Methodologies, tools for synthesis - Bimetallic synergy

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 these issues. In particular, we have developed bases derived from LiTMP (TMP = 2,2,6,6-tetramethylpiperidino), easily prepared by mixing the lithium amide with metal salts such as zinc chloride [1].

Synergic deprotometallation-functionalization sequences can be performed by recourse to these heterobimetallic combinations. 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. 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 molecule able to inhibit the kinase PIM [2-4]. It is also possible to functionalize heteroaromatics prone to nucleophilic attacks such as acridine [5].

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 [6].

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 [7].

The use of chiral bases for the enantioselective functionalization of monosubstituted ferrocenes (e.g. esters) was also studied in the group [8,9].

As LiTMP-mediated deprotometallation is common to numerous transformations studies in the group, we 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 [10].


[1]   In situ ‘Trans-metal trapping’: An efficient way to extend the scope of aromatic deprotometalation.
Mokhtari Brikci-Nigassa, N.; Bentabed-Ababsa, G.; Erb, W.; Mongin, F.
Synthesis 2018, 50, 3615.

[2]   Fused systems based on 2-aminopyrimidines: synthesis combining deprotolithiation-in situ zincation with N-arylation reactions and biological properties.
Hedidi, M.; Maillard, J.; Erb, W.; Lassagne, F.; Halauko, Y. S.; Ivashkevich, O. A.; Matulis, V. E.; Roisnel, T.; Dorcet, V.; Hamzé, M.; Fajloun, Z.; Baratte, B.; Ruchaud, S.; Bach, S.; Bentabed-Ababsa, G.; Mongin, F.
Eur. J. Org.
Chem. 2017, 5903 (Very Important Paper).

[3]   Functionalization of 9-thioxanthone at the 1-position: from arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest.
Mokhtari Brikci-Nigassa, N.; Nauton, L.; Moreau, P.; Mongin, O.; Duval, R. E.; Picot, L.; Thiéry, V.; Souab, M.; Baratte, B.; Ruchaud, S.; Bach, S.; Le Guevel, R.; Bentabed-Ababsa, G.; Erb, W.; Roisnel, T.; Dorcet, V.; Mongin, F.
Bioorg. Chem. 2020, 94, 103347.

[4]   From benzofuro-, benzothieno- and 10-methylindolo- [2,3-b]-fused benzothiopyrano[4,3,2-de]quinolines to the corresponding benzothiopyrano[4,3,2-de]1,8-naphthyridines: Synthesis and properties of these hexacyclic heteroaromatic compounds.
Mast, N.; Erb, W.; Nauton, L.; Moreau, P.; Mongin, O.; Roisnel, T.; Macaigne, M.; Robert, T.; Bach, S.; Picot, L.; Thiéry, V.; Hurvois, J.-P.; Mongin, F.
New J. Chem. 2023, 47, 258-283.

[5]   2-Aminobenzaldehyde, a common precursor to acridines and acridones endowed with bioactivities.
Zeghada, S.; Bentabed-Ababsa, G.; Mongin, O.; Erb, W.; Picot, L.; Thiéry, V.; Roisnel, T.; Dorcet, V.; Mongin, F.
Tetrahedron 2020, 76, 131435.

[6]   Iodothiophenes and related compounds as coupling partners in copper-mediated N-arylation of anilines.
Bouarfa, S.; Bentabed-Ababsa, S.; Erb, W.; Picot, L.; Thiéry, V.; Roisnel, T.; Dorcet, V.; Mongin, F.
Synthesis 2021, 53, 1271-1284.

[7]   Copper- and cobalt-catalyzed syntheses of thiophene-based tertiary amines.
Bouarfa, S.; Graβl, S.; Ivanova, M.; Langlais, T.; Bentabed-Ababsa, G.; Lassagne, F.; Erb, W.; Roisnel, T.; Dorcet, V.; Knochel, P.; Mongin, F.
Eur. J. Org.
Chem. 2019, 3244.

[8]   Enantioselective deprotometalation of N,N-dialkyl ferrocenecarboxamides using metal amides.
Hedidi, M.; Dayaker, G.; Kitazawa, Y.; Yoshii, T.; Kimura, M.; Erb, W.; Bentabed-Ababsa, G.; Chevallier, F.; Uchiyama, M.; Gros, P. C.; Mongin, F.
New J. Chem. 2019, 43, 14898-14907.

[9]   Enantioselective deprotometalation of alkyl ferrocenecarboxylates using bimetallic bases.
Dayaker, G.; Erb, W.; Hedidi, M.; Chevallier, F.; Blot, M.; Gros, P. C.; Hilmersson, G.; Roisnel, T.; Dorcet, V.; Bentabed-Ababsa, G.; Mongin, F.
New J. Chem. 2021, 45, 22579-22590.

[10]  Deprotonative metalation of methoxy-substituted arenes using lithium 2,2,6,6-tetramethylpiperidide: experimental and computational study.
Akimoto, G.; Otsuka, M.; Takita, R.; Uchiyama, M.; Hedidi, M.; Bentabed-Ababsa, G.; Lassagne, F.; Erb, W.; Mongin, F.
J. Org. Chem. 2018, 83, 13498