Lactim ethers, also

Individual methods for the synthesis of lactim ethers also depend on the nature of the starting materials, e.g., the transformation of 2,3-dimethyl-3-cyanomethylindolenine (28) to the tricyclic lactim ether (29) in the presence of sodium ethoxide61 (Scheme 6). 

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

Microwave irradiation greatly improved the reaction between the lactim ethers 157 and anthranilic acid, as regards yields, reaction time and also the integrity of the stereocenter, as shown by the results obtained for compounds 158 (R1 = (R)-Me R4 = H R2 = Me, 4-MeO-Bn, (CH2)2Ph, 2-naphthylmethyl) and 158 (R =(R)-Me R4 = Me R2 = indol-3-ylmethyl), prepared by both the conventional thermal and the microwave-assisted methods <2004SL803>. 

Bicyclic pyrimidin-4-ones (1100, R = H, n = 0-3 R = Me, n = 1) were also prepared from the appropriate lactim ether and EMME in the presence of ammonia or ammonium acetate [73JAP(K)34897 75MIP1]. Pyrimido[l,2-a]azepine-3-carboxylates (1100, R = H, Ph n = 2) were prepared in the reaction of 7-aminotetrahydro-2//-azepines (R = H, Ph n = 2) and EMME or in the reaction of O-methylcaprolactim and diethyl aminomethylenemalonate in ethanol [73JAP(K)34897 75MIP1]. 

The bicyclic system has also been prepared by annulation of a pyrimidine ring onto an existing thiazine (Scheme 97) the cyclization fails with acetamidine or d -methylthiourea <1996JHC235>. Alternatively, a pyrimidine ring is formed by reaction of guanidine with the lactim ether formed by 0-methylation of a 2-methoxycarbonyl-l,4-thiazin-2-one (Scheme 98)<1997JME2502>. 

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). 

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). 

By this practical — and resonably inexpensive — method the bis-lactim ether (20 b) of cyclo(L-Val-Gly)16), (20c) of cyclo(L-rLeu-Ala)17), (20d) of cyclo(L-fLeu-Gly)18), (21a) of cyclo(L-a-Methyldimethoxyphe-Gly)19) and (21b) of cyclo(L-a-Methyl-phe-Gly)20) were also prepared advantageously. 

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 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... 

Lactim ethers are used in the synthesis of dyes10,11 and other important classes of organic compounds. They are also of interest because of their biological activity12 and use as accelerators for polymerization.13... 

Similarly, the reaction of the hydrocarbostyrilspiran (17) with PC15 and POOlg and alcoholysis of the intermediate yielded the lactim ether (18), obtained also as a by-product in the reduction of diethyl di(o-nitrobenzyl)malonate.45... 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

Sulfonamides also condense with lactim ethers. It has been reported114 that in one case a lactim ether reacted with a sulfonamide group even in the presence of an aromatic amino group [Eq. (8)]. 

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. ... 

Brown and lenage " obtained the tricyclic imines 220 by treating anthranilonitrile 219 with lactim ethers (n = 2-4)at 150- 190°Cfor 24-36 hr. The tricyclic imines 220 were also synthesized through the cyclodehydration of anthranilonitrile (219) with lactams (n = 2-4,6) by the use of phosphorus pentoxide in boiling xylene. 

The cis derivatives 224 were also obtained in the reaction of the bicyclic azetidinones 223 and lactim ethers. - ... 

Dihydro-2-isopropyl-3.6-dimethoxypyrazine, a bis(lactim)ether, is converted into the 5-di-azo compound 1 by lithiation and diazo group transfer. The intermediate diazo compound reacts at room temperature with olefins such as cyclohexene to produce the cyclopropane derivatives with excellent diastereoselectivity . The derivative from cyclohexene is hydrolyzed by acid treatment to give methyl 7-cv(cfo-aminobicyclo[4.1.0]hcptane-7-carboxylate. The bis(lac-tim)ether diazo compound 1 is also involved in an exceptional asymmetric [2 + 1J cycloaddition producing cnantiomerically pure cyclopropenc derivatives4. Thus, reactions of the diazo compound with monosubstituted alkynes afford the spiro compounds as one diastereomer. Hydrolytic removal of the auxiliary and protection of the amino group provides enantiomerically pure methyl l-amino-2-arylcyclopropene-l-carboxylates in moderate overall yield. 

Transformation of imino-ether 595 into 1,4-disubstituted pyrazino[2,l-fc]quinazo-line-3,6-dione 596 in 48% yield resulted by reaction with anthranilic acid under MWI for 3 min, compared to a 16% yield produced by eonventional heating for 2h. Also, the double condensation of the feis-lactim ether 597 required 6 min to give 598 in 89% yield (Scheme 117) (04SL803), compared to a 54% yield by classical heating for lh(83AGE717). 

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of SchifI bases derived from a-amino-acid esters and good yields of /3-hydroxy-a-amino-acids are obtained. This type of compound is also prepared using the optically active imine (183) the t/trco-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88). The jS-hydroxy-a-amino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described. Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. L-Alanine, L-valine, and (S)-0,0-dimethyl-a-methyldopa have been used to prepare the heterocyclic intermediates (186), which give a range of amino-acids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187). ... 

Tlie bis-lactim-ether method described by Schollkopf and his co-workers has also been applied to the preparation of the / -a-vinylamino-acid (203) (Scheme 92). " A mixture of olefins (201) and (202) (80 20) is produced that leads to... 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Synthesis of Unsaturated a-Amino-acids.—The lactim ether (284) is converted into the enantiomerically pure unsaturated amino-acids (285) (Scheme 140) ethyl (J5)-2-formylamino-4-methoxybut-3-enoate and its 2-alkyl derivatives have also been prepared, using heterocyclic intermediates. ... 

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