Early Transition Metal Induced Intramolecular Cocyclisation / Elaboration Reactions Using a Cleavable Silicon Linker

Gareth D. Probert,^a Ross Harding,^a Richard J. Whitby*^a and Steven J. Coote^b

^aDepartment of Chemistry, Southampton University, Southampton, HANTS, SO17 1BJ, U.K; E-mail: rjw1@soton.ac.uk

^bGlaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, HERTS, SG1 2NY, U.K.

Abstract: 1,6- and 1,7-dienes and -enynes incorporating a silicon-oxygen or silicon-nitrogen link are co-cyclised with zirconocene(1-butene) or diisopropoxytitanium(propene) to give metallabicycles. Further elaboration followed by cleavage of the silicon-carbon bond using Tamao oxidation affords a wide variety of organic products.

The early transition metal induced intramolecular co-cyclisation of 1,n-dienes, -enynes, and -diynes to give metallacyclopent-anes, -enes, and -dienes is a useful method for carbon-carbon bond formation.¹ The wide variety of methods which have been developed for further elaboration of these metallacycles² promises to make them important intermediates in the synthesis of mono- and bicyclic compounds. Unfortunately the intermolecular co-cyclisation of alkenes and alkynes is a far more limited process³ so that routes to acyclic and monocyclic products are restricted. One potential solution is to temporarily connect the two π-components. Silicon has been widely used as a cleavable linker in Diels-Alder and 1,3-dipolar cycloadditions, and in radical chemistry⁴ where there are also great benefits from intramolecular reactions. In transition metal chemistry silaketal linkers have been used in ring closing metathesis cyclisations, and Dötz benzannulation reactions.⁵ We report below our initial results using a silicon linker in zirconium and titanium induced co-cyclisation reactions.

We chose to examine cases where a heteroatom - silicon bond is formed / cleaved during the temporary connection processes. Advantages included the fast and quantitative formation of N-Si and O-Si bonds, and that Tamao oxidation of carbon-silicon bonds (our chosen cleavage method) works well when the silicon carries an oxygen or nitrogen substituent.⁶

Reaction of N-allylaniline with chlorodimethylvinylsilane gave the diene 1a. Cocyclisation induced by zirconocene(1-butene), generated in situ from dibutylzirconocene (the `Negishi reagent')⁷ gave cleanly the zirconacycle trans-2a. In the analogous cyclisation of diallylaniline a 1 : 2.6 mixture of trans- and cis- fused zirconabicycles is formed initially, isomerising to a 2.5 : 1 mixture on heating.⁸ Heating the zirconacycle trans-2a (60deg.C, 4 h) did not cause any isomerisation. It is notable that 1,6-heptadiene gives exclusively the trans-fused zirconabicycle^2b so 1a resembles the all carbon analogue, rather than the amine where carbon replaces the silicon group. Aqueous work-up of 2a gave the silanol threo-4a.⁹ Tamao oxidation⁶ of the crude product gave the aminoalcohol 5a¹⁰ [experimental]as a the single threo-isomer. The stereochemistry of threo-5a was proven by conversion to the cyclic carbamate trans-6a and ¹H NMR studies.¹¹ A large excess of hydrogen peroxide was required for the Tamao oxidation (zirconium residues probably catalyse decomposition of hydrogen peroxide) and timing was critical for good yields. Isolation of substantial amounts of nitrobenzene when the reaction was left overnight confirmed that oxidation of the nitrogen was occurring. Acylation of the intermediate amino-silanol 4a gave a more reliable oxidation (~90% yield, and not time critical), but the overall yield was comparable.

It would be desirable to be able to vary the stereochemistry of the initial co-cyclisation. Treatment of 1a with the Ti(OⁱPr)4 / 2 ⁱPrMgCl reagent [in situ (ⁱPrO)2Ti(CH2=CHCH3)] recently developed by Sato¹² followed by protonation gave the silanol 4a as a ~ 1 : 4 threo : erythro mixture indicating that the presumed intermediate titanabicycle 3a was predominantly cis-fused. Tamao oxidation gave a 4.6 : 1 mixture of the amino alcohols erythro-5a and threo-5a in 35% overall yield from 1a.

The potentially more useful N-benzyl substrate 1b was examined next. Cyclisation with zirconocene(1-butene) followed by hydrolysis gave the silanols 4b as a 2 : 1 mixture of threo- and erythro- isomers. Heating the intermediate zirconacycle did not change the ratio. Attempted Tamao oxidation of 4b failed, presumably because the nitrogen is more easily oxidised than in 4a. N-Acylation of the crude silanols followed by Tamao oxidation gave a 1.8 : 1 mixture of the easily separable N-acyl aminoalcohols threo- and erythro-8b in an excellent overall yield. Deacylation and formation of the cyclic carbamates 6b was used to prove the relative stereochemistries.¹¹ Cyclisation of 1b with Ti(OⁱPr)4 / 2 ⁱPrMgCl followed by aqueous work-up gave a 1 : 5 mixture of threo- and erythro-4b indicating that the cis-fused titanacycle 3b predominates. Acylation and Tamao oxidation gave 8b in 31% yield as a 5 : 1 mixture of erythro : threo diastereoisomers.

Further elaboration of the zirconacycle intermediates is essential if efficient use is to be made of the metal. Carbonylation,^2a air oxidation,^2b and trimethylsilyl cyanide insertion / 4-octyne trapping^2c of 2a followed by aqueous work-up and Tamao oxidation gave the highly elaborated products 9, 10, and 11 in reasonable overall yields from N-allyl-N-(dimethylvinylsilyl)aniline 1a (Scheme 2). The dramatic increase in complexity in these sequences is a testament to the efficient use of the transition metal. Insertion of lithium chloroallylide, generated in situ from allyl chloride and lithium 2,2,6,6-tetramethylpiperidide (LiTMP), into 2a occurred without selection between the two available carbon-zirconium bonds to give a 1 : 1 mixture of 12 and 13 after work up with benzaldehyde^2d followed by protonolysis and Tamao oxidation.

Reaction of N-allylaniline with allylchlorodimethylsilane to give 14 followed by zirconocene induced co-cyclisation gave the metallacycle 15 as a 4 : 1 ratio of isomers (Scheme 3). Protonolysis and Tamao oxidation gave the aminoalcohols 16a and 16b in a 4 : 1 ratio. The stereochemistries were proven by conversion to the 3,4-dimethylpyrrolidines 17a and 17b, independently prepared by a known route.⁸ The initial co-cyclisation thus gave predominantly the trans-fused zirconabicycle. Heating the zirconacycle did not change the ratio of isomers. In the analogous co-cyclisation of N-allyl-N-(3-butenyl)benzylamine the kinetic product is a 4 : 1 mixture of cis : trans ring fusion, and the thermodynamic product a 1 : 1 mixture.¹³ With 1,7-octadiene the kinetic product is >80% cis-fused^8,14 and the thermodynamic product >97% trans-fused.

The elaboration of a propargylic amine was examined next. Reaction between N-(3-phenyl-2-propynyl)aniline and dimethylchlorovinylsilane gave the cyclisation precursor 18. Zirconocene induced co-cyclisation formed the zirconacycle 19 which underwent protonation and Tamao oxidation to give the aminoalcohol 20 in good yield (Scheme 4). Further elaboration of 19 by regiospecific insertion of lithium chloroallylide into the alkyl-zirconium bond¹⁵ followed by addition of benzaldehyde and Tamao oxidation gave the aminodiol 21. Carbonylation of 19 gave the silanol 22 in good yield, but unfortunately all attempts at Tamao oxidation lead only to decomposition.

Zirconocene induced co-cyclisation of -dienes and -enynes derived from allylic or propargylic alcohols and chlorodimethylvinylsilane failed as expected - rearrangement of the intermediate β-alkoxy-zirconocene η²-alkene or -alkyne moieties to allyl or propargyl zirconium species being well precedented.¹⁶ Homoallylic alcohols and homopropargylic alcohols do not suffer from the rearrangement problem and gave reasonable yields of elaborated products on reaction with chlorodimethylvinylsilane / cocyclisation / elaboration and Tamao oxidation (Scheme 5). Of note is that cyclisation of the 1,7-diene 23 gave exclusively the trans-fused zirconabicycle 24 and hence diacetate 25, the stereochemistry of the later being proven by independent synthesis.¹⁷ Carbonylation of the unsaturated zirconacycle 26 suffered the same fate as with 19 - the silicon substituted cyclopentenone was formed, but Tamao oxidation led to decomposition.

The formation and reactions of zirconocene(benzyne) complexes has been developed by Erker and Buchwald but intermolecular trapping with terminal alkenes is generally inefficient.¹⁸ Reaction of o-bromophenol with allylchlorodimethylsilane followed by bromine/lithium exchange, addition of (methyl)zirconocene chloride, and thermolysis gave the adduct 27 by intramolecular trapping of the in situ generated zirconocene(benzyne) complex (Scheme 6). Protonolysis, or carbonylation followed by protonolysis, then Tamao oxidation and acylation gave the products 28 and 29 in reasonable overall yields. The analogous zirconocene(benzyne) complex derived from 2-bromoanisole inserts alkenes exclusively into the bond remote to the methoxy group so the methods are complementary.

In conclusion we have shown that the early transition metal induced intramolecular co-cyclisation of dienes and enynes incorporating a cleavable silicon linker is an efficient process. Further elaboration of the intermediates has the potential to give a very wide range of organic structures, a few of which we have illustrated. The transformation may also be viewed as a heteroatom directed carbometallation of alkenes and alkynes. The co-cyclisation reaction of 1,6 and 1,7-dienes containing silicon-oxygen or silicon-nitrogen links in the connecting chain gives unexpected stereochemical results. Generally these resemble the all-carbon analogues, rather than the oxygen or nitrogen containing equivalents where the the silicon is replaced by carbon. A qualification is that the presence of the heteroatom speeds equilibration of the zirconacycles so that only thermodynamic mixtures are observed.

Acknowledgements. We thank the E.P.S.R.C. and Glaxo Wellcome for support of this work through the CASE scheme (GDP) and MRes program (RH). RJW thanks Zeneca, Pfizer, and Glaxo Wellcome for generous uncommitted support during the course of this work. We wish to acknowledge use of the E.P.S.R.C. chemical database service at Daresbury.¹⁹

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