Direct arylation of heteroaromatic compounds with congested, functionalised aryl bromides at low palladium/triphosphane catalyst loading

Article abstract of DOI:10.1002/chem.201100100

A new ferrocenyl triphosphane ligand associated to palladium was found to be an efficient catalyst for the direct coupling of highly congested, functionalised aryl bromides with a variety of heteroarenes. These coupling reactions can generally be performe

Full text of DOI:10.1002/chem.201100100

FULL PAPER
DOI: 10.1002/chem.201100100
Direct Arylation of Heteroaromatic Compounds with Congested,
Functionalised Aryl Bromides at Low Palladium/Triphosphane Catalyst
Loading
David Roy,[a] Sophal Mom,[b] Dominique Lucas,[b] Hꢀlꢁne Cattey,[b]
Jean-Cyrille Hierso,*[b] and Henri Doucet*[a]
Abstract: A new ferrocenyl triphos-
phane ligand associated to palladium
was found to be an efficient catalyst
for the direct coupling of highly con-
gested, functionalised aryl bromides
with a variety of heteroarenes. These
coupling reactions can generally be
performed by using a low-loading (0.1–
0.5 mol%) of the catalyst. The present
protocol tolerates important and useful
functional groups, which allows for fur-
ther elaboration into more sophisticat-
ed heterocyclic molecules. The straight-
forward arylation of heteroaromatic
compounds with congested ortho-sub-
stituted aryl bromides may permit fur-
ther convergent syntheses of diverse li-
gands, biologically active molecules
and molecular materials in only a few
steps.
À
Keywords: aryl bromides · C H ac-
tivation · ferrocenyl polyphosphane ·
heterocycles · palladium
Introduction
Until now, reports on palladium-catalysed direct aryla-
tions of heteroaromatic compounds describe the use of sev-
eral para- or meta-substituted aryl halides. The use of ortho-
substituted aryl halides for such reactions would be very
useful for the preparation of bioactive compounds, molecu-
lar materials or innovative ligands. Such sterically demand-
ing aryl halides have already been successfully employed by
the groups of Buchwald and Ackermann for the preparation
of hindered biaryls by Suzuki cross-coupling reactions.[7]
Conversely, for palladium-catalysed direct arylation reac-
tions with ortho-substituted aryl bromides, the functional
group tolerance needs to be extended. Moreover, better
yields need to be obtained for several substrates,[8–12] and di-
ortho-substituted aryl halides remain uncommon coupling
partners.[13–15] For furans or thiophenes a few examples of
couplings with di-ortho-substituted aryl bromides have been
described with a tetraphosphine[16] ligand.[13,14a] 2,6-Difluoro-
bromobenzene has also been employed as a coupling part-
ner.[14c,17a] The coupling of a thiophene derivative with 9-bro-
moanthracene, to give the 2-arylated thiophene in 40%
yield, has also been described.[14b] To the best of our knowl-
edge, the direct arylation of pyrroles with di-ortho-substitut-
ed aryl halides has never been reported.
Palladium-catalysed cross-coupling reactions between nucle-
ophilic organometallic reagents and electrophilic organic
halides or pseudo-halides (for example, Stille, Suzuki or Ne-
gishi reactions) have emerged as powerful synthetic tools
for the construction of carbon–carbon bonds.[1,2] Such cata-
lytic coupling processes are applied to a wide array of en-
deavours, which range from biological sciences to materials
chemistry. Their applications to heteroaromatic substrates
provide convergent synthetic routes to substituted heterocy-
clic structures. One of the major drawbacks of this method-
ology is the preparation of the organometallic reagents. Re-
cently, to avoid the use of such reagents, research has shifted
À
to the direct arylation of heteroaromatic substrates by C H
bond activation.[3–6] These couplings also avoid stoichiomet-
ric formation of metallic byproducts, from which undesired
contamination could be potentially appalling for pharma-
ceutical, agrochemical and related biological applications.
[a] D. Roy, Dr. H. Doucet
UMR-CNRS 6226, ꢀquipe “Catalyse et Organomꢀtalliques”
Universitꢀ de Rennes I
Despite these relevant advances, efficient catalytic sys-
tems for the coupling of a wide range of diversely ortho-
and, especially, di-ortho-substituted aryl halides to different
classes of heteroaromatic compounds have not been report-
ed to date. Herein, we disclose the use of a novel, air-stable
palladium/ferrocenyl triphosphane system for the direct ary-
lation of heteroaromatic compounds by ortho-substituted
aryl bromides, efficient at remarkably low catalyst loadings,
even for highly congested substrates.
Campus de Beaulieu, 35042 Rennes (France)
Fax : (+33)2-23-23-63-84
E-mail: henri.doucet@univ-rennes1.fr
[b] S. Mom, Prof. Dr. D. Lucas, Dr. H. Cattey, Prof. Dr. J.-C. Hierso
UMR-CNRS 5260 - Institut de Chimie Molꢀculaire
Universitꢀ de Bourgogne
9 avenue Alain Savary, 21078 Dijon (France)
Fax : (+33)3-80-39-36-82
E-mail: hiersojc@u-bourgogne.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100100.
Chem. Eur. J. 2011, 17, 6453 – 6461
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Table 1. Ligand screening for the direct arylation of 2-n-butylfuran with
Results and Discussion
2-bromotoluene catalysed by palladium/ferrocenyl di- or triphosphanes.[a]
Recently, we probed various ferrocenyl polyphosphane li-
gands[18] for use in direct arylations of heteroaromatic com-
pounds with unactivated and/or functionalised (R1 =4-CN is
electron-withdrawing group) aryl bromides.[19] We discov-
ered superior efficiency of ferrocenyl triphosphane ligands
relative to related mono-, di- and tetraphosphanes. We then
focused our efforts to provide an efficient palladium-cata-
lysed methodology for the challenging intermolecular aryla-
tion of functionalised aryl chlorides by using systems that in-
corporated modified ferrocenyl triphosphanes (Scheme 1).[20]
Entry Catalytic system Conversion of 2-bromotoluene [%] Yield [%]
1
2
3
4
5
6
7
Pd
Pd
Pd
Pd
Pd
Pd
Pd
G
56
59
71
49
84
82
75
53
55
67
46
80
78
71
[a] PdACTHUNGRTENUNG(OAc)2 (0.005 mmol), L (0.005 mmol), 2-bromotoluene (1 mmol),
2-n-butylfuran (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol), N,N-dime-
thylacetamide (DMAc), 150 8C, 16 h, under argon. [b] Without Bu4NBr.
Table 2. Direct arylation of heteroaromatic compounds with ortho-substi-
tuted aryl bromides with a phosphine-free catalyst.[a]
Scheme 1. Palladium-catalysed arylation of unactivated R1 =4-CN is elec-
tron withdrawing aryl bromides and functionalised aryl chlorides with
heteroaromatic compounds at low catalyst loadings (L1 and L2 are de-
picted in Scheme 2).
Entry
1
Product
Cat. [mol%]
0.1
Yield [%]
82
1
2
A further screening of the scope of the palladium catalytic
systems with associated ligands L1 and L2 (Scheme 2) used
2
3
1
0
À
in these promising C H direct activation/functionalisation
reactions revealed that these auxiliaries were moderately ef-
ficient in the coupling of hindered aryl bromides, such as 2-
bromotoluene (Table 1, entries 1 and 2). We had also ob-
served that the coupling of selected heteroaromatic com-
pounds with some ortho-substituted electron-deficient aryl
3
0.4
75
bromides proceeds very efficiently when PdACTHNURGTNEUNG(OAc)2 was used
4
5
6
4
5
6
1
0
90
42
as a catalyst in the absence of any ligand L (Table 2, en-
tries 5 and 8, arylation of 2-n-butyl furane and 2-n-butylthio-
phene).[17] The ligand-free coupling of 2-n-propylthiazole
with 2-bromotoluene and 2-bromoanthracene also proceeds
0.1
1
7
8
7
8
9
0.1
0.1
0.5
87
92
37
9
[a] PdACTHUNGRTENUNG(OAc)2 (cat.), aryl bromide (1 mmol), heteroaromatic compound
À
Scheme 2. Polyphosphane ligands for C H activation/functionalisation of
heteroarenes with sterically demanding ortho-substituted aryl bromides.
(2 mmol), KOAc (2 mmol), DMAc, 150 8C, under argon; yields are of
isolated products.
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Arylations of Heteroaromatic Compounds with Congested Aryl Bromides
FULL PAPER
satisfactorily (Table 2, entries 1 and 3). On the other hand,
the reaction of 2-bromotoluene with 2-n-butylthiophene or
1-methyl-2-acetylpyrrole in the presence of a phosphine-free
PdACHTUNGTRENNUNG(OAc)2 catalyst gave the coupling products 6 and 9 in
only 37 and 42% yield, respectively (Table 2, entries 6 and
9). Finally, the couplings of 2-n-butylfuran to 2-bromoto-
luene, and 2-n-propylthiazole to 2,6-dimethylbromobenzene
were totally inefficient under ligand-free conditions, even at
higher catalyst loadings (Table 2, entries 2 and 4).
Thus, we re-examined the modular features of our ligands
to design a system able to couple a wider array of heteroar-
omatic compounds with hindered aryl bromides and to over-
come the limitations encountered in the ligand-free palladi-
um-catalysed direct arylation of aryl bromides. The various
tuneable features involved in our ligand design are summar-
ised in Scheme 3.
Figure 1. ORTEP representation of the molecular structure of L5. Due to
the steric influences of the tBu and iPr groups the three phosphorus
atoms are pointing in the same direction, contrary to the structures re-
ported previously for related ligands L2[15b] and L4[21a]
.
palladium reactivity should be significant enough to pro-
mote cross-coupling of congested aryl bromides.
Scheme 3. Tuneable features in the design of ferrocenyl polyphosphane
ligands.
With a suitable palladium-based system indentified for
direct heteroarylation of ortho-hindered aryl bromides at
low catalyst loading, a performance survey of L5 in the reac-
tions with ortho- or di-ortho-substituted aryl bromides was
conducted (Scheme 4 and Tables 3–10).
Following these trends, several new ligands were synthes-
ised (Scheme 2). Ferrocenyl phosphanes L1–L6 were tested
and compared under identical reaction conditions (Table 1)
in the arylation of 2-n-butylfuran with 2-bromotoluene (an
inefficient coupling in the absence of L; Table 2, entry 4).
As expected, the ferrocenyl phosphanes L were generally
found to be useful auxiliaries for this palladium-catalysed
À
C H activation (Table 1). However, the best yield at a low
catalyst loading (5ꢂ10À3 mmol)[18f] was obtained by using L5
in combination with a Bu4NBr additive. In the absence of
this additive the coupling proceeds but a slightly lower yield
was obtained (Table 1, entries 5 versus 7). Ligand L6 also
produced fairly satisfactory results but was more difficult to
synthesise and complementary screening studies demon-
strated a slightly narrower scope relative to L5.
Scheme 4. Palladium-catalysed coupling of ortho- and di-ortho-substitut-
ed aryl bromides with heteroaromatic compounds.
With the PdACTHNUGTRENUNG(OAc)2/L5 catalytic system, the coupling of a
wide range of heteroarenes with 2-bromotoluene proceeds
in the presence of only 0.5 mol% catalyst to give the 5-ary-
lated products 6 and 9–13 in good yields (Table 3). The high-
est yields were obtained in the cases of 2-n-butylthiophene
and 1-(furan-2-yl)butan-1-one (Table 3, entries 1 and 5).
We next examined the reactivity of 2-bromobiphenyl
(Table 4). This aryl bromide was found to be less reactive
than 2-bromotoluene. In the presence of 2-n-butylfuran or
1-methyl-2-acetylpyrrole moderate yields of 39 and 41% of
14 and 17, respectively, were obtained (Table 4, entries 1
and 5). Much better results were obtained for the coupling
of this very hindered aryl bromide with functionalised thio-
phenes (Table 4, entries 2–4).
The X-ray diffraction structure of L5 was determined
(Figure 1) to clarify the specific features of this triphosphane
relative to the other ligands tested and, in particular, with
respect to the previously reported ligands L1 and L2.
Ligand L4 was also of comparative interest because it is the
analogue of L1 bearing a -PACHTNUGTRNEUNG(iPr)2 group instead of a PPh2
group.[15b,19,21] The most striking feature of L5 compared to
the other ligands depicted in Scheme 2 is the net eclipsed
position of P2 and P3, possibly due to the lower steric hin-
drance of the isopropyl groups. Therefore, upon chelation of
palladium with P1 and P2, the influence of P3 on the area of
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H. Doucet, J.-C. Hierso et al.
Table 3. Direct 5-arylation of heteroaromatic compounds with 2-bromo-
toluene (Scheme 4).[a]
all cases, the reaction was regioselective at the C5 position.
Conversely, 1,2-dimethylimidazole was recovered without
any reaction (Table 5, entry 12). In the course of these reac-
tions, no coupling of the hydroxymethyl function with the
aryl bromide was observed.
Entry
Product
Cat. [mol%]
Yield [%]
1
6
0.5
90
2
0.5
0.5
71
55
3[b]
Table 5. Direct arylation of heteroaromatic compounds with (2-bromo-
phenyl)-methanol (Scheme 4).[a]
10
11
Entry
Product
Cat. [mol%]
Yield [%]
4
0.5
68
1
18
19
20
21
1
78
5
6
0.5
0.1
91
38
2
3
0.1
0.05
86
60
12
7
13
9
0.5
74
4
5
0.1
0.5
81
58
8
0.5
0.5
69
63
9[b]
6
7
0.5
0.1
81
77
[a] PdACHTUNGTRENNUNG(OAc)2/L5 (1:1, cat.), 2-bromotoluene (1 mmol), heteroaromatic
compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol), DMAc, 150 8C,
16 h, under argon; yields are of isolated products. [b] Without Bu4NBr.
22
Table 4. Direct arylation of heteroaromatic compounds with 2-bromobi-
phenyl (Scheme 4).[a]
8
9
23
24
0.5
0.1
77
75
Entry
Product
Cat. [mol%]
Yield [%]
1
14
15
16
0.5
39
10
11
25
0.5
65
2
1
69
3
4
0.5
0.1
90
85
26
27
0.5
0.5
67
0
5
17
0.5
41
12
[a] PdACHTUNGTRENNUNG(OAc)2/L5 (1:1, cat.), 2-bromobiphenyl (1 mmol), heteroaromatic
compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol), DMAc, 150 8C,
16 h, under argon, yields are of isolated products.
[a] PdACTHNUGRTENUNG(OAc)2/L5 (1:1, cat.), (2-bromophenyl)-methanol (1 mmol), hetero-
aromatic compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol),
DMAc, 150 8C, 16 h, under argon; yields are of isolated products.
The direct heteroarylation of C2-substituted aryl bromides
that carry reactive functional groups would be useful for the
straightforward synthesis of novel ligands.[22] We anticipated
that the direct coupling of unprotected (2-bromophenyl)-
methanol with heteroaromatic compounds would be very
practical because it would avoid a protection/deprotection
sequence and, therefore, would provide a more environmen-
tally and economically attractive access to reactive arylated
heteroaromatic compounds. We observed that coupling of
(2-bromophenyl)-methanol proceeded with a wide range of
furan, thiophene and pyrrole derivatives in the presence of
as little as 0.1–0.5 mol% catalyst (Table 5, entries 1–11). In
The catalytic system tolerates other substituents at the C2
position of bromobenzene derivatives (Table 6). The cou-
pling reactions of (2-bromophenyl)-acetonitrile with thio-
phene-2-carbonitrile, and 1-bromo-2-diethoxymethylbenzene
with thiophene-2-carbonitrile or 1-(furan-2-yl)butan-1-one
gave 28–30 in moderate yields, due to limited conversions of
these aryl bromides.
We had previously observed that direct coupling of 9-bro-
moanthracene with heteroaromatic compounds is relatively
easy. For example, in the presence of 2-n-propylthiazole,
one of the most reactive heteroaromatic compounds for
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Arylations of Heteroaromatic Compounds with Congested Aryl Bromides
FULL PAPER
Table 6. Direct arylation of heteroaromatic compounds with 2-substitut-
ed aryl bromides (Scheme 4).[a]
Table 7. Direct arylation of heteroaromatic compounds with 9-bromoan-
thracene (Scheme 4).[a]
Entry
Product
Yield [%]
Entry
Product
Cat. [mol%]
Yield [%]
1
28
29
38
1
3
0.5
94
2
56
68
2
3
4
5
6
7
8
31
32
33
34
35
36
37
38
0.5
80
90
68
88
88
92
59
60
3
30
1
[a] PdACHTUNGTRENNUNG(OAc)2 (0.05 mmol), L5 (0.05 mmol), aryl bromide (1 mmol), heter-
oaromatic compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol),
DMAc, 150 8C, 16 h, under argon; yields are of isolated products.
0.5
0.5
0.5
0.5
0.5
0.5
direct arylation, use of a PdACHTNUGRTENUNG(OAc)2 catalyst (0.4 mol%)
without any auxiliary ligand allowed the coupling product 3
to be obtained in 75% yield (Table 2, entry 3).[17b] Converse-
ly, the direct coupling of 9-bromoanthracene to pyrroles has
never been reported and its reaction with a thiophene deriv-
ative gave the coupling product in only 40% yield.[14b] As
anticipated, in the presence of the PdACTHNUTRGENUG(N OAc)2/L5 catalyst
(0.5–1 mol%) the target products 3 and 31–38 were ob-
tained in good to excellent yields (Table 7). By using our
new protocol, only a minor influence of the nature of the
heteroaromatic compound was observed.
To confirm the wide scope of our system we also exam-
ined the coupling of 1-bromo-2-methylnaphthalene with a
range of heteroaromatic compounds (Table 8). Until now,
this more challenging electron-enriched reactant has not
À
been coupled with heteroaromatic compounds through C H
bond activation. Surprisingly, in most cases, yields similar to
those found for the coupling with 9-bromoanthracene were
obtained. In the presence of 1-(furan-2-yl)butan-1-one and
only 0.05 mol% of catalyst, the desired product 43 was ob-
tained in 90% yield (Table 8, entry 9). High yields of cou-
pling products 39, 40 and 46 were also obtained in the pres-
ence of the catalyst (0.5 mol%) and 2-n-propylthiazole, 2-n-
butylfuran or 2-n-butylthiophene, respectively (Table 8, en-
tries 1, 2 and 12). We also examined the reactivity of furfuryl
alcohol as a heteroaromatic substrate that bore an unpro-
tected hydroxyalkyl function. The coupling reaction to 1-
bromo-2-methylnaphthalene gave the target compound 45
in a satisfactory 68% yield (Table 8, entry 11). In the course
of this reaction, no ether formation was detected. In general,
the presence of Bu4NBr slightly improves the yields of the
coupling products (Table 8, entries 2 versus 4).
9
[a] PdACTHNUGRTENUNG(OAc)2/L5 (1:1, cat.), 9-bromoanthracene (1 mmol), heteroaromatic
compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol), DMAc, 150 8C,
16 h, under argon; yields are of isolated products.
other hand, in the presence of 2-n-butylfuran or 2-n-butyl-
thiophene the expected products 49 and 53 were only
formed in moderate 40 and 35% yields, respectively
(Table 9, entries 2 and 6). The coupling with 2-n-propylthi-
azole gave 2 in only 29% yield (Table 9, entry 1).
Finally, the reactivity of 2-bromo-3-methylbenzonitrile
was examined (Table 10). Due to the presence of a nitrile
substituent on the aromatic ring, the oxidative addition to
palladium was expected to be easier than the oxidative addi-
As reported in Table 9, the coupling of 2,6-dimethylbro-
mobenzene with heteroaromatic compounds was more chal-
lenging. With some heteroaromatic compounds, such as
methyl 2-methyl-3-furancarboxylate, furfuryl acetate or 1-
(furan-2-yl)butan-1-one, the coupling products 50–52 were
obtained in fairly good yields (Table 9, entries 3–5). On the
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6457

H. Doucet, J.-C. Hierso et al.
Table 8. Direct arylation of heteroaromatic compounds with 1-bromo-2-
methylnaphthalene (Scheme 4).[a]
Table 9. Direct arylation of heteroaromatic compounds with 2,6-dime-
thylbromobenzene (Scheme 4).[a]
Entry
Product
Cat. [mol%]
Yield [%]
Entry
Product
Yield [%]
1
2
29
1
39
40
41
42
0.5
88
2
3
0.5
0.1
0.5
0.5
92
62
72
77
2
3
4
5
49
40
57
56
71
35
4[b]
5[c]
50
51
52
53
6
0.5
72
7
8
0.5
0.1
61
53
9
43
44
0.05
90
6
[a] PdACTHUNGRTENUNG(OAc)2 (0.05 mmol), L5 (0.05 mmol), 2,6-dimethylbromobenzene
(1 mmol), heteroaromatic compound (2 mmol), KOAc (2 mmol), Bu4NBr
(1 mmol), DMAc, 150 8C, 16 h, under argon; yields are of isolated prod-
ucts.
10
11
0.5
0.5
79
68
45
46
47
48
Table 10. Direct arylation of heteroaromatic compounds with 2-bromo-3-
methylbenzonitrile (Scheme 4).[a]
12
13
14
0.5
0.1
0.05
93
61
57
Entry
Product
Yield [%]
1
54
55
92
15
16
0.5
0.05
68
62
2
93
17
0.5
0
3
4
5
56
57
58
59
90
91
93
52
[a] PdACHTUNGTRENNUNG(OAc)2/L5 (1:1, cat.), 1-bromo-2-methylnaphthalene (1 mmol), het-
eroaromatic compound (2 mmol), KOAc (2 mmol), Bu4NBr (1 mmol),
DMAc, 150 8C, 16 h, under argon; yields are of isolated products.
[b] Without Bu4NBr. [c] 2-n-Butylfuran (1.2 mmol).
tion of 2,6-dimethylbromobenzene. The reaction proceeded
to give products 54–58 in very high yields when furan or
thiophene derivatives were used as coupling partners
(Table 10, entries 1–5). The reaction of this aryl bromide
with 1-methyl-2-formylpyrrole was found to be less regiose-
lective and the 5-arylation product 59 was obtained in only
52% yield. Such couplings may allow the synthesis of axially
chiral biaryls that could be useful ligands.[22]
6
[a] PdACTHNUGRTENUNG(OAc)2 (0.05 mmol), L5 (0.05 mmol), 2-bromo-3-methylbenzonitrile
(1 mmol), heteroaromatic compound (2 mmol), KOAc (2 mmol), Bu4NBr
(1 mmol), DMAc, 150 8C, 16 h, under argon; yields are of isolated prod-
ucts.
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Arylations of Heteroaromatic Compounds with Congested Aryl Bromides
FULL PAPER
solvent was removed by heating the reaction vessel under vacuum and
the residue was charged directly onto a silica gel column. The products
were eluted with an appropriate ratio of diethyl ether and pentane.
Compound 2:[15b] The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and 2-n-propylthiazole (0.254 g, 2.00 mmol) afforded 2 in
29% (0.067 g) yield.
Compound 3:[17b] The reaction of 9-bromoanthracene (0.257 g,
1.00 mmol) and 2-n-propylthiazole (0.254 g, 2.00 mmol) afforded 3 in
94% (0.285 g) yield.
Compound 4:[13] The reaction of 2-bromotoluene (0.171 g, 1.00 mmol)
and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 4 in 80% (0.171 g)
yield.
Conclusion
We have designed and identified a novel ferrocenyl triphos-
phane ligand, useful for efficient direct heteroarylation of
highly congested and functionalised aryl bromides. These
coupling reactions were performed with low catalyst load-
ings (0.1–0.5 mol%). The PdACTHNUTRGNE(UNG OAc)2/L5 catalytic system tol-
erates important and useful functional groups, which can
allow for further elaboration into more sophisticated hetero-
cyclic molecules. The wide reactivity scope clearly demon-
strates the synthetic utility of this catalytic system. The pres-
ent study highlights the usefulness of robust tridentate phos-
Compound 6:[14a] The reaction of 2-bromotoluene (0.171 g, 1.00 mmol)
and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 6 in 90% (0.207 g)
yield.
À
phane catalytic auxiliaries in direct C H activation reactions
that involve congested ortho-substituted aryl bromides. A
number of the products prepared by the reported method
have not been described until now, thus, this procedure pro-
vides a convenient access to compounds otherwise not easily
prepared, especially by the use of more classical cross-cou-
pling methods. Finally, with regards to environmental con-
siderations, the advantages of a procedure that produces
only limited amounts of inert waste (in this case, acetic acid
and potassium bromide byproducts) has become increasing-
ly important, particularly for industrial processes. More de-
tailed ligand design studies will be reported in due time.
Compound 9:[11b] The reaction of 2-bromotoluene (0.171 g, 1.00 mmol)
and 1-methyl-2-acetylpyrrole (0.247 g, 2.00 mmol) afforded 9 in 69%
(0.147 g) yield.
Compound 10: The reaction of 2-bromotoluene (0.171 g, 1.00 mmol) and
methyl 2-methylfuran-3-carboxylate (0.280 g, 2.00 mmol) afforded 10 in
71% (0.163 g) yield.
Compound 11: The reaction of 2-bromotoluene (0.171 g, 1.00 mmol) and
furfuryl acetate (0.280 g, 2.00 mmol) afforded 11 in 68% (0.156 g) yield.
Compound 12: The reaction of 2-bromotoluene (0.171 g, 1.00 mmol) and
1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded 12 in 91%
(0.208 g) yield.
Compound 13: The reaction of 2-bromotoluene (0.171 g, 1.00 mmol) and
thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 13 in 74%
(0.147 g) yield.
Compound 14: The reaction of 2-bromobiphenyl (0.233 g, 1.00 mmol)
and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 14 in 39% (0.108 g)
yield.
Experimental Section
General: All catalytic reactions were performed in Schlenk tubes under
an argon atmosphere. N,N-Dimethylacetamide (DMAc) was of analytical
grade and was not distilled before use. Potassium acetate (purity=
99%+) was used. Commercial aryl bromides and heteroaromatic deriva-
tives were used without purification. 1H (300 MHz), 13C (75 MHz) and
31P NMR (75 MHz) spectra were recorded in CDCl3 solution at 298 K.
Chemical shifts (d) are reported in ppm relative to CDCl3 (1H: d=
7.26 ppm and 13C: d=77.0 ppm) (see the Supporting Information). Flash
chromatography was performed on silica gel (230–400 mesh). Syntheses
of ligands L1–L4 and L6 have been reported previously.[18, 21]
Compound 15: The reaction of 2-bromobiphenyl (0.233 g, 1.00 mmol)
and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 15 in 69%
(0.202 g) yield.
Compound 16: The reaction of 2-bromobiphenyl (0.233 g, 1.00 mmol)
and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 16 in 90%
(0.235 g) yield.
Compound 17: The reaction of 2-bromobiphenyl (0.233 g, 1.00 mmol)
and 1-methyl-2-formylpyrrole (0.219 g, 2.00 mmol) afforded 17 in 41%
(0.107 g) yield.
Synthesis of ligand L5: A solution of 1,2-bis(diphenylphosphino)-4-tert-
butylcyclopentadienyl lithium (5.60 g, 11.3 mmol) in THF (20 mL) was
added to a stirred suspension of FeCl2 (1.37 g, 10.8 mmol) in THF
(15 mL) at À808C. The reaction mixture was allowed to slowly warm to
RT and was stirred for 2 h. The reaction mixture was cooled to À808C
and a solution of di-isopropylphosphino-3-tert-butylcyclopentadienyl lith-
ium (2.65 g, 10.8 mmol) in THF (20 mL) was added. After the addition,
the reaction mixture was allowed to slowly warm to RT and was stirred
for 1 h. THF was removed in vacuo, the residue was dissolved in toluene
(30 mL) and the resulting solution was heated at reflux for 3 h. The
brown solution was filtered through silica to yield a mixture of ferrocenyl
phosphanes. This mixture was purified by column chromatography (alu-
mina gel, height 30 cm, diameter 5.5 cm), eluted firstly with 3:2 toluene/
heptane to separate the symmetric diphosphane, secondly with 1:1 tolu-
ene/heptane to elute pure L5 (2.0 g, 25%). Ligand L5 was stored and
weighed under air without any special precautions.
Compound 18: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 2-n-propylthiazole (0.254 g, 2.00 mmol) afforded 18 in
78% (0.182 g) yield.
Compound 19: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 19 in 86%
(0.198 g) yield.
Compound 20: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and methyl 2-methylfuran-3-carboxylate (0.280 g, 2.00 mmol)
afforded 20 in 81% (0.199 g) yield.
Compound 21: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and furfuryl acetate (0.280 g, 2.00 mmol) afforded 21 in 58%
(0.143 g) yield.
Compound 22: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded
22 in 81% (0.198 g) yield.
General procedure for coupling reactions: The aryl bromide (1.00 mmol),
heteroaromatic derivative (2.00 mmol), KOAc (2.00 mmol) and Bu4NBr
(1.00 mmol) were introduced to a Schlenk tube equipped with a magnetic
Compound 23: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 23 in
77% (0.190 g) yield.
stirrer bar. 1:1 PdACHTUNGTRENNUNG(OAc)2/L5 (0.05–1 mol%) and DMAc (3 mL) were
added and the Schlenk tube was purged several times with argon. The
Schlenk tube was placed in a pre-heated oil bath at 150 8C and reactants
were allowed to stir for 16 h. The reaction mixture was analysed by gas
chromatography to determine the conversion of the aryl bromide. The
Compound 24: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 24
in 75% (0.161 g) yield.
Chem. Eur. J. 2011, 17, 6453 – 6461
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6459

H. Doucet, J.-C. Hierso et al.
Compound 25: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 1-methyl-2-acetylpyrrole (0.247 g, 2.00 mmol) afforded
25 in 65% (0.149 g) yield.
Compound 47: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 47
in 68% (0.169 g) yield.
Compound 49: The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 49 in 40%
(0.091 g) yield.
Compound 26: The reaction of (2-bromophenyl)-methanol (0.187 g,
1.00 mmol) and 1-methyl-2-formylpyrrole (0.219 g, 2.00 mmol) afforded
26 in 67% (0.144 g) yield.
Compound 50: The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and methyl 2-methylfuran-3-carboxylate (0.280 g, 2.00 mmol)
afforded 50 in 57% (0.139 g) yield.
Compound 28: The reaction of (2-bromophenyl)-acetonitrile (0.196 g,
1.00 mmol) and thiophene 2-carbonitrile (0.218 g, 2.00 mmol), affords 28
in 38% (0.085 g) yield.
Compound 51: The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and furfuryl acetate (0.280 g, 2.00 mmol) afforded 51 in 56%
(0.137 g) yield.
Compound 29: The reaction of 1-bromo-2-diethoxymethylbenzene
(0.187 g, 1.00 mmol) and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) af-
forded 29 in 56% (0.161 g) yield.
Compound 52: The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded
52 in 71% (0.172 g) yield.
Compound 30: The reaction of 1-bromo-2-diethoxymethylbenzene
(0.187 g, 1.00 mmol) and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol)
afforded 30 in 68% (0.215 g) yield.
Compound 31:[13] The reaction of 9-bromoanthracene (0.257 g,
1.00 mmol) and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 31 in 80%
(0.240 g) yield.
Compound 53: The reaction of 2-bromo-1,3-dimethylbenzene (0.185 g,
1.00 mmol) and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 53 in
35% (0.085 g) yield.
Compound 54: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded
54 in 92% (0.233 g) yield.
Compound 32: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and furfuryl acetate (0.280 g, 2.00 mmol) afforded 32 in 90% (0.284 g)
yield.
Compound 55: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and 2-diethoxymethylfuran (0.340 g, 2.00 mmol) afforded 55
in 93% (0.265 g) yield.
Compound 33: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and methyl 2-methylfuran-3-carboxylate (0.280 g, 2.00 mmol) afforded 33
in 68% (0.215 g) yield.
Compound 56: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and furfuryl acetate (0.280 g, 2.00 mmol) afforded 56 in 90%
(0.230 g) yield.
Compound 34: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded 34 in 88%
(0.276 g) yield.
Compound 57: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 57
in 91% (0.204 g) yield.
Compound 35: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 35 in 88% (0.278 g)
yield.
Compound 58: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 58 in
93% (0.237 g) yield.
Compound 36: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and thiophene 2-carbonitrile (0.218 g, 2.00 mmol) afforded 36 in 92%
(0.262 g) yield.
Compound 59: The reaction of 2-bromo-3-methylbenzonitrile (0.196 g,
1.00 mmol) and 1-methyl-2-formylpyrrole (0.219 g, 2.00 mmol) afforded
59 in 52% (0.117 g) yield.
Compound 37: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and 1-methyl-2-formylpyrrole (0.219 g, 2.00 mmol) afforded 37 in 59%
(0.168 g) yield.
Compound 38: The reaction of 9-bromoanthracene (0.257 g, 1.00 mmol)
and 1-methyl-2-acetylpyrrole (0.246 g, 2.00 mmol) afforded 38 in 60%
(0.180 g) yield.
Acknowledgements
Compound 39: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and 2-n-propylthiazole (0.254 g, 2.00 mmol) afforded 39 in
88% (0.235 g) yield.
Support provided from the ANR program for Sustainable Chemistry De-
velopment (ANR-09-CP2D-03 CAMELOT), the Rꢀgion Bourgogne
(PARI SMT8), Rennes Mꢀtropole and the CNRS/University of Burgun-
dy (3MIM program, P4-project) is acknowledged. S. Royer is acknowl-
edged for technical assistance.
Compound 40: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and 2-n-butylfuran (0.248 g, 2.00 mmol) afforded 40 in 92%
(0.243 g) yield.
Compound 41: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and methyl 2-methylfuran-3-carboxylate (0.280 g, 2.00 mmol)
afforded 41 in 72% (0.202 g) yield.
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Compound 42: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and furfuryl acetate (0.280 g, 2.00 mmol) afforded 42 in 61%
(0.171 g) yield.
Compound 43: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and 1-(furan-2-yl)butan-1-one (0.276 g, 2.00 mmol) afforded
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Compound 44: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
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Compound 45: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
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Compound 46: The reaction of 1-bromo-2-methylnaphthalene (0.221 g,
1.00 mmol) and 2-n-butylthiophene (0.280 g, 2.00 mmol) afforded 46 in
93% (0.261 g) yield.
6460
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Chem. Eur. J. 2011, 17, 6453 – 6461

Arylations of Heteroaromatic Compounds with Congested Aryl Bromides
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[10] For examples of Pd-catalysed direct 5-arylations of thiazoles with
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[11] For examples of Pd-catalysed direct arylations of pyrroles or indoles
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Rossi, J. Org. Chem. 2008, 73, 5529–5535; b) S. Gracia, C. Cazorla,
Received: January 11, 2011
Published online: April 20, 2011
Chem. Eur. J. 2011, 17, 6453 – 6461
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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