Wagner-Meerwein rearrangement of benzo-and thieno-annelated spiroalkanols

The treatment of benzene solutions of 7,8-benzo-and 7,8-thieno-fused spiro[4.5]decan-6-ols with p - toluenesulfonic acid induced Wagner-Meerwein rearrangement resulting in a condensed three-ring system. In the case of the 6-methyl derivatives three different isomeric products were formed: two rearrangement products and the dehydration product featuring an exocyclic double bond. Variation of the reaction conditions led to the exclusive or preferred formation of one of the isomers.


Introduction
In the course of an attempted synthesis for a thiophene analogue of the isomorphinane system we dealt with a reaction of the type shown in Scheme 1.The unusual reaction conditions and the question of the regioselectivity in the formation of the double bond prompted us to analyze this rearrangement more closely.A literature search revealed several instances of exactly the type of conversion shown in Scheme 1, 1 where Ar is a (substituted) benzene ring, but no system with an other side chain instead of an aminoalkyl group was found.Therefore, we decided to investigate this reaction utilizing a methyl group as an example for a non-basic side chain and also thieno-annelated systems.

Synthesis of the spiro alcohols
The introduction of the spiro ring was achieved by double alkylation of an appropriate ketone with an α,ω -dibromo alkane.This method for synthesizing spiro-ketones 1a, 2 1b, 3 and 2 4 has been described before, and we followed the procedure with some minor modifications that reduced the formation of side products and allowed easier purification of the products.
For reasons of simplicity and easy detection by NMR we chose the methyl group as side chain of the alcohols to be rearranged.The methyl group was introduced with methyl lithium, since in our hands methyl magnesium halide, as described for the synthesis of 3a, 5,6 led to the formation of large amounts of the exocyclic alkenes 7 as side products.In addition, reduction with LiAlH 4 converted the thieno-annelated ketones 1b and 2 into the secondary alcohols 5 and 6, respectively (Scheme 2).

Rearrangements
Already the first experiments showed that three isomers were formed: Treatment of 3a with ptoluenesulfonic acid (TosOH) in benzene at 50 °C for 1 h produced a mixture of the exo-alkene 7a and the Wagner-Meerwein products 9a and 10a (Scheme 3).Variations of the reaction conditions allowed the selective synthesis of two of them: The reaction of of 3a with TosOH in a benzene solution at ambient temperature for 1 h afforded 7a, which can be synthesized by this method under much milder conditions than it was reported before 6 by heating to 170 °C with KHSO 4 .Heating a benzene solution of 3a and TosOH at reflux temperature for 6 hours formed exclusively 9a.Although analogues of 10a bearing an aminoalkyl side chain are known from isomorphinane syntheses, we failed in obtaining this isomer selectively.After testing several reagents (including ethanolic HCl, trifluoroacetic acid, boron trifluoride/acetic acid, and dioxane/sulfuric acid under various conditions), best results were achieved with a benzene solution of 3a and TosOH kept at 35 °C.Complete conversion of 3a required 7 days yielding a mixture of 10a and 9a (85:15) which we could not separate; both alkenes show almost identical R f values and boiling points (Scheme 3, X = CH=CH).The thieno-annelated alcohol 3b behaved completely analogous to 3a, except that the product ratio in the synthesis of 10b was slightly better (Scheme 3, X = S).
The experiments with spiranols were extended to the secondary alcohol 5; treatment of 5 with TosOH in a benzene solution at reflux temperature for 2 h furnished alkene 11 as the rearrangement product (Scheme 4).The reaction conditions applied to 3a and 3b affording the rearrangement products 9 and 10 converted also the exocyclic alkenes 7a and 7b into the respective isomers 9 and 10 with identical results.Even the conversion of the alkenes 10 into the thermodynamically more stable isomers 9 was possible under the same conditions that were utilized for the synthesis of the latter from the alcohols 3.
The above-described reaction conditions applied to spiro-cyclohexane alcohols gave different results.The tertiary alcohol 4 yielded only the exocyclic alkene 8 as the dehydration product (Scheme 5).All experiments aiming at the conversion of 6 resulted in complete decomposition.We did not detect any rearrangement product derived from a -presumably thermodynamically much less favorable -cycloheptano-annelated skeleton.Experimental Section General Procedures.Unless otherwise noted, chemicals were purchased from commercial suppliers and used without further purification.All solvents were distilled prior to use.Anhydrous diethyl ether and tetrahydrofuran were obtained by distillation from sodium/benzophenone, dry benzene by refluxing over P 2 O 5 .After isolation all products were purified by bulb-to-bulb distillation.TLC was performed on precoated plates (Merck TLC aluminium sheets silica 60F 254 ) with detection by UV light. 1 H and 13 C NMR spectra were recorded on a JEOL FX-90 spectrometer (TMS as internal standard, CDCl 3 as solvent, δ values in ppm).The starting materials 6,7-dihydrobenzo[b]thiophen-4(5H)-one 7 and 3,4-dihydronaphthalen-1(2H)-one 8 and from these the spiro-ketones 1a, 2 1b, 3 and 2 4 were synthesized according to known procedures.