Cu(OAc)2 Promoted ortho C (sp2)âH Amidation of 8-Aminoquinoline

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Cu(OAc)2 Promoted ortho C (sp2)-H Amidation of 8Aminoquinoline Benzamide with Acyl Azide: Selective Formation of Aroyl or Acetyl Amide Based on Catalyst Loading Tubai Ghosh, Pintu Maity, and Brindaban Chandra Ranu J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

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The Journal of Organic Chemistry

Cu(OAc)2 Promoted ortho C(sp2)−H Amidation of 8Aminoquinoline Benzamide with Acyl Azide: Selective Formation of Aroyl or Acetyl Amide Based on Catalyst Loading Tubai Ghosh, Pintu Maity, and Brindaban C. Ranu* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India

ABSTRACT: An efficient method for the C(sp2)–amidation of 8-aminoquinoline benzamide by acyl azide in the presence of copper acetate has

been

achieved via C-H activation.

Interestingly, the loading of copper acetate has strong influence on the outcome of the reaction. The use of one equivalent of copper acetate produces the corresponding aroyl amide, whereas, the use of two equivalents led to acetyl amide. A series of substituted benzoyl and acetyl amides have been obtained.

INTRODUCTION The amides are of much importance as compounds having amide functionality are found to possess useful activities as agrochemicals, insecticides, and drugs.1 Atorvastatin (a cholesterol controlling drug), Valsartan (blockade of angiotensin-II receptors), and Diltiazem (calcium channel blocker) are some of the representative examples.2 Moreover, the amide linkages are integral part of peptides and proteins. The amide units are also present in a vast array of natural products. Thus, amidation by a convenient and efficient way is of much interest. Traditionally, they are prepared by reaction of activated carboxylic acids such as acid chlorides and anhydrides

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with amines.3a-c However, these methods are associated with serious disadvantages of long reaction time, harsh conditions, low or moderate yields and generation of waste. Since then a plethora of improved methods for the amide formation have been developed.3d However, the issues of atom economy and generation of waste are not satisfactorily addressed. In recent years the transition metal catalyzed direct functionalization of a C-H bond via activation has received considerable attention as the process eliminates the prefuntionalization step and thus contributes to step and atom economy.4 Usually, a hetero-atom unit is employed for activation of an adjacent C-H moiety. Among several such groups an amide unit has been efficiently used for functionalization of the C-H bond.5 The 8-aminoquinoline is a pharmaceutically important molecule having different useful properties.6 The 8-aminoquinoline amide scaffold is an excellent directing unit and has been used for diverse functionalization.7 Thus we choose the amide of this molecule as an activating unit for amidation at an inert C-H position. These bis-amides may be of potential for biological activity.8 We report here the amidation of 8-aminoquinoline benzamide with benzoyl (acyl) azide catalyzed by copper acetate at room temperature (Scheme 1). Interestingly, when the reaction was performed with 1.2 equivalents of Cu(OAc)2 the corresponding benzoyl (acyl) amide was obtained, whereas use of 2 equivalents of Cu(OAc)2 led to the acetyl amide. To the best of our knowledge we are not aware of any such report. Although the transition metals such as Pd, Rh, Ir, Ru etc have been extensively used for C-H activation,4 the use of inexpensive and less toxic Cu is less explored.9 On the other hand, although dioxozolone has been extensively used for amidation10a the use of acyl azides is rather less explored for amidation.10b-10d In addition, the amidation using 8-aminoquinoline amide as an


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activating unit is also not reported. This prompted us to design this amidation reaction using Cu(OAc)2 and aroyl azide, which led to an interesting observation. Scheme 1: Copper Catalyzed C-H Amidation of sp2 C-H Bonds

Table 1. Optimization of Reaction Conditionsa,b

base

solvent

yield

1

entry

Cu(OAc)2.H2O

metal salt

K2CO3

CH3CN

19

2

Cu(OAc)2.H2O

K2CO3

DCE

-

3

Cu(OAc)2.H2O

K2CO3

DMF

17

4

Cu(OAc)2.H2O

K2CO3

DMSO

71

5

Cu(OAc)2.H2O

K2CO3

Toluene

-

6

Cu(OAc)2.H2O

K2CO3

MeOH

-

7

Cu(OAc)2.H2O

K2CO3

H2O

19

8

Cu(OAc)2.H2O

Cs2CO3

DMSO

-

9

Cu(OAc)2.H2O

NaOAC

DMSO

20

10

Cu(OAc)2.H2O

Na2CO3

DMSO

29

11

Cu(OAc)2.H2O

Et3N

DMSO

trace

12

Cu(OAc)2.H2O

K3PO4

DMSO

17

13

Cu(OAc)2.H2O

-

DMSO

-

14

Cu(OAc)2

K2CO3

DMSO

39

15

CuSO4.5H2O

K2CO3

DMSO

-

16

Cu(OTf)2

K2CO3

DMSO

trace

17

Cu(CO2CF3)2

K2CO3

DMSO

-

18

CuCl2.2H2O

K2CO3

DMSO

9

19

-

K2CO3

DMSO

-

20c

Cu(OAc)2.H2O

K2CO3

DMSO

15

21

Co(OAc)2

K2CO3

DMSO

-

22

Ni(OAc)2

K2CO3

DMSO

trace

23d

Cu(OAc)2.H2O

K2CO3

DMSO

61

24e

Cu(OAc)2.H2O

K2CO3

DMSO

69



a

Reaction conditions: a mixture of N-(quinolin-8yl)benzamide (1a, 0.1 mmol), 4-methylbenzoyl azide

(0.2 mmol), metal catalyst (1.2 equiv), base (2 equiv), solvent (2 mL) was stirred at room temperature for 12 h. bPercent yield of the isolated product. c20 mol %.d10 h. e14 h.

RESULTS AND DISCUSSION To optimize the reaction conditions, several experiments were performed with variation of catalysts, base, and solvent for a representative reaction of N-(quinolin-8-yl)benzamide and 4methylbenzoyl azide as model substrates. The results are summarized in Table 1. Initially when the reaction was carried out using 1.2 equivalents of Cu(OAc)2.H2O, 2 equivalents of K2CO3 as base in acetonitrile (CH3CN) at room temperature, the product 2-(4-methylbenzamido)-N(quinolin-8-yl)benzamide was formed in 19% yield (Table 1, entry 1). The change of solvent to dichloroethane (DCE) and N,N,-dimethylformamide did not show any promising result (Table 1, entries 2 and 3). Interestingly when DMSO was used as solvent the yield of the product was dramatically improved to 71%. However, a small amount (5%) of the corresponding acetamide was isolated (Table 1, entry 4). The other solvents such as toluene, methanol and water remained ineffective (Table 1, entries 5-7). Use of Cs2CO3 as base did not initiate the reaction (Table 1, entry 8). However other bases such as NaOAc, Na2CO3, Et3N and K3PO4 led to substantially lower yields (Table 1, entries 9-12). The reaction did not proceed at all in the absence of base (Table 1, entry 13). After varying several copper salts, it is found that the Cu(OAc)2.H2O is the best choice (Table 1, entries 14-18). It should be noted that no reactivity was observed in the absence of copper salts (Table 1, entry 19). Reducing the amount of Cu(OAc)2.H2O to 20 mol % lowered the yield to 15% (Table 1, entry 20). The use of other metal salts such as Co(OAc)2 and Ni(OAc)2 virtually did not lead to any reaction.(Table 1, entries 21, 22). The decrease of reaction


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time to 10 h lowered the yield (Table 1, entry 23). On the other hand, the increase of time beyond 12 h did not push the yield further (Table 1, entry 24). Thus, in a general experimental procedure, a mixture of quinoline-8-yl benzamide and benzoyl azide in DMSO was stirred at room temperature in the presence of Cu(OAc)2 and K2CO3 for 1016 hours (TLC). Standard work-up and purification by column chromatography provided the product. To test the generality of this reaction a variety of quinoline benzamides were subjected to reaction with diversely substituted benzoyl azides by this procedure. The results are summarized in Scheme 2. A broad range of electron rich and electron poor aromatic amides underwent reaction with benzoyl azides to produce the corresponding bis amide derivatives. Several functional groups such as methoxy, trifluoromethoxy, fluoro, chloro, bromo and iodo groups at different positions of both the benzamide and azide derivatives remained inert during the reaction conditions (6, 7, 10, 11, 14, 15, 20, 21 and 22-24) providing scope for the further derivatization of the products. In case of meta-substitued amides excellent regioselectivity was observed towards C-H amidation as the reaction occurs selectively at the less hindered position (9, 21, 22, 23, and 24). Both 1- and 2-naphthoic acid amide derivatives underwent efficient reaction to provide the corresponding products (12, 13 and 14). The reaction with heterocyclic (thiophene) amide derivatives was also successful (15). The tert-butyloxycarbonyl (BOC) group protected 4-amino aryl amide coupled successfully with 4-methylbenzoyl azide to produce the respective product (27). Scheme 2: Amidation of sp2 C-H Bonds Using Acyl Azide with 1.2 Equivalents of Cu-salt at Room Temperaturea,b



a

Reaction conditions: a mixture of N-(quinolin-8yl)benzamide (1a, 0.2 mmol), aroyl azide (0.4 mmol),

Cu(OAc)2.H2O (0.24 mmol), K2CO3 (2 equiv), DMSO (2 mL) was stirred at room temperature for 12 h. bisolated product. c14 h. d10 h. e16 h.

As mentioned earlier, a small amount of 2-acetamido-N-(quinolin-8-yl) benzamide was formed in the reaction when 1.2 equiv of copper salt was used. However if the amount of copper was increased to 2.0 equivalents, the 2-acetamido-N-(quinolin-8-yl) benzamide was obtained as major product together with a small amount of benzoyl amide. Notably, no side product was isolated. However, a considerable amount of the starting amide (15-20%) was recovered. A series of diversely substituted quinoline amide derivatives underwent reaction with aroyl (benzoyl) azides to provide the corresponding 2-acetamido derivatives under this condition in good to excellent yields irrespective of the nature of benzoyl azide moiety. The results are summarized in Scheme 3. Both electron releasing and electron withdrawing group substituted amides and aroyl azides reacted efficiently under the conditions (28-37).


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Scheme 3: Reaction of Benzamide and Acyl Azide in Presence of 2 Equivalents of Cu-salta,b

a

Reaction conditions: a mixture of N-(quinolin-8yl)benzamide (1a, 0.2 mmol), 4-methylbenzoyl azide

(0.5 mmol), Cu(OAc)2.H2O (0.4 mmol), K2CO3 (2 equiv), DMSO (2 mL) was stirred at room temperature for 16 h. bisolated product.c4-bromo benzoyl azide. d14 h. e8 h.

All these products were not reported earlier. They are obtained pure after column chromatography and are characterized properly by spectroscopic (1H NMR,

13

C NMR, HRMS)

data. The structures of one representative benzamide 5 and acetamide 35 were further confirmed via XRD analysis.11 The yields of products are considerably good. We also performed the reaction on a gram scale and the product 1 was isolated in 63% yield (Scheme 4), which demonstrates the scalability of this C-H amidation reaction. Scheme 4. Gram Scale Experiment



To understand the reaction mechanism a series of control experiments were performed (Scheme 5). To check whether the reaction is going through a radical pathway, a radical quencher TEMPO (Tetramethyl pyridinyl N-oxide) was added to the reaction mixture (Scheme 5a). No change in the reaction time and yield of product was observed. Thus the involvement of any radical intermediate was ruled out. When an intermolecular competition between 1a and [D]5-1a was performed, the ratio of C−H bond amidation products 1 and [D]4-1 was found to be 3.77. This result indicates that the C-H bond cleavage may be initiated during the rate-limiting step (Scheme 5b). During optimization of the reaction parameters it was observed that when 20 mol % of the copper salt was used 15% of the product 1 was formed and when 1.2 equivalent was employed the yield of product was raised to 71%. However addition 1.5 equiv of Ag2CO3 as an oxidant in combination with 20 mol% of Cu(OAc)2.H2O increased the yield to 46% (Scheme 5c). These results indicate that an equivalent amount of copper salt was required for C-H cyclometallation process. To gain better understanding of the formation of acetyl product (Scheme 3), we carried out kinetic isotope effect experiment with 1a and [D]5-1a using 2 equivalents of Cu(OAc)2. A significant kinetic isotope effect (KH/KD = 3.16) was observed Scheme 5. Mechanistic Investigation


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(Scheme 6a) indicating this step as rate determining one. It was observed that the acetamide was formed when 2 equivalents of Cu(OAc)2 was employed irrespective of the solvent used. Thus it is likely that the acetyl part is introduced from Cu(OAc)2. As outlined in Table 1 the reaction was not initiated using other Cu-salts such as CuCl2.2H2O or CuSO4.5H2O. However when these reactions are performed in the presence of 3 equivalents of acetic acid, the corresponding acetamide was formed. This further supports the hypothesis that the acetyl part was coming from acetate moiety of Cu(OAc)2.H2O (Scheme 6b). Next, to find the reaction process of the formation of acetamide product, the benzamide was subjected to further reaction using 2 equivalents of Cu(OAc)2. Interestingly, no acetamide was obtained eliminating the possibility of intermediacy of benzamide (Scheme 6c, eqn 1). When the reaction was carried out using acetyl azide in place of benzoyl azide, the corresponding acetamide was obtained. Hence, it is likely that acetyl azide was produced during the reaction process. To check this possibility, a reaction was set up with benzoyl azide and 2 equivalents of Cu(OAc)2 in the presence of K2CO3 in DMSO at room temperature. To our expectation the acetyl azide was obtained (HRMS analysis) (Scheme 6c, eqn 3). Nevertheless, if the same reaction was performed using other Cu-salts in place of Cu(OAc)2 no product was formed. Thus, the formation of acetyl azide from benzoyl azide under this condition was established. Surprisingly,

other

aliphatic

carboxyl

amide

such

as

propanecarboxyl

cyclohexanecarboxyl azide remained inert under the present reaction conditions.. Scheme 6: Control Experiments


azide

and


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6a. Kinetic Isotope Experiment D

O N H

O

D

Q

N H

+ D

Q Stanard conditions

D D [D]4-1a

1a

[D]4-28

28 +

KH/KD = 3.16 O N3

6b. Reactions with other Cu-salts in presence of acetic acid O

O

O N H

Q

N3

+

1a

Cu-salt (2.0 equiv) K2CO3 (2.0 equiv) AcOH (3 equiv) DMSO, rt, 16 h

N H NH O

28 without with AcOH AcOH 29% 36%

CuCl2.2H2O CuSO4.5H2O O

6c. Intermediate Investigation O Cu(OAc)2.H2O Q N (2.0 equiv) H K2CO3 (2.0 equiv) NH DMSO, rt, 16 h

N H NH

O

Q

Q (1)

O 28, 0% 1 O

O N H

O

Q +

Cu(OAc)2.H2O (2.0 equiv) N3 K CO (2.0 equiv) 2 3 DMSO, rt, 16 h

1a

N H NH

Q (2)

O 28, 41% O N3

O

O

Cu(OAc)2.H2O (2.0 equiv) K2CO3 (2.0 equiv) DMSO, rt, 16 h

N3

(3)

(Detected by HRMS analysis)

O

O

Q

N H +

O N3

+

N3

Cu(OAc)2.H2O (2.0 equiv) K2CO3 (2.0 equiv) DMSO, rt, 16 h

N H NH O 28, 58%

O Q N H NH

+

Q

O 1, trace

In accordance with the results of investigative control experiments, a mechanism has been suggested for the formation of both quinoline benzamide and acetamide, as outlined in Scheme 7. Initially, Cu(II) forms a cyclometallated intermediate with activation of adjacent C(sp2)-H bond.7p-x The formation of intermediate A is supported by HRMS analysis (See SI). The acyl azide then interacts with the metal center leading to the formation of intermediate B


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which is subsequently converted to intermediate C releasing N2.10,12 Finally protonolysis of intermediate C delivers the product 1 via reductive elimination with the regeneration of the active catalyst Cu(II)). On the other hand, when 2 equivalents of copper salt is used the acyl azide reacts with Cu(II) acetate in the presence of base K2CO3 to form acetyl azide which leads to the corresponding acetamide following a similar cycle. Scheme 7. Proposed Reaction Mechanism

CONCLUSION In conclusion, we have developed a convenient procedure for ortho-C(sp2)−H amidation of 8aminoquinoline benzamide with acyl azide promoted by copper(II) acetate via C-H activation. Selective formation of aroyl and acetyl amides was achieved based on catalyst loading. The use of one equivalent of Cu(OAc)2 produces the usual benzamide products, whereas two equivalents of Cu(OAc)2 under the same reaction conditions lead to the corresponding acetamides. This is interesting and is not reported earlier. The formation of unusual acetamide product was explained



based on control experiments. The remarkable feature of this reaction is the formation of quinoline tagged bis-amides, which might be of potential in pharmaceutical industry.8 The other attractive advantages are use of inexpensive and less toxic Cu-salt as catalyst, reaction at room temperature and good yield of products. We believe, this procedure will find useful applications for the synthesis of organo-bis amides.

EXPERIMENTAL SECTION General Experimental Information. NMR spectra were recorded on 500, 400, 300 MHz instruments for 1H spectra and 125, 100, 75 MHz instrument for 13C spectra. HRMS analysis was performed in a Qtof mass analyzer using ESI ionization method. Elemental analyses are done at our Institute using an autoanalyser.

Amides were prepared from 8-aminoquinoline and

corresponding acids according to literature procedures.13 Acyl azides were prepared from corresponding acyl chlorides according to literature procedures.14 Representative experimental procedure for the reaction of N-(quinolin-8-yl)benzamide and 4-methylbenzoyl azide to 2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (Scheme 2, 1) A dry screw cap tube (10 mL) equipped with a magnetic stirring bar was charged with N(quinolin-8-yl)benzamide (49 mg, 0.2 mmol), 4-methylbenzoyl azide (64 mg, 0.4 mmol), Cu(OAc)2.H2O (47 mg, 0.24 mmol, 1.2 equiv.), K2CO3 (55 mg, 0.4 mmol, 2 equiv.) and DMSO (2 mL). Then the reaction mixture was stirred at room temperature. After completion of the reaction (TLC) the mixture was extracted with EtOAc (3x20 mL). The organic phase was dried (Na2SO4) and evaporated to leave the crude product, which was purified by silica gel column chromatography (hexane –EtOAc, 94:6) to provide the pure 2-(4-methylbenzamido)-N(quinolin-8-yl)benzamide as a white solid (54 mg, 71%) . 1H NMR (300 MHz, Chloroform-d) δ


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12.21 (s, 1H), 10.86 (s, 1H), 8.96 – 8.89 (m, 2H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.03 – 7.95 (m, 3H), 7.66 – 7.57 (m, 3H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 – 7.24 (m, 1H), 2.44 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 167.7,

165.8, 148.7, 142.4, 140.9, 139.0, 136.6, 134.3, 133.3, 132.4, 129.6, 128.2, 127.6, 127.4, 127.2, 123.1, 122.4, 122.0, 121.9, 121.0, 117.0, 21.7. This above procedure was followed for all the reactions listed in Scheme 2. These compounds are not reported earlier and were characterized properly by their spectroscopic and spectrometric data (IR, 1H NMR, 13C NMR, HRMS and elemental analysis). General Procedure (Scheme 3) Representative experimental procedure for the reaction of N-(quinolin-8-yl)benzamide and 4-methylbenzoyl azide to 2-acetamido-N-(quinolin-8-yl)benzamide (Scheme 3, 28)

A dry screw cap tube (10 mL) equipped with a magnetic stirring bar was charged with N(quinolin-8-yl)benzamide (49 mg, 0.2 mmol), 4-methylbenzoyl azide (80 mg, 0.5 mmol, 2.5 equiv), Cu(OAc)2.H2O (79 mg, 0.4 mmol, 2.0 equiv.), K2CO3 (55 mg, 0.4 mmol, 2 equiv.) and DMSO (2 mL). Then the reaction mixture was stirred at room temperature. After completion of the reaction (TLC) the mixture was extracted with EtOAc (3x20 mL). The organic phase was dried (Na2SO4) and evaporated to leave the crude product, which was purified by silica gel column chromatography (hexane–EtOAc, 92:8) to provide the pure 2-acetamido-N-(quinolin-8yl)benzamide as a white solid (41 mg, 67%). 1H NMR (300 MHz, Chloroform-d) δ 11.16 (s, 1H), 10.79 (s, 1H), 8.85 (td, J = 5.9, 2.3 Hz, 2H), 8.76 – 8.64 (m, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.67 – 7.54 (m, 3H), 7.54 – 7.46 (m, 1H), 7.22 (dd, J = 7.6,



1.2 Hz, 1H), 2.25 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 169.2, 167.5, 148.7, 140.3, 139.0,

136.6, 134.2, 133.2, 129.9, 128.2, 127.4, 127.2, 123.2, 122.5, 122.0, 121.80, 120.9, 116.9, 25.6.

This above procedure was followed for all the reactions listed in Scheme 3. These compounds are not reported earlier and were characterized properly by their spectroscopic and spectrometric data (IR, 1H NMR, 13C NMR, HRMS and elemental analysis).

2-(4-Methylbenzamido)-N-(quinolin-8-yl)benzamide (1): White solid (54 mg, 71% ) m.p. 167169 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.21 (s, 1H), 10.86 (s, 1H), 8.96 – 8.89 (m, 2H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.03 – 7.95 (m, 3H), 7.66 – 7.57 (m, 3H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 – 7.24 (m, 1H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.7, 165.8, 148.7, 142.4, 140.9, 139.0, 136.6, 134.3, 133.3, 132.4, 129.6, 128.2, 127.6, 127.4, 127.2, 123.1, 122.4, 122.0, 121.90, 121.0, 117.0, 21.7. IR (cm1

): 3342, 2922, 2847, 1675, 1652, 1588, 1524, 1424, 750. HRMS: m/z calcd for C24H19N3NaO2:

404.1375 [M + Na]+; found: 404.1375. 4-Methyl-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (2): White solid (53 mg, 68%) m.p. 186-188 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.30 (s, 1H), 10.83 (s, 1H), 8.94 – 8.82 (m, 2H), 8.82 – 8.74 (m, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 8.03 – 7.97 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.68 – 7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.38 – 7.29 (m, 2H), 7.07 (ddd, J = 8.0, 1.7, 0.7 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 167.7, 165.8,

148.6, 144.3, 142.4, 141.0, 139.0, 136.60, 134.4, 132.4, 129.6, 128.2, 127.6, 127.5, 127.2, 124.0, 122.3, 122.2, 122.0, 118.2, 117.0, 22.2, 21.7. IR (cm-1): 3346, 2922, 2854, 1674, 1651, 1581, 1528, 1423, 745. HRMS: m/z calcd for C25H21N3NaO2: 418.1526 [M + Na]+ ; found: 418.1531.


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4-Ethyl-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (3): White solid (57 mg, 70%) m.p. 154-156 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.32 (s, 1H), 10.84 (s, 1H), 8.90 (dd, J = 7.0, 2.0 Hz, 1H), 8.86 (dd, J = 4.3, 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 8.06 – 7.95 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.68 – 7.52 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 2.78 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.7, 165.9, 150.5, 148.6, 142.4, 141.1, 139.0, 136.6, 134.4, 132.5, 129.6, 128.2, 127.6, 127.5, 127.3, 122.8, 122.2, 122.0, 121.1, 118.4, 116.9, 29.4, 21.7, 15.3. IR (cm-1): 3350, 2961, 2925, 1675, 1611, 1579, 1529, 1387, 744. HRMS: m/z calcd for C26H24N3O2: 410.1863 [M + H]+ ; found: 410.1864. 4-Butyl-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (4): White solid (64 mg, 73%) m.p. 153-155 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.33 (s, 1H), 10.83 (s, 1H), 8.90 (dd, J = 7.1, 1.9 Hz, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 – 7.97 (m, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.65 – 7.54 (m, 2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.08 (dd, J = 8.1, 1.7 Hz, 1H), 2.79 – 2.69 (m, 2H), 2.44 (s, 3H), 1.79 – 1.63 (m, 2H), 1.43 (dq, J = 14.5, 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H).

13

C NMR (75

MHz, CDCl3) δ 167.7, 165.8, 149.2, 148.6, 142.3, 141.0, 138.9, 136.6, 134.3, 132.4, 129.6, 128.2, 127.6, 127.4, 127.2, 123.3, 122.2, 121.9, 121.6, 118.3, 116.9, 36.2, 33.4, 22.6, 21.7, 14.1. IR (cm-1): 3346, 2956, 2929, 1675, 1650, 1579, 1526, 1423, 744. HRMS: m/z calcd for C28H27N3O2Na: 460.1995 [M + Na]+ ; found: 460.2001. 4-(Tert-butyl)-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (5): White solid (58 mg, 66%) m.p. 190-192 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.34 (s, 1H), 10.85 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.90 (dd, J = 7.1, 1.9 Hz, 1H), 8.85 (dd, J = 4.3, 1.7 Hz, 1H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H), 8.07 – 7.97 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.67 – 7.51 (m, 2H), 7.48 (dd, J =



Page 16 of 34

8.3, 4.2 Hz, 1H), 7.39 – 7.25 (m, 3H), 2.44 (s, 3H), 1.43 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 167.6, 165.9, 157.3, 148.6, 142.3, 141.0, 139.0, 136.6, 134.3, 132.5, 129.6, 128.2, 127.6, 127.45, 127.0, 122.2, 121.9, 120.3, 118.9, 118.0, 116.9, 35.6, 31.2, 21.7. IR (cm-1): 3345, 2964, 2867, 1652, 1611, 1532, 1442, 1422, 1328, 744. HRMS: m/z calcd for C28H28N3O2: 438.2176 [M + H]+ ; found: 438.2178. 4-Fluoro-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (6): White solid (61 mg, 77%) m.p. 199-201 oC. 1H NMR (400 MHz, Chloroform-d) δ 12.47 (s, 1H), 10.82 (s, 1H), 8.92 – 8.84 (m, 2H), 8.78 (dd, J = 11.9, 2.6 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.03 – 7.93 (m, 3H), 7.67 – 7.56 (m, 2H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.95 (ddd, J = 8.6, 7.4, 2.7 Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.0, 166.0, 165.5 (d, JC-F = 252 Hz), 148.7, 143.3 (d, JC-F = 13 Hz), 142.8, 139.0, 136.6, 134.1, 132.0, 129.7, 129.2 (d, JC-F = 10 Hz), 128.2, 127.7, 127.4, 122.3 (d, JC-F = 46 Hz), 117.0, 116.8, 116.8, 110.2 (d, JC-F = 22 Hz), 108.9 (d, JC-F = 24 Hz), 21.7. IR (cm-1): 3346, 2925, 2860, 1683, 1660, 1602, 1531, 1444, 746. Anal. calcd. for C24H18FN3O2: C, 72.17; H, 4.54; N, 10.52; found: C 72.29; H 4.89; N 10.60%. 2-(4-Methylbenzamido)-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide

(8):

Colorless

sticky liquid (67 mg, 75%). 1H NMR (300 MHz, Chloroform-d) δ 12.21 (s, 1H), 10.92 (s, 1H), 9.31 (s, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.90 – 8.85 (m, 1H), 8.23 (dd, J = 8.3, 1.6 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 4.9 Hz, 2H), 7.53 (dd, J = 8.0, 4.8 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H).

13

C NMR (126 MHz, CDCl3) δ 166.5, 165.9, 148.8,

142.9, 141.3, 138.9, 136.7, 133.8, 131.8, 129.7, 127.6 (q, JC-F = 42 Hz), 127.7, 123.5, 123.0, 122.2, 119.6, 118.9, 117.3, 21.7. IR (cm-1): 3335, 2925, 2850, 1658, 1613, 1586, 1528, 1426, 1335, 729. Anal. calcd. for C25H18F3N3O2: C, 66.81; H, 4.04; N, 9.35; found: C, 66.85; H, 4.05; N, 9.37%.


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3-(4-Methylbenzamido)-N-(quinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide (8): White solid (63 mg, 69%) m.p. 212-214 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.39 (s, 1H), 10.92 (s, 1H), 9.28 (d, J = 1.8 Hz, 1H), 8.93 (dd, J = 7.0, 2.0 Hz, 1H), 8.88 (dd, J = 4.3, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 8.07 – 8.01 (m, 3H), 7.80 – 7.74 (m, 2H), 7.67 – 7.59 (m, 2H), 7.54 – 7.45 (m, 4H), 7.44 – 7.40 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 165.9, 148.7, 146.0, 142.5, 141.5, 139.9, 139.0, 136.6, 134.3, 132.3, 129.6, 129.0, 128.4, 128.2, 127.7, 127.6, 127.5, 127.5, 122.4, 122.0, 121.6, 120.3, 119.3, 117.00, 21.7. IR (cm-1): 3343, 2980, 2922, 1669, 1641, 1528, 1441, 790. Anal. calcd. for C30H23N3O2: C, 78.75; H, 5.07; N, 9.18; found: C 78.89; H 5.19; N 9.22%. 5-Methyl-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (9): White solid (55 mg, 70%) m.p. 202-204 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.04 (s, 1H), 10.79 (s, 1H), 8.98 – 8.84 (m, 2H), 8.79 (d, J = 8.5 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.76 – 7.71 (m, 1H), 7.67 – 7.56 (m, 2H), 7.50 (dd, J = 8.3, 4.3 Hz, 1H), 7.43 (dd, J = 8.6, 2.0 Hz, 1H), 7.38 – 7.28 (m, 2H), 2.48 (s, 3H), 2.43 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 167.8, 165.7, 148.7,

142.3, 139.00, 138.3, 136.6, 134.3, 134.0, 132.7, 132.4, 129.5, 128.2, 127.6, 127.5, 127.4, 122.40, 122.0, 121.90, 121.1, 117.0, 21.7, 21.2. IR (cm-1): 3344, 2915, 1670, 1657, 1578, 1522, 1445, 789. Anal. calcd. for C25H21N3O2: C, 75.93; H, 5.35; N, 10.63; found: C, 75.98; H, 5.41; N, 10.67%. N-(6-Methoxyquinolin-8-yl)-4-methyl-2-(4-methylbenzamido)benzamide (10): White solid (64 mg, 74%) m.p. 183-185 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.31 (s, 1H), 10.79 (s, 1H), 8.84 – 8.75 (m, 1H), 8.69 (dd, J = 4.3, 1.6 Hz, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 8.3, 1.6 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 2.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.06 (dd, J = 8.2, 1.7 Hz, 1H), 6.84 (d, J = 2.7



Hz, 1H), 3.98 (s, 3H), 2.48 (s, 3H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.7, 165.9, 158.6, 146.0, 144.4, 142.4, 141.1, 135.7, 135.3, 135.2, 132.5, 130.4, 129.6, 129.3, 129.2, 127.7, 127.2, 124.0, 122.4, 122.2, 118.0, 109.8, 100.0, 55.8, 22.1, 21.6. IR (cm-1): 3341, 2922, 2857, 1668, 1620, 1542, 1525, 1463, 772. Anal. calcd. for C26H23N3O3: C, 73.39; H, 5.45; N, 9.88; found: C, 73.44; H, 5.52; N, 9.89%. 2-Benzamido-N-(6-methoxyquinolin-8-yl)-4-methylbenzamide (11): White solid (59 mg, 72%) m.p. 143-145 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.37 (s, 1H), 10.81 (s, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.69 (dd, J = 4.3, 1.6 Hz, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.15 – 8.04 (m, 3H), 7.87 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 5.2, 2.0 Hz, 3H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.12 – 7.04 (m, 1H), 6.85 (d, J = 2.7 Hz, 1H), 3.98 (s, 3H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.7, 165.8, 158.6, 146.0, 144.4, 141.0, 135.7, 135.3, 135.2, 131.91, 129.2, 128.9, 127.6, 127.2, 124.1, 122.4, 122.3, 118.1, 109.8, 100.0, 55.8, 22.2. IR (cm-1): 3340, 2924, 1676, 1653, 1581, 1529, 1451, 704. Anal. calcd. for C25H21N3O3: C, 72.98; H, 5.14; N, 10.21; found: C, 73.02; H, 5.19; N, 10.22%. 2-(4-Methylbenzamido)-N-(quinolin-8-yl)-1-naphthamide (12): White solid (59 mg, 68%) m.p. 187-189 oC. 1H NMR (300 MHz, Chloroform-d) δ 10.54 (s, 1H), 10.44 (s, 1H), 9.05 (dd, J = 7.1, 1.9 Hz, 1H), 8.73 (d, J = 9.1 Hz, 1H), 8.66 (dd, J = 4.2, 1.7 Hz, 1H), 8.29 – 8.21 (m, 1H), 8.18 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 9.9, 7.4 Hz, 3H), 7.70 – 7.58 (m, 2H), 7.57 – 7.47 (m, 2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H).

13

C NMR (126 MHz, CDCl3) δ 167.2, 165.7, 148.7, 142.7, 138.8, 136.4, 136.4, 134.2,

131.9, 131.7, 130.9, 130.4, 129.6, 128.8, 128.2, 127.9, 127.6, 127.4, 125.4, 124.7, 122.8, 122.0, 121.4, 121.0, 117.3, 21.7. IR (cm-1): 3348, 2968, 1680, 1658, 1574, 1519, 748. Anal. calcd. for C28H21N3O2: C, 77.94; H, 4.91; N, 9.74; found: C, 78.02; H, 5.01; N, 9.79%.


Page 18 of 34

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3-(4-Methylbenzamido)-N-(quinolin-8-yl)-2-naphthamide (13): White solid (61 mg, 71%) m.p. 191-193 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.94 (s, 1H), 10.97 (s, 1H), 9.35 (s, 1H), 8.95 (dd, J = 6.7, 2.3 Hz, 1H), 8.89 (dd, J = 4.3, 1.6 Hz, 1H), 8.48 (s, 1H), 8.23 (dd, J = 8.3, 1.7 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.95 (dd, J = 12.4, 8.2 Hz, 2H), 7.69 – 7.62 (m, 2H), 7.62 – 7.57 (m, 1H), 7.56 – 7.46 (m, 2H), 7.35 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H).

13

C NMR (126

MHz, CDCl3) δ 167.9, 165.8, 148.8, 142.4, 139.00, 138.1, 136.6, 135.9, 134.3, 132.4, 129.6, 128.8, 128.7, 128.5, 128.1, 127.6, 127.5, 125.8, 122.6, 122.1, 118.9, 117.2, 100.1, 21.7. IR (cm1

): 3345, 2920, 2842, 1655, 1628, 1571, 1452, 733. Anal. calcd. for C28H21N3O2: C, 77.94; H,

4.91; N, 9.74; found: C, 77.98; H, 4.95; N, 9.77%. 7-Bromo-3-(4-methylbenzamido)-N-(quinolin-8-yl)-2-naphthamide (14): White crystalline solid (71 mg, 70%) m.p. 196-198 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.97 (s, 1H), 10.95 (s, 1H), 9.27 (s, 1H), 8.94 (dd, J = 6.2, 2.7 Hz, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.43 (s, 1H), 8.24 (dd, J = 8.3, 1.7 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), 8.04 – 7.98 (m, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.58 (d, J = 1.9 Hz, 0H), 7.56 – 7.50 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 167.5, 165.9, 148.8, 142.5, 138.9, 136.9, 136.9,

136.7, 134.1, 132.2, 130.2, 130.0, 129.6, 129.3, 128.4, 128.2, 127.6, 127.5, 127.3, 123.3, 122.88, 122.8, 122.1, 117.8, 117.3, 21.7. IR (cm-1): 3335, 2922, 2853, 1667, 1612, 1544, 1531, 1471, 794. Anal. calcd. for C28H20BrN3O2: C, 65.89; H, 3.95; N, 8.23; found: C 65.95; H 4.19; N 8.42%. 3-(4-Fluorobenzamido)-N-(quinolin-8-yl)thiophene-2-carboxamide (15): Orange gummy liquid (54 mg, 69%). 1H NMR (300 MHz, Chloroform-d) δ 12.09 (s, 1H), 10.44 (s, 1H), 8.90 (dd, J = 4.3, 1.6 Hz, 1H), 8.83 (dd, J = 6.8, 2.1 Hz, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.21 (dd, J = 8.4, 1.7 Hz, 1H), 8.17 – 8.07 (m, 2H), 7.68 – 7.56 (m, 2H), 7.51 (dd, J = 8.5, 4.6 Hz, 2H), 7.21



(d, J = 8.6 Hz, 1H).

Page 20 of 34

13

C NMR (101 MHz, CDCl3) δ 165.4 (d, JC-F = 252 Hz), 163.5, 163.1,

148.7, 144.7, 138.7, 136.6, 134.2, 130.3 (d, JC-F = 3.0 Hz), 130.2 (d, JC-F = 9.0 Hz), 128.2, 128.2, 127.5, 123.6, 122.1 (d, JC-F = 15 Hz), 116.8, 116.1 (d, JC-F = 22 Hz), 114.0, 100.1. IR (cm-1): 3342, 2926, 1678, 1645, 1548, 1520, 1442, 743. Anal. calcd. for C21H14FN3O2S: C, 64.44; H, 3.61; N, 10.74; found: C, 64.50; H, 3.70; N, 10.75%. 3'-Methyl-3-(4-methylbenzamido)-N-(quinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide

(16):

Crystalline brown solid (68 mg, 72%) m.p. 207-209 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.09 (s, 1H), 10.90 (s, 1H), 8.98 (d, J = 8.7 Hz, 1H), 8.92 (dd, J = 6.8, 2.1 Hz, 1H), 8.84 (dd, J = 4.3, 1.5 Hz, 1H), 8.21 (dd, J = 8.3, 1.6 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 7.9 Hz, 2H), 7.84 (dd, J = 8.7, 2.0 Hz, 1H), 7.69 – 7.56 (m, 2H), 7.51 (d, J = 5.9 Hz, 2H), 7.48 (d, J = 4.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 6 Hz, 1H), 2.47 (s, 3H), 2.45 (s, 3H).

13

C NMR (126 MHz, CDCl3) δ 167.8, 165.8, 148.8, 142.5, 140.09, 139.8, 139.0,

138.8, 136.6, 136.2, 134.3, 132.4, 131.9, 129.6, 129.1, 128.4, 128.2, 127.9, 127.7, 127.4, 125.70, 124.2, 122.5, 122.3, 122.0, 121.8, 117.2, 21.7, 21.7. IR (cm-1): 3341, 2925, 2859, 1669, 1625, 1552, 1531, 1471, 790. Anal. calcd. for C31H25N3O2: C, 78.96; H, 5.34; N, 8.91; found: C, 79.02; H, 5.39; N, 8.93%. 2-(4-Ethylbenzamido)-N-(quinolin-8-yl)benzamide (17) White solid (59 mg, 75%) m.p. 161163 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.21 (s, 1H), 10.87 (s, 1H), 8.96 – 8.89 (m, 2H), 8.87 (dd, J = 4.3, 1.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.06 – 8.00 (m, 2H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.67 – 7.59 (m, 3H), 7.50 (dd, J = 8.3, 4.3 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.307.24 (m, 1H), 2.74 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.7, 165.9, 148.7, 140.9, 139.0, 136.6, 134.3, 133.3, 132.6, 128.4, 128.2, 127.7, 127.4, 127.26, 123.1, 122.4, 122.0, 121.9, 121.0, 117.0, 29.0, 15.4. IR (cm-1): 3341, 2965, 2935, 1675, 1659,


Page 21 of 34 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


1588, 1523, 1442, 754. HRMS: m/z calcd for C25H21N3NaO2: 418.1526 [M + Na]+ ; found: 418.1530. 2-(4-(Tert-butyl)benzamido)-N-(quinolin-8-yl)benzamide (18) White solid (64 mg, 76%) m.p. 179-181 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.22 (s, 1H), 10.86 (s, 1H), 8.98 – 8.89 (m, 2H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 8.07 – 8.01 (m, 2H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (dddd, J = 15.4, 8.6, 7.3, 1.9 Hz, 5H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.31 – 7.23 (m, 1H), 1.37 (s, 9H).

13

C NMR (75 MHz, CDCl3) δ 167.6, 165.8, 155.5, 148.6,

140.9, 139.0, 136.6, 134.3, 133.3, 132.3, 128.2, 127.5, 127.4, 127.2, 125.9, 123.1, 122.4, 121.99, 121.9, 121.0, 117.0, 35.1, 31.3. IR (cm-1): 3346, 2963, 2863, 1677, 1661, 1587, 1523, 1442, 759. Anal. calcd. for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92; found: C, 76.60; H, 5.99; N, 9.93%. 3,5-Dimethyl-N-(2-(quinolin-8-ylcarbamoyl)phenyl)benzamide (19) White solid (52 mg, 65%) m.p. 160-162 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.10 (s, 1H), 10.85 (s, 1H), 8.96 – 8.80 (m, 3H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.5 Hz, 1H), 7.68 (s, 2H), 7.65 – 7.52 (m, 3H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.32 – 7.21 (m, 1H), 7.18 (s, 1H), 2.43 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 167.5, 166.3, 148.6, 140.7, 138.9, 138.5, 136.5, 135.2, 134.3, 133.6, 133.2, 128.1, 127.4, 127.2, 125.4, 123.2, 122.4, 122.0, 122.0, 121.2, 116.9, 21.5. IR (cm-1): 3342, 2918, 2847, 1676, 1662, 1587, 1520, 755. HRMS: m/z calcd for C25H22N3O2: 396.1707 [M + H]+ ; found: 396.1707. 2-(4-Fluorobenzamido)-4-methyl-N-(quinolin-8-yl)benzamide (20): White solid (50 mg, 63%) m.p. 159-161 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.40 (s, 1H), 10.87 (s, 1H), 8.95 – 8.82 (m, 2H), 8.76 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 8.16 – 8.08 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.25 – 7.17 (m, 2H), 7.12 – 7.05 (m, 1H), 2.49 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 166.8, 166.3, 166.2 (d, JC-F = 230



Hz), 148.6, 144.4, 140.8, 139.0, 136.6, 134.3, 131.4 (d, JC-F = 3.75 Hz), 130.0 (d, JC-F = 9.0 Hz), 128.2, 127.5, 127.2, 124.2, 122.4, 122.1 (d, JC-F = 8.25 Hz), 118.0, 116.9, 115.9 (d, JC-F = 21.75 Hz),, 22.2. IR (cm-1): 3346, 2931, 1677, 1659, 1603, 1530, 1508, 1445, 1423, 757. Anal. calcd. for C24H18FN3O2: C, 72.17; H, 4.54; N, 10.52; found: C 72.29, H 4.61, N 10.61%. 2-(4-Fluorobenzamido)-5-methyl-N-(quinolin-8-yl)benzamide (21): White solid (52 mg, 65%) m.p. 176-178 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.13 (s, 1H), 10.83 (s, 1H), 8.92 – 8.86 (m, 2H), 8.77 (d, J = 8.5 Hz, 1H), 8.22 (dd, J = 8.3, 1.7 Hz, 1H), 8.14 – 8.05 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.51 (dd, J = 8.3, 4.3 Hz, 1H), 7.44 (dd, J = 8.6, 2.0 Hz, 1H), 7.20 (t, J = 8.7 Hz, 2H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.8, 165.1 (d, JC-F = 252 Hz), 164.5, 148.7, 139.0, 138.2, 136.6, 134.2, 134.1, 133.00, 131.4, 131.4, 123.0 (d, JC-F = 8.75 Hz), 128.2, 127.5 (d, JC-F = 10 Hz), 122.5, 121.9 (d, JC-F = 23.75 Hz), 121.0, 117.1, 115.9 (d, JC-F = 21.25 Hz), 21.2. IR (cm-1): 3344, 2925, 1674, 1650, 1602, 1524, 1508, 756. Anal. calcd. for C24H18FN3O2: C, 72.17; H, 4.54; N, 10.52; found: C 72.32, H 4.68, N 10.70%. 2-(4-Chlorobenzamido)-5-methyl-N-(quinolin-8-yl)benzamide (22): White solid (54 mg, 64%) m.p. 137-139 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.18 (s, 1H), 10.83 (s, 1H), 8.92 – 8.85 (m, 2H), 8.77 (d, J = 8.5 Hz, 1H), 8.22 (dd, J = 8.3, 1.7 Hz, 1H), 8.06 – 7.99 (m, 2H), 7.77 – 7.74 (m, 1H), 7.67 – 7.58 (m, 2H), 7.55 – 7.47 (m, 3H), 7.44 (dd, J = 8.6, 2.0 Hz, 1H), 2.49 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 167.8, 164.5, 148.7, 139.0, 138.2, 136.6, 134.2, 134.1,

133.7, 133.1, 129.1, 129.0, 128.2, 127.5, 127.5, 122.5, 122.0, 121.9, 121.0, 117.1, 21.3. IR (cm1

): 3340, 2920, 2857, 1677, 1662, 1568, 1525, 1444, 752. Anal. calcd. for C24H18ClN3O2: C,

69.31; H, 4.36; N, 10.10; found: C 69.40; H 4.39; N 10.22%. 2-(3-Chlorobenzamido)-5-methyl-N-(quinolin-8-yl)benzamide (23): Brown solid (56 mg, 67%) m.p. 188-190 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.20 (s, 1H), 10.86 (s, 1H), 8.96 –


Page 22 of 34

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8.88 (m, 2H), 8.86 (dd, J = 4.3, 1.6 Hz, 1H), 8.20 (dd, J = 8.3, 1.6 Hz, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.66 – 7.56 (m, 3H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.32 – 7.24 (m, 1H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.6, 166.1, 148.6, 140.8, 138.9, 138.7, 136.6, 135.1, 134.2, 133.3, 132.7, 128.7, 128.5, 128.1, 127.4, 127.2, 124.45, 123.2, 122.4, 122.0, 121.9, 121.1, 117.0, 21.6. IR (cm-1): 3343, 2922, 2850, 1677, 1649, 1588, 1523, 1423, 752. Anal. calcd. for C24H18ClN3O2: C, 69.31; H, 4.36; N, 10.10; found: C 69.37; H 4.38; N 10.19%. 5-Iodo-2-(4-methylbenzamido)-N-(quinolin-8-yl)benzamide (24): White solid (70 mg, 69%) m.p. 194-196 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.01 (s, 1H), 10.74 (s, 1H), 8.90 (dd, J = 4.3, 1.7 Hz, 1H), 8.88 – 8.83 (m, 1H), 8.71 (d, J = 8.9 Hz, 1H), 8.21 (td, J = 4.6, 4.0, 1.7 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.88 (dd, J = 8.9, 2.0 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.23=, 165.8, 148.9, 142.7, 141.9, 140.5, 136.6, 135.8, 134.0, 132.1, 129.6, 128.2, 127.7, 127.4, 123.8, 123.3, 122.8, 122.1, 117.3, 85.6, 21.7. IR (cm-1): 3334, 2931, 2850, 1677, 1644, 1592, 1534, 1500, 1424, 742. HRMS: m/z calcd for C24H19IN3O2: 508.0516 [M + H]+ ; found: 508.0519. N-(2-(Quinolin-8-ylcarbamoyl)phenyl)-1-naphthamide (25): White crystalline solid (59 mg, 71%) m.p. 209-211 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.44 (s, 1H), 10.91 (s, 1H), 8.96 (ddd, J = 9.3, 7.8, 1.6 Hz, 2H), 8.88 (dd, J = 4.3, 1.7 Hz, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.18 (ddd, J = 17.1, 8.4, 1.8 Hz, 2H), 8.10 – 7.96 (m, 3H), 7.96 – 7.87 (m, 1H), 7.73 – 7.55 (m, 5H), 7.51 (dd, J = 8.3, 4.3 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz, 1H).

13

C NMR (101 MHz, CDCl3) δ

167.7, 165.9, 148.7, 140.9, 139.0, 136.6, 135.2, 134.3, 133.4, 133.0, 132.4, 129.6, 128.8, 128.6, 128.2, 127.9, 127.9, 127.5, 127.3, 126.8, 124.0, 123.3, 122.5, 122.0, 121.1, 117.1. IR (cm-1):



Page 24 of 34

3338, 2924, 2860, 1674, 1661, 1587, 1521, 1423, 755. HRMS: m/z calcd for C27H19N3O2Na: 440.1369 [M + Na]+ ; found: 440.1375. N-(2-(Quinolin-8-ylcarbamoyl)phenyl)-2-naphthamide (26): White solid (61 mg, 73%) m.p. 204-206 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.44 (s, 1H), 10.91 (s, 1H), 8.96 (t, J = 9.4 Hz, 2H), 8.87 (s, 1H), 8.64 (s, 1H), 8.18 (dd, J = 16.1, 8.6 Hz, 2H), 8.02 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 6.7 Hz, 1H), 7.73 – 7.54 (m, 5H), 7.50 (dd, J = 7.8, 3.8 Hz, 1H), 7.28 (d, J = 12.6 Hz, 2H).

13

C NMR (126 MHz, CDCl3) δ 167.7, 165.9, 148.7, 140.9, 139.00, 136.6, 135.2, 134.3,

133.4, 133.0, 132.4, 129.6, 128.8, 128.6, 128.2, 127.9, 127.9, 127.50, 127.3, 126.8, 124.0, 123.3, 122.50, 122.0, 121.1, 117.1. IR (cm-1): 3353, 3055, 2923, 2854, 1675, 1660, 1588, 1523, 1443, 756. Anal. calcd. for C27H19N3O2: C, 77.68; H, 4.59; N, 10.07; found: C, 77.75; H, 4.66; N, 10.10. Tert-butyl

(3-(4-methylbenzamido)-4-(quinolin-8-ylcarbamoyl)phenyl)carbamate

(27):

White solid (78 mg, 78%) m.p. 223-225 oC. 1H NMR (300 MHz, Chloroform-d) δ 12.50 (s, 1H), 10.83 (s, 1H), 8.92 – 8.81 (m, 2H), 8.72 (d, J = 2.3 Hz, 1H), 8.19 (ddd, J = 8.3, 3.5, 1.7 Hz, 1H), 8.07 – 7.92 (m, 3H), 7.73 (dd, J = 8.8, 2.2 Hz, 1H), 7.64 – 7.54 (m, 2H), 7.52 – 7.47 (m, 1H), 7.36 – 7.31 (m, 2H), 6.91 (s, 1H), 2.44 (s, 3H), 1.54 (s, 9H).

13

C NMR (126 MHz, CDCl3) δ

167.4, 166.0, 152.5, 148.6, 148.4, 143.2, 142.5, 142.1, 139.0, 136.5, 136.5, 134.4, 132.4, 129.6, 128.7, 128.7, 128.2, 127.7, 127.7, 127.5, 122.2, 122.0, 121.8, 121.6, 118.1, 116.9, 116.6, 114.93, 112.5, 110.2, 81.3, 28.5, 21.7. IR (cm-1): 3337, 2983, 2925, 1735, 1648, 1602, 1596, 1522, 1411. HRMS: m/z calcd for C29H28N4NaO4: 519.2008 [M + Na]+; found: 519.2008. 2-Acetamido-N-(quinolin-8-yl)benzamide (28): White solid (41 mg, 67%) m.p. 144-146 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.16 (s, 1H), 10.79 (s, 1H), 8.85 (td, J = 5.9, 2.3 Hz, 2H), 8.76 – 8.64 (m, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.67 – 7.54


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(m, 3H), 7.54 – 7.46 (m, 1H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 2.25 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 169.2, 167.5, 148.7, 140.3, 138.9, 136.6, 134.2, 133.2, 129.9, 128.2, 127.4, 127.2, 123.2, 122.5, 122.0, 121.8, 120.9, 116.9, 25.6. IR (cm-1): 3330, 2928, 1693, 1662, 1578, 1520, 1450, 775. Anal. calcd. for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76; found: C, 70.82; H, 4.99; N, 13.80%. 2-Acetamido-4-methyl-N-(quinolin-8-yl)benzamide (29): White solid (47 mg, 73%) m.p. 143145 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.25 (s, 1H), 10.75 (s, 1H), 8.84 (ddd, J = 9.0, 5.4, 2.1 Hz, 2H), 8.54 (s, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.67 – 7.55 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 2.44 (s, 3H), 2.25 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 169.2, 167.6, 148.6, 144.2, 140.4, 139.0, 136.6, 134.3, 128.2,

127.45, 127.1, 124.0, 122.3, 122.1, 122.0, 118.0, 116.8, 25.6, 22.1. IR (cm-1): 3343, 2935, 1691, 1652, 1580, 1527, 1446, 790. HRMS: m/z calcd for C19H17N3NaO2+: 342.1213 [M + Na]+; found: 342.1214. 2-Acetamido-4-(tert-butyl)-N-(quinolin-8-yl)benzamide (30): Colorless gummy liquid (57 mg, 79%). 1H NMR (300 MHz, Chloroform-d) δ 11.27 (s, 1H), 10.77 (s, 1H), 8.90 – 8.76 (m, 3H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.66 – 7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.30 – 7.22 (m, 1H), 2.26 (s, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 169.3, 167.5, 157.2, 148.6, 140.5, 139.0, 136.6, 134.3, 128.2, 127.4, 126.9, 122.3, 122.0, 120.3, 118.8, 117.9, 116.8, 35.5, 31.2, 25.6. IR (cm-1): 3331, 2925, 2820, 1655, 162, 1528, 742. Anal. calcd. for C22H23N3O2: C, 73.11; H, 6.41; N, 11.63; found: C, 73.32; H, 6.44; N, 11.69. 2-Acetamido-4-methoxy-N-(quinolin-8-yl)benzamide (31): White solid (55 mg, 82%) m.p. 148-150 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.65 (s, 1H), 10.69 (s, 1H), 8.83 (dd, J = 4.3, 1.7 Hz, 1H), 8.78 (dd, J = 6.9, 2.1 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz,



Page 26 of 34

1H), 7.83 (d, J = 8.9 Hz, 1H), 7.61 – 7.51 (m, 2H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H), 6.72 (dd, J = 8.8, 2.7 Hz, 1H), 3.89 (s, 3H), 2.26 (s, 3H).

13

C NMR (75 MHz, CDCl3) δ 169.4, 167.3, 163.4,

148.5, 142.9, 138.9, 136.5, 134.3, 128.6, 128.1, 127.4, 122.1, 121.9, 116.6, 112.5, 110.0, 105.3, 55.7, 25.7. IR (cm-1): 3347, 2924, 2852, 1690, 1647, 1610, 1584, 1523, 789. HRMS: m/z calcd for C19H18N3O3: 336.1343 [M + H]+; found: 336.1344. 2-Acetamido-4-fluoro-N-(quinolin-8-yl)benzamide (32): White solid (48 mg, 73%) m.p. 151153 oC. 1H NMR (500 MHz, Chloroform-d) δ 11.43 (s, 1H), 10.74 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.80 (dd, J = 5.9, 3.0 Hz, 1H), 8.56 (dd, J = 11.8, 2.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.7 Hz, 1H), 7.91 (dd, J = 8.8, 6.0 Hz, 1H), 7.64 – 7.55 (m, 2H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 6.91 (ddd, J = 8.7, 7.5, 2.6 Hz, 1H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 166.8, 166.4 (d, JC-F = 250 Hz), 148.7, 142.7 (d, JC-F = 12 Hz), 138.9, 136.7, 134.1, 129.1 (d, JC-F = 10 Hz), 128.2, 127.4, 122.6, 122.1, 116.9, 116.6 (d, JC-F = 4 Hz), 110.1 (d, JC-F = 22 Hz), 108. 80 (d, JC-F = 27 Hz), 25.60. IR (cm-1): 3341, 2919, 1682, 1625, 1582, 1423, 765.

Anal. calcd. for

C18H14FN3O2: C, 66.87; H, 4.36; N, 13.00; found: C, 67.02; H, 4.29; N, 13.12. 2-Acetamido-4-iodo-N-(quinolin-8-yl)benzamide (33): Brown crystalline solid (60 mg, 70%) m.p. 148-150 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.16 (s, 1H), 10.77 (s, 1H), 9.14 (s, 1H), 8.90 – 8.81 (m, 1H), 8.80 (t, J = 4.5 Hz, 1H), 8.22 (dd, J = 8.3, 1.6 Hz, 1H), 7.65 – 7.56 (m, 5H), 7.51 (dd, J = 8.3, 4.3 Hz, 1H), 2.25 (s, 3H).

13

C NMR (126 MHz, CDCl3) δ 169.1, 167.0,

148.8, 141.0, 138.9, 136.7, 134.0, 132.3, 130.4, 128.2, 128.1, 127.4, 122.7, 122.1, 120.0, 117.0, 100.2, 25.5. IR (cm-1): 3331, 2928, 2850, 1662, 1562, 1521, 1440, 739. Anal. calcd. for C18H14IN3O2: C, 50.13; H, 3.27; N, 9.74;; found: C 50.28; H 3.41; N 10.12%. 2-Acetamido-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide (34): Orange liquid (55 mg, 74%). 1H NMR (300 MHz, Chloroform-d) δ 11.15 (s, 1H), 10.83 (s, 1H), 9.06 (d, J = 1.7 Hz,


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1H), 8.86 (dd, J = 4.3, 1.6 Hz, 1H), 8.82 (dd, J = 5.1, 3.9 Hz, 1H), 8.23 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 2.27 (s, 3H).13C NMR (126 MHz, CDCl3) δ 169.3, 166.3, 148.8, 140.7, 138.9, 136.7, 134.6 (q, JC-F = 32.76 Hz), 133.8, 128.2, 127.7, 127.4, 124.6, 123.5, 123.0, 122.5, 122.2, 119.6 (q, JC-F = 3.75 Hz), 118.7 (q, JC-F = 3.75Hz), 117.1, 25.5. IR (cm-1): 3337, 2931, 2850, 1700, 1660, 1586, 1528, 1426, 1334, 792. Anal. calcd. for C19H14F3N3O2: C, 61.13; H, 3.78; N, 11.26; found: C 61.32; H 4.01; N 11.30%. 3-Acetamido-N-(quinolin-8-yl)thiophene-2-carboxamide (35): Colorless crystalline solid (43 mg, 69%) m.p. 144-146 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.00 (s, 1H), 10.36 (s, 1H), 8.87 (dd, J = 4.3, 1.7 Hz, 1H), 8.74 (dd, J = 6.4, 2.6 Hz, 1H), 8.24 (d, J = 5.4 Hz, 1H), 8.19 (dd, J = 8.3, 1.7 Hz, 1H), 7.61 – 7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 2.27 (s, 3H).

13

C NMR (126 MHz, CDCl3) δ 168.0, 162.8, 148.6, 144.5, 138.7, 136.5, 134.3,

128.2, 128.0, 127.4, 123.7, 122.1, 122.0, 116.6, 113.1, 24.8. IR (cm-1): 3286, 3097, 1694, 1634, 1569, 1549, 1417, 770. Anal. calcd. for C16H13N3O2S: C, 61.72; H, 4.21; N, 13.50; found: C 61.95; H 4.33; N 13.62%. 3-Acetamido-3'-methyl-N-(quinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide (36): White solid (51 mg, 65%) m.p. 193-195 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.01 (s, 1H), 10.81 (s, 1H), 8.87 – 8.80 (m, 2H), 8.74 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.6 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 1H), 7.69 – 7.56 (m, 2H), 7.55 – 7.44 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 7.29 – 7.16 (m, 3H), 2.46 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.1, 167.6, 148.8, 140.0, 139.2, 139.0, 138.8, 136.6, 136.2, 134.3, 131.7, 130.3, 129.3, 129.1, 128.4, 128.2, 127.9, 127.4, 125.6, 124.2, 122.6, 122.2, 122.0, 121.7, 117.1, 25.5, 21.7. IR (cm-1): 3342,



2952, 2826, 1698, 1652, 1521, 1445, 756. Anal. calcd. for C25H21N3O2: C, 75.93; H, 5.35; N, 10.63; found: C, 76.13; H, 5.52; N, 10.69. Tert-butyl (3-acetamido-4-(quinolin-8-ylcarbamoyl)phenyl)carbamate (37): White solid (60 mg, 71%) m.p. 199-201 oC. 1H NMR (300 MHz, Chloroform-d) δ 11.51 (s, 1H), 10.76 (s, 1H), 8.89 – 8.73 (m, 2H), 8.52 – 8.44 (m, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 9.3 Hz, 1H), 7.60 (dd, J = 10.0, 6.3 Hz, 2H), 7.52 (td, J = 10.8, 8.2, 4.5 Hz, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.14 (s, 1H), 2.26 (s, 4H), 1.53 (s, 9H).

13

C NMR (126 MHz, CDCl3) δ 169.4,

167.3, 152.5, 148.7, 143.3, 141.5, 139.0, 136.5, 134.4, 128.6, 128.2, 127.4, 122.2, 122.0, 116.7, 114.7, 112.5, 110.1, 81.3, 28.5, 25.6. IR (cm-1): 3278, 2977, 2931, 1735, 1680, 1649, 1597, 1523, 1410, 774. HRMS: m/z calcd for C23H25N4O4+: 421.1870 [M + H]+; found: 421.1870. ASSOCIATED CONTENT Supporting Information The 1H and

13

C NMR spectra of all products, X-ray crystallography data and CIF files. This

material is available free of charge via the Internet at http:// pubs.acs.org. AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Notes Any additional relevant notes should be placed here. ACKNOWLEDGMENT Financial support from Indian National Science Academy, New Delhi under the offer of INSA Senior Scientist position to B. C. R is gratefully acknowledged.


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REFERENCES (1) (a) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science; Wiley-Interscience: New York, 2000. (b) Humphrey, J. M.; Chamberlin, A. R. Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides. Chem. Rev. 1997, 97, 2243-2266. (c) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Catalytic amide formation from non-activated carboxylic acids and amines. Chem. Soc. Rev. 2014, 43, 27142742. (d) Chaudhari, P. S.; Salim, S. D.; Sawant, R. V.; Akamanchi, K. G. Sulfated tungstate: a new solid heterogeneous catalystfor amide synthesis. Green Chem. 2010, 12, 1707-1710. (e) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases. J. Comb. Chem. 1999, 1, 55-68. (2) (a) Graul, A.; Castaner, J. Drugs Future. 1997, 22, 956-968. (b) Gasparo, M.; Whitebread, S. Regul. Pept. 1995, 59, 303. (c) Ananthanarayanan, V. S.; Tetreault, S.; Saint-Jean, A. Interaction of calcium channel antagonists with calcium: spectroscopic and modeling studies on diltiazem and its Ca2+ complex. J. Med. Chem. 1993, 36, 1324-1332. (3) (a) Montalbetti, C. A. G. N.; Falque, V. Amide bond formation and peptide coupling. Tetrahedron. 2005, 61, 10827-10852. (b) Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38, 606-631. (c) Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140-177. (d) Jursic, B. S.; Zdravkovdki, Z. A Simple Preparation of Amides from Acids and Amines by Heating of Their Mixture. Synth. Commun. 1993, 23, 2761-2770.



Page 30 of 34

(4) (a) Labinger, J. A.; Bercaw, J. E. Understanding and exploiting C–H bond activation. Nature. 2002, 417, 507-514. (b) Godula, K.; Sames, D. C-H Bond Functionalization in Complex Organic Synthesis. Science. 2006, 312, 67-72. (c) McDonald, R. I.; Liu, G. S.; Stahl, S. S. Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications. Chem. Rev. 2011, 111, 2981-3019. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)-Catalyzed C–H Bond Activation and Functionalization. Chem. Rev. 2012, 112, 5879-5918. (e) Rouquet, G.; Chatani, N. Catalytic Functionalization of C(sp2)-H and C(sp3)-H Bonds by Using Bidentate Directing Groups. Angew. Chem., Int. Ed. 2013, 52, 11726-11743. (f) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.Q.

Transition

metal-catalyzed

C–H

activation

reactions:

diastereoselectivity

and

enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242-3272. (g) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions. Chem. Rev. 2010, 110, 1147-1169. (h) Ackermann, L. Carboxylate-Assisted Ruthenium-Catalyzed Alkyne Annulations by C–H/Het–H Bond Functionalizations. Acc. Chem. Res. 2014, 47, 281-295. (5) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide Directing Group for C−H Functionalizations. Angew. Chem., Int. Ed. 2016, 55, 10578-10599. (6) (a) Michael, J. P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2008, 25, 166-187. (b) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Quinolines and structurally related heterocycles as antimalarials. Eur. J. Med. Chem. 2010, 45, 3245-3264. (c) Colomb, J.; Becker, G.; Fieux, S.; Zimmer, L.; Billard, T. Syntheses, Radiolabelings, and in Vitro Evaluations of Fluorinated PET Radioligands of 5-HT6 Serotoninergic Receptors. J. Med. Chem. 2014, 57, 3884-3890. (d) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles: Structures, Reactions, Synthesis, and Applications, 3rd ed.; John Wiley & Sons: New York, 2013.


Page 31 of 34 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


(e) Rouffet, M.; deOliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.; McCammon, J. A.; Cohen, S. M. From Sensors to Silencers: Quinoline- and Benzimidazole-Sulfonamides as Inhibitors for Zinc Proteases. J. Am. Chem. Soc. 2010, 132, 8232-8233. (7) (a) Shabashov, D.; Daugulis, O. Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp2and sp3 Carbon−Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 3965-3972. (b) Asako, S.; Ilies, L.; Nakamura, E. Iron-Catalyzed Ortho-Allylation of Aromatic Carboxamides with Allyl Ethers. J. Am. Chem. Soc. 2013, 135, 17755-17757. (c) Singh, B. K.; Jana, R. LigandEnabled, Copper-Promoted Regio- and Chemoselective Hydroxylation of Arenes, Aryl Halides, and Aryl Methyl Ethers. J. Org. Chem. 2016, 81, 831-841. (d) Du, C.; Li, P.-X.; Zhu, X.; Han, J.N.; Niu, J.-L.; Song, M.-P. Cobalt-Catalyzed Oxidative C–H/N–H Cross-Coupling: Selective and Facile Access to Triarylamines. ACS Catal. 2017, 7, 2810-2814. (e) Ni, J.; Li, J.; Fan, Z.; Zhang, A. Cobalt-Catalyzed Carbonylation of C(sp2)–H Bonds with Azodicarboxylate as the Carbonyl Source. Org. Lett. 2016, 18, 5960-5963. (f) Kathiravan, S.; Nicholls, I. A. Cobalt Catalyzed, Regioselective C(sp2)–H Activation of Amides with 1,3-Diynes. Org. Lett. 2017, 19, 4758-4761. (g) Wu, X.; Zhao, Y.; Ge, H. Direct Aerobic Carbonylation of C(sp2)–H and C(sp3)–H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source. J. Am. Chem. Soc. 2015, 137, 4924-4927. (h) Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Cobalt-catalysed siteselective intra- and intermolecular dehydrogenative amination of unactivated sp3 carbons. Nat. Commun. 2015, 6, 6462-6471. (i) Maity, S.; Kancherla, R.; Dhawa, U.; Hoque, E.; Pimparkar, S.; Maiti, D. Switch to Allylic Selectivity in Cobalt-Catalyzed Dehydrogenative Heck Reactions with Unbiased Aliphatic Olefins. ACS Catal. 2016, 6, 5493-5499. (j) Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M. R. Cobalt-Catalyzed sp2‐C−H Activation: Intermolecular Heterocyclization with Allenes at Room Temperature. Angew .Chem. Int. Ed. 2016, 55, 12361-



12365. (k) Tran, L. D.; Roane, J.; Daugulis, O. Directed amination of non-acidic arene C-H bonds by a copper-silver catalytic system. Angew. Chem., Int. Ed. 2013, 52, 6043-6046. (8) (a) Zhang, P.; Huang, W.; Wang, L.; Bao, L.; Jia, Z. J.; et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg. Med. Chem. Lett. 2009, 19, 2179-2185. (b) Marighetti, F.; Steggemann, K.; Karbaum, M.; Wiese, M. Scaffold Identification of a New Class of Potent and Selective BCRP Inhibitors. ChemMedChem. 2015, 10, 742-751. (9) (a) Zhang, C.; Tang, C.; Jiao, N. Recent advances in copper-catalyzed dehydrogenative functionalization via a single electron transfer (SET) process. Chem. Soc. Rev. 2012, 41, 34643484. (b) Daugulis, O.; Do, H.-Q.; Shabashov, D. Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds. Acc. Chem. Res. 2009, 42, 1074-1086. (c) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J. Q. Cu(II)-Mediated C–H Amidation and Amination of Arenes: Exceptional Compatibility with Heterocycles. J. Am. Chem. Soc. 2014, 136, 3354-3357. (d) Shang, M.; Sun, S.-Z.; Wang, H.-L.; Dai, H.-X.; Yu, J.-Q. Exceedingly fast copper(II)-promoted ortho C-H trifluoromethylation of arenes using TMSCF3. Angew. Chem., Int. Ed. 2014, 53, 10439-10442. (e) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Cu(OAc)2-Catalyzed Coupling of Aromatic C–H Bonds with Arylboron Reagents. Org. Lett. 2014, 16, 5666-5669. (f) Wang, H.-L.; Shang, M.; Sun, S.-Z.; Zhou, Z.-L.; Laforteza, B. N.; Dai, H.-X.; Yu, J. Q. Cu(II)-Catalyzed Coupling of Aromatic C–H Bonds with Malonates. Org. Lett. 2015, 17, 1228-1231. (g) Liu, T.; Myers, M.-C.; Yu, J. Q. Copper-Catalyzed Bromination of C(sp3 )-H Bonds Distal to Functional Groups. Angew. Chem. Int. Ed. 2017, 56, 306-309.


Page 32 of 34

Page 33 of 34 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


(10) (a) Hermann, G. N.; Bolm, C. Mechanochemical Rhodium(III)-Catalyzed C–H Bond Amidation of Arenes with Dioxazolones under Solventless Conditions in a Ball Mill. ACS Catal. 2017, 7, 4592-4596 and references cited therein. (b) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Catalytic activation of nitrogen derivatives with transition-metal complexes. Pure Appl. Chem. 2006, 78, 363-375. (c) Kim, J.; Chang, S. Iridium-catalyzed direct C-H amidation with weakly coordinating carbonyl directing groups under mild conditions. Angew. Chem., Int. Ed. 2014, 53, 2203-2207. (d) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Organic azides: “energetic reagents” for the intermolecular amination of C–H bonds. Chem. Commun. 2014, 50, 11440-11453 and references cited there in. (11) CCDC no. 1849955 (compound 5); CCDC no. 1849783 (compound 35). (12) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. Cu(II)-Catalyzed Functionalizations of Aryl C−H Bonds Using O2 as an Oxidant. J. Am. Chem. Soc. 2006, 128, 6790-6791. (13) Ano, Y.; Tobisu, M.; Chatani, N. Palladium-Catalyzed Direct ortho-Alkynylation of Aromatic Carboxylic Acid Derivatives. Org. Lett., 2012, 14, 354-357. (14) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. Iridium-Catalyzed Intermolecular Amidation of sp3 C–H Bonds: Late-Stage Functionalization of an Unactivated Methyl Group. J. Am. Chem. Soc. 2014, 136, 4141-4144.




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