Alcohols Methyllithium

Ethereal methyl1ithiurn (as the lithium bromide complex) was obtained by the submitters from Aldrich Chemical Company Inc. The checkers used 1.19 M methyl1ithiurn-lithium bromide complex in ether supplied by Alfa Products, Morton/Thiokol, Inc. The concentration of the methyllithium was determined by titration with 1.0 M tert-butyl alcohol in benzene using 1,10-phenanthroline as indicator. The submitters report that ethereal methyllithium of low halide content purchased from Alfa Products, Morton/Thiokol, Inc., gave similar results. 

One 1-ml aliquot is added to 1.0 ml of freshly-distilled 1,2-dibromo-ethane (bp 132°C) in an oven-dried flask which contains a static atmosphere of nitrogen or argon. After the resulting solution has been allowed to stand at 25°C for 5 min, it Is diluted with 10 rat of water and titrated for base content (residual base) to a phenolphthalein endpoint with standard 0.100 M hydrochloric acid. The second 1-mL aliquot is added cautiously to 10 ml of water and then titrated for base content (total base) to a phenol phthalein endpoint with standard aqueous 0.100 M hydrochloric acid. The methyllithium concentration is the difference between the total base and residual base concentrations.2 Alternatively, the methynithiura concentration may be determined by titration with a standard solution of sec-butyl alcohol employing 2,2 -bipyridyl as an indicator. 

Dihydromorphinone, Cj,Hjg03N, and derivatives. Dihydromorphinone (LIII MeO HO) is formed when morphine in solution is treated with relatively large quantities of platinum or palladium catalyst under various conditions.It melts at 262-3° and yields an oxime, m.p. > 234°. The hydrochloride is the drug known as dilaudid. On 0-methyla-tion dihydromorphinone yields dihydrocodeinone (see above), and when dissolved in ether and treated with methyllithium the corresponding tertiary alcohol, 6-methyldihydromorphine, CigHggOgN, m.p. 209-211°, Wd ° 14i7° (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and Rapoport... 

Precomplexation of 2-butylcyclopentanone with methylaluminum bis(2,6-di-hrt-butyI-4-methylphenoxide) (MAD), prior to the addition of methyllithium, leads to the exclusive formation of the equatorial alcohol via cis attack3 4. However, this methodology is apparently not applicable to 3-substituted cyclopentanones. Thus, addition of propylmagnesium bromide to... 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

Addition of methyllithium to a cyclic /i, y -epoxy-a,/i-unsaturated sulfone gave predominately the m-alcohol as product20. 

Photochemical [2 + 2]cycloaddition of (505) to (506) provided a mixture of head to tail and head to head isomers (507) and (508) which was not separated but was subjected to addition of methyllithium. The tertiary alcohols (509) and (510) obtained were readily separated on trituration and the desired compound (509) was converted... 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

Methyl isovalerate, azeotropic mixtures with butyl alcohols, 4 395t Methyl ketones, acetic anhydride used in synthesis, 1 148 Methyllithium, 14 249 15 147 Methylmagnesium chloride, 16 319 (R)-(—)-Methylmandelic acid chloride, chiral derivatizing reagent, 6 76t Methyl mercaptan production, 15 17 3-Methylmercaptopropionaldehyde (MMP), intermediate in methionine synthesis, 1 268, 269, 276... 

Olefins, conversion to alcohols, 53, 94 from tosylhydrazones and methyllithium, 51, 69 hydroboration-oxidation of,... 

Cutting and Parsons described the transformation of acetylenic alcohols 314 into allenyl phenyl thioethers 316 by a two-step procedure (Scheme 8.85) [174], Deprotonation of alkynes 314 with n-butyllithium is followed by addition of phenylsulfenyl chloride, forming sulfenyloxy intermediates which subsequently rearrange to allenic sulfoxides 315. Treatment of allenes 315 with methyllithium results in loss of the sulfoxide moiety to form allenyl sulfides 316 in reasonable yields. 

The less hindered peripheric secondary hydroxyl group of the key intermediate 28 was chemoselectively tosylated (29), submitted to an internal Wharton-Grob fragmentation (30). After attack on the carbonyl group (3i) with methyllithium and activation of the secondary alcohol as the corresponding tosylate, the resulting... 

When using methyllithium instead of methylmagnesium chloride for the alkylation of 12, the product is obtained in good yield (70%) however the dia-stereoselective ratio drops to 5 1 in favour of alcohol 13. 

An ethereal solution which was 1.38ilf in methyllithium was purchased from Foote Mineral Company. The concentration of methyllithium in ethereal solutions may be conveniently determined by a procedure described elsewhere in which the lithium reagent is titrated with 5ec-butyl alcohol, utilizing the charge transfer complex formed from bipyridyl or o-phenanthro-line and the lithium reagent as an indicator. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Methylcyclohexene, from 2-methyl-cyclohexanone tosylhydrazone and methyllithium, 51,69 Methylenecyclopropanes, 50,30 Methyl iodide, with triphenyl phosphite and cyclohexanol, 51,45 with triphenyl phosphite and neopentyl alcohol, 51,44 METHYL ftrans-2-IODO-l-TETRA-LIN)CARBAMATE, 51,112 Methyl (frans-2-iodo-l-tetralin)carba-mate, with potassium hydroxide to give 1,2,3,4-tetrahydronaph-thalene(l,2)imine, 51,53 Methyllithium, with camphor tosylhydrazone to give 2-bomene, 51, 66... 

In a similar manner, coccinelline (99) and precoccinelline (100) have been synthesized from 2,6-lutidine (351) (336,450). Thus, treatment of the monolithium derivative (153) of 351 with P-bromopropionaldehyde dimethylacetal gave an acetal, which was converted to the keto acetal (412) by treatment with phenyllithium and acetonitrile. Reaction of 412 with ethylene glycol and p-toluenesulfonic acid followed by reduction with sodium-isoamyl alcohol gave the cw-piperidine (413). Hydrolysis of 413 with 5% HCl gave the tricyclic acetal (414) which was transformed to a separable 1 1 mixture of the ketones (415 and 416) by treatment with pyrrolidine-acetic acid. Reaction of ketone 416 with methyllithium followed by dehydration with thionyl chloride afforded the rather unstable olefin (417) which on catalytic hydrogenation over platinum oxide in methanol gave precoccinelline (100). Oxidation of 100 with m-chloroperbenzoic acid yielded coccinelline (99) (Scheme 52) (336,450). 

Further transformations of a-alkyl-3-oxazolidineacetonitriles are possible. Addition of methyllithium to the cyano group followed by acid hydrolysis gave a morpholine derivative, from which a /i-amino alcohol was obtained as a diastereomeric mixture (d.r. 80 20)69. 

Birch reduction-alkylation of (2S)-2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine (1) gives products 2 in high diastereoselectivities29. In contrast to the previous examples, only one double bond remains in the product (if one equivalent of rm-butyl alcohol is used as proton donor). Formally this procedure is a stereoselective cis addition, and is thus particularly useful. Thus, two stereogenic centers are created in the same reaction step with high diastereoselectivities. Subsequent hydrolysis furnishes acids, whereas reaction with methyllithium yields chiral ketones29. 

---