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Teo, Yong Chua
Yan, Yaw Kai
This thesis involves the development of new strategies for the cross coupling of nitrogen nucleophiles with aryl or heteroaryl halides and their applications to the synthesis of pharmaceutical drugs.
I. CROSS COUPLING OF NITROGEN HETEROCYCLES WITH ARYL OR HETEROARYL HALIDES
A novel strategy for the N-arylation of nitrogen heterocycles with aryl and heteroaryl halides using a combination of MnF2 or MnCl2.4H2O/trans-1,2- diaminocylcohexane catalyst in water was developed. This is the first report of a cross-coupling protocol that is catalyzed solely by manganese which proceeded efficiently only when water was used as the reaction medium. The C-N coupling of azoles with aryl iodides afforded the corresponding products in moderate to excellent yields (up to 91%).
Another effective approach towards the synthesis of N-arylated azoles was accomplished by the ligand-free copper(I) oxide catalytic system. The protocol uses tetrabutylammonium bromide (TBAB) as the phase transfer agent with water as the solvent and shows good tolerance towards various functional groups (up to 90%).
II. CROSS COUPLING OF ALIPHATIC AMINES WITH ARYL HALIDES
The successful extension of the novel manganese catalytic system to N-arylation of aliphatic amines with various substituted aryl halides was achieved. An efficient and convenient protocol has been developed using a MnCl2.4H2O/L-proline catalyst and NaOtBu as the base in DMSO (up to 75% yield).
Similarly, the ligand-free copper catalytic system was effective for the cross-coupling of a variety of alkyl amines with various substituted aryl iodides. The versatile and operationally simple system tolerates hindered and functionalized amines/aryl halides and the N-arylated products are afforded in good to excellent yields (up to 93%).
III. CROSS COUPLING OF AMIDES WITH ARYL HALIDES
A convenient and efficient protocol has been developed for the cross coupling of amides and aryl iodides using the ligand-free copper(I) oxide catalyst in water. A variety of amide derivatives afforded the corresponding N-arylated products in moderate to good yields under the catalytic conditions (up to 88%).
A manganese/copper bimetallic catalytic system was developed for the preparation of N-arylated amides using trans-1,2-diaminocyclohexane as the ligand at 60oC in water. A variety of functional amides and differently substituted aryl halides afforded the corresponding N-arylated amides in good to excellent yields (up to 92%).
IV. CROSS COUPLING OF SULFONAMIDES WITH ARYL HALIDES
The application of the ligand-free catalysis to the N-arylation of sulfonamides with differently substituted aryl iodides using copper iodide afforded the products in good to excellent yield (up to 91%). This ligand-free coupling strategy is an attractive alternative to access various N-arylsulfonamides.
Subsequent application of our manganase/copper co-catalysis to the N-arylations of sulfonamides with differently substituted aryl iodides using N,N’- dimethylethylenediamine as ligand in water was achieved at a low operating temperature of 60oC. The environmental friendliness and low cost of the strategy render this method viable for application in larger industrial scales.
V. SYNTHESIS OF TRAZODONE AND CELECOXIB
Cross coupling reaction of C-N bond between an aliphatic amine with an aryl halide is described for the preparation of Trazodone. A facile and convenient method for the N-arylation of piperazine with 3-chloro-iodobenzene is accomplished using ligandfree copper(I) iodide as the catalyst and Cs2CO3 as the base in DMF.
A practical and efficient strategy has been developed for the cross coupling of N,N-dibenzyl-4-iodobenzenesulfonamide with nitrogen nucleophiles using low (0.5-1.0 mol%) CuI loading under ligand-free conditions (up to 98%). The application of this catalytic system to the synthesis of Celecoxib was successfully demonstrated.
|Appears in Collections:||Doctor of Philosophy (Ph.D.)|
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