Synergistic Pd/enamine catalysis: A strategy for the C-H/C-H oxidative coupling of allylarenes with unactivated ketones

Article abstract of DOI:10.1021/ol501584d

By combining catalytic nucleophilic enamine activation with Pd-catalyzed C-H activation of allylarenes, the first oxidative allylic alkylation of unactivated ketones was achieved. Mechanistically, the Pd-catalyzed allylic C-H activation and proline-cataly

Full text of DOI:10.1021/ol501584d

Letter
pubs.acs.org/OrgLett
Synergistic Pd/Enamine Catalysis: A Strategy for the C−H/C−H
Oxidative Coupling of Allylarenes with Unactivated Ketones
Shan Tang,† Xudong Wu,† Wenqing Liao,† Kun Liu,† Chao Liu,† Sanzhong Luo,*,‡ and Aiwen Lei*,†
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
‡Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognization and Function Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: By combining catalytic nucleophilic enamine
activation with Pd-catalyzed C−H activation of allylarenes, the
first oxidative allylic alkylation of unactivated ketones was
achieved. Mechanistically, the Pd-catalyzed allylic C−H
activation and proline-catalyzed ketone nucleophilic activation
worked synergistically for the oxidative cross-coupling between
allylarenes and unactivated ketones.
difficult for unactivated ketones to achieve α-allylation due to
he Pd-catalyzed allylic alkylation (Tsuji−Trost allylic
Talkylation) is an important and efficient strategy for their low α-C-H acidity, harsh reactions in typical enolate-
allylation processes are required.5 In this regard, new strategies
need to be developed for the oxidative cross-coupling between
allylic hydrocarbons and unactivated ketones.
C(sp3)−C(sp3) bond formation.1 Along with its development,
continuous efforts have been devoted to improve the efficiency
and expand the scope in this transformation.2 Most of the
efforts are focused on prefunctionalized allylic substrates in
which a reactive leaving group is installed for facile ionization to
form the π-allyl palladium intermediate. Echoing the pursuit of
atom-economic and sustainable chemistry, C−H activation and
functionalization have become the forefront of organic
synthesis.3 In this regard, oxidative Tsuji−Trost allylic
alkylation, which directly utilizes allylic hydrocarbons for
C(sp3)−C(sp3) coupling, has been developed over the recent
years.4 However, the carbon nucleophiles employed in these
studies are confined to those stabilized carbon anions wherein
two strong electron-withdrawing groups are adjacent to the
center atom (Scheme 1a). Unactivated nucleophilic hydro-
carbons, such as simple ketones, have not been realized in
oxidative Tsuji−Trost allylic alkylation until now. Mechanisti-
cally, the key step for the successful Tsuji−Trost allylic
alkylation is the nucleophilic attack by carbon nucleophile to
the in situ generated π-allyl Pd intermediate.4b,e Since it is
Over the past few years, organocatalysis has grown
spectacularly successfully to become one of the most exciting
research areas in modern organic synthetic chemistry.6
Compared with the well-established transition metal catalysis,
organocatalysis can promote organic transformations through
distinct activation modes.7 Therefore, the combination of
transition metal catalysts with organocatalysis represents a
powerful catalytic approach for developing new reactions.8
Among the developed dual catalysis systems, synergistic
combination of enamine activation catalysis with transition
metal catalysis has emerged and been proved to be a significant
strategy for the direct functionalization of unactivated ketones/
9
́
aldehydes. In 2006, Cοrdova and co-workers demonstrated the
first example of combining enamine activation catalysis with Pd
catalysis.10 This synergistic catalysis strategy promoted the
intermolecular α-allylic alkylation of unactivated ketones and
aldehydes with allylic acetates.11 Since then, efforts have been
taken to expand this synergistic strategy to other activated
allylic substrates such as allylic halides, allylic alcohols, allylic
amines, and allylic ethers.12 Nevertheless, synergistic catalysis
for alkenes without leaving groups has not yet been established
until now.
Scheme 1. Oxidative Tsuji−Trost Allylic Alkylation
Considering that transition metal (especially palladium)-
catalyzed allylic C−H activation has been established,13 we
assume that the combination of the nucleophilic activation by
enamine activation catalysis and allylic C−H activation by Pd
Received: June 2, 2014
© XXXX American Chemical Society
A
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Letter
catalysis might provide a chance to deal with the oxidative
Tsuji−Trost allylic alkylation for unactivated ketones (Scheme
1b). Based on the widely accepted mechanism of enamine
activation catalysis and palladium catalysis,7i,10 the oxidative
cross-coupling between allylic hydrocarbons and unactivated
ketones can be assumed to proceed through combined Pd/
enamine catalytic cycles shown in Scheme 2. Pd(II) has the
Table 1. Optimization of the Catalysts and Oxidant
Combination
a
b
entry
[Pd] cat.
Pd(PPh3)4
amine cat.
oxidant
BQ
yield (%)
1
2
3
A1
A2
A3
A4
A5
A6
A6
A6
A6
A7
A8
A6
A6
A6
A6
A6
trace
trace
trace
12
Pd(PPh3)4
BQ
Scheme 2. Mechanistical Assumption for the Oxidative
Cross-Coupling between Allylic Hydrocarbons and
Unactivated Ketones
Pd(PPh3)4
BQ
c
4
Pd(PPh3)4
BQ
5
6
7
8
9
Pd(PPh3)4
BQ
10
Pd(PPh3)4
BQ
30
[(η3-allyl)PdCl]2
PdCl2(PPh3)2
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
BQ
trace
trace
72
BQ
BQ
c
10
BQ
trace
trace
24
c
11
BQ
12
13
14
15
16
17
18
DMBQ
DDQ
Cl4-BQ
O2 (1 atm)
BQ
nd
nd
nd
nd
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
BQ
nd
ability to activate the allylic C−H bond, which will afford an
electrophilic π-allylpalladium intermediate.1a,b,4e Meanwhile,
the amine catalyst could react with the unactivated ketone to
generate an enamine intermediate. Then, the formation of
enamine increases nucleophilicity of the ketone substrate,
which might allow it to undergo nucleophilic attack to the in
situ generated π-allylpalladium.10,11b,12a This would lead to the
formation of an iminium intermediate that could afford the final
C(sp3)−C(sp3) bond formation product through a hydrolysis
process. Importantly, an oxidant is required for the oxidation of
Pd(0) to regenerated Pd(II), which will lead to the completion
of the Pd catalytic cycle.13b During all of these processes, the
compatibility of the oxidative condition will be the major
challenge for applying synergistic strategy to the cross-coupling
between allylic hydrocarbons and unactivated ketones.9,14 It is
worthy of noticing that rare methods have been successful in
the area of combining transition metal catalysis with organo-
catalysis.15 Therefore, discovering suitable combination of
catalysts and oxidants will be the key for achieving the
oxidative Tsuji−Trost allylic alkylation with unactivated
ketones.
We initiated our study on the direct oxidative coupling of
cyclohexanone (1a) with allylbenzene (2a) by applying
Pd(PPh3)4 as the catalyst and p-benzoquinone as the oxidant.
First, we tried primary amine catalysts, which showed good
nucleophilic activation capacity in our previous study.16
However, only trace amount of the desired product could be
observed (Table 1, entries 1−3). Further investigation showed
that secondary amine and primary amino acids exhibited better
reactivity (Table 1, entries 4 and 5). To our delight, the simple
secondary amino acid L-proline exhibited good reactivity and
furnished the desired product in 30% yield (Table 1, entry 6).
However, Pd(II) catalyst precursors such as [(η3-allyl)PdCl]2
and PdCl2(PPh3)2 showed poor reactivities in this trans-
formation, which indicated the importance of choosing a
suitable Pd complex (Table 1, entries 7 and 8).17 We were
pleased to find that the combination of Pd(OAc)2 with PPh3
showed an excellent reactivity, which afforded the desired
product in 72% yield (Table 1, entry 9). It is worthy of noting
that only the linear product was observed. Regretfully, racemic
A6
BQ
nd
a
Reaction conditions: 1a (0.50 mmol), 2a (1.0 mmol), [Pd] catalyst
(10 mol %), amine catalyst (20 mol %), and p-benzoquinone (1.5
b
equiv) in toluene (1.0 mL), 100 °C, 10 h. Yields shown were
determined by GC analysis with byphenyl as the internal standard, nd
c
= not detected. PhCOOH (20 mol %) was added.
product was obtained though optically pure L-proline was used
in this system.18 When simple pyrrolidine (A7) and methyl
pyrrolidine-2-carboxylate (A8) were applied as the amine
catalyst in the reaction system, the yield of the desired product
dropped dramatically (Table 1, entries 10 and 11).12a This
strict demand on the structure of the amine catalyst is due to
the fact that primary amine catalysts and simple pyrrolidine
could react with the oxidant BQ directly.19 As for the selection
of oxidant, a decreased yield of the coupling product was
obtained in the case of 2,6-dimethylbenzoquinone (DMBQ),
which demonstrated excellent reactivity for the oxidative Tsuji−
Trost allylic alkylation with activated ketones (Table 1, entry
12).4e,f Other oxidants such as 2,3-dicyano-5,6-dichlorobenzo-
quinone (DDQ), tetrachlorobenzoquinone (Cl4-BQ), and
oxygen failed to give the coupling product (Table 1, entries
13−15). Control experiments showed that Pd catalyst, amine
catalyst, and oxidant were all crucial for the successful oxidative
coupling (Table 1, entries 16−18). These results supported the
synergistic feature of this reaction system. Thus, the standard
condition was obtained as Pd(OAc)2 (10 mol %), PPh3 (20
mol %), L-proline (20 mol %), and p-benzoquinone (BQ, 1.5
equiv) in toluene (1.0 mL) at 100 °C with stirring for 10 h.20
Subsequently, we applied the optimized reaction conditions
to examine the functional group tolerance of allylarenes. To our
delight, para substituents on the phenyl ring afforded the
coupling products in good yields (Table 2, entries 1−4).
B
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Letter
acyclic ketones. The reaction with cyclopentanone and
cycloheptanone did proceed to afford the desired product,
but with reduced efficiency in our synergistic catalysis system
(Table 2, entries 10 and 11).12a,21 Furthermore, acyclic ketones
showed poor reactivity in this system when compared with the
cyclic ketones. A promising result was obtained when an excess
amount of acetone was used, affording the desired product in
21% yield (Table 2, entriy 12).
Table 2. Substrate Scope for the Synergistic Oxidative
Tsuji−Trost Allylic Alkylation
a
To demonstrate the synthetic utility of this synergistic
oxidative coupling reaction, a steroid 5α-cholestan-3-one (4),
which contains a six-membered cyclic ketone moiety, was
tested under the standard condition with allylbenzene.
Delightfully, direct α-alkylation product could be obtained in
a satisfactory 50% yield with a good regioselectivity (Scheme
3). Overall, this report, to the best of our knowledge, is the first
example for achieving C−H/C−H oxidative coupling of
unactivated ketones with allylarenes.
Scheme 3. Oxidative Tsuji−Trost Allylic Alkylation with 5α-
cholestan-3-one
In conclusion, a Pd/proline co-catalyzed oxidative cross-
coupling of unactivated ketones with allylic hydrocarbons was
achieved for the first time. The introduction of nucleophilic
activation through enamine activation catalysis enabled the
oxidative allylic alkylation with unactivated cyclic ketones. In
this transformation, palladium catalyst, amine catalyst, and p-
benzoquinone were all crucial for the direct oxidative coupling.
Importantly, this reaction provides an example for employing
synergistic catalysis in developing new oxidative coupling
reactions22 that are difficult to achieve through traditional
monocatalysis methods. Detailed mechanistic investigations
and improvement of this system into an asymmetric version are
underway in our laboratory and will be reported in due course.
a
Reaction condition: 1 (0.50 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.050
mmol), PPh3 (0.10 mmol), L-proline (0.10 mmol), and p-
benzoquinone (0.75 mmol) in toluene (1.0 mL), 100 °C, 10 h.
b
c
Yields shown are of isolated yields. Acetone (0.5 mL) in toluene (0.5
mL).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and copies of
1H, 13C, and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
Allybenzene with a strong electron-withdrawing CF3 sub-
stituent was less reactive than that with a strong electron-
donating OMe substituent in this transformation (Table 2,
entries 3 and 4). In addition, allylthiophene was also tested and
afforded the desired product in a good yield (Table 2, entry 5).
Afterward, we decided to apply the synergistic Pd/Enamine
catalysis strategy on a set of unactivated ketones. The oxidative
allylic alkylation reaction with allylbenzene proceeded well for
six-membered cyclic ketones to furnish the corresponding
allylation products (Table 2, entries 1, 6−9). Simple cyclo-
hexanone and 4-methyl cyclohexanone afforded the allylation
products in good yields (Table 2, entries 1 and 6). Delightfully,
1,4-cyclohexanedione monoethylene acetal gave the desired
product in an excellent yield of 86% (Table 2, entry 7). As for
3-methyl cyclohexanone, a mixture of two regioisomers was
obtained since there were two reactive sites (Table 2, entry 8).
Moreover, 4-oxacyclohexanone was also suitable in this
transformation, which afforded the desired product in 71%
yield (Table 2, entry 9). Finally, efforts were taken to expand
this synergistic oxidative coupling reaction to other cyclic and
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: luosz@iccas.ac.cn.
*E-mail: aiwenlei@whu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program (2011CB808600,
2012CB725302), the National Natural Science Foundation of
China (21390400, 21025206, 21272180, and 21302148), the
Research Fund for the Doctoral Program of Higher Education
of China (20120141130002), and the Program for Changjiang
Scholars and Innovative Research Team in University
C
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Letter
Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014,
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