Polar Organometallic Reagents. Группа авторов
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(Boc = tert‐butoxycarbonyl) directing group. The compatibility of this approach with, for example, keto groups enabled the fabrication of a putative meta‐magnesiated benzophenone 43 in high yield at −20 °C, ready for subsequent electrophilic quenching (Scheme 1.11, bottom).
In spite of the significant advantages to be had by using R2NMgCl(LiCl)‐type reagents, it was quickly seen that some moderately activated aromatics, e.g. tert‐butyl benzoate, reacted only modestly. This observation led to the development of a new class of mixed Li/Mg base. The reaction of R2NLi and MgCl2 in THF at 0 °C afforded (R2N)2Mg(LiCl)244. Whereas 41 failed to react significantly (7% ortho‐iodination after quenching with I2) with t‐BuO2CPh, 44 [amide = TMP, t‐Bu(c‐C6H11)N, t‐Bu(i‐Pr)N] performed excellently (77–90% ortho‐iodination). The tolerance of e.g. 44 TMP towards ketone, carbonate, and bis(dimethylamino)phosphonate groups allowed intriguing new applications in ortho functionalization. For example, the OP(O)(NMe)2 group selectively directed 4‐deprotonation via assumed 45 to give 46 on quenching. Moreover, the magnesiation of electron‐rich aromatics was made significantly more accessible than had hitherto been the case. This has been utilized to ortho‐magnesiate dimethyl‐1,3‐benzodioxan‐4‐one to give 47 in just 10 min at −40 °C en route to the preparation of 6‐hexylsalicylic acid, a natural product found in Pelargonium sidoides DC (Scheme 1.12) [68].
Scheme 1.11 Reactions of TMPMgCl(LiCl) 41 with 5‐bromopyrimidine (top) and a highly functionalized aromatic bearing ester groups (bottom).
Alkali metal magnesiate reagents have been developed recently. Their chemistry will be discussed at more length elsewhere. However, their often unique reactivity merits a summary here. TMEDA‐solvated sodium magnesiates, which have a lot in common with the structural chemistry of THF‐solvated mixed lithium‐magnesium amide complexes [69], initially demonstrated similar structural motifs to those seen in, for example, zincate chemistry (see Section 1.4.2) and elucidated in depth in Chapter 3 [70–72]. Briefly, convoluted chemistry of TMPMg(TMP)(n‐Bu)Na(TMEDA) 48 has been explored with respect to furan, which underwent α‐metalation via the formation of a transient intermediate that disproportionated to the inverse crown disodium dimagnesium hexafuryl tri(THF) complex (TMEDA)Mg2(2‐C4H3O)6Na2(THF)349 alongside TMEDA‐solvated Mg(TMP)3Na 50, the ion‐separated analogue of which ([(TMP)3Mg][Na(PMDETA)2] 51, PMDETA = N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine) proved isolable [71].
Although the chemistries of Grignard and Hauser reagents have long formed a staple of synthetic chemistry, recent interest has focused on their so‐called LiCl‐complexed ‘turbo’ variants. Their excellent solubility and the extensive new array of aromatic functionalizations allowed by these complexes have led to an interest in reagent structure as a means of understanding reactivity. However, it is only lately that the first solid‐state evidence has emerged (see Chapter 2). The turbo‐Hauser monomer (THF)(TMP)Mg(μ‐Cl)2Li(THF)252 was reported in 2008 to ortho‐magnesiate ethyl 3‐chlorobenzoate [73]. Meanwhile, the different reactivities of spirocyclic TMPMg(μ‐Cl)2Li(THF)253 were explained shortly thereafter [74]. Such structural work on turbo‐Hauser bases has been extended to the solution phase using Diffusion Ordered SpectroscopY (DOSY) [75, 76]. This approach has allowed the dissolution of 52 and 53 with retention of aggregation. Elaboration of the DOSY technique allowed the corroboration of ideas posited by the authors of the solid‐state work insofar as turbo reagent reactivity was attributed to the unsaturation of Mg after the loss of THF [77].
Scheme 1.12 Ortho‐magnesiation by TMP2Mg(LiCl)244 TMP of an aromatic bis(dimethylamino)phosphonate and of dimethyl‐1,3‐benzodioxan‐4‐one to give 46 and 47 en route to the preparation of 6‐hexylsalicylic acid.
1.3 Aromatic Ate Complex Chemistry: Metal/Halogen Exchange
1.3.1 Introduction
The halogen–metal exchange reaction for the direct formation of functionalized aryl metalates from aryl halides was studied for many years prior to the development of directed deprotonation using ate complexes. Indeed, it has proved one of the most useful processes for the preparation of aromatic lithio‐ and magnesio‐derivatives. However, despite the great potential of these species in synthetic applications, the wider use of organometals (beyond organolithiums and organomagnesiums) in this context has remained rather limited.
1.3.2 Zincates
Extending the earlier studies on forming aromatic and heteroaromatic zinc derivatives, the 1990s saw the development of halogen–zinc exchange reactions of aromatic halides using organozinc reagents to encompass the use of heterobimetallic ones. Lithium trialkylzincates (R3ZnLi) have long been established as versatile reagents for the 1,4‐addition of alkyl groups to α,β‐unsaturated ketones [78, 79]. However, investigation of the potential of less reactive lithium aryldimethylzincates for smoothly effecting 1,4‐addition represents a more recent development. Hence, a novel preparation of lithium aryldimethylzincates using the halogen–zinc exchange reaction of a range of aromatic halides with lithium trimethylzincate 54, followed by reaction of the resulting intermediates with electrophiles has been reported [80]. In the first step, iodobenzene was treated with 54 in THF at −78 °C for 1 h to give assumed 55 (R = H). The introduction of benzaldehyde (R′ = Ph) gave 1,2‐adduct 56 in 65% yield. Aromatic iodides with a para substituent were examined for the same reaction, and various functional groups were found to tolerate the halogen–zinc exchange reaction – the corresponding 1,2‐adducts being obtained in good yields (Scheme 1.13). Especially noteworthy was the observed compatibility of a nitro group with this reaction sequence. Thus, the reaction of the arylzincate with propionaldehyde proceeded smoothly with various substituents; the arylzincate from p‐iodoanisole gave the 1,2‐adduct in 66% yield, with this level of effectiveness maintained using the corresponding nitro substrate (68%).
In seeking to extend the portfolio of this early class of ate chemical reactivity, and with the aim of preparing a new class of indolylzinc derivatives, the direct halogen–zinc exchange reaction of 2‐ and 3‐iodoindoles with 54 was next studied [81]. Preparation of indolylzincate by the treatment of the 3‐iodoindole with lithium trimethylzincate at −78 °C in THF was followed by the introduction of benzaldehyde to give the desired alcohol