Palladium-catalyzed allylic alkylation of simple ketones with allylic alcohols and its mechanistic study

Article abstract of DOI:10.1002/anie.201403410

Allylic alcohols were directly used in Pd-catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20°C by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier. Concerted action: Allylic alcohols were directly used in the title reaction under mild conditions. The reaction smoothly proceeds by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier.

Full text of DOI:10.1002/anie.201403410

Angewandte
Chemie
DOI: 10.1002/anie.201403410
Homogeneous Catalysis
Palladium-Catalyzed Allylic Alkylation of Simple Ketones with Allylic
Alcohols and Its Mechanistic Study**
Xiaohong Huo, Guoqiang Yang, Delong Liu, Yangang Liu, Ilya D. Gridnev,* and
Wanbin Zhang*
Abstract: Allylic alcohols were directly used in Pd-catalyzed
allylic alkylations of simple ketones under mild reaction
conditions. The reaction proceeded smoothly at 208C by the
concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and
a hydrogen-bonding solvent, and does not require any addi-
tional reagents. A computational study suggested that methanol
plays a crucial role in the formation of the p-allylpalladium
complex by lowering the activation barrier.
Therefore, a simple and convenient method for the direct
use of allylic alcohols is highly desired.
We have demonstrated that allylic amines and allylic alkyl
ethers possessing challenging leaving groups have been
successfully utilized to form p-allylpalladium complexes
through hydrogen-bond activation (Scheme 1).[9] Just before
T
he palladium-catalyzed allylic alkylation is a powerful
À
synthetic tool for C C bond formation and has a broad range
of applications in the synthesis of biologically important
molecules.[1,2] One of the general features of this transforma-
tion is that substrates with a wide range of activated leaving
groups (acetates, carbonates, etc.) can be utilized to form p-
allylpalladium complexes.[3] However, the direct use of the
accessible allylic alcohols in Pd-catalyzed allylic alkylations
remains a challenge. It is worth noting that the use of allylic
alcohols as substrates would help to avoid the additional steps
required for the preparation of the corresponding activated
substrates and the formation of at least stoichiometric
amounts of waste both in the preparation and substitution
steps. Therefore, allylic alcohols are gaining increasing
attention as ideal substrates for palladium-catalyzed allylic
alkylation reactions[4–7] with regard to waste minimization and
sustainability.[8] While there have been some reports of Pd-
catalyzed allylic alkylations using allylic alcohols, most of
these methods required activators[4,6] or special ligands.[7]
Scheme 1. Reactions of allylic substrates with challenging leaving
groups. Bn=benzyl, Cy=cyclohexyl, dppf=1,1’-bis(diphenylphospha-
nyl)ferrocene, Nu=nucleophile.
the submission of this manuscript, Ohshima and co-workers
reported an interesting platinum- and pyrrolidine-catalyzed
direct allylic alkylation of b-keto carbonyl compounds
with allylic alcohols using acetic acid as an additive under
high temperature and microwave conditions.[5h,10] We herein
report a simple method for the direct use of allylic alcohols in
Pd-catalyzed allylic alkylations of simple ketones in the
presence of a pyrrolidine co-catalyst in alcohol solvents under
mild conditions, and a mechanistic study of this reaction
(Scheme 1).
[*] X. Huo, Prof. D. Liu, Prof. Y. Liu, Prof. W. Zhang
School of Pharmacy, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
Homepage: http://wanbin.sjtu.edu.cn
Dr. G. Yang, Prof. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University (China)
Initially, we investigated the Pd-catalyzed allylic alkyla-
tion of cyclohexanone with cinnamyl alcohol in several
solvents, using a [Pd(h3-C3H5)Cl]2/dppf catalyst system and
1.0 equivalent of pyrrolidine at 208C.[11] We found that the
reaction proceeded well in alcohol solvents and that methanol
showed the most promising results. The reaction temperature
and the amounts of cyclohexanone and pyrrolidine were also
screened and the optimal reaction conditions were: cinnamyl
alcohol/ketone = 1.1:1, 20 mol% pyrrolidine, and 2.5 mol%
[Pd(h3-allyl)Cl]2/dppf as a catalyst in methanol at 208C. The
effect of an acid as a co-catalyst was also explored, as it can
catalyze both the formation of the enamine and the ionization
of the leaving group.[5h,6b–d] The results suggested that our
Prof. I. D. Gridnev
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki 3-6, Aoba-ku, Sendai 9808578 (Japan)
E-mail: igridnev@m.tohoku.ac.jp
[**] Computational results in this research were obtained using super-
computing resources at the Information Synergy Center, Tokyo
Institute of Technology. This work was partially supported by the
National Natural Science Foundation of China (No. 21172143,
21172145, 21372152, and 21232004), the Nippon Chemical Indus-
trial Co., Ltd, Shanghai Jiao Tong University, and the CAMPUS Asia
Program of Tohoku University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403410.
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Table 2: Scope of different ketones and aldehydes.[a]
catalytic system was more effective in the absence of such an
acid co-catalyst.[11]
A number of allylic alcohols were examined (Table 1).
The reaction of allyl alcohol and crotyl alcohol with cyclo-
hexanone proceeded smoothly in high yields (Table 1,
entries 1 and 2). The allylic alkylation using cyclic or
disubstituted allylic alcohol gave the desired products in
moderate to high yields, when the reaction was carried out
using 40 mol% pyrrolidine at 408C. No 1,3-diene product was
formed (Table 1, entries 3–5).[12] Additionally, various cin-
Entry
Ketones/Aldehydes
t [h]
10
Yield [%][b]
1
2
92
97
12
3[c]
24/12[d]
52/97[d]
Table 1: Substrate scope of allylic alcohols.[a]
4
5
6
7
12
12
12
12
98
95
98
97
Entry
R1
R2
R3
t [h]
Yield [%][b]
1
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
8
93
2[c]
3[c]
4[c]
5[c]
6
12
24
24
24
12
12
12
12
12
18
94 (E/Z=11/1)
8[c]
24
92
À
À
(CH2)3
57
54
82
97
98
99
99
98
98
Me
Ph
Ph
3-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
Ph
H
Me
H
H
H
H
H
Ph
9[c]
24
24
66
70
10[c]
7
8
9
10
11
11[c]
18
92
[a] 0.50 mmol of ketones or aldehydes, 0.55 mmol of cinnamyl alcohol;
[b] yields of isolated products; [c] 40 mol% pyrrolidine, 408C;
[d] 0.50 mmol of cinnamyl alcohol, 1.50 mmol of cycloheptanone, 408C,
the yield is based on cinnamyl alcohol. MOM=methoxymethyl,
THP=tetrahydropyranyl.
[a] 0.50 mmol of cyclohexanone, 0.55 mmol of allylic alcohols; [b] yields
of isolated products; [c] 40 mol% pyrrolidine, 408C.
namyl alcohols with an electron-donating group or an
electron-withdrawing group on the phenyl ring (Table 1,
entries 6–10) and
a
1,3-diphenyl-substituted substrate
(Table 1, entry 11) all gave the desired products in excellent
yields.
Our methodology can be easily extended to bisallyl ethers
(Scheme 2). These substrates gave the desired products and
the corresponding allylic alcohols.[9b] The in situ generated
allylic alcohol was subsequently utilized in the reaction to give
another equivalent of the desired product.
To extend the applicability of this methodology, we
applied our catalytic system to an asymmetric synthesis
using a chiral ferrocene-based phosphinooxazoline ligand
(Scheme 3).[13] Allylic alcohol 1 was utilized in the Pd-
catalyzed asymmetric allylic alkylation of acetone, affording
the desired product in high yield and excellent enantioselec-
The scope of a series of ketones was investigated next
(Table 2). The reaction of cyclic ketones with cinnamyl
alcohol occurred rapidly with high yields. For example, the
reactions with cyclopentanone and cyclohexanone proceeded
smoothly with high activities and yields (Table 2, entries 1 and
2). However, a higher temperature and an excess ketone were
required for the reaction when cycloheptanone was used as
a substrate (Table 2, entry 3). 4-Substituted cyclohexanones
also furnished the allylated products in excellent yields
(Table 2, entries 4–7). Ketones that possess acid-labile
groups were compatible with our catalytic system (Table 2,
entries 5 and 6). In addition, a free hydroxy group in the
ketone substrate did not affect the reaction (Table 2, entry 7).
The product was obtained in an excellent yield when aromatic
ketones such as indanone were used (Table 2, entry 8). To our
delight, phenyl acetaldehyde could be subjected to the
reaction conditions, affording the desired products in 66%
yield and several unidentified by-products (Table 2, entry 9).
Butyraldehyde could also be used in the allylic alkylation
reaction, providing the desired product in 70% yield (Table 2,
entry 10). When an a-branched aldehyde, 2-phenylpropion-
aldehyde, was utilized in the reaction, the desired product was
obtained in excellent yield (Table 2, entry 11).
Scheme 2. Reactions of in situ generated allylic alcohols.
2
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alcohol was similar to that with allyl ether.[9b] When allyl
alcohol was used, N-allylpyrrolidine was also detected by
GC–MS during the reaction. As the reaction proceeds, N-
allylpyrrolidine is completely converted into the desired
product. However, allyl acetate, the most common substrate
in allylic alkylations, provided only 20% of the desired
product (Figure 2) and 80% N-allylpyrrolidine after 3 h, in
contrast to the reactions involving allyl ether and allyl alcohol.
The calculated energies of the ionization step demonstrate
that the easy ionization characteristic for the allyl acetate is
not beneficial for the formation of the desired product
(Figure 3). Apparently, the facile ionization promotes the
allylation of pyrrolidine rather than the ketone and slows
down the allylation of the ketone. We hypothesize that the
in situ generated acetic acid protonates the pyrrolidine, thus
subsequently inhibiting the formation of the enamine. Indeed,
when the reaction of allyl acetate was conducted with
2.0 equivalents of pyrrolidine, the desired product was
obtained with 100% conversion in 3 h.
Scheme 3. Asymmetric transformation.
tivity. The product 2 could be easily transformed into chiral 4-
oxo-2-phenylpentanoic acid 3,[9b] which is an important
intermediate for the synthesis of various therapeutic agents,
peptides, and bioactive natural products.[14]
From the results above, it is obvious that allylic alcohols
can be directly used in Pd-catalyzed allylic alkylation of
carbonyl compounds under mild conditions employing our
methodology. The synthetic importance of this process
prompted us to investigate the reaction mechanism.[15] We
carried out DFT calculations[16] for the C O bond cleavage of
allyl alcohol with the help of methanol (Figure 1). The results
À
Further calculations for the catalytic cycle were con-
ducted. As shown in Figure 1,
the first step is the ionization
of the OH group on the allylic
moiety to give a transient p-
allylpalladium complex 5 via
TS4-5 (Figure 4a). The in situ
generated enamine then
attacks the p-allylpalladium
complex 5, forming the
imine-palladium complex
6
via TS5-6 (Figure 4b). Our cal-
culations also showed that the
regeneration of the Pd cata-
lyst from catalyst–product
complex 6 does not require
the dissociation of the product
to give a 14-valence-electron
Pd complex, as has been
suggested previously.[15c] We
have thus discovered a mild
process
(DG = 16.3 kcal
molÀ1; at 298 K) for the sub-
Figure 1. Free energy profile of the Pd-catalyzed allylic alkylation of cyclohexanone with allyl alcohol. The
ligand was 1,2-bis(diphenylphosphino)ethane (dppe). TS=transition state.
À
suggest that the cleavage of the stable C O bond can be easily
achieved in methanol through hydrogen-bond activation. For
the same process in the absence of methanol, a much higher
activation barrier was obtained. The calculated results suggest
that methanol plays a crucial role in the formation of the p-
allylpalladium complex by lowering the activation energy and
stabilizing the resulting hydroxide.
To compare the reactivities of allyl substrates with
different leaving groups (OH, OEt, and OAc), the kinetics
1
of these reactions were measured by H NMR spectroscopy
and GC–MS. As shown in Figure 2, the rate of the reactions
Figure 2. Effect of leaving groups (OH, OEt, and OAc) on the reaction
yields. Reaction conditions: 0.50 mmol of substrates, 1.50 mmol of
cyclohexanone, 1.0 equiv of pyrrolidine, 6.0 mol% dppf, 2.5 mol%
[Pd(h3-allyl)Cl]2 in CD3OD (2 mL).
changed in the order OEt > OH @ OAc. These results indi-
cate that the nature of the leaving group has an important
effect on the rate of the reaction. The reaction utilizing allyl
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Figure 4. Optimized geometries of transition states TS4-5, TS5-6, TS6-4
bond lengths are given in ꢀ.
;
In summary, we have developed a palladium-catalyzed
allylic alkylation of simple ketones with allylic alcohols,
proceeding by the concerted action of a Pd catalyst, a pyrro-
lidine co-catalyst, and a hydrogen-bonding solvent. The
procedure does not require any additional reagents. In
a preliminary study, the Pd-catalyzed asymmetric allylic
alkylation of acetone was carried out with high yield and
excellent enantioselectivity. A computational study suggested
that methanol plays a crucial role in the formation of the p-
allylpalladium complex, by lowering the activation energy
and stabilizing the resulting hydroxide. Finally, a catalytic
cycle for the reaction under investigation has been proposed
using DFT calculations.
Received: March 17, 2014
Published online: && &&, &&&&
Keywords: allylic alcohol · allylic alkylation · DFT calculation ·
organocatalysis · palladium
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Communications
Homogeneous Catalysis
X. Huo, G. Yang, D. Liu, Y. Liu,
I. D. Gridnev,*
W. Zhang*
&&&& — &&&&
Concerted action: Allylic alcohols were
directly used in the title reaction under
mild conditions. The reaction smoothly
proceeds by the concerted action of a Pd
catalyst, a pyrrolidine co-catalyst, and
a hydrogen-bonding solvent, and does
not require any additional reagents. A
computational study suggested that
methanol plays a crucial role in the
formation of the p-allylpalladium com-
plex by lowering the activation barrier.
Palladium-Catalyzed Allylic Alkylation of
Simple Ketones with Allylic Alcohols and
Its Mechanistic Study
6
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