2 Green Chemistry of Coupling Reactions
The coupling reactions were carried out mostly under homogeneous conditions
[2]. Although homogeneous reactions have tremendous benefits in terms of ready
availability of the catalyst and defined structure, the separation of the catalyst
from the reaction products poses a problem. Some copper-catalyzed homogeneous methods require stoichiometric amounts of additional base that generates
copious amounts of solid waste as a by-product. In general, few reports are
available on heterogeneous cross-coupling reactions compared to the homogeneous reactions. Some of the heterogeneous methods have also been considered
as atom economic [3].
3 Copper-Catalyzed Coupling Reactions in Organic Synthesis
Homogeneous copper-catalyzed coupling reactions have been successfully applied
in the natural product synthesis. An excellent up-to-date review on the application
of copper-catalyzed methods in medicinal chemistry was recently published by
Evano, Blanchard, and Toumi [4]. Some selected examples are listed in Fig. 1,
wherein C–N bond formation was mediated by copper species.
Copper-catalyzed C–N bond formation was first applied in the total synthesis by
Ma et al. [5] for the synthesis of benzolactam 1 (Fig. 1), a protein kinase C inhibitor,
involving a coupling reaction between valine and aryl iodide. The compound
structure 2 shown is an intermediate for the synthesis of lotrafiban, a potent
glycoprotein IIb/IIIa receptor antagonist [6]. Copper-catalyzed methodology was
successfully utilized for the synthesis of compound 3, a potential intermediate for
the synthesis of tetrahydroquinoline alkaloid and martinellic acid [7]. Coupling of
cyclic aliphatic amines with iodoarenes was reported for the synthesis of
cyclopropanated iprodione, an analogous intermediate compound shown in 4 [8].
Compounds 5 and 6 are active intermediates for the synthesis of antibiotics,
namely, linezolid and toloxatone [9], prepared by the coupling of carbamate with
aryl bromides in the presence of copper and ligand. Furstner et al. have successfully
employed the copper-catalyzed protocol for the synthesis of compound 7, which is
an intermediate for the total synthesis of macrocyclic spermidine alkaloid
isooncinotine [10]. Ghosh et al. developed a method for the synthesis of compound
8 on a large scale using a copper catalyst and a ligand from oxazolidinone [11].
Buchwald and Chae reported the total synthesis of U86192, a potent hypertensive
agent via a step involving the copper catalyst for the synthesis of compound 9 using
aryl bromide and N-aryl, N-Boc hydrazide [12]. A biologically active compound
Nilotinib, (AMN107) useful for chronic myelogenous leukemia, shown in structure
10 was prepared by employing a copper-catalyzed protocol [13]. Compound 11 is
an intermediate for the synthesis of the naphthalenoid H3 antagonist prepared in
multi-gram scale from the corresponding bromo derivative and pyridazinone using
Recent Developments in Recyclable Copper Catalyst Systems for C–N Bond. . .
121
The coupling reactions were carried out mostly under homogeneous conditions
[2]. Although homogeneous reactions have tremendous benefits in terms of ready
availability of the catalyst and defined structure, the separation of the catalyst
from the reaction products poses a problem. Some copper-catalyzed homogeneous methods require stoichiometric amounts of additional base that generates
copious amounts of solid waste as a by-product. In general, few reports are
available on heterogeneous cross-coupling reactions compared to the homogeneous reactions. Some of the heterogeneous methods have also been considered
as atom economic [3].
3 Copper-Catalyzed Coupling Reactions in Organic Synthesis
Homogeneous copper-catalyzed coupling reactions have been successfully applied
in the natural product synthesis. An excellent up-to-date review on the application
of copper-catalyzed methods in medicinal chemistry was recently published by
Evano, Blanchard, and Toumi [4]. Some selected examples are listed in Fig. 1,
wherein C–N bond formation was mediated by copper species.
Copper-catalyzed C–N bond formation was first applied in the total synthesis by
Ma et al. [5] for the synthesis of benzolactam 1 (Fig. 1), a protein kinase C inhibitor,
involving a coupling reaction between valine and aryl iodide. The compound
structure 2 shown is an intermediate for the synthesis of lotrafiban, a potent
glycoprotein IIb/IIIa receptor antagonist [6]. Copper-catalyzed methodology was
successfully utilized for the synthesis of compound 3, a potential intermediate for
the synthesis of tetrahydroquinoline alkaloid and martinellic acid [7]. Coupling of
cyclic aliphatic amines with iodoarenes was reported for the synthesis of
cyclopropanated iprodione, an analogous intermediate compound shown in 4 [8].
Compounds 5 and 6 are active intermediates for the synthesis of antibiotics,
namely, linezolid and toloxatone [9], prepared by the coupling of carbamate with
aryl bromides in the presence of copper and ligand. Furstner et al. have successfully
employed the copper-catalyzed protocol for the synthesis of compound 7, which is
an intermediate for the total synthesis of macrocyclic spermidine alkaloid
isooncinotine [10]. Ghosh et al. developed a method for the synthesis of compound
8 on a large scale using a copper catalyst and a ligand from oxazolidinone [11].
Buchwald and Chae reported the total synthesis of U86192, a potent hypertensive
agent via a step involving the copper catalyst for the synthesis of compound 9 using
aryl bromide and N-aryl, N-Boc hydrazide [12]. A biologically active compound
Nilotinib, (AMN107) useful for chronic myelogenous leukemia, shown in structure
10 was prepared by employing a copper-catalyzed protocol [13]. Compound 11 is
an intermediate for the synthesis of the naphthalenoid H3 antagonist prepared in
multi-gram scale from the corresponding bromo derivative and pyridazinone using
Recent Developments in Recyclable Copper Catalyst Systems for C–N Bond. . .
121