Equivalent Loading of Directed Arenes in Pd(II)-Catalyzed Oxidative Cross-Coupling of Aryl C-H Bonds at Room Temperature

Article abstract of DOI:10.1021/acs.joc.0c02722

The unsymmetrical biaryls (Ar1-Ar2) produced by the catalytic cross-couplings of aryl halides (Ar1-halo) with aryl metallics (Ar2-M) in the loading ratio of 1:1 are popular in chemical synthesis. In contrast, there has been less precedence on the same biaryls produced effectively from two normal aryl C-H bonds with equivalent loading. Here, we report that, in a palladium/oxidant/acid catalytic system at room temperature, one arene (Ar1-H, 1 equiv) can highly selectively couple with the other one (Ar2-H, 1 equiv) to afford the target Ar1-Ar2 just by controlling the directing groups and the substituted groups on their phenyl rings. The utility of this one-one cross-coupling is also demonstrated by synthesis of a few bioactive molecules.

Full text of DOI:10.1021/acs.joc.0c02722

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Equivalent Loading of Directed Arenes in Pd(II)-Catalyzed Oxidative
Cross-Coupling of Aryl C−H Bonds at Room Temperature
Chong Mei, Mengdi Zhao, and Wenjun Lu*
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ABSTRACT: The unsymmetrical biaryls (Ar1−Ar2) produced by
the catalytic cross-couplings of aryl halides (Ar1−halo) with aryl
metallics (Ar2−M) in the loading ratio of 1:1 are popular in
chemical synthesis. In contrast, there has been less precedence on
the same biaryls produced effectively from two normal aryl C−H
bonds with equivalent loading. Here, we report that, in a
palladium/oxidant/acid catalytic system at room temperature,
one arene (Ar1−H, 1 equiv) can highly selectively couple with the
other one (Ar2−H, 1 equiv) to afford the target Ar1−Ar2 just by
controlling the directing groups and the substituted groups on their
phenyl rings. The utility of this one−one cross-coupling is also demonstrated by synthesis of a few bioactive molecules.
coupling partner is employed to avoid the formation of
homocoupling products and/or to accelerate the desired
reaction rate, the selectivity of cross-coupling should be good
in these cases.23b,30,31 However, it is not only to enormously
limit their applications in synthesis but also to sharply decrease
the actual yield of unsymmetrical biaryl based on two coupling
partners (Figure 1). In fact, enhancing both the actual yield
and selectivity of the one−one cross-couplings is always a
challenge to researchers, especially in type III reactions. Here,
we disclose a palladium-catalyzed oxidative one−one cross-
coupling of two directed aryl C−H bonds (Ar1−H and Ar2−
H) to prepare unsymmetrical biaryl (Ar1−Ar2) at room
temperature (Scheme 1c). The cross-coupling products and
selectivity are predictable and dependent on the directing
groups and other substituted groups of the coupling partners.
A variety of functional groups on aromatic rings are compatible
in this catalytic system, including −R, −NHCOR, −OR, −F,
−Cl, −Br, −CONHR, −CO2R, −CF3, etc., providing more
possibilities for biaryl building blocks in chemical synthesis.
INTRODUCTION
■
An unsymmetrical biaryl (Ar1−Ar2) is a common moiety in
many natural products, pharmaceuticals, and photoelectric
materials, having two different aromatic rings directly
connected to each other just by an aryl C−C bond.1−3 In
the preparation of unsymmetrical biaryls, apparently one of the
most convenient methods is cross-coupling of two different
arenes with equivalent loading (a 1:1 stoichiometry of coupling
partners) under mild conditions, which is called a one−one
cross-coupling here. For the one−one cross-couplings of two
coupling partners (A and B), they can be divided into three
types according to the homocouplings of A and/or B
happening or not under the same conditions, as shown in
Scheme 1. In type I, none of homocoupling products is
observed (neither AA nor BB) except the target product (AB).
In type II, only one homocoupling product is formed (AA or
BB). In type III, two homocoupling products are produced
(AA and BB). The classical transition-metal-catalyzed cross-
couplings of aryl halides (Ar1−halo) with aryl organometallics
(Ar2−M) belong to type I reactions, including the Kumada,
Suzuki, Stille, Negishi couplings, etc.4−17 Since neither aryl
halides nor aryl organometallics could undergo homocoupling
reactions under the selected conditions, two different
prefunctionalized arenes are used effectively as the equivalent
coupling partners to give the only cross-coupling products in
these reactions (Scheme 1a).18−20 In the past decade, as a kind
of more concise and elegant method, transition-metal-catalyzed
oxidative cross-couplings of simple or directed arenes (Ar1−H
and Ar2−H) were developed to afford unsymmetrical biaryls
(Ar1−Ar2). However, most of them are type II or III reactions
(Scheme 1b).21−29 If the differences are large enough between
two coupling partners on their character of aryl C−H bond,
steric hindrance, or other factors, and an excess of one
RESULTS AND DISCUSSION
■
In our studies on the preparation of unsymmetrical 2,2′-
bisanilides (protected 2,2′-diaminobiaryls) by Pd(II)-catalyzed
oxidative cross-coupling of aryl C−H bonds at room
temperature, we observed that N-(3-tolyl)pivalamide (Ar1−
Received: November 13, 2020
Published: January 14, 2021
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© 2021 American Chemical Society
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Scheme 1. One−One Cross-Couplings of Aryl C−H Bonds to Form Biaryls (Ar1−Ar2)
same reaction conditions, just changing the previous amide
directing group (−NHPiv),32 also as a protecting group in the
reaction to be a weak coordinating group (−NPhth) for
palladium complexes.33 It was delightfully found that unsym-
metrical 2,2′-bisanilides 3 (Ar1−Ar2) were obtained in 53%
yield after only half an hour, and the selectivity of cross-
coupling was remarkably increased to 89% (entry 3). After 3 h,
the isolated yield of 3 was up to 75% with keeping the high
selectivity (entry 4). In the absence of catalytic palladium(II)
acetate or potassium persulfate as an oxidant, no unsym-
1
metrical biaryl was detected by H NMR (Table 1), showing
that a Pd(II)/Pd(IV)/Pd(II) catalytic cycle should be involved
in the cross-coupling. The independent experiments on the
kinetic isotope effect (KIE) implied that any electrophilic C−
H activations by palladium were not the rate-determining steps
in all homocouplings and cross-couplings of arenes (Ar1−H
and Ar2−H) under the identical conditions (Scheme 3). The
competitive deuterations of two substrate arenes confirmed
that an arene with a strong directing group was easily attacked
by palladium(II) catalyst in the first C−H cleavage (Scheme
4). Thus, a reasonable reaction route is suggested and
supported by the experiments, density functional theory
(DFT) calculations, and previous reports. A couple of
substrates are employed here. One is Ar1−H bearing a
stronger directing group (−NHPiv) but a less electron-
donating substituted group (−Me), and the other is Ar2−H
bearing a weaker directing group (−NPhth) but a stronger
electron-donating substituted group (−OMe).
Figure 1. Actual yield of the unsymmetrical biaryl based on two
coupling partners. A and B are coupling partners; if A/B = 1, the yield
is 100%, but when A/B = 3, the actual yield is down to 50% based on
A and B.
H) coupled with N-(3-ethylphenyl)pivalamide (Ar2−H) (two
similar arenes) gave unsymmetrical 2,2′-bisanilides 1 (Ar1−
Ar2) in 50% yield with a statistical and maximum selectivity
(50%) (Scheme 2, entry 1).23b Definitely, it is a typical type III
reaction, and the reactivity of two coupling partners is almost
the same in the reaction. If the substituted group −Et on Ar2−
H was replaced by a more electron-rich one −OMe, then the
selectivity was decreased to 39% (less than 50%), and the
major product was its homocoupling product Ar2−Ar2 in 34%
yield since the aryl C−H bond of Ar2−H with the −OMe
group is more reactive than that of Ar1−H with the −Me group
through an electrophilic C−H activation (entry 2). Then, we
tried to test 2-(3-methoxyphenyl)isoindoline-1,3-dione as
Ar2−H instead of N-(3-methoxyphenyl)pivalamide under the
As shown in Scheme 5, there are two key selections to
guarantee a good selectivity in this one−one cross-coupling.
The first selection is that Ar1−H with −NHPiv group is more
attractive to palladium(II) species than Ar2−H with −NPhth
group to give a coordinating complex followed by its aryl
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Scheme 2. Pd(II)-Catalyzed One−One Cross-Coupling of Directed Arenes
a
Table 1. Pd(II)-Catalyzed Cross-Coupling of N-(m-Tolyl)pivalamide and 2-(3-Methoxyphenyl)isoindoline-1,3-dione
conv. (%)
yield (%)
b c
b
d
e
entry
1a (mmol)
2a (mmol)
0.4
1a
2a
8
1aa
3
2aa
8
selectivity (%)
f
1
f
2
0.4
0.2
f
3
0.2
0.4
0.3
0.2
0.1
4
93
73
78
94
n.d.
n.d.
4
4
5
6
7
8
89
57
9
0.1
0.2
0.3
0.4
0.2
0.2
60
79
54
55
30
95
3
8
20
53
20
13
24
69
45
36
89
74
4
g
9
10
0.2
0.2
10
97
10
81(75)
trace
10
50
88
h
a
Reaction conditions: substrates (0.4 mmol totally), Pd(OAc)2 (0.016 mmol), K2S2O8 (0.3 mmol), CF3CO2H (3 mmol), MeSO3H (1 mmol), 25
°C, 1 h. Conversions and yields are based on the substrate and determined by 1H NMR with CH2Br2 as an internal standard. The isolated yields are
in parentheses. Yield is based on 1a. Yield is based on all substrates. Yield is based on 2a. The selectivity of cross-coupling is calculated by 3/
(1aa + 3 + 2aa). Without K2S2O8. CF3CO2H (4 mmol) only. 3 h.
b
c
d
e
f
g
h
palladium(II) intermediate (Ar1−Pd(II)) formed via the first
C−H activation, as mentioned in the above competitive
deuterations. In this process, the generation of a more stable
Ar1−Pd(II) is faster than that of Ar2−Pd(II), which is helpful
to retard the formation of Ar2−Ar2 by reductive elimination of
Ar2−Pd(IV)−Ar2.34 In DFT calculations, Ar1-TS1 and Ar2-
TS1 represent the transition states of Pd(II) catalyst
coordinated with Ar1−H and Ar2−H, respectively, and the
free-energy barrier of Ar1-TS1 relative to its precursor complex
Ar1-Int0 is much lower than that of Ar2-TS1 relative to Ar2-
Int0 (Figure 2a,b). Compared with that of the −NHPiv group,
the coordination ability of the −NPhth group to Pd(II) is
much weaker, although a stronger electron-donating sub-
stituted group (OMe) on Ar2−H should slightly improve its
coordination ability. At the same time, as a directing group, it
ensures that the reaction takes place in its ortho position, so in
the first C−H activation, a minor quantity of the intermediate
Ar2−Pd(II) is generated, while Ar1−Pd(II) is the major
product. After an oxidation of Ar1−Pd(II) to Ar1−Pd(IV) and
the second C−H activation, two important intermediates Ar1−
Pd(IV)−Ar2 and Ar1−Pd(IV)−Ar1 are produced. The second
selection is the rate of reductive elimination of Ar1−Pd(IV)−
Ar2 to give Ar1−Ar2, which is faster than that of Ar1−Pd(IV)−
Ar1 to give Ar1−Ar1 because of the Ar2 phenyl ring bearing a
relatively weak coordinating group (−NPhth) and an electron-
rich substituted group (−OMe) to Pd(IV) species.35 In the
calculations, Ar1−Ar1−TS is a Pd(IV) reductive elimination
transition state of Ar1−H in its homocoupling and Ar1−Ar2−
TS is a Pd(IV) reductive elimination transition state of Ar1−H
and Ar2−H in their cross-coupling. The free-energy barrier of
Ar1−Ar2−TS is lower than that of Ar1−Ar1−TS, relative to
their reductive elimination intermediates Ar1−Pd(IV)−Ar2 and
Ar1−Pd(IV)−Ar1, respectively (Figure 2c,d). As a result, the
unsymmetrical biaryl Ar1−Ar2 is the major product, and Pd(II)
catalyst is also regenerated through a Pd(II)/Pd(IV)/Pd(II)
catalytic cycle. Overall, it is feasible to establish a palladium-
(II)-catalyzed oxidative cross-coupling of equivalent directed
aryl C−H bonds just by choosing and tuning the coordinating
ability of directing groups and the electron-donating ability of
aromatic substituted groups.
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Scheme 3. Kinetic Isotope Effect Experiments
Scheme 4. H/D Exchange Reactions
A general and simple guide to establish a catalytic one−one
cross-coupling of aryl C−H bonds is to keep the balance
between two coupling partners (Ar1−H and Ar2−H) on their
reactivity: one is not easy to undergo the reductive elimination
to form coupling products but easy to be attacked by the initial
catalyst (Ar1−H is less electron-rich and with stronger
coordinating ability) and the other is just the opposite (Ar2−
H is more electron-rich and with weaker coordinating ability).
According to this criterion, the scope of arene substrates was
investigated by the use of the effectively catalytic system of
Pd(OAc)2/K2S2O8/CF3CO2H-MeSO3H under air at room
temperature (Scheme 6). In the one−one cross-couplings of
two anilines to prepare 2,2′-diaminobiaryls, one aniline with
electron-withdrawing group such as −F, −Cl, −Br, −CO2Me,
or −CF3 group should be converted into an anilide with a
stronger coordinating group (−NHPiv). On the other hand,
the other aniline as its coupling partner substituted by an
electron-donating group such as −OMe, −Me, or −Et group,
its amino group (−NH2) should be transformed to a weaker
coordinating amide group (−NPhth). The former anilide is
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Scheme 5. Two Key Selections in the Pd(II)-Catalyzed One−One Cross-Coupling of Directed Arenes
Ar1−H, and the latter one is Ar2−H. When the halo groups
(−F, −Cl, and −Br) were the substituted groups of Ar1−H at
the meta positions, the yields of unsymmetric biaryls (5−7)
were good (74−84%) with a very high selectivity (87−90%) if
Ar2−H is bearing the −OMe group. Meanwhile, biaryls (23
and 26−29) were obtained in 55−65% yields if Ar2−H bears
−Me or −Et group. In contrast, the yields were poor (31−
46%), but the selectivities were good (82−89%) when halo
groups were at the para positions of Ar1−H (10, 11, 32, and
33). Remarkably, if Ar1−H contained a strong electron-
withdrawing group −CF3 or −CO2Me, then Ar2−H with weak
electron-donating groups like alkyl groups (24, 25, 30, and 31)
were preferred rather than those with the −OMe group (8 and
12) in the cross-couplings since the homocoupling of Ar2−H
compared with that of Ar1−H affected the yield and selectivity
much seriously in these cases. However, when Ar2−H has the
−OMe group, Ar1−H with a weak electron-donating group
(−Me, −Et) or without substituted group was also available to
give Ar1−Ar2 (4, 9, 13, and 15) in a moderate to good yield of
65−80% and a very high selectivity of >87%. For Ar1−H with
two −Me groups, the yields of Ar1−Ar2 (16 and 17) were still
over 65%. In addition, for Ar2−H with two different
substituted groups, the target compounds (18−22) were
produced in moderate to good yields (64−84%) and in high
selectivities (81−91%). Interestingly, although the homocou-
pling reaction of Ar2−H substituted by −OMe at the ortho
position was hindered, its cross-couplings (type II) were still
carried out very well to yield the sole 2,3′-bisanilides, ortho−
meta Ar1−Ar2 (34−38). Both regioselectivity and cross-
coupling selectivity of unsymmetrical biaryls could be 100%
if −Cl or −Br is the substituted group at the ortho position of
Ar1−H (35 and 36). An electron-withdrawing group such as
−CONHtBu or −CO2Et might also play the role of
coordinating group on Ar2−H, and the cross-coupling products
were still the major ones (39−42). However, pyridine or
pyridone as directing groups or ligands were not suitable for
these reactions in the presence of strong acids.36 When a
simple arene 3-chloroanisole as Ar2−H reacted with 3-
chloroanilide (Ar1−H with a strong directing group
−NHPiv), two unsymmetrical products 43 and 44 (∼1:1)
were obtained in 57% yield with 88% cross-coupling selectivity,
which were from the ortho and para positions of the −OMe
group on 3-chloroanisole, respectively. Moreover, when anisole
or o-xylene as Ar2−H reacted with N-(o-tolyl)pivalamide, the
unsymmetrical biaryls 45 and 46 could also be obtained in
moderate yields (60−62%) with high cross-coupling selectiv-
ities (81−82%). Other very electron-rich arenes, such as
phenols and 1,3,5-trimethoxylbenezene, were not available in
these couplings since they were easily oxidized by oxidants to
benzoquinone derivatives under the reaction conditions.
Overall, it indicates that two different arenes Ar1−H/Ar2−H
with equivalent loading can undergo a highly selective cross-
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Figure 2. M06 free-energy profiles for the coordination and reductive elimination mechanism (298.15 K, kcal/mol). (a, b) Free-energy barrier of
the coordination transition state Ar1−TS1 or Ar2−TS1 relative to a precursor complex Ar1-Int0 or Ar2-Int0 in each case. (c, d) Free-energy barrier
of the reductive elimination transition state Ar1−Ar1−TS or Ar1−Ar2−TS relative to the intermediate Ar1−Pd(IV)−Ar1 or Ar1−Pd(IV)−Ar2 in
each case.
coupling when Ar1−H with strong coordinating ability to
catalyst has a priority to give Ar1−Pd(II) species, and Ar2−H is
a relatively electron-rich arene to be beneficial in the reductive
elimination of Ar1−Pd(IV)−Ar2 to produce Ar1−Ar2 finally. In
these cases, a weak coordinating group of Ar2−H just enhances
the regioselectivity of products, but it should not hinder the
first selection as mentioned above.
Furthermore, a gram-scale one−one cross-coupling of two
anilides was also carried out smoothly under identical
conditions, and the isolated amount of biaryl 15 was 1.23 g
in 73% yield, which is higher than that in a small-scale test
(66% yield) (Scheme 7a). After deprotection of 15 to aniline
46 and an intramolecular coupling of amino groups, 3-
methoxybenzo[c]cinnoline 47, an herbicide product, was
obtained in 43% total yield based on two different anilides in
a 1:1 molar ratio as the starting compounds (Scheme 7b).37
Another lactam antitumor compound 49 was also prepared in
50% total yield based on its corresponding anilide and
benzamide in a three-step synthetic route (Scheme 7c).38
A
series of carbazole alkaloids such as glycosinine, mehanimbine,
mukoenine-A, and murrayamine-K could be conveniently
produced from various anilides. For example, glycosinine was
yielded based on compound 18 prepared in our one−one
cross-coupling of anilides (Scheme 7d).39
CONCLUSIONS
■
Compared with the traditional couplings of two different
prefunctionalized arenes, the catalytic cross-coupling of aryl
C−H/C−H bonds to yield unsymmetrical biaryls under mild
conditions is more concise and significant in modern synthesis.
However, the selectivity of cross-coupling product and the
ratio of substrate loading often limit the applications of aryl
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a b
,
Scheme 6. Scope of Pd(II)-Catalyzed One−One Cross-Coupling of Aryl C−H Bonds
a
Conditions: Ar1−H (0.2 mmol), Ar2−H (0.2 mmol), Pd(OAc)2 (5−10 mol%), K2S2O8 (1.5−2 equiv), CF3CO2H, MeSO3H at 25 °C for 3−24 h.
b
CF3CH2OH/CF3CO2H.
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Scheme 7. Synthetic Utility of Pd(II)-Catalyzed One−One Cross-Coupling of Aryl C−H Bonds
were measured with an SGWX-4 melting-point apparatus with a
microscope, produced by Shanghai INESA Physico-Optical Instru-
C−H/C−H cross-coupling reactions. The control of directing
groups and the corresponding substituted groups on phenyl
rings is an efficient and promising guide to accomplish
preparations of unsymmetrical biaryls from equivalent starting
arenes including anilides, benzamides, and benzoates in a
catalytic Pd(II)/oxidant/acid system at room temperature.
1
ment Co., Ltd. and are uncorrected. H and 13C NMR spectra were
recorded on Varian Mercury 400 Plus (400 MHz for 1H, 101 MHz for
1
13C), Bruker AVANCE III HD 400 (400 MHz for H, 101 MHz for
13C, 376 MHz for 19F), and Bruker AVANCE III HD 500 (500 MHz
for 1H, 126 MHz for 13C, 471 MHz for 19F) spectrometers and
referenced (calibrated) to residual solvent peaks: proton (CDCl3:
7.26 ppm, DMSO-d6: 2.50 ppm) and carbon (CDCl3: 77.160 ppm,
DMSO-d6: 39.520 ppm). Signal positions were recorded in δ ppm
with the abbreviations s, d, t, q, sept., br., and m denoting singlet,
doublet, triplet, quartet, septet, broad, and multiplet, respectively. All
NMR chemical shifts are expressed in ppm. All coupling constants, J,
are expressed in hertz. High-resolution mass spectrometry (HRMS)
was measured with an ACQUITYTM UPLC & Q-TOF MS Premier.
General Procedure for the Preparation of N-Phenyl-
pivalamide Derivatives (1a−t). To a stirring solution of aniline
(20 mmol) and triethylamine (2.53 g, 25 mmol) in dichloromethane
(50 mL) was added pivaloyl chloride (20 mmol) at 0 °C (ice/water
bath). The reaction mixture was stirred at 0 °C for 10 min. Then, the
EXPERIMENTAL SECTION
■
General. All reagents obtained from Alfa Aesar, Sigma-Aldrich,
TCI Chemicals, and Adamas-beta Fine Chemicals Suppliers were
used directly as supplied. Palladium acetate is bought from Alfa Aesar.
Potassium persulfate and trifluoroacetic acid are bought from
Adamas-beta. Methanesulfonic acid is bought from Shanghai
DEMO Medical Tech. Co., Ltd. Commercially available chemicals
and solvents were used without further purification, unless otherwise
stated. Progress of reaction was monitored by thin-layer chromatog-
raphy (TLC) using silica gel F254 plates and UV detection at 254 and
365 nm. Purification of the products was performed by flash column
chromatography using silica gel (200−300 mesh). Melting points
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reaction mixture was stirred at room temperature overnight.
Afterward, the solvent was evaporated and water (20 mL) was
added to the residue. Then, the mixture was extracted with ethyl
acetate (30 mL × 3), washed with brine (20 mL × 2), and dried over
anhydrous Na2SO4. Finally, the extract was concentrated and
recrystallized from petroleum ether/ethyl acetate mixture to afford
the amide.
N-(m-Tolyl)pivalamide (1a). White needles (3.18 g, 83% yield);
mp 127−128 °C (ref 23b, 127−128 °C); 1H NMR (400 MHz,
CDCl3) δ 7.43 (s, 1H), 7.30−7.26 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H),
6.92 (d, J = 7.6 Hz, 1H), 2.34 (s, 3H), 1.31 (s, 9H).
N-(3-Ethylphenyl)pivalamide (1b). White solid (3.04 g, 74%
yield); mp 113−115 °C (ref 23b, 113−115 °C); 1H NMR (400 MHz,
CDCl3) δ 7.45 (s, 1H), 7.36 (s, 1H, br), 7.31 (d, J = 8.0 Hz, 1H), 7.22
(t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H),
1.31 (s, 9H), 1.23 (t, J = 7.6 Hz, 3H).
N-(3-Methoxyphenyl)pivalamide (1c). White solid (3.03 g, 73%
yield); mp 123−125 °C (ref 23b, 123−125 °C); 1H NMR (400 MHz,
CDCl3) δ 7.39 (t, J = 2.4 Hz, 1H), 7.31 (s, 1H, br), 7.20 (t, J = 8.0
Hz, 1H), 6.95−6.89 (m, 1H), 6.66 (dd, J = 8.4, 2.4 Hz, 1H), 3.81 (s,
3H), 1.32 (s, 9H).
N-(2,4-Dimethylphenyl)pivalamide (1o). White solid (2.87 g, 70%
yield); mp 112−114 °C (ref 23b, 112−114 °C); 1H NMR (400 MHz,
CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H, br), 7.04−6.96 (m,
2H), 2.29 (s, 3H), 2.21 (s, 3H), 1.33 (s, 9H).
N-(3,4-Dimethylphenyl)pivalamide (1p). white solid (2.71 g, 66%
yield); mp 132−133 °C (ref 23b, 132−133 °C); 1H NMR (400 MHz,
CDCl3) δ 7.36 (d, J = 2.0 Hz, 1H), 7.25−7.15 (m, 2H), 7.06 (d, J =
8.0 Hz, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 1.31 (s, 9H).
N-(4-Bromo-3-methylphenyl)pivalamide (1q). White solid (3.78
1
g, 70% yield); mp 139−140 °C (ref 23b, 139−140 °C); H NMR
(400 MHz, CDCl3) δ 7.50 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.4 Hz,
1H), 7.26 (s, 1H, br), 7.20 (dd, J = 8.4, 2.4 Hz, 1H), 2.37 (s, 3H),
1.30 (s, 9H).
Methyl 3-Pivalamidobenzoate (1r).41 White solid (3.41 g, 73%
1
yield); mp 108−110 °C; H NMR (400 MHz, CDCl3) δ 8.03 (t, J =
2.0 Hz, 1H), 7.93 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.77 (dt, J = 8.0, 1.2
Hz, 1H), 7.46−7.34 (m, 2H), 3.91 (s, 3H), 1.33 (s, 9H).
N-(4-Fluorophenyl)pivalamide (1s). White solid (2.93 g, 75%
yield); mp 123−124 °C (ref 23b, 123−124 °C); 1H NMR (500 MHz,
CDCl3) δ 7.52−7.45 (m, 2H), 7.29 (s, 1H, br), 7.05−6.97 (m, 2H),
1.31 (s, 9H).
N-(2-Bromophenyl)pivalamide (1t). White solid (3.89 g, 76%
yield); mp 56−58 °C (ref 42, 59 °C); 1H NMR (400 MHz, CDCl3) δ
8.40 (dd, J = 8.4, 1.6 Hz, 1H), 8.01 (s, 1H, br), 7.53 (dd, J = 8.0, 1.6
Hz, 1H), 7.36−7.28 (m, 1H), 6.96 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H),
1.35 (s, 9H).
N-(3-Fluorophenyl)pivalamide (1d). White solid (2.93 g, 75%
yield); mp 110−112 °C (ref 23b, 110−112 °C); 1H NMR (400 MHz,
CDCl3) δ 7.53 (dt, J = 11.2, 2.4 Hz, 1H), 7.40 (s, 1H, br), 7.24 (td, J
= 8.0, 6.4 Hz, 1H), 7.13 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 6.79 (tdd, J =
8.4, 2.4, 0.8 Hz, 1H), 1.31 (s, 9H).
General Procedure for the Preparation of 2-Phenylisoindo-
line-1,3-dione Derivatives (2a−i). Phthalic anhydride (1.16 g, 7.8
mmol), aniline (8 mmol), and acetic acid (40 mL) were added to a
100 mL flask. The reaction mixture was stirred at 125 °C in a
preheated oil bath for 4 h. Then, the solvent was evaporated to 5 mL.
The residue was neutralized with saturated Na2CO3 solution.
Afterward, the mixture was extracted with dichloromethane (30 mL
× 3), washed with brine (20 mL × 2), and dried over anhydrous
Na2SO4. Finally, the extract was concentrated and recrystallized from
petroleum ether/dichloromethane mixture to afford the amide.
2-(3-Methoxyphenyl)isoindoline-1,3-dione (2a). Gray solid (1.42
N-(3-Chlorophenyl)pivalamide (1e). White solid (2.96 g, 70%
yield); mp 135−136 °C (ref 23b, 135−136 °C); 1H NMR (400 MHz,
CDCl3) δ 7.67 (t, J = 2.0 Hz, 1H), 7.36 (ddd, J = 8.0, 2.0, 1.2 Hz,
1H), 7.32 (s, 1H, br), 7.23 (t, J = 8.0 Hz, 1H), 7.07 (ddd, J = 8.0, 2.0,
1.2 Hz, 1H), 1.31 (s, 9H).
N-(3-Bromophenyl)pivalamide (1f). White solid (3.59 g, 70%
yield); mp 144−145 °C (ref 23b, 144−145 °C); 1H NMR (400 MHz,
CDCl3) δ 7.81 (t, J = 2.0 Hz, 1H), 7.41 (ddd, J = 8.0, 2.0, 1.2 Hz,
1H), 7.36 (s, 1H, br), 7.22 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.16 (t, J =
8.0 Hz, 1H), 1.30 (s, 9H).
N-(3-(Trifluoromethyl)phenyl)pivalamide(1g). White solid (3.63
1
g, 72% yield); mp 126−127 °C (ref 43, 128 °C); H NMR (400
1
g, 74% yield); mp 107−108 °C (ref 23b, 107−108 °C); H NMR
MHz, CDCl3) δ 7.99−7.93 (m, 2H), 7.83−7.77 (m, 2H), 7.41 (t, J =
8.0 Hz, 1H), 7.03 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.00−6.94 (m, 2H),
3.84 (s, 3H).
(400 MHz, CDCl3) δ 7.86 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51−
7.39 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 1.33 (s, 9H).
N-(4-Ethylphenyl)pivalamide (1h). White solid (2.46 g, 60%
yield); mp 106−108 °C (ref 23b, 106−108 °C); 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H, br), 7.14 (d, J = 8.4
Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.31 (s, 9H), 1.21 (t, J = 7.6 Hz,
3H).
2-(3-Methoxy-4-methylphenyl)isoindoline-1,3-dione (2b). White
1
solid (1.77 g, 85% yield); mp 180−181 °C; H NMR (500 MHz,
CDCl3) δ 7.98−7.92 (m, 2H), 7.82−7.76 (m, 2H), 7.25 (d, J = 8.0
Hz, 1H), 6.92 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.85
(s, 3H), 2.26 (s, 3H).
N-(4-Chlorophenyl)pivalamide (1i). White needle (3.60 g, 85%
yield); mp 149−150 °C (ref 23b, 149−150 °C); 1H NMR (400 MHz,
CDCl3) δ 7.52−7.45 (m, 2H), 7.37 (s, 1H, br), 7.29−7.23 (m, 2H),
1.30 (s, 9H).
2-(4-Chloro-3-methoxyphenyl)isoindoline-1,3-dione (2c). White
1
solid (1.32 g, 59% yield); mp 183−184 °C; H NMR (400 MHz,
CDCl3) δ 8.03−7.87 (m, 2H), 7.87−7.73 (m, 2H), 7.48 (d, J = 8.4
Hz, 1H), 7.09−6.97 (m, 2H), 3.93 (s, 3H).
N-(4-Bromophenyl)pivalamide (1j). White needles (3.84 g, 75%
yield); mp 152−153 °C (ref 23b, 152−153 °C); 1H NMR (400 MHz,
CDCl3) δ 7.42 (s, 4H), 7.32 (s, 1H, br), 1.31 (s, 9H).
N-(4-(Trifluoromethyl)phenyl)pivalamide (1k). White solid (3.63
2-(4-Bromo-3-methoxyphenyl)isoindoline-1,3-dione (2d). White
solid (1.48 g, 57% yield); mp 191−193 °C (ref 44, 190 °C); 1H NMR
(400 MHz, CDCl3) δ 8.00−7.91 (m, 2H), 7.85−7.77 (m, 2H), 7.66
(d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz,
1H), 3.92 (s, 3H).
1
g, 74% yield); mp 162−163 °C (ref 23b, 154−157 °C); H NMR
(400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz,
2H), 7.47 (s, 1H, br), 1.33 (s, 9H).
Methyl 4-(1,3-Dioxoisoindolin-2-yl)-2-methoxybenzoate (2e).
1
beige solid (1.55 g, 64% yield); mp 131−133 °C; H NMR (400
N-(o-Tolyl)pivalamide (1l). White powder (3.25 g, 85% yield); mp
110−112 °C (ref 23b, 110−112 °C); 1H NMR (400 MHz, CDCl3) δ
7.87 (d, J = 8.0 Hz, 1H), 7.25−7.14 (m, 3H), 7.06 (td, J = 7.6, 12 Hz,
1H), 2.26 (s, 3H), 1.34 (s, 9H).
MHz, CDCl3) δ 8.04−7.92 (m, 3H), 7.86−7.79 (m, 2H), 7.19−7.12
(m, 2H), 3.94 (s, 3H), 3.91 (s, 3H).
2-(m-Tolyl)isoindoline-1,3-dione (2f). White solid (1.70 g, 92%
yield); mp 174−176 °C (ref 45, 175−178 °C); 1H NMR (400 MHz,
CDCl3) δ 8.00−7.91 (m, 2H), 7.84−7.74 (m, 2H), 7.44−7.35 (m,
1H), 7.26−7.16 (m, 3H), 2.42 (s, 3H).
N-(2-Chlorophenyl)pivalamide (1m). White solid (3.22 g, 76%
1
yield); mp 72−74 °C (ref 40, 75−76 °C); H NMR (400 MHz,
CDCl3) δ 8.41 (dd, J = 8.4, 1.6 Hz, 1H), 8.02 (s, 1H, br), 7.36 (dd, J
= 8.0, 1.6 Hz, 1H), 7.27 (td, J = 8.4, 1.6 Hz, 1H), 7.02 (td, J = 8.0, 1.6
Hz, 1H), 1.35 (s, 9H).
2-(3-Ethylphenyl)isoindoline-1,3-dione (2g). White solid (1.63 g,
1
83% yield); mp 95−97 °C (ref 46, 105−107 °C); H NMR (400
MHz, CDCl3) δ 7.98−7.93 (m, 2H), 7.81−7.76 (m, 2H), 7.45−7.40
(m, 1H), 7.27−7.20 (m, 3H), 2.73 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6
Hz, 3H).
N-Phenylpivalamide (1n). White needles (2.66 g, 75% yield); mp
134−135 °C (ref 23b, 134−135 °C); 1H NMR (400 MHz, CDCl3) δ
7.53 (dd, J = 8.4, 0.8 Hz, 2H), 7.38−7.26 (m, 3H), 7.13−7.07 (m,
1H), 1.32 (s, 9H).
2-(3,4-Dimethylphenyl)isoindoline-1,3-dione (2h). White solid
1
(1.25 g, 64% yield); mp 188−189 °C (ref 47, 188−189 °C); H
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NMR (400 MHz, CDCl3) δ 8.02−7.88 (m, 2H), 7.82−7.74 (m, 2H),
7.27 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.0,
2.0 Hz, 1H), 2.31 (s, 3H), 2.31 (s, 3H).
Na2SO4. Then, the extract was concentrated. The residue was
dissolved in DOAc (10 mL), and phthalic anhydride (4.8 mmol) was
added. The reaction mixture was stirred at 125 °C for 4 h, and then
the solvent was evaporated to 4 mL. The residue was neutralized with
saturated Na2CO3 solution. Afterward, the mixture was extracted with
dichloromethane (20 mL × 3), washed with brine (10 mL × 2), and
dried over anhydrous Na2SO4. Finally, the extract was concentrated
and recrystallized from petroleum ether/dichloromethane mixture to
afford 2a−d (679.1 mg, 53% yield) as a cream solid: mp 122−123 °C;
1H NMR (400 MHz, CDCl3) δ 8.06−7.88 (m, 2H), 7.88−7.73 (m,
2H), 7.40 (s, 1H), 3.83 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
2-(2-Methoxyphenyl)isoindoline-1,3-dione (2i). White solid (1.44
1
g, 73% yield); mp 158−159 °C (ref 48, 158 °C): H NMR (400
MHz, CDCl3) δ 8.02−7.88 (m, 2H), 7.81−7.75 (m, 2H), 7.44 (ddd, J
= 8.4, 7.6, 1.6 Hz, 1H), 7.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.11−7.04 (m,
2H), 3.80 (s, 3H).
N-(tert-Butyl)-3-methoxybenzamide (2j). To a solution of 3-
methoxybenzoic acid (1.52 g, 10 mmol), tert-butylamine (0.71 g, 12
mmol), and triethylamine (2.23 g, 22 mmol) in dichloromethane (30
mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) (2.31 g, 12 mmol) and 1-hydroxybenzotriazole
(HOBT) (1.62 g, 12 mmol). The reaction mixture was stirred at
room temperature overnight. After completion of the reaction, the
mixture was washed with NaHCO3 (10 mL × 3) and brine (10 mL)
and dried over anhydrous MgSO4. Finally, the organic layer was
concentrated and recrystallized from petroleum ether/dichloro-
methane mixture to afford 2j (2.05 g, 99% yield) as a white solid:
mp 98−100 °C (ref 49, 102−104 °C); 1H NMR (400 MHz, CDCl3)
δ 7.33 (dd, J = 2.4, 1.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24−7.19
(m, 1H), 7.03−6.98 (m, 1H), 5.94 (s, 1H, br), 3.84 (s, 3H), 1.47 (s,
9H).
167.3, 160.0, 134.5, 132.6, 131.8, 129.6, 123.8, 118.6 (C−D, JC−D
=
25.3 Hz), 113.9 (C−D, JC−D = 25.2 Hz), 112.1 (C−D, JC−D = 24.7
Hz), 55.5 (CH3); HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C15H9D3NO3 257.1000, found 257.0990.
General Procedure 2A for the Preparation of Cross-
Coupling Products. Two substrates (0.2 mmol/0.2 mmol),
Pd(OAc)2 (3.6 mg, 0.016 mmol, 8 mol %), potassium persulfate
(81.1 mg, 0.3 mmol, 1.5 equiv), 2,2,2-trifluoroacetic acid (342.1 mg, 3
mmol, 15 equiv), and methanesulfonic acid (96.1 mg, 1 mmol, 5
equiv) were added in a 15 mL seal tube. The reaction mixture was
stirred at 25 °C for 3−24 h. Then, saturated NaHCO3 was added to
adjust pH to 7−8. Afterward, the mixture was extracted with CH2Cl2
(10 mL × 3), washed with brine, and dried over anhydrous Mg2SO4.
Finally, the extract was concentrated and the residue was purified by
flash column chromatography on silica gel to give products.
Preparation of Deturated Substrates. N-(3-Methyl-2,4,6-
trideturiumphenyl)pivalamide-d3 (1a−d). Compound 1a−d was
obtained according to a modified procedure from ref 50: In an oven-
dried Schlenk flask, SOCl2 (1 mL) was added into stirred D2O (5
mL) dropwise at room temperature. Then, the solution was heated to
reflux in a preheated oil bath and cooled to room temperature. m-
Toluidine (535.8 mg, 5 mmol) was added under nitrogen atmosphere,
and the reaction mixture was refluxed for 24 h under nitrogen. The
solvent was evaporated in vacuo, and the residue was dried for 2 h in
vacuo. The resulting residue was dissolved in D2O (5 mL), and SOCl2
(1 mL) was added dropwise at room temperature. The resulting
solution was refluxed for 24 h again. After four repetitions, the
reaction mixture was cooled to room temperature and dried for 2 h in
vacuo. Et3N (1.52 g, 15 mmol, 2.0 mL) and CH2Cl2 (20 mL) were
added to the resulting residue and stirred for 10 min. Pivaloyl chloride
(602.9 mg, 5 mmol, 0.4 mL) was dropped to the stirring solution at 0
°C (ice/water bath) for 10 min. Then, the reaction mixture was
stirred at room temperature overnight and the solvent was evaporated.
Water (20 mL) was added to the residue. Afterward, the mixture was
extracted with ethyl acetate (20 mL × 3), washed with brine (10 mL
× 2), and dried over Na2SO4. Finally, the extract was concentrated
and recrystallized from petroleum ether/ethyl acetate mixture to
afford 1a−d (641.2 mg, 66% yield) as a purple needle: mp 123−125
General Procedure 2B for the Preparation of Cross-
Coupling Products. Amide 1e (0.17 mmol), amides 2f or 2g (0.2
mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol, 8 mol %), potassium
persulfate (108.1 mg, 0.4 mmol, 2 equiv), 2,2,2-trifluoroacetic acid
(342.1 mg, 3 mmol, 15 equiv), and methanesulfonic acid (288.3 mg, 3
mmol, 15 equiv) were added in a 15 mL seal tube. After the reaction
mixture was stirred at 25 °C for 0.5 h, the second batch amide 1e
(0.02 mmol) was added. The reaction mixture was stirred
continuously. After 3 h, the last batch amide 1e (0.01 mmol) was
added. The reaction mixture was stirred continuously for 5 h. Then,
saturated NaHCO3 was added to adjust pH to 7−8. After that, the
mixture was extracted with CH2Cl2 (10 mL × 4), washed with brine,
and dried over anhydrous Mg2SO4. Finally, the extract was
concentrated and the residue was purified by flash column
chromatography on silica gel to give product.
N,N′-(4-Ethyl-4′-methyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dime-
thylpropanamide) (1). The reaction was performed according to
General Procedure 2A using amides 1a and 1b. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(16:1, v/v) gave 1 (24.4 mg, 31% yield) as a white solid: mp 125−127
°C (ref 23b, 125−127 °C); 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J
= 1.5 Hz, 1H), 8.19 (s, 1H), 7.19 (s, 1H, br), 7.17 (s, 1H, br), 7.14−
7.06 (m, 2H), 7.06−6.98 (m, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.41 (s,
3H), 1.26 (t, J = 7.5 Hz, 3H), 1.00 (s, 9H), 0.99 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3) δ 176.8, 176.8, 146.2, 139.8, 136.2, 136.1,
130.0, 129.8, 125.3, 125.0, 124.9, 124.1, 122.1, 121.0, 39.8, 29.2, 27.3,
27.3, 21.7, 15.8; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + Na]+ calcd for C25H34N2NaO2 417.2512, found 417.2522.
N,N′-(4-Methoxy-4′-methyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-di-
methylpropanamide) (2). The reaction was performed according to
General Procedure 2A using amides 1a and 1c. Purification by flash
column chromatography eluting with petroleum ether/dichloro-
methane (1/2, v/v) gave 2 (6.3 mg, 8% yield) as a white solid: mp
139−141 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.12 (d, J
= 2.4 Hz, 1H), 7.24 (s, 1H, br), 7.19 (s, 1H, br), 7.13−7.06 (m, 2H),
7.02 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 (s, 3H),
2.41 (s, 3H), 1.02 (s, 9H), 1.01 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 176.9, 176.8, 160.6, 139.9, 137.5, 136.4, 130.8, 130.3, 125.3,
124.2, 121.9, 119.1, 111.3, 105.7, 55.7, 40.0, 39.9, 27.4, 27.3, 21.8;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C24H33N2O3 397.2486, found 397.2479.
1
°C; H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H, br), 7.18 (s, 1H),
2.32 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
176.7, 138.7, 137.9, 128.3, 124.7 (C−D, JC−D = 24.1 Hz), 120.5 (C−
D, JC−D = 24.2 Hz), 116.8 (C−D, JC−D = 24.7 Hz), 39.7, 27.7, 21.4;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C12H15D3NO 195.1571, found 195.1564.
2-(3-Methoxy-2,4,6-trideturiumphenyl)isoindoline-1,3-dione-d3
(2a−d). Compound 2a−d was obtained according to a modified
procedure from refs 50, 51: In an oven-dried Schlenk flask, SOCl2 (1
mL) was added into stirred D2O (5 mL) dropwise at room
temperature. Then, the solution was heated to reflux in a preheated
oil bath and cooled to room temperature. 3-Methoxyaniline (615.8
mg, 5 mmol) was added under nitrogen atmosphere, and the reaction
mixture was refluxed for 24 h under nitrogen. The solvent was
evaporated in vacuo and the residue was dried for 2 h in vacuo. The
resulting residue was dissolved in D2O (5 mL), and SOCl2 (1 mL)
was added dropwise at room temperature. The resulting solution was
refluxed for 24 h again. After three repetitions, the reaction mixture
was cooled to room temperature. The solvent was evaporated in
vacuo, and the residue was dried for 2 h in vacuo. The resulting
residue was dissolved in D2O (5 mL), and K2CO3 (10 mmol) was
added at room temperature. The reaction mixture was stirred for 2 h
in room temperature. Afterward, the reaction mixture was extracted
with dichloromethane (20 mL × 3) and dried over anhydrous
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-4-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (3). The reaction was performed according
to General Procedure 2A using amides 1a and 2a. Purification by flash
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column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 3 (66.4 mg, 75% yield) as a white solid: mp 246−248
°C; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.5 Hz, 1H), 7.81 (s,
1H), 7.72−7.64 (m, 3H), 7.56 (s, 1H, br), 7.24 (d, J = 8.5 Hz, 1H),
7.07 (dd, J = 8.5, 2.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.87 (d, J =
8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.23 (s, 3H), 1.16
(s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.9, 167.6, 167.5,
160.1, 138.6, 135.8, 134.4, 134.3, 132.6 131.7, 131.6 (2C), 130.4,
129.1, 127.2, 125.1, 124.1, 123.9, 123.9, 115.9, 114.6, 55.7, 39.6, 27.4,
21.5; DEPT-135 (126 MHz, CDCl3) δ 134.4 (upward), 134.3
(upward), 132.6 (upward), 129.1 (upward), 125.1 (upward), 124.1
(upward), 123.9 (upward), 123.9 (upward), 115.9 (upward), 114.6
(upward), 55.7 (upward), 27.4 (upward), 21.5 (upward); HRMS
(ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C27H27N2O4 443.1965, found 443.1964.
129.1, 128.5, 127.1, 125.9, 124.0, 124.0, 122.4, 116.0, 114.9, 55.8,
39.7, 27.3; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M +
H]+ calcd for C26H24BrN2O4 507.0914, found 507.0915.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-4-(trifluoromethyl)-
[1,1′-biphenyl]-2-yl)pivalamide (8). The reaction was performed
according to General Procedure 2A (20 equiv of CF3CO2H as the
only solvent) using amides 1g and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (5:1, v/v)
1
gave 8 (43.7 mg, 44% yield) as a gray solid: mp 145−147 °C; H
NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.92−7.88 (m, 1H), 7.79−
7.69 (m, 4H), 7.28 (s, 1H), 7.20 (dd, J = 8.0, 1.2 Hz, 1H), 7.14 (dd, J
= 8.4, 2.4 Hz, 2H), 6.97 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 1.20 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.1, 167.5 (2C), 160.7,
2
136.9, 134.7, 134.6, 133.0, 132.0, 131.7, 131.6, 131.1 (C−F, JC−F
=
=
1
32.6 Hz), 130.0, 128.9, 124.5, 124.1, 124.1, 123.9 (C−F, JC−F
3
3
272.6 Hz), 120.6 (C−F, JC−F = 4.0 Hz), 120.0 (C−F, JC−F = 4.0
Hz), 116.2, 115.0, 55.8, 39.8, 27.4; 19F NMR (376 MHz, CDCl3) δ
−62.7; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+
calcd for C27H24F3N2O4 497.1683, found 497.1683.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4-ethyl-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (4). The reaction was performed according
to General Procedure 2A using amides 1b and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(4:1, v/v) gave 4 (73 mg, 80% yield) as a white solid: mp 183−185
N-(2′-(1,3-Dioxoisoindolin-2-yl)-5-ethyl-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (9). The reaction was performed according
to General Procedure 2A using amides 1h and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(4:1, v/v) gave 9 (59.3 mg, 65% yield) as a white solid: mp 154−156
°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 1H), 7.82 (d,
J = 8.4 Hz, 1H), 7.76−7.62 (m, 3H), 7.52 (s, 1H, br), 7.30 (d, J = 8.8
Hz, 1H), 7.10 (dd, J = 8.4, 2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.94
(d, J = 2.4 Hz, 1H), 6.83 (s, 1H), 3.89 (s, 3H), 2.48−2.31 (m, 2H),
1.18 (s, 9H), 0.91 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 176.8, 167.6, 167.6, 160.1, 140.3, 134.4, 134.3, 133.5, 132.1,
131.7, 131.7, 131.6, 130.6, 130.2, 128.5, 128.2, 123.9, 123.7, 123.7,
115.8, 114.7, 55.7, 39.5, 28.2, 27.4, 15.6; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C28H29N2O4 457.2122,
found 457.2124.
1
°C; H NMR (400 MHz, CDCl3) δ 7.92−7.82 (m, 2H), 7.78−7.64
(m, 3H), 7.59 (s, 1H, br), 7.27 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 8.8,
2.4 Hz, 1H), 6.96−6.88 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 3.88 (s,
3H), 2.55 (q, J = 7.6 Hz, 2H), 1.18 (s, 9H), 1.15 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 176.8, 167.6, 167.4, 160.1,
144.8, 135.8, 134.4, 134.3, 132.5, 131.7, 131.7, 131.5, 130.4, 129.2,
127.3, 123.8 (2C), 123.7, 122.8, 115.8, 114.6, 55.7, 39.6, 28.8, 27.4,
15.2; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+
calcd for C28H29N2O4 457.2122, found 457.2122.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4-fluoro-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (5). The reaction was performed according
to General Procedure 2A using amides 1d and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 5 (75 mg, 84% yield) as a white solid: mp 173−175
1
°C; H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 11.2, 2.8 Hz, 1H),
N-(5-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (10). The reaction was performed according
to General Procedure 2A (5 mol % of Pd(OAc)2) using amides 1i and
2a. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (5:1, v/v) gave 10 (38.9 mg, 42%
yield) as a white solid: mp 165−166 °C; 1H NMR (400 MHz,
CDCl3) δ 7.95−7.85 (m, 2H), 7.80−7.65 (m, 1H), 7.59 (s, 1H, br),
7.23 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.08 (dd, J =
8.8, 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H),
3.87 (s, 3H), 1.15 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.0, 167.6, 167.4, 160.6, 134.9, 134.7, 134.5, 132.2, 131.8, 131.6,
131.6, 131.5, 129.3, 129.2, 129.0, 128.8, 124.8, 124.1, 123.9, 116.0,
114.8, 55.8, 39.7, 27.4; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C26H24ClN2O4 463.1419, found 463.1422.
N-(5-Bromo-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (11). The reaction was performed according
to General Procedure 2A (5 mol % of Pd(OAc)2) using amides 1j and
2a. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (5:1, v/v) gave 11 (46.7 mg, 46%
yield) as a white solid: mp 150−152 °C; 1H NMR (400 MHz,
CDCl3) δ 7.94−7.83 (m, 2H), 7.76−7.65 (m, 3H), 7.57 (s, 1H, br),
7.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.15 (d, J =
2.0 Hz, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H),
3.87 (s, 3H), 1.14 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
176.9, 167.6, 167.3, 160.6, 135.4, 134.7, 134.5, 132.1 (2C), 132.0,
131.7, 131.7, 131.6, 128.9, 124.9, 124.9, 124.1, 123.9, 116.8, 116.0,
114.9, 55.8, 39.7, 27.4; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C26H24BrN2O4 507.0914, found 507.0915.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-5-(trifluoromethyl)-
[1,1′-biphenyl]-2-yl)pivalamide (12). The reaction was performed
according to General Procedure 2A (5 mol % of Pd(OAc)2) using
amides 1k and 2a. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (4:1, v/v) gave 12 (37.7
mg, 38% yield) as a gray solid: mp 115−116 °C; 1H NMR (500 MHz,
CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.75−
7.64 (m, 4H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.31−7.26 (m, 2H), 7.13
7.86−7.82 (m, 1H), 7.74−7.65 (m, 3H), 7.58 (s, 1H, br), 7.24 (d, J =
8.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (dd, J = 8.4, 6.4 Hz,
1H), 6.92 (d, J = 2.4 Hz, 1H), 6.61 (td, J = 8.4, 2.8 Hz, 1H), 3.87 (s,
3H), 1.15 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.8, 167.5,
1
3
167.3, 162.5 (C−F, JC−F = 245.2 Hz), 160.4, 137.6 (C−F, JC−F
=
=
3
11.8 Hz), 134.6, 134.5, 132.5, 132.1, 131.6, 131.4 130.5 (d, JC−F
4
9.4 Hz), 129.2, 124.9 (C−F, JC−F = 3.1 Hz), 123.9, 123.9, 116.0,
114.9, 110.8 (C−F, 2JC−F = 21.8 Hz), 109.9 (C−F, 2JC−F = 26.7 Hz),
55.7, 39.8, 27.3; 19F NMR (376 MHz, CDCl3) δ −111.7; HRMS
(ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C26H24FN2O4 447.1715, found 447.1714.
N-(4-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (6). The reaction was performed according
to General Procedure 2A using amides 1e and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 6 (78.7 mg, 85% yield) as a white solid: mp 197−199
1
°C; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.0 Hz, 1H), 7.89−
7.82 (m, 1H), 7.79−7.66 (m, 3H), 7.58 (s, 1H, br), 7.23 (d, J = 8.8
Hz, 1H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H), 6.96−6.85 (m, 3H), 3.87 (s,
3H), 1.15 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.5,
167.4, 160.5, 137.2, 134.6, 134.5, 134.3, 132.2, 131.8, 131.6, 131.4,
130.3, 129.1, 127.9, 124.1, 124.0, 123.9, 123.0, 116.0, 114.9, 55.8,
39.7, 27.3; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M +
H]+ calcd for C26H24ClN2O4 463.1419, found 463.1418.
N-(4-Bromo-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (7). The reaction was performed according
to General Procedure 2A using amides 1f and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 7 (75.1 mg, 74% yield) a white solid: mp 194−196
1
°C; H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.0 Hz, 1H), 7.89−
7.82 (m, 1H), 7.78−7.65 (m, 3H), 7.57 (s, 1H, br), 7.23 (d, J = 8.4
Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.0 Hz,
1H), 6.91 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H),
1.15 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.8, 167.4,
167.4, 160.5, 137.4, 134.6, 134.5, 132.2, 131.7, 131.6, 131.4, 130.6,
2724
https://dx.doi.org/10.1021/acs.joc.0c02722
J. Org. Chem. 2021, 86, 2714−2733

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(dd, J = 8.5, 2.5 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 3.90 (s, 3H), 1.17
(s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 177.0, 167.4, 167.4,
160.8, 139.5, 134.7, 134.5, 132.1, 132.0, 131.6, 131.4, 129.4, 128.5,
ether/ethyl acetate (5/1, v/v) gave 17 (59.3 mg, 65% yield) as a
yellow solid: mp 183−184 °C; 1H NMR (400 MHz, CDCl3) δ 7.91−
7.83 (m, 1H), 7.78−7.62 (m, 4H), 7.54 (s, 1H, br), 7.23 (d, J = 8.8
Hz, 1H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.75
(s, 1H), 3.86 (s, 3H), 2.14 (s, 3H), 2.01 (s, 3H), 1.15 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.6 (2C), 160.0, 137.0,
134.4, 134.3, 133.5, 132.7, 132.6, 131.8, 131.7, 131.6, 130.7, 130.2,
128.0, 125.0, 123.9, 123.8, 115.8, 114.5, 55.7, 39.5, 27.5, 19.8, 19.1;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C28H29N2O4 457.2122, found 457.2122.
3
3
126.7 (C−F, JC−F = 3.6 Hz), 125.9 (C−F, JC−F = 3.8 Hz), 125.6
2
1
(C−F, JC−F = 32.8 Hz), 124.0, 123.9 (C−F, JC−F = 271.9 Hz),
123.9, 122.4, 116.1, 115.3, 55.8, 39.9, 27.4; 19F NMR (471 MHz,
CDCl3) δ −62.4; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C27H24F3N2O4 497.1683, found 497.1685.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-3-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (13). The reaction was performed according
to General Procedure 2A using amides 1l and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 13 (63.7 mg, 72% yield) as a white solid: mp 202−204
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-5′-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (18). The reaction was performed according
to General Procedure 2A (60 equiv of CF3CO2H as the only solvent)
using amides 1n and 2b. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 18 (56.6
1
°C; H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 6.8 Hz, 1H), 7.75−
7.62 (m, 4H), 7.23 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 7.02
(dd, J = 8.4, 2.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.88−6.82 (m,
2H), 3.84 (s, 3H), 2.19 (s, 3H), 1.13 (s, 9H); 13C{1H} NMR (101
MHz, CDCl3) δ 177.2, 168.2, 167.7, 159.9, 137.3, 135.8, 134.7, 134.5,
134.4, 132.1, 131.9, 131.6, 131.6, 130.7, 130.4, 126.7, 126.4, 123.9,
123.8, 115.7, 113.9, 55.7, 39.0, 27.6, 18.4; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C27H27N2O4 443.1965,
found 443.1966.
1
mg, 64% yield) as a white solid: mp 196−198 °C; H NMR (400
MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.88−7.82 (m, 1H), 7.73−
7.63 (m, 3H), 7.60 (s, 1H, br), 7.23−7.16 (m, 1H), 7.12 (s, 1H), 7.00
(dd, J = 7.5, 1.5 Hz, 1H), 6.95−6.89 (m, 1H), 6.80 (s, 1H), 3.88 (s,
3H), 2.26 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
176.8, 167.9, 167.7, 158.2, 136.0, 134.4, 134.3, 133.0, 131.7, 131.6,
130.4, 129.8, 129.3, 128.8, 128.8, 128.6, 124.3, 123.8, 123.8, 123.7,
110.6, 55.7, 39.6, 27.4, 16.0; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C27H27N2O4 443.1965,
found 443.1975.
N-(3-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (14). The reaction was performed according
to General Procedure 2A (20 equiv of CF3CO2H as the only solvent)
using amides 1m and 2a. Purification by flash column chromatog-
raphy eluting with petroleum ether/ethyl acetate (5:1, v/v) gave 14
N-(5-Bromo-5′-chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-
4-methyl-[1,1′-biphenyl]-2-yl)pivalamide (19). The reaction was
performed according to General Procedure 2A using amides 1q and
2c. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (5:1, v/v) gave 19 (83.4 mg, 75%
yield) as a yellow solid: mp 114−116 °C; 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 6.8 Hz, 1H), 7.83 (s, 1H), 7.78−7.67 (m, 3H),
7.52 (s, 1H, br), 7.32 (s, 1H), 7.15 (s, 1H), 6.91 (s, 1H), 3.95 (s, 3H),
2.27 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.0, 167.4, 167.2, 155.6, 138.8, 135.1, 134.8, 134.6, 132.6, 132.4,
131.5, 131.4, 130.0, 129.7, 128.7, 126.3, 124.2, 124.1, 124.0, 119.8,
112.9, 56.6, 39.6, 27.4, 22.9; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C27H25BrClN2O4 555.0681,
found 555.0687.
1
(50.9 mg, 55% yield) as a white solid: mp 231−232 °C; H NMR
(500 MHz, CDCl3) δ 7.89−7.83 (m, 1H), 7.77−7.67 (m, 3H), 7.62
(s, 1H, br), 7.29 (dd, J = 8.0, 1.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H),
7.06−6.98 (m, 2H), 6.96 (dd, J = 7.5, 1.5 Hz, 1H), 6.85 (d, J = 2.5
Hz, 1H), 3.85 (s, 3H), 1.14 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ 177.3, 168.1, 167.6, 160.2, 138.5, 134.7, 134.5, 134.2, 134.0,
131.6, 131.5, 131.5, 130.9, 130.7, 129.8, 127.9, 127.6, 124.0 (2C),
115.6, 114.0, 55.8, 39.1, 27.5; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C26H24ClN2O4 463.1419,
found 463.1422.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-biphenyl]-2-
yl)pivalamide (15). The reaction was performed according to General
Procedure 2A using amides 1n and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (3/1, v/
v) gave 15 (56.6 mg, 66% yield) as a white solid: mp 211−213 °C; 1H
NMR (400 MHz, CDCl3) δ 7.99−7.91 (m, 1H), 7.88−7.81 (m, 1H),
7.73−7.63 (m, 3H), 7.60 (s, 1H, br), 7.27 (d, J = 8.8 Hz, 1H), 7.22−
7.16 (m, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (dd, J = 7.6, 1.6 Hz,
1H), 6.94−6.88 (m, 2H), 3.87 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR
(101 MHz, CDCl3) δ 176.9, 167.6, 167.5, 160.2, 136.0, 134.5 (2C),
134.4, 132.3, 131.6, 131.5, 130.3, 130.1, 129.4, 128.7, 124.2, 123.9,
123.8, 123.6, 115.9, 114.7, 55.7, 39.6, 27.4; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C26H25N2O4 429.1809,
found 429.1812.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-3,5-dimethyl-[1,1′-
biphenyl]-2-yl)pivalamide (16). The reaction was performed
according to General Procedure 2A (41 equiv of solvent;
CF3CO2H/CH3SO3H = 40:1) using amides 1o and 2a. Purification
by flash column chromatography eluting with petroleum ether/ethyl
acetate (5:1, v/v) gave 16 (59.3 mg, 65% yield) as a white solid: mp
88−89 °C; 1H NMR (500 MHz, CDCl3) δ 7.88−7.85 (m, 1H),
7.73−7.64 (m, 3H), 7.61 (s, 1H, br), 7.22 (d, J = 8.5 Hz, 1H), 7.01
(dd, J = 8.5, 2.5 Hz, 1H), 6.87 (s, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.66
(d, J = 1.5 Hz, 1H), 3.84 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H), 1.11 (s,
9H); 13C{1H} NMR (126 MHz, CDCl3) δ 177.4, 168.3, 167.4, 159.5,
136.8, 136.0, 135.6, 134.5, 134.4 (2C), 132.3, 132.0, 131.9, 131.6,
131.2, 130.7, 127.3, 123.9, 123.8, 115.6, 113.9, 55.7, 39.0, 27.6, 20.9,
18.2; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+
calcd for C28H29N2O4 457.2122, found 457.2124.
N-(4,5′-Dichloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-
biphenyl]-2-yl)pivalamide (20). The reaction was performed
according to General Procedure 2A using amides 1e and 2c.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (5:1, v/v) gave 20 (82.6 mg, 83% yield) as a
1
yellow solid: mp 195−196 °C; H NMR (400 MHz, CDCl3) δ 8.05
(s, 1H), 7.89−7.83 (m, 1H), 7.77−7.67 (m, 3H), 7.54 (s, 1H, br),
7.34 (s, 1H), 6.93 (s, 1H), 6.90 (d, J = 0.8 Hz, 2H), 3.95 (s, 3H), 1.17
(s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.3, 167.3,
155.7, 137.0, 134.8, 134.7 (2C), 132.5, 131.4, 131.3, 130.1 (2C),
130.0, 127.3, 124.5, 124.2, 124.1, 124.1, 123.8, 113.1, 56.6, 39.7, 27.3;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C26H23Cl2N2O4 497.1029, found 497.1032.
N-(5′-Bromo-4-chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-
[1,1′-biphenyl]-2-yl)pivalamide (21). The reaction was performed
according to General Procedure 2A using amides 1e and 2d.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (6/1, v/v) gave 21 (91 mg, 84% yield) as a yellow
solid: mp 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H),
7.91−7.83 (m, 1H), 7.76−7.66 (m, 3H), 7.54 (s, 1H, br), 7.52 (s,
1H), 6.94−6.85 (m, 3H), 3.94 (s, 3H), 1.17 (s, 9H); 13C{1H} NMR
(101 MHz, CDCl3) δ 176.9, 167.3, 167.2, 156.7, 137.0, 135.5, 134.8,
134.7, 134.7, 131.4, 131.3, 130.8, 130.3, 130.1, 127.2, 124.5, 124.1,
124.0, 123.8, 113.2, 112.8, 56.7, 39.7, 27.3; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C26H23BrClN2O4
541.0524, found 541.0526.
Methyl 4′-Chloro-6-(1,3-dioxoisoindolin-2-yl)-4-methoxy-2′-piv-
alamido-[1,1′-biphenyl]-3-carboxylate (22). The reaction was
performed according to General Procedure 2A using amides 1e and
2e. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (5:1, v/v) gave 22 (82.3 mg, 79%
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-4,5-dimethyl-[1,1′-
biphenyl]-2-yl)pivalamide (17). The reaction was performed
according to General Procedure 2A using amides 1p and 2a.
Purification by flash column chromatography eluting with petroleum
2725
https://dx.doi.org/10.1021/acs.joc.0c02722
J. Org. Chem. 2021, 86, 2714−2733

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
yield) as a yellow solid: mp 265−267 °C; 1H NMR (400 MHz,
CDCl3) δ 8.12 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.80−
7.68 (m, 4H), 7.55 (s, 1H, br), 7.00 (s, 1H), 6.98−6.82 (m, 2H), 3.96
(s, 3H), 3.86 (s, 3H), 1.15 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 176.8, 167.1, 167.0, 165.1, 159.6, 137.1, 135.2, 134.9, 134.8,
134.7, 134.6, 131.4, 131.3, 130.1, 128.6, 127.1, 124.4, 124.2, 124.1,
123.5, 121.4, 113.4, 56.6, 52.4, 39.7, 27.3; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C28H26ClN2O6 521.1474,
found 521.1477.
MS) with acetonitrile (m/z) [M + H]+ calcd for C27H26FN2O3
445.1922, found 445.1924.
N-(4-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-ethyl-[1,1′-biphen-
yl]-2-yl)pivalamide (27). The reaction was performed according to
General Procedure 2B using amides 1e and 2g. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(6:1, v/v) gave 27 (59.9 mg, 65% yield) as a white solid: mp 216−217
1
°C; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.0 Hz, 1H), 7.90−
7.83 (m, 1H), 7.76−7.67 (m, 3H), 7.55 (s, 1H, br), 7.39 (dd, J = 8.0,
1.2 Hz, 1H), 7.26−7.20 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.91 (dd, J
= 8.4, 2.0 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H),
1.13 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.7,
167.6, 146.5, 137.0, 134.6, 134.5, 134.4, 134.4, 131.7, 131.5, 131.3,
130.7, 130.0, 129.5, 129.2, 128.4, 124.2, 124.0, 123.9, 123.2, 39.7,
28.5, 27.3, 15.3; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C27H26ClN2O3 461.1626, found 461.1626.
N-(4-Bromo-2′-(1,3-dioxoisoindolin-2-yl)-4′-ethyl-[1,1′-biphen-
yl]-2-yl)pivalamide (28). The reaction was performed according to
General Procedure 2A (10 mol % of Pd(OAc)2; 2 equiv of K2S2O8; 30
equiv of solvent; CF3CO2H/CH3SO3H = 1:1) using amides 1f and
2g. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (6:1, v/v) gave 28 (60.6 mg, 60%
yield) as a beige solid: mp 211−213 °C; 1H NMR (400 MHz,
CDCl3) δ 8.26 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H),
7.76−7.66 (m, 3H), 7.55 (s, 1H, br), 7.38 (dd, J = 8.0, 1.6 Hz, 1H),
7.23 (dd, J = 6.8, 4.8 Hz, 2H), 7.25−7.20 (m, 1H), 6.89 (d, J = 8.4
Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H), 1.13 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.7, 167.6, 146.5,
137.2, 134.6, 134.5, 134.4, 131.6, 131.5, 131.3, 130.6, 130.3, 129.5,
129.1, 128.9, 127.1, 126.1, 124.0, 123.9, 122.4, 39.7, 28.5, 27.3, 15.3;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C27H26BrN2O3 505.1121, found 505.1122.
N-(4-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (23). The reaction was performed according
to General Procedure 2B using amides 1e and 2f. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(6:1, v/v) gave 23 (49.2 mg, 55% yield) as a white solid: mp 134−135
1
°C. H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.0 Hz, 1H), 7.89−
7.83 (m, 1H), 7.76−7.66 (m, 3H), 7.57 (s, 1H, br), 7.36 (ddd, J = 8.0,
1.6, 0.8 Hz, 1H), 7.23−7.21 (m, 2H), 6.94 (dd, J = 8.0, 0.4 Hz, 1H),
6.90 (dd, J = 8.4, 2.0 Hz, 1H), 2.47 (s, 3H), 1.14 (s, 9H); 13C{1H}
NMR (101 MHz, CDCl3) δ 176.9, 167.7, 167.6, 140.2, 137.0, 134.6,
134.5, 134.4, 134.2, 131.7, 131.5, 131.3, 130.7, 130.6, 130.4, 130.1,
128.3, 124.2, 124.0, 123.9, 123.2, 39.8, 27.3, 21.3; HRMS (ESI-Q/
TOF MS) with acetonitrile (m/z) [M + H]+ calcd for C26H24ClN2O3
447.1470, found 447.1471.
Methyl 2′-(1,3-Dioxoisoindolin-2-yl)-4′-methyl-2-pivalamido-
[1,1′-biphenyl]-4-carboxylate (24). The reaction was performed
according to General Procedure 2A (10 mol % of Pd(OAc)2) using
amides 1r and 2f. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (5:1, v/v) gave 24 (54.6
mg, 58% yield) as a white solid: mp 82−83 °C; 1H NMR (500 MHz,
CDCl3) δ 8.63 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.74−
7.59 (m, 5H), 7.40−7.32 (m, 1H), 7.26−7.19 (m, 2H), 7.08 (d, J =
8.0 Hz, 1H), 3.82 (s, 3H), 2.47 (s, 3H), 1.16 (s, 9H). 13C{1H} NMR
(126 MHz, CDCl3) δ 177.0, 167.6, 167.5, 166.8, 140.3, 136.2, 135.1,
134.6, 134.5, 134.4, 131.6, 131.4, 130.8, 130.6, 130.6, 130.3, 130.3,
129.3, 125.4, 124.7, 124.0, 123.9, 52.2, 39.7, 27.4, 21.3; HRMS (ESI-
Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for C28H27N2O5
471.1914, found 471.1917.
N-(4-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-5′-ethyl-[1,1′-biphen-
yl]-2-yl)pivalamide (29). Amide 1e (0.1 mmol), amide 2h (0.2
mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol, 8 mol %), potassium
persulfate (81.1 mg, 0.3 mmol, 1.5 equiv), 2,2,2-trifluoroacetic acid
(285.1 mg, 2.5 mmol, 12.5 equiv), and methanesulfonic acid (240.3
mg, 2.5 mmol, 12.5 equiv) were added in a 15 mL seal tube. After the
reaction mixture was stirred at 25 °C for 0.5 h, the second batch
amide 1e (0.05 mmol) was added. The reaction mixture was stirred
continuously. After 2 h, the third batch amide 1e (0.025 mmol) was
added. After 4 h, the last batch amide 1e (0.025 mmol) was added.
The reaction mixture was stirred continuously for 4 h. Then, saturated
NaHCO3 was added to adjust pH to 7−8. After that, the mixture was
extracted with CH2Cl2 (10 mL × 4), washed with brine, and dried
over anhydrous Mg2SO4. Finally, the extract was concentrated and the
residue was purified by flash column chromatography on silica gel
eluting with petroleum ether/ethyl acetate (10:1, v/v) to give 29
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′-methyl-4-(trifluoromethyl)-
[1,1′-biphenyl]-2-yl)pivalamide (25). The reaction was performed
according to General Procedure 2A (10 mol % of Pd(OAc)2) using
amides 1g and 2f. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 25 (54.8
1
mg, 57% yield) as a white solid: mp 119−121 °C; H NMR (500
MHz, CDCl3) δ 8.41 (s, 1H), 7.89−7.83 (m, 1H), 7.78−7.62 (m,
4H), 7.38 (d, J = 8.0 Hz, 1H), 7.25−7.21 (m, 2H), 7.19 (d, J = 8.0
Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 2.48 (s, 3H), 1.16 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) δ 177.1, 167.7, 167.6, 140.5,
136.6, 134.7, 134.6, 134.0, 133.3, 131.6, 131.4, 130.9, 130.9 (C−F,
2JC−F = 32.6 Hz), 130.8, 130.5, 130.4, 129.8, 124.0, 124.0, 123.9 (C−
1
F, 1JC−F = 272.6 Hz), 120.6 (C−F, 3JC−F = 3.8 Hz), 120.1 (C−F, 3JC−F
= 3.9 Hz), 39.8, 27.3, 21.3; 19F NMR (471 MHz, CDCl3) δ −62.7;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C27H24F3N2O3 481.1734, found 481.1734.
(50.7 mg, 55% yield) as a beige solid: mp 198−199 °C; H NMR
(400 MHz, CDCl3) δ 8.09 (d, J = 2.0 Hz, 1H), 7.89−7.82 (m, 1H),
7.77−7.65 (m, 3H), 7.57 (s, 1H, br), 7.16 (s, 1H), 7.10 (s, 1H), 6.94
(d, J = 8.0 Hz, 1H), 6.90 (dd, J = 8.0, 2.0 Hz, 1H), 2.36 (s, 3H), 2.32
(s, 3H), 1.14 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.9,
167.9, 167.8, 138.9, 138.7, 137.0, 134.5, 134.5, 134.3, 134.3, 132.4,
131.7, 131.6, 130.6, 130.0, 128.5, 128.1, 124.2, 124.0, 123.9, 123.3,
39.7, 27.3, 19.8, 19.5; HRMS (ESI-Q/TOF MS) with acetonitrile (m/
z) [M + H]+ calcd for C27H26ClN2O3 461.1626, found 461.1627.
Methyl 2′-(1,3-Dioxoisoindolin-2-yl)-4′,5′-dimethyl-2-pivalami-
do-[1,1′-biphenyl]-4-carboxylate (30). The reaction was performed
according to General Procedure 2A using amides 1r and 2h.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (6:1, v/v) gave 30 (54.3 mg, 56% yield) as a beige
N-(4-Fluoro-2′-(1,3-dioxoisoindolin-2-yl)-4′-ethyl-[1,1′-biphen-
yl]-2-yl)pivalamide (26). The reaction was performed according to
General Procedure 2A (10 mol % of Pd(OAc)2; 2 equiv of K2S2O8; 30
equiv of solvent; CF3CO2H/CH3SO3H = 1:1) using amides 1d and
2g. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (6:1, v/v) gave 26 (49.8 mg, 56%
yield) as a beige solid: mp 181−183 °C; 1H NMR (400 MHz,
CDCl3) δ 7.91−7.83 (m, 2H), 7.76−7.66 (m, 3H), 7.55 (s, 1H, br),
7.39 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.23 (d, J =
1.6 Hz, 1H), 6.98 (dd, J = 8.4, 6.4 Hz, 1H), 6.64 (td, J = 8.4, 2.8 Hz,
1H), 2.78 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H), 1.13 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 176.9, 167.7, 167.6, 162.5 (C−
1
solid: mp 109−112 °C; H NMR (400 MHz, CDCl3) δ 8.61 (d, J =
1.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.73−7.60 (m, 5H), 7.18 (s,
1H), 7.11 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), 2.37 (s,
3H), 2.32 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.0, 167.8, 167.8, 166.8, 138.8, 138.7, 136.1, 135.3, 134.6, 134.6,
134.6, 134.4, 131.8, 131.6, 131.5, 130.6, 129.3 127.8, 125.5, 124.9,
123.9, 123.9, 52.2, 39.7, 27.3, 19.8, 19.5; HRMS (ESI-Q/TOF MS)
1
3
F, JC−F = 245.3 Hz), 146.4, 137.4 (C−F, JC−F = 11.7 Hz), 134.6,
134.5, 134.5, 131.7, 131.6, 131.5, 131.0, 130.2 (C−F, 3JC−F = 9.5 Hz),
129.5, 129.2, 125.3 (C−F, 4JC−F = 3.3 Hz), 123.9, 123.9, 110.9 (C−F,
2JC−F = 21.8 Hz), 110.1 (C−F, JC−F = 26.7 Hz), 39.8, 28.5, 27.3,
2
15.3; 19F NMR (376 MHz, CDCl3) δ −111.8; HRMS (ESI-Q/TOF
2726
https://dx.doi.org/10.1021/acs.joc.0c02722
J. Org. Chem. 2021, 86, 2714−2733

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
with acetonitrile (m/z) [M + H]+ calcd for C29H29N2O5 485.2071,
found 485.2076.
123.8, 120.1, 112.0, 56.1, 39.4, 27.5; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C26H24ClN2O4 463.1419,
found 463.1421.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-4′,5′-dimethyl-4-(trifluorometh-
yl)-[1,1′-biphenyl]-2-yl)pivalamide (31). The reaction was performed
according to General Procedure 2A using amides 1g and 2h.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (7:1, v/v) gave 31 (55.4 mg, 56% yield) as a white
solid: mp 191−193 °C; 1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.76−7.66 (m, 4H), 7.21−7.17 (m, 2H),
7.13 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 1.16
(s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 177.0, 167.8, 167.8,
139.0, 136.6, 134.6, 134.5, 134.1, 133.5 (2C), 132.0, 131.6, 131.5,
N-(3-Bromo-3′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (36). The reaction was performed according
to General Procedure 2A using amides 1t and 2i. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(3:1, v/v) gave 36 (71 mg, 70% yield) as a white solid: mp 222−224
1
°C; H NMR (500 MHz, CDCl3) δ 8.01−7.88 (m, 2H), 7.82−7.72
(m, 2H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz,
1H), 7.30 (dd, J = 8.5, 1.5 Hz, 1H), 7.21−7.14 (m, 1H), 7.10 (s, 1H,
br), 7.05 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 1.18 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3) δ 177.0, 167.3, 155.1, 141.4, 134.3, 133.6,
132.3, 132.3, 131.9, 131.2, 130.2, 129.9, 128.6, 124.0, 123.8, 120.0,
112.0, 56.1, 39.3, 27.5; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C26H24BrN2O4 507.0914, found 507.0915.
N-(4-Chloro-3′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (37). The reaction was performed according
to General Procedure 2A (20 equiv of CF3CO2H as the only solvent)
using amides 1e and 2i. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (3:1, v/v) gave 37 (49 mg,
2
130.8 (C−F, JC−F = 32.7 Hz), 130.7, 129.7, 127.9, 124.0, 124.0,
1
3
123.9 (C−F, JC−F = 272.5 Hz), 120.7 (C−F, JC−F = 3.8 Hz), 120.2
(C−F, JC−F = 3.8 Hz), 39.8, 27.3, 19.8, 19.5; 19F NMR (471 MHz,
3
CDCl3) δ −62.7; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C28H26F3N2O3 495.1890, found 495.1893.
N-(2′-(1,3-Dioxoisoindolin-2-yl)-5-fluoro-4′-methyl-[1,1′-biphen-
yl]-2-yl)pivalamide (32). The reaction was performed according to
General Procedure 2A using amides 1s and 2f. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(7:1, v/v) gave 32 (28.4 mg, 33% yield) as a white solid: mp 134−136
1
53% yield) as a white solid: mp 96−98 °C; H NMR (500 MHz,
1
°C; H NMR (400 MHz, CDCl3) δ 7.91−7.86 (m, 1H), 7.86−7.80
CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 7.96−7.92 (m, 2H), 7.81−7.76
(m, 2H), 7.53 (s, 1H, br), 7.40 (dd, J = 8.5, 2.5 Hz, 1H), 7.24 (d, J =
2.0 Hz, 1H), 7.19−7.15 (m, 2H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 3.85
(s, 3H), 1.16 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.9,
167.2, 155.6, 136.4, 134.4, 134.3, 132.2, 131.7, 131.1, 131.0, 129.5,
129.0, 124.0, 123.9, 121.2, 121.1, 112.9, 56.2, 40.0, 27.4; HRMS (ESI-
Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C26H24ClN2O4 463.1419, found 463.1422.
(m, 1H), 7.76−7.67 (m, 3H), 7.55 (s, 1H, br), 7.35 (ddd, J = 8.0, 1.8,
0.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 1.2, 0.4 Hz, 1H),
6.95−6.89 (m, 1H), 6.75 (dd, J = 8.4, 2.8 Hz, 1H), 2.47 (s, 3H), 1.13
(s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.1, 167.9, 167.6,
159.1 (C-F, 1JC−F = 245.1 Hz), 140.1, 134.6, 134.5, 134.4, 132.9 (C-F,
4
3JC−F = 8.3 Hz), 132.0 (C-F, JC−F = 2.8 Hz), 131.7, 131.5, 131.1,
130.6, 130.3, 130.2, 126.1 (C−F, 3JC−F = 8.4 Hz), 124.1, 123.9, 115.9
2
2
N-(3′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-4-(trifluoromethyl)-
[1,1′-biphenyl]-2-yl)pivalamide (38). The reaction was performed
according to General Procedure 2A (20 equiv of CF3CO2H as the
only solvent) using amides 1g and 2i. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (3:1, v/v)
(C−F, JC−F = 22.8 Hz), 115.5 (C−F, JC−F = 22.0 Hz), 39.5, 27.4,
21.3; 19F NMR (376 MHz, CDCl3) δ −117.7; HRMS (ESI-Q/TOF
MS) with acetonitrile (m/z) [M + H]+ calcd for C26H24FN2O3
431.1765, found 431.1764.
N-(5-Chloro-2′-(1,3-dioxoisoindolin-2-yl)-4′-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (33). The reaction was performed according
to General Procedure 2A using amides 1i and 2f. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(7:1, v/v) gave 33 (27.7 mg, 31% yield) as a white solid: mp 175−177
1
gave 38 (75.5 mg, 76% yield) as a white solid: mp 142−143 °C; H
NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.97−7.92 (m, 2H), 7.82−
7.77 (m, 2H), 7.63 (s, 1H, br), 7.43 (dd, J = 8.5, 2.5 Hz, 1H), 7.39
(dd, J = 8.0, 1.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.5 Hz,
1H), 7.19 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 1.18 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3) δ 176.9, 167.1, 155.8, 136.0, 134.4, 133.7,
1
°C; H NMR (400 MHz, CDCl3) δ 7.94−7.87 (m, 2H), 7.76−7.67
(m, 3H), 7.57 (s, 1H, br), 7.38−7.33 (m, 1H), 7.24−7.20 (m, 2H),
7.18 (dd, J = 8.8, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 2.47 (s, 3H),
1.14 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.0, 167.8,
167.5, 140.3, 134.7, 134.7, 134.5, 134.1, 132.0, 131.7, 131.5, 131.2,
130.7, 130.5, 130.3, 129.3, 129.0, 128.8, 124.9, 124.1, 123.9, 39.7,
27.4, 21.3; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M +
H]+ calcd for C26H24ClN2O3 447.1470, found 447.1471.
2
132.1, 131.4, 130.8, 130.7 (C−F, JC−F = 32.2 Hz), 130.5, 129.1,
123.9 (C−F, 1JC−F = 272.5 Hz), 123.8, 121.2, 120.4 (C−F, 3JC−F = 3.9
3
Hz), 117.9 (C−F, JC−F = 3.9 Hz), 112.9, 56.1, 40.0, 27.3; 19F NMR
(471 MHz, CDCl3) δ −62.6; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C27H24F3N2O4 497.1683,
found 497.1684.
N-(3′-(1,3-Dioxoisoindolin-2-yl)-4′-methoxy-3-methyl-[1,1′-bi-
phenyl]-2-yl)pivalamide (34). The reaction was performed according
to General Procedure 2A using amides 1l and 2i. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(4:1, v/v) gave 34 (49.6 mg, 56% yield) as a white solid: mp 96−98
N-(tert-Butyl)-4-methoxy-2′-pivalamido-[1,1′-biphenyl]-2-car-
boxamide (39). The reaction was performed according to General
Procedure 2A using amides 1n and 2j. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (6:1, v/v)
1
gave 39 (51.3 mg, 67% yield) as a white solid: mp 167−169 °C; H
1
°C; H NMR (400 MHz, CDCl3) δ 7.95−7.88 (m, 2H), 7.80−7.74
NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H, br),
7.39−7.33 (m, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.23−7.17 (m, 2H),
7.08 (d, J = 8.5 Hz, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 6.21 (s, 1H,
br), 3.85 (s, 3H), 1.04 (s, 9H), 1.04 (s, 9H); 13C{1H} NMR (126
MHz, CDCl3) δ 177.0, 167.4, 159.5, 138.6, 135.7, 133.9, 131.4, 130.5,
128.7, 127.7, 125.5, 123.8, 116.9, 113.2, 55.6, 51.4, 39.5, 28.2, 27.4;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C23H30N2NaO3 405.2149, found 405.2151.
(m, 2H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.23−7.15 (m, 4H), 7.05 (d,
J = 8.4 Hz, 1H), 6.97 (s, 1H, br), 3.81 (s, 3H), 2.23 (s, 3H), 1.17 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.2, 167.3, 154.9, 138.4,
136.9, 134.3, 133.1, 132.4, 132.3, 131.4, 130.6, 130.2, 128.0, 127.2,
123.8, 120.2, 112.0, 56.1, 39.2, 27.6, 18.6; HRMS (ESI-Q/TOF MS)
with acetonitrile (m/z) [M + H]+ calcd for C27H27N2O4 443.1965,
found 443.1963.
N-(3-Chloro-3′-(1,3-dioxoisoindolin-2-yl)-4′-methoxy-[1,1′-bi-
phenyl]-2-yl)pivalamide (35). The reaction was performed according
to General Procedure 2A using amides 1m and 2i. Purification by
flash column chromatography eluting with petroleum ether/ethyl
acetate (4:1, v/v) gave 35 (70.4 mg, 76% yield) as a white solid: mp
N-(tert-Butyl)-4′-chloro-4-methoxy-2′-pivalamido-[1,1′-biphen-
yl]-2-carboxamide (40). The reaction was performed according to
General Procedure 2A using amides 1e and 2j. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(4:1, v/v) gave 40 (68.4 mg, 82% yield) as a white solid: mp 148−149
°C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.6 Hz, 1H), 7.83 (s,
1H), 7.24 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 (d,
J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.96−6.90 (m, 1H), 6.21 (s,
1H), 3.84 (s, 3H), 1.08 (s, 9H), 1.03 (s, 9H); 13C{1H} NMR (101
MHz, CDCl3) δ 177.1, 167.5, 159.6, 138.7, 136.9, 134.1, 132.4, 131.4,
1
226−227 °C; H NMR (500 MHz, CDCl3) δ 7.97−7.87 (m, 2H),
7.79−7.73 (m, 2H), 7.44−7.39 (m, 2H), 7.27−7.23 (m, 2H), 7.20 (d,
J = 2.0 Hz, 2H), 7.07−7.04 (m, 2H), 3.81 (s, 3H), 1.19 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) δ 177.3, 167.3, 155.1, 141.2,
134.3, 133.3, 132.3, 132.2, 131.7, 131.3, 130.3, 129.1, 129.1, 128.2,
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131.3, 126.6, 125.3, 123.9, 116.7, 113.1, 55.6, 51.5, 39.5, 28.2, 27.3;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C23H30ClN2O3 417.1939, found 417.1945.
CDCl3) δ 7.25−7.18 (m, 4H), 7.16−7.11 (m, 1H), 6.92 (d, J = 7.5
Hz, 2H), 6.85 (s, 1H, br), 3.83 (s, 3H), 2.24 (s, 3H), 1.14 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) δ 176.8, 159.1, 139.3, 136.7,
N-(tert-Butyl)-4-methoxy-2′-pivalamido-4′-(trifluoromethyl)-
[1,1′-biphenyl]-2-carboxamide (41). The reaction was performed
according to General Procedure 2A using amides 1g and 2j.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (6:1, v/v) gave 41 (56.8 mg, 63% yield) as a white
solid: mp 227−229 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H),
7.85 (s, 1H, br), 7.44 (dd, J = 8.0, 1.0 Hz, 1H), 7.30 (d, J = 8.0 Hz,
1H), 7.25 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.97 (dd, J =
8.5, 3.0 Hz, 1H), 6.13 (s, 1H, br), 3.85 (s, 3H), 1.06 (s, 9H), 1.05 (s,
9H); 13C{1H} NMR (126 MHz, CDCl3) δ 177.3, 167.5, 159.9, 138.8,
133.1, 132.1, 130.2, 129.9, 127.9, 127.0, 113.7, 55.4, 39.2, 27.7, 18.6.
N-(3,3′,4′-Trimethyl-[1,1′-biphenyl]-2-yl)pivalamide (46). The
reaction was performed according to General Procedure 2A (10
mol % of Pd(OAc)2; 17.5 equiv of solvent; CF3CO2H/CH3SO3H =
6:1; 2 equiv of K2S2O8) in 24 h using amide 1l and o-xylene.
Purification by flash column chromatography eluting with petroleum
ether/dichloromethane (1:2, v/v) gave 46 (35.5 mg, 60% yield) as a
white solid: mp 123−125 °C (ref 27b, 124−126 °C); 1H NMR (400
MHz, CDCl3) δ 7.24−7.19 (m, 2H), 7.18−7.12 (m, 2H), 7.08 (s,
1H), 7.03 (dd, J = 7.6, 1.6 Hz, 1H), 6.84 (s, 1H, br), 2.30 (s, 3H),
2.28 (s, 3H), 2.25 (s, 3H), 1.14 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 176.8, 139.4, 137.1, 136.6, 136.4, 135.8, 132.9, 130.3, 129.9,
129.7, 127.8, 127.0, 126.5, 39.2, 27.6, 19.9, 19.6, 18.7.
2
137.6, 136.5, 131.1, 131.0, 130.9 (C−F, JC−F = 32.7 Hz), 126.5,
1
3
123.9 (C−F, JC−F = 272.3 Hz), 121.9 (C−F, JC−F = 3.6 Hz), 121.0
(C−F, JC−F = 3.6 Hz), 116.7, 113.3, 55.7, 51.6, 39.5, 28.2, 27.3; 19F
NMR (471 MHz, CDCl3) δ −62.6; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C24H30F3N2O3 451.2203,
found 451.2203.
3
Homocoupling Products. N,N′-(4,4′-Dimethyl-[1,1′-biphenyl]-
2,2′-diyl)bis(2,2-dimethylpropanamide) (1aa). The reaction was
performed according to General Procedure 2A using amides 1a and
2a. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (16/1, v/v) gave 1aa (2.3 mg, 6%
Ethyl 2′-(1,3-Dioxoisoindolin-2-yl)-4-methoxy-4′-methyl-[1,1′-
biphenyl]-2-carboxylate (42). The reaction was performed according
to General Procedure 2A using amide 2f and ethyl 3-methox-
ybenzoate. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (6:1, v/v) gave 42 (38.2 mg, 46%
yield) as a yellow solid: mp 128−130 °C; 1H NMR (400 MHz,
CDCl3) δ 7.83−7.76 (m, 1H), 7.76−7.70 (m, 1H), 7.70−7.62 (m,
2H), 7.30 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 6.96 (dd, J =
8.4, 2.8 Hz, 1H), 4.18−4.01 (m, 2H), 3.76 (s, 3H), 2.43 (s, 3H), 1.00
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.3,
167.2, 167.1, 158.7, 138.2, 138.1, 134.2, 134.1, 132.5, 132.0, 131.7,
131.6, 131.4, 131.1, 129.7, 129.5, 129.1, 123.6 (2C), 117.5, 114.7,
61.1, 55.5, 21.1, 13.6; HRMS (ESI-Q/TOF MS) with acetonitrile (m/
z) [M + H]+ calcd for C25H22NO5 416.1492, found 416.1494.
N-(2′,4-Dichloro-4′-methoxy-[1,1′-biphenyl]-2-yl)pivalamide
(43). The reaction was performed according to General Procedure 2A
(20 equiv of CF3CO2H as the only solvent) using amide 1e and 1-
chloro-3-methoxybenzene. Purification by flash column chromatog-
raphy eluting with petroleum ether/ethyl acetate (16:1, v/v) gave 43
(19.7 mg, 28% yield) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ
8.44 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.13 (dd, J = 8.0,
2.0 Hz, 1H), 7.10−7.06 (m, 2H), 6.94 (dd, J = 8.5, 2.5 Hz, 1H), 3.87
(s, 3H), 1.08 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.5,
160.6, 137.0, 134.8, 134.5, 132.6, 131.1, 127.6, 123.9, 120.9, 115.3,
113.8, 55.8, 39.9, 27.4; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C18H20Cl2NO2 352.0866, found 352.0868.
N-(4,4′-Dichloro-2′-methoxy-[1,1′-biphenyl]-2-yl)pivalamide
(44). The reaction was performed according to General Procedure 2A
(20 equiv of CF3CO2H as the only solvent) using amide 1e and 1-
chloro-3-methoxybenzene. Purification by flash column chromatog-
raphy eluting with petroleum ether/ethyl acetate (16:1, v/v) gave 44
(20.4 mg, 29% yield) as a white solid: mp 60−61 °C; 1H NMR (500
MHz, CDCl3) δ 8.25 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H, br), 7.16−7.11
(m, 2H), 7.10−7.06 (m, 2H), 7.02 (d, J = 1.5 Hz, 1H), 3.82 (s, 3H),
1.10 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 176.6, 156.6,
136.9, 135.7, 134.5, 132.9, 131.5, 127.2, 124.9, 124.4, 122.2, 122.0,
112.0, 56.3, 39.7, 27.4; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C18H20Cl2NO2 352.0866, found 352.0868.
N-(4′-Methoxy-3-methyl-[1,1′-biphenyl]-2-yl)pivalamide (45). N-
(o-tolyl)pivalamide (0.2 mmol), anisole (0.2 mmol), Pd(OAc)2 (4.4
mg, 0.02 mmol, 10 mol %), potassium persulfate (108.1 mg, 0.4
mmol, 2 equiv), 2,2,2-trifluoroethanol (200.1 mg, 2 mmol, 10 equiv),
and 2,2,2-trifluoroacetic acid (228 mg, 2 mmol, 10 equiv) were added
in a 15 mL seal tube. The reaction mixture was stirred at 25 °C for 24
h. Then, saturated NaHCO3 was added to adjust pH to 7−8. After
that, the mixture was extracted with CH2Cl2 (10 mL × 3), washed
with brine, and dried over anhydrous Mg2SO4. Finally, the extract was
concentrated and the residue was purified by flash column
chromatography on silica gel eluting with petroleum ether/ethyl
acetate (10:1, v/v) to give 45 (36.9 mg, 62% yield) as a white solid:
mp 181−183 °C (ref 27b, 181−183 °C); 1H NMR (500 MHz,
1
yield) as a white solid: mp 158−160 °C (ref 23b, 158−160 °C); H
NMR (400 MHz, CDCl3) δ 8.19 (s, 2H), 7.19 (s, 2H, br), 7.07 (d, J =
7.6 Hz, 2H), 7.01 (dd, J = 7.6, 1.2 Hz, 2H), 2.40 (s, 6H), 1.00 (s,
18H).
N,N′-(4,4′-Diethyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1bb). The reaction was performed according to General
Procedure 2A using amides 1b and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (4/1, v/
v) gave 1bb (3.7 mg, 9% yield) as a white solid: mp 134−135 °C (ref
23b, 134−135 °C); 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 2H), 7.18
(s, 2H, br), 7.12 (d, J = 7.6 Hz, 2H), 7.04 (dd, J = 7.6, 1.2 Hz, 2H),
2.70 (q, J = 7.6 Hz, 4H), 1.26 (t, J = 7.6 Hz, 6H), 0.99 (s, 18H).
N,N′-(4,4′-Dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethyl-
propanamide) (1cc). The reaction was performed according to
General Procedure 2A using amides 1a and 1c. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(3:1, v/v) gave 1cc (9.5 mg, 23% yield) as a white solid: mp 78−81
°C (ref 23b, 78−81 °C); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J =
2.8 Hz, 2H), 7.25 (s, 2H, br), 7.10 (d, J = 8.4 Hz, 2H), 6.77 (dd, J =
8.4, 2.8 Hz, 2H), 3.88 (s, 6H), 1.02 (s, 18H).
N,N′-(4,4′-Difluoro-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1dd). The reaction was performed according to General
Procedure 2A using amides 1d and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (5:1, v/v)
gave 1dd (2.3 mg, 6% yield) as a white solid: mp 117−119 °C (ref
23b, 117−119 °C); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 11.2
Hz, 2H), 7.22−7.10 (m, 4H), 6.94 (td, J = 8.0, 2.4 Hz, 2H), 1.02 (s,
18H).
N,N′-(4,4′-Dichloro-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1ee). The reaction was performed according to General
Procedure 2A using amides 1e and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (5:1, v/v)
gave 1ee (0.8 mg, 2% yield) as a white solid: mp 195−197 °C (ref
1
23b, 195−197 °C); H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.0
Hz, 2H), 7.22 (dd, J = 8.0, 2.0 Hz, 2H), 7.15 (s, 2H, br), 7.12 (d, J =
8.0 Hz, 2H), 1.03 (s, 18H).
N,N′-(4,4′-Dibromo-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethyl-
propanamide) (1ff). The reaction was performed according to
General Procedure 2A using amides 1f and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 7 (1 mg, 2% yield) a white solid: mp 214−216 °C (ref
1
23b, 214−216 °C); H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 1.6
Hz, 2H), 7.37 (dd, J = 8.0, 1.6 Hz, 2H), 7.14 (s, 2H, br), 7.05 (d, J =
8.0 Hz, 2H), 1.03 (s, 18H).
N,N′-(4,4′-Bis(trifluoromethyl)-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-
dimethylpropanamide) (1gg). The reaction was performed accord-
ing to General Procedure 2A (20 equiv of CF3CO2H as the only
solvent) using amides 1g and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (5:1, v/v)
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gave 1gg (2.4 mg, 5% yield) as a white solid: mp 148−150 °C (ref
Procedure 2A using amides 1s and 2f. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (7:1, v/v)
gave 1ss (0.4 mg, 1% yield) as a white solid: mp 166−167 °C (ref
1
23b, 148−150 °C); H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 1.2
Hz, 2H), 7.53 (dd, J = 8.0, 1.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.25
(s, 2H, br), 1.02 (s, 18H).
1
23b, 166−167 °C); H NMR (500 MHz, CDCl3) δ 8.01−7.85 (m,
N,N′-(5,5′-Diethyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1hh). The reaction was performed according to General
Procedure 2A using amides 1h and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (4:1, v/v)
gave 1hh (0.4 mg, 1% yield) as a yellow solid: mp 81−84 °C (ref 23b,
81−84 °C); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 2H),
7.26 (dd, J = 8.4, 2.0 Hz, 2H), 7.17 (s, 2H, br), 7.05 (d, J = 2.0 Hz,
2H), 2.65 (q, J = 7.6 Hz, 4H), 1.23 (t, J = 7.6 Hz, 6H), 0.99 (s, 18H).
N,N′-(5,5′-Dichloro-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1ii). The reaction was performed according to General
Procedure 2A (5 mol % of Pd(OAc)2) using amides 1i and 2a.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (5:1, v/v) gave 1ii (0.4 mg, 1% yield) as a white
solid: mp 142−144 °C (ref 23b, 142−144 °C); 1H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.8, 2.4 Hz, 2H),
7.21 (d, J = 2.4 Hz, 2H), 7.17 (s, 2H, br), 1.03 (s, 18H).
1H), 7.21 (s, 2H, br), 7.14 (td, J = 8.5, 2.5 Hz, 2H), 6.92 (dd, J = 8.5,
2.5 Hz, 2H), 1.02 (s, 18H).
2,2′-(4,4′-Dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(isoindoline-
1,3-dione) (2aa). The reaction was performed according to General
Procedure 2A using amides 1p and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (2:1, v/v)
1
gave 2aa (11.6 mg, 23% yield) as a white solid: mp > 300 °C; H
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 2H), 7.77−7.64 (m,
6H), 7.47 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 8.4, 2.4 Hz, 2H), 6.59 (d,
J = 2.4 Hz, 2H), 3.75 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
167.7, 166.5, 159.6, 134.2, 134.1, 133.7, 132.7, 131.6, 130.7, 130.2,
123.7, 123.5, 115.1, 113.8, 55.5; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C30H21N2O6 505.1394, found
505.1400.
2,2′-(4,4′-Dimethoxy-5,5′-dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis-
(isoindoline-1,3-dione) (2bb). The reaction was performed according
to General Procedure 2A (60 equiv of CF3CO2H as the only solvent)
using amides 1n and 2b. Purification by flash column chromatography
eluting with petroleum ether/ethyl acetate (1:1, v/v) gave 2bb (3.2
N,N′-(5,5′-Dibromo-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethyl-
propanamide) (1jj). The reaction was performed according to
General Procedure 2A (5 mol % of Pd(OAc)2) using amides 1j and
2a. Purification by flash column chromatography eluting with
petroleum ether/ethyl acetate (5:1, v/v) gave 1jj (1.5 mg, 3%
1
mg, 6% yield) as a white solid: mp > 300 °C; H NMR (500 MHz,
CDCl3) δ 7.84−7.69 (m, 8H), 7.28 (s, 2H), 6.47 (s, 2H), 3.72 (s,
6H), 2.24 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.0, 166.8,
157.5, 134.4, 134.0, 132.8, 131.8, 129.9, 128.0, 127.8, 123.7, 123.4,
109.8, 55.5, 16.2; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C32H25N2O6 533.1707, found 533.1704.
1
yield) as a white solid: mp 205−207 °C (ref 23b, 205−207 °C); H
NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.56 (dd, J =
8.5, 2.5 Hz, 2H), 7.35 (d, J = 2.5 Hz, 2H), 7.18 (s, 2H, br), 1.03 (s,
18H).
N,N′-(3,3′-Dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethyl-
propanamide) (1ll). The reaction was performed according to
General Procedure 2A using amides 1l and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 1ll (1.5 mg, 4% yield) as a white solid: mp 245−246
2,2′-(5,5′-Dichloro-4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis-
(isoindoline-1,3-dione) (2cc). The reaction was performed according
to General Procedure 2A using amides 1q and 2c. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(1:1, v/v) gave 2cc (1.7 mg, 3% yield) as a white solid: mp > 300 °C;
1H NMR (400 MHz, CDCl3) δ 7.89−7.65 (m, 8H), 7.58 (s, 2H),
1
°C (ref 23b, 245−246 °C); H NMR (400 MHz, CDCl3) δ 7.33 (s,
2H, br), 7.22 (d, J = 7.2 Hz, 2H), 7.17 (t, J = 7.2 Hz, 2H), 6.98 (d, J =
7.2 Hz, 2H), 2.22 (s, 6H), 0.96 (s, 18H).
6.60 (s, 2H), 3.80 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
167.7, 166.0, 155.1, 134.4 (2C), 133.8, 132.5, 131.4, 129.8, 129.1,
124.1, 123.5, 123.3, 112.0, 56.4; HRMS (ESI-Q/TOF MS) with
acetonitrile (m/z) [M + H]+ calcd for C30H19Cl2N2O6 573.0615,
found 573.0619.
N,N′-([1,1′-Biphenyl]-2,2′-diyl)bis(2,2-dimethylpropanamide)
(1nn). The reaction was performed according to General Procedure
2A using amides 1n and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (3:1, v/
v) gave 1nn (0.4 mg, 1% yield) as a white solid: mp 120−122 °C (ref
2,2′-(5,5′-Dibromo-4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis-
(isoindoline-1,3-dione) (2dd). The reaction was performed according
to General Procedure 2A using amides 1e and 2d. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(1:1, v/v) gave 2dd (0.7 mg, 1% yield) as a white solid: mp > 300 °C;
1H NMR (400 MHz, CDCl3) δ 7.97−7.67 (m, 10H), 6.56 (s, 2H),
1
23b, 120−122 °C); H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.4
Hz, 2H), 7.48−7.41 (m, 2H), 7.25−7.20 (m, 4H), 7.19 (s, 2H, br),
0.98 (s, 18H).
N,N′-(3,3′,5,5′-Tetramethyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-di-
methylpropanamide) (1oo). The reaction was performed according
to General Procedure 2A (41 equiv of solvent; CF3CO2H/CH3SO3H
= 40:1) using amides 1o and 2a. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (5:1, v/v)
gave 1oo (3.3 mg, 8% yield) as a white solid: mp 255−258 °C (ref
23b, 255−258 °C); 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 2H, br),
7.00 (s, 2H), 6.78 (s, 2H), 2.27 (s, 6H), 2.16 (s, 6H), 0.96 (s, 18H).
N,N′-(4,4′,5,5′-Tetramethyl-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-di-
methylpropanamide) (1pp). The reaction was performed according
to General Procedure 2A using amides 1p and 2a. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(5:1, v/v) gave 1pp (10.6 mg, 26% yield) as a white solid: mp 168−
171 °C (ref 23b, 168−171 °C); 1H NMR (400 MHz, CDCl3) δ 8.10
(s, 2H), 7.18 (s, 2H, br), 6.95 (s, 2H), 2.31 (s, 6H), 2.24 (s, 6H), 1.01
(s, 18H).
N,N′-(5,5′-Dibromo-4,4′-dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis-
(2,2-dimethylpropanamide) (1qq). The reaction was performed
according to General Procedure 2A using amides 1q and 2c.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (5:1, v/v) gave 1qq (5.4 mg, 10% yield) as a white
solid: mp 204−205 °C (ref 23b, 204−205 °C); 1H NMR (400 MHz,
CDCl3) δ 8.15 (s, 2H), 7.35 (s, 2H), 7.16 (s, 2H, br), 2.43 (s, 6H),
1.03 (s, 18H).
3.80 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.6, 166.0,
156.0, 136.8, 134.4, 134.4, 132.5, 131.4, 130.1, 129.9, 124.1, 123.5,
112.4, 111.7, 56.5; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C30H19Br2N2O6 660.9604, found 660.9608.
Dimethyl 6,6′-Bis(1,3-dioxoisoindolin-2-yl)-4,4′-dimethoxy-[1,1′-
biphenyl]-3,3′-dicarboxylate (2ee). The reaction was performed
according to General Procedure 2A using amides 1e and 2e.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (1:1, v/v) gave 2ee (1.9 mg, 3% yield) as a white
1
solid: mp > 300 °C; H NMR (400 MHz, CDCl3) δ 8.06 (s, 2H),
7.86−7.71 (m, 8H), 6.67 (s, 2H), 3.92 (s, 6H), 3.81 (s, 6H); 13C{1H}
NMR (101 MHz, CDCl3) δ 165.6 (2C), 159.2, 136.2, 134.4 (2C),
134.2, 132.4, 131.3, 128.8, 124.1, 123.4, 120.5, 112.1, 56.3, 52.4;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C34H25N2O10 621.1504, found 621.1505.
2,2′-(4,4′-Dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis(isoindoline-1,3-
dione) (2ff). The reaction was performed according to General
Procedure 2B using amides 1e and 2f. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (1:1, v/v)
gave 2ff (1.9 mg, 4% yield) as a white solid: mp > 300 °C; 1H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 2H), 7.75−7.65 (m, 6H),
7.46 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.0, 1.2 Hz, 2H), 6.88 (s, 2H),
2.32 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 166.7,
138.9, 135.2, 134.1 (2C), 132.8, 132.6, 131.6, 130.0, 129.4, 129.0,
N,N′-(5,5′-Difluoro-[1,1′-biphenyl]-2,2′-diyl)bis(2,2-dimethylpro-
panamide) (1ss). The reaction was performed according to General
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123.7, 123.5, 21.2; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z)
[M + H]+ calcd for C30H21N2O4 473.1496, found 473.1498.
anhydrous Na2SO4. Finally, the extract was concentrated and the
residue was purified by flash column chromatography on silica gel
eluting with petroleum ether/ethyl acetate (1:1, v/v) to give 47 (85.7
mg, 80% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.34−
7.26 (m, 1H), 7.22 (dd, J = 7.6, 0.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H),
6.93 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.53 (dd, J = 8.4,
2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 4H, br);
13C{1H} NMR (101 MHz, CDCl3) δ 160.3, 145.3, 144.5, 131.9,
131.4, 128.6, 124.4, 118.7, 117.5, 115.5, 104.4, 101.0, 55.2.
2,2′-(4,4′-Diethyl-[1,1′-biphenyl]-2,2′-diyl)bis(isoindoline-1,3-
dione) (2gg). The reaction was performed according to General
Procedure 2A (10 mol % of Pd(OAc)2; 2 equiv of K2S2O8; 30 equiv
of solvent; CF3CO2H/CH3SO3H = 1:1) using amides 1d and 2g.
Purification by flash column chromatography eluting with petroleum
ether/ethyl acetate (1:1, v/v) gave 2gg (2.5 mg, 5% yield) as a white
1
solid: mp > 300 °C; H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.2
Hz, 2H), 7.69−7.57 (m, 6H), 7.42 (d, J = 8.0 Hz, 2H), 7.24 (dd, J =
8.0, 0.8 Hz, 2H), 6.83 (s, 2H), 2.57 (q, J = 7.6 Hz, 4H), 1.13 (t, J =
7.6 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 166.7,
144.9, 135.4, 134.1 (2C), 132.8, 132.6, 131.6, 129.4, 128.7, 127.8,
123.6, 123.4, 28.3, 14.9; HRMS (ESI-Q/TOF MS) with acetonitrile
(m/z) [M + H]+ calcd for C32H25N2O4 501.1809, found 501.1814.
2,2′-(4,4′,5,5′-Tetramethyl-[1,1′-biphenyl]-2,2′-diyl)bis-
(isoindoline-1,3-dione) (2hh). The reaction was performed according
to General Procedure 2A using amides 1r and 2h. Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate
(1:1, v/v) gave 2hh (1.5 mg, 3% yield) as a white solid: mp > 300 °C;
1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.0 Hz, 2H), 7.76−7.65
3-Methoxybenzo[c]cinnoline (48). Compound 48 was obtained
according to a modified procedure from ref 53: An oven-dried 25 mL
round-bottom flask equipped with a magnetic stir bar was charged
with 4-methoxy-[1,1′-biphenyl]-2,2′-diamine 47 (0.1 mmol) and
tBuONO (0.3 mmol) in 2,2,2-trifluoroethanol (10 mL). Then, the
reaction mixture was stirred at room temperature for 12 h. After
completion, the solid residue was removed by filtration through
cotton and the mixture solution was concentrated using a rotary
evaporator and purified by flash column chromatography on silica gel
eluting with petroleum ether/ethyl acetate (2:1, v/v) as the eluent to
1
give 48 (17.2 mg, 82% yield) as a yellow solid: mp 128−130 °C; H
NMR (500 MHz, CDCl3) δ 8.70 (dd, J = 8.0, 1.0 Hz, 1H), 8.48 (d, J
= 8.5 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H),
7.89−7.84 (m, 1H), 7.84−7.79 (m, 1H), 7.53 (dd, J = 9.0, 2.5 Hz,
1H), 4.06 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 160.4, 147.1,
145.3, 131.7, 131.4, 128.3, 123.8, 122.8, 121.4, 121.1, 115.5, 109.6,
56.0.
(m, 6H), 7.31 (s, 2H), 6.83 (s, 2H), 2.29 (s, 6H), 2.21 (s, 6H);
13C{1H} NMR (126 MHz, CDCl3) δ 168.1, 166.9, 137.8, 137.4,
135.5, 134.0 (2C), 133.7, 132.9, 131.8, 129.3, 127.0, 123.6, 123.4,
19.7, 19.7; HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M +
H]+ calcd for C32H25N2O4 501.1809, found 501.1813.
N2,N2′-Di-tert-butyl-4,4′-dimethoxy-[1,1′-biphenyl]-2,2′-dicar-
boxamide (2jj). The reaction was performed according to General
Procedure 2A using amides 1g and 2j. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (2:1, v/v)
8-Methoxyphenanthridin-6(5H)-one (49). Compound 4954 was
obtained according to a modified procedure from ref 55: A Schlenk
tube with a magnetic stir bar was charged with N-(tert-butyl)-4-
methoxy-2′-pivalamido-[1,1′-biphenyl]-2-carboxamide 39 (191.2 mg,
1
t
gave 2jj (1.2 mg, 3% yield) as a white solid: mp 139−140 °C; H
0.5 mmol), TsOH·H2O (475.5 mg, 5.0 equiv), and BuOH (1.0 mL)
NMR (500 MHz, CDCl3) δ 7.04 (d, J = 2.5 Hz, 2H), 7.01 (d, J = 8.5
Hz, 2H), 6.86 (dd, J = 8.5, 2.5 Hz, 2H), 6.71 (s, 2H), 3.83 (s, 6H),
1.15 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 169.1, 159.0,
138.8, 131.1, 131.1, 115.0, 111.9, 55.7, 51.6, 28.5; HRMS (ESI-Q/
TOF MS) with acetonitrile (m/z) [M + Na]+ calcd for
C24H32N2NaO4 435.2254, found 435.2265.
Diethyl 4,4′-Dimethoxy-[1,1′-biphenyl]-2,2′-dicarboxylate (2kk).
The reaction was performed according to General Procedure 2A using
amide 2f and ethyl 3-methoxybenzoate. Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (6:1, v/v)
gave 2kk (0.4 mg, 1% yield) as a white solid: mp 88−90 °C; 1H NMR
(400 MHz, CDCl3) δ 7.50 (d, J = 2.8 Hz, 2H), 7.11 (d, J = 8.4 Hz,
2H), 7.04 (dd, J = 8.4, 2.8 Hz, 2H), 4.05 (q, J = 7.2 Hz, 4H), 3.88 (s,
6H), 1.02 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
167.3, 158.5, 135.4, 131.8, 131.3, 117.5, 114.5, 60.9, 55.6, 13.9;
HRMS (ESI-Q/TOF MS) with acetonitrile (m/z) [M + H]+ calcd for
C20H23O6 359.1489, found 359.1491.
Gram-Scale Reaction. Procedure for the preparation of cross-
coupling product 15 on a gram scale: N-phenylpivalamide (1.06 g, 6
mmol), 2-(3-methoxyphenyl)isoindoline-1,3-dione (1.52 g, 6 mmol),
Pd(OAc)2 (107.8 mg, 0.48 mmol, 8 mol %), potassium persulfate
(2.43 g, 9 mmol, 1.5 equiv), 2,2,2-trifluoroacetic acid (10.26 g, 90
mmol, 15 equiv), and methanesulfonic acid (2.88 g, 30 mmol, 5
equiv) were added in a 100 mL round-bottom flask. The reaction
mixture was stirred at 25 °C for 12 h. Then, the solvent was
evaporated to 5 mL. Saturated NaHCO3 was added to adjust pH to
7−8. After that, the mixture was extracted with CH2Cl2 (100 mL ×
4), washed with brine, and dried over anhydrous Mg2SO4. Finally, the
extract was concentrated and the residue was purified by flash column
chromatography on silica gel eluting with petroleum ether/ethyl
acetate (3:1, v/v) to give 15 (1.23 g, 73% yield).
Synthesis of Bioactivity Molecules. 4-Methoxy-[1,1′-biphen-
yl]-2,2′-diamine (47). Compound 4752 was obtained according to a
modified procedure from ref 23b: Compound 15 (214.2 mg, 0.5
mmol) and sulfuric acid (10 M, 4.2 mL) were added in a 35 mL seal
tube in N2. The reaction mixture was stirred at 125 °C in a preheated
oil bath for 2 h. Then, sodium hydroxide (6 M) was added to it and
the pH was adjusted to 9. After that, the mixture was extracted with
EtOAc (20 mL × 3), washed with brine (20 mL), and dried over
under an N2 atmosphere. The resulting mixture was stirred at 140 °C
in a preheated oil bath for 24 h and then neutralized with Na2CO3
aqueous solution. After that, the mixture was extracted with ethyl
acetate and the combined organic layer was dried over sodium sulfate.
Concentration in vacuo followed by silica gel column purification with
petroleum ether/ethyl acetate (2:1, v/v) afforded 49 (111.4 mg, 99%
yield) as a white solid: mp 274−276 °C; 1H NMR (500 MHz,
DMSO-d6) δ 11.70 (s, 1H, br), 8.43 (d, J = 9.0 Hz, 1H), 8.29 (d, J =
8.0 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.49−7.39 (m, 2H), 7.34 (d, J
= 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 160.5, 159.0, 135.4, 128.4, 127.6, 127.1,
124.5, 122.6, 122.2, 121.6, 117.7, 115.9, 108.7, 55.4.
8-Methoxy-5-(4-methoxyphenethyl)phenanthridin-6(5H)-one
(50). Compound 5056 was obtained according to a modified
procedure from ref 55: A seal tube with a magnetic stir bar was
charged with compound 49 (22.5 mg, 0.1 mmol), KOH (14.0 mg,
0.25 mmol, 2.5 equiv), and acetone (1.0 mL). After stirring at room
temperature for 20 min, 1-(2-bromoethyl)-4-methoxybenzene (86.3
mg, 0.4 mmol, 4.0 equiv) was added dropwise with stirring, and then
the mixture was heated at 50 °C in an oil bath for 18 h. The reaction
was quenched by slow addition of 1 M HCl (3.0 mL) and then
quenched with Na2CO3 aqueous solution. The mixture was extracted
with ethyl acetate, and the combined organic layer was dried over
sodium sulfate. Concentration in vacuo followed by silica gel column
purification with petroleum ether/ethyl acetate (5:1, v/v) afforded 50
(27 mg, 75% yield) as a white solid: mp 139−140 °C; 1H NMR (500
MHz, CDCl3) δ 8.24 (dd, J = 8.0, 1.0 Hz, 1H), 8.21 (d, J = 9.0 Hz,
1H), 7.99 (d, J = 3.0 Hz, 1H), 7.57−7.45 (m, 2H), 7.37 (dd, J = 8.5,
3.0 Hz, 1H), 7.35−7.29 (m, 3H), 6.91 (d, J = 8.5 Hz, 2H), 4.63−4.51
(m, 2H), 3.97 (s, 3H), 3.82 (s, 3H), 3.08−2.99 (m, 2H); 13C{1H}
NMR (126 MHz, CDCl3) δ 161.2, 159.7, 158.6, 136.1, 130.8, 129.9,
128.7, 127.3, 126.9, 123.6, 123.1, 122.6 (2C), 119.8, 115.0, 114.3,
109.1, 55.8, 55.5, 44.9, 33.0.
2-Methoxy-3-methyl-9H-carbazole (51). Compound 5157 was
obtained according to a modified procedure from ref 58: An oven-
dried 10 mL Schlenk tube equipped with a magnetic stir bar N-(2′-
(1,3-dioxoisoindolin-2-yl)-4′-methoxy-5′-methyl-[1,1′-biphenyl]-2-
yl)pivalamide 18 (88.5 mg, 0.2 mmol) was dissolved in diethylene
glycol (1 mL), followed by addition of phosphoric acid (196 mg, 2
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mmol, 10 equiv) in. The reaction mixture was stirred at 200 °C on a
sand-bath heating mantle for 24 h until completion and cooled to rt.
Organic components were extracted with CH2Cl2 (10 mL × 3), and
the combined organic extracts were washed with brine (10 mL) and
dried over anhydrous MgSO4. Finally, the extract was concentrated
and the residue was purified by flash column chromatography on silica
gel using petroleum ether/ethyl acetate (5:1, v/v) as the eluent to give
51 (17.7 mg, 42% yield) as a yellow solid: mp 224−226 °C (ref 58,
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Corresponding Author
̌
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Wenjun Lu − Department of Chemistry, Shanghai Jiao Tong
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Mengdi Zhao − Department of Chemistry, Shanghai Jiao
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ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (grant no. 21372153) and Yangquan Coal Industry
(group) Co., Ltd. (YM18038) for financial support. Calcu-
lations were performed on the π 2.0 cluster at the Center for
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