Catalytic Asymmetric Conjugate Protosilylation and Protoborylation of 2-Trifluoromethyl Enynes for Synthesis of Functionalized Allenes

Article abstract of DOI:10.1021/acs.orglett.9b04647

The Cu-catalyzed 1,4-protosilylation and protoborylation of trifluoromethyl-substituted conjugated enynes were developed to access functionalized homoallenylsilanes and homoallenylboronates. This protocol also provides a general method to synthesize optic

Full text of DOI:10.1021/acs.orglett.9b04647

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Letter
Catalytic Asymmetric Conjugate Protosilylation and Protoborylation
of 2‑Trifluoromethyl Enynes for Synthesis of Functionalized Allenes
Chao Yang, Zheng-Li Liu, Dong-Ting Dai, Qi Li, Wei-Wei Ma, Meng Zhao, and Yun-He Xu*
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ABSTRACT: The Cu-catalyzed 1,4-protosilylation and protoborylation of trifluoromethyl-substituted conjugated enynes were
developed to access functionalized homoallenylsilanes and homoallenylboronates. This protocol also provides a general method to
synthesize optically active homoallenylsilanes and homoallenylboronates in moderate to excellent yields with high enantiomeric
excess by using new designed chiral bisoxazoline ligands. Simultaneously, the transformations of homoallenylsilanes and
homoallenylboronates were also explored to synthesize useful building blocks.
o date, various organoboron1 and organosilane2 reagents
four-carbon synthons in organic synthesis. Early in 1994,
Tsuch as aryl, vinyl, allenyl or propargyl, and allyl Suzuki and co-workers developed pioneering work related to
the copper-mediated coupling reaction between propargylic
electrophiles and Knochel’s (dialkoxyboryl)-methylzinc iodide
to synthesize homoallenylboronates but afforded product in
low to moderate yields.3 The synthetic value of the
homoallenylboronates was featured by their addition to the
carbonyl compounds for the synthesis of useful 1,3-dienyl
allylic alcohols.4 On the other hand, Brown and co-workers
reported an alternative method to prepare the homoallenyl-
boronates via one-carbon homologation of allenylboronates.5
Meanwhile, an approach of copper-catalyzed coupling reaction
of gem-borazirconocene alkanes with propargyl bromide to give
monosubstituted homoallenylboronate was explored by
Srebnik et al.6 In 2008, Moberg explored a Pt-catalyzed
coupling reaction between silylboronate and large group
substituted conjugated enynes to form silyl-substituted
homoallenylboronate derivatives.7 Except these examples,
only sporadic cases on the derivation of homoallenylboronates
were revealed.8 Similarly, only rare examples on the synthesis
of enantioenriched homoallenylsilanes have been reported,
Scheme 1. Strategies for the Synthesis of
Homoallenylsilanes and Homoallenylboronates
Received: December 28, 2019
compounds have been well documented for their versatile
transformations. In stark contrast, less attention has been
focused toward the study of homoallenylborons and
homoallenylsilanes despite their highly potential worth as
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A

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Scheme 2. Substrate Scope of Copper-Catalyzed Racemic
1,4-Protosilylation of CF3-Substituted Conjugated Enyne
Scheme 3. Substrate Scope of Copper-Catalyzed Racemic
1,4-Protoborylation of CF3-Substituted Conjugated
Enyne
a b
,
a b c
, ,
a
The reactions were run under the following reaction conditions: the
mixture of enyne 1 (0.2 mmol), 2a (0.3 mmol), CuBr (10 mol %),
and Et3N (10 mol %) was stirred in anhydrous EtOH (1 mL) at rt
b
c
under an argon atmosphere. Isolated yield. The loading of Et3N was
30 mol %, and the reaction time was 16 h. The loading of Et3N was
a
d
The reactions were run under the following reaction conditions: the
mixture of enyne 1 (0.2 mmol), 2b (0.3 mmol), CuBr (5 mol %), and
Et3N (10 mol %) was stirred in THF/H2O (2:1, 1 mL) at rt under an
30 mol %, and the reaction time was 17 h.
b
argon atmosphere for 6 h. The ratio of 4 and 5 was determined by
c
d
1H NMR analysis. Isolated yield. The loading of CuBr was 10 mol
e
f
which greatly restricted their utility as chiral reagents.9 In 2002,
Hiemstra and co-workers used the commercially available
enantiopure (S)-but-3-yn-2-ol as the starting material and
prepared an optically active allene trimethyl(penta-2,3-dien-1-
yl)silane to investigate the chirality transformation in an SE′
reaction.9b Subsequently, the first asymmetric synthesis of
enantioenriched homoallenylsilane products using a palladium
catalyst was reported by the Ogasawara and Hayashi group.9c
To the best of our knowledge, there is no method available to
synthesize the enantioenriched axially chiral trisubstituted
homoallenylsilanes. Despite these advances, the harsh reaction
conditions, the narrow substrate scope, and the lack of
diversity in application still spur us to discover practical and
sustainable methods to prepare the functionalized homoalle-
nylsilanes and homoallenylboronates and explore their new
utilization in organic transformation. More importantly,
regarding significance as privileged structural motifs in
medicinal chemistry as well as agrochemistry and functional
materials, CF3-substituted functional allenes are largely
ignored.10
%. The reaction time was 24 h. The solvents were the mixture of 1,4-
dioxane and H2O (2:1, 1 mL).
nylboronate can be used for the synthesis of chiral 1,3-dienyl
allylic alcohols with high stereofidelity.4
First, the 2-trifluoromethyl-1,3-enyne 1a and silylboronate
2a were chosen as model substrates to optimize the reaction
conditions (see the details in the Supporting Information
(SI)),13,14 and the optimized reaction conditions were
established as follows: in the presence of 10 mol % CuBr as
catalyst and 10 mol % Et3N as additive, the mixture of 1a and
2a in 1.0 mL of EtOH was stirred at room temperature for 12
h under an argon atmosphere. Then, various 2-trifluoromethyl-
1,3-enynes were subjected to this reaction (Scheme 2). It was
found that all the 2-trifluoromethyl-1,3-enynes could afford the
desired products in good to excellent yields (Scheme 2, 3a−
3m). Moreover, the aliphatic substituted enynes with different
functionalities were also compatible to give the desired
products (Scheme 2, 3n−3u).
Considering the fickle reactivity and wide usefulness of
organoboron reagents, bis(pinacolato)diboron 2b instead of 2a
was tested under modified optimized reaction conditions as
follows: in the presence of 5 mol % CuBr as the catalyst and 10
mol % Et3N as the additive, the mixture of 1a and 2b in 1.0 mL
of THF/H2O (2:1) solution was stirred at room temperature
for 6 h under an argon atmosphere (see the details in the SI).
Herein, we would like to communicate the copper-catalyzed
regioselective and enantioselective 1,4-protosilylation and
protoborylation reactions of 2-trifluoromethyl-1,3-enynes
with silylboronate or bis(pinacolato)diboron to generate the
homoallenylsilanes and homoallenylboronates, respectively
(Scheme 1).10f,j,11,12 In addition, enantioenriched homoalle-
B
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Table 1. Optimization of Reaction Conditions for Copper-
Catalyzed Asymmetric 1,4-Protosilylation of CF3-
Substituted Conjugated Enyne 1a
Scheme 4. Substrate Scope of Copper-Catalyzed
Asymmetric 1,4-Protosilylation of CF3-Substituted
Conjugated Enyne
a
a b
,
a
The reactions were run under the following reaction conditions: the
mixture of enyne 1 (0.2 mmol), 2a (0.3 mmol), Cu(eacac)2 (5 mol
%), L6 (6 mol %), and 4 Å molecular sieves (0.0125 g) in anhydrous
EtOH (1.0 mL) was stirred at −10 °C under argon for the
a
The reactions were run under the following reaction conditions: the
b
c
mixture of enyne 1a (0.2 mmol), 2a (0.3 mmol), Cu(eacac)2, L*, and
4 Å molecular sieves in anhydrous EtOH (1.0 mL) was stirred under
an argon atmosphere for the indicated time at the indicated
temperature. Isolated yield. The values of ee were determined by
HPLC. Cu(eacac)2 = copper ethylacetoacetate.
corresponding time. Isolated yield. 30 mol % Anhydrous Et3N was
added.
b
c
d
bidentate P−N ligands,16 bisoxazolines,13l pyridine-oxazo-
lines,17 etc. Fortunately, the use of 10 mol % CuBr catalyst
and 12 mol % bisoxazoline ligand L1 could afford the desired
product 3a′ in 46% yield and with 52% ee value in ethanol
solution at room temperature (Table 1, entry 1). Therefore,
different substituted bisoxazolines were tested for this reaction
(Table 1, entries 2−6). It was found that the ligand with an
isobutyl-substituent on the oxazoline ring afforded a better
result. Moreover, increasing the steric hindrance of the R1
group of the bisoxazoline ligand could improve the product’s
enantioselectivity significantly. Especially, in the presence of
ligand L6 with a 4-tert-butyl substituent on the phenyl ring, the
desired product was obtained in 62% yield and with 81% ee
(Table 1, entry 6). Moreover, the introduction of 4 Å MS to
the solution could improve the product’s yield up to 90% and
with the same ee value (Table 1, entry 7). After careful
screening of various copper catalysts and temperature, finally
the desired product 3a′ could be obtained in 93% yield and
with 90% ee in the presence of 5 mol % Cu(eacac)2
(Copper(II)-ethylacetoacetate) as th ecatalyst and 6 mol %
chiral bisoxazoline L6 as the ligand in anhydrous EtOH
solution at −10 °C (Table 1, entries 8−12).
As described in Scheme 3, the 1,4-protoborylation of
conjugated enynes toward homoallenylboronates gave yields
ranging from moderate to excellent along with the formation of
trace 1,2-protoborylation products, depending on the substrate
structure and electronic properties of its substituents. Most
aryl-substituted substrates could afford the desired homo-
allenylboronate product in moderate to high yield. Nonethe-
less, the substrate bearing 4-methoxyphenyl delivered
homoallenylboronate 4c and homopropargylboronate 5c in
81% total yield but with poor regioselectivity (66/34). This
could be attributed to the strong electron-donating effect of
the methoxy group. Similarly, only moderate ratios between
the homoallenylboronate 4 and homopropargylboronate 5
were observed when alkyl-substituted enynes were applied (4r
and 4s). Notably, the homoallenylboronate products could be
obtained in high yields when electron-withdrawing groups
were present on a distal position at the aliphatic chain (4t−
4w). Unfortunately, when the cyclohexyl substituted enyne was
applied in this reaction, only 3% desired product and 9%
homopropargylboronate were observed along with recovering
1
about 83% starting material judged from the crude H NMR
under the optimized reaction conditions.
Therefore, some typical CF3-substituted conjugated enynes
were subjected for the synthesis of enantioenriched homo-
allenylsilanes. In mostbut not allinstances, the 2-
trifluoromethyl-1,3-enynes afforded the desired homoallenylsi-
lanes in good to excellent yield and with up to 97% ee value
(Scheme 4, 3b′−3e′, 3j′−3t′). The long carbon chain and the
ones bearing other functionalities such as hydroxyl, ester,
chloro, and ether were also compatible to yield the desired
products, respectively. The absolute configuration of the
Considering the importance of enantioenriched allenyl
compounds for the synthesis of chiral natural products and
biologically active molecules,15 we embarked on investigating
the catalytic synthesis of optically active trifluoromethyl-
substituted homoallenylsilanes (Table 1). According to the
previous reports on copper-catalyzed asymmetric silyl-addition
reactions, we first screened various chiral ligands such as chiral
C
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Table 2. Optimization of Reaction Conditions for Copper-
Catalyzed Asymmetric 1,4-Protoborylation of CF3-
Substituted Conjugated Enyne 1a
Scheme 5. Substrate Scope of Copper-Catalyzed
Asymmetric 1,4-Protoborylation of CF3-Substituted
Conjugated Enyne
a
a b c
, ,
a
Reaction conditions: a mixture of enyne 1 (0.2 mmol), 2a (0.3
mmol), CuBr (5 mol %), L22 (6 mol %), and 4 Å molecular sieves
(0.0125 g) was stirred in hexane/methanol (1:2, 1 mL) at −10 °C
b
1
under argon for 24 h. The ratio of 4′ and 5 was determined by H
c
d
e
NMR analysis. Isolated yield. The reaction time was 25 h. The
values of ee were determined by a two-step derivation (see the details
in the SI).
for further screening (Table 2, entries 1−8). It was observed
that the enantiomer ratio of desired product could be
improved by increasing the steric effect of the substituents
on the chiral indeno-bisoxazolines ligands (entries 8, 9, 14, and
16). On the basis of these results, by replacing the substituent
with the more bulky tosyl protected piperidinyl group (L22),
the enantiomeric excess of product 4a′ was improved to 89%.
Finally, tuning the mixed solvents to hexane and methanol
could afford the homoallenylboronate 4a′ in 97% isolated yield
and 92% ee.
a
Unless noted otherwise, the reactions were run under the following
reaction conditions: the mixture of enyne 1a (0.2 mmol), 2a (0.3
mmol), Cu(I), L*, and 4 Å molecular sieves was stirred in the
indicated solvent (1 mL) under an argon atmosphere at the indicated
Subsequently, other CF3-substituted conjugated enynes were
evaluated (Scheme 5). The aryl-substituted enynes could all
afford the desired products in high to excellent yields and with
high enantiomeric excess. The absolute configuration of the
homoallenylboronate product 4l′ was determined to be (S) by
single-crystal X-ray diffraction analysis (CCDC No. 1960811).
Furthermore, the alkyl-substituted enyne such as 1u also
exhibited good reactivity, and the desired product 4u′ was
b
temperature for 24 h. Determined by 1H NMR analysis using
c
mesitylene as the internal standard. The values of ee were
d
determined by HPLC. Isolated yield, 4a′:5a > 99:1 (determined
1
by H NMR analysis).
homoallenylsilane product 3b′ was determined to be (R) by
single-crystal X-ray diffraction analysis of the recrystallized one
(>99% ee, CCDC No. 1877293).
Subsequently, we investigated the asymmetric 1,4-proto-
borylation of CF3-substituted conjugated enyne 1a with
bis(pinacolato)diboron 2b at the above-established reaction
conditions, the desired product was obtained in 87% NMR
yield but with moderate regioselectivity (4a′:5a′ = 79:21) and
4a′ with 77% ee. Next, different chiral ligands were evaluated
1
isolated in 82% yield (4u′:5u = 85:15, determined by H
NMR) and with up to 95% ee. On the other hand, an aromatic
enyne bearing an ortho-Cl showed slightly decreased
regioselectivity, likely due to the unfavorable steric hindrance.
To show the synthetic utility, gram-scale synthesis of
enantioenriched homoallenylsilane 3b′ and homoallenylboro-
nate 4a′ was initiated and found to proceed smoothly (Scheme
6A). When the compound 3a reacted with bis(pinacolato)-
D
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Scheme 6. Gram-Scale Synthesis and Derivatization of
Homoallenylsilanes and Homoallenylboronates
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04647.
Experimental procedures, characterization data (PDF)
Accession Codes
CCDC 1877293 and 1960811 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Yun-He Xu − Hefei National Laboratory for Physical Sciences at
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, China; State Key
Laboratory and Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, China; orcid.org/
0000-0001-8817-0626; Email: xyh0709@ustc.edu.cn
Authors
Chao Yang − Hefei National Laboratory for Physical Sciences at
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, China
Zheng-Li Liu − Hefei National Laboratory for Physical Sciences
at Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China
Dong-Ting Dai − Hefei National Laboratory for Physical
Sciences at Microscale and Department of Chemistry, University
of Science and Technology of China, Hefei 230026, China
Qi Li − Hefei National Laboratory for Physical Sciences at
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, China
Wei-Wei Ma − Hefei National Laboratory for Physical Sciences
at Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China
Meng Zhao − Hefei National Laboratory for Physical Sciences at
Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, China
diboron catalyzed by CuCl in the 2,2,2-trifluoroethanol
solution, a regioselective protoboronation product (E)-6 was
formed in 68% yield. When the solvent was changed to
methanol, a difluorosubstituted diene product (E)-7 was
obtained in good yield (72%) via tandem addition/
defluorination processes (Scheme 6B).18 Additionally, the
reaction of homoallenylboronates with benzaldehyde could
proceed with high fidelity of enantiotransfer to afford the
useful enantioenriched dienyl alcohols 8a and 8u (Scheme
6C). The oxidative derivatization of 4a′ afforded the
corresponding chiral homoallenol 9a in excellent yield and
with high enantiopurity.6a,8g,19 Subsequent conversion of axial
homoallenol 9a to central chiral product 2,5-dihydrofuran 11a
was achieved in 95% yield (based on 9a) and with 86% ee via
5-endo-trig cyclization (Scheme 6C).20
In summary, we have developed the regio- and enantiose-
lective copper-catalyzed 1,4-protosilylation and protoboryla-
tion of CF3-substituted conjugated enynes. This work provides
a practical and efficient method to prepare functionalized
enantioenriched homoallenylsilanes and homoallenyboronates.
Moreover, studies on application of homoallenylsilanes and
homoallenylboronates were also demonstrated. The axial-to-
central chirality transfer in the reactions of homoallenylboro-
nates with aldehydes and homoallenol to 2,5-dihydrofuran
could proceed with high fidelity. Further studies on the utility
of homoallenylsilanes and homoallenylboronates in organic
transformation are being pursued in our laboratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04647
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding support of the National
Natural Science Foundation of China (21871240, 21672198),
the State Key Program of National Natural Science Foundation
of China (21432009), the Fundamental Research Funds for
the Central Universities (WK2060190082), and the State Key
Laboratory of Elemento-organic Chemistry Nankai University
(201620).
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