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Synthesis of 1,2-Dialkyl-perhydro-quinolin-6-ones: A One Pot Birch Reduction as Key Step

Peter Stanetty, Olaf Kasemann, Martin Schmid, and Marko D. Mihovilovic*

Institute of Organic Chemistry Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria (EU)


The Birch reduction is a well established method for the conversion of aromatic cores to the corresponding dihydro compounds. Due to the low stability of the resulting enamine moiety this reaction causes problems when applied to some nitrogen containing heterocycles. However, in many cases these enamines serve as intermediates for a complete reduction of the aromatic core en route to the corresponding perhydro system. Procedures reported in the recent literature suffer from several disadvantages ranging from low yields (1), only partial reduction of the heterocyclic system (2), complex product mixtures (3), high pressure techniques (4), to rather complex and time consuming multi step approaches (5). In the present publication we would like to present our first results in applying the one-pot Birch reaction developed for the synthesis of 4-dimethylaminocyclohexanone (6) to the quinoline system en route to the title compounds.


1-Substituted Quinoline-Precursors

Precursors 2a/b were accessible in high yield by Raney-Ni reduction of quinoline 1 followed by reductive methylation and exhibited a comparable behavior during the reduction process to the model compound 4-dimethylaminocyclohexanone. For both N-substituted and unsubstituted compounds 2a and 2b the Birch protocol including a subsequent NaCNBH3 reduction step in a one-pot procedure gave an excellent to quantitative yield of reduced ketals 5a and 5b, respectively, representing a significant improvement to all methods known to us. Conversion to ketones 6a/b was carried out according to standard procedures. Absolute selectivity of the stereochemistry at the annelation site in favor of the trans product was observed and no traces of any cis-isomer were detected.

Initial reduction of the precursors 2a/b with lithium gives the intermediates 3a/b, which are converted to the enolethers 4a/b by treatment with NaCNBH3 at pH 4. All intermediates were detected by NMR-spectroscopy.



1,2-Disubstituted Quinoline-Precursors

For the synthesis of appropriate 1,2-disubstituted precursors we extended a procedure for the Ziegler-type addition of organolithium compounds to quinolines reported recently (7). The intermediate 7 of the initial attack in two position was trapped by quenching with MeI to give substitution at the nitrogen in a one pot reaction. Crude 8 was further reduced to give tetrahydro-compound 9 as substrate for the Birch/NaCNBH4 process.


In contrast to the unsubstituted aromatic heterocycle the formation of considerable amounts of the cis-fused system 12a was observed. We attribute this effect to a steric interaction of the sidechain with the hydrid reagent. Obviously the main attack vector of the reducing agent is blocked to some extent by the carbon chain. Therefore the energy difference between the two possible sides for the approach to the intermediate immonium structure is decereased, resulting in a mixture of cis- and trans-isomers.

It is noteworthy that the major isomer formed is the trans-axial compound 10a. It seems likely that the protonation step during the NaCNBH3 reduction is responsible for the different diastereochemistry at C-2. Introduction of a proton at C-4a results in a significant change of conformation according to calculations performed on semiempirical level, directing the side chain either into the axial or equatorial position. However, the energy difference is small, and the observed mixture is the result: only one 2-axial isomer trans-10a was isolated as the main product in 41% yield, while both 2-equatorial compounds 11a (18%) and 12a (10%) were observed. Calculations based on refined models are underway in order to provide more insight into the formation of the 3 diasteromers.

Further studies to investigate the influence of chain length as well as introduction of branched substituents on the stereochemistry of the Birch/NaCHBH3 sequence are in progress within our lab.



Raney-Ni Reduction

A solution of the quinoline 1 in MeOH/KOH was treated with Raney-Ni and gently refluxed until complete conversion. A general workup initiated by filtration through Celite gave the pure product after Kugelrohr distillation.


One Pot Birch/NaCNBH4 Reduction

A 30% solution of 2a/b (1 equiv.) in dry THF and dry MeOH (10 equiv.) was added to dry liquid ammonia condensed directly into the reaction vessel to form an approx. 10% reaction solution. Lithium chips (10 equiv.) were added slowly, maintaining the temperature at -35 ± 5°C. After the initially vigorous reaction had ceased the mixture was refluxed until the blue color disappeared. Ammonia and the organic solvents were evaporated by a stream of nitrogen at approx. 50°C and the residue was treated with dry THF and MeOH. The resulting solution was cooled to 5°C and brought to pH 4 by addition of methanolic HCl using bromocresol green as indicator. During the addition of NaCNBH3 pH 4 was maintained by treatment with methanolic HCl. When the pH showed no further change solid NaHCO3 and some NaOH were added and the solvents evaporated. The crude product obtained by a general work-up was refluxed overnight in a mixture of MeOH and methanolic HCl. Isolation of pure 5a/b was performed by Kugelrohr distillation.


1,2-Ziegler-type Substitution and Reduction of the Heterocyclic Core

A solution of n-BuLi (1 eq.) in dry THF was treated with 1 (1 eq.) in dry THF at 20°C, slowly brought to rt and stirred for one hour. Treatment with CH3I (2.5 eq) at 0°C, stirring for another hour at rt, followed by a general workup gave 8 without further purification and ready for the Raney-Ni reduction.


We would like to thank NOVARTIS Crop Protection Basel for generously funding this project.


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