Synthesis of 3-fluoro-2,5-disubstituted furans through ring expansion ofgem-difluorocyclopropyl ketones

Article abstract of DOI:10.1039/c9ob02713k

The synthesis of 3-fluoro-2,5-disubstituted furans fromgem-difluorocyclopropyl ketones was accomplished using trifluoromethanesulfonic acid (CF₃SO₃H) through ring expansion owing to the activation of the carbonyl group in the starting material. The present synthesis of 3-fluorofurans tolerates substrates designed for products with aromatic substituents at the C-2 and C-5 positions.

Full text of DOI:10.1039/c9ob02713k

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DOI: 10.1039/C9OB02713K
COMMUNICATION
Synthesis of 3-Fluoro-2,5-disubstituted Furans through Ring
Expansion of gem-Difluorocyclopropyl Ketones
Tsuyuka Sugiishi,a Chihori Matsumura,a Hideki Amii*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The synthesis of 3-fluoro-2,5-disubstituted furans from gem- difluorocyclopropane ring and a Brønsted acid were required to
difluorocyclopropyl ketones was accomplished using not only force gem-difluorocyclopropanes to open, but also
trifluoromethanesulfonic acid (CF3SO3H) through ring expansion enable ring expansion to produce 3-fluorofurans. 3-
owing to the activation of the carbonyl group in the starting Fluorofurans have also been generated in low yields as
material. The present synthesis of 3-fluorofurans tolerates byproducts in the acetal deprotection of the precursors of gem-
substrates designed for products with aromatic substituents at the difluorocyclopropyl ketones (Scheme 1a)8 and in the
C-2 and C-5 positions.
hydrobromination of gem-difluorocyclopropyl ketones (Scheme
1b).9 The ring opening of cyclopropyl ketones can occur through
either distal or proximal C-C bond cleavage. Cyclopropyl
ketones undergo hydrobromination through distal bond
cleavage (Scheme 1b)9 and react with nitriles through proximal
bond cleavage (Scheme 1c).10 Concerning with distal bond
cleavages, there are a few examples of furan synthesis from
geminal dichloro- or dibromo- cyclopropyl ketones.11 In the
synthesis of 3-fluorofurans that we will propose herein, the
distal bond would be cleaved (Scheme 1d). Furthermore, the
carbonyl group of a gem-difluorocyclopropyl ketone can be
utilized for the preparation of a five-membered ring framework
and the two fluorine atoms play a role in the conversion to a 3-
fluorofuran.
Many bioactive molecules contain heterocycles. Furans are a
ubiquitous type of heterocyclic compound and have been found
in pharmaceuticals, agrochemicals, and materials.1 However, a
few organofluorine compounds can be found in natural
products, and introducing fluorine atoms into organic
molecules may improve the efficiency or alter the properties of
non-fluorinated compounds in pharmaceutical, agricultural,
and materials chemistry.2 The installation of fluorine atoms on
furan rings is significant in organic synthesis; hence, several
useful
syntheses
of
3-fluorofurans
from
gem-
difluorohomopropargyl alcohols,3 2-fluoroalk-3-yn-1-ones,4 or
gem-difluorinated phosphonium5 have been reported. We
sought an alternative method for the synthesis of fluorofurans
using an original reagent as a fluorine source that would involve
neither the cyclization of acetylenes3,4 nor a radical reaction
with a photocatalyst.5 We previously reported a synthesis of
First, we prepared starting materials 2, featuring a carbonyl
group adjacent to the cyclopropane ring, through cycloaddition
of chalcone derivatives 1, which were synthesized easily from
benzaldehydes
and
acetophenones,
with
sodium
bromodifluoroacetate (BrCF2CO2Na)6 in diglyme at 180 °C for 20
min in 14–38% yields.
gem-difluorocyclopropanes
involving
sodium
bromodifluoroacetate (BrCF2CO2Na),6 and the characteristics of
gem-difluorocyclopropanes and the utilization of these
compounds as materials for promising heterocyclic compounds
containing fluorine atoms have recently attracted our attention.
However, it is known that the ring of gem-
difluorocyclopropanes are generally, rarely opened unless the
substrates are designed adequately.7 In our approach, it was
The results for the optimisation of the reaction conditions for
the synthesis of 3-fluorofuran 3a from gem-difluorocyclopropyl
ketone 2a are presented in Table 1. The effect of the solvent
was investigated using 2.0 equiv of trifluoromethanesulfonic
acid (CF3SO3H) at room temperature and a reaction time of 30
min. Desired compound 3a was obtained in 24% yield when 2,2-
found that
a carbonyl group adjacent to the gem-
difluoro-3-phenylcyclopropyl-phenylmethanone
2a
was
exposed to CF3SO3H in acetonitrile (entry 1). Although the
reaction condition was similar to that of the reported pyrrole
synthesis,10 the corresponding pyrrole product was not
obtained at all in entry 1. Toluene and dichloromethane were
suitable as solvents for this synthesis (entries 2 and 3), but
a. Division of Molecular Science, Graduate School of Science and Technology,
Gunma University, 1-5-1 Tenjin-Cho, Kiryu, Gunma, 376-8515, Japan.
† 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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dimethylformamide (DMF) and tetrahydrofuran (THF) were not groups of chalcones 1 determine the substituentsVaietwtAhreticl2e-Oanlninde
DOI: 10.1039/C9OB02713K
(entries 4 and 5). When the reaction temperature was lower 5-positions of 3-fluorofurans 3.
than room temperature, the yields of 3-fluorofuran 3a were
higher (entries 6–10), and the reaction performed at −20 °C
afforded the highest yield (entry 9). When the amount of
Conflicts of interest
CF3SO3H was reduced to 0.5 equivalents to cyclopropyl ketone
2a, a trace of 3-fluorofuran 3a was generated with only 20%
recovery of 2a suggesting that a stoichiometric amount of fresh
CF3SO3H is effective for this synthesis although CF3SO3H is
considered to be regenerated in situ (entry 11). In the presence
of H2SO4, desired compound 3a was generated in a low yield
(entry 12).12
There are no conflicts to declare.
Acknowledgements
We would like to acknowledge Grants-in-Aid for Scientific
Research, the financial support of Japan Society for the
Promotion of Science (JSPS) KAKENHI Grant Number 17K14479
Grant-in-Aid for Young Scientists B, the Association for the
Advancement of Science & Technology, Gunma University, the
financial support of JSPS KAKENHI Grant Number JP 16H04143
Grant-in-Aid for Scientific Research B, JP18H04235 in Middle
Molecular Strategy, 18H04381 in Precisely Designed Catalysts
with Customized Scaffolding, and Japan Science and Technology
Agency (JST) (ACT-C: Creation of Advanced Catalytic
Transformation for the Sustainable Manufacturing at Low
Energy, Low Environmental Load). We would like to thank
Editage (www.editage.com) for English language editing. We
would like to thank Technical Department, Tottori University for
HRMS measurement.
Next, the substrate scope of the present synthesis of 3-
fluorofurans 3 from cyclopropanes 2 was explored (Table 2).
Corresponding furans 3 were synthesized in moderate yields
when R1 on the benzene rings was a 4-methyl, 4-bromo, 4-
chloro, or 3-methoxy group (entries 2–5). Syntheses were also
successful when R2 on the benzoyl group of cyclopropyl ketones
2 was a 4-methyl, 4-bromo, 4-methoxy, or 3-methoxy group,
affording disubstituted fluorofurans 3 in moderate to high
yields (entries 6–9). Fluorofurans 3 with substituted aromatic
groups at both C-2 and C-5, such as those with R1 = 4-bromo and
R2 = 4-methyl (entry 10)13 or R1 = 4-bromo and R2 = 4-methoxy
(entry 11), were synthesized well using this method. When R1 =
4-methyl and R2 = 4-bromo (entry 12), that is, when the
substituents at C-2 and C-5 on synthesized 3-fluorofuran 3 were
reversed with respect to entry 10, the yield was not significantly
different. The screening of substrates for 2,5-disubstituted 3-
fluorofurans 3 revealed that we had complete control of the
aromatic functional groups at the C-2 and C-5 positions, as can
be seen from entries 2 and 6, 3 and 7, 5 and 9, and 10 and 12.
Scheme 3 shows a plausible mechanism for the above synthesis
of fluorofurans 3. CF3SO3H, which is a strong acid, would
coordinate with the oxygen atom of the carbonyl group in
cyclopropane 2 and then undergo a ring opening reaction to
generate benzylic carbocation intermediate 4. Subsequent
attack of the oxygen atom of the enol on the carbocation would
lead to the intramolecular cyclization of intermediate 4. Finally,
deprotonation and aromatization occur to furnish fluorofuran
3. In the case that the substrate was (2,2-difluoro-3-
heptylcyclopropyl)(phenyl)methanone, which has a normal
alkyl group instead of Ar1, the corresponding furan was not
observed but unaromatized 3,3-difluoro-2,3-dihydrofuran. The
result indicates that the aromatic substituents Ar1 accelerate
the aromatization in the end of the reaction mechanism.14
Conclusions
In summary, we have realized the regiospecific synthesis of 2,5-
disubstituted 3-fluorofurans 3 from gem-difluorocyclopropane
derivatives 2. CF3SO3H is necessary for the low-temperature
ring expansion of gem-difluorocyclopropane derivatives 2
containing a carbonyl group, affording 3-fluorofurans 3 in good
yields. The regioselectivity in the present synthesis of 3-
fluorofurans 3 is guaranteed when the starting material for the
cyclopropanation step is synthesized. Ultimately, the functional
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB02713K
Generation of 3-fluorofurans from gem-difluorocyclopropyl ketone derivatives (ref. 8,9)
F
F
F
F
F
(CO2H)2
Ph
+
(a)
Ph
4-CH3C6H4
4-CH3C6H4
110 oC, 6 h
4-CH3C6H4
Ph
O
O
O
O
36%
F
15%
distal bond cleavage
F
F
O
F
F
PentylPyr+Br-/CF3CO2H
Br
+
(b)
Ph
Ph
70 oC, 10 h
Ph
Ph
Ph
O
Ph
O
distal bond cleavage
76%
7%
Cleavage of gem-difluorocyclopropyl ketones at the proximal position (ref. 10)
F
F
CF3SO3H
CN
F
R
Ar
Ar
(c)
R
rt, 30 min
N
H
O
O
proximal bond cleavage
45-79%
Synthesis of 3-fluorofurans from gem-difluorocyclopropyl ketones (this work)
F
F
F
F
F
CF3SO3H
distal bond cleavage
-
+
Ar2
+
Ar1
Ar2
H
(d)
Ar1
Ar1
Ar2
- 20 oC, 30 min
O
O
O
59-80%
Scheme 1 Reactivities of gem-Difluorocyclopropane
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J. Name., 2013, 00, 1-3 | 3
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aReaction conditions: the reactions were carried out with gem-difluorocyclopropyl
View Article Online
R2
F
F
ketone 2 (0.1 mmol) and CF3SO3H (0.2 mmol) in CH2Cl2 (1.0 mL) at −20 °C for 30
DOI: 10.1039/C9OB02713K
O
BrCF2CO2Na
(4.0 equiv)
R1
min. bIsolated yields.
R1
diglyme, 180 °C
20 min
F
F
F
O
R2
CF3SO3H
Ar2
1
2, 14-38%
Ar1
Ar1
Ar2
O
Scheme 2 Preparation of Starting Materials 2 from Chalcones 1
O
2
3
Table 1 Optimization of Reaction Conditionsa
-HF
H
F
F
F
CF3SO3H
(2.0 equiv)
F
F
F
4
F
F
solvent, temp.
30 min
O
Ar2
OH
F
O
Ar2
Ar1
2a
3a
Ar1
Ar1
Ar2
-H
O
entry solvent
temp. yield of 3a
recovery of 2a
(%)
0
0
0
95b
0
0
0
0
0
0
20
77
H
O
H
(°C)
rt
rt
rt
rt
rt
10
0
−10
−20
−40
−20
−20
(%)
24b
44b
45b
4b
5b
52
68
74
80
75
Scheme 3. Plausible Reaction Mechanism
1
2
3
4
5
6
7
8
CH3CN
toluene
CH2Cl2
DMF
Notes and references
1
For selected reports on bioactive furans, see: (a) C. E.
Stephens, F. Tanious, S. Kim, W. D. Wilson, W. A. Schell, J. R.
Perfect, S. G. Franzblau, D. W. Boykin, J. Med. Chem. 2001, 44,
1741. (b) T. Wenzler, D. W. Boykin, M. A. Ismail, J. E. Hall, R. R.
Tidwell, R. Brun, Antimicrob. Agents Chemo. 2009, 53, 4185.
For selected reports on oligofurans, see: (c) X. Jin, D.; Shimon,
L. J. W. Sheberla, M. Bendikov, J. Am. Chem. Soc. 2014, 136,
2592. (d) O. Gidron, M. Bendikov, Angew. Chem. Int. Ed.
2014, 53, 2546. For reviews on furans, see: (e) A. V. Gulevich,
A. S. Dudnik, N. Chernyak, V. Gevorgyan, Chem. Rev. 2013,
113, 3084. (f) J. J. Li, Heterocyclic Chemistry in Drug Discovery,
Wiley, Hoboken, 2013, p119.
For reviews on organofluorine chemistry, see: (a) T. Hiyama,
K. Kanie, T. Kusumoto, Y. Morizawa, M. Shimizu,
Organofluorine Compounds: Chemistry and Application,
Springer-Verlag, Berlin, 2000. (b) R. D. Chambers, Fluorine in
Organic Chemistry, Blackwell, Oxford, 2004. (c) P. Kirsch,
Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH, Weinheim, 2013. (d) T. Sugiishi, M.
Matsugi, H. Hamamoto, H. Amii, RSC Adv. 2015, 5, 17269.
(a) H. L. Sham, D. A. Betebenner, J. Chem. Soc. Chem.
Commun. 1991, 1134. (b) S. Arimitsu, G. Hammond, J. Org.
Chem. 2007, 72, 8559. (c) P. Li, Z. Chai, G. Zhao, S.-Z. Zhu,
Synlett 2008, 2547. (d) S. Arimitsu, J. M. Jacobsen, G.
Hammond, J. Org. Chem. 2008, 73, 2886.
Y. Li, K. A. Wheeler, R. Dembinski, Org. Biomol. Chem. 2012,
10, 2395.
L. I. Panferova, A. V. Tsymbal, V. V. Levin, M. I. Struchkova, A.
D. Dilman, Org. Lett. 2016, 18, 996.
(a) K. Oshiro, Y. Morimoto, H. Amii, Synthesis 2010, 2080. (b)
For difluorocarbene sources and reported applications: C. Ni,
J. Hu, Synthesis 2014, 46, 842.
For ring opening reactions of gem-difluorocyclopropyl
compounds, see: (a) Y. Kobayashi, T. Taguchi, T. Morikawa, T.
Takase, H. Takanashi, Tetrahedron Lett. 1980, 21, 1047. (b) X.
Hang, Q. Chen, J. Xiao, J. Org. Chem. 2008, 73, 8598. (c) W. Xu,
I. Ghiviriga, Q. Chen, W. R. Dolbier, J. Fluorine Chem. 2010,
131, 958. (d) W. R. Jr. Dolbier, E. Cornett, H. Martinez, W. Xu,
J. Org. Chem. 2011, 76, 3450. (e) D. Orr, J. M. Percy, T. Tuttle,
A. R. Kennedy, Z. A. Harrison, Chem. Eur. J. 2014, 20, 14305.
(f) Y. Kageshima, C. Suzuki, K. Oshiro, H. Amii, Synlett 2015, 26,
63, and other references therein. (g) H. Takenaka, Y.
Masuhara, K. Narita, T. Nokami, T. Itoh, Org. Biomol. Chem.
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11c
12d
trace
19
aReaction conditions: the reactions were carried out with cyclopropane 2a (0.2
mmol) and CF3SO3H (0.4 mmol) in a solvent (1.0 mL) for 30 min. Isolated yields.
bDetermined by 19F NMR analysis using C6F6 as an internal standard. cCF3SO3H was
reduced to 0.5 equiv to cyclopropane 2a. dH2SO4 was used as the acid instead of
CF3SO3H.
2
3
Table 2 Screening of Substrates
F
F
R2
F
CF3SO3H
(2.0 equiv)
R1
R2
R1
CH2Cl2, -20 °C
30 min
O
O
2
3
entry
1
2
3
4
5
6
7
8
R1
H
R2
H
H
H
H
H
4-Me
4-Br
4-MeO
3-MeO
4-Me
4-MeO
4-Br
yield of 3 (%)b
4
5
6
80
64
73
71
59
76
80
74
65
75
77
70
4-Me
4-Br
4-Cl
3-MeO
H
7
H
H
H
9
10
11
12
4-Br
4-Br
4-Me
4 | J. Name., 2012, 00, 1-3
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2018, 16, 6106. (h) E.-A. M. A. Ahmed, A. M. Suliman, T.-J.
Gong, Y. Fu, Org. Lett. 2019, 21, 5645. (i) For a recently
published digest on transformations based on the ring
opening of gem-difluorocyclopropyl compounds: X. Song, C.
Xu, M. Wang, Tetrahedron Lett. 2017, 58, 1806.
W. Xu, Q.-Y. Chen, Org. Biomol. Chem. 2003, 1, 1151.
W. Xu, W. R. Dolbier, J. Salazar, J. Org. Chem. 2008, 73, 3535.
View Article Online
DOI: 10.1039/C9OB02713K
8
9
10 T.-P. Yang, J.-H. Lin, Q.-Y. Chen, J.-C. Xiao, Chem. Commun.
2013, 49, 9833.
11 (a) Y. Tanabe, K. Wakimura, Y. Nishii, Y. Muroya, Synthesis,
1996, 388. (b) E. Gopi, I. N. N. Namboothiri, J. Org. Chem. 2013,
78, 910.
12 Other acids, such as CH3CO2H, (CO2H)2, p-TsOH, CF3CO2H, and
aqueous HCl, were screened, but did not work at all in the
reaction, and starting material 2a was recovered. The yield of
desired compound 3a was lower when H2SO4 was used at a
temperature higher than the highest one applied for CF3SO3H
(see Supporting Information).
13 The compound data are consistent with those from a previous
synthesis. Y. Li, K. A. Wheeler, R. Dembinski, Adv. Synth. Catal.
2010, 352, 2761.
14 See Scheme S1 in Supporting Information.
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Organic & Biomolecular ChemisPtrayge 6 of 6
The synthesis of 3-fluoro-2,5-disubstituted furans from
gem-difluorocyclopropyl ketones was accomplished
using trifluoromethanesulfonic acid in good yields at
low temperature.
F
F
R2
F
R1
R2
R1
CF3SO3H
O
distal cleavage
O
59-80% yield