# What are aryl chlorides currently used for?

In a recent paper by Gustafson et al. (DOI: 10.1021/acs.orglett.6b02650) the authors open with the argument that

aryl chlorides are both versatile synthetic handles and common functionalities in drug discovery.

However, they fail to give examples of current use in industry and pharmaceutical research.

I know of only one reaction that aryl chlorides are used for, and that would be the Ullmann biaryl (ether) coupling. Are there any other ones for which aryl chlorides are a good starting material? And then, about the second part of the sentence: Why are aryl chlorides a common functionality in drug discovery? Is it simply that compounds are chlorinated and then compared to their unchlorinated analogues?

All in all, please provide examples for the quoted statement above.

1. Synthetic handles: for organometallic couplings (Sonogashira, Suzuki...), there is a selectivity ($\ce{aryl-I} > \ce{aryl-OTf} >\ce{aryl-Br} >\ce{aryl-Cl}$) that can be crucial in the total synthesis. You can make the other position ($\ce{aryl-I}$ or whatever) react first, then use modified conditions suitable for aryl chloride couplings (plenty of examples on this website). Or make an halogen exchange before coupling your chloro- position.
2. Common functionalities: halogen bonds can change binding affinities. Even if they are weaker than hydrogen bonds, they are specific (see C. Bissantz et al., J. Med. Chem., 2010, 53 (14), 5061–5084.). They can make interactions with electrophiles, nucleophiles, or with themselves (ex: $\ce{C-X...O}$ $\ce{sp^2}$ or $\ce{X...X}$). One example of molecule designed with chloroaryl moieties is represented here (see Furet et al., Bioorg. Med. Chem. Lett. 2012, 22 (10), 3498–3502, which shows the docking model). This is an inhibitor which blocks the binding pocket of the regulator protein MDM2. The 6-chloroindolyl moiety enables to fill a subpocket (TRP 23), while the p-chlorophenyl fills another one (Leu 26). The chlorine-chlorine interactions between the 6-chloroindolyl moiety and the triptophan residue in the protein was a key point in the design of this inhibitor, strongly enhancing the binding affinities.