Dimetallic Palladium-NHC Complexes: Synthesis, Characterization, and Catalytic Application for Direct C?H Arylation Reaction of Heteroaromatics with Aryl Chlorides

Title: Dimetallic Palladium–NHC Complexes: Synthesis,

Characterization and Catalytic Application for Direct C－H

Arylation Reaction of Heteroaromatics with Aryl Chlorides

Authors: Debalina Ghosh, Jhen-Yi Lee, Ya-Ting Kuo, and Hon Man

Lee

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901189

Link to VoR: http://dx.doi.org/10.1002/adsc.201901189

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

FULL PAPER

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Dimetallic Palladium–NHC Complexes: Synthesis,

Characterization, and Catalytic Application for Direct C–H

Arylation Reaction of Heteroaromatics with Aryl Chlorides

Jhen-Yi Lee,^a,bDebalina Ghosh,^a,bYa-Ting Kuo,^aand Hon Man Lee^a,*

a

Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan

E-mail: leehm@cc.ncue.edu.tw

b

Equal contribution

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.

Abstract.

A series of dimetallic palladium(II)–NHC It allows for the effective use of aryl chlorides to prepare

complexes comprised of 1,4-naphthalenyl or 9,10-anthracenyl arylated heterocycles, previously only accessible with the

spacer sandwiched between two imidazole rings was more reactive bromide counterparts. Importantly, the

successfully

synthesized.

These

complexes

were catalytic activity of the dimetallic precatalyst was found to

1

characterized by H and ¹³C{¹H} NMR spectroscopy and be higher than that of an analogous mononuclear complex.

elemental analysis. The structures of two dimetallic palladium

complexes and a related mononuclear palladium complex to

be used for comparative studies were further characterized by

X-ray diffraction. The dimetallic palladium complex with the

9,10-anthracenyl linker was very efficient in catalyzing direct

C–H arylation reactions of heteroaromatic compounds

(imidazoles, imidazo[1,2-a]pyridine, and thioazole) with

a broad range of aryl chlorides, employing a mild

monopalladium loading of 1.5 mol%.

Keywords: Carbene ligands; Palladium; C—H activation ;

Heterocycles; Aryl halides; Dinuclear palladium complex

reaction of imidazoles with aryl halides.^[6]Although

these palladium–NHC complexes were generally

effective in catalyzing the reaction with aryl iodides

and bromides, general catalyst systems capable of

utilizing a broad range of less reactive but inexpensive

aryl chlorides remain elusive. Ke and Liu et al.

reported on some highly bulky PEPPSI-themed

palladium–NHC complexes which enabled aryl

bromides to be effectively coupled under aerobic

conditions with a low Pd loading of 1 mol%.^[6d]

However, they were not efficient catalysts for aryl

chloride substrates such as 4-chlorobenzonitrile and 4-

chlorobenzaldehyde, giving low yields in the range of

22–29%. Recently, Singh et. al. developed palladium

complexes with chalcogenated amidate NHC ligands,

also capable of facilitating the direct arylation of

imidazoles with aryl bromides under aerobic

conditions and a mild Pd loading of 0.5–1 mol%.^[6g]

Nevertheless, only a single aryl chloride substrate was

successfully employed in the coupling reaction. It is

noteworthy that reports on palladium–NHC

precatalysts were based predominantly on

mononuclear complexes. Compared to mononuclear

complexes, dinuclear palladium–NHC complexes

exhibited improved catalytic activity in cross-coupling

reactions.^[7]Their superior activity may be attributable

Introduction

Palladium-catalyzed direct C–H arylation reactions of

heteroarenes with aryl halides offer an economical and

environmental-friendly approach for the construction

of heterobiaryls as they do not require stoichiometric

amounts of preliminary organometallic reagents,

thereby streamlining synthetic routes and reducing

waste.^[1]We have been interested in the preparation of

aryl imidazoles because these heterocyclic compounds

exhibit interesting biological activities^[2]and they are

important structural units in organic materials.^[3]

Arylated imidazoles can be conveniently prepared by

the direct arylation reaction of azoles. Palladium in

combination with phosphine and related ligands

represents the typical catalytic conditions in earlier

works,^[4]where a high palladium loading in the range

of 2.0–10 mol% was required. N-heterocyclic carbene

(NHC) ligands have attracted much attention in the

past two decades because they offer many advantages

over phosphine ligands such as superior activity,

stronger -donating properties, and better stability and

structural versatility.^[5]Recently, much effort has been

directed toward the use of preformed palladium–NHC

complexes for catalyzing the C5-direct arylation

1

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

to a higher local concentration of the metal in the

dimetallic systems, or in some cases, to favorable

supramolecular interactions between ligand and

substrate.^[7b,7d]An earlier study by Huynh et.al

demonstrated superior catalytic performance of

dinuclear palladium–NHC complexes in comparison

to those of their mononuclear equivalents in the direct

C5-arylation of 1-methylimidazoles.^[6c]The activity

with aryl chloride substrates was however still

unsatisfactory.

In view of possibly superior activities of dimetallic

precatalysts, in this study we develop new dimetallic

PEPPSI-themed^[8]palladium–NHC complexes and

investigate their potential in catalyzing direct arylation

reactions using aryl chlorides as substrates.

Fortunately, one of our new dimetallic palladium

complexes is highly effective in catalyzing the

coupling reaction between imidazoles and aryl halides.

Our studies show that compared to a similar

Scheme 1. Synthesis of ligand precursors.

The imidazolium salt precursors were reacted with

PdCl₂in the presence of pyridine in DMF at 50 C to

afford new palladium complexes 2a,b and 2d (Scheme

2 and 3). Dimetallic palladium(II) complexes 2a,b

featuring monodentate NHC moieties were obtained in

48–73% yields. For the dimetallic complex 2c,

featuring bidentate amidate/NHC groups, addition of

PPh₃was essential for the formation of pure compound

in 65% yield. The PPh₃ligand is trans to NHC moiety

as confirmed by X-ray structural analysis (vide infra).

The mononuclear complex 2d was similarly prepared

from imidazolium salt 1d in a good yield of 87%. The

successful coordination by ligands of 2a–b and 2d was

reflected by the absence of downfield NCHN signals

in their ¹H NMR spectra. For complex 2c, the

disappearance of both the NCHN and NH proton

signals at ca. 10 and 11 pm, respectively, confirmed the

bidentate ligand coordination. Notably, the ¹H NMR

signals in 2a–c are broad, reflecting the possibility of

mononuclear palladium complex,

palladium complex exhibits superior catalytic activity.

The dimetallic complex requires mild

a

dimetallic

a

monopalladium loading of 1.5 mol% to catalyze

reactions with a range of aryl chlorides, thus yielding

arylated imidazoles and related heterocycles which

were previously only accessible with the use of more

reactive aryl bromides or iodides.

Results and Discussion

We began by exploring a new NHC-based ditopic

ligand scaffold for the preparation of dimetallic

palladium complexes. Synthetic routes for all new

ligand precursors are shown in Scheme 1. Target

compounds were accessed by means of

straightforward synthetic steps, employing cheap

starting materials. A key feature of ligand scaffolds

1a–c is the 9,10-anthracenyl or 1,4-naphthalenyl

spacer sandwiched between two imidazole rings. For

comparison, ligand precursor 1d, needed for the

preparation of an analogous mononuclear complex

was also developed. Imidazolium salts 1a,b possess N-

methyl groups, which exclude the possibility of

bidentate chelation by the ligand. In contrast, the

amide functional groups in 1c offer the possibility of

NH deprotonation and consequently bidentate

chelation of the NHC ligand. Palladium complexes

with donor-functionalized NHC ligands had been used

in direct C–H arylation reactions of heterocycles.^[6e-g,9]

To obtain imidazolium salts 1a-d, the key

quaternization reaction between a N-substituted

imidazole and 2-chloro-N-phenylacetamide or its

derivative was achieved under reflux conditions.

Products were obtained as white solids of excellent

purity and in moderate to high yields (67–96%). They

were characterized by NMR spectroscopy, elemental

analysis, and high-resolution mass spectrometry. The

characteristic C2-proton signals were visible at ca. 10

ppm in the ¹H NMR spectrum. The NH signal for the

imidazolium chloride 1c was observed at ca. 11 ppm.

1

fluxional behavior of these complexes. In fact, the H

NMR of 2a suggests a symmetric nature of the

complex in solution, but a subsequent X-ray structural

analysis revealed that the two palladium centers adopt

different cis and trans coordination environments in

the solid-state. The pyridine ligand in 2d can be easily

replaced by PPh₃, forming 3d in 60% yield.

Interestingly, unlike 2c, 3d adopts a cis geometry as

revealed by X-ray structural analysis. Nevertheless,

for both complexes, the ³¹P NMR signals were

observed at ca. 27 ppm. These new solids are all air-

stable and readily soluble in solvents of high polarity

such as dichloromethane and DMF.

Scheme 2. Synthesis of Dinuclear Palladium–NHC

Complexes.

2

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

Figure 1. Molecular structure of 2a at 35 % probability level.

Hydrogen atoms except that on C36 are omitted for clarity.

The intramolecular non-hydrogen bonding interaction is

shown. Selected bond distances and angles (): Pd1—C1,

1.959(5); Pd1—N7, 2.027(5); Pd1—Cl1, 2.2891(16);

Pd1—Cl2, 2.3578(15); Pd2—C23, 1.946(6); Pd2—N8,

2.064(5); Pd2—Cl3, 2.283(2); Pd2—Cl4, 2.294(2); C1—

Pd1—N7, 90.01(19); C1—Pd1—Cl1, 89.35(15); Cl1—

Pd1—Cl2, 93.00(6); N7—Pd1—Cl2, 87.67(13); C1—

Pd1—Cl2, 176.29(16); N7—Pd1—Cl1, 179.22(14); C23—

Pd2—N8, 177.6(2); C23—Pd2—Cl3, 89.52(19); N8—

Pd2—Cl3, 90.71(19); C23—Pd2—Cl4, 88.56(19); N8—

Pd2—Cl4, 91.30(19); Cl3—Pd2—Cl4, 177.15(7).

Scheme 3. Synthesis of Mononuclear Palladium–NHC

Complexes.

Crystals of 2a, 2c, and 3d suitable for single-crystal

X-ray diffraction were grown from vapor diffusion

using the solvent combinations of acetonitrile/ether,

DMF/ether, and dichloromethane/ether respectively.

The crystallographic data are tabulated in Table S1 in

the

supplementary

electronic

information.

Interestingly, the coordination environments around

the two palladium centers of 2a are different (Figure

1); one adopts trans geometry, while the other is cis.

Such a structural arrangement can be explained by the

presence of a non-classical hydrogen bonding

interaction between Cl3 atoms in the trans PdCl₂unit

and the proton on the C36 atom of the pyridine ligand

in the cis PdCl₂unit (∠C－HˑˑˑCl = 142.8(4); C－

HˑˑˑCl = 2.796(2) Å). Further stabilization of the

structure comes from the weak  －  stacking

interaction between the 1,4-naphthalenyl group and

the pyridine ring (centroid to centroid distance = 4.1

Å; interplanar angle = 22).^[10]In the structure of 2c,

the dimetallic complex is situated on a crystallographic

two-fold rotation axis. In contrast to the structure of 2a,

the two NHC moieties in 2c exhibit an anti

conformation (Figure 2). The bidentate NHC/amidate

coordination around the palladium centers is

confirmed. The steric effect imposed by the bidentate

ligand leads to a cis disposition of the PPh₃ligand in

relation to the NHC group. No significant

intramolecular nonbonding interactions were observed.

The NHC and PPh₃moieties in 3d are also cis to each

other (Figure 3). The preference for the cis

configuration in mixed NHC/phosphine complexes is

well documented in the literature.^[6a,11]The palladium

center adopts a slightly distorted square planar

coordination environment with ∠P1—Pd1—Cl1

Figure 2. Molecular structure of 2c at 35 % probability level.

Hydrogen atoms are omitted for clarity. Only one of the two

disordered N-phenyl ring orientations is shown. Selected

bond distances and angles (): Pd1—C1, 1.961(6); Pd1—P1,

2.3268(17); Pd1—Cl1, 2.3268(17); Pd1—N3, 2.109(5);

C1—Pd1—P1, 98.42(16); C1—Pd1—N3, 83.4(2); Cl1—

Pd1—N3, 91.77(16); Cl1—Pd1—P1, 86.86(7); C1—Pd1—

Cl1, 174.03(18); N3—Pd1—P1, 171.59(16).

Figure 3. Molecular structure of 3d at 50 % probability

level. Hydrogen atoms are omitted for clarity. The

intramolecular non-hydrogen bonding interaction is shown.

Selected bond distances and angles (): Pd1—C1, 1.981(2);

Pd1—P1, 2.2593(5); Pd1—Cl1, 2.3773(5); Pd1—Cl2,

2.3426(5); C1—Pd1—P1, 95.61(6); C1—Pd1—Cl1,

88.07(6); Cl1—Pd1—Cl2, 91.173(19); Cl2—Pd1—P1,

(168.7(2))

and

∠C1—Pd—Cl2 (171.5(2)),

significantly distorted from linearity.

85.137(19); C1—Pd1—Cl,

178.59(6); Cl1—Pd1—P1,

176.300(19).

The catalytic potential of these new complexes in

direct arylation reactions of imidazoles and aryl

halides was investigated. The reaction between 1,2-

dimethylimidazole and 4-bromoacetophenone was

3

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

chosen as the benchmark reaction (Table 1). Based on

previous work reported by others and ourselves,^[6i]

initial conditions of 1 mol% monopalladium loading,

(entries 4－5), whereas other high polarity solvents

such as DMSO and NMP were not (entries 6－8). The

addition of pivalic acid (PivOH), which generated

K₂CO₃as the base, pivalic acid (PivOH) as the additive, potassium pivalate in situ, was essential for the

DMF as the solvent, and a reaction temperature of 130

C for 12 h were employed to screen for the most

active precatalyst. Different catalysts including

mononuclear and dinuclear complexes were tested; the

monopalladium loading was fixed at 1 mol% and thus

for mononuclear complex, the catalyst loading was 1

mol% and that for dimetallic complex was 0.5 mol%.

As shown in entry 2, the dimetallic Pd complex 2b was

the most active precatalyst, affording a quantitative

yield of product. Somewhat surprisingly, although

complex 2a bearing a 1,4-naphthalenyl spacer is

structurally similar to complex 2b featuring a 9,10-

anthracenyl linker, it gave a much poorer product yield

of 38% (entry 1), reflecting probably the importance

of steric effects. Complex 2c bearing bidentate

amidate/NHC moieties gave a similar poor yield of

40% (entry 3), reflecting the importance of vacant

coordination sites around the Pd atom in the catalytic

cycle. Significantly, both mononuclear complexes 2d

and 3d produced inferior yields to that of 2b (entries 4

and 5), justifying the use of dimetallic Pd precatalyst.

Complex 3d, with a PPh₃ligand delivered a good yield

of 74% (entry 5) compared to a poor product yield of

18% from complex 2d bearing a pyridine ligand (entry

4). The superiority of dimetallic complex 2b over

mononuclear complex 3d in catalyzing the reaction

was confirmed by the respective time-yield reaction

profiles (Figure S1 in ESI). Simple NHC-free

Pd(OAc)₂was shown to catalyze the reaction

effectively. Indeed, a quantitative yield of product was

also obtained with Pd(OAc)₂under our conditions

(entry 6). The NHC-free system was, however,

ineffective when applied to aryl chloride substrates

(vide infra). In contrast, free PdCl₂was ineffective in

catalyzing the reaction (entry 7).

reaction evidenced by a drastic reduction in yield in its

absence (entry 5 vs 8). The use of in situ generated

potassium pivalate was an established procedure in the

literature.^[4f]Entries 9 and 10 revealed that at a lower

monopalladium loading of 0.5 mol% (catalyst loading

of 2b = 0.25 mol%), DMA was preferable to DMF as

the solvent. Entries 10 and 11 indicate that free

Pd(OAc)₂was more effective than 2b when utilizing

an aryl bromide substrate. In sharp contrast, complex

2b was much more efficient than free Pd(OAc)₂in

catalyzing the reaction with 4-chloroacetophenone as

the substrate, delivering the coupled product in a fair

yield of 62% (entry 12 vs. 13). The optimal

temperature for the 4-chloroacetophenone reaction

was 130 C and no catalytic activity was observed

when the temperature was lowered to 110 C (entry

14). Increasing the monopalladium loading to 1.5

mol% (catalyst loading of 2b = 0.75 mol%) and

prolonging the reaction time to 18 h gave an optimal

yield of 95 % (entry 16). The higher catalytic activity

of the dimeric complex 2b compared with that of

mononuclear complex 3d was further confirmed as the

latter complex was totally inactive in the activation of

4-chloroacetophenone (entry 17). Hence, the optimal

reaction conditions were established as follows: 1.5

mol% monopalladium loading of 2b (catalyst loading

= 0.75 mol%), K₂CO₃as the base, PivOH as an

additive, DMA as the solvent, and a reaction

temperature of 130 C for 18 h.

Table 2. Optimizing Conditions ^a)

Entry

Cat.

Solvent

Base

X

mono-Pd

Yield (%)

loading

(mol%)

Table 1. Screening of Palladium Complexes ^a)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

a)

2b

DMF

DMA

DMSO

NMP

DMA

DMF

DMA

Cs₂CO₃Br

1

0.5

1

1.5

20

0

>99

2

K₃PO₄

KOAc

K₂CO₃

Br

Cl

Entry

Complex

Yields

43

16 ^d)

20

70

90

62

9

1

2

3

4

5

6

7

2a

2b

2c

2d

3d

38

>99

40

18

74

2b

Pd(OAc)₂

2b

Pd(OAc)₂

PdCl₂

>99

2

2b

3d

0 ^b)

83

95 ^c)

0 ^c)

a)

Reaction conditions: 1,2-dimethylimidazole (2

mmol), 4-bromoacetophenone (1 mmol), K₂CO₃(2

mmol), PivOH (0.3 mmol), DMF (3 mL), [Pd₂] cat.

(0.5 mol%) or PdX₂(1.0 mol%), 130 ºC, 12 h. GC

yield using benzophenone as an internal standard.

Reaction conditions: 1,2-dimethylimidazole (2

mmol), aryl halide (1 mmol), K₂CO₃(2 mmol),

PivOH (0.3 mmol), solvent (3 mL), catalyst (0.5－1.5

mol% monopalladium loading; for Pd(OAc)₂, the

catalyst loading equals the monopalladium loading;

for dimeric complex 2b, the catalyst loading equals

the monopalladium loading divided by 2), 130 ºC, 12

h. GC yield using benzophenone as an internal

standard.

After identifying the best dimetallic complex as

precatalyst, efforts were made to further optimize the

reaction conditions (Table 2). K₂CO₃was found to be

the best choice of base as other commonly used

inorganic bases gave inferior yields (entries 1－4).

Both DMF and DMA were suitable reaction solvents

b)

110 °C.

4

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

c)

18 h.

PivOH (0.3 mmol), DMA (3 mL), 2b (0.75 mol%),

130 ºC, 18 h. Isolated yield.

d)

In the absence of PivOH.

After the establishment of optimized conditions, the

substrate scope of our catalyst system with respect to

aryl chlorides was explored (Table 3). To demonstrate

the catalytic efficiency of our catalyst system, most of

the selected substrates were aimed at products which

in the literature had generally been prepared from aryl

bromides, but were inaccessible from the less reactive

aryl chlorides (vide infra). In general, activated aryl

chlorides such as 4-chloroacetopheone, 4-

chlorobenzaldehyde, methyl 4-chlorobenzoate, 4-

nitrochlorobenzene, 4-chlorobenzonitrile, and 4-

chlorobenzotrifluoride were able to couple smoothly

with 1,2-dimethylimidazole, affording 1,2,5-

trisubstituted imidazoles 4a-f with yields in a range of

46-75%. The arylation is highly regioselective,

predominantly affording only the C5-arylated

products. Desirably, deactivated electron-donating

aryl chloride substrates can be employed, exemplified

by a satisfactory yield of 61% for product 4h obtained

from 4-chloroanisole. The slightly electron-donating

4-chlorotoluene gave 4i in a good yield of 71%.

Somewhat surprisingly, an inferior yield of 53% for 4j

was obtained with electron-neutral chlorobenzene.

Even though 1,2-dimethylimidazole was in two-fold

excess, only one of the C－Cl bonds was activated

when 1,4-dichlorobenzene was used as the substrate,

giving 4 g in a 71% yield.

Interestingly, the yields from 4-chloroacetophenone

and its meta isomer were comparable (69% for 4a vs.

62% for 4a''), reflecting some tolerance for increased

steric crowding in the palladium species. However, the

steric hindrance from ortho-substituted aryl chloride

substrates became significant such that inferior

product yields were obtained (68% for 4b vs. 52% for

4b' and 75% for 4e vs. 52% for 4e'). Consistently, the

para isomer of chlorotoluene afforded the best yield of

71%, followed by a slightly lower yield of 67% for 4i''

from the meta isomer and an inferior yield of 52% for

4i', derived from the ortho isomer. The compound 4i''

with a meta-substituted methyl group is a new

compound. Besides substituted chlorobenzenes, other

aryl chlorides can also be employed as substrates. For

example, 1-chloronaphthalene gave 4k in a reasonable

yield of 63%, and 2- and 3-chloropyridines afforded

the products 4l and 4l' in yields of 53% and 48%,

respectively.

It is worth mentioning that literature reported

catalyst systems required the use of more reactive aryl

bromides for the preparation of 4a'',^[12]4b',^[12-13]

4c,^[6d,6i,12]4d,^{[6d,6g,6h,12-14]}4e',^[6f,12]4f,^[6d,12,15]4i,^{[6f,6h,6i,12-}

13,15b]

[6d,6g,6i,12-13,16]

4i',^[6f,12-13]4k,

4l,^{[6g,6h,12-13,15a,16]}and

4l'.^[14]The use of chloride analogs as reported herein

is unprecedented. In the case of 4e, 4g, and 4h, the only

previous example using aryl chlorides instead of

bromo analogs was likewise reported by us.^[6a]

Table 3. Substrate Scope of Aryl Chlorides in the

Reaction with 1,2-Dimethylimidzole ^a)

However, our earlier reported

palladium–

NHC/phosphine complex required the expensive and

air-sensitive PCy₃ligand, a high Pd loading (2.5

mol%), and MW irradiation to afford 4e, 4g, and 4h in

comparable yields of 63%, 55%, and 56%,

respectively. Even though chlorobenzene was

successfully applied in the formation of 4j, again high

Pd loading (2.5–5.0 mol%) and the PCy₃ligand were

required in the reported catalyst systems.^[6a,17]

To confirm the practicability of the catalyst system

in synthetic organic chemistry, the direct arylation

reaction between 1,2-dimethylimidazole and 4-

chlorobenzonitrile was successfully scaled up from 1

to 5 mmol, yielding 0.76 g, 77% of 4e (Scheme 4).

Scheme 4. The direct arylation reaction between 1,2-

dimethylimidazole and 4-chlorobenzonitrile in a preparative

scale.

In addition, heterocycles other than 1,2-

dimethylimidazole were tested (Table 4). Entries 1-3

indicate that 1-methylimidazoles can be applied as

substrates in the coupling reaction with aryl chlorides.

Despite the presence of an apparent acidic hydrogen

a) Reaction conditions: 1,2-dimethylimidazole (2

mmol), aryl halide (1 mmol), K₂CO₃(2 mmol),

5

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

on the C2 position of the heterocycle, the arylation is

regioselective, producing exclusively C5-arylated

products. 5a was obtained in a good yield of 73% when

electron-deficient 4-chloroacetophenone was used as

the substrate (entry 1). Interestingly, replacing the Me

group with an H in the C2 position of 1-

methylimidazole reduced both the electron-richness of

the heterocyclic ring and the steric hindrance around

the palladium species, leading to an increase in yield.

Specifically, the reaction between sterically hindered

2-chlorobenzonitrile and 1-methylimidazole gave 5e'

in a good yield of 68% (entry 2), whereas a lower yield

of 52% was obtained for 4e' in the reaction with 1,2-

dimethylimidazole and the same aryl chloride (Table

3). This observation is further confirmed when 2-

chlorotoluene was used as a substrate; a good yield of

71% for 5i' was obtained with 1-methylimidazole

(entry 3), but the yield was reduced to 52% when 1,2-

dimethylimidazole was used (see 4i' in Table 3). Entry

4 shows that 1-butylimidazole also reacted smoothly

with 4-chlorobenzonitrile to produce 6e, a new

compound, in a good yield of 82%. Imidazo[1,2-

a]pyridine derivatives are important heterocycles

displaying a range of biological activities.^[18]The new

catalyst system also allows for the use of 2-substituted

imidazo[1,2-a]pyridines in the coupling reaction with

activated 4-chlorobenzonitrile, affording 2,3-

disubstituted imidazo[1,2-a]pyridine 7e and a new

compound, 8e in good yields (entries 5 and 6).

However, the catalyst system failed to give any

coupling product when unsubstituted imidazo[1,2-

a]pyridine was employed. Arylthiazole derivatives are

also important heterocyclic compounds with a wide

range of biological and material applications.^[19]4-

Methyl-thiazole was successfully employed as a

substrate in the reaction with 4-chloroacetophenone,

producing the 4,5-disubstituted-thiazole 9a in a

mediocre yield of 45% (entry 7).

The superior catalytic performance of 2b was again

demonstrated in our preparation of 5i', ^{[6c, 20]}5e'_,^[21]and

9a,^{[6h,15a,19,22]}which were previously prepared

exclusively from the corresponding aryl bromides, not

chlorides. In a literature example, 2-bromotoluene was

used for the preparation of 5i' in the presence of 2.5－

5.0 mol% Pd loading and gave yields in the range of

35–68%, compared to a 71% yield for our reaction

conditions (see entry 3).^[6c,20]There were only two

catalyst systems reported for the preparation of 5a

from the less reactive 4-chloroacetophenone.^[6a,6c]

However, both these catalyst systems require 2.5

mol% of Pd loading and phosphine ligands, giving 32–

70% yields, compared to a 73% yield catalyzed by 2b

(see entry 1). Similarly, compound 7e was reported to

arise from 4-chlorobenzonitrile; however a 2.5 mol%

loading of Pd and the expensive PAd₂Bu ligand were

required to produce the same yield of 75% (see entry

5).^[23]

^a)Reaction conditions: heterocycle (2 mmol), aryl halide

(1 mmol), K₂CO₃(2 mmol), PivOH (0.3 mmol), DMA (3

mL), [Pd₂] cat. (0.75 mol%), 130 ºC, 18 h. Isolated yield.

For palladium-catalyzed direct arylation reactions

of heteroaromatics with aryl halides, electrophilic

aromatic substitution (S_EAr)^[4a,24], and concerted

metalation-deprotonation (CMD)^[15b,25]pathways have

the most experimental and theoretical support. The

absence of discrimination in the reactions of 1,2-

dimethylimidazole with aryl chlorides containing a

para electron-donating and electron-withdrawing

groups (see Table 3, 4h: –OMe, 61%; 4i: –CH₃, 71%;

4a: –COCH₃, 69%; 4e: –CN, 75%) seems to exclude

the S_EAr pathway.^[26]In addition, the general trend of

higher activity observed for 1-methylimidazole

compared to that for the more electron-rich 1,2-

dimethylimidazole (see Table 3 and Table 4) is

consistent with the CMD pathway. However, this

difference could be attributed to the steric bulk of an

additional methyl group (vide supra). To provide

further evidence, a competition experiment was

performed; electron-rich 1,2-dimethylimidazole was

allowed to compete with 2-methylimidazo[1,2-

a]pyridine in the reaction with 4-chlorobenzonitrile

(Scheme 5). For the electrophilic aromatic substitution

pathway,

the

more

electron-rich

1,2-

dimethylimidazole should be favored; but the product

ratio of 1:99 of 4e:7e suggests that the less-electron

rich 2-methylimidazo[1,2-a]pyridine is a superior

substrate, which is compatible with the CMD

mechanistic pathway. Furthermore, the crucial role of

the in situ generated potassium pivalate, which served

as a soluble proton transfer agent,^[4f,27]in the

Table 4. Direct Arylation Reaction of Heterocycles with

Aryl Chlorides ^a)

Entry

Substrate

Product

Yield (%)

6

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

di(1H-imidazol-1-yl)anthracene,^[31]

1-(4-bromophenyl)-

1H-imidazole^[32]were prepared according to the literature

procedures.

enhancement of catalytic activity also implies the

involvement of this pathway (see Table 2, entry 8).

It has been shown that palladium-catalyzed cross-

coupling reactions can also proceed via heterogeneous

mechanistic pathways.^[28]A mercury drop test^[29]was

performed on the benchmark reaction between 1,2-

Synthesis of 1,4-di(1H-imidazol-1-yl)naphthalene

To a 50 mL Schlenk flask, 1,4-dibromonaphthalene (2.0 g,

6.99 mmol), 1H-imidazole (1.19 g, 17.5 mmol), CuI (0.4 g,

2.09 mmol), and Cs₂CO₃(9.11 g, 28.0 mmol) were

dissolved in dry DMF (20 mL) under nitrogen atmosphere.

The solution was allowed to stir at 120 °C for 40 h. Solvent

was removed under vacuum and the residue was washed

with water and extracted with DCM. The extract was dried

over anhydrous MgSO₄and then purified by column

chromatography (MeOH/ethyl acetate). Yield: 0.93 g

dimethylimidazole

and

4-bromoacetophenone

catalyzed by 2b in order to understand the possible

involvement of heterogeneous species. In the presence

of mercury, the product yield was markedly reduced

from quantitative (see entry 2 in Table 1) to 37%. This

suggested that beside homogeneous pathways, the

possible involvement of heterogeneous species in the

catalytic cycle cannot be excluded.

1

(51 %). Mp = 215.1–215.8 °C. H NMR (CDCl₃): δ 6.95-

7.03 (m, 5H, Ar H), 7.30-7.40 (m, 5H, Ar H), 7.50 (s, 2H,

NCHN). ¹³C{¹H} NMR (DMSO-d₆): δ 122.9, 123.9, 128.6

(quaternary C), 128.9, 129.9, 131.0 (quaternary C), 140.4

(NCHN). HRMS (EI) m/z calcd for C₁₆H₁₂N₄[M]⁺260.1061,

found 260.1064.

Synthesis of 1,1'-(Naphthalene-1,4-diyl)bis(3-(2-

(methyl(phenyl)amino)-2-oxoethyl)-1H-imidazol-3-ium)

(1a)

A mixture of 1,4-di(1H-imidazol-1-yl)naphthalene (0.5 g,

1.92 mmol) and 2-chloro-N-methyl-N-phenylacetamide

(1.06 g, 5.76 mmol) in DMF (30 mL) was placed in a

o

Schlenk flask. The mixture was heated at 120 C for 12 h.

After cooling, the white solid was collected on a frit, washed

with DCM, and dried under vacuum.Yield: 1.16 g (96 %).

Mp = 271.3–272.5 °C. ¹H NMR (DMSO-d₆): δ 3.30 (s, 6H,

CH₃), 5.18 (s, 2H, CH₂), 7.52-7.72 (m, 12H, Ar H), 7.91 (s,

2H, Ar H), 8.12 (d, J = 15.0 Hz, 4H, Ar H), 8.25 (s, 2H, Ar

H), 9.87 (s, 2H, NCHN). ¹³C{¹H} NMR (DMSO-d₆): δ 38.1

(CH₃), 51.8 (CH₂), 122.8, 124.5, 125.5, 125.6, 128.3, 129.2,

129.3 (quaternary C), 130.8, 134.0 (quaternary C), 140.3

(NCHN), 141.9 (quaternary C), 165.1 (C=O). HRMS (ESI)

m/z calcd for C₃₄H₃₂N₆O₂[M–2Cl]²⁺278.1293, found

278.1287.

Scheme 5. Competition experiment.

Conclusion

A series of new ditopic bis(NHC) ligand precursors

with aromatic linkers and their dimetallic PEPPSI-

themed palladium complexes was successfully

synthesized. We demonstrated that a dimetallic

palladium complex was more effective than the related

mononuclear palladium complex in catalyzing C5-

direct arylation reactions of heterocycles with aryl

halides. The dimetallic palladium–NHC complex

bearing 9,10-anthracenyl spacer was the most efficient

precatalyst, enabling effective utilization of a broad

range of aryl chlorides. The catalyst system allows for

the effective use of aryl chlorides to prepare arylated

heterocycles which were previously accessible only

with the use of more reactive bromide or iodide

analogs. This work demonstrates the tractability of

dimetallic palladium catalyst motifs for use in direct

arylation reactions.

Synthesis

of

1,1'-(Anthracene-9,10-diyl)bis(3-(2-

(methyl(phenyl)amino)-2-oxoethyl)-1H-imidazol-3-ium)

(1b)

The compound was prepared with a similar procedure to that

of 1a. A mixture of 9,10-di(1H-imidazol-1-yl)anthracene

(0.5 g, 1.61 mmol) and 2-chloro-N-methyl-N-

phenylacetamide (0.59 g, 3.22 mmol) were used. Yield: 1.1

g (70 %). Mp = 307–308 °C. ¹H NMR (DMSO-d₆): δ 3.33

(s, 6H, CH₃), 5.29 (s, 4H, CH₂), 7.53–7.62 (m, 14H, Ar H),

7.89–7.93 (m, 4H, Ar H), 8.28–8.33 (m, 4H, imi H, Ar H),

10.06 (s, 2H, NCHN). ¹³C{¹H} NMR (DMSO-d₆): δ 37.9

(CH₃), 52.0 (CH₂), 122.3, 125.3, 126.1, 127.8 (quaternary

C), 128.2, 129.2, 129.4 (quaternary C), 130.3, 130.6, 141.4

(NCHN), 141.8 (quaternary C), 165.0 (C=O). HRMS (ESI)

m/z calcd for C₃₈H₃₄N₆O₂[M–2Cl]²⁺303.1371, found

303.1358.

Synthesis of 1,1'-(Naphthalene-1,4-diyl)bis(3-(2-oxo-2-

(phenylamino)ethyl)-1H-imidazol-3-ium) Chloride (1c)

Experimental Section

General Information

The compound was prepared with a similar procedure to that

of 1a. A mixture of 1,4-di(1H-imidazol-1-yl)naphthalene

(0.5 g, 1.92 mmol) and 2-chloro-N-phenylacetamide (0.65 g,

3.84 mmol) were used. Yield: 1.15 g (94 %). Mp = 213–

214 °C. ¹H NMR (DMSO-d₆): δ 5.52 (s, 4H, CH₂), 7.12 (t,

J = 6.0 Hz, 2H, Ar H), 7.37 (t, J = 9.0 Hz, 4H, Ar H), 7.71

(d, J = 6.0 Hz, 4H, Ar H), 7.80–7.83 (m, 2H, Ar H), 7.94–

7.96 (m, 2H, Ar H), 8.20 (s, 2H, Ar H), 8.25 (s, 2H, imi H),

8.32 (s, 2H, imi H), 9.96 (s, 2H, NCHN), 11.22 (s, 2H, NH).

¹³C{¹H} NMR (DMSO-d₆): δ 52.3 (CH₂), 119.7, 122.8,

124.3, 124.6, 125.3, 125.4, 129.0 (quaternary C), 129.4,

130.5, 133.8 (quaternary C), 139.0 (quaternary C), 140.1

(NCHN), 164.0 (C=O). HRMS (ESI) m/z calcd for

C₃₂H₂₈N₆O₂[M–2Cl]²⁺264.1136, found 264.1127.

All manipulations were performed under a dry nitrogen

atmosphere using standard Schlenk techniques. Solvents

were dried with standard procedures. Starting chemicals

were purchased from commercial source and used as

received. ¹H, ¹³C{¹H} and ³¹P{¹H} NMR spectra were

recorded at 300.13, 75.47 and 121.49 MHz, respectively, on

a Bruker AV-300 spectrometer. Elemental analyses were

performed on a Thermo Flash 2000 CHN-O elemental

analyzer. HRESI and HREI were carried out on a Thermo

Fisher LTQ Orbitrap XL mass spectrometer and a Thermo

Q Exactive Plus mass spectrometer, respectively, at

Instrument Center of National Chung Hsing University

(Taiwan). 1-(Naphthalen-1-yl)-1H-imidazole^[30]and 9,10-

7

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

Synthesis of 1-(2-(Methyl(phenyl)amino)-2-oxoethyl)-3-

The compound was prepared with a similar procedure to that

of 2a. A mixture of PdCl₂(0.051 g, 0.29 mmol), 1d (0.11 g,

0.29 mmol), pyridine (23.0 μL, 0.29 mmol), and K₂CO₃

(0.080 g, 0.58 mmol) were used. Yield: 0.15 g (87 %). Mp

(naphthalen-1-yl)-1H-imidazol-3-ium Chloride (1d)

A mixture 1-(naphthalen-1-yl)-1H-imidazole (1.0 g, 5.2

mmol) and 2-chloro-N-methyl-N-phenylacetamide (0.95 g,

5.2 mmol) in THF (30 mL) was placed in a Schlenk flask.

The mixture was heated under reflux for 24 h. After cooling,

the white solid was collected on a frit, washed with THF,

and dried under vacuum. Yield: 1.5 g (78 %). Mp = 188.3–

189.4 °C. ¹H NMR (DMSO-d₆): δ 3.29 (s, 3H, CH₃), 5.18 (s,

2H, CH₂), 7.51-7.85 (m, 10H, Ar H), 8.07 (s, 1H, imi H),

8.20-8.30 (m, 3H, imi H, Ar H), 9.79 (s, 1H, NCHN).

¹³C{¹H} NMR (CDCl₃): δ 37.9 (CH₃), 51.8 (CH₂), 120.7,

123.0, 124.5, 124.6, 125.2, 127.7, 128.7, 128.8, 130.3, 130.7

(quaternary C), 131.5, 134.0 (quaternary C), 139.6 (NCHN),

140.9 (quaternary C), 164.5 (C=O). HRMS (ESI) m/z calcd

for C₂₂H₂₀N₃O [M–Cl]⁺342.1606, found 342.1595.

1

=176.3–177.1 °C (dec.). H NMR (CDCl₃): δ 3.37 (s, 3H,

CH₃), 5.38 (s, 2H, CH₂), 7.15-7.21 (m, 3H, Ar H), 7.35-7.65

(m, 11H, imi H, Py H, Ar H), 7.91 (t, J = 6.0 Hz, 1H, Py H),

7.97 (d, J = 9.0 Hz, 1H, Ar H), 8.09 (d, J = 6.0 Hz, 1H, Ar

H), 8.57 (d, J = 3.0 Hz, 1H, Py H). ¹³C{¹H} NMR (CDCl₃):

δ 37.9 (CH₃), 51.8 (CH₂), 123.5, 124.2 (Py C), 124.6, 125.1,

126.8, 127.0, 127.3, 127.8, 128.0, 128.7, 129.8, 130.2, 134.2

(quaternary C), 135.2 (quaternary C), 137.9 (Py C), 142.4

(quaternary C), 151.1 (Py C), 152.4 (Pd―C), 166.1 (C=O).

Anal. Calc. for C₂₇H₂₄Cl₂N₄OPd: C, 54.24; H, 4.04; N, 9.37.

Found: C, 54.35; H, 4.12; N, 8.98 %.

Synthesis of Palladium Complex 3d

Synthesis of Dinuclear Palladium Complex 2a

To a 20 mL Schlenk flask containing 2d (0.11 g, 0.18 mmol)

and PPh₃(0.056 g, 0.21 mmol) in dichloromethane (10 mL)

was stirred at ambient temperature for 5h. The solvent was

removed completely under vacuum. The residue was

washed thoroughly with THF to afford a pale yellow solid.

To a 20 mL Schlenk flask containing PdCl₂(0.056 g, 0.32

mmol), 1a (0.1 g, 0.16 mmol), pyridine (25.7 μL and

potassium carbonate (0.13 g, 0.96 mmol) was added dry

1

o

Yield: 0.084 g (60 %). Mp = 267.7–268.4 °C. H NMR

DMF (8 mL). The mixture was allowed to stir at 50 C for

(CDCl₃): δ 3.24 (s, 3H, CH₃), 5.18 (d, J = 6.0 Hz, 2H, CH₂),

6.45 (d, J = 9.0 Hz, 1H, imi H), 6.82–8.01 (m, 27H, imi H,

Ar H), 9.05 (d, J = 9.0 Hz, 1H, Ar H). ¹³C{¹H} NMR

(CDCl₃): δ 37.9 (CH₃), 52.4 (CH₂), 121.1, 124.2, 126.0,

126.2, 127.3, 127.4, 127.7, 128.0, 128.2 (d, J = 11.3 Hz, Ar

C), 128.6, 129.0, 129.5 (quaternary C), 129.7 (quaternary C),

130.6 (d, J = 14.3 Hz, Ar C), 133.8 (d, J = 10.6 Hz, Ar C),

134.3 (quaternary C), 141.8 (quaternary C), 163.9 (Pd―C),

165.4 (C=O). ³¹P{¹H} NMR (CDCl₃): δ 26.9. Anal. Calc.

for C₄₀H₃₄Cl₂N₃OPPd: C, 61.61; H, 4.39; N, 5.39. Found: C,

61.97; H, 4.43; N, 5.40 %.

12 h. The solvent was completely removed under vacuum.

The residue was dissolved in dichloromethane. The organic

layer was then washed twice with water. After drying with

anhydrous magnesium sulfate, the solvent was completely

removed under vacuum. The residue was washed with

diethyl ether and filtered on a frit and dried under vacuum.

Air stable yellow solid was obtained. Yield: 0.12 g (73 %);

Mp 183.6-184.5 °C (dec.). ¹H NMR (CDCl₃): δ 3.37 (s, 6H,

CH₃), 5.26-5.45 (m, 4H, CH₂), 7.22-7.80 (m, 26H, imi H,

Py H, Ar H), 8.33-8.39 (m, 2H, Py H), 8.63 (d, J = 3.0 Hz,

2H, Py H). ¹³C{¹H} NMR (CDCl₃): δ 37.9 (CH₃), 51.8

(CH₂), 123.7, 124.1, 124.3 (Py C), 124.9, 126.5, 127.8,

128.0, 128.7 (quaternary C), 130.2, 130.3, 136.4 (quaternary

C), 138.0 (Py C), 142.4 (quaternary C), 151.1 (Py C), 166.0

(C=O), 166.1 (Pd―C). Anal. Calc. for C₄₄H₄₀Cl₄N₈O₂Pd₂:

C, 49.50; H, 3.77; N, 10.49. Found: C, 49.33; H, 3.66﹔N,

10.38 %.

General Procedure for Palladium-Catalyzed Direct C-H

Arylation Reaction of Heteroaromatic Compounds

In a Schlenk tube was charged with aryl chloride (1 mmol),

heteroaromatic (2 mmol), K₂CO₃(276 mg, 2.0 mmol),

PivOH (30 mol%), Pd precatalyst (0.5–1.5 mmol% of

monopalladium loading), and DMA (3 mL) under nitrogen

atmosphere. The reaction mixture was sealed and heated at

130 °C for 18 h. The reaction mixture was cooled to ambient

temperature, and H₂O (5 mL) was added, followed by

extraction with ethyl acetate (3 × 10 mL). The organic

phases were collected and dried over MgSO₄. All the

volatiles were removed in vacuo, and the crude product was

analyzed by GC chromatography using benzophenone as

internal standard or purified by column chromatography.

Each catalytic yield was an average of two runs.

Synthesis of Dinuclear Palladium Complex 2b

The compound was prepared with a similar procedure to that

of 2a. A mixture of PdCl₂(0.052 g, 0.30 mmol), 1b (0.1 g,

0.15 mmol), pyridine (23.8 μL, 0.30 mmol), and K₂CO₃

(0.12 g, 0.88 mmol) were used. Yield: 0.11 g (67 %). Mp

=190.3–191.5 °C. (dec.) ¹H NMR (DMSO-d₆): δ 3.46 (s, 6H,

CH₃), 5.61 (s, 4H, CH₂), 7.31-8.31 (m, 30H, imi H, Py H,

Ar H), 8.75 (d, J = 6.0 Hz, 2H, Py H). ¹³C{¹H} NMR

(DMSO-d₆): δ 37.8 (CH₃), 52.4 (CH₂), 125.1 (Py C), 125.3,

126.0, 127.3, 127.7 (quaternary C), 128.3, 128.4, 128.9,

130.4 (quaternary C), 130.6, 139.3 (Py C), 143.0

(quaternary C), 151.0 (Py C), 166.1 (C=O), 166.2 (Pd―C).

Anal. Calc. for C₄₈H₄₂Cl₄N₈O₂Pd₂: C, 51.58; H, 3.78; N,

10.02. Found: C, 51.52; H, 4.02; N, 10.47 %.

1,2-Dimethyl-5-(m-tolyl)-1H-imidazole (4i'')

Yellow liquid (124 mg, 67 %), ethyl acetate:hexane = 2:1,

R_f= 0.3; ¹H NMR (300MHz, CDCl₃) δ 7.34-7.29 (m, 1H),

7.17 (br s, 3H), 6.94 (s, 1H), 3.53 (s, 3H), 2.45 (s, 3H), 2.20

(s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 145.9, 138.4, 133.7,

130.5, 129.3, 128.6, 128.4, 125.7, 125.6, 31.4, 21.5, 13.7.

HRMS (EI) calcd for C₁₂H₁₄N₂[M]⁺: 186.1157, found:

186.1154.

Synthesis of Dinuclear Palladium Complex 2c

The compound was prepared with a similar procedure to that

of 2a. A mixture of PdCl₂(0.059 g, 0.34 mmol), 1c (0.10 g,

0.17 mmol), PPh₃(0.088 g, 0.34 mmol), and K₂CO₃(0.18 g,

1.3 mmol) were used. Yield: 0.10 g (65 %). Mp =194.4–

4-(1-Butyl-1H-imidazol-5-yl)benzonitrile (6e)

1

195.1 °C (dec.). H NMR (DMSO-d₆): δ 4.83 (d, J = 15.0

Hz, 2H, CH_aH_b), 5.77 (d, J = 12.0 Hz, 2H, CH_aH_b), 6.78-

7.56 (m, 46H, imi H, Ar H), 7.83-8.20 (m, 4H, Ar H).

¹³C{¹H} NMR (DMSO-d₆): δ 58.8 (CH₂), 119.9, 122.5,

123.7, 124.2, 124.4, 124.9, 127.3, 127.6, 128.6 (d, J = 9.8

Hz, Ar C), 129.2 (d, J = 12.1 Hz, Ar C), 130.0 (quaternary

C), 131.2, 132.9 (d, J = 9.8 Hz, Ar C), 132.4, 132.5, 133.8

(quaternary C), 134.3 (d, J = 18.0 Hz, Ar C), 148.9

(quaternary C), 161.6 (Pd―C), 168.4 (C=O). ³¹P{¹H} NMR

(DMSO–d₆): δ 26.6. Anal. Calc. for C₆₈H₅₄Cl₂N₆O₂P₂Pd₂: C,

61.27; H, 4.08; N, 6.30. Found: C, 61.62; H, 3.99; N, 6.11 %.

Yellow oil, (184 mg, 82 %), ethyl acetate:hexane = 3:1, R_f

= 0.3; ¹H NMR (300MHz, CDCl₃) δ 7.75 (d, J = 9.0Hz, 2H),

7.62 (s, 1H), 7.51 (d, J = 6.0Hz, 2H), 7.17 (s, 1H), 4.02 (t, J

= 9.0Hz, 2H), 1.68-1.59 (m, 2H), 1.31-1.19 (m,2H), 0.84 (t,

J = 9.0Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 139.6, 134.9,

132.6, 131.1, 129.8, 128.6, 118.6, 111.4, 45.5, 32.9, 19.6,

13.4. HRMS (EI) calcd for C₁₄H₁₅N₃[M]⁺: 225.1266, found:

225.1265.

Ethyl

3-(4-cyanophenyl)imidazo[1,2-a]pyridine-2-

carboxylate (8e).

Synthesis of Palladium Complex 2d

8

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

Off-white solid (186 mg, 64 %), Mp: 189.5-190.8 °C, ethyl

acetate:hexane = 1:3, R_f= 0.2; ¹H NMR (300MHz, CDCl₃)

δ 7.94 (d, J = 6.0Hz, 1H), 7.86 (d, J = 9.0Hz, 2H), 7.76 (d,

J = 9.0Hz, 1H), 7.68 (d, J = 9.0Hz, 2H), 7.36-7.28 (m, 1H),

6.90 (t, J = 6.0Hz, 1H), 4.41-4.34 (m, 2H), 1.34 (t, J = 6.0Hz,

3H); ¹³C NMR (75MHz, CDCl₃) δ 163.1, 144.8, 133.8,

132.9, 132.5, 131.5, 127.0, 126.8, 123.5, 119.4, 118.4, 114.5,

113.1, 61.3, 14.3. HRMS (EI) calcd for C₁₇H₁₃N₃O₂[M]⁺:

291.1008, found: 291.1011.

Functionalization I (Eds.: P. H. Dixneuf, H. Doucet),

Springer International Publishing, Cham, 2016, pp. 77-

102; g) J. Yamaguchi, K. Itami, Bull. Chem. Soc. Jpn.

2016, 90, 367-383; h) W. Wu, H. Xin, C. Ge, X. Gao,

Tetrahedron Lett. 2017, 58, 175-184.

[2] a) F. Bellina, S. Cauteruccio, R. Rossi, Tetrahedron

2007, 63, 4571-4624; b) J. Gising, M. T. Nilsson, L. R.

Odell, S. Yahiaoui, M. Lindh, H. Iyer, A. M. Sinha, B.

R. Srinivasa, M. Larhed, S. L. Mowbray, A. Karlén, J.

Med. Chem. 2012, 55, 2894-2898; c) R. Selig, M.

Goettert, V. Schattel, D. Schollmeyer, W. Albrecht, S.

Laufer, J. Med. Chem. 2012, 55, 8429-8439.

Mercury-drop test

In a Schlenk tube was charged with 4-bromoacetophene (1

mmol), 1,2-dimethylimidzole (2 mmol), K₂CO₃(276 mg,

2.0 mmol), PivOH (30 mol%), Pd precatalyst 2b (0.5

mmol%), and a drop of Hg in DMF (1 mL) under nitrogen

atmosphere. The reaction mixture was sealed and heated at

130 °C for 12 h. The workup procedure was the same of the

general procedure for the direct C－H arylation reaction.

The product yield was analyzed by GC chromatography

using benzophenone as internal standard. The catalytic yield

was an average of two runs.

[3] a) J. Kulhánek, F. Bureš, Beilstein J. Org. Chem. 2012,

8, 25-49; b) M. Lessi, C. Manzini, P. Minei, L. A. Perego,

J. Bloino, F. Egidi, V. Barone, A. Pucci, F. Bellina,

ChemPlusChem 2014, 79, 366-370.

[4] a) P.-A. Sommai, S. Tetsuya, K. Yoshiki, M. Masahiro,

N. Masakatsu, Bull. Chem. Soc. Jpn. 1998, 71, 467-473;

b) Y. Kondo, T. Komine, T. Sakamoto, Org. Lett. 2000,

2, 3111-3113; c) F. Bellina, S. Cauteruccio, L. Mannina,

R. Rossi, S. Viel, J. Org. Chem. 2005, 70, 3997-4005; d)

H. A. Chiong, O. Daugulis, Org. Lett. 2007, 9, 1449-

1451; e) F. Bellina, S. Cauteruccio, A. Di Fiore, C.

Marchetti, R. Rossi, Tetrahedron 2008, 64, 6060-6072;

f) B. Liégault, D. Lapointe, L. Caron, A. Vlassova, K.

Fagnou, J. Org. Chem. 2009, 74, 1826-1834; g) L.

Ackermann, A. Althammer, S. Fenner, Angew. Chem.

Int. Ed. 2009, 48, 201-204; h) B. Liégault, I. Petrov, S.

I. Gorelsky, K. Fagnou, J. Org. Chem. 2010, 75, 1047-

1060; i) V. O. Iaroshenko, A. Gevorgyan, S. Mkrtchyan,

K. Arakelyan, T. Grigoryan, J. Yedoyan, A. Villinger, P.

Langer, J. Org. Chem. 2015, 80, 2103-2119; j) Y. Ji, R.

E. Plata, C. S. Regens, M. Hay, M. Schmidt, T. Razler,

Y. Qiu, P. Geng, Y. Hsiao, T. Rosner, M. D. Eastgate, D.

G. Blackmond, J. Am. Chem. Soc. 2015, 137, 13272-

13281.

Single-crystal X-ray Diffraction

Samples were collected at 150(2) on a Bruker APEX II

equipped with a CCD area detector and a graphite

monochromator utilizing Mo K radiation ( = 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.^[33]

Absorption corrections were performed using the SADABS

program.^[34]All the structures were solved by direct

methods and refined by full-matrix least squares methods

against F²with the SHELXTL software package.^[35]All

non-H atoms were refined anisotropically. All H atoms were

fixed at calculated positions and refined with the use of a

riding model. Disordered ether molecules in 2a was refined

using a rigid model. Heavily disordered DMF solvent

molecules were found in an asymmetric unit of 2c and a

satisfactory refinement model was unable to achieve. Hence,

SQUEEZE procedure implemented in the PLATON

program suite was applied to remove the disordered solvent

contribution to the structural factors.^[36]Removing the DMF

molecules led to a total accessible void of 3174.0 Å and 972

electrons in the unit cell. These results were in good

agreement with the volume occupied by 24 DMF molecules

in the unit cell (127 Å³and 40 electrons per DMF^[37]). The

N-phenyl ring in 2c was disordered over two orientations of

equal occupancy, which were refined with rigid group

constraints. CCDC-1554094 (2a), -1554095 (2c), and -

1554096 (3d) contain the 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.

[5] a) W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G.

R. J. Artus, Angew. Chem. Int. Ed. 1995, 34, 2371-2374;

b) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,

1290-1309; c) S. Díez-González, N. Marion, S. P. Nolan,

Chem. Rev. 2009, 109, 3612-3676; d) M. N. Hopkinson,

C. Richter, M. Schedler, F. Glorius, Nature 2014, 510,

485; e) E. Peris, Chem. Rev. 2017, 118, 9988-10031.

Acknowledgements

[6] a) P. V. Kumar, W.-S. Lin, J.-S. Shen, D. Nandi, H. M.

Lee, Organometallics 2011, 30, 5160-5169; b) C.-H. Ke,

B.-C. Kuo, D. Nandi, H. M. Lee, Organometallics 2013,

32, 4775-4784; c) S. Guo, H. V. Huynh,

Organometallics 2014, 33, 2004-2011; d) X.-X. He, Y.

Li, B.-B. Ma, Z. Ke, F.-S. Liu, Organometallics 2016,

35, 2655-2663; e) J.-Y. Lee, J.-S. Shen, R.-J. Tzeng, I.

C. Lu, J.-H. Lii, C.-H. Hu, H. M. Lee, Dalton Trans.

2016, 45, 10375-10388; f) H.-H. Li, R. Maitra, Y.-T.

Kuo, J.-H. Chen, C.-H. Hu, H. M. Lee, Appl. Organomet.

Chem. 2018, 32, e3956; g) R. Bhaskar, A. K. Sharma, A.

K. Singh, Organometallics 2018, 37, 2669-2681; h) L.-

Q. Hu, R.-L. Deng, Y.-F. Li, C.-J. Zeng, D.-S. Shen, F.-

S. Liu, Organometallics 2018, 37, 214-226; i) Y.-Y. Lee,

We are grateful to the Ministry of Science and Technology of

Taiwan (MOST 107-2113-M-018-002) for financial support of this

work.

References

[1] a) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,

36, 1173-1193; b) L. Ackermann, R. Vicente, A. R.

Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792-9826; c)

G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009,

38, 2447-2464; d) J. M. Joo, B. B. Touré, D. Sames, J.

Org. Chem. 2010, 75, 4911-4920; e) L. G. Mercier, M.

Leclerc, Acc. Chem. Res. 2013, 46, 1597-1605; f) F.

Bellina, in C-H Bond Activation and Catalytic

9

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

H.-W. Zseng, Z.-H. Tsai, Y.-S. Su, C.-H. Hu, H. M. Lee,

[19] F.-M. Chen, D.-D. Lu, L.-Q. Hu, J. Huang, F.-S. Liu,

Organometallics 2019, 38, 805-815.

Org. Biomol. Chem. 2017, 15, 5731-5736.

[7] a) A. Prades, E. Peris, M. Alcarazo, Organometallics

2012, 31, 4623-4626; b) G. Guisado-Barrios, J. Hiller, E.

Peris, Chem. Eur. J. 2013, 19, 10405-10411; c) S. Ruiz-

Botella, E. Peris, Organometallics 2014, 33, 5509-5516;

d) E. Peris, Chem. Commun. 2016, 52, 5777-5787.

[20] F. Bellina, M. Lessi, C. Manzini, Eur. J. Org. Chem.

2013, 2013, 5621-5630.

[21] S. Mao, X. Shi, J.-F. Soulé, H. Doucet, Adv. Synth.

Catal. 2018, 360, 3306-3317.

[22] a) X.-X. He, Y.-F. Li, J. Huang, D.-S. Shen, F.-S. Liu,

J. Organomet. Chem. 2016, 803, 58-66; b) J. Roger, F.

Požgan, H. Doucet, J. Org. Chem. 2009, 74, 1179-1186;

c) A. Jakab, Z. Dalicsek, T. Soós, Eur. J. Org. Chem.

2015, 2015, 56-59.

[8] C. Valente, S. Çalimsiz, K. H. Hoi, D. Mallik, M. Sayah,

M. G. Organ, Angew. Chem. Int. Ed. 2012, 51, 3314-

3332.

[9] J. C. Bernhammer, H. V. Huynh, Organometallics 2014,

33, 1266-1275.

[23] H. Cao, Y. Lin, H. Zhan, Z. Du, X. Lin, Q.-M. Liang,

[10] C. Jiang, O. Blacque, T. Fox, H. Berke, Dalton Trans.

2011, 40, 1091-1097.

H. Zhang, RSC Adv. 2012, 2, 5972-5975.

[24] a) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem.

Soc. 2005, 127, 8050-8057; b) C.-H. Park, V. Ryabova,

I. V. Seregin, A. W. Sromek, V. Gevorgyan, Org. Lett.

2004, 6, 1159-1162.

[11] a) J. C. Bernhammer, N. X. Chong, R. Jothibasu, B.

Zhou, H. V. Huynh, Organometallics 2014, 33, 3607-

3617; b) Y. Han, L. J. Lee, H. V. Huynh,

Organometallics 2009, 28, 2778-2786.

[25] a) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem.

Soc. 2008, 130, 10848-10849; b) D. García-Cuadrado, P.

de Mendoza, A. A. C. Braga, F. Maseras, A. M.

Echavarren, J. Am. Chem. Soc. 2007, 129, 6880-6886.

[12] J. Roger, H. Doucet, Tetrahedron 2009, 65, 9772-9781.

[13] D. Nandi, S. S. Siwal, K. Mallick, ChemistrySelect

2017, 2, 1747-1752.

[26] I. Özdemir, S. Demir, B. Çetinkaya, C. Gourlaouen, F.

Maseras, C. Bruneau, P. H. Dixneuf, J. Am. Chem. Soc.

2008, 130, 1156-1157.

[14] M. Baghbanzadeh, C. Pilger, C. O. Kappe, J. Org.

Chem. 2011, 76, 8138-8142.

[15] a) J. J. Dong, J. Roger, C. Verrier, T. Martin, R. Le

Goff, C. Hoarau, H. Doucet, Green Chem. 2010, 12,

2053-2063; b) L. A. Perego, L. Grimaud, F. Bellina, Adv.

Synth. Catal. 2016, 358, 597-609.

[27] a) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006,

128, 16496-16497; b) L. M. Pardo, A. M. Prendergast,

M.-T. Nolan, E. Ó Muimhneacháin, G. P. McGlacken,

Eur. J. Org. Chem. 2015, 2015, 3540-3550.

[16] J.-S. Ouyang, Y.-F. Li, D.-S. Shen, Z. Ke, F.-S. Liu,

[28] a) M. R. Eberhard, Org. Lett. 2004, 6, 2125-2128; b)

Y.-C. Lin, H.-H. Hsueh, S. Kanne, L.-K. Chang, F.-C.

Liu, I. J. B. Lin, G.-H. Lee, S.-M. Peng, Organometallics

2013, 32, 3859-3869; c) E. C. Keske, O. V. Zenkina, R.

Wang, C. M. Crudden, Organometallics 2012, 31, 6215-

6221; d) V. P. Ananikov, I. P. Beletskaya,

Organometallics 2012, 31, 1595-1604; e) S. S. Zalesskiy,

V. P. Ananikov, Organometallics 2012, 31, 2302-2309;

f) A. V. Astakhov, O. V. Khazipov, A. Y. Chernenko, D.

V. Pasyukov, A. S. Kashin, E. G. Gordeev, V. N.

Khrustalev, V. M. Chernyshev, V. P. Ananikov,

Organometallics 2017, 36, 1981-1992.

Dalton Trans. 2016, 45, 14919-14927.

[17] G. Song, Y. Su, X. Gong, K. Han, X. Li, Org. Lett.

2011, 13, 1968-1971.

[18] a) M. L. Bode, D. Gravestock, S. S. Moleele, C. W.

van der Westhuyzen, S. C. Pelly, P. A. Steenkamp, H. C.

Hoppe, T. Khan, L. A. Nkabinde, Biorg. Med. Chem.

2011, 19, 4227-4237; b) B. Frett, N. McConnell, C. C.

Smith, Y. Wang, N. P. Shah, H.-y. Li, Eur. J. Med. Chem.

2015, 94, 123-131; c) A. K. Bagdi, S. Santra, K. Monir,

A. Hajra, Chem. Commun. 2015, 51, 1555-1575; d) S. J.

Tantry, S. D. Markad, V. Shinde, J. Bhat, G.

Balakrishnan, A. K. Gupta, A. Ambady, A. Raichurkar,

C. Kedari, S. Sharma, N. V. Mudugal, A. Narayan, C. N.

Naveen Kumar, R. Nanduri, S. Bharath, J. Reddy, V.

Panduga, K. R. Prabhakar, K. Kandaswamy, R. Saralaya,

P. Kaur, N. Dinesh, S. Guptha, K. Rich, D. Murray, H.

Plant, M. Preston, H. Ashton, D. Plant, J. Walsh, P.

Alcock, K. Naylor, M. Collier, J. Whiteaker, R. E.

McLaughlin, M. Mallya, M. Panda, S. Rudrapatna, V.

Ramachandran, R. Shandil, V. K. Sambandamurthy, K.

Mdluli, C. B. Cooper, H. Rubin, T. Yano, P. Iyer, S.

Narayanan, S. Kavanagh, K. Mukherjee, V.

Balasubramanian, V. P. Hosagrahara, S. Solapure, S.

Ravishankar, S. Hameed P, J. Med. Chem. 2017, 60,

1379-1399; e) P. V. S. Ramya, L. Guntuku, S. Angapelly,

C. S. Digwal, U. J. Lakshmi, D. K. Sigalapalli, B. N.

Babu, V. G. M. Naidu, A. Kamal, Eur. J. Med. Chem.

2018, 143, 216-231.

[29] J. A. Widegren, M. A. Bennett, R. G. Finke, J. Am.

Chem. Soc. 2003, 125, 10301-10310.

[30] J.-B. Lan, L. Chen, X.-Q. Yu, J.-S. You, R.-G. Xie,

Chem. Commun. 2004, 188-189.

[31] H.-J. Lee, P.-Y. Cheng, C.-Y. Chen, J.-S. Shen, D.

Nandi, H. M. Lee, CrystEngComm 2011, 13, 4814-4816.

[32] B. Sreedhar, G. T. Venkanna, K. B. Shiva Kumar, V.

Balasubrahmanyam, Synthesis 2008, 2008, 795-799.

[33] Bruker AXS Inc., Madison, Wisconsin, USA., 2007.

[34] G. M. Sheldrick, University of Göttingen, Germany,

1996.

[35] G. Sheldrick, Acta Crystallogr. 2008, A64, 112-122.

[36] A. Spek, Acta Crystallogr. 2015, C71, 9-18.

10

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

[37] I. Boldog, K. V. Domasevitch, J. Sanchiz, P. Mayer, C.

Janiak, Dalton Trans. 2014, 43, 12590-12605.

11

10.1002/adsc.201901189

Advanced Synthesis & Catalysis

FULL PAPER

Dimetallic Palladium–NHC Complexes: Synthesis,

Characterization and Catalytic Application for

Direct C－H Arylation Reaction of

Heteroaromatics with Aryl Chlorides

Adv. Synth. Catal. Year, Volume, Page – Page

Jhen-Yi Lee, Debalina Ghosh, Ya-Ting Kuo and

Hon Man Lee*

12

Article Doi

Dimetallic Palladium-NHC Complexes: Synthesis, Characterization, and Catalytic Application for Direct C?H Arylation Reaction of Heteroaromatics with Aryl Chlorides

DOI: 10.1002/adsc.201901189

Source and publish data:

Authors:

Article abstract of DOI:10.1002/adsc.201901189

Full text of DOI:10.1002/adsc.201901189

Products guided by the article

R&D Labs maybe for 1201005-74-4

Relevant to this article

Hot Product