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Arkivoc 2018, part ii, 72-80

Metal-free synthesis of α,α-difluorocyclopentanone derivatives via
regioselective difluorocyclopropanation/VCP rearrangement of silyl dienol ethers
Ryo Takayama, Kohei Fuchibe, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba,
Tsukuba, Ibaraki 305–8571, Japan
Email: junji@chem.tsukuba.ac.jp
Dedicated to Professor Kenneth K. Laali in celebration of his 65th birthday
Received 08-01-2017

Accepted 08-20-2017

Published on line 10-29-2017

Abstract
Silyl dienol ethers underwent chemoselective difluorocyclopropanation under mild conditions withdifluorocarbene, which was generated from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) using
1,8-bis(dimethylamino)naphthalene (proton sponge) as a catalyst. Successive vinylcyclopropane/cyclopentene(VCP) rearrangements readily proceeded to provide biologically promising 5,5-difluorocyclopent-1-en-1-yl silyl
ethers in a one-pot operation without the use of metal catalysts.

Keywords: Cyclopentanoid, difluorocarbene, difluorocyclopropanation, organocatalyst, vinylcyclopropane
rearrangement

DOI: https://doi.org/10.24820/ark.5550190.p010.290

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Introduction
An important cyclopentanone framework is found in a variety of bioactive natural products and their synthetic
intermediates. Their fluorinated counterparts are attracting much interest because of the biological effects ofintroducing fluorine.1,2 Till date, fluorinated cyclopentanone derivatives have been mostly synthesized byfluorination of cyclopentanones.3–6 However, these methods suffer from drawbacks relating to therequirement of time-consuming processes such as carbon-skeleton construction and fluorine installation as
well as the use of expensive fluorinating reagents.
We have already reported the synthesis of α,α-difluorocyclopentanones based on the strategy of
introducing difluoromethylene (Scheme 1).7 The reaction involves sequential (i) nickel-catalyzed
chemoselective difluorocyclopropanation of silyl dienol ethers via a difluorocarbene complex and (ii)regioselective vinylcyclopropane/cyclopentene (VCP) rearrangement.8–10 This method is efficient because theintroduction of fluorine substituents and the construction of the carbon skeleton are performed
simultaneously. The five-membered cyclic silyl enol ethers thus obtained can be transformed to α,αdifluorocyclopentanone derivatives.
Recently, we have also developed an organocatalytic method for the generation of difluorocarbene by thedecomposition of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA)11–13 (Scheme 2).14–17 The
compound 1,8-bis(dimethylamino)naphthalene (proton sponge) was an efficient catalyst for the generation of
difluorocarbene, with which silyl dienol ethers were chemoselectively transformed to the corresponding
difluoro(vinyl)cyclopropanes, leading to the generation of α-fluorocyclopentenones via a fluorine-directed and-activated Nazarov cyclization (Scheme 3, Path A).17 Thus, we envisioned that the organocatalytic generationof difluoro(vinyl)cyclopropanes followed by the aforementioned VCP rearrangement would result in a
desirable metal-free process for the synthesis of α,α-difluorocyclopentanones (Scheme 3, Path B).18, 19

Scheme 1. Ni-catalyzed synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers.

Scheme 2. Generation of difluorocarbene using organocatalysts.
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Scheme 3. Organocatalytic synthesis of fluorocyclopentanone derivatives.

Results and Discussion
VCP rearrangements of fluorine-free siloxyvinylcyclopropanes have been performed at high temperatures(330−600 °C).20–22 Fluorine substitution was reported to allow benign rearrangement conditions and render
the C−C bond cleavage regioselective.23–27 We first examined the temperature required for VCP
rearrangement using isolated difluoro(vinyl)cyclopropane 2a.17 Cyclopropane 2a, prepared from silyl dienol
ether 1a and difluorocarbene, was heated in p-xylene to give 5,5-difluorocyclopent-1-ene-1-yl silyl ether (cyclic
silyl enol ether, 3a, Table 1). Thus, the rearrangement took place even at 80 °C (Table 1, entries 1,2), which
was much lower than the temperature required for the VCP rearrangement of fluorine-free substrates. The
rearrangement was found to proceed quickly (30 min) at 140 °C, affording 3a in quantitative yield (Table 1,entry 6).
Table 1. Optimization of reaction conditions for VCP rearrangement

Entry
1
2
3
4
5
6

Temp
80 °C
80 °C
100 °C
100 °C
120 °C
140 °C

Time
1h
5h
1h
2h
0.5 h
0.5 h

3aa
32%
80%
85%
96%
92%
Quant.

Recovery of 2aa
67%
14%
13%
nd
4%
ndb

a 19F NMR yield based on an internal standard (CF ) C(C H CH ) .
3 2
6 4
3 2
b not detected.

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Next, the desired metal-free, one-pot sequence of difluorocyclopropanation and VCP rearrangement wasinvestigated (Table 2). Since, when a trace amount of acid remained in TFDA, decomposition of silyl dienol ethers 1
occurred predominantly during difluorocyclopropanation at room temperature, TFDA (1.5 equiv.) was added dropwise
to the preheated solution of silyl dienol ether 1a and the proton sponge (5 mol%) in p-xylene. The
difluorocyclopropanation/VCP rearrangement proceeded efficiently at 140 °C in a one-pot operation to afford cyclic silyl
enol ether 3a in 83% yield (Table 2, entry 1). When silyl dienol ether 1b was used as the substrate, the reaction
proceeded under the same conditions to afford 3b in 81% yield (Table 2, entry 2). The yield of 3b increased to 90% when
difluorocyclopropanation was performed at 60 °C17 followed by VCP rearrangement at 140 °C (Table 2, entries 3,4).

Table 2. Optimization of reaction conditions for sequential difluorocyclopropanation/VCP rearrangement

Entry
1
2
3
4

R1
Ph
Ph
Ph
Ph

R2
H
Me
H
Me

1
1a
1b
1a
1b

Conditions
140 °C, 30 min
140 °C, 30 min
60 °C, 15 min; then 140 °C, 30 min
60 °C, 15 min; then 140 °C, 30 min

3
3a 83a3b 81a3a 80b3b 90b

a 19F NMR yield based on an internal standard (CF ) C(C H CH ) . b Isolated yield.
3 2
6 4
3 2

Under optimized conditions, cyclic silyl enol ethers 3 with various substituents were synthesized (Table 3).
Silyl dienol ethers 1c–f, bearing electron-donating or -withdrawing aryl or alkyl groups at the terminal position(R1), afforded the corresponding cyclic silyl enol ethers 3c–f in 77–90% yields. Substrates 1b and 1g, bearing amethyl or a bromo substituent at the internal position (R2), afforded 3b and 3g in 90% and 83% yields,
respectively. When silyl dienol ether 1h with a cyclohexene ring was used as the substrate, 3h possessing a[4.3.0]bicyclononane structure was obtained in 66% yield.
Substrates 1i and 1j, bearing an alkyl substituent (i.e., an isopropyl group and a butyl group, respectively)on the enol ether moiety (R3), also successfully participated in the reaction.28 Silyl dienol ethers 1i and 1j (witha Z/E ratio of 92/8 and 94/6, respectively) underwent difluorocyclopropanation/VCP rearrangement, leading to
the diastereoselective formation of 3i and 3j in 45% and 49% yields (with a trans/cis ratio of >99/<1 and>99/<1, respectively). These substrates exclusively provided more thermodynamically stable trans-isomers,
probably because the ring closure avoided steric hindrance during the rearrangement.

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Table 3. Metal-free synthesis of cyclic silyl enol ethers 3a-ja

3a 80% (0.5 h)

3c 85% (0.5 h)

3d 81% (0.5 h)

3e 90% (0.5 h)

3f 77% (1 h)

3b 90% (1 h)

3g 83% (1 h)

3h 66% (2 h)3i 45%b (1 h)

3j 49%b (1 h)a Isolated yield (time). b 3i and 3j were isolated as mixtures with siloxydienes.28

The metal-free protocol described here was advantageous with respect to regioselectivity in the VCP
rearrangement step; this was exemplified by silyl dienol ether 1g (Scheme 4). Whereas 1g underwent metalfree difluorocyclopropanation/VCP rearrangement to give 3g as the sole five-membered product (Table 3),treatment of 1g with TFDA in the presence of a catalytic amount of a Ni complex afforded 3g in 72% yieldalong with the structural isomer 4,4-difluorocyclopent-1-en-1-yl silyl ether 6g in 8% yield (Scheme 4).29 Thus,
the advantage of the synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers 3 under metal-free conditions
was demonstrated.

Scheme 4. The disadvantage with the nickel-catalyzed protocol. a 19F NMR yield based on an internal standard(CF3)2C(C6H4CH3)2.

Conclusions
Metal-free difluorocyclopropanation/VCP rearrangement of silyl dienol ethers was successfully carried out
with difluorocarbene generated from TFDA using a proton sponge as an organocatalyst. This resulted incomplete regio- and stereoselective ring construction, leading to the efficient synthesis of biologicallypromising fluorinated cyclopentanones.
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Experimental Section
General. p-Xylene was stirred over anhydrous CaCl2, distilled after azeotoropic removal of water, and stored
over molecular sieves 4A. Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) was prepared according
to the literature.13 All of silyl dienol ethers (starting materials) 1a–j were prepared according to theliterature7,17 and the spectral data were in good agreement with those in the literature.7,17 1,8Bis(dimethylamino)naphthalene (proton sponge) and 1,1,1,3,3,3-hexafluoro-2,2-di(p-tolyl)propane (internal
standard for 19F NMR) was purchased from Tokyo Chemical Industry Co., Ltd. Proton sponge was recrystalized
from methanol/water.
Column chromatography and preparative thin layer chromatography (PTLC) were conducted on silica gel (Silica
Gel 60 N, Kanto Chemical Co., Inc. for column chromatography and Wakogel B-5F, Wako Pure Chemical
Industries, Ltd. for PTLC).
IR spectra were recorded on a Horiba FT-300S spectrometer by the attenuated total reflectance (ATR method).
NMR spectra were recorded on a Bruker AVANCE 500 or a Jeol JNM ECS-400 spectrometer in CDCl3 at 500 or
400 MHz (1H NMR), at 126 or 100 MHz (13C NMR), and at 470 or 376 MHz (19F NMR). Chemical shifts were
given in ppm relative to internal Me4Si (for 1H NMR: δ = 0.00), CDCl3 (for 13C NMR: δ = 77.0), and C6F6 (for 19F
NMR: δ = 0.0). High resolution mass spectroscopy (HRMS) was conducted with a Jeol JMS-T100GCV
spectrometer (EI, TOF).
Typical procedure for the synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers (3). Synthesis of 3a is
described as a typical procedure. The mixture of proton sponge (2.3 mg, 0.011 mmol), 1,1,1,3,3,3-hexafluoro2,2-di(p-tolyl)propane (6.2 mg, 0.019 mmol), and silyl dienol ether 1a (52 mg, 0.20 mmol) in p-xylene (2 mL)
was heated to 60 °C and TFDA (60 μL, 0.30 mmol) was added dropwise over 5 min. The resulting mixture wasstirred at 60 °C for 15 min. The reaction mixture was heated at 140 °C for 30 min and then cooled to room
temperature. The mixture was diluted with hexane (2 mL) and a saturated aqueous solution (10 mL) of sodiumhydrogen carbonate was added. Organic materials were extracted with hexane three times. The combined
extracts were dried over anhydrous sodium sulfate. The sulfate was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel(hexane) to afford 5,5-difluorocyclopent-1-en-1-yl silyl ether 3a as a yellow liquid (50 mg, 80% yield).
Spectral data of 3a, 3b, 3c, 3d, 3f, 3g, and 3h showed complete agreement with those in our previous paper.7
1-[tert-Butyl(dimethyl)silyloxy]-5,5-difluoro-3-[4-(trifluoromethyl)phenyl]cyclopent-1-en (3e). 1H NMR (400
MHz, CDCl3): δ 0.23 (s, 3H), 0.24 (s, 3H), 0.98 (s, 9H), 2.14 (dddd, J 17.2, 16.0, 11.6, 4.0 Hz, 1H), 2.84 (dddd, J
16.0, 16.0, 8.4, 8.4 Hz, 1H), 3.86 - 3.93 (m, 1H), 5.16 (d, J 2.0 Hz, 1H), 7.31 (d, J 8.0 Hz, 2H), 7.57 (d, J 8.0 Hz, 2H).
13C NMR (100 MHz, CDCl ): δ -4.8, -4.8, 18.2, 25.5, 40.5, 41.6 (dd, J 25, 25 Hz), 114.3 (dd, J 7, 7 Hz), 124.1 (q, J
3
270 Hz), 125.7, 125.8, 126.8 (dd, J 243, 243 Hz), 127.4, 148.1 (d, J 5 Hz), 149.3 (dd, J 25, 25 Hz).19F NMR (376MHz, CDCl3): δ 99.3 (s, 1F), 69.3 (dddd, J 8, 249, 17, 11, 8 Hz, 1F), 64.5 (dddd, J 249, 16, 12, 3 Hz, 1F). IR (neat):ν 2933, 2862, 1655, 1323, 1167, 1068, 835 cm-1. HRMS (70 eV, EI): m/z calcd. for C14H14F5OSi [M–t-Bu]+:
321.0734; Found: 321.0732.
1-[tert-Butyl(dimethyl)silyloxy]-5,5-difluoro-4-isopropyl-3-phenylcyclopent-1-ene (3i). 1H NMR (400 MHz,CDCl3): δ 0.20 (s, 3H), 0.21 (s, 3H), 0.86 (d, J 6.4 Hz, 3H), 0.97 (s, 9H), 1.04 (d, J 6.4 Hz, 3H), 2.02–2.20 (m, 2H),
3.50-3.58 (m, 1H), 5.04 (dd, J 1.8, 1.8 Hz, 1H), 7.21 (d, J 7.6 Hz, 2H), 7.22 (t, J 7.6 Hz, 1H), 7.30 (dd, J 7.6, 7.6 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ –4.9, –4.8, 18.2, 20.8, 21.5, 25.5, 27.9 (d, J 5 Hz), 46.3 (d, J 7 Hz), 58.5 (dd, J
19, 19 Hz), 115.9 (dd, J 9, 9 Hz), 126.7, 127.4 (dd, J 247, 247 Hz), 127.7, 128.6, 144.4 (d, J 5 Hz), 147.6 (dd, J 23,
23 Hz). 19F NMR (376 MHz, CDCl3): δ 52.1 (ddd, J 251, 13, 4 Hz, 1F), 70.5 (ddd, J 251, 19, 10 Hz, 1F).
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IR (neat): ν 2958, 2931, 2860, 1660, 1365, 1188, 1011, 839 cm-1. HRMS (70 eV, EI): m/z calcd. for C16H21F2OSi[M–t-Bu]+: 295.1330; Found: 295.1329.
3,4-Dibutyl-1-[tert-butyl(dimethyl)silyloxy]-5,5-difluorocyclopent-1-ene (3j). 1H NMR (400 MHz, CDCl3): δ
0.179 (s, 3H), 0.183 (s, 3H), 0.87–0.93 (m, 6H), 0.95 (s, 9H), 1.21–1.53 (m, 12H), 1.59–1.70 (m, 1H), 1.80–1.93(m, 1H), 5.09 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ –4.91, –4.85, 13.9, 14.0, 18.2, 22.9 (d, J 5 Hz), 25.5, 28.0,
28.1, 29.5, 30.0, 35.0 (d, J 5 Hz), 42.2 (d, J 7 Hz), 49.3 (dd, J 22, 22 Hz), 115.2 (dd, J 8, 8 Hz), 127.2 (dd, J 245,
245 Hz), 147.0 (dd, J 25, 25 Hz). 19F NMR (376 MHz, CDCl3): δ 53.5 (ddd, J 249, 11, 3 Hz, 1F), 69.8 (ddd, J 249,
20, 11 Hz, 1F). IR (neat): ν 2958, 2929, 2860, 1660, 1363, 1186, 1012, 839 cm-1. HRMS (70 eV, EI): m/z calcd. for
C15H27F2OSi [M–t-Bu]+: 289.1799; Found: 289.1799.
2-Bromo-1-[tert-butyl(dimethyl)silyloxy]-4,4-difluoro-3-phenylcyclopent-1-ene (6g). 1H NMR (500 MHz,CDCl3 ): δ 0.280 (s, 3H), 0.283 (s, 3H), 1.01 (s, 9H), 2.85 (ddd, J 16.5, 16.5, 7.5 Hz, 1H), 2.88–2.97 (m, 1H), 4.20
(dd, J 20.0, 4.5 Hz, 1H), 7.19–7.20 (m, 2H), 7.32–7.38 (m, 3H). 13C NMR (126 MHz, CDCl3): δ –4.0, –3.9, 18.1,
25.5, 43.3 (dd, J 28, 28 Hz), 60.8 (dd, J 28, 23 Hz), 95.6 (d, J 3 Hz), 124.4 (dd, J 259, 254 Hz), 128.1, 128.5, 129.1,
133.8 (dd, J 4, 4 Hz), 147.2 (dd, J 7, 4 Hz). 19F NMR (470 MHz, CDCl3): δ 65.5 (dddd, J 227, 14, 8, 5 Hz, 1F), 75.2
(dddd, J 227, 20, 18, 15 Hz, 1F). IR (neat): ν 2925, 2856, 1662, 1327, 1255, 1117, 912, 839 cm –1.
HRMS (70 eV, EI): m/z calcd. for C17H23BrF2OSi [M]+ : 388.0670; Found: 388.0669.
3-[tert-Butyl(dimethyl)silyloxy]-4,4-difluoro-6-methyl-1-phenylhepta-2,5-diene (7i). 1H NMR (400 MHz,CDCl3): δ 0.14 (s, 6H), 0.91 (s, 9H), 1.79 (td, J 3.2, 1.4 Hz, 3H), 1.84 (td, J 2.8, 1.4 Hz, 3H), 3.50–3.58 (m, 2H),
5.03 (t, J 1.8 Hz, 1H), 5.50 (tqq, J 13.3, 1.4, 1.4 Hz, 1H), 7.19–7.43 (m, 5H). 13C NMR (126 MHz, CDCl3): δ –4.7,
18.0, 25.5, 26.5, 29.7, 31.6 (t, J 4 Hz), 111.3, 118.0 (t, J 239 Hz), 120.7 (t, J 28 Hz), 125.9, 128.2, 128.4, 141.1,
142.7 (t, J 7 Hz), 146.0 (t, J 30 Hz). 19F NMR (376 MHz, CDCl3): δ 53.5 (br d, J 13 Hz). HRMS (70 eV, EI): m/z calcd.
for C16H21F2OSi [M–t-Bu]+: 295.1330; Found: 295.1330.
7-[tert-Butyl(dimethyl)silyloxy]-6,6-difluorotrideca-4,7-diene (7j). 1H NMR (400 MHz, CDCl3): δ 0.14 (s, 6H),
0.91 (s, 9H), 0.95–1.01 (m, 6H), 1.21–1.53 (m, 8H), 2.06–2.17 (m, 4H), 4.93 (t, J 8.0 Hz, 1H), 5.60–5.71 (m, 1H),
6.10 (dtt, J 15.6, 9.6, 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ –4.7, 13.6, 14.0, 18.1, 21.7, 22.5, 25.2, 25.6,
30.1, 31.4, 33.8, 113.9, 117.7 (t, J 240 Hz), 124.6 (t, J 28 Hz), 136.1 (t, J 10 Hz), 143.9 (t, J 30 Hz). 19F NMR (376MHz, CDCl3): δ 67.8 (ddd, J 10, 6, 3 Hz). HRMS (70 eV, EI): m/z calcd. for C15H27F2OSi [M–t-Bu]+: 289.1799;
Found: 289.1798.

Acknowledgements
This research is supported by JSPS KAKENHI Grant Number JP16K13943 (J.I.), JSPS KAKENHI Grant Number
JP16H01002 (J.I.), JSPS KAKENHI Grant Number JP15K05414 (K.F.). Shin-Etsu Chemical Co., Ltd., is gratefully
acknowledged for the generous gift of TBSCl.

Supplementary Material
1H, 13C, and 19F NMR data of new compounds (3e, 3i, 3j, 6g, 7i, and 7j) are shown.

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Orr, D.; Percy, J. M.; Tuttle, T.; Kennedy, A. R.; Harrison, Z. A. Chem. Eur. J. 2014, 20, 14305–14316.
https://doi.org/10.1002/chem.201403737
When the substrates 1i and 1j with an isopropyl group and a butyl group as R3 were employed, thecorresponding products 3i and 3j were obtained along with siloxydienes 7i and 7j as 1,5-hydrogen shift
products (3i:7i = 86:14, 3j:7j = 81:19) in 52% and 60% yields, respectively.

Although the formation mechanism of 6g is uncertain, it could be generated by a formal [4 +1]
cycloaddition30 or an oxidative addition of the C–C bond whose carbons are substituted by fluorine andsiloxy group in cyclopropane 2g to a Ni(0) complex followed by ring expansion and reductive elimination.
Fuchibe, K.; Aono, T.; Hu, J.; Ichikawa, J. Org. Lett. 2016, 18, 4502–4505.
https://doi.org/10.1021/acs.orglett.6b02085

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