Catalytic Domino Reaction of Ketones/Aldehydes with Me3SiCF2Br for the Synthesis of α-Fluoroenones/α-Fluoroenals

Article abstract of DOI:10.1021/acs.orglett.5b00488

A unique domino reaction of enolizable carbonyl compounds with Me₃SiCF₂Br to construct α-fluoroenones and α-fluoroenals is described to undergo the in situ formation of difluorocarbene and silyl enol ether, difluorocyclopropanation, desilylation, ring-opening, and defluorination sequence. In this tandem reaction, Me₃SiCF₂Br acts as not only the difluorocarbene source but also the TMS transfer agent as well as internal bromide and fluoride anion catalyst. It allows the transformations to occur smoothly under only a catalytic amount of n-Bu₄NBr as initiator.

Full text of DOI:10.1021/acs.orglett.5b00488

Letter
pubs.acs.org/OrgLett
Catalytic Domino Reaction of Ketones/Aldehydes with Me3SiCF2Br
for the Synthesis of α‑Fluoroenones/α-Fluoroenals
Xiaoning Song, Jian Chang, Dongsheng Zhu,* Jiaheng Li, Cong Xu, Qun Liu,* and Mang Wang*
Department of Chemistry, Northeast Normal University, Renmin Street 5268, Changchun 130024, P. R. China
S
* Supporting Information
ABSTRACT: A unique domino reaction of enolizable carbonyl com-
pounds with Me3SiCF2Br to construct α-fluoroenones and α-fluoroenals is
described to undergo the in situ formation of difluorocarbene and silyl enol
ether, difluorocyclopropanation, desilylation, ring-opening, and defluorina-
tion sequence. In this tandem reaction, Me3SiCF2Br acts as not only the
difluorocarbene source but also the TMS transfer agent as well as internal bromide and fluoride anion catalyst. It allows the
transformations to occur smoothly under only a catalytic amount of n-Bu4NBr as initiator.
nstallation of fluorine-containing skeletons into organic
molecules has become a powerful strategy in drug discovery
Scheme 1. Working Assumption on Catalytic Domino
Reaction of Ketones with TMSCF2Br
I
and new material design.1 Efficient use of organofluorine
reagents plays a key role for this purpose. The vinyl fluoride
unit has been found to be an isostere of the peptide bond.2a This
structural feature gives monofluoroolefin derivatives highly
important biological and pharmacological activities.2b,c Among
them, functionalized fluoroolefins have earned high interest3,4
due to their wide applications in the construction of various
fluoroorganic compounds. Thus, developing a new and practical
method for their synthesis is an important subject of this field.
Fluoroalkylsilanes are versatile fluoroalkylating reagents,5−10
among which easily available Me3SiCF2Br (TMSCF2Br) has
been developed as an effective difluorocarbene reagent6a,7−9
since the pioneering work by Hu7 and Dilman.8 As described in
Scheme 1A, the generation of difluorocarbene along with the
release of TMSBr from bromide anion-activated TMSCF2Br has
been proven to be a decisive step in the difluorocyclopropa(e)-
nations of alkenes/alkynes.7b Very recently, Dilman and co-
workers reported a difluorocyclopropanation of silyl enol ethers
with TMSCF2Br which was an important step in the
difluorohomologation of ketones (Scheme 1B).9a In fact,
although many difluorocyclopropanations of alkenes are
known,11−13 the investigation of synthetic applications of gem-
difluorocyclopropanes remains a challenge. To the best of our
knowledge, there are only a few examples of difluorocyclopropa-
nations of silyl enol ethers.9a,14 A little earlier, Amii et al.
developed a difluorocyclopropanation of silyl enol ethers by
using BrCF2CO2Na as difluorocarbene source in a two-step
synthesis of cyclic α-fluoroenones.14c In their work, difluor-
ohomologation products were obtained under basic condi-
tions.14c
difluorocyclopropanation (Scheme 1C, step c) might be possible
and evolve by further desilylation and a ring-opening sequence
(Scheme 1C, step d). To our delight, it was indeed the case. The
cascade reaction occurred smoothly leading to α-keto mono-
fluoroalkenes only catalyzed by n-Bu4NBr (TBAB) for initially
activating TMSCF2Br (Scheme 1C, catalytic cycle I) and in many
instances assisted by an external fluoride anion for accelerating
the desilylation of the resulting cyclic trimethylsilyl ether
intermediate (Scheme 1C, catalytic cycle II).
During our latest study on the reaction of ketones with
TMSCF2Br as a part of our continuing interest in synthetic
applications of fluoroalkylsilanes,5a,10 we hypothesized a catalytic
domino transformation in which the side product, oxophilic
TMSBr that formed along with difluorocarbene from
TMSCF2Br, might participate in the in situ generation of silyl
enol ethers from ketones (Scheme 1C, step b). Thus, a
Herein, we report this unique catalytic, domino reaction for
the synthesis of α-fluoroenones.14c,15 The method can be
extended to the synthesis of α-fluoroenals.16 Sufficient use of
Received: February 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
TMSCF2Br, broad scope of readily available starting materials,
tolerance for various functionality, and efficient transformations
made possible the development of a general and practical one-
pot approach for the assembly of fluorine-containing fragment
into the α-C−C bond in carbonyl compounds.
Clearly, synthesis of α-fluoroenones from ketones and
TMSCF2Br presents a promising synthetic strategy due to the
readily available starting materials and simple organofluorine
reagent. Thus, the scope of the reaction was thoroughly
investigated under the optimized reaction conditions (Table 1,
entry 8). As described in Scheme 2, the R substituents at the
phenyl ring of aromatic ketones 1, bearing either an electron-
donating or electron-withdrawing group at the different
We initially chose 4-acetobiphenyl 1a as a model substrate, and
its reaction with TMSCF2Br was investigated (Table 1).
a
Table 1. Screening the Reaction Conditions
Scheme 2. Scope of Enolizable Ketones for Catalytic Domino
a
Transformations
b
TMSCF2Br
(equiv)
TBAB/TBAF
(mol %)
time
(h)
yield
(%)
entry
temp (°C)
1
2
3
4
1.5
1.5
2
5/−
5/5
110
5
42
50
110/110
110/110
110/110
110/110
110/110
110/60
110/rt
90/rt
5/3
6/3
4/2
7/4
6/3
6/3
6/3
6/3
9
5/10
63
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
10/15
10/15
10/20
10/20
10/20
10/20
-/20
79
c
5
90
c
6
c
96
7
97
c
8
98
c
9
89
c
10
110
80
c
,
,
d
e
11
12
10/20
10/20
110/rt
110/rt
6/3
6/3
trace
41
c
a
Conditions: 1a (0.5 mmol), toluene (2.5 mL), in sealed tube.
Isolated yield. TMSCF2Br was added in two portions: 1.5 equiv of
b
c
TMSCF2Br for 2 h followed by 1 equiv of TMSCF2Br for additional
d
e
time. In DCE. In dioxane.
Generally, the reaction needed to be performed at around 110
°C in toluene, and excess TMSCF2Br was added in two portions
for better transformation. The addition of the catalysts was
followed by the order of TBAB for the activation of TMSCF2Br
and n-Bu4NF (TBAF) for the desilylation of cyclic intermediate.
As described in Table 1, entry 1, the reaction of 1a with
TMSCF2Br afforded 2a in 42% yield when 5 mol % of TBAB was
used. The use of 2 equiv of TMSCF2Br along with 5 mol % of
TBAB for 6 h and then with 10 mol % of TBAF for an additional
3 h afforded 2a in 63% yield (Table 1, entry 3). Increasing the
amount of TMSCF2Br and catalysts provided a notable
improvement (Table 1, entries 4−6). In the case of 10 mol %
of TBAB and then 20 mol % of TBAF, 2a was isolated in excellent
yield (Table 1, entry 6). It was found that the desilylation and
ring-opening process performed at room temperature also
afforded satisfactory results (Table 1, entry 8). At this time,
after 1a (0.5 mmol) reacted with TMSCF2Br (0.75 mmol) in 2
mL of toluene in the presence of TBAB (0.05 mmol) at 110 °C
for 2 h, the additional TMSCF2Br (0.5 mmol), which was
predissolved in 0.5 mL of toluene, was added to the reaction
mixture for another 4 h. Then, the reaction was allowed to cool to
room temperature and a solution of TBAF in THF (0.1 mmol)
was added to react 3 h. After a conventional workup, 2a was
isolated in 98% yield (for details, see the Supporting
Information). By comparison, the difluorocyclopropanation at
lower temperature was proven to be less efficient (Table 1, entry
9). Finally, a domino reaction catalyzed by TBAF (Table 1, entry
10) or performed in DCE or dioxane (Table 1, entries 11 and 12)
was investigated but gave inferior results.
a
Conditions: 1 (0.5 mmol), TMSCF2Br (2.5 equiv), TBAB (10 mol
%), TBAF (20 mol %), toluene (2.5 mL), in sealed tube, 110 °C then
rt. TMSCF2Br was added in two portions: 1.5 equiv of TMSCF2Br for
2 h followed by additional 1 equiv of TMSCF2Br for 4 h. Isolated
b
c
d
yield. Without TBAF. At 100 °C. 4 equiv of TMSCF2Br was used.
e
f
g
5 mol % of TBAB was used. 1H NMR yield. 30 mol % of TBAF was
h
used. 5 equiv of TMSCF2Br was used.
B
DOI: 10.1021/acs.orglett.5b00488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
positions, were compatible with the reaction to produce 2a−s in
good to high yields. It was noteworthy that this cascade reaction
was successful in the presence of various functional groups
including halogens (F, Cl, and Br), nitro, cyano, amino, alkoxyl,
alkylthio, and ester groups. Ketone 1f bearing a phenolic
hydroxyl functionality also underwent the domino process to
give 2f with comparable results, indicating that the method was
tolerant to acidic hydrogen, whereas the reaction seemed to be
sensitive to those ketones containing unprotected amino or
pyridyl groups and led to a complex mixture though 3-
acetylindole 1t, giving acceptable results. In comparison, N-
methyl-3-acetylindole 1u afforded α-fluoroenone 2u in 98%
yields.
In addition, 2v was isolated in 84% yield from 3-
acetylbenzothiophene 1v. Propiophenone derivatives gave 2w
and 2x with a cis relationship of the methyl and fluorine as the
major product. With double-acetyl benzene 1y as the substrate,
bisfluoroolefin 2y was also obtained in excellent yield. For cyclic
ketones, reactions afforded ring-expansion products 2z and 4a
efficiently. Considering the significance of the modulation of
drug intermediates by introducing a fluorine-containing skeleton,
estrone 3b was subjected to the identical reaction conditions.
Delightfully, the desired α-fluoroenone 4b was obtained in 79%
yield. During the investigations, we also found that no TBAF was
required for efficient transformations in the case of 1c, 1f, 1k, 1q,
1t, 1u, and 1x as the substrates.17
The regioselectivity of the reactions for the ketones with two
different sites for enolization was then investigated. As described
in Scheme 2, 4-phenyl-2-butanone 3c under the standard
reaction conditions furnished a mixture of three isomers 4c,
4c′, and 4c″ in 95% overall yields. By comparison, 1-phenyl-2-
propanones 3d−f provided thermodynamic products (Z)-4-aryl-
3-fluoro-3-buten-2-ones 4d−f as the sole products. When 1,1-
diphenyl-2-propanone 3g was selected as the substrate, the main
product was identified as 3-fluoro-1,1-diphenyl-3-buten-2-one
4g resulting from the kinetic silyl enol ether. Steric hindrance of
two phenyl rings may make difluorocyclopropanation difficult
and leads to the kinetic product in selectivity.
Driven by the important properties and applications of α-
fluorinated α,β-unsaturated carbonyl compounds in organic
synthesis3,4 and the simplicity of the present method, our next
effort targeted a series of investigations on broadening this
method to aldehydes. Thus, 2-phenylpropanal 5a and cyclo-
hexanecarbaldehyde 5b were subjected to the optimized
conditions. The successful formation of α-fluoroenal products
6 in reasonable yields indicated that the method could tolerate
aldehydes (Scheme 3).16
generation of two distinct reactive intermediates, difluorocar-
bene and silyl enol ether, which are combined into the final α-
carbonyl fluoroolefins. The side product, TMSBr, along with Br−
and F− released from TMSCF2Br contributes to the catalytic
domino procedures. The research provides a new and powerful
example for highly efficient application of simple fluoroalkylsi-
lanes in the construction of fluoroorganic compounds. Further
work focused on the extension of this new synthetic strategy is in
progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, analytical data for all compounds 2, 4,
and 6. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhuds206@nenu.edu.cn.
*E-mail: liuqun@nenu.edu.cn.
*E-mail: wangm452@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge National Natural Sciences Founda-
tion of China (21172031, 21272034 and 21372040), and
National Natural Science Foundation of Jilin
(20140101113JC) for financial support.
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■
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Organic Letters
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fluoride anion would be released for further catalytic cycle II (Scheme
1C).
D
DOI: 10.1021/acs.orglett.5b00488
Org. Lett. XXXX, XXX, XXX−XXX