Mild, Aqueous α-Arylation of Ketones: Towards New Diversification Tools for Halogenated Metabolites and Drug Molecules

Article abstract of DOI:10.1002/chem.201700680

The palladium-catalysed aqueous α-arylation of ketones was developed and tested for a large variety of reaction partners. These mild conditions enabled the coupling of aryl/alkyl-ketones with N-protected halotryptophans, heterocyclic haloarenes, and challenging base-sensitive compounds. The synthetic potential of this new methodology for the diversification of complex bioactive molecules was exemplified by derivatising prochlorperazine. The methodology is mild, aqueous and flexible, representing a means of functionalizing a wide range of halo-aromatics and therefore has the potential to be extended to complex molecule diversification.

Full text of DOI:10.1002/chem.201700680

A Journal of
Accepted Article
Title: Mild, aqueous α-arylation of ketones: towards new diversification
tools for halogenated metabolites and drug molecules
Authors: Enrico Marelli, Yohann Renault, Sunil V Sharma, Steven P
Nolan, and Rebecca Jane Miriam Goss
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201700680
Link to VoR: http://dx.doi.org/10.1002/chem.201700680
Supported by

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Mild, aqueous α-arylation of ketones: towards new diversification
tools for halogenated metabolites and drug molecules
Enrico Marelli*,[a] Yohann Renault,[a] Sunil V. Sharma,[a] Steven P. Nolan[b,c] and Rebecca J. M. Goss*[a]
Abstract: The palladium-catalyzed aqueous α-arylation of ketones
was developed and tested for a large variety of reaction partners.
These mild conditions enabled the coupling of aryl/ alkyl-ketones
with N-protected halotryptophans, heterocyclic haloarenes, and
challenging base-sensitive compounds. The synthetic potential of
this new methodology for the diversification of complex bioactive
molecules was exemplified by derivatising prochlorperazine. The
methodology is mild, aqueous and flexible, representing a means of
functionalizing a wide range of halo-aromatics and therefore has the
potential to be extended to complex molecule diversification.
towards this reaction.[11] As with many other Pd-catalyzed CC
reactions, a three-step minimal mechanism involves (Scheme
1): the Pd0 catalytic species 1 undergoes oxidative addition,
activating the C–X bond of the aryl (pseudo)halide 2 to afford
complex 3, followed by enolate transmetallation (5) and
reductive elimination generates the product 6. Notably, despite
thorough studies in this field, no aqueous procedure for the α-
arylation of ketones has yet been reported. A challenging aspect
of such chemistry, in aqueous condition, relates to the
unfavourable equilibrium between enolates and their protonated
form. This is due to the high pKa of this anionic species.[12] Other
enolate reactions (for example, aldol-type) have been achieved
in aqueous systems, taking into consideration the perturbation of
this equilibrium and using specially developed conditions.[13]
Attracted by the development of a platform for aqueous α-
arylation of ketones, as it would set the stage for the late-stage
functionalization of natural and new-to-nature biomolecules,
such as achieved in the GenoChemetic generation of natural
product analogues,[3c,h] we tackled the challenges reported
above, and we disclose here the first such aqueous
methodology.
The development of synthetic methods that are both mild and
general, for modification of complex substrates, has gained
increasing importance over the last decade.[1] The presence of a
carbon–halogen bond represents a useful chemical handle,
orthogonally enabling selective functionalization. Pd-catalyzed
Cross-Coupling (CC) reactions are at the forefront as a key
component within the developing toolbox of methodologies for
diversification of halogenated molecules.[2] Given their excellent
functional group tolerance and wide scope, CC methodologies
have therefore proved
a
valuable tool for late-stage
[Pd0L]
derivatization and labeling of biomolecules including proteins
and complex natural products. So far, mild and aqueous
methodologies for the Suzuki-Miyaura,[3] Mizoroki-Heck[4]
Sonogashira[5] and sulfination[6] reactions have been developed.
Other CCs, e.g. Buchwald-Hartwig and Negishi reactions, are
reported in aqueous conditions,[7] although their application in
complex molecule modification strategies is still unreported. The
development of aqueous/partially aqueous coupling conditions
enables reactions to be carried out on otherwise poorly soluble
compounds such as those mentioned above, as well as
permitting the use of milder bases.[8]
Ar
X
O
1
2
Ar
R
Oxidative
addition
R'
Reductive
elimination
6
Ar
PdII
X
Ar
PdII
Ar
PdII
L
3
R'
O
L
L
O
O
R
R
+ Base-
R'
R
5a
5
R'
Enolate
transmetalation
4
Enolate
C–O equilibrium
X-
The α-arylation of ketones is a CC reaction between an aryl
halide or pseudohalide and an enolate, formed in situ by
deprotonation of a ketone (a pronucleophile) by a base.[9] While
being a relatively recent discovery in the field,[10] the wide
distribution of the α-aryl carbonyl motif in industrially relevant
compounds or precursors, has driven an increasing interest
HBase
Scheme 1. The mechanism of Pd-catalyzed α-arylation of ketones according
to Hartwig.[9, 15a]
We particularly wished to achieve the diversification of
halotryptophans.[14] Tryptophan, an essential amino acid, is a
key component in many natural products and its presence in
proteins/peptides is crucial to their structural integrity and
fluorescence properties, which makes it a very exciting target for
derivatization.[3b,c] To this aim, we initiated our studies on a
model reaction comprising 5-Br-indole 2a and propiophenone 4a
in aqueous media. While propiophenone represents a common
model compound for this reaction,[15] heterocyclic electrophiles,
i.e. haloindoles, are generally more challenging reactants for CC
chemistry, because the intrinsic reactivity of heteroatom can
lead to Pd-poisoning and N-arylation.[1f] Initially, we screened a
number of phosphine and N-heterocyclic carbenes based
[a]
Enrico Marelli, Yohann Renault, Dr Sunil V. Sharma, Dr Rebecca J.
M. Goss
EaStCHEM, School of Chemistry and BSRC, University of St
Andrews, North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: rjmg@st-andrews.ac.uk
E-mail: enrico.marelli.chem@gmail.com
Prof. Dr Steven P. Nolan
Chemistry Department, College of Science, King Saud University,
Riyadh 11451 (Saudi Arabia)
Prof Dr. Steven P. Nolan
Department of Inorganic and Physical Chemistry, Universiteit Gent,
Krijgslaan 281-S3, 9000 Ghent, Belgium
[b]
[c]
Supporting information for this article is given via a link at the end of the
document.
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10.1002/chem.201700680
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COMMUNICATION
complexes in our model reaction (see supporting information for
With the optimal conditions in hand, we began to explore the
reaction scope and applicability to different substrates. At first,
we investigated the coupling of a series of haloindoles: 5-, 6-
and 7-Br-indole were all successfully coupled in high yields
(Scheme 2, entries 6a-6c). The effect of the halogen was
verified using 7-Cl- and 7-I-indoles: while the latter gave only a
slightly lower yield compared to its brominated congener, the
former required an increased catalyst loading (from 2 to 5 mol%,
entry 6c) to restore full conversion and a synthetically useful
yield. The use of different ketones was also tested: the CC of o-
methylacetophenone with 7-Br-indole resulted in fair yield of the
monoarylated compound 6d, with the contemporary formation of
the diarylated congener 6d’. The lack of mono-arylation
selectivity of [Pd(DtBPF)Cl2], when acetophenone derivatives
are used, is well known.[19] The reaction also proceeded well
with 3-pentanone pronucleophile, affording moderate yield of
product 6e.
details). Of all the pre-catalysts tested, only 1a,[16]
[Pd(DtBPF)Cl2]
(DtBPF=
1,1'-bis(di-tert-
butylphosphino)ferrocene), was found to be active in water/co-
solvent mixtures. The use of 1a in the α-arylation of ketones is
well known: its utility and limitations have been proven by
Colacot between 2007 and 2008, using temperatures between
R.T. and 100 °C, in THF or dioxane, and t-butoxide as base.[17]
Its commercial availability and high activity make it one of the
most used catalysts in this reaction.[15g-i] Once the pre-catalyst
was identified, we systematically screened for the optimum
base/solvent system, which play a crucial role in this CC.[17,18]
Table 1. Optimization of the conditions.
(tBu)2
P
Cl
[Pd(DtBPF)Cl2]
Fe
Pd
1a
Cl
P
H
O
(tBu)2
Base
2.5 equiv.
N
Br
O
+
R''
N
H
O
1a
R''
Dioxane/water 1:1,
0.5 M, T °C
6a
O
4a
2.0 equiv.
2a
0.2 mmol
NaOH 4.0 equiv.
R
NH
X
overnight
+
R
R'
N
Dioxane/H2O 1:1
60°C, 16 h
R'
H
2
4
6
Entry
[Pd]
(mol%)
Base
T (°C)
GC Conversion%[a]
(NMR Yield %[b]
)
H
N
O
O
O
1
2
2
2
2
2
5
5
2
NaOH
K3PO4
Na2CO3
NaOH
NaOH
NaOH
NaOH
60
60
60
80
60
80
60
>99 (65)
N
H
HN
6c
6a
6b
>99 (22)
X=Br, 84%
X=Br, 82%
X=Br, 90%
X=I, 85%
X=Cl, 81%a
3
>99 (41)
HN
HN
O
O
NH
O
4
>99 (70)
+
H
N
5
>99 (66)
6d'
X= Br, 9%
6e
6d
X=Br, 45%
X=Br, 69%
6
>99 (70)
O
COOH
HOOC
BocHN
7[c]
>99 (90)
BocHN
O
H
N
NH
O
Reaction conditions: Propiophenone (0.4 mmol, 2.0 equiv.), 5-Br-indole (0.2
mmol, 1 equiv.), base (0.5 mmol, 2.5 equiv.), [Pd(DtBPF)Cl2] 2-5 mol%,
dioxane/water 1:1 mixture (0.5 M), T°C, 16h. [a] Conversion measured by GC
analysis; [b] Yield measured by quantitative 1H-NMR using 1,3,5-tri-t-
butylbenzene as internal standard; [c] 4 equiv. propiophenone and 4 equiv.
base used, 84% isolated yield.
N
H
HOOC
NHBoc
6f
6g
6h
X=Br, 87%b
X=Cl, 70%b
X=Br, 94%b
Although we observed high GC conversions, based on
consumption of starting material (>99%, Table 1), NMR yields
were significantly lower (22-70%) even with increased Pd
loading or temperature (entries 1-6), or using different bases. In
GC analysis, no 5-Br-indole 2a was detected in the filtered
reaction mixtures. We hence postulated that a side reaction,
involving intermolecular coupling between the N–H bond and the
C–Br bond of 2a, may produce insoluble oligomers and could
perhaps be responsible for this discrepancy. Indeed, in
accordance with this hypothesis, increasing the amount of
ketone and base to 4 equiv. each forced the desired coupling by
the law of mass action (according to Le Chatelier’s principle),
leading to an increased NMR yield of 90%, and a satisfactory
84% isolated yield (entry 7).
Scheme 2. Aqueous arylation of ketones using N-unprotected haloindoles and
halotryptophan derivatives. Typical conditions: ketone (0.8 mmol, 4.0 equiv.),
haloindole (0.2 mmol, 1.0 equiv.), NaOH (0.8 mmol, 4.0 equiv.),
[Pd(DtBPF)Cl2] 2 mol%, dioxane/water 1:1 (0.5 M), 60°C, 16h. [a] 5 mol%
catalyst; [b] propiophenone (0.25 mmol, 5 equiv.) 0.05 mmol Halo-Tryptophan;
NaOH (0.2 mmol, 4 equiv.), [Pd(DtBPF)Cl2] 10 mol%; dioxane/water 1:1 (0.25
M), 60°C, 16h. Reactions are performed in triplicate, average isolated yields
are given after purification and errors are reported in Supporting Information.
The Pd-mediated modification of halotryptophans can often
be more demanding due to solubility issues as well as the
chelation of the catalyst.[20] Our attempts to perform the reaction
on fully unprotected 5-Br-tryptophan failed. To achieve the
desired CC with such a challenging system, we explored N-
protection of the halotryptophans. Employing N-Boc protected
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Br- and Cl-tryptophans, to our delight, this protocol was
successful in providing good yields in all the three cases (70-
94%, entries 6f-6h). Excitingly, the first example of α-arylation of
ketones using amino acid-derived aryl halides was achieved
under Pd-catalysis. Although Itami et.al. reported two examples
of such a reaction under Ni-catalysis, their protocol required
harsher conditions (150 °C in toluene) and was limited to fully
protected tyrosine derivatives.[21] To verify the retention of the S-
configuration at the amino acid stereocenter under the reaction
conditions, product 6h was derivatized and analyzed following
Marfey’s procedure.[22] Satisfyingly, no racemization was
observed (see Supporting Information for further details)
less efficient and a significantly lower yield was obtained (entry
6k). The effect of N-protection of 5-Br-indole was also studied:
functionalization of the N-benzylated derivative was possible,
again with a lower amount of ketone (2.0 equiv.), confirming the
operation of a side-reaction involving the unprotected indole N–
H bond (entry 6n). The compatibility with functional groups such
as nitro and nitrile (entries 6r and 6t respectively), that cannot
generally withstand the excess of strong base usually employed
in this reaction,[23] is a striking highlight of the synthetic potential
of the conditions we developed. Other heterocyclic cores, e.g.
quinoline, isoquinoline and pyridine, were also suitable
substrates (entries 6o-6q, 6s). The suitability of aryl-
benzylketone (entry 6p) was also tested, and a satisfactory yield
of the desired product 6p was obtained using 6-Cl-quinoline as
electrophilic coupling partner. Notably, lower amounts of ketone
and base were required in all of these cases (2.0 and 2.5 equiv.
respectively). The conditions we developed are comparable with
the current state-of-the-art: a catalyst loading of 2 mol% was
used for the general protocol developed by Colacot using 1a;[17]
while other authors needed an excess of ketone (2 equiv. or
more) and higher catalyst loadings to achieve reactivity, when
dealing with more challenging substrates, when using the same
catalyst.[24] Considering the challenges posed by an aqueous
system when working with anionic enolates (vide supra), our
system is remarkably efficient.
O
1a
O
X
NaOH 2.5 equiv.
+
R'''
R
R''
R
R'
2
4
Dioxane/H2O 1:1
60°C, 16 hours
6
R'
SO2
SO2
SO2
O
O
O
6k
6i
6j
F3C
O
X=Cl, 63%
X=Cl, 92%
X=Cl, 88%
N
N
N
O
O
O
To test the suitability of the protocol to real-world bioactive
molecules, we examined the chlorinated drug, prochlorperazine
2u, as a substrate (Scheme 4). Prochlorperazine, originally
developed as an antipsychotic, is currently used as an
antiemetic.[25] More recently, its antimicrobial activity has been
demonstrated.[26] 2u was reacted with propiophenone as
pronucleophile, obtaining high yield of the desired product 6u
(86%, Scheme 4). In this case, 4 equiv. of base and 5 mol%
catalyst loading were required. 2u was used as free amine,
obtained by basic extraction of the dimaleate salt which
constitutes its commercial formulation. This result, together with
those obtained with protected amino acids (entries 6f-6h),
highlights the potential of this methodology for the late-stage
functionalization of complex bioactive compounds.
O
6l
6m
X=Br, 95%
6n
X=Br, 92%
X=Br, 83%
N
N
O
O
6o
6p
X=Cl, 83%
X=Cl, 65%
NO2
O
O
N
6r
6q
X=Cl, 58%
X=Cl, 95%
CN
O
O
N
N
CF3
N
N
N
6t
6s
X=Cl, 19%
X=Cl, 74%
O
1a
N
S
O
NaOH 4.0 equiv.
Cl
N
S
Scheme 3. Aqueous ketone arylation using other haloarenes. Typical
conditions: ketone (0.8 mmol, 4.0 equiv.), haloindole (0.2 mmol, 1.0 equiv.),
NaOH (0.8 mmol, 4.0 equiv.), [Pd(DtBPF)Cl2] 2 mol%, dioxane/water 1:1 (0.5
M), T°C, 16h..Reactions are performed in triplicate, average isolated yields are
after purification and errors are reported in Supporting Information.
+
Dioxane/water 1:1,
60 °C, 16 h
4a
2.0 equiv.
2u
6u
86%
Scheme 4. Coupling of prochlorperazine with propiophenone under aquous
conditions. Isolated yield is reported after purification. Reaction performed in
triplicate.
To further explore the scope of this reaction, the arylation of
functionalized haloarenes was investigated using the optimised
method. Pleasingly, substrates with medicinally relevant
functional groups, i.e. sulphones and tertiary amines, were well
tolerated (entries 6i-6m). Both electron-poor and electron-rich
propiophenone derivatives were well suited and afforded high
yields (entries 6j, 6m), while cyclic ketone derivatives proved
In summary, the first protocol for the aqueous α-arylation of
ketones is reported. The conditions employed are relatively mild
and allow the coupling of a wide range of coupling partners
including those bearing sensitive functional groups that can not
tolerate strong bases usually required for this reaction. We have
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We thank the European Research Council (FP7/2007-
2013/ERC grant agreement no 614779 to RJMG) and (FP7
2009-2014/ERC agreement no 227817 to SPN) for
generous funding. We thank the EPSRC UK National Mass
Spectrometry Facility at Swansea University for assistance
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Keywords: Palladium • Aqueous coupling• Halogenated
compounds • Ketone arylation • Amino acids
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COMMUNICATION
COMMUNICATION
O
O
X
Don’t leave me dry: The first
Enrico Marelli, Yohann Renault,
Sunil V. Sharma, Steven P. Nolan
and Rebecca J. M. Goss
Pd, Base
R'''
+
R''
R
aqueous
α-arylation
of
R
Aq. Coupling
R'
ketones is reported. The
reaction shows wide functional
group compatibility, coupling
alkyl- and aryl-ketones with
heterocyclic and functionalized
haloarenes in fair to excellent
yields. The reaction scope
R'
N
Page No. – Page No.
N
O
Mild, aqueous α-arylation of
ketones: towards new
diversification tools for
halogenated metabolites and
drug molecules
H
O
N
N
S
includes
bromotryptophan derivatives,
representing potential
chloro-
and
X=Br
94%
X=Cl
86%
HOOC
a
NHBoc
platform for derivatization of
complex molecules.
+ 23 more examples
This article is protected by copyright. All rights reserved.