Piperidine Derivatives. XXIX. Octa- and Decahydroisoquinolines from 1-Methyl-3-carbethoxy-4-piperidone

Abstract

RECEIVED MAY 9, 1956 l-Methyl-3-carbethoxy-4-piperidone adds to methyl vinyl ketone t o yield the corresponding 3-( y-ketobutyl) derivative 11, which is readily deearbethoxylated and cyclized t o 1,2,3,4,6,7,8,9-octahydro-2-1nethyl-6-oxoisoqui1ioline (IV). This quinolone is converted by phenyllithiurn or phenylmagnesium bromide t o the 6-phenyl-6-hydroxyoctahydroisoquinoline V, which is readily rearranged by acid to the isomeric 10-hydroxy derivative VI. Both of these carbinols are dehydrated t o the hexahydroisoquinoline VII.This ketone was converted t o the 2-methyl-6-phenyl-6-acetoxyisoquinoline XI, which was found t o bc devoid of analgesic action.Hydrogenation converts I V t o the cis-decahydroisoquinolone VIII.The Michael addition of 1 -methyl-3-carbethoxy-4-piperidone (I) to methyl vinyl ketone proceeds in good yield (76y0) when carried out by the procedure, described in a previous paper of this series,2 for the addition of I to ethyl acrylate. The initial condensation product I1 could be separated and distilled, or be directly decarbethoxylated and cyclized by the method of Wilds and Close3 to the gctahydroisoquinolone IV. A small yield (3y0) of the ketoester 111, resulting from the cyclization of I1 before decarbethoxylation, geiierally accompanied IV.The octahydroisoquinolone IV was reported recently by Marchant and Pinder," who obtained it by two different procedures: (a) a Birch reduction of 1,2,3,4-tetrahydro-~-methoxy-3-methylisoqu~no-line followed by hydrolysis of the resulting hexahydroisoquinoline, and (b) the interaction of 4-diethylaminobutan-2-one with the keto ester I. Earlier, Georgian5 had reported the condensation of methyl vinyl ketone with I to form 2-methyl-6-oxo -9 -carbomethoxy -10 -hydroxydecahydroisoquinoline and the transformation of this product to IV by vigorous treatment with hydrochloric acid, but no details of this work were given.The reaction of phenyllithium with IV, followed by the decomposition of the resulting lithium salt with water, yielded the 6-phenyl-6-hydroxyoctahydroisoquinoline V in 007, yield. When phenylmagnesium bromide instead of phenyllithium was used with IV, and the magnesium salt decomposed with dilute acid, the isomeric I 0-hydroxy compound VI was the product. I t was obtained in only 55-6070 yield; 23-30% of unchanged I V was recovered. The presence of such an amount of the latter compound with the reaction product was doubtless the result of the enolization of the original unsaturated ketone IV by the Grignard reagent; the formation of thc 10-hydroxy derivative VI was due to the action of acid on the initially formed 6-hydroxy derivative V. This acid-catalyzed transformation of V into VI is quite facile and may be accomplished by simply dissolving V in 5% hydrochloric acid. The spectra of the carbinols V and VI were completely devoid of any carbonyl bands

Synthesis of 1,3,4,5,6,7,8,8a-octahydro-2-methyl-4a-phenylisoquinolin-6-ols. Novel fragments of the morphine molecule

“…The reaction mixture was cooled by adding ice and made basic by addition of NH4OH. Repeated extraction with CHClg yielded an oil which was distilled in vacuo: bp 170-180°( 0.5 mm); m/e 243 (M+); nmr (CDClg) 7-7.6 (m, 5, aromatic), 5.92 (t, 2, J = 3.5 Hz, CH=CH), 2.4 (s, 3, NCHg), 1.97 (s, 3, COCHg); ir =-max (liquid) 1710, 1660, 760, 700 cm'1; glc DC 530, 5% on Chromosorb G (acid washed and silanized) mesh 60/80, retention time 6.8 (69.5%), 7.6 min (30.5%) at 230°. Spectral data suggested that the major product was the 3•4 isomer and the minor product was the 4 •* isomer.…”

“…Ether (50 ml) was added to the solution, which was then left in a freezer for 36 hr. During this time, 0.065 g (20%) of orange picrate crystals precipitated: mp 118-119°; nmr (acetone-de) 8.6 (s, 2 H), 5.79 (m, 2 H), 5.28 (m, 2 ), 5.07 and 4.37 (m, 4 ) (N-H not observed).…”

Heteroatom directed photoarylation. Synthetic potential of the heteroatom oxygen

“…mp 186-188 °C). Column chromatography (silica gel) gave 26 (122 mg, 67%, oil): >H NMR 1.04 (3 H, triplet, 7 = 7 Hz), 1.2-3.3(12…”