Copper-Catalyzed Fluoroolefination of Silyl Enol Ethers and Ketones toward the Synthesis of β-Fluoroenones

Article abstract of DOI:10.1021/acs.orglett.7b03700

A general and facile synthetic method for β-fluoroenones from silyl enol ethers or ketones, with a copper-amine catalyst system, has been developed. The reaction proceeded by a tandem process of difluoroalkylation-hydrolysis-dehydrofluorination. This method is characterized by high yields, excellent Z/E ratios, a low-cost catalyst, and a broad substrate scope. The synthetic potential of β-fluoroenones has been demonstrated by the construction of various complicated organofluorine molecules.

Full text of DOI:10.1021/acs.orglett.7b03700

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Fluoroolefination of Silyl Enol Ethers and Ketones
toward the Synthesis of β‑Fluoroenones
Yanlin Li,† Jing Liu,† Shuang Zhao,† Xuzhao Du,† Minjie Guo,*,‡ Wentao Zhao,† Xiangyang Tang,†
and Guangwei Wang*,†
†Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University,
Tianjin 300072, P. R. China
‡Institute for Molecular Design and Synthesis, Health and Science Platform, Tianjin University, Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: A general and facile synthetic method for β-
fluoroenones from silyl enol ethers or ketones, with a copper−
amine catalyst system, has been developed. The reaction proceeded
by a tandem process of difluoroalkylation−hydrolysis−dehydro-
fluorination. This method is characterized by high yields, excellent
Z/E ratios, a low-cost catalyst, and a broad substrate scope. The
synthetic potential of β-fluoroenones has been demonstrated by the
construction of various complicated organofluorine molecules.
Scheme 1. Synthetic Routes to β-Fluoroenones
evelopment of practical strategies for the introduction of
Dfluorine and fluorine-containing functional groups is the
major issue in organofluorine chemistry.1 In particular, the
synthesisofmonofluoroolefinshasbeenthefocusofinterestsince
the resulting products provide important building blocks and
enormous potential of synthesis for various complex organo-
fluorine compounds.2
Recently, we have developed a copper−amine catalyzed
difluoro-/perfluoroalkylation of general alkenes and heteroar-
enes.3 In this context, we chose silyl enol ethers which contain
electron-rich alkene moieties as the substrate for difluoro-/
perfluoroalkylation. We propose that the expected product might
undergo hydrolysis to afford α-difluoro-/perfluoroalkylated
ketones due to the instability of silyl enol ethers. However,
instead of a difluoroalkylated ketone and difluoroalkylated
enolate, β-fluoroenones were obtained utilizing a copper−
amine catalyst system. To date, although the synthesis of α-
fluoroenones had been exploited successfully,4 the methods for
the synthesis of β-fluoroenones are rather limited. For example,
hydrofluorination of alkynyl or allenic ketones5 (Scheme 1a) and
deoxyfluorination of β-diketones led to Z/E isomeric mixtures of
β-fluoroenones6 (Scheme 1b). Oxidative fluoroolefination has
also been developed for the construction β-fluoroenones from
alkenes and ethyl trimethylsilyl difluoroacetic ester7 (Scheme 1c).
In addition, perfluoroalkylation of silyl enolates using cationic
perfluoroalkylating agents followed by base-mediated dehydro-
fluorination of perfluoroalkylated ketones has also been reported
to afford perfluoroalkyl substituted β-fluoroenone8 (Scheme 1d).
Therefore, the synthesis of β-fluoroenone from easily available
starting materials and cheap catalysts are still underdeveloped.
Inspired by our promising results, we aimed at optimizing the
conditionstoestablishaconvenientstrategyforthesynthesisofβ-
fluoroenone from ketones or enolate with ethyl bromodifluoro-
acetate, whichhasreceivedconsiderableinterestasaninexpensive
and commercially available difluoroalkyl source.9−13 The
expected β-fluoroenonesareamenable tovarious transforamtions
due to their multifunctionality.
Initially, the reaction of trimethylsilyl enol ether with 1.5 equiv
of ethyl bromodifluoroacetate (2a) was performed in the
presence of 10 mol % of CuI and 1.5 equiv of PMDETA
(pentamethyldiethylenetriamine) inacetonitrile (0.2 M) at 80 °C
under an inert atmosphere. Instead of forming the routine
Received: November 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
difluoroalkylated product, an unexpected product of β-
fluoroenones (3a) was afforded in a low yield (13%),
accompanied by the hydrolyzed byproduct acetophenone (4a)
(54%)(Table1,entry1). Theformationofβ-fluoroenonescanbe
with adistinct decrease ofZ/Eratio (Table1, entry17). Whenthe
amount ofTESClwasdecreased to0.5 equiv, aslightlylower yield
(85%) and lower Z/E ratio (13/1) were obtained (Table 1, entry
18). When the amount of CuI was decreased to 1 mol %, the yield
of the target product dropped to 6% together with 7% of
acetophenone and ∼70% of starting material (1a) being
recovered.
a
Table 1. Optimization of Reaction Conditions
With the optimized reaction conditions in hand (Table 1, entry
4), the substrate scope of silyl enol ethers has been explored
(Scheme 2). First, the substitutions on aromatic rings have been
b
b
entry
base
additive
sol.
3a (%) (Z/E) 4a (%)
Scheme 2. Copper-Catalyzed Fluoroolefination of Silyl Enol
Ethers with Ethyl Bromodifluoroacetate
c
1
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
PMDETA
TMEDA
TMPDA
none
MeCNN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
13 (12:1)
79 (12:1)
90 (22:1)
90 (44:1)
86 (14:1)
51 (12:1)
65 (12:1)
7
54
17
<1
<1
5
a
2
none
3
TMSCl
TESCl
TBSCl
TBSOTf
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
TESCl
4
5
6
<1
<1
<1
<1
<1
29
34
74
71
<1
5
7
8
toluene
dioxane
DMF
9
69 (13:1)
82 (11:1)
<5
10
11
12
13
14
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
NEt3
<1
pyridine
<1
d
15
PMDETA
PMDETA
PMDETA
PMDETA
88 (21:1)
86 (13:1)
86 (4:1)
85 (13:1)
e
16
f
17
<1
<1
g
18
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (1.0 mmol), 2a (1.5 mmol), base (1.5 mmol), and
CuI (10 mol %), in solvent (2 mL) at 60 °C under Ar for 12 h.
b
c
Detected by GC. Trimethylsilyl enol ether as reactant at 80 °C.
d
e
f
CuCl instead of CuI. CuBr instead of CuI. 0.5 equiv of PMDETA
g
was added. 0.5 equiv of TESCl was added.
derived from the Heck-type reaction−hydrolysis−dehydrofluori-
nation14 cascade reaction process of silyl enol ethers. The poor
stability oftrimethylsilyl enol ether may be responsible forthe low
yielding. To our delight, employment of more stable tert-
butyldimethylsilyl (TBS) enol ether improved the yield of target
product 3ato79% (Z/E =12/1) with theyieldof 4adecreasing to
17% (Table 1, entry 2). In order to completely inhibit the
hydrolysisofsilylenolethers, thetrimethylsilylchloride(TMSCl)
was utilized to trap the trace amount of moisture (Table 1, entry
3) and a 90% (Z/E = 22/1) yield of 3a was obtained under these
conditions. Then, different kinds of silyl chlorides were examined
(Table 1, entries 4−6), and the results indicated TMSCl, TESCl,
TBSCl afforded similar yields with acceptable Z/E ratios.
Considering the relative stability and appropriate boiling point
of TESCl, we chose TESCl as the optimal additive. Several other
solvents had been tried (Table 1, entries 7−10), and lower yields
resulted. It is noteworthy that PMDETA played a crucial role in
this reaction, as replacement with other ligands led to lower yields
(Table 1, entries 11−14). The superior results of PMDETA
should be attributed to its excellent capacity to facilitate the
generation and stabilization of related radicals by coordination
with the copper atom.15 Meanwhile, various cuprous salt catalysts
were investigated, which revealed that three different kinds of
cuproussaltcatalysts ledtosimilar yieldswithdifferentZ/Eratios.
The relatively stable CuI was chosen as the optimal catalyst
(Table 1, entries 15 and 16). When the dosage of PMDETA
decreased to0.5equiv, theyieldoftargetproductdroppedslightly
a
Reaction conditions: a mixture of silyl enol ethers (1) (1.0 mmol),
ethyl bromodifluoroacetate (2a) (1.5 mmol), CuI (0.1 mmol),
PMDETA (1.5 mmol), TESCl (1.0 mmol) in dry MeCN (2.0 mL)
was stirred at 60 °C for 14 h. 3.0 equiv of ethyl bromodifluoroacetate
(2a) was used at 80 °C for 2 h. TBSOTf was used instead of TESCl.
b
c
studied. Both electron-donating groups and weak electron-
withdrawing groups (3a−3j, 3l−3o, 3u) can lead to satisfactory
results, while strong electron-withdrawing groups (3k) led to a
moderate yield. Silyl enol ethers derived from heteroaromatic
ketonesalsogavegoodyields(3p−3t). Comparedwith3qand3r,
3p displayed a higher yield, which might be due to their different
coordination patterns. Cyclohexanone and cyclopentanone
derived silyl enol ether also led to desired products (3u, 3v) in
moderate to good yields. Another aliphatic silyl enol ether was
also examined, and 3w was achieved with a moderate yield and
remarkable Z/E ratio. Considering the possible Z/E isomer-
ization of activated olefins under light,16 parallel experiments for
3j as a model test have been conducted under light and dark
conditions, and similar results were obtained (see Supporting
Information (SI)).
B
DOI: 10.1021/acs.orglett.7b03700
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Organic Letters
Letter
Furthermore, the scope of gem-difluoromethylene and
perfluoroalkyl compounds was examined (Scheme 3). First, the
Both electron-donating and -withdrawing groups at different
locations of the benzene ring could be well tolerated, with the
electron-donating groups leading to higher yields while electron-
withdrawing groups led to slightly lower yields (Scheme 4).
Importantly, a multigram-scale experiment had been conducted
with 4a and 2a as starting material, and 3a was obtained in
satisfactory yield.
Scheme 3. Scope of gem-Difluoromethylene/Perfluoroalkyl
a
Compounds
To gain some insight into the mechanism, 2,2,6,6-tetramethyl-
1-piperidinoxyl (TEMPO) as a radical scavenger was added to
this reaction. The reaction was completely inhibited with
TEMPO−CF2CO2Et being isolated as the major product
(Scheme 5). On the basis of the above-mentioned results and
Scheme 5. TEMPO Experiment
relevant literature,3,14 a possible reaction mechanism was
proposed as illustrated in Scheme 6. Initially, oxidation of
a
Reaction conditions: a mixture of silyl enol ethers (1a) (1.0 mmol), 2
(1.5 mmol), CuI (0.1 mmol), PMDETA (1.5 mmol), TESCl (1.0
mmol) in dry MeCN (2.0 mL) was stirred at 70 °C for 14 h. At 80
°C for 4−6 h.
b
Scheme 6. Possible Mechanism
different kinds of gem-difluoromethylene compounds, such as
difluoroacetamides, difluoroacetophenone, and 2-(bromo-
difluoromethyl)benzo[d]oxazole, proved to be suitable sub-
strates, resulting in good yields with moderate to excellent Z/E
selectivities (5a−5f). Moreover, the perfluoroalkyl substrates
achieved satisfactory yields with excellent stereoselectivities (5g−
5i).
By comparing the preparation conditions (see SI) of silyl enol
etherswiththeoptimized β-fluoroolefinationconditions, theone-
pot method was designed which involved the in situ generation of
silyl enol ethers. Starting from acetophenone (4a), the reaction
proceeded smoothly in the presence of NaI, TBSCl, PMDETA,
and CuI (Scheme 4). However, in the absence of NaI, the yield
dropped to 5% dramatically with other conditions unchanged.
When TMSI, which might promote the enolization of ketone to
form silyl enol ethers, was applied, similar results were obtained.
copper(I) species by a fluoroalkyl reagent through a single
electrontransfer(SET)processresultsinacopper(II)speciesand
fluoroalkyl radical. Then, addition of the fluoroalkyl radical tosilyl
enolethergeneratesradicalspeciesAwhichcanbeoxidizedbythe
copper(II) species to afford carbocation species B and regenerate
the copper(I) species. β-H Elimination of B leads to
fluoroalkylated silyl enol ether 6 which might undergo the
hydrolysis−dehydrofluorination process or direct defluorosilyla-
tion reaction through a possible six-membered ring transition
state, either of which leading to a β-fluoroenone product.
With the optimized reaction conditions in hand, further
derivatization of β-fluoroenones was explored. A variety of
reaction types had been accomplished, such as selective reduction
ofacarbonylorolefinbond,olefinaddition, Diels−Alderreaction,
and epoxidation reaction (Scheme 7). A series of β-fluorinated
carbonyl derivatives had been obtained with good to excellent
yields, which indicate the diverse potential of β-fluoroenones as
key synthetic intermediates for construction of various fluorine-
containing compounds.
a
Scheme 4. Examples of One-Pot Method
a
In summary, the Cu-catalyzed reaction of ethyl bromodifluoro-
acetate and silyl enol ethers has been developed, which provides a
facile strategy toward the synthesis of β-fluoroenones. Various
substitutions on the phenyl ring of acetophones can be well
tolerated. Perfluoroalkyl iodides and various bromodifluoro-
Reaction conditions: a mixture of ketones (4) (1.0 mmol), 2 (2.5
mmol), CuI (0.1 mmol), PMDETA (1.5 mmol), TBSCl (1.5 mmol),
NaI (1.5 mmol) in dry MeCN (3.0 mL) was stirred at 60 °C for 14 h.
b
c
10 mmol scale experiment. TMSI (1.5 mmol) was used instead of
TBSCl/NaI.
C
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Organic Letters
Letter
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acetamide also serve as suitable substrates for this catalyst system.
Moreover, the one-pot strategy has been achieved which involved
in situ generation of silyl enol ethers directly from ketones. The
resulting β-fluoroenones have been successfully functionalized
through diverse types of reactions. A preliminary mechanistic
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03700.
Experimental procedures, spectral and analytical data,
copies of 1H, 13C, and 19F NMR spectra for new
compounds (PDF)
(10) (a) Xiao, Y.-L.; Guo, W.-H.; He, G.-Z.; Pan, Q.; Zhang, X. Angew.
Chem., Int. Ed. 2014, 53, 9909. (b) Feng, Z.; Min, Q.-Q.; Zhang, X. Org.
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885. (c) Shao, C.; Shi, G.; Zhang, Y.; Pan, S.; Guan, X. Org. Lett. 2015, 17,
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(12) Ye, Z.; Gettys, K. E.; Shen, X.; Dai, M. Org. Lett. 2015, 17, 6074.
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T.; Poisson, T.;Pannecoucke, X. Synthesis 2014, 46, 1859. (b)Caillot, G.;
Dufour, J.; Belhomme, M.-C.; Poisson, T.; Grimaud, L.; Pannecoucke,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanggw@tju.edu.cn.
*E-mail: gmj2016@tju.edu.cn.
ORCID
Guangwei Wang: 0000-0003-4466-9809
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (No.
2015CB856500), the Natural Science Foundation of Tianjin
(No. 16JCYBJC20100), and Tianjin City Thousand Talents
Program for support of this research.
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