α-Arylation, α-arylative esterification, or acylation: A stoichiometry-dependent trichotomy in the Pd-catalyzed cross-coupling between aldehydes and aryl bromides

Article abstract of DOI:10.1002/asia.201300724

Three′s company: The selective α-arylation and α-arylative esterification of linear and branched aldehydes is reported for a variety of bromoarenes. The acylation of aryl bromides can be achieved with linear aldehydes (see scheme). All these transformations were performed with a single [(N-heterocyclic carbene)Pd] catalyst through adjustment of the stoichiometry of the reagents and the appropriate base. Copyright

Full text of DOI:10.1002/asia.201300724

COMMUNICATION
COMMUNICATION
Three’s company: The selective a-ary-
lation and a-arylative esterification of
linear and branched aldehydes is
Cross-Coupling Reactions
Pradeep Nareddy,
reported for a variety of bromoarenes.
The acylation of aryl bromides can be
achieved with linear aldehydes (see
scheme). All these transformations
were performed with a single [(N-het-
erocyclic carbene)Pd] catalyst through
adjustment of the stoichiometry of the
reagents and the appropriate base.
Clꢀment Mazet*
&&&& — &&&&
a-Arylation, a-Arylative Esterification,
or Acylation: A Stoichiometry-Depen-
dent Trichotomy in the Pd-Catalyzed
Cross-Coupling between Aldehydes
and Aryl Bromides
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Pradeep Nareddy and Clꢁment Mazet
DOI: 10.1002/asia.201300724
a-Arylation, a-Arylative Esterification, or Acylation: A Stoichiometry-
Dependent Trichotomy in the Pd-Catalyzed Cross-Coupling between
Aldehydes and Aryl Bromides
Pradeep Nareddy and Clꢀment Mazet*[a]
As a clear testimony of its high synthetic potential, the
Pd-catalyzed a-arylation of enolates has attracted increased
interest over the last two decades.[1] Although the inherent
problems associated with any cross-coupling reaction using
aryl halides should not be neglected, taming the reactivity of
the carbonyl functionality under the necessary basic condi-
tions certainly constitutes the key challenge of these a-aryla-
tions.[1c,f] Therefore, not surprisingly, there exists a plethora
of examples with robust carbonyl functions such as amides,
esters, or ketones in which the optimized catalyst enables
the coupling reaction to proceed with a wide scope of aryl
halides and tolerates various functional groups. In contrast,
the number of efficient methods for the more sensitive alde-
hyde functionality is rather limited. Whereas the tendency
of these derivatives to undergo self-aldol condensation
under basic reaction conditions is the first barrier to over-
come, the marked reactivity difference between linear and
a-branched substrates constitutes another notorious difficul-
ty. Building on the early observations of Muratake et al. in
the syntheses of hesitine-type aconite alkaloids,[2] the Miura,
Buchwald, and Hartwig groups have developed protocols
that addressed most of these issues.[3–6] Thus, in the best
cases, both linear and a-branched aldehydes could be cou-
pled with electron-rich, electron-deficient, or sterically de-
manding aryl bromides and chlorides. Nonetheless, all these
methods require the use of air-sensitive and rather expen-
sive phosphine ligands, which might limit their widespread
application.
ers,[7] several research groups have utilized [(NHC)Pd] com-
plexes for the a-arylation of amides or ketones.[8,9] Nonethe-
less, no example of such catalyst was reported for the
a-arylation of the more sensitive aldehydes.[10] Herein, we
report first the successful development of the a-arylation of
linear and a-branched aldehydes by using a well-defined
[(NHC)Pd] complex. Second, and more importantly, we
disclose the discovery of an unexpected arylative esterifica-
tion of a-branched aldehydes and of an equally unexpected
intermolecular acylation of aryl bromides by simple adjust-
ment of the relative stoichiometry of the coupling partners
and the base by using the very same palladium catalyst
(Scheme 1).
Scheme 1. Pd-catalyzed a-arylation of aldehydes and competing process-
es.
At the outset of our investigations, we initially aimed at
developing a more practical protocol that would rely on the
use of air-stable Pd complexes supported by commercially
available N-heterocyclic carbene ligands (NHC). In addition
to their robustness, such systems are structurally highly
modular and enable fine-tuning of the electronic and steric
requirements associated with a-arylation processes. Indeed,
by following the impetus provided by Hartwig and co-work-
The versatile reactivity of NHC salts with aldehydes
prompted us to use well-defined palladium complexes rather
than in situ protocols to avoid undesired reactions to
occur.[11] Thus, 3a and 3b were initially selected and engag-
ed in the cross-coupling of octanal 1a with 4-(tert-butyl)bro-
mobenzene 2a in 1,4-dioxane at 808C using tBuOK as
a base (Table 1).[12,13] When an equimolar amount of these
three components was reacted in the presence of 5 mol% of
3a, the product of self-aldol condensation 4a was observed
exclusively. When the same reaction was carried out with 3b
instead (5 mol%), a barely separable mixture of aldol con-
densation product 4a and a-arylation product 5aa (30:70)
was obtained. After gradual optimization, it was found that
a 1:2:2 ratio between 1a, 2a, and tBuOK was the optimal
stoichiometry, delivering 5aa in 52% yield after purification.
By performing the reaction at 1008C, the a-arylation prod-
[a] P. Nareddy, Prof. Dr. C. Mazet
Department of Organic Chemistry
University of Geneva
30 quai Ernest Anserrmet
1211 Geneva-4 (Switzerland)
Fax : (+41)22-379-3215
E-mail: clement.mazet@unige.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300724.
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Table 1. Optimization study.[a]
When our optimized set of
reaction conditions was used
for the a-arylation of a-
branched aldehydes with 1d
and 2a as model substrates, the
corresponding a-arylated tert-
butyl ester 6da was obtained
exclusively.[16,17] No traces of
the initially expected a-arylat-
ed aldehyde were detectable
by inspection of the crude re-
action mixture. The product
was isolated in 64% yield after
purification by chromatogra-
phy. Intrigued by this result,
we first set out to delineate the
scope of this transformation
(Scheme 3). Electron-neutral
and electron-rich para-substi-
tuted aryl bromides were par-
ticularly well suited, and the
corresponding esters with a a-
quaternary center were all ob-
Entry
[Pd]
2a
tBuOK
(Y [equiv])
T [8C]
Conv [%][b]
4a/5aa[c]
5aa
(X
A
ACHTUNGTRENNUNG
Yield [%][d]
1
2
3
4
5
3a
3b
3b
3b
3b
1.0
1.0
2.0
2.0
2.0
1.0
1.0
1.0
2.0
2.0
80
80
80
80
100
>99
>99
>99
>99
>99
>99:1
nd[e]
nd
nd
52
30:70
nd[f]
12:88
1:99
68
[a] Average of at least two experiments: 1a (0.5 mmol). [b] Refers to consumption of 1a. [c] Determined by
1H NMR spectroscopy. [d] Isolated yield after column chromatography. [e] Not determined. [f] Complex mix-
ture.
uct 5aa could be generated exclusively and isolated in 68%
yield.
tained in good yields (4 examples, 61–77% yield). 4-Fluoro-
bromobenzene could also be coupled, although the corre-
sponding product was obtained in a lower yield (6di, 47%).
Interestingly, when 2-bromoanisole 2h was used, a 1:2 mix-
ture of a-arylated ester 6dh and a-arylated aldehyde 7dh
was obtained, thus indicating that our initial targets might
still be accessible. Prior to going in this direction, we sought
to gain preliminary insight into the role of the palladium
catalyst by performing a series of control experiments
(Table 2).
To this end, 7da, an a-aryl aldehyde bearing a quaternary
center, was prepared by using an independent procedure.[4]
When first treated with 2 equiv of tBuOK in 1,4-dioxane at
1008C, 7da was found to disproportionate in a 1:1 mixture
of the corresponding ester 6da and alcohol 8da in a Canni-
zzaro-type reaction (Table 2, entry 1). Next, when 7da was
treated with 1 equivalent of tBuOK in the presence of
5 mol% of 3b, a 5:1 ratio of 6da/8da was measured. When
2 equivalents of base were employed, this ratio decreased to
2:1, clearly indicating that the Pd-catalyzed esterification
and the base-assisted disproportionation reaction are com-
peting processes (Table 2, entries 2 and 3). Of note, in most
a-arylative esterifications, we did not measure significant
amounts of the alcohols in the crude mixtures. Attempts to
perform the a-arylation of ester 6e proved unsuccessful
(Scheme 4). Collectively, the results reported in Table 2 and
Scheme 3 suggest that a-arylation likely precedes esterifica-
tion. This is in line with the observation described in
Scheme 2.
Next, the scope of the intermolecular a-arylation of linear
aldehydes was investigated by using this set of reaction con-
ditions (Scheme 2). Gratifyingly, both linear and b-branched
aldehydes 1a–c could be coupled indifferently with electron-
rich or electron-neutral aryl bromides (2a–d), delivering the
corresponding products in 49 to 68% yield after purification
by column chromatography. Electron-deficient aryl bro-
mides such as 2e,f were also tolerated, although the yield of
the a-arylation products was slightly diminished (47–55%).
When 1a was engaged in the cross-coupling reaction with
either 2-bromotoluene 1g or 2-bromoanisole 2h, mixtures of
the expected a-arylated aldehyde 5ag–h and the corre-
sponding a-arylated tert-butyl ester 6ag–h were obtained (in
reaction with either 2-bromotoluene 1g or 2-bromoanisole
2h; ratios of 1:1.2 and 1:5, respectively). The arylated esters
could be isolated in 31 and 67% yield, respectively. On the
basis of this result, we propose that the intermolecular a-ar-
ylation takes place before esterification. Indeed, when only
1 equivalent of base was used, 5ah was obtained as the
major product. The much higher ratio measured in the cou-
pling between 1a and 2h suggests that the ortho-methoxy
substituent might serve as a directing group and facilitate in-
À
tramolecular C H activation of the aldehydic proton. Inter-
estingly, Martin and co-workers have recently observed
a similar esterification reaction in the Pd-catalyzed intramo-
lecular acylation of aryl bromides when the reaction was
carried out in the presence of methanol or n-butanol.[14] Sim-
ilarly, Wu and co-workers have developed an esterification-
hydroarylation of alkynylbenzaldehydes with aryl iodides in
methanol.[15] In the present study, coupling between two
sterically demanding partners such as 1b and 2g predomi-
nantly led to the formation of the a-arylation product 5bg.
We next searched for reaction conditions that favor the
direct a-arylation of a-branched aldehydes (1d–f). Gratify-
ingly, by simply decreasing the relative stoichiometry of
tBuOK to 1 equivalent, 7da was obtained exclusively as
judged by analysis of the crude reaction mixture and could
3
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Pradeep Nareddy and Clꢁment Mazet
Scheme 3. Scope of the a-arylative esterification of a-branched alde-
hydes.
Table 2. Control experiments for the arylative esterification.[a]
Entry
tBuOK
(X [equiv])
3b
Conv [%][b,c]
6da/8da[c]
N
(Y ACHTUNTGRENNUNG
Scheme 2. Scope for the a-arylation of linear aldehydes. [a] Along with
7% of 4a.
1
2
3
2.0
1.0
2.0
0
5
5
>99
>99
>99
1.0:1.0
5.0:1.0
2.0:1.0
[a] Average of at least two experiments: 7da (0.5 mmol). [b] Refers to
1
consumption of 7da. [c] Determined by H NMR spectroscopy.
be isolated in 61% yield (Scheme 5). This protocol turned
out to be relatively general and was extended to a vast array
of bromoarenes that lead to aldehydes with a a-quaternary
center. Electron-neutral and electron-rich aryl bromides
proved particularly well suited, and the coupling products
were isolated in yields that ranged from 47 to 63% (7da–d,
7ea, 7ed). Sterically demanding ortho-substituted electro-
philes delivered the product in moderate to good yields (44–
72%; 7dg, 7dj, 7ek). Slightly reduced yields were obtained
when electron-poor bromoarenes were employed (39–53%;
7de, 7ee, 7ei). Remarkably, even 2-phenylpropanal under-
went a-arylation with 2a, and the formally doubly arylated
aldehyde 7 fa was obtained as the sole detectable coupling
product (albeit in a modest 31% yield).
Scheme 4. Unsuccessful a-arylation of a-branched ester 6e.
Traces of self-aldol condensation or a-arylative esterifica-
tion were hardly detectable in the crude mixture, and the
ketone derivative 9aa was isolated in 55% after chromatog-
raphy. This Pd-catalyzed direct acylation reaction is recog-
nized as a challenging process with only a few precedents in
the literature.[18–20] We therefore sought to evaluate the
scope of this transformation. The process turned out to be
applicable to electron-rich, electron-neutral, and electron-
During our initial optimization studies, we found that if
an excess amount of tBuOK (5.5 equiv) were used in the
equimolar coupling between 1a and 2a, the a-arylation
product 5aa was obtained along with the acylation product
9aa in a 1:2.3 ratio (Scheme 6).
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Pradeep Nareddy and Clꢁment Mazet
fluorobromobenzene 2i was used, inseparable mixtures of
a-arylation and acylation products were obtained. Reactions
with a- and b-branched aldehydes delivered complex mix-
tures that were composed predominantly of a-arylated
esters and a-arylated aldehydes.
In conclusion, we have developed a practical protocol for
the a-arylation of linear and a-branched aldehydes by using
an air-stable and commercially available [(NHC)Pd] com-
plex. We also disclosed a less-common a-arylative esterifica-
tion of a-branched aldehydes and an unusual acylation of
aryl bromides with linear aldehydes by using the very same
catalyst. The reasons behind this mechanistic trichotomy are
not yet clear, and it is certainly premature to draw any de-
finitive mechanistic hypotheses. Yet it is remarkable that
only subtle changes in stoichiometry have such a profound
impact on the reaction outcome. In general, similar drastic
differences in reactivity are usually observed after modifica-
tion of the catalyst structure, and/or the reaction tempera-
ture or the use of additives.[14,21–23] Current efforts are now
directed towards deciphering the key mechanistic aspects of
these stoichiometry-dependent transformations.
Acknowledgements
This work was supported by the State Secretariat for Education and Re-
search, the Swiss National Science Foundation. Roche is also acknowl-
edged for support through an unrestricted grant.
Scheme 5. Scope of the a-arylation of a-branched aldehydes.
Keywords: acylation
·
arylation
·
cross-coupling
·
esterification · palladium
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[13] Identical results were obtained when using either commercial or
freshly synthesized batches of 3b. KOtBu was purchased from
Acros (98% purity) or freshly sublimed and kept under an inert at-
mosphere in a glovebox. Aryl chlorides were competent coupling
partners but generally delivered the coupling products in much
lower yield.
[23] D. Solꢁ, L. Vallverdffl, X. Solans, M. Font-Bardꢂa, J. Bonjoch, J. Am.
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1228.
Received: May 28, 2013
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