Synthesis and Characterization of Axially Chiral Imidazoisoquinolin-2

Sep 24, 2015 - The selective Suzuki cross-coupling of 1,3-dichloroisoquinoline with 2-substituted 1-naphthylboronic acids/esters followed by construct...
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Synthesis and Characterization of Axially Chiral Imidazoisoquinolin2-ylidene Silver and Gold Complexes Francisca Grande-Carmona,† Javier Iglesias-Sigüenza,† Eleuterio Á lvarez,‡ Elena Díez,*,† Rosario Fernández,*,† and José M. Lassaletta*,‡ †

Departamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), University of Seville, C/Prof. García González, 1, 41012 Sevilla, Spain ‡ Instituto de Investigaciones Químicas (CSIC-USe) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Avenida Américo Vespucio, 49, 41092 Sevilla, Spain S Supporting Information *

ABSTRACT: The selective Suzuki cross-coupling of 1,3-dichloroisoquinoline with 2-substituted 1-naphthylboronic acids/esters followed by construction of the imidazo[1,5-b]isoquinoline ring and alkylation constitutes a straightforward route to imidazolium salts fused into an axially chiral biaryl skeleton. Metalation of these azolium salts afforded the corresponding NHC silver complexes, which were used as carbene transfer agents for the synthesis of Au(I) derivatives.

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INTRODUCTION The axial chirality is one of the most fundamental tools being continuously used in many areas of asymmetric catalysis. Thus, functionalized biaryls such as BINOL, BINOL−phosphoric acids, BINAM, NOBIN, and QUINOX have significantly contributed to the spectacular development of asymmetric organocatalysis, while complexes based on axially chiral ligands constitute one of the most widely used families of catalysts for metal-catalyzed asymmetric transformations. Particularly, a plethora of useful reactions make use of P-ligands based on axially chiral biaryls: BINAP (and analogues such as BiPHEP, SEGPHOS, TUNEPHOS, GARPHOS, and FLUOROPHOS), QUINAP, X-MOP, etc. With the advent of N-heterocyclic carbenes (NHCs), several groups have also started programs for the development of diaminocarbene ligands showing a configurationally stable stereogenic axis. Namely, the groups of Rajanbabu,1 Hoveyda,2 Shi,3,4 Espinet,5 Toste,6 and Slaughter7 have developed NHC ligands and catalysts based on this motif (see representative examples in Figure 1). In the frame of our interest in new N-heterocyclic carbene architectures, we8 and Glorius9 simultaneously reported on the synthesis and coordination chemistry of heterobicyclic imidazo[1,5-a]pyridine-3-ylidenes (ImPy’s) I (Figure 2). The unique architecture of these ligands allows a priori specific strategies for the introduction of chirality. In our original paper, several “chiral at metal” C2-symmetric Rh(I) complexes II were selectively obtained from azolium salts with noncoordinating counteranions. Pd complexes III with heterobidentate C(ImPy),S ligands incorporate an alkyl chain with strategically located stereogenic centers able to control the configuration of the sulfur atom of a terminal thioether functionality. These complexes have been successfully used in asymmetric allylic alkylations.10 Later, Fürstner and co-workers reported on the © 2015 American Chemical Society

Figure 1. Axially chiral NHCs and related diaminocarbenes.

preparation of derivatives IV with the heterobicyclic carbene fused into a cyclophane skeleton, which can be electronically modulated by “through-space” communication of the aromatic rings.11 These interesting chiral structures, however, were not resolved and, hence, not used in asymmetric catalysis. Very recently, Scheidt and co-workers have also reported on a second family of planar chiral ImPy derivatives V that have found applications as organocatalysts and as ligands in Ni- and Cu-catalyzed reactions.12 Finally, we have recently reported on the synthesis of extremely bulky ligands VI, characterized by a 2,5-diphenylpyrrolidino group that provides a remarkable level Received: August 6, 2015 Published: September 24, 2015 5073

DOI: 10.1021/acs.organomet.5b00681 Organometallics 2015, 34, 5073−5080

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Organometallics

Scheme 2. Synthesis of Imidazo[1,5-b]isoquinolines 11−13

Figure 2. Chirality in ImPy ligands and catalysts.

of flexibility.13 We now wish to report on the synthesis and resolution of a new family of N-heterocyclic carbenes VII that results from the integration of the ImPy heterobicyclic system into a biaryl skeleton. Additionally, their Ag(I) and Au(I) complexes, along with preliminary results for the latter as catalysts in a [2+2] intermolecular cycloaddition are described herein.

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RESULTS AND DISCUSSION Synthesis of Neutral Heterocyclic Precursors. We envisaged that imidazopiridinium salts B should serve as suitable precursors for the desired ligands and/or metal complexes A. Azolium salts B should be easily obtained by alkylation of the corresponding 5-arylimidazo[1,5-b]isoquinolines C, which in turn could be prepared after imidazole ring construction from the cyano derivatives D (Scheme 1).

isoquinolines 5−7 in good to excellent yields. The cyanation of intermediates 5−7 proved to be a challenging reaction. Using 5 as a model substrate, the Rosenmund−von Braun reaction did not afford the desired cyano derivative, while poor reactivity was observed using several known catalyst/cyanide source combinations. Finally, the desired nitriles 8−10 were obtained in excellent yields using Pd2(dba)3, dppf, and Zn (powder) as the catalytic system and Zn(CN)2 as the cyanide source in N,N-dimethylacetamide (DMA), showing that the original method by Jin and Confalone15 can be applied to heteroaryl chlorides. The reduction of the cyano group also required optimization; common reagents such as LiAlH4 afforded complex reaction mixtures, while catalytic hydrogenation using Pd/C afforded moderate amounts of product only in the presence of added acid. Finally, catalytic hydrogenation by Pd(OH)2/C in the presence of HCl proved to be the method of choice to afford the corresponding aminomethyl derivatives as hydrochlorides. From these raw materials, a “one-pot” formylation/cyclization protocol using formic acid and POCl3 as reagents yielded the desired imidazoisoquinolines 11−13. These compounds proved to be rather light sensitive, but with a careful manipulation in the darkness, all of them were isolated in satisfactory overall yields. At this point, the resolution of the neutral heterobiaryl compounds was easily accomplished by means of preparative HPLC chromatography on chiral stationary phases.

Scheme 1. Retrosynthetic Analysis for the Target Complexes A

A straightforward route to neutral imidazo[1,5-b]isoquinolines C is outlined in Scheme 2. The strategy exploits the higher reactivity of the C(1)−Cl bond of 1,3dichloroisoquinoline 1 in Suzuki−Miyaura reactions.14 Thus, under optimized conditions, 1 can be regioselectively coupled with boronic acids 2 and 3 or the boronic acid pinacol ester 4 to afford the desired 3-chloro-1-(2-alkylnaphthalen-1-yl)5074

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Organometallics Scheme 4. Synthesis of Imidazolium Salts 18−25a

Additionally, 5-(2-cyclohexylnaphthalen-1-yl)imidazo[1,5-a]pyridine (17) has also been readily synthesized from N-[(6bromopyridin-2-yl)methyl]formamide (14) in only two steps. First, cyclization of 14 promoted by Et3N and Tf2O following the method recently reported by Shi16 afforded 5-bromoimidazopyridine (15) quantitatively; ensuing Suzuki−Miyaura coupling of this product with 2-cyclohexyl-1-naphthylboronic acid (16) afforded the desired product 17 in high yield. Once again, resolution of this racemic mixture was easily performed using preparative HPLC (Scheme 3). Scheme 3. Synthesis of Imidazo[1,5-a]pyridine, 17

a

The absolute configuration of 22 has been established for the NHCAg complex (see X-ray structure below). The absolute configuration of compounds 18−21 and 23−25 has been tentatively assigned assuming a uniform chromatographic behavior.

Finally, the azolium salts 18−25 were prepared by simple reaction of the enantiomerically pure heterocycles with alkylating reagents such as MeI, BnBr, or iPrI under standard conditions (Scheme 4).17 Synthesis of NHC-Ag Complexes. Representative silver complexes 28−30 have been prepared in excellent yields from imidazolium bromide 22 and imidazolium chlorides 26 and 27 using Ag2O in CHCl3 in accordance with the popular method by Lin18 (Scheme 5). No carbene resonances were observed in the 13C NMR spectrum of compound 28, indicative of a fluxional coordination behavior in solution.18,19 In contrast, the 13 C NMR spectra of complexes 29 and 30 indicated the presence of two different NHC-Ag species in solution. For instance, complex 29 (Figure 3) showed one Ccarbene peak as a broad singlet with no splitting at 167.6 ppm and a second Ccarbene signal at 168.1 ppm with a complex splitting pattern (two doublets) based upon the coupling constants JCAg = 240.5 and 279.5 Hz for both 109Ag and 107Ag isotopes, respectively. Complex 28 was crystallized by slow diffusion of n-hexane into a saturated CH2Cl2 solution, and its structure was determined by single-crystal X-ray diffraction (Figure 4). In the solid state, the complex was obtained as a cationic silver biscarbene, which possesses three [Ag(NHC)2]+ units per [Ag2Br5]3− counteranion, an unprecedented structure type.20 The naphthyl and imidazoisoquinolin-2-ylidene rings are oriented nearly perpendicular to each other. The average silver−carbene bond distance in the complex is 2.102 Å, slightly deviated from the usual range (2.067 to 2.092 Å) for similar biscarbene structures, presumably as a consequence of the steric repulsion between the very bulky NHC ligands. The X-ray structure also served to establish the absolute (Sa) configuration of the chiral axis.

Scheme 5. Synthesis of NHC-Silver and Gold Complexes 28−32

Recently, we have reported the first enantioselective intermolecular (4+2) cycloaddition reaction between allenes and dienes promoted by an axially chiral triazoloisoquinolin-3ylidene gold complex.21 The excellent enantiomeric induction observed prompted us to synthesize axially chiral imidazoisoquinolin-2-ylidene analogues and test their behavior in catalysis. The gold(I)-catalyzed [2+2] cycloaddition between styrenes and alkynes22 is a very challenging reaction that has never been reported in an enantioselective fashion.23 Taking into account 5075

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Organometallics Scheme 6. Gold-Catalyzed Intermolecular [2+2] Cycloaddition

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CONCLUSION A synthetic route for a novel class of ligands featuring an imidazole unit embedded in a rigid axially chiral cyclic frame has been developed. This method provides a straightforward access to axially chiral NHC gold(I) complexes by transmetalation from the corresponding silver(I) complexes. It is worth noting that in the previously reported examples II−VI of axially chiral NHCs (Figure 1), the NHC unit (or the acyclic diaminocarbene analogue) is simply attached to an axially chiral biaryl scaffold. In contrast, the heterobicyclic structure VII differs in that the NHC is an integral part of the stereogenic system. Moreover, the bond rotation restrictions inherent to the new ligand design force the orientation of the carbon−metal bond in a parallel direction with respect to the chiral axis, something that is particularly attractive for metal catalysts such as NHC-AgX or NHC-AuX with a preferred linear geometry. Work is currently in progress on the development of derivatives with a higher photochemical stability and application of these novel ligands in different metal-catalyzed asymmetric processes.

Figure 3. 13C NMR resonances for Ccarbene−Ag of complex 29.

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EXPERIMENTAL SECTION

Solvents were purified and dried by standard procedures. Flash chromatography was carried out on silica gel (0.040−0.063 mm). Melting points were recorded in a metal block and are uncorrected. 1H NMR spectra were recorded at 300 or 500 MHz; 13C NMR spectra were recorded at 75 or 125 MHz, with the solvent peak used as the internal reference. 1,3-Dichloroisoquinoline (1),24 2-methoxynaphthalen-1-ylboronic acid (2),25 2-methylnaphthalen-1-ylboronic acid (3),26 3-chloro-1-(2-methoxylnaphthalen-1-yl)isoquinoline (5),14 3chloro-1-(2-methylnaphthalen-1-yl)isoquinoline (6),21 2-tert-butyl-1chloronaphthalene,27 N-[(6-bromopyridin-2-yl)methyl]formamide (14),28 and 2-cyclohexylnaphthalen-1-ylboronic acid (16)21 were prepared following previously described procedures. Pure enantiomers 11−13 and 17 were obtained by resolution using HPLC on chiral stationary phases. Synthesis of 2-(2-(tert-Butyl)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4). NiCl2(PMe3)2 (171 mg, 5 mol %, 0.58 mmol), bis(pinacolato)diboron (4.47 g, 17.6 mmol), and CsF (3.55 g, 23.4 mmol) were dissolved in dry toluene (97 mL) under an argon atmosphere. Then, a solution of 2-tert-butyl-1-chloronaphthalene (2.55g, 11.7 mmol) in dry toluene (94 mL) and TMSOCH2CF3 (4.5 mL, 24.6 mmol) were added via syringe. The resulting mixture was heated under reflux overnight. Ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer was washed with saturated NH4Cl (2 × 10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (1:3 CH2Cl2−cyclohexane) to yield 4 (2.32 g, 64%) as a white solid. Mp: 169−170 °C. 1H NMR (500 MHz, CDCl3): δ 7.99−7.95 (m, 1H), 7.78−7.75 (m, 2H), 7.61 (d, 3JHH = 8.9 Hz, 1H), 7.43 (ddd, 3JHH = 8.4, 6.8 Hz; 4JHH = 1.6 Hz, 1H), 7.38 (ddd, 3JHH = 8.0, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 1.53 (s, 12H), 1.52 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 152.5, 136.4, 131.2, 128.7, 127.9, 127.1, 125.4, 125.0, 124.7, 84.3, 36.9, 32.3, 26.0. EIMS m/z: 310 (100, M+), 309 (28, M+ − 1), 195 (59), 101 (30), 83 (92). HRMS m/z: calcd for C20H27BO2 310.2104, found 310.2099.

Figure 4. ORTEP drawing of complex (Sa)-28. Thermal ellipsoids are drawn at the 50% probability level. H atoms and two cationic biscarbene units are omitted for clarity. Selected bond lengths [Å] and bond angles [deg]: Ag(3)−Ag(3) 2.8392(12), Ag(2)−C(30) 2.113(10), Ag(2)−C(59) 2.079(10), N(3)−C(30) 1.342(13), N(4)−C(30) 1.356(14), N(3)−C(40)−C(41)−C(42) −89.2(14), N(5)−C(69)−C(70)−C(71) −96.8(13).

that the reaction requires sterically hindered, monodentate ligands, we decided to synthesize the bulkier derivatives 31 and 32, which were easily prepared in a “one-pot” fashion by treatment of azolium salts 26 and 27 with Ag2O followed by transmetalation of the crude products with AuCl·SMe2 in good overall yields. Previous anion exchange from iodides 24 and 25 to chlorides 26 and 27 prevents Cl/I mixtures after transmetalation of the NHC-AgI intermediates with AuClSMe2. Complexes 31 and 32 were then used as precatalysts in the cycloaddition of phenylacetylene 33 and methylstyrene 34. The corresponding cationic complexes were generated in situ by addition of AgSbF6 as a chloride scavenger to obtain the expected cycloadduct 35 in good yields, although modest enantiomeric ratios of 65:35 and 58:42, respectively (Scheme 6). These results, though not yet useful from the synthetic viewpoint, suggest that the enantioselectivity correlates with the steric bulkiness of the ligand. 5076

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Article

Organometallics Synthesis of 3-Chloro-1-(2-tert-butylnaphthalen-1-yl)isoquinoline (7). A round-bottom flask was charged with 1,3dichloroisoquinoline 1 (2 g, 10 mmol), boronic ester 4 (2.20 g, 12 mmol), Pd(PPh3)4 (2.31 g, 20 mmol %), and Ag2CO3 (3.58 g, 13 mmol) under an argon atmosphere, and the mixture was dissolved in dry toluene (80 mL). The mixture was heated under reflux overnight. Ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer was washed with brine (2 × 10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (1:3 CH2Cl2−cyclohexane) to yield 7 (2.14 g, 62%) as a yellow foam. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, 3JHH = 9.0 Hz, 1H), 7.85−7.81 (m, 4H), 7.66 (ddd, 3JHH = 8.2, 6.6 Hz; 4JHH = 1.4 Hz, 1H), 7.39−7.36 (m, 2H), 7.35−7.31 (m, 1H), 7.15 (ddd, 3JHH = 8.4, 6.8 Hz; 4JHH = 1.4 Hz, 1H), 6.69 (dd, 3JHH = 8.7 Hz; 4JHH = 1.0 Hz, 1H), 1.12 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 163.4, 146.1, 144.5, 137.6, 133.5, 131.7, 131.6, 131.0, 129.1, 128.7, 128.0, 127.4, 127.4, 126.3, 126.1, 126.1, 126.0, 125.2, 119.2, 37.3, 32.5. EIMS m/z: 347 (42, M+, 37Cl), 346 (38, M+ + 1, 35Cl), 345 (100, M+, 35Cl), 330 (55), 315 (22), 310 (42). HRMS m/z: calcd for C23H20NCl 345.1284, found 345.1284. Palladium(0)-Catalyzed Cyanation of Aryl Chlorides 5−7. Synthesis of Compounds 8−10. General Procedure. Aryl chlorides 5−7 (6 mmol) were treated with Zn(CN)2 (423 mg, 3.6 mmol) in the presence of Pd2(dba)3 (109 mg, 2 mol %), dppf (133 mg, 4 mol %), and Zn (47 mg, 12 mol %) in DMA (25 mL) at reflux. The mixture was heated under reflux overnight. Ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer was washed with 2 N NH4OH (2 × 20 mL) and brine (2 × 20 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (1:6 → 1:2 EtOAc−cyclohexane) to yield compounds 8−10. 1-(2-Methoxynaphthalen-1-yl)isoquinoline-3-carbonitrile (8): white solid (1.82 g, 98%). Mp: 182−183 °C. 1H NMR (500 MHz, CDCl3): δ 8.25 (s, 1H), 8.05 (d, 3JHH = 9.1 Hz, 1H), 8.01 (d, 3JHH = 8.2 Hz, 1H), 7.88 (d, 3JHH = 7.8 Hz, 1H), 7.85−7.77 (m, 1H), 7.59− 7.57 (m, 2H), 7.44 (d, 3JHH = 9.1 Hz, 1H), 7.39−7.27 (m, 2H), 6.98 (d, 3JHH = 8.2 Hz, 1H), 3.78 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 160.6, 154.9, 135.3, 133.4, 131.7, 131.3, 130.3, 129.9, 129.0, 128.1, 127.9, 127.4, 127.4, 127.2, 126.8, 124.3, 123.9, 120.1, 118.3, 113.3, 56.5. EIMS m/z: 310 (87, M+), 309 (100), 294 (42). HRMS m/z: calcd for C21H13N2O 309.1028, found 309.1019. 1-(2-Methylynaphthalen-1-yl)isoquinoline-3-carbonitrile (9): white solid (1.44 g, 82%). Mp: 144−146 °C. 1H NMR (500 MHz, CDCl3): δ 8.28 (s, 1H), 8.03 (d, 3JHH = 8.2 Hz, 1H), 7.94 (d, 3JHH = 8.5 Hz, 1H), 7.90 (d, 3JHH = 8.2 Hz, 1H), 7.85−7.81 (m, 1H), 7.57 (ddd, 3JHH = 8.2, 7.0 Hz; 4JHH = 1.0 Hz, 1H), 7.51−7.46 (m, 2H), 7.44−7.40 (m, 1H), 7.29−7.24 (m, 1H), 6.92 (d, 3JHH = 8.5 Hz, 1H), 2.11 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 162.8, 135.3, 134.5, 133.0, 132.5, 132.0, 130.7, 129.3, 129.1, 128.6, 128.1, 127.6, 127.6, 127.3, 127.3, 126.8, 126.6, 125.2, 125.1, 118.1, 20.1. CIMS m/z: 295 (100, M+ + 1), 293 (85), 292 (18). HRMS m/z: calcd for C21H15N2 295.1235, found 295.1232. 1-(2-tert-Butylynaphthalen-1-yl)isoquinoline-3-carbonitrile (10): yellow foam (1.69 g, 84%). 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H), 8.02−7.94 (m, 2H), 7.90−7.73 (m, 3H), 7.58−7.33 (m, 3H), 7.15 (ddd, 3JHH = 8.4, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 6.61−6.53 (m, 1H), 1.08 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 164.9, 146.3, 134.6, 133.2, 131.8, 131.7, 131.7, 131.3, 131.2, 130.4, 129.1, 128.2, 127.6, 127.5, 127.4, 126.4, 126.1, 125.7, 125.4, 118.2, 37.4, 32.5. CIMS m/z: 337 (100, M+ + 1), 336 (65, M+), 321 (45), 169 (30). HRMS m/z: calcd for C24H21N2 337.1705, found 337.1701. Synthesis of Imidazo[1,5-b]isoquinolines 11−13. General Procedure. To a solution of carbonitriles 8−10 (6.4 mmol) in methanol (20 mL) were added Pd(OH)2/C (116 mg, 13 mol %) and concentrated HCl (588 μL, 19.2 mmol). The mixture was heated at 40 °C under a H2 atmosphere for 1 h, then filtered through a Celite pad, and the solvent was removed in vacuo. The residue was dissolved in methanol (4 mL), Et3N (2.6 mL, 19.2 mmol) was added, and the mixture was stirred at room temperature for 1 h and concentrated. The crude amine was dissolved in HCOOH (10 mL) and refluxed for 24 h.

The mixture was concentrated, and the resulting residue was dissolved in dry toluene (10 mL). POCl3 (1.8 mL, 19.2 mmol) was added, and the mixture was heated at 60 °C for 3 h. Then, ethyl acetate was added, and the organic layer was washed with saturated NaHCO3 (2 × 10 mL) and water (2 × 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (2:1 EtOAc−cyclohexane). Light was avoided during the whole process. Yields and characterization data for compounds 11−13 are as follows. 5-(2-Methoxynaphthalen-1-yl)imidazo[1,5-b]isoquinoline (11): orange solid (1.24 g, 60%). Mp: 182−183 °C. 1H NMR (500 MHz, CDCl3): δ 8.15 (d, 3JHH = 9.1 Hz, 1H), 8.08 (s, 1H), 7.94 (d, 3JHH = 8.2 Hz, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.59−7.56 (m, 1H), 7.51 (d, 3 JHH = 9.1 Hz, 1H), 7.39 (ddd, 3JHH = 8.2, 6.8 Hz; 4JHH = 1.1 Hz, 1H), 7.27 (ddd, 3JHH = 8.8, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 7.03−6.97 (m, 2H), 6.92−6.84 (m, 2H), 3.78 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 156.0, 132.7, 132.5, 130.9, 129.2, 128.5, 128.2, 127.9, 127.1, 125.6, 125.1, 124.8, 124.6, 124.6, 124.3, 123.8, 121.8, 118.8, 114.2, 113.4, 113.2, 56.4. EIMS m/z: 324 (100, M+), 323 (21), 313 (28), 307 (25). HRMS m/z: calcd for C22H16N2O 324.1263, found 324.1260. The racemic mixture was resolved by semipreparative HPLC on a Chiralpak IA column. Analytical Chiralpak IA, 70:30:0.1 heptane− THF−DEA, 1 mL/min, 30 °C, λ = 254.4 nm: first enantiomer, compound (−)-11, tR = 7.8 min, [α]25D = −339.2 (c 0.5, CHCl3); second enantiomer, compound (+)-11, tR = 10.1 min, [α]25D = +342.5 (c 0.5, CHCl3). 5-(2-Methylnaphthalen-1-yl)imidazo[1,5-b]isoquinoline (12): orange solid (0.81 g, 41%). Mp: 109−110 °C. 1H NMR (500 MHz, CDCl3): δ 8.10 (s, 1H), 8.04 (d, 3JHH = 8.5 Hz, 1H), 7.96 (d, 3JHH = 8.2 Hz, 1H), 7.87 (s, 1H), 7.61 (s, 1H), 7.61−7.57 (m, 2H), 7.46 (ddd, 3JHH = 8.2, 6.8 Hz; 4JHH = 1.0 Hz, 1H), 7.25 (ddd, 3JHH = 8.2, 6.8 Hz; 4JHH = 1.1 Hz, 1H), 7.06−7.01 (m, 1H), 6.97 (dd, 3JHH = 8.5 Hz; 4 JHH = 0.6 Hz, 1H), 6.88 (ddd, 3JHH = 9.1, 6.1 Hz; 4JHH = 1.1 Hz, 1H), 6.86−6.82 (m, 1H), 2.10 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 136.6, 132.6, 131.8, 130.8, 130.3, 129.0, 128.4, 128.3, 127.4, 127.1, 127.0, 126.9, 126.0, 125.8, 125.0, 124.3, 124.3, 124.0, 121.4, 119.2, 114.3, 19.5. EIMS m/z: 309 (46, M+ + 1), 308 (100, M+), 307 (27). HRMS m/z: calcd for C22H16N2 308.1313, found 308.1321. The racemic mixture was resolved by semipreparative HPLC on a Chiralpak IA column. Analytical Chiralpak IA, 80:20:0.1 heptane−iPrOH−DEA, 1 mL/min, 30 °C, λ = 226.1 and 253.2 nm: first enantiomer, compound (Ra)-12, tR = 5.5 min, [α]25D = −576.9 (c 0.25, CHCl3); second enantiomer, compound (Sa)-12, tR = 6.1 min, [α]25D = +551.5 (c 0.25, CHCl3). 5-(2-tert-Butylnaphthalen-1-yl)imidazo[1,5-b]isoquinoline (13): orange foam (1.20 g, 54%). 1H NMR (500 MHz, CDCl3): δ 8.11 (s, 1H), 8.06 (d, 3JHH = 9.0 Hz, 1H), 7.93−7.88 (m, 2H), 7.84 (s, 1H), 7.61−7.56 (m, 2H), 7.43 (ddd, 3JHH = 8.1, 6.8 Hz; 4JHH = 1.1 Hz, 1H), 7.14 (ddd, 3JHH = 8.4, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 7.05−7.00 (m, 1H), 6.91−6.80 (m, 2H), 6.69 (d, 3JHH = 8.8 Hz, 1H), 1.05 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 148.5, 132.5, 132.3, 130.6, 130.2, 128.9, 128.1, 127.9, 127.4, 127.3, 126.9, 126.1, 125.7, 124.9, 124.8, 124.7, 124.6, 122.7, 118.9, 114.2, 37.6, 31.5. EIMS m/z: 350 (4, M+), 341 (100), 326 (68), 292 (45), 169 (40). HRMS m/z: calcd for C25H22N2 350.1783, found 350.1773. The racemic mixture was resolved by semipreparative HPLC on a Chiralpak IC column. Analytical Chiralpak IC, 100:0.2 CH3CN−DEA, 1 mL/min, 30 °C, λ = 254.4 nm: first enantiomer, compound (−)-13, tR = 7.8 min, [α]25D = −241.2 (c 0.6, CHCl3); second enantiomer, compound (+)-13, tR = 11.6 min, [α]25D = +235.6 (c 0.6, CHCl3). Synthesis of 5-Bromoimidazo[1,5-a]pyridine (15). A solution of N-[(6-bromopyridin-2-yl)methyl]formamide (14) (2.33g, 10.8 mmol) in dry dichloromethane (75 mL) was cooled to −40 °C. Et3N (2.3 mL, 21.6 mmol) and Tf2O (3.6 mL, 21.6 mmol) were added dropwise. The mixture was stirred at room temperature for 4 h and concentrated. The residue was dissolved in EtOAc (10 mL), and saturated NH4Cl (10 mL) was added. The resulting precipitate was filtered and washed with EtOAc to yield the corresponding 15 (2.11 g, quant) as a white solid. 1H NMR (300 MHz, CD3OD): δ 9.73 (s, 1H), 8.22 (d, 4JHH = 1.5 Hz, 1H), 7.93 (d, 3JHH = 9.3 Hz, 1H), 7.53 (dd, 5077

DOI: 10.1021/acs.organomet.5b00681 Organometallics 2015, 34, 5073−5080

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Organometallics

δ 156.4, 134.3, 133.5, 132.1, 130.8, 129.7, 129.4, 129.3, 129.2, 129.1, 129.1, 128.6, 128.5, 128.4, 128.2, 127.8, 124.9, 124.8, 124.5, 122.8, 120.9, 115.3, 114.0, 112.4, 109.4, 56.9, 54.8. EIMS m/z: 415 (4, M+), 414 (9, M+ − 1), 324 (100), 310 (35), 142 (42). HRMS m/z: calcd for C29H22N2O 414.1732, found 414.1736. 2-Isopropyl-5-(2-methoxynaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Iodide (20). From (+)-11 (195 mg, 0.6 mmol) and isopropyl iodide (180 μL, 1.8 mmol) in dry dioxane, compound (+)-20 was obtained as a yellow solid (224 mg, 73%). Mp: 204−206 °C. [α]25D = +161.6 (c 0.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.98 (s, 1H), 8.85 (s, 1H), 8.58 (s, 1H), 8.25 (d, 3JHH = 9.2 Hz, 1H), 7.98 (d, 3JHH = 8.5 Hz, 1H), 7.77 (d, 3JHH = 8.9 Hz, 1H), 7.69−7.65 (m, 1H), 7.64 (d, 3JHH = 9.2 Hz, 1H), 7.55−7.51 (m, 1H), 7.44−7.40 (m, 1H), 7.36−7.28 (m, 1H), 7.14−7.09 (m, 1H), 6.89 (d, 3JHH = 8.5 Hz, 1H), 5.55 (m, 3JHH = 6.7 Hz, 1H), 3.95 (s, 3H), 1.71 (d, 3JHH = 6.7 Hz, 3H), 1.65 (d, 3JHH = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 167.7, 156.4, 134.3, 132.1, 130.9, 130.8, 130.0, 129.2, 129.2, 128.8, 128.6, 128.2, 127.9, 124.7, 124.6, 122.7, 119.0, 115.7, 113.9, 110.7, 109.6, 56.9, 55.0, 29.7. FAB-MS m/z: 367 (100, M+ + 1), 314 (19), 237 (17), 149 (11). HRMS m/z: calcd for C25H23N2O 367.1810, found 367.1811. (S a )-2-Methyl-5-(2-methylnaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Iodide (21). From (Sa)-12 (185 mg, 0.6 mmol) and methyl iodide (187 μL, 3 mmol) in dry THF, compound (Sa)-21 was obtained as a yellow solid (243 mg, 90%). Mp: 158−160 °C. [α]25D = +305.1 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.91 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H,), 8.11 (d, 3JHH = 8.5 Hz, 1H), 7.98 (d, 3JHH = 8.2 Hz, 1H), 7.80 (d, 3JHH = 9.1 Hz, 1H), 7.67 (d, 3JHH = 8.5 Hz, 1H), 7.52−7.44 (m, 1H), 7.36−7.24 (m, 2H), 7.21−7.09 (m, 1H), 6.99 (dd, 3 JHH = 9.1 Hz; 4JHH = 0.8 Hz, 1H), 6.76 (d, 3JHH = 8.2 Hz, 1H), 4.42 (s, 3H), 2.20 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 137.9, 132.5, 131.8, 130.9, 130.5, 129.6, 129.5, 129.1, 129.0, 128.3, 128.2, 128.0, 126.2, 124.7, 123.8, 123.6, 123.0, 120.2, 115.9, 115.0, 39.5, 20.4. EIMS m/z: 322 (4, M+ − 1), 308 (100), 307 (41), 142 (57). HRMS m/z: calcd for C23H18N2 322.1470, found 322.1460. (S a )-2-Benzyl-5-(2-methylnaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Bromide (22). From (Sa)-12 (185 mg, 0.6 mmol) and benzyl bromide (288 μL, 2.4 mmol) in dry THF, compound (Sa)-22 was obtained as a yellow solid (255 mg, 89%). Mp: 150−152 °C (dec). [α]25D = +253.4 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.98−8.92 (m, 2H), 8.50 (s, 1H), 8.09 (d, 3JHH = 8.5 Hz, 1H), 7.96 (d, 3 JHH = 8.2 Hz, 1H), 7.79−7.72 (m, 1H), 7.65 (d, 3JHH = 8.5 Hz, 1H), 7.52−7.42 (m, 3H), 7.31−7.21 (m, 5H), 7.11 (ddd, 3JHH = 9.2, 6.4 Hz; 4 JHH = 0.9 Hz, 1H), 6.96 (dd, 3JHH = 9.2 Hz; 4JHH = 0.9 Hz, 1H), 6.75−6.70 (m, 1H), 6.03 (br s, 2H), 2.15 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 137.9, 133.4, 132.6, 131.8, 131.0, 130.5, 129.9, 129.6, 129.5, 129.3, 129.2, 129.1, 129.0, 128.3, 128.0, 128.0, 126.2, 124.7, 123.9, 123.6, 123.0, 120.0, 116.0, 113.7, 55.0, 20.0. EIMS m/z: 398 (4, M+ − 1), 308 (100), 307 (42), 91 (54). HRMS m/z: calcd for C29H22N2 398.1783, found 398.1793. (S a)-2-Isopropyl-5-(2-methylnaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Iodide (23). From (Sa)-12 (185 mg, 0.6 mmol) and isopropyl iodide (180 μL, 1.8 mmol) in dry dioxane, compound (Sa)23 was obtained as a yellow solid (215 mg, 75%). Mp: 194−195 °C (dec). [α]25D = +234.6 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.18 (d, 4JHH = 2.1 Hz, 1H), 8.77 (s, 1H), 8.47 (d, 4JHH = 2.1 Hz, 1H), 8.13 (d, 3JHH = 8.5 Hz, 1H), 8.00 (d, 3JHH = 8.2 Hz, 1H), 7.82 (d, 3 JHH = 8.9 Hz, 1H), 7.68 (d, 3JHH = 8.5 Hz, 1H), 7.50 (t, 3JHH = 7.4 Hz, 1H), 7.33−7.27 (m, 2H), 7.14 (dd, 3JHH = 9.0, 6.4 Hz, 1H), 6.98 (d, 3 JHH = 9.0 Hz, 1H), 6.77 (d, 3JHH = 8.4 Hz, 1H), 5.31 (m, 3JHH = 6.7 Hz, 1H), 2.17 (s, 3H), 1.69 (d, 3JHH = 6.7 Hz, 3H), 1.64 (d, 3JHH = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 137.7, 132.6, 131.8, 130.9, 130.5, 129.9, 129.5, 129.5, 129.2, 129.1, 128.3, 128.2, 128.1, 126.3, 124.8, 123.7, 123.6, 123.0, 117.4, 116.6, 112.5, 55.3, 23.9, 23.5, 20.2. HRMS m/z: calcd for C25H23N2 351.1861, found 351.1855. 2-Isopropyl-5-(2-tert-butylnaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Iodide (24). From (+)-13 (210 mg, 0.6 mmol) and isopropyl iodide (180 μL, 1.8 mmol) in dry dioxane, compound (+)-24 was obtained as a yellow solid (265 mg, 85%). Mp: 190−192 °C (dec). [α]25D = +69.5 (c 0.1, CHCl3). 1H NMR (500 MHz,

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= 7.1 Hz; 4JHH = 0.8 Hz, 1H), 7.22 (dd, 3JHH = 9.3, 7.1 Hz, 1H). C NMR (75 MHz, CD3OD): δ 133.2, 127.5, 126.0, 123.4, 119.3, 114.4. CIMS m/z [M+ + 1], 199 (100, M+ + 1, 81Br), 197 (90, M+ + 1, 79 Br), 183 (37), 165 (31). HRMS m/z: calcd for C7H5N2Br 195.9636 (79Br), found 195.9633 (79Br); 197.9616 (81Br); found 197.9617 (81Br). Synthesis of 5-(2-Cyclohexylnaphthalen-1-yl)imidazo[1,5a]pyridine (17). A Schlenk tube was charged with 5-bromoimidazo[1,5-a]pyridine (15) (300 mg, 1.53 mmol) and Pd(PPh3)4 (97 mg, 5 mmol %) under an argon atmosphere, and the mixture was dissolved in dry dioxane (5 mL). 2-Cyclohexylnaphthalen-1-ylboronic acid (16) (136 mg, 0.54 mmol) and 2 M Cs2CO3 in water (1.5 mL) were added, and the mixture was heated at 100 °C for 48 h. Then, ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer was washed with brine (2 × 10 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (CH2Cl2 → 50:1 CH2Cl2−MeOH) to yield 17 (469 mg, 94%) as a white solid. Mp: 151−152 °C. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 3JHH = 8.8 Hz, 1H), 7.88 (d, 3JHH = 8.3 Hz, 1H), 7.62 (d, 3JHH = 8.8 Hz, 1H), 7.60−7.58 (m, 1H), 7.55 (s, 1H), 7.45 (ddd, 3JHH = 8.1, 6.8 Hz; 4JHH = 1.2 Hz, 1H), 7.34 (s, 1H), 7.31 (ddd, 3JHH = 8.3, 6.8 Hz; 4 JHH = 1.3 Hz, 1H), 7.21−7.19 (m, 1H), 6.92 (dd, 3JHH = 9.2, 6.5 Hz, 1H), 6.55 (dd, 3JHH = 6.5 Hz; 4JHH = 1.1 Hz, 1H), 2.43−2.31 (m, 1H), 1.77−1.73 (m, 2H), 1.72−1.57 (m, 3H), 1.56−1.44 (m, 1H), 1.32− 1.09 (m, 3H), 1.01−0.94 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 145.2, 132.3, 131.9, 131.8, 131.0, 130.3, 128.2, 127.5, 127.4, 127.1, 125.8, 124.8, 124.8, 120.4, 119.3, 117.3, 114.7, 42.0, 35.0, 33.6, 26.6, 26.5, 25.9. EIMS m/z: 326 (20, M+), 316 (100), 315 (72), 284 (38), 279 (65), 277 (55). HRMS m/z: calcd for C23H22N2 326.1783, found 326.1781. The racemic mixture was resolved by semipreparative HPLC on a Chiralpak IB column. Analytical Chiralpak IB, 70:30:0.1 heptane−iPrOH−DEA, 1 mL/min, 30 °C, λ = 226.1 nm: first enantiomer, compound (−)-17, tR = 6.7 min, [α]25D = −81.6 (c 0.25, CHCl3); second enantiomer, compound (+)-17, tR = 11.6 min, [α]25D = +73.1 (c 0.25, CHCl3). Synthesis of Imidazolium Salts 18−25. General Procedure. Neutral heterocycles 11−13 or 17 (0.6 mmol) was dissolved in dry THF or 1,4-dioxane (4 mL) under an argon atmosphere, and the corresponding alkyl halide was added (3−5 equiv). The mixture was stirred at reflux until total consumption of starting material (TLC, 24− 72 h), then concentrated, and the residue was purified by flash chromatography (CH2Cl2 → 50:2 CH2Cl2−MeOH). Light was avoided during the whole process. Starting materials, yields, and characterization data for compounds 18−25 are as follows. 2-Methyl-5-(2-methoxynaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Iodide (18). From (+)-11 (195 mg, 0.6 mmol) and methyl iodide (187 μL, 3 mmol) in dry THF, compound (+)-18 was obtained as a yellow solid (255 mg, 91%). Mp: 179−180 °C. [α]25D = +141.2 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.05 (s, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.21 (d, 3JHH = 9.2 Hz, 1H), 7.94 (d, 3JHH = 8.2 Hz, 1H), 7.74 (d, 3JHH = 8.9 Hz, 1H), 7.61 (d, 3JHH = 9.2 Hz, 1H), 7.38 (t, 3JHH = 7.5 Hz, 1H), 7.32−7.27 (m, 2H), 7.12−7.07 (m, 1H), 7.03 (d, 3JHH = 9.2 Hz, 1H), 6.84 (d, 3JHH = 8.4 Hz, 1H), 4.46 (s, 3H), 3.94 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 156.4, 134.2, 132.1, 130.8, 129.7, 129.1, 129.0, 128.6, 128.4, 128.3, 127.8, 124.9, 124.7, 124.6, 122.6, 121.2, 115.2, 113.9, 113.8, 109.5, 56.9, 39.3. EIMS m/z: 338 (8, M+ − 1), 324 (47), 144 (94), 142 (100), 84 (63). HRMS m/z: calcd for C23H18N2O 338.1419, found 338.1418. 2-Benzyl-5-(2-methoxynaphthalen-1-yl)imidazo[1,5-b]isoquinolinium Bromide (19). From (+)-11 (195 mg, 0.6 mmol) and benzyl bromide (288 μL, 2.4 mmol) in dry THF, compound (+)-19 was obtained as a yellow solid (288 mg, 97%). Mp: 154−156 °C. [α]25D = +491.2 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.34 (s, 1H), 8.59 (br s, 1H), 8.39 (s, 1H), 8.21 (d, 3JHH = 9.2 Hz, 1H), 7.92 (d, 3JHH = 8.1 Hz, 1H), 7.70 (d, 3JHH = 9.1 Hz, 1H), 7.62 (d, 3JHH = 9.2 Hz, 1H), 7.54−7.50 (m, 2H), 7.35 (ddd, 3JHH = 8.1, 6.8 Hz; 4JHH = 1.2 Hz, 1H), 7.29−7.26 (m, 3H), 7.24−7.20 (m, 2H), 7.09−6.95 (m, 2H), 6.84 (d, 3JHH = 8.5 Hz, 1H), 6.09 (d, 3JHH = 14.2 Hz, 1H), 6.02 (d, 3JHH = 14.2 Hz, 1H), 3.93 (s, 3H). 13C NMR (125 MHz, CDCl3): JHH 13

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DOI: 10.1021/acs.organomet.5b00681 Organometallics 2015, 34, 5073−5080

Article

Organometallics CDCl3): δ 9.44 (d, 4JHH = 2.0 Hz, 1H), 8.86 (s, 1H), 8.32 (d, 4JHH = 2.0 Hz, 1H), 8.16 (d, 3JHH = 9.0 Hz, 1H), 7.98−7.94 (m, 2H), 7.83 (d, 3 JHH = 8.9 Hz, 1H), 7.50−7.45 (m, 1H), 7.34−7.27 (m, 2H), 7.25− 7.20 (m, 1H), 7.16 (ddd, 3JHH = 9.0, 6.4 Hz; 4JHH = 1.1 Hz, 1H), 6.99−6.94 (m, 1H), 5.34 (m, 3JHH = 6.8 Hz, 1H), 1.67 (d, 3JHH = 6.8 Hz, 3H), 1.66 (d, 3JHH = 6.8 Hz, 3H), 1.02 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 149.3, 139.2, 132.6, 131.9, 131.3, 130.3, 129.7, 129.1, 128.6, 128.4, 128.1, 127.3, 126.8, 124.3, 123.1, 121.4, 117.0, 116.8, 114.0, 113.1, 55.4, 37.6, 31.6, 24.0, 23.6. FAB-MS m/z: 393 (16, M+), 330 (27), 315 (28), 149 (49), 71 (56), 57 (100). HRMS m/z: calcd for C28H29N2 393.2331, found 393.2317. 2-Isopropyl-5-(2-cyclohexylnaphthalen-1-yl)imidazo[1,5-a]pyridinium Iodide (25). From (+)-17 (196 mg, 0.6 mmol) and isopropyl iodide (180 μL, 1.8 mmol) in dry dioxane, compound (−)-25 was obtained as a yellow solid (268 mg, 90%). Mp: 175 °C (dec). [α]25D = −226.3 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.15 (s, 1H), 8.23 (d, 3JHH = 9.4 Hz, 1H), 8.17 (s, 1H), 8.10 (d, 3JHH = 8.7 Hz, 1H), 7.94 (d, 3JHH = 8.2 Hz, 1H), 7.66 (d, 3JHH = 8.7 Hz, 1H), 7.51 (ddd, 3JHH = 8.2, 6.8 Hz; 4JHH = 1.2 Hz, 1H), 7.46 (dd, 3 JHH = 9.4, 6.8 Hz, 1H), 7.40 (ddd, 3JHH = 8.3, 6.8 Hz; 4JHH = 1.4 Hz, 1H), 7.08 (d, 3JHH = 6.8 Hz, 1H), 7.06 (d, 3JHH = 8.3 Hz, 1H), 5.23 (m, 3JHH = 6.7 Hz, 1H), 2.23−2.14 (m, 1H), 1.80−1.62 (m, 5H), 1.59 (d, J = 6.7 Hz, 3H), 1.58 (d, J = 6.7 Hz, 3H), 1.56−1.54 (m, 1H), 1.30−1.18 (m, 2H), 1.16−1.01 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 145.9, 132.6, 132.4, 132.1, 131.1, 130.8, 128.8, 128.1, 126.5, 125.1, 124.9, 123.8, 123.3, 120.5, 120.5, 119.1, 115.2, 55.0, 42.4, 35.0, 33.7, 26.4, 26.2, 25.6, 23.7, 23.4. EIMS m/z: 369 (32, M+), 368 (95, M+ − 1), 326 (10), 236 (42), 84 (100), 83 (73). HRMS m/z: calcd for C26H29N2 369.2331, found 369.2329. Synthesis of Imidazolium Chlorides 26 and 27. General Procedure. Iodides (+)-24 and (−)-25 (0.6 mmol) were eluted through a Dowex 22 anion exchange resin column using methanol as eluant.29 The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2, dried with MgSO4, and concentrated to yield chlorides (+)-26 and (−)-27 in quantitative yield. Characterization data are as follows. 2-Isopropyl-5-(2-tert-butylnaphthalen-1-yl)imidazo[1,5-b]isoquinolinium chloride (26): yellow foam (257 mg, quant). [α]25D = +103.7 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.76 (d, 4JHH = 1.8 Hz, 1H), 8.85 (s, 1H), 8.31 (s, 1H), 8.15 (d, 3JHH = 9.0 Hz, 1H), 7.97−7.93 (m, 2H), 7.82 (d, 3JHH = 9.0 Hz, 1H), 7.48 (ddd, 3JHH = 8.0, 6.8 Hz; 4JHH = 1.1 Hz, 1H), 7.32−7.27 (m, 1H), 7.24−7.19 (m, 1H), 7.14 (ddd, 3JHH = 9.2, 6.4 Hz; 4JHH = 1.1 Hz, 1H), 6.94 (dd, 3JHH = 9.2 Hz; 4JHH = 1.1 Hz, 1H), 6.49 (dd, 3JHH = 8.6 Hz; 4JHH = 1.0 Hz, 1H), 5.38 (m, 3JHH = 6.7 Hz, 1H), 1.68−1.61 (m, 6H) 1.01 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 149.4, 132.6, 131.8, 131.4, 131.1, 130.2, 129.9, 129.1, 128.6, 128.4, 128.2, 128.2, 127.4, 126.8, 126.0, 124.3, 123.2, 121.7, 117.4, 116.7, 114.1, 55.3, 37.7, 31.5, 24.0, 23.7. HRMS m/z: calcd for C26H29N2 393.2331, found 393.2334. 2-Isopropyl-5-(2-cyclohexylnaphthalen-1-yl)imidazo[1,5-a]pyridinium chloride (27): yellow solid (243 mg, quant). Mp: 201−203 °C. [α]25D = −198.1 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.41 (s, 1H), 8.27 (br s, 1H), 8.18 (d, 3JHH = 9.3 Hz, 1H), 8.05 (d, 3 JHH = 8.7 Hz, 1H), 7.90 (d, 3JHH = 8.1 Hz, 1H), 7.61 (d, 3JHH = 8.7 Hz, 1H), 7.47−7.44 (m, 1H), 7.39 (dd, 3JHH = 9.3, 6.1 Hz, 1H), 7.35 (ddd, 3JHH = 8.3, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 7.04−7.02 (m, 2H), 5.32 (m, 3JHH = 6.7 Hz, 1H), 2.16−2.07 (m, 1H), 1.76−1.59 (m, 5H), 1.54 (d, 3JHH = 6.7 Hz, 3H), 1.53 (d, 3JHH = 6.7 Hz, 3H), 1.49−1.44 (m, 1H), 1.12−0.93 (m, 2H), 0.87−0.74 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 145.7, 132.4, 132.3, 131.9, 131.1, 130.9, 128.7, 127.9, 126.3, 124.9, 124.8, 123.8, 123.2, 120.5, 120.3, 119.2, 115.6, 54.7, 42.3, 34.8, 33.5, 26.3, 26.1, 25.4, 23.6, 23.2. HRMS m/z: calcd for C26H29N2 369.2331, found 369.2333. Synthesis of Silver Complexes 28−30. General Procedure. Imidazolium salt (0.3 mmol), Ag2O (42 mg, 0.18 mmol), and 4 Å molecular sieves were suspended in dry CHCl3 (5 mL) under an argon atmosphere and in darkness. The mixture was stirred at rt for 12 h and then filtered through a Celite pad. The solvent was evaporated to yield the corresponding silver complexes.

Silver complex (Sa)-28. From (Sa)-22, yellow foam (115 mg, 96%). H NMR (500 MHz, CDCl3): δ 8.20 (d, 3JHH = 8.5 Hz, 1H), 8.00 (d, 3 JHH = 8.3 Hz, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.63 (d, 3JHH = 8.5 Hz, 1H), 7.50−7.42 (m, 2H), 7.35−7.30 (m, 4H), 7.25−7.19 (m, 2H), 7.08−7.02 (m, 1H), 6.88 (d, 3JHH = 8.3 Hz, 1H), 6.82 (dd, 3JHH = 9.4, 6.2 Hz, 1H), 6.71 (d, 3JHH = 9.4 Hz, 1H), 5.61−5.50 (m, 2H), 2.11 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 136.3, 135.2, 134.0, 133.0, 132.2, 131.6, 131.5, 130.0, 129.3, 129.2, 129.1, 128.9, 128.3, 127.4, 127.4, 127.0, 126.9, 126.5, 125.9, 124.9, 123.7, 122.7, 114.0, 109.5, 58.5, 20.1. Silver complex 29. From (+)-26, yellow foam (165 mg, quant.). 1H NMR (500 MHz, CDCl3): δ 8.20 (d, 3JHH = 9.0 Hz, 1H), 7.99 (s, 1H), 7.97−7.92 (m, 2H), 7.72 (d, 4JHH = 2.0 Hz, 1H), 7.49−7.46 (m, 1H), 7.41 (ddd, 3JHH = 8.0, 6.8 Hz; 4JHH = 1.1 Hz, 1H), 7.13 (ddd, 3JHH = 8.3, 6.8 Hz; 4JHH = 1.3 Hz, 1H), 7.04 (dd, 3JHH = 8.9, 6.1 Hz, 1H), 6.81 (ddd, 3JHH = 9.3, 6.1 Hz; 4JHH = 1.1 Hz, 1H), 6.74−6.71 (m, 1H), 6.62−6.59 (m, 1H), 5.00 (m, 3JHH = 6.7 Hz, 1H), 1.59 (d, 3JHH = 6.7 Hz, 3H), 1.54 (d, 3JHH = 6.7 Hz, 3H), 1.11 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 168.1 (2 d, 1JC,Ag = 279.5 y 240.5 Hz, C−Ag), 167.6 (C−Ag), 148.2, 136.0, 132.8, 131.8, 131.7, 131.7, 131.1, 129.6, 128.7, 127.6, 127.1, 127.1, 126.9, 126.1, 125.9, 125.8, 124.2, 123.7, 113.8, 105.1, 56.9, 53.4, 37.7, 31.8, 29.7, 24.6, 24.0. Silver Complex 30. From (−)-27, yellow foam (153 mg, quant). 1H NMR (500 MHz, CDCl3): δ 8.15 (d, 3JHH = 8.7 Hz, 1H), 7.93 (d, 3JHH = 8.1 Hz, 1H), 7.65 (d, 3JHH = 8.7 Hz, 1H), 7.54−7.48 (m, 2H), 7.42 (t, 3JHH = 7.6 Hz, 1H), 7.29 (t, 3JHH = 7.6 Hz, 1H), 7.10 (d, 3JHH = 8.5 Hz, 1H), 7.06 (dd, 3JHH = 9.3, 6.6 Hz, 1H), 6.61 (d, 3JHH = 6.6 Hz, 1H), 4.81 (m, 3JHH = 6.7 Hz, 1H), 2.33−2.25 (m, 1H), 2.05−1.95 (m, 1H), 1.82−1.69 (m, 5H), 1.49 (d, 3JHH = 6.7 Hz, 3H), 1.47 (d, 3JHH = 6.7 Hz, 3H), 0.92−0.72 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 170.6 (2 d, 1JC,Ag = 275.0 y 237.2 Hz, C−Ag), 167.7 (C−Ag), 144.8, 137.0, 132.7, 132.4, 131.5, 131.3, 130.9, 128.9, 128.8, 127.4, 126.9, 125.8, 125.0, 124.2, 122.8, 117.2, 116.6, 107.7, 56.3, 42.6, 34.9, 34.0, 26.7, 26.5, 25.9, 24.2, 23.9. Synthesis of Gold Complexes 31 and 32. General Procedure. A solution of silver complex (0.15 mmol) and AuCl·Me2S (53 mg, 0.18 mmol) in dry toluene (3 mL) was stirred at rt in darkness for 12 h. The reaction was filtered through a Celite pad, and the solvent was evaporated. The residue was purified by flash chromatography (45:45:10 EtOAc−cyclohexane−CH2Cl2) to yield the corresponding gold complex. Gold complex (+)-31. From silver complex 29, yellow foam (70 mg, 75%). [α]25D = +53.5 (c 0.09, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.20 (d, 3JHH = 8.9 Hz 1H), 7.94−7.91 (m, 3H), 7.88 (d, 3 JHH = 9.1 Hz, 1H), 7.51−7.48 (m, 1H), 7.40 (ddd, 3JHH = 8.0, 6.8 Hz; 4 JHH = 1.0 Hz, 1H), 7.14 (ddd, 3JHH = 8.4, 6.9 Hz; 4JHH = 1.4 Hz, 1H), 7.09−7.01 (m, 1H), 6.83 (ddd, 3JHH = 9.3, 6.3 Hz; 4JHH = 1.1 Hz, 1H), 6.76−6.70 (m, 1H), 6.59 (br d, 3JHH = 8.5 Hz, 1H), 5.70 (m, 3JHH = 6.7 Hz, 1H), 1.74 (d, 3JHH = 6.7 Hz, 3H), 1.73 (d, 3JHH = 6.7 Hz, 3H), 1.13 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 160.4 (C−Au), 148.7, 136.4, 132.5, 130.9, 130.0, 128.5, 127.6, 127.4, 127.0, 127.0, 126.6, 126.0, 125.9, 124.8, 124.1, 124.1, 112.2, 104.0, 37 0.8, 31.7, 29.7, 22.0, 21.7. HRMS m/z: calcd for C28H28AuClN2 624.1607, found 624.1603. Gold complex (+)-32. From silver complex 30, yellow foam (76 mg, 84%). [α]25D = +13.8 (c 0.25, CHCl3). 1H NMR (500 MHz, CDCl3): δ 8.14 (d, 3JHH = 8.7 Hz, 1H), 7.93−7.88 (m, 1H), 7.61 (d, 3 JHH = 8.7 Hz, 1H), 7.50 (dd, 3JHH = 9.3 Hz, 4JHH = 1.2 Hz, 1H), 7.46 (s, 1H), 7.41 (ddd, 3JHH = 8.1, 6.8 Hz; 4JHH = 1.2 Hz, 1H), 7.30 (ddd, 3 JHH = 8.3, 6.8 Hz; 4JHH = 1.2 Hz, 1H), 7.11 (dd, 3JHH = 8.5 Hz; 4JHH = 1.2 Hz, 1H), 7.05 (dd, 3JHH = 9.3, 6.5 Hz, 1H), 6.60 (dd, 3JHH = 6.5 Hz; 4JHH = 1.2 Hz, 1H), 5.25 (m, 3JHH = 6.7 Hz, 1H), 2.34−2.27 (m, 1H), 1.79−1.60 (m, 5H), 1.51 (d, 3JHH = 6.7 Hz, 3H), 1.49 (d, 3JHH = 6.7 Hz, 3H), 1.32−1.18 (m, 3H), 0.91−0.80 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 162.4 (C−Au), 145.0, 136.7, 132.4, 132.3, 131.9, 130.7, 128.6, 128.4, 126.6, 125.4, 124.7, 124.3, 122.9, 117.3, 117.1, 107.0, 55.9, 42.8, 34.9, 33.3, 26.8, 26.5, 26.0, 23.7, 23.3. CIMS m/z: 600 (48, M+), 565 (100), 368 (24), 367 (38). HRMS m/z: calcd for C26H28AuN2Cl 600.1607, found 600.1611. 1

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DOI: 10.1021/acs.organomet.5b00681 Organometallics 2015, 34, 5073−5080

Article

Organometallics Gold(I)-Catalyzed [2+2] Cycloadditions. A solution of 33 (53 μL, 0.48 mmol) and 34 (21 μL, 0.16 mmol) in dry CH2Cl2 (0.3 mL) was added to a solution of gold(I) complex 31 or 32 (3 mol %) and AgSbF6 (3 mol %) in dry CH2Cl2 (0.08M). The reaction was stirred at room temperature for 36 h (GC-MS monitoring). Et3N (0.05 mL) was added, and the solvent was evaporated. The residue was purified by flash chromatography (pentane) to yield 35 in 71% and 57% yield, respectively.

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(18) Wang, H. M. J.; Lin, I. J. B. Organometallics 1998, 17, 972−975. (19) Hintermair, U.; Englert, U.; Leitner, W. Organometallics 2011, 30, 3726−3731. (20) Searching the Cambridge Structural Database (CSD) revealed the absence of structures containing the [Ag2Br5]3− cluster. The analogue [Ag2Br6]4− and [Ag2Br4]2− clusters, however, are known. Bringley, J. F.; Rajeswaran, M.; Olson, L. P.; Liebert, N. M. J. Solid State Chem. 2005, 178, 3074−3089. For a comprehensive review on the structure of Ag-NHC complexes see: Garrison, J. C.; Youngs, W. J. Chem. Rev. 2005, 105, 3978−4008. (21) Francos, J.; Grande-Carmona, F.; Faustino, H.; IglesiasSigüenza, J.; Díez, E.; Alonso, I.; Fernández, F.; Lassaletta, J. M.; López, F.; Mascareñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322− 14325. (22) López-Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292−9294. (23) Better enantioselectivites (up to 81% ee) have been achieved by Echavarren and co-workers using a dinuclear Josiphos-like complex: Results presented at the 7th Spanish-Portuguese-Japanese Organic Chemistry Symposium (June 23−26, 2015: Escofet, I.; GarcíaMorales, I.; López, L.; Ranieri, B.; Obradors, C.; Carreras J.; Echavarren A. M., Poster P61, p 157 of the Book of Abstracts). (24) Lee, C. H.; Bayburt, E. K.; DiDomenico, S., Jr.; Drizin, I.; Gomtsyan, A. R.; Koenig, J. R.; Perner, R. J.; Schmidt, R. G., Jr.; Turner, S. C.; White, T. K.; Zheng, G. Z. US Patent 2004/0157849 A1, 2004. (25) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743−756. (26) Clews, J.; Curtis, A. D. M.; Malkin, H. Tetrahedron 2000, 56, 8735−8746. (27) Isogai, Y.; Menggenbateer, N.; Khan, F.; Asao, N. Tetrahedron 2009, 65, 9575−9582. (28) Vázquez Á lvarez, A. Ph.D. Thesis, University of Seville, 2012. (29) The resin was washed thoroughly with methanol prior to use.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00681. 1 H and 13C NMR spectra for new compounds (PDF) Crystallographic data for (Sa)-28 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: ff[email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by MINECO (Grants CTQ2013-48164C2-1-P and 2-P), European FEDER funds, and the Junta de Andaluciá (Grant 2012/FQM 1078).

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REFERENCES

(1) Clyne, D. S.; Jin, J.; Genest, E.; Gallucci, J. C.; Rajanbabu, T. V. Org. Lett. 2000, 2, 1125−1128. (2) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954−4955. (3) Duan, W. L.; Shi, M.; Rong, G. B. Chem. Commun. 2003, 2916− 2917. (4) Wang, W.; Yang, J.; Wang, F.; Shi, M. Organometallics 2011, 30, 3859−3869. (5) Bartolomé, C.; García-Cuadrado, D.; Ramiro, Z.; Espinet, P. Inorg. Chem. 2010, 49, 9758−9764. (6) Wang, Y.-M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 12972−12975. (7) Handa, S.; Slaughter, L. M. Angew. Chem., Int. Ed. 2012, 51, 2912−2915. (8) Alcarazo, M.; Roseblade, S.; Cowley, A.; Fernández, R.; Brown, J.; Lassaletta, J. M. J. Am. Chem. Soc. 2005, 127, 3290−3291. (9) Burstein, C.; Lehmann, C. W.; Glorius, F. Tetrahedron 2005, 61, 6207−6217. (10) Roseblade, S. J.; Ros, A.; Monge, D.; Alcarazo, M.; Á lvarez, E.; Lassaletta, J. M.; Fernández, R. Organometallics 2007, 26, 2570−2578. (11) Fürstner, A.; Alcarazo, M.; Krause, H.; Lehmann, C. W. J. Am. Chem. Soc. 2007, 129, 12676−12677. (12) Check, C. T.; Jang, K. P.; Schwamb, C. B.; Wong, A. S.; Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2015, 54, 4264−4268. (13) Espina, M.; Rivilla, I.; Conde, A.; Díaz-Requejo, M. M.; Pérez, P. J.; Á lvarez, E.; Fernández, R.; Lassaletta, J. M. Organometallics 2015, 34, 1328−1338. (14) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1 1997, 927−934. (15) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271−3273. (16) Zhang, J.; Fu, J.; Su, X.; Wang, X.; Song, S.; Shi, M. Chem. Asian J. 2013, 8, 552−555. (17) Imidazolium salts are more stable than the corresponding neutral precursors and can be stored under argon for several weeks without decomposition. 5080

DOI: 10.1021/acs.organomet.5b00681 Organometallics 2015, 34, 5073−5080