Synthesis of C2-symmetric benzimidazolium salts and their application in palladium-catalyzed enantioselective intramolecular α-arylation of amides

Article abstract of DOI:10.3390/molecules21060742

A series of C₂-symmetric chiral benzimidazolium salts, the precursor of N-heterocyclic carbene ligands, were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding carbenes were tested in the asymmetric palladium-catal

Full text of DOI:10.3390/molecules21060742

molecules
Communication
Synthesis of C2-Symmetric Benzimidazolium Salts
and Their Application in Palladium-Catalyzed
Enantioselective Intramolecular α-Arylation
of Amides
Weiping He 1,3, Wei Zhao 1, Bihui Zhou 1,3, Haifeng Liu 1, Xiangrong Li 1, Linlin Li 1, Jie Li 1,
*
and Jianyou Shi 2,
*
1
School of Medicine, Zhejiang University City College, No. 48, Huzhou Road, Hangzhou 310015, China;
wphe2016@163.com (W.H.); zhaowei@zucc.edu.cn (W.Z.); 18868816170@163.com (B.Z.);
maplewandering@126.com (H.L.); lixr@zucc.edu.cn (X.L.); lill@zucc.edu.cn (L.L.)
Individualized Medication Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science &
Sichuan Provincial People’s Hospital, School of Medicine, Center for Information in Medicine,
University of Electronic Science and Technology of China, Chengdu 610072, China
2
3
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
*
Correspondence: lijie@zucc.edu.cn (J.L.); shijianyoude@126.com (J.S.); Tel.:+86-571-8801-6565 (J.L.)
Academic Editors: Diego A. Alonso and Isidro M. Pastor
Received: 14 April 2016; Accepted: 1 June 2016; Published: 8 June 2016
Abstract: A series of C2-symmetric chiral benzimidazolium salts, the precursor of N-heterocyclic carbene
ligands, were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding
carbenes were tested in the asymmetric palladium-catalyzed intramolecular α-arylation of amides,
affording chiral diarylmethanols with high yields and moderate enantioselectivities.
Keywords: N-heterocyclic carbene; benzimidazolium; Pd-catalyzed; asymmetric intramolecular
α-arylation
1. Introduction
Oxindoles (=1,3-dihydro-2H-indol-2-ones) bearing a quaternary stereogenic center at the C (3)
position represent a prominent structural motif in many natural products and biologically active
compounds [1–6], and the development of synthetic methods for these compounds is of great
importance in organic chemistry. Consequently, asymmetric transition metal-catalyzed reactions
that provide access to enantiomerically enriched 3-alkyl-3-aryl oxindoles were established over the
past decade: Overman’s elegant intramolecular Heck reactions [
7–9], Trost’s Pd- or Mo-mediated
allylic alkylations [10 12], and the Pd-catalyzed intramolecular -arylation of amides, which are the
–
α
focus of the present study.
Pioneered by Hartwig and co-workers, the intramolecular α-arylation of amides provides efficient
and direct access to chiral 3,3-disubstituted oxindoles. Bulky chiral N-heterocyclic carbene (NHC)
ligands worked best for the asymmetric transformation (up to 70% ee) [13]. This study was followed
by those of the groups of Glorius and Aoyama, but only moderate ee values were obtained [14
A significant improvement in this Pd-catalyzed asymmetric reaction was achieved by Kündig and
co-workers [17 21]. Since then, this chemistry has been expanded further and several other chiral
–16].
–
carbene ligands have been reported to give the desired product in excellent enantioselectivities
(Scheme 1). Dorta and co-workers reported new NHC ligands with chiral N-heterocycle and naphthyl
side chains and their successful application in a Pd-catalyzed asymmetric reaction. A series of
3-alkyl-3-aryl [22], 3-allyl-3-aryl [23], and 3-flouro-3-aryl [24] oxindoles were synthesized. Additionally,
conformationally restricted chiral ligands developed by Glorius [25] and Murakami [26] also showed
Molecules 2016, 21, 742; doi:10.3390/molecules21060742
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high asymmetric induction in this reaction. Despite the successes in this field, new efficient chiral NHC
ligands for this reaction are still needed. In this paper, we would like to report our investigation on the
enantioselective intramolecular α-arylation of amide with the new chiral carbene ligands incorporating
the benzimidazole skeleton (Scheme 1).
Scheme 1. Representative ligands in Pd-catalyzed asymmetric intramolecular arylation of amides.
2. Results
The synthesis of the benzimidazolium salt 3a as an N-heterocyclic carbene precursor is
representatively shown in Scheme 2. Buchwald-Hartwig coupling of 1,2-dibromobenzene with
(S)-α-methylbenzylamine gave the disubstituted product 1a in 80% yield. Next, treatment of diamine
with HCl in CH(OEt)3 gave the benzimidazolium salt 2a in 85% yield. The hygroscopic chloride salt
2a which became gel on exposure to the atmosphere was difficult to handle on the benchtop, but
this problem was solved by anion metathesis with NaI to give 3a. Other benzimidazolium salts 3b
–d
were prepared in the same manner. All of the benzimidazolium salts 3a were purified and fully
–
d
characterized by NMR and mass spectrometry. Furthermore, this method works equally well for
milligram and multigram quantities.
Scheme 2. Representative synthesis of benzimidazolium salt.
With the new chiral benzimidazolium salts in hand, we turned our attention to their application
in the Pd-catalyzed asymmetric intramolecular arylation of amides. Ligand precursors 3a
–d were
tested in the intramolecular -arylation of 4a following Hartwig’s in situ method (Table 1) [13]. Among
α

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the benzimidazolium salts screened, 3c possessing a cyclohexyl group as the R substituent gave better
asymmetric induction (40% ee, entry 3). With 3c as an N-heterocyclic carbene ligand precursor, the
use of other solvents such as 1,4-dioxane, toluene and THF gave less satisfactory results (entries 5–7).
Other bases such as KOtBu, LiOtBu, KOH, and LiOH gave no better results than NaOtBu (entries 8–11).
Different palladium sources were also investigated with 3c, and [Pd(allyl)Cl]2 emerged as the best
choice of catalyst precursor (entry 14). Upon lowering the reaction temperature to rt, almost no reaction
˝
occurred; however, a 41% conversion and 48% ee were observed at 50 C (Table 1, entries 16, 17).
Table 1. Chiral carbene ligands in the Pd-catalyzed intramolecular cylization of amide 4a to oxindole 5a
.
Entry a Ligand
[Pd]
T (˝C)
Solvent
Base
ee (%) c
Yield (%) b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3b
3c
3d
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
PdCl2
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
50
rt
DME
DME
DME
DME
dioxane
toluene
THF
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
51
63
98
95
98
98
96
72
´
14
9
40
9
25
17
30
25
´
LiOtBu
KOH
99
´
38
´
LiOH
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
99
96
99
54
41
trace
37
40
46
29
48
´
[Pd(allyl)Cl]2
Pd[P(C6H5)3]4
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Reaction condition: [Pd] (5 mol %), ligand (5 mol %), base (1.5 equiv), 12 h; b Isolated yields; c Determined by
a
chiral HPLC (CHIRALCEL OD Column) analysis.
In the next step, different 2-bromoanilides were applied in the reaction with salt 3c as a catalyst
precursor. As shown in Figure 1, various substrates worked well with 3c to give oxindoles in moderate
to good yields (28%–99%), and the best ee value was up to 50%.
Figure 1. The asymmetric reaction products.

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3. Experimental Section
3.1. General
MS spectra were measured on a Finnigan LCQDECA XP instrument and a Agilent Q-TOF 1290
LC/6224 MS system; 1H- and 13C-NMR spectra were obtained on Bruker AVANCE III 500 MHz and
600 MHz spectrometers (Bruker Co., Faellanden, Switzerland) with TMS as the internal standard;
silica gel GF254 and H (10–40 mm, Qingdao Marine Chemical Factory, Qingdao, China) were used for
TLC and CC. Unless otherwise noted, all reactions were carried out under an atmosphere of argon
or nitrogen.
3.2. Procedure for the Synthesis of Compounds 1a–d
Pd2(dba)3 (73.3 mg, 0.08 mmol) and ( )-BINAP (99.6 mg, 0.16 mmol) were dissolved in mesitylene
˘
˝
(10 mL) and the solution degassed for 15 min before being heated at 150 C for 10 min (solution
turns from deep purple to dark orange). Upon cooling sodium tert-butoxide (769 mg, 8.0 mmol),
(S)-α-methylbenzylamine (1212 mg, 10.0 mmol) and 1,2-dibromobenzene (472 mg, 2.0 mmol) were
added and the reaction mixture was heated to 150 ˝C for 16 h. The solution was allowed to cool and
filtered through a pad of celite. Solvents were removed under reduced pressure and the crude material
was purified by column chromatography eluting with light petroleum/ethyl acetate (50/1). Red oil
(430 mg, 68%); 1H-NMR spectra of 1a was identical to those reported in the literature [27].
Analogous compounds 1b
–
d
were prepared according to the similar procedure for 1a
: 8.31–7.39 (m, 14H), 6.41 (m, 4H), 5.35 (q, J = 6.4 Hz, 2H), 1.74 (t,
: 6.84–6.48 (m, 4H), 3.41–3.20 (m, 2H),
: 7.31 (m, 10H), 6.51 (m, 4H), 4.25 (t,
. 1b: 82%
yield; 1H-NMR (500 MHz, CDCl3)
δ
J = 9.2 Hz, 6H). 1c: 85% yield; 1H-NMR (500 MHz, CDCl3)
1.90–0.98 (m, 28H). 1d: 84% yield; 1H-NMR (500 MHz, CDCl3)
δ
δ
J = 6.5 Hz, 2H), 2.01–1.77 (m, 4H), 1.01 (t, J = 7.4 Hz, 6H).
3.3. Procedure for the Synthesis of Benzimidazolium Salts 3a–d
1a (411 mg, 1.3 mmol) was dissolved in 50 mL triethylorthoformate, then concentrated
hydrochloric acid (37% w/w, 7.8 mmol, 656 L of solution) was added at room temperature and
µ
the mixture was stirred for 30 min. Then the mixture was heated to 80 ˝C under air atmosphere for
12 h. After cooling to room temperature, ether (30 mL) was added. The precipitate was collected by
filtration. The collected solids were dissolved in MeOH (10 mL) stirred with 5 equiv NaI at room
temperature for 12 h. The collected solution was concentrated and the residue was allowed to react
with NaI again. After evaporation of volatiles, the residue was purified by column chromatography
(CH2Cl2/MeOH = 15/1) to give 3a (454 mg, 77%). The 1H-NMR and HRESIMS spectra of 3a were
similar to those reported in the literature [27].
Analogous compounds 3b
–
d
were prepared according to the similar procedure for 3a, HR-ESIMS,
20
1H- and 13C-NMR data see Supplementary Materials. 3b: 80% yield; rαsD = +157.8 (c 0.2, CH2Cl2);
1H-NMR (500 MHz, CDCl3)
δ: 11.47 (s, 1H), 8.16–7.25 (m, 18H), 7.08 (q, J = 6.9 Hz, 2H), 2.51 (d,
J = 6.9 Hz, 6H); 13C-NMR (125 MHz, CDCl3)
δ: 141.13, 134.02, 132.47, 130.19, 129.52, 127.65, 126.95,
126.38, 125.48, 124.82, 121.76, 114.36, 77.29, 76.78, 56.13, 21.09; HR-ESIMS: m/z 427.2294 [M
´
I]+ (calcd
: 11.23
20
for C31H27N2, 427.2169). 3c: 83% yield; rαsD = +0.5 (c 0.2, CH2Cl2); 1H-NMR (500 MHz, CDCl3)
δ
(s, 1H), 7.71 (m, 4H), 4.91–4.81 (m, 2H), 2.51–1.75 (m, 14H), 1.47–0.77 (m, 14H); 13C-NMR (125 MHz,
CDCl3)
HR-ESIMS: m/z 339.3016 [M
CH2Cl2); H-NMR (500 MHz, CDCl3)
2.88–2.74 (m, 4H), 1.07 (t, J = 7.3 Hz, 6H); 13C-NMR (125 MHz, CDCl3)
δ: 136.21, 131.05, 129.45, 129.27,
127.40, 127.08, 114.41, 77.29, 76.78, 65.16, 27.11, 11.04; HR-ESIMS: m/z 355.2381 [M
C25H27N2, 355.2169).
δ
: 141.29, 131.06, 126.91, 114.33, 77.30, 76.79, 61.42, 42.47, 29.69, 29.45, 25.66, 25.55, 25.49, 18.32;
20
´
I]+ (calcd for C23H35N2, 339.2795). 3d: 81% yield; rαsD
=
´
19.5 (c 0.2,
1
δ
: 11.82 (s, 1H), 7.66–7.32 (m, 14H), 6.03 (t, J = 7.9 Hz, 2H),
´
I]+ (calcd for

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3.4. Representative Procedure for the Pd-Catalyzed Intramolecular α-Arylation of Amides
Pd2(dba)3 (4.6 mg, 0.005 mmol), chiral benzimidazolium iodide 3c (carbene ligand precursor)
(4.7 mg, 0.01 mmol) and sodium tert-butoxide (29 mg, 0.3 mmol) were placed under N2 in a dry Schlenk
tube. Dimethoxyethane (DME) (0.05 M in substrate, freshly distilled over Na) was added and the
mixture was stirred for 5 min. The 2-bromo-N-alkylanilide (0.2 mmol) was then added as a solution in
DME (equal volume as above). The reaction was stirred at room temperature for 12 h. The reaction
was treated with aq. NH4Cl (2 mL) and extracted with ether (3
were washed with water (3 mL) and brine (3 mL), and dried over Na2SO4. Flash chromatography
ˆ
2 mL). The combined organic phases
afforded the product oxindoles. The enantiomeric purity of products 5a–m was determined by chiral
HPLC Analysis.
5a: 99% yield, 46% ee; The spectral data were comparable to those reported [17]. The ee
was determined by HPLC analysis with Daicel Chiralcel OD-H (hexane/i-PrOH = 99/1, flow
rate = 1.0 mL/min, tr (major) = 12.7 min, tr (minor) = 15.4 min); 5b: 66% yield, 44% ee; The
spectral data were comparable to those reported [17]. The ee was determined by HPLC analysis
with Daicel Chiralcel OD-H (hexane/i-PrOH = 99/1, flow rate = 1.0 mL/min, tr (major) = 14.5 min,
tr (minor) = 16.4 min); 5c: 58% yield, 24% ee; The spectral data were comparable to those reported [25].
The ee was determined by HPLC analysis with Daicel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (minor) = 13.7 min, tr (major) = 16.2 min); 5d: 99% yield, 27% ee; The
spectral data were comparable to those reported [21]. The ee was determined by HPLC analysis
with Daicel Chiralcel OD-H (hexane/i-PrOH = 99/1, flow rate = 1.0 mL/min, tr (minor) = 11.3 min,
tr (major) = 14.2 min); 5e: 85% yield 28% ee; The spectral data were comparable to those reported [15].
The ee was determined by HPLC analysis with Daicel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (minor) = 12.6 min, tr (major) = 15.7 min); 5f: 82% yield, 28% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 98/2,
flow rate = 1.0 mL/min, tr (minor) = 15.4 min, tr (major) = 20.2 min); 5g: 32% yield, 26% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (major) = 10.6 min, tr (minor) = 12.2 min); 5h: 81% yield, 42% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (major) = 10.7 min, tr (minor) = 12.1 min); 5i: 72% yield, 33% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (minor) = 11.3 min, tr (major) = 12.2 min); 5j: 35% yield, 34% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (major) = 11.9 min, tr (minor) = 15.3 min); 5k: 28% yield, 26% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (minor) = 11.3 min, tr (major) = 12.7 min); 5l: 68% yield, 50% ee;
The ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1,
flow rate = 1.0 mL/min, tr (major) = 11.6 min, tr (minor) = 13.6 min); 5m: 35% yield, 28% ee; The
ee was determined by HPLC analysis with Daciel Chiralcel OD-H (hexane/i-PrOH = 99/1, flow
rate = 1.0 mL/min, tr (minor) = 11.9 min, tr (major) = 13.2 min).
4. Conclusions
In conclusion, four chiral C2-symmetric benzimidazolium salts 3a–d have been prepared.
Their applicability in the Pd-catalyzed asymmetric intramolecular arylation of amides has been
demonstrated, and the corresponding oxindoles were obtained with high yields and moderate
enantiomeric excesses (up to 50%). Further application to other catalytic asymmetric reactions is
now in progress.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
6/742/s1.

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Acknowledgments: We are grateful to the National Natural Science Foundation of China (81302668) and
Hangzhou Science and Technology Information Institute of China (20150633B45).
Author Contributions: Jie Li and Jianyou Shi were the principle investigators of the project, designed the
experiments, and wrote the manuscript. Weiping He, Bihui Zhou, and Haifeng Liu performed the entire
experiments. Wei Zhao, Xiangrong Li, and Linlin Li interpreted the results and helped write the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3a–d are available from the authors.
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