Mild palladium-catalyzed regioselective direct arylation of azoles promoted by tetrabutylammonium acetate

Article abstract of DOI:10.1002/ejoc.201300704

A mild, general, and convenient palladium-catalyzed direct arylation of the 5-position of azoles with aryl bromides, efficiently promoted by tetrabutylammonium acetate, is described. 1-Methylpyrazole, oxazole, and thiazole reacted at 70°C in N,N-dimethyla

Full text of DOI:10.1002/ejoc.201300704

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
FULL PAPER
Direct Azole Arylation
1-Methylpyrazole, oxazole, and thiazole
have been regioselectively arylated at the 5-
position with aryl bromides in the presence
of Bu4NOAc and Pd(OAc)2 at only 70 °C,
whereas 1-methylimidazole required 110 °C
to react. This simple ligand-free reaction
was applied to a one-pot sequential direct
arylation of the 5- and 2-positions of ox-
azole to give the two natural products bal-
soxin and texaline.
F. Bellina,* M. Lessi, C. Manzini ... 1–11
Mild Palladium-Catalyzed Regioselective
Direct Arylation of Azoles Promoted by
Tetrabutylammonium Acetate
Keywords: Nitrogen heterocycles / Aryl-
ation / C–C coupling / Palladium / Regiose-
lectivity
0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
F. Bellina, M. Lessi, C. Manzini
FULL PAPER
DOI: 10.1002/ejoc.201300704
Mild Palladium-Catalyzed Regioselective Direct Arylation of Azoles Promoted
by Tetrabutylammonium Acetate
Fabio Bellina,*[a] Marco Lessi,[a] and Chiara Manzini[a]
Dedicated to Professor Renzo Rossi on the occasion of his 75th birthday
Keywords: Nitrogen heterocycles / Arylation / C–C coupling / Palladium / Regioselectivity
A mild, general, and convenient palladium-catalyzed direct
arylation of the 5-position of azoles with aryl bromides, ef-
ficiently promoted by tetrabutylammonium acetate, is de-
scribed. 1-Methylpyrazole, oxazole, and thiazole reacted at
70 °C in N,N-dimethylacetamide by using Pd(OAc)2 as the
catalyst precursor. Electron-poor and -rich functional groups,
including the free hydroxy group, are well tolerated in the
electrophilic partner. A variety of 5-aryl-1-methylimidazoles
were also very efficiently obtained simply by raising the re-
action temperature to 110 °C. This ligand-free protocol was
successfully applied to the one-pot synthesis of two bioactive
natural compounds, balsoxin and texaline, starting from ox-
azole by sequential direct arylation of the 5- and 2-positions.
broadest range of simple C-unsubstituted azoles. In con-
trast to the methods used for the direct arylation of C-sub-
stituted azoles,[6] in which the desired groups have to be
introduced at the early stage of the synthesis and are very
often necessary to achieve the required selectivity, the aryl-
ation of unsubstituted azoles allows the introduction of aryl
moieties on the parent azole frameworks at a late stage in
the synthesis. In their seminal paper on the direct arylation
of azoles, Miura and co-workers reported that 1-methyl-
1H-imidazole and thiazole may be regioselectively arylated
at the 5-position with aryl bromides or iodides at 140 °C in
DMF in the presence of 10 mol-% Pd(OAc)2, 20 mol-%
PPh3 and 2 equiv. of K2CO3 (for bromides) or Cs2CO3 (for
iodides).[7] However, this method suffers from problems of
regioselectivity and, as we demonstrated later,[8] PPh3 may
be involved in undesired aryl–aryl exchange reactions with
the aryl moiety of the halides. In 2009, Fagnou and co-
workers demonstrated that thiazole and 1-benzyl-1,2,3-tri-
azole are able to undergo regioselective 5-arylation when
treated with aryl bromides and K2CO3 in N,N-dimethyl-
acetamide (DMA) at 100 °C in the presence of 2 mol-%
Pd(OAc)2 and 4 mol-% PCy3HBF4.[9] The coupling also re-
quired 30 mol-% pivalic acid, which, according to the au-
thors, led to faster reactions. Unfortunately, very low yields
were observed when 1-methyl-1H-imidazole was used as the
coupling partner, and the protocol proved to be unsuitable
for the direct arylation of imidazole, 1-benzyl-1H-imid-
azole, and isoxazole. Finally, it is worth mentioning that
in a series of papers, Doucet and co-workers described a
phosphane-free method for the direct 5-arylation of 1-
methyl-1H-imidazole,[10] thiazole,[11] and 1-methyl-1H-pyr-
Introduction
Arylazoles are important structural units frequently
found in natural products,[1] pharmaceuticals,[2] agrochem-
icals,[3] and organic functional materials.[4] Owing to their
widespread applications, the development of straightfor-
ward synthetic methods, tolerant to functional groups, that
enable the direct and selective elaboration of heterocycles
under mild conditions has aroused considerable attention.[5]
The palladium-catalyzed direct arylation of azoles with aryl
halides has recently emerged as an attractive strategy for the
effective construction of aromatic Csp2–Csp2 bonds.[6] This
synthetic approach, unlike the traditional palladium-cata-
lyzed cross-coupling strategies involving pre-formed orga-
nometallic reagents, enables the direct elaboration of het-
erocyclic cores without the need to pre-activate both the
coupling partners. Moreover, the presence of one or more
heteroatoms in such structures contributes to electronic po-
larization and coordinating ability, which can be exploited
to differentiate between different C–H bonds when an ap-
propriate base/catalyst/solvent reaction system has been
found. However, despite the growing and widespread inter-
est of organic chemists in these reactions, there are relatively
few methods that appear to be generally applicable to the
palladium-catalyzed regioselective direct arylation of the
[a] Dipartimento di Chimica e Chimica Industriale, Università di
Pisa,
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-050-2219260
E-mail: bellina@dcci.unipi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300704.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
Palladium-Catalyzed Regioselective Arylation of Azoles
azole[12] with aryl bromides in the presence of 2 equiv. of pyrazoles. Thus, the impact of the base (2.0 equiv.) on the
KOAc and with a low loading of Pd(OAc)2 (0.1–1 mol-%). outcome of the reaction involving 1 and 1.5 equiv. of 2a in
This method provides the required 5-arylated azoles in low- the presence of Pd(OAc)2 (5 mol-%) as the catalyst precur-
to-satisfactory yields, but suffers in general from problems sor in DMA at 140 °C for 24 h was first evaluated
of regioselectivity when the arylation involves 1-methyl-1H- (Scheme 1).
pyrazole despite using a 4:1 molar ratio of this expensive
azole and the aryl bromide.[12] Moreover, this protocol
shares with all the others high reaction temperatures (130–
150 °C), which is a serious issue when thermolabile sub-
strates have to be used[13] and may cause security problems
during scale-up because sealed vessels are generally re-
quired.
Recent theoretical investigations revealed that a con-
certed metalation/deprotonation (CMD) pathway is of rele-
vance for the Pd-catalyzed direct arylation of azoles.[14,15]
In this mechanistic hypothesis, Pd(OAc)2 is generally the
transition-metal precatalyst, and a carboxylate (or carbon-
ate) anion plays a fundamental role in the C–H cleavage,
which occurs in the rate-determining step of this model
simultaneously with carbon–palladium bond formation. In
Scheme 1.
the light of these theoretical findings, and based on our
The results of this preliminary screening are reported in
knowledge of Pd-catalyzed direct arylations of π-electron-
Table 1. A mixture of the 5-arylated pyrazole 3a and the
rich heteroarenes,[8,16] we reasoned that common reaction
corresponding 4,5-diarylated derivative 4a was invariably
observed when the GLC yield of 3a was higher than 10%
(entries 5–11, Table 1), whereas 4a was not detected in the
conditions should be found for different azoles if they really
share the same mechanistic pathway when treated with aryl
halides. In the CMD mechanism the choice of an appropri-
crude reaction mixtures when lower GLC yields were re-
ate base represents an important element of catalyst design.
corded (entries 1–4 and 12, Table 1). These results, along
For this reason we decided to devote particular attention to
with the detection of traces (if any) of the other two iso-
studying the influence of the anionic base and its counter
meric 3- and 4-monoarylated pyrazoles, confirmed the
cation[17] on the outcome of the direct arylation of azoles
higher reactivity of the 5-position relative to the 4-position,
during a re-examination of all the reaction parameters. In
with the 3-position essentially being unreactive.[18]
this paper we describe the most recent results of these stud-
Table 1. Direct arylation of 1 with 2a: Preliminary screening of the
ies, which have allowed us to find a common mild protocol
for the regioselective Pd-catalyzed 5-arylation of 1-methyl-
pyrazole, oxazole, and thiazole with aryl bromides. This
protocol involves the use of tetrabutylammonium acetate
(Bu4NOAc) as the base under ligand-free conditions and
requires a reaction temperature of only 70 °C to achieve
good chemical yields. We were also able to perform the se-
lective direct 5-arylation of 1-methyl-1H-imidazole with
aryl bromides simply by raising the reaction temperature
to 110 °C. This convenient phosphane-ligand-free reaction
system, as far as we are aware, has never been used in re-
gioselective direct arylation reactions involving C-unsubsti-
tuted heteroarenes.
base.[a]
Entry
Base
Yield of 3a [%][b]
3a/4a
1
2
3
4
NaOAc
KOAc
CsOAc
AgOAc
Bu4NOAc
Bu4NOAc
KOAc
K2CO3
K2CO3
KHCO3
K3PO4
KF
6
8
7
1
100:0
100:0
100:0
100:0
86:14
89:11
88:12
85:15
90:10
86:14
90:10
100:0
5
54 (49)[c]
6[d]
7[e]
8
44
32
19
16
18
24
4
9[d]
10
11
12
[a] Unless otherwise stated, the reactions were carried out using by
1 (1.0 mmol), 2a (1.5 equiv.), Pd(OAc)2 (5 mol-%), and base
(2 equiv.) in DMA (5 mL) for 24 h at 140 °C. [b] GLC yield. In
parentheses, isolated yield. [c] 1-Methyl-4,5-di-p-tolyl-1H-pyrazole
(4a) was also isolated in 8% yield. [d] Reaction carried out in the
presence of 0.3 equiv. of pivalic acid. [e] Reaction carried out in the
presence of 1.0 equiv. of Bu4NCl.
Results and Discussion
We decided to investigate the Pd-catalyzed direct aryl-
ation of 1-methyl-1H-pyrazole (1) with 4-bromotoluene
(2a), chosen as a model coupling partner. The regioselective
synthesis of C-monoarylated pyrazoles represents a chal-
Although the selectivity of the arylation was little influ-
lenging target, and previous studies by Sames and co- enced by the base, its chemical nature had a deep impact
workers on SEM-protected pyrazole,[18] Mateos et al.[19] on the efficiency of the coupling reaction. In particular, the
and, as mentioned in the Introduction, Doucet and co- yield of 3a seems to be related to a specific cation/anion
workers[12] on 1 clearly indicated the difficulties in per- pair and not to a particular anion or cation (compare, for
forming a clean monoarylation on simple C-unsubstituted example, entries 1–5 or entries 2, 8, and 10–12, Table 1).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
F. Bellina, M. Lessi, C. Manzini
FULL PAPER
From these data it clearly emerges that Bu4NOAc repre- the efficiency of Bu4NOAc in promoting this particular
sents the best choice in terms of chemical yield (54% GLC) arylation.
for the regioselective direct 5-arylation of 1 with 2a in
Due to the fact that the yield obtained with Bu4NOAc
DMA (entry 5, Table 1). Potassium-containing bases as the base was slightly higher at 110 °C than at 140 °C
K2CO3, KHCO3, and K3PO4 also showed activity, albeit (compare entry 1 of Table 2 with entry 5 of Table 1), we de-
with significantly lower product yields (entries 8, 10, and cided to lower further the reaction temperature and found
11, Table 1). All the other bases were ineffective at 140 °C that an even better chemical yield was obtained when 1 was
in DMA, including KOAc, a base frequently used to pro- treated with 2a in the presence of Bu4NOAc and Pd(OAc)2
mote the direct arylation of azoles and that, in particular, in DMA at only 70 °C (entry 9, Table 2). However, an at-
was previously employed in the direct arylation of 1 with tempt to carry out the same reaction at 40 °C was unsuc-
aryl bromides at 150 °C in the same solvent.[12] Interest- cessful, and the precursors were recovered unchanged after
ingly, the low efficiency demonstrated in our hands by 24 h.
KOAc may be improved by performing the arylation of 1
The good result obtained in the preparation of 3a from
in the presence of 1.0 equiv. of Bu4NCl (entry 7, Table 1), 1 and 2a under the experimental conditions reported in en-
but the yield of 3a remained lower than that obtained by try 9 of Table 2 prompted us to extend this mild procedure
using Bu4NOAc. Note also the results obtained when to the selective preparation of 5-aryl-1-methyl-1H-pyrazoles
Bu4NOAc and K2CO3 were used in combination with 3 starting from 1 and commercially available para- and
30 mol-% pivalic acid (entries 6 and 9, Table 1), which, as ortho-substituted aryl bromides 2a–h by using 5 mol-%
already stated in the Introduction, is an additive commonly Pd(OAc)2 as the catalyst precursor and 2 equiv. of
used in direct arylation reactions in combination with inor- Bu4NOAc as the base in DMA as solvent at 70 °C
ganic bases.[6,9] In both cases, we observed yields lower than (Scheme 2). The results are reported in Table 3. Good
those obtained when the same reactions were carried out in chemical yields and C-5 regioselectivity were observed with
the absence of this carboxylic acid (entries 5 and 8, Table 1). electron-rich para-substituted aryl bromides 2a,b (entries 1
Taking into account these results, we then studied the and 2), and similar C-5 regioselectivity but slightly lower
influence of the palladium precatalyst and the solvent on yields were observed with electron-poor para-substituted
the efficiency and selectivity of our model reaction aryl bromides 2c, 2e, and 2f as the electrophilic partners
(Table 2). The reaction temperature for this second screen- (entries 3, 5, and 6, Table 3). Similarly to our observations
ing was set at 110 °C to allow a better comparison with during the preliminary screenings, the crude reaction mix-
solvents with boiling points lower than 140 °C. As regards tures were contaminated by the corresponding 4,5-di-
the catalyst precursor, the best results were obtained by arylated pyrazoles 4 (detected by GLC and GC–MS);
using Pd(OAc)2 or PdCl2 (entries 1 and 2, Table 2), with smaller amounts (16–18%) of 4 were produced with deacti-
poorer results in terms of yield obtained with [Pd2(dba)3] vated bromides 2a,b than with activated bromides 2c, 2e,
and [PdCl2(PhCN)2] (entries 3 and 4, Table 2). The reaction and 2f (20–30%).
was also successful with reduced palladium loading (en-
try 5, Table 2), but we proceeded with 5 mol-% Pd(OAc)2
for convenience. Moreover, from the data summarized in
Table 2, it clearly emerges that DMA is a better solvent
than toluene, dioxane, or N-methyl-2-pyrrolidone (NMP)
(entries 1 and 6–8, Table 2). Interestingly, the observed 3a/
4a molar ratio was always higher than 80%, which confirms
Table 2. Influence of solvent and Pd precatalyst on the direct aryl-
ation of 1 with 2a.[a]
Entry
Pd precatalyst
Solvent
Yield of 3a [%][b]
3a:4a[b]
1
2
3
[Pd(OAc)2]
[PdCl2]
[Pd2(dba)3]
DMA
DMA
DMA
58 (52)
56
38
82:18
84:16
91:9
Scheme 2. Pd-catalyzed direct arylation of 1-methyl-1H-pyrazole
(1) with aryl bromides 2a–h.
4
[PdCl2(MeCN)2] DMA
46
40
45
39
50 (47)
62 (58)
86:14
81:29
93:7
92:8
83:15
84:16
5[c]
6
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(OAc)2]
DMA
toluene
dioxane
NMP
In contrast to the results reported by Doucet and co-
workers,[12] good C-5 regioselectivity was observed irrespec-
tive of the electronic nature of the para substituent on the
aryl bromide 2. We argued that the possibility of lowering
the reaction temperature from 150 to 70 °C due to the suc-
cessful use of Bu4NOAc enhanced the kinetic discrimi-
nation among the C–H bonds with different dissociation
energies (ΔG‡ at 298 K for C–H bond cleavage in 1: C3
31.3, C4 28.5, C5 27.3 kcalmol–1).[14] As a consequence, a
7
8
9[d]
DMA
[a] Unless otherwise stated, the reactions were carried out by using
1 (1.0 mmol), 2a (1.5 equiv.), and Bu4NOAc (2.0 equiv.) in the pres-
ence of the selected Pd precatalyst (5 mol-% Pd) in a given solvent
(5 mL) for 24 h at 110 °C. [b] Yield and product ratio determined
by GLC. In parentheses, isolated yield. [c] Reaction performed by
using 1 mol-% of Pd(OAc)2. [d] Reaction performed at 70 °C.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
Palladium-Catalyzed Regioselective Arylation of Azoles
Table 3. Scope of the ligand-free Pd-catalyzed direct C-5 arylation
of 1-methyl-1H-pyrazole (1) with aryl bromides 2a–h promoted by
Bu4NOAc.[a]
Table 4. Scope of the ligand-free Pd-catalyzed direct 5-arylation of
oxazole (5), thiazole (6), and 1-methyl-1H-imidazole (7) with aryl
bromides 2a–k promoted by Bu4NOAc.[a]
Entry Ar
Reaction
time [h][b]
Product Yield Selectivity[d]
[%][c]
1
2
3
4
5
6
7
8
4-MeC6H4
24
23
46
24
48
48
24
24
3a
3b
3c
3d
3e
3f
58
58
46
47
41
30
42
50
0.84
0.84
4-MeOC6H4
4-O2NC6H4
2-MeC6H4
4-EtOOCC6H4
4-F3CC6H4
2-ClC6H4
0.70
0.78[e]
0.80
0.70
3g
3h
0.73[f]
0.76[e]
1-Naphthyl
[a] The reactions were carried out by using pyrazole 1 (1 mmol)
and bromide 2 (1.5 equiv.) at 70 °C in the presence of Pd(OAc)2
(5 mol-%) and Bu4NOAc (2.0 equiv.) in DMA (5 mL). [b] The reac-
tions were stopped when the conversion was higher than 95%, or
when they did not progress further. [c] Isolated yield. [d] 5-Arylated
pyrazole 3 (% GLC) with respect to all arylated products formed.
Unless otherwise stated, the main byproduct was the corresponding
diarylated pyrazole 4. [e] The crude reaction mixture was contami-
nated by ca. 7% of a regioisomeric monoarylated derivative. [f] The
crude reaction mixture was contaminated by ca. 14% of a re-
gioisomeric monoarylated derivative.
strong molar excess of 1 was not necessary to secure a high
regioselectivity.
This simple combination of Pd(OAc)2 and Bu4NOAc
proved also to be tolerant to some typical sterically hin-
dered bromides without the need for forcing reaction condi-
tions. In fact, 2-bromotoluene (2d), 2-chloro-1-bromobenz-
ene (2g), and 1-naphthyl bromide (2h) reacted readily with
1 at 70 °C to give the corresponding 5-arylated pyrazoles
3d, 3g, and 3h in 47, 42, and 50% isolated yields, respec-
tively (entries 4, 7, and 8, Table 3). Note, in these reactions,
variable amounts (7–14%) of a monoarylated regioisomeric
pyrazole (presumably the C-4 isomer)[12] were also detected
in the crude reaction mixtures.
Having successfully demonstrated the viability of the
Pd(OAc)2-catalyzed regioselective direct 5-arylation of 1
with bromides 2 in the presence of Bu4NOAc as base, we
proceeded to broaden the scope of this arylation reaction
by applying the optimized reaction conditions of entry 9 of
Table 2 to the synthesis of different classes of monoarylated
azoles. We found that 1,3-azoles also reacted at the 5-posi-
tion with a variety of activated and deactivated aryl brom-
ides 2 (Table 4).
In detail, oxazole (5) and thiazole (6) were efficiently and
regioselectively converted into the corresponding 5-arylated
derivatives 8a–d and 9a–d, respectively, by reaction with
1.5 equiv. of aryl bromides 2a–d (entries 1–4 and 6–9,
Table 4). Deactivated bromides 2a,b, activated 1-bromo-4-
nitrobenzene (2c), and ortho-substituted 2-bromotoluene
(2d) gave yields ranging from 49 to 72% and high selectivi-
ties when treated with 5 (entries 1–4, Table 4), whereas the
corresponding 5-arylated thiazoles 9a–d were obtained in
isolated yields of 59–70% with C-5 selectivities of up to
100% (entries 6–9, Table 4). For the first time, unprotected
4-bromophenol (2i) was used in a Pd-catalyzed direct aryl-
ation and 4-(oxazol-5-yl)phenol (8e) was isolated in 36%
[a] The reactions were carried out by using azole 5, 6, or 7 (1 mmol)
and aryl bromide 2 (1.5 equiv.) at 70 °C (entries 1–9) or 110 °C (en-
tries 10–15) in the presence of Pd(OAc)2 (5 mol-%) and Bu4NOAc
(2.0 equiv.) in DMA (5 mL). [b] The reactions were stopped when
the conversion was higher than 95%, or when they did not progress
further. [c] Isolated yield. [d] 5-Monoarylated azole (% GLC) with
respect to all arylated products formed.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
F. Bellina, M. Lessi, C. Manzini
FULL PAPER
yield by the reaction of 2i with oxazole (5) after 48 h at 2 equiv. of K2CO3 as the base, and DMF as solvent at
70 °C (entry 5, Table 4). Note, this convenient synthetic 110 °C.[16e] For comparison, imidazole 10b was obtained in
method for the direct 5-arylation of 5 and 6 competes favor- 49% yield by applying our older method, and ortho-substi-
ably with previously reported protocols. In fact, Strotman tuted aryl bromides did not react at all. The use of Bu4-
et al. investigated the regioselective direct 5-arylation of ox- NOAc at 110 °C in DMA also gave better results than those
azole (5) with (hetero)aryl bromides in DMA for 16 h at reported by Doucet and co-workers in 2009.[10] In that case,
110 °C in a sealed vial in the presence of 5 mol-% Pd- their harsh low catalyst loading method [0.5–0.01 mol-%
(OAc)2, 3 equiv. of K2CO3, and 0.4 equiv. of pivalic acid, Pd(OAc)2, 2 equiv. of KOAc in DMA at 150 °C] gave signif-
but a two-fold excess of 5 was required to gain high regio- icantly lower yields when electron-rich aryl bromides 2a and
selectivities (90–100%) and 10 mol-% of the air-sensitive 2b were used (40 and 42% isolated yields, respectively),
di(1-adamantyl)-n-butylphosphane (CataCXium A) was whereas results similar to those reported here were de-
employed as the Pd ligand.[20] As regards thiazole (6), Rault scribed when a typical electron-poor aryl bromide, 4-
and co-workers reported in 2009 that a small library of 5- bromobenzonitrile (2j), was used (76% yield).
arylthiazoles 9 may be regioselectively obtained in yields of
From our data it emerges that the experimental order of
27–63% by treating 6 with electron-rich, electron-poor, and reactivity for the three 1,3-azoles, that is, oxazole Ͼ thiazole
heteroaryl bromides.[21] The coupling reactions were carried Ͼ 1-methylimidazole, parallels the calculated Gibbs free en-
out in the presence of 5 mol-% [Pd(PPh3)4] and 3 equiv. of ergy for the cleavage of the C5–H bond for a CMD reaction
KOAc. However, a strong molar excess (5 equiv.) of the mechanism[14] (ΔG‡ at 298 K: oxazole 23.5, thiazole 23.7,
azole was once again required to attain good regioselectiv- methylimidazole 25.0 kcalmol–1). This experimental order
ity and drastic reaction conditions (150 °C in a sealed tube) of reactivity is distinctly different to that reported for com-
were necessary to reduce reaction times. Interestingly, they mon electrophilic substitution reactions carried out in non-
also reported that the ligand-free conditions previously re- acidic media (1-methylimidazole Ͼ oxazole Ͼ thiazole),[22]
ported for the same coupling [2 equiv. of 6, 1 equiv. of 2, which allows us to reasonably exclude an alternative SEAr
2 equiv. of KOAc, 0.4 mol-% Pd(OAc)2, DMA, 130 °C in a mechanistic pathway, which has also been postulated for
sealed tube][11] gave poorer results in their hands.
direct arylations involving these heteroaromatics.[7]
As a result of the good results described above, and tak-
ing into account our previously reported procedure for the
direct ligand-free 2-arylation of 1,3-azoles,[16a–16c] we ar-
gued that it might also be possible to achieve the one-pot
sequential 5- and 2-diarylation of 1,3-azoles with different
aryl bromides. To probe the feasibility of this approach, we
attempted the one-pot synthesis of two bioactive natural
2,5-diaryloxazoles, balsoxin (11) and texaline (12), isolated
from the plant species Amyris in the Caribbean
(Scheme 3).[23] In the first step, 1.1 equiv. of oxazole (5)
A highly efficient direct 5-arylation was also achieved were treated with 1.0 equiv. of 4-bromo-1,2-dimethoxyben-
when 1-methyl-1H-imidazole (7) was treated with a number zene (2l) or 5-bromobenzo[d][1,3]dioxole (2m) at 70 °C in
of aryl bromides provided that the reaction temperature was DMA. The use of 5 mol-% Pd(OAc)2 and 2.0 equiv. of Bu4-
raised to 110 °C (entries 10–15, Table 4), yields higher than NOAc as initial quantities proved to be effective for the
80% resulted from the reaction of 7 with electron-rich 4- sequential reactions, and no additional catalyst or base was
bromotoluene (2a) and 4-bromoanisole (2b; entries 10 and necessary in the second step. After 24 h, the 2-arylation was
11), and good yields were also obtained when electron-neu- achieved simply by adding 1.5 equiv. of (hetero)aryl brom-
tral bromobenzene (2k), electron-poor 4-bromobenzonitrile ides bromobenzene (2k) or 3-bromopyridine (2n) to the re-
(2j), and 1-bromo-4-nitrobenzene (2c) were used as cou- action pot along with 2 equiv. of CuI to give after 24 h at
pling partners (75, 69, and 45% isolated yields, respectively; 110 °C the required balsoxin (11) and texaline (12) in iso-
entries 15, 14, and 12). As was observed for pyrazole 1 and lated yields of 39 and 38%, respectively (Scheme 3).[24]
also the parent 1,3-azoles 5 and 6, the reaction also proved
to be tolerant towards the ortho-substituted aryl bromide,
2-bromotoluene (2d); in fact, 1-methyl-5-(2-methylphenyl)-
1H-imidazole (10d) was isolated in a satisfactory 68% yield
(entry 13). Invariably, very good regioselectivity was ob-
served, with typically less than 10% (GLC) of the corre-
sponding 2,5-diarylated imidazoles found to contaminate
the crude reaction mixtures. Note that this new protocol for
the regioselective 5-arylation of 7 gave identical regioselec-
tivities but higher isolated yields than the procedure re-
ported by us in 2008, in which we employed 5 mol-%
Pd(OAc)2 and 10 mol-% P(2-furyl)3 as the catalyst system, Scheme 3. One-pot synthesis of balsoxin (11) and texaline (12).
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
Palladium-Catalyzed Regioselective Arylation of Azoles
Undoubtedly, the efficiency and very high regioselectivity action media are employed, and may explain the efficiency
demonstrated by this ligand-free protocol at mild reaction of Bu4NOAc in promoting this class of C–C bond-forming
temperatures and without the need of employing a strong reaction.
molar excess of the heteroaromatic partner has to be attrib-
uted to the use of Bu4NOAc as the base. Its efficacy in
promoting such ligand-free direct arylations, in our opin-
ion, may be motivated not only by the well-known ability
of ammonium salts to act as metal stabilizers in the absence
Conclusions
In this study we have developed a simple, mild, and effec-
tive method for the regioselective Pd-catalyzed direct 5-aryl-
ation of several C-unsubstituted azoles with aryl bromides
starting from preliminary screenings of the role of bases,
catalyst precursors, solvents, and reaction temperature on
the efficiency and selectivity of the monoarylation of 1-
methyl-1H-pyrazole (1). The observed C-5 regioselectivity
is in agreement with the calculated Gibbs free energies for
the cleavage of C–H bonds of azoles under the hypothesis
of a CMD mechanistic pathway.[14] Note that under phos-
phane-ligand-free conditions, Bu4NOAc was effective at
only 70 °C in promoting the direct arylation of azoles for
which the regioselectivity of C–H bond metalation is con-
trolled by different contributions to the reactivity.[14] An im-
portant consequence of our results is that lipophilic organic
acetates may in general secure better performances at lower
temperatures than their inorganic counterparts (such as
KOAc) in transformations carried out in organic solvents
because they grant better solubility and effective transition-
metal stabilization. We believe that our findings will be an
important clue for future progress towards the development
of highly efficient and more general direct arylation reac-
tions.
of phosphanes or other ancillary ligands (the so-called
“Jeffery conditions”),[25,26] but also by the fact that organic
ionic bases have good solubility and are fully ionized in
organic solvents.[27] In fact, we noted that arylations involv-
ing Bu4NOAc gave yellow to deep-orange solutions, in con-
trast to the reactions carried out in the presence of inor-
ganic bases, which usually give rise to dark-brown hetero-
geneous reaction mixtures. These last features may lead, as
a consequence, to an improved availability in solution of
the acetate anion,[28] which can then play better its key role
in the concerted metalation/deprotonation pathway (CMD)
postulated for these Pd-catalyzed reactions (Figure 1), as al-
ready mentioned.[14]
Figure 1. Proposed CMD pathway for the ligand-free Pd-catalyzed
direct 5-arylation of azoles with aryl bromides 2 mediated by
Bu4NOAc. Coordinating species around Pd (such as solvent mole-
cules or ammonium salts) have been omitted for simplicity.
Experimental Section
General: Precoated silica gel 60 F254 aluminium sheets from Fluka
were used for TLC analyses. GLC analyses were performed by
using two types of capillary columns: an Alltech AT-35 bonded
FSOT column (30 mϫ0.25 mm i.d.) and an Alltech AT-1 bonded
FSOT column (30 mϫ0.25 mm i.d.). Purification by flash
chromatography was performed by using silica gel Merck 60 (par-
ticle size 0.040–0.063 mm). EI-MS spectra were recorded at 70 eV
by GLC–MS. NMR spectra were recorded at room temperature at
In particular, the role of Bu4NOAc may be of relevance
in the anionic ligand-exchange step that may occur at the
aryl palladium intermediate I, producing the palladium
acetate intermediate II, which then follows the CMD path- 200 (1H) and 50.3 MHz (13C) and are referenced to TMS or to the
residual protons of deuteriated solvents. All reactions were per-
formed under argon by using standard syringe and septa tech-
niques. The completion of the reactions and the composition of the
reaction mixtures were established by GLC and GLC–MS analyses
of samples of the crude reaction mixtures filtered through a short
plug of Celite and eluted with additional EtOAc.
way via a six-membered transition state TS. DFT calcula-
tions evidenced that this path is energetically more favor-
able than a pathway involving a σ-bond metathesis, in
which it is the bromine atom that induces deprotonation
via TS-I.[29]
1-Methyl-1H-pyrazole (1), oxazole (5), thiazole (6), 1-methyl-1H-
imidazole (7), 4-bromotoluene (2a), 4-bromoanisole (2b), 4-bromo-
nitrobenzene (2c), 2-bromotoluene (2d), ethyl 4-bromobenzoate
(2e), 1-bromo-4-(trifluoromethyl)benzene (2f), 1-bromo-2-chloro-
benzene (2g), 2-bromonaphthalene (2h), 4-bromophenol (2i), 4-
bromobenzonitrile (2j), bromobenzene (2k), 4-bromo-1,2-dimeth-
oxybenzene (2l), 5-bromobenzo[d][1,3]dioxole (2m), 3-bromopyr-
idine (2n), Pd(OAc)2, Bu4NOAc, CuI, anhydrous DMA were com-
Hence, if the lower-energy pathway involves a bromine/
acetate exchange, this may become a limiting step for the
entire process when bases that are poorly soluble in the re- mercially available and used as received.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
F. Bellina, M. Lessi, C. Manzini
FULL PAPER
Procedure for the Screening of the Reaction Conditions for the Pd-
Catalyzed 5-Arylation of 1-Methyl-1H-pyrazole (1) with 4-Bromo-
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 159.1, 138.3, 133.0,
129.5 (2 C), 127.1, 121.8, 113.9 (2 C), 55.1, 32.1 ppm. MS (EI): m/z
toluene (2a): A mixture of 1-methyl-1H-pyrazole (1) (82 mg, (%) = 189 (13), 188 (100), 174 (7), 173 (61), 145 (10). The spectral
1.0 mmol), palladium catalyst (0.05 mmol), 4-bromotoluene (2a)
(0.18 mL, 0.26 g, 1.5 mmol), base (2.0 mmol) in the selected solvent
(5 mL) was stirred under argon for 24 h at the temperature reported
in Tables 1 and 2. After cooling to room temperature, the crude
reaction mixture was diluted with AcOEt, naphthalene was added
as internal standard, and the resulting mixture was analyzed by
GLC and GC–MS. Table 1 and Table 2 summarize the results of
this screening.
properties of this compound are in agreement with those previously
reported.[12]
1-Methyl-5-(4-nitrophenyl)-1H-pyrazole (3c): The crude reaction
product, which was obtained by Pd-catalyzed reaction of 1 with 2c
(entry 3, Table 3), was purified by flash chromatography on silica
gel with a mixture of CH2Cl2 and acetone (98:2) as eluent to give
3c (0.20 g, 46%) as a yellow solid, m.p. 75–77 °C. 1H NMR
(200 MHz, CDCl3): δ = 8.33 (m, 2 H), 7.65 (m, 2 H), 7.57 (d, J =
1.9 Hz, 1 H), 6.47 (d, J = 1.9 Hz, 1 H), 3.98 (s, 3 H) ppm. 13C
NMR (50.3 MHz, CDCl3): δ = 147.6, 141.4, 139.0, 136.9, 129.4 (2
C), 124.0 (2 C), 107.4, 38.0 ppm. MS (EI): m/z (%) = 204 (12), 203
(100), 173 (20), 103 (11), 89 (10). The physical and spectral proper-
ties of this compound are in agreement with those previously re-
ported.[12]
1-Methyl-5-(p-tolyl)-1H-pyrazole (3a) and 1-Methyl-4,5-di-p-tolyl-
1H-pyrazole (4a): The crude reaction mixture (entry 5, Table 1) was
concentrated under reduced pressure and the residue was purified
by flash chromatography on silica gel with a mixture of toluene
and AcOEt (70:30 + 0.1% Et3N) as eluent. Concentration of the
first eluted chromatographic fractions allowed isolation of com-
pound 4a (16 mg, 8% yield) as a pale-yellow solid, m.p. 162–164 °C
1H NMR (200 MHz, CDCl3): δ = 7.70 (s, 1 H), 7.20 (m, 4 H), 7.04
(m, 4 H), 3.79 (s, 3 H), 2.41 (s, 3 H), 2.28 (s, 3 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ = 139.7, 138.5, 137.3, 135.4, 130.2, 129.9,
129.4, 129.0, 127.5, 127.1, 120.7, 31.2, 21.4, 21.0 ppm. MS (EI):
m/z (%) = 263 (21), 262 (100), 261 (19), 247 (10), 232 (6), 202 (4),
189 (4), 130 (4). C18H18N2 (262.35): calcd. C 82.41, H 6.92, N
10.68; found C 82.84, H 6.89, N 10.73.
1-Methyl-5-(o-tolyl)-1H-pyrazole (3d): The crude reaction product,
which was obtained by Pd-catalyzed reaction of 1 with 2d (entry 4,
Table 3), was purified by flash chromatography on silica gel with a
mixture of toluene and AcOEt (70:30 + 0.1% Et3N) as eluent to
give 3d (80 mg, 47%) as a pale-yellow oil. 1H NMR (200 MHz,
CDCl3): δ = 7.53 (d, J = 1.9 Hz, 1 H), 7.28 (m, 4 H), 6.19 (d, J =
1.9 Hz, 1 H), 3.65 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 142.3, 138.2, 137.4, 130.4, 130.1 (2 C), 128.9, 125.6,
106.2, 36.5, 19.8 ppm. MS (EI): m/z (%) = 172 (100), 171 (57), 144
(70), 128 (16), 115 (20). C11H12N2 (172.23): calcd. C 76.71, H 7.02,
N 16.27; found C 76.65, H 7.06, N 16.22.
Concentration of the last eluted chromatographic fractions allowed
isolation of compound 3a (84 mg, 49%) as a light-yellow oil. 1H
NMR (200 MHz, CDCl3): δ = 7.49 (d, J = 1.9 Hz, 1 H), 7.27 (m,
4 H), 6.26 (d, J = 1.9 Hz, 1 H), 3.87 (s, 3 H), 2.39 (s, 3 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ = 143.4, 138.3, 138.2, 129.2 (2
C), 128.5 (2 C), 127.7, 105.7, 37.4, 21.2 ppm. MS (EI): m/z (%) =
173 (13), 172 (100), 171 (33), 157 (9), 144 (10), 130 (9), 128 (9), 115
(9).The spectral properties of this compound are in agreement with
those previously reported.[30] This compound was also obtained in
isolated yields of 52 and 58% from the Pd-catalyzed reactions of 1
and 2a carried out at 110 °C (entry 1, Table 2) or at 70 °C (entry 9,
Table 2 and entry 1, Table 3).
Ethyl 4-(1-Methyl-1H-pyrazol-5-yl)benzoate (3e): The crude reac-
tion product, which was obtained by Pd-catalyzed reaction of 1
with 2e (entry 5, Table 3), was purified by flash chromatography on
silica gel with a mixture of toluene and AcOEt (80:20) as eluent to
1
give 3e (95 mg, 41%) as a yellow oil. H NMR(200 MHz, CDCl3):
δ = 8.13 (m, 2 H), 7.53 (d, J = 1.6 Hz, 1 H), 7.51 (m, 2 H), 6.38
(d, J = 1.6 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.92 (s, 3 H), 1.42
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 165.9,
142.4, 138.6, 134.8, 130.2, 129.8 (2 C), 128.4 (2 C), 106.5, 61.1,
37.7, 14.3 ppm. MS (EI): m/z (%) = 231 (11), 230 (78), 202 (24),
186 (16), 185 (100). C13H14N2O2 (230.27): calcd. C 67.81, H 6.13,
N 12.17; found C 67.89, H 6.11, N 12.21.
General Procedure for the Palladium-Catalyzed Direct 5-Arylation
of 1-Methyl-1H-pyrazole (1), Oxazole (5), Thiazole (6), and 1-
Methyl-1H-imidazole (7) with Aryl Bromides 2a–k: Pd(OAc)2
(11.2 mg, 0.05 mmol), Bu4NOAc (0.60 g, 2.0 mmol), and aryl
bromide 2 (1.5 mmol), if a solid, were placed in a flame-dried reac-
tion vessel. The reaction vessel was fitted with a silicon septum,
evacuated, and back-filled with argon. This sequence was repeated
twice. DMA (5 mL), aryl bromide 2 (1.5 mmol), if a liquid, and the
appropriate azole 1, 5, 6, or 7 (1.0 mmol) were then added success-
ively under a stream of argon by syringe at room temperature. The
resulting mixture was stirred at 70 °C (for azoles 1, 5, and 6) or at
110 °C (for azole 7) under argon for the period of time reported in
Table 3 and Table 4. After cooling to room temperature, the reac-
tion mixture was diluted with EtOAc, filtered through a plug of
Celite, and eluted with additional EtOAc and CH2Cl2. The filtrate
was concentrated under reduced pressure and the residue purified
by flash chromatography on silica gel. This procedure was used to
prepare compounds 3b–h, 8a–e, 9a–d, and 10a–f (Table 3).
5-[4-(Trifluoromethyl)phenyl]-1-methyl-1H-pyrazole (3f): The crude
reaction product, which was obtained by Pd-catalyzed reaction of
1 with 2f (entry 6, Table 3), was purified by flash chromatography
on silica gel with a mixture of toluene and AcOEt (85:15 + 0.1%
Et3N) as eluent to give 3f (68 mg, 30%) as a pale-yellow oil. 1H
NMR (200 MHz, CDCl3): δ = 7.72 (m, 2 H), 7.55 (m, 2 H), 7.54
(d, J = 1.9 Hz, 1 H), 6.37 (d, J = 1.9 Hz, 1 H), 3.92 (s, 3 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ = 142.0, 138.7, 134.3, 130.1, 129.0
(2 C), 125.6 (q, J = 3.7 Hz, 2 C), 123.9 (q, J = 272 Hz, CF3), 106.6,
37.6 ppm. MS (EI): m/z (%) = 227 (13), 226 (100), 225 (47), 207
(9), 198 (9). C11H9F3N2 (226.20): calcd. C 58.41, H 4.01, N 12.38;
found C 58.35, H 3.99, N 12.42.
5-(2-Chlorophenyl)-1-methyl-1H-pyrazole (3g): The crude reaction
product, which was obtained by Pd-catalyzed reaction of 1 with 2g
(entry 7, Table 3), was purified by flash chromatography on silica
gel with a mixture of toluene and AcOEt (90:10 + 0.1% Et3N) as
eluent to give 3g (82 mg, 42%) as a pale-yellow oil. 1H NMR
(200 MHz, CDCl3): δ = 7.54 (d, J = 1.9 Hz, 1 H), 7.341 (m, 5 H),
5-(4-Methoxyphenyl)-1-methyl-1H-pyrazole (3b): The crude reac-
tion product, which was obtained by Pd-catalyzed reaction of 1
with 2b (entry 2, Table 3), was purified by flash chromatography
on silica gel with a mixture of toluene and AcOEt (60:40 + 0.1%
1
Et3N) as eluent to give 3b (0.11 g, 58%) as a yellow oil. H NMR 6.27 (d, J = 1.9 Hz, 1 H), 3.72 (s, 3 H) ppm. 13C NMR (50.3 MHz,
(200 MHz, CDCl3): δ = 7.48 (d, J = 1.9 Hz, 1 H), 7.32 (m, 2 H),
6.97 (m, 2 H), 6.24 (d, J = 1.9 Hz, 1 H), 3.85 (s, 3 H), 3.83 (s, 3
CDCl3): δ = 140.2, 138.2, 134.2, 131.8, 130.3, 129.94, 129.71, 126.7,
106.9, 36.9 ppm. MS (EI): m/z (%) = 194 (32), 193 (23), 192 (100),
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
Palladium-Catalyzed Regioselective Arylation of Azoles
191 (33), 156 (12). C10H9ClN2 (192.65): calcd. C 62.35, H 4.71, N δ = 9.85 (s, OH), 8.35 (s, 1 H), 7.56 (m, 2 H), 7.47 (s, 1 H), 6.89
14.54; found C 62.40, H 4.69, N 14.59.
(m, 2 H) ppm. 13C NMR (50.3 MHz, [D6]DMSO): δ = 157.6, 150.8,
150.6, 125.6 (2 C), 119.4, 118.5, 115.6 (2 C) ppm. MS (EI): m/z (%)
= 161 (100), 133 (20), 121 (19), 106 (30), 105 (29). C9H7NO2
(161.16): calcd. C 67.07, H 4.38, N 8.69; found C 66.91, H 4.40, N
8.62.
1-Methyl-5-(1-naphthyl)-1H-pyrazole (3h): The crude reaction
product, which was obtained by Pd-catalyzed reaction of 1 with 2h
(entry 8, Table 3), was purified by flash chromatography on silica
gel with a mixture of toluene and AcOEt (80:20 + 0.1% of Et3N)
as eluent to give 3h (0.11 g, 50%) as a pale-yellow solid, m.p. 87–
5-(p-Tolyl)thiazole (9a): The crude reaction product, which was ob-
1
90 °C. H NMR (200 MHz, CDCl3): δ = 7.88 (m, 2 H), 7.63 (d, J tained by Pd-catalyzed reaction of 6 with 2a (entry 6, Table 4), was
= 1.8 Hz, 1 H), 7.47 (m, 5 H), 6.34 (d, J = 1.8 Hz, 1 H), 3.61 (s, 3 purified by flash chromatography on silica gel with a mixture of
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 141.2, 138.4, 133.4, toluene and AcOEt (90:10 + 0.1% Et3N) as eluent to give 9a
132.00, 129.2, 128.3, 128.2, 128.1, 126.7, 126.1, 125.2, 124.9, 107.5,
36.9 ppm. MS (EI): m/z (%) = 209 (16), 208 (100), 207 (40), 180
(23), 153 (27). The spectral properties of this compound are in
agreement with those previously reported.[12]
(0.11 g, 65%) as a pale-yellow solid, m.p. 82–84 °C. 1H NMR
(200 MHz, CDCl3): δ = 8.69 (s, 1 H), 8.02 (s, 1 H), 7.44 (m, 2 H),
7.18 (m, 2 H), 2.35 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ
= 151.4, 139.3, 138.4, 138.3, 129.6 (2 C), 128.1, 126.7 (2 C),
21.2 ppm. MS (EI): m/z (%) = 176 (12), 175 (100), 148 (32), 147
(43), 115 (17). The spectral properties of this compound are in
agreement with those previously reported.[33]
5-(p-Tolyl)oxazole (8a): The crude reaction product, which was ob-
tained by Pd-catalyzed reaction of 5 with 2a (entry 1, Table 4), was
purified by flash chromatography on silica gel with a mixture of
toluene and AcOEt (90:10) as eluent to give 8a (92 mg, 58%) as a
5-(4-Methoxyphenyl)thiazole (9b): The crude reaction product,
yellow solid, m.p. 38–41 °C. 1H NMR (200 MHz, CDCl3): δ = 7.88 which was obtained by Pd-catalyzed reaction of 6 with 2b (entry 7,
(s, 1 H), 7.51 (m, 2 H), 7.28 (s, 1 H), 7.19 (m, 2 H), 2.35 (s, 3
Table 4), was purified by flash chromatography on silica gel with a
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 151.7, 150.2, 138.7, mixture of toluene and AcOEt (92:8) as eluent to give 9b (0.13 g,
129.5 (2 C), 124.9, 124.3 (2 C), 120.6, 21.4 ppm. MS (EI): m/z (%) 67%) as a bright-yellow solid, m.p. 89–92 °C. 1H NMR (200 MHz,
= 159 (100), 131 (26), 130 (38), 104 (34), 103 (21), 91 (21). The
spectral properties of this compound are in agreement with those
previously reported.[31]
CDCl3): δ = 8.68 (s, 1 H), 7.97 (s, 1 H), 7.48 (m, 2 H), 6.92 (m, 2
H), 3.82 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 159.8,
151.2, 139.2, 138.0, 128.2 (2 C), 123.6, 114.5 (2 C), 55.4 ppm. MS
(EI): m/z (%) = 191 (100), 176 (58), 149 (20), 148 (27), 121 (20).
The spectral properties of this compound are in agreement with
those previously reported.[21]
5-(4-Methoxyphenyl)oxazole (8b): The crude reaction product,
which was obtained by Pd-catalyzed reaction of 5 with 2b (entry 2,
Table 4), was purified by flash chromatography on silica gel with a
mixture of toluene and AcOEt (80:20) as eluent to give 8b (85 mg,
49%) as a yellow solid, m.p. 45–48 °C. 1H NMR (200 MHz,
5-(4-Nitrophenyl)thiazole (9c): The crude reaction product, which
was obtained by Pd-catalyzed reaction of 6 with 2c (entry 8,
CDCl3): δ = 7.89 (s, 1 H), 7.57 (m, 2 H), 7.23 (s, 1 H), 6.94 (m, 2 Table 4), was purified by flash chromatography on silica gel with a
H), 3.82 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 159.7,
151.4, 149.7, 125.8 (2 C), 120.5, 119.9, 114.2 (2 C), 55.3 ppm. MS
(EI): m/z (%) = 176 (11), 175 (100), 160 (37), 132 (27), 77 (22). The
spectral properties of this compound are in agreement with those
previously reported.[20]
mixture of toluene and AcOEt (80:20) as eluent to give 9c (0.14 g,
70%) as a yellow solid, m.p. 139–141 °C. H NMR: δ = 8.93 (s, 1
1
H), 8.29 (m, 2 H), 8.26 (s, 1 H), 7.76 (m, 2 H) ppm. 13C NMR: δ
= 154.2, 147.4, 141.1, 137.4, 127.4 (2 C), 126.2, 124.5 (2 C) ppm.
MS (EI): m/z (%) = 206 (100), 176 (26), 148 (20), 133 (27), 89 (53).
C9H6N2O2S (206.22): calcd. C 52.42, H 2.93, N 13.58; found C
52.35, H 2.95, N 13.63.
5-(4-Nitrophenyl)oxazole (8c): The crude reaction product, which
was obtained by Pd-catalyzed reaction of 5 with 2c (entry 3,
Table 4, was purified by flash chromatography on silica gel with a
mixture of toluene and AcOEt (80:20) as eluent to give 8c (0.11 g,
5-(o-Tolyl)thiazole (9d): The crude reaction product, which was ob-
tained by Pd-catalyzed reaction of 6 with 2d (entry 9, Table 4), was
57%) as a yellow solid, m.p. 135–137 °C. 1H NMR (200 MHz, purified by flash chromatography on silica gel with a mixture of
CDCl3): δ = 8.31 (m, 2 H), 8.06 (s, 1 H), 7.84 (m, 2 H), 7.59 (s, 1
toluene and AcOEt (90:10) as eluent to give 9d (0.10 g, 59%) as a
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 151.9, 149.5, 147.4, pale-yellow oil. 1H NMR (200 MHz, CDCl3): δ = 8.79 (s, 1 H),
133.4, 124.9 (2 C), 124.7, 124.5 (2 C) ppm. MS (EI): m/z (%) = 190 7.84 (s, 1 H), 7.27 (m, 4 H), 2.37 (s, 3 H) ppm. 13C NMR
(100), 160 (43), 132 (25), 89 (91), 63 (21). The spectral properties of
this compound are in agreement with those previously reported.[32]
(50.3 MHz, CDCl3): δ = 152.5, 141.5, 137.3, 136.3, 130.7, 130.6,
130.1, 128.5, 126.0, 21.0 ppm. MS (EI): m/z (%) = 176 (12), 175
(95), 148 (49), 147 (100), 115 (52). C10H9NS (175.25): calcd. C
68.53, H 5.18, N 7.99; found C 68.59, H 5.15, N 8.06.
5-(o-Tolyl)oxazole (8d): The crude reaction product, which was ob-
tained by Pd-catalyzed reaction of 5 with 2d (entry 4, Table 4), was
purified by flash chromatography on silica gel with a mixture of
toluene and AcOEt (90:10) as eluent to give 8d (0.11 g, 72%) as a
pale-yellow oil. 1H NMR (200 MHz, CDCl3): δ = 7.96 (s, 1 H),
1-Methyl-5-(p-tolyl)-1H-imidazole (10a): The crude reaction prod-
uct, which was obtained by Pd-catalyzed reaction of 7 with 2a (en-
try 10, Table 4), was purified by flash chromatography on silica gel
7.67 (m, 1 H), 7.27 (m, 4 H), 2.48 (s, 3 H) ppm. 13C NMR with a mixture of CH2Cl2 and MeOH (96:4) as eluent to give 10a
(50.3 MHz, CDCl3): δ = 150.8, 150.1, 134.9, 131.0, 128.5, 127.0,
126.9, 126.1, 124.1, 21.7 ppm. MS (EI): m/z (%) = 159 (100), 132
(35), 131 (44), 130 (49), 104 (36). The spectral properties of this
compound are in agreement with those previously reported.[20]
(0.14 g, 81%) as a yellow oil. 1H NMR (200 MHz, CDCl3): δ =
7.49 (s, 1 H), 7.26 (m, 2 H), 7.25 (m, 2 H), 7.07 (s, 1 H), 3.63 (s, 3
H), 2.39 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 138.7,
137.6, 133.3, 129.3 (2 C), 128.3 (2 C), 127.6, 126.7, 32.4, 21.2 ppm.
MS (EI): m/z (%) = 173 (13), 172 (100), 171 (17), 144 (14), 130
(16). The spectral properties of this compound are in agreement
with those previously reported.[10]
4-(Oxazol-5-yl)phenol (8e): The crude reaction product, which was
obtained by Pd-catalyzed reaction of 5 with 2i (entry 5, Table 4),
was purified by flash chromatography on silica gel with a mixture
of toluene and THF (80:20) as eluent to give 8e (58 mg, 36%) as a
colorless solid, m.p. 229–230 °C. 1H NMR (200 MHz, [D6]DMSO):
5-(4-Methoxyphenyl)-1-methyl-1H-imidazole (10b): The crude reac-
tion product, which was obtained by Pd-catalyzed reaction of 7
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
F. Bellina, M. Lessi, C. Manzini
FULL PAPER
with 2b (entry 11, Table 4), was purified by flash chromatography
on silica gel with a mixture of CH2Cl2 and MeOH (96:4) as eluent
to give 10b (0.15 g, 82%) as a light-yellow solid, m.p. 73–75 °C. 1H
tially added to the resulting deep-orange solution under a stream
of argon. The reaction mixture was heated to 110 °C and stirred at
this temperature for 8 h. After cooling to room temperature, the
NMR (200 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.30 (m, 2 H), 7.02 (s, reaction mixture was diluted with AcOEt and poured into a satu-
1 H), 6.96 (m, 2 H), 3.83 (s, 3 H), 3.61 (s, 3 H) ppm. 13C NMR rated aqueous NH4Cl solution. The resulting mixture was basified
(50.3 MHz, CDCl3): : δ = 159.1, 138.3, 132.3, 129.6 (2C), 127.1,
121.8, 113.9 (2C), 55.1, 32.1 ppm. MS (EI): m/z (%) = 189 (12),
188 (100), 174 (10), 173 (82), 145 (17). The spectral properties of
this compound are in agreement with those previously reported.[16e]
with a few drops of aqueous NH4OH, stirred in the open air for
0.5 h, and then extracted with AcOEt. The organic extract was
washed with water, dried, and concentrated under reduced pressure,
and the residue was purified by flash chromatography on silica gel
with a mixture of toluene and AcOEt (70:30) as eluent. The chro-
matographic fractions containing the required compound were col-
lected and concentrated to give 11 (0.11 g, 39%) as a light-yellow
1-Methyl-5-(4-nitrophenyl)-1H-imidazole (10c): The crude reaction
product, which was obtained by Pd-catalyzed reaction of 7 with 2c
(entry 12, Table 4), was purified by flash chromatography on silica
gel with a mixture of CH2Cl2 and MeOH (96:4) as eluent to give
10c (92 mg, 45%) as a yellow-orange solid, m.p. 169–171 °C. 1H
NMR (200 MHz, CDCl3): δ = 8.30 (m, 2 H), 7.63 (s, 1 H), 7.61
(m, 2 H), 7.28 (s, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 146.7, 140.1, 136.2, 131.3, 130.2, 128.1 (2 C), 124.1 (2
C), 33.1 ppm. MS (EI): m/z (%) = 203 (100), 173 (19), 130 (17),
103 (16), 89 (32). The spectral properties of this compound are in
agreement with those previously reported.[34]
1
solid, m.p. 97–98 °C. H NMR (200 MHz, CDCl3): δ = 8.11 (m, 2
H), 7.49 (m, 3 H), 7.35 (s, 1 H), 7.30 (dd, J = 1.9, 8.4 Hz, 1 H),
7.20 (d, J = 1.9 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 3.99 (s, 3 H),
3.94 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 160.5, 151.1,
149.3, 149.2, 130.1, 128.7, 127.4, 126.1, 122.1, 121.0, 117.2, 111.4,
107.3, 55.99, 55.95 ppm. MS (EI): m/z (%) = 282 (20), 281 (100),
266 (23), 238 (11), 107 (11). The spectral properties of this com-
pound are in agreement with those previously reported.[24c]
5-(Benzo[d][1,3]dioxol-5-yl)-2-(pyridin-3-yl)oxazole (Texaline, 12):
Pd(OAc)2 (11.2 mg, 0.05 mmol) and Bu4NOAc (0.60 g, 2.0 mmol)
were added to a flame-dried reaction vessel. The reaction vessel
was fitted with a silicon septum, evacuated, and back-filled with
argon. This sequence was repeated twice. DMA (5 mL), 5-bromo-
benzo[d][1,3]dioxole (2m; 0.12 mL, 0.20 g, 1.0 mmol), and oxazole
(5; 72 mL, 76 mg, 1.1 mmol) were then added successively under a
stream of argon by syringe at room temperature. The resulting mix-
ture was stirred at 70 °C under argon for 48 h. CuI (0.38 g,
2.0 mmol) and 3-bromopyridine (2n; 0.15 mL, 0.24 g, 1.5 mmol)
were then sequentially added to the resulting brown solution under
a stream of argon. The reaction mixture was heated to 110 °C and
stirred at this temperature for 24 h. After cooling to room tempera-
ture, the reaction mixture was diluted with AcOEt and poured into
a saturated aqueous NH4Cl solution. The resulting mixture was
basified with a few drops of aqueous NH4OH, stirred in the open
air for 0.5 h, and then extracted with AcOEt. The organic extract
was washed with water, dried, and concentrated under reduced
pressure, and the residue was purified by flash chromatography on
silica gel with a mixture of toluene and AcOEt (50:50) as eluent.
The chromatographic fractions containing the required compound
were collected and concentrated to give 12 (0.10 g, 38%) as a light-
yellow solid, m.p. 167–169 °C. 1H NMR (200 MHz, CDCl3): δ =
9.30 (br. s, 1 H), 8.67 (d, J = 3.7 Hz, 1 H), 8.31 (dt, J = 8.0, 1.9 Hz,
1 H), 7.40 (dd, J = 8.0, 4.8 Hz, 1 H), 7.32 (s, 1 H), 7.22 (dd, J =
8.1, 1.7 Hz, 1 H), 7.14 (d, J = 1.6 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1
H), 6.01 (s, 2 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 158.2,
152.0, 150.9, 148.4, 148.3, 147.5, 133.3, 123.8, 123.7, 122.6, 121.8,
118.7, 109.0, 105.0, 101.6 ppm. MS (EI): m/z (%) = 267 (16), 266
(100), 181 (11), 153 (27), 63 (9). The spectral properties of this
compound are in agreement with those previously reported.[24c]
1-Methyl-5-(o-tolyl)-1H-imidazole (10d): The crude reaction prod-
uct, which was obtained by Pd-catalyzed reaction of 7 with 2d (en-
try 13, Table 4), was purified by flash chromatography on silica gel
with a mixture of CH2Cl2 and MeOH (98:2) as eluent to give 10d
(0.12 g, 68%) as a light-brown oil. 1H NMR (200 MHz, CDCl3): δ
= 7.55 (s, 1 H), 7.27 (m, 4 H), 6.97 (s, 1 H), 3.42 (s, 3 H), 2.19 (s,
3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 138.0, 137.8, 131.9,
131.0, 130.1, 129.0, 128.7 (2 C), 127.9, 125.6 (2 C), 31.6, 20.0 ppm.
MS (EI): m/z (%) = 172 (100), 171 (24), 144 (50), 131 (24), 130
(62). C11H12N2 (172.23): calcd. C 76.71, H 7.02, N 16.27; found C
76.77, H 6.99, N 16.24.
4-(1-Methyl-1H-imidazol-5-yl)benzonitrile (10e): The crude reaction
product, which was obtained by Pd-catalyzed reaction of 7 with 2j
(entry 14, Table 4), was purified by flash chromatography on silica
gel with a mixture of CH2Cl2 and MeOH (96:4) as eluent to give
10e (0.13 g, 69%) as a light-yellow solid, m.p. 148–151 °C. MS (EI):
m/z (%) = 159 (12), 158 (100), 130 (16), 116 (13), 103 (13), 89 (12).
1H NMR (200 MHz, CDCl3): δ = 7.73 (m, 2 H), 7.59 (s, 1 H), 7.53
(m, 2 H), 7.22 (s, 1 H), 3.75 (s, 3 H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 140.5, 134.3, 132.5 (2 C), 131.6, 129.8, 128.3 (2 C),
118.5, 111.2, 33.0 ppm. The spectral properties of this compound
are in agreement with those previously reported.[10]
1-Methyl-5-phenyl-1H-imidazole (10f): The crude reaction product,
which was obtained by Pd-catalyzed reaction of 7 with 2k (entry 15,
Table 4), was purified by flash chromatography on silica gel with a
mixture of CH2Cl2 and MeOH (96:4) as eluent to give 10f (0.12 g,
1
75%) as a pale-yellow oil. H NMR (200 MHz, CDCl3): δ = 7.42
(s, 1 H), 7.32 (m, 5 H), 7.01 (s, 1 H), 3.58 (s, 3 H) ppm. 13C NMR
(50.3 MHz, CDCl3): δ = 139.1, 128.8, 128.7 (2 C), 128.5 (2 C),
128.1, 127.9, 127.0, 32.5 ppm. MS (EI): m/z (%) = 158 (100), 130
(17), 116 (13), 103 (12), 89 (12). The spectral properties of this
compound are in agreement with those previously reported.[16e]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for 3a–h, 4a, 8a–e, 9a–d, 10a–f, 11,
5-(3,4-Dimethoxyphenyl)-2-phenyloxazole (Balsoxin, 11): Pd(OAc)2
(11.2 mg, 0.05 mmol) and Bu4NOAc (0.60 g, 2.0 mmol) were added
to a flame-dried reaction vessel. The reaction vessel was fitted with
a silicon septum, evacuated, and back-filled with argon. This se-
quence was repeated twice. DMA (5 mL), 4-bromo-1,2-dimethoxy-
benzene (2l; 0.14 mL, 0.22 g, 1.0 mmol), and oxazole (5; 72 mL,
76 mg, 1.1 mmol) were then added successively under a stream of
argon by syringe at room temperature. The resulting mixture was
stirred at 70 °C under argon for 24 h. CuI (0.38 g, 2.0 mmol) and
bromobenzene (2k) (0.16 mL, 0.24 g, 1.5 mmol) were then sequen-
and 12.
Acknowledgments
The authors thank the University of Pisa for financial support.
[1] For selected recent examples, see: a) K. Higuchi, T. Kawasaki,
Nat. Prod. Rep. 2007, 24, 843–868; b) P. K. Cheplogoi, D. A.
Mulholland, P. H. Coombes, M. Randrianarivelojosia, Phyto-
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30704
/KAP1
Date: 16-07-13 11:15:41
Pages: 11
Palladium-Catalyzed Regioselective Arylation of Azoles
chemistry 2008, 69, 1384–1388; c) B. J. Morinaka, J. R. Pawlik, [16] a) F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel,
T. F. Molinski, J. Org. Chem. 2010, 75, 2453–2460.
Eur. J. Org. Chem. 2006, 693–703; b) F. Bellina, S. Cauteruccio,
R. Rossi, Eur. J. Org. Chem. 2006, 1379–1382; c) F. Bellina, C.
Calandri, S. Cauteruccio, R. Rossi, Tetrahedron 2007, 63, 1970–
1980; d) F. Bellina, S. Cauteruccio, A. Di Fiore, C. Marchetti,
R. Rossi, Tetrahedron 2008, 64, 6060–6072; e) F. Bellina, S.
Cauteruccio, A. Di Fiore, R. Rossi, Eur. J. Org. Chem. 2008,
5436–5445.
[2]
For representative recent examples, see: a) B. Schmidt, D. Ge-
issler, Eur. J. Org. Chem. 2011, 4814–4822; b) J. Gising, M. T.
Nilsson, L. R. Odell, S. Yahiaoui, M. Lindh, H. Iyer, A. M.
Sinha, B. R. Srinivasa, M. Larhed, S. L. Mowbray, A. Karlén,
J. Med. Chem. 2012, 55, 2894–2898; c) R. Selig, M. Goettert,
V. Schattel, D. Schollmeyer, W. Albrecht, S. Laufer, J. Med.
Chem. 2012, 55, 8429–8439.
a) P. Leroux, C. Lanen, R. Fritz, Pestic. Sci. 2006, 36, 255–261;
b) W. Kramer, U. Schirmer (Eds.), Modern Crop Protection
Compounds, Wiley-VCH, Weinheim, Germany, 2007, and refer-
ences cited therein.
[17] The importance of the role of cations inevitably introduced as
counterions of inorganic bases has recently also been addressed
in a recent study on the antagonistic effects of anionic bases in
palladium-catalyzed Suzuki–Miyaura reactions: C. Amatore,
A. Jutand, G. le Duc, Chem. Eur. J. 2012, 18, 6616–6625.
[18] R. Goikhman, T. L. Jacques, D. Sames, J. Am. Chem. Soc.
2009, 131, 3042–3048.
[19] C. Mateos, J. Mendiola, M. Carpintero, J. M. Mìnguez, Org.
Lett. 2010, 12, 4924–4927.
[20] N. A. Strotman, H. R. Chobanian, Y. Guo, J. He, J. E. Wilson,
Org. Lett. 2010, 12, 3578–3581.
[3]
[4]
ˇ
a) J. Lim, T. A. Albright, B. R. Martin, O. S. Milijanic´, J. Org.
Chem. 2011, 76, 10207–10219; b) C. Wang, H. Dong, W. Hu,
Y. Liu, D. Zhu, Chem. Rev. 2012, 112, 2208–2267; c) J. Kulká-
nek, F. Buresˇ, Beilstein J. Org. Chem. 2012, 8, 25–49; d) Z. Chi,
X. Zhang, B. Xu, X. Zhou, C. Ma, Y. Zhang, S. Liu, J. Xu,
Chem. Soc. Rev. 2012, 41, 3878–3896; e) H.-H. Liu, Y. Chen,
Tetrahedron 2013, 69, 1872–1876.
For representative reviews, see: a) J. Hassan, M. Sévignon, C.
Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359–
1470; b) B. Godoi, R. F. Schumacher, G. Zeni, Chem. Rev.
2011, 111, 2937–2980; c) D. Zhao, J. You, C. Hu, Chem. Eur.
J. 2011, 17, 5466–5492; d) A. V. Gulevich, A. S. Dudnik, N.
Chernyak, V. Gevorgyan, Chem. Rev. 2013, 113, 3084–3213.
For representative reviews on the direct arylation of azoles, see:
a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107,
174–238; b) F. Bellina, S. Cauteruccio, R. Rossi, Curr. Org.
Chem. 2008, 12, 774–790; c) F. Bellina, R. Rossi, Tetrahedron
2009, 65, 10269–10310; d) G. P. McGlacken, L. M. Bateman,
Chem. Soc. Rev. 2009, 38, 2447–2464; e) L. Ackermann, R.
Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–
9826; f) J. Roger, A. L. Gottumukkala, H. Doucet, ChemCat-
Chem 2010, 2, 20–40; g) J. Yamaguchi, K. Itami, A. D. Yamag-
uchi, Angew. Chem. Int. Ed. 2012, 51, 8960–9009; h) L. G.
Mercier, M. Leclerc, Acc. Chem. Res. 2013, article ASAP; DOI:
10.1021/ar3003305.
[21] N. Primas, A. Bouillon, J.-C. Lancelot, H. El-Kashef, S. Rault,
Tetrahedron 2009, 65, 5739–5746.
[5]
[6]
[22] L. I. Belen’kii, D. Chuvylkin, Chem. Het. Comput. 1997, 32,
1319–1343.
[23] a) B. Burke, H. Parkins, A. M. Talbot, Heterocycles 1979, 12,
349–351; b) X. A. Dominguez, G. de la Fuenta, A. G. Gonza-
lez, M. Reina, I. Timon, Heterocycles 1988, 27, 35–38.
[24] For previous multistep syntheses of balsoxin and texaline in-
volving transition-metal-catalyzed direct arylation reactions,
see: a) C. Verrier, T. Martin, C. Hoarau, F. Marsais, J. Org.
Chem. 2008, 73, 7383–7386; b) S. A. Ohnmacht, P. Mamone,
A. J. Culshaw, M. F. Greaney, Chem. Commun. 2008, 1241–
1243; c) F. Besseliévre, F. Mahuteau-Betzer, D. S. Grierson, S.
Piguel, J. Org. Chem. 2008, 73, 3278–3280; d) T. Yamamoto,
K. Muto, M. Komiyama, J. Canivet, J. Yamaguchi, K. Itami,
Chem. Eur. J. 2011, 17, 10113–10122.
[25] M. T. Reetz, E. Westermann, Angew. Chem. Int. Ed. 2000, 39,
165–168.
[26] For recent examples of transition-metal-mediated direct aryl-
ation under Jeffery conditions, see: a) F. Bellina, F. Benelli, R.
Rossi, J. Org. Chem. 2008, 73, 5529–5535; b) N. I. Abdo, A. A.
El-Shehawy, A. A. El-Barbary, J.-S. Lee, Eur. J. Org. Chem.
2012, 5540–5551; c) G. Trippé-Allard, J.-C. Lacroix, Tetrahe-
dron 2013, 69, 861–866.
[7]
[8]
S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, M. Nomura,
Bull. Chem. Soc. Jpn. 1998, 71, 467–473.
F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel, J.
Org. Chem. 2005, 70, 3997–4005.
[27] H.-J. Xu, Y.-Q. Zhao, X.-F. Zhou, J. Org. Chem. 2011, 76,
[9] B. Liégault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
J. Org. Chem. 2009, 74, 1826–1834.
8036–8041, and references cited therein.
[28] For a review on the role of carboxylate anions in transition-
metal-catalyzed direct arylations, see: L. Ackermann, Chem.
Rev. 2011, 111, 1315–1345.
[10] J. Roger, H. Doucet, Tetrahedron 2009, 65, 9772–9781.
[11] J. Roger, F. Pozgan, H. Doucet, J. Org. Chem. 2009, 74, 1179–
ˇ
1186.
[29] K. Fagnou, Top. Curr. Chem. 2010, 292, 35–56, and references
[12] A. Beladhria, K. Beydoun, H. Ben Ammar, R. Ben Salem, H.
Doucet, Synthesis 2011, 2553–2560.
cited therein.
[30] M. R. Grimmet, K. H. R. Lim, R. T. Weavers, Aust. J. Chem.
1979, 32, 2203–2213.
[31] E. Vedejs, L. M. Luchetta, J. Org. Chem. 1999, 64, 1011–1014.
[32] D. J. Pippel, C. M. Mapes, N. S. Mani, J. Org. Chem. 2007, 72,
5828–5831.
[33] J. Jensen, N. Skjærbæk, P. Vedsøc, Synthesis 2001, 128–134.
[34] M. Baghbanzadeh, C. Pilger, C. O. Kappe, J. Org. Chem. 2011,
76, 8138–8142.
[13] For an example of substrate instability at high temperature un-
der standard arylation conditions, see: T. E. Storr, A. G. Firth,
K. Wilson, K. Darley, C. G. Baumann, I. J. S. Fairlamb, Tetra-
hedron 2008, 64, 6125–6137.
[14] S. J. Gorelsky, Coord. Chem. Rev. 2013, 257, 153–164, and ref-
erences cited therein.
[15] A. Petit, J. Flygare, A. T. Miller, G. Winkel, D. H. Ess, Org.
Lett. 2012, 14, 3680–3683.
Received: May 14, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11