Nickel-Catalyzed Carbonylation of Difluoroalkyl Bromides with Arylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.8b04070

A nickel-catalyzed carbonylative difluoroalkylation reaction with arylboronic acids under 1 atm of CO has been developed. The reaction proceeds under mild reaction conditions with high efficiency and high functional group tolerance. Preliminary mechanistic studies reveal that the arylacyl nickel complex is the key intermediate to circumvent the formation of labile fluoroacyl nickel, and bimetallic oxidative addition is likely the key step to facilitate the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.8b04070

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Nickel-Catalyzed Carbonylation of Difluoroalkyl Bromides with
Arylboronic Acids
Hai-Yang Zhao, Xing Gao, Shu Zhang, and Xingang Zhang*
†
†
‡
,†
†Key Laboratory of Organofluorine 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
‡
School of Materials and Energy, University of Electronic Science and Technology of China, 2006 Xiyuan Avenue, West High-Tech
Zone, Chengdu, Sichuan 611731, China
*
S Supporting Information
ABSTRACT: A nickel-catalyzed carbonylative difluoroalkylation reaction with arylboronic acids under 1 atm of CO has been
developed. The reaction proceeds under mild reaction conditions with high efficiency and high functional group tolerance.
Preliminary mechanistic studies reveal that the arylacyl nickel complex is the key intermediate to circumvent the formation of
labile fluoroacyl nickel, and bimetallic oxidative addition is likely the key step to facilitate the catalytic cycle.
ransition-metal-catalyzed carbonylation reactions are
efficient strategies to access carbonyl compounds. Over
Scheme 1. Hypothesis for Ni-Catalyzed Carbonylation of
Fluoroalkyl Halides
T
the past several decades, numerous carbonylation reactions
have been developed and impressive achievements have been
1
made in this area via palladium catalysis. For practical
applications, the development of cost-efficient Earth-abundant
metals, especially catalysts that are based on first-row transition
metals (such as nickel) for carbonylative cross-couplings
remains highly desirable. In contrast to palladium-catalyzed
carbonylation reactions, similar carbonylation reactions using
nickel catalysts have not been well-developed, because of the
2
diminished reactivity of nickel toward carbonylation.
Recently, a few examples of nickel-catalyzed carbonylation
3
reactions with CO surrogates have been reported. For nickel-
catalyzed carbonylative fluoroalkylation reactions, however,
formidable challenges still remain because, compared to their
none fluorinated counter parts, the fluoroacyl nickel complexes
fluorinated compounds for life and materials sciences, but
[
Ni(CO)R , R = fluoroalkyl] are even more susceptible to
f f
currently there have been limited approaches to synthesize the
decarbonylation to generate fluoroalkyl nickel complexes
(CO)Ni-R ], because of the strong electron-withdrawing
7
valuable motif in a cost-efficient and straightforward manner.
[
f
4
To circumvent the formation of labile fluoroacyl nickel
effect of fluoroalkyl group (Scheme 1). In addition, the
complex [Ni(CO)R ], we envisioned an alternative pathway
strong σ-type binding between fluoroalkyl groups and nickel
f
5
(Scheme 1) to access difluoroalkyl ketones: the trans-
metalation of a nucleophile with nickel-catalyst generates a
nickel complex [Ni-Nu] I, which subsequently undergoes
carbonyl insertion to produce acyl nickel complex [Ni(CO)-
Nu] II. Complex II reacts with difluoroalkyl halides via
(
Ni-R ) is less prone to undergo carbonyl insertion. As a
f
consequence, no example of nickel-catalyzed carbonylative
fluoroalkylation reaction has been reported thus far.
As part of our ongoing study on transition-metal-catalyzed
6
fluoroalkylation reaction via cross-coupling, herein, we
demonstrate the feasibility of nickel-catalyzed carbonylative
difluoroalkylation. The resulting difluoroalkyl ketones are a
prominent structural motif in the synthesis of various useful
Received: December 20, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxidative addition to produce the key intermediate [R Ni-
efficiency (see Table 1, entries 6 and 7, as well as the SI).
f
(
CO)Nu] III. Finally, reductive elimination of III delivers the
Among the tested nickel sources, NiCl ·DME remained the
2
final product and regenerates the nickel catalyst.
best one. Finally, the optimal reaction conditions were
identified by increasing the ratio of 1a/2a from 1:2 to 1.5:1
with 3.0 equiv of K CO as a base and 20 mol % H O as an
As a result, we disclose the first example of nickel-catalyzed
carbonylation of difluoroalkyl halides with arylboronic acids
under 1 atm of carbon monoxide (CO). The direct use of CO
in nickel-catalyzed carbonylation reactions are not usual;
because of the high affinity of CO to nickel, the ready
formation of toxic and unreactive nickel complexes Ni(CO) L
under atmosphere of CO will hamper the nickel species to
catalyze the reaction. The current catalytic system is not
affected by the use of CO, and can efficiently catalyze
carbonylation of a variety of arylboronic acids and difluoroalkyl
2
3
2
additive at 65 °C, providing 3a in 82% yield upon isolation
3
(
Table 1, entry 9). However, the use of 1.0 equiv of 1a led to
only a 56% yield of 3a (see the SI). The role of water is
3
probably to facilitate the transmetalation step by activating the
8
9
arylboronic acid. No product was observed without nickel
catalyst or ligand, thus demonstrating the essential of role of
Ni/L3 in the promotion of the reaction (see the SI).
With the optimized reaction conditions in hand, a wide
1
2
bromides (BrCF R, where R = alkynyl, CO Et, CONR R ,
2
2
range of arylboronic acids were examined to react with 2a
HetAr) under mild reaction conditions with high functional
group tolerance, providing a cost-efficient access to difluor-
oalkyl ketones.
Considering the synthetic versatility of the carbon−carbon
triple bond (CC) that can provide a good platform for
downstream transformations, we focused our initial study on
the Ni-catalyzed carbonylation reaction of gem-difluoropro-
pargyl bromide 2a with arylboronic acid 1a under 1 atm of CO
(
Scheme 2). Overall, this transformation allows a wide range of
aryl boronic acids with moderate to high yields and exhibits
high functional group tolerance (3f−3r), even toward aryl
bromide (3n) and phenol moiety (3q). Heteroaromatic rings,
such as dibenzo[b,d]thiophene, carbazole, and pyridine-
containing boronic acids are also suitable substrates (3s−3v).
Scheme 2. Ni-Catalyzed Carbonylation of Arylboronic Acids
(Table 1). To our delight, a 38% yield of carbonylated product
a
1
with Difluoroalkyl Bromides 2
Table 1. Representative Results for Optimization of Ni-
a
Catalyzed Carbonylation of 1a with 2a
b
entry
[Ni]
ligand
yield of 3a/4a (%)
1
2
3
4
5
6
7
NiCl ·DME
L1
L2
L3
L4
L5
L3
L3
L3
L3
38/ND
31/ND
52/ND
41/ND
3/41
11/ND
35/ND
70/<1
2
NiCl ·DME
2
NiCl ·DME
2
NiCl ·DME
2
NiCl ·DME
2
NiCl2
NiCl (dppe)
2
c
8
c d
NiCl ·DME
2
9 ,
NiCl ·DME
88 (82)/<1
2
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0
b
equiv), 2a (2.0 equiv), dioxane (2 mL), 80 °C, 24 h. Determined by
19
F NMR using fluorobenzene as an internal standard; the number
c
given in parentheses is the isolated yield. 1a (1.5 equiv), 2a (0.3
mmol, 1.0 equiv). 65 °C. 20 mol % H O was used.
d
2
3
a was obtained without observation of cross-coupling side
product 4a when the reaction was performed with 1a (1.0
equiv), 2a (2.0 equiv), and 1 atm of CO in the presence of
NiCl ·DME (10 mol %), bipyridyl (L1) (10 mol %), and
2
K CO (2.0 equiv) in dioxane at 80 °C (Table 1, entry 1). A
2
3
survey of the ligand reveals that bipyridyl-based ligand 4,4′-
t
di- BuBpy (L3) is the optimal choice, providing 3a in 52%
yield (Table 1, entry 3; for details, see the Supporting
Information (SI)). 1,10-Phenanthroline (L4) is also a suitable
ligand, but a slightly lower yield was obtained (Table 1, entry
a
Reaction conditions (unless otherwise specified): 1 (0.45 mmol, 1.5
b
4
). In contrast, when terpyridine (L5) was examined, 4a
instead of 3a was provided as a major product (Table 1, entry
). The choice of nickel source is also critical to the reaction
equiv), 2a (0.3 mmol, 1.0 equiv), dioxane (2 mL). Gram-scale
synthesis. 1.0 equiv of arylboronic acid was used, the yield was
determined by F NMR.
c
1
9
5
B
DOI: 10.1021/acs.orglett.8b04070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The scalability and reliability of the current process has been
demonstrated by the gram-scale synthesis of 3a. Most
importantly, this transformation can also be applied to the
late-stage synthesis of difluoroalkylated bioactive molecules. As
shown in 3w and 3x, the late-stage difluoroalkylation of
Fenofibrate and tyrosine-derived arylboronic acids proceeded
smoothly, thus providing a potential opportunity to discover
some new interesting bioactive molecules.
Scheme 4. Transformations of Compound 3
1
0
The reaction is not restricted to 2a, as aliphatic gem-
difluoropropargyl bromides are also applicable to the reaction,
leading to the corresponding products efficiently (Scheme 3,
Scheme 3. Ni-Catalyzed Carbonylation of Arylboronic Acids
a
1
with Difluoroalkyl Bromides 2
To gain mechanistic insight into the current nickel-catalyzed
carbonylative process, we performed specific studies on the key
step reactions that are likely occurring in this catalytic cycle
(
Scheme 5). First, in the reaction with methanol under 1 atm
Scheme 5. Mechanistic Studies
a
Reaction conditions: 1 (1.5 equiv), 2 (0.3 mmol, 1.0 equiv), dioxane
(
2 mL).
5
a−5d). However, aromatic gem-difluoropropargyl bromide
led to poor yield due to significant defluorination side
reactions. Other difluoroalkyl bromides, including bromodi-
fluoroacetate, bromodifluoroacetamides, and heteroaryldifluor-
omethyl bromide, are all competent coupling partners and
provided the corresponding difluoroalkyl ketones with high
efficiency (5e−5n). Unfortunately, unactivated difluoroalkyl
bromides failed to provide the desired products. Again,
excellent functional group tolerance is observed. In particular,
the successful carbonylation of amino-acid-derived bromodi-
fluoroacetamide is highly relevant to the medicinal chemistry
(
5m), in light of the important applications of difluoalkyl
11
ketone-based peptides in anti-HIV agents.
The utility of the current process can also be demonstrated
by the synthesis of a variety of fluorinated compounds from 3a
through transformations of the CC bond and carbonyl
group (Scheme 4). Wittig reaction of 3a leads to alkene 6
efficiently (Scheme 4a). The silyl group can be readily
deprotected by TBAF (Scheme 4a) and the resulting terminal
alkyne 7 can function as a good platform for diversity-oriented
synthesis (Scheme 4b). Hydrogenation of 7 under different
reaction conditions selectively provided alkene 8 and alcohol 9
with high efficiency. A fluorinated furan ring can also be
efficiently constructed from 7 by reduction of carbonyl group
of CO in the presence of NiCl ·DME (0.5 equiv) and K CO
3
2
2
in dioxane at 65 °C, arylboronic acid 1a provided methyl
arylcarboxylate 12 in 30% yield (Scheme 5a), whereas
difluoroalkyl bromides 2a or 2b did not afford any methyl
12
esters (Scheme 5b). These results suggest that an arylacyl
nickel complex [ClNi(L)(CO)Ar] B is likely involved in the
current catalytic cycle, consistent with our initial proposal in
Scheme 1. Second, the formation pathway of complex B is
verified by the immediate transformation of an aryl nickel
13
with NaBH , followed by cyclization and defluorination. The
complex A1, which is a plausible active species generated
from the transmetalation of nickel precursor with aryl boronic
acid, into the arylacyl nickel complex B1 in 62% yield in the
presence of CO (1 atm) in CD Cl at room temperature
4
Sonogashira reaction of 7 with 3-iodothiophene also proceeds
smoothly, providing a complementary method to access gem-
difluoromethlenated heteroaromatic alkyne.
2
2
C
DOI: 10.1021/acs.orglett.8b04070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
14
within 15 min (Scheme 5c). The resulting acyl nickel
complex B1 showed high reactivity toward gem-difluoropro-
pargyl bromide 2a and provided the corresponding ketone in
Scheme 7. Proposed Reaction Mechanism
9
6
5% yield at room temperature (Scheme 5d). Furthermore, a
6% yield of 15 without observation of cross-coupling side
product 16 from the reaction of A1 with 2a and CO suggests
the fast reaction rate of the current carbonylation reaction over
the Ni-catalyzed difluoroalkylation reaction (Scheme 5e).
These results clearly demonstrate that the production of
difluoroalkyl ketone via an arylacyl nickel(II) intermediate is a
reasonable pathway. To identify whether a difluoroalkyl radical
is involved in the catalytic cycle, a radical clock experiment has
been performed (Scheme 6a). A ring-expanded product 18 was
Scheme 6. Trapping Difluoroalkyl Radical
supported with cyclic voltammograms of B1 and 2a in CH Cl
2
2
20
(
see Figure S6 in the SI).
In conclusion, we have developed the first example of nickel-
catalyzed carbonylative fluoroalkylation reaction. In sharp
contrast to the previous nickel-catalyzed carbonylation
3
reactions using CO surrogates, the present carbonylation
proceeds smoothly under mild reaction conditions using 1 atm
of CO. The reaction allows a wide range of arylboronic acids
and difluoroalkyl bromides with high functional group
tolerance, providing a cost-efficient and straightforward access
to difluoroalkyl ketones. Notably, many of the resulting
difluoroalkyl ketones bearing a CC bond are previously
unknown and can function as versatile building blocks for
diversified synthesis of various useful fluorinated compounds
that are of great interest in life and materials sciences.
Preliminary mechanistic studies reveal that an arylacyl nickel
complex exists in the current catalytic cycle, which
subsequently undergoes a bimetallic oxidative addition with
difluoroalkyl bromide, followed by reductive elimination to
produce the difluoroalkyl ketones.
obtained in 14% yield when the reaction mixture of B1 and 2a
15
was treated with α-cyclopropyl styrene 17, implying that a
difluoroalkyl radical may be generated between B1 and 2a. The
formation of a difluoroalkyl radical was further confirmed by
the EPR study of reaction of 2a with spin-trapping agent
phenyl tert-butyl nitrone (PBN) in the presence of B1 (see
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04070.
16
Scheme 6b, as well as the SI). Given the facts that a 95%
yield of 15 was obtained from the stoichiometric reaction of
acyl nickel complex B1 with 2a (Scheme 5d) and a
difluoroalkyl radical is involved in the reaction, we propose
Detailed experimental procedures, and characterization
data for new compounds (PDF)
17
that a bimetallic oxidative addition is the key step to generate
AUTHOR INFORMATION
Corresponding Author
■
the difluoroalkyl ketone.
On the basis of above results and previous reports,
18,3f
a
*
E-mail: xgzhang@mail.sioc.ac.cn.
plausible reaction mechanism is proposed (Scheme 7). The
II
ORCID
reaction is initiated by a transmetalation of [Ni (L )X ] with
n
2
the aryl boronic acid to generate an aryl nickel(II) complex
Xingang Zhang: 0000-0002-4406-6533
Author Contributions
II
[
ArNi (L )X] A. Subsequently, insertion of CO into complex
n
II
A produces the arylacyl nickel(II) complex [Ar(CO)Ni (L )-
n
All authors have given approval to the final version of the
manuscript.
Notes
X] B. Complex B reacts with difluoroalkyl bromide 2 to
generate a difluoroalkyl radical species and a nickel(III)
III
complex [Ar(CO)Ni (L )X ] C. The difluoroalkyl radical is
n
2
The authors declare no competing financial interest.
then trapped by another arylacyl nickel(II) complex B to afford
III
the key intermediate [Ar(CO)Ni (L )CF R(X)] D, which
n
2
ACKNOWLEDGMENTS
undergoes reductive elimination to produce the difluoroalkyl
■
I
ketone and nickel(I) complex [Ni (L )X] E. Finally, E reacts
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21425208, 21672238,
21790362, and 21421002), the National Basic Research
Program of China (973 Program) (No. 2012CB821600), the
n
with the newly formed nickel(III) complex C via a
comproportionation reaction to regenerate nickel(II) catalyst
II
19
[
Ni (L )X ] and B. The formation of nicke(II) species was
n 2
D
DOI: 10.1021/acs.orglett.8b04070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Strategic Priority Research Program of the Chinese Academy
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