Mixing O-Containing and N-Containing Directing Groups for C-H Activation: A Strategy for the Synthesis of Highly Functionalized 2,2′-Biaryls

Article abstract of DOI:10.1021/acs.joc.7b02863

A strategy combining O- and N-containing directing groups has been developed for the synthesis of 2,2′-biaryl via Pd-mediated C-H bond activation and oxidative coupling. This new transformation may proceed through a mechanism involving Pd(II) and Pd(IV) intermediates. We found the use of PTSA and HFIP to be critical for the reaction and suggest that these reagents could serve as efficient ligands for this C-C bond formation. This methodology provides broad functional group tolerance, excellent reactivity, and high yields.

Full text of DOI:10.1021/acs.joc.7b02863

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Article
Mixing O-Containing and N-Containing Directing Groups for C–H Activation:
A Strategy for the Synthesis of Highly Functionalized 2,2’-Biaryls
Chao Zhang, Yugang Song, Zhihui Sang, Lingpeng Zhan, and Yu Rao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02863 • Publication Date (Web): 06 Feb 2018
Downloaded from http://pubs.acs.org on February 6, 2018
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Mixing O-Containing and N-Containing Directing Groups for C–H
Activation: A Strategy for the Synthesis of Highly Functionalized
2,2’-Biaryls
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†
Chao Zhang,† Yugang Song,† Zhihui Sang,† Lingpeng Zhan,‡ and Yu Rao*,
† MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key
Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing
100084, P.R. China
‡MOE Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry
for Living Biosystems, Institute of Chemistry, University of Chinese Academy of Sciences, Beijing
100049, China
*Correspondence to: Yu Rao, 314, Renꢀhuan Building, Tsinghua University, Beijing, China, 100084.
Email: yrao@tsinghua.edu.cn, Tel:+86ꢀ10ꢀ6278ꢀ2025
Abstract
A strategy combining Oꢀ and Nꢀcontaining directing groups has been developed for the synthesis
of 2,2’ꢀbiaryl via Pdꢀmediated C–H bond activation and oxidative coupling. This new transformation
may proceed through a mechanism involving involving Pd(II) and Pd(IV) intermediates. We found
the use of PTSA and HFIP to be critical for the reaction, and suggest that these reagents could serve
as efficient ligands for this C–C bond formation. This methodology provides broad functional group
tolerance, excellent reactivity and high yields.
Introduction
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Transition metal catalyzed C–H activation has emerged as a powerful strategy for modern
organic synthesis in the last decade1. In most studies, the use of coordinating moieties as directing
groups, such as Nꢀcontaining2 or Oꢀcontaining3 functions, has emerged as a practical and essential
strategy for siteꢀselective functionalization. Directing groups (DGs) can position the transition metal
to activate the proximate C–H bond with their coordinating ability, thus resulting in high levels of
regioselective functionalization. Among DGs, Nꢀcontaining groups (e.g., amide, anilide) and
Oꢀcontaining groups (e.g., ketone4, ester5, carbamate6) have been widely employed in the recent
years, exhibiting unique efficiency in C–H functionalization.
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Over the last few years, constructing a carbonꢀcarbon bond directly from two simple C–H bonds
has emerged as a powerful method for organic synthesis7. Typically, these studies employed an aryl
substrate containing a DG and a coupling partner without such a group. Achieving high selectivity
between two arene coupling partners remained challenging. For example, reactions between two
substrates containing different DGs, inevitably produced homocoupled biaryls as major products
instead of the desired crossꢀcoupled products under current conditions. Up to date, only very few
examples employing two different DGs have been reported. Recently, the Shi group reported two
examples using carboxylic acidꢀcontaining reactants to couple with benzyl thioethers8 or phenols9,
which generated intramolecularly cyclized 2,2’ꢀbiaryl lactones (Scheme 1a). More recently, the Song
group combined 8ꢀaminoquinoline amide and 2ꢀphenylpyridine to prepare difunctionalized biaryls
with high regioselectivity10 (Scheme 1b). Other Oꢀcontaining groups (e.g., ketone, ester, carbamate,
etc) have also been employed as DGs, which provided additional synthetic routes for the synthesis of
2,2’ꢀbiaryls. However, these reactions were usually restricted to substrates containing weakly
coordinating groups and had to be conducted under harsh conditions, such as using the strong acid
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TfOH as an additive11 (Scheme 1c).
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Scheme 1. Oxidative Coupling of Arenes Controlled by Two Different Directing Groups.
Inspired by the work of the Shi group using Oꢀcontaining DGs and the study of Song and
coworkers employing Nꢀbased DGs, we wondered whether a single reaction system could tolerate
the Nꢀcontaining DGs, such as amide and anilide, with Oꢀcontaining DGs, such as ketones, esters
and carbamates, to afford crossꢀcoupled 2,2’ꢀbiaryls (Scheme 1d). It is necessary to point out that
these two types of directing groups were normally difficult to be combined in one single reaction
system because of the different reactivity. C–H functionalization directed by the Oꢀcontaining DGs is
generally incompatible with the majority of Nꢀcontaining substrates because the strongly
coordinating nitrogen atoms often outcompete other directing groups for catalyst binding, thus
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preventing activation of the CꢀH bonds proximate to Oꢀcontaining DGs. For instance, to activate a
C–H bond ortho to the amide or anilide groups, several equivalents of AcOH or TFA were sufficient
to promote the reaction. On the other hand, strongly acidic TfOH had to be used as the additive to
activate the proximate C–H bond of ketones or esters,. Thus, overcoming the mismatch of these two
types of coordianting groups is a critical issue that needs to be addressed. Furthermore, this would
provide a readily accessible route for the synthesis of variably functionalized 2,2’ꢀbiaryl scaffolds.
Results and discussion
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Our goal was to find suitable conditions for combining Oꢀ and Nꢀcontaining DGs in one single
reaction system. As illustrated in Table 1, based on our previous results11, we first tested the
combination of 1a/1b in a 3:1 ratio. However, no desired product was obtained (Entry 1). Next, we
reversed the ratio of substrates to 1:3. To our delight, the target product was obtained in 8% yield,
whereas the remaining 1a was converted into the homocoupled product in this case (Entry 2). Based
on this result, we decided to test the mixed acid systems, which combined TfOH with other ligands,
to see if the generally employed ligand combinations might be beneficial. Then, various additives
were screened. Upon addition of reagents bearing a hydroxyl group, such as EtOH and phenol, no
desired product was detected (Entries 3-4). We thus turned to some common carboxylic acids.
Indeed, benzoic acid, AcOH and PivOH as additives provided the desired products in low yields
(Entries 5-7). The efficiency of this crossꢀcoupling protocol was improved by using TFA, which
resulted in higher yields compared to the previously used carboxylic acids (23% yield) (Entry 8).
Addition of water improved the yield to 30% and resulted in higher selectivity (Entry 9). Based on
these results, we wondered if an acid additive containing a defined amount of water was helpful.
Thus, we turned to PTSA (TsOH.H2O). Indeed, PTSA had a beneficial effect on the yield, which was
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improved to 40% (Entry 10). Notably, almost no homocoupling of the aryl ketone was observed in
this case, and the rest of the reactant could be recovered. The amount of PTSA also played an
important role in promoting the crossꢀcoupling process. To our delight, the yield could be
significantly improved to 72% when two equivalents of PTSA were added (Entry 11). Further
increasing the amount of PTSA to three equivalents, however, reduced the yield of the desired
product to 61% yield and resulted in inferior selectivity (Entry 12). Moreover, no desired product
was observed in the absence of oxidants, ligands or the palladium catalyst, which implied each of
these components played a crucial role in this reaction system (Entry 13).
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Table 1. Optimization of Reaction Conditions.
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Standard conditions: 1a 0.1 mmol, Pd(OAc)2 0.10 equiv, NaIO4 1.6 equiv, K2S2O8 3.0 equiv, HFIP
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1.5 mL, 70 C. [a] NMR yield [b] Isolated yield. 1aa, homocoupling of 1a; 1bb, homocoupling of
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1b.
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Based on the above observations, a preliminary mechanistic experiment was set up to illustrate
the definitive role of PTSA in the reaction. As shown in Scheme 2, the desired heterocoupled product
1c was obtained in 72% yield when the ratio of 1a/1b was 1:3, while the product of homocoupling of
1b could only be isolated in 5% yield and 70% of 1b was recovered (Scheme 2A). On the other hand,
1c was only obtained in 6% yield when the ratio of 1a/1b was 1:1 (Scheme 2B). When the ratio of
1a/1b was 3:1, 1c could not be obtained, but homocoupling of 1a was isolated in 76% yield and only
12% of 1a was recovered, and more than 90% of 1b could be recovered (Scheme 2C). While we
failed to isolate the cyclopalladated complex of 1b, we got the complex of the reaction intermediate
2 and 2’ from the precursor 1a using a stoichiometric amount of Pd(OAc)2 successfully. As shown in
Scheme 2D, when the reaction intermediate 2 and 1b were employed as the reaction partners, 1c
could only be obtained in 8% yield. Interestingly, when we combined 2’ with 1b, the yield of 1c
could be remarkably improved to 82% (Scheme 2E). These results could give some clues that 1a
might coordinate to the Pd(II) first. Furthermore, we could conclude that the homocoupling of ketone
1a was the most preferred process, followed by the crossꢀcoupling and finally by the homocoupling
of benzamide 1b. In addition, we suspected that PTSA might serve as a suitable ligand to stabilize
the Pd(II) and Pd(IV) intermediates, which helped to promote the reaction process. Furthermore,
when 1d was used as the substrate, trace amounts of C–O bond formation product 1e were observed
(Scheme 2F), which implied that HFIP may serve as an effective ligand.
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O
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H
H
N
N
O
N
O
Ada
H
O
O
O
Ada
O
Ada
O
N
Ada
1b
H
8
9
1a
1aa
1bb
5%
0.0075 mmol
1c
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A 1a, 0.10 mmol; 1b, 0.30 mmol
recovered 1b 70%
4%
72%
0.072 mmol
0.0020 mmol
(0.21 mmol)
B 1a, 0.10 mmol; 1b, 0.10 mmol
recovered 1b 50%
65%
0.033 mmol
trace
6%
0.0060 mmol
Not detected
(0.050 mmol)
C 1a, 0.30 mmol; 1b, 0.10 mmol
recovered 1a 12%
(0.036 mmol)
76%
0.114 mmol
Not detected
recovered 1b 90%
(0.090 mmol)
2
D
H
N
O
O
PdII OTf
O
Oxidants, TfOH
N
H
Ada
Ada
O
O
HFIP, 60 oC
Ada
2
1b
1c 8%
2
E
F
H
N
O
O
PdII
OTs
O
Oxidants, PTSA
N
H
HFIP, 60 oC
Ada
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2'
1b
1c 82%
CF3
O
H
O
F3C
H
N
Pd(II), Oxidants, PTSA
N
Ada
HFIP, 60 oC
O
O
1d
1e 4%
Scheme 2. Mechanism Investigation.
On the basis of these results, a possible mechanism for this reaction was suggested and is
illustrated in Scheme 3. In the pathway A, step (i) involves the chelation of palladium to carbonyl
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oxygen atom from the ketone and the formation of adimeric Pd complex. In the second step (ii),
Pd(II) can be oxidized into a possible Pd(IV) intermediate,12 followed by the ligand exchange with
the benzamide during the third step (iii). The final step (iv) involves C–C bond forming reductive
elimination to afford the desirable product and turn Pd(IV) back into Pd(II). In another potential
pathway B, the Pd(II) dimer may first go through a Pd(III) intermediate13, which is then further
oxidized to Pd(IV). After reductive elimination, the desired 2,2'ꢀdifunctional biaryl product may be
obtained.
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2
2
O
PdII
OTs
O
PdII
OTs
O
R
R
R
O
O
(ii)
R
(i)
path B
path A
L'
Ada
Ada
L
O
PdIV
L
O
O
Pd(II), PTSA, HFIP
PdIII
O
PdIII
CF3
L
F
F
L
=
O
H
O
S
O
O
S
F
(iii)
(iv)
O
O
Tol
loT
OH
OH
L
L
O
O
H
O
PdIV
O
PdIV
O
N
N
N
N
O
N
L'
L'
H
H
Ada
Ada
O
Ada
Scheme 3. The Proposed Mechanism.
With the optimal conditions in hand, we started to examine the reaction scope. As illustrated in
Table 2, a broad range of highly diverse and complex 2,2’ꢀdifunctional biaryls (2a-2k) were
effectively constructed in good yields. We first tested the unsubstituted benzophenone as a starting
material, from which the desired product 2a could be obtained in satisfactory yields. For other
benzophenones, electronꢀrich (2b) and electronꢀdeficient (2c-2d) functional groups were well
tolerated. We could also get the desired compound in 51% yield using the sterically hindered
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orthoꢀsubstituted benzophenone (2e). Besides aromatic groups, alkyl groups includingl the
adamantyl and tertꢀbutyl groups (2f-2g) were also compatible with the reaction conditions. Notably,
ketones containing easily oxidizable αꢀproton could also be effectively transformed into the desired
product (2h) with excellent chemoselectivity. When benzamides bearing electronꢀdeficient groups,
such as Cl, were tested, the crossꢀcoupling products could be obtained in 65%ꢀ70% yields (2i-2j).
Benzamides containing electronꢀrich groups, such as methoxyl group, were crossꢀcoupled equally
efficiently (2k). Even the orthoꢀfluoro substituted benzamide performed well in this reaction, which
gave the desired product in 72% yield (2l). To our delight, the new reaction demonstrated
compatibility with all these functional groups by generating the desired products in good yields.
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Table 2. Testing the Scope of the Reaction: Oxidative Coupling of Ketones with Benzamides.[a]
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O
O
R1
O
R3
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7
R4
Pd(OAc)2, Oxidants
R3
N
R4
R1
O
R2
H
PTSA, HFIP, 60 O
C
N
R2
H
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H
H
H
N
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N
N
O
O
O
O
O
O
Cl
Cl
2c 82%, 0.082 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2a 80%, 0.080 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2b 60%, 0.060 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5%
(0.0075 mmol)
Selectivity ratio > 32:3:1
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 32.8:3:1
Selectivity ratio > 24:3:1
H
N
H
H
N
N
F
O
O
O
O
O
O
Ada
F
2d 71%, 0.071 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2e 51%, 0.051 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2f 60%, 0.060 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5%
(0.0075 mmol)
Selectivity ratio > 28.4:3:1
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 24:3:1
Selectivity ratio > 20.4:3:1
Cl
O
H
H
H
N
N
N
O
O
nBu
O
O
O
2g 69%, 0.069 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2h 50%, 0.050 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2i 65%, 0.065 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5%
(0.0075 mmol)
Selectivity ratio > 27.6:3:1
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 26:3:1
Selectivity ratio > 20:3:1
O
Cl
O
F
H
N
H
N
H
N
nBu
O
nBu
O
nBu
O
O
O
Cl
Cl
2j 70%, 0.070 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2k 62%, 0.062 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
2l 72%, 0.072 mmol
Homo-coupling of ketone < 5%
(0.0025 mmol)
Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5% Homo-coupling of benzamide < 5%
(0.0075 mmol)
Selectivity ratio > 28:3:1
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 28.8:3:1
Selectivity ratio > 24.8:3:1
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[a] Isolated yields are shown. Ketone 0.1 mmol, Benzamide 3.0 equiv, Pd(OAc)2 0.10 equiv, NaIO4
1.6 equiv, K2S2O8 3.5 equiv, PTSA 4.0ꢀ6.0 equiv, HFIP 1.5 mL. Selectivity ratio = (cross-coupling
product) : (homocoupling of benzamide) : (homocoupling of ketone)
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We then tried to apply the developed conditions to further combinations merging Oꢀ and
Nꢀcontaining DGs. As illustrated in Table 3, in addition to benzamides, benzophenone also reacted
with phenylacetamide (3a) as well as difluoroꢀbenzoyl protected anilide (3b) to furnish the desired
crossꢀcoupling products. Carbamates also showed good compatibility with benzamide, anilide as
well as phenylacetamideꢀderivatized coupling partners (3c-3h) in moderate to good yields.
Furthermore, it was observed that this reaction system could also combine esterꢀcontaining aryls with
anilide to afford, for example, compound 3i in 60% yield (3i). In addition, another type of directing
group, succinimide, also showed good compatibility with dichloroꢀsubstituted anilide to give 3j in 61%
yield. These 2,2’ꢀdifunctional biaryls can further serve as useful building blocks for constructing a
variety of heterocycle scaffolds and related bioactive molecules.
Table 3. Oxidative Coupling Controlled by Two Different Directing Groups.[a]
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R1
FG2
FG1
FG2
FG1
R2
Pd(OAc)2, Oxidants
R1
R2
PTSA, HFIP, 40-60 O
C
Substrate 1
Substrate 2
R
O
O
F
F
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O
nBu
O
N
O
N
F
H
H
N
O
H
N
O
F
3a 66%, 0.066 mmol
Homo-coupling of substrate 1 < 5% Homo-coupling of substrate 1 < 5%
(0.0025 mmol) (0.0025 mmol)
Homo-coupling of substrate 2 < 5% Homo-coupling of substrate 2 < 5%
3b 70%, 0.070 mmol
3c, R= Me, 73%, 0.073 mmol
3d, R= OMe, 60%, 0.060 mmol
Homo-coupling of substrate 1 < 5%
(0.0025 mmol)
Homo-coupling of substrate 2 < 5%
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 26.4:3:1
(0.0075 mmol)
Selectivity ratio > 28:3:1
3c, selectivity ratio > 28.4:3:1
3d, selectivity ratio > 28.4:3:1
N
O
O
O
O
N
O
O
N
O
O
nBu
N
H
N
H
H
N
O
nBu
O
3e 65%, 0.065 mmol
Homo-coupling of substrate 1 < 5% Homo-coupling of substrate 1 < 5%
(0.0025 mmol) (0.0025 mmol)
Homo-coupling of substrate 2 < 5% Homo-coupling of substrate 2 < 5%
3f 72%, 0.072 mmol
3g 43%, 0.043 mmol
Homo-coupling of substrate 1 < 5%
(0.0025 mmol)
Homo-coupling of substrate 2 < 5%
(0.0075 mmol)
(0.0075 mmol)
Selectivity ratio > 26:3:1
(0.0075 mmol)
Selectivity ratio > 28.8:3:1
Selectivity ratio > 17.2:3:1
Cl
N
Cl
O
O
O
F
F
O
nBu
F
N
O
N
H
H
H
N
O
N
O
O
F
O
3h 63%, 0.063 mmol
3i 60%, 0.060 mmol
3j 61%, 0.061 mmol
Homo-coupling of substrate 1 < 5%
(0.0025 mmol)
Homo-coupling of substrate 2 < 5%
(0.0075 mmol)
Homo-coupling of substrate 1 < 5% Homo-coupling of substrate 1 < 5%
(0.0025 mmol) (0.0025 mmol)
Homo-coupling of substrate 2 < 5% Homo-coupling of substrate 2 < 5%
(0.0075 mmol)
Selectivity ratio > 25.2:3:1
(0.0075 mmol)
Selectivity ratio > 24:3:1
Selectivity ratio > 24.4:3:1
[a] Isolated yields are shown. Substrate 1 0.1 mmol, Substrate 2 3.0 equiv, Pd(OAc)2 0.10 equiv,
NaIO4 1.6 equiv, K2S2O8 3.5 equiv, PTSA 4.0 equiv, HFIP 1.5 mL. Selectivity ratio =
(cross-coupling product) : (homocoupling of substrate 2) : (homocoupling of substrate 1)
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In conclusion, we have developed a new strategy which can combine Oꢀ and Nꢀcontaining DGs
to provide diverse biaryl compounds., This transformation might proceed through a mechanism
involving two different CꢀH activation steps involving distinct Pd(II) and Pd(IV) complexes. PTSA
and HFIP facilitate the reaction and may serve as ligands in the mechanism. The developed method
features broad functional group tolerance, excellent reactivity and high product yields. Further
synthetic applications of this reaction are in progress in our laboratory.
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Experimental section
I. Materials and Methods
All commercial materials (Alfa Aesar, Aladdin, J&K Chemical LTD.) were used without further
purification. All solvents were analytical grade. The potassium persulfate were ground to powder.
Ⅲ
The 1H NMR and 13C NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer in
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CDCl3 using TMS or solvent peak as a standard. All C NMR spectra were recorded with complete
proton decoupling. Lowꢀresolution mass spectral analyses were performed with a Waters AQUITY
UPLCTM/MS. All reactions were carried out in sealed tube with Teflon cap. Analytical TLC was
performed on Yantai Chemical Industry Research Institute silica gel 60 F254 plates and flash column
chromatography was performed on Qingdao Haiyang Chemical Co. Ltd silica gel 60 (200ꢀ300mesh).
The rotavapor was BUCHI’s Rotavapor Rꢀ3.
II. General Procedure for the 2,2’-Biaryls Synthesis: Pd(OAc)2 10% mmol, NaIO4 1.2ꢀ1.6 equiv,
K2S2O8 3.0ꢀ4.0 equiv and the starting material (substrate 1 0.1mmol, substrate 2 3.0 equiv) were
dissolved in commercial hexafluoroisopropanol (HFIP) 1.5 ml in a sealed tube. Following that,
TfOH or TsOH.H2O (3.6ꢀ4.4 equiv) was added into the reaction solution. The mixture was heated for
5ꢀ8 hours at 35ꢀ60 oC. After completion of the reaction, the mixture was cooled to room temperature
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and then saturated NaHCO3 was added to quench the reaction. The reaction mixture was diluted with
DCM and washed once with saturated aqueous NaHCO3. The resulting mixture was concentrated in
vacuum and then purified by column chromatography on 200−300 mesh silica gel to afford the
desired products.
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III. Data of products
2'-((3r,5r,7r)-adamantane-1-carbonyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (1c)
Following the general procedure, (3r,5r,7r)ꢀadamantanꢀ1ꢀyl(pꢀtolyl)methanone (26 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16
mmol), K2S2O8 (81 mg, 0.30 mmol), HFIP 1.5 ml and TsOH.H2O (3.1 equiv, 60 mg) were used. The
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reaction mixture was stirred at 70 C for 6 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.3). Finally, compound 1c (27.9 mg, white solid) was isolated in 72% yield. Mp
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134.6−135.8 °C. HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.64 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H),
7.54ꢀ7.50 (m, 1H), 7.38ꢀ7.29 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 6.99 (dd, J = 7.2 Hz, J =
0.4 Hz, 1H), 2.54 (d, J = 5.2 Hz, 1H), 2.33 (s, 3H), 2.05 (s, 3H), 2.94ꢀ1.88 (m, 6H), 1.77ꢀ1.68 (m,
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6H); CꢀNMR (100 MHz, CDCl3) δ (ppm) 215.2, 170.1, 139.6, 139.5, 138.3, 137.7, 136.7, 131.4,
128.8, 128.7, 128.5, 128.0, 127.3, 125.2, 46.7, 39.5, 36.5, 28.2, 26.3, 21.4; IR (neat) vmax 3314, 2904,
2851, 1656 cmꢀ1; HRMS (ESIꢀTOF) calcd for C26H30NO2 [M+H]+: 388.2277, found 388.2278.
N-(2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)phenyl)pivalamide (1e)
Following the general procedure, (3r,5r,7r)ꢀadamantanꢀ1ꢀyl(pꢀtolyl)methanone (26 mg, 0.10 mmol),
Nꢀmethylbenzamide (54 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16
mmol), K2S2O8 (81 mg, 0.30 mmol), HFIP 1.5 ml and TsOH.H2O (5.2 equiv, 100 mg) were used. The
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reaction mixture was stirred at 60 C for 8 h. After completion of the reaction, the residue was
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purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
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4:1, Rf = 0.4). Finally, compound 1e (4.2 mg, colorless syrup) was isolated in 4% yield. HꢀNMR
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(400 MHz, CDCl3) δ (ppm) 8.47 (d, J = 8.0 Hz, 1H), 8.01 (br, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.08 (t, J
= 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.93ꢀ4.88 (m, 1H), 1.32 (s, 9H); 13CꢀNMR (100 MHz,
CDCl3) δ (ppm) 176.9, 146.2, 129.6, 125.4, 124.0, 121.4, 114.0, 40.2, 27.5; 19FꢀNMR (400 MHz,
CDCl3) δ (ppm) ꢀ73.63; IR (neat) vmax 3458, 2964, 1680, 1524 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C14H16NO2F6 [M+H]+: 344.1085, found 344.1087.
Preparation of dimeric Pd complex (2)
To a 15ml sealedꢀtube were added adamantanꢀ1ꢀylꢀ(4ꢀmethylꢀphenyl)ꢀmethanone 1a (102 mg, 0.40
mmol), Pd(OAc)2 (102 mg, 0.45 mmol) and 1ml DCE. The tube was sealed and stirred at 40 oC for 5
minutes. Then TfOH (45 mg, 0.3 mmol) was added. The vial was stirred at the 40 oC for 2.5 min and
then cooled to room temperature. The reaction mixture was filtered and washed with 2 mL mixture
of petroleum ether/DCE (1:1) to give the desired OTf’s bridged palladacycle product 2 as yellow
needles (189 mg, 93%) that can be characterized by NMR. This palladacycle compound was stable at
1
room temperature in the dry solid state for about one week but sensitive to moisture. HꢀNMR (400
MHz, DMSOꢀd6) δ (ppm) 8.14 (d, J = 8.4 Hz, 2H), 7.50 (s, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.34 (s,
6H), 2.14 (s, 12H), 2.09 (s, 6H), 1.84ꢀ1.74 (m, 12H); 13CꢀNMR (100 MHz, DMSOꢀd6) δ (ppm)
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155.3, 146.7, 141.6, 133.10, 126.8, 120.7 (q, JCꢀF = 320 Hz), 46.9, 35.6, 27.5, 22.2; FꢀNMR (400
MHz, DMSOꢀd6) δ (ppm) ꢀ77.74. Spectral data are in agreement with literature values.4d
Preparation of dimeric Pd complex (2’)
To a 15ml sealedꢀtube were added adamantanꢀ1ꢀylꢀ(4ꢀmethylꢀphenyl)ꢀmethanone 1a (102 mg, 0.40
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mmol), Pd(OAc)2 (102 mg, 0.45 mmol) and 1ml HFIP. The tube was sealed and stirred at 50 C for
2.5 minutes. Then PTSA (90 mg, 0.46 mmol) was added. The vial was stirred at the 50 oC for 15 min
and then cooled to room temperature. The reaction mixture was filtered and washed with 2 mL
mixture of petroleum ether/DCE (1:1) to give the desired OTs’s bridged palladacycle product 2’ as
yellow needles (73 mg, 86%) that can be characterized by NMR. This palladacycle compound was
stable at room temperature in the dry solid state for about one week but sensitive to moisture.
1HꢀNMR (400 MHz, DMSOꢀd6) δ (ppm) 8.14 (d, J = 8.4 Hz, 2H), 7.50 (s, 2H), 7.47 (d, J = 8.0 Hz,
4H), 7.13ꢀ7.10 (m, 6H), 2.34 (s, 6H), 2.28 (s, 6H), 2.14 (s, 12H), 2.09 (s, 6H), 1.84ꢀ1.74 (m, 12H);
13CꢀNMR (100 MHz, DMSOꢀd6) δ (ppm) 155.3, 146.7, 145.8, 141.6, 137.6, 133.1, 128.0, 126.8,
125.5, 46.9, 35.6, 27.5, 22.2, 20.8.
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2'-benzoyl-N-methyl-[1,1'-biphenyl]-2-carboxamide (2a)
Following the general procedure, benzophenone (19 mg, 0.10 mmol), Nꢀmethylbenzamide (42 mg,
0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg, 0.14 mmol), K2S2O8 (100 mg, 0.37
mmol), HFIP 1.5 ml and TsOH.H2O (5.5 equiv, 100 mg) were used. The reaction mixture was stirred
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at 60 C for 8 h. After completion of the reaction, the residue was purified by column
chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally,
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compound 2a (25.4 mg, white solid) was isolated in 80% yield. Mp 111.4−112.6 °C. HꢀNMR (400
MHz, CDCl3) δ (ppm) 7.91 (d, J = 7.6 Hz, 2H), 7.66ꢀ7.62 (m, 2H), 7.50 (d, J = 7.2 Hz, 3H),
7.45ꢀ7.41 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.14 (br, 1H), 6.94 (d, J = 7.6 Hz, 1H), 2.58 (d, J = 4.8
Hz, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 199.2, 170.3, 141.4, 138.1, 137.9, 137.4, 136.8,
134.1, 131.0, 130.8, 130.7, 129.4, 128.8, 128.7, 128.5, 128.3, 128.0, 126.9, 26.4; IR (neat) vmax 3342,
3059, 2918, 1662 cmꢀ1; HRMS (ESIꢀTOF) calcd for C21H18NO2 [M+H]+: 316.1338, found 316.1332.
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N,5'-dimethyl-2'-(4-methylbenzoyl)-[1,1'-biphenyl]-2-carboxamide (2b)
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Following the general procedure, diꢀpꢀtolylmethanone (21 mg, 0.10 mmol), Nꢀmethylbenzamide (42
mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (44 mg, 0.20 mmol), K2S2O8 (81 mg, 0.30
mmol), HFIP 1.5 ml and TsOH.H2O (5.0 equiv, 95 mg) were used. The reaction mixture was stirred
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at 60 C for 6 h. After completion of the reaction, the residue was purified by column
chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally,
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compound 2b (20.6 mg, colorless syrup) was isolated in 60% yield. HꢀNMR (400 MHz, CDCl3) δ
(ppm) 7.80 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.38ꢀ7.28 (m, 5H), 7.21ꢀ7.17 (m, 2H), 7.14
(s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 2.59 (d, J = 4.7 Hz, 3H), 2.45 (s, 3H), 2.40 (s, 3H); 13CꢀNMR (100
MHz, CDCl3) δ (ppm) 198.9, 170.4, 145.0, 141.6, 141.1, 138.4, 137.3, 135.3, 134.6, 131.6, 131.0,
129.5, 129.3, 128.8, 128.3, 127.9, 127.5, 126.9, 26.4, 21.9, 21.6; IR (neat) vmax 3312, 2923, 1737,
1642, 1604 cmꢀ1; HRMS (ESIꢀTOF) calcd for C23H22NO2 [M+H]+: 344.1651, found 344.1649.
5'-chloro-2'-(4-chlorobenzoyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (2c)
Following the general procedure, bis(4ꢀchlorophenyl)methanone (26 mg, 0.10 mmol),
Nꢀbutylꢀ4ꢀchlorobenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (27 mg,
0.12 mmol), K2S2O8 (86 mg, 0.30 mmol), HFIP 1.2 ml and TfOH (3.5 equiv, 33 uL, in this case,
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PTSA was replaced by TfOH) were used. The reaction mixture was stirred at 65 C for 8 h. After
completion of the reaction, the residue was purified by column chromatography on 200−300 mesh
silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally, compound 2c (34 mg, yellow
solid) was isolated in 82% yield. Mp 128.6−129.5 °C. 1HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.81 (d,
J = 8.4 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.44 (m, 3H), 7.47ꢀ7.44 (m, 3H), 7.37ꢀ7.33 (d, J = 7.6 Hz,
1H), 6.93 (d, J = 7.2 Hz, 2H), 2.64 (d, J = 4.8 Hz 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 169.7,
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143.2, 140.9, 137.0, 136.9, 136.8, 135.9, 135.0, 132.0, 131.1, 129.7, 129.2, 129.0, 128.5, 128.3,
127.3, 77.5, 77.2, 76.8, 26.5; IR (neat) vmax 3417, 2921, 1655, 1646 cmꢀ1; HRMS (ESIꢀTOF) calcd
for C21H16Cl2NO2 [M+H]+: 384.0558, found 384.0556.
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2'-(2,4-difluorobenzoyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (2d)
Following the general procedure, (2,4ꢀdifluorophenyl)(phenyl)methanone (22 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16
mmol), K2S2O8 (100 mg, 0.35 mmol), HFIP 1.5 ml and TfOH (4.0 equiv, 37 uL) were used. The
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reaction mixture was stirred at 60 C for 6 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.25). Finally, compound 2d (24.7 mg, colorless syrup) was isolated in 71% yield. 1HꢀNMR
(400 MHz, CDCl3) δ (ppm) 7.79ꢀ7.74 (m, 1H), 7.64 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.53ꢀ7.49 (m,
1H), 7.44ꢀ7.39 (m, 2H), 7.37ꢀ7.33 (m, 2H), 7.29ꢀ7.25 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.01ꢀ6.96 (m,
1H), 6.91ꢀ6.85 (m, 1H), 6.81ꢀ6.81 (m, 1H), 2.60 (d, J = 4.8 Hz, 3H); 13CꢀNMR (100 MHz, CDCl3) δ
(ppm) 194.9, 170.2, 166.3 (dd, JCꢀF = 256 Hz, JCꢀF = 11.8 Hz), 162.7 (dd, JCꢀF = 258 Hz, JCꢀF = 12.7
Hz), 140.7, 139.1, 138.1, 137.2, 134.1 (dd, JCꢀF = 10.5 Hz, JCꢀF = 7.8 Hz), 131.4, 131.1, 129.6, 129.2,
128.3, 128.03, 128.00 (d, JCꢀF = 2.2 Hz), 127.4, 122.6 (dd, JCꢀF = 10.6 Hz, JCꢀF = 3.5 Hz), 112.3 (dd,
JCꢀF = 21.5 Hz, JCꢀF = 3.5 Hz), 105.3 (t, JCꢀF = 25.5 Hz); IR (neat) vmax 3327, 2920, 1649, 1607 cmꢀ1;
HRMS (ESIꢀTOF) calcd for C21H16F2NO2 [M+H]+: 352.1149, found 352.1140.
N-methyl-2'-(2-methylbenzoyl)-[1,1'-biphenyl]-2-carboxamide (2e)
Following the general procedure, phenyl(oꢀtolyl)methanone (20 mg, 0.10 mmol),
Nꢀbutylꢀ4ꢀchlorobenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg,
0.16 mmol), K2S2O8 (108 mg, 0.36 mmol), HFIP 1.2 ml and TsOH.H2O (6.4 equiv, 125 mg) were
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used. The reaction mixture was stirred at 60 oC for 8 h. After completion of the reaction, the residue
was purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate
= 2:1, Rf = 0.25). Finally, compound 2e (16.8 mg, colorless syrup) was isolated in 51% yield.
1HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.65 (dd, J = 0.4 Hz, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.50 (dd, J = 1.6Hz, J = 7.2 Hz, 1H), 7.47ꢀ7.43 (m, 1H), 7.39ꢀ7.32 (m, 4H), 7.30ꢀ7.24 (m, 3H), 7.05
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(d, J = 6.8 Hz, 2H), 2.60 (d, J = 4.9 Hz, 3H), 2.48 (s, 3H); CꢀNMR (100 MHz, CDCl3) δ (ppm)
201.1, 170.3, 141.3, 140.4, 139.5, 138.5, 137.2, 136.7, 132.6, 132.5, 132.1, 131.1, 130.9, 129.4,
129.1, 128.8, 128.3, 128.0, 127.1, 125.6, 77.5, 77.2, 76.8, 26.4, 21.3; IR (neat) vmax 3317, 2924, 1646
cmꢀ1; HRMS (ESIꢀTOF) calcd for C22H20NO2 [M+H]+: 330.1494, found 330.1504.
2'-(adamantane-1-carbonyl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (2f)
Following the general procedure, ((3r,5r,7r)ꢀadamantanꢀ1ꢀyl)(phenyl)methanone (24 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg, 0.14
mmol), K2S2O8 (86 mg, 0.32 mmol), HFIP 1.3 ml and TsOH.H2O (4.2 equiv, 80 mg) were used. The
o
reaction mixture was stirred at 60 C for 8 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.30). Finally, compound 2f (23 mg, white solid) was isolated in 60% yield. Mp
1
174.5−175.9 °C. HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.64 (d, J = 7.2 Hz, 1H), 7.48ꢀ7.45 (m, 1H),
7.40ꢀ7.31 (m, 5H), 7.23ꢀ7.21 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 2.53 (d, J = 4.8 Hz, 3H), 2.06 (s, 3H),
1.92 (d, J = 18.0 Hz, 6H), 1.77ꢀ1.68 (m, 6H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 215.3, 170.1,
139.5, 139.3, 138.1, 137.8, 130.1, 129.4, 128.9, 128.8, 128.5, 128.2, 126.7, 125.0, 77.5, 77.2, 76.8,
46.7, 39.5, 36.5, 28.1, 26.2; IR (neat) vmax 3295, 2900, 2850, 1679, 1637 cmꢀ1; HRMS (ESIꢀTOF)
calcd for C25H28NO2 [M+H]+: 374.2120, found 374.2129.
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N-methyl-2'-pivaloyl-[1,1'-biphenyl]-2-carboxamide (2g)
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Following the general procedure, 2,2ꢀdimethylꢀ1ꢀphenylpropanꢀ1ꢀone (17 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg, 0.14
mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.3 ml and TsOH.H2O (4.2 equiv, 80 mg) were used. The
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reaction mixture was stirred at 60 C for 8 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.30). Finally, compound 2g (20 mg, white solid) was isolated in 69% yield. Mp
1
103.4−104.7 °C. HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.64 (d, J = 7.2 Hz, 1H), 7.48ꢀ7.46 (m, 1H),
7.37ꢀ7.30 (m, 5H), 7.24ꢀ7.22 (m, 1H), 7.00 (d, J = 7.6Hz, 1H), 2.54 (d, J = 4.8 Hz, 3H),1.27 (s, 9H);
13CꢀNMR (100 MHz, CDCl3) δ (ppm) 216.2, 170.1, 139.8, 139.3, 138.2, 137.7, 130.9, 129.6, 129.0,
128.5, 128.2, 126.8, 124.8, 77.5, 77.2, 76.8, 44.4, 28.3, 26.2; IR (neat) vmax 3322, 2960, 2927, 1658
cmꢀ1; HRMS (ESIꢀTOF) calcd for C19H22NO2 [M+H]+: 296.1651, found 296.1647.
2'-isobutyryl-N,5'-dimethyl-[1,1'-biphenyl]-2-carboxamide (2h)
Following the general procedure, 2ꢀmethylꢀ1ꢀ(pꢀtolyl)propanꢀ1ꢀone (17 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg, 0.14
mmol), K2S2O8 (81 mg, 0.30 mmol), HFIP 1.3 ml and TsOH.H2O (3.1 equiv, 60 mg) were used. The
o
reaction mixture was stirred at 60 C for 8 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
1
2:1, Rf = 0.30). Finally, compound 2h (15 mg, colorless syrup) was isolated in 50% yield. HꢀNMR
(400 MHz, CDCl3) δ (ppm) 7.66 (d, J = 7.6Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H),
7.29 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H),
3.39ꢀ3.33 (m, 1H), 2.56 (d, J = 4.8 Hz, 3H), 2.36 (s, 3H), 1.16ꢀ1.11 (m, 6H); 13CꢀNMR (100 MHz,
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CDCl3) δ (ppm) 170.4, 141.6, 140.9, 139.0, 137.1, 135.8, 132.0, 128.5, 128.3, 127.8, 127.1, 77.5,
77.2, 76.8, 38.3, 29.8, 26.3, 21.5; IR (neat) vmax 3316, 2970, 2930, 1654 cmꢀ1; HRMS (ESIꢀTOF)
calcd for C19H22NO2 [M+H]+: 296.1651, found 296.1652.
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2'-benzoyl-N-butyl-5-chloro-[1,1'-biphenyl]-2-carboxamide (2i)
Following the general procedure, benzophenone (19 mg, 0.10 mmol), Nꢀbutylꢀ4ꢀchlorobenzamide
(70 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16 mmol), K2S2O8 (100 mg,
0.40 mmol), HFIP 1.5 ml and TsOH.H2O (6.5 equiv, 130 mg) were used. The reaction mixture was
o
stirred at 70 C for 10 h. After completion of the reaction, the residue was purified by column
chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally,
1
compound 2i (25 mg, colorless syrup) was isolated in 64% yield. HꢀNMR (400 MHz, CDCl3) δ
(ppm) 7.93ꢀ7.91 (m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.55ꢀ7.50 (m, 3H),
7.47ꢀ7.45 (m, 2H), 7.34ꢀ7.30 (m, 3H), 6.92 (d, J = 2.0 Hz, 1H), 3.26ꢀ3.21 (m, 1H), 2.95ꢀ2.92 (m, 1H),
1.00ꢀ0.85 (m, 4H), 0.70ꢀ0.67 (m, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 198.9, 168.4, 140.3,
139.8, 137.7, 136.6, 136.1, 135.0, 134.3, 131.1, 130.9, 129.9, 128.9, 128.8, 128.6, 128.3, 127.4, 77.5,
77.2, 76.8, 39.4, 31.2, 19.9, 13.8; IR (neat) vmax 3313, 2918, 1647 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C24H23ClNO2 [M+H]+: 392.1417, found 392.1414.
N-butyl-5,5'-dichloro-2'-(4-chlorobenzoyl)-[1,1'-biphenyl]-2-carboxamide (2j)
Following the general procedure, bis(4ꢀchlorophenyl)methanone (25 mg, 0.10 mmol),
Nꢀbutylꢀ4ꢀchlorobenzamide (68 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg,
0.16 mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.5 ml and TfOH (4.2 equiv, 39 uL) were used. The
o
reaction mixture was stirred at 70 C for 10 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
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2:1, Rf = 0.25). Finally, compound 2j (32 mg, colorless syrup) was isolated in 70% yield. HꢀNMR
(400 MHz, CDCl3) δ (ppm) 7.83 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz,
2H), 7.45 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 7.40ꢀ7.32 (m, 3H), 7.11 (t, J = 4.8 Hz, 1H), 6.90 (d, J =
2.0 Hz, 1H), 3.27 (q, J = 6.4 Hz, 1H), 2.97 (t, J = 6.0 Hz, 1H), 1.05ꢀ1.00 (m, 4H), 0.75ꢀ7.71 (m, 3H);
13CꢀNMR (100 MHz, CDCl3) δ (ppm) 196.5, 167.9, 142.1, 141.2, 138.3, 137.5, 135.8, 135.7, 135.3,
134.7, 132.1, 131.2, 130.1, 129.9, 129.4, 128.8, 128.6, 127.7, 77.5, 77.2, 76.8, 39.4, 31.4, 20.0, 13.9;
IR (neat) vmax 3312, 2959, 2930, 1645 cmꢀ1; HRMS (ESIꢀTOF) calcd for C24H21Cl3NO2
[M+H]+:460.0638, found 460.0638.
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2'-benzoyl-N-butyl-4-methoxy-[1,1'-biphenyl]-2-carboxamide (2k)
Following the general procedure, benzophenone (19 mg, 0.10 mmol), Nꢀbutylꢀ3ꢀmethoxybenzamide
(63 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg, 0.13 mmol), K2S2O8 (96 mg,
0.35 mmol), HFIP 1.5 ml and TsOH.H2O (6.5 equiv, 130 mg) were used. The reaction mixture was
o
stirred at 60 C for 10 h. After completion of the reaction, the residue was purified by column
chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally,
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compound 2k (24 mg, colorless syrup) was isolated in 62% yield. HꢀNMR (400 MHz, CDCl3) δ
(ppm) 7.93 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.53ꢀ7.46 (m, 3H), 7.41 (d, J = 4.4Hz, 2H),
7.34 (d, J = 7.2 Hz, 1H), 7.30ꢀ7.28 (m, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.72
(dd, J = 2.8 Hz, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.24 (s, 1H), 2.95 (s, 1H), 0.99ꢀ0.89 (m, 4H), 0.69 (t, J
= 7.2 Hz, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 199.3, 169.3, 159.2, 141.2, 138.6, 138.3, 136.8,
134.1, 131.6, 130.8, 130.6, 130.3, 130.0, 128.8, 128.2, 126.7, 116.2, 112.5, 77.5, 77.2, 76.8, 55.5,
39.4, 31.2, 19.9, 13.9; IR (neat) vmax 3314, 2958, 2931, 1648 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C25H26NO3 [M+H]+:388.1913, found 388.1915.
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2'-benzoyl-N-butyl-3-fluoro-[1,1'-biphenyl]-2-carboxamide (2l)
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Following the general procedure, benzophenone (19 mg, 0.10 mmol), Nꢀbutylꢀ2ꢀfluorobenzamide
(60 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16 mmol), K2S2O8 (96 mg,
0.35 mmol), HFIP 1.5 ml and TsOH.H2O (6.5 equiv, 130 mg) were used. The reaction mixture was
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stirred at 65 C for 12 h. After completion of the reaction, the residue was purified by column
chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate = 2:1, Rf = 0.25). Finally,
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compound 2l (27 mg, white solid) was isolated in 72% yield. Mp 134.3−135.6 °C. HꢀNMR (400
MHz, CDCl3) δ (ppm) 7.90ꢀ7.88 (m, 2H), 7.67ꢀ7.63 (m, 1H), 7.54ꢀ7.48 (m, 3H), 7.46ꢀ7.40 (m, 3H),
7.29ꢀ7.27 (m, 1H), 7.16ꢀ7.10 (m, 1H), 7.06ꢀ7.01 (m, 1H), 6.72 (d, J = 7.2 Hz, 1H), 3.23 (s, 1H), 2.96
(s, 1H), 0.95 (s,4H), 0.71ꢀ0.67 (m, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 198.8, 164.7, 159.6 (d,
J
CꢀF = 250 Hz), 140.2 (d, JCꢀF = 3.7 Hz), 139.7 (d, JCꢀF = 2.2 Hz), 138.1, 136.8, 134.1, 131.0, 130.8,
130.0 (d, JCꢀF = 9.9 Hz), 128.8, 128.5, 127.2, 126.2 (d, JCꢀF = 17.2 Hz), 124.2 (d, JCꢀF = 3.1 Hz), 115.6,
115.4, 39.2, 31.2, 19.9, 13.8; IR (neat) vmax 3256, 2957, 2930, 1667, 1647 cmꢀ1; HRMS (ESIꢀTOF)
calcd for C24H23FNO2 [M+H]+: 376.1713, found 376.1708.
(E)-N-butyl-2-(2'-((hydroxyimino)(p-tolyl)methyl)-5'-methyl-[1,1'-biphenyl]-2-yl)acetamide
(3a’)
Following
the
general
procedure,
diꢀpꢀtolylmethanone
(21
mg,
0.10
mmol),
Nꢀbutylꢀ2ꢀphenylacetamide (60 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg,
0.16 mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.5ml and TsOH.H2O (4.2 equiv, 80 mg) were used.
The reaction mixture was stirred at 60 oC for 16 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.25). Finally, compound 3a was calculated in 66% yield (calculated based on the NMR
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with pꢀnitrobenzaldehyde as a standard). Then to a solution of 3a in pyridine 1.5 mL, NH2OH.HCl
10.0 eq was added and refluxed for 8 h, after purification, we finally got 3a’, the structure of 3a’
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could confirm the structure of 3a (white solid). Mp 132.1−133.2 °C. HꢀNMR (400 MHz, CDCl3) δ
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(ppm) 7.36 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.14 (q, J = 7.2 Hz, 2H), 7.06ꢀ7.01 (m, 1H),
6.96 (d, J = 8.8 Hz, 5H), 6.99 (d, J = 7.2 Hz, 1H), 5.56 (t, J = 5.6Hz, 1H), 3.26ꢀ3.17 (m, 2H),
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3.14ꢀ2.97 (m, 2H), 2.37 (s, 3H), 2.27 (s, 3H), 1.34ꢀ1.14 (m,4H), 0.85 (t, J = 7.2 Hz, 3H); CꢀNMR
(100 MHz, CDCl3) δ (ppm) 171.4, 158.0, 141.0, 140.5, 139.0, 138.8, 134.0, 133.2, 131.3, 130.5,
130.4, 129.9, 129.0, 128.4, 128.3, 127.7, 126.6, 77.5, 77.2, 76.8, 41.5, 39.5, 31.7, 21.5, 21.4, 20.1,
13.9; IR (neat) vmax 3270, 2954, 2923, 1647, 1615 cmꢀ1; HRMS (ESIꢀTOF) calcd for C27H30N2O2
[M+H]+: 415.2386, found 415.2386.
2,6-difluoro-N-(5'-methyl-2'-(4-methylbenzoyl)-[1,1'-biphenyl]-2-yl)benzamide (3b)
Following the general procedure, 2,6ꢀdifluoroꢀNꢀphenylbenzamide (24 mg, 0.10 mmol),
diꢀpꢀtolylmethanone (60 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16
mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.5ml and TfOH (3.2 equiv, 30 uL) were used. The
o
reaction mixture was stirred at 60 C for 5 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
1
2:1, Rf = 0.30). Finally, compound 3b (32 mg, colorless syrup) was isolated in 70% yield. HꢀNMR
(400 MHz, CDCl3) δ (ppm) 8.14 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.36ꢀ7.25
(m, 6H), 7.14 (d, J = 8.0 Hz, 1H), 7.05ꢀ7.03 (m, 2H), 6.89 (t, J = 8.0 Hz, 2H), 2.45 (s, 3H), 2.36 (s,
3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 198.0, 170.1, 160.2 (dd, JCꢀF = 251 Hz, JCꢀF = 6 Hz),
158.7, 144.4, 140.9, 137.4, 136.7, 135.0, 134.8, 133.4, 131.8 (t, JCꢀF = 10 Hz), 130.4, 130.0, 129.1,
128.7, 128.6, 128.2, 125.2, 124.0, 114.7 (t, JCꢀF = 22 Hz), 112.2 (dd, JCꢀF = 5.6 Hz, JCꢀF = 1.9 Hz),
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21.8, 21.5; IR (neat) vmax 3310, 2922, 2852, 1655 cmꢀ1; HRMS (ESIꢀTOF) calcd for C28H22F2NO2
[M+H]+: 442.1619, found 442.1618.
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2'-(2,6-difluorobenzamido)-4-methyl-[1,1'-biphenyl]-2-yl dimethylcarbamate (3c)
Following the general procedure, mꢀtolyl dimethylcarbamate (18 mg, 0.10 mmol),
2,6ꢀdifluoroꢀNꢀphenylbenzamide (70 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35
mg, 0.16 mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.5 ml and TfOH (3.2 equiv, 30 uL) were used.
The reaction mixture was stirred at 45 oC for 10 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.40). Finally, compound 3c (30 mg, colorless oil) was isolated in 73% yield. 1HꢀNMR (400
MHz, CDCl3) δ (ppm) 8.28 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.46ꢀ7.38 (m, 1H), 7.34ꢀ7.28 (m, 1H),
7.22ꢀ7.20 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.89ꢀ6.86 (m, 2H), 2.75 (s, 5H), 2.73 (s,
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3H), 2.39 (s, 3H); CꢀNMR (100 MHz, CDCl3) δ (ppm) 160.1 (dd, JCꢀF = 249 Hz, JCꢀF = 6.0 Hz),
158.8, 155.1, 149.2, 140.0, 135.5, 131.8 (t, JCꢀF = 10 Hz), 131.2, 130.8, 129.5, 128.6, 128.2, 126.9,
124.8, 123.6, 114.7 (t, JCꢀF = 26 Hz), 112.2ꢀ111.9 (m), 36.6, 36.2, 21.3; IR (neat) vmax 3396, 2918,
2850, 1705, 1691 cmꢀ1; HRMS (ESIꢀTOF) calcd for C23H21F2N2O3 [M+H]+: 411.1520, found
411.1521.
2'-(2,6-difluorobenzamido)-4-methoxy-[1,1'-biphenyl]-2-yldimethylcarbamate (3d)
ollowing the general procedure, 3ꢀmethoxyphenyl dimethylcarbamate (20 mg, 0.10 mmol),
2,6ꢀdifluoroꢀNꢀphenylbenzamide (75 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35
mg, 0.16 mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.5 ml and TfOH (3.2 equiv, 30 uL) were used.
The reaction mixture was stirred at 40 oC for 15 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
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2:1, Rf = 0.40). Finally, compound 3d (26 mg, colorless oil) was isolated in 60% yield. 1HꢀNMR (400
MHz, CDCl3) δ (ppm) 8.28 (d, J = 8.4 Hz, 1H), 7.82 (br, 1H), 7.43ꢀ7.39 (m, 1H), 7.33ꢀ7.28 (m, 1H),
7.21ꢀ7.19 (m, 3H), 6.90ꢀ6.84 (m, 3H), 6.75 (s, 1H), 3.83 (s, 1H), 2.75 (s, 3H), 2.73 (s, 3H); 13CꢀNMR
(100 MHz, CDCl3) δ (ppm) 161.0 (d, JCꢀF = 255 Hz), 160.6, 154.8, 150.3, 135.7, 132.0, 131.8 (t, JCꢀF
= 10 Hz), 131.0, 129.3, 128.6, 124.8, 123.3, 122.9, 114.7 (t, JCꢀF = 18 Hz), 112.2, 112.1 (t, JCꢀF = 25
Hz), 55.7, 36.7, 36.3; IR (neat) vmax 3253, 2924, 1706, 1687 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C23H21F2N2O4 [M+H]+: 427.1469, found 427.1472.
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5-(tert-butyl)-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-yl dimethylcarbamate (3e)
Following the general procedure, 4ꢀ(tertꢀbutyl)phenyl dimethylcarbamate (23 mg, 0.10 mmol),
Nꢀmethylbenzamide (42 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (35 mg, 0.16
mmol), K2S2O8 (108 mg, 0.40 mmol), HFIP 1.3 ml and TsOH.H2O (6.5 equiv, 130 mg) were used.
The reaction mixture was stirred at 35 oC for 14 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.15). Finally, compound 3e (23 mg, white solid) was isolated in 65% yield. Mp
1
217.5−217.9 °C. HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.73 (t, J = 4.4 Hz, 1H), 7.39ꢀ7.34 (m, 3H),
7.31ꢀ7.27 (m, 2H), 7.14 (d, J = 3.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 2.98 (s, 3H), 2.69 (s, 3H), 2.53
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(d, J = 4.8 Hz, 3H), 1.30 (s, 9H); CꢀNMR (100 MHz, CDCl3) δ (ppm) 170.2, 155.3, 149.3, 146.1,
137.7, 135.0, 133.4, 129.7, 129.3, 128.7, 128.6, 127.9, 125.8, 122.1, 77.5, 77.2, 76.8, 36.7, 36.4, 34.7,
31.6, 26.4; IR (neat) vmax 3336, 2965, 2932, 1699, 1659 cmꢀ1; HRMS (ESIꢀTOF) calcd for
C21H27N2O3 [M+H]+: 355.2022, found 355.2021.
5-(tert-butyl)-2'-(butylcarbamoyl)-4'-methyl-[1,1'-biphenyl]-2-yl dimethylcarbamate (3f)
Following the general procedure, 4ꢀ(tertꢀbutyl)phenyl dimethylcarbamate (23 mg, 0.10 mmol),
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Nꢀbutylꢀ3ꢀmethylbenzamide (59 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg,
0.14 mmol), K2S2O8 (96 mg, 0.36 mmol), HFIP 1.5 ml and TsOH.H2O (5.2 equiv, 100 mg) were used.
The reaction mixture was stirred at 35 oC for 14 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.15). Finally, compound 3f (30 mg, white solid) was isolated in 72% yield. Mp
156.2−156.8 °C. 1HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.54 (s, 1H), 7.34 (dd, J = 2.0 Hz, J = 8.4 Hz,
1H), 7.27 (s, 1H), 7.16 (s, 3H), 7.05 (d, J = 8.4 Hz, 1H), 3.02ꢀ2.97 (m, 5H), 2.71 (s, 3H), 2.38 (s, 3H),
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1.29 (s, 9H), 1.04 (s, 4H), 0.74 (t, J = 6.8 Hz, 3H); CꢀNMR (100 MHz, CDCl3) δ (ppm) 169.5,
155.2, 149.1, 146.3, 137.7, 137.6, 133.5, 132.2, 130.0, 129.7, 129.4, 128.9, 125.6, 122.0, 77.5, 77.2,
76.8, 39.8, 36.7, 36.4, 34.7, 31.6, 30.8, 21.2, 20.1, 13.9; IR (neat) vmax 3301, 2958, 2870, 1707, 1652
cmꢀ1; HRMS (ESIꢀTOF) calcd for C25H35N2O3 [M+H]+: 411.2648, found 411.2651.
3-(2-(butylcarbamoyl)-4-methoxyphenyl)naphthalen-2-yl dimethylcarbamate (3g)
Following the general procedure, naphthalenꢀ2ꢀyl dimethylcarbamate (22 mg, 0.10 mmol),
Nꢀbutylꢀ3ꢀmethoxybenzamide (64 mg, 0.30 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), NaIO4 (30 mg,
0.14 mmol), K2S2O8 (90 mg, 0.32 mmol), HFIP 1.5 ml and TsOH.H2O (5.2 equiv, 100 mg) were used.
The reaction mixture was stirred at 35 oC for 14 h. After completion of the reaction, the residue was
purified by column chromatography on 200−300 mesh silica gel (Petroleum ether: Ethyl acetate =
2:1, Rf = 0.20). Finally, compound 3g (19 mg, white solid) was isolated in 65% yield. Mp
119.2−120.3 °C. 1HꢀNMR (400 MHz, CDCl3) δ (ppm) 7.80 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H), 7.62 (s,
1H), 7.50ꢀ7.44 (m, 2H), 7.29ꢀ7.25 (m, 3H), 6.96 (dd, J = 2.8 Hz, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.23
(q, J = 6.4 Hz, 1H), 3.04 (s, 3H), 2.74 (s, 4H), 0.90ꢀ0.66 (m, 4H), 0.27 (t, J = 6.8 Hz, 3H); 13CꢀNMR
(100 MHz, CDCl3) δ (ppm) 169.3, 159.2, 155.3, 147.1, 139.4, 133.3, 132.9, 131.8, 131.3, 130.9,
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