Design and Synthesis of TY-Phos and Application in Palladium-Catalyzed Enantioselective Fluoroarylation of gem-Difluoroalkenes

Article abstract of DOI:10.1002/anie.202008262

The first example of highly enantioselective fluoroarylation of gem-difluoroalkenes with aryl halides is presented by using a new chiral sulfinamide phosphine (Sadphos) type ligand TY-Phos. N-Me-TY-Phos can be easily synthesized on a gram scale from readily available starting materials in three steps. Salient features of this work including readily available starting materials, good yields, high enantioselectivities as well as broad substrate scope make this approach very practical and attractive. Notably, the asymmetric synthesis of an analogue of a biologically active molecule is also reported.

Full text of DOI:10.1002/anie.202008262

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Accepted Article
Title: Design, Synthesis of TY-Phos and Application in Palladium-
Catalyzed Enantioselective Fluoroarylation of gem-
Difluoroalkenes
Authors: Junliang Zhang, Tao-Yan Lin, Zhangjin Pan, Youshao Tu,
Shuai Zhu, Hai-Hong Wu, Yu Liu, and Zhimin Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008262
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10.1002/anie.202008262
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Design, Synthesis of TY-Phos and Application in Palladium-
Catalyzed Enantioselective Fluoroarylation of gem-
Difluoroalkenes
Tao-Yan Lin, Zhangjin Pan, Youshao Tu, Shuai Zhu, Hai-Hong Wu, Yu Liu, Zhiming Li,* and Junliang
Zhang*
Dedicated to 70th anniversary of Shanghai Institute of Organic Chemistry, CAS
Abstract: The first example of highly enantioselective fluoroarylation
of gem-difluoroalkenes with aryl halides is presented by using a new
chiral sulfinamide phosphine (Sadphos) type ligand TY-Phos. N-Me-
TY-Phos can be easily synthesized on a gram scale from readily
available starting materials in 3 steps. Salient features of this work
including readily available starting materials, good yields, high
enantioselectivities as well as broad substrate scope make this
approach very practical and attractive. Notably, the asymmetric
synthesis of an analogue of a biologically active molecule is also
reported.
gem-Difluoroalkenes are increasingly being exploited as versatile
fluorinated building blocks in organofluorine synthesis[1] via mono-
defluorinative[2] or fluorine retentive[3] functionalization reactions.
Over the past decade, by taking advantage of easily available
gem-difluoroalkenes as reliable trifluoromethyl (CF3) precursors,
many chemists reported a conceptually novel protocol for the
expedient synthesis of CF3-containing molecules through an
additional fluorine source via a radical pathway or an anion/ cation
mechanism (Scheme 1)，which are supplement to the typical
trifluoromethylation reaction.[4] In 2014, Hu and co-workers
demonstrated the formation of α-trifluoromethylated benzylsilver
species from the reaction of gem-difluoroalkene with AgF for the
first time, and which undergoes rapid C-AgI bond homolysis in-
situ to afforded the α-CF3 benzyl radical[5]. Recently, Feng et al.[6]
reported a photoredox-coupled F-nucleophilic addition induced
allylic alkylation of gem-difluoroalkenes via the α-CF3 benzyl
radical intermediate (Scheme 1, a). In contrast, Feng & Loh
group[7] and Malcolmson et al.[8] realized palladium-catalyzed
fluorinative allylation and arylation of gem-difluoroalkenes via α-
CF3 carbanion intermediate, and the first attempt to palladium-
catalyzed asymmetric fluoroallylation of gem-difluoroalkenes with
allyl tert-butyl carbonate was done by Feng and Loh group.[7a]
[*] T.-Y. Lin, Prof. Dr. Z. Li, Prof. Dr. J. Zhang
Department of Chemistry, Fudan University, 2005 Songhu Road,
Shanghai 200438, China.
E-mail:zmli@fudan.edu.cn
junliangzhang@fudan.edu.cn
T.-Y. Lin, Z. Pan, Prof. Dr. H.-H. Wu
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China Normal
Scheme 1. Trifluoromethylation of gem-difluoroalkenes.
University, Shanghai 200062, China
Y. Tu, Prof. Dr. Y. Liu
College of Chemistry and Life Science,
Advanced Institute of Materials Science,
Changchun University of Technology, Changchun 130012, China
However, only up to 56:44 er was achieved in Feng and Loh's
catalytic system after examining a variety of chiral ligands. In
addition, Kobayashi[9] and Jiang[10] demonstrated that α-CF3
carbanion intermediate could be intercepted by CO2 or
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
bromoalkyne, furnishing the α-CF3-carboxylic acids or α-CF3-
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and PC-Phos[22] were not efficient either, but N-Me-Xu-Phos
gave a promising result with 18% yield albeit with only 51:49 er.
We found that the substituents on the phosphine have a
significant impact on this reaction. Thus, a new chiral sulfinamide
phosphine type ligand, named TY-Phos was designed by
changing the substituent of the phosphine from cyclohexyl of N-
Me-Xu-Phos to the tert-butyl to increase the steric hindrance
(Scheme 3). To our delight, the N-Me-TY1 showed higher
reactivity and enantioselectivity compared to N-Me-Xu1. Inspired
by this promising result, we varied the R group (N-Me-TY2-7).
halides, respectively (Scheme 1, b). In 2018, α-CF3 carbocation
intermediate was report by Wang[11] and Hu[12], which generated
from gem-difluoroalkenes with a F+ source and applied to
aminofluorination and fluoro-hydroxylation, respectively (Scheme
1, c).
Despite that
a number of methodologies have been
developed for the construction of CF3-containing molecules from
gem-difluoroalkenes, none of those method is enantioselective
version.[7a] Herein, we wish to report the first example of highly
enantioselective fluoroarylation of gem-difluoroalkenes with aryl
halides enabled by the palladium and a new type of chiral
sulfonamide phosphine (Sadphos) ligand, so called TY-Phos
(Scheme 1, d), providing an easy access to chiral 1,1,1-trifluoro-
2-arylalkanes.[13] The incorporation of a fluoride or trifluoromethyl
group in an organic molecule often significantly alters the physical,
chemical, and biological properties compared to a nonfluorinated
organic molecule.[14] (Bis)arylethanes, in particular, with a
hydroxyl group or alkoxyl or hydroxyl group at the ortho-positition
of the aryl, are ubiquitous structural motifs found in an array of
biologically active natural products and pharmaceuticals (Figure
1).[15] For example, (-)-Curcuphenol is a natural product and has
been isolated from the marine sponge Didiscus flavus.[15a]
Racemic 1a and 1b have been found to have excellent tubulin
binding properties and antitumor activity.[15b] Therefore, the
development of highly efficient methods for synthesis of chiral
1,1,1-trifluoro-2-arylalkanes is in high demand.
Scheme 2. Screening of known ligands.
Figure 1. Biologically active compounds and pharmaceuticals bearing
(bis)arylethane subunit.
Inspired by the Feng and Loh's elegant work on the racemic
synthesis of non-symmetric α,α-disubstituted trifluoroethane
derivatives,[7b] we became interested in whether chiral ligands
could be applied to the palladium-catalyzed asymmetric
fluoroarylation of gem-difluoroalkenes with aryl halides. However,
this hypothesis faced considerable challenges (Scheme 1, d): (1)
catalytic amount of chiral ligand versus an excess amount of AgF
will make the intermediate I may have no chiral ligand; (2) AgF
competitive binding with palladium to chiral ligand,[16] it may
weaken or even completely eliminate the enantioselectivity of this
reaction; (3) according to Hu's findings,[5] intermediate I can
generate trifluorobenzyl radical, which will lead to the
racemization of intermediate I; (4) referring to the work of
Tredwell[13c] and Jarvo,[17] the intermediate II may also undergo
racemization for the same reason; (5) how to avoid
hydrofluorination[18] of intermediate
I
rather than the
transmetalation; (6) how to avoid β-H elimination of intermediate
II when the R is alkyl group.
Initially, our investigations began with methyl 4-(2,2-
difluorovinyl)benzoate 2a and 1-iodo-2-methoxybenzene 3a, and
a series of known chiral ligands was screened (Scheme 2).
Unfortunately, commercially available ligands L1-L7 showed low
reactivity and enantioselectivity. Meanwhile, our group developed
[19]
Sadphos, such as Ming-Phos,
Xiang-Phos,[20] Xu-Phos[21]
Scheme 3. Optimization of the TY-Phos ligands.
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Gratifyingly, the er value can be increased to 90.5:9.5, when the
R was triptycenyl group (N-Me-TY7), but only 43% yield was
obtained. We attribute this to the silver intermediate I might
undergo other transformations (i.e.hydrolysis) before the
transmetallation reaction with palladium(II) intermediate
generated via the oxidative addition. With the knowledge that
electron-rich phosphine ligands could promote the oxidative
addition of aryl halides with palladium(0).[23] Therefore, we
introduced electron-donating groups into the aryl moiety of N-Me-
TY-Phos structured as N-Me-TY8 and N-Me-TY9 with methoxy
and alkyl groups, respectively. Gratifyingly, the product 4aa was
obtained in 95% yield with 92.5:7.5 er with the use of N-Me-TY9
as the chiral ligand. Notably, One-pot and gram scale synthesis
of TY-Phos and N-Me-TY-Phos could be achieved from the di-
tert-butylphosphine borane (for more details, please see the
supporting information). The absolute configuration of TY-Phos
was unambiguously determined via X-ray crystallography
analysis.[24] Further screening of the palladium salts, reaction
temperatures and solvents failed to give better results either
(Table S1, ESI). The optimal reaction conditions are described as
follows: [allylPdCl]2 as the catalyst, N-Me-TY9 as the chiral ligand
in cyclohexane at 70 oC for 16 h.
in 53-99% yields with 91:9-98.5:1.5 er. The absolute configuration
of (S)-4ae was unambiguously determined via X-ray
crystallography analysis.[24] Notably, the aryl bromides are also
suitable for this reaction (4ac, 4ae, 4ah, 4ai and 4ak). The
reaction showed a high chemoselectivity when the aryl halides
contain both iodide and bromide (4aj, 4ar), in which the reaction
selectively take place at the iodide position. There is an obvious
substituent effect on the enantioselectivity of this reaction. The
4am-4ar were obtained in 61-95% yields with 85:15-96:4 er
values when no substituent at the ortho-position of the aryl iodides,
indicating that the steric hindrance at ortho-position is beneficial
to the enantioselectivity. Gratifyingly, the disubstituted aryl iodide
(3at-3aw) delivered the corresponding products (4at-4aw) in
moderate to good yields with high er.
Having the optimal reaction conditions in hand, we first
investigated the generality of the aryl halides (Scheme 4). A good
tolerance towards both electron-donating substituents (4aa-4ag)
and electron-withdrawing substituents (4ah-4al) at the ortho-
position of the aryl iodides delivered the corresponding products
Scheme 5. Substrate scope of gem-difluoroalkenes. [a] Unless otherwise noted,
all reactions were carried out with 0.2 mmol of 2, 0.4 mmol of 3c, AgF (1.2 equiv),
2.5 mol% [allylPdCl]2 and 11 mol% N-Me-TY9 in 2.0 mL of cyclohexane, 70 oC
under Ar for 16 h. [b] The reaction was conducted with 2 (0.4 mmol), 3c (0.2
mmol), AgF (0.4 mmol). [c] N-Me-TY10 was used as chiral ligand.
Scheme 4. Substrate scope of aryl halides. [a] Unless otherwise noted, all
reactions were carried out with 0.2 mmol of 2a, 0.4 mmol of 3, AgF (1.2 equiv),
2.5 mol% [allylPdCl]2 and 11 mol% N-Me-TY9 in 2.0 mL of cyclohexane, 70 oC
under Ar for 16 h. [b] N-Me-TY10 was used as chiral ligand (for N-Me-TY10,
please see the supporting information).
Subsequently, we turned our attention to investigate the
scope of the current reaction with respect to the gem-
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difluoroalkenes (Scheme 5). To our delight, a good tolerance to
both electron-donating groups (4cc-4ec) and electron-
withdrawing groups (4gc-4ic) at the para-position of the gem-
difluoroalkenes was observed, delivering the desired products in
76-86% yields with 95:5-98:2 er. Whereas the substrates with an
electron- donating groups (4jc-4kc) delivered higher er value than
those with an electron-withdrawing groups (4lc-4mc) at the meta-
position of the gem-difluoroalkenes. The 4nc and 4oc were
obtained with relatively lower er value due to a steric hindrance.
The gem-difluoroalkenes 3pc-3rc were compatible to produce the
desired products (4pc-4rc) with excellent yields and
enantioselectivities. Notably, the aliphatic gem-difluoroalkene
also successfully gave the desired products 4sc-4vc in 58-76%
yields with 91.5:8.5-95:5 er. Moreover, the gem-difluoroalkenes
3tc-3vc derived from cinnamaldehyde also participated in this
reaction to afford the desired products 4wc-4yc in 51-63% yields
with 95.5:4.5-96:4 er. Finally, the examples of across coupling
partner (4en-4fy) were obtained in 51-96% yields with 87.5:12.5-
93:7 er.
Scheme 7. NMR spectroscopic studies.
Finally, in order to show the practicability of this method, a
gram-scale reaction was carried out, producing the desired
product 4ac in 78% yield with 98:2 er. Additionally, 4ez, which is
an analogue of biologically active molecule 1b, could be made in
67% yield with 91.5:8.5 er.
Figure 2. Linear effects syudy.
Scheme 6. Gram-scale reaction and asymmetric synthesis of a biologically
active molecule 1b's analogue 4eu.
In summary, we have developed a highly enantioselective
palladium-catalyzed fluoroarylation of gem-difluoroalkenes with
aryl halides by using of a newly designed Sadphos type ligand N-
Me-TY9 as the chiral ligand, which provides an efficient method
for the synthesis of chiral 1,1,1-trifluoro-2-arylalkanes. The salient
features of this reaction include readily available starting materials,
high yields and enantioselectivity and broad substrate scope. The
In order to gain insights of the reaction mechanism, we
performed some control experiments. A well-known radical-
trapping reagent such as TEMPO or BHT was added to the
current reaction (Eq. 1). The yield and er only slightly decreased,
which might exclude the radical pathway.[5] In addition, we
discovered that both silver fluoride and palladium can be
coordinated with N-Me-TY9. As observed by 31P NMR
spectroscopy, it appeared two new phosphine peaks (J109Ag31P =
968.8 Hz, J107Ag31P = 840.9 Hz) when AgF and N-Me-TY9 were
stirred in toluene-d8 at 80 °C for 1 h (Scheme 7, a). It was similar
to the result reported by Malcolmson and co-workers.[8] The 31P
NMR spectrum showed three new phosphine peaks at 54.3, 52.1
and 49.6 ppm after palladium catalyst and N-Me-TY9 stirred in
cyclohexane at 25 °C for 1 h (Scheme 7, b). However, the 31P
NMR spectrum showed two new doublet of doublets peaks after
palladium catalyst, AgF and N-Me-TY9 stirred in cyclohexane at
80 °C for 1 h, indicating the formation of a new [Pd-Ag-N-Me-TY9]
species (Scheme 7, c).[25] The relationship between the ee value
of N-Me-TY9 and that of (S)-4ac was investigated (Figure 2). A
linear effect was observed, which indicates that an active
catalyst/ligand being of a monomeric nature and the reaction
possessing a first-order dependence on catalyst.
mechanism
of
this
palladium-catalyzed
asymmetric
fluoroarylation of gem-difluoroalkenes has been investigated by
NMR spectroscopy. However, the nature of the reaction
mechanism on how to control enantioselectivity remain unclear.
Further studies including DFT calculations and synthetic
applications of this reaction, and the application of TY-Phos or N-
Me-TY-Phos in other transition metal-catalyzed asymmetric
transformations are underway and will be reported in the due
course.
Acknowledgements
We gratefully acknowledge the funding support of NSFC
(21672067, 21702063, 21921003), and the Innovative Research
Team of Ministry of Education.
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Conflict of interest
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The authors declare no conflict of interest.
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Keywords: gem-Difluoroalkene • Fluoroarylation • Palladium •
TY-Phos • Ligand Design
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This article is protected by copyright. All rights reserved.

10.1002/anie.202008262
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Tao-Yan Lin, Zhangjin Pan, Youshao
Tu, Shuai Zhu, Hai-Hong Wu, Yu Liu,
Zhiming Li,* and Junliang Zhang*
Page No. – Page No.
Design, Synthesis of TY-Phos and
Application in Palladium-Catalyzed
Enantioselective Fluoroarylation of
gem-Difluoroalkenes
The first example of highly enantioselective fluoroarylation of gem-difluoroalkenes
with aryl halides is presented by using a new chiral sulfinamide phosphine
(Sadphos) type ligand (TY-Phos). The salient features of this reaction include
readily available starting materials, high yields and enantioselectivity and broad
substrate scope.
This article is protected by copyright. All rights reserved.