Exploring Green Solvents Associated to Pd/C as Heterogeneous Catalyst for Direct Arylation of Heteroaromatics with Aryl Bromides

Article abstract of DOI:10.1002/adsc.201800596

Metal residues are certainly one of the major sources of contamination of products in metal-catalyzed direct arylation reactions. We found that the use of only 1 mol% of the heterogeneous catalyst Pd/C promotes very efficiently the direct arylations of most heteroaromatics. In the presence of this catalyst and potassium acetate as the base, the direct arylation of thiophenes, furans, pyrroles, thiazoles, imidazoles or isoxazoles, using aryl bromides as coupling partners, proceeds highly regioselectively and in moderate to very high yields. With several heteroarenes both electron-deficient and electron-rich aryl bromides were tolerated; moreover, with the most reactive heteroarenes, the Pd/C catalyst tolerated green solvents such as diethyl carbonate, 3-methylbutan-1-ol and pentan-1-ol, affording a synthetic scheme with low environmental impact. (Figure presented.).

Full text of DOI:10.1002/adsc.201800596

Title: Exploring Green Solvents Associated to Pd/C as Heterogeneous
Catalyst for Direct Arylation of Heteroaromatics with Aryl
Bromides
Authors: Shuxin Mao, Xinzhe Shi, Jean-Francois Soulé, and Henri
Doucet
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10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
Exploring Green Solvents Associated to Pd/C as Heterogeneous
Catalyst for Direct Arylation of Heteroaromatics with Aryl
Bromides
Shuxin Mao,[a] Xinzhe Shi,[a] Jean-François Soulé*[a] and Henri Doucet*[a]
Abstract: Metal residues are certainly one of the major sources of
the C-H bond activation of heteroaromatics using Pd(PPh3)4
catalyst.[1] Since these seminal results, the so-called Pd-
catalyzed “direct arylation” of heteroarenes was demonstrated to
be an extremely powerful method for the preparation of a wide
contamination of products in metal-catalyzed direct arylation
reactions.
We found that the use of only 1 mol% of the
heterogeneous catalyst Pd/C promotes very efficiently the direct
arylations of most heteroaromatics. In the presence of this catalyst
and potassium acetate as the base, the direct arylation of
thiophenes, furans, pyrroles, thiazoles, imidazoles or isoxazoles,
using aryl bromides as coupling partners, proceeds highly
regioselectively and in moderate to very high yields. With several
heteroarenes both electron-deficient and electron-rich aryl bromides
were tolerated; moreover, with the most reactive heteroarenes, the
Pd/C catalyst tolerated green solvents such as diethyl carbonate, 3-
methylbutan-1-ol and pentan-1-ol, affording a synthetic scheme with
low environmental impact.
variety of arylated heterocycles.[2,3]
This methodology is
environmentally attractive, as the major reaction by-product is
HX associated to a base, instead of the metallic salts mixture
which is produced under the more classical Suzuki, Negishi or
Stille cross-coupling reactions.[4] However, in most cases, direct
arylations are currently performed using homogeneous
palladium-catalysts, producing metal and ligands residues,
which are a major issue in the pharmaceutical chemistry and
also for some materials possessing specific optical properties.
Moreover, these homogeneous catalysts are generally
associated with relatively toxic solvents such as DMA, DMF,
NMP, or dioxane.[5-10]
Introduction
In recent years, a few solvents which can be considered as
“green”[11] according to P. Anastas principles, have been
The access to arylated heteroaromatics is a very important
research field in organic synthesis due to the physical or
employed
for
Pd-catalysed
direct
arylations
of
heteroaromatics.[12-17] For example, water was employed by
Greaney and Djakovitch for the arylation of some 5-membered
biological properties of such derivatives.
For example,
Dantrolene, Canagliflozin, Zolpidem, Atorvastatin, and
Valdecoxib are currently employed for the treatment of various
diseases (Figure 1).
ring heterocycles;[13] whereas, Ackermann employed
a
polyethylene glycol solvent for the direct arylation of triazoles.[14]
Carbonates, ethers or alcohols have been used as the solvents
for the arylation of heteroarenes.[15-17] All these reactions were
performed using homogeneous Pd-catalysts.
A
few examples of Pd-catalyzed direct arylations of
heteroarenes using heterogeneous palladium catalysts have
been described.[18-24] The first one was reported in 1982 and
employed Pd/C catalyst, but it was limited to isoxazoles as
heteroarene and HMPT, which is considered as a toxic solvent,
was used.[20]
In 2013, Glorius et al. reported the
heterogeneously catalyzed direct -arylation of benzothiophenes
with aryl chlorides using Pd/C catalyst in the presence of 10
mol% CuCl2.[21] One year later, this group extended the use of
Pd/C catalyst to the C4-arylation of thiophenes using aryl
iodonium salts as aryl source and ethanol or water/ethanol
mixtures as green solvents.[22] Only 1,2,3-triazole has been
successfully employed in Pd-catalyzed direct arylation with aryl
halides as aryl source using a heterogeneous catalyst in a green
Figure 1. Examples of pharmaceuticals containing an arylated heteroaromatic
solvent.[18]
employed -valerolactone as renewable solvent associated with
5 mol% Pd/C. To our knowledge, the reactivity of other
For this reaction, Ackermann, Vaccaro et al.
In 1990, Ohta et al. discovered that the arylation of several
heteroaromatics using aryl halides as aryl source proceed via
heteroaromatics and the influence of other “green” solvents
using Pd/C catalyst for direct arylations with aryl halides as aryl
source has not been described.
[a]
Mr Shuxin Mao, Mrs Xinzhe Shi, Dr. Jean-François Soulé, Dr. Henri
The use of the heterogeneous catalyst Pd/C presents several
advantages: 1) it is not air or moisture sensitive and therefore
easy to handle, 2) it can be easily removed from the product by
simple filtration at the end of the reaction, 3) the product is
contaminated with very low amount of Pd residues, 4) there is
no phosphine residues, 5) it is easily available at an affordable
Doucet
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France.
E-mail: jean-francois.soule@univ-rennes1.fr; henri.doucet@univ-
rennes1.fr
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/adsc.201800596
Advanced Synthesis & Catalysis
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cost, and 6) recycling of the recovered Pd/C is generally
possible.
side-products. A high yield in 7 was also obtained for the
reaction
of
2-bromobenzonitrile
in 3-methylbutan-1-ol.
Herein, we report on the use of Pd/C for the direct arylations of a
wide range of heteroaromatic derivatives with aryl bromides
using, in several cases, solvents which can be considered as
“green” and which are available on large scale at an affordable
cost (Figure 2):
1) diethyl carbonate (DEC) which displays several advantages
such as a high biodegradability, low acute toxicity and a low
environmental impact in the course of its synthesis as it can be
prepared from CO2 and bioethanol;[25]
2) cyclopentyl methyl ether (CPME) which also presents several
advantageous features such as limited miscibility in water which
allows easy separation, low formation of peroxides (compared
with THF or diisopropyl ether). Moreover, CPME can be
manufactured by the addition of MeOH to cyclopentene which
produces no apparent waste;[26]
Thiophene 2-carbonitrile also reacted nicely with 4-
bromobenzonitrile and 4-bromoacetophenone using 1 mol% of
10% Pd/C catalyst in DMA affording 8 and 9 in 87% and 90%
yields, respectively. Then, thiophenes substituted by ester or
acetyl functions at C2 position were employed. In both cases,
high yields in the expected coupling products 10 and 11 were
obtained. 2-n-Pentylthiophene also underwent C5-arylation with
3-bromopyridine to give product 12 in 90% yield. The use of p-
tolylboronic acid as aryl source instead of 4-bromobenzene for
the preparation of 5, under the same conditions, but using
Cu(OAc)2 as oxidant gave no coupling product.
3) 3-methylbutan-1-ol and pentan-1-ol which are biodegradable,
are not considered as hazardous air pollutant solvents, are
unlikely to have any adverse health effects, as they are found in
several alcoholic beverages, and can be prepared by
fermentation or by the reduction of 1-valeraldehyde or 3-
methylbutyraldehyde with hydrogen.
Figure 2. Green solvents employed for Pd/C catalyzed arylations
Results and Discussion
The first set of reactions using 2-n-pentylthiophene and 4-
bromobenzonitrile as coupling partners was carried out under
previously reported reaction conditions, but using 1 mol% of
10% Pd/C as the catalyst (Scheme 1).[5a] In the presence of the
polar solvent N,N-dimethylacetamide (DMA), a high yield in the
desired C5-arylated thiazole 1 was obtained. No formation of
other arylated or diarylated thiophenes was detected by GC/MS
analysis. As DMA is not a desirable solvent in terms of “green
chemistry”, the outcome of this reaction using four “greener“
solvents was studied. The reaction in DEC or CPME with 1
mol% of 10% Pd/C catalyst afforded 1 in only 21% and <5%
yields, respectively, due to partial conversions of 4-
bromobenzonitrile. Conversely, 3-methylbutan-1-ol and pentan-
1-ol afforded 1 in high yields with complete conversions of the
aryl bromide.
Scheme 1. Pd/C catalyzed coupling of thiophene derivatives with aryl
bromides.
The reactivity of several furan derivatives in the presence of 1
mol% Pd/C catalyst was also examined (Scheme 2). The
arylation of furan derivatives had been previously reported to
proceed nicely in DMA using PdCl(C3H5)(dppb) as the
catalyst.[6d]
A poor reactivity of 2-n-butylfuran with 4-
bromobenzonitrile was observed in DEC; whereas the reactions
performed in 3-methylbutan-1-ol or DMA gave the desired
product 13 in 43% and 71% yields, respectively. The arylation
of 2-n-butylfuran in DMA using 1 mol% of 10% Pd/C catalyst
also tolerated 4-acetyl- 4-methyl- or 2-cyano-substituents on the
aryl bromide affording 14-16 in 67-88% yields. A good yield in
product 17 was also obtained for the reaction with 3-
bromopyridine. Under the same conditions, the reaction of 2-
ethylbenzofuran with 4-bromobenzonitrile gave 18 in 83% yield.
Then,
a set of aryl bromides was reacted with 2-n-
pentylthiophene using 1 mol% of 10% Pd/C catalyst. High yields
were generally obtained for the coupling of 2-n-pentylthiophene
with aryl bromides in DMA. Both electron-withdrawing and
electron-donating substituents were tolerated. It should be
mentioned that for the reaction with 4-bromonitrobenzene, a
higher yield in 4 was obtained using 3-methylbutan-1-ol instead
of DMA as the solvent, due to the formation of a lower amount of
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Scheme 3. Pd/C catalyzed coupling of pyrrole derivatives with aryl bromides.
Then, we examined the reactivity of thiazoles with a set of aryl
bromides in the presence of 1 mol% of 10% Pd/C. Firstly,
various solvents were investigated for the arylation of 2-
isopropyl-4-methylthiazole with 4-bromobenzonitrile using Pd/C
as heterogeneous catalyst (Scheme 4). In the presence of the
polar solvent DMA, a very high yield into the desired C5-arylated
thiazole 23 was obtained. Then, the outcome of this reaction
using four “greener“ solvents was studied. The reaction using,
CPME and 1 mol% of 10% Pd/C catalyst afforded 23 in only
48% yield due to a partial conversion of 4-bromobenzonitrile.
Conversely, DEC, 3-methylbutan-1-ol and pentan-1-ol gave 23
in very high yields (94-97%) with complete conversions of the
aryl bromide. The yield in 23 was very similar for a reaction
Scheme 2. Pd/C catalyzed coupling of (benzo)furan derivatives with aryl
bromides.
performed on
a larger scale (5 mmol of 2-isopropy-4-
methylthiazole instead of 1 mmol) in 10 mL of 3-methylbutan-1-
ol.
The use of 1 mol% of 10% Pd/C catalyst for the C2-arylation of
1-methylpyrrole was also successful; however, for these
reactions, a larger excess of the heteroarene (4 equiv.) was
employed in order to avoid the formation of 2,5-diarylated
The reaction of several other para-substituted electron-deficient
aryl
bromides
such
as
ethyl
4-bromobenzaldehyde,
4-bromobenzoate or
4-
4-
pyrroles as side-products (Scheme 3).
With 2- and 4-
bromoacetophenone,
bromonitrobenzene with 2-isopropy-4-methylthiazole in 3-
methylbutan-1-ol using 1 mol% of 10% Pd/C also gave the
bromobenzonitriles, good yields in the desired coupling products
19 and 22 were obtained in DMA and in 3-methylbutan-1-ol.
Conversely, a moderate yield of 20 was obtained for the reaction
of 1-methylpyrrole with ethyl 4-bromobenzoate in 3-methylbutan-
1-ol, due to the formation of degradation products. With this aryl
bromide, the use of DMA as the solvent allowed to obtain 20 in a
desired products 24-27 in very high yields.
4-
Fluorobromobenzene afforded the coupling product 28 in a
higher yield in DEC (97%) than in 3-methylbutan-1-ol (85%).
The presence of the electron-donating para-substituents, methyl,
t-butyl and methoxy on the aryl bromide was also tolerated
providing 29-31 in 72-92% yields. The reaction of 2-isopropy-4-
higher yield.
The reaction of 1-methylpyrrole with 4-
bromotoluene gave the target product 21 in only 52% yield, as
large amount of 4,4'-dimethyl-1,1'-biphenyl arising from the
homo-coupling of 4-bromotoluene was also produced.
methylthiazole
with
4-bromo-N,N-dimethylaniline
in
3-
methylbutan-1-ol gave 32 in only 41% yields due to partial
conversion of the aniline derivative; however, the use of DMA as
the solvent allowed to increase the yield to 78%. As expected,
the
reactivity
of
the
meta-substituted
3,5-
bis(trifluoromethyl)bromobenzene was found to be similar to
para-substituted aryl bromides. The reactivity of four ortho-
substituted aryl bromides was also examined. Due to their
coordination and/or steric properties, ortho-substituents on aryl
halides may have an important influence on the yields of Pd-
catalysed reactions. 2-Cyano-, 2-trifluoromethyl- and 2-fluoro-
substituents were tolerated, affording 34, 36 and 37 in 85-94%
yields, when the reactions were performed in 3-methylbutan-1-ol
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or in DEC. The reaction with 2-bromonitrobenzene gave 35 in
lower yields due to the formation of several unidentified
degradation products.
This novel environmentally friendly
protocol using DEC or 3-methylbutan-1-ol and 1 mol% of 10%
Pd/C was also effective for the direct couplings of 2-isopropyl-4-
methylthiazole with 3-bromopyridine or 3-bromoquinoline. With
these substrates, the target products 38 and 39 were obtained in
88-96% yields. 2-Ethyl-4-methylthiazole which is slightly less
hindered than 2-isopropyl-4-methylthiazole exhibits a similar
reactivity.
Its reaction with 4-bromobenzonitrile and 4-
bromopropiophenone in 3-methylbutan-1-ol or DEC using 1
mol% Pd/C gave 40 and 41 in 95-96% yields.
Scheme 5. Pd/C catalyzed coupling of 1-methylimidazole with aryl bromides.
4-Arylisoxazoles are important structures due to their specific
biological properties. For example, Valdecoxib (Figure 1) and
Parecoxib, which contain this unit, are nonsteroidal anti-
inflammatory drugs. The reaction of 3,5-dimethylisoxazole with
4-bromobenzonitrile in the presence of 1 mol% of 10% Pd/C
catalyst in DMA gave the C4-arylated isoxazole in 93% yield
(Scheme 6). Similar yields were obtained for the coupling of
3,5-dimethylisoxazole with ethyl 4-bromobenzoate and 2-
bromobenzonitrile; whereas a lower yield in 48 was obtained
with electron-rich 4-bromoanisole. The use of 3-methylbutan-1-
ol as solvent for the arylation of 3,5-dimethylisoxazole was
ineffective.
Scheme 6. Pd/C catalyzed coupling of 3,5-dimethylisoxazole with aryl
bromides.
Scheme 4. Pd/C catalyzed coupling of thiazole derivatives with aryl bromides.
Among heterocycles, imidazo[1,2-a]pyridines and imidazo[1,2-
b]pyridazines display very important biological properties. For
example, Zolpidem (Figure 1) is actually employed for the short-
term treatment of insomnia, Miroprofen is a nonsteroidal anti-
inflammatory drug and Ponatinib which contains an imidazo[1,2-
b]pyridazine unit is used for the treatment of leukemia.
Therefore, the discovery of effective procedures for the direct
coupling of these two heteroarenes with aryl bromides is
important for biochemists. We first studied the reactivity of
imidazo[1,2-a]pyridine with para-substituted aryl bromides, using
1 mol% of 10% Pd/C catalyst in 3-methylbutan-1-ol. In all cases,
very high yields of the expected coupling products 50-52 were
We also studied the direct arylation of 1-methylimidazole using 1
mol% of 10% Pd/C catalyst (Scheme 5). In the course of this
reaction, both positions C2 and C5 of imidazole might have been
arylated. Using our procedure, in the presence of 2- or 4-
bromobenzonitrile in DMA, a regioselective C5-arylation was
observed, affording 42 and 44 in high yields. Moreover, good
yields of target compounds 43 and 45 were obtained using the
deactivated aryl bromide 4-bromotoluene, or a heteroarene.
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obtained. A lower yield in 53 was obtained for the reaction with
2-bromobenzonitrile in 3-methylbutan-1-ol, but the use of DMA
as solvent afforded 53 in 92% yield. 3-Bromoquinoline was
found to be very reactive in 3-methylbutan-1-ol, as 54 was
obtained in 94% yield. The reactivity of imidazo[1,2-b]pyridazine
is quite similar, as in all cases including with 2-bromobenzonitrile
and 4-bromoanisole, the desired products 55-60 were obtained
in good yields using 3-methylbutan-1-ol as the solvent.
Moreover, high yields in 55 and 56 were also obtained in DEC.
thiophenes, furans, pyrroles, imidazoles or isoxazoles using aryl
bromides as coupling partners proceeds highly regioselectively,
and in moderate to very high yields. It should be mentioned that
with several heteroarenes, both electron-deficient and electron-
rich aryl bromides were reactive under these conditions, and a
wide range of functionalities such as acetyl, propionyl, formyl,
ester, nitro, nitrile, trifluoromethyl, chloro, fluoro, methoxy or
amino on the aryl bromide is tolerated. Moreover, with the most
reactive heteroarenes, this arylation could be performed in the
“green” and renewable solvents 3-methylbutan-1-ol, pentan-1-ol
or DEC. The use of a phosphine-free heterogeneous catalyst
for such reactions reduces wastes and simplify purification
procedure, and as the major by-products of these couplings are
KBr/AcOH, this process is environmentally and economically
attractive.
Experimental Section
Typical experiment for coupling reactions: The reaction of the aryl
bromide (1 mmol), heteroaromatic (1.5 mmol) and KOAc (0.196, 2 mmol)
in the presence of 10% Pd/C (0.011 g, 1 mol%) in the appropriate solvent
(5 mL) (see schemes) under argon at 150 °C during 16 h, affords the
corresponding product after cooling, evaporation of the solvent and
filtration on silica gel (pentane/ether).
4-(5-Pentylthiophen-2-yl)benzonitrile (1)[28]
4-Bromobenzonitrile
(0.182 g, 1 mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 1 in
91% (0.232 g) yield as a colourless oil. 1H NMR (400 MHz, CDCl3): 
7.65-7.57 (m, 4H), 7.23 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 2.83
(t, J = 7.5 Hz, 2H), 1.78-1.66 (m, 2H), 1.42-1.34 (m, 4H), 0.92 (t, J = 7.5
Hz, 3H). 13C NMR (100 MHz, CDCl3):  148.4, 139.2, 138.9, 132.6,
125.6, 125.4, 124.8, 118.9, 109.8, 31.2, 30.2, 22.3, 13.9.
1-(4-(5-Pentylthiophen-2-yl)phenyl)ethan-1-one
(2)
4-
Bromoacetophenone (0.199 g, 1 mmol) and 2-pentylthiophene (0.231 g,
1.5 mmol) affords 2 in 91% (0.247 g) yield as a yellow solid: mp 94-96 °C.
1H NMR (400 MHz, CDCl3):  7.93 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz,
2H), 7.25 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 2.82 (t, J = 7.5 Hz,
2H), 2.59 (s, 3H), 1.78-1.66 (m, 2H), 1.41-1.33 (m, 4H), 0.92 (t, J = 7.5
Hz, 3H). 13C NMR (100 MHz, CDCl3):  197.2, 147.7, 140.0, 139.1,
135.2, 129.0, 125.4, 125.0, 124.3, 31.2, 30.2, 26.4, 22.3, 13.9. elemental
analysis: calcd (%) for C17H20OS (272.41): C 74.96, H 7.40; found: C
74.90, H 7.60.
Scheme 7. Pd/C catalyzed coupling of imidazo[1,2-a]pyridine and imidazo[1,2-
b]pyridazine with aryl bromides.
The mechanism of such direct arylations using Pd/C catalyst
was not elucidated.[27] In 2003, Conlon et al. reported that the
Suzuki-Miyaura reaction using heterogeneous Pd/C catalyst has
a homogeneous component due to the formation of soluble Pd-
Ethyl 4-(5-pentylthiophen-2-yl)benzoate (3) Ethyl 4-bromobenzoate
(0.229 g, 1 mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 3 in
88% (0.266 g) yield as a brown oil. 1H NMR (400 MHz, CDCl3):  8.02 (d,
J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 3.6 Hz, 1H), 6.76 (d,
J = 3.6 Hz, 1H), 4.38 (q, J = 7.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 1.78-
1.66 (m, 2H), 1.47-1.34 (m, 7H), 0.94 (t, J = 7.5 Hz, 3H). 13C NMR (100
MHz, CDCl3):  166.1, 147.3, 140.2, 138.8, 130.0, 128.4, 125.2, 124.7,
124.1, 60.7, 31.1, 30.1, 22.3, 14.2, 13.9. elemental analysis: calcd (%)
for C18H22O2S (302.43): C 71.49, H 7.33; found: C 71.40, H 6.98.
species during the reaction.[27a]
They assumed that the
desorption of palladium from Pd/C occurs after oxidative addition
of the aryl halide on the Pd/C surface, which generates a soluble
Pd(II) species. As the direct arylations reported here employ
quite similar reaction conditions, a homogeneous component in
the catalytic cycle is also possible.
2-(4-Nitrophenyl)-5-pentylthiophene (4) 4-Bromonitrobenzene (0.202
g, 1 mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 4 in 67%
(0.184 g) yield as a yellow solid: mp 60-62 °C. 1H NMR (400 MHz,
CDCl3):  8.20 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.29 (d, J =
3.6 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 1.77-1.66
(m, 2H), 1.44-1.32 (m, 4H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz,
Conclusions
In summary, we demonstrated that Pd/C is an efficient catalyst
for the direct arylation of a wide range of heteroaromatics. In the
presence 1 mol% of 10% Pd/C, the direct arylation of thiazoles,
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CDCl3):  149.3, 146.2, 141.0, 138.8, 125.9, 125.6, 125.4, 124.4, 31.2,
30.3, 22.4, 14.0. elemental analysis: calcd (%) for C15H17NO2S (275.37):
C 65.43, H 6.22; found: C 65.34, H 6.12.
J = 2.0 Hz, 1H), 8.44 (dd, J = 4.8, 1.4 Hz, 1H), 7.77 (ddd, J = 8.0, 2.2, 1.7
Hz, 1H), 7.22 (ddd, J = 8.0, 4.8, 0.6 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H),
6.75 (d, J = 3.6 Hz, 1H), 2.80 (t, J = 7.5 Hz, 2H), 1.75-1.63 (m, 2H), 1.40-
1.28 (m, 4H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): 
147.9, 147.1, 146.6, 137.6, 132.4, 130.7, 125.3, 123.9, 123.5, 31.3, 31.2,
30.2, 22.4, 14.0. elemental analysis: calcd (%) for C14H17NS (231.36): C
72.68, H 7.41; found: C 72.78, H 7.57.
2-Pentyl-5-(p-tolyl)thiophene (5) 4-Bromotoluene (0.171 g, 1 mmol)
and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 5 in 90% (0.220 g)
yield as a colourless oil. 1H NMR (400 MHz, CDCl3):  7.46 (d, J = 8.1
Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6
Hz, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.36 (s, 3H), 1.78-1.65 (m, 2H), 1.43-
1.33 (m, 4H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): 
145.1, 141.7, 136.7, 132.0, 129.4, 125.4, 124.8, 122.1, 31.4, 31.3, 30.2,
22.4, 21.1, 14.0. elemental analysis: calcd (%) for C16H20S (244.40): C
78.63, H 8.25; found: C 78.90, H 8.02.
4-(5-Butylfuran-2-yl)benzonitrile (13)[6c] 4-Bromobenzonitrile (0.182 g,
1 mmol) and 2-butylfuran (0.186 g, 1.5 mmol) affords 13 in 71% (0.160 g)
yield as a yellow solid: mp 58-60 °C. 1H NMR (400 MHz, CDCl3):  7.68
(d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 3.3 Hz, 1H), 6.11
(d, J = 3.3 Hz, 1H), 2.70 (t, J = 7.5 Hz, 2H), 1.67 (quint., J = 7.5 Hz, 2H),
1.43 (sext., J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz,
CDCl3):  158.5, 150.1, 134.9, 132.5, 123.3, 119.1, 109.4, 109.1, 107.6,
30.0, 27.9, 22.2, 13.4.
2-(4-Methoxyphenyl)-5-pentylthiophene (6)[29] 4-Bromoanisole (0.187
g, 1 mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 6 in 76%
(0.198 g) yield as a white solid: mp 62-64 °C. 1H NMR (400 MHz,
CDCl3):  7.49 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 3.6 Hz, 1H), 6.90 (d, J =
8.4 Hz, 2H), 6.73 (d, J = 3.6 Hz, 1H), 3.83 (s, 3H), 2.82 (t, J = 7.5 Hz, 2H),
1.77-1.66 (m, 2H), 1.44-1.32 (m, 4H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR
(100 MHz, CDCl3):  159.5, 145.4, 142.2, 128.4, 127.4, 125.5, 122.3,
114.9, 56.0, 32.0, 30.9, 23.1, 14.7.
1-(4-(5-Butylfuran-2-yl)phenyl)ethan-1-one
(14)[15a]
4-
Bromoacetophenone (0.199 g, 1 mmol) and 2-butylfuran (0.186 g, 1.5
mmol) affords 14 in 82% (0.198 g) yield as a white solid: mp 43-45 °C.
1H NMR (400 MHz, CDCl3):  7.94 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz,
2H), 6.70 (d, J = 3.3 Hz, 1H), 6.10 (d, J = 3.3 Hz, 1H), 2.70 (t, J = 7.5 Hz,
2H), 2.59 (s, 3H), 1.67 (quint., J = 7.5 Hz, 2H), 1.43 (sext., J = 7.5 Hz,
2H), 0.96 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):  197.3, 158.0,
150.9, 135.2, 134.9, 128.9, 122.9, 108.4, 107.4, 30.1, 27.9, 26.4, 22.2.
2-(5-Pentylthiophen-2-yl)benzonitrile (7) 2-Bromobenzonitrile (0.182 g,
1 mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 7 in 93%
(0.237 g) yield as a colourless oil. 1H NMR (400 MHz, CDCl3):  7.71 (dd,
J = 8.0, 0.8 Hz, 1H), 7.65-7.53 (m, 2H), 7.51 (d, J = 3.6 Hz, 1H), 7.33 (td,
J = 8.0, 1.7 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 2.86 (t, J = 7.5 Hz, 2H),
1.79-1.67 (m, 2H), 1.47-1.34 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H). 13C NMR
(100 MHz, CDCl3):  148.4, 137.7, 136.5, 134.2, 132.7, 129.1, 127.3,
126.8, 125.2, 119.0, 109.2, 31.2, 31.1, 30.0, 22.3, 13.9. elemental
analysis: calcd (%) for C16H17NS (255.38): C 75.25, H 6.71; found: C
75.08, H 6.98.
2-Butyl-5-(p-tolyl)furan (15)[6a] 4-Bromotoluene (0.171 g, 1 mmol) and
2-butylfuran (0.186 g, 1.5 mmol) affords 15 in 67% (0.143 g) yield as a
yellow oil. 1H NMR (400 MHz, CDCl3):  7.53 (d, J = 8.1 Hz, 2H), 7.17 (d,
J = 8.1 Hz, 2H), 6.48 (d, J = 3.3 Hz, 1H), 6.04 (d, J = 3.3 Hz, 1H), 2.70 (t,
J = 7.5 Hz, 2H), 2.36 (s, 3H), 1.67 (quint., J = 7.5 Hz, 2H), 1.43 (sext., J =
7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H).
2-(5-Butylfuran-2-yl)benzonitrile (16)[6c] 2-Bromobenzonitrile (0.182 g,
1 mmol) and 2-butylfuran (0.186 g, 1.5 mmol) affords 16 in 88% (0.198 g)
yield as a yellow oil. 1H NMR (400 MHz, CDCl3):  7.82 (d, J = 8.6 Hz,
1H), 7.64 (d, J = 8.6 Hz, 1H), 7.55 (td, J = 7.8, 1.3 Hz, 1H), 7.24 (td, J =
7.8, 1.1 Hz, 1H), 7.20 (d, J = 3.3 Hz, 1H), 6.15 (d, J = 3.3 Hz, 1H), 2.71 (t,
J = 7.5 Hz, 2H), 1.67 (quint., J = 7.5 Hz, 2H), 1.43 (sext., J = 7.5 Hz, 2H),
0.96 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):  157.9, 147.9,
134.0, 133.4, 132.7, 126.3, 125.3, 119.1, 111.3, 107.6, 106.0, 29.9, 27.7,
22.2, 13.7.
5-(4-Cyanophenyl)thiophene-2-carbonitrile (8)[17] 4-Bromobenzonitrile
(0.182 g, 1 mmol) and 2-thiophenecarbonitrile (0.164 g, 1.5 mmol)
affords 8 in 87% (0.183 g) yield as a yellow solid: mp 212-214 °C. 1H
NMR (400 MHz, CDCl3):  7.73 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz,
2H), 7.63 (d, J = 3.9 Hz, 1H), 7.39 (d, J = 3.9 Hz, 1H).
5-(4-Acetylphenyl)thiophene-2-carbonitrile
(9)[17]
4-
Bromoacetophenone (0.199 g, 1 mmol) and 2-thiophenecarbonitrile
(0.164 g, 1.5 mmol) affords 9 in 90% (0.204 g) yield as a yellow solid: mp
162-164 °C. 1H NMR (400 MHz, CDCl3):  8.01 (d, J = 8.5 Hz, 2H), 7.69
7.93 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 3.9 Hz, 1H), 7.39 (d, J = 3.9 Hz, 1H),
2.62 (s, 3H).
3-(5-Butylfuran-2-yl)pyridine (17)[6c]
3-Bromopyridine (0.158 g, 1
mmol) and 2-butylfuran (0.186 g, 1.5 mmol) affords 17 in 79% (0.159 g)
yield as a yellow oil. 1H NMR (400 MHz, CDCl3):  8.87 (s, 1H), 8.42 (d,
J = 4.8 Hz, 1H), 7.86 (dd, J = 8.0, 2.2 Hz, 1H), 7.24 (dd, J = 8.0, 4.8 Hz,
1H), 6.61 (d, J = 3.3 Hz, 1H), 6.07 (d, J = 3.3 Hz, 1H), 2.68 (t, J = 7.5 Hz,
2H), 1.67 (quint., J = 7.5 Hz, 2H), 1.40 (sext., J = 7.5 Hz, 2H), 0.94 (t, J =
7.5 Hz, 3H).
4-(5-Acetylthiophen-2-yl)benzonitrile (10)[17]
4-Bromobenzonitrile
(0.182 g, 1 mmol) and 2-acetylthiophene (0.189 g, 1.5 mmol) affords 10
in 79% (0.179 g) yield as a yellow solid: mp 166-168 °C. 1H NMR (400
MHz, CDCl3):  7.72 (d, J = 8.5 Hz, 2H), 7.70-7.65 (m, 3H), 7.40 (d, J =
3.9 Hz, 1H), 2.57 (s, 3H).
4-(2-Ethylbenzofuran-3-yl)benzonitrile (18)[6d]
4-Bromobenzonitrile
(0.182 g, 1 mmol) and 2-ethylbenzofuran (0.219 g, 1.5 mmol) affords 18
in 83% (0.205 g) yield as a white solid: mp 114-116 °C. 1H NMR (400
MHz, CDCl3):  7.77 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.53 (d,
J = 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.26 (t,
J = 8.0 Hz, 1H), 2.90 (q, J = 7.5 Hz, 2H), 1.38 (t, J = 7.5 Hz, 3H). 13C
NMR (100 MHz, CDCl3):  157.2, 154.0, 138.0, 132.5, 129.4, 127.8,
124.1, 123.0, 119.0, 118.8, 114.9, 111.1, 110.5, 20.3, 12.8.
Ethyl
5-(4-cyanophenyl)thiophene-2-carboxylate
(11)[8d]
4-
Bromobenzonitrile (0.182 g, 1 mmol) and ethyl thiophene-2-carboxylate
(0.234 g, 1.5 mmol) affords 11 in 84% (0.216 g) yield as a yellow solid:
mp 134-136 °C. 1H NMR (400 MHz, CDCl3):  7.77 (d, J = 3.9 Hz, 1H),
7.72 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 3.9 Hz, 1H),
4.37 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H).
4-(1-Methylpyrrol-2-yl)benzonitrile (19)[7c] 4-Bromobenzonitrile (0.182
g, 1 mmol) and N-methylpyrrole (0.324 g, 4 mmol) affords 19 in 84%
(0.153 g) yield as a white solid: mp 102-104 °C. 1H NMR (400 MHz,
3-(5-Pentylthiophen-2-yl)pyridine (12) 3-Brompyridine (0.158 g, 1
mmol) and 2-pentylthiophene (0.231 g, 1.5 mmol) affords 12 in 90%
(0.208 g) yield as a colourless oil. 1H NMR (400 MHz, CDCl3):  8.81 (d,
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
CDCl3):  7.70 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 6.82 (t, J =
2.2 Hz, 1H), 6.38 (dd, J = 3.6, 1.7 Hz, 1H), 6.27 (dd, J = 3.6, 2.6 Hz, 1H),
3.75 (s, 3H).
2-Isopropyl-4-methyl-5-(4-nitrophenyl)thiazole
(27)
4-
Bromonitrobenzene (0.202 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 27 in 96% (0.251 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  8.24 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz,
2H), 3.28 (sept., J = 7.5 Hz, 1H), 2.51 (s, 3H), 1.42 (d, J = 7.5 Hz, 6H).
13C NMR (100 MHz, CDCl3):  177.0, 148.9, 146.5, 139.4, 129.3, 128.2,
123.8, 33.3, 23.0, 16.5. elemental analysis: calcd (%) for C13H14N2O2S
(262.33): C 59.52, H 5.38; found: C 59.60, H 5.49.
Ethyl 4-(1-methylpyrrol-2-yl)benzoate (20)[30] Ethyl 4-bromobenzoate
(0.229 g, 1 mmol) and N-methylpyrrole (0.324 g, 4 mmol) affords 20 in
76% (0.174 g) yield as a yellow solid: mp 61-63 °C. 1H NMR (400 MHz,
CDCl3):  8.11 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 6.79 (t, J =
2.2 Hz, 1H), 6.38 (dd, J = 3.6, 1.7 Hz, 1H), 6.26 (dd, J = 3.6, 2.6 Hz, 1H),
4.43 (q, J = 7.6 Hz, 2H), 3.74 (s, 3H), 1.45 (t, J = 7.6 Hz, 3H).
5-(4-Fluorophenyl)-2-isopropyl-4-methylthiazole
(28)
4-
Fluorobromobenzene (0.175 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.211 g, 1.5 mmol) affords 28 in 97% (0.228 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  7.36 (dd, J = 8.6, 5.3 Hz, 2H), 7.07 (t, J = 8.6
Hz, 2H), 3.27 (sept., J = 7.5 Hz, 1H), 2.42 (s, 3H), 1.40 (d, J = 7.5 Hz,
6H). 13C NMR (100 MHz, CDCl3):  175.3, 162.1 (d, J = 247.8 Hz), 146.9,
130.8 (d, J = 8.1 Hz), 129.3, 128.5 (d, J = 3.5 Hz), 115.6 (d, J = 21.8 Hz),
33.3, 23.2, 15.9. elemental analysis: calcd (%) for C13H14FNS (235.32):
C 66.35, H 6.00; found: C 66.20, H 5.74.
1-Methyl-2-(p-tolyl)pyrrole (21)[7c] 4-Bromotoluene (0.171 g, 1 mmol)
and N-methylpyrrole (0.324 g, 4 mmol) affords 21 in 52% (0.089 g) yield
as a yellow oil. 1H NMR (400 MHz, CDCl3):  7.30 (d, J = 8.3 Hz, 2H),
7.21 (d, J = 8.3 Hz, 2H), 6.70 (t, J = 2.2 Hz, 1H), 6.22-6.18 (m, 2H), 3.65
(s, 3H), 2.38 (s, 3H).
2-(1-Methylpyrrol-2-yl)benzonitrile (22)[7c] 2-Bromobenzonitrile (0.182
g, 1 mmol) and N-methylpyrrole (0.324 g, 4 mmol) affords 22 in 87%
(0.158 g) yield as a white solid: mp 94-96 °C. 1H NMR (400 MHz,
CDCl3):  7.74 (d, J = 7.8 Hz, 1H), 7.61 (td, J = 7.8, 1.4 Hz, 1H), 7.44 (d,
J = 7.8 Hz, 1H), 7.40 (td, J = 8.5, 1.2 Hz, 1H), 6.80 (t, J = 2.2 Hz, 1H),
6.42 (dd, J = 3.6, 1.7 Hz, 1H), 6.26 (dd, J = 3.6, 2.6 Hz, 1H), 3.62 (s, 3H).
2-Isopropyl-4-methyl-5-(p-tolyl)thiazole (29) 4-Bromotoluene (0.171 g,
1 mmol) and 2-isopropyl-4-methylthiazole (0.211 g, 1.5 mmol) affords 29
in 92% (0.212 g) yield as a yellow oil. 1H NMR (400 MHz, CDCl3):  7.31
(d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 3.27 (sept., J = 7.5 Hz, 1H),
2.46 (s, 3H), 2.38 (s, 3H), 1.41 (d, J = 7.5 Hz, 6H). 13C NMR (100 MHz,
CDCl3):  174.8, 146.4, 137.2, 130.4, 129.5, 129.2, 128.9, 33.3, 23.2,
21.1, 16.0. elemental analysis: calcd (%) for C14H17NS (231.36): C 72.68,
H 7.41; found: C 72.64, H 7.32.
4-(2-Isopropyl-4-methylthiazol-5-yl)benzonitrile
(23)
4-
Bromobenzonitrile (0.182 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 23 in 97% (0.234 g) yield as a white solid: mp
58-60 °C. 1H NMR (400 MHz, CDCl3):  7.70 (d, J = 8.5 Hz, 2H), 7.53 (d,
J = 8.5 Hz, 2H), 3.30 (sept., J = 7.5 Hz, 1H), 2.50 (s, 3H), 1.42 (d, J = 7.5
Hz, 6H). 13C NMR (100 MHz, CDCl3):  176.8, 148.5, 137.4, 132.3,
129.4, 128.6, 118.5, 110.8, 33.4, 23.1, 16.4. elemental analysis: calcd
(%) for C14H14N2S (242.34): C 69.39, H 5.82; found: C 69.14, H 5.78.
5-(4-(tert-Butyl)phenyl)-2-isopropyl-4-methylthiazole (30)
4-tert-
Butylbromobenzene (0.213 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.211 g, 1.5 mmol) affords 30 in 89% (0.243 g) yield as a colourless oil.
1H NMR (400 MHz, CDCl3):  7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.1 Hz,
2H), 3.28 (sept., J = 7.5 Hz, 1H), 2.47 (s, 3H), 1.41 (d, J = 7.5 Hz, 6H),
1.35 (s, 9H). 13C NMR (100 MHz, CDCl3):  174.9, 150.4, 146.5, 130.4,
129.6, 128.8, 125.5, 34.6, 33.3, 31.2, 23.2, 16.1. elemental analysis:
calcd (%) for C17H23NS (273.44): C 74.67, H 8.48; found: C 74.81, H 8.31.
4-(2-Isopropyl-4-methylthiazol-5-yl)benzaldehyde
(24)
4-
Bromobenzaldehyde (0.185 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 24 in 94% (0.230 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  9.98 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.54 (d,
J = 8.5 Hz, 2H), 3.25 (sept., J = 7.5 Hz, 1H), 2.48 (s, 3H), 1.38 (d, J = 7.5
Hz, 6H). 13C NMR (100 MHz, CDCl3):  191.3, 176.5, 148.3, 138.8,
134.9, 129.9, 129.2, 129.1, 33.3, 23.0, 16.4. elemental analysis: calcd
(%) for C14H15NOS (245.34): C 68.54, H 6.16; found: C 68.30, H 6.01.
2-Isopropyl-5-(4-methoxyphenyl)-4-methylthiazole
(31)
4-
Bromoanisole (0.187 g, 1 mmol) and 2-isopropyl-4-methylthiazole (0.211
g, 1.5 mmol) affords 31 in 72% (0.178 g) yield as a colourless oil. 1H
NMR (400 MHz, CDCl3):  7.33 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz,
2H), 3.84 (s, 3H), 3.25 (sept., J = 7.5 Hz, 1H), 2.43 (s, 3H), 1.40 (d, J =
7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):  174.7, 159.0, 146.2, 130.4,
130.2, 124.8, 114.0, 55.3, 33.3, 23.2, 16.0. elemental analysis: calcd (%)
for C14H17NOS (247.36): C 67.98, H 6.93; found: C 68.12, H 6.78.
1-(4-(2-Isopropyl-4-methylthiazol-5-yl)phenyl)ethan-1-one (25)
4-
Bromoacetophenone (0.199 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 25 in 97% (0.251 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  7.96 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz,
2H), 3.27 (sept., J = 7.5 Hz, 1H), 2.59 (s, 3H), 2.48 (s, 3H), 1.39 (d, J =
7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):  197.2, 176.3, 148.0, 137.4,
135.7, 129.3, 128.9, 128.6, 33.3, 26.5, 23.1, 16.4. elemental analysis:
calcd (%) for C14H17NOS (259.37): C 69.46, H 6.61; found: C 69.38, H
6.40.
4-(2-Isopropyl-4-methylthiazol-5-yl)-N,N-dimethylaniline (32)
4-
Bromo-N,N-dimethylaniline (0.200 g, mmol) and 2-isopropyl-4-
1
methylthiazole (0.211 g, 1.5 mmol) affords 32 in 78% (0.203 g) yield as a
yellow oil. 1H NMR (400 MHz, CDCl3):  7.29 (d, J = 8.3 Hz, 2H), 6.74 (d,
J = 8.3 Hz, 2H), 3.27 (sept., J = 7.5 Hz, 1H), 2.99 (s, 6H), 2.45 (s, 3H),
1.40 (d, J = 7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):  174.0, 149.8,
145.5, 131.1, 130.0, 120.2, 112.2, 40.4, 33.3, 23.3, 16.1. elemental
analysis: calcd (%) for C15H20N2S (260.40): C 69.19, H 7.74; found: C
69.00, H 7.88.
Ethyl 4-(2-isopropyl-4-methylthiazol-5-yl)benzoate (26)
Ethyl 4-
bromobenzoate (0.229 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 26 in 95% (0.274 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  8.05 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz,
2H), 4.37 (q, J = 7.5 Hz, 2H), 3.25 (sept., J = 7.5 Hz, 1H), 2.48 (s, 3H),
1.43-1.35 (m, 9H). 13C NMR (100 MHz, CDCl3):  176.0, 166.0, 147.8,
137.1, 129.7, 129.4, 129.1, 128.7, 60.9, 33.3, 23.0, 16.3, 14.2. elemental
analysis: calcd (%) for C16H19NO2S (289.39): C 66.41, H 6.62; found: C
66.58, H 6.45.
5-(3,5-Bis(trifluoromethyl)phenyl)-2-isopropyl-4-methylthiazole (33)
3,5-Bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and 2-isopropyl-
4-methylthiazole (0.211 g, 1.5 mmol) affords 33 in 96% (0.339 g) yield as
a colourless oil. 1H NMR (400 MHz, CDCl3):  7.87 (s, 2H), 7.85 (s, 1H),
3.33 (sept., J = 7.5 Hz, 1H), 2.51 (s, 3H), 1.45 (d, J = 7.5 Hz, 6H). 13C
NMR (100 MHz, CDCl3):  177.1, 148.9, 135.0, 132.0 (q, J = 33.5 Hz),
129.0 (m), 127.3, 123.1 (q, J = 273.0 Hz), 121.0 (m), 33.5, 23.1, 16.1.
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10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
elemental analysis: calcd (%) for C15H13F6NS (353.33): C 50.99, H 3.71;
found: C 51.20, H 3.64.
elemental analysis: calcd (%) for C16H16N2S (268.38): C 71.61, H 6.01;
found: C 71.42, H 5.88.
2-(2-Isopropyl-4-methylthiazol-5-yl)benzonitrile
(34)
2-
4-(2-Ethyl-4-methylthiazol-5-yl)benzonitrile
(40)[8a]
4-
Bromobenzonitrile (0.182 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 34 in 94% (0.227 g) yield as a colourless oil.
1H NMR (400 MHz, CDCl3):  7.73 (dd, J = 7.8, 1.4 Hz, 1H), 7.60 (td, J =
7.8, 1.4 Hz, 1H), 7.48-7.42 (m, 2H), 3.28 (sept., J = 7.5 Hz, 1H), 2.34 (s,
3H), 1.40 (d, J = 7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):  177.2,
149.9, 136.1, 133.3, 132.5, 131.8, 128.3, 125.5, 117.7, 113.5, 33.3, 23.0,
16.0. elemental analysis: calcd (%) for C14H14N2S (242.34): C 69.39, H
5.82; found: C 69.50, H 5.98.
Bromobenzonitrile (0.182 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.190
g, 1.5 mmol) affords 40 in 96% (0.219 g) yield as a white solid: mp 54-
56 °C. 1H NMR (400 MHz, CDCl3):  7.71 (d, J = 8.5 Hz, 2H), 7.54 (d, J
= 8.5 Hz, 2H), 3.04 (q, J = 7.5 Hz, 2H), 2.51 (s, 3H), 1.43 (t, J = 7.5 Hz,
3H).
1-(4-(2-Ethyl-4-methylthiazol-5-yl)phenyl)propan-1-one (41)
4-
Bromopropiophenone (0.213 g, 1 mmol) and 2-ethyl-4-methylthiazole
(0.190 g, 1.5 mmol) affords 41 in 96% (0.248 g) yield as a colourless oil.
1H NMR (400 MHz, CDCl3):  7.97 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz,
2H), 2.98 (q, J = 7.5 Hz, 4H), 2.47 (s, 3H), 1.38 (t, J = 7.5 Hz, 3H), 1.22 (t,
J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3):  199.9, 171.1, 148.0,
137.0, 135.5, 129.8, 128.9, 128.3, 31.7, 26.9, 16.3, 14.2, 8.2. elemental
analysis: calcd (%) for C15H17NOS (259.37): C 69.46, H 6.61; found: C
69.60, H 6.51.
2-Isopropyl-4-methyl-5-(4-nitrophenyl)thiazole
(35)
2-
Bromonitrobenzene (0.202 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.212 g, 1.5 mmol) affords 35 in 66% (0.173 g) yield as a yellow oil. 1H
NMR (400 MHz, CDCl3):  7.94 (dd, J = 8.1, 1.2 Hz, 1H), 7.61 (td, J = 7.5,
1.3 Hz, 1H), 7.54 (td, J = 7.5, 1.3 Hz, 1H), 7.44 (dd, J = 8.0, 1.3 Hz, 1H),
3.29 (sept., J = 7.5 Hz, 1H), 2.21 (s, 3H), 1.41 (d, J = 7.5 Hz, 6H). 13C
NMR (100 MHz, CDCl3):  177.1, 150.0, 149.5, 133.6, 132.4, 129.3,
126.9, 124.4, 123.9, 33.3, 23.1, 15.5. elemental analysis: calcd (%) for
C13H14N2O2S (262.33): C 59.52, H 5.38; found: C 59.47, H 5.20.
4-(1-Methylimidazol-5-yl)benzonitrile (42)[9e]
4-Bromobenzonitrile
(0.182 g, 1 mmol) and 1-methylimidazole (0.123 g, 1.5 mmol) affords 42
in 84% (0.154 g) yield as a white solid: mp 146-148 °C. 1H NMR (400
MHz, CDCl3):  7.70 (d, J = 8.4 Hz, 2H), 7.56 (bs, 1H), 7.50 (d, J = 8.4 Hz,
2H), 7.20 (bs, 1H), 3.71 (s, 3H).
2-Isopropyl-4-methyl-5-(2-(trifluoromethyl)phenyl)thiazole (36)
2-
(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 2-isopropyl-4-
methylthiazole (0.212 g, 1.5 mmol) affords 36 in 87% (0.248 g) yield as a
colourless oil. 1H NMR (400 MHz, CDCl3):  7.72 (d, J = 7.5 Hz, 1H),
7.52 (t, J = 7.5 Hz, 1H), 746 (td, J = 7.5 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H),
3.27 (sept., J = 7.5 Hz, 1H), 2.14 (s, 3H), 1.39 (d, J = 7.5 Hz, 6H). 13C
NMR (100 MHz, CDCl3):  176.5, 149.6, 133.7, 131.4, 131.1, 130.6 (q, J
= 29.8 Hz), 128.7, 126.2 (q, J = 5.3 Hz), 125.4, 123.6 (q, J = 273.8 Hz),
33.2, 23.1, 15.5. elemental analysis: calcd (%) for C14H14F3NS (285.33):
C 58.93, H 4.95; found: C 58.99, H 4.20.
1-Methyl-5-(p-tolyl)imidazole (43)[9e] 4-Bromotoluene (0.171 g, 1 mmol)
and 1-methylimidazole (0.123 g, 1.5 mmol) affords 43 in 73% (0.125 g)
yield as a white solid: mp 40-42 °C. 1H NMR (400 MHz, CDCl3):  7.31
(d, J = 8.1 Hz, 2H), 7.53 (bs, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.09 (bs, 1H),
3.67 (s, 3H), 2.42 (s, 3H).
2-(1-Methylimidazol-5-yl)benzonitrile (44) 2-Bromobenzonitrile (0.182
g, 1 mmol) and 1-methylimidazole (0.123 g, 1.5 mmol) affords 44 in 82%
(0.150 g) yield as a white solid: mp 156-158 °C. 1H NMR (400 MHz,
CDCl3):  7.71 (d, J = 8.4 Hz, 1H), 7.61 (td, J = 7.8, 1.3 Hz, 1H), 7.52 (bs,
1H), 7.44 (td, J = 7.8, 1.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.16 (bs, 1H),
3.56 (s, 3H). 13C NMR (100 MHz, CDCl3):  139.8, 133.6, 133.2, 132.9,
131.0, 130.3, 129.3, 128.8, 117.9, 113.0, 32.3. elemental analysis: calcd
(%) for C11H9N3 (183.21): C 72.11, H 4.95; found: C 72.00, H 4.87.
5-(2-Fluorophenyl)-2-isopropyl-4-methylthiazole
(37)
2-
Fluorobromobenzene (0.175 g, 1 mmol) and 2-isopropyl-4-methylthiazole
(0.211 g, 1.5 mmol) affords 37 in 93% (0.218 g) yield as a colourless oil.
1H NMR (400 MHz, CDCl3):  7.38-7.30 (m, 2H), 7.20-7.12 (m, 2H), 3.31
(sept., J = 7.5 Hz, 1H), 2.36 (s, 3H), 1.42 (d, J = 7.5 Hz, 6H). 13C NMR
(100 MHz, CDCl3):  176.9, 159.7 (d, J = 248.8 Hz), 149.2, 132.1 (d, J =
2.6 Hz), 129.8 (d, J = 8.1 Hz), 124.1 (d, J = 3.8 Hz), 123.0, 120.0 (d, J =
15.3 Hz), 116.0 (d, J = 22.2 Hz), 33.3, 23.2, 15.9 (d, J = 2.8 Hz).
elemental analysis: calcd (%) for C13H14FNS (235.32): C 66.35, H 6.00;
found: C 66.54, H 5.78.
3-(1-Methylimidazol-5-yl)pyridine (45)[9e] 3-Bromopyridine (0.158 g, 1
mmol) and 1-methylimidazole (0.123 g, 1.5 mmol) affords 45 in 80%
(0.127 g) yield as a white solid: mp 124-126 °C. 1H NMR (400 MHz,
CDCl3):  8.70 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 1.4 Hz, 1H), 7.72 (dt,
J = 8.0, 1.9 Hz, 1H), 7.59 (bs, 1H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H), 7.19
(bs, 1H), 3.71 (s, 3H).
2-Isopropyl-4-methyl-5-(pyridin-3-yl)thiazole (38)
3-Bromopyridine
(0.158 g, 1 mmol) and 2-isopropyl-4-methylthiazole (0.211 g, 1.5 mmol)
affords 38 in 95% (0.207 g) yield as a colourless oil. 1H NMR (400 MHz,
CDCl3):  8.68 (bs, 1H), 8.55 (bs, 1H), 7.70 (dd, J = 7.9, 1.5 Hz, 1H), 7.32
(dd, J = 7.7, 5.0 Hz, 1H), 3.25 (sept., J = 7.5 Hz, 1H), 2.45 (s, 3H), 1.40
(d, J = 7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):  176.4, 146.6, 148.4,
148.2, 136.1, 128.8, 126.5, 123.3, 33.4, 23.1, 16.0. elemental analysis:
calcd (%) for C12H14N2S (218.32): C 66.02, H 6.46; found: C 65.87, H
6.34.
4-(3,5-Dimethylisoxazol-4-yl)benzonitrile (46)[10] 4-Bromobenzonitrile
(0.182 g, 1 mmol) and 3,5-dimethylisoxazole (0.144 g, 1.5 mmol) affords
46 in 93% (0.184 g) yield as a white solid: mp 113-115 °C. 1H NMR (400
MHz, CDCl3):  7.73 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 2.42 (s,
3H), 2.27 (s, 3H).
Ethyl 4-(3,5-dimethylisoxazol-4-yl)benzoate (47)[31]
Ethyl 4-
2-Isopropyl-4-methyl-5-(quinolin-3-yl)thiazole (39) 3-Bromoquinoline
(0.208 g, 1 mmol) and 2-isopropyl-4-methylthiazole (0.211 g, 1.5 mmol)
affords 39 in 96% (0.257 g) yield as a yellow oil. 1H NMR (400 MHz,
CDCl3):  8.99 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.12 (d, J =
8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.57 (t, J =
8.0 Hz, 1H), 3.30 (sept., J = 7.5 Hz, 1H), 2.54 (s, 3H), 1.44 (d, J = 7.5 Hz,
6H). 13C NMR (100 MHz, CDCl3):  176.4, 150.6, 148.4, 147.0, 135.1,
129.6, 129.2, 127.7, 127.5, 127.2, 126.7, 125.9, 33.4, 23.1, 16.1.
bromobenzoate (0.229 g, 1 mmol) and 3,5-dimethylisoxazole (0.144 g,
1.5 mmol) affords 47 in 92% (0.225 g) yield as a white solid: mp 68-70 °C.
1H NMR (400 MHz, CDCl3):  8.09 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz,
2H), 4.38 (q, J = 7.6 Hz, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.38 (t, J = 7.6
Hz, 3H). 13C NMR (100 MHz, CDCl3):  166.0, 165.6, 158.2, 135.1,
129.9, 129.5, 128.8, 115.9, 61.0, 14.2, 11.5, 10.7.
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
4-(4-Methoxyphenyl)-3,5-dimethylisoxazole (48)[10] 4-Bromoanisole
(0.187 g, 1 mmol) and 3,5-dimethylisoxazole (0.144 g, 1.5 mmol) affords
48 in 75% (0.152 g) yield as a colourless oil. 1H NMR (400 MHz, CDCl3):
 7.17 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H), 2.38 (s,
3H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3):  164.8, 159.0, 158.8,
130.3, 122.6, 116.2, 114.2, 55.3, 11.5, 10.8.
3-(4-Chlorophenyl)imidazo[1,2-b]pyridazine
(57)[15b]
4-
Bromochlorobenzene (0.191 g, 1 mmol) and imidazo[1,2-b]pyridazine
(0.178 g, 1.5 mmol) affords 57 in 93% (0.213 g) yield as a yellow solid:
mp 144-146 °C. 1H NMR (400 MHz, CDCl3):  8.47 (d, J = 4.0 Hz, 1H),
8.13 (d, J = 9.0 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.48 (d, J
= 8.5 Hz, 2H), 7.15 (dd, J = 9.0, 4.0 Hz, 1H).
2-(3,5-Dimethylisoxazol-4-yl)benzonitrile (49)[10] 2-Bromobenzonitrile
(0.182 g, 1 mmol) and 3,5-dimethylisoxazole (0.144 g, 1.5 mmol) affords
49 in 91% (0.180 g) yield as a white solid: mp 115-117 °C. 1H NMR (400
MHz, CDCl3):  7.76 (d, J = 7.8 Hz, 1H), 7.66 (td, J = 7.9, 1.4 Hz, 1H),
7.49 (td, J = 8.5, 1.2 Hz, 1H),7.32 (d, J = 7.8 Hz, 1H), 2.35 (s, 3H), 2.19
(s, 3H).
3-(4-Methoxyphenyl)imidazo[1,2-b]pyridazine (58)[15b] 4-Bromoanisole
(0.187 g, 1 mmol) and imidazo[1,2-b]pyridazine (0.178 g, 1.5 mmol)
affords 58 in 90% (0.202 g) yield as a yellow solid: mp 76-78 °C. 1H
NMR (400 MHz, CDCl3):  8.37 (dd, J = 4.4, 1.4 Hz, 1H), 8.00 (dd, J =
9.1, 1.4 Hz, 1H), 7.98-7.92 (m, 3H), 7.06-6.98 (m, 3H), 3.85 (s, 3H).
2-(Imidazo[1,2-b]pyridazin-3-yl)benzonitrile
(59)[15b]
2-
4-(Imidazo[1,2-a]pyridin-3-yl)benzonitrile (50)[9f] 4-Bromobenzonitrile
(0.182 g, 1 mmol) and imidazo[1,2-a]pyridine (0.177 g, 1.5 mmol) affords
50 in 94% (0.206 g) yield as a yellow solid: mp 175-177 °C. 1H NMR
(400 MHz, CDCl3):  8.38 (d, J = 6.8 Hz, 1H), 7.84-7.72 (m, 4H), 7.69 (d,
J = 8.2 Hz, 2H), 7.29 (dd, J = 8.6, 6.8 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H).
Bromobenzonitrile (0.182 g, 1 mmol) and imidazo[1,2-b]pyridazine (0.178
g, 1.5 mmol) affords 59 in 96% (0.211 g) yield as a yellow solid: mp 214-
216 °C. 1H NMR (400 MHz, CDCl3):  8.47 (dd, J = 4.2, 1.0 Hz, 1H),
8.23 (s, 1H), 8.18 (dd, J = 9.2, 1.3 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.86
(dd, J = 7.8, 1.0 Hz, 1H), 7.75 (td, J = 7.8, 1.3 Hz, 1H), 7.54 (t, J = 7.7,
1.0 Hz, 1H), 7.23 (dd, J = 9.2, 4.2 Hz, 1H).
1-(4-(Imidazo[1,2-a]pyridin-3-yl)phenyl)ethan-1-one
(51)[9f]
4-
Bromoacetophenone (0.199 g, mmol) and imidazo[1,2-a]pyridine
1
3-(Pyridin-3-yl)imidazo[1,2-b]pyridazine (60)[15b]
3-Bromopyridine
(0.177 g, 1.5 mmol) affords 51 in 96% (0.226 g) yield as a yellow solid:
mp 160-162 °C. 1H NMR (400 MHz, CDCl3):  8.35 (d, J = 6.9 Hz, 1H),
8.04 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.70-7.60 (m, 3H), 7.19 (t, J = 7.2
Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H). 2.59 (s, 3H).
(0.158 g, 1 mmol) and imidazo[1,2-b]pyridazine (0.178 g, 1.5 mmol)
affords 60 in 88% (0.172 g) yield as a yellow solid: mp 112-114 °C. 1H
NMR (400 MHz, CDCl3):  9.23 (d, J = 1.8 Hz, 1H), 8.58 (dd, J = 4.8, 1.4
Hz, 1H), 8.46-8.36 (m, 2H), 8.10 (s, 1H), 8.02 (dd, J = 7.2, 1.6 Hz, 1H),
7.39 (dd, J = 8.0, 4.8 Hz, 1H), 7.09 (dd, J = 9.2, 4.4 Hz, 1H).
3-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (52)[9f]
4-Bromoanisole
(0.187 g, 1 mmol) and imidazo[1,2-a]pyridine (0.177 g, 1.5 mmol) affords
52 in 93% (0.208 g) yield as a white solid: mp 85-87 °C. 1H NMR (400
MHz, CDCl3):  8.24 (d, J = 6.8 Hz, 1H), 7.68-7.60 (m, 2H), 7.45 (d, J =
8.8 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0Hz, 2H), 6.76 (t, J =
6.8 Hz, 1H), 3.85 (s, 3H).
Acknowledgments
We thank CNRS and ANR for financial support.
2-(Imidazo[1,2-a]pyridin-3-yl)benzonitrile (53)[9f] 2-Bromobenzonitrile
(0.182 g, 1 mmol) and imidazo[1,2-a]pyridine (0.177 g, 1.5 mmol) affords
53 in 92% (0.201 g) yield as a white solid: mp 148-150 °C. 1H NMR (400
MHz, acetone-d6):  8.35 (d, J = 6.8 Hz, 1H), 7.99 (dd, J = 7.8, 0.8 Hz,
1H), 7.92-7.80 (m, 3H), 7.71-7.62 (m, 2H), 7.36 (ddd, J = 8.6, 6.8, 1.1 Hz,
1H), 6.99 (td, J = 6.8, 0.9 Hz, 1H).
Keywords: Palladium • Heterogeneous catalysis • Direct
arylation • C-H bond activation • Atom economy • Green solvents
[1]
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A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji, T.
Nakata, N. Tani, Y. Aoyagi, Heterocycles 1990, 31, 1951-1958.
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3-Bromoquinoline
(0.208 g, 1 mmol) and imidazo[1,2-a]pyridine (0.177 g, 1.5 mmol) affords
54 in 94% (0.230 g) yield as a yellow solid: mp 146-148 °C. 1H NMR
(400 MHz, CDCl3):  9.12 (d, J = 2.1 Hz, 1H), 8.38 (dt, J = 7.0, 1.0 Hz,
1H), 8.32 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.3 Hz,
1H), 7.86 (s, 1H), 7.80-7.70 (m, 2H), 7.61 (td, J = 7.0, 1.1, 1H), 7.27 (ddd,
J = 8.6, 6.8, 1.1 Hz, 1H), 6.87 (td, J = 6.8, 0.9 Hz, 1H).
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(55)[15b]
4-
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L. Ackermann, Modern arylation methods, Eds.: Wiley Online Library,
2009.
Bromobenzonitrile (0.182 g, 1 mmol) and imidazo[1,2-b]pyridazine (0.178
g, 1.5 mmol) affords 55 in 95% (0.209 g) yield as a white solid: mp 159-
161 °C. 1H NMR (400 MHz, CDCl3):  8.44 (d, J = 4.3 Hz, 1H), 8.22 (d, J
= 8.5 Hz, 2H), 8.15 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.5 Hz,
2H), 7.13 (dd, J = 9.0, 4.3 Hz, 1H).
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3-(4-Nitrophenyl)imidazo[1,2-b]pyridazine
(56)[15b]
4-
Bromonitrobenzene (0.202 g, 1 mmol) and imidazo[1,2-b]pyridazine
(0.178 g, 1.5 mmol) affords 56 in 96% (0.230 g) yield as a yellow solid:
mp 207-209 °C. 1H NMR (400 MHz, acetone-d6):  8.6 (dd, J = 4.3, 1.3
Hz, 1H), 8.52 (d, J = 8.9 Hz, 2H), 8.42 (s, 1H), 8.33 (d, J = 8.9 Hz, 2H),
8.15 (dd, J = 8.2, 1.6 Hz, 1H), 7.37 (dd, J = 8.2, 4.3 Hz, 1H).
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
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For selected examples of direct arylations of imidazoles and
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10.1002/adsc.201800596
Advanced Synthesis & Catalysis
FULL PAPER Very Important Publication
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FULL PAPER
Shuxin Mao, Xinzhe Shi, Jean-François
Soulé,* Henri Doucet*
Pd/C as Heterogeneous Catalyst for
Direct Arylation of Heteroaromatics
with Aryl Bromides
Text for Table of Contents
This article is protected by copyright. All rights reserved.