Selective E to Z isomerization of 1,3-Dienes Enabled by A Dinuclear Mechanism

The E/Z stereocontrol in a C=C bond is a fundamental issue in olefin synthesis. Although the thermodynamically more stable E geometry is readily addressable by thermal Z to E geometric isomerization through equilibrium, it has remained difficult to undergo thermal geometric isomerization to the reverse E to Z direction in a selective manner, because it requires kinetic trapping of Z-isomer with injection of chemical energy. Here we report that a dinuclear PdI−PdI complex mediates selective isomerization of E-1,3-diene to its Z-isomer without photoirradiation, where kinetic trapping is achieved through rational sequences of dinuclear elementary steps. The chemical energy required for the E to Z isomerization can be injected from an organic conjugate reaction through sharing of common Pd species.

T he E/Z stereocontrol of a C=C moiety has been a central issue in olefin chemistry. Significant efforts have been made to obtain the thermodynamically less stable Z-alkenes as a kinetically preferred product, because Z-alkenes are contained in many natural products, biologically active molecules, and synthons for organic synthesis 1,2 . Several bond-construction methods have been developed to obtain Z-alkene selectively, such as syn 1,2-adition to alkynes, stereoretentive cross-coupling using Z-vinyl reagents, Z-selective olefin metathesis, modified Wittig reactions, and Z-selective double bond migration [3][4][5][6][7][8][9][10] . In view of the fact that an E/Z mixture of alkenes in which a thermodynamically more stable E-alkene is the major isomer can be readily obtained by a common alkene construction method such as the Wittig reaction, the E to Z geometric isomerization may also become a powerful method to address to Z-alkenes. Despite its potential usefulness, however, the E to Z geometric isomerization of alkenes is not straightforward. Although photoirradiation of several alkenes leads to the E to Z isomerization 1,[11][12][13] , Z stereoselection under photoirradiation is sometimes incomplete, mainly because a photochemical E/Z ratio depends on a photostationary state derived from an excited state structure 1,14,15 . Moreover, it has been difficult to undergo E to Z geometric isomerization without photoirradiation, because an equilibrium of a reversible E/Z isomerization lies largely to the side of E-alkenes (Fig. 1a). The claims that thermal E to Z isomerization of 1,3-dienes proceeds in the presence of a cobalt catalyst 16 have proven erroneous recently. There has been no rational mechanism that allows kinetic trapping of Z-alkenes through a thermal E/Z isomerization. For example, E/Z geometric isomerization of alkenes is efficiently mediated or catalyzed by a transition metal hydride ([M]−H) 17 , where the production of Z-alkenes is disfavored due to the difficulty of kinetic discrimination of one of two diastereotopic β-H atoms during β-H elimination 10 , in addition to the rapid reversibility of migratory insertion and β-H elimination (Fig. 1b). Any other established mechanisms involving transition metal species such as (allylic C-H oxidative addition)-(reductive elimination), (allylic C-H radical abstraction)-addition, and (nucleophile/electrophile addition)-elimination 18-21 also preferentially gives Ealkene over Z-alkene. It is noted that even a technique using 1,2addition and 1,2-elimination reactions has been considered as a formal E to Z isomerization, in which an E-alkene is initially converted to an isolable C-C single bonded organic product through syn (or anti) addition, and then 1,2-anti (or syn) elimination reaction gives a corresponding Z-alkene [22][23][24] . Thus, it is highly desirable to develop a mechanism that enables straightforward, selective E to Z geometric isomerization of alkenes.
We envisioned that a dinuclear M-M bonded species might promote E to Z isomerization through a rational mechanism. Our strategy is based on the following hypotheses; i) an M-M bonded species that can accommodate alkenes at its semi-bridging or bridging coordination site undergoes stereoretentive syn addition to an E-alkene, ii) subsequent stereoinversion at the α-carbon center of the dimetalated intermediate generates the Z-equivalent intermediate, that then gives Z-alkene selectively via dinuclear syn elimination, and iii) as an alternative to ii), dinuclear anti elimination from the syn addition product gives Z-alkene selectively (Fig. 1c). Concerning the pathway i)→ii), the previous stereochemical study by our group proved that the dinuclear addition and elimination of a Pd-Pd moiety to/from 1,3,5-trienes occur in a highly stereoretentive (syn) manner, although the stereoinversion in a bi-π-allyl dinuclear adduct is very slow in the absence of Pd 0 impurities 25 . If the stereoinversion at the α-carbon center occurs reversibly, the Z-equivalent intermediate is expected to become a major component because the metal moieties, which are usually the most sterically demanding groups, prefer an antiperiplanar conformation with a transoid R 1 -C-C-R 2 geometry (Fig. 1c). The pathway i)→iii) may be considered when the stereoinversion at the α-carbon center is very slow or inaccessible, although the selective dinuclear anti elimination giving Z-alkenes has not been reported. When synthetically important 1,3-dienes are used as the alkene substrate, these mechanisms involve dimetallated intermediates having either η 1 -σ-M or η 3 -π-M ( Fig. 1d) 26,27 .
Here, we report that a dinuclear Pd I -Pd I complex has the ability to mediate selective isomerization of E-1,3-diene to its Zisomer without photoirradiation. We demonstrate that the sequence of dinuclear elementary steps involving either pathway i)→ii) or i)→iii) provides a rational way to obtain Z-1,3-dienes. Furthermore, we also show that the chemical energy required for the E to Z isomerization can be injected from an organic conjugate reaction through sharing of common Pd species, making the net process exergonic (Fig. 1a).
We then examined the kinetic trapping of Z-2 from 3-transoidantifacial through syn elimination (Fig. 2d), although the rapid π-σπ allyl-Pd interconversion can cause elimination of E-2 via the reverse way of the formation of 3-transoid-antifacial from E-2. Bis (diphenylphoshino)methane (dppm) has been used as a good

In case of fast inversion
In case that inversion is very slow or inaccessible Fig. 1 Isomerization of alkenes. a A qualitative energy profile of Z-alkenes and E-alkenes. An M-M complex may promote E to Z geometric isomerization of alkenes through a dinuclear mechanism. The chemical energy required for the E to Z isomerization may come from the reaction energy of a coupled reaction (A + B → C + D), where the common M-M species are shared, making the net reaction exergonic. b A simplified model for the mononuclear metal hydride pathway which is a representative and conventional mechanism for Z to E isomerization. c A dinuclear M-M pathway that enables kinetic trapping of Z-alkene. d The key intermediates for the isomerization of 1,3-diene.  (1 equiv)  Fig. 2 The dinuclear addition of a Pd I -Pd I moiety to substituted 1,3-dienes. a The dinuclear addition to 5-methylhexa-2,4-dienoate (2), and subsequent dinuclear elimination giving Z-diene selectively. b ORTEP for 3-transoid-antifacial (30% probability ellipsoids; counteranions are omitted for clarity). c The allyl π-σ-π interconversion for the rapid stereoinversion mechanism. d The ligand survey for stereoretentive elimination of Z-2. The reactions were carried out in CD 3 NO 2 at room temperature. dppm = bis(diphenylphosphino)methane.
[a] At −30°C. e Yields of Z-1,3-dienes after isolation. Typically, the diene was added to a CH 3 NO 2 solution of 1, and stirred for 30 min. The reaction mixture was cooled to −30°C, and then COT was added and the mixture was stirred for 15 min.

Injection of chemical energy through conjugate reactions.
Finally, we demonstrated that the concept of conjugate reactions is applicable to the present E to Z isomerization of 1,3-diene, where the required chemical energy is injected from a coupled reaction by sharing of a common metal species (Fig. 1a). In biological systems, many endergonic chemical reactions are operated by energetic coupling with an exergonic reaction such as ATP-hydrolysis, that makes the net reaction system exergonic 43 . However, it is rare that the concept of the conjugate reaction system is applied to the reaction-design of artificial metal mediated-hill or catalyzed up-hill organic transformations. Although the above mentioned E to Z isomerization of 2 is driven thermodynamically by the organometallic complexation reaction of 1 with COT to yield the complex 4, a conjugate reaction system in which the E to Z isomerization is energetically coupled with a downhill reaction (A + B → C + D in Fig. 1a) could give a net exergonic system. Furthermore, regeneration of 1 after the coupled down-hill reaction is highly desirable. We developed the oxidative double amination of COT by using 1 for the organic coupled reaction. The reaction of 4 with a secondary amine such as pyrrolidine (2 equiv) at 0°C in the presence of dibenzylideneacetone (dba) (5 equiv) gave a disubstituted 9-azabarbaralane (17) 44 (58% yield) and Pd 2 (dba) 3 (18) 45-47 (71% yield) (Fig. 4a). The molecular structure of the fluxional molecule 17 was confirmed by X-ray structure analysis (Fig. 4b). The formation of 17 might involve the nucleophilic amine-attack at one of the η 3 -allyl moieties in 4, subsequent deprotonation, intramolecular nucleophilic attack at the central carbon of the remaining η 3 -allyl moiety, and reductive elimination. The resultant Pd 0 complex 18 can be converted to the Pd I -Pd I complex 1 in 90% yield by treatment with [Cp 2 Fe][BF 4 ] in CH 3 CN-CH 2 Cl 2 at room temperature (Fig. 4a), although the selective synthesis of a Pd I 2 complex by one-electron oxidation of Pd 0 or one-electron reduction of Pd II has been rarely reported 48 . Thus, merging the up-hill E to Z isomerization of 1,3-diene and the downhill oxidative double amination of COT gave a net exergonic conjugate reaction system, where delivery of the Pd I -Pd I species or its equivalent from one reaction to another gives a closed cycle (Fig. 4a).
For the anti elimination mechanism, the downhill oxidative protonation reaction of TEMPO becomes the coupled reaction for the up-hill E to Z alkene isomerization of 11. That is, protonation of the TEMPO-adduct 13 with HBF 4 ·Et 2 O in CH 3  In summary, we have described E to Z isomerization of 1,3dienes mediated by the dinuclear M-M bonded species. The E → Z stereocontrol can be achieved by a rational dinuclear mechanism that allows kinetic trapping of Z-1,3-diene. Furthermore, the concept of the conjugate reaction system demonstrated in this work may provide a basis to promote the metal-mediated up-hill organic transformation through energetic coupling with an exergonic reaction.

Methods
General procedure. All manipulations were conducted under a nitrogen atmosphere using standard Schlenk or drybox techniques. Unless specified, all reagents were purchased from commercial suppliers and used without purification. Solvents were purified according to the standard procedures. For experimental details, spectroscopic characterization data, X-ray crystallographic data, and details of quantum calculations, see the Supplementary Information.   Fig. 3 Isomerization of (E,E)-diene to (Z,E)-diene. a Reaction scheme to access (2Z,4E)-isomer of methyl 5-phenylpenta-2,4-dienoate (11) through geometric isomerization. b ORTEP for 13 (50% probability ellipsoids; counter anion is omitted for clarity). c Yields of (2Z,4E)-1,3-dienes from the corresponding (2E,4E)-1,3-dienes. Typically, the diene was added to a solution of 1 in CH 3 NO 2 /CH 3 CN (v/v = 95:5) at room temperature, and stirred for 15 min. The reaction mixture was then cooled to −20°C and a solution of TEMPO (4 equiv) was added and stirred for 5 min.
reaction mixture, and then the reaction mixture was cooled at 0°C. After addition of pyrrolidine (22.4 mg, 3.20 × 10 −1 mmol) at 0°C, the reaction mixture was stirred at the temperature for 2 h. The violet precipitate in suspension was then separated by decantation, and the supernatant was concentrated in vacuo. The solution was diluted with CHCl 3 , and filtered through a silica gel pad. The silica gel pad was washed with CHCl 3 . The product was extracted by MeOH/CHCl 3 (v/v = 1:5), and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (MeOH/CHCl 3 (v/v = 1:10)) to give 9-aza-barbaralane 17 (24.2 mg, 9.00 × 10 −2 mmol, 58% yield) as a red solid. The single crystal of 17 suitable for X-ray diffraction analysis was obtained by recrystallization from CH 2 Cl 2 /diethyl ether at −30°C. The violet precipitate separated by decantation was washed with CH 3 CN and diethyl ether and dried in vacuo to yield Pd 2 (dba) 3 (18) in 71% yield (Yield was determined by the free dba/Pd 2 (dba) 3 molar ratio from 1 H NMR).

Data availability
The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information files, as well as from the corresponding author upon reasonable request. The X-ray crystallographic coordinates for structures reported in this study (3- Fig. 4 The conjugate reaction system for the uphill E to Z isomerization. a E to Z isomerization of 1,3-diene is energetically coupled with oxidative double amination of cyclooctatetraene. The reaction conditions: CH 3 CN, 0°C, 2 h, for 4 to 18; CH 3 CN/CH 2 Cl 2 , r.t., 1 h for 18 to 1. b ORTEP for 17 (30% probability ellipsoids).