Palladium Catalyzed Regioselective Synthesis of Substituted Biaryl Amides through Decarbonylative Arylation of Phthalimides

Article abstract of DOI:10.1021/acs.joc.8b03157

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 ortho-substituted biarylamides in high yields through unique carbonyl (CO) replacement. The reaction proceeds through a ligand-free condition and is well tolerant to the diverse functionality of both imide and halide units. The reaction negates any requirement of organometallic reagent and needs a shorter reaction time and comparatively lower temperature as required for previously reported decarbonylative processes.

Full text of DOI:10.1021/acs.joc.8b03157

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Article
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
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Palladium Catalyzed Regio-selective Synthesis of Substituted
Biaryl Amides through Decarbonylative Arylation of
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Phthalimides
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Partha Kumar Samanta, and Papu Biswas*
Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur,
Howrah 711 103, West Bengal, India.
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ABSTRACT
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X
O
O
33 examples
R1
Pd
up to 86% yield
no need of organometallic
reagent
N R1
N
H
Ar
CO
O
Ar
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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 ortho-
substituted 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
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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.
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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
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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 cost-
ineffective. Another major disadvantage which makes the processes unfruitful for synthesis is
possibility of the formation of mono and diarylated products (Figure 1).
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Previous works
O
N
H
O
Ph
O
Pd(OAc)2 (20 mol%), PPh3,
Cs2CO3 (4.0 equiv), 110o C
N
H
Ph
I
Ph
N
H
Aryl halides
(4 equiv)
Benzamides
Ph
O
Pd(OAc)2 (10 mol%)
AgOAc (1.0 equiv)
I
O
N
H
N
H
COPh
OMe
110oC, 10h
O
Ph
OMe
-
Aryl halides
Ketoamides
I
O
Pd(OAc)2 (10 mol%)
Mn(OAc)2 (1.0 equiv)
O
N
H
N
H
Ar
NHR2
NHR2
Na2CO3, t-AmOH
Ar
R1
120oC
Aryl halides
Benzamides
O
Ni(cod)2 (1.0 equiv)
bipy (1.1 equiv)
O
R1
N
R2Zn R2
H
N
R1
R2
1,4-dioxane/THF, 95oC
O
Pthalimides
Diorganozinc
Our work
O
Pd(OAc)2 (5 mol%)
KOtBu (20 mol%)
X
O
R1
N
H
N
R1
Ar
DMF, 110oC
Ar
O
Pthalimides
Aryl halides
X = I, Br
R1 = aryl, benzyl
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 cross-
coupling 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.
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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
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O
O
catalyst, solvent
N
H
I
OMe
N
base, temperature
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O
OMe
3aa
1a
2a
Entry
Catalyst
Base
Temperature Time
Solvent
Yield
(%)b
85
(h)
(C)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Cs2CO3
K2CO3
K3PO4
NaOtBu
NaOH
KOH
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
110
100
130
110
110
110
110
110
110
110
110
110
110
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
10
12
12
12
12
12
12
12
12
DMF
water
THF
Ndc
trace
12
dioxane
NMP
DMSO
ethanol
toluene
xylene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
10
nd
nd
nd
62
45
38
52
61
40
40
85
84
60
87
88
66
86
72
trace
40
42
trace
nd
82
9
10d
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12
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17
18e
19
20
21
22
23f
24g
25h
26
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28
29i
30j
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
-
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Pd(PPh3)2Cl2
Pd(PPh3)4
-
Pd(OAc)2
a Reaction conditions (until unless specified): 1a (1.0 mmol), 2a (1.0 mmol), catalyst
(11.2 mg, 5 mol%), base (20 mol%), solvent (3 mL), reaction performed under inert
atmosphere. Isolated yield. cnd = Product not detected. Reaction performed in un-
b
d
distilled DMF. Reaction performed with 1 equivalent base. fReaction performed with
e
22.4 mg catalyst (10 mol%). gReaction performed with 3 mol% (6.7 mg) catalyst.
hReaction performed without any base. Reaction performed without any catalyst.
i
jReaction 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).
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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 80-
85% 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
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Table 2. Substrate Scope for Decarbonylative Arylation of Phthalimides and Aryl
halidesa, b
7
8
9
R'
Pd(OAc)2 (5 mol%)
KOtBu (20 mol%)
O
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15
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17
18
19
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21
22
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O
N
X
R
R'
DMF, 110oC, 12h
N
R
H
O
2
1
3
OMe
NO2
O
O
O
O
O
N
N
N
N
H
N
H
H
H
H
3aa
3ab
3ac
3ba
3ca
I:85%, Br:80%
I:80%, Br:78%
I:82%, Br:79%
I:75%, Br:70%
I:80%, Br:76%
OMe
Br
OMe
CH3
CH3
CH3
OMe
O
OMe
O
O
O
O
N
H
N
N
H
N
H
N
H
H
3cd
3cc
3da
3db
3cb
I:85%, Br:80%
I:85%, Br:80%
I:86%, Br:81%
I:84%, Br:80%
I:81%, Br:76%
OMe
OMe
S
N
OMe
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
3eb
3ec
3dc
3ea
3fa
I:78%, Br:75%
I:80%, Br:76%
I:85%, Br:80%
I:84%, Br:78%
I:85%, Br:80%
Br
OMe
N
S
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
3fb
3ga
3fc
3fd
3fe
I:83%, Br:75%
I:85%, Br:80%
I:80%, Br:76%
I:85%, Br:75%
I:76%, Br:75%
Br
OMe
Br
Cl
Cl
Cl
Cl
EtOOC
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
3ha
3hb
3gb
3hc
3hd
I:81%, Br:76%
I:65%, Br:50%
I:85%, Br:75%
I:85%, Br:74%
I:84%, Br:80%
Br
OMe
OMe
Br
OMe
Br
Br
Br
O
O
O
O
O
O
N C4H9
N
H
N
H
N
H
N
N
Ph
Ph
H
H
H
3ia
3ic
I:85%, Br:76%
3ib
3la
I:70%, Br:62%
3jb
I:82%, Br:75%
3ja
I:84%, Br:80%
I:80%, Br:74%
I:85%, Br:80%
a Reaction conditions (until unless specified): 1a (1.0 mmol), 2a (1.0 mmol), catalyst (11.2 mg, 5 mol%),
b
KOtBu (22.5 mg, 20 mol%), DMF (3 mL), reaction performed under inert atmosphere. 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).
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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
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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
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aryl halide which again evident from C 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
NH2
COOH
O
optimized
condition
Ph
Ph
N
3aa
Pdt
nd
Ph
N
H
Ph
X
H
COOH
4
2a
trace
sole pdt.
nd = not detected
O
O
2.
optimized
condition
O
H
N Ph
N Ph
product
nd
Ph
X
N
O
Ph
H
O
O
2a
other unsuccesfull substrates
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O
3.
O
optimized
condition
N
N
N
Ph
X
H
N
Ph
O
3ka
product
nd
2a
3k
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.
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Pd(OAc)2
KOtBu
O
O
DMF/
H+
N
N
H
Ar
O
(A)
LnPd(0)
Product

/
F
n
M
o
i
D
t
i
d
d
a
Ar
L = DMF
O
e
v
i
t
a
O
d
i
N
x
o
N
Pd
Pd
X
(F)
O
re
d
u
c
ti
v
e
e
li
m
in
a
ti
o
n
(B)
O
N
Pd
O
N
oxidative addition
X
Ar
Ar-X
O
(E)
Pd
OC
N
(C)
Pd
Decarbonylation
CO
(D)
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.
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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
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1
provided in the literature. H NMR spectra were recorded on a Bruker Advance III 300, 400
and 700 MHz NMR spectrometer. NMR spectra were recorded at room temperature with
1
CDCl3 or DMSO-d6 as the solvent. Chemical shifts (δ) of H NMR spectra are reported in
ppm relative to residual solvent signals (CHCl3 in CDCl3: δ = 7.26 ppm, DMSO in DMSO-
d6: 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
1
13
following the same procedure and products were characterized by H NMR and C NMR
spectra.
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General Method for Decarbonylative Coupling of phthalimide with an aryl halide
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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.
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Analytical Data for N-substituted Phthalimides
2-Phenylisoindoline-1,3-dione (Table 2, Entry 1a)26:
1
White solid (20.8 gm, Yield 85%), mp: 205–208 ºC (lit. 205 ºC). H 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:
1
Pale yellow solid (23 gm, Yield 78%), mp: 248–250 ºC (lit. 250–252 ºC). H 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:
1
White crystalline solid (22.3 gm, Yield 86%), mp: 208–210 ºC (lit. 207–209 ºC). H 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:
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White solid (23.6 gm, Yield 85%), mp: 142 ºC (lit. 143–145 ºC). H 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).
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2-(o-Tolyl)isoindoline-1,3-dione (Table 2, Entry 1e)37:
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17
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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):
1
Crystalline solid (22.6 gm, Yield 82%), mp: 164–166 ºC. H 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 =
13
8Hz), 2.233 (s, 3H), 2.045 (s, 3H). C{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):
1
White solid (22.0 gm, Yield 80%), mp: 190–193 ºC. H 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:
1
Light yellow solid (22.6 gm,Yield 80%), mp: 194 ºC (lit. 194–196 ºC). H 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:
1
White solid (27 gm, Yield 82%), mp: 202 ºC (lit. 206 ºC). H 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:
5
6
7
8
1
White solid, (22.8 gm, Yield 84%), mp: 112 ºC (lit. 113–115 ºC). H 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).
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2-(Pyridin-2-yl)isoindoline-1,3-dione (Table 2, Entry 1k)18:
1
White solid (19.7 gm, Yield 80%), H 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:
1
White solid (18 gm, Yield 80%), mp: 34 ºC (lit. 32–36 ºC). H 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:
1
White solid (I : 257 mg, 85% yield; Br : 242 mg, 80% yield), H 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
13
Hz), 3.826 (s, 3H); C{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:
1
White solid (I : 229 mg, 80% yield; Br : 223 mg, 78% yield), H 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); C{1H} NMR (175MHz,
13
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,
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127.9, 123.2, 120.1, 20.9. HRMS (ESI -TOF) m/z: calcd for C20H17NONa [M+Na]+
310.1208; found 310.1213.
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N-Phenyl-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ac) 33:
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White solid (I : 223 mg, 82% yield; Br : 215 mg, 79% yield), H 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 =
13
8.4 Hz), 7.053 (t, 1H, J = 7.7, 7.0 Hz), 6.925 (s, NH); C{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):
1
White solid (I : 238 mg, 75% yield; Br : 222 mg, 70% yield), H 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,
13
1H, J = 7.35 Hz), 7.260 (s, NH); C{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):
1
White solid (I : 229 mg, 80% yield; Br : 218 mg, 76% yield), H 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):
1
White solid (I : 243 mg, 81% yield; Br : 228 mg, 76% yield), H 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,
13
NH), 2.391 (s, 3H), 2.279 (s, 3H); C{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):
5
6
1
White solid (I : 269 mg, 85% yield; Br : 253 mg, 80% yield), H NMR (700 MHz, CDCl3):
7
8
9
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.
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4'-Bromo-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3cd):
1
White solid (I : 311 mg, 85% yield; Br : 292 mg, 80% yield), H 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):
1
White solid (I : 286 mg, 86% yield; Br : 269 mg, 81% yield), H 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),
13
3.763 (s, 3H); C{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):
1
White solid (I : 266 mg, 84% yield; Br : 253 mg, 80% yield), H 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):
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White solid (I : 258 mg, 85% yield; Br : 242 mg, 80% yield), H NMR (700 MHz, CDCl3):
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6
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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),
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6.756 (d, 2H, J = 8.4 Hz), 3.746 (s, 3H); C{1H} NMR (175MHz, CDCl3) δC 167.2, 156.6,
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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).
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4'-Methoxy-N-(o-tolyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ea):
1
White solid (I : 266 mg, 84% yield; Br : 247 mg, 78% yield), H 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):
1
White solid (I : 224 mg, 78% yield; Br : 216 mg, 75% yield), H 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):
1
White solid (I : 234 mg, 80% yield; Br : 222 mg, 76% yield), H 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):
1
White solid (I : 281 mg, 85% yield; Br : 264 mg, 80% yield), H 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),
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1.55 (s, 3H); C{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.
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N-(2,5-Dimethylphenyl)-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3fb):
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White solid (I : 249 mg, 83% yield; Br : 225 mg, 75% yield), H 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):
1
White solid (I : 323 mg, 85% yield; Br : 285 mg, 75% yield), H 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),
13
6.883 (d, J = 7.6 Hz, 1H), 6.768 (d, J = 8.0 Hz, 2H), 2.231 (s, 3H), 1.627(s, 3H). C{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):
1
White solid (I : 229 mg, 76% yield; Br : 226 mg, 75% yield), H 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,
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123.3, 122.6, 21.1, 16.9. HRMS (ESI -TOF) m/z: calcd for C20H19N2O [M+H]+ 303.1497;
found 303.1489.
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N-(2,6-Dimethylphenyl)-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ga):
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White solid (I : 281 mg, 85% yield; Br : 264 mg, 80% yield), H 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):
1
White solid (I : 248 mg, 81% yield; Br : 233 mg, 76% yield), H 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):
1
White solid (I : 246 mg, 65% yield; Br : 189 mg, 50% yield), H 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):
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1
White solid (I : 328 mg, 85% yield; Br : 285 mg, 74% yield), H NMR (400 MHz, CDCl3):
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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,
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NH); C{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):
1
White solid (I : 281 mg, 80% yield; Br : 260 mg, 74% yield), H 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); C{1H} NMR (100MHz, CDCl3) δC 167.2, 139.6, 136.6,
13
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):
1
White solid (I : 324 mg, 85% yield; Br : 305 mg, 80% yield), H 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); C{1H} NMR (100MHz, CDCl3) δC 167.4,
13
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):
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White solid (I : 366 mg, 85% yield; Br : 327 mg, 76% yield), H 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.
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N-Benzyl-4'-methoxy-[1,1'-biphenyl]-2-carboxamide(Table 2, Entry 3ja):
1
White solid (I : 266 mg, 84% yield; Br : 253 mg, 80% yield), H 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); C{1H}
13
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):
1
White solid (I : 299 mg, 82% yield; Br : 273 mg, 75% yield), H 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):
1
Colourless liquid (I : 198 mg, 70% yield; Br : 175 mg, 62% yield), H 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). C{1H} NMR
13
(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
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This material is available free of charge via the Internet at http://pubs.acs.org. H and C,
HRMS data and FT-IR spectra of compounds (PDF).
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AUTHOR INFORMATION
Corresponding Author
*E-mail: papubiswas_besus@yahoo.co.in
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).
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