Nickel-Mediated Cross-Coupling of Boronic Acids and Phthalimides for the Synthesis of Ortho-Substituted Benzamides

Article abstract of DOI:10.1021/acs.joc.9b03396

The decarbonylative coupling of phthalimides with aryl boronic acids provides ready access to a broad range of ortho-substituted benzamides. This nickel-mediated methodology extends reactivity from previously described air-sensitive diorganozinc reagents of limited availability to easily handled and widely commercially available boronic acids. The decarbonylative coupling is tolerant of a broad range of functional groups and demonstrates little sensitivity to steric factors on either of the coupling partners.

Full text of DOI:10.1021/acs.joc.9b03396

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Article
Nickel-Mediated Cross-Coupling of Boronic Acids and
Phthalimides for the Synthesis of Ortho-Substituted Benzamides
Ethan M Heyboer, Rebecca L Johnson, Megan R Kwiatkowski, Trey C Pankratz, Mason C
Yoder, Kimberly S DeGlopper, Grace C Ahlgrim, Joseph M. Dennis, and Jeffrey Bruce Johnson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03396 • Publication Date (Web): 29 Jan 2020
Downloaded from pubs.acs.org on February 2, 2020
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Nickel-Mediated Cross-Coupling of Boronic Acids and Phthalimides for the
Synthesis of Ortho-Substituted Benzamides
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Ethan M. Heyboer, Rebecca L. Johnson, Megan R. Kwiatkowski, Trey C. Pankratz,
Mason C. Yoder, Kimberly S. DeGlopper, Grace C. Ahlgrim, Joseph M. Dennis, and
Jeffrey B. Johnson*
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Department of Chemistry, Hope College, Holland, MI 49423
jjohnson@hope.edu
TOC Graphic:
Ni(COD)2
O
O
2,2'-bipyridine
Ar
R
B(OH)2
THF, 55 °C
N
R
N
H
Ar
O
R: 8 examples
Ar: 18 examples
Up to 90% yield
* selective o-arylation
* versatile boronic
acid coupling partner
Abstract:
The decarbonylative coupling of phthalimides with aryl boronic acids provides ready access to a
broad range of ortho-substituted benzamides. This nickel-mediated methodology extends
reactivity from previously described air-sensitive diorganozinc reagents of limited availability to
easily-handled and widely commercially available boronic acids. The decarbonylative coupling
is tolerant of a broad range of functional groups and demonstrates little sensitivity to steric
factors on either of the coupling partners.
Introduction:
The advent of cross-coupling methodology has revolutionized organic synthesis.1 In addition to
traditional halide and pseudohalides, ever increasing numbers of nucleophilic and electrophilic
coupling partners are being utilized in such processes, with innumerable previously unknown
retrosynthetic disconnects now available. Ketones2 and aldehydes3,4,5,6,7,8 have been
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demonstrated to undergo decarbonylative cross-coupling to generate new carbon-carbon single
bonds, 9 as have carboxylic acids,10 esters,11 anhydrides,12,13 imides and isatins,14 and amides.15
These processes lead to a broad range of products. Along these same lines, our group has
investigated the use of phthalimides as decarbonylative cross-coupling reagents.16
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In our previous work, phthalimides were shown to successfully couple with diorganozinc
reagents in a nickel-mediated decarbonylative process to selectively generate ortho-substituted
benzamides (Scheme 1), of interest due to their potential biological activity.17,18 Although the
previously developed decarbonylative methodology is efficient and modular, it is significantly
limited by access to the diorganozinc species. Only diphenyl-, diethyl-, and dimethyl-zinc are
commercially available; all other diorganozinc reagents require preparation via air-sensitive and
tedious lithium-halogen exchange and reaction with zinc chloride. This process necessarily limits
the functional groups amenable within the reaction. Representing a further drawback, only one of
the two organic substituents of the diorganozinc is ultimately incorporated into the product. With
an eye toward increasing the scope of amenable substrates and eliminating the need for
pyrophoric and/or highly air sensitive organometallics, we explored the use of boronic acids as
mild, bench-stable cross-coupling partners for the arylative decarbonylation of phthalimides.19,20
Scheme 1. Methods for the nickel-mediated decarbonylative cross coupling of phthalimides.
Previous method:
O
O
Ni(COD)2
R
2,2'-bipyridine
N
R
R'
2Zn
N
+
H
1,4-dioxane
95 °C
R'
O
R: 10 examples
R': 14 examples
Up to 96% yield
This work:
O
O
Ni(COD)2
R
2,2'-bipyridine
N
R
Ar
N
+
B(OH)2
H
THF, 55 °C
Ar
O
Results and Discussion:
The desired decarbonylative coupling product can be obtained with the use of aryl boronic acids
as the nucleophilic coupling partner. The optimized conditions, which include the use of air-
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sensitive Ni(COD)2 (COD = 1,5-cyclooctadiene), 2,2’-bipyridine (bipy), potassium carbonate
and phenyl boronic acid in THF, produce ortho-aryl benzamide 2 in 90% yield as determined by
GC/MS (Table 1, entry 1). Initial reaction conditions, very similar to those utilized with
diorganozinc reagents, produced 2 in 55% yield (entry 2), a modest conversion that was
complicated by the presence of decarbonylated reduction product 3, a nearly inseparable
byproduct. Utilizing ester-substituted N-aryl phthalimide 1 as a test substrate, a variety of
solvents, metal sources, ligands, and additives were examined. These experiments, briefly
summarized in Table 1, led to the identification of conditions that maximized the amount of the
desired product formed while also minimizing the amount of the reduction product.21 As will be
shown, this reaction is amenable with a broad range of both aryl boronic acid and phthalimide
substrates.
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Table 1. Optimization of the decarbonylative coupling of phthalimides with aryl boronic acids.
O
O
O
Ni(COD)2, bipy
Ph B(OH)2
O
OEt
O
O
OEt
N
N
K2CO3
THF, 55 °C, Ar
H
OEt
N
H
O
2
3
1
Entry
Change from Standard Conditionsa
Crude Yield of 2b
1
2
3
4
5
6
7
None
90
55
<5
45
20
<5
<5
No K2CO3
with NaI instead of K2CO3
In DME at 75 °C
In dioxane at 100 °C
Phenyl boronic acid pinacol ester
PPh3 (2 equiv) instead of bipy
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No Ni(COD)2
<5
<5
19
9
Ni(acac)2 with Mn0 instead of Ni(COD)2
Ni(COD)2 (20 mol%), bipy (22 mol%)
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a) Standard Conditions: Phthalimide 1 (0.5 mmol, 1.0 equiv), Ni(COD)2 (1.0 equiv),
bipyridine (1.1 equiv), phenyl boronic acid (2.0 equiv), and K2CO3 (2.2 equiv) in THF
(2.0 mL) at 55 °C under an inert atmosphere. b) Determined by GC/MS or 1H NMR.
Upon identification of optimal reaction conditions, the boronic acid scope was explored using
ester-substituted N-aryl phthalimide 1 (Table 2). Reactions using electronically diverse boronic
acids proceeded well. In many cases, however, isolated yields were significantly lower than
starting material conversion due to the challenge of separating the reduction byproduct from the
desired product. Notably, the decarbonylative coupling reactivity can be expanded to coupling
partners with nucleophile-sensitive functionality (entries 3 and 7). These and similar compounds
are not accessible via the previously described diorganozinc coupling, as ketones, nitriles, and
esters are incompatible with the harsh conditions required to form the diorganozinc nucleophiles.
The reaction demonstrates little sensitivity to steric factors, as reactions utilizing ortho-, meta-,
and para- substituted aryl boronic acids proceed with similar efficiencies. While a broad range of
aryl boronic acids are competent in the reaction, alkyl boronic acids lead to only traces of the
desired benzamide product. While a mixture of compounds are produced, the reduction product
is the major compound in these reactions.
Table 2. Scope of boronic acids with N-(ester)aryl phthalimide 1
O
O
O
OEt
O
Ni(COD)2, bipy
N
+
R
B(OH)2
N
K2CO3
THF, 55 °C, Ar
OEt
H
O
1
R
Entrya
1
R (boronic acid)
Ph
Product
Yield (GC)
(%)b
Yield (%)
67
2
90
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4-OMe-C6H4
4-CN-C6H4
3-CF3-C6H4
3,5-(CF3)2-C6H3
2-Me-C6H4
2-C(O)Me-C6H4
Me
4
85
91
83
94
88
83
<5
<5
25
14
50
54
20
58
-
5
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10
11
iPr
-
a) Standard Conditions: Phthalimide 1 (0.5 mmol, 1.0 equiv), Ni(COD)2 (1.0 equiv),
bipyridine (1.1 equiv), boronic acid (2.0 equiv), and K2CO3 (2.2 equiv) in THF (2.0 mL)
at 55 °C under an inert atmosphere. b) Determined by GC/MS or 1H NMR.
Additional aryl boronic acids were also examined using the parent N-phenylphthalimide 12 as
the starting material (Table 3). As observed with the ester-substituted phthalimide, the reaction
proceeds smoothly with a large range of electronically diverse aryl boronic acids, from simple
ethers and alkyl groups to amines, sulfides and fluorinated species. The direct comparison of
ortho-, meta-, and para- methoxy-substituted aryl boronic acids (entries 3, 8, and 11) makes it
clear that substrate substitution pattern has little impact on the efficiency of the reaction. The
generality of the methodology is of significant value owing to the large range of commercially
available aryl boronic acids.
Table 3. Scope of boronic acids with N-phenylphthalimide 12
O
O
Ni(COD)2, bipy
Ph
N
N Ph
+
R
B(OH)2
H
K2CO3
R
THF, 55 °C, Ar
O
12
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Entrya
R (Boronic Acid)
4-NMe2-C6H4
4-SMe-C6H4
4-OMe-C6H4
4-Me-C6H4
Product
13
Yield (GC) (%)b Yield (%)
1
87
82
78
76
88
99
85
83
79
68
84
68
70
51
59
71
90
61
58
43
20
62
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3
15
4
16
5
4-F-C6H4
17
6
4-CF3-C6H4
18
7
4-C(O)Me-C6H4
3-OMe-C6H4
3,5-(CF3)2-C6H3
2-F-C6H4
19
8
20
9
21
10
11
22
2-OMe-C6H4
23
a) Standard Conditions: N-phenyl phthalimide 12 (0.5 mmol, 1.0 equiv), Ni(COD)2 (1.0
equiv), bipyridine (1.1 equiv), boronic acid (2.0 equiv), and K2CO3 (2.2 equiv) in THF
(2.0 mL) at 55 °C under an inert atmosphere. b) Determined by GC/MS or 1H NMR.
The reaction is also quite tolerant of a variety of readily accessible aryl-substituted
phthalimides.22 Reactions with N-phenyl imides substituted with electron deficient groups
proceed efficiently (Table 4, entries 1-4), generating the desired arylative decarbonylation
products in high yields. Electronically neutral (entries 5-8) or rich (entries 9-13) substrates also
work well. Consistent with previous observations, reaction yields were largely independent of
substitution patterns on the arene: ortho-, meta-, and para-methoxy substituted N-phenyl imides
all underwent reaction with similar efficiencies (entries 9-11).
Unfortunately, attempts to utilize N-alkyl phthalimides result in no appreciable yield of the
desired decarbonylative coupling product and primarily return unreacted starting material.23
Table 4. Variation of phthalimides with electron deficient boronic acids.
O
O
Ni(COD)2, bipy
R'
N R'
+
R
B(OH)2
N
K2CO3
THF, 55 oC, Ar
H
6
O
R
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Entrya R’ (Imide)
R (Boronic Acid)
Product Yield (GC) Yield (%)
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8
9
(%)b
87
91
76
85
82
93
81
75
86
67
85
79
91
1
3,5-(CF3)2-C6H3
2-C(O)Me-C6H4
3-C(O)Me-C6H4
4-CF3-C6H4
24
25
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36
70
76
61
65
68
64
38
39
69
52
58
62
72
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2
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
3,5-(CF3)2-C6H3
2-F-C6H4
3
4
3-CF3-C6H4
5
3-C(O)Me-C6H4
4-CF3-C6H4
6
2-F-C6H4
7
2-F-C6H4
2-F-C6H4
8
4-Cl-C6H4
3-CF3-C6H4
9
4-OMe-C6H4
3-OMe-C6H4
2-OMe-C6H4
2-OMe-C6H4
4-OMe-C6H4
2-C(O)Me-C6H4
2-C(O)Me-C6H4
2-C(O)Me-C6H4
3-C(O)Me-C6H4
4-CF3-C6H4
10
11
12
13
a) Standard Conditions: Phthalimide (0.5 mmol, 1.0 equiv), Ni(COD)2 (1.0 equiv),
bipyridine (1.1 equiv), boronic acid (2.0 equiv), and K2CO3 (2.2 equiv) in THF (2.0 mL)
at 55 °C under an inert atmosphere. b) Determined by GC/MS.
To further demonstrate utility, the reaction was performed on a gram scale with N-
phenylphthalimide 12 and 4-trifluoromethylphenyl boronic acid (Scheme 2). The reaction
proceeded smoothly, producing the desired decarbonylative coupling product 18 in 87% isolated
yield.
Scheme 2. Gram-scale decarbonylative coupling of 12 and 4-trifluoromethylphenyl boronic acid
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O
CF3
O
N
Ni(COD)2, bipy
H
+
N
THF, 55 oC, Ar
18
CF3
O
B(OH)2
12
10
11
12
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1.01 g
87% yield
1.01g
Proposed Mechanism
The proposed mechanism, based largely upon the analysis of similar reactions by our group, is
provided in Scheme 3.24 It is hypothesized that the nickel(0) and bipy combine to form
catalytically active species A, which inserts into the imide to create 6-membered metalacycle B.
Metalacycle B undergoes decarbonylation, leading to 5-membered metalacycle C which
transmetalates with the boronic acid to generate intermediate D.25 Reductive elimination from D
to generate E yields the desired product upon acidic workup. The reductive elimination step
simultaneously regenerates a new nickel(0) species that was initially envisioned to lose carbon
monoxide and regenerate nickel complex A, closing the catalytic cycle. Unfortunately, the
strength of the nickel-carbonyl bond prevents ready dissociation and a failure to achieve
catalysis.26,27 Efforts to identify conditions to accelerate carbonyl dissociation and induce
catalysis are described below.
In contrast to the pathway described above, decarbonylation and transmetalation could also occur
in the reverse order. Transmetalation of metalacycle B with the boronic acid yields intermediate
F, which can undergo subsequent decarbonylation to generate the common intermediate D
(Scheme 4). Although the mechanistic pathway has yet to be investigated, the sequence shown in
Scheme 3 is considered the more likely, as the latter pathway has the potential to undergo
reductive elimination from F to generate the keto-amide, but no such species have been
observed.
Scheme 3. Proposed mechanism
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O
O
Ph
N
5
6
7
8
N Ph
B(OH)2
Ar
[Ni]0
[Ni]0
CO
O
E
A
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O
O
Ph
N
Ph
N
B(OH)2
[Ni]
[Ni] CO
O
B
Ar
D
O
(HO)2B-Ar
N Ph
[Ni]
C
CO
Scheme 4. Alternative mechanistic proposal
O
Ph
N
B(OH)2
O
[Ni] CO
O
D
Ph
Ph
Ar
Ar-B(OH)2
N
N
B(OH)2
[Ni] Ar
[Ni]
O
Ph
N
O
F
B
O
B(OH)2
Ar
O
not observed
Efforts toward Catalysis
In order to further improve the utility of the current methodology, efforts were made to render
the reaction catalytic in nickel (Scheme 5). As previously mentioned, the lack of catalyst
turnover is largely attributed to the strength of the nickel-carbonyl bond that stems from
backbonding from the metal into a pi* orbital of the carbon monoxide. Literature examples
demonstrating catalytic nickel decarbonylation typically rely on two facets: high temperatures
and electron deficient substrates.28 In addition, we rationalized that π-accepting ligands such as
phosphines or N-heterocyclic carbenes (NHC) could weaken the nickel-carbonyl bond and thus
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promote the dissociation of carbon monoxide. Using 10 mol% of the nickel precatalyst with 11
mol% of the ligand, a number of solvents, ligands, and additives were tested and examined for
turnover.29 Despite significant screens, results were modest at best, peaking with the observation
of 3 catalyst turnovers when performed with the isopropyl-substituted NHC ligand 38 (Scheme
5). It is anticipated that the achievement of reasonably efficient catalysis will necessitate the use
of a different transition metal with a lesser affinity for carbon monoxide, but to date, no such
system has been discovered.
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Scheme 5. Efforts toward catalysis
O
Ni(COD)2 (10 mol%)
O
O
OEt
40
ligand
(11%)
O
K2CO3 (2.2 equiv)
+
N
N
H
THF, 55 oC, Ar
OEt
2
B(OH)2
O
1
36%
Cl
iPr
iPr
N
N
iPr iPr
38
Conclusion
In summary, this method for the nickel-mediated decarbonylative coupling of phthalimides and
boronic acids provides ready and selective access to ortho-substituted benzamides, a common
motif within compounds with demonstrated bioactivity. The use of aryl boronic acids as coupling
partners allows the incorporation of ketones, nitriles and other nucleophile-sensitive functionality
not amenable in previous methodology. The wide range of functional group tolerance on both
coupling partners, tied with the efficient preparation of phthalimides and the commercial
availability of boronic acids, provides a route to innumerable ortho-substituted benzamides via a
simple and robust chemical transformation.
Experimental Section
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General Methods. All reactions were carried out under an atmosphere of nitrogen or argon in
oven dried glassware with magnetic stirring. Solvents, including toluene, tetrahydrofuran, and
diethyl ether, were purged with argon and passed through two columns of neutral alumina or
molecular sieves. All starting materials are commercially available and used without purification
or prepared according to procedures provided. All phthalimides were obtained commercially or
prepared via the condensation of phthalic acid with the appropriate amine in either refluxing
toluene (Dean-Stark conditions) or in refluxing acetic acid.22
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1H and 13C NMR spectra were obtained using standard acquisition parameters and are referenced
to TMS unless otherwise noted. HRMS was measured on an electrospray ionization (ESI)
apparatus using time-of-flight (TOF) mass spectrometry. Crude yields were determined by 1H
NMR or through GC/MS using xylene, triphenylphosphine, or mesitylene as standards.
General Method for Decarbonylative Coupling of Phthalimides with Boronic Acids will be
illustrated with a specific example. 2,2’-bipyridyl (85.8 mg, 0.55 mmol), potassium carbonate
(151.8 mg, 1.10 mmol), N-phenyl phthalimide 12 (111.6 mg, 0.50 mmol), and 4-
(trifluoromethyl)phenyl boronic acid (152.0 mg, 1.0 mmol) were combined in an oven-dried 10
mL round-bottomed flask equipped with a stir bar. The flask was transferred to a nitrogen
atmosphere glove box where Ni(COD)2 (190.0 mg, 0.5 mmol) was added and the flask was sealed
with a septum. The flask was removed from the glove box, and THF (2 mL) was added via syringe.
The solution was then heated and stirred in a 55 °C oil bath for 18 h. The resulting mixture was
cooled to room temperature, and diethyl ether (5 mL) was added. The reaction was quenched with
2 M aqueous HCl (5 mL). The product was extracted with diethyl ether (3 × 15 mL), and the
combined organic layers were washed with brine (2 × 15 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting product was purified by column
chromatography (hexane:EtOAc, 9:1) to provide 18 in 90% yield.
Gram-Scale Method for the Decarbonylative Coupling of Phthalimide 1 with Phenyl
Boronic Acid. 2,2’-bipyridyl (542 mg, 3.47 mmol), potassium carbonate (1.048 g, 7.51 mmol),
N-phenyl phthalimide 12 (1.009 g, 3.42 mmol), and 4-trifluorophenyl boronic acid (819 mg, 4.31
mmol, 1.25 equiv) were combined in an oven-dried 100 mL round-bottomed flask equipped with
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a stir bar. The flask was transferred to a nitrogen atmosphere glove box where Ni(COD)2 (950
mg, 3.45 mmol) was added and the flask was sealed with a septum. The flask was removed from
the glove box and THF (35 mL) was added via cannula. The solution was then heated and stirred
in a 55 °C oil bath for 18 h. The resulting mixture was cooled to room temperature and quenched
with 2 M aqueous HCl (25 mL). The product was extracted with diethyl ether (3 × 50 mL) and
the combined organic layers were washed with brine (2 × 25 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting product was purified by column
chromatography (hexane:EtOAc, 9:1) to provide 18 in 87% yield.
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General Method for the Catalytic Decarbonylative Coupling of Phthalimides with Boronic
Acids will be illustrated with a specific example. 1,3-Bis(2,6-di-i-propylphenyl)imidazolium
chloride (38) (22.8 mg, 0.054 mmol), potassium carbonate (152.7 mg, 1.10 mmol), N-para ester
phthalimide 1 (135.5 mg, 0.46 mmol), and phenyl boronic acid (110.2 mg, 0.90 mmol) were
combined in an oven-dried 100 mL round-bottomed flask equipped with a stir bar. The flask was
transferred to a nitrogen atmosphere glove box where Ni(COD)2 (13.0 mg, 0.47 mmol) was
added and the flask sealed with a septum. The flask was removed from the glove box and THF (2
mL) was added via syringe. The solution was then heated and stirred in a 55 °C oil bath for 18 h.
The resulting mixture was cooled to room temperature and diethyl ether (5 mL) was added. The
reaction was quenched with 2 M aqueous HCl (5 mL). The product was extracted with diethyl
ether (3 × 15 mL) and the combined organic layers were washed with brine (2 × 15 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The resulting product was
purified by column chromatography (hexane:EtOAc, 9:1) to provide 2 in 36% yield.
Ethyl 4-([1,1’-biphenyl]-2-carboxamido)benzoate (2): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 2 (116 mg, 0.34 mmol, 67% yield) as a white flaky solid. Rf = 0.32 (2:1 hex:EtOAc). 1H
NMR (400 MHz, CDCl3): δ 7.91 (t, J = 8.6 Hz, 3H), 7.51-7.40 (mult, 8H), 7.17 (d, J = 7.8 Hz,
2H), 7.00 (s, 1H), 4.33 (q, J = 7.3 Hz, 2H), 1.37 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 167.1, 166.1, 141.6, 139.8, 139.7, 134.7, 131.1, 130.6, 130.4, 129.8, 129.1, 128.9,
128.3, 128.1, 126.1, 118.7, 60.8, 14.3. IR (diamond ATR) 3052, 2997, 2972, 2930, 1708 cm-1.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H20NO3 346.1438; Found 346.1420.
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Ethyl 4-(4'-methoxy-[1,1'-biphenyl]-2-ylcarboxamido)benzoate (4): Prepared according to
the general procedure for decarbonylation with boronic acids. Column chromatography with 9:1
hex:EtOAc yielded 4 (47 mg, 0.13 mmol, 25% yield) as a white powder. Rf = 0.29 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 7.8 Hz, 1H),
7.54 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 3H), 7.24 (d, J = 8.1 Hz,
2H), 7.14 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.37 (t, J = 7.2
Hz, 3H) 13C {1H} NMR (100 MHz, CDCl3) δ 167.4, 166.1, 159.7, 141.7, 139.3, 134.6, 131.9,
131.0, 130.6, 130.5, 130.1, 129.7, 127.6, 126.0, 118.8, 114.5, 60.8, 55.4, 14.3. IR (diamond
ATR), 3287, 3253, 3187, 3115, 3067, 2977, 2930, 2893, 2832, 1716, 1705 cm-1. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C23H22NO4, 376.1543; Found 376.1552.
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Ethyl 4-(4’-cyano-[1,1’-biphenyl]-2-carboxamido)benzoate (5): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 9:1
hex:EtOAc yielded 5 (26 mg, 0.07 mmol, 14% yield) as a white flaky solid. Rf = 0.21 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.3 Hz, 2H), 7.96 (br s, 1H), 7.89 (d, J
= 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.62-7.49 (mult, 5H), 6.91 (d, J = 8.2 Hz, 1H), 4.38 (qrt,
J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.2, 165.9,
159.8, 142.0, 134.5, 134.2, 132.3, 132.0, 130.9, 130.8, 129.0, 127.1, 126.3, 119.3, 119.2, 116.3,
103.8, 61.0, 14.4. IR (diamond ATR) 3305, 3059, 2963, 2227, 1701, 1685, 1664, 1594 cm-1.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H19N2O3, 371.1390; Found 371.1382.
Ethyl 4-(3'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)benzoate (6): Prepared
according to the general procedure for decarbonylation with boronic acids. Column
chromatography with 9:1 hex:EtOAc yielded 6 (103 mg, 0.25 mmol, 50% yield) as a yellow oil.
Rf = 0.30 (2:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2H), 7.79 (d, J =
7.8 Hz, 1H), 7.75 (s, 1H), 7.63 (t, J = 6.1 Hz, 1H), 7.59 (td, J = 7.4, 1.3 Hz, 2H), 7.52 (td, J =
7.4, 1.3 Hz, 2H), 7.47 (t, J = 7.1 Hz, 1H) 7.29 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 4.33 (q, J = 7.1
Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 167.2, 166.0, 141.4,
140.5, 138.2, 135.4, 132.1, 131.4 (q, J = 33 Hz), 131.2, 130.7, 130.4, 129.3, 129.1, 128.6, 126.4,
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125.3 (q, J = 4 Hz), 124.8 (q, J = 4 Hz), 123.9 (q, J = 273 Hz), 118.8, 60.9, 14.3. IR (diamond
ATR) 1713, 1690, 1607, 1593, 1516 cm-1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H19F3NO3, 414.1312; Found 414.1310.
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Ethyl 4-(3',5'-bis(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)benzoate (7): Prepared
according to the general procedure for decarbonylation with boronic acids. Column
chromatography with 9:1 hex:EtOAc yielded 7 (130 mg, 0.27 mmol, 54% yield) as a greenish
powder. Rf = 0.32 (2:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.2 Hz, 2H),
7.92 (s, 2H), 7.85 (s, 1H), 7.75 (dd, J = 7.5, 1.1 Hz, 1H), 7.63 (td, J = 7.5, 1.3 Hz, 1H), 7.57 (td,
J = 7.5, 1.3 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.38 (s, 1H), 4.35 (q, J =
7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.9, 166.0, 141.8,
141.1, 137.2, 135.8, 132.0 (q, J = 34 Hz), 131.3, 130.8, 130.6, 129.2, 128.8, 128.4, 126.7, 123.1
(q, J = 272 Hz), 121.6 (mult, J = 3 Hz), 118.9, 61.0, 14.3. IR (diamond atr) 3329, 2921, 2241,
1689, 1663, 1594, 1525 cm-1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18F6NO3,
482.1185; Found 482.1172.
Ethyl 4-(2'-methyl-[1,1'-biphenyl]-2-ylcarboxamido)benzoate (8): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 9:1
hex:EtOAc yielded 8 (36 mg, 0.10 mmol, 20% yield) as a white flaky solid. Rf = 0.42 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 7.6, 1.3 Hz, 1H), 7.88 (d, J = 8.6 Hz,
2H), 7.58 (td, J = 7.6, 1.5 Hz, 1H), 7.53 (td, J = 7.6, 1.5 Hz, 1H), 7.42-7.38 (mult, 2H), 7.36-
7.32 (mult, 2H), 7.29 (s, 1H), 7.28 (dd, J = 7.6, 1.3 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 4.32 (q, J
= 7.1 Hz, 2H), 2.11 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.1,
165.8, 141.7, 139.8, 139.1, 136.7, 133.7, 131.4, 131.0, 130.6, 130.5, 130.3, 129.3, 128.9, 128.2,
126.8, 125.9, 118.6, 60.8, 19.9, 14.3. IR (diamond atr) 3224, 3107, 3058, 3015, 2984, 2925,
2901, 1685, 1607, 1592 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C23H22NO3, 360.1594;
Found 360.1600.
Ethyl 4-(2'-acetyl-[1,1'-biphenyl]-2-ylcarboxamido)benzoate (9): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
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hex:EtOAc yielded 9 (112 mg, 0.29 mmol, 58% yield) as white crystals. Rf = 0.26 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): 9.12 (s, 1H), 7.77 (dd, J = 8.8 Hz, 1.9 Hz, 2H), 7.70
(dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.60 (dd, J = 7.4 Hz, 1.6 Hz, 1H), 7.22 (dd, J = 8.7 Hz, 1.9 Hz, 2H),
7.28-7.42 (mult, 4H), 6.94 (dd, J = 7.5 Hz, 1.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H),
1.27 (t, J = 7.0 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) 207.0, 167.8, 166.2, 142.4, 139.5,
138.7, 136.7, 131.6, 131.2, 130.5, 130.0, 128.8, 128.5, 128.1, 127.9, 127.2, 125.5, 118.4, 60.7,
30.9, 29.6, 14.3. IR (diamond ATR): 3121, 3082, 2987, 1712, 1701, 1632, 1518 cm-1. HRMS
(ESI-TOF) m/z [M+H]+ Calcd for C24H22NO4, 388.1543; Found 388.1542.
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4'-(Dimethylamino)-N-phenylbiphenyl-2-carboxamide (13): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 10:1
hex:EtOAc yielded 13 (107 mg, 0.34 mmol, 68% yield) as a yellow solid. Rf = 0.55 (in 2:1
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hex:EtOAc). mp 158 °C. H NMR (400 MHz, CDCl3): 7.81 (d, J = 7.2 Hz,1H), 7.42, (t, J = 7.5
Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.20-7.04 (mult, 4H), 7.02 (br s, 1H),
6.97 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.6 Hz, 2H), 2.90 (s, 6H). 13C {1H} NMR (100 MHz,
CDCl3) 167.5, 150.4, 139.8, 137.9, 134.7, 130.6, 130.4, 129.78, 129.75, 128.8, 127.2, 127.0,
124.2, 120.1, 112.8, 40.5. IR (diamond ATR) 3299, 3059, 2889, 1659, 1611, 1529, 1440, 1320
cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C21H21N2O, 317.1648; Found 317.1652.
4'-(Methylthio)-N-phenylbiphenyl-2-carboxamide (14): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 14 (112 mg, 0.35 mmol, 70% yield) as a white solid. Rf = 0.28 (in 2:1 hex:EtOAc). mp
155-156 °C. 1H NMR (400 MHz, CDCl3): 7.77 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H),
7.39 (t, J = 7.3 Hz, 1H), 7.36-7.29 (mult, 3H), 7.27-7.05 (mult, 6H), 7.00 (t, J = 7.3 Hz, 1H),
6.88 (br s, 1H) 2.41 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 167.3, 138.9, 137.6, 136.4,
135.3, 130.7, 130.3, 129.5, 129.2, 128.9, 128.88, 127.9, 126.8, 124.5, 120.0, 15.7. IR (diamond
ATR) 3383, 2965, 2846, 1658, 1608, 1539, 1432, 1324, 1242 cm-1. HRMS (ESI-TOF) m/z
[M+H]+ Calcd for C20H18NOS, 320.1104; Found 320.1093.
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4'-Methoxy-N-phenylbiphenyl-2-carboxamide (15): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 15 (78 mg, 0.26 mmol, 51% yield) as a white solid. Rf = 0.41 (2:1 hex:EtOAc). 1H NMR
(400 MHz, CDCl3): δ 7.80 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.39-7.33 (mult, 4H),
7.16 (d, J = 7.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.9 Hz,
2H), 6.88 (s, 1H), 3.76 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 167.3, 160.6, 139.2, 137.6,
135.2, 132.1, 130.0, 129.5, 129.4, 129.0, 128.8, 127.5, 124.3, 119.9, 114.4, 55.4. IR (diamond
ATR) 3238, 3183, 3129, 3059, 3002, 2962, 2839, 1653, 1599, 1289 cm-1. HRMS (ESI-TOF) m/z
[M+H]+ Calcd for C20H18NO2, 304.1332; Found 304.1321.
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4'-Methyl-N-phenylbiphenyl-2-carboxamide (16): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 16 (86 mg, 0.30 mmol, 59% yield) as a white solid. Rf = 0.39 (in 2:1 hex:EtOAc). mp
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148-149 °C. H NMR (400 MHz, CDCl3): 7.87 (d, J = 7.0 Hz, 1H), 7.52, (dt, J = 7.5, 1.3 Hz,
1H), 7.45 (dt, J = 7.6, 1.3 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27-7.20
(mult, 4H), 7.13 (d, J = 7.7 Hz, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.95 (br s, 1H), 2.39 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) 167.2, 139.6, 137.9, 137.6, 137.0, 135.2, 130.6, 130.4, 129.7,
129.5, 128.8, 128.7, 127.7, 124.3, 119.9, 21.2. IR (diamond ATR) 3282, 3053, 3020, 2921, 1656,
1599, 1536, 1438, 1322 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C20H18NO, 288.1383;
Found 288.1382.
4'-Fluoro-N-phenylbiphenyl-2-carboxamide (17): Prepared according to the general procedure
for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc yielded 17
(105 mg, 0.36 mmol, 71% yield) as a white solid. Rf = 0.37 (in 2:1 hex:EtOAc). 1H NMR (400
MHz, CDCl3): δ 7.82 (d, J = 7.6 Hz, 1H), 7.54 (td, J = 7.6, 1.6 Hz, 1H), 7.50-7.44 (mult, 3H),
7.40 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.9 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.14-7.06 (mult, 3H),
6.92 (s, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ 167.2, 162.7 (d, J = 248 Hz), 138.4, 137.5,
135.9 (d, J = 3 Hz), 135.6, 130.6 (d, J = 33 Hz), 130.5, 130.4, 129.3, 129.0, 128.0, 124.6, 119.9,
115.9 (d, J = 22 Hz). IR (diamond ATR), 3220, 3182, 3127, 3060, 3038, 2919, 2850, 1648, 1620
cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H15FNO, 292.1132; Found 292.1124.
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N-Phenyl-4'-(trifluoromethyl)biphenyl-2-carboxamide (18): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 9:1
hex:EtOAc yielded 18 (307 mg, 0.45 mmol, 90% yield) as a white solid. Rf = 0.38 (in 2:1
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hex:EtOAc). mp 148 °C (dec). H NMR (400 MHz, CDCl3): 7.74 (d, J = 7.1 Hz, 1H), 7.63-7.43
(mult, 6H), 7.37 (d, J = 7.5 Hz, 1H), 7.21-7.08 (mult, 4H), 7.02 (t, J = 7.3 Hz, 1H), 6.86 (br s,
1H). 13C {1H} NMR (100 MHz, CDCl3) 167.0, 143.6, 138.3, 137.3, 135.9, 130.8, 130.0, 129.1,
129.05, 129.0, 128.6, 125.7 (qrt, JC-F = 3.7 Hz), 124.8, 124.1 (qrt, JC-F = 271 Hz), 122.7, 119.9.
IR (diamond ATR) 2920, 2849, 1650, 1443, 1324, 1119 cm-1. HRMS (ESI-TOF) m/z [M+H]+
Calcd for C20H15F3NO, 342.1100; Found 342.1096.
4'-Acetyl-N-phenyl-[1,1'-biphenyl]-2-carboxamide (19): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 4:1 hex:EtOAc
yielded 19 (96 mg, 0.31 mmol, 61% yield) as colorless, spine-like crystals. Rf = 0.19 (3:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.01 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H),
7.62-7.49 (mult, 4H), 7.45 (d, J = 8.2 Hz, 1H), 7.18-7.29 (mult, 4H), 7.08 (t, J = 7.1 Hz, 1H),
6.98 (s, 1H), 2.60 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 197.7, 167.2, 144.7, 138.6, 137.5,
136.4, 135.8, 130.8, 130.3, 129.02, 129.01, 128.98, 128.8, 128.5, 124.7, 119.9, 26.7. IR
(diamond ATR): 3078, 2997, 2956, 1709, 1689, 1654, 1632, 1523 cm-1. HRMS (ESI-TOF) m/z
[M+H]+ Calcd for C21H18NO2, 316.1332; Found 316.1321.
3'-Methoxy-N-phenylbiphenyl-2-carboxamide (20): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 20 (88 mg, 0.29 mmol, 58% yield) as an off white solid. Rf = 0.15 (in 2:1 hex:EtOAc).
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mp 104-105 °C. H NMR (400 MHz, CDCl3): 7.82 (d, J = 7.7 Hz, 1H), 7.46 (dt, J = 7.3, 1.8 Hz,
1H), 7.40 (dt, J = 7.5, 1.8 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.15 (d, J =
7.8 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 7.01-6.83 (mult, 5H), 3.68 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) 167.1, 160.0, 141.4, 139.4, 137.6, 135.2, 130.6, 130.2, 130.0, 129.6, 128.8, 128.0,
124.4, 121.2, 120.0, 114.2, 114.1, 55.4. IR (diamond ATR) 3380, 3065, 2957, 2848, 1659, 1650,
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1537, 1440, 1322 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C20H18NO2, 304.1332; Found
304.1330.
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N-Phenyl-3',5'-bis(trifluoromethyl)biphenyl-2-carboxamide (21): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 9:1
hex:EtOAc yielded 21 (90 mg, 0.22 mmol, 43% yield) as a white flaky solid. Rf = 0.42 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 2H), 7.84 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H),
7.59 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.1 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.31-7.28 (mult, 5H),
7.13-7.10 (mult, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.8, 142.0, 137.1, 136.2, 131.9 (q,
J = 33 Hz), 130.9, 130.4, 129.1, 129.0, 128.8, 128.7, 128.3, 125.1, 123.1 (q, J = 272 Hz), 121.5
(mult, J = 4 Hz), 120.1. IR (diamond ATR), 3202, 3132, 3039, 1639, 1620, 1598, 1546 cm-1.
HRMS (ESI-TOF) m/z [M+H]+ Calcd for C21H14F6NO, 410.0974. Found 410.0966.
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2'-Fluoro-N-phenyl-[1,1'-biphenyl]-2-carboxamide (22): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 22 (amount, 0.10 mmol, 20% yield) as a white flaky solid. Rf = 0.42 (2:1 hex:EtOAc). 1H
NMR (400 MHz, CDCl3): 7.86 (d, J = 7.6 Hz, 2H), 7.61-7.31 (mult, 7H), 7.19-6.98 (mult, 5H).
13C {1H} NMR (100 MHz, CDCl3) 166.8, 159.5 (d, J = 243 Hz), 137.6, 136.3, 133.4, 131.2,
130.6, 130.1 (d, J = 8.1 Hz), 129.1, 128.9, 128.8, 128.5, 127.6, (d, J = 16 Hz), 127.1, 120.2,
120.0, 115.9 (d, J = 22 Hz). IR (diamond ATR): 3078, 3022, 2972, 1652, 1620, 1478 cm-1..
HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H15FNO, 292.1132; Found 292.1110.
2'-Methoxy-N-phenylbiphenyl-2-carboxamide (23): Prepared according to the general
procedure for decarbonylation with boronic acids. Column chromatography with 9:1 hex:EtOAc
yielded 23 (94 mg, 0.31 mmol, 62% yield) as a white solid. Rf = 0.18 (in 2:1 hex:EtOAc). mp
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128 °C. H NMR (400 MHz, CDCl3): 7.85 (d, J = 7.5 Hz, 1H), 7.47 (dt, J = 7.5, 1.7 Hz, 1H),
7.40 (dt, J = 7.4, 1.5 Hz, 1H), 7.34 – 7.22 (mult, 4H), 7.18 – 7.06 (mult, 4H), 7.02 (t, J = 7.4,
1H), 6.95 (tt, J = 7.1, 1.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.59 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) 166.8, 156.4, 137.9, 136.0, 135.8, 131.0, 130.7, 130.1, 129.9, 129.0, 127.9, 127.0,
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124.0, 121.3, 119.5, 111.1, 55.6. IR (diamond ATR) 2957, 2870, 1774, 1687, 1599, 1536 cm-
1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C20H18NO2, 304.1332. Found 304.1334.
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2'-Acetyl-N-(3,5-bis(trifluoromethyl)phenyl)-[1,1'-biphenyl]-2-carboxamide (24): Prepared
according to the general procedure for decarbonylation with boronic acids. Column
chromatography with 4:1 hex:EtOAc yielded 24 (158 mg, 0.35 mmol, 70% yield) as a dark
yellow, viscous oil. Rf = 0.12 (4:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): 9.49 (s, 1H), 7.76
(dd, J = 7.5 Hz, 1.56 Hz, 1H), 7.71-7.66 (mult, 3H), 7.51-7.40 (mult, 5H), 7.26-7.22 (mult, 1H)
7.03 (dd, J = 7.5 Hz, 1.4 Hz, 1H), 2.70 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 206.7, 168.1,
139.6, 139.3, 138.8, 138.6, 136.2, 132.0 (q, J = 33 Hz), 131.8, 131.3, 130.4, 128.8, 128.6, 128.2,
128.1, 127.0, 123.1 (q, J = 271 Hz), 119.0, 117.1 (q, J = 4 Hz), 29.8. IR (diamond ATR): 3067,
2987, 2980, 1709, 1685, 1643, 1452 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for
C23H16F6NO2, 452.1080; Found 452.1065.
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3'-Acetyl-N-(3,5-bis(trifluoromethyl)phenyl)-[1,1'-biphenyl]-2-carboxamide (25): Prepared
according to the general procedure for decarbonylation with boronic acids. Column
chromatography with 2:1 hex:EtOAc yielded 25 (171 mg, 0.38 mmol, 76% yield) as white
crystals. Rf = 0.390 (1:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.09 (s, 1H), 7.97 (dt, J = 7.8
Hz, 1.3 Hz, 1H), 7.83 (dd, J = 7.6 Hz, 1.1 Hz, 1H), 7.75-7.59 (mult, 5H), 7.59-7.47 (mult, 4H),
7.23 (br s, 1H), 2.58 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 197.5, 167.5, 140.3, 138.8 (q, J
= 4 Hz), 137.8, 134.6, 133.4, 132.3 (q, J = 33 Hz), 131.5, 130.6, 129.4, 129.2, 128.6, 128.2,
128.15, 122.9 (q, J = 272 Hz), 119.6 (mult), 118.0, 117.9 (mult), 26.6. IR (diamond ATR) 3123,
3019, 2973, 1708, 1691, 1632 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C23H16F6NO2,
452.1080; Found 452.1069.
N-(3,5-bis(trifluoromethyl)phenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (26):
Prepared according to the general procedure. Column chromatography with 9:1 hex:EtOAc
yielded 26 (143 mg, 0.30 mmols, 61% yield) as a white flaky solid. Rf = 0.42 (2:1 hex:EtOAc).
1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8 Hz, 2H), 7.63-7.53 (mult,
7H), 7.46 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H). 13C {1H} NMR (100 MHz, CDCl3) 167.1, 143.3,
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138.7, 138.4, 134.5, 132.4 (q, J = 33 Hz), 131.5, 130.6 (q, J = 33 Hz), 130.5, 129.3, 129.1, 128.8,
125.9 (mult, J = 4 Hz), 123.8 (q, J = 270 Hz), 122.9 (q, J = 270 Hz), 119.4, 118.0 (mult, J = 4
Hz). IR (diamond ATR): 3247, 3175, 3081, 1656, 1619, 1571 cm-1. HRMS (ESI-TOF) m/z
[M+H]+ Calcd for C22H13F9NO, 478.0848; Found 478.0819.
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N-(3,5-bis(trifluoromethyl)phenyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (27):
Prepared according to the general procedure. Column chromatography with 9:1 hex:EtOAc
yielded 27 (155 mg, 0.32 mmol, 65% yield) as a white powder. Rf = 0.47 (2:1 hex:EtOAc). 1H
NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 7.9, 1.0 Hz, 1H), 7.72 (s, 1H), 7.63 (t, J = 10.7 Hz,
3H), 7.60 (dd, J = 7.7, 1.4 Hz, 2H) 7.55 (mult, 3H), 7.48 (t, J = 7.6 Hz, 1H), 7.30 (s, 1H). 13C
{1H} NMR (100 MHz, CDCl3) δ 167.4, 140.5, 138.7, 138.4, 134.7, 132.4 (q, J = 33 Hz), 132.1,
131.6 (q, J = 33 Hz), 131.5, 130.5, 129.6, 129.1, 128.7, 125.3 (mult, J = 3 Hz), 125.0 (mult, J =
3 Hz), 123.8 (q, J = 272 Hz), 123.0 (q, J = 272 Hz), 119.6, 118.0 (mult, J = 4 Hz). IR (diamond
ATR) 3229, 3071, 2980, 1656, 1617, 1598, 1542 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for
C22H13F9NO, 478.0848; Found 478.0817.
3'-Acetyl-N-(2-fluorophenyl)-[1,1'-biphenyl]-2-carboxamide (28): Prepared according to the
general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
hex:EtOAc yielded 28 (113 mg, 0.34 mmol, 68% yield) as a colorless film. Rf = 0.15 (2:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.27 (t, J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.95 (td, J =
8.0, 1.4 Hz, 1H), 7.83 (dd, J = 7.7, 1.1 Hz, 1H), 7.67 (d, J = 7.70 Hz, 1H), 7.59 (td, J = 7.5, 1.6
Hz, 1H), 7.52 (dt, J = 7.6, 1.5 Hz, 1H), 7.50-7.40 (mult, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.04-6.91
(mult, 3H) 2.57 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 197.8, 167.2, 152.3 (d, J = 240 Hz),
140.2, 138.9, 137.6, 135.4, 133.3, 131.0, 130.6, 129.1 (d, J = 4 Hz), 128.6, 128.3, 127.9, 126.1,
126.0, 124.7, 124.5, 121.6, 114.7 (d, J = 19 Hz), 26.7. IR (diamond ATR) 3017, 2987, 2870,
1707, 1690, 1639, 1548, 1274 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C21H17FNO2,
334.1238; Found 334.1225.
N-(2-Fluorophenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (29): Prepared
according to the general procedure. Column chromatography with 9:1 hex:EtOAc yielded 29
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(115 mg, 0.32 mmol, 64% yield) as a white flaky solid. Rf = 0.44 (2:1 hex:EtOAc). 1H NMR
(400 MHz, CDCl3): δ 8.28 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H),
7.59 (t, J = 7.6 Hz, 3H), 7.53 (triplet of doublets, J = 7.6, 1.3 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H),
7.26 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (mult, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ
167.0, 152.3 (d, J = 243 Hz), 143.4, 138.6, 135.5, 131.0, 130.5, 130.2 (q, J = 32 Hz), 129.1,
128.5, 126.0 (d, J = 10 Hz), 125.7 (q, J = 3 Hz), 124.7 (d, J = 8 Hz), 124.6, 124.5, 124.1 (q, J =
272 Hz) 121.6, 114.7 (d, J = 19 Hz). IR (diamond ATR) 3240, 3189, 3135, 3067, 3023, 1653,
1619, 1601, 1537 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C20H14F4NO, 360.1006. Found
360.0983.
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2'-fluoro-N-(2-fluorophenyl)-[1,1'-biphenyl]-2-carboxamide (30): Prepared according to the
general procedure. Column chromatography with 9:1 hex:EtOAc yielded 30 (59 mg, 0.19 mmol,
38% yield) as an off white powder. Rf = 0.42 (2:1 hex:EtOAc. 1H NMR (400 MHz, CDCl3): 8.33
(t, J = 8.5 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H),
7.48-7.32 (mult, 4H), 7.22 (t, 7.2 Hz, 1H), 7.14-6.94 (mult, 4H). 13C {1H} NMR (100 MHz,
CDCl3) 165.7, 158.5 (d, J = 250 Hz), 151.3 (d, J = 243 Hz), 135.0, 132.7, 130.4, 130.0 (d, J = 3
Hz), 129.9, 129.2 (d, J = 8 Hz), 127.7, 127.4, 126.3 (d, J = 15 Hz), 125.3 (d, J = 10 Hz), 123.6
(d, J = 4 Hz), 123.5 (d, J = 4 Hz), 123.3 (d, J = 8 Hz), 120.6, 114.8 (d, J = 22 Hz), 113.6 (d, J =
19 Hz). IR (diamond ATR) 3079, 3024, 3053, 2969, 1668, 1489, 1457 cm-1. HRMS (ESI-TOF)
m/z [M+H]+ Calcd for C19H14F2NO, 310.1038; Found 310.1057.
N-(4-Chlorophenyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (31) Prepared
according to the general procedure. Column chromatography with 9:1 hex:EtOAc yielded 31 (73
mg, 0.19 mmol, 39% yield) as an off white powder. Rf = 0.37 (2:1 hex:EtOAc). 1H NMR (400
MHz, CDCl3): δ 7.78 (d, J = 7.4 Hz, 1H), 7.75 (s, 1H), 7.62 (d, J = 7.9 Hz, 2H) 7.58 (td, J = 7.5,
1.4 Hz, 1H) 7.52 (t, J = 7.7 Hz, 1H), 7.51 (td, J = 7.7, 1.4 Hz, 1H) 7.45 (d, J = 7.5 Hz, 1H) 7.21
(d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H) 6.94 (s, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ
167.1, 140.6, 138.1, 135.9, 135.5, 132.1, 131.4 (q, J = 32 Hz), 131.0, 130.4, 129.8, 129.3, 129.1,
129.0, 128.6, 125.3 (q, J = 4 Hz), 124.8 (q, J = 4 Hz), 123.9 (q, J = 272 Hz), 121.1. IR (diamond
ATR) 3236, 3179, 3115, 3060, 2924, 2851, 1648, 1595, 1535 cm-1. HRMS (ESI-TOF) m/z
[M+H]+ Calcd for C20H14ClF3NO, 376.0711. Found 376.0710.
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2'-Acetyl-N-(4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide (32): Prepared according to
the general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
hex:EtOAc yielded 32 (119 mg, .35 mmol, 69% yield) as a yellow film. Rf = 0.15 (4:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.71 (s, 1H), 7.77 (dd, J = 7.7, 1.4 Hz, 1H), 7.68 (d, J
= 7.2 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.43 (t, J = 1.8 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.39
(d, J = 1.4 Hz, 1H), 7.30-7.26 (mult, 1H), 7.08 (t, J = 2.2 Hz, 2H), 7.00 (dd, J = 7.5, 1.3 Hz, 1H),
6.71 (t, J = 2.3 Hz, 2H), 3.72 (s, 3H), 2.63 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 205.2,
167.3, 156.1, 139.9, 138.8, 138.7, 137.0, 131.5, 131.4, 131.3, 129.7, 128.7, 128.5, 128.0, 127.8,
127.2, 121.3, 113.9, 55.4, 30.9. IR (diamond ATR) 3089, 2987, 2920, 1716, 1686, 1642, 1616,
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1452 cm-1. HRMS (ESI+) HRMS (ESI-TOF) m/z [M+H]+ Calcd for C22H20NO3 , 346.1438;
Found 346.1452.
2'-Acetyl-N-(3-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide (33): Prepared according to
the general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
hex:EtOAc yielded 33 (90 mg, 0.26 mmol, 52% yield) as an off white, clumpy solid. Rf = 0.43
(1:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.87 (s, 1H), 7.77 (dd, J = 7.6, 1.0 Hz, 1H), 7.68
(dd, J = 7.5, 1.1 Hz, 1H), 7.48-7.37 (mult, 5H), 7.07-6.98 (mult, 3H), 6.63 (d, J = 7.8 Hz, 1H),
6.54 (dd, J = 8.5, 2.4 Hz, 1H), 3.47 (s, 3H), 2.64 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3)
205.3, 167.6, 159.9, 139.7, 139.4, 138.8, 138.7, 137.0, 131.6, 131.3, 129.8, 129.4, 128.7, 128.5,
128.0, 127.8, 127.3, 111.8, 109.7, 105.2, 55.2, 29.6. IR (diamond ATR): 3057, 3012, 2992, 1712,
1695, 1662, 1421 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C22H20NO3, 346.1438. Found
346.1418.
2'-Acetyl-N-(2-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide (34): Prepared according to
the general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
hex:EtOAc yielded 34 (100 mg, 0.29 mmol, 58% yield) as a yellowish/brown film. Rf = 0.39 (1:1
hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 7.3
Hz, 1H), 7.71 (dd, J = 7.6, 1.0 Hz, 1H), 7.49-7.36 (mult, 5H), 7.31 (d, J = 7.6 Hz, 1H), 7.08 (dd,
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J = 7.3, 1.6 Hz, 1H), 6.96 (td, J = 8.0, 1.6 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.3 Hz,
1H), 3.63 (s, 3H), 2.45 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) 204.8, 166.7, 165.1, 141.3,
138.5, 137.9, 137.7, 135.7, 130.6, 130.2, 129.5, 129.0, 128.8, 127.7, 127.5, 127.4, 127.1, 126.9,
126.1, 124.5, 117.35, 117.33, 59.7, 28.6. IR (diamond ATR): 3012, 2967, 1711, 1683, 1673,
1612, 1583, 1475 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C22H20NO3, 346.1438. Found
346.1447.
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3'-Acetyl-N-(2-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide (35): Prepared according to
the general procedure for decarbonylation with boronic acids. Column chromatography with 4:1
hex:EtOAc yielded 35 (107 mg, 0.31 mmol, 62% yield) as a yellow/white, oily film. Rf = 0.12
(4:1 hex:EtOAc). 1H NMR (400 MHz, CDCl3): 8.38 (d, J = 8.2 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J
= 8.0 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.59-7.44 (mult,
4H), 6.99 (t, J = 7.9 Hz, 1H), 6.93 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 7.7, 1H), 3.56 (s, 3H), 2.53 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3) 197.9, 167.1, 147.8, 140.4, 138.8, 137.4, 136.2, 133.5,
130.7, 130.5, 129.2, 128.9, 128.2, 127.5, 123.9, 121.0, 119.6, 109.7, 55.4, 26.6. IR (diamond
ATR): 3097, 3012, 2967, 1709, 1669, 1582, 1464 cm-1. HRMS (ESI-TOF) m/z[M+H]+ Calcd for
C22H20NO3, 346.1438. Found 346.1429.
N-(4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (36): Prepared
according to the general procedure for decarbonylation with boronic acids. Column
chromatography with 1:1 hex:EtOAc yielded 36 (134 mg, 0.36 mmol, 72% yield) as an off
white, flaky solid. Rf = 0.27. 1H NMR (400 MHz, CDCl3): 7.81 (dd, J = 7.5 Hz, 1.1 Hz, 1H),
7.69 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.57-7.50 (mult, 2H), 7.45 (dd, J = 7.6 Hz, 1.1
Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.82 (broad s, 1H), 6.81 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) 167.0, 156.8, 143.7, 138.2, 136.0, 130.7, 130.4, 130.3, 129.9,
129.1, 129.0, 128.5, 125.8, 125.7, 121.8, 114.2, 55.5. IR (diamond ATR) 3209, 3124, 3053,
3018, 2963, 1638, 1467, 1321 cm-1. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C21H17F3NO2,
372.1206; Found 372.1183.
Supporting Information Available
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Optimization results and NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Acknowledgements The authors thank the National Science Foundation (CHE-1148719 and
CHE-1764118) and the Henry Dreyfus Teacher-Scholar Award Program (TH-15-030) for
funding. J.B.J. acknowledges support from the Hope College Schaap Scholars Program. Grants
from the NSF for the purchase of NMR spectrometers (CHE-0922623) and GC/MS
instrumentation (CHE-0952768) are also gratefully acknowledged.
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17 For example, see: Tsunoda, T.; Yamazaki, A.; Iwamoto, H.; Sakamoto, S. Practical Synthesis of N-{4-[(2-Methyl-
4,5-dihydroimidazo[4,5-d][1]benzazepin- 6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide Monohydrochloride:ꢀ
an Arginine Vasopressin Antagonist. Org. Process Res. Dev. 2003, 7, 883-887. MaGlacken, G. P.; Bateman, L. M.
Recent advances in aryl–aryl bond formation by direct arylation. Chem. Soc. Rev. 2009, 38, 2447 and references
therein.
18 C-H activation and photoredox arylation pathways may also be used to access these species: a) Kalyani, D.
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H Functionalization and Visible-Light Photocatalysis. J. Am. Chem. Soc. 2011, 133, 18566-18569. Also b) Gao,
P.; Liu, L.; Shi, Z.; Yuan, Y. Iridium(III)-catalyzed regioselective direct arylation of sp2 C–H bonds with
diaryliodonium salts. Org. Biomol Chem, 2016, 14, 7109-7113.
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20 A similar coupling utilizing aryl halides to coupling with phthalimides has been recently reported: Samanta, P. K.;
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Arylation of Phthalimides. J. Org. Chem. 2019, 84, 3968-3976.
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21 Reactions with low yields of 2 primarily resulted in recovered starting material with moderate (~20%) amounts of
reduction product 3. The source of the reduction product remains unknown. Drying the aryl boronic acid prior to use
reduces but does not completely eliminate its formation.
22 Bilyard, K. G.; Garratt, P. J.; Hunter, R.; Lete, E. Comparative study of the reactions of dilithiated vicinal diesters
and dilithiated 1,2-dicarboximides with methyl iodide, α,ω-dihalides, α,ω-ditosylates and ω -bromo esters. J. Org.
Chem. 1982, 47, 4731-4736.
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23 No obvious cleavage of the N-alkyl bond was observed. See Rahman, M. M.; Buchspies, J.; Szostak, M. N-
Acylphthalimides: Efficient Acyl Coupling Reagents in Suzuki–Miyaura Cross-Coupling by N–C Cleavage
Catalyzed by Pd–PEPPSI Precatalysts Catalysts, 2019, 9, 129.
24 See reference 16b for the mechanistic investigation of a similar reaction with diorganozinc reagents.
25 Transmetallation to form the o-boronic acid may also be possible, which could subsequently be the source of the
reduction product.
26 Ni_CO bond strengths have been estimated to be anywhere from 28.3 to 47.1 kcal/mol; see: Sunderlin, L. S.;
-
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Wang, D.; Squires, R. R. Metal (iron and nickel) carbonyl bond strengths in Fe(CO)n and Ni(CO)n . J. Am. Chem.
Soc. 1992, 114, 2788.
27 Li, J.; Schreckenbach, G.; Ziegler, T. A Reassessment of the First Metal-Carbonyl Dissociation Energy in M(CO)4
(M = Ni, Pd, Pt), M(CO)5 (M = Fe, Ru, Os), and M(CO)6 (M = Cr, Mo, W) by a Quasirelativistic Density Functional
Method. J. Am. Chem. Soc. 1995, 117, 486.
28 Hu, J.; Zhao, Y.; Liu, J.; Zhang, Y.; Shi, Z. Nickel-Catalyzed Decarbonylative Borylation of Amides: Evidence
for Acyl C-N Bond Activation. Angew. Chem. Int. Ed. 2016, 55, 8718-8722.
29 See supporting information for full details.
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