Chloro analogs

Activated compounds such as 5-nitropyrimidin-2-one and 1-methyl-5-nitro-2-pyridone form the 2-chloro analogs with thionyl chloride 223b. 312b displacement of the —O—SO—Cl group. In reactions... 

Chloropyrimidine is aminated with alcoholic ammonia at 130° while 4-chloro-2-methyl- and 4-chloro-6-methyl-pyrimidine yield the corresponding 4-amino derivatives at 100°. 4-Aminopyrimi-dine is not prepared from the chloro analog because of facile self-quatemization (see Section III, B, 2 for comments on factors involved) of the latter. 

Substituents in the 6-position (cf. 267) show appreciable reactivity. 6-Bromo-as-triazine-3,5(2j, 4j )-dione (316) undergoes 6-substitution with secondary amines or hydrazine, with mercaptide anions or thiourea (78°, 16 hr), with molten ammonium acetate (170°, 24 hr, 53% yield), and with chloride ion during phosphorous oxychloride treatment to form 3,5,6-trichloro-as-triazine. The latter was characterized as the chloro analog of 316 by treatment with methanol (20°, heat evolution) and hydrolysis (neutral or acid) to the dioxo compound. The mercapto substituent in 6-mercapto-as-triazine-3,5(2iI,4if)-dione is displaced by secondary... 

The limited data available for 2,4-dichloroquinoline (Table X, line 9) show a substantially greater rate of methoxylation than for the 2- and 4-chloro analogs (Table X, line 6 and Table XI, line 2), as a result of activation (lowering of E ) by the additional chlorine substituent. Unequal mutual activation (cf. Section III, B, 2) by these substituents is indicated by the rate ratio of 1.9 1 for 4- to 2-substi-tution in the dichloro compound and of 25 1 for the two mono-chloro compounds. 

Diamino-6,6-dialkyl-7-oxo derivatives were converted with POCI3 (106°, 46 min) to 7-chloro analogs which were then 7-thionated with hydrosulfide ion. °... 

Alkylation of the p-chloro analog (102) of the monosubsti-tuted piperazine with m-methylbenzyl chloride (103) yields the... 

The p-chloro analog of phentermine has much the same activity as the parent compound, with perhaps a somewhat decreased activity on the central nervous system. Alkylation of p-chloro-benzyl chloride with the carbanion obtained from treatment of 2-nitropropane with strong base affords the compound containing the required carbon skeleton (74). Catalytic reduction of the nitro group yields chlorphentermine (75). ... 

Intermediate arylamidine, 6S, is prepared by the aluminum chloride-catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (67), Amidine, 65, is then converted to its N-chloro analog (69) by means of sodium hypochlorite. On base treatment, this apparently undergoes a nitrene insertion reaction to produce thiabendazole (70), ... 

The parent drug of this series, promazine (24), was prepared originally as an antihistamine. Following the identification of the more potent chloro analog as an antipsychotic, it too came into use for that indication. The drug is prepared by straightforward alkylation of phenothiazine with w-C3-chloropropyl)di-methylamine by means of sodium hydride in xylene. ... 

Interestingly, when the chloro analog was transmetallated and treated with 3-ethoxy cyclohexen-l-one, the expected enone (XI) was not observed, but an enone with a mass of 34 units greater than (XI) was noticed. It also indicated the enone carried the chloro analog. It was presumed that the hetero atoms in the heterocycle present in the starting material (VIII) had performed a directed metallated lithiation providing a different enone bearing the chloro moiety. 

In a similar way, Kim and Bunnett (1970) demonstrated that the substitution of amino group for iodine in iodotrimethylbenzene proceeds via the ion-radical mechanism, in contrast to the bromo and chloro analogs. The reaction of 5- and 6-halo-l,2,4-trimethylbenzenes with potassium amide in liquid ammonia gives rise to 5- and 6-aminoderivatives. This is the cine-substitution reaction (see Scheme 4.12). 

The product is a mixture of stereoisomers. The chloro analog, antimetabolite acivicin, was prepared in a similar manner from vinylglycine and dichlor-oformaldoxime (80JOC4817 82TL4563). /3-Isoxazolylalanines were prepared by 1,3-dipolar cycloadditions of nitrile oxides to substituted acetamidomalonates (Scheme 23) (92JMC107). 

Treatment of L-Ser-OMe with 3-bromocyclopentene after the hydroxy group was replaced with iodide gave in the presence of 2,2 -azobisisobutyro-nitrile (AIBN) and tri-w-butyltin hydride a mixture of stereoisomers. These stereoisomers were separated and transformed into (lS,35,5S)-54 and (lR,35,5R)-isomer 55, which are precursors of the potent angiotensinconverting enzyme inhibitors [89H(28)957], Isomer 54 was also obtained from N-acetylserine methyl ester which was converted into its chloro analog and reacted with cyclopentenepyrrolidine (84TL4479). 

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