Cyclization of amines

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

Hg2+ interacts with the allene moiety to mediate the cyclization of amine 300 [146]. Finally the C-Hg bond in 301 can be cleaved by reduction with NaBH4. 

A few synthetic applications of palladium catalysis appeared this year. The palladium-catalyzed cyclization of amino allenes 58 occurs with coupling of aryl iodides or vinyl triflates at the 3-position <990L717, 99SL324>. The cyclization can also proceed by the exo-trig pathway, but under suitable reaction conditions the piperidine 59 is prepared selectively. The intramolecular cyclization of amines onto N-allylbenzotriazoles similarly affords piperidines <99JOC6066>. 

Table 32 Cyclization of Amines and N-Alkoxyamines to 2,6-Disubstituted Piperidine Derivatives (Equation 114)...

For larger cycles, tosylamide or high-dilution amide condensations were mostly used. In addition, cyclization of amines and aldehydes to get Schiff bases (mostly for [2+2] or [3+3] cyclizations) is convenient. Metal template synthesis is useful only in special cases. Polycycles are conveniently prepared from appropriately protected cycles. 

Fig. 49. Mannich cyclization of aminic substrates with fomialdchyde (1=1 molar ratio).

A 1,2-anti preference was also observed in the cyclization of amine 3, in this case irrespective of double-bond geometry34. 

Joule then expanded this chemistry to include intramolecular cyclizations of amines [40]. In the presence of sodium hydride, the amide 79 underwent addition to C-3. Expulsion of phenylsulfinate and tautomerization yielded the ketone 80 in 80% yield. Deprotection with sodium hydroxide yielded the free amine 81 in 85% yield. Reactions of this style provided access to the alkaloids, hydroxycryptolepine, cryptolepine, and quindoUne (83). 

Allylation of amines. Trost and Genet have synthesized several ring systems characteristic of alkaloids by intramolecular allylation (cyclization) of amines catalyzed by Pd(0). 

Another intramolecular cyclization of amine 58 is the last step in the pyrrolo[3,2-fiflpyrimidine analogue 59 synthesis. Intermediate 58 formed in situ from nitro precursor 57 by reduction with tin(II) chloride is a key step of this version of Leimgruber-Batcho synthesis leading to formation of 59 finally. This simple three-step route to 59 started from the coupling of electron-poor dichloronitropyrimidine 54 with p-fluoroenamine 55 to form alkene 56. Regioselective nucleophilic... 

Scheme 7.7 Proposed mechanism for ruthenium-catalyzed cyclization of amines with alkynes.

Scheme 4-126. Tetrahydroindoles by oxidative cyclization of amine tethered (Ti -diene)iron complexes.

---