Dimers chiral lithium amides

Stoddart and coworkers40 have synthesized a chiral lithium amide with C2-symmetry and two chelating methoxy groups from the amine (R,R)-di(a-methoxymethylbenzyl)amine (7). This lithium amide was crystallized from a hexane solution and X-ray analysis revealed a dimeric structure where both lithiums are tetracoordinated, (Li-7)2. 

Mixtures of lithioacetonitrile and chiral lithium amides with both one and two internally coordinating methoxy groups, Li-8, Li-10 and Li-14 respectively, have recently been subject to detailed NMR studies in our laboratory64,65. Mixed dimers are favored... 

The rate constant for the lithium-lithium exchange within the mixed complexes of chiral lithium amides and lithioacetonitrile also differ, depending on the structure. The C-lithiated structures are significantly less fluxional than the /V-lithiated mixed dimers. The activation energy, AG, has been determined for two C-lithiated nitrile complexes in Et20... 

A kinetic investigation using 20 in the deprotonation of cyclohexene oxide revealed that the composition of the activated complexes was different from that assumed in the theoretical model. The reaction orders showed that an activated complex is built from one molecule of chiral lithium amide dimer and one molecule of epoxide 1. Such activated complexes have been computationally modeled by the use of PM3 and optimized structures are displayed in Figure A44. 

Ahlberg and coworkers noted that in some cases the enantioselectivity was increased when running the deprotonations with equimolar amounts of the novel bulk bases and the chiral lithium amide113. This finding initiated a detailed mechanistic investigation using isotopically labeled compounds and multinuclear NMR spectroscopy and kinetics, to elucidate the nature of the reagents and transition states in the deprotonations. They discovered that mixed dimers 23 and 24 are formed in solution from monomers of chiral lithium amide 20 and bulk base 21 and 22, respectively (Scheme 73). 

In the development of chiral lithium amides which result in higher ee, the effect of a diverse set of substituents R and R in 38 was examined. It was shown that ee increases as the size of substituent R becomes bulkier, and also as the amount of fluorine in R increases. In THF, 38a occurs as a monomeric structure M-38a in either the presence or absence of HMPA. Fluorinated base 38b has also been shown to be monomeric in THF, consistent with structure M-38b where the fluorine atoms do not act as internal chelating ligands. In the presence of LiCl, the solution structure of labeled 38b was examined by Li and NMR in THF-ds- The Li- N coupling patterns showed that mixed dimer MD-6 was formed, as also illustrated with 38a. The absolute configuration of the products renders the OD-1 structure of transition state TS-1 most likely (Fig. 7) [58]. 

The 6Li, 15N and 13C NMR spectra of the a-aminoalkoxide-LiHMDS mixed dimer, where LiHMDS = lithium hexamethyldisilazide, showed the presence of a pair of conformers.7 6Li and 15N couplings and 6Li, ll HOESY data gave structural information for chiral lithium amides with chelating sulfide groups, e.g. (3).8... 

The two chiral lithium amides were found to form symmetrically solvated dimers in diethyl ether (DEE). The addition of tetrahydrofuran (THF) and of l,3-dimethyl-3,4,5,6-tetrahydro-2-(l//)-pyrimidinone (DMPU) did not affect the Li NMR chemical shift due to a very strong internal coordination. The Li and Li MAS-NMR signals of fast ionic conducting Li2 2xMgi+xCl4 have... 

The developed model for the deprotonation activated complexes described above has been used as a starting point for structural modification of the lithium amide in order to increase the energy difference between the diastereomeric-activated complexes and thus the stereoselectivity. Computational chemistry has been used to predict the stereoselectivity with modified chiral lithium amides. Some of these designed novel lithium amides have been synthesized and investigated experimentally with respect to their stereoselectivity. One of these is the lithium amide 5 (shown in Scheme 8 as monomer 5a) which, like the previously discussed lithium amides, appear to be a dimer (5b or 5c) in THF solution as shown by multinuclear NMR spectroscopy and computational chemistry [19,38]. 

The results led us to investigate the composition of the reagent solutions by multinuclear NMR spectroscopy. These studies revealed that under these new conditions 5 was no longer present as a homodimer, i.e., a 5 molecule is complexed with another 5 molecule. Instead the results showed new dimers -heterodimers 8 or 9, respectively. A monomer of 5 forms complex with a monomer of a bulk base and these heterodimers are the new reagents rather than homodimers of the chiral lithium amide (Scheme 12) [20-22]. 

Similar to the LDA dimers 52 in solution and in the crystal, the chiral amide 72a forms a bis-solvated dimer 82 as shown by the crystal structure [92] and NMR studies in THF [93]. The dimeric structure 83 was found in the case of Koga s base 75 (X = CH2) wherein hthium adopts a threefold coordination by chelation and not by coordination to THF [94] (Scheme 2.23). Similar dimeric structures were confirmed more recently by a variety of NMR techniques for chiral lithium amides derived from valinol [95]. 

Scheme 2.23 Dimeric structures of chiral lithium amide bases and their mixed aggregates with lithium halides.

The proUne-derived diamidobinaphthyl dilithium salt S,S,S)-66, which is dimeric in the sohd state and can be prepared via deprotonation of the corresponding tetraamine with n-BuLi, represents the first example of a chiral main-group-metal-based catalyst for asymmetric intramolecular hydroamination reactions of aminoalkenes [241], The unique reactivity of (S,S,S)-66, (Fig. 17) which allowed reactions at or below ambient temperatures with product enantioselec-tivities of up to 85% ee (Table 17) [241, 243] is believed to derive from the close proximity of the two lithium centers chelated by the proline-derived substituents. More simple chiral lithium amides required significantly higher reaction temperatures and gave inferior selectivities. 

The lithium amide analogue with only one chiral center derived from (1-phenylethyl) benzyl amine (2) has been found to crystallize as a disolvated dimer from a THF solution, (Li-2)2 2THF. With PMDTA added, the lithium amide crystallized as a monomer solvated by one triamine molecule, Li-2 PMDTA, showing the coordinating strength of PMDTA29. 

Koga and coworkers30-32 have studied the lithium amides of several chiral l-phenyl-2-(l-piperidino)ethylamines with various substituents on the secondary nitrogen (3). NMR studies of the 15N and 6Li labelled lithium amides showed that they exist as monomers in THF, Li-3 2T1I1. and dimethoxyethane solvents, respectively. In Et20 and in toluene solution, symmetrically coordinated dimers, (Li-3)2, were observed. Addition of HMPA to either of the solutions resulted in monomers. 

In the presence of the corresponding pyrrolidine diamine, the chiral lithium pyrrolidide amide yields dimeric chelates composed of a lithium pyrrolidide amide dimer solvated by a pyrrolidine diamine, (Li-6)2 6, as shown by NMR spectroscopy39. The lithium amide gives two 6Li NMR signals in a 1 1 ratio. The addition of TMEDA to Li-6 results in a similar complex where TMEDA coordinates to the lithium pyrrolidide amide dimer, (Li-6)2 TMEDA. 

Li-C couplings have been collected for a series of lithium reagents by Reich and co-workers, who studied their chelation and aggregation with potential 5-, 6-, and 7-ring chelating ether and amine ortho substituents. The couplings have been also applied by Hilmersson and Malmros in their studies on mixed dimer and mixed trimer complexes of -BuLi and a chiral hthium amide. 

Terminal epoxides 29 have also been proven to efficiently undergo a dimerization reaction promoted by hindered lithium amides, thereby leading to 2-ene-l,4-diols 30 as the final products. Such a reaction, which exploits the carbenoid character of Hthiated oxiranes, works at best when neat terminal epoxides are slowly added to a hexane/i-BuOMe mixture of lithium amide (Scheme 7). The synthetic utiHty of this methodology has been illustrated for the synthesis of D-mannitol and D-iditol in only three steps starting from chiral non-racemic (S)-tritylglycidyl ether (20050L2305). 

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