Article Visible-Light Photocatalytic E to Z of Activated Olefins and Its Application for the Syntheses of Coumarins

Kun Zhan and Yi Li * Department of , Xi’an Jiaotong-Liverpool University, Suzhou 215123, China; [email protected] * Correspondence: [email protected]; Tel.: +86-0512-8816-1431

Received: 17 October 2017; Accepted: 7 November 2017; Published: 9 November 2017

Abstract: Photocatalytic isomerization of thermodynamically stable E- to less stable Z-alkene has been the subject of numerous studies, being successfully achieved mainly under UV irradiation. Recent development of visible light photoredox has witnessed it emerging as a powerful tool for the access of new structural complexity and many challenging targets. Herein, we report a visible light-promoted E to Z isomerization of cinnamates. When E- of cinnamates was irradiated with blue light in the presence of an organo-photocatalyst, fac-Ir(ppy)3, Z-isomer was exclusively obtained in high yields and with good selectivity. The mild, convenient reaction condition has made this protocol an effective synthetic methodology, which was subsequently implemented in an efficient synthesis of coumarins.

Keywords: E to Z isomerization; ; visible-light; photoredox catalyst; coumarin

1. Introduction Photocatalysis under UV activation have been studied and developed for many decades and show capability of promoting the construction of a wide variety of nontraditional bonds in organic synthesis [1–3]. Recently, visible light photocatalysis emerged as an attractive strategy for activation of small , when the is initiated mainly by the light-absorbing photocatalyst, providing mild conditions and high tolerance [4–8]. Alkene has been widely used in organic synthesis as one of the most important building blocks and the essential intermediates in numerous organic transformations. The synthesis of alkene, especially alkene with specific geometry, had been the area of many efforts since the early era of organic chemistry, and is still the field of invention for modern organic synthesis. Over the decades, many methods have been established to obtain the thermodynamically more stable E-alkenes, however the reliable approaches to access the less stable Z-alkene are far less common [9–12]. For example, traditional Wittig reaction with unstable yield [13], alkyne hydrogenation, silicon-based stereospecific elimination and contemporary cross-coupling reaction [14], and cross-metathesis [15] are among a few methods which have so far enjoyed widespread applications, due to their simplicity, convenience, and relatively high geometrical control. The direct photocatalytic E to Z isomerization of alkene, still considered as a fancy reaction in textbooks, has not yet won recognition as an orthodox method for the synthesis of Z-alkene and is a reaction of last resort. However, it has been well established that photochemical activation via a sensitizer, traditionally iodine [16], dyes; and currently photocatalyst [17], riboflavin [18], etc. can convert light into chemical and assist to circumvent the ‘uphill’ energy barrier of E to Z isomerization of alkene. The rotational barrier, which restricts the rotation about the on the ground state, mitigates when the olefin is subjected to the photochemical excitation at an appropriate wavelength. Promotion of an electron by excitation from a π orbital to a π* orbital decreases the bond

Catalysts 2017, 7, 337; doi:10.3390/catal7110337 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 337 2 of 9 appropriate wavelength. Promotion of an electron by excitation from a π orbital to a π* orbital decreases the bond order and permits the rotation and subsequent relaxation to the ground state [19]. The isomerization of alkenes starts with triplet and singlet excited states, and a change in geometry leads toCatalysts this 2017twisted, 7, 337 intermediate in form of zwitterionic or diradical. The sensitizers with2 of a 9 triplet state have higher energy than that of the of the substrates, proving to be efficient for isomerizationorder and [20]. permits the rotation and subsequent relaxation to the ground state [19]. The isomerization Numerousof alkenes starts studies with on triplet theoretical and singlet perspectives excited states, and and synthetic a change inapplications geometry leads have to thisbeen twisted conducted. In 2014,intermediate Weaver discovered in form of zwitterionic an isomerization or diradical. of E The‐alkene sensitizers to Z‐isomer with a triplet using state blue have LED higher (light energy‐emitting diode)than source, that via of the a photochemical excited state of the pumping substrates, mechanism, proving to be mediated efficient for by isomerization transition‐metal [20]. photocatalyst Numerous studies on theoretical perspectives and synthetic applications have been conducted. [21]; however, the application of this method was limited to an allylamine system (Scheme 1a). In In 2014, Weaver discovered an isomerization of E-alkene to Z-isomer using blue LED (light-emitting 2015, Gilmourdiode) source, reported via a photochemical a bio‐inspired, pumping catalytic mechanism, E to Z mediatedisomerization by transition-metal of activated photocatalyst olefin, (Scheme [21]; 1b), translatinghowever, Nature the’ applications falvin‐mediated of this method photo was‐isomerization limited to an into allylamine the prototype system (Scheme of small1a). In 2015, [18]. The transformationGilmour reported was a bio-inspired,successfully catalytic achievedE toviaZ aisomerization selective UV of‐light activated irradiation olefin, (Scheme at 402 1nm.b), More recently,translating Wang andNature’s Zhaifalvin-mediated disclosed a blue photo-isomerization‐light‐promoted into carbon–carbon the prototype double of small bond molecule isomerization [18]. and itsThe application transformation in the was syntheses successfully of achieved quinolines via a selectivein the absence UV-light of irradiation photocatalyst at 402 nm. [22]. More recently, DuringWang and our Zhai investigation disclosed a of blue-light-promoted synthetic utilities carbon–carbon of visible‐lightdouble photoredox bond isomerization catalysts and for its carbon– application in the syntheses of quinolines in the absence of photocatalyst [22]. carbon coupling reaction, it was noticed that the (E)‐ethyl cinnamates could undergo an isomerization During our investigation of synthetic utilities of visible-light photoredox catalysts for to formcarbon–carbon its Z‐isomer couplingin the presence reaction, of it photoredox was noticed catalyst, that the this (E)-ethyl observation cinnamates prompted could undergo us to explore the probabilityan isomerization and potential to form its ofZ-isomer this transformation. in the presence of Herein, photoredox we catalyst,report the this observationoutcomes of prompted this work, in which usE to Z explore isomerization the probability occurred and potential when E of‐activated this transformation. olefins were Herein, irradiated we report with the blue outcomes light in the presenceof this of organic work, in photocatalyst, which E to Z isomerization fac‐Ir(ppy)3 occurred, to form when its Z‐Eisomer-activated in high olefins yields were irradiatedand good with selectivity (Schemeblue 1c), light and in the presencesynthetic of applications organic photocatalyst, of this transformationfac-Ir(ppy)3, to form was its perfectlyZ-isomer demonstrated in high yields by a facile synthesisand good selectivityof coumarins (Scheme (Scheme1c), and 1d). the syntheticWhile the applications alkene isomerization of this transformation has been was achieved perfectly mostly demonstrated by a facile synthesis of coumarins (Scheme1d). While the alkene isomerization has been with UV activation, this transformation could easily progress via the activation of visible‐light with achieved mostly with UV activation, this transformation could easily progress via the activation of a photoredoxvisible-light catalyst. with a photoredox catalyst.

SchemeScheme 1. Photocatalytic 1. Photocatalytic E to Z isomerizationisomerization of olefins.of olefins.

Catalysts 2017, 7, 337 3 of 9

2. ResultsCatalysts and2017, Discussion7, 337 3 of 9 Starting from the first observation, we further investigated the photo‐isomerization of (E)‐ethyl cinnamates2. Results under and Discussionvarious reaction conditions. It was verified that this transformation occurred in the presence Startingof fac‐Ir(ppy) from the3 first(5 mol observation, %) under we visible further‐light investigated irradiation the photo-isomerization with blue light, ofleading (E)-ethyl to the formationcinnamates of its under Z‐isomer various with reaction a modest conditions. selectivity It was of verifiedZ/E 65:35 that (Table this transformation 1, entry 1). The occurred reaction in was carriedthe out presence at room of fac temperature-Ir(ppy)3 (5 moland %)finished under in visible-light a quantitative irradiation yield, withthe products blue light, were leading purified to the after a simpleformation filtration of its to Z-isomer remove with the a catalyst modest selectivityfrom the ofreactionZ/E 65:35 mixture. (Table1 ,Further entry 1). experiments The reaction wasrevealed that carriedthe photocatalyst out at room temperaturewas essential and for finished the success in a quantitative of this reaction, yield, the no products isomerization were purified product after could be detecteda simple in filtration the absence to remove of catalyst the catalyst (entry from 2). Encouraged the reaction by mixture. the initial Further results, experiments we examined revealed several catalysts,that the sensitizers photocatalyst for wasthis essential photo‐catalytic for the success transformation of this reaction, and no we isomerization found that product transition could‐metal photoredoxbe detected catalysts in the would absence generally of catalyst catalyze (entry 2). this Encouraged reaction, but by theproduced initial results, diverse we Z examined/E selectivity, several catalysts, sensitizers for this photo-catalytic transformation and we found that transition-metal iridium catalyst performed better than its ruthenium counterpart (entries 3 and 4), with fac‐Ir(ppy)3 photoredox catalysts would generally catalyze this reaction, but produced diverse Z/E selectivity, as the catalyst of choice to give the best selectivity. The varied catalytic activities could directly relate iridium catalyst performed better than its ruthenium counterpart (entries 3 and 4), with fac-Ir(ppy)3 to theas different the catalyst emissive of choice to give of the the best catalysts selectivity. used in The the varied investigation. catalytic activitiesfac‐Ir(ppy) could3 catalyst, directly which has a greater emissive energy (494 nm, 57.8 kcal mol−1) than the Ru(bpy)3Cl2 catalyst (615 nm, 46.5 relate to the different emissive energies of the catalysts used in the investigation. fac-Ir(ppy)3 catalyst, −1 −1 kcal whichmol ) has [8,23], a greater supposedly emissive energyefficiently (494 nm,promotes 57.8 kcal the mol energy) than transfer the Ru(bpy) to the3Cl 2substrate,catalyst (615 its nm, longer excited46.5‐state kcal mollifetime−1)[8 ,could23], supposedly also facilitate efficiently this promotesprocess [24]. the energy It is worth transfer noting to the that substrate, (−)‐riboflavin its longer only showedexcited-state marginal lifetime effect could on the also isomerization facilitate this processunder [visible24]. It islight worth condition, noting that compared (−)-riboflavin with its significantonly showed performance marginal under effect onUV the light isomerization (entry 5). under Rose visible Bengal, light the condition, organic compared sensitizers, with did its not performsignificant well either, performance the Z/E under ratio UVcould light only (entry reached 5). Rose 8:92 Bengal, in 24 h the under organic the sensitizers, reaction conditions did not perform (entry 6). well either, the Z/E ratio could only reached 8:92 in 24 h under the reaction conditions (entry 6). Table 1. Selected optimization of reaction conditions 1 Table 1. Selected optimization of reaction conditions 1.

Loading of Cat. Other Entry Catalyst Loading of Solvent Other Z/E Ratio 2 Entry Catalyst (mol %) Solvent Conditions Z/E Ratio 2 Cat. (mol %) Conditions 1 fac-Ir(ppy)3 5 MeCN - 65:35 1 fac‐Ir(ppy)3 5 MeCN ‐ 65:35 2 none 5 MeCN - 1:99 2 none 5 MeCN ‐ 1:99 3 Ru(bpy)3Cl2 5 MeCN - 18:82 + 43 Ir(ppy)Ru(bpy)2(dtbbpy)3Cl2 55 MeCNMeCN ‐ -18:82 31:69 54 Ir(ppy) (−)-riboflavin2(dtbbpy)+ 55 MeCNMeCN ‐ -31:69 8:92 65 Rose(−)‐riboflavin bengal 55 MeCNMeCN ‐ -8:92 6:94 7 fac-Ir(ppy) 5 acetone - 37:63 6 Rose bengal3 5 MeCN ‐ 6:94 8 fac-Ir(ppy)3 5 DMF - 2:98 3 97 facfac-Ir(ppy)‐Ir(ppy)3 55 acetone DCM ‐ -37:63 2:98 108 facfac-Ir(ppy)‐Ir(ppy)3 3 55 THFDMF ‐ -2:98 2:98 119 facfac-Ir(ppy)‐Ir(ppy)3 3 35 MeCNDCM ‐ -2:98 68:32 12 fac-Ir(ppy)3 1 MeCN - 75:25 10 fac‐Ir(ppy)3 5 THF ‐ 2:98 13 fac-Ir(ppy)3 1 MeCN DIPEA 72:28 11 fac‐Ir(ppy)3 3 MeCN ‐ 68:32 14 fac-Ir(ppy)3 1 MeCN degassed 73:27 12 fac‐Ir(ppy)3 1 MeCN ‐ 75:25 1 Reaction conditions: Reactions were performed with 0.2 mmol of substrates in indicated solvent (0.1 M) at room temperature13 in the presencefac‐Ir(ppy) of catalyst3 under 24 h1 of blue light irradiation.MeCN 2 Z/EDIPEAratios were determined72:28 by GC/MS (gas –mass14 fac‐Ir(ppy) spectrometry).3 1 MeCN degassed 73:27 1 Reaction conditions: Reactions were performed with 0.2 mmol of substrates in indicated solvent (0.1 M)A screening at room temperature of common in solvents the presence had identified of catalyst acetonitrile under 24 h asof theblue best light solvent irradiation. for this 2 Z reaction,/E ratios providingwere determined the best by efficiency GC/MS (gas and Zchromatography–/E ratio of the products, spectrometry). the reaction carried out in other solvents either afforded worse selectivity (such as acetone) or were not productive at all (such as DMF (dimethylformamide),A screening of common DCM solvents (dichloromethane), had identified and THF acetonitrile (tetrahydrofuran)) as the best (entries solvent 7–10). for In this contrast, reaction, providingWeaver the et al.best [21 efficiency] described and that Z the/E photochemical ratio of the products, isomerization the reaction of cinnamyl carried derived out amine in other worked solvents eitherwell afforded in all these worse solvents. selectivity Currently, (such it is as not acetone) clear why or the were same not trend productive was not observed at all in(such this case,as DMF (dimethylformamide), DCM (dichloromethane), and THF (tetrahydrofuran)) (entries 7–10). In contrast, Weaver et al. [21] described that the photochemical isomerization of cinnamyl derived amine worked well in all these solvents. Currently, it is not clear why the same trend was not observed in this case, as a reductive quenching mechanism was proposed in their studies. It is likely

Catalysts 2017, 7, 337 4 of 9 as a reductive quenching mechanism was proposed in their studies. It is likely that these solvents stabilize the radical cation intermediate involved, while acetonitrile helps to elongate the lifetime of triplet excited states [25–29] or stabilize biradical intermediates in an energy transfer mechanism as suggested for our work. Acetone, a typical solvent which can be used as a sensitizer, was not effective enough by itself to achieve good transformation in this reaction. While the presence of photocatalyst was indispensable for the success of this reaction (entry 2), it is interesting to observe that the efficiency of E to Z isomerization was facilitated by the lower loading of photocatalyst for the reaction, which supposedly helps to reduce the self-quenching and avoid the general issue related to the lack of light penetration into solution, due to the high molar extinction coefficients of the photocatalyst (entries 11 and 12). The better results were obtained with 1 mol % of photocatalyst used in the reaction with the concentration of substrate at 0.1 M. The effect of external base on this isomerization was also studied with N,N-diisopropylethylamine (DIPEA, 10 mol %), (entry 13), there was no obvious influence noticed on the reaction efficiency. In their work, Weaver reported that the presence of air prevented the isomerization of allylamine from occurring [21], however, our experiments did not show that our reaction was air-sensitive, degassing the reaction mixture did not make the results any different (entry 14). With the optimized reaction conditions in hand, we continued to examine the scope of E-olefins applicable in such transformation (Scheme2). Various ( E)-ethyl cinnamates—with electron-donating, electron-withdrawing, and neutral at the para-position of ring—could proceed effectively to give the isomerization product (Z)- with modest of selectivity (1a–1g). The electronic properties of these substituents did not show apparent effects on the selectivity of this transformation, the Z/E selectivity of these reactions fell in the range from 60:40 to 75:25. Under the reaction condition, the substituents, such as F-, MeO-, Cl-, CF3-, and Br-, were well tolerated, there were no other byproducts could be detected along with the two isomers of the alkene, which made this reaction clean and practically very easy for workup. In addition, when (E)-cinnamyl aldehyde, (E)-α,β-unsaturated ketones were subjected to the reaction conditions, the corresponding Z-isomers were obtained with similar selectivity (1h–1j). The selectivity of this isomerization could be greatly enhanced by small modifications of the structures, when a , such as methyl- or ethyl- was introduced onto the β-position of double bond in (E)-ethyl cinnamates (1k–1m), a Z/E ratio as high as 98:2 could be attained. As reported by Gilmour in their seminal work [18], adjustment of the A 1,3-strain in the Z isomer by subtle alteration of the substitution on the double bond system could control efficiently the geometric outcome of this isomerization. Consistent with their findings, the isomerization of heterocycle substituted ethyl acrylates (2n, 2o, 2p), even with a β-substituent, could not reproduce the high selectivity shown by their aromatic counterparts, as the replacement of the six-membered aromatic ring with the less bulky five-membered heterocyclic ring reduces A 1,3-strain in the Z isomer, leading to an erosion of selectivity. Further investigation revealed that this visible light E to Z photoisomerization only occurred on the studied cinnamates system, the efforts on the other structural system, which lacks the essential conjugation when either the aromatic ring or the carbonyl functional group is missing (1q, 1r), were disappointingly futile, indicating the limitations of this isomerization. The photoisomerization of alkene has been studied extensively using higher-energy UV light for the activation of the isolated double bond. The direct energy transfer generates the excited states of the substrate, which induces cleavage of the double bond to form , biradicals, or radical pairs, providing a chance for the isomerization to proceed. On the other hand, the introduction of conjugated π system to the double bond can significantly decrease the energy gap between the ground state and excited state, making it possible for the isomerization to occur with low-energy light to be used as the source of activation, especially with the aid of photocatalysts, which have witnessed great development in the past decade. Catalysts 2017, 7, 337 5 of 9 Catalysts 2017, 7, 337 5 of 9

Scheme 2.2.Scope Scope of photocatalyticof photocatalytic isomerization isomerization of α,β -unsaturatedof α,β‐unsaturated carbonyl compounds.carbonyl compounds.a Reaction a Reaction conditions: (E)‐α,β‐unsaturated carbonyl compound (0.2 mmol) and fac‐Ir(ppy)3 (0.002 conditions: (E)-α,β-unsaturated carbonyl compound (0.2 mmol) and fac-Ir(ppy)3 (0.002 mmol, mmol,1 mol %)1 mol were %) dissolved were dissolved in 2 mL MeCN,in 2 mL at MeCN, room temperature at room temperature under 24 hunder of blue 24 light h of irradiation; blue light b c irradiation;b Isolated Yields; Isolatedc Z/Yields;E ratios Z were/E ratios determined were determined by GC/MS. by GC/MS.

From the results of our work, it is clearly demonstrated that organo‐photoredox catalyst—such From the results of our work, it is clearly demonstrated that organo-photoredox catalyst—such as fac‐Ir(ppy)3—can facilitate the energy transfer from visible light to the cinnamates system for the as fac-Ir(ppy) —can facilitate the energy transfer from visible light to the cinnamates system for the activation of 3the double bond. A plausible pathway was thus proposed, based on the literature activation of the double bond. A plausible pathway was thus proposed, based on the literature precedents [18,30] and experimental data (Scheme 3). Absorbing a photon, the photocatalyst PC(S0) precedents [18,30] and experimental data (Scheme3). Absorbing a photon, the photocatalyst PC(S 0) in its singlet ground state is excited to the first singlet excited state *PC(S1), which relaxes to the lowest in its singlet ground state is excited to the first singlet excited state *PC(S1), which relaxes to the energy triplet excited state *PC(T1) via successive fast intersystem crossing (ISC) (–orbital lowest energy triplet excited state *PC(T ) via successive fast intersystem crossing (ISC) (spin–orbital coupling) and internal conversion (vibrational1 relaxation). Since the transition of the triplet excited coupling) and internal conversion (vibrational relaxation). Since the transition of the triplet excited state to the singlet ground state is spin forbidden, the triplet excited state *PC(T1) is reasonably long state to the singlet ground state is spin forbidden, the triplet excited state *PC(T ) is reasonably lived. In photocatalysis, the photo‐excited catalyst can be quenched by the substrates via1 outer‐sphere long lived. In photocatalysis, the photo-excited catalyst can be quenched by the substrates via single electron transfer (SET) or energy transfer (ET) processes, leading to productive transformation. outer-sphere single electron transfer (SET) or energy transfer (ET) processes, leading to productive It is difficult to completely exclude a single electron transfer (SET) pathway in our visible‐light transformation. It is difficult to completely exclude a single electron transfer (SET) pathway in our photocatalytic E‐to‐Z isomerization, However, this pathway was ruled out as the addition of a visible-light photocatalytic E-to-Z isomerization, However, this pathway was ruled out as the addition sacrificial reductant (e.g., trimethylamine, N,N‐Diisopropylethylamine), the classical strategy to of a sacrificial reductant (e.g., trimethylamine, N,N-Diisopropylethylamine), the classical strategy promote photoredox reaction [8,31], did not facilitate this transformation. Thus, we tentatively to promote photoredox reaction [8,31], did not facilitate this transformation. Thus, we tentatively proposed that an energy transfer process occurs between the photo‐excited triplet state *PC(T1) and proposed that an energy transfer process occurs between the photo-excited triplet state *PC(T ) and the accessible low energy triplet state of cinnamates substrate in this isomerization. The triplet–triplet1 the accessible low energy triplet state of cinnamates substrate in this isomerization. The triplet–triplet energy transfer regenerates the ground state of the photocatalyst and results in the substrate of an excited triplet state to engage in the photochemical isomerization reactions.

Catalysts 2017, 7, 337 6 of 9 energy transfer regenerates the ground state of the photocatalyst and results in the substrate of anCatalysts excited 2017 triplet, 7, 337 state to engage in the photochemical isomerization reactions. 6 of 9

Scheme 3.3.Plausible Plausible pathway pathway for thefor visible-light the visible photocatalytic‐light photocatalyticE to Z isomerization. E to Z isomerization. PC: photocatalyst; PC:

Q:photocatalyst; quencher (substrate); Q: quencher ISC: intersystem(substrate); crossing;ISC: intersystem S0: singlet crossing; ground state;S0: singlet S1: first ground singlet state; excited S1: state;first

andsinglet T1 :excited first triplet state; excited and T1 state.: first triplet excited state.

The selectivity of the isomerization is reliant on the different rates of the photoquenching of the excited photocatalyst by the two isomers. There is strong evidence [18,21] [18,21] to suggest that E-isomer‐isomer quenches the photoexcited state of the catalyst at a speed much much faster faster that that its its counterpart counterpart of of ZZ‐-isomer,isomer, thus resulting in the buildup of Z-isomer‐isomer in thisthis process,process, which, in turn,turn, is relatedrelated with physical structures of the two isomers, as better conjugation is possessed in the E-isomer‐isomer and the substituents on the Z-double‐double bond are forced out of planeplane byby thethe stericsteric hindranceshindrances toto generategenerate deconjugationdeconjugation in Z-isomer.‐isomer. Under thethe optimized reactionreaction condition,condition, thethe bestbest ZZ//E ratio we could manage to achieve for the isomerization of (E)-ethyl)‐ethyl cinnamates was 75:25 in 24 h. A time-coursetime‐course analysis of the reaction of (Z)-ethyl)‐ethyl cinnamates,cinnamates, monitored monitored by by GC/MS, GC/MS, revealed revealed that thisthat photo-stationarythis photo‐stationary state could state be could reached be inreached 2 h. Interestingly, in 2 h. Interestingly, the selectivity the selectivity of isomerization of isomerization could be could finely be tuned finely by tuned the introduction by the introduction of more substituentsof more substituents on the double on the bond double or the bond aromatic or the ring aromatic itself, which ring affectsitself, which the degree affects of deconjugationthe degree of indeconjugationZ-isomer. in Z‐isomer. Encouraged by this successful isomerization of cinnamates, we reckoned that this facile isomerization of alkenes under mild reaction conditions created an attractive synthetic methodology to circumvent circumvent the the encumbrance encumbrance rendered rendered by bythe thedouble double bond, bond, thus useful thus useful for application for application in organic in organicsynthesis. synthesis. Coumarins, the important structural motifs in natural products and bioactive compounds, exhibiting broad biological activities, have have been been the the targets for many organic syntheses [32–34]. [32–34]. Among many successful methods developed over the years, cyclization of ortho-hydroxycinnamates‐hydroxycinnamates via double-bonddouble‐bond isomerization was the one which was generallygenerally convenient from easily obtained starting material and and afforded afforded the the coumarins coumarins in in very very good good yields. yields. A Atraditional traditional method method adopted adopted to toovercome overcome the the kinetic kinetic and and energetic energetic barrier barrier against against this this isomerization isomerization includes includes high high temperatures, boron tribromide, and nucleophile. The first first synthesis via photochemical double double-bond‐bond isomerization was achieved by HoraguchiHoraguchi [[35],35], whenwhen aa 400400 WW high-pressurehigh‐pressure mercurymercury lamplamp waswas employed. employed. We decided decided to to test test our our optimized optimized reaction reaction conditions conditions on the onsynthesis the synthesis of coumarin of coumarinand were anddelighted were to delighted found that to the found transformations that the transformations could completed could in 24 h completed (Scheme 4). in Generally 24 h (Scheme ortho‐(4E).)‐ Generallyhydroxycinnamates,ortho-(E)-hydroxycinnamates, which contain various which substituents, contain various underwent substituents, the visible underwent light‐promoted the visible E‐to‐ light-promotedZ isomerizationE-to-Z readilyisomerization and the generated readily Z and isomers the generated could undergoZ isomers lactonization could undergo smoothly lactonization to afford smoothlythe coumarin to afford compounds the coumarin in very compounds high yields in very (4a– high4j). This yields effectively (4a–4j). This demonstrated effectively demonstratedthe synthetic thepotential synthetic of this potential protocol of for this future protocol applications for future in applications the target synthesis. in the target synthesis.

Catalysts 2017, 7, 337 7 of 9 Catalysts 2017, 7, 337 7 of 9

a SchemeScheme 4. 4.Synthesis Synthesis of of coumarin coumarin compounds compounds viavia photochemical isomerization. isomerization. Reactiona Reaction conditions: conditions: Specified ortho‐hydroxycinnamates (0.2 mmol) and fac‐Ir(ppy)3 (0.002 mmol, 1 mol %) were dissolved Specified ortho-hydroxycinnamates (0.2 mmol) and fac-Ir(ppy)3 (0.002 mmol, 1 mol %) were dissolved in 2 mL MeCN, the mixture was stirred under blue light irradiation for 24 h at room temperature. b in 2 mL MeCN, the mixture was stirred under blue light irradiation for 24 h at room temperature. Isolated yields. b Isolated yields. 3. Experimental Details 3. Experimental Details 3.1. General Procedure for the Isomerization of α,β‐Unsaturated Carbonyl Compounds 3.1. General Procedure for the Isomerization of α,β-Unsaturated Carbonyl Compounds The specified α,β‐unsaturated carbonyl compound (0.2 mmol) and fac‐Ir(ppy)3 (0.002 mmol, 1 molThe %) specified were dissolvedα,β-unsaturated in 2 mL MeCN, carbonyl the mixture compound was stirred (0.2 mmol) under andblue faclight-Ir(ppy) (36 W,3 (0.002fluorescent mmol, 1 molbulb, %) peak were wavelength dissolved 445 in 2 nm, mL FWHM MeCN, (full the mixture width at was half stirredmaximum) under 50 blue nm) lightirradiation (36 W, for fluorescent 24 h at bulb,room peak temperature. wavelength The 445 reaction nm, FWHMwas monitored (full width by GC at‐MS half (Agilent maximum) 5975C 50 Triple nm) Axis irradiation GC‐MS, forSanta 24 h atClara, room temperature.CA, USA). After The the reaction trans‐isomer was monitored reaches maximum by GC-MS conversion (Agilent 5975C to cis‐ Tripleisomer, Axis MeCN GC-MS, is Santaremoved Clara, under CA, USA). reduced After pressure. the trans-isomer The crude product reaches was maximum purified conversion by flash chromatography to cis-isomer, MeCN using is removedn‐ under and diethyl reduced pressure. as eluent. The crude product was purified by flash chromatography using n-hexane and as eluent. 3.2. General Procedure for the Synthesis Ortho‐Hydroxycinnamates (3) 3.2. General Procedure for the Synthesis Ortho-Hydroxycinnamates (3) To a solution of salicylaldehyde (10 mmol) in dry CH2Cl2 (40 mL) was added (carbethoxymethylene)triphenylphosphoraneTo a solution of salicylaldehyde (10 mmol) in (15 dry mmol, CH2Cl 1.52 (40 equiv.) mL) was and added the reaction (carbethoxymethylene) mixture was triphenylphosphoranestirred at room temperature (15 mmol, for 2 1.5 h. After equiv.) the and reaction the reaction completed, mixture the solvent was stirred was concentrated at room temperature under forreduced 2 h. After pressure. the reactionThe residue completed, was purified the by solvent flash waschromatography concentrated using under n‐hexane reduced and pressure. ethyl Theacetate residue as eluent was purified(see Supplementary by flash chromatography Materials). using n-hexane and ethyl acetate as eluent (see Supplementary Materials). 3.3. General Procedure for the Synthesis of Coumarin (4) 3.3. General Procedure for the Synthesis of Coumarin (4) The specified ortho‐hydroxycinnamates (0.2 mmol) and fac‐Ir(ppy)3 (0.002 mmol, 1 mol %) were dissolved in 2 mL MeCN, the mixture was stirred under blue light (36 W, fluorescent bulb) irradiation The specified ortho-hydroxycinnamates (0.2 mmol) and fac-Ir(ppy)3 (0.002 mmol, 1 mol %) were dissolvedfor 24 h inat 2room mL MeCN,temperature. the mixture The reaction was stirred was monitored under blue by lightGC‐MS. (36 When W, fluorescent the reaction bulb) completed, irradiation forMeCN 24 h at was room removed temperature. under The reduced reaction pressure. was monitored The crude by GC-MS. product When was the purified reaction by completed, flash MeCNchromatography was removed using under n‐hexane reduced and pressure. ethyl acetate The crude as eluent product (see was Supplementary purified by flashMaterials). chromatography using n-hexane and ethyl acetate as eluent (see Supplementary Materials). 4. Conclusions 4. ConclusionsIn summary, we have discovered that the isomerization of thermodynamically stable E‐alkene to less‐stable Z‐alkene could be achieved under visible‐light irradiation in the presence of organo‐ In summary, we have discovered that the isomerization of thermodynamically stable E-alkene photocatalyst, fac‐Ir(ppy)3. Z‐isomer of cinnamates could be easily obtained in good yields and to less-stable Z-alkene could be achieved under visible-light irradiation in the presence of organo-

Catalysts 2017, 7, 337 8 of 9

photocatalyst, fac-Ir(ppy)3. Z-isomer of cinnamates could be easily obtained in good yields and selectivity. Consistent with the previous report, the selectivity of isomerization was able to be tuned by the introduction of substituents on the double bond or the aromatic ring itself. The mild, convenient reaction conditions make this transformation an effective methodology for organic synthesis, which was properly demonstrated with a successful application in the synthesis of biological active coumarin compounds.

Supplementary Materials: The following are available online at www.mdpi.com/2073-4344/7/11/337/s1, Experimental procedure and spectral data for the precursors and final products. Acknowledgments: The authors thank the Jiangsu Science and Technology Program (Basic Research Program) (Grant No. BK20131180) for the funding, and XJTLU RDF (Research Development Fund) for PhD scholarship to K.Z. Author Contributions: Y.L. conceived and designed the experiments; K.Z. performed the experiments and analyzed the data; Y.L. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.


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