Direct and Regioselective C-H Oxidative Difluoromethylation of Heteroarenes

Article abstract of DOI:10.1021/jacs.8b08135

The difluoromethyl group (CF₂H) is of great interest in the area of medicinal chemistry. However, the investigation of molecular scaffolds containing this group has been hampered by the limitation of synthetic methods for the introduction of CF

Full text of DOI:10.1021/jacs.8b08135

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Communication
Direct and Regioselective C#H Oxidative Difluoromethylation of Heteroarenes
Sheng-Qing Zhu, Yin-Li Liu, Huan Li, Xiu-Hua Xu, and Feng-Ling Qing
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Direct and Regioselective C─H Oxidative Difluoromethylation of
Heteroarenes
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ShengꢀQing Zhu,† YinꢀLi Liu,† Huan Li,‡ XiuꢀHua Xu,† and FengꢀLing Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 345 LinglingLu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North RenminLu, Shanghai
201620, China
Supporting Information Placeholder
CF2H sources respectively. However, these radical processes
ABSTRACT: The difluoromethyl group (CF2H) has great interest
mainly focused on the Nꢀcontaining heteroaromatic substrates
(pyridines, pyrroles, pyrimidines, pyrazines, purines, etc.), and in
some cases a mixture of regioisomers were formed. Thus, the
development of new C─H regioselective difluoromethylation of
other heteroaromatic compounds (Oꢀ or Sꢀcontaining heterocycles)
is highly desirable.
in the area of medicinal chemistry. However, the investigation of
molecules scaffolds containing this group has been hampered by
the limitation of synthetic methods for the introduction of CF2H
into heteroarenes. Herein we disclose a new strategy for the direct
introduction of difluoromethyl group into heteroarenes via the
copper mediated C─H oxidative difluoromethylation of hetꢀ
eroarenes with TMSCF2H. This mild and regioselective method
enables the convenient synthesis of a range of difluoromethylated
Scheme 1.C─H Difluoromethylation of Heteroarenes
heteroarenesin high yields.
The usage of 9,10ꢀ
phenanthrenequinone (PQ) as an oxidant is critical to the success
of this new difluoromethylation reaction.
It is wellꢀrecognized that the introduction of fluoroalkyl groups
into heteroarenes frequently has a dramatic impact on their physiꢀ
cal, chemical, and biological properties.1 Consequently, the fluorꢀ
inated heteroarenes have attached increasing interest in the drug
discovery.2 Among them, the difluoromethylated heteroarenes
such as thiazopyr (herbicide),3a fluxapyroxad (fungicide),3b and
deracoxib (antiꢀinflammatory drug)3c have shown promising bioꢀ
logical activities, probably because the difluoromethyl group
(CF2H) is normally considered as a lipophilic and metabolically
stable hydrogenꢀbond donor.4 Traditional approaches to difluoroꢀ
methylated heteroarenes mainly include deoxyfluorination of
heteroaromatic aldehydes,5 difluorination of benzylic C─H
bonds,6 construction of heteroaromatic systems from CF2Hꢀ
containing building blocks,7 and transformation of CF2Rꢀ
containing heteroarene precursors.8 Recently, the transitionꢀmetalꢀ
assisted difluoromethylation of heteroaromatic compounds (halꢀ
ides,9 boronic acids,10 zinc reagents,11 and diazonium salts12) have
been developed for the synthesis of difluoromethylated hetꢀ
eroarenes. But these protocols rely on the prefunctionalized subꢀ
strates.
Normally, the transitionꢀmetal assisted C─H functionalization
involves the first formation of the metal intermediate and folꢀ
lowed by reaction with electrophilic15 or nucleophilic16 coupling
partners. However, to the best of our knowledge, the transitionꢀ
metal assisted C─H difluoromethylation has not been reported yet.
We reasoned that the following two problems might make C─H
difluoromethylation challenging: (1) the lack of practical electroꢀ
philic difluoromethylating reagents17 hampered the development
of electrophilic coupling pathway (Scheme 1d); (2) the relative
instability of CF2H anion18 resulted in the difficult of the
transmetalation of metal intermediates with nucleophilic difluoꢀ
romethylating reagents (Scheme 1e). As difluoromethyl metal
complexes (LnMCF2H, M = Zn, Ag, Cu) are involved in difluoꢀ
romethylation reactions,9aꢀc,f,i,12 we envisioned that the crossꢀ
Over the past decade, the direct transformation of ubiquitous
C─H bonds has emerged as a straightforward and atomꢀ
economical functionalization method.13 In 2012, Baran and coꢀ
workers reported a direct C─H difluoromethylation of hetꢀ
eroarenes with Zn(SO2CF2H)2 through a radical pathway (Scheme
1a).14a Very recently, Maruoka14b and Nielsen14c disclosed the
radical
difluoromethylation
of
heteroarenes
using
ArI(OCOCF2H)2 (Scheme 1b) or CF2HCO2H (Scheme 1c) as the
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coupling of heteroarenes and LnMCF2H under oxidative condiꢀ
tions might be feasible. In continuation of our research interest in
oxidative fluoroalkylation reactions,19 we disclose here the oxidaꢀ
tive C─H difluoromethylation of heteroarenes with [CuCF2H]
complexes generated in situ from TMSCF2H and copper salt
(Scheme 1f). This protocol provides a convenient and regioselecꢀ
tive access to a variety of difluoromethylated Nꢀ and/or O(S)ꢀ
containing heteroarenes, which are difficultly obtained by radical
difluoromethylation.
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4
5
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8
9
With the optimized reaction conditions in hand, we then evaluꢀ
ated the scope of copperꢀmediated direct difluoromethylation of
oxazoles (Table 2). The mild reaction conditions allow the tolerꢀ
ance of electronically diverse functionalities, including alkyl,
methoxy, methylthio, dimethylamino, halide, trifluoromethyl,
nitro, and cyano substituents (1cꢀ1k). 5ꢀNaphthyloxazole 1l unꢀ
derwent this transformation smoothly, affording 2l in high yield.
Importantly, oxazoles (1mꢀo) bearing a heteroaryl ring were suitꢀ
able to give the desired products (2mꢀo) in good yields and excelꢀ
lent chemoselectivites. Besides aryl substituted oxazoles, alkenyl
and alkyl substituted oxazoles (1p and 1q) could also be emꢀ
ployed in this protocol.
We initiated our studies by exploring the oxidative difluroꢀ
methylation of oxazoles. The oxazole motif is widely found in
pharmaceuticals.20 However, no method is available for the direct
introduction of ꢀCF2H group into oxazoles. Thus, we chose 5ꢀ(4ꢀ
(tertꢀbutyl)phenyl)oxazole (1a) as the model substrate to optimize
the reaction conditions (Table 1). The oxidative difluoromethylaꢀ
tion reaction was firstly conducted with 1a and TMSCF2H in the
presence of CuCl, phen(1,10ꢀphenanthroline), and an oxidant
(DTBP (diꢀtertꢀbutyl peroxide) or Ag2CO3). To our disappointꢀ
ment, the reactions failed to deliver the desired product 2a (entries
1 and 2). Only trace of 2a was detected in the absence of phen
(entry 3). Further screening of the oxidants showed that the oxiꢀ
dant was crucial and only 9,10ꢀphenanthrenequinone (PQ) could
promote the desired reaction in 45% yield (entry 6).The use of
different copper salts revealed that CuCN was optimal (entries 7ꢀ
10). Subsequently, switching DMF to NMP or DMA resulted in
higher yields (entries 11 and 12). When the reaction was perꢀ
formed at lower or higher temperature, no better results were
achieved (entries 13 and 14). To our surprise, the addition of phen
led to a significantly diminished yield (entry 15). Finally, the
yield of 2a was improved to 89% by increasing the amounts of
TMSCF2H, tꢀBuOK, CuCN, and PQ (entry 16).
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Table 2. Substrate Scope of C─H Difluoromethylation of
Oxazolesa
N
CuCN (3.0 equiv)
PQ (1.8 equiv)
t-BuOK (4.5 equiv)
NMP, rt, 6 h
N
+
TMSCF2H
(3.0 equiv)
R
CF2H
R
H
O
O
1
2
N
N
N
CF2H
CF2H
O
CF2H
O
O
t-Bu
MeO
F
i-Pr
2a, 81%
2b, 63%
2c, 75%
N
N
N
CF2H
CF2H
CF2H
O
O
O
Me2N
MeS
Br
2f, 67%
2d, 87%
2e, 83%
N
N
N
O
CF2H
O
CF2H
CF2H
CF2H
Table 1. Optimization of Reaction Conditionsa
O
F3C
2g, 70%
2i, 84%
2h, 58%
N
N
N
O
CF2H
O
CF2H
NC
O
entry Cu salt
ligand
oxidant
solvent yield(%)b
2k, 77%
2j, 60%
2l, 78%
NO2
1
2
3
4
CuCl
CuCl
CuCl
CuCl
phen
phen
—
DTBP
Ag2CO3
DTBP
DMF
DMF
DMF
DMF
0
0
trace
0
N
O
N
O
N
CF2H
CF2H
CF2H
O
N
S
—
Ag2CO3
N
2o, 71%
2m, 83%
2n, 52%
5
6
7
8
CuCl
CuCl
CuI
—
—
—
—
—
—
—
—
—
—
phen
—
PhI(OAc)2 DMF
trace
45
38
39
54
46
75
63
68
71
18
89
BnO
N
PQ
PQ
PQ
PQ
PQ
PQ
PQ
PQ
PQ
PQ
PQ
DMF
DMF
DMF
DMF
DMF
NMP
DMA
NMP
NMP
NMP
NMP
N
CF2H
CF2H
O
Ph
O
CuTc
CuCN
CuSCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
2q, 53%
2p, 68%
9
aReaction conditions: 1 (0.2mmol), TMSCF2H (0.6mmol), CuCN
10
11
12
13c
14d
15
16e
t
(0.6 mmol), BuOK (0.9mmol), 9,10ꢀphenanthrenequinone (0.36
mmol), NMP (4.0 mL), under Ar, rt, 6 h, isolated yields.
This oxidative C─H difluoromethylation was extended to other
heteroarenes. As shown in Table 3, a series of heteroarenes inꢀ
cluding thiazole (3), imidazole (4), 1,3,4ꢀoxadiazole (5), benꢀ
zo[d]oxazole (6), benzo[d]thiazole (7), benzo[b]thiophene (8),
pyridine (9), and thiophene (10) were all compatible to afford the
corresponding difluoromethylated products 13ꢀ20. It was noteꢀ
worthy that the CF2H group was regioselectively attached to the
more acidic carbon of the heteroaromatic ring. In the cases of
imidazole (4), benzo[b]thiophene (8), pyridine (9), and thiophene
aReaction conditions: 1a (0.1 mmol), TMSCF2H (0.2mmol), tꢀ
BuOK (0.3mmol), Cu salt (0.2 mmol), ligand (0.2 mmol), oxidant
b
(0.12mmol), solvent (2.0 mL), under Ar, rt, 6 h. Yields deterꢀ
mined by 19F NMR spectroscopy using trifluoromethylbenzene as
c
e
an internal standard. 0 oC. d50 oC. TMSCF2H (0.3mmol), tꢀ
BuOK (0.45mmol), CuCN (0.3 mmol), PQ (0.18mmol).
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(10), the substitution of electronꢀwithdrawing groups is necessary
gated. As shown in Scheme 2, the oxidative difluoromethylation
of thiazolo[5,4ꢀc]pyridine (23) and 5ꢀ(quinoxalinꢀ6ꢀyl)oxazole (24)
bearing several potential reactive sites took place exclusively on
the more acidic carbon of azole rings, affording the difluoromethꢀ
ylated products 25 and 26. On the other hand, compounds 23 and
24 underwent radical difluoromethylation to give products 27 and
28, in which the CF2H group was connected to the more electronꢀ
poor carbon adjacent to the nitrogen atoms of the heteroarenes.
These results clearly demonstrated the complementarity and orꢀ
thogonality of oxidative and radical difluoromethylation reactions.
for these transformations. Remarkably, this procedure is also apꢀ
plicable for the lateꢀstage C─H difluoromethylation of biologicalꢀ
ly relevant compounds. For example, thiabendazole (fungicide
and parasiticide)21 derivative 11 was converted to product 21 in 82%
yield. Furthermore, neosalvianen (natural product isolated from
Salvia miltiorrhiza)22 analog 12 underwent this oxidative difluoꢀ
romethylation reaction to give compound 22 in 85% yield. Unforꢀ
tunately, other types of heteroarenes including caffeine, pyrimiꢀ
dine, and 1,3,5ꢀtriazine only afforded trace amounts of the desired
products.
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12
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To gain insight into the reaction mechanism of the CꢀH oxidaꢀ
tive difluoromethylation, a competition reaction was conducted
with equivalent amount of compounds 8 and 29 (Scheme 3a). The
difluoromethylation of 8 took place exclusively to afford product
18 in 64% yield, and no conversion was observed for less acidic
substrate 29. This experimental result showed that the deprotonaꢀ
tion of the acidic CꢀH bond of herteroarene with base was crucial
to the oxidative difluoromethylation. Furthermore, the addition
order of the substrates was important for this reaction. Under the
standard procedures, TMSCF2H, 1a, and PQ must be successively
added to the mixture of tꢀBuOK and CuCN in NMP (Scheme 3b).
If 1a was added before TMSCF2H, only trace of 2a was observed.
These result demonstrated that difluoromethylcopper complex
must be generated firstly. Finally, the oxidative coupling of 1a
with the isolated (IPr)Cu(CF2H)9i failed to give the desired prodꢀ
uct 2a (Scheme 3c). We assumed that the bulky IPr ligand might
deactivate the CuCF2H specie for this reaction, which was conꢀ
sistent with the experimental observation (Table 1, entry 15). On
the basis of the above experimental results and reported mechaꢀ
nisms for similar reactions,19e,23 a preliminary reaction mechanism
was proposed (Scheme 4). First, treatment of TMSCF2H with tꢀ
BuOK and CuCN gave CuCF2H and Cu(CF2H)2ꢀ.9b,c Then, deproꢀ
tonation of hereroarene with tꢀBuOK and transmetalation delivꢀ
ered intermediate A. Finally, oxidation of intermediate A with
PQ24 followed by reductive elimination afforded the desired prodꢀ
uct.
Table 3. C─H Difluoromethylation of Other Heteroarenesa
aReaction conditions: 3ꢀ12 (0.2mmol), TMSCF2H (0.6mmol),
Scheme 3.Mechanistic Investigation
CuCN
(0.6
mmol),
t-BuOK
(0.9mmol),
9,10ꢀ
phenanthrenequinone (0.36 mmol), NMP (4.0 mL), under Ar, rt, 6
b
h, isolated yields. Yields determined by 19F NMR spectroscopy
using trifluoromethylbenzene as an internal standard.
Scheme 2.Comparison withOxidative and Radical C─H
Difluoromethylation
To further understand the scope and limitation of this protocol,
the CꢀH difluorometylation of the same heteroarenes under this
oxidative and Baran’s radical14a reaction conditions was investiꢀ
Scheme 4.Proposed Reaction Mechanism
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In conclusion, we have developed a copperꢀmediated oxidative
C─H difluoromethylation of a variety of heteroarenes including
oxazloe, thiazole, imidazole, 1,3,4ꢀoxadiazole, benzo[d]oxazole,
benzo[d]thiazole, benzo[b]thiophene, pyridine, thiophene, and
thiazolo[5,4ꢀc]pyridine. This protocol provides a new method for
selective synthesis of the difluoromethylated heteroarenes that
were not accessible by the reported reactions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS
Publications
website.
Detailed experimental procedures and spectra data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*flq@mail.sioc.ac.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
National Natural Science Foundation of China(21332010,
21421002), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000), and Youth
Innovation Promotion Association CAS (No. 2016234) are
greatly acknowledged for funding this work.
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