One-Pot Reaction of Carboxylic Acids, Ynol Ethers, and m-CPBA for Synthesis of α-Carbonyloxy Esters

Article abstract of DOI:10.1021/acs.orglett.9b02323

A novel one-pot reaction of carboxylic acids, ynol ethers, and m-CPBA for the synthesis of α-carbonyloxy esters in the presence of Ag₂O is described. This process provides a direct approach to α-carbonyloxy esters with the achievement of format

Full text of DOI:10.1021/acs.orglett.9b02323

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Reaction of Carboxylic Acids, Ynol Ethers, and m‑CPBA for
Synthesis of α‑Carbonyloxy Esters
Linwei Zeng,† Hironao Sajiki,*,‡ and Sunliang Cui*,†
†Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
‡Laboratory of Organic Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: A novel one-pot reaction of carboxylic acids,
ynol ethers, and m-CPBA for the synthesis of α-carbonyloxy
esters in the presence of Ag2O is described. This process
provides a direct approach to α-carbonyloxy esters with the
achievement of formation of three C−O bonds. The protocol
is featured with readily available starting materials and broad
substrate scope. Control reactions and isotope-labeling reactions were conducted to elucidate a plausible mechanism.
and co-workers established a Ag2O-catalyzed regio- and
stereoselective addition of carboxylic acids to ynol ethers
toward formation of α-acyloxy enol esters (Scheme 1A).7
Interestingly, the α-acyloxy enol esters could serve as
versatile synthons in organic synthesis. For example, Wharton
reported that α-acyloxy enol esters could react with carboxylic
acids and amines to deliver anhydrides and amides,
respectively.8 Moreover, Kita revealed that ynol ethers could
serve as coupling reagents for ester and lactone synthesis from
hydroxyl compounds and carboxylic acids.9 In addition, Kita
also reported a Semmer−Wolff aromatization between cyclo-
hexanone oxime and α-acyloxy enol esters.10
Despite these advances, the development of ynol ethers in
multicomponent reactions remains continuously interesting
and important because multicomponent reactions could
achieve the construction of molecules with remarkable
structural diversity and brevity.11 Previously, our group
established a three-component synthesis of tetrahydroisoqui-
nolines (THIQs) from ynol ethers, carboxylic acids, and
dihydroisoquinolines (DHIQs) (Scheme 1B).12 In addition,
we developed a one-pot synthesis of β-keto esters via a DMAP-
promoted intramolecular rearrangement of in situ generated α-
acyloxy enol esters from ynol ethers and carboxylic acids.13
Encouraged by these results,8c,d,14 we hypothesized that the in
situ generated α-alkoxy enol intramolecular Baeyer−Villiger
reaction cascade would deliver α-carbonyloxy esters directly.
Herein, we wish to report a one-pot reaction of carboxylic
acids, ynol ethers, and m-CPBA for synthesis of α-carbonyloxy
esters (Scheme 1C).
namides and ynol ethers are electron-rich alkynes which
1
Yexhibit versatile properties in organic synthesis. Typically,
these alkynes would show dual electronic and nucleophilic
reactivities. Typically, the addition reaction of electron-rich
alkynes and carboxylic acids has been investigated for divergent
transformation in organic synthesis.2,3 For example, Lam and
co-workers reported an efficient and regioselective addition
between carboxylic acids and ynamides under the promotion
of Pd(OAc)2.4 Bi established a catalyst-free addition between
ynamides and carboxylic acids for accessing α-acyloxy
enamides (Scheme 1A),5 while Zhao developed a racemiza-
tion-free synthesis of amides and peptides in which an in situ
generated α-acyloxy enamide intermediate from ynamides and
carboxylic acids was involved in the process.6 Meanwhile, Zhu
Scheme 1. Reactions of Carboxylic Acids and Ynol Ethers
We commenced our study by investigating the silver oxide
catalyzed reaction between benzoic acid 1a and ynol ether 2a.
Initially, we carried out the reaction by mixing 1a, 2a, and 5
mol % of Ag2O in dioxane at 100 °C to deliver α-alkoxy enol
ester intermediate 4a and then added 3-chloroperoxybenzoic
Received: July 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
acid (m-CPBA) to test the rearrangement at ambient
temperature. To our delight, a desired α-carbonyloxy ester
3a was indeed formed and isolated in 83% yield (Table 1, entry
Scheme 2. Scope of Carboxylic Acids
a
Table 1. Reaction Optimization
b
entry
catalyst
Ag2O
Ag2O
AgOTf
Ag2CO3
AgBF4
Cu(OAc)2
Cu(OTf)2
Zn(OTf)2
none
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
m-CPBA
H2O2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
83
0
53
77
73
trace
trace
trace
0
59
53
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
m-CPBA
9
10
11
12
13
Ag2O
Ag2O
Ag2O
Ag2O
toluene
THF
DMF
47
trace
82
c
14
Ag2O
dioxane
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), and Ag2O (5
mol %) were added to solvent (2 mL) and heated at 100 °C for 5 h,
and then the additive (1.5 equiv) was added at ambient temperature
b
and kept at the same temperature. Yield refers to isolated product.
c
m-CPBA (1.25 mmol) was used.
1
1). The product was identified by H NMR, 13C NMR, and
MS analysis. Replacing m-CPBA with hydrogen peroxide
would completely suppress the cascade reaction, while only 4a
was isolated (entry 2). Meanwhile, the utilization of other
silver salts, such as AgOTf, AgBF4, and Ag2CO3, was less
effective, and the products could be formed in slightly lower
yields (entries 3−5). When Cu(OAc)2, Cu(OTf)2, and
Zn(OTf)2 were used as catalysts, no products were observed
(entries 6−8). The next survey of solvents revealed that DCE,
toluene, THF, and DMF were not optimal and the yields
would decrease (entries 10−13). In addition, when the amount
of m-CPBA was increased to 5 equiv, the yield was not
improved significantly (entry 14).
With the optimized reaction conditions in hand, we next
tested the substrate scope. As shown in Scheme 2, a variety of
substituted benzoic acids could proceed well in this one-pot
reaction to deliver products in moderate to good yields, and
valuable groups such as nitro, methoxy, chloro, trifluoromethyl,
and fluoro were tolerated (3b−3i). Meanwhile, the naphthyl
carboxylic acids and heterocyclic carboxylic acids including
pyrrole, furan, and thiophene could participate in this process
to produce the corresponding α-carbonyloxy esters (3j−3n).
Aliphatic carboxylic acids, including 4-nitrophenylacetic acid,
3-thiopheneaectic acid, isopropyl acid, cyclopropyl carboxylic
acid, tetrahydro-2H-pyran-4-carboxylic acid, and piperidine-4-
carboxylic acid, were also applicable in this one-pot reaction
(3o−3t). Notably, when N-protected amino acids including
glycine, L-alanine, L-proline, and β-alanine were subjected to
this process, the products could be formed in good yields (3u−
3y). In addition, the products generated from L-alanine (3v)
and L-proline (3x) showed dr values of 53:47 and 54:46,
a
Reaction conditions: 1 (0.25 mmol), 2a (0.25 mmol) and Ag2O (5
mol %) were added to dioxane (2 mL) and heated at 100 °C for 5 h,
then m-CPBA (1.5 equiv) was added and the solution was stirred at
ambient temperature for another 12 h. Yields refer to isolated
products.
respectively. Furthermore, the structure of 3u was unambig-
uously confirmed by X-ray analysis.
On the other hand, the scope of ynol ethers was also tested.
As shown in Scheme 3, a series of aryl-substituted ynol ethers
were subjected to this one-pot reaction to react with carboxylic
acids, and various products were obtained in moderate to good
yields. The substituted groups in the benzene ring including p-
methyl, p-methoxy, p-fluoro, p-chloro, o-chloro, and m-methyl
were all amenable (3z−3k′). Interestingly, 2-naphthyl- and
thiophene-2-yl-substituted ynol ethers were also compatible to
deliver the desired 3l′ and 3m′ in 80% and 69% yields,
respectively. In addition, the methoxy ynol ether was also
applicable in this one-pot reaction to furnish 3n′ in 79% yield.
Meanwhile, the aliphatic and terminal ynol ether could engage
in this process to deliver the products 3o′ and 3p′, albeit in
B
DOI: 10.1021/acs.orglett.9b02323
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 3. Scope of Ynol Ethers
Scheme 4. Gram-Scale Reaction and Application
Scheme 5. Control Reaction
stepwise reaction was also conducted (Scheme 5B). The
intermediate 4a could be isolated in excellent yield (95%),
which was subjected to reaction with m-CPBA to deliver 3a in
85% yield. Furthermore, an isotope-labeling reaction was
performed (Scheme 5C). An 18O-labeled benzoic acid 18O-1a
was prepared and subjected to reaction with 2a. The 18O-
labeled 3a was generated in 82% yield, in which the labeled
oxygen atom was incorporated in both carbonyl groups.
On the basis of these results and the literature,4,8,9,16 the
plausible reaction mechanism was proposed in Scheme 6.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.25 mmol) and Ag2O (5
mol %) were added to dioxane (2 mL) and heated at 100 °C for 5 h,
then m-CPBA (1.5 equiv) was added and the solution was stirred at
ambient temperature for another 12 h. Yields refer to isolated
products.
slightly lower yields. Therefore, this one-pot reaction offers an
efficient and direct approach to α-carbonyloxy esters.15
To test the synthetic utility of this one-pot reaction, a gram-
scale reaction of benzoic acid 1a and ynol ether 2a was
conducted. Gratifyingly, the reaction proceeded well, and 1.2 g
of α-carbonyloxy ester 3a was formed in 84% yield (Scheme
4A). Furthermore, the anti-inflammatory drug naproxen was
subjected to reaction with ynol ether 2a under standard
conditions (Scheme 4B), and the desired product 3q′ was
generated in 85% yield (dr 53:47). Thus, this protocol
provides a convenient method for the late-stage functionaliza-
tion of biological interesting molecules.
Scheme 6. Proposed Reaction Mechanism
To probe the reaction mechanism, control reactions were
conducted. Two typical ynamides 2m and 2n were prepared
and subjected to the reaction with benzoic acid 1a to furnish
the corresponding α-acyloxy enamides 5 and 7,4,5 which were
next treated with m-CPBA (Scheme 5A). With respect to 5,
the desired product 6 was formed in only 32% yield, while the
reaction of 7 did not deliver any product. Meanwhile, a
C
DOI: 10.1021/acs.orglett.9b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Initially, the α-alkoxy enol ester 4 was formed from carboxylic
acid 1 and ynol ether 2 under the promotion of catalytic Ag2O.
Subsequently, there are two plausible reaction pathways. For
pathway A, the carbonyl group of α-alkoxy enol ester 4 is
added by m-CPBA to deliver intermediate A, which transforms
to α-carbonyloxy ester 3 via a Baeyer−Villiger type reaction
and fragment cascade. With respect to pathway B, the alkenyl
C−C double bond of α-alkoxy enol ester 4 was epoxidized by
m-CPBA to give intermediate B, which rapidly rearranged to
give the final product 3.
In summary, a novel one-pot reaction of carboxylic acids,
ynol ethers, and m-CPBA for synthesis of α-carbonyloxy esters
has been developed. The protocol features readily available
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02323.
■
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Full experimental procedures, characterization data, and
NMR spectral data (PDF)
Accession Codes
CCDC 1916376 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: sajiki@gifu-pu.ac.jp.
*E-mail: slcui@zju.edu.cn.
ORCID
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Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005.
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Hironao Sajiki: 0000-0003-2792-6826
Sunliang Cui: 0000-0001-9407-5190
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful for financial support from Zhejiang University
and the Key R & D Plan of Zhejiang Province (2019C03082).
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DOI: 10.1021/acs.orglett.9b02323
Org. Lett. XXXX, XXX, XXX−XXX