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Solvent-Free Mizoroki-Heck Reaction Applied to the Synthesis of Abscisic catalysts Article SolventSolvent-Free‐Free Mizoroki-HeckMizoroki‐Heck Reaction Applied to the Synthesis of Abscisic Acid and Some Derivatives Geoffrey DumonteilDumonteil, IDMarie, Marie-Aude‐Aude Hiebel Hiebel andID Sabineand Sabine Berteina Berteina-Raboin‐Raboin * * ID Institut de Chimie Organique et Analytique (ICOA), UniversitUniversitéé d’Orld’Orléanséans UMR CNRS 7311,7311, BPBP 6759,6759, rue de Chartres, 45067 Orleans CEDEX 2, France; Geoffrey.Dumonteil@sanofi[email protected] (G.D.);(G.D.); [email protected]‐aude.hiebel@univ‐orleans.fr (M. (M.-A.H.)‐A.H.) * Correspondence: [email protected];sabine.berteina‐raboin@univ‐orleans.fr; Tel.: +33-238-494-856+33‐238‐494‐856 Received: 28 February 2018; Accepted: 13 March 2018; Published: date 15 March 2018 Abstract: Abscisic acid acid (ABA) (ABA) is is a a natural natural product, product, which which is is a a well well-known‐known phytohormone. phytohormone. However, However, this molecule has recently exhibited interesting biological activities, emphasizing the the need for a simple and direct access to new analogues based on the ABA framework. Our strategy relies on a palladopallado-catalyzed‐catalyzed Mizoroki Mizoroki-Heck‐Heck cross cross-coupling‐coupling as as key key reaction performed in solvent and ligand free conditions. After a careful optimization,optimization, wewe succeededsucceeded inin accessingaccessing variousvarious ((EE//Z))-dienes‐dienes and (E/EE//ZZ)‐)-trienestrienes in in moderate moderate to to good good yields yields without without isomerization isomerization and and applied applied the the same same approach approach to the synthesis of ABA in an environmentally sound manner. Keywords: MizorokiMizoroki-Heck;‐Heck; abscisic acid; solvent solvent-free‐free 1. Introduction Polyenic scaffolds scaffolds constitute constitute an an important important functionality functionality among among organic organic compounds compounds and and have have a higha high synthetic synthetic interest interest since since medicinally medicinally relevant relevant molecules molecules and and natural natural products products exhibit diene fragments (Figure 1 1))[ [1].1]. OH O OMe OH HO EtO O Modiolin Dolatrienic acid OH O O OH O N H HO O N Abscisic acid Trichostatin A Figure 1. ExamplesExamples of biologically active natural products containing diene moieties. Several synthetic methods have therefore been developed to obtain these carotenoid moieties in Several synthetic methods have therefore been developed to obtain these carotenoid moieties in iterative process or in convergent methods [2]. Traditionally, the olefination reaction was extensively iterative process or in convergent methods [2]. Traditionally, the olefination reaction was extensively used. However, it is often associated with the uncontrolled production of E and Z isomers which may used. However, it is often associated with the uncontrolled production of E and Z isomers which may require careful purification [3]. Then transition metal‐catalyzed cross‐coupling reactions galvanized require careful purification [3]. Then transition metal-catalyzed cross-coupling reactions galvanized the synthesis of these complex conjugated molecules. Catalysts such as ruthenium [4], zirconium [5– the synthesis of these complex conjugated molecules. Catalysts such as ruthenium [4], zirconium [5–7], 7], zinc [8] and nickel [9] were successfully used. The use of palladium has been widely reported with zinc [8] and nickel [9] were successfully used. The use of palladium has been widely reported with Negishi [10,11], Stille [12–15], Suzuki‐Miyaura [16–18], Sonogashira [19], Kumada‐Tamao [20] and Catalysts 2018, 8, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts Catalysts 2018, 8, 115; doi:10.3390/catal8030115 www.mdpi.com/journal/catalysts Catalysts 2018, 8, x FOR PEER REVIEW 2 of 9 Mizoroki‐Heck [21–25] cross‐coupling reactions [26–28]. Lately, the use of single unsaturated units as building blocks was promoted to respond to the challenging but crucial control of the configuration of the double bond generated [29–33]. In our effort to develop environmentally benign tools [34–36], we herein report the use of the Mizoroki‐Heck reaction, which requires simple and directly accessible starting materials to build stereocontrolled dienes and trienes. Unlike other cross‐ coupling approaches, which may require several steps to install the pre‐activated partners, the Mizoroki‐Heck reaction enables the direct formation of dienes from terminal olefin substrates. The Catalysts 2018, 8, 115 2 of 9 efficiency of our method was then evaluated in the synthesis of abscisic acid, an important phytohormone [37–43] which has been recently reported to have interesting biological effects [44,45]. Negishi [10,11], Stille [12–15], Suzuki-Miyaura [16–18], Sonogashira [19], Kumada-Tamao [20] and 2.Mizoroki-Heck Results and Discussion [21–25] cross-coupling reactions [26–28]. Lately, the use of single unsaturated units as building blocks was promoted to respond to the challenging but crucial control of the configuration 2.1.of the Optimization double bond of the generated Mizoroki [‐29Heck–33 reaction]. In our effort to develop environmentally benign tools [34–36], we hereinTo achieve report the the optimized use of the conditions, Mizoroki-Heck the cross reaction,‐coupling which reaction requires of simple 1‐ethenyl and‐3 directly‐methylcyclohex accessible‐ 2starting‐en‐1‐ol materials 1 with methyl to build (2 stereocontrolledZ)‐3‐iodobut‐2‐ dienesenoate and 2 was trienes. selected Unlike as other the model cross-coupling reaction approaches, under the whichstandard may conditions require several previously steps todescribed install the by pre-activated Cossy and partners,co‐workers the (Table Mizoroki-Heck 1, entry reaction1) [46]. Surprisingly,enables the direct only formation degradation of dienes was observed. from terminal Since olefin conjugated substrates. products The efficiency are prompted of our to method make wasversatile then rearrangement evaluated in the [47,48], synthesis the ofreaction abscisic was acid, next an performed important phytohormonein a flask protected [37–43 from] which natural has light.been recentlyA small reportedamount of to the have expected interesting product biological 3a was effects isolated [44,45 along]. with the side product 4 (entry 2). The formation of 4 can be explained by a 1,3‐rearrangement of the allylic alcohol, a transformation 2. Results and Discussion previously described by Qu and co‐workers under a thermal activation in water [48]. The use of acetonitrile2.1. Optimization moreover of the Mizoroki-Heckof an additional Reaction ligand induced no positive change (entries 3 and 4) [49]. However, a significant improvement was obtained by replacing silver acetate by silver carbonate and 1.5 equiv.To achieve of silver the carbonate optimized proved conditions, to be the the cross-coupling optimized amount reaction (entries of 1-ethenyl-3-methylcyclohex-2- 5–7). A moderate heating is recommendeden-1-ol 1 with methyl since the (2Z formation)-3-iodobut-2-enoate of 3a was significantly2 was selected reduced as the modelat 80 °C. reaction under the standard conditionsNext, neat previously conditions described were tried, by and Cossy even and if the co-workers reaction mixture (Table1 ,was entry a thick 1) [ paste,46]. Surprisingly,the expected productonly degradation 3a was isolated was in observed. similar yield Since (63%) conjugated in a considerably products shorter are prompted time (1 h vs. to 17 make h). To versatile the best ofrearrangement our knowledge, [47, 48this], theis the reaction first example was next of performedneat Mizoroki in a‐Heck flask protected reaction for from the natural formation light. of Adienes. small Theamount vinylation of the expected of acrylic product substrates3a washas been isolated already along reported with the in side solvent product‐free4 conditions(entry 2). The but formationit usually requiresof 4 can the be explaineduse of a ligand, by a 1,3-rearrangement palladium supported of the catalyst, allylic palladium alcohol, a nanocatalyst transformation or microwave previously activationdescribed by[50–57]. Qu and Finally, co-workers 2 was underintroduced a thermal in excess, activation in one in waterportion [48 or]. in The sequential use of acetonitrile addition, withoutmoreover improving of an additional the yield ligand (entries induced 10 and no 11). positive Hence changethe optimized (entries reaction 3 and 4) conditions [49]. However, were as a follows:significant in improvementa flask protected was from obtained light, by 1 (1.2 replacing equiv.) silver and acetate2 (1 equiv.) by silver in presence carbonate of Pd(OAc) and 1.5 equiv.2 (5 mol of %)silver and carbonate Ag2CO3 (1.5 proved equiv.) to be at the 50 °C optimized for 1 h. It amount should (entries be noted 5–7). that A working moderate under heating an inert is recommended atmosphere ◦ didsince not the improve formation the of yield3a was of the significantly products 3a reduced and 4 (entry at 80 12).C. TableTable 1. Optimization 1. Optimization of of the the Mizoroki Mizoroki-Heck‐Heck reaction reaction between between1 and 1 and2. 2. 1 2 Additive Time Yield Entry 1 2 Additive Solvent Time Yield Entry (equiv.) (equiv.) (equiv.) Solvent (h) 3:4 (%) 1(equiv.) 1.2 (equiv.) 1 (equiv.) AgOAc (1.1) DMF(h) 173:4 0:0(%)a 1 21.2 1.2 1 1AgOAc AgOAc (1.1) (1.1)DMF DMF 17 17 0:05:4 a b 2 31.2 1.2 1 1AgOAc AgOAc (1.1) (1.1)DMF MeCN 17 17 5:49:0 b b AgOAc (1.1) 3 41.2 1.2 1 1 AgOAc (1.1) MeCNMeCN 17 17 9:09:20 b b P(oTol)3 (0.1) AgOAc (1.1) b,c 4 51.2 1.2 1 1 Ag2CO3 (1.5)MeCN MeCN 17 17 9:2063:0 b b,c 6 1.2 1P(oTol) Ag3 (0.1)2CO3 (2) MeCN 17 63:0 b,c 5 71.2 1.2 1 1Ag2CO Ag3 2(1.5)CO3 (1.1)MeCN MeCN 17 17 63:054:0 b,c 8 1.2 1 Ag CO (1.5) MeCN 17 10:0 b,c,d 6 1.2 1 Ag2CO32 (2) 3 MeCN 17 63:0 b,c 9 1.2 1 Ag CO (1.5) none 1 63:0 b,c 2 3 b,c 7 1.2 1 Ag2CO3 (1.1) MeCN 17 54:0 b,c 10 1 2 Ag2CO3 (1.5) none 1 60:0 b,c 11 1 1 + 1 Ag2CO3 (1.5) none 1 50:0 b,d 12 1.2 1 Ag2CO3 (1.5) none 1 62:0 a The reaction was performed under natural light.
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