Synthesis of novel 3-heterospiro[5.5]undecanes

Synthetic strategies leading to novel 3-heterospiro[5.5]undecan-9-ones are described. Starting from aliphatic 4-substituted heterocyclic aldehydes (1-methyl-4-piperidine carboxaldehyde, 4-formyl-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 2 H -tetrahydrothiopyran-4- carboxaldehyde, and 2 H -tetrahydropyran-4-carboxaldehyde) 3-heterospiro[5.5]undec-7-en-9-ones were made by Robinson annelation and upon further hydrogenation gave the desired 3-heterospiro[5.5]undecan-9-ones.


Introduction
Over the last years, the preparation and reactions of new spirocyclic compounds have been among our major research interests. 1Within this long-term project the present paper 2 deals with syntheses of novel 3-heterospiro [5.5]undecan-9-ones represented by the general formula of Scheme 1.As depicted in Scheme 2 these target systems were obtained by treatment of the appropriate 4-carboxaldehydes with methyl vinyl ketone to give 3-heterospiro [5.5]undec-7-en-9-ones via Robinson annelation.Hydrogenation of these key intermediates then yielded the desired final products.

Results and Discussion
Preparation of the heterocyclic 4-carboxaldehydes Although these products are already known, additional work had to be done to improve the yields to the extent desired for utilizing these compounds as starting materials in ensuing sequences.
2H-Tetrahydrothiopyran-4-carboxaldehyde ( 14) proved to be difficult to synthesize.In our first attempts the aldehyde was prepared in analogy to the piperidines by the Wittig reaction route (Table 1, X = S).Although this sequence was already described in the patent literature, 8 and each of the two steps gave yields of approx.76%, it turned out to be not very attractive (owing to the lengthy isolation of 4-methoxymethylene-2H-tetrahydrothiopyran (12), the handling of unpleasant-smelling compounds, and difficult separation of the enol ether from the Wittig by-product triphenylphosphine).So, a different route for the preparation of 2Htetrahydrothiopyran-4-carboxaldehyde (14) was envisaged.The preparation of aldehydes through Lewis-acid-promoted rearrangement of a spiro oxirane is a known procedure, but attempts to rearrange 1-oxa-6-thiaspiro[2.5]octane (13) 9 by using the usual Lewis acids (e.g., boron trifluoride etherate, zinc chloride, or magnesium bromide etherate) did not yield the desired product.In most cases 13 was recovered, or -under more vigorous reaction conditionsonly decomposition was observed.LiI/THF

Scheme 3
After detailed experimental studies appropriate reaction conditions could be developed: lithium iodide (highly concentrated, and used in a large excess, in dry THF) was found to be the only Lewis-type acid for promoting the rearrangement of 1-oxa-6-thiaspiro[2.5]octane (13) to 2H-tetrahydrothiopyran-4-carboxaldehyde (14) in a reasonable yield.Additionally, the yield could be improved remarkably by use of a Soxhlet apparatus, from which lithium iodide was gradually washed into the reaction vessel.
2H-Tetrahydropyran-4-carboxaldehyde (20) 10 was accessed via a different synthetic approach, using 4H-tetrahydropyran-4,4-dicarboxylic acid diethyl ester (17), 11 readily available from bis-(2-chloroethyl)ether and diethyl malonate as the initial starting materials.The following saponification/decarboxylation sequence towards 2H-tetrahydropyran-4-carboxylic acid (18) has been described with-12 or without- 13 isolation of the intermediate dicarboxylic acid.We have developed a modified one-pot procedure by refluxing 17 with 6M aq.HCl followed by removal of ethanol by distilling it off as ethanol/water azeotrope, in order to gain a higher reflux temperature in the reaction mixture to promote decarboxylation.

Robinson annelation to 3-heterospiro[5.5]undec-7-en-9-ones
This reaction step, consisting of a condensation and an ensuing Michael-type addition, was carried out under basic conditions using Triton B solution 16 in all cases, except for preparing 3oxaspiro [5.5]undec-7-en-9-one (21).The latter was obtained in higher yield using phosphoric acid as catalyst.It turned out that under these conditions the formation of difficultly separable by-products was diminished, although the conversion of the starting aldehyde was not complete.Hydrogenation reaction.This step was straightforward for all spiro ketones, which could be obtained in high yields.The hydrogenation had to be performed in ethyl acetate as solvent in order to avoid possible ketalization, which might occur on performing the reaction in the commonly used solvent methanol. 17The hydrogenation was mostly done at ambient temperature, except for the synthesis of 3-thiaspiro [5.5]undecan-9-one (16), where an elevated temperature together with a larger amount of hydrogenation catalyst and longer reaction time was required for complete conversion in order to overcome the catalyst-poisoning exhibited by the sulfur atom.The title compounds obtained are of interest as synthetic building blocks in heterocyclic chemistry and are currently being investigated as intermediates for the synthesis of pharmaceutically relevant substituents.
Melting points were determined on a Kofler hot stage and are uncorrected.Elemental analyses were performed at the Microanalytical Laboratory of the Institute of Physical Chemistry at the University of Vienna.

Table 3 .
Hydrogenation of enones The lower layer was made alkaline with 20% sodium hydroxide solution and extracted with diethyl ether; the upper layer was concentrated, made alkaline with 20% sodium hydroxide solution, and extracted with diethyl ether.The combined ethereal layers were dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off at atmospheric pressure.The resulting yellow liquid was distilled under reduced pressure to give a moderately stable colorless liquid (7.82 g, 87%), bp 60-62 °C/8 mbar (lit. 1-Methyl-4-piperidinecarboxaldehyde (3).Concentrated hydrochloric acid (6.5 ml) was added to a solution of 4-(methoxymethylene)-1-methylpiperidine (2) (10.0 g, 70.8 mmol) in THF (130 ml) and stirred for one hour.
Methyl vinyl ketone (8.62 g, 123 mmol) was added to a solution of 1-methyl-4-piperidinecarboxaldehyde (3) (7.82 g, 61.5 mmol) in dry tbutanol (150 ml) at 15 °C, under nitrogen.Then Triton-B (40% in methanol, 16.71 g, 40 mmol) was added, causing a spontaneous rise of temperature to 40 °C.Stirring at ambient temperature was continued for 1 h, then the red reaction mixture was diluted with water and extracted with ethyl acetate.The combined organic phases were washed with saturated sodium bicarbonate solution twice, and concentrated.Then 8% acetic acid was added and the solution washed with ethyl acetate.The aqueous phase was made alkaline with 20% sodium hydroxide solution, and extracted with ethyl acetate.After addition of charcoal, drying over anhydrous sodium sulfate, and filtration, the solvent was distilled off.