Reductive -alkylation

In principle, the reductive alkylation of coal involves treatment of coal with an alkali metal in tetra-hydrofuran in the presence of naphthalene whereby a coal polyanion is produced that is capable of undergoing further reaction with, say, an alkali halide. The resnlting product has been presumed to be the alkylated coal but the relatively straightforward chanistry is, in fact, a complex sequence of reactions. For example, ether bridges are also cleaved under the conditions of the reaction as are carbon bonds. That the former can happen makes the resulting product mix somewhat more complex than if ethers were not cleaved but the cleavage of carbon-carbon bonds ensures the complexity of the product mix as well as the chemistry involved in the process. 

even though the evidence appears to indicate that coal can be selectively cleaved by the technique of reductive alkylation to lower-molecular-weight fragments thereby allowing 

FIGURE 10.21 Molecular weight distribution of the product from coal ethylation. (From Sternberg, H.W. et al Fuel, 50,432, 1971.) 

Obviously, there are many facets to this particular reaction that need to be resolved before the data can be used with any degree of certainty to project to the chemical nature of coal. 

Following solid phase peptide assembly (0.05 mmol scale), and after removal of the final AP-amine protecting group, remove excess DMF from the resin bed. 

Add 2-hydroxy-4-methoxybenzaldehyde (39 mg, 0.25 mmol), followed by glacial acetic acid (15 l,l, giving 2% v/v in DMF). 

Remove any excess DMF, and ensure that the resin is suspended in 1.5 ml DMF. 

Add sodium borohydride (8 mg, 0.20 mmol), immediately followed by 0.20 ml of methanol. 

Add further amounts of sodium borohydride 12 mg, 0.30 mmol) portionwise over a period of 30 min. 

---

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

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. 

Reductive alkylations and aminations requite pressure-rated reaction vessels and hiUy contained and blanketed support equipment. Nitrile hydrogenations are similar in thein requirements. Arylamine hydrogenations have historically required very high pressure vessel materials of constmction. A nominal breakpoint of 8 MPa (- 1200 psi) requites yet heavier wall constmction and correspondingly more expensive hydrogen pressurization. Heat transfer must be adequate, for the heat of reaction in arylamine ring reduction is - 50 kJ/mol (12 kcal/mol) (59). Solvents employed to maintain catalyst activity and improve heat-transfer efficiency reduce effective hydrogen partial pressures and requite fractionation from product and recycle to prove cost-effective. 

The Leuckart reaction uses formic acid as reducing agent. Reductive alkylation using formaldehyde, hydrogen, and catalyst, usually nickel, is used commercially to prepare methylated amines. These tertiary amines are used to prepare quaternary ammonium salts. 

Primary and secondary amines are usually converted to tertiary amines using formaldehyde and hydrogen in the presence of a catalyst (eqs. 5 and 6). This process, known as reductive alkylation (222), is attractive commercially. The desired amines are produced in high yields and without significant by-product formation. Quatemization by reaction of an appropriate alkylating reagent then follows. 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

The N,]S -dialkyl-/)-PDAs are manufactured by reductively alkylating -PDA with ketones. Alternatively, these compounds can be prepared from the ketone and -lutroaruline with catalytic hydrogenation. The /V-alkyl-/V-aryl- -PDAs are made by reductively alkylating -nitro-, -nitroso-, or /)-aminodipheny1 amine with ketones. The AijAT-dialkyl- PDAs are made by condensing various anilines with hydroquinone in the presence of an acid catalyst (see Amines-aromatic,phenylenediamines). 

Pyrrole has been condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 22). Although acid-catalyzed hydroxy-methylation is not a practical possibility, by addition of a reducing agent to the reaction mixture overall reductive alkylation can be achieved (Scheme 23). 

The Fcm derivative is prepared from amino acids on treatment with formylferro-cene and Pd-phthalocyanine by reductive alkylation (60-89% yield). It is cleaved with 2-thionaphthol/CF3COOH. Its primary advantage is its color, making it easily detected. ... 

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. 

Application of the reductive alkylation process to the -20-ketone (4) yields the 17a-alkyl derivatives (5a-c). As expected, the presence of the angular 13-methyl group favors the approach of the alkyl iodide from the a-side. ... 

Rearrangement of a,/B-epoxy ketones to ftdicarbonyl isomers, 307 Reductive alkylation, 97 Reductive cleavage of halo ethers, 264 Reductive degradation of 19-substitutional steroids, 277, 278 Reformatsky reaction, 139 Removal of the C-10 substituent in steroids. 272... 

Fluormated pyrroles are obtained from 2,5-dimethylpyrrole by reductive alkylation with perfluoroaldehyde hydrates [174] (equation 149)... 

---