Palladium-Catalyzed Tunable Carbonylative Synthesis of Enones and Benzofulvenes

Article abstract of DOI:10.1002/chem.201901530

A palladium-catalyzed four-component carbonylative coupling reaction involving aryl halides, internal alkynes, arylboronic acids, and CO has been developed for the first time. All-carbon substituted α-unsaturated ketones and benzofulvenes can be selectively obtained in a highly regio- and stereocontrolled manner. Using Cu(TFA)₂ as the additive, a series of tetrasubstituted α-unsaturated ketones were prepared in moderate to high yields. Using more acidic Lewis acid Cu(OTf)₂ as the additive, multisubstituted benzofluvenes were synthesized in moderate yields. This efficient methodology involved the formation of three new C?C bonds, and provided a divergent method for the quick construction of multisubstituted α-unsaturated ketones and benzofulvenes from easily available starting materials.

Full text of DOI:10.1002/chem.201901530

A Journal of
Accepted Article
Title: Palladium-Catalyzed Tunable Carbonylative Synthesis of Enones
and Benzofulvenes
Authors: Xiao-Feng Wu, Jin-Bao Peng, Fu-Peng Wu, and Anke
Spannenberg
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.201901530
Link to VoR: http://dx.doi.org/10.1002/chem.201901530
Supported by

Chemistry - A European Journal
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COMMUNICATION
Palladium-Catalyzed Tunable Carbonylative Synthesis of Enones
and Benzofulvenes
[
a]
Jin-Bao Peng, Fu-Peng Wu, Anke Spannenberg, and Xiao-Feng Wu*
Abstract:
A
palladium-catalyzed four-component carbonylative
such as the direct cross-coupling or carbonylative cross-coupling
of aryl halides and the organometallic compounds. We proposed
that the addition of Lewis acid would activate the triple bond and
facilitate the intermolecular bifunctionalization of the alkynes
(Scheme 1, eq. b). Herein, we report the first palladium-
catalyzed intermolecular arylcarbonylative coupling of internal
coupling reaction involving aryl halides, internal alkynes, arylboronic
acids, and CO has been developed for the first time. All-carbon
substituted 훼-unsaturated ketones and benzofulvenes can be
selectively obtained in a high regio- and stereo-controlled manner.
Using Cu(TFA)
unsaturated ketones were prepared in moderate to high yields.
Using more acidic Lewis acid Cu(OTf) as the additive, multi-
substituted benzofluvenes were synthesized in moderate yields. This
2
as the additive, a series of tetra-substituted 훼,훽-
alkynes with aryl halides and arylboronic acids. Using Cu(TFA)
2
2
as the additive, a series of tetra-substituted 훼,훽-unsaturated
ketones were prepared in moderate to high yields. The
efficient methodology involved the formation of three new C-C bonds, arylcarbonylation reaction proceeds in
a high regio- and
and provided a divergent method for the quick construction of multi-
substituted 훼,훽 -unsaturated ketones and benzofulvenes from easily
available starting materials.
stereoselective manner and the syn adduct of aryl and acyl
group to the carbon-carbon triple bond has been obtained.
Interestingly, we found that the use of more acidic Cu(OTf) as
2
the additive can lead to the production of multi-substituted
benzofulvenes. In our control experiments, no interchange
between enones and benzofulvenes could be obtained.
Diversified synthesis is one of the core targets of organic
chemistry. On one hand, transformations such as domino
reactions and multi-components reactions, can increase the
1
-4
efficiency in new chemical bonds formation significantly. On
the other hand, selectivity controlled transformations can
5
-8
proliferating the products obtainable from the same substrates.
It is especially interesting that the selectivity of the products is
tuned by slightly modifying the catalyst system.
Among
the
various
transition
metal-catalyzed
transformations, carbonylative reaction is an efficient method for
incorporating C1 synthons into organic compounds to give
9
-13
various carbonyl-containing compounds.
From the point view
of diversity, the transition metal-catalyzed arylcarbonylative
coupling of internal alkynes with aryl halides and organometallic
compounds should provide an efficient and direct method for the
synthesis of tetra-substituted enones and related compounds.
Surprisingly, although the synthesis of tetra-substituted olefins
via the transition metal catalyzed carbometalation of alkynes has
1
4-15
Scheme 1. Carbonylative Synthesis of tetra-Substituted Enones.
been widely studied,
scarcely reported and proven to be challenge. In 2007, Chatani
and co-workers reported Rh(I)-catalyzed carbonylation
reaction of alkynes with 2-bromophenylboronic acids to prepare
the carbonylative version has been
a
In order to establish this tunable system, 4-chloro-
iodobenzene 1a, 3-hexyne 2a and phenylboronic acid 3a were
selected as the model substrates. After extensive studies,
enones and benzofulvenes can be selectively produced in good
yields respectively (For details see Supporting Information).
Under the optimized reaction conditions, we investigated the
generality of the arylcarbonylative coupling reaction. Firstly, as
summarized in Table 1-i, a series of different (hetero)aryl iodides
were applied to the optimized conditions and the corresponding
conjugated ketones were obtained in moderate to good yields.
Aryl halides bearing electron-withdrawing groups (Table 1, 4a-
4f) gave better yields than electron-donating group substituted
ones (Table 1, 4g-4h). Functional groups such as carbonyl
1
6
multi-substituted indenones (Scheme 1, eq. a). However, to
the best of our knowledge, there is no literature for the synthesis
of all-carbon substituted 훼,훽-unsaturated ketones been reported
to date. One of the most important challenges of this type of
reaction is the existence of several competing side-reactions
[
a]
Dr. J.-B. Peng, F.-P. Wu, Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou 310018, People’s Republic of China
E-mail: Xiao-Feng.Wu@catalysis.de
Dr. A. Spannenberg, Prof. Dr. X.-F. Wu,
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-
Einstein-Straβe 29a, 18059 Rostock, Germany
(
Table 1, 4e) and cyano group (Table 1, 4f) were compatible in
this transformation.
Supporting information for this article is given via a link at the end of
the document.
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a
Table 1. Substrate Scope: Synthesis of tetra-Substituted Enones.
a
Reaction conditions: iodobenzene (0.50 mmol), alkyne (0.60 mmol), arylboronic acid (1.0 mmol), Pd(acac)
2
(3 mol %), P(o-tolyl)
2 2 2 3
O+HCO H, 2 mmol), Na CO (3 equiv.), DCM (2 mL), 90 ºC, 12 h, isolated yield. For the unsymmetrical alkynes, the regioisomeric ratio (r.r.) was
1
3 2
(6 mol %), Cu(TFA) (2 equiv.),
b
[
CO] (Ac
c
d
-
+
determined by H NMR analysis of the isolated products. (PhBO)
3
2 3 2
was used instead of PhB(OH) . PhBF K was used instead of PhB(OH)
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COMMUNICATION
In
addition
to
substituted
iodobenzenes,
1-
unsymmetrical alkynes with two similar substituents, two
unseparable regioisomers were formed in this reaction. However,
when unsymmetrical alkynes with one alkyl and one aryl
substituents were used in this reaction, the desired products
were obtained in moderate to good yields with acceptable
regioselectivity (Table 1-iv, 4x-4ai). Steric difference of the two
substituents on the carbon-carbon triple bond affected the
regioselectivity significantly. For example, when 1-phenyl-1-
propyne were used to the standard conditions, 4x was obtained
in 59% yield with 7:1 regioselectivity. Similar regioselectivities
were obtained when 1-(p-substituted-phenyl)-1-propynes were
used as the substrates (Table 1-iv, 4z, 4af and 4ag). However,
when 1-(o-substituted-phenyl)-1-propynes were used in this
reaction, excellent regioselectivities (>15:1) were obtained
(Table 1-iv, 4y, 4aa-4ag). The stereochemistry and configuration
of the products were assigned based on X-ray crystal structure
analysis of 4ad (CCDC: 1869004) as a representative example
iodonaphthalene and heteroaryl iodides such as 3-
iodothiophene were also tolerated and the corresponding
products were conveniently generated in 75% and 46% yields,
respectively. With respect to arylboronic acids, several
phenylboronic acids with different substitution at different
positions have been examined (Table 1-ii). Generally, electron-
donating group substituted phenylboronic acids delivered the
desired tetra-substituted 훼,훽-unsaturated ketones in moderate to
high yields (Table 1, 4k-4n). Poor yield was found when
electron-deficient arylboronic acid was used (Table 1, 4o).
Sterically bulky phenylboronic acid resulted in a decreased yield
Table 1, 4m). In addition to phenylboronic acid, other
phenylboron compounds were also tested in this
arylcarbonylative coupling reaction. Triphenylboroxin (PhBO)
was found to be a suitable coupling partner and provided the
product 4a in 86% yield. Potassium phenyltrifluoroborate gave a
decreased yield of 32%. However, phenylboronic esters such as
pinacol and neopentylglycol ester were ineffective and only trace
amount of 4a was detected.
Subsequently, we turned our attention to test the generality
of the alkynes. Symmetrical dialkylethynes such as 4-octyne and
-decyne were well tolerated and produced the corresponding
enones in 93% and 79% yields, respectively (Table 1, 4p and
q). However, moderate yields (39%-56%) were obtained when
symmetrical diarylethynes were used (Table 1, 4r-4w). The
decrease in yields might result from the lower electron density
and higher steric hindrance of the diarylethynes. For
(
3
1
7
(Table 1-iv).
The aryl segments from aryl halides were
attached at the carbon atom having the alkyl substituents, while
the aryl segments from the arylboronic acids were carbonylated
at the carbon atom having the aryl groups. Then several alcohol,
ether, ester and amino substituted unsymmetrical alkynes were
prepared and tested as well (Table 1-iv, 4aj-4am). To our delight,
moderate to good yields can be isolated under our standard
conditions. Additionally, four examples of vinyl iodides were
transformed successfully and gave the desired products in
moderate yields (Table 1-v, 4an-4aq).
5
4
a
Table 2. Substrate Scope: Synthesis of multi-Substituted Benzofulvenes.
a
Reaction conditions: iodobenzene (0.50 mmol), alkyne (0.60 mmol), arylboronic acid (1.5 mmol), Pd(acac)
•Et O (20 mol %), [CO] (Ac O+HCO H, 2 mmol), Na CO (3 equiv), DCM (2 mL), 85 ºC, 12 h, isolated yield. Z/E ratio was determined by GC using dodecane
as internal standard.
2 3 2
(3 mol %), P(o-tolyl) (6 mol %), Cu(OTf) (2 equiv.),
BF
3
2
2
2
2
3
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COMMUNICATION
During the investigation of the effect of the additives, small
amount of indene derivative 5a was obtained when more acidic
However, no interchange between enone and benzofulvene
could be observed under our experiments (Scheme 2, a-c).
Cu(OTf)
2
was used as the additive. It is generally known that
Additionally, under conditions B and in the absence of
indene derivative, including methyleneindene (benzofulvene), is
one of the most important carbocycles in organic chemistry. This
framework present frequently in many natural products and
phenylboronic acid, only trace amount of indenone could be
detected (Scheme 2, d). No benzofulvene could be formed from
indenone and phenylboronic acid neither (Scheme 2, e). It’s
important to mention that by-products including benzophenone
which from carbonylative coupling between iodobenzene and
phenylboronic acid, and alkyne hydration could be detected
during the optimization process.
1
8-21
biologically active compounds.
Indenes have also been
as well as ligands for metal
Several strategies have been developed for the
2
2-26
widely used in materials
complexes.
2
7-29
3
0
synthesis of 1H-indenes and benzofulvenes. Owing to the
importance of this structure, we optimized the reaction
conditions for the formation of 5a (see details in SI). Using
In summary, we have developed the first palladium
catalyzed intermolecular arylcarbonylative coupling of internal
Cu(OTf)
decreased yield was obtained in the absence of BF
details in SI), multi-substituted benzofulvene 5a was obtained in
8% yield with Pd(OAc) /P(o-tolyl) catalyst system at 85 ℃
Table 2, 5a). As summarized in Table 2-i, 4-octyne and 5-
2
as the additive and BF
3
·Et
2
O as a co-catalyst (Slightly
alkynes with aryl halides and arylboronic acids. Using Cu(TFA)
2
3
·Et O, see
2
as the additive, a series of tetra-substituted 훼,훽-unsaturated
ketones were prepared in moderate to high yields. The
6
2
3
arylcarbonylation reaction proceeds in
a high regio- and
(
stereoselective manner and the syn adduct of aryl and acyl
group to the carbon-carbon triple bond has been obtained. In
decyne afforded the corresponding indene products 5b and 5c
in 63% and 55% yields, respectively. A range of electron-
donating group substituted iodobenzenes were applied to the
optimized condition and the corresponding products were
successfully produced in moderate yields (Table 2-ii, 5d-5i). It
should be noted that for the reaction of iodonaphthalene, the
cyclization prefers to take place at the α-position (Table 2-ii, 5j
and 5k). For example, a 6-6-5 tricyclic compound 5j was
obtained in 57% yield when 2-iodonaphthalene was used in this
reaction. While the reaction of 1-iodonaphthalene provided
phenalene derivative 5k where the cyclization occurred at the 1’-
position. On the other hand, a range of substituted arylboronic
acids were also tested in this transformation. The corresponding
products were obtained in moderate yields (Table 2-iii, 5l-5q).
addition, we found that when more acidic Lewis acid Cu(OTf)
2
been used as the additive, multi-substituted benzofluvenes can
be produced selectively. This efficient methodology involved the
formation of three new C−C bonds, and provided a divergent
method for the quick construction of multi-substituted 훼,-
unsaturated ketones and benzofulvenes from easily available
31
starting materials.
Acknowledgements
The authors thank the financial supports from NSFC (21772177,
21801225).
Keywords: palladium catalyst • carbonylation • cascade reaction
•
selectivity control • cyclization
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COMMUNICATION
Jin-Bao Peng, Fu-Peng Wu, Anke
Spannenberg, and Xiao-Feng Wu*
Page No. – Page No.
Palladium-Catalyzed Tunable
Carbonylative Synthesis of Enones
and Benzofulvenes
Text for Table of Contents
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