Aerobic α-hydroxylation of β-keto esters and amides by co-catalysis of SmI3 and I2 under mild base-free conditions

Article abstract of DOI:10.1016/j.tetlet.2016.05.052

A clean base-free α-hydroxylation of β-keto esters and amides has been developed, in which air was used as the oxygen source and SmI₃ and I₂ were applied as the catalysts, affording the corresponding α-hydroxylated 1,3-dicarbonyl pro

Full text of DOI:10.1016/j.tetlet.2016.05.052

Accepted Manuscript
Aerobic α-Hydroxylation of β-Keto Esters and Amides by Co-catalysis of
SmI and I under Mild Base-free Conditions
3
2
Shun-Ming Yu, Kai Cui, Fei Lv, Zhen-Yu Yang, Zhu-Jun Yao
PII:
S0040-4039(16)30575-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.052
TETL 47671
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 April 2016
9 May 2016
13 May 2016
Please cite this article as: Yu, S-M., Cui, K., Lv, F., Yang, Z-Y., Yao, Z-J., Aerobic α-Hydroxylation of β-Keto
Esters and Amides by Co-catalysis of SmI and I under Mild Base-free Conditions, Tetrahedron Letters (2016),
3
2
doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.052
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Aerobic α-Hydroxylation of β-Keto Esters
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and Amides by Co-catalysis of SmI
under Mild Base-free Conditions
3
and I
2
*
Shun-Ming Yu, Kai Cui, Fei Lv, Zhen-Yu Yang,

and Zhu-Jun Yao

1
Tetrahedron Letters
Aerobic α-Hydroxylation of β-Keto Esters and Amides by Co-catalysis of SmI and I
3
2
under Mild Base-free Conditions
a
a
b
a,
a,b,
Shun-Ming Yu, Kai Cui, Fei Lv, Zhen-Yu Yang * and Zhu-Jun Yao 
a
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
b
Road, Shanghai 200032; State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin
Road, Nanjing, Jiangsu 210023, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A clean base-free α-hydroxylation of β-keto esters and amides has been developed, in which air
was used as the oxygen source and SmI and I were applied as the catalysts, affording the
3
2
Received in revised form
Accepted
Available online
corresponding -hydroxylated 1,3-dicarbonyl products in good to excellent yields under mild
conditions. Mechanism discussion shows that both two oxygen atoms of dioxygen are utilized
and incorporated into the product through a unique free-radical process.
2
016 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic oxidation
1
,3-dicarbonyl compound
Samarium(III) iodide
Free radical
Catalysis
—
——

Corresponding author. Tel. and fax: +86 21 54925123; e-mail: yaoz@sioc.ac.cn

2
Tetrahedron
α-Hydroxy-β-keto esters and amides moiety is a ubiquitous,
important synthetic intermediary and common structural unit of a
wide range of natural products and pharmaceutical compounds1,
serving as an important contributor to biological activities
(
Figure 1). Great interest of synthetic community has been
Catalyst
5 mol%)
Co-catalyst or
additive
2a
(%)
received to resolve the concise syntheses of such structural
motifs. Quite a number of useful methods have been developed2
for the preparation of α-hydroxy-β-dicarbonyl moieties,
Entry
Solvent(s) T (h)
(
b
1
2
SmI
SmI
SmI
2
Seignette salt
---
THF/H
2
O
O
24
24
82
80
3
including approaches based on asymmetric enol epoxidation.
2
THF/H
2
Among these, direct oxidations of 1,3-dicarbonyl compounds4
3
4
5
3
---
---
THF
THF/H
THF/H
THF/H
THF/H
THF/H
24
24
8
50
90
95
95
NR
95
with various oxidants, such as high valence metal oxides,
SmI
SmI
SmI
3
2
O
2
O
2
O
2
O
2
O
3
I
I
2
2
(1 mol%)
(1 mol%)
---
c
6
3
8
7
8
a
Sm(OTf)
Sm(OTf)
3
3
I
2
(1 mol%)
8
b
A mixure of THF and water (5:1) was used as the solvent.
Seignette salt (5 mol%) was applied; Reaction underwent in
darkness.
c
Optimization of the hydroxylation reaction conditions was
performed upon the oxidation of substrate 1a (Table 1). In the
2 2
presence of SmI (5 mol%) in THF/H O (5:1 v/v), similar results
were achieved either in the presence and absence of Seignette salt
2
+
(
entries 1 and 2). Because Sm is extremely sensitive to O
2
and
3
+
3+
could be quickly oxidized to Sm in air, a stable Sm salt (SmI
3
)
was then employed in the following reactions. Removal of water
slowed down the reaction (entry 3). It mentioned that the
solubility of SmI and O in the reaction medium might effect on
Figure 1. Several bioactive natural molecules bearing α-hydroxy-
β-dicarbonyl moiety.
3
2
3
a,5
6
7
the reaction efficiency, and addition of water would help to
overcome such a problem (entry 4). Furthermore, application of
iodide (1 mol%) as the co-catalyst significantly increased the rate
of the reaction (entry 5), and even in the darkness (entry 6). In
order to authenticate the role of iodine in the reaction, another
peroxide,
oxygen catalyzed by metal catalysts, were frequently reported
Figure 2). However, many of the earlier methods often require
peracid, high-valence iodidum, and molecular
8-12
(
stoichiometric amounts of organic oxidants or heavy metals and
present disadvantages of high costs of materials and producing
salt Sm(OTf)
the two reactions catalyzed with Sm(OTf)
3
was applied. With or without 1 mol% of iodine,
(5 mol%) showed
toxic wastes and byproducts. Recent report also showed that I
could be applied to the similar α-hydroxylation under UV
irradiation. It was believed that high-energy UV light plays as
the initiator of the free radical process. In this work, we want to
report a new direct -hydroxylation of various β-keto esters and
amides by using air (oxygen) as the clean oxidant under the
2
3
13
significant difference (entries 7 and 8). These evidences clearly
define that iodine also plays crucial roles in the reaction, and
eventually help us to propose an appropriate reaction mechanism.
Under the above optimized conditions, reactions of a variety of
1,3-dicarbonyl esters were firstly examined (Figure 3). Most of
the substrates including different α,γ-substituents and ester
groups could be smoothly oxidized by air, giving the
corresponding -hydroxylated products in good yields, except
the reactions for 2b, 2f, 2t, and 2u. A number of earlier efforts on
the synthesis of 2b through similar mechanism were also
3 2
catalysis of SmI and I (Figure 2). This new cheap and
environmentally friendly method provides an easily operational
and high-yielding catalytic transformation to the -hydroxylated
products (up to 95% yield) without the assistance of light and
base.
13,14
unsuccessful,
and so as in this study. The failure may be due
to insufficient formation of the cyclic enolate with Sm(III) (see
below text for more discussion on the mechanism). Unsuccessful
synthesis of 2f might be due to the disruption of radical process
by its internal olefin functionality, while steric hindrance may be
accountable in the failure of 2t. The negative result for 2u might
be caused by the insufficient coordination ability to generate the
2
3
essential cyclic transition state among carbonyl sp -oxygen or sp
ester-oxygen), cyano nitrogen, and samarium(III). Substrates
having substituents with π-electron system at β-γ position to
carbonyl (phenyl and vinyl) suffered with limited success,
because interaction of π-electrons with samarium results in
failure of forming cyclic transition state.
Figure 2. α-Hydroxylation of 1,3-dicarbonyl compounds.
Our initial discovery was observed on the reaction of methyl 2-
methyl-3-oxobutanoate (1a) with catalytic amount of SmI (5
2
mol%) in the open air (Table 1). Long-time stirring of the
mixture in the presence of Seignette salt (5 mol%) at room
temperature afforded a high-yield single product (entry 1), which
was elucidated as the corresponding α-hydroxylated product 2a
by the NMR and MS methods. The high efficiency of the
observed hydroxylation reaction promoted us to further optimize
and investigate this reaction, as well as the unknown catalytic
capability of Sm(III) salts.
a
Table 1. Optimization of reaction conditions.

3
the starting materials were recovered (Table 2). Based on such
observation, a possible radical process through the C−I bond
cleavage was therefore excluded.
a
Table 2. Transformation of iodo-intermediates 3.
a
Entry
Catalyst
Co-catalyst
---
Solvent(s)
THF
Result
NR
NR
NR
NR
1
2
3
4
SmI
SmI
3
3
I
2
THF/H
2
O
Sm(OTf)
Sm(OTf)
3
3
---
THF
I
2
THF/H
2
O
a
5
2
mol% of Sm(III) salt and 1 mol% of I were used under
standard conditions. NR = no reaction.
Source of the newly introduced oxygen in the products was also
18
investigated. An experiment was conducted using O-labelled
water as the co-solvent. Oxygen isotopic abundance
measurement of the product 2a through HRMS method revealed
that air was the only source of that oxygen (Scheme 1).
3 2
Figure 3. SmI (5 mol%) and I (1 mol%) co-catalyzed aerobic
α-hydroxylation of 1,3-dicarbonyl esters.
18
Scheme 1. Experiment in O-isotope labeling water.
Unlike those for esters, less methods are available for the -
hydroxylation of amides since it is yet to be investigated
thoroughly. Similar reagents were reported to apply in the
To explain the newly developed aerobic hydroxylation of 1,3-
dicarbonyl compounds by co-catalysis of SmI
3 2
and I , an
1
4
7,15
transformation, including oxone, high-valence iodidum,
appropriate mechanism was proposed based on the above results
and control experiments (Figure 5). The 1,3-dicarbonyl
compound should be the only reducing agent in this quick
oxidation, because a single high-yielding hydroxylated product is
afforded after the reaction without any additional reductant. Both
oxygen atoms of dioxygen molecule are believed to be utilized
and incorporated into the product, affording two equivalents of
the product. Strong Lewis acidity and high oxygen-affinity of
Sm(III) promotes 1,3-dicarbonyl substrate 1 to quickly undergo
1
6
peroxide,
catalysts.
and molecular oxygen catalyzed by metal
11b,12b,17,18
To explore the application scope of the above
aerobic hydroxylation conditions, a number of β-keto amides
were also examined under the optimized conditions (Figure 4).
Combinative use of 5 mol% of SmI and 1 mol% of iodine did
3
offer good yields of -hydroxylated products. However, these
reactions were found to slow down significantly. Further
experimental trials showed that the reactions could be speeded up
by increasing the amount of iodine up to 2 mol%. Finally,
syntheses of 2v-2ab were carried out in acceptable times using 5
21
enolization, producing a cyclic enolate A, in which Sm(III)
3
prefers to coordinate with the sp oxygens, and releasing one
19
mol% of SmI
3
and 2 mol% of iodine as the catalysts. Again,
molecule of HI. Traditionally, completion of such an enolization
impressive yields were observed for all the products (Figure 4),
not only for N-mono-substituted amides, but also for N,N-di-
substituted amides.
Figure 4. Aerobic α-hydroxylation of 1, 3-dicarbonyl amides
catalyzed with SmI (5 mol%) and I (2 mol%).
3 2
Literature work mentioned that similar aerobic hydroxylation of
,3-dicarbonyl compounds might proceed through a 2-iodo-
1
16
intermediate 3, in which the C−I bond was broken to generated
a carbon radical and furnish the final hydroxylation. To check
2
0
such a possibility, compounds 3a and 3c were prepared and
examined under the standard conditions of aerobic oxidation. The
results showed that the four tested reactions didn’t happen and all
Figure 5. A proposed mechanism for the catalytic process.

4
Tetrahedron
needs the assistance of a base (to remove HI and move the
Acknowledgments
equilibrium to the product side). According to the variable
reaction times with different substrates in this study, Sm(III) is
This work was financially supported by National Natural Science
Foundation of China (21202188 and 21532002), and Ministry of
Science and Technology of the People’s Republic of China
(SS2013AA090203).
3
thought to predominately coordinate with sp oxygens rather than
2
21
sp oxygens in the cyclic enolate A. Enolate A then transfers an
electron to iodine to form free radical species B, which
subsequently reacts with dioxygen and generates a peroxide free
radical C. The peroxide radical C couples with its precursor B to
form a symmetrical dimeric intermediate D. The dimer D
undergoes homolytic O-O cleavage, affording two molecules of
oxy-radical E. Eventually, the oxy-radical E abstracts a hydrogen
from previously in situ generated HI, furnishing the hydroxylated
product 2 and dropping off half mole of iodine (Figure 5).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at xxxxxx.
References and notes
A possible alternative supramolecular mechanism is also
proposed to explain this type of C-H hydroxylation reaction
1
.
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Figure 6. An alternative possible supramolecular mechanism.
1
In summary, we have developed a new aerobic hydroxylation of
β-keto esters and amides by co-catalysis of SmI and I under
3 2
mild base-free conditions in this work. Possible mechanisms
were proposed to explain the crucial catalytic roles of Sm(III)
2
and I based on experimental evidences. This newly developed
method, using air as the clean oxidant, not only presents wide
applicability and good functional group tolerance, but also shows
great advantages of high-yielding, economic green process and
ease of operation. We believe it is valuable in future organic
synthesis and helpful to understand the unknown catalytic
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5
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Highlights for MS#TETL-D-16-00728
Aerobic α-Hydroxylation of β-Keto Esters and Amides by Co-catalysis of SmI
3
and I under Mild
2
Base-free Conditions
*
∗
Shun-Ming Yu, Kai Cui, Fei Lv, Zhen-Yu Yang, and Zhu-Jun Yao




Clean base-free α-hydroxylation of β-keto esters and amides with air.
The first report of new binary catalytic system of SmI
3
and I .
2
Wide scope of substrates, excellent yields, mild conditions.
Both two oxygen atoms of dioxygen are utilized and incorporated into the product through a
unique free-radical process.