Hydrogen-bond-activated palladium-catalyzed allylic alkylation via allylic alkyl ethers: Challenging leaving groups

Article abstract of DOI:10.1021/ol5000988

C-O bond cleavage of allylic alkyl ether was realized in a Pd-catalyzed hydrogen-bond-activated allylic alkylation using only alcohol solvents. This procedure does not require any additives and proceeds with high regioselectivity. The applicability of this transformation to a variety of functionalized allylic ether substrates was also investigated. Furthermore, this methodology can be easily extended to the asymmetric synthesis of enantiopure products (99% ee).

Full text of DOI:10.1021/ol5000988

Letter
pubs.acs.org/OrgLett
Hydrogen-Bond-Activated Palladium-Catalyzed Allylic Alkylation via
Allylic Alkyl Ethers: Challenging Leaving Groups
Xiaohong Huo,† Mao Quan,‡ Guoqiang Yang,‡ Xiaohu Zhao,† Delong Liu,*,† Yangang Liu,†
and Wanbin Zhang*,†,‡
‡
†School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: C−O bond cleavage of allylic alkyl ether was
realized in a Pd-catalyzed hydrogen-bond-activated allylic
alkylation using only alcohol solvents. This procedure does
not require any additives and proceeds with high regioselectiv-
ity. The applicability of this transformation to a variety of
functionalized allylic ether substrates was also investigated.
Furthermore, this methodology can be easily extended to the
asymmetric synthesis of enantiopure products (99% ee).
alladium-catalyzed allylic alkylation is a reliable and widely
Pused method for the formation of multiple types of bonds
and has been extensively used in total synthesis.1,2 Tremendous
progress has been made toward the development of
increasingly elaborate nucleophiles and catalysts to facilitate
the aforementioned reaction.3 However, despite significant
advances, Pd-catalyzed allylic substitution reactions are still
limited predominantly to substrates possessing good leaving
groups (i.e., allylic acetates and carbonates);2,3 unactivated
leaving groups such as ethers and amines remain difficult to
utilize. More recently, allylic amines have been successfully
employed in the Tsuji−Trost reaction by utilizing strong acids,4
minicyclic tension,5 and hydrogen bond activation.6 Unfortu-
nately, a facile method for the direct use of the accessible allylic
alkyl ethers remains a challenge.
range of reaction conditions than allylic amines, we herein
report a general and convenient method for the direct use of
allylic alkyl ethers in Pd-catalyzed allylic alkylations via
hydrogen bond activation (Scheme 1).
Scheme 1. Challenging Leaving Groups
O-Based compounds are ubiquitous in nature and synthetic
systems;7 thus, metal-catalyzed cleavage of the C−O bond of
ethers remains a topic of interest.8−11 Importantly, the high
stability of the C−O bond of allylic ethers means the substrates
are compatible with most reaction conditions (e.g., LiAlH4, n-
BuLi, Grignard reagents, oxidants, etc.). However, allylic ethers
are not commonly used in Pd-catalyzed allylic alkylation
reactions because their high stabilities often require the use of
stoichiometric quantities of strong Lewis acids10 or special
substrates,11 such as vinyl epoxides and allylic aryl ethers. These
substrates suffer from limited substrate scope, thus limiting
their potential use in organic synthesis. We therefore believed it
would be beneficial if simple allylic alkyl ethers such as −OMe,
−OEt, or −OCy could be directly used in Pd-catalyzed allylic
alkylation reactions under mild conditions.
We first carried out the reaction using allyl propyl ether as
the substrate, an enamine generated in situ as the nucleophile,
and a [Pd(η3-allyl)Cl]2/dppf catalytic system (Table 1). The
effects of solvent on the reaction were first explored. The
results suggested that protic solvents (MeOH, EtOH, and n-
PrOH) could promote the reaction (entries 1−3). However,
when aprotic solvents (toluene, DMSO, and DMF) were used,
the reaction was unsuccessful. Lowering the acidity of the protic
solvents led to decreased reactivity and prolonged reaction
times. Use of low reaction temperatures or different amounts of
cyclohexanone and pyrrolidine were also investigated (entries
4−6). Taking multiple factors into consideration, the optimal
reaction conditions were determined to be as follows: 1 equiv
of pyrrolidine, [Pd(η3-allyl)Cl]2/dppf as a catalyst in MeOH at
20 °C.
In order to clarify the role of methanol in hydrogen bond
participation, Pd2(dba)3 was used to prevent the generation of
Our group recently introduced a strategy employing allylic
amines (LG = −NR1R2) as allylic reagents in Pd-catalyzed
allylic alkylation reactions in the presence of pyrrolidine with
alcohol solvents.6,12 Considering that allylic alkyl ethers are
comparatively more accessible and compatible with a wider
Received: January 11, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope of Allylic Alkyl Ethers
b
c
entry
temp (°C)
solvent
pKa
t (h)
yield (%)
1
2
3
4
20
20
20
0
MeOH
EtOH
15.5
15.9
16.1
15.5
15.5
15.5
15.5
15.5
3
12
18
18
4
95
95
95
35
95
89
92
93
n-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
d
5
20
20
20
20
e
6
48
12
12
f
7
g
8
a
Reactions of 1a (0.50 mmol) with 2a (1.50 mmol) were performed in
1.0 equiv of pyrrolidine using 6.0 mol % of dppf and 2.5 mol % of
[Pd(η3-C3H5)Cl]2 in solvent (2 mL) at 20 °C; See ref 15. Isolated
b
c
d
e
f
yields. 20 mol % of pyrrolidine. 1.5 equiv of 2a. Pd2(dba)3 instead of
g
[Pd(η3-C3H5)Cl]2 under reflux. 3.0 equiv of enamine was used. dppf
= 1,1′-bis(diphenylphosphino)ferrocene.
HCl from the catalyst precursor. No change in reaction yield
was observed (entry 7), thus indicating this reaction is not
affected by catalytic amounts of HCl. In addition, N-
allylpyrrolidine was detected by GC−MS during the reaction.
As the reaction proceeds, N-allylpyrrolidine is completely
converted into the desired product.6 It has been reported that
the allylammonium cation can promote the deallylation of
allylic ethers.13 In order to avoid the formation of the
allylammonium cation, an enamine was used in this reaction,
smoothly providing the desired product (entry 8). These results
suggested that our reaction conditions are not significantly
affected by the presence of the allylammonium cation.
Furthermore, a computational study suggested that MeOH
plays a crucial role in the formation of the Pd−allyl complex by
lowering the activation energy and stabilizing the resulting
hydroxide and alkyloxide ion.14
Several substituted allylic ethers were subjected to the
optimized conditions described above (Table 2). The reactions
of linear allylic alkyl ethers with cyclohexanone proceeded
smoothly, with comparable reaction activity and high yields
(entries 1−3). In contrast, the use of branched substrates,
phenyl ether, and benzyl ether resulted in decreased reaction
activity. Nevertheless, the desired products were still obtained
by using longer reaction times and/or by using an equivalent
amount of pyrrolidine (entries 4−7). 2-Methylallylic ether was
also amenable to the reaction conditions, giving the desired
product in high yield (entry 8). Notably, regioisomeric methyl-
or phenyl-substituted allylic ethers gave identical products
(entries 9−12). Additionally, high yields were also obtained by
using 1,3-disubstituted allylic substrates with an equivalent of
pyrrolidine (entries 13−15).
a
Reactions of 1 (0.50 mmol) with 2a (1.50 mmol) were performed; all
b
c
data are the average of two experiments. Isolated yields. 1.0 equiv of
pyrrolidine. Products with 1:1 dr, determined by H NMR.
d
1
a free hydroxyl group was also subjected to our reaction
conditions, and the desired products were obtained in high
yield (entry 7). Excellent yields were also obtained when using
an aromatic ketone such as indone (entry 8). To expand the
scope of our catalytic system, phenyl acetaldehyde was also
used in the allylic alkylation reaction. The corresponding
alcohols of the desired products were obtained in moderate
yields (entry 9). These results suggested both ketones and
aldehyde are suitable for this reaction.
When considering atom economy and the number of
synthetic steps, it is important to exploit the inherent reactivity
of functional groups.16 Alkyl ethers may be the ideal functional
groups for this purpose. The use of these groups may improve
the overall efficiency of a synthetic route by reducing the need
for protecting groups or exploiting new synthetic pathways. At
first, we explored functional group compatibility of the allylic
ether, (E)-1-bromo-4-(3-ethoxyprop-1-enyl)benzene, by sub-
jecting it to different reactions such as a Suzuki coupling,17
Bouveault aldehyde synthesis,18 and oxidation and reduction
reactions (Scheme 2, A). The allylic ether displayed excellent
functional group tolerance. All the functionalized allylic ethers
A broad range of carbonyl compounds were then investigated
for the formation of C−C bonds in this reaction using allylic
propyl ether (Table 3). The reactions with cyclopentanone and
cyclohexanone proceeded smoothly with high activities and
yields (entries 1−2). However, a prolonged reaction time and a
higher temperature were required for the reaction using
cycloheptanone (entry 3). The substituents at the 4-position
of cyclohexanone did not appear to affect the reaction, and the
ketones possessing acid-labile groups could also be used in our
catalytic system (entries 4−6). In addition, a ketone possessing
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Letter
a
a
Table 3. Different Ketones and Aldehyde
Scheme 3. Asymmetric Transformation
a
Reagents and conditions: for the asymmetric allylic alkylation, see the
Supporting Information.
20% yield, even under reflux conditions. The product 3nj was
successfully applied to the synthesis of chiral γ-oxocarboxylic
acid, which is an important intermediate for the synthesis of
various peptides, therapeutic agents, and bioactive natural
products.20 Although the product 3′oa was obtained with a low
degree of diastereoselectivity,21 the chiral phenylacetic acid
derivatives 6 (97% ee) can be readily obtained by oxidation,
esterification, and reduction. The enantiopure motif 6 could
then be used for the synthesis of the selective antimuscarinic
agent 7.22
To conclude, we have developed a hydrogen-bond-activated
Pd-catalyzed allylic alkylation reaction of allylic alkyl ethers with
carbonyl compounds. The procedure does not require any
additives and proceeds with high regioselectivity. A series of
allylic alkyl ethers could be utilized using this methodology,
providing excellent results. This methodology can be extended
to the synthesis of enantiopure intermediates which can be used
for the synthesis of chiral γ-oxo-carboxylic acid and phenyl-
acetic acid derivatives.
a
Reactions of 1a (0.50 mmol) with 2 (1.50 mmol) were performed
with 20 mol % of pyrrolidine; all data are the average of two
experiments. Isolated yields. 1.0 equiv of pyrrolidine. 10.0 equiv of
aldehyde was used in EtOH. Yield of the corresponding alcohol from
the desired product reduced with NaBH4 for easy isolation.
b
c
d
e
Scheme 2. Compatibility of Allylic Ethers
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compounds characterization, HPLC
spectra, and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dlliu@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
Notes
could be used in Pd-catalyzed allylic alkylation reactions,
providing excellent yields (Scheme 2, B).
The authors declare no competing financial interest.
To further explore the applicability of this methodology, we
applied our catalytic system to an enantioselective reaction
using a chiral ferrocene-based phosphinooxazoline ligand
(Scheme 3).19 Allylic ethers 1n and 1o were studied in the
Pd-catalyzed asymmetric allylic alkylation using acetone (2j)
and 2a as nucleophiles. The desired products were obtained in
high yields and excellent enantioselectivities. The use of (E)-
((pent-3-en-2-yloxy)methyl)benzene as a substrate was also
explored, with the desired product being obtained in less than
ACKNOWLEDGMENTS
■
This work was partially supported by the National Natural
Science Foundation of China (No. 21172143, 21172145,
21372152, and 21232004), Nippon Chemical Industrial Co.,
Ltd., Shanghai Jiao Tong University (SJTU), and the
Instrumental Analysis Center of SJTU. We thank Prof. Tsuneo
Imamoto and Dr. Masashi Sugiya of Nippon Chemical
Industrial Co., Ltd., for helpful discussions. We also thank
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Letter
(14) For more details, see the Supporting Information.
(15) McMurry, J. E. Organic Chemistry, 6th ed.; Brooks/Cole:
Belmont, CA, 2003.
Prof. Ilya D. Gridnev of Tohoku University for his help with the
computational study.
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