Cyclizations under Basic Conditions

A-Salicoyl derivatives of 3-amino-2-halopyridines cyclize under basic conditions to pyrido-[2,3-/ ][l, 4]benzoxazcpin-6(5//)-ones this has been shown for the cyclization of 7V-(2-chloro-4,6-dimethyl-3-pyridyl)salicylamide 41... 

Coupling of the aminomethylindole 2-558 with acrolein in a Michael manner followed by a HWE reaction with phosphonates 2-560 afforded 2-561 which cyclized under basic conditions to give the desired product 2-566 via the intermediates 2-562-2-565 in 55 % yield (Scheme 2.127). The reaction sequence was also conducted in a stepwise manner, resulting in a greatly reduced yield this clearly demonstrates again the advantage of domino strategies over conventional methods. 

Sequential Mannich reaction of ester 210a or nitrile 210b, alkylation and displacement of quaternary ammonium salt affords azides 211. Further hydrogenation can be followed by intramolecular cyclization under basic conditions into pyrrolo-benzodiazepinone 212 (Scheme 44 (1994JHC1317, 1994S164)). 

Using a/n-dihaloalkanes the alkylation can be stopped at the monoalkylation stage. Oxidation of the intermediate gives halo alcohols which can be cyclized under basic conditions to the optically active cyclic ethers. 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

The enaminonitriles 55a and c react with 12 in refluxing pyridine to give 59a and b. In contrast, 12 and 55b react in acetic acid to give the oxa-zinopyrazolo[l,5-a]pyrimidines 60. It is assumed that the amino function in 12 adds to the activated double bond in 55 to yield the intermediate adduct 56, which loses chloroform to yield 57. This cyclizes under basic conditions to yield 59a and b. In acetic acid, the 58 that is formed is converted under the reaction conditions to the oxazino[4,5 5,6 ]pyrazolo[I,5-a]pyrimidine derivative 60 (77ZN(B)I478). 

Only a few examples of the formation of 1,2,4-triazines by this fragment combination have been published, all cases being 1,2,4-benzotriazine syntheses. 2-Nitroaniline reacts with cyanamides to give 2-nitrophenylguanidines (601) which cyclize under basic conditions to 3-amino-l,2,4-benzotriazine 1-oxides (602) <78HC(33)189, p.699). With benzoyl isothiocyanate it affords Ar-(2-nitrophenyl)-N -benzoylthiourea (603), which cyclizes to l,2,4-benzotriazine-3-thione 1-oxide (604) (80MI21900).. 

Experimental evidence in support of this was provided by Stork, Cama, and Coulson (8) who studied the cyclization under basic conditions (KHH2> NHj-DME) of epoxynitriles 24 and 26. They observed that the formation of the cyclohexane ring 124- 25) was indeed easier than that of the cyclopentane ring (26- 27). 

Cyclization of 2-(2-pyridylaminomethylene)glutarate 156 in ethanolic sodium ethylate for 15 minutes at room temperature afforded only 4-oxo-4//-pyrido[l,2-fl]pyrimidine-3-propionate 157 [84JCS(P1)1799]. The 6-methyl, 6-hydroxy, and 6-acetamido derivatives of glutarate 157 could not be cyclized under basic conditions. 

Haloalkylamines are problematic reagents which will readily polymerize or cyclize under basic conditions and must always be stored as ammonium salts. Because anilines are not very basic, their direct alkylation with salts of haloalkylamines under neutral or acidic reaction conditions can sometimes be achieved... 

The successful application of sulfanyl amines in the diastereoselective and enantioselective synthesis of as-3,4-disubstituted /3-sultams has been reported (Scheme 56). The protocol is based on the oxidation of the 1,2-aminothiols 178 with hydrogen peroxide and ammonium heptamolybdate. Chlorination of the resulting /3-aminosulfonic acids was achieved using phosgene. The /3-aminosulfonyl chlorides 179 obtained were cyclized under basic conditions and without epimerization to yield the t -3,4-disubstituted /3-sultams 180 (>96% de, ee) (Table 13) <2005S1807>. 

Conversion to benzazepine was achieved under acidic conditions via hydrogenation in alcoholic solvents to form 25, which did not require isolation. Intermediate 25 was directly cyclized under basic conditions to give crystalline lactam 26. The base-mediated ring closure proceeded from the cis/trans mixture of 25 by epimerization of the benzylic methine permitting formation of the cyclic amide from the cis isomer. Finally, conversion of 26 to the desired benzazepine (8) was accomplished by in situ borane reduction and 8 was isolated as the tosylate salt in 81% yield. 

Chloroacetyl enaminones cyclize under basic conditions (see equation 220) to 3-hydroxypyrroles, thus demonstrating the nucleophilic character of the enaminedione nitrogen, which however can be used only for cyclization after its deprotonation297 (equation 225). 

Tetrahydrofurans can be synthesized by intramolecular substitution reactions. y-Bromo or iodo alcohols are common starting materials that readily cyclize under basic conditions. Tetrahydrofuran derivative 3 is obtained after radical coupling of iodide 1 with pent-4-en-l-ol... 

Carbon-carbon bond formation /3 to sulfur is little known for the monocycles, again perhaps because of poor accessibility of precursors, but is very common for the preparation of thiochromanones. Frequently, a dicarboxylic acid or ester is cyclized under basic conditions, and decarboxylation affords the keto compound, from which the unsubstituted system may readily be obtained (76JCS(P1)749). A more modern reaction is shown in equation (81) (73TL4315). Me... 

The imidazo[5,l-A]oxazole ring system has been synthesized. Nitroimidazole 221 was alkylated with an a-bromo acetophenone to give a mixture of ketones 222 and 223 in a 1 3 ratio. Compound 223 was then cyclized under basic conditions to give the corresponding imidazo[5,l-A]oxazoles 224 (Scheme 66) <1999H1081>. 

Standard transformation of the diacetonomannose provided 6-0-tosyl-5-0-protected lactone 19, which was reduced to lactole with diisobutyl hydride. Cyclization under basic conditions afforded 1,6-anhydromannofuranose 20, which can be deprotected easily at the C-5 position. 

Examples of pyridazine synthesis from azines involve reaction between tetrafluoroformaldazine and perfluorosuccinyl fluoride in the presence of cesium fluoride to give a perfluoropyridazine, or via ketazine anions, as for acetophenone azine [Eq. (3)]. The azine from benzyl monohydrazone and ethyl acetoacetate or benzoylacetate is cyclized under basic conditions into the pyridazine 17. ... 

Using iV-silylaldimines as electrophiles, aminoalcohols (41) are obtained as reaction products, which after chlorination followed by cyclization under basic conditions lead to the formation of tetrahydroisoquinolines (42) (Figure 1) (00JHC1061). When ketones derived from D-fructose, and D-glucose, as well as (9-ethoxymethyl-substituted estrone and (-)-menthone are used as electrophiles, diols (36f)-(36i)... 

Ethoxycarbonylhydrazones of a-hydroxy ketones readily cyclize under basic conditions to 3//-l,3,4-oxadiazin-2(6/f)-ones, e.g. formation of 2.35... 

With 51 in hand, hydrogenation under acidic conditions was readily achieved in alcoholic solvents to form 28, which was cyclized under basic conditions to give lactam 29. Finally, conversion of lactam 29 to the desired benzazepine 6 was accomplished by borane reduction (generated in situ) to form benzazepine 6, isolated as the tosylate salt in 81% yield. The reduction could also be accomplished with lithium aluminum hydride. This route was efficient and robust, as it uses... 

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