Synthesis of heteroarylated polyfluorobiphenyls via palladium-catalyzed sequential sp2 C-H bonds functionalizations

Article abstract of DOI:10.1021/jo400221x

The higher reactivity of C5-H bonds of heteroarenes as compared to C-H bonds of bromopolyfluorobenzenes for palladium-catalyzed direct arylation allows the selective synthesis of the polyfluoroaryl-heteroarenes in moderate to high yields, without C-H bond

Full text of DOI:10.1021/jo400221x

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Note
Synthesis of Heteroarylated Polyfluorobiphenyls via Palladium-
catalyzed Sequential sp2 C-H Bonds Functionalizations
Tao Yan, Lu Chen, Christian Bruneau, Pierre H Dixneuf, and Henri Doucet
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400221x • Publication Date (Web): 27 Feb 2013
Downloaded from http://pubs.acs.org on February 28, 2013
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Page 1 of 19
The Journal of Organic Chemistry
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Synthesis of Heteroarylated Polyfluorobiphenyls via
Palladium-catalyzed Sequential sp2 C-H Bonds
Functionalizations
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Tao Yan, Lu Chen, Christian Bruneau, Pierre H. Dixneuf, Henri Doucet*
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Centre of Catalysis and Green
Chemistry”, Campus de Beaulieu, 35042 Rennes, France. henri.doucet@univ-rennes1.fr
Graphical abstract
F
F (H)
Br
F (H)
F (H)
H
Z
R1
Z
R1
F
F
[Pd]
[Pd], ArBr
F
F (H)
Y
Y
H
DMAc, KOAc,
150 °C
DMAc, KOAc,
150 °C
+
F (H)
F (H)
F
R2
F
Z
R1
H
Y
Y = O, S
Z = C, N
Abstract: The higher reactivity of C5-H bonds of heteroarenes as compared to C-H bonds of bromopolyfluorobenzenes for
palladium-catalyzed direct arylation allows the selective synthesis of the polyfluoroaryl-heteroarenes in moderate to high
yields, without C-H bond functionalization of the polyfluorobenzene ring. In most cases, low loading of Pd(OAc)2 catalyst
(0.5-1 mol%) was employed. Then, from these heteroarylated polyfluorobenzenes, the palladium-catalysed C-H bond
functionalization of the polyfluorobenzene ring allows the synthesis of heteroarylated polyfluorobiphenyls.
The palladium-catalyzed direct arylation of several (hetero)aromatics via direct C–H bond activation using aryl halides has
brought a synthesis revolution in recent years.1-3 Such couplings are very attractive to replace classical palladium-catalysed
reactions such as Stille, Suzuki or Negishi couplings as they do not require the preliminary synthesis of one or two
organometallic derivatives.1 Several bioactive compounds contain a (poly)fluorobenzene motif. For example, Atorvastatin
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Page 2 of 19
and Fluvastatin are used for lowering blood cholesterol, Rufinamide is an anticonvulsant and Robanacoxib is a non-steroidal
anti-inflammatory drug (Fig. 1). Therefore, the discovery of general simple routes to functionalize (poly)fluorobenzenes has
potential for medicinal chemistry. More importantly, the tetrafluorobenzene unit also has potential for the production of
molecular materials for optics.4
1
2
3
4
5
6
7
8
9
F
F
O
F
N
N
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NHPh
O
O
N
NH2
F
F
NH
CO2H
N
F
F
F
Cl
N
R
O
NHR
Flucloxacillin
Et
Atorvastatin
Rufinamide
Robenacoxib
Figure 1. Examples of bioactive fluorobenzene derivatives.
Several examples of palladium-catalyzed direct arylation of heteroaromatics with aryl halides have been reported.1-3
Fagnou and co-workers and other groups have already reported examples of palladium-catalyzed direct arylations of
polyfluorobenzenes5-9 with aryl halides. They observed that C-H bonds bearing two fluoro substituents at the ortho position
in pentafluorobenzene, tetrafluorobenzenes or even 1,3,5-trifluorobenzene, could be arylated with aryl halides (Scheme 1,
top).5a-c In 2012, Zhang and co-workers have reported the coupling of 3-bromo-1,2,4,5-tetrafluorobenzene with iodoanisole
to give the 4-bromo-2,3,5,6-tetrafluoro-4'-methoxybiphenyl using 5 mol% of Pd(OAc)2 associated to 10 mol% of PPh3 as
catalyst (Scheme 1, middle).10 In the course of this reaction, no cleavage of the C-Br bond of the tetrafluorobenzene
derivative was observed.
On the other hand, to our knowledge, the selective direct heteroarylation of tri- or tetra-fluorobromobenzenes without C-H
bond activation of the polyfluorobenzene moiety has not been described (Scheme 1, bottom). The discovery of an effective
method, for the sequential functionalization of C-H and C-Br bonds of bromopolyfluorobenzenes with heteroarenes,
especially under low catalyst loading conditions would be considerable advantage for simpler access to fluoro-containing
poly(hetero)aryls.
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The Journal of Organic Chemistry
Previous work5
ArX +
F
F
F
F
1
2
3
4
5
6
7
8
F
F
F
F
[Pd]
H
F
Ar
F
base
Previous work10
F
F
F
F
F
F
[Pd]
+
ArI
H
Br
Ar
Br
9
base
10
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F
F
This work
F
F
F (H)
F (H)
Br
[Pd]
H
H
H
base
Y
Y
+
F
F (H)
ArBr
F (H)
F
F (H)
[Pd], base
F
Ar
Y
F (H)
F
Scheme 1. Palladiumꢀcatalyzed direct arylation using polyfluorobenzene derivatives
Here, we wish to report (i) the efficient palladium-catalyzed heteroarylation of bromopolyfluorobenzenes, without C-H
bond activation of the fluorobenzenes moiety, with a wide variety of heteroarenes using low loadings of a phosphine-free
palladium catalyst; (ii) the subsequent reactivity of these formed heteroarylated polyfluorobiphenyls for palladium-catalysed
C-H bond functionalization at the polyfluorobenzene ring to produce heteroarylated polyfluorobiphenyls.
As the free energy of activation for direct arylation via Concerted Metalation Deprotonation (CMD)11,12 pathway calculated
by Fagnou and co-workers for 1,3-difluorobenzene or pentafluorobenzene are quite similar to those of furan, thiophene and
thiazole, the outcome of the reaction of bromopolyfluorobenzenes with heteroarenes in the presence of palladium-catalysts
was quite unpredictable and needed to be investigated (Figure 2).
F
F
F
N
H
H
S
Y
F
H
H
Y = S 25.6
Y = O 25.3
21.9
25.4
23.7
F
F
F
Figure 2. Free energy of activation (ꢁG‡298K, kcal mol−1) for direct arylation via the CMD pathway involving an
acetate ligand with the [Pd(C6H5)(PMe3)(OAc)] catalyst.11
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2-Methyl-2-thiophen-2-yl-[1,3]dioxolane and 3-bromo-1,2,4,5-tetrafluorobenzene were employed as model substrates for
our study (Scheme 2, Table 1). We initially examined the influence of the nature of the base on aryl bromide conversion for
this reaction using DMAc as the solvent and 0.5 mol% Pd(OAc)2 catalyst. We had previously observed that these reaction
conditions allowed the coupling of several heteroaromatics with aryl bromides.2f K2CO3 or Cs2CO3 gave low conversion of
3-bromo-1,2,4,5-tetrafluorobenzene (Table 1, entries 1 and 2). On the other hand, in the presence of acetate salts, NaOAc,
KOAc or CsOAc as the base, high conversions of 3-bromo-1,2,4,5-tetrafluorobenzene were observed, and the coupling
product 1a, retaining the C-H bond of fluorinated aryl group, was isolated in 60-74% yields (Table 1, entries 3-5). In all
cases, no formation of product 1b was detected. Thus these experiments show that the activation of the thienyl C5-H bond is
easier than that of the C6-H bond of 3-bromo-1,2,4,5-tetrafluorobenzene. The good performance of acetate as the base/ligand
is consistent with the CMD pathway.12
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2
3
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F
F
H
S
+
O
H
O
Pd(OAc)2
base
S
O
F
F
O
F
F
F
F
1a
F
F
F
Br
H
Br
H
F
F
F
F
F
1b not detected
Scheme 2. Coupling of 3ꢀbromoꢀ1,2,4,5ꢀtetrafluorobenzene with 2ꢀmethylꢀ2ꢀthiophenꢀ2ꢀylꢀ[1,3]dioxolane
Table 1: Influence of reaction conditions on the 5ꢀ
arylation of 2ꢀmethylꢀ2ꢀthiophenꢀ2ꢀylꢀ[1,3]dioxolane
with 3ꢀbromoꢀ1,2,4,5ꢀtetrafluorobenzene (Scheme 2)
Entry Solvent Base
Temp. Conv. Yield in 1a
(°C)
150
(%)
10
2
(%)
-
1
2
3
4
5
6
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
K2CO3
Cs2CO3 150
NaOAc 150
-
96
84
98
98
65
74
60
40a
KOAc
CsOAc 150
KOAc 150
150
Conditions: Pd(OAc)2 (0.005 equiv.), 3-bromo-1,2,4,5-
tetrafluorobenzene (1 equiv.), 2-methyl-2-thiophen-2-yl-
[1,3]dioxolane (1.5 equiv.), base (2 equiv.), 16 h, conv. of 3-
bromo-1,2,4,5-tetrafluorobenzene, isolated yields. a formation of
unidentified side-products was also observed.
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The Journal of Organic Chemistry
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9
Then, 3-bromo-1,2,4,5-tetrafluorobenzene was coupled with a set of heteroarenes in the presence of 0.5-1 mol%
Pd(OAc)2, KOAc as the base in DMAc (Scheme 3). Selective 5-arylations of the heteroarenes were observed using 2-
methylthiophene and ethyl thiophene-2-carboxylate to give 2 and 3 in 62% and 60% yields, respectively. Good yields were
also obtained for the coupling of 2-isopropyl-4-methylthiazole or 2-ethyl-4-methylthiazole with 3-bromo-1,2,4,5-
tetrafluorobenzene to give 4 and 5 in 61% and 66% yield, respectively. It should be noted that 2-n-butylfuran could also be
employed to give 6 in 72% yield. However 2 mol% of the more stable and more electron-rich catalyst PdCl(C3H5)(dppb)13b
had to be employed to obtain a high conversion of the aryl bromide. On the other hand, quite good yields in 7 and 8 were
obtained from 2-furylmethyl acetate or 2-diethoxymethylfuran using 0.5 mol% Pd(OAc)2 catalyst. In all cases, no formation
of 1b was detected by GC/MS analysis of the crude mixture.
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FG
F
F
F
F
Y
Pd(OAc)2
0.5 mol%
FG
Y
H
F
Z
H
KOAc, DMAc,
150 °C, 16 h
+
Z
F
2-8
Br
H
F
F
F
F
F
F
F
F
F
F
F
F
N
R1
R3
S
S
O
R2
F
F
R1
Yield (%)
2 62
R2
Me
H
R3
Yield (%)
Yield (%)
61*
66
Me
4
5
6 72**
7 70
nBu
CO2Et 3 60
CH2OAc
CH(OEt)2
8 53
* using 1% Pd(OAc)2
** using 2% PdCl(C3H5)(dppb), 48 h
Scheme 3. Heteroarylation of 3ꢀbromoꢀ1,2,4,5ꢀtetrafluorobenzene
The di-heteroarylation of 1,4-dibromo-2,3,5,6-tetrafluorobenzene using 2-methyl-2-thiophen-2-yl-[1,3]dioxolane as the
coupling partner was then examined (Scheme 4). The desired product 9 was obtained in 81% yield using 1 mol% Pd(OAc)2
catalyst. This method gives a simple access to compounds displaying useful n-channel semiconductors properties.4e
H
Pd(OAc)2
1 mol%
S
+
O
O
F
F
F
F
F
KOAc, DMAc,
150 °C
F
F
Br
Br
S
S
O
O
O
O
F
9 81%
Scheme 4. Diꢀheteroarylation of 1,4ꢀdibromoꢀ2,3,5,6ꢀtetrafluorobenzene
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The reactivity of 1-bromo-2,3,5-trifluorobenzene was then evaluated for C2 heteroarylation (Scheme 5). This reagent was
successfully coupled with 2-methyl-2-thiophen-2-yl-[1,3]dioxolane, 2-methylthiophene or 2-ethyl-4-methylthiazole to give
the desired products 10-12 in 70-78% yields. Slower reactions and lower yields were observed in the presence of 2-n-
butylfuran or acetic acid furan-2-ylmethyl ester as coupling partners to give 13 and 14 in 51% and 60% yields, respectively.
1
2
3
4
5
6
7
8
9
FG
F
Y
Pd(OAc)2
0.5 mol%
FG
Y
10
11
12
13
14
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60
H
H
Z
+
KOAc, DMAc,
150 °C, 16 h
Z
F
F
F
10-14
Br
H
F
F
F
N
F
F
F
S
F
F
2
1
O
S
12 70%
R
R
F
F
F
1
2
Yield (%)
13 51
14 60
R
R
Yield (%)
78
75
10
11
C(Me)(OCH CH O)
nBu
CH OAc
2
2
Me
2
Scheme 5. Heteroarylation of 1ꢀbromoꢀ2,3,5ꢀtrifluorobenzene
The coupling of 2-bromo-1,3,5-trifluorobenzene with 2-methyl-2-thiophen-2-yl-[1,3]dioxolane was then studied (Scheme 6).
In the presence of 0.5 mol% Pd(OAc)2, 15 was obtained in 69% yield. Again, under these reaction conditions, the two C-H
bonds of this trifluorobenzene derivative were found to be unreactive.
H
O
S
+
Pd(OAc)2
0.5 mol%
O
F
H
H
F
H
H
KOAc, DMAc,
150 °C
F
S
Br
F
O
F
O
15 69%
F
Scheme 6. Heteroarylation of 2ꢀbromoꢀ1,3,5ꢀtrifluorobenzene
Finally, we examined the reactivity of 1-bromo-3,5-difluorobenzene (Scheme 7). The direct coupling of this substrate with 2-
phenylimidazolopyrimidine has already been reported using 8 mol% Pd(OAc)2 associated to 16 mol% PPh3 as catalyst.13
Using again 0.5 mol% Pd(OAc)2 and KOAc in DMAc, the desired coupling products 16 and 17 were obtained in 69% and
80% yields from 2-methyl-2-thiophen-2-yl-[1,3]dioxolane and 2-ethyl-4-methylthiazole as the coupling partners.
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F
1
2
3
4
5
6
7
Y
FG
H
Z
+
S
Pd(OAc)2
0.5 mol%
O
F
F
O
16 69%
H
F
F
KOAc, DMAc,
150 °C, 16 h
or
N
Br
H
8
9
S
H
10
11
12
13
14
15
16
17
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51
52
53
54
55
56
57
58
59
60
F
17 80%
Scheme 7. Heteroarylation of 1ꢀbromoꢀ3,5ꢀdifluorobenzene
Then, the reactivity of the polyfluorobenzene moiety of some of the previously obtained heteroarylated polyfluorobenzene
derivatives was evaluated for arylation via C-H bond activation (Scheme 8). 2-Methyl-2-[5-(2,3,5,6-tetrafluorophenyl)-
thiophen-2-yl]-[1,3]dioxolane 1a in the presence of 4-bromobenzaldehyde and 2 mol% PdCl(C3H5)(dppb) catalyst gave the
desired coupling product 18 in 76% yield. It should be noted that the use of 0.5 mol% Pd(OAc)2 catalyst for this reaction led
to a very low yield in 18. A similar reactivity was observed with 3-bromoacetophenone or 3-bromopyridine to give 19 and
20 in 75% and 66% yields. Then, 2-ethyl-4-methyl-5-(2,3,5,6-tetrafluorophenyl)-thiazole 5 was reacted with ethyl 4-
bromobenzoate and 3-bromobenzonitrile. The desired products 21 and 22 were isolated in 80% and 72% yields. Finally, 23
and 24 were obtained in 66% and 71% yields from 2-n-butyl-5-(2,3,5,6-tetrafluorophenyl)-furan 6 and 2-bromonaphthalene
or 3-bromonitrobenzene as the coupling partners. This coupling arylation of fluorinated arene C-H bonds following the
cross-coupling of heterocycles C-H bonds offers a unique access to a variety of heteroaryl-polyfluoroaryl-aryl derivatives.
F
F
FG
Z
Y
H
F
F
PdCl(C3H5)(dppb)
F
F
F
F
R
1a, 5 or 6
FG
2 mol%
Y
+
KOAc, DMAc,
150 °C
Z
Br
R
18-24
1
2
F
F
F
F
F
R
R
N
S
S
Y
O
F
F
F
O
1
2
R
Yield (%)
R
Y
Yield (%)
4-CO Et 21 80
3-CN
4-CHO
3-COMe CH 19 75
CH 18 76
2
22 72
H
N
20 66
F
F
F
F
O
O
nBu
24 71%
nBu
F
F
F
F
NO
2
23 66%
Scheme 8. 4ꢀArylation of 1ꢀheteroarylꢀ2,3,5,6ꢀtetrafluorobenzenes
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For the couplings with 1-thiazolyl-2,3,5-trifluorobenzene 10, both positions C4 and C6 on the benzene moiety might have
been arylated (Scheme 9). However, with both 4-bromobenzaldehyde and 3-bromopyridine only the arylation at C4 to give
25 and 26 in 81% and 55% yields was observed. This is certainly due to the higher acidity of C4 position.
1
2
3
4
5
6
7
8
9
F
H
F
F
F
O
H
25 81%
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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59
60
S
O
F
F
O
F
F
PdCl(C3H5)(dppb)
2 mol%
O
O
10
+
or
KOAc, DMAc,
150 °C, 20 h
S
N
(Het)ArBr
O
F
O
26 55%
Scheme 9. Regioselective 4ꢀarylation of 1ꢀthienylꢀ2,3,5ꢀtrifluorobenzene
So far, very few examples of palladium-catalyzed direct arylations at C2 of 1,3-difluorobenzene derivatives have been
reported.5a However, we found that the catalytic arylation of the difluorobenzene ring of 17 also proceeded nicely with
various aryl bromides to give compounds 27-29 in good yields (Scheme 10). In all cases, a regioselective arylation at the C-
H adjacent to the two C-F was observed. It should be noted that from 4-chlorobromobenzene, no cleavage of the C-Cl bond
was observed to give 28 in 77% yield allowing further transformations.
H
H
F
F
H
N
N
H
S
S
F
FG
H
F
17
PdCl(C3H5)(dppb)
2 mol%
FG
Yield (%)
+
4-NO2 27 70
4-Cl 28 77
2-CN 29 76
KOAc, DMAc,
150 °C, 20 h
Br
FG
Scheme 10. Regioselective 4ꢀarylation of 1ꢀthiazolylꢀ3,5ꢀdifluorobenzene
In summary, we have demonstrated that C-H bonds of several heteroarenes are more reactive than the C-H bonds of bromo
di-, tri- and tetra-fluorobenzenes towards palladium-catalyzed direct arylation. The selective access to new heteroarylated
polyfluorobenzenes from bromopolyfluorobenzenes and heteroarenes using only 0.5 mol% of Pd(OAc)2 as the catalyst
precursor is reported. The acidity of the C-H bonds adjacent to two ortho C-F bonds of arenes has been profitably used for
their further palladium-catalyzed functionalization. This strategy allows straightforward synthesis of heteroarylated
polyfluorobiphenyls in good yields via two sequential successive catalytic direct arylations.
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Experimental section
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General procedure for palladium-catalyzed direct arylations of bromopolyfluorobenzenes
The reaction of the aryl bromide (1 mmol), heteroarene (1.5 mmol) and KOAc (0.196 g, 2 mmol) at 150 °C during
16 h in DMAc (4 mL) in the presence of Pd(OAc)2 (1.12 mg, 0.005 mmol) or (2.24 mg, 0.01 mmol) (see schemes)
under argon affords the coupling products 1-8 and 10-17 after evaporation of the solvent and purification on silica
gel. Eluent pentane:diethylether 9:1 for compounds 1-5, 7, 8, 10, 12-17; pentane:diethylether 4:1 for compound 6;
pentane for compound 11.
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2-Methyl-2-[5-(2,3,5,6-tetrafluorophenyl)-thiophen-2-yl]-[1,3]dioxolane (1a)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g, 2
mmol) affords 1a in 74% (0.235 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 3.8 Hz, 1H), 7.10 (d, J = 3.8 Hz, 1H), 6.98 (tt, J = 9.5, 7.4 Hz, 1H), 4.12-
3.97 (m, 4H), 1.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.6 (t, J = 3.6 Hz), 146.1 (dm, J = 247.0 Hz), 143.4
(dm, J = 249.8 Hz), 130.5 (t, J = 6.0 Hz), 127.2 (m), 124.3, 115.1 (m), 107.1, 104.0 (t, J = 22.9 Hz), 65.1, 27.6.
Elemental analysis: calcd (%) for C14H10F4O2S (318.29): C 52.83, H 3.17; found: C 53.02, H 3.30.
2-Methyl-5-(2,3,5,6-tetrafluorophenyl)-thiophene (2)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-methylthiophene (0.196 g, 2 mmol) affords 2 in 62%
(0.152 g) yield; amorphous white solid; mp 43-45℃.
1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 3.8 Hz, 1H), 6.95 (tt, J = 9.5, 7.4 Hz, 1H), 6.84 (d, J = 3.8 Hz, 1H), 2.56
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 146.2 (dm, J = 246.8 Hz), 143.4 (dm, J = 249.8 Hz), 143.3 (t, J = 4.0 Hz),
130.6 (t, J = 6.0 Hz), 125.7, 125.2 (m), 115.4 (m), 103.4 (t, J = 22.9 Hz), 15.1. Elemental analysis: calcd (%) for
C11H6F4S (246.22): C 53.66, H 2.46; found: C 53.50, H 2.59.
Ethyl 5-(2,3,5,6-tetrafluorophenyl)-thiophene-2-carboxylate (3)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and ethyl thiophene-2-carboxylate (0.312 g, 2 mmol)
affords 3 in 60% (0.182 g) yield; amorphous yellow solid; mp 82-84℃.
1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 3.8 Hz, 1H), 7.56 (d, J = 3.8 Hz, 1H), 7.06 (tt, J = 9.5, 7.4 Hz, 1H), 4.40
(q, J = 7.3 Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 161.8, 146.4 (dm, J = 246.8 Hz), 143.6
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(dm, J = 249.8 Hz), 136.0 (t, J = 4.0 Hz), 133.8 (m), 132.9, 114.3 (m), 130.6 (t, J = 5.9 Hz), 105.3 (t, J = 22.9 Hz),
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61.5, 14.3. Elemental analysis: calcd (%) for C13H8F4O2S (304.26): C 51.32, H 2.65; found: C 51.49, H 2.36.
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2-Isopropyl-4-methyl-5-(2,3,5,6-tetrafluorophenyl)-thiazole (4)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-isopropyl-4-methylthiazole (0.282 g, 2 mmol) affords
4 in 61% (0.176 g) yield; yellow oil.
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1H NMR (400 MHz, CDCl3): δ 7.10 (tt, J = 9.5, 7.4 Hz, 1H), 3.32 (sept., J = 7.5 Hz, 1H), 2.32 (s, 3H), 1.43 (d, J =
7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 179.2, 152.5, 146.3 (dm, J = 246.8 Hz), 143.7 (dm, J = 249.8 Hz),
113.6, 113.0 (m), 106.1 (tm, J = 22.7 Hz), 33.4, 23.0, 16.1. Elemental analysis: calcd (%) for C13H11F4NS
(289.29): C 53.97, H 3.83; found: C 53.80, H 3.58.
2-Ethyl-4-methyl-5-(2,3,5,6-tetrafluorophenyl)-thiazole (5)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol) affords 5 in
66% (0.181 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.11 (tt, J = 9.5, 7.4 Hz, 1H), 3.05 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.42 (t, J = 7.5
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 174.4, 152.5, 146.3 (dm, J = 246.8 Hz), 143.7 (dm, J = 249.8 Hz), 114.0,
112.8 (m), 106.2 (tm, J = 22.7 Hz), 26.9, 16.0, 14.0. Elemental analysis: calcd (%) for C12H9F4NS (275.27): C
52.36, H 3.30; found: C 52.48, H 3.17.
2-n-Butyl-5-(2,3,5,6-tetrafluorophenyl)-furan (6)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-n-butylfuran (0.258 g, 2 mmol) affords 6 in 72%
(0.196 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 6.95 (tt, J = 9.5, 7.4 Hz, 1H), 6.86 (d, J = 3.1 Hz, 1H), 6.17 (d, J = 3.1 Hz, 1H), 2.72
(t, J = 7.3 Hz, 2H), 1.69 (quint., J = 7.3 Hz, 2H), 1.42 (sext., J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 158.6, 146.3 (dm, J = 246.8 Hz), 143.7 (dm, J = 249.8 Hz), 140.0 (m), 115.0 (t, J = 6.5 H
112.0 (m), 107.0, 103.2 (t, J = 22.7 Hz), 29.9, 27.8, 22.2, 13.8. Elemental analysis: calcd (%) for C14H12F4O
(272.24): C 61.77, H 4.44; found: C 61.78, H 4.59.
Acetic acid 5-(2,3,5,6-tetrafluorophenyl)-furan-2-ylmethyl ester (7)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and acetic acid furan-2-ylmethyl ester (0.280 g, 2 mmol)
affords 7 in 70% (0.201 g) yield; amorphous yellow solid; mp 55-57℃.
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1H NMR (400 MHz, CDCl3): δ 7.02 (tt, J = 9.5, 7.4 Hz, 1H), 6.89 (d, J = 3.1 Hz, 1H), 6.58 (d, J = 3.1 Hz, 1H), 5.13
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(s, 2H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.5, 151.0, 146.4 (dm, J = 246.8 Hz), 143.0 (dm, J = 249.8
Hz), 142.7 (t, J = 3.0 Hz), 114.8 (t, J = 6.3 Hz), 112.2, 111.4 (m), 104.4 (t, J = 22.7 Hz), 57.9, 20.8. Elemental
analysis: calcd (%) for C13H8F4O3 (288.19): C 54.18, H 2.80; found: C 54.25, H 2.99.
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2-Diethoxymethyl-5-(2,3,5,6-tetrafluorophenyl)-furan (8)
3-Bromo-1,2,4,5-tetrafluorobenzene (0.229 g, 1 mmol) and 2-diethoxymethylfuran (0.340 g, 2 mmol) affords 8 in
53% (0.168 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.00 (tt, J = 9.5, 7.4 Hz, 1H), 6.89 (d, J = 3.1 Hz, 1H), 6.59 (d, J = 3.1 Hz, 1H), 5.61
(s, 1H), 3.75-3.60 (m, 4H), 1.25 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 153.7, 146.4 (dm, J = 246.8 Hz), 142.9
(dm, J = 249.8 Hz), 141.8 (m), 114.5 (t, J = 6.3 Hz), 111.4 (m), 109.7, 104.1 (t, J = 22.7 Hz), 96.2, 61.6, 15.1.
Elemental analysis: calcd (%) for C15H14F4O3 (318.26): C 56.61, H 4.43; found: C 56.80, H 4.32.
1,4-Di(2-methyl-2-thiophen-2-yl-[1,3]dioxolane)-2,3,5,6-tetrafluorobenzene (9)
1,4-Dibromo-2,3,5,6-tetrafluorobenzene (0.308 g, 1 mmol), 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.680 g, 4
mmol) and KOAc (0.392 g, 4 mmol) at 150 °C during 16 h in DMAc (4 mL) in the presence of Pd(OAc)2 (2.24 mg,
0.01 mmol) affords 9 in 81% (0.394 g) yield after evaporation of the solvent and crystalization in
dichloromethane/diethyl ether; amorphous yellow solid; mp 143-145℃.
1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 3.6 Hz, 2H), 7.11 (d, J = 3.6 Hz, 2H), 4.15-3.95 (m, 8H), 1.82 (s, 6H).
13C NMR (100 MHz, CDCl3): δ 150.5, 143.8 (dm, J = 247.0 Hz), 130.3, 127.4, 124.4, 112.4 (m), 107.1, 65.1, 27.6.
Elemental analysis: calcd (%) for C22H18F4O4S2 (486.50): C 54.31, H 3.73; found: C 54.50, H 3.64.
2-Methyl-2-[5-(2,3,5-trifluorophenyl)-thiophen-2-yl]-[1,3]dioxolane (10)
1-Bromo-2,3,5-trifluorobenzene (0.211 g, 1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g, 2 mmol)
affords 10 in 78% (0.234 g) yield; colourless oil.
1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 3.8 Hz, 1H), 7.10-7.08 (m, 1H), 7.05 (d, J = 3.8 Hz, 1H), 6.88-6.77 (m,
1H), 4.12-3.97 (m, 4H), 1.81 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.5 (dd, J = 244.8, 11.1 Hz), 151.0 (dt, J =
250.9, 13.6 Hz), 149.3 (d, J = 3.5 Hz), 144.0 (dd, J = 248.0, 11.1 Hz), 134.4 (m), 127.5 (d, J = 7.1 Hz), 124.9,
124.7 (t, J = 11.2 Hz), 109.3 (d, J = 25.1 Hz), 107.0, 103.7 (dd, J = 27.7, 21.4 Hz), 65.0, 27.5. Elemental analysis:
calcd (%) for C14H11F3O2S (300.30): C 55.99, H 3.69; found: C 56.19, H 3.48.
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2-Methyl-5-(2,3,5-trifluorophenyl)-thiophene (11)
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1-Bromo-2,3,5-trifluorobenzene (0.211 g, 1 mmol) and 2-methylthiophene (0.196 g, 2 mmol) affords 11 in 75%
(0.171 g) yield; amorphous yellow solid; mp 43-45℃.
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1H NMR (300 MHz, CDCl3): δ 7.30 (d, J = 3.8 Hz, 1H), 7.06-7.00 (m, 1H), 6.83-6.72 (m, 2H), 2.53 (s, 3H). 13C
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NMR (75 MHz, CDCl3): δ 157.4 (dd, J = 244.8, 11.1 Hz), 151.0 (dt, J = 250.9, 13.6 Hz), 144.0 (dd, J = 248.0, 11.1
Hz), 142.0 (d, J = 4.1 Hz), 132.6 (m), 127.7 (d, J = 7.1 Hz), 126.3, 125.0 (t, J = 11.2 Hz), 109.0 (d, J = 25.1 Hz),
103.1 (dd, J = 27.7, 21.4 Hz), 15.2. Elemental analysis: calcd (%) for C11H7F3S (228.23): C 57.89, H 3.09; found:
C 57.90, H 3.30.
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2-Ethyl-4-methyl-5-(2,3,5-trifluorophenyl)-thiazole (12)
1-Bromo-2,3,5-trifluorobenzene (0.211 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol) affords 12 in
70% (0.180 g) yield; amorphous yellow solid; mp 44-46℃.
1H NMR (400 MHz, CDCl3): δ 7.00-6.90 (m, 1H), 6.90-6.82 (m, 1H), 3.03 (q, J = 7.3 Hz, 2H), 2.37 (s, 3H), 1.40 (t,
J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.7, 157.2 (dd, J = 244.8, 11.1 Hz), 150.7 (dt, J = 250.9, 13.6
Hz), 150.5, 144.4 (dd, J = 248.0, 11.1 Hz), 122.9 (m), 121.2, 113.1 (d, J = 24.5 Hz), 105.1 (dd, J = 27.7, 21.4 Hz),
26.9, 16.1, 14.1. Elemental analysis: calcd (%) for C12H10F3NS (257.28): C 56.02, H 3.92; found: C 56.17, H 4.08.
2-n-Butyl-5-(2,3,5-trifluorophenyl)-furan (13)
1-Bromo-2,3,5-trifluorobenzene (0.211 g, 1 mmol) and 2-n-butylfuran (0.258 g, 2 mmol) affords 13 in 51% (0.129
g) yield; yellow oil.
1H NMR (300 MHz, Aceton d6): δ 7.35-7.30 (m, 1H), 7.15-7.05 (m, 1H), 6.88 (d, J = 3.1 Hz, 1H), 6.30 (d, J = 3.1
Hz, 1H), 2.74 (t, J = 7.3 Hz, 2H), 1.68 (quint., J = 7.3 Hz, 2H), 1.42 (sext., J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 157.8 (dd, J = 244.8, 11.1 Hz), 157.6, 150.7 (dt, J = 250.9, 13.6 Hz), 144.4 (m),
143.0 (dm, J = 247.8, Hz), 121.7 (t, J = 10.6 Hz), 112.9 (d, J = 12.1 Hz), 107.7, 106.5 (d, J = 26.2 Hz), 102.6 (dd, J
= 27.9, 21.4 Hz), 30.1, 27.7, 22.2, 13.8. Elemental analysis: calcd (%) for C14H13F3O (254.25): C 66.14, H 5.15;
found: C 66.02, H 5.24.
Acetic acid 5-(2,3,5-trifluorophenyl)-furan-2-ylmethyl ester (14)
1-Bromo-2,3,5-trifluorobenzene (0.211 g, 1 mmol) and acetic acid furan-2-ylmethyl ester (0.280 g, 2 mmol) affords
14 in 60% (0.162 g) yield; amorphous yellow solid; mp 41-44℃.
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1H NMR (400 MHz, CDCl3): δ 7.35-7.30 (m, 1H), 6.90 (d, J = 3.1 Hz, 1H), 6.88-6.77 (m, 1H), 6.55 (d, J = 3.1 Hz,
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250.9, 13.6 Hz), 150.0, 146.7 (m), 120.9 (m), 113.1, 112.7 (d, J = 12.3 Hz), 107.1 (d, J = 27.7 Hz), 103.8 (dd, J =
27.8, 21.3 Hz), 57.8, 20.8. Elemental analysis: calcd (%) for C13H9F3O3 (270.20): C 57.79, H 3.36; found: C 57.70,
H 3.40.
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2-Methyl-2-[5-(2,4,6-trifluorophenyl)-thiophen-2-yl]-[1,3]dioxolane (15)
2-Bromo-1,3,5-trifluorobenzene (0.211 g, 1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g, 2 mmol)
affords 15 in 69% (0.207 g) yield; amorphous yellow solid; mp 56-58℃.
1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 3.8 Hz, 1H), 7.05 (d, J = 3.8 Hz, 1H), 6.76 (t, J = 8.5 Hz, 2H), 4.12-3.97
(m, 4H), 1.81 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.0 (dt, J = 250.3, 16.0 Hz), 159.8 (ddd, J = 252.0, 14.5,
9.8 Hz), 148.8 (t, J = 3.1 Hz), 128.9 (t, J = 5.2 Hz), 127.9, 124.0, 108.9 (m), 107.2, 100.7 (tm, J = 28.5 Hz), 65.0,
27.6. Elemental analysis: calcd (%) for C14H11F3O2S (300.30): C 55.99, H 3.69; found: C 56.14, H 3.79.
2-[5-(3,5-Difluorophenyl)-thiophen-2-yl]-2-methyl-[1,3]dioxolane (16)
1-Bromo-3,5-difluorobenzene (0.193 g, 1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g, 2 mmol)
affords 16 in 69% (0.194 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.16 (d, J = 3.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 3.8 Hz, 1H), 6.70 (tt, J
= 7.8, 2.1 Hz, 1H), 4.12-3.97 (m, 4H), 1.79 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.3 (dd, J = 248.2, 3.1 Hz),
148.4, 141.2 (t, J = 2.9 Hz), 137.4 (t, J = 10.5 Hz), 125.1, 124.2, 108.4 (d, J = 18.9 Hz), 107.0, 102.5 (t, J = 25.5
Hz), 65.0, 27.4. Elemental analysis: calcd (%) for C14H12F2O2S (282.31): C 59.56, H 4.28; found: C 59.41, H 4.14.
5-(3,5-Difluorophenyl)-2-ethyl-4-methyl-thiazole (17)
1-Bromo-3,5-difluorobenzene (0.193 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol) affords 17 in 80%
(0.191 g) yield; yellow oil.
1H NMR (400 MHz, CDCl3): δ 6.92 (d, J = 8.4 Hz, 2H), 6.75 (tt, J = 7.8, 2.1 Hz, 1H), 3.00 (q, J = 7.3 Hz, 2H), 2.47
(s, 3H), 1.39 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.1, 162.9 (dd, J = 249.0, 13.2 Hz), 148.2, 135.5
(t, J = 10.3 Hz), 128.5 (t, J = 2.8 Hz), 111.9 (d, J = 18.8 Hz), 102.8 (t, J = 25.3 Hz), 26.9, 16.2, 14.2. Elemental
analysis: calcd (%) for C12H11F2NS (239.29): C 60.23, H 4.63; found: C 60.14, H 4.72.
General procedure for palladium-catalyzed direct arylations of 1a, 4, 6, 10 and 17
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The reaction of the aryl bromide (1.5 mmol), 1a, 4, 6, 10 or 17 (1 mmol) and KOAc (0.196 g, 2 mmol) at 150 °C
during 20 h in DMAc (4 mL) in the presence of PdCl(C3H5)(dppb)14 (12.2 mg, 0.02 mmol) under argon affords the
coupling products 18-29 after evaporation of the solvent and purification on silica gel. Eluent pentane:diethylether
9:1 for compounds 18, 24; pentane:diethylether 4:1 for compounds 25, 27-29; pentane:diethylether 3:2 for
compounds 19, 20, 22, 26; pentane:diethylether 7:3 for compounds 21, 23.
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2',3',5',6'-Tetrafluoro-4'-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-biphenyl-4-carbaldehyde (18)
2-Methyl-2-[5-(2,3,5,6-tetrafluorophenyl)-thiophen-2-yl]-[1,3]dioxolane 1a (0.318 g,
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bromobenzaldehyde (0.278 g, 1.5 mmol) affords 18 in 76% (0.321 g) yield; amorphous white solid; mp 131-132℃.
1H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 3.8 Hz,
1H), 7.13 (d, J = 3.8 Hz, 1H), 4.14-3.97 (m, 4H), 1.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 191.5, 150.9 (m),
144.0 (dm, J = 250.0 Hz, 4C), 136.4, 133.4, 130.9, 130.6 (t, J = 6.3 Hz), 129.7, 127.1 (m), 124.4, 117.2 (m), 114.3
(m), 65.1, 27.6. Elemental analysis: calcd (%) for C21H14F4O3S (422.39): C 59.71, H 3.34; found: C 59.81, H 3.24.
1-{2',3',5',6'-Tetrafluoro-4'-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-biphenyl-3-yl}-ethanone (19)
2-Methyl-2-[5-(2,3,5,6-tetrafluorophenyl)-thiophen-2-yl]-[1,3]dioxolane 1a (0.318 g,
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bromoacetophenone (0.298 g, 1.5 mmol) affords 19 in 75% (0.327 g) yield; amorphous yellow solid; mp 84-86℃.
1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz,
1H), 7.52 (d, J = 3.8 Hz, 1H), 7.12 (d, J = 3.8 Hz, 1H), 4.14-3.97 (m, 4H), 2.65 (s, 3H), 1.83 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 197.3, 150.7, 144.0 (dm, J = 250.0 Hz, 4C), 137.5, 134.6, 130.5 (t, J = 4.0 Hz), 130.1, 129.0,
128.9, 127.9, 127.2 (m), 124.4, 107.1, 65.1, 27.6, 26.6. Elemental analysis: calcd (%) for C22H16F4O3S (436.42):
C 60.55, H 3.70; found: C 60.41, H 3.89.
3-{2,3,5,6-Tetrafluoro-4-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-phenyl}-pyridine (20)
2-Methyl-2-[5-(2,3,5,6-tetrafluorophenyl)-thiophen-2-yl]-[1,3]dioxolane 1a (0.318 g, 1 mmol) and 3-bromopyridine
(0.237 g, 1.5 mmol) affords 20 in 66% (0.261 g) yield; amorphous yellow solid; mp 134-136℃.
1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 8.70 (d, J = 3.7 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 3.8 Hz,
1H), 7.45 (dd, J = 7.8, 5.0 Hz, 1H), 7.12 (d, J = 3.8 Hz, 1H), 4.12-3.98 (m, 4H), 1.83 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 150.9 (t, J = 3.9 Hz), 150.5, 150.1, 145.3 (dm, J = 250.0 Hz, 4C), 137.4, 130.6 (t, J = 6.1 Hz), 127.0 (m),
124.4, 123.9, 123.5, 115.1 (t, J = 16.8 Hz), 114.4 (t, J = 14.8 Hz), 107.1, 65.1, 27.6. Elemental analysis: calcd (%)
for C19H13F4NO2S (395.37): C 57.72, H 3.31; found: C 57.50, H 3.58.
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Ethyl 4'-(2-ethyl-4-methylthiazol-5-yl)-2',3',5',6'-tetrafluoro-biphenyl-4-carboxylate (21)
2-Ethyl-4-methyl-5-(2,3,5,6-tetrafluorophenyl)-thiazole 5 (0.275 g, 1 mmol) and ethyl 4-bromobenzoate (0.343 g,
1.5 mmol) affords 21 in 80% (0.338 g) yield; amorphous yellow solid; mp 123-125℃.
1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 4.42 (q, J = 7.3 Hz, 2H), 3.06 (q, J
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= 7.3 Hz, 2H), 2.37 (s, 3H), 1.48-1.40 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 174.3, 165.9, 152.8, 144.2 (dm, J =
250.0 Hz, 4C), 131.6, 131.3, 130.2, 129.8, 119.8 (t, J = 16.4 Hz), 113.8, 111.8 (t, J = 18.3 Hz), 61.3, 27.0, 16.2,
14.3, 14.0. Elemental analysis: calcd (%) for C21H17F4NO2S (423.42): C 59.57, H 4.05; found: C 59.60, H 3.89.
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4'-(2-Ethyl-4-methylthiazol-5-yl)-2',3',5',6'-tetrafluorobiphenyl-3-carbonitrile (22)
2-Ethyl-4-methyl-5-(2,3,5,6-tetrafluorophenyl)-thiazole 5 (0.275 g, 1 mmol) and 3-bromobenzonitrile (0.273 g, 1.5
mmol) affords 22 in 72% (0.271 g) yield; amorphous yellow solid; mp 124-126℃.
1H NMR (400 MHz, CDCl3): δ 7.80-7.50 (m, 4H), 3.00 (q, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 174.4, 152.9, 144.0 (dm, J = 250.0 Hz, 4C), 134.4, 133.6, 132.8, 129.7, 128.6,
118.3 (t, J = 16.2 Hz), 118.0, 113.6, 112.7, 112.5 (t, J = 17.4 Hz), 27.0, 16.2, 14.0. Elemental analysis: calcd (%)
for C19H12F4N2S (376.37): C 60.63, H 3.21; found: C 60.47, H 3.02.
2-n-Butyl-5-(2,3,5,6-tetrafluoro-4-naphthalen-2-ylphenyl)-furan (23)
2-n-Butyl-5-(2,3,5,6-tetrafluorophenyl)-furan 6 (0.272 g, 1 mmol) and 2-bromonaphthalene (311 g, 1.5 mmol)
affords 23 in 66% (0.263 g) yield; amorphous yellow solid; mp 98-100℃.
1H NMR (400 MHz, CDCl3): δ 8.03-7.85 (m, 4H), 7.60-7.53 (m, 3H), 6.90 (d, J = 3.1 Hz, 1H), 6.21 (d, J = 3.1 Hz,
1H), 2.75 (t, J = 7.3 Hz, 2H), 1.71 (quint., J = 7.3 Hz, 2H), 1.45 (sext., J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 158.6, 144.9 (dm, J = 250.0 Hz, 2C), 142.5 (dm, J = 250.0 Hz, 2C), 140.6 (m), 133.2,
133.0, 130.0, 128.3, 128.2, 127.7, 127.2, 127.0, 126.5, 124.9, 117.9 (t, J = 16.8 Hz), 114.9 (t, J = 6.7 Hz), 110.4 (t,
J = 13.8 Hz), 107.1, 30.0, 27.8, 22.2, 13.8. Elemental analysis: calcd (%) for C24H18F4O (398.39): C 72.35, H
4.55; found: C 72.54, H 4.36.
2-n-Butyl-5-(2,3,5,6-tetrafluoro-3'-nitrobiphenyl-4-yl)-furan (24)
2-n-Butyl-5-(2,3,5,6-tetrafluorophenyl)-furan 6 (0.272 g, 1 mmol) and 1-bromo-3-nitrobenzene (0.303 g, 1.5 mmol)
affords 24 in 71% (0.279 g) yield; amorphous yellow solid; mp 89-91℃.
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1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz,
1H), 6.93 (d, J = 3.1 Hz, 1H), 6.21 (d, J = 3.1 Hz, 1H), 2.75 (t, J = 7.3 Hz, 2H), 1.71 (quint., J = 7.3 Hz, 2H), 1.45
(sext., J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.1, 148.4, 142.5 (dm, J = 250.0
Hz), 144.8 (d, J = 250.0 Hz), 140.2 (m), 136.1, 129.7, 129.2, 125.3, 123.9, 115.7 (t, J = 6.8 Hz), 115.1 (t, J = 16.8
Hz), 111.7 (t, J = 12.0 Hz), 107.3, 29.9, 27.8, 22.2, 13.8. Elemental analysis: calcd (%) for C20H15F4NO3 (393.33):
C 61.07, H 3.84; found: C 61.18, H 3.97.
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2',3',6'-Trifluoro-4'-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-biphenyl-4-carbaldehyde (25)
2-Methyl-2-[5-(2,3,5-trifluorophenyl)-thiophen-2-yl]-[1,3]dioxolane 10 (0.300 g, 1 mmol) and 4-bromobenzaldehyde
(0.278 g, 1.5 mmol) affords 25 in 81% (0.327 g) yield; amorphous yellow solid; mp 103-105℃.
1H NMR (400 MHz, Acetone d6): δ 10.15 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 3.8
Hz, 1H), 7.58-7.50 (m, 1H), 7.16 (d, J = 3.8 Hz, 1H), 4.12-3.97 (m, 4H), 1.75 (s, 3H). 13C NMR (125 MHz, aceton
d6): δ 193.5, 156.8 (dm, J = 244.8 Hz), 152.6 (d, J = 4.7 Hz), 150.3 (dm, J = 250.9 Hz), 146.0 (dm, J = 248.0 Hz),
138.7, 135.8, 135.4 (m), 132.9, 131.3, 129.9 (d, J = 5.3 Hz), 126.9, 125.9 (t, J = 10.2 Hz), 119.1 (m), 111.2 (d, J =
27.0 Hz), 108.6, 66.8, 28.7. Elemental analysis: calcd (%) for C21H15F3O3S (404.40): C 62.37, H 3.74; found: C
62.18, H 3.60.
3-{2,3,6-Trifluoro-4-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-phenyl}-pyridine (26)
2-Methyl-2-[5-(2,3,5-trifluorophenyl)-thiophen-2-yl]-[1,3]dioxolane 10 (0.300 g, 1 mmol) and 3-bromopyridine
(0.237 g, 1.5 mmol) affords 26 in 55% (0.207 g) yield; amorphous yellow solid; mp 99-101℃.
1H NMR (400 MHz, Acetone d6): δ 8.77 (s, 1H), 8.68 (d, J = 3.7 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 3.8
Hz, 1H), 7.59-7.50 (m, 2H), 7.16 (d, J = 3.8 Hz, 1H), 4.12-3.97 (m, 4H), 1.75 (s, 3H). 13C NMR (100 MHz,
Acetone d6): δ 152.6 (d, J = 4.7 Hz), 152.3 (m), 151.8, 147.0 (dm, J = 250.9 Hz), 139.3, 137.2 (dm, J = 250.9 Hz),
135.3, 129.9 (d, J = 5.3 Hz), 126.9, 126.3, 125.9 (t, J = 11.9 Hz), 117.0 (m), 111.1 (d, J = 27.0 Hz), 108.5, 66.8,
28.7. Elemental analysis: calcd (%) for C19H14F3NO2S (377.38): C 60.47, H 3.74; found: C 60.40, H 3.91.
5-(2,6-Difluoro-4'-nitrobiphenyl-4-yl)-2-ethyl-4-methylthiazole (27)
5-(3,5-Difluorophenyl)-2-ethyl-4-methylthiazole 17 (0.239 g, 1 mmol) and 1-bromo-4-nitrobenzene (0.303 g, 1.5
mmol) affords 27 in 70% (0.252 g) yield; amorphous yellow solid; mp 120-122℃.
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1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.02 (q, J
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= 7.3 Hz, 2H), 2.54 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.6, 159.6 (dd, J = 250.8,
7.8 Hz), 148.7, 147.6, 135.5, 135.4 (t, J = 8.3 Hz), 131.3, 128.1 (t, J = 2.8 Hz), 123.5, 115.0 (t, J = 17.8 Hz), 112.3
(d, J = 19.8 Hz), 26.9, 16.4, 14.2. Elemental analysis: calcd (%) for C18H14F2N2O2S (360.38): C 59.99, H 3.92;
found: C 60.11, H 3.78.
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5-(4'-Chloro-2,6-difluorobiphenyl-4-yl)-2-ethyl-4-methylthiazole (28)
5-(3,5-Difluorophenyl)-2-ethyl-4-methylthiazole 17 (0.239 g, 1 mmol) and 1-bromo-4-chloro-benzene (0.286 g, 1.5
mmol) affords 28 in 77% (0.269 g) yield; amorphous yellow solid; mp 67-69℃.
1H NMR (400 MHz, CDCl3): δ 7.46-7.42 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 3.01 (q, J = 7.3 Hz, 2H), 2.52 (s, 3H),
1.41 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.2, 159.6 (dd, J = 250.8, 7.8 Hz), 148.4, 134.5, 134.4
(t, J = 8.3 Hz), 131.5, 128.6, 128.4, 127.1, 115.0 (m), 112.2 (d, J = 19.8 Hz), 26.9, 16.4, 14.2. Elemental analysis:
calcd (%) for C18H14ClF2NS (349.83): C 61.80, H 4.03; found: C 61.89, H 3.94.
4'-(2-Ethyl-4-methylthiazol-5-yl)-2',6'-difluorobiphenyl-2-carbonitrile (29)
5-(3,5-Difluorophenyl)-2-ethyl-4-methylthiazole 17 (0.239 g, 1 mmol) and 2-bromobenzonitrile (0.273 g, 1.5 mmol)
affords 29 in 76% (0.258 g) yield; amorphous yellow solid; mp 129-131℃.
1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 7.4 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.11 (d, J = 8.4
Hz, 2H), 3.02 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.5,
159.7 (dd, J = 250.8, 7.8 Hz), 148.7, 135.9 (t, J = 10.9 Hz), 133.1, 132.7, 132.5, 131.7, 129.0, 128.2, 117.5, 114.1,
114.0 (t, J = 18.8 Hz), 112.2 (d, J = 19.8 Hz), 26.9, 16.4, 14.2. Elemental analysis: calcd (%) for C19H14F2N2S
(340.39): C 67.04, H 4.15; found: C 67.19, H 4.01.
Acknowledgment We are grateful to the “Chinese Scholarship Council” for a grant to L. C and to the “Fondation
Rennes1” for a master grant to T. Y. We thank CNRS and “Rennes Metropole” for providing financial support.
Supporting Information Available 1H and 13C NMR spectra of compounds 1-29. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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(1) (a) Ames, D. E.; Opalko, A. Synthesis 1983, 234. (b) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A.; Kurihara, T.;
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(4) (a) Mayer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (b) Crouch, D. J.;
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P. N.; Hursthouse, M. B. Chem. Mater. 2005, 17, 6567. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d)
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(5) For palladium-catalyzed direct arylations of pentafluorobenzene: (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (b) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097. (c) Rene,
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1128.
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(8) For oxidative-coupling palladium-catalyzed reactions wih polyfluorobenzenes: (a) Wei, Y.; Su, W. J. Am. Chem.
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(13) For an example of palladium-catalyzed direct heteroarylation of 1-bromo-3,5-difluorobenzene: Ermolat'ev, D. S.;
Gimenez, V. N.; Babaev, E. V.; Van der Eycken, E. J. Comb. Chem. 2006, 8, 659.
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