Synthesis of 3-fluoro-2,5-disubstituted furans and further derivative reactions to access fluorine-containing 3,3′-bifurans and tetrasubstituted furans

Article abstract of DOI:10.1055/s-2008-1078053

2,5-Disubstituted 3-fluorofurans were synthesized in 42-99% yield via DBU-promoted cyclization reactions of electrondeficient gem- difluorohomopropargyl alcohols. Starting from these compounds, a series of fluorinated 3,3′-bifurans and tetrasubstituted fu

Full text of DOI:10.1055/s-2008-1078053

LETTER
2547
Synthesis of 3-Fluoro-2,5-Disubstituted Furans and Further Derivative
Reactions to Access Fluorine-Containing 3,3¢-Bifurans and Tetrasubstituted
Furans
Synthesis of
3
e
-Fluoro-2,5
n
-Disubstitute
g
d
Furans Li, Zhuo Chai, Gang Zhao,* Shi-Zheng Zhu*
Key Laboratory of Organofluorine Chemistry and Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn; E-mail: zhusz@mail.sioc.ac.cn
Received 29 May 2008
Table 1 Synthesis of 2,5-Disubstituted 3-Fluorofurans 2a
Abstract: 2,5-Disubstituted 3-fluorofurans were synthesized in
42–99% yield via DBU-promoted cyclization reactions of electron-
deficient gem-difluorohomopropargyl alcohols. Starting from these
compounds, a series of fluorinated 3,3¢-bifurans and tetrasubstituted
furans were also prepared through a fluorine-directed ortho-func-
tionalization process.
R1
OH
F
DBU
R1
R2
THF, 60 °C
O
R2
F
F
1
2
Key words: fluorinated furans, neighboring-group effects, cycliza-
tion reaction, DBU, coupling
Entry
Reactant
Product
Yield
(%)b
1
2
1a
1b
1c
1d
1e
1f
R1 = Ph; R2 = Ph
2a
2b
2c
2d
2e
2f
80
93
88
99
92
89
87
78
97
62
63
75
45
86
42
R1 = Ph; R2 = p-ClC6H4
R1 = Ph; R2 = p-BrC6H4
R1 = Ph; R2 = m-BrC6H4
R1 = Ph; R2 = o-BrC6H4
R1 = Ph; R2 = p-FC6H4
R1 = Ph; R2 = m-FC6H4
R1 = Ph; R2 = o-FC6H4
R1 = Ph; R2 = 2-furyl
Furan and polysubstituted furans are not only important
structural units present in many natural products and phar-
maceuticals,1 but also versatile building blocks in organic
synthesis.2 Thus, the synthesis of this type of compounds
has triggered much interest among organic chemists.3–6
Although organofluorine compounds usually exhibit
unique properties in a wide range of applications, which
justifies the steadily growing number of new organofluo-
rine products appearing every year,7 the methods avail-
able for the synthesis of fluorine-containing furans are
rather limited compared to those for nonfluorinated
furans, especially in the case of fluorinated polysubstitut-
ed furans.8–10 On the other hand, due to the high
electronegativity of the fluorine atom, the introduction of
fluorine into an aromatic ring could often render the
neighboring C–H bond susceptible to nucleophilic at-
tacks, which may allow the transformation of some easily
accessible simple fluorinated compounds into complex
fluorinated structures. In this field, Schlosser and co-
workers have done much work in using this strategy to
synthesize polysubstituted fluorinated pyridines.11 We re-
port herein that such a strategy could also be applied to the
electron-rich furan system to synthesize a variety of
polysubstituted fluorinated furans with 2,5-disubstituted
3-fluorinated furans as the basic building block.
3
4
5
6
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
13
14
15
1j
R1 = Ph; R2 = 2,4-Cl2C6H3 2j
R1 = Ph; R2 = 4-BnOC6H4 2k
1k
1l
R1 = Ph; R2 = p-MeC6H4
R1 = Ph; R2 = p-MeOC6H4 2m
2l
1m
1n
1o
R1 = Ph; R2 = Et
2n
2o
R1 = n-pentyl; R2 = Ph
a Reactions were run on a 1.0-mmol scale with DBU (3 equiv).
b Yield of the isolated product after column chromatography.
ther the substrate generality or the chemical yield of the
desired product still requires further investigation for
practical uses.
Our research commenced with the preparation of 2,5-di-
substituted 3-fluorofurans through the base-promoted nu-
cleophilic cyclization of the electron-deficient gem-
difluorohomopropargyl alcohols 1.9 Although such a
transformation has been realized by a stoichiometric
amount of t-BuOK9 or a catalytic amount of AgNO3,7 ei-
After screening of several different bases including Et3N,
NaH, NaOH, K2CO3, and KF–Al2O3 with compound 1a as
the probe substrate, DBU was found to be the best pro-
moter for this transformation, giving the desired cycliza-
tion product 2a in 80% yield (Table 1, entry 1). The scope
of this reaction system was next examined with a variety
of gem-difluorohomopropargyl alcohols 1 (Table 1). In
general, when the substituent R1 was an aromatic (phenyl)
SYNLETT 2008, No. 16, pp 2547–2551
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078053; Art ID: W08508ST
© Georg Thieme Verlag Stuttgart · New York

2548
P. Li et al.
LETTER
Table 2 Synthesis of 3,3¢-Bifurans 3a
group, good to excellent yields of 2 were obtained for both
(R2) aromatic and aliphatic substituents, albeit with signif-
icantly lower yields observed when there was an electron-
donating substituent on the phenyl ring of R2 (Table 1, en-
tries 11–13); changing the position of substituents on the
phenyl ring of R2 did not seem to have a considerable in-
fluence on the product yields (Table 1, entries 3–8).12
However, when R1 was an aliphatic substituent such as n-
pentyl, the yield of the desired product (2o) decreased dra-
matically (Table 1, entry 15).
R2
F
O
R1
F
F
a) n-BuLi
R1
R1
O
b) CuBr, O2
–78 °C to r.t
R2
O
R2
3
2
Entry
Reactant
Product
Yield
(%)b
Having successfully developed an easy protocol for the
synthesis of 2,5-disubstituted 3-fluorofurans 2, we then
embarked on the study of utilizing these easily available
compounds for the preparation of the interesting fluorinat-
ed furans of more complex structures. Normally, it is dif-
ficult for the hydrogen atom at the 3- or 4-position of furan
to undergo deprotonation when treated with n-butyllithi-
um. In this case, we found that the neighboring fluorine
atom clearly facilitated such a process and the resulting
organolithium intermediate could be very useful for fur-
ther derivative transformations. After several experimen-
tal trials, we were pleased to find that a series of fluorous
3,3¢-bifurans could be obtained in acceptable yields by
simply treating 2 with n-butyllithium followed by the me-
diation of CuBr in the presence of molecular oxygen
(Table 2).13 It was found that neither the electronic nature
nor the position of the substituents on the phenyl ring of
R2 had an effect on the reaction yields. Moreover, when an
alkyl substituent was present at the 2- or 5-position of the
furan ring, the reaction still proceeded smoothly to furnish
the desired products (Table 2, entries 7 and 8). In view of
the few methods available for the synthesis of 3,3¢-bi-
furans,14 the present procedure provides a facile way for
the preparation of this type of compounds.15
1
2
3
4
5
6
7
8
2a
2b
2f
R1 = Ph; R2 = Ph
3a
3b
3f
60
41
40
40
47
35
32
35
R1 = Ph; R2 = p-ClC6H4
R1 = Ph; R2 = p-FC6H4
R1 = Ph; R2 = m-FC6H4
R1 = Ph; R2 = o-FC6H4
R1 = Ph; R2 = p-MeOC6H4
R1 = Ph; R2 = Et
2g
2h
2m
2n
2o
3g
3h
3m
3n
3o
R1 = n-pentyl; R2 = Ph
a Reactions were run on a 0.5 mmol scale.
b Yield of the isolated product after column chromatography.
proceeded smoothly to give the corresponding products
4a–h in moderate to excellent yields.16 It is worthy of
mention that some compounds such as 4c and 4f may
serve as valuable building blocks for combinatorial chem-
istry and other derivative reactions.17
In conclusion, we have successfully developed a DBU-
promoted cyclization reaction of electron-deficient gem-
difluorohomopropargyl alcohols to form synthetically
useful 3-fluoro 2,5-disubstituted furans and have demon-
strated the utility of this type of compounds by their facile
conversions into 3,3¢-bifurans and fluorinated tetrasubsti-
tuted furans.
Subsequently, we also examined the reactions of the orga-
nolithium intermediate 2 with several different electro-
philic reagents such as PhCHO, PhCOCl, DMF, NFSI,
CO2 and NBS to provide a series of fluorinated tetrasub-
stituted furans (Table 3). Satisfyingly, all the reactions
Table 3 Synthesis of Tetrasubstituted Fluorinated Furans 4a
R2
O
R2
a) n-BuLi
O
R1
R1
b) E+
F
F
E
–78 °C to r.t
2
4
Entry
1
E+
Product (4a–h)
Yield (%)b
71
CHO
O
F
HO
4a
Synlett 2008, No. 16, 2547–2551 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Fluoro-2,5-Disubstituted Furans
2549
Table 3 Synthesis of Tetrasubstituted Fluorinated Furans 4a (continued)
R2
O
R2
a) n-BuLi
O
R1
R1
b) E+
F
F
E
–78 °C to r.t
2
4
Entry
2
E+
Product (4a–h)
Yield (%)b
85
O
Cl
O
F
O
4b
3
DMF
80
O
F
O
H
4c
4
5
NFSIc
59
95
O
F
F
4d
CO2
O
F
HOOC
4e
6
7
NBS
75d
99
O
F
Br
4f
CHO
O
F
HO
4g
8
62
CHO
O
F
HO
4h
a Reactions were run on a 0.5 mmol scale.
b Yield of the isolated product after column chromatography.
c NFSI: N-fluorobenzenesulfonimide.
d Yield determined by 19F NMR analysis.
Synlett 2008, No. 16, 2547–2551 © Thieme Stuttgart · New York

2550
P. Li et al.
LETTER
The organic layer was washed with brine and dried over
anhyd Na2SO4. After evaporation of the solvent under
reduced pressure, the crude product was purified by column
chromatography on silica gel to afford 2c as a white solid
(279 mg, 88%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
2c: mp 95–96 °C. IR: 1631, 1598, 1490, 1430, 1397, 1075,
922, 691 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.67–7.75
(m, 4 H), 7.10–7.44 (m, 5 H), 6.66 (s, 1 H). 13C NMR (100
MHz, CDCl3): d = 150.7 (d, 1JCF = 256.0 Hz), 150.5 (d,
3JCF = 8.2 Hz), 134.9 (d, 2JCF = 20.1 Hz), 131.8, 130.0, 128.7,
128.2, 127.7 (d, 3JCF = 5.2 Hz), 124.8 (d, 4JCF = 5.2 Hz),
123.7, 120.6, 99.2 (d, 2JCF = 20.1 Hz). 19F NMR (282 MHz,
CDCl3, CFCl3 as the external standard): d = –160.4 (s).
LRMS: m/z (%) = 316 (100) [M+], 318 (98.47) [M+ + 2], 319
(17.59), 209 (21.35), 207 (14.17), 189 (14.46), 159 (14.64),
133 (27.90). Anal. Calcd for C16H10BrFO (315.99): C, 60.59;
H, 3.18. Found: C, 60.40; H, 3.37.
Generous financial support from the National Natural Science
Foundation of China, the QT Program and the Shanghai Natural
Science Council is gratefully acknowledged.
References and Notes
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Kodansha: Tokyo, 1974. (e) Sargent, M.; Dean, F. M. In
Comprehensive Heterocyclic Chemistry, Vol. 3; Bird, C. W.;
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599–656. (f) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(2) (a) Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58,
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T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54,
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L. Z.; Chen, C. W.; Lee, C. F.; Wu, C. C.; Luh, T. Y. Chem.
Commun. 2002, 2336. (d) Dudnik, A. S.; Georgyan, V.
Angew. Chem. Int. Ed. 2007, 46, 5195.
(4) Ram, R. N.; Kumar, N. Tetrahedron Lett. 2008, 49, 799.
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W.-M.; Liang, Y.-M. J. Org. Chem. 2005, 70, 6980.
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(13) For reviews on the synthesis of biaryl compounds, see:
(a) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser,
M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005,
44, 5384. (b) Hassan, J.; Sévignon, M.; Gossi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. For examples
of the use of the copper(I) salt–O2 combination in this field,
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Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500. (d) Lin,
G.-Q.; Zhong, M. Tetrahedron: Asymmetry 1997, 8, 1369.
(e) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1962. (f) Lipshutz, B. H.; Siegmann, K.;
Garcia, E.; Kayser, F. J. Am. Chem. Soc. 1993, 115, 9276.
(14) (a) Jeevanandam, A.; Narkunan, K.; Ling, Y.-C. J. Org.
Chem. 2001, 66, 6014. (b) Hou, X.-L.; Cheung, H. Y.; Hon,
T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955. (c) Luo, F. T.; Bajji, A. C.;
Jeevanandam, A. J. Org. Chem. 1999, 64, 1738.
(15) Typical Procedure for the Synthesis of 3b from 2b: Under
an atmosphere of argon, n-butyllithium (0.63 mL, 1.0 mmol)
was added dropwise to a stirred solution of 2b (136 mg, 0.5
mmol) in THF (3 mL) at –78 °C. Then the reaction mixture
was stirred for 40 min at this temperature before CuBr (81
mg, 0.60 mmol) was added and stirred for another 40 min.
Then the system was equipped with an oxygen balloon and
was allowed to warm to r.t. (the reaction solution slowly
turned black during this process). After 8 h, 1.0 N HCl (2
mL) was added to quench the reaction and the aqueous layer
was extracted with CH2Cl2 and dried over Na2SO4. The
crude product was purified by column chromatography on
silica gel to afford 3b as a white solid (64 mg, 47%).
3b: mp 177–178 °C. IR: 3143, 1636, 1492, 1400, 919, 824,
687 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.60–7.70 (m, 8
H), 7.42–7.45 (m, 4 H), 7.26–7.36 (m, 6 H). 13C NMR (100
MHz, CDCl3): d = 148.8 (d, 1JCF = 257.0 Hz), 147.7 (d,
3JCF = 9.0 Hz), 135.2 (d, 2JCF = 18.6 Hz), 133.1, 129.9, 129.1,
128.8, 128.7, 127.0, 126.9, 124.9, 103.2 (d, 2JCF = 15.6 Hz).
19F NMR (282 MHz, CDCl3, CFCl3 as the external
(9) (a) Xu, W.; Chen, Q.-Y. Org. Biomol. Chem. 2003, 1, 1151.
(b) Lee, K.; Zhou, W.; Kelley, L.-L. C.; Momany, C.; Chu,
C. K. Tetrahedron: Asymmetry 2002, 13, 1589. (c) Moon,
H. R.; Kim, H. O.; Jeong, L. S. J. Chem. Soc., Perkin Trans.
1 2002, 1800. (d) Qing, F.-L.; Gao, W.-Z.; Ying, J. J. Org.
Chem. 2000, 65, 2003. (e) Forrest, A. K.; Ohanlon, P. J.
Tetrahedron Lett. 1995, 36, 2117; and references cited
therein.
(10) Sham, H.-L.; Betebenner, D.-A. J. Chem. Soc., Chem.
Commun. 1991, 73, 1134.
standard): d = –160.8 (s). LRMS: m/z (%) = 542 (100) [M+],
543 (42.97), 544 (72.01), 545 (25.67), 546 (14.78), 383
(15.56), 338 (6.20), 320 (12.79). HRMS: m/z calcd for
C32H18Cl2F2O2: 542.0652; found: 542.0661.
(11) For a recent review, see: (a) Schlosser, M.; Mongin, F.
Chem. Soc. Rev. 2007, 36, 1161. For recent examples, see:
(b) Heiss, C.; Marzi, E.; Mongin, F.; Schlosser, M. Eur. J.
Org. Chem. 2007, 669. (c) Bobbio, C.; Schlosser, M. J. Org.
Chem. 2005, 70, 3039. (d) Schirok, H.; Figueroa-Pérez, S.;
Thutewohl, M.; Paulsen, H.; Kroh, W.; Klewer, D. Synlett
2007, 251.
(12) Typical Procedure for the Synthesis of 2c from 1c: To a
solution of 1c (337 mg, 1 mmol) in anhyd THF (3 mL) was
added DBU (3 equiv, 0.45 mL), and the mixture was stirred
at 60 °C for 8 h. Then the reaction was quenched with H2O
(2 mL), and the aqueous layer was extracted with EtOAc.
(16) Typical Procedure for the Synthesis of 4a from 2a: Under
an atmosphere of argon, n-butyllithium (0.38 mL, 0.6 mmol)
was added dropwise to a stirred solution of 2a (119 mg, 0.5
mmol) in THF (3 mL) at –78 °C. Then the reaction mixture
was stirred for 40 min at this temperature before benzal-
dehyde (64 mg, 0.6 mmol) was added and the system was
allowed to warm to r.t. After disappearance of the substrate
benzaldehyde (monitored by TLC), the reaction was
quenched with sat. NH4Cl. The aqueous layer was extracted
Synlett 2008, No. 16, 2547–2551 © Thieme Stuttgart · New York

LETTER
with EtOAc and dried over Na2SO4. The crude product was
Synthesis of 3-Fluoro-2,5-Disubstituted Furans
2551
LRMS: m/z (%) = 344 (100) [M+], 105 (48.91), 77 (41.89),
345 (27.06), 133 (11.84), 267 (11.09), 79 (9.95), 189 (7.16).
HRMS: m/z calcd for C23H17FO2: 344.1206; found:
344.1213.
purified by column chromatography on silica gel to afford 4a
as a colorless oil (122 mg, 71%).
4a: IR: 3366, 3059, 1640, 1495, 1437, 1170, 1015, 839, 693
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.54–7.76 (m, 6 H),
7.30–7.44 (m, 9 H), 6.13 (d, J = 6.0 Hz, 1 H), 2.44 (d, J = 6.0
(17) (a) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett.
2005, 7, 1769. (b) Sauers, R. R.; Van Arnum, S. D. J. Comb.
Chem. 2004, 6, 350. (c) Srinivasan, A.; Reddy, V. R. M.;
Narayanan, S. J.; Sridevi, B.; Pushpan, S. K.; Ravikumar,
M.; Chandrashekar, T. K. Angew. Chem., Int. Ed. Engl.
1997, 36, 2598.
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 148.8 (d, 1JCF
=
260.0 Hz), 147.1 (d, 3JCF = 7.0 Hz), 135.9 (d, 2JCF = 18.7 Hz),
141.5, 130.1, 128.7, 128.5, 127.8, 127.2, 126.6, 126.1,
123.6, 123.5, 116.0 (d, 2JCF = 13.4 Hz), 67.7. 19F NMR (282
MHz, CDCl3, CFCl3 as the external standard): d = –161.7 (s).
Synlett 2008, No. 16, 2547–2551 © Thieme Stuttgart · New York