Ring Expansion Fluorination of Unactivated Cyclopropanes Mediated by a New Monofluoroiodane(III) Reagent

Article abstract of DOI:10.1002/anie.202108589

Herein, we report a new strategy for carbon?carbon bond scission and intramolecular ring expansion fluorination of unactivated cyclopropanes, which was accomplished with a new hypervalent fluoroiodane(III) reagent 1. This novel method delivers medicinally relevant 4-fully substituted fluoropiperidines in moderate to high yields with excellent regio- and diastereoselectivity. Reagent 1, which has an N-acetylbenziodazole framework, was readily synthesized via three steps in 76 % overall yield and was characterized by NMR spectroscopy and X-ray crystallography. Owing to the presence of a secondary I???O bonding interaction between the λ³-iodane atom and the carbonyl oxygen of the acetyl group of the N-acetylbenziodazole framework, 1 has excellent stability and can be stored at ambient temperature for 6 months without any detectable decomposition. Density functional theory calculations and experimental studies showed that the reaction proceeds via a carbocation intermediate that readily combines with a fluoride ion to generate the product.

Full text of DOI:10.1002/anie.202108589

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Ring Expansion Fluorination of Unactivated Cyclopropanes
Mediated by a New Monofluoroiodane(III) Reagent
Authors: Jing Ren, Feng-Huan Du, Meng-Cheng Jia, Ze-Nan Hu, Ze
Chen, and Chi Zhang
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10.1002/anie.202108589
Angewandte Chemie International Edition
RESEARCH ARTICLE
Ring Expansion Fluorination of Unactivated Cyclopropanes Mediated by a
New Monofluoroiodane(III) Reagent
Jing Ren, Feng-Huan Du, Meng-Cheng Jia, Ze-Nan Hu, Ze Chen, and Chi Zhang*
Dedication to the 100th anniversary of chemistry at Nankai University
[*]
J. Ren, F.-H. Du, M.-C. Jia, Z.-N. Hu, Z. Chen, Prof. Dr. C. Zhang
State Key Laboratory of Elemento-Organic Chemistry, The Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University 94
Weijin Road, Tianjin 300071 (China)
E-mail: zhangchi@nankai.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
reasoned that a hypervalent fluoroiodane species might be a
useful electrophile for this purpose. Fluorinated organic
compounds have recently found a broad array of applications in
pharmaceutical chemistry, agrochemistry, and materials
science.[7] Two studies have indicated that hypervalent iodine
reagents can be used for highly regioselective 1,3-difluorination
reactions of unactivated cyclopropanes.[8a,b] However,
intramolecular ring expansion fluorination reactions of
unactivated cyclopropanes with electrophiles remain unexplored,
which we attribute to the formidable challenge involved in
controlling the chemoselectivity and regioselectivity of the
reactions.[9] We hypothesized that if a nucleophilic substituent
were present on an unactivated cyclopropane substrate,
intramolecular ring expansion fluorination might be achievable. In
fact, we can now report that we have developed a new
hypervalent fluoroiodane(III) reagent that not only activates the
C–C bond of unactivated cyclopropanes with high regioselectivity
but also effects subsequent ring expansion fluorination reactions
of the cyclopropanes to form fluorinated large rings from the small
Abstract: Herein, we report a new strategy for carbon–carbon bond
scission and intramolecular ring expansion fluorination of unactivated
cyclopropanes, which was accomplished with a new hypervalent
fluoroiodane(III) reagent 1 developed in our laboratory. This novel
method
delivers
medicinally
relevant
4-fully
substituted
fluoropiperidines in moderate to high yields with excellent regio- and
diastereoselectivity. Reagent 1, which has an N-acetylbenziodazole
framework, was readily synthesized via three steps in 76% overall
yield and was characterized by NMR spectroscopy and X-ray
crystallography. Owing to the presence of a secondary I···O bonding
interaction between the λ3-iodane atom and the carbonyl oxygen of
the acetyl group of the N-acetylbenziodazole framework, 1 has
excellent stability and can be stored at ambient temperature for 6
months without any detectable decomposition. Density functional
theory calculations and experimental studies showed that the reaction
proceeds via a carbocation intermediate that readily combines with a
fluoride ion to generate the product.
rings in
a single step. The resulting 4-fully substituted
Introduction
fluoropiperidines are of importance because such structural units
are present in numerous biologically active molecules, such as
the experimental drug befiradol,[10] T-type Ca2+ channel
regulators,[11] a lipid synthesis modulator,[12] and molecules with
anti-inflammatory activity.[13]
Cyclopropanes, which are the smallest carbocycles and have
high ring strain due to their unique bonding mode, are valuable
building blocks for the synthesis of pharmaceuticals,
agrochemicals, and natural products by means of C–C bond
cleavage reactions.[1] Although C–C bond cleavage can be
viewed as a destructive reaction, it is quite useful for the synthesis
of complex molecules and has thus attracted considerable
attention from synthetic chemists.[2] Generally speaking, although
the release of ring strain offers a thermodynamic driving force,
controlling the selectivity of C–C bond cleavage and the
regioselectivity of subsequent ring expansion reactions remains
difficult, especially in the case of unactivated cyclopropanes.[3]
Most of the known strategies for cyclopropane ring-opening have
relied on the assistance of certain functional groups, such as
donor–acceptor (D–A) substituents on the strained ring, or
oxidative addition of transition metals to form metallacyclobutane
intermediates from the cyclopropanes.[2a,4] There are two major
strategies for achieving C–C bond cleavage in non-D–A
cyclopropanes: one is to produce free radical species via single-
electron transfer (Scheme 1a),[5] and the other relies on
electrophilic activation with a Lewis acid (Scheme 1b).[6] We
Scheme 1. Strategies for C–C bond cleavage in non-D-A cyclopropane.
Results and Discussion
1
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10.1002/anie.202108589
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RESEARCH ARTICLE
Hypervalent iodine reagents are multipurpose functional-
group-transfer reagents;[14] and aryl-λ3-iodanes, which contain an
I–F bond, have been used as efficient monofluorine-transfer
reagents.[15] p-(Difluoroiodo)toluene is often used for synthesis of
fluorinated compounds,[16] and cyclic fluorine-containing
hypervalent iodine(III) compounds fluoro-benziodoxolone
reagent[17] and fluoro-benziodoxole reagent[18] have been
reported as well (Figure 1). These compounds have
benziodoxolone and benziodoxole skeletons, respectively, and
both of them have an I–O bond. Various fluorination reactions
mediated by them have been explored.[19] The utility of fluoro-
benziodoxolone reagent is somewhat limited by its reported
sensitivity to moisture and glass bottles.[19f] In addition to these
five-membered I–O heterocycles, as five-membered I–N
heterocycles, benziodazoles, has not been reported as a
hypervalent iodine(III) reagents containing I–F bond so far, and
thus we set about to synthesize such a reagent. We speculated
that a monofluorine-transfer reagent having a benziodazole
skeleton might show unique reactivity. We were particularly
interested in N-acetylbenziodazoles because we expected that a
secondary I···O bonding interaction between the λ3-iodane atom
and the carbonyl oxygen of the acetyl group would stabilize such
a reagent and that the excellent liposolubility of the N-
acetylbenziodazole skeleton would facilitate the desired fluorine-
transfer reaction. These characteristics were demonstrated by a
hypervalent trifluoromethylthio-iodine(III) reagent reported by our
group in 2020.[20] Herein, we report a new fluoroiodane(III)
reagent (1) with an N-acetylbenziodazole skeleton and its use for
intramolecular ring expansion fluorination reactions of
unactivated cyclopropanes.
Scheme 2. Synthesis of fluoroiodane(III) reagent 1.
A single crystal of 1 was obtained by diffusion of n-hexane
into a saturated solution of 1 in CHCl3 at ambient temperature,
and X-ray crystallographic analysis of the crystal showed that the
F(1)–I(1)–N(1) bond angle was 164.96°and that the C(1)–I(1)–
F(1) and C(1)–I(1)–N(1) bond angles (87.1° and 77.9°,
respectively) deviated from 90° (Figure 2). These results
demonstrated that 1 had the distorted T-shaped structure that is
typical of aryl-λ3-iodanes such as phenyliodine diacetate. The
I(1)–F(1) bond length was 2.062 Å, and the I(1)···O(2) distance of
2.8854 Å was considerably shorter than the sum of the van der
Waals radii of the two atoms (3.50 Å), indicating the existence of
secondary bonding, which would improve the stability of 1.
Compound 1 was neither air nor moisture sensitive and could be
stored at ambient temperature for 6 months without any
detectable decomposition. Thermogravimetric analysis showed
that it decomposed at 225 °C to give a brown tar. In addition,
reagent 1 has the highest I-F bond dissociation energy among
three cyclic fluoroiodane(III) reagents.[21] (see SI for details).
Figure 1. Two existing cyclic fluoroiodane(III) reagents.
Compound 1 was synthesized in 76% overall yield by means
of a three-step procedure (Scheme 2). First, acetylation of 2-
iodobenzamide afforded N-acetyl-2-iodobenzamide, which was
treated with t-BuOCl to give a hypervalent chloroiodine(III)
intermediate. All our initial attempts to obtain the desired
fluoroiodane(III) compound by means of ligand-exchange
reactions of the hypervalent chloroiodine(III) intermediate with
common fluorinating agents such as KF, CsF, and AgF failed.
However, treatment of the intermediate with AgF2 generated
desired compound 1 in excellent yield as a white solid, which was
characterized by 1H, 13C, and 19F NMR spectroscopy. Notably, the
ligand-exchange reaction could be scaled up to 20.0 grams with
little effect on the yield.
Figure 2. X-ray crystal structure of 1.
With fluoroiodane(III) reagent 1 in hand, we explored its
fluorine-transfer reactivity in a intramolecular ring expansion
fluorination reaction of unactivated cyclopropanes, using 4-
methyl-N-(2-(1-methylcyclopropyl)ethyl)benzenesulfonamide
(2a) as a model substrate. 2a contains two types of σ-bonds with
π-character: the sterically hindered but electron-rich proximal C–
C bond and the less substituted distal C–C bond which has
reduced steric hindrance (Scheme 3). The intramolecular ring
expansion fluorination might proceed presumably through three
pathways in the presence of fluoroiodane(III) reagent 1: reagent
1 first would activate the distal C–C bond with less steric
hindrance to form iodonium intermediate, which is then attacked
by a nucleophilic substituent in the substrate to obtain a five-
membered ring. The following fluorine anion attack to the five-
membered ring would yield the five-membered fluorination
product (pathway a). Or 1 would first activate the proximal C–C
bond to form an iodonium intermediate, and when attacked by a
2
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10.1002/anie.202108589
Angewandte Chemie International Edition
RESEARCH ARTICLE
3
4
DCM/MeNO2
(9/1)
DCM/MeNO2
(9/1)
DCM/MeNO2
(9/1)
1.5
1.3
BF3•OEt2
(0.4 equiv)
BF3•OEt2
2
2
89
89
trace
trace
nucleophilic substituent in the substrate, it would form a 4-exo
cyclization fluorination product (pathway b) or
a 6-endo
(0.3 equiv)
cyclization fluorination product (pathway c). The myriad of
possibilities escalates the difficulty of intramolecular ring
expansion fluorination reaction of unactivated cyclopropanes.
5[c]
6
1.3
1.3
1.3
1.3
−
24
3
n.d.
27
n.d.
38
DCM/MeNO2
(9/1)
DCM/MeNO2
(9/1)
DCE/MeNO2
(9/1)
BF3•THF
(0.3 equiv)
AgBF4
(0.3 equiv)
BF3•OEt2
(0.3 equiv)
7
24
3
28
33
8
51
24
[a] Reaction conditions: cyclopropane 2a (0.15 mmol, 1.0 equiv), reagent 1 (1.2–
1.5 equiv), and a Lewis acid were stirred in 3 mL of solvent at rt. [b] Yield after
purification by column chromatography. [c] The recovery of 2a was 94%.
With the optimal reaction conditions established, we explored
the generality of the method by testing various cyclopropanes 2
(Table 2). First, we changed the amine protecting group of
substrate 2a. When the protecting group was p-
nitrobenzenesulfonyl, benzenesulfonyl, or methanesulfonyl, the
intramolecular ring expansion fluorination reaction smoothly gave
the corresponding target 4-fluoropiperidines (3b–d) in 64–83%
yields (entry 1). However, when benzoyl-protected substrate 2e
was used, the intramolecular ring expansion fluorination did not
occur; 93% of the starting material was recovered. And, other
non–sulfonyl–protected substrates 2e' including Cbz, Fmoc, Boc,
did not afford the desired fluorinated piperidine products. On the
basis of these results, we carried out the remainder of the
experiments with tosyl-protected gem-disubstituted substrates
bearing various R1 groups. When R1 was n-propyl, we obtained a
71% yield of desired product 3f (entry 2), the structure of which
was unambiguously confirmed by X-ray crystallography (Figure
3). A benzyl group was also compatible with reaction conditions,
although the amount of BF3·Et2O had to be increased from 30
mol% to 1 equiv; under these conditions, desired products 3g and
3g’ were obtained in 79% and 80% yield, respectively (entry 3).
Next, we investigated reactions of cyclopropanes bearing
substituted phenyl groups at R1. Both electron-donating
substituents (methyl, tert-butyl, 3,5-dimethyl, methoxy) and
electron-withdrawing atoms (fluoro, chloro, bromo) on the phenyl
ring were well tolerated, affording desired products 3h–3p in 56–
79% yields (entries 4–12). Cyclopropanes bearing a naphthalene
or thiophene ring were suitable, providing 3q and 3r (in 60% and
46% yields, respectively; entries 13 and 14). Importantly, we also
investigated the diastereoselectivity of the reaction (entries 15–
17). Specifically, reactions of 2s–2u smoothly gave
corresponding products 3s–3u in satisfactory yields with cis/trans
selectivities ranging from 6:1 to 20:1. When p-
nitrobenzenesulfonyl-protected substrate 2s', 2t' were tried, the
reaction still proceeded well and afforded desired products 3s',
3t' in 86% and 87% yield, respectively. The structures and
stereochemistries of these products were established by 1H NMR
and nuclear overhauser effect experiments (see the SI for details).
Furthermore, we confirmed that the cis isomer was the major
product by means of single-crystal X-ray diffraction analysis of 3s
(Figure 3). This compound showed a typical chair conformation
with the large p-toluenesulfonyl group in an equatorial position
and the fluorine atom and the cyclohexyl group in axial positions.
The tolerance test of functional groups with Lewis basic center,
especially ketone and ester groups, was carried out. It was found
that the ketone group was incompatible with the present reaction,
Scheme 3. Possible pathways for the intramolecular ring expansion fluorination
of unactivated cyclopropane.
To our delight, reaction of 2a and 1 (1.2 equiv) afforded 4-
fluoro-4-methyl-1-tosylpiperidine (3a, 70% yield) in the presence
of BF3·Et2O (0.4 equiv) in anhydrous dichloromethane (DCM) at
room temperature for 6 h, along with a 15% yield of 4-methyl-1-
tosyl-1,2,3,6-tetrahydropyridine (4a) (Table 1, entry 1). In this
reaction, we did not detect five-membered fluorinated product
and 4-exo-cyclization fluorinated product, indicating that the
reagent 1 has excellent regioselectivity for the intramolecular ring
expansion fluorination reaction of unactivated cyclopropane.
Encouraged by this result, we carried out some experiments
aimed at optimizing the chemical yield of 3a. Increasing the
amount of 1 from 1.2 to 1.5 equiv increased the yield of 3a to 81%
(entry 2). The formation of elimination product 4a suggested that
the reaction might proceed via a carbocation intermediate.
Considering that nitromethane can stabilize carbocations
because of their high dielectric constants (ε = 36.16),[22] we
carried out a reaction with nitromethane as a cosolvent.
Specifically, reaction of 2a and 1 (1.5 equiv) in the presence of
BF3·Et2O (0.4 equiv) in 9:1 (v/v) DCM/MeNO2 (3 mL) for 2 h
afforded an 89% yield of 3a with only a trace of 4a (entry 3);
moreover, the addition of nitromethane markedly shortened the
reaction time. Decreasing the amount of 1 to 1.3 equiv and the
amount of BF3·Et2O to 0.3 equiv did not affect the yield of 3a
(entry 4). However, in the absence of BF3·Et2O, the reaction did
not occur; 94% of starting material 2a was recovered (entry 5).
Replacing BF3·Et2O with AgBF4 or BF3·THF gave inferior results
(entries 6 and 7), as did using 9:1 (v/v) 1,2-dichlorethane/MeNO2
as the solvent (entry 8).
Table 1. Optimization of reaction conditions.[a]
Solvent
(v/v)
1
Lewis acid
Time
(h)
Yield (%)[b]
Entry
(equiv)
3a
4a
1
2
DCM
1.2
BF3•OEt2
(0.4 equiv)
BF3•OEt2
6
70
15
DCM
1.5
6
81
5
(0.4 equiv)
3
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10.1002/anie.202108589
Angewandte Chemie International Edition
RESEARCH ARTICLE
although an ester group containing compound could afford the
desired product in a low yield (see the SI for details).
Table 2. Substrate scope of intramolecular ring expansion fluorination reaction
mediated by 1[a]
3f
3s
Figure 3. ORTEP drawings of 3f and 3s with thermal ellipsoids at 50%
probability.
As efficient fluorine-transfer reagents, fluoro-benziodoxolone
reagent and fluoro-benziodoxole reagent have previously been
used for various fluorination reactions,[19] and we were curious
about how they would perform in the present reaction of
unactivated cyclopropanes (Scheme 4). When we tested fluoro-
benziodoxolone reagent in a reaction with 2a, none of the desired
product (3a) was detected, and the recovery of 2a was 92%; in
addition, reaction of fluoro-benziodoxole reagent and 2a afforded
3a in only 7% yield. Thus, of the three reagents, fluoroiodane(III)
reagent 1, with its N-acetylbenziodazole skeleton, gave the best
results for the intramolecular ring expansion fluorination reaction
of unactivated cyclopropanes.
Scheme 4. Intramolecular ring expansion fluorination reaction with two existing
cyclic fluoroiodane(III) reagents.
Next, we explored the mechanism of the present reaction
(Scheme 5). Adding BF3·Et2O to a DCM solution of 1 resulted in
the gradual formation of a white insoluble material A, which we
isolated, purified, and characterized by 1H, 13C, 19F, 11B NMR
spectroscopy, ion chromatography, and ESI-HRMS (Scheme 5a).
Its 13C NMR spectrum showed a peak at 117.12, which was in the
typical region for hypervalent iodane(III) compounds and which
we attributed to the C–I ipso-carbon. 11B NMR spectra usually
show a broad peak (>10 Hz); however, when the boron nucleus
is in a fully centrosymmetric environment, relaxation is relatively
slow, and a sharp peak is observed. When BF3 combines with a
−
[a] Reaction conditions, unless otherwise noted: substrate 2 (0.15 mmol, 1.0
equiv), reagent 1 (1.3 equiv), BF3·Et2O (0.3 equiv), 9:1 (v/v) DCM/MeNO2 (3
mL), rt, Ar. PG = protecting group. [b] Isolated yields are reported; n.r. = no
reaction, dr = diastereomeric ratio. [c] The recovery yield of 2e was 93%. [d] n.d.
= no detected, the recovery of starting material is 53%, 72%, and 32%
respectively. [e] DCM (3 mL) was used as the solvent. [f] Reaction conditions:
substrate 2 (0.1 mmol, 1.0 equiv), reagent 1 (1.3 equiv), BF3·Et2O (1.0 equiv),
9:1 (v/v) DCM/MeNO2 (3 mL), rt, Ar. [g] The starting material recovery yield of
2g, 2h, 2i, 2j, 2m, 2n, 2o, and 2p were 13%, 14%, 16%, 19%, 36%, 22%, 27%,
and 20% respectively.
fluorine ion to form BF4 , the electrons around the boron nucleus
are symmetrically arranged, and owing to the resulting shielding
effect, the boron peak tends to appear at high field, as was
observed in the spectrum of the white insoluble material.
Furthermore, ion chromatographic analysis of the material
showed it to have a retention time of 11.540 min, which was
−
nearly identical to that of the BF4 from a diaryliodonium
tetrafluoroborate standard (11.523 min) (see the SI for details).
4
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10.1002/anie.202108589
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RESEARCH ARTICLE
Hence, we concluded that the boron atom in BF3·Et2O was
bonded to the fluorine atom of 1 (F-coordination), thus polarizing
its I(III)−F bond, and generating new hypervalent iodane(III)
species A (as shown in Scheme 5). In 2016, Xue and Cheng et
al. carried out computational studies of silver-mediated geminal
difluorination reactions of styrenes with fluoro-benziodoxole
reagent, and their results suggested that a Lewis acid can
activate fluoro-benziodoxole reagent through F-coordination.[23]
To confirm the intermediacy of A, we carried out an intramolecular
ring expansion fluorination reaction with A in the absence of
BF3·Et2O (Scheme 5b). Specifically, when 2a was treated with A
in 1:1 (v/v) DCM/MeNO2 (3 mL) at 0 ℃ for 15 min, desired product
3a was obtained in 70% yield. This result illustrates that A was a
key intermediate in our intramolecular ring expansion fluorination
reaction.
Scheme 6. Experiment to probe the intermediacy of a tertiary carbocation.
To gain insight into the mechanism of the intramolecular
ring expansion fluorination reactions, we performed density
functional theory calculations on the reaction of cyclopropane
2d and fluoroiodane(III) reagent 1 (Figure 4). The calculations
showed that intermediate A, which is formed by reaction of 1
and BF3·OEt2, is more stable than 1 by 3.2 kcal mol−1.
Intermediate
A
dissociates to generate electrophilic
iodane(III) cation IM1. Subsequently, IM1-promoted cleavage
of the cyclopropane C–C bond of 2d, which has an energy
barrier of 20.2 kcal mol−1, yields tertiary carbocationic
−
intermediate IM2 via TS1. IM2 is fluorinated by BF4 to give
IM3, which reacts with BF3 to form thermodynamically more
stable intermediate IM4. Then the nucleophilic nitrogen atom
of IM4 attacks the activated carbon atom bonded to I(III),
forming an imide anion and six-membered ring intermediate
IM5 via TS3; this process has an activation energy of 13.2
kcal mol−1 relative to IM4. Finally, product 3d is generated by
facile proton abstraction from IM5 by the imide anion. The
Gibbs free energy profile of the overall reaction pathway
indicates that the C-C bond cleavage process is the rate-
limiting step, with an activation energy of 20.2 kcal mol−1.
Scheme 5. Mechanistic experiments.
In addition, we carried out an experiment to ascertain
whether the present reaction proceeded via a carbocation
intermediate. Under the standard conditions, a substrate with an
isopropyl group at R1 (2v) gave a 38% yield of fluorinated
piperidine 3v and a 35% yield of rearranged fluorinated product
3v′. The formation of 3v′ might be attributable to a 1,2-H shift
reaction of a tertiary carbocation intermediate (Scheme 6).
Figure 4. DFT-computed potential energy profile for the reaction between 2d and reagent 1. The calculated Gibbs free energy in DCM is showed in the parentheses.
(standard state: 25℃, 1 mol L-1.)
5
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10.1002/anie.202108589
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RESEARCH ARTICLE
On the basis of the above-described results and literature
studies,[6h,8b] we propose that these reactions proceed via the
pathway shown in Scheme 7. First, activation of 1 by the Lewis
acid (BF3·Et2O) generates iodane(III) intermediate A, which
undergoes electrophilic attack by the sterically hindered C–C
bond of 2 to give carbocationic intermediate B. Then the
tetrafluoroborate anion present in the system fluorinates the
tertiary carbocation of B, and boron trifluoride activates the
carbonyl oxygen of the acetyl group to produce intermediate C,
which further polarizes the C–I(III) bond. Subsequently,
intramolecular nucleophilic attack on the C–I(III) bond by the
amino group, along with reductive elimination of hypervalent
iodine(III) intermediate C, affords cyclic intermediate D and imide
anion E. Acting as a base, imide anion E captures a proton from
D to generate S-2 and product 3. Notably, fluoroiodane(III)
reagent 1 could be regenerated in two steps by oxidation of
recovered S-2 and subsequent ligand exchange with AgF2.
To further demonstrate the synthetic utility of fluoroiodane(III)
reagent 1, we have studied some known reactions using
fluoroiodane(III) reagent 1 as shown in Scheme 9.
Scheme 9. Known reactions mediated by fluoroiodane(III) reagent 1.
Conclusion
In conclusion, we have developed the first method for the
intramolecular ring expansion fluorination of unactivated
cyclopropanes under mild reaction conditions. The method, which
uses newly developed hypervalent fluoroiodane(III) reagent 1 and
a Lewis acid, affords a diverse array of 4-fully substituted
fluoropiperidines in high yields with excellent regio- and
diastereoselectivity. Furthermore, we experimentally verified the
mode by which the Lewis acid activates reagent 1. DFT studies
indicated that the reaction proceeds through
a classical
Scheme 7. Proposed mechanism for the intramolecular ring expansion
fluorination of unactivated cyclopropanes.
carbocation which readily combines with a fluoride ion to furnish
the product. Studies focused on expanding the utility of 1 are
currently in progress in our laboratory.
To exhibit the potential utility of our reaction for the synthesis
of biologically active molecules, we carried out the reaction of 2a
and 1 on a gram scale (Scheme 8) and were gratified to find that
3a was obtained in 87% yield, which is only slightly lower than the
yield of the small-scale reaction. The arylsulfonyl group of 3a
could easily be removed by treatment with Mg/MeOH to give 4-
fluoropiperidium salt 5, and the salt could readily be converted to
6 (85% yield), which showed significantly higher activity than the
commercial hypolipidemic drugs lovastatin and clofibrate.[24]
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21472094, 21772096, and
22071116) and the National Key Research and Development
Program of China (No. 2017YFD020030202). We thank Prof.
Ping-Ping Tang and Prof. Wei-Wei Zi for their valuable
suggestions. We also thank Mr. Jun-Jie Li for his work in part of
computational study.
Keywords: C-C bond cleavage • ring expansion fluorination •
cyclopropanes • hypervalent fluoroiodane(III) reagent • DFT
calculations • 4-fully substituted fluoropiperidines
[1]
[2]
a) H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, J. Tanko, T. Hudlicky,
Chem. Rev. 1989, 89, 165-198; b) J. Salaun, Chem. Rev. 1989, 89,
1247-1270; c) O. G. Kulinkovich, Chem. Rev. 2003, 103, 2597-2632; d)
A. Reichelt, S. F. Martin, Acc. Chem. Res. 2006, 39, 433-442; e) C. A.
Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051-3060; f) P. Tang,
Y. Qin, Synthesis, 2012, 44, 2969-2984; g) C. Ebner, E. M. Carreira,
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Scheme 8. Demonstration of synthetic utility.
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Entry for the Table of Contents
Ring Expansion Fluorination. A new strategy for C-C bond cleavage and intramolecular ring expansion fluorination of unactivated
cyclopropanes has been developed. The reaction consists of C-C bond scission and ring expansion fluorination, which are both
promoted by a new hypervalent fluoroiodane(III) reagent 1 developed in our laboratory.
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