Synthesis of Enynic and Allenic Orthoesters via Defluoromethoxylation of 2-Trifluoromethyl-1,3-enynes

Article abstract of DOI:10.1021/acs.orglett.1c00311

In this protocol, the chemoselective defluoromethoxylation reactions of 2-trifluoromethyl-1,3-enynes were developed. The enynic and allenic orthoesters were selectively produced in good to excellent yields via multiple substitution processes under mild reaction conditions, respectively. The enynic orthoester products were proved capable of acting as efficient "platform molecules"to access various functionalized allenyl compounds.

Full text of DOI:10.1021/acs.orglett.1c00311

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Letter
Synthesis of Enynic and Allenic Orthoesters via
Defluoromethoxylation of 2‑Trifluoromethyl-1,3-enynes
Dong-Ting Dai, Jian-Lin Xu, Zhi-Yuan Chen, Zi-Lu Wang, and Yun-He Xu*
Cite This: Org. Lett. 2021, 23, 1898−1903
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ABSTRACT: In this protocol, the chemoselective defluoromethox-
ylation reactions of 2-trifluoromethyl-1,3-enynes were developed. The
enynic and allenic orthoesters were selectively produced in good to
excellent yields via multiple substitution processes under mild reaction
conditions, respectively. The enynic orthoester products were proved
capable of acting as efficient “platform molecules” to access various
functionalized allenyl compounds.
rthoester skeletons have been widely found in many
natural products such as dahuribirins, resiniferatoxins,
a double bond containing the CF3 group reacts with a
nucleophile, the fluorine atom of the allyl group may leave as
the leaving group. When the trifluoromethylalkenes are
subjected to nucleophilic attack at the γ-position carbon
atom with respect to the fluorine substituent, the formation of
1,1-difluoro-1-alkenes (SN2′-type reaction) can be accessed
(Scheme 1a). On the contrary, the nucleophilic substitution
can happen in the 1,1-difluoro-1-alkenes at the vinylic CF2
carbon atom (Scheme 1b),10 which will provide the mono-
fluoro-substituted alkenes through an addition−elimination
process (SNV reaction). Therefore, combined with these two
defluorination pathways,11 the 2-trifluoromethyl-1,3-enynes
O
trigocherrins, and medicinal compounds like tetrodotoxin,
orthosomycines, and so on.1 Recently, the application of
orthoesters in material science and supramolecular chemistry
has also attracted considerable attention from chemists.2
Importantly, because of their highly reactive properties, they
have been extensively applied as acylating agents,3 coupling
partners,4 and protecting groups in organic synthesis.5
Therefore, many efforts have been made to discover practical
and efficient methodologies to access functionalized orthoest-
ers. Unfortunately, the need for specific starting materials and
harsh reaction conditions in the traditional methods still largely
restricts the compatibility of different functional groups in the
reactions and the types of products.6 For example, in the
literature previously reported on the synthesis of orthoesters by
imidates, the preparation of imidates requires the reaction of a
cyanide group in the action of hydrogen chloride gas and
methanol, and the conditions are still relatively harsh.6e
Recently, few to no examples of the electrosynthesis of
orthoesters have emerged as efficient alternatives, as they
allowed more general and easily available compounds to be
used as starting materials.7 However, to date, all cases reported
are limited to only the synthesis of relatively simple aliphatic
and aryl-substituted orthoesters. To enlarge the substrate scope
and the skeleton diversity of orthoesters, the development of
new and reliable methods to install different functionalities in
the molecules is highly desirable. It is well known that both the
enynic and the allenic fragments are very important building
blocks in organic synthesis due to their flexible transformation
abilities.8 It is worth noting that so far, the preparation of
functionalized enynic and allenic orthoesters has remained
challenging, possibly due to the lack of compatible starting
materials and the potential instability of products according to
the traditionally synthetic methods.9 Trifluoromethylvinyl
compounds are well known as highly reactive species. When
Scheme 1. Defluorinative Substitution via the SN2′ or SNV
Process
Received: January 27, 2021
Published: February 24, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00311
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1898−1903
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a
Table 1. Optimization of Reaction Conditions
b
c
b
b
entry
CH3OM (x equiv)
solvent
T (°C)
time (h)
2a (%) (Z/E)
3a (%)
4a (%)
1
2
3
4
5
6
7
8
CH3OK (2.5)
CH3OK (2.5)
CH3OK (2.5)
CH3OK (2.5)
CH3OK (2.5)
CH3OK (2.5)
CH3OK (3.0)
CH3OK (3.5)
CH3OK (4.0)
CH3OK (4.0)
CH3OK (4.0)
CH3OLi (4.0)
CH3ONa (4.0)
CH3OK (5.5)
CH3OK (5.5)
CH3OK (6.5)
CH3OK (7.0)
CH3OLi (7.0)
CH3ONa (7.0)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
CH3OK (7.5)
1,2-dimethoxyethane
methyl formate
methyl formate
chlorobenzene
benzotrifluoride
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
tetrahydrofuran
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methyl formate
methanol
70
0
22
22
22
22
22
22
18
18
18
18
18
18
18
18
22
22
22
22
22
22
22
22
22
22
22
22
22
22
53 (58/42)
93 (57/43)
88 (57/43)
0
trace
35 (58/42)
29 (60/40)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
11
6
8
0
25
6
2
0
2
0
70
70
70
70
70
70
70
50
30
30
30
30
30
30
30
30
30
25
30
40
50
60
30
30
30
30
7
trace
11
0
0
0
0
0
0
0
39
40
62
0
8
88
99
99
98
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0
96
trace
trace
22
0
0
0
13
17
53
60
65
3
32
38
0
57
59
45
37
34
51
5
0
chlorobenzene
benzotrifluoride
1,2-dichloroethane
trace
trace
0
4
0
a
Unless noted otherwise, the reaction was conducted according to the following conditions: 1 (0.2 mmol) and CH3OK in anhydrous solvent (1.0
b
1
mL) were stirred for the indicated time at the indicated temperature (oil bath) under an argon atmosphere. Yield was determined by H NMR
using mesitylene as the internal standard. Z/E ratio was determined by H NMR of the crude product.
c
1
were chosen to react with the potassium methoxide. The
enynic and allenyl orthoesters are hypothesized to form via
multiple SN2′ and SNV substitution processes, respectively. It
was found that the solvents and the amount of potassium
methoxide used in reaction are crucial for selectively forming
the different orthoester products (Scheme 1).
in excellent yield, but the influence of temperature was not
noticeable (Table 1, entries 7−11) (determined by 1H NMR).
When the loading of CH3OK was further increased to 7 equiv
and the solvent was changed to methyl formate, a higher yield
of allenic orthoester 4a was obtained (entry 17). Methyl
formate was used as a solvent because it was decomposed into
CH3OH and CO under the action of CH3OK, and CH3OH
acted as a proton source to participate in the reaction;14
however, when we tried to promote the conversion of 1a to 4a
product via tuning the temperatures, the solvents, and CH3OM
(M = Li, Na), no better result was observed. (Table 1, entries
18−28).
The study was initiated by investigating the methoxylation of
2-trifluoromethyl-1,3-enyne 1a with CH3OK in dimethoxy-
ethane (DME) at 70 °C under an argon atmosphere (Table 1,
entry 1). It was found that the major product 2a (Z/E
configuration was determined by measuring the nuclear
Overhauser effect (NOE) of compound 2b; 2b and 2a have
the same structure, and the only difference is that the methyl
group on the para-benzene ring) was generated via SN2′ and
SNV processes along with the formation of a trace amount of
Next, with the optimal conditions for the synthesis of enynic
orthoester 3a in hand, the substrate scope of 2-trifluoromethyl-
1,3-enynes was investigated (Figure 1). First, different aryl-
substituted 2-trifluoromethyl-1,3-enynes were subjected to this
reaction. The substrates bearing electron-donating or electron-
withdrawing groups on the phenyl ring were well tolerated to
give the corresponding products in good to excellent yields. It
is worth noting that halides and free amine were also
compatible to afford the desired product in moderate to
excellent yields, which permitted the products to be further
functionalized in the next step. Moreover, the naphthyl-
substituted enyne was also smoothly converted to the enynic
orthoester 3p. Finally, when heteroaryls, such as thienyl- and
1
orthoester products 3a and 4a (determined by H NMR).
Triggered by this result, a variety of solvents, temperatures, and
reaction times were carefully examined. It was found that up to
a 93% yield of 2a was obtained when methyl formate was used
as the solvent at 0 °C (Table 1, entry 2). Furthermore, to
improve the yields of orthoester products, other solvents and
CH3OM (M = Li, Na) were also tested in the reaction.
Unfortunately, no obvious effect was observed for improving
the yields. Surprisingly, when the amount of CH3OK used in
the reaction was increased to 4 equiv, product 3a was formed
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Figure 2. Substrate scope for the synthesis of allenic orthoester 4.
Unless noted otherwise, the reaction was conducted according to the
following conditions: 1 (0.2 mmol) and CH3OK in anhydrous methyl
formate (1.0 mL) were stirred at 30 °C (oil bath) for 22 h under an
argon atmosphere. Isolated yield.
Figure 1. Substrate scope for the synthesis of enynic orthoester 3.
Unless noted otherwise, the reaction was conducted according to the
following conditions: The 2-trifluoromethyl-1,3-enyne 1 (0.2 mmol)
and CH3OK in anhydrous tetrahydrofuran (THF) (1.0 mL) were
stirred at 30 °C (oil bath) for 18 h under an argon atmosphere.
Isolated yield.
Scheme 2. Transformation of Enynic Orthoester 3a to
Different Functionalized Allenes
quinolinyl-substituted 1,3-enynes, were applied as the sub-
strates, the corresponding products 3q and 3r were obtained in
88 and 75% yields, respectively. We tried various ROKs (R =
i
t
Et, Pr, Bu), but gem-dialkoxy enynes 11−13 were produced
instead of product 3 (Supporting Information).
After that, the scope of allenic orthoesters 4 was also
examined. Similarly, the substrates bearing different functional
groups on the phenyl ring such as methoxyl, fluoro,
trifluoromethyl, chloro, cyano, and so on were all well
tolerated and converted to the corresponding allenic
orthoesters in satisfactory yields under the optimized
conditions (Figure 2). It should be noted that the thienyl-
substituted 1,3-enyne was also converted to compound 4l in
i
56% isolated yield. In addition, different ROKs (R = Et, Pr,
tBu) were tried as nucleophiles. However, the corresponding
products were not formed because of transesterification.
To further demonstrate the utility of the orthoesters, the
synthetic applications of product 3a were investigated. First,
the gram-scale synthesis of 3a was realized under the standard
reaction conditions. Next, the cyanation of orthoester 3a with
cyanoamine and SiCl3OTf furnished the corresponding
cyanoacetal 5 in high yield (Scheme 2, (2)).12 Enynic esters
are known as one kind of active and useful enyne in organic
synthesis. However, aryl-substituted enynic esters were not
stable enough for isolation. Therefore, a common method to
use this kind of active compound is preparing its dilute
solutions.13 Herein the enynic ester (3a) can easily be handled
with concentrated HCl to provide the enynic ester product in
high yield. Therefore, the aryl-substituted enynic esters
obtained here can be used as good candidate precursors of
the enynic esters. Furthermore, when 3a was treated with
dimethyl malonate in dimethylformamide (DMF), the
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corresponding allenic orthoester product 7 was formed in 99%
yield (Scheme 2, (4)). Similarly, when the nucleophile was
changed to methyl 2-(diethoxyphosphoryl)acetate, the corre-
sponding byproduct could be generated and further converted
to functionalized allenic ester 8 in 94% yield in the presence of
concentrated HCl (aq). Finally, the enynic ester (3a) reacted
with p-toluenesulfamide under basic conditions to furnish 9 in
49% yield. The above examples show that the enynic
orthoester is a very flexible building block to construct various
functionalized allenes.
To disclose the possible mechanisms from the 2-
trifluoromethyl-1,3-enyne to the enynic and allenic orthoesters,
the controlled experiments were carried out, and the results are
shown in Scheme 3. Mono-fluoro-substituted enyne 2a
conditions. Similarly, from the gem-dimethoxy enyne 10, the
enynic orthoester 3a (Scheme 3A) was smoothly formed under
the standard reaction conditions (Table 1, entry 11). From the
enynic orthoester 3a, the allenic orthoester 4a (Scheme 3A)
was also obtained in 29% yield under the developed reaction
conditions (Table 1, entry 17). To better validate the
conclusion, some additional control experiments were
administered. First, under the standard reaction conditions
(Table 1, entry 11), a 92% yield of enynic orthoester 3a
(Scheme 3B, eq 1) was achieved from mono-fluoro-substituted
enyne 2a, and a 59% yield of 14 (Scheme 3B, eq 3) could be
formed by changing MeOK to EtOK. In addition, mono-
fluoro-substituted enyne 2a could convert to allenic orthoester
4a (Scheme 3B, eq 2) in 58% yield under the developed
reaction conditions (Table 1, entry 17). We found that a 50%
yield of allenic orthoester 4a (Scheme 3B, eq 4) could be
achieved from gem-dimethoxy enyne 10 under the developed
reaction conditions.
Scheme 3. Mechanistic Study of the 2-Trifluoromethyl-1,3-
a
enyne to Form the Enynic and Allenyl Orthoesters
In summary, we have developed selective and diverse
defluoromethoxylation reactions of trifluoromethyl-substituted
1,3-enynes. Under mild reaction conditions, the enynic and
allenyl orthoesters were obtained in good to excellent yields. In
addition, the transformations of enynic orthoesters were also
studied, which proved this class of compounds to be efficient
and flexible “platform molecules” for the synthesis of various
functionalized allenes.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00311.
Experimental details, characterization data, and spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Yun-He Xu − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, P. R. China;
orcid.org/0000-0001-8817-0626; Email: xyh0709@
ustc.edu.cn
Authors
Dong-Ting Dai − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Jian-Lin Xu − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, P. R. China
Zhi-Yuan Chen − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Zi-Lu Wang − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, P. R. China
a
Unless noted otherwise, the reaction was conducted according to the
following conditions: 1 (0.2 mmol) and CH3OK in anhydrous solvent
(1.0 mL) were stirred for the indicated time at the indicated
temperature under an argon atmosphere. Isolated yield. Yield was
determined by H NMR using mesitylene as the internal standard.
b
c
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00311
1
Notes
(Scheme 3A) was formed in 87% yield via the treatment of
1a with 2.5 equiv of CH3OK in methyl formate at 0 °C. On the
contrary, the defluoromethoxylation product gem-dimethoxy
enyne 10 (Scheme 3A) was obtained in excellent yield using
7.5 equiv of CH3OK in 1,2-dichloroethane (DCE) at −10 °C
from compound 1. The controlled experiment proved that 10
(Scheme 3A) could also be generated from the mono-fluoro-
substituted enyne compound 2a under the same reaction
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding support of the National
Natural Science Foundation of China (21871240, 21672198)
and the Fundamental Research Funds for the Central
Universities (WK2060000017).
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2,9,10-trioxatricyclo[4.3.1.03,8]decanes. Tetrahedron 2004, 60, 5077−
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