Alkylation of ethyl glycinate

Ethyl glycinate was heated with excess TMSNEtj in the presence of a catalytic amount of ammonium sulphate at 120 °C, until no more diethylamine distilled out. The product was distilled directly (75%), b.p. 100°C/10mmHg. 

To a solution of the silylatcd glycinate (50 mmol) in ether (50 ml), cooled to —10 to 0°C, was added a solution of sodium hexamethyldisilazide (55 mmol) in ether (100 ml) with stirring. Stirring was continued at ambient temperature for a short time, and then the alkyl halide (50 mmol) was added dropwise. The mixture was heated under reflux for 10-15 h, cooled, filtered, and the product was distilled directly (52-70%). 

The alkyl halides used were Mel, EtI and PhCH2Br. 

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Aldehydes, 43 a-Chiral, 112 a/MJnsaturated, 85,110 /3-Aldchydosi lanes, 22 Aldol reaction, directed, 139 Alkoxytrimethylsilanes, 122 Alkyl lithium. 67 Alkyl silyl ethers, 91-97,127 Alkylation, 33 of ethyl glycinate, 88-89 t-Alkylation, 111-135... 

On the other hand, the synthesis of Shih and Bayley is based on the C -alkylation of ethyl N-(diphenylmethylene)glycinate by 3-[4-(iodomethyl)phenyl]-3-(trifluoromethyl)-3//-diazirine (57) (Scheme 13). The precursor for the diazirine-containing alkylating reagent is the O-protected benzyl alcohol 53J1251... 

The introduction of alkyl groups at the a-carbon of amino acids has been accomplished most efficiently by formation of imine esters. For example, the benzaldehyde imine of ethyl glycinate can be deproton-ated and alkylated (equation 39)." Other imines also have been used." Optical activity has been introduced by using chiral palla um ligands during the alkylation step, ° chiral alcohols to form the ester, and chiral ketones to form the imine." Alkylation of 2-pyrrole acetate esters has been accomplished in a similar fashion." ... 

Ethonam (99), an imidazole derivative with a very different substitution pattern, is also reported to possess antifungal activity. To prepare it, alkylation of aminotetralin 94 with methylchloro-acetate gives the glycine derivative 95. Heating with formic acid then affords the amide 96 this compound is then reacted with ethyl formate to yield hydroxymethylene ester 97. Reaction with isothio-cyanic acid gives the imidazole-2-thiol 98. (The... 

Michael addition of methylene imines with alkenes under solid Iiquid two-phase conditions provides a route to substituted a-amino acids [26, 27] (Scheme 6.22). When ethyl glycine is (V-protected with (S)-menthone, C-alkylation under soliddiquid... 

The electron-deficient alkene (5.2 mmol) in MeCN (5 ml) is added to an intimate mixture of powdered K2C03 (1 g) and NaOH (0.2 g), the (S)-menthone-protected ethyl glycine (1.27 g, 5 mmol), and TBA-Br (0.16 g, 0.5 mmol) in MeCN (20 ml). The mixture is stirred for 1 h at 0°C and then filtered. The solid is washed with MeCN (10 ml) and the combined organic solutions are evaporated and the residue is taken up in Et20. The ethereal solution is washed well with H20, dried (MgS04), and evaporated to produce the alkylated imine, which can be converted into the amino acid upon hydrolysis with aqueous acid. 

Stereochemical control of a reaction can also be achieved using non-chiral catalysts, when a chiral centre already exists in the reactant, as for example in the reaction of cyano- or methoxycarbonylmethyl phosphonates with 3-hydroxy-2-(S)-alkylated products are obtained with ca. 40% de of the 2(S)-3(R)-diastereoisomers [11]. Similarly, when ethyl glycine is Ar-protected with (S)-menthone, C-alkylation under soliddiquid conditions using a non-chiral catalyst (6.4.5) provides a route to chiral a-substituted amino acids with optimum enantiomeric excesses of up to 47% [12],... 

Commercially available ethyl nitroacetate is an interesting pronucleophile, because it can serve as the synthetic equivalent of either nitromethane or glycine. The ethoxycarbonyl group can also be considered as a protecting group against dialkylation. The allylic alkylation with ethyl nitroacetate did not require an additional base (salt-free conditions). As a consequence of the high acidity of the chirality center a to N, 1 1 mixtures of epimers were formed. 

Lipo-amino acid derivatives are readily obtained in good yields by direct alkylation of amino acids esters with the related alkyl halides, e.g. farnesyl bromide, under careful control of the reaction conditions to avoid exhaustive alkylation of the amino group. 128 Alternatively, peptoid chemistry is applied for N-alkylation of glycine ester via reaction of alkyl amines, e.g. hexadecylamine, with ethyl bromoacetate. 36,98 ... 

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],... 

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

The above iodides have been used as 1 -labelled building blocks in the preparations of [3-nC]tyrosine, (9-methyl[3-nC]tyrosine, /7-chloro[3-nC]phenylalanine and / -fluoro[3-JlC]phenylalanine by alkylations of glycine derivatives241. The [nC]ethyl ether derivatives (using sodium ethoxide as nucleophile) and 3-nitrophenyl-4-methoxy[(Z-nC]benzyl ether (using sodium 3-nitrophenolate) have been synthesized also, employing 4-methoxy(ar-14C)benzyl iodide 18324. ... 

The adducts are useful for preparation of alkylated amino acids. An example is the preparation of 2-amino-4-pentynoic acid (4) from ethyl glycinate (3). 

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... 

Table 2.5 Room temperature alkylation of tert-butyl A -ldiphe-nylmethylene)-glycinate using (15,2,S, 4,S, 5Af l R)-l-(anthracen-9-ylmethyl)-5-ethyl-2-[benzyloxy(quinolin-4-yl)methyl]-l-azoniabi-cyclo[2.2.2]octane bromide as catalyst.

Comforth et al have devised a flexible method of synthesizing oxazoles ( 9) from the condensation of an imino ether (88) and ethyl glycinate hydrochloride, followed by reaction with an alkyl formate and potassium alkoxide, and cyclization of the product in hot acetic acid. The reported yields in various stages are fairly good. 

This approach was reinvestigated by Liskamp s group during the synthesis of peptoids and retro-peptoid analogues of Leu-enkephalin and substance R In this study, A-substituted glycine precursors were obtained by alkylation of appropriate primary amines with ethyl bromoacetate. Subse-... 

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