Lactim ethers alkylation

Alkylation of the 3-lactim ether, (4A)-3-ethoxy-4-isopropyl-l,4-dihydropyrazino[2,l-3]quinazolin-6-one with BnBr gave pure l,4-/ra r-diastereomer. The higher diastereoselectivity - as compared to the lactams - was explained by the fully boat conformation of the piperazine ring in the lactim ethers <2005TA3160>. 

A new route has been developed for the efficient formation of the variably substituted indolo[2,3-a]quinolizine ring system, starting from a properly substituted 2-piperidone (103, 104). For the preparation of octahydroindolo-quinolizine (1), the unsubstituted 2-piperidone 139 was treated with triethox-onium tetrafluoroborate. Then the corresponding lactim ether 140 was alkylated with 3-chloroacetylindole followed by a subsequent two-step reduction process and Bischler-Napieralski ring closure. Finally, reduction of the C=N bond afforded ( )-l (104). 

The hfs-lactim ether (190) was metallated with BuLi regiospecifically in the alanine part of the molecule to produce, after the reaction with alkyl halides, the (3R)-adducts... 

The earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

Subsequently, the asymmetric synthesis of stereospecifically monodeu-terated 1-aminocyclopropane-l-carboxylic acids (IS, 2R) and (IS, 2S) has also been achieved by a modification of the above route (89JOC270). The essential step involves an intramolecular alkylation on a lactim ether anion (Scheme 64). 

In the course of O-alkylation with triethyloxonium tetrafluoroborate, the lactim ethers of 1,4-dihydro-3(2//)-isoquinoIinones were obtained (75JMC395). These are useful starting materials for reactions with amines resulting in 1,4-dihydro-3-isoquinolylamines (85EUP139296). By means of bifunctional amines, further condensed hetero-ring compounds could be synthesized (73JMC633). 

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

On hydrolysis the alkylated bis-lactim ethers 8 yield (besides L-Ala-OCH3) the corresponding (R)-a-methylamino acid methyl esters 11. Their ee is 85% corresponding to the de of table 1 and taking into account 93 % ee of 6 9). 

Also ketones and aldehydes react with the lithiated bis-lactim ether 7 with rather high asymmetric induction to give the aldol-type adduct 13 (Table 2). Like alkyl halides, the carbonyl compounds enter trans to the methyl group at C-6 i.e. (R)-configuration is induced at C-3 13). 

Of course, the (3S)-compounds would also be formed if D-valine would be employed as chiral auxiliary. Hence, this method with valine as chiral auxiliary reagent solves the problem of enantioselective synthesis of a-methyl amino acids satisfactorily. Probably it can also be used — mutatis mutandis — for the asymmetric synthesis of a variety of a-alkyl amino acids, provided, the corresponding bis-lactim ether (type I) with valine as C-6 is regiospecifically metallated by butyl-lithium. This, for instance, is not be case with the mixed bis-lactim ether (20c) of cyclo(L-Leu-D,L-Ala)17). 

The bis-lactim ether 20b of cyclo(L-Val-Gly) reacts regiospecifically with butyllithium to afford the lithium compound 31. The addition products (32) are formed with alkyl halides in good chemical yields and — depending on R — with 65->95 % de16). They have the (3R)-configuration, as derived either from the H-nmr-spectrum of 32 (Table 4) or, indirectly, from the sign of rotation of the (R)-amino acid methyl ester (34) obtained by hydrolysis. 

Apart from methyl iodide, all alkyl halides react with de >95% with the lithiated bis-lactim ether 35 of cyclo(L-rLeu-Gly) 20d (Table 5). De can be determined either at the stage of the adducts 36 or, indirectly, via ee of the (R)-amino acid methyl esters (type 34) liberated on hydrolysis (2 equivalents 0.1 N HCI, r.t.)18). Although this system works exceedingly well — in fact, it could be the solution to the problem as far as this approach is concerned —, the method has one disadvantage at the tima... 

The bis-lactim ether 21a of 44 and glycine reacts with butyllithium to the lithium compound 45 which affords with alkyl halides in good chemical yields the (3R> alkylation products 46 with 70-95 % de (Table 7) 19 25>. The de values were determined either from the nmr-spectrum of 46 or, indirectly, from ee of the (R)-amino acid esters (type 34) obtained from 46 by hydrolysis (2 equivalents 0.25 N HC1, r.t.). 

The chemistry of O-alkyl derivatives of lactams (lactim ethers) is one of the least studied aspects of lactam chemistry. The lactams themselves have been much investigated in the preparation of polymers, in connection with penicillin (/3-lactams),1 and also because of the tendency of certain substituted derivatives to ring-close to cyclols, cylopeptides, or cyclodepsipeptides.2,3 A review on lactams has appeared.4... 

A detailed study of the action of dialkyl sulfates on caprolactam (1) was undertaken by Benson and Cairns.16 They found that the outcome depended on the molecular proportions of the reactants. Slow addition of the alkylating agent increased the yield of lactim ethers (2), whereas excess dialkyl sulfates decreased the yield because of the preferential formation of N-alkyl derivatives (3). Benson and Cairns proposed that 3 was formed via 2 and 4 as follows. 

In recent years the alkylation of lactams has been achieved using tertiary oxonium salts, particularly triethyloxonium fluoroborate.19,20 This reaction proceeds via cation formation (cf. 5). Treatment of the salt with base leads to the lactim ether. 

No comparison between trialkyloxonium fluoroborates and dialkyl sulfates has been made, but analysis of available data shows that oxonium salts are more generally applicable reagents for the preparation of lactim ethers. The alkylation of 3-carbethoxypiperid-2-one (7)25 and morpholin-3-one (8)32 with dimethyl sulfate failed, but with triethyloxonium fluoroborate these compounds gave 2-ethoxy-3-carbethoxy-3,4,5,6-tetrahydropyridine (9) and 3-ethoxy-3,4-dehydro-morpholine (10) in excellent yield. The selective character of triethyloxonium fluoroborate is shown in its reaction with 3,3-diethyl-5-methylpiperidine-2,4-dione (11 ).25 Reaction of 11 with the calculated quantity of dimethyl sulfate resulted in alkylation of the carbonyl group in position 4 with formation of 12, but reaction of 11 with triethyloxonium fluoroborate gave the lactim ether (13). 

Trialkyloxonium fluoroborates give better yields of lactim ethers than other alkylating agents because of the selectivity of these reagents in the O-alkylation of lactams. This was borne out by Meerwein at al.,42 who arranged carbonyl compounds according to their capacity to undergo alkylation with oxonium salts as follows lactams > acyclic amides > lactones > carboxylic esters > ketones > aldehydes. 

Reactions involving loss of the entire alkoxyl group (Scheme 8). The thermal rearrangement of lactim ethers to iV-alkyl lactams is a... 

The alkylation of markedly acidic substances by lactim ethers is a reaction of the first type. Lactim ethers have been used as alkylating agents for imino compounds such as uric acid (39), xanthines, and hypoxanthine,08 and for the esterification of organic acids.09... 

Finally, it should be noted that the investigations of Bredereck60,129 and Meerwein et al.130,131 on the preparation of lactam acetals have significantly widened the scope of utility of O-alkyl derivatives of lactams, and have extended some of the reactions of lactim ethers, discussed in this review, to N-substituted lactam acetals. 

Stephen and Stephen set out from 2-chloro-3,4,5,6-tetrahydropyridine and methyl anthranilate and obtained the pyrido[2,l-i>]quinazolinone 205 (R = R = H, n = 1) in 75% yield. Alkyl anthranilates were also treated with lactim ethers and lactams. ... 

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