Ammonia reductive alkylation

The benzyl 1C methoxy group is then removed by metal-ammonia reduction. Alkylation with p-nitrophenethyl bromide would then give the intermediate 78. Reduction of the nitro group would thus afford verilopam (79). The same... 

Cyclohexadienones with a wide variety of alkyl substituents at C4 are readily available by alkali metal in ammonia reduction-alkylations" of methyl 2-methoxybenzoate to give cyclohexa-1,4-dienes followed by bis-allylic oxidation by pyridinium dichromate and /ert-butyl hydroperoxide. ... 

Method 3. Reductive alkylation reaction of an amine or ammonia and hydrogen with an aldehyde or ketone over a hydrogenation catalyst. 

Dicyclohexylarnine may be selectively generated by reductive alkylation of cyclohexylamine by cyclohexanone (15). Stated batch reaction conditions are specifically 0.05—2.0% Pd or Pt catalyst, which is reusable, pressures of 400—700 kPa (55—100 psi), and temperatures of 75—100°C to give complete reduction in 4 h. Continuous vapor-phase amination selective to dicyclohexylarnine is claimed for cyclohexanone (16) or mixed cyclohexanone plus cyclohexanol (17) feeds. Conditions are 5—15 s contact time of <1 1 ammonia ketone, - 3 1 hydrogen ketone at 260°C over nickel on kieselguhr. With mixed feed the preferred conditions over a mixed copper chromite plus nickel catalyst are 18-s contact time at 250 °C with ammonia alkyl = 0.6 1 and hydrogen alkyl = 1 1. 

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

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... 

Diphenylisoinclole (29) can be prepared by a modified Leuckart reaction of o-dibenzoylbenzene (46), using an ammonium salt of formic acid the process is essentially a reductive alkylation of ammonia, accompanied by cyclization, and leads to 29 in 44% yield with ammonium formate, and 47 in 28% yield with methylammonium formate. 1,3-Diphenylisoindole. (29) can also be obtained in good yield by the reaction of 46 with 1,1-dimethylhydrazine. ... 

Alkylation lo yield a leriiary amine may occur easily if the formation involves cyclization (ii). Catalysts may have a marked influence. In reductive alkylation of ammonia wilh cyclohexanones, more primary amine was formed over Ru and Rh and more secondary amine over Pd and Pt. Reduction of the ketone to an alcohol is an important side reaction over ruthenium. 

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... 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

Present methods for solubilizing coal (including reductive alkylation in tetrahydrofuran (15) or liquid ammonia (8)) entail cleavage of oxygen ethers, scission of C-C bonds in certain polyaryl-substituted ethylenes and, in the case of reactions in tetrahydrofuran, extensive elimination of hetero-atoms (16). 

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>. 

Sodium cyanoborohydride NaBIpCN in methanol is the reagent of choice for the reductive alkylation of ammonia, primary aliphatic and aromatic amines and secondary aliphatic amines with aldehydes and relatively unhindered ketones (equation 53). 

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]. 

Eschweiler-Clarke modification org chem A modification of the Leuckart reaction, involving reductive alkylation of ammonia or amines (except tertiary amines) by formaldehyde and formic acid. esh,vTl-3r klark. mad-o-fo ka-shon ... 

Treatment of aldehydes or ketones with ammonia, primary or secondary amines in reducing media is called reductive alkylation (of ammonia or amines) or reductive amination (of aldehydes or ketones). Reducing agents are most frequently hydrogen in the presence of catalysts such as platinum, nickel or Raney nickel [955], complex borohydrides [705, 954, 955], formaldehyde or formic acid [522]. 

Reductive alkylation of ammonia should give primary amines, reductive alkylation of primary amines secondary amines, and reductive alkylation of secondary amines tertiary amines. In reality, secondary and even tertiary amines are almost always present to varying extents since the primary amines formed in the reaction of the carbonyl compounds with ammonia react with the carbonyl compounds to give secondary amines, and the secondary amines similarly afford tertiary amines according to Scheme 128. In addition, secondary amines may be formed, especially at higher temperatures, by additional reactions shown in Scheme 129. Depending on the ratios of the carbonyl compounds to ammonia or amines, different classes of amines predominate. 

The order in which the steps are performed is quite flexible. The synthesis of the antiandrogen dutasteride thus starts with the construction of the side chain at 17. The reaction of acid (44-1) with the aniline (46-1) poceeds to afford the amide (46-2). Ring A of the steroid is then opened to the corresponding keto-acid (46-3) with a concomitant loss of carbon 4 by means of the permanganate-periodate combination. Reductive alkylation with ammonia then affords the saturated lactam (46-4). 

Indole 12b, prepared by Fischer indolization of 11b (Scheme 1), was also converted to sumatriptan (1) according to Scheme 3. The dimethylamino group was incorporated via a two-step procedure. First, aminolysis of 12b with ammonia provided the aminoethyl compound 17, albeit in low yield. Then reductive alkylation of 17 with formaldehyde in the presence of NaBHt gave sumitriptan (1). 

Reductive Alkylation of Ammonia or Amines Hydro,dialkylamino-de-oxo-bisubstitution... 

When an aldehyde or a ketone is treated with ammonia or a primary or secondary amine in the presence of hydrogen and a hydrogenation catalyst (heterogeneous or homogeneous), reductive alkylation of ammonia or the amine (or reductive amination of the carbonyl compound) takes place.165 The reaction can formally be regarded as occurring in the following manner (shown for a primary amine), which probably does correspond to the actual sequence of steps 166... 

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