Post‐Metalation Structural Insights into the Use of Alkali‐Metal‐Mediated Zincation for Directed ortho‐Metalation of a Tertiary Aromatic Amide

Abstract

Introduced in 1999 by Kondo et al., [1] lithium di-tert-butyltetramethylpiperidinozincate (LiTMP-zincate) is a highly chemoselective base for directed ortho-metalation (DoM) of alkyl benzoates, alkyl benzamides, and related azaaromatics. [2,3] This important reagent is but one of a growing number of alkali-metal zincate compounds that are attracting much attention from synthetic chemists in respect of their often special reactivities/selectivities, [4] and in certain cases, catalytic action [5] towards organic substrates. Much of our knowledge of these synthetic applications comes at the end of the reaction sequence, when all active metal-organic materials have been exhausted, [6] and is usually derived from isolated, metal-free products obtained by the in situ interception of metalated intermediates by electrophilic quenching. Scheme 1 illustrates this method for the sequential orthometalation/iodination of N,N-diisopropylbenzamide by a LiTMP-zincate/I 2 combination, [1] a reaction sequence that is relevant to the present study. In general, surprisingly little well-defined information exists on the chemistry taking place "at the coalface", that is, about the natures of the starting alkali-metal zincate reagents themselves and the metalated intermediates they generate prior to the final, electrophilic quenching, step. To fully understand this chemistry and develop it rationally, such information is indispensable, particularly in the case of LiTMP-zincate and related ambident reagents which in theory could exhibit either alkyl or amido (or both) reactivity towards organic substrates. In the preceding Communication in this issue we discussed the structures of the TMP-zincate reagent [(thf)Li(m-tmp)(mtBu)Zn(tBu)] and the related tertiary aromatic amide complex [{(iPr) 2 NC(Ph)(=O)}Li(m-tmp)(m-tBu)Zn(tBu)], thus providing valuable structural information on zincate bases prior to them taking part in metalation reactions. [7] Herein, in reporting the first application of a sodium TMP-zincate reagent in directed ortho-metalation, we shed light on the selective ligand transfer effecting ortho-metalation of N,Ndiisopropylbenzamide, by successfully isolating and crystallographically characterizing the ortho-metalated "intermediate". Furthermore, by similarly elucidating the ortho-metalated structure generated by the analogous lithium TMPzincate system (not the original Kondo reagent but a new TMEDA-complexed variant), we have uncovered an intriguing "alkali-metal effect", as it transpires that the sodium zincate and lithium zincate reagents behave differently towards the aromatic tertiary amide. We also discuss how these mixed-metal ortho-metalated structures deviate in Scheme 1. Synthesis of N,N-diisopropyl-2-iodobenzamide by a standard metalation/electrophilic-interception strategy.

Pre‐Metalation Structural Insights into the Use of Alkali‐Metal‐Mediated Zincation for Directed ortho‐Metalation of a Tertiary Aromatic Amide

“…[6] It is tempting to state that this is irrefutable evidence that 5 actually is a genuine DoM precomplex; however, doubts must remain in the absence of corroborative kinetic information as Collum and co-workers have cautioned through a thought-provoking study of the ortho-lithiation of anisole by nBuLi/TMEDA that suggests that methoxy-lithium interactions are negligible in the rate-limiting transition structure. [13] Interpreting 5 as a DoM precomplex, the structure establishes that the first point of coordination of the substrate remains the alkali metal (as it is in conventional directed ortho-lithiation) even though the ensuing metalation is strictly a zincation.…”

“…While this might reasonably explain the initial elimination of alkane, it would appear that subsequently amine is also eliminated as the final product is the bis(benzamide) [(tmeda)Li{2-[1-C(O)N(iPr) 2 ]C 6 H 4 } 2 Zn(tBu)]. [6] Clearly, these mixed-metal, mixed-ligand bases are highly complicated systems and much mechanistic/structural work remains to be done before the intricacies of their chemistry can be fully unraveled.…”

“…In a significant implication for the mechanism of directed ortho-metalation [4] generally and in TMP-zincate chemistry specifically, we also report the synthesis and crystal structure of the tertiary aromatic amide-complexed [{(iPr) 2 NC(Ph)(=O)}Li(m-tmp)(m-tBu)Zn(tBu)] (5), which can be formally regarded as a possible representative complex of the "complex-induced proximity effect" type [5] involved in the ortho-zincation of N,N-diisopropylbenzamide. [6] In Kondo and co-workers original preparation of 3, [3] tBu 2 Zn is added to lithium TMP in neat THF solution at À78 8C, and the mixture warmed to room temperature then utilized as is (in situ) in a metalation application with a protic substrate. Under these conditions, the polar solvent THF undoubtedly solvates lithium, and the "precomplex" 3 (which strictly should include THF in its formulation) is most certainly highly soluble in the vast excess of polar solvent.…”

Deprotonierende Metallierungen mit 'at‐Verbindungen: Synergie, Synthese und Strukturaufbau

“…Für die gerichtete ortho-Zinkierung (DoZ) des tertiären aromatischen Amids N,N-Diisopropylbenzamid wurden Untersuchungen angestellt, die Aufschluss über die Strukturen vor und nach der Metallierung geben und dadurch Hinweise auf den Mechanismus liefern. [93,94] Vor der Metallierung liegt in Hexan eine synergetische Lithiumzinkatmischung aus LTMP und tBu 2 Zn vor, die mit dem Amid zum 1:1-Donor-Akzeptor-Komplex [{(iPr) 2 NC(Ph)( = O)}Li(m-tmp) (m-tBu)Zn(tBu)] (88) Was speziell die gerichtete Metallierung betrifft, wurden die interessantesten Ergebnisse bei AMMZ-Reaktionen von Anilinderivaten beobachtet. [96] Das mit einem schwach ortho-dirigierenden Substituenten ausgestattete N,N-Dimethylanilin geht mit PhLi [97] und BuLi [98] ortho-Metallierungen ein, wobei im ersten Fall geringe Ausbeuten und im zweiten Fall hohe Ausbeuten resultieren.…”

Regio‐ und chemoselektive Metallierung von Arenen und Heteroarenen mit gehinderten Metallamidbasen

“…Infolgedessen konzentrierten sich jüngste Untersuchungen auf Dimetall-TMP-Basen, wie Magnesiate, [84][85][86][87][88] Zinkate, [89,90] Aluminate, [91,92] Cadmate, [93] Chromate, [94] Manganate [95] und Ferrate. [94] Das TMP-Anion in diesen Reagentien ist ausnahmslos der einzige oder zumindest der aktivste Basenligand, der die Metallierung des Substrats ermçglicht.…”