Reductive alkylation of alcohols

Reductive Alkylation of Alcohols C-Hydro-O-alkyl-addition... 

Reductive alkylation of alcohols 9-40 Reduction of carboxylic esters 9-60 Reduction of peroxides... 

Additional reactions which need to be highlighted are the reductive alkylation of alcohols and amines with aldehydes leading to the green synthesis of ethers and amines. These reactions are generally catalyzed by palladium [35]. This reaction can replace the classical Williamson s synthesis of ethers which requires an alcohol and an alkyl halide together with a base, and always results in the concomitant production of salt. The choice of Pd/C as catalyst is due to the low efficiency of this metal for the competitive carbonyl reduction. Analysis of the... 

Scheme 19 The palladium catalyzed reductive alkylation of alcohols with an aldehyde.

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. 

Platinum and rhodium sulfided catalysts are very effective for reductive alkylation. They are more resistant to poisoning than are nonsulfided catalysts, have little tendency to reduce the carbonyl to an alcohol, and are effective for avoidance of dehydrohalogenation in reductive alkylation of chloronitroaromatics and chloroanilines (14,15). Sulfided catalysts are very much less active than nonsulfided and require, for economical use, elevated temperatures and pressures (300-2(KX) psig, 50-l80 C). Most industrial reductive alkylations, regardless of catalyst, are used at elevated temperatures and pressures to maximize space-time yields and for most economical use of catalysts. 

Reductive alkylation by alcohol solvents may occur as an unwanted side reaction 22,39), and it is to avoid this reaction that Freifelder (20) recom mends ruthenium instead of nickel in pyridine hydrogenation. Alkylation by alcohols may occur with surprising ease 67). Reduction of 18 in ethanol over 10% palladium-on carbon to an amino acid, followed bycyclization with /V,/V-dicyclohexylcarbodiimide gave a mixture of 19 and 20 wiih the major product being the /V-ethyl derivative 49,50). By carrying out the reduction in acetic acid, 20 was obtained as the sole cyclized product 40). 

The reduction of nitrobenzene to aniline is a major industrial process at the heart of the production of polyurethanes, and it is also often used as a marker reaction to compare activities of catalysts [1,2], It can be performed over a variety of catalysts and in a variety of solvents. As well as its main use in polymethanes, aniline is used in a wide range of industries such as dyes, agrochemicals, by further reaction and functionalisation. Reductive alkylation is one such way of functionalising aromatic amines [3, 4], The reaction usually takes place between an amine and a ketone, aldehyde or alcohol. However it is possible to reductively alkylate direct from the nitro precursor to the amine and in this way remove a processing step. In this study we examined the reductive alkylation of nitrobenzene and aniline by 1-hexanol. 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Birch reduction-alkylation of (2S)-2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine (1) gives products 2 in high diastereoselectivities29. In contrast to the previous examples, only one double bond remains in the product (if one equivalent of rm-butyl alcohol is used as proton donor). Formally this procedure is a stereoselective cis addition, and is thus particularly useful. Thus, two stereogenic centers are created in the same reaction step with high diastereoselectivities. Subsequent hydrolysis furnishes acids, whereas reaction with methyllithium yields chiral ketones29. 

On use as homogeneous catalysts in the asymmetric reductive alkylation of benzaldehyde with diethylzinc to form secondary alcohols, the corresponding dendritic titanium-TADDOL complexes having either chiral or achiral dendrons gave enantiomeric excesses (ee) of up to 98.5 1.5 at a conversion of 98.7% (for the catalyst with GO dendrons). With larger dendrons the reduction of the ee to 94.5 5.5 (G4) remained within reasonable limits, while the drop in conversion to 46.8% (G4) proved to be drastic. In comparison, the unsubstituted Ti-TAD-DOL complex gave an ee of 99 1 with complete conversion. This negative den-... 

Reductive alkylation of ammonia may proceed under mild conditions over nickel catalysts. In examples using Raney Ni, temperatures ranging from 40 to 150°C and hydrogen pressures of 2-15 MPa have been used to obtain satisfactory results.3,4 In general, the reductive alkylation of ammonia with carbonyl compounds may produce primary, secondary, and tertiary amines, as well as an alcohol, a simple hydrogenation product of the carbonyl compound (Scheme 6.1). The selectivity to respective amine depends primarily on the molar ratio of the carbonyl compound to ammonia, although the nature of catalyst and structure of the carbonyl compound are also important factors for the selectivity. As an example, the reaction of benzaldehyde in the presence of 1 equiv of ammonia in ethanol over Raney Ni gave benzylamine in an 89.4% yield while with 0.5 molar equivalent of ammonia dibenzylamine was obtained in an 80.8% yield (eq. 6.1).4... 

In the reductive alkylation of ammonia with cyclohexanone, Skita and Keil found that, although cyclohexylamine was obtained in 50% yield over a nickel catalyst, over colloidal platinum dicyclohexylamine was produced as the predominant product even in the presence of an excess molar equivalent of ammonia. Steele and Rylander compared the selectivity to primary amine, secondary amine, and alcohol in the reductive alkylation of ammonia with 2- and 4-methylcyclohexanones over 5% Pd-, 5% Rh-, and 5% Ru-on-carbon as catalysts.18 As seen from the results shown in Table 6.2, the formation of secondary amine is greatly depressed by the methyl group at the 2 position. Thus over Pd-C the secondary amine was formed predominantly with cyclohexanone and 4-methylcyclohexanone while the primary amine was produced in 96% selectivity with 2-methylcyclohexanone. Over Ru-C the alcohol was formed quantitatively with 4-methylcyclohexanone without the formation of any amines, whereas with 2-methylcyclohexanone the alcohol was formed only to an extent of 57%, accompanied by the formation of 4 and 39% of the secondary and primary amines, respectively. These results indicate that secondary amine formation is affected by the steric hindrance of the methyl group to a much greater extents than is the formation of the primary amine or the alcohol. The results with Ru-C and Rh-C also indicate... 

Rhenium sulfide was the most active and hydrogenated excess ketone to the corresponding alcohols. The platinum metal sulfides were found to be more active than the base metal sulfides and highly selective for the formation of (V-alkylarylamines. They usually produce a pure product with little or no side reactions, require no excess above the stoichiometric amount of ketone, and are active at relatively low pressures of hydrogen. An example with (V-phenyl-p-phcnylencdiaminc is shown in eq. 6.15.37 Platinum metal sulfides may also be used for the reductive alkylation of aliphatic amines and their nitroalkane precursors with aliphatic ketones. 

Tertiary arylamines were prepared in good yields by hydrogenation of an alcoholic solution of a nitro compound and an aldehyde over Raney Ni in the presence of triethy-lamine hydrochloride or, better, over platinum oxide in the presence of acetic acid (eq. 6.22).48 Base metal and platinum metal sulfides are also effective to the reductive alkylation of nitro compounds with ketones36,37 as in an example shown in eq. 6.23. 

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 studies on the reduction and reductive alkylation of 2-acetylnaphthalenes (184) afforded mixtures of dihydro and tetrahydro derivatives. In one case, the alcohol (188) was the major product. A comprehensive examination of the reductive process and quenching methods has been carried out recent-... 

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