Lithium intermediates

An analogous procedure was realized in the selenium series 4H-selenopyran 136 (R = H) was converted with LDA at -77°C to a lithium intermediate (R = Li), which gave ethyl ester 183 by successive treatments with C02 and MeCHN2 (90AG450). 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

Whereas deprotonation and halogen-lithium exchange represent the most common methods to access allenic and propargylic lithium intermediates, several less direct routes to more functionalized analogues have also been reported. Additions of various lithium acetylides to acylsilanes followed by Mel or EtI afforded alkylated allenyl silyl ethers (Table 9.4) [10]. The adducts were analyzed after hydrolysis to the related enones. 

A similar situation takes place when an unsaturated chlorinated ketal is used as starting material. When the /S-chloro unsaturated ketal 140 (R = H) was submitted to a DTBB-catalyzed (5%) lithiation in THF at —78 °C, the corresponding lithium intermediate 141 was generated, which after reaction with different electrophiles at the same temperature gave, after hydrolysis, the expected products 142 (Scheme 52)"". ... 

S-Alkyl Ai,Ai-dialkylmonothiocarbamates have sufficient kinetic acidity for being de-protonated by means of alkyllithium. When applying i-BuLi/(—)-sparteine (11) to the 5-butyl derivative 184 and trapping the lithium intermediates 185 and epi-lS5 by electrophiles, the products 186 and ewf-186 are formed with low enantiomeric excesses (equation 42). Control experiments revealed that not only the rapid interconversion of 185 and epi-lSS is the problem, but also the degree of stereodifferentiation in the deprotonation step is low . 

Some alkenyl carbamates leading to configurationally labile lithium intermediates could be subjected to asymmetric homoaldol reaction with less efficiency (Scheme 6) these reactions have not been optimized yet Azs... 

A conscientious investigation of the stereochemical features was undertaken, including Li and NMR studies of the lithium intermediates . The epimeric ratio is kinetically controlled in the deprotonation step by a high preference for the 1-pro-R-H in 398a, and the stereocentre is configurationally stable at —78°C. The ratio of l-endo-399 and its epimer (Li behind the plane) was found to be 96 4. The interconversion of the E/Z-isomers l-endo-399 and l-exo-399 at — 78°C is slower than the rate of alkylation with... 

According to Widdowson, [(methoxymethoxy)benzene]tricarbonylchromium (448) was deprotonated with enantiotopos differentiation by n-BuLi/(—)-sparteine (11), and the lithium intermediate 449 was trapped by various electrophiles to give the products 451 with ee values up to 97% (equation 122) . Surprisingly, opposite enantiomers are formed when stoichiometric or excess amounts of base are applied. The authors presume that in the dilithium intermediate 450 the C—Li bond (in the rear) has a higher reactivity than the other one (pointed to the front). The deprotonation procedure was also applied to a couple of 1,4-disubstituted chromium complexes . 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

SCHEME 24. Preparation of fluoro-substituted alkenyl zincs via lithium intermediates... 

Metallic lithium in the form of a suspension has been used to polymerize isoprene (97) but the system is not too suitable for an exact analysis of the mechanism. The conversion-time curves are sigmoidal in shape. Minoux (66) has shown that the overall rate is not very dependent on the amount of lithium dispersion used as expected if the organo-lithium intermediates are highly associated. The molecular weight of the polymer is more dependent on quantity of lithium used. The observed kinetic behaviour is very similar to that shown in lithium alkyl initiation. This suggests that apart from differences in the initiation step, the mechanisms are quite similar. 

The kinetically controlled deprotonation of allylic carbamate esters (29) by n-BuLi-(—)-sparteine has preferentially removed the pro-S proton, leading to the lithium intermediate (S)-(30) (Scheme 14).85 Trapping experiments with chlorotrimethylsilane has afforded the a-substitution products, with R-configuration. 

The relative reactivities of pyridine, 3-picoline, and 3-ethylpyridine toward phenyllithium have been measured under various conditions by a competitive technique and found to be in the order 3-pico-line > pyridine > 3-ethylpyridine.252 By carrying out reactions using an equimolar mixture of pyridine and 3-picoline and a large excess of phenyllithium, it has been possible to obtain yields of the phenyl-pyridines of over 80%, provided short reaction times and low temperatures are used. It has also been shown that the low yields usually obtained in such reactions are due to the fact that the dihydropyridyl-lithium intermediates form by-products, probably by polymerization (the intermediate dihydropyridine is a ct s-butadiene-like system and, in the presence of a Ziegler-type catalyst, can be expected to polymerize readily). The a-complexes from 3-picoline and phenyllithium polymerize faster than that from pyridine and phenyllithium, but there is no selective removal of the isomeric dihydropicolyllithium intermediates to form by-products, both isomers undergoing side-reactions at virtually the same rate. 

Fig. 17.73. Ketone —> alkane reduction via enol phospho-noamidates (for one way to prepare A, see Figure 13.24) and enol dialkylphosphates (one way to prepare B is to use a combination of the methods depicted in Figures 13.20 and 13.25). The cleavage of the Cjjj2—0 bond of the substrates occurs in analogy to the electron transfers in the formation of methylmagnesium iodide (Figure 17.44). The alkenyl-lithium intermediates are pro-tonated in the terminating step to afford the target alkenes.

The use of aryllithium instead of the Grignard reagent resulted in a higher ratio of cis-isomer formation [34], In reaction calorimetric studies, it was found that both steps, the formation of 3-methoxyphenyllithium and its addition to ketone, are pretty exothermic with worst-case temperature rises of up to 62 and 133 °C, respectively. The lithium intermediate has to be kept at very low reaction temperatures to prevent decomposition. We concluded that a continuous reaction may be a good alternative to batch synthesis to improve the reaction yield and to minimize the safety concerns because of the exothermicity of the reaction sequence. 

Methoxyphenyllithium and cyclohexanone were reacted in a batch mode at —10 and —65 °C to give yields of 32 and 80%, the expected tertiary alcohol, respectively [34]. Such temperature effect was also planned to be used in the microreactor. The metal-halogen exchange step could be performed at —14 ° C with 17 s residence time and the lithium intermediate further reacted with cyclohexanone in batch mode at —40°C. Lower temperatures were not possible because of chiller limitations, and the availability of only one microreactor accounted for the combined continuous flow-batch processing. In this way, a yield of 87% yield at a throughput of 54g/h was achieved. 

The lithium intermediate is unstable, even at temperatures as low as 60 °C. Only a continuous process with a short residence time between the two reactions was allowed to avoid decomposition and have sufficient selectivity for an economical process [44]. Clogging is a major issue for the first process. Owing to heat release issues, high dilution is applied, and the recycling of the solvent was an important issue that needed to be considered. 

Dimethylisothiazole formed a similar ring cleavage product, and 4-methylisothiazole, although lithiated predominantly in the 5-position, gave a small proportion of a nitrile, possibly via an isothiazolyl-3-lithium intermediate (Scheme 28).103 A 4-bromo... 

We recently reported a convenient and efficient synthetic route to new 3-substituted 2,3-dihydrobenzo[h]furans 278 based on the tandem cyclization-y-alkylation of 2-bromophenyl ( )-3-phenyl-2-propenyl ether 276 whose operational simplicity could find favor in many applications161. Previous attempts using 2-bromophenyl (E)-2-propenyl ether failed because the cyclic intermediate underwent a y -elimination. We thought that a likely strategy to overcome the y-elimination in the cyclic (2,3-dihydrobenzo[h]furanyl)methyllithium intermediate could be substitution by a phenyl moiety that could provide increased resonance stabilization to the cyclic lithium intermediate 277 (Scheme 85). 

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