Catalytic hydrogenation reductive alkylation

The first step is the catalytic hydrogenation (reduction) of the 2—alkyl-an-thraquinone to 2—alkyl-anthrahydroquinone. Pd is the preferred reduction catalyst on gauze carriers or in suspension, although Ni and other hydrogenation catalysts can be used [108,109,126-129], This reaction step is operated at temperatures around 40°C and at pressures up to 5 bar. Only 50% conversion is achieved to limit the amount of side reactions [108],... 

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). 

Condensation of the anion obtained on reaction of acetonitrile with sodium amide, with o-chlorobenzophenone (36), affords the hydroxynitrile, 37. Catalytic reduction leads to the corresponding amino alcohol (note that the benzhydryl alcohol is not hydrogenolyzed). Reductive alkylation with formaldehyde and hydrogen in the presence of Raney nickel gives the antitussive a-gent, chlorphedianol (39). °... 

The hydrogenation in the presence of Pd/G is also effective for the d compounds to amines. The Michael addition of nitromethime to 2-alkenoic esters followed by catalytic hydrogenation using 10% Pd/G in acetic acid md hydrolysis is a convenient method for the preparation of 3-alkyl-4-aminobut moic acids, which are importimt y-amino acids for biological snidy fEq. 6.48. The reduction c m be carried out at room temperanire md atmospheric pressure. 

Note that the Wolff-Kishner reduction accomplishes the same overall trans-fonnation as the catalytic hydrogenation of an acylbenzene to yield an alkyl-benzene (Section 16.10). The Wolff-Kishner reduction is more general and more useful than catalytic hydrogenation, however, because it works well with both alkyl and atyl ketones. 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Dithionite-mediated reductive activation of mitomycin C has been employed in the study of its DNA alkylation chemistry.6,63 However, dithionite activated mitomycin C possesses different DNA alkylation properties than that activated by catalytic hydrogenation and enzymatic reduction. We postulated that a new alkylating species is produced by dithionite reductive activation resulting in different reactivity than the iminium methide species. To investigate dithionite-mediated reductive activation further, we treated 13 C-labeled analogues of WV-15 with dithionite and carried out spectral and product studies. 

A combination of cat. Ybt and A1 is effective for the photo-induced catalytic hydrogenative debromination of alkyl bromide (Scheme 28) [69]. The ytterbium catalyst forms a reversible redox cycle in the presence of Al. In both vanadium- and ytterbium-catalyzed reactions, the multi-component redox systems are achieved by an appropriate combination of a catalyst and a co-reductant as described in the pinacol coupling, which is mostly dependent on their redox potentials. 

An unexpected reaction occurs when 2-alkyl-4(5)-nitroimidazoles (27 R = alkyl) are reduced in protic solvents [92JCS(P1)2779]. Catalytic hydrogenation of 2-methyl-4(5)-nitroimidazole (27 R = Me) in a solution of acetic anhydride and acetic acid gave 4,4 -diacetamido-2,2 -dimethyl-5,5 -diimidazole (32 yield 10%) in addition to the expected 4-acetamido-l-acetyl-2-methylimidazole (28%). Similarly, reduction of the 2-alkyl-4(5)-nitroimidazoles (27 R = Me, Et, iPr) in ethanol solution in the presence of diethyl ethoxymethylenemalonate [EMME (135)] gives predominantly the 5,5 -diimidazole adducts (33). The formation of these products (33) is believed to involve an electrophilic addition of the starting material (27) to the electron-rich aminoimidazoles (25) [92JCS(P1)2779]. Interestingly, replacement of ethanol by dioxane suppressed diimidazole formation. 

The hydrogenations become analogous to those involving HMn(CO)5 (see Section II,D), and to some catalyzed by HCo(CN)53 (see below). Use of bis(dimethylglyoximato)cobalt(II)-base complexes or cobaloximes(II) as catalysts (7, p. 193) has been more thoroughly studied (189, 190). Alkyl intermediates have been isolated with some activated olefinic substrates using the pyridine system, and electronic and steric effects on the catalytic hydrogenation rates have been reported (189). Mechanistic studies have appeared on the use of (pyridine)cobaloxime(II) with H2, and of (pyridine)chlorocobaloxime(III) and vitamin B12 with borohydride, for reduction of a,/3-unsaturated esters (190). Protonation of a carbanion... 

The double bond in indole and its homologs and derivatives is reduced easily and selectively by catalytic hydrogenation over platinum oxide in ethanol and fluoroboric acid [456], by sodium borohydride [457], by sodium cyanoborohydride [457], by borane [458,459], by sodium in ammonia [460], by lithium [461] and by zinc [462]. Reduction with sodium borohydride in acetic acid can result in alkylation on nitrogen giving JV-ethylindoline [457]. 

Alkyl chlorides are with a few exceptions not reduced by mild catalytic hydrogenation over platinum [502], rhodium [40] and nickel [63], even in the presence of alkali. Metal hydrides and complex hydrides are used more successfully various lithium aluminum hydrides [506, 507], lithium copper hydrides [501], sodium borohydride [504, 505], and especially different tin hydrides (stannanes) [503,508,509,510] are the reagents of choice for selective replacement of halogen in the presence of other functional groups. In some cases the reduction is stereoselective. Both cis- and rrunj-9-chlorodecaIin, on reductions with triphenylstannane or dibutylstannane, gave predominantly trani-decalin [509]. 

As in catalytic hydrogenation, in reduction with metals alkyl pyridyl ketones make a complex picture. 

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