Synthesis of the 1,8‐diazaspiro[4.5] decane system

Abstract

111Several years ago we described the preparation of 1veratrylcarbonyl-l-azaspiro[4.5]decane (2) by the acidcatalyzed s piroa mi d a t i o n of N-[ 3-( 1-c y cl o h ex en-1-yl)propyl ] -2-(3,4-dimethoxyphenyl)acetamide (1) (2). We have utilized this process for the synthesis of the hitherto unreported 1,8-diazaspiro[4.5]decane system, which is the subject of this Note. Treatment of 4(2-~arbamoylethyl)pyridine (3) (3) withbenzyl chloride gave quaternary salt 4 which was reduced with sodium borohydride to tetrahydropyridine 5 (4). Reduction of 5 with lithium aluminum hydride afforded amine 7 which was converted to amides 8a, 8b and 8c.Unlike neutral amide 1, which was cyclized readily to 2 by polyphosphoric acid a t 25", basic amides 8a, 8b and 8c were stable in this medium to 150"; at higher temperatures 8a, 8b and 8c were converted slowly to complex mixtures according to thin-layer chromatography. Like 1, neutral amides 9a and 9b, prepared by treatment of 8a and 8b with ethyl and methyl chloroformate (5), respectively, were cyclized smoothly to spiro[4.5]decanes 10a and lob.The spectral properties (see Experimental) of spiro-[4.5]decanes 10a and 10b were consistent with the structures assigned to these compounds by analogy with the transformation of I to 2.Cyclization of amide 5 with polyphosphoric acid at 145" afforded l-oxa-8-azaspiro[4.5] decane (6) (6), the infrared spectrum of which exhibited an intense absorption band at 1770 cm-' , characteristic of a y-lactone (7). C"2 I 3 CI-5

Synthetic morphinans and hasubanans. VI. Total synthesis of 3-hydroxyisomorphinans, 3-hydroxyhasubanans, and 3,9-dihydroxyhasubanans

“…This cyclization at the time of execution appeared to be a novel synthetic approach t o a wide variety of heterocyclic compounds, particularly pyrrolidines and piperidines. Subsequently, we found two recorded examples in the literature describing the synthesis of spirolactams VI (Scheme 2) (13) and VIII (14,15), from the respective cyclohexenyl derivatives V and VII.…”