Alkylation amino ethylated products

Katritzky and Harris reported in 1992 the use of diethylzinc for the chiral amino alcohol-mediated enantioselective addition to the C=N bond in these compounds (Scheme 12) [34]. These substrates act as masked activated N-acylimines. Of the large variety of Hgands available for the catalytic asymmetric reactions of dialkylzinc reagents,the sterically constrained P-dialkylamino alcohol, (-)-N,N-dibutylnorephedrine (DBNE) 18, prepared by alkylation of commercially available norephedrine, was selected for this study. Some preliminary experiments conducted with the use of -(aminobenzyl)benzotriazoles gave the ethylated product, but with no enantioselectivity. Diethylzinc (Et2Zn) was found to react even in the absence of a chiral promoter. The behavior of the less reactive N-(amidobenzyl)benzotriazoles 19a-g was then investigated. 

The benzimidazolyl and indazolyl anions react straightforwardly on nitrogen with electrophilic alkylating agents, though mixtures of N-1- and N-2-substituted products can result in the latter case. For example, amination with hydroxylamine 0-sulfonic acid gives a 2 1 ratio of 1-amino-l//-indazole and 2-amino-2f/-indazole or to take another example, the ratio of A -1 to A -2-ethylated products from methyl indazol-3-ylcarboxylate can vary from 1 1 to 18 1 depending on the base and the solvent. ... 

Reductive alkylation by alcohol solvents may occur as an unwanted side reaction 22,39), and it is to avoid this reaction that Freifelder (20) recom mends ruthenium instead of nickel in pyridine hydrogenation. Alkylation by alcohols may occur with surprising ease 67). Reduction of 18 in ethanol over 10% palladium-on carbon to an amino acid, followed bycyclization with /V,/V-dicyclohexylcarbodiimide gave a mixture of 19 and 20 wiih the major product being the /V-ethyl derivative 49,50). By carrying out the reduction in acetic acid, 20 was obtained as the sole cyclized product 40). 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

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],... 

A/-[ F]Fluoropyridinium tiiflate reacts with alkyl- and arylmagnesium salts (Grignard reagents) as well as enolates (Scheme 23) to yield the corresponding radiofluorinated products, often in high radiochemical yields. Examples are the syntheses of [ F]fluorobenzene (62%), 1-p F]fluorohexane (78%), diethyl 2-p F]fluoro-2-phenylmalonate (58%) and ethyl 3-amino-2-p F]fluoropropionate (23%) [83]. 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

Alkylation of the exocyclic amino group of the 4-amino-6-phenylpyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxide 95, shown in Equation (14), with ethyl iodide and potassium carbonate in acetone gave the corresponding 4-ethyl-amino derivative 96 in a clean and efficient manner, although the researchers noted that the procedure is not general due to competitive formation of dialkylated products <2000JME4219>. The procedure described in Section 10.20.6.3 (Equations 10 and 11) is, in fact, a more efficient entry to 4-alkylamino pyrazino[2,3-c] [ 1,2,6]thiadiazine 2,2-dioxide. 

The corresponding ethylation proceeds in lower yields, and may be suppressed entirely by the presence of substituents elsewhere in the nucleus (e.g. 192 R = Ph).171 The attempted introduction of higher alkyl, allyl, and benzyl residues also failed.171 The derivative (204) obtained with phenacyl bromide is readily ring-closed to the diheterocycle 205.171 Diphenyl- and triphenyl-methyl halides, on the other hand, alkylate 5-amino-1,2,4-thiadiazoles in the exocyclic amino group,171 as shown by the lower basicity of the resulting products (e.g. 202). 

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