Phosphonium Ylide-Mediated Programmable Fluorination to Access Mono- And Difluoromethylarenes

Article abstract of DOI:10.1021/acs.orglett.1c00457

Compounds bearing fluorinated moieties are pervasive in a wide range of pharmaceuticals and agrochemicals. The installation of fluorinated units is a persistently vital task in synthetic chemistry, where facile and manipulable assays are highly demanding.

Full text of DOI:10.1021/acs.orglett.1c00457

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Letter
Phosphonium Ylide-Mediated Programmable Fluorination to Access
Mono- and Difluoromethylarenes
Yu Zheng, Zhen-Zhen Xie, Xian-Chen He, Yan-Shan Chen, Wen-Shuo Cheng, Kai Chen,
Hao-Yue Xiang,* Xiao-Qing Chen,* and Hua Yang*
Cite This: Org. Lett. 2021, 23, 2538−2542
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ABSTRACT: Compounds bearing fluorinated moieties are
pervasive in a wide range of pharmaceuticals and agrochemicals.
The installation of fluorinated units is a persistently vital task in
synthetic chemistry, where facile and manipulable assays are highly
demanding. Herein, we establish a general and programmable
fluorination strategy for the modular assembly of mono- and
difluoromethylarenes through the controllable deprotonation and
fluorination of phosphonium ylides. Moreover, the rational
combination of the reaction sequence allows the rapid construction
of diversified fluorine-containing arenes.
Scheme 1. Synthetic Profiles for Mono- And
Difluoromethylated Arenes
renes containing organofluorine units such as CF3, CF2H,
and CFH2 groups have proven to be particularly valuable
A
in pharmaceuticals, radiopharmaceuticals, agrochemicals, and
materials, which is prominently attributed to the benefits of
“magic fluorine effects” that alter the affinity, solubility,
permeability, metabolism, and lipophilicity of the correspond-
ing chemical entities.1 Up until now, extensive efforts have
been devoted to the development of efficient strategies to
access these fluorine-containing arenes.2 In contrast to the
well-established pathways for trifluoromethylated substances,3
the methods for the syntheses of mono- and difluoromethy-
lated scaffolds are rather less explored. In this respect, the
exploration of a new synthetic approach to assemble mono-
and difluoromethylated arenes has been a flourishing direction
during the past few decades.4,5
With the advent of new fluoroalkylation reagents, impressive
advances in the transition-metal-mediated assembly of CF2-
and CFH2-bearing compounds through C−C bond formation
have been achieved (Scheme 1a).6 Another major pathway
relies on the nucleophilic substitution reaction of benzylic
derivatives to generate a C−F bond, serving as a straightfor-
ward process to form fluorinated arenes.7 In these trans-
formations, the preinstallation of a functional group was mostly
required to offer a reaction site for the fluorinating reagents.
Several radical strategies were recently developed to realize the
direct fluorination of benzylic C−H under photocatalytic
conditions to prepare mono- and difluorinated arenes.8 In
addition, a silver-catalyzed oxidative activation of C−H bonds
by the Selectfluor reagent for direct difluorination was
developed by Tang’s group.9 Despite these advances, a new
strategy is still highly desirable to face the increasing needs for
CF2- and CFH2-bearing arenes.
Received: February 8, 2021
Published: March 19, 2021
https://doi.org/10.1021/acs.orglett.1c00457
Org. Lett. 2021, 23, 2538−2542
© 2021 American Chemical Society
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Letter
In 2020, Young and co-workers unveiled an unprecedented
case of a P-mediated protocol for the selective hydro-
defluorination of trifluoromethyl groups wherein a phospho-
nium salt was involved (Scheme 1b).10 Considering the
electronic features and chemical reactivity of phosphonium
ylide, we rationalized that installing a phosphonium ylide
moiety at the benzylic position would remarkably activate the
α-H, favoring its deprotonation and the following electrophilic
fluorination. It can be expected that the deprotonation of
phosphonium ylides might be modulated by manipulating the
base, which would thus offer an adjustable and general pathway
to assemble mono- and difluoromethyl arenes (Scheme 1c).
Simultaneously, the deprotonated phosphonium salts could be
captured by other electrophiles, such as D2O, MeI, and
aldehyde, to provide synthetic opportunities for broad and
valuable fluorine-containing scaffolds,11 which would set up a
versatile platform for synthetic and medicinal chemistry.
To validate our design, we sought to study the fluorination
of ([1,1′-biphenyl]-4-ylmethyl)triphenyl-phosphonium bro-
mide (1a) with N-fluorobenzenesulfonimide (NFSI, 2a)
(Table 1). As expected, using 4 equiv of KOt-Bu(solid) and
3 equiv of NFSI yielded the desired difluorinated product 3a in
a 30% yield after work-up with an aqueous K2CO3 solution
(Table 1, entry 1). Increasing the equivalence of both KOt-Bu
and NFSI slightly promoted the chemical yield of 3a (Table 1,
entries 2 and 3, respectively). It was found that the reaction
temperature and base in the fluorination step were crucial to
the reaction efficiency and chemoselectivity. The chemical
yield of 3a significantly increased to 83% when the fluorination
transformation process was performed at 45 °C (Table 1,
entries 4−6). Notably, a small amount of the monofluorinated
product 4a was isolated even with excess amount of NFSI at a
relatively lower temperature, which encouraged us to further
optimize the conditions to regulate the reaction chemo-
selectivity. Interestingly, a KOt-Bu solution (1.0 M in THF)
was beneficial for yielding they monofluorinated product
compared with the corresponding solid KOt-Bu (Table 1,
entry 8). Other bases, such as NaOt-Bu, LiOt-Bu, KOH, and
NaOH, were also tested but gave inferior results (Table 1,
entries 8−11, respectively). Thereafter, we shifted our
attention to investigate the reaction conditions for mono-
fluorination. Simultaneously lowering the loading of NFSI and
the base in addition to decreasing the reaction temperature
resulted in an improved chemical yield of 4a (Table 1, entry
12), albeit with a poor chemoselectivity. Screening of the base
revealed that n-BuLi (1.6 M in THF) was the optimal choice
for monofluorination (Table 1, entries 13−16). Increasing the
amount of NFSI to 3 equiv led to a better yield (Table 1, entry
17), while reducing the amound of NFSI prejudiced this
transformation (Table 1, entry 18).
With these conditions in hand, we next set out to evaluate
the scope of this new fluorination protocol, and a wide range of
di- and monofluoromethylarenes were rapidly furnished. First,
the generality for the difluoronation reaction of various ylides 1
was evaluated (Scheme 2). The reaction proceeded well for
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of the Difluorination Transformation
2a
(equiv)
T
(°C)
yield (100%) (3a/
4a)
ab
,
entry
base (equiv)
1
2
3
4
5
6
7
8
3
4
4
4
4
4
4
4
4
4
4
2
2
2
2
2
3
1
KOt-Bu (s) (4)
KOt-Bu (s) (4)
KOt-Bu (s) (5)
KOt-Bu (s) (5)
KOt-Bu (s) (5)
KOt-Bu (s) (5)
KOt-Bu/THF (5)
NaOt-Bu (s) (5)
LiOt-Bu (s) (5)
KOH (s) (5)
60
60
60
50
45
40
45
45
45
45
45
0
0
0
0
0
0
0
30/trace
39/trace
43/trace
75/8
83/6
70/9
54/25
64/11
55/12
45/15
43/14
34/35
10/75
13/60
12/59
9/63
e
9
10
11
12
13
14
15
16
17
18
NaOH (s) (5)
KOt-Bu (s) (1.05)
f
n-BuLi (1.05)
e
KN(TMS)2 (1.05)
LiN(TMS)2 (1.05)
e
g
LDA (1.05)
f
n-BuLi (1.05)
n-BuLi (1.05)
7/81
21/45
f
a
Reaction conditions are as follows: (i) 1a (0.4 mmol) and base (x
equiv) in THF at 0 °C for 30 min under Ar; (ii) a solution of NFSI 2a
(x equiv) in THF (4 mL) was added, and the mixture was stirred for
another 12 h at the specified temperature; (iii) 4 equiv of K2CO3 in
H2O (4.0 mL) was added, and the mixture was stirred at 45 °C.
b
c
Isolated yields. Reaction times of 1 h for entries 1−11 and 12 h for
d
entries 12−18. Reaction times of 12 h for entries 1−11 and 1 h for
e
entries 12−18. The corresponding solution of base in THF (1.0 M)
f
g
was used. n-BuLi in THF (1.6 M) was used. LDA in THF (2.0 M)
was used.
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Organic Letters
pubs.acs.org/OrgLett
Letter
aromatic substrates bearing electron-donating or electron-
withdrawing groups, providing the desired products 3a−3l in
good yields. Specifically, a variety of biologically important
moieties, such as amide and sulphonamide segments, were
well-tolerated. Naphthalene analogues also delivered the
corresponding products 3m−3o in modest yields. Notably,
biologically relevant nitrogen-containing heterocycles 1p−1r
were also amenable to this difluorination process, which would
greatly broaden the versatility of this protocol in drug
discovery. Interestingly, this developed platform also provided
a new route to access the difluorination of styrylides 1s−1u,
significantly expanding the substrate scope of this strategy.
Unfortunately, substrates with methoxy and nitro groups were
unsuitable for this protocol. It should be noted that although
the traditional method for the synthesis of difluoromethylated
arenes through the deoxyfluorination of aldehydes provided a
powerful route to these molecules, the functional-group
compatibility was usually very poor due to the extremely
high reactivity of the fluorination reagent used, such as N,N-
diethylaminosulfur trifluoride (DAST).
type of deuteriomonofluorination protocol is greatly attractive
for medicinal studies.
Furthermore, noting the flexibility of this fluorination
protocol, we finally customized various reaction sequences to
demonstrate the practicality and versatility of this protocol
(Scheme 4). First, an alternative electrophile (MeI) was
Scheme 4. Programmable Sequences of the Developed
Fluorination Reaction
Encouraged by the above results, we subsequently evaluated
the potential of the monofluorination process (Scheme 3).
Scheme 3. Scope of the Monofluorination Transformation
employed to initially capture the deprotonated ylide 1a
(Scheme 4a). The newly generated methylated ylide could
be further fluorinated under the standard reaction conditions,
delivering the desired product 5a. The deuterated product 5a′
was similarly prepared utilizing CD3I and D2O. Additionally,
the in situ-generated fluorinated ylide reacted with an aldehyde
to undergo a Wittig-type pathway, giving the fluorine-
substituted styrene 6 (Scheme 4b). Ultimately, an alternative
one-pot procedure on a gram-scale starting from benzyl
bromide was also established to deliver the desired di- and
monofluorinated products (Scheme 4, c and d), leaving this
platform more synthetically adjustable.
In summary, by fully taking the advantage of reactivity of
phosphonium ylides, a programmable fluorination platform
was established. This platform has been proven to be highly
efficient and flexible, concurrently providing facile access to a
range of valuable di- and monofluoromethylarenes. Besides,
deuteriomonofluorinated arenes were also readily assembled
by simply using deuterium oxide. Moreover, customizable
sequences were also designed and realized by rationally
combining various valuable transformations, further expanding
the potential of this fluorination platform. Further exploration
on the use of the newly developed strategy in other
transformations is underway in our laboratory.
Noting that excess unreacted NFSI obstructed the workup step
in some cases, 1.95 equiv of PPh3 was added to quench NFSI
before the hydrolysis step. Under these conditions, a broad
range of substrates proceeded smoothly with the monofluori-
nation, providing the desired products 4a−4f. As for
heterocyclic substrates, comparably lower yields for the
monofluorinated products 4g−4h were obtained. Additionally,
the corresponding deuteriomonofluorinated products 4a′−4h′
were facilely prepared by simply switching H2O to D2O in the
final hydrolysis step. No deuteriomonofluorinated product was
detected during the difluoronation sequences in the presence
of D2O, presumably because the hydrolysis step for the
difluorinated ylide was too quick to be captured further by
other electrophiles. Notably, deuteration is an efficient tool to
alter drug pharmacokinetics.12 Considering the significance of
both the deuterated and fluorinated units, the success of this
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Organic Letters
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00457.
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Experimental details and characterization data for new
compounds, including NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Hao-Yue Xiang − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-7404-4247;
Email: hyangchem@csu.edu.cn
Xiao-Qing Chen − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-8768-8965;
Email: xqchen@csu.edu.cn
Hua Yang − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China;
Email: xianghaoyue@csu.edu.cn
Authors
Yu Zheng − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Zhen-Zhen Xie − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Xian-Chen He − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Yan-Shan Chen − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Wen-Shuo Cheng − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Kai Chen − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00457
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (22078370,
22003077, 21776318, 72088101, and 81703365) and the
Natural Science Foundation of Hunan Province (2017JJ3401),
Central South University.
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17, 5413−5419. (b) Fu, X. P.; Xue, X. S.; Zhang, X. Y.; Xiao, Y. L.;
Zhang, S.; Guo, Y. L.; Leng, X.; Houk, K. N.; Zhang, X. Controllable
Catalytic Difluorocarbene Transfer Enables Access to Diversified
Fluoroalkylated Arenes. Nat. Chem. 2019, 11, 948−956. (c) Zhu, S.
Q.; Liu, Y. L.; Li, H.; Xu, X. H.; Qing, F. L. Direct and Regioselective
C−H Oxidative Difluoromethylation of Heteroarenes. J. Am. Chem.
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B.; Zhang, W.; Hu, J. Iron-Catalyzed Difluoromethylation of Arylzincs
with Difluoromethyl 2-Pyridyl Sulfone. J. Am. Chem. Soc. 2018, 140,
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