C4-Selective C-H Arylation of Thiazoles Enabled by Boronic Acids


Direct functionalization of carbon-hydrogen bonds (C-H activation) has recently emerged as a powerful method for C-C bond formation. Over the past 5 years, the Itami group have developed unique catalytic systems that can preferentially activate and arylate less reactive C-H bonds on heteroarenes. In particular, the group has looked at selective arylation of thiazoles. Thiazoles are often seen in drug discovery and late stage functionalization of this structure at all positions would be useful.

The three C-H bonds on the thiazole are chemically nonequivalent. Pd-catalysed arylation of C-H bonds of thiazoles occur preferentially at the positions α to the sulfur atom (C2 and/or C5). Under basic conditions, the C2 position is preferentially deprotonated and so under conditions with a strong base, C2 arylation occurs preferentially in C-H activation. Whereas electrophiles act preferentially at the C5 positon, so under conditions in C-H activation where the nucleophilicity of the thiazole is dominant, then C5 arylation preferentially occurs. There is therefore a need for C4 selective arylation.

yusuf-1

Figure 1. General reactive of thiazole in C-H activation. Source : (Tani, Uehara, Yamaguchi, & Itami, 2014)

Itami et al found the key to functionalization at C4 position of thiazoles was the use of boronic acids (Kirchberg et al., 2011). The reaction conditions were optimized and it was found that various nitrogen-based bidentate ligands were effective and that TEMPO was the best oxidant to use. The system worked very well on thiohenes and thiazoles where yields were generally over 75% and selectivity for thiazoles were over 85%.

yusuf-2

Figure 2. Conditions to produce C4 selective products. Source: (Kirchberg et al., 2011)

The authors propose that C4-selective arylation occurs through a Heck-like concerted arylpalladation across the thiazole C=C bond (Kirchberg et al., 2011). This neat synthetic route allows multiple functionalisation of thiazoles in a selective manner through a catalyst control approach. A paper published by the same group shows how this technique was utilised in the programmed synthesis of arylthiazoles (Tani et al., 2014). This route was also used to allow late-stage functionalisation of potential HDAC inhibitors (Sekizawa et al., 2014) and potential antibiotics (Lohrey et al., 2014) demonstrating the use of this method on a variety of substrates. The methodology has also been used to functionalise furans to assess late stage SAR of KL001 derivatives which are modulators of the mammalian circadian clock (Oshima et al., 2015).

C-H functionalisation has generated significant attention from the synthetic chemistry community because it is a powerful tool to form C-C bonds. The selective arylation of thiazoles at all positions by C-H activation is now possible thus allowing a very streamlined and efficient drug discovery process when using the thiazole core. Yamaguchi et al have recently produced an overview of C-H activation strategies for the rapid synthesis of biologically active compounds  (Yamaguchi, Yamaguchi, & Itami, 2012).

Blog written by Yusuf Ali

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s