Page 1076 - Advanced Organic Chemistry Part B - Reactions & Synthesis

1052 Some other examples of metal-catalyzed substitutions are given in Scheme 11.10.
Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation
CHAPTER 11
of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as
Aromatic Substitution ligands and Cs CO was used as the base. Entry 2 is an example of amination by
Reactions 2 3
a primary amine. The ligand used in this case was N,N-diethylsalicylamide. These
conditions proved effective for a variety of primary amines and aryl bromides with
both ERG and EWG substituents. Entry 3 is an example of more classical conditions.
The target structure is a phosphodiesterase inhibitor of a type used in treatment of
asthma. Copper powder was used as the catalyst.
The remainder of the entries in Scheme 11.10 depict palladium-catalyzed
reactions. Entries 4 to 6 are examples of aminations of aryl chlorides. In Entry 4, a
Pd(II) salt with a hindered phosphine ligand was used as the catalyst. Entry 5 uses
the Pd(0)-tri-(t-butyl)phosphine complex as the catalyst in conjunction with a phase
transfer salt. The reaction was done in a water-toluene mixture and these conditions
were applicable to chlorides with both ERG and EWG substituents. Entry 6 used the
biphenyl ligand 4 (see p. 1046). LiHMDS was a particularly good base in this case.
Entries 7 to 11 use bromides (or iodides) as reactants and t-alkoxides as bases. In cases
where the catalyst source is a Pd(II) salt, catalyst activation by reduction is necessary.
Entry 12 is a large-scale amination carried out using the imine of benzophenone as
the nucleophile, with subsequent hydrolysis to provide the amine. Entries 13 and 14
use aryl triflates as reactants. Again, the palladium sources must be reduced as part
of catalyst activation. Entry 15 is an example of arylation of an amide. The condi-
tions are similar to those for amination, and subsequent studies have shown that many
other nonbasic nitrogen compounds can be arylated (e.g. see p. 1049). Entries 16 to
19 involve alkoxide and phenoxide nucleophiles. The best ligands for these reactions
seem to be highly hindered phosphines.

11.4. Aromatic Substitution Reactions Involving Radical Intermediates

11.4.1. Aromatic Radical Substitution

Aromatic rings are moderately reactive toward addition of free radicals (see
Part A, Section 12.2) and certain synthetically useful substitution reactions involve
free radical substitution. One example is the synthesis of biaryls. 175

. .
X + X H X

There are some inherent limits to the usefulness of such reactions. Radical substi-
tutions are only moderately sensitive to substituent directing effects, so substituted
reactants usually give a mixture of products. This means that the practical utility
is limited to symmetrical reactants, such as benzene, where the position of attack

175
W. E. Bachmann and R. A. Hoffman, Org. React., 2, 224 (1944); D. H. Hey, Adv. Free Radical Chem.,
2, 47 (1966).