Continuous Flow Z-stereoselective Olefin Metathesis: Development and Applications in the Synthesis of Pheromones and Macrocyclic Odorant Molecules
The first continuous flow Z-selective olefin metathesis process is reported. Key to realizing this process was the adequate choice of stereoselective catalysts combined with the design of an appropriate continuous reactor setup. The designed continuous process permits various self-, cross-and macro-ring-closing-metathesis reactions, delivering products in high selectivity and short residence times. This technique is exemplified by direct application to the preparation of a range of pheromones and macrocyclic odorant molecules and culminates in a telescoped Z-selective cross-metathesis/Dieckmann cyclisation sequence to access (Z)-Civetone, incorporating a serial array of continually stirred tank reactors.
<!>O O O<!>Ru<!>Entry for the Table of Contents
<p>Olefin metathesis 1 has rapidly emerged as a powerful synthetic tool to construct carbon-carbon double bonds. The versatility of olefin metathesis is evident from its successful application to natural product synthesis, 2 the valorisation of renewable feedstocks 3 or the preparation of new materials such as polymers. 4 The gamut of applications is largely due to the development of efficient, well-defined, air stable and easy to handle catalysts, such as the ruthenium-arylidene complexes which demonstrate high tolerance towards various organic functionalities. 1 A significant challenge for catalyst design has been the selective formation of Z-alkenes. As numerous highly valuable molecules feature a Z-alkene moiety, special attention has recently been focused on the development of a new class of Ru-based complexes to enable high selectively towards Z-olefins (Figure 1). 5 Cyclometalated Ru-catalyst Ru-1 (Grubbs) 6 and monothiolate Ru-catalyst Ru-2 (Jensen) 7 have proved to be highly Z-stereoselective in cross-metathesis (CM) of terminal olefins (up to >99:1) while stereoretentive dithiolate catalyst Ru-3 (Hoveyda) 8 efficiently promoted the transformation of Z-olefins into corresponding Z-products by retaining the stereochemical information (up to >99:1). Recently, we described the synthesis of a cost-effective Z-selective cyclometalated Ru-catalyst Ru-4 9 featuring an unsymmetrical unsaturated NHC (U2-NHC) ligand accessible through a multicomponent process. 10 Apart from its high versatility and excellent Z-selectivity demonstrated in self-, cross-and ring-openingpolymerization metathesis, the novel cyclometalated catalyst Ru-4 showed impressive robustness in reactive media affording good fidelity of high Z-selectivity over time, surpassing previously described Rucatalysts. This sought-after feature led us to focus our attention on the development of a continuous flow Z-selective process. Over the last decade, continuous flow olefin metathesis has been well studied; with specific emphasis on the Ru-catalysts employed (both hetero-and homogeneous), and a variety of reactor designs, with varying degrees of success. 11 However, continuous flow Z-selective Ru-catalysis has not been reported and remains elusive. In order to realise an effective continuous process, careful attention must be given to both the catalyst choice and the continuous reactor design (Figure 1,b) -but success in this area paths the way to the continuous preparation of a variety of pheromone and odorant molecules. Herein, we describe the first continuous flow Zstereoselective olefin metathesis involving a Teflon AF-2400 tube-intube reactor. 12 We initiated our study by investigating the application of a Teflon AF-2400 tube-in-tube semi-permeable membrane reactor to the Zselective process. Preliminary results highlighted that application of a 'vacuum-on' across the membrane, versus 'vacuum-off' delivered a clear benefit in terms of yield/productivity (See Supplementary Information (SI) for further details). Taking this further, the selfmetathesis of ethyl 9-decenoate under continuous flow condition using a 1 mL Teflon AF-2400 tube-in-tube reactor 12 was explored in more detail against a focused collection of catalysts Ru-1, Ru-4 and Ru-5 (Scheme 1. For the gram-scale synthesis of Ru-4,-5 and X-ray characterisation of Ru-5, see SI, Scheme S1 and Figure S4). In the event despite an excellent 95/5 Z/E ratio observed with Ru-1 within 0.5 h, the selectivity dropped gradually as the conversion increased reaching 78% after 3 h of reaction (Scheme 2,a). Curiously, the novel Ru-5 catalyst showed a lower range of Z-selectivity over time (87 to 69%) than its parent Ru-1 although the resulting diester 6 was produced in a higher yield (84%, Scheme 2,b). 13,14 Interestingly, DIPP-containing cyclometalated Ru-4 demonstrated excellent catalytic performance in the flow reactor affording the desired internal olefin with 78% conversion and very high 97% Z-selectivity after 3 hours (Scheme 2,c).</p><p>It is worth underlining that continuous flow metathesis can be conducted outside a glovebox while batch conditions require an open vessel inside the glovebox to efficiently remove the ethylene and reach high conversions. [h] 13% of SM-product were detected by 1 H NMR.</p><p>[i] Catalyst loading: 0.5 mol% (10-17 mM in THF).</p><p>[j] 5% of isomerized by-product from allylbenzene were detected by 1 H NMR.</p><p>Having identified the combination of Ru-4 and a Teflon AF-2400 vacuum-on tube-in-tube design as the most efficient combination to achieve continuous Z-selective catalysis, a range of several cross-and self-metathesis transformations were explored in a larger 3 mL reactor (Scheme 2). Initially running a range of substrates through the reactor with a two-hour residence time and 1 mol% catalyst loading led to moderate to good conversions and yields. Notably, all CM products were formed in excellent Z-selectivity, ranging from 94 to 98.5%, with the exception of allylic alcohol 11 which afforded a Z/E ratio of 80/20. Using the designed flow reactor rig, highly valuable semiochemicals 15-17, 16 acting as potential bio-pesticides against Lepidoptera (moth) and Tenebrio Molitor (beetle), were efficiently produced on a 6 mmol scale (12 times the standard substrate scope scale) with a slight alteration of Z-selectivity (96-97%). Furthermore, a 0.5 mol%, Ru-4 loading was sufficient to promote the self-metathesis of allyl-benzene and other unfunctionalized linear terminal alkenes furnishing, after 2 hours, the corresponding internal Z-olefins 12-14 in excellent selectivity (up to 98%) and moderate to good yields. We next turned our attention to the macro-RCM reaction of terminal olefins. Typically, macro-RCM requires higher dilution than CM so as to minimise the competitive oligomerization reaction; reaction concentration therefore becomes a variable. 14 As depicted in Table 1 entries 1 and 2, similar catalytic performances were observed with Ru-1 and Ru-5 in the formation of the 16-membered macrocycle 19 when the reaction was run at 20 mM 17 in 1,2-dichloroethane (70 °C, 3 hours residence time, 70% and 75% isolated yield respectively). Nevertheless, the Z-selectivity still remained moderate reaching 86% and 82% respectively. To our delight, Ru-4 showed an impressive 97/3 Z/E ratio although a significantly lower productivity was observed (24% isolated yield, Table 1, entry 3). By increasing the residence time to 4.5 h (entry 15 [a] [Lepidoptera, Moth] 0.5 mmol, 58% conv. (52%) [b] 98.5/1.5 Z/E ratio [d] Me 4 8 [a] Me 5 Me 7</p><p>AcO 17 [a] [Tenebrio Molitor, Bettle] 0.5 mmol, 75% Conv. [b] (59%) [c] 98/2 Z/E ratio 4 Me AcO 3</p><p>16 [a] [Lepidoptera, Moth] 0.5 mmol, 55% conv. (43%) [d] 98/2 Z/E ratio [d] 6</p><p>Me HO 9</p><p>10 [e] 3 AcO AcO 9 [a] Me HO 7</p><p>11 [e][g] 7 [a] 6 mmol, 75% Conv. [b] (60%) [c] 97/3 Z/E ratio 67% conv. (57%) [b] 96/4 Z/E ratio [b] 75% conv. [b] (62%) [c] 98/2 Z/E ratio [d] 59% conv. (58%) [b] 98.5/1.5 Z/E ratio [d] 70% conv. [b] (41%) [c] 92/8 Z/E ratio [f] Ph Ph Me Me 13 [i] 14 [i] 12 [i] 58% conv. (52%) [b], [j] 95/5 Z/E ratio [d] 80% conv. (76%) [b] 95/5 Z/E ratio [d] 57% conv. (54%) [b] 98/2 Z/E ratio [d] Ru-4 (0.5-1 mol%)</p><p>X M in THF (55%) [d] 97/3 Z/E ratio 6 mmol, 80% Conv. [b] (75%) [b] 96/4 Z/E ratio (neat)</p><p>4), the yield could be slightly improved without any alteration of Zselectivity demonstrating again the excellent stability of Ru-4. Notably, at a higher concentration (50 mM), similar isolated yield and Zselectivity were observed but a competitive oligomerization occurred (entry 5). Applying these conditions for Ru-4 and Ru-5 (Table 1 entries  2 and 3) in the context of highly desirable macrocyclic odorant molecules, cyclometalated Ru-4 surpassed Ru-5 in the mRCM (at 20 mM) providing (Z)-civetone 20, 18 which was isolated in 44% yield and excellent 95% Z-selectivity. Surprisingly, Ru-4 was inefficient toward (Z)-yuzu lactone 21, 19 where a higher productivity was reached with the parent Ru-5 (32% isolated yield) but the Z/E ratio remained moderate (82/18). Given the deficiencies found in our efforts towards continuous flow Zselective metathesis, namely moderate Z/E ratios observed in CM involving allylic alcohols (product 11, Scheme 2) and moderate performance in mRCM reactions, we investigated the catalytic performance of the stereoretentive catecholdithiolate catalyst Ru-3 20 (Scheme 3). To our delight, the rapid reaction (within 5 min.) between cis-butenediol and 1-undecene led to the desired internal olefin 11 with a remarkable 99% Z-selectivity and a moderate 56% yield. It is worth noting that without vacuum, a slightly lower productivity and selectivity were observed despite the limited production of ethylene observed here. Interestingly, the in situ generated Ru-3, which avoids the requirement of a glove-box led to 11 with the same efficiency (see SI for details). 21 Furthermore, the stereoretentive Ru-3 catalyst was also able to produce internal olefins 7, 22 and 23 with moderate to good yields and excellent Z/E ratios (up to >99/1). Unfortunately, Ru-3 was inefficient towards the mRCM leading to (Z)-yuzu lactone 21, delivering a low 7% yield despite a prolonged residence time and higher reaction temperature. As some amounts of dimer by-product were also detected, we suspect that the semi-permeable membrane reactor is unable to efficiently remove the 1-butene co-product. At last, due to the dilution condition (20 mM) required to produce Zcivetone 20 via macro-RCM (Table1), we envisaged an alternative synthetic route that involves a macrocyclization via a Dieckmann reaction of the Z-diester 6. 22 Such a proposed route sets a challenge for continuous flow reactor design. Similarly to mRCM, macro-Dieckmann cyclisations also requires careful control over the reactive intermediate concentration, so as to favor cyclisation over oligomerization.</p><p>Reactions of this type are controlled in batch by dropwise addition of one of the components to keep the concentration of intermediate low, favoring cyclisation (Scheme 4, b). 18 Design of a reactor to achieve this in flow requires multiple injection points along the length of the reactor, where, at each point a portion of one component is introduced via a mixer to the flowing stream. Depending on the rate of reaction there may need to be a maturing period for the reaction prior to the next 'injection' or 'drop' of material. This can be achieved using a continuous stirred-tank reactor design (CSTR), which can also accommodate active stirring (Scheme 4, c). The use of multiple injection points and CSTRs is also a good reactor design if there is the risk of fouling, bridging or precipitation in the reactor.</p><p>Scheme 4. Reactor design considerations for the continuous macro-Dieckmann cyclisation reaction.</p><!><p>with Ru-4 62% conv. [a] (44%) [b] 95/5 Z/E ratio [a] with Ru-5 74% conv. [a] (55%) [b] 70/30 Z/E ratio [a] with Ru-4 25% conv. [a] (6%) [e] nd Z/E ratio with Ru-5 61% conv. [a] (32%) [b] 82/18 Z/E ratio [a] 1 2 3 4 5 70 75 24 32 30 [d] Yield [b] Entry Catalyst Time (h) conv. (%) [a] conc. @ tee (mM) 22 [a] 57% conv. [c] (48%) [d] 99/1 Z/E ratio [c] Me HO 5 23 [a] 66% conv. [c] (60%) [d] 98/2 Z/E ratio [c] Me HO 7 11 [a] 67% conv. [c] (56%) [d] 99/1 Z/E ratio [c] Me AcO 7 7 [b] 63% conv. [c] (49%) [c] >99/1 Z/E ratio [e] O O 13 21 [f] [Yuzu Lactone] 45% conv. [c] 7% yield. [c,g] Ru-3 (5 mol%)   56 mM in THF Teflon AF-2400 tube-in-tube 25 °C 5 min</p><!><p>ethylene/1-butene without vaccum: 61% conv. [c] (49%) [d] 96/4 Z/E ratio [c] with in situ Ru-3: 67% conv. [c] (49%) [d] 99/1 Z/E ratio [c]  Deprotonations, or reactions incorporating organometallic reagents can encounter fouling or precipitation issues. Preliminary experimentation with a flow system which simply combined LiHMDS with a full equivalent of diester 6 at a tee-piece, highlighted the propensity to form a precipitate and block the reactor. With this in mind we opted for a reactor design consisting of a serial array of CSTRs. 23 Incorporating this into a semi-continuous process targeting Civetone, we began with a larger scale self-metathesis of the biosourced ethyl 9-decenoate 5 catalyzed by cyclometalated Ru-4. Pleasingly, after 3 hours inside the 3 mL tube-in-tube reactor, 6 was isolated in good yield (71%; 1.27 g) and excellent 96% Z-selectivity (Scheme 5, a). Diester 6 was then diluted in THF and split across 5 input feeds. The base, lithium bis(trimethylsilyl)amide (LiHMDS) was used in large excess; such pseudo-first order conditions in base favour macrocyclization. LiHMDS was introduced into the serial CSTR reactor through input port 1 where it met the first portion of diester in tank 1 of the reactor and progressed through the reactor cascade to meet a total of 5 portions of diester before exiting to a batch collection flask (Scheme 5, b). The flowing output was collected into a stirring RBF and a solution of aqueous sodium hydroxide was added and heating commenced to saponify the cyclized ester intermediate (Scheme 5, c).</p><p>Treatment of the b-keto acid with sulfuric acid induced decarboxylation and furnished (Z)-Civetone in 62% yield, which is a comparable yield for the batch preparation of this material via a Dieckmann cyclisation approach.</p><p>In summary, we have developed the first continuous flow Zstereoselective olefin metathesis. Key to achieving this was finding the right combination of catalyst and reactor design. Among a selection of Z-stereoselective Ru-complexes, cyclometalated Ru-4 as well as dithiolated Ru-3 catalysts have proven to be the most efficient toward the formation of Z-internal olefins. Moderate to good yields and remarkable Z-selectivity (up to >99%) were obtained in various CM and mRCM allowing for the production of highly valuable pheromones and macrocyclic odorant molecules. Additionally, the continuous flow total synthesis of (Z)-Civetone was successfully achieved in >98% Zselectivity and 48% yield over 3 steps from a biosourced raw material via a Z-selective CM followed by a Dieckmann cyclisation involving serial array of CSTRs.</p><!><p>The first continuous flow Z-stereoselective olefin metathesis was described with a set of Z-stereoselective Ru-catalysts. Good productivity and excellent Z-selectivity (up to >99%) were obtained in the formation of various internal olefins including highly desirable pheromones and macrocyclic odorant molecules. A telescoped Z-selective cross-metathesis/Dieckmann cyclisation sequence to access (Z)-Civetone, incorporating a serial array of continually stirred tank reactors was also reported.</p>