Tetrahedron Letters, 2003, vol. 44, # 34 p. 6483 - 6486

TETRAHEDRON

LETTERS

Tetrahedron Letters 44(2003)6483–6486

Pergamon

Sequential isomerization and ring-closing metathesis:masked

styryl and vinyloxyaryl groups for the synthesis of

benzo-fused heterocycles

Willem A.L.van Otterlo,*E.Lindani Ngidi and Charles B.de Koning

Molecular Sciences Institute ,School of Chemistry ,University of the Witwatersrand ,PO Wits ,2050,Johannesburg ,South Africa

Received 6May 2003;accepted 20June 2003

Abstract—The use of an aryl allyl ether and an arylallyl group as masked vinyl ether and 1-propenylphenyl groups for ring-closing metathesis (RCM)leading to the synthesis of benzo-fused heterocycles was demonstrated by using a ruthenium-mediated isomerization followed by a ruthenium-mediated RCM reaction.This resulted in the syntheses of a variety of products including two substituted benzo[1,4]dioxins,a naphtho[2,3-b ][1,4]dioxin,a 2H -chromene and a benzo[b ]furan.?2003Elsevier Ltd.All rights reserved.

The recent literature contains a myriad of examples of the application of ruthenium-mediated ring-closing metathesis (RCM).1–5The RCM catalyst of choice for this transformation is the Grubbs’second-generation catalyst 1owing to its activity,stability and tolerance to various functional groups and solvent impurities.

However,amongst the large numbers of examples described in reviews,very few utilize RCM for the metathesis of vinyl ether 6–8or silyl enol ether 9,10groups.RCM using Grubbs’catalysts on substrates containing electron-rich vinylic ole?ns are known to be problematic 7,8and earlier this year we communicated the ?rst examples of high-yielding metathesis reactions with aryl vinyl ethers (e.g.the conversion of precursor 2into 4H -chromene 3.)11Nishida and co-workers also recently published the related intramolecular RCM of substituted enamines 4to give indoles 5in excellent yields.12This paper has prompted us to divulge our successes in the RCM of other substrates containing electron-rich ole?ns.Furthermore,we demonstrate the in situ isomerization of aryl allyl ethers or arylallyl groups into aryl 1-propenyl ethers or 1-propenylben-

zenes,respectively,prior to RCM.This strategy thus obviates the need to synthesize the required aryl vinyl ethers or styrenes directly,the synthesis of which can be problematic.

1.Benzo[1,4]dioxins

Previously we have shown that as part of our ongoing interest in the synthesis of benzo-fused bicyclic molecules,13–16we were able to use RCM to synthesize 4H -chromenes,naphthols and indenols,11all of which are found as structural units in natural products.Firstly,following our success in accomplishing RCM on the vinyl ether-containing substrates,we decided to test the boundaries of this methodology by the intramolecular RCM of molecules containing aryl-bis-O -vinylic ole?ns.This would then give us benzo[1,4]dioxins,17which are interesting compounds with promising anti-tumour activity.Coudert has recently published an approach to their synthesis.18Our methodological approach is shown in the disconnection of compound 6to the bis(vinyloxy)aryl precursors 7.

Figure 1.

*Corresponding author.Tel.:Int +27+11+717-6707;fax:Int +27+11+717-6749;e-mail:willem@aurum.chem.wits.ac.za

0040-4039/$-see front matter ?2003Elsevier Ltd.All rights reserved.doi:10.1016/S0040-4039(03)01545-4

W .A .L .6an Otterlo et al ./Tetrahedron Letters 44(2003)6483–6486

6484Three differently substituted catechols 8a –c were sub-jected to vinylation with tetravinyltin and copper(II)acetate,according to a recently published procedure,19to afford the bis(vinyloxy)compounds 9a –e in rather poor yields (Scheme 1).20These yields were lower than expected and we postulate that competing formation of copper –catechol complexes probably contributes to the limited success of the reactions.Furthermore in cases 8a and 8b the experiments were poorly reproducible and often gave complex mixtures of vinylated products.Only 2,3-bis(vinyloxy)naphthalene 9c was easily iso-lated.21,22When it was treated with catalyst 1under standard reaction conditions,the corresponding known compound,naphtho[2,3-b ][1,4]dioxin 10c ,was pro-duced.18To the best of our knowledge this is the ?rst use of the RCM methodology to synthesize this class of compounds,and the ?rst synthesis of the 1,4-benzodi-oxins by direct ring-closure methods.17

2.Isomerizations of arylallyl and aryloxyallyl groups

followed by RCM The O -vinylation reaction used above has the disadvan-tage of using stoichiometric amounts of copper acetate and an environmentally unfriendly,atom uneconomical tetravinylstannyl reagent.Thus,having experienced problems with the synthesis of the bis(vinyloxy)ethers in the synthesis of the benzo[1,4]dioxins,we decided to investigate an alternative approach.The isomerization of aryloxyallyl ethers has attracted signi ?cant attention in the last few years and several groups have used ef ?cient transition metal catalysts to achieve this goal.Examples include the use of catalysts based on the metals ruthenium,23iridium 24and rhodium.25Since phenols are easily O -allylated by well established meth-ods to produce 11,subsequent isomerization should provide a useful aryl vinyl ether 12as depicted in the disconnection https://www.sodocs.net/doc/5110377935.html,pound 12would then be available for ruthenium-mediated RCM.The ?rst experimental sequence involved the isomeriza-tion of commercially available 2-allylphenol 13with [RuClH(CO)(PPh 3)3].23This was followed by alkylation of the phenol with allyl bromide and K 2CO 3to give 14in excellent yield over two steps (Scheme 2).Subsequent treatment of this substrate with catalyst 1then afforded 2H -chromene 1526in excellent yield.27Other approaches to 2H -chromenes,of which abundant examples exist in Nature,28using ruthenium-mediated RCM have already been communicated.29–32However,the major difference in our work is that the intramolec-ular RCM occurred between an allyloxy substituent and a styrene .Using this ruthenium-catalyzed allyl /pro-penyl isomerization reaction therefore extends the sub-strates available in this approach as allyl groups ortho to a substituent on an aromatic ring are often easy to introduce,e.g.by Claisen rearrangement,Kumada cou-pling,directed ortho -metalation 33and electrochemical coupling.34

In addition,synthesis of benzo[1,4]dioxins was more readily accomplished using our new allylation /isomer-ization /RCM procedure.Bis(O -allylation)of catechols 8a –c afforded compounds 16a –c in good yields (Scheme 3).This was then followed by in situ isomerization as described before to afford the aryl bis(vinyl)ethers 17a –c .The formation of the product was monitored by 1

H NMR spectroscopy and the acid-sensitive enol ether intermediates 17were not isolated.Grubbs ’catalyst 1was then added directly to the reaction mixture,and the desired benzo[1,4]dioxins 10a –c were obtained in good yields.27Other reported examples of ‘one-pot ’multistep reactions featuring RCM include RCM /hydrogenation 11,35and RCM /isomerization 36,37sequences.We have thus been successful in synthesizing compounds with the benzo[1,4]dioxin structure using a simple three-step two-reaction process.The desired compounds were readily formed and this methodology should stimulate further exploration of the properties of this class of organic molecules.

Scheme 1.a .R 1,R 2=H;b .R 1=Me,R 2=H;c .R 1,R 2=fused benzene ring.Reagents and conditions :For c .(a)Cu(OAc)2,Sn(vinyl)4,acetonitrile,O 2,rt,47%;(b)5%catalyst 1,toluene,67%,70–80°C.

Scheme 2.Reagents and conditions :(a)[RuClH(CO)(PPh 3)3](1%),toluene,80°C,90%;(b)allyl bromide,K 2CO 3,acetone,re ?ux,86%;(c)5%catalyst 1,CDCl 3,rt,>80%(by 1H NMR spectroscopy).

W .A .L .6an Otterlo et al ./Tetrahedron Letters 44(2003)6483–64866485

Scheme 3.a .R 1,R 2=H;b .R 1=Me,R 2=H;c .R 1,R 2=fused benzene ring;Reagents and conditions :(a)allyl bromide,K 2CO 3,acetone,re ?ux,16a 76%,16b 93%,16c 96%;(b)[RuClH(CO)(PPh 3)3](1%),toluene-d 8,80°C (complete by 1H NMR spectroscopy);(c)5%catalyst 1,toluene-d 8,yields over two steps:10a 38>70%(by 1H NMR spectroscopy),10b 39>70%(by 1H NMR spectroscopy,isolated yield after chro-matography 58%),10c 18>90%(by 1H NMR spectroscopy).

readily undergo ruthenium-mediated RCM reactions.42We are currently extending this work to the synthesis of natural products and other interesting systems.

Acknowledgements

This work was supported by the National Research Foundation (NRF,GUN 2053652),Pretoria,and the University of the Witwatersrand (University Research Council).We also thank the Mellon Postgraduate Men-toring Programme (sponsored by the Andrew W.Mel-lon Foundation)for generous funding.Professor J.P.Michael is thanked for many helpful discussions.

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