Article Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Ru-Based Catechothiolate Complexes Bearing an Unsaturated NHC Ligand: Effective Cross-Metathesis Catalysts for Synthesis of (Z)‑α,βUnsaturated Esters, Carboxylic Acids, and Primary, Secondary, and Weinreb Amides Zhenxing Liu,†,# Chaofan Xu,†,# Juan del Pozo,† Sebastian Torker,*,†,‡ and Amir H. Hoveyda*,†,‡ †
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, 67000 Strasbourg, France
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‡
S Supporting Information *
ABSTRACT: Despite notable progress, olefin metathesis methods for preparation of (Z)-α,β-unsaturated carbonyl compounds, applicable to the synthesis of a large variety of bioactive molecules, remain scarce. Especially desirable are transformations that can be promoted by ruthenium-based catalysts, as such entities would allow direct access to carboxylic esters and amides, or acids (in contrast to molybdenum- or tungsten-based alkylidenes). Here, we detail how, based on the mechanistic insight obtained through computational and experimental studies, a readily accessible ruthenium catechothiolate complex was found that may be used to generate many α,β-unsaturated carbonyl compounds in up to 81% yield and ≥98:2 Z/E ratio. We show that through the use of a complex bearing an unsaturated N-heterocyclic carbene (NHC) ligand, for the first time, products derived from the more electron-deficient esters, acids, and Weinreb amides (vs primary or secondary amides) can be synthesized efficiently and with high stereochemical control. The importance of the new advance to synthesis of bioactive compounds is illustrated through two representative applications: an eight-step, 15% overall yield, and completely Zselective route leading to an intermediate that may be used in synthesis of stagonolide E (vs 11 steps, 4% overall yield and 91% Z, previously), and a five-step, 25% overall yield sequence to access a precursor to dihydrocompactin (vs 13 steps and 5% overall yield, formerly).
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INTRODUCTION An endothermic, often turnover-limiting, step in a catalytic cycle is typically followed by an exothermic process; as such, any lowering of the energy barrier for the former event, although seemingly minute, can lead to notable improvements in efficiency. The degree to which subtle modifications within a catalyst structure impact the energetics of a process, including those that can impede catalyst decomposition, are crucial. However, implementing such alterations requires a certain degree of mechanistic appreciation. A recent example in stereoselective olefin metathesis1 is in regards to catalyst variations meant to stabilize or circumvent the formation of unstable methylidene species.2 Another instance relates to the impact of a pair of chlorine atoms within the catechothiolate ligand of Ru-1a3 (Scheme 1a); the carbenes derived from Ru1b4 are longer-living because of the attenuation in electron density of the sulfide ligands.5 The emergence of Ru-1c6 was based on the idea that the syn-to-NHC mcb (NHC, Nheterocyclic carbene; mcb, metallacyclobutane) can better accommodate a larger alkene substrate (Scheme 1a). We recently faced the problem of insufficient catalyst longevity while considering the development of cross-metathesis reactions that generate (Z)-α,β-unsaturated carboxylic acids, esters, or amides, compounds frequently needed for stereo© XXXX American Chemical Society
selective synthesis of bioactive molecules (e.g., motualevic acid B7 and 6-nor-absicic acid,8 Scheme 1b); Weinreb amides, which are convenient precursors to aldehydes and ketones (e.g., en route to dihydrocompactin,9 Scheme 1b), are especially versatile. These reactions would complement Wittig-type olefin synthesis or partial hydrogenation of an internal ynonate, which are at times moderately stereoselective (particularly with amides).10 Over-reduction would no longer be an issue, and the starting materials would be more readily available (vs an alkyne) and/or robust (vs an aldehyde). Strongly basic conditions (e.g., KH,11 KOt-Bu,12 KHMDS)13 to perform a reaction or to hydrolyze an ester to an acid, low temperatures (−78 °C),10,14 and/or stoichiometric amounts of toxic additives (e.g., 18-crown-6)11 would not be needed. Only a limited number of (Z)-α,β-unsaturated t-butyl enoates can be obtained by cross-metathesis (Scheme 1c);15 these reactions are promoted by Mo-based monoaryloxide pyrrolide (MAP) complexes, which readily decompose in the presence of a carboxylic acid, and relinquish their catalytic activity when an α,β-unsaturated amide is involved (Scheme 1c). Cross-metathesis protocols for synthesis of (Z)-α,β-unsaturated carbonyl Received: March 1, 2019
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DOI: 10.1021/jacs.9b02318 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Article
Journal of the American Chemical Society Scheme 2. Initial Experimental Findingsa
Scheme 1
a Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Experiments were run in duplicate or more. See the Supporting Information for details.
enoate after 8 h at ambient temperature. Although 2a and 3a were generated in >98:2 Z/E selectivity, extensive catalyst decomposition was observed along with formation of trisubstituted α,β-unsaturated ester byproducts 4a and 4b (Scheme 2; according to analysis of 1H NMR spectra).18 Mechanistic Analysis. In a reaction that is expected to generate a (Z)-α,β-unsaturated carboxylate, productive crossmetathesis reaction likely proceeds via ts1productive, mcbproductive, and then ts2productive (Scheme 3). An alternative nonproductive route might be facilitated by an electron-withdrawing carboxyl group at Cα in mcbnonproductive because the presence of this moiety would stabilize the electron density buildup at the carbon of the Cα−Ru bond.19 Density functional theory (DFT) studies, carried out on complexes lacking the two Cl substituents for simplicity, revealed to us that the carboxylic substituent can lower the barrier to metallacyclobutane distortion20,21 (→ mcbdistorted), reducing the severity of trans influence caused by the Cα−Ru and Ru−S(cis) bonds (see mcbnonproductive → tsdistorted → mcbdistorted; Scheme 3). The CNHC−Ru−Cα angle in a saturated complex thus widens from 91.0° in mcbnonproductive to 115.8° in mcbdistorted.18 DFT studies further indicated that mcbdistorted can be the gateway to catalyst decomposition, which may occur by β-hydride elimination,20−22 rendered feasible by the availability of a vacant ligation site, to generate a trisubstituted enoate (see mcbdistorted → tsβ‑H elim → π-allyl → trisub enoate; Scheme 3). We reasoned that by lowering the electron-donating ability of the NHC ligand we might be able to diminish the trans influence in mcbproductive therefore minimizing the significance of the stabilization caused by a carboxylate unit at Cα of mcbnonproductive. This led us to consider a Ru catechothiolate complex with an unsaturated NHC ligand. Our plan was partly based on acidity (pKa) measurements23 and 31P and 79Se NMR chemical shifts for NHC-phosphinide24 and NHC-selenium25 adducts, suggesting that the saturated NHCs are stronger σdonors and better π-acceptors.26 Moreover, the positive effect of an unsaturated NHC ligand in a Ru-based catalyst on tacticity of ring-opening metathesis polymerization of norbornene was recently documented.27 While we were aware that earlier investigations with dichloro Ru carbene complexes had shown that catalysts bearing a saturated NHC are in fact more effective in promoting olefin metathesis,28−30 we appreciated that a clear picture, vis-à-vis, the electronic differences between saturated and unsaturated NHC ligands, has yet to emerge. Although Tolman electronic
compounds preferentially deliver E isomers (substrate control).16 Herein, we provide the details of an investigation where by examination of the mechanistic principles, a readily accessible Ru-based catechothiolate catalyst was identified for efficient and stereoselective cross-metathesis reactions that afford (Z)-α,βunsaturated carboxylic esters, acids, Weinreb amides, and primary and secondary amides.
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RESULTS AND DISCUSSION Preliminary Experimental Findings. Initial studies showed that the available Ru-based complexes would be largely ineffective. As a reminder, we used disubstituted alkenes as starting materials because Ru catechothiolate complexes decompose readily in the presence of most monosubstituted alkenes (unstable methylidene).2 To address this problem, we recently introduced a strategy, namely, through in situ capping of the terminal alkene.2 Furthermore, many (Z)-1,2-disubstituted alkenes are commercially or readily accessible, and catalytic cross-metathesis reaction offers a convenient method for converting such entities to considerably more valuable alkenes. Cross-metathesis reaction between (Z)-butenoic benzyl ester (1a) or carboxylic acid (1b) and (Z)-hex-3-ene (Scheme 2) in the presence of Ru-1c, suitable for other challenging cases (e.g., trisubstituted allylic alcohols and ethers),17 was inefficient. With 5.0 mol % Ru-1c there was 32% consumption of the starting B
DOI: 10.1021/jacs.9b02318 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society Scheme 3. DFT Studies Regarding Factors Leading to Catalyst Decomposition and the Byproducts Formeda
a See the Supporting Information for details. ts, transition state; NHC, N-heterocyclic carbene; mcb, metallacyclobutane; β-H elim, β-hydride elimination.
parameters, which signify combined σ-donor and π-acceptor properties, are similar for the two NHC types,31 redox potential values obtained experimentally for Ir-32 and Ru-based33 complexes are inconclusive, indicating that the saturated variants could be stronger or weaker electron donors compared to their unsaturated counterparts. It was for the following reasons that we ultimately decided to probe the chemistry of Ru-1d (Scheme 4): (a) There are fundamental differences between reactions of dichloro and catechothiolate catalysts. Most notably, whereas transforma-
tions proceed via anti-to-NHC metallacyclobutanes in the earlier system, syn-to-NHC metallacyclobutanes are involved with bidentate catechothiolates;3 this enhances the impact of steric pressure induced by an NHC ligand. (b) DFT studies indicated that the presence of an unsaturated NHC lowers the barrier to mcbproductive (ΔGrel = 12.4 kcal/mol for ts2productive vs 13.4 kcal/mol for the saturated complex; Scheme 3). Furthermore, formation of mcbdistorted (ΔGrel = 19.2 kcal/mol for tsdistorted vs 18.0 kcal/mol for the saturated complex) and βhydride elimination (ΔGrel = 15.3 kcal/mol for tsβ‑Helim vs 13.9 kcal/mol for the saturated complex) become energetically more demanding, which should result in a longer catalyst life span. These variations may be attributed to differences in trans influence, which are probably stronger in a complex with a saturated NHC. Specifically, DFT investigations (Scheme 3) revealed that the Ru−S(trans) bond might be longer in mcbproductive with a saturated NHC (2.423 vs 2.418 Å, respectively), and could thus be higher in energy than its corresponding unsaturated analogue (ΔGrel = 11.6 vs 11.0 kcal/ mol, respectively).(c) With the more “upwardly” oriented N-aryl moieties in an unsaturated NHC ligand (see mcb-I′ vs mcb-I, Scheme 4), there might be less of a driving force toward structural distortions that lessen the barrier to mcbdistorted. Proof-of-Principle Experiments. Efficiency Profile Is Substrate-Dependent. To probe the validity of the above hypotheses, we determined the efficiency of cross-metathesis reaction between (Z)-hex-3-ene and different (Z)-butenoic acid derivatives in the presence of Ru-1d versus Ru-1c (Scheme 5; ≥98% Z in all cases). In contrast to the reaction with Ru-1c, affording 2a in 28% yield (Scheme 5), the transformation with Ru-1d afforded the same product in 78% yield. Furthermore, although the transformations with carboxylic acid 1b and Weinreb amide 1c in the presence of Ru-1c proceeded to 32− 35% conversion (25% yield), (Z)-disubstituted alkene products 3a and 5a were isolated in 68−70% yield when unsaturated
Scheme 4
C
DOI: 10.1021/jacs.9b02318 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society Scheme 5. Cross Methods with Ru Complexes 1c versus 1da
illustrate the higher activity and longer life span of the unsaturated complex. We reasoned that β-hydride elimination should be less favored if the catalyst derived from Ru-1c and a deuteriumsubstituted alkene were to be used, resulting in higher yielding cross-metathesis reaction. In the event, whereas the reaction with saturated complex Ru-1c, 1a-d2, and (Z)-hexene-d2 was more efficient than when 1a was used (47% vs 28% yield, respectively; Scheme 6), there was minimal change when Ru-1d was involved (78−81% yield). When the rate of β-hydride elimination is reduced there is a narrower gap between the efficiency of processes carried out with Ru-1c and Ru-1d. X-ray Structures of the Ru Complexes. We then focused on gathering insight regarding the following questions: (a) Why are reactions that generate a (Z)-α,β-unsaturated carboxylic ester, a carboxylic acid, or a Weinreb amide higher yielding with unsaturated complex Ru-1d (vs Ru-1c)? (b) Why does the same distinction not extend to transformations of primary and secondary amides? We began by obtaining the X-ray crystal structures of Ru-1c and Ru-1d (Scheme 7). The slightly shorter Ru−CNHC bond
a Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios were determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Experiments were run in duplicate or more. See the Supporting Information for details.
Scheme 7. X-ray Crystal Structures of Ru Complexes 1c versus 1da
complex Ru-1d was used. The reactions of secondary amide 1d and primary amide 1e efficiently afforded 6a and 7a, respectively, regardless of the catalyst involved, raising several intriguing mechanistic questions. Enoate Byproducts. With the knowledge that reactions are higher yielding in several key cases with unsaturated complex Ru-1d, we decided to determine whether catalyst decomposition is a factor. We investigated the process involving enoate 1a and (Z)-hex-3-ene (Scheme 6), establishing that trisubScheme 6. Gauging the Influence of β-Hydride Eliminationa
a
See the Supporting Information for details.
length in imidazolium-containing Ru-1d (2.055 vs 2.072 Å for Ru-1c) and the more distorted CNHC−Ru−S(trans) (further from linearity; 139.6° vs 149° for Ru-1c) are contrary to our initial expectation, which was based on higher Lewis basicity of, and stronger trans influence caused by, a saturated NHC ligand. This apparent anomaly is likely due to crystal packing forces. While there appears to be π−π interaction34 between the dithiolate ligand and one of the aryl groups on the NHC in Ru1d (i.e., smaller CNHC−Ru−S(trans) angle), the same type of association seems to be disrupted in Ru-1c by either the positioning of the 2-fluoro-6-methyl phenyl moiety (Scheme 7), the isopropoxy group, or the aromatic ring of the benzylidene of a neighboring molecule in the crystal.18 The Ru−S(trans) bond length in Ru-1c, as would be predicted (weaker π−π association and stronger trans influence), is somewhat longer than in Ru-1d (2.283 vs 2.265 Å). An aspect of these X-ray structures that is less susceptible to crystal packing forces, but is equally informative, relates to the N−CNHC−N bond angles.23 The larger corresponding value of 106.5° for saturated complex Ru-1c (vs N−CNHC−N angle = 103.9° for Ru-1d) likely means that the N-aryl substituents are
a Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Experiments were run in duplicate or more. See the Supporting Information for details.
stituted alkenes 4a and 4b are indeed formed as byproducts in the transformations with Ru-1c and Ru-1d (by GC-MS analysis18). Moreover, the enoates were generated in distinct ratios: ∼70:30 for Ru-1c and ∼20:80 for Ru-1d, respectively. Because 4a arises from reaction of starting enoate 1a while 4b is derived from product 2a, the aforementioned ratios further D
DOI: 10.1021/jacs.9b02318 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society Scheme 8. Examination of the Influence of Enoate Structure on the Rate of Olefin Metathesisa
a Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Experiments were run in duplicate or more. See the Supporting Information for details.
Scheme 9. Scope of the Method: Synthesis of (Z)-α,β-Unsaturated Carboxylic Estersa
a
Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Condition A: 1.0 equiv of monosubstituted olefin, 1.0 mol % Ru-1d, 5.0 equiv of (Z)butene, thf, 22 °C, 1 h; 5.0 equiv. (Z)-enoate, 5.0 mol % Ru-1d, 100 Torr, thf, 1 h, ambient pressure, 7 h. Condition B: 1.0 equiv of monosubstituted olefin, 1.0 mol % Ru-1d, 5.0 equiv of (Z)-butene, thf, 22 °C, 1 h; 5.0 equiv of (Z)-enoate, 4.0 mol % Ru-1d, 100 Torr, thf, 1 h, ambient pressure, 7 h; 4.0 mol % Ru-1d, 100 Torr, thf, 1 h, ambient pressure, 11 h. Condition C: 1.0 equiv of monosubstituted olefin, 5.0 equiv of (Z)-enoate, 4.0 mol % Ru-1d, 100 Torr, thf, 1 h, ambient pressure, 7 h; 4.0 mol % Ru-1d, 100 Torr, thf, 1 h, ambient pressure, 11 h. Experiments were run in duplicate or more. See the Supporting Information for details.
ability of the nitrogen atoms, which are attached to a sp3hybridized carbon in Ru-1c (vs sp2-hybridized C in Ru-1d). Impact of Alkene Structure on Rate of Olefin Metathesis. A possible reason why cross-metathesis with a primary or a secondary amide (1d and 1e) is efficient, no matter which Ru catechothiolate complex is used, is because these alkenes are more electron-rich (vs an α,β-unsaturated ester, acid, or Weinreb amide), and as a result, catalyst decomposition is
further projected toward the dithiolate ligand, increasing the steric pressure associated with the formation of a syn-to-NHC metallacyclobutane. A wider N−CNHC−N angle indicates that in catalysts derived from Ru-1c, where there is an NHC with nonbonding electrons in an orbital that has higher p-character, there is stronger trans influence in the derived metallacyclobutanes. The same electronic factor is in all likelihood exacerbated by the weaker inductive (electron-withdrawing) E
DOI: 10.1021/jacs.9b02318 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society
efficiency was observed. The examples provided in Scheme 10 are illustrative.
slower. This hypothesis is in line with the fact that there is minimal conversion when an enone, an enal, or an alkenyl nitrile, which are even more electron-deficient, is used. To probe further, we examined the difference between homometathesis of alkyl-substituted alkene 8 and its crossmetathesis with α,β-unsaturated ester 1a (Scheme 8). Although symmetrical alkene 9 was generated with similar efficiency with Ru-1c or Ru-1d, cross-metathesis product 10 was formed faster with the latter unsaturated complex (52% conversion to ∼1:3 9:10 vs 20% conversion to ∼3:1 9:10 with Ru-1c). Control experiments underscored two more points:18 (a) The abovementioned difference in chemoselectivity does not arise from the ability of Ru-1d to react with 9 and convert it to crossmetathesis product 10. (b) A Lewis base can diminish the catalytic activity of a Ru catechothiolate complex.35 Furthermore, a carboxylic ester is more detrimental to the activity of Ru1d compared to Ru-1c, probably because of the somewhat higher Lewis acidity of the former, causing it to coordinate more readily with the Lewis basic carboxyl group. We also investigated the relative rates of homometathesis of alkyl-substituted alkene 8 and its cross-metathesis reaction with benzyl ester 1a (Scheme 8; by 19F NMR spectroscopy). Regardless of whether Ru-1c or Ru-1d was used, conversion of 8 to symmetrical 9 proceeded at similar rates. However, whereas homometathesis of 8 was slightly more facile than its cross-metathesis with Ru-1d (khomo/kcross = 1.5; Scheme 8), there was a greater rate difference when Ru-1c was used ((khomo/ kcross = 4.6). These data show that although reactions are faster with Ru-1d it is with the more electron-deficient substrate that efficiency of the reactions with the saturated complex (Ru-1c) suffers significantly. As before, we attribute this to the reduced trans influence in mcbproductive (NHC−Ru−S(trans)) which lowers the barrier to productive metathesis, rendering entities derived from Ru-1d catalytically more active. (Z)-α,β-Unsaturated Esters. To explore the scope of the method, we began with (Z)-α,β-unsaturated esters, which were obtained in 55−76% yield and 96:4 to >98:2 Z/E selectivity (Scheme 9). This included products bearing a benzyl (2b−k) or the more hindered tert-butyl ester (2l,m) group. Reactions proceeded readily in the presence of an aldehyde (2f), a carboxylic acid (2g), an unprotected indole (2i), or an unprotected phenol (2k), many of which (except for an unprotected indole) are functional units that quickly disable Mo- and W-based as well as certain Ru-based complexes.4 Formation of sterically hindered, α-branched (Z)-alkene 2m is noteworthy. Benzylic olefins, sterically demanding β-branched starting materials, emerged as suitable substrates. We developed several sets of conditions, optimal depending on the circumstances. As noted previously, unless hindered (i.e., α-branched) terminal olefins were used, initial capping with Zbutene was required.2 Subsequently, with 1.0 mol % Ru-1d and (Z)-butene (thf, 22 °C, 1 h) and (Z)-butene removal (100 Torr), either one (5.0 mol %, Condition A) or two batches (4.0 mol % each, Condition B) of Ru-1d may be added. As the syntheses of 2b−d, and 2k indicate, yields were higher when the Ru complex was added sequentially (Condition B). In the case of an α-branched alkene (cf. 2m), where homocoupling and formation of the sensitive Ru-methylidene is slow, there is no need for capping (Condition C). It should be noted that cross-metathesis reactions can be performed by mixing two (Z)-alkene substrates and a single batch of Ru-1d. However, when the reaction mixture was treated with two sequential batches of Ru-1d (Scheme 10) higher
Scheme 10. Feasibility of Single-Batch Processesa
a Reactions were carried out under N2 atmosphere. Conversion and Z/E ratios determined by analysis of 1H or 13C NMR spectra of unpurified product mixtures (±2%). Experiments were run in duplicate or more. See the Supporting Information for details.
(Z)-α,β-Unsaturated Acids. The approach can be used to synthesize (Z)-α,β-unsaturated carboxylic acids directly (e.g., 3b−f, Scheme 11). These entities cannot be prepared easily by Wittig-type olefin synthesis (regardless of stereochemistry) and access via the corresponding carboxylic esters demands basic or acidic conditions, which raise functional group compatibility issues and/or cause olefin isomerization. Despite the higher catalyst loading (see Condition D, Scheme 11), the ability to access 3g directly by cross-metathesis can improve the efficiency of a multistep sequence; this is underscored in the context of a route leading to naturally occurring antifungal/cytotoxic agent stagonolide E (Scheme 11). Enantiomerically pure 1,3-diene 11, obtained in seven steps and 28% overall yield from commercially available materials, was converted to (Z)-carboxylic acid 3g in 53% yield and >98:2 Z/E selectivity. The eight-step procedure, delivering 3g in 15% overall yield, compares favorably with the previously shortest reported 11-step sequence, carried out in the context of a total synthesis of the natural product,14 affording the same intermediate in 4% overall yield and as a 91:9 Z/E mixture of isomers (from a Horner−Wadsworth−Emmons reaction). (Z)-α,β-Unsaturated Weinreb Amides. We were able to access a number of different (Z)-α,β-unsaturated N-methoxy-Nmethyl (Weinreb) amides (5b−i, Scheme 12). Unlike when Mo- or W-based catalysts are involved (see Scheme 1c), the Lewis basic amide moiety did not adversely impact efficiency. This set of products are notable because they can be efficiently transformed to (Z)-enones36 or (Z)-enals,37 which similar to (Z)-α,β-unsaturated alkenyl nitriles,38 cannot be directly prepared by the present strategy (98:2 Z/E selectivity. Ensuing protection of the two hydroxy groups and alkylation generated (Z)-α,β-unsaturated ketone 13 in 62% overall yield (for two steps) without any loss of stereoisomeric purity (Scheme 12). This five-step route, which delivers 13 in 25% overall yield, is superior to the formerly reported 13-step sequence that furnishes the same product in just 5% overall yield (>98:2 Z/E, by partial ynone hydrogenation). (Z)-α,β-Unsaturated Secondary and Primary Amides. We prepared a number of different (Z)-α,β-unsaturated secondary (6b−i, Scheme 13a) or primary amides (7a−c, Scheme 13b); this class of products were generated in similar yields with either Ru-1c or Ru-1d. On the basis of the mechanistic principles that were already discussed, with a less electron-withdrawing carbonyl-containing substituent, there is less stabilization of electron density at Cα in an mcbnonproductive (see Scheme 3), and competitive decomposition is diminished. It is worth noting that a primary amide may be easily converted to the corresponding (Z)-unsaturated alkenyl nitrile by treatment with commercially available Burgess reagent for just 15 min at room temperature (see 14, Scheme 13b).39,40 As the final note, we have been unable to obtain appreciable conversion to any of the desired aryl- or heteroaryl-substituted (Z)-α,β-unsaturated carbonyl products (
