A-Alkylation reactions

A. Alkylation Reaction of Toluene as Model Compound with Epichlorohydrin... 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

In the case of ring-nitrogen atoms, A-acylation and A-alkylation reactions have been described. Thus, Scheme 16 shows that compound 115 was subjected to acetylation <1999J(P1)1067>. If the reaction is carried out with acetic anhydride in pyridine under an argon atmosphere for 15 h, the acetyl compound 117 can be obtained. The same reaction mixture, however, when left to stand for 7 days, undergoes a further acetylation step to yield the acetate 118. 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

Direct Sn2 and SnI A -alkylation reactions using purines have been documented previously <1996CHEC-II(7)397>. As stated, N-9 products tend to predominate however, mixtures are often obtained with N-7 as the secondmost nucleophilic center, with N-1 and N-3 products occasionally present to a lesser degree (Table 2). 

Phenylsulfonylcyclobutanes have sufficiently acidic a-protons to undergo a-alkylation reactions. For example, phenylsulfonylcyclobutane, on alkylation with l-bromo-4-methylpent-2-ene gave l-(4-methylpent-2-cnyl)-1-phenylsulfonylcyclobutane (8),152 and (1R, 2S, 3S )-1,2-dimethyl-3-phenylsulfonylcyclobutane gave (l/ , 2/ , 3S )-l-(l-acetoxy-2-methylpropyl)-2,3-dimethyl-1-phenylsulfonylcyclobutane (9) on reaction with isobutyraldehyde followed by treatment with acetic anhydride.133... 

This process is called direct a alkylation. Even the formation of ferf-butyladaman-tane was observed in the superacid-catalyzed alkylation of adamantane with isobutylene necessitating a highly crowded, unfavorable tertiary-tertiary interaction. This provides further evidence for the a-alkylation reaction, as adamantylation of isobutylene with any subsequent isomerization does not lead to this isomer. 

A convenient approach to synthesize novel selenium-(3-lactams, namely 3-selena-l-dethiacephems 200, was accomplished via the regioselective iodocycli-zation reaction (Scheme 73) [103]. The key starting materials, alkyne-selenoureas 201, for this approach were readily prepared by the A-alkylation reaction of the corresponding previously known propargyl-azetidinones with a wide variety of isoselenocyanates under basic conditions. First, the reaction of (3-alkyne-selenourea... 

An alternative and convenient a-alkylation reaction uses a 1-alkyl-2,4,6-triphenylpyridinium tetrafluoroborate with the monosodio derivative of a primary or secondary nitroalkane.202... 

An unexpected aromatization that takes place during the A-alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-l //-pyrazolc-5-carboxylic acid methyl esters, giving rise to a mixture of l-alkyl-3-(2-nitrobenzoyl)-4,5-dihydro-1 II-pyrazole-5-carboxylic acid methyl esters and 1 -al kyl-3-(2-ni trobcnzoyl)-1 //-pyrazole-5-carboxylic acid methyl esters is reported. It is suggested that reaction involves both inter- and intra-molecular oxidation by the nitro group.107... 

Chiral P-hydroxy esters and l,3-dioxan-4-ones are well-known substrates for diaster-oselective a-alkylation reactions developed by Frater [20] and Seebach [21]. These chiral compounds are available in both enantiomeric forms, and have been also ami-nated at the a-carbon with high stereoselectivity. 

Quinoxalin-2(l//)-ones undergo A-alkylation reaction with haloalkanes or dimethyl sulfate in alkaline medium and quinoxaline-2,3(l//,4//)-dione is A-alkylated using... 

Isoxazole-supported selenium resins, produced via 1,3-dipolar cycloaddition of nitrile oxides with propargyl selenium resin, were subjected to a-alkylation reactions with various electrophiles, leading to 3-aryl-5-i4-substituted ethenylisoxazoles in satisfactory yields (62-78%) and purity (90-99%). Compound 238 gave olefin 240, through selenoxide elimination from the a-alkylation product 239 (Scheme 56) <2003OL4649>. 

Chiral oxazolidinone auxiliaries derived from D-xylose were applied by Koell et al. [156]. The oxazolidinones were acylated with various acid halides furnishing imides, which are substrates for a-alkylation reactions. For example, the butyric acid derivative 213 was deprotonated with LDA to give the (Z)-configured enolate 214, which was reacted with methyl iodide (Scheme 10.71). The methylated product 215 was formed in a moderate yield of 45% and a diastereomeric ratio of 7 1. The approach of the electrophile occurred from the less hindered /-face of the enolate... 

SCHEME 10.71 WAcylated sugar-derived chiral oxazolidinones are substrates for asymmetric a-alkylation reactions. 

The above results led to an explosion of interest in the use of lithium enolates in a-alkylation reactions. It was quickly demonstrated that specific lithium enolates of a variety of unsymmetrical ketones could be trapped with the more reactive alkylating agents in liquid ammonia or aprotic solvents such as... 

On the one hand, thioacetals of a,B-unsaturated ketones resulting from the a-alkylation reaction reported above have been transformed efficiently into the corresponding unsaturated ketones on reaction with mercury(II) chloride and oxide in methanol (Scheme 71, entry or on reaction - with... 

The proton-proton HNCH spin-spin coupling in A-methylaniline is affected by the p fa value of the proton acceptor partner. PhsPO, PhsAsO and F ions are used in order to elucidate this dependence. The importance of the hydrogen bonding interaction is observed also in aniline reactions. In fact, the addition of potassium fluoride to the reaction mixtures of anilines and alkyl halides strongly enhances the A-alkylation reaction because the nucleophilicity of aromatic amines is increased by hydrogen bond interaction with fluoride ion151. 

The need for new classes of strong non-ionic, non-nucleophilic bases has led Palacios and co-workers to investigate ylide (101) and its polymer-supported analogue (102) in this capacity. It was found that ylides (101) and (102) acted as versatile bases for selective A -alkylation reactions of P-amino phosphine... 

Xu, W., Mohan, R. and Morrissey, M.M. (1998) Polymer supported bases in solution phase synthesis. 2. A convenient method for A-alkylation reactions of weakly acidic heterocycles. Bioorganic Medicinal Chemistry Letters, 8, 1089-1092. 

Due to the strong basicity, high steric hindrance and low quaternizability of polymer-supported superbase reagents, several types of O- and A -alkylation reactions have been reported, with the goal of contributing to combinatorial chemistry [45-58]. For example. 

A-Alkylation Reactions. The 9-BBN complexes of diamines such as 1,8-diaminonaphthalene and 2-aminobenzylamine serve as substrates for selective iV-alkylation. N-chelated borane complexes undergo regioselective mono-(V-alkylation with an alkyl halide under basic conditions without further alkylation. Hydrolysis of the corresponding intermediate provides the mono-iV-alkyl-ated product in excellent yields (eq 53). In this case, the 9-BBN chelation of the diamine both protects the aromatic amine and activates the benzylic amine. 

Mack et al. carried out A -alkylation reaction in ball mill (8000M SpexCertiprep Mixer Mill, stainless steel) [46], Reaction of 4-bromobenzyl bromide 257 with urea and sodium hydroxide yielding di-(4-bromobenzyl) urea 258 proved that chemical reactions under high-speed ball-milling conditions could be manipulated in order to increase the nucleophilicity of an otherwise weakly nucleophilic substance (Scheme 3.68). Here the hydroxide deprotonates the urea, increasing the nucleophilicity of the nitrogen. Withont NaOH, there was a negligible conversion to a dialkyl urea product. 

The cyclopropanation of activated olefins by cascade Michael/a-alkylation reaction using a-halomalonates or bromonitromethane as functionalized pronucleophiles has also been faced with the application of H-bonding catalysis. 

Piperidines, like cyclohexanes, adopt a preferred chair conformation. Much controversy centred over the years on the question as to whether in piperidines it is the A-substituent (or A-hydrogen) or the A-lone pair which adopts an equatorial or axial orientation some confusion arose because of the results from A-alkylation reactions, the products from which do not necessarily reflect ground state conformational populations. Both an A-hydrogen and an A-alkyl substituent adopt an equatorial orientation, though in the former case the equatorial isomer is favoured by only a small margin. ... 

A domino Michael/a-alkylation reaction between bromoacetoacetates and a,fS-unsaturated aldehydes provides the 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99% ee (for further details see Chapter 10) [37]. Similarly, an approach using enones 45 and bromonitromethane 46 has been used in organocatalytic nitro-cyclopropanation reaction to give 47 (Scheme 7.8)... 

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

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