Blue Light Promoted Difluoroalkylation of Aryl Ketones: Synthesis of Quaternary Alkyl Difluorides and Tetrasubstituted Monofluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.0c01294

A facile and cost-effective method for the preparation of fluoroalkylated compounds has been described by the direct photoexcitation of halofluoroalkanes with blue light absorptivity, enabling the difluoroalkylation of aryl ketones. The methodology has provided an efficient, mild, and catalyst-free synthetic method for quaternary difluoroalkylated arenes and tetrasubstituted monofluoroalkenes.

Full text of DOI:10.1021/acs.orglett.0c01294

pubs.acs.org/OrgLett
Letter
Blue Light Promoted Difluoroalkylation of Aryl Ketones: Synthesis of
Quaternary Alkyl Difluorides and Tetrasubstituted
Monofluoroalkenes
Kangkui Li, Jingchao Chen,* Chunhui Yang, Keyang Zhang, Chunxiang Pan, and Baomin Fan*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01294
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ABSTRACT: A facile and cost-effective method for the
preparation of fluoroalkylated compounds has been described by
the direct photoexcitation of halofluoroalkanes with blue light
absorptivity, enabling the difluoroalkylation of aryl ketones. The
methodology has provided an efficient, mild, and catalyst-free
synthetic method for quaternary difluoroalkylated arenes and
tetrasubstituted monofluoroalkenes.
Scheme 1. Difluoroalkylation Reactions of Aryl Ketones
luorine has special and extreme properties, which make
Forganofluorine compounds show unique physical and
chemical properties and occupy an important position in
medicine, pesticides and material science.1 In particular, the
incorporation of a fluorine atom may lead to dramatically
different chemical or stereochemical properties in the bio-
logical activity of organic compounds, including improvement
of the metabolic stability, modulation of acidity and basicity,
and increase of the dipole moments. This can strongly
influence the pharmacokinetic properties, binding affinity,
and bioavailability of a lead compound in drug discovery.2 In
the past few years, the preparation of fluoroalkylated
compounds has received much attention due to its important
role in medicinal chemistry. Compared with the maturity of
various methods of fluorofunctionalization,3 the incorporation
of the CF2 group via the transition-metal-catalyzed difluor-
oalkylation has been less explored, although it has been
represented as a powerful and efficient method for the
preparation of these valuable organic molecules.4 In this
field, the addition of halofluoroalkanes to the unsaturated
compounds by the atom transfer radical addition (ATRA)
strategy has appeared as a powerful synthetic method with
advantages of easy availability of the starting material and great
synthetic versatility of the addition products.5 With the goal of
developing a low cost method for the synthesis of
difluoroalkylated arenes, prominent research has been under-
taken recently by using the first-row transition metals.6 The
recently developed direct C−H fluoroalkylation is also an
attractive methodology with high efficiency. Impressively, the
group of Wang has successfully reported a copper-catalyzed
difluoroalkylation of silyl enol ethers,6f Wang et al. also
demonstrated the elegant difluoroalkylation of tertiary aryl
ketones with cobalt catalyst and a nickel-catalyzed difluor-
oalkylation of aryl ketones (Scheme 1).7 By taking advantage
of the visible light and photocatalyst, Zhu’s group has studied
the synthesis of a fluorinated 1,4-unsaturated dicarbonyl
compound with the radical addition of enol acetate.8 However,
more attractive methods with simple reaction conditions still
remain unexplored.
Received: April 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01294
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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The concept of green chemistry has led to further
requirements for the investigation of atom-economical
synthetic methods. As a result, the development of visible-
light-promoted photocatalyzed reactions has emerged as an
attractive methodology that has been greatly investigated in the
past decade.9 As a continuation of previous work on our
previous investigations on the photocatalyzed synthetic
methodology,10 we became interested in whether the direct
photoexcitation of halofluoroalkanes by visible light absorptiv-
ity11 could offer an efficient method for the preparation of
fluoroalkylated compounds. Herein, a difluoroalkylation of aryl
ketones, which has provided an efficient, mild, and catalyst-free
synthetic method for quaternary difluoroalkylated arenes and
tetrasubstituted monofluoroalkenes, is reported.
the reactions in dark and natural light gave 2a in decreased
yields of 52% and 73%, respectively (Table 1, entries 14 and
15). As ethyl difluorobromoacetate (BrCF2CO2Et) is an
inexpensive and bench-stable privileged fluorinated building
block compared with ethyl difluoroiodoacetate
(ICF2CO2Et),12 efforts were devoted to the study of its
application in current reaction. By using BrCF2COOEt instead
of ICF2COOEt, the reaction yield was decreased to 31%
(Table 1, entry 16). Finally, the use of excessive BrCF2COOEt
in the presence of LDA was identified as the optimal reaction
conditions (Table 1, entry 17, see the Supporting Information
for details).
Subsequently, the scope of aryl ketones was examined first
with ethyl difluoroiodoacetate as the difluoromethyl synthon
(Scheme 2). In general, a wide range of cyclic and acyclic
Initial trials were carried out with the reaction of 2-phenyl-
3,4-dihydronaphthalen-1(2H)-one 1a and ethyl difluoroiodoa-
cetate by the irradiation with a blue LED at −20 °C (Table 1).
Scheme 2. Scope of Difluoroalkylation of Tertiary Aryl
a
Ketones
a
Table 1. Optimization of Reaction Conditions
b
entry
base (equiv)
solvent
temp (°C)
yield (%)
1
2
3
4
LiHMDS (1.1)
Cs2CO3 (1.1)
KOH (1.1)
THF
THF
THF
THF
THF
THF
THF
TBME
CH3CN
toluene
THF
THF
THF
THF
THF
THF
THF
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
0
−40
−20
−20
−20
−20
−20
87
nd
trace
76
tBuOK (1.1)
5
6
7
8
LDA (1.1)
74
90
85
84
66
85
86
90
95
52
73
31
63
NaHMDS (1.1)
KHMDS (1.1)
NaHMDS (1.1)
NaHMDS (1.1)
NaHMDS (1.1)
NaHMDS (1.1)
NaHMDS (1.1)
NaHMDS (1.6)
NaHMDS (1.6)
NaHMDS (1.6)
NaHMDS (1.6)
LDA (1.1)
9
10
11
12
c
13
c d
,
14
15
16
c e
,
f
g
17
a
Reaction conditions: 1a (0.2 mmol), ICF2COOEt (0.4 mmol), in
solvent (2 mL) with the presence of a base was irradiated by 30 W
b
c
d
a
blue LED for 6 h. Isolated yield. Reaction for 2 h. Reaction in dark.
Reaction conditions A (ICF2COOEt was used): 1 (0.2 mmol),
e
f
Reaction in natural light. BrCF2COOEt (0.4 mmol) was used
ICF2COOEt (0.4 mmol), and NaHMDS (0.32 mmol) in THF (2
mL) irradiated by 30 W blue LED at −20 °C for 2 h. Reaction
conditions B (BrCF2COOEt was used): 1 (0.2 mmol), BrCF2COOEt
(0.8 mmol), and LDA (0.22 mmol) in THF (1 mL) irradiated by 30
g
instead of ICF2COOEt. The reaction was performed with
BrCF2COOEt (0.8 mmol) instead of ICF2COOEt with the use of
LDA (0.22 mmol) in THF (1 mL).
b
W blue LED at −20 °C for 12 h. The yield given in parentheses was
obtained by using BrCF2COOEt (0.8 mmol) instead of ICF2COOEt
(conditions B). Using LiHMDS instead of NaHMDS.
We were pleased to find that the initial tested LiHMDS has
allowed the generation of 2a as the corresponding difluor-
oalkylation product in 87% yield (Table 1, entry 1). Some
other bases were tested next; the use of Cs2CO3 and KOH
c
tertiary aryl ketones were transformed smoothly to afford the
difluoroalkylated product with quaternary carbon centers with
satisfactory results. Among them, the reaction yields were
suppressed by the substrates with sterically more demanding
groups in the α-positions (2a−d). Further studies indicated
that modulation of the electronic properties of the α-
substituents groups had a limited influence on the reaction
outcomes (2e−j). With naphthalene as the α-substituent, a
moderate yield was obtained probably due to steric effects
(2k). Cyclic aryl ketones with −OMe or −F groups were
t
failed to promote the reaction, whereas BuOK and LDA gave
decreased yields (Table 1, entries 2−5). The next tested
NaHMDS exhibited the best performance to afford 2a in 90%
yield (Table 1, entries 6 and 7). Some aprotic solvents were
also screened at different temperatures but did not affect the
yield substantially (Table 1, entries 8−12). As our final piece of
optimization, 2a was obtained in 95% yield by increasing the
amount of NaHMDS to 1.6 equiv (Table 1, entry 13). Control
experiments have established the requirement of LED light, as
B
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smoothly difluoroalkylated with excellent yields (2l−m).
Cyclic aryl ketones with α-alkyl substituents participated well
in the current reaction by using LiHMDS instead of NaHMDS
in some cases (2n−q). Both tertiary aryl ketones with five-
membered carbon rings and even O-containing chromanone
also performed well (2r,s). We were pleased to notice that the
acyclic tertiary aryl ketone was also applicable in the current
transformation (2t), and the substituents on the acyclic aryl
ketones were found to have limited influence to the reaction
efficiency (2u−ac). It should be noted that the reaction with
1aa was sluggish after reaction for 1 h, finally resulting in a
moderate yield. Acyclic aryl ketones with two alkyl groups at
the α-position were viable substrates for the difluoroalkylation
(2ad). Donepezil, a famous medicine for the treatment of
Alzheimer’s disease,13 was successfully transformed into the
corresponding difluoro derivative in 75% yields (2ae), which
may be valuable in the research and development of
acetylcholinesterase inhibitors. In addition, it should be
noted that ethyl difluorobromoacetate is an alternative
difluoroalkylation reagent in the present reaction, albeit with
reduced reaction yields (given in parentheses).
The difluoroalkylation of aryl ketones with secondary C−H
bonds was also studied. The light-induced reactions have
afforded the tetrasubstituted monofluoroalkenes in excellent
stereoselectivities without exception under the standard
conditions (Scheme 3). For instance, the secondary aryl
ketones with phenyl and tolyl substituents were transformed
into the monofluoroalkenes with the reaction of ethyl
difluoroiodoacetate (4a−d). However, ethyl difluorobromoa-
cetate was less reactive in the reaction with 1,2-diphenyletha-
none; only 20% of the monofluoroalkene was detected after 12
h (4a). To our delight, we found that the reaction with ethyl
difluoroiodoacetate as fluoroalkylation reagent tolerated a
range of electron-releasing or electron-withdrawing aryl
substituents without significant attenuation of the yield (4e−
o). In contrast, the difluoroalkylation of propiophenone
afforded the difluoroalkylation product in a relatively low
yield (4p).
Next, the mechanism of the present reaction was verified by
some control experiments (Scheme 4). The difluoroalkylation
Scheme 4. Control Experiments
of tertiary aryl ketone 1a under the standard reaction
conditions was completely quenched by 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO), and the trapped product 5 was
observed by GC−MS and 19F NMR analysis. Another control
experiment in the presence of β-piene has generated the
desired difluoroalkylated product 2a together with the ring-
opening product 6 in 21% isolated yield. These results
indicated that an active difluoroalkyl radical was generated
by the direct photoexcitation of ethyl difluoroiodoacetate with
blue light and participated in the difluoroalkylation.
A proposed mechanism is outlined in Scheme 4 on the basis
of the results of control experiments and related references
(Scheme 5).7,10,14c−g The reactions are initiated with the
Scheme 3. Scope of Difluoroalkylation of Secondary Aryl
Ketones
Scheme 5. Proposed Reaction Mechanism
difluoroalkyl radical A, which is generated directly by
photoexcitation of ethyl difluoroiodoacetate or ethyl difluor-
obromoacetate. Then addition of the difluoroalkyl radical A to
enol anion B gives the radical anion intermediate C.
Subsequently, intermediate C could abstract an iodine or
bromine atom to result in formation of the anion intermediate
D, which is transformed to the difluoroalkylation product 1 by
releasing an iodide or bromine ion. In the case of aryl ketone 2
with a hydrogen in α-position, it may be further converted to
the tetrasubstituted monofluoroalkene 4a by the elimination of
HF.
Reaction conditions: 3 (0.2 mmol), ICF2COOEt (0.4 mmol), and
NaHMDS (0.32 mmol) in THF (2 mL) irradiated by 30 W blue LED
a
at −20 °C for 3 h. The reaction was performed using 3a (0.2 mmol),
BrCF2COOEt (0.8 mmol), and LDA (0.22 mmol) in THF (1 mL)
b
In conclusion, the blue light induced difluoroalkylation of
aryl ketones is successfully developed under the catalyst-free
conditions. The reaction proceeds with excellent substrate
scope and good functional group tolerance under mild
irradiated by 30 W blue LED at −20 °C for 12 h; Using LiHMDS
instead of NaHMDS. Note: Yields refer to the total isolated yield of
E- and Z-products; the E/Z ratio was determined by 19F NMR and 1H
NMR spectroscopy.
C
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Experimental procedures and characterization data
(PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Jingchao Chen − Key Laboratory of Chemistry in Ethnic
Medicinal Resources (Yunnan Minzu University), State Ethnic
Affairs Commission & Ministry of Education, Yunnan Minzu
University, Kunming 650031, Yunnan, China;
́
(e) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212. (f) Liang, S.
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J. Am. Chem. Soc. 2016, 138, 13858−13861. (j) Ma, J.-A.; Cahard, D.
Chem. Rev. 2004, 104, 6119−6146.
Email: chenjingchao84@163.com
Baomin Fan − School of Chemistry and Environment and Key
Laboratory of Chemistry in Ethnic Medicinal Resources
(Yunnan Minzu University), State Ethnic Affairs Commission
& Ministry of Education, Yunnan Minzu University, Kunming
650031, Yunnan, China; orcid.org/0000-0003-1789-3741;
Email: adams.bmf@hotmail.com
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Kangkui Li − Key Laboratory of Chemistry in Ethnic Medicinal
Resources (Yunnan Minzu University), State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu
University, Kunming 650031, Yunnan, China
Chunhui Yang − Key Laboratory of Chemistry in Ethnic
Medicinal Resources (Yunnan Minzu University), State Ethnic
Affairs Commission & Ministry of Education, Yunnan Minzu
University, Kunming 650031, Yunnan, China
Keyang Zhang − Key Laboratory of Chemistry in Ethnic
Medicinal Resources (Yunnan Minzu University), State Ethnic
Affairs Commission & Ministry of Education, Yunnan Minzu
University, Kunming 650031, Yunnan, China
Chunxiang Pan − Key Laboratory of Chemistry in Ethnic
Medicinal Resources (Yunnan Minzu University), State Ethnic
Affairs Commission & Ministry of Education, Yunnan Minzu
University, Kunming 650031, Yunnan, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21961045, 21572198), the Applied Basic Research
Project of Yunnan Province (2017FA004, 2018FB021), and
Yunnan Provincial Key Laboratory Construction Plan Funding
of Universities for their financial support.
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