Palladium-Catalyzed Carbonylative Synthesis of α-Branched Enones from Aryl Iodides and Arylallenes

Article abstract of DOI:10.1021/acs.orglett.0c00015

In this communication, an interesting carbonylation protocol for the preparation of α-branched enones has been established. Starting from readily available aryl iodides and allenes, with formic acid as the CO source and reductant, moderate to good yields of the desired enones were isolated. Although it is a carbonylation methodology, the use of a CO source can avoid the manipulation of CO gas directly. Notably, this procedure also presents the first example on carbonylative synthesis of α-branched enones.

Full text of DOI:10.1021/acs.orglett.0c00015

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Carbonylative Synthesis of α‑Branched Enones
from Aryl Iodides and Arylallenes
Hui-Qing Geng, Le-Cheng Wang, Chen-Yang Hou, and Xiao-Feng Wu*
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ABSTRACT: In this communication, an interesting carbonylation
protocol for the preparation of α-branched enones has been
established. Starting from readily available aryl iodides and allenes,
with formic acid as the CO source and reductant, moderate to
good yields of the desired enones were isolated. Although it is a
carbonylation methodology, the use of a CO source can avoid the manipulation of CO gas directly. Notably, this procedure also
presents the first example on carbonylative synthesis of α-branched enones.
Scheme 1. Methodologies for α-Branched Enone
Preparation
α-Branched enone is an interesting class of α,β-unsaturated
ketones which contains a terminal alkene group. This special
structural moiety has been proven to be related with
distinguished biological activity and synthetic applications.1,2
For example, etacrynic acid (Trade name: Edecrin), as a loop
diuretic, has been used to treat high blood pressure and
diseases that cause swelling such as congestive heart failure,
liver failure, and kidney failure.1a In 2012, Jun and co-workers
developed a novel procedure for the synthesis of pyridine
derivatives which can only be achieved by using α-branched
enones as one of the starting materials.2b Due to the
recognized importance, various procedures have been
developed for their preparation (Scheme 1).3−9 Traditional
protocols usually need several steps from the specific substrates
(Scheme 1, eqs 1−3).3−5 Palladium-catalyzed cross-coupling of
acid chlorides with organotin reagents (Scheme 1, eq 4)6 or
α,β-unsaturated ketones with allylic acetates (Scheme 1, eq 5)
have been developed as well.7 More recently, methodologies
based on α-methylenation of ketones have also been developed
(Scheme 1, eq 6).8 Besides the difference on catalysts applied,
various methylene sources have been explored, including
DMSO, DMF, CH2Br2, HCHO, and so on. Remarkably, Jun
and co-workers achieved an attractive pathway on rhodium-
catalyzed hydroacylation of terminal alkynes with aldehydes
(Scheme 1, eq 7).9 α-Branched enones were produced in high
yields and with high regioselectivity from both aliphatic and
aromatic alkynes and aldehydes.
On the other hand, palladium-catalyzed carbonylative
coupling reactions of aryl halides have already been accepted
as a powerful toolbox for the synthesis of carbonyl-containing
compounds. However, compared with nucleophiles such as
amines, alcohols, organometallic reagents, and alkynes, allenes
are much less studied in carbonylative cross-coupling
reactions.10,11 Here, we developed a new procedure for the
preparation of α-branched enones from aryl iodides and
allenes. With formic acid as the CO source and reductant,
good yields of the desired enones were isolated successfully.
Here it is important to mention that the use of formic acid as a
CO source, which can be produced from CO2 hydrogenation,
Received: January 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00015
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Proposed Reaction Mechanism
entry
ligand
PPh3
PCy3
PtBu3
BuPAd2
DPPP
solvent
yield and ratio
1
2
3
4
5
DMF
DMF
DMF
DMF
20 (3:2)
19 (4:1)
25 (3:1)
44 (7:1)
<1
DMF
6
7
8
9
10
11
12
13
Xantphos
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
DMF
<1
DMSO
MeCN
THF
toluene
DMSO
DMSO
DMSO
44 (9:1)
39 (9:1)
12 (2:1)
8 (3:1)
45 (12:1)
48 (10:1)
b
b c
,
b cd
, ,
74 (8:1)
Initially, phenylallene and iodobenzene were selected as the
model substrates to establish this procedure (Table 1). Due to
the existence of several nucleophiles, the reaction mixture is
very much complexed. To our delight, the desired product can
be obtained with PdCl2 and PPh3 as the catalyst system in
DMF with NEt3 as the base and HCO2H as the reductant
(Table 1, entry 1). However, after careful analysis, a mixture of
two products resulted in a 3:2 ratio. Then various phosphine
ligands were tested immediately. Among the tested ligands,
similar results were obtained with PCy3 or PtBu3 as the ligand
(Table 1, entries 2 and 3). Delightfully, 44% yield of the
products with 7:1 ratio was achieved with BuPAd2 as the ligand
e
65
a
Reaction conditions: phenylallene 1a (0.5 mmol), iodobenzene 2a
(0.6 mmol), HCOOH (2 mmol), PdCl2 (3 mol %), ligand
(monophosphine 6 mol %; bidentate ligand 3 mol %), NEt3 (1
mmol), CO (CH3C(O)−O−(O)CH + Et3N, 2 mmol), solvent (2
b
mL), 80 °C, 16 h, yields, and ratio were determined by GC. HCO2H
c
d
e
(1.5 mmol). PhI (1.0 mmol). Ligand (9 mol %). Isolated yield.
can avoid the manipulation of highly toxic carbon monoxide
gas.
a
Scheme 2. Palladium-Catalyzed Carbonylative Synthesis of α-Branched Enones
a
Reaction conditions: allene (0.5 mmol), aryl iodide (1 mmol), HCOOH (1.5 mmol), PdCl2 (3 mol %), BuPAd2 (9 mol %), NEt3 (1 mmol), CO
(AcOOCH + Et3N, 2 mmol), DMSO (2 mL), 80 °C, 16 h, isolated yields.
B
https://dx.doi.org/10.1021/acs.orglett.0c00015
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Letter
(Table 1, entry 4). To our surprise, only a trace amount of the
desired product could be detected when chelating phosphine
ligands were tested (Table 1, entries 5 and 6). Different
solvents were tested with BuPAd2 as the ligand subsequently
(Table 1, entries 7−10). DMSO was shown to be the best
reaction media for this transformation (Table 1, entry 7). The
ratio of the desired 3a product can be further improved with
decreased loading of HCO2H (Table 1, entry 11). Finally, by
modifying the loadings of iodobenzene and ligand, the target
product 3a can be isolated in 65% yield successfully (Table 1,
entry 13; for more details on optimization, see the Supporting
Information). Our model reaction has been performed with a
CO balloon as well, and comparable results can be obtained
using formic acid as the CO source. However, special attention
should be pained during the process due to the high toxicity of
CO gas.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00015.
■
sı
General comments, optimization details, general proce-
dure, analytic data, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Xiao-Feng Wu − Zhejiang Sci-Tech University,
Hangzhou, People’s Republic of China, and Leibniz-
̈
̈
Institut fur Katalyse e. V. an der Universitat Rostock,
Rostock, Germany; orcid.org/0000-0001-6622-3328;
Email: xiao-feng.wu@catalysis.de
With the best reaction conditions in hand, testing of the
substrate generality and limitation of this methodology were
performed subsequently (Scheme 2). Numbers of aryl iodides
were tested at the first step, and in general, moderate to good
yields of the desired α-branched enones can be obtained
(Scheme 2, 3b−3j). Besides methoxy, fluoride, and chloride
functional groups, sterically bulky 2,6-dimethyl-substituted aryl
iodide can gave the target product in 56% isolated yield as well
(3b). In the testing of allenes, good yields of the corresponding
products can be achieved as well (Scheme 2, 3j−3r).
Remarkably, 2,3-butadien-2-ylbenzene can also be applied as
the starting material and delivers the corresponding 2-
methylene-1,3-diphenylbutan-1-one in 69% yield (3r). It is
important to mention that aliphatic allenes and internal allenes
were tested under our standard conditions without exception,
but only a trace amount of the desired products could be
detected. Many other terminal allenes and aryl iodides were
also tested, and the desired products could be formed;
however, due to the complexity of the reaction mixture, we
have difficulty getting the pure products, and therefore they are
not included in the manuscript (for a list of the failed
substrates, see the Supporting Information).
A possible reaction pathway has been proposed based on our
results (Scheme 3).12 Initially, a Pd0 complex will be generated
from the palladium precursor. After oxidative addition with aryl
iodide, the organopalladium complex A is formed which will
produce acylpalladium complex B as one of the key
intermediates after the coordination and insertion of the CO
from formic acid. As demonstrated in the literature,10,11 the
palladium catalyst usually prefers the carbon in the middle
when reacting with allenes. Then allene coordinates with the
acylpalladium complex B, and palladium inserts into the allene
to give complex C. The iodide in complex C will be exchanged
by formic acid via X ligand exchange to produce complex D. A
decarboxylation step will occur together with a rearrangement
process to form the palladium complex E which will eliminate
the final desired enone product and meanwhile release Pd0 for
the next catalytic cycle. Here, due to the increase, the solubility
of CO in DMSO can further facilitate the CO insertion step.
In summary, an interesting palladium-catalyzed carbon-
ylative procedure for the synthesis of α-branched enones from
aryl iodides and allenes has been established. With formic acid
as the CO source and reductant, moderate to good yields of
the desired enones were isolated. Remarkably, this procedure
also presents the first example on carbonylative synthesis of α-
branched enones.
Other Authors
Hui-Qing Geng − Zhejiang Sci-Tech University,
Hangzhou, People’s Republic of China
Le-Cheng Wang − Zhejiang Sci-Tech University,
Hangzhou, People’s Republic of China
Chen-Yang Hou − Zhejiang Sci-Tech University,
Hangzhou, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00015
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the financial support from the National
Natural Science Foundation of China (21772177).
■
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