Piperazine, reaction + chloroformates

This compound can be prepared by the reaction of cinnamoyl chloride with benzhydryl-piperazine. The reaction is carried out in dry benzene under reflux. The benzene is then evaporated, the residue taken up in chloroform, washed with dilute HCI and then made alkaline. 

To a solution of 17.2g (0.10 mol) of 3-bromopropionyl chloride in 100 ml of anhydrous benzene was added dropwise with stirring a solution of 8.6 g (0.10 mol) of anhydrous piperazine in 20 ml of dry chloroform over a period of 30 minutes. The temperature rose spontaneously to 45°C during the addition. After the temperature ceased to rise, stirring was continued for another hour. The reaction mixture was then filtered to remove the piperazine hydrochloride by-product. The filtrate was evaporated to dryness and the residue recrystallized from ethanol to obtain the desired N,N -bis-(3-bromopropionyl) piperazine as a white crystalline sol id melting at 103°C to 104°C. The identity of the product was further established by elemental analysis. 

Nitroindole-2-carboxylic acid (0.86 g), l-[3-(N-isopropyl)amino-2-pyridinyl]piperazine (0.43 g), l-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g) and THF (4 ml), were stirred at 20-25°C for 3 hr then the reaction mixture was dissolved in chloroform (50 ml) and extracted with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (200 g silica) eluting with ethyl acetate/hexane (50/50), the appropriate fractions were pooled and concentrated to give l-[5-nitroindolyl-2-carbonyl]-4-[3-(l-methylethylamino)-2-pyridinyl]piperazine, mp 153°-154°C. 

The p-DVB-piperazine adducts can also undergo self condensation whereby the macromonomers formed exhibit rather low molecular weights, and are insoluble in the reaction mixture (benzene or THF). They dissolve only upon the addition of an acid or in hot chloroform. Free-radical copolymerization of this macromonomer with styrene was carried out in benzene in the presence of some acetic acid (to obtain a homogeneous reaction mixture) to yields of about 20% M). Here again separation of the unreacted macromonomer is possible, and the polyamine content of the graft copolymer is very close to the amount contained in the reaction mixture. 

In the case of primary aliphatic amines, the reaction products are dramatically affected by the solvent employed. For instance, in the presence of solvents apt to produce a specific solvation of amines (chloroform, and an amine chlorohydrate solution in methylene dichloride), the reaction with hexachloride precursors terminates to yield the trisubstituted product DD D" formed via route A. At the same time, the use of some other solvents (such as benzene, 1,4-dioxane, THF, methylene dichloride, DMF, and alcohols, or the corresponding amine media) led to the formation of the sole tetrasubstituted product (DD"D"). In addition, in the case of sterically unhindered primary amines an alternative isomer (D D D") is not isolated, which indicates reaction route A and a specific control of the tie reaction in the transition state by solvation interactions and intramolecular hydrogen bonds. In the case of the dichloride FeBd2(C12Gm)(BF)2 precursor, with both primary (cyclohexylamine) and secondary (diethylamine and piperazine) aliphatic amines, only a monosubstituted product of the Bd2D type is formed in chloroform, whereas in some other solvents, a diamine clathrochelate of the Bd2D" type is obtained with both sterically hindered and unhindered primary aliphatic amines. 

Kinetic measurements of the reaction between chloroformates and amines are difficult because of the great speed of the reactions. Rate coefficients have been estimated [118] to be about 10 to 10 Imole sec . Reaction times have been of the order of five minutes at 0—5°C in benzene-water systems [173], and 10—30 minutes at 60°C in order to get high molecular weights when using piperazine [174]. 

Catalytic synthesis of l-ethyl>6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid ethyl ester (Norfloxacin ethyl ester) (15a). To a dry 15 mL recovery flask equipped with a reflux condenser was added 13 (150 mg, 0.5 mmole), (R)-binap (10 mg, 0.017 mmole), cesium carbonate (360 mg, 0.950 mmole), piperazine (215 mg, 2.5 mmole), Pd2(dba)3 (10 mg, 0.010 mmole), and 1.5 mL of DMF. The reaction vessel was purged with nitrogen and heated to reflux. After three hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by thin-layer chromatography on a 500 micron silica gel preparative plate with an elution mixture of chloroform methanol water ammonia (80 20 2 0.2) to give 101 mg of 15a as an off-white solid in 58% yield and, separately, 29 mg of 17 as a light brown solid in 22% yield. Using this procedure, the yield of 15a... 

Based on an aminoalkylurethane linker attached to the Wang resin 155, Zaragoza et al. developed a solid-phase synthesis of 1,2,3-triazoles. Thus, as shown in Scheme 4.1.30, Wang resin 84 was primarily treated with 4-nitrophenyl chloroformate 153 in the presence of pyridine to give 154 and then reacted with piperazine in DMF to produce 155. Subsequent reaction with a freshly prepared solution of 3-oxobutyric acid phenyl ester afforded resin-bound 3-oxobutyryl piperazine 156. In the presence of triethylorthoformate, the condensation of 156 with primary aliphatic amines readily produced the corresponding 3-amino-2-butenoic acid amides attached to the solid support (157). 

Two papers described novel general conversions of diamines into piperazines. Taylor et al ° reacted phenylene diamines with a-epoxy nitriles or sulphones to synthesize tetrahydro-quinoxalines in yields of between 30 and 90%, and Lai reported an interesting preparation of the l,3,3,5,5-pentasubstituted-2-piperazinones (340) and (341) from ethylene diamines (339) via a phase-transfer-catalysed reaction with ketones and chloroform this latter was... 

---