Reactivity of (poly)fluorobenzamides in palladium-catalysed direct arylations

Article abstract of DOI:10.1039/c6ra12165a

The influence of fluoro-substituents on secondary and tertiary benzamides on the regioselectivity of palladium-catalysed direct arylations was studied. With most (poly)fluoro-substituted tertiary benzamides, the arylations proceed very regioselectively at ortho-positions of the fluoro substituents using 1 mol% of air-stable palladium catalysts and PivOK/DMA as the reaction conditions. With the 3,5-difluoro-substituted secondary benzamides, quite regioselective arylations at C4-positions were observed. For these reactions, a variety of substituents on the aryl bromide, such as ester, propionyl, acetyl, formyl, nitro, nitrile, trifluoromethyl, chloro, fluoro or methyl, was tolerated. These results reveal that under our reaction conditions, fluoro substituents act as better directing groups than amides in the palladium-catalysed direct arylations.

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Reactivity of (poly)fluorobenzamides in palladium-catalysed direct
arylations
Nouria Laidaoui,a,b,c Mian He,a Douniazad El Abed,*,b Jean-François Soulé,*,a and Henri Doucet*,a
Received 00th January 20xx,
Accepted 00th January 20xx
The influence of fluoro-substituents on secondary and tertiary benzamides on the regioselectivity of palladium-catalysed
direct arylations was studied. With most (poly)fluoro-substituted tertiary benzamides, the arylations proceed very
regioselectively at ortho-positions of the fluoro substituents using 1 mol% of air-stable palladium catalysts and PivOK/DMA
as the reaction conditions. With the 3,5-difluoro-substituted secondary benzamides, quite regioselective arylations at C4-
positions were observed. For these reactions, a variety of substituents on the aryl bromide, such as ester, propionyl,
acetyl, formyl, nitro, nitrile, trifluoromethyl, chloro, fluoro or methyl was tolerated. These results reveal that under our
reaction conditions, fluoro substituents act as better directing groups than amides in the palladium-catalysed direct
arylations.
DOI: 10.1039/x0xx00000x
www.rsc.org/
substituted biaryls.1 However, such couplings require the
preliminary synthesis of organometallic derivatives.
Moreover, they provide a stoichiometric amount of metallic
Introduction
Several bioactive compounds contain both amide and fluoro
substituents on arenes. For example, Vidofludimus is an oral
immunomodulator inhibiting dihydroorotate dehydrogenase,
Radezolid is an antibiotic developed for the treatment of
multi-drug–resistant infections and Flumazenil is used to treat
benzodiazepine overdoses (Fig. 1). Therefore, the discovery of
general simple routes for access to amide-substituted
fluorobenzene derivatives has potential for medicinal
chemistry.
salts as side-products. Fagnou et al. reported in 2006 the Pd-
catalysed direct arylation2 of polyfluorobenzenes,3 using aryl
halides as coupling partners (Scheme 1, a). Since these results,
the palladium-catalysed direct arylation of polyfluorobenzenes
with aryl halides has proved to be a powerful method for the
synthesis of a variety of polyfluoro-substituted biaryls.4 On the
other hand, Miura et al. reported in 2000 the Pd-catalysed C2-
arylation of benzamides (Scheme 1, b).5 Then, several groups
extended the C2-arylation of benzamides.6 The reports of
Fagnou and Miura revealed that both fluoro and amide-
substituents on benzenes act as directing groups for such
couplings. However, little is known on the reactivity of fluoro-
substituted benzamides in palladium-catalysed direct
arylation. Chatani et al. reported in 2014 that the Ni-catalysed
direct arylation of a 4-fluorobenzamide containing an 8-
aminoquinoline moiety proceeds at ortho-position of the
OMe
F
F
N
CO2H
HN
N
CO2Et
N
O
Vidofludimus
O
Flumazenil
O
N
N
NH
NH
F
HN
amide group (Scheme 1, c).7 An
α-amino ester (or acid) moiety
N
O
Radezolid
also acts as directing group for selective Pd-catalysed ortho-C-
H activation of fluorobenzamides (Scheme 1, d and e).8
Weinreb amide was also successfully employed as directing
group to promote the C2-arylation of a 4-fluorobenzamide
derivative (Scheme 1, f).9 Finally, Ackermann et al. reported in
2015 Co-catalysed direct C2-arylation of a 4-fluorobenzamide
(Scheme 1, g).10 It should be mentioned that to our
knowledge, so far no examples of direct arylation at ortho-
position of fluoro-substituents of fluorobenzamides has been
reported. Therefore, the discovery of a procedure allowing a
general access with a high regioselectivity to such biaryls is
desirable.
O
Figure 1. Examples of bioactive amide containing fluorobenzenes
Pd-catalysed reactions such as Suzuki or Negishi couplings
allow the formation of a wide variety of fluoro- or amide-
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Herein, starting from a set of (poly)fluorobenzamides as the fluoro-substituent than that of the tertiary amide
reactants, we report i) on the reactivity and regioselectivity of substituent (Scheme 2, top). It should be mentioned that
benzene derivatives containing both fluoro and secondary or when the fluoro substituent on N,N-diethyl-4-fluorobenzamide
tertiary amide substituents; ii) on the access to a variety of was replaced by chloro- or methoxy-substituents, under the
amide-substituted (poly)fluorobiphenyls using a variety of aryl same conditions using again 4-bromonitrobenzene as coupling
bromides as coupling partners (Scheme 1, bottom).
partner, only traces (<5%) of coupling products were detected
by GC/MS analysis of the crude mixtures. These results
confirm the strong directing and activating effect of a fluoro
substituent on benzenes. From a mixture of N,N-diethyl-3-
fluorobenzamide and 4-bromonitrobenzene, under the same
a) Fagnou3
F
F
Pd(OAc)2 5 mol%
PtBu2Me HBF4 10 mol%
H
+
Br
Br
K2CO3, DMA, 120 °C
reaction conditions, only the coupling product 2, arising from
F
F
coupling at para-position from the amide substituent was
isolated (Scheme 2, middle). N,N-diethyl-2-fluorobenzamide
and 4-bromonitrobenzene was also arylated regioselectively at
85%
b) Miura5
O
O
O
NHPh
NHPh
Pd(OAc)2 5 mol%
PPh3 30 mol%
the ortho-position of the fluoro-substituent affording
3 in 28%
H
+
yield (Scheme 2, bottom). These three reactions gave poor
yields due to partial conversions of the aryl bromides, however
they clearly demonstrate that, under these conditions, fluoro-
substituents act as better directing groups than tertiary amides
in the Pd-catalysed direct arylation of fluorobenzamides.
According to Gorelsky,11c the fluorine substituents on arenes,
Cs2CO3, DMF, 110 °C
37%
c) Chatani7
O
NHR
NHR
Ni(OTf)2 2.5 mol%
H
+
I
NaHCO3, toluene,
160 °C
96%
F
R = 8-aminoquinoline
d) Chatani8a
F
especially at the ortho-position, favour
a
Concerted
Metallation Deprotonation (CMD) transformation.11
O
CO2Me
NH
H
NEt2
O
O
O
CO2Me
Br
Pd(OAc)2 10 mol%
NH
F
+ I
Br
AgOAc, t-Amyl-OH,
NEt2
H
100 °C
O
F
PdCl2 1 mol%
F
e) Chen8b
39%
NH
NO2
1.5 equiv.
PivOK, DMA,
150 °C, 16 h
O
CO2H
CO2H
+
F
NH
H
1 32%
Br
NO2
Pd(OAc)2 10 mol%
+ I
NaOAc, DMSO, 120 °C
1 equiv.
O
77%
F
F
F
f) Wang9
OMe
NEt2
H
O
O
O
OMe
NEt2
N
N
Pd(OAc)2 5 mol%
H
+ I
PdCl2 1 mol%
F
HOTf, AgOTF, DCE,
80 °C
1.5 equiv.
71%
NH
F
PivOK, DMA,
150 °C, 16 h
F
+
g) Ackermann10
2
31%
Br
NO2
H
O
O
O2N
NH
Co(acac)2 / N-heterocyclic
carbene 10 mol%
1 equiv.
H
+Cl
H
CyMgCl, DMPU, 60 °C
53%
F
F
This work
F
Et2N
F
PdCl2 1 mol%
O
F
[Pd]
NO2
+
Br
1.5 equiv.
O
O
PivOK, DMA,
150 °C, 16 h
R'
R'
base
+
Et2N
F
3
28%
NR2
NR2
O
Br
NO2
Scheme 1. Metal-catalysed direct arylation of fluoro- and/or amide-
substituted benzenes
1 equiv.
Scheme 2. Regioselectivity of palladium-catalysed direct arylation of
a set of N,N-diethylfluorobenzamides.
Results and discussion
The use of N,N-diethyl-3,5-difluorobenzamide and 4-
bromobenzonitrile as the coupling partners in the presence of
1 mol% Pd(OAc)2 catalyst and AcOK as the base at 150 °C in
DMA selectively gave the coupling product 4a, arising from a
regioselective coupling at C4 position, which is flanked by the
We
first
examined
the
reaction
of
N,N-
diethylfluorobenzamides with 4-bromonitrobenzene (Scheme
2). N,N-diethyl-4-fluorobenzamide and 4-bromonitrobenzene
in the presence of 1 mol% PdCl2 using PivOK as base/ligand,
gave regioselectively 1, revealing a better directing effect of
2 | J. Name., 2012, 00, 1-3
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two fluoro substituents, in 63% yield with 100% conversion of bromides (Scheme 3). The electron-deficient para-substituted
the aryl bromide (Table 1, entry 1). It is known that the aryl bromides, 4-bromopropiophenone, 4-bromonitrobenzene,
presence of additional fluoro substituents on the arene ethyl 4-bromobenzoate and 4-trifluoromethylbromobenzene
amplifies the acidity of the C-H bond at their ortho-position regioselectively gave the desired products
and leads to a lower CMD activation energy.11c The influence yields. A high yield of 83% in
5-8 in 81-88%
9
was also obtained using 4-
of some reaction conditions was investigated. The use of chlorobromobenzene as reaction partner. Moreover, no
PivOK as the base for the reaction with 4-bromobenzonitrile cleavage of the C-Cl bond was observed, allowing further
allowed to increase the yield in 4a from 63% to 77% by transformations.
Even 4-fluorobromobenzene was
reduction of 4-bromobenzonitrile homo-coupling side-product successfully coupled with N,N-diethyl-3,5-difluorobenzamide
formation (Table 1, entry 2). On the contrary, the use of K2CO3 to provide 10 in 76% yield. Meta-substituted aryl bromide, 3-
as base, which had been found to be very effective by Fagnou nitrobenzene gave 11 in 88% yield. Both 2-bromonaphthalene
and co-workers for the arylation of 1,3-difluorobenzene using and 2-bromobenzonitrile also gave the desired products 12
5 mol% Pd(OAc)2 associated to 10 mol% PtBu2Me.HBF4 as and 13 in high yields. We also employed two heteroaryl
catalyst (Scheme 1, a), gave 4a in only 24% yield due to a poor bromides. From 3-bromopyridine and 3-bromoquinoline,
conversion of 4-bromobenzonitrile (Table 1, entry 3).3 Then, regioselective reactions were also observed affording 14 and
we examined the influence of several other reaction 15 in 61% and 87% yields, respectively. Electron-rich aryl
conditions for this coupling. The use of 1 mol% PdCl2 catalyst bromide, 4-bromotoluene also led to a good yield of 78% in
instead of Pd(OAc)2 gave 4a in a slightly higher yield of 80% the biaryl derivative 16
.
(Table 1, entry 4). On the other hand, the use of both DMF
and NMP as the solvents, with PivOK as the base, afforded 4a
in lower yields, and both xylene and pentan-1-ol were
ineffective for this reaction (Table 1, entries 5-8). A lower
catalyst loading of 0.5 mol% of PdCl2 was also employed using
DMA as the solvent, affording 4a in 79% yield (Table 1, entry
9). In all cases, no formation of the other regioisomer 4b was
detected by GC/MS analysis of the crude mixtures; whereas,
some 4-bromobenzonitrile homo-coupling side-product
formation was observed.
F
O
H
Et2N
F
F
F
O
PdCl2 1 mol%
1.5 equiv.
+
R
PivOK, DMA,
150 °C, 16 h
Et2N
Br
5-16
R
1 equiv.
F
F
F
O
O
O
NO2
Et2N
Et2N
F
F
5 85%
6 82%
Table 1. Influence of the reaction conditions for the palladium-
catalysed direct arylation of N,N-diethyl-3,5-difluorobenzamide
with 4-bromobenzonitrile.[a]
F
O
O
CO2Et
CF3
Et2N
Et2N
7 88% F
9 83%
8 81% F
F
F
O
O
Cl
F
Et2N
Et2N
F
F
10 76%
F
NO2
F
O
O
Et2N
11 88%
Et2N
12 84%
F
F
F
F
CN
F
F
Catalyst
(mol%)
Yield in 4a
Entry
Base
Solvent
Conv. (%)
O
O
(%)
Et2N
Et2N
N
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (1)
Pd(OAc)2 (1) PivOK
Pd(OAc)2 (1) K2CO3
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (0.5)
AcOK
DMA
DMA
DMA
DMA
DMF
100
100
46
100
100
100
<10
85
63
77
24
80
58
67
<5
<5
79
13 85%
14 61%
F
F
O
O
PivOK
PivOK
PivOK
PivOK
PivOK
PivOK
Me
Et2N
N
Et2N
F
F
15 87%
16 78%
NMP
xylene
pentan-1-ol
DMA
Scheme 3. Palladium-catalysed direct 4-arylation of N,N-diethyl-3,5-
difluorobenzamide.
100
[a]
4-Bromobenzonitrile
(1
equiv.),
N,N-diethyl-3,5- We then studied the reactivity of N,N-diethyl-2,4-
difluorobenzamide (1.5 equiv.), base (2 equiv.), 16 h, 150 °C.
difluorobenzamide and N,N-diethyl-2,4,5-trifluorobenzamide
(Scheme 4). Again, regioselective arylations at the C-H bonds
flanked by the two fluorine atoms was observed. The two
electron-deficient aryl bromides, 4-bromonitrobenzene and 4-
bromobenzonitrile were successfully employed with N,N-
In order to assess the full scope of the aryl bromide coupling
partner for reaction with N,N-diethyl-3,5-difluorobenzamide,
we undertook a systematic study with a set of (hetero)aryl
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diethyl-2,4-difluorobenzamide, affording 17 and 18 in 79% and conditions. The reaction of N-n-butyl-3,5-difluorobenzamide
81% yields, respectively. N,N-Diethyl-2,4,5-trifluorobenzamide with 4-bromobenzonitrile using PivOK as base in DMA gave a
was regioselectively arylated by 4-bromobenzonitrile, 2-(4- mixture of 25a and 25b in 70:30 ratio (Table 2, entry 1). Under
bromophenyl)acetonitrile and 3-bromoquinoline at C3- these conditions, the C-H bond flanked by two fluorine atoms
position to provide 19-21 in 53-81% yields. An additional atom was the most reactive. The use of a mixture of PivOK and
at C5-position of the benzamide derivative exhibits a minor Cs2CO3 as base in DMA led to products 25a and 25b in 10:90
effect on the reactivity and has no effect on the ratio, but with a low conversion of 4-bromobenzonitrile. Less
regioselectivity, as C6-arylated benzamide was not detected.
polar solvents such as xylene or chlorobenzene afforded larger
amounts of product 25b than the reactions performed in DMA
(Table 2, entries 7 and 10). These results seem to indicate that
the formation of regioisomer 25b comes from a coordination
assisted mechanism due to amide deprotonation by the
base;12 whereas, the formation of 25a certainly proceeds via a
concerted-metallation-deprotonation mechanism (CMD).
Table 2. Influence of the reaction conditions for the palladium-catalysed direct
arylation of N-n-butyl-3,5-difluorobenzamide with 4-bromobenzonitrile.[a]
Scheme 4. Palladium-catalysed direct 3-arylation of N,N-
diethyl-2,4-difluorobenzamide
trifluorobenzamide.
and
N,N-diethyl-2,4,5-
The arylation of N,N-diethyl-2,3-difluorobenzamide led to a
regioselective arylation in favour of the C-H bond flanked by
one fluorine atom (Scheme 5). From 4-bromoacetophenone
and 4-bromonitrobenzene, products 22 and 23 were obtained
in 61% and 64% yields, respectively. Surprisingly, N,N-diethyl-
3,4-difluorobenzamide was regioselectively arylated at C5
affording 24 in low yield. These results confirm that a tertiary
amide substituent on benzene acts as a poor directing group
compared to fluoro substituents.
Catalyst
(mol%)
Additive
(equiv.)
Conv.
(%)
Ratio
25a:25b
Yield in
25a (%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
0.5
2
4
4
4
4
4
4
4
–
–
–
DMA
DMA
DMA
DMA
DMA
35
65
100
0
25
0
40
85
72
32
89
35
70:30
70:30
69:31
25
45
61
tBuOK (1)
Cs2CO3 (1)
PCy3 (0.08)
10:90
DMA
–
–
–
–
–
xylene
1,4-dioxane
CPME
ClC6H5
xylene
xylene
31:69
50:50
54:46
44:56
56:44
42:58
10
11[b]
12
4
4
4
F
F
Cs2CO3 (1)
F
F
O
[a] PdCl2, 4-bromobenzonitrile (1 equiv.), 2,4-difluorochlorobenzene (1.5
equiv.), base (2 equiv.), 16 h. [b] PdCl(C3H5)(dppb)13 was used instead of
PdCl2.
O
H
R
Et2N
+
PdCl2 1 mol%
1.5 equiv.
Et2N
R
COMe
NO2
DMA, PivOK,
150 °C, 16 h
Yield (%)
22 61
23 64
Then, we studied the reactivity of N-n-butyl-3,5-
difluorobenzamide with a set of aryl bromides (Scheme 6). In
all cases, mixtures of C2- and C4-arylated products were
obtained. The highest selectivity was obtained with quite
congested 2-bromobenzonitrile, as 28a was produced in 95%
regioselectivity and in 76% yield. The use of N-tert-butyl-3,5-
difluorobenzamide led to quite similar regioselectivities than
N-n-butyl-3,5-difluorobenzamide. For example, it’s coupling
with 4-bromobenzonitrile gave 29a and 29b in 76:24 ratio. In
the presence of 2-bromobenzonitrile, a regioselectivity of 88%
in 32a was obtained.
Br
R
1 equiv.
F
F
O
F
O
Et2N
PdCl2 1 mol%
F
Br
CN
Et2N
+
DMA, PivOK,
150 °C, 16 h
1 equiv.
H
24 36%
1.5 equiv.
CN
Scheme 5. Palladium-catalysed direct arylation of N,N-diethyl-2,3-
difluorobenzamide and N,N-diethyl-3,4-difluorobenzamide.
In order to compare the reactivity of tertiary and secondary
amides, the arylation of both N-n-butyl-3,5-difluorobenzamide
and N-tert-butyl-3,5-difluorobenzamide was explored (Table 2
and scheme 6). With both substrates, the formation of
mixtures of C2- and C4-arylated benzamides was observed.
The regioselectivity partially depends on the reaction
4 | J. Name., 2012, 00, 1-3
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To better understand the amine substituent influence on the
catalyst for such couplings, we performed a competition
reaction (Scheme 8). From an equimolar mixture of 3,5-
difluorobenzamide and N,N-diethyl-3,5-difluorobenzamide
using 4-bromobenzonitrile as the coupling partner, in the
presence of 4 mol% PdCl2, only the formation of 2a arising
from coupling with N,N-diethyl-3,5-difluorobenzamide was
detected in very low yield. The partial conversion of 4-
bromobenzonitrile reveals that the non-reactivity of 3,5-
difluorobenzamide is certainly due to a partial poisoning of the
catalyst by 3,5-difluorobenzamide.
F
F
F
F
O
O
H
R
HN
R
HN
R
+
26a-33a
PdCl2 4 mol%
R
1.5 equiv.
+
PivOK, DMA,
150 °C, 16 h
F
Br
O
R
1 equiv.
HN
R
F
26b-33b
F
F
F
O
O
O
NO2
HN
HN
nBu
nBu
F
26a 68% (26a:26b 79:21)
27a 70% (27a:27b 81:19)
F
F
CN
O
O
CN
HN
HN
tBu
F
nBu
F
29a 66% (29a:29b 76:24)
28a 76% (28a:28b >95:5)
Scheme 8. Competition reaction using an equimolar mixture of 3,5-
F
F
O
O
O
difluorobenzamide and N,N-diethyl-3,5-difluorobenzamide.
NO2
HN
HN
tBu
F
tBu
F
Conclusions
30a 70% (30a:30b 83:17)
31a 66% (31a:31b 79:21)
In summary, the Pd-catalysed direct arylation of 3,5-difluoro-
substituted secondary benzamides, affords mixtures of
F
F
F
CN
O
O
regioisomers; and
a
3,5-difluoro-substituted primary
HN
N
HN
benzamide was found to be unreactive. On the other hand,
fluoro substituents act as better directing groups than tertiary
amides in the palladium-catalysed direct arylation of
(poly)fluorobenzamides. With tertiary benzamides, high
regioselectivities in favour of arylations at the C-H bond
flanked by the fluorine atoms were obtained. To our
knowledge these are the first examples of metal-catalysed
direct arylations at ortho-position of fluoro-substituents of
(poly)fluorobenzamides. These arylations were performed
using only 1 mol% of a commercially available air-stable
catalyst. Moreover, a variety of substituents on the aryl
bromide such as ester, propionyl, acetyl, formyl, nitro, nitrile,
trifluoromethyl, chloro, fluoro or methyl was tolerated. The
major by-products of such couplings are a base associated to
HBr; moreover the method avoids the preliminary preparation
of organometallic derivatives reducing the number of steps to
prepare these compounds. For these reasons, this process
gives an simple and environmentally attractive access to
arylated (poly)fluorobenzamides.
tBu
F
tBu
32a 63% (32a:32b 88:12)
33a 64% (33a:33b 76:24)
Scheme 6. Palladium-catalysed direct 4-arylation of N-n-butyl-
3,5-difluorobenzamide
difluorobenzamide.
and
N-tert-butyl-3,5-
It should be mentioned that, under the same reaction
conditions, the primary benzamide 3,5-difluorobenzamide was
found to be completely unreactive, as no formation of 34 was
detected (Scheme 7). The Hammet constants14 of amide
substituents on benzenes (Scheme 7) seems to reveal that the
difference of reactivity of primary and secondary
difluorobenzamides does not come from electronic factors,
but more likely from the poisoning of the catalyst.
Experimental
DMA (N,N-dimethylacetamide) (99%) was purchased from Acros.
PdCl2 (99%) was purchased from Aldrich. These compounds were
not purified before use.
Scheme 7. Attempt of palladium-catalysed direct arylation of 3,5-
difluorobenzamide.
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Journal Name
General
procedure
for
the
synthesis
of
the 3.3 Hz), 127.6 (d, J = 13.2 Hz), 123.8, 122.7(d, J = 3.7 Hz), 114.8 (d, J
(poly)fluorobenzamides: The reaction of the (poly)fluorobenzoyl = 24.3 Hz), 43.4, 39.5, 14.3, 12.9.
chloride (10 mmol) and primary or secondary amine (10 mmol) at
25 °C during 16 h in NEt3 (15 mL) and CH2Cl2 (15 mL) affords the N,N-Diethyl-2-fluoro-4'-nitrobiphenyl-3-carboxamide (3) From 4-
(poly)fluorobenzamide after evaporation of the solvent and filtration on bromonitrobenzene (0.202 g,
silica gel. fluorobenzamide (0.292 g, 1.5 mmol), 3 was obtained in 28% (0.088
g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.33 (d, J = 8.2 Hz,
1
mmol) and N,N-diethyl-2-
δ
N,N-diethyl-2,4,5-trifluorobenzamide: The reaction of 2,4,5- 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.51 (td, J = 7.5, 1.8 Hz, 1H), 7.41 (td, J
trifluorobenzoyl chloride (1.94 g, 10 mmol) and diethylamine (0.730 g, = 7.5, 1.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 3.63 (m, 2H), 3.29 (q, J =
10 mmol) affords N,N-diethyl-2,4,5-trifluorobenzamide in 78% (1.80 g) 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H). 13C NMR
yield. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 7.14 (td, J = 6.0, 5.0 Hz, (100 MHz, CDCl3, 25 °C): δ = 165.6, 154.9 (d, J = 250.1 Hz), 147.5,
1H), 6.94 (dd, J = 6.2, 6.0 Hz, 1H), 3.51 (q, J = 7.6 Hz, 2H), 3.18 (q, J 141.6, 131.1 (d, J = 2.8 Hz), 129.9 (d, J = 3.3 Hz), 128.9 (d, J = 4.4
= 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H), 1.07 (t, J = 7.6 Hz, 3H). 13C Hz), 127.4 (d, J = 13.5 Hz), 126.5 (d, J = 20.0 Hz), 125.1 (d, J = 4.1
NMR (100 MHz, CDCl3, 25 °C):
δ = 163.9, 153.2 (ddd, J = 247.9, 19.5, Hz), 123.8, 43.1, 39.3, 14.1, 12.8. Elemental analysis: calcd (%) for
2.8 Hz), 150.5 (ddd, J = 254.0, 14.4, 12.0 Hz), 147.0 (ddd, J = 248.0, C17H17FN2O3 (316.32): C 64.55, H 5.42; found: C 64.69, H 5.57.
12.8, 3.8 Hz), 121.3 (dt, J = 21.2, 5.7 Hz), 116.7 (ddd, J = 19.1, 5.7,
1.4 Hz), 106.1 (dd, J = 27.8, 21.0 Hz), 43.1, 39.5, 14.0, 12.7.
4'-Cyano-N,N-diethyl-2,6-difluorobiphenyl-4-carboxamide
(4a)
From 4-bromobenzonitrile (0.182 g, 1 mmol) and N,N-diethyl-3,5-
N,N-diethyl-3,4-difluorobenzamide: The reaction
of
3,4- difluorobenzamide (0.320 g, 1.5 mmol), 4a was obtained in 80%
difluorobenzoyl chloride (1.76 g, 10 mmol) and diethylamine (0.730 g, (0.251 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
δ
= 7.76 (d, J = 8.1
10 mmol) affords N,N-diethyl-2,4,5-trifluorobenzamide in 72% (1.53 g) Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 3.55 (q, J =
yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.22-7.05 (m, 2H), 3.46 7.6 Hz, 2H), 3.33 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.20 (t, J
(q, J = 7.6 Hz, 2H), 3.22 (q, J = 7.6 Hz, 2H), 1.25-1.00 (m, 6H). 13C = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
= 167.9, 159.5
NMR (100 MHz, CDCl3, 25 °C): = 168.8, 151.7 (dd, J = 248.0, 12.0 (dd, J = 252.4, 6.8 Hz), 139.6 (t, J = 9.0 Hz), 133.3, 132.1, 131.0 (t, J
δ
δ
δ
Hz), 150.1 (dd, J = 250.7, 11.9 Hz), 134.0 (m), 122.8 (dd, J = 6.6, 4.0 = 2.0 Hz), 118.4, 117.4 (t, J = 18.1 Hz), 112.4, 110.3 (d, J = 27.6 Hz),
Hz), 117.4 (d, J = 17.5 Hz), 116.1 (d, J = 18.4 Hz), 43.3, 39.5, 13.9, 43.3, 39.5, 14.2, 12.8. Elemental analysis: calcd (%) for C18H16F2N2O
12.7.
(314.33): C 68.78, H 5.13; found: C 68.68, H 5.21.
General procedure for the synthesis of 1-33: The reaction of the N,N-Diethyl-2,6-difluoro-4'-propionylbiphenyl-4-carboxamide (5)
aryl bromide (1 mmol), (poly)fluorobenzamide derivative (1.5 mmol) From 4-bromopropiophenone (0.213 g, 1 mmol) and N,N-diethyl-3,5-
and PivOK (0.248 g, 2 mmol) at 150 °C during 16 h in DMA (3 mL) in difluorobenzamide (0.320 g, 1.5 mmol), 5 was obtained in 85% (0.293
the presence of PdCl2 (1.8 mg, 0.01 mmol or 7.1 mg 0.04 mmol) (see g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
schemes) under argon affords the arylation product after evaporation 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.2 Hz, 2H), 3.56 (m, 2H),
of the solvent and filtration on silica gel.
3.34 (m, 2H), 3.05 (q, J = 7.6 Hz, 2H), 1.30-1.15 (m, 9H). 13C NMR
(100 MHz, CDCl3, 25 °C): = 200.2, 168.2, 159.7 (dd, J = 251.8, 7.1
N,N-Diethyl-6-fluoro-4'-nitrobiphenyl-3-carboxamide (1) From 4- Hz), 138.9 (t, J = 9.0 Hz), 136.7, 133.1, 130.5, 127.9, 118.3 (t, J =
bromonitrobenzene (0.202 g, mmol) and N,N-diethyl-4- 18.5 Hz), 110.2 (d, J = 27.8 Hz), 43.3, 39.6, 31.9, 14.3, 12.8, 8.2.
fluorobenzamide (0.292 g, 1.5 mmol), 1 was obtained in 32% (0.101 Elemental analysis: calcd (%) for C20H21F2NO2 (345.38): C 69.55, H
g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.33 (d, J = 8.2 Hz, 6.13; found: C 69.30, H 6.04.
δ = 8.06 (d, J = 8.1 Hz,
δ
1
δ
2H), 7.74 (d, J = 8.2 Hz, 2H), 7.53 (dd, J = 7.3, 2.1 Hz, 1H), 7.48-7.42
(m, 1H), 7.25 (dd, J = 10.3, 8.2 Hz, 1H), 3.56 (m, 2H), 3.34 (m, 2H), N,N-Diethyl-2,6-difluoro-4'-nitrobiphenyl-4-carboxamide (6) From
1.50-1.00 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ
= 169.7, 4-bromonitrobenzene (0.202 g,
159.8 (d, J = 252.4 Hz), 147.5, 141.5, 134.1 (d, J = 4.0 Hz), 129.9 (d, difluorobenzamide (0.320 g, 1.5 mmol), 6 was obtained in 82% (0.274
J = 3.4 Hz), 129.1 (d, J = 3.2 Hz), 128.7 (d, J = 8.8 Hz), 127.1 (d, J = g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.32 (d, J = 8.1 Hz,
1 mmol) and N,N-diethyl-3,5-
δ
13.6 Hz), 123.9, 116.6 (d, J = 23.3 Hz), 43.3, 39.5, 14.2, 12.9. 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.7 Hz, 2H), 3.56 (m, 2H),
Elemental analysis: calcd (%) for C17H17FN2O3 (316.32): C 64.55, H 3.34 (m, 2H), 1.25 (m, 3H), 1.20 (m, 3H). 13C NMR (100 MHz, CDCl3,
5.42; found: C 64.40, H 5.37.
25 °C):
9.0 Hz), 135.2, 131.3 (t, J = 2.1 Hz), 123.5, 117.1 (t, J = 18.1 Hz),
N,N-Diethyl-2-fluoro-4'-nitrobiphenyl-4-carboxamide (2) From 4- 110.4 (d, J = 27.6 Hz), 43.3, 39.6, 14.3, 12.8. Elemental analysis:
bromonitrobenzene (0.202 g, mmol) and N,N-diethyl-3- calcd (%) for C17H16F2N2O3 (334.32): C 61.07, H 4.82; found: C 61.31,
fluorobenzamide (0.292 g, 1.5 mmol), 2 was obtained in 31% (0.098 H 4.67.
g) yield in 90% purity. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.34 (d,
J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.35- Ethyl
7.22 (m, 2H), 3.59 (bs, 2H), 3.35 (bs, 2H), 1.30-1.18 (m, 6H). 13C (7) From ethyl 4-bromobenzoate (0.229 g, 1 mmol) and N,N-diethyl-
NMR (100 MHz, CDCl3, 25 °C): = 169.1, 159.3 (d, J = 251.7 Hz), 3,5-difluorobenzamide (0.320 g, 1.5 mmol), 7 was obtained in 88%
147.5, 141.5, 139.6 (d, J = 7.5 Hz), 130.8 (d, J = 3.1 Hz), 129.8 (d, J = (0.318 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.16 (d, J = 8.1
δ = 167.9, 159.5 (dd, J = 252.4, 6.8 Hz), 147.7, 139.8 (t, J =
1
δ
4'-(diethylcarbamoyl)-2',6'-difluorobiphenyl-4-carboxylate
δ
δ
Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.2 Hz, 2H), 4.40 (t, J =
6 | J. Name., 2012, 00, 1-3
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7.6 Hz, 2H), 3.56 (m, 2H), 3.34 (m, 2H), 1.42 (t, J = 7.6 Hz, 3H), 1.28- difluorobenzamide (0.320 g, 1.5 mmol), 12 was obtained in 84%
1.17 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C): = 168.2, 166.1, (0.284 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.01 (s, 1H),
δ
δ
159.7 (dd, J = 251.8, 7.1 Hz), 138.9 (t, J = 9.0 Hz), 133.0, 130.5, 7.95 (d, J = 8.1 Hz, 1H), 7.93-7.87 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H),
130.2 (t, J = 1.8 Hz), 129.5, 118.4 (t, J = 18.5 Hz), 110.2 (d, J = 27.8 7.57-7.51 (m, 2H), 7.11 (d, J = 7.4 Hz, 2H), 3.56 (m, 2H), 3.34 (m,
Hz), 61.2, 43.3, 39.5, 15.2, 14.3, 12.8. Elemental analysis: calcd (%) 2H), 1.30-1.15 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ
= 168.4,
for C20H21F2NO3 (361.38): C 66.47, H 5.86; found: C 66.70, H 5.99.
159.9 (dd, J = 252.4, 6.8 Hz), 138.2 (t, J = 9.0 Hz), 132.9, 129.8,
128.2, 127.8, 127.6, 127.4, 126.6, 126.3, 125.8, 119.3 (t, J = 18.1 Hz),
110.0 (d, J = 27.6 Hz), 43.3, 39.5, 14.1, 12.7. Elemental analysis:
N,N-Diethyl-2,6-difluoro-4'-(trifluoromethyl)biphenyl-4-
carboxamide (8) From 4-trifluoromethylbromobenzene (0.225 g, 1 calcd (%) for C21H19F2NO (339.38): C 74.32, H 5.64; found: C 74.17, H
mmol) and N,N-diethyl-3,5-difluorobenzamide (0.320 g, 1.5 mmol), 8 5.47.
was obtained in 81% (0.289 g) yield. 1H NMR (400 MHz, CDCl3,
25 °C):
= 7.3 Hz, 2H), 3.56 (m, 2H), 3.34 (m, 2H), 1.30-1.18 (m, 6H). 13C From 2-bromobenzonitrile (0.182 g, 1 mmol) and N,N-diethyl-3,5-
NMR (100 MHz, CDCl3, 25 °C): = 168.2 (t, J = 2.4 Hz), 159.7 (dd, J = difluorobenzamide (0.320 g, 1.5 mmol), 13 was obtained in 85%
151.9, 7.0 Hz), 139.2 (t, J = 9.0 Hz), 132.2, 130.7, 130.6 (q, J = 32.6 (0.267 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.83 (d, J = 8.1
δ
= 7.75 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.04 (d, J 2'-Cyano-N,N-diethyl-2,6-difluorobiphenyl-4-carboxamide
(13)
δ
δ
Hz), 124.0 (q, J = 272.2 Hz), 125.3 (q, J = 3.7 Hz), 117.9 (t, J = 18.4 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.49 (d, J =
Hz), 110.3 (d, J =19.9 Hz), 43.3, 39.5, 14.2, 12.8. Elemental analysis: 8.1 Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 3.56 (m, 2H), 3.34 (m, 2H), 1.35-
calcd (%) for C18H16F5NO (357.32): C 60.50, H 4.51; found: C 60.34, H 1.15 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 168.0, 159.6
4.32.
(dd, J = 252.4, 6.8 Hz), 140.7 (t, J = 8.8 Hz), 133.1, 132.7, 132.4,
131.7, 129.2, 117.4, 115.9 (t, J = 19.7 Hz), 113.9, 110.3 (d, J = 27.3
(9) Hz), 43.4, 39.5, 14.2, 12.8. Elemental analysis: calcd (%) for
4'-Chloro-N,N-diethyl-2,6-difluorobiphenyl-4-carboxamide
From 4-bromochlorobenzene (0.191 g, 1 mmol) and N,N-diethyl-3,5- C18H16F2N2O (314.33): C 68.78, H 5.13; found: C 68.89, H 5.04.
difluorobenzamide (0.320 g, 1.5 mmol), 9 was obtained in 83% (0.268
g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
2H), 7.42 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.3 Hz, 2H), 3.56 (m, 2H), bromopyridine
3.34 (m, 2H), 1.30-1.18 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C): difluorobenzamide (0.320 g, 1.5 mmol), 14 was obtained in 61%
= 168.3, 159.7 (dd, J = 251.2, 7.1 Hz), 138.5 (t, J = 9.0 Hz), 134.7, (0.177 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.72 (s, 1H),
δ
= 7.47 (d, J = 8.1 Hz, N,N-Diethyl-3,5-difluoro-4-(pyridin-3-yl)benzamide (14) From 3-
(0.158 g, mmol) and N,N-diethyl-3,5-
1
δ
δ
131.5 (t, J = 1.8 Hz), 128.6, 126.8, 118.1 (t, J = 18.5 Hz), 110.1 (d, J = 8.84 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 4.9
28.0 Hz), 43.3, 39.5, 14.2, 12.8. Elemental analysis: calcd (%) for Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 3.56 (m, 2H), 3.32 (m, 2H), 1.35-
C17H16ClF2NO (323.76): C 63.06, H 4.98; found: C 63.24, H 5.18.
1.15 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 168.0, 159.6
(dd, J = 252.4, 6.8 Hz), 150.3, 149.2, 139.4 (t, J = 8.7 Hz), 127.8,
4'-Fluoro-N,N-diethyl-2,6-difluorobiphenyl-4-carboxamide
(10) 125.0, 123.4, 115.7 (t, J = 19.7 Hz), 110.3 (d, J = 27.6 Hz), 43.3, 39.6,
From 4-bromofluorobenzene (0.175 g, 1 mmol) and N,N-diethyl-3,5- 14.2, 12.8. Elemental analysis: calcd (%) for C16H16F2N2O (290.31): C
difluorobenzamide (0.320 g, 1.5 mmol), 10 was obtained in 76% 66.20, H 5.56; found: C 66.00, H 5.68.
(0.233 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
2H), 7.16 (t, J = 8.1 Hz, 2H), 7.04 (d, J = 7.3 Hz, 2H), 3.56 (m, 2H), N,N-Diethyl-3,5-difluoro-4-(quinolin-3-yl)benzamide (15) From 3-
3.34 (m, 2H), 1.30-1.18 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C): bromoquinoline (0.208 g,
mmol) and N,N-diethyl-3,5-
= 168.4 (t, J = 2.4 Hz), 162.3 (d, J = 248.5 Hz), 159.7 (dd, J = 250.8, difluorobenzamide (0.320 g, 1.5 mmol), 15 was obtained in 87%
7.2 Hz), 138.3 (t, J = 9.0 Hz), 132.0 (dt, J = 8.2, 1.9 Hz), 124.3 (d, J = (0.296 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 9.00 (s, 1H),
δ = 7.50-7.40 (m,
1
δ
δ
3.4 Hz), 118.3 (t, J = 18.5 Hz), 115.5 (d, J = 21.7 Hz), 110.2 (d, J = 8.32 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.79 (t,
28.2 Hz), 43.3, 39.5, 14.2, 12.8. Elemental analysis: calcd (%) for J = 8.2 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 3.57
C17H16F3NO (307.31): C 66.44, H 5.25; found: C 66.57, H 5.17.
(m, 2H), 3.35 (m, 2H), 1.35-1.15 (m, 6H). 13C NMR (100 MHz, CDCl3,
25 °C): = 168.0, 159.6 (dd, J = 252.4, 6.8 Hz), 150.7, 147.2, 139.4 (t,
(11) J = 8.7 Hz), 137.7, 130.4, 129.1, 128.1, 127.5, 127.2, 122.0, 115.9 (t,
δ
N,N-Diethyl-2,6-difluoro-3'-nitrobiphenyl-4-carboxamide
From 3-bromonitrobenzene (0.202 g, 1 mmol) and N,N-diethyl-3,5- J = 19.7 Hz), 110.4 (d, J = 27.6 Hz), 43.3, 39.5, 14.2, 12.8. Elemental
difluorobenzamide (0.320 g, 1.5 mmol), 11 was obtained in 88% analysis: calcd (%) for C20H18F2N2O (340.37): C 70.58, H 5.33; found:
(0.294 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 8.36 (s, 1H), C 70.29, H 5.47.
8.29 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.67 (t, J = 7.7 Hz,
1H), 7.08 (d, J = 7.4 Hz, 2H), 3.56 (m, 2H), 3.34 (m, 2H), 1.30-1.15 N,N-Diethyl-2,6-difluoro-4'-methylbiphenyl-4-carboxamide
(16)
(m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ
= 168.0, 159.6 (dd, J = From 4-bromotoluene (0.171 g,
252.4, 6.8 Hz), 148.2, 139.5 (t, J = 9.0 Hz), 136.3, 130.1, 129.4, 125.3 difluorobenzamide (0.320 g, 1.5 mmol), 16 was obtained in 78%
(t, J = 2.1 Hz), 123.4, 116.7 (t, J = 18.1 Hz), 110.3 (d, J = 27.6 Hz), (0.236 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.36 (d, J = 7.8
43.3, 39.6, 14.2, 12.8. Elemental analysis: calcd (%) for C17H16F2N2O3 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 6.3 Hz, 2H), 3.54 (m,
(334.32): C 61.07, H 4.82; found: C 61.27, H 4.80.
2H), 3.33 (m, 2H), 2.41 (s, 3H), 1.30-1.18 (m, 6H). 13C NMR (100
MHz, CDCl3, 25 °C): = 168.9, 159.9 (dd, J = 250.4, 7.5 Hz), 138.5,
N,N-Diethyl-3,5-difluoro-4-(naphthalen-2-yl)benzamide (12) From 137.8 (t, J = 9.0 Hz), 130.0, 129.1, 125.4, 119.3 (t, J = 18.7 Hz), 110.0
2-bromonaphthalene (0.207 g, mmol) and N,N-diethyl-3,5- (d, J = 28.5 Hz), 43.3, 39.5, 21.3, 14.3, 12.8. Elemental analysis:
1 mmol) and N,N-diethyl-3,5-
δ
δ
1
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calcd (%) for C18H19F2NO (303.35): C 71.27, H 6.31; found: C 71.30, H N,N-Diethyl-2,4,5-trifluoro-3-(quinolin-3-yl)benzamide (21) From
6.50.
3-bromoquinoline (0.208 g,
trifluorobenzamide (0.347 g, 1.5 mmol), 21 was obtained in 81%
(17) (0.290 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 9.01 (s, 1H),
1
mmol) and N,N-diethyl-2,4,5-
N,N-Diethyl-2,6-difluoro-4'-nitrobiphenyl-3-carboxamide
δ
From 4-bromonitrobenzene (0.202 g, 1 mmol) and N,N-diethyl-2,4- 8.33 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (t,
difluorobenzamide (0.320 g, 1.5 mmol), 17 was obtained in 79% J = 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.26 (m, 1H), 3.61 (q, J = 7.6
(0.264 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.40 (ddd, J = 8.5, 7.3, 6.1 Hz, 1H), 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ
= 8.33 (d, J = 8.1 Hz, 2H), 3.31 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.17 (t, J =
= 163.7, 150.8 (dd,
δ
7.08 (dd, J = 9.0, 1.4 Hz, 1H), 3.58 (q, J = 7.6 Hz, 2H), 3.26 (q, J = 7.6 J = 246.3, 6.2 Hz), 150.5, 148.3 (dd, J = 246.3, 6.2 Hz), 147.7, 147.6
Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H). 13C NMR (dd, J = 246.3, 13.5 Hz), 137.7, 130.6, 129.4, 128.2, 127.4, 127.3,
(100 MHz, CDCl3, 25 °C):
δ = 164.8, 159.7 (dd, J = 254.3, 6.2 Hz), 121.8 (dt, J = 22.7, 5.1 Hz), 121.3, 117.5 (dd, J = 21.5, 15.2 Hz),
155.2 (dd, J = 155.3, 8.1 Hz), 147.7, 135.2, 131.2, 129.1 (dd, J = 10.4, 115.7 (dd, J = 19.3, 4.5 Hz), 43.2, 39.5, 14.0, 12.7. Elemental
6.2 Hz), 123.5, 122.4 (dd, J = 20.6, 4.2 Hz), 116.7 (t, J = 18.0 Hz), analysis: calcd (%) for C20H17F3N2O (358.36): C 67.03, H 4.78; found:
112.5 (dd, J = 24.5, 3.1 Hz), 43.2, 39.4, 14.1, 12.8. Elemental C 67.24, H 5.00.
analysis: calcd (%) for C17H16F2N2O3 (334.32): C 61.07, H 4.82; found:
C 61.34, H 4.53.
4'-Acetyl-N,N-diethyl-2,3-difluorobiphenyl-4-carboxamide
(22)
From 4-bromoacetophenone (0.199 g, 1 mmol) and N,N-diethyl-2,3-
4'-Cyano-N,N-diethyl-2,6-difluorobiphenyl-3-carboxamide
(18) difluorobenzamide (0.320 g, 1.5 mmol), 22 was obtained in 61%
From 4-bromobenzonitrile (0.182 g, 1 mmol) and N,N-diethyl-2,4- (0.202 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
δ
= 8.07 (d, J = 8.4
difluorobenzamide (0.320 g, 1.5 mmol), 18 was obtained in 81% Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.35-7.20 (m, 2H), 3.61 (q, J = 7.6
(0.254 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.77 (d, J = 8.1 Hz, 2H), 3.30 (q, J = 7.6 Hz, 2H), 2.67 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H),
Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.37 (ddd, J = 8.5, 7.3, 6.1 Hz, 1H), 1.17 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
= 197.5,
δ
δ
7.10 (dd, J = 9.0, 1.4 Hz, 1H), 3.58 (q, J = 7.6 Hz, 2H), 3.26 (q, J = 7.6 164.1 (d, J = 2.5 Hz), 147.8 (dd, J = 253.8, 13.7 Hz), 147.0 (dd, J =
Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H). 13C NMR 250.5, 14.5 Hz), 138.7, 136.8, 130.5 (d, J = 10.2 Hz), 129.1 (d, J = 3.1
(100 MHz, CDCl3, 25 °C):
δ = 164.8, 159.8 (dd, J = 246.3, 6.2 Hz), Hz), 128.6, 127.0 (d, J = 15.7 Hz), 125.4, 122.8, 43.1, 39.4, 26.7,
155.1 (dd, J = 254.0, 6.6 Hz), 133.4, 132.6, 131.1, 128.9 (dd, J = 10.3, 14.1, 12.9. Elemental analysis: calcd (%) for C19H19F2NO2 (331.36): C
6.2 Hz), 125.5, 122.3 (dd, J = 20.4, 4.0 Hz), 118.4, 117.0 (t, J = 18.0 68.87, H 5.78; found: C 69.04, H 5.79.
Hz), 112.3 (t, J = 23.0 Hz), 43.1, 39.4, 14.0, 12.8. Elemental analysis:
calcd (%) for C18H16F2N2O (314.33): C 68.78, H 5.13; found: C 68.75, N,N-Diethyl-2,3-difluoro-4'-nitrobiphenyl-4-carboxamide
H 5.03. From 4-bromonitrobenzene (0.202 g, 1 mmol) and N,N-diethyl-2,3-
difluorobenzamide (0.320 g, 1.5 mmol), 23 was obtained in 64%
4'-Cyano-N,N-diethyl-2,5,6-trifluorobiphenyl-3-carboxamide (19) (0.214 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.35 (d, J = 7.8
From 4-bromobenzonitrile (0.182 g, mmol) N,N-diethyl-2,4,5- Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.35-7.20 (m, 2H), 3.62 (q, J = 7.6
trifluorobenzamide (0.347 g, 1.5 mmol), 19 was obtained in 53% Hz, 2H), 3.31 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H), 1.17 (t, J =
(0.176 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C): = 7.77 (d, J = 8.1 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
= 164.1 (d, J = 2.5
(23)
δ
1
δ
δ
Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.25-7.17 (m, 1H), 3.58 (q, J = 7.6 Hz), 147.7, 147.6 (dd, J = 253.8, 13.8 Hz), 147.0 (dd, J = 250.5, 14.3
Hz, 2H), 3.27 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.15 (t, J = Hz), 140.5, 129.8, 129.4 (d, J = 10.1 Hz), 127.7 (d, J = 15.8 Hz),
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 163.6, 150.1 (d, J 125.5, 124.0, 123.1, 43.2, 39.4, 14.1, 12.8. Elemental analysis: calcd
= 246.0 Hz), 147.5 (ddd, J = 253.0, 14.5, 6.8 Hz), 147.3 (ddd, J = (%) for C17H16F2N2O3 (334.32): C 61.07, H 4.82; found: C 61.18, H
248.7, 13.8, 3.4 Hz), 132.4, 132.2, 130.9 (m), 121.8 (dm, J = 22.2 Hz), 4.99.
118.8 (dd, J = 20.5, 14.9 Hz), 118.2, 115.8 (dd, J = 9.2, 4.4 Hz),
113.0, 43.2, 39.5, 14.0, 12.7. Elemental analysis: calcd (%) for 4'-Cyano-N,N-diethyl-5,6-difluorobiphenyl-3-carboxamide
(24)
From 4-bromobenzonitrile (0.182 g, 1 mmol) and N,N-diethyl-3,4-
difluorobenzamide (0.320 g, 1.5 mmol), 24 was obtained in 36%
(0.113 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.78 (d, J = 8.3
C18H15F3N2O (332.32): C 65.06, H 4.55; found: C 62.17, H 4.58.
4'-(Cyanomethyl)-N,N-diethyl-2,5,6-trifluorobiphenyl-3-
δ
carboxamide (20) From 2-(4-bromophenyl)acetonitrile (0.196 g, 1 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.33-7.22 (m, 2H), 3.55 (bs, 2H),
mmol) N,N-diethyl-2,4,5-trifluorobenzamide (0.347 g, 1.5 mmol), 20 3.35 (bs, 2H), 1.30-1.10 (m, 6H). 13C NMR (100 MHz, CDCl3, 25 °C):
was obtained in 61% (0.211 g) yield. 1H NMR (400 MHz, CDCl3,
25 °C): = 7.50-7.46 (m, 4H), 7.20-7.15 (m, 1H), 3.84 (s, 2H), 3.59 (q, 138.4, 134.0 (m), 132.5, 129.6, 123.4, 118.4, 115.8 (d, J = 18.8 Hz),
J = 7.6 Hz, 2H), 3.27 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.15 112.5, 43.4, 39.6, 14.0, 12.8. Elemental analysis: calcd (%) for
(t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C): 13C NMR C18H16F2N2O (314.33): C 68.78, H 5.13; found: C 69.02, H 4.94.
(100 MHz, CDCl3, 25 °C): = 164.0, 150.5 (d, J = 246.0 Hz), 148.0
(ddd, J = 253.0, 14.5, 6.8 Hz), 147.5 (ddd, J = 248.7, 13.7, 3.6 Hz), N-n-Butyl-4'-cyano-2,6-difluorobiphenyl-4-carboxamide
130.9, 128.2, 127.7, 121.5 (dm, J = 18.0 Hz), 119.8 (dd, J = 21.0, 15.3 From 4-bromobenzonitrile (0.182 g, mmol) and N-butyl-3,5-
Hz), 117.4, 114.9 (dd, J = 20.7, 5.6 Hz), 43.2, 39.5, 23.5, 14.0, 12.7. difluorobenzamide (0.320 g, 1.5 mmol), 25a was obtained in 61%
Elemental analysis: calcd (%) for C19H17F3N2O (346.34): C 65.89, H (0.191 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.79 (d, J = 8.1
δ = 168.4, 150.7 (dd, J = 248.0, 12.0), 148.1 (dd, J = 250.0, 11.9),
δ
δ
=
δ
(25a)
1
δ
4.95; found: C 65.77, H 4.98.
Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 6.10 (s,
8 | J. Name., 2012, 00, 1-3
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1H), 3.50 (q, J = 7.6 Hz, 2H), 1.65 (quint., J = 7.6 Hz, 2H), 1.45 (sext., (dd, J = 251.8, 7.7 Hz), 138.4 (t, J = 8.4 Hz), 133.3, 132.0, 131.0 (m),
J = 7.6 Hz, 2H), 1.00 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 119.0 (t, J = 18.2 Hz), 118.4, 112.5, 110.7 (d, J = 27.4 Hz), 52.2, 28.7.
25 °C):
δ = 164.5, 159.8 (dd, J = 252.0, 6.8 Hz), 137.2 (t, J = 8.6 Hz), Elemental analysis: calcd (%) for C18H16F2N2O (314.33): C 68.78, H
133.1, 132.1, 131.0 (t, J = 2.3 Hz), 119.3, 118.4, 112.6, 110.7 (d, J = 5.13; found: C 68.64, H 5.02.
27.4 Hz), 40.1, 31.6, 20.1, 13.7. Elemental analysis: calcd (%) for
C18H16F2N2O (314.33): C 68.78, H 5.13; found: C 68.89, H 5.24. 25b N-tert-Butyl-2,6-difluoro-4'-formylbiphenyl-4-carboxamide
(30a)
1
was also isolated in low yield: H NMR (400 MHz, CDCl3, 25 °C):
δ
=
From 4-bromobenzaldehyde (0.185 g, 1 mmol) and N-tert-3,5-
7.75 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.8 Hz, difluorobenzamide (0.320 g, 1.5 mmol), 30a was obtained in 70%
1H), 7.03 (t, J = 8.0 Hz, 1H), 5.31 (s, 1H), 3.19 (q, J = 7.6 Hz, 2H), (0.222 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 10.10 (s, 1H),
1.26 (quint., J = 7.6 Hz, 2H), 1.15 (sext., J = 7.6 Hz, 2H), 0.85 (t, J = 8.02 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.0 Hz,
δ
7.6 Hz, 3H).
2H), 5.97 (s, 1H), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ =
191.7, 163.9, 158.7 (dd, J = 251.7, 6.9 Hz), 138.1 (t, J = 8.5 Hz),
N-n-Butyl-2,6-difluoro-4'-formylbiphenyl-4-carboxamide
(26a) 136.2, 134.6, 131.0, 129.6, 119.7 (t, J = 18.3 Hz), 110.5 (d, J = 27.7
From 4-bromobenzaldehyde (0.185 g, 1 mmol) and N-butyl-3,5- Hz), 52.2, 28.8. Elemental analysis: calcd (%) for C18H17F2NO2
difluorobenzamide (0.320 g, 1.5 mmol), 26a was obtained in 68% (317.33): C 68.13, H 5.40; found: C 68.02, H 5.54.
(0.215 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
8.00 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 7.8 Hz, N-tert-Butyl-2,6-difluoro-4'-nitrobiphenyl-4-carboxamide
2H), 6.29 (s, 1H), 3.50 (q, J = 7.6 Hz, 2H), 1.65 (quint., J = 7.6 Hz, From 4-bromonitrobenzene (0.202 g, mmol) and N-tert-3,5-
2H), 1.45 (sext., J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). 13C NMR difluorobenzamide (0.320 g, 1.5 mmol), 31a was obtained in 66%
(100 MHz, CDCl3, 25 °C): = 8.34 (d, J = 8.1
= 191.7, 164.6, 159.8 (dd, J = 251.7, 6.9 (0.220 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
Hz), 137.0 (t, J = 8.6 Hz), 136.2, 134.6, 131.0, 129.6, 120.0 (t, J = Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.99 (s,
18.3 Hz), 110.6 (d, J = 27.7 Hz), 40.1, 31.6, 20.2, 13.8. Elemental 1H), 1.50 (s, 9H). 13C NMR (100 MHz, CDCl3, 25 °C):
= 163.8 (t, J =
analysis: calcd (%) for C18H17F2NO2 (317.33): C 68.13, H 5.40; found: 2.4 Hz), 159.7 (dd, J = 252.2, 6.7 Hz), 147.8, 138.6 (t, J = 8.5 Hz),
δ = 10.10 (s, 1H),
(31a)
1
δ
δ
δ
C 68.41, H 5.24.
135.1, 131.3 (t, J = 2.2 Hz), 123.6, 118.7 (t, J = 18.3 Hz), 110.7 (d, J =
27.5 Hz), 52.3, 28.8. Elemental analysis: calcd (%) for C17H16F2N2O3
N-n-Butyl-2,6-difluoro-4'-nitrobiphenyl-4-carboxamide (27a) From (334.32): C 61.07, H 4.82; found: C 61.02, H 4.99.
4-bromonitrobenzene (0.202 g, mmol) and N-butyl-3,5-
difluorobenzamide (0.320 g, 1.5 mmol), 27a was obtained in 70% N-tert-Butyl-2'-cyano-2,6-difluorobiphenyl-4-carboxamide
(0.234 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 8.35 (d, J = 8.3 From 2-bromobenzonitrile (0.182 g, mmol) and N-tert-3,5-
Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 6.20 (s, difluorobenzamide (0.320 g, 1.5 mmol), 32a was obtained in 63%
1H), 3.50 (q, J = 7.6 Hz, 2H), 1.65 (quint., J = 7.6 Hz, 2H), 1.45 (sext., (0.198 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.82 (d, J = 8.0
J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.50 (d, J =
25 °C):
= 164.1, 159.8 (dd, J = 252.3, 6.7 Hz), 147.5, 137.1 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 6.06 (s, 1H), 1.48 (s, 9H). 13C
8.2 Hz), 134.7, 130.9 (t, J = 2.3 Hz), 123.2, 118.7 (t, J = 18.3 Hz), NMR (100 MHz, CDCl3, 25 °C): = 164.0, 159.7 (dd, J = 251.7, 6.9
1
(32a)
δ
1
δ
δ
δ
110.4 (d, J = 27.5 Hz), 39.8, 31.3, 19.8, 13.4. Elemental analysis: Hz), 139.4 (t, J = 8.2 Hz), 133.1, 132.7, 132.4, 131.5, 129.3, 117.5 (t,
calcd (%) for C17H16F2N2O3 (334.32): C 61.07, H 4.82; found: C 61.30, J = 19.9 Hz), 117.4, 113.8, 110.5 (d, J = 27.3 Hz), 52.2, 28.7.
H 4.64.
Elemental analysis: calcd (%) for C18H16F2N2O (314.33): C 68.78, H
5.13; found: C 68.87, H 5.24.
N-n-Butyl-2'-cyano-2,6-difluorobiphenyl-4-carboxamide
(28a)
From 2-bromobenzonitrile (0.182 g,
difluorobenzamide (0.320 g, 1.5 mmol), 28a was obtained in 76% bromoquinoline (0.208 g, 1 mmol) and N-tert-3,5-difluorobenzamide
(0.239 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C): = 7.84 (d, J = 7.8 (0.320 g, 1.5 mmol), 33a was obtained in 64% (0.218 g) yield. 1H
Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.51 (d, J = NMR (400 MHz, CDCl3, 25 °C): = 9.01 (s, 1H), 8.32 (s, 1H), 8.18 (d,
1 mmol) and N-butyl-3,5- N-tert-Butyl-3,5-difluoro-4-(quinolin-3-yl)benzamide (33a) From 3-
δ
δ
7.8 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 6.21 (s, 1H), 3.50 (q, J = 7.6 Hz, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.62
2H), 1.65 (quint., J = 7.6 Hz, 2H), 1.45 (sext., J = 7.6 Hz, 2H), 1.01 (t, (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 6.03 (s, 1H), 1.51 (s, 9H).
J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ δ = 163.9, 160.1 (dd, J = 251.7,
= 164.8, 159.7 13C NMR (100 MHz, CDCl3, 25 °C):
(dd, J = 252.0, 6.6 Hz), 138.2 (t, J = 8.5 Hz), 133.1, 132.7, 132.4, 7.0 Hz), 150.9, 147.5, 138.2 (t, J = 8.2 Hz), 137.6, 130.5, 129.3,
131.5, 129.3, 117.8 (t, J = 19.7 Hz), 117.3, 113.9, 110.6 (d, J = 27.7 128.2, 127.5, 127.2, 122.0, 117.7 (t, J = 19.9 Hz), 110.6 (d, J = 27.3
Hz), 40.1, 31.6, 20.1, 13.7. Elemental analysis: calcd (%) for Hz), 52.2, 28.8. Elemental analysis: calcd (%) for C20H18F2N2O
C18H16F2N2O (314.33): C 68.78, H 5.13; found: C 68.70, H 5.00.
(340.37): C 70.58, H 5.33; found: C 70.40, H 5.21.
N-tert-Butyl-4'-cyano-2,6-difluorobiphenyl-4-carboxamide
(29a)
Acknowledgements
From 4-bromobenzonitrile (0.182 g,
difluorobenzamide (0.320 g, 1.5 mmol), 29a was obtained in 66%
(0.207 g) yield. 1H NMR (400 MHz, CDCl3, 25 °C):
= 7.77 (d, J = 8.1
1 mmol) and N-tert-3,5-
We thank the Centre National de la Recherche
Scientifique and “Rennes Metropole” for providing
financial support.
δ
Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 6.00 (s,
1H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 163.9, 159.7
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J. Name., 2013, 00, 1-3 | 9
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Journal Name
Yuen, M. Charoensak, C. M. So, C. Kuhakarn and F. Y. Kwong,
Chem. Asian J., 2015, 10, 857-861.
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RSC Advances
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DOI: 10.1039/C6RA12165A
Under PdCl2/PivOK as reaction conditions, fluoro substituents act as better directing groups than amides in the
palladium-catalysed direct arylations.