Deprotonative lithiation is a powerful tool to functionalize regioselectively aromatic compounds, and monometallic lithium reagents such as alkyllithiums and lithium amides have largely been employed to achieve this goal. Nevertheless, only substrates with high C-H acidity are in general amenable to deprotonative lithiation. In addition, the conversion of sensitive substrates requires strictly controlled reaction conditions due to the low compatibility between functions and organolithiums. One main topic of our group is to use bimetallic combinations in order to address this compatibility issue. In particular, we have developed bases derived from LiTMP (TMP = 2,2,6,6-tetramethylpiperidino), easily prepared by mixing the lithium amide with copper(I) chloride [1] or zinc chloride [2]. While a lithiocuprate base is formed with the former [1], either a zinc amide or zinc chloride can act as in situ trap with the latter [2]. Synergic deprotometallation-functionalization sequences can be performed by recourse to these heterobimetallic combinations.
One main application of the lithium-copper “ate” base is the synthesis of diaryl ketones by simply reacting the generated lithium aryl cuprates with aroyl chlorides [1]. With suitably substituted diaryl ketones, subsequent elaboration is possible, for example by a palladium-catalyzed auto-tandem process, as shown below [3].
While the lithium-copper “ate” base is particularly useful to prepare diaryl ketones [1], the lithium-zinc combinations allow these ketones to undergo further functionalizations. For example, when a mixture of diaryl ketone and ZnCl2 is treated by LiTMP, the aryllithium first formed is trapped by the zinc salt that acts as an in situ trap. By this way, unwanted reactions between the organolithium and the ketone are minimized [4].
By varying the amount of base employed, it is possible to favour either mono- or dideprotometallation. In the pyridine series below, difunctionalization was possible in the presence of acidifying fluoro groups while monofunctionalization was always observed with methoxy groups [5].
In the oxazolopyrazine series, while the monofunctionalization proved non-regioselective due to very close acidities, performing sequential deprotometallation-iodine trapping sequences afforded the corresponding diiodide, easily involved in a double Suzuki coupling [6].
While iodolysis is usually performed after deprotometallation using the lithium-zinc bases, we recently extended the range of compatible electrophiles to bromine and trichloroisocyanuric acid in order to access brominated and chlorinated derivatives, respectively.7 In addition to halogenolyses and Negishi-type coupling, we also found possible to intercept an arylzinc generated by this method in copper-catalyzed amination reactions. Although the reaction with π-deficient heteroaromatic substrates such as diazines currently remains a challenge, it worked well with benzothiophene which benefits from stable arylzinc derivatives.8
Finally, as LiTMP-mediated deprotometallation is common to numerous transformations studies in the group, we recently disclosed its mechanism in the presence of a zinc trap. From experimental and computational studies, it appeared that deprotolithiation by monomeric LiTMP is the more likely pathway before stabilizing transmetallation to arylzinc.9
Iodinated aromatics that we are able to easily prepare by using our methodologies are of interest since they can be involved in transition-metal-catalyzed cross-coupling reactions, as exemplified below with the cascade formation of polycycles of biological interest.10
When the iodo group occupies the position next to the ketone function, many subsequent functionalizations can be performed. It is for example possible to build a 2-aminopyrimidine core which is often found in compounds of biological interest. Such a sequence from thioxanthone led to a molecule able to inhibit the kinase PIM1.11
For more information : Florence Mongin, William Erb
