D
H. Jin et al.
Letter
Synlett
Table 4 Reaction of some Substituted Fluoroarenes with Cyclopropanola
Funding Information
The authors are grateful for the financial support from the Natural
Science Foundation of China (21476194) and the National Key Re-
Cs2CO3
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search and Development Program of China (2016YFB0301800).
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Entry Substrate
Cyclopropa- Time
Temp
(°C)
Yield
(%)b
nol (equiv.)
1.6
(h)
Supporting Information
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Supporting information for this article is available online at
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References and Notes
Br
(1) Chandru, H.; Sharada, A. C.; Bettadaiah, B. K. Bioorg. Med. Chem.
2007, 15, 7696.
(2) Chen, S.; Jiang, J.; Li, H. US7709518, 2010.
F
2
1.5
15
125
(3) Isozaki, H.; Takigawa, N.; Kiura, K. Cancers 2015, 7, 763.
(4) Alconcel, L. S.; Deyerl, H.; Michael Declue, A. J. Am. Chem. Soc.
2001, 123, 3125.
(5) Petinskii, A. A.; Shostakovskii, S. M.; Kositsyna, É. I. Bull. Acad.
Sci. USSR, Div. Chem. Sci. 1972, 21, 1720.
(6) Li, S.; Chiu, G.; Pulito, V. L. Med. Chem. 2009, 5, 15.
(7) Zammit, S. C.; Cox, A. J.; Gow, R. M. Bioorg. Med. Chem. Lett.
2009, 19, 7003.
(8) Castro Palomino, L. J. C.; Terricabras Belart, E.; Erra Sola, M.
US8536165, 2013.
F
Br
F
3
1.4
1.5
10
2
120
rt
36.8
62.7
OCH3
Cl
4
N
(9) Zhang, P.; Dong, J.; Zhong, B. Bioorg. Med. Chem. Lett. 2015, 25,
3738.
(10) Chiu, G.; Li, S.; Connolly, P. J. Bioorg. Med. Chem. Lett. 2007, 17,
3930.
(11) Li, J.; Wu, Y.; Guo, Z. Bioorg. Med. Chem. Lett. 2014, 24, 2648.
(12) Ajdačić, V.; Nikolić, A.; Simić, S. Synthesis 2018, 50, 119.
(13) Diemer, V.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011,
327.
F
Br
F
5
1.5
1.6
5
8
50
85
68.1
56.5
N
N
F
Br
CH3
6
F
(14) Ouellet, S. G.; Bernardi, A.; Angelaud, R. Tetrahedron Lett. 2009,
50, 3776.
(15) Chambers, R. D.; Martin, P. A.; Sandford, G. J. Fluorine Chem.
2008, 129, 998.
a Typical conditions: 1.5 equiv. of Cs2CO3 in DMF under nitrogen atmo-
sphere.
b Determined by HPLC (Hypersil ODS, 30 °C, = 254 nm, acetonitrile/H2O =
50:50) analysis.
(16) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(17) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(18) The Synthesis of 1-(Cyclopropyloxy)-2-nitrobenzene under
the Optimal Reaction Conditions – General Procedure
Into a 25 mL single-necked round-bottom flask 2-fluoronitro-
benzene (0.30 g, 2.1 mmol), DMF (4 mL), and cyclopropanol
(0.18 g, 3.2 mmol) were successively added under N2 protection.
After that, the mixture was stirred. And Cs2CO3(1.04 g, 3.2
mmol) was put into the flask at nitrogen atmosphere. Then the
resulting mixture started to be heated to 75 °C in a water bath.
The reaction was followed by TLC and HPLC. After the reaction
was complete, the resulting mixture was diluted with H2O (30
mL) and extracted with AcOEt (3 × 10 mL). Then the combined
organic phase was washed with saturated aqueous NaCl (3 × 10
mL) and dried over Na2SO4 for 0.5 h. After that, the organic
phase was concentrated under reduced pressure to give crude
product. Further, column chromatography (eluent: petroleum
ether/ethyl acetate = 10:1) on silica gel was needed to afford the
pure product as a yellow oily liquid in 92.6% yield (0.35 g).
Data for 1-(Cyclopropyloxy)-2-nitrobenzene as Typical
Example
In summary, we have developed a general and practical
method for preparing arylcyclopropyl ether derivatives via
selective SNAr reaction of various commercially available
substituted fluoroarenes with cyclopropanol; the presence
of 1.5 equiv. of Cs2CO3 and the solvent DMF as well as rela-
tively mild conditions are required. The scope and general-
izability of this method were assessed. We found that the
position, electronic character, and steric effect of the sub-
stituent on the aryl ring may influence the reactivity. The
substrates bearing strong electron-withdrawing groups on
the ortho or para positions of fluorine give excellent selec-
tivity and high yield. Meanwhile, this SNAr reaction is also
valid for selected fluoropyridine derivatives. This work may
offer an alternative and general strategy for organic and
medicinal chemistry.
1H NMR (600 MHz, CHCl3-d): = 7.83 (dd, J = 8.2, 1.6 Hz, 1 H),
7.55 (m, 1 H), 7.48 (dd, J = 8.4, 1.2 Hz, 1 H), 7.08–7.03 (m, 1 H),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E