Direct acylation of aryl bromides with aldehydes by palladium catalysis

Article abstract of DOI:10.1021/ja804351z

A new protocol for the direct acylation of aryl bromides with aldehydes is established. It appears to involve palladium-amine cooperative catalysis, affording synthetically important alkyl aryl ketones in moderate to excellent yields in a straightforward manner, and broadening the scope of metal-catalyzed coupling reactions. Copyright

Full text of DOI:10.1021/ja804351z

Published on Web 07/18/2008
Direct Acylation of Aryl Bromides with Aldehydes by Palladium Catalysis
Jiwu Ruan, Ourida Saidi, Jonathan A. Iggo, and Jianliang Xiao*
Department of Chemistry, LiVerpool Centre for Materials and Catalysis, UniVersity of LiVerpool,
LiVerpool L69 7ZD, U.K.
Received June 9, 2008; E-mail: j.xiao@liv.ac.uk
Alkyl aryl ketones are fundamental intermediates in the pharma-
ceutical, fragrance, dye, and agrochemical industries.1 They are usually
synthesized by the traditional Friedel-Crafts acylation, which involves
handling hazardous reagents and fails with electron-deficient arenes.2
Hydroacylation allows for direct access to these ketones from aldehydes
and olefins, but generally requires chelation assistance for C-H
activation and for inhibiting decarbonylation.3 Acylation of aryl halides
offers another direct approach. However, there are only a few reported
examples of acylation of aryl iodides with aldehydes; these are
catalyzed by bimetallic systems and require a chelating auxiliary on
the aldehydes, affording alkyl aryl ketones in low yields.4–6 In related
studies, aryl boronate salts have been acylated with aldehydes to give
diaryl ketones,7 which could also be obtained by coupling of aryl
iodides with N-pyrazyl aldimines or N-tert-butylhydrazones followed
by hydrolysis.8,9 Herein we disclose an efficient, palladium-catalyzed
direct acylation reaction of aryl bromides with aldehydes, affording
alkyl aryl ketones in one step.
The Heck reaction of aryl halides with the electron-rich olefin
vinyl ethers or enamides provides yet another indirect method for
accessing alkyl aryl ketones, where the aryl group inserts at the
carbon R to the heteroatom and hydrolysis results in the ketone
(Scheme 1).10–12 As is known, under basic conditions or in the
presence of a secondary amine, an aldehyde can equilibrate with
an enolate or enamine, thus generating an olefin similar to that used
in the well-established Heck reaction (Scheme 1). Enlightened by
this, we reasoned that, if the enolate or enamine could be formed
in situ, we might be able to obtain ketones directly from aryl halides
and aldehydes via the Heck coupling.
With this hypothesis in mind, we set out to examine the acylation
of 1-bromo-4-methoxybenzene (1a) with octanal (2f) in the presence
Scheme 1
Table 2. Acylation of 1a with Various Aldehydes (2a-k)a
Table 1. Screening Conditions for the Acylation of 1a with 2fa
entry
ligand
additive
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
PPh3
dppf
KF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
toluene
0
0
0
<2
<2
6
87
<2
20
60
50
<2
80
83
78
7
K2CO3
KOBut
Et3N
L-proline
pyrrolidine
pyrrolidine, 4Å MS
n-BuNH2, 4Å MS
n-Bu2NH, 4Å MS
morpholine, 4Å MS
piperidine, 4Å MS
L-proline, 4Å MS
pyrrolidine, 4Å MS
pyrrolidine, 4Å MS
pyrrolidine, 4Å MS
pyrrolidine, 4Å MS
pyrrolidine, 4Å MS
BINAP
dppp
dppp
6
a All reactions were carried out with 1a (1.0 mmol), 2f (1.2 equiv), 2
equiv of additive, Pd(dba)2 (2 mol %), and ligand (3 mol %) in 4 mL of
solvent at 115 °C for 6 h. 4Å MS: 4Å molecular sieves, 1 g when
added; dppp: 1,3-bis(diphenylphosphino)propane; dppf: 1,1′-bis(di-
phenylphosphino)ferrocene; BINAP: 2,2′-bis(diphenylphosphino)-1,1′-
binaphthalene. b Isolated yields of ketone.
a Reactions were carried out with 1a (1.0 mmol), 2a-k (1.2 equiv),
pyrrolidine (2 equiv), 4Å MS (1 g), Pd(dba)2 (2 mol %), and dppp (3
mol %) in 4 mL of DMF at 115 °C for 6 h. b Isolated yields. c Two
equivalents of aldehyde used.
9
10510 J. AM. CHEM. SOC. 2008, 130, 10510–10511
10.1021/ja804351z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Acylation of Aryl Bromides (1b-m) with 2d,i-ka
point and self-condensation, a low yield was obtained with
propionaldehyde (entry 1).
We next extended the acylation to a series of aryl bromides
(1b-m) coupling with hexanal (2d) and the functionalized alde-
hydes 2i-k. As summarized in Table 3, the reactions afforded
moderate to excellent yields of ketones 3. As may be expected,10c
ortho substitution on the arene ring decreases the yield (entry 2).
It appears that aryl bromides with electron-withdrawing or very
electron-donating groups also tend to furnish lower yields. Good
results were again obtained when using the aldehydes 2i-k (entries
13-15). We also examined the acylation of 2-bromothiophene
(1m); a moderate yield was recorded (entry 12).
The hypothesis in Scheme 1 implies that, in the case of an
enamine, the overall acylation can be catalytic in the amine since
it should be regenerated following hydrolysis of the Heck coupling
product. To further probe the mechanism, we then studied the
acylation of 1a with 2f by using 20 mol % of pyrrolidine and 1
equiv of K2CO3 as base under otherwise identical conditions to
those above. 3f was obtained in 85% isolated yield.15 This compares
well with the result in Table 2, suggesting that pyrrolidine indeed
acts as a catalyst, presumably converting the aldehyde into a highly
reactive electron-rich olefin for palladium to seize and as a base
under the conditions of Tables 2 and 3 to neutralize the HBr released
from the Heck reaction, as hypothesized in Scheme 1. It is
interesting to note that, under similar conditions but without
pyrrolidine and 4Å MS added, the coupling reaction of aldehydes
with aryl bromides led to R-arylated aldehydes instead of ketones,
as shown by Hartwig very recently.16
In summary, we have developed an efficient protocol for the
direct acylation of aryl bromides with various aldehydes, obtaining
alkyl aryl ketones in moderate to excellent yields. The reaction
appears to involve cocatalysis of palladium and amine. Studies into
the mechanism and further application of the reaction will be the
focus of future work.
Acknowledgment. We thank the EPSRC (EP/F000316) for
support.
a The conditions were the same as in Table 2. b Isolated yields.
c Only one bromo group reacted.
Supporting Information Available: Experimental details and
analytic data (NMR, IR, MS, and elemental analysis). This material is
available free of charge via the Internet at http://pubs.acs.org.
of a base, using Pd(dba)2-phosphine as catalyst precursor. The
results are summarized in Table 1. The desired ketone 3f was not
obtained with inorganic bases (entries 1-3), and changing the base
to Et3N led to only a small amount of 3f being formed (entry 4).
We then turned attention to secondary amines, which are prone to
forming enamines with the aldehyde.13 To our delight, an encour-
aging result was obtained when pyrrolidine was used (entry 6). We
then tested a range of other additives under various conditions. The
results show that the combination of pyrrolidine and 4Å MS affords
the best yield of ketone 3f (entry 7). No reaction occurred using
4Å MS alone, and lower yields resulted with other amines (entries
8-12). While ligands show insignificant effects on the acylation
(entries 13-15), solvents impact dramatically on the reaction
(entries 16 and 17).
References
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(15) Under the same conditions but in 10 h reaction time, 3k, 3l, 3t, and 3u
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Having established the optimized conditions, we then tested the
acylation of 1a with various aldehydes 2a-k. The results are shown
in Table 2. As can be seen, the reactions afforded good to excellent
yields of ketones 3. In particular, very good results were obtained
for the functionalized aldehydes 2j,k (entries 10 and 11), providing
a better way for preparing functionalized alkyl aryl ketones,
synthetically useful intermediates for pharmaceutical compounds,
such as Fluoxetine and analogues.14 However, due to the low boiling
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