Reactions of gem-Difluorinated Phosphonium Salts Induced by Light

Article abstract of DOI:10.1021/acs.orglett.6b00117

gem-Difluorinated phosphonium salts, which are readily obtained from aldehydes and difluoromethylene phosphobetaine, can serve as a source of radicals under reductive conditions. An iridium complex or Hantzsch ester was used as a one-electron reducing agent when irradiated with visible light. The fluorinated radicals were trapped with various alkenes, leading to products either via a photoredox cycle (for the iridium catalyst) or via a hydrogen atom transfer (for the Hantzsch ester).

Full text of DOI:10.1021/acs.orglett.6b00117

Letter
pubs.acs.org/OrgLett
Reactions of gem-Difluorinated Phosphonium Salts Induced by Light
†
†,‡
†
†
Liubov I. Panferova, Artem V. Tsymbal, Vitalij V. Levin, Marina I. Struchkova,
,†
and Alexander D. Dilman*
†
N.D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russian Federation
‡
*
S Supporting Information
ABSTRACT: gem-Difluorinated phosphonium salts, which
are readily obtained from aldehydes and difluoromethylene
phosphobetaine, can serve as a source of radicals under
reductive conditions. An iridium complex or Hantzsch ester
was used as a one-electron reducing agent when irradiated with
visible light. The fluorinated radicals were trapped with various
alkenes, leading to products either via a photoredox cycle (for
the iridium catalyst) or via a hydrogen atom transfer (for the
Hantzsch ester).
he importance of gem-difluorinated compounds for
medicinal chemistry has stimulated intensive studies for
Table 1. Reaction of 4-Chlorobenzaldehyde
1
T
Scheme 1. Generation of Fluorinated Radicals
a
entry
cat. (mol %)
eosin Y (1)
Ru(bipy) Cl (0.5)
light
yield of 8a (%)
1
2
3
4
5
blue LED
0
0
blue LED
3
2
b
Ir(ppy) (0.5)
400 nm LED
400 nm LED
79 (73 )
3
0
the synthesis of compounds of this type. Besides classic
Ir(ppy) (0.5)
0
2
3
approaches based on deoxofluorination and the application of
a
Determined by 19F NMR of reaction mixtures with 4-fluorotoluene as
3
building blocks, the use of difluorocarbene and related
reagents has recently emerged as an attractive method for the
straightforward access to CF -substituted products.
Visible-light-mediated reactions came to the forefront of
organic chemistry during past few years. The simplicity of
procedures defined by the ready availability of light sources
household bulbs or cheap LED strips) in combination with
novel synthetic opportunities have sparked the interest of many
research groups toward this field. Frequently, the role of light is
to activate a catalyst to serve as a reducing agent with respect to
b
an internal standard. Isolated yield of 9a.
4
−7
2
generation of functionalized fluorinated radical species 3
(Scheme 1).
13
8
Phosphonium salt 5a, generated from 4-chlorobenzaldehyde
7
(
4a), phosphobetaine 1, and chlorosilane, was selected as a
(
model substrate, and its reaction with silyl enol ether 6a derived
from 4-bromoacetophenone (7a) was evaluated (Table 1).
Reactions were performed in the presence of propylene oxide
(2 equiv) to remove chlorosilane. The reaction mixture
containing a photocatalyst was irradiated using an LED strip.
With the sodium salt of eosin Y and Ru(bipy) Cl , starting salt
9
a substrate. Perfluorinated bromides and iodides, as well as
10
11
12
iodine(III) reagents, sulfochlorides, and sulfonium salts,
3
2
proved to be good substrates for accepting one electron with
concomitant generation of fluorinated radicals. Herein, we
demonstrate that gem-difluorinated phosphonium salts 2, which
can be generated from readily available difluoromethylene
5
a remained unaffected. There was no reaction without light or
Received: January 13, 2016
7
phosphabetaine (1), can be involved in visible-light-induced
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Synthesis of Furans 9
Scheme 2. Proposed Photoredox Mechanism
Scheme 3. Reaction of Hantzsch Ester
photocatalyst. With the iridium catalyst, fac-Ir(ppy) , primary
3
product 8a was formed in 79% yield (entry 3). However,
attempts to purify ketone 8a or the corresponding desilylated
alcohol by column chromatography were unsuccessfulupon
elution, the gradual formation of furan 9a was noted.
Accordingly, the reaction mixture was treated with toluene-
sulfonic acid at reflux for 30 min to effect cyclization, and furan
9
a was isolated in 73% yield.
Under the optimized conditions, a series of aldehydes were
reacted with silyl enol ethers 6 derived from ketones 7 (Table
). However, preparation of analytically pure silyl enolates 6
2
requires distillation, which requires gram-scale experiments.
Therefore, we employed a more practical millimole scale
procedure for the synthesis of enolates 6 involving silylation of
ketones 7 with the Me SiCl/NaI/NEt system, followed by
3
3
non-aqueous workup. The crude enolates 6 had >95% purity
and were used for reactions with salts 5 without further
purification.
Aromatic and heteroaromatic aldehydes usually gave good
yields of furans 9. Importantly, enolizable aldehydes also gave
products, though in slightly reduced yields (Table 2, entries 5,
6
, and 13). Unfortunately, reaction of silyl enol ether derived
from cyclohexanone with salt 5a did not give product, and salt
a remained unconsumed. The reason for this phenomenon is
5
a
not clear at present.
Aldehyde 4 (1 equiv), 1 (1.2 equiv), Me SiCl (1.5 equiv), 6a (1.3
3
equiv) or 7 (1.5 equiv), Ir(ppy) (0.5 mol %), propylene oxide (2
equiv), TsOH (1 equiv). Isolated yield. Irradiation time was 12 h.
Concerning the mechanism, we speculate that the photo-
catalytic cycle starts with single electron reduction of
3
b
c
B
DOI: 10.1021/acs.orglett.6b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Reactions of Salts 5 with Acrylonitrile
compound 16a was also observed in about 10% yield, evidently
17
formed by hydrogen atom transfer to fluorinated radical 10.
Increasing the amount of Hunig’s base neither increased the
̈
yield nor affected the ratio of 14/16.
A series of aldehydes were involved in reaction with
phosphobetaine 1 and subsequent coupling with acrylonitrile
(
Table 3). Typically, good yields of products 15 were observed
for aromatic substrates. Phenylacetic aldehyde also worked well
entry 6). At the same time, in reactions of cinnamaldehyde
(
and hydrocinnamaldehyde, no products were formed.
In summary, the cleavage of the carbon−phosphorus bond in
difluorinated phosphonium salts by means of light-induced
reducing agents with the generation of a radical species was
described. The gem-difluorinated radical may interact either
with electron-rich or with electron-poor alkenes under
photoredox or hydrogen atom transfer conditions, respectively.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00117.
Experimental procedures, compound characterization
data, and copies of NMR spectra for all compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: adil25@mail.ru.
■
*
Notes
The authors declare no competing financial interest.
a
Isolated yield.
ACKNOWLEDGMENTS
This work was supported by the Russian Science Foundation
(Project 14-13-00034).
■
phosphonium salt 5, generating radical 10 together with
triphenylphosphine. Addition of the fluorinated radical to the
electron-rich double bond provides radical species 11, which is
oxidized by the iridium complex, affording primary product 8
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DOI: 10.1021/acs.orglett.6b00117
Org. Lett. XXXX, XXX, XXX−XXX