Regioselective Vinylation of Remote Unactivated C(sp3)?H Bonds: Access to Complex Fluoroalkylated Alkenes

Article abstract of DOI:10.1002/anie.201812927

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical-mediated functionalization of C(sp³)?H bonds by a hydrogen-atom transfer process, the site-selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C-centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri-/di-/mono-fluoromethyl and perfluoroalkyl groups.

Full text of DOI:10.1002/anie.201812927

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Accepted Article
Title: Regioselective Vinylation of Remote Unactivated C(sp3)-H
Bonds: Access to Complex Fluoroalkylated Alkenes
Authors: Shuo Wu, Xinxin Wu, Dongping Wang, and Chen Zhu
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10.1002/anie.201812927
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Regioselective Vinylation of Remote Unactivated C(sp3)-H Bonds:
Access to Complex Fluoroalkylated Alkenes
Shuo Wu,§, [a] Xinxin Wu,§, [a] Dongping Wang,[a] and Chen Zhu*[a]
Dedication ((optional))
Abstract: Regioselective incorporation of a particular functional
group into aliphatic sites by direct activation of unreactive C-H bonds
is of great synthetic value. Despite advances in radical-mediated
functionalization of C(sp3)-H bonds via HAT process, the site-
selective vinylation of remote C(sp3)-H bonds still remains
underexplored. Herein we report
a
new protocol for the
regioselective vinylation of unactivated C(sp3)-H bonds. The remote
C(sp3)-H activation is promoted by C-centered radical instead of the
commonly used N- and O-radicals. The reaction possesses high
product diversity and synthetic efficiency, furnishing a plethora of
synthetically valuable E-alkenes bearing tri-/di-/mono-fluoromethyl
and perfluoroalkyl groups.
Direct functionalization of inert C(sp3)-H bonds represents one of
the most ingenious and advanced tactics in synthetic chemistry.
Though the past few decades have witnessed a spurt of
progress in this area, enormous challenges still remain with
reactivity and selectivity.[1] Generally, transition-metal catalysis
takes advantage of installing an extra directing group to gain the
reactivity and/or regiocontrol in C(sp3)-H activation.[2] Radical-
mediated hydrogen atom transfer (HAT) provide an important
alternative to the transition-metal catalyzed approaches.[3]
Nevertheless, this process is largely dependent upon the
inherent characters of C-H bonds that the abstraction of tertiary
C(sp3)-H bonds is more feasible than secondary and primary
ones. The reaction with multiple reactive sites usually proceeds
without regiocontrol to afford a mixture of regioisomers.
Scheme 1. Regioselective Functionalization of Remote C(sp3)-H Bonds via
Radical Translocation Pathways.
Radical translocation processes mediated by O- or N-
centered radicals offer a great potential to address the selectivity
issue.[4] Pioneering works from Barton harnessed nitrite esters
derived from alcohols to generate alkoxy radicals that trigger the
regioselective C(sp3)-H oxidation via remote HAT (Scheme 1a).[5]
The Hofmann-Löffler-Freytag reaction delivers N-radicals by
homolysis of the preformed N-halogenated amines to engender
the C(sp3)-H halogenation and subsequent annulation (Scheme
1b).[6] Over the past few decades, many precursors have been
exploited to generate N- or O-centered radicals for HAT
reactions.[7] Recent breakthroughs in the formation of N- or O-
However, oxidative conditions are usually required, and proton-
coupled electron transfer (PCET) is sometimes sought to reduce
the high oxidation potentials of N-H or O-H bonds under basic
conditions.[8] Compared with these advances, functionalization of
remote C(sp3)-H bonds mediated by C-centered radicals lags far
behind.[9] Herein we disclose a new protocol for regioselective
vinylation of remote C(sp3)-H bonds, which is promoted by C-
centered radical instead of the common N- and O-radicals
(Scheme 1d). Under mild conditions a variety of unreactive
C(sp3)-H bonds are stereospecifically converted to E-olefins via
sequential HAT and olefin migration.[10] Mechanistically, the
active alkenyl radical I obtained by addition of external radical to
the alkyne enables 1,5-HAT to generate alkyl radical II. The
bond dissociation energy (BDE) difference between olefinic
C(sp2)-H bond (~110 kcal/mol) and aliphatic C(sp3)-H bond
(~100 kcal/mol) facilitates this 1,5-HAT process.[11] The in situ
formed olefin functions as the acceptor of alkyl radical, leading
to the cyclopentanol intermediate III. Cleavage of the cyclic C-C
σ- bond of III affords the alkenylated products after olefin
migration. From one precursor a portfolio of olefin derivatives
can be obtained by simply varying the extrinsic radicals,
manifesting high product diversity and synthetic efficiency of the
protocol. Considering that the propargyl alcohols are prepared
[7a-c]
[7n-p,t]
radicals direct from unmodified N-H
or O-H
bonds
massively increase the atom- and step-economy of C(sp3)-H
activation by means of radical translocation (Scheme 1c).
[a]
S. Wu, Dr. X. Wu, D. Wang, and Prof. Dr. C. Zhu
Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science
Soochow University
199 Ren-Ai Road, Suzhou, Jiangsu 215123 (China)
E-mail: chzhu@suda.edu.cn
§
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 2. Generality of Protocol and Scope of Trifluoromethyl Alkenes.
Reaction conditions: 1 (0.2 mmol), Togni’s reagent II (0.3 mmol, 1.5 equiv.),
fac-Ir(ppy)3 (0.006 mmol, 3 mol %), and K2HPO4 (0.3 mmol, 1.5 equiv.) in ethyl
acetate (2 mL) with 30W blue LEDs irradiation at RT. Yields of isolated
products are given. [a] Togni’s reagent II (0.4 mmol, 2.0 equiv.) and K2HPO4
(0.4 mmol, 2.0 equiv.), added in two portions. [b] Togni’s reagent II (0.6 mmol,
3.0 equiv.) and K2HPO4 (0.6 mmol, 3.0 equiv.).
within one-step from ketones and result in the alkenylated
ketones, this method paves a new avenue for the late-stage
vinylation of ketones.
Concerning the importance of fluorine-containing groups
that often improve the chemical, physical, and biological
properties of bioactive molecules,[12] production of the
fluoroalkyl-substituted alkenes via direct vinylation of unactivated
C(sp3)-H bonds would remarkably boost the synthetic value of
this protocol.[13] With this idea in mind, we firstly investigated the
addition of CF3 radical to propargyl alcohols 1, aiming to
selectively convert δ-C(sp3)-H bonds to trifluoromethyl alkene.[14]
After an extensive survey of reaction parameters, it was found
that CF3 radical was readily delivered in the presence of fac-
Ir(ppy)3 and Togni’s reagent II irradiated by visible light,[15] which
triggered the following 1,5-HAT and intramolecular olefin
migration to lead to the desired C-H vinylation. The addition of
K2HPO4 slightly improved the reaction yields. Then the
generality of protocol was evaluated with the optimized reaction
conditions (Scheme 2). The reaction demonstrated a broad
functional group compatibility that propargyl alcohols bearing
either electron-rich (e.g. alkyl 1b-c, ether 1d) or deficient (e.g.
halide 1f-h, CF3 1i, OCF3 1j, cyano 1k, ester 1l) aryl substituents
resulted in the E-olefin products 2 in good yields. The steric
character (para-, meta-, and ortho-) of substituents did not have
much influence on the reaction outcome. The CF3 radical was
added exclusively to the terminal alkyne regardless of the
presence of another internal alkyne, showing
a unique
chemoselectivity (2m). Various heteroaryls such as thienyl (1p),
quinolyl (1q), pyridyl (1r-s) as well as alkyl (1t) propargyl
alcohols were also suitable substrates to afford the
Scheme 3. Scope of Di-/ mono-fluoromethyl Alkenes. Reaction conditions: 1a
(0.2 mmol), BrCF2R or BrCHFR (0.3 mmol, 1.5 equiv.), fac-Ir(ppy)3 (0.006
mmol, 3 mol %), and K2HPO4 (0.3 mmol, 1.5 equiv.) in ethyl acetate (2 mL)
with 30W blue LEDs irradiation at RT. Yields of isolated products are given. [a]
Addition of extra nBu4NBr (0.3 mmol, 1.5 equiv.).
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10.1002/anie.201812927
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COMMUNICATION
corresponding products in synthetically useful yields. In addition
to tertiary C(sp3)-H bonds, a variety of unactivated secondary
C(sp3)-H bonds were readily functionalized. The case of 1w
indicated that the vinylation exclusively took place at δ-carbon
via 1,5-HAT without the occurrence of competitive HAT
processes at other positions of aliphatic chain. Even in the
existence of adjacent tertiary C-H bonds, the reaction offered a
precise regioselectivity for the less reactive secondary C-H
bonds (1x). Substrate control allowed for moderate
diastereoselectivity during the vinylation with either cyclic (1y) or
linear alkanes (1z). Other type of C(sp3)-H bonds, such as the α-
C-H bonds of ethers (1aa-ab) and benzylic C-H bonds (1ac-ad),
were also readily transformed into the desired olefin products.
The substrate scope of 1 could be further extended by
replacement of acetylene with other alkynes (1ae-af). The CF3
radical was incorporated to internal alkynes regardless of steric
congestion, leading to the tri-substituted trifluoromethyl alkenes.
In contrast to the above di-substituted alkenes, the configuration
of 2ae and 2af was assigned to Z based on the NOE analysis.
Notably, this method provided a novel approach for the
regiospecific late-stage vinylation of complex natural products,
e.g. lithocholic acid derivative (2ag). The protocol was also apt
to the modification of cycloketones, affording the γ-olefinated
cyclopentadecanone 2ah that is hard to synthesize otherwise.
It can be anticipated that by variation of the extrinsic
radicals the reaction would result in different type of olefinated
products, illustrating broad product diversity. To verify the
hypothesis, the protocol was applied to transform the unreactive
C(sp3)-H bonds into di- or mono-fluoromethyl alkenes (Scheme
3).[16] With 1a as substrate, fluoroalkylation reagents such as
To gain deeper insights into the reaction mechanism, we
firstly investigated the reaction with the TBS-protected propargyl
alcohol 5. The reaction still afforded the desired product 2a
albeit in low yield, supporting the proposal that the 1,5-HAT is
promoted by the alkenyl radical generated from acetylene rather
than the commonly used alkoxy radical from hydroxyl group
(Scheme 5a). The abstraction step is selectivity-determining,
thus the preferential abstraction of H rather than D by the alkenyl
radical is to be expected regardless of what the rate-determining
step is. The deuterium-labelling experiment (H/D ~9.0) provided
the concrete support (Scheme 5b). The asymmetric C(sp3)-H
vinylation by this strategy so far remains difficult as the reaction
with enantiopure 1x (>99% ee) resulted in the corresponding
optical active product 2x with modest enantioselectivity (41% ee)
(Scheme 5c).
bromodifluoroacetate,
bromodifluoroacetamide,
bromodifluoroacetophenone,
bromofluoroacetate were
and
investigated in the reaction. A set of di-/mono-fluoromethyl olefin
products 3a-d were readily obtained via visible-light-mediated
photoredox catalysis.
As the analogue of trifluoromethyl, perfluoroalkyl groups
have extensively industrial applications in multiple fields. This
protocol also provided an efficient approach for production of
perfluoroalkyl alkenes via the perfluoroalkylation of 1a (Scheme
4). Perfluoroalkyl including trifluoromethyl radicals were
Scheme 5. Mechanistic Studies..
In summary, we have described an efficient C-centered
radical-mediated remote C(sp3)-H vinylation for the first time.
The transformation proceeds via the sequence of unusual
alkenyl radical-promoted HAT process and intramolecular olefin
migration, furnishing the synthetically valuable olefin products
smoothly
generated
from
oxidation
of
sodium
perfluoroalkanesulfinates with phenyliodine bis(trifluoroacetate)
(PIFA) and added to 1a, leading to a series of the C(sp3)-H
alkenylated products E-2a and 4a-d in good yields. Notably, the
reaction provided a comparable yield of E-2a even at gram-scale, with exclusive site-selectivities. By simple variation of the
indicating the practicality of the method.
extrinsic radicals a wide range of olefins bearing different
functional groups such as tri-/ di-/ monofluoromethyl and
perfluoroalkyl are obtained, manifesting high product diversity
and synthetic efficiency. The protocol offers an efficient strategy
for the late-stage functionalization of complex natural products,
and opens a new vista for the remote C(sp3)-H vinylation.
Acknowledgements
C.Z. is grateful for the financial support from the National Natural
Science Foundation of China (21722205), the Project of
Scheme 4. Scope of Perfluoroalkyl Alkenes. Reaction conditions: 1a (0.2
mmol), CnF2n+1SO2Na (0.4 mmol, 2.0 equiv.), and PIFA (0.4 mmol, 2.0 equiv.)
in ethyl acetate (2 mL) at RT. Yields of isolated products are given.
Scientific
and Technologic
Infrastructure of Suzhou
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Entry for the Table of Contents (Please choose one layout)
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Shuo Wu, Xinxin Wu, Dongping Wang,
Chen Zhu*
Page No. – Page No.
Regioselective Vinylation of Remote
Unactivated C(sp3)-H Bonds: Access
to Complex Fluoroalkylated Alkenes
Give and Take: Regioselective incorporation of a particular functional group into
aliphatic sites by direct activation of unreactive C-H bonds always remains
challenging. Herein we report a new protocol for the regioselective vinylation of
unactivated C(sp3)-H bonds. The remote C(sp3)-H activation is promoted by C-
centered radical instead of the commonly used N- and O-radicals. The reaction
possesses high product diversity and synthetic efficiency, furnishing a plethora of
synthetically valuable E-alkenes bearing tri-/di-/mono-fluoromethyl and
perfluoroalkyl groups.
This article is protected by copyright. All rights reserved.