Selective C(sp3)?H and C(sp2)?H Fluorination of Alcohols Using Practical Auxiliaries

Article abstract of DOI:10.1002/anie.201808021

Selective introduction of fluorine into molecules by the cleavage of inert C?H bonds is of central academic and synthetic interest, yet remains challenging. Given the central role of alcohols in organic chemistry as the most ubiquitous building blocks, a

Full text of DOI:10.1002/anie.201808021

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Accepted Article
Title: Selective C(sp3)-H and C(sp2)-H Fluorination of Alcohols Using
Practical Auxiliaries
Authors: Yang-Jie Mao, Shao-Jie Lou, Hong-Yan Hao, and Danqian
Xu
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3
2
Selective C(sp )-H and C(sp )-H Fluorination of Alcohols Using
Practical Auxiliaries
Yang-Jie Mao, Shao-Jie Lou*, Hong-Yan Hao and Dan-Qian Xu*
Dedicated to Professor Zhen-Yuan Xu on the occasion of his 80th birthday
3
Abstract: Selective introduction of fluorine into molecules via the
cleavage of inert C-H bonds is of central academic and synthetic
interest, yet remains challenging. Given the central role of alcohols
in organic chemistry as the most ubiquitous building blocks, a
group developed a Pd(II)-catalyzed enantioselective C(sp )-H
fluorination of 2-alkyl benzaldehyde derivatives using a chiral
[
12]
bidentate transient directing group.
To the best of our
2
3
knowledge, neither C(sp )-H nor C(sp )-H fluorination of alcohols
has been reported due to the underdeveloped C-H
transformation of alcohols and the challenging formation of C-F
bonds. Given the central role of alcohols in organic chemistry,
new strategies for the site-selective C-H fluorination of simple
alcohols are highly desirable.
3
2
versatile and selective C(sp )-H and C(sp )-H fluorination of simple
alcohols enabled by novel designed exo-directing groups was
2
developed for the first time. C(sp )-H bond fluorination was achieved
by using simple acetone oxime as auxiliary, whereas a new, modular
and easily accessible bidentate auxiliary was developed for the
efficient and site-selective fluorination of various primary methyl,
3
methylene and benzylic C(sp )-H bonds. Fluorinated alcohols can
readily be accessed by the removal of auxiliaries, which significantly
expands the synthetic prospect of the present protocol.
Alcohols are considered to be among the most important and
ubiquitous building blocks in organic chemistry. The hydroxy
groups can readily be transformed into various functional groups
such as alkenes, haloalkanes, aldehydes, ketones, carboxylic
acids, and esters, which are described as basic reactions in
many textbooks in organic chemistry. Thus, the direct C-H bond
transformation of alcohols is undoubtedly of great interest to the
chemists.
On the other hand, organic fluorides are linchpin in
[1]
pharmaceuticals, agrochemicals and materials. Thus, C-F
bond construction has been of great interest as well as a long-
standing challenge to the chemical society.[2] Among the
established fluorination protocols, direct replacement of simple
and inert C-H bonds to the corresponding C-F bonds not only
retains the molecular size, but dramatically enhances the
lipophilicity, bioavailability and metabolic stability in comparison
with their non-fluorinated analogues. In the recent years,
substantial efforts have been devoted to the chelation-assisted
2
3
Scheme 1. Selective C(sp )-H and C(sp )-H fluorination of alcohols enabled
by exo-directing strategies
2
[3]
aromatic C(sp )-H bond fluorination of aryl heterocycles,
masked amines,[4] carboxylic acids, aldehydes, ketones[7] and
[5]
[6]
phenols,[8] etc. In addition, Pd(II)-catalyzed direct electrophilic
aromatic C(sp )-H fluorination was also realized by Ritter.
However, the selective catalytic fluorination of the inert C(sp )-H
bonds remains challenging[10] and mainly focused on the β-
fluorination of masked carboxylic acids.[11] Very recently, Yu’s
The last decade has witnessed the emergence of transition
2
[9]
metal catalyzed C-H functionalization using directing groups as
3
[13]
intramolecular ligands.
The design of novel directing groups
enriches the scope of C-H functionalization by improving the
reactivity as well as selectivity. For instance, hydroxyl itself as an
O-donor ligand directing group was less efficient due to the
weakly coordinating ability to the transition metals, thus novel
strategies using masked alcohols as auxiliaries were developed
for the C-H bond functionalization of alcohols.[13c, 14] Among
these, Dong[15] and Sanford[16] developed an elegant exo-
directing strategy to enable the selective C-H bond
functionalization of oximes on the oxygen side. Very recently,
several C-H bond transformations including the C(sp )-H
sulfonyloxylation,[ intramolecular alkoxylation,
[*]
Y.-J. Mao, S.-J. Lou, H.-Y. Hao and D.-Q. Xu
College of Chemical Engineering
Zhejiang University of Technology
Catalytic Hydrogenation Research Center, State Key Laboratory
Breeding Base of Green Chemistry-Synthesis Technology
18 Chaowang Road, Hangzhou (China)
3
E-mail: loushaojie@zjut.edu.cn; chrc@zjut.edu.cn.
17]
[18]
[19]
amidation
olefination[21] were
2
[20]
and the C(sp )-H bond acetoxylation,
Supporting information for this article is given via a link at the end of
the document
developed by using this strategy. However, the structural
modifications of the previous auxiliaries (simple ketones, aryl
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Angewandte Chemie International Edition
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COMMUNICATION
aldehydes) are difficult to realize in a modular fashion, which
may limit the diversity of C-H transformations, such as the
challenging C-H bond fluorination of alcohols (Scheme 1, a). In
the context of these limitations, we became intrigued in
establishing a novel family of highly modular exo-type bidentate
auxiliaries for various C-H functionalization. Herein, as part of
our continuous interest in the C-H bond fluorination of diverse
selectively fluorinated at the C-H bond with the bromo group
intact (Table 1, 2d). Moreover, α-substituted benzyl alcohols
also underwent mono-fluorination smoothly (Table 1, 2l-2o).
Notably, fluorination of masked phenethyl alcohol also occurred
at the remote ortho position via a 7-membered palladacycle
intermediate (Table 1, 2p).
2
Having established the C(sp )-H bond fluorination of alcohols,
[
7-8]
2
fundamental compounds,
we report a selective C(sp )-H and
we turned our attention to the more challenging fluorination of
3
3
C(sp )-H fluorination of alcohols by using the exo-directing
the inert C(sp )-H bonds. In principle, C-F bond formation is
catalytic mode for the first time (Scheme 1, b). A simple acetone
oxime ether enabled the remote aromatic C(sp )-H bond
usually more sluggish in the competing reductive eliminations
from high-valent PdIV species due to the poor nucleophilicity of
fluorine anion. Indeed, fluorinating reagent NFSI was mainly
used as a bystanding oxidant[23] for the formation of other
chemical bonds such as C-O bond and C-N bond in the previous
2
fluorination under a Pd-nitrate catalysis, whereas a newly
developed bidentate auxiliary derived from pyruvamide enabled
3
the selective fluorination of more challenging inert C(sp )-H
3
[17, 19b]
bonds (Scheme 1, c).
C(sp )-H bond functionalization of alcohols.
Only cyclic
3
Aromatic C-H bond functionalization of alcohols has remained
underdeveloped due to the lack of suitable auxiliaries to stabilize
the transition metals. Oximes were recently found as exo-
directing groups for the C-H bond functionalization of alcohols.
However, in comparison with their endo counterparts, relatively
lower efficiency as well as limited reaction types was observed
due to the flexible and remote coordinating / directing mode
between the substrates and catalysts. Encouraged by our recent
methylene C(sp )-H were fluorinated in moderate yields as side
3
reactions. No efficient C(sp )-H bond fluorination of alcohols has
3
been developed to date. We started our C(sp )-H fluorination
[
19]
with the cyclohexanone oxime and Dong’s bidentate quinolin-
8-carbonyl oximes.[
17, 24]
Though they showed good compatibility
in the previous C(sp )-H transformations,[25] no desired
fluorinated products were detected when these neutral
monodentate (L-type) or bidentate (L, L-type) oxime auxiliaries
were used (Table 2, DG 1, 2 and 2’). We envisioned that
modifying the oxime auxiliaries might be able to control the PdIV
reductive elimination pathway towards C-F bond formation.
Given the advantage and successful application of bidentate,
3
[
7]
nitrate-promoted aromatic C-H bond fluorination of oximes , we
envisioned that the C-H fluorination of the challenging aromatic
alcohols might be feasible with a more electrophilic palladium-
nitrate catalysis.
3
monoanionic auxiliaries (L, X-type) in the C(sp )-H bond
functionalizations,[26] we proposed to replace one neutral N-
donor ligand by an anionic motif to stabilize the high-valent
palladium complexes and facilitate the C−F bond formation.[27]
Pyruvic acid is a simple, readily available skeleton and
perfectly matches our proposal for the auxiliary design.[
Various pyruvamides derived from pyruvic acid and amines were
prepared and investigated for the β-fluorination of isoamyl
alcohol. As shown in Table 2, the Weinreb-type amide gave no
fluorinated product (DG 3). An attempt to utilize a tridentate
auxiliary also failed (DG 4). To our delight, simple N-cyclohexyl
pyruvamide and pyruvanilide gave promising results and the
desired products were detected in 10% and 21% yield
respectively (DG 5 and 6). Encouraged by this result, various
Table 1. Aromatic C-H bond fluorination of alcohols
28]
Al
pyruvanilides were next surveyed (DG 7-9 and DG ). Gratefully,
though electron-donating amides were less efficient, electron-
withdrawing amides exhibited good reactivity towards β-
fluorination.
Especially
when
the
N-pentafluorophenyl
pyruvamide was used as the bidentate auxiliary, 95% yield of
the desired product was observed. The weakly coordinating
nature of the electron-withdrawing pyruvamide is likely
responsible for the dramatic increase of the reactivity in C-F
bond formation according to the previous reports.[13c, 29] Finally,
the negative results of using pentafluorophenol pyruvate (DG
Conditions:
1
(0.3 mmol), Pd(OAc)
2
(0.03 mmol), NFSI
=
N-
fluorobenzenesulfonimide (0.6 mmol), AgNO
mL) were added to a test tube, the mixture was stirred at the indicated
temperature for 12 h. NFSI (3.0 equiv.) was used.
3
(0.15 mmol) and EtOAc (3.0
a
1
0) and N-methyl-N-pentafluorophenyl pyruvamide (DG 11) as
At the outset of this fluorination project, O-(2-methylbenzyl)-
acetoxime (1a) was treated with Pd catalyst, nitrate promoter
and NFSI in various solvents. To our delight, ortho C-H bond
fluorinated product 2a was obtained in 82% isolated yield in
EtOAc. As anticipated, nitrate additives were indispensable in
this transformation, and only 44% yield of 2a was detected in the
auxiliaries confirmed the necessity and superiority of this
bidentate, monoanionic auxiliary in the C(sp )-H bond
3
fluorination of alcohols. In comparison with the previous report,
our auxiliary is highly modular and easily accessible through
simple amidation of pyruvic acid with diverse amines, and may
thus find application in various C-H bond functionalizations with
different transition metals by adjusting the electronic nature of
the bidentate auxiliaries.
With the optimized conditions in hand, the substrate scope of
the β-fluorination was then investigated (Table 3). Methyl C-H
bonds in the β-position of primary, secondary, and tertiary
absence of AgNO
3
(see the SI for details).[22]
The scope of the reaction was next explored under the
optimized conditions. Generally, the reaction tolerated various
functional groups such as alkyls, halogens, phenyl and alkoxyls
(
Table 1, 2a-2k). The ortho bromo-substituted substrate was
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3
3
Table 2. Screening of auxiliaries for C(sp )-H bond fluorination of alcohols.
Table 3. Scope of C(sp )-H bond fluorination of alcohols
2
Standard conditions: DG X (0.1 mmol), Pd(OAc) (0.01 mmol), NFSI = N-
fluorobenzenesulfonimide (0.2 mmol.), and PhCl (1.0 mL) were added to a test
tube, the mixture was stirred at 75 oC for 24 h. Yields were determined by GC-
MS analysis using dodecane as internal standard. The isolated yield is given
in parenthesis.
alcohols were fluorinated smoothly in moderate to excellent
yields (Table 3, 4a-4f). Difluorination was observed for the tert-
butanol derived substrate bearing three available methyls C-H
bonds (Table 3, 4f), whereas mono-fluorination was detected in
excellent selectivity for the iso-propanol derived substrate (Table
3
,
4d). Various functional groups such as aryls, ethers,
cyclopropane, esters and thiophene were well tolerated (Table 3,
g-4o). In addition, β-fluorination selectivity was further
4
confirmed by the X-ray crystal structure of product 4n. To our
3
delight, less reactive methylene C(sp )-H bonds were also
accommodated in this transformation. Fluorination of cyclic
methylene C-H bonds even in more complex structures was also
feasible, giving the mono-fluorinated products in good yields
(
Table 3, 4p-4r & 4t). However, the methylene C-H bonds in
cyclododecanol-derived substrate exhibited similar reactivity to
the more challenging acyclic methylene C-H bonds, which
required elevated reaction temperature to achieve comparable
yields (Table 3, 4s & 4u-4w). In addition, due to its flexible 12-
membered-ring, the stereoselectivity of 4s was insufficient in
comparison with the substrates bearing more rigid 6-membered
3
ring. Next, the benzylic C(sp )-H bond fluorination of phenylethyl
alcohols was investigated (Table 3, 4x-4ae). Notably, the
reactions gave excellent β-fluorination selectivity at the benzylic
position, even when aromatic C(sp )-H bonds were available in
2
Standard conditions a: 3 (0.3 mmol), Pd(OAc) (0.03 mmol, 10 mol%), NFSI =
N-fluorobenzenesulfonimide (0.6 mmol, 2.0 equiv.), and PhCl (3.0 mL) were
added to a test tube, the mixture was stirred at indicated temperatures for 24
2
h. Conditions b: 3 (0.3 mmol), Pd(OAc)
Ag CO (0.6 mmol), L-leucine (0.03 mmol), and PhCl (3.0 mL) were added to
a test tube, the mixture was stirred at 120 C for 24 h. c Pd(OAc)
NFSI = (3.0 equiv.). DCE (3.0 mL) was used instead of PhCl (3.0 mL).
2
(0.03 mmol), NFSI (0.6 mmol),
the same molecules. The selectivity was thus complementary to
2
3
2
the aforementioned aromatic C(sp )-H bond fluorination of
o
2
(20 mol%),
acetone oxime-based phenylethyl alcohol (Table 1, 2p). It is
noteworthy that functionalization of acyclic methylene C-H bonds
or benzylic C-H bonds was much less efficient in the previous
exo-directing reports, which further demonstrated the superiority
of our new auxiliary. Moreover, remarkably high chemo- and
d
e
Reactions were performed under N
used.
2
atmosphere and extra dry solvent was
site-selectivity were observed by using the new exo-amide-imine
Furthermore, the removal of the directing group can be readily
achieved by the Raney Ni catalyzed reduction or molybdenum
Al
(
DG ) auxiliary even when multiple reactive C–H bonds are
presented in a single molecule (e.g. 4h, 4w, 4x), which is of
great importance in the selective late-stage C-H fluorination of
complex alcohols.
hexacarbonyl mediated cleavage of the N-O bond, giving the
[21]
corresponding fluorinated alcohols in high yields
(Scheme 2).
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COMMUNICATION
easily accessible and removable, which might have broad
application prospect in various challenging C-H bond
functionalization in the near future. Further explorations on the
development of new reactions with the novel modified
pyruvamide auxiliaries are ongoing in our lab.
Acknowledgements
The authors acknowledge the China Postdoctoral Science
Foundation (No. 2014M560494) and the Postdoctoral Science
Foundation of Zhejiang Province for financial support.
Scheme 2. Installation and removal of DGs.
3
2
3
Keywords: C(sp )-H fluorination • C(sp )-H fluorination • alcohol
• exo-directing • bidentate auxiliary
With the intriguing bidentate auxiliary assisted C(sp )-H
fluorination established, several mechanistic experiments were
conducted to get further insight into the reaction. Firstly, a dimer
palladium complex was obtained to further establish the
proposed mode of interaction between the bidentate auxiliary
and the palladium (see the SI for details). For better
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7
(Scheme 3, c & d), which suggested
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In conclusion, we have developed a general and selective
2
3
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Angewandte Chemie International Edition
10.1002/anie.201808021
COMMUNICATION
COMMUNICATION
Yang-Jie Mao, Shao-Jie Lou*, Hong-Yan
Hao and Dan-Qian Xu*
Page No. – Page No.
3
2
Selective C(sp )-H and C(sp )-H
Fluorination of Alcohols Using
Practical Auxiliaries
3
2
A versatile and selective C(sp )-H and C(sp )-H fluorination of simple alcohols
enabled by a novel design of exo-directing groups was developed for the first time.
2
C(sp )-H bond fluorination was achieved by using simple acetone oxime as
auxiliary, whereas a new and modularly accessible bidentate auxiliary was
developed for the efficient and site-selective fluorination of more challenging C(sp )-
3
H bonds of diverse primary methyl, methylene and benzylic C-H bonds.
This article is protected by copyright. All rights reserved.