Aqueous α-Arylation of Mono- and Diarylethanone Enolates at Low Catalyst Loading

Article abstract of DOI:10.1002/adsc.201701596

Acetophenone and deoxybenzoin derivatives are selectively α-arylated using a combination of very small amounts of palladium acetate and diphenylphosphine oxide as catalyst system and water as the only solvent. Target di- and triarylethanones are isolated virtually free of metal residues, and the reaction is amenable to gram-scale. A mechanistic proposal based on TEM images, poisoning experiments, kinetic plot and ESI-MS spectrometry is also provided. (Figure presented.).

Full text of DOI:10.1002/adsc.201701596

Title: Aqueous α-arylation of mono- and diarylethanone enolates at low
catalyst loading
Authors: Iratxe Astarloa, Raul SanMartin, María Teresa, and Esther
Domínguez
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701596
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Aqueous -arylation of mono- and diarylethanone enolates at
low catalyst loading
Iratxe Astarloa,a Raul SanMartin,a* María Teresa Herreroa and Esther Domíngueza,*
a
Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country
(UPV/EHU) Sarriena auzoa, z/g 48940 Leioa, Spain
Fax: (+34)-946012748; phone: (+34)-946015435; e-mail: raul.sanmartin@ehu.eus
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Water is a non-toxic, non-flammable solvent with a
Acetophenone and deoxybenzoin derivatives are selectively high heat capacity at a cheap price. Very high
Abstract.
-arylated using a combination of very small amounts of
palladium acetate and diphenylphosphine oxide as catalyst
system and water as the only solvent. Target di- and
triarylethanones are isolated virtually free of metal
residues, and the reaction is amenable to gram-scale. A
mechanistic proposal based on TEM images, poisoning
experiments, kinetic plot and ESI-MS spectrometry is also
provided.
selectivities and reaction rates have been found for a
number of “on water” processes,[7] and the
combination of metal catalysis and water is becoming
increasingly common in reactions such as cross
couplings and direct arylations,[8,9] conjugated
additions,[10]
hydroformylations,[11]
oxidation
processes,[12] hydrogenations,[13] isomerizations and
polymerizations,[14] and olefin metathesis reactions,[15]
among others.[16] With regard to the efficiency in
metal-catalyzed reactions, it is not only essential for a
more sustainable use of limited resources but also a
pivotal requirement for the reduction of metal
contents in biologically active synthetic compounds,
thus avoiding cumbersome purification steps (several
crystallizations, scavenger resins, etc.).[17]
Keywords: water; palladium; aryl halides; ketones
Among the compounds bearing the α-aryl carbonyl
motif, 1,2-diaryl- and 1,2,2-triarylethanones are
present in a number of natural products and
biologically active compounds (Gramidenoxybenzoin
It is therefore highly desirable to develop an
efficient method for the palladium-catalyzed -
arylation of ketones enolates in water. Following our
research on 1,2-diaryl and 1,1,2-triarylethanones,[18]
we envisaged that the use of a phosphine oxide ligand
and water could be the key to a significantly more
efficient arylative approach. After the pioneering
work by Li,[19] several palladium-phosphinous acid
complexes have been used for Suzuki, Heck,
Sonogashira, Kumada-Corriu, Hiyama, Stille,
Negishi, N- and S-arylation, oxidative esterification
of aldehydes, nucleophilic and conjugated arylation
with arylsiloxanes, and related reactions,[20] some of
them carried out in water.[16b-c,20g-l] However, to the
best of our knowledge, there has been only one report
on an intramolecular palladium-catalyzed -arylation
of amides in the presence of a 5 mol% of Pd(OAc)2
and a 10 mol% of (1-Ad)2P(O)H in 1,4-dioxane.[20r]
Herein, we report a very efficient catalytic
procedure for the intermolecular -arylation of
ketone enolates using water as the only solvent. In
addition to the low catalyst loadings achieved, the
catalytic system is based on commercially available
and relatively inexpensive palladium(II) acetate and
diphenylphosphine oxide.
A-H,
Belamphenone,
O-Desmethylangolensin,
Sitaxentan (TBC-11251), inter alia).[1] In addition,
these privileged carbonyl compounds have been used
as the main ingredients of flame retardants and other
advanced materials,[2] and as intermediates for the
synthesis of natural products and phase III- and
marketed drugs such as Tamoxifen, Droloxifene,
Daidzein, Oxcarbazepine, (+)-AM-8553 and AMG
232,[1f,1j,3a-g] and several heterocyclic systems (e.g.
dibenzophenanthridines,
phenantrofurans,
isoindoloisoquinolines, triazoles and indazoles).[3h-l]
A straightforward approach to 1,2-diaryl- and
1,2,2-triarylethanones relies on the -arylation of
ketone enolates, a reaction that has evolved
remarkably over the past two decades.[3b,4] However,
most of the commonly used palladium and nickel
catalysts require relatively high catalyst loadings (10-
0.5 mol% of the metal catalyst). With regard to
palladium-catalyzed arylation of acetophenones and
other aryl ketones, the efficient systems described by
the groups of Nolan[5a-b] and Colacot[5c] using catalyst
amounts as low as 0.2-0.02- mol % should be noted.
Interestingly, there is only one report of palladium-
catalyzed -arylation of ketone in aqueous media,[6]
although 2.5 mol% of Pd2(dba)3 and 10 mol% of
(tBu)3PHBF4 were required respectively.
1
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
Table 1. Palladium-catalyzed phenylation of deoxybenzoin 1a with bromobenzene 2a. Optimization assays[a]
Entry [Pd]
ligand
base
additive
H2O (M) T (ºC)[b] t (h)
3a (%)[c]
<5
<5
<5
19
22
34
26
40
1
Pd(OAc)2
K3PO4 (3 equiv.)
Cs2CO3 (3 equiv.)
K3PO4 (3 equiv.)
K3PO4 (3 equiv.)
K3PO4 (3 equiv.)
Cs2CO3 (3 equiv.) TBAB (10 mol%) 1
Cs2CO3 (1.5 equiv.) TBAB (5 mol%) 0.1
Cs2CO3 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1 equiv.)
K3PO4 (1 equiv.)
K3PO4 (1 equiv.)
K3PO4 (1 equiv.)
K3PO4 (1 equiv.)
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.25
1
1
1
160
140
150
160
160
150
160
160
160
160
160
160
160
160
160
160
160
150
140
160
160
160
160
160
160
160
160
160
160
24
24
24
12
12
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
2
PdCl2
Ph2P(O)H
Ph2P(O)H
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TBAB (50 mol%) 0.5
TBAB (10 mol%) 0.5
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
TBAB (5 mol%) 0.5
TBAB (5 mol%) 0.5
TBAB (5 mol%) 0.1
TBAB (5 mol%) 0.5
TBAB (5 mol%) 0.5
67
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Pd(COD)Cl2 Ph2P(O)H
Pd(COD)Cl2 Ph2P(O)H
Pd/C
Pd2dba3
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
< 5
< 5
< 5
< 5
99 (97)
6
17
51
65
21
84
59
67
12-78d
<5
14
<5
<5
<5
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
K3PO4 (1.3 equiv.) TBAB (5 mol%)
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
2
tBu2P(O)H K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
Ph3PO
Ph3P
Ph2PCl
Ph2P(O)H
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.)
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
K3PO4 (1.3 equiv.) TBAB (5 mol%) 0.5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NiBr2
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
Ph2P(O)H
0.5
CuI
<5
[a] Reaction conditions: Deoxybenzoin 1a (0.4 mmol), bromobenzene 2a (1.2 mmol), metal source (10-2 mol%), ligand (10-
2 mol%), base, additive.
[b] Temperature of the heating bath. A thermocouple probe was used to adjust and to monitor the temperature of the heating
bath.
[c] NMR yields determined using 3,4,5-trichloropyridine as an internal standard. Isolated yields are shown in parentheses.
[c] Range of NMR yields (set of 5 assays) determined using 3,4,5-trichloropyridine as an internal standard.
A number of palladium sources, ligands, bases,
additives and temperatures were screened for the
coupling of model substrates deoxybenzoin 1a with
bromobenzene 2a. A limit of 0.01 mol% was
established for the amount of both palladium sources
and ligand in these initial assays. From this survey it
became apparent that only by heating above 120ºC
was target triarylethanone 3a isolated in appreciable
yields. In addition, bases such as Et3N, K2CO3,
Na2CO3, NaOAc, or NaOH or non-phosphorus
ligands (pyrazole, IMesCl, pyridine or TMEDA)
provided negligible results. As shown in Table 1, a
further optimization of the parameters was then
performed, showing that Pd(OAc)2 was much more
effective than other Pd(II) and Pd(0) sources and that
better yields were obtained using phosphorus ligands
combined with potassium phosphate as a base.
Another distinctive feature was the need of catalytic
n
amounts of Bu4NBr as an additive. Higher amounts
of the latter trialkylammonium salt or the use of bases
other that K3PO4 led to the formation of
diphenylmethane in variable amounts, a phenomenon
already described by Leadbeater and col.[21] In order
to avoid this side-reaction and to increase the yield of
3a further adjustments on the dilution, catalytic
amount of nBu4NBr, temperature and the nature of the
phosphorus ligand were made.
2
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
Table 2. Substrate scope for the -arylation of
Table 3. Substrate scope for the-diarylation of aryl
deoxybenzoin.[a]
methyl ketones.[a]
[a]
Isolated yields. Reaction conditions: 1a (0.4 mmol), 2
(1.2 mmol), K3PO4 (0.52 mmol), Bu4NBr (5 mol%),
Pd(OAc)2 (10-2 mol%), Ph2P(O)H (10-2 mol%), H2O (0.8
mL), 160ºC, 24h.
[b] Iodobenzene was used as the arylating agent.
[c] K3PO4 (1.2 mmol), 48h.
[d] 3-Iodotoluene was used as the arylating agent.
[e] Pd(OAc)2 (5x10-2 mol%), Ph2P(O)H (5x10-2 mol%).
[f]
K3PO4 (1.2 mmol), Pd(OAc)2 (5x10-2 mol%), Ph2P(O)H
(5x10-2 mol%), 48h.
In this regard, although acceptable results were
obtained in some cases from Ph2PCl, a lack of
reproducibility was also observed, probably due to
the partial formation of Ph2POH. However,
reproducible results were obtained from several
phosphine oxides, and among them, Ph2P(O)H turned
out to be the most effective, providing target 3a in
almost quantitative yields (Table 1, entry 14). Blank
experiments in the absence of the palladium source,
phosphine oxide, base or additive were also carried
out in order to test the need for all the
ingredients/components of the optimized procedure.
Finally, other metal sources were also tested in
replacement of Pd(OAc)2.
[a]
Isolated yields. Reaction conditions: 4 (0.4 mmol), 2
(1.2 mmol), K3PO4 (1.2 mmol), Bu4NBr (5 mol%),
Pd(OAc)2 (10-2 mol%), Ph2P(O)H (10-2 mol%), H2O (0.8
mL), 160ºC, 48h.
[b] Pd(OAc)2 (5x10-2 mol%), Ph2P(O)H (5x10-2 mol%).
[c]
K3PO4 (0.52 mmol), Pd(OAc)2 (5x10-2 mol%),
Ph2P(O)H (5x10-2 mol%).
[d] 24h.
3
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
Several aryl bromides 2 were submitted to the
optimized reaction conditions to provide 1,2,2-
triarylethanones 3a-h shown in Table 2. Moderate to
good yields were obtained in all cases, even from
electronically deactivated substrates bearing electron-
donating groups. Slight variations in the reaction time,
catalyst loading or amount of base were required in
some cases to get a higher yield. Interestingly, the use
of an excess of the aryl halide reagent neither induced
o-arylation nor provoked the formation of
polyarylation products.
Table 4. Substrate scope for the-monoarylation of aryl
methyl ketones.[a]
In addition, two iodoarenes, iodobenzene and m-
iodotoluene, were also coupled with deoxybenzoin to
provide the corresponding triarylethanones 3a and 3c
respectively. The formation of the sterically crowded
2-(naphthalen-1-yl)-1,2-diphenylethan-1-one
3h
should be noted. However, ortho-substituted 3g was
obtained with a moderate yield from 1-bromo-2-
fluorobenzene, and unreacted starting materials were
recovered from the reactions with chlorobenzene and
1,2-dibromobenzene.
As shown in Table 3, the same procedure was then
applied to a number of acetophenones and other aryl
methyl ketones 4 and aryl bromides 2. 1,1-Diarylated
products 3a-x were efficiently prepared in good
yields from sterically and electronically divergent
methyl ketone derivatives. Besides, regarding the
bromoarene coupling partner, good results were
obtained from neutral and electron-rich aryl bromides,
whereas the use of electron-deficient bromo- and
iodoarenes
(e.g.
4-bromobenzonitrile,
3-
bromobenzaldehyde,
1-bromo-4-
1-bromo-3-
1-iodo-4-nitrobenzene,
[a]
(trifluoromethyl)benzene,
(trifluoromethyl)benzene,
Isolated yields. Reaction conditions: 4 (0.4 mmol), 2
(0.8 mmol), K3PO4 (0.52 mmol), Bu4NBr (5 mol%),
Pd(OAc)2 (5x10-2 mol%), Ph2P(O)H (5x 10-2 mol%), H2O
(0.8 mL), 160ºC, 24h.
methyl 2-iodobenzoate) had a deleterious effect on
the reaction outcome (yields <5%).[22] Interestingly,
sterically bulky ketones such as 1-(naphthalen-1-
yl)ethan-1-one and 1-(phenanthren-9-yl)ethan-1-one
provided ,-diarylation products 3s-t and 3w-x with
moderate yields. As in the case of the arylation of
deoxybenzoin, no reaction was observed with 1,2-
dibromobenzene as the arylating agent. Unfortunately,
only starting material was recovered from aromatic
ketones other than 1,2-diaryl- and 1,2,2-
triarylethanones (propiophenone, 1-indanone, or 4-
chomanone).
A reduction in the number of equivalents of the
arylating agent allowed the selective monoarylation
of acetophenone, acetonaphthone, 2-acetylthiophene
and 2-acetylpyridine. Table 4 shows a number of 1-
(hetero)aryl-2-aryl-ethanones 1b-j prepared by this
procedure. Moderate to good results were obtained
from o-substituted or sterically hindered bromoarenes
(see ketones 1b-f), and in this case, monoarylation
was performed even with a bromoarene bearing an
[b] Pd(OAc)2 (10-2 mol%), Ph2P(O)H (10-2 mol%).
[c] 48h.
[d] K3PO4 (1.2 mmol).
Hence, considering the potential industrial interest
of the reported procedure, a gram-scale diarylation of
1a was carried out, furnishing triarylethanone 3a with
excellent yield (92%) and selectivity (>99%).
Furthermore, ICP-MS measurement of the palladium
content in the latter diarylated ketone revealed
extremely low contamination level, with a value
below the detection limit of 0.1 ppm and therefore
safe for oral or parentheral administration in terms of
trace palladium content.[23]
Transmission electron microscopy (TEM) images
from the reaction crude showed the presence of a few
scattered palladium nanoparticles with a diameter of
3-7 nm (Figure 1). In this regard, the interference
caused by the presence of potassium ion derived from
the base K3PO4 was avoided by using a cationic
exchange resin (Dowex).
electron-withdrawing
substituent
(1-bromo-4-
(trifluoromethyl)benzene) to provide ethanone 1g,
albeit with a moderate yield (40%).
4
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
Table 5. Summary of poisoning experiments.
Entry
Additive
Conv. (%)[a]
Figure 1. TEM images of the crude.
1
2
3
4
5
Hg (one drop)
0
CS2 (0.5 eq. per metal atom)
CS2 (2.0 eq. per metal atom)
PPh3 (0.03 eq. per metal atom)
PPh3 (0. 3 eq. per metal atom)
PPh3 (4.0 eq. per metal atom)
Py (150 eq. per metal atom)
PVPy (300 eq. per metal atom)
82
88
83
81
93
97
8
6
7b)
8c)
[a]
Measured by 1H-NMR. 3,4,5-Trichloropyridine was
used as internal standard
[b] Py: Pyridine.
[c] PVPy: Polyvinylpyridine.
Figure 2. Conversion rate (%) of deoxybenzoin 1a vs
time.
A complete inhibition of the reaction in the
presence of a drop of mercury (positive mercury drop
test)[24] was observed, and a substantial decrease in
the conversion rate was also detected when
comparing reactions performed in the presence of
overstoichiometric amounts of pyridine and
polyvinylpyridine (PVP)[25] (Table 5, entries 1, and 7
vs 8).
In contrast with this evidence indicative of the
participation of palladium nanoparticles, the kinetic
plot conversion rate vs time (Figure 2) showed
neither induction time nor sigmoidal shape and
therefore the participation of homogeneous catalytic
species cannot be discarded. Moreover, the addition
of other poisoning agents in sub- and
overstoichiometric amounts25 had no effect on the
reaction outcome.
On account of the above experiments, we propose
that the catalytic cyclic starts with an initial, fast in
situ formation of Pd(0) species[26] A and B which
undergo oxidative addition leading to Pd(II)
complexes C and D.[27] Ligand exchange would
generate palladium enolates E or F which upon
reductive elimination would provide target
triarylethanone 3a and regenerate Pd(0) complexes A
and B by complexation with diphenylphosphinous
acid (Scheme 1). Transient species A-F were detected
by ESI-MS spectroscopy.[22]
Scheme 1. Tentative catalytic cycle for the aqueous -
arylation of deoxybenzoin 1a in the presence of Pd(OAc)2-
Ph2P(H)O.
To sum up, a number of di- and triarylethanones
have been prepared by an efficient palladium-
catalyzed -arylation of acetophenone and
deoxybenzoin
derivatives
on
water.
This
advantageous catalyst system is based on very small
5
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10.1002/adsc.201701596
Advanced Synthesis & Catalysis
Na2SO4 and filtered, and the solvents were removed in
vacuo. Purification by flash column chromatography
(Hexane:EtOAc) provided target 1,2,2-triarylethanones 3a-
h. (see the Supporting Information Section)
amounts of
a
commercially available, cheap
phosphine oxide together with palladium acetate and
TBAB. This unprecedented combination of very low
catalyst loading and water as a solvent allows for
isolation of products with minimal traces of residual
palladium. On the basis of the data derived from
TEM images, poisoning experiments and kinetic plot,
a tentative mechanism based on the participation of
palladium phosphinous acid complexes is suggested.
Acknowledgements
This research was supported by the Basque Government (IT-774-
13) and the Spanish Ministry of Economy and Competitiveness
(CTQ2013-46970-P and CTQ2017-86630-P). I. A. thanks the
Basque Government for a predoctoral scholarship. Finally, the
technical and human support provided by SGIker of UPV/EHU is
gratefully acknowledged.
Experimental Section
General Information
References
Commercially available reagents were used throughout
1
without purification unless otherwise stated. H and 13C
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NMR spectra were recorded on a Bruker AC-300
1
instrument (300 MHz for H and 75.4 MHz for 13C) at 20
ºC. Chemical shifts () are given in ppm downfield from
Me4Si and are referenced as internal standard to the
1
residual solvent (unless indicated) CDCl3 (d=7.26 for H
and d=77.00 for 13C). Coupling constants, J, are reported in
hertz (Hz). Melting points were determined in a capillary
tube and are uncorrected. TLC was carried out on SiO2
(silica gel 60 F254, Merck), and the spots were located
with UV light. Flash chromatography was carried out on
SiO2 (silica gel 60, Merck, 230–400 mesh ASTM). IR
spectra were recorded on Perkin–Elmer 1600 FT and
JASCO FTIR-4100 infrared spectrophotometers as KBr
plates or thin films, and only noteworthy absorptions are
reported in cm-1. Drying of organic extracts during work-
up of reactions was performed over anhydrous Na2SO4.
Evaporation of solvents was accomplished with a Büchi
rotatory evaporator. ICP-MS measurements were carried
out on a Thermo Elemental X7 Series ICP-MS equipped
with an ASX-520 autosampler. MS spectra were recorded
on an Agilent 5975 mass spectrometer under electronic
impact (EI) conditions or on an Acquity UPLC-
Spectrometer of Mass QTOF from Waters under
electrospray ionization (ESI). HRMS were recorded using
a Micromass GCT spectrometer by electronic impact (EI)
or electrospray ionization (ESI). Reactions carried out
under microwave irradiation were performed using a CEM
Discover 1-300W system equipped with a built-in pressure
[2] a) L. Zhang, W. Wu, Y. Zhong, S. Zhu, Z. Wang, Z.
Zou, RSC Adv. 2015, 5, 87609-87615; b) M. W.
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measurement sensor and
a
vertically focused IR
temperature measurement sensor.
General Procedure for the α-arylation of deoxybenzoin.
Deoxybenzoin 1a (0.4 mmol), aryl halide 2 (1.2 mmol),
potassium
phosphate
(0,52
mmol)
and
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solution of palladium(II) acetate (20 µL of a 2·10-6
M
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diphenylphosphine oxide (20 µL of a 2·10-6 M solution in
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heated in an oil bath at 160 ºC for 24 h. After cooling, the
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extracted with EtOAc (3 x 15 mL). The combined organic
layers were washed with brine, dried over anhydrous
6
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Advanced Synthesis & Catalysis
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8
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