Prins cyclization in ionic liquid hydrogen fluoride salts: Facile and highly efficient synthesis of 4-fluorinated tetrahydropyrans, thiacyclohexanes, and piperidines

Article abstract of DOI:10.1002/ejoc.200800872

Prins cyclization of homoallylic alcohols with various aldehydes was investigated in ionic liquid hydrogen fluoride (HF) salts, which played roles as a reaction medium, a catalyst, and a fluorine source. The reaction afforded the corresponding 4-fluorinat

Full text of DOI:10.1002/ejoc.200800872

FULL PAPER
DOI: 10.1002/ejoc.200800872
Prins Cyclization in Ionic Liquid Hydrogen Fluoride Salts: Facile and Highly
Efficient Synthesis of 4-Fluorinated Tetrahydropyrans, Thiacyclohexanes, and
Piperidines
Yuichiro Kishi,[a] Shinsuke Inagi,[a] and Toshio Fuchigami*[a]
Keywords: Cyclization / Ionic liquids / Fluorine / Heterocycles
Prins cyclization of homoallylic alcohols with various alde- tem. In order to apply this method to the synthesis of other 4-
hydes was investigated in ionic liquid hydrogen fluoride (HF)
salts, which played roles as a reaction medium, a catalyst,
fluorinated heterocyclic compounds, we also carried out thia-
Prins and aza-Prins cyclization in HF salt and successfully
and a fluorine source. The reaction afforded the correspond- obtained 4-fluorinated thiacyclohexanes and piperidines,
ing 4-fluorinated tetrahydropyrans in excellent yields with a
high stereoselectivity (cis form exclusively). When benzalde-
hydes having a strongly electron-donating group at the para
position were used, the stereoselectivity was lost in this sys-
respectively.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
sis of fluorinated tetrahydropyrans is useful for exploration
of new pharmaceuticals. However, there have been only a
few reports on the synthesis of fluorinated tetrahydropy-
rans.[8] Unfortunately, the yields were unsatisfactory and/or
hydroxylated byproducts were always formed in these cases.
We focused attention on the acidic protons and the fluo-
ride ions that were contained at a high concentration in
ionic liquid HF salts. Protonation of aldehydes promotes
the Prins cyclization; furthermore, a wealth of fluoride ions
would make fluorination smoother.
In this paper, we report the highly efficient and stereose-
lective synthesis of 4-fluorinated tetrahydropyrans by Prins
cyclization in ionic liquid HF salts. In addition, thia-Prins
and aza-Prins cyclization in HF salts were also demon-
strated to provide the corresponding 4-fluorinated thiacy-
clohexanes and piperidines, respectively.
Introduction
Organofluorine compounds are in great demand in me-
dicinal, agrochemical, and material sciences. Because they
are not always naturally occurring, selective fluorination of
organic compounds is of much importance. Electrochemical
selective fluorination has been established in our group by
using ionic liquid hydrogen fluoride (HF) salts like Et3N–
nHF and Et4NF–nHF (n = 3–5) as a supporting electrolyte
and a fluorine source.[1] Ionic liquids have unique physical
and chemical properties and have recently received much
attention. For example, ionic liquids are employed in or-
ganic synthesis as green reaction media instead of volatile
organic compounds (VOC).[2] In recent years, we have de-
veloped VOC-free electrochemical selective fluorination
systems in neat HF salts.[3] In contrast, ionic liquid HF salts
such as Et3N–3HF[4] and 1-ethyl-3-methylimidazolium
fluoride–2.3HF [EMIMF(HF)2.3
[5]
]
have been demon-
strated to be safe and easy to handle for chemical fluorina-
tion.
Results and Discussion
Recent progress of Prins cyclization is noticeable in syn-
thetic chemistry. It is well known as a powerful synthetic
reaction that can produce halogenated, acetoxylated, and
hydroxylated tetrahydropyrans.[6] A number of biologically
active natural compounds containing tetrahydropyran rings
have been discovered to date.[7] Hence, the efficient synthe-
At first, we investigated to find the most suitable ionic
liquid HF salts as a protic acid catalyst for Prins cyclization.
As shown in Figure 1, Et3N–3HF and Et3N–4HF hardly
promoted the reaction of 1a with 2a, whereas Et3N–5HF
and Et4NF–5HF catalyzed efficiently, and the reaction was
finished in ca. 10 min. Therefore, it is clear that ionic liquid
HF salts containing higher contents of hydrogen fluoride
are effective. Olah et al. reported a similar tendency in the
fluorination of alcohols with dimethyl ether–nHF.[9] An ex-
cess amount of acidic protons derived from the HF salt
could protonate the contaminating H2O, which would pro-
hibit nucleophilic attack of H2O.
[a] Department of Electronic Chemistry, Tokyo Institute of Tech-
nology,
4259 Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax: +81-45-924-5406
E-mail: fuchi@echem.titech.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 103–109
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
103

Y. Kishi, S. Inagi, T. Fuchigami
FULL PAPER
anyl cation, and it was the most stable conformation calcu-
lated by B3LYP/6-31G. Hence, the nucleophilic attack of
complex polyhydrogen fluoride occurred from the equato-
rial position exclusively.[12]
Figure 1. Time course of the yield of 3 in various HF salts.
We then investigated Prins cyclization of various alde-
hydes and homoallylic alcohols in Et4NF–5HF at room
temperature. The generality of the reaction is shown in
Table 1. Prins cyclization of an aliphatic aldehyde (1a), an
alicyclic aldehyde (1b), and an aromatic aldehyde (1c) with
a homoallylic alcohol (2a) was successfully carried out to
afford the corresponding fluorinated tetrahydropyrans in
excellent yields with high stereoselectivity (cis products were
formed exclusively).[10] Regardless of the substituents at the
para position of the benzaldehyde (Table 1, entries 4 and
5), the desired products were obtained in a similar manner.
Furthermore, the reaction of 1-substituted homoallylic
alcohols with aldehydes (Table 1, entries 6 and 7) also pro-
ceeded to provide 2,4,6-trisubstituted tetrahydropyrans
quantitatively.
Scheme 1. Plausible mechanism of Prins cyclization.
As mentioned above, Prins cyclization in HF salts pro-
ceeded in a highly stereoselective manner. However, we
could not control the stereoselectivity of the cyclization
products when p-anisaldehyde (1f) and p-hydroxybenzalde-
hyde (1g) were used as aldehydes (Table 2). Despite the fact
that such aldehydes gave the corresponding 4-fluorinated
tetrahydropyrans in high yields, the stereochemistry of the
products was found to be a mixture of cis and trans isomers.
The plausible mechanism of this isomerization is shown in
Scheme 2. Electron-donating group (OCH3 or OH) at the
para position o the benzene ring would promote ring open-
ing and contribute to the stabilization of the resulting open-
chain benzyl cation. The intermediate would undergo recy-
clization to form trans isomers in an equilibrium reaction.
Indeed, the treatment of the separated cis isomer with HF
salts for 6 h lead to a stereoisomeric mixture.
Table 1. Prins cyclization of various aldehydes with homoallylic
alcohols in Et4NF–5HF.
Entry
Aldehyde 1
Homoallylic
alcohol 2
Time
[min]
Product
Yield
[%][a]
1
2
3
4
5
6
7
1a (R1 = C7H15)
1b (R1 = cyclohexyl)
1c (R1 = Ph)
2a (R2 = H)
2a (R2 = H)
2a (R2 = H)
2a (R2 = H)
2a (R2 = H)
2b (R2 = C7H15)
2c (R2 = Ph)
10
20
20
20
90
3
4
5
6
7
8
9
quant.
93
quant.
quant.
96
Next, we demonstrated Prins cyclization of various
ketones and homoallylic alcohols for the scope and limita-
tion of this reaction system. Notably, only cyclic ketones
afforded the desired spiro-type products (Table 3). However,
open-chain ketones like 2-octanone and aromatic ketone-
like acetophenone did not afford the cyclized products at
1d (R1 = p-NO2Ph)
1e (R1 = p-MePh)
1a (R1 = C7H15)
1c (R1 = Ph)
10
120
quant.
98
[a] Isolated yield.
According to the common reaction mechanism of Prins all. This is in sharp contrast to the successful trimethylsilyl
cyclization, high stereoselectivity observed here is explained iodide (TMSI) mediated Prins cyclization of various
as shown in Scheme 1. The intermediate oxonium ion (A) ketones with homoallylic alcohols.[13]
forms the more favorable chair-like transition state to avoid
The reusability of the ionic liquid was studied on the re-
severe 1,3-diaxial interaction. Alder et al.[11] reported that action of 1a (0.2 mmol) with 2a (0.2 mmol) in Et4NF–5HF
the C+–H bond was semiaxial in the chair 4-tetrahydropyr- (3 mL:78 mmol of HF). Fluorinated product 3 could be
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Prins Cyclization in Ionic Liquid Hydrogen Fluoride Salts
Table 2. Prins cyclization of benzaldehyde derivatives having an
electron-donating group at the para position with homoallylic
alcohol.
Table 3. Prins cyclization of various ketones with 2a in Et4NF–
5HF.
Yield [%][a]
(cis/trans)
Entry
Aldehyde 1
Product
1
2
1f (R1 = OMe)
1g (R1 = OH)
10
11
90 (45:55)
88 (43:57)
[a] Determined by 19F NMR spectroscopy.
[a] Determined by 19F NMR spectroscopy. [b] Isolated yield.
In order to survey the versatility of this methodology, we
applied it to the synthesis of 4-fluorothiacyclohexanes and
4-fluoropiperidines. Thiacyclohexane rings and piperidine
rings are key components contained in many natural prod-
ucts and possessing peculiar biological activities.[14] Li et
al.[15] reported thia-Prins cyclization and Martin et al.[16]
demonstrated aza-Prins cyclization. However, there has
been no report on synthesis of fluorinated thiacyclohexanes
and few reports on the synthesis of fluorinated piperidines
by Prins-type cyclization.[17]
Scheme 2. Mechanism of isomerization of 4-fluorotetrahydropyr-
ans having an electron-donating group.
As shown in Table 4, Prins cyclization of various kinds
of aldehydes and homoallylic thiol (17a) was successfully
easily separated by simple extraction with hexane, and the performed to provide 4-fluorothiacyclohexanes in excellent
residual ionic liquid was then reused for the reaction. The yields. Although cis products were obtained selectively
yield of 3 was more than 90% for up to five cycles, indicat- (higher than 92%),[18] a small amount of trans product was
ing the reusability of the ionic liquid for Prins cyclization. also formed. When we used 1-substituted homoallylic thiols
However, due to the generation of H2O and the consump- (Table 4, entries 4 and 5), 2,4,6-trisubstituted 4-fluorothia-
tion of HF, the yield of 3 gradually decreased over the cyclohexanes were obtained in high-to-excellent yields. Be-
course of more cycles. If removal of H2O from the “used” fore the reactions were complete, we could detect the di-
reaction media and addition of HF could be achieved, the thioacetal compound, which is one of the intermediates of
ionic liquid HF salts would be an ideal reaction medium this reaction. Under the acidic conditions, the dithioacetal
for Prins cyclization with reusability.
would be deprotected again and form the cyclic products.
Table 4. Prins cyclization of various aldehydes with homoallylic thiols in Et4NF–5HF.
Entry
Aldehyde 1
Homoallylic
thiol 17
Time
[min]
Product
Yield [%][a]
(cis/trans)[b]
1
2
3
4
5
1a (R1 = C7H15)
1b (R1 = cyclohexyl)
1c (R1 = Ph)
17a (R2 = H)
17a (R2 = H)
17a (R2 = H)
17b (R2 = C5H11)
17c (R2 = Ph)
40
60
60
90
10
18
19
20
21
22
98 (92:8)
98 (95:5)
quant. (96:4)
72 (96:4)
1k (R1 = C5H11)
1c (R1 = Ph)
quant. (96:4)
[a] Total isolated yield of both diastereomers. [b] Determined by 19F NMR spectroscopy.
Eur. J. Org. Chem. 2009, 103–109
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105

Y. Kishi, S. Inagi, T. Fuchigami
FULL PAPER
Table 5. Prins cyclization of various aldehydes with homoallylic thiols in Et4NF–5HF.
Entry
Aldehyde 1
Homoallylic
alcohol 23
Time
[h]
Product
Yield [%]
(cis/trans)[b]
1
2
3
4
5
6
7
8
1a (R1 = C7H15)
1a (R1 = C7H15)
1b (R1 = cyclohexyl)
1c (R1 = Ph)
23a (R2 = H)
24
1
2
24
24
0.5
0.5
24
24
25
26
27
28
29
30
31
0
23b (R2 = Ts)
quant.[a] (88:12)
quant.[a] (92:8)
17[b] (82:18)
18[b] (83:17)
92[a] (93:7)
23b (R2 = Ts)
23b (R2 = Ts)
1d (R1 = p-NO2Ph)
1a (R1 = C7H15)
1b (R1 = cyclohexyl)
1c (R1 = Ph)
23b (R2 = Ts)
23c (R2 = CO2Me)
23c (R2 = CO2Me)
23c (R2 = CO2Me)
97[a] (95:5)
29[a] (97:3)
[a] Total isolated yield of both diastereomers. [b] Determined by 19F NMR spectroscopy.
NMR spectra are given in δ (ppm) from internal TMS, CDCl3, and
monofluorobenzene (–36.5 ppm), respectively. EI mass spectra were
recorded with a Shimadzu GCMS-QP5050A mass spectrometer.
HR mass spectra were recorded with a JEOL The MStation JMS-
700.
Furthermore, we carried out Prins cyclization of various
aldehydes and homoallylic amines.[10] The reaction of 1a
with homoallylic amine 23a did not proceed at all, because
of the predominant protonation of the amino group of 23a
in Et4NF–5HF. To solve the problem, we introduced an
electron-withdrawing tosyl group onto the nitrogen atom of
23a. Because the basicity of 23a decreased, aza-Prins cycli-
zation proceeded smoothly to provide 4-fluoropiperidines
in excellent yields (Table 5, entries 2 and 3). However, the
reaction of benzaldehyde (1c) with 23b did not proceed well,
because the reactivity of aromatic aldehydes was lower than
that of aliphatic aldehydes (Table 5, entry 4). The nucleo-
philicity of homoallylic amine can be controlled by intro-
duction of the weaker electron-withdrawing ester group.[19]
Consequently, the yield of the reaction with benzaldehyde
was improved (Table 5, entry 8). Similarly to the case of
thia-Prins cyclization, cis products were obtained as the
main stereoisomers; however, the stereoselectivity in these
cases was slightly lower relative to that observed in the thia-
Prins cyclization.
Materials: 1-Octanal (1a), cyclohexanecarboxaldehyde (1b), benzal-
dehyde (1c), 4-nitrobenzaldehyde (1d), p-tolualdehyde (1e), p-anis-
aldehyde (1f), p-hydroxybenzaldehyde (1g), cyclopentanone (1h),
cyclohexanone (1i), cycloheptanone (1j), 1-hexanal (1k), 3-buten-1-
ol (2a), 1-phenyl-3-buten-1-ol (2c), and 3-buten-1-amine (23a) were
purchased and used without purification. 1-Undecen-4-ol (2b),[10b]
3-buten-1-thiol (17a),[20] 1-nonene-4-thiol (17b),[15] 1-phenyl-3-but-
ene-1-thiol (17c),[15] and N-(3-butenyl)-p-toluenesulfonamide (23b)
[21] were synthesized according to literature procedures. Et3N–3HF,
Et3N–4HF, Et3N–5HF, Et4NF–4HF, and Et4NF–5HF were kindly
supplied by Morita Chemical Industries Co. Ltd. (Japan). Caution:
Ionic liquid HF salts are toxic and may cause serious burns if they
come in contact with unprotected skin. Therefore, they should be
handled carefully at all times. It is recommended to use hand pro-
tection.
N-(3-Butenyl)carbamate (23c):[22] To a stirred solution of 3-buten-
1-amine (0.36 g, 5.0 mmol) and potassium carbonate (0.90 g,
6.5 mmol) in CH3OH (30 mL) was added methyl chloroformate
(1.18 g, 12.5 mmol) dropwise at 0 °C. The reaction mixture was
stirred for 2 h at room temperature and then water (50 mL) was
added. The mixture was extracted with CH2Cl2 (3ϫ30 mL), and
the organic phase was evaporated to give a clear oil (0.57 g,
4.4 mmol, 88%).
Conclusions
We successfully carried out the synthesis of various 4-
fluorinated tetrahydropyrans in excellent yields by Prins cy-
clization in ionic liquid HF salts. The stereochemistry of
the products was controlled except for the use of p-anisal-
dehyde and p-hydroxybenzaldehyde. We also demonstrated
successful thia-Prins and aza-Prins reactions in Et4NF–
5HF. The synthetic method is very convenient and widely
applicable, and it is an environmentally friendly process, be-
cause VOCs are not required. Through this study, it has
been suggested that ionic liquid HF salts would be usable
for a variety of fluorination reactions.
General Procedure for Prins Cyclization: Prins cyclization of various
aldehydes or ketones (0.2 mmol) and homoallylic alcohols, thiols,
or amines (0.2 mmol) was carried out in Et4NF–5HF (3 mL) by
using a plastic cell at room temperature. The conversion of starting
materials was monitored by TLC. After the starting materials were
consumed, the reaction mixture was passed through a short column
of silica gel eluting with ethyl acetate to remove the fluoride salt.
The eluent was evaporated under vacuum. Then, the almost-pure
product was obtained. For the thia- or aza-Prins cyclization, the
products were obtained as stereoisomeric mixtures of cis and trans
forms. Then, the diastereomeric ratio was calculated by 19F NMR
spectroscopy. Next, after the products were purified by silica gel
column chromatography (hexane/ethyl acetate), the total isolated
yields of both stereoisomeric mixtures were calculated.
Experimental Section
General: 1H, 13C, and 19F NMR spectra were recorded with a
JEOL JNM EX-270 (1H: 270 MHz, 13C: 67.8 MHz, 19F: 254 MHz)
spectrometer in CDCl3. The chemical shifts for 1H, 13C, and 19F
cis-4-Fluoro-2-phenyltetrahydropyran (5): Colorless oil. 1H NMR
(270 MHz, CDCl3): δ = 7.35–7.22 (m, 5 H), 4.95–4.65 (m, JH,F
=
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Prins Cyclization in Ionic Liquid Hydrogen Fluoride Salts
49.1 Hz, 1 H), 4.33–4.27 (m, 1 H), 4.24–4.15 (m, 1 H), 3.60–3.49
(m, 1 H), 2.38–2.28 (m, 1 H), 2.15–2.06 (m, 1 H), 1.94–1.68 (m, 2
H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 141.1 (d, J = 1.7 Hz),
128.3, 127.7, 125.7, 89.3 (d, J = 176.1 Hz), 77.8 (d, J = 11.2 Hz),
65.4 (d, J = 12.1 Hz), 40.5 (d, J = 17.2 Hz), 33.0 (d, J = 17.3 Hz)
ppm. 19F NMR (254 MHz, CDCl3): δ = –93.1 (m) ppm. MS: m/z
= 80 [M]+, 179 [M – H]+, 105, 91, 77, 51. HRMS: calcd. for
C11H13FO 180.0950; found 180.0949.
4.27–4.12 (m, 2 H), 3.60–3.50 (m, 1 H), 2.32–2.23 (m, 1 H), 2.15–
2.06 (m, 1 H), 1.93–1.72 (m, 2 H) ppm. 13C NMR (67.8 MHz,
CDCl3): δ = 155.4, 132.5 (d, J = 1.8 Hz), 127.5, 115.3, 89.3 (d, J =
175.9 Hz), 77.7 (d, J = 11.3 Hz), 65.4 (d, J = 11.7 Hz), 40.0 (d, J
= 17.2 Hz), 32.9 (d, J = 17.6 Hz) ppm. 19F NMR (254 MHz,
CDCl3): δ = –93.1 (m) ppm. MS: m/z = 196 [M]+, 179, 131, 121,
107, 94, 77, 65, 55. HRMS: calcd. for C11H13FO2 196.0900; found
196.0895.
trans-11: Colorless oil. 1H NMR (270 MHz, CDCl3): δ = 7.26–7.19
(m, 2 H), 6.81–6.75 (m, 2 H), 5.20–4.98 (m, JH,F = 48.1 Hz, 1 H),
4.94 (s, 1 H), 4.71–4.66 (m, 1 H), 4.02–3.97 (m, 2 H), 2.19–1.71 (m,
4 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 155.4, 133.0, 127.5,
115.3, 86.7 (d, J = 167.9 Hz), 74.2, 63.1, 38.0 (d, J = 20.4 Hz), 30.5
(d, J = 20.5 Hz) ppm. 19F NMR (254 MHz, CDCl3): δ = –109.1
(m) ppm. MS: m/z = 196 [M]+, 179, 131, 121, 107, 94, 77, 65, 55.
HRMS: calcd. for C11H13FO2 196.0900; found 196.0899.
cis-4-Fluoro-2-(4-nitrophenyl)tetrahydropyran (6): Colorless oil. 1H
NMR (270 MHz, CDCl3): δ = 8.21 (d, J = 8.9 Hz, 2 H), 7.52 (d,
J = 8.5 Hz, 2 H), 5.00–4.70 (m, JH,F = 49.0 Hz, 1 H), 4.46–4.42
(m, 1 H), 4.29–4.20 (m, 1 H), 3.65–3.54 (m, 1 H), 2.42–2.34 (m, 1
H), 2.20–2.12 (m, 1 H), 1.95–1.58 (m, 2 H) ppm. 13C NMR
(67.8 MHz, CDCl3): δ = 148.4 (d, J = 1.7 Hz), 147.2, 126.3, 123.6,
88.7 (d, J = 176.8 Hz), 76.5 (d, J = 11.4 Hz), 65.4 (d, J = 12.1 Hz),
40.5 (d, J = 17.9 Hz), 32.8 (d, J = 17.7 Hz) ppm. 19F NMR
(254 MHz, CDCl3): δ = –93.7 (m) ppm. MS: m/z = 224 [M – H]+,
208, 178, 150, 107, 77, 59. HRMS: calcd. for C11H12FNO3
225.0801; found 225.0803.
9-Fluoro-6-oxaspiro[4.5]decane (12): Colorless oil. 1H NMR
(270 MHz, CDCl3): δ = 4.94–4.67 (m, JH,F = 49.3 Hz, 1 H), 3.91–
3.81 (m, 1 H), 3.60–3.51 (m, 1 H), 2.02–1.37 (m, 12 H) ppm. 13C
NMR (67.8 MHz, CDCl3): δ = 88.0 (d, J = 171.8 Hz), 83.4 (d, J =
6.7 Hz), 58.9 (d, J = 7.8 Hz), 41.0 (d, J = 17.3 Hz), 38.9 (d, J =
2.1 Hz), 36.0, 32.3 (d, J = 18.4 Hz), 23.8, 23.5 ppm. 19F NMR
(254 MHz, CDCl3): δ = –99.5 (m) ppm. MS: m/z = 158 [M]+, 129,
116, 101, 84, 67, 55. HRMS: calcd. for C9H15FO 158.1107; found
158.1105.
cis-4-Fluoro-2-p-tolyltetrahydropyran (7): Colorless oil. 1H NMR
(270 MHz, CDCl3): δ = 7.22 (d, J = 8.1 Hz, 2 H), 7.14 (d, J =
8.1 Hz, 2 H), 4.92–4.62 (m, JH,F = 49.1 Hz, 1 H), 4.28–4.12 (m, 2
H), 3.57–3.47 (m, 1 H), 2.32 (s, 3 H), 2.30–2.24 (m, 1 H), 2.12–2.04
(m, 1 H), 1.92–1.66 (m, 2 H) ppm. 13C NMR (67.8 MHz, CDCl3):
δ = 138.1 (d, J = 1.7 Hz), 137.3, 128.9, 125.7, 89.3 (d, J =
175.9 Hz), 77.6 (d, J = 11.2 Hz), 65.3 (d, J = 12.1 Hz), 40.5 (d, J
= 16.7 Hz), 33.0 (d, J = 17.3 Hz), 21.1 ppm. 19F NMR (254 MHz,
CDCl3): δ = –93.0 (m) ppm. MS: m/z = 194 [M]+, 179, 119, 105, 91,
77, 65, 55. HRMS: calcd. for C12H15FO 194.1107; found 194.1107.
4-Fluoro-1-oxaspiro[5.5]undecane (13): Colorless oil. 1H NMR
(270 MHz, CDCl3): δ = 5.01–4.73 (m, JH,F = 49.3 Hz, 1 H), 3.91–
3.82 (m, 1 H), 3.64–3.54 (m, 1 H), 2.04–1.25 (m, 14 H) ppm. 13C
NMR (67.8 MHz, CDCl3): δ = 87.3 (d, J = 171.3 Hz), 73.2 (d, J =
7.3 Hz), 57.5 (d, J = 7.8 Hz), 41.6 (d, J = 17.2 Hz), 37.3 (d, J =
2.2 Hz), 33.7, 32.5 (d, J = 18.4 Hz), 25.9, 21.7, 21.4 ppm. 19F NMR
(254 MHz, CDCl3): δ = –99.1 (m) ppm. MS: m/z = 172 [M]+, 129,
116, 55. HRMS: calcd. for C10H17FO 172.1263; found 172.1262.
cis-4-Fluoro-2,6-diheptyltetrahydropyran (8): Colorless oil. 1H
NMR (270 MHz, CDCl3): δ = 4.80–4.50 (m, JH,F = 49.4 Hz, 1 H),
3.22 (m, 2 H), 2.10–2.03 (m, 2 H), 1.64–1.27 (m, 26 H), 0.88 (t, J
= 6.4 Hz, 6 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 89.8 (d, J
= 174.0 Hz), 74.9 (d, J = 11.2 Hz), 38.7 (d, J = 16.2 Hz), 36.1 (d,
J = 1.7 Hz), 31.9, 29.6, 29.3, 25.7, 22.7, 14.2 ppm. 19F NMR
(254 MHz, CDCl3): δ = –93.1 (m) ppm. MS: m/z = 300 [M]+, 201,
181, 163, 127, 113, 95, 81, 69, 55. HRMS: calcd. for C19H37FO
300.2828; found 300.2823.
4-Fluoro-1-oxaspiro[5.6]dodecane (14): Colorless oil. 19F NMR
(254 MHz, CDCl3): δ = –97.9 (m) ppm. MS: m/z = 186 [M]+, 143,
129, 116, 84, 69, 55.
cis-4-Fluoro-2-heptylthiacyclohexane (cis-18): Colorless oil. 1H
NMR (270 MHz, CDCl3): δ = 4.54–4.25 (m, JH,F = 46.9 Hz, 1 H),
2.83–2.60 (m, 3 H), 2.42–2.33 (m, 2 H), 1.83–1.27 (m, 14 H), 0.88
(t, J = 6.7 Hz, 3 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 91.6
(d, J = 170.6 Hz), 42.1 (d, J = 12.3 Hz), 41.2 (d, J = 18.8 Hz), 35.8,
34.0 (d, J = 20.1 Hz), 31.8, 29.5, 29.2, 26.9, 26.6 (d, J = 13.4 Hz),
22.7, 14.2 ppm. 19F NMR (254 MHz, CDCl3): δ = –90.4 (m) ppm.
MS: m/z = 218 [M]+, 161, 143, 119, 101, 99, 73, 67, 55. HRMS:
calcd. for C12H23FS 218.1504; found 218.1507.
cis-4-Fluoro-2-(4-methoxyphenyl)tetrahydropyran (cis-10): Colorless
oil. 1H NMR (270 MHz, CDCl3): δ = 7.28–7.23 (m, 2 H), 6.90–
6.85 (m, 2 H), 4.93–4.63 (m, JH,F = 49.1 Hz, 1 H), 4.27–4.12 (m, 2
H), 3.78 (s, 3 H), 3.58–3.48 (m, 1 H), 2.33–2.25 (m, 1 H), 2.13–2.05
(m, 1 H), 1.95–1.66 (m, 2 H) ppm. 13C NMR (67.8 MHz, CDCl3):
δ = 159.0, 133.3 (d, J = 2.1 Hz), 127.1, 113.7, 89.3 (d, J =
176.3 Hz), 77.4 (d, J = 11.7 Hz), 65.3 (d, J = 11.7 Hz), 55.2, 40.3
(d, J = 17.0 Hz), 32.9 (d, J = 17.3 Hz) ppm. 19F NMR (254 MHz,
CDCl3): δ = –93.0 (m) ppm. MS: m/z = 210 [M]+, 209 [M – H]+,
179, 135, 122, 108, 91, 77, 65, 55. HRMS: calcd. for C12H15FO2
210.1056; found 210.1055.
trans-18: 19F NMR (254 MHz, CDCl3): δ = –108.7 (m) ppm.
cis-2-Cyclohexyl-4-fluorothiacyclohexane (cis-19): White solid; m.p.
1
39–40 °C. H NMR (270 MHz, CDCl3): δ = 4.52–4.23 (m, JH,F
=
46.8 Hz, 1 H), 2.79–2.57 (m, 3 H), 2.43–2.33 (m, 2 H), 1.83–1.05
(m, 13 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 92.3 (d, J =
170.1 Hz), 48.4 (d, J = 11.7 Hz), 42.5, 38.3 (d, J = 19.0 Hz), 34.2
(d, J = 20.1 Hz), 30.4, 30.3, 26.6 (d, J = 13.9 Hz), 26.4 ppm. 19F
NMR (254 MHz, CDCl3): δ = –89.5 (m) ppm. MS: m/z = 202
[M]+, 119, 99, 85, 73, 55. HRMS: calcd. for C11H19FS 202.1191;
found 202.1189.
trans-10: Colorless oil. 1H NMR (270 MHz, CDCl3): δ = 7.28–7.25
(m, 2 H), 6.90–6.84 (m, 2 H), 5.16–4.97 (m, JH,F = 48.0 Hz, 1 H),
4.72–4.67 (m, 1 H), 4.01–3.96 (m, 2 H), 3.78 (s, 3 H), 2.16–1.69 (m,
4 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 158.8, 134.1, 127.0,
113.6, 86.9 (d, J = 167.9 Hz), 73.7, 63.1, 55.2, 38.4 (d, J = 20.1 Hz),
30.7 (d, J = 20.2 Hz) ppm. 19F NMR (254 MHz, CDCl3): δ =
–109.1 (m) ppm. MS: m/z = 210 [M]+, 209 [M – H]+, 179, 135, 122,
108, 91, 77, 65, 55. HRMS: calcd. for C12H15FO2 210.1056; found
210.1058.
trans-19: 19F NMR (254 MHz, CDCl3): δ = –108.8 (m) ppm.
cis-4-Fluoro-2-phenylthiacyclohexane (cis-20): White solid; m.p. 54–
1
cis-4-Fluoro-2-(4-hydroxylphenyl)tetrahydropyran (cis-11): Colorless
oil. 1H NMR (270 MHz, CDCl3): δ = 7.19–7.14 (m, 2 H), 6.69–
6.63 (m, 2 H), 6.32 (s, 1 H), 4.94–4.64 (m, JH,F = 49.1 Hz, 1 H),
55 °C. H NMR (270 MHz, CDCl3): δ = 7.37–7.23 (m, 5 H), 4.66–
4.37 (m, JH,F = 46.6 Hz, 1 H), 3.96–3.90 (m, 1 H), 2.93–2.73 (m, 2
H), 2.61–2.43 (m, 2 H), 2.18–2.03 (m, 1 H), 1.94–1.76 (m, 1 H)
Eur. J. Org. Chem. 2009, 103–109
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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107

Y. Kishi, S. Inagi, T. Fuchigami
FULL PAPER
ppm. 13C NMR (67.8 MHz, CDCl3): δ = 140.4, 128.6, 127.6, 127.3, 65, 51. HRMS: calcd. for C18H20FNO2S 333.1199; found 333.1199.
91.8 (d, J = 171.2 Hz), 46.2 (d, J = 13.4 Hz), 41.5 (d, J = 19.4 Hz),
trans-27: 19F NMR (254 MHz,CDCl3): δ = –105.4 (m) ppm.
33.6 (d, J = 20.1 Hz), 28.1 (d, J = 14.4 Hz) ppm. 19F NMR
cis-4-Fluoro-2-(4-nitrophenyl)-N-tosylpiperidine (cis-28):[23] 19F
NMR (254 MHz, CDCl3): δ = –100.1 (m) ppm.
(254 MHz, CDCl3): δ = –90.2 (m) ppm. MS: m/z = 196 [M]+, 176,
161, 147, 135, 121, 105, 91, 77, 65, 51. HRMS: calcd. for C11H13FS
196.0722; found 196.0718.
trans-28: Yellow solid; m.p. 155–157 °C. 1H NMR (270 MHz,
CDCl3): δ = 8.15 (d, J = 8.7 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H),
7.50 (d, J = 8.8 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 5.36–5.34 (m,
1 H), 4.98–4.80 (m, JH,F = 46.9 Hz, 1 H), 3.87–3.83 (m, 1 H), 3.40–
3.29 (m, 1 H), 2.73–2.64 (m, 1 H), 2.45 (s, 3 H), 2.12–1.23 (m, 3
H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 147.2, 143.8, 137.4,
129.9, 127.3, 127.2, 126.8, 123.4, 85.8 (d, J = 171.5 Hz), 52.9, 36.7
(d, J = 2.1 Hz), 32.1 (d, J = 19.4 Hz), 28.8 (d, J = 21.2 Hz), 21.7
ppm. 19F NMR (254 MHz, CDCl3): δ = –107.0 ppm. MS: m/z =
378 [M]+, 256, 223, 155, 91. HRMS: calcd. for C18H19FN2O4S
378.1050; found 378.1060.
trans-20: 19F NMR (254 MHz, CDCl3): δ = –110.2 (m) ppm.
cis-4-Fluoro-2,6-dipentylthiacyclohexane (cis-21): Colorless oil. 1H
NMR (270 MHz, CDCl3): δ = 4.53–4.24 (m, JH,F = 46.8 Hz, 1 H),
2.82–2.73 (m, 2 H), 2.42–2.34 (m, 2 H), 1.60–1.27 (m, 18 H), 0.89
(t, J = 6.8 Hz, 6 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 91.9
(d, J = 170.0 Hz), 41.3 (d, J = 12.7 Hz), 41.1 (d, J = 19.0 Hz), 35.6,
31.7, 26.6, 22.5, 14.1 ppm. 19F NMR (254 MHz, CDCl3): δ = –90.9
(m) ppm. MS: m/z = 260 [M]+, 231, 189, 119, 115, 87, 67, 55.
HRMS: calcd. for C15H29FS 260.1974; found 260.1980.
trans-21: 19F NMR (254 MHz, CDCl3): δ = –107.2 (m) ppm.
cis-4-Fluoro-N-methoxycarbonyl-2-phenylpiperidine (cis-31): Yellow
oil. 1H NMR (270 MHz, CDCl3): δ = 7.39–7.21 (m, 5 H), 5.67 (m,
1 H), 4.82–4.52 (m, JH,F = 48.8 Hz, 1 H), 4.27–4.22 (m, 1 H), 3.76
(s, 3 H), 2.88–2.74 (m, 2 H), 2.08–1.93 (m, 2 H), 1.80–1.61 (m, 1
H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 156.2, 138.4, 128.8,
126.9, 125.8, 87.1 (d, J = 172.9 Hz), 53.3 (d, J = 13.2 Hz), 53.0,
38.2 (d, J = 12.4 Hz), 34.3 (d, J = 18.8 Hz), 32.3 (d, J = 18.8 Hz)
ppm. 19F NMR (254 MHz, CDCl3): δ = –99.2 (m) ppm. MS: m/z
= 237 [M]+, 205, 190, 178, 160, 143, 130, 118, 104, 91, 77, 59, 51.
HRMS: calcd. for C13H16FNO2 237.1165; found 237.1169.
cis-4-Fluoro-2,6-diphenylthiacyclohexane (cis-22): White solid; m.p.
104–106 °C. 1H NMR (270 MHz, CDCl3): δ = 7.39–7.22 (m, 10
H), 4.82–4.53 (m, JH,F = 46.4 Hz, 1 H), 4.12–4.07 (m, 2 H), 2.69–
2.61 (m, 2 H), 2.25–2.10 (m, 2 H) ppm. 13C NMR (67.8 MHz,
CDCl3): δ = 139.8 (d, J = 1.1 Hz), 128.6, 127.7, 127.3, 46.5 (d, J =
13.9 Hz), 40.7 (d, J = 19.7 Hz) ppm. 19F NMR (254 MHz, CDCl3):
δ = –90.3 (m) ppm. MS: m/z = 272 [M]+, 239, 181, 167, 147, 137,
121, 115, 91, 77, 65, 51. HRMS: calcd. for C17H17FS 272.1035;
found 272.1039.
trans-22: 19F NMR (254 MHz, CDCl3): δ = –108.8 (m) ppm.
trans-31: 19F NMR (254 MHz, CDCl3): δ = –105.4 (m) ppm.
cis-4-Fluoro-2-heptyl-N-tosylpiperidine (cis-25): Colorless oil. 1H
NMR (270 MHz, CDCl3): δ = 7.72 (d, J = 8.1 Hz, 2 H), 7.29 (d,
J = 8.1 Hz, 2 H), 4.86–4.57 (m, JH,F = 48.5 Hz, 1 H), 4.18–4.16
(m, 1 H), 3.97–3.92 (m, 1 H), 3.08–2.98 (m, 1 H), 2.42 (s, 3 H),
1.96–1.90 (m, 2 H), 1.52–1.23 (m, 14 H), 0.88 (t, J = 6.7 Hz, 3 H)
ppm. 13C NMR (67.8 MHz, CDCl3): δ = 143.1, 138.1, 129.6, 126.7,
87.0 (d, J = 172.4 Hz), 53.6 (d, J = 12.8 Hz), 38.8 (d, J = 12.8 Hz),
34.2 (d, J = 18.3 Hz), 31.8, 31.3 (d, J = 18.8 Hz), 31.1, 29.2, 29.1,
26.5, 22.7, 21.6, 14.1 ppm. 19F NMR (254 MHz, CDCl3): δ = –99.9
(m) ppm. MS: m/z = 256, 236, 155, 91, 55. HRMS: calcd. for
C19H30FNO2S 355.1981; found 355.1989.
Supporting Information (see footnote on the first page of this arti-
cle): H and C NMR spectra of new compounds.
1
13
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific Research
(No. 17073008) in Priority Area “Science of Ionic Liquids” (Area
Number 452) and a Grant-in-Aid for Scientific Research (B) (No.
20350071).
trans-25: 19F NMR (254 MHz, CDCl3): δ = –104.2 (m) ppm.
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1H NMR (270 MHz, CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2 H), 7.30
(d, J = 8.2 Hz, 2 H), 4.81–4.51 (m, JH,F = 48.7 Hz, 1 H), 3.98–3.92
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1.87–1.82 (m, 1 H), 1.76–1.62 (m, 1 H), 1.52–1.33 (m, 1 H) ppm.
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12.6 Hz), 39.9 (d, J = 12.3 Hz), 33.5 (d, J = 19.1 Hz), 31.1 (d, J =
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Published Online: November 18, 2008
Eur. J. Org. Chem. 2009, 103–109
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