Base-promoted [1,4]-Wittig rearrangement of chalcone-derived allylic ethers leading to aromatic β-benzyl ketones

Article abstract of DOI:10.1039/c5ra03846d

n-BuLi-promoted [1,4]-Wittig rearrangement of allylic ethers was developed successfully in this work, in which the Wittig rearrangement reaction provided a facile approach to the synthesis of aromatic β-benzyl ketones under mild reaction conditions.

Full text of DOI:10.1039/c5ra03846d

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Base-promoted [1,4]-Wittig rearrangement of
chalcone-derived allylic ethers leading to aromatic
Cite this: RSC Adv., 2015, 5, 33818
b-benzyl ketones†
Received 4th March 2015
Accepted 7th April 2015
ab
b
a
a
a
Pei-Sen Gao, Fei Ye, Xiao-Yun Dong, Yun Chen, Zi-Wei Gao,*
a
ab
Wei-Qiang Zhang and Li-Wen Xu*
DOI: 10.1039/c5ra03846d
www.rsc.org/advances
n-BuLi-promoted [1,4]-Wittig rearrangement of allylic ethers was chemoselectivity. Notably, different from [2,3]-and [1,2]-
developed successfully in this work, in which the Wittig rearrangement Wittig rearrangement, [1,4]-Wittig rearrangement is unique
reaction provided a facile approach to the synthesis of aromatic b- in its ability to generate stereodened enolates and the ketone
8
benzyl ketones under mild reaction conditions.
derivatives (Scheme 1). And it has been demonstrated that
the role of base and solvent was key to the reactivity and
different reaction pathways, [1,4]- or [2,3]-Wittig rear-
Since Wittig and L ¨o hmann reported the rst example of 1,2-
alkyl migration from an oxygen atom to a carbanion center in
the rearrangement reaction of benzylic ethers with phenyl-
8d
rangement. In this regard, Maleczka and coworkers have
recently reported their ndings on the [1,4]-Wittig rear-
rangement of a-benzyloxyallylsilanes or a-alkoxysilanes to a-
substituted acylsilanes, in which the [1,4]-Wittig rearrange-
ment provided a unique method for the synthesis of a variety
1
lithium in 1942, Wittig arrangement of ethers to alcohols has
been proven to be a synthetically useful reaction in organic
2
synthesis. Especially in the past years, [1,2]- and [2,3]-Wittig
9
of synthetically useful acylsilanes. Nonetheless, the substrate
rearrangements are a particularly attractive for the synthesis
of secondary alcohols with both variations having found
scope of the [1,4]-Wittig rearrangement of allylic ethers is not
well documented and thus its potential in synthetic organic
chemistry needs to be further elucidated.
To the best of our knowledge, no reports of base-mediated
1,4]-Wittig rearrangement of general allylic benzyl ethers, and
the Wittig rearrangement of chalcone-derived allylic ethers with
benzylic groups is unclear (Scheme 2). On the basis of our
previous ndings on [1,2]-Wittig rearrangement of THP (tetra-
3
,4
widespread use in synthesis. In this context, we have ever
reported a facile and practical methodology for the prepara-
tion of chiral alcohols via [1,2]-Wittig rearrangement, in
which the axially chiral monoalkylated BINOLs could be
[
0
converted into optically pure 1,1 -binaphthalene-2-a-arylme-
0
3
thanol-2 -ols (Ar-BINMOLs) with axial and sp -central chirality
through the axial-to-central chirality transfer during the
10
5,6
hydropyran) acetal compounds and monoalkylated BINOLs,
neighbouring lithium-assisted [1,2]-Wittig rearrangement
5
(
NLAWR). This work provided a springboard for the synthesis
and application of a series of Ar-BINMOL-based chiral ligands
6
in versatile catalytic asymmetric transformations. Although
the earlier investigation on [1,4]-Wittig rearrangement of
allylic ethers have also been demonstrated in the past
7
decades, relative to its [1,2]- and [2,3]-counterparts, the
research work of [1,4]-Wittig rearrangement remained limited
because of its narrow scope of this method and imperfect
a
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education
(
MOE), School of Chemistry and Chemical Engineering, Shaanxi Normal University,
Xi'an 710062, P. R. China. E-mail: licpxulw@yahoo.com; Fax: +86-571-28867756
b
Key Laboratory of Organosilicon Chemistry, Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou 310012, P. R. China. E-mail:
liwenxu@hznu.edu.cn; Fax: +86 2886 5135; Tel: +86 2886 5135
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c5ra03846d
Scheme 1 Possible pathways for the different variations of Wittig
rearrangement of allylic ethers with benzylic group.
1
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t-BuLi, gave low or moderate yields at the same reaction
temperature. The use of sodium and potassium bases led to
almost no [1,4]-Wittig rearrangement reaction. When LiHDMS
or t-BuLi was used as base in this reaction, only moderate yield
was obtained (33–42% yields). Thus n-BuLi proved to be supe-
rior to t-BuLi and other lithium bases, leading to high conver-
sion of the allylic ether 1a. Notably, the THF was found to be
2
better solvent than Et O in this reaction. And interestingly, we
did not nd the formation of 3a that could be obtained via [2,3]-
or [1,2]-Wittig rearrangement in the presence of n-BuLi. The
ketone 2a could be isolated as the only product in this rear-
rangement reaction. These results showed the strong base and
Scheme 2 What's the product of base-promoted Wittig rearrange-
ment of chalcone-derived allylic ether (1a)?
0
relative thermodynamic stabilities of C1 and C2 anions might
favor the [1,4]-Wittig rearrangement over [2,3]-Wittig rear-
2
c,9,15c
we continued to establish a simple Wittig rearrangement of rangement.
Although deprotonation at benzylic carbon
0
chalcone-derived allylic ethers to the facile synthesis of center (Ph-CH
2
(C1 )-O) is associated with [2,3]-Wittig rear-
aromatic b-benzyl ketones. Fortunately, we successfully nd the rangement as well, we suggested the deprotonation at the
0
[
1,4]-Wittig rearrangement was the major pathway for this benzylic carbon center (C1 ) led to the formation of a higher
transformation of carbon–oxygen bond cleavage and subse- reactive benzylic anion than that of allylic carbon (Ph-CH(C2)–
quent new carbon–carbon bond-forming reaction.
CH]CH) anion because of steric repulsion. Thus the method
Initially, the rearrangement precursor 1a was prepared by allows providing a straightforward alternative for preparing the
the allylic alkylation of allylic acetate with benzylic alcohols in rather elusive g-arylated ketones that are synthetically useful
11
the presence of palladium catalyst. Then the Wittig rear- intermediates in organic synthesis and have been found in as
12
rangement of allylic ether 1a was investigated under different basic backbone in natural products.
condition showed in Table 1. Employing, 1.2 equivalents of
With the optimized conditions in hand, the scope of the
n-BuLi in hexane as base, allylic ether 1a was rearrangement allylic ethers was investigated in the next study. As shown in
ꢁ
smoothly under low temperature (ꢀ40 C). Good yield (80%) of Scheme 3, various chalcone-derived allylic ethers (1) possessing
the b-benzyl ketone 2a was achieved via [1,4]-Wittig rearrange- a variety of substitution pattern involving a benzylic group were
ment. With this preliminary study complete, we tested different subjected to the reaction conditions. Reactions of 1b and 1c,
lithium, sodium, or potassium bases in the Wittig rearrange- which have para-substituted methyl or methoxyl group on
ment of allylic ether 1a. The control experiments revealed that benzylic ether moiety, proceeded to provide the corresponding
other strong bases, such as NaOtBu, LiHDMS, KOtBu, and products 2b and 2c, respectively, in good yield. The substrate 1d
with steric group on two ortho-substituted methyl groups also
gave good yield of product 2d. Interestingly, the tri-
Table 1 Optimizing the [1,4]-Wittig rearrangement of chalcone- uoromethoxyl group on the allylic ether did not affect the [1,4]-
derived allylic ether 1a
Wittig rearrangement obviously due to the promising conver-
sion (62% isolated yield) in this reaction. Not surprisingly,
substituted chalcones with electron-donor group as starting
material for the construction of corresponding allylic ether
substrates, were also exhibited to be good substrates in the [1,4]-
Wittig rearrangement. However, the allylic ethers with electron-
decient substituents, such as CF , NO , and halides (Cl, Br, I)
3
2
a
b
Entry
Base
Solvent
Yield of 2a (%)
were not suitable substrates because of poor conversions or
dehalogenation.
1
2
3
4
5
6
7
8
9
n-BuLi
NaOtBu
LiHDMS
KOtBu
n-BuLi
t-BuLi
NaOtBu
KOtBu
n-BuLi
n-BuLi
n-BuLi
n-BuLi
THF
80
<5
42
<5
65
33
<5
<5
57
24
68
77
DCM
DCM
DCM
Et O
2
THF
THF
THF
DCM
MeCN
DMAc
Toluene
In order to synthesize the chiral aromatic b-benzyl ketone,
additional investigation of such [1,4]-Wittig rearrangement
involved application to possible enantioselective trans-
formation of chiral allylic ether. In our previous report, we
demonstrated successfully its effectiveness of our novel chiral
phosphine ligand (CycloN2P2-Phos) in palladium-catalyzed
asymmetric allylic etherication (AAE) of general alcohols and
silanols (Scheme 4), which afforded the corresponding allylic
1
1
1
0
1
2
13
ethers with excellent enantioselectivities (93–99% ee). Thus we
applied the chiral allylic ether (R)-1a (96% ee) in the [1,4]-Wittig
rearrangement. Unfortunately, the [1,4]-Wittig rearrangement
of chiral allylic ether resulted in racemic product 2a. On the
other hand, the result illustrated in Scheme 5 provides
a
The Wittig rearrangement was carried out with 0.5 mmol of allylic
ꢁ
ether 1a, 0.6 mmol of n-BuLi in hexane, in THF, at ꢀ40 C, for 6 h.
b
Isolated yield of 2a, and the selectivity was perfect because product
3
a of [2,3]-Wittig rearrangement was not detected in this reaction.
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Scheme 6 Possible mechanism of base-promoted [1,4]-Wittig rear-
rangement of allylic ether 1.
Scheme
3 [1,4]-Wittig rearrangement of chalcone-derived allylic
ethers to aromatic b-benzyl ketones.
On the basis of these results and previous reports on base-
2,3,5,15
mediated benzylic rearrangement,
a plausible mecha-
nism for the conversion of allylic ether 1 to aromatic b-benzyl
ketone 2 is illustrated in Scheme 6. In the radical pathway (Path
A), the treatment of allylic benzyl ether 1 with strong base (such
as n-BuLi) leads to the formation of allylic or benzylic anion (I)
by deprotonation at the benzylic position, which is a common
intermediate for variations of Wittig rearrangement. And then
the dissociative process involving the formation of a pair of
radicals and subsequent recombination occur to form the
enolate (III). Upon workup, protonation of the enolate would
generate the intermediate IV and the total product 2a. The
alternative reaction pathway looks possibly for the intra-
molecular nucleophilic addition of benzylic anion to double
bond, and then performs a Claisen-like 1,4-sigamatropic rear-
rangement followed protonation of enolate intermediate to
form the observed product 2a (Path B). However, the [1,4]-Wittig
rearrangement of chiral allylic ether 1a revealed that the Path B
is not reasonable or major pathway because there is no ee value
for the desired product 2a. In addition, we found that the [1,4]-
Wittig rearrangement did not occur in the presence of 2,2,4,4-
tetramethyl-1-piperidinyloxy (TEMPO), in which the direct
evidence supported the radical pathway (Path A) in the
proposed mechanism.
Scheme 4 Synthesis of chiral allylic ethers through Pd/CycloN2P2-
Phos-catalyzed asymmetric allylic etherification of various alcohols
with allylic acetates.
considerable information about the likely radical mechanism of
14
the Wittig rearrangement. The conversion of chiral substrate
a to racemic product 2a suggests this mechanism of this
1
unusual rearrangement involves the formation of enolate
3
2
intermediate that make the stereogenic sp carbon-center to sp
carbon center.
Conclusions
In summary, we have discovered an unusual [1,4]-Wittig rear-
rangement reaction of chalcone-derived allylic ethers upon
deprotonation with n-BuLi. The reactions produce potentially
useful aromatic b-benzyl ketone in moderate to good yields with
unprecedented selectivity. It appears to proceed via radical
Scheme 5 [1,4]-Wittig rearrangement of chiral allylic ether 1a (96% ee). alkylation and enolate intermediate. Further studies will be
33820 | RSC Adv., 2015, 5, 33818–33822
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directed toward improving enantioselectivity of [1,4]-Wittig
rearrangement and expanding the scope of these
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Acknowledgements
This Project was supported by the National Natural Science
Founder of China (no. 21173064 and 21472031), Fundamental
Research Funds for the Central Universities (GK201501005),
Shaanxi hundred talents program, and Zhejiang Provincial
Natural Science Foundation of China (LR14B030001).
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