Boron-substituted difluorocyclopropanes: New building blocks of gem-difluorocyclopropanes

Article abstract of DOI:10.1021/ol702851t

Cycloaddition of difluorocarbene to alkenyl boronates 3 gave boron-substituted gem-difluorocyclopropanes 2 in stereospecific fashion. Upon treatment with lithium carbenoids, cyclopropyl boronates 2 underwent one-carbon homologation to afford a variety of gem-difluorocyclopropanes in good yields.

Full text of DOI:10.1021/ol702851t

ORGANIC
LETTERS
2008
Vol. 10, No. 5
769-772
Boron-Substituted
Difluorocyclopropanes: New Building
Blocks of gem-Difluorocyclopropanes
Yasutaka Fujioka and Hideki Amii*
Department of Chemistry, Graduate School of Science, Kobe UniVersity,
Kobe 657-8501, Japan
amii@kobe-u.ac.jp
Received November 26, 2007
ABSTRACT
Cycloaddition of difluorocarbene to alkenyl boronates 3 gave boron-substituted gem-difluorocyclopropanes 2 in stereospecific fashion. Upon
treatment with lithium carbenoids, cyclopropyl boronates 2 underwent one-carbon homologation to afford a variety of gem-difluorocyclopropanes
in good yields.
Organofluorine compounds are widely used in the medicinal,
agricultural, and material sciences.1 In particular, fluorine-
containing cyclopropanes have received a great deal of
attention due to their biological activities. For instance,
sitafloxacin (DU-6859a) which has a fluorocyclopropyl
moiety is a quinolone antimicrobial agent.2 Zosuquidar
trihydrochloride (LY335979‚3HCl) possessing a gem-di-
fluorocyclopropane framework has been studied for its ability
to reverse resistance to chemotherapy.3 Certain gem-difluo-
rocyclopropane derivatives show potentially unique biologi-
cal activities such as degradation of oncogenic proteins,4
DNA alkylation,5,6 and insecticidal properties.7 In recent
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10.1021/ol702851t CCC: $40.75
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years, introducing difluorocyclopropyl moieties into biomol-
ecules such as nucleosides8,9 and amino acids10 has been a
topic of considerable interest. Furthermore, transformations
involving regioselective ring-opening of gem-difluorocyclo-
propanes provides a variety of useful fluoroorganic com-
pounds.11-14 Therefore, the development of general building
blocks for gem-difluorocyclopropanes is of significant im-
portance.
we present a stereospecific preparation and synthetic ap-
plications of boryl-substituted difluorocyclopropanes 2, new
gem-difluorocyclopropane building blocks (Scheme 2).
Scheme 2
One of the useful difluorocyclopropane building blocks
is a difluorocyclopropyl anion equivalent, which can react
with various electrophiles. It is known that deprotonation of
gem-difluorocyclopropanes upon exposure to organolithium
reagents procceeds even at low temperature. However, the
resultant anions possessing lithium as a counterion are too
unstable to suppress facile â-fluoride elimination.15 To avoid
defluorination from difluorocyclopropyl moieties, Taguchi
developed the reactions of silyl-substituted difluorocyclo-
propanes with aldehydes in the presence of a catalytic amount
of fluoride anion to give the corresponding cyclopropyl-
carbinols successfully (Scheme 1).16 Besides silyl substitu-
When 1-phenylvinylboronic acid pinacol ester (3a) was
treated with sodium chlorodifluoroacetate23 (8 equiv to 3a)
in diglyme at 180 °C for 15 min (Method A), cycloaddition
of difluorocarbene to 3a took place to afford (2,2-difluoro-
1-phenylcyclopropyl)borate 2a in 61% yield (entry 1 in Table
1). As a source of difluorocarbene24 in this case, the use of
sodium chlorodifluoroacetate gave a better result than that
of trimethylsilyl fluorosulfonyldifluoroacetate (TFDA)/NaF
system25 (14% yield). Other examples of the formation of
boryl difluorocyclopropanes 2 are given in Table 1. The
reactions of 1-substituted vinylboronic esters 3b and 3c
possessing alkyl and alkoxymethyl groups26 also gave the
Scheme 1
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Org. Lett., Vol. 10, No. 5, 2008

synthetically useful application of boryl difluorocyclopro-
panes 2 has been made for one-carbon homologation using
lithium carbenoids.29-32 Treatment of 2a with chlorometh-
yllithium (1.3 equiv) in THF at -78 °C followed by warming
to room-temperature gave homologated boronic ester 4a in
95% yield (Table 2, entry 1). Under similar reaction con-
Table 1. Synthesis of Boron-Substituted Difluorocyclopropanes
Table 2. One-Carbon Homologation of Borates 2
a pin ) -OCMe2CMe2O-. b Isolated yield
ditions, boronic esters 2b and 2f also gave the corresponding
cyclopropylmethyl borates 4 in good yields (entries 2 and 3
in Table 2). In each case, the one-carbon homologation
proceeded smoothly in a highly controlled manner. Note-
worthily, neither cleavage of the difluorocyclopropane rings
nor dehydrofluorination was observed upon exposure to
carbanionic reagents (lithium carbenoids).
a pin ) -OCMe2CMe2O-. b The reaction was carried out using
ClCF2CO2Na (8 equiv) for 15 min (Method A) or using ClCF2CO2Na (3-4
1
equiv) for 5-8 h (Method B). c Isolated yield. d Determined by H NMR
e
analysis. ClCF2CO2Na (8 equiv) was used.
corresponding adducts in 80% and 59% yields, respectively
(entries 2, 3). In general, cycloaddition reactions of difluo-
rocarbene to alkenes proceed in a stereospecific manner. The
use of (E)- and (Z)-alkenyl borates such as 3d-f27,28 is
anticipated to deliver cis- and trans-substituted boryl cyclo-
propanes 2d-f. However, the reactivities of alkenyl borates
3d-f were too low to obtain the desired adducts 2d-f
(<15% yields, 180 °C, 15 min) due to the electronic effect
One-carbon homologation of boryl difluorocyclopropanes
2 was combined with H2O2/NaOH oxidation (Scheme 3).33
Scheme 3
of boryl groups. According to Barnett’s modification,3b
a
slow addition technique worked well for difluorocyclopro-
panation of vicinal disubstituted alkenes 3d-f; the yields of
2d-f were improved to 50%, 71%, and 46%, respectively,
when the reactions were carried out at 180 °C along with
adding diglyme solution of sodium chlorodifluoroacetate over
the course of 8 h by the use of syringe pump (Method B,
entries 4-6). Cyclic (trisubstituted) boronate 3g26 also
underwent difluorocyclopropanation to form the fused ring
system 2g in 74% yield. Combined with well-established
protocols for regio- and stereoselective synthesis of alkenyl
borates 3,26-28 difluorocyclopropanation of 3 gave new
borylated building blocks 2 in high stereochemical fidelity.
Next, we explored selective transformations of boryl
functionalities in difluorocyclopropanes 2. In particular, the
Without isolation of the intermediate 4a, cyclopropyl bor-
onate 2a was converted cleanly to (difluorocyclopropyl)-
methanol 5 in 90% overall yield. Furthermore, cyclopropyl-
methyl borate 4a reacted with chloromethyllithium (1.3
(27) Preparation of (E)-alkenylboronic esters: (a) Pereira, S.; Srebnik,
M. Organometallics 1995, 14, 3127-3128. (b) Wang, Y. D.; Kimball, G.;
Prashad, A. S.; Wang, Y. Tetrahedron Lett. 2005, 46, 8777-8780.
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J. Org. Chem. 1994, 59, 6871-6873.
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Org. Lett., Vol. 10, No. 5, 2008
771

equiv) in THF to afford cyclopropylethyl borate 6 in 61%
yield. Thereby, stepwise two-carbon homologation34 of boryl
difluorocyclopropane 2a was achieved with these operations
proceeding without incident.
Various lithium carbenoids are applicable for homologa-
tion of (difluorocyclopropyl)borates 2 (Scheme 4). An allylic
ronate 7 as a mixture of diastereomers (8.3/1). On the other
hand, the use of dichloromethyllithium allowed the insertion
of a chloromethyl group into the C-B bond in 2a to form
borate 8. R-Chloroboronic ester 8 was oxidized by H2O2/
NaOH to provide chloroacetal intermediate 9,37 which was
readily converted to aldehyde 10 in 70% overall yield from
2a. Formally, the transformation of the boronate moiety in
2a to a formyl group was successfully accomplished via the
reaction sequence.
In conclusion, we have disclosed the first synthesis of
boron-substituted gem-difluorocyclopropanes 2 in a stereo-
specific fashion. To demonstrate the synthetic utility of boryl
functionalities in 2, homologation with lithium carbenoids
and the subsequent oxidation afforded a variety of gem-
difluorocyclopropanes. Further studies such as asymmetric
synthesis of boryl difluorocyclopropanes 2 are underway to
explore the useful applications.
Scheme 4
Acknowledgment. This work is dedicated to the late
Professor Yoshihiko Ito. The financial support of the Ministry
of Education, Culture, Sports, Science and Technology of
Japan (Grant-in-Aid for Scientific Research (B), No. 18350054
and Grant-in-Aid for Scientific Research on Priority Areas
“Chemistry of Concerto Catalysis”, No. 19028046) is grate-
fully acknowledged. We thank Prof. Masahiko Hayashi
(Kobe University) for his useful suggestions.
borate functionality35 was constructed by the use of R-chlo-
roallyllithium.36 Addition of R-chloroallyllithium to a THF
solution of 2a at -78 °C gave the homologated R-vinylbo-
Supporting Information Available: Details of experi-
mental procedures and characterization data (1H, 13C, and
19F NMR, IR, and mass spectrometry) for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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OL702851T
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772
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