Versatile synthesis of dissymmetric diarylideneacetones via a palladium-catalyzed coupling-isomerization reaction

Article abstract of DOI:10.1055/s-0032-1316811

As a twofold Michael system, the diarylideneacetone core is of particular interest in organic synthesis and for therapeutic applications. To overcome the drawbacks of the classical Claisen-Schmidt protocol, a new methodology for the synthesis of dissymmetric (hetero)diarylideneacetones has been developed. Conditions were optimized with a Box-Behnken design of experiment. The milder reaction conditions allow the efficient preparation of fluorinated, or heteroaromatic, dissymmetric diarylideneacetones which cannot be obtained through the classical Claisen-Schmidt protocol. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316811

PAPER
▌3829
paper
Versatile Synthesis of Dissymmetric Diarylideneacetones via a Palladium-
Catalyzed Coupling–Isomerization Reaction
Diarylideneacetones via a Palladium-Catalyzed CIR
Thibault Gendron,a,b Elisabeth Davioud-Charvet,a Thomas J. J. Müller*b
a
European School of Chemistry, Polymers and Materials, Bioorganic and Medicinal Chemistry, UMR CNRS 7509, 25 rue Becquerel,
67087 Strasbourg Cedex 2, France
b
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1,
40225 Düsseldorf, Germany
Fax +49(211)8114324; E-mail: thomasjj.mueller@uni-duesseldorf.de
Received: 21.09.2012; Accepted after revision: 24.10.2012
reagents and products that withstand drastic concentrated
Abstract: As a twofold Michael system, the diarylideneacetone
basic or acidic reaction conditions can be used. Further-
core is of particular interest in organic synthesis and for therapeutic
more, heteroaromatic diarylideneacetones are very diffi-
applications. To overcome the drawbacks of the classical Claisen–
Schmidt protocol, a new methodology for the synthesis of dissym-
cult to obtain through this aldol approach.11 In particular,
metric (hetero)diarylideneacetones has been developed. Conditions pyridyl-substituted penta-1,4-dien-3-ones have been syn-
were optimized with a Box–Behnken design of experiment. The
milder reaction conditions allow the efficient preparation of fluori-
nated, or heteroaromatic, dissymmetric diarylideneacetones which
drawbacks, dissymmetric DAAs are not rapidly obtained
cannot be obtained through the classical Claisen–Schmidt protocol.
thesized via a much longer and complex Horner–
Wadsworth–Emmons approach.12 Finally, besides these
via the Claisen–Schmidt protocol since the synthesis re-
quires two condensation steps: first a benzalacetone is
Key words: heterocycles, catalysis, cross-coupling, isomerization,
palladium, solvent effects, substituent effects
synthesized, and then allowed to react with a second benz-
aldehyde to give the desired dissymmetric DAA.13 This
procedure usually results in lower yields as various by-
products are formed.14
The diarylideneacetone (DAA) core, namely 1,5-diaryl-
penta-1,4-dien-3-one, is a widely represented structure,
both in synthetic and naturally occurring compounds. In
the field of advanced organic chemistry, dibenzylidene-
acetone has been found to be very useful, especially in or-
ganometallic catalysis; its uses as a ligand in the Suzuki–
Miyaura coupling,1 or in the Heck reaction,2 is well docu-
mented. Diarylideneacetones can also be used as a starting
material for the synthesis of highly substituted cyclopen-
tenones through a Nazarov-type cyclization.3 Their use in
multicomponent reactions has been demonstrated, leading
to the synthesis of highly functionalized vinylpyrazoline
or indazole derivatives.4 Besides these synthetic uses,
DAAs have also been considered as promising lead com-
pounds for the treatment of several diseases. Fairly close
to the natural compound curcumin, known for numerous
medicinal applications,5 DAAs are currently being evalu-
ated for their use in cancer therapy.6 Their antioxidant ac-
tivities have also turned out to be very promising,7 as well
as their effects on the regulation of the inflammatory pro-
cess.8 More recently, the use of diarylideneacetone deriv-
atives as radiolabeled probes for β-amyloid plaque
imaging has been proposed.9
Ar2CHO
NaOH, EtOH
acetone
NaOH
O
O
Ar1CHO
Ar1
Ar1
diarylideneacetone
Ar2
benzalacetone
Scheme 1 Claisen–Schmidt synthesis of diarylideneacetones (when
Ar1 = Ar2, the reaction is performed in one pot)
In order to circumvent these drawbacks and to develop a
novel approach allowing the one-pot synthesis of dissym-
metric (hetero)diarylideneacetones under mild conditions,
we investigated a new, convenient catalytic pathway. Pre-
viously, we have reported a catalytic procedure for the
synthesis of chalcones.15 This methodology, called the
coupling–isomerization reaction (CIR), is based on a
Sonogashira coupling followed by an in situ isomeriza-
tion, under basic conditions. Initially conducted under
thermal conditions, the protocol was considerably im-
proved by the use of microwave irradiation (Scheme 2).16
O
PdCl2(PPh3)2 (5 mol%)
OH
Diarylideneacetones are usually synthesized by a
Claisen–Schmidt reaction (Scheme 1).10 Although this
straightforward procedure usually gives good yields, only
CuI (1 mol%)
Br
Ph
+
Ph
Et3N, THF, MW
96%
NC
NC
Scheme 2 Synthesis of chalcones via a microwave-assisted cou-
pling–isomerization reaction
SYNTHESIS 2012, 44, 3829–3835
Advanced online publication: 15.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316811; Art ID: SS-2012-T0742-OP
© Georg Thieme Verlag Stuttgart · New York

3830
T. Gendron et al.
PAPER
Considering the structural similarities between chalcones hand, with nonnucleophilic tertiary amines such as
and diarylideneacetones, we aimed at adapting the CIR DIPEA and triethylamine, the reaction worked well (Ta-
procedure to the synthesis of diarylideneacetones. Here, ble 1, entries 5 and 6). In the case of DIPEA, the coupling
we report the first synthetic results and the optimization of reaction occurred but the isomerization seemed to be
the reaction of unsaturated propargyl alcohols with (het- slower, resulting in lower yield. The higher steric hin-
ero)aryl halides, leading to (hetero)diarylideneacetones drance of DIPEA likely explains the lower reactivity com-
by palladium-catalyzed coupling and isomerization under pared to triethylamine. Consequently, triethylamine was
microwave irradiation.
selected as the base for this reaction.
The initial attempts were made using 4-bromobenzonitrile Although the choice of solvent under conventional heat-
(1a) and 1-phenylpent-1-en-4-yn-3-ol (2a) as starting ma- ing is very important, it becomes even more crucial for re-
terials. The catalytic system was composed of bis(triphe- actions under microwave irradiation.17 Taking into
nylphosphane)palladium(II) dichloride [PdCl2(PPh3)2] account these specificities, four different solvents were
and copper iodide as a cocatalyst, without any additional tested: tetrahydrofuran (THF), 1,4-dioxane, N,N-dimeth-
ligand. The reaction was carried out in tetrahydrofuran at ylformamide (DMF), and neat triethylamine. All four sol-
120 °C (dielectric heating) for 30 minutes with triethyl- vents resulted in satisfactory yields but THF was clearly
amine as the base of choice (Scheme 3). These conditions less efficient than the others. 1,4-Dioxane, DMF, and neat
were selected further to previous studies on the synthesis triethylamine showed comparable results (Table 1, entries
of chalcones.15,16 The desired product 3a was obtained in 7–9); however, as 1,4-dioxane resulted in the highest yield
40% yield. From this encouraging result, we then opti- and is much easier to remove during workup, it was se-
mized the reaction conditions. In order to make this pro- lected as the solvent for this reaction.
cess easier, we established an HPLC method for the
quantitative determination of product 3a (λmax = 325 nm).
With such a selective and accurate quantification method,
Table 1 Optimization of the Discrete Factors in the Reaction of 1a
with 2aa
we were able to study the effects of discrete factors (base,
solvent, and catalyst) as well as continuous factors (irradi-
ation time, temperature, and concentration).
Entry Base
Solvent
Catalyst
Yieldb (%)
of 3a
1
Cs2CO3
THF
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
5
Br
2
DBU
THF
0
O
NC
3
pyrrolidine
piperidine
DIPEA
Et3N
THF
0
1a
CuI (2 mol%)
PdCl2(PPh3)2 (3 mol%)
+
4
THF
0
O
Et3N, THF
120 °C (MW), 30 min
5
THF
21
40
58
52
62
60
NC
3a 40%
R1
2a R1 = H
6
THF
7
Et3N
DMF
neat Et3N
Scheme 3 First result on the synthesis of 3a via the coupling–
isomerization reaction
8
Et3N
9
Et3N
1,4-dioxane PdCl2(PPh3)2
1,4-dioxane Pd(PPh3)4
Since the isomerization step of the CIR is a base-catalyzed
process, the choice of the base is expected to be crucial.
Six bases were selected according to their pKa values and
their nucleophilic properties: cesium carbonate, triethyl-
amine, piperidine, pyrrolidine, N,N-diisopropylethyl-
amine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (Table 1). An inorganic base like cesium carbon-
10
Et3N
a Reactions at 0.3 M, with base (5 equiv), heated at 120 °C under mi-
crowave irradiation for 30 min.
b HPLC yields.
ate resulted in a limited amount of the desired product The first step in the CIR is a Sonogashira coupling which
(Table 1, entry 1). Switching to organic bases, with the is usually performed using a palladium–phosphane ligand
use of DBU, no product was detected (Table 1, entry 2). complex as a catalyst in the presence of a catalytic amount
Although 4-bromobenzonitrile (1a) was still present in the of a copper(I) salt, most often copper iodide. Regarding
mixture, neither the desired product nor the 1-phenylpent- the palladium precatalyst, Pd(PPh3)4 or PdCl2(PPh3)2 are
1-en-4-yn-3-ol (2a) was detected. DBU as a base might be most commonly used in this type of reaction.18 We evalu-
too strong, inducing decomposition of the unsaturated ated them both and the yields were 60% and 62%, respec-
propargyl alcohol, probably by the retro-Favorskii reac- tively (Table 1, entries 9 and 10). In all cases, 20 mol% of
tion. In the case of pyrrolidine, both starting materials triphenylphosphane was added to the reaction mixture to
were entirely consumed to form a new product, not the de- stabilize the palladium catalyst.16
sired one, that we were not able to identify (Table 1, entry
For gathering a maximum of information with a minimum
3). With piperidine, no reaction occurred and the starting
of experiments, we decided to apply the Design of Exper-
materials were still present (Table 1, entry 4). On the other
iment (DoE) methodology. Here, a Box–Behnken design
Synthesis 2012, 44, 3829–3835
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diarylideneacetones via a Palladium-Catalyzed CIR
3831
(BBD) was chosen.19 This design uses a centered quadrat- insights gained on the CIR.15b Ongoing studies are direct-
ic model to calculate the three-dimensional representation ed toward developing optimal conditions for the imple-
(response surfaces) of multivariate systems, allowing the mentation of the propargyl alcohols 2 into domino
optimization of the process.20 Three factors required 15 sequences where the sensitive diarylideneacetone func-
experiments for the development of a BBD. Conditions tionality is in situ transformed to give more thermally sta-
for each run were chosen based on the specific matrix of ble cyclization products. On the other hand, heteroaryl
experiments of the BBD (for the conditions and yields of halides, such as pyridyl, pyrimidinyl, and thiazolyl halides
the 15 experiments, see Supporting Information). Multi- were transformed uneventfully, in good yields, to substi-
variate quadratic regression of the raw results allows the tuted heteroarylideneacetones otherwise difficult to ac-
plotting of response surfaces, which helps to depict prima- cess (Table 2, entries 6–8 and 10–12), even in the case of
ry trends and to achieve a better understanding of the sys- a fluorinated pyridine 1i as the substrate (Table 2, entry
tem (Figure 1).
11). On the propargylic alcohol substrate 2, both electro-
neutral and electron-rich phenyl substituents are well tol-
erated (Table 2, entries 2, 7, 9, and 10). In addition, we
also demonstrated that this procedure can be easily scaled
up, as product 3a was successfully obtained on a 10-mmol
scale in 68% yield using the same optimized conditions
(Table 2, entry 1).
Even at first glance, it was apparent that temperature has
a drastic influence on the yield. A maximum was clearly
reached around 120 °C; higher or lower temperatures re-
sulted in a significant decrease in the yield (Figure 1, plots
a and b). The molarity also plays an important role: higher
seems to be better, but a plateau was reached between 0.5
and 0.6 mol·L–1 (Figure 1, plots a and c). Finally, the ef- In conclusion, we have described a new synthetic method-
fect of irradiation hold time is less obvious as no tendency ology for the synthesis of dissymmetric (hetero)diaryli-
could be clearly detected (Figure 1, plots b and c). Nonlin- deneacetones which overcomes many drawbacks of the
ear specific effects of microwave irradiation might ex- classical Claisen–Schmidt reaction. Starting from an aryl
plain this and make the hold-time term (and its halide and an unsaturated propargyl alcohol, this proce-
combinations) statistically nonsignificant for the model.17 dure allows the rapid one-pot synthesis of diarylideneace-
In order to confirm these primary trends, an algorithmic tones under the mild conditions of a palladium-catalyzed
calculation was performed.21 Here, the maximal yield was coupling–isomerization reaction. The optimized reaction
predicted to reach 59% after 45 minutes of microwave ir- conditions were applied to several substrates, giving the
radiation at a temperature of 120 °C and at a concentration desired products in moderate to good yield. The scope of
of 0.55 mol·L–1. To evaluate this expectation, we per- the reaction was demonstrated, underlined by the synthe-
formed an experiment with starting materials 1a and 2a sis of fluorinated, or heteroaromatic, dissymmetric di-
under the calculated optimal reaction conditions. The final arylideneacetones which cannot be obtained through the
yield after isolation and purification was 65%, confirming Claisen–Schmidt pathway.
the computed prediction.
The methodology under these optimized conditions was
then extended to the synthesis of several dissymmetric
(hetero)dibenzylideneacetones 3 (Table 2). With respect
to the aryl halide 1, the reaction proved to be fairly general
for electron-deficient aryl halides (Table 2, entries 1, 2,
and 9); however, under the standard conditions, electron-
rich aryl halides could not be successfully transformed
into the title compounds (Table 2, entries 3–5). This be-
havior is in agreement with the prior general mechanistic
Cinnamaldehydes, ethynylmagnesium bromide, aryl halides, palla-
dium catalysts, copper iodide, amines, and triphenylphosphane
were obtained from Sigma Aldrich and were used without further
purification. Unsaturated propargyl alcohols were synthesized by
ethynylation of the corresponding cinnamaldehyde. Unsaturated
propargyl alcohol 2a was obtained following the published proce-
dure,22 while product 2b was prepared as described below. THF,
1,4-dioxane, and DMF were dried by passage through an activated
alumina column under argon and degassed by bubbling of argon for
15 min. Et3N and DIPEA were freshly distilled over KOH under ar-
gon and stored over KOH.
Figure 1 Plots of response surfaces. Hold values: a) duration = 45 min, b) molarity = 0.55 M, c) temperature = 120 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3829–3835

3832
T. Gendron et al.
PAPER
Table 2 Scope of the Reactiona
Entry
1
(Hetero)aryl halide 1
Propargyl alcohol 2
Diarylideneacetone 3
Yieldb (%)
O
Br
65
1a
1b
2a
2a
R1 = H
3a
68c
NC
NC
O
I
2
3b
55
F3C
F3C
O
I
3
4
5
1c
1d
1e
2a
2a
2a
3c
<5
0
O
I
3d
O
Br
3e
0
MeO
N
MeO
O
Br
N
6
7
8
1f
2a
2a
2a
3f
65
42
50
·HCl
N
N
O
Br
1g
1h
3g
3h
N
·HCl
N
O
N
I
N
·HCl
O
9
1b
1g
1i
2b
2b
2b
2b
R1 = NMe2
3i
58
54
52
62
F3C
NMe2
O
10
11
12
3j
3k
3l
N
NMe2
O
N
Br
N
F
F
NMe2
O
N
S
N
1j
Br
S
NMe2
a Reactions on a 1-mmol scale, using the optimized conditions.
b Isolated yields.
c Scale-up; reaction performed on a 10-mmol scale.
Synthesis 2012, 44, 3829–3835
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diarylideneacetones via a Palladium-Catalyzed CIR
3833
All reactions were performed in standard microwave glassware,
which was dried, flushed with argon, and sealed. Two chemistry-
dedicated microwave reactors (Biotage and CEM) were used with
comparable results. Temperature and pressure were automatically
controlled by the apparatus. Flash chromatography was performed
on silica gel 60 (230–400 mesh, 40–63 μm) purchased from E. Mer-
ck. Thin-layer chromatography was performed on aluminum sheets
coated with silica gel 60 F254 purchased from E. Merck. UV–vis
spectra were recorded on a Varian Cary 50 spectrophotometer.
HPLC experiments were performed on a Hewlett Packard HPLC
with dual UV–vis detection (254 and 325 nm). Samples (0.8 μL)
were eluted on a Nucleosil silica column with CH2Cl2 containing
1 vol% of i-PrOH for 30 min at 0.60 mL·min–1. IR spectra were re-
corded on a Perkin–Elmer Spectrum One spectrophotometer. NMR
spectra were recorded on Bruker AC 200, 300, 400, or 500 MHz in-
struments with solvent peaks as reference. Carbon multiplicities
were assigned by Distortionless Enhancement by Polarization
Transfer (DEPT) and Heteronuclear Single Quantum Correlation
(HSQC) experiments. The 1H signals were assigned by 2D experi-
ments (COSY). ESI-HRMS data were recorded on a Bruker mi-
crOTOF spectrometer. Melting points were measured on a Stuart
Melting Point 10 apparatus and are given uncorrected.
Mp 146 °C.
IR (neat): 1674, 1601, 1337, 1188, 982, 826, 763, 695 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 7.75 (d, 3J = 16.4 Hz, 1 H, vinyl-
ic), 7.72 (m, 4 H, ArH), 7.69 (d, 3J = 15.5 Hz, 1 H, vinylic), 7.66–
7.64 (m, 2 H, ArH), 7.44 (m, 3 H, ArH), 7.18 (d, 3J = 15.5 Hz, 1 H,
vinylic), 7.09 (d, 3J = 16.4 Hz, 1 H, vinylic).
13C NMR (125 MHz, CD2Cl2): δ = 188.3, 144.1, 140.7, 139.6,
135.0, 133.0, 131.1, 129.4, 129.0, 128.8, 128.5, 125.7, 118.8, 113.7.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H13NO: 282.089; found:
282.089.
(1E,4E)-1-Phenyl-5-[4-(trifluoromethyl)phenyl]penta-1,4-dien-
3-one (3b)
Pure, pale yellow powder; yield: 166 mg (55%).
Mp 142–143 °C.
IR (neat): 1653, 1593, 1322, 1107, 1066, 981, 826, 760, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.79 (d, 3J = 16.0 Hz, 1 H, vinyl-
3
ic), 7.76 (d, J = 16.0 Hz, 1 H, vinylic), 7.77–7.67 (m, 4 H, Ar),
7.67–7.60 (m, 2 H, Ph), 7.45 (m, 3 H, Ph), 7.17 (d, 3J = 16.0 Hz, 1
H, vinylic), 7.10 (d, 3J = 16.0 Hz, 1 H, vinylic).
(E)-1-[4-(Dimethylamino)phenyl]pent-1-en-4-yn-3-ol (2b)
In a dry three-necked round-bottomed flask were introduced anhyd
THF (5 mL) and 1 M ethynylmagnesium bromide in THF (18 mL).
The solution was cooled at –78 °C and (E)-3-[4-(dimethylami-
no)phenyl]acrylaldehyde (1.23 g, 7 mmol) in anhyd THF (7 mL)
was added dropwise over 10 min at –78 °C under stirring and argon.
The mixture was next allowed to warm to r.t. and the reaction was
carried out for 2 h under stirring and argon. The reaction was sub-
sequently quenched with sat. aq NH4Cl (20 mL). The product was
extracted with Et2O (3 × 30 mL) after the aqueous layer was adjust-
ed to pH ~10 with NaHCO3. The combined organic layers were
dried (MgSO4), filtered, and evaporated to dryness. The orange
crude powder was recrystallized (hexanes–toluene, 4:6) to give 2b
as a pure brown powder; yield: 1.10 g (79%).
13C NMR (75.5 MHz, CDCl3): δ = 188.7, 144.2, 141.4, 138.4 (m,
Cq), 134.8, 132.1 (q, 2JC-F = 32 Hz, Cq), 131.0, 129.2, 128.7, 128.6,
3
1
127.6, 125.9 (q, JC-F = 3.6 Hz, CH), 125.5, 123.8 (q, JC-F
=
271 Hz, Cq).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H13F3O: 325.081;
found: 325.081.
(1E,4E)-1-Phenyl-5-(pyrimidin-2-yl)penta-1,4-dien-3-one
Hydrochloride (3f)
Pure, fine yellow powder; yield: 178 mg (65%).
Mp 164 °C (dec).
IR (neat): 1662, 1604, 1595, 1504, 1386, 1238, 1200, 1061, 994,
986, 813, 780, 692 cm–1.
3
1H NMR (300 MHz, DMSO-d6): δ = 8.92 (d, J = 4.9 Hz, 2 H, H-
Mp 123–125 °C.
4/6 pyrimidine), 7.83 (m, 2 H, Ph), 7.78 (d, 3J = 16.0 Hz, 1 H, vinyl-
ic), 7.77 (d, 3J = 15.8 Hz, 1 H, vinylic), 7.64 (d, 3J = 15.8 Hz, 1 H,
vinylic), 7.52 (d, 3J = 4.6 Hz, 1 H, H-5 pyrimidine), 7.47 (d,
3J = 16.0 Hz, 1 H, vinylic), 7.46 (m, 3 H, Ph).
3
1H NMR (300 MHz, acetone-d6): δ = 7.30 (d, J = 8.7 Hz, 2 H,
ArH), 6.71 (d, 3J = 8.7 Hz, 2 H, ArH), 6.63 (d, 3J = 15.8 Hz, 1 H, vi-
nylic), 6.10 (dd, 3J = 15.8, 6.3 Hz, 1 H, vinylic), 4.97 [ddd, 3J = 6.3,
5.9 Hz, 4J = 2.0 Hz, 1 H, CH(OH)], 4.53 (d, 3J = 5.9 Hz, 1 H, OH),
2.98 (d, 4J = 2.0 Hz, 1 H, alkyne), 2.95 [s, 6 H, N(CH3)2].
13C NMR (75.5 MHz, DMSO-d6): δ = 188.7, 162.3, 157.7, 143.9,
140.6, 134.4, 133.3, 130.8, 128.9, 128.8, 125.2, 121.0.
HRMS (ESI+): m/z [M + Na]+ calcd for C15H12N2O: 259.084;
found: 259.084.
13C NMR (50.3 MHz, acetone-d6): δ = 151.5, 131.8, 128.5, 125.6,
125.4, 113.2, 85.5, 74.4, 63.1, 40.5.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.37; H, 7.52; N, 6.94.
(1E,4E)-1-Phenyl-5-(pyridin-4-yl)penta-1,4-dien-3-one Hydro-
chloride (3g)
Pure, fine yellow powder; yield: 115 mg (42%).
1,5-Diarylpenta-1,4-dien-3-ones 3; General Procedure
An aryl halide 1 (1 mmol, 1 equiv), an unsaturated propargyl alco-
hol 2 (1.2 mmol, 1.2 equiv), PdCl2(PPh3)2 (21 mg, 0.03 mmol,
3 mol%), CuI (4 mg, 0.02 mmol, 2 mol%), and Ph3P (52 mg,
0.2 mmol, 20 mol%) were introduced in a 10-mL microwave vial
flushed with argon. The mixture was solubilized with a soln of an-
hyd Et3N (700 μL, 5 mmol, 5 equiv) in anhyd degassed 1,4-dioxane
(1.3 mL). The solution was heated under microwave irradiation at
120 °C for 45 min. The reaction mixture was poured into a mix of
1 M aq HCl (10 mL) and sat. aq NH4Cl (10 mL), and this was ex-
tracted with EtOAc (3 × 15 mL). The combined organic layers were
dried (MgSO4), filtered, and evaporated to dryness to give crude
product which was purified by flash chromatography.
Mp 190 °C (dec).
IR (neat): 1655, 1634, 1602, 1505, 1335, 1189, 979, 812, 767, 729,
691 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.97 (d, J = 6.4 Hz, 2 H, H-
3
2/6 pyridine), 8.38 (d, 3J = 6.4 Hz, 2 H, H-3/5 pyridine), 8.05–7.85
(m, 3 H, vinylic), 7.82 (m, 2 H, Ph), 7.49 (m, 3 H, Ph), 7.33 (d,
3J = 16.8 Hz, 1 H, vinylic).
13C NMR (75.5 MHz, DMSO-d6): δ = 188.4, 150.2, 144.8, 143.0,
137.0, 134.4, 133.4, 131.0, 129.1, 128.7, 125.7, 125.1.
HRMS (ESI+): m/z [M + H]+ calcd for C16H13NO: 236.107; found:
Where indicated, the free base was dissolved in Et2O (5 mL) and
1.25 M HCl in EtOH (2 mL) was added. The suspension was fil-
tered to recover the hydrochloride salt of the desired compound.
236.106.
(1E,4E)-1-Phenyl-5-(pyridin-2-yl)penta-1,4-dien-3-one Hydro-
chloride (3h)
Pure, fine yellow powder; yield: 136 mg (50%).
4-[(1E,4E)-3-Oxo-5-phenylpenta-1,4-dien-1-yl]benzonitrile (3a)
Pure, light yellow powder; yield: 169 mg (65%).
Mp 155 °C (dec).
Scale-up on 10 mmol; yield: 1.75 g (68%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3829–3835

3834
T. Gendron et al.
PAPER
IR (neat): 1661, 1614, 1462, 1304, 1197, 1109, 979, 771, 692 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C18H17FN2O: 297.140;
found: 297.139.
1H NMR (300 MHz, DMSO-d6): δ = 8.83 (d, 3J = 5.6 Hz, 1 H, H-6
pyridine), 8.38–8.26 (m, 2 H, pyridine), 8.09 (d, 3J = 16.4 Hz, 1 H,
vinylic), 7.99 (d, 3J = 15.9 Hz, 1 H, vinylic), 7.84 (d, 3J = 16.4 Hz,
1 H, vinylic), 7.84–7.81 (m, 1 H, pyridine), 7.81 (m, 2 H, Ph), 7.47
(m, 3 H, Ph), 7.29 (d, 3J = 15.9 Hz, 1 H, vinylic).
13C NMR (75.5 MHz, DMSO-d6): δ = 188.2 (Cq), 149.5 (Cq pyri-
dine), 145.5 (CH), 144.7 (CH), 142.6 (CH), 135.7 (Cq), 134.4 (CH),
131.5 (CH), 130.9 (CH), 129.1 (CH phenyl), 128.8 (CH phenyl),
126.3 (CH), 126.0 (CH), 125.9 (CH).
(1E,4E)-1-[4-(Dimethylamino)phenyl]-5-(1,3-thiazol-2-yl)pen-
ta-1,4-dien-3-one (3l)
Pure, dark purple powder; yield: 176 mg (62%).
Mp 176 °C.
IR (neat): 1594, 1558, 1524, 1346, 1186, 1099, 1074, 1000, 811,
771 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, 3J = 3.2 Hz, 1 H, H-4 thi-
azole), 7.80 (d, 3J = 15.8 Hz, 1 H, vinylic), 7.76 (d, 3J = 15.8 Hz, 1
H, vinylic), 7.53 (d, 3J = 8.7 Hz, 2 H, ArH), 7.46 (d, 3J = 3.2 Hz, 1
H, H-5 thiazole), 7.43 (d, 3J = 15.8 Hz, 1 H, vinylic), 6.88 (d,
3J = 15.8 Hz, 1 H, vinylic), 6.73 (d, 3J = 8.7 Hz, 2 H, ArH), 3.07 [s,
6 H, N(CH3)2].
HRMS (ESI+): m/z [M + Na]+ calcd for C16H13NO: 258.089; found:
258.088.
(1E,4E)-1-[4-(Dimethylamino)phenyl]-5-[4-(trifluorometh-
yl)phenyl]penta-1,4-dien-3-one (3i)
Pure, bright orange powder; yield: 200 mg (58%).
13C NMR (75.5 MHz, CDCl3): δ = 187.9, 164.6, 152.1, 145.3,
Mp 179–180 °C.
144.7, 132.5, 130.6, 129.5, 122.5, 121.2, 120.7, 112.0, 40.2.
IR (neat): 1648, 1600, 1587, 1524, 1321, 1162, 1118, 1108, 1065,
981, 826, 810 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C16H16N2OS: 285.106;
found: 285.105.
1H NMR (500 MHz, CDCl3): δ = 7.76 (d, 3J = 15.6 Hz, 1 H, vinyl-
ic), 7.72 (d, 3J = 16 Hz, 1 H, vinylic), 7.70 (m, 4 H, ArH), 7.55 (d,
Acknowledgment
3
3J = 9 Hz, 2 H, ArH), 7.17 (d, J = 16 Hz, 1 H, vinylic), 6.89 (d,
3J = 15.6 Hz, 1 H, vinylic), 6.72 (d, 3J = 8.5 Hz, 2 H, ArH), 3.07 [s,
This work was supported by the Fonds der Chemischen Industrie,
the Deutscher Akademischer Austauschdienst (DAAD, scholarship
for T.G.), the collaborative center SFB 544 (B14 project), the Cen-
tre National de la Recherche Scientifique (CNRS), the University of
Strasbourg (UMR 7509 CNRS-UdS), the ANRémergence program
(grant SCHISMAL to E.D.C.), and the International Center for
Frontier Research in Chemistry in Strasbourg (www.icfrc.fr). T.G.
is grateful to the MENRT (French Ministry of Research) for his
PhD salary. We would like to thank Prof. D. Wolbert for his valuab-
le advice on the DoE methodology.
6 H, N(CH3)2].
13C NMR (75.5 MHz, CDCl3): δ = 188.5, 152.4, 145.2, 140.1, 138.9
2
(m, Cq), 131.4 (q, JC-F = 32.5 Hz, Cq), 130.7, 128.5, 128.1, 126.0
3
(q, JC-F = 3.8 Hz, Ar), 123.9 (q, 1JC-F = 269 Hz, Cq), 122.5, 120.8,
112.1, 40.3.
HRMS (ESI+): m/z [M + H]+ calcd for C20H18F3NO: 346.141;
found: 346.140.
(1E,4E)-1-[4-(Dimethylamino)phenyl]-5-(pyridin-4-yl)penta-
1,4-dien-3-one (3j)
Pure orange powder; yield: 150 mg (54%).
Supporting Information for this article is available online at
Mp 192 °C (dec).
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
IR (neat): 1662, 1634, 1609, 1509, 1197, 1131, 1114, 992, 836, 819
cm–1.
References
3
1H NMR (300 MHz, CDCl3): δ = 8.68 (d, J = 6.0 Hz, 2 H, H-2/6
pyridine), 7.76 (d, 3J = 15.6 Hz, 1 H, vinylic), 7.61 (d, 3J = 15.9 Hz,
1 H, vinylic), 7.54 (d, 3J = 8.5 Hz, 2 H, ArH), 7.46 (d, 3J = 6.0 Hz,
2 H, H-3/5 pyridine), 7.25 (d, 3J = 15.9 Hz, 1 H, vinylic), 6.87 (d,
3J = 15.6 Hz, 1 H, vinylic), 6.71 (d, 3J = 8.5 Hz, 2 H, ArH), 3.07 [s,
6 H, N(CH3)2].
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IR (neat): 1605, 1559, 1523, 1475, 1434, 1371, 1345, 1226, 1186,
1098, 982, 855, 803 cm–1.
3
1H NMR (300 MHz, CDCl3): δ = 8.54 (d, JH-F = 2.7 Hz, 1 H, H-6
pyridine), 7.77 (d, 3J = 15.9 Hz, 1 H, vinylic), 7.68 (d, 3J = 15.6 Hz,
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3
2
130.5, 128.8, 125.8 (d, JC-F = 5 Hz), 123.3 (d, JC-F = 19 Hz),
122.5, 121.4, 112.0, 40.2.
Synthesis 2012, 44, 3829–3835
© Georg Thieme Verlag Stuttgart · New York

PAPER
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3829–3835