Reductive alkylation selectivity

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. 

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... 

Besides large differences in activity, large differences in selectivity also occur. Usually the reduction of selectivity is caused by the occurrence of side reactions, such as isomerization and alkylation of the solvent. The extent to which these side reactions occur depends upon the kind of reactant,... 

This was also accomplished with BaRu(0)2(OH)3. The same type of conversion, with lower yields (20-30%), has been achieved with the Gif system There are several variations. One consists of pyridine-acetic acid, with H2O2 as oxidizing agent and tris(picolinato)iron(III) as catalyst. Other Gif systems use O2 as oxidizing agent and zinc as a reductant. The selectivity of the Gif systems toward alkyl carbons is CH2 > CH > CH3, which is unusual, and shows that a simple free-radical mechanism (see p. 899) is not involved. ° Another reagent that can oxidize the CH2 of an alkane is methyl(trifluoromethyl)dioxirane, but this produces CH—OH more often than C=0 (see 14-4). ... 

Table 17.3. Activity and selectivity during reductive alkylation of aromatic amines...

The BS2 catalyst was more selective toward the formation of the dialkylated product than the Pd catalysts tested. The activity of BS2 for DAE-MIBK reaction was slower than that with acetone due to steric effects posed by the larger ketone. Here again, the imine tends to rapidly cychze to form imidazolidines or pyrimidines. Figure 17.2 shows the stepwise formation of various side products observed during the reductive alkylation of DAE with acetone. 

The reductive alkylation of DAP with acetone led to high conversions and selectivity to the dialkylated product over Al, Bl, and BS2 catalysts. The ASl catalyst, which typically has lower activity than the Al or Pt-based catalysts showed greater formation of heterocycles. These results indicate that a more active catalyst, a shorter reaction time, a higher operating temperature, or sterically hindered amines/ketones will help minimize the formation of the heterocycles. Similar high selectivities were obtained with DAP-MIBK reaction over BSl and BS2 catalysts with no heterocycles being formed. However, over Al, the undesired heterocyclic compound was over 15%. This indicates that the reaction between diamines and ketones has a significant potential to form heterocyclic compounds unless the interaction between these is kept to a minimum by the use of a continuous flow reactor as proposed by Speranza et al. (16) or by other methods. 

The current work indicates that sulfided platinum catalysts are, in general, more active and selective than Pt, Pd, or sulfided Pd catalysts for reductive alkylation of primary amines with ketones. The choice of the catalyst preparation parameters, especially the support, plays a major role in determining the performance of the catalyst. Diamines, especially of lower molecular weight, tend to react with ketones even at room temperature to form heterocycles such as imidazolidine, diazepanes, and pyrimidines. Hence, a continuous reactor configuration that minimizes the contact between the amine and the ketone, along with a highly active catalyst is desired to obtain the dialkylated product. In general, sulfided Pt appears to be more suited for the reductive alkylation of ethylenediamine while unsulfided Pd or Pt may also be used if 1,3-diaminopropane is the amine. 

The development of facial selective addition reactions of cyclohexa-1,4-dienes 7 and 14 has greatly extended the value of the asymmetric Birch reduction-alkylation. For example, amide directed hydrogenation of 15 with the Crabtree catalyst system occurs with outstanding facial selectivity iyw to the amide carbonyl group to give 16 (Scheme 5)."... 

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. 

As an example, the propagation steps for the reductive alkylation of alkenes are shown in Scheme 7.1. For an efficient chain process, it is important (i) that the RjSi radical reacts faster with RZ (the precursor of radical R ) than with the alkene, and (ii) that the alkyl radical reacts faster with the alkene (to form the adduct radical) than with the silicon hydride. In other words, the intermediates must be disciplined, a term introduced by D. H. R. Barton to indicate the control of radical reactivity [5]. Therefore, a synthetic plan must include the task of considering kinetic data or substituent influence on the selectivity of radicals. The reader should note that the hydrogen donation step controls the radical sequence and that the concentration of silicon hydride often serves as the variable by which the product distribution can be influenced. 

Reductive alkylation is an efficient method to synthesize secondary amines from primary amines. The aim of this study is to optimize sulfur-promoted platinum catalysts for the reductive alkylation of p-aminodiphenylamine (ADPA) with methyl isobutyl ketone (MIBK) to improve the productivity of N-(l,3-dimethylbutyl)-N-phenyl-p-phenylenediamine (6-PPD). In this study, we focus on Pt loading, the amount of sulfur, and the pH as the variables. The reaction was conducted in the liquid phase under kinetically limited conditions in a continuously stirred tank reactor at a constant hydrogen pressure. Use of the two-factorial design minimized the number of experiments needed to arrive at the optimal solution. The activity and selectivity of the reaction was followed using the hydrogen-uptake and chromatographic analysis of products. The most optimal catalyst was identified to be l%Pt-0.1%S/C prepared at a pH of 6. 

In the same manner as for l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines 8 (vide supra), Birch reduction-alkylation of pyrrolobenzoxazepinones, e.g., 1. gives mainly the a-alkylation products (see Table 6)26,2R u. The chemical yields and diastereoselectivities are usually excellent, except for alkylation with iodomethane when the diastereoselectivity is moderate26. The facial selectivity is opposite to that observed upon direct Birch reduction-alkylation of the ortho-methoxy derivatives, i.e., 2-alkoxymethyl-l-(2-methoxybenzoyl)pyrrolidines (vide supra). 

A rather more complex tertracyclic indole based compound lowers blood pressure by selective blockade of a 1-adrenergic receptors. Reaction of the anion from indole (72-1) with butyrolactone (72-2) leads to the scission of the carbon-oxygen bond in the reagent and the formation of the alkylated product (72-3). The acid is then cyclized onto the adjacent 2 position to give the ketone (72-4) by treatment with a Lewis acid such as polyphosphoric acid. Reaction with bromine then leads to the brominated ketone (72-5). This is subjected to reductive alkylation with ethylene... 

Figure 3.1. Selection of aldehydes R1 CHO successfully used in the reductive alkylation of primary aniline 12.

Trimethyl orthoformate has been used as a solvent by Campbell and co-workers for site-selective monoalkylation in SPPSi1 % Trimethyl orthoformate was previously shown to be a highly efficient dehydrating solvent for the formation of imines. 112 Thus, dividing the reductive alkylation step into two separate substeps of (1) imine formation followed by solvent removal and (2) reduction, resulted in on-resin monoalkylation of various amino acids and dipeptides (Scheme 26). 

To avoid the production of diastereomers during reductive alkylation of Pro residues, the corresponding dipeptide should be first synthesized and the central amide bond subsequently selectively reduced with diborane (see Section 10.7.1.2.1). 

The reductive alkylation of methyl pyruvate with and the t-butyl esters of amino acids using Pd/C catalyst leads to the formation of iminodicarboxylic acids such as 67 in selectivities of 29-75% d.e. depending on the amino acid and solvent used (hexane gave the best results). Hydrolysis of the t-butyl ester to the acid 68 followed by hypochlorite-promoted decarboxylation and imine hydrolysis leads to the formation of ( -alanine 69 in correspondingly high e.e.s278,281. The likely decarboxylation mechanism as far as the imine stage is shown in Scheme 65. 

Reductive alkylation of -caprolactone (1 equiv) with a 2 0.25 mixture of Grignard reagent and Zn(BH4)2 affords monoalkylated diols, which can be further selectively oxidized with tetrapropylammonium perruthenate (TPAP) into the expected monoalkylated lactones <2002CR571>. 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

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