Ethyl phase transfer alkylation

Figure 4.23 Phase-transfer alkylation of ethyl 2-oxocyclopentane carboxylate with benzyl bromide in the presence of TBAB.

The asymmetric alkylation of glycine derivatives constitutes a general means of accessing a wide range of natural and unnatural oc-amino acids.111 Recently it has been established that the quaternary ammonium salt, (lS,2S,4S,5/ ,l / )-l-anthracen-9-yl)methyl-2-[benzyloxy(quinolin-4-yl)methyl]-5-ethyl-l-azoniabicyclo [2.2.2]octane bromide, is a highly effective catalyst in the asymmetric liquid-liquid phase-transfer alkylation of tert-butyl AI-(diphenylmethylene)glycinate. Subsequent hydrolysis of the imine provides access to a wide range of a-amino acid fcrt-butyl... 

The question of where carbanions will attack 2,4-dichloronitrobenzene is addressed. Experimental evidence is presented that such carbon acids as alkylsubstituted phenyl-acetonitriles and ethylmalonate ester which contain a methine group prefer nucleophilic aromatic substitution in the para-pos X on whereas active methylene compounds like desoxybenzoin, diethyl malonate, ethyl cyanoacetate and phenylacetonitrile prefer attack at the ortho-cYAoiine. A variety of conditions was used including strong base in DMSO but most of the cases are phase transfer alkylation conditions. 

A AlI lation. 1-Substitution is favored when the indole ring is deprotonated and the reaction medium promotes the nucleophilicity of the resulting indole anion. Conditions which typically result in A/-alkylation are generation of the sodium salt by sodium amide in Hquid ammonia, use of sodium hydride or a similar strong base in /V, /V- dim ethyl form am i de or dimethyl sulfoxide, or the use of phase-transfer conditions. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Preparation of the donor 46 was started from 4,6-0-benzylidene protected thiomannoside 47 (Scheme 7.24). Alkylation with p-allyloxybenzyl chloride under phase transfer conditions78 was followed by 3-O-silylation and Pd(0)-mediated deallylation79 to give 48. The phenolic OH group was alkylated with ethyl 6-bromohexanoate and carboxylic acid, liberated by alkaline hydrolysis, was reacted with PEG monomethyl ether (MW -5000) under Mitsunobu conditions to afford 46. 

Methyl esters undergo trans-esterification with the quaternary ammonium salts at high temperature and the reaction has been used with some effect for the preparation of, for example, n-butyl esters by heating the methyl ester with tetra-n-butylammo-nium chloride at 140°C [31]. Optimum yields (>75%) are obtained in HMPA or in the absence of a solvent. A two-step (one-pot) trans-esterification under phase-transfer catalysed conditions in which the carboxylate anion generated by initially hydrolysis of the ester is alkylated has been reported for Schiff s bases of a-amino acids [32] and for A-alkoxycarbonylmethyl [1-lactams [33]. Direct trans-esterification of methyl and ethyl esters with alcohols under basic catalytic conditions occurs in good yield in the presence of Aliquat [34, 35]. 

Alkylation of trifluoro- and trichloroacetamides with a-bromoacetic esters has been utilized for the synthesis of a wide range of a-aminoacetic acids [11-13] (Table 5.13). Hydrolysis of the intermediate a-trihaloacetamidoacetic esters with methanolic potassium hydroxide converts the methyl and ethyl esters directly into the amino carboxylic acids. /-Butyl a-aminoacetates are more stable, but they are hydrolysed under phase-transfer catalytic conditions (see Chapter 9.2). Reaction of the trihaloacetamides with 1,4-dibromobutane and 1,5-dibromopentane and subsequent hydrolysis provides a simple route to pyrrolidine-2-carboxylic acid (75%) and piperidine-2-carboxylic acid (58%) [11, 12],... 

C-Alkylation of ethyl l,3-dithiane-2-carboxylate (for preparation, see 4.1.6) under mild soliddiquid phase-transfer catalytic conditions [32, 33] provides a potentially useful route to a-ketoesters. 

Glycopyranosyl halides react with ethyl acetoacetate and pentan-2,4-dione under soliddiquid phase-transfer catalytic conditions, using potassium phosphate as the base, providing the C-alkylated derivatives (40-60%) ]94],... 

A mechanistic study of acetophenone keto-enol tautomerism has been reported, and intramolecular and external factors determining the enol-enol equilibria in the cw-enol forms of 1,3-dicarbonyl compounds have been analysed. The effects of substituents, solvents, concentration, and temperature on the tautomerization of ethyl 3-oxobutyrate and its 2-alkyl derivatives have been studied, and the keto-enol tautomerism of mono-substituted phenylpyruvic acids has been investigated. Equilibrium constants have been measured for the keto-enol tautomers of 2-, 3- and 4-phenylacetylpyridines in aqueous solution. A procedure has been developed for the acylation of phosphoryl- and thiophosphoryl-acetonitriles under phase-transfer catalysis conditions, and the keto-enol tautomerism of the resulting phosphoryl(thiophosphoryl)-substituted acylacetonitriles has been studied. The equilibrium (388) (389) has been catalysed by acid, base and by iron(III). Whereas... 

Some difficulty has been encountered with the TV-alkylation (e.g. with ethyl bromoacetate) of 2,3,4,5-tetrahydro-l//-l-benzazepin-5-one (31 R = H) (74JCS(P1)1828). The pharmacological activity (Section 5.16.5) of TV-substituted 5H-dibenz[6,/]azepine and its 10,11-dihydro derivatives has resulted in an intensive study of the TV-alkylation of these ring systems (74CRV101). Generally, alkylation is effected with an alkyl halide or tosylate in the presence of base. Phase transfer TV-alkylations of 5H- dibenz[6,/]azepine have been reported. The method, however, is less successful with the 10,11-dihydro derivatives (79MI51600). 

The higher acidity of pyrroles and indoles bearing electron-withdrawing substituents at the a- or /3-positions permits their alkylation under mildly basic conditions, but although the thallium salt of 2-formylpyrrole is Af-alkylated, the corresponding alkylation of the thallium salts of ethyl pyrrole-2-carboxylate yields a complex mixture of products resulting from iV-alkylation and transesterification (B-77MI30502). N-Alkylation of pyrrolyl and indolyl esters is most conveniently effected under phase-transfer conditions. 

Amino acid synthesis (8, 389). Alkylation of the aldimine (1) from glycine ethyl ester and /j-chlorobenzaldehyde under phase-transfer conditions offers a general route to amino acids. Either liquid-liquid phase-transfer or solid-liquid phase-transfer catalytic conditions are satisfactory with active halides, but alkylation with allylic halides and less active alkyl halides is best effected under ion-pair extraction conditions (6,41), with 1 equiv. of tetra-n-butylammonium hydrogen sulfate (76-95% yields).1... 

The salient feature of le as a chiral phase-transfer catalyst is its ability to catalyze the asymmetric alkylation of glycine methyl and ethyl ester derivatives 4 and 5 with excellent enantioselectivities. Since methyl and ethyl esters are certainly more susceptible towards nucleophilic additions than tert-butyl ester, the synthetic advantage of this process is clear, and highlighted by the facile transformation of the alkylation products (Scheme 5.3) [8],... 

Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Having determined the most appropriate extraction from plasma we investigated the simultaneous derivati-zation of A9-THC and ll-hydroxy-A9-THC. We have claimed that ethylation of 11-hydroxy-A9-THC proceeded by phase transfer catalysis (7). However, it is known that quaternary ammonium hydroxides are capable of catalyzing alkylations with alkyl iodides in aproptic solvents (8). Furthermore, we had not demonstrated that A9-THC could be derivatized under the same conditions as ll-hydroxy-A9-THC. We found that the minimum requirement for the reaction to proceed is the presence of water, which probably increases the degree of ionization of the quaternary ammonium hydroxide. However, in order for the reaction to go to completion, at least 0.1N NaOH is necessary. This supports the contention that this derivatization is, to some extent, a phase transfer catalyzed alkylation. 

Alkylation of (4) with ethyl bromo acetate was effected under phase-transfer conditions with powdered potassium hydroxide and tetrabutyl ammonium bromide in tetrahydrofuran to yield compound (5), and the azide function in (5) was then reduced by catalytic hydrogenation (over Pd/C) to give (6). The aminoester (6) was resolved into its enantiomers via... 

Alkylation of pyrazolo[3,4-triethyl orthoformate gives the N-l ethyl derivative <88KGS914>. Phase-transfer methylation of 4-methoxy-l//-pyrazolo[3,4-d]pyrimidines gives a mixture (2 1) of N-l and N-2 methylated derivatives <85JOC1847>. 

Alkyl Aryl Telluriums2 (Reduction with Thiourea Dioxide) To a solution of 1.0 mmol diaryl ditellurium in 7.5 ml tetrahydrofuran are added 0.108 g (1.0 mmol) thiourea dioxide, 30 mg 2HT (phase transfer reagent), and 2.0 mmol of the alkyl bromide. To this mixture are added 7.5 ml of a 50% aqueous solution of sodium hydroxide. The mixture is stirred for several hours at 20°. The organic phase is separated. The aqueous phase is extracted three times with 20 ml ethyl acetate. The organic phase and the ethyl acetate extracts are combined and dried with anhydrous magnesium sulfate. The mixture is filtered and the solvents evaporated from the filtrate. The residue is chromatographed on silica gel with ethyl acetate as mobile phase. 

The procedure described here for compound 1 is a scaleup of a published method.6 Phase-transfer catalysis7 and concentrated alkali are used to effect a one-pot conversion of diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of 1-cyanocyclopropanecar-boxylic acid (86%) by the use of ethyl cyanoacetate and 1-acetyl-cyclopropanecarboxylic acid (69%) by use of ethyl acetoacetate.6... 

Deng, R., Wang, Y., and Jiang, Y. 1994. Solid-liquid phase transfer catalytic synthesis X The rapid alkylation of ethyl acetoacetate under microwave irradiation. Synthetic Communications, 24 111-15. 

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