Palladium-catalysed direct arylation of heteroaromatics bearing unprotected hydroxyalkyl functions using aryl bromides

Article abstract of DOI:10.1002/adsc.200900793

Heteroaromatics bearing unprotected hydroxyalkyl functions can be arylated using aryl or heteroaryl bromides, via palladium-catalysed carbonhydrogen bond activation/arylation. Good yields were generally obtained using 0.01-0.5 mol% of the air-stable palladium acetate complex as the catalyst. The nature of the base was found to be crucial for the selectivity of this reaction. Potassium acetate led to the direct arylation products whereas caesium car-bonate led to the formation of the ether. This procedure is certainly more atom-economic than other methods for the preparation of such compounds, as no protection/ deprotection sequence of the hydroxyalkyl function and no preparation of an organometallic derivative is required.

Full text of DOI:10.1002/adsc.200900793

FULL PAPERS
DOI: 10.1002/adsc.200900793
Palladium-Catalysed Direct Arylation of Heteroaromatics Bear-
ing Unprotected Hydroxyalkyl Functions using Aryl Bromides
a
b,
a,
ˇ
Julien Roger, Franc Pozgan, * and Henri Doucet *
a
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS – Universitꢀ de Rennes, “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
Fax : (+33)-2-2323-6939; phone: (+33)-2-2323-6384; e-mail: henri.doucet@univ-rennes1.fr
b
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
E-mail: franc.pozgan@fkkt.uni-lj.si
Received: November 13, 2009; Revised: January 26, 2010; Published online: March 4, 2010
Abstract: Heteroaromatics bearing unprotected hy- bonate led to the formation of the ether. This proce-
droxyalkyl functions can be arylated using aryl or dure is certainly more atom-economic than other
heteroaryl bromides, via palladium-catalysed carbon- methods for the preparation of such compounds, as
hydrogen bond activation/arylation. Good yields no protection/deprotection sequence of the hydrox-
were generally obtained using 0.01–0.5 mol% of the yalkyl function and no preparation of an organome-
air-stable palladium acetate complex as the catalyst. tallic derivative is required.
The nature of the base was found to be crucial for
the selectivity of this reaction. Potassium acetate led Keywords: atom economy; catalysis; C H activation;
to the direct arylation products whereas caesium car- heteroarenes; palladium
À
Introduction
tion/deprotection sequence, and therefore should pro-
vide a more environmentally and economically attrac-
The preparation of biaryl derivatives is an important tive access to such arylated heteroaromatics. Some
field of research in organic chemistry, and several arylated (hydroxyalkyl)thiophenes have been de-
methods for the preparation of such products have scribed to be useful compounds.[12] However, to the
been described.[1] The arylation of several heteroaro- best of our knowledge, the direct arylation of hetero-
À
matics via a C H bond activation using aryl halides aromatics such as thiophenes or furans bearing unpro-
to prepare such biaryls has been reported in recent tected hydroxyalkyl function has not been described.
years.[2] Some palladium-catalysed decarboxylative In the course of our studies on the direct arylation of
couplings for the arylation of heteroarenes have also thiophenes, we have recently reported one example of
been described.[3] For such coupling reactions, no such a reaction using 2-(thiophen-2-yl)ethanol.[13] The
preparation of an organometallic derivative is re- expected coupling product had been obtained in 58%
quired. This is an advantage compared to more classi- yield using 1 mol% of palladium associated to a tetra-
cal cross-coupling procedures such as the Suzuki,[4a,b] dentate phosphine ligand.
Stille,[4c] or Negishi reactions.[4d] Moreover, the direct
Therefore, the scope of such reactions needs to be
arylation reaction provides only HX associated to a largely extended to a wider variety of heteroaromatics
base as by-product and therefore is very interesting and aryl halides. Moreover, higher yields for the cou-
both in terms of atom economy and relatively inert pling with such compounds have to be obtained, espe-
wastes. However, despite the fact that this procedure cially using lower catalyst loadings, in order to obtain
has been widely applied in recent years for the syn- economically viable procedures. Here, we wish to
thesis of arylthiophenes,[5] arylfurans,[6] arylpyrroles,[7] report on the reaction of heteroaromatics bearing un-
aryloxazoles,[8] arylthiazoles,[9] or other arylated he- protected hydroxyalkyl functions with a set of elec-
ACHTUNGTRENNUNG
teroaromatics,[10] relatively few results have been re- tronically and sterically diverse aryl bromides at low
ported using heteroaromatics bearing unprotected re- catalyst loadings using a phosphine-free palladium
active functional groups such as amino or hydroxyalk- catalyst.
yl.[11]
The direct use of heteroaromatics bearing unpro-
tected functions would be very useful in organic syn-
thesis since it would allow one to avoid the protec-
696
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 696 – 710

Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
Results and Discussion
We have recently reported that phosphine-free
PdACHTUNGTRENNUNG(OAc)2 or [PdClCAHUTNGTRNE(NUGN C3H5)]2 are very powerful cata-
lysts for the direct arylation of furans, thiophenes, pyr-
roles or thiazoles.[5f,6i,7e,9d] With these heteroaromatics,
several reactions can be performed with as little as
0.5–0.001 mol% of catalyst. At elevated temperature,
when PdACHTUNGTRENNUNG(OAc)2 is employed as the catalyst precursor,
soluble palladium(0) colloids or nanoparticles are
formed. These nanoparticles seem to produce mono-
meric or dimeric anionic palladium complexes that
are very active catalysts.
First, we examined the reactivity of thiophen-2-yl-
methanol for the palladium-catalysed coupling reac-
tion with 4-bromobenzonitrile using 0.1 mol% of
PdACHTUNGTRENNUNG(OAc)2 as the catalyst precursor, DMAc as the sol-
vent and AcOK as the base at 1508C in the absence
of ligands (Scheme 1, Table 1). Using these condi-
tions, the expected 5-arylation product 1a was ob-
tained in high selectivity. The formation of traces of
1b due to the acetylation of the hydroxy group was
also observed. Then, we examined the influence of
Scheme 1.
Table 1. Influence of the reaction conditions for palladium-catalysed coupling of thiophen-2-ylmethanol with 4-bromobenzo-
nitrile (Scheme 1).[a]
Entry
[Pd]
Pd(OAc)2
Ratio substrate/catalyst
Solvent
Base
Conversion [%]
Yield of 1a [%]
1
2
3
4
5
6
7
8
G
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
10000
1000
1000
1000
1000
1000
1000
1000
1000
1000
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
AcONa
AcOCs
Na2CO3
K2CO3
Cs2CO3
K3PO4
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
96
100
36
82[b]
80[b]
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2/2 PPh3
Pd(OAc)2/dppb
Pd(OAc)2/dppe
= [PdCl(C3H5)]2
(C3H5)]2/2 PPh3
(C3H5)]2/dppe
(OAc)2
Pd(OAc)2
T
ACHTUNGTRENNUNG
E
R
T
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
T
T
R
R
R
E
23
trace
100
100
100
100
100
56
0
96
88
90
0[c]
13[d]
90[b]
69[e]
73[e]
20
9
NMP
10
11
12
13
14
15
16
17
18
19
20
21
DMSO
dioxane
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
–
(83)[b]
72[f]
80[b]
82[b]
81[b]
57[e]
70[e]
58[e]
84[b,g]
40[h]
G
93
A
100
100
100
100
100
48
1
ACHTUNGTRENNUNG
2
1
= [PdClACHTUNGTRENNUNG
= [PdClACHTUNGTRENNUNG
2
1
2
Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a]
Reaction conditions: 4-bromobenzonitrile (1 equiv.), thiophen-2-ylmethanol (2 equiv.), base (2 equiv.), 16 h, 1508C, GC
and NMR conversion of 4-bromobenzonitrile, yield in parenthesis is isolated.
The formation of 5–9% of 1b was also observed.
An important amount of 1d and 1e was formed.
A mixture of 1d, 1e and benzonitrile was also formed.
An important amount of 1c was formed.
1.2 equiv. of thiophen-2-ylmethanol were employed.
Reaction temperature 1308C.
Reaction temperature 1008C.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
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Julien Roger et al.
FULL PAPERS
the base on the product distribution for this reaction. and 0.5–0.01 mol% PdACTHNUTRGNEUNG(OAc)2 as the reaction condi-
Na2CO3 or K2CO3 gave poor conversions of 4-bromo- tions. In the presence of electron-deficient aryl bro-
benzonitrile and, 1a was obtained only in traces mides such as 4-bromobenzaldehyde, 4-bromoaceto-
(Table 1, entries 3 and 4). These results might be ex- phenone, 4-bromonitrobenzene, 4-trifluoromethylbro-
plained by Fagnouꢂs concerted metalation–deprotona- mobenzene or methyl 4-bromobenzoate, and
tion (CMD) mechanism, which involves a coordina- 0.1 mol% catalyst, the products 2–6 were obtained in
tion of the base to the palladium complex.[5g] A quite 74–90% yields (Table 2, entries 2–8). 4-Fluorobromo-
selective reaction was observed in the presence of benzene was found to be less reactive. With this aryl
Cs2CO3. However, with this base, the major product bromide, the oxidative addition to palladium is rela-
of the reaction was ether 1d instead of the desired tively slow, and a yield of 61% was obtained in the
compound 1a (Table 1, entry 5). The formation of presence of 0.1 mol% of catalyst (Table 2, entries 9
ethers using palladium catalysts and Cs2CO3 as the and 10).
base is known.[14] We also examined the influence of
The use of a higher catalyst loading did not effect
the solvent for this reaction. The use of DMF or NMP any improvement in the yield. For such phosphine-
gave 1a in relatively high yield, but the formation of free procedures, low catalyst loadings have to be em-
an important amount of formylthiophene 1c was also ployed (less than 0.5 mol%). Under relatively high
observed (Table 1, entries 8 and 9). DMSO gave 1a in palladium concentrations (>1 mol%), so-called “pal-
only 20% yield (Table 1, entry 10). Dioxane was ladium black” forms more rapidly. This “palladium
found to be ineffective to promote this reaction black” is generally inactive for such catalyzed reac-
(Table 1, entry 11). In the presence of a smaller tions. Consequently the conversions of aryl bromides
excess of thiophen-2-ylmethanol (1.2 equiv, instead of and the yields of coupling products are generally not
2 equiv,) in the presence of KOAc, DMAc and increased by a higher catalyst loading. With strongly
0.1 mol% Pd
lower conversion of 4-bromobenzonitrile was ob- bromo-N,N-dimethylaniline, no coupling product was
served (Table 1, entries 7 and 13). We also examined formed in the presence of 0.5–0.1 mol% Pd(OAc)2
the influence of the palladium source. Pd(OAc)2 gave (Table 2, entries 13–16). The oxidative addition of the
very cleanly 1a in high yield, whereas, [PdCl(C3H5)]2 aryl bromides to palladium seems to be the rate-limit-
ACHTUNGTRENNUNG(OAc)2 as the reaction conditions, a deactivated aryl bromides, 4-bromoanisole or 4-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
gave a mixture of 1a and 1c (Table 1, entries 1 and ing step of the catalytic cycle with this catalyst. As ex-
17). A few reactions were also performed using palla- pected, 3-bromobenzaldehyde gave the target com-
dium associated to phosphine ligands. The presence pound 11 in high yield using 0.1 mol% of catalyst
of such ligands for the coupling with 4-bromobenzoni- (Table 2, entry 17). Even the congested aryl bromides,
trile was found to be of no help, as the selectivities in 2-bromobenzaldehyde or 1-bromonaphthalene gave
favour of the formation of 1a and the conversions of the coupling products 12 and 13 in high yields
4-bromobenzonitrile were not improved (Table 1, en- (Table 2, entries 18 and 19). Five heteroaryl bromides,
tries 14–16, 18 and 19). Then, we performed the reac- such as 3-bromopyridine or 5-bromopyrimidine have
tion using a substrate/catalyst ratio of 10000, with also been employed. In all cases the desired products
PdACHTUNGTRENNUNG(OAc)2 as the catalyst precursor, KOAc as the base 14–18 were obtained in high yields using only
in DMAc at 1508C (Table 1, entry 12). A high conver- 0.1 mol% of PdACTHNURGTNEUNG(OAc)2 as the catalyst (Table 2, en-
sion of 4-bromobenzonitrile, and a very selective reac- tries 20–27).
tion in favour of the formation of 1a was observed.
Then, we examined the reactivity of 2-(thiophen-2-
Using these reaction conditions, 1a was isolated in yl)ethanol (Scheme 3, Table 3). High yields of the 5-
83% yield. Finally, a lower reaction temperature of arylated thiophenes 19, 21 and 22 were obtained in
1008C instead of 1508C was found to give 1a in only the presence of 4-bromoacetophenone, 3-bromoben-
40% yield (Table 1, entry 20). At this temperature, zonitrile or 3-bromopyridine and 0.1 mol% of catalyst
most of the aryl bromide was recovered unreacted.
(Table 3, entries 1, 4 and 6). It should be noted that
Then, the scope and limitations of the coupling of the reaction of 4-bromoacetophenone with 2-(thio-
thiophen-2-ylmethanol using other aryl bromides was phen-2-yl)ethanol using 1 mol% cis,cis,cis-1,2,3,4-
investigated (Scheme 2, table 2). First, we studied the tetrakis(diphenylphosphinomethyl)cyclopentane/0.5·
reactivity of para-substituted aryl bromides. These re-
ACHTUNGTRENGU[N PdClACHTUTGNREN(NNGU C3H5)]2 as the catalyst gave 19 in only 58%
actions were performed using DMAc, AcOK, 1508C yield.[13] In the presence of electron-deficient aryl bro-
mides, the addition of phosphine ligands to the reac-
tion mixture, for the direct arylation of thiophene de-
rivatives, appears to be quite unsuccessful in most
cases.[2h] With activated aryl bromides, the oxidative
addition to phosphine-free palladium species is very
fast. On the other hand, the use of a slightly deacti-
Scheme 2.
vated aryl bromide, 4-bromotoluene, using this phos-
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Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
Table 2. Palladium-catalysed direct coupling of thiophen-2-ylmethanol with aryl bromides (Scheme 2).[a]
Entry
1
Aryl bromide
Product
Substrate/Catalyst ratio
10000
Yield [%]
83
1a
2
2
3
4
1000
10000
1000
83
75
84
2
3
5
3
10000
1000
1000
1000
200
74
74
90
81
52
61
44
77
0
6
4
7
5
8
6
9
7
10
11
12
13
14
15
16
7
1000
200
8
8
1000
200
9
9
1000
200
0
10
10
0
1000
0
17
18
19
11
12
13
1000
1000
1000
81
82
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Table 2. (Continued)
Entry
Aryl bromide
Product
Substrate/Catalyst ratio
Yield [%]
87
20
14
14
15
16
1000
10000
1000
1000
21
22
23
41
76
81
24
25
17
17
1000
83
39
10000
26
18
18
1000
84
53
27
10000
[a]
Reaction conditions: Pd
ACHTUNGTRENNUNG
1508C.
Again, the use of electron-rich aryl bromides gave
disappointing results. 4-Bromotoluene, 4-bromoani-
sole or 4-bromo-N,N-dimethylaniline gave 29–31 in
only 10–15% yields, due to a partial conversion of
these aryl bromides (Table 4, entries 7–9). Electron-
deficient meta- or ortho-substituted aryl bromides,
such as 3-bromobenzonitrile, 3-nitrobromobenzene,
3,5-bis(trifluoromethyl)bromobenzene or 2-bromo-
Scheme 3.
phine-free procedure led to 20 in a low yield (Table 3, benzaldehyde, gave the coupling products 32–36 in
entry 3). moderate to good yields (Table 4, entries 10–14). Fur-
The direct use of furan derivatives in organic syn- furyl alcohol was also successfully arylated with 3-bro-
thesis, such as furfuryl alcohol, is an important field mopyridine or 3-bromoquinoline (Table 4, entries 16
of research in green chemistry, since they can be ob- and 17).
tained from agricultural wastes rich in pentosan poly-
The reaction is not limited to the use of heteroaro-
mers. The reactivity of furfuryl alcohol is quite similar matics bearing a primary hydroxyalkyl functionality.
to that of thiophen-2-ylmethanol. In the presence of In the reaction of 1-(furan-2-yl)ethanol with 4-bromo-
the electron-deficient aryl bromides, 4-bromoaceto- benzonitrile or 4-bromopyridine, 40 or 43 were ob-
phenone, 4-bromobenzaldehyde, 4-bromobenzonitrile, tained in 79% and 76% yields, respectively
4-bromonitrobenzene or 4-trifluoromethylbromoben- (Scheme 5, Table 5, entries 1 and 5). As expected, the
zene, the coupling products 23–27 were obtained in electron-rich aryl bromide, 4-tert-butylbromobenzene,
62–80% yield using only 0.1 mol% of PdACHTNUTRGNE(NUG OAc)2 as was recovered unreacted (Table 5, entry 3). The cou-
the catalyst (Scheme 4, Table 4, entries 1–5). In most pling of 1-(furan-2-yl)ethanol with 2-bromobenzalde-
cases, the formation of traces of 5-arylfuran-2-ylmeth- hyde gave 42 in only 46% yield due to the formation
yl acetates was detected as the major side-products. of unidentified side-products (Table 5, entry 3).
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Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
Table 3. Palladium-catalysed direct coupling of 2-(thiophen-2-
yl)ethanol with aryl bromides (Scheme 3).[a]
Entry Aryl bromide
Product
Yield
[%]
Scheme 4.
Scheme 5.
1
2
3
19
19
20
79
64[a]
23
(2-Methylfuran-3-yl)methanol was also found to be
very reactive heterocycle for this reaction
(Scheme 6). With this reactant, the 5-arylated furan
4
5
21
77
a
21
22
57[b]
76
6
[a]
Reaction conditions: PdACTHNUTRGNE(UGN OAc)2 (0.001 equiv.), aryl bromide
(1 equiv.), 2-(thiophen-2-yl)ethanol (2 equiv.), AcOK
(2 equiv.), DMAc, 16 h, 1508C.
[b]
Pd
A
Scheme 6.
Table 4. Palladium-catalysed direct coupling of furfuryl alcohol with aryl bromides (Scheme 4).[a]
Entry
1
Aryl bromide
Product
Yield [%]
72
23
2
3
4
5
6
7
8
9
24
25
26
27
28
29
30
31
62
75
76
80
52
15
10
10
10
32
64
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Julien Roger et al.
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Table 4. (Continued)
Entry
Aryl bromide
Product
Yield [%]
56
11
33
34
12
62
13
14
35
36
37
63
67
61
15
16
38
39
64
65
17
[a]
Reaction conditions: Pd
DMAc, 16 h, 1508C.
ACHTUNGRTEN(NUNG OAc)2 (0.001 equiv.), aryl bromide (1 equiv.), furfuryl alcohol (2 equiv.), AcOK (2 equiv.),
44 was obtained very regioselectively in 67% yield
using only 0.1 mol% of catalyst. In the presence of
0.01 mol% of catalyst, a conversion of 63% of 4-bro-
mobenzonitrile and a yield of 51% of 44 was ob-
tained.
Then, we examined the reactivity of two thiazole
derivatives bearing either a 2-hydroxymethyl or a 4-
hydroxyethyl substituent (Scheme 7 and Scheme 8).
The reaction of 2-hydroxymethylthiazole with 3-bro-
mopyridine in the presence of 0.1 or 0.5 mol% of cat-
alyst gave no coupling product. Both reactants were
recovered unreacted. On the other hand, 2-(2-methyl-
thiazol-4-yl)ethanol was successfully coupled with 4-
bromobenzaldehyde in the presence of 0.5 mol% of
Scheme 7.
PdACTHNUTRGENUG(N OAc)2 to give 46 in 61% yield.
Finally, the reaction of (5-methylisoxazol-3-yl)me-
thanol with 4-bromobenzonitrile gave 47 in only 38%
yield (Scheme 9). In the course of this reaction, the
formation of an important amount of biphenyl-4,4’-di-
carbonitrile was also observed.
In order to extend this coupling procedure to other
unprotected heteroaromatics, we also studied the re-
action of furfurylamine with 4-trifluoromethylbromo-
Scheme 8.
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Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
Table 5. Palladium-catalysed direct coupling of 1-(furan-2-yl)-
Conclusions
ACHTUNGTRENNUNG
ethanol with aryl bromides (Scheme 5).[a]
In summary, a wide variety of aryl bromides can be
employed for the direct arylation of heteroaromatics
bearing an unprotected hydroxyalkyl moiety. This re-
action allows the synthesis of functionalised 5-arylat-
ed heteroarenes without any protection/deprotection
sequence. These couplings can be performed using
low catalyst loadings (0.5–0.01 mol%) of an air-stable
and phosphine-free catalyst. Therefore there is no
need to eliminate phosphine derivatives at the end of
the reaction. Moreover, under such low catalyst con-
centrations ammonium salts as palladium stabilizing
agents are not needed, thus reducing the amount of
wastes. A wide range of functions such as acetyl,
formyl, ester, nitro, trifluoromethyl, fluoro or nitrile
on the aryl bromide are tolerated. It should be noted
that an important number of the products prepared
by this method has never been described so far, indi-
cating that this procedure provides a convenient
access to compounds which cannot be very easily pre-
pared using more classical cross-coupling methods. Fi-
nally, due to environmental considerations, the ad-
vantage of such an inert wastes procedure (formation
of acetic acid and potassium bromide) should become
increasingly important for industrial processes.
Entry Aryl bromide
Product
Yield
[%]
1
2
3
40
40
41
79
59[b]
0
4
42
43
46
76
5
[a]
Reaction conditions: PdACTHNUTRGNE(UGN OAc)2 (0.001 equiv.), aryl bromide
(1 equiv.), 1-(furan-2-yl)ethanol (2 equiv.), AcOK (2 equiv.),
DMAc, 16 h, 1508C.
PdACHTUNGTRENNUNG(OAc)2 (0.0001 equiv.).
[b]
Experimental Section
General Remarks
All reactions were run under argon in Schlenk tubes using
vacuum lines. DMAc analytical grade was not distilled
before use. Potassium acetate (99%) was used. Commercial
aryl halides and heteroarene derivatives were used without
1
purification. H and 13C NMR spectra were recorded with a
Bruker 200 or 300 MHz spectrometer in CDCl3 solutions.
Chemical shifts are reported in ppm relative to CDCl3 (7.25
1
for H NMR and 77.0 for 13C NMR). Flash chromatography
was performed on silica gel (230–400 mesh).
General Procedure for Coupling Reactions
Scheme 9.
In a typical experiment, the aryl bromide (1 mmol), hetero-
aryl derivative (2 mmol), AcOK (0.196 g, 2 mmol) and Pd-
AHCTUNGRTEGNUN(N OAc)2 (see Tables) were dissolved in DMAc (5 mL) under
an argon atmosphere. The reaction mixture was stirred at
1508C for 16 h. Then, the solvent was evaporated and the
crude product was purified by silica gel column chromatog-
raphy.
4-[5-(Hydroxymethyl)thiophen-2-yl]benzonitrile (1a)
Scheme 10.
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
benzene (Scheme 10). However, under these reaction
conditions, the expected coupling product 49 was not
detected.
PdACHTUNGTERNNU(NG OAc)2 (0.022 mg, 0.0001 mmol) affords the correspond-
1
ing product 1a; yield: 0.178 g (83%). H NMR (300 MHz,
CDCl3): d=1.27 (br s, 1H), 4.87 (s, 2H), 7.03 (d, J=3.3 Hz,
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1H), 7.30 (d, J=3.3 Hz, 1H), 7.66 (m, 4H); 13C NMR
(75 MHz, CDCl3): d=60.1, 110.5, 118.8, 124.9, 125.8, 126.5,
132.7, 138.6, 141.9, 146.0; anal. calcd. for C12H9NOS
(215.27): C 66.95, H 4.21; found: C 66.80, H 4.32.
1H), 7.33 (d, J=3.3 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 8.20
(d, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 60.1,
124.4, 125.5, 125.7, 126.6, 140.4, 141.4, 146.6, 146.7; anal.-
calcd. for C11H9NO3S (235.26): C 56.16, H 3.86; found: C
56.24, H 4.04.
Traces were also observed of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate 1b: 1H NMR (300 MHz,
CDCl3): d=2.18 (s, 3H), 5.31 (s, 2H), 7.05 (d, J=3.3 Hz,
1H), 7.30 (d, J=3.3 Hz, 1H), 7.60–7.65 (m, 4H) and 1c:[15]
1H NMR (300 MHz, CDCl3): d=7.50 (d, J=3.3 Hz, 1H),
7.60–7.80 (m, 5H), 9.92 (s, 1H).
{5-[4-(Trifluoromethyl)phenyl]thiophen-2-yl}methanol
(5)
The reaction of 4-trifluoromethylbromobenzene (0.225 g,
1 mmol), thiophen-2-ylmethanol (0.228 g, 2 mmol) and
AcOK (0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in
1
1d: H NMR (300 MHz, CDCl3): d=5.29 (s, 2H), 7.04 (d,
J=8.2 Hz, 2H), 7.05 (m, 1H), 7.14 (d, J=3.4 Hz, 1H), 7.37
(d, J=5.0 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=65.1, 104.5, 115.6, 119.0, 126.8, 126.9,
127.4, 134.0, 137.7, 161.4.
the presence of PdACTHNUTRGNE(UNG OAc)2 (0.22 mg, 0.001 mmol) affords the
corresponding product 5; 0.232 g (90%). 1H NMR
(300 MHz, CDCl3): d=1.60 (br s, 1H), 4.87 (s, 2H), 7.02 (d,
J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.63 (d, J=8.5 Hz,
2H), 7.70 (d, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=60.2, 124.0 (q, J=272.0 Hz), 124.1, 125.7, 125.8 (m),
126.5, 129.5 (q, J=32.5 Hz), 137.6, 142.6, 145.0; anal. calcd.
for C12H9F3OS (258.26): C 55.81, H 3.51; found: C 55.90, H
3.44.
1e:[16] 1H NMR (200 MHz, CDCl3): d=3.05 (s, 3H), 3.15
(s, 3H), 6.69 (d, J=15.2 Hz, 1H), 7.03 (dd, J=5.1, 3.7 Hz,
1H), 7.21 (d, J=3.7 Hz, 1H), 7.30 (d, J=5.1 Hz, 1H), 7.79
(d, J=15.2 Hz, 1H).
4-[5-(Hydroxymethyl)thiophen-2-yl]benzaldehyde (2)
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
4-[5-(Hydroxymethyl)thiophen-2-yl]benzoic Acid
Methyl Ester (6)
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
The reaction of methyl 4-bromobenzoate (0.215 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
sponding product 2; yield: 0.181 g (83%). 1H NMR
(300 MHz, CDCl3): d=1.25 (br s, 1H), 4.85 (s, 2H), 7.02 (d,
J=3.3 Hz, 1H), 7.32 (d, J=3.3 Hz, 1H), 7.71 (d, J=8.5 Hz,
2H), 7.86 (d, J=8.5 Hz, 2H), 9.98 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=60.2, 124.8, 125.8, 126.6, 130.4, 135.1,
140.0, 142.6, 145.9, 191.5; anal. calcd. for C12H10O2S
(218.27): C 66.03, H 4.62; found: C 66.10, H 4.54.
ence of PdACTHNURGTNEUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 6; yield: 0.201 g (81%). 1H NMR
(300 MHz, CDCl3): d=2.20 (br s, 1H), 3.92 (s, 3H), 4.84 (s,
2H), 7.00 (d, J=3.3 Hz, 1H), 7.28 (d, J=3.3 Hz, 1H), 7.63
(d, J=8.5 Hz, 2H), 8.01 (d, J=8.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=52.1, 60.2, 124.2, 125.3, 126.5, 128.8,
130.2, 138.5, 143.1, 145.0, 166.7; anal. calcd. for C13H12O3S
(248.30): C 62.88, H 4.87; found: C 62.99, H 4.80.
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.30 (s, 3H), 5.31 (s, 2H).
Before purification, traces of the corresponding 5-aryl-
AHCTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.18 (s, 3H), 5.53 (s, 2H).
1-{4-[5-(Hydroxymethyl)thiophen-2-yl]phenyl}-
ethanone (3)
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
[5-(4-Fluorophenyl)thiophen-2-yl]methanol (7)
The reaction of 4-fluorobromobenzene (0.175 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 3; yield: 0.195 g (84%). 1H NMR
(300 MHz, CDCl3): d=1.29 (br s, 1H), 2.61 (s, 3H), 4.86 (s,
2H), 7.02 (d, J=3.3 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.65
(d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=26.6, 60.2, 124.3, 125.4, 126.5, 129.1,
135.7, 138.7, 142.8, 145.3, 197.4; anal. calcd. for C13H12O2S
(232.30): C 67.21, H 5.21; found: C 67.40, H 5.37.
ence of PdACTHNURGTNEUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 7; yield: 0.127 g (61%). 1H NMR
(300 MHz, CDCl3): d=2.20 (br s, 1H), 4.81 (s, 2H), 6.96 (d,
J=3.3 Hz, 1H), 7.06 (t, J=8.0 Hz, 2H), 7.09 (d, J=3.3 Hz,
1H), 7.52 (dd, J=8.0 and 5.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=60.1, 116.0 (d, J=21.8 Hz), 122.7, 126.4, 127.4
(d, J=7.9 Hz), 130.6 (d, J=3.4 Hz), 143.4, 143.5, 163.9 (d,
J=247.1 Hz); anal. calcd. for C11H9FOS (208.25): C 63.44, H
4.36; found: C 63.34, H 4.24.
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.18 (s, 3H), 5.31 (s, 2H).
Before purification, traces of the corresponding 5-aryl-
AHCTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.18 (s, 3H), 5.29 (s, 2H).
[5-(4-Nitrophenyl)thiophen-2-yl]methanol (4)
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol), thi-
ophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
(5-p-Tolylthiophen-2-yl)methanol (8)
Pd
(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
The reaction of 4-bromotoluene (0.171 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
product 4; yield: 0.174 g (74%). 1H NMR (300 MHz,
CDCl3): d=2.15 (br s, 1H), 4.86 (s, 2H), 7.02 (d, J=3.3 Hz,
704
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Adv. Synth. Catal. 2010, 352, 696 – 710

Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
Pd
(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
133.6, 141.7, 143.9; anal. calcd. for C15H12OS (240.32): C
74.97, H 5.03; found: C 75.10, H 4.87.
product 8; yield: 0.157 g (77%). 1H NMR (300 MHz,
CDCl3): d=2.38 (br s, 1H), 2.19 (s, 3H), 4.83 (s, 2H), 6.99
(d, J=3.3 Hz, 1H), 7.13 (d, J=3.3 Hz, 1H), 7.20 (d, J=
8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=21.1, 60.3, 122.2, 125.7, 126.4, 129.5, 131.5, 137.5,
142.8, 144.8; anal. calcd. for C12H12OS (204.29): C 70.55, H
5.92; found: C 70.39, H 5.98.
Before purification, traces of the corresponding 5-aryl-
AHCTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.30 (s, 3H), 5.31 (s, 2H).
[5-(Pyridin-3-yl)thiophen-2-yl]methanol (14)[17]
The reaction of 3-bromopyridine (0.158 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.48 (s, 3H), 5.31 (s, 2H).
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 14; yield: 0.166 g (87%). 1H NMR (300 MHz,
CDCl3): d=3.60 (br s, 1H), 4.83 (s, 2H), 6.95 (d, J=3.3 Hz,
1H), 7.16 (d, J=3.3 Hz, 1H), 7.20–7.30 (m, 1H), 7.82 (d, J=
8.0 Hz, 1H), 8.42 (d, J=4.8 Hz, 1H), 8.78 (s, 1H).
3-[5-(Hydroxymethyl)thiophen-2-yl]benzaldehyde
(11)
The reaction of 3-bromobenzaldehyde (0.185 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
[5-(Pyridin-4-yl)thiophen-2-yl]methanol (15)[18]
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
The reaction of 4-bromopyridine hydrochloride (0.194 g,
1 mmol), thiophen-2-ylmethanol (0.228 g, 2 mmol) and
AcOK (0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in
sponding product 11; yield: 0.177 g (81%). 1H NMR
(300 MHz, CDCl3): d=2.24 (br s, 1H), 4.86 (s, 2H), 7.01 (d,
J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.55 (t, J=7.5 Hz,
1H), 7.79 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 8.07
(s, 1H), 10.04 (s, 1H); 13C NMR (75 MHz, CDCl3): d=60.1,
123.7, 126.4, 126.5, 128.7, 129.6, 131.4, 135.3, 136.9, 142.6,
144.5, 192.1; anal. calcd. for C12H10O2S (218.27): C 66.03, H
4.62; found: C 65.90, H 4.54.
the presence of PdACTHNUTRGNE(UNG OAc)2 (0.22 mg, 0.001 mmol) affords the
corresponding product 15; yield: 0.145 g (76%). 1H NMR
(300 MHz, CDCl3): d=3.55 (br s, 1H), 4.81 (s, 2H), 6.95 (d,
J=3.3 Hz, 1H), 7.12 (d, J=3.3 Hz, 1H), 7.45 (d, J=6.3 Hz,
2H), 8.50 (d, J=6.3 Hz, 2H).
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
[5-(Pyrimidin-5-yl)thiophen-2-yl]methanol (16)
(200 MHz, CDCl3): d=2.24 (s, 3H), 5.31 (s, 2H).
The reaction of 5-bromopyrimidine (0.159 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
2-[5-(Hydroxymethyl)thiophen-2-yl]benzaldehyde
(12)
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 16; yield: 0.156 g (81%). 1H NMR (300 MHz,
CDCl3): d=3.20 (br s, 1H), 4.87 (s, 2H), 7.02 (d, J=3.3 Hz,
1H), 7.26 (d, J=3.3 Hz, 1H), 8.87 (s, 2H), 9.07 (s, 1H);
13C NMR (75 MHz, CDCl3): d=59.9, 125.1, 126.3, 128.7,
135.7, 147.0, 153.1, 156.9; anal. calcd. for C9H8N2OS
(192.24): C 56.23, H 4.19; found: C 56.18, H 4.27.
The reaction of 2-bromobenzaldehyde (0.185 g, 1 mmol),
thiophen-2-ylmethanol (0.228 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 12; yield: 0.179 g (82%). 1H NMR
(300 MHz, CDCl3): d=3.64 (br s, 1H), 4.83 (s, 2H), 6.86 (d,
J=3.3 Hz, 1H), 6.99 (d, J=3.3 Hz, 1H), 7.43 (t, J=7.5 Hz,
1H), 7.46 (d, J=8.5 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.94
(d, J=8.5 Hz, 1H), 10.11 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=59.6, 125.6, 127.7, 127.9, 129.2, 130.9, 133.5,
133.7, 137.9, 138.2, 146.6, 192.2; anal. calcd. for C12H10O2S
(218.27): C 66.03, H 4.62; found: C 66.17, H 4.67.
Before purification, traces of the corresponding 5-aryl-
AHCTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.18 (s, 3H), 5.30 (s, 2H).
[5-(Quinolin-3-yl)thiophen-2-yl]methanol (17)
The reaction of 3-bromoquinoline (0.208 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
(200 MHz, CDCl3): d=2.30 (s, 3H), 5.27 (s, 2H).
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 17; yield: 0.200 g (83%). 1H NMR (300 MHz,
CDCl3): d=4.70 (s, 2H), 5.65 (br s, 1H), 7.04 (d, J=3.3 Hz,
1H), 7.62 (t, J=7.5 Hz, 1H), 7.63 (d, J=3.3 Hz, 1H), 7.71
(t, J=7.5 Hz, 1H), 7.95–8.05 (m, 2H), 8.50 (s, 1H), 9.24 (s,
1H); 13C NMR (75 MHz, CDCl3): d=58.4, 124.7, 125.3,
127.1, 127.2, 127.5, 128.0, 128.6, 129.2, 130.1, 138.4, 146.4,
147.6, 147.8; anal. calcd. for C14H11NOS (241.31): C 69.68, H
4.59; found: C 69.54, H 4.59.
[5-(Naphthalen-1-yl)thiophen-2-yl]methanol (13)
The reaction of 1-bromonaphthalene (0.207 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 13; yield: 0.178 g (74%). 1H NMR (300 MHz,
CDCl3): d=2.30 (br s, 1H), 4.92 (s, 2H), 7.11 (d, J=3.3 Hz,
1H), 7.15 (d, J=3.3 Hz, 1H), 7.45–7.65 (m, 4H), 7.89 (d, J=
8.5 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.29 (d, J=8.5 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=59.9, 125.0, 125.4,
125.6, 125.8, 126.2, 126.9, 127.9, 128.1, 128.2, 131.5, 132.1,
[5-(Isoquinolin-4-yl)thiophen-2-yl]methanol (18)
The reaction of 4-bromoisoquinoline (0.208 g, 1 mmol), thio-
phen-2-ylmethanol (0.228 g, 2 mmol) and AcOK (0.196 g,
Adv. Synth. Catal. 2010, 352, 696 – 710
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asc.wiley-vch.de
705

Julien Roger et al.
FULL PAPERS
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
sponding product 22; yield: 0.156 g (76%). 1H NMR
(300 MHz, CDCl3): d=3.11 (t, J=7.5 Hz, 2H), 3.37 (br s,
1H), 3.94 (m, 2H), 6.88 (d, J=3.3 Hz, 1H), 7.18 (d, J=
3.3 Hz, 1H), 7.29 (dd, J=8.0, 4.5 Hz, 1H), 7.80 (d, J=
8.0 Hz, 1H), 8.44 (d, J=4.5 Hz, 1H), 8.74 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=33.7, 62.9, 123.6, 124.0, 126.7, 130.5,
132.6, 138.3, 142.6, 146.2, 147.6; anal. calcd. for C11H11NOS
(205.28): C 64.36, H 5.40; found: C 64.40, H 5.35.
product 18; yield: 0.202 g (84%). 1H NMR (300 MHz,
CDCl3): d=4.92 (s, 2H), 5.10 (br s, 1H), 7.07 (d, J=3.3 Hz,
1H), 7.09 (d, J=3.3 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.67
(t, J=7.5 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 8.20 (d, J=
8.3 Hz, 1H), 8.33 (s, 1H), 9.13 (s, 1H); 13C (75 MHz,
CDCl3): d=59.7, 124.5, 125.6, 126.6, 127.4, 127.9, 128.2,
131.1, 134.1, 137.2, 142.7, 146.6, 151.8; anal. calcd. for
C14H11NOS (241.31): C 69.68, H 4.59; found: C 69.69, H
4.68.
1-{4-[5-(Hydroxymethyl)furan-2-yl]phenyl}ethanone
(23)
Before purification, traces of the corresponding 5-aryl-
ACHTUNGTRENNUNG
thiophen-2-ylmethyl acetate were also observed: 1H NMR
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol),
furfuryl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
(200 MHz, CDCl3): d=2.30 (s, 3H), 5.28 (s, 2H).
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
1-{4-[5-(2-Hydroxyethyl)thiophen-2-yl]phenyl}-
ethanone (19)[13]
product 23; yield: 0.156 g (72%). 1H NMR (200 MHz,
CDCl3): d=1.74 (br s, 1H), 2.61 (s, 3H), 4.70 (s, 2H), 6.43
(d, J=3.3 Hz, 1H), 6.75 (d, J=3.3 Hz, 1H), 7.74 (d, J=
8.5 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H); 13C NMR (50 MHz,
CDCl3): d=26.5, 57.5, 108.2, 110.2, 123.4, 128.9, 134.6, 135.4,
152.6, 155.0, 197.6; anal. calcd. for C13H12O3 (216.23): C
72.21, H 5.59; found: C 72.41, H 5.47.
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol),
thiophen-2-ylethanol (0.256 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 19; yield: 0.194 g (79%). 1H NMR (300 MHz,
CDCl3): d=2.98 (t, J=7.5 Hz, 2H), 2.50 (s, 3H), 3.82 (m,
2H), 3.95 (br s, 1H), 6.78 (d, J=3.3 Hz, 1H), 7.20 (d, J=
3.3 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.93 (d, J=8.3 Hz,
2H).
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.11 (s, 3H), 2.61 (s, 3H), 5.12 (s, 2H), 6.53 (d, J=3.4 Hz,
1H), 6.76 (d, J=3.4 Hz, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.98
(d, J=8.6 Hz, 2H).
2-(5-p-Tolylthiophen-2-yl)ethanol (20)
4-[5-(Hydroxymethyl)furan-2-yl]benzaldehyde (24)
The reaction of 4-bromotoluene (0.171 g, 1 mmol), 1 mmol),
thiophen-2-ylethanol (0.256 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
The reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol),
furfuryl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 20; yield: 0.050 g (23%). 1H NMR (300 MHz,
CDCl3): d=1.67 (br s, 1H), 2.36 (s, 3H), 3.07 (t, J=7.5 Hz,
2H), 3.89 (m, 2H), 6.82 (d, J=3.3 Hz, 1H), 7.10 (d, J=
3.3 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz,
2H); 13C NMR (750 MHz, CDCl3): d=21.1, 33.6, 63.4, 122.4,
125.5, 126.5, 129.5, 131.6, 137.1, 139.8, 143.2; anal. calcd. for
C13H14OS (218.32): C 71.52, H 6.46; found: C 71.67, H 6.34.
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 24; yield: 0.125 g (62%). 1H NMR (200 MHz,
CDCl3): d=1.79 (br s, 1H), 4.70 (s, 2H), 6.44 (d, J=3.3 Hz,
1H), 6.79 (d, J=3.3 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.89
(d, J=8.4 Hz, 2H), 9.98 (s, 1H); 13C (50 MHz, CDCl3): d=
57.5, 108.9, 110.3, 123.8, 130.3, 134.7, 135.8, 152.3, 155.3,
191.7; anal. calcd. for C12H10O3 (202.21): C 71.28, H 4.98;
found: C 71.27, H 4.89.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.11 (s, 3H), 5.12 (s, 2H), 6.54 (d, J=3.3 Hz, 1H), 6.81 (d,
J=3.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz,
2H), 9.99 (s, 1H).
3-[5-(2-Hydroxyethyl)thiophen-2-yl]benzonitrile (21)
The reaction of 3-bromobenzonitrile (0.182 g, 1 mmol), thio-
phen-2-ylethanol (0.256 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 21; yield: 0.176 g (77%). 1H NMR (300 MHz,
CDCl3): d=2.39 (br s, 1H), 3.05 (t, J=7.5 Hz, 2H), 3.87 (m,
2H), 6.83 (d, J=3.3 Hz, 1H), 7.15 (d, J=3.3 Hz, 1H), 7.39
(t, J=7.8 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.66 (d, J=
8.3 Hz, 1H), 7.73 (s, 1H); 13C NMR (75 MHz, CDCl3): d=
33.4, 62.9, 112.7, 118.4, 124.1, 126.7, 128.4, 129.3, 129.5,
130.0, 135.5, 139.6, 142.4; anal. calcd. for C13H11NOS
(229.30): C 68.09, H 4.84; found: C 67.98, H 4.80.
4-[5-(Hydroxymethyl)furan-2-yl)benzonitrile (25)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 25;
1
yield: 0.150 g (75%). H NMR (200 MHz, CDCl3): d=1.93
(br s, 1H), 4.68 (s, 2H), 6.43 (d, J=3.3 Hz, 1H), 6.76 (d, J=
3.3 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz,
2H); 13C NMR (50 MHz, CDCl3): d=57.3, 108.9, 109.9,
110.2, 118.8, 123.7, 132.4, 134.4, 151.6, 155.4; anal. calcd. for
C12H9NO2 (199.21): C 72.35, H 4.55; found: C 72.42, H 4.59.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.11 (s, 3H), 5.11 (s, 2H), 5.53 (d, J=3.3 Hz, 1H), 6.78 (d,
2-[5-(Pyridin-3-yl)thiophen-2-yl]ethanol (22)
The reaction of 3-bromopyridine (0.158 g, 1 mmol),
1 mmol), thiophen-2-ylethanol (0.256 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
706
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 696 – 710

Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
J=3.3 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz,
2H): 13C NMR (50 MHz, CDCl3): d=20.8, 57.8, 108.8, 110.5,
113.0, 118.7, 124.0, 132.4, 134.1, 150.6, 152.3.
Traces of 4-(5-hydroxymethylfuran-3-yl)benzonitrile were
also isolated: 1H NMR (200 MHz, CDCl3): d=1.97 (br s,
1H), 4.71 (s, 2H), 6.60 (d, J=1.8 Hz, 1H), 7.47 (d, J=
1.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.70 (d, J=8.2 Hz,
2H).
(0.22 mg, 0.001 mmol) affords the corresponding product 29;
yield: 0.028 g (15%). H NMR (300 MHz, CDCl3): d=1.86
1
(br s, 1H), 2.36 (s, 3H), 4.66 (s, 2H), 6.36 (d, J=3.2 Hz,
1H), 6.54 (d, J=3.2 Hz, 1H), 7.19 (d, J=8 Hz, 2H), 7.57 (d,
J=8 Hz, 2H); 13C (75 MHz, CDCl3): d=21.3, 57.6, 104.9,
109.9, 123.8, 128.0, 129.3, 137.3, 153.2, 154.2; anal. calcd. for
C12H12O2 (188.22): C 76.57, H 6.43; found: C 76.70, H 6.45.
[5-(4-Methoxyphenyl)furan-2-yl]methanol (30)[20]
[5-(4-Nitrophenyl)furan-2-yl]methanol (26)
The reaction of 4-bromoanisole (0.187 g, 1 mmol), furfuryl
alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol) at
1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
The reaction of 4-bromonitrobenzene (0.202 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of Pd
(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 30;
yield: 0.020 g (10%). H NMR (200 MHz, CDCl3): d=1.79
(br s, 1H), 3.83 (s, 3H), 4.65 (s, 2H), 6.35 (d, J=3.2 Hz,
1H), 6.45 (d, J=3.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.60
(d, J=8.8 Hz, 2H).
1
(0.22 mg, 0.001 mmol) affords the corresponding product 26;
yield: 0.167 g (76%). 1H NMR (200 MHz, DMSO-d6): d=
4.49 (d, J=5.8 Hz, 2H), 5.40 (t, J=5.8 Hz, 1H), 6.52 (d, J=
3.3 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.92 (d, J=8.9 Hz,
2H), 8.28 (d, J=8.9 Hz, 2H); 13C NMR (50 MHz, DMSO-
d6): d=55.8, 109.9, 111.1, 123.7, 124.4, 136.1, 145.7, 150.2,
157.8; anal. calcd. for C11H9NO4 (219.19): C 60.27, H 4.14;
found: C 60.21, H 4.00.
{5-[4-(Dimethylamino)phenyl]furan-2-yl}methanol
(31)
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.12 (s, 3H), 5.13 (s, 2H), 6.56 (d, J=3.4 Hz, 1H), 6.84 (d,
J=3.4 Hz, 1H), 7.80 (d, J=8.9 Hz, 2H), 8.25 (d, J=8.9 Hz,
2H).
The reaction of 4-bromo-N,N-dimethylaniline (0.200 g,
1 mmol), furfuryl alcohol (0.196 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACTHNURGTNEUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 31; yield: 0.022 g (10%). 1H NMR
(200 MHz, CDCl3): d=1.72 (br s, 1H), 2.99 (s, 6H), 4.64 (s,
2H), 6.33 (d, J=3.3 Hz, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.73
(d, J=8.9 Hz, 2H), 7.55 (d, J=8.9 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d=40.4, 57.7, 102.7, 110.0, 112.3, 119.5,
125.0, 149.8, 152.1, 154.9; anal. calcd. for C13H15NO2
(217.26): C 71.87, H 6.96; found: C 71.70, H 7.05.
{5-[4-(Trifluoromethyl)phenyl]furan-2-yl}methanol
(27)
The reaction of 4-trifluoromethylbromobenzene (0.225 g,
1 mmol), furfuryl alcohol (0.196 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
3-[5-(Hydroxymethyl)furan-2-yl]benzonitrile (32)
sponding product 27; yield: 0.194 g (80%). 1H NMR
(300 MHz, CDCl3): d=1.67 (br s, 1H), 4.69 (s, 2H), 6.42 (d,
J=3.3 Hz, 1H), 6.72 (d, J=3.3 Hz, 1H), 7.62 (d, J=8.3 Hz,
2H), 7.76 (d, J=8.3 Hz, 2H); 13C (75 MHz, CDCl3): d=
57.3, 107.7, 110.2, 123.7, 124.2 (q, J=272.0 Hz), 125.7 (q, J=
3.6 Hz), 129.2 (q, J=32.5 Hz), 133.7, 152.4, 154.7; anal.
calcd. for C12H9F3O2 (242.19): C 59.51, H 3.75; found; C
59.60, H 4.01.
The reaction of 3-bromobenzonitrile (0.182 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 32;
1
yield: 0.128 g (64%). H NMR (200 MHz, CDCl3): d=1.90
(br s, 1H), 4.68 (s, 2H), 6.49 (d, J=3.3 Hz, 1H), 6.69 (d, J=
3.3 Hz, 1H), 7.48 (m, 2H), 7.86 (td, J1 =1.9 Hz, J2 =6.9 Hz,
1H), 7.93 (m, 1H); 13C NMR (50 MHz, CDCl3): d=57.4,
107.6, 110.1, 112.8, 118.5, 127.0, 127.6, 129.4, 130.4, 131.7,
151.3, 154.8; anal calcd. for C12H9NO2 (199.21): C 72.35, H
4.55; found: C 72.40, H 4.57.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.11 (s, 3H), 5.11 (s, 2H), 6.52 (d, J=3.4 Hz, 1H), 6.70 (d,
J=3.4 Hz, 1H), 7.50 (m, 2H), 7.87 (m, 1H), 7.94 (m, 1H).
[5-(4-Fluorophenyl)furan-2-yl]methanol (28)[19]
The reaction of 4-fluorobromobenzene (0.175 g, 1 mmol),
furfuryl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 28; yield: 0.100 g (52%). 1H NMR (200 MHz,
CDCl3): d=1.78 (br s, 1H), 4.66 (s, 2H), 6.37 (d, J=3.3 Hz,
1H), 6.53 (d, J=3.3 Hz, 1H), 7.07 (m, 2H), 7.64 (m, 2H).
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.10 (s, 3H), 5.10 (s, 2H), 6.48 (d, J=3.3 Hz, 1H), 6.55 (d,
J=3.3 Hz, 1H), 7.08 (m, 2H), 7.64 (m, 2H).
[5-(3-Nitrophenyl)furan-2-yl]methanol (33)
The reaction of 3-bromonitrobenzene (0.202 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 33;
1
yield: 0.123 g (56%). H NMR (200 MHz, CDCl3): d=1.79
(5-p-Tolylfuran-2-yl)methanol (29)
(br s, 1H), 4.70 (s, 2H), 6.44 (d, J=3.3 Hz, 1H), 6.76 (d, J=
3.3 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz,
1H), 8.09 (d, J=8.0 Hz, 1H), 8.49 (s, 1H); 13C NMR
(50 MHz, CDCl3): d=57.4, 108.0, 110.2, 118.3, 121.7, 129.1,
The reaction of 4-bromotoluene (0.171 g, 1 mmol), furfuryl
alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol) at
1508C in dry DMAc (5 mL) in the presence of PdACTHUNRGTNEUNG(OAc)2
Adv. Synth. Catal. 2010, 352, 696 – 710
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
707

Julien Roger et al.
FULL PAPERS
129.6, 132.1, 148.5, 151.3, 154.9; anal. calcd. for C11H9NO4
(219.19): C 60.27, H 4.14; found: C 60.21, H 4.17.
[5-(Naphthalen-1-yl)furan-2-yl]methanol (37)
The reaction of 1-bromonaphthalene (0.207 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.12 (s, 3H), 5.12 (s, 2H), 6.54 (d, J=3.3 Hz, 1H), 6.78 (d,
J=3.3 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz,
1H), 8.11 (d, J=8.0 Hz, 1H), 8.50 (br s, 1H).
(0.22 mg, 0.001 mmol) affords the corresponding product 37;
1
yield: 0.137 g (61%). H NMR (300 MHz, CDCl3): d=1.97
(br s, 1H), 4.74 (s, 2H), 6.50 (d, J=3.2 Hz, 1H), 6.68 (d, J=
3.2 Hz, 1H), 7.52 (m, 3H), 7.74 (d, J=7.2 Hz, 1H), 7.87 (m,
2H), 8.40 (m, 1H); 13C NMR (75 MHz, CDCl3): d=57.5,
109.5, 109.9, 125.2, 125.3, 125.8, 126.1, 126.5, 128.3, 128.4,
128.5, 130.2, 133.8, 153.2, 153.9; anal. calcd. for C15H12O2
(224.25): C 80.34, H 5.39; found: C 71.41, H 5.07.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.12 (s, 3H), 5.18 (s, 2H), 6.61 (d, J=3.2 Hz, 1H), 6.70 (d,
J=3.2 Hz, 1H), 7.51 (m, 3H), 7.75 (d, J=7.2 Hz, 1H), 7.87
(m, 2H), 8.40 (m, 1H).
{5-ACHTUNGTRENNUNG[3,5-Bis(trifluoromethyl)phenyl]furan-2-yl}-
methanol (34)
The reaction of 3,5-bis(trifluoromethyl)bromobenzene
(0.293 g, 1 mmol), furfuryl alcohol (0.196 g, 2 mmol) and
AcOK (0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in
the presence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the
corresponding product 34; yield: 0.192 g (62%). 1H NMR
(200 MHz, CDCl3): d=1.67 (br s, 1H), 4.71 (s, 2H), 6.45 (d,
J=3.4 Hz, 1H), 6.80 (d, J=3.4 Hz, 1H), 7.73 (s, 1H), 8.06
(s, 2H); 13C NMR (50 MHz, CDCl3): d=57.5, 108.6, 110.4,
120.5 (sept, J=3.8 Hz), 123.2 (m), 123.4 (q, J=3.2 Hz),
132.1 (q, J=33.5 Hz), 132.4, 150.9, 155.3; anal. calcd. for
C13H8F6O2 (310.19): C 50.34, H 2.60; found: C 50.40, H 2.74.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.12 (s, 3H), 5.13 (s, 2H), 6.55 (d, J=3.4 Hz, 1H), 6.81 (d,
J=3.4 Hz, 1H), 7.75 (s, 1H), 8.07 (s, 2H).
[5-(Pyridin-3-yl)furan-2-yl]methanol (38)
The reaction of 3-bromopyridine (0.158 g, 1 mmol), furfuryl
alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol) at
1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 38;
1
yield: 0.112 g (64%). H NMR (200 MHz, CDCl3): d=2.70
(br s, 1H), 4.68 (s, 2H), 6.40 (d, J=3.3 Hz, 1H), 6.68 (d, J=
3.3 Hz, 1H), 7.30 (dd, J=4.8 and 8.0 Hz, 1H), 7.91 (d, J=
8.0 Hz, 1H), 8.46 (d, J=4.8 Hz, 1H), 8.90 (d, J=1.8 Hz,
1H); 13C NMR (50 MHz, CDCl3): d=56.9, 107.4, 109.7,
123.6, 126.9, 131.0, 144.6, 147.4, 150.2, 155.5; anal. calcd. for
C10H9NO2 (175.18): C 68.56, H 5.18; found: C 68.47, H 5.27.
2-[5-(Hydroxymethyl)furan-2-yl]benzaldehyde (35)
The reaction of 2-bromobenzaldehyde (0.185 g, 1 mmol),
furfuryl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
[5-(Quinolin-3-yl)furan-2-yl]methanol (39)
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 35; yield: 0.128 g (63%). 1H NMR (200 MHz,
CDCl3): d=2.23 (br s, 1H), 4.69 (s, 2H), 6.46 (d, J=3.3 Hz,
1H), 6.57 (d, J=3.3 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.60
(t, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.96 (d, J=
7.5 Hz, 1H), 10.37 (s, 1H); 13C NMR (50 MHz, CDCl3): d=
57.3, 109.9, 112.1, 127.95, 127.99, 128.2, 132.8, 133.1, 133.6,
150.7, 155.8, 192.5; anal. calcd. for C12H10O3 (202.21): C
71.28, H 4.98; found: C 71.41, H 5.07.
The reaction of 3-bromoquinoline (0.208 g, 1 mmol), furfuryl
alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol) at
1508C in dry DMAc (5 mL) in the presence of PdACHTUNGTRENNUNG(OAc)2
(0.22 mg, 0.001 mmol) affords the corresponding product 38;
yield: 0.147 g (65%). 1H NMR (200 MHz, DMSO-d6): d=
4.52 (d, J=5.6 Hz, 2H), 5.37 (t, J=5.6 Hz, 1H), 6.51 (d, J=
3.3 Hz, 1H), 7.21 (d, J=3.3 Hz, 1H), 7.68 (m, 2H), 8.03 (t,
J=7.6 Hz, 2H), 8.54 (s, 1H), 9.29 (d, J=2.1 Hz, 1H);
13C NMR (50 MHz, DMSO-d6): d=55.8, 108.5, 109.5, 123.7,
127.3, 127.5, 128.0, 128.3, 128.8, 129.3, 146.4, 146.9, 149.8,
156.6; anal. calcd. for C14H11NO2 (225.24): C 74.65, H 4.92;
found: C 74.71, H 5.06.
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.13 (s, 3H), 5.16 (s, 2H), 6.57 (d, J=3.4 Hz, 1H), 6.85 (d,
J=3.4 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz,
1H), 7.86 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.40
(br s, 1H), 9.20 (br s, 1H).
Traces of the corresponding 5-arylfuran-2-ylmethyl ace-
tate were also isolated: 1H NMR (200 MHz, CDCl3): d=
2.11 (s, 3H), 5.13 (s, 2H), 6.57 (d, J=3.4 Hz, 1H), 6.60 (d,
J=3.4 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz,
1H), 7.70 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 10.39
(s, 1H).
2-[5-(Hydroxymethyl)furan-2-yl)benzonitrile (36)
The reaction of 2-bromobenzonitrile (0.182 g, 1 mmol), fur-
furyl alcohol (0.196 g, 2 mmol) and AcOK (0.196 g, 2 mmol)
at 1508C in dry DMAc (5 mL) in the presence of PdACTHNUTRGNEUNG(OAc)2
4-[5-(1-Hydroxyethyl)furan-2-yl]benzonitrile (40)
(0.22 mg, 0.001 mmol) affords the corresponding product 36;
1
yield: 0.133 g (67%). H NMR (200 MHz, CDCl3): d=1.90
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), 1-
furan-2-ylethanol (0.224 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
(br s, 1H), 4.70 (s, 2H), 6.46 (d, J=3.4 Hz, 1H), 7.23 (d, J=
3.4 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H),
7.69 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3): d=57.1, 106.3, 110.1, 111.0, 118.9, 125.7,
127.0, 132.8, 134.0, 149.3, 155.1; anal. calcd. for C12H9NO2
(199.21): C 72.35, H 4.55; found: C 72.20, H 4.37.
PdACTHNUGTRENNG(U OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 40; yield: 0.168 g (79%). 1H NMR (300 MHz,
CDCl3): d=1.60 (d, J=6.6 Hz, 3H), 2.50 (br s, 1H), 4.96 (q,
J=6.6 Hz, 1H), 6.36 (d, J=3.3 Hz, 1H), 6.73 (d, J=3.3 Hz,
708
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 696 – 710

Palladium-Catalysed Direct Arylation of Heteroaromatics Bearing Unprotected Hydroxyalkyl Functions
1H), 7.60 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H); 13C
(75 MHz, CDCl3): d=21.3, 63.5, 107.7, 108.8, 109.9, 118.9,
123.7, 132.4, 134.4, 151.0, 159.0; anal. calcd. for C13H11NO2
(213.23): C 73.22, H 5.20; found: C 73.30, H 5.31.
129.7, 135.8, 149.2, 166.1, 192.1; anal. calcd. for C13H13NO2S
(247.31): C 63.13, H 5.30; found: C 63.41, H 5.13.
4-(3-Hydroxymethyl-5-methylisoxazol-4-yl)benzo-
nitrile (47)
2-[5-(1-Hydroxyethyl)furan-2-yl]benzaldehyde (42)
The reaction of 4-bromobenzonitrile (0.182 g, 1 mmol), (5-
methylisoxazol-3-yl)methanol (0.226 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
The reaction of 2-bromobenzaldehyde (0.185 g, 1 mmol), 1-
furan-2-ylethanol (0.224 g, 2 mmol) and AcOK (0.196 g,
2 mmol) at 1508C in dry DMAc (5 mL) in the presence of
ence of PdACTHNURGTNEUNG(OAc)2 (2.2 mg, 0.01 mmol) affords the corre-
sponding product 47; yield: 0.082 g (38%). 1H NMR
(300 MHz, CDCl3): d=2.35 (s, 3H), 2.95 (br s, 1H), 4.69 (s,
2H), 7.55 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H); 13C
(75 MHz, CDCl3): d=11.8, 55.4, 111.4, 114.9, 118.5, 129.6,
132.6, 134.6, 160.9, 167.0; anal. calcd. for C12H10N2O2
(214.22): C 67.28, H 4.71; found: C 67.40, H 4.80.
PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corresponding
product 42; yield: 0.100 g (46%). 1H NMR (300 MHz,
CDCl3): d=1.61 (d, J=6.6 Hz, 3H), 2.10 (br s, 1H), 4.97 (q,
J=6.6 Hz, 1H), 6.40 (d, J=3.3 Hz, 1H), 6.56 (d, J=3.3 Hz,
1H), 7.42 (t, J=7.9 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.68
(d, J=8.3 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 10.37 (s, 1H);
13C NMR (75 MHz, CDCl3): d=21.4, 63.7, 107.5, 111.9,
128.0, 128.1, 128.2, 132.9, 133.2, 133.5, 159.3, 192.3; anal.
calcd. for C13H12O3 (216.23): C 72.21, H 5.59; found: C
72.33, H 5.71.
Acknowledgements
J. R. is grateful to “Ministꢀre de la Recherche” for a grant.
We thank the Centre National de la Recherche Scientifique
and “Rennes Metropole” for providing financial support and
the Slovenian Research Agency (P1-0230-0103) for partial fi-
nancial support to F.P.
1-[5-(Pyridin-4-yl)furan-2-yl]ethanol (43)
The reaction of 4-bromopyridine hydrochloride (0.194 g,
1 mmol), 1-furan-2-ylethanol (0.224 g, 2 mmol) and AcOK
(0.196 g, 2 mmol) at 1508C in dry DMAc (5 mL) in the pres-
ence of PdACHTUNGTRENNUNG(OAc)2 (0.22 mg, 0.001 mmol) affords the corre-
sponding product 43; yield: 0.144 g (76%). 1H NMR
(300 MHz, CDCl3): d=1.59 (d, J=6.6 Hz, 3H), 2.80 (br s,
1H), 4.95 (q, J=6.6 Hz, 1H), 6.36 (d, J=3.3 Hz, 1H), 6.79
(d, J=3.3 Hz, 1H), 7.45 (d, J=6.0 Hz, 2H), 8.51 (d, J=
6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.5, 63.4,
107.6, 109.5, 117.6, 137.5, 149.8, 150.2, 159.7; anal. calcd. for
C11H11NO2 (189.21): C 69.83, H 5.86; found: C 69.80, H 5.99.
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 696 – 710