Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes: Scope and limitations

Article abstract of DOI:10.1039/c9ob02712b

Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain a range of monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts have displayed the broadest scope for direct fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives, diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene group to alkenes giving access to the challenging products-fluorocyclopropane derivatives. Interplay between the reactivity of the starting materials and stability of the fluorocyclopropanes formed determines the outcome of the process.

Full text of DOI:10.1039/c9ob02712b

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OrPgleanasice&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/C9OB02712B
ARTICLE
Johnson–Corey–Chaykovsky Fluorocyclopropanation of Double
Activated Alkenes: Scope and Limitations
Armands Kaziaa, Renate Melngailea, Anatoly Mishneva, and Janis Veliksa*
Received 00th January 20xx,
Accepted 00th January 20xx
Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S‐monofluoromethyl‐S‐phenyl‐
DOI: 10.1039/x0xx00000x
2,3,4,5‐tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain
a
range of
monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts display the broadest scope for direct
fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives,
diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene
group to alkenes giving access to the challanging products - fluorocyclopropane derivatives. An interplay between reactivity
of starting materials and stability of formed fluorocyclopropanes determines the outcome of the process.
even on a large scale13, constitute considerable drawbacks, such
as the use of low boiling, or environmentally concerning
reagents, or suffer from limited substrate scope. Until recently,
fluorocarbenoid species were considered a very unstable and
difficult to work with species14a. However, recent progress has
showed feasibility and even remarkable stability of the
fluorocarbenoid species to be effectively used in synthesis14.
Introduction
The fluorine atom is commonly found in many pharmaceuticals1
and agrochemicals2 due to its unique ability to improve the
range of molecular properties. For instance, bioisosteric
replacement of hydrogen with fluorine often enhances
pharmacophysical properties of drug candidates3. On the other
hand, a cyclopropane moiety can be found both in natural
products and many pharmaceutical drugs4. Cyclopropane can
act as configurationally stable bioisosteric replacement of a
double bond and, in general, it can improve metabolic stability,
lipophilicity and solubility of the potential drug candidate. The
fluorocyclopropanes5– a combination of both chemical entities
– cyclopropylgroup and fluorine, is less common, however, is a
very interesting substructure to be used in medicinal chemistry
for drug discovery. This is exemplified by fluorocyclopropyl-
containing pharmaceuticals, such as Sitafloxacin6, Tyk2 JH 2
kinase inhibitors7. Upon lead optimization the fluorine test,
where fluorine atom is introduced in various positions of an
active molecule is a routine nowadays8. However, incorporation
of a fluorine atom into a cyclopropane moiety poses many
synthetic challenges. Direct fluorination of cyclopropane
requires pre-functionalized cyclopropanes9. An alternative
approach towards these structures is the use of vinylfluorides
which are exposed to carbenoid chemistry10. Much more
Fig.
1
Fluoromethylsulfonium reagent
fluoromethylene transfer.
1
for:
A
Fluoromethylation;
B
perspective from
a versatility point of view is direct
Our recent work has demonstrated that an alternative to
halomethane or freon is the solid, bench stable and easy-to-use
S‐monofluoromethyl‐S‐phenyl‐2,3,4,5‐
fluorocarbene or fluorocarbenoid addition to alkenes. For this
transformation, freons (CHFX2)11 or fluoromethylsulfoximine
reagents12 are currently used. These methods, though, used
tetramethylphenylsulfonium tetrafluoroborate (1) (Fig. 1). This
sulfur fluromethylylide precursor, originally developed for
electrophilic fluoromethylation15 (CH2F-), can be used efficiently
as a fluoromethylene transfer (CHF=) reagent to ketones,
aldehydes16a, vinylsulfones and vinylsulfonamides16b. Pursuing
our research program on fluoromethylene transfer chemistry
we aimed to investigated scope and limitation of
a.Latvian Institute of Organic Synthesis
Aizkraukles 21, Riga LV-1006
Latvia .
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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8
NaH (4)a
1,4-dioxf
4a 95
1/1.2
fluoromethylsulfonium reagent
1 for the synthesis of
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DOI: 10.1039/C9OB02712B
fluorocyclopropane derivatives. Herein, we demonstrate that
fluoromethylsulfonium salt is a highly efficient and user
a Addition at RT. b Addition at -78 oC, then warmed to RT.
1
1H NMR yield determined using 1 equiv EtOAc as internal
c
friendly reagent for the Jonhnson-Corey-Chaykovsky
fluorocyclopropanation of double activated alkenes.
standart (Isolated yield). d Sulfonium reagent
0.11 M. f 0.082 M.
1
conc. 0.17 M. e
The aryl substituted fluorocyclopropyl-cyanoesters 5a-d were
formed with high isolated yields as a mixture of diastereomers.
Results and discussion
Initially, for the fluorocyclopropanation reaction arylidene
malononitrile 2a was selected as a model substrate. It was
encouraging to observe the formation of the desired
fluorocyclopropane 3a under the initially selected, non-
optimized reaction conditions (Table 1, entry 1). After solvent
screening (entries 1-4) 1,4-dioxane turned out to be the most
efficient reaction media (entry 4) and NaH was identified as an
optimal base (entry 4 vs 5) affording the fluorocyclopropanated
product 3a with moderate 1H NMR yield. Unfortunately
isolation of the dicyano- substituted fluorocyclopropanes 3a
was unsuccessful due to instability of the formed products. In
turn,
the
fluorocyclopropanation
of
ethyl
benzylydenecyanoacetate 4a was found to be highly efficient
(Table
1).
The
resulting
cyanoacetate
derived
fluorocyclopropane 5a turned out to be
a
stable and
chromatographically isolable product which was obtained in
excellent yield. After adjustment a concentration (entries 6-8)
of the optimal reaction conditions are as follows: to a solution
of 4a (1 equiv) and
1 (2 equiv) in dry 1,4-dioxane (0.17 M of 1)
under Ar atmosphere 60% NaH (4 equiv) was added at room
temperature. Under the optimized reaction conditions a
substrate scope was further investigated (Scheme 1).
Table 1 Optimization of fluorocycolpropanation reaction of
arylidene malononitrile 2a
Base
Yield
d.r.
Nr.
Solventd
SM
3a,5a, %c cis/trans
(equiv)
1.
2.
3.
4.
NaH (2.5)a CDCl3
NaH (2.5)a THF
2a 15
2a 44
2a 17
2a 55
1/1.28
1/1.35
1/1.08
1/1
NaH (2.5)a MeCN
NaH (2.5)a 1,4-diox
n-BuLi
THF
5.
2a 18
1/1.12
(2.2)b
Scheme 1. Substrate scope for Johnson–Corey–Chaykovsky
fluorocyclopropanation reaction. Reaction conditions: To a
6
7
NaH (4)a
1,4-diox
4a 85
1/1.7
solution of
4 (0.21 mmol, 1 equiv), 1 (1.6 equiv) in 1,4-dioxane
NaH (4)a
1,4-dioxe
4a 100 (99)
1/1.24
(3 mL) under Ar atmosphere was added NaH (60 % in paraffin
2 | J. Name., 2012, 00, 1-3
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oil, 4.0 equiv) at RT unless otherwise stated. The reaction In order, to summarize the scope and limitations of the current
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mixture was stirred at RT till completion (TLC control). a Isolated fluorocyclopropanation
yields (NMR yields using 1.0 equiv. of EtOAc as an internal fluoromethylsulfonium salt
of
activateDdOI: 10.1039/C9OB02712B
1 we compared the reactivity of
alkenes
using
b
c
reference). d.r. determined for the crude reaction mixture.
various monosubstituted Michael acceptors (Fig. 2 B and C) with
double activated ones. The reactivity is well correlated with
electrophylicities19 of the corresponding activated Michael
Reaction performed at 0 oC. d THF used as a solvent.
As shown on the example of product 5b, the original acceptors. The phenylvinyl sulfoxide does not react, however,
configuration at the positions C-1 and C-3 was transferred from the corresponding sulfone readily involves in the reaction16a
a starting material alkene E-4b which applies to all aryl- setting the boundary of the utility of this reaction. Double
substituted fluorocyclopropanes 5a-d, 5h in a cyanoester series. activated arylidene and methylidene derivatives are a good fit
This results in the formation of only two diastereomers instead for this reaction. Stronger EWG groups facilitate the
of 4 possible. Sterically demanding anthracenyl derivative 5b fluorocyclopropanation reaction (Fig. 2 C), however, in the case
was formed in excellent NMR yield and increased d.r albeit it of arylidene derivatives the decreased stability of the formed
could only be isolated with low yield due to its poor stability. products can be observed. The EWG groups on the aryl-ring
This suggests that steric bulk at the position C-1 in the resulting contribute to the improved stability of the fluorocyclopropanes,
cyclopropane can improve the stereoselectivity at the fluorine but those with EDG are of poor stability. The balance between
bearing center (C-2). The alkyl-substitution of cyanoesters 4e,f,j reactivity and stability illustrate the landscape and scope of the
is compatible with the fluorocyclopropanation protocol giving process under discussion.
products 5e,f,j in low to good isolated yields. However, the
sterically small methyl substitution does not provide transfer of
the stereochemistry of the double bond geometry into the
product. Methyl- substituted fluorocyclopropane 5e was
obtained as a mixture of all four diastereomers.
Pyridine as a substituent was not compatible with the reaction
conditions, despite the full conversion of the starting material
4g the formation of fluorocyclopropanation product 5g was not
observed. The limitation of the fluorocyclopropanation are
substrates containing electron rich aromatic double bond
substituents due to obvious instability of the reaction products.
The furan derivative 4h efficiently undergoes fluoromethylene
transfer as detected by NMR, however, the product 5h
decomposed upon chromatographic purification.
Arylidene malonate derivatives 4k-t are well suited substrates
for the fluorocyclopropanation reaction giving the products 5k-
t
in low to very good yields as a mixture of diastereomers.
Electron withdrawing groups (4n,o,p) and halogen (4l,m) on the
aryl moiety of the arylydene malonates furnished good to
excellent yields of the fluorocyclopropanes . Olefins with
electron rich aryl groups and unsubstituted phenyl substituents
5k, 5r, 5s) gave products with moderate NMR yields which
4
5
(
were prone to decompose upon isolation. This observation is in
line with the stability and kinetics of donor-acceptor (D-A)
cyclopropanes where generally electron donating groups
increase the cyclopropane cleavage rate18.. The barbituric acid
derivative 4u involves readily in fluorocyclopropanation
reaction affording the fluorocyclopropane 5u with good NMR
yield, however, the isolated yield of the product is rather low.
Further, we investigated cyclopropanation of β-unsubstituted
substrates 4v-x. β-Unsubstituted substrates participate readily
in the fluorocyclopropanation process giving stable, isolable
products 5v-x in moderate to high yields.
Fig. 2 Scope and limitations of the Johnson-Corey-Chaykovsky
fluorocyclopropanation reaction. An ester group influence on
A
the reactivity and stability of phenylsubstituted cyclopropanes
a
5
. Standard reaction conditions unless otherwise stated.
Isolated yields (NMR yields using 1.0 equiv. of EtOAc as an
b
internal reference). d.r. determined for the crude reaction
c
d
mixture. Solvent – dry MeCN. Solvent – dry THF.
balance of reactivity and stability parameters of the
flurocyclopropanation process. The influence of substitutents
B The
C
on the reactivity of Michael acceptors: (x) no reaction; (v)
suitable substrates.
As a fluorocyclopropane 5k with unsubstitued phenyl group at
cyclopropane was prone to decomposition we opted to alter
the ester functionality (Fig. 2 A). This eventually led to the
finding that the benzyl esters 5ab are stable products compared
to the other esters 5y,k,z,aa broadening their potential
application.
In order to get a clearer understanding of the parameters for
successful fluorocyclopropanation, we performed several
control experiments (Scheme 2). For example, benzylidene
barbiturate 4ac readily participated in fluorocyclopropanation
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reaction giving good NMR yield of the corresponding were exposed to the corresponding ring extension reaction
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cyclopropane 5ac, however, upon chromatographic isolation affording only single diastereomers cis,cDisO-8I:n10a.1n0d39/tCra9nOsB,0c2is7-182nB
only 5-membered rearrangement product 6ac was obtained correspondingly. It is noteworthy that the rotation across the
(Scheme 2A). Donor-acceptor cyclopropanes are known to C(4)-C(5) bond takes place resulting in inversion of relative
involve in various ring-extension reactions18. The substrate 5ac configuration of fluorine and aryl- substituents of fluorofuranes
displays an example of intramolecular rearrangement process
which is in line with Mayr’s20 observations where arylidene [3+2] cycloaddition reaction mechanism21a. Interestingly that
barbiturates in Corey-Chaykovsky reaction give similar 5- fluorocyclopropane scaffold displays remarkable stability
8 which is in a good agreement with the previously proposed
5
membered product. This is explained to proceed via initial under strongly basic conditions. Ester 5l can be readily
formation of a cyclopropane intermediate rather than the O- hydrolyzed by using KOH (Scheme 2 C) to give salt 7l in a good
attack to the betaine intermediate of the Corey-Chaykovsky isolated yield. This opens an avenue for the potential synthesis
reaction which is in line with our observations. Utilization of D- of
a fluorocyclopropyl analogues of biologically active
A cyclopropane21 properties of fluorocyclopropanes opens compounds22.
5
perspective for the further synthetic application of these
scaffolds. Under unoptimized conditions, fluorocyclopropane 5l
involved in Sc(OTf)3 mediated [3+2] ring-extension reaction
with p-bromobenzaldehyde as a dipolarophile to give new
fluorinated furan scaffold 8l (Scheme 2 B). The process
appeared to be highly diastereoselective with respect to
stereocentres at C-2- and C-5 as only 2 diastereomers of 8l were
observed.
Conclusions
We have demonstrated that diarylfluoromethylsulfonium salt
can be efficiently used for fluoro-Johnson-Corey-Chaykovsky
reaction to afford a range of fluorocyclopropane derivatives.
We have investigated scope and limitations of the
fluorocyclopropanation reaction which displays the balance
between reactivity of substrates and stability of the products.
1
5
The fluorocyclopropane derivatives 5 are an interesting class of
chemical entities with potential application in medicinal
chemistry and as well as the intermediates to access new
monofluorinated scaffolds by involving them in further
reactions.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support by ERDF project Nr.1.1.1.5/17/A/003. The
authors wish to thank Prof. Dr. Aigars Jirgensons for scientific
discussion. Arturs Sperga for the synthesis of 1. Andulis Smidlers
for technical assistance. LIOS analytical service for NMR (Juris
Popelis, Marina Petrova), MS (Solveiga Grinberga, Dace
Hartmane, Valerija Krizanovska, Baiba Gukalova) and elemental
analysis (Emma Sarule).
Notes and references
1
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Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem.
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Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–
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2
3
4
Fluorine containing agrochemicals: (a) T. Fujiwara and D.
O’Hagan, J. Fluorine Chem., 2014, 167, 16–29. (b)
Fluorinated motifs as bioisosters: N. A. Meanwell, J. Med.
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T. T. Talele, J. Med. Chem., 2016, 59, 8712–8756.
Scheme 2 Properties and further functionalization options of
fluorocyclopropanes 5.
Cyclopropene 9l was detected as the major side product of this
transformation. In order to probe the observed stereochemical
outcome, isolated trans-5n and cis-5n fluorocyclopropanes
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5
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