An expedient route to substituted furansvia olefin cross-metathesisTimothy J. Donohoe1 and John F. Bower

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA UK

Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved December 23, 2009 (received for review November 20, 2009)

The olefin cross-metathesis (CM) reaction is used extensively in or-ganic chemistry and represents a powerful method for the selectivesynthesis of differentially substituted alkene products. Surpris-ingly, efforts to integrate this remarkable process into strategiesfor aromatic and heteroaromatic construction have not been re-ported. Such structures represent key elements of the majorityof small molecule drug compounds; methods for the controlled pre-paration of highly substituted derivatives are essential tomedicinalchemistry. Here we show that the olefin CM reaction, in combina-tion with an acid cocatalyst or subsequent Heck arylation, providesa concise and flexible entry to 2,5-di- or 2,3,5-tri-substituted furans.These cascade processes portend further opportunities for the re-giocontrolled preparation of other highly substituted aromatic andheteroaromatic classes.

catalysis ∣ cembranolide ∣ Heck reaction

Ruthenium catalyzed olefin metathesis has become a remark-ably powerful tool for organic chemistry (1–5). In recent

years, the potential of ring-closing olefin metathesis (RCM) asa key step for the preparation of aromatic and heteroaromaticcompounds has begun to be realized (6–8). Studies from ourown laboratory have delineated versatile RCM-based protocolsfor the regiodefined synthesis of pyridines, pyridazines, furans,and pyrroles (9–15). Despite the evident potential of these meth-ods it is notable that any RCM-based approach is reliant upon thea priori construction of a suitable precursor, which necessarilydetracts from synthetic convergency and flexibility. A related ap-proach involves the use of olefin cross-metathesis (CM) as a keystep. Here both fragment coupling and strategic C=C bond for-mation are unified and, as such, potentially greater efficienciesare afforded. Despite this potential, and presumably due to per-ceived problems associated with double bond geometry, olefinCM-based methodologies for aromatic and heteroaromatic con-struction have not, to the best of our knowledge, been disclosed.Herein we report the successful implementation of this concept interms of a versatile and direct entry to disubstituted andtrisubstituted furans. It is likely that these studies will set the stagefor the development of general olefin CM-based entries to otheraromatic and heteroaromatic classes of varying ring sizes(Scheme 1, top).

Substituted furans are prevalent in natural products and phar-maceuticals and also represent useful intermediates in synthesis.Convergent de novo approaches to furans that embody high levelsof flexibility andpredictable regiocontrol areofparticular value yetare relatively uncommon (16–22). Specifically, methods thatemploy simple starting materials, enable facile substituent intro-duction, andare concise are likely tobeof significance tobothmed-icinal chemistry and total synthesis. Our approach to furans reliesupon the intermediacy of trans-γ-hydroxyenones 3 that are acces-sible via the established olefin CM of readily available allylic alco-hols 1 and enones 2 (Scheme 1, Bottom) (23). Here we show that atandemolefinCM-acid catalysed isomerization cascade provides adirect entry to differentially 2,5-disubstituted furans 4. Addition-ally, Heck reaction of the olefin CM products enables a tandemarylation-furan formation cascade to afford 2,3,5-trisubstitutedfurans 5 directly. As such, the trans-γ-hydroxyenone intermediates

serve as highly versatile surrogates for 1,4-dicarbonyl com-pounds, especially as the final furan substitution pattern is pro-grammed by the oxidation level of the allylic alcohol and enonecomponents. The net result is an exceptionally concise and con-trolled approach to this class of heteroaromatic compounds.

Results and DiscussionIn our initial studies, we focused upon the formation of furan 8aby the olefin CM of allylic alcohol 6a with methyl vinyl ketone 7a.Here we found that, using the Grubbs–Hoveyda second genera-tion catalyst (G-H II), the synthesis of the trans-hydroxyenoneintermediate was straightforward. Subsequent addition of a vari-ety of Brønsted or Lewis acids to the reaction medium was thenevaluated to promote isomerization and condensation. Fromthese initial assays we established that catalytic quantities ofPPTS effected efficient furan formation. Furan formation pre-sumably occurs via initial isomerization of the trans-hydroxye-none metathesis product to either the corresponding 1,4-dicarbonyl compound or the cis-hydroxyenone. We have not,

Scheme 1 Cross-metathesis as an approach to di- and trisubstituted furans.

Author contributions: T.J.D. and J.F.B. designed research; J.F.B. performed research, T.J.D.and J.F.B. analyzed data, and T.J.D. and J.F.B. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 3279.1To whom correspondence should be addressed. E-mail: timothy.donohoe@chem.ox.ac.uk.

This article contains supporting information online at www.pnas.org/cgi/content/full/0913466107/DCSupplemental.

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as of yet, been able to unambiguously distinguish these pathways.However, our preliminary investigations suggest that furan for-mation from trans-hydroxyenones is faster than from analogous1,4-dicarbonyl compounds. This would implicate a trans- to cis-isomerization pathway (24).

At this stage, and given the known compatibility of Grubbs’type catalyst systems and acids (25), we considered whether boththe ruthenium and acid catalysts could be employed from the out-set. Gratifyingly, this proved to be the case and, under optimizedconditions, allylic alcohol 6a was converted to furan 8a in 82%yield. Notably, increased overall efficiencies were observed usingthis tandem approach compared to the stepwise alternative.These conditions are generally applicable to a range of enonecomponents and enable the introduction of aryl, heteroaryl, cy-clopropyl, and diverse alkyl substituents in good to excellent yield(Table 1).

Examination of the scope of the allylic alcohol component re-vealed a greater degree of substrate sensitivity, presumably as thisis the site of cross-metathesis initiation (Table 2). Under opti-mized conditions, alkyl, aryl, and heteroaryl substituents couldall be introduced onto the furan core via the corresponding allylicalcohol (6b-g) in moderate to excellent yield. The catalyst systemis, however, sensitive to the steric bulk of this component, and theintroduction of a t-butyl substituent was achieved in only 36%yield (Entry 6) with the remainder of the mass balance consistinglargely of starting material. This defines a current limitation butalso portends further increases in scope as more efficient metath-esis catalysts become available.

It is pertinent to consider the role of the allylic alcohol hydro-xyl group in promoting the efficient CM reactions described here.Recent work has highlighted the enhanced metathesis efficiencyof allylic alcohols compared to their corresponding ethers (26,27), and our own preliminary observations are consistent with

these findings. As evidenced by Hoveyda, it is possible that hy-drogen bonding between the allylic alcohol derived carbeneand a ruthenium chloride ligand is crucial in expediting subse-quent CM to the electron deficient enone (27).

Given our ongoing interest in cembranolide natural productssuch as deoxypukalide 15 (28), we were interested in assessingwhether this furan synthesis could be employed in an intramole-cular setting to provide an entry to the macrocyclic furan corepresent in many compounds of this class (Scheme 2). Such anapproach would unite the direct nature of the methodology pre-sented herein with the established utility of olefin metathesis formacrocycle formation (29). Wadsworth–Emmons olefination ofundecenal using the modified phosphonate reagent 9 affordedacrylamide 10 in 90% yield. This species underwent efficient con-jugate addition with the Gilman cuprate derived from n-BuLi togenerate 11. This route demonstrates the feasibility of installingthe C-1 substitution present in the cembranolide natural pro-ducts. Note that organocuprate 1,4-additions onto Weinreb acry-lamides have not previously been reported; we have found thatcareful control of reaction temperature and time are essential inpreventing the known ene-type degradation of the intermediatesilyl ketene aminal (30). Oxidative cleavage of the terminal olefinyielded 12, and this was subjected to double addition of vinylGrignard to set-up the tethered allylic alcohol-enone metathesisprecursor 13. Exposure of this species to our previously describedconditions but under higher dilution, afforded the 13-ring macro-cyclic furan system 14 in excellent yield. Here prolonged reactiontimes were required to effect (a) complete metathesis and (b)complete conversion of the intermediate hydroxyenone to thecorresponding furan.

Table 1. Tandem CM-furan formation: Scope of the enonecomponent

Ph(CH2)2

OH O

R

G-H II (5 mol%)PPTS (2.5 mol%)

CH2Cl2 (0.25 M) 40 oC, 24h

Ph(CH2)2O R

(100 mol%) (250 mol%)8a-f7a-f6a

Entry Enone Product Yield, %

1

Me

O

7a

Ph(CH2)2O Me

8a

82

2

Et

O

7b

Ph(CH2)2 O Et

8b

71

3

cHex

O

7c

Ph(CH2)2O

8c

54

4

Ph

O

7d

Ph(CH2)2O Ph

8d

76

5 OTsN

7e

Ph(CH2)2 OTsN

8e

56

6 OPh

7f

Ph(CH2)2O

Ph8f

63

Table 2. Tandem CM-furan formation: scope of the allylic alcoholcomponent

R

OH O

Me

G-H II (5 mol%)PPTS (2.5 mol%)

CH2Cl2 (0.25 M) 40 oC, 24h

R O Me

(100 mol%) (500 mol%)l-g8a7g-b6

Entry Allylic Alcohol Product Yield, %

1 OHPh

6b

O MePh

8g

76

2* OH

N

Br 6c

O MeN

Br

8h

61

3† OH

Br 6d

O MeBr

8i

53

4 OH

6e

O Me

8j

65

5 OHBnO

6f

O MeBnO

8k

51

6‡

t-Bu

OH

6g

t -Bu O Ph

8l

36

*The reaction was run at 70 °C.†The reaction was run at 0.17 M.‡Phenyl vinyl ketone was employed as the enone component and thereaction was run at 60 °C.

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The formation of trisubstituted furans is potentially enabled bythis methodology. However, the use of allylic alcohols or enonespossessing 1,1-disubstitution affords only traces of the corre-sponding trisubstituted furan under the conditions reported inTables 1 and 2. This is due to inefficiencies associated with themetathesis step. Undeterred, we decided to examine Heck aryla-tion of the trans-hydroxyenone CM products, and after some ex-perimentation we found that exposure of hydroxyenone 16a andbromotoluene to the mild Heck protocol reported by Fu (31) re-sulted in the formation of furan 17a in 80% yield (Scheme 3).Under these conditions, only traces of furan 8a (<10%) resultingfrom cyclisation of hydroxyenone 16a in advance of Heck aryla-tion were observed. This sequence is amenable to the introduc-tion of diverse aryl substituents at C-3 and generally excellentoverall yields of the furan products 17a-f are achieved. Variationof the hydroxyenone component adds further flexibility and facil-itates regiodefined switching of the substituents at the 2- or 5-po-sitions of the furan ring (c.f. 16b→18 and 16c→20). In the case offuran 18, traces of 1,4-dicarbonyl 19 were also isolated, presum-ably formed via either base or Pd-H mediated isomerization ofthe starting enone 16b; notably this component did not cyclizeto the corresponding furan under the reaction conditions. Thissequence can also be used in an intramolecular setting. Accord-ingly, enone 16d underwent efficient Heck cyclization to affordtricyclic furan 21 along with significant quantities of 1,4-dicarbo-nyl derivative 22. Again, this component did not cyclize under thereaction conditions, even upon extended reaction times, and pre-sumably arises via isomerization after the Heck reaction.

The use of a Heck reaction to trigger aromatization is of inter-est. Our current understanding of this process finds precedence inthe known stereochemical outcome of Heck reactions onto trans-acrylates under the conditions employed here (Scheme 4) (31).Syn-carbopalladation of the enone I mandates σ-bond rotationof II in advance of β-hydride elimination to deliver intermediateIII; this scenario assumes that β-hydride elimination occurs fasterthan epimerization of the σ-Pd bond via an η-3 oxy-π-allyl palla-dium species (32). Cis-hydroxyenones such as III are known toexist in equilibrium with their corresponding hemiketals IV(33) and have been observed to undergo spontaneous furan for-mation (to V) by loss of water (34). To corroborate this mechan-ism, trans-enone 23 was subjected to the Heck conditions andfound to deliver arylated product 24 where the substituents pre-sent in the starting material now reside in a cis-arrangement, as

evidenced by diagnostic NOE enhancements (see SI Text). Athigher conversions, the ratio of 24 to isomeric products decreases.Although this result establishes the feasibility of trans- to cis-iso-merization during the Heck process, the concomitant formationof isomeric products (as an inseparable mixture and character-ized by mass spectrometry only) prevents definitive confirmationthat β-hydride elimination generates the cis-product directly.Note that general Heck protocols involving β-alkylated enoneshave not been reported, presumably due to facile secondaryisomerization of the initial adducts (35, 36). Furan formationvia the intermediacy of the corresponding 1,4-dicarbonyl (whichcould potentially arise after Heck arylation) is discounted as 25did not afford furan 18 when exposed to the Heck conditions.Additional evidence discounting this pathway lies in our inabilityso far to convert 1,4-dicarbonyl 22 to furan 21, even under forcingconditions (see Scheme 3).

ConclusionsIn summary, unique examples of the use of olefin CM as a meansof accessing heteroaromatic compounds have been described.The present work illustrates the power of this approach in termsof highly direct and controlled entries to di- and trisubstitutedfurans. The synthesis of the latter relies upon the strategic em-ployment of a Heck arylation to effect C-C bond formation withconcomitant aromatisation. The chemistry described here, whichcapitalizes upon readily available components, is both direct andregiocontrolled. As such, widespread application is anticipated.

Scheme 2 RCM-furanization approach to the cembranolide macrocycle.

Scheme 3 CM-Heck approach to trisubstituted furans. Asterisks indicate con-tamination with ca. 5% of non-arylated furan.

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MethodsFull experimental details and compound characterization data are includedin SI Text.

General Procedure for the Synthesis of 2,5-Disubstituted Furans. A resealablereaction tube, fitted with a magnetic follower, was charged with Grubbs–Ho-veyda second generation catalyst (5 mol%) and PPTS (2.5 mol%). The tubewas then sealed with a rubber septum and purged with argon. Argonsparged CH2Cl2 (0.25Mwith respect to the allylic alcohol employed) was thenadded via syringe, and the tube was cooled to −78 °C prior to sequential ad-dition of the requisite enone (250 mol% or 500 mol%) and allylic alcohol(100 mol%). The rubber septum was then replaced with a screw cap andthe tube was heated at 40 °C (oil bath temperature) for 24 h. After coolingto room temperature, the reaction mixture was concentrated in vacuo andthe residue was filtered through a short cartridge of SiO2 (eluting with 10∶1petrol-EtOAc). The fractions containing the target furan were combined andconcentrated in vacuo. Purification of the residue by flash column chroma-tography afforded the corresponding furan.

General Procedure for the Synthesis of 2,3,5-Trisubstituted Furans. (A) OlefinCM step: An argon purged reaction flask, fitted with a magnetic follower,was charged with Grubbs–Hoveyda second generation catalyst (2.5 mol%)and argon sparged CH2Cl2 (0.25 M with respect to the allylic alcohol em-ployed). The requisite enone (500 mol%) and allylic alcohol (100 mol%) werethen added sequentially via syringe. The mixture was stirred at room tem-perature for 24 h and then concentrated in vacuo. Purification of the residueby flash column chromatography afforded the corresponding trans-γ-hydro-xyenone. (B) Heck step: A reaction tube, fitted with magnetic follower, wascharged with Pd2ðdbaÞ3 (5 mol%), Pt-Bu3HBF4 (20 mol%), and (if solid) thecorresponding aryl bromide (250 mol%). The tube was sealed with a septumand purged with argon. The requisite trans-γ-hydroxyenone (100 mol%), thecorresponding aryl bromide (if liquid) (250 mol%), anhydrous p-dioxane(0.1 M with respect to the enone component) and then Cy2NMe (250 mol%) were added sequentially via syringe. The mixture was then heated ateither 70 °C or 85 °C for 16 h. The mixture was cooled to room temperatureand filtered through a short cartridge of SiO2 (eluting with 10∶1 petrol-EtOAc). The fractions containing the target furan were combined and con-centrated in vacuo. Purification of the residue by flash column chromatogra-phy afforded the corresponding furan.

ACKNOWLEDGMENTS. We thank the EPSRC for supporting this project. Merckis thanked for unrestricted funding.

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Scheme 4 Proposed mechanism for the tandem Heck-furan formation se-quence and some preliminary mechanistic experiments.

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