MnO2-promoted carboesterification of alkenes with anhydrides: A facile approach to γ-lactones

Article abstract of DOI:10.1039/c5cc08867d

An efficient carboesterification of alkenes with anhydrides promoted by MnO₂ has been developed to afford functionalized γ-lactones in good to excellent yields. This method shows a broad substrate scope and provides a valuable and convenient synthetic tool for constructing γ-lactones.

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MnO2-Promoted Carboesterification of Alkenes with Anhydrides: A
Facile Approach to γ-Lactones
Lihuan Wu,+a,b Zhenming Zhang,+a Jianhua Liao,a Jianxiao Li,a Wanqing Wua and Huanfeng Jiang*,a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient carboesterification of alkenes with anhydrides
promoted by MnO2 has been developed to afford
functionalized γ-lactones in good to excellent yields. This
method shows a broad substrate scope and provides a
10 valuable and convenient synthetic tool for constructing γ-
lactones.
γꢀLactone skeleton is an important moiety in natural products,
many of which show exceptional biological and pharmaceutical
properties.1 Representative γꢀlactones are found in natural
15 products and biologically active molecules, such as (+)ꢀ
harzialactone A,2 longilactone3 and plakolide A4, as shown in
Figure 1. In addition, alkane γꢀlactones can also be widely used as
ingredients in perfumes and food additives due to their pleasant
odor.5 Over the past few decades, many methods for obtaining γꢀ
20 lactones have been developed through constructing a single ester
bond (Scheme 1a).6 So γꢀlactones could be obtained from linear
substrates such as carboxylic acids,7 hydroxyl nitriles,8 keto
esters,9 and so on.10 In recent years, impressive achievements
have also been achieved in the asymmetric synthesis of γꢀ
25 lactones.11 In particular, the direct preparation of enantioenriched
lactones from keto alcohols via ketone hydroacylation has
attracted much attention.12 Despite the significant progress that
has been achieved along these lines, the main restrictive
limitation is that the linear substrates were obtained by multiple
30 steps. So the simple and available substrates are highly desirable.
Scheme 1. Synthetic strategies of γꢀlactones
45 works of radical addition of acetic acid to alkenes to construct γꢀ
lactones in the presence of Mn(III) were reported by Heiba and
Bush.19 As our continued interest in synthesizing heterocyclic
compounds,20 we reported several new strategies for γꢀlactones.
One efficient method is palladiumꢀcatalyzed intermolecular or
50 intramolecular carboesterification of alkenes with alkynes.21
Another
interesting
method
is
the
Cuꢀcatalyzed
carboesterification of alkenes with acetic anhydride under O2,
however, the nonterminal alkenes showed low reactivities.22
Herein, we would like to report a new method for the formation
55 of γꢀlactones directly from alkenes and anhydride in a single step
promoted by MnO2. Relatively low cost of MnO2 and broad
substrate scope are the important merits of this reaction.
Our initial investigation of carboesterification reactions
focused on the cyclization of styrene 1a with anhydride in the
60 presence of MnO2, LiBr and NaOAc (Table 1). To our delight,
when 1a was treated with MnO2 (2.0 equiv), NaOAc (1.0 equiv)
and LiBr (0.2 equiv.) in 1 mL of Ac2O, we found that the
carboesterification of styrene indeed proceeded smoothly at 120
oC to give the γꢀlactone product 2a in excellent yield (Table 1,
65 entry 1). The reaction did not occur without MnO2 and further
investigation showed that 1.2 equiv of MnO2 was the optimal
Figure 1. γꢀLactoneꢀcontaining natural products
Table 1. Optimization of the reaction conditions a
35
Difunctionalization of alkenes is a very important reaction in
organic synthesis because of their high potential for application in
natural product and drug synthesis.13, 14 Recent progress in this
research area has also been reported with regard to
carboamination,15 carbohalogenation16 and carbocyclization17 of
40 alkenes by transition metal catalysis. Among these alkene
difunctionalization reactions, carboesterification of alkenes is a
useful approach to γꢀlactones (Scheme 1 b).18 The pioneering
MnO2
(equiv)
Time
(h)
Yield
(%) b
Entry
Base
Additive
1
2
MnO2 (2.0) NaOAc
ꢀꢀ NaOAc
LiBr
LiBr
12
12
93
N.D.
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40 Table 2. Substrate Scope of Alkenes a,b
3
MnO2 (1.0) NaOAc
MnO2 (0.5) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) ꢀꢀ
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
ꢀꢀ
12
12
3
90
37
4
MnO2 (1.2 equiv.)
NaOAc (1.0 equiv.)
LiBr (0.2 equiv.)
O
R1
O
R1
5
6 c
94 (90)
70
R3
R2
O
5
R2
R3
R4
R4
Ac2O, 120 o
C
7
3
48
2
1
8
MnO2 (1.2) Pyridine
MnO2 (1.2) KOH
MnO2 (1.2) tꢀBuONa
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
MnO2 (1.2) NaOAc
3
44
O
O
O
O
O
F
O
O
9
3
92
10
11
12
13
14
15 d
16 e
3
86
3
81
2a 92%
2b 85%
2c 86%
2d 89%
NBS
LiCl
KBr
LiBr
LiBr
3
52
O
O
O
O
O
O
O
O
O
3
82
3
91
Cl
Br
O2N
F
3
N.D.
N.D.
2g 84%
2e 81%
2f
2h
79%
O
84%
O
3
O
O
O
O
O
a The reaction was carried out with 1 (0.50 mmol), MnO2 , base (1 equiv)
and additive (0.2 equiv) in Ac2O (1.0 mL) at 120 oC. b Determined by GC
using dodecane as the internal standard. Data in parentheses is the yield of
O
2j 92%
2k 91%
2l 88%
2i 89%
isolated product. Under 100 oC. Ac2O/DMF = 1/4 (v/v, 1 mL).
c
d
e
O
5
Ac2O/DMSO = 1/4 (v/v, 1 mL).
O
O
O
O
O
O
O
result (Table 1, entries 7ꢀ10). Slightly lower yield was obtained
without LiBr, and the reaction system became more complex.
Different additives were also tested, such as NBS, LiCl, and KBr,
but the reaction did not proceed well (Table 1, entries 11ꢀ14).
N
Ph
Ph
Ph
Ph
S
2n 72%
2o 88%
2p 95%
2m 87%
O
O
O
O
O
O
O
O
10 However, when other solvents such as DMF or DMSO were used,
the yield of 2a dropped dramatically. Thus, the optimal reaction
conditions were MnO2 (1.2 equiv), NaOAc (1.0 equiv), and LiBr
(0.2 equiv) in 1 mL of Ac2O at 120 oC (Table 1, entry 5).
Under the optimized reaction conditions, we then examined the
15 substrate scope of this alkene carboesterification reaction. As
summarized in Table 2, the substituents at the paraꢀ, metaꢀ, and
orthoꢀpositions of the arene ring did not affect the efficiency in
this reaction system (2bꢀ2d). A series of substituted styrenes,
Ph
Ph
Ph
Ph
2t 75%
Ph
2q 91%
2s 83%
2r 87%
trans/cis = 1.6/1
trans/cis = 1/1
O
O
O
O
O
O
O
O
Ph
Ph
O
Ph
2u 81%
2x 82%
2w 83%
2v 82%
a
Reaction conditions: 1 (0.5 mmol), MnO2 (1.2 equiv), NaOAc (1.0
t
equiv), LiBr (0.2 equiv) in Ac2O (1.0 mL) at 120 oC for 3 h. Yields
b
including some with electronꢀdonating groups (Me, Bu, OMe)
referred to isolated yields.
20 and some with electronꢀwithdrawing groups (F, Cl, Br, NO2),
were converted into the corresponding γꢀlactones in good to
excellent yields (2a-2k). In addition, multisubstituted styrene
could be also transferred to the desired product in 88% yield (2l).
Interestingly, good yields could be obtained when using 2ꢀ
25 vinylnaphthalene (2m) and 4ꢀmethylꢀ5ꢀvinylthiazole (2n) as the
substrates. To our delight, the transformations of 1,1ꢀdisubstituted
alkenes could be proceeded efficiently under the optimized
conditions, affording the desired products 2o and 2p in 88% and
95% yields, respectively. Furthermore, good yields could be
30 obtained when 1,2ꢀdisubstituted alkenes (2qꢀ2s) were employed
in this reaction. It is especially worth mentioning that when
trisubstituted alkenes were used, the desired products 2t and 2u
were isolated in 75% and 81% yields. Linear alkenes containing
aryl groups (2vꢀ2x) were also suitable for this reaction to give the
35 corresponding products in good yields. Disappointingly, no
desired product was observed when 1,1,2,2ꢀtetraphenylethene
was used as the substrate in this reaction.
45 decꢀ1ꢀene were found to be the suitable substrate and converted
to the corresponding cyclization products 2y and 2z in 63% and
61% yields, respectively. It is worth mentioning that the product
2y and 2z as common components were found in both white wine
and red wine.5a Interestingly, the noncyclization byproduct acids
50 with an unpleasant smell could be also observed (2y-1 and 2z-1).
Table 3. Carboesterification of aliphatic alkenes a
a Reaction conditions: alkenes (0.5 mmol), MnO2 (1.2 equiv), NaOAc (1.0
equiv), LiBr (0.2 equiv) in 1.0 mL of Ac2O at 120 oC for 3 h.
55
Next, the carboesterification reactions of aryl alkenes with
propionic anhydride were also examined (Table 4). When the
styrene was used as the substrate, 78% yield of the corresponding
γꢀlactone (3a) was obtained and the trans/cis ratio was ~1/1. The
aryl alkenes with different substituents such as ꢀCl and ꢀBr could
Additionally, we examined the generality of this novel reaction
process with respect to aliphatic alkenes (Table 3). Octꢀ1ꢀene and
60 be also transferred to the desired products (3b and 3c) in good
yields with trans/cis ratio equaling ~ 1/1.
2
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Table 4. Carboesterification of alkenes with propionic anhydride a
MnO2
O
O
O
O
O
O
base
-
O
CH2
O
CH2
O
II
I
R
Mn(III)
Mn(II)
radical addition
O
O
O
O
O
R
R
R = linear alkene
O
product
III
R
OH
byproduct
Acid
40
a Reaction conditions: alkenes (0.5 mmol), MnO2 (1.2 equiv), KOH (1.0
equiv), LiBr (0.2 equiv) in 1.0 mL of (CH3CH2CO)2O at 120 oC for 5 h.
Scheme 2. Plausible reaction mechanism
We are grateful to the National Natural Science Foundation of
China (21172076 and 21420102003), and the Fundamental
Research Funds for the Central Universities (2015ZY001).
5
In addition, a satisfactory result (83% isolated yield) was
obtained when the reaction was performed on gramꢀscale under
the standard conditions (eq. 1).
To gain insight into the mechanism of the reaction, several
control experiments were performed (eq. 2). When the radical
45 Notes and references
10 scavengers such as TEMPO and BHT were used in the reaction
system under the standard conditions, both could inhibit this
carboesterification process, indicating that a radical pathway
should be involved.
+ These authors contributed equally to this work.
a School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, China. Fax: +86 20ꢀ87112906; Tel:
+86 20ꢀ87112906; Eꢀmail: jianghf@scut.edu.cn
50 b College of Chemistry and Chemical Engineering, Zhaoqing University,
Zhaoqing 526060, P. R. China
† Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H, 19F and 13C
NMR spectra for selected compounds. See DOI: 10.1039/b000000x/
55
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Based on the above results, we proposed a tentative mechanism
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30
In summary, we have developed a new radical cyclization
method for the formation of C(sp3)ꢀC(sp3) and CꢀO bonds via
MnO2ꢀpromoted carboesterification of alkenes with anhydrides,
which provides a facile approach to γꢀlactone skeletons. This
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DOI: 10.1039/C5CC08867D
A new radical cyclization method for the formation of C(sp3)-C(sp3) and C-O bonds via
MnO2-promoted alkene carboesterification with anhydrides is developed.