Lactim ethers

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

Racemic and chiral syntheses of some indolo[2,3-<2]quinolizidine alkaloids through a lactim ether route 98H(47)525. 

Treatment of bis-lactim ether 420 with BuLi, then with cw-l,4-dichloro-2-butene in the presence of Nal afforded 3,4,9,9n-tetrahydro-6//-pyrido[l,2-fl]pyrazin-4-one (421) with 96% diastereomeric excess (97TA1855). Reaction of l,2-diphenyl-6-methyl-quinoxaline with 1,4-dichlorobutane in THF in the presence of Na at —78°C afforded a 3 1 mixture of 4a,5-diphenyl-9-methyl-l,2,3,4-tetrahydro-4a//-pyrido[l,2-n]quinoxaline and 4-(4-chlorobutyl)-2,3-diphenyl-6-methyl-1,4-dihydroquinoxaline (98JHC1349). 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

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. ... 

The high simple diastereoselectivities observed running the [4-1-3] cycloadditions raised the question concerning the induction of chirality. Preliminary experiments involving chiral menthyloxy Fischer carbenes 169 (R = (-)-men-thyl) resulted in the formation of the diastereomeric lactim ethers 173-1 and 173-2 in a 7 3 ratio, which could be separated by means of a crystallization. A final acidic hydrolysis gave the enantiomerically pure e-caprolactams 175 and ent-175 and the acyclic esters, respectively. No signs of racemization have been detected,Eqs. (18,19) [39b]. 

Imino ethers and, in particular, lactim ethers [141] such as O-ethylpyrrolidone 384a [142] or O-trimethylsilylcaprolactam 384b, which is formed, in equilibrium with N-trimethylsilylcaprolactam, on treatment of caprolactam with HMDS 2, condense readily with activated methylene compounds such as methyl or ethyl cyanoacetate to the y9-enamino esters 385 a and 385 b [140] whereas O-alkylureas such as 2-methoxyimidazoline 386 [143-146] afford products such as 387. 

Treatment of bis-lactim ether 393 with BuLi, then with t -l,4-dichioro-2-butene in the presence of Nal afforded 3,4,9,9a-tetrahydro-6//-pyrido[l,2-tf]pyrazin 4-one 394 with a 96% de (Equation 72) <1997TA1855>. 

The l,4-dihydro-pyrazino[2,l- ]quinazoline lactim ether 48 oxidized to give 49 with 2,3-dichloro-5,6-dicyano-/>-benzoquinone (DDQ) (Equation 3) <20030L3205>. 

Aza-Diels-Alder reaction between the lactim ether 49, as azadiene, and 3-methyleneoxindole, as dienophile, resulted in an isomeric mixture of the aza-Diels-Alder products 55 and 56 (Equation 4) <20030L3205>. 

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>. 

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>. 

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). 

Cyclic lactim ethers (465, n = 0 and 1, R2 = see below, R5 = OMe) were condensed with Meldrum s acid (421) in the presence of a catalytic... 

The five- and six-membered isopropylidene 2-azacycloalkylidenemalo-nates (468, n = 0 and 1, R2 = R4 = H) were prepared in 94% and 76% yields, respectively, in the reactions of Meldrum s acid (421) and the appropriate cyclic lactim ether (465, n = 0 and 1, R2 = H, R5 = OMe) in the presence of triethylamine in boiling benzene overnight (79JOC3089). Under these conditions, caprolactim methyl ether did not react, but if the latter reaction was carried out in the presence of acetic acid and piperidine in boiling benzene overnight, a seven-membered cyclic compound (468, n = 2, R2 = R4 = H) was obtained in 58% yield (79JOC3089). 

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 tri- and tetracyclic derivatives 321-323 were prepared in the reactions of 312-315 and lactim ethers instead of acyclic imidates [79JCS(P1)1765 82JCS(P1)2801 83JCS(P2)237 90PHA109 94MI1]. 

With lactam acetals (98), cyclic imidic chlorides (99) (X = Cl), lactim ethers (99) (X = OMe), or certain iminium salts (100) amidoximes form 5-(aminoalkyl) substituted oxadiazoles (Scheme 37)... 

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