Selective Aerobic Oxygenation of Tertiary Allylic Alcohols with Molecular Oxygen

Article abstract of DOI:10.1002/anie.201903690

Aerobic epoxidation of tertiary allylic alcohols remains a significant challenge. Reported here is an efficient and highly chemoselective copper-catalyzed epoxidation and semipinacol rearrangement reaction of tertiary allylic alcohols with molecular oxygen. The solvent 1,4-dioxane activates dioxygen, thereby precluding the addition of a sacrificial reductant.

Full text of DOI:10.1002/anie.201903690

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Accepted Article
Title: Highly Selective Aerobic Oxygenation of Tertiary Allylic Alcohols
with Molecular Oxygen
Authors: Ning Jiao, Bencong Zhu, Tao Shen, Xiaoqiang Huang, Song
Song, and Yuchao Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903690
Angew. Chem. 10.1002/ange.201903690
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10.1002/anie.201903690
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Highly Selective Aerobic Oxygenation of Tertiary Allylic Alcohols
with Molecular Oxygen
Bencong Zhu, Tao Shen, Xiaoqiang Huang, Yuchao Zhu, Song Song, Ning Jiao*
Abstract: Aerobic epoxidation of tertiary allylic alcohols remains a
significant challenge. Herein, we report an efficient and highly
chemoselective copper-catalyzed epoxidation and semipinacol
rearrangement reaction of tertiary allylic alcohols with molecular
oxygen. The solvent 1,4-dioxane activates dioxygen, thereby
avoiding the addition of sacrificial reductant.
Epoxidation of allylic alcohols plays an important role in organic
synthesis,[1] since it provides a straightforward approach to
epoxy alcohols that are widely used as building blocks for the
synthesis of natural products and pharmaceuticals.[2]
Scheme 1. Epoxidation of tertiary allylic alcohols with O2.
Significantly, the groups of Sharpless,[3] Katsuki,[4] Yamamoto,[5]
among others,[6] independently have developed asymmetric
With our continued interests in copper catalytic system, we
variants of this transformation through the use of transition metal
catalysts. These reactions rely on Ti, Nb, V, Mo, or Hf species in
conjunction with a stoichiometric oxidant including peracids,
organic and inorganic peroxides, and H2O2. Nevertheless, the
stoichiometric use and disposal of such peroxides raise
problems from safe and environmental viewpoints. In addition,
the application of H2O2 sometimes results in poor
chemoselectivity owing to the ring expansion of epoxy alcohols
to triols.
began our investigation of this transformation by attempting the
oxidation of 1-(1-phenylvinyl) cyclobutanol 1a (Table 1) Initially,
when CuBr2 and pyridine severed as the catalyst and ligand
respectively, epoxide 2a was obtained in 38% yield (entry 1).
The screening of various copper catalysts showed that Cu(OAc)2
delivered 2a with superior efficiency (entry 2, also see SI).
Replacing pyridine with other nitrogen-based ligands including 1,
10-phenanthroline, bipyridine and TMEDA didn’t improve the
outcome of epoxides (see SI). Interestingly, the reaction without
ligand yielded 2a in 78% NMR yield and 72% isolated yield,
which was the optimized conditions for epoxidation (entry 3).
Other solvents including THF, toluene, DCE, and MeCN failed to
generate any product (see SI).
Molecular oxygen represents a clean, cheap and abundant
8]
oxidant,[7,
and could be a more desirable choice for
epoxidations.[9] However, efficient oxygenation reactions with O2
are considered difficult.[10] To achieve the epoxidation of allylic
alcohols with O2, sacrificial reducing reagents,[11] such as
aldehydes, are required to activate O2 and generate peroxides in
situ. Another yet-unsolved problem is the epoxidation of tertiary
allylic alcohols with molecular oxygen. This is likely due to a lack
of coordinating ability resulting from the steric bulk of the
Table 1. Reaction Conditions Investigation[a]
substrate (Scheme 1a).[5d]
. Therefore, developing efficient
epoxidations of tertiary allylic alcohols with O2 is highly desirable.
Herein, we report a novel Cu-catalyzed aerobic oxygenation of
sterically demanding allylic tertiary alcohols. (Scheme 1b). The
following significance exists in this report: (1) Inexpensive
copper catalysts and environmentally friendly molecular oxygen
are employed; (2) To the best of our knowledge, this presents a
novel epoxidation of tertiary allylic alcohols with O2; (3) 1,4-
Dioxane was disclosed as both solvent and a new oxygen atom
transmitter, thereby avoiding the employment of sacrificial
aldehydes in the reported aerobic epoxidations; (4) The
selectivity is very high without the triols byproducts formation.
Entry
[Cu]
CuBr2
Ligand
pyridine
pyridine
--
T oC
90
90
90
90
90
80
80
80
2a[b]
38%
3a[b]
trace
trace
trace
11%
53%
58%
63%
74%
1
2
Cu(OAc)2
Cu(OAc)2
Cu(CH3CN)4PF4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
65%
78%(72%[f])
3
4
pyridine
TMEDA
TMEDA
TMEDA
TMEDA
54%
5
trace
6[c]
7[c, d]
8[c, d, e]
trace
trace
trace
[a] Reaction conditions: 1a (0.2 mmol), Cu catalyst (10 mol %), ligand (20
mol %), 1,4-dioxane (2 mL) stirred under O2 for 12 h. [b] 1H NMR yields
using Cl2CHCHCl2 as internal standard. [c] Reaction time was 18 h. [d]
Mg(OTf)2 (10 mol %) was added. [e] H2O (0.5 equiv) was added. [f] Isolated
yields. TMEDA = tetramethylethylenediamine.
[*]
B. Zhu, T. Shen, X. Huang, Y. Zhu, Dr. S. Song, and Prof. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
Prof. N. Jiao
It is noteworthy that a same trace amount of byproduct was
detected in the above conditions screening reactions. Further
careful characterization experiments demonstrated 3a was a
product. This attracted our
kind of α-hydroxymethyl
cyclopentanones are useful synthons. We then turned to
optimize the conditions for semipinacol rearrangement. When
Cu(CH3CN)PF6 was employed as the catalyst, 3a was obtained
State Key Laboratory of Organometallic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
Fax: (+) 86-10-82805297
E-mail: jiaoning@pku.edu.cn
Homepage: http://sklnbd.bjmu.edu.cn/nj
[12]
semipinacol rearrangement
attention, because this
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201903690
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in 11% yield with the formation of 2a in 54% yield (entry 4). The
employment of strongly Lewis acidic Cu(OTf)2 performed well in
the presence of nitrogen-base ligands, among which TMEDA
was the most effective (entry 5, slso see SI). The addition of
catalytic amount of Lewis acid Mg(OTf)2 and 0.5 equivalent of
H2O, intended to accelerate the rearrangement process, further
improved the reaction outcome, delivering 3a in 74% yield
(entries 7 and 8). Therefore, excellent chemoselectivity could be
achieved by simply altering the copper salt employed.
that the epoxidation is stereospecific. The structures of epoxides
were determined by the 3J (H,H) coupling constants (see SI).
Scheme 3. Reaction conditions: see entry 3, Table 1. Isolated yields. [a]
Cu(OAc)2 (20 mol %) was used as the catalyst. [b] Cu(acac)2 (10 mol %) was
used as the catalyst.
Furthermore,
the
substrate
scope
of
semipinacol
rearrangement reaction was explored (Scheme 4). The methyl
group at the ortho, meta or para position of the phenyl ring was
compatible, albeit with relatively lower yields (3b, 3c, 3ac). Other
cyclobutanol derivatives with substituents on aromatic ring went
smoothly, affording products in good yields (3d-3f, 3ab).
Scheme 2. Reaction conditions: see entry 3, Table 1. Isolated yields. [a] The
reaction was conducted in gram-scale (8.0 mmol). [b] CuO (10 mol %) was
used as the catalyst. [c] The allylic alcohol was used as a mixture of isomers
with a E/Z ratio of 4:1.
The substrate scope of aerobic epoxidation was evaluated
under the optimized conditions (Scheme 2). A series of aryl-
substituted allylic alcohols (2b-f) were sufficiently reactive under
the chosen conditions, leading to the products in moderate to
good yields. Secondary and tertiary alcohols bearing different
substituents in R1 and R2 positions reacted to generate epoxide
products with high efficiencies, but diastereoselectivity was low
(2g-2i, 2k-2p) Substrates with five, six or seven-membered rings
worked smoothly, providing epoxides in moderate yields (2q-2s).
In addition, a methyl group at the R3 position was demonstrated
to be tolerated (2t). Notably, epoxidation of the substrate with
high steric hindrance at α position of the hydroxyl group was
found to be highly diastereoselectivity (2u).
Scheme 4. Reaction conditions: see entry 8, Table 1. Isolated yields.
Epoxy alcohols are highly useful intermediates and building
blocks in synthesis. This aerobic epoxidation transformation
could be performed in gram-scale (2a, Scheme 2), revealing the
great potential for further applications. Nucleophilic additions of
2t by water or sodium azide in water, opened the ring to afford
triols 4 or azido-substituted diols 5, which map well onto many
natural products and pharmaceuticals, including antibiotics
(Scheme 5).[13]
In addition, 3-aryl propenols were then investigated (Scheme
3). Substituents at the R1 and R2 position were well tolerated
(2v-2z). In the case of tertiary allylic alcohols with
polysubstituted carbon-carbon double bond, epoxy alcohols
were obtained in moderate to good yields (52-90% yields, 2aa-
2cc). The E-olefins afforded the trans-epoxides (2v-2bb), while
the Z-olefins afforded the cis-epoxides (see Eq. S13), indicating
Scheme 5. Synthetic application. (i) H2O, 60 oC; (ii) 2 equiv NaN3, H2O, 60 oC.
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To explore the mechanism, several control experiments were
conducted. The 18O label experiments indicated that the oxygen
atom in the epoxides is derived from molecular oxygen instead
of water (Eqs. 1 and 2). In addition, this epoxidation was
completely inhibited by the addition of radical scavenger such as
TEMPO or BHT, suggesting that a radical process might be
involved (see SI). Moreover, when TEMPO was added after 3
hours, an adduct 6 derived from TEMPO, O2 and 1,4-dioxane
was detected by HRMS (Eq. 3). Inspiringly, an adduct 8 was
obtained though separation when a sulfonyl oxime ether reagent
Based on these results, a plausible mechanism is proposed
(Scheme 6). Initially, oxidation of 1, 4-dioxane by copper(II) via
single-electron transfer (SET) process occurs to generate
radical-cation which furnishes radical intermediate A through
further deprotonation process.[15] A is then trapped by O2 and
Cu(I) resulting in copper(II) peroxide intermediate B stabilized by
anomeric effect .[8c, 16] Subsequent O-O bond homolysis followed
by directed radical addition to substrate 1a forms intermediate C
with the formation of oxygen-centered radical species D. Then,
radical epoxidation gives product 2a with the regeneration of
copper(I) species. In the presence of Lewis acid, product 2a
would undergo rearrangement delivering product 3a.[12] In line
with literature report and our mechanistic studies, intermediate B
could undergo further fragmentation and reaction with anisic
acid to afford compound 9[14]. In the final step, the Cu(I) could be
reoxidized to Cu(II) by O2. We cannot rule out the pathway that
7 was added as the radical trap (Eq. 4).
Furthermore,
compound 9 was observed in 71% yield in the presence of 4-
methoxybenzoic acid through a reported β-scission ring-opening
process[14] (Eq. 5). These results indicate that 1,4-dioxane was
involved in the molecular oxygen activation and underwent
further fragmentation process as reported.[14] When substrate 10
without the hydroxyl group was subjected to the standard
conditions, desired epoxide 11 was only obtained in 10% yield
together with the formation of 9% of ketone 12 (Eq. 6). Notably,
the o-methylated derivatives could also produce epoxide in 48%
yields (Eq. 7, also see Eq. S11, SI). These data highlight that the
oxygen atom plays a significant role in promoting reactivity and
preventing undesirable overoxidation.
species
D abstract the hydrogen from the solvent and
regenerated radical A for the chain reaction. In addition,
intermediate D undergoes β-scission ring-opening process[17a]
driven by stabilizing the three-electron “half-bond” transition
state,[17b] to produce intermediate E which could be trapped by
TEMPO or sulfonyl oxime ether reagent 7 leading to the
detection of adduct 6 or 8 respectively.
Scheme 6. Proposed Mechanism
In conclusion, we report
a
novel copper-catalyzed
oxygenation of tertiary allyl alcohols with molecular oxygen
which previously posed a significant challenge. A wide range of
epoxides and α-hydroxymethyl cyclopentanones are synthesized
in good to excellent yield (up to 90%) with catalyst-dependent
chemoselectivities. Mechanistic studies demonstrate that 1,4-
dioxane serves as the solvent and the oxygen atom transmitter,
thereby avoiding the requirement of additional sacrificial agents
in the present aerobic epoxidation chemistry. Further exploration
of aerobic oxygenation reaction through the activation of O2 by
1,4-dioxane are ongoing in our laboratory.
To verify the possibility of epoxide 2a as the intermediate for
the formation of the rearrangement product 3a, a kinetic diagram
was conducted under standard conditions for the generation of
3a. As displayed in Figure S2 (see SI), epoxide 2a was firstly
detected and was consumed after an initial increase, while 3a
appeared and gradually increased after a certain reaction time.
This clearly demonstrates that epoxides are the key
intermediates for the seminal rearrangement.[12]
Acknowledgements
Financial support from the National Basic Research Program of
China (973 Program) (No. 2015CB856600), the National Natural
Science Foundation of China (21632001, 81821004, 21871011),
the Drug Innovation Major Project (2018ZX09711-001), and the
Open Research Fund of Shanghai Key Laboratory of Green
Chemistry and Chemical Processes are greatly appreciated. We
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Keywords: Molecular oxygen • Oxygenation• Allylic alcohols •
Rearrangement • Chemoselectivity
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Layout 2:
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Bencong Zhu, Tao Shen, Xiaoqiang
Huang, Yuchao Zhu, Song Song and
Ning Jiao*
Page No. – Page No.
Highly Selective Aerobic Oxygenation
of Tertiary Allylic Alcohols with
Molecular Oxygen
Text for Table of Contents
Text for Table of Contents
This work realized a novel and highly chemoselective copper-catalyzed epoxidations and semipinacol rearrangement reactions of
tertiary allylic alcohols with molecular oxygen, which are previously difficult to be achieved. 1,4-dioxane was proved as the solvent
and an oxygen atom transmitter, thereby avoiding the requirement of additional sacrificial agents.
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