Carbonates: Eco-friendly solvents for palladium-catalysed direct arylation of heteroaromatics

Article abstract of DOI:10.1039/c0gc00229a

The palladium-catalysed direct 2-, 4- or 5-arylation of a wide range of heteroaromatics with aryl halides proceed in moderate to good yields using the eco-friendly solvents carbonates. The best yields were obtained using benzoxazole or thiazole derivatives. The arylation of furan, thiophene, pyrrole, imidazole or isoxazole derivatives was found to require a more elevated reaction temperature. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0gc00229a

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Carbonates: eco-friendly solvents for palladium-catalysed direct arylation
of heteroaromatics†
Jia Jia Dong,a Julien Roger,a Ce´cile Verrier,b Thibaut Martin,b Ronan Le Goff,a Christophe Hoarau*b and
Henri Doucet*a
Received 18th June 2010, Accepted 22nd September 2010
DOI: 10.1039/c0gc00229a
The palladium-catalysed direct 2-, 4- or 5-arylation of a wide range of heteroaromatics with aryl
halides proceed in moderate to good yields using the eco-friendly solvents carbonates. The best
yields were obtained using benzoxazole or thiazole derivatives. The arylation of furan, thiophene,
pyrrole, imidazole or isoxazole derivatives was found to require a more elevated reaction
temperature.
The direct arylation of heteroaromatics is an important field for
research in organic synthesis due to the biological or physical
properties of the aryl-heteroaryl derivatives.1 Ohta and co-
workers reported in 1985–1992 that the direct 2- or 5-arylation
of several heteroaromatics with aryl halides proceed in moderate
to good yields using Pd(PPh3)4 as the catalyst and DMAc as the
solvent.2 Since these exciting results, the palladium-catalysed
direct arylation of heteroaryl derivatives with aryl halides or
triflates has proved to be a very powerful method for the
synthesis of a wide variety of arylated heterocycles.3–10 This
reaction provides a cost-effective and environmentally attractive
access for the preparation of such compounds. Indeed, the
major by-products of the reaction are a base associated to
HX, instead of metallic salts produced under classical cross-
coupling procedures such as Suzuki, Negishi or Stille reactions.
Moreover, the method avoids the preliminary preparation of
a requisite organometallic reducing then the number of steps
to prepare these compounds. However, these reactions were
currently performed in most cases using relatively toxic solvents
such as DMF, DMAc, NMP or dioxane. A few palladium-
catalysed direct arylations of heteroaromatics have also been
performed using toluene, xylene or mesitylene.3 The direct
arylation of oxazoles, thiazoles or indazoles using water11 as
the solvent has been reported by Greaney. Rene´ and Fagnou
have developed biphasic conditions using a mixture of water
and EtOAc for the direct arylation of thiophenes.12 Recently,
polyethylene glycol (PEG 20000) has been found to be a useful
solvent for the direct arylation of triazoles.13
mentally friendly alternative to standard polar solvents. Since a
few years ago, carbonates have been employed successfully for
some classical metal-catalysed reactions such as enantioselective
hydrogenation, alkene metathesis, carbonylation, oxidation,
hydroxylation, Sonogashira coupling, Heck vinylation or allylic
alkylation.15 The ruthenium-catalysed direct arylation of 2-
arylpyridines has also been reported recently by Fischmeister,
Dixneuf and co-workers.16 However, to our knowledge, so
far, carbonates have not been employed as the solvents for
palladium-catalysed direct arylations.17 The use of this family of
solvent would provide a cost-effective and environmentally at-
tractive procedure for the preparation of arylated heteroarenes.
Herein, we wish to report on the use of diethylcarbonate and
propylene carbonate for palladium-catalysed direct 2-, or 5-
arylation of a wide range of heteroaromatic derivatives.
In order to determine the suitability of these solvents
for palladium-catalysed direct arylations, a first set of di-
rect arylation reactions of several heteroarenes with 4-
bromoacetophenone was carried out under previously re-
ported reaction conditions but using diethylcarbonate as
the solvent.4h,5f,6e,9e Employing the 2-n-butylthiophene, 2-n-
butylfuran or 2-formyl-N-methylpyrrole and 4-bromoaceto-
phenone as coupling partners, at 130 ◦C during 17 h, the
corresponding 5-arylation products were obtained in low yields.
On the other hand, at this temperature, the direct aryla-
tion of benzoxazole proceeded nicely using only 1 mol% of
PdCl(C3H5)(dppb) as the catalyst to provide 1 in 85% isolated
yield (Scheme 1, Table 1, entries 1 and 2). Interestingly, this
latter reaction performed in diethylcarbonate was found to be
more selective than in DMF,9e DMAc, NMP or dioxane since
using this solvent, fewer traces of unidentified side-products were
detected (Table 1, entries 3–6).
Carbonates, such as diethylcarbonate or propylene carbonate,
are polar, aprotic, nontoxic, and biodegradable solvents.14 Based
on these properties, such carbonates should offer an environ-
aInstitut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ de
Rennes 1 “Catalyse et Organometalliques”, Campus de Beaulieu, 35042,
Rennes, France. E-mail: henri.doucet@univ-rennes1.fr; Fax: +33
0223236939; Tel: +33 0223236384
bInstitut de Chimie Organique Fine (IRCOF) associe´e au CNRS (UMR
6014), INSA et Universite´ de Rouen, BP08 76131, Mont Saint Aignan,
France. E-mail: christophe.hoarau@insa-rouen.fr; Fax: +33
0235522962; Tel: +33 0235522401
† Electronic supplementary information (ESI) available: NMR data of
new compounds. See DOI: 10.1039/c0gc00229a
Scheme 1 Coupling of benzoxazole with 4-bromoacetophenone.
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Table 1 Influence of the reaction conditions for palladium catalysed
direct coupling of benzoxazole with 4-bromoacetophenone (Scheme 1)
Table 2 Palladium-catalysed coupling of benzoxazole with para-
substituted aryl bromides (Scheme 2)
Entry
Catalyst
Solvent
Conversion (%)a
Entry Aryl bromide
1
Product
Yield (%)a
92
1
2
3
4
5
6
Pd(OAc)2
diethylcarbonate
diethylcarbonate
DMF
DMAc
NMP
11
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
PdCl(C3H5)(dppb)
91 (85)
(78)b
31
79 (51)
88 (73)
2
77
dioxane
a Conditions: Pd (0.01 eq.), benzoxazole (2 eq.), 4-bromoacetophenone
(1 eq.), Cs2CO3 (2 eq.), 17 h, 130 ◦C, conversion of 4-
bromoacetophenone, yield in parenthesis is isolated. b Pd (0.05 eq.),
100 ◦C.
3
87b
90c
87d
25b
85c
83d
62b
50d
4
Then, we studied the scope and limitations of this pro-
cedure, using other aryl bromides (Scheme 2, Tables 2–4).
4-Bromobenzaldehyde, 4-bromopropiophenone or 4-trifluoro-
methylbromobenzene reacted with benzoxazole gave the ex-
pected products 2, 3 and 5 in 77–92% yields (Table 2, en-
tries 1, 2 and 4). Slower reactions were observed using 4-
bromobenzonitrile or methyl 4-bromobenzoate. However, using
longer reaction time (72 h), very high conversions of these
aryl bromides and high yields of coupling products 4 and 6
were obtained (Table 2, entries 3 and 5). A lower yield of
25% of 7 was obtained using 4-bromonitrobenzene, due to a
moderate conversion of this aryl bromide (Table 2, entry 6).
This is probably due to a partial poisoning of the palladium
catalyst. Using the electron-rich aryl bromides, 4-bromotoluene
or 4-bromoanisole, the products 9 and 10 were obtained in
83% and 62% yields, respectively (Table 2, entries 8 and 9).
With these two reactants, long reaction times (72 h) had to
be employed in order to obtain high conversions. 4-N,N-
Dimethylaminobromobenzene led to a moderate yield of 11
(Table 2, entry 10). This is certainly due to a slow oxidative
addition of this strongly deactivated aryl bromide to palladium.
With this catalyst, the oxidative addition of the aryl bromides
to palladium appears to be the rate-limiting step of the catalytic
cycle. For all these reactions, a very high selectivity in favour
of the formation of 2–11 was observed. Moreover, the stability
of these products seems to be higher than in DMF, and very
limited amount of side-products due to partial degradation was
detected.9e
5
6
7
8
9
10
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), benzoxazole (2 eq.), aryl
bromide (1 eq.), Cs2CO3 (2 eq.), diethylcarbonate, 130 ◦C, 17 h, isolated
yields. b Reaction time 48 h. c Reaction time 24 h. d Reaction time 72 h.
actions, due to their steric or coordination properties. Or-
tho-substituted 2-bromobenzaldehyde, 2-bromobenzonitrile, 2-
bromobenzotrifluoride or 2-fluorobromobenzene reacted with
benzoxazole gave 15–18 in 62–90% yields (Table 2, entries
4–6). Remarkably, the reaction was also successfully realized
with the congested and slightly deactivated aryl bromide, 2-
bromotoluene to give 19, albeit in moderate 50% yield (Table 2,
entry 8).
Next, we explored the reactivity of benzoxazole with het-
eroaryl bromides. The results depicted in Table 4 also revealed
clearly the good performance of the novel friendly protocol
in direct coupling with benzoxazole. Selective reactions were
observed using 2-, 3- or 4-bromopyridines, 3-bromoquinoline,
4-bromoisoquinoline or 5-bromopyrimidine. With these sub-
strates the target products 20–25 were obtained in 64–91% yields.
The reaction in the presence of 4-bromoisoquinoline was found
to be quite slow. However, a high yield of 24 was obtained after
48 h (Table 4, entry 5).
Scheme 2 Coupling of benzoxazole with aryl bromides.
Then, the reactivity of three meta-substituted aryl bro-
mides was examined (Table 3). As expected, similar results
than in the presence of para-substituted aryl bromides were
obtained. 3-Bromobenzaldehyde, 3-bromobenzonitrile or 3,5-
bis(trifluoromethyl)bromobenzene gave 12–14 in 85–88% yields
(Table 3, entries 1–3).
Ortho-substituents on aryl bromides generally have a more
important influence on the yields of palladium-catalysed re-
It should be noted that the direct coupling of benzoxazole
with 4-bromoacetophenone using propylene carbonate as the
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Table 3 Palladium-catalysed coupling of benzoxazole with meta- or
ortho-substituted aryl bromides (Scheme 2)
Table 4 Palladium-catalysed coupling of benzoxazole with heteroaryl
bromides (Scheme 2)
Entry
1
Aryl bromide
Product
Yield (%)a
85
Entry Heteroaryl bromide Product
1
Yield (%)a
71
2
3
4
88
64b
91
2
3
88
86
5
6
80c
90c
4
62
5
6
7
8
84b
90b
78b
50
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), benzoxazole (2 eq.), het-
eroaryl bromide (1 eq.), Cs2CO3 (2 eq.), diethylcarbonate, 130 ◦C, 24 h,
isolated yields. b Cs2CO3 3 eq. c Reaction time 48 h.
Scheme 4 Coupling of ethyl oxazole-4-carboxylate with aryl halides.
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), benzoxazole (2 eq.), aryl
bromide (1 eq.), Cs2CO3 (2 eq.), diethylcarbonate, 130 ◦C, 17 h, isolated
yields. b Reaction time 48 h.
pling of ethyl oxazole-4-carboxylate with 4-bromoacetophenone
under previously designed conditions Pd(OAc)2/P(oTol)3,9g in
diethylcarbonate as the solvent, gave the expected 2-arylated
oxazole 26 in 56% yield (Table 5, entry 1). It should be noted
that the use of PdCl(C3H5)(dppb) as the catalyst proved to be
less effective, leading to a poor conversion of starting material
(<20%) within 48 h. Under the same experimental conditions,
the direct arylation of ethyl oxazole-4-carboxylate with several
iodo and bromo(hetero)aromatics bearing electron-attractive as
well as electron-donating groups were successfully achieved to
afford 2-arylated oxazoles 27–30 in good yields (Table 5, entries
2, 4–6). Notably, the novel friendly catalyst system preserve
the regiochemical outcome of the direct arylation at the 2-
position and proved to be as efficient as the previously designed
system.9g Indeed, in the course of this reaction, complete
conversion of starting material was observed and the 5-arylated
and 2,5-diarylated oxazole-4-carboxylates were isolated in very
low yields (<10%). Interestingly, under the same conditions,
activated chloro(hetero)aromatics (Table 5, entry 3) appeared
to be also useful coupling partners to give selectively the
Scheme 3 Coupling of benzoxazole with 4-bromoacetophenone using
propylene carbonate as the solvent.
solvent also proceeded nicely, to give 1 in 78% yield (Scheme 3).
This solvent is also considered as a “green” alternative to DMF,
NMP or DMAc.14,15
As a practical and valuable functionalised oxazole substrate,
ethyl oxazole-4-carboxylate was recently successfully evaluated
in palladium-catalyzed regioselective 2-(hetero)arylation with
a broad variety of iodo, bromo and chloro(hetero)aromatics
(Scheme 4).9a,9g Pleasingly, a preliminary assay of direct cou-
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Table 5 Palladium-catalysed coupling of ethyl oxazole-4-carboxylate
derivatives with aryl halides (Scheme 4)
Table 6 Palladium-catalysed coupling of thiazole derivatives with aryl
halides
Entry Aryl bromide
1
Product
Yield (%)a
56
Entry Aryl bromide
1
Product
Yield (%)a
82
2
3
4
5
6
69b
88
2
3
74b
83
74b
80c
80
4
5
76
78
6
7
8
84
85
86c
7
8
82
82d
9
93d
72d
9
80
10
11
87d
78b
10
a Conditions: Pd(OAc)2 (0.05 eq.), P(oTol)3 (0.1 eq.), ethyl oxazole-4-
carboxylate (2 eq.), aryl halide (1 eq.), Cs2CO3 (2 eq.), diethylcarbonate,
110 ◦C, 18 h, isolated yields. b 5-Arylation and 2,5-diarylation products
were also isolated (<10%). c 2,5-Diarylation product was also isolated
(<10%). d Oxazole derivative: 1 eq.
12
13
14
80
81
73
2-(hetero)arylated oxazole-4-carboxylates 27 and 31 in good
yields.
Moreover, the 5-arylated and heteroarylated oxazoles9g
showed also a good reactivity in the same experimental condi-
tions providing the 2,5-di(hetero)aryled oxazole-4-carboxylates
32–34 (Table 5, entries 8–10).
Then, we examined the reactivity of thiazole derivatives for
the direct arylation in diethylcarbonate (Table 6). Using the
quite similar reaction conditions PdCl(C3H5)(dppb), 130 ◦C and
KOAc instead of Cs2CO3, 2-n-propylthiazole was successfully re-
gioselectively arylated on carbon 5. The reaction was found to be
15
76c
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Table 6 (Contd.)
Entry Aryl bromide
16
Table 7 Palladium-catalysed coupling of 2-n-butylfuran with aryl
bromides
Product
Yield (%)a
53e,f
Entry Aryl bromide
1
Product
Yield (%)a
70b
2
56
17
18
70g
3
4
61c
62b
83g
5
6
84c
85
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), thiazole derivative (2 eq.),
aryl halide (1 eq.), KOAc (2 eq.), diethylcarbonate, 130 ◦C, 24 h, isolated
◦
yields. b 24 h. c 67 h. d 140 C. e Pd(OAc)2 (0.05 eq.), P(oTol)3 (0.1 eq.),
Cs2CO3 (2 eq.), 110 ◦C, 18 h. f 2,5-Diphenylatedthiazole was isolated in
23% yield. g Pd(OAc)2 (0.05 eq.), P(oTol)3 (0.1 eq.), iodobenzene (2 eq.),
thiazole derivative (1 eq.), Cs2CO3 (2 eq.), 130 ◦C, 18 h.
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), furan derivative (2 eq.), aryl
bromide (1 eq.), KOAc (2 eq.), diethylcarbonate, 140 ◦C, 23 h, isolated
yields. b 72 h. c 43 h.
slower than in DMAc,8d however, very high yields of compound
35–42 were obtained (Table 6, entries 1–8). As expected, the use
of 2-ethyl-4-methylthiazole also allowed the synthesis of the 5-
arylated thiazoles 43–45 in high yields (Table 6, entries 9–11).
We also studied this reaction using 4-methylthiazole (Table 6,
entries 12–15). With this substrate, we could have observed the
formation of the 2- or 5-arylation products. However, in all cases,
only the 5-arylation products 46–49 were isolated.
product 48 was obtained (Scheme 5). Using these reaction
conditions, the coupling with 2-bromobenzonitrile gave 49 in
52% yield.
The structurally-related thiazole-4-carboxylate series was re-
cently successfully evaluated in palladium-catalyzed direct (het-
ero)arylation with halo(hetero)aromatics.8c Starting with tert-
butylthiazole-4-carboxylate, both P(o-tol)3 and Cy-JohnPhos
ligands in DMF were selected for the coupling of iodoaromatics
and bromo- and chloroaromatics, respectively, in DMF as
solvent, whilst the use of toluene under the same conditions led
to a better selectivity for the 5-position, albeit in more modest
yields.8c Thus, the preliminary assay of direct coupling of tert-
butylthiazole-4-carboxylate with iodobenzene under previously
designed conditions Pd(OAc)2/P(oTol)3 in diethylcarbonate as
the solvent was consistent with our previous observations
in toluene. Indeed, the 5-phenylthiazole-4-carboxylate 50 was
isolated as the major product in 53% yield (Table 6, entry 16).
Nevertheless, under the same conditions but by allowing the
temperature to 130 ◦C, the 5-arylated thiazole-4-carboxylate
were also successful phenylated providing the 2,5-diarylated
thiazole-4-carboxylates 51 and 52 in good yields independently
to the electronic effect on the aromatic (Table 6, entries 17 and
18).
Scheme 5 Coupling of benzothiazole with 4-bromobenzaldehyde.
The direct use of furan derivatives is an important field for
research in green chemistry, since some of them can be obtained
from agricultural wastes rich in pentosan polymers. Our first
attempts to arylate 2-n-butylfuran with 4-bromoacetophenone
using 130 ◦C as the reaction temperature gave very low yields of
55. On the other hand, we observed that using a more elevated
reaction temperature of 140 ◦C, a moderate yield of 55 could be
obtained after 23 h. As the catalyst appears to be quite stable in
this solvent, the use of longer reaction times (43 or 72 h) allowed
to obtain the 5-arylated furans in good yields (Table 7). For
example, after 43 or 72 h, the reaction of 2-n-butylfuran with
2-bromobenzonitrile or 4-bromoacetophenone gave 59 and 55
in 84% and 70% yields, respectively. In all cases, the reaction was
very regioselective in favour of the 5-arylation.
Benzothiazole was found to be less reactive than benzox-
azole. However, when we employed a more elevated temper-
ature (140 ◦C instead of 130 ◦C), for the coupling with 4-
bromobenzaldehyde, a high yield of 89% of the 2-arylated
The reactivity or 2-n-butylthiophene was found to be similar
◦
to 2-n-butylfuran (Table 8). When we employed 140 C as the
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Table 8 Palladium-catalysed coupling of 2-n-butylthiophene with aryl
bromides
Table 9 Palladium-catalysed coupling of 2,4-dimethylisoxazole with
aryl bromides
Entry Aryl bromide
1
Product
Yield (%)a
63
Entry
1
Aryl bromide
Product
Yield (%)a
71
2
3
78
46
2
3
47
23
4
53
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), 2,4-dimethylisoxazole
(2 eq.), aryl bromide (1 eq.), KOAc (2 eq.), diethylcarbonate, 140 ◦C,
72 h, isolated yields.
5
6
81b
71
Table 10 Palladium-catalysed coupling of 1-methyl-2-formylpyrrole
with aryl bromides
Entry Aryl bromide
1
Product
Yield (%)a
61b
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), thiophene derivative (2 eq.),
aryl bromide (1 eq.), KOAc (2 eq.), diethylcarbonate, 140 ◦C, 72 h,
isolated yields. b 17 h.
reaction temperature, a variety of aryl bromides was coupled to
give 61–66 in moderate to good yields. Again, the arylation was
highly regioselective in favour of the 5-arylation. The moderate
yields obtained in the presence of methyl 4-bromobenzoate
or 3,5-bis(trifluoromethyl)bromobenzene are due to partial
conversions of these aryl bromides.
2
3
33
35
Then, three arylated isoxazoles have been prepared via the
direct 4-arylation of 3,5-dimethylisoxazole (Table 9).10 The
yields strongly depend on the nature of the aryl bromides. A
good yield of 71% of 67 was obtained in the presence of 4-
bromoacetophenone; whereas, the use of 2-bromobenzonitrile
gave 69 in only 23% yield.
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), 1-methyl-2-formylpyrrole
(2 eq.), aryl bromide (1 eq.), Cs2CO3 (2 eq.), diethylcarbonate, 140 ◦C,
72 h, isolated yields. b 42 h.
1-Methyl-2-formylpyrrole has a poor reactivity for direct
arylation in diethylcarbonate (Table 10). Much slower reactions
than in DMAc were observed,6e and low to moderate yields were
obtained. For example the coupling of 4-bromobenzonitrile with
this reactant gave the 5-arylated pyrrole 71 in only 33% yield.
We have already reported the direct 5-arylation of a range
of imidazole derivatives in DMAc.7f Again, the arylations were
found to be slower in diethylcarbonate than in DMAc, however,
the reactions were very clean using a range of aryl bromides
(Table 11). High conversions of 4-bromoacetophenone, 4-
bromobenzonitrile or 3-bromopyridine were observed, and 73,
74 and 76 were obtained in high yields. On the other hand,
only a partial conversion of 4-trifluoromethylbromobenzene was
observed leading to a moderate yield of 75.
for the direct arylation of several heteroaromatic derivatives.
In the presence of diethylcarbonate or propylene carbonate
and ◦1 mol% PdCl(C3H5)(dppb) as the catalyst precursor at
130 C, the direct 2-arylation of benzoxazole, ethyl oxazole-4-
carboxylate or the 5-arylation of thiazoles using aryl bromides
as coupling partners proceeds in moderate to high yields.
The direct arylation of furan, thiophene, pyrrole, imidazole
or isoxazole derivatives was found to require a more elevated
reaction temperature (140 ◦C) to give high yields of coupling
products. It should be noted that a wide range of functions such
as acetyl, propionyl, formyl, ester, nitrile, trifluoromethyl, fluoro
or methoxy on the aryl halide is tolerated. The major by-product
of these couplings is CsX or KX/AcOH instead of metallic
salts with more classical coupling procedures. For these reasons,
this novel process should give an economically viable and
environmentally attractive access to arylated heteroaromatics.
In conclusion, these results demonstrate that carbonates,
which are considered to be “green solvents”, can be advanta-
geously employed as an alternative to the solvents usually used
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2-(4-Formylphenyl)-benzoxazole (2)20
Table 11 Palladium-catalysed coupling of 1,2-dimethylimidazole with
aryl bromides
4-Bromobenzaldehyde (0.184 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 2 in 92% (0.205 g) yield.
Entry
1
Aryl bromide
Product
Yield (%)a
85b
2-(4-Propionylphenyl)-benzoxazole (3)9e
4-Bromopropiophenone (0.213 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 3 in 77% (0.193 g) yield.
2
3
4
81
48
65
Methyl 4-benzoxazol-2-yl-benzoate (4)9e
Methyl 4-bromobenzoate (0.215 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 4 in 87% (0.220 g) yield.
2-(4-Trifluoromethylphenyl)-benzoxazole (5)9e
4-Trifluoromethylbromobenzene (0.225 g, 1 mmol) and benzox-
azole (0.238 g, 2 mmol) affords 5 in 90% (0.237 g) yield.
4-Benzoxazol-2-yl-benzonitrile (6)9e
a Conditions: PdCl(C3H5)(dppb) (0.01 eq.), 1,2-dimethylimidazole
(2 eq.), aryl bromide (1 eq.), KOAc (2 eq.), diethylcarbonate, 140 ◦C,
72 h, isolated yields. b 48 h.
4-Bromobenzonitrile (0.182 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 6 in 87% (0.192 g) yield.
2-(4-Nitrophenyl)-benzoxazole (7)9e
Experimental
4-Bromonitrobenzene (0.182 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 7 in 25% (0.060 g) yield.
Diethylcarbonate was purchased from Acros Organics and was
not purified before use. Heteroarenes, propylene carbonate,
KOAc and Cs2CO3 were purchased from Alfa Aesar and
were not purified before use. Ethyl oxazole-4-carboxylate was
prepared from ethyl isocyanoacetate according to Scho¨llkopf
procedure.18
2-(4-Fluorophenyl)-benzoxazole (8)9e
4-Bromofluorobenzene (0.175 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 8 in 85% (0.181 g) yield.
2-(4-Methylphenyl)-benzoxazole (9)9e
Preparation of the PdCl(C3H5)(dppb) catalyst:19
4-Bromotoluene (0.171 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 9 in 83% (0.174 g) yield.
An oven-dried 40 mL Schlenk tube equipped with a mag-
netic stirring bar under argon atmosphere, was charged with
[Pd(C3H5)Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol).
10 mL of anhydrous dichloromethane were added, then the
solution was stirred at room temperature for twenty minutes.
The solvent was removed in vacuum. The yellow powder
was used without purification. 31P NMR (81 MHz, CDCl3)
d = 19.3 (s).
2-(4-Methoxyphenyl)-benzoxazole (10)9e
4-Bromoanisole (0.187 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 10 in 62% (0.140 g) yield.
2-(4-Dimethylaminophenyl)-benzoxazole (11)9e
(4-Bromophenyl)-dimethylamine (0.200 g, 1 mmol) and benzox-
azole (0.238 g, 2 mmol) affords 11 in 50% (0.119 g) yield.
Typical experiment for coupling reactions
The reaction of the aryl halide (1 mmol), heteroaromatic
(2 mmol) and Cs2CO3 (0.651 g, 2 mmol) or KOAc (0.196,
2 mmol) (see Tables) at 130–140 ◦C (see Tables and Schemes) in
diethylcarbonate (5 mL) in the presence of PdCl(C3H5)(dppb)
(6.1 mg, 0.01 mmol) or Pd(OAc)2 (0.05 eq.)/P(oTol)3 (0.1 eq.),
(see Tables and Schemes) under argon affords the corre-
sponding product after evaporation and filtration on silica gel
(pentane/ether).
2-(3-Formylphenyl)-benzoxazole (12)
3-Bromobenzaldehyde (0.184 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 12 in 85% (0.190 g) yield.
3-Benzoxazol-2-yl-benzonitrile (13)9e
3-Bromobenzonitrile (0.182 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 13 in 88% (0.194 g) yield.
2-(4-Acetylphenyl)-benzoxazole (1)9e
2-(3,5-Bistrifluoromethylphenyl)-benzoxazole (14)9e
4-Bromoacetophenone (0.199 g, 1 mmol) and benzoxazole
3,5-Bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and
(0.238 g, 2 mmol) affords 1 in 85% (0.202 g) yield.
benzoxazole (0.238 g, 2 mmol) affords 14 in 86% (0.285 g) yield.
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2-(2-Formylphenyl)-benzoxazole (15)
Ethyl 2-phenyloxazole-4-carboxylate (28)9g
2-Bromobenzaldehyde (0.184 g, 1 mmol) and benzoxazole
Iodobenzene (0.204 g, 1 mmol) and ethyloxazole-4-carboxylate
(0.238 g, 2 mmol) affords 15 in 62% (0.138 g) yield.
(0.282 g, 2 mmol) affords 28 in 74% (0.161 g) yield.
2-Benzoxazol-2-yl-benzonitrile (16)9e
Ethyl 2-(4-Methoxyphenyl)-oxazole-4-carboxylate (29)9g
2-Bromobenzonitrile (0.182 g, 1 mmol) and benzoxazole
Iodoanisole (0.234 g, 1 mmol) and ethyloxazole-4-carboxylate
(0.238 g, 2 mmol) affords 16 in 84% (0.185 g) yield.
(0.282 g, 2 mmol) affords 29 in 80% (0.198 g) yield.
Ethyl 2-quinolin-3-yloxazole-4-carboxylate (30)9g
2-(2-Trifluoromethylphenyl)-benzoxazole (17)
2-Trifluoromethylbromobenzene (0.225 g, 1 mmol) and benzox-
azole (0.238 g, 2 mmol) affords 17 in 90% (0.237 g) yield.
3-Bromoquinoline (0.208 g, 1 mmol) and ethyloxazole-4-
carboxylate (0.282 g, 2 mmol) affords 30 in 80% (0.214 g) yield.
2-(2-Fluorophenyl)-benzoxazole (18)9e
Ethyl 2-pyridin-2-yl-oxazole-4-carboxylate (31)9g
2-Bromofluorobenzene (0.175 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 18 in 78% (0.166 g) yield.
2-Chloropyridine (0.113 g, 1 mmol) and ethyloxazole-4-
carboxylate (0.282 g, 2 mmol) affords 31 in 82% (0.179 g) yield.
2-(2-Methylphenyl)-benzoxazole (19)9e
5-(4-Cyanophenyl)-2-(4-methoxyphenyl)-oxazole-4-carboxylic
acid ethyl ester (32)
2-Bromotoluene (0.171 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 19 in 50% (0.105 g) yield.
4-Bromoanisole (0.065 g, 0.35 mmol) and ethyl 5-(4-
cyanophenyl)oxazole-4-carboxylate9g (0.085 g, 0.35 mmol) af-
fords 32 in 82% (0.100 g) yield.
2-Pyridin-2-yl-benzoxazole (20)9h
2-Bromopyridine (0.158 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 20 in 71% (0.139 g) yield.
2-(4-Cyano-phenyl)-5-(4-methoxy-phenyl)-oxazole-4-carboxylic
acid ethyl ester (33)
2-Pyridin-3-yl-benzoxazole (21)9e
4-Iodobenzonitrile (0.080 g, 0.35 mmol) and ethyl 5-(4-
methoxyphenyl)oxazole-4-carboxylate9g (0.086 g, 0.35 mmol)
affords 33 in 93% (0.113 g) yield.
3-Bromopyridine (0.158 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 21 in 88% (0.173 g) yield.
2-Pyridin-4-yl-benzoxazole (22)9e
2-(4-Methoxyphenyl)-5-pyridin-4-yl-oxazole-4-carboxylic acid
ethyl ester (34)
4-Bromopyridine hydrochloride (0.194 g, 1 mmol) and benzox-
azole (0.238 g, 2 mmol) affords 22 in 64% (0.126 g) yield.
4-Bromoanisole (0.065 g, 0.35 mmol) and ethyl 5-(pyridin-4-
yl)oxazole-4-carboxylate9g (0.076 g, 0.35 mmol) affords 34 in
72% (0.082 g) yield.
3-Benzoxazol-2-ylquinoline (23)9e
3-Bromoquinoline (0.208 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 23 in 91% (0.224 g) yield.
4-(2-Propylthiazol-5-yl)acetophenone (35)8a
4-Bromoacetophenone (0.199 g,
propylthiazole (0.254 g, 2 mmol) affords 35 in 82% (0.201 g)
1
mmol) and 2-n-
4-Benzoxazol-2-ylisoquinoline (24)
yield.
4-Bromoisoquinoline (0.208 g, 1 mmol) and benzoxazole
(0.238 g, 2 mmol) affords 24 in 80% (0.197 g) yield.
5-4-(Trifluoromethyl)phenyl-2-propylthiazole (36)8a
2-Pyrimidin-5-ylbenzoxazole (25)9e
4-Trifluoromethylbromobenzene (0.225 g, 1 mmol) and 2-n-
propylthiazole (0.254 g, 2 mmol) affords 36 in 74% (0.201 g)
yield.
5-Bromopyrimidine (0.159 g, 1 mmol) and benzoxazole (0.238 g,
2 mmol) affords 25 in 90% (0.177 g) yield.
3-(2-Propylthiazol-5-yl)benzaldehyde (37)8d
Ethyl 2-(4-acetylphenyl)-oxazole-4-carboxylate (26)
3-Bromobenzaldehyde (0.184 g, 1 mmol) and 2-n-propylthiazole
4-Bromoacetophenone (0.199 g, 1 mmol) and ethyloxazole-4-
(0.254 g, 2 mmol) affords 37 in 83% (0.192 g) yield.
carboxylate (0.282 g, 2 mmol) affords 26 in 56% (0.145 g) yield.
Ethyl 2-(4-cyanophenyl)-oxazole-4-carboxylate (27)9g
2-(2-Propylthiazol-5-yl)benzonitrile (38)8a
4-Iodobenzonitrile (0.229 g, 1 mmol) and ethyloxazole-4-
2-Bromobenzonitrile (0.182 g, 1 mmol) and 2-n-propylthiazole
carboxylate (0.282 g, 2 mmol) affords 27 in 69% (0.167 g) yield.
(0.254 g, 2 mmol) affords 38 in 76% (0.173 g) yield.
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5-Naphthalen-2-yl-2-propylthiazole (39)21
tert-Butyl 5-(4-cyanophenyl)-2-phenyl-thiazole-4-carboxylate
(51)
2-Bromonaphthalene (0.207 g, 1 mmol) and 2-n-propylthiazole
(0.254 g, 2 mmol) affords 39 in 78% (0.197 g) yield.
Iodobenzene (0.110 g, 0.70 mmol) and tert-butyl 5-(4-
cyanophenyl)thiazole-4-carboxylate22 (0.077 g, 0.35 mmol) af-
fords 51 in 70% (0.068 g) yield.
3-(2-Propylthiazol-5-yl)pyridine (40)8d
3-Bromopyridine (0.158 g, 1 mmol) and 2-n-propylthiazole
(0.254 g, 2 mmol) affords 40 in 84% (0.171 g) yield.
tert-Butyl 5-(4-methoxyphenyl)-2-phenyl-thiazole-4-carboxylate
(52)
4-(2-Propylthiazol-5-yl)pyridine (41)9i
Iodobenzene (0.110 g, 0.70 mmol) and tert-butyl 5-(4-
methoxyphenyl)thiazole-4-carboxylate22 (0.079 g, 0.35 mmol)
affords 52 in 83% (0.082 g) yield.
4-Bromopyridine hydrochloride (0.194 g, 1 mmol) and 2-n-
propylthiazole (0.254 g, 2 mmol) affords 41 in 85% (0.174 g)
yield.
4-Benzothiazol-2-yl-benzaldehyde (53)23
2-(2-Propylthiazol-5-yl)quinoline (42)8d
4-Bromobenzaldehyde (0.184 g, 1 mmol) and benzothiazole
(0.270 g, 2 mmol) affords 53 in 89% (0.213 g) yield.
3-Bromoquinoline (0.208 g, 1 mmol) and 2-n-propylthiazole
(0.254 g, 2 mmol) affords 42 in 86% (0.219 g) yield.
2-Benzothiazol-2-yl-benzonitrile (54)24
4-(2-Ethyl-4-methylthiazol-5-yl)benzaldehyde (43)8a
2-Bromobenzonitrile (0.182 g, 1 mmol) and benzothiazole
(0.270 g, 2 mmol) affords 54 in 52% (0.123 g) yield.
4-Bromobenzaldehyde (0.184 g,
1 mmol) and 2-ethyl-4-
methylthiazole (0.254 g, 2 mmol) affords 43 in 80% (0.185 g)
yield.
2-n-Butyl-5-(4-acetylphenyl)furan (55)5f
4-Bromoacetophenone (0.199 g, 1 mmol) and 2-n-butylfuran
(0.248 g, 2 mmol) affords 55 in 70% (0.170 g) yield.
2-(2-Ethyl-4-methylthiazol-5-yl)benzonitrile (44)8d
2-Bromobenzonitrile (0.182 g,
methylthiazole (0.254 g, 2 mmol) affords 44 in 87% (0.199 g)
1 mmol) and 2-ethyl-4-
Methyl 4-(5-n-butyl-furan-2-yl)-benzoate (56)5b
yield.
Methyl 4-bromobenzoate (0.215 g, 1 mmol) and 2-n-butylfuran
(0.248 g, 2 mmol) affords 56 in 56% (0.145 g) yield.
4-(2-Ethyl-4-methylthiazol-5-yl)-pyridine (45)8d
2-n-Butyl-5-(4-cyanophenyl)furan (57)5b
4-Bromopyridine hydrochloride (0.194 g, 1 mmol) and 2-ethyl-
4-methylthiazole (0.254 g, 2 mmol) affords 45 in 78% (0.159 g)
yield.
4-Bromobenzonitrile (0.182 g, 1 mmol) and 2-n-butylfuran
(0.248 g, 2 mmol) affords 57 in 61% (0.137 g) yield.
4-(4-Methylthiazol-5-yl)-acetophenone (46)8d
2-n-Butyl-5-(3-formylphenyl)furan (58)5b
4-Bromoacetophenone (0.199 g, 1 mmol) and 4-methylthiazole
3-Bromobenzaldehyde (0.184 g, 1 mmol) and 2-n-butylfuran
(0.198 g, 2 mmol) affords 46 in 80% (0.174 g) yield.
(0.248 g, 2 mmol) affords 58 in 62% (0.141 g) yield.
4-(4-Methylthiazol-5-yl)-benzonitrile (47)8d
2-(5-n-Butylfuran-2-yl)benzonitrile (59)5f
4-Bromobenzonitrile (0.182 g, 1 mmol) and 4-methylthiazole
2-Bromobenzonitrile (0.182 g, 1 mmol) and 2-n-butylfuran
(0.198 g, 2 mmol) affords 47 in 81% (0.162 g) yield.
(0.248 g, 2 mmol) affords 59 in 84% (0.189 g) yield.
3-(4-Methylthiazol-5-yl)-acetophenone (48)
2-n-Butyl-5-(3-quinolyl)furan (60)5b
3-Bromoacetophenone (0.199 g, 1 mmol) and 4-methylthiazole
3-Bromoquinoline (0.208 g, 1 mmol) and 2-n-butylfuran
(0.198 g, 2 mmol) affords 48 in 73% (0.159 g) yield.
(0.248 g, 2 mmol) affords 60 in 85% (0.213 g) yield.
3-(4-Methylthiazol-5-yl)-quinoline (49)
4-(5-n-Butylthiophen-2-yl)acetophenone (61)4c
3-Bromoquinoline (0.208 g, 1 mmol) and 4-methylthiazole
4-Bromoacetophenone (0.199 g,
1
mmol) and 2-n-
(0.198 g, 2 mmol) affords 49 in 76% (0.172 g) yield.
butylthiophene (0.280 g, 2 mmol) affords 61 in 63% (0.163 g)
yield.
tert-Butyl 5-phenylthiazole-4-carboxylate (50)
4-(5-n-Butylthiophen-2-yl)benzonitrile (62)4c
Iodobenzene (0.055 g, 0.35 mmol) and tert-butylthiazole-4-
carboxylate8c (0.027 g, 0.35 mmol) affords 50 in 53% (0.037 g)
yield.
4-Bromobenzonitrile (0.182 g, 1 mmol) and 2-n-butylthiophene
(0.280 g, 2 mmol) affords 62 in 78% (0.188 g) yield.
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Methyl 4-(5-n-butylthiophen-2-yl)-benzoate (63)4c
Methyl 4-bromobenzoate (0.215 g, mmol) and 2-n-
4-(2,3-Dimethylimidazol-4-yl)-benzonitrile (74)7f
4-Bromobenzonitrile (0.182 g, mmol) and 1,2-
1
1
butylthiophene (0.280 g, 2 mmol) affords 63 in 46% (0.126 g)
dimethylimidazole (0.192 g, 2 mmol) affords 74 in 81%
yield.
(0.160 g) yield.
5-(4-Trifluoromethylphenyl)-1,2-dimethylimidazole (75)7f
2-3,5-Bis(trifluoromethyl)phenyl-5-n-butylthiophene (64)4h
4-Trifluoromethylbromobenzene (0.225 g, 1 mmol) and 1,2-
dimethylimidazole (0.192 g, 2 mmol) affords 75 in 48% (0.115 g)
yield.
3,5-Bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and 2-
n-butylthiophene (0.280 g, 2 mmol) affords 64 in 53% (0.187 g)
yield.
5-(3-Pyridyl)-1,2-dimethylimidazole (76)7f
2-(5-Butylthiophene-2-yl)benzonitrile (65)4h
3-Bromopyridine (0.158 g, 1 mmol) and 1,2-dimethylimidazole
2-Bromobenzonitrile (0.182 g, 1 mmol) and 2-n-butylthiophene
(0.192 g, 2 mmol) affords 76 in 65% (0.112 g) yield.
(0.280 g, 2 mmol) affords 65 in 81% (0.195 g) yield.
3-(5-n-Butylthiophen-2-yl)pyridine (66)4c
Acknowledgements
3-Bromopyridine (0.158 g, 1 mmol) and 2-n-butylthiophene
(0.280 g, 2 mmol) affords 66 in 71% (0.154 g) yield.
J. R. is grateful to “Ministe`re de la Recherche” for a grant.
We thank the CNRS and “Rennes Metropole” for providing
financial support and C. Fischmeister for helpful discussions.
4-(3,5-Dimethylisoxazol-4-yl)-acetophenone (67)10
4-Bromoacetophenone (0.199 g,
dimethylisoxazole (0.192 g, 2 mmol) affords 67 in 71%
1
mmol) and 3,5-
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2-Bromobenzonitrile (0.182 g,
dimethylisoxazole (0.192 g, 2 mmol) affords 69 in 23%
(0.046 g) yield.
1
mmol) and 3,5-
5-(4-Acetylphenyl)-1-methyl-2-formylpyrrole (70)6e
4-Bromoacetophenone (0.199 g, 1 mmol) and 1-methyl-2-
formylpyrrole (0.219 g, 2 mmol) affords 70 in 61% (0.139 g)
yield.
4-(5-Formyl-1-methylpyrrol-2-yl)-benzonitrile (71)6e
4-Bromobenzonitrile (0.182 g, 1 mmol) and 1-methyl-2-
formylpyrrole (0.219 g, 2 mmol) affords 71 in 33% (0.069 g)
yield.
5-(4-Formylphenyl)-1-methyl-2-formylpyrrole (72)6e
4-Bromobenzaldehyde (0.184 g, 1 mmol) and 1-methyl-2-
formylpyrrole (0.219 g, 2 mmol) affords 72 in 35% (0.075 g)
yield.
5-(4-Acetylphenyl)-1,2-dimethylimidazole (73)7f
4-Bromoacetophenone (0.199 g,
dimethylimidazole (0.192 g, 2 mmol) affords 73 in 85%
(0.182 g) yield.
1
mmol) and 1,2-
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