Palladium(II)-Catalyzed Oxidative Homo- and Cross-Coupling of Aryl

Subscriber access provided by Kent State University Libraries

Palladium(II)-Catalyzed Oxidative Homo- and Cross-Coupling of Aryl ortho-sp2C-H Bonds of Anilides at Room Temperature Chong Mei, and Wenjun Lu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00120 • Publication Date (Web): 03 Apr 2018 Downloaded from http://pubs.acs.org on April 3, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Palladium(II)-Catalyzed Oxidative Homo- and Cross-Coupling of Aryl ortho-sp2C-H Bonds of Anilides at Room Temperature Chong Mei and Wenjun Lu* Department of Chemistry, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China E-mail: [email protected]

R1

R2

O R2

H N H

R1 O

R4 +

H N H

R3 O

cat. Pd(OAc)2 K2S2O8 MsOH/CF3CO2H 25 oC, 2~48 h

NH R2 R4

NH 2 NH 2

HN

O R4 R3 R 1, R3 = tBu, iPr, nPr, Et, Me, Ph, etc. R 2, R4 = MeO, Me, Et, F, Cl, Br, I, CO 2Et, CF3, etc. Homo-coupling: 38 examples, isolated yield up to 93% Cross-coupling: 20 examples, isolated yield up to 73%, selectivity up to 98%

ABSTRACT: Preparation of secondary 2,2'-bisanilides has been successfully achieved through an oxidative coupling of aryl ortho-sp2C-H bonds of anilides in the presence of catalytic Pd(OAc)2 and K2S2O8 as an oxidant in MsOH/CF3CO2H (TFA) at room temperature (25 oC). The aromatic rings of anilides substituted by various electron-donating or electron-withdrawing groups are tolerant in these coupling reactions. 2,2'-Diaminobiaryls are very important structural units in functional molecules, such as organocatalysts1 and ligands2 for transition-metal catalysts. Among them, secondary 2,2'-bisanilides with their conformational isomers and stereodynamics are also greatly studied by medicinal and synthetic chemists.3 Nevertheless, a traditional synthesis of symmetric 2,2'-diaminobiaryls is from 2-iodonitrobenzene through the Ullmann reaction followed by a reduction of nitro groups.4 Unsymmetric 2,2'-diaminobiaryls can be prepared by the Suzuki−Miyaura reaction using two

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

different prefunctionalized arenes.5 Obviously, these are multiple-step processes accompanying with many wastes generated. Currently direct oxidative homocoupling of aryl sp2C-H bonds of aryl amines or anilides to afford 2,2'-diaminobiaryl products is limited to electron-rich substrates such as naphthylamine or dimethoxyanilide.6 On the other hand, the examples of oxidative cross-coupling are reported rarely, and the yields of dimerization products are poor.7 Most recently, Waladvogel and co-workers disclosed a direct anodic cross-coupling of anilides to give unsymmetric 2,2'-bisanilides in 40-74% yields at 50 oC.8 However, it is still necessary that anilide substrates are more electron-rich arenes. Herein, we present Pd(II)-catalyzed oxidative homo- and cross-couplings of various anilides with electron-donating groups (EDGs) or electron-withdrawing groups (EWGs) via dual aryl sp2C-H activation to afford symmetric and unsymmetric 2,2'-bisanilides respectively in moderate to excellent yields at room temperature (25 oC) (Scheme 1). In fact, to establish a selectively oxidative coupling of simple aryl sp2C-H bonds to form new aryl sp2C-sp2C bonds is always a challenge to researchers.9 In the past decade, some progress has been made in the preparation of 2,2'-biaryls via aryl ortho-sp2C-H bond activation in transition-metal (TM) catalysis. For example, Sanford and co-workers reported the first synthesis of symmetric 2,2'-biaryls through Pd(II)-catalyzed oxidative homo-coupling of 2-phenylpyridine derivatives using Oxone as an oxidant at 25 oC in 2006.10,11 Since then, other directing-group-containing arenes including phenylacetamides,12a aryloxazolines,12b benzoic acids,12c amioquinoline benzamides,12d benzophenones,12e etc. have been found to proceed transition-metal-catalyzed dimerization smoothly via aryl ortho-sp2C-H bond activation. In these oxidative coupling reactions, either


Page 2 of 51

Page 3 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


electron-rich or electron-deficient arenes can be employed as substrates generally. However, although amides are the more effective directing groups in many functionalizations of aryl sp2C-H bonds,13 oxidative coupling of anilides to prepare their 2,2'-biaryls has not been achieved in homogeneous palladium catalysis until now.14 Scheme 1. Oxidative Couplings of Anilides

Homo-Coupling Reaction It is found that Pd(OAc)2 (catalyst)/K2S2O8 (oxidant)/acid CF3CO2H (TFA) system is very effective to the oxidative coupings of various simple arenes15 and β-acyloxylation16 of primary sp3C-H bond directed by simple amide group. Based on these reports, the Pd(II) catalytic system was chosen initially in the oxidative homo-coupling of anilides. An anilide substituted by a weak electron-withdrawing group (EWG), N-(p-chlorophenyl)pivalamide 1a was employed as a test substrate, and the results are listed in Table 1.



In TFA at room temperature (25 oC), the target homo-coupling product, 2,2'-bisanilide 2aa was detected just in 37% yield with a 73% conversion of 1a. (Table 1, Entry 1) Many byproducts including phenol and 1,4-benzoquinone derivative were formed by oxidations of 1a at the same time. When acetic acid (AcOH) and 2,2,2-trifluoroethanol (TFE) was used instead of TFA respectively, 2aa was not found at 25 oC. After the temperature was up to 80 oC, acyloxylation or alkyloxylation obviously happened, but 2aa was still not produced in these weak acidic solvents. (Entries 2 and 3) In a neutral solvent 1,2-dichloroethane (DCE), no effective reactions were observed. (Entry 4) However, in a more acidic solvent methanesulfonic acid (MsOH) at 25 oC, 2aa was formed in 42% yield, a little better than in TFA, but the substrate 1a was decomposed much more. (Entry 5) Then, we tried to adjust the acidity and to control the amount of acidic solvent for accelerating the reaction rate of homo-coupling of 1a in this catalytic system. Gratefully, after many studies, it was found that the yield of homo-coupling product 2aa could be improved to 75% when MsOH/TFA (1:1, 10 equiv) was used as a mixed solvent at 25 oC (Entry 6). Certainly, dimerization products could not be prepared in the absence of either Pd(OAc)2 or K2S2O8. (Entries 7 and 8) In contrast, although the homo-coupling of 1a could occur, other oxidants including Na2S2O8, (NH4)2S2O8, and Oxone were not as effective as K2S2O8 under the similar conditions. (Entries 9−11) Thus, an effective catalytic system, Pd(OAc)2/K2S2O8/MsOH/TFA was established for the oxidative coupling of anilides at room temperature.


Page 4 of 51

Page 5 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Pd(II)-Catalyzed Homo-Coupling of N-(p-chlorophenyl)pivalamide (1a) to Give Its 2,2'-Bisanilide (2aa)a

a

entry

oxidant

solvent

1 2

K2S2O8 K2S2O8

TFA AcOH

3b 4b 5 6 7c 8 9

K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 Na2S2O8

TFE DCE MsOH MsOH/TFA MsOH/TFA MsOH/TFA MsOH/TFA

10 11

(NH4)2S2O8 Oxone

MsOH/TFA MsOH/TFA

conv. (%) 73 99 99 89

yield of 2aa(%) 37 -b trace 42 75(69) 32, 32d 68 47

Conditions: substrate (0.4 mmol, 1 equiv), Pd(OAc)2 (8 mol %), oxidant (1 equiv), solvent (0.2 mL),

MsOH/TFA = 1:1, 18 h. Yield based on substrate and determined by 1H NMR, CH2Br2 as an internal standard. Isolated yield in parentheses. b80 oC. cWithout Pd(OAc)2. d36 h.

In the investigation of the reaction scope, many N-phenylpivalamides with various substituted groups were tested. As shown in Table 2, for the anilides containing EDGs such as -Me and -Et group, the isolated yields of all 2,2'-bisanilides were from 62% to 93% in the presence of only 4 mol % Pd(OAc)2 with a ratio of MsOH/TFA 1:3 at 25 oC. Under the identical conditions, the simple N-phenylpivalamide

1b

could

give

its

2,2'-bisanilide

2bb

(N,N'-([1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)) in 56%. When there were alkyl substituted groups at meta-position of N-phenylpivalamides, the excellent yields (over 90%) of



dimerization products were obtained in short time. In contrast, for those anilides with EWGs, more loading of catalyst (8 mol % Pd(OAc)2) with more acidic solvent (MsOH/TFA 1:1) was necessary in the homo-coupling reactions. All halogen atoms including F, Cl, Br, and I as substituted groups on N-phenylpivalamides were available in these dimerization reactions and the yields were from 43% to 83%. However, the anilides with very electron-deficient groups such as -CO2Et , -CF3 and -NO2 give their corresponding 2,2'-bisanilide in poor yields because the homo-couplings were very slow compared with either the decompositions at room temperature or the oxidations at higher temperature in acidic solvents. Moreover, those anilides with steric hindered groups such as N-(3,5-dimethylphenyl)pivalamide 1v could not be dimerized under the conditions. Table 2 Scope of Homo-Coupling of N-Phenylpivalamidea


Page 6 of 51

Page 7 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3 Homo-Coupling of Anilides with Different N-acyl groupsa

Meanwhile, amides (–NHCOR) as the directing groups of anilides were also investigated, and the results are listed in Table 3. Among these R groups (R = tBu, iPr, nPr, Et, Me and Ph), tBu group was the first choice to give the highest yields in almost all cases, and iPr group was the second one. But the performances of others were fluctuant with various substituted aromatic rings. When the directing group was methylsulfonyl or trifluoroacetyl, the substrates would decompose more quickly and no homo-coupling products were obtained no matter how electron-rich the anilides might be. Thus, it seems that more electron-donating R groups are beneficial to the oxidative dimerization reactions. Cross-Coupling Reaction It is more significant and difficult to establish any oxidative cross-coupling of two different inert C-H bonds. In the cross-coupling of anilides, not only side reactions such as decomposition and



Page 8 of 51

oxidation but also homo-coupling would be avoided if it is possible. However, as shown in Table 4, the maximum selectivity of cross-coupling product was ~50% when N-(m-tolyl)isobutyramide 1d1 and N-(m-ethylphenyl)pivalamide 1g (1:1) were employed as substrate partners with similar structure and chemical characters, which is consistent with the statistical distribution. A simple way to enhance the selectivity is to choose two substrates with different reactivity in the cross-coupling reaction.

Electronical

and

steric

effects

are

still

considered

first.

For

example,

N-(3,5-dimethylphenyl)isobutyramide 1v1 with EDG and steric hindrance for ortho-position was used

as

one

substrate

since

it

underwent

its

homo-coupling

reaction

hardly.

N-(p-chlorophenyl)pivalamide 1a with EWG was selected as the partner in their cross-coupling reaction. As expected, the selectivity was 90% with a product yield of 67% when the ratio of them was 1:3. The ratio of MsOH/TFA was 1:1 to keep C-H activation of 1a happening very well. For normal anilides without steric hindrance, the selectivity could be over 50% if one active anilide with EDG and another inactive one with EWG were employed, and the ratio of substrates, the amount and ratio of acidic solvent, loading of catalyst, etc. were tuned carefully in their cross-couplings. In the cross-coupling of N-(m-tolyl)isobutyramide 1d1 with N-(p-chlorophenyl)pivalamide 1a, the ratio of 1d1/1a was down to 1:14 for blocking the homo-coupling of active anilide 1d1, and 100 equiv of MsOH/TFA (1:1) was added for reducing the homo-coupling of inactive 1a by decreasing the concentration of 1a. Meanwhile, more loading of Pd(OAc)2 (16 mol %) could accelerate the rate of cross-coupling of 1d1 with 1a. In this catalytic system at room temperature, the corresponding unsymmetric 2,2'-bisanilide was obtained as a major product in 68% yield with a cross-coupling selectivity of 67%.


Page 9 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 4 Pd(II)-Catalyzed Cross-Coupling of Anilidesa

According to the above principles and methods on cross-coupling reactions, many anilide partners were studied further, as shown in Table 5. Anilides with different amide directing groups and substituted by EDG such as -Me or -OMe group were chosen as active anilides (Ar-H). Other anilides with EWG including -F, -Cl, -Br, -I, -CF3 and -CO2Et group were inactive ones (Ar'-H). After tuning the ratio of substrates (Ar-H/Ar'-H), the amount of MsOH/TFA, reaction time and so on, unsymmetric 2,2'-bisanilides from two kinds of anilides were prepared in moderate isolated yields (49-73%) and all selectivites were over 50%. Of course, when an active anilide with steric hindered 1v was employed, the selectivites were very good, up to 98% and the ratios of substrates could be 1:1. Interestingly, those inactive anilides containing very electron-deficient groups such as -CO2Et and -CF3 could undergo the cross-couplings very well at room temperature even though they were not available in their homo-couplings. Meanwhile, 1v could also react with 1d1 (9:1) substituted by methyl group smoothly to afford an unsymmetric 2,2'-bisanilide 2vd1 in 80% yield with a selectivity of 95%, which is a cross-coupling of two anilides with EDG groups.



Table 5 Scope of Cross-Coupling of Anilidesa

Furthermore, unsymmetric or symmetric 2,2'-bisanilides (2) were readily converted to their corresponding 2,2'-diaminobiaryls (3) as shown in experimental section and SI, which are very useful compounds in synthesis. In summary, oxidative homo- and cross-couplings of anilides to afford symmetric and unsymmetric 2,2'-bisanilides respectively have been established at room temperature. A catalytic Pd(OAc)2/K2S2O8/MsOH/TFA system is very effective in these dimerization processes. Anilides not only containing EDGs but also EWGs are available in the couplings. By tuning the ratio of reaction partners and the amount of MsOH/TFA, the cross-coupling products could be obtained as major ones.

EXPERIMENTAL SECTION General. All reagents and solvent were obtained from commercial sources and used without further purification. Progress of reaction was monitored by thin-layer chromatography (TLC) using


Page 10 of 51

Page 11 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


silica gel F254 plates and UV detection at 254 and 365 nm. Purification of the coupling products was performed by flash column chromatography using silica gel (200-300 mesh). Melting points were measured with XT4A Microscopic Melting-point Detector, produced by Beijing Keyi Electro-optic Instrument Plant. 1H and

13

C NMR spectra were recorded on a Bruker AVANCE III

HD 400 (400 MHz) spectrometer 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., app. and m denoting singlet, doublet, triplet, quartet, septet, broad, apparent and multiplet respectively.

19

F

NMR spectra were recorded on the same spectrometer listed above at 376 MHz and were referenced in the same way. All NMR chemical shifts are quoted in ppm. All coupling constants, J, are quoted in Hz. HRMS were measured with ACQUITYTM UPLC & Q-TOF MS Premier. General Procedure for the Preparation of Substrates. To a stirring solution of aniline (20 mmol), Et3N (2.5298 g, 25 mmol) in CH2Cl2 (50 mL), was added dropwise acyl chloride (20 mmol) at 0 oC (ice/water bath) for 10 minutes. Then, the reaction mixture was stirred at room temperature overnight. Water (20 mL) was added to the crude mixture after the mixture was evaporated. After that, the reaction mixture was extracted with ethyl acetate (30 mL×3), washed with brine (20 mL×2), and dried over anhydrous Na2SO4. Then, the extract was concentrated and recrystallization from hexane/ethyl acetate mixture to afford the amide. N-(p-chlorophenyl)pivalamide (1a). white needle (3.60 g, 85% yield); m.p. 149–150 oC (lit.17 148-149 oC); 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.44 (m, 2H), 7.35 (s, 1H, br), 7.29 – 7.22 (m, 2H), 1.30 (s, 9H).



N-phenylpivalamide (1b). white needles (2.66 g, 75% yield); m.p. 134–135 oC (lit.18 132–133 o

C); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 2H), 7.36 (s, 1H, br), 7.31 (t, J = 8.0 Hz,

2H), 7.09 (t, J = 7.4 Hz, 1H), 1.31 (s, 9H). N-(o-tolyl)pivalamide (1c). white powder (3.25 g, 85% yield); m.p. 110–112 oC (lit.13a 110–112 o

C); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H, br), 7.24 – 7.12 (m, 2H),

7.06 (td, J = 7.6, 1.2 Hz, 1H), 2.23 (s, 3H), 1.33 (s, 9H). N-(m-tolyl)pivalamide (1d). white needles (3.18 g, 83% yield); m.p. 127–128 oC (lit.13a 125 oC); 1

H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.30 – 7.25 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.92 (d,

J = 7.2 Hz, 1H), 2.33 (s, 3H), 1.31 (s, 9H). N-(p-tolyl)pivalamide (1e). white needles (2.49 g, 65% yield); m.p. 119–120 oC (lit.19 118 oC); 1

H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 7.34 (s, 1H, br), 7.11 (d, J = 8.4 Hz, 2H),

2.30 (s, 3H), 1.30 (s, 9H). N-(2-ethylphenyl)pivalamide (1f). white solid (3.61 g, 88% yield); m.p. 103–105 oC; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 7.29 (s, 1H, br), 7.21 (m, 2H), 7.14 – 7.07 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.34 (s, 9H), 1.25 (t, J = 7.6 Hz, 3H). N-(3-ethylphenyl)pivalamide (1g). white solid (3.04 g, 74% yield); m.p. 113–115 oC (lit.20 121–122 oC); 1H NMR (400 MHz, CDCl3) δ 7.45 (t, J = 1.6 Hz, 1H), 7.30 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.98 – 6.92 (m, 1H), 2.63 (q, J = 7.6 Hz, 2H), 1.32 (s, 9H), 1.23 (t, J = 7.6 Hz, 3H). N-(4-ethylphenyl)pivalamide (1h). white solid (2.46 g, 60% yield); m.p. 106–108 oC. (lit.20 117–118 oC); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H, br), 7.13 (d, J = 8.8 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.30 (s, 9H), 1.21 (t, J = 7.6 Hz, 3H).


Page 12 of 51

Page 13 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N-(2,4-dimethylphenyl)pivalamide (1i). white solid (2.87 g, 70% yield); m.p. 112–114 oC (lit.21 111.5 oC); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H, br), 7.00 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 1.33 (s, 9H). N-(3,4-dimethylphenyl)pivalamide (1j). white solid (2.71 g, 66% yield); m.p. 132–133 oC (lit.22 130 oC); 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.35 (m, 2H), 7.22 (dd, J = 8.4, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 1.30 (s, 9H). N-(4-bromo-3-methylphenyl)pivalamide (1k). white solid (3.78 g, 70% yield); m.p. 139–140 o

C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H,

br), 7.20 (dd, J = 8.4, 2.8 Hz, 1H), 2.36 (s, 3H), 1.30 (s, 9H). N-(3-fluorophenyl)pivalamide (1l). white solid (2.93 g, 75% yield); m.p. 110–112 oC (lit.23 112.5–113 oC); 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H, br), 7.51 (dt, J = 11.2, 2.4 Hz, 1H), 7.20 (td, J = 8.0, 6.4 Hz, 1H), 7.13 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 6.76 (tdd, J = 8.2, 2.4, 1.0 Hz, 1H), 1.29 (s, 9H). N-(3-chlorophenyl)pivalamide (1m). white solid (2.96 g, 70% yield); m.p. 135–136 oC (lit.24 124–126 oC); 1H NMR (400 MHz, CDCl3) δ 7.68 (t, J = 2.0 Hz, 1H), 7.41 – 7.29 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 7.13 – 7.01 (m, 1H), 1.31 (s, 9H). N-(3-bromophenyl)pivalamide (1n). white solid (3.59 g, 70% yield); m.p. 144–145 oC (lit.25 137–138 oC); 1H NMR (400 MHz, CDCl3) δ 7.80 (t, J = 2.0 Hz, 1H), 7.44 (s, 1H, br), 7.40 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 1.29 (s, 9H). N-(3-iodophenyl)pivalamide (1o). pale solid (3.94 g, 65% yield); m.p. 146–147 oC; 1H NMR (400 MHz, CDCl3) δ 7.95 (t, J = 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (m, 2H), 7.00 (t,



J = 8.0 Hz, 1H), 1.29 (s, 9H). N-(4-fluorophenyl)pivalamide (1p). white solid (2.93 g, 75% yield); m.p. 123–124 oC (lit.26 121–123 oC); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.41 (m, 2H), 7.30 (s, 1H, br), 7.06 – 6.95 (m, 2H), 1.31 (s, 9H). N-(4-bromophenyl)pivalamide (1q). white needles (3.84 g, 75% yield); m.p. 152–153 oC (lit.27 150.3–151.8 oC); 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 4H), 7.30 (s, 1H, br), 1.31 (s, 9H). N-(4-iodophenyl)pivalamide (1r). white solid (3.82 g, 63% yield); m.p. 147–149 oC (lit.28 150 o

C); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.55 (m, 2H), 7.42 – 7.27 (m, 3H), 1.30 (s, 9H). ethyl 3-pivalamidobenzoate (1s). pale solid (3.99 g, 80% yield); m.p. 62–63 oC (lit.25 59–60

o

C); 1H NMR (400 MHz, CDCl3) δ 8.02 – 7.91 (m, 2H), 7.78 (dt, J = 7.6, 1.4 Hz, 1H), 7.48 – 7.35

(m, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H). ethyl 4-pivalamidobenzoate (1t). white solid (3.79 g, 76% yield); m.p. 86–89 oC (lit.21 93 oC); 1

H NMR (400 MHz, CDCl3) δ 8.05 – 7.93 (m, 2H), 7.67 – 7.58 (m, 2H), 7.48 (s, 1H, br), 4.35 (q, J

= 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H). N-(3-(trifluoromethyl)phenyl)pivalamide(1u). white solid (3.63 g, 74% yield); m.p. 107–108 o

C (lit.29 107–109 oC); 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.45 (s,

1H, br), 7.42 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 1.33 (s, 9H). N-(3,5-dimethylphenyl)pivalamide (1v). white solid (2.42 g, 59% yield); m.p. 126-127 oC (lit.29 126–127oC); 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, br), 7.18 (s, 2H), 6.74 (s, 1H), 2.29 (s, 6H), 1.30 (s, 9H). N-(3-methoxyphenyl)pivalamide (1w). white solid (3.03 g, 73% yield); m.p. 123–125 oC (lit.30


Page 14 of 51

Page 15 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


125–126 oC); 1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 2.4 Hz, 1H), 7.32 (s, 1H, br), 7.20 (t, J = 8.0 Hz, 1H), 6.93 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 6.66 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 3.81 (s, 3H), 1.31 (s, 9H). N-(3-nitrophenyl)pivalamide (1x). yellow solid (2.09 g, 47% yield); m.p. 108–109 oC (lit.31 108–109 oC); 1H NMR (400 MHz, CDCl3) δ 8.39 (t, J = 2.2 Hz, 1H), 7.99 – 7.91 (m, 2H), 7.56 (s, 1H, br), 7.48 (td, J = 8.2, 1.6 Hz, 1H), 1.34 (s, 9H). N-(4-chlorophenyl)isobutyramide (1a1). white solid (2.29 g, 58% yield); m.p. 149–150 oC (lit.32 149–150 oC); 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz, 2H), 7.36 – 7.20 (m, 3H), 2.49 (sept, J = 6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). N-(4-chlorophenyl)propionamide (1a2). white solid (3.16 g, 86% yield); m.p. 137–139 oC (lit.33 137–139 oC); 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 3H), 7.25 (dd, J = 8.8, 1.2 Hz, 2H), 2.38 (q, J = 7.6 Hz, 2H), 1.23 (td, J = 7.6, 1.2 Hz, 3H). N-(4-chlorophenyl)acetamide (1a3). white solid (2.75 g, 81% yield); m.p. 183–184 oC (lit.34 180–181 oC); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.8 Hz, 2H), 7.33 – 7.26 (m, 2H), 7.24 (s, 1H, br), 2.17 (s, 3H). N-phenylisobutyramide (1b1). white solid (1.93 g, 59% yield); m.p. 104–105 oC (lit.35 104–105 o

C); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.21 (s, 1H,

br), 7.10 (t, J = 7.6 Hz, 1H), 2.51 (sept, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). N-(m-tolyl)isobutyramide (1d1). white solid (2.76 g, 78% yield); m.p. 81–82 oC (lit.36 83 oC); 1

H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.37 – 7.27 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.91 (d,

J = 7.6 Hz, 1H), 2.50 (sept, J = 6.8 Hz, 1H), 2.32 (s, 3H), 1.24 (d, J = 6.8 Hz, 6H).



N-(m-tolyl)butyramide (1d2). white solid (3.44 g, 97% yield); m.p. 39–41 oC; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H, br), 7.43 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 2.34 (t, J = 7.4 Hz, 2H), 2.27 (s, 3H), 1.80 – 1.69 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). N-(m-tolyl)propionamide (1d3). white solid (2.29 g, 70% yield); m.p. 77–78 oC (lit.37 79–81 o

C); 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.24 – 7.15 (m, 2H),

6.91 (d, J = 7.6 Hz, 1H), 2.38 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H). N-(m-tolyl)acetamide (1d4). cream solid (2.75 g, 92% yield); m.p. 64–66 oC (lit.38 64–66 oC); 1

H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H, br), 7.36 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.16 (t, J =

7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 2.29 (s, 3H), 2.14 (s, 3H). N-(m-tolyl)benzamide (1d5). gray solid (3.59 g, 85% yield); m.p. 123–124 oC (lit.39 124–125 o

C); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.81 (m, 3H), 7.57 – 7.51 (m, 2H), 7.50 – 7.44 (m, 2H),

7.42 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 2.36 (s, 3H). N-(p-tolyl)isobutyramide (1e1). white solid (2.34 g, 66% yield); m.p. 107–108 oC (lit.36 108– 109 oC); 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H, br), 7.42 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 2.51 (sept, J = 6.8 Hz, 1H), 2.29 (s, 3H), 1.21 (d, J = 6.8 Hz, 6H). N-(2-ethylphenyl)isobutyramide (1f1). white solid (2.30 g, 60% yield); m.p. 104–106 oC; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.25 – 7.17 (m, 2H), 7.12 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H, br), 2.67 – 2.51 (m, 3H), 1.29 (d, J = 7.2 Hz, 6H), 1.24 (t, J = 7.4 Hz, 3H). N-(3,4-dimethylphenyl)isobutyramide (1j1). white solid (2.68 g, 70% yield); m.p.137–138 oC (lit.40 137 oC); 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 1.6 Hz, 1H), 7.25 (s, 1H, br), 7.22 (dd, J


Page 16 of 51

Page 17 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


= 8.0, 2.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 2.49 (sept, J = 6.8 Hz, 1H), 2.22 (s, 3H), 2.21 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H). N-(3,4-dimethylphenyl)butyramide (1j2). white solid (3.06 g, 80% yield); m.p. 74–75 oC (lit.41 71.5–72.5 oC); 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H, br), 7.32 (s, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.30 (t, J = 7.6 Hz, 2H), 2.21 (s, 3H), 2.20 (s, 3H), 1.80 – 1.68 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). N-(3,4-dimethylphenyl)propionamide (1j3). white solid (2.84 g, 80% yield); m.p. 103–104 oC (lit.41 105.5–106.5 oC); 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H, br), 7.32 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.0, 2.4 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 2.35 (q, J = 7.6 Hz, 2H), 2.20 (s, 6H), 1.21 (t, J = 7.6 Hz, 3H). N-(3,4-dimethylphenyl)acetamide (1j4). white solid (2.81 g, 86% yield); m.p. 96–98 oC (lit.41 97–98 oC); 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H, br), 7.26 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 2.09 (s, 3H). N-(3,5-dimethylphenyl)isobutyramide (1v1). white solid (2.14 g, 56% yield); m.p. 149–151 oC (lit.40 143 oC); 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H, br), 7.18 (s, 2H), 6.73 (s, 1H), 2.49 (sept, J = 6.8 Hz, 1H), 2.27 (s, 6H), 1.23 (d, J = 6.8 Hz, 6H). N-(3-methoxyphenyl)isobutyramide (1w1). white solid (3.59 g, 93% yield); m.p. 60–61 oC (lit.36 60–61 oC); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H, br), 7.37 (t, J = 2.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 8.0, 1.2 Hz, 1H), 6.64 (dd, J = 8.0, 2.0 Hz, 1H), 3.77 (s, 3H), 2.51 (sept, J = 6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H).



General Procedure 1A for the Homo-Coupling Reaction. Amide (0.4 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol, 4 mol %), Potassium persulfate (108.1 mg, 0.4 mmol, 1 equiv), 2,2,2-trifluoroacetic acid (342.1 mg, 3.0 mmol, 0.15 mL), methanesulfonic acid (96.1 mg, 1.0 mmol, 0.05 mL) were added in 35 mL seal tube. The reaction mixture was stired at 25 oC for 3 h. After that, saturated NaHCO3 (10.0 mL) was added to it. The solution was extracted with CH2Cl2 (10 mL×3) and washed with brine (10 mL), and dried over anhydrous Mg2SO4. Then, the extract was concentrated and the residue was purified by flash column chromatography on silica gel to give product. General Procedure 1B for the Homo-Coupling Reaction. Amide (0.4 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol, 8 mol %), Potassium persulfate (108.1 mg, 0.4 mmol, 1 equiv), 2,2,2-trifluoroacetic acid (228.0 mg, 2.0 mmol, 0.10 mL), methanesulfonic acid (192.2 mg, 2.0 mmol, 0.10 mL) were added in 35 mL seal tube. The reaction mixture was stired at 25 oC for 18 h. After that, saturated NaHCO3 (10.0 mL) was added to it. The solution was extracted with CH2Cl2 (10 mL×3) and washed with brine (10 mL), and dried over Mg2SO4. Then, the extract was concentrated and the residue was purified by flash column chromatography on silica gel to give product. General Procedure 1C for the Homo-Coupling Reaction. Amide (1.6 mmol, 4 equiv), Pd(OAc)2 (7.2 mg, 0.032 mmol, 8 mol %), Potassium persulfate (108.1 mg, 0.4 mmol), 2,2,2-trifluoroacetic acid (342.1 mg, 3.0 mmol, 0.15 mL), methanesulfonic acid (96.1 mg, 1.0 mmol, 0.05 mL) were added in 35 mL seal tube. The reaction mixture was stired at 40 oC for 48 h. After that, saturated NaHCO3 (10.0 mL) was added to it. The solution was extracted with CH2Cl2 (20


Page 18 of 51

Page 19 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mL×3) and washed with brine (10 mL), and dried over Mg2SO4. Then, the extract was concentrated and the residue was purified by flash column chromatography on silica gel to give product. N,N'-(5,5'-dichloro-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2aa).

The

reaction was performed according to the general procedure 1B using amide 1a. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2aa (58.0 mg. yield: 69%) as white solid; m.p. 142–144 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 8.8, 2.4 Hz, 2H), 7.20 (s, 2H, br), 7.19 (d, J = 2.4 Hz, 2H), 1.02 (s, 18H); 13

C NMR (100 MHz, CDCl3) δ 177.2, 134.5, 130.3, 130.1, 129.8, 129.7, 124.6, 39.7, 27.2; HRMS

(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H26Cl2N2NaO2 443.1264; found 443.1262. N,N'-([1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2bb). The reaction was performed according to the general procedure 1A using amide 1b. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2bb (39.2 mg, 56% yield) as white solid; m.p. 120–122 oC; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 2H), 7.49 – 7.40 (m, 2H), 7.26 – 7.21 (m, 4H), 7.18 (s, 2H, br), 0.99 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.9, 136.1, 129.9, 129.7, 128.3, 124.8, 122.1, 39.7, 27.3. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H29N2O2 353.2224; found 353.2234. N,N'-(3,3'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2cc).

The

reaction was performed according to the general procedure 1A in 9h using amide 1c. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2cc (52.3 mg, 69% yield) as white solid; m.p. 245–246 oC; 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H,



Page 20 of 51

br), 7.20 (dd, J = 7.2, 1.2 Hz, 2H), 7.15 (t, J = 7.6 Hz, 2H), 6.93 (dd, J = 7.2, 0.8 Hz, 2H), 2.21 (s, 6H), 0.95 (s, 18H);

13

C NMR (100 MHz, CDCl3) δ 178.3, 138.4, 137.0, 134.3, 129.9 (two overlapped

peaks), 126.9, 38.9, 27.3, 18.2; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H33N2O2 381.2537; found 381.2546. N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2dd).

The

reaction was performed according to the general procedure 1A using amide 1d. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2dd (70.8 mg, 93% yield) as yellow solid; m.p. 158–160 oC; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 2H), 7.19 (s, 2H, br), 7.06 (d, J = 7.6 Hz, 2H), 7.00 (dd, J = 7.6, 1.2 Hz, 2H), 2.39 (s, 6H), 0.99 (s, 18H);

13

C

NMR (100 MHz, CDCl3) δ 176.8, 139.7 136.0, 129.8, 125.3, 124.8, 122.0, 39.7, 27.2, 21.7; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H33N2O2 381.2537; found 381.2544. N,N'-(5,5'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2ee).

The

reaction was performed according to the general procedure 1A using amide 1e. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2ee (47.0 mg, 62% yield) as yellow solid; m.p. 140–142 oC; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 8.4, 1.6 Hz, 2H), 7.15 (s, 2H, br), 7.02 (d, J = 1.6 Hz, 2H), 2.35 (s, 6H), 1.00 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.7, 134.3, 133.4, 130.3, 129.9, 128.7, 122.2, 39.6, 27.2, 20.9; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H33N2O2 381.2537; found 381.2541. N,N'-(3,3'-diethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2ff).

The

reaction was performed according to the general procedure 1A in 9h using amide 1f. Purification


Page 21 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 2ff (55.0 mg, 67% yield) as white solid; m.p. 193–196 oC; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H, br), 7.26 – 7.16 (m, 4H), 6.98 (dd, J = 6.4, 2.4 Hz, 2H), 2.67 – 2.49 (m, 4H), 1.17 (t, J = 7.6 Hz, 6H), 0.95 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 178.6, 142.8, 139.0, 133.9, 128.2, 127.3, 127.1, 38.8, 27.3, 25.0, 14.7; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C26H37N2O2 409.2850; found 409.2868. N,N'-(4,4'-diethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2gg).

The

reaction was performed according to the general procedure 1A using amide 1g. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1:1, v/v) gave 2gg (73.5 mg, 90% yield) as white solid; m.p. 134–135 oC; 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); 13C NMR (100 MHz, CDCl3) δ 176.8, 146.2, 136.2, 129.9, 125.1, 124.1, 121.0, 39.8, 29.1, 27.3, 15.8; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C26H37N2O2 409.2850; found 409.2858. N,N'-(5,5'-diethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2hh).

The

reaction was performed according to the general procedure 1A (solvent is only 10 equiv TFA) in 48h using amide 1h. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 2hh (30.2 mg, 37% yield) as yellow solid; m.p. 81–84 oC; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 2H), 7.26 (dd, J = 8.4, 2.0 Hz, 2H), 7.18 (s, 2H, br), 7.05 (d, J = 2.0 Hz, 2H), 2.64 (q, J = 7.6 Hz, 4H), 1.23 (t, J = 7.6 Hz, 6H), 0.99 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.9, 140.9, 133.7, 129.0, 128.9, 128.9, 122.4, 39.6, 28.4, 27.3, 15.9; HRMS



Page 22 of 51

(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C26H37N2O2 409.2850; found 409.2853. N,N'-(3,3',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2ii).

The reaction was performed according to the general procedure 1A in 4h using amide 1i. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 2ii (59.2 mg, 72% yield) as white solid; m.p. 255–258 oC; 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 2H, br), 7.01 (s, 2H), 6.79 (s, 2H), 2.27 (s, 6H), 2.17 (s, 6H), 0.96 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 178.4, 138.2, 136.6, 136.5, 131.6, 130.4, 127.4, 38.9, 27.3, 21.0, 18.1; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C26H37N2O2 409.2850; found 409.2851. N,N'-(4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2jj).

The reaction was performed according to the general procedure 1A using amide 1j. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (6/1, v/v) gave 2jj (71.9 mg, 88% yield) as white solid; m.p. 168–171 oC; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 2H), 7.18 (s, 2H, br), 6.94 (s, 2H), 2.29 (s, 6H), 2.23 (s, 6H), 1.00 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.8, 137.9, 133.7, 132.9, 131.0, 125.4, 122.8, 39.7, 27.3, 20.0, 19.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C26H36N2NaO2 431.2669; found 431.2679. N,N'-(5,5'-dibromo-4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2kk). The reaction was performed according to the general procedure 1A using amide 1k. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2kk (77.5 mg, 72% yield) as white solid; m.p. 204–205 oC; 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); 13C NMR (100 MHz, CDCl3) δ 177.0, 139.7, 135.1, 133.3, 126.6, 124.6, 120.0, 39.8, 27.3, 23.2; HRMS (ESI-Q/TOF MS) with


Page 23 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Acetonitrile (m/z): [M+Na]+ calcd for C24H30Br2N2NaO2 559.0566; found 559.0560. N,N'-(4,4'-difluoro-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2ll).

The

reaction was performed according to the general procedure 1B in 3h using amide 1l. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (2/1, v/v) 2ll (48.9 mg, 63% yield) as white solid; m.p. 117–119 oC; 1H NMR (400 MHz, CDCl3) δ8.28 – 8.13 (m, 2H), 7.24 – 7.09 (m, 4H), 6.99 – 6.89 (m, 2H), 1.01 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.9, 163.4 (d, JC-F = 247 Hz), 137.9 (d, JC-F = 12 Hz), 131.4 (d, JC-F = 9 Hz), 122.1 (d, JC-F = 3 Hz), 111.5 (d, JC-F = 22 Hz), 109.1 (d, JC-F = 28 Hz), 39.9, 27.2;

19

F NMR (376 MHz, CDCl3) δ -109.2; HRMS

(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H26F2N2NaO2 411.1855; found 411.1856. N,N'-(4,4'-dichloro-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2mm).

The

reaction was performed according to the general procedure 1B in 3h using amide 1m. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2mm (70.0 mg, 83% yield) as white solid; m.p. 195–197 oC; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.0 Hz, 2H), 7.22 (dd, J = 8.0, 2.0 Hz, 2H), 7.15 (s, 2H, br), 7.11 (d, J = 8.0 Hz, 2H), 1.03 (s, 18H);

13

C NMR (100 MHz, CDCl3) δ 177.0, 137.1, 135.9, 130.9, 125.5, 125.0, 122.3, 39.9, 27.3;

HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H26Cl2N2NaO2 443.1264; found 443.1270. N,N'-(4,4'-dibromo-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2nn).

The

reaction was performed according to the general procedure 1B in 3h using amide 1n. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1:1, v/v) gave 2nn



Page 24 of 51

(79.6 mg, 78% yield) as white solid; m.p. 214–216 oC; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.0 Hz, 2H), 7.37 (dd, J = 8.0, 2.0 Hz, 2H), 7.15 (s, 2H, br), 7.04 (d, J = 8.0 Hz, 2H), 1.03 (s, 18H); 13


(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H27Br2N2O2 509.0434 found 509.0449. N,N'-(4,4'-diiodo-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2oo).

The

reaction was performed according to the general procedure 1B in 3h using amide 1o. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (2/1, v/v) gave 2oo (77.3 mg, 64% yield) as white solid; m.p. 208–211 oC; 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 2.0 Hz, 2H), 7.57 (dd, J = 8.0, 1.6 Hz, 2H), 7.13 (s, 2H, br), 6.89 (d, J = 8.0 Hz, 2H), 1.02 (s, 18H); 13


(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H26I2N2NaO2 626.9976; found 626.9984. N,N'-(5,5'-difluoro-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2pp).

The

reaction was performed according to the general procedure 1A (1.5 equiv K2S2O8) in 48h using amide

1p.

Purification

by

flash

column

chromatography

eluting

with

petroleum

ether/dichloromethane (1/1, v/v) gave 2pp (33.4 mg, 43% yield) as white solid; m.p. 166–167 oC; 1

H NMR (400 MHz, CDCl3) δ 8.01 – 7.85 (m, 2H), 7.24 (s, 2H, br), 7.17 – 7.08 (m, 2H), 6.91 (dd, J

= 8.4, 3.2 Hz, 2H), 1.01 (s, 18H);

13

C NMR (100 MHz, CDCl3) δ 177.6, 159.8 (d, JC-F = 247 Hz),

132.1 (d, JC-F = 8 Hz), 131.9 (d, JC-F = 3 Hz), 126.2 (d, JC-F = 8 Hz), 116.5 (d, JC-F = 21 Hz), 116.3 (d, JC-F = 20 Hz), 39.5, 27.2;

19

F NMR (376 MHz, CDCl3) δ -116.2; HRMS (ESI-Q/TOF MS) with


Page 25 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Acetonitrile (m/z): [M+Na]+ calcd for C22H26F2N2NaO2 411.1855; found 411.1859. N,N'-(5,5'-dibromo-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2qq).

The

reaction was performed according to the general procedure 1B using amide 1q. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (2/1, v/v) gave 2qq (69.8 mg, 68% yield) as white solid; m.p. 205–207 oC; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.8, 2.4 Hz, 2H), 7.35 (d, J = 2.4 Hz, 2H), 7.18 (s, 2H, br), 1.03 (s, 18H); 13


(ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H27Br2N2O2 509.0434; found 509.0441. N,N'-(5,5'-diiodo-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2rr). The reaction was performed according to the general procedure 1B using amide 1r. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (2/1, v/v) gave 2rr (54.0 mg, 45% yield) as white solid; m.p. 113–115 oC; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 8.8, 2.0 Hz, 2H), 7.53 (d, J = 2.0 Hz, 2H), 7.17 (s, 2H, br), 1.03 (s, 18H);

13

C NMR (100

MHz, CDCl3) δ 177.1, 138.8, 138.4, 135.7, 129.9, 124.7, 88.3, 39.8, 27.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H26I2N2NaO2 626.9976; found 626.9980. Diethyl

2,2'-dipivalamido-[1,1'-biphenyl]-4,4'-dicarboxylate

(2ss). The

reaction

was

performed according to the general procedure 1C using amide 1s. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2ss (20.9 mg, 21% yield) as white solid; m.p. 151–154 oC; 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 7.94 (d, J = 8.0 Hz, 2H), 7.29 (s, 2H, br), 7.25 – 7.28 (m, 2H), 4.41 (q, J = 7.2 Hz, 4H), 1.42 (t, J = 7.2 Hz, 6H), 1.02 (s,



18H);

13

Page 26 of 51

C NMR (100 MHz, CDCl3) δ 177.3, 166.0, 136.0, 134.2, 132.1, 129.8, 126.4, 124.7, 61.6,

39.7, 27.3, 14.5. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C28H37N2O6 497.2646; found 497.2663. Diethyl

6,6'-dipivalamido-[1,1'-biphenyl]-3,3'-dicarboxylate

(2tt). The

reaction

was

performed according to the general procedure 1C using amide 1t. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (9/1, v/v) gave 2tt (49.7 mg, 50% yield) white solid; m.p. 206–207 oC; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.8 Hz, 2H), 8.15 (dd, J = 8.8, 2.0 Hz, 2H), 7.94 (d, J = 2.0 Hz, 2H), 7.27 (s, 2H, br), 4.37 (qd, J = 7.2, 1.0 Hz, 4H), 1.38 (t, J = 7.2 Hz, 6H), 1.00 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.9, 165.7, 140.0, 131.8, 131.6, 126.5, 126.2, 121.0, 61.4, 40.0, 27.2, 14.4; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C28H37N2O6 497.2646; found 497.2661. N,N'-(4,4'-bis(trifluoromethyl)-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2uu). The reaction was performed according to the general procedure 1C using amide 1u. Purification by flash column chromatography eluting with petroleum ether/dichloromethane (1/1, v/v) gave 2uu (26.4 mg, 27% yield) as white solid; m.p. 148–150 oC; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, 2H, J = 0.8 Hz), 7.53 (dd, J = 7.6, 0.8 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.24 (s, 2H, br), 1.03 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 177.3, 136.6, 132.48 (q, JC-F = 33 Hz), 131.7, 130.4, 123.67 (q, JC-F = 273 Hz), 121.78 (q, JC-F = 4 Hz), 120.20 (q, JC-F = 4 Hz), 39.8, 27.2; 19F NMR (376 MHz, CDCl3) δ -62.9. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H27F6N2O2 489.1971; found 489.1978.


Page 27 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N,N'-(4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2ww).

N-(3-methoxyphenyl)pivalamide (82.9 mg, 0.4 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol, 8 mol %), Potassium persulfate (162.2 mg, 0.6 mmol, 1.5 equiv), methanol (256.3 mg, 8.0 mmol, 0.30 mL), methanesulfonic acid (76.8 mg, 0.8 mmol, 0.05 mL) were added in 35 mL seal tube. The reaction mixture was stired at 25 oC for 3 h. After that, saturated NaHCO3 (10.0 mL) was added to it. The solution was extracted with CH2Cl2 (10 mL×3) and washed with brine (10 mL), and dried over Mg2SO4. Then, the extract was concentrated and the residue was purified by flash column chromatography on silica gel with a gradient eluent of petroleum ether/ethyl acetate (6/1, v/v) to give 2ww (49.5 mg, 60% yield) as a white solid. m.p. 78–81 oC; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.8 Hz, 2H), 7.25 (s, 2H, br), 7.09 (d, J = 8.4 Hz, 2H), 6.76 (dd, J = 8.4, 2.8 Hz, 2H), 3.87 (s, 6H), 1.02 (s, 18H);

13

C NMR (100 MHz, CDCl3) δ 176.8, 160.6, 137.7, 131.1, 118.5, 111.3, 105.4,

55.6, 40.0, 27.4; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H33N2O4 413.2435; found 413.2450. N,N'-(4,4'-dinitro-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2xx).

The

reaction was performed according to the general procedure 1C using amide 1x. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2xx (1.0 mg, 1% yield) as brown solid; m.p. 226–227 oC; 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.4 Hz, 2H), 8.14 (dd, J = 8.4, 2.4 Hz, 2H), 7.39 (s, 2H, br), 7.36 (d, J = 8.4 Hz, 2H), 1.06 (s, 18H). 13C NMR (100 MHz, CDCl3) δ 177.5, 149.0, 137.0, 135.4, 130.6, 120.1, 119.4, 39.8, 27.2. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H27N4O6 443.1925; found 443.1923.



Page 28 of 51

N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide)

(2d1d1).

The

reaction was performed according to the general procedure 1A using amide 1d1. Purification by flash column chromatography eluting with petroleum ether:ethyl acetate (4/1, v/v) gave 2d1d1 (55.8 mg, 79% yield) as white solid; m.p. 85–88 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 7.6, 0.4 Hz, 2H), 6.97 (s, 2H, br), 2.40 (s, 6H), 2.25 (sept, J = 6.8 Hz, 2H), 1.02 (d, J = 6.8 Hz, 6H), 1.00 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 175.6, 139.6, 135.7, 130.2, 125.7, 125.5, 123.0, 36.5, 21.6, 19.5, 19.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H28N2NaO2 375.2043; found 375.2059. N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)dibutyramide

(2d2d2).

The

reaction

was

performed according to the general procedure 1A using amide 1d2. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2d2d2 (47.8 mg, 68% yield) as yellow solid; m.p. 38–42 oC; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 8.0, 1.2 Hz, 2H), 6.92 (s, 2H, br), 2.41 (s, 6H), 2.13 – 2.07 (m, 4H), 1.61 – 1.47 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H);

13

C NMR (100 MHz, CDCl3) δ 171.9, 139.5, 135.6, 130.4,

125.8, 125.7, 123.3, 39.4, 21.6, 18.9, 13.7; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H28N2NaO2 375.2043; found 375.2054. N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)dipropionamide (2d3d3). The reaction was performed according to the general procedure 1A using amide 1d3. Purification by flash column chromatography eluting with petroleum ether:ethyl acetate (4/1, v/v) gave 2d3d3 (41.3 mg, 64% yield) as yellow solid; m.p. 124–126 oC; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.01 (dd, J = 7.6, 1.2 Hz, 2H), 6.93 (s, 2H, br), 2.39 (s, 6H), 2.14 (q, J = 7.6 Hz, 4H), 1.02


Page 29 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 139.5, 135.5, 130.4, 125.8, 125.5, 123.3, 30.5, 21.6, 9.5; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C20H24N2NaO2 347.1730; found 347.1736. N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)diacetamide(2d4d4).

The

reaction

was

performed according to the general procedure 1A using amide 1d4. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) gave 2d4d4 (36.3 mg, 61% yield) as white solid; m.p. 187–189 oC; 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.02 (dd, J = 7.6, 0.8 Hz, 2H), 6.97 (s, 2H, br), 2.39 (s, 6H), 1.94 (s, 6H);

13

C NMR (100

MHz, CDCl3) δ 169.2, 139.4, 135.4, 130.5, 126.1 (two overlapped peaks), 123.8, 24.3, 21.6. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C18H21N2O2 297.1598; found 297.1599. N,N'-(4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)dibenzamide

(2d5d5).

The

reaction

was

performed according to the general procedure 1A using amide 1d5. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2d5d5 (53.0 mg, 63% yield) as yellow solid; m.p. 160–162 oC; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.87 (s, 2H, br), 7.58 – 7.51 (m, 4H), 7.49 – 7.43 (m, 2H), 7.39 – 7.33 (m, 4H), 7.19 (d, J = 7.6 Hz, 2H), 7.09 (ddd, J = 7.6, 1.6, 0.8 Hz, 2H), 2.46 (s, 6H);

13

C NMR (100 MHz, CDCl3) δ 165.6, 139.9, 135.9, 134.5,

132.0, 130.3, 128.9, 126.9, 125.9, 125.4, 122.7, 21.8; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C28H24N2NaO2 443.1730; found 443.1733. N,N'-(4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide) (2j1j1). The reaction was performed according to the general procedure 1A using amide 1j1. Purification by



flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2j1j1 (58.4 mg, 77% yield) as yellow solid; m.p. 178–181 oC; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 6.93 (s, 4H), 2.32 – 2.21 (m, 14H), 1.04 – 0.99 (m, 12H);

13

C NMR (100 MHz, CDCl3) δ 175.6, 137.7,

133.4, 133.2, 131.3, 126.2, 123.7, 36.4, 20.0, 19.5, 19.4, 19.3; RMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C24H32N2NaO2 403.2356; found 403.2359. N,N'-(4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)dibutyramide (2j2j2). The reaction was performed according to the general procedure 1A using amide 1j2. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (8/1, v/v) gave 2j2j2 (51.7 mg, 68% yield) as yellow solid; m.p. 96–99 oC; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 2H), 6.92 (s, 2H), 6.88 (s, 2H, br), 2.30 (s, 6H), 2.23 (s, 6H), 2.10 (m, 4H), 1.55 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.9, 137.7, 133.4, 133.3, 131.5, 126.6, 124.1, 39.3, 20.0, 19.3, 18.9, 13.7; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C24H32N2NaO2 403.2356; found 403.2356. N,N'-(4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)dipropionamide (2j3j3). The reaction was performed according to the general procedure 1A using amide 1j3. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2j3j3 (51.4 mg, 73% yield) as yellow solid; m.p. 129–132 oC; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 2H), 6.93 (s, 2H), 6.85 (s, 2H, br), 2.30 (s, 6H), 2.24 (s, 6H), 2.15 (q, J = 7.6 Hz, 4H), 1.04 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 137.7, 133.4, 133.2, 131.5, 126.2, 123.9, 30.5, 20.0, 19.3, 9.6; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H28N2NaO2 375.2043; found 375.2064.


Page 30 of 51

Page 31 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N,N'-(4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diyl)diacetamide(2j4j4). The reaction was performed according to the general procedure 1A using amide 1j4. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) gave 2j4j4 (49.8 mg, 77% yield) as white solid; m.p. 95–98 oC; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 2H), 7.03 (s, 2H, br), 6.91 (s, 2H), 2.27 (s, 6H), 2.22 (s, 6H), 1.91 (s, 6H);

13

C NMR (100 MHz, CDCl3) δ 169.4, 137.5,

133.8, 133.0, 131.6, 127.2, 124.7, 24.1, 19.9, 19.3. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C20H25N2O2 325.1911; found 325.1915. N,N'-(5,5'-dichloro-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide)

(2a1a1).

The

reaction was performed according to the general procedure 1B using amide 1a1. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 2a1a1 (32.3 mg, 41% yield) as white solid; m.p. 160–163 oC; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 8.8, 2.4 Hz, 2H), 7.16 (d, J = 2.8 Hz, 2H), 7.09 (s, 2H, br), 2.30 (sept, J = 6.8 Hz, 2H), 1.03 (d, J = 7.2 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.1, 134.2, 131.1, 130.7, 130.0, 129.7, 125.6, 36.2, 19.3, 19.2; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C20H22Cl2N2NaO2 415.0951; found 415.0959. N,N'-(5,5'-dichloro-[1,1'-biphenyl]-2,2'-diyl)dipropionamide (2a2a2). The reaction was performed according to the general procedure 1B using amide 1a2. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2a2a2 (38.0 mg, 52% yield) as white solid; m.p. 203–204 oC; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 8.8, 2.8 Hz, 2H), 7.19 (d, J = 2.4 Hz, 2H), 6.87 (s, 2H, br), 2.21 – 2.14 (m, 4H), 1.04 (t, J = 7.6 Hz, 6H);

13

C NMR (100 MHz, CDCl3) δ 172.9, 134.1, 130.5 (two overlapped peaks), 130.2,



Page 32 of 51

129.9, 125.1, 30.4, 9.5. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C18H19Cl2N2O2 365.0818; found 365.0825. N,N'-(5,5'-dichloro-[1,1'-biphenyl]-2,2'-diyl)diacetamide

(2a3a3).

The

reaction

was

performed according to the general procedure 1B using amide 1a3. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) gave 2a3a3 (22.2 mg, 33% yield) as white solid; m.p. 248–249 oC; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H, br), 7.62 (m, 2H), 7.43 (dd, J = 8.8, 2.4 Hz, 2H), 7.27 (d, J = 2.8 Hz, 2H), 1.80 (s, 6H);

13

C NMR (100 MHz,

DMSO-d6) δ 168.8, 134.8, 132.9, 130.5, 128.8, 128.2, 127.1, 23.1. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C16H15Cl2N2O2 337.0505; found 337.0509. N,N'-([1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide)

(2b1b1).

The

reaction

was

performed according to the general procedure 1A in 4h using amide 1b1. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2b1b1 (31.1 mg, 48% yield) as yellow solid; m.p. 127–129 oC; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.0 Hz, 2H), 7.45 – 7.39 (m, 2H), 7.25 – 7.20 (m, 2H), 7.18 (dd, J = 7.6, 2.0 Hz , 2H), 7.03 (s, 2H, br), 2.50 – 2.11 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H), 0.98 (d, J = 6.8 Hz, 6H);

13

C NMR (100 MHz, CDCl3) δ

175.7, 135.8, 130.2, 129.5, 129.1, 125.0, 123.0, 36.4, 19.4, 19.3. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C20H25N2O2 325.1911; found 325.1915. N,N'-(5,5'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide)

(2e1e1).

The

reaction was performed according to the general procedure 1A using amide 1e1. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2e1e1 (33.2 mg, 47% yield) as yellow solid; m.p. 102–106 oC; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz,


Page 33 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 7.21 (dd, J = 8.4, 1.6 Hz, 2H), 6.99 (d, J = 1.6 Hz, 2H), 6.95 (s, 2H, br), 2.34 (s, 6H), 2.26 (sept, J = 6.8 Hz, 2H), 1.01 (d, J = 6.8 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H);

13


175.7, 134.7, 133.1, 130.6, 129.8, 129.7, 123.2, 36.3, 20.9, 19.4, 19.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H29N2O2 353.2224; found 353.2239. N,N'-(3,3'-diethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide) (2f1f1). The reaction was performed according to the general procedure 1A in 9h using amide 2f1. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) gave 2f1f1 (67.3 mg, 88% yield) as white solid; m.p. 162–163 oC; 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 2H, br), 7.26 – 7.17 (m, 4H), 6.97 (dd, J = 7.2, 2.0 Hz, 2H), 2.69 – 2.50 (m, 4H), 2.26 (sept, J = 6.8 Hz, 2H), 1.18 (t, J = 7.6 Hz, 6H), 0.92 (d, J = 6.8 Hz, 6H), 0.81 (d, J = 7.2 Hz, 6H);

13


177.3, 142.7, 139.0, 133.4, 128.2, 127.4, 127.2, 35.7, 31.1, 24.9, 19.4, 19.2, 14.7; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C24H32N2NaO2 403.2356; found 403.2355. General Procedure 2A for the Cross-Coupling Reaction. Amide 1 (0.2 mmol), Amide 2 (0.2 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol, 8 mol %), Potassium persulfate (108.1 mg, 0.4 mmol, 2.0 equiv), 2,2,2-trifluoroacetic acid (342.1 mg, 3.0 mmol, 0.15 mL), methanesulfonic acid (480.5 mg, 1.0 mmol, 0.05 mL) were added in 35 mL seal tube. The reaction mixture was stired at 25 oC for 3 h. After that, saturated NaHCO3 (10.0 mL) was added to it. The solution was extracted with CH2Cl2 (10 mL×3) and washed with brine (10 mL), and dried over Mg2SO4. Then, the extract was concentrated and the residue was purified by flash column chromatography on silica gel to give product.



General Procedure 2B for the Cross-Coupling Reaction. Amide 1 (0.1 mmol), Amide 2 (1.4 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol, 16 mol %), Potassium persulfate (35.1 mg, 0.13 mmol, 1.3 equiv), 2,2,2-trifluoroacetic acid (570.1 mg, 5.0 mmol, 0.30 mL), methanesulfonic acid (480.5 mg, 5.0 mmol, 0.25 mL) were added in 35 mL seal tube. The reaction mixture was stired at 25 oC for 8 h. After that, saturated NaHCO3 (25.0 mL) was added to it. The solution was extracted with CH2Cl2 (20 mL×3) and washed with brine (20 mL), and dried over Mg2SO4. Then, 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-dimethylpropanamide) (2dg). The reaction was performed according to the general procedure 2A using amide 1d and 1g. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (16:1, v/v) gave as 2dg (24.4 mg, 31% yield) as white solid; m.p. 125–127 oC; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 1.2 Hz, 1H), 8.20 (s, 1H), 7.19 (s, 1H, br), 7.17 (s, 1H, br), 7.10 (m, 2H), 7.06 – 7.00 (m, 2H), 2.70 (q, J = 7.6 Hz, 2H), 2.41 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H), 1.00 (s, 9H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.8, 176.8, 146.3, 139.8, 136.2, 136.1, 130.0, 129.8, 125.3, 125.0, 124.9, 124.1, 122.1, 121.0, 39.8, 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-(4-ethyl-2'-isobutyramido-4'-methyl-[1,1'-biphenyl]-2-yl)pivalamide (2d1g). The reaction was performed according to the general procedure 2A using amide 1d1 and 1g. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (12/1, v/v) gave 2d1g (34.3 mg, 45% yield) as yellow solid; m.p. 118–120 oC; 1H NMR (400 MHz, CDCl3) δ 8.23 – 8.09 (m,


Page 34 of 51

Page 35 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 7.21 (s, 1H, br), 7.10 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.01 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 6.94 (s, 1H, br), 2.70 (q, J = 7.6 Hz, 2H), 2.41 (s, 3H), 2.25 (sept, J = 7.2 Hz, 1H), 1.28 (t, J = 7.6 Hz, 3H), 1.06 – 0.95 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 177.0, 175.4, 146.1, 139.6, 136.1, 135.9, 130.1, 130.0, 125.4, 125.4, 125.0, 124.3, 122.4, 121.4, 39.8, 36.5, 29.1, 27.3, 21.7, 19.4, 19.3, 15.6; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C24H32N2NaO2 403.2356; found 403.2368. N-(4-fluoro-2'-isobutyramido-4'-methyl-[1,1'-biphenyl]-2-yl)pivalamide (2d1l). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:3; solvent = 40 equiv) in 2h using amide 1d1 and 1l. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (12/1, v/v) gave 2d1l (18.0 mg, 49% yield) as white solid; m.p. 141–143 oC; 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 11.2, 2.8 Hz, 1H), 8.13 (s, 1H), 7.30 (s, 1H, br), 7.15 (dd, J = 8.4, 6.4 Hz, 1H), 7.12 – 7.02 (m, 2H), 6.91 (td, J = 8.4, 2.8 Hz, 1H), 6.81 (s, 1H, br), 2.42 (s, 3H), 2.26 (sept, J = 7.2 Hz, 1H), 1.04 (d, J = 7.2 Hz 3H), 1.01 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.0, 175.4, 163.1 (d, JC-F = 247 Hz), 140.2, 137.8 (d, JC-F = 12 Hz), 135.8, 131.2 (d, JC-F = 9 Hz), 130.2, 125.8, 124.1, 123.2, 122.9, 111.2 (d, JC-F = 22 Hz), 108.9 (d, JC-F = 27 Hz), 39.9, 36.6, 27.2, 21.7, 19.4, 19.4;

19

F NMR (376 MHz, CDCl3) δ -110.2. HRMS (ESI-Q/TOF

MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H28FN2O2 371.2129; found 371.2137. N-(2'-isobutyramido-4'-methyl-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)pivalamide(2d1u). The reaction was conducted on 0.05 mmol scale (8.9 mg of 1d1; Ar:Ar' = 1:30; solvent = 200 equiv) according to general procedure 2B in 8h. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2d1u (12.2 mg, 58% yield) as white



Page 36 of 51

solid; m.p. 120–122 oC; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.01 (s, 1H), 7.51 – 7.37 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.79 (s, 1H, br), 2.42 (s, 3H), 2.26 (sept, J = 6.8 Hz, 1H), 1.04 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.3, 175.7, 140.5, 136.9, 135.3, 132.1, 131.7 (q, JC-F = 33 Hz), 130.7, 129.7, 126.3, 125.0, 124.0, 123.9 (q, JC-F = 273 Hz), 121.1 (q, JC-F = 4 Hz), 119.0 (q, JC-F = 4 Hz), 39.9, 36.4, 27.2, 21.7, 19.4, 19.3;

19

F NMR (376 MHz, CDCl3) δ -62.7. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z):

[M+H]+ calcd for C23H28F3N2O2 421.2097; found 421.2104. N-(5-chloro-2'-isobutyramido-4'-methyl-[1,1'-biphenyl]-2-yl)pivalamide

(2d1a).

The

reaction was performed according to the general procedure 2B using amide 1d1 and 1a. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2d1a (23.2 mg , 60% yield) as yellow solid; m.p. 58–60 oC; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.39 (dd, J = 8.8, 2.4 Hz, 1H), 7.25 (s, 1H, br), 7.19 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 0.4 Hz, 2H), 6.84 (s, 1H, br), 2.41 (s, 3H), 2.28 (sept, J = 6.8 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H), 1.02 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1, 175.6, 140.3, 135.4, 134.9, 130.4, 130.1, 129.8, 129.6, 129.4, 126.1, 124.7, 123.6, 123.5, 39.8, 36.5, 27.3, 21.7, 19.4, 19.4; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H27ClN2NaO2 409.1653; found 409.1658. N-(5-bromo-2'-isobutyramido-4'-methyl-[1,1'-biphenyl]-2-yl)pivalamide

(2d1q).

The

reaction was performed according to the general procedure 2B using amide 1d1 and 1q. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (40/5/1, v/v) gave 2d1q (26.7 mg , 62% yield) as white solid; m.p. 59–62 oC; 1H NMR (400


Page 37 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.51 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.27 (s, 1H, br), 7.06 (s, 2H), 6.88 (s, 1H, br), 2.40 (s, 3H), 2.28 (sept, J = 6.8 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H), 1.01 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H);

13

C NMR (100 MHz, CDCl3) δ 177.1,

175.6, 140.3, 135.4, 135.3, 132.9, 132.2, 130.8, 129.8, 126.1, 124.8, 123.8, 123.7, 117.2, 39.8, 36.4, 27.2, 21.7, 19.4, 19.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H27BrN2NaO2 453.1148; found 453.1169. N-(5'-chloro-4-methyl-2'-pivalamido-[1,1'-biphenyl]-2-yl)benzamide (2d5a). The reaction was performed according to the general procedure 2B using amide 1d5 and 1a. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (40/5/1, v/v) gave 2d5a (23.0 mg, 55% yield) as white solid; m.p. 64–67 oC; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H, br), 7.57 – 7.51 (m, 2H), 7.51 – 7.44 (m, 1H), 7.43 – 7.36 (m, 3H), 7.34 (s, 1H, br), 7.25 (s, 1H), 7.14 – 7.11 (m, 1H), 7.10 (dd, J = 8.0, 1.2 Hz, 1H), 2.46 (s, 3H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.1, 165.7, 140.5, 135.5, 134.8, 134.3, 132.2, 130.3, 130.1, 130.0, 129.8, 129.6, 129.0, 126.9, 126.1, 124.4, 123.4, 122.9, 39.8, 27.3, 21.8; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C25H25ClN2NaO2 443.1497; found 443.1508. N-(5'-bromo-4-methyl-2'-pivalamido-[1,1'-biphenyl]-2-yl)benzamide (2d5q). The reaction was performed according to the general procedure 2B using amide 1d5 and 1q. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (40/5/1, v/v) gave 2d5r (24.7 mg, 53% yield) as white solid; m.p. 74–77 oC; 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H, br), 7.59 – 7.52 (m, 3H), 7.51 – 7.46 (m, 1H), 7.44



Page 38 of 51

– 7.36 (m, 3H), 7.34 (s, 1H, br), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.0, 1.2 Hz, 1H), 2.47 (s, 3H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.1, 165.7, 140.6, 135.5, 135.4, 134.4, 133.1, 132.5, 132.2, 130.2, 130.1, 129.0, 127.0, 126.1, 124.1, 123.6, 122.8, 117.3, 39.9, 27.3, 21.8; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C25H25BrN2NaO2 487.0992; found 487.0999. N,N'-(4-fluoro-4'-methoxy-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide)

(2wl).

The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:14; 60 equiv solvent; 1.5 equiv K2S2O8) in 12h using amide 1w and 1l. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (20/5/1, v/v) gave 2wl (25.6 mg, 64% yield) as white solid; m.p. 136–139 oC; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 11.2, 2.8 Hz, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.29 (s, 1H, br), 7.20 – 7.15 (m, 1H), 7.13 (s, 1H, br), 7.09 (d, J = 8.4 Hz, 1H), 6.96 – 6.86 (m, 1H), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 3.88 (s, 3H), 1.02 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 176.9, 176.8, 163.2 (d, JC-F = 247 Hz), 160.8, 138.1 (d, JC-F = 12 Hz), 137.4, 131.5 (d, JC-F = 9 Hz), 131.0, 122.4, 118.1, 111.5, 111.2 (d, JC-F = 22 Hz), 108.5 (d, JC-F = 28 Hz), 106.0, 55.7, 40.0 (two overlapped peaks), 27.3, 27.3; 19F NMR (376 MHz, CDCl3) δ -109.8; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C23H29FN2NaO3 423.2054; found 423.2062. N,N'-(4-chloro-4'-methoxy-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2wm). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:12; 50 equiv solvent; 1.5 equiv K2S2O8) in 12h using amide 1w and 1m. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (40/5/1, v/v) gave


Page 39 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2wm (23.8 mg, 57% yield) as white solid; m.p. 105–107 oC; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.26 (s, 1H, br), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 – 7.10 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 8.4, 2.8 Hz, 1H), 3.87 (s, 3H), 1.03 (s, 9H), 1.02 (s, 9H);

13

C NMR (100 MHz, CDCl3) δ 176.9, 176.8, 160.9, 137.6, 137.2, 135.4, 131.4, 130.8, 125.4,

124.5, 121.2, 118.1, 111.6, 106.2, 55.7, 40.0, 40.0, 27.3, 27.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C23H29ClN2NaO3 439.1759; found 439.1765. N,N'-(4-bromo-4'-methoxy-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2wn). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:12; 50 equiv solvent; 1.5 equiv K2S2O8) in 12h using amide 1w and 1n. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (10/5/1, v/v) gave 2wn (24.0 mg, 52% yield) as yellow solid; m.p. 101–104 oC; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.25 (s, 1H, br), 7.12 (s, 1H, br), 7.07 (m, 2H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 (s, 3H) , 1.03 (s, 9H) , 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.9, 176.8, 160.9, 137.7, 137.2, 131.6, 130.7, 127.5, 126.0, 124.1, 123.4, 118.3, 111.6, 106.3, 55.7, 40.0, 40.0, 27.3, 27.3; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C23H29BrN2NaO3 483.1254; found 483.1251. N-(4-chloro-2'-isobutyramido-4'-methoxy-[1,1'-biphenyl]-2-yl)pivalamide

(2w1m).

The

reaction was performed according to the general procedure 2B (Ar:Ar' = 1:12; 50 equiv solvent; 1.5 equiv K2S2O8) in 12h using amide 1w1 and 1m. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (20/5/1, v/v) gave 2w1m (22.5 mg, 56% yield) as white solid; m.p. 124–126 oC; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.0 Hz, 1H), 8.03



Page 40 of 51

(d, J = 2.8 Hz, 1H), 7.27 (s, 1H, br), 7.19 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H, br), 6.78 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 (s, 3H), 2.27 (sept, J = 6.8 Hz, 1H), 1.03 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 177.0, 175.5, 160.8, 137.5, 137.1, 135.4, 131.5, 130.9, 125.7, 124.7, 121.6, 118.2, 111.6, 106.6, 55.7, 39.9, 36.7, 27.3, 19.4, 19.4; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C22H27ClN2NaO3 425.1602; found 425.1610. N-(4-bromo-2'-isobutyramido-4'-methoxy-[1,1'-biphenyl]-2-yl)pivalamide

(2w1n).

The

reaction was performed according to the general procedure 2B (Ar:Ar' = 1:12; 50 equiv solvent; 1.5 equiv K2S2O8) in 12h using amide 1w1 and 1n. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (20/5/1, v/v) gave 2w1n (25.0 mg, 56% yield) as white solid; m.p. 128–131 oC; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 7.26 (s, 1H, br), 7.06 (d, J = 8.4 Hz, 2H), 6.87 (s, 1H, br), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 3.86 (s, 3H), 2.27 (sept, J = 6.8 Hz, 1H), 1.14 – 0.95 (m, 15H); 13

C NMR (100 MHz, CDCl3) δ 177.0, 175.5, 160.8, 137.6, 137.0, 131.7, 130.8, 127.6, 126.4, 124.5,

123.4, 118.4, 111.6, 106.7, 55.7, 39.9, 36.6, 27.3, 19.4, 19.4; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C22H28BrN2O3 447.1278; found 447.1308. N,N'-(5'-fluoro-4,6-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2vp). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:4; 40 equiv solvent; 1.1 equiv K2S2O8) in 6h using amide 1v and 1p. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (20/5/1, v/v) gave 2vp (27.9 mg, 70% yield) as white solid; m.p. 170–172 oC; 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 9.2, 5.6 Hz, 1H),


Page 41 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.77 (s, 1H), 7.21 (s, 1H, br), 7.14 – 7.08 (m, 1H), 7.04 (s, 1H, br), 6.96 (s, 1H), 6.84 (dd, J = 8.4, 2.8 Hz, 1H), 2.36 (s, 3H), 1.97 (s, 3H), 0.98 (s, 9H), 0.96 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 177.3, 177.0, 159.5 (d, JC-F = 246 Hz), 139.6, 137.0, 135.7, 132.6, 130.0 (d, JC-F = 8 Hz), 127.7, 125.2, 124.4 (d, JC-F = 8 Hz), 121.5, 116.5 (d, JC-F = 22 Hz), 115.8 (d, JC-F = 22 Hz), 39.6, 39.5, 27.2 (two overlapped peaks), 21.5, 20.0;

19

F NMR (376 MHz, CDCl3) δ -117.1; HRMS (ESI-Q/TOF MS)

with Acetonitrile (m/z): [M+H]+ calcd for C24H32FN2O2, 399.2442; found 399.2448. N,N'-(5'-chloro-4,6-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2,2-dimethylpropanamide) (2va). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:3; 40 equiv solvent; 1.1 equiv K2S2O8) in 6h using amide 1v and 1a. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (20/5/1, v/v) gave 2va (29.4 mg, 71% yield) as white solid; m.p. 187–190 oC; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.38 (dd, J = 8.8, 2.8 Hz, 1H), 7.25 (s, 1H, br), 7.11 (d, J = 2.4 Hz, 1H), 6.99 (s, 1H, br), 6.96 (s, 1H), 2.36 (s, 3H), 1.98 (s, 3H), 0.98 (s, 9H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.2, 176.9, 139.8, 137.1, 135.7, 135.2, 129.6 (two overlapped peaks), 129.2, 129.2, 127.7, 124.7, 123.3, 121.4, 39.7, 39.6, 27.2, 27.2, 21.6, 20.0; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H32ClN2O2 415.2147; found 415.2157. Ethyl 2',4'-dimethyl-6,6'-dipivalamido-[1,1'-biphenyl]-3-carboxylate (2vs). The reaction was performed according to the general procedure 2B (nAr = 0.2 mmol; 20 equiv solvent; MsOH:TFA=1:1; 1.1 equiv K2S2O8) in 6h using amide 1v and 1s. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 3wu (60.0 mg. 66% yield) as white solid; m.p. 116–118 oC; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.8 Hz, 1H), 8.11



Page 42 of 51

(dd, J = 8.8, 2.0 Hz, 1H), 7.88 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.42 (s, 1H, br), 7.01 – 6.96 (m, 1H), 6.92 (s, 1H, br), 4.42 – 4.30 (m, 2H), 2.38 (s, 3H), 1.98 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.00 (s, 9H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.0, 166.0, 140.7, 139.9, 137.3, 135.9, 131.4, 131.2, 127.6, 126.2, 126.1, 124.1, 121.1, 120.4, 61.2, 40.0, 39.6, 27.2, 27.2, 21.6, 20.1, 14.5; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C27H36N2NaO4 475.2567; found 475.2571. N-(5-fluoro-2'-isobutyramido-4',6'-dimethyl-[1,1'-biphenyl]-2-yl)pivalamide

(2v1p). The

reaction was performed according to the general procedure 2B (Ar:Ar' = 1:4; 40 equiv solvent; 1.1 equiv K2S2O8) in 6h using amide 1v1 and 1p. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2v1p (25.0 mg, 65% yield) as white solid; m.p. 164–166 oC; 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.10 (m, 1H), 7.72 (s, 1H), 7.24 (s, 1H, br), 7.15 – 7.08 (m, 1H), 6.97 (s, 1H), 6.86 – 6.81 (m, 2H), 2.36 (s, 3H), 2.23 (sept, 6.8 Hz, 1H), 1.96 (s, 3H), 0.98 (m, 12H), 0.91 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.2, 175.9, 159.6 (d, JC-F = 246 Hz), 139.6, 137.1, 135.5, 132.6, 130.4 (d, JC-F = 8 Hz), 127.9, 125.8, 124.8 (d, JC-F = 8 Hz), 122.0, 116.6 (d, JC-F = 22 Hz), 115.8 (d, JC-F = 22 Hz), 39.6, 36.3, 27.2, 21.5, 20.0, 19.4, 19.2

19

F

NMR (376 MHz, CDCl3) δ -117.1; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C23H29FN2NaO2 407.2105; found 407.2115. N-(5-chloro-2'-isobutyramido-4',6'-dimethyl-[1,1'-biphenyl]-2-yl)pivalamide

(2v1a). The

reaction was performed according to the general procedure 2B (Ar:Ar' = 1:3; 40 equiv solvent; 1.1 equiv K2S2O8) in 6h using amide 1v1 and 1a. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 2v1a (27 mg, 67% yield) as white solid; m.p.


Page 43 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


155–157 oC; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 (s, 1H, br), 7.10 (d, J = 2.4 Hz, 1H), 6.97 (s, 1H), 6.74 (s, 1H, br), 2.37 (s, 3H), 2.23 (sept, J = 6.8 Hz, 1H), 1.97 (s, 3H), 1.02 – 0.95 (m, 12H), 0.92 (d, J = 6.8 Hz, 3H);

13

C NMR (100

MHz, CDCl3) δ 177.0, 175.8, 139.7, 137.2, 135.5, 135.2, 129.7 (two overlapped peaks), 129.4, 129.3, 127.9, 125.1, 123.6, 121.9, 39.7, 36.3, 27.2, 21.6, 20.1, 19.4, 19.2; HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+Na]+ calcd for C23H29ClN2NaO2 423.1810; found 423.1821. N-(2'-isobutyramido-4,4',6-trimethyl-[1,1'-biphenyl]-2-yl)pivalamide (2vd1). The reaction was performed according to the general procedure 2B (Ar:Ar' = 9:1; 40 equiv solvent; 1.1 equiv K2S2O8) in 12h using amide 1v and 1d1. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (12/1, v/v) gave 2vd1 (26.7 mg, 70% yield) as white solid; m.p. 169– 171 oC; 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.96 (s, 1H), 7.09 (s, 1H, br), 7.04 (dd, J = 7.6, 0.8 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.86 (s, 1H, br), 2.41 (s, 3H), 2.37 (s, 3H), 2.22 (sept, J = 6.8 Hz, 1H), 1.97 (s, 3H) , 1.00 (d, J = 6.8 Hz, 3H) , 0.98 (d, J = 6.8 Hz, 3H), 0.96 (s, 9H); 13

C NMR (100 MHz, CDCl3) δ 177.0, 175.4, 139.6, 139.3, 137.4, 136.3, 136.1, 129.8, 127.1, 125.6,

124.6, 123.5, 122.5, 120.1, 39.7, 36.6, 27.3, 21.7, 21.6, 20.2, 19.4, 19.3. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H33N2O2 381.2537; found 381.2538. N-(2'-isobutyramido-4',6'-dimethyl-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)pivalamide (2v1u). The reaction was performed according to the general procedure 2B (Ar:Ar' = 1:4; 40 equiv solvent; 1.1 equiv K2S2O8) using amide 1v1 and 1u. Purification by flash column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (10/5/1, v/v) gave 2v1u (31.7 mg, 73% yield) as white solid; m.p. 191–192 oC; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.74 (s, 1H),



Page 44 of 51

7.46 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (s, 1H, br), 7.22 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.70 (s, 1H, br), 2.38 (s, 3H), 2.20 (sept, J = 6.8 Hz, 1H), 1.94 (s, 3H), 1.02 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.2, 175.8, 139.9, 137.2, 137.1, 135.4, 131.6 (q, JC-F = 33 Hz), 131.2 (d, JC-F = 1 Hz), 130.5, 128.1, 125.3, 123.9 (q, JC-F = 273 Hz), 122.2, 121.2 (q, JC-F = 4 Hz), 119.1 (q, JC-F = 4 Hz), 39.8, 36.3, 27.2, 21.5, 20.0, 19.3, 19.2;

19

F NMR (376 MHz,

CDCl3) δ -62.7. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C24H30F3N2O2 435.2254; found 435.2251. General Procedure 4A for the Hydrolysis of 2,2'-bisanilides.42 2,2'-Bisanilides (0.1 mmol) and hydrochloric acid (12 mol/L, 0.8 mL) were added in 35 mL seal tube in N2. The reaction mixture was stired at 125 oC for 1 day. After that, sodium hydroxide (6 mol/L) was added to it and the pH adjusted to 9. The solution was extracted with EtOAc (15 mL×2) and washed with brine (10 mL), and dried over anhydrous Na2SO4. Then, the extract was concentrated to give product. General Procedure 4B for the Hydrolysis of 2,2'-bisanilides.43 2,2'-Bisanilides (0.1 mmol) and sulfuric acid (10 mol/L, 0.84 mL) were added in 35 mL seal tube in N2. The reaction mixture was stired at 125 oC for 2 days. After that, sodium hydroxide (6 mol/L) was added to it and the pH adjusted to 9. The solution was extracted with EtOAc (15 mL×2) and washed with brine (10 mL), and dried over anhydrous Na2SO4. Then, the extract was concentrated to give product. 3,3'-dimethyl-[1,1'-biphenyl]-2,2'-diamine (3cc). The reaction was performed according to the general procedure 4B in 4 days using 2cc. brown solid (19.5 mg, 92% yield); m.p. 144–146 oC; 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J = 7.6, 0.8 Hz, 2H), 7.01 (dd, J = 7.6, 1.2 Hz, 2H), 6.78 (t, J = 7.6 Hz, 2H), 3.56 (s, 4H, br), 2.24 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 142.5, 130.0, 128.8, 124.5,


Page 45 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


122.6, 118.4, 18.0. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C14H17N2 213.1386; found 213.1392. 4,4'-dimethyl-[1,1'-biphenyl]-2,2'-diamine (3dd). The reaction was performed according to the general procedure 4A in 1 day using 2dd. brown solid (20.0 mg, 94% yield); m.p. 118–120 oC; 1

H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 7.6 Hz, 2H), 6.66 (d, J = 7.6 Hz, 2H), 6.62 (s, 2H), 3.65 (s,

4H, br), 2.32 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 144.2, 138.6, 131.1, 121.9, 119.8, 116.3, 21.4. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C14H17N2 213.1386; found 213.1392. 4,4',5,5'-tetramethyl-[1,1'-biphenyl]-2,2'-diamine

(3jj).

The

reaction

was

performed

according to the general procedure 4A in 1 day using 2jj. brown oil (22.4 mg, 93% yield); 1H NMR (400 MHz, CDCl3) δ 6.90 (s, 2H), 6.61 (s, 2H), 3.36 (s, 4H, br), 2.23 (s, 6H), 2.19 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 141.9, 136.9, 132.2, 126.9, 122.6, 117.3, 19.7, 18.8. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C16H21N2 241.1699; found 241.1708. 4,4'-dichloro-[1,1'-biphenyl]-2,2'-diamine (3mm). The reaction was performed according to the general procedure 4B in 2 days using 2mm. brown oil (24.9 mg, 98% yield); 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 8.0 Hz, 2H), 6.88 – 6.69 (m, 4H), 3.77 (s, 4H, br); 13C NMR (100 MHz, CDCl3) δ 145.4, 134.7, 132.2, 121.7, 118.9, 115.4. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C12H11Cl2N2 253.0294; found 253.0301. 5'-chloro-4-methyl-[1,1'-biphenyl]-2,2'-diamine

(3d1a).

The

reaction

was

performed

according to the general procedure 4B in 2 days using 2d1a. brown oil (21.4 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.07 (m, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H),



6.66 (dd, J = 7.6, 0.8 Hz, 1H), 6.61 (s, 1H), 3.43 (s, 4H, br), 2.31 (s, 3H);

Page 46 of 51

13

C NMR (100 MHz,

CDCl3) δ 143.9, 143.0, 139.3, 130.9 (two overlapped peaks), 128.5, 126.2, 123.2, 120.7, 120.0, 116.7, 116.5, 21.4. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z): [M+H]+ calcd for C13H14ClN2 233.0840; found 233.0846. 4,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-2,2'-diamine (3v1u). The reaction was performed according to the general procedure 4B in 30h using 2v1u. brown solid (26.0 mg, 93% yield); m.p. 79–81 oC; 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0, 0.8 Hz, 1H), 7.02 (s, 1H), 6.57 (s, 1H), 6.49 (s, 1H), 3.71 (s, 4H, br), 2.28 (s, 3H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.0, 144.3, 139.0, 137.8, 131.7, 131.1 (q, JC-F = 32.0 Hz), 126.3 (d, JC-F = 1 Hz), 124.4 (q, JC-F = 272 Hz), 121.5, 119.5, 115.3 (q, JC-F = 4 Hz), 113.9, 111.8 (q, JC-F = 4 Hz), 21.4, 20.0;

19

F NMR (376 MHz, CDCl3) δ -62.7. HRMS (ESI-Q/TOF MS) with Acetonitrile (m/z):

[M+H]+ calcd for C15H16F3N2 281.1260; found 281.1266.

ASSOCIATED CONTENT Supporting Information The supporting Information is available free of charge on the ACS Publications website at DOI: Supplementary details, 1H and 13C NMR spectra of all of the new compounds (PDF)

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]


Page 47 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank the National Natural Science Foundation of China (Grant No. 21372153) for financial support.

REFERENCES (1) (a) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713. (b) Guizzetti, S.; Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247. (c) Zhao, H. W.; Yue, Y. Y.; Li, H. L.; Song, X. Q.; Sheng, Z. H.; Yang, Z.; Meng, W.; Yang, Z. Synlett 2013, 24, 2160. (2) (a) Zhang, F. Y.; Pai, C. C.; Chan, A. S. C. J. Am. Chem. Soc. 1998, 120, 5808. (b) Wang, Y. M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 12972. (c) Nakatsuka, H.; Yamamura, T.; Shuto, Y.; Tanaka, S.; Yoshimura, M.; Kitamura, M. J. Am. Chem. Soc. 2015, 137, 8138. (d) Mikami, K.; Aikawa, K.; Yusa, Y. Org. Lett. 2002, 4, 95. (e) Scarborough, C. C.; McDonald, R. I.; Hartmann, C.; Sazama, G. T.; Bergant, A.; Stahl, S. S. J. Org. Chem. 2009, 74, 2613. (f) Aikawa, K.; Mikami, K. Chem. Commun. 2005, 46, 5799. (g) Liu, L. J.; Wang, F.; Wang, W.; Zhao, M. X.; Shi, M. Beilstein J. Org. Chem. 2011, 7, 555. (3) (a) Mazzanti, A.; Chiarucci, M.; Prati, L.; Bentley, K. W.; Wolf, C. J. Org. Chem. 2016, 81, 89. (b) Jung, K.; Kim, H.; Lee, G. H.; Kang, D.; Park, J.; Kim, K. M.; Chang, Y.; Kim, T. J. Med. Chem. 2011, 54, 5385. (c) Jung, K.; Kim, H.; Park, J.; Nam, K. S.; Lee, G. H.; Chang, Y.; Kim, T. ACS Med.



Chem. Lett. 2012, 3, 1003. (d) Toyama, H.; Nakamura, M.; Hashimoto, Y.; Fujii, S. Bioorganic Med. Chem. 2015, 23, 2982. (4) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312. (c) Zhao, H.; Mao, G.; Han, H.; Song, J.; Liu, Y.; Chu, W.; Sun, Z. RSC Adv. 2016, 6, 41108. (5) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) González, R. R.; Liguori, L.; Carrillo, A. M.; Bjørsvik, H.-R. J. Org. Chem. 2005, 70, 9591. (c) Slevin, A.; Koolmeister, T.; Scobie, M. Chem. Commun. 2007, 24, 2506. (6) (a) Smrčina, M.; Lorenc, M.; Hanuš, V.; Sedmers, P.; Kočovský, P. J. Org. Chem. 1992, 57, 1917. (b) Moreno, I.; Tellitu, I.; Etayo, J.; SanMartín, R.; Domínguez, E. Tetrahedron 2001, 57, 5403. (7) Smrčina, M.; Vyskočil, Š.; Máca, B.; Polášek, M.; Claxton, T. A.; Abbott, A. P.; Kočovsky, P. J. Org. Chem. 1994, 59, 2156. (8) Schulz, L.; Enders, M.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2017, 56, 4877. (9) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (d) Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787. (e) Lu, W.; Zhou, L. Oxidation of C−H Bonds; John Wiley & Sons, Inc.: Hoboken, NJ, 2017. (10) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047. (11) (a) Lyons, T. W.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 4455. (b) Higgs, A. T.; Zinn, P. J.; Sanford, M. S. Organometallics 2010, 29, 5446. (c) Ye, Y.; Ball, N. D.; Kampf, J. W.;


Page 48 of 51

Page 49 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 14682. (12) (a) Pintori, D. G.; Greaney, M. F. Org. Lett. 2011, 13, 4553. (b) Oi, S.; Funayama, R.; Hattori, T.; Inoue, Y. Org. Lett. 2008, 64, 2006. (c) Gong, H.; Zeng, H.; Zhou, F.; Li, C.-J. Angew. Chem., Int. Ed. 2015, 54, 5718. (d) Grigorjeva, L.; Daugulis, O. Org. Lett. 2015, 17, 1204. (e) Zhang, C.; Rao, Y. Org. Lett. 2015, 17, 4456. (f) Guo, Y.; Yu, K.-K.; Xing, L.-H.; Liu, H.-W.; Wang, W.; Ji, Y.-F. Adv. Synth. Catal. 2017, 359, 410. (13) (a) Brasche, G.; García-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. (b) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1, 331. (c) Xu, H.; Shang, M.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2015, 17, 3830. (d) Jiang, T.-S.; Wang, G.-W. J. Org. Chem. 2012, 77, 9504. (14) Fujimoto, S.; Matsumoto, K.; Iwata, T.; Shindo, M. Tetrahedron Lett. 2017, 58, 973. (15) (a) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973. (b) Rong, Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376. (c) Zhou, L.; Lu, W. Organometallics 2012, 31, 2124. (16) (a) Zhou, L.; Lu, W. Org. Lett. 2014, 16, 508. (b) Zhao, R.; Lu, W. Org. Lett. 2017, 19, 1768. (17) Good, N. E. Plant Physiol. 1961, 36, 788. (18) Shi, F.; Li, J.; Li, C.; Jia, X. Tetrahedron Lett. 2010, 51, 6049. (19) Hellwinkel, D.; Lämmerzahl, F.; Hofmann, G. Chem. Ber. 1983, 116, 3375. (20) Zhao, Q.; Besset, T.; Poisson, T.; Bouillon, J. P.; Pannecoucke, X. European J. Org. Chem. 2016, 2016, 76. (21) Degnan, W. M.; Shoemaker, C. J. J. Am. Chem. Soc. 1946, 68, 104. (22) Baldwin J.; Swanson A.; Cha J.; Murphy J. Tetrahedron. 1986, 42, 3943. (23) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler, L. T.;



Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; Erickson-Viitanen, S. K. J. Med. Chem. 2000, 43, 2019. (24) Guilarte, V.; Castroviejo, M. P.; García-García, P.; Fernández-Rodríguez, M. A.; Sanz, R. J. Org. Chem. 2011, 76, 3416. (25) Phipps, R. J.; Gaunt, M. J. Science. 2009, 323, 1593. (26) Kyba, E. P.; Liu, S.; Chockalingam, K.; Reddy, B. R. J. Org. Chem. 1988, 35, 3513. (27) Sasaki, K.; Crich, D. Org. Lett. 2011, 13, 2256. (28) El-Zahraa, F.; El-Basil, S.; El-Sayed, M.; Ghoneim, K. M.; Khalifa, M. Die Pharmazie. 1979, 34, 12. (29) Zhu, Y.; Sergeyev, S.; Franck, P.; Orru, R. V. A.; Maes, B. U. W. Org. Lett. 2016, 18, 4602. (30) Soll, R. M.; Guinosso, C.; Asselin, A. J. Org. Chem. 1988, 53, 2844. (31) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272. (32) Ghaffarzadeh, M.; Akhavan, P. Chem. Lett. 2014, 43, 1417. (33) De Feo, R. J.; Strickler, P. D. J. Org. Chem 1963, 28, 2915. (34) Liu, L.-F.; Liu, H.; Pi, H.-J.; Yang, S.; Yao, M.; Du, W.; Deng, W.-P. Synth. Commun. 2011, 41, 553. (35) P. Metz, C. Mues. Tetrahedron, 1988, 44, 6841. (36) Joshi, B. P.; Hosangadi, B. D. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry. 1978, 16, 1067. (37) Meth-Cohn, O.; Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc. Perkin Trans. 1 1981, 1537.


Page 50 of 51

Page 51 of 51 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(38) Lee, Y. M.; Moon, M. E.; Vajpayee, V.; Filimonov, V. D.; Chi, K. W. Tetrahedron. 2010, 66, 7418. (39) Fan, W.; Yang, Y.; Lei, J.; Jiang, Q.; Zhou, W. J. Org. Chem. 2015, 80, 8782. (40) Shilpa; Gowda, B. T. Zeitschrift für Naturforschung, A Phys. Sci. 2007, 62, 84. (41) Warner, P. L.; Bardos, T. J. J. Med. Chem. 1970, 13, 407. (42) (a) Tian, T.; Zhong, W. H.; Meng, S.; Meng, X. B.; Li, Z. J. J. Org. Chem. 2013, 78, 728. (b) Park, J.; Lee, J.; Chang, S. Angew. Chem., Int. Ed. 2017, 56, 4256. (43) (a) Stokes, B. J.; Vogel, C. V; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884. (b) Tapolcsányi, P.; Krajsovszky, G.; Andó, R.; Lipcsey, P.; Horváth, G.; Mátyus, P.; Riedl, Z.; Hajós, G.; Maes, B. U. W.; Lemière, G. L. F. Tetrahedron 2002, 58, 10137.


Palladium(II)-Catalyzed Oxidative Homo- and Cross-Coupling of Aryl

Recommend Documents