Nickel-Catalyzed N -Arylation of Amides with (Hetero)aryl Electrophiles by Using a DBU/NaTFA Dual-Base System

Article abstract of DOI:10.1055/a-1337-6459

The first nickel-catalyzed N -arylation of amides with (hetero)aryl (pseudo)halides employing an organic amine base is described. By using a bis(cyclooctadienyl)nickel/8-[2-(dicyclohexylphosphinyl)phenyl]-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane catalyst mixture in combination with DBU/NaTFA as a dual-base system, a diversity of (hetero)aryl chloride, bromide, tosylate, and mesylate electrophiles were successfully cross-coupled with structurally diverse primary amides, as well as a selection of secondary amide, lactam, and oxazolidone nucleophiles.

Full text of DOI:10.1055/a-1337-6459

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–E
cluster
A
Modern Nickel-Catalyzed Reactions
T. Lundrigan et al.
Cluster
Synlett
Nickel-Catalyzed N-Arylation of Amides with (Hetero)aryl Electro-
philes by Using a DBU/NaTFA Dual-Base System
Travis Lundrigan
Joseph P. Tassone
Mark Stradiotto*
Ni(COD)2/L (5 mol%)
L = CyPAd-DalPhos
H
R2
O
X
N
R1 het
+
R1
het
R2 NH2
O
DBU/NaTFA, 100 °C
0
0
0
0
-
0
0
0
2-6
9
1
3
-5
1
6
0
X = Cl, Br, OTs, OMs
22 examples, 70–95%
82% average yield
Department of Chemistry, Dalhousie University, Halifax,
Nova Scotia B3H 4R2, Canada
mark.stradiotto@dal.ca
Published as part of the Cluster
Modern Nickel-Catalyzed Reactions
MDeMeaprakaiClrSotmmtrrraaeerdnskpit.osootnrtfoadCdihnioegtmtAoius@trhdyoa,lr.Dcalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
Received: 19.11.2020
Accepted after revision: 15.12.2020
Published online: 15.12.2020
C(sp2)–N cross-coupling of primary amides and (hete-
ro)aryl electrophiles, spanning both halides and phenol de-
rivatives, by use of the air-stable precatalyst (PAd-Dal-
Phos)Ni(o-tolyl)Cl (PAd-DalPhos = L1; see Scheme 2 be-
low).10,11
DOI: 10.1055/a-1337-6459; Art ID: st-2020-k0603-c
Abstract The first nickel-catalyzed N-arylation of amides with (hete-
ro)aryl (pseudo)halides employing an organic amine base is described.
Until recently, metal catalyst systems for amide N-aryla-
tion commonly made use of strong bases (e.g., t-BuONa) or
relatively weak inorganic bases (e.g., Cs2CO3, K3PO4, and
K2CO3), with the latter being required when employing sub-
strates featuring base-sensitive addenda. While generally
effective, the poor solubility of such inorganic bases in or-
ganic reaction media gives rise to a number of complica-
tions, including clogging/stirring issues and unpredictable
reaction kinetics associated with the batch-specific mor-
phology of the base (e.g., particle size). An elegant solution
to this problem was reported by Simmons and co-workers
in 2019,12 whereby a combination of a weak-amine Brønsted
base (1,8-diazabicyclo[5.4.0]undec-7-ene; DBU) and so-
dium trifluoroacetate (NaTFA) was employed successfully in
Pd-catalyzed C(sp2)–N cross-couplings of (hetero)aryl chlo-
rides with primary amides or anilines (Scheme 1). The ad-
vantage of the DBU/NaTFA dual-base system, besides being
readily available and inexpensive, is that the NaTFA additive
helps sequester any soluble halide anions from DBU·HX,
By
using
a
bis(cyclooctadienyl)nickel/8-[2-(dicyclohexylphos-
phinyl)phenyl]-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadaman-
tane catalyst mixture in combination with DBU/NaTFA as a dual-base
system, a diversity of (hetero)aryl chloride, bromide, tosylate, and
mesylate electrophiles were successfully cross-coupled with structurally
diverse primary amides, as well as a selection of secondary amide, lac-
tam, and oxazolidone nucleophiles.
Key words nickel catalysis, C–N cross-coupling, amides, arylation
The ubiquitous nature of amides in biologically relevant
molecules and functional materials1 provides motivation
for developing practical methods of preparing derivatives of
such compounds, including metal-catalyzed syntheses.2
The Pd-catalyzed N-arylation of amides through intermo-
lecular C(sp2)–N cross-couplings with (hetero)aryl electro-
philes, as developed initially by Shakespeare3 and by
Buchwald and co-workers,4 represents an effective means
of accessing N-arylated amides. Continual advances in an-
cillary ligand design5 have given rise to highly effective Pd-
based catalysts for the N-arylation of primary and second-
ary amides with a variety of (hetero)aryl electrophiles.6
Notwithstanding such progress, the cost and scarcity of Pd,
as well as the pursuit of an expanded substrate scope, pro-
vides impetus for the development of nonprecious-metal
catalysts for use in these transformations.7 In this vein, Cu-
based catalysts have proven highly effective in mediating
the N-arylation of amides.8 Although such catalysts are typ-
ically ineffective for use with inexpensive and abundant
(hetero)aryl chloride or phenol-derived electrophiles, some
important breakthroughs have been made in this regard.9 In
2016, we reported the first broadly useful Ni-catalyzed
Simmons, 2019:
Pd/L (5 mol%)
H
O
Cl
N
R2
R1 het
+
R1
het
R2 NH2
DBU/NaTFA, 60 °C
X = Cl
O
This work:
Ni(COD)2/L (5 mol%)
L = CyPAd-DalPhos
DBU/NaTFA, 100 °C
X = Cl, Br, OTs, OMs
Scheme 1 Palladium-catalyzed C–N cross-coupling of amides employ-
ing an organic amine ‘dual-base’ system (DBU/NaTFA), and the nickel-
catalyzed transformations reported herein.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Lundrigan et al.
Cluster
Synlett
which have been shown to coordinate to catalytic interme-
diates, thereby inhibiting catalysis.12 Newman and co-
workers recently employed DBU in high-throughput
screenings of Pd-catalyzed amination chemistry, thereby
demonstrating the utility of mild organic amine bases in
cross-coupling reactions in batch and flow processes.13
As part of our ongoing research program focused on de-
veloping new and synthetically useful Ni-catalyzed cross-
coupling chemistry, we recently reported a successful ap-
plication of the Simmons12 dual-base strategy in the N-ary-
lation of fluoroalkylamines with (hetero)aryl electrophiles
by using (PAd2-DalPhos)Ni(o-tolyl)Cl (PAd2-DalPhos = L2;
see Scheme 2 below) as a precatalyst.14 The success of these
C(sp2)–N cross-couplings involving generally poor fluoroal-
kylamine nucleophiles akin to amides,15 when paired with
the dearth of reports documenting Ni-catalyzed amide
cross-couplings of this type generally,16 led us to explore
the utility of DalPhos and other prominent ligands in the
development of the first Ni-catalyzed amide cross-cou-
plings of (hetero)aryl (pseudo)halides in the presence of a
weak organic amine base. The results of these investiga-
tions are disclosed below.
O
Cl
N
O
O
HN
N
Ni(COD)2/L (10 mol%)
O
+
NH2
DBU/NaTFA (2.0 equiv)
1,4-dioxane, 110 °C, 18 h
1a
1.1 equiv
1b
2a
(PCg)
R = o-tol, PAd-DalPhos (L1)
R = Ph, PhPAd-DalPhos (L2)
R = Cy, CyPAd-DalPhos (L3)
60% (40%)
95% (<5%)
95% (<5%)
PR2
P
P
O
PR2 = PCg, PAd2-DalPhos (L4) 55% (40%)
O
O
O
O
O
PPh2
Fe
S
O
P
PPh2
PPh2
PPh2
DPPF (L7)
35% (65%)
XantPhos (L6)
0% (100%)
ThioPad-DalPhos (L5)
55% (40%)
PCy2
N
N
N
N
PCy2
Fe
We began by investigating the cross-coupling of 2-fura-
mide (1a) and 4-chloroquinaldine (1b) employing catalyst
mixtures of 10 mol% of Ni(COD)2 (COD = 1,5-cyclooctadie-
nyl) with 10 mol% of each of the ligands L1–10 (Scheme 2).
Included in our ligand screen were the DalPhos ligands L1–
5,17 which have proved successful in Ni-catalyzed C(sp2)–N
cross-coupling, as well as other commercially available bis-
phosphine and NHC ancillary ligands that have been fruitful
in Pd-catalyzed C(sp2)–N cross-couplings of amides (L6 and
L7) or in the Ni-catalyzed C(sp2)–N cross-coupling of alter-
native nucleophiles (L8–10). Poor to moderate conversions
into the product 2a were observed for ligands outside the
DalPhos family, the most successful being JosiPhos (CyPF-
Cy) (L8), which showed comparable catalytic abilities to
some DalPhos ligands (L1, L4, and L5). However, PhPAd-Dal-
Phos (L2) and CyPAd-DalPhos (L3) afforded high conver-
sions into 2a. To differentiate the catalytic performance of
these two ligands, the catalyst loading was decreased [5
mol% of Ni(COD)2 and L]. At this loading, and following a
brief examination of solvent and temperature in which tol-
uene and 100 °C proved optimal, CyPAd-DalPhos (L3)
proved to be superior to PhPAd-DalPhos (L2), affording 2a
in 88% isolated yield (Scheme 3).
Attempts were made to employ the air-stable precata-
lysts (L)Ni(o-tolyl)Cl (L = L2,17f L317b), which have historical-
ly shown superior capabilities to those of the analogous
Ni(COD)2/L mixtures in C(sp2)–N cross-coupling.18 However,
with the dual-base system under the conditions examined
in our study, such precatalysts showed inferior perfor-
mance, requiring higher catalyst loadings and elevated tem-
peratures to achieve comparable conversions. For example
(L3)Ni(o-tolyl)Cl, in the presence or absence of added COD,
proved inferior (88% versus >95% conversion into 2a) to
IPr (L9)
JosiPhos (CyPF-Cy) (L8)
SIPr (L10)
0% (100%)
0% (100%)
60% (35%)
Scheme 2 Ligand screen for the Ni-catalyzed C–N cross-coupling of
amides by using DBU/NaTFA, employing 2-furamide (1a) and 4-chloro-
quinaldine (1b; 0.12 mmol scale, 0.12 M) as test substrates. Conver-
sions were estimated on the basis of calibrated GC data and are
reported as the percentage of 2a, with the percentage of residual 1b
shown in parentheses; the mass balance is attributable to unidentified
products.
Ni(COD)2/CyPAd-DalPhos (L3) catalyst mixtures (Ni/L = 5
mol% each, toluene, 100 °C; see Supporting Information, Ta-
ble S1) in the formation of 2a from 1a and 1b. When the
temperature was reduced to 80 °C, the Ni(COD)2/CyPAd-
DalPhos system still afforded a high conversion into 2a,
whereas the precatalyst (L3)Ni(o-tolyl)Cl afforded negligi-
ble amounts of 2a, with unreacted 1b. Therefore, we con-
tinued our synthetic investigations by employing
Ni(COD)2/CyPAd-DalPhos (L3).
In exploring the scope of reactivity, we determined that
the use of 5 mol% Ni(COD)2/CyPAd-DalPhos (L3) in toluene
at 100 °C for 18 hours generally represented the most effec-
tive conditions, although several reactions were found to
proceed efficiently at temperatures as low as 80 °C. An ar-
ray of functionalized (hetero)aryl (pseudo)halides (X = Cl,
Br, OTs, OMs) were successfully cross-coupled to (hetero)ar-
omatic or alkyl primary amides, affording isolated yields of
≥70% (Scheme 3).19 The heterocyclic amides 2-furamide and
thiophene-2-carboxamide were shown to be competent
coupling partners with both aryl and hetaryl (quinaldine
and quinoxaline) electrophiles to give secondary amides
2a–e. Electronically varied benzamides were also well tol-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

C
T. Lundrigan et al.
Cluster
Synlett
erated, including those bearing electron-donating (4-me-
thoxybenzamide) or electron-withdrawing [3,5-bis(trifluo-
romethyl)benzamide] groups, leading to 2f–j. The ability to
conduct gram-scale reactions was demonstrated by a suc-
cessful synthesis of amide 2f (1.37 g, 85% isolated yield)
from 4-chlorobenzonitrile (1.0 g).20 Throughout, control ex-
periments established that negligible conversion was
achieved in the absence of Ni(COD)2/CyPAd-DalPhos. More-
over, on focusing on the formation of 2f specifically, the ex-
clusion of NaTFA resulted in poor conversions (<5% for Ar-
OTs; ~50% for ArCl). Nicotinamide and isonicotinamide
were shown to produce fruitful pairings, giving 2k and 2l,
respectively. The primary alkyl amides acetamide, cyclo-
hexanecarboxamide, and cyclopropanecarboxamide were
compatible with the heterocyclic electrophiles 2-chloroqui-
noxaline and 6-chloroquinoxaline, affording products 2m–
o. Cross-couplings employing 2-chlorobenzonitrile and 2′-
chloroacetophenone were performed to investigate toler-
ance toward ortho-substitution of the electrophile; these
reactants proved compatible, forming products 2p and 2q.
Pyridine electrophiles could also be employed in this chem-
istry (2r). This method is partially limited, in that electron-
rich aryl electrophiles (e.g., 4-chloroanisole) were found to
be generally poor reaction partners under the conditions
employed, as negligible conversions of the starting materi-
als were observed. However, the dual-base system tolerated
a variety of functional groups that typically display sensi-
tivity to strong bases, including carbonyl-containing (alde-
hyde, ketone, ester), nitrile, or trifluoromethyl groups. Note
that there was no evidence of any Ni-mediated bond activa-
tion with potentially vulnerable groups such as ester, ni-
trile, or cyclopropyl fragments, thereby demonstrating the
functional-group tolerance of this catalyst system.
Ni(COD)2/L (5 mol%)
L = CyPAd-DalPhos
O
X
H
N
R2
R1
het
+
R2 NH2
1.1 equiv
DBU/NaTFA (2.0 equiv)
toluene, 100 °C, 18 h
R1
het
O
2
X = Cl (unless stated), Br, OTs, OMs
O
We also observed that the catalyst system successfully
cross-coupled lactams of various ring sizes to give products
3a and 3b (Scheme 4). An oxazolidone substrate was also
found to be compatible with this chemistry, affording prod-
uct 3c. Proof-of-principle experiments leading to tertiary
amides 3d and 3e established the viability of using acyclic
secondary amide nucleophiles in this chemistry, although
these are significantly more challenging than primary or
cyclic secondary amide substrates. Examples of such Ni-cat-
alyzed transformations are limited to a single report from
Sankar and Babu, involving exclusively the 2-picolinamide
group as a ligand/directing group for the transformation.11b
O
O
S
HN
H
N
N
N
Ph
O
O
O
N
N
H
2b, 86%, 80%a
2c, 91%
2a, 88%
S
H
H
N
S
H
N
N
O
O
NC
O
O
O
O
2f, 95%, 92%,b 76%c
2d, 77%
2e, 92%
OMe
F3C
OMe
H
N
H
H
N
N
N
N
Ni(COD)2/L (5 mol%)
R3
O
Cl
+
O
L = CyPAd-DalPhos
O
O
R3
R1
N
R2
het
O
R2
N
DBU/NaTFA (2.0 equiv)
toluene, 100 °C, 18 h
O
R1
het
H
2g, 85%
2h, 91%, 88%b
2i, 70%
O
N
1.1 equiv
3
N
CF3
H
N
N
O
O
N
H
N
NC
H
N
O
Ph
O
O
CF3
O
NC
N
O
O
O
2k, 74%
2j, 78 %
2l, 70%
O
3a, 84%
3b, 87%
3c, 94%
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
N
2m, 71%
2n, 83%
2o, 94%
3d, 66%
3e, 48%
OMe
O
CN
H
Scheme 4 Ni-catalyzed C–N cross-coupling of secondary amides with
(hetero)aryl chlorides. The reaction time is unoptimized. Yields of isolat-
ed products are reported.
H
N
O
MeO
N
N
N
H
O
O
O
2p, 78%
2q, 70%
2r, 86%
In summary, we have established the first Ni-catalyzed
C(sp2)–N cross-coupling of amides and (hetero)aryl (pseu-
do)halides with a combination of DBU as a weak amine
Brønsted base and NaTFA as a halide scavenger. Having
Scheme 3 Scope of the Ni-catalyzed C–N cross-coupling of primary
amides with (hetero)aryl (pseudo)halides. The reaction time is unopti-
mized. Yields of isolated products are reported. X = Cl unless otherwise
noted. a X = Br. b X = OTs. c X = OMs.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

D
T. Lundrigan et al.
Cluster
Synlett
identified Ni(COD)2/CyPAd-DalPhos as the optimal catalyst
system for use under these dual-base conditions, a series of
primary and secondary amides were cross-coupled with a
variety of (hetero)aryl halide and sulfonate electrophiles.
The results disclosed herein further establish Ni-catalyzed
C(sp2)–N cross-coupling as a complementary and competi-
tive alternative to Pd and Cu catalysis.
(12) Beutner, G. L.; Coombs, J. R.; Green, R. A.; Inankur, B.; Lin, D.;
Qiu, J.; Roberts, F.; Simmons, E. M.; Wisniewski, S. R. Org.
Process Res. Dev. 2019, 23, 1529.
(13) Kashani, S. K.; Jessiman, J. E.; Newman, S. G. Org. Process Res.
Dev. 2020, 24, 1948.
(14) McGuire, R. T.; Yadav, A. A.; Stradiotto, M. Angew. Chem. Int. Ed.
2020, in press DOI: 10.1002/anie.202014340.
(15) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822.
(16) The following report contains a single entry involving a Ni-cata-
lyzed C(sp2)–N cross-coupling of an aryl bromide and an amide
employing DBU as the base: Kawamata, Y.; Vantourout, J. C.;
Hickey, D. P.; Bai, P.; Chen, L.; Hou, Q.; Qiao, W.; Barman, K.;
Edwards, M. A.; Garrido-Castro, A. F.; deGruyter, J. N.;
Nakamura, H.; Knouse, K.; Qin, C.; Clay, K. J.; Bao, D.; Li, C.; Starr,
J. T.; Garcia-Irizarry, C.; Sach, N.; White, H. S.; Neurock, M.;
Minteer, S. D.; Baran, P. S. J. Am. Chem. Soc. 2019, 141, 6392.
(17) (a) Lavoie, C. M.; MacQueen, P. M.; Rotta-Loria, N. L.; Sawatzky,
R. S.; Borzenko, A.; Chisholm, A. J.; Hargreaves, B. K. V.;
McDonald, R.; Ferguson, M. J.; Stradiotto, M. Nat. Commun.
2016, 7, 11073. (b) Tassone, J. P.; MacQueen, P. M.; Lavoie, C. M.;
Ferguson, M. J.; McDonald, R.; Stradiotto, M. ACS Catal. 2017, 7,
6048. (c) Lavoie, C. M.; Stradiotto, M. ACS Catal. 2018, 8, 7228.
(d) Clark, J. S. K.; Ferguson, M. J.; McDonald, R.; Stradiotto, M.
Angew. Chem. Int. Ed. 2019, 58, 6391. (e) Clark, J. S. K.; McGuire,
R. T.; Lavoie, C. M.; Ferguson, M. J.; Stradiotto, M. Organometal-
lics 2019, 38, 167. (f) Tassone, J. P.; England, E. V.; MacQueen, P.
M.; Ferguson, M. J.; Stradiotto, M. Angew. Chem. Int. Ed. 2019,
58, 2485.
Funding Information
We are grateful to the NSERC of Canada (Discovery Grant RGPIN-
2019-04288 for M.S.), the Government of Canada (Vanier-CGS for
J.P.T.), the Killam Trusts, the Province of Nova Scotia, and Dalhousie
University for their support of this work.
N
aturalScie
n
ces
a
n
d
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g
in
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erin
g
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C
o
u
n
cil
o
f
Canada(R
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P
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N-2
0
1
9-0
4
2
8
8)
Acknowledgment
We thank Dr. Michael Lumsden and Mr. Xiao Feng (Dalhousie) for
technical assistance in the acquisition of NMR and MS data.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1337-6459. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
(18) Hazari, N.; Melvin, P. R.; Beromi, M. M. Nat. Rev. Chem. 2017, 1,
0025.
(19) N-Arylation of Amides with Aryl Electrophiles (Figures 3 and
4); General Procedure
References and Notes
(1) The Amide Linkage: Selected Structural Aspects in Chemistry, Bio-
chemistry and Materials Science; Arthur, G.; Breneman, C. M.;
Liebman, J. F., Ed.; Wiley-Interscience: New York, 2000.
(2) Dunetz, J. R.; Magano, J.; Weisenburger, G. A. Org. Process Res.
Dev. 2016, 20, 140.
(3) Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035.
(4) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
(5) Ligand Design in Metal Chemistry: Reactivity and Catalysis;
Stradiotto, M.; Lundgren, R. J., Ed.; Wiley: Chichester, 2016.
(6) For lead references, see: (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001. (b) Hicks, J.
D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 16720. (c) Crawford, S. M.; Lavery, C. B.; Stradiotto,
M. Chem. Eur. J. 2013, 19, 16760. (d) Young, I. S.; Glass, A.-L.;
Cravillion, T.; Han, C.; Zhang, H.; Gosselin, F. Org. Lett. 2018, 20,
3902.
In a N2-filled glovebox, a screw-capped vial containing a mag-
netic stirrer bar was charged with Ni(COD)2 (5 mol%), CyPAd-
DalPhos (5 mol%), the appropriate aryl (pseudo)halide (0.45
mmol, 1.0 equiv, 0.12 M), DBU (2.0 equiv), NaTFA (2.0 equiv),
and the appropriate amide (1.1 equiv), followed by the addition
of toluene (3.75 mL). The vial was sealed with a cap containing a
PTFE septum, removed from the glovebox, and placed in a tem-
perature-controlled aluminum heating block set to 100 °C for 18
h, with magnetic stirring. The vial was then removed from the
heating block and left to cool to rt. The crude reaction mixture
was filtered through a short plug of Celite and silica gel (3:1
v/v), eluting with EtOAc. The volatile materials were evaporated
in vacuo, and the crude product was purified by flash-column
chromatography.
N-(2-Methylquinolin-4-yl)-2-furamide (2a)
(7) Catalysis Without Precious Metals; Bullock, R. M., Ed.; Wiley-
VCH: Weinheim, 2010.
Synthesized according to the general procedure and purified by
flash column chromatography (silica gel; 30% EtOAc–hexanes)
to give a pale-yellow solid; yield: 100 mg (0.40 mmol, 88%).
1H NMR (500 MHz, CDCl3):  = 8.87 (s, 1 H), 8.34 (s, 1 H), 8.08 (d,
J = 8.4 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 1 H), 7.71 (ddd, J = 8.3, 7.1, 1.2
Hz, 1 H), 7.62–7.61 (m, 1 H), 7.57–7.54 (m, 1 H), 7.36–7.35 (m, 1
H), 6.64 (dd, J = 3.5, 1.8 Hz, 1 H), 2.76 (s, 3 H). 13C{1H} UDEFT
NMR (125.8 MHz, CDCl3):  = 160.2, 156.3, 148.3, 147.5, 145.0,
140.1, 129.8, 125.9, 118.8, 118.4, 116.7, 113.2, 111.3, 25.8.
HRMS-ESI: m/z [M + H]+ calcd for C15H13N2O2: 253.0972; found:
253.0980.
(8) For lead references and a review, see: (a) Goldberg, I. Ber. Dtsch.
Chem. Ges. 1906, 39, 1691. (b) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
(c) Monnier, F.; Taillefer, M. Top. Organomet. Chem. 2013, 46,
173.
(9) (a) De, S.; Yin, J.; Ma, D. Org. Lett. 2017, 19, 4864. (b) Chang, R.
K.; Clairmont, B. P.; Lin, S.; MacArthur, A. H. R. Organometallics
2019, 38, 4448.
(10) Lavoie, C. M.; MacQueen, P. M.; Stradiotto, M. Chem. Eur. J. 2016,
22, 18752.
N-(4-Benzoylphenyl)-2-furamide (3a)
(11) For other examples of Ni-catalyzed amide cross-couplings
employing aryl chlorides, see: (a) Moghaddam, F. M.; Tavakoli,
G.; Moafi, A.; Saberi, V.; Rezvani, H. R. ChemCatChem 2014, 6,
3474. (b) Sankar, R.; Babu, S. A. Asian J. Org. Chem. 2017, 6, 269.
Synthesized according to the general procedure and purified by
flash column chromatography (silica gel; 20% EtOAc–hexanes)
to give a colorless solid; yield: 100 mg (0.38 mmol, 84%). 1H
NMR (500 MHz, CDCl3):  = 7.87–7.84 (m, 2 H), 7.79–7.76 (m, 4
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E

E
T. Lundrigan et al.
Cluster
Synlett
H), 7.60–7.56 (m, 1 H), 7.49–7.46 (m, 2 H), 3.93 (t, J = 7.1 Hz, 2
H), 2.66 (t, J = 8.1 Hz, 2 H), 2.21 (quintet, J = 7.6 Hz, 2 H). 13C{1H}
UDEFT NMR (125.8 MHz, CDCl3):  = 195.8, 174.8, 143.2, 138.0,
133.1, 132.3, 131.4, 130.0, 128.4, 118.8, 48.7, 33.0, 18.1. HRMS-
ESI: m/z [M + Na]+ calcd for C17H15NNaO2: 288.0995; found:
288.0998.
denser was attached to the reaction vessel under a positive
pressure of N2, and magnetic stirring was initiated. After 18 h
(unoptimized), the crude reaction mixture was cooled to rt and
filtered through a short plug of Celite and silica gel (3:1 v/v),
eluting with EtOAc. Volatile materials were evaporated in vacuo,
and the crude product was purified by flash-column chroma-
tography (silica gel, 20% EtOAc–hexanes) to give a pale-yellow
solid; yield: 1.37 g (6.18 mmol, 85%).
(20) N-(4-Cyanophenyl)benzamide (2f); Gram-Scale Synthesis
In a N2-filled glovebox, an oven-dried 250 mL round-bottomed
Schlenk flask was charged with Ni(COD)2 (100 mg, 0.363
mmol), CyPAd-DalPhos (178 mg, 0.363 mmol), 4-chlorobenzo-
nitrile (1.0 g, 7.27 mmol), benzamide (0.969 g, 8.00 mmol),
NaTFA (1.98 g, 14.5 mmol), DBU (2.17 mL, 14.5 mmol), and
toluene (60 mL). A magnetic stirrer bar was added and the flask
was sealed with a rubber septum, removed from the glovebox,
and placed in an oil bath preheated to 100 °C. A reflux con-
1H NMR (500 MHz, CDCl3):  = 8.01 (s, 1 H), 7.88–7.86 (m, 2 H),
7.81–7.79 (m, 2 H), 7.67–7.64 (m, 2 H), 7.61–7.58 (m, 1 H),
7.53–7.50 (m, 2 H). 13C{1H} UDEFT NMR (125.8 MHz, CDCl3):  =
166.0, 142.2, 134.3, 133.5, 132.7, 129.2, 127.3, 120.1, 118.9,
107.6. HRMS-ESI: m/z [M
245.0685; found: 245.0686.
+
Na]+ calcd for C14H10N2NaO:
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–E