Prof. Zhaobin Wang’s team at Westlake University’s School of Science has come up with a new titanium catalytic system to effectively convert carboxylic acid derivatives and gem-dihaloalkanes into valuable ketones. Their new protocol could offer broad utility in synthetic chemistry and facilitate further explorations in low-valent early transition-metal catalysis.

Ketones widely occur in natural products and biologically active compounds, and represent one of the most versatile functional groups in organic synthesis. However, despite remarkable progress in transition-metal-catalyzed ketone synthesis in recent years, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. 

Now, in a new study, Prof. Wang’s group has demonstrated that a Titanium-based catalytic system could effectively promote ketone synthesis from widely available carboxylic acids and their derivatives (esters, amides) with easily accessed gem-dihaloalkanes.

Their research was recently published in the Journal of the American Chemical Society under the title “Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes.” 

(Figure 1. Representative ketone synthesis from carboxylic derivatives.)

To develop this novel approach, the researchers utilized commercially available Cp₂TiCl₂, along with magnesium or zinc powder and trimethyl silane.

The researchers found that their new method proceeds with good functional group compatibility and is applicable to the late-stage modifications of bioactive molecules. Notably, it could achieve the direct catalytic olefination of carboxylic acids.

This new method represents the first example of Ti catalyzed olefination of carboxylic acids, according to the researchers. It features a sequence of olefination and electrophilic transformation and good functional group compatibility and allows rapid access to various functionalized ketones.

Similarly, another notable feature of this protocol is that it allows chiral ketones as well as α-functionalized ketones to be easily accessed, offering greater utility in synthetic chemistry.

Given the broad availability and synthetic diversity of carboxylic derivatives, the researchers anticipate that their protocol will find broad utility in synthetic chemistry and facilitate further explorations in low-valent early transition-metal catalysis.

Learn more about Prof. Zhaobin Wang's research group and their work here.