Organolithium with hydrazones

The easiest way to make oxidizable silanes is by condensation of an organolithium with the inexpensive dimethyldimethoxysilane. If enolates have to be silylated, it may be preferable to use the more reactive chlorodimethylalkoxysilanes. Introduced by Dieter Enders, a-lithiated RAMP- and SAMP-hydrazones (e.g., 78) are enolate-like species having an impressive track record for stereocontrolled synthesis. The chiral auxiliary enables the stereoselective introduction of the silicon substituent. Having oxidatively cleaved the hydrazone to restore the original carbonyl function, the latter may be diastereoselective reduced to either an (/ )- or (5)-alcohoI. The ultimate silicon/oxygen displacement thus produces either a meso- or a dl-Aio (Scheme 1-55). ... 

In order to prove the utility of this method and to ascertain the absolute configuration of the products, (S)-alanine has been enantioselectively prepared. The key step is the addition of methyllithium to the AjA -dimethyl hydrazone acetal 4c, derived from diol 3c. In accordance with 13C-NMR investigations it can therefore be assumed that all major diastereomers resulting from the addition of organolithium reagents to hydrazone acetals 4a-c derived from diols 3a, 3b or 3c (Table 3, entries 1 -6) have an S configuration at the newly formed stereogenic center. 

The N-N bond of polystyrene-bound hydrazines, which are prepared by reaction of organolithium compounds with resin-bound hydrazones [457], can be cleaved by treatment with borane to yield a-branched, primary amines (Entry 9, Table 3.23). An additional example of reductive cleavage to yield amines is shown in Entry 10 (Table 3.23), in which a resin-bound a,a-disubstituted nitroacetic ester undergoes decarboxylation and reduction to the primary amine upon treatment with lithium aluminum hydride. 

Imidazolidine-derived organolithium compounds 468 have been prepared by deprotonation of the corresponding IV-acylated imidazolidines with two equivalents of s-BuLi at — 78 °C. The best results have been obtained with the fraws-l,2-diaminocyclohexane-derived imidazolidine 472, so its anion 473 reacted with different electrophiles to give compounds 474 in moderated yields, which gave the expected hydrazones 471 as described above (Scheme 124)676,677. Other imidazolidines suffered deprotonation at the 4-position... 

The reaction of alkyllithium reagents with acyclic and cyclic tosylhydrazones can lead to mixtures of elimination (route A) and addition (route B) products (Scheme 22). The predominant formation of the less-substituted alkene product in the former reaction (Shapiro Reaction) is a result of the strong preference for deprotonation syn to the N-tosyl group. Nucleophilic addition to the carbon-nitrogen tosyl-hydrazone double bond competes effectively wiA a-deprotonation (and alkene formation) if abstraction of the a-hydrogens is slow and excess organolithium reagent is employed. Nucleophilic substitution is consistent with an Su2 addition of alkyllithium followed by electrophilic capture of the resultant carbanion. 

Threo diastereoselectivity is consistent with a chelation-controlled (Cram cyclic model) organolithium addition (Figure 8a). Since five-membered chelation of lithium is tenuous, an alternative six-membered chelate involving the dimethylamino nitrogen atom of the thermodynamically less stable (Z)-hydrazone (in equilibrium with the ( )-isomer) cannot be discounted. The trityl ether (entry 4, Table 9) eliminates the chelation effect of the oxygen atom such that the erythro diastereomer predominates (via normal Felkin-Ahn addition) (Figure 8b). 

The reactions of organolithium, -magnesium, -zinc, -copper, and -titanium reagents with aldehydes, ketones, acetals, imines and hydrazones will be described in this section. The reactions of enolates and enamines will be subsequently examined ( 6.8 to 6.10). 

Ort/io-substituted benzaldehyde complexes have been prepared in high enantiomeric purity (97% ee), and in a one-pot sequence, from an optically pure hydrazone derivative, readily available from -q -benzaldehyde chromium tricarbonyl and SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolidine]. The novelty derives from the combined use of a diastereoselective orthoaddition reaction of an organolithium nucleophile and a hydride abstraction with a triphenylmethyl cation. The subsequent acid hydrolysis serves to remove the hydrazone group, thus liberating the aldehyde functionality (Scheme 6.13). 

In 1996, Yamamoto and coworkers reported that organolithium (t-BuLi, n-BuLi, PhLi)-initiated oligomerization of hydrocinnamaldehyde tran -l-amino-2,3-diphenylaziridine hydrazone 22 afforded oligo(phenylpropylidene) with M = 1,500 2,500 in 43 --67% yield [78], The polymerization proceeded as shown in Scheme 59, where the nucleophilic attack of a carbanion to C = N bond in 22 followed by elimination of N2 and stilbene generated a secondary carbanion as a propagating chain end. 

One of the most successful classes of chiral auxiliaries for asymmetric synthesis is that of Enders proline-based hydrazines, namely (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 74) and its (R)-enantiomer RAMP (Scheme 11.11) [68]. Enders has reported that chiral hydrazones such as 75 undergo diastereoselective additions with organolithium reagents. The facile removal of the auxiliary by reductive cleavage of the N-N bond enables it as a versatile tool for the synthesis of a wide range of chiral secondary amines [69, 70]. As shown in Scheme 11.11, the secondary amine 77 was thus prepared in 73 % overall yield and 93 % ee [69]. 

Oxazolines [158-161], imines (e.g., 33 [159], Scheme 14.14) [159-161] and hydrazones [162] have been used to promote an a addition pathway, an effect ascribed to precoordination of the incoming organolithium by the side-chain heteroatom. Similar a addition can be achieved with heteroatom donor substituents by careful control of conditions and choice of nucleophile [163-165] overcoming the natural y3 control of the donor group. 

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