Facile and highly efficient synthesis of fluorinated heterocycles via Prins cyclization in ionic liquid hydrogen fluoride salts

Article abstract of DOI:10.1039/b806389c

Prins cyclization of homoallylic alcohols, thiols, and amines with various aldehydes in an ionic liquid HF salt (Et₄NF·5HF) afforded the corresponding 4-fluorinated heterocycles in excellent yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806389c

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Facile and highly efficient synthesis of fluorinated heterocycles via Prins
cyclization in ionic liquid hydrogen fluoride saltsw
Yuichiro Kishi, Hirokatsu Nagura, Shinsuke Inagi and Toshio Fuchigami*
Received (in Cambridge, UK) 16th April 2008, Accepted 8th May 2008
First published as an Advance Article on the web 24th June 2008
DOI: 10.1039/b806389c
Prins cyclization of homoallylic alcohols, thiols, and amines with
various aldehydes in an ionic liquid HF salt (Et
Therefore, it is clear that ionic liquid HF salts containing a
higher content of hydrogen fluoride are effective. Excess acidic
protons derived from the HF salt would protonate the con-
4
NFÁ5HF) afforded
the corresponding 4-fluorinated heterocycles in excellent yields.
taminating H
We then investigated the Prins cyclization of various alde-
hydes and homoallylic alcohols in Et
2 2
O, prohibiting the nucleophilic attack of H O.
Organofluorine compounds are key materials in medicinal, agro-
chemical, and material sciences. Hence, it is of great importance
to develop environmentally benign selective fluorination systems.
In our laboratory, electrochemical partial fluorination has been
NFÁ5HF at room tem-
4
perature. 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) has been successfully carried out to afford the
corresponding fluorinated tetrahydropyrans in excellent yields
with high stereoselectivity (cis products were formed exclu-
established by using ionic liquid HF salts like Et
Et NFÁnHF (n = 3B5) as a supporting electrolyte and a fluorine
3
NÁnHF and
4
1
source. Ionic liquids have unique physical and chemical proper-
ties, and have recently received much attention. For example,
2
ionic liquids are used in organic synthesis as green solvents. We
9
sively). Regardless of substituents at the para position of
have developed solvent-free electrochemical partial fluorination
3
systems in recent years. On the other hand, ionic liquid HF salts
benzaldehyde (entries 4, 5), the desired products were obtained
in a similar manner. Furthermore, the reaction of 1-substituted
homoallylic alcohols with aldehydes (entries 6, 7) also proceeded
to provide 2,4,6-trisubstituted tetrahydropyrans quantitatively.
According to a common reaction mechanism of Prins
cyclization, the high stereoselectivity observed here is ex-
plained as shown in Scheme 1. The intermediate oxonium
ion forms the more favorable chair-like transition state,
4
such as Et
2
to handle for chemical fluorination.
3
NÁ3HF and 1-ethyl-3-methylimidazolium fluorideÁ
5
.3HF [EMIMF(HF)2.3] have been shown to be safe and easy
It is well known that Prins cyclization is a powerful synthetic
reaction that can produce halogenated, acetoxylated, and
6
hydroxylated tetrahydropyrans. Many biologically active
1
0
natural compounds containing tetrahydropyran rings have
7
been discovered so far. Therefore, the efficient synthesis of
avoiding a severe 1,3-diaxial interaction. Alder et al. re-
+
ported that the C –H bond was semi-axial in the chair 4-
fluorinated tetrahydropyrans is useful for exploration of new
pharmaceuticals. However, there have been only a few reports
tetrahydropyranyl cation and it was the most stable confor-
mation calculated by B3LYP/6-31G. Hence, the nucleophilic
attack of complex polyhydrogen fluoride occurred from the
8
on the synthesis of fluorinated tetrahydropyrans. Unfortu-
1
1
nately, the yields were unsatisfactory and/or hydroxylated by-
products were formed in these cases.
equatorial position exclusively.
We focused our attention on the acidic protons and the fluoride
ions that were contained at a high concentration in ionic liquid HF
salts. The protons would catalyze Prins cyclization, furthermore, a
wealth of fluoride ions would make fluorination smoother.
Herein we report the highly efficient synthesis of fluorinated
six-membered heterocycles via Prins cyclization in ionic liquid
HF salts without use of any organic solvents.
At first, we investigated to find the most suitable ionic liquid
HF salts as a protic acid catalyst for Prins cyclization. As
shown in Fig. 1, Et
the reaction of 1a with 2a, while Et
3
NÁ3HF and Et NÁ4HF hardly promoted
3
3
NÁ5HF and Et NFÁ5HF
4
catalyzed efficiently and the reaction finished in ca. 10 min.
Department of Electronic Chemistry, Tokyo Institute of Technology,
4259 Nagatsuta, Midori-ku, Yokohama 226-8502, Japan.
E-mail: fuchi@echem.titech.ac.jp; Fax: +81-45-924-5406;
Tel: +81-45-924-5406
w Electronic supplementary information (ESI) available: Experimental
procedures and full spectroscopic data for all new compounds. See
DOI: 10.1039/b806389c
Fig. 1 Time course of the product yield in various HF salt ionic
liquids at room temperature.
3
876 | Chem. Commun., 2008, 3876–3878
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Table 1 Prins cyclization of various aldehydes with homoallylic
alcohols in Et
NFÁ5HF
4
a
Homoallylic Reaction
alcohol time/min Product
Yield
(%)
Entry Aldehyde
1
10
Quant.
93
2
20
3
4
20
20
Quant.
Quant.
Scheme 1 Plausible mechanism of Prins cyclization.
performed to provide 4-fluorothiacyclohexanes in excellent
yields. Although cis products were obtained selectively (higher
than 92%), a small amount of trans products were also formed.
Furthermore, we carried out Prins cyclization of various
aldehydes with homoallylic amines. The reaction of 1a with
homoallylic amine (15a) did not proceed at all because of the
5
6
7
90
96
predominant protonation of amino group of 15a in Et
5
4
NFÁ
10
Quant.
98
HF. To solve this problem, we introduced an electron-with-
drawing tosyl group into the nitrogen atom of 15a. Since the
basicity of 15a decreased, aza-Prins cyclization proceeded
smoothly to provide 4-fluoropiperidines (Table 3, entries 2
and 3). However, the reaction of benzaldehyde (1c) with 15b
hardly proceeded, because the reactivity of aromatic aldehydes
was lower than that of aliphatic aldehydes. Similarly to the
case of thia-Prins cyclization, cis products were obtained as a
main stereoisomer, however the stereoselectivity in these cases
was little lower compared with that observed in the case of
thia-Prins cyclization.
120
a
Isolated yield.
Finally, the reusability of the ionic liquid was demonstrated
Next, we hoped to demonstrate the Prins cyclization of
various ketones and homoallylic alcohols with this reaction
system. However, the ketones have shown quite low or no
reactivity. On the other hand, Sabitha et al. reported tri-
methylsilyl iodide (TMSI) mediated Prins cyclization of var-
on the reaction of 1a (0.2 mmol) with 2a (0.2 mmol) in Et
5
4
NFÁ
HF (3 ml). The fluorinated product 3 could be easily sepa-
rated by extraction with hexane and the residual ionic liquid
was then reused for the repeating reaction. The yield of 3 was
more than 90% for up to 5 cycles, indicating the reusability of
the ionic liquid for Prins cyclization.
1
2
ious ketones and homoallylic alcohols. Therefore, this result
indicates that the protons of Et
4
NFÁ5HF have a poor ability to
In conclusion, we successfully carried out the synthesis of
various fluorinated six-membered heterocycles in excellent
yields via Prins cyclization in ionic liquid HF salts. This
synthetic method is very convenient and widely applicable,
and an environmentally friendly process because no organic
solvents are required. Through this study, it has been
activate the carbonyl groups. However, interestingly, only a
cyclic ketone reacted to afford the spiro product (Scheme 2).
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 products and
13
14
possessing peculiar biological activities. Li et al. reported a
15
thia-Prins cyclization and Martin et al. demonstrated an aza-
Prins cyclization. However, there has been no report on the
synthesis of fluorinated thiacyclohexanes and few reports on the
16
synthesis of fluorinated piperidines via a Prins-type cyclization.
As shown in Table 2, Prins cyclizations of various kinds of
Scheme 2 Prins cyclization of cyclic ketone with homoallylic alcohol
NFÁ5HF.
aldehydes and a homoallylic thiol (11a) have been successfully
in Et
4
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Table 2 Prins cyclization of various aldehydes with homoallylic
thiols in Et
NFÁ5HF
Table 3 Prins cyclization of various aldehydes with homoallylic
NFÁ5HF
4
amines in Et
4
Homoallylic Reaction
time/h
Yield (%)
b
(cis/trans)
a
Yield (%)
(cis/trans)
Homoallylic Reaction
Entry Aldehyde amine
Product
b
Entry Aldehyde thiol
time/min Product
1
24
0
1
40
98 (92 : 8)
98 (95 : 5)
a
2
3
1
2
Quant.
(
2
60
60
88 : 12)
a
Quant.
(
92 : 8)
3
Quant.
96 : 4)
(
b
4
24
17
(82 : 13)
a
b
Total isolated yields of both diastereomers. Determined by
19
F NMR.
a
b
Total isolated yields of both diastereomers. Determined by
19
F NMR.
suggested that ionic liquid HF salts would be usable for a
variety of fluorination reactions.
This study was supported by the Grant-in-Aid for Scientific
Research (No. 17073008) in Priority Area ‘‘Science of Ionic
Liquids’’ (Area Number 452) from the Ministry of Education,
Culture, Sports, Science and Technology.
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878 | Chem. Commun., 2008, 3876–3878
This journal is ꢀc The Royal Society of Chemistry 2008