Ynamide-Mediated Thionoester and Dithioester Syntheses

Article abstract of DOI:10.1021/acs.orglett.0c02402

A novel ynamide-mediated synthesis of thionoesters and dithioesters is described. The selective addition reactions of various monothiocarboxylic acids with ynamide furnish α-thioacyloxyenamides, which undergo transesterification with nucleophilic -OH or -SH species to afford thionoesters and dithioesters, respectively. The broad substrate scope, mild reaction conditions, and excellent yields make this method an attractive synthetic approach to thionoesters and dithioesters.

Full text of DOI:10.1021/acs.orglett.0c02402

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Letter
Ynamide-Mediated Thionoester and Dithioester Syntheses
Chaochao Yao, Jinhua Yang, Xiaobiao Lu, Shuyu Zhang, and Junfeng Zhao*
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ABSTRACT: A novel ynamide-mediated synthesis of thionoesters
and dithioesters is described. The selective addition reactions of
various monothiocarboxylic acids with ynamide furnish α-
thioacyloxyenamides, which undergo transesterification with
nucleophilic −OH or −SH species to afford thionoesters and
dithioesters, respectively. The broad substrate scope, mild reaction conditions, and excellent yields make this method an attractive
synthetic approach to thionoesters and dithioesters.
hionoesters and dithioesters are important compounds
due to the presence of a thiocarbonyl group, which imparts
conversion of esters into the corresponding thiocarbonyl esters
12
T
involves the use of thionating reagents such as P4S10 and
them with unique properties and reactivities.1 Both of these
classes of esters have been used as intermediates in a broad range
of organic transformations.2 For example, thionoesters can be
readily transformed into difluoroalkyl ethers3 or thioamides.4
Thionoesters can also serve as the precursors for ethers5 and
1,4,2-oxathiazoles.6 Very recently, Pluth and co-workers have
demonstrated that thionoesters and dithioesters could function
as cysteine-selective H2S donors.7 Although thionoesters and
dithioesters are ester analogs, their syntheses are more
complicated and challenging than those of esters.2 Thionoesters
and dithioesters are typically prepared from Pinner intermedi-
ates (Scheme 1, eq a).8 Unfortunately, the coformation of
Lawesson’s reagent (Scheme 1, eq c).13 While this strategy
provides a wide range of thionoesters, the poor reactivity of the
ester functionality leads to low reaction efficiency, a long
reaction time, and poor chemoselectivity between ester and
amide functional groups.14,15 Alternatively, the use of thioacylat-
ing reagents and transesterification reactions has provided more
convenient synthetic approaches to thionoesters (Scheme 1, eq
d
16 and e2,17). However, most thioacylating reagents are highly
reactive and unstable.18 Additionally, the preparation of
thioacylating reagents requires tedious multiple-step reactions
and the use of malodorous thionating reagents. Considering the
versatile applications of thionoesters and dithioesters, highly
efficient strategies for their syntheses are in great demand.
Herein, we report a novel ynamide-mediated synthetic approach
to thionoesters and dithioesters, in which α-thioacyloxyena-
mides act as the thioacylating reagents.
Scheme 1. Syntheses of Thionoesters and Dithioesters
Over the past three decades, ynamides have been widely used
in a broad range of organic transformations because of their
versatile reactivity.19 We previously demonstrated that ynamides
could serve as racemization-free coupling reagents for amide
bond formation.20 Later, we found that α-thioacyloxyenamides
formed from the selective addition reaction of monothiocarbox-
ylic amino acids with ynamides could be used as the efficient
racemization-free thioacylating reagents for site-specific incor-
poration of a thioamide substituent into a growing peptide
backbone.21 Notably, the protection of hydroxyl groups in the
side chain of Ser, Thr, and Tyr is not necessary during thioamide
bond formation which is mainly attributed to the lower
nucleophilicity of the hydroxyl group compared to that of the
thioamide side products is often a major concern in this
strategy.9 Dithioacids are ideal starting materials for thionoester
and dithioester syntheses but are unstable and difficult to
prepare, particularly aliphatic dithioacids.10 The addition
reaction of alcohols or thiols with thioketenes offers an attractive
alternative approach to thionoesters and dithioesters (Scheme 1,
eq b). However, thioketenes are unstable and can only be
isolated at very low temperatures.11 A general strategy for direct
Received: July 19, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02402
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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pubs.acs.org/OrgLett
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a
free amino group. Transesterifications can be promoted by acid
or base catalysts,15,17 and this strategy has been successfully
applied to the transesterification of α-acyloxyenamides with
alcohol and phenol derivatives.22 Based on these advances, we
hypothesized that α-thioacyloxyenamide could act as a thioacyl
donor for thionoesters. Our preliminary study revealed that
transesterification of α-thioacyloxyenamide 1a with 4-tert-
butylphenol 2a proceeded smoothly in acetonitrile (CH3CN)
at room temperature using N,N-diisopropylethylamine
(DIPEA) as the base (Table 1, entry 1). Further, the reaction
Scheme 2. Substrate Scope of the Hydroxyl Species
a
Table 1. Optimization of the Reaction Conditions
entry
solvent
base
yield (%)
b
1
CH3CN
CH3CN
CH3CN
CH3CN
DCM
DMF
Acetone
THF
DIPEA
Et3N
68
72
85
91
80
85
82
81
90
72
b
2
3
4
5
6
7
8
DMAP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
9
CH3CN
CH3CN
d
10
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol, 2 equiv), base
b
(0.02 mmol, 0.2 equiv), solvent (1 mL), rt, 10 min, isolated yield. 2
h. Cs2CO3 (0.01 mmol, 0.1 equiv). Cs2CO3 (0.005 mmol, 0.05
c
d
equiv), 50 min.
a
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol, 2 equiv), Cs2CO3
b
(0.01 mmol, 0.1 equiv), CH3CN (1.0 mL), rt, isolated yield. 2 (2.0
mmol, 20 equiv).
conditions were optimized to establish a robust protocol for the
thionoester synthesis (Table 1). The base catalyst played a
crucial role in this transesterification reaction (Table 1, entries
1−4). CH3CN was identified to be the optimal solvent system
(Table 1, entries 4−8). Reducing the loading of Cs2CO3 from 20
mol % to 10 mol % had no detrimental effect on the reaction
efficiency (Table 1, entries 4 and 9). However, further
decreasing the Cs2CO3 loading to 5 mol % led to a reduced
yield, even with a prolonged reaction time (Table 1, entry 10).
With the optimized reaction conditions in hand, we next
investigated the scope of phenols and alcohols 2 using α-
thioacyloxyenamide 1a as a model thioacyl donor (Scheme 2).
Phenols containing both electron-donating (p-tBu, p-OCF3, p-
OMe, p-SMe) and electron-withdrawing (p-CN, p-CF3, o-Br)
substituents reacted smoothly to afford the desired products in
good to excellent yields (84%−94%). Transesterification
products of trisubstituted (3i) and sterically hindered phenols
(3h) could also be obtained in excellent yields under the
standard reaction conditions. Additionally, a complex substrate,
such as estrone, could also serve as a nucleophile to provide the
desired product in good yield (3l). Although the reaction
efficiency of alcohols was lower than that of phenols, all the
thionoesters of various alcohols could be obtained in good to
excellent yields albeit with an excess amount of alcohols.
Excellent selectivity was observed for the transesterifications of
polyfunctionalized phenols, such as 4-(2-hydroxyethyl)phenol
and 4-aminophenol (3j and 3k). A variety of primary and
secondary alcohols were compatible with this protocol (3m−t).
Interestingly, the primary hydroxyl group could be selectively
thioacylated in the presence of secondary and tertiary hydroxyl
groups (3u and 3v).
We subsequently extended our methodology to the
dithioesters, which are important but have received less
attention than thioamides and thionoesters due to the lack of
synthetic strategies. Under the standard reaction conditions, the
transesterification reaction between 1b and 4a offered the
expected compound 5a in only 40% yield (data not shown). To
our delight, an excellent yield of compound 5a (90%) was
obtained when the reaction was carried out under a nitrogen
atmosphere with 1.2 equiv of 1b (Scheme 3). Exploring the
substrate scope of thiophenols revealed that both electron-
donating and electron-withdrawing substituents were compat-
ible with the reaction, providing the target dithioesters in good
to excellent yields (5a−5g). Interestingly, transesterification of
alkyl thiols was also viable without the requirement of excess
thiols or long reaction times (5h−5j). Notably, dithioester was
produced exclusively when 2-mercaptoethanol was used as the
substrate due to the stronger nucleophilicity of −SH compared
to −OH (5k). Sterically bulky substrates, such as cyclo-
hexanethiol and tert-butyl mercaptan, were also compatible
with this strategy (5l and 5m). The sulfhydryl group of Cys can
also react with α-thioacyloxyenamide to give the corresponding
dithioesters (5n), thus providing an opportunity for the
chemical modification of peptides and proteins. This trans-
esterification reaction could also be extended to a seleno
nucleophile, with phenylselenol reacting with α-thioacyloxy-
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https://dx.doi.org/10.1021/acs.orglett.0c02402
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a
a
Scheme 3. Substrate Scope of the Sulfhydryl Species
Scheme 4. Substrate Scope of α-Thioacyloxyenamides
a
Reaction conditions: 1b (0.12 mmol, 1.2 equiv), 4 (0.1 mmol),
Cs2CO3 (0.01 mmol, 0.1 equiv), CH3CN (1.0 mL), N2, rt, 5 min,
isolated yield.
enamide to produce Se-phenyl benzoselenothioate (5o) in 83%
yield. This preliminary result is promising for the development
of a general synthetic approach to thioselenoesters.
These encouraging results prompted us to extend the reaction
to other α-thioacyloxyenamides, which could be easily prepared
in good yields by the selective addition reaction of
monothiocarboxylic acids with ynamide (MYTsA) (for details,
see Supporting Information).21 As shown in Scheme 4, a broad
range of α-thioacyloxyenamides reacted with alcohol and thiol
derivatives smoothly to give the desired products in good to
excellent yields. Heterocyclic aromatic moieties, such as furan
and thiophene, could also be tolerated to produce the
corresponding thionoesters (7h and 7i). Note that thionoesters
7g and 7n, which cannot be prepared by using thionating
reagents and methylthionobenzoate methods, can be obtained
in excellent yields under the standard reaction conditions.17
Additionally, α-thioacyloxyenamides derived from aliphatic
monothiocarboxylic acids are also valid substrates for the
synthesis of thionoesters (7j and 7k) and dithioesters (7o−7r).
To further illustrate the utility of this method, gram-scale
synthesis was performed, and 1.12 g of thionoester 3m was
obtained in 80% yield. In addition, 3m was successfully
transformed into a series of valuable compounds according to
the reported methods (for details, see the Supporting
Information).
a
Reaction conditions for the first step: 6 (0.45 mmol), MYTsA (0.3
mmol), m-xylene (2.0 mL), N2, −40 °C, 8 h. Reaction conditions for
the second step: 1 (0.1 mmol), 2 (0.2 mmol, 2 equiv), Cs2CO3 (0.01
mmol, 0.1 equiv), CH3CN (1.0 mL), rt, 10 min, isolated yield.
(0.12 mmol, 1.2 equiv) and 4 (0.1 mmol), Cs2CO3 (0.01 mmol, 0.1
b
1
equiv), CH3CN (1.0 mL), N2, rt, 5 min.
the target thionoesters and dithioesters in good to excellent
yields. Undoubtedly, this simple and efficient strategy for the
synthesis of thionoesters and dithioesters will find broad
application in the field of organic chemistry.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02402.
Experimental procedures, compound characterization
data, and copies of NMR spectra (PDF)
In conclusion, we have developed a novel and efficient
synthetic strategy for thionoesters and dithioesters with α-
thioacyloxyenamides, which could be prepared easily from the
selective addition reaction of monothiocarboxylic acids with
ynamide (MYTsA), as the thioacyl donor. A broad range of
nucleophilic −OH and −SH species and monothiocarboxylic
acids were compatible with the reaction conditions and afforded
AUTHOR INFORMATION
Corresponding Author
■
Junfeng Zhao − College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, China;
orcid.org/0000-0003-4843-4871; Email: zhaojf@
jxnu.edu.cn
C
https://dx.doi.org/10.1021/acs.orglett.0c02402
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Authors
pubs.acs.org/OrgLett
Letter
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̈
Tetrahedron 1977, 33, 449−452.
Chaochao Yao − College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, China
Jinhua Yang − College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, China;
orcid.org/0000-0002-5425-7421
Xiaobiao Lu − College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, China
Shuyu Zhang − College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02402
Notes
(16) Yeo, S. K.; Choi, B. G.; Kim, J. D.; Lee, J. H. A Convenient
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21762021, 91853114).
■
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