Tunable Single and Double γ-C?H Arylation of Phenylacetamides Directed by o-Aminophenols

Article abstract of DOI:10.1002/adsc.201900866

The cheap and easily available o-aminophenols (OAPs) have been identified as practical directing component for the Pd-catalyzed aromatic γ-C?H bond arylation of phenylacetamides. Notably, the selective single and double arylation of the C?H bond(s) in the

Full text of DOI:10.1002/adsc.201900866

FULL PAPER
DOI: 10.1002/adsc.201900866
Tunable Single and Double γ-CÀ H Arylation of Phenylacetamides
Directed by o-Aminophenols
a
a
b
a,
Zhi Tu, Yi Du, Xiaoji Cao, and Yunyun Liu *
a
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
+
86 791 8812 0380
E-mail: chemliuyunyun@jxnu.edu.cn
Research Center of Analysis and Measurement, Zhejiang University of Technology, Hangzhou, 310014 P. R. China
b
Manuscript received: July 13, 2019; Revised manuscript received: August 28, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900866
Abstract: The cheap and easily available o-aminophenols (OAPs) have been identified as practical directing
component for the Pd-catalyzed aromatic γ-CÀ H bond arylation of phenylacetamides. Notably, the selective
single and double arylation of the CÀ H bond(s) in the γ-potion has been independently realized by simply
modifying reaction conditions. The catalytic system of Pd(CF OO) /K S O /K CO enables the selective single
3
2
2
2
8
2
3
CÀ H arylation. On the other hand, the catalysis of Pd(OAc) in the presence of KIO /K CO induces the
2
3
2
3
selective arylation of both γ-CÀ H bonds.
Keywords: o-Aminophenol; Phenylacetamide; γ-CÀ H activation; Selective; Arylation
1. Introduction
as γ-position is much less available. Representatively,
the 8-aminoquinoline (AQ) directed intramolecular γ-
Directed CÀ H bond activation constitutes presently the CÀ H amination for the synthesis of pyrrolidin-2-ones
[5]
major and one of the most promising tactics in the has been reported by Chen et al. Moreover, Maiti and
designation of efficient organic synthesis. To improve co-workers have developed the AQ-directed γ-CÀ H
[
6]
the efficiency and atom economy of directed CÀ H alkenylation of phenylacetamides by Pd-catalysis.
activation, numerous efforts have been made over the Later on, the AQ-directed γ-arylation of similar N-AQ
past decades. As important criteria, the low cost and amides, the Pd/Ag-co-catalyzed arylation of free
[1]
[7]
[8]
easy availability of the directing group (DG) precursor NH -phenylacetamides, and the AQ-directed γ-CÀ H
2
[9]
are thus highly favorable. Recently, the simple OAPs arylation of indolyl-2-carboxamides have been suc-
have been identified as practical DG precursors in a cessively realized by us and others. Complementarily,
series of different CÀ H activation reactions. In 2017, the alkyl amides with N-AQ structure have been
[
10]
Liu and Wan et al reported the OAP-assisted 2,6- successfully elaborated in γ-site by CÀ H arylation
[11]
diarylation reactions of benzamides via the Pd- and alkenylation, respectively. And extensive efforts
[2]
catalyzed β-CÀ H activation. Later on, this DG was in the activation of γ-CÀ H bond have also led to the
[12]
found as effective fragment in assisting the tandem achievements
on
the
γ-fluorination,
γ-
[13]
CÀ H olefination and intramolecular hydroamination alkeneylation of simple phenylacetamides, as well as
[14]
[15]
for the synthesis of isoindolinones with Rh-/Cu-co- the arylation
and alkenylation
of γ-vinyl CÀ H
[3]
catalyst system. Rather recently, Panda and Sahoo bond. Regardless these significant advances, it is also
developed the tandem synthesis of alkenyl functional- noticeable that most of the aforementioned works
ized benzoxazoles via a key CÀ H alkenylation with employ AQ as the DG, and only a few alternatives are
palladium
catalysis
4]
using
OAP-functionalized available. In addition, when more than one identical
[
benzamides. In despite of these inspiring works, CÀ H bonds in the reactive sites are available, the
more different CÀ H bond activation reactions assisted chemo-selectivity of single and double activation is
by such DGs are yet to explore.
hard to control. Accordingly, searching for more
On the other hand, in most catalytic CÀ H activa- diverse DGs which allow the efficient, and particularly,
tions of amides, the transformation takes place at the tunable mono- and di-CÀ H activation at γ-position(s)
β-position. The selective activation on other sites such is yet highly demanding. Given our research interests
Adv. Synth. Catal. 2019, 361, 1–10
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[16]
in CÀ H activation/functionalization reactions as well enable the expected reaction (entry 3, Table 1). Using
as the inherent functions of OAP structure as building Pd(TFA)2 and PdCl2 in parallel experiment gave
[17]
[18]
blocks, materials precursors and core structure in inferior results, respectively (entries 4–5, Table 1).
[19]
bioactive molecules,
we report herein the tunable Subsequently, varying the additive species to AgOAc,
single and double arylation of the γ-CÀ H bonds in KIO and Cu(OAc) suggested that KIO was amongst
3
2
3
phenylacetamides with OAPs as the DG precursors.
the most favourable additive (entries 6–8, Table 1).
Increasing the loading of additive did not improve the
reaction (entry 9, Table 1), and decreasing the amount
of base led to reduced yield of 3a (entry 10, Table 1).
2. Results and Discussion
To start the investigation, the reaction of OAP- Later on, the experiments using different base additives
functionalized phenylacetamide 1a and iodobenzene (entries 11–13, Table 1) and reaction media (en-
2
a was selected for the potential CÀ H arylation. When tries 14–17, Table 1) resulted in no better results.
Pd(OAc) was used as catalyst, the 2,6-diphenylated Furthermore, conducting the reaction under different
2
phenylacetamide 3a was obtained in 37% yield temperatures proved the 110°C was the most proper
(
entry 1, Table 1). Interestingly, using Ag CO3 as temperature (entries 18–19, Table 1). Finally, increas-
2
oxidative additive led to evident increase in the yield ing or reducing the loading of Pd(OAc) didn’t provide
2
of 3a (entry 2, Table 1), and Ag CO alone could not better yield (entries 20–21, Table 1), either.
2
3
Based on the results from the optimization study,
the scope of this double arylation reaction was studied
by using OAP-functionalized phenylacetamides 1 with
various substituents as well as different aryl iodides.
As presented in Scheme 1, the aryl iodides, including
electron enriched (3b, 3d, 3e–3m, Scheme 1), elec-
tron deficient (3n–3p, 3r, Scheme 1) as well as
heteroaryl (3c, 3q and 3s, Scheme 1) iodides were all
smoothly tolerated in the synthesis. A tendency was
that the electron withdrawing group functionalized aryl
iodides gave rise to corresponding products with lower
Table 1. Optimization on the conditions for selective di-
[a]
arylation of phenylacetamide.
entry catalyst/additive
[b]
base
solvent yield (%)
1
2
3
4
5
6
7
8
9
1
Pd(OAc) /–
K CO3
EtOH 37
EtOH 56
EtOH nr
EtOH 27
EtOH 33
EtOH 38
EtOH 69
EtOH trace
EtOH 68
EtOH 45
EtOH 24
2
2
Pd(OAc) /Ag CO
K CO3
2
2
3
2
–/Ag CO3
K CO3
2
2
Pd(TFA) /Ag CO
K CO3
2
2
3
2
PdCl /Ag CO
K CO3
2
2
3
2
Pd(OAc) /AgOAc
K CO3
2
2
Pd(OAc) /KIO3
K CO3
2
2
Pd(OAc) /Cu(OAc)2 K CO3
2
2
[
c]
Pd(OAc) /KIO3
K CO3
2
2
[
d]
0
Pd(OAc) /KIO3
K CO3
2
2
11
Pd(OAc) /KIO3
Cs CO3
2
2
12
13
14
15
16
17
18
19
20
21
Pd(OAc) /KIO3
C H ONa EtOH 22
2 5
NaHCO3 EtOH 24
2
Pd(OAc) /KIO3
2
Pd(OAc) /KIO3
K CO3
2
DMSO nr
2
Pd(OAc) /KIO3
K CO3
K CO3
2
H O
DCE
nr
nr
2
2
2
Pd(OAc) /KIO3
2
Pd(OAc) /KIO3
K CO3
MeOH 31
EtOH 33
EtOH 60
MeOH 60
MeOH 21
2
2
[
[
[
[
e]
Pd(OAc) /KIO3
K CO3
2
2
f]
Pd(OAc) /KIO3
K CO3
2
2
g]
h]
Pd(OAc) /KIO3
K CO3
2
2
Pd(OAc) /KIO3
K CO3
2
2
[a]
Gerenal conditional: 1a (0.2 mmol), 2a (0.6 mmol), catalyst
(10 mol%), additive (1 equiv), base (4 equiv) in solvent
(
2 mL), stirred at 110°C in sealed tube for 8 h.
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
Isolated yield based on 1a.
KIO (2.0 equiv).
3
Base (2.0 equiv).
Reaction at 100°C.
Reaction at 120°C.
g]
h]
Pd(OAc) (20 mol%).
Scheme 1. Scope of the 2,6-diarylation of OAP-functionalized
phenylacetamides.
2
Pd(OAc) (5 mol%).
2
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Table 2. Optimization on the selective mono-CÀ H arylation
[a]
reaction
[b]
entry Catalyst/additive
solvent yield (4a/3a%)
1
2
3
4
5
6
7
8
9
1
Pd(OAc) /K S O
8
EtOH
EtOH
EtOH
EtOH
EtOH
53/36
34/41
80/9
39/34
57/25
42/18
0/0
2
2
2
PdCl /K S O
8
2
2
2
Pd(CF COO) /K S O
8
3
2
2
2
Pd(CF COO) /KIO
3
3
2
Pd(CF COO) /Ag CO
3
3
2
2
Pd(CF COO) /Cu(OAc) EtOH
3
2
2
[
[
[
c]
d]
e]
Pd(CF COO) /K S O
EtOH
EtOH
EtOH
MeOH 21/16
DMSO 14/trace
MeCN 57/26
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
3
2
2
2
8
8
8
8
8
8
8
Pd(CF COO) /K S O
0/trace
trace/trace
3
2
2 2
Pd(CF COO) /K S O
3
2
2 2
0
Pd(CF COO) /K S O
3
2
2 2
1
1
Pd(CF COO) /K S O
3 2 2 2
Pd(CF COO) /K S O
3 2 2 2
12
13
14
15
16
17
[
[
[
[
[
[
f]
g]
h]
i]
Pd(CF COO) /K S O
55/25
43/11
43/19
37/16
52/6
3
2
2 2
Pd(CF3COO) /K S O
8
2
2
2
Pd(CF COO) /K S O
8
3
2
2
2
Pd(CF COO) /K S O
3
2
2
2
8
8
8
j]
Pd(CF COO) /K S O
3
2
2 2
k]
Scheme 2. Scope of the single arylation of OAP-functionalized
phenylacetamides (yiel in the parenthesis was given by 2 mmol
scale reaction).
18
Pd(CF COO) /K S O
3
2
2 2
0/0
[a]
Gerenal conditional: 1a (0.2 mmol), 2a (0.4 mmol), Pd-
catalyst (10 mmol%), oxidant (1.0 equiv), K CO (4.0 equiv),
2
3
solvent (2 ml), stirred at 110°C in sealed tube for 8 h.
Isolated yield based on 1a.
NaOH as base.
[
[
[
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
yield (3n–3p, 3r, Scheme 1). On the other hand, the
substitution of different types in the amide phenyl ring
was also generally applicable for the expected reac-
tions, wherein no evident effect of the substituent
property to the reaction result was observed (3h–3q,
Scheme 1). More notably, the OAP itself containing
additional functionalized structures could be easily
accessed and they participated the CÀ H arylation
reactions with satisfactory results (3e–3g and 3r–3s,
Scheme 1), demonstrating the individual advantage of
the present method in quickly generating high molec-
ular diversity.
EtONa as base.
NaHCO as base.
3
Reaction at 90°C.
g]
h]
i]
K CO (2.0 equiv).
2 3
Pd(CF COO) (20 mol%).
3
2
Pd(CF COO) (5 mol%).
3
2
j]
With 0.2 mmol 2a.
PhBr was used as aryl source.
k]
Table 2). Lowering the temperature resulted in de-
In order to probe the reaction conditions enabling creased product yield (entry 13, Table 1). The loading
the selective single CÀ H arylation, we again turned to of base additive and Pd-catalyst were also screened,
screening the reaction parameters. Delightfully, em- but no further improvement was achieved (entries 14–
ploying K S O as the additive was found to provide 16, Table 2). Furthermore, reducing the loading 2a
2
2
8
the single arylated product 4a with 53% yield together caused lower yield of 4a (entry 17, Table 2). On the
with the double arylated product 3a (entry 1, Table 2). other hand, employing bromobenezne as the alternative
Screening the palladium catalyst led to the excellent aryl source didn’t provide any arylated product
result of 80% yield of 4a by using Pd(CF COO)
(entry 18, Table 2).
3
2
(entries 2–3, Table 2). The variation on the oxidative
Correspondingly, the synthetic scope of this single
additive to KIO , Ag CO or Cu(OAc) turned out to arylation reaction was then investigated. As outlined in
3
2
3
2
be not favorable (entries 4–6, Table 2). In addition, the Scheme 2, the selective synthesis of single arylated
employment of NaOH, EtONa or NaHCO as base phenylacetamides 4 displayed excellent scope to both
3
species didn’t afford the expected product (entries 7–9, substrates. Aryl iodides functionalized with electron
Table 2). Subsequently, this reaction was performed in donating (4b–d, 4f, 4h, 4j–l, 4n–o, 4s and 4u,
MeOH, DMSO and MeCN, respectively, but much Scheme 2) and withdrawing (4c, 4g, 4m, 4p and 4t,
lower yield of 4a was acquired (entries 10–12, Scheme 2) group(s) as well as heteroaryl iodide (4r,
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more, the formation of the aryl CÀ Pd bond takes place
to give intermediate B with the assistance of base. A
classical oxidative addition of aryl iodide to Pd-site in
B then gives rise to the complex C as another
intermediate. The following reductive elimination of C
provides arylated intermediate D. The decomposition
of the palladacycle in D in the presence of KOAc
offers the product 4 and regenerates the Pd(OAc)2
catalyst. Simultaneously, the oxidative transformation
of the KI side-product to other species may promote
the reaction to move to the positive direction, which
accounts for the result that employment of oxidant
improves the target product yield. The repeated
catalytic cycle on the other reactive CÀ H bond, on the
other hand, affords the double arylated products 3. As
for the chemo-selectivity, the variation on the loading
of aryl iodide is a basic factor inducing the selective
single and double arylation. In addition, the anion in
Pd(CF COO) might be a less effective ligand for the
Scheme 3. Deprotection of the single arylated product.
3
2
Pd-insertion into the other γ-CÀ H bond after the first
arylation, thus enables the reaction to stop at the stage
of single arylation.
3
. Conclusion
Scheme 4. The proposed reaction mechanism.
In conclusion, we have developed a new method for
the γ-CÀ H arylation of phenylacetamides with the
Scheme) were well tolerated for to the expected assistance of OAPs and palladium catalysis. Beside the
synthesis. Analogously, the aryl iodides containing easy availability and diversity of OAP precursors, the
electron withdrawing substitution provided corre- present method exhibits tunable selectivity of single
sponding products with slightly lower yield. In and double arylation on the two identical γ-CÀ H bonds
addition, the phenylacetamides with various substitu- by simply modifying reaction conditions. Besides
ents such as halogen and alkoxyl in the phenyl disclosing the new function of OAP in directing
fragment also smoothly took part in the reactions (4e– aromatic CÀ H arylation at γ-position, this method
4
n, Scheme 2). What’s more, broad substrate tolerance provides a facile and practical new route to access
in the OAP was identified by the synthesis of diversity enriched phenylacetamides bearing biaryl and
corresponding products (4o–4v, Scheme 2). All the triaryl substructure.
products were afforded with good to excellent yields
under the present conditions, and the scale up reaction
to 2 mmol also gave fine result in the reaction
Experimental Section
synthesizing 4a (Scheme 2).
General Procedure for the Synthesis of Double
In subsequent study, the deprotection of the OAP Arylated Phenylacetamides 3
fragment from compound 4a was conducted. As
In a 25 mL sealed tube equipped with a stirring bar were
charged with amide 1 (0.2 mmol), aryl iodide 2 (0.6 mmol), Pd
shown in Scheme 3, the tandem treatment with NaOH
and Na SO /HCl provided biaryl-based phenylacetic
acid 5 with fine yield. In addition, to examine the role
of the hydroxyl in 1, the N-phenyl phenylacetamide
2
3
(OAc) (0.02 mmol), KIO (0.2 mmol), K CO (0.8 mmol) and
2
3
2
3
EtOH (2 mL). The tube was then sealed with Teflon cap and
subjected to oil bath heating at 110 C and stirring for 8 h. Upon
°
was employed to react with iodobenezene under the completion, the reaction was allowed to cool down to room
standard conditions of the double arylation, but not any temperature, and 10 mL water was added to the vessel. The
arylated product was observed, confirming the indis- heterogeneous mixture was extracted with ethyl acetate (3×
1
0 mL).The combined organic phase was dried over Na SO .
2 4
pensable function of the chelating hydroxyl group in 1
for the CÀ H arylation reaction.
After filtration, the acquired solution was collected and the
solvent was removed at reduced pressure. The residue was
subjected to silica gel column chromatography to give pure
products by using mixed petroleum ether and ethyl acetate (v/
v=20:1) as eluent.
2
Based on the in hand results and pervious report,
we proposed the possible reaction mechanism. As
shown in Scheme 4, the reaction starts from the
incorporation of the Pd-catalyst to substrate 1 forming
Pd(II)-complex A in the presence of base. Further-
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2
-([1,1’:3’,1’’-Terphenyl]-2’-yl)-N-(2-hydroxyphenyl)
2-(4,4’’-Dimethyl-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-hydroxy-
4-methylphenyl)acetamide (3g). Yellow solid; mp 195–
1
acetamide (3a). Yellow solid; mp 110–111°C; H NMR
1
(400 MHz, CDCl ): δ 8.51 (s, 1 H), 7.44–7.33 (m, 12 H), 7.07
196°C; H NMR (400 MHz, CDCl ): δ 8.66 (s, 1 H), 7.40 (d,
3
3
(t, J=7.8 Hz, 1 H), 6.94 (d, J=7.8 Hz, 2 H), 6.77 (t, J=
J=7.2 Hz, 1 H), 7.30 (d, J=7.6 Hz, 2 H), 7.26 (d, J=4.2 Hz, 2
H), 7.21 (d, J=8.0 Hz, 5 H), 6.87 (s, 1 H), 6.77 (s, 1 H), 6.58
(d, J=8.0 Hz, 1 H), 6.44 (d, J=8.0 Hz, 1 H), 3.69 (s, 2 H),
1
3
7
.6 Hz, 1 H), 6.61 (d, J=7.8 Hz, 1 H), 3.70 (s, 2 H); C NMR
(100 MHz, CDCl ): δ 171.8, 149.1, 143.9, 141.2, 130.0, 129.5,
3
1
3
1
3
29.2, 128.7, 127. 8, 127.8, 127.4, 125.4, 122.1, 120.3, 120.1,
2.38 (s, 6 H), 2.25 (s, 3 H); C NMR (100 MHz, CDCl ): δ
3
+
9.0; ESI-HRMS: Calcd for C H NO [M+H] 380.1645;
171.6, 148.8, 143.7, 138.1, 137.4, 137.3, 129.8, 129.3, 128.9,
127.6, 121.7, 120.8, 120.5, 38.8, 21.2, 20.8; ESI-HRMS: Calcd
26
22
2
found: 380.1643.
+
for C H NO [M+H] 422.2115, found 422.2111.
29
28
2
2
-(4,4’’-Dimethyl-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-hydroxy-
1
phenyl)acetamide (3b). Yellow solid; mp 117–118°C;
H
N-(2-Hydroxyphenyl)-2-(5’-methoxy-4,4’’-dimethyl-
NMR(400 MHz, CDCl ):δ 8.64 (s, 1 H), 7.40 (d, J=7.0 Hz, 1
[1,1’:3’,1’’-terphenyl]-2’-yl)acetamide (3h). Yellow solid; mp
3
1
H), 7.31 (d, J=7.6 Hz, 2 H), 7.27 (s, 1 H), 7.25 (s, 2 H), 7.21
187–188°C; H NMR (400 MHz, CDCl ): δ 8.72 (s, 1 H), 7.25–
3
(d, J=8.0 Hz, 4 H), 7.08 (t, J=7.0 Hz, 1 H), 6.95 (d, J=
7.19 (m, 7 H), 7.08 (t, J=7.8 Hz, 1 H), 7.00 (s, 1 H), 6.95 (d,
J=8.2 Hz, 1 H), 6.87 (s, 2 H), 6.78 (t, J=7.6 Hz, 1 H), 6.61 (d,
J=7.8 Hz, 1 H), 3.83 (s, 3 H), 3.62 (s, 2 H), 2.37 (s, 6 H); C
8
1
.0 Hz, 2 H), 6.78 (t, J=7.6 Hz, 1 H), 6.59 (dd, J=8.0 1.3 Hz,
1
3
13
H), 3.72 (s, 2 H), 2.38 (s, 6 H); C NMR (100 MHz, CDCl ):
3
δ 172.0, 149.1, 143.8, 138.3, 137.5, 130.0, 129.7, 129.4, 129.1,
27.8, 127.3, 125.5, 122.1, 120.2, 120.2, 39.0, 21.3; ESI-
NMR (100 MHz, CDCl ): δ 172.3, 145.0, 138.1, 137.4, 129.3,
3
1
128.8, 127.2, 125.4, 121.9, 121.3, 120.0, 120.0, 115.4, 55.4,
+
+
HRMS: Calcd for C H N O [M+H] 408.1958; found:
38.2, 21.2; ESI-HRMS: Calcd for C H NO [M+H]
28
26
2
29 28
3
408.1948.
438.2064, found 438.2061.
2
-(2,6-Di(thiophen-2-yl)phenyl)-N-(2-hydroxyphenyl)
2-(5’-Fluoro-4,4’’-dimethyl-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-
1
acetamide (3c). Yellow solid; mp 158–159°C; H NMR
hydroxyphenyl)acetamide (3i). Yellow solid; mp 210–211°C;
1
(400 MHz, CDCl ): δ 8.61 (s, 1 H), 7.52 (d, J=7.2 Hz, 2 H),
H NMR (400 MHz, CDCl ): δ 8.54 (s, 1 H), 7.24–7.20 (m, 7
3
3
7.45–7.42 (m, 1 H), 7.38 (dd, J=3.2, 1.6 Hz, 2 H), 7.17 (s, 1
H), 7.07 (d, J=7.0 Hz, 1 H), 7.03 (d, J=8.8 Hz, 2 H), 6.97–
H), 7.12–7.08 (m, 4 H), 7.00 (d, J=8.0 Hz, 1 H), 6.81 (d, J=
6.91 (m, 2 H), 6.81–6.76 (m, 1 H), 6.63 (d, J=7.8 Hz, 1 H),
1
3
13
7.2 Hz, 1 H), 6.77–6.74 (m, 1 H), 3.95 (s, 2 H); C NMR
3.63 (s, 2 H), 2.37 (s, 6 H); C NMR (100 MHz, CDCl ): δ
3
(
100 MHz, CDCl ): δ 171.9, 149.2, 141.4, 136.6, 132.0, 131.7,
171.6, 162.2 (d, JC-F =247 Hz), 148.8, 145.8 (d, JC-F =9.0 Hz),
3
1
27.9, 127.7, 127.7, 127.5, 126.5, 125.5, 122.3, 120.5, 120.2,
137.8, 137.3, 129.4, 128.7, 127.2, 125.3, 121.9, 120.0 (d, JC-F =
+
39.7; ESI-HRMS: Calcd for C H NO S [M+H] 392.0773;
25 Hz), 116.5 (d, JC-F =21 Hz), 38.32, 21.18; ESI-HRMS: Calcd
22
18
2 2
+
found: 392.0770.
for C H FNO [M+H] 426.1864, found 426.1860.
28
25
2
N-(2-Hydroxyphenyl)-2-(3,3’’,5,5’’-tetramethyl-[1,1’:3’,1’’-ter-
2-(5’-Chloro-4,4’’-dimethyl-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-
phenyl]-2’-yl)acetamide (3d). Yellow solid; mp 134–135°C;
hydroxyphenyl)acetamide (3j). Yellow solid; mp 142–143°C;
1
1
H NMR (400 MHz, CDCl ): δ 8.68 (s, 1 H), 7.40 (dd, J=8.0,
H NMR (400 MHz, CDCl ): δ 8.50 (s, 1 H), 7.30 (s, 2 H),
3
3
7
7
.0 Hz, 1 H), 7.30 (d, J=7.4 Hz, 2 H), 7.10–7.06 (m, 1 H),
.00–6.95 (m, 7 H), 6.81–6.76 (m, 1 H), 6.60 (d, J=8.0 Hz, 1
7.24-7.21 (m, 8 H), 7.11–7.07 (m, 1 H), 6.95 (d, J=8.2 Hz, 1
H), 6.79 (t, J=7.6 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 3.64 (s, 2
1
3
13
H), 3.71 (s, 2 H), 2.31 (s, 12 H); C NMR (100 MHz, CDCl ):
H), 2.37 (s, 6 H); C NMR (100 MHz, CDCl ): δ 171.5, 149.0,
3
3
δ 172.1, 149.3, 144.1, 141.1, 138.3, 129.8, 129. 5, 129.3, 127.6,
145.4, 137.9, 137.1, 133.2, 129.7, 129.1, 128.9, 128.5, 127.4,
125.4, 122.1, 120.3, 120.1, 38.6, 21.3; ESI-HRMS: Calcd for
1
27.4, 127.0, 125.5, 122.1, 120.2, 120.1, 39.1, 21.4; ESI-
+
+
HRMS: Calcd for C H NO [M+H] 436.2271; found:
C H ClNO [M+H] 442.1568; found: 442.1579.
30
30
2
28 25
2
4
36.2262.
N-(2-Hydroxyphenyl)-2-(5’-methoxy-3,3’’,5,5’’-tetramethyl-
[1,1’:3’,1’’-terphenyl]-2’-yl)acetamide (3k). Yellow solid; mp
N-(5-Chloro-2-hydroxyphenyl)-2-(4,4’’-dimethyl-[1,1’:3’,1’’-
1
terphenyl]-2’yl)acetamide (3e). Yellow solid; mp 102–103°C;
219–220°C; H NMR (400 MHz, CDCl ): δ 8.74 (s, 1 H), 7.11–
3
1
H NMR (400 MHz, CDCl ): δ 8.52 (s, 1 H), 7.42 (t, J=7.6 Hz,
7.06 (m, 1 H), 7.06-6.95 (m, 7 H), 6.86 (s, 2 H), 6.79 (t, J=
8.0 Hz, 1 H), 6.61 (d, J=7.6 Hz, 1 H), 3.84 (s, 3 H), 3.62 (s, 2
3
1
7
2
1
1
H), 7.31 (d, J=7.6 Hz, 2 H), 7.24 (d, J=4.0 Hz, 7 H), 7.04–
.00 (m, 1 H), 6.88–6.79 (m, 2 H), 6.56 (s, 1 H), 3.72 (s, 2 H),
.40 (s, 6 H); C NMR (101 MHz, DMSO-d ) δ 175.5, 151.2,
48.4, 143.8, 141.5, 136.0, 134.2, 134.0, 132.8, 131.9, 128.5,
1
3
H), 2.31 (s, 12 H); C NMR (100 MHz, CDCl ): δ 172.4,
3
13
145.2, 140.9, 138.2, 129.3, 127.2, 126.7, 125.4, 121.9, 121.5,
120.1, 112.0, 115.2, 55.4, 38.3, 21.3; ESI-HRMS: Calcd for
6
+
27.3, 125.8, 121.3, 44.2, 25.9; ESI-HRMS: Calcd for
C H NO [M+H] 466.2377, found 466.2375.
31
32
2
+
C H ClNO [M+H] 442.1568; found: 442.1563.
2
8
25
2
2
-(5’-Fluoro-3,3’’,5,5’’-tetramethyl-[1,1’:3’,1’’-terphenyl]-2’-
2
-(4,4’’-Dimethyl-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-hydroxy-
yl)-N-(2-hydroxyphenyl)acetamide (3l). Yellow solid; mp
1
5
-methylphenyl)acetamide (3f). Yellow solid; mp 226–227°C;
236–237°C; H NMR (400 MHz, CDCl ): δ 8.58 (s, 1 H), 7.08
3
1
H NMR (400 MHz, CDCl ): δ 8.38 (s, 1 H), 7.40 (d, J=
(t, J=7.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 4 H), 6.95 (d, J=
9.8 Hz, 5 H), 6.79 (t, J=7.4 Hz, 1 H), 6.63 (d, J=7.8 Hz, 1 H),
3
7.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 2 H), 7.25–7.20 (m, 7 H),
1
3
6
2
1
1
.90–6.83 (m, 3 H), 6.35 (s, 1 H), 3.70 (s, 2 H), 2.38 (s, 6 H),
.22 (s, 3 H); C NMR (100 MHz, CDCl ): δ 171.6, 146.6,
43.7, 138.2, 137.3, 129.8, 129.3, 129.0, 127.8, 127.6, 124.9,
22.3, 119.8, 38.9, 21.2, 20.3; ESI-HRMS: Calcd for
3.63 (s, 2 H), 2.30 (s, 12 H); C NMR (100 MHz, CDCl ): δ
3
13
171.8, 161.2 (d, JC-F =246.0 Hz), 149.0, 146.0 (d, JC-F =
9.0 Hz), 140.1, 138.3, 129.5, 127.2, 126.6, 125.3, 121.9, 120.1
(d, JC-F =10.0 Hz), 116.3(d, JC-F =21.0 Hz), 116.23, 38.40,
3
+
C H NO [M+H] 422.2115, found 422.2111.
2
9
28
2
Adv. Synth. Catal. 2019, 361, 1–10
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
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FULL PAPER
asc.wiley-vch.de
+
+
2
1.27; ESI-HRMS: Calcd for C H FNO [M+H] : 454.2177,
20.8; ESI-HRMS: Calcd for C H Cl NO [M+H] 462.1022,
27 22 2 2
30
29
2
found 454.2174.
found 462.1019.
2
-(5’-Chloro-3,3’’,5,5’’-tetramethyl-[1,1’:3’,1’’-terphenyl]-2’-
2-(2,6-Di(thiophen-2-yl)phenyl)-N-(2-hydroxy-4-meth-
1
yl)-N-(2-hydroxyphenyl)acetamide (3m). Yellow solid; mp
ylphenyl)acetamide (3s). Yellow solid; mp 160–161°C; H
1
1
20–121°C; H NMR (400 MHz, CDCl ): δ 8.54 (s, 1 H), 7.30
NMR (400 MHz, CDCl ): δ 8.62 (s, 1 H), 7.50 (d, J=7.6 Hz, 2
3
3
(s, 2 H), 7.08 (t, J=7.6 Hz, 1 H), 7.00 (s, 2 H), 6.95 (d, J=
H), 7.39 (dd, J=22.8, 6.2 Hz, 3 H), 7.11–7.05 (m, 4 H), 6.81
1
3
7
3
1
1
.8 Hz, 5 H), 6.79 (t, J=7.6 Hz, 1 H), 6.62 (d, J=7.8 Hz, 1 H),
(s, 1 H), 6.62 (s, 2 H), 3.92 (s, 2 H), 2.26 (s, 3 H); C NMR
1
3
.63 (s, 2 H), 2.30 (s, 12 H); C NMR (101 MHz, CDCl ): δ
71.6, 149.1, 145.6, 140.0, 138.5, 133.2, 129.7, 129.5, 128.3,
27.4, 126.8, 125.4, 122.1, 120.3, 120.2, 38. 7, 21.4; HRMS
(100 MHz, CDCl ): δ 171.6, 148.8, 141.3, 136.5, 131.9, 131.6,
3
3
127.7, 127.6, 127.5, 126.4, 122.8, 122.0, 121.0, 120.5, 39.5,
+
20.8; ESI-HRMS: Calcd for C H NO S [M+H] 406.0930,
23
19
2 2
+
(ESI): Calcd for C H ClNO [M+H] : 470.1881; found:
found 406.0926.
30
29
2
470.1861.
2
-(4,4’’-Dichloro-5’-methoxy-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-
General Procedure for the Synthesis of Single
Arylated Phenylacetamides 4
(2-hydroxyphenyl)acetamide (3n). Yellow solid; mp 190–
1
1
91°C; H NMR (400 MHz, CDCl ): δ 8.42 (s, 1 H), 7.37 (dd,
3
In a 25 mL sealed tube equipped with stirring bar were charged
with amide 1 (0.2 mmol), aryl iodide (0.4 mmol), Pd(CF COO)2
J=8.4, 2.0 Hz, 4 H), 7.30 (dd, J=8.2, 2.0 Hz, 4 H), 7.09 (d,
J=7.4 Hz, 1 H), 6.96 (d, J=8.2 Hz, 2 H), 6.84 (d, J=2.0 Hz, 2
3
1
3
(0.02 mmol), K S O (0.2 mmol), K CO (0.8 mmol) and EtOH
H), 6.69 (d, J=7.8 Hz, 1 H), 3.84 (s, 3 H), 3.52 (s, 2 H);
NMR (100 MHz, CDCl ): δ 158.3, 148.6, 143.9, 139.4, 133.9,
C
2
2
8
2
3
(2 mL). The tube was then sealed with Teflon cap and subjected
3
to oil bath heating at 110°C and stirring for 8 h. Upon
completion, the reaction was allowed to cool down to room
temperature, and 10 mL water was added. The heterogeneous
mixture was extracted with ethyl acetate (3×10 mL). The
combined organic phase was dried over Na SO . After filtration,
the acquired solution was collected and the solvent was
removed at reduced pressure. The residue was subjected to
silica gel column chromatography to give pure products by
using mixed petroleum ether and ethyl acetate (v/v=10:1) as
eluent.
1
3
4
30.3, 128.8, 127.2, 121.9, 121.7, 120.4, 119.9, 115.5, 55.5,
+
8.1; ESI-HRMS: Calcd for C H Cl NO [M+H] :
27
22
2
3
78.0971, found 478.0970.
N-(2-Hydroxyphenyl)-2-(4,4’’,5’-trichloro-[1,1’:3’,1’’-terphen-
2
4
1
yl]-2’-yl)acetamide (3o). Yellow solid; mp 150–151°C;
H
NMR (400 MHz, CDCl ): δ 8.15 (s, 1 H), 7.38 (d, J=8.2 Hz, 4
3
H), 7.30 (d, J=6.4 Hz, 5 H), 7.11 (d, J=7.6 Hz, 1 H), 6.95 (d,
J=8.0 Hz, 2 H), 6.83 (t, J=7.5 Hz, 1 H), 6.75 (d, J=7.8 Hz, 1
13
H), 3.53 (s, 2 H); C NMR (100 MHz, CDCl ): δ 170.8, 148.4,
3
1
1
44.1, 138.3, 134.3, 133.2, 130.3, 129.6, 128.9, 128.4, 127.2,
25.1, 121.9, 120.5, 119.3, 38.4; ESI-HRMS: Calcd for
+
C H Cl NO [M+H] : 482.0476, found 482.0473.
Procedure for the 2mmol Scale Reaction Providing
2
6
19
3
2
4
a
2-(4,4’’-Dibromo-5’-fluoro-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-
hydroxyphenyl)acetamide (3p). Yellow solid; mp 216–217°C;
In a 50 mL sealed tube were charged with amide 1a (2 mmol),
iodobenzene 2a (4 mmol), Pd(CF COO) (0.2 mmol), K S O
(2 mmol), K CO (8 mmol) and EtOH (5 mL). The tube was
2 3
1
H NMR (400 MHz, CDCl ): δ 8.18 (s, 1 H), 7.54 (d, J=
.2 Hz, 4H), 7.26 (d, J=2.0 Hz, 3 H), 7.09 (d, J=6.6 Hz, 1 H),
3
3
2
2
2
8
8
7
8
.02 (d, J=8.6 Hz, 2 H), 6.97–6.92 (m, 2 H), 6.84 (t, J=
then sealed with Teflon cap and subjected to oil bath heating at
13
.0 Hz, 1 H), 6.74 (d, J=7.0 Hz, 1 H), 3.52 (s, 2 H); C NMR
110°C and stirring for 8 h. Upon completion, the reaction was
(
100 MHz, CDCl ): δ 171.0, 161.1 (d, J =248.0 Hz), 148.4,
allowed to cool down to room temperature, and 15 mL water
was added. The heterogeneous mixture was extracted with ethyl
acetate (3×20 mL). The combined organic phase was dried
over Na SO . After filtration, the acquired solution was
3
C-F
1
1
3
5
44.6 (d, JC-F =8.0 Hz), 139.0, 131.8, 130.6, 127.2, 125.1,
22.4, 121.9, 120.5, 119.7, 116.6 (d, JC-F =22.0 Hz), 116.5,
+
8.2; ESI-HRMS: Calcd for C H Br FNO [M+H]
26
19
2
2
2
4
53.9761, found 553.9766.
collected and the solvent was removed at reduced pressure. The
residue was subjected to silica gel column chromatography to
give pure product with 58% (351 mg) isolated yield by using
mixed petroleum ether and ethyl acetate (v/v=10:1) as eluent.
2
-(4-Chloro-2,6-di(thiophen-2-yl)phenyl)-N-(2-hydroxyphen-
1
yl)acetamide (3q). Yellow solid; mp 197–198°C; H NMR
(400 MHz, CDCl ): δ 8.35 (s, 1 H), 7.40 (s, 2 H), 7.29 (d, J=
3
4
6
.6 Hz, 2 H), 7.04–6.97 (m, 5 H), 6.89 (d, J=7.8 Hz, 1 H),
N-(2-Hydroxyphenyl)-2-(o–tolyl)acetamide (4a). Yellow
1
3
1
.79-6.72 (m, 2 H), 3.78 (s, 2 H); C NMR (100 MHz, CDCl ):
liquid; H NMR (400 MHz, CDCl ): δ 8.65 (s, 1 H), 7.42–7.37
3
3
δ 171.3, 148.7, 140.0, 138.1, 133.2, 131.4, 130.3, 128.0, 127.7,
27.3, 126.9, 122.2, 120.5, 119.7, 39.1; ESI-HRMS: Calcd for
(m, 5 H), 7.36–7.28 (m, 4 H), 7.10-7.04 (m, 1 H), 6.94 (d, J=
8.0 Hz, 1 H), 6.80-6.76 (m, 2 H), 3.74 (s, 2 H); C NMR
1
3
1
+
C H ClNO S [M+H] 426.0384, found 426.0380.
(100 MHz, CDCl ): δ 171.4, 148.6, 131.4, 130.8, 130.7, 129.0,
2
2
16
2
2
3
1
4
28.7, 128.3, 128.2, 127.7, 127.1, 125.4, 121.9, 120.3, 119.6,
2
-(4,4’’-Dichloro-[1,1’:3’,1’’-terphenyl]-2’-yl)-N-(2-hydroxy-4-
+
1.6; ESI-HRMS: Calcd for C H NO [M+H] : 304.1332,
20
18
2
methylphenyl)acetamide (3r). Yellow solid; mp 156–157°C;
found 304.1328.
1
H NMR (400 MHz, CDCl ): δ 8.29 (d, J=6.0 Hz, 1 H), 7.34–
3
7
.25 (m, 8 H), 7.21 (d, J=6.6 Hz, 2 H), 6.80 (d, J=8.4 Hz, 1
N-(2-Hydroxyphenyl)-2-(4’-methyl-[1,1’-biphenyl]-2-yl)
1
H), 6.71 (d, J=8.8 Hz, 1 H), 6.59–6.53 (m, 1 H), 6.51–6.43 (m,
1
NMR (100 MHz, CDCl ): δ 171.1, 148.5, 142.6, 139.4, 133.8,
acetamide (4b). Yellow solid; mp 130–131°C; H NMR
1
3
H), 3.52 (d, J=8.8 Hz, 2 H), 2.20 (d, J=9.0 Hz, 3 H);
C
(400 MHz, CDCl ): δ 8.70 (s, 1 H), 7.43–7.37 (m, 3 H), 7.34–
3
7.31 (m, 1 H), 7.20 (t, J=7.8 Hz, 4 H), 7.09–7.04 (m, 1 H),
6.95 (d, J=8.0 Hz, 1 H), 6.81–6.73 (m, 2 H), 3.75 (s, 2 H),
3
130.5, 129.9, 129.6, 128.7, 127.6, 121.8, 121.1, 120.3, 38.8,
Adv. Synth. Catal. 2019, 361, 1–10
6
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1
3
+
2
1
1
.38 (s, 3 H); C NMR (101 MHz, CDCl ): δ 171.69, 148.88,
76.8, 41.2, 21.4; ESI-HRMS: Calcd for C H ClNO [M+H] :
22 21 2
366.1255; found: 366.1252.
3
42.88, 137.66, 137.62, 131.60, 131.03, 130.83, 129.55, 128.98,
28.34, 127.40, 125.45, 122.07, 120.37, 120.02, 41.75, 21.30;
ESI-HRMS: Calcd for C H NO [M+H] : 318.1489; found:
+
2-(4-Chloro-2-(thiophen-2-yl)phenyl)-N-(2-hydroxyphenyl)
21
20
2
1
acetamide (4i).Yellow solid; mp 112–113°C;
H NMR
318.1485.
(
400 MHz, CDCl ): δ 8.43 (s, 1 H), 7.46 (s, 1 H), 7.38–7.33 (m,
3 H), 7.09–7.04 (m, 3 H), 6.96–6.91 (m, 2 H), 6.83–6.77 (m, 1
H), 3.82 (s, 2 H); C NMR (100 MHz, C DCl ): δ 170.7, 148.3,
136.6, 133.9, 132.40, 131.5, 130.9, 128.9, 127.8, 127.6, 127.2,
126.8, 125. 3, 122.0, 120.5, 119.4, 41.3; ESI-HRMS: Calcd for
3
2
-(4’-Bromo-[1,1’-biphenyl]-2-yl)-N-(2-hydroxyphenyl)
1
13
acetamide (4c). Yellow solid; mp 112–113°C; H NMR
3
(
7
8
(
1
1
400 MHz, CDCl ): δ 8.46 (s, 1 H), 7.55 (d, J=8.2 Hz, 2 H),
3
.43 (d, J=5.0 Hz, 3 H), 7.31 (d, J=7.0 Hz, 2 H), 7.18 (d, J=
.4 Hz, 2 H), 6.97 (d, J=8.0 Hz, 1 H), 6.82–6.79 (m, 2 H), 3.72
+
C H ClNO S [M+H] : 344.0507, found 344.0503.
19
18
2
13
s, 2 H); C NMR (100 MHz, CDCl ): δ 171.2, 148.6, 139.4,
31.8, 131.4, 130.8, 130.7, 129.0, 128.7, 128.7, 128.4, 128.3,
27.3, 125.3, 121.9, 120.4, 112.0, 119.8, 41.6; ESI-HRMS:
3
2
-(5-Fluoro-4’-methyl-[1,1’-biphenyl]-2-yl)-N-(2-hydroxy-
1
phenyl)acetamide (4j). Yellow solid; mp 148–149°C; H NMR
+
(400 MHz, CDCl ): δ 8.55 (s, 1 H), 7.36 (dd, J=8.4, 5.6 Hz, 1
3
Calcd for C H BrNO [M+H] : 382.0437, found 382.0433.
20
17
2
H), 7.22 (d, J=7.8 Hz, 2 H), 7.17 (d, J=8.0 Hz, 2 H), 7.09–
2
-(3’,5’-Dimethyl-[1,1’-biphenyl]-2-yl)-N-(2-hydroxyphenyl)
7.01 (m, 3 H), 6.94–6.86 (m, 2 H), 6.81–6.76 (m, 1 H), 3.68 (s,
1
13
acetamide (4d). Yellow solid; mp131-132°C; H NMR
2 H), 2.37 (s, 3 H); C NMR (100 MHz,CDCl ) δ: 171.3, 162.0
3
(400 MHz, CDCl ): δ 8.75 (s, 1 H), 7.42–7.35(m, 3 H), 7.33–
(d, JC-F =247 Hz), 148.4, 144.8 (d, JC-F =8 Hz), 137.9, 136.64,
132.3 (d, JC-F =8 Hz), 129.5, 128.7, 127.4, 127.1, 125.4, 121.9,
120.4, 119.4, 117.5 (d, JC-F =20 Hz), 115.0 (d, JC-F =21 Hz),
3
7
6
.29 (m, 1 H), 7.08–7.00 (m, 2 H), 6.93 (d, J=12.0 Hz, 3 H),
13
.77 (d, J=4.4 Hz, 2 H), 3.73 (s, 2 H), 2.31 (s, 6 H); C NMR
+
(101 MHz, CDCl ) δ 171.7, 148.9, 143.1, 140.5, 138.5, 131.5,
40.84, 21.18; ESI-HRMS: Calcd for C H FNO [M+H] :
3
21 19
2
130.8, 130.8, 129.5, 128.3, 128.2, 127.4, 126.9, 125.4, 122.1,
336.1394, found 336.1391.
1
+
20.3, 120.1, 41.8, 21.4; ESI-HRMS: Calcd for C H NO [M
H] : 332.1645; found: 332.1637.
22
22
2
+
2-(5-Fluoro-3’,5’-dimethyl-[1,1’-biphenyl]-2-yl)-N-(2-
hydroxyphenyl)acetamide (4k). Yellow solid; mp 119–120°C;
1
2
-(5-Chloro-[1,1’-biphenyl]-2-yl)-N-(2-hydroxyphenyl)
H NMR (400 MHz, CDCl ): δ 8.60 (s, 1 H), 7.36 (dd, J=8.4,
3
1
acetamide (4e). Yellow solid; mp 108–109°C; H NMR
5.6 Hz, 1 H), 7.09–7.00 (m, 4 H), 6.92 (d, J=17.4 Hz, 3 H),
1
3
(400 MHz, CDCl ): δ 8.42 (s, 1 H), 7.41 (t, J=7.8 Hz, 3 H),
6.85–6.76 (m, 2 H), 3.68 (s, 2 H), 2.30 (s, 6 H); C NMR
3
7
.35–7.25 (m, 4 H), 7.20 (s, 1 H), 7.08 (t, J=6.8 Hz, 1 H), 6.95
(100 MHz, CDCl ): δ 171.3, 162.0 (d, J =246 Hz), 148.4,
3
C-F
(
d, J=8.0 Hz, 1 H), 6.80 (d, J=13.4 Hz, 2 H), 3.69 (s, 2 H);
145.0 (d, JC-F =8.0 Hz), 139.5, 138.5, 132.3 (d, JC-F =8.0 Hz),
129.7, 127.4, 127.1, 126.6, 125.3, 121.1 (d, JC-F =154.0 Hz),
119.5, 117.4 (d, JC-F =21.0 Hz), 114.9 (d, JC-F =21.0 Hz), 40.9,
13
C NMR (100 MHz, CDCl ): δ 170.9, 148.7, 144.4, 139.5,
3
1
1
34.0, 132.2, 130.8, 130.2, 129.0, 128.5, 128.3, 127.5, 125.4,
22.1, 120.5, 112.0, 41.1; ESI-HRMS: Calcd for C H Cl NO
+
21.3; ESI-HRMS: Calcd for C H FNO [M+H] : 350.1551,
20
17
2
22 21
2
+
[M+H] : 338.0942; found: 338.0948.
found 350.1547.
2
-(5-Chloro-4’-methyl-[1,1’-biphenyl]-2-yl)-N-(2-hydroxy-
1
N-(2-Hydroxyphenyl)-2-(5-methoxy-4’-methyl-[1,1’-biphen-
1
phenyl)acetamide (4f). Yellow solid; mp 117–118°C; H NMR
yl]-2-yl)acetamide (4l). Yellow solid; mp 149–150°C;
H
(400 MHz, CDCl ): δ 8.49 (s, 1 H), 7.34 (s, 2 H), 7.24 (d, J=
NMR (400 MHz, CDCl ): δ 8.78 (s, 1 H), 7.31 (d, J=8.4 Hz, 1
3
3
4.8 Hz, 3 H), 7.17 (d, J=8.0 Hz, 2 H), 7.10–7.05 (m, 1 H), 6.94
H), 7.23–7.17 (m, 4 H), 7.08–7.04 (m, 1 H), 6.95–6.91 (m, 2
(
d, J=8.0 Hz, 1 H), 6.84–6.77 (m, 2 H), 3.69 (s, 2 H), 2.38 (s,
H), 6.87 (d, J=2.6 Hz, 1 H), 6.79–6.74 (m, 2 H), 3.82 (s, 3 H),
13
13
3
1
1
H); C NMR (101 MHz, CDCl ): δ 171.1, 148.7, 144.4,
3.67 (s, 2 H), 2.38 (s, 3 H); C NMR (100 MHz, CDCl ): δ
3
3
38.2, 136.5, 133.9, 132.1, 130.8, 130.2, 129.3, 128.8, 128.3,
172.0, 148.6, 144.1, 137.6, 131.9, 129.4, 128.7, 127.1, 125.4,
123.5, 121.9, 120.2, 119.7, 116.2, 113.8, 55.4, 40.8, 21.2; ESI-
27.4, 125.4, 122.1, 120.5, 119.9, 41.1, 21.3; HRMS (ESI):
+
+
Calcd for C H ClNO [M+H] : 352.1099; found: 352.1094.
HRMS: Calcd for C H NO [M+H] : 348.1594, found
21
19
2
22 22
3
3
48.1591.
2
-(4’,5-Dichloro-[1,1’-biphenyl]-2-yl)-N-(2-hydroxyphenyl)
1
acetamide (4 g). Yellow solid; mp 141–142°C; H NMR
2-(4’-Chloro-5-methoxy-[1,1’-biphenyl]-2-yl)-N-(2-hydroxy-
1
(400 MHz, CDCl ): δ 8.18 (s, 1 H), 7.32–7.27 (m, 4 H), 7.21 (s,
phenyl)acetamide (4m). Yellow solid; mp 141–142°C;
H
3
1
H), 7.14 (d, J=8.0 Hz, 2 H), 7.00 (t, J=7.6 Hz, 1 H), 6.87
NMR (400 MHz, CDCl ): δ 8.50 (s, 1 H), 7.32 (d, J=8.3 Hz, 2
3
(dd, J=14.6, 7.8 Hz, 2 H), 6.75 (t, J=7.2 Hz, 1 H), 3.57 (s, 2
H), 7.17 (t, J=7.4 Hz, 3 H), 7.05–7.00 (m, 1 H), 6.91–6.87 (m,
13
13
H); C NMR (100 MHz, CDCl ): δ 170.5, 148.2, 137.7, 134.3,
2 H), 6.78– 6.69 (m, 3 H), 3.77 (s, 3 H), 3.57 (s, 2 H);
C
3
1
1
33.8, 132.1, 130.4, 130.2, 130.1, 129.0, 128.5, 127.1, 125.2,
21.9, 120.6, 119.3, 40.9; ESI-HRMS: Calcd for C H Cl NO
NMR (100 MHz, CDCl ): δ 171.7, 159.2, 148.7, 138.8, 134.0,
132.0, 130.2, 128.9, 127.3, 123.4, 121.9, 120.4, 119.9, 116.2,
3
20
16
2
2
+
[M+H] : 372.0553, found 372.0550.
114.2, 55.4, 40.7; ESI-HRMS: Calcd for C H ClNO [M+
21
19
3
+
H] : 368.1048, found 368.1045.
2-(5-Chloro-3’,5’-dimethyl-[1,1’-biphenyl]-2-yl)-N-(2-
hydroxyphenyl)acetamide (4h). Yellow solid; mp 120–121°C;
N-(2-Hydroxyphenyl)-2-(5-methoxy-3’,5’-dimethyl-[1,1’-bi-
1
1
H NMR (400 MHz, CDCl ): δ 8.54 (s, 1 H), 7.34 (d, J=
.2 Hz, 2 H), 7.31 (s, 1 H), 7.19 (s, 1 H), 7.02 (s, 1 H), 6.94 (d,
phenyl]-2-yl)acetamide (4n). Yellow solid; mp 154–155°C; H
3
1
NMR (400 MHz, CDCl ): δ 8.82 (s, 1 H), 7.31 (d, J=8.4 Hz, 1
3
J=8.0 Hz, 1 H), 6.89 (s, 2 H), 6.79 (d, J=3.8 Hz, 2 H), 3.69
H), 7.09–7.04 (m, 1 H), 7.01 (s, 1 H), 6.97–6.90 (m, 4 H), 6.86
1
3
(
s, 2 H), 2.31 (s, 6 H); C NMR (100 MHz, CDCl ): δ 171.1,
(d, J=2.6 Hz, 1 H), 6.80–6.75 (m, 1 H), 6.71 (d, J=7.8 Hz, 1
3
1
3
1
1
48.8, 144.6, 139.4, 138.7, 133.9, 132.1, 130.7, 130.1, 129. 9,
28.2, 127.4, 126.7, 125.3, 122.1, 120.5, 120.0, 77.5, 77.2,
H), 3.82 (s, 3 H), 3.67 (s, 2 H), 2.31 (s, 6 H); C NMR
(100 MHz, CDCl ): δ 172.1, 159.1, 144.3, 140.4, 138.4, 131.8,
3
Adv. Synth. Catal. 2019, 361, 1–10
7
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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+
1
5
3
29.4, 127.2, 126.6, 125.3, 121.9, 120.2, 119.8, 115.9, 113.9,
HRMS: Calcd for C H Cl NO [M+H] : 372.0553, found
20 16 2 2
372.0550.
+
5.4, 40.9, 21.3; ESI-HRMS: Calcd for C H NO [M+H] :
23
24
3
62.1751, found 362.1746.
N-(5-Chloro-2-hydroxyphenyl)-2-(3’,5’-dimethyl-[1,1’-bi-
1
N-(2-Hydroxyphenyl)-2-(4’-methyl-[1,1’-biphenyl]-2-yl)
phenyl]-2-yl)acetamide (4u). Yellow solid; mp 144–145°C; H
1
acetamide (4o). Yellow solid; mp 161–162°C; H NMR
NMR (400 MHz, CDCl ): δ 8.70 (s, 1 H), 7.42–7.38 (m, 3 H),
3
(400 MHz, CDCl ): δ 8.72 (s, 1 H), 7.40–7.37 (m, 2 H), 7.34–
7.35–7.31 (m, 1 H), 7.07–7.03 (m, 2 H), 6.93 (s, 2 H), 6.87 (d,
3
7
3
2
1
1
.30 (m, 1 H), 7.25–7.23 (m, 1 H), 7.21 (s, 1 H), 7.20–7.14 (m,
H), 6.77 (s, 1 H), 6.58 (s, 2 H), 3.73 (s, 2 H), 2.38 (s, 3 H),
.24 (s, 3 H); C NMR (100 MHz, CDCl ): δ 171.4, 148.5,
42.7, 137.6, 137. 5, 131.6, 130.9, 130.7, 129.4, 128.9, 128.2,
28.1, 122.8, 121.8, 120.9, 120.3, 41.6, 21.2, 20.8; ESI-HRMS:
J=8.6 Hz, 1 H), 6.66 (d, J=2.4 Hz, 1 H), 3.78 (s, 2 H), 2.35
(s, 6 H); C NMR (100 MHz, CDCl ) δ 171.9, 147.6, 142.9,
140.6, 138.4, 131.3, 130.9, 130.8, 129.6, 128.4, 128.4, 127.1,
127.0, 126.4, 124.8, 121.8, 121.1, 41.9, 21.5; ESI-HRMS: Calcd
for C H Cl NO [M+H] : 366.1255; found: 366.1256.
1
3
3
13
3
+
22
21
2
+
Calcd for C H NO [M+H] : 332.1645, found 332.1641.
22
22
2
2
-([1,1’-Biphenyl]-2-yl)-N-(2-hydroxy-5-methylphenyl)
1
2
-(4’-Chloro-[1,1’-biphenyl]-2-yl)-N-(2-hydroxy-4-meth-
acetamide (4v). Yellow solid; mp 130–131°C; H NMR
1
ylphenyl)acetamide (4p). Yellow solid; mp 156–157°C; H
(400 MHz, CDCl ): δ 8.44 (s, 0 H), 7.40 (dd, J=5.8, 3.4 Hz, 3
3
NMR (400 MHz, CDCl ): δ 8.50 (s, 1 H), 7.43–7.37 (m, 5 H),
H), 7.21 (t, J=8.8 Hz, 4H), 7.14 (s, 1 H), 6.89–6.83 (m, 2 H),
3
7.30 (d, J=5.4 Hz, 1 H), 7.20 (d, J=9.8 Hz, 2 H), 6.78 (s, 1
6.51 (d, J=1.8 Hz, 1 H), 3.75 (s, 2 H), 2.40 (s, 3 H), 2.20 (s, 3
H); C NMR (100 MHz, CDCl ): δ 171.4, 146.4, 137.6, 137.4,
1
3
13
H), 6.63 (q, J=7.8 Hz, 2 H), 3.70 (s, 2 H), 2.25 (s, 3 H);
C
3
NMR (100 MHz, C DCl ): δ 171.1, 148.4, 141.6, 138.9, 137.6,
130.9, 130.7, 129.4, 128.9, 128.2, 128.1, 127.8, 122.3, 119.61,
3
+
1
1
31.5, 130.8, 130.7, 130.3, 128.8, 128.6, 128.2, 121.7, 121.1,
41.7, 21.2, 20.3; ESI-HRMS: Calcd for C H NO [M+H] :
22
22
2
20.3, 41.5, 20.8; ESI-HRMS: Calcd for C H ClNO [M+
332.1645, found 332.1641.
21
19
2
+
H] : 352.1099, found 352.1095.
2
-([1,1’:4’,1’’-Terphenyl]-2-yl)-N-(2-hydroxy-4-meth-
Deprotection of Compound 4a
1
ylphenyl)acetamide (4q). Yellow solid; mp 146–147°C; H
In a 25 mL sealed tube equipped stirring bar were charged with
a (0.2 mmol), NaOH (8 mmol) and MeOH (4 mL). The tube
was then sealed with Teflon cap and the vessel was stirred at
NMR (400 MHz, CDCl ): δ 8.69 (s, 1 H), 7.69–7.60 (m, 4 H),
3
4
7
.47–7.37 (m, 8 H), 7.13 (s, 1 H), 6.80 (s, 1 H), 6.62–6.54 (m, 2
1
3
H), 3.80 (s, 2 H), 2.26 (s, 3 H); C NMR (100 MHz, CDCl ): δ
3
1
30°C for 48 h. Subsequently, the reaction was allowed to cool
1
1
2
3
48.6, 140.6, 139.4, 137.6, 130.8, 129.6, 129.5, 128.9, 128.4,
28.2, 127.6, 127.4, 127.1, 122.7, 121.8, 121.0, 120.4, 41.6,
0.8; ESI-HRMS: Calcd for C H Cl NO [M+H] :
down to room temperature, the reaction mixture was then
diluted with water (2 mL), and treated with Na SO solution
+
2
3
27
24
2
2
(0.2 g in 2 mL water), and acidified to pH=2 with 0.5 M
94.1802, found 394.1799.
hydrochloric acid. The resulting suspension was further stirred
at rt for 3 h, and extracted with EtOAc (3×10 mL). The
combined organic phase was washed with brine, dried over
anhydrous Na SO , concentrated, and purified by silical gel
N-(2-Hydroxy-4-methylphenyl)-2-(2-(thiophen-2-yl)phenyl)
1
acetamide (4r). Yellow solid; mp 119–120°C; H NMR
(
400 MHz, CDCl ): δ 8.59 (s, 1 H), 7.42 (dd, J=5.4, 2.8 Hz, 1
3
2
4
H), 7.35-7.31 (m, 3 H), 7.18 (s, 1 H), 7.03–7.00 (m, 1 H), 6.97
column chromatography with the elution of mixed petroleum
(
d, J=3.0 Hz, 1 H), 6.71 (s, 1 H), 6.54 (t, J=8.3 Hz, 2 H), 3.80
ether and EA (v/v=2:1).
1
3
(s, 2 H), 2.17 (s, 3 H); C NMR (100 MHz, CDCl ): δ 171.2,
3
8
1
2
-([1,1’-Biphenyl]-2-yl)acetic acid (5). H NMR (400 MHz,
1
1
48.6, 137.6, 135.0, 131.8, 131.2, 129.0, 128.3, 127.7, 127.1,
13
CDCl ): δ 7.41–7.22 (m, 9 H), 3.62 (s, 2 H); C NMR
3
26.3, 122.7, 121.9, 121.0, 120.3, 41.9, 20.8; ESI-HRMS: Calcd
+
(100 MHz, CDCl ): δ 178.3, 142.7, 141.0, 131.1, 130.4, 130.3,
3
for C H NO S [M+H] : 324.1053, found 324.1049.
19
18
2
1
29.3, 128.3, 127.6, 127.4, 127.3, 38.6.
N-(5-Chloro-2-hydroxyphenyl)-2-(4’-methyl-[1,1’-biphenyl]-
1
2
(
7
8
(
-yl)acetamide (4s). Yellow solid; mp 169–170°C; H NMR
400 MHz, CDCl ): δ 8.54 (s, 1 H), 7.40 (d, J=3.2 Hz, 3 H),
3
Acknowledgements
.35-7.32 (m, 1 H), 7.25 (d, J=6.8 Hz, 2 H), 7.19 (d, J=
.0 Hz, 2 H), 7.02-7.00 (m, 1 H), 6.85 (d, J=8.6 Hz, 1 H), 6.78
This work is financially supported by the National Natural
Science Foundation of China (no. 21562024).
13
d, J=2.4 Hz, 1 H), 3.76 (s, 2 H), 2.41 (s, 3 H); C NMR
(
100 MHz, CDCl ): δ 171.7, 147.2, 137.6, 137.5, 131.2, 130.9,
3
1
1
30.7, 129.5, 128.8, 128.3, 128.3, 126.8, 126.3, 124.8, 121.6,
20.6, 41.8, 21.2; ESI-HRMS: Calcd for C H ClNO [M+ References
21
19
2
+
H] : 352.1099, found 352.1095.
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3
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(
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Adv. Synth. Catal. 2019, 361, 1–10
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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!

FULL PAPER
Tunable Single and Double γ-CÀ H Arylation of Phenylaceta-
mides Directed by o-Aminophenols
Adv. Synth. Catal. 2019, 361, 1–10
Z. Tu, Y. Du, X. Cao, Y. Liu*