Cyclopalladation in the Periphery of a NHC Ligand as the Crucial Step in the Synthesis of Highly Active Suzuki–Miyaura Cross-Coupling Catalysts

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Accepted Article

Title: Cyclopalladation in the Periphery of a NHC Ligand as the Crucial

Step in the Synthesis of Highly Active Suzuki-Miyaura Cross-

Coupling Catalysts

Authors: Agnes Fizia, Maximilian Gaffga, Johannes Lang, Yu Sun,

Gereon Niedner-Schatteburg, and Werner R. Thiel

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Cyclopalladation in the Periphery of a NHC Ligand as the Crucial

Step in the Synthesis of Highly Active Suzuki-Miyaura Cross-

Coupling Catalysts

Agnes Fizia,^[a]Maximilian Gaffga,^[a,b], Johannes Lang,^[a,b]Yu Sun,^[a]Gereon Niedner-Schatteburg^[a,b]

and Werner R. Thiel*^[a]

Abstract: Starting from 2,4-dichloropyrimidine, 4-(2-dialkylamino)pyr-

imidinyl functionalized mesitylimidazolium chlorides are accessible in

a five-step reaction sequence. Two routes leading to palladium NHC

complexes derived from these ligands have been worked out: By

transmetallation with the corresponding NHC-AgCl complexes, C,N-

coordinated palladium(II) complexes can be obtained. Treatment of

palladium dichloride with the imidazolium salts in pyridine and in the

presence of K₂CO₃gives cyclometallated and thus C,C-coordinated

compounds. The reactivity of all these compounds was investigated

in detail as well as their performance in the catalytic Suzuki-Miyaura

cross-coupling reaction. It turned out, that the C,C-coordinated deriv-

atives exhibit high catalytic activities in the coupling of arylboronic

acids with aryl chlorides, which is in agreement with the generally

accepted mechanistic ideas on the substrate activation.

complexes originate back to the pioneering work of Öfele and

Wanzlick in the late 1960ies,^[8]the synthesis of the first free NHC

derivative can be considered as the starting point for a broad

application of NHCs as ligands in transition metal and main group

element chemistry. NHCs have turned out to be excellent σ-donor

ligands.^[9]By means of structural and thermodynamic studies it

was shown that the σ-donation of NHCs is better than of electron

rich phosphines such as tricyclohexyl phosphine.^[10]In addition to

the -donation there is a small contribution of π-backbonding in

the M-NHC bond, which should not be neglected.^[7c,11]

The pronounced transfer of electron density from the NHC ligand

to the metal site makes these ligands ideal candidates for applic-

ations in catalytic reactions wherein an oxidative addition of a sub-

strate takes place. It therefore is not surprising, that the first

application of an NHC ligand in homogeneous catalysis was re-

ported for a C,C-cross-coupling reaction.^[12]The Suzuki-Miyaura

cross-coupling reaction, that converts aryl halides and aryl

boronic acids into biaryl derivatives is frequently used as a test

reaction to evaluate the catalytic activity of novel palladium-NHC

complexes in C,C-coupling reactions.^[13]

Recently, we were able to show, that chelating ligands bearing a

4-(2-amino)pyrimidinyl unit readily undergo cyclometallation (CH-

activation) in the ortho-position of the pyrimidinyl ring, as long as

a tertiary amino group is attached. Combinations of the 4-(2-

amino)pyrimidinyl group with a pyridine donor resulting in N,N-

chelating ligands (Scheme 1), allowed to obtain ruthenium cata-

lysts that perform the transfer hydrogenation of ketones with

isopropanol as the hydrogen source even in the absence of a

base.

Introduction

More than 100 years ago, Tschugajeff realized the synthesis of

the first stable carbene complexes,^[1]but it took another 55 years

to finally clarify the structure of these compounds.^[2]With the in-

ventions of Fischer ^[3]and Schrock,^[4]carbene chemistry became

a main topic in organometallic chemistry and catalysis. However,

it was Arduengo et al. who succeeded in synthesizing the first free

member of the N-heterocyclic carbene (NHC) familiy,^[5]wherein

the carbene is stabilized electronically by the π-donating and the

σ-acceptor properties of the two neighboring nitrogen atoms.^[6]

A

further improvement of the stability of these compounds can be

realized by introducing sterically demanding substituents at the

nitrogen atoms. There are numerous publications and reviews

discussing the steric and electronic properties of N-heterocyclic

carbenes.^{[ 7 ]}Although the first structurally characterized NHC

[a]

[b]

Dr. Agnes Fizia, Dr. Maximilian Gaffga, Dr. Yu Sun, Prof. Dr.

Gereon Niedner-Schatteburg, Prof. Dr. Werner R. Thiel*

Fachbereich Chemie

Technische Universität Kaiserslautern

Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern

E-mail: thiel@chemie.uni-kl.de

Scheme 1. Chelating ligands resp. ligand precursors bearing a 4-(2-amino)pyr-

imidinyl substituent.

Dr. Maximilian Gaffga, Prof. Dr. Gereon Niedner-Schatteburg

Forschungszentrum OPTIMAS

Technische Universität Kaiserslautern

67663 Kaiserslautern, Germany

As the result of theoretical and spectroscopic investigations, this

special feature can be assigned to the cyclometallation of the

ligand occurring in-situ.^[14]This provides a carbanion coordinating

Supporting information for this article is given via a link at the end of

the document.

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to the ruthenium(II) center which acts as an internal base. There

are just a few further examples in the literature that are compar-

able to this mechanism: Whittlesey et al. reported a NHC ruthe-

nium complex which undergoes CH-activation at the mesityl sub-

stituent of the NHC ligand. This gives access to a ruthenium(II)

hydrido complex, that also catalyzes the transfer hydrogenation

without a basic additive.^{[ 15 ]}During the last three years, the

importance of CH-activation steps (cyclometallation) occurring at

aromatic moieties for catalytic reactions was further documented

for formic acid dehydrogenation, dehydrogenative silylation,

reductive amination of aromatic aldehydes and ammonia-borane

dihydrogenation.^[16]The according mechanisms were in some

cases supported by theoretical calculations.^[17]

The positive effect of the cyclometallation occurring especially at

the 4-(2-dialkylamino)pyrimidinyl group turned out not to be

restricted solely to our example of the ruthenium catalyzed

transfer hydrogenation. Combining phosphines with the 4-(2-ami-

no)pyrimidinyl moiety (Scheme 1) gave novel, formally P,N-don-

ating chelate ligands. Coordination to palladium dichloride resul-

ted in the expected P,N-chelate complexes for primary and sec-

ondary amino units but to C,N-coordination (cyclometallation) as

soon as a tertiary amino unit was attached to the pyrimidinyl

ring.^[18]Again, the coordination mode has a strong impact on the

catalytic activity of the palladium complexes: Compared to the

P,N-coordinated compounds, the C,N-coordinated derivatives

show strongly enhanced activities in the Suzuki-Miyaura cross-

coupling reaction as well as in decarboxylative cross-couplings.^[19]

It therefore seemed reasonable to investigate combinations of 4-

(2-amino)pyrimidines and NHC ligands, to evaluate the cooper-

ation of both donor sites in a chelating system. To the best of our

knowledge, such ligands have never been described before.

Such compounds are accessible from 1 by introducing a benzyl-

oxy substituent as the protecting group in the 4-position. In the

reaction sequence shown in Scheme 2, the first step, the syn-

thesis of 4-benzyloxy-2-chloropyrimidine (2) is crucial: Since 2010

there are overall five patents and publications in the literature

describing the synthesis of high-prized 2. Again, the problem is in

the parallel formation of the regioisomer 2-benzyloxy-4-chloro-

pyrimidine (2’).^[21]None of these methods gives an isomer ratio

2:2’ better than 75:25. Generally, the two regioisomers 2 and 2’

were further converted by nucleophilic substitution reactions and

the separation of the regioisomers was carried out on a later step

of the reaction sequence. Based on the method of Wang and

Tiansheng^[21e]we developed a new protocol leading to compound

2 in 76% yield with a purity of >98% after recrystallization from

methanol (two times). For a positive outcome of the synthesis, it

is absolutely essential to work at low temperatures in a polar, non-

protic solvent.

Scheme 2. Synthesis of the 2-dialkylamino-4-chloropyrimidines 6a-d: i)

C₆H₅CH₂OK (from KO^tBu and C₆H₅CH₂OH, 1:2, thf, 30 min, refl.), dmf, -50 °C,

1 h, r.t., 12 h; ii) HNR₂, thf, 0-100 °C, 90 min – 15 h; iii) 3 bar H₂, Pd/C (10%),

MeOH, r.t., 3 h; iv) POCl₃, 80 °C, 16 h; v) 1,2-C₆H₄Cl₂, 185 °C, 3-6h.

Results and Discussion

Ligand synthesis

Pyrimidines are six-membered aromatic N-heterocyclic com-

pounds with two nitrogen atoms in the 1- and 3-position. Due to

the presence of the two nitrogen atoms, all carbon atoms in the

direct neighborhood are activated for nucleophilic aromatic sub-

stitution reactions, especially when functionalized with electron

withdrawing substituents. This makes commercially available 2,4-

dichloropyrimidine (1) a suitable starting compound for the syn-

thesis of NHC-functionalized pyrimidines. Since the 4-position of

1 is expected to show an enhanced reactivity towards nucleophilic

aromatic substitution reactions,^[20]the introduction of an imidazole

substituent in this position was first considered as the starting

point of a reaction sequence leading to the desired NHC-function-

alized 2-aminopyrimidines. However, this approach solely led to

a hardly separable mixture of both possible regioisomers which

requested an alternative strategy to be developed. We looked for

routes leading to intermediates with a 4-chloro substituent, which

should allow the subsequent reaction with an N-substituted imid-

azole resulting in the formation of the corresponding imidazolium

derivative.

The 2-benzyloxy-4-chloro substitution pattern of compound 2

could unambiguously be proven by means heteronuclear multiple

bond correlation (HMBC) NMR spectroscopy (Supp. Info.). It fur-

thermore was confirmed by a single crystal X-ray structure ana-

lysis. Compound 2 crystallizes in the orthorhombic space group

P2₁2₁2₁with two molecules in the unit cell. Figure 1 shows the

molecular structure of 4 in the solid state.

Figure 1. Molecular structure of compound 4 in the solid state. Characteristic

bond lengths [Å] and angles [°]: C1-N1 1.307(2), C1-N2 1.330(2), C1-Cl1

1.748(2), N1-C1-N2 130.31(14), N1-C1-Cl1 115.54(11), N2-C1-Cl1 114.14(10).

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In the following step, the dialkylamino group is introduced via a

nucleophilic aromatic substitution of the chloro substituent in 2.

Compounds 3a-d are obtained in yields higher than 85%. How-

ever, while the strong nucleophiles piperidine and pyrrolidine

already react at low temperatures, heating under reflux is required

for diethylamine and working at 100 °C in an autoclave for dime-

thylamine. Pd/C-catalyzed hydrogenolysis then splits off the ben-

zyloxy group in the 4-position resulting in the formation of the

hydroxylpyrimidines 4a-d in almost quantitative yields. Subse-

quent transformation with POCl₃leads to the desired 4-chloro-2-

dialkylaminopyrimidines 5a-d in yields of 80-95%. There is almost

treated with an excess of Ag₂O in CH₂Cl₂in the dark giving yields

of 65-75% (Scheme 3).

1

no influence of the nature of the amino group on the H and ¹³C

Scheme 3. Synthesis of the NHC silver complexes 7a-d. i) CH₂Cl₂, r.t., 2 d.

NMR data of the 4-chloro derivatives 5a-d: While the resonance

of the proton in the 5-position appears at 6.29-6.74 ppm, the

signal for the proton in the 6-position shifts strongly to lower field

and is observed at 7.99-8.15 ppm. All ¹³C NMR resonances for

carbon atoms next to nitrogen atoms are found at approx. 158-

163 ppm and the signal for the carbon atom in the 5-position is

observed shifted to higher field at approx. 108 ppm.

As expected, the ¹H and the ¹³C NMR resonances in the

backbone of the imidazole rings of 7a-d shift to a higher field

compared to the cationic precursors 6a-d. The intensity of the ¹³

C

NMR signal of the quarternary carbene carbon atom is low due to

coupling to the silver isotopes ¹⁰⁷Ag and ¹⁰⁹Ag. It was observed

for 7c at 182.0 ppm, being typical for NHC silver complexes

In the final step of the ligand synthesis sequence, compounds 5a-

bearing a mesityl substituent.^[26]For the coupling constants ¹J_AgC

,

[22]

d are reacted with N-mesitylimidazole

at elevated tempera-

only a mean value could be calculated (163 Hz). The ¹⁰⁹Ag NMR

resonance of 7c was found at 622.3 ppm, which is in agreement

with data from the literature.^[27]By slow evaporation of the solvent

from a concentrated CH₂Cl₂solution, colorless crystals of 7a

being suitable for an single crystal X-ray structure analysis could

be obtainned. 7a crystallizes in the orthorhombic space group

Pbca. Figure 2 shows the molecular structure of 7a in the solid

state.

tures to produce the desired imidazolium derivatives 6a-d in yields

between 80 and 98%. It should be mentioned at this point, that

we did not find any limitation for this transformation caused by the

nature of the substituent at the imidazole precursor: aliphatic as

well as aromatic substituents show similar reactivities, which

opens up the access to a wide range of new imidazolium cations.

The S_NAr reaction occurring at the 4-position of the aminopyr-

imidine ring causes a pronounced shift of most of the ¹H and ¹³

C

NMR resonances of the pyrimidine as well as of the imidazole site

to lower field. ¹H NMR samples recorded in D₂O or CD₃OD did not

show the typical imidazolium resonance at >10 ppm, due to a

rapid H/D-exchange. However, in the ¹³C NMR spectra of such

samples, the carbon atom that is situated between the two nitro-

gen atoms of the imidazolium ring appears at approx. 137.5 ppm

showing the typical 1:1:1 coupling pattern of a CD unit (¹J_CDca.

35 Hz), which clearly proves the formation of the imidazolium

system.

Figure 2. Molecular structure of compound 7a in the solid state. Characteristic

bond lengths [Å] and angles [°]: Ag1-Cl1 2.3416(7), Ag1-C5 2.085(2), N1-C1

1.358(3), N2-C1 1.354(3), N3-C5 1.368(3), N4-C5 1.343(3), N5-C1 1.347(3),

Cl1-Ag1-C5 169.95(6), Ag1-C5-N3 125.67(15), Ag1-C5-N4 129.96(15), N1-C1-

N2 125.70(19), N1-C1-N5 117.41(19), N2-C1-N5 116.89(18).

Synthesis of palladium complexes

For the synthesis of palladium(II) NHC complexes bearing an am-

inopyrimidine substituent two routes were worked out. The direct

reaction of PdCl₂with the imidazolium chlorides 6a-d in thf and in

the presence of K₂CO₃fails. According to the NMR data obtained,

the products of these transformations are zwitterionic adducts

The silver(I) centre in 7a is coordinated almost linearly, the C-Ag

and the Ag-Cl distances are typical for neutral complexes of the

type (NHC)AgCl.^[24a,27]While the mesityl ring is oriented almost

perpendicular to the imidazole unit (dihedral angle: 77.2°), the

pyrimidine ring and the imidazole unit show a torsion of only 23.9°.

This is due to a close contact of the protons of one of the NMe₂

methyl groups to the chlorido ligand. However, high-resolution

NMR spectroscopy proves a rapid interconversion of the two

NMe₂methyl units in solution by rotation around the C1-N5 bond.

Since it turned out to be impossible to obtain palladium(II) NHC

complexes 8a-d by simply reacting Pd(OOCCH₃)₂with the imid-

azolium precursors 6a-d,^[12,28]NHC transfer from the NHC silver(I)

-

wherein one of the pyrimidine nitrogen atoms is bound to a PdCl₃

anion. The first successful route to NHC palladium(II) complexes

of 6a-d includes an NHC transfer via the NHC silver complexes

7a-d. The second route follows the classical procedure for the

synthesis of the PEPPSI-type complexes.^[23]During the last dec-

ade, NHC silver complexes have attracted attention as catalysts,

antimicrobal compounds, pharmaceuticals and emitting compo-

nents in OLEDs (organic light-emitting diodes).^[24]Their main im-

pact in preparative chemistry however is to transfer NHC ligands

to other metal centers under mild conditions.^[25]To synthesize the

NHC silver complexes 7a-d, the imidazolium salts 6a-d were

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complexes was applied to access N,C-coordinated palladium(II)

derivatives. Reacting the NHC silver(I) compounds 7a,c,d with

(C₆H₅CN)₂PdCl₂gave the corresponding dichlorido(NHC)palla-

dium(II) complexes in yields of 85-95% (Scheme 4). The sterically

most hindered diamino derivative 8b could not be obtained purely

this way although its presence in the reaction mixture was proven

by means of NMR spectroscopy.

resonances of a coordinating pyridine moieties are observed in

the ¹H as well as in the ¹³C NMR spectra. Application of different

1D and 2D NMR techniques allowed a complete assignment of

the ¹H and ¹³C NMR signals (Supp. Info.).

The cyclometallated palladium complexes 9a,b,d could be ob-

tained in crystalline form allowing to investigate their structural

properties by means of single crystals X-Ray structure analysis.

Figure 3 shows the molecular structures of 9a,b,d in the solid

state, Table 1 summarizes the most characteristic bond parame-

ters.

Scheme 4. Synthesis of the N,C-coordinated palladium(II) complexes 8a,c,d. i)

(C₆H₅CN)₂PdCl₂, thf, r.t., 48 h.

Comparison of the ¹H NMR spectra of the palladium(II) complexes

8a,c,d and their silver(I) congeners shows a pronounced shift of

the pyrimidine resonances to lower field (1.1-1.9 ppm), proving

the coordination of the pyrimidine site to the palladium(II) centre.

Furthermore, a cyclometallation at the pyrimidine can be excluded,

since the characteristic doublets for the two pyrimidine protons

are still present. There is no remarkable difference in the chemical

shifts of the imidazolylidene protons between the palladium(II)

and the silver(I) complexes. For compound 8c, two sets of pyrrol-

idinyl protons are observed, which can be explained by a hindered

rotation around the CN bond. The ¹³C NMR resonances of the

carbene carbon atoms are now found at 160-161 ppm.

By reacting the imidazolium precursors 6a-d with PdCl₂and 5

equiv. of K₂CO₃in pyridine for 16 h at 80 °C, the cyclometallated

palladium(II) complexes 9a-d could be obtained in good yields

(Scheme 5).

Scheme 5. Synthesis of the N,C-coordinated palladium(II) complexes 9a-d. i)

PdCl₂, K₂CO₃, pyridine, 80 °C, 16 h.

Figure 3. Molecular structure of compounds 9a,b,d in the solid state.

Complexes 9a-d possess structures similar but not identical to

those of PEPPSI-type systems (see structure discussion below)

1

and again show typical NMR spectra: In the H NMR spectrum,

there is a characteristic singlet for the remaining proton at the

pyrimidine ring, which is observed at 8.66 ppm almost indepen-

dent of the NR₂substituent. The ¹³C NMR resonance of the

metallated pyrimidine carbon atom is found at 112-113 ppm, and

the signal for the carbene carbon atom is found at 170.2 ppm,

which is clearly deshielded compared to 8a,c,d. Furthermore, the

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complexes under the conditions of the Suzuki-Miyaura coup-

ling.^[23g,29]Dimeric chloride-bridged NHC-palladium catalysts for

cross-coupling reactions had been published by Nolan et al. and

Cazin et al..^[30]

Table 1. Characteristic bond lengths [Å] and angles [°] and dihedral angles [°]

of compounds 9a,b,d.

9a ^[a]

9b

9d

Pd1-N6

2.131(4)/2.116(6)

2.334(2)/2.335(2)

2.004(5)/1.993(6)

1.981(5)/1.993(7)

173.1(2)/172.2(2)

80.7(2)/79.1(3)

88.6(2)/88.2(2)

176.5(2)/177.3(2)

92.5(2)/93.3(2)

98.3(2)/99.5(2)

3.5(6)/3.5(8)

2.129(2)

2.3528(4)

1.999(2)

1.987(2)

172.59(6)

79.72(8)

89.87(5)

174.95(9)

92.93(6)

97.53(7)

-0.3(3)

2.126(2)

2.347(1)

2.005(2)

1.991(2)

171.46(6)

79.52(8)

88.85(5)

178.33(8)

92.81(6)

98.84(7)

3.2(2)

Pd1-Cl1

Pd1-C3

Pd1-C5

C5-Pd1-Cl1

C5-Pd1-C3

N6-Pd1-Cl1

N6-Pd1-C3

Cl1-Pd1-C3

C5-Pd1-N6

C5-N3-C2-C3

[a] There are two crystallographically independent molecules in the unit cell of

compound 9a.

The bond parameters are quite similar for all complexes invest-

igated and are closely related to the data that were reported for

PEPPSI-type palladium complexes in the past.^[23]However, there

is one pronounced difference: While for classical PEPPSI-type

complexes bearing non-chelating NHC ligands, the pyridine li-

gand is found coordinated in the trans-position to the NHC ligand,

the auxiliary donor is found in trans-orientation to the carbanion in

compounds 9a,b,d. Compound 9b forms a column like structure

wherein a cyclic trimer of water molecules undergoes hydrogen

bonding to the chloride ligand at the palladium(II) center.

Solutions of compounds 9a,b,d in weakly coordinating organic

solvents readily decompose at room temperature giving insoluble,

pale yellow solids. To elucidate the molecular structure of these

precipitates, the material derived from compound 9d by heating

to reflux in thf was investigated by means of solid-state ¹³C NMR

spectroscopy (Supp. Info.). The spectrum shows the expected

signals of the C,C-coordinating NHC ligand with four resonances

at  > 160 ppm (aromatic carbon atoms next to the nitrogen

atoms) and seven resonances at δ = 145-110 ppm that can be

assigned to the other aromatic carbon atoms of the NHC ligand.

The aliphatic carbon atoms next to the piperidinyl nitrogen atom

give two signals speaking for a frozen rotation around the pipe-

ridinylpyrimidinyl bond in the solid state. The same is true for the

next two carbon atoms in the piperidinyl ring and the two methyl

groups in the ortho-position of the mesityl ring. In summary, this

proves the persistence of the C,C-coordinating NHC ligand. How-

ever, the resonances of the pyridine ligand are no longer

detectable. According to the solid-state NMR data and the results

of elemental analysis, most likely a loss of the pyridine ligand of

9d occurs, resulting in the chloride bridged dimer 10 (Scheme 6).

The isotope pattern of the dimer 10 can additionally be observed

in the ESI mass spectrum of the precursor 9a. A similar loss of

the pyridine ligand was postulated to occur for PEPPSI-type

Scheme 6. Dissociation and association of pyridines C,C-coordinated NHC

palladium(II) complexes.

By heating compound 10 in pyridine for a few minutes, the solid

completely dissolves with the regeneration of 9d. This in addition

opens up a simple route to introduce other pyridine donors, which

was exemplarily investigated for 3-chloro- and 2-methylpyridine,

resulting in the NHC palladium complexes 9d-Cl and 9d-Me

(Scheme 6). According to the presence of four chemically inequi-

valent protons at the pyridine site, there are now four new

1

resonances in the H NMR spectra and five new resonances in

the ¹³C NMR spectra of 9d-Cl and 9d-Me, which could be

assigned by means of 2D NMR spectroscopy. Furthermore, the

mesityl substituents now give rise to a double set of signals for

the ortho- and meta-positions at low temperatures. By analyzing

the temperature dependent ¹H NMR spectra of compound 9d-Cl,

a barrier for the rotation around the Pd-pyridine bond of 46.5±2

kJ∙mol^-1was calculated.

Single crystals being suitable for X-ray structure analysis could be

obtained from compound 9d-Me. Figure 4 shows the molecular

structure of 9d-Me in the solid state.

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Figure 4. Molecular structure of compound 9d-Me in the solid state. Charac-

teristic bond lengths [Å], angles [°] and dihedral angles [°]: Pd1-Cl1 2.3414(6),

Pd1-N6 2.131(2), Pd1-C3 1.996(2), Pd1-C5 1.981(2), Cl1-Pd1-N6 88.45(6),

Cl1-Pd1-C3 93.36(7), Cl1-Pd1-C5 172.48(7), N6-Pd1-C3 173.91(9), N6-Pd1-

C5 98.70(9), C3-Pd1-C5 79.77(10), C5-N3-C2-C3-0.8(3).

Scheme 7. Reactivity of compound 9d vs. hydrochloric acid.

After further stirring of the mixture at pH = 2 for 24 h, the reson-

ances of 9d completely disappeared. Aside to the signals of

compound 11d, now there are resonances that can be assigned

to compound 8d (Supp. Info.), proving the dissociation of the

pyridine ligand under more acidic conditions. After 48 h at pH = 2,

complete decomposition occurred.

The bond parameters found for 9d-Me are in complete agreement

with the data found for compounds 9a,b,d. The pyridine methyl

group is disordered over two positions.

Reactivity of the palladium complexes

From these results it can be concluded that the reaction of the

imidazolium salts 6a-d with palladium dichloride directly leads to

the cyclometallated derivatives 9a-d when carried out at elevated

temperatures in a stabilizing solvent (pyridine) and in the presen-

ce of a base. However, in the presence of chloride anions and

under acidic conditions, first the Pd-C_pyrimbond of the cyclometal-

lated complexes 9a-d is cleaved. In a second step, the Pd-N_pyrid

is broken, and finally the Pd-NHC bond is protonated.

Complex 11b being structurally closely related to 11d, was ob-

tained as a side-product in yields up to 33 % when 6b was reacted

similar to the formation of 9b but under circumstances where the

base was not sufficiently accessible, either due to insufficient stir-

ring of the reaction mixture or due to the application of a strongly

agglomerated K₂CO₃. 11b was isolated by means of preparative

HPLC and characterized spectroscopically and by single crystal

X-ray structure analysis. Figure 5 shows the molecular structure

of 11b in the solid state. The bond parameters found for 11b are

in complete agreement with the data found for PEPPSI-type

palladium(II) complexes.^[23]

Since the outcome of the complexation reaction so strongly de-

pends on the reaction conditions, we investigated the cyclometal-

lation as well as the cleavage of the Pd-C_pyrimbond in more detail.

By treatment of compound 8d with 6 equiv. of K₂CO₃in pyridine-

d₅in an NMR tube, the selective formation of 9d_D, bearing a pyr-

idine-d₅ligand, was observed. The reaction sets in at approx.

80 °C and proceeds slowly to 95% conversion during 16 h. No

compound other than 8d and 9d_Dcould be detected by means of

¹H NMR spectroscopy. To elucidate the reversibility of the cyclo-

metallation, compound 9d was dissolved in a two-phase mixture

of dichloromethane and a saturated solution of NH₄Cl, which was

treated with diluted HCl until pH = 4. After stirring the mixture for

24 h, a part of the organic phase was removed and dried under

vacuum. The rest was brought to pH = 2 by addition of HCl and

1

stirred for further 24 h (discussion: see below). In the H NMR

spectrum measured from the mixture obtained after 24 h at pH =

4, there are two sets of signals (Supp. Info.). Besides the well-

known signals of compound 9d, there are the resonances that can

be expected for the PEPPSI-type complex 11d (Scheme 7). Two

doublets for the imidazolylidene protons ( = 8.05, 7.05 ppm, ³J_HH

= 2.1 Hz), proving that the Pd-C_NHCbond was conserved, three

multiplets of a coordinating pyridine ligand ( = 8.72, 7.73, 7.28

ppm) a singlet for the mesityl proton ( = 7.07 ppm) and two

doublets for the pyrimidine protons ( = 8.94, 8.58 ppm, ³J_HH= 5.3

Hz). 11d therefore has to contain one pyridine ligand, the Pd-

C_pyrimbond has to be cleaved and the Pd-N_pyrimbond is not yet

established. ESI mass spectrometry revealed, besides the signals

of [9d+H]⁺and it’s fragments, a signal at m/z = 603 that

corresponds to [11d+H]⁺.

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is specific to the Pd-C isomer, leads exclusively to fragments exhi-

biting attached H₂O molecules. In contrast, the Pd-N coordinated

isomer undergoes HCl elimination through proton abstraction

from the methyl group of the mesitylene. The negatively charged

carbon atom of the methyl group then coordinates to the Pd center

facilitating a (distorted) square planar coordination sphere. Accor-

dingly, excitation of a pyrimidinyl ring mode, which is specific to

the Pd-N isomer, leads exclusively to fragments without attached

H₂O molecules (sole HCl loss). The HCl elimination is in compe-

tition to MeCN expulsion from both Pd-N and Pd-C isomers, in

particular when pumping the CH stretching modes of the various

methyl groups.

Suzuki-Miyaura cross-coupling reactions

In the past, N-Heterocyclic carbene ligands turned out to have a

highly positive impact on the performance of palladium catalysts

in the Suzuki-Miyaura cross-coupling reaction. In combination

with sterically demanding substituents at the NCH core, the ac-

tivation of chloroarenes became possible e.g. by implementation

of palladium complexes of the type [Pd(NHC)(allyl)Cl] ^[31]and by

palladium(I) complexes having the composition [(NHC)₂Pd₂(²-

allyl)(²-Cl)].^[32]Structurally more closer related to our systems are

palladium complexes of the type (NHC)Pd(Cl)₂(pyridine) often

denoted as PEPPSI complexes.

From a mechanistic point of view, the Pd^IIsite is reduced to Pd⁰

in the first step of the catalytic cycle, which then enables the oxid-

ative addition of the substrate. It was postulated for the PEPPSI-

type catalysts that during this reduction, the pyridine and at least

one of the chlorido ligands dissociate.^[23g,29]This allows to a

certain extent the tuning the reactivity of the catalyst by the nature

of these ligands. In this context it seemed to be interesting to

evaluate complexes 9a-d for their performance in the Suzuki-

Miyaura cross-coupling reaction. Similar to PEPPSI-type comple-

xes they possess a labile pyridine ligand. However, this pyridine

ligand is attached in the trans-position to the carbanionic ligand

and not in the trans-position to the NHC-ligand as in PEPPSI-type

complexes. Furthermore, according to the reactivity studies dis-

cussed above, it seems plausible that the Pd-C_pyrimbond should

stay intact under the basic conditions of the Suzuki-Miyaura

cross-coupling reaction, leading to quite electron-rich and thus

strongly nucleophilic Pd⁰intermediates.

Figure 5. Molecular structure of compound 11b in the solid state. Characteristic

bond lengths [Å], angles [°] and dihedral angles [°]: Pd1-Cl1 2.296(1), Pd1-Cl2

2.311(1), Pd1-N6 2.087(3), Pd1-C5 1.969(3), Cl1-Pd1-Cl2 178.71(3), Cl1-Pd1-

N6 88.97(8), Cl1-Pd1-C5 90.91(8), Cl2-Pd1-N6 90.03(8), Cl2-Pd1-C5 90.03(8),

N6-Pd1-C5 176.29(11), Cl2-Pd1-N6-C21-53.2(2), Cl2-Pd1-C5-N4 95.8(2), C5-

N4-C4-C3-30.2(4), C5-N5-C8-C9-89.3(4).

By means of ESI mass spectrometry it could be proven, that com-

plexes 9a-d undergo complete exchange of the pyridine ligand for

an acetonitrile ligand, when stirred for 16 h in an acetonitrile

solution giving the compounds 9a_AN-9d_AN. A closer investigation

of the fragmentation behavior of the protonated species 9bH⁺-

9dH⁺and 9b_ANH⁺-9d_ANH⁺under CID (collision induced dis-

sociation, collision gas: He) conditions showed pronounced differ-

ences between these two types of compounds. While all pyridine

derivatives show the expected sigmoidal CID curves, and require

almost identical energies for the dissociation process, the aceto-

nitrile complexes exhibit a bimodal dissociation behavior that

strongly depends on the nature of the amino substituent attached

to the pyrimidine ring. This provides strong evidence for the co-

existence of different isomers in the case of isolated 9b_ANH⁺-

9d_ANH⁺.

To explore these isomers, we pursued further IR spectroscopic

studies of the isolated complexes 9b_ANH⁺-9d_ANH⁺in the gas-

phase. These results go much beyond the scope of the present

study and shall soon be published elsewhere in more detail.

Nevertheless, we may emphasize some relevant findings at this

point: The IR spectra - in conjunction with DFT modelling - strong-

ly suggest the coexistence of two main isomers exhibiting either

a Pd-C or a Pd–N binding motif. The Pd-C coordinated isomers

are energetically favored by ΔH = 8-9 kJ/mol in all three cases.

Furthermore, the IR-MPD spectrum of 9b_ANH⁺exhibits a very pro-

nounced mode dependent fragmentation behavior. This effects

originates from the distinct fragmentation behavior of the Pd-C

and Pd–N isomers. The Pd-C coordinated isomer undergoes HCl

elimination by proton abstraction from N5H of the pyrimidine ring.

The resulting fragment species exhibits an under coordinated Pd

center as evident through a subsequent attachment of ubiquitous

H₂O molecules to the fragment ions within the Paul ion trap.

Accordingly, excitation of the NH stretching vibration mode, which

For the evaluation of catalysts 9a-d in the Suzuki-Miyaura cross-

coupling reaction, the reaction conditions were optimized in the

first step with 4-chlorotoluene and phenylboronic acid as the sub-

strates and 1 mol% of 9d as the catalyst. A series of solvents

i

(MeOH, EtOH, PrOH, ethyleneglycol, THF, dioxane, dimethoxy-

ethane), as well as the bases (2 equiv. of K^tOBu, K₂CO₃, K₃PO₄,

KOH) were tested. The reactions were carried out at 80 °C for 1

h. First it turned out that alcohols in combination with K₃PO₄as

the base gave the best results. Next mixtures of water and

alcohols with K₃PO₄were investigated leading to a further

increase of yields. Depending on the reaction conditions (Table

1), varying amounts of biphenyl were obtained in addition to the

major product 4-methylbiphenyl.

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investigation of the reaction time showed, that under the given

conditions, the conversions come to end after 60 min (Table 3).

Therefore, a reaction time of 30 min was defined for the com-

parison of the catalyst activities. A further increase of the reaction

temperature to 90 °C as well as of the amount of catalyst to 2

mol% slightly improved the yields of the products.

Table 1. Optimization of the solvent for the coupling of 4-chlortoluene and

phenylboronic in the presence of 9d.

entry ^[a]

solvents (v/v)

yields [%] ^[b]

1

ⁱPrOH/H₂O (1:3)

ⁱPrOH/H₂O (1:2)

ⁱPrOH/H₂O (1:1)

ⁱPrOH/H₂O (2:1)

EtOH/H₂O (1:3)

EtOH/H₂O (1:2)

EtOH/H₂O (1:1)

EtOH/H₂O (2:1)

MeOH/H₂O (1:3)

MeOH/H₂O (1:2)

MeOH/H₂O (1:1)

MeOH/H₂O (2:1)

64/8

58/7

61/7

65/8

19/4

25/6

63/12

44/26

12/2

22/3

25/4

46/6

2

Table 3. Investigation of the reaction time for the coupling of 4-chlortoluene

and phenylboronic in the presence of 9d.

3

entry ^[a]

reaction time [min]

yields [%] ^[b]

23/4

4

1

2

3

4

5

15

30

60

1440

i

42/6

6

61/8

7

65/8

8

66/8

9

[a] 20 mL glas vial, 3 mL of PrOH/H₂O (2:1), 1.0 equiv. of 4-chlortoluene,

1.2 equiv. of phenylboronic acid, 1 mol% of 9d, 2.0 equiv. of K₃PO₄, 80 °C

30 min. [b] 4-methylbiphenyl/biphenyl.

10

11

12

[a] 20 mL glas vial, 3 mL of solvent, 1.0 equiv. of 4-chlortoluene, 1.2 equiv.

of phenylboronic acid, 1 mol% of 9d, 2.0 equiv. of K₃PO₄, 80 °C, 1 h. [b] 4-

methylbiphenyl/biphenyl.

For the comparison of the palladium complexes under identical

conditions and for the investigation of the substrate scope, the

following experiments were carried out at 90 °C. Table 4 sum-

marizes the results. Obviously, there are strong differences in the

activities related to the binding mode of the NHC ligand. The C,N-

coordinated type 8 complexes, exhibit poor reactivities. If the

mechanism of the catalyst activation is the same as for PEPPSI-

type complexes, one can consider, that the chelating coordination

stays preserved, implying a minimum coordination number of 2

on a neutral Pd⁰species, if both chlorido ligands dissociate. The

steric shielding by the mesityl group and the 4-(2-amino)pyrimid-

inyl group is strong, resulting in weak palladium nucleophiles and

thus in poor activities. This is true as long as the reduction and

subsequent decomposition of the palladium catalysts 8 are rapid

with respect to the cyclometallation reaction, which might lead to

complexes of the type 9 under the basic conditions of the Suzuki-

Miyaura cross coupling reaction. In contrast, for complexes of

types 9, reduction to Pd⁰will give anionic Pd⁰species being less

sterically shielded than in the former case, since the 2-amino

substituent now points away from the palladium center. It there-

fore is reasonable, that the activities of these complexes are high.

Furthermore, there are slight variations of the activities that are

related to the steric impact of the 2-amino group (the bigger, the

better) and the electronic/steric features of the leaving pyridine

ligand. Complex 11d might behave as a classic PEPPSI-type

complex or might rapidly be converted to 9d under the given

reaction conditions.

Thus, a 2:1 mixture of ⁱPrOH and water (entry 4) was taken as the

starting point for the following experiments. First the influence of

the base was reinvestigated (Table 2), proving, that K₃PO₄still

was the best choice.

Table 2. Optimization of the base for the coupling of 4-chlortoluene and

phenylboronic in the presence of 9d.

entry ^[a]

base

yields [%] ^[b]

1

2

3

4

5

K₃PO₄

NaHCO₃

K₂CO₃

KOH

65/8

22/4

55/6

16/28

30/5

K^tOBu

i

[a] 20 mL glas vial, 3 mL of PrOH/H₂O (2:1), 1.0 equiv. of 4-chlortoluene,

1.2 equiv. of phenylboronic acid, 1 mol% of 9d, 2.0 equiv. of the base, 80 °C,

1 h. [b] 4-methylbiphenyl/biphenyl.

In the absence of any base, there was no conversion at all. More

than 2.0 equiv. of K₃PO₄gave more of the side-product. The

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Table 5. Evaluation of the substrate scope of the Suzuki-Miyaura cross-

coupling catalysts 9a-d, 4-chloro benzenes

Table 4. Comparison of different palladium complexes for the coupling of 4-

chlortoluene and phenylboronic.

entry ^[a]

chloro arene

boronic acid

product

yields [%]

entry ^[a]

palladium complex

yields [%] ^[b]

9a: 96

9b: >99

9c: 97

9d: >99

1

8a

9

2

8c

6

9a: >99

9b: >99

9c: >99

9d: >99

3

8d

9

2

3

4

9a

53

63

48

61

43

51

55

10

1

9a: 69

9b: 61

9c: 81

9d: 80

5

9b

6

9c

7

9d

9a: 99

9b: 99

9c: 83

9d: 99

8

9dCl

9

9dMe

9a: 40

9b: 53

9c: 43

9d: 39

10

11

12

13

11d

5

6

7

PdCl₂

(PPh₃)₂PdCl₂

9a: 45

(PhCN)₂PdCl₂

2

9a: 15

9b: 3

9c: 13

9d: 16

i

[a] 20 mL glas vial, 3 mL of PrOH/H₂O (2:1), 1.0 equiv. of 4-chlortoluene,

1.2 equiv. of phenylboronic acid, 1 mol% of the catalyst, 2.0 equiv. of K₃PO₄,

90 °C, 30 min. [b] 4-methylbiphenyl, a few % of biphenyl were observed for

active systems.

9a: 39

9c: 24

9d: 36

8

9

9a: 46

9c: 46

Since the cyclometallated complexes 9a-d are all capable to con-

vert the quite unreactive 4-chlorotoluene into the Suzuki-Miyaura

cross-coupling product in reasonable yields, it seemed promising,

to investigate the substrate scope of these catalysts. For this pur-

pose, electronically activated and deactivated chloroarenes were

reacted with a series of arylboronic acid derivatives under the

optimized reaction conditions. Tables 5 and 6 summarize the

results.

9a: 27

9b: 7

9c: 18

9d: 18

10

11

9a: 20

9b:36

9c: 22

9d: 32

i

[a] 20 mL glas vial, 3 mL of PrOH/H₂O (2:1), 1.0 equiv. of the 4-chloro

benzene, 1.2 equiv. of phenylboronic acid, 1 mol% of the catalyst, 2.0 equiv.

of K₃PO₄, 90 °C, 30 min.

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acid derivatives. Mechanistic investigations show, that the

additional pyridine ligand, that is present in the coordination

sphere of the C,C-coordinated palladium(II) species dissociates

reversibly, leading to poorly soluble dimeric complexes. Treat-

ment of the C,C-coordinated palladium(II) compounds with HCl at

pH4 results in a protonation of the palladium-coordinated

carbanion under preservation of the palladium pyridine bond. The

latter ligand dissociates at lower pH values. In a final protonation

step the palladium carbene bond is broken. These protonations

give an idea on the different strengths of the palladium ligand

interactions in the C,C-coordinated palladium(II) complexes and

furthermore make sure that the C,C-coordinated palladium(II)

complexes are stable under the basic conditions of the Suzuki-

Miyaura-coupling reaction. The important result of the

investigations discussed above is that cyclometallation is an

efficient and very simple tool to drastically improve the activity of

cross-coupling catalysts. This is not only interesting from a

mechanistic point of view but it might give an idea to people

working in this field to develop new and maybe even better

catalysts.

Table 6. Evaluation of the substrate scope of the Suzuki-Miyaura cross-

coupling catalysts 9a-d, 1-chloro naphthalene, 2,6-dimethylchloro benzene

and 2-chloro quinoline.

entry ^[a]

chloro arene

boronic acid

product

yields [%]

9a: 82

9c: 91

9d: 84

1

2

9d: 89

9a: 97

9b: 93

9c: 86

9d: 81

3

4

5

9a: 4

9b: 4

9c: 1

9d: 4

9a: 51

9b: 46

9c: 46

9d: 48

9a: 84

9b: 91

9c: 88

9d: 89

Experimental Section

6

7

8

General remarks. Syntheses requiring the exclusion of oxygen and

humidity were carried out under an atmosphere of dinitrogen. Dichloro-

methane, diethyl ether, n-pentane, tetrahydrofurane and toluene were

dried with MBraun MB-SPS solvent dryer. NMR spectra in solution were

recorded with Bruker AVANCE DPX 200 (¹H: 200.1 MHz, ¹³C: 50.3 MHz),

Bruker AVANCE DPX 400 (¹H: 400.1 MHz, ¹³C: 100.6 MHz), Bruker

AVANCE DPX 600 (¹H: 600.1 MHz, ¹³C: 150.9 MHz) spectrometers. The

chemical shifts are calibrated by using the solvent resonances. For the

assignment of the NMR data, see the Supporting Information. Solid state

NMR measurements were performed on a 500 MHz Bruker Avance III

widebore NMR spectrometer. Elemental analyses (C,H,N) were deter-

mined in the microanalytic laboratories of the Fachbereich Chemie using

a Elementar Analysetechnik vario Micro cube. The X-ray structure analy-

ses were obtained with Oxford Diffraction Gemini S Ultra diffractometer

(for further details: see below).

9a: 15

9a: 4

9b: 2

9c: 4

9d: 3

[a] 20 mL glas vial, 3 mL of ⁱPrOH/H₂O (2:1), 1.0 equiv. of the chloro arene,

1.2 equiv. of phenylboronic acid, 1 mol% of the catalyst, 2.0 equiv. of K₃PO₄,

90 °C, 30 min.

Electrospray ionization mass spectrometry (ESI-MS) was performed with

two ion trap instrument (Bruker Esquire 6000). The investigated cations

were produced in the positive electrospray ionization mode. The scan

speed was 13000 m/z s in normal resolution scan mode (0.3 fwhm / m/z).

The scan range was at least 70 to 1500 m/z. Sample solutions of comple-

xes 9b_ANH⁺-9d_ANH⁺in acetonitrile at concentrations of approximately 10^-4

M were continuously infused into the ESI chamber at a flow rate of 2 µl/min

using a syringe pump. Dissolving the complexes in CH₂Cl₂and adding

100 µl of pyridine to the sample solution leads to the formation of

complexes 9bH⁺-9dH⁺. We used nitrogen as the drying gas at a flow rate

of 3.0 to 4.0 l/min heated to 220 and 300°C. We sprayed the solutions at

a nebulizer gas pressure of 3 to 4 psi with the electrospray needle held at

4.5 kV. Helium was used as a buffer gas with a partial pressure of about

3 x 10^-3mbar inside the ion trap. BrukerEsquireControl 5.3 software

controlled the instrument and data analysis was performed using the Data

Analysis 4.0 software.

The four catalysts show almost identical activities. Chloroarenes

that are less electron rich give excellent yields. The yields drop for

chloroarenes that are equipped with electron donating substi-

tuents. An even more severe loss of yield is observed for boronic

acids that carry sterically demanding substituents.

Conclusions

Depending on the reaction conditions C,N- and C,C-coordinated

palladium(II) complexes are accessible from 4-(2-dialkylamino)-

pyrimidinyl functionalized mesitylimidazolium chlorides. These

two types of C-C-coupling catalysts showed pronounced differen-

ces in activities in the Suzuki-Miyaura-coupling of chloroarenes,

which explains by the nature of the palladium(0) intermediate that

is formed in the first step of the catalytic cycle. The C,C-

coordinated palladium(II) complexes give anionic and thus

strongly nucleophilic palladium(0) species, which allows us to

perform the coupling reactions with low catalyst loadings and

short reaction times on a wide range of chloroarene and boronic

In the following we exemplarily provide typical procedures for each class

of compound to keep the length of the manuscript acceptable. All other

syntheses can be found in the Supporting Information.

4-Benzyloxy-2-chloropyrimidine (2). 8.86 g (79.0 mmol) of KO^tBu and

17.09 g (158.0 mmol) of benzylic alcohol were suspended in 50 mL of dry

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thf and heated to reflux for 30 min. After cooling to 0 °C, the mixture was

added slowly to a suspension of 12.0 g (79.0 mmol) 2,4-dichloropyrimidine

in 60 mL of dry N,N-Dimethylformamide which was cooled to -50 °C. The

mixture was stirred for 1 h at -50 °C, slowly heated to r.t, stirred for further

12 h at this temperature and then poured onto 250 mL of ice. The precip-

itate formed was filtered off, washed with water and dried under vacuum.

Twofold recrystallization from MeOH gave an analytically pure product.

Yield: 9.21 g (76%) of a colorless solid. Elemental analysis calcd. for

C₁₁H₉ClN₂O (220.66): C 59.88, H 4.11, N 12.70, found: C 60.05, H 4.28,

N 12.73%. ¹H NMR (CDCl₃, 400.1 MHz):  5.43 (s, 2 H, H-5), 6.71 (d, ³J_HH

= 5.6 Hz, 1 H, H-3), 7.47-7.36 (m, 5 H, H_Ph), 8.31 (d, ³J_HH= 5.6 Hz, 1 H, H-

2). ¹³C{¹H} NMR (CDCl₃, 100.6 MHz):  170.3 (C-4), 160.3 (C-1), 159.0 (C-

2), 135.3 (C-6), 128.8 (C-8), 128.8 (C-9), 128.7 (C-7), 107.5 (C-3), 69.3

(C-5).

General procedure for the synthesis of the NHC palladium(II) com-

plexes 8a,c,d. 0.5 mmol of 7a,c,d and 0.5 mmol of (C₆H₅CN)₂PdCl₂were

dissolved in 10 mL of dry thf and stirred at r.t. for 48 h. The resulting brown

suspension was filtered over Celite^®and the solvent was removed under

vacuum. Compounds 8a,c,d were obtained as beige solids in yields of 85-

95%. For analytical data refer to the Supporting Information.

General procedure for the synthesis of the NHC palladium(II) com-

plexes 9a-d. 1 mmol of PdCl₂, 5 mmol of finely powdered K₂CO₃, 3.5 mL

of pyridine and 1.1 mmol of 6a-d were stirred at 80 °C for 16 h. After cooling

to r.t., the mixture was diluted with 10 mL of CH₂Cl₂and filtered over Celite^®.

The solvent was removed under vacuum and the raw product was recryst-

allized from thf. 9a-d were obtained as yellow solids in yields of 87-95%. %.

For analytical data refer to the Supporting Information.

²-Chlorido[3-(2-(piperidinyl)pyrimidin-4-yl-5-ido)-1-mesityl-1H-imid-

azolylidene]palladium(II) dimer (10). Stirring a solution of 284 mg (0.5

mmol) of 9d for 16 h in 5 mL of thf at 67 °C resulted in the precipitation of

a pale yellow microcrystalline solid. The precipitate was filtered off, washed

with of CH₂Cl₂, and dried under vacuum. Yield: 244 mg (>99 %). Elemental

analysis calcd. for C₄₂H₄₈Cl₂N₁₀Pd₂(976.66): C 51.56, H 4.95, N 14.34,

found: C 51.72, H 5.07, N 14.19%. ¹³C{¹H} solid-state NMR (126 MHz): δ

169 (C-5), 166 (C-4), 163 (C-2), 161 (C-1), 143 (C-11), 137 (C-10), 134

(C-8), 133 (C-9), 126 (C-7), 118 (C-6), 114 (C-3), 47 (C-14b), 46 (C-14a),

30 (C-15b), 29 (C-15a), 27 (C-16b), 26 (C-16a), 21 (C-13), 19 (C-12).

4-Benzyloxy-2-dimethylaminopyrimidine (3a). 24 mL (165 mmol) of a

solution of dimethylamine in water (40%) were added to a solution of 5.84

g (27 mmol) of compound 2 in 25 mL of acetonitrile. The mixture was

heated for 90 min to 100 °C in an autoclave. Then the solvent was stripped

off and the residue was dissolved in diethylether. The organic solution was

washed with water (325 mL) and dried over MgSO₄. The solvent was

removed under vacuum yielding 5.50 g (91%) of 3a as a yellow oil. Ele-

mental analysis calcd. for C₁₃H₁₅N₃O (229.28): C 68.10, H 6.59, N 18.33,

found: C 67.91, H 6.51, N 18.37%. ¹H NMR (CDCl₃, 400.1 MHz):  7.98 (d,

³J_HH= 5.6 Hz, 1 H, H-2), 7.34-7.16 (m, 5 H, H_Ph), 5.90 (d, ³J_HH= 5.6 Hz, 1

H, H-3), 5.27 (s, 2 H, H-5), 3.06 (s, 6 H, H-6). ¹³C{¹H} NMR (CDCl₃, 100.6

MHz):  169.0 (C-4), 162.2 (C-2), 158.0 (C-1), 137.1 (C_Ph), 128.4 (C_Ph),

128.0 (C_Ph), 95.8 (C-3), 67.3 (C-5), 36.9 (C-6).

General procedure for the addition of pyridines to 10. Compound 10

was suspended in an excess of 3-chloro- resp. 2-methylpyridine and

heated to reflux for 5 min. The excess of pyridine was removed under

vacuum and the resulting solid was dissolved in CH₂Cl₂. Precipitation with

diethylether resulted in analytically pure samples in almost quantitative

yields. For analytical data refer to the Supporting Information.

General procedure for the hydrogenative deprotection of 3a-d. 38

mmol of compounds 3a-d were suspended under an atmosphere of N₂in

40 mL of methanol. 202 mg (0.19 mmol) of Pd/C (10 wght.-%) were added

and the mixture was stirred at r.t. under a pressure of 3 bar of H₂for 16 h.

After filtration over Celite®, the solvent was removed and the products

were recrystallized from ethylacetate, giving 4a-d as colorless solids in

yields of 95-99%. For analytical data refer to the Supporting Information.

Dichlorido[3-(2-(diethylamino)pyrimidin-4-yl-5-ido)-1-mesityl-1H-im-

idazolylidene](pyridine)palladium(II) (11b). 180 mg (1 mmol) of PdCl₂,

700 mg (5 mmol) of K₂CO₃, 3.5 mL of pyridine and 1.1 mmol of 6b were

stirred at 80 °C for 12 h. After cooling to r.t., the mixture was diluted with

10 mL of CH₂Cl₂and filtered over Celite^®. The solvent was removed under

vacuum and the raw product was purified by preparative HPLC (n-

hexane/ethyl acetate = 1/2). Yield after removal of the solvents under

vacuum: 127 mg (33%) of a yellow solid. Elemental analysis calcd. for

C₂₅H₃₀PdCl₂N₆(591.87): C 50.73, H 5.11, N 14.20, found: C 51.03, H 5.31,

N 13.95%. ¹H NMR (CD₂Cl₂, 400.1 MHz):  9.14 (d, ³J_HH= 5.3 Hz, 1 H, H-

2), 8.75-8.69 (m, 2 H, H-16), 8.59 (d, ³J_HH= 5.3 Hz, 1 H, H-3), 8.10 (d, ³J_HH

= 2.2 Hz, 1 H, H-6), 7.78-7.70 (m, 1 H, H-18), 7.32-7.23 (m, 2 H, H-17),7.08

(s, 2 H, H-10), 7.04 (d, ³J_HH= 2.2 Hz, 1 H, H-7), 3.71 (q, ³J_HH= 7.0 Hz, 4

H, H-14), 2.39 (s, 3 H, H-13), 2.29 (s, 6 H, H-12), 1.25 (t, ³J_HH= 7.1 Hz, 6

H, H-15). ¹³C{¹H} NMR (CD₂Cl₂, 100.6 MHz):  161.4 (C-5), 160.4 (C-2),

158.0 (C-1), 154.2 (C-4), 151.9 (C-16), 140.1 (C-8), 138.6 (C-18), 136.9

(C-9), 135.8 (C-11), 129.7 (C-10), 124.9 (C-17), 124.9 (C-6), 121.6 (C-7),

102.2 (C-3), 42.7 (C-14), 21.5 (C-13), 19.4 (C-12), 13.4 (C-15).

General procedure for the chlorinating deoxygenation of compounds

4a-d. 40 mmol of compounds 4a-d and 160 mmol POCl₃were heated to

80 °C for 16 h. After cooling to r.t. the volume of the mixture was reduced

to 40 mL under vacuum and the residual liquid was added drop-wise to 50

mL of crushed ice. Under continuous stirring, the mixture was neutralized

by addition of conc. NH₃, whereby the temperature was kept below 25 °C

by addition of ice. The resulting suspension was extracted with CH₂Cl₂

(425 mL), the combined organic solutions were washed with conc. K₂CO₃

and dried over MgSO₄. After removing the solvent under vacuum, the 4-

chloro-2-dialkylaminopyrimidines 5a-d were obtained in yields of 80-95%

as pale beige solids. For analytical data refer to the Supporting Information.

General procedure for the synthesis of the imidazolium chlorides 6a-

d. 16 mmol of compound 5a-b and 19 mmol of 1-mesityl-1H-imidazol were

dissolved in 15 m of 1,2-dichlorobenzene and heated to reflux for 6 h. After

cooling to r.t., the precipitated product was filtered off and washed with

ethylacetate. Recrystallization from water/EtOH (1:2) gave the products

6a-d as colorless solids in yields > 90%. For analytical data refer to the

Supporting Information.

General procedure for the palladium ctalyzed Suzuki-Miyaura cross-

coupling reactions: All catalyses were carried out in 20 mL glass vials

(VWR) equipped with a crimp-cap septum. The boronic acid, the catalyst

and the base were weighed out into the vial. The same was done with solid

chloroarene substrates. A small magnetic stirring bar was added and the

vial was closed with the crimp-cap septum. Then the vial was set under

vacuum for 10 min and flushed with dinitrogen. This procedure was repea-

ted three times. Liquid chloroarenes were added at this point into the vial

via a syringe. Then the solvent was added. The vial was put into a pre-

heated heating block and the mixture was stirred at the given temperature

for the requested reaction time. The reaction was quenched by addition of

3 mL of a saturated aqueous NH₄Cl solution. 3 mL of ethyl acetate were

General procedure for the synthesis of the NHC silver(I) complexes

7a-d. 1 mmol of the imidazolium salts 6a-d and 0.56 mmol of Ag₂O were

suspended in 10 mL of dry CH₂Cl₂and stirred at r.t. for 2 d. The mixture

was filtered over Celite^®to remove unreacted Ag₂O and half of the solvent

was removed under vacuum. Addition of 30 mL of n-pentane results in

precipitation of the products. 7a-d were obtained in yields of 65-75% as

colorless solids. For analytical data refer to the Supporting Information.

10.1002/chem.201702877

Chemistry - A European Journal

FULL PAPER

added and the mixture was stirred in the air for 3 min. 0.5 mL of the organic

phase were removed filtered over a small pad of MgSO₄and silica, which

was then rinsed with 1 mL of ethylacetate. 1 µl of tetradecane were added

as the internal standard to determine the yields (GC). For the determin-

ation of the response factors of the substrates and the products, four differ-

rent concentrations were measured by GC. Products of several experi-

ments with identical substrates were sampled, purified by preparative

HPLC and characterized by NMR spectroscopy.

1557018-1557024 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 .

Acknowledgements

This work was supported by the German research foundation

DFG within the transregional collaborative research center

SFB/TRR 88 “Cooperative effects in homo and heterometallic

complexes” (3MET) and by the state research center OPTIMAS.

A. F. thanks the Cusanuswerk for supporting her PhD thesis with

a grant.

X-ray structure analyses: Crystal data and refinement parameters for

compounds 2,7a, 9a-b, 9d, 9d-Me and 11b are collected in Table 7. The

structures were solved using direct methods (SIR92 ³³), completed by

subsequent difference Fourier syntheses, and refined by full-matrix least-

squares procedures.³⁴For compounds 2, 9b, 9d, 9d-Me and 11b, semi-

empirical absorption corrections from equivalents (Multiscan) were carried

out, while analytical numeric absorption corrections were applied on com-

plexes 7a and 9a.³⁵All non-hydrogen atoms were refined with anisotropic

displacement parameters. In the structure of complex 9b, one H₂O mole-

cule was co-crystallzied with one unit of the target main structure. The

hydrogen atoms (H1A and H1B) attached to the oxygen atom O1, were

located in the difference Fourier synthesis, and were refined semi-freely

with the help of a distance restraint, while constraining their U-values to

1.2 times the U(eq) value of O1. All the other hydrogen atoms were placed

in calculated positions and refined by using a riding model. CCDC

Keywords: N-heterocyclic carbene • aminopyrimidine •

palladium • cyclometallation • Suzuki-Miyaura cross-coupling

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Entry for the Table of Contents (Please choose one layout)

Layout 1:

FULL PAPER

C,C- vs. C,N-coordination! Two

different modes of coordinating an

aminopyrimidine to the palladium site

of C-C coupling catalysts give rise for

largely different reactivities.

Agnes Fizia, Maximilian Gaffga,

Johannes Lang, Yu Sun, Gereon

Niedner-Schatteburg and Werner R.

Thiel*

Page No. – Page No.

Cyclopalladation in the Periphery of a

NHC Ligand as the Crucial Step in the

Synthesis of Highly Active Suzuki-

Miyaura Cross-Coupling Catalysts

10.1002/chem.201702877

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Table 7. Crystal data and refinement parameters for compounds 2,7a, 9a-b, 9d, 9d-Me and 11b.

2

7a

9a

9b

9d

9d-Me

11b

empirical formula

C₁₁H₉ClN₂O

220.65

C₁₈H₂₁AgClN₅

450.72

C₂₃H₂₅ClN₆Pd

527.34

C₂₅H₃₁ClN₆OPd

573.41

0.29x0.19x0.15

150(2)

C₂₆H₂₉ClN₆Pd

567.40

C₂₇H₃₁ClN₆Pd

581.43

C₂₅H₃₀Cl₂N₆Pd

591.85

formula weight

crystal size [mm]

0.42x0.17x0.16

150(2)

0.440x0.266x0.219

150(2)

0.587x0.337x0.261

150(2)

0.30x0.10x0.10

150(2)

0.25x0.24x0.20

150(2)

0.366x0.167x0.102

150(2)

T [K]

 [Å]

1.54184

orthorhombic

P2₁2₁2₁

7.2001(1)

11.4437(2)

12.2989(2)

90

1.54184

orthorhombic

Pbca

0.71073

triclinic

1.54184

trigonal

P-3

1.54184

monoclinic

P2₁/n

0.71073

monoclinic

P2₁/c

0.71073

orthorhombic

Pbca

crystal system

space group

a [Å]

P-1

17.2758(1)

11.3341(1)

18.5708(1)

90

7.8679(2)

15.9968(8)

18.2935(10)

91.549(4)

91.419(3)

96.300(3)

2286.81(8)

4

23.4266(2)

7.9990(1)

90

7.9949(1)

17.8480(3)

17.8907(4)

90

7.7833(1)

23.2637(3)

14.3953(2)

90

15.3871(5)

9.7162(5)

33.7676(11)

90

b [Å]

c [Å]

[°]

[°]

90

101.203(2)

90

99.601(1)

90

[°]

90

120

90

V [Å³]

Z

1013.38(3)

4

3636.27(4)

8

3801.76(9)

6

2504.23(8)

4

2570.02(6)

4

5048.4(3)

8



_calcd.[g cm^-3]

1.446

1.647

1.532

1.503

1.505

1.503

1.557

 [mm^-1]

-range [^o]

refl. coll.

3.112

10.326

0.951

7.110

7.161

0.854

0.973

5.28-62.59

6885

4.762-62.722

24974

2.805-32.420

25136

3.77-62.70

28047

3.53-62.80

10364

2.79-32.41

32093

2.752-32.424

21233

indep. refl.

1617

2903

25136

4067

4016

8593

8314

[R_int= 0.0189]

[R_int= 0.0275]

[R_int= 0.0355]

[R_int= 0.0237]

[R_int= 0.0205]

[R_int= 0.0335]

[R_int= 0.0444]

data/restr./param.

1617/0/137

2903/0/231

25136/0/560

4067/2/318

4016/0/310

8593/0/331

8314/0/312

final

R

indices

0.0212, 0.0562

0.0219, 0.0554

0.0533, 0.1276

0.0210, 0.0548

0.0222, 0.0589

0.0438, 0.0892

0.0503, 0.0887

[I>2(I)] ^a

R indices (all data)

GooF ^b

0.0214, 0.0563

1.161

0.0223, 0.0557

0.0595, 0.1311

0.0216, 0.0551

0.0230, 0.0594

0.0492, 0.0908

0.0751, 0.0966

1.076

1.176

1.063

1.028

1.310

1.112

Flack parameter

0.579(13)

-

Δρ_max

/

_min(e∙Å^-3)

0.117/-0.175

0.415/-0.752

1.979/-3.034

0.489/-0.324

0.418/-0.331

0.651/-1.342

0.819/-1.722

2 1/2

^aR1 = ||F_o| - |F_c||/|F_o|, R2 = [(F_o²- F_c²)²/F_o

] . .

^bGooF = [(F_o²- F_c²)²/(n-p)]^1/2

Article Doi

Cyclopalladation in the Periphery of a NHC Ligand as the Crucial Step in the Synthesis of Highly Active Suzuki–Miyaura Cross-Coupling Catalysts

DOI: 10.1002/chem.201702877

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Article abstract of DOI:10.1002/chem.201702877

Full text of DOI:10.1002/chem.201702877

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