Alkylation step

With the catalysis of strong Lewis acids, such as tin(IV) chloride, dipyrromethenes may aiso be alkylated. A very successful porphyrin synthesis involves 5-bromo-S -bromomethyl and 5 -unsubstituted 5-methyl-dipyrromethenes. In the first alkylation step a tetrapyrrolic intermediate is formed which cyclizes to produce the porphyrin in DMSO in the presence of pyridine. This reaction sequence is useful for the synthesis of completely unsymmetrical porphyrins (K.M. Smith, 1975). 

By performing two successive alkylation steps the malonic ester synthesis can be applied to the synthesis of a a disubstituted derivatives of acetic acid... 

A reaction analogous to the alkylation step of reaction (7.Q) can account for the association of an aluminum species with chain ends ... 

Chromium carbene complexes like 13, which are called Fischer carbene complexes, can conveniently be prepared from chromium hexacarbonyl 11 and an organolithium compound 12, followed by an O-alkylation step ... 

The reactive species is the corresponding enolate-anion 4 of malonic ester 1. The anion can be obtained by deprotonation with a base it is stabilized by resonance. The alkylation step with an alkyl halide 2 proceeds by a Sn2 reaction ... 

Many historical ways to make ionic liquids proved to be impractical on larger scales. Sometimes expensive starting materials are used (anion-exchange with silver salts, for example [2]), or very long reaction times are necessary for the alkylation steps, or filtration procedures are included in the synthesis, or hygroscopic solids have to be handled. All these have to be avoided for a good synthesis on larger scales. 

The malonic ester synthesis can also be used to prepare cydoalkane-carboxvlic acids. For example, when 1,4-dibromobutanc is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intrcunotecidariy to yield a cyclic product. Hydrolysis and decarboxylation then give cvclopentanecarboxylic acid. Three-, four-, five-. 

Although reactions required 2 days to reach completion in the presence of stoichiometric amounts of sulfide, they became impracticably long (28 days) when 10% sulfide was employed, due to the slow alkylation step. The alkylation step was... 

The procedure described here for the preparation of succinimide silver salt is a modification of one reported for the formation of the silver derivative of maleimide. The alkylation step is modeled after the procedure of Comstock and Wheeler/ who prepared 2-ethoxypyrrolin-5-one in unspecified 3deld, and is an improvement over a later procedure developed in the laboratories of the submitters/ The general scheme has been successfully applied to the preparation of a variety of 2-ethoxypyrrolin-5-ones (Table 1) as well as 6-ethoxy- and 6-propoxy-4,5-dihydro-2(3H)-pyridone from the corresponding five- and six-membered cyclic imides/... 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

To pursue the development of environmentally benign synthesis routes for ionic liquids, the alkylation step (Menschutkin reaction) was investigated by the authors in detail. The preparation of the ionic liquid 1-hexyl-3-methyhmidazohum chloride ([CeMlMJCl) was taken as a representative experiment (Scheme 7.2). The process parameters temperature (T = 70-100°C), solvent (ethanol, xylene, cyclohexane, n-heptane, solvent free), concentration of the N-base (c = 1.6-6.7 M), molar ratio n n = 1 0.5-1 4) and reaction time (f = 10-144 h) were investigated. In addition, the N-base was altered in order to proof the transferability of the reaction parameters. 

Examples of this approach to the synthesis of ketones and carboxylic acids are presented in Scheme 1.4. In these procedures, an ester group is removed by hydrolysis and decarboxylation after the alkylation step. The malonate and acetoacetate carbanions are the synthetic equivalents of the simpler carbanions that lack the additional ester substituent. 

The (3-keto sulfoxides can be alkylated via their anions. Inclusion of an alkylation step prior to the reduction provides a route to ketones with longer chains. 

It would not work to use propyne and 2-bromopropane for the alkylation step of... 

As an illustration of this principle, a volatile polar molecule is a byproduct, eliminated as a result of the microwave heating (Eq. 4), and the equilibrium is shifted to completion. The second effect of irradiation is activation of the alkylation step itself (Eq. 5). All the reagents can be used in the theoretical stoichiometry. Some indicative results are given in Tab. 5.4 [9]. 

The intriguing point is that the actual alkylation step may be the same at the anode and cathode, presumably by alkyl radicals which, in analogy to the Paneth reaction, alkylate the metal. The lifetime of the radical ion, reactivity of the radical ion or the radical towards the metal, stabilization of the radical by adsorption on the electrode surface, stabilization of each of the intermediates by solvation, their build-up in the double layer, the potential applied, all have an important contribution to the outcome. In certain cases the ET takes place catalytically, by a mediator or under the influence of surface effects17. It is therefore important to keep in mind the possible subtle differences between cases described below that otherwise appear similar. 

The reactions of primary amines with BENAs proceed in a more complex fashion (499, 521). In the absence of steric hindrance in the amine, terminal BENAs are readily and rapidly involved in double j3-oximino-alkylation with primary amines (Scheme 3.245, product A7)- To stop the process at the mono-alkylation step (intermediate A), a large excess of amine should be used. 

The N, C -coupling reactions of primary amines with BENAs are very sensitive to steric factors in BENAs. For example, the reactions with terminal BENAs are difficult to stop at the mono-alkylation step, whereas in internal BENAs, it is very difficult to isolate the bis-coupling product. A special procedure, based on this fact, enables one to synthesize bis-oximes (460) containing various oximinoalkyl substituents at the nitrogen atom. It should be emphasized that diastereoselectivity of /V,( -coupling reactions of amines with terminal BENA is very low. 

Ethylation, which involves an unstable ethylcarbenium ion as intermediate, is much slower (1500 times over AICI3) than isopropylation. It is also the case in benzene alkylation with propene for the undesired formation of n-propylbenzene, which involves a primary n-propyl carbocation. Furthermore, as alkyl substituents activate the aromatic ring, consecutive alkylation of the primary product occurs with a greater rate than the first alkylation step ( 2 > i)-... 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

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