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Alkyne Hydroamination and Iminoamination

Alkyne Hydroamination is an atom-ecomomical method for the generation of imines via the direct addition of an amine N–H bond to a C–C triple bond. In some Group-4 complexes, the mechanism for the reaction proceeds through an imido (A in the figure below), which undergoes a [2 + 2]-cycloaddition reaction with the C–C triple bond to produce an azatitanacyclobutene intermediate (B). In the hydroamination catalytic cycle (shown in red/purple) the metallacycle undergoes protonolysis to reform the imido. 

A new multicomponent coupling scheme discovered in our group is shown in blue, iminoamination, which derived from trapping of intermediate B with an isonitrile to form a 5-membered metallacycle C. This new metallacycle then undergoes protonolysis to reform the imido A and a new product from C–C and C–N bond formation, a tautomer of a 1,3-diimine. 

There are three aspects to this chemistry that our group currently explores:

1) Control of catalyst structure and electronic properties to improve selectivity and reactivity for this process

2) Use of the 1,3-diimines produced in these reactions for heterocyclic synthesis, i.e., organic methodology using the products of the multicomponent coupling

3) Applications of the process in various areas like natural product synthesis and other areas. 

 

1) The catalysts used for this process are usually based on two different ancillary ligand frameworks, which are shown below. One of the advantages of titanium catalysis is the abundance of the metal. Titanium is the second most abundant transition metal in the earth's crust after iron. As a result, inexpensive easily prepared ancillaries are a must as expensive ligands would obviate any advantage of using titanium in the first place. To this end, the ligand below are prepared in a single step from inexpensive and commercially available compounds like pyrrole. 

Naturally, derivatives of these and alternatives are always of interest as well, and several new designs are in preparation for testing.

Our focus is largely on the multicomponent chemistry, but the hydroamination reaction is not without some utility. The usual products of the hydroamination of alkynes with primary amines are imines. The reaction can be used with enynes to generate α,β-unsaturated imines that might be difficult to prepare using condensation reactions with carbonyls. These imines were shown to be applicable to the synthesis of hydropyridines via a one-pot hydroamination, C–H activation, alkyne insertion, and electrocyclization methodology.

Simple hydroamination can also be used with 1,4-diynes and 1,5-diynes to generate pyrroles. One of the triple bonds is hydroaminated to produce an imine that undergoes rapid cyclization to the corresponding pyrrole.

The utility of the iminoamination reaction is currently under exploration. The products are tautomers of 1,3-diimines, and the focus is on one-pot procedures that produce substituted heterocycles. We have completed initial methodological studies on the quinoline, pyrimidine, and pyrazole syntheses.

 

We are now looking at a few applications of these new methodologies. One that has been completed was a synthesis of the natural product withasomnine, which is a pyrazole-based central nervous system depressant.

Other applications, like the 2-(methylester)pyrrole synthesis shown, are under development. In addition, we are looking at applications of these methodologies to organic dyes for solar cells, to the synthesis of a class of proteosome inhibitors, and to other natural products with biological activity.  

 

Selected references on this topic from our group:

“Titanium Dipyrrolylmethane Derivatives: Rapid Intermolecular Alkyne Hydroamination”, Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586-587.

“A Titanium-Catalyzed 3-Component Coupling to Generate α,β-Unsaturated β-Iminoamines”, Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880-1.

“α,β-unsaturated Imines from Titanium Hydroamination and Functionalization by C–H Activation”, Cao, C.; Li, Y.; Shi, Y.; Odom, A. L. Chem. Commun. 2004, 2002-2003.

“New C–N and C–C Bond Forming Reactions Catalyzed by Titanium Complexes”, Odom, A. L. Dalton Transactions (Perspective Article and Cover Art) 2005, 225-233.

“A Multicomponent Coupling Sequence for Direct Access to Substituted Quinolines”, Majumder, S.; Gipson, K. R.; Odom, A. L. Organic Letters 2009, 11, 4720.

“Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction and Synthesis of Withasomnine”, Majumder S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. Advanced Synthesis and Catalysis 2009, 351, 2013.

“Titanium-catalyzed one-pot multicomponent coupling reactions for direct access to substituted pyrimidines”, Majumder, S.; Odom, A. L. Tetrahedron 2010, 66, 3152. 

 

Graduate Program in Chemistry at Michigan State University