Palladium-Catalyzed Mono-α-arylation of Acetone at Room Temperature

Article abstract of DOI:10.1002/chem.201500834

The first examples of acetone mono-α-arylation at room temperature are described, enabled by use of a [Pd(cinnamyl)Cl]₂/JosiPhos catalyst system. (Hetero)aryl chloride, bromide, and iodide electrophiles featuring or lacking ortho-substitution, and comprising a range of functionalities (e.g., alkoxy, cyano, fluoro, trifluoromethyl, or alkenyl) and heteroaryl motifs (e.g., pyrrole, pyridine, isoquinoline, quinoline, quinaldine, (benzo)thiophene, benzothiazole, or benzodioxole) were successfully accommodated. Proof-of-principle experiments confirm that other (hetero)aryl methyl ketones can also be employed in such room temperature mono-α-arylations. The established substrate scope is the most extensive reported to date for acetone mono-α-arylation under any conditions, and more generally represents the first room temperature ketone mono-α-arylations employing a structurally diverse set of (hetero)aryl chlorides. Chill out: The first examples of acetone mono-α-arylation at room temperature are described. The substrate scope is the most extensive reported to date for acetone mono-α-arylation under any conditions, and represents the first room temperature ketone mono-α-arylations employing a diverse set of (hetero)aryl chlorides.

Full text of DOI:10.1002/chem.201500834

DOI: 10.1002/chem.201500834
Communication
&
Cross-Coupling
Palladium-Catalyzed Mono-a-arylation of Acetone at Room
Temperature
Preston M. MacQueen, Alicia J. Chisholm, Breanna K. V. Hargreaves, and Mark Stradiotto*[a]
source, and ancillary ligand design,[8] has enabled a range of
Abstract: The first examples of acetone mono-a-arylation
reaction partners to be accommodated in the palladium-cata-
at room temperature are described, enabled by use of
lyzed mono-a-arylation of carbonyl compounds.[6a–d,9] Notewor-
a [Pd(cinnamyl)Cl]2/JosiPhos catalyst system. (Hetero)aryl
thy reports on related copper- and nickel-catalyzed[10,11] trans-
chloride, bromide, and iodide electrophiles featuring or
formations have also appeared recently.
lacking ortho-substitution, and comprising a range of
Notwithstanding such progress, a number of important chal-
functionalities (e.g., alkoxy, cyano, fluoro, trifluoromethyl,
lenges remain. The development of catalysts that exhibit high
or alkenyl) and heteroaryl motifs (e.g., pyrrole, pyridine,
levels of selectivity with sterically unbiased (hetero)aryl electro-
isoquinoline, quinoline, quinaldine, (benzo)thiophene,
phile/carbonyl compound pairings has proven to be difficult.
benzothiazole, or benzodioxole) were successfully accom-
This is due in part to the fact that the initially formed mono-a-
modated. Proof-of-principle experiments confirm that
arylation product features a-CH protons that are more acidic
other (hetero)aryl methyl ketones can also be employed
than those in the starting carbonyl compound, resulting in
in such room temperature mono-a-arylations. The estab-
more facile enolate formation and uncontrolled polyarylation.
lished substrate scope is the most extensive reported to
These and other factors make the use of acetone, the most
date for acetone mono-a-arylation under any conditions,
structurally simple ketone, a formidable challenge for most cat-
and more generally represents the first room temperature
alyst systems,[12] despite the fact that the palladium-catalyzed
ketone mono-a-arylations employing a structurally diverse
mono-a-arylation of alternative methyl carbonyl compounds
set of (hetero)aryl chlorides.
was established during the initial development of the field
nearly twenty years ago.[13]
The selective mono-a-arylation of acetone was first reported
by our group in 2011,[14] employing a [Pd(cinnamyl)Cl]2/Mor-
The development of palladium-catalyzed CÀC cross-coupling
DalPhos[15] catalyst system (X=Cl, Br, I, tosylate, mesylate); a se-
reactions has transformed the way in which chemists approach
organic synthesis on benchtop and industrial scales.[1] Follow-
lection of other palladium catalysts featuring either closely re-
ing the Nobel Prize-winning contributions by Heck,[2] Negishi,[3]
and Suzuki,[4] a range of alternative CÀC bond-forming proto-
cols have been developed.[5] Among these, the mono-a-aryla-
tion of carbonyl (and related) compounds has emerged as an
effective Csp2ÀCsp3 bond-forming methodology that does not
require pre-formation of an organometallic reaction partner.[6]
The synthetic potential of such protocols is underscored by
the prevalence of the a-aryl carbonyl moiety in key synthetic
intermediates as well as target molecules of biological and me-
dicinal interest.[7]
lated ortho-phenylene P,N-ligands (X=Cl, Br),[16] or XantPhos
(X=imidazolylsulfonate),[17] have subsequently proven capable
of promoting such transformations (Figure 1). Very recently we
demonstrated that the mono-a-arylation of acetone using the
[Pd(cinnamyl)Cl]2/Mor-DalPhos catalyst system can be incorpo-
Prior to the development of modern palladium-catalyzed
methods, the a-arylation of carbonyl compounds typically re-
quired the use of activated aryl halides in combination with
pre-formed enolate nucleophiles, resulting in low substrate
scope, poor functional group tolerance given the harsh reac-
tion conditions employed, and the required use of air-sensitive
and/or toxic reagents. However, recent advances in catalyst de-
velopment, including optimization of the base, palladium
[a] P. M. MacQueen, A. J. Chisholm, B. K. V. Hargreaves, Prof. Dr. M. Stradiotto
Department of Chemistry, Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: mark.stradiotto@dal.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500834.
Figure 1. Palladium-catalyzed mono-a-arylation of acetone.
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Communication
rated into the one-pot, multicomponent synthesis of 2-methyl-
indoles, a core structure found within Indomethacin (non-ster-
oidal anti-inflammatory), Oxypertine (antipsychotic), and Pano-
binostat (anti-cancer).[18] The carbonylative mono-a-arylation of
acetone has also been achieved.[19]
the utility of [Pd(cinnamyl)Cl]2/CyPF-tBu mixtures in room-tem-
perature reactions of acetone. We were pleased to observe
that the use of this catalyst system enabled the formation of
1 in 57% isolated yield under the conditions outlined in
Figure 2. Extending the reaction time from 24 to 48 h while
employing 7.5 mol% Pd (both unoptimized parameters) al-
lowed for the isolation of 1 in 87% yield from 4-biphenyl bro-
mide. Notably, the use of alternative bases under analogous
conditions resulted in negligible consumption of 4-biphenyl
bromide (K2CO3), incomplete consumption (<50%) of 4-bi-
phenyl bromide and conversion to 1 (K3PO4), or complete con-
sumption of 4-biphenyl bromide with formation of multiple
unidentified products and negligible conversion to 1 (NaOtBu
or NaN(SiMe3)2).
Whereas the use of acetone as both the ketone reactant and
solvent is attractive in the synthesis of 1-(hetero)aryl-propan-2-
one derivatives, each of the catalyst systems reported thus far
for acetone mono-a-arylation employ reaction temperatures
(ꢀ808C, in some cases using a co-solvent) that exceed the
boiling point of acetone (568C). As such, the identification of
alternative catalysts that are capable of promoting such trans-
formations at room temperature would represent an important
advance. Indeed, it is worthy of mention that while progress
has been made with regard to the development of myriad pal-
ladium-catalyzed room temperature transformations using rela-
tively inexpensive and abundant (hetero)aryl chloride reaction
partners,[15,20] related examples of room temperature ketone
mono-a-arylation chemistry are limited to four table entries in-
volving (IPr)Pd-catalyzed transformations of propriophenone
(41–75%).[21] Herein, we report the first examples of acetone
mono-a-arylation chemistry conducted at room temperature,
which is achieved through use of a palladium catalyst system
featuring the JosiPhos[22] ligand variant CyPF-tBu depicted in
Figure 1.
Having identified the [Pd(cinnamyl)Cl]2/CyPF-tBu catalyst
system as being effective for the room temperature mono-a-
arylation of acetone with 4-biphenyl bromide (7.5 mol% Pd),
we turned our attention to exploring the scope of reactivity
with substituted aryl chlorides, bromides, and iodides
(Figure 3). Employing 4-biphenyl chloride as a coupling partner
under analogous conditions afforded 1 in 88% isolated yield. A
selection of para-substituted 4-chlorobiphenyl derivatives fea-
turing methyl, trifluoromethyl, methoxy, or cyano substituents
was also accommodated under these conditions (2–5, 50–
69%), although increased catalyst loadings proved beneficial
(10 mol% Pd; 3–5, 71–86%). A series of ortho-, meta-, and
para-substituted halogenated anisoles proved to be effective
substrates (6–8, 64–83%), as did 4-chloro-3-methylanisole (9,
78%) and 2-bromobiphenyl (10, 70%). Halogenated xylene
(11, 60%; 12, 80%), fluorobenzene (13, 62%), styrene (14,
64%), and napthyl (15, 57%; 16, 77%) derivatives were also ac-
commodated.
Our initial efforts to identify a catalyst system for the palladi-
um-catalyzed mono-a-arylation of acetone at room tempera-
ture focused on the use of [Pd(cinnamyl)Cl]2/Mor-DalPhos
under conditions similar to those that we employed with suc-
cess at 908C,[14a] with the exception of using higher catalyst
loadings and a longer reaction time (Figure 2). Poor results
were obtained in the test reaction with 4-biphenyl bromide, af-
fording 1 in 12% isolated yield. Similarly poor results were ob-
tained when using BrettPhos (16%), a ligand developed by the
Buchwald group that has proven to be effective in other
classes of challenging monoarylation reactions conducted at
room temperature.[23] Reports from the Hartwig group have es-
tablished the utility of the Solvias CyPF-tBu JosiPhos ligand
variant in otherwise difficult palladium-catalyzed ammonia
monoarylation reactions conducted at elevated tempera-
tures,[24] as well as in room temperature CÀS cross-cou-
plings.[20f] Given the similar conceptual challenges presented
by acetone mono-a-arylation chemistry, we sought to evaluate
Figure 3. Scope of palladium-catalyzed mono-a-arylation of acetone em-
ploying substituted aryl halides (yields of isolated products reported).
[a] Using 0.025 mmol [Pd(cinnamyl)Cl]2.
Figure 2. Ligand screen for the palladium-catalyzed mono-a-arylation of ace-
tone at room temperature (yields of isolated 1 reported).
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Given the ubiquity of heterocyclic motifs in medicinal, bio-
logical, and natural products chemistry, we sought to evaluate
the compatibility of electrophilic coupling partners featuring
such functionality in the mono-a-arylation of acetone at room
temperature using the [Pd(cinnamyl)Cl]2/CyPF-tBu catalyst
system (Figure 4). It is worthy of mention that while selected
Figure 5. Palladium-catalyzed mono-a-arylations of alternative (hetero)aryl
methyl ketone substrates (yields of isolated products reported).
chlorides, bromides, and iodides featuring or lacking ortho-sub-
stitution, and comprising a range of substituents (e.g., alkoxy,
cyano, fluoro, trifluoromethyl, alkenyl) and heterocyclic struc-
tures (e.g., pyrrole, pyridine, isoquinoline, quinoline, quinal-
dine, (benzo)thiophene, benzothiazole, benzodioxole). Prelimi-
nary experimentation confirmed that other (hetero)aryl methyl
ketones can also be accommodated in such room temperature
mono-a-arylation chemistry. The established substrate scope is
notable in that it is the most extensive reported to date for
the mono-a-arylation of acetone under any reaction condi-
tions, and represents the first room temperature ketone mono-
a-arylations employing a structurally diverse set of (hetero)aryl
chlorides. Future research efforts will be directed toward devel-
oping increasingly effective catalysts for room temperature
mono-a-arylation chemistry, as well as in the application of
such transformations in the construction of useful target mole-
cules.
Figure 4. Scope of palladium-catalyzed mono-a-arylation of acetone em-
ploying aryl halides featuring heterocyclic functionality (yields of isolated
products reported). [a] Using 0.025 mmol [Pd(cinnamyl)Cl]2. [b] Isolated as
the hydrochloride salt.
transformations of heterocycle-containing substrates have
been featured in past reports on palladium-catalyzed acetone
mono-a-arylation conducted at elevated temperature,[14,16–18]
such coupling partners have for the most part been over-
looked in this chemistry. In this context we were pleased to
observe that substituted pyrrole (17), pyridine (18, 19), isoqui-
noline (20), quinoline (21, 22), quinaldine (23), (benzo)thio-
phene (24, 25), benzothiazole (26), and benzodioxole (27) cou- Acknowledgements
pling partners functioned well in our newly developed room
temperature acetone mono-a-arylation chemistry (Figure 4,
51–94%).
We thank NSERC of Canada, the Killam Trusts, and Dalhousie
University for their generous support of this work. We also
thank Solvias for the gift of some of the JosiPhos ligand used
in this study.
Though the room-temperature mono-a-arylation chemistry
that we describe above was conducted exclusively using ace-
tone as the nucleophilic reaction partner, proof-of-principle ex-
periments confirmed that other (hetero)aryl methyl ketone
substrates can also be employed (Figure 5). In test cross-cou-
plings with acetophenone, heteroaryl chlorides featuring ben-
zothiophene (28, 67%), benzothiazole (29, 95%), and quinoline
(30, 88%) core structures each proved to be suitable sub-
strates. The incorporation of heterocyclic functionality into
both of the reaction partners also proved to be feasible, as evi-
denced by the successful room temperature cross-coupling of
5-chloro-benzo[b]thiophene with each of 2-acetylthiophene
and 2-acetylfuran to afford 31 (82%) and 32 (53%), respective-
ly.
Keywords: arylation · cross-coupling · Josiphos · palladium ·
room temperature
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Published online on June 26, 2015
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