Cu(I) (Scheme 2, Eq. (4)). For other interesting results allowing C(Ar)–N coupling
in ligand-free conditions and not described in this chapter (see [72–78]).
It is likely that in all these “ligand-free” methods, the solvent and/or the base acts
as ligands of copper, though with less efficiency than the chelating ligands
presented earlier. Our experience showed that with our ligand-free conditions
(5–10% copper loading at 82
C, aromatic bromides) good performance is not
always reproducible for reactions conducted on an industrial scale. This problem
could be only partially solved by using higher copper loading (20% [Cu]) and/or
higher temperatures. However reactions conducted on an industrial scale are
questionable with regard to residual toxicity under such conditions. This highlights
the fact that ligands do not only allow or accelerate the reactions but also improve
their reproducibility and make them inherently safer in terms of operating
conditions and residual toxicity.
For interesting results allowing C(Ar)–N(azoles) and/or C(Ar)–N(cyclic amides)
formations and not described in Sect. 1, see the following [56, 79–133].
2.2 Coupling Reactions of Aryl Halides with Alkyl
and Aryl Amines and with Noncyclic Amides
The renaissance of the catalytic Ullmann coupling has also led to numerous new
methods allowing the condensation of aryl iodides and bromides, with aliphatic
amines, anilines, hydrazines, amino alcohols, noncyclic amides, and other
substrates (Scheme 3).
After the first works on the copper-catalyzed arylation of alkyl amines in the
presence of ethylene glycol (2 equiv.) L15 [134] or diethylsalicylamide (5–20 mol%)
L16 [135] as ligands, Buchwald reported in 2006 a room-temperature procedure for
this type of reaction (Scheme 4). The condensation of primary or secondary alkyl
amines [136, 137], and amino alcohols (selective N- versus O-arylation) with aryl
iodides was performed at 25
C, thanks to the help of cheap 1,3-diketone ligands L17
associated with CuI (5%). Harsher conditions (90
C) had to be applied from aryl
bromides (Scheme 4).
Twieg et al. published in 2003 one of the first examples of a copper catalytic
system that was able to promote the coupling of aryl iodides or bromides with alkyl
amines. The N,N-dimethylaminoethanol L18 associated with CuI as precatalyst
(10 mol%) was used at mild temperature conditions (60–90
C) both as solvent and
ligand (Scheme 5) [138].
In 2007, Fu reported room-temperature systems based either on N-phenyl
hydrazone (L19) or on rac-BINOL (L20) (Scheme 6) [139, 140]. These ligands,
combined with CuI or CuBr (10 mol%), revealed good reactivity for the N-arylation
from aryl iodides of aliphatic amines and/or amino acids.
Some years ago Ma showed that amino acid L-proline L6 and glycine derivatives
L7 were very efficient ligands of copper for the coupling of alkyl amines and aniline
Copper-Catalyzed C(aryl)–N Bond Formation
179
in ligand-free conditions and not described in this chapter (see [72–78]).
It is likely that in all these “ligand-free” methods, the solvent and/or the base acts
as ligands of copper, though with less efficiency than the chelating ligands
presented earlier. Our experience showed that with our ligand-free conditions
(5–10% copper loading at 82
C, aromatic bromides) good performance is not
always reproducible for reactions conducted on an industrial scale. This problem
could be only partially solved by using higher copper loading (20% [Cu]) and/or
higher temperatures. However reactions conducted on an industrial scale are
questionable with regard to residual toxicity under such conditions. This highlights
the fact that ligands do not only allow or accelerate the reactions but also improve
their reproducibility and make them inherently safer in terms of operating
conditions and residual toxicity.
For interesting results allowing C(Ar)–N(azoles) and/or C(Ar)–N(cyclic amides)
formations and not described in Sect. 1, see the following [56, 79–133].
2.2 Coupling Reactions of Aryl Halides with Alkyl
and Aryl Amines and with Noncyclic Amides
The renaissance of the catalytic Ullmann coupling has also led to numerous new
methods allowing the condensation of aryl iodides and bromides, with aliphatic
amines, anilines, hydrazines, amino alcohols, noncyclic amides, and other
substrates (Scheme 3).
After the first works on the copper-catalyzed arylation of alkyl amines in the
presence of ethylene glycol (2 equiv.) L15 [134] or diethylsalicylamide (5–20 mol%)
L16 [135] as ligands, Buchwald reported in 2006 a room-temperature procedure for
this type of reaction (Scheme 4). The condensation of primary or secondary alkyl
amines [136, 137], and amino alcohols (selective N- versus O-arylation) with aryl
iodides was performed at 25
C, thanks to the help of cheap 1,3-diketone ligands L17
associated with CuI (5%). Harsher conditions (90
C) had to be applied from aryl
bromides (Scheme 4).
Twieg et al. published in 2003 one of the first examples of a copper catalytic
system that was able to promote the coupling of aryl iodides or bromides with alkyl
amines. The N,N-dimethylaminoethanol L18 associated with CuI as precatalyst
(10 mol%) was used at mild temperature conditions (60–90
C) both as solvent and
ligand (Scheme 5) [138].
In 2007, Fu reported room-temperature systems based either on N-phenyl
hydrazone (L19) or on rac-BINOL (L20) (Scheme 6) [139, 140]. These ligands,
combined with CuI or CuBr (10 mol%), revealed good reactivity for the N-arylation
from aryl iodides of aliphatic amines and/or amino acids.
Some years ago Ma showed that amino acid L-proline L6 and glycine derivatives
L7 were very efficient ligands of copper for the coupling of alkyl amines and aniline
Copper-Catalyzed C(aryl)–N Bond Formation
179