Identifying the Roles of Amino Acids, Alcohols and 1,2-Diamines as Mediators in Coupling of Haloarenes to Arenes

Abstract

Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KO(t)Bu or NaO(t)Bu since the first report in 2008. Very recently, we showed that the reactivity of some of these additives (e.g., compounds 6 and 7) could be explained by the formation of organic electron donors in situ, but the role of other additives was not addressed. The simplest of these, alcohols, including 1,2-diols, 1,2-diamines, and amino acids are the most intriguing, and we now report experiments that support their roles as precursors of organic electron donors, underlining the importance of this mode of initiation in these coupling reactions.

A study of diketopiperazines as electron-donor initiators in transition metal-free haloarene–arene coupling

“…19 This easy process afforded the expected diketopiperazines in good to excellent yields. The coupling reactions of several halobenzenes with benzene were made using a substoichiometric amount of DKP, with an excess of potassium tert-butoxide used to deprotonate the DKP, forming an enolate that can act as an electron donor (Scheme 3).…”

“…23 We also reported 19 that the DKP 24, synthesized so that only one position is available for deprotonation, is able to promote the coupling reaction of iodobenzenes with benzene efficiently. Therefore, we propose that only one deprotonation happens and that this is necessary and sufficient for the reaction to be initiated.…”

“…A N,N -dipropyl diketopiperazine 6 has already been reported by our group and was used as an electron donor under basic conditions. 19 This DKP was found to be a good initiator of coupling reactions with iodobenzenes. Herein, we report diketopiperazines 7-10, with different substituents on the nitrogens, all including a phenyl ring in order to improve the DKP solubility in benzene.…”

“…[18][19][20] Understanding the nature of this process is the key to extrapolating this transition metalfree cross-coupling reaction to aryl bromides and chlorides which remain more challenging substrates than aryl iodides. We recently reported a study on organic additives and mechanistic studies on their ability to initiate cross-coupling reactions under basic conditions.…”

“…We recently reported a study on organic additives and mechanistic studies on their ability to initiate cross-coupling reactions under basic conditions. 19 We have been particularly interested in amino acids as additives since the report of proline and sarcosine as initiators under basic conditions. 11 Amino acids can undergo condensation to form peptides 21 and also cyclic dipeptides under microwave conditions.…”