOF) calcd. for C15
H
12
O
4
(M ): 256.0736,
found: 256.0742.
General procedure of synthesis of diarylcarboxylic acid (1z, 1aa)6
To a solution of 2-hydroxyarylcarboxylic acid (11.5 mmol), Cs CO
mmol) in 100 mL DMF was added iodomethane (0.75 mL, 12 mmol) stirred at room
temperature for 1.5 h, taken up in EtOAc, and washed with H O, NaHCO (sat.), and
2
3
(1.87 g, 5.7
2
3
brine, dried over Na
2
SO
4
, and concentrated in vacuo. The crude methyl ester was
o
dissolved in dichloromethane (100 mL) under argon, cooled to -78 C, and
treatmented with Et
3
N (3.2 mL, 23 mmol) was followed by the dropwise addition of
o
Tf
2
O (2.13 mL, 12.6 mmol). The mixture was stirred at -78 C for 30 min and then
warmed to room temperature overnight. The mixture was diluted with ether and washed
with 1N HCl. The aqueous layer was back-extracted with additional ether, and the combined
organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The product
was purified by column chromatography. 2-methoxycarbonylaryl triflate was added to
phenylboronic acid (1.2 g, 10 mmol) and K
3
PO (2.5 g, 12 mmol) dissolved in
4
dioxane (25 mL). The reaction mixture was degassed three times and charged with
S12

Argon, after which Pd (PPh
3
4
) (5 mol%, 290 mg, 0.25 mmol) was added. The reaction
o
mixture was heated to 110 C for 4 h. The resulting reaction mixture was cooled to
room temperature and added to water, the product was extracted with
dichloromethane three times. The combined organic phases were dried with Na
2
SO
4
and the solvent was evaporated via vacuo. The product was purified by column
chromatography to give a colourless liquid. The methyl 2-arylbenzoate was dissolved
o
in a solution of 1 g NaOH in 15 mL H
2
O and 15 mL MeOH and stirred at 50 C for 6
h. MeOH was removed under vacuum and the reation mixture was diluted with H
and washed with Et O. The aqueous phase was acidified with 3N HCl, then extracted
with Et O three times. The combined organic phase was washed with H O and brine,
dried over Na SO , filtered and the filtration was evaporated under reduced pressure
to give the desired product as a solid.
2
O,
2
2
2
2
4
2
-phenyl-5-chlorobenzoic acid (1z):
1H NMR (400 MHz, CDCl
J = 8.3, 2.3 Hz, 1H), 7.35 – 7.26 (m, 3H), 7.26 – 7.19 (m, 3H).
13C NMR (101 MHz, CDCl
) δ 171.8, 142.0, 140.0 133.5, 132.6,
32.2, 130.7 (2C), 128.5, 128.3, 127.9. HRMS (ESI) calcd. for
Cl ([M-H] ) 231.0207, found 231.0211.
3
) δ 7.85 (d, J = 2.3 Hz, 1H), 7.45 (dd,
Cl
CO H
2
3
1z
1
-
C
13
H
8
O
2
3
-phenyl-2-naphthioc acid (1aa):
1H NMR (400 MHz, CDCl
3
) δ 8.48 (s, 1H), 7.89 (d, J = 8.0 Hz,
CO H
2
1
H), 7.80 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.54 (ddd, J = 8.2,
.0, 1.3 Hz, 1H), 7.49 (ddd, J = 8.0, 7.0, 1.3 Hz, 1H), 7.39 –
7
1
aa
7
.28 (m, 5H). 13C NMR (101 MHz, CDCl
) δ 173.8, 141.3, 139.3, 134.9,
3
1
32.6, 131.6, 130.4, 128.9, 128.8, 128.2, 127.9, 127.7, 127.3, 127.0. HRMS (ESI) calcd. for
-
C
17
H
11
O
2
([M-H] ) 247.0754, found 247.0758.
General procedure of synthesis of diarylcarboxylic acid (1x, 1y)7
-Bromo-arylcarboxylic acid (4.3 g, 20 mmol), phenylboronic acid (2.9 g, 24
mmol), and LiOH·H O (1.85 g, 44 mmol). 60 mL NMP and 60 mL H O was added
followed by Pd (dba)
2
2
2
2
3
(275 mg, 0.3 mmol) under a nitrogen blanket, and the reaction
S13

o
mixture was heated to 65 C for 24 h. After cool to room temperature, the reaction
mixture was acidified to pH=3 with 3N HCl, and extracted with diethyl ether three
times. The combined organic layers were dried over Na
2
SO and the solvent was
4
removed under reduced pressure. The product was purified by column
chromatography.
2
-phenyl-4-methylbenzoic acid (1x):
1H NMR (400 MHz, CDCl
.32 (m, 5H), 7.25 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 2.46 (s, 1H).
13C NMR (101 MHz, CDCl
) δ 173.0, 143.8, 142.9, 141.4, 132.2,
31.2, 128.6, 128.1, 128.0, 127.4, 126.4, 21.6. HRMS (ESI) calcd.
3
) δ 7.91 (d, J = 8.0 Hz, 0H), 7.45 –
CO H
2
7
3
1
x
1
-
for C14
H
11
O ([M-H] ) 211.0754, found 211.0758.
2
2
-phenyl-3-methylbenzoic acid (1y):
1H NMR (400 MHz, CDCl
.5 Hz, 1H), 7.44 – 7.31 (m, 4H), 7.18 (dd, J = 5.1, 2.9 Hz, 2H), 2.11
3
) δ 7.81 (d, J = 7.8 Hz, 1H), 7.46 (d, J =
CO H
2
7
1
3
(
s, 3H). C NMR (101 MHz, CDCl
3
) δ 172.4, 142.7, 140.1, 137.7,
1y
1
34.1, 130.2, 128.7, 128.1 (2C), 127.2, 127.1, 20.9. HRMS (ESI)
-
calcd. for C14
H
11
O
2
([M-H] ) 211.0754, found 211.0759.
General Procedure of Pd(OAc)
Activation/C-O Cyclization:
2
-Catalyzed Carboxyl-Directed C-H
In a 35 mL sealed tube, 4.0 mL t-BuOH was added to a mixture of
diaryl-carboxylic acid 1 (0.2 mmol, 1.0 equiv.), Pd(OAc) (2.2 mg, 0.01 mmol, 5
mol%), N-acetylglycin (3.5 mg, 0.03 mmol, 0.15 equiv.), KOAc (39.2 mg, 0.4 mmol,
2
2
.0 equiv.), PhI(OAc)
2
(128.8 mg, 2.0 equiv.) under air. The tube was sealed with a
o
Teflon lined cap and the reaction mixture was stirred at 80 C for 12 h. After cooling
to room temperature, the mixture was concentrated under vacuum and the residue was
purified by column chromatography on silica gel with a gradient eluent of petroleum
ether, ethyl acetate and dichloromethane to give the corresponding products.
S14

1
2
a: H NMR (400 MHz, CDCl
3
) δ 8.42 (ddd, J = 8.0, 1.4, 0.5 Hz,
O
1
H), 8.14 (d, J = 8.1 Hz 1H), 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 7.84
O
(
ddd, J = 8.1, 7.3, 1.4 Hz, 1H), 7.60 (ddd, J = 8.3, 7.4, 1.1 Hz, 1H),
1
3
7
.52 – 7.46 (m, 1H), 7.41 – 7.32 (m, 2H). C NMR (101 MHz,
) δ 161.2, 151.4, 134.9, 134.8, 130.6, 130.5, 129.0, 124.6,
2
a
CDCl
3
1
1
22.8, 121.8, 121.3, 118.1, 117.8. HRMS (APCI) calcd. for C13
H
9
O
([M+H]+):
2
97.0597, found: 197.0592.
1
2
b: H NMR (400 MHz, CDCl
3
) δ 8.39 (dd, J = 8.0, 1.0 Hz, 1H),
O
8
7
1
.09 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.81 (ddd, J =
O
.9, 7.7, 1.4 Hz, 1H), 7.55 (ddd, J = 7.6, 7.6, 1.1 Hz, 1H), 7.18 (s,
1
3
H), 7.15 (d, J = 8.1 Hz, 1H), 2.46 (s, 3H). C NMR (101 MHz,
) δ 161.5, 151.4, 141.4, 135.1, 134.9, 130.7, 128.5, 125.8,
2
b
CDCl
3
1
2
22.6, 121.6, 121.0, 118.0, 115.6, 21.6. HRMS (APCI) calcd. for C14
H
11
O
([M+H]+):
2
11.0754, found: 211.0747.
1
2
c: H NMR (400 MHz, CDCl
3
) δ 8.36 (ddd, J = 8.0, 1.4, 0.5
O
Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H),
.78 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H), 7.50 (ddd, J = 8.2, 7.3, 1.1
Hz, 1H), 6.92 (dd, J = 8.8, 2.6 Hz, 1H), 6.87 (d, J = 2.5 Hz,
O
7
OMe
2c
1
3
1
H), 3.89 (s, 3H). C NMR (101 MHz, CDCl ) δ 161.5, 161.5,
3
152.6, 135.2, 134.9, 130.5, 127.7, 123.8, 121.1, 120.0, 112.4, 111.2, 101.7, 55.7.
+
HRMS (APCI) calcd. for C14
H
11
O
3
([M+H] ): 227.0703, found: 227.0697.
1
2
d: H NMR (400 MHz, CDCl
3
) δ 8.40 (dd, J = 8.0, 1.4 Hz, 1H),
O
O
8.09 – 8.01 (m, 2H), 7.84 (ddd, J = 8.1, 7.4, 1.4 Hz, 1H), 7.59
1
3
(
ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.13 – 7.05 (m, 2H). C NMR
101 MHz, CDCl ) δ 163.6 (d, J = 251.3 Hz), 160.9, 152.3 (d, J =
2.3 Hz), 135.2, 134.4, 130.8, 128.9, 124.5 (d, J = 9.9 Hz), 121.6,
F
(
3
2
d
1
1
20.6 (d, J = 0.9 Hz), 114.7 (d, J = 3.2 Hz), 112.5 (d, J = 22.4 Hz), 105.2 (d, J = 25.3
+
Hz). HRMS (EI-TOF) calcd. for C13
H
7
O
2
F (M ): 214.0430, found: 214.0427.
S15

1
2
e: H NMR (400 MHz, CDCl
3
) δ 8.40 (ddd, J = 8.0, 1.4, 0.5 Hz,
H), 8.11 – 8.05 (m, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.84 (ddd, J
8.1, 7.3, 1.4 Hz, 1H), 7.61 (ddd, J = 8.3, 7.4, 1.1 Hz, 1H), 7.39
O
1
O
=
1
3
Cl (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.5, 2.1 Hz, 1H). C NMR
101 MHz, CDCl ) δ 160.6, 151.6, 136.0, 135.2, 134.1, 130.8,
2e
(
3
1
29.3, 125.1, 123.9, 121.8, 121.0, 118.0, 116.8. HRMS (EI-TOF) calcd. for
+
C
13
H
7
O
2
Cl (M ): 230.0135, found: 230.0130.
1
2
f: H NMR (400 MHz, CDCl
3
) δ 8.40 (d, J = 7.9 Hz, 1H), 8.08
O
O
(d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.84 (ddd, J = 7.7,
7
.7, 1.1 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 1.8 Hz,
Br
13
1
H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H). C NMR (101 MHz, CDCl
3
)
2
f
δ 160.5, 151.6, 135.2, 134.0, 130.8, 129.4, 127.9, 124.0, 123.8,
+
1
21.7, 121.1, 120.9, 117.2. HRMS (APCI) calcd. for C13
H
8
O
2
Br ([M+H] ): 274.9702,
found: 274.9695.
1
2
g: H NMR (400 MHz, CDCl
3
) δ 8.45 (dd, J = 7.9, 1.0 Hz,
H), 8.19 (t, J = 8.1 Hz, 2H), 7.90 (ddd, J = 7.7, 7.4, 1.4 Hz,
H), 7.69 (ddd, J = 7.7, 7.6, 1.0 Hz, 1H), 7.64 (s, 1H), 7.60 (dd,
O
O
1
1
1
3
CF3 J = 8.3, 1.1 Hz, 1H). C NMR (101 MHz, CDCl
3
) δ 160.4,
2g
1
51.2, 135.3, 133.6, 132.4 (q, J = 33.5 Hz), 131.0, 130.3,
1
23.8, 123.4, (q, J = 272.6 Hz),122.3, 121.9, 121.2 (q, J = 3.8 Hz), 115.4 (q, J = 4.0
+
Hz). HRMS (EI-TOF) calcd. for C14
H
7
O
2
F
3
(M ): 264.0398, found: 264.0349.
1
2
h: H NMR (400 MHz, CDCl
3
) δ 8.44 (dd, J = 8.0, 1.0 Hz,
O
1H), 8.17 (t, J = 8.5 Hz, 2H), 7.95 – 7.85 (m, 3H), 7.67 (ddd, J
O
1
3
=
7.6, 7.5, 1.1 Hz,1H), 2.67 (s, 3H). C NMR (101 MHz,
CDCl ) δ 196.6, 160.7, 151.2, 138.5, 135.2, 133.7, 130.9, 130.2,
3
O
124.0, 123.3, 122.5, 122.1, 121.9, 118.0, 26.8. HRMS (EI-TOF)
2
h
+
calcd. for C15
H
10
O
3
(M ): 238.0630, found: 238.0636.
1
2
i: H NMR (400 MHz, CDCl
3
) δ 8.38 (dd, J = 7.9, 1.0 Hz,
O
O
1H), 8.13 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.95
S16
CO2Et
2
i

(
td, J = 4.3, 1.6 Hz, 2H), 7.85 (td, J = 7.8, 1.4 Hz, 1H), 7.63 (ddd, J = 7.6, 7.6, 1.0 Hz,
1
3
1
1
1
2
H), 4.42 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ
3
65.3, 160.6, 151.0, 135.1, 133.8, 132.3, 130.8, 130.0, 125.3, 122.9, 122.4, 121.8,
+
19.0, 61.6, 14.4. HRMS (EI-TOF) calcd. for C16
H
12
O
4
(M ): 268.0736, found:
68.0736.
1
2
j: H NMR (400 MHz, CDCl
3
) δ 8.43 – 8.36 (m, 1H), 8.11 (dd, J
O
=
–
11.2, 3.9 Hz, 1H), 7.87 – 7.78 (m, 2H), 7.62 – 7.53 (m, 1H), 7.31
O
1
3
7.22 (m, 2H), 2.46 (d, J = 3.2 Hz, 3H). C NMR (101 MHz,
) δ 161.4, 149.4, 134.8, 134.7, 134.1, 131.4, 130.6, 128.7,
122.8, 121.6, 121.3, 117.6, 117.5, 21.2. HRMS (EI-TOF) calcd. for
CDCl
3
2
j
+
C
14
H
10
O
2
(M ): 210.0681, found: 210.0684.
1
2
k: H NMR (400 MHz, CDCl
3
) δ 8.42 (ddd, J = 7.9, 1.4, 0.5 Hz,
O
O
1H), 8.08 (d, J = 8.1 Hz, 1H), 7.83 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H),
.60 (ddd, J = 8.3, 7.4, 1.1 Hz, 1H), 7.51 (d, J = 2.9 Hz, 1H), 7.32
7
13
(
d, J = 9.0 Hz, 1H), 7.06 (dd, J = 9.0, 2.9 Hz, 1H), 3.91 (s, 3H). C
OMe
NMR (101 MHz, CDCl ) δ 161.3, 156.4, 145.6, 134.7, 134.6,
3
2k
1
30.6, 129.0, 121.7, 121.4, 118.7, 118.2, 117.2, 106.3, 55.9. HRMS (APCI) calcd. for
+
C
14
H
11
O
3
([M+H] ): 227.0703, found: 227.0696.
1
2
l: H NMR (400 MHz, CDCl
3
) δ 8.40 (dd, J = 8.0, 0.9 Hz, 1H),
O
8
.01 (d, J = 8.1 Hz, 1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.69 (dd, J =
O
F
9.1, 2.9 Hz, 1H), 7.62 (ddd, J = 7.6, 7.5, 1.0 Hz, 1H), 7.33 (dd, J =
1
3
9
.0, 4.7 Hz, 1H), 7.18 (ddd, J = 9.0, 7.7, 2.9 Hz, 1H). C NMR
(101 MHz, CDCl ) δ 160.8, 159.4 (d, J = 243.4 Hz), 147.5 (d, J =
3
2
l
2
1
.1 Hz), 135.1, 134.0 (d, J = 2.7 Hz), 130.8, 129.7, 122.0, 121.3, 119.4 (d, J = 8.6 Hz),
19.3 (d, J = 8.3 Hz), 117. (d, J = 24.2 Hz), 108.9 (d, J = 24.9 Hz). HRMS (EI-TOF)
+
calcd. for C13
H
7
O
2
F (M ): 214.0430, found: 214.0428.
1
2
m: H NMR (400 MHz, CDCl
3
) δ 8.37 (dd, J = 7.9, 0.9 Hz, 1H),
O
O
8
.01 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (ddd, J = 7.9,
7.7, 1.3 Hz, 1H), 7.61 (ddd, J = 7.6, 7.6, 0.9 Hz, 1H), 7.40 (dd, J =
Cl
S17
2
m

1
3
8
.8, 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H). C NMR (101 MHz, CDCl ) δ 160.6,
3
149.7, 135.1, 133.6, 130.8, 130.4, 130.1, 129.7, 122.7, 121.8, 121.3, 119.4, 119.2.
+
HRMS (EI-TOF) calcd. for C13
H
7
O
2
Cl (M ): 230.0135, found: 230.0130.
1
2
8
7
7
n: H NMR (400 MHz, CDCl
3
) δ 8.44 (dd, J = 7.9, 0.9 Hz, 1H),
O
.33 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.90 (ddd, J = 8.1,
.4, 1.4 Hz, 1H), 7.73 (dd, J = 8.6, 1.6 Hz, 1H), 7.67 (ddd, J = 7.6,
O
1
3
.5, 1.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H). C NMR (101 MHz,
) δ 160.4, 153.3 (d, J = 1.1 Hz), 153.3, 135.4, 133.7, 131.0,
CF3
CDCl
3
2
n
1
1
30.0, 127.3 (q, J = 3.5 Hz), 127.2 (q, J = 33.1 Hz), 123.9, (q, J = 272.1 Hz), 122.0,
21.5, 120.6 (q, J = 4.0 Hz), 118.7, 118.6. HRMS (EI-TOF) calcd. for C14
H
7
O F
2 3
+
(
M ): 264.0398, found: 264.0367.
1
2
o: H NMR (400 MHz, CDCl
3
) δ 8.78 (d, J = 2.0 Hz, 1H), 8.41
O
(
dd, J = 8.0, 1.0 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.13 (dd, J =
O
8
.6, 2.0 Hz, 1H), 7.87 (ddd, J = 8.1, 7.4, 1.4 Hz, 1H), 7.64 (ddd, J
13
=
8.1, 8.0, 1.0 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H). C
) δ 166.2, 160.6, 154.3, 135.3, 134.2,
CO Me
2
NMR (101 MHz, CDCl
3
2o
131.5, 130.8, 129.6, 126.7, 125.2, 122.3, 121.3, 118.2, 118.1, 52.6. HRMS (EI-TOF)
+
calcd. for C15
H
10
O
4
(M ): 254.0579, found: 254.0575.
1
2
p: H NMR (400 MHz, CDCl
3
) δ 8.51 (dd, J = 7.9, 1.3 Hz, 1H),
O
O
8
.40 (d, J = 8.4 Hz, 1H), 7.84 (ddd, J = 7.8, 7.3, 1.6 Hz, 1H), 7.60
(
ddd, J = 7.6, 7.5, 1.0 Hz, 1H), 7.39 – 7.33 (m, 1H), 7.28 (dd, J =
13
8
.2, 1.0 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 2.91 (s, 3H). C NMR
2
p
(101 MHz, CDCl
3
) δ 161.3, 152.3, 136.3, 136.1, 134.4, 130.9, 129.4,
1
28.9, 128.2, 126.3, 122.2, 117. 6, 116.3, 25.6. HRMS (APCI) calcd. for C14
H
11
O
2
+
(
[M+H] ): 211.0754, found: 211.0748.
1
2
q: H NMR (400 MHz, CDCl
3
) δ 8.99 (dd, J = 8.4, 0.5 Hz, 1H),
O
8
.42 (ddd, J = 7.9, 1.5, 0.4 Hz, 1H), 7.77 (ddd, J = 8.5, 7.3, 1.6 Hz,
H), 7.53 (ddd, J = 7.9, 7.4, 1.1 Hz, 1H), 7.38 (t, J = 8.3 Hz, 1H),
O
1
MeO
7.00 (dd, J = 8.3, 1.1 Hz, 1H), 6.86 (dd, J = 8.3, 0.8 Hz, 1H), 4.04
2
q
S18

1
3
(
s, 3H). C NMR (101 MHz, CDCl
3
) δ 161.5, 158.5, 152.7, 134.8, 134.7, 130.2,
1
30.0, 128.1, 127.6, 121.1, 110.5, 108.4, 107.0, 56.1. HRMS (EI-TOF) calcd. for
+
C
14
H
10
O
3
(M ): 226.0630, found: 226.0625.
1
2
r: H NMR (400 MHz, CDCl
3
) δ 8.56 (d, J = 8.3 Hz, 1H), 8.47
O
(
dd, J = 7.9, 1.5 Hz,1H), 7.86 (ddt, J = 8.4, 7.3, 1.3 Hz, 1H), 7.64
ddd, 1H), 7.43 (td, J = 8.3, 5.8 Hz, 1H), 7.22 (dt, J = 8.3, 1.1 Hz,
O
(
1
3
F
1H), 7.09 (ddd, J = 12.3, 8.3, 1.2 Hz, 1H). C NMR (101 MHz,
CDCl ) δ 160.8, 160.6 (d, J = 254.0 Hz), 152.3 (d, J = 6.5 Hz),
35.4 (d, J = 1.9 Hz), 132.5 (d, J = 4.6 Hz), 130.7, 130.1 (d, J = 11.3 Hz), 129.3 (d, J
2
r
3
1
=
1.7 Hz), 126.8 (d, J = 21.8 Hz), 121.3, 113.8 (d, J = 3.5 Hz), 112.2 (d, J = 23.6 Hz),
+
1
08.5 (d, J = 13.2 Hz). HRMS (APCI) calcd. for C13
H
8
O
2
F ([M+H] ): 215.0503,
found: 215.0498.
1
2
s: H NMR (400 MHz, CDCl
J = 8.3 Hz, 1H), 8.53 – 8.46 (m, 1H), 7.98 – 7.84 (m, 3H), 7.70 –
.59 (m, 2H), 7.55 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.48 (d, J = 8.9
3
) δ 8.76 (d, J = 8.6 Hz, 1H), 8.64 (d,
O
O
7
1
3
Hz, 1H). C NMR (101 MHz, CDCl
31.6, 131.5, 130.6, 129.4, 129.3, 128.1, 127.8, 126.3, 125.4, 124.9,
22.3, 117.5, 112.4. HRMS (APCI) calcd. for C17
([M+H]+):
3
) δ 161.2, 150.2, 135.3, 134.3,
1
2s
1
H
11
O
2
2
47.0754, found: 247.0747.
1
2
1
1
t: H NMR (400 MHz, CDCl
3
) δ 8.56 (s, 1H), 8.44 (dd, J = 7.9,
O
.0 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.96 (dd, J = 8.1, 0.6 Hz,
H), 7.91 – 7.83 (m, 2H), 7.77 (s, 1H), 7.61 (ddd, J = 7.6, 7.5, 1.1
O
Hz, 1H), 7.54 (dd, J = 8.1, 1.4 Hz, 1H), 7.51 (dd, J = 8.1, 1.4 Hz,
1
3
1
H). C NMR (101 MHz, CDCl ) δ 161.1, 148.8, 134.9, 134.7,
3
2
t
1
34.1, 130.8, 130.3, 129.1, 128.3, 127.7, 127.3, 125.8, 122.6,
+
1
22.1, 121.5, 118.2, 113.6. HRMS (APCI) calcd. for C17
H
11
O
2
([M+H] ): 247.0754,
found: 247.0750.
1
2
u: H NMR (400 MHz, CDCl ) δ 8.35 (dd, J = 8.0, 0.8 Hz, 1H),
3
O
O
7
.75 (td, J = 7.9, 1.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49 (ddd, J
S19
S
2
u

1
3
=
7.7, 7.7, 1.1 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 5.4 Hz, 1H). C NMR
(101 MHz, CDCl
3
) δ 161.1, 150.0, 134.3, 132.8, 130.1, 126.8, 124.5, 121.0, 117.7,
+
1
17.5, 115.1. HRMS (EI-TOF) calcd. for C11
H
6
O
2
S (M ): 202.0089, found: 202.0081.
1
2
7
7
v: H NMR (400 MHz, CDCl
3
) δ 8.00 (dd, J = 8.0, 1.4 Hz, 1H),
O
.96 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.43 (ddd, J = 8.5,
.2, 1.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.33 – 7.24 (m, 2H), 2.85
O
1
3
(
s, 3H). C NMR (101 MHz, CDCl
3
) δ 160.5, 151.4, 144.5, 136.2,
2
v
134.0, 132.3, 130.3, 124.3, 123.1, 119.8 (2C), 118.4, 117.4, 24.0.
+
HRMS (EI-TOF) calcd. for C14
H
10
O
2
(M ): 210.0681, found: 210.0674.
) δ 8.19 (s, 1H), 8.01 (dd, J = 11.5,
1
2
w: H NMR (400 MHz, CDCl
3
O
O
4.9 Hz, 2H), 7.62 (dd, J = 8.2, 1.4 Hz, 1H), 7.44 (ddd, J = 8.5, 7.2,
13
1
.5 Hz, 1H), 7.32 (ddd, J = 8.4, 7.9, 1.2 Hz, 2H), 2.49 (s, 3H). C
NMR (101 MHz, CDCl ) δ 161.4, 151.0, 139.2, 136.1, 132.2,
3
2
w
1
30.3, 129.9, 124.5, 122.6, 121.7, 121.1, 118.2, 117.7, 21.3. HRMS (EI-TOF) calcd.
+
for C14
H
10
O
2
(M ): 210.0681, found: 210.0669.
1
2
x: H NMR (400 MHz, CDCl
3
) δ 8.25 (d, J = 8.1 Hz, 1H), 8.02
O
(
dd, J = 7.9, 1.5 Hz, 1H), 7.87 (s, 1H), 7.45 (ddd, J = 8.5, 7.2, 1.5
O
Hz, 1H), 7.37 (dd, J = 8.1, 0.9 Hz, 1H), 7.35 – 7.28 (m, 2H), 2.54
1
3
(
s, 3H). C NMR (101 MHz, CDCl
3
) δ 161.3, 151.6, 146.0, 134.8,
2
x
1
30.6, 130.4, 130.3, 124.5, 122.8, 121.9, 118.9, 118.2, 117.8, 22.4.
+
HRMS (EI-TOF) calcd. for C14
H
10
O
2
(M ): 210.0681, found: 210.0675.
) δ 8.32 (dd, J = 7.9, 1.4, 0.4 Hz, 1H),
1
2
y: H NMR (400 MHz, CDCl
3
O
8
.26 (dd, J = 8.3, 1.3 Hz, 1H), 7.59 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H),
O
7
.46 – 7.38 (m, 2H), 7.35 (dd, J = 8.2, 1.4 Hz, 1H), 7.27 (ddd, J =
13
7
.7, 7.1, 1.6 Hz, 1H), 2.85 (s, 3H). C NMR (101 MHz, CDCl ) δ
3
2y
1
61.9, 151.4, 139.2, 135.2, 133.8, 129.8, 129.4, 128.4, 127.3, 124.1,
+
123.0, 119.9, 118.1, 25.5. HRMS (EI-TOF) calcd. for C14
H
10
O
2
(M ): 210.0681,
found: 210.0689.
1
2
z: H NMR (400 MHz, CDCl
3
) δ 8.33 (d, J = 2.3 Hz, 1H), 8.04
O
Cl
O
S20
2z

(
d, J = 8.6 Hz, 1H), 7.99 (dd, J = 8.3, 1.5 Hz, 1H), 7.75 (dd, J = 8.6, 2.3 Hz, 1H), 7.52
1
3
–
1
7.45 (m, 1H), 7.39 – 7.31 (m, 2H). C NMR (101 MHz, CDCl ) δ 160.1, 151.2,
3
35.2, 135.1, 133.3, 130.9, 130.1, 124.9, 123.5, 122.9, 122.6, 118.0, 117.4. HRMS
+
(
EI-TOF) calcd. for C13
H
7
O
2
Cl (M ): 230.0135, found: 230.0127.
1
2
8
7
aa: H NMR (400 MHz, CDCl ) δ 9.03 (s, 1H), 8.55 (s, 1H),
3
O
.23 (dd, J = 7.5, 2.2 Hz, 1H), 8.03 (dd, J = 13.3, 8.4 Hz, 2H),
.69 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.60 (ddd, J = 8.1, 6.9, 1.1
O
1
3
Hz, 1H), 7.51 – 7.44 (m, 1H), 7.41 – 7.33 (m, 2H). C NMR
101 MHz, CDCl ) δ 161.5, 150.9, 136.2, 132.8, 132.5, 130.2,
2
aa
(
3
129.7, 129.6 (2C), 128.2, 127.2, 124.7, 122.9, 120.7, 119.2, 118.4, 118.0. HRMS
+
(
EI-TOF) calcd. for C17
H
10
O
2
(M ): 246.0681, found: 246.0675.
1
O
2ab: H NMR (400 MHz, CDCl
3
) δ 8.22 (d, J = 7.6 Hz, 1H), 7.66
O
(
d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H),
1
3
7
.20 (t, J = 8.6 Hz, 2H), 2.46 (s, 3H), 2.42 (s, 3H). C NMR (100
) δ 162.1, 151.3, 137.0, 136.5, 135.6, 134.8, 129.0,
28.0, 127.7, 127.2, 124.9, 119.3, 114.1, 22.1, 22.0. HRMS
MHz, CDCl
3
2ab
1
+
(
EI-TOF) calcd. for C15
H
12
O (M ): 224.0837, found: 224.0844.
2
Total Synthesis of cannabinol:
2
2
5
2
3
2
2
5
11
11
5
2
11
2
2
5
11
5
11
5
11
S21

2
-(4-pentylphenyl)-4-methylbenzoic acid (3):
nitrogen-filled schlenk tube was charged in sequence with
-bromo-4-methylbenzoic acid (4.3 g, 20 mmol), 4-pentylphenylboronic acid (4.6 g,
4 mmol), and LiOH·H O (1.85 g, 44 mmol). 60 mL NMP and 60 mL H O was
(dba) (275 mg, 0.3 mmol) under a nitrogen blanket, and the
A
2
2
2
2
added followed by Pd
2
3
o
reaction mixture was heated to 65 C for 24 h. After cool to room temperature, the
reaction mixture was acidified to pH=3 with 3N HCl, and extracted with diethyl ether
three times. The combined organic layers were dried over Na
2
SO and the solvent was
4
removed under reduced pressure. The product was purified by column
chromatography (silica gel, petroleum ether/diethyl ether = 5:1 to 3:1) to give a white
solid in 82% yield (4.64 g).
1H NMR (400 MHz, CDCl
) δ 7.78 (d, J = 7.9 Hz, 1H), 7.18
7.14 (m, 2H), 7.14 – 7.06 (m, 4H), 2.56 (t, J = 7.8 Hz, 2H),
.34 (s, 3H), 1.65 – 1.52 (m, 2H), 1.34 – 1.22 (m, 4H), 0.88
CO H
3
2
–
2
–
3
13
3
0.78 (m, 3H). C NMR (101 MHz, CDCl ) δ 173.8, 143.9, 142.8,
1
42.1, 138.6, 132.3, 131.2, 128.5, 128.3, 127.9, 126.5, 35.8, 31.8, 31.1, 22.7, 21.6, 14.2. HRMS
+
(
EI-TOF) calcd. for C19
H
22
O
2
(M ): 282.1620, found: 282.1581.
3
-pentyl-9-methyl-6H-benzo[c]chromen-6-one (4)
In a 500 mL sealed tube, 276 mL t-BuOH was added to a mixture of xx (3.9 g, 13.8
mmol), Pd(OAc)
2
(155 mg, 0.69 mmol, 5 mol%), N-acetylglycin (243 mg, 2.07
mmol), KOAc (2.71 g, 27.6 mmol), PhI(OAc)
2
(8.9 g, 27.6 mmol) under air. The tube
o
was sealed with a Teflon lined cap and the reaction mixture was stirred at 80 C for 12
h. After cooling to room temperature, the mixture was concentrated under vacuum
and the palladium and salt were filtered, the filter cake was washed with ethyl acetate,
and the filtrate was concentrated in vacuo, and the residue was purified by column
chromatography on silica gel with a gradient eluent of petroleum ether/ethyl
acetate/dichloromethane (100:1:10) to give 4 (3.3 g, 85%) as a white solid.
S22

1H NMR (400 MHz, CDCl
(d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 7.24 (dd, J = 8.1, 0.9 Hz,
H), 7.08 – 7.00 (m, 2H), 2.59 (t, J = 7.7 Hz, 2H), 2.44 (s,
H), 1.63 – 1.52 (m, 2H), 1.31 – 1.21 (m, 4H), 0.82 (t, J =
) δ 8.15 (d, J = 8.1 Hz, 1H), 7.82
3
O
O
1
3
4
1
3
7
.0 Hz, 3H). C NMR (101 MHz, CDCl ) δ 161.6, 151.6,
3
1
3
2
46.2, 145.9, 135.1, 130.6, 129.7, 124.9, 122.6, 121.7, 118.5, 117.3, 115.7, 35.8, 31.5,
+
0.8, 22.6, 22.4, 14.1. HRMS (EI-TOF) calcd. for C19
80.1451.
H
20
O
2
(M ): 280.1463, found:
2
-(2-methoxy-4-pentyl)-4-methylbenzoic acid (5):
To a solution of xx (2.5 g, 8.9 mmol) in anhydrous THF (54 mL) was added
o
MeONa (1.2 g, 22.3 mmol) in an ice bath. The mixture was stirred at 35 C for 1 h,
o
then MeI (8.3 mL, 133.7 mmol) was added. The temperature was risen to 45 C, the
o
resulting mixture was stirred overnight. After cooling to 0 C, 27 mL MeOH and 27
o
mL NaOH (6.6 M) was added to the mixture, then heat to 55 C for 6 h. The reaction
o
was acidified to pH = 3 with 4N HCl at 0 C, and extracted with diethyl ether three
times. The combined organic phase was dried over Na
2
SO , filtered and the filtration
4
was evaporated under reduced pressure. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 15:1 to 8:1, and then petroleum
ether/diethyl ether = 8:1) to provide 5 (2.02 g, 72%) as a pale yellow solide, and
recover 0.53 g 4 (21%).
1H NMR (400 MHz, CDCl
) δ 7.82 (d, J = 7.9 Hz, 1H), 7.17
3
CO H
2
(
dd, J = 7.9, 1.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.13 (s,
1
H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.67 (d, J = 1.1 Hz, 1H),
.68 (s, 3H), 2.63 (t, J = 7.8 Hz, 2H), 2.40 (s, 3H), 1.73 –
MeO
5
3
1
3
1
.61 (m, 2H), 1.43 – 1.31 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H). C NMR (101 MHz,
CDCl
3
) δ 173.3, 156.2, 144.3, 142.9, 139.4, 132.5, 130.2, 129.6, 128.0, 127.8, 127.7,
1
20.9, 110.9, 55.2, 36.3, 31.8, 31.2, 22.7, 21.6, 14.2. HRMS (EI-TOF) calcd. for
+
C
20
H
24
O
3
(M ): 312.1725, found: 312.1724.
S23

1
-methoxy-3-pentyl-9-methyl-6H-benzo[c]chromen-6-one (6):
In a 150 mL sealed tube, 37 mL t-BuOH was added to a mixture of xx (3.9 g, 1.86
mmol), Pd(OAc)
2
(20.8 mg, 0.09 mmol, 5 mol%), N-acetylglycin (32.6 mg, 0.28
mmol), KOAc (364 mg, 3.71 mmol), PhI(OAc)
2
(1.2 g, 3.71 mmol) under air. The
o
tube was sealed with a Teflon lined cap and the reaction mixture was stirred at 100 C
for 12 h. After cooling to room temperature, the mixture was concentrated under
vacuum and the palladium and salt were filtered, the filter cake was washed with ethyl
acetate, and the filtrate was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel with an eluent of petroleum ether/ethyl
acetate/dichloromethane (100:1:16) to furnish 6 (294 mg, 51%) as a white solid, and
petroleum ether/diethyl ether (4:1) to recover 5 (159 mg, 27%).
1H NMR (400 MHz, CDCl
Hz, 1H), 7.31 (dd, J = 8.1, 1.0 Hz, 1H), 6.83 (d, J = 1.6 Hz,
H), 6.67 (d, J = 1.4 Hz, 1H), 4.04 (s, 3H), 2.66 (t, J = 7.7
Hz, 2H), 2.52 (s, 3H), 1.72 – 1.62 (m, 2H), 1.42 – 1.29 (m,
) δ 8.74 (s, 1H), 8.29 (d, J = 8.1
3
O
O
1
MeO
6
1
3
4
H), 0.91 (t, J = 6.9 Hz, 3H). C NMR (101 MHz, CDCl
3
) δ
1
1
61.8, 158.3, 152.8, 145.8, 145.6, 134.9, 130.2, 128.8, 127.4, 118.3, 110.1, 107.4,
06.1, 56.0, 36.2, 31.6, 30.7, 22.7, 22.6, 14.1. HRMS (EI-TOF) calcd. for C20
H
22
O
3
+
(
M ): 310.1569, found: 310.1572.
Cannabinol8
Cannabinol (356.6 mg, 72% for three steps) was obtained through three steps
8
following the reported methods as a white solid.
1H NMR (400 MHz, CDCl
) δ 8.16 (dd, J = 1.1, 0.5 Hz, 1H),
3
O
7
6
1
.14 (d, J = 7.9 Hz, 1H), 7.06 (ddd, J = 7.9, 1.7, 0.6 Hz, 1H),
.43 (d, J = 1.6 Hz, 1H), 6.27 (d, J = 1.6 Hz, 1H), 5.31 (s,
H), 2.48 (t, J = 7.9 Hz, 2H), 2.38 (s, 3H), 1.64 – 1.55 (m,
HO
cannabinol
1
3
8
H), 1.36 – 1.27 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). C NMR (101 MHz, CDCl ) δ
3
S24

1
3
3
54.8, 153.2, 144.7, 137.0 (2C), 127.7 (2C), 126.6, 122.7, 110.9, 110.0, 108.8, 77.5,
5.7, 31.6, 30.6, 27.2, 22.7, 21.7, 14.2. HRMS (EI-TOF) calcd. for C21
10.1933, found: 310.1940.
H
26
O
(M+):
2
Discussion of Mechanism:
With 1a under standard reaction conditions for 1 h, trace possible acetoxylation
product 1ac observed by TLC and none checked by GC-MS (decomposed at high
temperature), compared with standard compound 1ac. We also subjected the
suggested intermediate 1ac to the catalytic system. It was found that C–H
activation/C–O cyclization products 2ac (23%) and 2ad (17%) were obtained along
with lactone 2a (38%) (Eq. 1), whereas neither of them was observed with 1a used
directly (entry 20, Table 1). Because 1ac may be generated in low concentration and
phenol was then afforded by following rapid hydrolysis, the real catalytic system is
possible to be different from Eq. 1. In this context, the stepwise route involve
acetoxylation followed by condensation can’t be excluded at this stage.
Procedure of synthesis of 2-(2-acetoxy)phenylbenzoic acid (1ac)
To a solution of 2a (528 mg, 2.69 mmol) in anhydrous THF (12 mL) was added
tBuOK (604 mg, 5.38 mmol) in an ice bath. The mixture was stirred at room
o
temperature for 1 h, then Ac
2
O (8.3 mL, 133.7 mmol) was added under -78 C,
warmed to room temperature and stirred over night. After evaporation of the solvent
under reduced pressure, the residue was dissolved in 27 mL DCM, 9 mL TFA was
added to the reaction mixture, and stirred for 6 hours. The solvent was removed and
the product was purified by flash column chromatography (petroleum ether/ethyl
S25

acetate = 8:1 to 4:1) to provide 1ac (502.6 mg, 73%) as a pale yellow solid, and
recover 39.4 mg 2a (20%).
2
-phenyl-3-acetoxybenzoic acid (1ac):
CO H 1H NMR (400 MHz, CDCl
) δ 7.95 (d, J = 7.8 Hz, 1H), 7.56 (t, J =
3
2
7
3
.6 Hz, 1H), 7.47 – 7.28 (m, 5H), 7.11 (d, J = 8.0 Hz, 1H), 1.97 (s,
1
3
H). C NMR (101 MHz, CDCl ) δ 172.3, 169.6, 147.6, 137.9, 134.1,
3
AcO
ac
1
132.4, 131.5, 130.6, 130.4, 130.4, 129.1, 128.0, 126.5, 122.1, 20.6.
+
HRMS (ESI) calcd. for C15
H
13
O
4
([M+H] ) 257.0808, found 257.0796.
1
O
2ac: H NMR (400 MHz, CDCl
3
) δ 8.54 (d, J = 8.3 Hz, 1H), 8.47
O
(dd, J = 7.9, 1.1 Hz, 1H), 7.82 (td, J = 7.9, 1.6 Hz, 1H), 7.61 (td, J =
7.5, 1.0 Hz, 1H), 7.47 (t, J = 8.2 Hz, 1H), 7.31 (dd, J = 8.3, 1.3 Hz,
AcO
ac
13
1
H), 7.07 (dd, J = 8.1, 1.2 Hz, 1H), 2.50 (s, 3H). C NMR (101
2
MHz, CDCl ) δ 168.7, 160.8, 152.4, 148.2, 135.1, 133.3, 131.0,
3
1
29.8, 129.2, 125.5, 121.9, 120.2, 115.9, 112.1, 21.7.HRMS (EI-TOF) calcd. for
+
C
15
H
10
O
4
(M ): 254.0579, found: 254.0577.
1
2
ad: H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.15 (dd, J = 8.3,
O
O
0.5 Hz, 1H), 8.29 (dd, J = 7.9, 1.1 Hz, 1H), 7.93 (ddd, J = 8.5, 7.3,
1
1
.6 Hz, 1H), 7.64 (ddd, J = 7.6, 7.2, 1.1 Hz, 1H), 7.36 (t, J = 8.2 Hz,
H), 6.93 (dd, J = 8.2, 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.2 Hz, 1H).
HO
ad
2
13C NMR (101 MHz, DMSO) δ 160.4, 156.6, 152.2, 135.1, 134.6,
1
30.2, 129.4, 128.0, 127.1, 120.1, 112.0, 107.7, 106.1. HRMS (EI-TOF) calcd. for
+
C
13
H
8
O
3
(M ): 246.0473, found: 246.0472.
References:
(
(
(
1) Korolev, D. N.; Bumagin, N. A. Tetrahedron Lett. 2006, 47, 4225.
2) Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 14006.
3) Prastaro, A.; Ceci, P.; Chiancone, E.; Boffi, A.; Cirilli, R.; Colone, M.; Fabrizi, G.;
Stringaro, A.; Cacchi, S. Green Chem. 2009, 11, 1929.
S26

(
(
(
4) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu,
J.-Q. J. Am. Chem. Soc. 2007, 129, 3510.
5) (a) Wang, L.; Prabhudas, B.; Clive, D. L. J. J. Am. Chem. Soc. 2009, 131, 6003. (b)
Haack, T.; Kurtkaya, S.; Snyder, J. P.; Georg, G. I. Org. Lett. 2003, 5, 5019.
6) (a) Anderson, M. O.; Sherrill, J.; Madrid, P. B.; Liou, A. P.; Weisman, J. L.;
DeRisi, J. L.; Guy, R. K. Bioorg. Med. Chem. 2006, 14, 334. (b) Hussain, I.;
Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P.
J. Org. Chem. 2007, 72, 6255.
(
(
7) Houpis, I. N.; Huang, C.; Nettekoven, U.; Chen, J. G.; Liu, R.; Canters, M. Org.
Lett. 2008, 10, 5601.
8) Teske, J. A.; Deiters, A. Org. Lett. 2008, 10, 2195.
S27

1
13
Copies of H and C NMR Spectra
S28

S29

CO H
2
Br
CO H
Br
1f
S30