Palladium-catalyzed oxidative rearrangement of tertiary allylic alcohols to enones with oxygen in aqueous solvent

Article abstract of DOI:10.1021/ol502578h

A one-pot procedure for Pd(TFA)₂-catalyzed 1,3-isomerization of tertiary allylic alcohols to secondary allylic alcohols followed by a Pd(TFA)₂/neocuproine-catalyzed oxidative reaction to β-disubstituted-α,β-unsaturated kenones was developed. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502578h

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Oxidative Rearrangement of Tertiary Allylic
Alcohols to Enones with Oxygen in Aqueous Solvent
Jingjie Li,† Ceheng Tan,† Jianxian Gong,*,† and Zhen Yang*,†,‡,§
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for
Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
§Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5
Yushan Road, Qingdao 266003, China
S
* Supporting Information
ABSTRACT: A one-pot procedure for Pd(TFA)2-catalyzed 1,3-isomerization of
tertiary allylic alcohols to secondary allylic alcohols followed by a Pd(TFA)2/
neocuproine-catalyzed oxidative reaction to β-disubstituted-α,β-unsaturated
kenones was developed.
he broad utility of β-disubstituted α,β-unsaturated ketones
tertiary allylic alcohols to afford enones using aqueous
TD (Figure 1) in organic synthesis has continued to attract hydrogen peroxide as an oxidant.8
1
Pd-catalyzed allylation with allylic alcohols as substrates has
considerable synthetic efforts to develop more efficient
methods for these ketones’ syntheses.2 The alkylative carbonyl
transposition of β-disubstituted α,β-unsaturated carbonyl
compounds (Figure 1), which entails a 1,2-addition of A by
organometallic reagents to form B, followed by isomerization of
tertiary allylic alcohol B to C, and oxidation of C to the
corresponding β-disubstituted α,β-unsaturated ketones D,
represents a practical strategy that extends the synthetic
latitude of this transformation.
been widely utilized for the construction of C−C and C−N
bonds in organic synthesis,9 and the catalytic conversion of
allylic alcohols has been examined in most cases through in situ
activation of a hydroxy group with the aid of Lewis acids (e.g.,
Ti(OPri)4, BEt3, BPh3, and SnCl2)10 or by conversion into the
esters of inorganic acids (e.g., As2O3, B2O3, and CO2).11 It is
noteworthy that these reactions are usually carried out in
organic solvents. A challenging question, from both an
economical and an environmental point of view, is if such a
sequential transformation could be achieved based on allylic
alcohol in aqueous solution under aerobic conditions. We
hypothesized that Pd-catalyzed 1,3-isomerization of allylic
alcohols12−17 in the absence of Lewis acid or activating agents
in aqueous solution followed by Pd-catalyzed aerobic oxidation
of the resultant allylic alcohols would allow us to achieve a
direct Pd-catalyzed oxidative rearrangement of allylic alcohols18
to their corresponding β-disubstituted α,β-unsaturated ketones
in a one-pot reaction fashion19 (Figure 1, B to D). Herein, we
report our discovery of a Pd-catalyzed oxidative rearrangement
of tertiary allylic alcohols under aerobic conditions, yielding the
corresponding enals or enones in good to excellent yields.
Our initial effort toward the proposed chemistry was to
search for optimized reaction conditions to achieve 1,3-
isomerization of allylic alcohols. We tested several Pd catalysts
in different solvents (Table 1). Among the catalysts we
screened, Pd(TFA)2 (1 mol %) was proved to be the best
catalyst when the reaction was carried in a mixed solvent of
Figure 1. Alkylative carbonyl transposition of β-disubstituted α,β-
unsaturated ketones.
The oxidative rearrangement of tertiary allylic alcohols to β-
disubstituted α,β-unsaturated carbonyl compounds has been
explored intensively, and some representative examples include
(1) oxochromium(VI)-based reagents (Collins reagent, PCC or
PDC);3 (2) 2-iodoxybenzoic acid (IBX)-based oxidative
rearrangement of tertiary allylic alcohols;4 (3) TEMPO-derived
oxoammonium salts as oxidative reagents;5 (4) 2-iodoxybenze-
nesulfonic acid (IBS)-catalyzed oxidative rearrangement of
tertiary allylic alcohols to enones with oxone;6 and (5) copper-
catalyzed aerobic oxidative rearrangement of tertiary allylic
alcohols.7 Recently, Pt-black has also been reported to be an
effective agent to catalyze the oxidative rearrangement of
Received: September 1, 2014
Published: October 3, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol502578h | Org. Lett. 2014, 16, 5370−5373

Organic Letters
Letter
a
Table 1. Evaluation of Catalytic Conditions
Table 2. Scope and Limitations of Catalytic 1,3-
Isomerization
a
b
loading
yield /conv
entry
catalyst
(mol %)
solvent
toluene
(%)
1
2
3
4
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
Pd(MeCN)4(BF4)2
1
1
1
1
<5
CH2Cl2
CH3CN
<5
<5
CH3CN/H2O
(5:1)
46 (94)
5
6
7
8
9
Pd(OAc)2
Pd2(dba)3
PdCl2
1
CH3CN/H2O
(5:1)
no reaction
no reaction
<5
1
CH3CN/H2O
(5:1)
1
CH3CN/H2O
(5:1)
Pd(TFA)2
Pd(TFA)2
1
CH3CN/H2O
(5:1)
85 (92)
82 (88)
0.2
CH3CN/H2O
(5:1)
a
Reactions were conducted with 1a (0.5 mmol) in solvent (2.5 mL).
Isolated yields.
b
CH3CN/H2O (entry 8). When the catalyst loading was
reduced to 0.2 mol %, no significant decrease of the reaction
yield was observed (entry 9). Interestingly, when Pd-
(MeCN)4(BF4)2 was used as in organic solvents including
toluene, dichloromethane, or acetonitrile, only a trace amount
of isomerized product 2a was observed (entries 1−3).
However, when the reaction was carried out in a mixed solvent
of CH3CN and water, 46% yield was obtained (entry 4).
The scope and limitation of this catalytic system are
demonstrated in Table 2. Five-, six-, and seven-membered-
ring based cyclic substrates readily responded to give the
expected β-disubstituted α,β-unsaturated ketones in good to
excellent yields (Table 2, entries 1−15). In particualr, five-
membered substrates were relatively reactive and could carry
out the rearrangement reaction at 0 °C. It is also worthwhile to
mention that when the substrate had a substituent at the 3-
position, the product yield decreased presumably because of the
substrate’s steric effect (entry 11). Several acyclic tertiary allylic
alcohols (entries 16−18) were also examined. Although the
expected rearrangement could proceed, both temperature and
catalyst loading are necessary to increase to achieve relative
good yields. The reaction of furan-substituted substrate 1t
occurred in excellent yield (entry 19). However, the nitrogen-
containing heterocycle substrate 1u gave no desired product,
probably due to the deactivation of palladium catalyst caused by
the strongly coordinating effect of nitrogen atom (entry 20).
To achieve the proposed reaction for a one-pot synthesis of
β-disubstituted α,β-unsaturated ketones from their correspond-
ing allylic alcohols, we then began to investigate Pd-catalyzed
aerobic oxidative reaction of the resultant allylic alcohols under
the isomerization conditions.
a
Reaction conditions: substrate (1.0 mmol), Pd(TFA)2 (0.2 mol %) in
b
c
CH3CN (5 mL), and H2O (1 mL). Isolated yields. Reactions were
carried out for 1 h. Pd(TFA)2 (0.4 mol %) was used. Reactions were
carried out for 0.5 h. The starting material 1u was recoverd.
d
e
f
acyclic allylic alcohol 1q, conditions B were employed to realize
the rearrangement step, and enone 3q was isolated in 69% yield
with 24% of starting material recovered (entry 14) (see the
Supporting Information).
To ascertain the effect of Pd(TFA)2 on the 1,3-isomerization
of allylic alcohols, we conducted control experiments with
substrate 1a (Scheme 1). No isomerization was observed when
substrate 1a was stirred under the same conditions listed in
Table 2 in the absence of Pd(TFA)2, indicating Pd(TFA)2 was
essential to the 1,3-isomerization of allylic alcohols. Methyl
We found out that this type of one-pot reaction could be
realized by addition of Pd(TFA)2, neocuproine, and LiOH·
H2O to the existing solution of the Pd-catalyzed 1,3-
isomerization (Table 3). The reactions were performed at 80
°C for 20 h, and we can make the following observations: (1)
six- and seven-membered-ring based substrates gave the
corresponding β-disubstituted α,β-unsaturated ketones in
good to excellent yields (Table 3, entries 1−13). (2) For
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Organic Letters
Letter
a
Table 3. One-Pot Oxidative Reactions of Allylic Alcohols
Figure 2. Proposed catalytic cycle of 1,3-isomerization of allylic
alcohol catalyzed by Pd(TFA)2.
followed by nucleophilic addition to afford product and
regenerate catalyst. The regiochemistry of this reaction is
governed by the stability of product. This mechanism is similar
to that proposed by McCubbin and Hall.15c,16b,20
In summary, we have developed an efficient one-pot reaction
of Pd catalysis for the conversion of tertiary allylic alcohols into
their corresponding enals or enones. The reaction proceeds via
the Pd-catalyzed isomerization of tertiary allylic alcohols
followed by Pd-catalyzed aerobic oxidation. Overall, the study
has been carried out in a reasonably divergent fashion that
shows the scope and applicability.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedure, H and 13C NMR spectra,
1
and X-ray data information. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
a
Conditions A: substrate (1.0 mmol), Pd(TFA)2 (0.2 mol %) at 40 °C
for 4 h; then Pd(TFA)2 (1 mol %), neocuproine (1 mol %), LiOH·
H2O (6 mol %) at 80 °C for 20 h under an O2 balloon. Conditions B:
substrate (1 mmol), Pd(TFA)2 (0.2 mol %) at 80 °C for 4 h; then
Pd(TFA)2 (1 mol %), neocuproine (1 mol %), and LiOH·H2O (6 mol
*E-mail: gongjx@pku.edu.cn.
*E-mail: zyang@pku.edu.cn.
Notes
b
%) at 80 °C for 20 h under an O2 balloon. Isolated yields.
The authors declare no competing financial interest.
Scheme 1. Syntheses of Compounds 2a, 4, and 6
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Science Foundation of China (Nos. 21372016 and 21402002),
National 863 Program (2013AA090203), and NSFC-Shandong
Joint Fund for Marine Science Research Centers (U1406402).
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