Isomeric Palladium Complexes Bearing Imidazopyridine-Based

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

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Isomeric Palladium Complexes Bearing Imidazopyridine-Based Abnormal Carbene Ligands: Synthesis, Characterization, and Catalytic Activity in Direct C−H Arylation Reaction Yan-Yi Lee, Han-Wei Zseng, Zong-Han Tsai, Yong-Siang Su, Ching-Han Hu, and Hon Man Lee* Department of Chemistry, National Changhua University of Education, Changhua, Taiwan 50058

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S Supporting Information *

ABSTRACT: A series of “abnormal” NHC ligand precursors based on imidazopyridines and their corresponding NHCpalladium diiodide complexes were prepared. Our study included the first report on a palladium complex with an abnormal NHC ligand derived from imidazo[1,5-a]pyridine. DFT calculation on the free ligands confirmed the higher electron-donating properties of the abnormal NHC ligands than their normal NHC isomers. The structural properties of all the complexes were studied in detail by single-crystal X-ray diffraction studies, revealing that, in general, Pd−carbene bond distances in palladium complexes with abnormal NHCs were longer than those in their isomers with normal NHCs. A significant trans influence is observed in the palladium complexes with abnormal NHC ligands. But in the complexes with normal NHC ligands, both Pd−carbene and Pd−N bond distances are short. Catalytic studies revealed that the palladium complexes were very efficient in catalyzing direct C−H arylation between 1,2-dimethylimidazole and aryl halides using a low Pd loading of 0.5 mol %. The difference in catalytic activity between the normal and abnormal isomers is, however, small.

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Chart 1. Isomeric Palladium Complexes of N-Heterocyclic Carbene Complexes

INTRODUCTION After the first isolation of stable crystalline N-heterocyclic carbene (NHC) by Arduengo et al.,1 NHC ligands have attracted much interest, and they are now ubiquitous in organometallic chemistry because of their wide applicability in catalysis.2−14 Imidazole-based NHC ligands usually bind to a metal center via its C2 atom. Crabtree et al. first showed that an alternative binding mode via C4/C5 atom was also possible.15 Since then, the so-called “abnormal NHCs” (aNHCs) have been attracting much interest16−20 because it has been shown that aNHCs are even stronger electron donors than normal NHCs (nNHCs).21−28 In some cases, transition metal complexes with aNHC ligands outperformed those with nNHC ligands in catalytic reactions such as transfer hydrogenation,29,30 alkene hydrogenation,26 Suzuki−Miyaura coupling reaction,24,31,32 Mizoroki−Heck coupling reaction,33 direct C−H arylation reaction,33 and decarboxylative coupling reaction,33 etc. For the preparation of imidazole-based aNHC, one of the common synthetic routes is to protect C2 imidazolium position to avoid the nNHC binding.21 Such protection is, however, not necessary for imidazo[1,2-a]pyridine-based aNHC since it contains no NCHN. In this regard, others and we have prepared palladium complexes with aNHC ligands derived from this fused ring heterocycle (A134−36 and A233,37 in Chart 1). An early study by Lassaletta et al. has shown that imidazo[1,5-a]pyridine is a versatile platform for stable free aNHCs and their transition-metal complexes, and the aNHC ligand is among the strongest σ© XXXX American Chemical Society

donors as revealed by the ν(CO) stretching frequency of its rhodium dicarbonyl complex.38 Palladium complex A3 based on imidazo[1,5-a]pyridine is, however, still unknown in the literature. In contrast to aNHC derived from imidazo[1,2a]pyridine, protection of the C2 position becomes necessary for that based on imidazo[1,5-a]pyridine isomer. Chart 2 shows the resonance structures for the corresponding free aNHC ligands. Noteworthy, all the free aNHC are mesoionic with no resonance form having all-neutral formal charges. Strictly speaking, therefore, they should be termed as mesoionic carbenes (MICs).20,39−41 The free aNHC in A3(a3) derived from imidazo[1,5-a]pyridine is worthy of Received: November 3, 2018

A

DOI: 10.1021/acs.organomet.8b00806 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics Chart 2. Resonance Structures of Free aNHC Ligands

Scheme 1. Synthesis of Isomeric NHC Ligand Precursorsa

investigation since both free aNHCs derived from imidazo[1,2a]pyridine (a1 and a2) can have positive charge delocalized on the six-member ring, whereas the positive charge is limited only to the five-member ring in a3. It is also worth mentioning that a variety of pyrido-annelated N-heterocyclic carbenes, which are structurally related to a1−3, were shown to have high donor property.42−44 Direct arylation reaction between heteroarenes and aryl halides is a highly desirable strategy for the construction of heterobiaryls because a preliminary organometallic reagent is not necessary, and hence there are fewer reaction steps with a reduction in waste.45−52 Typically, a high palladium loading of 2.5−5.0 mol % was required for this catalytic reaction. Previously, we reported PEPPSI-themed53 PdCl2 complexes with aNHC ligands (A2), which were effective in direct arylation for the formation of heterobiaryls.33 A relative high 2.5 mol % of Pd loading was, however, required. On the basis of this work, herein we aimed at the preparation and systematic investigation on a family of isomeric PEPPSI-themed PdI2 complexes with nNHC and aNHC ligands derived from imidazopyridines. The use of weakly coordinating iodide ligands may be beneficial in catalysis as shown by theoretical calculation on palladium bis(NHC)PdX2 complexes (X = halide).54 Their potential applicability in catalyzing direct arylation reaction between 1,2-dimethylimidazole and aryl halides was exploited. To our delight, these complexes are effective with a low 0.5 mol % of Pd loading.

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a

Reaction conditions: (i) MeI, THF, 100 °C, 12 h.

phenylimidazo[1,2-a]pyridine can be obtained in one step via the aforementioned Pd-catalyzed direct arylation reaction between imidazo[1,2-a]pyridine and bromobenzene.57 The reaction is highly regioselective, and the formation of 2phenylimidazo[1,2-a]pyridine isomer is disfavored due to the electronic repulsion between the nitrogen lone pair and Pd−C bond.48 For the synthesis of aNHC precursors 1c and 2c, the starting compound 2-substituted imidazo[1,5-a]pyridine can be obtained in two steps,59 using acetyl and benzoyl chlorides, respectively. The methyl and phenyl groups in these compounds are the C2 imidazolium protection groups in the ligands precursors. In all these ligand precursors, the CH proton on the fivemember ring was subject to deprotonation for the formation of free carbene and subsequently Pd−carbene bond. Among compounds 1 with two electron-donating methyl substituents, the nNHC ligand precursor 1n possesses the most downfield shifted CH proton at 9.67 ppm due to its disposition among two nitrogen atoms. The corresponding NCHC protons in the aNHC ligand precursors 1a−c were more upfield and observed in a narrow range of 8.06−8.20 ppm. For compounds 2 with one methyl group and one phenyl substituent, the chemical resonance of the CH proton is more downfield compared with that in 1. For instance, the NCHN proton in 2n was observed at 10.25 ppm, compared with that at 9.67 ppm in 1n. The NCHC protons in the aNHC ligand precursors 2a−c were observed in the range of 8.44−8.64 ppm. The general upfield shift of signals in 1 relative to 2 reflects the more electronrichness in the heterocyclic rings of the former compounds. Electronic Structures of Free Ligands. To evaluate the σ donor strength of the free ligands, the electronic structures of the free ligands were computed by theoretical calculations

RESULTS AND DISCUSSION

Synthesis of Ligand Precursors. Two series of ligand precursors, which are ionic salts with iodide anions, were prepared. In the first series, the compounds contain two donating methyl wingtip groups (1), whereas each compound has one methyl and one phenyl group in the second series (2). In each series, there are four structural isomers, consisting of three aNHC ligand precursors (a−c) and one nNHC precursor (n). Precursors 1n,55 2a,34 and 2n56 were reported previously. In general, they can be obtained via the quaternization reaction between an appropriate nitrogencontaining heterocyclic compound (imidazopyridine or benzimidazole) and iodomethane with good yields in the range of 75−91% (Scheme 1). The starting imidazopyridine and benzimidazole compounds were synthesized according to reported procedures.33,57−60 Notably for the synthesis of aNHC precursor 1b, a three-step procedure was required for the preparation of the starting compound 3-methylimidazo[1,2-a]pyridine.58 But for the preparation of precursor 2b, 3B


Article

Organometallics Table 1. HOMO and LUMO of the Free Carbene Ligands

using density functional theory (DFT) as implemented in the Gaussian 09 suite of programs.61 The geometries of these free ligands in their ground state were optimized at the B3LYP62,63/6-31G(d,p) level. Table 1 shows the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) of the free ligands. As expected, the HOMOs are mainly the lone-pair orbitals of the metal-bound carbon atoms. In line with the previous findings,22 the high HOMO energy levels and small HOMO− LUMO energy gaps suggest that aNHC ligands are stronger σdonors than their nNHC isomers, which is in agreement with the local anionic character in the metal-bound carbons of aNHCs. The ligands with two electron-donating methyl groups are stronger donors than those with one methyl and one phenyl groups, which is also in agreement with the NMR data. The larger HOMO−LUMO energy gaps in 1c′ (ΔE = 4.10 eV) and 2c′ (ΔE = 3.78 eV) compared with those in other free aNHC ligands (ΔE = 3.60−3.66 eV) are consistent with their lesser numbers of possible resonance structures (vide supra). Interestingly, all the free aNHC ligands were stronger electron donors than the versatile 1,3-dimesitylimidazolin-2-ylidene (IMes) nNHC ligand, which has a calculated HOMO energy level of −5.46 eV under our condition. It should be noted, however, that the HOMO−LUMO energies and gaps should be viewed in a relative manner; i.e., they should be compared among the related species, and are obtained from the same level of theory. In Table 1, 1n′ has been studied using a different density functional and basis set, the computed HOMO and LUMO energies and energy gap are different from our results.64 Synthesis of Palladium Complexes. After obtaining the two sets of ligand precursors, their palladium complexes were prepared (Scheme 2). The previously reported complexes 3n65

Scheme 2. Synthesis of Palladium Complexes

and 4a34 were prepared according to our procedures. Slightly different complexation conditions were required with different ligand precursors. In general, a suitable palladium precursor such as PdCl2 or PdI2 was allowed to react with the ligand precursors in refluxing pyridine in the presence of K2CO3 and KI. For complexes 3c and 4c, however, a two-step procedure involving an initial reaction between Pd(OAc)2 and the corresponding ligand precursors and an subsequent reaction with pyridine was necessary for obtaining pure products. All the eight complexes were produced in very pure forms with satisfactory yields in the range of 75−86%. They are stable in air and soluble readily in common organic solvents such as CH2Cl2 and THF. C


Article

Organometallics

Figure 1. Molecular structure of isomers 3a−c at 50% probability level.

Figure 2. Molecular structure of isomers 4a−c and 4n at 50% probability level.

Table 2. Selected Bond Distances (Å) and Angles (deg) around Pd in 3a−c and 3n Pd−I1 Pd−I2 Pd−N Pd−C N−Pd−I1 N−Pd−I2 I1−Pd−C I2−Pd−C I1−Pd−I2 C−Pd−N

3a

3b

3c

3na

3nb

2.6126(5) 2.6080(5) 2.130(3) 1.967(4) 91.06(8) 93.43(8) 87.18(11) 88.34(11) 174.426(15) 178.23(14)

2.6049(6) 2.6085(5) 2.115(5) 1.977(5) 91.23(13) 91.34(13) 88.66(15) 88.76(15) 177.21(2) 179.7(2)

2.5913(11) 2.6194(11) 2.113(9) 1.975(11) 91.1(3) 92.2(3) 88.8(3) 88.4(3) 172.59(5) 176.4(4)

2.628 2.624 2.115 1.984 92.59 89.99 89.36 88.15 174.54 177.83

2.5999(3) 2.5953(4) 2.095(3) 1.964(3) 92.87(8) 89.84(8) 89.23(9) 88.15(9) 174.542(13) 177.71(12)

a

Reported structural data measured at 100 K using synchrotron radiation (ref 65). bReacquired structural data measured at 150 K using sealed Xray tube.

130.2,34 131.9, 117.5, and 162.7 ppm, respectively. It should be noted that while the carbenic carbon resonances for 3b/4b (128.8 and 131.9 ppm) fall into the usual range of similar compounds,33 the corresponding resonances for 3a (106.1 ppm) and 3c/4c (114.6 and 117.5 ppm) are largely upfield, reflecting the shielding effect of the localized high electron density on the carbenic carbon atoms. For comparison, the signal for the metal-bound carbon atom in the related PdaNHC complex, namely, N,N-methylene-di-[(N′-methyl-2methyl)imidazol-4-ylidene]PdI2, was observed at 125 ppm.26 Despite possessing the same ligand scaffold, the carbenic

The successful formation of the palladium complexes was reflected by the disappearance of the downfield NCHN or NCHC proton signals in their 1H NMR spectra. To confirm unambiguously the chemical shift of the metal-bound carbenic carbon, complexes 3a−c were further characterized by 2D heteronuclear multiple bond correlation (HMBC) experiments (see the Supporting Information). The 2D NMR experiment gives correlations between C and H atoms separated by two or three bonds. The signals for the carbenic carbons in 3a−c and 3n were revealed at 106.2, 128.8, 114.6, and 161.2 ppm, respectively. The corresponding signals in 4a−c and 4n were at D


Article

Organometallics

which Pd−aNHC and Pd−nNHC share similar Pd−C distances have been reported.31−33 Comparing with the average bond length of 1.99(3) Å (seen in 41 crystallographically determined palladium complexes with aNHC ligands in the literature),66 the Pd−carbene bond distances in our aNHC complexes are slightly shorter. Carbene ligands with pyridine annulation has been suggested to have enhanced π-accepting character in the Rh−nNHC complex, Rh(nhc)(CO)2Cl (nhc = imidazo[1,5-a]pyridin-3-ylidenes).67 Hence, these short bonds may be attributable to the enhanced πaccepting character of ligands with the presence of low lying LUMOs (vide supra). Interestingly, a significant trans influence is observed in the aNHC complexes (Figure 3). For example,

carbon signal for 3a (106.2 ppm) is surprisingly much more upfield in comparison with that for 4a (130.2) reported by Ghosh et al.34 Overall, the more downfield shift of carbenic signals in 4 compared to those in 3 is again attributable to the less electron richness in their heterocyclic rings due to the presence of one methyl group and one phenyl group instead of two donating methyl groups as in 3. As expected, among the four isomeric complexes in each set, the carbenic carbon signals in the nNHC complexes are the most downfield. Structural Aspects. To acquire comparative structural data, the solid-state structures of all the complexes were established by single-crystal X-ray diffraction analysis. Figure 1 and 2 show their molecular structures. Selected bond distances and angles are tabulated in Table 2 and 3. Crystallographic Table 3. Selected Bond Distances (Å) and Angles (deg) around Pd in 4a−c and 4n Pd−I1 Pd−I2 Pd−N3 Pd−C1 N−Pd−I1 N−Pd−I2 I1−Pd−C I2−Pd−C I1−Pd−I2 C−Pd−N

4a

4b

4c

4n

2.5917(8) 2.5774(8) 2.117(6) 1.973(7) 94.06(18) 90.52(18) 87.3(2) 88.3(2) 174.91(3) 175.7(3)

2.6055(6) 2.5874(6) 2.103(5) 1.983(5) 90.26(14) 88.69(14) 91.76(17) 89.42(17) 175.02(2) 177.4(2)

2.6245(11) 2.5868(11) 2.130(9) 1.966(11) 92.6(2) 92.4(2) 88.6(3) 86.3(3) 173.89(4) 178.6(4)

2.6155(6) 2.5944(6) 2.082(5) 1.964(5) 90.09(13) 89.71(13) 92.91(17) 88.16(17) 170.85(2) 174.0(2)

Figure 3. A plot of Pd−C and Pd−N distances in aNHC and nNHC complexes.

among the three aNHC complexes 4a−c, complex 4b exerts the weakest trans influence with the longest Pd−C bond of 1.983(5) Å, which in turn exhibits the shortest Pd−N bond of 2.103(5) Å. In contrast, the binding property of nNHC ligand is markedly different from that of aNHC ligand, reflecting from the fact that even though the nNHC ligands bind strongly in 3n and 4n, their trans pyridine ligands exhibit short Pd−N bonds of 2.082(5) and 2.095(3) Å, respectively. It is of interest to examine the C−C and C−N bond distances of the annulated pyridine ring in the carbene ligands of the palladium complexes (Figure 4). Consistent with the

data were given in Tables S1 and S2 in the SI. The crystal structure of complex 4a was determined previously,34 a different polymorph was, however, obtained in our hand. In the previous structure, 4a crystallizes in the Pn monoclinic unit cell with two molecules of the complex in an asymmetric unit. In contrast, the new polymorph features a single molecule of 4a in the P21/n monoclinic unit cell. Also, the extent of rotation of the phenyl ring with respect to the heterocyclic ring plane in the complex is different in these two polymorphs. In the published structure, the two dihedral angle in the two molecules of 4a are ca. 55° and 65°, whereas in the new polymorph a corresponding angle of ca. 44° was observed. The crystal structure of 3n was also very recently reported.65 This published data was acquired using synchrotron as radiation source at 100 K. For a comparative purpose, structural data of 3n was obtained at 150 K under the same conditions of the other structures. A major difference in the Pd−C bonds are observed in these two data sets (see Table 2). For structural discussion, our reacquired data set was used. All the palladium complexes adopt distorted square-planar geometry. For each of the complexes, the I−Pd−I bond angle shows larger derivation from linearity than the C−Pd−N bond angle. Among the complexes, the aNHC complex 4c shows the largest difference between these two angles; the two linear bond angles around the Pd atom are 173.89(4) and 178.6(4)°, respectively. Because of the more donating nature of aNHC ligands, shorter Pd−C bond distances in Pd−aNHC complexes are expected. The two nNHC complexes 3n and 4n exhibit an identical Pd−carbene bond distance of 1.964 Å. However, the Pd−C bonds in aNHC complexes are similar or even slightly longer with bond length in the range of 1.966(11)−1.983(5) Å. In fact, the metal−carbene distance is insensitive to the change in bond order, and several cases in

Figure 4. Selected C−C and C−N bond distances (Å) in the carbene ligands of complexes 3 and 4.

resonance structures of their free carbene ligands (see a3 in Chart 1), aNHC ligands derived from imidazo[1,5-a]pyridine in 3c and 4c exhibit the most pronounced effect of localization of the double bonds, and much elongated C−C and C−N bonds above 1.41 Å are present in the pyridine rings. Contrastingly, the nNHC ligands in 3n and 4n show extensive conjugation in the annulated rings. E


Article

Organometallics Table 5. Screening of Palladium Complexesa

Catalysis. The aforementioned preparation of 3phenylimidazo[1,2-a]pyridine was a vivid example of direct arylation for the preparation of heterobiaryls. We investigate the potential catalytic applicability of the two series of palladium carbene complexes for the reaction. The reaction between 1,2-dimethylimidazole and 4-bromoacetophenone was taken as the benchmark reaction (Table 4).68,69 Initially, Table 4. Screening of Conditionsa

entry

Pd loading (mol %)

solvent

base

additives

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.2 1.0

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMA DMSO NMP Dioxane THF Toluene DMF DMF

K3PO4 KOAc NaOAc Cs2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

PivOH PivOH PivOH PivOH PivOH − CH3CO2H CF3CO2H PhCO2H PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH

15 41 21 26 93 3 24 0 6 82 34 79 0 17 37 88 95b

entry

cat

yield (%)b

1 2 3 4 5 6 7 8 9 10 11

3a 3b 3c 3n 4a 4b 4c 4n Pd(OAc)2 PdI2 PdCl2

79 87 77 93 83 89 83 85 35 22 0

a

Reaction conditions: 1,2-dimethylimidazole (2 mmol), 4-bromoacetophenone (1 mmol), K2CO3 (2 mmol), PivOH (0.3 mmol), DMF (3 mL), Pd cat. (0.5 mol %), 130 °C, 12 h. bGC yield using benzophenone as an internal standard.

93%) was observed, and the nNHC complex 3n delivered the best yields (93%, entry 4), albeit only slightly better than complex 3b (87%, entry 2). A plot of yield versus time for the reactions catalyzed by 3b and 3n confirmed the slightly superior catalytic activity of 3n (see Figure S1 in the SI). Noteworthy, this very small difference in yields delivered by the Pd aNHC complex 3b and the Pd nNHC complex 3n can be attributed solely to the difference in the electronic effect of their carbene ligands, as these isomeric complexes share the same steric environment around the palladium centers. Entries 9 and 10 clearly demonstrated the effectiveness of the carbene ligands in the reaction as the ligand-free Pd(OAc)2 and PdI2 delivered much inferior yields (entries 9 and 10). The reaction failed when ligand-free PdCl2 was used (entry 11). Overall, the difference in activities between the palladium complexes bearing ligands with two electron-donating methyl groups and those with one methyl and one phenyl group is small. A similar small difference in activities was also observed between palladium complexes with aNHC and nNHC ligands. These results are in stark contrast to our previous work on relevant dichloropalladium complexes with nNHC and aNHC ligands; a higher catalytic activity was observed using PdCl2-aNHC complex in the direct C−H arylation reaction.33 These findings imply that besides the σ donor property of carbene ligand, the effect of halide coligand is also important for an effective catalyst system in direct arylation reaction. An example in which aNHC complex was less effective than its isomeric nNHC complex in catalysis is also known.71 Finally, the substrate scope of the catalyst precursor 3n was tested (Table 6). Entries 1−4 show that activated aryl bromides were effectively utilized as substrates to afford coupled products with good to excellent yields. Electrondonating 4- and 3-bromoanisole were also successfully used as substrate affording good yields (entries 5 and 6). However, the catalyst system failed to produce couple product with highly bulky 2-bromoanisole (entry 7). The use of slightly electrondonating to electron-neutral substrates also afforded the coupled products smoothly (entries 8−11). When 1-bromo4-chlorobenzene was used as substrate, the arylation occurred selectively at the carbon site bearing the Br atom (entry 12).

a

Reaction conditions: 1,2-dimethylimidazole (2 mmol), 4-bromoacetophenone (1 mmol), K2CO3 (2 mmol), PivOH (0.3 mmol), DMF (3 mL), 3n (0.5 mol %), 130 °C, 12 h. GC yield using benzophenone as an internal standard. bIsolated yield.

complex 3n (0.5 mol %) was used for the optimization of reaction conditions because of its easy accessibility. A screening of different bases revealed that K2CO3 produced a very good 93% yield (entry 5). Other bases such as KOAc and Cs2CO3 produced much lower yields (entries 1−4). The use of pivalic acid (PivOH) was essential, as the catalytic activity was entirely stopped in its absence (entry 6) or when other similar acids such as acetic acid, trifluoroacetic acid, or benzoic acid were used (entries 7−9). Finally, a range of solvents of different polarity were tested, and DMF was proven to be the best solvent (entries 5 vs 10−15). A reduction of 11% in product yield was observed when DMF was substituted with DMA or DMAc, which is similar to DMF in structure and a common solvent for direct C−H arylation reaction (entries 10 vs 5).33,68−70 Finally, the Pd loading was optimized, and entries 5 vs 16−17 reflect that a low 0.5 mol % Pd loading represents the best choice. Hence, the optimized conditions were as follows: 0.5 mol % Pd loading, DMF as solvent, K2CO3 as base, and a reaction temperature of 130 °C for 12 h in the presence of pivalic acid (PivOH) as additive. With the optimized conditions in hand, we proceeded to the screening of different palladium precatalysts (Table 5). For the complexes 4, the yields fell into a narrow range of 83−89% (entries 5−8), and the aNHC complex 4b delivered only a slightly better yield than the other complexes (entry 6). But among the complexes 3, a slightly wider range of yields (77− F


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Organometallics Table 6. Substrate Scopea

(50%), together with unreacted 4-bromoacetophenone were isolated. No palladium complex 3b was, however, recovered. These results imply a significant difference in the catalytic behavior between the two complexes. While the more stable Pd nNHC complex 3n could ensure a continuous supply of catalytic active species, the fast generation of Pd(0) in the case of Pd aNHC complex 3b may lead to the undesirable fast formation of inactive Pd black, thus offsetting the supposedly faster reaction rate. The fast generation of Pd(0) from 3b may commence via the coupling reaction between the aNHC ligand and the Ar group from 4-bromoacetophenone. However, in both cases of 3b and 3n, no coupling product resulting from the coupling between the carbene ligand and Ar group was observed. It is also possible that the similar catalytic activity in these complexes might due to the decoordination of the ligands and the subsequent formation of heterogeneous active species, which is commonly observed in C−C coupling reaction.65,72

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CONCLUSIONS In summary, two series of PEPPSI-themed PdI2 complexes with carbene scaffolds of different electron-donating property were prepared and structurally characterized. Each of the series contains three isomers of Pd−aNHC complex and a Pd− nNHC isomer. The carbene scaffold is based on imidazopyridines, and the first example of using imidazo[1,5-a]pyridine for the preparation of palladium aNHC complexes is reported. The higher electron-donating properties of the aNHC free ligands was confirmed by theoretical calculations. Structural analysis revealed that Pd−carbene bond distances in Pd− aNHC complexes were slightly longer than those in their PdnNHC isomers in spite of stronger electron-donating property of the aNHCs ligands. A significant trans influence is observed in the six Pd−aNHC complexes, but both Pd−carbene and trans Pd−N bonds are short in the two Pd−nNHC complexes. Despite the difference in electronic structures between free carbenes derived from imidazo[1,5-a]pyridine and imidazo[1,2-b]pyridine, their palladium complexes share similar catalytic properties. All the complexes were very effective in direct C−H arylation reaction between 1,2-dimethylimidazole and aryl bromides, allowing the use of a low 0.5 mol % Pd loading. But unlike our previous findings, there is only a small difference in catalytic activities between Pd−nNHC and their Pd−aNHC isomers. The difference in activity between complexes of the two ligand sets with different electron donating property is also insignificant. An early conclusion is that besides the σ donor property of carbene ligand, the effect of halide coligand is also important for an effective catalyst system in direct arylation reaction. Investigation on using the corresponding palladium dichloride complexes in the catalytic reaction is ongoing in our lab.

a

Reaction conditions: 1,2-dimethylimidazole (2 mmol), aryl halide (1 mmol), K2CO3(2 mmol), PivOH (0.3 mmol), DMF (3 mL), 3n (0.5 mol %), 130 °C, 12 h. Isolated yields.

The use of 4-chloroacetophene, however, afforded only a mediocre yield of 48% (entry 13). Further Insight. As mentioned above, the difference in catalytic activities between palladium complexes with aNHC and nNHC ligands is somewhat small, despite the stronger electron donating property of aNHC ligands. To gain further insight on the behavior of the Pd aNHC complex 3b and the Pd nNHC complex 3n, we conducted a pair of stoichiometric reactions between the palladium complexes and excess 4bromoacetophone in DMF mimicking the catalytic conditions at 130 °C for 5 h but without the addition of the imidazole coupling partner. In both cases, a dark solution was formed with the formation of palladium black observed on the wall of the reaction vessels. After extraction, the solution was then purified by column chromatography. In the case of 3n, unreacted 4-bromoacetophenone and palladium complex (ca. 15%) were recovered. Contrastingly in the case of 3b, an Ullmann-type homocoupling product, 4,4′-diacetylbiphenyl

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EXPERIMENTAL SECTION

General Information. All manipulations were performed under a dry nitrogen atmosphere using standard Schlenk techniques. Pyridine was used as received. Other solvents were dried with standard procedures. Starting chemicals were purchased from commercial source and used as received. 1H and 13C{1H} NMR spectra were recorded at 300.13 and 75.47 MHz, respectively, on a Bruker AV-300 spectrometer. Elemental analyses were performed on a Thermo Flash 2000 CHN-O elemental analyzer. ESI-MS was carried out on a Finnigan/Thermo Quest MAT 95XL mass spectrometer at National Chung Hsing University (Taiwan). 2-Methylimidazo[1,2-a]pyridine,57 2-phenylimidazo[1,2-a]pyridine,57 3-methylimidazo[1,2G


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Organometallics a]pyridine,58 3-phenylimidazo[1,2-a]pyridine,33 3-phenylimidazo[1,5a]pyridine,59 1-phenylbenzimidazole,60 1n,55 2a,34 2n,56 3n,65 and 4a34 were prepared according to the literature procedures. 3Methylimidazo[1,5-a]pyridine was prepared according to the literature procedure,59 and its identification was confirmed by the comparison with the reported NMR data.73 Synthesis of 1a. A mixture of 2-methylimidazo[1,2-a]pyridine (3.0 g, 0.02 mol) and methyl iodide (1.4 mL, 0.02 mol) in THF (20 mL) was placed in a Schlenk flask. The mixture was heated under reflux for 12 h. After the mixture was cooled, the colorless solid was collected on a frit, washed with THF, and dried under vacuum. Yield: 4.92 g (79%). mp = 194−195 °C. 1H NMR (DMSO-d6) δ 2.50 (s, 3H, CH3), 3.91 (s, 3H, CH3), 7.46 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.93 (t, 3 JHH = 9.0 Hz, 1H, Ar H), 8.16 (d, 3JHH= 9.0 Hz, 1H, Ar H), 8.20 (s, 1H, imi H), 8.87 (d, 3JHH = 6.0 Hz, 1H, Ar H). 13C{1H} NMR (DMSO-d6) δ 10.1 (CH3), 31.6 (CH3), 111.4, 112.4, 117.4, 129.2, 133.1, 135.6 (quaternary C), 139.5 (quaternary C). HRMS (ESI) m/z calcd for C9H11N2 [M − I]+ 147.0922, found 147.0920. Synthesis of 1b.74 The compound was prepared by a procedure similar to that for 1a. A mixture of 3-methylimidazo[1,2-a]pyridine (3.0 g, 0.02 mol) and methyl iodide (1.4 mL, 0.02 mol) were used. A colorless solid was obtained. Yield: 4.66 g (75%). mp = 223−224 °C. 1 H NMR (DMSO-d6) δ 2.58 (s, 3H, CH3). 4.03 (s, 3H, CH3), 7.57 (t, 3 JHH = 6.0 Hz, 1H, Ar H), 8.00−8.06 (m, 2H, imi H, Ar H), 8.19 (d, 3 JHH = 9.0 Hz, 1H, Ar H), 8.78 (d, 3JHH = 6.0 Hz, 1H, Ar H). 13C{1H} NMR (DMSO-d6) δ 9.0 (CH3), 34.2 (CH3), 111.6, 117.1, 123.2 (quaternary C), 123.8, 127.6, 133.1, 139.4 (quaternary C). HRMS (ESI) m/z calcd for C9H11N2 [M − I]+ 147.0922, found 147.0916. Synthesis of 1c.75 The compound was prepared with a similar procedure to that of 1a. A mixture of 3-methylimidazo[1,5-a]pyridine (3.0 g, 0.02 mol) and methyl iodide (1.4 mL, 0.02 mol) were used. A colorless solid was obtained. Yield: 5.66 g (91%). mp = 186−187 °C. 1 H NMR (DMSO-d6) δ 2.90 (s, 3H, CH3). 4.08 (s, 3H, CH3), 7.09− 7.21 (m, 2H, Ar H), 7.80 (d, 3JHH = 9.0 Hz, 1H, Ar H), 8.14 (s, 1H, imi H), 8.47 (d, 3JHH = 6.0 Hz, 1H, Ar H). 13C{1H} NMR (DMSOd6) δ 10.1 (CH3), 36.4 (CH3), 113.9, 117.0, 118.6, 123.3, 124.0, 128.2 (quaternary C), 135.4 (quaternary C). HRMS (ESI) m/z calcd for C9H11N2 [M − I]+ 147.0922, found 147.0914. Synthesis of 2b. The compound was prepared with a similar procedure to that of 1a. A mixture of 3-phenylimidazo[1,2-a]pyridine (3.0 g, 0.02 mol) and methyl iodide (1.0 mL, 0.02 mol) were used. A colorless solid was obtained. Yield: 4.20 g (81%). mp = 188−189 °C. 1 H NMR (DMSO-d6) δ 4.12 (s, 3H, CH3). 7.54 (t, 3JHH = 9.0 Hz, 1H, Ar H), 7.64−7.74 (m, 5H, Ar H), 8.10 (t, 3JHH = 6.0 Hz, 1H, Ar H), 8.30 (d, 3JHH = 9.0 Hz, 1H, Ar H), 8.51 (s, 1H, imi H), 8.81 (d, 1H, 3JHH = 6.0 Hz, Ar H). 13C{1H} NMR (DMSO-d6) δ 34.5 (CH3), 112.2, 118.2, 125.0, 125.3 (quaternary C), 126.4 (quaternary C), 127.3, 129.6, 130.1, 130.9, 134.0, 140.0 (quaternary C). HRMS (ESI) m/z calcd for C14H13N2 [M − I]+ 209.1079, found 209.1078. Synthesis of 2c.76 The compound was prepared with a similar procedure to that of 1a. A mixture of 3-phenylimidazo[1,5-a]pyridine (3.0 g, 0.02 mol) and methyl iodide (1.0 mL, 0.02 mol) were used. A colorless solid was obtained. Yield: 4.41 g (85%). mp = 206−207 °C. 1 H NMR (DMSO-d6) δ 4.02 (s, 3H, CH3), 7.13 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.32 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.78−7.88 (m, 5H, Ar H), 7.98 (d, 3JHH = 9.0 Hz, 1H, Ar H), 8.14 (d, 3JHH = 6.0 Hz, 1H, Ar H), 8.44 (s, 1H, imi H), 13C{1H} NMR, 13C{1H} NMR (DMSO-d6) δ 37.2 (CH3), 115.6, 118.4, 119.0, 121.3 (quaternary C), 123.0, 125.2, 129.2 (quaternary C), 130.3, 131.4, 132.9, 134.5 (quaternary C). HRMS (ESI) m/z calcd for C14H13N2 [M − I]+ 209.1079, found 209.1070. Synthesis of 3a. A mixture of 1a (0.1 g, 0.36 mmol), PdCl2 (0.065 g, 0.36 mmol), K2CO3(0.25 g, 1.82 mmol), and KI (0.30 g, 1.82 mmol) in pyridine (5 mL) was placed in a Schlenk flask. The mixture was heated under reflux for 12 h. After the mixture was cooled, dichloromethane was added, and the organic phase was washed with water twice. The extract was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to give a crude solid, which was further washed with diethyl ether. The yellowish solid was then

collected on a frit and dried under vacuum. Yield: 0.16 g (76%). mp = 248−249 °C. Anal. Calcd for C14H15I2N3Pd: C, 28.72; H, 2.58; N, 7.18. Found: C, 28.42; H, 2.28; N, 6.98%. 1H NMR (CDCl3) δ 2.66 (s, 3H, CH3), 3.76 (s, 3H, CH3), 7.13 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.26−7.32 (m, 3H, Py H, Ar H), 7.48 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.69 (t, 3JHH = 9.0 Hz, 1H, Py H), 9.10 (d, 3JHH = 6.0 Hz, 2H, Py H), 9.22 (d, 3JHH = 6.0 Hz, 1H, Ar H). 13C{1H} NMR (CDCl3) δ 13.2 (CH3), 30.6 (CH3), 106.2 (Pd−C), 107.8, 113.8, 124.2 (Py C), 128.7, 132.6, 133.7 (quaternary C, CCH3), 137.2 (Py C), 141.0 (quaternary C, ipso), 153.7 (Py C). Synthesis of 3b. A mixture of 1b (0.1 g, 0.36 mmol), PdI2 (0.13 g, 0.36 mmol), and K2CO3(0.25 g, 1.8 mmol) in pyridine (5 mL) was placed in a Schlenk flask. The mixture was heated under reflux for 48 h. The same workup procedure as that for 3a was used. A yellowish solid was obtained. Yield: 0.16 g (75%). mp = 261−262 °C. Anal. Calcd for C14H15I2N3Pd: C, 28.72; H, 2.58; N, 7.18. Found: C, 28.71; H, 2.44; N, 6.70%. 1H NMR (CDCl3) δ 2.71 (s, 3H, CH3), 4.28 (s, 3H, CH3), 7.08 (t, 3JHH = 6.0 Hz, 1H, Ar H), 7.28−7.36 (m, 3H, Py H, Ar H), 7.44 (d, 3JHH = 9.0 Hz, 1H, Ar H), 7.70 (t, 3JHH = 6.0 Hz, 1H, Py H), 7.89 (d, 3JHH = 6.0 Hz, 1H, Ar H), 9.09 (d, 3JHH = 6.0 Hz, 2H, Py H). 13C{1H} NMR (CDCl3) δ 11.9 (CH3), 37.9 (CH3), 108.3, 114.3, 122.0, 122.3 (quaternary C), 124.3 (Py C), 125.4, 128.8 (Pd− C), 137.2 (Py C), 140.1 (quaternary C), 153.7 (Py C). Synthesis of 3c. A mixture of 1c (0.1 g, 0.36 mmol), Pd(OAc)2 (0.082 g, 0.36 mmol), and KI (0.067 g, 0.40 mmol) in DMF was allowed to stir at 70 °C for 12 h. The reaction mixture was filtered and the solvent was evaporated to give a crude solid. Then pyridine (0.02 mL, 0.26 mmol) in DMF was added, and the mixture was stirred at 70 °C for another 12 h. The same workup procedure as that for 3a was used. An organic solid was obtained. Yield: 0.24 g (86%). mp = 181− 182 °C. Anal. Calcd for C14H15I2N3Pd: C, 28.72; H, 2.58; N, 7.18. Found: C, 28.92; H, 2.40; N, 6.79%. 1H NMR (CDCl3) δ 2.73 (s, 3H, CH3), 4.31 (s, 3H, CH3), 6.68 (t, 3JHH = 9.0 Hz, 1H, Ar H), 6.78 (t, 3 JHH = 9.0 Hz, 1H, Ar H), 7.30 (t, 3JHH = 6.0 Hz, 2H, Py H), 7.46 (d, 3 JHH = 6.0 Hz, 1H, Ar H), 7.69 (t, 3JHH = 9.0 Hz, 1H, Py H), 7.97 (d, 3 JHH = 9.0 Hz, 1H, Ar H), 9.10 (d, 3JHH = 9.0 Hz, 2H, Py H). 13C{1H} NMR (CDCl3) δ 9.8 (CH3), 40.4 (CH3), 114.6 (Pd−C), 116.9, 117.8, 119.6, 124.3 (Py C), 125.4, 130.0 (quaternary C), 131.3 (quaternary C), 137.3 (Py C), 153.8 (Py C). Synthesis of 4b. The complex was prepared with a similar procedure to that of 3b. A mixture of 2b (0.1 g, 0.29 mmol), PdI2 (0.11 g, 0.29 mmol), and K2CO3(0.20 g, 1.45 mmol) in pyridine (5 mL) was used. The mixture was heated under reflux for 12 h. A yellow solid was obtained. Yield: 0.15 g (79%). mp = 221−223 °C. Anal. Calcd for C19H17I2N3Pd: C, 35.24; H, 2.65; N, 6.49. Found: C, 35.19; H, 2.62; N, 6.51%. 1H NMR (CDCl3) δ 4.38 (s, 3H, CH3). 7.00 (t, 3 JHH = 6.0 Hz, 1H, Ar H), 7.21−7.26 (m, 2H, Ar H), 7.38 (t, 3JHH = 9.0 Hz, 1H, Py H), 7.49 (t, 3JHH = 6.0 Hz, 2H, Ar H), 7.56−7.67 (m, 3H, Py H, Ar H), 8.04 (d, 3JHH = 6.0 Hz, 2H, Ar H), 8.20 (d, 3JHH = 6.0 Hz, 1H, Ar H), 8.95 (d, 3JHH = 6.0 Hz, 2H, Py H). 13C{1H} NMR (CDCl3) δ 38.3 (CH3), 108.8, 114.5, 122.6, 124.2 (Py C), 126.3 (quaternary C), 126.8, 128.9, 129.3 (quaternary C), 130.5, 131.9 (Pd−C), 137.2 (Py C), 140.3 (quaternary C), 155.2 (Py C). Synthesis of 4c. The complex was prepared with a similar procedure to that of 3c. A mixture of 2c(0.1 g, 0.30 mmol), Pd(OAc)2 (0.067 g, 0.30 mmol), and KI (0.054 g, 0.33 mmol) in DMF was allowed to stir at 70 °C for 12 h. An orange solid was obtained. Yield: 0.22 g (76%). mp = 190−191 °C. Anal. Calcd for C19H17I2N3Pd: C, 35.24; H, 2.65; N, 6.49. Found: C, 35.36; H, 2.49; N, 6.28%. 1H NMR (CDCl3): δ 4.27 (s, 3H, CH3), 6.70−6.80 (m, 2H, Ar H), 7.31 (t, 3JHH = 6.0 Hz, 2H, Py H), 7.47−7.63 (m, 6H, Ar H), 7.70 (t, 3JHH = 9.0 Hz, 1H, Py H), 8.06 (d, 3JHH = 9.0 Hz, 1H, Ar H), 9.12 (d, 3JHH = 9.0 Hz, 2H, Py H). 13C{1H} NMR (CDCl3) δ 41.2 (CH3), 117.5 (Pd−C), 118.1, 118.2, 120.1, 123.2 (quaternary C), 124.3 (Py C), 125.3, 130.0, 130.2, 131.4, 132.0 (quaternary C), 133.4 (quaternary C), 137.3 (Py C), 153.8 (Py C). Synthesis of 4n. A mixture of 1-phenylbenzoimidazole 2n (0.10 g, 0.30 mmol), PdI2 (0.11 g, 0.30 mmol), and K2CO3(0.21 g, 1.5 mmol) in pyridine (5 mL) was placed in a Schlenk flask. The mixture was H


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Organometallics heated at 80 °C for 12 h. The solvent was then completely removed under vacuum. Dichloromethane was added, and the organic phase was washed with water twice. The organic layer was then dried with anhydrous MgSO4. The solvent was removed under vacuum again. The residue was purified by column chromatography on silica gel column using 30:70 ethyl acetate and n-hexane mixture (30:70 v/v) as eluent. An orange solid was obtained. Yield: 0.16 g (82%). mp = 212− 213 °C. Anal. Calcd for C19H17I2N3Pd: C, 35.24; H, 2.65; N, 6.49. Found: C, 35.16; H, 2.88; N, 6.39%. 1H NMR (CDCl3) δ 4.28 (s, 3H, CH3). 7.17−7.22 (m, 3H, Ar H), 7.26−7.34 (m, 2H, Py H, Ar H), 7.43 (d, 3JHH = 6.0 Hz, 1H, Ar H), 7.53−7.69 (m, 4H, Py H, Ar H), 7.98 (d, 3JHH = 9.0 Hz, 2H, Ar H), 8.79 (d, 3JHH = 6.0 Hz, 2H, Py H). 13 C{1H} NMR (CDCl3) δ 36.2 (CH3), 109.9, 110.9, 123.2, 123.3, 124.4 (Py C), 128.4, 129.2, 129.2, 135.0 (quaternary C), 135.8 (quaternary C), 137.1 (quaternary C), 137.5 (Py C), 153.4 (Py C), 162.7 (Pd−C). Direct Arylation Reaction. Typically, a mixture of aryl halide (1.0 mmol), 1,2-dimethylimidazole (2.0 mmol), K2CO3 (2.0 mmol). PivOH (0.3 mol), and Pd precatalyst (0.5 mmol %) was dissolved in DMF (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 130 °C in a preheated oil bath for 12 h. After the mixture was cooled, dichloromethane (10 mL) was added. The solution was poured into water (50 mL) and extracted with dichloromethane (3 × 25 mL). The combined extract was washed with brine, dried over anhydrous MgSO4, and evaporated to dryness under vacuum to give the crude product, which was analyzed by GC chromatography using benzophenone as internal standard or purified by column chromatography. Each catalytic yield was an average of two runs. Reaction of Palladium Complexes with 4-Bromoacetophenone. A mixture of palladium complex (3n or 3b) (0.20 g, 0.34 mmol), 4-bromoacetophenone (0.14 g, 0.68 mmol), and K2CO3 (0.094 g, 0.68 mmol) was heated at 130 °C for 5 h in DMF. After reaction, dichloromethane was added, and the organic phase was washed twice with water. The solvent was then removed under vacuum and the residue was then purified by column chromatography. In the case of 3n, unreacted 4-bromoacetophenone and palladium complex (15%) were recovered. In the case of 3b, unreacted 4-bromoacetophenone and 4,4′-diacetylbiphenyl77 (55%) was isolated. Single-Crystal X-ray Diffraction. Typically, crystals suitable for single-crystal X-ray diffraction studies were obtained by slow evaporation of a dichloromethane solution containing the compound in the presence of n-hexane vapor. For crystals of 3a, the solvent combination of acetone and methanol was used instead. Samples were collected at 150(2) K on a Bruker APEX II equipped with a CCD area detector and a graphite monochromator utilizing Mo Kα radiation (λ = 0.71073 Å). The unit cell parameters were obtained by least-squares refinement. Data collection and reduction were performed using the Bruker APEX2 and SAINT software.78 Absorption corrections were performed using the SADABS program.79 All the structures were solved by direct methods and refined by full-matrix least-squares methods against F2 with the SHELXTL software package.80 All non-H atoms were refined anisotropically. Structure of 4c is racemic-twinned, and the twin refinement afforded a final Flack parameter of 0.28(5). All H atoms were fixed at calculated positions and refined with the use of a riding model. CCDC files 1872409 (3a), 1872412 (3b), 1872413 (3c), 1872422 (3n) 1872414 (4a), 1872416 (4b), 1872418 (4c), and 1872420 (4n) contain supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.

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Crystallographic data, NMR spectra of ligand precursors, palladium complexes, and coupled products, coordinates of optimized structures (PDF) Supporting data (XYZ) Accession Codes

CCDC 1872409, 1872412−1872414, 1872416, 1872418, 1872420, and 1872422 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: [email protected]. ORCID

Ching-Han Hu: 0000-0002-7427-8174 Hon Man Lee: 0000-0002-9557-3914 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Ministry of Science and Technology of Taiwan (MOST 106-2113-M-018-001) for financial support of this work.

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REFERENCES

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* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00806. I


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