Pyrrolidino

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Pteridine, 2,4-diamino-7-pyrrolidino-hydrolysis, 3, 294 synthesis, 3, 290 Pteridine, 2,4-diamino-7-styryl-synthesis, 3, 319 Pteridine, 2,4-dichloro-properties, 3, 267 Pteridine, 4,6-dichloro-reaction... 

Pyrrolidino[l,2-6][l,3,4]oxadiazoline, 5-phenyl-biological activity, 6, 1024 Pyrrolidino[2,1 -6][1,3]oxazolidines synthesis, 5, 137 Pyrrolidino[l,2-6]pyrazolines synthesis, 5, 148... 

To a 3QQ-mL, round-bottomed flask fitted with a water separator, (Note 1) which contains 15 g of Linde 4A molecular sieve l/16-1nch pellets and Is filled with toluene, are added 7.3 g (0.04 mol) of cyclododecanone, 11.4 g (0.16 mol) of pyrrolidine, 100 mL of toluene, and 0.57 g (0.004 mol) of boron trifluoride etherate. The solution is heated under reflux for 20 hr. The water separator is replaced by a distillation head, and about 90 mL of the toluene is removed by distillation at atmospheric pressure. The residue containing l-(N-pyrrolidino)-l-cyclododecene (1) is used in the next step without further purification (Note 2). 

Pure l-(N-pyrrolidino)-l-cyclododecene, bp 144 C (1.5 inn), may be isolated by distillation through a Vlgreux column. 

The action of methylmagnesium iodide on 3-pyrrolidino-A -4-ketones (19) gives the 4a-methyl-4l -hydroxy steroids (20). ... 

Reactions of polyhydroxyl compounds such as carbohydrates with DAST lead to replacement of one or two hydroxyl groups by fluorine, more fluorine atoms are not introduced even when a large excess of the reagent is used [132, 139, 147] Although diethylaminosulfur tnfluonde (DAST) is the most popular, other dialkylaminosulfuranes, such as diisopropylamino- [95] pyrrolidino [95 109 /27], dimethylamino- [148], piperidino- [148] and particularly morpholinosulfur trifluonde [148,149, ISO], are also used as fluonnating agents to convert alcohols into fluorides... 

Notwithstanding the expected and also observed high reactivity of the intermediate immonium ions, the stabilization of the exocyclic double bond in the pyrrolidino derivative evidently prevents rapid nucleophilic attack of water and the hydration of this ion to the amino alcohol becomes a slow general base-catalyzed process in weakly acidic solutions [Eq. (6)]. 

Similarly alkylation (55) of l-N-pyrrolidino-2-methyl-l-propene (22) with propargyl bromide gave initial N alkylation to (23) with subsequent rearrangement to the allene (24). 

The course of alkylation is also influenced by the steric arrangement of the enamine. 1-Pyrrolidino-l-cycloheptene gave approximately equal quantities of the C- and N-alkylated products in dioxane, while 1-pyrroli-dino-l-cyclooctene, and 1-pyrrolidino-l-cyclononene afforded N-alkylated products exclusively under similar eonditions (29). The reason for N alkylation in the eight- and nine-membered ring compounds is to be found in the conformation of these rings, which prevents full interaction of the unshared electrons on nitrogen with the n eleetrons of the double bond. 

One of the advantages of the enamine alkylation reaction over direct alkylation of the ketone under the influenee of strong base is that the major product is the monoalkylated derivative 29,32). When dialkylation is observed, it occurs at the least substituted carbon in contrast to alkylation with base, where the a-disubstituted product is formed. Dialkylation becomes the predominant reaction when a strong organic base is added and an excess of alkyl halide is used (29). Thus 1-N-pyrrolidino-l-cyclo-hexene (28) on treatment with two moles of allyl bromide in the presence of ethyl dicyclohexylamine (a strong organic base which is not alkylated under the reaction conditions) gave a 95 % yield of 2,6-diallylcyclohexanone (29). 

The 2,2 -dialkylation of enamines has been used for the synthesis of novel bi- and trieyeloketones (id). Alkylation of 1-N-pyrrolidino-l-cyclohexene (28) with 1,4-diiodobutane gave a 15% yield of bicyelo[1.3.4]-10-decanone (35), while alkylation with o-xylylenedibromide gave a 31 % yield of 2,6-o-xylyleneeyelohexanone (36). 

Alkylation of enamino ketones occurs on oxygen, as would be expected from the site of protonation. Thus 4-N-pyrrolidino-3-penten-2-one (47) gave N-(2-ethoxy-2-penten-4-ylidene)-pyrrolidinium iodide (48) on alkylation with ethyl iodide (22), and the enamino ketones derived from 5,5-... 

A particularly interesting case is the reaction of the enamino ketone (47), which under similar conditions gives the intermediate product (80), which then undergoes cyclization to the benzene derivative dimethyl 3-pyrrolidino-5-methyl phthalate (81). 

Enamines have been observed to act both as dienophiles (46-48) and dienes (47,49) (dienamines in this case) in one-step, Diels-Alder type of 1,4 cycloadditions with acrylate esters and their vinylogs. This is illustrated by the reaction between l-(N-pyrrolidino)cyclohexene (34) and methyl t/-a i-2,4-pentadienoate (35), where the enamine acts as the dienophile to give the adduct 36 (47). In a competitive type of reaction, however, the... 

The reaction of an alicyclic enamine with benzyne intermediate yields simple arylation products and/or 1,2-cycloaddition products, depending upon the reaction conditions 102). This is illustrated by the reaction of l-(N-pyrrolidino)cyclohexene with benzyne (86) (obtained from fluoro-benzene and butyl lithium or o-bromofluorobenzene and lithium amalgam), which produces benzocyclobutene 87 102). 

Bifunctional molecules undergo intermolecular cyclizations with enamines through simple alkylations 112-114) and acylations 115). For example, the reaction between l-(N-pyrrolidino)cyclopentene and 1,4-diiodobutane produces, after hydrolysis, ketospirans 92 and 93 113). 

The cycloaddition of nitrones to enamines results in the formation of an isoxazolidine (179,180). The reaction of l-(N-pyrrolidino)- -phenyl-ethylene (133) with nitrone 134 producing isoxazolidine 135 illustrates this type of cycloaddition (180). 

Similarly, a-trichloromethylamines (522) were obtained by decomposition of trichloroacetic acid in morpholine enamines, but an amide ester was formed from sodium trichloroacetate and the imonium salt of pyrrolidino-cyclohexene (523). The product is presumably derived from opening of an intermediate dichloroaziridinium salt. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

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