Amides cyclization

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

Several syntheses of thienobenzazepines have been reported in the literature however, they generally require the use of reagents and/or reaction conditions which present challenges on a preparative scale. In this manuscript we describe a new and efficient synthesis of the thieno[2,3-c]benzazepine tricycle that involves a key selective reduction-intramolecular amidation cyclization process and enables large-scale preparation of these important compounds. 

Catalytic amidation/cyclization step in a pesticide intermediate... 

This application was performed on a lab-scale reactor and later in a miniplant-scale reactor. The reaction studied was the vapor phase catalytic amidation/cyclization step in a pesticide process. As shown in Figure 2, two reactions are taking place on the catalyst bed. 

Figure 2 Vapor phase catalytic amidation/cyclization reaction in a pesticide process monitored by on-line HPLC.

Figure 3 Sampling system for catalytic amidation/cyclization reaction in pesticide intermediate.

Figure 4 Dynamic dilution of sample for HPLC analysis of amidation/cyclization reaction. Transfer solvent methoxyethanol flow rate 1 ml/min. Detection refractive index.

Figure 5 Separation of reactor product of amidation/cyclization reaction. Columns ...

Allylamines may be converted directly to oxazolidinones through condensation with CO2, to form carbamate salts, and treatment with iodine (equation 64 and Table 20).166 High stereoselectivity was obtained only in cases where the a-substituent was hydroxymethyl (entry 5) or the amine was secondary and the substituent was phenoxymethyl (entry 4). The results with primaiy amines are comparable to those for amide cyclizations shown in equation (57). 

DFIT-induced fluoro-Pummerer reactions of N-substituted-2-(phenylsul-fanyl)acetamides have also been reported (Scheme 37) [107]. With some amides, cyclization of the Pummerer intermediate was competitive with fluorination, and in other cases, fluorination was preempted by sulfoxide formation. 

The chiral amine 51 has been used to develop the synthesis of imidazolium 52 which was attached to palladium(II) (Scheme 36). Preliminarily studies in the asymmetric amide cyclization (Scheme 7) showed a good catalytic activity (70% yield) albeit with with low ee (9%) for that particular reaction [95]. 

Scheme VI/24. Synthesis of cyclic depsipeptides via direct amide cyclization [92]. a) HCI, toluene, 100°.

The shortcomings of the method in Chart IV have been overcome by an acid-catalyzed ester-amide cyclization step as outlined in Chart V. For example, reaction of ethyl hydrazinoacetate hydrochloride with potassium cyanate proceeded smoothly in aqueous solution to give ethyl 3-aminohydantoate which was converted into the respective 3-(benzylideneamino)hydantoate, by reaction with a substituted ben-... 

When hydantoins are treated with acetic anhydride, sodium hypochlorite, or nitiric acid, substitution takes place at the N-l position, followed by the formation of a 1,3-disubstituted hydantoin.1 Intramolecular processes yield only the amide cyclized products (102).255,256... 

A recent synthesis of armepavine is of special interest because of the means by which the phenolic hydroxyl was introduced. p-Nitrophenyl-acetyl chloride was condensed with 3,4-dimethoxyphenethylamine and the resulting amide cyclized in the usual way by treatment with phosphorus oxychloride in chloroform. The methiodide of the generated dihydroiso-quinoline on reduction yielded the amino compound LXXXVII, which was diazotized and boiled with dilute sulfuric acid. The DL-armepavine thus obtained (m.p. 166°) yielded an 0-methyl ether (m.p. 92°), which on Hofmann degradation gave rise to a methine (m.p. 87°) and a vinylstilbene (m.p. 79°). Their properties were the same as those of the compounds obtained from the natural base (111a). 

However, Battersby and Openshaw (52) supplied proof of the nuclear structure of these alkaloids in a total synthesis of dl-rubreme-tihium bromide, although the synthesis did not fix the double bonds in unambiguous positions. The half ester chloride of malonic acid was condensed with 3,4-dimethoxyphenethylamine, the amide cyclized with phosphorus pentoxide, and the derived dihydroisoquinoline reduced to XLVII. The latter was condensed with ethyl a-aldehydobutyrate and the mixture reduced to XLVIII, which by Dieckmann condensation... 

Finally, several palladium-catalyzed processes appear to occur by insertion of alkenes into palladium amides. Cyclizations of aminoalkenes in the presence of aryl halides to form P5nrolidines appear to occur by intramolecular insertion of alkenes into palladium amides. One example of the cyclizations of aminoalkenes in the presence of aryl halides is shown in Equation 9.89a. The relative stereochemistry of the aryl group and the nitrogen in the ring structure of the product indicates that syn addition of palladium and nitrogen occurred across the alkene. 

The in situ formation of a ketimine provided the cyclization precursor, which furnished on imine arylation the densely functionalized dibenzodiazepine derivative (Scheme 13.96). When the keto functionality was replaced by an ester moiety, which is reactive toward ammonia under the reaction conditions, an amide cyclization precursor is generated in situ (Scheme 13.97). The arylation of the spawned amide by the aryl chloride fragment furnished the dibenzoxazepinone derivatives in good to excellent yields. 

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