Highly effective copper-mediated gem-difluoromethylenation of arylboronic acids

Article abstract of DOI:10.1039/c4cc03321c

A copper-mediated gem-difluoromethylenation of aryl, heteroaryl and vinyl boronic acids with bromodifluoromethylated oxazole or thiazole derivatives has been developed. This novel reaction showed an excellent functional group tolerance and wide substrate scope, providing facile access to practical application in drug discovery and development. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03321c

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Highly effective copper-mediated
gem-difluoromethylenation of arylboronic acids†
Cite this: Chem. Commun., 2014,
50, 7527
Guobin Ma,a Wen Wan,*a Qingyang Hu,a Haizhen Jiang,a Jing Wang,a
Shizheng Zhub and Jian Hao*ab
Received 4th May 2014,
Accepted 20th May 2014
DOI: 10.1039/c4cc03321c
www.rsc.org/chemcomm
A copper-mediated gem-difluoromethylenation of aryl, heteroaryl and aryl boronic acids with difluoroalkyl halides becomes a ‘‘young
vinyl boronic acids with bromodifluoromethylated oxazole or thiazole generation’’ in the synthesis of difluoromethylation arenes. Therefore,
derivatives has been developed. This novel reaction showed an excellent more and more attention has been focused on this promising synthetic
functional group tolerance and wide substrate scope, providing facile strategy. For instance, Shen reported Cu-mediated aerobic difluoro-
access to practical application in drug discovery and development.
alkylation of arylboronic acids in moderate yields (Scheme 1a).10
Recently, Zhang developed Pd-catalyzed difluoroalkylation of aryl
Due to the unique properties of the difluoromethylene group (CF2), boronic acids with bromodifluoromethylated phosphonate, bromo-
functionalized difluoromethylated arenes are widely prevalent in difluoromethylated carboxylic acid derivatives, and 3-bromo-3,3-
biologically active pharmaceuticals, agrochemicals and organic func- difluoropropene (Scheme 1b).11 Despite these important advances,
tional materials.1 Indeed, the CF2 fragment is usually considered as most of the current strategies for gem-difluoromethylenation are
a bioisostere to an ethereal oxygen atom, a carbonyl group,2 which still suffering from one or more limitations, such as the use of
leads to increased dipole moments, enhanced acidity of its neigh- expensive Pd-catalysts, unavailable or unstable difluoroalkyl reagents,
boring groups, and conformational changes.3 As a key component of higher reaction temperature, a limited substrate scope or generality,
identical and non-identical twin drugs, the composition of the etc. Hence, it is highly desirable to develop new methods and
linkage which acts as a bridge connection of both pharmacophores stable and readily available difluoroalkyl reagents to address these
is the priority to be considered in drug design and innovation.4 issues. Our group is always interested in the functionalization of
Based on the above understanding, the linker which contains bromodifluoromethylated oxazole or thiazole analogues,12 which
the gem-difluoromethylene component is proposed to be one of may be good substrates for the difluoromethylenation reaction.
the most valuable linkages for binding two pharmacophores. For Thus, we describe herein the first example of Cu-mediated gem-
example, A79285 containing a central gem-difluoromethylene difluoromethylenation of aryl, heteroaryl and vinyl boronic acids
motif is an excellent inhibitor of HIV-1 aspartic protease.5 with inexpensive and readily available bromodifluoromethylated
Although significant progress has been made in trifluoromethyla- heterocyclic compounds as a simple and efficient reaction protocol for
tion6 and difluoromethylation7 of arenes in recent years, mild and practical application in drug discovery and development (Scheme 1c).
efficient strategies for the introduction of gem-difluoromethylene This new method proceeds under mild conditions without the
moieties into aromatic compounds have been less explored,8 due need for any additives, and provides a variety of aryldifluoro-
to the shortage of the gem-difluoromethylene source and the methylated heterocyclic compounds with high efficiency and
instability of difluoroalkyl intermediates.
excellent functional-group compatibility.
A general approach of introducing the difluoromethylene group
was on the basis of the transitional metal mediated or catalyzed
coupling reaction between aryl halides and difluoroalkyl halides.9
Compared with traditional methods, cross-coupling reaction of
a School of Materials Science and Engineering, Department of Chemistry,
Shanghai University, Shanghai 200444, China. E-mail: wanwen@staff.shu.edu.cn,
jhao@shu.edu.cn
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03321c
Scheme 1 Preparation of difluoromethylene derivatives.
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Table 1 Optimization of reaction conditions
Table 2 The scope of gem-difluoromethylenated arylboronic acids with 2a
Entry
[Cu]
1a : 2 : [Cu]
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Cu2O
CuI
CuBr
CuCl
Cu(OTf)*1/2Ph
CuBr2
Cu(OAc)2
Cu(CO2CF3)2
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 1
1 : 2 : 2
1 : 2 : 2
1 : 2 : 2
1 : 2 : 2
1 : 2 : 2
1 : 3 : 3
1 : 3 : 3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMSO
DCM
CH3CN
NMP
NMP
0
20
49
38
32
0
40
8
56
82
77
72
0
9
10
11
12
13
14
15
16
0
97 (85b)
81c
a 19F NMR yields. Isolated yields. Under N2.
b
c
We initially focused on the gem-difluoromethylenation of
phenylboronic acid 1a with bromodifluoromethylated benzox-
azole 2. Reaction conditions were evaluated to optimize the cross-
coupling gem-difluoromethylenation (Table 1). It was found that
1a and 2 were treated with CuI at room temperature for 16 h in
NMP to give the desired cross-coupling gem-difluoromethylenated
product 3a in 20% yield based on the 19F NMR and LC-MS
analysis (Table 1, entry 2). After switching Cu salts from CuX
(X = I, Br, or Cl) to CuX2 (X = Br, OAc, or CO2CF3), the yield of 3a
improved to 49% (Table 1, entries 3–8). Fortunately, the yield of
product 3a enhanced to 82% when Cu0 powder (2.0 equiv.) was
added to the reaction mixture. The solvent effects in this reaction
were also examined. It was found that the reaction could be
a
Isolated yields.
carried out in DMF, DMSO or NMP, among which NMP was and position on the aromatic ring (3e–3g, 3r–3t). Arylboronic acids
proved to be the best (Table 1, entries 9–14). Notably, the yield of containing electron-donating groups were readily converted into
the reaction was significantly decreased and no new signals could the corresponding products in moderate to good yields (3e–3h).
be detected by 19F NMR, indicating that there was no new While substrates with electron-withdrawing groups, such as trifluoro-
fluorine-containing Cu complex formed when bipy or phen was methyl (3m), cyano (3n), acetyl (3o), formyl (3p), nitro (3q), and ester
added to this reaction (ESI,† Table S1). The addition of phosphine (3r–3t), gave the corresponding gem-difluoromethylenated arenes in
ligands such as Ph3P, DPPP, or DPPF was also ineffective. Further moderate to excellent yields. Carbonyl groups such as ketone, ester,
investigation of the influence of the bases on the reaction indicated and aldehyde (3o–3t) could be survived, although the conventional
that the reactions were completely shut down, when the base, such nucleophilic fluoroalkylation attack generally occurred in carbonyl
as KOAc, Na2CO3, Cs2CO3 or t-BuOK, was employed. A quick carbon. Importantly, the halogenated arylboronic acids were effec-
screening of the reactant ratio revealed that 1a :2:Cu = 1:3:3 was tively converted into the corresponding difluoromethylated products,
the ideal ratio of reactants in the formation of 3a (97% by 19F NMR, whereas a substitution of the corresponding halide was never or rarely
entry 15). In addition, the N2 atmosphere has a negative effect on observed (3i–3l). This situation is remarkable, because the most
this gem-difluoromethylenation reaction, affording 3a in a slightly common difluoromethylation reactions substitute halides, especially
lower 19F NMR yield of 81% (entry 16).
iodides.9 Therefore, the new transformation shows a reaction pathway
With the optimized reaction conditions in hand, the scope that is orthogonal to common routes. Interestingly, the heterocyclic
of the gem-difluoromethylenation with a number of arylboronic arylboronic acids and vinyl boronic acids could be successfully
acids was investigated (Table 2). A wide range of arylboronic gem-difluoromethylenated to afford products in moderate yields
acids were readily converted into the corresponding gem- (3u–3y). It is particularly noteworthy that the 1,4-phenylenedi-
difluoromethylenation arenes in moderate to excellent yields. boronic acid was a suitable substrate for transformation to
The results were almost independent of the substituent type afford the bis-difluoromethylenated product (3z).
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Table 3 gem-Difluoromethylenated arylboronic acids with 4–6a
Scheme 2 Plausible mechanistic pathways.
radical inhibitor, and 1,4-dinitrobenzene, an electron-transfer
scavenger, had a negligible impact on the yield of reactions
under an air atmosphere. These results suggest against a purely
free radical pathway.
The unique effectiveness of Cu in this reaction is mechanistically
intriguing. Therefore, we carried out a few control reactions to probe
for the possible mechanism. First, activated Cu powder was reacted
with 2 in NMP under air. No new product was detected by 19F NMR
and reactant 2 was fully recovered. This result indicated that
[ArCF2Cu] is not formed in the aforementioned reaction. When we
applied a stoichiometric amount of PhB(OH)2 with Cu powder, a
biphenyl product was afforded in 76% yield, suggesting that [PhCu]
intermediates play an important role in the reaction.16 To our
delight, the desired product 3a was observed in 23% yield when a
coupling reaction was conducted by treating 2 with [PhCu] prepared
according to a procedure reported by Costa.17
On the basis of these observations, the proposed reaction
mechanisms were depicted in Scheme 2. Arylboronic acid is
first converted to the [Aryl-CuI] intermediate in the presence
of Cu powder and air. This cuprate of aryl copper species
could either react with 2 by oxidative addition to form a
CuIII(ArCF2)(Aryl) species, followed by reductive elimination to
give Aryl-CF2–Ar, or directly initiate an SN2-type substitution
(or s-bond metathesis) reaction at the CF2 center to release the
desired product 3. There was also a possibility that [CuI]
participates in the same reaction (Table 1, entry 3).
In summary, we have disclosed the first example of a simple
and highly efficient Cu-mediated gem-difluoromethylenation of a
variety of aryl, heteroaryl and vinyl boronic acids with inexpensive
bromodifluoromethylated heterocyclic compounds. The transforma-
tions were performed in air at room temperature without the need
for sealed reaction vessels and, importantly, a ligand, a base, or an
additive was not necessary. The remarkable functional group
tolerance and a wide substrate scope mean that this reaction will
find wide applications in the discovery and development of various
drugs. Ongoing studies are focused on probing the mechanism
and developing related Cu-catalyzed gem-difluoromethylenation
transformations.
a
b
Isolated yields. 50 1C under a N2 atmosphere.
Bromodifluoromethylated oxazolic and thiazolic derivatives 4–6
were also applied in this cross-coupling reaction, which proceeded
smoothly to afford the gem-difluoromethylenated arenes in good
to excellent yields (Table 3). Methyl-substituted bromodifluoro-
methylated benzoxazole 4 was converted into the corresponding
gem-difluoromethylenated arenes 7a–7c in 75%–95% yields.
Bromodifluoromethylated benzothiazole was also a suitable
substrate, providing compounds 8a–8e in good yields. Interest-
ingly, the bromodifluoromethylated dihydrooxazole derivative 6
afforded 9 in synthetically useful yield. It is noteworthy that
dihydrooxazoles have important applications in the design of
drug molecules and chiral catalysts. Thus, this method provided
a convenient and facile route for such valuable building blocks.
However, 2-(bromodifluoro-methyl)-1-butyl-benzoimidazole was
ineffective under the optimized conditions.
The oxazoles are useful equivalents of protected acid13 and there-
fore can be easily converted to various functional groups, such as
formyl (CHO), carbonyl (CQO), ester (CO2R), etc.14 We believe that
this versatility makes difluoromethylenated oxazoles useful in the
synthesis of new CF2 building units. To demonstrate this synthetic
potential, we tested the transformation of 3d to 2-([1,10-biphenyl]-4-yl)-
2,2-difluoroacetic acid with zinc chloride in 14% HCl/EtOH at 80 1C,
affording 65% yield (ESI,† S16). Difluoroacetic acid is known to be
an important precursor for the construction of the difluoro-
methyl7b or trifluoromethyl group.15 Therefore, this new strategy
can be applied to the synthesis of a large number of fluorine-
containing drug candidates.
This work was financially supported by the National Natural
Science Foundation of China (21072127, 21032006, 21172141,
and 21302121). We also thank the Instrumental Analysis and
Research Centre of Shanghai University for assistance.
It has previously been shown that a Cu0 can initiate the
generation of radicals from difluoroalkyl halides through single
electron transfer (SET).9d To identify whether a radical pathway is
involved in the Cu-mediated transformation, several experiments
were conducted (ESI,† Table S2). Experimental studies showed that
the yields of the Cu-mediated gem-difluoromethylenation of phenyl-
boronic acid were almost identical in the presence or absence of
ambient light. Furthermore, the addition of hydroquinone, a known
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