Pyrrolidines, from tetrahydrofuran

The extension of the cyclization from tetrahydrofurans and pyrrolidines to car-bocycles leads to a sharp decrease in the yield of cyclized product. This is due to the slower cyclization rate of 5-hexenyl radicals compared to 5-(3-oxahexenyl) radicals, which favors the competing bimolecular coupling to the acyclic product. Three measures help to increase the yield in these cyclizations. 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

Catalytic hydrogenation converts pyrrole and furan into the corresponding saturated heterocycles, pyrrolidine and tetrahydrofuran. Since thiophene poisons most catalysts, tetrahydrothiophene is synthesized instead from open-chain compounds. 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

Loss of formaldehyde is not only among the low critical energy processes of oxi-rane and oxetane molecular ions, but also of larger cyclic ethers such as tetrahy-drofurane and tetrahydropyran. [219] Again, imine loss from/V-heterocycles [220] behaves analogously. The mass spectra of tetrahydrofuran, pyrrolidine, tetrahydropyran, and piperidine are compared below (Fig. 6.52). The strong [M-H] peaks in all of those four spectra are due to a-cleavage. 

A dry 250-ml., one-necked, round-bottomed flask is equipped with a magnetic stirrer and a three-way stopcock. The flask is charged with 4 g. (0.053 mole) of ethyl nitrite (Note 1), 4 g. of dry tetrahydrofuran (Note 2), and 2.35 g. (0.033 mole) of pyrrolidine (Note 3) The stopcock is closed (Note 4), and the mixture is stirred at room temperature for 2 days Excess ethyl nitrite, tetrahydrofuran, and the ethanol formed are removed from the N-nitrosopyrrolidine (Note 5) by stirring at 25° under reduced pressure (10 mm., water aspirator, Note 6) for 2 hours. The stopcock is fitted with a rubber septum, the air in the system is replaced by dry argon (Notes 4 and 7), and 50 ml. of tetrahydrofuran is injected by syringe. A solution of lithium diisopropylamide is prepared in a separate dry 100-ml. flask by adding 21.1 ml (0 034 mole) of a 1.61 M solution of butyllithium in hexane (Note 8) to a solution of 4.76 ml. (0.034 mole) of diisopropylamine (Note 9) in 25 ml of tetrahydrofuran at -78° (dry ice-methanol bath) with... 

The saturated heterocyclic rings are shown in black, and names for the most important ring types are given some (like piperidine, morpholine)you will need to remember others (tetrahydrofuran, pyrrolidine) are more obviously derived from the names for aromatic heterocycles that we wi II. discuss in the next chapter. Someef -these compounds (nicotine, coniine, cocaine) are plant products fall the class called alkaloids. Alkaloids are discussed in Chapter 51. Another important class of saturated heterocycles, sugars, will reappear rt Chapter 49. 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

---