Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for α-Deprotonation and Stereocontrol

Kessar, S. V.; Singh, Paramjit

doi:10.1021/cr950082n

Cited by 129 publications

(47 citation statements)

References 112 publications

(126 reference statements)

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“…Usually a-metalations of amines [13] have high kinetic barriers and would conventionally be considered impossible for only mildly electropositive zinc, but here the barrier must be reduced substantially by the close proximity of the tethered tBu 2 Zn and TMEDA units which sets up a favorable intramolecular Zn-H exchange reaction with loss of BuH. [14] As aforementioned, loss of the halogen substituent distinguishes this new alkali metal mediated zincation (AMMZn) reaction from those of "LiZn(TMP)(tBu) 2 ", which, when intercepted by electrophiles, give polysubstitut- Communications ed haloarenes. Emphasizing the strong solvent dependency of AMMZn reactions, significantly the former was performed in hexane solution containing TMEDA, whereas the latter were performed in THF solution with no TMEDA.…”

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confidence: 99%

Synergic Synthesis of Benzannulated Zincabicyclic Complexes, α‐Zincated N Ylides, through Sodium‐TMEDA‐Mediated Zincation of a Haloarene

et al. 2009

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The zinc-hydrogen exchange reaction has undergone a remarkable transformation in recent times from obscurity to a novel alternative, and in many cases the preferred option, to long-established lithiation methods for generating aromatic organometallic intermediates suitable for subsequent functionalization. Simple zinc reagents (alkyls, amides), as kinetically sluggish bases, are generally useless for such applications. Installing high metalation power within a zinc reagent usually requires a more complex composition, in which reactivity is boosted through cooperative effects between its different components. Modified from their magnesiating "turbo-Grignard" reagents, Knochels three-component systems [(TMP) 2 Zn·2MgCl 2 ·2 LiCl] [1] and [{iPr(tBu)N} 2 Zn· 2MgCl 2 ·2 LiCl][2] are excellent complex zincators for both aromatic and heteroaromatic substrates (TMP is 2,2,6,6-tetramethylpiperidide). Formally a two-component lithium amide-zinc alkyl mixed complex, "[LiZn(TMP)(tBu) 2 ]" introduced by Kondo and Uchiyama, is also a potent chemo-and regioselective zincator for similar substrates.[3]Our own group has contributed the related sodium TMPzincate [(TMEDA)·Na(m-TMP)(m-tBu)Zn(tBu)] [4] (1), which depending on the organic substrate can execute regioselective ortho-, meta-, or dizincation in reactions that have been structurally defined.[5]Here we report the first investigation of the surprising reactivity of 1 towards an aryl halide, namely chlorobenzene. Fully characterized by X-ray crystallography and NMR spectroscopy, the unexpected final product isolated from this reaction is the remarkable zwitterionic benzannulated bicyclic zinc complex [{1-Zn(tBu)} À -{2-N(Me)(CH 2 )CH 2 -CH 2 NMe 2 } + -C 6 H 4 ] (2). Formation of 2 can be rationalized by a novel four-step ortho-zincation, zincate (or sodium chloride) elimination, azazincation-addition, amine a-zincation sequence. An intermediate along this path formed prior to the final step (amine a-zincation), [{1-Zn(tBu) 2 } À -{2-N(Me) 2 CH 2 CH 2 NMe 2 } + -C 6 H 4 ] (Int), has also been isolated from the reaction and crystallographically characterized.In the few previous studies of reactions of aryl halides and TMP-zincates, [6] no experimental evidence has been collected on the chemistry taking place between the limits of the starting materials and the zinc-free quenched products. Therefore, to shed light on the critical metal (and bimetal) activity stage of these reactions, our primary objective was to get inside these limits by isolating and characterizing representative zinc-containing intermediates. This was realized through the synthesis of 2, which were isolated as small colorless block crystals in 20.7 % yield from the equimolar reaction of 1 and chlorobenzene in hexane solution.Since it was reported earlier [6] that reaction of [LiZn-(TMP)(tBu) 2 ] with haloarenes followed by electrophilic trapping produced polyfunctional haloarenes (i.e., with retention of the original halogen substituent), we expected 2 to be an ortho-zincated chlorobenzene derivative. Sur...

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confidence: 99%

Synergic Synthesis of Benzannulated Zincabicyclic Complexes, α‐Zincated N Ylides, through Sodium‐TMEDA‐Mediated Zincation of a Haloarene

et al. 2009

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“…On another hand, N-activation by BF 3 has been used as an alternative to N-oxides to promote the ortho-lithiation of pyridines. The metallation of BF 3 -pyridine adducts using LiTMP in DEE at −78 • C is tolerant to acid or chelating-directing groups (4-methylpyridine [40] and 4-(dimethylamino)pyridine [41]) but surprisingly does not work with quinoline or isoquinoline [42].…”

Section: Metallation Of Dipolar Adducts Of Pyridines (N-oxides or Bf mentioning

confidence: 99%

Lithiated Aza‐Heterocycles in Modern Synthesis

Fort

Comoy

2014

Lithium Compounds in Organic Synthesis

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Introduction Functional nitrogen-containing heteroaromatic compounds, especially sixmembered ones (pyridines, diazines, quinolines, and their fused derivatives), have attracted the attention of chemists worldwide because they play an important role in the development of new pharmaceuticals [1], agrochemicals [2], catalysts [3], or materials [4] (including polymers).Besides the classical reactions (i.e., electrophilic heteroaromatic substitutions on heterocycles or single electron-transfer (SET) mediated reactions with brominated derivatives) [5] and ex nihilo ring syntheses [6], metallation reactions providing organolithium compounds are of particular interest because they allow the direct functionalization starting from bare or sparsely substituted heterocycles intrinsically more acidic than similar benzene-ring systems. However, the strong bases used for metallation as well as the prepared organolithiums also exhibit a large propensity for nucleophilic addition. Further, though numerous methods have been described for the single derivatization, multiple functionalization often appears much more sensitive and difficult because of the complexation or aggregation phenomena observed either with primary substituents or with the nitrogen atom in the heterocycle itself. These complex phenomena, together with the variation in reaction conditions (temperature, solvent, ratio), produce various competitive reaction pathways. Thus, an arsenal of methodologies has then been developed to tune the regio-, chemio-, and sometimes stereoselectivities. The goal is generally to control these additional influences, providing variation of kinetic or thermodynamic acidity at various sites susceptible to lithiation.With a special focus on pyridines, quinolines, diazines, and fused pyridinic compounds, this chapter describes organolithium tools that allow (i) direct derivatization of bare N-containing heteroaromatics; (ii) metallation of dipolar adducts of pyridines and analogs; (iii) halogen/Li exchanges; (iv) ring metallation by using directing metallation groups; (v) lithiation invoking an halogen dance; and (vi) lateral and remote lithiations (Scheme 15.1). Next, the usefulness of these tools, often Lithium Compounds in Organic Synthesis: From Fundamentals to Applications, First Edition. Edited by Renzo Luisi and Vito Capriati.

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“…[1] Used originally as a means to induce deprotonation at the 2-position of pyridines (1, Figure 1), [2] the majority of studies in this field have focused on lithiation of formally sp 3 -hybridized carbon atoms a to nitrogen in cyclic amines such as tetrahydroisoquinolines [3,4] (2), Troegers base [5] (3), isoindolines [6] (4), aziridines [7] (5), pyrrolidines [3] (6) and indolizidines [8] (7). For several of these substrates (4-6), lithiation of prochiral a-methylene groups with alkyllithiums in the presence of the chiral diamine (À)-sparteine gives enantiomerically enriched products after electrophile quench.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Lithiation of Boron Trifluoride‐Activated Aminoferrocenes: An Experimental and Computational Investigation

et al. 2010

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Tertiary aminoferrocenes complexed to boron trifluoride (BF 3 ) are shown to undergo asymmetric lithiation with alkyllithiums in the presence of bulky chiral 1,2-diaminocyclohexane ligands. This reaction represents the first BF 3 -activated asymmetric lithiation of a prochiral aromatic amine and the first such transformation to be mediated by a chiral di-A C H T U N G T R E N N U N G amine other than (À)-sparteine. The process provides rapid access to a broad range of enantiomerically enriched 2-substituted-1-aminoferrocenes, including derivatives with uncommon substitution patterns that are of interest in catalysis. The enantioselectivity of the process is high enough (87:13 to 91:9 er) to allow for isolation of single enantiomers of several products after simple recrystallization as either the free aminoferrocenes or their ammonium fluoroborate salts. Both antipodes of the planar chiral 2-substituted-1-aminoferrocene products are accessible, as confirmed by single crystal X-ray diffraction analysis of two compounds with opposite relative stereochemistry. Single-point calculation of thirty-two different transition states of the reaction at the M06-2X/6-311 + gA C H T U N G T R E N N U N G (2d,2p) level produced a computational model that correctly predicted both the sense and extent of chiral induction. Three factors appeared to play important roles in determining enantioinduction during lithiation of BF 3 -complexed tertiary aminoferrocenes: (i) the maintenance of a highly organized eight-membered ring transition state; (ii) the existence of a strong Li···F contact which placed the chiral diamine ligand in close proximity to the ferrocene substrate; (iii) the orientation of the sterically demanding N-alkyl groups of the chiral diamine additives, either away or towards, the aminoferrocene and the alkyllithium. The model may serve as a predictive tool for the rational design of new ligands for this and related asymmetric lithiations.

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Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for α-Deprotonation and Stereocontrol

Cited by 129 publications

References 112 publications

Synergic Synthesis of Benzannulated Zincabicyclic Complexes, α‐Zincated N Ylides, through Sodium‐TMEDA‐Mediated Zincation of a Haloarene

Synergic Synthesis of Benzannulated Zincabicyclic Complexes, α‐Zincated N Ylides, through Sodium‐TMEDA‐Mediated Zincation of a Haloarene

Lithiated Aza‐Heterocycles in Modern Synthesis

Asymmetric Lithiation of Boron Trifluoride‐Activated Aminoferrocenes: An Experimental and Computational Investigation

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