Macrocyclic N-Heterocyclic Carbenes: Synthesis and Catalytic

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

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Macrocyclic N‑Heterocyclic Carbenes: Synthesis and Catalytic Applications Anibal R. Davalos, Eric Sylvester, and Steven T. Diver* Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, New York 14260-3000, United States

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ABSTRACT: A synthesis of two macrocyclic N-heterocyclic carbenes (NHCs) is reported. An advanced intermediate could be differentiated to access either imidazolium or dihydroimidazolium salts. Deprotonation gave a nucleophilic carbene that promoted the intramolecular Michael−Stetter reaction. The NHC also served as a ligand for transition metal catalysts, giving a metathesis catalyst that catalyzed alkene and ene-yne metathesis and a Pd catalyst that promoted Suzuki couplings.

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INTRODUCTION N-Heterocyclic carbenes (NHCs) are versatile ligands for metal catalysis.1 As strong σ donors, they tend to be firmly bound to the metal. The electronic and steric properties can be tuned through the nitrogen heterocycle or through the N-aryl substituents.2 In alkene metathesis, the presence of the NHC dramatically increased reactivity and improved chemoselectivity of the Grubbs catalysts.3 Accordingly, the NHC has been extensively modified to achieve further catalyst improvements.4 Nolan5 and others6 showed that Pd−NHCs provide significant reactivity in the cross-coupling of aryl chlorides due to their electron-rich nature, and Organ created a family of welldefined bulky NHC−Pd catalysts suitable for diverse crosscoupling reactions.7 In addition, N-heterocyclic carbenes are nucleophilic catalysts that promote C−C bond formation, another exciting area of catalysis.8 An N-heterocyclic carbene in a macrocycle is unique9 and creates additional possibilities for catalysis beyond simple NHC−metal binding. With an NHC embedded in the macrocycle, the metal may be organized inside the cavity, directing reactivity in an enclosed environment. Macrocyclic structures may offer additional benefits such as molecular recognition, binding of substrates, and increased stability of catalytic intermediates.10 Despite these potential benefits, complex NHCs can be difficult to synthesize. In this work, we developed a new and facile synthesis of a macrocyclic NHC. We designed and synthesized a macrocyclic NHC using a modular approach that could access different azolium subunits in order to produce dihydroimidazole or imidazole carbenes11 (Scheme 1). In this article, we report the synthesis of two macrocyclic NHCs and two macrocyclic NHC−metal complexes. In addition, proof for the molecular structure was obtained by a single-crystal X-ray structure of an imidazolium salt, a macrocyclic Hoveyda−Grubbs carbene complex, and a macrocyclic Pd(II) complex. Last, we demonstrate catalysis applications of two macrocyclic NHC−metal complexes in organometallic chemistry. A flexible synthesis of macrocyclic NHC precursors and metal complexes was sought to better understand the © XXXX American Chemical Society

Scheme 1. Macrocyclic Azolium Salts

conformation and structure so that bifunctional catalysts can be made in the future. Embedding the NHC into a macrocyclic ring may permit dual, possibly synergistic, functions from the ligand and the macrocycle. Though supramolecular catalysis is a long-term goal, this study focused on the synthesis and metalation of the NHC ligand. Structural characterization would help to understand its orientation, structure, and reactivity. Deprotonation of the C2 position of the azolium ring provides an NHC that can either serve as a nucleophile in its own right or can ligate to metals. A rigid structure was expected on the basis of molecular modeling, where the gentle downward sweep of the aromatic rings appended to the azolium was fixed by the macrocyclic ring, thereby restricting rotation of the NHC. However, at the outset, it was unclear if such a rigid NHC could be metalated. The reactivity of the NHC−metal complexes was expected to depend on their conformation. Depending on the orientation, geometry, and ligands at the metal, it was unknown whether the metal fragment would be able to fold into the macrocyclic interior or whether it would orient outside the cavity. The direct goal of this work is to develop a workable and modular synthesis of macrocyclic NHC ligands. For maximum versatility, we desired a flexible synthesis that could access either imidazole or dihydroimidazole carbenes. As new ring structures with unknown conformation, we were also Received: March 11, 2019

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DOI: 10.1021/acs.organomet.9b00152 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics Scheme 2. Preparation of Sidewalls and Key Intermediate 8

Scheme 3. Synthesis of Macrocyclic Imidazolium Salt 1

of 7 with glyoxal produced bisimine 8 in good yield. Bisimine 8 served as the precursor to the two different azolium macrocycles. First the imidazolium-containing macrocycle was accessed from the advanced intermediate 8 (Scheme 3). The azolium ring was forged prior to RCM. Cyclization of 8 with CH3CH2OCH2Cl12 gave the imidazolium salt 9 in good yield. The RCM step was conducted under high dilution (0.5 mM) and required some optimization. The second generation Grubbs catalyst (G2) gave complete conversion and good yield but required protracted reaction times. The Hoveyda complex (HG2) did not lead to complete conversions. Interestingly, the best catalyst was found to be the first generation Grubbs catalyst (Cy3P)2Cl2RuCHPh (G1), which resulted in 98% conversion in a 4 h reaction time under the same conditions. Gratifyingly, the RCM product precipitated from the reaction mixture; it was isolated by means of a simple filtration. The RCM gave an inconsequential mixture of 60:40 E/Z isomers; hydrogenation then provided the macrocycle 1 in 68% overall yield from bisimine 8 (three steps). The dihydroimidazolium tetrafluoroborate salt was synthesized based on a different heterocyclization step but employed a similar macrocyclic ring closure (Scheme 4). First, bisimine 8 was reduced to 1,2-diamine 10 and then cyclized with (EtO)3CH in the presence of NH4BF4 to provide dihydroimidazolium salt 11. Alternative acids can be used in the cyclization step to provide dihydroimidazolium salts with different counterions; we focused on the tetrafluoroborate as we expected it to be less hygroscopic. The same RCM/ hydrogenation sequence was applied. Similar to the above RCM, the optimum catalyst was found to be G1, which provided a 60:40 ratio of intermediate E/Z isomers which were reduced directly to dihydroimidazolium (imidazolinium) salt 2 in good yield. Through the three steps from 8, a 69% overall yield was obtained. The entire synthetic sequence from 3 and 4

interested in determining structure of both the NHC ligands and their metal complexes. Metal complexes proved capable as catalysts for alkene metathesis applications and for Suzuki couplings.

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RESULTS AND DISCUSSION

The macrocyclic NHC was synthesized by halves to simplify the synthesis. Macrocycles 1 and 2 were dissected into two halves down an imaginary vertical line bisecting the C2 of the azolium ring and the C3−C4 bond of the n-hexyl chain joining the bottom aromatic rings (Scheme 1). Ring closure of the C3−C4 bond was envisioned by ring-closing metathesis (RCM) and hydrogenation. Because we needed access to both imidazole and dihydroimidazole carbenes, we sought an advanced intermediate that could be separately converted to either heterocycle. Bisimines produced by condensation of two anilines and glyoxal provide this versatility as the bisimine can be alternatively cyclized to give an imidazolium salt or reduced and cyclized to give a dihydroimidazolium salt. The synthesis began with construction of the diarylated dibenzofuran sidewalls by successive Pd-catalyzed crosscouplings (Scheme 2). Aniline 3 was coupled to excess 4 using Pd(PPh3)4 as the catalyst, giving aniline 5 in very good yield. Though Suzuki coupling has been performed in the presence of anilines, the high yield and lack of any byproducts is noteworthy. In the second step, boronic acid 6 was coupled to 5 under similar conditions. Initially, high yields of 7 were obtained with benzene or toluene as solvents at reflux temperatures, but an inseparable, isomerized byproduct was also formed. Any alkene chain walking made characterization difficult and would result in smaller ring sizes, thus altering the interior dimension of the final macrocycle. Use of THF− methanol completely suppressed alkene isomerization and delivered coupling product 7 in excellent yield. The reduced isomerization can be attributed to the lower reaction temperature in this binary solvent system. Last, condensation B


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Organometallics

metal. However, this flexibility might also be observed in metal complexes, giving multiple conformations. Second, the ring was square but not box-shaped; flattened biaryls could explain this observation. Some of the phenyl−dibenzofuran torsion angles were smaller than the ideal orthogonal arrangement. In contrast, the imidazolium ring was nearly perpendicular to the 2,6-dimethylphenyl ring, owing to the ortho-substitution. Last, two conformations of the alkane chain were observed with equal occupancy in the unit cell, and only one conformation is depicted in Chart 1. Each macrocyclic azolium salt catalyzed an intramolecular Michael−Stetter reaction (eq 1). Typically, aromatic azolium

Scheme 4. Synthesis of Macrocyclic Dihydroimidazolium Salt 2

to either azolium salt 1 or 2 could be scaled to gram scale and completed in a short time period. The macrocyclic azolium salts showed only minor changes in their proton NMR spectra. Comparison of the acyclic 9 to cyclic 1 is illustrative. The diagnostic C2 proton of the imidazolium ring shifted slightly from 9.91 to 9.82 ppm upon cyclization. Similarly, small chemical shift differences were found in the backbone imidazolium protons, shifting from 8.51 to 8.48 ppm on cyclization. Last, the aromatic methine protons of the 2,6-dimethylphenyl groups shifted slightly downfield from 8.14 to 8.19 ppm. These relatively small effects are probably due to the large dimension of the ring, with minimal transannular anisotropic effects from distant aromatic rings. The structure of 1 was verified by a single-crystal X-ray structure (Chart 1). The solid-state structure showed an unexpected conformation. First, the azolium ring, and the C1− H (ORTEP numbering), in particular, was not pointing directly inside the cavity but tipped outward somewhat. This was considered promising for metalation as the NHC would be able to adopt an extra-annular conformation to react with the

salts such as 1 (and their aromatic congeners, triazolium salts) are used to promote this reaction and tend to be used most frequently in nucleophilic catalysis.8b Saturated NHCs such as 2 are less commonly used for nucleophilic catalysis applications. Aromatic (1) and nonaromatic (2) azolium salts have similar pKa values,13 but their nucleophilic properties may be dramatically attenuated by the steric demand and/or conformation of the macrocyclic ring. To investigate their nucleophilic properties, we compared azolium salts 1 and 2 as catalysts for a classic intramolecular Michael−Stetter reaction. The reactivity was compared in each case to the corresponding acyclic IMes (1,3-bis(2,4,6-trimethylphenyl)imidazolium) or H2IMes (1,3-bis(2,4,6-trimethylphenyl)dihydroimidazolium) catalysts. Each of the new macrocyclic NHC catalysts were found to promote the reaction in eq 1 with comparable yields, illustrating similar electronic properties and steric demand in this reaction.

Chart 1. X-ray Structure of Imidazolium Salt 1a

a

Ellipsoids drawn at 50% probability. Hydrogen atoms have been omitted for clarity. Select torsion angles (deg): C1−N1−C3−C8 72.02, C5− C6−C11−C12 7.36, and C17−C22−C23−C28 36.87. Complete atom numbering is available in the submitted crystallographic files. C


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Organometallics Next, 2 was metalated to form a Hoveyda-type Ru−carbene complex (eq 2). Interestingly, salt 2 was insoluble in benzene

Scheme 5. Metathesis Reactions Promoted by Ru1

but was found to dissolve completely as the neutral carbene was generated upon deprotonation with potassium hexamethyldisilazide (KHMDS). Addition of the first generation Hoveyda complex, followed by warming to 80 °C for a 2 h period, resulted in complete ligand exchange to give Ru1 in good yield. To achieve complete conversion of the starting Ru−carbene, a slight excess of the macrocyclic NHC 2 was needed. Ru1 was obtained as a green solid with a characteristic carbene proton at δ 16.65 ppm. The structure of Ru1 was determined by a single-crystal Xray study (Chart 2). Crystals of Ru1 (mp 181 °C) were grown from benzene. First, the nature of the Ru−carbene bonding is similar to that observed for other Hoveyda-type complexes: the Ru−O bond length is 2.422 Å, the RuC bond length is 1.831 Å, and the Cl−Ru−Cl angle is 160°.14 The long Ru−O bond may be due to steric repulsion between the i-PrO group and the adjacent macrocyclic bridge. The C1−Ru distance is 1.961 Å, longer than average for Hoveyda complexes (usually 1.78− 1.83 Å),14 as might be expected for a bulky NHC ligand. The macrocycle is extended to one side of the metal and does not envelop the metal inside, as was expected.15 Interestingly, all of the aromatic dihedral angles are skewed (top rings, 36.6 and 29.3°; bottom rings, 37.2 and 39.2°), which may allow conformational freedom to the ring and results in a flattened box shape. Last, the dimension of the macrocycle can be seen by measuring the average distance from the nitrogen atoms of the azole ring to C27 and C36, which is ∼7 Å across. The macrocyclic Ru−carbene performed alkene and ene-yne metathesis (Scheme 5). Evaluation of Ru1 in these reactions

was intended to gauge reactivity of the ruthenium−carbene as the NHC is bulky and because the bridging group of the macrocycle may have impacted metathesis activity. The crystal structure in Chart 2 shows that the metal−carbene of the precatalyst and the bridge of the macrocycle are on the same side (in the solid state). This structural feature is unusual and unlike steric hindrance imparted by bulky 2,6-disubstitution on a N,N-diarylated NHC such as SIPr (1,3-bis(2,6diisopropylphenyl)imidazolium). First, self-metathesis of allylbenzene proceeded in high yield, at very low catalyst loading (eq 3), following the procedure of Grubbs et al.16 The results compared favorably to that obtained with the Hoveyda complex HG2 and gave similar E/Z ratio. We were also interested in ethenolysis, which finds application in renewable energy. Conversion of seed oils to fuels requires highly efficient and robust catalysts.17 We anticipated that the macrocycle might protect the RuCH2 intermediate from bimolecular decomposition,18 due to the bulk and proximal macrocyclic bridge feature seen in the solid-state structure. Ethenolysis in eq 4 was conducted at elevated ethylene pressure and compared to commercially available Hoveyda−Grubbs complex HG2. A superior yield was obtained with macrocyclic Ru1. Although promising, further studies on stability of catalytic intermediates are needed. An ene-yne metathesis was catalyzed by Ru1 under standard conditions, giving the 1,3diene in 68% NMR yield as a 1.4:1.0 E/Z mixture (eq 5). Last, the RCM of imidazolium 9 gave 80% conversion to a 69:31 E/

Chart 2. X-ray Structure of Ru−Carbene Complex Ru1a

a

Ellipsoids drawn at 50% probability. Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å): C1−Ru1 1.981; Ru1−C62 1.831; Ru1−O1 2.242; C11−Ru1 2.346. Select torsion angles (deg): C6−C7−C12−C13 37.60; C23−C22−C24−C29 37.22. Select bond angles (deg): Cl1−Ru−Cl2 160.12; N1−C1−Ru1 119.1; N2−C1−Ru1 134.3. For all atom numbering, please refer to the submitted crystallographic files. D


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Organometallics Z mixture under the standard conditions of the RCM used to form the macrocyclic azolium salts above (CH2Cl2, reflux).19 Similarly, incomplete conversion was seen using Hoveyda− Grubbs-type complexes such as HG2. A Pd complex was synthesized next. We synthesized Pd1 following Organ’s procedure (eq 6 in Scheme 6),7 used to

The Pd complex Pd1 was found to promote cross-coupling (Scheme 6). The complex Pd1 catalyzed a benchmark Suzuki coupling between phenylboronic acid and chlorobenzene (eq 7).20 Pd1 also catalyzed the cross-coupling of 5 with 6 shown in Scheme 2, giving 7 in 98% NMR yield.19 At increased temperatures, Pd1 promoted the Buchwald−Hartwig coupling of morpholine with chlorobenzene, giving the aniline product in 81% isolated yield (eq 8).

Scheme 6. Synthesis of Pd1 and Pd-Catalyzed CrossCouplings

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CONCLUSIONS In conclusion, a modular synthesis of macrocyclic azolium salts was developed and applied to nucleophilic and metal-based catalysis. Modules were joined through Suzuki coupling, and the macrocycle was formed through ring-closing alkene metathesis and subsequent hydrogenation. An advanced intermediate could be converted into either the imidazolium or dihydroimidazolium salts, lending versatility to this NHC synthesis. Each azolium salt proved to be competent nucleophiles able to promote an intramolecular Michael− Stetter reaction. A Ru−carbene catalyst that incorporated the macrocyclic ligand was active in alkene and ene-yne metathesis. Structural studies revealed a flattened box structure that positions the Ru−carbene moiety alongside the macrocyclic ring. A bulky Pd(II) complex was synthesized bearing the macrocyclic NHC, which adopted a belt-like structure in the solid state. The Pd(NHC) was found to promote Suzuki couplings and a Buchwald−Hartwig amination. Synthesis of rigidified macrocycles based on the modular synthesis developed here is ongoing in our lab for applications as robust and selective organometallic catalysts.

attach hindered NHCs to Pd. Use of excess 1 was needed to limit formation of an unwanted dimer. Isolated Pd1 was fully characterized and produced X-ray-quality crystals by slow crystallization from chloroform. The structure of Pd1 shown in Chart 3 has similarities with the structure of the free imidazolium salt and the Ru−carbene complex Ru1. The pyridine ligand is located trans to the macrocyclic NHC ligand and is positioned to the side of the macrocycle rather than located inside the macrocycle. Instead of the macrocyclic NHC enveloping the metal, the macrocyclic NHC forms a belt-like structure off to the side of the Pd− NHC bond. Both the 2,6-dimethylphenyl−benzofuran bond (e.g., C7−C12) and the benzofuran−phenyl bonds (e.g., C22−C24) are skewed from an ideal 90° dihedral angle. Two representative dihedral angles are provided in the legend of Chart 3.

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EXPERIMENTAL SECTION

General Information. All glassware was oven-dried prior to use. All reactions were performed under a nitrogen or an argon atmosphere, unless otherwise noted. The solvents THF, diethyl ether, and CH2Cl2 were purified by passing through activated alumina columns using a solvent purification system under N2. The aromatic solvents toluene and benzene were purified by passing through Q5 and activated alumina columns. Ruthenium−carbene catalysts were obtained from Materia, Inc. All chemicals were purchased as reagent grade from commercial suppliers and used without further purification, unless otherwise noted. Quenching agents KO2CCH2NC

Chart 3. X-ray Structure of Pd(II) Complex Pd1a

a Ellipsoids drawn at 50% probability. Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å): C1−Pd1 1.969; Pd1−N3 2.106; Pd1−Cl1 2.316; Pd1−Cl2 2.329 Å. Select torsion angles (deg): C8−C7−C12−C17 27.05; C23−C22−C24−C29 48.45. For all atom numbering, please refer to the submitted crystallographic files.

E


Article

Organometallics were prepared and used as reported previously.21 1H and 13C NMR spectra were recorded on a Varian Mercury-300, Varian Inova-400, or Varian Inova-500. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane and referenced to CDCl3 (7.26 ppm for 1H and 77.0 ppm for 13C), DMSO (2.50 ppm for 1H and 39.5 ppm for 13C), (CD3)2CO (2.05 ppm for 1H and 29.9, 206.7 for 13C), CD3CN (1.96 for 1H and 1.79, 118.3 for 13C), and CD3OD (4.87, 3.31 for 1H and 49.1 for 13C). Coupling constants (J) are reported in hertz (Hz), and multiplicities are abbreviated as singlet (s), broad singlet (br s), doublet (d), doublet of doublets (dd), triplet (t), triplet of doublets (td), and multiplet (m). Gas chromatography data were obtained using a Shimadzu GC-17A gas chromatograph equipped with an Agilent J&W HP-5 column. Instrument conditions: inlet temperature = 280 °C; detector temperature = 280 °C; hydrogen flow = 1 mL/min; air flow = 0.9 mL/min; constant column flow = 25 mL/min. GC Method: 40 °C for 4 min, followed by a temperature increase of 25 °C/min to 300 °C and a subsequent isothermal period at 300 °C for 55 min (total run time = 70 min). 4-(6-(4-(But-3-en-1-yl)phenyl)dibenzo[b,d]furan-4-yl)-2,6dimethylaniline (7). The synthesis was adapted from a previously published procedure.22 In an oven-dried Schlenk tube charged with 5 (2.7 g, 7.38 mmol, 1 equiv) and 6 (3.9 g, 22.1 mmol, 3 equiv), THF (220 mL), methanol (70 mL), and 2 M Na2CO3 (aq) solution (11.1 mL, 22.1 mmol, 3 equiv) were added. The mixture was sparged with nitrogen for 5 min. Then, Pd(PPh3)4 (0.852 g, 0.74 mmol, 0.1 equiv) was added, and the system was stirred and refluxed for 14 h. The reaction was allowed to cool to room temperature before being transferred to a separatory funnel containing dichloromethane (300 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel and 10% EtOAc in hexanes as eluent afforded 3.05 g (99%) of aniline 7 as a white solid: mp 179−180 °C; analytical TLC (20% EtOAc in hexanes) Rf 0.28; 1H NMR (500 MHz, CDCl3, ppm) δ 7.89 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.62 (s, 2H), 7.58 (dd, J = 8.5, 8.5 Hz, 2H), 7.32 (dd, J = 7.6, 7.6 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.88 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.07 (d, J = 17.0 Hz, 1H), 5.00 (d, J = 10.3 Hz, 1H), 3.42 (br s, 2H), 2.74 (t, J = 7.7 Hz, 2H), 2.40 (dt, J = 7.7, 6.6 Hz, 2H), 2.21 (s, 6H); 13C NMR (126 MHz, CDCl3, ppm) δ 153.29, 153.25, 142.74, 141.42, 138.21, 134.03, 128.72, 128.68 (2C), 126.13, 125.84, 125.68, 125.48, 125.44, 125.11, 124.84, 123.32, 123.23, 121.76, 119.53, 118.42, 115.14, 35.61, 35.29, 17.89; FT-IR (ATR, cm−1) 2921, 2870, 1590, 1484, 1433, 1399, 1065, 867, 838, 773, 737; HR-MS (ESI) m/z calcd for C30H27NO ([M + Na]+), 440.1984, found 440.1985, error 0.1 ppm. N,N′-(Ethane-1,2-diylidene)bis(4-(6-(4-(but-3-en-1-yl)phenyl)dibenzo[b,d]furan-4-yl)-2,6-dimethylaniline) (8). The synthesis was adapted from a previously published procedure.23 In a 100 mL round-bottom flask equipped with a stir bar, 7 (2.5 g, 6.0 mmol, 2 equiv) was dissolved in THF (50 mL) and ethanol (10 mL). Then, 40 wt % of an aqueous glyoxal solution (0.435 mL, 3.0 mmol, 1 equiv) was added, followed by two drops of formic acid. The solution was stirred for 24 h at room temperature. Abundant yellow precipitate was observed and filtered off, followed by a cold methanol wash and drying under high vacuum. The remaining solution was stirred overnight, and a second batch of product was recovered. Purification by recrystallization using methanol gave 1.8 g (68%) of diimine 8 as yellow needles: changes from yellow to dark brown at 258 °C; analytical TLC (10% EtOAc in hexanes) Rf 0.32 (product degrades on silica gel); 1H NMR (500 MHz, CDCl3, ppm) δ 8.34 (s, 2H), 8.00 (d, J = 7.8 Hz, 4H), 7.97−7.30 (m, 4H), 7.86 (s, 4H), 7.75 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.49−7.43 (m, 4H), 7.40 (d, J = 7.8 Hz, 4H), 5.98 (ddt, J = 16.5, 10.2, 6.7 Hz, 2H), 5.16 (d, J = 16.5, 2H), 5.08 (d, J = 10.2 Hz, 2H), 2.86 (t, J = 7.7 Hz, 4H), 2.51 (dt, J = 7.7, 6.7 Hz, 4H), 2.40 (s, 12H); 13C NMR (126 MHz, CDCl3) δ 163.58, 153.31, 153.26, 149.39, 141.57, 138.05, 133.85, 132.67, 128.69, 128.62 (2C), 126.92 (2C), 126.34, 125.99, 125.49, 124.98, 124.95, 124.88, 123.35, 123.33, 119.51, 115.09, 35.53, 35.20, 18.59; FT-IR (ATR, cm1) 2921, 2870, 1590, 1484, 1433, 1399, 1065, 867, 838, 773,

737; HR-MS (ESI) m/z calcd for C62H52N2O2 ([M + H]+) 857.4107, found 857.4104, error −0.3 ppm. 1,3-Bis(4-(6-(4-(but-3-en-1-yl)phenyl)dibenzofuranyl)-2,6dimethylphenyl)-1H-imidazol-3-ium Chloride (9). In a 500 mL round-bottom flask, 8 (1.8 g, 2.1 mmol, 1 equiv), THF (285 mL), and chloromethyl ethyl ether (0.893 mL, 10.5 mmol, 5 equiv) were added. The reaction solution was stirred at 45 °C overnight before evaporating 3/4 of the solvent. The rest of the mother liquor was diluted with ether, centrifuged, and decanted. This process was repeated five times. The precipitate was isolated and dried in vacuo to obtain 1.6 g (85%) of product 9 as a beige solid: changes from beige to dark brown at 246 °C; analytical TLC (10% MeOH in dichloromethane) Rf 0.39; 1H NMR (500 MHz, DMSO, ppm) δ 9.89 (s, 1H), 8.49 (s, 2H), 8.27 (d, J = 7.5 Hz, 2H), 8.20 (d, J = 7.5 Hz, 2H), 8.12 (s, 4H), 7.96 (d, J = 7.3 Hz, 4H), 7.91 (d, J = 7.3 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.59 (dd, J = 7.5, 7.3 Hz, 2H), 7.54 (dd, J = 7.5, 7.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 4H), 5.93−5.81 (m, 2H), 5.06 (d, J = 17.1 Hz, 2H), 4.97 (d, J = 10.0 Hz, 2H), 2.76 (t, J = 7.3 Hz, 4H), 2.41−2.37 (m, 4H), 2.34 (s, 12H); 13C NMR (126 MHz, DMSO, ppm) δ 152.98, 152.94, 141.96, 139.18, 138.44, 138.10, 135.62, 133.47, 133.37, 129.25, 129.19, 128.88, 127.24, 127.11, 125.39, 125.32, 125.06, 124.54, 124.50, 124.45, 123.48, 121.94, 120.79, 115.73, 35.31, 34.67, 17.73; FT-IR (ATR, cm−1) 2850, 2100, 1545, 12477, 1261, 1022, 1065, 797; HR-MS (ESI) m/z calcd for C63H53N2O2 [M]+ 869.4102, found 869.4084, error 2.0 ppm. Macrocyclic Imidazolium Chloride (1). In a 2 L oven-dried three-neck flask equipped with a stir bar and a water condenser under nitrogen atmosphere, a solution of 9 (0.440 g, 0.486 mmol, 1 equiv) in CH2Cl2 (540 mL, 0.9 mM) was prepared. To the solution was added first generation Grubbs catalyst (0.040 g, 0.048 mmol, 0.1 equiv), and the mixture was kept under nitrogen with an open needle at the top of the condenser as an ethylene exhaust. The reaction was refluxed for 12 h before being quenched with the carboxylate isocyanide catalyst KO2CCH2NC (0.067 g, 0.54 mmol, 0.4 equiv). After being stirred for 30 min, the reaction mixture was filtered through a pad of silica gel and concentrated. The product was washed with ether, centrifuged, and decanted. This process was repeated four times with 20 mL portions of ether to isolate 0.380 g (89%) of the alkenyl imidazolium macrocycle as a beige solid with a 60:40 E/Z mixture: 1H NMR (400 MHz, DMSO, ppm) δ 9.82−9.80 (m, 1H), 8.48 (m, 3H), 8.28 (d, J = 7.4 Hz, 2H), 8.19 (d, J = 10.1 Hz, 2H), 8.15 (s, 4H), 7.99−7.95 (m, 6H), 7.76 (m, 2H), 7.65−7.50 (m, 4H), 7.50−7.38 (m, 4H), 5.64−5.48 (m, 2H), 2.76−2.53 (m, 4H), 2.39− 2.25 (m, 18H). There was no further characterization; the crude product was taken to the next step. In a shielded Fischer−Porter pressure tube equipped with a stir bar and a regulator attached to a hydrogen tank, alkenyl macrocycle intermediate (0.381 g, 0.430 mmol, 1 equiv), CH2Cl2 (150 mL), methanol (125 mL), and Pd/C (0.184 g, 0.152 mmol, 10 wt %, 0.35 equiv) were added, followed by purging with nitrogen. Then, the flask was pressurized with hydrogen to 14.5 psig. The flask was slightly evacuated and repressurized with hydrogen three times before being sealed. Finally, the hydrogen tank was closed and disconnected from the regulator. The reaction mixture was stirred at constant pressure (14.5 psig) and at room temperature for 24 h. Then, the pressure was released and the mixture filtered through a pad of silica gel. The product was washed with ether, centrifuged, and decanted. This process was repeated five times to afford 0.344 g (90%) of macrocyclic imidazolium chloride 1 as a white solid: changes from white to dark brown at 305 °C; analytical TLC (10% MeOH in dichloromethane) Rf 0.23; 1H NMR (400 MHz, DMSO, ppm) δ 9.82 (s, 1H), 8.48 (s, 2H), 8.29 (d, J = 7.7 Hz, 2H), 8.24−8.16 (m, 6H), 8.03−7.95 (m, 6H), 7.77 (d, J = 7.5 Hz, 2H), 7.63 (dd, J = 7.7, 7.6 Hz, 2H), 7.55 (dd, J = 7.6, 7.5 Hz, 2H), 7.42 (d, J = 7.9 Hz, 4H), 2.70 (t, J = 6.9 Hz, 4H), 2.35 (s, 12H), 1.80−1.69 (m, 4H), 1.51−1.40 (m, 4H); 13C NMR (126 MHz, DMSO, ppm) δ 153.03, 152.96, 148.44, 146.06, 144.42, 143.90, 142.73, 139.18, 137.93, 137.88, 135.55, 133.36, 133.34, 129.13, 129.04, 128.82, 127.07, 126.77, 125.32, 124.47, 122.00, 120.69, 34.96, 30.42, 28.73, 17.64; FT-IR (ATR, cm−1) 2970, 1575, 1407, 1380, 1310, 1042, 810, 748; HR-MS (ESI) F


Article

Organometallics m/z calcd for C61H51N2O2 [M]+ 843.3945, found 843.3942, error −0.3 ppm. N1-(4-(6-(4-(But-3-en-1-yl)phenyl)-5a,9a-dihydrodibenzofuranyl)-2,6-dimethylphenyl)-N2-(4-(6-(4-(but-3-en-1-yl)phenyl)dibenzofuranyl)-2,6-dimethylphenyl)ethane-1,2-diamine (10). In an oven-dried round-bottom flask equipped with a stir bar, 8 (2.4 g, 2.8 mmol, 1 equiv) was dissolved using THF. Then, the solution was cooled to 0 °C, and LiAlH4 (0.213 g, 5.6 mmol, 2 equiv) was added. The mixture was stirred overnight at room temperature. Then, the reaction was diluted with ether, cooled to 0 °C, and quenched by slow, successive addition of H2O (0.213 mL), 15% NaOH solution (0.213 mL), and H2O (0.634 mL). The mixture was stirred for 30 min before the addition of anhydrous magnesium sulfate. The quenched reaction was filtered and concentrated in vacuo. The crude reaction was purified using silica gel and 10% EtOAc in hexanes as eluent to give 2.4 g (98%) of diamine 10 as a white solid: changes from white to dark brown solid at 210 °C; analytical TLC (10% EtOAc in hexanes) Rf 0.23; 1H NMR (500 MHz, CDCl3) δ 7.98−7.95 (m, 6H), 7.94 (d, J = 7.5 Hz, 2H), 7.76 (s, 4H), 7.70 (dd, J = 7.7, 7.5 Hz, 4H), 7.47−7.40 (m, 4H), 7.35 (d, J = 7.9 Hz, 4H), 6.05−5.87 (m, 2H), 5.10 (d, J = 17 Hz, 2H), 5.02 (d, J = 10 Hz, 2H), 3.66 (br s, 2H), 3.40 (s, 4H), 2.80 (t, J = 7.7 Hz, 4H), 2.49 (s, 12H), 2.46−2.40 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 153.23 (2C), 141.47, 138.02, 133.89, 129.63, 129.33, 129.25 (2C), 128.64, 128.61, 126.25, 125.77, 125.48, 125.28, 124.93, 124.85, 123.26, 123.23, 119.45, 118.96, 115.03, 48.91, 35.47, 35.15, 18.97; FT-IR (ATR, cm−1) 2960, 2890, 1601, 1522, 1463, 1413, 1088, 845, 827, 769; HR-MS (ESI) m/z calcd for C62H56N2O2 ([M + H]+) 861.4415, found 861.4419, error −0.6 ppm. 1-(4-(6-(4-(But-3-en-1-yl)phenyl)-5a,9a-dihydrodibenzofuranyl)-2,6-dimethylphenyl)-3-(4-(6-(4-(but-3-en-1-yl)phenyl)dibenzofuranyl)-2,6-dimethylphenyl)-4,5-dihydro-1H-imidazol-3-ium (11). In a round-bottom flask, 10 (2.5 g, 2.9 mmol, 1 equiv) and NH4BF4 (0.305 g, 2.9 mmol, 1 equiv) were suspended in triethyl orthoformate (10 mL, excess). The reaction mixture was stirred at 120 °C overnight, whereupon a white precipitate was observed on the walls of the flask. The reaction was allowed to cool to room temperature before being diluted with ether. The mixture was centrifuged and decanted. This process was repeated four times with 10 mL portions of ether to obtain 2.6 g (94%) of product 11 as a white solid: changes from white to dark brown at 240 °C; analytical TLC (10% methanol in dichloromethane) Rf 0.25; 1H NMR (300 MHz, CD3CN) δ 8.39 (s, 1H), 8.16 (d, J = 7.6 Hz, 2H), 8.11 (d, J = 7.5 Hz, 2H), 7.97 (s, 4H), 7.94 (d, J = 7.6 Hz, 4H), 7.81 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H), 7.58−7.51 (m, 4H), 7.45 (d, J = 7.6 Hz, 4H), 5.95 (m, 2H), 5.11 (d, J = 17.2 Hz, 2H), 5.02 (d, J = 10.1 Hz, 2H), 4.61 (s, 4H), 2.83 (t, J = 7.7 Hz, 4H), 2.59 (s, 12H), 2.47 (dt, J = 7.7, 7.0, 4H); 13C NMR (126 MHz, CD3CN) δ 159.68, 153.07 (2C), 142.09, 138.28, 137.94, 136.30, 133.60, 132.43, 129.26, 128.85, 128.61, 126.79, 126.55, 125.46, 125.03, 124.50, 123.88, 123.80, 123.59, 121.10, 120.07, 114.61, 51.43, 35.19, 34.67, 17.38; FT-IR (ATR, cm−1) 2780, 2080, 1520, 1189, 1243, 1001, 908, 690; HR-MS (ESI) m/z calcd for C63H55N2O2 [M]+ 871.4258, found 871.4237, error 2.4 ppm. Macrocyclic Dihydroimidazolium Tetrafluoroborate (2). In a 2 L oven-dried three-neck flask equipped with a stir bar and a water condenser under nitrogen atmosphere, a solution of 11 (1.3 g, 1.4 mmol, 1 equiv) in CH2Cl2 (1.5 L, 0.9 mM) was prepared. To the solution was added first generation Grubbs catalyst (0.112 g, 0.14 mmol, 0.1 equiv) and kept under nitrogen with an open needle at the top of the condenser as an ethylene exhaust. The reaction was refluxed for 12 h before being quenched with the carboxylate isocyanide catalyst KO2CCH2NC (0.067 g, 0.54 mmol, 0.4 equiv). After being stirred for 30 min, the reaction mixture was filtered through a pad of silica gel and concentrated. The product was washed with ether, centrifuged, and decanted. This process was repeated four times with 20 mL portions of ether to isolate 1.14 g (90%) of alkenyl dihydroimidazolium macrocycle as a beige solid with a 60:40 E/Z mixture: analytical TLC (10% MeOH in dichloromethane) Rf 0.23; 1 H NMR (400 MHz, DMSO) δ 9.84−9.78 (m, 1H), 8.55−8.44 (m,

3H), 8.28 (d, J = 7.2 Hz, 2H), 8.20 (d, J = 7.3 Hz, 1H), 8.16 (s, 1H), 8.05−7.89 (m, 2H), 7.85−7.74 (m, 10H), 7.65−7.50 (m, 26H), 7.47−7.38 (m, J = 6.4 Hz, 20H), 5.60 (br s, 5H), 5.49 (br s, 2H), 2.83−2.76 (m, 19H), 2.44−2.37 (m, 18H), 2.34 (s, 4H). No further characterization was performed; the crude product was taken to the next step. In a shielded Fischer−Porter pressure tube equipped with a stir bar and a regulator attached to a hydrogen tank, alkenyl macrocycle intermediate (0.250 g, 0.27 mmol, 1 equiv), CH2Cl2 (200 mL), methanol (50 mL), and Pd/C (0.100 g, 0.94 mmol, 10 wt %, 0.35 equiv) were added, followed by purging with nitrogen. Then, the flask was pressurized with hydrogen to 14.5 psig. The flask was slightly evacuated and repressurized with hydrogen three times before being sealed. Finally, the hydrogen tank was closed and disconnected from the regulator. The reaction mixture was stirred at constant pressure (14.5 psig) and at room temperature for 24 h. Then, the pressure was released and the mixture filtered through a pad of silica gel. The product was washed with ether, centrifuged, and decanted. This process was repeated five times to afford 0.230 g (92%) of macrocycle 2 as a white solid: changes from white to dark brown at 293 °C; analytical TLC (10% MeOH in dichloromethane) Rf 0.12; 1H NMR (500 MHz, DMSO) δ 9.12 (s, 1H), 8.23 (d, J = 7.5 Hz, 2H), 8.17 (d, J = 7.5 Hz, 2H), 8.05 (s, 4H), 7.97−7.90 (m, 6H), 7.74 (d, J = 7.5 Hz, 2H), 7.56 (dd, J = 7.7, 7.5 Hz, 2H), 7.52 (dd, J = 7.7, 7.5 Hz, 2H), 7.41 (d, J = 7.9 Hz, 4H), 4.62 (s, 4H), 2.70 (t, J = 7.0 Hz, 4H), 2.56 (s, 12H), 1.73 (br s, 4H), 1.44 (br s, 4H); 13C NMR (126 MHz, DMSO) δ 160.79, 152.93, 152.86, 142.59, 137.04, 136.66(2C), 133.42, 133.31, 129.17, 129.03, 128.76, 127.04, 126.69, 125.32, 125.04, 124.47(2C), 124.42, 123.25, 121.78, 120.71, 51.49, 34.95, 30.32, 28.70, 17.93; FT-IR (ATR, cm−1) 2925, 1632, 1436, 1400, 1180, 1051, 783, 740; HR-ESI MS m/z calcd for C61H53N2O2 [M]+ 845.4102, found 845.4101, error −0.1 ppm. Synthesis of Ru1. The synthesis was adapted from a previously published literature procedure.24 An oven-dried 20 dram vial charged with 2 (93 mg, 99.7 μmol, 1 equiv), previously dried overnight using a drying pistol and equipped with a stir bar, was placed inside a glovebox. Then, benzene (15 mL) and KHMDS (22.0 mg, 109.7 μmol, 1.1 equiv) were added. Note: Compound 2 was slightly soluble in benzene, but after addition of the base, it dissolved completely, giving a persistent orange/yellow solution. The contents were stirred at room temperature for 5 min before the addition of the first generation Hoveyda catalyst (48 mg, 80.8 μmol, 0.8 equiv) and heated to 80 °C for 2 h. The reaction mixture was allowed to cool to room temperature before being filtered through a silica plug. The filtrate was concentrated and purified by flash chromatography on silica gel using 10% ethyl acetate−hexanes as eluent to obtain 68 mg (74%) of the desired complex as a dark green solid: changes from to dark green solid to a black solid at 181 °C; analytical TLC (20% EA in hexanes) Rf 0.22; 1H NMR (500 MHz, CD2Cl2) δ 16.65 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 8.04−7.99 (m, 8H), 7.98−7.90 (m, 6H), 7.85 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 7.7 Hz, 2H), 7.54 (dd, J = 7.6, 7.5 Hz, 2H), 7.50 (dd, J = 7.7, 7.6 Hz, 2H), 7.26 (dd, J = 7.5, 7.2 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.27 (dd, J = 7.2 and 7.6 Hz, 1H), 4.70−4.61 (m, 1H), 4.33 (s, 4H), 2.70 (s, 12H), 2.59−2.40 (m, 4H), 1.60−1.55 (m, 4H), 1.35−132 (m, 4H), 1.10 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 270.48, 213.28, 179.53, 153.36, 152.16, 145.10, 143.06, 136.57, 132.75, 130.66, 129.04, 128.87, 128.21, 125.90, 125.59, 125.03, 124.80, 123.40, 122.58, 122.04, 120.07, 119.35, 112.20, 75.10, 37.41, 37.08, 35.46, 32.74, 31.92, 30.44, 30.03, 29.70, 29.35, 28.85, 27.08, 22.68, 20.98, 19.72, 14.12; FT-IR (ATR, cm−1) 3027, 2919, 2850, 1909, 1727, 1621, 1589, 1452, 1427, 1183, 775, 742; HR-MS (ESI) m/z calcd for C71H64ClN2O3Ru [M + CH3CN] 1170.3915, found 1170.3876, error −4.3 ppm. Synthesis of Pd1. The synthesis was adapted from a previously published procedure.25 In open air, a 20 dram vial was charged with macrocycle 1 (20 mg, 22.7 μmol, 1 equiv), K2CO3 (15.7 mg, 114 μmol, 5 equiv), and PdCl2 (3.6 mg, 20.5 μmol, 0.9 equiv). This was followed by the addition of 0.4 mL of DMSO and 0.6 mL of 3chloropyridine. The reaction mixture was stirred for 24 h at 80 °C. G


Article

Organometallics

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The reaction was then allowed to cool to room temperature before being filtered through a silica plug with a pad of Celite on top. The complex was eluted using CH2Cl2 and concentrated in vacuo. The DMSO/3-chloropyridine solvent mixture was removed by Kugelrohr distillation. The solid was washed with pentane and recrystallized from CH2Cl2 to obtain 19 mg (78%) of product Pd1 as a white yellowish solid: changes to dark brown at 235 °C; analytical TLC (20% EtOAc in hexanes) Rf 0.22 (decomposes on silica); 1H NMR (500 MHz, CDCl3, ppm) δ 8.61 (s, 1H), 8.48 (d, 1H), 8.03−7.96 (m, 12 H), 7.87 (d, J = 7.7 Hz, 2H), 7.72 (d, J = 7.7 Hz, 2H), 7.51−7.42 (m, 4H), 7.41 (d, J = 7.9 Hz, 4H), 7.31−7.30 (m,1H), 7.29 (s, 2H), 6.81 (dd, J = 8.0 Hz, 5.07 Hz, 1H), 2.62 (t, J = 6.9 Hz, 4H), 2.60 (s, 12 H), 1.85−1.75 (m, 4H), 1.50−1.41 (m, 4H); 13C NMR (75 MHz, DMSO) δ 153.00, 152.98, 152.93, 148.89, 143.03, 137.59, 137.30, 136.34, 136.28, 135.78, 135.59, 135.58, 133.07, 133.04, 132.98, 129.20, 128.66, 126.63, 125.12, 124.99, 124.66, 124.58, 124.47, 124.08, 124.07, 121.44, 120.73, 35.29, 30.76, 28.87, 19.46; FT-IR (ATR, cm−1) 2921, 2852, 1738, 1629, 1632, 1550, 1456, 1376, 776, 775, 743; HR-MS (ESI) m/z calcd for C66H54Cl3N3O2Pd ([M + H]+) 1132.2389, found 1132.2412, error −0.9 ppm.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.9b00152. Ligand synthesis, preparation of organometallic complexes, procedures for ene-yne and alkene metathesis, cross-coupling reactions, and spectroscopic data (PDF) Accession Codes

CCDC 1897290−1897291 and 1901375 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: diver@buffalo.edu. ORCID

Steven T. Diver: 0000-0003-2840-6726 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge support from the National Science Foundation through CHE-1300702 and CHE1566162. We thank Dr. Joe Clark for preliminary studies on a related macrocycle, Umicore for supplying Hoveyda−Grubbs catalysts, and Prof. Jason Benedict (UB Chemistry) for assistance solving the crystal structures.

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REFERENCES

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Macrocyclic N-Heterocyclic Carbenes: Synthesis and Catalytic

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