Reductive alkylation Lithium-Ammonia

REDUCTIVE ALKYLATION Lithium-Ammonia. p-Toluenesulfonyihydra-zine. 

Weiss and his associates have studied the reductive alkylation of the 3-ethylene ketal of pregna-5,16-diene-3,20-dione (81) as a route to the 3-ethylene ketals of 17a-alkylpregn-5-ene-3,20-diones. The unsaturated ketone is reduced in ammonia-tetrahydrofuran using the theoretical quantity of lithium... 

Deghenghi et al studied the reductive alkylation of 16-dehydropregneno-lone acetate in ammonia-tetrahydrofuran using excess lithium and alkyl iodides. Alkylation with methyl iodide followed by reacetylation of the 3-hydroxyl group affords 17a-methylpregnenolone acetate in 20% yield after purification by column chromatography. Ethyl iodide affords the 17a-ethyl analog in 40% yield, but n-propyl iodide affords the 17a-propyl compound in only a 12 % yield. 

A useful alternate procedure which allows the generation and alkylation of the less stable enolate anion has been reported by Stork.This method takes advantage of the fact that the thermodynamically less stable enolate anion formed in the lithium ammonia reduction of a conjugated enone... 

Unless a proton donor is added, the lithium-ammonia reduction of an cnone leads to the lithium enolate and lithium amide. The latter is a sufficiently strong base to rapidly convert the mono-alkylated ketone into its enolate, which can be further alkylated. The function of the... 

ALCOHOL represents a convenient method of converting allyl alcohol to 2-substituted 1-propanols, while a one-pot reaction sequence of alkylation (alkyl lithium) and reduction (lithium—liquid ammonia) provides excellent yields of AROMATIC HYDROCARBONS FROM AROMATIC KETONES AND ALDEHYDES. 

Additionally, it was found that the double reductive alkylation of the 2,5-diester 66 could be achieved under Birch conditions (Li/NH3) to produce the 3-pyrroline 67. On the basis of a mechanistic postulate that such reductions do not involve transfer of a proton from ammonia, the authors discovered that the same reduction could be performed in THF (no ammonia) with lithium metal and catalytic amounts of naphthalene as an electron shuttle, thereby making this reaction more practicable on a large scale <00TL1327>. 

One final example worth mentioning is the reductive alkylation/arylation with lithium and alkyl/aryl halides in liquid ammonia. This is a two-step process in which negatively charged nanotubes are formed via electron transfer from the metal. This step is relatively easy and fast due to the CNTs electron sink properties, and it enables exfoliation of the tubes through electrostatic repulsion in the second stage, the alkyl/aryl halides react with the charged tubes to form a radical anion which can dissociate into the alkyl radical and the halide anion, with the former species undergoing addition to the CNT sidewalls [42]. 

Ring opening is common in the alkali metal and liquid ammonia reduction of furans unless an anion stabilizing group is present, so most work has been done with derivatives of furancarboxylic acids. Treatment of furan-2-carboxylic acid with lithium and ammonia at -78 °C followed by rapid addition of ammonium chloride affords 2,5-dihydrofuran-2-carboxylic acid (80%). Reductive alkylation similarly gives 2-alkyl-2,5-dihydrofuran-2-carboxylic acids. This method has been used in a synthesis of rosefuran, the intermediate dihydrofuran (66) being converted into the product (67) by oxidative decarboxylation with... 

Desulfuration a-alkylation of -keto sulfones.1 Reductive alkylation of sul-fones is routinely carried out by a-alkylation of the enolate followed by desulfuration (Al/Hg). It can also be effected in one pot by desulfuration with lithium in liquid ammonia, which generates an enolate that can be alkylated. The yield is markedly enhanced by conversion of the lithium enolate to an alkylstannyl enolate by addition of Bu3SnCl with HMPT as cosolvent. 

Zirconium(IV) isopropoxide, 352 Reductive alkylation of aromatic rings Birch reduction, 32 (S)-Prolinol, 261 of carbonyl groups Trityl perchlorate, 339 of other substrates Lithium-Ammonia, 158 Reductive cleavage (see also Reduction of epoxides)... 

The proper double-bond stereochemistry may be achieved by using 2-heptyne as a reactant in the final step. Lithium-ammonia reduction of 2-heptyne gives the trans alkene hydrogenation over Lindlar palladium gives the cis isomer. The first task is therefore the alkylation of propyne to 2-heptyne. 

Reductive alkylation of carbon nanotubes using lithium and alkyl halides yields sidewall-functionalized nanotubes soluble in common organic solvents. Billups group prepared dodecylated SWCNTs from raw HiPCO tubes using lithium and dodecyl iodide in liquid ammonia and demonstrated the occurrence of exten-... 

The use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(l//)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with l-chloro-3-iodopropane or 1-chloro -iodobu-tane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178). 

Gtmnal alkylation af ketones. Coates and Sowerby have reported a new method for site-selective geminal alkylation of ketones which involves reduction of the n-butylthiomethylene derivative of the ketone by lithium-ammonia to give a methyl-substituted cnolatc anion which can be alkylated in situ. The ketone, for example cyclohexanone (I), is condensed with ethyl formate and then transformed into the n-butylthiomethylene derivative (2) by reaction with n-butyl mercaptan (2, 53-54). This is then reduced with excess lithium in liquid ammonia at -33° with 2 eq. of a proton donor (water is usually used to avoid ovcralkylation). The lithium cnolate is then... 

The method of choice for the preparation of the 1,4-dihydro compound (99) therefore entails reduction of (95) with lithium in ammonia in the absence of alcohol, followed by quenching with ammonium chloride. Acid (99) is also susceptible to rearrangement under acidic conditions, however, and the isomer (100) is formed at pH 4-5 (conditions which might readily prevail during the isolation procedure). 3-Methoxybenzoic acid (95) undergoes reductive alkylation at C-1 without difficulty, and has been used extensively in synthesis. 

Methoxy-l-naphthoic acids (107 R = H, OMe) have been reduced with lithium or sodium in ammonia, with no loss of the ortho methoxy substituent being reported. Thus, in the presence of ethanol the 1,4-dihydro acids (108 R = H) are obtained, while reduction in the absence of a proton source and quenching with methyl iodide affords the alkylated acids (108 R = H, OMe, R = Me). The conditions used for the reductive alkylation in the earlier examples (Na/NH3/-70 C) would enhance retention of the... 

A systematic study of the reductive alkylation of acetophenones revealed that the desired transformation (Scheme 30) required a careful selection of reagents and conditions. The best results were obtained from reduction by potassium in ammonia at -78 °C, with t-butyl alcohol as the proton source. Exchange of the potassium counterion of the enolate (152 M = K) for lithium then ensured regioselective alkylation at C-1 to give (153) in 80-90% yields (Scheme 30). Metals other than potassium as the reductant led to undesirable side reactions with the carbonyl group, which included simple reduction to the methylcar-binol and ethylbenzene (lithium or sodium), while the absence of a proton source or presence of a strong... 

Early reports indicated that 1-tetralones are reduced by sodium or lithium in liquid ammonia at -33 °C to the corresponding tetralols or tetralins, although a very recent study has shown that up to seven products (four of them dimeric) may be formed when lithium is utilized. Nevertheless, the reductive alkylation conditions applied successfully to the ring reduction of acetophenone also succeed with 1-tetralones. 1-Tetralone itself was transformed into (165) in 60% yield, while modifications to the original procedure allowed the methoxylated derivatives (166) to (169) to be prepared in excellent yields. ... 

Stoik et al. have shown that heteroannular extended dienolates such as (73), which contain substituents at both the a- and y-positions, undergo predominantly equatorial alkylation (Scheme 35). The dienolate (73) was product by lithium-ammonia reduction of the tricyclic dienone (72) and the product of its alkylation wiA I-bromo-3-chloro-2-butene and hydrolysis of the resulting enol ether, i.e. (74), was a key intermediate in a short, highly stereoselective synthesis of ( )-adrenosterone. It was pointed out that equatorial alkylation is obtained with dienolates such as (73) and related compounds brcause a peri interaction (Me OMe) of the a- and y-substituents forces the ring a to adopt a half-boat conformation in which the a-face of the ir-system is accessible to attack. 

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