An efficient class of bis-NHC salts: Applications in Pd-catalyzed reactions under mild reaction conditions

Article abstract of DOI:10.1039/c8ra04094j

This study describes an efficient class of bis-N-heterocyclic carbene (bis-NHC) salts that can be easily made from commercially available and inexpensive starting materials. The application of these salts to Pd-catalyzed reactions is described. The palladium (Pd) catalyst generated in situ was highly effective under mild reaction conditions.

Full text of DOI:10.1039/c8ra04094j

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An efficient class of bis-NHC salts: applications in
Pd-catalyzed reactions under mild reaction
conditions†
Cite this: RSC Adv., 2018, 8, 26407
*
Chien-Cheng Chiu, Hui-Tzu Chiu, Dong-Sheng Lee
and Ta-Jung Lu
Received 14th May 2018
Accepted 26th June 2018
This study describes an efficient class of bis-N-heterocyclic carbene (bis-NHC) salts that can be easily made
from commercially available and inexpensive starting materials. The application of these salts to Pd-
catalyzed reactions is described. The palladium (Pd) catalyst generated in situ was highly effective under
mild reaction conditions.
DOI: 10.1039/c8ra04094j
rsc.li/rsc-advances
calculation.4e They revealed that the introduction of an electron-
donating groups at the para position in the aryl substitution on
Introduction
imidazolium salts reduced the reaction barrier of the rate-
determining step. To retain the advantage of an effective skel-
eton and further increase the electronic properties of bis-NHC,
we used 1-(4-methoxyphenyl)benzimidazole as the main scaf-
fold. This skeleton allows a high-potential modication through
straightforward synthetic methods. In addition, the linker
between the benzimidazole rings provides the exibility to the
bis-NHC–Pd complexes. Herein, we report the preparation of
bis-benzimidazolium salts and the effects of different catalytic
treatments in Pd-catalyzed coupling reactions.
Palladium-catalyzed carbon–carbon bond formation is one of
the most versatile and useful tools for the synthesis of phar-
maceutical compounds, advanced materials, and agricultural
products.1 In the past decade, N-heterocyclic carbenes (NHCs)
and their palladium complexes have demonstrated a high
catalytic efficiency.2 In particular, bis-NHC-derived palladium
complexes possess two strong metal–carbene bonds that are
more stable than the corresponding complexes of similar
monodentate carbene ligands. In addition, bis-NHC-derived
palladium complexes offer many advantages, such as a supe-
rior control over the coordination sphere and tunable proper-
ties including their chirality. Recently, several bidentate bis-
NHC–Pd complexes have been synthesized and efficient activity
has been obtained in Pd-catalyzed reactions.3–5 However, Pd-
catalyzed reactions are oen carried out at a high reaction
temperature in the presence of the bis-NHC–Pd catalytic
system. Not only is the use of low boiling point compounds
limited, but also the compounds are easily decomposed under
a high temperature. It is very important to develop an efficient
catalyst that allows the reaction to be carried out under mild
reaction conditions.
Results and discussion
Synthesis of bis-NHC salts
The ligand syntheses started with the coupling of benzimid-
azole and 4-iodoanisole in the presence of copper(I) iodide (CuI)
and 8-hydroxyquinalidine to form the desired product 2 with
a quantitative yield.7 The bis-benzimidazolium salts 1 were
obtained with an 89–96% yield through heating 2 with various
ꢀ
dibromides in N,N-dimethylformamide (DMF) at 80 C for 6 h
and then 130 ꢀC for 16 h in Scheme 1. To prevent the quick
formation of a precipitate, DMF was used as the solvent and
a two-stage heating system was needed in the preparation of the
bis-benzimidazolium salts 1.
Our group previously developed a series of bis-NHC salts that
demonstrated good-to-excellent catalytic activity in Pd-catalyzed
Suzuki–Miyaura coupling reactions of aryl bromides (Fig. 1).6
Generally, because it increases the electron-richness of bis-
NHC, the bis-NHC–Pd catalytic system has a high activity in
the oxidative addition step. In 2014, Strassner et al. discussed
the mechanistic cycles of a Mizoroki–Heck reaction catalyzed by
Catalyst testing for the Suzuki–Miyaura reaction
Biaryls formed via Suzuki–Miyaura cross-coupling are crucial
scaffolds for pharmaceutical and natural products, advanced
materials, and agrochemicals. The Suzuki–Miyaura cross-
coupling reaction is also one of the most crucial methods for
testing the efficiency of the catalyst. A general test protocol for
the coupling reaction was developed by using the 4-bromoani-
sole 3a and phenylboronic acid 4a in a model study (Table 1).
Initially, the reactions were performed using Pd(OAc)2, salts 1,
bis-NHC–Pd using
a
density functional theory (DFT)
Department of Chemistry, National Chung-Hsing University, Taichung, 402, Taiwan.
E-mail: dslee@mail.nchu.edu.tw; Fax: +886-4-22862547
† Electronic supplementary information (ESI) available. CCDC 1551115 and
1536791. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8ra04094j
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Fig. 1 Structure of bis-benzimidazolium salts 1.
and K3PO4$H2O in 1,4-dioxane at 60 ꢀC for 24 h (entries 1–3). 1c temperature with a 1 : 1 Pd/1c ratio (entry 6). The reactions
was the optimal choice (entry 3), but a low conversion (40%) failed when acetonitrile or tetrahydrofuran (THF) were used as
yield was obtained. Using our previous report,6 the conversion solvents (entries 7 and 8). The reaction could be completed in
yield was increased aer modifying the reaction conditions the presence of tert-butanol (t-BuOH) (entry 9). Then, different
using a two-stage temperature process. Under the two-stage bases were sꢀcreened under a standard two-stage heating
ꢀ
temperature conditions, the Pd/ligand ratio was varied condition (60 C for 1 h followed by 30 C for 24 h) (entries 10
because low conversions may be attributed to catalytically and 11) which using t-BuOH as the solvent. Although both
inactive bis-ligated species generated from an excess quantity of K2CO3 and K3PO4$H2O showed excellent conversion yields
ligands.8 The results revealed an excellent conversion (91%) and (entries 9 and 10), K3PO4$H2O was selected for further studies
yield (86%) for the coupling reaction conducted at room according to our previous works.6,9 Further studies
Scheme 1 The synthesis of bis-benzimidazolium salts 1.
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Table 1 Optimization of the reaction conditions for Suzuki–Miyaura coupling catalyzed by 1/Pd
Pd(OAc)2
(mol%)
Entry
Ligand (mol%)
Conditiona
Base
Solvent
Conv.b
Yield (%)c
1
2
3
4
5
6
7
8
1a (3.0)
1b (3.0)
1c (3.0)
1c (3.0)
1c (2.0)
1c (1.0)
1c (1.0)
1c (1.0)
1c (1.0)
1c (1.0)
1c (1.0)
1c (0.5)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
A
A
A
B
B
B
B
B
B
B
B
B
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K3PO4$H2O
K2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
MeCN
0
—
—
—
—
—
86
—
—
99
99
—
99
22
40
19
54
91
<1
4
>99
>99
16
>99
THF
9
t-BuOH
t-BuOH
t-BuOH
t-BuOH
10
11
12
t-BuOK
K3PO4$H2O
a
Condition A: 3a (1.0 mmol), 4a (1.5 mmol), Pd(OAc)2 (1.0 mol%), bis-NHC 1 (as indicated), K3PO4$H2O (3.0 mmol) and 1,4-dioxane (3.0 mL) were
stirred under N2 for 24 h at the indicated temperature. Condition B: Pd(OAc)2 (1.0 mol%), bis-NHC 1 (as indicated), K3PO4$H2O (3.0 eq. to Pd), and
1,4-dioxane (3.0 mL) were stirred under N2 at 60 ꢀC for 1 h, followed by 3a (1.0 mmol), 4a (1.5 mmol), and K3PO4$H2O (3.0 mmol) at 30 ꢀC for 24 h.
b
Determined by 400 MHz NMR. c Isolated yield.
demonstrated that the reaction could be completed even when system was compatible with a wide range of functional groups,
only 0.5 mol% of Pd/1c was employed (entry 12), which was then including methoxy, nitro, ketone, aldehyde and ester. Difficult
used as our standard reaction condition for the substrate scope Pd-catalyzed di-ortho-substituted biaryl syntheses were also
exploration.
achieved in the presence of Pd(OAc)2/1c with a particularly high
A wide range of aryl bromides were tested for the cross- chemoselectivity at room temperature.
coupling reaction in the presence of the Pd(OAc)2/1c
(0.5 mol%) catalyst at room temperature. The results are
summarized in Table 2. The coupling reaction of substrates
with electron-donating or electron-withdrawing groups on the
meta- or para-position of aryl bromide 3 provided excellent
yields (entries 1–13), whereas the mono-ortho-substituted biar-
yls resulted in moderate-to-excellent yields (entries 14–16).
Sterically hindered di-ortho-substituted products were also ob-
tained in good-to-excellent yields (entries 17–20). Both the 1ꢀ
and 3ꢀ amino groups remained intact aer transformation, with
99% and 70% yields, respectively (entries 21 and 22). The
catalytic system demonstrates high chemoselectivity at room
temperature because that no Buchwald–Hartwig amination
product was observed. The substrate scope could be further
extended to benzyl halides with favorable yields (entries 23 and
24). The corresponding aryl bromides with naphthylboronic
acid could generate various coupling products with excellent
yields (entries 25–31). Furthermore, we demonstrated the high
efficiency of this catalytic system. 4-Bromoanisole 3a could be
coupled with phenylboronic acid 4a with an 87% yield with Pd
loadings down to 0.005 mol% (entry 2). 40-Bromoacetophenone
3d was a possible substrate, generating the corresponding
coupling product with a 99% yield with Pd loadings down to
0.0005 mol% at room temperature (entry 7). The catalytic
Catalyst testing for the Mizoroki–Heck reaction
The Mizoroki–Heck reaction is a useful method to prepare
alkylated olens involving an sp2 carbon. In general, it is carried
out in polar solvents such as N-methyl-2-pyrrolidone (NMP),
N,N-dimethylacetamide (DMA) or N,N-dimethylformamide
(DMF), in the presence of a base at a high temperature (100–150
ꢀC). A more effective catalytic system for the Mizoroki–Heck
reaction under milder conditions is needed to tolerate the
coupling of low-boiling olens with aryl halides. First, we
studied the use of the bis-NHC–Pd catalytic system generated in
situ from Pd(OAc)2 and bis-NHC 1c with a 1 : 1 ratio for the
Mizoroki–Heck reaction of 4-bromoacetophenone 3d with
methyl acrylate 6a with K3PO4$H2O as a base and DMF as the
solvent at 60 ꢀC. However, only a 4% conversion yield was
achieved. Next, we increased the conversion yield to 75% by
replacing Pd(OAc)2 with Pd(dba)2 (entry 1). The reaction was
ꢀ
carried out at 60 C in a variety of bases and solvents and the
experimental results are summarized in Table 3. Using other
bases such as triethylamine (Et3N), K2CO3, KOtBu and KF in the
presence of the solvents, toluene, dioxane, acetonitrile or t-
BuOH resulted in low conversion yields. When CsF in DMF was
employed, the conversion yield of 7da was improved to 99%
(entry 6).
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Table 2 The coupling reaction of aryl bromides with arylboronic acids catalyzed by 1c/Pda
Entry
3 (R])
4
Conv.b
Yield (%)c
1
4-OMe (3a)
4-OMe (3a)
4-OMe (3a)
4-t-Bu (3b)
4-CO2Me (3c)
4-COMe (3d)
4-COMe (3d)
4-COMe (3d)
4-COEt (3e)
4-COEt (3e)
4-COEt (3e)
3-COEt (3f)
4-CHO (3g)
2-CHO (3h)
2,4-DiNO2 (3i)
2-Me (3j)
2,6-DiMe (3k)
1-Bromo-2-methylnaphthalene (3l)
1-Bromo-2-methoxynaphthalene (3m)
1-Bromo-2,3-dimethoxynaphthalene (3n)
4-NH2 (3o)
2-N,N-DiMe (3p)
2-Methylbenzyl (3q)
4-Methlylbenzyl (3r)
4-OMe (3a)
4-t-Bu (3b)
4-CO2Me (3c)
4-COMe (3d)
4-COEt (3e)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
>99
>99
19
>99
>99
>99
>99
10
>99
>99
81
>99
>99
>99
>99
>99
98
>99
>99
>99
>99
86
>99
>99
>99
>99
>99
>99
>99
>99
>99
5aa (99)
5aa (87)
5aa (–)
5ba (99)
5ca (98)
5da (99)
5da (99)
5da (–)
2d
3e
4
5
6
7e
8f
9
5ea (99)
5ea (85)
5ea (72)
5fa (99)
5ga (99)
5ha (84)
5ia (99)
5ja (70)
5ka (85)
5la (99)
5ma (99)
5na (99)
5oa (99)
5pa (70)
5qa (89)
5ra (77)
5ab (99)
5bb (96)
5cb (97)
5db (95)
5eb (99)
5 (96)
5ob (99)
10d
11e
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3-COEt (3f)
4-NH2 (3o)
a
Reaction conditions: Pd(OAc)2 (0.5 mol%), bis-NHC 1c (0.5 mol%), K3PO4$H2O (3.0 mol%) and t-BuOH (3.0 mL) were stirred under N2 at 60 ꢀC for
b
c
1 h, followed by 3 (1.0 mmol), 4 (1.5 mmol), and K3PO4$H2O (3.0 mmol) at 30 ꢀC for 24 h. Determined by 400 MHz NMR. Isolated yield.
d
f
Pd(OAc)2/1c (0.005 mol%) was used. e Pd(OAc)2/1c (0.0005 mol%) was used. Pd(OAc)2/1c (0.00005 mol%) was used.
Aer optimizing the reaction conditions, the substrate scope substituent. Aryl iodides with electron-donating groups, such
of the Mizoroki–Heck reaction was extended to a variety of as methoxy group 3a0, reacted with methyl acrylate 6a or acry-
substituted aryl bromides/iodides and substituted olens lonitrile 6f to form the desired products with a 98% or 71%
(Table 4). Aryl bromides with electron-withdrawing groups, yield, respectively (entries 10 and 12). Iodobenzene 3t was
such as ketones and aldehydes, reacted with styrene to provide coupled with olens including methyl acrylate 6a, acrylonitrile
the corresponding products at high yields at 60 ꢀC (entries 2 and 6f, and styrene 6b with yields between 72% and 96% (entries 9,
3). 4-Bromobenzaldehyde 3g can be coupled with 3-nitrostyrene 11 and 13). Indeed, the bis-NHC–Pd catalytic system exhibited
6c or methyl acrylate 6a with 96% and 98% yields (entries 4 and a high catalytic reactivity under mild conditions that present the
5), respectively. Even a moderate yield (61%) was achieved by successful application to low boiling-point acrylonitrile and aryl
treating 4-bromobenzaldehyde 3g and deactivating 2-vinyl- halides.
naphthelene 6d (entry 6). Moderate yields were achieved by
treating 4-bromobenzaldehyde 3g or ethyl 4-bromobenzoate 3s
with electron-donating groups on the olen moiety 3a (entries 7
and 8). The bis-NHC–Pd catalytic system exhibited less reactivity
Catalyst testing for the Friedel–Cras reaction
The Friedel–Cras alkylation reaction of indoles with nitro-
alkenes is one of the most crucial methods for preparing
tryptamine and its derivatives. There are very few reports on
toward aryl bromides with
a strong electron-donating
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Table 3 Optimizing the reaction conditions for Mizoroki–Heck reaction catalyzed by 1c/Pda
Entry
Base
Solvent
Conv.b
Entry
Base
Solvent
Conv.b
1
2
3
4
5
K3PO4$H2O
K2CO3
KOtBu
KF
DMF
DMF
DMF
DMF
DMF
75
7
8
6
18
6
7
8
9
CsF
CsF
CsF
CsF
CsF
DMF
99
6
9
5
14
Toluene
Dioxane
tBuOH
CH3CN
Et3N
10
a
Reaction condition: 3d (1.0 mmol), 6a (1.5 mmol), Pd(dba)2 (1.0 mol%), bis-NHC 1c (1.0 mol%), base (3.0 mmol) and solvent (5.0 mL) were stirred
under N2 for 24 h at 60 ꢀC. b Conversion was determined by 400 MHz NMR.
Table 4 Mizoroki–Heck reactions with different substituents catalyzed by 1c/Pda
Entry
X
R1
R2
Yield (%)b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
I
I
I
I
I
4-COMe
4-COEt
4-CHO
4-CHO
4-CHO
4-CHO
4-CHO
4-CO2Et
H
4-MeO
H
4-MeO
H
CO2Me
C6H5
C6H5
7da (94)
7eb (93)
7gb (96)
7gc (96)
7ga (98)
7gd (61)
7ge (67)
7se (66)
7ta (96)
7aa (98)
7tf (78)
7af (71)
7tb (72)
3-NO2-C6H4
CO2Me
2-Naphthyl
4-MeO-C6H4
4-MeO-C6H4
CO2Me
CO2Me
CN
9
10
11
12
13
CN
C6H5
a
Reaction condition: 2 (1.0 mmol), 3 (1.5 mmol), Pd(dba)2 (1.0 mol%), bis-NHC 1c (1.0 mol%), CsF (3.0 mmol) and DMF (5.0 mL) were stirred under
N2 for 24 h at 60 ꢀC. b Isolated yield.
Friedel–Cras alkylation catalyzed by bis-NHC–Pd. In fact, the for the Friedel–Cras alkylation reaction catalyzed by bis-NHC–
Pd(II) complex can catalyze a Friedel–Cras reaction as a Lewis Pd.
acid.10 In 2008, Shi et al. have reported the synthesis of a bis-
In general, the acid-catalyzed conjugate addition of indoles
NHC–Pd complex derived from binaphthyl-2,20-diamine as well requires careful control of the acidity to prevent polymeriza-
as its application for the Friedel–Cras alkylation reaction of tion.12 In 2011, Stephens et al. reported that sodium methoxide
indole with nitrostyrene.11 The Friedel–Cras reaction was (NaOMe) led to the polymerization of the nitrostyrene.13 In fact,
performed in the presence of 5 mol% bis-NHC–Pd complex and the use of a base was necessary for the in situ formation of the
5 equiv. of indole. Using low loadings of the bis-NHC–Pd bis-NHC–Pd complex from bis-NHC and Pd(OAc)2. To avoid
complex and reducing the equivalents of indole are challenging polymerization in basic conditions, the corresponding bis-
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Table 5 Screening optimized reaction condition for Friedel–Crafts alkylation reactiona
Pd/1c–Ag
complex ratio
Entry
Pd salt (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
Pd(OAc)2 (2.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
4/1
2/1
1/1
2/1
2/1
24
24
24
24
12
66
61
78
96
83
a
Reaction conditions: nitrostyrene 8a (0.5 mmol), indole 9a (1.5 mmol), Pd salt (as indicated), 1c–Ag complex (as indicated), and isopropanol (3.0
mL) are stirred for 24 h at 30 ꢀC under N2. b Isolated yield.
NHC–Ag complex was employed as a carbene transfer agent to
A wide range of substituted nitrostyrene compounds were
form the bis-NHC–Pd complex. The Friedel–Cras alkylation coupled with indole derivatives and examined in the presence of
reactions were tested in isopropyl alcohol (IPA) by the reaction 2.0 mol% of the Pd(OAc)2/1c–Ag catalyst in IPA at room
of indole (3.0 equiv.) with nitrostyrene at 30 ꢀC (Table 5). When temperature and the results are summarized in Table 6. The
varying the Pd(OAc)2/1c–Ag complex ratio from 4 : 1 to 1 : 1, we results revealed that both electron-donating groups (8b–8d) and
established that the ratio of 2 : 1 provided the optimal yield at electron-withdrawing groups (8e–8g) on the nitroalkenes can
96% (entry 4) (Fig. 2).
form the corresponding products with favorable yields (70–
ꢁ
Fig. 2 Solid-state molecular structure of 1c–Ag. Hydrogen atoms, PF6 and solvent molecules are omitted for clarity.
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Table 6 The Friedel–Crafts alkylation reaction of alkenes and indoles catalyzed by 1c–Ag/Pda
8
9
Entry
R1
R2
R3
Yield (%)b
1
2
3
4
5
6
7
8
C6H5 (8a)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10aa (96)
10ba (86)
10ca (70)
10da (81)
10ea (80)
10fa (71)
10ga (70)
10ha (87)
10ia (90)
10bb (95)
10eb (94)
10jb (85)
10kb (98)
10hb (92)
10lb (91)
10mb (93)
10ab (90)
10ac (56)
10ad (61)
10ae (90)
10af (92)
2-MeC6H4 (8b)
3-MeC6H4 (8c)
4-MeC6H4 (8d)
2-ClC6H4 (8e)
3-ClC6H4 (8f)
4-ClC6H4 (8g)
2-Thiophen (8h)
1-Naphthyl (8i)
2-MeC6H4 (8b)
2-ClC6H4 (8e)
4-MeOC6H4 (8j)
2-Naphthyl (8k)
2-Thiophen (8h)
2-MeNC4H3 (8l)
C6H5CHCH (8m)
C6H5 (8a)
9
H
10
11
12
13
14
15
16
17
18c
19
20
21
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
2-Me
1-Me
2-Me
2-Me
2-Me
H
H
6-F
5-Cl
5-Me
C6H5 (8a)
C6H5 (8a)
C6H5 (8a)
C6H5 (8a)
a
Reaction condition: Pd(OAc)2 (2.0 mol%), 1c–Ag (1.0 mol%), 8 (0.5 mmol), 9 (1.5 mmol), and IPA (3.0 mL) were stirred under N2 at 30 ꢀC for 24 h.
b
Isolated yield. c The reaction was conducted at 80 ꢀC for 24 h.
86%) (entries 2–7). In addition, the catalytic system performed present at the 5-position and a methyl group is attached on the
well with thiophene and naphthalene as substituents on the 2-position of the indole, produced a 90% yield (entry 20).
nitroalkenes with 87% and 90% yields, respectively (entries 8 Electron-donating groups at the 2- and 5-positions of the indole
and 9). The alkylation reaction using 2-methylindole 9b with also increase its nucleophilicity, which led to a 92% of yield
nitroalkenes was also studied. Our experimental results aer transformation (entry 21) (Fig. 3).
demonstrated that when 9b was employed in the catalytic
system, the yields were superior to those with 9a (entries 10–17).
The electron-donating group on the C2 position of the indole
Conclusion
increased the nucleophilicity of the indole. The yield using
substrates with substituents in the ortho position were
increased from 86% to 95% (entry 2 vs. entry 10) and from 80%
to 94% (entry 5 vs. entry 11), respectively. Heterocyclic systems,
and the Friedel–Cras alkylation reaction. This was true
such as thiophene and N-methylpyrrole, could also be used in
the catalytic system with 92% and 91% yields, respectively
(entries 14 and 15). Conjugated nitroalkene 8m could still
undergo the 1,4-addition instead of the 1,6-addition with a high
regioselectivity and a 93% yield (entry 16). The reactivity of
indole with substituents on the nitrogen decreased drastically.
A 56% yield was obtained at 80 ꢀC for 24 h (entry 18). A uorine
atom on the 6-position of indole decreased its nucleophilicity
and only provided a 61% yield for the Friedel–Cras alkylation
product (entry 19). Compound 9e, where a chlorine atom is
In summary, the bis-NHC–Pd catalytic system exhibited a wide
range of applications for the Pd-catalyzed reactions, such as the
Suzuki–Miyaura reaction, the Mizoroki–Heck coupling reaction,
whether it was generated from bis-NHC and Pd(OAc)2 in situ at
60 ꢀC or using 1c–Ag with Pd(OAc)2 via transmetallation at
ꢀ
30 C. The catalytic activity of the bis-NHC–Pd catalytic system
underwent successful coupling reaction with high activities at
1.0 mol% catalyst loading. The catalytic system exhibited a high
selectivity between Suzuki–Miyaura cross-coupling and Buch-
wald–Hartwig amination reactions at room temperature. The
aryl–vinyl coupling reaction of low boiling-point acrylonitrile
with aryl halides was possible under mild conditions. The
catalytic system could form the corresponding adducts with
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Fig. 3 Solid-state molecular structure of 1c–Pd. Hydrogen atoms, PF6ꢁ and solvent molecules are omitted for clarity.
favorable yields whether highly steric, electron-donating, or
electron-withdrawing groups were attached on the nitroalkene.
Moreover, the Friedel–Cras adducts with indoles bearing
different substituents were obtained, which overcome the
issues encountered when the reaction is catalyzed by Lewis
acids at ambient temperature.
Typical reaction procedure
General procedures for Suzuki–Miyaura coupling reaction.
All manipulations were carried out under nitrogen using dried
solvent. The mixture of Pd(OAc)2 (0.5 mol%), 1c (0.5 mol%),
K3PO4$H2O (1.5 mol%) and t-BuOH (3.0 mL) were stirred under
ꢀ
N2 at 60 C for 1 h, followed by addition of aryl halide 3 (1.0
mmol), arylboronic acid 4a or 4b (1.5 mmol), and ꢀK3PO4$H2O
(3.0 mmol). The reaction mixture was stirred at 30 C for 24 h.
Aer completion of the reaction, monitored by TLC, the reac-
tion was quenched by water (3.0 mL). The aqueous layer was
extracted with EtOAc (3.0 mL ꢂ 3). The combined organic layers
were dried over anhydrous MgSO4 and then ltered. The solvent
was evaporated under reduced pressure and the corresponding
crude product of the Suzuki–Miyaura coupling reaction was
puried by chromatography.
General procedures for Mizoroki–Heck coupling reaction. All
manipulations were carried out under nitrogen using dried
solvent. Olen 6 (1.50 mmol), aryl halide 3 (1.00 mmol), CsF
(2.00 mmol), bis-NHC 1c (1.0 mol%) and Pd(dba)2 (1.0 mol%)
were charged to the Schlenk tube. Further dry DMF (5.0 mL) was
added. The mixture was stirred at 60 ꢀC for 24 h. Aer
completion of the reaction, monitored by TLC, the reaction was
quenched by water (5.0 mL). The aqueous layer was extracted
with EtOAc (5.0 mL ꢂ 3). The combined organic layers were
dried over anhydrous MgSO4 and then ltered. The solvent was
evaporated under reduced pressure and the corresponding
crude product of the Mizoroki–Heck coupling reaction was
puried by chromatography.
Experimental section
Materials and methods
Reactions were analyzed using pre-coated silica gel 60 (F-254)
plates (0.2 mm layer thickness). All products were puried by
column chromatography (silica gel, 0.040–0.063 mm) using n-
hexane/ethyl acetate as the eluent. Melting points were deter-
mined using a Mel-Temp 1001D (Barnstead/Thermo) digital
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on a Varian Mercury 400 spectrometer in
a solution CDCl3 with chemical shis (d) given in ppm relative
to TMS. J-values are given in Hz. Chloroform (d ¼ 7.26) was used
as internal standard in the 1H NMR spectra. The central peak of
CDCl3 (d ¼ 77.0) was used as internal standard in the 13C NMR
spectra. High resolution mass spectra were recorded using
a Finnigan/Thermo Quest MAT 95XL mass spectrometer. Mass
spectra were obtained using either electron impact (EI) or
electrospray ionization (ESI) method. The further details for
catalysts synthesis and characterization can be found in the
ESI.†
26414 | RSC Adv., 2018, 8, 26407–26415
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General procedures for Friedel–Cras alkylation reaction. All
RSC Advances
4 For selected samples for bis-NHC–Pd catalyzed Mizoroki–
¨
Heck coupling reaction, see: (a) S. Demir, I. Ozdemir and
manipulations were carried out under nitrogen using HPLC
grade isopropanol. Indole 9 (1.50 mmol), nitroalkene 8 (0.50
mmol), 1c–Ag (0.50 mol%), and Pd(OAc)2 (1.0 mol%) were
charged to the Schlenk tube. Isopropanol (3.0 mL) was added.
The mixture was stirred at 30 ꢀC for 24 h. Aer completion of the
reaction, monitored by TLC, the reaction was quenched by
water (3.0 mL). The aqueous layer was extracted with EtOAc
(3.0 mL ꢂ 3). The combined organic layers were dried over
anhydrous MgSO4 and then ltered. The solvent was evaporated
under reduced pressure and the corresponding crude product
of the FriedelꢁCras alkylation reaction was puried by
chromatography.
B. Cetinkaya, Appl. Organomet. Chem., 2009, 23, 520–523;
(b) J. D. Blakemore, M. J. Chalkley, J. H. Farnaby,
L. M. Guard, N. Hazari, C. D. Incarvito, E. D. Luzik, Jr. and
H. W. Suh, Organometallics, 2011, 30, 1818–1829; (c)
D. S. Clyne, J. Jin, E. Genest, J. C. Gallucci and
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H. M. Lee, C. Y. Lu, C. Y. Chen, W. L. Chen, H. C. Lin,
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5825; (e) C. Allolio and T. Strassner, J. Org. Chem., 2014, 79,
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5 For selected samples for bis-NHC–Pd catalyzed reaction, see:
(a) J. M. Asensio, P. Gomez-Sal, R. Andres and E. de Jesus,
Dalton Trans., 2017, 46, 6785–6797; (b) Y. J. Cho, Y. N. Lim,
W. Yoon, H. Yun and H. Y. Jang, Eur. J. Org. Chem., 2017,
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M. F. Ward and W. T. A. Harrison, Tetrahedron Lett., 2004,
45, 5703–5706; (e) M. C. Perry, X. Cui and K. Burgess,
Tetrahedron: Asymmetry, 2002, 13, 1969–1972; (f) C. Zhang
and M. L. Trudell, Tetrahedron, 2000, 41, 595–598; (g)
A. B. Mullick, M. S. Jeletic, A. R. Powers, I. Ghiviriga,
K. A. Abboud and A. S. Veige, Polyhedron, 2013, 52, 810–
819; (h) Z. Liu and M. Shi, Tetrahedron: Asymmetry, 2009,
20, 119–123.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the Ministry of Science and Technology of the
Republic of China (106WFA0550361) for nancial support.
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RSC Adv., 2018, 8, 26407–26415 | 26415