Gem-Difluorination of Methylenecyclopropanes (MCPs) Featuring a Wagner-Meerwein Rearrangement: Synthesis of 2-Arylsubstituted gem-Difluorocyclobutanes

Article abstract of DOI:10.1021/acs.orglett.1c00767

The geminal difluorocyclobutane core is a valuable structural element in medicinal chemistry. Strategies for gem-difluorocyclobutanes, especially the 2-substituted cases, are limiting and often suffer from harsh reaction conditions. Reported herein is a m

Full text of DOI:10.1021/acs.orglett.1c00767

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Letter
gem-Difluorination of Methylenecyclopropanes (MCPs) Featuring a
Wagner−Meerwein Rearrangement: Synthesis of 2‑Arylsubstituted
gem-Difluorocyclobutanes
Peng-Peng Lin, Long-Ling Huang, Si-Xin Feng, Shuang Yang, Honggen Wang, Zhi-Shu Huang,
and Qingjiang Li*
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ABSTRACT: The geminal difluorocyclobutane core is a valuable
structural element in medicinal chemistry. Strategies for gem-
difluorocyclobutanes, especially the 2-substituted cases, are limiting
and often suffer from harsh reaction conditions. Reported herein is
a migratory gem-difluorination of aryl-substituted methylene-
cycloproanes (MCPs) for the synthesis of 2-arylsubstituted gem-
difluorocyclobutanes. Commercially available Selectfluor (F-
TEDA-BF4) and Py·HF were used as the fluorine sources. The
protocol proceeds via a Wagner−Meerwein rearrangement with
mild reaction conditions, good functional group tolerance, and
moderate to good yields. The product could be readily transformed to gem-difluorocyclobutane-containing carboxylic acid, amine,
and alcohol, all of which are useful building blocks for biologically active molecule synthesis.
yclobutanes, as the second most strained carbocycles, are
Cintriguing structural motifs frequently found in naturally
occurring products and biologically active molecules.1 Due to
their high structural rigidity and defined substituent spatial
conformation, cyclobutanes are usually defined as privileged
structural elements for structure-based drug discovery in
medicinal chemistry.2 In addition, they also serve as versatile
building blocks in synthetic transformations such as ring-
expansion or ring-cleavage reactions by releasing their inherent
strain energies (ca. 26.7 kcal mol−1).3 On the other hand,
Figure 1. Representative drugs or bioactive compounds containing
organofluorine compounds are increasingly utilized in
the fluorocyclobutane moiety.
pharmaceutical, agrochemical, and materials sciences.4 The
incorporation of fluorine or fluorinated moieties into organic
synthetic applications. DAST or its derivative-mediated direct
molecules often improves the biological properties of parent
deoxyfluorination of 2-substituted cyclobutanones seems to be
compounds, including lipophilicity, metabolic stability, bio-
a convenient and valuable method to provide 2-substituted
availability, and binding affinity.5 Therefore, the above
gem-difluorocyclobutanes (Scheme 1b).9 Nevertheless, only
combined fluorinated cyclobutane structure might possess
scattered examples are successful when a 2-alkyl substrate was
broad biological profiles and find more potential applications
employed.9a−c The replacement of alkyl with a phthalimido
in medicinal chemistry (Figure 1).6
group led to a drastically decreased yield of 5−12%.9d It should
Although a great deal of methods have been developed to
be noted that the reaction conditions of this deoxyfluorination
access diversely substituted fluorocyclobutanes,7 to date, only a
are not compatible with 2-aryl cyclobutanones.10 Alternatively,
handful of methods exist for the synthesis of 2-substituted gem-
difluorocyclobutanes.8,9,11 Among these, thermal [2 + 2]
cycloaddition could typically be applied to the synthesis of 2-
Received: March 5, 2021
Published: April 1, 2021
substituted gem-difluorocyclobutanes by the reaction of alkenes
with gem-difluoroallene derivatives (Scheme 1a).8 The need for
high temperature, the difficulty of handling gaseous gem-
difluoroallene, and the intrinsic chemoselectivity for the two
orthogonal double bonds on allenes limit its widespread
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 3088−3093
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unprecedented.17 The reaction proceeds under mild reaction
conditions with good functional group tolerance. Remarkably,
further oxidation of the aryl ring of these products by RuCl3/
NaIO4 affords 2,2-difluorocyclobutane-1-carboxylic acid, which
can be readily converted to a diverse array of gem-
difluorocyclobutane-containing compounds.
Scheme 1. Synthesis of 2-Substituted gem-
Difluorocyclobutanes and Difunctionalizations of
Methylenecyclopropanes (MCPs)
Initially, the migratory germinal difluorination reaction of 4-
biphenylmethylenecyclopropane (1a) was studied in the
presence of both electrophilic fluorine source Selectfluor and
nucleophilic fluorine source Py·HF. To our delight, after
extensive exploration, the desired product 4-(2,2-difluoro-
cyclobutyl)-1,1′-biphenyl (2a) could be obtained in 80%
isolated yield under the optimized reaction conditions of 1a
(0.2 mmol), Selectfluor (1.5 equiv), Py·HF (96.0 equiv HF),
and pyridine (6.0 equiv) in toluene (1.0 mL) at 40 °C for 4 h
(eq 1; see Supporting Information for details). It should be
noted that no special exclusion of air and moisture is needed.
With the optimized reaction conditions in hand, we next
investigated the substrate scope of this migratory gem-
difluorination reaction. As illustrated in Scheme 2, the
transformation was found to be general to a diverse array of
phenyl-substituted MCPs. A variety of commonly encountered
functional groups, regardless of the electronic nature, at
different positions of the benzene ring were well tolerated,
giving the corresponding products in moderate to good yields.
Substituents such as alkyl (2c, 2e, 2r), benzyloxy (2d), halides
(2f−i, 2m, 2q, 2r), nitro (2j, 2n), cyano (2k, 2o, 2p), and
ester (2l) were valuable functional handles for further
derivatization. The lower yield of 2i might stem from the
side oxidation of aryliodides in the presence of Selectfluor.18
Notably, ortho-substituted substrates gave relatively lower
yields, presumably for steric reasons (2m−2o, 2q, and 2r).
Furthermore, decreasing the loadings of Py·HF (to 64.0 equiv)
for some substrates bearing electron-neutral and electron-
donating groups, such as 2b−2d, and 2s, was beneficial for
maintaining a satisfactory yield. The gem-difluorination of
naphthyl-substituted MCPs produced the desired products in
good yields (2t and 2u). However, the reaction of 2-thienyl-
(1x), 3-pyridyl- (1y), or 6-quinolyl-substituted (1z) MCPs did
not give the corresponding gem-difluorocyclobutanes, probably
due to the strong coordination of heteroatoms (O and N) to
hydrogen fluoride. The use of 1-alkyl-1-aryl-substituted MCP
was also successful (2u and 2v). Interestingly, when the 1,1-
diphenylsubstituted substrate was subjected to the standard
reaction conditions, desired product 2w was obtained in 34%
yield, accompanied by a substantial amount of direct ring-
opening difluorination side product 2w′. Unfortunately, the
current reaction conditions were not compatible with simple
alkylmethylenecyclopropanes. For instance, the use of (3-
cyclopropylidenepropyl)benzene (1aa) gave no trace of the
desired product, resulting in a complex mixture.
AIBN-triggered intramolecular 4-exo-trig radical cyclization of
gem-difluorinated selenide was also feasible to access
polysubstituted gem-difluorocyclobutanes, with poor diaster-
eoselectivity being observed and prefunctionalized raw
materials being needed (Scheme 1c).11 Considering the
potential applications of 2-substituted gem-difluorocyclobu-
tanes and the drawbacks of their synthesis methods, it is still
highly desirable to develop a new synthetic methodology for
the construction of such important molecules.
Methylenecyclopropane and its derivatives (MCPs),12
featuring an exocyclic double bond on the cyclopropane ring,
have emerged as versatile synthetic building blocks in a
number of intriguing transformations.13 Among these diverse
transformations, the ring expansion of MCPs via rearrange-
ment was demonstrated to be a useful strategy to construct
four-membered carbocycles.14 In continuation of our interest
in organofluorine synthesis,15 we envisioned that 2-substituted
gem-difluorocyclobutanes might be accessible via a Wagner−
Meerwein rearrangement of MCPs in the presence of
electrophilic and nucleophilic fluorine sources. Although
previous reports showed that the directly ring-opened
aminofluorination reaction of MCPs was observed in the
presence of a strong nucleophile and an electrophilic
fluorination reagent such as Selectfluor or NFSI,16 we
postulated that a weak nucleophilic fluoride ion might make
the rearrangement proceed smoothly. Herein, we disclose our
recognition of the migratory gem-difluorination of 2-arylsub-
stituted MCPs via Wagner−Meerwein rearrangement for the
synthesis of 2-arylsubstituted gem-difluorocyclobutanes by
using Selectfluor/Py·HF (Scheme 1d). To the best of our
knowledge, the combination of Selectfluor and Py·HF as the
electrophilic and nucleophilic fluorine sources for the gem-
difluorinations of organic molecules in one system is
The structure of compound 2l was unequivocally confirmed
by X-ray crystallographic analysis of its derivative 4 (CCDC
1977603), which was synthesized by lithium aluminum
hydride reduction of the methyl ester followed by protection
of the corresponding primary alcohol with p-nitrobenzoyl
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Scheme 2. Synthesis of 2-Arylsubstituted gem-
Difluorocyclobutanes
Scheme 3. Structure Determination of the Products, Gram-
Scale Synthesis, and Product Derivatization
a
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), Selectfluor (1.5
equiv), Py·HF (96.0 equiv HF), pyridine (6.0 equiv), toluene (1 mL),
b
c
air, 40 °C. Py·HF (64.0 equiv HF). CCl4 was used instead of
d
toluene. AgCl (20 mol %) was used instead of pyridine, 24 h.
with good efficiency. On the other hand, through EDCI/
HOBt-mediated amidation of carboxylic acid with amine, the
gem-difluorocyclobutane moiety could be introduced into
bioactive molecules, such as the antisenile dementia drug
memantine,21 affording the corresponding drug-derived
compound 9 with an unoptimized 45% yield. In addition,
treatment of acid 5 with o-phenylenediamine (OPD) in the
presence of EDCI and DMAP followed by hydrochloric acid
produced the condensation product 2-gem-difluorocyclobutyl
benzimidazole 10 with a 54% yield. Finally, the oxidation of 5
with Na2S2O8 triggered a metal-free decarboxylative radical
alkylation22 of N-acrylamide 11 and a C−H functionalization
cascade to provide gem-difluorocyclobutane-containing oxin-
dole 12 in 41% yield with a diastereometric ratio of 3:2.
To gain insight into the current migratory gem-difluorination
reaction, several mechanistic experiments were carried out
(Scheme 4). The reaction of 4-biphenylmethylenecyclobutane
(13) under standard conditions gave the desired migratory
gem-difluorination product 14 along with major 1,2-difluori-
nated product 15, while the reaction of acyclic alkene 16
completely produced 1,2-difluorination product 17 (97%
yield), and no trace of rearrangement product was observed
(Scheme 4a). These results indicated that the existence of a
chloride/DMAP in an overall yield of 60% (Scheme 3a). To
demonstrate the synthetic practicality of this protocol, a scale-
up synthesis of gem-difluorocyclobutane 2a was performed
(Scheme 3b). And, 0.93 g of 2a was obtained in 76% yield
under the standard reaction conditions with a prolonged
reaction time (to 5 h). The synthetic utility of this
methodology was evidenced by a rapid preparation of 2,2-
difluorocyclobutane-1-carboxylic acid 5, a potential fluorinated
building block for medicinal chemistry (Scheme 3c).
Previously, Grygorenko and co-workers reported the synthesis
of compound 5 in a total yield of 23% via 8 steps starting from
2-bromo-1,1-dimethoxyethane (6).9a By using our developed
new methodology, carboxylic acid 5 could be easily accessible
with a 25% total yield starting from a 25.0 mmol scale of 1b
through a one-pot two-step sequence, involving migratory gem-
difluorination and following by oxidation19 of the phenyl ring
of 2b to carboxyl by RuCl3/NaIO4. Remarkably, the obtained
acid 5 can be used as a versatile building block to access
various gem-difluorocyclobutane-containing compounds. Re-
duction of 5 with LiAlH4 smoothly delivered alcohol 7, and the
carboxyl group within 5 could be converted to the
corresponding amine derivative 8 via Curtius rearrangement20
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through a two-electron process. The regioselectivity of this
electrophilic fluorination might stem from the capability of the
aryl group to stabilize the formed benzylic cation. Thereafter,
in the presence of the weak nucleophilic fluoride ion, Wagner−
Meerwein rearrangement takes place preferentially to forge an
α-fluorinated cyclobutyl cation B, which is then attacked by the
fluoride to provide the 2-arylsubstituted gem-difluorocyclobu-
tane product 2a. The driving force of this rearrangement is the
release of the high strain energy of cyclopropane and a
stabilizing effect of the fluorine atom to its bound carbocation.
In summary, we have developed a migratory gem-
difluorination reaction of aryl-substituted methylenecyclo-
propanes (MCPs) via Wagner−Meerwein rearrangement by
using Selectfluor and Py·HF as fluorine sources. The protocol
enables a facile and efficient construction of 2-aryl gem-
difluorocyclobutane derivatives, which would be otherwise
challenging to be prepared. Broad substrate scope, good
functional group tolerance, and moderate to good yields were
observed. Mechanistic studies suggest that the electrophilic
fluorination of double bonds with Selectfluor involves a two-
electron transfer process. The synthetic utility of the reaction
was demonstrated by further transformations of the products
to several useful gem-difluorocyclobutane-containing building
blocks such as carboxylic acid, amine, and alcohol.
Scheme 4. Mechanistic Studies and Proposed Reaction
Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00767.
Detailed experimental procedures, spectroscopic charac-
1
terization of all reported compounds, and H and 13C
NMR spectra (PDF)
Accession Codes
CCDC 1977603 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
strained cyclopropyl moiety on the substrate is important for
the Wagner−Meerwein rearrangement reactivity. In addition,
further control experiments were carried out to trace the
source of two incorporated fluorine atoms within the products
(Scheme 4a). When 1a was subjected to the standard reaction
conditions with omission of Selectfluor or Py·HF, no or only
trace amount of the desired 2a was isolated, indicating that the
two fluorine atoms arise from both Selectfluor and Py·HF.
Typically, two possible processes have been proposed for
Selectfluor-mediated fluorination of alkenes, including the
single-electron transfer (SET)23 and two-electron process.24
To determine whether a radical intermediate was formed via a
SET process in such reactions, the radical trapping and clock
experiments were conducted. The employment of TEMPO or
BHT as a radical scavenger in the reaction of 1a only slightly
decreased the reactivity (Scheme 4b). Furthermore, the
reaction of a radical clock substrate 19 under our conditions
mainly afforded the 1,2-difluorinated product 20, without the
detection of a ring-opening product (Scheme 4b). These
results, along with the use of toluene as the reaction media,
suggested that a possible single-electron transfer pathway
might not be involved in the reaction.
AUTHOR INFORMATION
Corresponding Author
■
Qingjiang Li − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China; State Key Laboratory of Natural and
Biomimetic Drugs, Peking University, Beijing 100191, P. R.
China; orcid.org/0000-0001-5535-6993;
Email: liqingj3@mail.sysu.edu.cn
Authors
Peng-Peng Lin − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China
On the basis of the above observations and the preceding
literatures,24 a plausible reaction mechanism for this migratory
gem-difluorination of MCPs is proposed and outlined in
Scheme 4c. Initially, the interaction between the double bond
within 1a and the electrophilic fluorinating reagent Selectfluor
delivers the β-fluorinated cyclopropylcarbinyl cation species A
Long-Ling Huang − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China
Si-Xin Feng − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
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Letter
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Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China
Shuang Yang − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China
Honggen Wang − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China; orcid.org/0000-0002-9648-6759
Zhi-Shu Huang − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. China; orcid.org/0000-0002-6211-5482
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Guangdong Basic
and Applied Basic Research Foundation (2019A1515011322
and 2020A1515010624), the Fundamental Research Funds for
the Central Universities (19ykpy124), the National Natural
Science Foundation of China (81930098), the Key-Area
Research and Development Program of Guangdong Province
(2020B1111110003), the Guangdong Provincial Key Labo-
ratory of Chiral Molecule and Drug Discovery (2019B03030-
1005), and the State Key Laboratory of Natural and
Biomimetic Drugs, Peking University (K20170210).
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