Lithiation, reductive

Among the a-hetero-substituted chiral organometallic reagents, a-lithio ethers 2 are an important class of compounds. A general route to these compounds is the reductive lithiation of a-(phcnylthio) ethers 1 with lithium (dimethylamino)naphthalenide (I.DMAN)4,5. The generality of this method lies in the ready availability of various types of a-(phenylthio) ethers. 

Until recently, the main route to simple a-lithiosilanes was addition of organolithiums to vinylsilanes, with all the obvious limitations involved. However, reductive lithiation (8) of phenylthioacetals using lithium 1-dimethylaminonaphthalenide (LDMAN) makes the following general Iprocess of considerable value ... 

Reductive lithiation, 68 Reductive silylation, 26 Reformatsky reaction, 71 Riihlmann condensation, 134,139... 

Keywords Cyanohydrin acetonide alkylations. Reductive decyanations, Oxocarbenium ions. Reductive lithiation... 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

Lithio-l,3-dioxanes are prepared by reductive lithiation of 4-(phenylthio)-l,3-dioxanes and by transmetallation of the corresponding 4-(tributylstannyl)-l,3-dioxanes. This section describes the use of 4-lithio-l,3-dioxanes in the synthesis ofsyn- and anfz-l,3-diols. 

Later work examined substituent effects on kinetically controlled alkylations [68, 69] (Scheme 32). Substitution at the 5-position is well tolerated in these reactions. Reductive lithiation of a series of 4-phenylthio-l,3-dioxanes and quenching of the axial alkyllithium intermediate with dimethyl sulfate provided the flzzfz -l,3-diols in good yield, with essentially complete selectivity. 

The use of excess lithium LiDBB in reductive lithiations is a drawback for preparative-scale reactions. A modification of Yus procedure [72, 73] allowed for the generation of a-alkoxylithium reagents under catalytic conditions [45] (Scheme 35). Slow addition of the phenyl sulfide 185 to a suspension of lithium... 

There can be significant differences in the rates of elimination of the stereoiso-meric (3-hydroxysilanes. Van Vranken and co-workers took advantage of such a situation to achieve a highly stereoselective synthesis of a styryl terpene. (The lithiated reactant is prepared by reductive lithiation see p. 625). The syn adduct decomposes rapidly at -78° C but because of steric effects, the anti isomer remains unreacted. Acidification then promotes anti elimination to the desired /i-isomer.275... 

Of particular note here is that, besides the organolithium derivative, the solvent also plays an important role [191] Me20 was found to be a highly effective for the in-situ production of the radical anion 2-354 from its precursor N,N-dimethylammo naphthalene. For the reductive lithiation of the thioethers and the following steps, the addition of pre-cooled Et20 combined with subsequent removal of the Me20 under reduced pressure gave the best results. 

Diols from Lithium P-Lithioalkoxides Generated by the Reductive Lithiation of Epoxides 2,5-Dimethyl-2,4-hexanediol. 

The silicon analogue 74 u5) also appears to be a potentially useful conjunctive reagent in this sequence even though silicon appears to retard the rearrangement71 It is generated by silylation of 37a followed by reductive lithiation (Eq. 90). The... 

DIOLS FROM LITHIUM [5-LITHIOALKOXIDES GENERATED BY THE REDUCTIVE LITHIATION OF EPOXIDES ... 

Although lithium p-lithioalkoxides can also be generated from p halo alcohols by deprotonation and subsequent reductive lithiation of the carbon-halogen bond73 8 or from p-halo ketones by organolithium addition to the carbonyl group followed by reductive lithiation,8 the current method is more direct as well as more convenient, since epoxides are readily available either commercially or by a variety of procedures. 

B. Mudryk and T. Cohen 173 1,3-DIOLS FROM LITHIUM p-LITHIOALKOXIDES GENERATED BY THE REDUCTIVE LITHIATION OF EPOXIDES 2,5-DIMETHYL-2,4-HEXANEDIOL... 

Dialkoxymethyllithium compounds, for example 2-lithio-l,3-dioxan (311), are generated in situ as shown in equation 69, either by reductive lithiation of a phenyl thioether with a lithium arene or by transmetallation of the corresponding trialkylstannyl compound. Subsequent quenching with electrophiles leads to the usual alkylated or functionalized species ... 

Whereas the halogen-lithium exchange is of limited importance for the generation of a-lithiated ethers, the reductive lithiation of 0/S-acetals has been applied more frequently, the versatility being enhanced by remarkable diastereoselective variants. Thus, a single diastereomer of the lithium carbenoid 52 results from the diastereomeric mixture 51 (equation 34) . Representative examples of a-lithiated ethers generated by this method and their reactions with electrophiles are given in Table 4. 

TABLE 4. Representative examples of a-lithiated alkyl ethers, generated by reductive lithiation of a-phenylthio and a-phenylsulfonyl ethers, and reactions with electrophiles... 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

If further acidic C—H bonds in the molecule cause problems, the tin-trick can be applied. The asymmetric deprotonation of a bifunctional carbamate (39a) is accomplished at an early stage and the masked carbanionic centre carried through the synthesis as a stan-nyl group. For instance, the (S)-5-silyloxy-l-tributylstannyl-pentyl carbamate 39b (> 95% ee) was produced by the usual means and converted by standard steps via the aldehyde 78 into the allyl chloride 79 (equation 17) . Lithiodestannylation of 79 by n-BuLi proceeds faster than reductive lithiation in the allylic position to form the lithiocarbamate 80,... 

The /3-position of an enamine system is much more difficult to meta-late than the a-position because of the higher electron density on the /3-carbon, and so additional activation, or stronger base systems, are often required for efficient reaction. Thus, successful /3-lithiation of the 3-(phenylthio)enamine of morpholine can be achieved because of the stabilizing effect of the sulfur atom, whereas reductive lithiation of the same species can be achieved with lithium napthalenide or lithium in liquid ammonia (Scheme 131) [82JCR(M)621,82JCR(S)48]. Similar /3-lithioenam-... 

The reductive lithiation of a-alkoxy phenylsulfides is a slow process (typically 0.5-1 h at -78°C) and lowering the LUMO of the electron acceptor by using, for example, an anomeric sulfone, leads to a much faster electron transfer [11]. Reductive lithiation of sulfone 22 is fast (less than 1 min) and leads to similar a-lithio reagents to those described above and Scheme 8 shows examples of simple a-C-2-deoxyglycosides 23 and 24 prepared by this protocol. The most interesting feature of anomeric sulfones is that alkylation prior to the reductive desulfonylation event is achievable. In this way, a one-pot four-step sequence... 

Lithio-l-methoxycyclopropane can be generated by reductive lithiation of 1-methoxy-l-phenylsulfanylcyclopropane with lithium 1-dimethylaminonaphthalenide (Method A)146,147 or lithium 4,4 -di-f< r/-butylbiphenylide (Method B)148 in tetrahydrofuran at — 78 °C. 1-Lithio-l-methoxycyclopropanc reacts with enones and enals to produce 1-methoxycyclo-propanemethanols, which rearrange to vinylcyclobutanones 1 using tetrafluoroboric acid in tetrahydrofuran (Method C) 146,147 or triflic anhydride in the presence of 2,6-di-f 77-butyl-4-methylpyridine in dichloromethane (Method D).148 The latter method avoids destruction of acid-sensitive products (Table 11). 

Like their sulfur counterparts (Section 3.2.4.4.2.), 1 -lithiocyclopropyl selenides 1, as generated by reductive lithiation of bis(selanyl)cyclopropanes 173 with butyllithium in diethyl ether or tetrahydrofuran, react with aldehydes or ketones to give /Lhydroxy selenides 2, which rearrange to cyclobutanones 3 on treatment with p-toluenesulfonic acid in wet benzene.174 175 The method was used in a total synthesis of a-cuparenone.175... 

Lithium naphthalenide has been used for reductive lithiation of thioketals (8, 306 9, 284), but has the disadvantage that naphthalene is sometimes difficult to separate from final products of alkylation. In such cases, lithium I -(dimethylamino)-naphthalenide can be used advantageously since dimethylaminonaphlhalene is removed from reaction mixtures by extraction with dilute acid.1... 

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