Decarboxylative and Deaminative Alkylation of Difluoroenoxysilanes via Photoredox Catalysis: A General Method for Site-Selective Synthesis of Difluoroalkylated Alkanes

Article abstract of DOI:10.1021/acs.orglett.0c02997

A general method for site-selective difluoroalkylation of alkyl carboxylic redox esters with difluoroenoxysilanes through photoredox-catalyzed decarboxylative reaction has been developed. The reaction can also be extended to aliphatic amine derived pyridinium salts. This method has the advantages of high efficiency, mild reaction conditions, and broad substrate scope, including primary, secondary, and sterically hindered tertiaryl alkyl substrates, providing a general and practical route for applications in organic synthesis and pharmaceutical studies.

Full text of DOI:10.1021/acs.orglett.0c02997

pubs.acs.org/OrgLett
Letter
Decarboxylative and Deaminative Alkylation of
Difluoroenoxysilanes via Photoredox Catalysis: A General Method
for Site-Selective Synthesis of Difluoroalkylated Alkanes
Heng Song, Ran Cheng, Qiao-Qiao Min, and Xingang Zhang*
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ABSTRACT: A general method for site-selective difluoroalkyla-
tion of alkyl carboxylic redox esters with difluoroenoxysilanes
through photoredox-catalyzed decarboxylative reaction has been
developed. The reaction can also be extended to aliphatic amine
derived pyridinium salts. This method has the advantages of high
efficiency, mild reaction conditions, and broad substrate scope,
including primary, secondary, and sterically hindered tertiaryl alkyl substrates, providing a general and practical route for applications
in organic synthesis and pharmaceutical studies.
Scheme 1. Strategies for the Synthesis of Difluoroalkylated
Alkanes
he site selective introduction of fluorinated functionality
Tinto organic molecules for precise molecular engineering
has emerged as an important topic of organic synthesis,
because of the widespread applications of organofluorinated
compounds in pharmaceuticals, agrochemicals, and advanced
functional materials.1 The past decade has witnessed
impressive achievements in the area, most of which focus on
the site-selective fluoroalkylation of (hetero)aromatic com-
pounds.2 However, the site-selective fluoroalkylation, partic-
ularly, difluoroalkylation, of aliphatic substrates at unactivated
position remains challenging.2d,3 Due to the unique properties
of difluoromethylene (CF2) group, the site-selective introduc-
tion of the CF2 moiety into an aliphatic chain can cause the
conformational change, increase the dipole moment, and
improve the metabolic stability of the bioactive molecules.4
Specifically, the presence of a CF2 adjacent to a carbonyl group
can increase its electrophilicity, thus rendering the α,α-
difluoroketones as the effective enzyme inhibitors.5 As such,
the site-selective difluoroalkylation has become a useful
strategy in the drug discovery and development. For example,
bioactive molecules bearing a CF2 moiety have been used as
cholesterol esterase inhibitor6 and anticancer7 and antivirus
agents.8
Traditional methods to synthesize difluoroalkylated com-
pounds include the transformation of the carbonyl groups,
alkenes, and alkynes (Scheme 1A).9 Despite the high efficiency
of this functionality-based strategy, the introduction of a CF2 at
any position on the aliphatic chain through this strategy
remains challenging due to its moderate functional group
compatibility or relatively limited substrate scope. Recently, we
developed a transition-metal-catalyzed difluoroalkylation strat-
egy, providing an alternative approach to access difluoroalky-
lated alkanes (Scheme 1B).10 However, the reaction of
unactivated secondary and tertiary aliphatic substrates remains
Received: September 8, 2020
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© XXXX American Chemical Society
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Letter
a hurdle. To overcome these limitations and meet the high
demand of discovering new CF2-containing bioactive mole-
cules, a radical transformation would be an attractive strategy,
as the radical reactions usually are not sensitive to the steric
effect.11 For practical applications, we sought to use
inexpensive and widely available aliphatic carboxylic acids as
the starting materials, which can be easily transformed into N-
(acyloxy)phthalimides.12 These redox esters can efficiently
generate alkyl radicals via a single electron transfer (SET)
pathway in the presence of photocatalyst.13
We hypothesized that once the alkyl radical A was generated
between N-(acyloxy)phthalimide and the excited photo-
catalyst, the difluoroalkylated compound would be efficiently
accessed with a suitable radical-trapping difluoroalkylating
reagent, such as difluoroenoxysilane previously used for the
visible-light-initiated difluoroalkylation of arene diazonium
salts14 (Scheme 1C). In this process, the newly generated
alkyl radical B was oxidized by the photocatalyst to form a
carbon cation species C, which subsequently underwent
desilylation to produce the difluoroalkyl ketone. This radical
strategy would enable difluoroalkylation of an array of
unactivated primary, secondary, and tertiary aliphatic sub-
strates, thus providing a general approach to access
difluoroalkylated alkanes.
DMA and DMSO were comparable with DMF, and CH3CN
was slightly less effective (entry 5, for details see the
Supporting Information). But the ethereal solvent 1,4-dioxane
almost suppressed the reaction (entry 6). Decreasing the
reaction temperature to room temperature slightly diminished
the reaction efficiency with an 85% yield of 3a obtained (entry
7). Essentially, no reaction occurred in the absence of
photocatalyst or blue light irradiation (entries 8 and 9),
demonstrating that the [Ir]-catalyst and blue light play an
essential role in promoting the reaction.
With the viable reaction conditions in hand, we examined
the difluoroalkylation of a variety of redox-esters 1. Overall, the
reaction was not sensitive to the steric effect. Good to high
yields were obtained with primary, secondary, and tertiary alkyl
carboxylic esters. As illustrated in Scheme 2, cyclic secondary
Scheme 2. Photoredox-Catalyzed Decarboxylative
a
Alkylation of Difluoroenoxysilanes 2
Accordingly, we chose aryl-substituted difluoroenoxysilanes
2 as the difluoroalkylating reagents. Due to the electron-
withdrawing effect of the fluorine atom, these electron-
deficient alkenes are favorable to reacting with a nucleophilic
alkyl radical. We began our studies from the reaction of
secondary alkyl carboxylic redox-ester 1a with p-toyl
substituted difluoroenoxysilane 2a under photoredox reaction
conditions (Table 1). We found that the use of commercially
Table 1. Representative Results for Optimization of
Photoredox-Catalyzed Decarboxylative Alkylation of
a
Difluoroenoxysilane 2a with 1a
b
entry
reaction conditions
Standard conditions
[Ir(dtbbpy)(ppy)2]PF6 instead of fac-Ir(ppy)3
Ir[dF(CF3)ppy]2(dtbbpy)PF6 instead of fac-Ir(ppy)3
Ru(bpy)3(PF6)2 instead of fac-Ir(ppy)3
CH3CN instead of DMF
1,4-Dioxane instead of DMF
reaction run at room temperature
w/o blue LED
yield (%), 3a
1
2
3
4
5
6
7
8
9
94 (94)
76
26
8
87
10
85
0
a
Reaction conditions (unless otherwise specified): 1 (0.5 mmol, 1.0
equiv), 2 (1.5 mmol, 3.0 equiv), DMF (5 mL) at 60 °C for 48 h.
b
Gram-scale reaction: 1 (4 mmol, 1.0 equiv), 2 (12 mmol, 3.0 equiv),
DMF (40 mL) at 60 °C for 48 h.
alkyl redox esters furnished the corresponding products
efficiently (3a−3d). High yields were obtained with piper-
idine-, tetrahydropyran-, and cyclohexane-derived substrates
(3a−3c). A four-membered azetidine derivative was also
applicable to the reaction, and an even higher yield (98%) was
obtained by gram-scale synthesis (3d). Since CF2 and azetidine
are pharmaceutically relevant structural motifs, the current
process may have potential applications in medicinal
chemistry. The reaction was not restricted to the cyclic
substrates, as the acyclic secondary alkyl redox esters
underwent the difluoroalkylation smoothly (3e and 3f). An
unactivated secondary heptyl substituted ester provided the
corresponding product 3e with high efficiency. A phenyl-
alanine-derived substrate was also a competent coupling
partner with an 81% yield obtained (3f). The generality of
w/o fac-Ir(ppy)3
3
a
Reaction conditions (unless otherwise specified): 1a (0.5 mmol, 1.0
b
equiv), 2a (1.5 mmol, 3.0 equiv). Determined by 19F NMR using
fluorobenzene as an internal standard and number in parentheses is
isolated yield.
available photocatalyst fac-Ir(ppy)3 (1 mol %) in DMF under
blue light (12 W, 460−465 nm) irradiation could provide the
desired product 3a in 94% yield upon isolation (entry 1). A
slightly lower yield was obtained with [Ir(dtbbpy)(ppy)2]PF6
as the catalyst (entry 2). However, other photocatalysts,
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ru(bpy)3(PF6)2, led to
poor yields (entries 3 and 4). Among the tested solvents,
B
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this method can also be demonstrated by difluoroalkylation of
tertiary redox esters (3g−3j). Although the sterically hindered
tertiary alkyl radicals are more stable and less reactive than
primary and secondary alkyl radicals, high yields were still
obtained. Pivalic acid and 2,2-dimethylbutanoic acid derived
substrates underwent the difluoroalkylation efficiently (3g and
3h), and even as high as a 92% yield of 3i was provided.
Adamantane carboxylate was also amenable to the reaction
without difficulty (3j). With respect to primary alkyl redox
esters, the corresponding difluoroalkylated products 3k and 3l
could be readily prepared through the current process. In
addition, difluoroenoxysilanes with different aryl substituents
were also competent coupling partners (3m and 3n),
demonstrating the generality of this method further.
substrate 1q underwent the difluoroalkylation efficiently. Most
remarkably, the dipeptide-based redox-ester 1s also exhibited
high reactivity, providing the α,α-difluoroalkyl ketone-contain-
ing peptide 3s in 72% yield with 1:1 dr. Since α,α-
difluoroketones are susceptible to forming ketal/hemiketal-
type adducts with an enzyme active site, and the electron-
withdrawing effect can stabilize the resulting tetrahedral
adducts,15 this method provides potential opportunities for
applications in discovering a new enzyme inhibitor of
medicinal interest.
Although considerable efforts have been made on the
catalytic fluoroalkylation reactions, practical methods with a
low catalyst loading to efficiently prepare fluoroalkylated
compounds are rare.16 In this context, gram-scale reaction of
redox-ester 1a and difluoroenoxysilane 2a with 0.01 mol % of
photocatalyst was conducted and provided the difluoroalky-
lated product 3a in 84% yield (Scheme 5A). In this reaction,
We also found that the reaction showed excellent trans-
selectivity with cyclopropanecarboxylic acid derivatives as the
coupling partner (Scheme 3). Both trans- and cis-2-
Scheme 3. trans-Selective Synthesis of 3o from trans- and
cis-Redox-Esters 1o
Scheme 5. Gram-Scale Synthesis with 0.01 mol % Catalyst
Loading and Photoredox-Catalyzed Deaminative Alkylation
of Difluoroenoxysilanes
phenylcyclopropane-1-carboxylic acid derived redox esters
(1o) solely afforded trans-difluoroalkylated cyclopropane 3o
with high efficiency, indicating that a planar cyclopropyl radical
is involved in the reaction.
The utility of this method has also been demonstrated by the
late-stage difluoroalkylation of pharmaceuticals and peptides.
As shown in Scheme 4, gemfibrozil, a drug used for the
treatment of hyperlipidemias, could be successfully modified
by reaction of its redox-ester 1p with difluoroenoxysilane 2a in
95% yield on gram scale. Similarly, indomethacin derived
only 1.3 equiv of redox-ester 2a was used, thus demonstrating
the reliability and practicability of this protocol. In addition to
alkyl carboxylic esters, the aliphatic amine derived pyridinium
salts 4 were also applicable to the reaction (Scheme 5B).
Piperidine-based pyridinium salt 4a underwent the difluor-
oalkylation smoothly, leading to 3a in a comparable yield.
Pyridinium salt 4b bearing a phenylalanine moiety was also a
suitable substrate with the carboxylic ester intact (Scheme 5B,
3t),17 thus providing a complementary method to the
decarboxylative process, in which the amine group was
reserved (Scheme 2, 3f).
Scheme 4. Late-Stage Modification of Pharmaceuticals and
Peptide
Importantly, the resulting difluoroalkylaryl ketones can serve
as a versatile building block for diversified synthesis of
fluorinated compounds. As depicted in Scheme 6A, the p-
toyl acyl (pMe-C6H4CO) group could be readily removed to
generate difluoromethylated alkanes 5. Ketones 3 bearing
cyclic or acyclic secondary alkyl groups all provided the
corresponding products efficiently (5a−5c). Even tertiary alkyl
substituted ketone 3p, which is derived from the pharmaceut-
ical gemfibrozil, underwent the reaction smoothly (5d),
offering good opportunities for modification of the bioactive
molecules further. Although the transition-metal-catalyzed
difluoroalkylation represents a modern strategy to prepare
fluorinated compounds,2d,10 the difluoromethylation of tertiary
C
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Scheme 6. Transformations of Compound 3
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02997.
Detailed experimental procedures, and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Xingang Zhang − College of Chemistry, Henan Institute of
Advanced Technology, Zhengzhou University, Zhengzhou
450001, China; Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China; orcid.org/
0000-0002-4406-6533; Email: xgzhang@mail.sioc.ac.cn
Authors
Heng Song − College of Chemistry, Henan Institute of Advanced
Technology, Zhengzhou University, Zhengzhou 450001, China
Ran Cheng − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
Qiao-Qiao Min − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02997
Notes
The authors declare no competing financial interest.
alkyl remains a challenging topic. The current process can
overcome this limitation, thus featuring the advantages of this
method.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21931013, 21672238,
21790362, and 21421002) and the Strategic Priority Research
Program of the Chinese Academy of Sciences (No.
XDB20000000).
The difluoroalkylaryl ketones can also be used for the
preparation of α,α-difluoroalkyl carboxylic esters through
Baeyer−Villiger oxidation (Scheme 6B). Given the important
applications of fluorinated amino acids in medicinal chemistry
and chemical biology,18 the resulting protected fluorinated
amino acid 6a and α,α-difluoro-β-amino acid 6b may have
potential applications in the design of peptide based bioactive
molecules. Furthermore, reduction of the ketone carbonyl
group provided the alcohol efficiently (Scheme 6C), thus
demonstrating the synthetic utility of this protocol further.
In conclusion, we have developed a general method to
prepare difluoroakylated alkanes through photoredox-catalyzed
decarboxylative and deaminative alkylation of difluoroenox-
ysilanes. The reaction proceeds under mild reaction conditions
and allows difluoroalkylation of an array of primary, secondary,
and tertiary alkyl carboxylic redox esters with high efficiency,
excellent site selectivity, and broad substrate scope, including
pharmaceuticals and peptides. The synthetic utility of this
protocol has also been demonstrated by the gram-scale
synthesis of difluoroalkylated alkane with low catalyst loading
(0.01 mol %, 8400 TON), representing a practical method for
fluoroalkylation. The resulting difluoroalkyl ketones can serve
as a versatile building block for diversified synthesis of
fluorinated compounds, including difluoromethylated alkanes
bearing a quaternary carbon center that otherwise are difficult
to prepare through conventional methods, thus paving a new
way in the preparation of fluorinated compounds of interest in
the medicinal chemistry and chemical biology.
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