Palladium Catalyzed Regio-selective Synthesis of Substituted Biaryl

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Palladium Catalyzed Regio-selective Synthesis of Substituted Biaryl Amides through Decarbonylative Arylation of Phthalimides Partha Kumar Samanta, and Papu Biswas J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03157 • Publication Date (Web): 05 Mar 2019 Downloaded from http://pubs.acs.org on March 5, 2019

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

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The Journal of Organic Chemistry

Palladium Catalyzed Regio-selective Synthesis of Substituted Biaryl

Amides

through

Decarbonylative

Arylation

of

Phthalimides Partha Kumar Samanta, and Papu Biswas* Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Howrah 711 103, West Bengal, India.

ACS Paragon Plus Environment

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

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ABSTRACT X

O 1

N R O

Ar

O

Pd

N H CO

Ar

R1

33 examples up to 86% yield no need of organometallic reagent site selective arylation

The Pd(OAc)2 catalyzed cross-coupling of N-substituted phthalimides with aryl halide provides a single step direct access of a wide range of synthetically appealing orthosubstituted biarylamides in high yields through unique carbonyl (CO) replacement. The reaction proceeds through ligand-free condition and well tolerant to the diverse functionality of both imide and halide units. The reaction negate any requirement of organometallic reagent, need shorter reaction time and comparatively lower temperature as required for previously reported decarbonylative processes.


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INTRODUCTION Demand for novel transition metal catalyzed cross-coupling methods for the formation of C–C bonds increases enormously for the synthesis of natural products, pharmaceuticals, and organic materials.1 The recent trend of cross-coupling reactions comprises various methods including coupling of broad range of functional groups with controlled regio-chemistry or stereochemistry which enhances the complexity of newly formed molecules. Amongst all the available methods, the cross-coupling reaction through decarbonylative fashion has drawn much attention in recent years as it provides a means of controlled functional group modiﬁcation. Since being first reported in 1965,2 decarbonylative coupling has been achieved with functional groups including aldehydes, carboxylic acids, isopropenyl esters, and carboxylic anhydrides.312 For the past few decades, several efforts have been made to increase the scope for the use of alternative electrophile such as amide, ester, imides etc. instead of conventional electrophiles. Aromatic esters, amides and imides are readily available and inexpensive molecular scaffolds. Owing to their ease of handling and facile preparation, they have been used as convenient building blocks in organic synthesis. Despite extensive studies regarding the utility of amides as a directing group for region-selective functionalization13-15 it has been difficult for chemists to use amides as intermediates in a synthetic sequence due to the robustness of the C(acyl)–N bonds.16 With the aim of making C(acyl)–N bond reactive, recently Nicatalyzed decarbonylative addition of phthalimides with alkynes17 and dienes18 has been reported to get access to diverse isoquinolone derivatives. Other NiCatalyzed cross-coupling reactions such as decarbonylative reduction of amides to aromatic hydrocarbons,19 decarbonylative amination,20 and borylation21 have also been reported (Figure 1). Few research groups employed Pd catalyst for decarbamoylative C–H arylation of 1,3azoles with aromatic amides in the presence of oxidants,22 decarbonylative Heck reaction of aromatic amides23 and Nacylsaccharins with alkenes.24 Rh based catalyst also used for decarbonylative Mizoroki– Heck type reaction for C–H arylation25 and Ru-Catalyst for unmasking amides through protodecarbonylation.26. Inspired from these excellent efforts we explore a ligand-free Pd(OAc)2 catalyzed decarbonylative cross-coupling of Nsubstituted phthalimides as a coupling partner with aryl halide which gives us a single step direct source of a wide range of ortho-substituted benzamides. These orthoarylbenzamides are not only important for the synthetic chemist but also very useful in medicinal chemistry.27 Recent efforts on the rational design of safer



Page 4 of 27

drug highly focused on negative allosteric modulators (NAM).28 Orthoaryl substituted phenyl benzamides were found to be more potent than a lead molecule, KAB1829 as negative allosteric modulators which made their synthesis more important for the chemist. Literature survey reveals that regioselective arylation of benzanilides with aryl triflates or halides under palladium catalysis can afford orthoaryl benzamides.30-32 But there are several disadvantages regarding lack of regioselectivity, need of directing group, inferior accessibility of amide precursor, requirement of an excess amount of base, oxidant and prolonged reaction time which make these protocols more difficult, hazardous and costineffective. Another major disadvantage which makes the processes unfruitful for synthesis is possibility of the formation of mono and diarylated products (Figure 1). Previous works

O N H

O N H

Ph I

Pd(OAc)2 (20 mol%), PPh3, Cs2CO3 (4.0 equiv), 110o C

I

O N H Ph

O

Ketoamides

Ph

O N H

Aryl halides (4 equiv)

Benzamides

Ph

Ph

Pd(OAc)2 (10 mol%) AgOAc (1.0 equiv)

O N H

110oC, 10h

COPh

OMe

OMe

Aryl halides I

O N H

NHR2

Ar

R

R2Zn R2

O

Pthalimides

N H

NHR2

Ar

Aryl halides

O N R1

O

Na2CO3, t-AmOH 120oC

1

Benzamides

Pd(OAc)2 (10 mol%) Mn(OAc)2 (1.0 equiv)

Ni(cod)2 (1.0 equiv) bipy (1.1 equiv)

O

1,4-dioxane/THF, 95oC

R2

N H

R1

Diorganozinc

Our work X

O 1

N R

Ar

Pd(OAc)2 (5 mol%) KOtBu (20 mol%) DMF, 110oC

O

Pthalimides R1

= aryl, benzyl

O N H

R1

Ar

Aryl halides X = I, Br

Figure 1. Schematic Presentation of Different Approach for O-aryl Substituted Amide Synthesis To remove these drawbacks, search of new cross coupling strategy is compulsory. To the best of our knowledge Johnson et al. first presented nickel mediated Negishi type


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coupling of phthalimide with diorganozinc partner for the synthesis of orthosubstituted benzamides.33 Here nickel complex is needed in stoichiometric amount and source of nucleophilic partner was again organometallic (diorganozinc) reagent which is quite expensive and their commercial availability also quite limited which makes this process waste productive and complex to handle. This leads us to explore a catalytic process where phthalimide unit undergoes site-selective monoarylation with aryl halides in presence of catalytic amount of base and Pd(OAc)2 as catalyst under ligand-free condition. This crosscoupling strategy gives a direct access to C–C bond formation from imides unit and provides site-selective arylation through unique replacement of carbon monoxide and significant tolerance to a wide range of functional group in both imide and halide units. RESULTS AND DISCUSSION Optimization of Reactions Condition Initially, we investigated the decarbonylative arylation of Nsubstituted phthalimide with aryl halide using Nphenylphthalimide (1a) and piodoanisole (2a) as model substrates (Table 1). In a typical reaction, a mixture of 1a (1 mmol) and 2a (1 mmol) was allowed to react in presence of Pd(OAc)2 (11.2 mg, 5 mol%) and KOtBu (20 mol%) at 120 ºC for 12h in 3 mL dry solvent under an inert atmosphere. Optimization of various parameters viz. effect of solvents, bases, temperature, time and catalyst were thoroughly investigated. Various common organic solvents like DMF, water, THF, dioxane, NMP, DMSO, ethanol, toluene and xylene (Table 1, entries 19) were screened thoroughly. Introducing DMF as solvent combined with Pd(OAc)2 and KOtBu as base gave an excellent result. Other polar solvents like dioxane, THF, DMSO, ethanol, and water were not found to be suitable for this reaction. Use of NMP as solvent instead of DMF also afforded moderate yield whereas nonpolar solvents like toluene or xylene were found to be inappropriate. Furthermore, dry DMF is mandatory for this cross-coupling as the use of un-distilled solvent reduces the yield drastically (entry 10). This result ensured that the presence of trace amount of water inhibits the catalytic activity of Pd(OAc)2 and H2O acts as a proton source and pushing the reaction towards formation of phenyl benzamide as a product through protonation of the reaction intermediate.



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Table 1. Optimization of Reactions Conditions for Decarbonylative arylation of Phthalimide O

O I

N

OMe

catalyst, solvent base, temperature

N H

O

OMe

1a

Entry

2a

Catalyst

Base

Temperature Time (h) (C) 1 Pd(OAc)2 KOtBu 120 12 2 Pd(OAc)2 KOtBu 120 12 3 Pd(OAc)2 KOtBu 120 12 4 Pd(OAc)2 KOtBu 120 12 5 Pd(OAc)2 KOtBu 120 12 6 Pd(OAc)2 KOtBu 120 12 7 Pd(OAc)2 KOtBu 120 12 8 Pd(OAc)2 KOtBu 120 12 9 Pd(OAc)2 KOtBu 120 12 10d Pd(OAc)2 KOtBu 120 12 11 Pd(OAc)2 Cs2CO3 120 12 12 Pd(OAc)2 K2CO3 120 12 13 Pd(OAc)2 K3PO4 120 12 14 Pd(OAc)2 NaOtBu 120 12 15 Pd(OAc)2 NaOH 120 12 16 Pd(OAc)2 KOH 120 12 17 Pd(OAc)2 KOtBu 110 12 18e Pd(OAc)2 KOtBu 110 12 19 Pd(OAc)2 KOtBu 100 12 20 Pd(OAc)2 KOtBu 130 12 21 Pd(OAc)2 KOtBu 110 24 22 Pd(OAc)2 KOtBu 110 10 23f Pd(OAc)2 KOtBu 110 12 24g Pd(OAc)2 KOtBu 110 12 25h Pd(OAc)2 110 12 26 PdCl2 KOtBu 110 12 27 Pd(PPh3)2Cl2 KOtBu 110 12 28 Pd(PPh3)4 KOtBu 110 12 29i KOtBu 110 12 30j Pd(OAc)2 KOtBu 110 12 a Reaction conditions (until unless specified): 1a (1.0 mmol), 2a

3aa

Solvent

Yield (%)b DMF 85 water Ndc THF trace dioxane 12 NMP 70 DMSO 10 ethanol nd toluene nd xylene nd DMF 62 DMF 45 DMF 38 DMF 52 DMF 61 DMF 40 DMF 40 DMF 85 DMF 84 DMF 60 DMF 87 DMF 88 DMF 66 DMF 86 DMF 72 DMF trace DMF 40 DMF 42 DMF trace DMF nd DMF 82 (1.0 mmol), catalyst

(11.2 mg, 5 mol%), base (20 mol%), solvent (3 mL), reaction performed under inert atmosphere. bIsolated yield.

cnd

= Product not detected. dReaction performed in un-

distilled DMF. eReaction performed with 1 equivalent base. fReaction performed with 22.4 mg catalyst (10 mol%). gReaction performed with 3 mol% (6.7 mg) catalyst. hReaction jReaction

performed without any base. iReaction performed without any catalyst. performed with pbromoanisole.

After the screening of solvents, the reaction was examined with different bases viz. Cs2CO3, K2CO3, K3PO4, NaOtBu, NaOH and KOH (Table 4.1, entries 1116). Among all bases, KOtBu (20 mol %) was found to be the most suitable base to provide the highest yield (entry 17). After gradually increasing the percentage of base to the equivalent amount no observable change in yield was observed (Table 1, entry 18). Decreasing the reaction temperature to 110ºC, no considerable change in the yield was observed, but a further


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decrease in temperature provided inferior yield (entry 19). Increasing temperature up to 130ºC produced no considerable improvement in the yield (87%, entry 20). Increment of the reaction time by another 12 h, no countable increases in the yield was observed (88%, entry 21), while shortening the reaction time from 12 h to 10 h gave inferior yield (entry 22). Thus the reaction produced highest yield of 85% when it was carried out in dry DMF in presence of Pd(OAc)2 (11.2 mg, 5 mol%) and 20 mol% KOtBu base at 110ºC for 12 h under inert atmosphere (entry 17). Next, with an increase in the amount of the catalyst (10 mol%), minor improvement in the yield of biaryl amides (entry 23) was observed, whereas reducing the amount of the catalyst (3 mol%) gave much lower yield (72%, entry 24). A reaction performed without base produced only trace yield (entry 25). The performance of other palladium (II) salts like PdCl2, Pd(PPh3)2Cl2, Pd(0) salt viz. Pd(PPh3)4 were also examined under optimized conditions and were found ineffective compared to Pd(OAc)2 (entries 26– 28). The reaction did not proceed at all when the reaction was performed without catalyst (entry 29). Next reaction of Nphenylphthalimide (1a) was tested with p–bromoanisole (2b) under the same optimized conditions. It gave a slightly lower yield compared to piodoanisole confirming greater reactivity of iodo towards decarbonylative arylation (entry 30). Substrate scope of Decarbonylative Arylation With this optimized reaction conditions in hand, substrate scope for imide unit was thoroughly investigated first. As can be noticed from Table 2, the reactions of N−arylphthalimides with different electron donating group (OMe, Me) attached to the phenyl ring at para position underwent the decarbonylative arylation efficiently to afford 8085% yields (Table 2, entries 3ca and 3dc) and for electron withdrawing group (NO2) reaction afforded 75% yield with reduced activity (entries 3ba). Ortho, meta and para substitution at the Nsubstituted phenyl ring were found to be well tolerant without any remarkable influence upon the reaction yields (Table 2, entries 3cb, 3ea, 3fb, 3ga, 3ha and 3ia). To our delight sterically challenged 2, 5 and 2, 6 disubstituted anilines furnished corresponding amides smoothly in excellent yields (8385%, entries 3fa3gb). In case of Nsubstituted benzyl unit, the reaction also produced very good yields (8284%, entries 3ja and 3jb). The reaction also provided significant functional group tolerance on imide unit, including halides (Cl, Br), ethers, nitro with excellent yields up to 86% (entries 3ba, 3ha



Page 8 of 27

Table 2. Substrate Scope for Decarbonylative Arylation of Phthalimides and Aryl halidesa, b

R' Pd(OAc)2 (5 mol%) KOt Bu (20 mol%)

O N

X

R

R'

O N H

DMF, 110oC, 12h

O

2

1

R

3

OMe O

O

O

N H

N H

3ab I:80%, Br:78%

3ac I:82%, Br:79%

N H

3aa I:85%, Br:80%

OMe

CH3

O

CH3

N H

3ba I:75%, Br:70%

CH3

O

3ca I:80%, Br:76%

OMe

O

3cd I:85%, Br:80%

N H

3da I:86%, Br:81%

3db I:84%, Br:80% OMe

OMe OMe

O

N

O

N H

S

O

N H

N H

3eb I:78%, Br:75%

3ea I:84%, Br:78%

O

O

N H

N H

3dc I:85%, Br:80%

3ec I:80%, Br:76%

3fa I:85%, Br:80%

Br S

O

OMe N

O

O

N H

3fc I:80%, Br:76%

O N H

3fd I:85%, Br:75%

N H

3ga I:85%, Br:80%

3fe I:76%, Br:75%

Br

OMe

Br Cl

O

O

N H

3ia I:80%, Br:74%

Br

O N H

3ib I:85%, Br:80%

Br

O N H

3ic I:85%, Br:76%

N H

3hd I:84%, Br:80%

3hc I:85%, Br:74%

OMe

OMe

Br

O

O

O N H

Ph

3ja I:84%, Br:80%

Cl

O

N H

3hb I:65%, Br:50%

Br

Cl

O

N H

OMe

Br

Cl

O

3ha I:81%, Br:76%

3gb I:85%, Br:75%

O

EtOOC

N H

N H

a

O

N H

N H

3fb I:83%, Br:75%

OMe

O

N H

N H

3cc I:85%, Br:80%

N H

OMe

N H

3cb I:81%, Br:76%

O

N H

Br

O

NO2

O

N H

Ph

3jb I:82%, Br:75%

N H

C4H9

3la I:70%, Br:62%

Reaction conditions (until unless specified): 1a (1.0 mmol), 2a (1.0 mmol), catalyst (11.2 mg, 5 mol%),

KOtBu (22.5 mg, 20 mol%), DMF (3 mL), reaction performed under inert atmosphere. b Isolated yields are reported.


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3ic). With very limited scope of imide backbone in hand, we tried the reaction using succinimide and saturated cyclohexane ring containing succinimide. Unfortunately both the reaction failed to provide any separable amount of desired product (Scheme 1). N(2pyridyl)phthalimide also failed to produce any product under the same reaction conditions (Scheme 1). To improve the synthetic utility of the reaction, a wide range of substrates scope for halide units was also examined. Electronically rich OMe and Me group substituted aryl halides at para position gave excellent yields (entries 3aa, 3ab, 3cb, 3cc, 3da, 3db, 3fa, 3ga, 3hd and 3ib). Again aryl halides unit having another halide (Br) substitution at para position were found to be well resilient under same reaction conditions giving solely monoarylated product without any doubly coupled product (entries 3cd, 3fb, 3gb, 3hc, 3ic and 3jb). Aryl halides having heteroatomic functionalities like pyridine, thiophene underwent reaction smoothly with imide units to provide ortho substituted products in 78−80% yields (entries 3eb, 3ec, 3fc and 3fe). To our delight aryl halide having ortho ester group underwent reaction

smoothly

to

give

corresponding

2'((4chlorophenyl)carbamoyl)[1,1'biphenyl]4carboxylate in 78% yield prior to hydrolysis under basic condition (entry 3hb). Aryl halides having –Br and OMe substitution at para position underwent arylation with Nbenzyl phthalimide efficiently to furnish 82 and 83% yields, respectively (entries 3ja and 3jb). Reaction of 2–butylisoindoline-1,3-dione with 4–methoxy aryl halide produced comparatively lower yield (70%, entry 3la) than N–aryl substituted phthalimide. Control Experiments To obtain insight about the reaction mechanism few control experiments were conducted. 2(Phenylcarbamoyl)benzoic acid was first reacted with iodobenzene under the standard reaction conditions. Benzoic acid and aniline were obtained as the major products which eliminated the initiation of reaction via hydrolysis of phthalimide ring under basic condition prior to the decarbonylation process (Scheme 1). The monoarylated product formed exclusively when reaction was performed in presence of excess aryl halide. The fact confirms that

Formation of monoarylated product exclusively without any diarylated product in

presence of excess aryl halide guided us to consider the fact that there is no coordination of amide anion generated in situ to intermediary arylpalladium species which again supports the formation of cyclo-palladium intermediate E (Scheme 2). Moreover, imide unit with



Page 10 of 27

saturated cyclic backbone did not react which indicate that ring strain probably the driving force of initial decarbonylation process. Again 2pyridin2ylisoindole1,3dione does not produce the desired product (3ka, Scheme 1) under the same reaction conditions, indicated that coordination of pyridine N with Pd prevents the formation of cyclopalladium intermediate E (Scheme 2). From FT-IR (Supporting Information) spectra of crude product, it was found that a strong carbonyl peak at 1648 cm1 due to amide bond confirms the absence of any ketamide (4aa) in the reaction mixture expected from direct coupling of imide with aryl halide which again evident from 13C spectra of product where a single carbonyl carbon peak at ~170 ppm was observed. These findings again assist the cross-coupling reaction proceeds through a decarbonylative fashion. 1.

O

optimized condition

Ph

N H COOH

Ph

4 2.

Ph

2a

H O

Ph

N H

optimized condition

X

Pdt 3aa nd sole pdt. O

O

N Ph O

other unsuccesf ull substrates

O Ph

N

nd = not detected O

N Ph

product nd

2a

5

COOH

Ph

trace

H O N Ph

3.

X

NH2

O

N

X

optimized condition

O N H

N

Ph

O

3k

2a

product 3ka nd

Scheme 1. Control Experiments Reaction Mechanism Considering experimental findings from control reaction done and based on previously reported works1726,33 on decarbonylative cross-coupling, it is presumed that reaction proceeds through Pd(0) formation at 110 C in presence of DMF and KOtBu.34a-d The formation of Pd(0) in presence of DMF and base at 100C where DMF itself acts as reducing agent was previously demonstrated by Albéniz et al.34d Next, the oxidative insertion of Pd in between nitrogen-carbonyl bond of imide takes place to produce intermediate C which was previously reported for nickel-based decarbonylative reactions.1724 Subsequent


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decarbonylation of intermediate C produces palladocycle D followed by oxidative addition of aryl halide to give Pd(IV) intermediate E.34e-g Reductive elimination of intermediate E afforded a Pd(II) intermediate F. The product obtained from the intermediate F and the Pd(0) regenerated in presence of DMF (Scheme 2). The detailed mechanistic study is under progress in our laboratory. Pd(OAc)2 O

DMF/

N H Ar

KOt Bu

O

+

N

H

Product

F/ M D

Ar O

O (A)

LnPd(0)

L = DMF

N Pd X

dat oxi

iv

n itio d d ea O

N Pd

(F)

O (B)

reductive elimination O N Pd Ar (E)

O

oxidative addition

X Ar-X

N Pd OC

O N

Pd

(D)

Decarbonylation

(C)

CO

Scheme 2. Proposed Mechanism Conclusion In summary, a general, region-selective Pd-catalyzed reaction enabling conversion of cheap and easy accessible precursor phthalimides into biaryl amides was developed. The current process offers a simple solution for transformation that usually requires several steps and/or the use of strongly basic organometallic reagents producing huge waste. This methodology provides site-selective and operationally simple arylation to benzamide unit through unique release of carbon monoxide and significantly tolerance to a wide range of functional group in both imides and halide units. This work represents a new entry for the activation and functionalization of challenging C–C, C−O and C−N(R2) bonds. The important of biarylamides in chemistry, biology and especially in medicinal chemistry, make this process more acceptable for the pharmaceutical industry. We anticipate that the presented method will inspire new synthetic routes in future.



Page 12 of 27

EXPERIMENTAL SECTION Materials and Techniques All reactions were carried out under nitrogen or argon atmosphere. All the solvents were distilled prior to use. DMF was distilled with CaH2 under the inert condition, passed through two columns of neutral alumina or molecular sieves and purged with argon. All starting materials are either commercially available or prepared according to procedures provided in the literature. 1H NMR spectra were recorded on a Bruker Advance III 300, 400 and 700 MHz NMR spectrometer. NMR spectra were recorded at room temperature with CDCl3 or DMSO-d6 as the solvent. Chemical shifts (δ) of 1H NMR spectra are reported in ppm relative to residual solvent signals (CHCl3 in CDCl3: δ = 7.26 ppm, DMSO in DMSOd6: δ = 2.50 ppm); data are reported as br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet; J values are given in Hz. Infrared spectra were recorded on a Fourier transform infrared (FTIR) spectrometer in thin films. High-resolution mass spectrometry (HRMS) data were acquired by electron spray ionization on a Q-ToF microquadrupole mass spectrometer. General Method for the Synthesis of N-Phenylphthalimide Derivatives All phthalimides were prepared via the condensation of phthalic anhydride with the appropriate amine in DMF (Scheme S1).26,35 Aniline (10.12 g, 0.11mol) and phthalic anhydride (16.3 g, 0.11 mol) were dissolved separately in dimethylformamide (DMF, 50 mL) to get clear solutions A and B, respectively. Solution C obtained by dropwise addition of solution B gradually into solution A. After constant stirring of solution C for 2 h at 25°C, a solution of phosphorous pentoxide (10 g) dissolved in H2SO4 and DMF (1:7) mixture was added to it. After the addition of this mixture into solution C, it was stirred at 70° C for another 2 h. The solution was then cooled in an ice bath and poured into cold water. The white precipitate was filtered, washed with distilled water, recrystallized from ethanol and dried overnight in an oven at 60° C. The yield was 85% and melting point was determined to be 209° C. Other derivatives were prepared following the same procedure and products were characterized by 1H NMR and spectra.


13C

NMR

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General Method for Decarbonylative Coupling of phthalimide with an aryl halide The general method has been illustrated with a specific example. Pd(OAc)2 (11.2 mg), piodo anisole (234 mg, 1 mmol), and Nphenylphthalimide (223 mg, 1mmol) were combined in an oven-dried 10 mL schlenk tube and sealed with a septum. The flask was evacuated and refilled with argon three times. Next DMF (3 mL) was added via syringe, followed by KOtBu (22.4 mg, 20 mol%) under a constant flow of argon. The septum was then replaced by glass stopper and suspension was degassed by sonication under vacuum followed by filling with argon. The solution mixture was then suspended in an oil bath and allowed to stir for 12 h at 110o C. The reaction mixture was cooled to room temperature, the stopper was removed, and the reaction mixture was diluted with EtOAc (15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (7:3 hexane: ethylacetate) to provide 3aa in 85% yield. Isolated products were characterized by 1H NMR, 13C NMR and HRMS. Analytical Data for N-substituted Phthalimides 2-Phenylisoindoline-1,3-dione (Table 2, Entry 1a)26: White solid (20.8 gm, Yield 85%), mp: 205–208 ºC (lit. 205 ºC). 1H NMR (400MHz, CDCl3): δH 7.894–7.863 (m, 2H), 7.727–7.696 (m, 2H), 7.457–7419 (m, 2H,), 7.380–7.314 (m, 3H). 2-(4-Nitrophenyl)isoindoline-1,3-dione (Table 2, Entry 1b)36: Pale yellow solid (23 gm, Yield 78%), mp: 248–250 ºC (lit. 250–252 ºC). 1H NMR (400MHz, CDCl3): δH 8.419–8.390 (m, 2H), 8.047–8.016 (m, 2H), 7.900–7.866 (m, 2H,), 7.809–7.786 (m, 2H). 2-(p-Tolyl)isoindoline-1,3-dione (Table 2, Entry 1c)36: White crystalline solid (22.3 gm, Yield 86%), mp: 208–210 ºC (lit. 207–209 ºC). 1H NMR (400MHz, CDCl3): δH 7.832–7.811 (m, 2H), 7.676–7.654 (m, 2H,), 7.249–7.227 (m, 2H,), 7.037–7.015 (m, 2H), 2.268 (s, 3H). 2-(4-Methoxyphenyl)isoindoline-1,3-dione (Table 2, Entry 1d)36:



White solid (23.6 gm, Yield 85%), mp: 142 ºC (lit. 143–145 ºC). 1H NMR (400MHz, CDCl3): δH 7.832–7.811 (m, 2H), 7.676–7.654 (m, 2H), 7.249–7.227 (m, 2H,), 6.927–6.905 (s, 2H), 3.739 (s, 3H). 2-(o-Tolyl)isoindoline-1,3-dione (Table 2, Entry 1e)37: White crystalline solid (22.4 gm, Yield 86%), mp: 183–185 ºC. 1H NMR (400MHz, CDCl3): δH 7.892–7.871 (m, 2H), 7.728–7.707 (m, 2H), 7.292–7.232 (s, 3H), 7.129 (d, 1H), 2.136 (s, 3H). 13C NMR (100MHz, CDCl3) δC 167.39, 136.56, 134.35, 132.04, 131.18, 130.60, 129.48, 128.75, 126.90, 123.79, 18.06. 2-(2,5-Dimethylphenyl)isoindoline-1,3-dione (Table 2, Entry 1f): Crystalline solid (22.6 gm, Yield 82%), mp: 164–166 ºC. 1H NMR (400MHz, CDCl3): δH 7.824–7.803 (m, 2H), 6.654–7.632 (m, 2H,), 7.128 (d, 1H, J = 7.6Hz), 7.059 (d, 1H, J = 8Hz), 2.233 (s, 3H), 2.045 (s, 3H). 13C{1H} NMR (100MHz, CDCl3) δC 167.5, 136.7, 134.4, 133.3, 132.0, 131.0, 130.4, 128.8, 129.2, 123.7, 20.9, 17.6. HRMS (ESI -TOF) m/z: calcd for C16H14NO2 [M+H]+ 252.1025; found 252.1022. 2-(2,6-Dimethylphenyl)isoindoline-1,3-dione(Table 2, Entry 1g): White solid (22.0 gm, Yield 80%), mp: 190–193 ºC. 1H NMR (400MHz, CDCl3): δH 7.893– 7.872 (m, 2H), 7.729–7.708 (m, 2H), 7.213–7.175(m, 1H), 7.105 (d, 2H, J= 7.2Hz), 2.233 (s, 3H), 2.045(s, 3H). 13C{1H} NMR (100MHz, CDCl3) δC 167.3, 136.9, 134.4, 132.00, 129.8, 128.8, 129.5, 128.5, 123.8, 18.1. HRMS (ESI-TOF) m/z: calcd for C16H14NO2 [M+H]+ 252.1025; found 252.1024. 2-(4-Chlorophenyl)isoindoline-1,3-dione (Table 2, Entry 1h)36: Light yellow solid (22.6 gm,Yield 80%), mp: 194 ºC (lit. 194–196 ºC). 1H NMR (400MHz, CDCl3): δH 7.873–7.841 (m, 2H,), 7.731–7.692 (m, 2H,), 6.388 (d, 2H, J = 8.0 Hz), 6.328 (d, 2H, J = 8.4 Hz). 2-(4-Bromophenyl)isoindoline-1,3-dione (Table 2, Entry 1i)38: White solid (27 gm, Yield 82%), mp: 202 ºC (lit. 206 ºC). 1H NMR (400MHz, CDCl3): δH7.863–7.831 (m, 2H,), 7.721–7.684 (m, 2H,), 7.389–7.367 (m, 2H), 7.189 (d, 2H, J = 7.2 Hz).


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2-Benzylisoindoline-1,3-dione (Table 2, Entry 1j)37: White solid, (22.8 gm, Yield 84%), mp: 112 ºC (lit. 113–115 ºC). 1H NMR (400MHz, CDCl3): δH 7.775–7.745 (m, 2H), 7.633–7.612 (m, 2H), 7.357 (d, 2H, J=7.6)7.260–7.184 (m, 3H), 4.771(s, 2H). 2-(Pyridin-2-yl)isoindoline-1,3-dione (Table 2, Entry 1k)18: White solid (19.7 gm, Yield 80%), 1H NMR (400MHz, CDCl3): δH 8.641–8.630 (m, 1H), 7.926–7.846 (m, 3H), 7.759–7.716 (m, 2H,), 7.416 (d, 1H, J=8.0HZ), 7.354–7.322(m, 1H). 13C

NMR (100MHz, CDCl3) δC 166.7, 148.3, 146.9, 134.8, 133.9, 131.5, 129.5, 126.9, 124.0,

123.8. 2-Butylisoindoline-1,3-dione(Table 2, Entry 1l)39: White solid (18 gm, Yield 80%), mp: 34 ºC (lit. 32–36 ºC). 1H NMR (400MHz, CDCl3): δH 7.761–7.739 (m, 2H), 7.635–7.613 (m, 2H), 3.600 (t, J = 7.2 Hz, 3H), 1.593–1.536 (m, 2H), 1.311–1.254 (m, 2H), 0.861 (t, J = 7.2 Hz, 3H).

Analytical Data for Biaryl Amides 4'-Methoxy-N-phenyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3aa)33: White solid (I : 257 mg, 85% yield; Br : 242 mg, 80% yield), 1H NMR (700 MHz, CDCl3): δH 7.855 (d, 1H, J = 7.0 Hz), 7.518 (t, 1H, J = 7.4 Hz),7.454–7.406 (m, 4H), 7.260–7.234 (m, 4H), 7.177 (d, 1H, J = 8.4 Hz), 7.069 (t, 1H, J = 7.4 Hz), 7.009 (s, NH), 6.967 (d, 1H, J = 8.4 Hz), 3.826 (s, 3H);

13C{1H}

NMR (175MHz, CDCl3) δC 167.1, 159.6, 139.2, 137.7, 135.2,

132.1, 130.7, 130.4, 130.1, 129.6, 128.9, 127.5, 124.4, 120.0, 55.4; HRMS (ESI -TOF) m/z: calcd for C20H18NO2 [M+H]+ 304.1338; found 304.1338. 4'-Methyl-N-phenyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ab) 33: White solid (I : 229 mg, 80% yield; Br : 223 mg, 78% yield), 1H NMR (700 MHz, CDCl3): δH7.858 (d, 1H, J = 7.0 Hz), 7.648 (d, 1H, J = 7.7 Hz), 7.504–7.381 (m, 8H), 7.340 (t, 1H, J = 7.0 Hz), 7.192 (d, 2H, J = 7.7 Hz), 6.951 (s, NH), 2.157 (s, 3H);

13C{1H}

NMR (175MHz,

CDCl3) δC 167.2, 140.0, 139.6, 135.5, 134.1, 130.6, 130.3, 129.5, 129.3, 129.0, 128.9, 128.1,



127.9, 123.2, 120.1, 20.9. HRMS (ESI -TOF) m/z: calcd for C20H17NONa [M+Na]+ 310.1208; found 310.1213. N-Phenyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ac) 33: White solid (I : 223 mg, 82% yield; Br : 215 mg, 79% yield), 1H NMR (700 MHz, CDCl3): δH 7.890 (d, 1H, J = 8.4 Hz), 7.556–7.403 (m, 8H), 7.225 (t, 2H, J = 7.7 Hz),7.110 (d, 2H, J = 8.4 Hz), 7.053 (t, 1H, J = 7.7, 7.0 Hz), 6.925 (s, NH); 13C{1H} NMR (175MHz, CDCl3) δC 167.1, 139.6, 134.4, 130.7, 130.4, 129.6, 129.2, 129.0, 128.9, 128.1, 127.9, 126.6, 124.4, 123.8, 120.0. HRMS (ESI -TOF) m/z:

calcd for C19H16NO [M+H]+ 274.1232; found

274.1227. 4'-Nitro-N-phenyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ba): White solid (I : 238 mg, 75% yield; Br : 222 mg, 70% yield), 1H NMR (700 MHz, CDCl3): δH 8.373 (d, 2H, J = 9.1 Hz), 8.263 (d, 1H, J = 8.4 Hz), 8.006–7.994 (m, 2H), 7.899 (d, 1H, J = 7.7 Hz), 7.858–7.846 (m, 3H), 7.771 (d, 2H, J = 9.1 Hz), 7.600 (d, 1H, J = 7.7Hz), 7.525 (t, 1H, J = 7.35 Hz), 7.260 (s, NH);

13C{1H}

NMR (100MHz, CDCl3) δC 166.4, 165.8, 146.4,

143.8, 135.0, 132.7, 131.4, 129.1, 127.2, 126.4, 125.2, 124.5, 124.2, 119.4. HRMS (ESI TOF) m/z: calcd for C19H15N2O3 [M+H]+ 319.1083; found 319.1082. N-(p-Tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ca): White solid (I : 229 mg, 80% yield; Br : 218 mg, 76% yield), 1H NMR (400 MHz, CDCl3): δH 7.798 (d, 1H, J = 7.2 Hz), 7.450 (d, 1H, J = 7.8 Hz), 7.410–7.314 (m, 7H), 6.960–6.897 (m, 4H), 6.783 (s, NH), 2.191 (s, 3H);

13C{1H}

NMR (175MHz, CDCl3) δC 167.2, 140.0,

135.5, 134.1, 130.6, 130.3, 129.5, 129.3, 128.9, 128.9, 128.1, 127.9, 123.2, 120.1, 20.9. HRMS (ESI -TOF) m/z: calcd for C20H17NONa [M+Na]+ 310.1208; found 310.1213. 4'-Methyl-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3cb): White solid (I : 243 mg, 81% yield; Br : 228 mg, 76% yield), 1H NMR (700 MHz, CDCl3): δH 7.874 (d, 1H, J = 7.7 Hz), 7.519 (t, 1H, J = 7.4 Hz),7.467–7.445 (m, 1H), 7.407 (d, 1H, J = 7.7 Hz), 7.368 (d, 2H, J = 7.7 Hz),7.245 (d, 2H, J = 7.7 Hz),7.047–7.010 (m, 4H), 6.878 (s, NH), 2.391 (s, 3H), 2.279 (s, 3H); 13C{1H} NMR (175MHz, CDCl3) δC 167.2, 139.5, 137.9, 135.1, 134.3, 130.6, 130.4, 129.8, 129.6, 129.3, 128.7, 127.7, 126.5, 123.7, 120.0, 21.2, 20.9. HRMS (ESI -TOF) m/z: calcd for C21H19NONa [M+Na]+ 324.1364; found 324.1365.


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4'-Methoxy-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3cc): White solid (I : 269 mg, 85% yield; Br : 253 mg, 80% yield), 1H NMR (700 MHz, CDCl3): δH 7.967–7.956 (m, 4H), 7.840 (d, 1H, J = 7.7 Hz), 7.501 (t, 1H, J = 7.7, 7.0 Hz),7.443–7.390 (m, 4H), 7.069–7.039 (m, 4H), 3.826 (s, 3H), 2.282 (s, 3H);

13C{1H}

NMR (175MHz,

CDCl3) δC 167.4, 159.5, 139.1, 135.3, 135.1, 134.1, 132.2, 130.6, 130.1, 129.5, 129.3, 127.5, 120.8, 114.4, 55.4, 20.9. HRMS (ESI -TOF) m/z: calcd for C21H20NO2 [M+H]+ 318.1494; found 318.1483. 4'-Bromo-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3cd): White solid (I : 311 mg, 85% yield; Br : 292 mg, 80% yield), 1H NMR (400 MHz, CDCl3): δH 7.667 (d, 1H, J = 7.6 Hz), 7.458–7.422 (m, 3H), 7.387–7.352 (m, 1H), 7.305 (d, 1H, J = 7.6 Hz), 7.247 (d, 2H, J = 8.4 Hz), 7.029–6.973 (m, 4H), 6.951 (s, NH), 2.212 (s, 3H); 13C{1H}

NMR (175MHz, CDCl3) δC 167.2, 138.8, 138.3, 135.7, 134.9, 134.4, 132.0, 130.7,

130.4, 130.2, 129.5, 129.1, 128.1, 122.4, 120.0, 20.9. HRMS (ESI -TOF) m/z: calcd for C20H16BrNO [MH]+ 366.0489; found 366.0492. 4'-Methoxy-N-(4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3da): White solid (I : 286 mg, 86% yield; Br : 269 mg, 81% yield), 1H NMR (700 MHz, CDCl3): δH7.851 (d, 1H, J = 7.7 Hz), 7.441 (t, 1H, J = 7.4 Hz),7.418–7.391 (m, 4H), 7.073 (d, 2H, J = 8.4 Hz),6.972 (d, 2H, J = 8.4 Hz),6.851 (s, NH), 6.785 (d, 2H, J = 9.1 Hz), 3.836 (s, 3H), 3.763 (s, 3H); 13C{1H} NMR (175MHz, CDCl3) δC 167.3, 159.6, 156.5, 139.1, 135.3, 132.2, 130.7, 130.5, 130.3, 130.1, 129.5, 127.5, 121.9, 114.4, 114.0, 55.5, 55.4. HRMS (ESI -TOF) m/z: calcd for C21H20NO3 [M+H]+ 334.1443; found 334.1433. N-(4-Methoxyphenyl)-4'-methyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3db): White solid (I : 266 mg, 84% yield; Br : 253 mg, 80% yield), 1H NMR (700 MHz, CDCl3): δH 7.762 (d, J = 6.8 Hz, 1H), 7.473–7.362 (m, 2H), 7.324 (d, J = 7.6 Hz, 1H), 7.279 (d, J = 8.0 Hz, 2H), 7.162 (d, J = 8.0 Hz, 2H), 6.959 (d, J = 8.8 Hz, 2H), 6.804 (s, 1H), 6.691 (d, J = 8.8 Hz, 2H), 3.731 (s, 3H), 2.314 (s, 3H); 13C{1H} NMR (175MHz, CDCl3) δC 167.2, 139.5, 156.5, 137.9, 135.3, 131.7, 130.6, 130.3, 129.6, 129.5, 128.8, 127.7, 127.0, 121.8, 114.3, 114.0, 55.5, 21.2. HRMS (ESI -TOF) m/z: calcd for C21H20NO2 [M+H]+ 318.1494, found 318.1483. N-(4-Methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3dc):



Page 18 of 27

White solid (I : 258 mg, 85% yield; Br : 242 mg, 80% yield), 1H NMR (700 MHz, CDCl3): δH 7.848 (d, 1H, J = 7.0 Hz), 7.526 (t, 2H, J = 6.3 Hz), 7.471–7.398 (m, 6H), 6.877 (s, NH), 6.756 (d, 2H, J = 8.4 Hz), 3.746 (s, 3H); 13C{1H} NMR (175MHz, CDCl3) δC 167.2, 156.6, 140.1, 139.5, 135.4, 131.6, 130.6, 130.3, 129.5, 129.0, 128.9, 128.1, 127.9, 121.9, 114.2, 114.0, 55.4. LCMS m/z: (rel intensity): 304.1(MH+, 100), 305.1(22). 4'-Methoxy-N-(o-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ea): White solid (I : 266 mg, 84% yield; Br : 247 mg, 78% yield), 1H NMR (400 MHz, CDCl3): δH 7.809 (d, 1H, J = 7.2 Hz), 7.759 (d, 1H, J = 8.8 Hz), 7.478–7.309 (m, 5H), 7.099 (t, 1H, J= 7.4 Hz), 6.974–6.878 (m, 2H), 6.868 (d, 2H, J = 8.4 Hz), 6.821 (s, NH), 3.729 (s, 3H), 1.604 (s, 3H); 13C{1H} NMR (100MHz, CDCl3) δC 167.7, 159.7, 138.8, 135.9, 132.2, 131.9, 130.6, 130.7, 130.5, 130.3, 130.2, 129.6, 128.9, 127.5, 127.1, 126.7. 124.8, 121.9, 114.5, 55.4, 16.8. HRMS (ESI -TOF) m/z: calcd for C21H20NO2 [M+H]+ 318.1494; found 318.1483. 2-(Pyridin-2-yl)-N-(o-tolyl)benzamide(Table 2, Entry 3eb): White solid (I : 224 mg, 78% yield; Br : 216 mg, 75% yield), 1H NMR (300 MHz, CDCl3): δH8.552 (d, 1H, J = 5.6 Hz), 7.717 (d, 2H, J = 7.2 Hz), 7.651 (t, 2H, J =6.6 Hz),7.521–7.426 (m, 4H), 7.197–6.946 (m, 4H), 1.897 (s, 3H);

13C{1H}

NMR (75MHz, CDCl3) δC 167.7,

158.0, 149.1, 138.3, 136.8, 136.3, 135.6, 130.1, 128.9, 128.8, 125.9, 124.1, 123.3, 122.5, 21.1. HRMS (ESI -TOF) m/z: calcd for C19H16N2ONa [M+Na] + 311.1160; found 311.1156. 2-(Thiophen-2-yl)-N-(o-tolyl)benzamide(Table 2, Entry 3ec): White solid (I : 234 mg, 80% yield; Br : 222 mg, 76% yield), 1H NMR (400 MHz, CDCl3): δH 7.868–7.845 (m, 1H), 7.681 (d, 1H, J = 7.6 Hz), 7.281 (d, 1H, J = 9.2 Hz),7.445–7.358 (m, 3H), 7.164–7.100 (m, 2H), 7.029–6.95 (m, 3H), 1.762 (s, 3H);

13C{1H}

NMR (100MHz,

CDCl3) δC 167.7, 141.2, 136.6, 135.7, 134.6, 131.7, 131.1, 130.6, 129.5, 128.6, 128.4, 127.7, 127.1, 125.9, 125.3, 122.8, 16.5. HRMS (ESI -TOF) m/z: calcd for C18H16NSO [M+H]+ 294.0953; found 294.0950. N-(2,5-Dimethylphenyl)-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3fa): White solid (I : 281 mg, 85% yield; Br : 264 mg, 80% yield), 1H NMR (400 MHz, CDCl3): δH 7.757 (d, 1H, J = 7.6 Hz), 7.707 (s, 1H), 7.434–7.415 (m, 1H),7.381–7.307 (m, 4H), 6.881–6.833 (m, 3H), 6.734 (d, 1H, J = 7.6 Hz),6.778 (s, NH), 3.731 (s, 3H), 2.229 (s, 3H), 1.55 (s, 3H);

13C{1H}

NMR (100MHz, CDCl3) δC 167.7, 159.7, 138.8, 136.4, 135.8, 135.6,


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132.3, 130.5, 130.2, 129.6, 127.5, 125.5, 124.9, 122.3, 114.5, 55.4, 21.3, 16.4. HRMS (ESI TOF) m/z: calcd for C22H22NO2 [M+H]+ 332.1651; found 332.1653. N-(2,5-Dimethylphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3fb): White solid (I : 249 mg, 83% yield; Br : 225 mg, 75% yield), 1H NMR (400 MHz, CDCl3): δH 7.783 (d, 1H, J = 7.6 Hz), 7.718–7.680 (m, 1H), 7.478–7.290 (m, 7H), 7.176–7.157 (m, 1H),6.923 (d, 1H, J = 7.6 Hz), 6.824 (d, 1H, J = 8.4 Hz), 6.813 (s, NH), 2.221 (s, 3H), 1.484 (s, 3H); 13C{1H} NMR (100MHz, CDCl3) δC 167.5, 139.4, 135.6, 134.3, 132.0, 130.4, 130.3, 130.1, 129.0, 128.0, 125.5, 123.9, 122.3, 21.2, 16.3. HRMS (ESI -TOF) m/z: calcd for C21H20NO [M+H]+ 302.1545; found 302.1539. N-(2,5-Dimethylphenyl)-2-(thiophen-2-yl)benzamide(Table 2, Entry 3fc): yellow solid (I : 245 mg, 80% yield; Br : 233 mg, 76% yield), 1H NMR (400 MHz, CDCl3): δH 7.738 (s, 1H), 7.687 (d, J = 7.6 Hz, 1H), 7.468–7.351 (m, 3H), 7.284 (d, J = 5.6 Hz, 1H), 7.131 (d, J = 3.2 Hz, 1H), 6.983–6.946 (m, 2H), 6.881 (d, J = 7.2 Hz, 1H), 6.762 (d, J = 7.6 Hz, 1H), 2.242 (s, 3H), 1.704 (s, 2H).

13C{1H}

NMR (100MHz, CDCl3) δC 167.4, 140.9,

136.5, 136.6, 135.4, 131.5.3, 130.7, 130.3, 130.1, 129.2, 128.3, 127.4 126.7, 125.6, 122.1, 21.1, 16.5. HRMS (ESI -TOF) m/z: calcd for C19H18NOS [M+H]+ 308.1109; found 308.1112. 4'-Bromo-N-(2,5-dimethylphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3fd): White solid (I : 323 mg, 85% yield; Br : 285 mg, 75% yield), 1H NMR (400 MHz, CDCl3): δH 7.707 (d, J = 6.8 Hz, 1H), 7.582 (s, 1H), 7.475–7.382 (m, 4H), 7.306 (t, J = 7.4 Hz, 3H), 6.883 (d, J = 7.6 Hz, 1H), 6.768 (d, J = 8.0 Hz, 2H), 2.231 (s, 3H), 1.627(s, 3H).

13C{1H}

NMR (100MHz, CDCl3) δC 167.5, 138.9, 138.0, 136.6, 136.0, 135.3, 132.1, 130.6, 130.3, 129.3, 128.2, 125.9 122.7, 122.5, 51.2, 16.5. HRMS (ESI -TOF) m/z: Calcd for C21H19BrNO [M+H]+ 380.0650; found 380.0653.

N-(2,5-Dimethylphenyl)-2-(pyridin-2-yl)benzamide(Table 2, Entry 3fe): White solid (I : 229 mg, 76% yield; Br : 226 mg, 75% yield), 1H NMR (400 MHz, CDCl3): δH 8.652 (d, 1H, J = 6.4 Hz), 7.823–7.526 (m, 8H),7.296–7.255 (m, 1H), 6.998 (d, 1H, J = 10.0 Hz), 6.867 (d, 1H, J = 10.0 Hz), 2.319 (s, NH), 1.915 (s, 3H); 13C{1H} NMR (100MHz, CDCl3) δC 167.9, 158.1, 149.2, 138.3, 136.8, 136.3, 135.6, 130.1, 128.9, 128.8, 125.8, 124.0,



123.3, 122.6, 21.1, 16.9. HRMS (ESI -TOF) m/z: calcd for C20H19N2O [M+H]+ 303.1497; found 303.1489. N-(2,6-Dimethylphenyl)-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ga): White solid (I : 281 mg, 85% yield; Br : 264 mg, 80% yield), 1H NMR (400 MHz, CDCl3): δH 7.721 (d, 1H, J = 7.2 Hz), 7.456 (d, 1H, J = 8.4 Hz), 7.435 (d, 1H, J = 7.2 Hz),7.371 (d, 1H, J = 8.4 Hz),7.302–7.250 (m, 1H),6.987–6.865 (m, 2H), 6.849 (d, 2H, J = 8.4 Hz), 6.631 (s, NH), 3.753 (s, 3H), 1.941 (s, 3H);

13C{1H}

NMR (100MHz, CDCl3) δC 167.9, 159.5,

135.4, 133.6, 132.8, 131.2, 130.7, 130.2, 130.1, 128.2, 127.3, 127.3, 114.3, 113.7, 55.4, 55.4, 18.4. HRMS (ESI -TOF) m/z: calcd for C22H22NO2 [M+H]+ 332.1651; found 332.1653. 4'-Bromo-N-(2,6-dimethylphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3gb): White solid (I : 323 mg, 85% yield; Br : 285 mg, 75% yield), 1H NMR (300MHz, CDCl3) δH 7.805 (d, 1H, J = 7.6 Hz ), 7.622–7.604 (m, 1H), 7.349–7.499 (m, 4H) 7.270 (d, 2H, J= 8.4 Hz), 7.037-6.968 (m, 2H), 6.927(d, 1H, J = 8.0 Hz), 6.776(s, NH), 2.159 (s, 3H), 1.921 (s, 3H).

13C{1H}

NMR (75MHz, CDCl3) δC 167.9, 139.3, 138.6, 136.1, 135.6, 135.43, 131.8,

130.7, 130.4, 128.7, 128.3, 127.9, 127.5, 127.4, 127.3, 122.2, 18.5, 18.3. HRMS (ESI -TOF) m/z: calcd for C21H19BrNO [M+H]+ 380.0650; found 380.0651. N-(4-Chlorophenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ha): White solid (I : 248 mg, 81% yield; Br : 233 mg, 76% yield), 1H NMR (400 MHz, CDCl3): δH 7.782–7.763 (m, 1H), 7.528–7.451 (m, 2H), 7.413–7.312 (m, 5H), 7.240–7.218 (m, 1H), 7.090 (d, 2H, J = 8.8 Hz), 6.959 (d, 2H, J = 8.8 Hz), 6.87 (s, NH); 13C{1H} NMR (100MHz, CDCl3) δC 167.47, 139.60, 131.98, 131.81, 130.93, 130.38, 129.60, 129.05, 128.83, 128.78, 128.22, 127.98, 122.58. HRMS (ESI -TOF) m/z: calcd for C19H15ClNO [M+H]+ 308.0842; found 308.0844. Ethyl 2'-((4-chlorophenyl)carbamoyl)-[1,1'-biphenyl]-2-carboxylate(Table 2, Entry 3hb): White solid (I : 246 mg, 65% yield; Br : 189 mg, 50% yield), 1H NMR (400MHz, CDCl3):δH7.763–7.720 (m, 1H), 7.402–7.280 (m, 3H), 7.002 (d, 1H, J = 7.2 Hz), 6.818 (d, 1H, J= 7.6 HZ), 6.707 (d, 1H, J= 7.2 HZ), 4.094-4.053 (m, 2H), 0.890 (t, 3H, J= 7.0 Hz); 13C{1H}

NMR (100MHz, CDCl3) δC 167.8, 166.0, 138.5, 136.1, 135.6, 131.7, 130.7, 130.3,

130.1, 128.7, 128.2, 127.9, 127.4, 127.4, 127.2, 122.4, 122.2, 60.1, 18.5. HRMS (ESI -TOF) m/z: calcd for C22H19ClNO3 [M+H]+ 380.1053; found 380.1056.


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4'-Bromo-N-(4-chlorophenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3hc): White solid (I : 328 mg, 85% yield; Br : 285 mg, 74% yield), 1H NMR (400 MHz, CDCl3): δH 7.756 (d, 1H, J = 8.0 Hz), 7.516–7.444 (m, 3H), 7.399–7.361 (m, 1H), 7.313 (d, 1H, J = 7.6 Hz),7.223 (d, 2H, J = 8.4 Hz), 7.137 (d, 2H, J = 8.8 Hz), 7.070 (d, 2H, J = 8.8), 7.023 (s, NH);

13C{1H}

NMR (100MHz, CDCl3) δC 167.3, 138.7, 138.4, 138.0, 136.0, 135.2, 132.0,

130.3, 130.3, 129.7, 129.2, 128.2, 122.5, 121.1. HRMS (ESI -TOF) m/z: calcd for C19H14BrClNO [M+H]+ 385.9947; found 385.9959. N-(4-Chlorophenyl)-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3hd): White solid (I : 283 mg, 84% yield; Br : 269 mg, 80% yield), 1H NMR (300MHz, CDCl3) δH 7.843–7.822 (m, 1H), 7.561–7.521 (m, 1H), 7.471–7.381 (m, 4H,) 7.210 (d, 2H, J = 8.4 Hz), 7.143–7.121 (m, 2H), 7.086 (s, 1H), 6.986-6.964 (m, 2H), 3.846 (s, 3H).

13C{1H}

NMR

(75MHz, CDCl3) δC 167.4, 159.6, 139.2, 136.2, 134.8, 132.0, 130.9, 130.4, 130.0, 129.5, 128.9, 127.6, 121.1, 114.4, 55.4. HRMS (ESI -TOF) m/z: calcd for C20H17ClNO2 [M+H]+ 338.0948; found 338.0957. N-(4-Bromophenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ia): White solid (I : 281 mg, 80% yield; Br : 260 mg, 74% yield), 1H NMR (400 MHz, CDCl3): δH 7.761 (d, 1H, J = 7.6 Hz), 7.474 (d, 1H, J = 6.8 Hz), 7.447–7.305 (m, 7H), 7.229 (d, 2H, J = 8.4 Hz), 6.917–6.895 (m, 3H);

13C{1H}

NMR (100MHz, CDCl3) δC 167.2, 139.6, 136.6,

134.9, 132.0, 131.8, 130.9, 130.4, 129.6, 129.1, 128.8, 128.8, 128.2, 129.0, 121.4. HRMS (ESI -TOF) m/z: calcd for C19H15BrNO [M+H]+ 352.0337; found 352.0336. N-(4-Chlorophenyl)-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ib): White solid (I : 324 mg, 85% yield; Br : 305 mg, 80% yield), 1H NMR (400 MHz, CDCl3): δH 7.741 (d, 1H, J = 7.6 Hz), 7.441 (t, 1H, J = 7.6 Hz), 7.371–7.243 (m, 6H), 6.990–6.928 (m, 3H), 6.875 (d, 2H, J = 8.4 Hz), 3.774 (s, 3H);

13C{1H}

NMR (100MHz, CDCl3) δC 167.4,

159.6, 139.2, 136.7, 134. 8, 132.0, 131.8, 130.9, 130.4, 130.0, 129.6, 127.6, 121.4 116.9, 114.5, 55.4. HRMS (ESI -TOF) m/z: calcd for C20H17BrNO2 [M+H]+ 382.0443; found 382.0441. 4'-Bromo-N-(4-bromophenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ic):



Page 22 of 27

White solid (I : 366 mg, 85% yield; Br : 327 mg, 76% yield), 1H NMR (400 MHz, CDCl3): δH 7.689 (d, 1H, J = 7.2 Hz), 7.531–7.460 (m, 3H), 7.433–7.370 (m, 1H), 7.332–7.285 (m, 3H),7.242 (d, 2H, J = 8.4 Hz), 7.028 (d, 2H, J = 8.8 Hz), 6.933 (s, NH);

13C{1H}

NMR

(100MHz, CDCl3) δC 167.2, 138.7, 138.4, 136.5, 132.2, 132.1, 132.0, 131.0, 130.3, 130.3, 129.2, 128.3, 122.5, 121.4, 117.3. HRMS (ESI -TOF) m/z: calcd for C19H14Br2NO [M+H]+ 431.9422; found 431.9423. N-Benzyl-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ja): White solid (I : 266 mg, 84% yield; Br : 253 mg, 80% yield), 1H NMR (400 MHz, CDCl3): δH 7.62–7.60 (m, 1H), 7.36–7.34 (m, 1H), 7.30–7.28 (m, 1H), 7.24–7.17 (m, 3H), 7.14–7.12 (m, 3H), 6.85–6.77 (m, 4H), 5.50 (s, 1H), 4.265 (d, 2H, J = 2.8 Hz), 3.741 (s, 3H); 13C{1H} NMR (100MHz, CDCl3) δC 169.6, 159.4, 139.1, 137.5, 135.5, 132.5, 130.2, 130.1, 129.9, 128.8, 128.5, 127.8, 127.4, 127.3, 114.1, 55.3, 44.1. HRMS (ESI -TOF) m/z: calcd for C21H20NO2 [M+H]+ 318.1494; found 318.1489. N-Benzyl-4'-bromo-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3jb): White solid (I : 299 mg, 82% yield; Br : 273 mg, 75% yield), 1H NMR (400 MHz, CDCl3): δH 7.59(d, 1H, J = 7.2 Hz), 7.41–7.32 (m, 5H), 7.23 (d, 1H, J = 7.6 Hz), 7.19–7.15 (m, 4H), 6.86–6.82 (m, 2H), 5.45 (s, NH), 4.287 (d, 2H, J = 2.8 Hz);

13C{1H}

NMR (100 MHz,

CDCl3) δC 169.5, 138.8, 136.6, 135.2, 132.2, 130.1, 129.9, 129.8, 128.7, 128.4, 127.6, 127.2, 127.1, 122.0, 121.9, 44.0. HRMS (ESI -TOF) m/z: calcd for C20H16BrNO [M+H]+ 366.0494; found 366.0488. N-Butyl-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3la): Colourless liquid (I : 198 mg, 70% yield; Br : 175 mg, 62% yield), 1H NMR (400 MHz, CDCl3): δH 7.569 (d, J = 7.6 Hz, 1H), 7.352 (d, J = 7.6 Hz, 1H), 7.314–7.278 (m, 1H), 7.247 (d, J = 8.4 Hz, 3H), 6.860 (d, J = 8.8 Hz, 2H), 5.384 (s, 1H), 3.755 (s, 3H), 3.109–3.061 (m, 2H), 1.174–1.102 (m, 2H), 0.992–0.914 (m, 2H), 0.856 (t, J = 6.6 Hz, 3H).

13C{1H}

NMR

(100MHz, CDCl3) δC 169.8, 159.4, 135.6, 132.5, 131.4, 130.1, 130.0, 129.9, 128.8, 128.5, 126.9, 114.03, 55.3, 39.6, 31.0, 19.9, 13.8. HRMS (ESI -TOF) m/z: calcd for C18H22NO2 [M+H]+ 284.1651; found 284.1643.


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ASSOCIATED CONTENT Supporting Information This material is available free of charge via the Internet at http://pubs.acs.org. 1H and

13C,

HRMS data and FT-IR spectra of compounds (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Papu Biswas: 0000-0002-7697-849X Notes The authors declare no competing financial interest. ACKNOWLEDGMENT PKS is indebted to UGC-India for JRF (ID-131818). REFERENCES 1. (a) Miyaura, N. Ed.; Cross-Coupling Reactions: A Practical Guide. Springer, Berlin, 2002. (b) de Meijere, A.; Diederich, F. Metal-catalyzed Cross-Coupling Reactions, 2nd Ed.; Wiley-VCH: Weinheim, Germany, 2004. 2. Tsuji, J.; Ohno, K. Organic syntheses by means of noble metal compounds XXI. Decarbonylation of aldehydes using rhodium complex. Tetrahedron Lett. 1965, 6, 3969–3971. 3. Kreis, M.; Palmelund, A.; Bunch, L.; Madsen, R. A General and Convenient Method for the Rhodium‐Catalyzed Decarbonylation of Aldehydes. Adv. Synth.Catal. 2006, 348, 2148–2154. 4. Iwai,

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