Steric factors reductive alkylation

This paper discusses the need for more stringent catalyst requirements for the reductive alkylation of secondary to tertiary amines. We illustrate the major importance of steric factors, with respect to both the amine and ketone and discuss the relative effectiveness of several catalysts. One obtains excellent yields with the more reactive and unhindered ketone, such as cyclohexanone and acetone, and relatively unhindered secondary amines. 

Two different types of coupling processes have been cited for pyridine. The first involves the carboxylation and subsequent alkylation of the carboxylate salt to form the 1,4-dihydro-1,4-dicarboxyalkyl product (6). Reductive carboxylation of 2,2 -bipyridyl (1) followed a slightly different pathway, giving the l,4-dihydro-4,5-dicarboxyethyl product (7).36 Apparently, steric factors favor electrophilic attack on the / carbon. 

The quaternization of 1-substituted imidazoles is usually easy unless steric factors intervene, or strongly electron-attracting groups are present, for example, 1-acylimidazoles can only be alkylated at N(3) with powerful alkylating agents such as methyl fluorosulfonate or trialkyloxonium fluoroborates. Trimethyloxonium fluoroborate does not methylate 1-dimethylaminosulfonylimidazole. Regiospecific synthesis of 3-substituted L-histidines can be achieved by alkylation of Ar-/-butoxycarbonyl-l-phenacyl-L-histidinc methyl ester at N(3), followed by reductive removal of the phenacyl group (Scheme 15). 

Above 250 °C, deamination of the reagent is observed and styrene is formed. Below this temperature, however, it is possible to obtain A-methyl-a-methylben-zylamine with good selectivity (90% selectivity at 20% conversion, 220 °C). The selectivity towards the N,N-dimethylated product is lower at the same conversion than with the other primary amine already tested, i. e. the -oetylamine (38 % at 84 % conversion for a-benzylamine and 57 % at 60 % conversion for n-octyla-mine). The NH group is bound to a secondary carbon in a-methylbenzylamine, whereas it is linked to a primary carbon in -octylamine. This steric factor explains the different reaetivity. This relatively good selectivity for monomethyla-tion can be regarded as an advantage compared with reductive alkylation. 

Reduction of cyclohexanones. Doyle and West have conducted extensive investigations on the reduction of cyclohexanones by organosilanes in acidic media. Steric factors play a dominant role in the stereochemical outcome. However, inductive effects of alkyl substituents in the silane are pronounced. The geometry of transition states in this hydride transfer has been discussed. 

Andersson and coworkers investigated the role of solvation, dispersion, and steric effects on the enantioselectivity. The authors results agree with the fact that gas-phase B3LYP calculations describe the drop in enantioselectivity of 2,3,4,5,6-pentafluoroacetophenone compared to acetophenone where steric and electrostatic effects are the only major effects, but the approximation is too crude to reproduce quantitatively the extent of enantioselection observed experimentally. In order to extract the isolated contributions of steric effects, the authors correlated the same energetic parameter with respect to an empirical steric parameter called STERIMOL B1 [132]. Their results showed that bulkier alkyl groups tend to decrease the enantioselectivity, which correlates well with the B1 parameter. Based on this observation, it seems that an intrinsic steric factor enhances or depresses the enantioselectivity in the reduction of acetophenone and other n-alkyl aryl ketones. However, a generalized rationalization of this effect is not trivial, and investigation of similar catalysts reveals only a small role for steric effects [105, 109]. 

Similar trends were observed in a complementary study using the palladium complexes 14 and 15 comprising sterically identical normal and abnormal bis(imidazolylidene) ligands (Scheme 5.4). ° In the presence of chlorine, complex 14 was stable and did not react, whereas the abnormal carbene complex decomposed to [PdCU] " and a doubly chlorinated bisimidazolium dication 16. This outcome was explained by oxidative CI2 addition to complex 15, followed by reductive Ccarbene Cl bond formation. Obviously, this process was unfavourable with normally bound imidazolylidenes. It is worth noting that an analogue of complex 15 with no alkyl substituents at the C5 and C5 positions induced reductive Ccarbene-Ccarbene bond formation. The higher propensity of abnormal carbenes to be reductively cleaved was rationalised by the enhanced electron donor properties of the non-classical carbenes, which made them more susceptible towards elimination processes. Evidently, steric factors could be ruled out in these systems. 

However, the 0-alkyl derivatives are potentially unstable with respect to thermal elimination of a carbonyl compound and consequent reduction to the corresponding lactam. A combination of steric and electronic factors may permit this decomposition, i.e., 133 -a- 134, to occur at quite moderate temperatures. The 0-methyl derivative of the benzalphthalimidine (132) undergoes slow loss of formaldehyde at 177° (Ti/a in dimethyl sulfoxide 40 minutes), but this elimination is much faster in certain thiohydroxamic acid derivatives, e.g., 135, which lose benzaldehyde readily at 139° in dimethyl sulfoxide (T1/2 6 minutes). The outstanding example of this decomposition, however,... 

Recent studies [382] have provided rate data for cycloaddition reactions. Accordingly, steric effects at the electrophile site, and the capacity of the added unsaturated component RCH=CH2 to stabilize radicals and cations, play a vital role, the importance of which is reflected in a rate decrease for R = Ph OR > vinyl > alkyl by a factor of 100-300. In principle, the observed trends follow those for addition of car-bocations to alkenes [292]. A study of the [2-1-1] cycloaddition of 4-methoxystyrene also emphasizes the importance of the rapid one-electron reduction of the intermediate dimer radical cation [383]. A direct view of 4-center 3-electron cyclobutane [384] and bisdiazene-oxide [385] radical cations has been obtained with polycyclic, rigid systems. 

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