Synthesis of novel N-heterocyclic carbene-oxazoline palladium complexes and their applications in suzuki-miyaura cross-coupling reaction

Article abstract of DOI:10.1055/s-0033-1338848

A series of novel N-heterocyclic carbene-oxazoline ligands were synthesized in six steps. Palladium complexes were obtained by deprotonation of the benzimidazole salts and subsequent ligation with Pd(OAc)₂ in THF. Different types of cyclic bis- and tetrapalladium complexes were achieved by modifying substituent of oxazoline group. The structures of these palladium complexes were characterized by NMR and X-ray diffraction analysis. Catalytic properties of these Pd-complexes were tested by Suzuki-Miyaura cross-coupling reaction. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338848

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▌1255
cluster
Synthesis of Novel N-Heterocyclic Carbene-Oxazoline Palladium Complexes
and Their Applications in Suzuki–Miyaura Cross-Coupling Reaction
Synthesis of Novel Carbene-Oxazoline Palladium Complexes
Peng Gu,a Qin Xu,*a Min Shi*a,b
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China
University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: mshi@mail.sioc.ac.cn
Received: 18.04.2013; Accepted after revision: 02.05.2013
molecular square like [A]8+ (Figure 1), which was first
Abstract: A series of novel N-heterocyclic carbene-oxazoline li-
synthesized by Fujita et al.12 and subsequently studied by
gands were synthesized in six steps. Palladium complexes were ob-
Stang13 and others.14 NHCs as an important class of li-
tained by deprotonation of the benzimidazole salts and subsequent
ligation with Pd(OAc)2 in THF. Different types of cyclic bis- and
gands in organometallic chemistry have also been used in
tetrapalladium complexes were achieved by modifying substituent the field of supramolecular assembly.15 Typical NHC–
metal molecular squares like [B]8+ (Figure 1) has been ob-
of oxazoline group. The structures of these palladium complexes
were characterized by NMR and X-ray diffraction analysis. Catalyt-
tained by Hahn and co-workers in 2012,16 and the mole-
ic properties of these Pd-complexes were tested by Suzuki–Miyaura
cule was built up from four platinum corners by the
cross-coupling reaction.
ligation of four platinum atoms with the carbon atoms of
Key words: N-heterocyclic carbene, oxazoline, palladium com-
plex, Suzuki–Miyaura cross-coupling reaction
two classical bis(diaminocarbene) and two di(NH, O-
NHC) ligands. According to the related literature, the use
of NHCs as building blocks in metal-directed supramolec-
ular chemistry has only been explored recently.15 Most of
N-Heterocyclic carbenes (NHCs) and their transition met-
supramolecules were built by linear bidentate ligand and
al complexes have rapidly been explored since the first
selected metal within at least two steps. Herein we wish to
synthesis of an isolable carbene species by Arduengo et al.
report an effective way to selectively synthesize tetranu-
in 1991.1 N-Heterocyclic carbene ligands have quite dif-
clear or binuclear supramolecular complexes of nonlinear
ferent properties with general phosphine ligands by stron-
NHC-oxazoline ligand with Pd(OAc)2 in only one step.
Catalytic activities of these Pd catalysts were tested by
Suzuki–Miyaura cross-coupling reaction.
ger σ-donor but weaker π-acceptor abilities.2 NHC ligands
can be easily used to complex with most of main group el-
ements and transition metals, such as Pd,3 Rh,4 Ru,5 Ir6
Initially, we attempted to synthesize the desired chiral
and Au.7 Especially, most of metal complexes ligated with
benzimidazole-oxazoline ligand 5, and the synthetic route
NHC ligands are air/moisture stable, which makes han-
is shown in Scheme 1.17 Methyl 3-aminobenzoate was
dling of these complexes become much more convenient.8
used as the starting material to react with 1-bromo-2-ni-
A range of very active catalysts ligated with NHC ligands
trobenzene in the presence of Pd(OAc)2/DPE-phos cata-
lytic system to give the Buchwald coupling product 1 in
96% yield. Subsequently compound 1 with Pd/C under H2
have been obtained. Examples for the use of NHC ligands
in modern synthesis are numerous, such as Grubbs NHC-
Ru complexes catalyzed metathesis,5a–c Nolan’s NHC-Pd
atmosphere (1 atm) was refluxed in methanol overnight to
and Organ’s PEPPSI NHC-Pd complexes catalyzed cou-
produce the desired compound 2 in 90% yield. Cycliza-
tion of compound 2 in the presence of triethyl orthofor-
mate and a catalytic amount of TsOH at 100 °C gave the
corresponding benzimidazole derivative 3 in 86% yield,
which was further treated with chiral amino alcohol in the
presence of Cs2CO3 in toluene to afford the corresponding
amide 4. Finally, cyclization of chiral amide 4 in the pres-
ence of thionyl chloride and MeONa gave the correspond-
pling reactions,9 NHC-Ir complexes catalyzed
hydrogenations6a and hydrosilylation reactions catalyzed
by Shi’s NHC-Rh complexes,4a,b indicating the remark-
able achievements with NHC ligated metal complexes.
Metallosupramolecular self-assembly has been a field of
intensive research since Lehn first demonstrated the spon-
taneous formation of a double helical complex from bi-
pyridine and Cu(I).10 Subsequently a large number of
ing desired chiral benzimidazole-oxazoline compound 5
in good yield.
metallosupramolecules have been obtained by self-assem-
bly.11 Among the early supramolecular assemblies were
Next, the reaction of aryl-substituted benzimidazole-oxa-
zoline compound 5 with methyl iodide in acetonitrile un-
SYNLETT 2013, 24, 1255–1259
Advanced online publication: 17.05.2013
DOI: 10.1055/s-0033-1338848; Art ID: ST-2013-R0358-C
© Georg Thieme Verlag Stuttgart · New York
der reflux afforded the corresponding benzimidazole salts
6a and 6b in excellent yields (Scheme 2), which could be
smoothly transformed to the corresponding NHC-oxazo-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1256
P. Gu et al.
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NH2
Pd N
H2N
N Pd
O
H2N
NH2
O
N
I
N
R2I
N
N
N
N
N
N
MeCN, reflux
1 d
R1
R1
R2
(R)-6a: R1 = Ph, R2 = Me
(R)-6b: R1 = Bn, R2 = Me
(R)-6e: R1 = Ph, R2 = i-Pr
(R)-5a: R1 = Ph
(R)-5b: R1 = Bn
N
N
R2
H2N
NH2
R1
Pd
N
N
Pd
O
I
N
NH2
H2N
[A]8+
Pd
I
N
N
P
P
N
N
N
N
O
Pt
Pt
P
P
R2
R1
N
N
Pd(OAc)2, KI
N
R1
R2
HN
O
O
O
O
NH
I Pd
I
THF, 60 °C
28 h
I
Pd I
N
N
N
O
HN
P
NH
P
I
N
N
N
N
N
Pd
N
Pt
P
Pt
P
N
R2
I
O
R1
[B]8+
(R)-7a: R1 = Ph, R2 = Me, 76%
(R)-7b: R1 = Bn, R2 = Me, complex
(R)-7e: R1 = Ph, R2 = i-Pr, 42%
Figure 1 Structure of molecular squares [A]8+ and [B]8+
line Pd(II) complexes 7a and 7b upon treating with
Pd(OAc)2 and KI in THF, respectively. The H NMR
Scheme 2 Synthesis of NHC-oxazoline tetra-Pd complexes 7a, 7b
and 7e
1
spectra of complex 7a indicated two methyl signals at δ =
3.46 ppm and 3.38 ppm and the ratio of the two methyl
signals was 1:1 along with two sets of alkyl group signals.
Unfortunately pure Pd complex 7b could not be obtained
by column chromatography or recrystallization, although
two sets of alkyl group signals as those of complex 7a (see
Supporting Information).
However, the accurate structures of these Pd complexes
could not be confirmed. Attempts to get single crystals of
complex 7a for X-ray diffraction were not successful be-
cause the single crystals of complex 7a obtained from the
1
its crude H NMR spectra also showed the characteristic
Cs2CO3, Pd2(dba)3
Br
HN
COOMe
DPE-phos
HN
COOMe
H2, Pd/C
+
NH2
NO2
toluene, 80 °C, 16 h
MeOH, 60 °C, 18 h
H2N
COOMe
NO2
2, 90%
1, 96%
R
R
*
*
OH
Cs2CO3
TsOH, HC(OEt)3
H2N
OH
NH
N
COOMe
N
100 °C, 12 h
toluene, 80 °C, 1 d
N
O
N
3, 86%
(R)-4a: R = Ph, 92%
(R)-4b: R = Bn, 90%
(S)-4c: R = i-Pr, 85%
(S)-4d: R = t-Bu, 88%
O
N
1) SOCl2, DCE
0–40 °C, 5 h
N
N
*
R
2) MeONa, MeOH
reflux, overnight
(R)-5a: R = Ph, 90%
(R)-5b: R = Bn, 75%
(S)-5c: R = i-Pr, 82%
(S)-5d: R = t-Bu, 85%
Scheme 1 Synthesis of chiral benzimidazole-oxazoline pre-ligands 5
Synlett 2013, 24, 1255–1259
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Novel Carbene-Oxazoline Palladium Complexes
1257
n-hexane–CH2Cl2 solvent system effloresced easily with- propyl- and tert-butyl-substituted pre-ligands 5c and 5d
in a few seconds after they were removed from mother li- were obtained with the same synthetic method as shown
quor. The collected diffraction data did not allow a in Scheme 1. Then their benzimidazole salts were ob-
completely anisotropic refinement of the model. But they tained smoothly and were used to complex with
turned out to be sufficient enough to solve the structure Pd(OAc)2, affording the corresponding NHC-oxazoline
which was obtained as a cyclic tetrapalladium molecule. Pd complexes 7c and 7d in good yields (Scheme 3).
Encouraged by the result, many solvent systems such as
Et2O, EtOAc, acetone, CHCl3, and acetonitrile were cho-
sen to stabilize the single crystals. Unfortunately, high-
O
O
N
I
N
quality single crystals suitable for the X-ray diffraction
could not be obtained. Next, we tried to change the N-sub-
stituent of benzimidazole from methyl group to isopropyl
group in order to increase the steric hindrance which
might improve the stability of the Pd complex. Then we
followed the previous synthetic route shown in Scheme 2
simply by exchanging methyl iodide with isopropyl io-
dide to smoothly prepare complex 7e as a yellow powder.
Its 1H NMR spectra showed the similar two sets of alkyl
group signals. Finally its stable single crystal was ob-
tained from the mixed solvent of n-hexane and chloro-
form. The structure of complex 7e has been confirmed by
X-ray diffraction. The ORTEP drawing is shown in Fig-
ure 2 and the CIF data are presented in the Supporting In-
formation. According to the crystal data, the complex 7e
is built up from four neutral palladium(II) corners that are
connected by bonds formed between palladium and the li-
gands end to end. The NHC ligand and another oxazoline
ligand are trans-chelated with Pd atom and the Pd com-
plex seems to be a distorted square molecule. The Pd com-
plexes of 7a and 7e, having S-configuration, could be also
obtained using (S)-5a as the starting materials. Their spec-
troscopic data are consistent with their enantiomers, sug-
gesting that the absolute configuration had no effect on
the coordination mode of these palladium complexes.
MeI
N
N
MeCN, reflux
1 d
N
N
R
R
(S)-6c: R = i-Pr
(S)-6d: R = t-Bu
(S)-5c: R = i-Pr
(S)-5d: R = t-Bu
O
N
Pd(OAc)2, KI
N
R
N
THF, 60 °C, 28 h
I
Pd
N
I
I
Pd I
R
N
N
(S)-7c: R = i-Pr, 56%
(S)-7d: R = t-Bu, 71%
O
Scheme 3 Synthesis of NHC-oxazoline bis-Pd complexes 7c and 7d
1
The H NMR spectra of complexes 7c and 7d only gave
one set of alkyl group signals, suggesting that the struc-
tures of complexes 7c and 7d are totally different from
that of Pd complex 7e. The structure of oxazoline-NHC
Pd complex 7d was confirmed by the X-ray diffraction.
Suitable single crystals were obtained from n-hexane–
CH2Cl2 solvent system. The ORTEP drawing is shown in
Figure 3. The complex 7d is built up from two neutral pal-
ladium(II) corners formed in same way as that in complex
7e. The NHC ligand and another oxazoline ligand are also
trans-chelated with palladium atom and the molecule is
twisted as a rectangle. The structure of complex 7d is
highly symmetrical and all the corresponding bond
lengths and angles are exactly the same; for example, the
bond lengths of Pd1–C1 and Pd1A–C1A are both
1
1.947(3) Å. The one set of alkyl group signals in the H
NMR spectra can be appropriately explained by its X-ray
crystal structure.
The catalytic activities of these NHC bis- or tetrapalladi-
um complexes were evaluated by Suzuki–Miyaura cross-
coupling reaction. Initially, we tested the Suzuki coupling
of phenyl bromide and 4-methoxyphenylboronic acid us-
ing palladium catalysts 7a, 7c, 7d and 7e under the stan-
dard reaction conditions [80 °C, isopropanol as solvent,
potassium tert-butoxide (1.5 equiv) as base].18 The corre-
sponding biaryl products were obtained in good yields
(Table 1, entries 1–4). Obviously phenyl-substituted cata-
lyst 7a showed the best catalytic activity with the isolated
yield of 86% (Table 1, entry 1). Next we chose Pd com-
plex 7a as the catalyst to test the influence of halogen sub-
stituent. Phenyl iodide showed excellent reactivity with
quantitative yield (Table 1, entry 6). The biaryl products
Figure 2 Molecular structure of complex 7e. Ellipsoids are shown at
30% probability. All hydrogen atoms and solvent molecular are omit-
ted for charity. Selected bond lengths [Å] and angles [°] for 7e are as
follows: Pd1–N1 2.053(7), Pd1–C91 1.960(9), Pd1–I1 2.6296(13),
N2–C16 1.381(10), C91–Pd1–N1 173.5(3)°, C91–Pd1–I2 88.3(3)°,
N1–Pd1–I1 91.3(3)°, C10–C11–C12 116.5(7)°.
Encouraged by this finding, we next started to investigate
the influence of the substituent on oxazoline ligand. Iso-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1255–1259

1258
P. Gu et al.
CLUSTER
responding palladium complexes were obtained from li-
gation of these ligands with Pd(OAc)2. Two different
types of cyclic bis- and tetrapalladium complexes were
obtained by changing the substituent of oxazoline from al-
kyl group to phenyl group. The examples of square Pd su-
pramolecular synthesis in one step are quite rare. In fact,
we have found another effective method for the synthesis
of metallosupramolecule by self-assembly. We assumed
that these phenomena may be due to the fact that the tet-
rapalladium complexes could be stabilized by the substi-
tuted aryl group in oxazoline moiety. Finally, the catalytic
activities of these palladium catalysts were tested by
Suzuki–Miyaura cross-coupling reaction. The palladium
complex 7a showed the best catalytic activity and the cor-
responding biaryl products were obtained in moderate to
excellent yields.
Figure 3 Molecular structure of complex 7d. Ellipsoids are shown
at 30% probability. All hydrogen atoms are omitted for charity. Se-
lected bond lengths [Å] and angles [°] for 7d are as follows: Pd1–C1
1.947(3), Pd1–N3A 2.127(2), Pd1–I1 2.5929(3), N1–C1 1.355(3),
N3–C15 1.267(3), C1–Pd1–N3A 173.87(11)°, C1–Pd1–I1 86.68(8)°,
N1–C1–N2 106.5(2)°, I1–Pd1–I2 174.365(9)°.
Acknowledgment
We thank the Shanghai Municipal Committee of Science and Tech-
nology (11JC1402600), the National Basic Research Program of
China [(973)-2010CB833302], the Fundamental Research Funds
for the Central Universities, and the National Natural Science Foun-
from bromo- and chlorobenzene were obtained in 90%
and 43% yields, respectively (Table 1, entries 5 and 7).
Nolan’s NHC-Pd catalysts have obtained excellent results
under mild conditions in the same coupling reaction.9a,b dation of China for financial support (21072206, 20472096,
20872162, 20672127, 21102166, 21121062 and 20732008).
We assumed that the coordinated iodine atom and the co-
ordination mode may cause lower catalytic activity in the
coupling reaction than those of Nolan’s catalysts, which
Supporting Information for this article is available online at
were also consistent with our previous work.3d Finally,
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
different types of substituent were tested under the stan-
dard conditions. The coupling product from 2-bromotolu-
ene and phenylboronic acid was achieved in 86% yield
(Table 1, entry 8), but the product from 2-fluorophenyl
bromide was obtained in 70% yield (Table 1, entry 9).19
References and Notes
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In conclusion, a series of novel NHC-oxazoline ligands on
phenyl scaffold were synthesized in six steps, and the cor-
Table 1 NHC-Pd(II) Complexes Catalyzed Suzuki–Miyaura Reaction
R2
R1
NHC-Pd (1 mol%), KOt-Bu
X
B(OH)2
+
i-PrOH, 80 °C, 16 h
R3
9
10
8
Entrya
Pd cat.
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Yield (%)b
1
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mL) were carried out at 80 °C for 16 h.
b Isolated yield.
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(19) General Procedure of the NHC-Pd Catalyzed Suzuki–
Miyaura Cross-Coupling Reaction: NHC-Pd (1.25 or 2.5
μmol, 1 mol% Pd), aryl halide (0.5 mmol, 1 equiv),
arylboronic aid (0.6 mmol, 1.2 equiv), potassium tert-
butoxide (0.75 mmol, 1.5 equiv) were added into a tube
under argon, and the solvent i-PrOH (2 mL) was added into
the tube via a syringe. The mixture was stirred for 16 h at 80
°C. After the reaction completed, H2O was added to the
mixture, and the aqueous phase was extracted with EtOAc (3
×). The combined organic solvent was dried over anhyd
Na2SO4 and removed in vacuo. The residue was purified by
flash column chromatography on silica gel column with
petroleum ether as an eluent to give the desired biaryl
products 8 in good to excellent yields.
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Synlett 2013, 24, 1255–1259

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