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ChemComm
Page 3 of 5
DOI: 10.1039/C8CC04643C
Journal Name
COMMUNICATION
Entry
1
1
R1
R2, R3
R4
H
H
H
H
H
H
H
H
H
H
H
Ph
4 (yield %)a
Customized Scaffolding and JSPS KAKENHI Grant Number
JP18K05116 (T.F.) in Grant-in-Aid for Scientific Research (C).
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Me, Me
Et, Et
4a (85)
4b (86)
4c (74)
4d (93)
4e (69)
4f (60)
4g (52)
4h (70, 50b)
4i (77)
2
Ph
3
Ph
Me, Ph
Notes and references
4
Ph
Me, 4-MeOC6H4
Me, 4-ClC6H4
CF3, Ph
5
Ph
1
Fluorine in Heterocyclic Chemistry vol. 1 and 2, ed. V.
Nenajdenko, Springer, Heidelberg, 2014.
6
Ph
2
M. J. Sofia, D. Bao, W. Chang, J. Du, D. Nagarathnam, S.
Rachakonda, P. G. Reddy, B. S. Ross, P. Wang, H.-R. Zhang, S.
Bansal, C. Espiritu, M. Keilman, A. M. Lam, H. M. M. Steuer,
7
Ph
–(CH2)4–
–(CH2)5–
t-Bu, H
8
Ph
9
Ph
C. Niu, M. J. Otto and P. A. Furman, J. Med. Chem., 2010, 53
7202–7218.
,
10
11
12
1j
1k
1l
4-MeC6H4
4-ClC6H4
Ph
Et, Et
4j (72)
4k (71)
4l (52)
3
4
V. Gandhi and W. Plunkett, Canser Res., 1990, 50, 3675–
3680.
C.-S. Chang, M. Negishi, T. Nakano, Y. Morizawa, Y.
Matsumura and A. Ichikawa, Prostaglandins, 1997, 53, 83–
90.
Et, Et
Me, Me
a Isolated yield. b 1 mmol scale.
5
For selected reviews on electrophilic fluorination, see: (a) S.
D. Taylor, C. C. Kotoris and G. Hum, Tetrahedron, 1999, 55,
3-Fluoro-2,5-dihydrofurans
4 obtained in this protocol
were successfully transformed into 4-fluorofuran-2(5H)-ones
5
12431–12477; (b) R. P. Singh and J. M. Shreeve, Acc. Chem.
Res., 2004, 37, 31–44; (c) P. T. Nyffeler, S. G. Durón, M. D.
Burkart, S. P. Vincent and C.-H. Wong, Angew. Chem., Int.
Ed., 2005, 44, 192–212; (d) A. S. Kiselyov, Chem. Soc. Rev.,
2005, 34, 1031–1037.
For selected reviews on nucleophilic fluorination, see: (a) R.
P. Singh and J. M. Shreeve, Synthesis, 2002, 2561–2578; (b) J.
Wu, Tetrahedron Lett., 2014, 55, 4289–4294.
For recent reports on nucleophilic 5-endo-trig cyclisation,
see: (a) K. Tong, J. Tu, X. Qi, M. Wang, Y. Wang, H. Fu, C. U.
Pittman, Jr. and A. Zhou, Tetrahedron, 2013, 69, 2369–2375;
(b) D. En, G.-F. Zou, Y. Guo and W.-W. Liao, J. Org. Chem.,
2014, 79, 4456–4462; (c) C. P. Johnston, A. Kothari, T.
Sergeieva, S. I. Okovytyy, K. E. Jackson, R. S. Paton and M. D.
via the oxidation of the methylene moiety without the
elimination of the fluorine substituent (Scheme 3). Treatment
of 4b and 4h with CrO3 and 3,5-dimethylpyrazole afforded the
corresponding 4-fluorofuranones 5b and 5h in 63% and 76%
yields, respectively.17 The oxidation efficiency of fluorinated
6
7
dihydrofurans 4 was comparable to that of fluorine-free
dihydrofurans as reported in the literature.18 Since furanones
often exhibit antifungal effects, the obtained fluorofuranones
might also possess such bioactivities.19
5
Smith, Nat. Chem., 2015, 7, 171–177; (d) R. Kapoorr, S. N.
Singh, S. Tripathi and L. D. S. Yadav, Synlett, 2015, 26, 1201–
1206; (e) K. Sharma, J. R. Wolstenhulme, P. P. Painter, D.
Yeo, F. Grande-Carmona, C. P. Johnston, D. J. Tantillo and M.
D. Smith, J. Am. Chem. Soc., 2015, 137, 13414–13424; (f) B.
M. Williams and D. Trauner, Angew. Chem., Int. Ed., 2016,
55, 2191–2194; (g) A. W. Markwell-Heys and J. H. George,
Org. Biomol. Chem., 2016, 14, 5546–5549; (h) T. Xiao, L. Li
and L. Zhou, J. Org. Chem., 2016, 81, 7908–7916; (i) B. Zhang,
X. Zhang, J. Hao and C. Yang, Org. Lett., 2017, 19, 1780–1783.
(j) J. Hao, T. Milcent, P. Retailleau, V. A. Soloshonok, S.
Ongeri and B. Crousse, Eur. J. Org. Chem., 2018, 3688–3692.
For Baldwin’s rules, see: (a) J. E. Baldwin, J. Chem. Soc.,
Chem. Commun., 1976, 734–736; (b) J. E. Baldwin, J. Cutting,
W. Dupont, L. Kruse, L. Silberman and R. C. Thomas, J. Chem.
Soc., Chem. Commun., 1976, 736–738.
(a) J. Ichikawa, Y. Wada, T. Okauchi and T. Minami, Chem.
Commun., 1997, 1537–1538; (b) J. Ichikawa, M. Fujiwara, Y.
Wada, T. Okauchi and T. Minami, Chem. Commun., 2000,
1887–1888; (c) J. Ichikawa, Y. Wada, M. Fujiwara and K.
Sakoda, Synthesis, 2002, 1917–1936; (d) T. Fujita, K. Sakoda,
M. Ikeda, M. Hattori and J. Ichikawa, Synlett, 2013, 24, 57–
60; (e) T. Fujita, M. Ikeda, M. Hattori, K. Sakoda and J.
Ichikawa, Synthesis, 2014, 46, 1493–1505.
8
9
Scheme 3 Synthesis of 4-fluorofuranones
5
In summary, we demonstrated the synthesis of ring-
fluorinated furan derivatives based on single sp3 C–F bond
activation of difluorinated alkenes. 2,2-Difluorohomoallylic
alcohols underwent
a normally disfavoured 5-endo-trig
cyclisation at room temperature with the aid of potassium
hydride to afford 3-fluoro-2,5-dihydrofurans. Furthermore, the
resulting 3-fluoro-2,5-dihydrofurans underwent oxidation by
CrO3 and afforded 4-fluorofuranones. Since 3-fluorofurans
have so far been synthesised by multistep routes,15,17 our
protocol is important as a method for providing a series of 3-
fluorinated furan derivatives, which would serve as
pharmaceuticals and agrochemicals.
10 (a) J. Ichikawa, Y. Iwai, R. Nadano, T. Mori and M. Ikeda,
Chem. Asian J., 2008, , 393–406; (b) J. Ichikawa, J. Synth.
Org. Chem. Jpn., 2010, 68, 1175–1184.
3
11 For similar SN2'-type reactions, see: (a) K. Fuchibe, M.
Takahashi and J. Ichikawa, Angew. Chem., Int. Ed., 2012, 51
,
12059–12062; (b) M. Bergeron, D. Guyader and J.-F. Paquin,
Org. Lett., 2012, 14, 5888–5891; (c) J. Yang, A. Mao, W. Zhu,
X. Luo, C. Zhu, Y. Xiao and J. Zhang, Chem. Commun., 2015,
51, 8326–8329; (d) T. Fujita, K. Sugiyama, S. Sanada, T.
Ichitsuka and J. Ichikawa, Org. Lett., 2016, 18, 248–251; (e) T.
This work was financially supported by JSPS KAKENHI Grant
Number JP18H04234 (J.I.) in Precisely Designed Catalysts with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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