Decarboxylative nucleophilic difluoromethylation of aldehydes and imines

Article abstract of DOI:10.1016/j.tet.2018.06.062

The high demand for the biologically active CF₂H-molecules has stimulated significant efforts to develop efficient methods for the installation of CF₂H functionality. We found that phenylsulfonyl difluoroacetate salt (PhSO₂

Full text of DOI:10.1016/j.tet.2018.06.062

Accepted Manuscript
Decarboxylative nucleophilic difluoromethylation of aldehydes and imines
Jia Chen, Jin-Hong Lin, Ji-Chang Xiao
PII:
S0040-4020(18)30777-4
10.1016/j.tet.2018.06.062
TET 29658
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 May 2018
Revised Date: 25 June 2018
Accepted Date: 28 June 2018
Please cite this article as: Chen J, Lin J-H, Xiao J-C, Decarboxylative nucleophilic difluoromethylation of
aldehydes and imines, Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.062.
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Decarboxylative Nucleophilic
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Difluoromethylation of aldehydes and imines
Jia Chen, Jin-Hong Lin, and Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences
X
o
XH
X
o
1) 50 C
50 C
+ PhSO2CF2CO2K
o
2) 80 C Ar
H
Ar
CF2SO2Ph
Ar
CF2H
X = O
X = O or NTs

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Decarboxylative nucleophilic difluoromethylation of aldehydes and imines
Jia Chena, Jin-Hong Lina, and Ji-Chang Xiaoa,*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: jchxiao@sioc.ac.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The high demand for the biologically active CF2H-molecules has stimulated significant efforts to
develop efficient methods for the installation of CF2H functionality. We found that
phenylsulfonyl difluoroacetate salt (PhSO2CF2CO2 K+) could directly undergo decarboxylation
-
-
under warming conditions to produce active anion (PhSO2CF2 ) without the need of any base or
Available online
additive, thus allowing for the subsequent nucleophilic (phenylsulfonyl)difluoromethylation of
aldehydes or imines to give PhSO2CF2-alcohols or -amines, respectively. Interestingly, the
removal of PhSO2 group was achieved simply by elevating the reaction temperature for the
conversion of aldehydes to afford CF2H-ketones.
Keywords:
Decarboxylative
Nucleophilic
Difluoromethylation
Aldehydes
2009 Elsevier Ltd. All rights reserved
.
Imines
a base or an initiator,5-9 or suffer from tedious synthetic
procedures10, thus limiting their applicability.
1. Introduction
Difluoromethyl group (CF2H) is known to be a bioisostere of
OH and SH unit and can act as a lipophilic hydrogen bond donor
to improve the binding selectivity and cell membrane
permeability within the realm of drug design.1 CF2H-containing
pharmaceuticals and agrochemicals such as Eflornithine,
Deracoxib, Dithiopyr and Sulfentrazone have been successively
developed. Consequently, significant efforts have been devoted
to the exploration of efficient protocols for the incorporation of
CF2H functionality.2 Two strategies have been well established,
direct difluoromethylation3 and indirect difluoromethylation4.
Indirect approaches usually involve a two-step procedure
including the first incorporation of a CF2X (X = auxiliary group)
moiety and the subsequent removal of the auxiliary group X to
obtain CF2H-products. Direct difluoromethylation is a one-step
process and thus is a more straightforward strategy. However, the
presence of an auxiliary group may modify the reactivity of
difluoromethylation reagents, or lead to the changes in physical
state of the reagents for more convenient operations (for instance,
a solid reagent may be obtained by incorporating an auxiliary
group into a volatile reagent). Therefore, if the auxiliary group
can be easily removed, indirect difluoromethylation may still be
an attractive strategy.
We recently developed an efficient difluorocarbene reagent
- 11
-
Ph3P+CF2CO2 .
Decarboxylation of Ph3P+CF2CO2 under
warming conditions could directly generate difluorocarbene
intermediate via the dissociation of P-CF2 bond. We speculated
that phenylsulfonyl difluoroacetate salt (PhSO2CF2CO2 M+) may
-
also directly undergo decarboxylation by warming to produce
active anion (PhSO2CF2-) without the need of any base or
additive, thus allowing for the subsequent nucleophilic reaction.
Indeed, nucleophilic (phenylsulfonyl)difluoromethylation of
-
aldehydes or imines with potassium salt (PhSO2CF2CO2 K+) was
achieved efficiently at 50 oC to afford alcohols or amines,
respectively (Scheme 1). Surprisingly, for the reaction of
aldehydes, elevating the reaction temperature could remove
PhSO2 group to give difluoromethyl ketones. This is the first
example of heat-promoted convenient removal of PhSO2 group
from PhSO2CF2 moiety.
Scheme 1. This work.
As phenylsulfonyl group (PhSO2) can modify reactivity of
PhSO2-reagents due to its strong electron-withdrawing nature and
the group may be easily removed under reductive or basic
conditions,5 it has become one of the most widely used auxiliary
groups in indirect difluoromethylation protocols. Various
PhSO2CF2-type reagents, such as PhSO2CF2H,6,5b PhSO2CF2Br,7
PhSO2CF2SiMe3,8 PhSO2CF2IIII,9 and [PhSO2CF2S+-R2 TfO-],10
have appeared. But these reagents are required to be activated by
2. Results and discussion

2
Tetrahedron
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Table 1. Screening reaction conditionsa
entry
ratiob
solvent
temp. (oC)
time (h)
yield (%)c
1
2
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:2
CH2Cl2
p-xylene
THF
40
40
40
40
40
40
40
40
40
30
50
60
80
50
50
5
5
N.D.
N.D.
N.D.
35
3
5
4
DMF
5
5
CH3CN
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
51
6
5
17
7
6
55
8
7
63
9
10
7
65
10
11
12
13
14
15
18
7
65
7
52
7
N.D.
79
7
7
76
aReaction conditions: aldehyde 1a (0.2 mmol) and 2 in a solvent (2 mL). N.D.
= not detected; bmolar ratio of 1a:2; cthe yields were determined by 19F NMR
spectroscopy.
Initial
attempts
showed
that
the
Scheme 2. (Phenylsulfonyl)difluoromethylation of aldehydes and
imines. Reaction conditions: substrate 1(0.5 mmol) and 2 (0.75
mmol) in CH3CN (5 mL) at 50 C for 7 h. All yields were isolated
(phenylsulfonyl)difluoromethylation of aldehyde 1a with
potassium salt 2 (PhSO2CF2CO2K) proceeded smoothly in a polar
solvent (Table 1, entries 4-6) and acetonitrile seemed to be more
suitable (entry 5). Extending the reaction time from 5 h to 7 h
increased the yield to 63% (entry 8), and no further increase in
the yield was observed with longer reaction time (entry 9 vs. 8).
Lowering the reaction temperature decreased the yield
dramatically (entry 10 vs. 8). Interestingly, as the reaction
temperature was elevated, the yield was decreased (entry 12 vs.
o
yields.
As mentioned above (Table 1, entry 13), elevating the reaction
temperature to 80 oC led to the disappearance of alcohol product
3a (Scheme 3). Surprisingly, a difluoromethyl ketone (4a) was
observed. This ketone should be formed via a nucleophilic
addition process. Decarboxylation of potassium salt 2 under
warming conditions generates anion A, which would readily
attack the aldehyde to produce adduct B. An equilibrium is
established between intermediates B and C via 1,2-hydrogen
shift. β-Elimination of a sulfonyl group from intermediate C
furnishes enol D, tautomerization of which affords
difluoromethyl ketone 4a.
o
8), and no desired alcohol 3a was detected by elevating to 80 C
(entry 13). A good yield was obtained by increasing the loading
of potassium salt 2 to 1.5 equiv (entry 14), but further increasing
the loading did not increase the yield (entry 15).
With the optimal reaction conditions in hand (Table 1, entry
14), we then investigated the substrate scope of the nucleophilic
(phenylsulfonyl)difluoromethylation of aldehydes and imines
(Scheme 2). Various aryl aldehydes were converted into the
desired products in moderate to good yields (3a-3h). A strong
electron-donating group would lead to the decrease in the yield
(3e), probably because the carbonyl group was deactivated. In
contrast to aryl aldehydes, alkyl aldehydes showed lower
reactivity and a low yield was obtained (3i). The optimal reaction
Scheme 3. The observation of difluoromethyl ketone.
conditions
could
also
be
applied
to
(phenylsulfonyl)difluoromethylation of tosyl-protected imines to
afford the corresponding amines in high yields (3j-3o).
The attempts to achieve an efficient conversion of aldehyde 1a
into difluoromethyl ketone 4a were not successful. The
optimization of the reaction conditions revealed that the ketone
could be obtained in 42% yield by further heating adduct B
formed from the reaction of aldehyde 1a with salt 2 at a reaction
o
temperature of 50 C. The substrate scope was then investigated
under these conditions (Scheme 4). Although low yields were
obtained for this PhSO2-removal process, this is the first example
of heat-promoted removal of PhSO2 group from PhSO2CF2
moiety. The removal of PhSO2 group was not observed for the
reaction of imines.

3
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Scheme 4. The conversion of aldehydes into difluoromethyl ketones.
Isolated yields. Reaction conditions: substrate 1(0.5 mmol) and 2
(0.75 mmol) in CH3CN (5 mL) at 50 oC for 7 h and then 80 oC for 3
h. aThe yield was determined by 19F NMR spectroscopy.
3. Conclusion
In summary, we have described the decarboxylative
difluoromethylation of aldehydes and imines with potassium
-
phenylsulfonyl difluoroacetate (PhSO2CF2CO2 K+) simply under
warming conditions. Interestingly, elevating the reaction
temperature for the conversion of aldehydes led to the direct
removal of phenylsulfonyl group to afford difluoromethyl
ketones. This work represents the first protocol for heat-
promoted removal of PhSO2 group from PhSO2CF2 moiety.
Potassium phenylsulfonyl difluoroacetate may become an
efficient difluoromethylation reagent because of its facile
synthetic route, ease of handling and the possibility for
convenient removal of PhSO2 group.
Acknowledgments
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We thank National Basic Research Program of China
(2015CB931903), the National Natural Science Foundation
(21421002, 21472222, 21502214, 21672242), the Chinese
Academy of Sciences (XDA02020105, XDA02020106), and Key
Research Program of Frontier Sciences (CAS) (QYZDJ-SSW-
SLH049) for financial support.
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