Selective O-difluoromethylation of 1,3-diones using S-(difluoromethyl) sulfonium salt

Article abstract of DOI:10.1016/j.cclet.2019.03.036

A facile and highly efficient approach for selective O-difluoromethylation of 1,3-diones by recently developed bench-stable S-(difluoromethyl)sulfonium salt was described. And a broad range of difluoromthyl enol ethers were readily accessed in good to exc

Full text of DOI:10.1016/j.cclet.2019.03.036

Accepted Manuscript
Title: Selective O-difluoromethylation of 1,3-diones using
S-(difluoromethyl) sulfonium salt
Authors: Guo-Kai Liu, Xin Li, Wen-Bing Qin, Wei-Feng Lin,
Li-Ting Lin, Jia-Yi Chen, Jian-Jian Liu
PII:
DOI:
Reference:
S1001-8417(19)30131-7
https://doi.org/10.1016/j.cclet.2019.03.036
CCLET 4872
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Chinese Chemical Letters
Please cite this article as: Liu G-Kai, Li X, Qin W-Bing, Lin W-Feng,
Lin L-Ting, Chen J-Yi, Liu J-Jian, Selective O-difluoromethylation of 1,3-
diones using S-(difluoromethyl) sulfonium salt, Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.03.036
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Communication
Selective O-difluoromethylation of 1,3-diones using S-(difluoromethyl)
sulfonium salt
Guo-Kai Liu, Xin Li, Wen-Bing Qin, Wei-Feng Lin, Li-Ting Lin, Jia-Yi Chen, Jian-Jian Liu
School of Pharmaceutical Sciences, Shenzhen University Health Science Centre, Shenzhen University, Shenzhen 518060, China
ARTICLE INFO
ABSTRACT
A facile and highly efficient approach for selective O-difluoromethylation of 1,3-diones by
recently developed bench-stable S-(difluoromethyl)sulfonium salt was described. And a broad
range of difluoromthyl enol ethers were readily accessed in good to excellent yields under mild
reaction conditions. Mechanistic studies revealed that the O-difluoromethylation reaction
proceeds mainly via a difluorocarbene pathway.
Article history:
Received 22 February 2019
Received in revised form 15 March 2019
Accepted 18 March 2019
Available online
Keywords:
Difluorocarbene
Difluoromethyl enol ethers
1,3-Diones
O-Difluoromethylation
S-(Difluoromethy)sulfonium salt
The difluoromethyl ethers represent a valuable class of
organofluorine compounds, which are wide applied in
pharmaceuticals [1], agrochemicals [2] and materials [3].
Particularly, the difluoromethoxy group (OCF2H) is an important
structural motif in medicinal chemistry and drug discovery, since
it is capable of acting as a lipophilic hydrogen-bond donor [4].
For example, pantoprazole is used for the treatment of
gastrohelcoma, which is well known as an irreversible proton
pump inhibitor [5], and roflumilast, a phosphodiesterase inhibitor,
is employed to treat chronic obstructive pulmonary disease
(COPD) [6], GRN-529 is in clinic trials stage as a candidate drug
for treatment of autistic children [7] (Fig. 1). Therefore, the
synthesis of organic molecules containing OCF2H group have
attracted considerable attention in the past decades.
Conventionally, organic molecules bearing OCF2H moiety are
prepared by O-difluoromethylation of phenols and alcohols with
in situ generated difluorocarbene [8], and a lot of difluorocarbene
precusors such as TMSCF2Br, ClF2CCOONa, PDFA,
BrCF2CO2Et, FSO2CF2COOH, HCF2OTf, HCF3, and CF2Br2
have been developed for this purpose. However, these
methodologies recorded previously mainly focus on the
difluoromethylation of phenols and aliphatic alcohols to form the
difluoromethyl ethers, few protocols for the synthesis of
difluoromethyl enol ethers are reported. Up to date, only three
groups documented the approaches for the access to
difluoromethyl enol ethers (Scheme 1). Shibata and coworkers
disclosed selective O-difluoromethylation of 1,3-diones by S-
(bromodifluoromethyl)diaryl sulfonium salts mediated by a
strong organic base, but excess of 2.0 equiv. of substrates were
required due to the nature of the reagents, although a wide range
of 1,3-diones are applicable to the reaction in good to excellent
yields [9] (Scheme 1a). Weng et al. reported that ethyl
difluoromethylation of 1,3-diones. However, this protocol
required a high reaction temperature [10] (Scheme 1b), besides,
usage of DMF as solvent also limits its applicability because of
troublesome work up process. Afterwards, Xiao group described
a mild process for the synthesis of difluoromethyl enol ethers
from 1,3-diones via direct transfer of the CF2H group and
difluocarbene pathway, although only limited examples were
demonstrated [11] (Scheme 1c). Later on, Xiao and co-workers
also reported a protocol of O-difluoromethylation of 1,3-diones
using PDFA as the difluorocarbene precursor [12]. And very
recently, we designed and synthesized the bench-stable S-
(difluoromethyl) sulfonium salts
1 as a highly efficient
electrophilic difluoromengylating reagent and difluorocarbene
source [13]. As a part of our continuous research for the
development of efficient methodologies for the synthesis of
fluoro-organic compounds, we are herein interested in the
potentiality of our reagent 1 for the difluoromethylation of 1,3-
diones to furnish the difluoromethyl enol ethers. And the results
showed that a widevariety of 1,3-dions can smoothly occur
reaction to give corresponding difluoromethyl enol ethers in
good to excellent yields under mild conditions (Scheme 1d).
Fig. 1. Drugs containing OCF2H building block
chlorodifluoroacetate is
 Corresponding authors.
a
suitable reagent for the O-
———
E-mail addresses: gkliu@szu.edu.cn

as 1b and 1c also gave the comparable results under the same
conditions (entries 2, 3). Encouraged by these results, we further
examined other bases, including organic and inorganic bases
(entries 4-8). P2-Et also performed good to provided 3a in 87%
isolated yield (entry 4), but the weak organic base Et3N led to a
lower yield of 58% (entry 5). It was worth noting that organic
bases were superior to inorganic bases in this reaction system,
probably arising from the worse solubility of inorganic bases in
dichloromethane (entries 6-8). Next, the reaction temperature
was surveyed, and reaction proceeding at both -40 oC and
ambient temperature gave the similar yields to that of conducting
at 0 oC (entries 9-10), ascertaining that this process is not
sensitive to reaction temperature, and possessing a wide window
of temperature. Finally, the effect of solvents was investigated,
usage of THF instead of dichloromethane slightly decreased
yield to 83% (entry 11), and 3a was afforded in a visibly lower
yield of 76% when the reaction was carried out in the acetonitrile
(entry 12). Thus, dichloromethane was identified as the best
choice.
With the optimized reaction conditions in hand, we evaluated
the capability and generality of this protocol for the O-
difluoromethylation of various 1,3-diones. As shown in Scheme
2, a broad range of 1, 3-cyclopentanediones 2a-f with different
substituents at the C-2 position were applicable to this process to
afford corresponding difluoromethyl enol ethers 3a-f in excellent
yields. Notably, a wide variety of 1, 3-indandiones 2g-m bearing
various substituents at C-2 position were also tolerated to furnish
O-difluoromethylation products in good to high yields.
Furthermore, 1, 3-cyclohexanediones were also the suitable
substrates, and a series of 1, 3-cyclohexanediones 2n-z were
smoothly transferred into corresponding difluoromethyl enol
ethers 3n-z in high to excellent yields. And same to 1, 3-
Scheme 1. Synthesis of difluoromethyl enol ethers from 1, 3-diones.
Table 1
Survey of reaction conditions.a
cylcopentanediones
substrates,
1,
3-cyclohexanediones
possessing diverse substituents at C-2 position, including
halogen (2o), methyl (2p), benzyl (2q-v), also provided desired
products 3o-v in excellent yields. It was worth noting that a
variety of functional groups such as fluoro, chloro, bromo, nitrile,
or nitro moieties on the aromatic rings, were tolerance in this
reaction. Besides, 1, 3-cyclohexanediones having methyl,
isopropyl, phenyl, and dimethyl substituents at C-5 position were
all compatible with this approach to produce corresponding
difluoromethyl enol ethers in high to excellent yields.
Remarkably, acyclic 1, 3-dione 2aa could also undergo O-
difluoromethylation under the standard reaction conditions to
deliver difluoromethyl enol ethers, albeit in a lower isolated yield
of 39%.
According to the mechanism proposed by other groups, the O-
difluoromethylation of 1, 3-diones might occur via direct transfer
of CF2H group and difluorocarbene process. In order to gain
more information in our case, control experiment was carried out.
The usage of deuterium-labelled reagent [D]-1a instead of 1a,
deuterium-labelled product [D]-3a was obtained in 18% yield,
but 58% 3a was observed (Scheme 3a), indicating that the
reaction would be likely proceed involving in difluorocarbene
process as the main pathway. Therefore, on the basis of the
experimental data above and literatures reported previously by
other groups, we propose the reaction mechanism as shown in
Scheme 3c. 1,3-Diones was treated by base to deliver enolate
Entry
1
2
3
4
5
6
7
8
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Base
1
Temp. (oC)
0
0
0
0
0
0
0
Yield (%)b
DBU
DBU
DBU
P2-Et
Et3N
K2CO3
Na2CO3
NaOH
DBU
DBU
DBU
DBU
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
87
85
87
87
58
40
66
64
87
86
83
76
0
9
-40
RT
0
10
11
12
CH3CN
0
a
Reaction conditions (unless otherwise specified): 2a (0.5 mmol), 1, base
(1.0 equiv.), solvent (3.0 mL), 20 min.
b Isolated yields.
Our research commenced with the optimization of reaction
conditions, 2-methyl-1,3-cyclopentanedione 2a was chosen as a
model substrate, and the results was summarized in Table 1.
when 2a and 1a were treated by 1.0 equiv. of DBU in the
dichloromethane at 0 oC, exclusive O-difluorothylation pruduoct,
difluoromethyl enol ether 3a, was isolated in 87% yield (entry 1),
and no C-selective difluoromethylation product was detected in
this case. Thus, it is very interesting in contrast to the protocol of
the C-selective difluoromethylation of β-ketoesters with 1a
reported recently by us [12a]. Furthermore, other reagents such

anion A. Subsequently, A react with difluorocarbene generated
from reagent 1 and base or A to give difluoromethylated anion B,
followed by protonating to form difluromomethyl enol ether
(path I, Scheme 3b). However, the direct attack of enolate anion
to CF2H moiety of sulfonium salt could not be ruled out (path II,
Scheme 3c).
Scheme 3. Control experiments and plausible reaction mechanism for the O-
difluoromethylation of 1,3-diones by S-(difluoromethyl)sulfonium salt 1.
Acknowledgment
This work was supported by the Science and Technology
Foundation of Shenzhen, Shenzhen Science and Technology
Innovation Committee (No. JCYJ20170818143001461). We
thank Instrumental Analysis Center of Shenzhen University (Xili
Campus) for analytical work.
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Graphical Abstract
A facile and highly efficient approach for selective O-
difluoromethylation of 1,3-diones with S-(difluoromethyl)sulfonium
salt was developed, and a wide variety of difluoromethyl enol ethers
were readily synthesized.