Synthesis of Difluoroalkylated Heteroarenes via Difluorocarbene

Article abstract of DOI:10.1021/acs.orglett.1c02603

A diversity-oriented and C2-selective synthesis of difluoroalkyl-substituted heteroarenes from three fragments, N-methoxyazinium salts, difluorocarbene, and electrophilic or radical reagents, is described. The reaction proceeds via the addition of difluorinated phosphorus ylide to in situ methylated heteroarene N-oxides, leading to phosphonium salts, which can undergo further transformations under basic or photoinduced conditions.

Full text of DOI:10.1021/acs.orglett.1c02603

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Letter
Synthesis of Difluoroalkylated Heteroarenes via Difluorocarbene
Alexey L. Trifonov and Alexander D. Dilman*
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ABSTRACT: A diversity-oriented and C2-selective synthesis of
difluoroalkyl-substituted heteroarenes from three fragments, N-
methoxyazinium salts, difluorocarbene, and electrophilic or radical
reagents, is described. The reaction proceeds via the addition of
difluorinated phosphorus ylide to in situ methylated heteroarene N-
oxides, leading to phosphonium salts, which can undergo further
transformations under basic or photoinduced conditions.
luorinated substituents on aromatic scaffolds may have a
profound impact on the biological properties of the small
elimination of methanol, to α-pyridyl-substituted phospho-
nium salts 2 (Scheme 2). Considering that fluorinated
F
molecules1 by enhancing their metabolic stability.2 Azines play
an important role in medicinal chemistry,3 and the use of the
difluoromethylene unit as a link to connect a heterocycle to
other medicinally relevant fragments has recently been
employed as a strategy to protect the heteroaromatic system
from detrimental in vivo oxidation.4 Despite the potential of
this concept for medicinal chemistry, the development of
processes leading to complex structures containing the gem-
difluoromethylene unit is still a demanding challenge. Indeed,
the majority of the known methods for the installation of
complex gem-difluorinated groups require multistep syntheses.5
Modification of the trifluoromethyl6 and difluoromethyl7
groups was recently reported to address this challenge, but in
this approach, the prior introduction of fluorinated substituents
is needed (Scheme 1). Other methods include transition-
Scheme 2. Concept
Scheme 1. Modification of the Fluorinated Groups
phosphonium salts can behave as equivalents of carbanions11
and as sources of radicals,12 subsequent transformations of
salts 2 furnish difluoroalkyl-substituted azines. In this process,
difluorocarbene serves as a key fluorinated building block
capable of forming two bonds with different fragments.13
The difluorinated phosphorus ylide14 exists in equilibrium
with difluorocarbene and triphenylphosphine,15 and it should
be formed in situ in the presence of an electrophile.16 We
applied a combination of (bromodifluoromethyl)-
trimethylsilane and hexamethylphosphoramide (HMPA)
metal-catalyzed cross-couplings, which may require compli-
cated fluorinated reagents5,8 and free-radical processes,9 which
suffer from the regioselectivity problem.10
Received: August 4, 2021
Herein we describe a methodology to access a series of
diverse difluorinated compounds via a site-selective C−H
functionalization of azine N-oxides 1. Our idea is based on the
interaction of N-methoxyazinium salts with the phosphorus
ylide generated from difluorocarbene, leading, after the
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because this method allows us to generate difluorocarbene at
low temperatures.17 It should be noted that TMSCF2Br is
commercially available, but it can also be readily prepared.18
Quinoline N-oxide 1a was selected as a model substrate, and
its C−H fluoroalkylation was evaluated (Table 1). In the
Scheme 3. Isolated Phosphonium Salts
Table 1. Optimization Studies
a
b
Isolated yield. Yield determined by 19F NMR.
a b
,
Scheme 4. Difluoromethylation of Azine N-Oxides
a
no.
deviations
yield of 2a (%)
1
2
3
4
5
6
7
8
none
72
-
no MeOTf
−30 °C
20 °C
MeCN instead of CH2Cl2
DMF instead of MeCN
3.0 equiv of Me3SiCF2Br
2.0 equiv of HMPA
no HMPA
63
<5
68
44
50
17
-
9
10
11
DMPU instead of HMPA
8
-
Ph3P+CF2CO2 at 50 °C in stage (b)
−
a
Determined by 19F NMR with internal standard (PhCF3).
reaction between 1a and the in situ generated ylide, a complex
mixture was formed, which did not contain the expected salt
2a. To obtain the azinium ion, N-oxide 1a was briefly treated
with methyl triflate in dichloromethane at room temperature.
Then, the solvent was exchanged with acetonitrile followed by
the addition of the silicon reagent, HMPA and triphenylphos-
phine. Under the optimized conditions, salt 2a was formed in
72% yield. Cooling of the reaction mixture was crucial, as the
yield dramatically deteriorated if the temperature was increased
to 20 °C (entry 4). A large excess of the silicon reagent (4.5
equiv) was needed, presumably because it served to scavenge
methanol formed during the reaction.
Salts 2 obtained in the solution can be directly used in
further transformations (vide infra); however, if desired, they
can be isolated in the individual form and fully characterized.
For example, salts 2c,e were obtained on a gram scale, and
their structures were supported by X-ray diffraction analysis
(Scheme 3). These compounds are moisture-sensitive and
should be stored under an inert atmosphere.
Under the optimized conditions, a series of azine N-oxides 1
were subjected to the methylation with subsequent interaction
with the difluorinated ylide. The resulting reaction mixtures
containing phosphonium salts 2 were treated with triethyl-
amine and water to effect hydrolytic cleavage of the carbon−
phosphorus bond,16 affording azines 3 bearing the difluor-
omethyl group (Scheme 4).
The reaction works with N-oxides of pyridine, quinoline, and
isoquinoline. The process shows the excellent C2 selectivity of
nucleophilic addition, whereas other regioisomers have never
been detected. Interestingly, when the N-oxide of 2-
methylquionline was evaluated, no four-substituted fluoroalky-
lation product was formed, along with the decomposition of
a
Standard conditions: (a,b) As in Table 1; (c) NEt3 (5 equiv), H2O
b
c
(excess), rt, 12 h. Isolated yields of 3 based on 1 are shown. Because
d
of product volatility, the yield was determined by 19F NMR. D2O
was used instead of H2O.
Me3SiCF2Br. The difference in reactivities between the two-
and four-positions is in accord with the behavior of conjugated
iminium ions toward fluorinated nucleophiles.19 The reaction
tolerates arylsulfide and arylselenide fragments, a silyl group in
the pyridine ring, and thiophene and furane fragments. For the
substrate bearing a double bond, difluorocyclopropanation
products have not been observed. The use of D2O instead of
B
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water at the hydrolysis stage allows facile access to the product
having the deuterodifluoromethyl group. It should be noted
that previous reports on the synthesis of CF2D-substituted
arenes were mainly based on H/D20 or F/D21 exchange.
To demonstrate the potential of pyridine functionalization
beyond difluoromethylation, several transformations of phos-
phonium salts 2 were evaluated (Scheme 5). First, we applied
Finally, we considered the application of phosphonium salts
in photoinduced reactions involving the reductive cleavage of
the P−C bond. Attempted reactions of in situ formed salts 2
gave low product yields. Fortunately, the isolated salt 2e was
successfully coupled to a silyl enol ether and a vinyl
trifluoroborate (in the presence of an iridium photocatalyst)
or to tert-butyl acrylate (in the presence of Hantzsch ester)
under blue light-emitting diode (LED) irradiation (Scheme 6).
a b
,
Scheme 5. Reactions of 2 with Aldehydes and CuBr
a
Scheme 6. Photoinduced Radical Reactions
a
Reagents: for 6a,b, 1% Ir(ppy)3; for 6c, Hantzsch ester (2 equiv).
b
Yield was determined by 19F NMR analysis due to poor silica gel
stability. The HF elimination product was isolated in 39% yield; see
c
d
the SI for details. Isolated yield. E/Z ratio 1.9:1.
In summary, a C2-selective method for the C−H
fluoroalkylation of azine N-oxides is described. The key
intermediates in this reaction are difluorinated phosphonium
salts, which serve as equivalents of fluorinated carbanions and
radicals. In this process, various fluorinated compounds are
assembled from three components: heteroaromatic substrate,
difluorocarbene, and electrophilic or radical reagent.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02603.
Experimental procedures, compound characterization
data, and copies of NMR spectra for all compounds
(PDF)
a
b
Standard conditions for the synthesis of 2 as in Table 1. Isolated
yields are based on 1.
Accession Codes
CCDC 2101396−2101397 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Xiao’s protocol employing the basic activation of phosphonium
salts.11 For the reaction mixtures containing salts 2, the solvent
was exchanged with N,N-dimethylacetamide followed by
treatment with aldehydes and cesium carbonate. In this
process, salts 2 behave as equivalents of pyridyl-substituted
difluorinated carbanions, leading to alcohols 4. Then, we
performed the photoinduced copper-mediated displacement of
phosphonium moiety by bromide,22 providing pyridines 5,
which have the bromodifluoromethyl group at the C2 position.
It is worth mentioning that the developed procedures for the
synthesis of compounds 4 and 5 were carried out in one flask
starting from N-oxides 1.
AUTHOR INFORMATION
■
Corresponding Author
Alexander D. Dilman − N. D. Zelinsky Institute of Organic
Chemistry, 119991 Moscow, Russian Federation;
orcid.org/0000-0001-8048-7223; Email: adil25@mail.ru
C
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Alexey L. Trifonov − N. D. Zelinsky Institute of Organic
Chemistry, 119991 Moscow, Russian Federation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02603
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Science Foundation
(project 20-13-00112).
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