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Multicomponent Synthesis of Diverse o-Arylated Benzamides via o-Aminophenol (OAP) Directed C(sp2)-H Arylation Yunyun Liu, Yi Zhang, and Jie-Ping Wan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01375 • Publication Date (Web): 02 Aug 2017 Downloaded from http://pubs.acs.org on August 2, 2017

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The Journal of Organic Chemistry

Multicomponent Synthesis of Diverse o-Arylated Benzamides via o-Aminophenol (OAP) Directed C(sp2)-H Arylation Yunyun Liu,* Yi Zhang and Jie-Ping Wan* College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China Email: [email protected]; [email protected]

ABSTRACT. o-Aminophenol (OAP) has been discovered as practical precursor of directing group (DG) in the palladium-catalyzed aromatic C-H arylation of benzamides. This newly identified, simple and low cost DG has exhibited broad substrate tolerance in the rapid synthesis of various o-arylated benzamides via direct assemblies of benzoyl chlorides, aryl iodides and different o-aminophenols in the form of step economical multicomponent reaction.

INTRODUCTION The C-H activation is inarguably one most powerful tool in modern organic synthesis which plays crucial role in the areas of natural product

ACS Paragon Plus Environment


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synthesis,1 drug discovery2 and material synthesis.3 Among the currently known tactics enabling the C-H bond activation and functionalization, the directed C-H activation wherein a DG is employed to assist the transformation of latent C-H bond is regarded as the most widely applicable and reliable protocol, since

the presence of a proper DG is capable of inducing the

reaction selectivity and facilitating the bond transformation by stabilizing the reaction intermediate.4 The past decade has witnessed spectacular progress in the research of directed C-H activation reactions, and unprecedented sophistication in the types, functions as well as innovative concepts around the DG-based synthesis have been disclosed. Currently, a massive number of different DGs, including the monodentate DG,5 bidentate DG,6 and many other effective DGs7 are available for assisting the activation of C-H bonds of different types. In despite the notable advances in the DG-assisted C-H activation, challenges also exist and remain yet to address. One of the major problems is the rare availability of practical DG precursors with satisfactory stability and low cost. The even more serious challenge is that most of the known directed C-H activation reactions suffers from the cumbersome operations in installing the DG to substrates and/or removing the DG from products. Therefore, tremendous efforts have been made in recent years to overcome the problems of the low atom economy resulting from the lengthy operation. Gratifyingly, a variety of effective strategies and concepts, including traceless DG,4c,8


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deciduous DG,9 transient/catalytic DG10 and in situ DG generation11 etc have been conceived and accomplished to guide more efficient directed C-H activation reactions. However, considering the high cost, hard substructure variation or limited application scope in the type of C-H bond transformation, developing new bidentate DG which address one or more of these restrictions is still highly desirable to complement the chemistry of directed C-H activation. During our efforts in developing step-efficient C-H activation reactions, we have reported in 2015 the 8-aminoquinoline (AQ) directed benzamide Ar-H arylation reactions by the in situ DG installation, which represents the first example free-of prior DG installation in AQ directed C-H activation reactions.12 Under the inspiration of this work, the γ-C-H arylation of phenylacetamides,13 the β-C(sp3)-H arylation of alkyl amides14 and the o-sulfenylation of the Ar-H bond(s) in bemzamides15 have been consequently realized. While the general applicability of such tandem reaction-based C-H arylation has been gradually validated, the high cost and limited variability of the AQ remain as issues requiring further improvement.16 Based on our sustaining efforts in devising facile and practical C-H activation reactions, we report herein the first example of the OAP directed ortho-arylation of the Ar-H bond(s) in the in situ generated benzamides via three-component reactions of o-aminophenols, benzoyl chlorides and aryl iodides. The o-aminophenols act as the DG precursors in the reactions which display advantages not only in the quite easy availability and low cost, but also in the direct utility without any prior elaboration as well as



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the easy variation in substructure for the synthesis of products containing diverse OAP fragments. RESULTS AND DISCUSSION To begin the work, the reaction of OAP (1a), benzoyl chloride (2a) and p-methoxy iodobenzene (3a) was tentatively run in the presence of Pd(OAc)2 and K2CO3 in heating toluene, from which fair yield of the C-H arylated product 4a was successfully observed with different catalyst loading (entries 1-3, Table 1). Subsequent efforts in employing different palladium reagents did not lead to the improvement in the yield of 4a (entries 4-7, Table 1). Altering the base additive of different properties gave no better result, either (entries 8-12, Table 1). Notably, increasing the amount of K2CO3 from 2 equiv. to 4 equiv. enabled the production of 4a with evidently higher yield (entries 13-15, Table 1), which could be ascribed to the extra base consumption in promoting the in situ amidation between 1a and 2a. Interestingly, further investigation in screening the reaction medium using solvents such as p-xylene, dioxane, DCM, DMSO and MeCN proved that MeCN was a good medium for the C-H activation reaction by affording 4a with even enhanced yield (entries 16-20, Table 1). Table 1 Optimization on the OAP directed Ar-H arylationa I O

OH

Pd cat., base

Cl NH2 1a

2a

Entry Catalyst

solvent, T OMe 3a

Base

MeO

O

OAP

OMe

4a

Solvent


Yieldb (%)

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1

Pd(OAc)2

K2CO3

toluene

37

2c

Pd(OAc)2

K2CO3

toluene

35

3d

Pd(OAc)2

K2CO3

toluene

22

4

PdCl2

K2CO3

toluene

32

5

Pd(Ph3P)4

K2CO3

toluene

36

6

Pd/C

K2CO3

toluene

trace

7

PdCl2(Ph3P)2 K2CO3

toluene

34

8

Pd(OAc)2

Cs2CO3

toluene

21

9

Pd(OAc)2

NaHCO3 toluene

trace

10

Pd(OAc)2

t-BuOK

toluene

20

11

Pd(OAc)2

NaOH

toluene

trace

12

Pd(OAc)2

DBU

toluene

trace

13e

Pd(OAc)2

K2CO3

toluene

51

14f

Pd(OAc)2

K2CO3

toluene

66

15g

Pd(OAc)2

K2CO3

toluene

65

16f

Pd(OAc)2

K2CO3

p-xylene

24

17f

Pd(OAc)2

K2CO3

1,4-dioxane 30

18f

Pd(OAc)2

K2CO3

CH3CN

87

19f

Pd(OAc)2

K2CO3

DCM

trace

20f

Pd(OAc)2

K2CO3

DMSO

trace

a

General conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3a (0.9 mmol), catalyst (5 mol%), base (0.6 mmol), solvent (2 mL), stirred at 110 oC or reflux (heating at 90 oC) for 12 h. bIsolated yield. cPd(OAc)2 (10 mol%). dPd(OAc)2 (3 mol%). eK2CO3 (0.9 mmol). f K2CO3 (1.2 mmol). gK2CO3 (1.5 mmol). To disclose the scope of this one-pot C-H arylation protocol, the entries employing 1a, various benzoyl chlorides without or with para-substitution, and



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different aryl iodides were examined. As showing in Table 2, this double C-H arylation reaction displayed broad tolerance to both the benzoyl chloride and aryl idodide components. While conventional functional groups with both electron withdrawing and donating property in the substrates smoothly took part in the synthesis, the entry employing strong electron withdrawing group such nitro functionalized aryl iodide was found to give corresponding product (4k, Table 2) with slightly lower yield, all other entries provided the double arylated benzamides 4 with excellent yield, demonstrating the high efficiency of OAP as DG in this double C-H arylation reaction. Notably, the X-ray single crystal diffraction on 4b was conducted to confirm the products structure on the basis of other spectral analysis (see Fig. S1 in the SI for the ORTEP structure).17 Further efforts in individual experiment examining other

coupling

reagents,

including

bromobenzene,

4-bromoacetophenone,

2-bromopyridine, 2-iodothiophene and PhOTs did not provide the expect C-H arylated product. What’s more, the primary effort in derivation of the model compound 4a via intramolecular C-N bond construction was made, however, following the catalytic method in literature,19 no expect cyclised product was provided. Table 2 Scope of the one-pot double C-H arylationa


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Entry R1

R2

Product Yieldb (%)

1

H

4-OMe

4a

87

2

H

4-Me

4b

93

3

H

4-Cl

4c

88

4

H

4-Br

4d

86

5

H

3,5-dimethyl 4e

92

6

Me

H

4f

87

7

Me

4-Me

4g

90

8

Me

4-OMe

4h

89

9

Me

4-Cl

4i

83

10

Me

4-Br

4j

81

11

Me

4-NO2

4k

79

12

Me

3-Me

4l

91

13

Me

3,5-dimethyl 4m

90

14

OMe

H

4n

88

15

OMe

4-Me

4o

93

16

OMe

4-OMe

4p

90

17

OMe

4-Cl

4q

86

18

OMe

3-Me

4r

91

19

OMe

3,5-dimethyl 4s

92

20

Cl

4-Me

4t

87

21

Cl

4-OMe

4u

85

22

CO2Me H

4v

79

a

General conditions: 1 (0.3 mmol), 2 (0.3 mmol), 3 (0.9 mmol), Pd(OAc)2 (5 mol%), K2CO3 (1.2 mmol) in CH3CN (2 mL), refluxed (heating at 90 oC) for 12 h. bIsolated

yield.



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In subsequent investigation on the substrate scope, the reactions employing benzoyl chlorides containing ortho- and meta-substitutent which resulted in the presence of two different ortho-C-H bonds were then performed. As expected, the steric effect produced by the substituent induced the reaction to selectively give single C-H arylated products 5. As outlined in Table 3, benzoyl chlorides with ortho- or meta-methyl group reacted with iodobenzenes containing alkyl, alkoxyl, halogen and nitro substitution to provide products 5 all with excellent yield via the direct three-component operation. Table 3 Scope of the one-pot single C-H arylationa,b

a

General conditions: 1a (0.3 mmol), 2 (0.3 mmol), 3 (0.45 mmol), Pd(OAc)2 (5 mol%), K2CO3 (1.2 mmol) in CH3CN (2 mL), refluxed (heating at 90 oC) for 12 h. b Isolated yield.


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The synthesis of all products 4 and 5 clearly defined the general applicability of the OAP in assisting the benzamide ortho-C-H arylation reaction as DG. However, besides revealing the utility of this useful new DG, another notable advantage of the present work was the simple operation by directly subjecting three reactants. To verify the other important feature of the three-component reaction in generating product diversity, the synthesis to products of type 4 by using different o-aminophenols were then run under the standard reaction conditions. Delightfully, the brief examination on the reactions afforded the expected products 4w-4z with also excellent yields (Scheme 1). Whilst providing the rapid synthetic route to diverse products, the successfully execution of these three-component reactions also demonstrated their potential application in rapidly screening the efficient DG via simple variation in the substructure of the DG precursors.

Scheme 1 Brief scope of o-aminophenols in the C-H arylation

To demonstrate the function of the hydroxyl group in OAP, a control experiment employing aniline as alternative amine substrate to reaction with benozyl chloride and iodobenzene was conducted under the standard condition. No expect C-H arylated product was observed in this experiment (Eq 1), implying that the hydroxyl group in OAP was indispensable for the Pd-catalyzed reaction by acting as chelating site. In



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addition, the KIE experiment employing equal amount of 2a and 2a-d5 to react with 1a and 3a provided the product 4a and corresponding deuterium labelled product 4a-d3, with the ratio of 4.3 :1 (Eq 2), suggesting that C-H arylation might be a rate determining step. H

O Cl

I

NH2

standard condition

no C-H arylation

(1)

H D

O 1a

standard Cl condition

D Cl D

3a 2a 0.15 mmol

D

O

D

D (2)

4a

D

D 2a-d5 0.15 mmol

MeO 4a/4a-d3 = 4.3

OAP O 4a-d3

OMe

In term of the reaction mechanism, the bidentate feature of OAP indicates that the C-H activation process takes place through similar states as those ones in the directed arylation using analogous bidentate DG.6d As depicted in Scheme 2, the first step of the three-component reaction is the base promoted formation of benzamide 6 from benzoyl chloride and o-aminophenol. The Pd(OAc)2 then incorporates 6 to give Pd complex A with the assistance of K2CO3 wherein the ligand may be OAc-, the reaction medium or the heteroatom in substrate, and A can be further converted to complex B via the intramolecular C-H palladation. The oxidative addition of aryl iodide to B leads to the formation of another Pd complex C which undergoes subsequent reductive elimination to form o-arylated Pd species D. The decomposition of D to the Pd(II) catalyst allows the next round C-H arylation process and give simultaneously the single arylated product 5. When another reactive C-H bond


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presents, the double arylated product 4 can be afforded via the repeated catalytic cycle.

Scheme 2 The plausible reaction mechanism

CONCLUSION In conclusion, we have identified o-aminophenol as a highly efficient DG precursor enabling the directed ortho-C-H arylation of in situ generated benzamides in straightforward three-component reactions of benzoyl chlorides, o-aminophenols and aryl iodides. The present work discloses not only the low cost and simple OAP as a practical new bidentate DG, but also the step efficient three-component one-pot C-H activation protocol in the synthesis of highly diversified products.

EXPERIMENTAL SECTION



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General information All chemicals and solvents used in the experiments were obtained from commercial sources and used directly without further treatment. The 1H and

13

C NMR were

recorded in 400 MHz apparatus using CDCl3 or DMSO-d6 as solvent. The frequencies for 1H NMR and

13

C NMR test are 400 MHz and 100 MHz, respectively. The

chemical shifts were reported in ppm using TMS as internal standard. HRMS results were tested under ESI model in an MS spectrometer equipped with TOF analyzer. The melting points were tested in a X-4A instrument without correcting temperature. General procedure for the synthesis of benzamides 4 and 5 In a 25 mL round bottom flask equipped with a condenser were located o-aminophenol 1 (0.3 mmol), acyl chloride 2 (0.3 mmol), iodobenzene 3 (0.9 mmol in the synthesis of 4)/(0.45 mmol in the synthesis of 5), Pd(OAc)2 (0.015 mmol), K2CO3 (1.2 mmol) and CH3CN (2 mL). The mixture was refluxed at 82 oC (external heating at 90 oC) for 12 h. Upon completion (TCL), the vessel was allowed to cool down to room temperature, and 10 mL water was added. The heterogeneous mixture was extracted with ethyl acetate (3 ×10 mL). The combined organic phase was dried over Na2SO4. After filtration, the acquired solution was collected and the solvent was removed at reduced pressure. The residue was subjected to silica gel column chromatography to give pure products by using mixed petroleum ether and ethyl acetate (VPET: VEA = 10:1).


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N-(2-Hydroxyphenyl)-2,6-di(p-methoxyphenyl) benzamide (4a). Yield: 87%, 111 o

1

mg; white solid; mp 217-219 C; Rf = 0.25; H NMR (400 MHz, DMSO-d6): δ = 9.51

(s, 1 H), 9.28 (s, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 4 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 5 H), 6.75 (d, J = 7.6 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 3.74 (s, 6 H);

13

C NMR (100 MHz, DMSO-d6): δ =

168.2, 159.2, 149.1, 139.8, 136.1, 133.0, 130.2, 129.4, 129.0, 125.8, 123.3, 119.3, 116.8, 114.1, 55.6; ESI-HRMS Calcd for C27H24NO4 [M + H]+ 426.1700, found 426.1704.

N-(2-Hydroxyphenyl)-2,6-ditolyl benzamide (4b). Yield: 93%, 110 mg; white solid; mp 206-208 oC; Rf = 0.43; 1H NMR (400 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 7.6 Hz, 4 H), 7.23 (d, J = 7.6 Hz, 4 H), 7.08 (s, 1 H), 7.05 (t, J = 7.8 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 6.63 (t, J = 7.4 Hz, 1 H), 5.80 (d, J = 8.0 Hz, 1 H), 2.39 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 169.9, 149.7, 141.0, 137.7, 137.1, 133.7, 130.1, 129.5, 129.3, 128.4, 127.5, 125.5, 122.2, 120.1, 119.8, 21.2; ESI-HRMS Calcd for C27H24NO2 [M + H]+ 394.1802, found 394.1808.

N-(2-Hydroxyphenyl)-2,6-di(p-chlorophenyl) benzamide (4c). Yield: 88%, 114 mg; white solid; mp 253-255 oC; Rf = 0.18; 1H NMR (400 MHz, DMSO-d6): δ = 9.62 (s, 1 H), 9.30 (s, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 4 H), 7.45-7.43 (m, 6 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.92 (t, J = 7.8 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6): δ = 167.4, 149.7, 139.4, 138.8,



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136.4, 132.8, 130.9, 129.6, 128.6, 126.2, 125.6, 124.1, 119.2, 116.5; ESI-HRMS Calcd for C25H17Cl2KNO2 [M + K]+ 472.0268, found 472.0287. N-(2-Hydroxyphenyl)-2,6-di(p-bromophenyl) benzamide (4d). Yield: 86%, 134 mg; white solid; mp 278-280 oC; Rf = 0.22; 1H NMR (400 MHz, DMSO-d6): δ = 9.67 (s, 1

H), 9.36 (s, 1 H), 7.63-7.57 (m, 5 H), 7.49 (d, J = 8.4 Hz, 4 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6): δ = 167.4, 149.7, 139.7, 138.8, 136.2, 131.5, 131.3, 129.7, 129.6, 126.2, 125.6, 124.1, 121.4, 119.2, 116.5; ESI-HRMS Calcd for C25H17Br2NNaO2 [M + Na]+ 543.9518, found 543.9525. N-(2-Hydroxyphenyl)-2,6-di(3,5-dimethylphenyl) benzamide (4e). Yield: 92%, 116 mg; white solid; mp 234-236 oC; Rf = 0.37; 1H NMR (400 MHz, CDCl3): δ = 7.64 (s,

1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 2 H), 7.10 (s, 5 H), 7.06 (s, 1 H), 7.03 (s, 2 H), 6.93 (d, J = 8.4 Hz, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 5.87 (d, J = 7.6 Hz, 1 H), 2.31 (s, 12 H);

13

C NMR (100 MHz, CDCl3): δ = 170.0, 150.1, 141.2, 140.0,

138.4, 133.6, 130.0, 129.5, 129.2, 127.5, 126.3, 125.4, 122.4, 120.0, 119.9, 21.3; ESI-HRMS Calcd for C29H27NNaO2 [M + Na]+ 444.1934, found 444.1921. N-(2-Hydroxyphenyl)-2,6-diphenyl 4-methylbenzamide (4f). Yield: 87%, 99 mg; white solid; mp 269-271 oC; Rf = 0.50; 1H NMR (400 MHz, CDCl3): δ = 7.81 (s, 1 H),

7.48 (d, J = 7.2 Hz, 4 H), 7.45-7.39 (m, 6 H), 7.29 (s, 2 H), 7.07 (s, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.62 (t, J = 7.4 Hz, 1 H), 5.74 (d, J = 8.0 Hz, 1 H), 2.49 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.8, 149.7, 141.1, 140.3, 140.2,


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131.1, 130.2, 128.8, 128.5, 127.9, 127.5, 125.4, 122.2, 120.1, 119.9, 21.4; ESI-HRMS Calcd for C26H22NO2 [M + H]+ 380.1645, found 380.1638. N-(2-Hydroxyphenyl)-2,6-ditolyl 4-methylbenzamide (4g). Yield: 90%, 110 mg; white solid; mp 221-223 oC; Rf = 0.45; 1H NMR (400 MHz, CDCl3): δ = 8.01 (s, 1 H),

7.36 (d, J = 7.6 Hz, 4 H), 7.23 (t, J = 8.2 Hz, 6 H), 7.07 (s, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.62 (t, J = 7.4 Hz, 1 H), 5.75 (d, J = 8.0 Hz, 1 H), 2.46 (s, 3 H), 2.38 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 170.1, 149.7, 141.1, 140.2, 137.6, 137.3, 130.9, 130.1, 129.5, 128.3, 127.4, 125.6, 122.2, 120.0, 119.9, 21.4, 21.2; ESI-HRMS Calcd for C28H26NO2 [M + H]+ 408.1958, found 408.1959. N-(2-Hydroxyphenyl)-2,6-di(p-methoxylphenyl) 4-methylbenzamide (4h). Yield: 89%, 117 mg; white solid; mp 243-245 oC; Rf = 0.15; 1H NMR (400 MHz, DMSO-d6):

δ = 9.37 (s, 1 H), 9.29 (s, 1 H), 7.44 (d, J = 8.4 Hz, 4 H), 7.17 (s, 2 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.93-6.88 (m, 5 H), 6.74 (d, J = 8.0 Hz, 1 H), 6.65 (t, J = 7.8 Hz, 1 H), 3.74 (s, 6 H), 2.41 (s, 3 H);

13

C NMR (100 MHz, DMSO-d6): δ = 168.5, 159.0, 149.0,

139.7, 138.8, 133.4, 133.1, 130.2, 129.6, 126.3, 125.8, 123.2, 119.3, 116.8, 114.0, 55.5, 21.2; ESI-HRMS Calcd for C28H26NO4 [M + H]+ 440.1856, found 440.1865. N-(2-Hydroxyphenyl)-2,6-di(p-chlorophenyl) 4-methylbenzamide (4i). Yield: 83%, 111 mg; white solid; mp 256-258 oC; Rf = 0.45; 1H NMR (400 MHz, DMSO-d6): δ =

9.55 (s, 1 H), 9.33 (s, 1 H), 7.53 (d, J = 8.0 Hz, 4 H), 7.43 (d, J = 8.4 Hz, 4 H), 7.26 (s, 2 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 2.43 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6,



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

149.5, 139.5, 139.2, 138.8, 133.7, 132.7, 130.9, 130.1, 128.5, 126.1, 125.8, 123.8, 119.2, 116.6, 21.2; ESI-HRMS Calcd for C26H20Cl2NO2 [M + H]+ 448.0866, found 448.0883.

N-(2-Hydroxyphenyl)-2,6-di(p-bromophenyl) 4-methylbenzamide (4j). Yield: 81%, 130 mg; white solid; mp 277-279 oC; Rf = 0.20; 1H NMR (400 MHz, DMSO-d6): δ =

9.55 (s, 1 H), 9.34 (s, 1 H), 7.57 (d, J = 8.4 Hz, 4 H), 7.47 (d, J = 8.4 Hz, 4 H), 7.26 (s, 2 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 2.44 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6, 149.6, 139.8, 139.2, 138.8, 133.6, 131.5, 131.2, 130.1, 126.1, 125.8, 123.9, 121.4, 119.2, 116.6, 21.2; ESI-HRMS Calcd for C26H19Br2NNaO2 [M + Na]+ 557.9675, found 557.9675.

N-(2-Hydroxyphenyl)-2,6-di(p-nitrophenyl) 4-methylbenzamide (4k). Yield: 79%, 111 mg; white solid; mp 296-298 oC; Rf = 0.12; 1H NMR (400 MHz, DMSO-d6): δ =

9.68 (s, 1 H), 9.39 (s, 1 H), 8.26 (d, J = 8.8 Hz, 4 H), 7.82 (d, J = 8.4 Hz, 4 H), 7.40 (s, 2 H), 6.99 (d, J = 8.0 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H), 2.48 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ = 166.9, 150.1, 147.4, 147.2, 139.6, 138.2, 134.0, 130.8, 130.5, 126.3, 125.3, 124.6, 123.7, 119.1, 116.2, 21.1; ESI-HRMS Calcd for C26H20N3O6 [M + H]+ 470.1347, found 470.1349.

N-(2-Hydroxyphenyl)-2,6-di(m-methylphenyl) 4-methylbenzamide (4l). Yield: 91%, 111 mg; white solid; mp 235-237 oC; Rf = 0.33; 1H NMR (400 MHz, CDCl3): δ = 7.81


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(s, 1 H), 7.33-7.25 (m, 8 H), 7.20 (d, J = 7.2 Hz, 2 H), 7.06-7.02 (m, 2 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.64 (t, J = 8.0 Hz, 1 H), 5.76 (d, J = 8.0 Hz, 1 H), 2.47 (s, 3 H), 2.36 (s, 6 H);

13

C NMR (100 MHz, CDCl3): δ = 170.0, 149.9, 141.2, 140.2, 140.2, 138.5,

131.0, 130.1, 129.2, 128.7, 128.6, 127.5, 125.5, 122.3, 120.1, 119.9, 21.4; ESI-HRMS Calcd for C28H26NO2 [M + H]+ 408.1958, found 408.1962. N-(2-Hydroxyphenyl)-2,6-di(3,5-dimethylphenyl) 4-methylbenzamide (4m). Yield: o

1

90%, 117 mg; white solid; mp 232-234 C; Rf = 0.65; H NMR (400 MHz, CDCl3): δ =

7.77 (s, 1 H), 7.25 (s, 2 H), 7.09 (s, 5 H), 7.05 (s, 1 H), 7.01 (s, 2 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H), 5,83 (d, J = 8.0 Hz, 1 H), 2.45 (s, 3 H), 2.31 (s, 12 H); 13C NMR (100 MHz, CDCl3): δ = 170.2, 150.1, 141.2, 140.2, 140.1, 138.4, 130.9, 130.0, 129.4, 127.5, 126.3, 125.6, 122.4, 120.0, 119.9, 21.4, 21.3; ESI-HRMS Calcd for C30H29KNO2 [M + K]+ 474.1830, found 474.1804. N-(2-Hydroxyphenyl)-2,6-diphenyl 4-methoxylbenzamide (4n). Yield: 88%, 104 mg; white solid; mp 233-235 oC; Rf = 0.15; 1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H),

7.49-7.40 (m, 10 H), 7.06 (s, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.97 (s, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 6.61 (t, J = 7.6 Hz, 1 H), 5.68 (d, J = 8.0 Hz, 1 H), 3.90 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.6, 160.3, 149.8, 143.0, 140.1, 128.8, 128.4, 128.1, 127.5, 126.6, 125.5, 122.2, 120.1, 119.9, 114.9, 55.6; ESI-HRMS Calcd for C26H22NO3 [M + H]+ 396.1594, found 396.1599. N-(2-Hydroxyphenyl)-2,6-ditolyl 4-methoxylbenzamide (4o). Yield: 93%, 118 mg; white solid; mp 230-232 oC; Rf = 0.20; 1H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H),



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

7.32 (d, J = 8.0 Hz, 4 H), 7.20 (d, J = 8.0 Hz, 4 H), 7.12 (s, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 6.92-6.89 (m, 3 H), 6.59 (t, J = 7.6 Hz, 1 H), 5.71 (d, J = 7.6 Hz, 1 H), 3.86 (s, 3 H), 2.37 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 170.0, 160.2, 149.7, 143.0, 137.8, 137.3, 129.5, 128.2, 127.4, 126.5, 125.7, 122.2, 120.0, 119.8, 114.7, 55.6, 21.2; ESI-HRMS Calcd for C28H26NO3 [M + H]+ 424.1907, found 424.1903. N-(2-Hydroxyphenyl)-2,6-di(p-methoxylphenyl) 4-methoxylbenzamide (4p). Yield: o

1


8.07 (brs, 1 H), 7.35 (d, J = 8.4 Hz, 4 H), 7.20 (s, 1 H), 7.02 (t, J = 7.8 Hz, 1 H), 6.92-6.89 (m, 7 H), 6.62 (t, J = 7.6 Hz, 1 H), 5.86 (d, J = 8.0 Hz, 1 H), 3.87 (s, 3 H), 3.80 (s, 6 H);

13

C NMR (100 MHz, CDCl3): δ = 170.1, 160.1, 159.5, 149.6, 142.6,

132.4, 129.5, 127.4, 126.5, 125.7, 122.3, 120.1, 119.7, 114.6, 114.2, 55.6, 55.4; ESI-HRMS Calcd for C28H25KNO5 [M + K]+ 494.1364, found 494.1385. N-(2-Hydroxyphenyl)-2,6-di(p-chlorophenyl) 4-methoxylbenzamide (4q). Yield: 86%, 119 mg; white solid; mp 166-168 oC; Rf = 0.45; 1H NMR (400 MHz, DMSO-d6):

δ = 9.47 (s, 1 H), 9.31 (s, 1 H), 7.52 (d, J = 8.0 Hz, 4 H), 7.40 (d, J = 8.0 Hz, 4 H), 6.96-6.94 (m, 3 H), 6.87 (t, J = 7.4 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.61 (t, J = 7.4 Hz, 1 H), 3.84 (s, 3 H);

13

C NMR (100 MHz, DMSO-d6): δ = 167.1, 159.0, 149.0,

140.1, 138.8, 132.4, 130.3, 128.7, 128.1, 125.6, 125.4, 123.3, 118.7, 116.0, 114.4, 55.5; ESI-HRMS Calcd for C26H20Cl2NO3 [M + H]+ 464.0815, found 464.0817. N-(2-Hydroxyphenyl)-2,6-di(m-methylphenyl) 4-methoxylbenzamide (4r). Yield: 91%, 115 mg; white solid; mp 177-179 oC; Rf = 0.28; 1H NMR (400 MHz, CDCl3): δ =


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7.88 (s, 1 H), 7.32-7.24 (m, 6 H), 7.20 (d, J = 7.2 Hz, 2 H), 7.09 (s, 1 H), 7.02 (t, J = 7.8 Hz, 1 H), 6.95 (s, 2 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.62 (t, J = 7.6 Hz, 1 H), 5.75 (d, J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 2.35 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 169.3, 159.7, 149.4, 142.6, 139.6, 138.1, 128.6, 128.3, 128.2, 127.0, 126.0, 125.1, 124.9, 121.8, 119.5, 119.3, 114.3, 55.1, 20.9; ESI-HRMS Calcd for C28H26NO3 [M + H]+ 424.1907, found 424.1910.

N-(2-Hydroxyphenyl)-2,6-di(3,5-dimethylphenyl)

4-methoxylbenzamide

(4s).

Yield: 92%, 124 mg; white solid; mp 220-222 oC; Rf = 0.62; 1H NMR (400 MHz,

CDCl3): δ = 7.83 (s, 1 H), 7.09 (s, 4 H), 7.06 (s, 1 H), 7.03 (s, 3 H), 6.94-6.91 (m, 3 H), 6.65 (t, J = 7.6 Hz, 1 H), 5.79 (d, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 2.31 (s, 12 H); 13

C NMR (100 MHz, CDCl3): δ = 170.0, 160.1, 150.1, 143.2, 140.1, 138.5, 129.6,

127.4, 126.4, 126.2, 125.6, 122.3, 120.0, 119.9, 114.6, 55.6, 21.3; ESI-HRMS Calcd for C30H30NO3 [M + H]+ 452.2220, found 452.2236. N-(2-Hydroxyphenyl)-2,6-ditolyl 4-chlorobenzamide (4t). Yield: 87%, 111 mg; white solid; mp 240-242 oC; Rf = 0.58; 1H NMR (400 MHz, DMSO-d6): δ = 9.60 (s, 1 H), 9.36 (s, 1 H), 7.46-7.42 (m, 6 H), 7.18 (d, J = 8.0 Hz, 4 H), 7.09 (d, J = 7.2 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H), 2.29 (s, 6 H);

13

C NMR (100 MHz, DMSO-d6): δ = 167.0, 149.2, 142.0, 137.6, 136.5, 135.2,

133.6, 129.3, 128.9, 128.5, 125.9, 123.6, 119.2, 116.4, 21.2; ESI-HRMS Calcd for C27H23ClNO2 [M + H]+ 428.1412, found 428.1416.



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-Hydroxyphenyl)-2,6-di(p-methoxylphenyl) 4-chlorobenzamide (4u). Yield: o

1


7.71 (s, 1 H), 7.38-7.34 (m, 6 H), 7.24 (s, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.93-6.89 (m, 5 H), 6.64 (t, J = 7.6 Hz, 1 H), 5.98 (d, J = 7.6 Hz, 1 H), 3.80 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 168.6, 159.3, 148.9, 141.8, 135.2, 131.6, 130.5, 129.0, 128.4, 127.1, 124.8, 121.8, 119.8, 119.2, 113.8, 54.9; ESI-HRMS Calcd for C27H23ClNO4 [M + H]+ 460.1310, found 460.1312.

N-(2-Hydroxyphenyl)-2,6-diphenyl 4-(methoxycarbonyl)benzamide (4v). Yield 79%, 100 mg; pale yellow solid; mp 211-213 oC; Rf = 0.14; 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 2 H), 7.48-7.41 (m, 11 H), 7.28 (d, J = 6.4 Hz, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H), 5.92 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3 H); 13C NMR (100 MHz, CDCl3): 168.6, 166.1, 149.5, 141.4, 139.0, 137.6, 131.5, 130.3, 128.9, 128.5, 128.4, 127.7, 125.1, 122.4, 120.4, 119.7, 52.6; ESI-HRMS Calcd for C27H22NO4 [M + H]+ 4241543, found 424.1542. N-(2-Hydroxy-4-methylphenyl)-2,6-diphenyl benzamide (4w). Yield: 84%, 96 mg; white solid; mp 275-277 oC; Rf = 0.35; 1H NMR (400 MHz, CDCl3): δ = 7.62 (s, 1 H),

7.59-7.55 (m, 1 H), 7.49-7.47 (m, 5 H), 7.45-7.42 (m, 4 H), 7.40-7.38 (m, 3 H), 7.02 (s, 1 H), 6.71 (s, 1 H), 6.42 (d, J = 8.4 Hz, 1 H), 5.68 (d, J = 7.6 Hz, 1 H), 2.20 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.4, 149.4, 141.0, 140.0, 137.8, 133.9, 130.1, 129.5, 128.8, 128.5, 128.0, 122.7, 122.0, 121.0, 120.3, 20.9; ESI-HRMS Calcd for C26H21KNO2 [M + K]+ 418.1204, found 418.1185.


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N-(2-Hydroxy-4-methylphenyl)-2,6-ditolyl benzamide (4x). Yield: 93%, 114 mg; o

1

white solid; mp 230-232 C; Rf = 0.50; H NMR (400 MHz, CDCl3): δ = 7.78 (s, 1 H),

7.51 (t, J = 7.6 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 4 H), 7.18 (d, J = 8.0 Hz, 4 H), 7.08 (s, 1 H), 6.69 (s, 1 H), 6.41 (d, J = 8.0 Hz, 1 H), 5.73 (d, J = 8.0 Hz, 1 H), 2.36 (s, 6 H), 2.19 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.7, 149.3, 141.0, 137.7, 137.6, 137.2, 133.8, 130.0, 129.5, 129.3, 128.4, 123.0, 122.1, 120.9, 120.1, 21.2, 20.9; ESI-HRMS Calcd for C28H26NO2 [M + H]+ 408.1958, found 408.1961.

N-(2-Hydroxy-4-chlorophenyl)-2,6-ditolyl benzamide (4y). Yield: 92%, 118 mg; white solid; mp 166-168 oC; Rf = 0.25; 1H NMR (400 MHz, DMSO-d6): δ = 9.84 (s, 1

H), 9.45 (s, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.41-7.35 (m, 6 H), 7.17-7.12 (m, 5 H), 6.77 (s, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 2.30 (s, 6 H);

13

C NMR (100 MHz,

DMSO-d6): δ = 168.0, 150.1, 139.9, 137.8, 137.0, 136.0, 129.4, 129.2, 129.2, 129.0, 128.9, 125.3, 124.4, 119.0, 116.1, 21.2; ESI-HRMS Calcd for C27H23ClNO2 [M + H]+ 428.1412, found 428.1412.

N-(2-Hydroxy-4-chlorophenyl)-2,6-di(p-chlorophenyl) benzamide (4z). Yield: 90%, o

1

126 mg; hite solid; mp 215-217 C; Rf = 0.13; H NMR (400 MHz, DMSO-d6): δ =

10.02 (brs, 1 H), 9.66 (s, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 4 H), 7.43 (d, J = 6.8 Hz, 6 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.78 (s, 1 H), 6.72 (d, J = 8.4 Hz, 1 H); 13

C NMR (100 MHz, DMSO-d6): δ = 166.9, 150.2, 138.8, 138.2, 135.8, 132.3, 130.4,

129.1, 129.1, 128.8, 128.1, 124.6, 124.3, 118.4, 115.3; ESI-HRMS Calcd for C25H17Cl3NO2 [M + H]+ 468.0319, found 468.0313.



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-Hydroxyphenyl)-2-methyl-6-phenyl benzamide (5a). Yield: 90%, 82 mg; white solid; mp 135-137 oC; Rf = 0.33; 1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1 H), 7.40-7.30 (m, 7 H), 7.24 (d, J = 7.2 Hz, 2 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 6.25 (d, J = 7.6 Hz, 1 H), 2.45 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 170.1, 148.9, 140.0, 139.8, 136.5, 134.5, 130.0, 129.8, 128.9, 128.5, 127.9, 127.6, 127.3, 125.4, 122.2, 120.4, 119.4, 19.9; ESI-HRMS Calcd for C20H18NO2 [M + H]+ 304.1332, found 304.1332. N-(2-Hydroxyphenyl)-2-methyl-6-(tolyl) benzamide (5b). Yield: 95%, 90 mg; white solid; mp 164-166 oC; Rf = 0.25; 1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 1 H), 7.43 (s, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.21 (t, J = 9.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.99 (t, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 6.34 (d, J = 7.6 Hz, 1 H), 2.42 (s, 3 H), 2.31 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 170.3, 148.8, 139.8, 137.7, 137.1, 136.3, 134.6, 129.9, 129.5, 128.4, 127.6, 127.2, 125.6, 122.2, 120.3, 119.3, 21.1, 19.8; ESI-HRMS Calcd for C21H20NO2 [M + H]+ 318.1489, found 318.1491. N-(2-Hydroxyphenyl)-2-methyl-6-(p-methoxylphenyl) benzamide (5c). Yield: 92%, o

1

92 mg; white solid; mp 136-138 C; Rf = 0.80; H NMR (400 MHz, CDCl3): δ = 8.61

(s, 1 H), 7.39-7.31 (m, 4 H), 7.23 (t, J = 7.4 Hz, 2 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.92-6.87 (m, 3 H), 6.68 (t, J = 7.6 Hz, 1 H), 6.30 (d, J = 7.2 Hz, 1 H), 3.76 (s, 3 H), 2.46 (s, 3 H);

13

C NMR (100 MHz, CDCl3): δ = 170.4, 159.4, 148.9, 139.4, 136.4,

134.4, 132.2, 130.0, 129.7, 129.4, 127.5, 127.3, 125.5, 122.2, 120.3, 119.5, 114.3, 55.4, 19.9; ESI-HRMS Calcd for C21H20NO3 [M + H]+ 334.1438, found 334.1442.


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N-(2-Hydroxyphenyl)-2-methyl-6-(p-chlorophenyl) benzamide (5d). Yield: 88%, 89 o

1

mg; white solid; mp 162-164 C; Rf = 0.20; H NMR (400 MHz, CDCl3): δ = 8.41

(brs, 1 H), 7.50 (s, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.34-7.28 (m, 4 H), 7.24-7.21 (m, 2 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.72 (t, J = 7.4 Hz, 1 H), 6.49 (d, J = 8.0 Hz, 1 H), 2.43 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.8, 148.6, 138.5, 138.3, 136.4, 134.6, 134.0, 130.0, 130.0, 129.8, 128.9, 127.4, 127.3, 125.3, 121.9, 120.6, 119.2, 19.7; ESI-HRMS Calcd for C20H17ClNO2 [M + H]+ 338.0942, found 338.0944.

N-(2-Hydroxyphenyl)-2-methyl-6-(p-nitrophenyl) benzamide (5e). Yield: 86%, 90 mg; white solid; mp 171-173 oC; Rf = 0.1; 1H NMR (400 MHz, DMSO-d6): δ = 9.73

(s, 1 H), 9.57 (s, 1 H), 8.24 (d, J = 7.6 Hz, 2 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.46 (t, J = 7.4 Hz, 1 H), 7.39 (d, J = 7.2 Hz, 1 H), 7.35-7.29 (m, 2 H), 6.98 (t, J = 7.4 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.74 (t, J = 7.6 Hz, 1 H), 2.45 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ = 167.3, 149.6, 147.2, 146.6, 137.0, 136.8, 135.0, 130.1, 129.9, 128.9, 127.0, 125.9, 125.1, 124.3, 123.2, 118.8, 116.0, 19.1; ESI-HRMS Calcd for C20H16N2NaO4 [M + Na]+ 371.1002, found 371.0984. N-(2-Hydroxyphenyl)-2-methyl-6-(m-methylphenyl) benzamide (5f). Yield: 93%, 89 mg; white solid; mp 174-176 oC; Rf = 0.29; 1H NMR (400 MHz, CDCl3): δ = 8.51

(s, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.31 (s, 1 H), 7.27-7.18 (m, 5 H), 7.13 (d, J = 7.2 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 1 H), 6.89 (d, J = 8.0 Hz, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 6.25 (d, J = 7.6 Hz, 1 H), 2.46 (s, 3 H), 2.28 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 170.2, 149.1, 140.0, 139.9, 138.6, 136.5, 134.4, 129.9, 129.7, 129.2, 128.8, 128.6,



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127.5, 127.3, 125.6, 125.4, 122.2, 120.3, 119.5, 21.4, 19.9; ESI-HRMS Calcd for C21H20NO2 [M + H]+ 318.1489, found 318.1477. N-(2-Hydroxyphenyl)-2-methyl-6-(3,5-dimethylphenyl) benzamide (5g). Yield: 91%, 90 mg; white solid; mp 184-186 oC; Rf = 0.40; 1H NMR (400 MHz, CDCl3): δ =

8.48 (s, 1 H), 7.37-7.33 (m, 2 H), 7.25-7.19 (m, 2 H), 7.03-6.99 (m, 3 H), 6.94 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 6.32 (d, J = 7.2 Hz, 1 H), 2.43 (s, 3 H), 2.23 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 170.3, 149.1, 140.1, 139.9, 138.5, 136.4, 134.4, 129.9, 129.6, 129.5, 127.5, 127.3, 126.4, 125.5, 122.3, 120.3, 119.4, 21.3, 19.9; ESI-HRMS Calcd for C22H22NO2 [M + H]+ 332.1645, found 332.1653.

N-(2-Hydroxyphenyl)-2-phenyl-5-methyl benzamide (5h). Yield: 85%, 77 mg; white solid; mp 165-167 oC; Rf = 0.25; 1H NMR (400 MHz, CDCl3): δ = 9.04 (s, 1 H), 7.71 (s, 1 H), 7.47-7.37 (m, 6 H), 7.32 (d, J = 7.6 Hz, 1 H), 7.16 (s, 1 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H), 5.88 (d, J = 7.6 Hz, 1 H), 2.44 (s, 3 H);

13

C NMR (100 MHz, CDCl3): δ = 169.3, 149.1, 139.6, 138.2, 137.4,

133.0, 132.3, 130.5, 130.5, 129.3, 129.0, 128.2, 127.4, 125.4, 122.1, 120.2, 119.9, 21.0; ESI-HRMS Calcd for C20H17NNaO2 [M + Na]+ 326.1151, found 326.1151. N-(2-Hydroxyphenyl)-2-(tolyl)-5-methyl benzamide (5i). Yield: 94%, 89.5 mg; white solid; mp 185-187 oC; Rf = 0.53; 1H NMR (400 MHz, CDCl3): δ = 9.07 (s, 1 H), 7.65 (s, 1 H), 7.34-7.23 (m, 7 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H), 6.01 (d, J = 8.0 Hz, 1 H), 2.40 (s, 6 H);


13

C NMR (100 MHz,

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CDCl3): δ = 169.5, 149.0, 138.0, 137.8, 137.5, 136.7, 133.0, 132.2, 130.6, 130.3, 129.9, 128.9, 127.2, 125.6, 122.1, 120.1, 119.7, 21.2, 21.0; ESI-HRMS Calcd for C21H19NNaO2 [M + Na]+ 340.1308, found 340.1307. N-(2-Hydroxyphenyl)-2-(p-methoxylphenyl)-5-methyl benzamide (5j). Yield: 93%, 93 mg; white solid; mp 160-162 oC; Rf = 0.23; 1H NMR (400 MHz, CDCl3): δ = 9.04

(s, 1 H), 7.63 (s, 1 H), 7.38 (s, 1 H), 7.34-7.24 (m, 4 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.96-6.91 (m, 3 H), 6.68 (t, J = 7.6 Hz, 1 H), 6.15 (d, J = 8.0 Hz, 1 H), 3.81 (s, 3 H), 2.40 (s, 3 H);

13

C NMR (100 MHz, CDCl3): δ = 169.6, 159.6, 148.9, 137.6, 137.0,

133.0, 132.2, 131.7, 130.6, 130.3, 130.2, 127.2, 125.6, 122.2, 120.2, 119.6, 114.6, 55.5, 21.0; ESI-HRMS Calcd for C21H20NO3 [M + H]+ 334.1438, found 334.1419. N-(2-Hydroxyphenyl)-2-(p-bromophenyl)-5-methyl benzamide (5k). Yield: 90%, o

1

103 mg; white solid; mp 191-193 C; Rf = 0.40; H NMR (400 MHz, DMSO-d6): δ =

9.60 (s, 1 H), 9.38 (s, 1 H), 7.58-7.52 (m, 3 H), 7.47 (s, 1 H), 7.40-7.33 (m, 4 H), 6.98 (t, J = 7.2 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.77 (t, J = 7.2 Hz, 1 H), 2.41 (s, 3 H); 13

C NMR (100 MHz, DMSO-d6): δ = 167.8, 148.7, 139.2, 137.1, 136.1, 135.3, 131.1,

130.6, 130.5, 129.8, 128.6, 125.8, 125.4, 123.0, 120.6, 118.9, 115.9, 20.5; ESI-HRMS Calcd for C20H17BrNO2 [M + H]+ 382.0437, found 382.0452. N-(2-Hydroxyphenyl)-2-(p-nitrophenyl)-5-methyl benzamide (5l). Yield: 87%, 91 mg; white solid; mp 184-186 oC; Rf = 0.11; 1H NMR (400 MHz, DMSO-d6): δ = 9.59

(s, 1 H), 9.47 (s, 1 H), 8.25 (d, J = 8.0 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.54 (s, 2 H), 7.43 (s, 2 H), 6.98 (t, J = 7.2 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.77 (t, J = 7.4



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Hz, 1 H), 2.44 (s, 3 H);

13

C NMR (100 MHz, DMSO-d6): δ = 167.4, 149.0, 147.0,

146.5, 138.2, 136.4, 134.7, 130.7, 130.0, 129.7, 128.8, 125.6, 125.6, 123.5, 123.4, 118.9, 115.8, 20.6; ESI-HRMS Calcd for C20H17N2O4 [M + H]+ 349.1183, found 349.1186.

N-(2-Hydroxyphenyl)-2-(m-methylphenyl)-5-methyl benzamide (5m). Yield: 92%, 88 mg; white solid; mp 170-172 oC; Rf = 0.38; 1H NMR (400 MHz, CDCl3): δ = 9.06

(s, 1 H), 7.72 (s, 1 H), 7.37-7.30 (m, 3 H), 7.27-7.21 (m, 4 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 5.88 (d, J = 8.0 Hz, 1 H), 2.43 (s, 3 H), 2.36 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 169.4, 149.2, 139.6, 139.1, 138.0, 137.6, 132.8, 132.2, 130.6, 130.5, 129.7, 129.2, 129.0, 127.4, 126.1, 125.5, 122.1, 120.2, 119.9, 21.4, 21.0; ESI-HRMS Calcd for C21H19KNO2 [M + K]+ 356.1047, found 356.1031.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: . 1H/13C NMR spectra for all products, the 1H NMR of the products from KIE experiment, and the crystal structure of 4b (PDF), crystallographic data of 4b (CIF) AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (J.-P.W.). *E-mail: [email protected] (Y.L.). Notes


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The authors declare no competing financial interest.

ACKNOWLEDGEMENTS The work is financially supported by National Natural Science Foundation of China (21562024, 21562025) and the Science Fund for Distinguished Young Scholars of Jiangxi Province (20162BCB23023).

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During the preparation of this manuscript, Watkins et al reported that the N-(2-aminophenyl)acetamide which could be generated from the N-acylatio of simple commercial o-phenylenediamine is applicable DG in the mono-Ar-H arylation of benzamides, but the prior installation of the DG via separate step is also employed: Reddy, M. D.; Blanton, A. N.; Watkins, E. B. J. Org. Chem. 2017, 82, 5080.

17

CCDC 1546993 (4b) contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif.

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