Reactivity of 3-substituted fluorobenzenes in palladium-catalysed direct arylations with aryl bromides

Article abstract of DOI:10.1002/adsc.201400038

The influence of both electron-withdrawing and electron-donating substituents such as nitro, nitrile, chloro, bromo and methoxy at C-3 on fluorobenzenes for their palladium-catalysed direct C-2 arylation has been explored. With electron-withdrawing substituents, the reaction proceeds nicely using 2-4 mol% of an air-stable palladium complex and potassium pivalate/dimethylacetamide (PivOK/DMA) as catalytic system; and in general, a very regioselective arylation at C-2 was observed. Moreover, a variety of substituents on the aryl bromide coupling partner, such as benzoyl, formyl, nitro, nitrile, chloro and methyl, and also heteroaryl bromides were tolerated.

Full text of DOI:10.1002/adsc.201400038

FULL PAPERS
DOI: 10.1002/adsc.201400038
Reactivity of 3-Substituted Fluorobenzenes in Palladium-
Catalysed Direct Arylations with Aryl Bromides
Tao Yan,a Liqin Zhao,a Mian He,a Jean-FranÅois Soulꢀ,a Christian Bruneau,a
and Henri Douceta,*
a
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS – Universitꢀ de Rennes “Organomꢀtalliques matꢀriaux et
Catalyse”, Campus de Beaulieu, 35042 Rennes, France
Fax : (+33)-(0)2-2323-6939; phone: (+33)-(0)2-2323-6384; e-mail: henri.doucet@univ-rennes1.fr
Received: January 10, 2014; Revised: March 17, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400038.
Abstract: The influence of both electron-withdraw- gioselective arylation at C-2 was observed. More-
ing and electron-donating substituents such as nitro, over, a variety of substituents on the aryl bromide
nitrile, chloro, bromo and methoxy at C-3 on fluoro- coupling partner, such as benzoyl, formyl, nitro, ni-
benzenes for their palladium-catalysed direct C-2 ar- trile, chloro and methyl, and also heteroaryl bro-
ylation has been explored. With electron-withdraw- mides were tolerated.
ing substituents, the reaction proceeds nicely using
2–4 mol% of an air-stable palladium complex and
À
potassium
pivalate/dimethylacetamide
(PivOK/ Keywords: aryl halides; atom economy; C H bond
DMA) as catalytic system; and in general, a very re- functionalization; direct arylation; palladium
Introduction
Palladium-catalysed reactions such as Stille, Suzuki
or Negishi couplings allow the efficient synthesis of
The fluorobiACHTUNGTRENNUNG
(hetero)aryl motif is found in several bio- a wide variety of biaryls.[1] However, these couplings
active compounds. For example, Flurbiprofen and Di- require the preliminary synthesis of organometallic
flunisal are non-steroidal anti-inflammatory drugs, derivatives. Moreover, these reactions provide a stoi-
Brequinar is employed for the treatment of some can- chiometric amount of metallic side products. In 2006,
cers and Flucloxacillin and Radezolid are antibiotics Fagnou and co-workers reported the palladium-cata-
(Figure 1). Therefore, the discovery of general simple lyzed direct arylations[2,3] of polyfluorobenzenes,[4,5]
routes for access to fluorobiphenyls has potential with aryl halides (Scheme 1, top). Since these results,
value for medicinal chemistry.
the palladium- or copper-catalysed direct arylation of
tri-, tetra- and especially pentafluorobenzenes[6] with
aryl halides has proved to be a powerful method for
the synthesis of a variety of poly-fluoro-containing
biaryls.[4–8] On the other hand, little is known on the
reactivity of monofluorobenzenes[9–11] for palladium-
catalysed direct arylation. Fagnou and co-workers
have reported a single example of direct arylation of
fluorobenzene (Scheme 1, middle).[4a] Using 5 mol%
PdACHTUNGRTENN(UG OAc)2 associated to 10 mol% PAHCTUNGTRNE(NUGN t-Bu)2Me·HBF4 as
catalyst, and 4-bromotoluene as the coupling partner,
they obtained the C-2 arylated fluorobenzene in 8%
yield. In a few cases, it has been demonstrated that
a carboxylic acid group directs the arylation at ortho-
position(s).[9] This method has been employed by
Daugulis and co-workers for direct diarylation at C-2
and C-6 of 3-fluorobenzoic acid (Scheme 1, mid-
dle).[9a] The p-complexation of fluorobenzenes to
Figure 1. Examples of bioactive fluorobiACTHNUGRTENUNG(hetero)aryls.
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Scheme 1. Pd-catalysed direct arylation of (poly)fluorobenzenes.
Cr(CO)3 also enhances their reactivity allowing Pd- 1 (Table 1). In the presence of 2 mol% PdCl
ACHTUNGTRENNUNG(C3H5)
catalysed C-2 arylation in high yields.[10a] A few meta-
AHCTUNGTRENNUNG
arylations of trifluoromethylbenzenes containing 1 was formed regioselectively and without cleavage of
a fluoro-substituent,[10b] or using other metals as cata- the C Br bond of 1-bromo-3-fluorobenzene moiety.
À
lysts[11] have also been reported.
However, 1 was obtained in only 31% yield due to
As very few examples of palladium-catalysed direct a moderate conversion of both 4-bromobenzonitrile
arylations of monofluorobenzene derivatives have and 1-bromo-3-fluorobenzene and also to the forma-
been reported, the influence of the substituents on tion of 4,4’-dicyanobiphenyl in low yield. The use of
fluorobenzenes allowing a more general access to flu- DMF and NMP as the solvents, with KOAc as the
orobiphenyls, especially using fluorobenzenes bearing base, did not allow any improvement of the yield in
useful functional groups, needed to be investigated.
1 and the formation of unidentified side-products was
Herein, starting from a set of 3-substituted fluoro- observed (Table 1, entries 2 and 3). Xylene was com-
benzenes as reactants, we report (i) on the electronic pletely ineffective for this reaction and 4-bromoben-
influence of fluorobenzene substituents on their reac- zonitrile was recovered (Table 1, entry 4). Then, we
tivity for palladium-catalysed direct arylation; (ii) on examined the influence of several bases for this reac-
the access to a variety of fluorobiphenyls using a varie- tion. CsOAc, NaOAc or K2CO3 led to 1 in very low
ty of fluorobenzenes and aryl bromides.
yields (Table 1, entries 5–7). On the other hand, the
use of PivOK in the presence of 2 mol% PdCl(C3H5)
AHCTUNGTREGUN(NN dppb) catalyst selectively gave 1 in 45% yield. A
ACHTUNGTRENNUNG
Results and Discussion
higher catalyst loading of 4 mol% allowed an increase
in the yield of 1 to 69% (Table 1, entries 8 and 9). It
It is generally considered that, in the course of palla- should be noted that under these conditions, the use
dium-catalysed direct arylation with polyfluoroben- of fluorobenzene instead of 1-bromo-3-fluorobenzene
zenes, the most electron-deficient fluorinated arene led only to a trace amount of coupling product (de-
reacts preferentially.[4a] Therefore, based on previous tected by GC/MS analysis). This result confirms that
results,[12] we first examined the reaction of 1-bromo- the presence of a bromo-substituent at C-3 of fluoro-
3-fluorobenzene with 4-bromobenzonitrile to form benzene enhances the reactivity of the C-2 position.
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Reactivity of 3-Substituted Fluorobenzenes in Palladium-Catalysed Direct Arylations
Table 1. Influence of the reaction conditions for the palladium-catalysed direct 2-arylation of 1-bromo-3-fluorobenzene with
4-bromobenzonitrile.[a]
Entry
[Pd] catalyst [mol%]
Base
Solvent
Conversion [%]
Yield in 1 [%]
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
4
KOAc
KOAc
KOAc
KOAc
CsOAc
NaOAc
K2CO3
PivOK
PivOK
DMA
DMF
NMP
xylene
DMA
DMA
DMA
DMA
DMA
56
91
42
4
34
79
13
51
93
31
18
–
–
–
5
–
45
69
[a]
PdClACHTUNGTRENNUNG(C3H5)ACHTUNGTRENNUNG(dppb), 4-bromobenzonitrile (1 equiv.), 1-bromo-3-fluorobenzene (1.5 equiv.), base (2 equiv.), 1508C, 16 h,
conversion of 4-bromobenzonitrile.
Scheme 2. Palladium-catalysed 2-arylation of 1-bromo-3-fluorobenzene with aryl bromides.
For all these reactions, no arylation of 1-bromo-3-bro-
mobenzene with itself was observed due to the faster
oxidative addition of 4-bromobenzonitrile to palladi-
um.
Then, we extended the scope of the coupling of 1-
bromo-3-fluorobenzene to 4-bromobenzaldehyde and
3-bromoquinoline (Scheme 2). The desired products 2
and 3 were obtained in only 41% and 43% yields due
to the formation of 4-bromobenzaldehyde and 3-bro-
moisoquinoline homo-coupling side-products.
The Hammet constants for ortho-chloro and ortho-
fluoro substituents on benzenes are very similar (0.20
vs. 0.24).[13] Therefore, 1-chloro-3-fluorobenzene was
expected to be a suitable coupling partner for palladi-
um-catalysed direct arylations. Indeed, we observed
that its couplings with 4-bromobenzonitrile, 4-bromo-
benzaldehyde and 4-bromonitrobenzene proceeded
quite nicely to give 4–6 in 48–51% yields (Scheme 3).
3-Bromobenzonitrile and 3- or 4-bromopyridines
were found to be slightly less reactive, and 5 mol%
catalyst had to be employed to obtain high conver-
sions of these aryl bromides.
Scheme 3. Palladium-catalysed direct 2-arylation of 1-
chloro-3-fluorobenzene with aryl bromides.
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Scheme 4. Palladium-catalysed direct 3-arylation of 1,2-di-
chloro-4-fluorobenzene with aryl bromides.
The introduction of a second chloro-substituent on
fluorobenzene allowed us to obtain higher yields of
coupling products (Scheme 4). The electron-deficient
meta-substituted aryl bromide, 3-bromonitrobenzene,
in the presence of 1,2-dichloro-4-fluorobenzene gave
the desired product 10 in 64% yield (Scheme 4). A
similar yield of 58% in 11 was obtained using 3-bro-
À
mopyridine. Again, no cleavage of both C Cl bonds
was observed, allowing further transformations. How-
ever, with this reactant, another arylation product
(likely arylation at C-5 of 1,2-dichloro-4-fluoroben-
zene) was detected by GC/MS of the crude mixture.
We then examined the reactivity of 1,4-dichloro-2-
fluorobenzene (Scheme 5). A second chloro-substitu-
ent at this position appears to activate position C-3
and also to prevent arylation at less favourable sites.
With this reactant, in all cases very regioselective ary-
Scheme 5. Palladium-catalysed direct 3-arylation of 1,4-di-
chloro-2-fluorobenzene with aryl bromides.
lations were observed. Moreover, in most cases high benzene with 3-bromoquinoline (Scheme 6). A mix-
yields of the desired coupling products were obtained. ture of 2- and 4-arylation products 24a and 24b was
For example, from 4-bromobenzonitrile, 4-bromoben- obtained in an 85:15 ratio. This result seems to con-
zaldehyde, 4-bromopropiophenone or 4-bromonitro- firm the directing effect of fluoro substituents for
benzene, 12–15 were obtained in 67–82% yields. The such arylations.
presence of meta-substituents on the aryl bromide
1-Fluoro-3-methoxybenzene was found to be much
was also tolerated as 3-bromobenzonitrile and 3-bro- less reactive than 1-chloro-3-fluorobenzene, as its re-
monitrobenzene, afforded 16 and 17 in 64% and 68% action with 5-bromopyrimidine led to a moderate
yields, respectively. On the other hand, no formation conversion of this heteroaryl bromide (Scheme 7,
of products 18 and 19 was observed in the presence of top). Moreover, a poor regioselectivity was observed
the electron-rich aryl bromides, 4-bromotoluene or 4- as the C-2 and C-4 arylation products 25a and 25b
bromoanisole. Pyridines, quinolines or pyrimidines were produced in a 24:17 ratio. This lack of regiose-
are probably the most common heterocyclic motifs lectivity is certainly due to the electron-donating
found in pharmaceutically active compounds. We ob- effect of the methoxy substituent (Hammet constants
served that such heteroaryl bromides are also suitable for an MeO ortho-substituent: À0.39). However, the
coupling partners. The reaction of 3- or 4-bromopyri- higher reactivity of 1-fluoro-3-methoxybenzene vs.
dines, 3-bromoquinoline or 5-bromopyrimidine with fluorobenzene reveals that the arylation of fluoroar-
1,4-dichloro-2-fluorobenzene in the presence of 2–4 enes does not only depend on the electron-withdraw-
mol% PdCl
20–23 in 60–79% yields (Scheme 5, bottom).
In order to further demonstrate the influence of 1,2-dimethoxybenzene
ACHTUNGTRENNUNG(C3H5)ACHTGNUTRENNUNG
fluoro substituents on the regioselectivity of the aryla- (Scheme 7, bottom). Again, a mixture of the arylation
tion, we studied the coupling of 3,5-difluorochloro- products 26a and 26b was obtained in a 27:19 ratio.
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Reactivity of 3-Substituted Fluorobenzenes in Palladium-Catalysed Direct Arylations
As shown in the above sections, the introduction of
an electron-withdrawing group such as Br or Cl in the
meta-position of the fluorine atom of monofluoroben-
À
zenes enhances the reactivity of the C H bond at the
ortho-position. We next investigated others electron-
withdrawing groups. Firstly, we tested the reactivity of
2-fluoro-1-methyl-4-nitrobenzene with 4-bromobenzo-
nitrile or 3-bromoquinoline. Under the standard con-
ditions, the coupling products 27 and 28 were ob-
tained in 37% and 29% yields, respectively
(Scheme 8). The methyl group at the C-1 position of
the starting materials blocks this position and the ary-
lation took place mainly in the C-3 position. Howev-
er, trace amounts of another arylated product were
detected in the crude mixtures.
Scheme 6. Palladium-catalysed direct arylation of 3,5-di-
fluorochlorobenzene with 3-bromoquinoline.
Next, we turned our attention to the CN group,
which is less electron-withdrawing than the NO2
group (Hammet constants for NO2: 0.8, for CN: 0.71).
Using 3-fluoro-4-methylbenzonitrile as the coupling
partner, moderate to good yields of 29–31 and 33
were observed using diverse aryl bromides such as 4-
bromobenzonitrile, 4-bromobenzaldehyde, 3-bromoni-
trobenzene, or 3-bromoquinoline. Moreover, from
ortho-substituted 2-bromotoluene, 32 was also ob-
tained in high yield (Scheme 9). In contrast to the
NO2 substituent, with the CN substituent the aryla-
tion took place only at the C-2 position and no other
coupling products were detected by GC/MS analysis
of the crude mixture.
From the previous experiments, we have shown
that the introduction of a bromo-substituent at C-3 of
fluorobenzene has an activating effect (Table 1,
Scheme 2). We next selected 4-bromo-2-fluoro-1-me-
thoxybenzene as substrate. The effect of both m-OMe
and o-Br substituents led to similar yields as the reac-
tions with 1-halo-3-fluorobenzene. Reactions with 3-
bromobenzonitrile, 3-bromoquinoline or 5-bromopyri-
midine afforded 34, 35, and 36 in 38–48% yields
(Scheme 10).
The Hammet constants of ortho- and meta-substitu-
ents on benzenes (Figure 2) seems to be quite effec-
À
tive to rationalise the reactivity of C-2 H of 3-substi-
tuted fluorobenzenes. For Cl or F substituents, the
s constant is 0.20 or 0.24, respectively and they are
Scheme 7. Palladium-catalysed arylations of 1-fluoro-3-me-
thoxybenzenes with aryl bromides.
Scheme 8. Palladium-catalysed 3-arylation of 2-fluoro-1-methyl-4-nitrobenzene with aryl bromides.
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Figure 2. Calculated Hammet constants for meta- or ortho-
substituents on benzenes.[13]
tained in a 71:29 ratio. As expected, an equimolar
mixture of 4-fluoro-1,2-dimethoxybenzene and 1,3-di-
fluorobenzene using 3-bromoquinoline as the cou-
pling partner led to a mixture of 26a+26b and 38 in
a 24:76 ratio, confirming a deleterious influence of
methoxy substituents on benzene for such couplings.
From, an equimolar mixture of 2-fluoro-1-methyl-4-
nitrobenzene and 1,3-difluorobenzene, again 37 was
the major product with a 27:37 ratio of 33:67. It
should be noted that with this mixture of reactants,
only a partial conversion of 4-bromobenzonitrile was
observed indicating a partial poisoning of the catalyst
by the nitro function. Finally, an equimolar mixture of
3-fluoro-4-methylbenzonitrile and 1,3-difluorobenzene
gave 32 and 37 in a 42:58 ratio. In summary, electron-
withdrawing substituents at C-3 of fluorobenzenes
such as chloro or cyano favour the reaction; whereas
electron-donating substituents such as methoxy are
less favourable. The reactivity order determined by
these competition experiments does not correlate
Scheme 9. Palladium-catalysed 2-arylation of 3-fluoro-4-
methylbenzonitrile with aryl bromides.
Scheme 10. Palladium-catalysed 3-arylation of 4-bromo-2-
fluoro-1-methoxybenzene with aryl bromides.
more reactive than 3-fluoroanisole (so OMe À0.39).
A meta-substituent with a donating effect such as
a chloro (sm Cl 0.37) also favours the reaction.
In order to gain more insight into the influence of
substituents on fluorobenzene, we also performed six
competition reactions to probe the substituent prefer-
ence of this catalyst system for such couplings
(Scheme 11). From an equimolar mixture of 1,3-di-
fluorobenzene and 1-chloro-3-fluorobenzene using 4-
bromobenzonitrile as the coupling partner, in the
presence of 2 mol% PdClACTHNUTRGENNUG(C3H5)ACHTUGNTREN(NNGU dppb) catalyst, the
formation of a mixture of 4 and 37 in a 41:59 ratio
was obtained. This result indicates that a chloro-sub-
À
stituent at an ortho-position of a C H is a slightly less
activating group than a fluoro substituent. A very sim-
ilar result was obtained from a mixture of 1,3-di-
ACHTUNGTRENNUNGfluoroACHTUNGTRENNUNGbenzene and 1-bromo-3-fluorobenzene, with
a ratio of products 1:37 of 38:62. On the other hand,
1,4-dichloro-2-fluorobenzene was found to be more
reactive than 1,3-difluorobenzene, as from an equimo-
Scheme 11. Competitive experiments using equimolar mix-
tures of fluorobenzenes for palladium-catalysed direct aryla-
lar mixture of these reactants, 12 and 37 were ob- tions.
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Reactivity of 3-Substituted Fluorobenzenes in Palladium-Catalysed Direct Arylations
then the solution was stirred at room temperature for
twenty minutes. The solvent was removed under vacuum.
The yellow powder was used without purification. 31P NMR
(81 MHz, CDCl3): d=19.3 (s).
with the Hammet constants. Gorelsky recently ration-
alised the regioselectivity and reactivity for palladi-
um-catalysed direct arylation of arenes by a combina-
tion of two factors: (i) arene distortion energy due to
substituents and (ii) interaction energies with the
metal catalyst.[14] This combination of factors might
General Procedure for the Synthesis of 1–33
À
explain why the less acidic C H bond on 1-fluoro-3-
À
As a typical experiment, the reaction of the aryl bromide
(1 mmol), fluorobenzene derivative (1.5 mmol) and PivOK
(0.280 g, 2 mmol) at 1508C during 16 h in DMA (3 mL) in
methoxybenzene is more reactive than the C H
bonds of fluorobenzene. The arene distortion energy
in 1-fluoro-3-methoxybenzene appears to be more fa-
the presence of PdClACTHNUTRGENN(UG C3H5)CAHTUNGTRNE(NUGN dppb) (12.2 mg, 0.02 mmol)
À
vourable for C H activation than that in fluoroben-
zene.
(see Tables or Schemes) under argon affords the arylation
product after evaporation of the solvent and filtration on
silica gel.
6’-Bromo-2’-fluorobiphenyl-4-carbonitrile (1): From 4-bro-
mobenzonitrile (0.182 g, 1 mmol) and 1-bromo-3-fluoroben-
Conclusions
zene (0.262 g, 1.5 mmol), 1 was obtained; yield: 0.190 g
1
The influence of both electron-withdrawing and elec- (69%). H NMR (400 MHz, CD3CN, 258C): d=7.84 (d, J=
8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz,
2H), 7.36 (q, J=7.3 Hz, 1H), 7.25 (t, J=9.0 Hz, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=159.5 (d, J=
250.3 Hz), 139.1, 131.9, 131.0, 130.6 (d, J=9.0 Hz), 129.1 (d,
J=18.2 Hz), 128.8 (d, J=3.5 Hz), 123.5 (d, J=2.8 Hz),
118.5, 115.1 (d, J=22.9 Hz), 112.2; elemental analysis: calcd.
(%) for C13H7BrFN (276.10): C 56.55, H 2.56; found: C
56.37, H 2.39.
tron-donating substituents such as nitro, nitrile,
chloro, bromo and methoxy at C-3 on fluorobenzenes
for their palladium-catalysed direct C-2 arylation has
been explored. With electron-withdrawing substitu-
ents, the reaction proceeds nicely using 2–4 mol% of
an air-stable palladium catalyst and PivOK in DMA;
and in general, a very regioselective arylation at C-2
was observed. Moderate to high yields in C-2 arylated
3-substituted fluorobenzenes were obtained using
6’-Bromo-2’-fluorobiphenyl-4-carbaldehyde (2): From 4-
bromobenzaldehyde (0.185 g, 1 mmol) and 1-bromo-3-fluo-
chloro, bromo or cyano substituents at C-3 on the flu- robenzene (0.262 g, 1.5 mmol),
2 was obtained; yield:
0.114 g (41%). 1H NMR (400 MHz, CD3CN, 258C): d=
10.07 (s, 1H), 8.00 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz,
1H), 7.55 (d, J=8.1 Hz, 2H), 7.36 (q, J=7.3 Hz, 1H), 7.25
(t, J=9.0 Hz, 1H); 13C NMR (100 MHz, CD3CN, 258C): d=
193.2, 160.3 (d, J=250.3 Hz), 141.4, 137.2, 132.0 (d, J=
9.4 Hz), 131.8, 130.5 (d, J=18.6 Hz), 130.2, 129.8 (d, J=
3.3 Hz), 124.2 (d, J=3.1 Hz), 116.0 (d, J=23.1 Hz); elemen-
tal analysis: calcd. (%) for C13H8BrFO (279.10): C 55.94, H
2.89; found: C 56.14, H 3.11.
orobenzenes. On the other hand, electron-donating
substituents at C-3 of fluorobenzenes such as a me-
thoxy substituent are less favourable and led to mix-
tures of regioisomers and low yields; although such
substrates are more reactive than fluorobenzene.
These arylations were performed using an air-stable
catalyst and an inexpensive base. Moreover, a variety
of substituents such as benzoyl, formyl, nitro, or ni-
trile on the bromobenzene coupling partner was toler-
3-(2-Bromo-6-fluorophenyl)-quinoline (3): From 3-bromo-
ated. The major by-products of these reactions are quinoline (0.208 g, 1 mmol) and 1-bromo-3-fluorobenzene
(0.262 g, 1.5 mmol), 3 was obtained; yield: 0.130 g (43%).
1H NMR (400 MHz, CD3CN, 258C): d=8.84 (s, 1H), 8.28 (s,
1H), 8.12 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.82
(t, J=8.0 Hz, 1H), 7.69–7.60 (m, 2H), 7.42 (q, J=7.3 Hz,
1H), 7.31 (t, J=9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3,
258C): d=160.3 (d, J=250.3 Hz), 151.2, 147.4, 137.3, 130.6
(d, J=9.0 Hz), 130.1, 129.3, 128.8 (d, J=3.4 Hz), 128.1,
127.6, 127.5 (d, J=18.4 Hz), 127.4, 127.0, 124.6 (d, J=
2.9 Hz), 115.1 (d, J=23.0 Hz); elemental analysis: calcd.
(%) for C15H9BrFN (302.14): C 59.63, H 3.00; found: C
59.91, H 2.87.
a base associated to HBr, and the method avoids the
preliminary preparation of an organometallic reduc-
ing the number of steps to prepare these compounds.
For these reasons, this process gives an economically
viable and environmentally attractive access to fluoro-
biphenyl derivatives.
Experimental Section
2’-Chloro-6’-fluorobiphenyl-4-carbonitrile (4): From 4-bro-
mobenzonitrile (0.182 g, 1 mmol) and 1-chloro-3-fluoroben-
zene (0.195 g, 1.5 mmol), 4 was obtained; yield: 0.118 g
DMA (N,N-dimethylacetamide) (99%) was purchased from
Acros. KOAc (99%), [PdACHTUNRGTNE(NUG C3H5)Cl]2 (56.5%) and dppb [1,4-
bis(diphenylphosphino)butane] (98%) were purchased from
Alfa Aesar. These compounds were not purified before use.
1
(51%). H NMR (400 MHz, CDCl3, 258C): d=7.75 (d, J=
8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.35–7.30 (m, 2H),
7.15–7.06 (m, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=
159.2 (d, J=249.8 Hz), 137.3, 133.8 (d, J=4.0 Hz), 131.9,
131.1, 130.1 (d, J=9.4 Hz), 127.2 (d, J=18.3 Hz), 125.7 (d,
J=3.6 Hz), 118.6, 114.5 (d, J=22.8 Hz), 112.2; elemental
analysis: calcd. (%) for C13H7ClFN (231.65): C 67.40, H
3.05; found: C 67.57, H 3.18.
(dppb) Catalyst[15]
Preparation of the PdClACTHNUTGRENN(UG C3H5)ACHTUGNTRENNUGN
An oven-dried 40-mL Schlenk tube equipped with a magnet-
ic stirring bar under argon atmosphere, was charged with
[Pd
ACHTUNGTRENNUNG(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg,
1 mmol). 10 mL of anhydrous dichloromethane were added,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
Tao Yan et al.
2’-Chloro-6’-fluorobiphenyl-4-carbaldehyde (5): From 4-
bromobenzaldehyde (0.185 g, 1 mmol) and 1-chloro-3-fluo-
robenzene (0.195 g, 1.5 mmol), 5 was obtained; 0.112 g
132.7 (d, J=4.0 Hz), 130.9 (d, J=9.8 Hz), 129.4, 129.2 (d,
J=4.0 Hz), 128.3 (d, J=19.2 Hz), 125.2, 123.5, 115.3 (d, J=
24.1 Hz); elemental analysis: calcd. (%) for C12H6Cl2FNO2
(286.09): C 50.38, H 2.11; found: C 50.51, H 2.01.
1
(48%). H NMR (400 MHz, CDCl3, 258C): d=10.09 (s, 1H),
7.98 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.35–7.30
(m, 2H), 7.15–7.06 (m, 1H); 13C NMR (75 MHz, CDCl3,
258C): d=191.8, 159.2 (d, J=249.8 Hz), 138.8, 135.9, 133.9
(d, J=4.0 Hz), 131.0, 129.8 (d, J=9.4 Hz), 129.4, 127.7 (d,
J=18.5 Hz), 125.6 (d, J=3.5 Hz), 114.4 (d, J=23.0 Hz); ele-
mental analysis: calcd. (%) for C13H8ClFO (234.65): C 66.54,
H 3.44; found: C 66.40, H 3.21.
2-Chloro-6-fluoro-4’-nitrobiphenyl (6): From 4-bromoni-
trobenzene (0.202 g, 1 mmol) and 1-chloro-3-fluorobenzene
(0.195 g, 1.5 mmol), 6 was obtained; yield: 0.128 g (51%).
1H NMR (400 MHz, CDCl3, 258C): d=8.32 (d, J=8.1 Hz,
2H), 7.56 (d, J=8.1 Hz, 2H), 7.35–7.30 (m, 2H), 7.17–7.08
(m, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=159.4 (d,
J=249.8 Hz), 147.7, 139.2, 133.9 (d, J=3.8 Hz), 131.4, 130.3
(d, J=9.5 Hz), 126.9 (d, J=18.3 Hz), 125.7 (d, J=3.3 Hz),
123.4, 114.5 (d, J=22.9 Hz); elemental analysis: calcd. (%)
for C12H7ClFNO2 (251.64): C 57.28, H 2.80; found: C 57.04,
H 2.61.
3-(2,3-Dichloro-6-fluorophenyl)-pyridine (11): From 3-
bromopyridine (0.158 g, 1 mmol) and 1,2-dichloro-4-fluoro-
benzene (0.247 g, 1.5 mmol), 11 was obtained; yield: 0.140 g
1
(58%). H NMR (400 MHz, CDCl3, 258C): d=8.66 (d, J=
3.8 Hz, 1H), 8.59 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.49 (dd,
J=8.8, 5.4 Hz, 1H), 7.41 (dd, J=7.8, 3.8 Hz, 1H), 7.09 (t,
J=8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=
158.5 (d, J=249.8 Hz), 150.4, 149.6, 137.5, 133.0 (d, J=
4.1 Hz), 130.6 (d, J=8.9 Hz), 129.1 (d, J=3.8 Hz), 128.7,
127.2 (d, J=19.5 Hz), 123.1, 115.2 (d, J=24.3 Hz); elemental
analysis: calcd. (%) for C11H6Cl2FN (242.08): C 54.58, H
2.50; found: C 54.31, H 2.37.
3’,6’-Dichloro-2’-fluorobiphenyl-4-carbonitrile (12): From
4-bromobenzonitrile (0.182 g, 1 mmol) and 1,4-dichloro-2-
fluorobenzene (0.247 g, 1.5 mmol), 12 was obtained; yield:
1
0.218 g (82%). H NMR (400 MHz, CD3CN, 258C): d=7.69
(d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.33 (t, J=
7.8 Hz, 1H), 7.19 (d, J=9.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 258C): d=155.2 (d, J=251.5 Hz), 136.6, 132.1 (d, J=
2.8 Hz), 132.0, 130.9, 130.6, 128.4 (d, J=18.4 Hz), 125.9 (d,
J=4.3 Hz), 120.5 (d, J=19.2 Hz), 118.3, 112.7; elemental
analysis: calcd. (%) for C13H6Cl2FN (266.10): C 58.68, H
2.27; found: C 58.41, H 2.04.
2’-Chloro-6’-fluorobiphenyl-3-carbonitrile (7): From 3-bro-
mobenzonitrile (0.182 g, 1 mmol) and 1-chloro-3-fluoroben-
zene (0.195 g, 1.5 mmol), 7 was obtained; yield: 0.106 g
1
(46%). H NMR (400 MHz, CDCl3, 258C): d=7.72 (d, J=
8.1 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.57 (t,
J=7.8 Hz, 1H), 7.35–7.30 (m, 2H), 7.15–7.06 (m, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=160.4 (d, J=
249.8 Hz), 134.7, 134.0 (d, J=3.7 Hz), 133.9, 133.8, 131.8,
130.1 (d, J=9.5 Hz), 129.0, 126.7 (d, J=18.6 Hz), 125.7 (d,
J=3.6 Hz), 118.4, 114.5 (d, J=22.8 Hz), 112.6; elemental
analysis: calcd. (%) for C13H7ClFN (231.65): C 67.40, H
3.05; found: C 67.27, H 3.17.
3-(2-Chloro-6-fluorophenyl)-pyridine (8): From 3-bromo-
pyridine (0.158 g, 1 mmol) and 1-chloro-3-fluorobenzene
(0.195 g, 1.5 mmol), 8 was obtained; yield: 0.099 g (48%).
1H NMR (400 MHz, CDCl3, 258C): d=8.65 (d, J=4.1 Hz,
1H), 8.62 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.40 (dd, J=7.8,
4.1 Hz, 1H), 7.35–7.30 (m, 2H), 7.15–7.06 (m, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=160.3 (d, J=
249.8 Hz), 150.7, 149.3, 137.7, 134.5 (d, J=3.9 Hz), 130.0 (d,
J=9.5 Hz), 128.7, 125.6 (d, J=3.7 Hz), 125.4, 123.0, 114.4 (d,
J=23.0 Hz); elemental analysis: calcd. (%) for C11H7ClFN
(207.63): C 63.63, H 3.40; found: C 63.47, H 3.41.
3’,6’-Dichloro-2’-fluorobiphenyl-4-carbaldehyde
(13):
From 4-bromobenzaldehyde (0.185 g, 1 mmol) and 1,4-di-
chloro-2-fluorobenzene (0.247 g, 1.5 mmol), 13 was ob-
tained; yield: 0.180 g (67%). 1H NMR (400 MHz, CDCl3,
258C): d=10.08 (s, 1H), 7.99 (d, J=8.1 Hz, 2H), 7.52 (d,
J=8.1 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.27 (d, J=9.8 Hz,
1H); 13C NMR (100 MHz, CDCl3, 258C): d=191.7, 155.5 (d,
J=251.3 Hz), 138.0, 136.2, 132.2 (d, J=2.6 Hz), 130.8, 130.3,
129.6, 129.0 (d, J=18.5 Hz), 125.8 (d, J=4.3 Hz), 120.4 (d,
J=19.2 Hz); elemental analysis: calcd. (%) for C13H7Cl2FO
(269.10): C 58.02, H 2.62; found: C 58.27, H 2.47.
(3’,6’-Dichloro-2’-fluorobiphenyl-4-yl)-phenylmethanone
(14): From 4-bromobenzophenone (0.261 g, 1 mmol) and
1,4-dichloro-2-fluorobenzene (0.247 g, 1.5 mmol), 14 was ob-
tained; yield: 0.252 g (73%). 1H NMR (400 MHz, CD3CN,
258C): d=7.89 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H),
7.67 (t, J=7.8 Hz, 1H), 7.60–7.50 (m, 5H), 7.40 (d, J=
9.8 Hz, 1H); 13C NMR (100 MHz, CD3CN, 258C): d=196.7,
156.5 (d, J=248.0 Hz), 138.7, 138.2, 137.0, 133.6, 133.2 (d,
J=2.6 Hz), 131.5, 131.0, 130.7, 130.6, 130.1 (d, J=18.5 Hz),
129.4, 127.1 (d, J=4.3 Hz), 120.9 (d, J=19.2 Hz); elemental
analysis: calcd. (%) for C19H11Cl2FO (345.19): C 66.11, H
3.21; found: C 66.02, H 3.17.
4-(2-Chloro-6-fluorophenyl)-pyridine (9): From 4-bromo-
pyridine hydrochloride (0.194 g, 1 mmol) and 1-chloro-3-flu-
orobenzene (0.195 g, 1.5 mmol), 9 was obtained; yield:
1
0.091 g (44%). H NMR (400 MHz, CD2Cl2, 258C): d =8.69
(d, J=3.8 Hz, 2H), 7.38–7.30 (m, 4H), 7.15–7.06 (m, 1H);
13C NMR (100 MHz, CD2Cl2, 258C): d =159.9 (d, J=
249.8 Hz), 150.2, 141.0, 134.0 (d, J=4.2 Hz), 130.8 (d, J=
9.5 Hz), 126.7, 126.1 (d, J=3.7 Hz), 125.4, 114.9 (d, J=
22.9 Hz); elemental analysis: calcd. (%) for C11H7ClFN
(207.63): C 63.63, H 3.40; found: C 63.71, H 3.57.
3,6-Dichloro-2-fluoro-4’-nitrobiphenyl (15): From 4-bro-
monitrobenzene (0.202 g, 1 mmol) and 1,4-dichloro-2-fluoro-
benzene (0.247 g, 1.5 mmol), 15 was obtained; yield: 0.203 g
1
(71%). H NMR (400 MHz, CDCl3, 258C): d=8.34 (d, J=
8.1 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.42 (t, J=7.8 Hz,
1H), 7.29 (d, J=9.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
258C): d=155.5 (d, J=251.3 Hz), 147.9, 138.4, 132.1 (d, J=
2.6 Hz), 131.2, 130.8, 128.1 (d, J=18.5 Hz), 126.0 (d, J=
4.3 Hz), 123.6, 120.6 (d, J=19.2 Hz); elemental analysis:
calcd. (%) for C12H6Cl2FNO2 (286.09): C 50.38, H 2.11;
found: C 50.48, H 2.19.
2,3-Dichloro-6-fluoro-3’-nitrobiphenyl (10): From 3-bro-
monitrobenzene (0.202 g, 1 mmol) and 1,2-dichloro-4-fluoro-
benzene (0.247 g, 1.5 mmol), 10 was obtained; yield: 0.183 g
1
(64%). H NMR (400 MHz, CDCl3, 258C): d=8.35–8.28 (m,
1H), 8.23 (s, 1H), 7.70–7.65 (m, 2H), 7.53 (dd, J=8.8,
5.4 Hz, 1H), 7.12 (t, J=8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 258C): d=158.2 (d, J=249.8 Hz), 148.2, 136.2, 134.0,
8
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FULL PAPERS
Reactivity of 3-Substituted Fluorobenzenes in Palladium-Catalysed Direct Arylations
3’,6’-Dichloro-2’-fluorobiphenyl-3-carbonitrile (16): From
3-bromobenzonitrile (0.182 g, 1 mmol) and 1,4-dichloro-2-
fluorobenzene (0.247 g, 1.5 mmol), 16 was obtained; yield:
9.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, 258C): d =158.5,
127.6, 155.8 (d, J=251.5 Hz), 132.6 (d, J=2.9 Hz), 131.4,
126.6, 126.1 (d, J=4.4 Hz), 123.4 (d, J=18.2 Hz), 120.8 (d,
J=19.0 Hz); elemental analysis: calcd. (%) for C10H5Cl2FN2
(243.06): C 49.41, H 2.07; found: C 49.32, H 2.05.
1
0.170 g (64%). H NMR (400 MHz, CD2Cl2, 258C): d=7.80–
7.70 (m, 1H), 7.67 (s, 1H), 7.65–7.60 (m, 2H), 7.44 (t, J=
7.8 Hz, 1H), 7.31 (d, J=9.8 Hz, 1H); 13C NMR (100 MHz,
CD2Cl2, 258C): d=156.0 (d, J=251.5 Hz), 134.9, 134.0,
133.6, 132.8 (d, J=2.8 Hz), 132.7, 131.0, 129.7, 128.4 (d, J=
18.4 Hz), 126.4 (d, J=4.2 Hz), 120.8 (d, J=19.0 Hz), 118.6,
113.2; elemental analysis: calcd. (%) for C13H6Cl2FN
(266.10): C 58.68, H 2.27; found: C 58.78, H 2.32.
3-(2,4-Dichloro-6-fluorophenyl)quinoline (24a) and 3-(2,6-
dichloro-4-fluorophenyl)quinoline (24b): From 3-bromoqui-
noline (0.208 g, 1 mmol) and 1,3-dichloro-5-fluorobenzene
(0.178 mL, 1.5 mmol), 24a and 24b were obtained as a mix-
ture; yield: 0.224 g (77%) in an 85:15 ratio. 1H NMR
(300 MHz, CDCl3, 258C): d=8.89 (bs, 0.85H, 24a), 8.81 (d,
J=2.1 Hz, 0.15H, 24b), 8.20 (bs, 1.7H, 24a), 8.18 (bs, 0.15H,
24b), 8.13 (d, J=1.9 Hz, 0.15H 24b), 7.89 (dd, J=1.5 and
7.7 Hz, 1H, 24a and 24b), 7.8 (ddd, J=1.6, 7.0, and 8.8 Hz,
1H, 24a and 24b) 7.62 (ddd, J=1.0, 6.6 and 7.9 Hz, 1H, 24a
and 24b), 7.42 (t, J=1.9 Hz, 0.85H, 24a), 7.25 (s, 0.15H,
24b), 7.22 (dd, J=2.0 and 8.8 Hz, 0.85H, 24a), 6.86 (s,
0.15H, 24b); 13C NMR (75.5 MHz, CDCl3, 258C): d=160.3
(d, J=254.0 Hz), 150.9, 147.5, 137.7, 135.4 (d, J=4.7 Hz),
135.1 (d, J=12.0 Hz), 130.4, 129.2, 128.0, 127.4, 127.2, 126.0
(d, J=2.7 Hz), 125.0, 124.3 (d, J=18.7 Hz), 115.6 (d, J=
26.6 Hz); elemental analysis: calcd. (%) for C15H8ClF2N
(275.68): C 65.35, H 2.92; found: C 65.17, H 3.11.
3,6-Dichloro-2-fluoro-3’-nitrobiphenyl (17): From 3-bro-
monitrobenzene (0.202 g, 1 mmol) and 1,4-dichloro-2-fluoro-
benzene (0.247 g, 1.5 mmol), 17 was obtained; yield: 0.194 g
1
(68%). H NMR (400 MHz, CDCl3, 258C): d=8.24 (d, J=
8.2 Hz, 1H), 8.19 (s, 1H), 7.64–7.58 (m, 2H), 7.35 (t, J=
7.8 Hz, 1H), 7.22 (d, J=9.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 258C): d=155.6 (d, J=251.5 Hz), 148.2, 136.2, 133.4,
132.4 (d, J=2.4 Hz), 130.7, 129.4, 127.8 (d, J=18.4 Hz),
125.9 (d, J=4.2 Hz), 125.3, 123.6, 120.6 (d, J=19.0 Hz); ele-
mental analysis: calcd. (%) for C12H6Cl2FNO2 (286.09): C
50.38, H 2.11; found: C 50.18, H 2.25.
3-(3,6-Dichloro-2-fluorophenyl)-pyridine (20): From 3-
bromopyridine (0.158 g, 1 mmol) and 1,4-dichloro-2-fluoro-
benzene (0.247 g, 1.5 mmol), 20 was obtained; yield: 0.148 g
5-(2-Fluoro-6-methoxyphenyl)-pyrimidine (25a) and 5-(2-
fluoro-4-methoxyphenyl)-pyrimidine (25b): From 5-bromo-
pyrimidine (0.159 g, 1 mmol) and 1-fluoro-3-methoxyben-
zene (0.189 g, 1.5 mmol), 25a and 25b; yields: 0.049 g (24%)
and 0.034 g (17%), respectively.
1
(61%). H NMR (400 MHz, CD3OD, 258C): d=8.61 (d, J=
3.6 Hz, 1H), 8.53 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.60–7.50
(m, 2H), 7.41 (d, J=9.8 Hz, 1H); 13C NMR (100 MHz,
CD3OD, 258C): d=157.1 (d, J=251.5 Hz), 150.9, 150.3,
139.9 (d, J=0.9 Hz), 134.0 (d, J=2.5 Hz), 132.2, 130.3, 127.8
(d, J=18.6 Hz), 127.4 (d, J=4.2 Hz), 125.2, 121.5 (d, J=
19.1 Hz); elemental analysis: calcd. (%) for C11H6Cl2FN
(242.08): C 54.58, H 2.50; found: C 54.41, H 2.49.
1
25a: H NMR (400 MHz, CDCl3, 258C): d=9.16 (s, 1H),
8.81 (s, 2H), 7.36 (q, J=7.9 Hz, 1H), 6.89–6.78 (m, 2H),
3.82 (s, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=160.3
(d, J=247.1 Hz), 158.0 (d, J=2.2 Hz), 157.8 (d, J=6.5 Hz),
157.2, 130.8 (d, J=10.9 Hz), 126.2, 111.6 (d, J=17.3 Hz),
108.5 (d, J=22.8 Hz), 106.8 (d, J=3.0 Hz), 56.1; elemental
analysis: calcd (%) for C11H9FN2O (204.20): C 64.70, H
4.44; found: C 64.87, H 4.28.
4-(3,6-Dichloro-2-fluorophenyl)-pyridine (21): From 4-
bromopyridine hydrochloride (0.194 g, 1 mmol) and 1,4-di-
chloro-2-fluorobenzene (0.247 g, 1.5 mmol), 21 was ob-
1
1
tained; yield: 0.181 g (75%). H NMR (400 MHz, CD3OD,
25b: H NMR (400 MHz, CDCl3, 258C): d=9.17 (s, 1H),
258C): d=8.67 (d, J=4.9 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H),
7.25–7.18 (m, 3H); 13C NMR (100 MHz, CD3OD, 258C): d=
156.5 (d, J=251.5 Hz), 150.5, 142.6, 133.2 (d, J=2.9 Hz),
132.4, 128.7 (d, J=18.5 Hz), 127.5 (d, J=4.4 Hz), 126.7,
121.6 (d, J=18.9 Hz); elemental analysis: calcd. (%) for
C11H6Cl2FN (242.08): C 54.58, H 2.50; found: C 54.41, H
2.49.
8.89 (s, 2H), 7.36 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.8 Hz,
1H), 6.78 (d, J=12.5 Hz, 1H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=161.8 (d, J=1.4 Hz), 158.0 (d,
J=250.8 Hz), 157.1, 156.0 (d, J=4.0 Hz), 130.3 (d, J=
5.1 Hz), 129.7, 114.2 (d, J=14.3 Hz), 111.1 (d, J=3.0 Hz),
102.4 (d, J=25.9 Hz), 55.7.
3-(6-Fluoro-2,3-dimethoxyphenyl)-quinoline (26a) and 3-
(2-fluoro-4,5-dimethoxyphenyl)-quinoline (26b): From 3-
bromoquinoline (0.208 g, 1 mmol) and 4-fluoro-1,2-dime-
thoxybenzene (0.234 g), 26a and 26b were obtained; yields:
0.076 g (27%) and 0.054 g (19%), respectively.
3-(3,6-Dichloro-2-fluorophenyl)-quinoline (22): From 3-
bromoquinoline (0.208 g, 1 mmol) and 1,4-dichloro-2-fluoro-
benzene (0.247 g, 1.5 mmol), 22 was obtained; yield: 0.231 g
1
(79%). H NMR (400 MHz, CDCl3, 258C): d =8.89 (s, 1H),
1
8.19 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.8 Hz,
1H), 7.78 (d, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.41
(t, J=7.8 Hz, 1H), 7.30 (d, J=9.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 258C): d =156.0 (d, J=251.5 Hz), 150.8,
147.6, 137.4, 132.9 (d, J=2.9 Hz), 130.5, 130.3, 129.3, 128.1,
127.3, 127.1, 126.8 (d, J=18.5 Hz), 125.9 (d, J=4.1 Hz),
125.2, 120.5 (d, J=19.1 Hz); elemental analysis: calcd. (%)
for C15H8Cl2FN (292.13): C 61.67, H 2.76; found: C 61.57, H
2.89.
26a: H NMR (400 MHz, CDCl3, 258C): d=9.00 (s, 1H),
8.27 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz,
1H), 7.75 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 6.95–
6.92 (m, 2H), 3.91 (s, 3H), 3.62 (s, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=153.2 (d, J=241.3 Hz), 150.9
(d, J=1.6 Hz), 148.5 (d, J=3.0 Hz), 146.5 (d, J=5.4 Hz),
146.0, 136.4 (d, J=2.0 Hz), 128.7, 128.1, 127.1, 126.7, 125.7,
124.0, 119.9 (d, J=16.9 Hz), 111.6 (d, J=10.0 Hz), 109.5 (d,
J=23.9 Hz), 59.9, 55.4; elemental analysis: calcd. (%) for
C17H14CFNO2 (283.30): C 72.07, H 4.98; found: C 72.27, H
5.14.
5-(3,6-Dichloro-2-fluorophenyl)-pyrimidine (23): From 5-
bromopyrimidine (0.159 g, 1 mmol) and 1,4-dichloro-2-fluo-
robenzene (0.247 g, 1.5 mmol), 23 was obtained; yield:
1
26b: H NMR (400 MHz, CDCl3, 258C): d=9.08 (s, 1H),
1
0.146 g (60%). H NMR (400 MHz, CDCl3, 258C): d =9.28
8.27 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz,
(s, 1H), 8.78 (s, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.32 (d, J=
1H), 7.72 (t, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 6.99
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(d, J=7.3 Hz, 1H), 6.79 (d, J=11.6 Hz, 1H), 3.93 (s, 6H);
13C NMR (100 MHz, CDCl3, 258C): d=154.3 (d, J=
242.1 Hz), 150.8 (d, J=3.8 Hz), 150.1 (d, J=9.7 Hz), 147.0,
145.9 (d, J=2.5 Hz), 135.0 (d, J=3.4 Hz), 129.5, 129.2, 128.9
(d, J=2.1 Hz), 127.9, 127.8, 126.9, 116.3 (d, J=15.0 Hz),
112.4 (d, J=4.7 Hz), 100.8 (d, J=28.6 Hz), 56.6, 56.3.
258C): d=156.9 (d, J=249.6 Hz), 147.2, 134.8 (d, J=
1.6 Hz), 132.4, 131.2 (d, J=5.6 Hz), 131.0, 129.9 (d, J=
18.5 Hz), 128.7, 128.0 (d, J=4.8 Hz), 124.0 (d, J=2.5 Hz),
123.0, 116.0 (d, J=4.3 Hz), 110.2 (d, J=4.2 Hz), 14.3 (d, J=
4.2 Hz); elemental analysis: calcd. (%) for C14H9FN2O2
(256.23): C 65.62, H 3.54; found: C 65.78, H 3.40.
2’-Fluoro-3’-methyl-6’-nitrobiphenyl-4-carbonitrile
From 4-bromobenzonitrile (0.182 g, 1 mmol) and 2-fluoro-1-
(27):
6-Fluoro-5,2’-dimethylbiphenyl-2-carbonitrile (32): From
2-bromotoluene (0.171 g, 1 mmol) and 3-fluoro-4-methyl-
benzonitrile (0.203 g, 1.5 mmol), 32 was obtained; yield:
methyl-4-nitrobenzene (0.232 g, 1.5 mmol), 27 was obtained;
1
1
yield: 0.095 g (37%). H NMR (400 MHz, CDCl3, 258C): d=
0.144 g (64%). H NMR (300 MHz, CDCl3, 258C): d=7.48
7.70 (d, J=9.0 Hz, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.35–7.30
(m, 3H), 2.34 (d, J=2.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3, 258C): d=157.8 (d, J=252.0 Hz), 147.3, 136.2, 132.4,
132.1 (d, J=19.2 Hz), 131.6 (d, J=6.1 Hz), 129.9 (d, J=
1.5 Hz), 129.1, 123.2 (d, J=21.4 Hz), 120.1 (d, J=4.4 Hz),
118.6, 112.7, 15.4 (d, J=3.7 Hz); elemental analysis: calcd.
(%) for C14H9FN2O2 (256.23): C 65.62, H 3.54; found: C
65.48, H 3.44.
(d, J=8.0 Hz, 1H), 7.42–7.35 (m, 2H), 7.34–7.28 (m, 2H),
7.23 (dd, J=7.2, 0.8 Hz, 1H), 2.41 (d, J=2.1 Hz, 3H), 2.19
(s, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=156.9 (d,
J=248.7 Hz), 135.5, 131.6 (d, J=22.3 Hz), 130.7, 130.3,
130.0 (d, J=5.6 Hz), 129.3, 128.7, 128.3, 127.3 (d, J=4.2 Hz),
124.9, 116.2 (d, J=3.8 Hz), 111.2 (d, J=4.9 Hz), 18.6 (d, J=
1.9 Hz), 14.2 (d, J=4.1 Hz); elemental analysis: calcd. (%)
for C15H12FN (225.26): C 79.98, H 5.37; found: C 79.78, H
5.17.
3-(2-Fluoro-3-methyl-6-nitrophenyl)-quinoline (28): From
3-bromoquinoline (0.208 g, 1 mmol) and 2-fluoro-1-methyl-
4-nitrobenzene (0.232 g, 1.5 mmol), 28 was obtained; yield:
3-Fluoro-4-methyl-2-quinolin-3-ylbenzonitrile (33): From
3-bromoquinoline (0.208 g, 1 mmol) and 3-fluoro-4-methyl-
benzonitrile (0.102 g, 1.5 mmol), 33 was obtained; yield:
1
0.082 g (29%). H NMR (400 MHz, CDCl3, 258C): d=8.76
1
(s, 1H), 8.11 (s, 1H), 8.75 (d, J=8.0 Hz, 1H), 7.79–7.68 (m,
3H), 7.53 (t, J=8.1 Hz, 1H), 7.33 (t, J=8.1 Hz, 1H), 2.35 (s,
3H); 13C NMR (100 MHz, CDCl3, 258C): d=158.3 (d, J=
249.5 Hz), 149.9, 147.7, 147.4, 136.0, 131.8 (d, J=19.1 Hz),
131.2 (d, J=5.5 Hz), 130.2, 129.3, 128.0, 127.4, 127.2, 124.4,
121.4 (d, J=20.6 Hz), 119.9 (d, J=4.0 Hz), 14.2; elemental
analysis: calcd. (%) for C16H11FN2O2 (282.27): C 68.08, H
3.93; found: C 68.17, H 3.90.
0.136 g (52%). H NMR (400 MHz, CDCl3, 258C): d=8.91
(s, 1H), 8.25 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.83 (d, J=
8.2 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H),
7.45 (d, J=7.8 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 2.33 (s,
3H); 13C NMR (100 MHz, CDCl3, 258C): d=158.1 (d, J=
248.7 Hz), 150.4 (d, J=2.3 Hz), 147.7, 137.2, 131.9 (m),
130.5, 129.3, 129.2 (d, J=4.4 Hz), 128.9, 128.2, 127.3, 127.2,
125.1, 117.2 (d, J=3.7 Hz), 111.6 (d, J=4.4 Hz), 15.2; ele-
mental analysis: calcd, (%) for C17H11FN2 (262.28): C 77.85,
H 4.23; found: C 77.89, H 4.09.
6’-Bromo-2’-fluoro-3’-methoxybiphenyl-3-carbonitrile
(34): From 3-bromobenzonitrile (0.182 g, 1 mmol) and 4-
bromo-2-fluoro-1-methoxybenzene (0.102 g, 1.5 mmol), 34
was obtained; yield: 0.128 g (42%). 1H NMR (400 MHz,
CDCl3, 258C): d=7.66–7.61 (m, 1H), 7.58 (s, 1H), 7.52–7.48
(m, 2H), 7.34 (dd, J=8.9, 2.0, 1H), 6.84 (t, J=8.7 Hz, 1H),
3.84 (s, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=149.9
(d, J=251.5 Hz), 147.6 (d, J=11.0 Hz), 135.6, 134.7, 133.8,
131.9, 129.1, 129.0 (d, J=15.1 Hz), 128.0 (d, J=4.8 Hz),
118.5, 114.2 (d, J=2.9 Hz), 113.3 (d, J=2.0 Hz), 112.6, 56.5;
elemental analysis: calcd. (%) for C14H9BrFNO (306.13): C
54.93, H 2.96; found: C 55.11, H 3.08.
6-Fluoro-5-methylbiphenyl-2,4’-dicarbonitrile (29): From
4-bromobenzonitrile (0.182 g, 1 mmol) and 3-fluoro-4-meth-
ylbenzonitrile (0.203 g, 1.5 mmol), 29 was obtained; yield:
1
0.172 g (73%). H NMR (400 MHz, CDCl3, 258C): d=7.72
(d, J=8.3 Hz, 2H), 7.53 (d, J=7.8 Hz, 2H), 7.43 (d, J=
7.9 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 2.34 (d, J=1.9 Hz,
3H); 13C NMR (100 MHz, CDCl3, 258C): d =157.7 (d, J=
249.0 Hz), 136.5, 132.3, 132.1 (d, J=5.6 Hz), 132.0, 130.7 (d,
J=1.6 Hz), 130.5 (d, J=19.2 Hz), 129.1 (d, J=4.8 Hz),
118.3, 117.0 (d, J=4.1 Hz), 113.0, 111.0 (d, J=4.5 Hz), 15.2
(d, J=4.0 Hz); elemental analysis: calcd. (%) for C15H9FN2
(236.24): C 76.26, H 3.84; found: C 76.40, H 3.99.
6-Fluoro-4’-formyl-5-methylbiphenyl-2-carbonitrile (30):
From 4-bromobenzaldehyde (0.203 g, 1 mmol) and 3-fluoro-
4-methylbenzonitrile (0.203 g, 1.5 mmol), 30 was obtained;
3-(6-Bromo-2-fluoro-3-methoxyphenyl)-quinoline
(35):
1
yield: 0.098 g (41%). H NMR (400 MHz, CDCl3, 258C): d=
From 3-bromoquinoline (0.208 g, 1 mmol) and 4-bromo-2-
fluoro-1-methoxybenzene (0.102 g, 1.5 mmol), 35 was ob-
tained; yield: 0.153 g (46%). 1H NMR (400 MHz, CDCl3,
258C): d=8.80 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 8.06 (s,
1H), 7.76 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.48
(t, J=7.8 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.81 (t, J=
6.7 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3,
258C): d=151.1 (d, J=1.6 Hz), 150.2 (d, J=250.3 Hz), 147.5
(d, J=11.9 Hz), 147.4, 137.2, 130.0, 129.2, 128.0, 127.9 (d, J=
4.7 Hz), 127.7 (d, J=15.1 Hz), 127.4 (d, J=18.3 Hz), 126.9,
114.0 (d, J=3.2 Hz), 113.9, 56.4, elemental analysis: calcd.
(%) for C16H11BrFNO (332.17): C 57.85, H 3.34; found: C
57.99, H 3.10.
10.0 (s, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.59 (d, J=8.3 Hz,
2H), 7.43 (d, J=7.9 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 2.34
(d, J=2 Hz, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=
191.7, 157.7 (d, J=245.6 Hz), 137.8, 136.5, 132.0, 131.8 (d,
J=5.9 Hz), 131.3 (d, J=19.0 Hz), 130.7 (m), 129.8, 129.1 (d,
J=4.5 Hz), 117.3 (d, J=4.4 Hz), 111.9 (d, J=4.9 Hz), 15.3
(d, J=3.9 Hz); elemental analysis: calcd. (%) for
C15H10FNO (239.24): C 75.30, H 4.21; found: C 75.09, H
4.07.
6-Fluoro-5-methyl-3’-nitrobiphenyl-2-carbonitrile
(31):
From 1-bromo-3-nitrobenzene (0.202 g, 1 mmol) and 3-
fluoro-4-methylbenzonitrile (0.203 g, 1.5 mmol), 31 was ob-
tained; yield: 0.118 g (46%). 1H NMR (300 MHz, CDCl3,
258C): d=7.48 (d, J=8 Hz, 1H), 7.42–7.35 (m, 2H), 7.34–
7.28 (m, 2H), 7.23 (dd, J=7.2 and 0.8 Hz, 1H), 2.41 (d, J=
2.1 Hz, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3,
5-(6-Bromo-2-fluoro-3-methoxyphenyl)-pyrimidine (36):
From 5-bromopyrimidine (0.159 g, 1 mmol) and 4-bromo-2-
fluoro-1-methoxybenzene (0.102 g, 1.5 mmol), 36 was ob-
tained; yield: 0.108 g (38%). 1H NMR (400 MHz, CDCl3,
10
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Reactivity of 3-Substituted Fluorobenzenes in Palladium-Catalysed Direct Arylations
258C): d=9.19 (s, 1H), 8.70 (s, 2H), 7.38 (dd, J=8.9, 2.0 Hz,
1H), 6.89 (t, J=8.7 Hz, 2H), 3.86 (s, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=158.2, 157.6 (d, J=1.6 Hz),
150.1 (d, J=252.2 Hz), 147.7 (d, J=11.7 Hz), 128.8, 128.3 (d,
J=4.8 Hz), 124.4 (d, J=15.6 Hz), 114.8 (d, J=2.4 Hz), 113.4
(d, J=1.6 Hz), 56.6; elemental analysis: calcd (%) for
C11H8BrFN2O (283.10): C 46.67, H 2.85; found: C 46.47, H
3.12.
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Supporting Information
1
Copies of H and 13C NMR spectra of the new compounds
are available in the Supporting Information.
Acknowledgements
We are grateful to the “Fondation Rennes1” for a master
grant to T. Y and to the “Chinese Scholarship Council” for
a PhD grant to Z. L.
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12 Reactivity of 3-Substituted Fluorobenzenes in Palladium-
Catalysed Direct Arylations with Aryl Bromides
Adv. Synth. Catal. 2014, 356, 1 – 12
Tao Yan, Liqin Zhao, Mian He, Jean-FranÅois Soulꢀ,
Christian Bruneau, Henri Doucet*
12
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