Ni-Catalyzed Defluorination for the Synthesis of gem-Difluoro-1,3-dienes and Their [4 + 2] Cycloaddition Reaction

Article abstract of DOI:10.1021/acs.orglett.8b03841

A nickel-catalyzed defluorination of α-trifluoromethylated allyl/propargyl carbonates using bis(pinacolato)diboron (B₂pin₂) as a reactant is described. The reaction proceeds under relatively mild reaction conditions, providing conjug

Full text of DOI:10.1021/acs.orglett.8b03841

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni-Catalyzed Defluorination for the Synthesis of gem-Difluoro-1,3-
dienes and Their [4 + 2] Cycloaddition Reaction
Minqi Zhou,† Jian Zhang,‡ Xing-Guo Zhang,*,† and Xingang Zhang*,‡
†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
‡Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed defluorination of α-trifluoromethylated allyl/propargyl carbonates using bis(pinacolato)-
diboron (B2pin2) as a reactant is described. The reaction proceeds under relatively mild reaction conditions, providing
conjugated gem-difluoroalkenes in moderate to good yields. Applications of the resulting 1,1-difluoro-1,3-dienes by [4 + 2]
cycloaddition reactions with maleimide led to cyclic fluorinated products efficiently.
Scheme 1. Synthesis of Conjugated gem-Difluoroalkenes
from Trifluoromethyl-Substituted Allylic Substrates
he synthesis and applications of fluorinated compounds
Thave attracted extensive attention, because of their
importance in agrochemicals, pharmaceuticals, and functional
materials.1 Over the past decades, impressive progress has been
made in the synthesis of fluorinated compounds and transition-
metal catalyzed fluorination and fluoroalkylations have
emerged as a powerful strategy to introduce fluorinated groups
into the organic molecules.2 We have also pursued the
development of catalytic fluoroalkylation reactions by using
transition metals as catalysts,2c especially sustainable and
Earth-abundant transition-metals, such as nickel.3 Inspired by
our recent nickel-catalyzed cross-coupling reactions,3 we
postulate that the α-trifluoromethyl nickel intermediate could
undergo a β-defluorination process to produce gem-difluor-
oalkenes, rather than traditional reductive elimination by
employing B2pin2 as a promoter, in which the formation of
strong B−F bond (ca. 150 kcal/mol)4 would be a driving force
to facilitate the C−F bond cleavage5 (Scheme 1b). gem-
Difluoroalkenes are versatile building blocks in organic
synthesis6 and have wide applications in pharmaceuticals,
because the difluorovinylidene moiety has been considered to
be a carbonyl mimic.7 Therefore, the synthesis of gem-
difluoroalkenes has attracted significant interest.8 Previously,
Kitazume9 reported a synthesis of conjugated gem-difluor-
oalkenes via copper-catalyzed β-fluoride elimination of CF3-
substituted allylic acetate with Grignard reagents (Scheme 1a).
Herein, we report a nickel-catalyzed defluorination of readily
available α-trifluoromethylated allyl/propargyl carbonates with
equiv of B2pin2 2, 10 mol % NiCl2·DME, 10 mol % 2,2′-
bipyridine (bpy) and 1.5 equiv of t-BuOK in DME at 30 °C for
12 h and provided the desired product 3a in 12% yield (Table
1, entry 1). Encouraged by this result, a survey of a series of
reaction parameters, such as base, reaction temperature, and
solvent, was conducted (Table 1, entries 2−12). Among the
tested bases (Table 1, entries 2−4), NaOMe was the best
choice, providing 3a in 40% yield (Table 1, entry 3); while no
3a was obtained in the absence of base (Table 1, entry 5).
10
B2pin2 (Scheme 1b).
We began our study by using α-trifluoromethylated allyl
carbonate E-1a as a model substrate, and the results are
summarized in Table 1. Initially, E-1a was treated with 1.5
Received: December 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03841
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Ni-Catalyzed Defluorination of
Trifluoromethylated Allyl/Propargyl Carbonates 1 with
a
B2pin2 2
b
temperature
yield
entry
ligand
base
solvent
(°C)
(%)
1
2
3
4
5
6
7
8
9
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
t-BuOK
t-BuONa
NaOMe
Cs2CO3
none
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
DME
DME
DME
DME
DME
DME
DME
DME
THF
dioxane
CH3CN
DMF
DME
DME
30
30
30
30
30
60
70
80
70
70
70
70
70
70
12
33
40
nr
nr
50
54
49
48
44
nr
nr
55
34
10 bpy
11 bpy
12 bpy
13 4,4′-diMe-bpy NaOMe
14 4,4′-dit-Bu-
NaOMe
bpy
15 6,6′-diMe-bpy NaOMe
DME
DME
70
70
30
65
16 4,4′-diOMe-
NaOMe
bpy
c
17
4,4′-diOMe-
NaOMe
DME
70
82
bpy
c
18
c d
none
NaOMe
NaOMe
DME
DME
70
70
nr
nr
,
19
4,4′-diOMe-
bpy
a
Reaction conditions (unless otherwise specified): E-1a (0.3 mmol,
b
1.0 equiv), 2 (1.5 equiv), DME (2 mL). Determined by 19F NMR,
using fluorobenzene as an internal standard. nr = no reaction.
a
Reaction conditions (unless otherwise specified): E-1 (0.6 mmol, 1.0
equiv), 2 (1.5 equiv), DME (4 mL). Number in the parentheses is the
c
d
yield determined by 19F NMR, using fluorobenzene as an internal
Reaction runs for 6 h. Reaction runs in the absence of NiCl2·DME.
b
c
standard. Reaction runs for 7 h. t-Butyl carbonate was used as a
d
substrate. E-1 (1.2 mmol, 1.0 equiv), 2 (1.5 equiv), DME (8 mL).
Increasing the reaction temperature to 70 °C benefited the
reaction efficiency and 54% yield of 3a was obtained (Table 1,
entry 7). But higher reaction temperature diminished the yield
(Table 1, entry 8). Ethereal solvents proved to be critical for
the reaction (Table 1, entries 8−10) and DME remains the
optimal reaction medium; other solvents, such as CH3CN and
DMF, showed no activity (Table 1, entries 11 and 12). A
screening of the ligands (Table 1, entries 13−16) showed that
an electron-rich bipyridyl-based ligand (4,4′-diOMe-bpy)
could provide 3a in 82% yield by shortening the reaction
time to 6 h (Table 1, entry 17). The absence of Ni or ligand
led to no product (Table 1, entries 18 and 19), demonstrating
that Ni and ligand play an essential role in promotion of the
reaction.
With the optimized reaction conditions in hand, the scope of
substrates E-1 was then examined with B2pin2 (Scheme 2).
Substrates bearing electron-donating or electron-withdrawing
substituents all underwent the current defluorination process
smoothly (3e, 3h, and 3i). In addition, both meta- and ortho-
substitutions on the aromatic ring were compatible with the
reaction conditions, providing the corresponding products 3c
and 3d in moderate yields. The low isolated yield of 3a is
because of its volatility. Important functional groups, such as
chloride, bromide, and ester, exhibits good tolerance to the
reaction (3f, 3g, 3h). However, pyridyl-containing substrates
were not applicable to the reaction. In the cases of preparation
of 3g and 3h, t-butyl carbonates instead of methyl carbonates
were used, because of their ready availability. The branched
allyl carbonates with substituents on the CC double bond
did not interfere with the reaction efficiency, but a Z/E mixture
(Z/E = 1.3:1) of 3j was obtained when trisubstituted E-alkene
E-1j was examined, indicating that a π-allyl nickel complex is
involved in the reaction, as a result a Z/E mixture of 3j was
obtained. The Z/E isomers of the products was characterized
1
by H NMR and 19F NMR. However, a diphenyl-substituted
1,3-diene 3k with 71% yield was obtained when the substituent
R2 was a phenyl group. Moreover, allyl carbonates bearing alkyl
groups were also applicable to the reaction, providing the
corresponding products in good yields with a Z/E mixture. For
examples, substrates bearing active functional groups, such as
heterocyclic furyl group and remote CC double bond,
afforded gem-difluoro-1,3-dienes 3m and 3n in 52% and 60%
yields, respectively. Notably, α-trifluoromethylated propargylic
carbonates were also suitable substrates and furnished enynes
3o and 3p smoothly.
On the basis of the previous reports,5b,c,11 and the fact that
the use of 10 mol % Ni(cod)2 as a catalyst could also lead to 3a
in 37% yield, a plausible mechanism via a Ni(0/II) cycle was
proposed in Scheme 3 (path I): The reaction is initiated by
reduction of [NiIILn] with B2pin2 to generate Ni0Ln species
A,5b,11c which subsequently undergoes oxidative addition with
allyl carbonate 1 to produce π-allylnickel complex [allyl(Ln)-
NiII] B. Transmetalation of complex B with B2pin2 affords π-
allylborylnickel species[allyl(Ln)NiIIBpin] C. Finally, β-fluoride
elimination with the coordination of B to F atom as a driving
force produces the gem-difluoroalkene 3. The resulting nickel
B
DOI: 10.1021/acs.orglett.8b03841
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed Reaction Mechanisms
Scheme 4. Transformations of gem-Difluoro-1,3-dienes
Importantly, the resulting dienes 6 can be readily converted
to fluorinated aromatic compounds via oxidation. For instance,
compound 6a was aromatized with DDQ to afford compound
7 in 76% yield (Scheme 4b). This selective sequential C−F
bond cleavage strategy is noteworthy, because, from the readily
available α-trifluoromethylated allyl carbonates, we can easily
access different fluorinated structural motifs that are of interest
in life and materials sciences.
In conclusion, we have developed an efficient method for the
synthesis of gem-difluoro-1,3-dienes and gem-difluoro-1-en-3-
ynes15 by nickel-catalyzed defluorination of α-trifluoromethy-
lated allyl/propargyl carbonates. The resulting conjugated
dienes and enynes could serve as versatile building blocks for
the organic synthesis. Applications of the resulting conjugated
gem-difluoro-1,3-dienes by [4 + 2] cycloadditions with N-(4-
bromophenyl)maleimide could lead to different fluorinated
compounds. The advantages of this protocol are the synthetic
simplicity and selective sequential cleavage of C−F bonds from
the CF3 group, thus providing a useful route for applications in
organic synthesis and related chemistry. Further studies to
uncover the reaction mechanism are now in progress in our
laboratory.
fluoride [Bpin(Ln)NiII−F] complex D undergoes reductive
elimination to regenerate active nickel species Ni0Ln, along
with Bpin-F. However, a nickel(I/III) catalytic cycle cannot be
ruled out. In this pathway (path II), initially, a borylnickel
complex [LnNiIBpin] E is generated by reaction of nickel(II)
catalyst with B2Pin2.11a,b Subsequently, complex E undergoes
oxidative addition with allyl carbonate 1 to produce π-
allylborylnickel intermediate [allyl(Ln)NiIIIBpin] F.11a Finally,
the product 3 is formed via β-fluoride elimination with the
coordination of B to F atom as a driving force.12 The resulting
nickel fluoride [Bpin(Ln)NiIII−F] undergoes reductive elimi-
nation to produce nickel(I) species G and Bpin-F. Trans-
metalation of G with B2pin2 regenerates active nickel complex
E.
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.8b03841.
Detailed experimental procedures, and characterization
data for new compounds (PDF)
Diels−Alder reactions are widely used for the synthesis of
six-membered rings,13 while the inactivated gem-1,1-difluoro-
1,3-dienes have rarely been utilized as dienes, because of their
poor reactivity.14 We found that Diels−Alder reaction of N-(4-
bromophenyl)maleimide 4 could provide the corresponding
cycloadducts efficiently. But other dienophiles, such as
acrylonitrile and methyl isopropenyl ether, failed to provide
desired products. As shown in Scheme 4a, subjecting N-(4-
bromophenyl)maleimide 4 to gem-difluoro-1,3-dienes 3
proceeded smoothly. However, the cycloadducts 5 were
unstable upon silica gel chromatography, which underwent
the elimination of HF to provide the 1,3-diene products 6 in
good yields. It should be mentioned that even the inactive
substrate 3f bearing an electron-withdrawing group on the
aromatic ring was still applicable to the cycloaddition,
providing the corresponding product 6c in 62% yield.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xgzhang@mail.sioc.ac.cn (X. Zhang).
*E-mail: zxg@wzu.edu.cn (X.-G. Zhang).
ORCID
Xing-Guo Zhang: 0000-0002-4539-7166
Xingang Zhang: 0000-0002-4406-6533
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b03841
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Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21425208, 21672238, and
21421002), the National Basic Research Program of China
(973 Program) (No. 2015CB931900), the Strategic Priority
Research Program of the Chinese Academy of Sciences (No.
XDB20000000) and Natural Science Foundation of Zhejiang
Province (No. LR15B020002).
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