Page 1034 - Advanced Organic Chemistry Part B - Reactions & Synthesis

1010 of activated aromatics. Although this procedure does not avoid the special precautions
necessary for manipulation of elemental fluorine, it does provide a system with much
CHAPTER 11 greater selectivity. Acetyl hypofluorite shows a strong preference for o-fluorination of
Aromatic Substitution alkoxy and acetamido-substituted rings. N-Fluoro-bis-(trifluoromethansulfonyl)amine
Reactions
(N-fluorotriflimide) displays similar reactivity and can fluorinate benzene and activated
aromatics. 24

F
3
CH O + (CF SO ) NF CH O + CH O F
2 2
3
3
3
69% 24%
Several N-fluoro derivatives of 1,4-diazabicyclo[2.2.2]octane are useful for aromatic
fluorination. 25
Iodinations can be carried out by mixtures of iodine and various oxidants such as
periodic acid, 26 I O , 27 NO , 28 and Ce(NH (NO . 29 A mixture of cuprous iodide
3 6
3 2
2
5
2
and a cupric salt can also effect iodination. 30
CH 3 CH 3
+ CuI + CuCl 2
I
CH 3 CH 3 ~70%

Iodination of moderately reactive aromatics can be effected by mixtures of iodine and
silver or mercuric salts. 31 Hypoiodites are presumably the active iodinating species.
Bis-(pyridine)iodonium salts can iodinate benzene and activated derivatives in the
presence of strong acids such as HBF or CF SO H. 32
4 3 3
Scheme 11.2 shows some representative halogenation reactions. Entries 1 and 2
involve Lewis acid–catalyzed chlorination. Entry 3 is an acid-catalyzed chlorination
using NCS as the reagent. Entry 4 shows a high-yield chlorination of acetanilide by
t-butyl hypochlorite. This seems to be an especially facile reaction, since anisole is
not chlorinated under these conditions, and may involve the N-chloroamide as an
intermediate. Entry 5 describes a large-scale chlorination done with NCS. The product
was used for the synthesis of sulamserod, a drug candidate.

24 S. Singh, D. D. DesMarteau, S. S. Zuberi, M. Whitz, and H.-N. Huang, J. Am. Chem. Soc., 109, 7194
(1987).
25
T. Shamma, H. Buchholz, G. K. S. Prakash, and G. A. Olahn, Israel J. Chem., 39, 207 (1999); A. J. Poss
and G. A. Shia, Tetrahedron Lett., 40, 2673 (1999); T. Umemoto and M. Nagayoshi, Bull. Chem. Soc.
Jpn., 69, 2287 (1996).
26 H. Suzuki, Org. Synth., VI, 700, (1988).
27
L. C. Brazdil and C. J. Cutler, J. Org. Chem., 61, 9621 (1996).
28
Y. Noda and M. Kashima, Tetrahedron Lett., 38, 6225 (1997).
29 T. Sugiyama, Bull. Chem. Soc. Jpn., 54, 2847 (1981).
30
W. C. Baird, Jr., and J. H. Surridge, J. Org. Chem., 35, 3436 (1970).
31 Y. Kobayashi, I. Kumadaki, and T. Yoshida, J. Chem. Res. (Synopses), 215 (1977); R. N. Hazeldine
and A. G. Sharpe, J. Chem. Soc., 993 (1952); W. Minnis, Org. Synth., II, 357 (1943); D. E. Janssen
and C. V. Wilson, Org. Synth., IV, 547 (1963); N.-W. Sy and B. A. Lodge, Tetrahedron Lett., 30, 3769
(1989).
32
J. Barluenga, J. M. Gonzalez, M. A. Garcia-Martin, P. J. Campos, and G. Asensio, J. Org. Chem., 58,
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