Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-(polyfluorobenzyl)benzamides in Pd-catalyzed C–H bond arylation

Article abstract of DOI:10.1016/j.crci.2019.10.001

The influence of fluoro substituents on the aryl group of N-methyl-N-benzylacetamides and N-methyl-N-benzylbenzamides on the regioselectivity of palladium-catalyzed direct arylations was studied. With these (poly)fluoro-substituted tertiary benzamides, th

Full text of DOI:10.1016/j.crci.2019.10.001

C. R. Chimie xxx (xxxx) xxx
Contents lists available at ScienceDirect
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ꢀ
Full paper / Memoire
Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and
N-methyl-N-(polyfluorobenzyl)benzamides in Pd-catalyzed
CeH bond arylation
,
b
,
, c
Mohamed Elhadi Benhalouche a c, Hai-Yun Huang a, Abdellah Miloudi b
,
Henri Doucet a , Jean-François Soule
Universite de Rennes, CNRS, ISCR UMR 6226, 35000, Rennes, France
,
*
, *
ꢀ a
a
ꢀ
b
ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire de chimie fine, Departement de chimie, Faculte des sciences exactes et appliquees, Universite Oran-1, BP1524, El Mnaouer,
31100, Oran, Algeria
c
ꢀ
ꢀ
ꢀ
Departement des classes preparatoires en sciences et technologies, Ecole nationale polytechnique d’Oran e Maurice-Audin, BP1523, El
Mnaouer, 31100, Oran, Algeria
a r t i c l e i n f o
a b s t r a c t
Article history:
The influence of fluoro substituents on the aryl group of N-methyl-N-benzylacetamides
and N-methyl-N-benzylbenzamides on the regioselectivity of palladium-catalyzed direct
arylations was studied. With these (poly)fluoro-substituted tertiary benzamides, the ary-
lations proceed very regioselectively at the CeH bond flanked by two fluoro substituents
using 2.5 mol% of air-stable palladium catalysts and PivOK/N,N-dimethylacetamide (DMA)
as the reaction conditions. For these reactions, a variety of substituents on the aryl bro-
mide, such as ester, propionyl, acetyl, formyl, nitro, nitrile, methoxy, or methyl, was
tolerated. Nitrogen-containing heteroaryl bromides were also successfully used. These
results reveal that under our reaction conditions, fluoro substituents act as better directing
groups than amides in palladium-catalyzed direct arylations.
Received 21 August 2019
Accepted 2 October 2019
Available online xxxx
Keywords:
Palladium
Fluorine
Biaryl
Amines
CeH bond functionalizations
© 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
aromatics, e.g., BalzꢀSchiemann reaction, often required
harsh reaction conditions,[2] which limit the scope of this
Polyfluorinated benzylamines are widely used as phar-
maceuticals, agrochemicals, and imaging materials
(Fig. 1).[1] As an example, Taradenacin, which is an anti-
muscarinic agent, contains a 3,4,5-trifluorobenzylamine
group. The difluorinated benzylamine larotrectinib is a
drug for the treatment of cancer, and the baloxavir mar-
boxil is an antiviral medication for treatment of influenza A
transformation.[3] More recently, fluoroaromatics were
prepared from aryl (pseudo)halides or aryl metallic de-
rivatives via transition metalecatalyzed fluorinations.[4]
However, this strategy required to use prefunctionalized
starting materials. The CeH bond fluorination has also been
reported but required the preinstallation of directing
groups and/or the use of expensive fluorine sources.[5] The
discovery of simple and efficient methods to access to
fluorinated molecules with broad molecular diversity re-
mains an important challenge for both academic research
groups and chemical companies.
and influenza B. Pexmetinib, which includes
a 3-
fluorobenzylamine group, is an antiinflammatory drug,
and trelagliptin is a drug used for the treatment of type 2
diabetes. Previous methods for the synthesis of fluorinated
Recently, transition metalecatalyzed regioselective
CeH bond functionalization has emerged as a suitable tool
to access molecular diversity with a minimum number of
manipulations.[6] In 2006, Fagnou et al.[7] reported the
* Corresponding authors.
E-mail addresses: henri.doucet@univ-rennes1.fr (H. Doucet), jean-
francois.soule@univ-rennes1.fr (J.-F. Soule).
ꢀ
https://doi.org/10.1016/j.crci.2019.10.001
1631-0748/© 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

2
M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
F
S
HO
F
F
F
F
F
H
N
N
N
F
N
O
O
N
HN
F
O
N
N
O
O
N
O
O
N
N
OCO2Me
Baloxavir marboxil
Tarafenacin
Larotrectinib
O
F
O
tBu
NH
N
NH
N
N
H2N
N
N
O
O
F
NC
Trelagliptin
OH
N
N
Pexmetinib
Fig. 1. Relevant pharmaceuticals containing a (poly)fluorinated benzylamine scaffold.
first example of palladium-catalyzed CeH bond arylation of
(poly)fluorobenzene derivatives using aryl halides as
coupling partners (Fig. 2a). The reaction generally took
place at ortho-position of fluorine atoms allowing the
preparation of fluorinated biphenyls in good yields from
commercially available fluorinated raw materials. However,
the regioselectivity can be affected by the presence of an
additional substituent leading to mixtures of para- or meta-
fluorobiphenyl derivatives.[8] We have shown that using
Pd/KOPiv/DMA as a catalytic system, (poly)fluorobenzene
bearing a benzoxazole,[9] a pyridine,[10] or an amide[11]
group reacted preferentially at the CeH bond flanked by
two fluorine atoms (Fig. 2b). To the best of our knowledge,
no example of Pd-catalyzed CeH bond arylation of poly-
fluorinated benzylamines was reported so far. Such sub-
strates are challenging because previous reports have
shown that benzylamine derivatives such as sulfinyl iso-
butyramide,[12] picolinamide,[13] and pyrazine-2-
carboxamide preferentially react at the ortho-position of
the methylamine group (Fig. 2c).
for CeH bond arylation of polyfluorobenzene derivatives
[namely, 2.5 mol% of Pd(OAc)2 associated with 2 equiva-
lents of KOAc in DMA at 150 ꢁC], the desired biphenyl
product 1a was not obtained. A similar reactivity trend was
observed with N-(2,3,5,6-tetrafluorobenzyl)acetamide (b)
(Table 1, entry 2). The lack of reactivity of these two sub-
strates might be explained by the presence of NH function,
which could inhibit the palladium activity. Therefore, we
decided to investigate the reactivity of N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide (c). We were pleased
to find that under the same reaction conditions, the desired
biphenyl product 1c was obtained in 45% yield (Table 1,
entry 3). Then, we explored the effect of several reaction
parameters (i.e., base, palladium sources and solvent). The
use of K2CO3 as base inhibited the reaction, while the use of
PivOK as base slightly improved the yield of 1c to 58%
(Table 1, entries 4 and 5). In both cases, we observed partial
conversions of 4-bromobenzonitrile; therefore, other
sources of palladium were tested. No improvement was
observed using 2.5 mol% PdCl2(CH3CN)2, whereas the use of
a palladium diphosphine catalyst [PdCl(C3H5)(dppb)] gives
1c in 89% yield with a full conversion of the aryl bromide
(Table 1, entries 6 and 7). A partial conversation was ob-
tained using only 1 mol% of this Pd catalyst (Table 1, entry
8). No improvement was observed by changing DMA to
DMF or xylene (Table 1, entries 9 and 10).
Herein, starting from
a set of N-methyl-N-(poly-
fluorobenzyl)acetamides and an N-methyl-N-(poly-
fluorobenzyl)benzamide as reactants, we report (i) on the
reactivity and regioselectivity for the direct arylation of
benzene units containing both fluoro and N-methyl tertiary
amide substituents and (ii) on the access to a variety of N-
protected-methylamineesubstituted (poly)fluorobiphenyls
using avarietyof aryl bromides as coupling partners (Fig. 2d).
Having determined the best conditions to arylate the
CeH bond of N-methyl-N-(2,3,5,6-tetrafluorobenzyl)acet-
amide (c), we turned our attention to the scope of aryl
bromides (Scheme 1). Other aryl bromides bearing an
electron-withdrawing substituent at the para-positions e
such as ethyl ester and formyl groups e well reacted to
afford the biphenyl products 2 and 3 in 87% and 84% yield,
respectively. The reaction was more sluggish when 4-
bromoanisole was used, as the desired acetamide 4 was
2. Result and discussion
We first investigated the reactivity of nonprotected
(2,3,5,6-tetrafluorophenyl)methanamine
(a)
in
Pd-
catalyzed CeH bond arylation with 4-bromobenzonitrile
(Table 1, entry 1). Using our previous reaction conditions
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
3
Fig. 2. Pd-catalyzed CeH bond arylation of polyfluorinated benzylamines.
isolated in only 51% yield because of a partial conversion of
bromobenzoate, respectively.
A
similar regioselectivity
this electron-rich aryl bromide. Similarly, the coupling be-
tween c and 3-bromotoluene led to the formation of 5 in
53% yield. The reaction was not very sensitive to steric
factors as 2-bromobenzaldehyde and 2-bromobenzonitrile
reacted well with c to give the biphenyl products 6 and 7 in
87% and 78% yield, respectively. The reaction also tolerated
the use of nitrogen-containing heteroaryl bromides such as
3-bromoquinoline and 3-bromopyridine, as the products 8
and 9 were isolated in good to excellent yields.
Then, we investigated the reactivity of N-methyl-N-
(2,3,5-trifluorobenzyl)acetamide (d) in Pd-catalyzed CeH
bond arylation with aryl bromides (Scheme 2). Although
this substrate bears two CeH bonds, the reaction regiose-
lectively occurred only at the CeH bond flanked by the
two-fluorine atoms, affording the biphenyls 10 and 11 in
good yields from 4-bromobenzonitrile and ethyl 4-
has been previously observed with 6-substituted 1,2,4-
trifluorobenzene derivatives.[7a, 10] This regioselectivity
might be assigned to a lower Gibbs free energies of acti-
vation (D
Gs) of the cleavage of CeH bond adjacent to two
fluorine atoms in concerted metalation deprotonation
(CMD) process.[14]
We also explored the reactivity of N-(3,5-
difluorobenzyl)-N-methylbenzamide (e) in Pd-catalyzed
CeH bond arylation with aryl bromides (Scheme 3). In line
with the previous reports on arylation of 1,3-
difluorobenzene derivatives,[7a, 9ꢀ10] reaction between
the difluorinated benzyl-N-methylbenzamide
e and 4-
bromobenzonitrile led to the single regioisomer 12 in 67%
yield. The arylation again took place at the CeH bond
flanked by the two fluorine atoms. The coupling reactions
with other aryl bromides para-substituted by an electron
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

4
M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
Table 1
Reactivity of (2,3,5,6-tetrafluorophenyl)methanamine (a), N-(2,3,5,6-tetrafluorobenzyl)acetamide (b), and N-methyl-N-(2,3,5,6-tetrafluorobenzyl)acetamide
(c) in Pd-Catalyzed CeH bond arylation with 4-bromobenzonitrile.
Entry
Reactant a, b, or c
[Pd] catalyst
Base
Yield (%)
1
2
3
4
5
6
7
a
b
c
c
c
c
c
c
c
c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KOAc
KOAc
KOAc
K2CO3
PivOK
PivOK
PivOK
PivOK
PivOK
PivOK
0
0
45
0
58
41
89
76
21
0
Pd(OAc)2
PdCl2(CH3CN)2
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
8a
9b
10c
a
Using 1 mol% of Pd catalyst.
In dimethylformamide (DMF).
In xylene.
b
c
F
F
F
F
PdCl(C3H5)(dppb)
R
F
(2.5 mol%)
F
R
PivOK (2 equiv.)
DMA, 150 ºC
Br
F
F
Me
N
Me
N
16 h
Me
Me
O
O
c (1.5 equiv.)
OMe
F
F
F
F
F
F
Me
R
R =
F
F
F
CO Et
2 87%
3 84%
4 51%
2
R =
Me
N
F
Me
N
F
Me
N
F
CHO
Me
Me
Me
CHO
CN
6
7
71%
88%
5 53%
MeO
O
O
O
F
F
F
N
F
N
F
F
Me
N
F
Me
9 78%
Me
N
F
Me
8 87%
O
O
Scheme 1. Scope of (hetero)aryl bromides in Pd-catalyzed CeH bond arylation of N-methyl-N-(2,3,5,6-tetrafluorobenzyl)acetamide (c).
withdrawing group (e.g., nitro, formyl, ethyl ester or ben-
zoyl) afforded the 2,6-difluoro-[1,10-biphenyl] derivatives
13e16 in 54e66% yields. From N-(3,5-difluorobenzyl)-N-
methylbenzamide (e) and 2-bromobenzonitrile, the desired
coupling product 17 was isolated in only 42% yield. More-
over, 3-bromoquinoline was successfully used as aryl source
to provide an efficient access to the 2-(2,6-difluorophenyl)
quinoline derivative 18 in 58% yield.
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
5
R
F
F
F
PdCl(C3H5)(dppb)
F
R
(2.5 mol%)
F
F
PivOK (2 equiv.)
DMA, 150 ºC
16 h
Br
Me
N
Me
N
Me
Me
O
O
d (1.5 equiv.)
R =
CN
10
79%
75%
CO Et
11
2
Scheme 2. Scope of aryl bromides in Pd-catalyzed CeH bond arylation of N-methyl-N-(2,3,5-trifluorobenzyl)acetamide (d).
F
F
PdCl(C3H5)(dppb)
(2.5 mol%)
R
R
PivOK (2 equiv.)
DMA, 150 ºC
Br
F
F
Ph
N
Ph
N
16 h
Me
Me
O
O
N
e (1.5 equiv.)
R
N
F
F
F
CN
F
F
F
Ph
N
Ph
N
Ph
R =
Me
17 42%
Me
Me
CN
12 67%
13 61%
14 54%
15 63%
16 66%
O
O
O
NO2
18 58%
CHO
CO2Et
COPh
Scheme 3. Scope of (hetero)aryl bromides in Pd-catalyzed CeH bond arylation of N-(3,5-difluorobenzyl)-N-methylbenzamide (e).
ꢁ
The reactivity and regioselectivity was not sensitive to
the substitution pattern of the fluorine atoms, provided that
the CeH bond remained flanked by two fluorine atoms
(Scheme 4). As an example, N-(2,4-difluorobenzyl)-N-
methylacetamide (f) underwent CeH bond arylation in the
presence of 2.5 mol% of Pd(OAc)2 associated with 2
equivalents of KOAc in DMA at 150 C. The biphenyl prod-
ucts 19e21 were regioselectively obtained in 55e76% yields
from 4-bromobenzonitrile, 1-bromo-4-nitrobenzene, and
3-bromobenzonitrile. Again, 3-bromoquinoline displayed
good reactivity, affording the 3-arylquinoline 22 in 58%
yield.
R
PdCl(C3H5)(dppb)
F
F
(2.5 mol%)
F
F
R
PivOK (2 equiv.)
DMA, 150 ºC
16 h
Br
Me
N
Me
Me
N
Me
N
Me
O
O
O
f (1.5 equiv.)
F
F
R =
Me
4-CN
4-NO2
3-CN
19 76%
20 55%
21 65%
N
22 58%
Scheme 4. Scope of (hetero)aryl bromides in Pd-catalyzed CeH bond arylation of N-(2,4-difluorobenzyl)-N-methylacetamide (f).
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

6
M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
3. Conclusion
methylacetamide (1.22 g, 16.8 mmol, 1.12 equiv) or N-
methylbenzamide (2.27 g, 16.8 mmol, 1.12 equiv) in DMF
(8 mL) was slowly added. After 30 min at room tempera-
ture, polyfluorobenzylbromide (15 mmol, 1 equiv) was
added concurrently over 1 h. A water bath was used to
maintain the temperature below 40 ꢁC. The resulting
mixture was stirred overnight at room temperature and
then poured into a mixture of 20% NH4Cl (50 mL) and Et2O
(50 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (2 x 50 mL). The organic layers
were combined and washed with H2O (3 x 50 mL) and then
brine (50 mL). The organic layer was dried (Na2SO4), and
the solvent was removed to afford a residue. The crude
mixture was purified by silica column chromatography to
afford the desired arylated product.
In summary, we have demonstrated that Pd-catalyzed
direct arylation of electron-deficient arenes such as
1,2,4,5-tetrafluorobenzyl, 1,2,4-trifluorobenzyl, or 1,3-
difluorobenzyl, bearing N-methylacetamide or N-methyl-
benzamide groups, always reacted via the cleavage of the
CeH bond flanked by two fluorine atoms, whereas the CeH
bonds at ortho-position of N-methylacetamide or N-meth-
ylbenzamide remained untouched. These fluorine-directed
CeH bond functionalizations proceed with an easy-to-
handle diphosphine Pd catalyst and PivOK as base in
DMA. This procedure tolerates a wide variety of sub-
stituents on the aryl bromides such as nitro, cyano, ester,
ketone, formyl, and heteroaryl bromides with pyridinyl or
quinolyl units. The reaction is not limited to activated aryl
bromides, as electron-donating substituents such as
methoxy and methyl are also tolerated. Owing to the
importance of polyfluorinated benzylamines and poly-
fluorinated biphenyls in pharmaceutical and material sci-
ences, this methodology could find applications in late-
stage modifications via regioselective CeH bond arylation
to discover new active fluorinated molecules.
4.4. N-Methyl-N-(2,3,5,6-tetrafluorobenzyl)acetamide (c)
Following the general procedure A using 3-(bromo-
methyl)-1,2,4,5-tetrafluorobenzene (3.64 g, 15 mmol), the
residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 70-30) to afford the desired com-
ꢁ
pound c (3.25 g, 92%) as a yellow solid (Mp ¼ 85e97 C):
1H NMR (400 MHz, CDCl3)
d (ppm) 7.08e6.86 (m, 1H),
4. Experimental section
4.80 & 3.55 (s, 2H), 2.91 & 2.73 (s, 3H), 2.15 & 1.98 (s, 3H).
Observed complexity is due to the mixture of rotamers.
4.1. General
13C NMR (100 MHz, CDCl3)
d (ppm) 170.4 & 170.2, 145.7
(dm, J ¼ 250.4 Hz), 145.1 & 145.7 (dm, J ¼ 250.4 Hz), 116.5
& 115.6 (t, J ¼ 17.0 Hz), 106.2 & 105.2 (t, J ¼ 22.7 Hz), 42.3
& 39.2, 35.8 & 32.0, 21.4 & 20.9. Observed complexity is
due to the mixture of rotamers. Elemental analysis: calcd
(%) for C10H9F4NO (235.18): C 51.07, H 3.86; found: C
51.21, H 4.03.
All reactions were carried out under argon atmosphere
with standard Schlenk-tube techniques. High-performance
liquid chromatography (HPLC)egrade DMA was stored
under argon and used without further purification. 1H and
13C nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker AV III 400 MHz NMR spectrometer
equipped with BBFO probe head. Chemical shifts (d) were
reported in parts per million relative to residual chloroform
(7.26 ppm for 1H; 77.0 ppm for 13C), and constants were
reported in Hertz. 1H NMR assignment abbreviations were
the following: singlet (s), doublet (d), triplet (t), quartet (q),
doublet of doublets (dd), doublet of triplets (dt), and
multiplet (m). All reagents were weighed and handled in
air.
4.5. N-Methyl-N-(2,3,5-trifluorobenzyl)acetamide (d)
Following the general procedure A using 3-(bromo-
methyl)-2,4,5-trifluorobenzene (3.38 g, 15 mmol), the res-
idue was purified by flash chromatography on silica gel
(heptane-EtOAc, 70-30) to afford the desired compound
d (3.06 g, 94%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
d
(ppm) 6.88e6.56 (m, 2H), 4.55 & 4.52 (s, 2H), 2.95 & 2.87
(s, 3H), 2.08 & 2.07 (s, 3H). Observed complexity is due to
the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
(ppm)
4.2. Preparation of the PdCl(C3H5)(dppb) catalyst
d
171.0 & 170.8, 157.8 (dm, J ¼ 250.1 Hz), 150.1 (dm, J ¼
250.1 Hz), 145.5 (dm, J ¼ 245.8 Hz), 127.8 (dd, J ¼ 8.6,
13.8 Hz), 111.1 & 109.2 (td, J ¼ 3.2, 24.1 Hz), 104.4 (dd, J ¼
20.9, 27.6 Hz), 48.0 & 44.0, 36.1 &33.6, 21.6 & 21.1. Observed
complexity is due to the mixture of rotamers. Elemental
analysis: calcd (%) for C10H10F3NO (217.19): C 55.30, H 4.64;
found: C 55.48, H 4.87.
An oven-dried 40-mL Schlenk tube equipped with a
magnetic stirring bar under argon atmosphere was charged
with [Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg,
1 mmol). Ten milliliters of anhydrous dichloromethane
were added; then, the solution was stirred at room tem-
perature for 20 minutes. The solvent was removed in vac-
uum. The powder was used without purification. (31P NMR
381 MHz, CDCl3)
d
¼ 19.3 (s).[15]
4.6. N-(3,5-Difluorobenzyl)-N-methylbenzamide (e)
4.3. General procedure A for synthesis of N-methyl-N-
(polyfluorobenzyl)acetamides (c-d and f) and N-(3,5-
difluorobenzyl)-N-methylbenzamide (e)
Following the general procedure A using 1-(bromo-
methyl)-3,5-difluorobenzene (3.11 g, 15 mmol), the residue
was purified by flash chromatography on silica gel (hep-
tane-EtOAc, 70-30) to afford the desired compound e
(3.60 g, 92%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
To a DMF (10 mL) solution of sodium hydride (60%
dispersion in mineral oil) (0.719 g, 0.431 g corrected for
d
(ppm) 7.44e7.28 (m, 6H), 6.87e6.80 (m, 1H), 6.78e6.69
mineral oil, 18 mmol, 1.2 equiv)
a solution of N-
(m, 1H), 4.71 & 4.47 (s, 2H), 2.94 & 2.86 (s, 3H). Observed
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
7
complexity is due to the mixture of rotamers. 13C NMR
(100 MHz, CDCl3)
249.1 Hz), 141.2 (m), 135.8, 130.0, 128.7, 127.2, 110.7(m),
103.2 (m), 50.5, 37.4. Observed complexity is due to the
mixture of rotamers. Elemental analysis: calcd (%) for
(%) for C17H12F4N2O (336.29): C 60.72, H 3.60; found: C
60.89, H 3.56.
d
(ppm) 172.5 & 172.0, 163.5 (dm, J ¼
4.10. Ethyl 20,30,50,60-tetrafluoro-4'-((N-methylacetamido)
methyl)-[1,10-biphenyl]-4-carboxylate (2)
C
15H13F2NO (261.27): C 68.96, H 5.02; found: C 69.19, H
6.15.
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide (c) (176 mg, 0.75mmol)
and ethyl 4-bromobenzoate (115 mg, 0.5 mmol), the residue
was purified by flash chromatography on silica gel (heptane-
EtOAc, 60-40) to afford the desired compound 2 (167 mg,
87%) as a yellow solid (Mp ¼ 102e105 ꢁC): 1H NMR (400 MHz,
4.7. N-(2,4-Difluorobenzyl)-N-methylacetamide (f)
Following the general procedure A using 1-(bromo-
methyl)-2,4-difluorobenzene (3.11 g, 15 mmol), the residue
was purified by flash chromatography on silica gel (hep-
tane-EtOAc, 70-30) to afford the desired compound f
(2.69 g, 90%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
CDCl3) d (ppm) 8.17e8.08 (m, 2H), 7.55e7.44 (m, 2H), 4.74 &
4.66 (s, 2H), 4.39 (q, J ¼ 7.1 Hz, 2H), 3.05 & 2.99 (s, 3H), 2.11 &
2.06 (s, 3H), 1.38 (t, J ¼ 6.7 Hz, 3H). Observed complexity is
due to the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d
(ppm) 7.31 & 7.11 (q, J ¼ 6.9, 7.6 Hz, 1H), 6.92e6.72 (m,
d
(ppm) 170.7 & 170.5,166.1 &166.0,145.8 (dm, J ¼ 252.2 Hz),
2H), 4.57 & 4.51 (s, 2H), 2.96 & 2.90 (s, 3H), 2.15 & 2.11 9s,
143.7 (dm, J ¼ 247.8 Hz), 131.8 & 131.4 (brs), 131.5 & 131.2,
130.2,129.9,129.8,120.3 & 119.3 (t, J ¼ 16.4 Hz),115.6 & 114.6
(t, J ¼ 17.2 Hz), 61.4 & 61.3, 42.6 & 39.8, 36.3 & 32.6, 21.8 &
21.3, 14.4. Observed complexity is due to the mixture of
rotamers. Elemental analysis: calcd (%) for C19H17F4NO3
(383.35): C 59.53, H 4.47; found: C 59.62, H 4.71.
3H). Observed complexity is due to the mixture of rotam-
ers. 13C NMR (100 MHz, CDCl3)
d (ppm) 170.6 (2), 162.1
&161.8 (dd, J ¼ 14.2, 248.1 Hz), 160.6 & 161.0 (dd, J ¼ 11.8,
248.2 Hz), 131.2 (m), 129.0 (dd, J ¼ 5.8, 9.7 Hz), 128.0 &
126.6, 120.1 & 119.3 (d, J ¼ 3.7 Hz), 111.2 & 111.1 (d, J ¼
21.1 Hz), 103.9 & 103.2 (t, J ¼ 25.7 Hz), 47.5 & 43.3, 35.5 &
32.9, 21.3 & 20.8. Observed complexity is due to the
mixture of rotamers. Elemental analysis: calcd (%) for
4.11. N-Methyl-N-((2,3,5,6-tetrafluoro-40-formyl-[1,10-
biphenyl]-4-yl)methyl)acetamide (3)
C
10H11F2NO (199.20): C 60.30, H 5.57; found: C 60.45, H
5.29.
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
4.8. General procedure B for synthesis of fluorinated
biphenyls
0.75 mmol) and 4-bromobenzaldehyde (93 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 50-50) to afford the desired compound
3 (143 mg, 84%) as a yellow solid (Mp ¼ 93e95 ꢁC): 1H NMR
To a 25 mL oven dried Schlenk tube, (polyfluorobenzyl)
acetamide (0.75 mmol), (hetero)arylbromide (0.5 mmol),
PivOK (140 mg,1 mmol), DMA (2 mL) and PdCl(C3H5)(dppb)
(7.7 mg, 0.012 mmol) were successively added. The reaction
mixture was evacuated by vacuum-argon cycles (5 times)
and stirred at 150 ꢁC (oil bath temperature) for 16 h (see
tables and schemes). After cooling the reaction at room
temperature and concentration, the crude mixture was
purified by silica column chromatography to afford the
desired arylated product.
(400 MHz, CDCl3)
d (ppm) 10.10 & 10.08 (s, 1H), 8.05e7.96
(m, 2H), 7.70e7.60 (m, 2H), 4.76 & 4.69 (s, 2H), 3.09 & 2.92
(s, 3H), 2.31 & 2.13 (s, 3H). Observed complexity is due to
the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
191.7 & 191.6, 170.8 & 170.6, 145.8 (dm, J ¼ 252.2 Hz), 143.9
(dm, J ¼ 249.1 Hz), 136.8 & 136.6, 133.5 & 133.0, 131.0 (m),
129.9 & 129.9, 118.9 & 116.1 (t, J ¼ 16.3 Hz), 42.7 &40.0, 36.5
& 32.6, 21.8 & 21.3. Observed complexity is due to the
mixture of rotamers. Elemental analysis: calcd (%) for
C
4.06.
17H13F4NO2 (339.29): C 60.18, H 3.86; found: C 60.02, H
4.9. N-((40-Cyano-2,3,5,6-tetrafluoro-[1,10-biphenyl]-4-yl)
methyl)-N-methylacetamide (1c)
4.12. N-Methyl-N-((2,3,5,6-tetrafluoro-40-methoxy-[1,10-
biphenyl]-4-yl)methyl)acetamide (4)
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 4-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 70-30) to afford the desired compound
1c (150 mg, 89%) as a white solid (Mp ¼ 130e132 ꢁC): 1H
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 4-bromoanisole (94 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 70-30) to afford the desired compound 4
(87 mg, 51%) as a white solid (Mp ¼ 108e110 ꢁC): 1H NMR
NMR (400 MHz, CDCl3)
d (ppm) 7.81e7.74 (m, 2H),
7.61e7.54 (m, 2H), 4.79 & 4.69 (s, 2H), 3.01 & 2.90 (s, 3H),
2.29 & 2.11 (s, 3H). Observed complexity is due to the
(400 MHz, CDCl3) d (ppm) 7.44e7.37 (m, 2H), 7.06e6.99 (m,
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d
(ppm)
2H), 4.76 & 4.66 (s, 2H), 3.86 & 3.86 (s, 3H), 3.04 & 2.90 (s,
3H), 2.30 & 2.12 (s, 3H). Observed complexity is due to the
170.8 & 170.5, 147.7 (dm, J ¼ 252.2 Hz), 143.5 (dm, J ¼
246.2 Hz), 132.5 & 132.4, 132.1 & 131.7 (brs), 131.0, 118.3,
118.2 & 118.0, 116.5 & 115.3 (t, J ¼ 17.2 Hz), 113.5 & 113.2,
42.7 &40.1, 36.6 & 32.6, 21.8 & 21.3. Observed complexity is
due to the mixture of rotamers. Elemental analysis: calcd
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
170.6 & 170.5, 145.7 (dm, J ¼ 252.2 Hz), 143.8 (dm, J ¼
251.1 Hz), 131.4 (m), 120.0 (t, J ¼ 16.5 Hz), 119.4, 119.0, 114.2,
114.1, 114.0 & 113.8, 55.4 & 44.3, 42.5 & 39.3, 36.0 & 32.4,
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

8
M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
21.8 & 21.2. Observed complexity is due to the mixture of
rotamers. Elemental analysis: calcd (%) for C17H15F4NO2
(341.31): C 59.83, H 4.43; found: C 59.98, H 4.21.
247.8 Hz), 133.5 (m), 133.1 (m), 131.7 & 131.6, 131.2 (t, J ¼
3.3 Hz), 130.2, 130.0, 117.5, 117.0 (m), 114.0, 42.8 & 29.9, 36.5
& 32.7, 21.9 & 21.4. Observed complexity is due to the
mixture of rotamers. Elemental analysis: calcd (%) for
C17H12F4N2O (336.29): C 60.72, H 3.60; found: C 60.91, H
3.82.
4.13. N-Methyl-N-((2,3,5,6-tetrafluoro-30-methyl-[1,10-
biphenyl]-4-yl)methyl)acetamide (5)
Following the general procedure B using N-methyl-N-
4.16. N-Methyl-N-(2,3,5,6-tetrafluoro-4-(quinolin-3-yl)
benzyl)acetamide (8)
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 3-bromotoluene (85 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 60-40) to afford the desired compound 5
(86 mg, 53%) as a yellow solid (Mp ¼ 48e50 ꢁC): 1H NMR
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 3-bromoquinoline (104 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 60-40) to afford the desired compound 8
(158 mg, 87%) as yellow solid (Mp ¼ 104e106 ꢁC): 1H NMR
(400 MHz, CDCl3) d (ppm) 7.49e7.33 (m, 1H), 7.29e7.21 (m,
3H), 4.76 & 4.66 (s, 2H), 3.04 & 2.91 (s, 3H), 2.40 (s, 3H), 2.30
& 2.12 (s, 3H). Observed complexity is due to the mixture of
rotamers. 13C NMR (100 MHz, CDCl3)
d
(ppm) 170.6 & 170.4,
(400 MHz, CDCl3) d (ppm) 9.01e8.93 (m, 1H), 8.34e8.26 (m,
145.7 (dm, J ¼ 246.9 Hz), 143.8 (dm, J ¼ 245.6 Hz), 138.5 &
128.3, 130.6 (m), 130.2 (m), 128.7 & 128.6, 128.6 & 128.5,
127.2 & 126.8, 121.1 &120.4 (t, J ¼ 16.9 Hz), 114.5 & 113.5 (t, J
¼ 17.3 Hz), 42.5 & 39.5, 36.0 & 32.4, 21.7 & 21.4, 21.6 & 21.2.
Observed complexity is due to the mixture of rotamers.
Elemental analysis: calcd (%) for C17H15F4NO (325.31): C
62.77, H 4.65; found: C 62.81, H 4.86.
1H), 8.19e8.10 (m, 1H), 7.93e7.86 (m, 1H), 7.83e7.75 (m,
1H), 7.66e7.56 (m, 1H), 4.78 & 4.70 (s, 2H), 3.09 & 2.93 (s,
3H), 2.31 & 2.13 (s, 3H). Observed complexity is due to the
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
170.7 & 170.4, 150.4 & 150.2 (t, J ¼ 2.7 Hz), 147.9 & 147.8,
145.8 (dm, J ¼ 250.6 Hz), 144.0 (dm, J ¼ 247.8 Hz), 137.7 &
137.7, 130.9 & 130.7, 129.4 & 129.4, 128.2, 127.5, 127.4 (m),
120.9 & 120.5,117.9 & 116.9 (t, J ¼ 16.6 Hz), 116.0 & 114.8 (t, J
¼ 17.2 Hz), 42.6 & 39.8, 36.3 & 32.5, 21.7 & 21.2. Observed
complexity is due to the mixture of rotamers. Elemental
analysis: calcd (%) for C19H14F4N2O (362.33): C 62.98, H
3.89; found: C 63.12, H 4.09.
4.14. N-Methyl-N-((2,3,5,6-tetrafluoro-20-formyl-[1,10-
biphenyl]-4-yl)methyl)acetamide (6)
Following the general procedure B using N-methyl-N-
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 2-bromobenzaldehyde (93 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 40e60) to afford the desired com-
pound 6 (120 mg, 71%) as a colorless oil: 1H NMR (400 MHz,
4.17. N-Methyl-N-(2,3,5,6-tetrafluoro-4-(pyridin-3-yl)
benzyl)acetamide (9)
Following the general procedure B using N-methyl-N-
CDCl3)
d
(ppm) 9.93 & 9.92 (s, 1H), 8.03 (d, J ¼ 7.6 Hz, 1H),
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
7.78e7.59 (m, 2H), 7.44e7.35 (m, 1H), 4.78 & 4.70- (s, 2H),
3.08 &2.93 (s, 3H), 2.30 & 2.13 (s, 3H). Observed complexity
is due to the mixture of rotamers. 13C NMR (100 MHz,
0.75 mmol) and 3-bromopyridine (79 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 70-30) to afford the desired compound 9
(122 mg, 78%) as a yellow solid (Mp ¼ 84e86 ꢁC): 1H NMR
CDCl3)
d
(ppm) 190.5, 170.8 & 170.6, 145.5 (dm, J ¼
249.3 Hz), 143.8 (dm, J ¼ 247.8 Hz), 134.3, 134.1 (m), 132.1 &
131.8, 130.9, 130.4 & 130.2, 127.9 & 127.9 (t, J ¼ 2.9 Hz), 118.7
& 117.2 (d, J ¼ 17.8 Hz), 116.1 &114.7 (d, J ¼ 18.3 Hz), 42.7 &
39.8, 36.4 & 32.6, 21.8 & 21.1. Observed complexity is due to
the mixture of rotamers. Elemental analysis: calcd (%) for
(400 MHz, CDCl3) d
(ppm) 1H NMR (400 MHz, CDCl3)
d
8.73e8.68 (m, 1H), 8.68e8.65 (m, 1H), 7.83e7.74 (m, 1H),
7.47e7.36 (m, 1H), 4.78 & 4.68 (s, 2H), 3.07 & 2.90 (s, 3H),
2.29 & 2.11 (s, 3H). Observed complexity is due to the
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
C
4.01.
17H13F4NO2 (339.29): C 60.18, H 3.86; found: C 60.22, H
170.8 & 170.5, 150.5 (m), 150.3, 145.8 (dm, J ¼ 250.6 Hz),
143.8 (dm, J ¼ 247.8 Hz), 137.5, 124.0, 123.7 & 123.6, 117.8 &
116.8 (t, J ¼ 16.6 Hz), 116.1 & 114.9 (t, J ¼ 17.2 Hz), 42.7 &
39.9, 26.4 & 32.6, 21.8 & 21.1. Observed complexity is due to
the mixture of rotamers. Elemental analysis: calcd (%) for
4.15. N-((20-Cyano-2,3,5,6-tetrafluoro-[1,10-biphenyl]-4-yl)
methyl)-N-methylacetamide (7)
C
15H12F4N2O (312.27): C 57.70, H 3.87; found: C 57.89, H
Following the general procedure B using N-methyl-N-
3.62.
(2,3,5,6-tetrafluorobenzyl)acetamide
(c)
(176
mg,
0.75 mmol) and 2-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 70-30) to afford the desired compound
7 (148 mg, 88%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
4.18. N-((40-Cyano-2,3,6-trifluoro-[1,10-biphenyl]-4-yl)
methyl)-N-methylacetamide (10)
Following the general procedure B using N-methyl-N-
(2,3,5-trifluorobenzyl)acetamide (d) (163 mg, 0.75 mmol)
and 4-bromobenzonitrile (91 mg, 0.5 mmol), the residue
was purified by flash chromatography on silica gel (hep-
tane-EtOAc, 70-30) to afford the desired compound 10
(126 mg, 79%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.89e7.81 (m,1H), 7.79e7.70 (m,1H), 7.66e7.58 (m,
1H), 7.53e7.44 (m, 1H), 4.79 & 4.71 (s, 2H), 3.08 & 2.93 (s,
3H), 2.17 & 2.14 (s, 3H). Observed complexity is due to the
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d
(ppm)
170.8 & 170.6, 145.7 (dm, J ¼ 249.3 Hz), 143.5 (dm, J ¼
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
9
d
(ppm) 7.80e7.70 (m, 2H), 7.63e7.43 (m, 2H), 7.05e6.76
(m, 1H), 4.66 & 4.63 (s, 2H), 3.08 & 2.00 (s, 3H), 2.17 (s, 3H).
Observed complexity is due to the mixture of rotamers. 13
NMR (100 MHz, CDCl3)
(ppm) 171.3 & 171.1, 154.8 (dm, J ¼
chromatography on silica gel (heptane-EtOAc, 60-40) to
afford the desired compound 13 (117 mg, 61%) as yellow
solid (Mp ¼ 150e152 ꢁC): 1H NMR (400 MHz, CDCl3)
C
d
d
(ppm) 8.31 (d, J ¼ 8.8 Hz, 2H), 7.66 (d, J ¼ 8.7 Hz, 2H),
247.4 Hz), 147.6 (ddd, J ¼ 7.1, 15.2, 252.2 Hz), 146.0 (ddd, J ¼
3.7, 13.9, 245.0 Hz), 133.2 & 132.8, 132.3 & 132.2, 131.0 (m),
127.7 (dd, J ¼ 8.8, 14.2 Hz), 118.5 & 118.4, 117.2 (dd, J ¼ 14.7,
20.2 Hz), 112.9 & 112.6, 111.6 & 109.5 (td, J ¼ 3.4, 25.5 Hz),
48.2 & 44.5, 36.6 & 34.0, 21.8 & 21.4. Observed complexity
is due to the mixture of rotamers. Elemental analysis: calcd
(%) for C17H13F3N2O (318.29): C 64.15, H 4.12; found: C
64.21, H 4.01.
7.52e7.40 (m, 5H), 7.09e6.83 (m, 2H), 4.77 & 4.57 (brs, 2H),
3.08 & 3.00 (brs, 3H). Observed complexity is due to the
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
172.0, 160.1 (d, J ¼ 249.2 Hz), 147.7, 141.2, 135.6, 131.4, 130.2,
128.7, 127.2 (m), 124.1, 123.7, 123.6, 111.4 (m), 50.6, 37.3.
Elemental analysis: calcd (%) for C21H16F2N2O3 (362.38): C
65.97, H 4.22; found: C 66.12, H 4.45.
4.22. N-((2,6-Difluoro-40-formyl-[1,10-biphenyl]-4-yl)
methyl)-N-methylbenzamide (14)
4.19. Ethyl 20,30,60-trifluoro-4'-((N-methylacetamido)methyl)-
[1,10-biphenyl]-4-carboxylate (11)
Following the general procedure
difluorobenzyl)-N-methylbenzamide
B
(e)
using N-(3,5-
(196 mg,
Following the general procedure B using N-methyl-N-
(2,3,5-trifluorobenzyl)acetamide (d) (163 mg, 0.75 mmol)
and ethyl 4-bromobenzoate (115 mg, 0.5 mmol), the res-
idue was purified by flash chromatography on silica gel
(heptane-EtOAc, 70-30) to afford the desired compound 11
(135 mg, 75%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
0.75 mmol) and 4-bromobenzaldehyde (93 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 70-30) to afford the desired compound
14 (98 mg, 54%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d
(ppm) 10.07 (s, 1H), 7.97 (d, J ¼ 8.3 Hz, 2H), 7.65 (d, J ¼
d
(ppm) 8.16e8.07 (m, 2H), 7.57e7.46 (m, 2H), 6.94 & 6.78
8.0 Hz, 2H), 7.56e7.37 (m, 5H), 7.12e6.76 (m, 2H), 4.77 &
4.55 (s, 2H), 3.08 & 2.99 (s, 3H). Observed complexity is due
to the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
(ddd, J ¼ 2.1, 5.4, 9.7 Hz, 1H), 4.66 & 4.62 (s, 2H), 4.40 (q, J ¼
5.8, 6.6 Hz, 2H), 3.06 & 2.99 (s, 3H), 2.17 (s, 3H), 1.40 (t, J ¼
7.1 Hz, 3H). Observed complexity is due to the mixture of
d
(ppm) 191.9, 172.9, 160.2 (d, J ¼ 252.3 Hz), 140.6, 138.3,
rotamers. 13C NMR (100 MHz, CDCl3)
d
(ppm) 171.3 & 171.0,
136.0, 135.8 (d, J ¼ 11.3 Hz), 131.1, 130.2, 130.2 (d, J ¼ 7.9 Hz),
129.7, 128.7, 127.1, 126.8, 111.4, 103.0, 52.9, 37.6. Elemental
analysis: calcd (%) for C22H17F2NO2 (365.38): C 72.32, H
4.69; found: C 72.21, H 4.56.
166.2, & 166.1, 155.0 (dm, J ¼ 249.4 Hz), 147.7 (ddd, J ¼ 7.5,
14.9, 251.4 Hz), 146.0 (ddd, J ¼ 3.7, 13.9, 244.3 Hz), 132.9 &
132.5, 130.9 & 130.7, 130.2 (m), 129.7 & 129.6, 126.8 & 126.2
(dd, J ¼ 8.8, 14.1 Hz), 118.2 (dd, J ¼ 15.0, 20.5 Hz), 111.4 &
109.4 (td, J ¼ 3.4, 25.6 Hz), 61.3, 48.2 & 44.3, 36.5 & 34.0,
21.8 & 21.4, 14.3. Observed complexity is due to the mixture
of rotamers. Elemental analysis: calcd (%) for C19H18F3NO3
(365.35): C 62.46, H 4.97; found: C 62.58, H 5.10.
4.23. Ethyl 20,60-difluoro-4'-((N-methylbenzamido)methyl)-
[1,10-biphenyl]-4-carboxylate (15)
Following the general procedure
difluorobenzyl)-N-methylbenzamide
B
(e)
using N-(3,5-
(196 mg,
4.20. N-((40-Cyano-2,6-difluoro-[1,10-biphenyl]-4-yl)methyl)-
N-methylbenzamide (12)
0.75 mmol) and ethyl 4-bromobenzoate (115 mg,
0.5 mmol), the residue was purified by flash chromatog-
raphy on silica gel (heptane-EtOAc, 60-40) to afford the
desired compound 15 (129 mg, 63%) as a colorless oil: 1H
Following the general procedure
difluorobenzyl)-N-methylbenzamide
B
(e)
using N-(3,5-
(196 mg,
NMR (400 MHz, CDCl3)
d
(ppm) 8.13 (d, J ¼ 8.4 Hz, 2H), 7.54
0.75 mmol) and 4-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 60-30) to afford the desired compound
12 (121 mg, 67%) as a white solid (Mp ¼ 123e125 ꢁC): 1H
(d, J ¼ 8.2 Hz, 2H), 7.48e7.41 (m, 5H), 7.06e6.81 (m, 2H),
4.76 & 4.60 (s, 2H), 4.41 (q, J ¼ 7.1 Hz, 2H), 3.09 & 2.98 (s,
3H), 1.41 (t, J ¼ 7.1 Hz, 3H). Observed complexity is due to
the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
NMR (400 MHz, CDCl3)
d
(ppm) 7.75 (d, J ¼ 8.5 Hz, 2H), 7.59
171.9, 166.4,160.3 (d, J ¼ 251.8 Hz),140.2,135.8,133.6,130.4,
(d, J ¼ 8.2 Hz, 2H), 7.51e7.42 (m, 5H), 7.08e6.79 (m, 2H),
4.77 &4.55 (s, 2H), 3.09 & 2.99 (s, 3H). Observed complexity
is due to the mixture of rotamers. 13C NMR (100 MHz,
130.1, 128.6, 128.7, 127.2 (brm), 111.2 (m), 61.2, 50.5, 37.6,
14.5. Elemental analysis: calcd (%) for
C24H21F2NO3
(409.43): C 70.41, H 5.17; found: C 70.58, H 5.29.
CDCl3)
d
(ppm) 171.7, 159.8 (d, J ¼ 253.4 Hz), 140.9, 135.4,
131.9, 131.0, 129.9, 128.5, 127.0, 118.5, 111.9, 111.4, 50.3, 37.5.
Elemental analysis: calcd (%) for C22H16F2N2O (362.38): C
72.92, H 4.45; found: C 73.08, H 4.21.
4.24. N-((40-Benzoyl-2,6-difluoro-[1,10-biphenyl]-4-yl)
methyl)-N-methylbenzamide (16)
Following the general procedure
difluorobenzyl)-N-methylbenzamide
0.75 mmol) and 4-bromobenzophenone (131 mg,
0.5 mmol), the residue was purified by flash chromatog-
raphy on silica gel (heptane-EtOAc, 60-40) to afford the
desired compound 16 (145 mg, 66%) as a brown oil: 1H
B
(e)
using N-(3,5-
(196 mg,
4.21. N-((2,6-Difluoro-40-nitro-[1,10-biphenyl]-4-yl)methyl)-
N-methylbenzamide (13)
Following the general procedure
B
using N-(3,5-
(196 mg,
difluorobenzyl)-N-methylbenzamide
(e)
0.75 mmol) and 1-bromo-4-nitrobenzene (101 mg,
NMR (400 MHz, CDCl3)
d (ppm) 7.96e7.80 (m, 4H),
0.5 mmol), the residue was purified by flash
7.68e7.56 (m, 4H), 7.56e7.39 (m, 6H), 6.95 (d, J ¼ 6.4 Hz,
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

10
M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
2H), 4.78 & 4.68 (s, 2H), 3.09 & 2.99 (s, 3H). Observed
19 (114 mg, 76%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d (ppm) 7.80e7.70 (m, 2H), 7.64e7.54 (m, 2H), 7.37 & 7.17
complexity is due to the mixture of rotamers. 13C NMR
(100 MHz, CDCl3)
d
(ppm) 196.2, 171.9, 160.2 (d, J ¼
(td, J ¼ 6.4, 8.4 Hz, 1H), 7.05 & 6.98 (td, J ¼ 1.3, 9.0 Hz, 1H),
250.2 Hz),140.3,137.5,137.3,135.7,135.5,133.3,132.6,130.3,
130.1, 130.1, 130.0, 128.6, 128.4, 127.2, 111.2 (m), 54.7 & 50.5,
37.6 & 33.5. Observed complexity is due to the mixture of
rotamers. Elemental analysis: calcd (%) for C28H21F2NO2
(441.48): C 76.18, H 4.79; found: C 75.98, H 4.51.
4.62 & 4.57 (s, 2H), 3.05 & 2.95 (s, 3H), 2.17 & 2.14 (s, 3H).
Observed complexity is due to the mixture of rotamers. 13
C
NMR (100 MHz, CDCl3)
d
(ppm) 171.1 & 171.0, 158.9 (dd, J ¼
6.4, 250.0 Hz), 157.7 (dd, J ¼ 6.5, 249.6 Hz), 134.2 & 133.7,
132.5e132.1 (m), 131.4e130.9 (m), 128.6 (dd, J ¼ 6.3,
10.1 Hz), 121.1 & 120.4 (dd, J ¼ 3.8, 16.6 Hz), 118.7 & 118.6,
116.5 (t, J ¼ 18.7 Hz), 112.3 & 112.0 (d, J ¼ 3.9 Hz), 112.2 (m),
48.4 & 44.5 (d, J ¼ 4.5 Hz), 36.4 & 33.6 (d, J ¼ 1.3 Hz), 21.9 &
21.4. Observed complexity is due to the mixture of rotam-
ers. Elemental analysis: calcd (%) for C17H14F2N2O (300.31):
C 67.99, H 4.70; found: C 68.23, H 4.67.
4.25. N-((20-Cyano-2,6-difluoro-[1,10-biphenyl]-4-yl)methyl)-
N-methylbenzamide (17)
Following the general procedure
difluorobenzyl)-N-methylbenzamide
B
using N-(3,5-
(196 mg,
(e)
0.75 mmol) and 2-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 60-40) to afford the desired compound
17 (76 mg, 42%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
4.28. N-((2,6-Difluoro-40-nitro-[1,10-biphenyl]-3-yl)methyl)-
N-methylacetamide (20)
d
(ppm) 7.80 (d, J ¼ 7.6 Hz, 1H), 7.69 (td, J ¼ 1.3, 7.7 Hz, 1H),
Following the general procedure
difluorobenzyl)-N-methylacetamide
B
(f)
using N-(2,4-
(149 mg,
7.54 (dt, J ¼ 1.0, 7.6 Hz, 1H), 7.49 (d, J ¼ 7.7 Hz, 2H),
7.46e7.41 (m, 4H), 7.09e6.86 (m, 2H), 4.79 & 4.56 (s, 2H),
3.09 & 2.00 (s, 3H). Observed complexity is due to the
0.75 mmol) and 1-bromo-4-nitrobenzene (101 mg,
0.5 mmol), the residue was purified by flash chromatog-
raphy on silica gel (heptane-EtOAc, 40e60) to afford the
desired compound 20 (88 mg, 55%) as a brown solid (Mp ¼
mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
172.5 & 172.1, 160.2 (d, J ¼ 254.7 Hz), 141.7, 135.6, 133.2,
132.7, 131.8, 130.1, 129.1, 128.7, 127.2, 117.7, 114.1, 111.8 (m),
110.2 (m), 54.7 & 50.5, 37.7 & 31.1. Observed complexity is
due to the mixture of rotamers. Elemental analysis: calcd
(%) for C22H16F2N2O (362.38): C 72.92, H 4.45; found: C
73.13, H 4.58.
90e93 ꢁC): 1H NMR (400 MHz, CDCl3)
d (ppm) 8.34e8.28
(m, 2H), 7.64 (d, J ¼ 8.7 Hz, 2H), 7.39 &7.20 (td, J ¼ 6.4,
8.4 Hz,1H), 7.07 & 7.00 (t, J ¼ 8.8 Hz,1H), 4.63 & 4.59 (s, 2H),
3.04 & 2.96 (s, 3H), 2.17 & 2.15 (s, 3H). Observed complexity
is due to the mixture of rotamers. 13C NMR (100 MHz,
CDCl3)
d
(ppm) 171.2, 159.0 (dm, J ¼ 250.4 Hz), 157.8 (dm, J
4.26. N-(3,5-Difluoro-4-(quinolin-3-yl)benzyl)-N-
methylbenzamide (18)
¼ 251.6 Hz), 147.8 & 147.7, 136.2 & 135.6, 131.5, 128.7 (m),
123.6 (m), 121.3 (d, J ¼ 16.7 Hz), 116.1 (t, J ¼ 18.6 Hz), 112.2
(m), 48.4 & 44.5, 36.5 & 33.7, 21.9 & 21.5. Observed
complexity is due to the mixture of rotamers. Elemental
analysis: calcd (%) for C16H14F2N2O3 (320.30): C 60.00, H
4.41; found: C 60.29, H 4.42.
Following the general procedure
difluorobenzyl)-N-methylbenzamide
B
(e)
using N-(3,5-
(196 mg,
0.75 mmol) and 3-bromoquinoline (104 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 60-40) to afford the desired compound 18
(113 mg, 58%) as a yellow solid (Mp ¼ 154e156 ꢁC): 1H NMR
4.29. N-((30-Cyano-2,6-difluoro-[1,10-biphenyl]-3-yl)methyl)-
N-methylacetamide (21)
(400 MHz, CDCl3) d (ppm) 9.00 (s, 1H), 8.30 (s, 1H), 8.16 (d, J
¼ 8.4 Hz, 1H), 7.88 (d, J ¼ 7.9 Hz, 1H), 7.81e7.73 (m, 1H),
7.64e7.57 (m, 1H), 7.54e7.39 (m, 5H), 7.11e6.84 (m, 2H),
4.80 & 4.58 (s, 2H), 3.11 & 3.01 (s, 3H). Observed complexity
is due to the mixture of rotamers. 13C NMR (100 MHz,
Following the general procedure
difluorobenzyl)-N-methylacetamide
0.75 mmol) and 3-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 50-50) to afford the desired compound
21 (98 mg, 65%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
B
(f)
using N-(2,4-
(149 mg,
CDCl3)
d
(ppm) 171.8 (brs), 160.4 (d, J ¼ 252.0 Hz), 151.1,
147.5 & 147.4, 140.5 (brs), 137.4, 135.6 & 135.3, 130.1, 130.0,
129.3 & 129.2, 128.5, 128.1 & 127.9, 127.6, 127.3 & 127.0,
122.4, 114.1 (t, J ¼ 21.2 Hz), 111.4 (d, J ¼ 24.7 Hz), 110.3 (m),
54.4 & 50.4, 37.4 & 33.4. Observed complexity is due to the
mixture of rotamers. Elemental analysis: calcd (%) for
d
(ppm) 7.76 (s, 1H), 7.74e7.65 (m, 2H), 7.63e7.52 (m, 1H),
7.38 & 7.17 (td, J ¼ 6.5, 8.4 Hz, 1H), 7.05 & 6.99 (td, J ¼ 1.3,
9.0 Hz, 1H), 4.63 & 4.58 (s, 2H), 3.03 & 2.96 (s, 3H), 2.17 &
2.15 (s, 3H). Observed complexity is due to the mixture of
C
24H18F2N2O (388.42): C 74.21, H 4.67; found: C 74.28, H
rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm) 171.2 & 171.1,
4.51.
159.0 (dd, J ¼ 6.4, 249.7 Hz), 157.8 (dd, J ¼ 6.5, 249.4 Hz),
134.9 & 134.8, 134.0 & 133.9, 132.1 &131.9, 131.1 (dd, J ¼ 6.3,
10.1 Hz), 133.7 & 130.3, 129.4 & 129.3, 128.4 (dd, J ¼ 6.3,
10.1 Hz), 121.1 & 120.4 (dd, J ¼ 3.8, 16.6 Hz), 118.6 & 118.4,
116.1 (t, J ¼ 18.8 Hz), 113.0 & 112.8, 112.3 & 112.1 (d, J ¼
3.9 Hz), 112.2 & 112.0 (d, J ¼ 3.9 Hz), 48.4 & 44.5 (d, J ¼
4.5 Hz), 36.4 & 33.7 (d, J ¼ 1.4 Hz), 21.9 & 21.4. Observed
complexity is due to the mixture of rotamers. Elemental
analysis: calcd (%) for C17H14F2N2O (300.31): C 67.99, H
4.70; found: C 67.91, H 4.65.
4.27. N-((40-Cyano-2,6-difluoro-[1,10-biphenyl]-3-yl)methyl)-
N-methylacetamide (19)
Following the general procedure
difluorobenzyl)-N-methylacetamide
0.75 mmol) and 4-bromobenzonitrile (91 mg, 0.5 mmol),
the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 50-50) to afford the desired compound
B
(f)
using N-(2,4-
(149 mg,
Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001

M. Elhadi Benhalouche et al. / C. R. Chimie xxx (xxxx) xxx
11
[5] V. Gouverneur, R. Szpera, D.F.J. Moseley, L.B. Smith, A.J. Sterling,
Angew. Chem. Int. Ed. (2019), https://doi.org/10.1002/
anie.201814457.
4.30. N-(2,4-Difluoro-3-(quinolin-3-yl)benzyl)-N-
methylacetamide (22)
[6] a) F. Kakiuchi, T. Kochi, Synthesis (2008) 3013e3039;
b) T. Satoh, M. Miura, Synthesis (2010) 3395e3409;
c) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Commun. 46 (2010) 677e685;
d) S.H. Cho, J.Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 40 (2011)
5068e5083;
Following the general procedure
difluorobenzyl)-N-methylacetamide
0.75 mmol) and 3-bromoquinoline (104 mg, 0.5 mmol), the
residue was purified by flash chromatography on silica gel
(heptane-EtOAc, 50-50) to afford the desired compound 22
(95 mg, 58%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
B
(f)
using N-(2,4-
(149 mg,
e) N. Kuhl, M.N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew.
Chem. Int. Ed. 51 (2012) 10236e10254;
f) B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 41 (2012) 5588e5598;
g) J. Wencel-Delord, F. Glorius, Nat. Chem. 5 (2013) 369;
h) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv. Synth. Catal. 356
(2014) 17e117;
i) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front.
1 (2014) 843e895;
j) M.R. Yadav, R.K. Rit, M. Shankar, A.K. Sahoo, Asian J. Org. Chem. 4
(2015) 846e864;
d
(ppm) 9.30 (d, J ¼ 2.3 Hz, 1H), 8.47 (d, J ¼ 2.1 Hz, 1H), 8.19
(d, J ¼ 8.5 Hz, 1H), 7.95 (d, J ¼ 8.0 Hz, 1H), 7.78 (ddd, J ¼ 1.4,
6.9, 8.4 Hz, 1H), 7.71e7.58 (m, 1H), 7.39e7.28 & 7.18e7.08
(m, 1H), 6.95e6.73 (m, 1H), 4.58 & 4.51 (s, 2H), 2.97 & 2.91
(s, 3H), 2.16 & 2.13 (s, 3H). Observed complexity is due to
k) K. Hirano, M. Miura, Chem. Lett. 44 (2015), 878-873;
the mixture of rotamers. 13C NMR (100 MHz, CDCl3)
d (ppm)
ꢀ
l) C.B. Bheeter, L. Chen, J.-F. Soule, H. Doucet, Catal. Sci. Technol. 6
171.0, 162.4 (dd, J ¼ 11.8, 248.5 Hz), 161.2 (dd, J ¼ 11.9,
248.3 Hz), 149.7 & 147.8, 134.0, 131.8 (dd, J ¼ 5.9, 9.6 Hz),
130.9, 130.1, 129.5, 129.1 (dd, J ¼ 5.8, 9.7 Hz), 128.2, 128.0,
127.6, 120.4 (d, J ¼ 11.5 Hz), 111.8 & 111.7 (dd, J ¼ 3.8,
21.1 Hz), 104.5 & 103.5 (t, J ¼ 25.4 Hz), 48.1 & 43.9 (d, J ¼
3.8 Hz), 36.1 & 22.6, 21.9 & 21.4. Observed complexity is due
to the mixture of rotamers. Elemental analysis: calcd (%) for
(2016) 2005e2049;
m) T. Cernak, K.D. Dykstra, S. Tyagarajan, P. Vachal, S.W. Krska,
Chem. Soc. Rev. 45 (2016) 546e576;
n) S. Sengupta, G. Mehta, Tetrahedron Lett. 58 (2017) 1357e1372;
o) X. Lu, S.-J. He, W.-M. Cheng, J. Shi, Chin. Chem. Lett. 29 (2018)
1001e1008;
p) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz,
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ꢀ
q) S. Mao, H. Li, X. Shi, J.-F. Soule, H. Doucet, ChemCatChem 11
(2019) 269e286.
C
19H16F2N2O (326.35): C 69.93, H 4.94; found: C 70.22, H
[7] a) M. Lafrance, C.N. Rowley, T.K. Woo, K. Fagnou, J. Am. Chem. Soc.
128 (2006) 8754e8756;
5.28.
b) M. Lafrance, D. Shore, K. Fagnou, Org. Lett. 8 (2006) 5097e5100;
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11922e11932;
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Acknowledgements
The authors thank the Algerian “Ministry of Higher
Education and Scientific Research” for a fellowship to M.E.B.
and the CNRS and Universite Rennes-1 for financial sup-
port. H.-Y. H. thanks the China Scholarship Council for
fellowships.
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c) Y. Wang, K. Zhou, Q. Lan, X.-S. Wang, Org. Biomol. Chem. 13
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Please cite this article as: M. Elhadi Benhalouche et al., Reactivity of N-methyl-N-(polyfluorobenzyl)acetamides and N-methyl-N-
(polyfluorobenzyl)benzamides in Pd-catalyzed CeH bond arylation, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.10.001