DIRECTED ORTHO METALATION

RECENT PUBLICATIONS

• Directed Metalation of Arenes with Organolithiums, Lithium Amides, and Superbases by F. R. Leroux* and J. Mortier*, Chapter 26, in Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, edited by J. Mortier, John Wiley & Sons, Inc., Hoboken NJ, USA (2016)

The metalation of arenes in the vicinity of an appropriate directing metalation group (DMG) by organolithiums, lithium amides, and superbases is one of the most powerful method for the regioselective preparation of synthetically useful polyfunctional arenes.

This chapter aims to provide a broad understanding of the theory and practices of aromatic metalation reactions, which allow direct functionalization of unactivated aromatic C—H bonds by the stoichiometric formation of aryllithium(potassium) intermediates, namely, (i) directed ortho metalation (DoM) of arenes bearing one or more DMGs, (ii) directed remote metalation (DreM) of polyarenes, (iii) peri metalation of naphthalenes, and (iv) metalation of metal-complexed arenes (mainly chromium complexes). The main analytical methods and techniques (crystallography, NMR spectroscopy, quantitative analysis) and important synthetic applications are presented to highlight the recent advances of these techniques and their impact for improving the design of pharmaceutical compounds and organic materials.

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 Asymmetric Nucleophilic Aromatic Substitution by A.-S. Castanet, A. Boussonnière and J. Mortier*, Chapter 8, in Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, edited by J. Mortier, John Wiley & Sons, Inc., Hoboken NJ, USA (Book Chapter) (2016)

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 M. Belaud-Rotureau, A.-S. Castanet, T. H. Nguyen, J. Mortier* “Uncatalyzed CO2Li-Mediated SNAr Reaction of Unprotected Benzoic Acids via Silicon Trickery” Aust. J. Chem. 201669, 307

The alkyl and aryllithium nucleophilic aromatic substitution (SNAr) displacement of a fluoro or methoxy group from unprotected 2-fluoro/methoxybenzoic acids is discussed. It was discovered that a TMS group located at the C6-position ortho to the carboxyl group shields effectively the carboxylate against nucleophilic attack, thus reducing dramatically ketone formation, and reorients nucleophilic substitution to the C2-position. The reactions with fluoro-substituted substrate 7 proceed efficiently; in contrast, the use of methoxy-functionalized benzoic acid 8 only affords moderate yields with s-BuLi and PhLi. This uncatalyzed coupling reaction, which provides a direct access to biaryl compounds, presumably proceeds by an addition–elimination sequence via intermediate formation of a resonance-stabilized pentavalent silalactone-Meisenheimer complex.

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• T. T. T. Nguyen, A. Boussonnière, E. Banaszak, A.-S. Castanet, K. P. P. Nguyen, J. Mortier* “Chemoselective Deprotonative Lithiation of Azobenzenes. Reactions and Mechanisms” J. Org. Chem. 201479, 2775   Supporting Information

Whereas standard strong bases (n-BuLi, s-BuLi/TMEDA, n-BuLi/t-BuOK, TMPMgCl·LiCl, and LDA) reduce the N═N bond of the parent azobenzene (Y = H), aromatic H→Li permutation occurs with LTMP when a suitable director of lithiation (Y = OMe, CONEt2, F) is present in the benzene residue of the azo compound. The method allows direct access to new substituted azobenzenes.

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D. Tilly,* J. Mortier*Directed Remote Aromatic Metalations: Mechanisms and Driving Forces (review) Chem. Eur. J. 2012183804 

Directed remote aromatic metalations are useful synthetic transformations allowing for rapid regioselective access to elaborate highly substituted carbocyclic aromatic and heteroaromatic systems. This review unravels the tangle of data reported on directed remote aromatic metalations. Through a careful analysis of critically selected examples, advanced rationalizations of remote metalation regioselectivities are presented. These extend beyond the complex-induced proximity effect (CIPE). Mechanisms, driving forces, and parameters influencing remote metalations are discussed. An understanding of these metalation mechanisms enables more accurate predictability of justification of regiochemical outcomes of these useful synthetic transformations.

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R. Aissaoui, A. Nourry, A. Coquel, T. T. H. Dao, A. Derdour, J.-J. Helesbeux, O. Duval, A.-S. Castanet, J. Mortier*Ortho-Lithium/Magnesium Carboxylate-Driven Aromatic Nucleophilic Substitution Reactions on Unprotected Naphthoic Acids” J. Org. Chem. 201277, 718  Supporting Information

Substitution of an ortho-fluoro or methoxy group in 1- and 2-naphthoic acids furnishing substituted naphthoic acids occurs in good to excellent yields upon reaction with alkyl/vinyl/aryl organolithium and Grignard reagents, in the absence of a metal catalyst without the need to protect the carboxyl (CO2H) group. This novel nucleophilic aromatic substitution is presumed to proceed via a precoordination of the organometallic with the substrate, followed by an addition/elimination.

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M. Belaud-Rotureau, T. T. Le, T. H. T. Phan, T. H. Nguyen, R. Aissaoui, F. Gohier, A. Derdour, A.-S. Castanet, K. P. P. Nguyen, J. Mortier* [Université du Maine]Synthesis of N-Aryl and N-Alkyl Anthranilic Acids via SNAr Reaction of Unprotected 2-Fluoro and 2-Methoxybenzoic Acids by Lithioamides Org. Lett201012, 2406   Supporting Information

Substitution of the fluoro or methoxy group in unprotected 2-fluoro- and 2-methoxybenzoic acids to afford N-aryl and N-alkyl anthranilic acids occurs upon reaction with lithioamides under mild conditions in the absence of a metal catalyst.

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D. Tilly, J.-m. Fu, B.-p. Zhao, M. Alessi, A.-S. Castanet, V. Snieckus*, J. Mortier* [Université du Maine] “On the Mechanism of the Directed ortho and remote Metalation Reactions of N,N-Dialkylbiphenyl-2-carboxamides” Org. Lett. 201012, 68   Supporting Information

A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (4) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5 whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4 with 7 whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).

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N. T. T. Chau, T.-H. Nguyen, A.-S. Castanet, K. P. P. Nguyen, and J. Mortier*[Université du Maine] Competition of Substituents for Ortho Direction of Metalation of Veratric Acid Tetrahedron 200864, 10552 
LTMP (5 equiv) metalates randomly veratric acid (1). Under external quench conditions, the thermodynamically more stable lithium 2-lithio-3,4-dimethoxybenzoate (2) reacts with a variety of electrophiles to give versatile building units that are not easily accessible by conventional means. Under in situ quench conditions (LTMP/TMSCl), a reversal of regioselectivity is observed and 6-trimethylsilyl-3,4-dimethoxybenzoic acid (10) is formed predominantly.

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A.-S. Castanet, D. Tilly, J.-B. Véron, S. S. Samanta, A. De, T. Ganguly, J. Mortier*[Université du Maine] Combined directed ortho-metalation, remote-metalation and Stille cross-coupling strategies. Concise stereoselective synthesis of polysubstituted 9H-fluoren-9-one” Tetrahedron 2008, 64, 3331 
The new sequential stereoselective synthesis of diversely substituted 9H-fluoren-9-ones by ortho-lithiation/Bu3SnCl quench of unprotected benzoic acids followed by Stille cross-coupling reaction and remote metalation is reported.

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T.-H. Nguyen, N. T. T. Chau, A.-S. Castanet, K. P. P. Nguyen, and J. Mortier* [Université du Maine] “First General, Direct, and Regioselective Synthesis of Substituted Methoxybenzoic Acids by Ortho MetalationJ. Org. Chem. 200772, 3419
New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78 C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0 C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed (Table 1).

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T.-H. Nguyen, A.-S. Castanet, J. Mortier* [Université du Maine] “Directed ortho-metalation of unprotected benzoic acids. Methodology and regioselective synthesis of useful contiguously 3- and 6-substituted 2-methoxybenzoic acid building blockOrg. Lett. 20068, 765  Supporting Information
By treatment with s-BuLi/TMEDA at -78 C, unprotected 2-methoxybenzoic acid is deprotonated exclusively in the position ortho to the carboxylate. A reversal of regioselectivity is observed when the acid is treated with n-BuLi/t-BuOK. These results are of general utility for the one-pot preparation of a variety of very simple 3- and 6-substituted 2-methoxybenzoic acids that are not easily accessible by conventional means. The potential usefulness of the method is demonstrated by the expedient synthesis of lunularic acid.

 

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J. Mortier,* T.-H. Nguyen, D. Tilly, A.-S. Castanet [Université du Maine] “Does phenothiazine give a dianion on addition of two equivalents of strong base?Arkivoc 2007, vi, 47
A careful analysis of results obtained by different authors allowed us to unravel the pathway of the metalation reaction of phenothiazine (1) by n-BuLi (2 equiv). The reaction is shown not to yield a dilithio species as believed. Electrophiles such as RCONMe2 (R = H, Ph, 4-MeOC6H4), RCO2H (R = Ph and Me) and CO2 assist a second deprotonation.

 

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D. Tilly, S. S. Samanta, A.-S. Castanet, A. De, J. Mortier* [Université du Maine] “The expedient and regioselective metalation of unprotected 2-, 3- and 4-biphenyl carboxylic acidsEur. J. Org. Chem. 2006, 174
Unprotected biphenyl-2-carboxylic acid can be cleanly metalated with sec-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution. The remote C2-position is attacked by the superbasic mixture of n-butyllithium and potassium tert-butoxide (LICKOR, 3.5 equiv.) in THF or benzene at 20-60 °C. The resulting dianion cyclizes to give the fluorenone skeleton. The metalation reactions of biphenyl-3- and -4-carboxylic acids are also described.

 

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D. Tilly, A.-S. Castanet, J. Mortier* [Université du Maine] “On the mechanism of the metalation of 2-(pyridin-3-yl)benzoic acid derivativesTetrahedron Lett. 200647, 1121
The mechanism of the metalation of 2-(pyridin-3-yl)benzoic acid derivatives with strong bases is discussed.

 

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T.-H. Nguyen, N. T. T. Chau, A.-S. Castanet, K. P. P. Nguyen, J. Mortier* [Université du Maine] “Toward a Better Understanding on the Mechanism of Ortholithiation. Tuning of Selectivities in the Metalation of Meta-Anisic Acid by an Appropriate Choice of the BaseOrg. Lett. 20057, 2445  Supporting Information
If employed in THF at 0 C, LTMP metalates meta-anisic acid at the doubly activated position. In contrast, n-BuLi/t-BuOK deprotonates position C-4 preferentially at low temperature. Functionalization at C-6 requires protection of the C-2 site beforehand. As a result of these findings, a new mechanism is proposed for the heteroatom-directed ortholithiation of aromatic compounds.

 

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T. K. Pradhan, A. De*, J. Mortier [Université du Maine] “Application of directed metalation in synthesis. Part 8: Interesting example of chemoselectivity in the synthesis of thioaurones and hydroxy ketones and a novel anionic ortho-Fries rearrangement used as tool in the synthesis of thienopyranones and fluorenonesTetrahedron 200561, 9007
Chemoselective synthesis of thioaurones or 3-hydroxy benzo[b]thiophen-2-aryl ketones, 1-hydroxy naphtho[2,1-b]thiophen-2-aryl ketones and chalcones from N,N-diethyl-ortho-methyl sulfanyl aryl amides were described. (Benzo[b]thiophen-2-yl) alkylates and (naphtho[2,1-b]thiophen-2-yl) alkylates undergo a novel anionic ortho-Fries rearrangement leading to (3-hydroxy benzo[b]thiophen-2-yl) and (1-hydroxy naphtho[2,1-b]thiophen-2-yl) alkyl ketones. The hydroxy ketones were used as intermediates in the synthesis of wide range of benzothienopyranones and thiafluorenones.

 

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D. Tilly, S. S. Samanta, A. De, A.-S. Castanet, J. Mortier* [Université du Maine] “Contribution to the Study of the Mechanism of the Directed Remote-Metalation. Evidence for the Intermediacy of a Geminal Dimetallo Dialkoxide C(OM)2 (M = Li, K), First Doubly Charged Director of Ortho-Metalation“ Org. Lett. 20057, 827  Supporting Information
The mechanism of the metalation of 2-biphenyl carboxylic acid (1) with the Lochmann-Schlosser superbase was determined by deuteriolysis. Both ortho (C3) and remote (C2′) positions are metalated. The C2′-metalated species 2 cyclizes instantaneously. Under suitable conditions, the doubly charged geminal dimetallo dialkoxide group C(OM)2 4 directs metalation in the adjacent position (C1), affording a stable 1-metallo-9H-fluorene-9,9-dimetallo dialkoxide 5 that can be trapped by diverse electrophiles to give 1-substituted 9H-fluoren-9-ones 7 and 9 after acidic workup.

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F. Gohier, A.-S. Castanet, J. Mortier* [Université du Maine]  “The First Regioselective Metalation and Functionalization of Unprotected 4-Halobenzoic Acids“ J. Org. Chem. 200570, 1501   Supporting Information
By treatment with s-BuLi, s-BuLi/TMEDA, or t-BuLi at ~-78 C, 4-fluoro- and 4-chlorobenzoic acids (1a,b) are metalated preferentially in the position adjacent to the carboxylate. A complete reversal in regioselectivity is observed for 1a when treated with LTMP; a sequential process involving a rapid intraaggregate lithiation through a quasi dianion complex “QUADAC” is postulated to explain the unusual reactivity of Me2S2 and I2.

 

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F. Gohier, A.-S. Castanet, J. Mortier* [Université du Maine] “Selectivities in reactions of organolithium reagents with unprotected 2-halobenzoic acids“ Org. Lett. 20035, 1919  Supporting Information
Exposing 2-fluorobenzoic acid (1a) to 2.2 equiv of LTMP at ca. -78 C leads to deprotonation at the 3-position whereas 2-chloro/bromobenzoic acids (1b,c) are lithiated adjacent to the carboxylate. The resulting dianions 3Li-1a and 6Li-1b,c are trapped as such by chlorotrimethylsilane. In the absence of internal quench, 6Li-1b,c isomerize to the more stable 3Li-1b,c. The latter eliminate lithium halide and set free benzyne-3-carboxylate (2) that reacts regioselectively with LTMP to give 3-tetramethylpiperidinobenzoic acid (3).

 

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F. Gohier, J. Mortier* [Université du Maine] “Ortho-metalation of unprotected 3-bromo and 3-chlorobenzoic acids with hindered lithium dialkylamides“ J. Org. Chem. 200368, 2030   Supporting Information 1 Supporting Information 2
Upon treatment of 3-chloro/bromobenzoic acids with hindered lithium dialkylamides (LDA or LTMP) at -50 C, lithium 3-chloro/bromo-2-lithiobenzoates are generated. These dianions can be trapped as such to afford after electrophilic quenching a variety of simple 2-substituted-3-chloro/bromobenzoic acids. The 3-bromo-2-lithiobenzoate is less stable than the corresponding 3-chloro derivative and partly eliminates lithium bromide, thus setting free lithium 2,3- and 3,4-dehydrobenzoates that can be intercepted in situ with the hindered base.

 

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D. Tilly, S. S. Samanta, F. Faigl, J. Mortier* [Université du Maine] ”Combined directed ortho metalation—intramolecular Friedel-Crafts connections. Regiospecific route to 1-substituted fluoren-9-ones“ Tetrahedron Lett. 200243, 8347
ortho-Substituted-2-biphenyl carboxylic acids of the type 3a–j were prepared by the tandem metalation sequence from 2-biphenyl carboxylic acid 1 with sec-butyllithium in THF at -78°C followed by quenching with electrophiles. The carboxylic acids 3a–f were converted into 1-substituted fluorenones 4a–f upon treatment with methanesulfonic acid.

 

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