Ring-Closing Metathesis Reactions of Bis(enynes): Selectivity and

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Ring-Closing Metathesis Reactions of Bis(enynes): Selectivity and Surprises Debra J Wallace, and Robert A. Reamer J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo500815q • Publication Date (Web): 23 May 2014 Downloaded from http://pubs.acs.org on June 2, 2014

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The Journal of Organic Chemistry

Ring-Closing Metathesis Reactions of Bis(enynes): Selectivity and Surprises Debra J Wallace* and Robert A Reamer Department of Process Chemistry Merck Research Laboratories PO Box 2000 Rahway NJ, 07065, USA [email protected]

Abstract

A study of the ring-closing metathesis reactions of two bis(enynes) is presented. These substrates, which contain two alkenes and two alkynes, as well as a resident stereocenter, can potentially generate metathesis products resulting from many reaction pathways. In this paper we present our results on these reactions, show how small changes in reaction conditions can lead to different product ratios and attempt to provide a rational for the outcomes.

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INTRODUCTION Over the past two decades the ruthenium-mediated ring-closing metathesis reaction has become one of the most widely used synthetic transformations in organic chemistry, and many groups have successfully incorporated such reactions into the synthesis of natural and unnatural products.1

In some cases the careful design of starting materials has allowed for multiple rings

to be formed in a single synthetic step from acylic starting materials.2-4 The ability to generate more than one ring has found particular success when employing enyne metathesis;5 in these substrates the first ring-closing event generates a new ruthenium vinyl carbene which is available for further reaction with other carbon multiple bonds within the molecule.6 For example, in dienyne metathesis7 reaction of the intermediate ruthenium vinyl carbene with a second olefin leads to a fused bicyclic structure in a cascade type process. In contrast, multiple ring-closing reactions of alkenes rely on two discrete ring closing events, each requiring an intermolecular reaction between catalyst and substrate. Previously our group has explored the double ringclosing metathesis of tetraenes such as 1, which lead to spirocyclic molecules of general structure 2 via two separate ring closing steps (Scheme 1).8 As part of our continuing interest in this area the ring-closing metathesis reactions of bis(enynes) 3 and 4 were considered.

These

substrates, which contain two alkenes and two alkynes, can potentially generate metathesis products resulting from many reaction pathways. In this paper we present our results on ringclosing metathesis reactions of these compounds, show how small changes in reactions conditions can lead to different product ratios and attempt to provide a rationale for the outcomes.


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Scheme 1: Bis(enynes) for ring-closing metathesis study RESULTS AND DISCUSSION Synthesis of substrates: Compound 3 was prepared in 71% yield from the previously described 58b by reaction with sodium hydride and propargyl bromide. Compound 4 was prepared in two steps from 6 by reaction with propargylmagnesium bromide to give 7, followed by allylation with allyl bromide and sodium hydroxide. This final step was hindered by formation of a rearrangement by-product 8, which predominated when employing sodium hydride as base. After screening a number of different conditions the use of sodium hydroxide in DMF9 was found to be optimum giving a 2:1 ratio of 4:8 and allowing for isolation of 57% of 4 after chromatography (Scheme 2).



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Scheme 2: Synthesis of 3 and 4 Ring-Closing Metathesis of 3: Initial studies were conducted using 3 and a typical “second generation” catalyst, 9.10 Reaction of a dichloromethane solution of 3 with 20 mol% 9 gave, after three hours, two major products in a 1:2 ratio, along with a number of minor components.11 After separation these were confirmed to be spirocyclic compounds 10a and 10b formed in 50% combined yield (Scheme 3). NMR studies allowed for assignment of the major isomer as 10b, based on an NOE between the aromatic ortho proton and the olefinic proton in the 5-membered ring, which was lacking in 10a. A number of the minor reaction components showed incorporation of the aromatic portion of the catalyst moiety, suggesting incomplete turnover of initially generated alkenes. Repeating the reaction under an ethylene atmosphere gave a cleaner reaction profile; 10a and 10b were isolated in 74% yield, again in a 1:2 ratio. We propose this reaction proceeds by initial reaction of the catalyst with one of the alkyne moieties followed by cyclization onto a hindered vinyl group to afford 11a and b or 12a and b. A second intermolecular event is then required between catalyst and the remaining alkyne to initiate the second ring closure. The relative contribution of these two pathways to the reaction outcome has not been determined as no significant quantities of the putative mono-cyclic intermediates 11 or


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12 were detected under the reaction conditions. In an attempt to stall the reaction at these intermediates a reduced catalyst load was used (4 mol% of 9). In this case incomplete conversion was seen, but the only products detected were once again 10a and 10b, with 70% of starting material recovered. This result suggests that formation of the first ring is the rate determining step, and the monocyclic intermediates are rapidly consumed in a fast second step, explaining their non-detection.

Scheme 3: Ring-closing metathesis of 3 promoted by 9 Reaction of 3 with a typical “first generation” catalyst, 1312 was then evaluated. In the absence of ethylene 30% conversion to one major product was seen, along with several minor components. Based on real-time HPLC analysis an intermediate was initially generated which subsequently converted to final product; notably neither the intermediate nor product had been seen in reactions of 3 with catalyst 9. After isolation the major product was found to be a single stereoisomer of tricycle 14, presumably resulting from an intramolecular Diels-Alder reaction between the diene and alkyne moieties in either 11 or 12. Intermolecular Diels-Alder reactions



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of dienes formed in an enyne metathesis reaction, with an external dienophile have been extensively reported13 and intramolecular variants following enyne cross metathesis reactions are also known;14 however instances where both the metathesis and the Diels-Alder steps are intramolecular are less common,15 and to the best of our knowledge this is the first example where the sequence occurs in a single step. NOE studies showed the vinyl group, the central methine proton and the benzylic proton were all cis to each other allowing for assignment of stereochemistry as shown (Scheme 4).

Scheme 4: Ring-closing metathesis and Diels-Alder reactin of 3 promoted by 13

Attempts to isolate the transient intermediate 11 or 12, or trap with an external dienophile were unsucessful due to the rapid conversion to the intramolecular Diels-Alder product. Notably product 14 could arise from either a six or five membered ring intermediate, but only from one stereoisomer of each, i.e. from 11b or 12a. Carrying out the ring-closing reaction of 3 with 13 under an ethylene atmosphere allowed for complete conversion of starting material and reduced the number of minor by-products. After three hours the same intermediate as previously was seen, this was subsequently consumed to give four products. Two were the known spirocycles 10a and 10b in a 1:2 ratio, accounting for about 30% of the total mixture. The balance of material was split equally between the Diels-


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Alder product 14 and a second new product, determined to be cyclopropane 15 (Scheme 5). The stereochemistry in 15 was determined on the basis of a number of NOE experiments. Firstly the cyclopropane group was shown to be “back” based on an NOE between the cyclopropane methylene and the olefin as shown. Unambiguous assignment of the quaternary center was more challenging due lack of diagnostic NOEs between the 5 and 6 membered rings, however an NOE between the aromatic ortho-protons and the cyclopropane methine allowed for final assignment as shown. NOE

PCy3 Cl Ru 13 Cl PCy Ph

H O

3

3

N

10a + 10b + 14 + CH2Cl2 CH2CH2

O

10% 20% 35%

Ts N Ph Ts 15, 35%

H

H

NOE

Scheme 5: Ring-closing metathesis of 3 promoted by 13 under an ethylene atmosphere Formation of the cyclopropane is interesting from a mechanistic standpoint. Although cyclopropanes are often observed as minor by-products in metathesis reactions due to catalyst decomposition,16,17 in this case the quantities generated are in excess of the catalyst loading. A catalytic tandem cyclopropanation/dienyne metathesis has been previously reported and is thought to result from interplay of catalyst decomposition through a reductive elimination pathway and a non-carbenic enyne bond reorganization.18 As such an enyne starting material is required to both generate the cyclopropane and give pathways to allow metal carbene regeneration; indeed we confirmed that re-submission of 10a or 10b to the reactions conditions (catalyst 13 and ethylene) did not generate any cyclopropane. Compound 15 appears to be formed from the same intermediate that generates the Diels-Alder product19 and based on the



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stereochemistry in 14 and 15 the intermediate is thought to be 11b. Certainly, initial formation of a 5-membered ring would be favored on kinetic grounds and was observed in our previous work on tetraenes.8d,e Moreover formation of 11b could account for formation of all products other than 10a – which constitutes 95:5. 22. Although assignment of stereochemistry based on the absence of NOE interactions is non-optimum, in this case we are confident of the interpretation, as the data can be compared to that obtained for spirocycles 10a and 10b where both isomers were available for study.


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23. To simplify structures ligands on ruthenium are not shown in the intermediate vinyl carbenes.


Ring-Closing Metathesis Reactions of Bis(enynes): Selectivity and

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