Intramolecular fluorocyclizations of unsaturated carboxylic acids with a stable hypervalent fluoroiodane reagent

Article abstract of DOI:10.1002/anie.201507790

A new class of fluorinated lactones was prepared by the intramolecular fluorocyclizations of unsaturated carboxylic acids by using the stable fluoroiodane reagent in combination with AgBF₄. This unique reaction incorporates a cyclization, an aryl migration, and a fluorination all in one step. The fluoroiodane reagent, prepared easily from fluoride, can also be used without a metal catalyst to give moderate yields within just 1 hour, thus demonstrating that it is a suitable reagent for developing new ¹⁸F-labelled radiotracers for PET imaging. All in one: A new class of lactones containing a tertiary alkyl fluoride was prepared in high yields by using a stable fluoroiodane reagent. This unique reaction incorporates a cyclization, an aryl migration, and a fluorination all in one step.

Full text of DOI:10.1002/anie.201507790

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507790
German Edition: DOI: 10.1002/ange.201507790
Fluorination
Intramolecular Fluorocyclizations of Unsaturated Carboxylic Acids
with a Stable Hypervalent Fluoroiodane Reagent
Gemma C. Geary, Eric G. Hope, and Alison M. Stuart*
Abstract: A new class of fluorinated lactones was prepared by
the intramolecular fluorocyclizations of unsaturated carbox-
ylic acids by using the stable fluoroiodane reagent in combi-
nation with AgBF4. This unique reaction incorporates a cycli-
zation, an aryl migration, and a fluorination all in one step. The
fluoroiodane reagent, prepared easily from fluoride, can also
be used without a metal catalyst to give moderate yields within
just 1 hour, thus demonstrating that it is a suitable reagent for
developing new 18F-labelled radiotracers for PET imaging.
tion[5] and aminofluorinations.[6] However, these reagents are
normally made from elemental fluorine making them pro-
hibitively expensive for large-scale applications.[7] Nucleo-
philic fluoride sources are much more attractive in terms of
cost and for the preparation of 18F-labelled radiotracers for
medical diagnostics. Surprisingly, there has only been one
report of a nucleophilic fluorolactonization. Difluoroiodo-
toluene, in the presence of pyridine-6HF, gave fluorinated g-
lactones in moderate yields (40–50%).[8] In contrast, the
intramolecular aminofluorinations of alkenes using nucleo-
philic sources of fluoride have been well-studied for the
synthesis of 3-fluoropyrrolidines, 3-fluoropiperidines, and 3-
fluoroazepanes.[9] The disadvantage is that most of these
reactions used HF-pyridine, which is highly corrosive and has
to be handled in specialized Teflon reaction vessels.
F
luorinated heterocycles, which are highly sought after
building blocks for the pharmaceutical and agrochemical
industries, can be accessed in a single step by the intra-
molecular fluorocyclization of alkenes.[1] g-Butyrolactones
are common structural motifs found in a variety of natural
products which exhibit a wide range of biological properties
(Figure 1).[2] Since the benzyl-substituted g-lactones 3 have
As part of our research program on designing new
fluorination synthetic strategies,[10,11] we reported the syn-
thesis of the novel fluorinating reagent 4 based on the cyclic
hypervalent iodine(III) skeleton (see Figure 2). The key
feature of 4 is that it is easily prepared by nucleophilic
fluorinations,[11a,12b] but it can simulate electrophilic fluorina-
tions with 1,3-dicarbonyl substrates and styrenes to create
[11,13]
À
new C F bonds.
The chelate sidearm makes 4 a much
more stable and easy to handle powder compared to the
difluoroiodoarenes,[8,14] and it can be used in standard
laboratory glassware.[15] Earlier this year, Szabó and co-
workers demonstrated that 4 can be used for the intra-
molecular fluorocyclizations of unsaturated amines, alcohols,
and malonates in the presence of transition-metal cata-
lysts.[13b] Herein, we report an unusual reaction which
combines an intramolecular fluorocyclization with an aryl
migration to deliver novel lactones containing a tertiary alkyl
fluoride using 4 and AgBF4 (Figure 2). In contrast, the
fluorolactonizations of unsaturated carboxylic acids with
fluoraza reagents are reported to give g-lactones containing
a primary alkyl fluoride.[4a,d] The fluoroiodane 4 therefore
provides the unique opportunity to prepare fluorinated
analogues of benzyl-substituted g-lactones, which are cur-
rently inaccessible with fluoraza reagents.
Figure 1. Examples of naturally occurring benzyl-substituted g-butyro-
lactones.[2]
shown anticancer and anti-inflammatory activities,[3e] new
synthetic strategies have been developed for their construc-
tion,[3] but as far as we are aware, no one has prepared any
fluorinated analogues.
To date, work on the fluorolactonizations of unsaturated
carboxylic acids has focused on using fluoraza reagents in
combination with a base.[4] These electrophilic fluorinating
reagents have also been used successfully for the preparation
of fluorinated cyclic ethers and amines by fluoroetherifica-
[*] Dr. A. M. Stuart
Department of Chemistry, University of Leicester
Leicester, LE1 7RH (UK)
E-mail: Alison.Stuart@le.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507790.
Figure 2. Overview of fluorolactonizations. Tf =trifluoromethane-
sulfonyl.
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Table 1: Optimization of fluorocyclization conditions.[a]
Table 2: Fluorocyclizations with 4 and AgBF4.[a]
Entry Substrate
Product
Yield [%][b,c]
88 (81)
1
2
3
4
5
6
79 (65)
93 (68)
85 (77)
80 (79)
84 (67)
Entry
4
(eq.)
Additive
T
t
Yield [%][b]
[8C] [h] 5a 6a
7
1
2
2
2
2
2
2
1
1
1.5
1.5
0
none
Et3N·3HF (3 eq.)
KF (3 eq.)
[Cu(MeCN)4]PF6 (0.3 eq.)
AgBF4 (0.3 eq.)
AgBF4 (1 eq.)
AgBF4 (1 eq.), mol. sieves
AgBF4 (1 eq.), mol. sieves
AgBF4 (0.4 eq.), mol. sieves 40 18
AgBF4 (1 eq.), mol. sieves
AgBF4 (1 eq.), mol. sieves
60 24
60 24 19 35
60 24 94
60 24
60 24
40 18
40 18 11 76
40 18
0
0
9
0
0
21
23
75
2
6
3
3[c]
4[c]
5
0
0
0
0
0
0
4
6
7
8
9
1
5
93
86
10
40 18 92
40
0
0
3
11[d,e] 1.5
1
1
88 (81)
[a] Reaction conditions: 5a (0.36 mmol), fluoroiodane 4, and the
additive were stirred in CH2Cl2 (0.2 mL). No solvent was used in entry 2.
4 Š molecular sieves (0.09 g) were added to the reaction in entries 7–10.
[b] Yield determined by 1H NMR spectroscopy with naphthalene
(1.0 equiv) as an internal standard. [c] Reaction conducted in CH3CN.
[d] The reaction was scaled up to 0.71 mmol of 5a. [e] Yield of isolated
product given within parentheses.
7
8
46 (38)
90 (86)
To probe the feasibility of an intramolecular fluorocycli-
zation, the preliminary investigation and optimization studies
were carried out with 5a (Table 1). Treatment of 5a with 4
and TREAT-HF at 608C for 24 hours resulted in an encour-
aging 35% yield of 5-benzyl-5-fluorodihydrofuran-2(3H)-one
(6a; entry 2). However, 6a was not produced when the
fluoroiodane was used without an additive (entry 1) and the
addition of KF inhibited the reaction completely (entry 3). In
contrast, the introduction of Lewis acids, [Cu(MeCN)4]PF6
and AgBF4 catalytically (entries 4 and 5) or stoichiometrically
(entry 6), generated increasing amounts of 4-oxo-5-phenyl-
pentanoic acid (7; up to 75%). We were encouraged by the
latter result because 7 was probably formed by the hydrolysis
of the competing hydroxy-substituted lactone, 5-benzyl-5-
hydroxydihydrofuran-2(3H)-one. The addition of 4 Š molec-
ular sieves (entry 7) prevented water competing with fluoride
as the nucleophile and changed the reaction completely, thus
affording a 76% yield of 6a. When 1.5 equivalents of
fluoroiodane were used, the yield increased to 93%, but it
dropped slightly to 86% with 0.4 equivalents of AgBF4. As
expected, the fluorocyclization of 5a did not proceed without
4 (entry 10). The reaction proceeded well within just 1 hour at
408C, thus delivering 6a in an 81% yield by using 1 equiv-
alent of AgBF4 and 1.5 equivalents of 4 in the presence of 4 Š
molecular sieves (entry 11).
9
67 (48)
81 (69)
10
11
12
98 (76)
43 (32)
[a] Reaction conditions: Substrate 5 (0.7 mmol), 4 (1.1 mmol), AgBF4
(0.7 mmol), and 4 Š molecular sieves (0.18 g) were stirred in CH2Cl2
(0.4 mL) at 408C for 1 h. [b] Yield determined by 1H NMR spectroscopy
with naphthalene (1.0 equiv) as an internal standard. [c] Yield of isolated
product within parentheses.
showing that the reaction was unaffected by the introduction
of either electron-donating or electron-withdrawing substitu-
ents onto the aromatic ring. The fluorocyclization of 5-
phenyl-5-hexenoic acid (entry 7) was also studied to inves-
tigate if d-lactones could be accessed using this methodology,
but 6g was isolated in only a moderate yield (38%).
Isobenzofuranones are privileged structures which appear in
numerous natural products and can have useful biological
properties.[16] On changing the substrate structure to 2-(1-
The scope of the reaction was probed with a series of
unsaturated carboxylic acids and the results are presented in
Table 2. The mild reaction conditions were compatible with
a number of functional groups on the aromatic ring, including
alkoxy (entry 2), alkyl (entry 3), halide (entries 4 and 5), and
trifluoromethyl (entry 6) substituents. The fluorinated lac-
tones 6b–f were each isolated in high yields (65–79%), thus
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phenylvinyl)-benzoic acid (5h) (entry 8), the more electron-
rich terminal phenyl group underwent the phenyl migration,
rather than the aromatic backbone, and the fluorinated
isobenzofuranone 6h was isolated in 86% yield. Substitution
at the 4-position of the terminal aromatic ring was tolerated
well with halides (entries 10 and 11), thus giving high yields
(69–76%), but a slightly lower yield was obtained with the
methyl substituent (entry 9). In entry 12, however, the
aromatic backbone underwent the phenyl migration, thus
resulting in a d-lactone fused to an aromatic ring (6l). The low
32% yield was due to elimination problems and formation of
the alkene in conjugation with the aromatic ring, thus giving
3-methyl-1H-isochromen-1-one (8l) in 12% yield (see the
Supporting Information). The novel products generated with
4 are different to those reported from the fluorolactonizations
of 5a and 5h with electrophilic fluorinating reagents; these
reactions afforded g-lactones containing a primary alkyl
fluoride (Figure 3).[4a,d]
hydroxy group occurs at the more-substituted carbon atom
because it is better able to stabilize the partial positive charge
and is therefore more electrophilic. The p donation of the
aromatic ring results in the phenonium ion intermediate 14
with the iodoaryl group acting as an excellent leaving group.
Finally, 14 is ring opened by fluoride, thus resulting in 6a with
fluorination at the quaternary center. A similar aryl migration
has also been reported in the difluorination of styrenes using
4, and in the intramolecular lactonization of 5a with
(diacetoxyiodo)benzene.[13a,17] The same mechanism can be
used to rationalize all of the results in Table 2. In compounds
5h–k the more-electron-rich terminal aromatic ring under-
went the aryl migration, whereas in 5l the aromatic backbone
underwent the aryl migration to form the d-lactone 6l.
Since 4 is easily prepared from simple anionic fluoride
salts, it is an attractive reagent for preparing 18F-labelled
radiotracers for PET imaging. To explore its potential
application for synthesizing 18F-labelled lactones, we further
investigated the fluorocyclization of 5a using molecular sieves
as the only additive (see Table S1 in the Supporting Informa-
tion). This protocol would ensure that the fluoride could only
be provided by 4 and was not coming from the tetrafluoro-
borate anion of the silver catalyst, as reported by Szabó and
co-workers in the difluorination of styrenes.[13a] Without any
metal catalyst we obtained a 63% yield of 6a (Scheme 1). A
short reaction time is essential in view of the short half-life of
18F (110 min) and on reducing the reaction time from 18 to
The proposed mechanism for the fluorolactonizations is
shown in Figure 4. In the first step the metal catalyst activates
the fluoroiodane to form 11 which undergoes an electrophilic
addition to the alkene in 5a to give the cyclic iodonium
intermediate 12. An intramolecular nucleophilic attack of the
Scheme 1. Fluorocyclization with fluoroiodane 4 and molecular sieves.
1 hours, the yield of 6a fell from 63 to 46% yield (see
Table S1). After further optimization (see Table S1), 6a was
produced in a good 58% yield within just 1 hour at 408C in
acetonitrile by using 1.5 equivalents of 4.
Figure 3. Fluorocyclizations with fluoraza reagents.[4a,d]
This new fluorination protocol was applied to a small
series of unsaturated carboxylic acids (Table 3). These
promising results suggest that 4 holds great potential for
preparing novel 18F-labelled heterocycles and developing new
PET tracers, which are currently inaccessible with conven-
tional nucleophilic fluorination chemistry.
In conclusion, we have developed a new and mild method
for the synthesis of fluorinated lactones using the air- and
moisture-stable 4 in combination with AgBF4. This unusual
reaction combines an intramolecular fluorocyclization with
an aryl migration to deliver novel lactones, which contain
a tertiary alkyl fluoride. In contrast, the same reactions with
fluoraza reagents provide lactones containing a primary alkyl
fluoride. Furthermore, the fluorination can also proceed
without a metal catalyst in 1 hour, thus demonstrating clearly
that 4 is suitable for the production of new 18F-labelled
radiotracers for PET imaging.
Figure 4. Proposed mechanism for the intramolecular fluorocycliza-
tions.
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Table 3: Fluorocyclizations with 4 and molecular sieves.[a]
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Entry
Substrate
Product
Yield [%][b,c]
58 (54)
1
2
3
55 (50)
61 (50)
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[a] Reaction conditions: Substrate 5 (0.7 mmol), fluoroiodane 4
(1.1 mmol), and 4 Š molecular sieves (0.18 g) were stirred in CH3CN
(0.4 mL) at 408C for 1 h. [b] Yield determined by 1H NMR spectroscopy
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Experimental Section
General procedure with metal catalyst: The substrate 5 (0.71 mmol),
fluoroiodane 4 (0.30 g, 1.07 mmol), AgBF4 (0.14 g, 0.71 mmol), and
4 Š molecular sieves (0.18 g) were stirred in dichloromethane
(0.4 mL) at 408C for 1 h. The solvent was then removed and product
6 was purified by column chromatography.
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General procedure without metal catalyst: The substrate 5
(0.71 mmol), fluoroiodane 4 (0.30 g, 1.07 mmol), and 4 Š molecular
sieves (0.18 g) were stirred in acetonitrile (0.4 mL) at 408C for 1 h.
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chromatography.
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Keywords: cyclizations · fluorine · hypervalent compounds ·
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[15] The thermal stability of fluoroiodane
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Received: August 20, 2015
Published online: October 9, 2015
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Angew. Chem. Int. Ed. 2015, 54, 14911 –14914