Benzyllithiums substitution

These aspects have been investigated for a number of substituted benzyllithium systems—Q -(phenylthio)benzyllithium (3), a-phenyl-a-lithiodithiane (4) and a-trimethylsilyl... 

The naphthalene-catalyzed (2.5%) lithiation of phthalan 330 (or its substituted derivatives ) in THF at room temperature allowed the preparation of the functionalized benzyllithium intermediate 331, which reacted with electrophiles at —78°C to give, after hydrolysis, the corresponding functionalized benzyl alcohols 332 (Scheme 97). When carbon dioxide was used as the electrophilic reagent, the corresponding 5-lactone was directly obtained . When carbonyl compounds were used as electrophiles, the cyclization of the resulting products 332 under acidic conditions (85% H3PO4) allows the synthesis of substituted isochromans. 

Beak and coworkers found the (—)-sparteine-complex of iV-Boc-Af-(p-methoxyphe-nyl)benzyllithium 244, obtained from 243 by deprotonation with n-BuLi/(—)-sparteine (11) in toluene, to be configurationally stable (equation 57) . On trapping 244 with different electrophiles, the substitution products 245 are formed with high ee. Efficient addition reactions with imines and aldehydes have also been reported. The p-methoxyphenyl residue is conveniently removed by treatment with cerinm ammoninm nitrate (CAN). 

The closely related a-(pyrid-2-ylthio)benzyllithium (257) has a higher configurational stability, and equilibration with the chiral ligand prior to the substitution step is required , indicating that a dynamic thermodynamic resolution is important (equation 61). Depending on the method of calculation, (7 )-257 255b was found to be by 1.42 to 1.92 kcalmoD ... 

Since carbohthiations usually proceed as syn additions, 458 is expected to be formed first. Due to the configurationally labile benzylic centre it epimerizes to the trani-substitu-ted chelate complex epi-45S. The substitution of epi-458 is assumed to occur with inversion at the benzylic centre. Sterically more demanding reagents (t-BuLi) or the well-stabilized benzyllithium do not add. The reaction works with the same efficiency when other complexing cinnamyl derivatives, such as ethers and primary, secondary, or tertiary amines, are used as substrates . A substoichiometric amount (5 mol%) of (—)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ewf-459, since the opposite enantiotopic face of the double bond is attacked . 

The carbolithiation of styiyl carbamates such as 486 by alkyllithium/(—)-sparteine (11) leads to configurationally stable benzyllithium compounds 487, which have been further substituted by electrophiles (equation 133) °. However, only low enantioselectivities could be achieved with (—)-sparteine (11) (e.r. = 70 30) or (—)-o -isosparteine (14) (e.r. ... 

A number of cycloalkyl-, vinyl-, aryl-, and benzyllithium compounds (predominantly benzyl-lithiums) are converted into fluoro derivatives in good to excellent yields, e.g. formation of 4, 5, and 6 19 however, when this method was applied to the synthesisof 3-fluorobenzocyclobutene from the lithium salt a violent explosion occurred when the reaction mixture was warmed from — 70 C to room temperature.20 Various fluoro-substituted thiophenes 7 are obtained when the starting compounds (thiophene, 2-methylthiophene, etc.) arc transformed with al-kyllithium compounds to the corresponding lithium derivatives then fluorinated with perchloryl fluoride at 0 C.21 Potassium tricyanomethanidc is converted at —15 C in triglyme into tricyanofluoromethane in 81 % yield.22... 

A related isomerization, that of phenylacetylcobalt carbonyl to o-toluyl-cobalt carbonyl, has recently been studied (143). It also appears to proceed via a tricarbonyl but could not proceed via Eqs. (9) and (10). This rearrangement has much in common with the so-called abnormal reactions of benzyl Grignard and benzyllithium reagents to produce ortho-substituted products (13, 13f). It is possible that a cyclic intermediate similar to that postulated in the Grignard rearrangements may be involved, Eq. (87). 

Ahlbrecht, H. Harbach, J. Hoffmann, R. W. Ruhland, T. On the racemization of a-hetero-substituted benzyllithium compounds. Liebigs Ann. Chem. 1995, 211-216. 

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. 

Tertiary analogues 183 of 180 are also configurationally stable at -78 °C.80 182 can be deprotonated and kept for 8 h at -78 °C with little loss of enantiomeric purity. It is consequently possible to make either enantiomer of the protected amine 184 from the appropriate amine 182, of which both enantiomers are available by virtue of the invertive substitution reactions characteristic of tin electrophiles (see section 6.1.4).82 83 Tertiary O-substituted benzyllithiums also have high configurational stability (see above). 

Three types of secondary benzyllithium are known which are configurationally stable on the macroscopic timescale, and they too each contain powerful lithium-coordinating oxygen atoms. One is the N-Boc amino substituted 180 discussed above.80 Partial configurational stability is evident in a close analogue of 180.81... 

Scheme 6.1.5 Stereospecificity in the electrophilic substitution of an a-carbamoyloxy benzyllithium...

Altering the structure of the benzyllithium by introducing a ring creates indanylcarbamate 38. Its reactions follow a similar pattern to benzyllithium 37 but with a general shift towards retentive substitution (scheme 6.1.6).38 The principal defectors from inversion with 37 to retention with 38 are C02 and MeOCOCl. 

Scheme 6.1.9 Invertive electrophilic substitutions of a non-hetero substituted benzyllithium...

In agreement with Walborsky s results and a recent X-ray structure determination of a-cyano-benzyllithium the calculations nicely show that H2C-CN (0.5 kcal mol and Me2CCN (0 kcal mol have almost no inversion barrier while the a-cyano cyclopropyl anion has a sizeable one (9.3 kcal mol ). Whether in the case of the CHO and COOH substituted cyclopropyl anions a pyramidal configuration with a very small barrier (0.7 and 1.9 kcal mol respectively) exists, is not clear. The barrier may be an artifact of the small basis set, and the enolates may well be planar. In any case, the calculations are again in agreement with the experimental result according to which kgx/ rac case of the optically active cyclopropyl phenyl ketone ( —)-(/ )-252 is unity (see Section IV.B.l.a). 

Lithium naphthalenide, LN. 15,190-191 18, 217-218 19,199-200 20,224-225 O—C bond cleavage. P-Ketols result from epoxy ketones on exposure to LN. Various benzyllithiums are formed by reductive lithiation, for example, of 4-aryl-1,3-dioxanes, (V-substituted 2-aryloxazolidines, and benzyl pivalates. ... 

The (Z)- or (E)-phenylhexenyl carbamates 172 are smoothly deprotonated by s-BuLi/(-)-sparteine, and the lithium compound cyclizes during approximately 20 h at -78°C to form the (cyclopentyl)benzyllithium 173 which is in equilibrium with its epimer 174 [Eq. (45)] [110]. Trapping this mixture yields the essentially enantiomerically and diastereomerically pure side-chain substituted fra s-2-benzylcyclopentyl carbamates 175 in fair yields. Some of the intermediate 174 is lost due to 1,3-elimination resulting in formation of the achiral bicycle [3.1.0] hexane derivative 176 [111, 112]. Related results have been reported by Nakai et al., when allowing the ( )-6-phenylhex-5-enyl Md f-diisopropylcarb-amate to react under similar conditions [111]. 

---