Me3SiCF2Br-Self-Assisted Domino Reaction: Catalytic Synthesis of α,α-Difluorocyclopentanones from Methylvinylketones

Article abstract of DOI:10.1021/acs.orglett.7b00611

A complete self-assistance strategy based on Me₃SiCF₂Br was used in the domino conversion of methylvinylketones into α,α-difluorinated cyclopentanones. Initiated by 5 mol % of nBu₄NBr, the multistep reaction occurred in on

Full text of DOI:10.1021/acs.orglett.7b00611

Letter
pubs.acs.org/OrgLett
Me3SiCF2Br-Self-Assisted Domino Reaction: Catalytic Synthesis of
α,α-Difluorocyclopentanones from Methylvinylketones
Jian Chang,† Cong Xu,† Jie Gao,† Fengyun Gao,† Dongsheng Zhu,*,† and Mang Wang*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of Chemistry, Northeast Normal
University, Changchun 130024, P. R. China
‡State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. China
S
* Supporting Information
ABSTRACT: A complete self-assistance strategy based on Me3SiCF2Br was used in
the domino conversion of methylvinylketones into α,α-difluorinated cyclopentanones.
Initiated by 5 mol % of nBu4NBr, the multistep reaction occurred in one pot under
mild conditions via the in situ formation of silyl dienol ethers, difluorocyclo-
propanation, thermal vinylcyclopropane−cyclopentene rearrangement, and desilyla-
tion. The process takes advantage of the multitasking capability of Me3SiCF2Br as the
difluorocarbene source, a silicon-based transfer agent, and a bromine anion releaser.
Scheme 1. Strategies for the Synthesis of α,α-
Difluorocyclopentanones
omino reactions allow for rapid construction of complex
Dmolecules from simple substrates in an economically
favorable way.1 In this regard, the cascade sequences achieved
by means of a catalytic self-assistance strategy of the reactant
undoubtedly provide a more ecologically and remarkably
desirable approach to organic synthesis. Here, we reported a
catalytic domino transformation of methylvinylketones to α,α-
difluorinated cyclopentanones by the use of Me3SiCF2Br
(TMSCF2Br). The process takes advantage of the multitasking
capability of TMSCF2Br as the :CF2 source, a TMS transfer
agent, and the Br− releaser. The method avoids the presynthesis
of silyl dienol ethers and also does not require either the
catalyst for difluorocyclopropanation or an external desilylating
reagent.
α,α-Difluorinated ketone is a privileged subset of medicinal
and bioactive molecules.2−4 Among them, cyclic α,α-difluori-
nated ketones are notable examples.4a−c As a consequence,
reliable methods for their synthesis are valuable for developing
new drug candidates and biological probes. However, current
work is limited to the construction of difluorinated ketone
scaffolds.3a,5,6 A facile and efficient approach for the synthesis of
cyclic analogs has not been established. It was reported that
α,α-difluorocyclopentanones could be prepared via the
fluorinations of the corresponding cyclopentanones (Scheme
1A), including either by a direct nucleophilic α-fluorination5b,7
or by a deoxygenative fluorination−oxidation sequence.8 This
kind of strategy requires the preconstruction of a cyclo-
pentanone skeleton and usually suffers from hazardous
fluorinating reagents. Moreover, the regioselectivity of the
fluorination, in the case of those cyclopentanones bearing
multiple reaction sites as the substrates, still remains a
challenging issue. On the other hand, the synthesis of α,α-
difluoroketones from readily available fluorocarbon precursors
represents a complementary route.3a,6 However, this strategy is
seldom applied for the synthesis of difluorinated cyclic ketones
though it is versatile and more convergent in essence, and is
also suited for regioselective synthesis of libraries of fluorinated
chemicals.
In 2015, Ichikawa and co-workers reported a preparation of
α,α-difluorocyclopentanones starting from methylvinylketones
by use of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl) acetate
(TFDA, Scheme 1B, Ichikawa’s work).9 The conversion was
achieved via four separate steps including presynthesis of silyl
dienol ethers, Ni-catalyzed difluorocyclopropanation, thermal
vinylcyclopropane−cyclopentene (VCP) rearrangement,10,11
and desilylation. During our research on the synthetic
applications of fluoroalkylsilanes,12,13 we have described a
nBuN4Br (TBAB)-catalyzed difluorocyclopropanation of eno-
lizable ketones13 by using TMSCF2Br as a difluorocarbene
source. We then successfully carried out a ring-opening and
defluorination reaction to prepare α-fluoroenones13a and o-
fluoronaphthols13b by treating the resulting siloxyldifluoro-
Received: February 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00611
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Organic Letters
Letter
cyclopropanes with nBuN4F (TBAF). Lately, we developed a
well-controlled ring-opening and intramolecular SNV type
reaction of siloxyldifluorocyclopropanes in the presence of
stoichiometric Cu or Ag salt via a metal difluorohomoenolate
species for the synthesis of α,α-difluorocyclopentenones.13c We
anticipated that further advances in the unique chemistry of
TMSCF2Br would enable a catalytic domino transformation1
for the incorporation of a difluoromethylene fragment into the
α-position of the carbonyl by utilizing a complete self-assistance
strategy. Considering the ready availability of methylvinylke-
tones and the possibility of the VCP rearrangement of
siloxylvinyldifluorocyclopropane,9 we explore the reaction of
methylvinylketones with TMSCF2Br (Scheme 1B, this work).
In this letter, we report that this catalytic process could indeed
be achieved, allowing the development of a direct and efficient
route to a wide range of functionalized α,α-difluorocyclo-
pentanone derivatives.
Initially, the reaction of (Z)-3-benzoyl-4-phenyl-3-buten-2-
one 1a with TMSCF2Br was selected as a model system to
identify the reaction conditions. Delightfully, upon treatment of
1a with 2.5 equiv of TMSCF2Br in the presence of 2.5 mol %
TBAB in toluene at 100 °C, the desired 5-benzoyl-2,2-difluoro-
4-phenylcyclopentanone could be obtained in its enolic form
(Table 1) according to its NMR, MS spectra, and further by its
methylvinylketones 1 by using TMSCF2Br as a fluorocarbon
precursor. As presented in Table 2, most tested conversions
a
Table 2. Catalytic Synthesis of 2 from 1 and TMSCF2Br
b
entry
R1
EWG
R2
yield (%)
1
Ph
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
CO2Me
CO2Et
CO2Bn
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
H
2a, 86 (86)
2b, 80 (89)
2c, 76 (92)
2d, 80 (82)
2e, 71 (90)
2f, 70 (95)
2g, 90 (94)
2h, 80 (94)
2i, 79 (85)
2j, 89 (91)
2k, 85 (93)
2l, 69 (82)
2m, 76 (84)
2n, 60 (65)
2o, 70 (73)
2p, 61 (85)
2q, 71 (88)
2r, 76 (87)
2s, 73 (89)
2
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-BnOC6H4
2-naphthyl
4-FC6H4
3
4
5
6
7
8
9
2-FC6H4
10
11
12
13
14
15
16
17
18
19
20
4-ClC6H4
4-BrC6H4
4-CNC6H4
3-CNC6H4
4-NO2C6H4
4-MeO2CC6H4
4-CF3C6H4
N-Me-3-indolyl
2-furyl
a
Table 1. Screening of the Reaction Conditions
2-thienyl
c
cyclopropyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-naphthyl
3-ClC6H4
2t, 64 (73)
d
21
2u, 84 (89)
2v, 80 (90)
2w, 85 (92)
2x, 59 (93)
2y, 65 (80)
2z, 55 (77)
2aa, 67 (83)
2ab, 43 (60)
b
d
entry
TBAB (mol %)
solvent
toluene
temp (°C)
yield (%)
22
d
23
1
2
2.5
5
100
100
100
100
100
100
90
73
d
24
toluene
toluene
1,4-dioxane
MeCN
DCE
84
d
25
3
10
5
85
d
26
4-CNC6H4
4-MeOC6H4
4-MeOC6H4
Ph
4
76
d
27
5
5
86
d
28
6
5
trace
86 (86)
e
29
2ac, (40)
7
5
toluene
toluene
MeCN
toluene
f
c
2ac′, 2ac″ (75)
complex
8
5
80
75
d
30
Ph
CN
H
9
5
90
53
a
10
5
110
86
General reaction conditions: 1 (0.2 mmol), TMSCF2Br (2.5 equiv),
b
1
a
toluene (1.0 mL), in a sealed tube, 7 h. Isolated yields. H NMR
yields were in parentheses by using 1,3,5-trimethoxybenzene as an
General reaction conditions: 1a (0.2 mmol), TMSCF2Br (2.5 equiv),
b
solvent (1.0 mL), in a sealed tube, 7 h. 1H NMR yield by using 1,3,5-
trimethoxybenzene as internal standard. Isolated yield was in
parentheses. 13% yield of 3 was obtained. 24% of 1a was recovered
c
internal standard. A mixture of two keto−enol isomers was obtained.
d
c
d
The reaction was performed in MeCN (1.0 mL), at 100 °C for 8 h.
e
Trace amount of 2ac′ was detected. 50% of 1ac remained.
along with 7% yield of 3.
f
TMSCF2Br (5 equiv). 2ac′ and 2ac′′ were obtained in 1:5 mixture.
X-ray data.14 By increasing the amount of the TBAB catalyst,
the yield of the cyclic enol product 2a could reach 85% (entries
2 and 3). A screen of other solvents revealed that both 1,4-
dioxane and MeCN could give 2a in good yield (entries 4 and
5), but DCE was inert for the reaction (entry 6). A lower
temperature led to somewhat less efficiency of the conversion
from siloxyldifluorovinylcyclopropane intermediate 3 to the
final product 2a (entries 7−9), while a higher temperature did
not provide a better experimental result (entry 10).
from 1 to 2 are highly efficient, while the isolated yields of 2 are
somewhat low in some cases (such as Table 2, entries 3, 5, 6,
12, and 13) due to the inefficient chromatographic purification
process. In general, there is to be a lack of significant electron
effects of the R1 substituent in 1 on the reaction efficiency. α-
Benzoyl methylvinylketones 1b−g bearing electron-donating
aromatic R1 afforded the desire 2b−g in 82−95% NMR yields
(entries 2−7). And substrates 1h−p with electron-deficient
aromatic R1 also gave 2h−p in 73−94% NMR yields (entries
8−16). By comparison, those substrates with a stronger
With the optimized reaction conditions (Table 1, entry 7),
we then evaluated the reactivities of various structurally diverse
B
DOI: 10.1021/acs.orglett.7b00611
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Letter
electron-deficient substituent (such as NO2 or CO2Me) on the
phenyl ring gave 2 in relatively lower yields (entries 14 and 15).
Heteroaromatic ring-substituted methylvinylketones 1q−s
could be used for the present domino reactions (entries 17−
19). In the case of 1t having an aliphatic cyclopropyl group, the
reaction worked well furnishing a mixture of 2t and its keto
isomer 2t′ in good yield (entry 20). In addition, when α-
alkoxycarbonyl methylvinylketones 1u−ab were prepared for
the reaction, corresponding α,α-difluorocyclopentanones 2u−
ab were also obtained (entries 21−28). R2-Substituted
vinylketones 1aa and 1ab gave 2aa and 2ab in lower yields
under the identical reaction conditions (entries 27 and 28).
When α-acetylated methylvinylketone 1ac was selected as the
substrate, 2ac along with 2ac′15 was obtained (entry 29). By
increasing the amount of TMSCF2Br, the reaction gave 2ac′
and 2ac″16 as the products (entry 29). Moreover, α-cyano
methylvinylketone 1ad could not provide the desired product
(entry 30) despite further efforts in optimizing the reaction
conditions.
Encouraged by the above experimental results, we further
investigated the domino conversion of methylvinylketones
1ae−aj without an α-substituent and made a comparison with
Ichikawa’ work (Scheme 3).9 By using TMSCF2Br as the
Scheme 3. Synthesis of 4/5 from 1 and TMSCF2Br
On the basis of our previous work13 and the VCP
rearrangement reactions,9−11 it was reasonable to propose a
catalytic domino mechanism for the above transformation. As
described in Scheme 2, Br−-activated TMSCF2Br first produced
difluorocarbene agent and TBAB as the initiator, 1ae could
smoothly undergo a tandem enolization−silylation, difluoro-
cyclopropanation, VCP rearrangement, and desilylation se-
quence to furnish α,α-difluorocyclopentanone 4a in 92% NMR
yield. It was true that 4a was sensitive toward chromatographic
purification as observed in Ichikawa’s experiments and, thus,
had to be derivatized to oxime 5a by further reacting with a 1.5
equiv amount of hydroxylamine hydrochloride for isolation.
Similarly, 1af−aj also gave the corresponding oximes 5b−f in
good yields by the reaction with TMSCF2Br and then with
hydroxylamine hydrochloride in one pot. Clearly, a direct and
easy transformation from readily available methylvinylketones
to α,α-difluorocyclopentanones9 was realized in the present
work by the use of 5 mol % of TBAB without any additional
silylation agent, metal catalyst for difluorocyclopropanation,
and desilylation agent.
Scheme 2. Proposed Mechanism
Additionally, when methylvinylketones 1ak−am with an α-
alkyl or α-aryl substituent were prepared and treated with
TMSCF2Br under standard reaction conditions, the reactions
stopped at the cyclic difluorinated silyl enol ethers 6a−c, a type
of intermediate III as described in Scheme 2, by analyzing the
1H NMR spectra of the reaction mixture (Scheme 4). No
Scheme 4. Synthesis of 6/7 from 1 and TMSCF2Br
CF2 and TMSBr. Silyl dienol ether I was then formed in situ by
the reaction of methylvinylketone 1 and TMSBr along with
releasing HBr to the reaction mixture. Next, difluorocyclo-
propanation of I with CF2 gave vinyldifluorocyclopropane II
followed by a thermal ring opening and recyclization (VCP
rearrangement) leading to cyclic difluorinated silyl enol ether
III. Finally, α,α-difluorocyclopentanone 2 was obtained by the
desilylation with the assistance of HBr resulted from the former
step.
desired α,α-difluorocyclopentanones were detected. However,
decompositions of 6 during chromatography purification
resulted in less than 10% isolated yields of 6. Interestingly, a
small amount of byproducts were isolated and identified to be
the oxygenated cyclopentenones 7, which were likely formed
via the desilylation of 6, defluorination, and hydrolysis
sequence.17 Considering that TBAB or HBr that existed in
the reaction mixture was the potential initiator for the
desilylation of 6, either TBAB (1.5 equiv) or HBr (47%
aqueous) was added to the reaction mixture after 1ak−am were
consumed. As we expected, 7a−c were isolated in moderate to
Compared with the method developed by Ichikawa’ group,9
the present work described a remarkably simple and catalytic
domino transformation of methylvinylketones to α,α-difluori-
nated cyclopentanones. Notably, our method does not need
any catalysts for either difluorocyclopropanation or desilylation.
Once TMSCF2Br is initially activated by a catalytic amount of
TBAB, the cascade reaction will occur in a self-assisted manner.
Besides generating difluorocarbene, the internal “TMS” and
“Br” can be released from TMSCF2Br during the reaction for all
the following steps.
C
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good yields, respectively, by using aqueous HBr and stirring at
room temperature for 4 h (Scheme 4).
In conclusion, we have successfully developed a simple and
efficient domino transformation of methylvinylketones to α,α-
difluorocyclopentanone derivatives using unique TMSCF2Br as
a difluorocarbene agent. A complete self-assistance strategy
based on TMSCF2Br enables the conversion to occur smoothly
under the catalysis of 5 mol % of TBAB via the in situ formation
of silyl dienol ethers, difluorocyclopropanation, thermal ring
opening and recyclization rearrangement, and desilylation. This
process represents the first example for the catalytic synthesis of
difluorinated cyclic compounds from fluorocarbon precursors.
The reliable installation of a difluoromethylene fragment at the
α-position of readily available ketones makes the method well-
suited for wide applications in organic synthesis and drug
design. Further work on the application and extension of the
scope of the protocol are currently under investigation in our
laboratory.
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́
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00611.
33, 247. (b) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (c) Baldwin, J. E.
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683. (b) Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.; Wang, M.; Liu, Q.
Chem. - Eur. J. 2013, 19, 9104. (c) Zheng, G.; Ma, X.; Li, J.; Zhu, D.;
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(14) CCDC 1521772 contains the supplementary crystallographic
data for 2a for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
uk/data_request/cif.
■
S
Experimental procedures, analytical data for new
compounds (PDF)
Crystallographic data for 2a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhuds206@nenu.edu.cn.
*E-mail: wangm452@nenu.edu.cn.
ORCID
(15) 2ac′ was formed by further difluorocyclopropanation, ring
opening, and defluorination of the acetyl group of 2ac.
(16) 2ac″ was formed by further difluorocyclopropanation, ring
opening, and protonation of the acetyl group of 2ac.
(17) Fuchibe, K.; Takayama, R.; Yokoyama, T.; Ichikawa, J. Chem. -
Eur. J. 2017, 23, 2831.
Mang Wang: 0000-0001-8006-4626
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Sciences Foundation of China
(NNSFC-21372040 and 21672032) and the State Key
Laboratory of Fine Chemicals (KF1502) for funding support
of this research.
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