Preparation of aromatic γ-hydroxyketones by means of Heck coupling of aryl halides and 2,3-dihydrofuran, catalyzed by a palladium(ii) glycine complex under microwave irradiation

Article abstract of DOI:10.1039/d0nj02630a

A series of aromatic γ-hydroxyketones were prepared by means of Heck coupling reaction of aryl halides and 2,3-dihydrofuran, catalyzed by PdCl2·Gly2 and under microwave irradiation. This synthetic transformation involves the formation of an aryl-dihydrofuranoic intermediate, followed by an unusual opening of the heterocycle promoted by a water molecule and the formation of the ketone carbonyl function through keto-enol tautomerism. This journal is

Full text of DOI:10.1039/d0nj02630a

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and J. B. González-Campos, New J. Chem., 2020, DOI: 10.1039/D0NJ02630A.
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Preparation of aromatic -hydroxyketones by means of Heck
coupling of aryl halides and 2,3-dihydrofuran, catalyzed by
palladium(II) glycine complex under microwave irradiation
Received 00th January 20xx,
Accepted 00th January 20xx
Juan C. Jiménez-Cruz,a Ramón Guzmán-Mejía,a Eusebio Juaristi,*b,c Omar Sánchez-Antonio,b Marco
A. García-Revilla,*d J. Betzabe González-Campos,a Judit Aviña-Verduzco*a
DOI: 10.1039/x0xx00000x
A series of aromatic γ-hydroxyketones were prepared by means of Heck coupling reaction of aryl halides and 2,3-
dihydrofuran, catalyzed by PdCl2·Gly2 and under microwave irradiation. This synthetic transformation involves the formation
of an aryl-dihydrofuranoic intermediate, followed by an unusual opening of the heterocycle promoted by a water molecule
and the formation of the ketone carbonyl function through keto-enol tautomerism.
arylation of 2-substituted-2,3-dihydrofuran using Pd(dba)2 and
(R)-BINAP as catalyst.
Introduction
Another interesting development in Pd-catalyzed methodology
Palladium is a transition metal that is widely employed in
organic synthesis for C C bond formation via cross-coupling
reactions.1 In this regard, a particularly useful methodology
where palladium involvement is essential corresponds to the
coupling reaction developed by Heck in 1968.2 The so-called
consists in the study of the involved reaction mechanisms. One
of the methods employed for the study of reaction mechanisms
in solution is electrospray ionization mass spectrometry (ESI-
MS) as well as tandem ESI-MS/MS. This is a technique that
gently transfers ionic species or ionized forms of neutral species
(reaction intermediaries) directly from solution to the gas
phase, allowing the identification of transient species that
cannot be identified by other spectroscopic techniques.11 In this
regard, a few years ago Eberlin et al.12 proposed a mechanism
for the Heck reaction between alkenes and 4-methoxybenzene
−
Heck reaction consists in the formation of a C−C bond between
an alkene and an aryl halide catalyzed by palladium, in the
presence of a base, and has been employed for example, in the
preparation of highly relevant synthetic intermediates.3
On the other hand, in the last years the use of microwave
irradiation as a convenient source of energy has gained
significant importance for improvement of the Heck coupling
reaction.4 In this context, Larhed et al.5 employed aryl bromides
and aryl iodides for the efficient preparation of aryl-substituted
olefins in the presence of Pd(OAc)2, while Xie et al.6 achieved
arylation of various olefins in less than 2 minutes reaction time
with Pd/C catalyst under microwave irradiation. Furthermore,
Andersson et al.7 employed microwave activation in the
asymmetric cross coupling of aryl tosylates and 2,3-
dihydrofuran, employing phosphine-thiazol complexes of
diazonium
tetrafluoroborate
catalyzed
by
dibenzylideneacetone-palladium. In particular, Eberlin et al.
detected ionic species arising from oxidative addition.
Moreover, the proposed intermediaries were identified as
responsible for C−C bond formation via migratory insertion. In
this sense, a significant number of mechanistic studies have
been supported by theoretical modeling.13 For example,
Gooßen et al.14 described the mechanism of the oxidative
addition of aryl halides to Pd catalysts with base on DFT
calculations. Recently, Rueping et al.15 using hybrid functional
GGA-DFT and PBE0, described the addition of inactivated alkyl
bromides to α,β-insaturated acids via Heck coupling. Also very
recently, Grimaud et al.16 reported the reaction mechanism in
the opening of a benzofuran ring promoted by palladium.
Pd2(dba)3.8
A most interesting finding consisted in the
enantioselective arylation of 2,3-dihydrofuran accomplished by
Morel et al.9 when using Pd(OAc)2 as catalyst and proline salts
dissolved in ionic liquid, whereas Xu et al.10 performed the
a. Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San
Nicolás de Hidalgo. Edificio B-1, planta baja Ciudad Universitaria, 58030 Morelia,
Michoacán, México
Results and Discussion
Owing to the importance of the Heck reaction, one central field
of interest has been the development of novel Pd catalysts. In
this sense, the use of amino acids such as N,N-dimethylglycine,
N,N-dimethyl--alanine and N,N-dimethyl--aminobutyric acid
that are used as ligands in Pd catalysts have afforded excellent
results in the Heck reaction of aryl halides.17 We decided to
b. Departamento de Química, Centro de Investigación y de Estudios Avanzados.
Avenida Instituto Politécnico Nacional # 2508, 07360 Ciudad de México, México.
c. El Colegio Nacional. Donceles No. 104, Centro Histórico, 06020 Ciudad de México,
México.
d. Departamento de Química, Universidad de Guanajuato. Noria Alta s/n, 36050
Guanajuato, Gto., México.
Electronic Supplementary Information (ESI) available: Characterization data for all
compounds, figures and coordinates of structures of minima along the catalytic
cycle. See DOI: 10.1039/x0xx00000x
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1 and examined it as a catalyst In a further attempt to obtain Heck product 2-aryl-2,3-
1
2
3
4
5
6
7
8
prepare the PdCl2·Gly2 complex
View Article Online
in the Heck coupling of aryl halides and 2,3-dihydrofuran.
Catalyst PdCl2·Gly2 ( ) was prepared via reaction between 0.84 using anhydrous DMF solvent in order to prevent opening of the
mmol of glycine and 0.42 mmol of palladium chloride (II) (PdCl2) furan ring by water attack. However, hydroxy-ketone was
under reflux in acetonitrile (CH3CN) for 24 hours. Suitable obtained again in 22 % yield. Table 1 summarizes the results
crystals of were obtained by crystallization from CH2Cl2/MeOH when ethanol, THF, DMSO, and water itself were used as
(1:1) and a single crystal was subjected to X-ray diffraction solvent. The highest yield of
analysis18 (Figure 1). The structure showed that the complex watts of MW power (entry 2, Table 1).
presents square geometry where the chlorine atoms are
dihydrofuran, the reaction depicted in ScDhOemI: 1e0.210w39a/sD0reNpJ0e2a6t3e0dA,
1
2
1
2 was observed with DMF and 60
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Table 1. Solvent effect on the Pd catalyzed reaction between 4-iodophenol and 2,3-
DHF under MW activation.
oriented trans and two glycine molecules are also attached to
the Pd. Additionally, it was confirmed that the carboxylic groups
were esterified during the crystallization process.
Entry
Solvent
MW, power (W)
Time (min)
Yield (%)
1a
2
DMF
---
1440
30 (60)
30
26
DMF
60
61(79)
3
DMF
100
150
60(150)
60(150)
60
60
53
0
Figure 1. X-ray diffraction crystallographic structure and conformation of 1.
4
DMF
30
5a
6a
7
THF
30(60)
30
With complex 1 in hand, its ability to catalyze the Heck coupling
reaction between 4-iodophenol (one equivalent) and 2,3-
dihydrofuran (2,3-DHF, five equivalents) was evaluated,
employing three equivalents of diisopropyl ethyl amine (DIPEA)
as base, dimethylformamide (DMF) as solvent, and under
microwave activation (60 W, for 30 minutes). Unexpectedly, this
reaction afforded γ-hydroxy-ketone
anticipated 4-(2,3-dihydrofuranyl)-phenol.19 Product
result of phenol insertion at position 2 of the heterocyclic ring,
followed by ring opening (Scheme 1).
DMSO
MeCN
0
30
0
8
Acetone
1,4-dioxane
ethylene glycol
MeOH
EtOH
60
30
0
9
60
30
0
10a
11
12
13
14
60
30
0
2
(61 % yield) instead of the
is the
60
30
0
2
60
30
0
H2O
60
30
0
H2O/EtOH
60
30
0
a Oil bath at 80° C and 24 h of reaction time.
In order to corroborate the influence of water in the ring
opening and formation of hydroxy-ketone , the reaction was
2
carried out in a closed vessel microwave synthesizer, anhydrous
DMF and with addition of water (2 and 4 equiv.) at 3 bar
pressure (Table 2). The reaction does not proceed in anhydrous
solvents, whereas highest yield of
addition of 4 equivalents of water.
2 was observed with the
Scheme 1. Heck reaction between 4-iodophenol and 2,3-dihydrofuran.
Table 2. Water effect on the reaction between 4-iodophenol and 2,3-DHF.
The structure of product 2 was determined from analysis of the
corresponding 1H and 13C spectra; furthermore, mass
spectrometry exhibits the molecular ion M+ with m/z 180.08,
instead of the ion at 162.07 that would be expected for the
normal Heck product. Finally, the γ-hydroxyl group was
Entry
H2O
Time (min)
Yield (%)
MW power
(W)
characterized by oxidation of primary alcohol
dichromate (PDC) in methylene dichloride at ambient
temperature that afforded aldehyde in 79 % yield (Scheme 2).
2 with pyridinium
3
1
---
60
30
15
30
15
15
0
0
2
---
140
60
3
2 equiv.
2 equiv.
4 equiv.
79
95
96
4a
5b
140
140
Scheme 2. Selective oxidation of γ-hydroxy-ketone 2 to aldehyde 3.
a 3 bar pressure, b 5 bar pressure. The reaction did not proceed when water was
replaced by nucleophiles such as ethylenediamine, MeOH and EtOH.
2 | J. Name., 2012, 00, 1-3
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On the other hand, the reaction did not take place when Table 3. Scope of the reaction, preparation of hydroxy ketones 4-14.
View Article Online
DOI: 10.1039/D0NJ02630A
Pd(OAc)2 alone was used. By contrast, hydroxy-ketone
2 was
obtained in 23% yield under Pd(OAc)2·Gly2 and 4% yield under
PdCl2 catalysis (Scheme 3) confirming the importance of glycine
as a ligand in catalyst 1.
8
9
Yield
Entry
Ar-X
Product
(%)
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79a
95b
1
51a
89b
Scheme 3. Glycine ligand effect on the Heck reaction.
2
Aromatic γ-hydroxyketones are molecules of high synthetic
value, since they constitute important analogs of well-known
non-steroidal anti-inflammatory agents,20 and are useful
precursors in the preparation of GABA as well as other
compounds with inhibitory activity over endonucleases of the
virus influenza,21 inhibitors of tumoral growth,22 and natural
chalcones with antifungal activity.23 Considering the importance
22a
<2b
71a
92b
37c
3
of aromatic γ-hydroxy-ketones of type
2, it was decided to
41c
prepare a series of analogs 10 by reaction of 2,3-DHF with
4
-
several substituted 4-iodophenols as well as 1-
bromonaphthalene (Table 3). It is appreciated that the desired
γ-hydroxy-ketones 4-10 are obtained in good 80 to 98 % yield
(entries 2-7 in Table 3). Best results are achieved by carrying out
the high pressure reaction in a closed vessel, obtaining the 4-
hydroxy-1-(4-benzyloxyphenyl)butan-1-one (9) in 98% yield
76a
4
5
6
85b
80a
(entry 5 in Table 3). On the other hand, reaction between 2,3-
DHF and 4-iodophenyl acetate (entry 7) proceeded with
98b
hydrolysis of the acetyl group providing compound
reaction with 4-iodoanisol afforded two products, 4-hydroxy-1-
(4-methoxyphenyl)-butan-1-one ( ) in 89 % yield (entry 2) and
4-hydroxy-1,4-bis(methoxyphenyl)-butan-1-one ( ) in 22 %
2. The
52a
4
5
90b
yield. By the same token, when microwave power and the
reaction time were increased ethoxy-4-iodobenzene afforded
4-hydroxy-1-(4-ethoxyphenyl)-butan-1-one (
4-hydroxy-1,4-bis(ethoxyphenyl)-butan-1-one (
(entry 3, Table 3). Derivatives and are produced by double
6
) in 92% yield and
7
8
21a
7
) in a 41% yield
5
7
Heck coupling (entry 2 and 3), while reaction with iodopyrazine
provided the compound 11, through homocoupling of the
iodopyrazine (entry 8). Finally, to explore the scope of the
reaction, it was decided to use dihydro-2H-pyran as substrate
instead of 2,3-DHF (entry 9-11, Table 3), obtaining the double
98a,b
9
63a
20c
58c
addition products 12
, 13 and 14, while simultaneously
recovering the starting aryl halide.
10
11
a
b
CEM reactor 60 W, 30 minutes, open vessel. Microwave synthesizer Biotage 100 W,
15 minutes, closed vessel. c CEM reactor 120 W, 90 minutes.
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A suitable crystal24 of product
5
was obtained by crystallization A plausible mechanism for the catalytic cycle leVaiedwinAgrtictleoOntlhinee
DOI: 10.1039/D0NJ02630A
from hexane/acetone (8:2) and was subjected to X-ray formation of aromatic γ-hydroxy-ketones 2-10 is presented in
diffraction analysis (Figure 2).25 The structure that was Scheme 4. According to this proposal, the first step involves the
determined confirms the presence of the carbonyl and hydroxyl reduction of the catalyst palladium Pd(II) to Pd(0), favoured in
groups, and it can be appreciated that adopts a stretched DMF, to give complex
conformation where these groups adopt an anti-orientation.
B
. This is followed by the oxidative
addition of aryl halide to catalyst , which involves Pd(0) to
Pd(II) oxidation to provide intermediate C.26 Subsequent
addition of 2,3-dihydrofuran provides π complex , which
enables C C bond formation between the olefin and the
aromatic ring in syn fashion to afford intermediate . The
1
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E
−
F
regiochemistry of the migration step is understood in terms of
the negative charge that is highly localized at the ipso C atom,
that is transferred to the positive
ether generating the
-complex on the beta-carbon 27
of water at the activated benzylic position gives rise to species
with subsequent opening of the furan ring.
-carbon atom of the vinyl
Figure 2. X-ray diffraction crystallographic structure of γ-hyroxyketone 5 showing its
solid-state conformation.

.
Addition
G
Scheme 4. Plausible mechanism for the palladium-catalyzed formation of aryl γ-hydroxy-ketones 2-10.
As expected from a typical Heck mechanism,28 the catalytic K 29
cycle is completed by rotation of the new C C bond in order to separation of enol
orient the benzylic hydrogen syn-periplanar to the palladium via tautomerization. The π complex
), inducing β-hydride elimination to produce π complex intermediate M 30
metal ( subsequently giving rise to 2
,
with concomitant regeneration of the catalyst, as well as
, that gives rise to aryl γ-hydroxy-ketone
could also lead to
. Seeking to
−
L
2
K
I
,
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support the proposed mechanism, in particular in order to was submitted to 5 mol % of
1
, 3 equiv. of N,N-diisVoiepwroArpticylleeOtnhlinyel
DOI: 10.1039/D0NJ02630A
identify the most important catalytic species with m/z ratio amine, in DMF and 8 equiv. of deuterium oxide, in the
280.3 [M+Na], the Heck coupling reaction with 4-iodophenol microwave reactor at 60 W. The reaction does not proceed,
and 2,3-DHF in oil bath was monitored by ESI-MS (Figure 3 top). recovering substrate 9.
The loss of atomic palladium isotope ion [106Pd+Na]+ of m/z
130.2 (60%) characteristic Pd(0) together with four ionic
species, was detected after one hour of reaction. The most
abundant of the recorded ions being that of m/z 450 (100%)
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that was identified as intermediate [
F
]+, product of syn
+
insertion. Besides, product [
C
]
resulting from the oxidative
addition of aryl halide, of m/z 436 (7%) was also detected.
Finally, the opening of the ring was clearly detected as [
]+ and
]+, with m/z 520 and 612, respectively, formed by the addition
of one water molecule to active catalytic species
G
[
H
F.
Scheme 5. Heck reaction in the presence of D2O.
Interestingly, the composition of the mixture of cationic
intermediates does not change significantly after 6 hours
DFT calculations, at the PBE0/TZDP(COSMO-DMF)//PBE0/DZ
level of theory, have confirmed the plausibility of the catalytic
cycle mechanism showed in Scheme 4. Energetic profiles
showing minima along the potential energy surface are
displayed in Figure 4. The largest energetic drop observed
(Figure 3 bottom) and highlights the presence of ion [D
]+, a
species with m/z 380.3 arising from oxidative addition of aryl
halide with a DMF molecule attached to the metal center (see
Scheme 4).
corresponds to the catalyst reduction, going from
represents an exergonic process of 42.4 kcal/mol. By contrast,
the oxidative addition of furan and iodine is an endoergic
A to B and
process of 5.9 kcal/mol to reach
DMF represents a drop of 10.6 kcal/mol in energy, giving
structure . Addition of 2,3-dihydrofuran to obtain increases
the energy by about 16.6 kcal/mol. Observe that the π-complex
formation of this structure enables C C bond formation
between the olefin and the aromatic ring to get with an
exergonicity of 24.8 kcal/mol. Regarding the possibility that
C. Substitution of iodine by
D
E
−
F
F
triggers the elimination of the catalyst, we have calculated the
energetic cost of such elimination and the results suggest that
this process is not possible because the end product of this
elimination would be 114.37 kcal/mol higher in energy. In
addition, it is evident that in intermediate F glycine is taking part
in a hydrogen bond with the phenyl moiety, stabilizing the
energy of the molecule (Details in the Supporting Information)
and increasing the binding strength of the catalyst with the
molecule in process of being transformed. In addition, breaking
a palladium-carbon bond will result in a large activation energy,
making this reaction path rather unlikely. Addition of water to
Figure 3. Top, ESI-MS spectrum following the adition of 2,3-DHF. Bottom, ESI-MS
spectrum after 6 hours of reaction.
F
gives rise to
rotation of the new C
syn-periplanar to the palladium metal to get
in only 2.4 kcal/mol. On the other hand, three different
pathways seem feasible to obtain product and recover the
active catalyst through and . Formation of complex from I
G
with a small energetic cost of 4.8 kcal/mol. The
C bond to orient the benzylic hydrogen
increases energy
−
Support for the mechanism advanced in Scheme 4 was also
provided by the fact that condensation of 1-benzyloxy-4-
iodobenzene and 2,3-DHF, in the presence of 2 equiv. of
deuterium oxide (Scheme 5) afforded 1-(4-(benzyloxy)phenyl)-
I
2
K
M
K
4-hydroxybutan-1-one-2,2-d2
(
9
-d2,
86%
deuterium
increases energy content by 5.6, 6.8 and 11.4 kcal/mol for DMF,
iodine and chlorine, respectively. Formation of oxygen complex
incorporation) which is in line with water being incorporated in
the final aryl-γ-hydroxy-ketones. In this context, when the
reaction was carried out with iodoanisole (Scheme 5), products
M
increases energy by 1.1 kcal/mol in the case of X = Cl, but
results in a reduction of 2.8 and 12.9 kcal/mol for X = iodine and
X = DMF, respectively. Regarding the formation of γ-hydroxy-
ketone 2, it is observed that the product with X = DMF is the
most stable, followed by X = iodine with 5.9 kcal/mol and by the
compound with X = chlorine with an energy of 9.3 kcal/mol.
Finally, the recovery of the catalyst is an endergonic process of
20.9, 24.3 and 30.2 kcal/mol for X = Cl, X = I and X = DMF,
4
and
5
containing two deuteriums at the carbonyl’s alpha
takes place via a
position, suggest that formation of
5
tautomeric process subsequent to β-hydride elimination. To
corroborate that the deuterium incorporation to Cα occurs as
part of the catalytic cycle and not as an exchange by deuterium
of the alpha carbonyl protons of γ-hydroxy-ketone formed,
9
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G-I-J-H is showed in the orange inset, compute the energy of two electrons located in the highest
1
2
3
4
5
6
7
8
respectively. Sub-cycle
View Article Online
being
kcal/mol.
Regarding the estimation of the energy associated to the between reduction-oxidation potentials has been discussed
reduced palladium species (
), we proceeded in the following previously by Dance.31
J
the most stable structure, with a relative energy of 7.9 occupied molecular orbital (HOMO) oDfOBI:.10S.1u0c3h9/Dp0rNoJc0e2d6u30rAe
ensures the adequate energetic comparison. The relationship
B
manner. The overall reduction reaction from
modelled in the following way:
A
to
B
was The calculation of energetic barriers is fundamental for the
description of the kinetic characteristics of a chemical reaction.
The kinetic description of the present catalytic cycle is in
progress.
9
푨 + 2 풆−
→ 푩
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Reduced palladium is only present in species
B, for this reason Details of structures, coordinates and other computation details
in order to include in the overall mechanism it is needed to are placed in the Supplementary Material.
B
Figure 4. Energetic profile for the modeled mechanism for the palladium-catalyzed formation of aryl γ-hydroxy-ketones based on Scheme 4. Color code: carbon atoms
as grey spheres, nitrogen atoms as blue spheres, oxygen atoms as red spheres, hydrogen atoms as white spheres, palladium atoms as orange spheres, chlorine atoms
as green spheres, iodine atoms as purple spheres. The final part of profile shows three ramifications depending on the substituent, green profile holds for X = chlorine,
purple profile holds for X = iodine, red profile holds for X = DMF. The inset in orange represents the energetic profile of the G-I-J-H sub-cycle.
Furthermore, the formation of double Heck intermediates may
be explained through the plausible mechanistic pathway
advanced in Scheme 6. Oxidative addition of aryl halide to
reduced catalyst
B
provides intermediate
C
and subsequent
that
addition of aryl-hydroxyketone provides intermediary
suffers β-hydride elimination to form π complex Q.32 The aryl
O
migratory insertion in the carbonyl group gives rise to oxygen
complex R 33
,
which gives rise to the final hydroxy-ketone, with
concomitant regeneration of the catalyst trough reductive
elimination of N 34
.
Scheme 6. Plausible mechanism of double Heck reaction.
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On the other hand, the homo-coupling product 11 is particularly
interesting since the synthesis of bis-heteroaryls usually requires of
Ullmann reductive homo-coupling reaction catalyzed by Pd/C. The
Ullman reaction is carried out under elevated temperatures in the
presence of reducing agents such as H2(g), Zn, In, and inorganic salts
to regenerate the Pd(0) active species from Pd(II).35,36 A plausible
reaction mechanism is shown in Scheme 7. The oxidative addition of
points were measured with a Fischer model 1237 aVpiepwaArratitculesOannlinde
are uncorrected. IR spectra were recorded on a Thermo
DOI: 10.1039/D0NJ02630A
Scientific Nicolet iS10 apparatus. NMR spectra were obtained
with Varian Mercury plus (100 and 400 MHz) spectrometer.
Mass spectra were obtained with Thermo Scientific ISQ CT
spectrometer using electronic impact ionization. High
resolution mass spectrometry data were obtained with a
Thermo Scientific Q Exactive Plus spectrometer. The EDX
spectrum was obtained with Bruker AXS Microanalysis GmbH
electronic microscope. Crystallographic data were collected
with Bruker D8 Venture X-ray diffractometer with a PHOTON 2
detector. The γ-hydroxyketones were synthesized in CEM
Discover microwave 201A15, 20 MHz and in Biotage® Initiator
organic microwave synthesizer.
Computational details: Geometries along the catalytic cycle
where calculated. Single points at the PBE0/TZDP(COSMO-DMF)
over full optimizations at the PBE0/DZ level of theory where
performed using the Amsterdam Density Functional software.43
An exploration of the possible conformations of all geometries
where addressed, the resulting geometries with the lowest
energies where used to study the catalytic mechanism. The final
minimum geometries along the catalytic cycle where confirmed
by calculation of frequencies.
Glycine palladium (II) chloride (1). Palladium chloride (PdCl2)
(200 mg, 1.22 mmol) dissolved in CH3CN was heated to reflux
for 2h under N2 atmosphere and to the resulting mixture was
added glycine (177 mg, 2.36 mmol). The reaction was heated to
reflux for 20 h. The reaction was quenched carefully with ice-
cold H2O. The solid obtained was filtered and washed with cold
ethanol and CH3CN. Yellow solid (0.239 g, 85 %); mp. 184-187 °C
(CH3OH/CH2Cl2). 1H NMR (400 MHz; DMSO-d6; TMS) δ ppm: 3.75
(2H, s, NH2), 3.70 (2H, s, CH2). 13C NMR (100 MHz; DMSO-d6;
TMS) δ ppm: 168.0, 52.5. m/z: 269 (M+, 4%), 235(29), 219(20),
45(100); IR vmax/cm-1: 3299, 3241, 2970, 2579, 1698, 1436,
1249, 1063, 926, 708.
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2-iodopyrazine to the reduced catalyst forms complex
C. The
replacement of iodo with DIPEA followed by another oxidative
addition of 2-iodopyrazine affords the complex Pd(IV) U and its
reductive elimination produces the 2,2’-bis-pyrazine 11.37
Scheme 7. Plausible mechanism of homocoupling reaction of 2-iodopirazine.
Finally, oxidation of γ-hydroxy-ketone 2 with Jones reagent provided
4-(4-hydroxyphenyl)-4-oxobutanoic acid (15)38 (CAS No. 56872-39-
0),39 a keto-acid with choleretic40 and antiaggregation41 activity
(Scheme 8). Moreover, this is an important synthon in the synthesis
of bioactive compounds that are used as binding and inhibiting
agents of the endonuclease influenza virus.21 Finally, γ-hydroxy-
ketone 2 is an intermediate for the synthesis of aryl gpr120 receptor
agonist.42
General procedure for the preparation of γ-hydroxy-
phenylketones, and their analytical data.
Procedure A.
A
mixture of aryl halide (1 equiv.),
diisopropylethylamine (3 equiv.) and 2,3-dihydrofuran (5.1 equiv.) in
3 ml of DMF and 0.2 ml of H2O was treated with catalyst 1 (5 mol%).
The resulting mixture was placed in a microwave reactor provided
with a condenser and irradiated at 60 watts of power for a period of
30 min.
Procedure B.
A
mixture of aryl halide (1 equiv.),
diisopropylethylamine (3 equiv.) and 2,3-dihydrofuran (5.1 equiv.) in
1 ml of DMF and 0.2 ml of H2O was treated with catalyst 1 (5 mol%)
in a closed vessel. The resulting mixture was placed in a Microwave
Synthesizer Biotage and irradiated at 100 watts of power for 15 min
with the pressure indicated in each case.
Scheme 8. Selective oxidation of γ-hydroxy-ketone 2 to carboxylic acid 15.
Procedure C.
A
mixture of aryl halide (1 equiv.),
diisopropylethylamine (3 equiv.) and 3,4-dihydro-2H-pyran or 2,3-
dihydrofuran (5.1 equiv.) in 3 ml of DMF and 0.2 ml of H2O was
treated with catalyst 1 (5 mol%). The resulting mixture was placed in
a microwave reactor provided with a condenser and irradiated at 120
watts of power for a period of 30 min.
Experimental
Materials and methods
Column chromatography was carried out with Merck Silica Gel
(70-230 Mesh). TLC was performed with Merck 60-F25 plates
employing UV light and iodine vapor for visualization. Melting
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In the procedures A, B and C the reaction mixture was washed with 92(12). IR vmax/cm-1: 3315, 2953, 2848, 1663, 1597 1242, 1169,
H2O and the product was extracted with EtOAc (3x20 ml). The 1021, 833, 808.
combined organic phase was dried with Na2SO4 and concentrated
View Article Online
DOI: 10.1039/D0NJ02630A
under vacuum.
4-Hydroxy-1-(4-hydroxyphenyl)-butan-1-one (2). It was and 4-hydroxy-1,4-bis(4-methoxyphenyl)butan-1-one-2,2-d2
obtained by the procedures A and B. The crude product was (5-d2)
-d2 1H NMR (400 MHz; CDCl3; TMS) δ ppm: 7.97 (2H, d,
4-Hydroxy-1-(4-methoxyphenyl)-butan-1-one-2,2-d2,
(4-d2)
.
4
purified by chromatography using a mixture hexane/EtOAc (1:1) J = 8.9 Hz, Ar-H), 6.94 (2H, d, J = 8.9 Hz, Ar-H), 3.88 (3H, s, CH3),
to provide the product, whose experimental properties were in 3.74 (2H, t, J = 6.0 Hz, CH2), 3.08 (1H, m, CH2, 50% deuterium
agreement with those reported in the literature.44a White solid incorporation), 2.01 (3H, m, CH2, OH). 13C NMR (100 MHz;
(32 mg, 79% procedure A and 23 mg, 95% procedure B), mp 112- CDCl3; TMS) δ ppm: 199.2, 163.5, 130.3, 129.85, 113.7, 62.4,
10
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114 °C (Hex/Acetone). 1H NMR (400 MHz; CD3OD; TMS) δ ppm: 55.4, 35.0, 26.9, 26.9. -d2 1H NMR (400 MHz; CDCl3; TMS) δ
5
7.89 (2H, d, J = 8.8 Hz, Ar-H), 6.83 (2H, d, J = 8.8 Hz, Ar-H), 3.62 ppm: 7.93 (2H, d, J = 9.0 Hz, Ar-H), 7.30 (2H, d, J = 8.5 Hz, Ar-H),
(2H, t, J = 6.4 Hz, CH2), 3.02 (2H, t, J = 7.3 Hz, CH2), 1.89 (2H, qt, 6.92 (2H, d, J = 9.0 Hz, Ar-H), 6.89 (2H, d, J = 8.7 Hz, Ar-H), 4.77
J = 6.5, 7.4 Hz, CH2). 13C NMR (100 MHz; CD3OD; TMS) δ ppm: (1H, t, J = 6.3 Hz, CH), 3.87 (3H, s, CH3), 3.81 (3H, s, CH3), 3.05
201.1, 163.7, 131.7, 130.0, 116.2, 62.3, 35.3, 28.5. m/z: 162 (M- (0.5H, m, CH2, 78% deuterium incorporation), 2.46 (1H, s, OH),
18, 83%), 133(17), 121(100), 93(15); IR vmax/cm-1: 3431, 3145, 2.17 (2H, m, J = 6.8 Hz, CH2). 13C NMR (100 MHz, CDCl3) δ ppm:
2970, 1654, 1582, 1206, 1046, 1015, 827.
4-(4-Hydroxyphenyl)-4-oxobutanal (3). 25 mg (0.13 mmol) of
199.1, 163.4, 159.0, 136.5, 130.3, 129.8, 126.9, 113.8, 113.6,
73.3, 55.4, 55.2, 34.5, 33.1.
2
it was treated with 3 equiv. (15 mg, 0.41 mmol) of pyridinium 1-(4-Ethoxyphenyl)-4-hydroxybutan-1-one (6). The crude
dichromate (PDC) in methylene dichloride at ambient product was purified by chromatography using a mixture
temperature for 3 h, the reaction mixture was washed with hexane/EtOAc (7:3) to afford the expected product, whose
water and the product was extracted with AcOEt (3X15 ml), experimental properties were in agreement with those
dried with Na2SO4 and concentrated under vacuum. The crude reported in the literature.44e,f Yellow oil (32 mg, 71% procedure
1
product was purified by chromatography using a mixture A; 26 mg; 92% procedure B and 9 mg, 37% procedure C). H
hexane/EtOAc (8:2), to provide the product, whose NMR (400 MHz; CDCl3; TMS) δ ppm: 7.95 (2H, d, J = 8.9 Hz, Ar-
experimental properties were in agreement with those H), 6.92 (2H, d, J = 8.9 Hz, Ar-H), 4.10 (2H, q, J = 7.0 Hz, CH2),
1
reported in the literature.44b Oil white (19 mg, 79 %). H NMR 3.74 (2H, t, J = 6.0 Hz, CH2), 3.09 (2H, t, J = 6.9 Hz, CH2), 2.17 (1H,
(400 MHz; CDCl3; TMS) δ ppm: 9.91 (1H, s, CHO), 7.93 (2H, d, J = s, OH), 2.05–1.96 (2H, m, CH2), 1.44 (3H, t, J = 7.0 Hz, CH3). 13
C
8.8 Hz, Ar-H), 6.88 (2H, d, J = 8.8 Hz, Ar-H), 5.53 (1H, s, OH), 3.28 NMR (100 MHz; CDCl3; TMS) δ ppm: 199.2, 162.9, 130.3, 129.6,
(2H, t, J = 6.4 Hz, CH2), 2.92 (2H, t, J = 6.4 Hz, CH2). 13C NMR (100 114.1, 63.7, 62.3, 34.9, 27.0, 14.6. m/z: 207 (M-18, 100%),
MHz; CDCl3; TMS) δ ppm: 201.0, 196.3, 160.1, 130.6, 115.3, 161(27),149(84), 133(23), 121(93). IR vmax/cm-1: 3201, 2971,
37.6, 30.6.
2930, 1671, 1598, 1239, 1168, 1041, 840.
4-Hydroxy-1-(4-methoxyphenyl)-butan-1-one, (4) and 4- 1,4-bis(4-Ethoxyphenyl)-4-hydroxybutan-1-one
(7)
.
The
hydroxy-1,4-bis(4-methoxyphenyl)butan-1-one (5). The crude General procedure C was followed and the crude product was
product was purified by chromatography using a mixture purified by chromatography using a mixture hexane/EtOAc
1
hexane/EtOAc (7:3), obtaining two products
and B) and
were in agreement with those reported in the literature.44c,d 6.90 (2H, d, J = 8.9 Hz, Ar-H), 6.87 (2H, d, J = 8.7 Hz, Ar-H), 4.77
Compound was isolated as a white solid, (28 mg, 51% (1H, t, J = 5.6 Hz, CH), 4.09 (2H, q, J = 7.0 Hz, CH2), 4.03 (2H, q, J
4
(procedures A (8:2). Clear oil (16 mg, 41%). H NMR (400 MHz; CDCl3; TMS) δ
5
(procedure A), whose experimental properties ppm: 7.92 (2H, d, J = 8.9 Hz, Ar-H), 7.29 (2H, d, J = 8.7 Hz, Ar-H),
4
procedure A and 22 mg, 89 % procedure B) mp 104-106 °C = 7.0 Hz, CH2), 3.04 (2H, m, CH2), 2.42 (1H, s, OH), 2.17 (2H, m,
1
(Hex/AcOEt). H NMR (400 MHz; CDCl3; TMS) δ ppm: 7.97 (2H, CH2), 1.44 (3H, t, J = 7.0 Hz, CH3), 1.41 (3H, t, J = 7.0 Hz, CH3). 13
C
d, J = 9.0 Hz, Ar-H), 6.94 (2H, d, J = 8.9 Hz, Ar-H), 3.87 (3H, s, NMR (100 MHz; CDCl3; TMS) δ ppm: 199.1, 162.9, 158.3, 136.3,
CH3), 3.74 (,2H, t, J = 6.0 Hz, CH2), 3.09 (2H, t, J = 6.9 Hz, CH2), 130.3, 129.7, 126.9, 114.4, 114.0, 73.3, 63.7, 63.4, 34.4, 33.1,
2.15 (1H, s, OH), 2.01 (2H,m, CH2). 13C NMR (100 MHz; CDCl3; 14.8, 14.6. m/z: 310 (M-18, 4%), 149(100), 121(69), 93(19).
+
TMS) δ ppm: 199.2, 163.5, 130.4, 129.8, 113.7, 62.4, 55.4, 35.0, HRMS (ESI-MS, m/z): calcd. for [C20H24O4 ] 328.1669; found
27.0. m/z: 194 (M+, 4%), 176 (83), 150(79), 135(100), 107(26), 328.1625.
92(22). IR vmax/cm-1: 3357, 2932, 1676, 1596, 1361, 1018, 827, 4-Hydroxy-1-(naphthalen-1-yl)butan-1-one (8). The crude
764. Compound
5
1
is a crystalline solid (14 mg, 22%); mp 67-69 product was purified by chromatography using a mixture was
°C (Hex/CH2Cl2). H NMR (400 MHz; CDCl3; TMS) δ ppm: 7.93 purified by chromatography using hexane. Experimental
(2H, d, J = 9.0 Hz, Ar-H), 7.30 (2H, d, J = 8.8 Hz, Ar-H), 6.92 (2H, properties were in agreement with those reported in the
d, J = 9.0 Hz, Ar-H), 6.89 (2H, d, J = 8.7 Hz, Ar- H), 4.77 (1H, t, J = literature.44e Yellow oil (53 mg, 76% procedure A and 23 mg,
6.3 Hz, CH), 3.87 (3H, s, CH3), 3.81 (3H,s, CH3), 3.05 (2H, dd, J = 85% procedure B). 1H NMR (400 MHz; CDCl3; TMS) δ ppm: 8.58
7.6, 6.9 Hz, CH2), 2.46 (1H, s, OH), 2.17 (2H, m, CH2). 13C NMR (1H, d, J = 8.4 Hz, Ar-H), 7.99 (1H, d, J = 8.2 Hz, Ar-H), 7.90 (2H,
(100 MHz; CDCl3; TMS) δ ppm: 199.2, 163.5, 159.0, 136.5, 130.4, dd, J = 9.3, 8.3 Hz, Ar-H), 7.63–7.48 (3H, m, Ar-H), 3.79 (2H, t, J
129.9, 127.0, 113.8, 113.8, 73.3, 55.4, 55.3, 34.5, 33.2. m/z: = 5.9 Hz, CH2), 3.22 (2H, t, J = 6.9 Hz, CH2), 2.13–2.05 (2H, m,
299(M-18, 2 %), 280(79), 265(87), 164(44), 151(50), 135(100), CH2), 1.73 (1H, s, OH). 13C NMR (100 MHz; CDCl3; TMS) δ ppm;
204.8, 135.9, 133.9, 132.6, 130.0, 128.4, 127.8, 127.4, 126.4,
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125.7, 124.3, 62.3, 38.8, 27.3. m/z: 196 (M-18, 100%), 165(46), 2.04 (1H, s, OH), 1.93 – 1.80 (2H, m, CH2), 1.81–1.68 (2H, m,
View Article Online
155(100), 127(75). IR vmax/cm-1: 3470, 2928, 1678, 1508, 1239, CH2). C NMR (100 MHz; CDCl3; TMS) DδOIp: p10m.1:03199/D80.8N,J0123673.01A,
13
1065, 802, 775.
136.7, 134.4, 130.2, 127.1, 113.8, 113.6, 73.8, 55.4, 55.2, 38.5,
4-Hydroxy-1-(4-(benzyloxy)phenyl)butan-1-one (9). The crude 37.8, 20.64. m/z: 296(M-18, 17%), 147(26), 135(100), 121 (27),
+
product was purified by chromatography using a mixture 91(20). HRMS (ESI-MS, m/z): calcd. for [C19H22O4 ] 314.1522;
hexane/EtOAc (8:2) to afford the expected product, whose found 314.1469.
experimental properties were in agreement with those 1,5-bis(4-Ethoxyphenyl)-5-hydroxypentan-1-one (13). The
reported in the literature.44g,f White solid (49 mg, 80% crude product was purified by chromatography using
procedure A and 34 mg, 80% procedure B); mp 94-96 °C hexane/AcOEt (8:2). Clear oil (8 mg, 20% procedure C). 1H NMR
(Hex/Acetone). 1H NMR (400 MHz; CDCl3; TMS) δ ppm: 7.97 (2H, (400 MHz; CDCl3; TMS) δ ppm: 7.91 (2H, d, J = 8.9 Hz, Ar-H), 7.27
d, J = 8.8 Hz, Ar-H), 7.44-7.34 (5H, m, Ar-H), 7.01 (2H, d, J = 8.7 (2H, d, J = 8.5 Hz, Ar-H), 6.90 (2H, d, J = 8.9 Hz, Ar-H), 6.86 (2H,
Hz, Ar-H), 5.14 (2H, s, CH2), 3.74 (2H, t, J = 5.6 Hz, CH2), 3.09 (2H, d, J = 8.7 Hz, Ar-H), 4.65, (1H, t, J = 6.0 Hz, CH), 4.09 (2H, q, J =
t, J = 6.9 Hz, CH2), 2.04-1.97 (2H, m, CH2), 1.87 (1H, s, OH). 13C 7.0 Hz, CH2), 4.02 (2H, q, J = 7.0 Hz, CH2), 2.95 (2H, dd, J = 11.0,
NMR (100 MHz; CDCl3; TMS) δ ppm: 199.1, 162.6, 136.1, 130.3, 7.0 Hz, CH2), 2.01 (1H, s, OH), 1.92 – 1.82 (2H, m, CH2), 1.82 –
128.6, 128.2, 127.4, 114.5, 70.1, 62.4, 35.0, 27.0. m/z: 252(M- 1.67 (2H, m, CH2), 1.42 (6H, dt, J = 13.8, 7.0 Hz, CH3). 13C NMR
18, 18%), 91(100). IR vmax/cm-1: 3335, 2979, 1675, 1601, 1249, (100 MHz; CDCl3; TMS) δ ppm: 198.8, 162.7, 157.2, 136.5, 131.7,
9
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1171, 1014, 621, 741.
130.2, 129.8, 129.7, 127.0, 125.8, 114.3, 114.0, 73.9, 63.7, 63.4,
4-Hydroxy-1-(4-(benzyloxy)phenyl)butan-1-one-2,2-d2 (9-d2). 38.5, 37.8, 20.6, 14.8, 14.6. m/z: 324(M-18, 8%), 161(14),
1H NMR (400 MHz; CDCl3; TMS) δ ppm: 7.96 (2H, d, J = 8.8 Hz, 149(100), 133(17), 121(45). HRMS (ESI-MS, m/z): calcd. for
+
Ar-H), 7.47–7.31 (5H, m, Ar-H), 7.01 (1H, d, J = 8.8 Hz, Ar-H), 5.13 [C21H26O4 ] 342.1825; found 342.1782.
(1H, s, CH2), 3.73 (2H, t, J = 6.0 Hz, CH2), 3.09 (0.5H, t, J = 6.9 Hz, 1,5-bis(4-(Benzyloxy)phenyl)-5-hydroxypentan-1-one
(14).
CH2, 86% deuterium incorporation), 2.06 (1H, s, OH), 1.99 (2H, The crude product was purified by chromatography using
t, J = 6.1 Hz, CH2).13C NMR (100 MHz; CDCl3; TMS) δ ppm: 199.2, hexane/AcOEt (8:2). White solid (34 mg, 58% procedure C); mp
162.6, 136.1, 130.3, 130.0, 128.6, 128.2, 127.4, 114.5, 70.0, 108-109 °C (Hex/CH2Cl2). 1H NMR (400 MHz; CDCl3; TMS) δ ppm:
62.3, 26.9, 26.9. m/z: 254.12 (M-18, 5.0%), 252(93), 91(100).
7.92 (2H, d, J = 8.9 Hz, Ar-H), 7.46 – 7.24 (12H, m, Ar-H), 6.99
1-([1,1'-Biphenyl]-4-yl)-4-hydroxybutan-1-one (10). The crude (2H, d, J = 8.9 Hz, Ar-H), 6.95 (2H, d, J = 8.7 Hz, Ar-H), 5.12 (2H,
product was purified by chromatography using a mixture s, CH2), 5.05 (2H, s, CH2), 4.66 (1H, t, J = 6.0 Hz, CH2), 2.95 (2H,
hexane/EtOAc (7:3) to afford the expected product, whose dd, J = 10.7, 7.0 Hz, CH2), 2.04 (1H, s, OH), 1.93 – 1.81 (2H, m,
experimental properties were in agreement with those CH2), 1.81 – 1.68 (2H, m, CH2). 13C NMR (100 MHz; CDCl3; TMS)
reported in the literature.44i Oil colorless (17 mg, 52% procedure δ ppm: 198.7, 162.5, 158.2, 136.9, 136.1, 130.2, 130.1, 128.6,
A and 30 mg, 90% procedure B). 1H NMR (400 MHz; CDCl3; TMS) 128.5, 128.2, 127.9, 127.4, 127.1, 114.7, 114.5, 73.8, 70.0, 70.0,
δ ppm: 8.06 (2H, d, J = 8.5 Hz, Ar-H), 7.69 (2H, d, J = 8.5 Hz, Ar- 38.51, 37.8, 20.6. m/z: 467 (M+, 1%), 147(27), 107(60), 91(69),
+
H), 7.63 (2H, d, J = 7.1 Hz, Ar-H), 7.53 – 7.44 (2H, m, Ar-H), 7.44 55(100). HRMS (ESI-MS, m/z): calcd. for [C31H30O4 ] 466.2139;
– 7.37 (1H, m, Ar-H), 3.77 (2H, t, J = 6.0 Hz, CH2), 3.18 (2H, t, J = found 466.2101.
6.9 Hz, CH2), 2.05 (2H, qt, J = 6.8 Hz, CH2), 1.83 (1H, s, OH). 13
C
4-(4-Hydroxyphenyl)-4-oxobutanoic acid (15). A mixture of 15
NMR (100 MHz; CDCl3; TMS) δ ppm: 200.1, 145.7, 139.8, 135.5, mg (0.083 mmol) of arylhydroxyketone, in 5 ml of acetone was
128.9, 128.6, 128.2, 127.2, 62.3, 35.3, 26.9. m/z: 240(M+, 1%), treated with 20 mg (9.2 mmol) of CrO3 in H2SO4 (Jones reagent). The
222(100), 181(84), 152(91). IR vmax/cm-1: 3436, 2932, 2864, resulting mixture was allowed to react at room temperature for 20
1681, 1639, 1263, 1024, 562.
h; the reaction mixture was washed with H2O and the product was
2,2'-Bipyridine (11). For homocoupling the general procedure B extracted with CH2Cl2 (3x5 ml). The combined organic phase was
was followed and the crude product was purified by dried with Na2SO4 and concentrated under vacuum. The crude
chromatography using a mixture hexane/Acetone (7:3) to product was purified by chromatography using a mixture of
afford 11, whose experimental properties were in agreement hexane/EtOAc (7:3) to provide pure acid 15
, whose
with those reported in the literature.44j Crystalline solid (20 mg, experimental properties were in agreement with those
98%); mp 72-74 °C (CH2Cl2/Acetone). 1H NMR (400 MHz; DMSO- reported in the literature.38,39 White solid (09 mg, 60%), mp 151-
d6; TMS) δ ppm: 9.48 (2H, d, J = 1.4 Hz, Ar-H), 8.82–8.79 (2H, m, 152 °C. 1H NMR (400 MHz, CD3OD, TMS) δ ppm: 7.90 (2H, d, J =
Ar-H), 8.78 (2H, d, J = 2.5 Hz, Ar-H). 13C NMR (100 MHz; DMSO- 8.8 Hz, Ar-H), 6.83 2H, (d, J = 8.8 Hz, 1Ar-H), 3.24 (2H, t, J = 6.4
d6; TMS) δ ppm: 148.6, 145.7, 144.2, 142.6. m/z: 156(M-1, Hz, CH2), 2.66 (2H, t, J = 6.4 Hz, CH2). 13C NMR (100 MHz; CD3OD;
100%), 106(21), 105(15). IR vmax/cm-1: 3315, 2953, 2848, 1663, TMS) δ ppm: 199.1, 176.8, 163.7, 131.6, 129.8, 116.2, 33.9, 29.0.
1597 1242, 1169, 1021, 833, 808.
5-Hydroxy-1,5-bis(4-methoxyphenyl)pentan-1-one (12). The
Conclusions
Palladium(II) glycine complex
general procedure C was followed and the residue was purified
1
by chromatography using hexane. Clear oil (25 mg, 63%); H
1 is an efficient catalyst for the
NMR (400 MHz; CDCl3; TMS) δ ppm: 7.92 (2H, d, J = 8.9 Hz, Ar-
H), 7.28 (2H, d, J = 8.6 Hz, Ar-H), 6.92 (2H, d, J = 8.9 Hz, Ar-H),
6.88 (2H, d, J = 8.7 Hz, Ar-H), 4.66 (1H, t, J = 6.2 Hz, CH), 3.87
(3H, s, CH3), 3.80 (3H, s, CH3), 2.95 (2H, dd, J = 10.9, 6.9 Hz, CH2),
preparation of aryl-γ-hydroxy-ketones, which were obtained via
Heck coupling reaction, followed by the addition of one
molecule of water and simultaneous ring opening. Palladium
promoted β-hydride elimination at the benzylic position is
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1
2
3
4
5
6
7
8
9
4
a) C. S. García, P. M. Uberman and S. E. Martín, Beilstein J. Org.
Chem., 2017, 13, 1717-1727; b) E. CDinOi,I: E10..1P0e3Vt9ire/iDwcc0AiNrtiJac0lne2dO6n3Ml0inAe.
accompanied by recovery of the catalyst and formation of the
hydroxy-ketone product via keto-enol tautomerism. The
present synthetic methodology benefits from microwave
activation and simplifies significantly the preparation of aryl-γ-
hydroxy-ketones in short, less than 30 minutes reaction time.
Theoretical calculations at the PBE0/TZDP(COSMO-DMF) level
provide convincing evidence to support the proposed
mechanism of the catalytic cycle.
Taddei, Catalysts, 2017,
Catalysts 2020, 10, 4; d) M. Larhed and A. Hallberg, Drug
Discov. Today, 2001, , 406-416; e) R. K. Arvela and N. E.
7, 89; c) K. S. M. Salih and Y. Baqi,
6
Leadbeater, J. Org. Chem., 2005, 70, 1786-1790; f) B. K. Singh,
N. Kaval, S. Tomar, E. V. d. Eycken and V. S. Parmar, Org.
Process Res. Dev., 2008, 12, 468-474; g) K. Dhara, B. Parasar,
A. J. Patil and J. Dash, Synth. Commun., 2019, 49, 859-868; h)
K. M. Dawood, Tetrahedron 2007, 63, 9642-9651.
M. Larhed and A. Hallberg, J.Org. Chem., 1996, 61, 9582-9584.
X. Xie, J. Lu, B. Chen, J. Han, X. She and X. Pan, Tetrahedron
Lett., 2004, 45, 809-811.
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11
12
13
14
15
16
17
18
19
20
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22
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59
60
5
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Conflicts of interest
There are no conflicts to declare.
7
8
P. Kaukoranta, K. Källström and P. G. Andersson, Adv. Synth.
Catal., 2007, 349, 2595-2602.
a) M. Shibasaki, E. M. Vogl and T. Ohshima, Adv. Synth. Catal.,
2004, 346, 1533-1552; b) F. Ozawa, A. Kubo and T. Hayashi, J.
Am. Chem. Soc., 1991, 113, 1417-1419.
A. Morel, E. Silarska, A. M. Trzeciak and J. Pernak, Dalton
Trans., 2013, 42, 1215-1222.
Acknowledgements
9
We are indebted to Coordinación de la Investigación Científica
(CIC), Universidad Michoacana de San Nicolás de Hidalgo, for
financial support. We also thank Consejo Nacional de Ciencia y
Tecnología (CONACYT, México) for financial support via grants
No. 220945 and 269863 knowledgements. We thank National
Laboratory UG-UAA-CONACYT for supercomputing resources
and M.A. G-R thank to UG-DAIP for financial support.
10 H. Li, S. L. Wan, C. H. Ding, B. Xu and X. L. Hou, RSC Adv., 2015,
, 75411-75414.
11 a) C. M. Whitehouse, R. N. Dreyer, M. Yamashita and J. B.
Fenn, Anal. Chem., 1985, 57, 675-679; b) P. Chen, Angew.
Chem. Int. Ed., 2003, 42, 2832-2847; c) L. S. Santos, C. H.
Pavam, W. P. Almeida, F. Coelho and M. N. Eberlin, Angew.
Chem. Int. Ed., 2004, 43, 4330-4333; d) L. S. Santos, G. B.
5
Rosso, R. A. Pilli and M. N. Eberlin, J. Org. Chem., 2007, 72
,
5809-5812; e) L. S. Santos, B. A. DaSilveira Neto, C. S. Consorti,
C. H. Pavam, W. P. Almeida, F. Coelho, J. Dupont and M. N.
Eberlin, J. Phys. Org. Chem., 2006, 19, 731-736.
Notes and references
1
a) D. Roy and Y. Uozumi, Adv. Synth. Catal., 2018, 360, 602-
625; b) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew.
Chem. Int. Ed. Engl., 2009, 48, 5094-5115; c) U. Christmann
and R. Vilar, Angew. Chem. Int. Ed. Engl., 2005, 44, 366-374;
d) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem. Int.
Ed. Engl., 2005, 44, 4442-4489; e) F. Erdemir, A. Aktaş, D.
Barut Celepci and Y. Gök, Chem. Pap., 2020, 74, 99-112; f) J. P.
Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651-2710; g)
12 A. A. Sabino, A. H. L. Machado, C. R. D. Correia and M. N.
Eberlin, Angew. Chem. Int. Ed., 2004, 43, 2514-2518.
13 a) K. Morokuma and D. G. Musaev, Computational Modeling
for Homogeneous and Enzymatic Catalysis: A Knowledge-Base
for Designing Efficient Catalysis, John Wiley & Sons, 2008; b)
N. Y. Kozitsyna, S. E. Nefedov, A. P. Klyagina, A. A. Markov, Z.
V. Dobrokhotova, Y. A. Velikodny, D. I. Kochubey, T. S.
Zyubina, A. E. Gekhman, M. N. Vargaftik and I. I. Moiseev,
Inorg. Chim. Acta, 2011, 370, 382-387; c) G. Ujaque and F.
Maseras, Principles and Applications of Density Functional
Theory in Inorganic Chemistry I (Eds. N. Kaltsoyannis, J. E.
McGrady), Springer Berlin Heidelberg, Berlin, 2004.
14 L. J. Gooßen, D. Koley, H. Hermann and W. Thiel, Chem.
Commun., 2004, 2141-2143.
15 R. Kancherla, K. Muralirajan, B. Maity, C. Zhu, P. E. Krach, L.
Cavallo and M. Rueping, Angew. Chem., 2019, 131, 3450-
3454.
P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116
,
12564-12649.
2
a) M. Oestreich, The Mizoroki-Heck Reaction, John Wiley &
Sons, 2009; b) R. F. Heck, Acc. Chem. Res., 1979, 12, 146-151;
c) T. Mizoroki, K. Mori and A. Ozaki, Bull. Chem. Soc. Jpn.,
1971, 44, 581-581; d) K. S. Bloome, R. L. McMahen and E. J.
Alexanian, J. Am. Chem. Soc., 2011, 133, 20146-20148; e) R. F.
Heck, J. Am. Chem. Soc., 1968, 90, 5518-5526; f) R. F. Heck, J.
Am. Chem. Soc., 1969, 91, 6707-6714; g) T. Jia, M. Zhang, H.
Jiang, C. Y. Wang and P. J. Walsh, J. Am. Chem. Soc., 2015, 137
,
16 L. A. Perego, S. Wagschal, R. Grüber, P. Fleurat-Lessard, L. El
Kaïm and L. Grimaud, Adv. Synth. Catal., 2019, 361, 151-159.
17 a) M. T. Reetz, E. Westermann, R. Lohmer and G. Lohmer,
Tetrahedron Lett., 1998, 39, 8449. b) X. Cui, Z. Li, Ch. Z. Tao, Y.
13887-13893; h) A. F. Littke and G. C. Fu, J. Am. Chem. Soc.,
2001, 123, 6989-7000; i) R. F. Heck and J. P. Nolley, J. Org.
Chem., 1972, 37, 2320-2322; j) M. Beller and A. Zapf, Synlett,
1998, 1998, 792-793.
Xu, J. Li, L. Liu and Q. X. Guo, Org. Lett., 2006,
8, 2467.
3
a) J. J. Masters, D. K. Jung, S. J. Danishefsky, L. B. Snyder, T. K.
Park, R. C. A. Issacs, C. A. Alaimo and W. B. Young, Angew.
Chem. Int. Ed. Engl., 1995, 34, 452-455; b) D. Solé, J. Bonjoch,
18 Crystal data for : C6H14Cl2N2O4Pd, monoclinic, space group
1
P21/c, a = 9.0537(3) Å, b = 12.1660(4) Å, c = 5.4933(2) Å, α =
90°, β = 96.599(10)°, γ = 90°, V = 601.06(4) Å3, crystal size:
0.3x0.14x0.04 mm3, R1 = 0.0247 (wR2 = 0.0505). CCDC
1997097 contains the supplementary crystallographic data
for this structure. This data can be obteined free of charge
from The Cambridge Crystallographic Data Center via
http://www.ccdc.cam.ac.uk/data_request/cif.
S. García-Rubio, E. Peidró and J. Bosch, Chem. Eur. J., 2000, 6,
655-665; c) S. J. Danishefsky, J. J. Masters, W. B. Young, J. T.
Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G.
Bornmann, C. A. Alaimo, C. A. Coburn and M. J. Di Grandi, J.
Am. Chem. Soc., 1996, 118, 2843-2859; d) V. H. Rawal and S.
Iwasa, J. Am. Chem. Soc., 1994, 59, 2685-2686; e) Ç. Yolacan,
19 a) R. Amengual, E. Genin, V. Michelet, M. Savignac and J.P.
Genêt, Adv. Synth. Catal., 2002, 344, 393-398; b) C. Wu and J.
Zhou, J. Am. Chem. Soc., 2014, 136, 650-652; c) M. G. Lauer,
M. K. Thompson and K. H. Shaughnessy, J. Org. Chem., 2014,
79, 10837-10848; d) A. R. Hajipour, Z. Khorsandi and H.
E. Bagdatli, N. Öcal and D. E. Kaufmann, Molecules, 2006, 11
603-614; f) J. C. Namyslo and D. E. Kaufmann, Synlett, 1999,
,
,
6
804-806; g) S. C. Clayton and A. C. Regan, Tetrahedron Lett.,
1993, 34, 7493-7496; h) J. R. Malpass and C. D. Cox,
Tetrahedron Lett., 1999, 40, 1419-1422.
Farrokhpour, RSC Adv., 2016, 6, 59124-59130.
10 | J. Name., 2012, 00, 1-3
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Please do not adjust margins
Journal Name
ARTICLE
View Artic,le2O3n3li4ne-
1
2
3
4
5
6
7
8
20 a) S. Asirvatham, B. V. Dhokchawle and S. J. Tauro, Arab. J. 40 R.R Burtner and J. M Brown, J. Am. Chem. Soc., 1953, 75
Chem., 2019, 12, 3948-3962; b) J. Kim, S. Kang, S. Hong, S.
2340.
Yum, Y. M. Kim and Y. Jung, Eur. J. Med. Chem., 2012, 48, 36- 41 M. Kuchař, B. Brunová, J. Grimová, V.
DOI: 10.103R9/eDjh0NoJle0c2,630VA.
Čepelák, Collect. Czech. Chem. Commun., 1986, 51, 2617-
2625.
44.
21 B. M. Baughman, P. Jake Slavish, R. M. DuBois, V. A. Boyd, S.
W. White and T. R. Webb, ACS Chem. Biol., 2012,
7
, 526-534.
42 J. Ma, A. Novack, I. Nashashibi, P. Pham, C. J. Rabbat, J. Song,
X. Chen, U.S. Patent Application No. 12/582,610. 2010. b) S.
Høg, P. Wellendorph, B. Nielsen, K. Frydenvang, I. F. Dahl, H.
22 a) D. Desai, L. Chang and S. Amin, Cancer Lett., 1996, 108, 263-
270; b) W. Huang, Z. Dong, Y. Chen, F. Wang, C. J. Wang, H.
Peng, Y. He, G. Hangoc, K. Pollok, G. Sandusky, X. Y. Fu, H. E.
Broxmeyer, Z. Y. Zhang, J. Y. Liu and J. T. Zhang, Oncogene,
2016, 35, 783-792.
9
Brauner-Osborne and R. P Clausen, J. Med. Chem., 2008, 51
,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8088-8095.
43 a) G. te Velde, F.M. Bickelhaupt, E.J. Baerends, C. Fonseca
Guerra, S.J.A. van Gisbergen, J.G. Snijders and T. Ziegler, J
Comput Chem., 2001, 22, 931-967; b) C. Fonseca Guerra, J.G.
Snijders, G. te Velde and E.J. Baerends, Theor Chem Acc.,
1998, 99, 391-403; c) ADF2014, SCM, Theoretical Chemistry,
23 K. L. Lahtchev, D. I. Batovska, S. P. Parushev, V.M. Ubiyvovk
and A. A. Sibirny, Eur. J. Med. Chem., 2008, 43, 2220-2228.
24 Crystal data for 5: C18H20O4, monoclinic, space group P21, a
= 11.1124(5) Å, b = 5.2113(2) Å, c = 13.3792(6) Å, α = 90°, β =
93.648(2)°, γ = 90°, V = 773.22(6) Å3, crystal size: 0.3x0.1x0.04
mm3, R1 = 0.0584 (wR2 = 0.1435). CCDC 1874939 contains the
Vrije
Universiteit,
Amsterdam,
The
Netherlands,
http://www.scm.com.
supplementary crystallographic data for this structure. This 44 a) S. Chang, D. P. Fernando and S. King, Org. Process. Res. Dev.,
data can be obteined free of charge from The Cambridge 2001, , 141-143; b) H. Johannes and M. Snoeck, 1999. WO
Crystallographic Data Center via 9913871 A2. United States; c) K. Fuji, Y. Usami, Y. Kiryu and M.
http://www.ccdc.cam.ac.uk/data_request/cif. Node, Synthesis, 1992, , 852-858; d) W. S. Murphy and S.
5
9
25 a) O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard
and H. Puschmann, J. Appl. Cryst., 2009, 42, 339-341. b) G.
Sheldrick, Acta Cryst., 2015, A71, 3-8. c) Sheldrick, Acta Cryst.,
2015, C71, 3-8.
Wattanasin, Tetrahedron Lett., 1980, 21, 3517-3520; e) H.
Fujioka, H. Komatsu, A. Miyoshi, K. Murai and Y. Kita,
Tetrahedron Lett., 2011, 52, 973-975; f) National Center for
Biotechnology Information. PubChem Compound Database;
26 a) C. Amatore, M. Azzabi and A. Jutand, J. Am. Chem.
CID
=
65092192,
Soc., 1991, 113
,
8375-8384. b) V. V. Grushin and H.
https://pubchem.ncbi.nlm.nih.gov/compound/94255955; g)
Q. Li and P. Zhang, Acta Chim. Sinica, 1990, 48, 913-919; h) P.
Hu, M. Tan, L. Cheng, H. Zhao, R. Feng, W. J. Gu and W. Han,
Nat. Commun., 2019, 10, 2425; i) D. Delorme, S. Woo. Patent
WO 2001070675-A2. 2001; j) National Center for
Alper, Organometallics, 1993, 12, 1890-1901. c) A. Jutand,
The Mizoroki-Heck Reaction, 1st ed., (Ed. M. Oestreich), John
Wiley & Sons. Great Britain, 2009. d) B. M. M. Wheatley and
B. A. Keay, J. Org. Chem. 2007, 72, 7253-7259.
27 a) W. Cabri and I. Candian, Acc. Chem. Res., 1995, 28, 2-7. b)
K. K. Hii, T. D. W. Claridge and J. M. Brown, Helv. Chim. Acta,
2001, 84, 3043-3056. c) M. M. S. Andappan, P. Nilsson, H. von
Schenck and M. Larhed, J. Org. Chem., 2004, 69, 5212-5218.
28 A. L. Lee, Org. Biomol. Chem., 2016, 14, 5357-5366.
29 T. Hayashi, Synlett, 2001, 2001, 0879-0887.
Biotechnology Information. PubChem Database. CID
82111939,https://pubchem.ncbi.nlm.nih.gov/compound/82
=
111939; k) V. KomReddy, D.P. Rillema, H. Nguyen and L. Kadel,
J. Heterocycl. Chem., 2019, 56, 972-979.
30 N. Miyaura, Synlett, 2009, 2009, 2039-2050.
31 I. Dance, Inorg. Chem. 2006, 45, 5084–5091.
32 a) S. Gowrisankar, A. G. Sergeev, P. Anbarasan, A.
Spannenberg, H. Neumann and M. Beller, J. Am. Chem. Soc.,
2010, 132, 11592-11598. b) J. A. Mueller, C. P. Goller, M. S.
Sigman, J. Am. Chem. Soc., 2004, 126, 9724-9734. c) W. G.
Lloyd, J. Org. Chem., 1967, 32, 2816-2819.
33 a) T. Verheyen, L. van Turnhout, J. K. Vandavasi, E.S. Isbrandt,
W. M. De Borggraeve and S. G. Newman, J. Am. Chem.
Soc., 2019, 141, 6869-6874. b) X. Gai, R. Grigg, S. Collard and
J. E. Muir, Chem. Commun., 2000, 18, 1765-1766.
34 J. Twilton, M. Christensen, D. A. DiRocco, R. T. Ruck, I. W.
Davies and D. W. MacMillan, Angew. Chem., 2018, 130, 5467-
5471.
35 a) D. D. Hennings, T. Iwama and V. H. Rawal, Org. Lett., 1999,
1
, 1205-1208. b) V. Penalva, J. Hassan, L. Lavenot, C. Gozzi and
M. Lemaire, Tetrahedron Lett., 1998, 39, 2559-2560. c) C. Qi,
X. Sun, C. Lu, J. Yang, Y. Du, H. Wu and X. M. Zhang, J.
Organomet. Chem., 2009, 694, 2912-2916.
36 L. Shao, Y. Du, M. Zeng, X. Li, W. Shen, S. Zuo and C. Qi, Appl.
Organomet. Chem., 2010, 24, 421-425.
37 F. T. Luo, A. Jeevanandam and M. K. Basu, Tetrahedron Lett.,
1998, 39, 7939-7942.
38 R. Martin and J. P. Buisson, Aromatic Hydroxyketones:
Preparation and Physical Properties (Vol. 1). Springer.
Dordrecht, The Netherlands, 2009.
39 National Center for Biotechnology Information. PubChem
Database.
CID=237130,
https://pubchem.ncbi.nlm.nih.gov/compound/237130
(accessed on July 12, 2020).
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DOI: 10.1039/D0NJ02630A
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The synthesis of phenyl-γ-hydroxyketones through Heck coupling
and subsequent opening of the tetrahydrofuran ring by the
nucleophilic attack of a water molecule catalyzed by PdCl2·Gly2
under microwave irradiation.
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32.8 Kcal
26.8 Kcal
-3.4 Kcal
Bond C=O
O
Cat.
PdCl2-Gly2
MW
I
O
OH
Bond C-C
+
R
R
H2O