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Hydrohydrazination and Iminohydrazination

Hydrohydrazination is a reaction related to hydroamination involving the addition of a hydrazine to a carbon-carbon unsaturation. This reaction was first reported in 2002 as a titanium-catalyzed process involving 1,1-disubstituted hydrazines and alkynes. In our initial report, we provided two different catalysts for the reaction. One catalyst was a 6-coordinate pyrrolyl-based complex, Ti(dap)2(NMe2)2 (1). The other catalyst was a thiolate-based compound with the very electron-deficient SC6F5 ancillaries.

The products were hydrazones. The reaction is applicable to internal and terminal alkynes and can be stopped at the hydrazone if desired for modification.

 

If an aryl-substituted hydrazine was employed, addition of acid provided the indoles via one-pot hydrohydrazination/Fischer indole cyclization of both terminal and internal alkynes if desired. In general, zinc dichloride was used in the Fischer cyclization.

It has since been found that several metals, including late transition metals and even zinc with noncoordinating anions are active for hydrohydrazination/Fischer cyclization with terminal alkynes only. These schemes, due to the Lewis acidity of the catalyst, lead to indoles and are not reported as hydrazone syntheses as well.

While hydrohydrazination is a reaction of potential utility in and of itself, one of the reasons our group studies hydrohydrazination is to learn more about related multicomponent coupling chemistry. The pyrrole-based catalyst 1 is also a catalyst for the multicomponent coupling reaction, iminohydrazination, between 1,1-disubstituted hydrazines, alkynes, and isonitriles shown below.

In the course of these studies, several new hydrazido(2–) titanium complexes were discovered, which were among the first in this class of compounds to be structurally characterized. One example is shown below, which is a possible intermediate in the iminohydrazination process shown above.

In addition, we have developed a catalyst applicable to monosubstituted hydrazines like phenylhydrazine based on the bis(dap) design. Below is one example using a simple terminal chlorinated alkyne that was explored. Internal alkynes can also be used with this catalyst with monosubstituted hydrazines.

 

 

Selected references on this topic from our group:

“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. Republished in Ian P. Rothwell: A Special Commemorative Issue, Royal Society of Chemistry Publishing, 2006, p. 225.

“Titanium Catalyzed Intermolecular Alkyne Hydroamination by 1,1-Disubstituted Hydrazines”, Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853-2856.

“Titanium-Catalyzed Iminohydrazination of Alkynes”, Banerjee, S.; Cao, C.; Shi, Y.; Odom, A. L. J. Organometallic Chem. 2005, 690, 5066-5077.

“Synthesis and Structure of a Titanium Hydrazido(2–) Complex”, Banerjee, S.; Odom, A. L. Organometallics 2006, 25, 3099-3101.

“Titanium-Catalyzed Hydrohydrazination with Monosubstituted Hydrazines: Catalyst Design, Synthesis, and Reactivity”, Banerjee, S.; Barnea, E.; Odom, A. L. Organometallics 2008,27, 1005-1014.

The Graduate Program in Chemistry at Michigan State University