DFT-assisted design and evaluation of bifunctional copper(I) catalysts for the direct intermolecular addition of aldehydes and ketones to alkynes
Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Despite prior reports of intramolecular (Coniaene-type) reactions and confirmation here that Cu(I)-based catalysts are effective, NMR studies indicated that a dual catalytic approach using separate amine and pi-acid catalysts may not be feasible for intermolecular reactions due to undesirable enamine competition with alkynes for metal complexation. Bifunctional precatalysts were designed with tridentate ligands and potentially hemilabile heterocyclic spacers, expected to be suitable for the binding of pi-acidic metals such as copper (I) and silver (I). The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated. The calculated free energy changes upon carbon-carbon bond formation were used to prioritize catalyst designs, and several modular precatalysts were selected and prepared, with a focus on thiazole-containing systems synthesized via a 9-step sequence. Catalysts were screened for the direct addition of aldehydes and ketones to several internal and terminal alkynes. The precatalysts were combined with several different transition metal salts, and their structures studied with 1 H NMR and x-ray crystallography. Despite the lack of observed intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for C-C bond formation, and the combined results suggest that more rigid complexes may be necessary to catalyze direct intermolecular additions of aldehydes/ketones to alkynes.
<!>INTRODUCTION<!>This investigation<!>Intramolecular (Conia-ene) reaction screening<!>Intermolecular studies related to dual catalysis<!>Design of bifunctional catalysts and evaluation with density functional theory (DFT) calculations<!>Table 3. DFT calculations for bifunctional catalysis of C-C bond formation with acetone and 1-butyne<!>Scheme 1. Synthesis of glycine-based precatalysts<!>Reaction screening<!>X-ray crystal and NMR studies<!>CONCLUSIONS<!>General information: DFT calculations<!>General information: Synthesis<!>Methyl (2S,3R)-2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-hydroxybutanoate (15)<!>Methyl (2S)-2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-oxobutanoate (16).<!>Methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-5-methyl-1,3-thiazole-4-carboxylate (17).<!>Methyl 2-({benzyl[(tert-butoxy<!>Tert-butyl N-{[4-(aminomethyl)-5-methyl-1,3-thiazol-2-yl]methyl}-N-benzylcarbamate (21).<!>({2-[(Benzylamino)methyl]-5-methyl-1,3-thiazol-4-yl}methyl)[(quinolin-8-yl)methyl]amine (22a<!>2-{[({2-[(Benzylamino)methyl]-5-methyl-1,3-thiazol-4-yl}methyl)amino]methyl}phenol (22b<!>2-{[({2-[(Benzylamino<!>Tert-butyl 2-{[(2S,3R)-3-hydroxy-1-methoxy-1-oxobutan-2-yl]carbamoyl}pyrrolidine-1-carboxylate (23)<!>Tert-butyl 2-{[(2S
<p>R 3 H</p><!><p>The controlled formation of carbon-carbon bonds under mild conditions with unactivated substrates continues to be an important focus of modern organic methodology research. The identification of catalysts for such transformations has been facilitated by several enabling technologies that have flourished in recent decades, the most fundamental of which is transition metal complexes that are capable of stabilizing multiple catalytic intermediates. A complementary technology that has exploded since 2000 1 is the use of organocatalysts for carbon-carbon bond formation, 2 most commonly for the activation of aldehydes and ketones with amine-based catalysts. The use of dual organo/transition metal catalysts has further increased the range of transformations available to the organic chemist, [3][4][5][6] though a natural limitation to this approach is that separate homogeneous catalysts have the potential of poisoning each other. A related strategy is the use of multifunctional (typically bifunctional) catalysts with separate active sites positioned on a single molecule. Amino acids may be the simplest examples of bifunctional catalysts; 1 more complex examples possessing separate Lewis base and transition metal functionality have been reported, 7 but have arguably not yet enabled transformations that are impossible with monofunctional or dual catalyst systems. Nonetheless, a number of promising examples have been reported over the years using bifunctional Lewis acid/Lewis base catalysts, including Ito and Hayashi's gold(I)/amino-catalyzed asymmetric isocyanoacetate aldol reaction, 8 Shibasaki's aluminum(III)/phosphine oxide catalysts for asymmetric cyanosilylation of aldehydes, 9 and Lectka's bifunctional cinchona alkaloid/Lewis acid catalysts for asymmetric β-lactam synthesis. 10 We hypothesize that rationally designed, bifunctional catalysts, in particular those with carefully positioned Lewis acid/Lewis base pairs, will facilitate specific bond formations not feasible using dual catalyst systems. Our first efforts in this area involved the design of bifunctional organo/transition metal catalysts for direct aldol reactions, 11,12 an approach also explored in depth by Mlynarski [13][14][15] and Wang. [16][17][18] Expanding upon this approach, we endeavored to design bifunctional catalysts for direct additions of pronucleophiles, such as aldehydes and ketones, to unactivated alkenes and alkynes. Intramolecular direct additions of aldehydes and ketones to unactivated alkenes and alkynes have been reported; Widenhoefer has reported palladium (II) and platinum(II)-catalyzed cyclization of alkene-tethered β-diketones, 19,20 and Conia-ene type reactions with alkyne-tethered activated methylene substrates have been reported with a variety of transition metals. 21 Conia-ene type reactions with unactivated aldehydes and ketones are challenging, due to unfavorable equilibria with active enol nucleophiles. The use of dual amine catalysts (for aldehyde or ketone activation) and transition metal catalysts (for alkyne activation) for these intramolecular carbocyclizations has been reported by Kirsch, 22 Dixon, 23 Jørgensen, 24 Che, 25 and Michelet. [26][27][28][29]</p><!><p>The respective intermolecular direct addition reactions of aldehydes/ketones to unactivated alkenes/alkynes are rare. Widenhoefer reported the direct addition of stabilized carbon nucleophiles (1,3-dicarbonyl compounds) to ethylene and propylene using Pd(II) and Pt(II) catalysts. 20 Nakamura has also reported the metal-catalyzed addition of 1,3-dicarbonyl compounds 30 and stabilized enamines 31 to alkynes using In(OTf)3. Dong has reported simple bifunctional rhodium-based catalysts for the direct addition of ketones to alkenes, 32 as well as enamines 33 and ketones 34 to alkynes. More commonly, such transformations are instead performed by preactivating the pronucleophile and/or the electrophile prior to a palladium-or nickel-catalyzed cross-coupling reaction between an enolate anion and an alkenyl halide to generate a β-γ unsaturated product. 35 MacMillan has also reported a dual copper(II)/amine catalyst system for the coupling of aldehydes with alkenylboronic acids under mild conditions. 36 Though attractive for their mild conditions, we hypothesized that the reported dual catalytic systems for intramolecular carbocyclizations may be unsuitable for intermolecular additions due to the fact that enamine intermediates could outcompete alkyne substrates for coordination to 𝜋-acidic metals. We reasoned that bifunctional catalysts with discrete amine and 𝜋-acidic sites could be designed that could promote net intermolecular reactions between aldehydes/ketones and alkynes via a catalytic intramolecular carbon-carbon bond formation step, with the catalyst itself bringing the reactants together to form favorable macrocyclic intermediates within the putative catalytic cycle (Figure 1). Herein is described our early efforts towards the design, synthesis, and testing of such bifunctional catalysts for direct additions of aldehydes and ketones to unactivated alkynes.</p><!><p>In order to determine which metal Lewis acid and ligand combinations could be suitable for incorporation into a bifunctional catalyst, we elected to use an intramolecular reaction as a model. The formyl-alkyne substrate (1a) reported by Michelet 28 was used in a Conia-ene type reaction to screen a variety of metals with precedent for activating alkynes, together with cyclohexylamine as the organocatalyst for presumed enamine generation (Table 1). The best results were obtained with the group 11 salts copper (I), silver (I), and gold (I) (entries 1, 3 and 6). With its affordability, functional group tolerance (including protic solvents), good precedent for use in Conia-ene reactions, and its compatibility with a variety of ligand types, we decided to investigate Cu(I) in greater detail. Consistent with the report from Michelet, 28 we discovered that a Cu(II) source (Cu(OTf)2) could be conveniently used (entry 14), which we propose is reduced to an active Cu(I) species by a fraction of the enamine formed from the substrate and cyclohexylamine. We found that reactions with these Cu(II) salts tolerated a range of different ligands, including 1,3-propanediol, bipy, pyridine-2-carboxamide, 2picolinic acid, PhBOX, and TADDOL. We were enthusiastic about identifying ligand-accelerated reactions, 37 however we did not observe any substantial improvement in yield or obvious rate accelerations with different ligands relative to the unligated copper salts, though we can't rule out the possibility that the cyclohexylamine could double as a ligand for copper. The tolerance for various ligands in these Cu(I)-catalyzed reactions nonetheless prompted us to explore several heterocyclic ligand scaffolds that were already in hand for use in bifunctional catalyst systems (vide infra). a Formyl alkyne (0.020 g, 0.079 mmol) was added to a 1.5 mL HPLC vial followed by cyclohexylamine (1.8 𝜇L, 0.016 mmol). 10 min. later, the metal salt (0.012 mmol) was added and reactions stirred for 16 h. Reaction mixtures were filtered through a silica plug, condensed, and yields measured by 1 H NMR using pentachloroethane as an internal standard. b Reagents were mixed in the glove box. c Bu4NCl (1.0 eq) was added.</p><!><p>Prior to proceeding with our strategy to build novel bifunctional catalysts, we wanted to rule out the obvious possibility of using the dual catalyst conditions for intermolecular reactions that were productive for intramolecular reactions. We are not aware of any reported successful nor unsuccessful attempts at such intermolecular reactions with unactivated aldehydes/ketones and alkynes using Cu(I) catalysts. We hypothesized that such reactions could be precluded by the fact that electron-rich enamine intermediates could displace the alkynes and simply act as competing ligands for the 𝜋-acid. To test this hypothesis, we performed several NMR studies (Figure 2). A downfield shift in the 1 H NMR signal of the alkyne proton of phenylacetylene was observed upon its addition to (2,2'-dipyridylamine)CuOTf, from 3.07 ppm to 4.01 ppm in CDCl3 (Figure 2). This is consistent with formation of Cu-alkyne complex 2; an x-ray crystal structure of the related CuBF4 complex was obtained (Figure 3, left). Upon addition of the enamine derived from cyclohexanone and pyrrolidine, the signal for the uncoordinated alkyne appeared at 3.07 ppm. Evidence for enamine coordination to the metal was observed as the vinyl enamine proton moves upfield from 4.29 ppm to 3.99 ppm. This chemical shift is observed with or without the presence of the alkyne, suggesting that coordination of the enamine to the metal is highly favored over alkyne coordination. The formation of 1,2-addition product 3 was subsequently observed, which presumably forms via addition of a Cu-acetylide to a transient iminium ion. Variations of this transformation, in the form of 3-component reactions (ketone, amine, and alkyne), were recently reported by Larsen 38 and Ma. 39 We also attempted stoichiometric reactions with putative internal alkyne complexes, which yielded no detectable products.</p><!><p>The challenge of using Cu(I) to promote intermolecular reactions with alkynes as electrophiles prompted us to start investigating the hypothesis that pseudo-intramolecular reactions promoted by a bifunctional catalyst could be productive. We elected to prioritize our ideas for novel catalysts with input from DFT geometry optimizations and energy calculations. To evaluate the feasibility of such calculations with Cu(I) complexes, we calculated the structure of the cationic version of (2,2'-dipyridylamine)Cu(I) using the functional B3PW91, 40 with the LANL2DZ 40 basis set for Cu, and cc-pVDZ 41 for all other atoms. The resulting minimized structure (Figure 3, right) was in excellent agreement with the xray structure (Figure 3, left), with both structures showing copper with a distorted tetrahedral coordination geometry, neglecting the BF4 anion in the crystal structure.</p><p>Using this DFT method, we computed structures and energies of putative alkyne complexes, as well as the organocopper adducts obtained after the desired intramolecular C-C bond formation between the enamine and the alkyne. We reasoned that unfavorable energetics for this step in a catalytic cycle would make the desired reaction unlikely, and promising catalysts will be reasonably exergonic for this step, which is depicted at the top of Table 2. The decrease in enthalpy for addition to the alkyne should outweigh the entropic costs of bringing the reacting partners together, which leads to the formation of a more constrained macrocycle. An advantage to our strategy is that the constrained approach of the enamine to the alkyne will facilitate future transition state calculations; we should emphasize that our present efforts utilize only ground state calculations of postulated catalytic intermediates.</p><p>Our initial catalyst designs are an extension of the amino acid-derived heterocyclic systems that we initially designed for asymmetric aldol reactions. 11,12 We reasoned that precatalysts with tridentate metal binding motifs would form more stable complexes with predictable coordination geometries, relative to the bidentate systems we explored previously. We also reasoned that heterocycles could act as hemilabile ligands, thus increasing flexibility during parts of the catalytic cycle and potentially permitting the relief of macrocyclic ring strain. Physical and computer models indicated that  2) may be able to access favorable transition state geometries for C-C bond formation, but importantly should not undergo self-quenching whereby the amine (or intermediate enamine) can coordinate (and poison) the Cu(I) in an intramolecular fashion.</p><p>The addition of the enamine to the alkyne could proceed in a syn or anti fashion, to generate the organometallic adducts cis- (5) or trans-(6) (Table 2). Using acetone and acetylene as reaction partners, formation of the cis adducts was consistently calculated to be more exergonic than the trans adducts, presumably due to increased ring strain in the trans adducts. Assuming that both transition states are feasible, and that the difference in alternative transition state energies would be proportional to the enthalpy differences between the cis and trans adducts (Bell-Evans-Polanyi principle), 42 we would expect the cis adducts to form preferentially.</p><p>Variation of the heterocycle was also explored computationally. Using a glycine-derived catalyst with a phenolate as the "eastern" ligand, calculations with imidazoles, oxazoles, and thiazoles as "western" ligands were undertaken (entries 1-6). The free energy changes with the thiazoles were most favorable among these examples, with the cis-adduct calculated to be -2.9 kcal/mol lower in energy than the alkyne complex (entry 5). The analogous proline-derived catalyst was also computed to give the cis-adduct preferentially (entry 7).</p><p>Examination of the amine portion of the ligand revealed that the N-benzyl derived precatalyst (e.g. entry 9) was favored over the N-methyl or proline-derived precatalysts (entries 5, 7), with the free energy change for the formation of the cis-adduct calculated to be -3.8 kcal/mol (entry 9). It was hypothesized that the increased steric bulk with the Nbenzyl substituent would also help prevent undesirable 2:1 ligand-metal complexes observed by us with other precatalysts synthesized for asymmetric aldol reactions. 12 The proline-based precatalyst was calculated to be less favorable (𝜟G = -2.1 kcal/mol) (entry 7), presumably due to the increased strain on the macrocyclic adduct structure from the constrained nature of the amine. The eastern portion of the precatalyst was also examined via introduction of phenolate, quinoline, and phosphine moieties (entries 9-15). Consistent with the previous trend, the cis-adducts of the N-benzyl quinoline-based precatalyst (e.g. entry 11, 𝜟G = -10.2 kcal/mol) were calculated to be favored over the proline analogs (e.g. entry 13, -5.5 kcal/mol). Additionally, we reason that the more favorable free energy changes calculated with the quinoline-and phosphine-based catalysts is due to the increased cationic character of the metal center, relative to the the phenolate complexes (e.g. entry 11 and 15 vs entry 5). The diphenylphosphine analogs (e.g. entry 15) gave similar results to the quinolines, and also provided the only favorable result for a trans-adduct (entry 16). Unfortunately, initial attempts to synthesize the desired phosphine-based precatalysts failed due to oxidation of the phosphine during column chromatography.</p><p>To confirm that more complex alkynes might also be feasibly used, we performed DFT calculations using 1-butyne as an acceptor (Table 3). The results with acetone and 1-butyne predict thermodynamically favorable adduct formations. Calculations were run for the cis-adduct only for these substrates for comparative purposes given the trend observed in Table 2 showing the trans-adduct to be less favorable in almost all cases. Addition to the terminal carbon of the alkyne (giving adduct 8) or internal carbon (giving 9) was compared with two quinoline-based complexes (Table 3), and the addition to the terminal alkyne carbon was predicted to be more favorable with both. In addition to favorable thermodynamic transformation from enamine complex to adduct, we also wished to examine the distance and orientation of the enamine with respect to the alkyne in the alkyne complex (e.g. 10, Figure 4). Even though we did not attempt to determine transition state structures, it appears that the enamine and alkyne could adopt suitable positions for productive reactions. In adduct complexes such as 11, we commonly observed de-coordination of the thiazole nitrogen from the metal center. The hemilabile nature of this coordination may allow the adduct to adopt a macrocyclic species with reduced strain. a All calculations used functional B3PW91, basis set LANL2DZ for copper, and basis set cc-pVDZ for all other atoms, using DCM as solvent.</p><!><p>Bn H 9 -2.4 a All calculations used functional B3PW91, basis set LANL2DZ for copper, and basis set cc-pVDZ for all other atoms, using DCM as solvent. Enamine and alkyne carbons are highlighted in yellow in the calculated structures.</p><!><p>Our next objective was to develop modular syntheses of desirable heterocyclic precatalysts. Our results are summarized in Schemes 1 and 2. Based on our DFT calculations, we focused on thiazole-containing precatalysts, initially using N-Boc glycine (12) as starting material (Scheme 1). Amide coupling with threonine methyl ester 13, followed by Dess-Martin Periodinane (DMP) oxidation, yielded the known dipeptidyl ketone 16 in good yield. Heating with Lawesson's reagent provided the thiazole 17, 43 followed by N-benzylation using sodium hydride and benzyl bromide in DMF to give 18. Reduction of the ester proceeded cleanly with sodium borohydride and catalytic sodium triacetoxyborohydride. Mesylation of the primary alcohol (19) and addition of sodium azide generated azide 20, which was reduced with hydrogen and catalytic palladium on carbon. The resulting primary amine 21 could be combined in a Stepwise attempts to reduce the pre-formed imine with sodium borohydride yielded identical results. The use of acetic acid as a solvent was discovered to suppress the formation of the overalkylated byproduct, though reactions with these substrates were difficult to push to completion. A sulfonic acid resin (Amberlyst 15 ® ) was effective for both Boc removal and trapping the final diamine products, which allowed impurities to be washed away and the desired products released in high purity after basification with ammonia in methanol. Analogous proline-based precatalysts (29a-d) were generated using an identical strategy, with similar results (Scheme 2).</p><!><p>With a focused library of precatalysts in hand, we proceeded to test them in a variety of reaction screens, utilizing GC-MS to analyze each reaction. For initial screening, cyclopentanone was selected due to its well-established reactivity for enamine formation. 44,45 Internal alkynes were chosen as initial substrates due to the possibility that terminal alkynes may form undesired copper-acetylide species. Results from a representative solvent screen with precatalyst 22a are given in Table 4. Polar solvents (entries 1-6) yielded no reaction at 50 °C. It is plausible that the coordinating nature of these solvents prevented interaction of the metal salt with the substrates. Chloroform and toluene (entries 7-10) also showed only starting material after reaction at 50 °C. Nitromethane and THF (entries 13-16) produced an unknown, undesired byproduct that was also present in a control reaction run in THF where the hexyne had been omitted (entry 17). DCE and dioxane (entries 18-21) led to consumption of cyclopentanone, but gave complex, intractable mixtures of products. Given the use of DCE in the analogous intramolecular carbocyclization reactions, we explored additional substrates in this solvent with our library of precatalysts (Table 5). This screening showed that phenol based precatalysts (22b-d and 29bd) were inactive under the reaction conditions. Quinoline-based precatalysts (22a and 29a) showed complex mixtures of products. Analysis of these mixtures showed that GC-MS peaks were common amongst reactions with shared substrates. For example, reactions with acetone (Table 5, entries 1-5) contained a similar mixture of common byproducts. Similarly, reactions with 2-hexyne (entries 4, 9, 14, 19) also yielded a set of common byproducts that did not correspond to any desired products nor their derivatives, such as multiple alkenylation products, as determined by GC-MS and NMR of scaled up reactions. No GC-MS peaks were identified that were unique to a specific set of substrates, which would have suggested a unique and potentially desirable reaction. Based on the GC-MS data, we believe that the products formed under these conditions are primarily due to carbonyl-carbonyl or alkyne-alkyne coupling reactions. GC-MS evidence for aldol self-condensation products was observed in some cases, most notably when phenylacetaldehyde was used as the carbonyl compound (entries 11-15). A second prominent byproduct seen via GC-MS for samples that contained phenylacetylene (entries 1, 6, 11, 16) was 1,4-diphenylbutadiyne. The presence of this byproduct in these samples was confirmed by comparison of the GC-MS traces to that of a commercial sample of 1,4-diphenylbutadiyne.</p><p>To ensure that we could detect desired product formation, a control reaction was run to confirm that trace amounts of desired product could be detected in our crude reaction mixtures via GC-MS. An authentic sample for the addition of acetone to phenylacetylene (30) was synthesized according to a protocol reported by Trofimov. 46 Two parallel reactions were set up containing acetone and phenylacetylene substrates (Table 5, entry 1), and one reaction was doped with the positive control (30) at 5 mol%. After stirring at 50 ºC for 24 h, both reactions were analyzed via GC-MS. The positive control was detected in the reaction that was doped and it was not detected in the undoped reaction.</p><p>A range of acidic additives were additionally tested for the addition of cyclopentanone to 2-hexyne, along with the non-coordinating base 2,6-di-tert-butylpyridine (Table 6). No reactions were observed in any cases that previously led to consumption of substrates, such as the control reaction with no additive (entry 7). In a glovebox, precatalyst 22a (2 mg, 0.005 mmol) was dissolved in DCE (0.5 mL) and added to (CH3CN)4CuBF4 (0.005 mmol) in a 1.5 mL HPLC vial. The alkyne (0.130 mmol) and carbonyl compound (0.026 mmol) were added as solutions in DCE (0.150 and 0.100 mL, respectively). The vials were removed from the glovebox and shaken at 50 °C for 16 h. Crude reaction mixtures were condensed and analyzed directly by GC-MS. b Results: A: No reaction; B: complex mixture; C: carbonyl-derived byproducts observed, as determined by a control reaction without the alkyne. c Reaction heated to 95 °C. e Samples were diluted with 5 mL water and extracted with ether (3 x 2 mL), before being condensed and analyzed by GC-MS.</p><!><p>Concurrent with our efforts to screen catalysts and reaction conditions, we attempted to obtain single crystals of various Cu(I) complexes to corroborate our DFT studies. It was necessary to develop a protocol to cope with the additional challenge of keeping oxygen sensitive Cu(I) complexes in an inert atmosphere throughout the course of the crystallization (see Experimental Section). Unfortunately, attempts to obtain single crystals of Cu(I) complexes with our precatalysts have been unsuccessful. Crystallization trials were run with all precatalysts, however efforts focused mainly on 22a, 29a, and 29d, particularly because 22a and 29a showed the greatest apparent reactivity in reaction screens. Due to its polar, non-coordinating nature, nitromethane was chosen as the strong solvent and ultimately a 1:1 nitromethane : benzene mixture was chosen as the strong solvent with ether or pentane as the weak solvent. Samples containing phenolbased precatalysts 22b-d and 29b-d led to the formation of (CH3CN)4CuBF4 crystals in 1:1 nitromethane : benzene with either ether or pentane as the weak solvent . This observation suggests that ligand affinity for Cu(I) may not be as high as anticipated. Deprotonation of precatalysts 22d and 29d using NaH prior to complexation of (CH3CN)4CuBF4 yielded similar results. However, (CH3CN)4CuBF4 crystals were not observed in samples containing the quinoline-based precatalysts. In these cases, oiling out of the precatalyst was observed. Exploration of a range of Cu(I) salts as well as Zn(II), Ag(I), and In(III) salts with 22a eventually yielded a Ag(I) crystal with a 2:2 ligand to metal stoichiometry (Figure 5). Both ligands are bridging the Ag(I) ions, which are non-equivalent. Ag1 has a linear geometry via coordination from the N-benzyl N4 and secondary N6 amino groups from two different ligands, but the complex could also be described as having a seesaw geometry with additional coordination possible from quinoline N5 and thiazole N3. Ag2 has a distorted trigonal planar coordination geometry (chelated by thiazole N7, secondary amine N8, and N-benzyl N2). It is also disordered in the structure, present in two different positions due to pyramidal inversion of the benzylamine nitrogen (N8). Of special note is that neither of the metals are coordinated to all three of the desired coordinating groups of the precatalyst, namely the quinoline, thiazole, and the secondary amine proximal to the quinoline. Coordination of the Nbenzylamine (required as an aminocatalyst), instead of the quinoline, as observed in the bimetallic structure in Figure 6, could provide an explanation for the lack of activity of this catalyst class. The lack of a single, well-defined catalyst complex, as well as undesired coordination of the organocatalytic amine to metal centers, is also consistent with 1 H NMR experiments. Addition of (CH3CN)4CuBF4 to bifunctional precatalyst 22a in CD3NO2, with the sample prepared in the glovebox to inhibit Cu(II) formation, showed significant broadening of the ligand peaks with subtle chemical shift changes in the quinoline proton signals of roughly 0.1 ppm (see Supporting Information, Figure S1). Addition of phenylacetylene further broadened the ligand peaks almost completely into the baseline with a minor additional downfield shift of the most downfield quinoline proton. The acetylene proton was also slightly shifted from its original position, however it is unknown if this shift is due to interaction with ligand-bound or free copper (I). Broadening of the ligand (precatalyst) peaks upon addition of the metal is indicative of a slow exchange (on the NMR timescale) between different complexes. The lack of discrete and characterizable Cu(I) complexes may be due to diverse coordination complexes that may be facilitated by the organocatalytic amine. We hypothesize that alternative coordination geometries, in particular hindered square planar complexes, may be more suitable for promoting intermolecular direct additions to alkynes.</p><!><p>We have investigated a strategy for the design and prioritization of potential bifunctional catalysts using as a guide DFT calculations of putative catalytic intermediates before and after C-C bond formation. This strategy was applied for the first time to novel Cu(I) complexes containing tridentate, heterocyclic ligands. We conclude that the designed bifunctional systems may not have sufficient affinity for Cu(I), or may undergo a range of dynamic coordination modes that precludes the formation of effective catalysts or well-characterizable complexes suitable for the desired direct additions of aldehydes and ketones to alkynes. Studies continue in our laboratories using alternative scaffolds with significantly greater rigidity.</p><!><p>Starting points for enamine-alkyne complex calculations were set by starting with the enamine-Cu(I)-acetylene complex (before C-C bond formation) and adduct (after C-C bond formation) from Table 2, entry 5. These complexes were drawn within the Avogadro 46 molecular visualization program and subjected to preliminary optimization with molecular mechanics. The alkyne and enamine carbons were fixed at a specific orientation and distance while the rest of the molecule was optimized using the auto-optimization feature (force field set to UFF, 4 steps per update, and steepest descent algorithm). The resulting coordinates were added to the Gaussian 09 input file for DFT calculations. Subsequent calculations of different precatalysts/substrates were preoptimized in Avogadro as described above, while keeping the enamine-alkyne starting orientation and distance from the original calculation constant. Starting adduct complexes were preoptimized using molecular mechanics as decribed above.</p><p>Geometries were then optimized and energies were calculated by DFT using the B3PW91 functional and the basis sets LANL2DZ for all metals and cc-pVDZ for other atoms, using the PCM solvation model with dichloromethane. Enthalpies and free energies were calculated at 298.15 K using unscaled harmonic vibrational frequencies. All calculations were performed with Gaussian 09 on the Père cluster at Marquette University.</p><!><p>A Vacuum Atmospheres Co. Omni-Lab glovebox was used for weighing out air sensitive materials, as noted in the detailed protocols. All reactions utilized magnetic stirring unless otherwise noted. All reagents and solvents were purchased from commercial vendors and used as received. NMR spectra were recorded on Varian 300 MHz or 400 MHz spectrometers as indicated. Proton and carbon chemical shifts are reported in parts per million (ppm; δ) relative to tetramethylsilane, CDCl3, or d6-DMSO ( 1 H δ 0, 13 C δ 77.16, or 13 C δ 39.5, respectively). NMR data are reported as follows: chemical shifts, multiplicity (obs = obscured, app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, sxt = sextet, m = multiplet, comp = complex overlapping signals); coupling constant(s) in Hz; integration. Unless otherwise indicated, NMR data were collected at 25 °C. Flash chromatography was performed using Biotage SNAP cartridges filled with 40-60 µm silica gel, or C18 reverse phase columns (Biotage® SNAP Ultra C18 or Isco Redisep® Gold C18Aq) on Biotage Isolera systems, with photodiode array UV detectors. Analytical thin layer chromatography (TLC) was performed on Agela Technologies glass plates with 0.25 mm silica gel with F254 indicator. Visualization was accomplished with UV light (254 nm) and aqueous potassium permanganate (KMnO4) stain followed by heating, unless otherwise noted. Tandem liquid chromatography/mass spectrometry (LC-MS) was performed on a Shimadzu LCMS-2020 with autosampler, photodiode array detector, and single-quadrupole MS with ESI and APCI dual ionization, using a Peak Scientific nitrogen generator. Unless otherwise noted, a standard LC-MS method was used to analyze reactions and reaction products: Phenomenex Gemini C18 column (100 x 4.6 mm, 3 µm particle size, 110 A pore size); column temperature 40 °C; 5 µL of sample in MeOH or CH3CN at a nominal concentration of 1 mg/mL was injected, and peaks were eluted with a gradient of 25−95% CH3CN/H2O (both with 0.1% formic acid) over 5 min., then 95% CH3CN/H2O for 2 min. Purity was measured by UV absorbance at 210 or 254 nm. High-resolution mass spectra were obtained at the University of Wisconsin-Milwaukee Mass Spectrometry Laboratory with a Shimadzu LCMS-IT-TOF with ESI and APCI ionization. Gas chromatography/mass spectrometry (GC-MS) was performed with Agilent Technologies 6850 GC with 5973 MS detector, and Agilent HP-5S or Phenomenex Zebron ZB-5MSi Guardian columns (30 m, 0.25 mm ID, 0.25 µm film thickness). Preparative HPLC was performed on a Shimadzu LC-20AP preparative HPLC with autosampler, dual wavelength detector, and fraction collector. Method: Column: Phenomenex Gemini C18 semi-preparative (250 x 10 mm, 5 µm particle size, 110 Å pore size); Mobile Phase: Solvent A: H2O w/ 0.1% formic acid; Solvent B: MeOH w/ 0.1% formic acid; Peak collection: measured by UV absorbance at 210 or 254 nm; Sample Injection: 0.3 mL (2 mL sample loop) of sample in DMSO; Flow Rate: 6.0 mL/min; Gradient: 0 to 1.5 min.: 25% MeOH, 1.5 min. to 12 min.: 25% to 95% MeOH, 12 min to 19 min: 95% MeOH. IR spectra were obtained as a thin film on ZnSe plate using a Thermo Scientific Nicolet iS5 spectrometer. Optical rotations were measured with a Rudolph Research Analytical Autopol polarimeter at λ = 589 nm, using a 2 mL cell with 10 cm path length. Specific rotations are reported as follows: [α]D T °C (c = g/100 mL, solvent). A VWR ® Analog vortex mixer fitted with a 5 x 5" sample box was used to shake reaction samples.</p><p>Alkyne and carbonyl stock solutions used for screening were made outside of the glovebox and purged with argon for 10 min. before being brought into the glovebox for use. Ligand solutions for crystallizations of Cu(I) complexes were made on the benchtop and purged with argon for 10 min. before being brought into the glovebox for use.</p><!><p>. N-Boc glycine (12) (6.28 g, 35.9 mmol) and L-threonine methyl ester, HCl salt (13) (6.08 g, 35.9 mmol) were added to a 500 mL round bottom flask with stir bar and dissolved with DCM (250 mL). HOBt (6.04 g, 39.4 mmol) was added followed by DIPEA (15.6 mL, 89.6 mmol), and sealed with a septum. The reaction stirred for 3 min. until the solids dissolved, then EDC HCl (7.56 g, 39.4 mmol) was added. The reaction stirred for 16 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LCMS to confirm reaction completion. The reaction was washed with half saturated sodium bicarbonate (2 x 250 mL), and 0.1 N HCl (2 x 250 mL). The combined aqueous washes were saturated with NaCl and extracted with EtOAc (3 x 250 mL). The combined organics were washed with brine. dried over sodium sulfate, filtered, and condensed to give the title compound as a clear oil (8.00 g, 77%). The crude product was pushed forward without further purification. This compound has been previously reported and characterized (CAS# 67864-88-4). 1 H NMR (400 MHz, CDCl3) δ = 1.20 (d, J = 8.2 Hz, 3 H), 1.45 (s, 9 H), 3.75 (s, 3 H), 3.88 (br s, 2 H), 4.34 (br s, 1 H), 4.58 (d, J = 8.6 Hz, 1 H), 5.72 (br s, 1 H), 7.26 (d, J = 8.2 Hz, 1 H).</p><!><p>Alcohol 15 (7.20 g, 24.9 mmol) was added to a 1 L round bottom flask with stir bar followed by DCM (600 mL) and Dess-Martin periodinane (12.62 g, 29.8 mmol). The flask was sealed with a septum and purged with nitrogen. The reaction was stirred for 1.5 h before water (0.45 mL, 24.8 mmol) was added, and the reaction stirred for another 3 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was poured on to a 10% sodium thiosulfate solution (400 mL) and stirred for 20 min. The organic layer was separated, washed with saturated aq. sodium bicarbonate (2 x 250 mL) and brine, then dried over sodium sulfate, filtered, and condensed to give the title compound as a yellow oil (5.80 g, 81%). The crude product was pushed forward without further purification. This compound has been previously reported and characterized (CAS# 1166831-50-0).</p><!><p>Ketone 16 (5.84 g, 20.3 mmol) was added to a 250 mL round bottom flask with stir bar followed by anhydrous THF (150 mL) under a nitrogen atmosphere. Lawesson's Reagent (12.29 g, 30.4 mmol) was added and the flask was fitted with a reflux condenser before the apparatus was sealed with a septum and purged with nitrogen for 15 min., before being heated to reflux for 16 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was condensed to an oil, then dissolved in EtOAc (250 mL) and washed with saturated sodium bicarbonate (2 x 250 mL). The aqueous washes were extracted with EtOAc (100 mL), and the combined organics were washed with brine and condensed to a yellow oil. The oil was adsorbed onto SiO2 (25 g), then purified by flash chromatography (100 g SiO2 cartridge; 0 to 100% EtOAc/hexanes gradient) to yield the title compound as a yellow oil (3.12 g, 53%). This compound has been previously reported and characterized (CAS# 232280-95-4). 1 H NMR (400 MHz, CDCl3) δ = 1.47 (s, 9 H), 2.74 (s, 3 H), 3.92 (s, 3 H), 4.55 (s, 2 H), 5.47 (br s, 1 H).</p><!><p>)carbonyl]amino}methyl)-5-methyl-1,3-thiazole-4-carboxylate (18). Carbamate 17 (3.00 g, 10.5 mmol) was added to an oven dried 250 mL round bottom flask with stir bar containing 4 Å molecular sieves (1.0 g). The flask was sealed with a septum and flushed with nitrogen, then anhydrous DMF (75 mL) was added. After 1 h the DMF solution was syringed away from the sieves into a second 250 mL oven round bottom flask with stir bar sealed under nitrogen. The sieves were rinsed with DMF under nitrogen (1 x 10 mL). Benzyl bromide (1.65 mL, 9.63 mmol) was added via syringe followed by NaH (0.545 g, 13.6 mmol). The reaction was stirred for 16 h under nitrogen. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was diluted with ether (250 mL), quenched with saturated aqueous ammonium chloride (150 mL), then diluted with water (750 mL). The organic layer was separated and the aqueous layer was saturated with solid NaCl, then extracted with ether (2 x 75 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and condensed to afford a light brown oil. The crude was purified by flash chromatography (50 g SiO2 cartridge; 0 to 45% EtOAc/hexanes gradient) to give the title compound as a yellow oil (2.30 g, 58%). TLC Rf = 0.33 (70:30 hexane:EtOAc); 1 H NMR (300 MHz, CDCl3) δ = 1.33 -1.73 (m, 9 H), 1.51 (s, 9 H), 2.75 (s, 3 H), 3.93 (s, 3 H), 4.48 (s, 2 H), 4.63 (d, J = 1.0 Hz, 2 H), 7.28 (t, J = 8.8 Hz, 5 H); 13 C NMR is complicated due to rotamers. 13   (19). Ester 18 (2.00 g, 5.31 mmol) was added to an oven dried 100 mL round bottom flask with stir bar followed by sodium triacetoxyborohydride (0.059 g, 0.27 mmol), and sodium borohydride (0.433 g, 11.2 mmol). The flask was sealed with a septum and purged with nitrogen before anhydrous THF (30 mL) was added via cannula. The reaction was stirred for 5 min., then anhydrous methanol (0.86 mL, 21.3 mmol) was added via syringe over 5 min. The reaction was heated at 35 °C for 16 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was diluted with EtOAc (50 mL) and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was saturated with solid NaCl, then extracted with 10% MeOH in DCM (3 x 75 mL). The combined organics were washed with brine and condensed to give the title compound as a yellow oil (1.93 g, 104%). The crude material was moved forward without purification. TLC Rf = 0.31 (50:50 hexane:EtOAc); 1 H NMR (300 MHz, CDCl3) δ = 1.48 (br s, 9 H), 2.36 (br s, 3 H), 4.27 -4.83 (m, 6 H), 7.26 (s, 5 H); 13 C NMR is complicated due to rotamers. 13 C NMR (75 MHz, CDCl3) δ = 11.2, 28.6, 47.7, 47.9, 50.1, 50.8, 58.0, 77.5, 81. 1, 127.6, 127.8, 128.4, 128.7,  130.1, 130.4, 137.7, 137.9, 150.7, 155.3, 155.7, 165.1, 165.5; IR (film) 3439, 1683, 1495, 1407, 700 cm −1 ; HRMS (ESI + ) calculated for C18H25N2O3S [M+H] 349.1586, found 349.1547. (20). Alcohol 19 (1.90 g, 5.45 mmol) was added to an oven dried 50 mL round bottom flask with stir bar. The flask was sealed under nitrogen and anhydrous DCM (30 mL) was added followed by mesyl chloride (0.63 mL, 8.18 mmol) and triethylamine (1.14 mL, 8.18 mmol). The reaction was warmed to 30 °C and stirred for 12 h. The DCM was removed via rotary evaporator, and the crude oil was taken up into anhydrous DMF (30 mL). Sodium azide (0.425 g, 6.54 mmol) was added in one portion and the reaction stirred for 6 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was diluted with ether (250 mL) and water (750 mL), and the organic layer was separated and the aqueous layer extracted with ether (2 x 100 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and condensed to give a brown oil. The oil was dissolved with minimal DCM and purified by flash chromatography (25 g SiO2 cartridge; 0 to 22% EtOAc:hexanes gradient) to give the title compound as a yellow oil (2.20 g, 51%). TLC Rf = 0.47 (80:20 hexane:EtOAc); 1 H NMR (300 MHz, CDCl3) δ = 1.48 (s, 9 H), 2.43 (s, 3 H), 4.33 (s, 2 H), 4.41 -4.67 (m, 4 H), 7.16 -7.40 (m, 5 H). 13 C NMR is complicated due to rotamers. 13 C NMR (75 MHz, CDCl3) δ = 11.5, 28.6, 47.6, 47.9, 50.0, 50.7, 77.</p><!><p>Azide 20 (1.10 g , 2.95 mmol) was added to a 250 mL pressure flask with stir bar followed by methanol (70 mL). The flask was purged with argon, then 10% Pd/C (0.470 g, 0.442 mmol) was added. The reaction flask was attached to a Parr hydrogenator, evacuated, and backfilled with hydrogen to 2 atm x 3. The reaction was stirred vigorously under 2 atm of hydrogen for 3 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction mixture was passed through a pad of Celite, then concentrated to afford the title compound as a yellow oil (0.955 g, 93%). The crude product was used directly without further purification. TLC Rf = 0.39 (80:20 hexane:EtOAc);</p><!><p>). Amine 21 (0.200 g, 0.576 mmol) was added to an oven dried 20 mL vial with stir bar followed by glacial acetic acid (4.5 mL). Next, quinoline-8-carbaldehyde (0.105 g, 0.633 mmol) and sodium triacetoxyborohydride (0.146 g, 0.691 mmol) were added. The vial was purged with nitrogen and the reaction was stirred for 16 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. 1.0 N aq. NaOH was added until the pH was greater than 12. The aqueous solution was saturated with NaCl and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and condensed to give a dark red/brown oil. The oil was dissolved with DCM (10 mL) and Amberlyst ® 15 ion exchange resin (2 g) was added. The crude was stirred with the resin for 12 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction the product had bound completely to the resin. The resin was filtered and washed with EtOAc (50 mL). The washed resin was placed in a 50 mL round bottom flask with 3.5 N ammonia in methanol (30 mL) and stirred for 3 h. The resin was filtered and washed with 3.5 N ammonia in MeOH until no further material eluted, as detected by TLC. The combined washes were condensed to give a brown oil, which was dissolved with minimal DCM and purified by flash chromatography (5 g SiO2; 0-12% 0.5 N NH4 in MeOH:DCM) to give the title compound as a dark red oil (168 mg, 75%). TLC Rf = 0.73 (90:10 MeOH:DCM); 1</p><!><p>). Amine 21 (0.150 g, 0.432 mmol) was added to an oven dried 100 mL round bottom flask with stir bar followed by anhydrous THF (35 mL). Next, salicylaldehyde (0.063 g, 0.52 mmol) and sodium triacetoxyborohydride (0.137 g, 0.648 mmol) were added. The vial was sealed under nitrogen and stirred for 16 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LCMS to confirm reaction completion. The reaction was washed with saturated ammonium chloride and the aqueous layer extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and condensed to give a yellow oil. The oil was dissolved with DCM (10 mL) and Amberlyst ® 15 ion exchange resin (2 g) was added. The crude was stirred with the resin for 12 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm the product had bound completely to the resin. After stirring the resin was filtered and washed with EtOAc before being placed in a 50 mL round bottom flask with 3.5 N ammonia in methanol and stirred for 3 h. The resin washed with 3.5 N ammonia in MeOH unil no further material could be seen coming off the resin by TLC. Combined washes were condensed to give a yellow oil. The compound was purified by flash chromatography (12 g C18 cartridge; 15 to 95% MeOH:H2O gradient) to afford the title compound as a pale yellow oil (70 mg, 45%). TLC Rf = 0.53 (90:10 DCM:MeOH); 1 H NMR (400 MHz, CDCl3 δ = 2.30 (s, 3 H), 3.76 (s, 2 H), 3.87 (s, 2 H), 3.94 (s, 2 H), 4.03 (s, 2 H), 6.77 (t, J = 1.0 Hz, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 7.4 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.22 -7.30 (m, 1 H), 7.30 -7.41 (m, 4 H); 13</p><!><p>)methyl]-5-methyl-1,3-thiazol-4-yl}methyl)amino]methyl}-4-chlorophenol (22c). Prepared as described for 22b. Purified by flash chromatography (5 g SiO2 cartridge; 0 to 12% 0.5 N NH4 in MeOH:DCM gradient) then (12 g C18 cartridge; 15 to 95% MeOH:H2O gradient) to afford the title compound as a pale yellow oil (56 mg, 33%). TLC Rf = 0.50 (90:10 DCM:MeOH); 1</p><!><p>. N-Boc-Lproline (14) (5.38 g, 24.5 mmol) and L-threonine methyl ester, HCl salt (13) (4.16 g, 24.5 mmol) were added to a 1.0 L round bottom flask with stir bar containing DCM (400 mL). HOBt (4.13 g, 27.0 mmol) was added followed by TEA (8.60 mL, 61.7 mmol) and EDC HCl (5.17 g, 27.0 mmol). The reaction was stirred for 20 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion.The reaction was washed with half saturated aq. sodium bicarbonate (2 x 200 mL) and 0.2 N HCl (2 x 200 mL). The combined aqueous washes were extracted with DCM (2 x 100 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and condensed to give the title compound as a colorless oil (5.91 g, 73%). The crude product was pushed forward without further purification. This compound has been previously reported and characterized (CAS# 80897-23-0). 1</p><!><p>)-1-methoxy-1,3-dioxobutan-2-yl]carbamoyl}pyrrolidine-1-carboxylate (24). Alcohol 23 (5.91 g, 17.9 mmol) was added to a 1 L round bottom flask with stir bar followed by DCM (300 mL) and Dess-Martin periodinane (8.35 g, 19.7 mmol). The flask was sealed with a septum and flushed with nitrogen. The reaction was stirred for 3 h before water (0.322 mL, 17.9 mmol) was added and the reaction stirred for another 3 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LC-MS to confirm reaction completion. The reaction was poured on to a 10% sodium thiosulfate solution (400 mL) and stirred for 45 min until both layers turned clear. The organic layer was separated, washed with saturated aq. sodium bicarbonate (2 x 100 mL) and brine, then dried over sodium sulfate, filtered, and condensed to give a yellow oil. The crude was purified by flash chromatography (100 g SiO2</p>