Nickel/NHC-Catalyzed Asymmetric C?H Alkylation of Fluoroarenes with Alkenes: Synthesis of Enantioenriched Fluorotetralins

Article abstract of DOI:10.1002/anie.201907387

Chiral polyfluoroarene derivatives are an important scaffold in chemistry. An unprecedented enantioselective C?H alkylation of polyfluoroarenes with alkenes is described. The reaction employs bulky chiral N-heterocyclic carbene (NHC) ligands for nickel catalysts to enable exclusive activation of C?H bonds over C?F bonds and complete endo-selective C?H annulation and excellent enantioselectivity. A wide variety of chiral fluorotetralins, compounds otherwise difficultly accessed but serve as important bioisosteric analogs of both tetralin and heterocycle units for drug design, are expediently synthesized from easily available substrates. To our knowledge, this is the first example of catalytic enantioselective C?H functionalization of polyfluoroarenes.

Full text of DOI:10.1002/anie.201907387

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Accepted Article
Title: Nickel/NHC-Catalyzed Asymmetric C–H Alkylation of
Fluoroarenes with Alkenes: Synthesis of Enantioenriched
Fluorotetralins
Authors: Yuan Cai, Xiaodong Ye, Sheng Liu, and Shi-Liang Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907387
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10.1002/anie.201907387
Angewandte Chemie International Edition
COMMUNICATION
Nickel/NHC-Catalyzed Asymmetric C–H Alkylation of
Fluoroarenes with Alkenes: Synthesis of Enantioenriched
Fluorotetralins
Yuan Cai, Xiaodong Ye, Sheng Liu, Shi-Liang Shi*
Abstract: Chiral polyfluoroarene derivatives are an important
scaffold in chemistry. An unprecedented enantioselective C–H
alkylation of polyfluoroarenes with alkenes is described. The reaction
employs bulky chiral N-heterocyclic carbene (NHC) ligands for nickel
catalysts to enable exclusive activation of C–H bonds over C–F
bonds and complete endo-selective C–H annulation and excellent
enantioselectivity. A wide variety of chiral fluorotetralins, compounds
otherwise difficultly accessed but serve as important bioisosteric
analogs of both tetralin and heterocycle units for drug design, are
expediently synthesized from easily available substrates. To our
knowledge, this is the first example of enantioselective C–H
functionalization of polyfluoroarenes.
Scheme 1. Catalytic Asymmetric Synthesis of Fluorotetralins
Pharmaceuticals containing fluoroarenes display unique
properties due to the presence of fluorine atoms, which is the
most electronegative element and can adjust molecular polarity,
pKa-value, lipophilicity, and metabolic stability.1 In materials
science, control of the relative orientation of several C–F bonds
on the polyfluoroarenes unit leads to the design of highly polar
compounds, such as dielectric materials used in liquid crystals
(Figure 1).2 Thus, the construction and modification of
fluoroarene derivatives have emerged as a fundamental organic
transformation, and much effort has been devoted to this area.3
Among them, the C–H functionalization of readily available
fluoroarenes is the most atom- and step-economical method.4,5
Despite recent progress in racemic reactions,5 the direct
asymmetric C–H functionalization6 of polyfluoroarenes remains
unknown. Importantly, an enantioselective C–H activating
cyclization of polyfluoroarenes to access optically active
fluorotetralin skeletons has not been reported, though these
fluorotetralins serve as important bioisosteres of both tetralin
and heterocycle scaffolds for drug design,7 and are commonly
found in pharmaceuticals and materials (Figure 1).8
Typically, tetralin systems are synthesized through Friedel–
Crafts type cyclization of aryl derivatives9 or hydrogenation of
naphthalene derivatives10. However, these two methods are not
applicable to chiral fluorotetralin synthesis due to the challenges
associated with chemo-, regio-, and stereocontrol and the facile
hydrodefluorination side reaction11 (Scheme 1A and B). To our
knowledge, there are no general catalytic methods for the
asymmetric synthesis of unfunctionalized fluorotetralins. In this
context, we surmised that a Ni-catalyzed asymmetric C–H
alkylation of easily available alkene tethered fluoroarenes via an
intramolecular hydroarylation might provide an efficient
construction of chiral fluorotetralin derivatives (Scheme 1C).12,13
However, we noted that several daunting challenges exist in this
strategy. First, the competitive alkene isomerization via a facile
Ni-promoted chain-walking process needs to be suppressed.14
Second, selective activation of C–H bonds over multiple C–F
bonds
are
required,
although
experimental15
and
computational16 studies have suggested that Ni(0) complex
exclusively favor oxidative addition into C–F bonds instead of C–
H bonds in polyfluoroarenes.17 Third, polyfluoroaryl-metal bonds
are particularly strong and unreactive.18 Thus, harsh reaction
conditions and/or ligand-accelerated catalysis is required. Fourth,
the complete regiocontrolled reaction of alkenes and arenes is
nontrivial yet crucial for gaining a decent isolated yield. Finally,
whereas earth-abundant nickel is broadly applied in cross-
coupling reactions,19 the Ni-catalyzed enantioselective C–H
activation has rarely reported, as its enantiocontrol is generally
difficult to achieve and results are highly sensitive to ligand
employed.20 However, we reasoned that the identification of a
suitable class of chiral ligands for nickel catalyst could address
Figure 1. Examples of drugs and materials bearing polyfluoroarene and
fluorotetralin scaffolds.
the challenges as mentioned above, thus providing
straightforward synthesis of chiral fluorotetralins.
a
[*]
Y. Cai, X. Ye, S. Liu, Prof. Dr. S.-L. Shi
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
E-mail: shiliangshi@sioc.ac.cn
To this end, we recently developed a family of chiral NHCs 21
,
namely ANIPE and SIPE type ligands, and successfully applied
in the first Ni-catalyzed enantioselective C–H cyclization of
pyridines with alkenes.22 As part of our ongoing endeavors in
this field, we report herein the first enantioselective C–H
alkylation of fluoroarenes enabled by a Ni/NHC catalysis,
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907387
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affording chiral fluorotetralins in excellent levels of chemo-,
regio- and enantiocontrol from easily available substrates.
We commenced our study by using alkene 1a as the model
substrate, which was readily prepared in one step from
Table 1. Reaction Optimizationa
inexpensive
2,3,4,5-tetrafluorobenzyl
bromide
and
2-
methylallylmagnesium chloride, for the synthesis of fluorotetralin
2a in the presence of Ni(cod)2 and supporting ligands (Table 1).
At first, a series of commonly used chiral phosphine and NHC
ligands were found to be ineffective for this C–H alkylation
reaction.23 However, the use of our ANIPE ligand (L1) gave
exclusively endo-selective C–H annulated product (2a) in
quantitative yield and high enantioselectivity (91% ee, entry 1).
Interestingly, neither isomers originating from alkene chain-
walking isomerization nor exo-cyclized products was observed.
We rationalized that a bulky NHC on Ni could both accelerate
the reductive elimination step to avoid isomerization and favor
the endo-cyclization pathway for steric reasons. Remarkably,
although structurally similar NHC-stabilized Ni(0) complexes
were reported to activate C–F bonds over C–H bonds in
polyfluoroarenes,15,16 no C–F bonds cleavage was observed in
the current system. We reasoned that our bulky NHC favors the
formation of active monomeric Ni/NHC catalyst22b thus
facilitating C–H bond activation instead. Further screening using
a bulkier ligand L2 slightly improved the enantioselectivity, while
the SIPE ligand L3 afford the optimal result, providing 2a in
quantitative yield with 94% ee (entries 2-3). However, the
condition based on L3 was inapplicable to a styrene-based
substrate 1d, and the alkene isomerization occurred
predominantly (entry 4). Next, extensive screening identified L2
as the best ligand for 1d delivering 2d in nearly quantitative yield
with 97% ee (entry 6). Surprisingly, the use of both bulkier
saturated ligand (L4) and the unsaturated NHC (L5) dramatically
decreased the enantioselectivity or reactivity, indicating the
subtle change on ligand structure strongly affect the
performance of the nickel catalyst (entries 7-10). Finally, we
found that various types of ether or nonpolar solvents were all
comparably effective for this transformation, affording 2a in
excellent yield and enantioselectivity.23
With the optimized set of reaction conditions, we first surveyed
the scope of fluoroarenes part for this enantioselective C–H
alkylation reaction. As shown in Table 2, an array of chiral
fluorotetralin derivatives were prepared in excellent yields (89-
96%) with very high levels of enantioselectivity (93-99%) (2a-2l).
Remarkably, the reaction was successfully applied to various
tetrafluoro-, trifluoro- and difluoroarene substrates with fluorine
substituents at different positions. The use of difluoroarene
substrates is particularly intriguing as these compounds are
generally ineffective for C–H functionalization reactions.5
Moreover, the ortho-C–H bond of the fluorine substituent was
exclusively alkylated to afford endo-cyclized products (2i, 2j).
Unsurprisingly, the use of monofluoro-substituted substrates
resulted in low yield (<10%), as the alkene isomerization
occurred predominantly. Importantly, two examples of gram-
scale reactions (5 mmol) were successfully performed in the
presence of lower loading of catalyst (2.5 mol%) to deliver
products in high yield and enantioselectivity as before,
highlighting the practicality of this method (2a, 2d).
[a] Reactions were performed on a 0.2 mmol scale. [b] Determined by GC and
NMR analyses; an isolated yield is shown in parentheses. [c] Determined by
HPLC analysis with a chiral stationary phase.
competent substrates furnishing fluorotetralin products in high
yield and enantioselectivity (2m-2q). Styrene type substrates
possessing either electron-rich and electron-poor substituents
smoothly participated in this transformation. The mild catalytic
conditions tolerated many functional groups, including an ether
(2r), an amine (2s), a trifluoromethyl group (2t), an ester (2v),
amides (2w, 2y), and
a ketone (2x). Most remarkably,
substrates bearing acidic proton, such as a secondary amide
and phenols (2y, 2z, 3a), underwent the C–H cyclization
smoothly with high levels of enantiocontrol. Moreover,
substrates possessing medicinally important heterocycles, such
as morpholine (2s), quinoline (3b), benzofuran (3c), indole (3d,
3g) and pyrrole (3f), were all compatible. Aside from 1,1-dialkyl
alkenes and styrenes, the use of enamines and a 1,3- diene also
delivered fluorotetralin products in high yield and
enantioselectivity (3f, 3g, 3h).24 It is noteworthy that in all cases,
endo-selective C–H cyclization product generated exclusively,
and no C–F cleavage was observed. It is practically
advantageous that the annulated products bearing low polarity
(without N and O atoms), which are expected to be inseparable
from starting materials and possible isomers, could be purified
by simple filtration through a short silica gel pad, indicating the
complete and exclusive transformation into desired products.25
Finally, the absolute stereochemistry of 2l and 3e was
determined by single crystal X-ray analysis.26
In addition to providing chiral fluorotetralins as bioisosteric
analogs, another critical advantage of the current protocol is its
applicability in the late-stage modification of highly functionalized
synthetic intermediates. To demonstrate this concept, we
subjected the styrenes derived from two wildly prescribed drugs,
We next investigated the scope of alkenes using a variety of
tetrafluoroarene substrates. Various bulky alkenes were all
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Table 2. Substrate Scopea
[a] Yields of isolated products on a 0.3 mmol scale. L3 was used for 1,1-dialkyl alkene substrates, while L2 was used for other types of substrates. [b] 2.5 mol%
catalyst. [c] L2 was used. [d] 48 h. [e] 10 mol% catalyst. [f] Using 1.5 equiv tBuONa. [g] Reaction was run at 120 oC in toluene.
clofibrate and loratadine, to our reaction conditions. The
reaction proceeded successfully delivering the chiral
fluorotetralin derivatives (4, 5) in high efficiency and selectivity,
exemplifying the potential of the current method in the rapid
diversification of medicinally relevant molecules.
We next performed additional experiments to get some
mechanistic insights. When we subjected d-1b to standard
conditions, complete transfer of deuterium to the benzylic
position of 2b was observed (Figure 2A). Besides, there was
no significant kinetic isotope effect in the intramolecular or
intermolecular competitive experiment (KIE = 1.5, Figure 2B),
indicating C–H cleavage might not be the rate-determining
step. Moreover, a competition experiment using two different
substrates (d-1b and 1r) suggest that there was no deuterium
scrambling distribution (Figure 2C). These findings indicate
that direct ligand-to-ligand hydrogen transfer28 from
fluoroarenes to the alkene probably be the favored pathway
(Figure 2D, path a). However, the pathway involving C–H
oxidative addition of Ni(0) and alkene insertion cannot be
excluded at this stage (Figure 2D, path b). Regardless of
which pathway the reaction undergoes, the employment of
SIPE and ANIPE type chiral NHC ligands, which are highly
sterically demanding and highly electron-donating, is
apparently critical to not only the exclusive activation C–H
bonds over C–F bonds but also the challenging reductive
elimination step and complete endo-selective cyclization, thus
leading to excellent chemo-, regio- and enantiocontrol of this
challenging nickel catalyzed C–H alkylation of fluoroarenes.
In conclusion, we have developed the first enantioselective
catalytic C–H functionalization of polyfluoroarenes. The
unprecedented asymmetric C–H cyclization of fluoroarenes
with alkenes was achieved by the use of chiral bulky NHC
ligands for nickel catalysts. This reaction tolerates a broad
scope of functional group and heterocycles, converts various
readily available tetrafluoro-, trifluoro, and difluorobenzenes
tethered alkenes, including 1,1-dialkyl alkenes, styrenes,
dienes, and enamines, to valuable chiral fluorotetralins,
To further demonstrate the synthetic utility of our
hydroarylation
protocol,
we
conducted
several
transformations using 2f based on rich chemistry of
polyfluoroarenes, and in all cases, the excellent enantiomeric
excess was completely conserved (Scheme 2). For example,
the Pd-catalyzed C–H arylation and heteroarylation reaction
furnished bi-aryls in high efficiency (6, 7).5a Besides, the use
of a Ni-catalyzed C–H alkenylation originally reported by
Nakao and co-workers gave a polyfluorostyrene in high yield
(8).13d Furthermore,
a
Ni-promoted hydrodefluorination
delivered a chiral tetralin product (9).27 Thus, the combination
of the current asymmetric C–H alkylation method with the
hydrodefluorination process provides an efficient formal
enantioselective hydroarylation of simple arenes, which is a
challenging, yet important transformation.
Scheme 2. Transformation of Chiral Fluorotetralin 2f
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Figure 2. Mechanistic studies and the proposed catalytic cycle
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Efforts to further expand the scope of this type of reaction are
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This work is supported by the NSFC (91856111, 21690074,
21871288, 21821002), the “1000-Youth Talents Plan”, and
the CAS (XDB 20000000). We thank Prof. Yiming Wang for
proofreading this manuscript.
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Keywords: asymmetric hydroarylation • C-H alkylation •
chiral NHC ligand • fluoroarenes • nickel catalysis
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10.1002/anie.201907387
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yuan Cai, Xiaodong Ye, Sheng Liu, Shi-
Liang Shi*
Page No. – Page No.
Nickel/NHC-Catalyzed Asymmetric C–
H Alkylation of Fluoroarenes with
Alkenes: Synthesis of
Text for Table of Contents
Enantioenriched Fluorotetralins
The first enantioselective C–H functionalization of polyfluoroarenes is reported. This unprecedented asymmetric C–H alkylation of
fluoroarenes with alkenes is enabled by using NHC/Ni catalysis, to furnish chiral fluorotetralins in high efficiency and excellent levels
of chemo-, regio- and enantiocontrol.
This article is protected by copyright. All rights reserved.