Sulfides reductive lithiation

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... 

Reductive lithiation of allyl phenyl sulfides.1 This reagent is particularly useful for preparation of allyllithium reagents at temperatures at which the anions are stable. Moreover, regioselectivity in reactions can be achieved by conversion to allyltitanium(IV) complexes by metal exchange with Ti(0-/-Pr)4. Thus the un-symmetrical anion formed from the allyl sulfide 1 with LDMAN reacts with cro-tonaldehyde to give a mixture of 1,2- and 1,4-adducts. The 1,2-adduct 2 can be obtained in high yield as two diastereomers (9 1) by use of the allyltitanium complex (equation I). 

Cycloalkenyllithiums.3 Alkenyllithiums are usually prepared by reductive lithiation of trisylhydrazones of ketones with butyllithium, but this method fails with the hydrazones of cyclic ketones. However, the cycloalkenyl sulfides, prepared by reaction of cyclic ketones with thiophenol, can be reductively lithiated with LDBB at -78°. This lithiation fails in the case of cyclopentenyl sulfides, but is useful in the case of the vinyl sulfides obtained from 6-, 7-, and 8-membered cycloalkanones. 

The first step in the reductive lithiation of alkyl phenyl sulfides (Screttas-Cohen process) consists of preparing the reducing reagent in stoichiometric amounts. Lithium naphthalenide, for example, is made from lithium and naphthalene. The sulfide is added drop wise to this reducing reagent. The mechanism of reduction corresponds step by step to the one outlined in Figure 17.44, except that the dissolved radical anion is the source of the electrons, as opposed... 

Fig. 17.46. Reductive lithiation of an alkyl aryl sulfide (Screttas-Cohen process) and an alkyl chloride (Screttas-Yus process).

Although allylic lithiation by deprotonation of non-heterosubstituted compounds is possible using superbases (see section 2.6), in most cases allylic lithiation requires a directing heteroatom. (Non-heterosubstituted allyllithiums are best produced by reductive lithiation of allyl ethers or allyl sulfides - see section 4.4.) One of the few cases where this heteroatom is not a to the new organolithium is shown below the p-lithiation of a homoallylic amide 137. The reaction is particularly remarkable because of the possibility of competing deprotonation... 

The synthesis of organolithiums by reductive lithiation of phenylsulfides owes its importance to the ease with which the sulfides can be formed.8 Unlike halides, sulfides are not electrophilic, and self-coupling side reactions do not pose a problem. 

The simple reductive lithiation and quench of dithioacetals means that a-functionalised - and in particular, a-silylated sulfides are very easy to prepare. Cohen has exploited this in a number of ways for example, a ketenedithioacetal 70 can be used to generate an a-lithiovinylsilane 71 if a silyl halide is used as the electrophile in the first step.85... 

Lithiosilanes derived from cyclopropane dithiocetals add to aldehydes to give precursors for Peterson olefinations - one of the best ways of making alkylidene cyclopropanes. In the example below, the lithiated allyl sulfide 72 adds cleanly to a ketene dithioacetal to give cyclopropane 73. Successive reductive lithiations give silane 74 and then a mixture of... 

Other thioacetal-type functional groups are good starting materials for reductive lithiation for example, a-lithioether 79 is readily made by oxidation of a sulfide to a thioacetal 78 followed by reductive lithiation.87... 

California Red Scale is a worldwide citrus pest which can be controlled by means of the pheromone 60. Cohen used reductive lithiation to generate versatile allylic nucleophiles applicable to this type of target.6 The allyl sulfide 61 is lithiated by BuLi and reacts with butenyl bromide a to sulfur to yield 63. Reductive lithiation (Li, DBB) of the product yields allyllithium 64. A regioselective reaction of this nucleophile with formaldehyde at the more substituted terminus is ensured by transmetallation to the allyl titanium 65, which gives 66 after treatment with formaldehyde and bromination. 

A second molecule of the lithiated sulfide 62 is then used to introduce the next allylic unit, and reductive lithiation of the product 67 gives allyllithium 68. On this occasion, reaction at the less substituted terminus of the allyl system is required, and this can be achieved by transmetallation (at low temperature, to preserve the cis configuration) to the allylcerium 69. Reaction with formaldehyde followed by acetylation gives the pheromone 60 contaminated by less than 2% of the undesired E isomer. 

When there is no programmed radical cyclization reaction as discussed in the preceding section, the anomeric radical generated under reductive metallation conditions will obviously be reduced to an organometallic. This is no longer radical chemistry but the radical initiation will impose the stereoselectivity of the anionic process that follows if kinetic conditions are maintained. This situation is observed in the reductive lithiation with lithium naphthalenide (LN) of derivatives 10 where X can be Cl, SPh, or SOjPh (Fig. 13), a process first reported on cyclic a-alkoxyphenyl sulfides. ... 

Several other applications of this method have been published. Reductive lithiation of l-(trimethyl-silyl)cyclopropyl phenyl sulfide gives a-lithio(trimethylsilyl)cyclopropane, which reacts with carbonyl... 

Reductive lithiation of a-silyl sulfides 135 by means of aromatic radical anions, such as lithium naphthalenide (LN), lithium 4,4 -di-tert-butylbiphenyUde (LDBB) or lithium l-(dimethylamino)naphthalenide (LDMAN), gives the corresponding a-sUyl carbanions, which can be utilized in Peterson reactions (Scheme 2.85) [241-247]. LDMAN and LDBB usually offer higher reduction potentials than LN. 

A companion reagent to the ylide is the corresponding metalated sulfide 30 which arises by the lithiation of 29 with n-butyllithium 66). The latter forms by base closure of 28. Since closure of 28 b involves use of n-butyllithium, the cyclopropyl sulfide 29 simply becomes an intermediate which is metalated in situ to give 30 directly67). A non-metalation sequence involves 32 which undergoes reductive... 

An interesting Fe-catalyzed SN2 -like carbene insertion reaction using diazo compounds and allyl sulfides (the Doyle-Kirmse reaction) was reported by Carter and Van Vranken in 2000 [20], Various allyl thioethers were reacted with TMS-diazomethane in the presence of catalytic amounts of Fe(dppe)Cl2 to furnish the desired insertion products with moderate levels of stereocontrol [Equation (7.6), Scheme 7.14]. The products obtained serve as versatile synthons in organic chemistry, e.g. reductive desulfurization furnishes lithiated compounds that can be used in Peterson-type oleftnations to yield alkenes [Equation (7.7), Scheme 7.14] [21]. 

With sulfides as intermediates, alkenes can be used as precursors to organolithiums with regioselectivity in the formation of 56 determined by whether a radical11 or polar73 thiol addition is employed. Easy lithiation of phenyl benzyl sulfide 57 makes substituted benzyllithiums such as 58 readily available.73 Reductive C-S cleavage is probably the best way of making benzylic organolithiums. 

Intermediates 663 can be prepared by tin-lithium transmetallation with w-BuLi from a-stannylated vinyl sulfides974. Starting from l,l-bis(arylsulfanyl)ethenes, a reductive metallation with lithium naphthalenide at —70°C is a very efficient approach to lithiated vinyl sulfides975,976. Other methods involved bromine-lithium exchange977 or addition of methyl or phenyllithium to thioketenes978. A convenient method for the preparation of l-(methylsulfanyl) and l-(phenylsulfanyl) vinyllithiums was the treatment of 2-methoxyethyl sulfides with 2 equiv of w-BuLi-TMEDA at — 30 °C979. 

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