Table 3 Regioselective fluorination of ethers 17 with l3-iodane 3a
Entry
17 (R1, R2, R3, R4)
18 Yieldb (%)
1
2
3
4
5
6
7
17a (H, H, H, Et)
17b (H, H, H, Prn)
63 (44)
52 (45)
0c
56 (51)
79 (63)
63 (65)
74 (67)
17c (H, H, H, But)
17d (H, H, Me, Me)
17e (Me, Me, H, Me)
17f (H, CH2OMe, H, Me)
17g (Me, CH2OMe, H, Me)
Scheme 5 Reaction of benzyl, phenethyl and phenylbutyl ethers 12.
Reaction conditions: iodane 3 (3 equiv.)/BF3–Et2O (3 equiv.)/H2O
(0.5 equiv.)/CH2Cl2/45 1C/6 h/N2.
a
Reaction conditions: iodane 3 (3 equiv.)/BF3–Et2O (3 equiv.)/H2O
(0.5 equiv.)/CH2Cl2/45 1C/6 h/N2. b 1H NMR yields. In parentheses
regioselective formation of these substitution products 7 and 10.
Phenol 10 will be further oxidized to p-benzoquinone under these
conditions.19 In fact, analogous 4-propylphenol was readily
oxidized to p-benzoquinone (24%) with complex 3 without using
BF3–Et2O (CD2Cl2/room temperature/10 min). Diaryl-l3-iodane
5b was found to be stable under these conditions, indicating that
the formation of 7 does not involve the intermediacy of 5b.20
Ring-expanding 1,2-shift of the carbon–carbon bond with
reductive elimination of PhI in 9, yielding dication 11, seems to
be a high energy process, which is in marked contrast to the
reaction of 3-phenylpropanol with complex 3 (Scheme 2).17
Further evidences for the neighboring etheric oxygen atom
participation can be drawn from the reaction of methyl ethers
12 (Scheme 5). Both benzyl 12a and phenethyl ethers 12b did
not show any evidences for the formation of para-fluorination
products 13, but instead produced diaryl-l3-iodanes 14 and 15
selectively. On the other hand, competition between para-
fluorination (19%) and para-phenyl-l3-iodanation (24%)
was observed in the reaction of 4-phenylbutyl methyl ether
(12c). These results as well as the facile para-fluorination of
3-phenylpropyl ether 6 seem to reflect differences in stability
between putative spirodiene intermediates 16, being produced
by the neighboring group participation. Winstein and
co-workers reported that the rates of solvolysis of
MeO(CH2)nOBs (Bs = p-BrC6H4SO2) in ethanol at 75 1C
decrease in the order [n (relative rates to BunOBs)] 4 (20.4) 4 5
(2.84) 4 3 (0.67) 4 2 (0.25), because of neighboring methoxy
group participation.21 These results are in good agreement
with our para-selective fluorination of 6 and 12c.
c
are isolated yields. Chromanyl-l3-iodane complex 4 (14%) and
3-phenylpropanol (72%) were obtained.
alkoxy substituents plays an essential role. This is the first
example of para-selective fluorination of simple alkylarenes.
Notes and references
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4 J. W. Clader, J. Med. Chem., 2004, 47, 1.
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79, 259; (c) S. D. Taylor, C. C. Kotoris and G. Hum, Tetrahedron,
1999, 55, 12431.
6 M. Zupan, in The Chemistry of Functional Groups, Supplement D,
ed. S. Patai and Z. Rappoport, Wiley, New York, 1983, ch. 15.
7 O. Lerman, Y. Tor, D. Hebel and S. Rozen, J. Org. Chem., 1984,
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8 J. Kollonitsch, L. Barash and G. A. Doldouras, J. Am. Chem. Soc.,
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9 S. Stavber and M. Zupan, J. Org. Chem., 1985, 50, 3609.
10 G. S. Lal, G. P. Pez and R. G. Syvret, Chem. Rev., 1996, 96,
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11 V. Grakauskas, J. Org. Chem., 1970, 35, 723.
12 R. E. Banks, J. Fluorine Chem., 1998, 87, 1.
13 (a) T. Umemoto and G. Tomizawa, J. Org. Chem., 1995, 60, 6563;
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14 V. Snieckus, F. Beaulieu, K. Mohri, W. Han, C. K. Murphy and
F. A. Davis, Tetrahedron Lett., 1994, 35, 3465.
15 M. Ochiai, K. Miyamoto, M. Shiro, T. Ozawa and K. Yamaguchi,
J. Am. Chem. Soc., 2003, 125, 13006.
16 M. Ochiai, T. Suefuji, K. Miyamoto, N. Tada, S. Goto, M. Shiro,
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17 K. Miyamoto, M. Hirobe, M. Saito, M. Shiro and M. Ochiai, Org.
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18 M. Ochiai, in Chemistry of Hypervalent Compounds, ed. K.-y.
Akiba, Wiley-VCH, New York, 1999, p. 359.
19 For oxidation of para-substituted phenols to p-quinols with
aryl-l3-iodanes, see: A. McKillop, L. McLaren and R. J.
K. Taylor, J. Chem. Soc., Perkin Trans. 1, 1994, 2047.
20 (a) B. Wang, L. Qin, K. D. Neumann, S. Uppaluri, R. L. Cerny and
S. G. DiMagno, Org. Lett., 2010, 12, 3352; (b) S. Martin-Santamaria,
M. A. Carroll, C. M. Carroll, C. D. Carter, V. W. Pike, H. S. Rzepa
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21 S. Winstein, E. Allred, R. Heck and R. Glick, Tetrahedron, 1958, 3, 1.
We are pleased to find that the neighboring group participation
provides an excellent method for the regioselective para-
fluorination of a variety of 3-phenylpropyl ethers 17 (Table 3).
The para-selective fluorination of 17 appears to be relatively
sensitive to the nature of substituents on the carbon atoms
attached to the etheric oxygen atom: for instance, introduction
of methyl groups (17a and 17d) and an ethyl group (17b) resulted
in slightly decreased yields of fluorination products. Sterically
hindered tert-butyl ether 17c did not undergo fluorination and
afforded a mixture of chromanyl-l3-iodane complex 4 (14%) and
3-phenylpropanol (72%), probably via acid-catalyzed deprotection
of the tert-butyl group (Table 3, entry 3). b,b-Dimethyl ether
17e and bis(methoxymethyl)ethylbenzenes 17f and 17g
selectively produced good yields of p-fluorobenzenes 18e–g.
Thus, we have developed a hypervalent phenyl-l3-iodane-
mediated para-selective aromatic fluorination of 3-phenyl-
propyl ethers, in which neighboring group participation of
c
3412 Chem. Commun., 2011, 47, 3410–3412
This journal is The Royal Society of Chemistry 2011