Amines reductive lithiation

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. 

Alternative strategies for the generation of a-heteroatom-substituted organolithiums were then developed (Scheme 7-61), such as the reductive lithiation of a-phenylthio ethers or phenylthio amines [67]. 

The resolution required for the synthesis of 288 or 291 can be avoided by making them by asymmetric reduction or by asymmetric alkylation of an aldehyde . The amines 291 (R = Et or w-Bu) formed in this way are lithiated with diastereoselectivity similar to, or greater than, that achieved with 288. a-Ethyl and a-butylphosphines 294 incidentally may show even higher selectivity than the more widely used a-methylphosphine ligand PPEA 283. 

The reductive ring opening of six-membered nitrogen-containing heterocycles was studied with A-phenyltetrahydroisoquinoline (391). Its lithiation with lithium and a catalytic amount of DTBB (4.5%) afforded the benzylic intermediate 392, which was allowed to react with electrophiles giving, after hydrolysis, functionalized amines 393 (Scheme 110) . It is noteworthy that in the reaction with carbon dioxide, instead of the corresponding lactam, amino acid 393 with X = CO2H was exclusively isolated. 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaUy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphorus [7723-14-0]y produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-lithiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has litde commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Enamidines (2). Lithiation of 1 followed by treatment with aldehydes or ketones results in Peterson olefination to give a mixture of isomeric enamidines (2) in good yield. These enamidines can be used to convert the carbonyl compounds used in (heir preparation to homologated amines, aldehydes, and ketones. Conversion to a mclhylaminc involves reduction with sodium borohydride (pH 6) to an aminal, which is then hydrolyzed by dilute acid. The sequence can be carried out from 1 without isolation of any intermediates (equation I). 

Fraser, R. R. Mansour, T. S. Aridity measurements with lithiated amines steric reduction and electronic enhancement of acidity. /. Org. Chem. 1984, 49, 3442-3443. 

Formamidines such as 81 may be lithiated with s-BuLi or r-BuLi and give stabilised organolithiums 82 which react with a wide range of electrophiles. Cleavage is much easier than cleavages in the amide series acidic methanolysis gives a secondary amine 83 while hydride reduction gives a tertiary amine 84.57... 

Isochromanones on condensation with p-phenylethyl amines, followed by Bischler-Napieralski cyclisation and NaBH reduction furnish berbine alkaloids in good to excellent yields. The 7,8-dimethoxy and mcthylenedioxy isochromanones prepared by lithiation methods provide the 9,10-oxygenated berbine alkaloids, such as tetra-hydropalmatine 51a canadine stylopine 57c , sinactine... 

E)-Allylic amines. Reaction of the lithiated methylphosphonate ester with a nitrile, followed by addition of an aldehyde, furnishes a conjugated imine with an ( )-configuration. Immediate reduction (e.g., with NaBH4) gives the allylic amine. 

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

Ruhland reported a novel solid-phase C2-lithiation of the indole ring [279] using a linker that resembled the MOM-protecting group (Scheme 16). Lithiation of resin-bound indole 73 was accomplished by treatment with tert-butyllithium in toluene followed by quenching with benzonitrile. Reductive cleavage of 74 then gave amine 75 in an overall yield of 2%, proof of principle that this type of transformation is possible. 

A chiral ligand mediated approach to lithiation-substitutions of allylic amines has also been well developed. Weisenburger and Beak demonstrated that lithiation of doubly protected allylic amines 141 in the presence of the chiral ligand (-)-sparteine (5), and substitution with a variety of electrophiles provided highly enantioenriched enecarbamate products 142 (Scheme 44) [100]. The authors demonstrated that the intermediate organolithium could be viewed as either an aldehyde P-homoenolate or y-lithioamine synthetic equivalent by hydrolysis or reduction and deprotection of the enecarbamates, respectively. 

We next examined the reactivity of the stable iminium ion 63a (Scheme 27). When the iminium 63a was treated with NaOAc or NaNs, only the starting material was recovered. The reaction of 63a with -BuLi or lithiated dithiane gave complex mixtures. The stronger basic nucleophiles, like -BuLi and lithiated dithiane, may attack both the iminium carbon (C23) and the hyperconjugated carbons (C5) to give complex mixtures (Fig. 17). However, the reduction of iminium 63a with NaBH4 afforded the saturated propellane derivative 69. The reaction of iminium 63a with NaCN ° provided nitrile 70 then reduction of the nitrile 70 produced amine 71 in a... 

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