Alkynylamines cyclization

Cyclic imines. Alkynylamines cyclize under the influence of (MeCN)4CuPF(,. Diaryl ethers. The phenol-aryl halide coupling is promoted by CS2CO3 and (MeCN)4CuPF(,. 

Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

For 4-alkynylamines, IH in the presence of PdCl2(MeCN)2 proceeds by two competitive processes a major 5-Exo-Dig cyclization and a minor 6-Endo-Dig one (Eq. 4.70) [278]. 

Mannich cyclization. Reaction of the alkynylamine 1 with formaldehyde, sodium iodide (3 equiv.), and camphorsulfonic acid (CSA, 1 equiv.) results directly in the piperidine 2 in 81-90% yield. In the absence of Nal, no cyclization is observed even after a reaction at 100° for 3 hours. The vinylic iodide group is useful for elaboration to exocyclic tetrasubstituted double bonds. 

The usefulness of nucleophile-promoted Iminium Ion-alkyne cyclizations derives from the ready availability of alkynylamines and the subsequent transformations of the cyclization products made possible because of their vinylic functionality (e.g., equations 1 and 2). Equation 2 illustrates use of this chemistry to elaborate an exocyclic tetrasubstituted double bond with complete stereooontrol. Net "reductive iminium ion alkyne cyclizations can be accomplished by dehalogenation of vinyl halide cyclization products. The conversion illustrated in equation 3 is a key step in an efficient, practical synthesis of the cardiotonic frog alkaloid pumiliotoxin A. ... 

Scheme 82. Heterocyclization of Alkynylamines, Amides, Alcohols, and Carboxylic Acids via (a) Cyclization-Protonolysis, (b) Cyclocarbonylation, (c) Cyclization-Esterification, and (d) Cyclization—Reductive Elimination3...

The formaldiminium ion formed from the reaction of 4-hexynylamine (90 R = R = Me) with paraformaldehyde and camphorsulfonic acid is reported not to cyclize when heated for 1 h at 1(X) C in the weakly nucleophilic solvent acetonitrile. However, when nucleophilic salts are added the 3-alkylidene-piperidines (91) are formed in good yields (Scheme 32). Attempted cyclizations of (90) in the presence of weaker nucleophiles such as benzenethiol or methanol were less effective, the former yielding <15% of the expected alkylidenepiperidine product, while the latter provided no products of cyclization. If the strong nucleophile iodide is employed, even a weakly nucleophilic terminal alkyne can be successfully cyclized. In all of these cyclizations of 4-alkynylamines only formation of a six-membered ring product was observed. The (2)-stereochemistry of the alkylidene side chain evolves from antarafacial addition of the internal iminium cation and the external nucleophile to the alkyne. 

A study of 3-alkynylamines (92) addressed the question of endocyclic versus exocyclic ring closure in nucleophile-assisted alkyne cyclizations (equation 9). Cyclizations of the formaldiminium ion derived from (92) occurred only in the endocyclic sense affording tetrahydropyridines (93). Terminal as well as substituted alkynes were observed to react with endocyclic regioselectivity in the presence of a variety of nucleophiles. 

Cyclization. On treatment with La[N(SiMe3)2]3, a 4-alkynol forms the alkoxide which cyclizes to give 2-methylenetetrahydrofuran the isomer with endocyclic double bond is also formed from 3,4-pentadienol. A modified trisfhexamethyldisilazide) of lanthanum (and of several other rare earth metals) (1) catalyzes intramolecular hydroamina-tion of alkynylamines and the products also undergo hydrosilylation. ... 

Cyclization. 4-Alkynylamines undergo cyclization to pyrrolines under the influence of Me2TiCl2. In some cases, chain extension at the alkyne terminal can be effected. 

PyrroUnes andpyrrolizines. Cyclization of 4-alkynylamines is readily promoted by... 

Aliphatic alkynylamines also undergo cyclization even without a protecting amino group (Scheme 23). Thus, 3-alkynylamines give l-pyrrolines in good yield via 5-endo-dig cyclization, whereas 5-alkynylamines undergo a 5-exo-dig cyclization to afford 2,3,4,5-tetrahydropyridines. In the case of 4-alkenylamines, both five- and six-membered cyclic imines are produced. 

In terms of synthetic planning, it must be noted that a transition-metal catalyst is not required for this cyclization. o-Alkynylamines can be cyclized to indoles under basic conditions, especially if the nitrogen atom has an electron-withdrawing substituent to lower the pKa. Just such a base-catalysed cyclization was employed in a synthesis of goniomitine (Scheme 6.20), after a Sonogashira reaction was employed to synthesize the substrate. Similarly, benzofurans are easily prepared by base catalysed cyclization as in a synthesis of Ailanthoidol (Scheme 2.115). The transition-metal catalysed cyclization is of particular importance when... 

Intramolecular Reactions of Alkynes with Carboxylic Acids, Alcohols, and Amines. Addition of carboxylic acids, alcohols, and amines to alkynes via oxypaUadation and aminopallada-tion proceeds with catalysis by Pd salts. Intramolecular additions are particularly facile. Unsaturated y-lactones are obtained by the treatment of 3-alkynoic acid and 4-alkynoic acid with Pd(PhCN)2Cl2 in THF in the presence of Et3N (eq 54), and -lactones are obtained from5-alkynoic acids. 5-Hydroxyalkynes are converted to the cyclic enol ethers (eq 55). The oxypalla-dation is a irons addition. Thus stereoselective enol ether formation by reaction of the alkynoic alcohol with Pd(PhCN)2Cl2, followed by reduction with ammonium formate, has been applied to the synthesis of prostacyclin (eq 56). Intramolecular addition of amines affords cyclic imines. 3-Alkynylamines are cyclized to 1-pyrrolines while 5-alkynylamines are converted to 2,3,4,5-tetrahydropyridines (eq 57). ... 

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