Furfuryl Cation Induced Three-Component Reaction to Synthesize Triazole-Substituted Thioesters

Article abstract of DOI:10.1002/ejoc.202000299

A furfuryl cation induced three-component thioesterification reaction between thiols, 5-bromo-2-furylcarbinols and azides is reported. This metal-free method relies on the acetyl chloride/HFIP-mediated cascade formal [3+2] cycloaddition/ring-opening/thioesterification, which allows the efficient construction of a series of complex triazole-thioesters linked with an (Z)-olefin. Selenols are also suitable for this strategy. Further derivatization of thioesters highlighted the potential utility of our method.

Full text of DOI:10.1002/ejoc.202000299

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Furfuryl Cation Induced Three-Component Reaction to
Synthesize Triazole-Substituted Thioesters
Authors: Ying Zhong, Xiaoming Xu, Qingzhao Xing, Song Yang, Jing
Gou, Ziwei Gao, and Binxun Yu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000299
Link to VoR: https://doi.org/10.1002/ejoc.202000299
01/2020

10.1002/ejoc.202000299
European Journal of Organic Chemistry
COMMUNICATION
Furfuryl Cation Induced Three-Component Reaction to Synthesize
Triazole-Substituted Thioesters
Ying Zhong,[a] Xiaoming Xu,[a] Qingzhao Xing,[a] Song Yang,[c] Jing Gou,[b] Ziwei Gao,*[a] and Binxun Yu*[a]
[a]
Y. Zhong, X. Xu, Q. Xing, Prof. Dr. Z. Gao and Prof. Dr. B. Yu
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry & Chemical Engineering, Shaanxi Normal University,
Xi’an 710062, China.
E-mail: yubx@snnu.edu.cn, http://www.chem.snnu.edu.cn/teach_show.aspx?id=1558
zwgao@snnu.edu.cn, http://www.chem.snnu.edu.cn/teach_show.aspx?id=1524
Prof. Dr. J. Gou
Shaanxi Key Laboratory for Advanced Energy Devices, Shaanxi Normal University, Xi’an 710062, China
S. Yang
[b]
[c]
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, 213164, China
Supporting information for this article is given via a link at the end of the document.
Abstract: A furfuryl cation induced three-component thioesterification
reaction between thiols, 5-bromo-2-furylcarbinols and azides is
reported. This metal-free method relies on the acetyl chloride/HFIP-
metal-free). The 3-CR is capable of building up the complex
thioesters, featuring a conjugated (Z)--ene--triazole.
mediated
cascade
formal
[3+2]
cycloaddition/ring-
opening/thioesterification, which allows the efficient construction of a
series of complex triazole-thioesters linked with an (Z)-olefine. The
selenols are also suitable for this strategy. Further derivatization of
thioesters highlighted the potential utility of our method.
[1]
Because of the weaker orbital overlap relative to esters,
thioesters have gained widespread applications as synthetic
intermediates for acyl transfer reaction, including native chemical
ligation, [2] functional group transformation into an ester, [3] amide,
[4]
aldehyde [5] or ketone. [5, 6] Also, thioether moieties, including
both chain and cyclic forms, are widely found in diverse natural
products.[1e] Particular, thioester has been employed as an
elegant moiety for asymmetric aldol, [7] Mannich [8] and Michael
reactions. [9] In nature, the thioester group plays a pivotal role in
metabolism and cellular function regulation. [10]
Given the significance of thioesters, some noteworthy
Scheme 1. Representative methods for thioester synthesis in comparison with
the present work
methods for synthesizing thioesters have been subsequently
[1]
developed over the past few decades (Scheme 1a).
The
The methods to form the structurally more diverse thioesters
directly from readily available biomass derivatives has high
synthetic value. Biomass-derived furan is a highly crucial
synthetic tool because of its low aromaticity. [20] It does not only
traditional methods for thioester formation are the coupling
between a thiol or disulfide and an activated carboxylic acid, [11] or
[12]
the reaction of a thioacid with an electrophile.
Several
alternative synthetic approaches have been established including
can serve as masked alkenes, enol ethers, [21] 1,4-diketones, [22]
[13]
the oxidative thioesterification of aldehydes
and the
[23]
and carboxylic acids,
but also usually can allow for facile
thiocarbonylation of alkenes, [14] alkynes [15] or organic halides [16,
4] with CO gas. Jiang and co-workers reported a Pd-catalyzed CO
insertion cross-coupling between organosilicon compounds and
thiosulfates, that represented an odorless thioesterification
method. [17a] An elegant transition-metal-free synthesis of an α-
ketothioester via the three-component reaction of an α-hydroxyl
ketone, elemental sulfur and a benzyl halide was developed by
the same group. [17b] Nonetheless, several limitations have been
observed in some approaches including the use of highly reactive
[24-25, 26]
recyclization reactions into different carbo
and
heterocycles. [27] However, to the best of our knowledge, a direct
transformation from furans to thioesters has never been achieved
in organic synthesis. Recently, we developed a method for the
dearomatized [3+2] cycloaddition of furans with organo azides
under the Lewis acid conditions, which enables a convenient and
high-efficient synthesis of triazoles. [28] The corresponding three-
component reactions (3-CRs) have also been explored by us to
[28b, c]
afford β-triazole-acrylamides and -acrylates.
With the
oxidants, expensive metal catalysts, long reaction times, harsh
purpose to further dig this strategy, our effort focused on
developing a furan-based thioesterification with thiols and azides,
which could be initiated by a furfuryl cation induced cascade
reaction (Scheme 1b). In our previous furan recyclizations, the
stoichiometric Lewis acids, such as TiCl4 or SnCl4 were applied,
[18]
reaction conditions, and others.
So, the thioesterification
reactions under metal-free conditions have attracted the attention
[19]
of chemists,
because they are desired particularly in the
pharmaceutical synthesis. Herein, we reported the first
thioesterification reaction based on a furan dearomatization
strategy, which is carried out via a novel three-component
reaction (3-CR) and under mild reaction condition (air tolerant and
1
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10.1002/ejoc.202000299
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Acid screen for three-component reaction
Entry [a]
Condition [equiv]
Temp. [°C] / Time [h] /Atmosphere
Yield [%] [b]
1
2
SnCl4 (1.1), CH2Cl2
-20–rt/1.0/N2
-20–rt/1.0/N2
rt–80/1.0//N2
rt–80/5.0/N2
rt–80/5.0/N2
-20/1.5/N2
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
-20/1.5/air
rt–80/5.0/air
-20–rt/1.0/N2
-20/1.2/air
-20/1.5/air
Trace
Trace
TiCl4 (1.1), CH2Cl2
3
ZnCl2 (1.1), CH2Cl2
0
4
Dy(OTf)3 (1.1), CH2Cl2
0
5
Sc(OTf)3 (1.1), CH2Cl2
0
6
AcCl (1.5), CH2Cl2/HFIP = 1/5
AcCl (1.5), CH2Cl2/HFIP = 1/5
pTsCl (1.5), CH2Cl2/HFIP = 1/5
(COCl)2 (0.75), CH2Cl2/HFIP = 1/5
CCl3COCl (1.5), CH2Cl2/HFIP = 1/5
AcCl (1.5), CH2Cl2/IPA = 1/5
72 [c] + trace [d]
71 [c] + trace [d]
39 [c] + 20 [d]
22 [c] + 18 [d]
20 [c]+ 14 [d]
Trace
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4 M HCl in dioxane (1.5), CH2Cl2/HFIP = 1/5
2 M HCl in EtOAc (1.5), CH2Cl2/HFIP = 1/5
TfOH (1.5), CH2Cl2/HFIP = 1/5
CAS (1.5), CH2Cl2/HFIP = 1/5
pTsOH·H 2O (1.5), CH2Cl2/HFIP = 1/5
TFA (1.5), CH2Cl2/HFIP = 1/5
15 [c] + 25 [d]
10 [c] + 30 [d]
20 [c] + 20 [d]
16 [c] + 22 [d]
18 [c] + 15 [d]
Trace
Ca(NTf2)2 (1.1), Bu4NPF6 (1.1), CH2Cl2
H instead of Et of 2a, TiCl4 (1.1), CH2Cl2
H instead of Et of 2a, AcCl (1.5), CH2Cl2/HFIP = 1/5
Cl instead of Br of 2a, AcCl (1.5), CH2Cl2/HFIP = 1/5
0
Trace
48 [c] + trace [d]
60 [c] + trace [d]
[a] Conditions: 5-bromo-furfurylcarbinol 2a (0.5 mmol), cyclohexyl azide 3a (0.7 mmol), p-methoxythiophenol 1a (0.35 mmol), solvent (1.2 mL). [b] Isolated yield. c
Only the Z isomer of 4a was observed by 1H NMR. [d] disulfide. Abbreviations: PMP = p-methoxyphenyl; Cy = cyclohexyl; HFIP = hexafluoroisopropanol; IPA =
isopropyl alcohol; CAS = (±)-camphorsulfonic acid; TFA = trifluoroacetic acid.
which might not be suitable for using thiol due to its strong
coordination. Herein, searching a stable and readily available
furfuryl cation promoter and avoiding the using of metal reagent
would be our major concerned issue in this 3-CR. Moreover, we
expect the reaction cannot only be realized under a mild air
atmosphere, but also avoiding homocoupling of thiol to disulfide
prior to the thioesterification.
solutions also is presented, which can lead to lower acidity than
the TiCl4 system. Inspired by Aubꢀ’s work, we prefer to use AcCl-
generated HCl due to AcCl is generally easier to handle and more
resistant to hydrolysis in air. Furthermore, the inferiority for the
coordination of thiols with Lewis acids could be ruled out if
AcCl/HFIP was used, because of 1 equivalent AcCl could only
induce the formation of furfuryl cation before the addition of thiols.
To our delight, the combination of AcCl/CH2Cl2/HFIP was shown
to be a sufficiently mild condition to afford the desired thioester
product 4a in high yield (entry 6). Interestingly, the nearly identical
yield was obtained when the same condition was set up in an
open-flask without N2 protection. However, a trace disulfide was
observed (entry 7). The double bond between thioester and
As
a model reaction for furan thioesterification, we
examined the reaction of p-methoxythiophenol 1a, 5-bromo-
furfurylcarbinol 2a and cyclohexyl azide 3a in the presence of
several furfuryl cation promoters (Table 1). The use of strong
Lewis acids such as SnCl4 and TiCl4, which were used for
previous furan dearomatized triazole synthesis, only gave a trace
amount of thioester 4a along with complex unidentified
byproducts (entries 1 and 2). Other Lewis acids that exist
relatively weak coordination with thiophenol such as ZnCl2,
Dy(OTf)3 and Sc(OTf)3 failed to afford the desired product, even
were heated to 80 °C in a sealed tube and the reaction time was
expanded to 5h (entries 3−5). The seminal work by the group of
Aubꢀ showed that the intramolecular Schmidt reaction of alkyl
azides and ketones could be achieved by HCl, that in situ
formation from the reaction of acyl chloride with
hexafluoroisopropanol (HFIP). [29] A buffering effect of HCl/HFIP
1
triazole was determined as a Z-configuration with H NMR. The
more reactive acid chlorides, such as pTsCl, Cl3CCOCl and
(COCl)2, could afford 4a in meager yields along with the formation
of an amount of disulfide (entries 8−10). Instead of HFIP,
isopropanol was used and the reaction hardly proceeded (entry
11). Direct using HCl in dioxane or EtOAc solutions was found to
give the worse results with 15% or 10% yields of 4a (entries 12
and 13). The low product yields were observed in the presence of
the other Brønsted acids such as TfOH, CAS and pTsOH·H2O
(entries 14−16). A trace of desired product was obtained when
2
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10.1002/ejoc.202000299
European Journal of Organic Chemistry
COMMUNICATION
mL), -20 oC; only the Z-isomer was observed by 1H NMR in each example;
isolated purified yield. [b] trace of disulfide was observed.
using TFA condition (entry 17). Air and moisture-stable
Ca(NTf2)2/Bu4NPF6 could not promote the 3-CR reaction (entry
18). [30] Next, we investigated the primary furfuryl alcohol for the
reaction using AcCl/HFIP as the initiator, which gave the
thioesters in 48% yield (entry 20). Finally, The substrate that
contains a chlorine instead of bromine on the 5-position of the
furan was also suitable for this conversion and offered the product
4a in 60% yield (entry 21).
We then used this one-pot protocol to test a range of
different 2-furfurylcarbinol 2 and azides 3 under the optimal
conditions with p-methoxythiophenol 1a (Table 3). Secondary 5-
bromo-furfuryl alcohols with a wide variety of side chains,
including n-butyl, methyl, isopropyl and allyl are capable of
reacting with cyclohexyl azide 2a to furnish the corresponding
triazole 4k−m and 4o in moderate yields. Although benzylic
adducts usually could generate the more reactive furfuryl cations
and gave the satisfying yields in our previous works, the
thioesterification of 4p only afforded a 30% yield. Albeit cyclohexyl
substituted substrate 2h exists more steric hindrance effects
when approaching with another cyclohexyl azide 3a, the reaction
still can produce the desired triazole-thioester 4q in 46% yield.
Subjecting alkyl azides 3b and 3c to optimized 3-CR conditions
generated thioesters 4r and 4s in good yield. A series of acidic
sensitive benzylic azides was studied, leading to the desired
product 4t−w in good yield. A more flexible n-octyl azide did not
interrupt the reactivity and gave a long tail product 4x in 78% yield.
We then investigated the generality of this thioesterification
of 2a with various thiols using cyclohexyl azide 3a as reaction
partner and AcCl/HFIP in an open-flask as the most effective
condition. These results are summarized in Table 2. The aryl
thiols 1a−c smoothly reacted with 2a and 3a in one pot, giving the
corresponding triazole-thioesters 4a−c in satisfying yields.
Electron-rich thiophenol 1a is more reactive and afforded
relatively high yield. However, a trace amount of homocoupling
products still can be observed in these reaction systems. Similarly,
various aliphatic thiols 1d−j were investigated for this 3-CR.
Benzylic thiols 1d and 1e smoothly reacted. The latter is not stable
enough under the acidic condition and gave the corresponding
product 4e in 42% yield, which might be caused by the electron-
donating effect of -OMe on the phenyl ring. Allylic thiol 1f is
compatible in this cascade reaction. When secondary and primary
thiols 1g−i were employed, the alkyl thioesters 4g−i were
obtained in 52−74% yields. A similar result was obtained when
EtSH was used. Significantly, the generation of disulfide for the
alkanethiol system was not detected. Because aryl thiols have a
lower bond dissociation energy (S−H) than alkanethiols, resulting
in the more facile formation of homocoupling products.
Table 3. Azide and 5-bromo-2-furfurylcarbinol scopes of 3-CR [a, b]
Table 2. Thiol scope of AcCl/HFIP promoted 3-CR [a]
[a] Condition: 5-bromo-furfurylcarbinol 2 (0.5 mmol), azide 3 (0.7 mmol), p-
methoxythiophenol 1a (0.35 mmol), AcCl (0.5 mmol), HFIP (1.0 mL) and CH2Cl2
(0.2 mL), -20 oC; only the Z-isomer was observed by 1H NMR in each example;
isolated purified yield. [b] trace of disulfide was observed.
Selenol ester is also an essential structural motif that can be
widely applied as building blocks of heterocycles and precursors
[a] Conditions: 5-bromo-furfurylcarbinol 2a (0.5 mmol), cyclohexyl azide 3a (0.7
mmol), thiol 1 (0.35 mmol), AcCl (0.5 mmol), HFIP (1.0 mL) and CH2Cl2 (0.2
3
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10.1002/ejoc.202000299
European Journal of Organic Chemistry
COMMUNICATION
of acyl radicals and anions, etc. [1c] To our delight, treatment of 5-
bromo-furylcarbinols 2a and azide 3a with phenyl and benzylic
selenols under the same reaction condition can afford triazole-
selenoesters 6a and 6b in 50% and 34% yields (Scheme 2). Far
as we knew, this also could be the first example for synthesizing
a selenoester starting from an aromatic heterocycle.
Scheme 4. Further transformations. Abbreviations: CuTc = copper(I)
thiophene-2-carboxylate; TFP = tri(2-furyl)phosphine.
A plausible mechanism is proposed in Scheme 5. Aubꢀ’s
group has demonstrated the combination of AcCl with HFIP could
generate the HCl in situ. We also found that direct using HCl in
dioxane or EtOAc could achieve this transformation, although the
desired product was observed in low yields (Table 1, entries 12
and 13). So, as a superior acidic species, HCl could induce the
dehydroxylation of furylcarbinols in our 3-CR. A formal [3+2]
cycloaddition occurs between the resulting oxocarbenium I and
the azides. The aromatization of triazole and the subsequently
ring-opening of furan deliver the delocalized enolate cation III. The
critical step is the trapping of this intermediate by thiols, and
stereospecifically yield the desired (Z)-β-triazole-thioacrylates.
Further studies are underway to help elucidate the mechanism of
this cascade transformation.
Scheme 2. Selenol ester synthesis via 3-CR
Usually, aryl thioester is an active acyl radical precursor
under a UV irradiation. [31] A brief investigation into the olefin-
isomerization of , -unsaturated thiophenolesters indicated that
a UV light source (50W LED, 385−395 nm) could lead a
remarkable transformation from Z to E configuration (Scheme 3).
[28c] The latter is thermodynamically more favored. Importantly, the
aryl thioester group is undisrupted in this single-step conversion.
Scheme 3. Photoisomerization of thiol ester
Next, we examined the derivatization of the triazole-
thioester, as summarized in Scheme 4. A Stille coupling of 4y with
tri(n-butyl)vinylstannane under the Liebeskind conditions afforded
[6f]
dienone 8.
A Sonogashira type coupling of 4y with
phenylacetylene delivered ynone 9 in 64% yield. [5a] Interestingly,
the cis double-bonds were converted into trans simultaneously by
the conditions of overnight at room temperature. Perhaps the
highly conjugated system could facilitate the isomerization of
olefin. By comparison, the organolithium or Grignard reagents
Scheme 5. Proposed reaction mechanism
could be utilized to convert cis-enamidyl triazoles into cis-ketones
[28b]
in our previous studies.
So, these Pd-catalysed
In summary, we have developed a mild and efficient
thioesterification of 5-bromo-2-furylcarbinols, promoting by a
latent Brønsted acid condition of low-cost AcCl in HFIP. This
cascade reaction is sturdy with a broad diversity of thiols and
azides, that could synthesize a variety of complex thioesters with
a triazole moiety and connected by a (Z)-olefin. The synthetic
versatility of the resulting products due to the unique reactivity of
the thioester group are additional benefits of our methodology.
Work on further applications and its mechanism studies is
currently underway in our laboratory.
transformations could be the complementary derivatization
methods for the furan-based triazole synthesis. Reduction of 4y
[5a]
under the Fukuyama conditions (Et3SiH, 10% Pd/C)
gave
aldehyde 10 in 71% yield, that the double-bond can be
hydrogenated as well. These conversions also further proved that
oxidation−addition of Pd complexes with thioester is effortless and
triazole under Pd(0) conditions is compatible. The structure of 4y
and 7c were determined by single crystal X-ray diffraction
analysis (CCDC no. 1955457 and 1955458). The configuration of
olefins for the other products was assigned by analogy to 4y and
7c, and also with 1H NMR.
Experimental Section
Typical Procedure for Three-Component Reaction.
To a solution of azide 3 (0.7 mmol) in HFIP (1 mL) was added acetyl
chloride (0.5 mmol) at -20 °C in an open flask. Thiol 1 (0.35 mmol) and a
solution of 2 (0.5 mmol) in DCM (0.2 mL) were subsequently added into
4
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10.1002/ejoc.202000299
European Journal of Organic Chemistry
COMMUNICATION
the mixture. The resulting solution was stirred for 1.5 hours at -20 °C and
then quenched with saturated NaHCO3 (5 mL). The mixture was extracted
with DCM (3 × 10 mL). The combined organic layers were washed with
brine (5 mL) and dried over Na2SO4. The solution was concentrated by
rotary evaporator under reduced pressure gave a residue, which was
purified by using flash column chromatography with petroleum ether/ethyl
acetate as eluent to afford the product 4.
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Acknowledgements
This research was financially supported by National Natural
Science Foundation of China (21772117), Natural Science Basic
Research Plan in Shaanxi Province of China (2018JM2050), and
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology. We are also grateful to Ms. Xin-Ai Guo and Mr. Min-
Zhen Wang for NMR analysis, Dr. Hua-Min Sun for X-ray
crystallographic analysis of compound 4y and 7c, and Ms. Juan
Fan for mass spectrometric analysis (Shaanxi Normal University).
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Keywords: thioester • furan • dearomatization • triazole • multi-
component reactions
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Key Topic: Furan Chemistry
Furfuryl Cation Induced Three-Component Reaction to Synthesize Triazole-Substituted
Thioesters
A metal-free three-component thioesterification between thiols, 5-bromo-2-furylcarbinols and azides that provides rapid access to
thioesters bearing a triazole moiety, highlighted by the cascade [3+2] cycloaddition/furan ring-opening/thioesterification, is disclosed.
The selenols are also suitable for this reaction. The new reaction features simple reaction conditions of AcCl/HFIP and a general
substrate scope.
7
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