Synthesis of chiral benzene-based tetraoxazolines and their application in asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes

Article abstract of DOI:10.1016/j.catcom.2014.04.013

A series of new chiral benzene-based tetraoxazoline ligands were prepared in good yields through the reaction of 1,2,4,5-benzenetetracarboxylic acid and chiral β-amino alcohols by continuous removal of water, and the asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes was tested using the chiral catalysts, which were generated in situ by refluxing the above ligands and anhydrous zinc chloride in solvent. In most case, good yields (up to 99%) and excellent enantioselectivities (up to 98% ee) were obtained.

Full text of DOI:10.1016/j.catcom.2014.04.013

Synthesis of chiral benzene-based tetraoxazolines and their application in
asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes
Wei-Jie Li
PII:
DOI:
Reference:
S1566-7367(14)00159-9
doi: 10.1016/j.catcom.2014.04.013
CATCOM 3881
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
2 March 2014
4 April 2014
17 April 2014
Please cite this article as: Wei-Jie Li, Synthesis of chiral benzene-based tetraoxazolines
and their application in asymmetric Friedel-Crafts alkylation of indole derivatives with
nitroalkenes, Catalysis Communications (2014), doi: 10.1016/j.catcom.2014.04.013
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ACCEPTED MANUSCRIPT
Synthesis of chiral benzene-based tetraoxazolines and their application in asymmetric
Friedel-Crafts alkylation of indole derivatives with nitroalkenes
Wei-Jie Li a,*
a Department of Chemistry, Hanshan Normal University, Chaozhou 521041, P. R. China
* Corresponding author. Tel./fax: (+86)-754-88915674
E-mail: weijieli1688@126.com
ABSTRACT
A series of new chiral benzene-based tetraoxazoline ligands were prepared in good yields
through the reaction of 1,2,4,5-benzenetetracarboxylic acid and chiral -amino alcohols by
continuous removal of water, and the asymmetric Friedel-Crafts alkylation of indole
derivatives with nitroalkenes was tested using the chiral catalysts, which were generated in
situ by refluxing the above ligands and anhydrous zinc chloride in solvent. In most case, good
yields (up to 99%) and excellent enantioselectivities (up to 98% ee) were obtained.
Keywords:
Tetraoxazoline
Asymmetric catalysis
Friedel-Crafts alkylation

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Indole derivative
Nitroalkene
1. Introduction
Chiral oxazoline-based compounds are a class of privileged ligands and exist in a wide
variety of forms containing mono-, bis- or multi-oxazolines. Andreasch firstly synthesized
oxazoline-based compounds in 1884 [1], and until 1984, Brunner et al. introduced
oxazoline-based ligands into asymmetric catalytic reactions [2]. Since then, a number of
mono- and bis-oxazolines, derived from different linkages, backbones and amino alcohols,
have already been applied to different types of asymmetric reactions [3, 4]. Trisoxazolines
first emerged in 1993 [5]. Later, several types of trisoxazolines were developed and found
widespread utility in asymmetric catalysis [6-9] and molecular recognition [10, 11]. However,
in sharp contrast to the great success of mono-, bis- or tris-oxazolines, the development and
application of tetraoxazolines are still lacking. Zhang and coworkers have reported the
synthesis and applications of biphenyl-linked tetraoxazolines in asymmetric Wacker-type
cyclization [12, 13]. Our group have also tried to apply several tetraoxazolines, derived from
ethylenediaminetetraacetic acid or ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraac-
etic acid, to the asymmetric hydrosilylation of aromatic ketones, however, they gave low
enantioselectivities due to the flexible linkers of oxazoline rings [14]. Most recently, we have
introduced benzene as a rigid linker unit and have synthesized tetraoxazoline 1a (Fig. 1) [15].

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O
O
O
O
O
N
N
N
N
N
N
O
1a
2
O
O
R
R
R
R
N
N
N
N
O
O
1
1b: R=CH(CH3)2
1c: R=Bn
1d: R=CH3
Fig. 1. Structures of chiral oxazolines.
This improvement make its bivalent copper ion catalyst exhibit efficient catalytic activities
and high enantioselectivities in the same reaction. The ligand 1a has more tunable chiral
spaces than bisoxazoline 2 due to its four cavities, and it may selectively coordinate with
metal cations and increase the stability of active intermediates, so that the chiral catalyst
might be air- and water-tolerant. As an extension of my project, I design the benzene-based
tetraoxazolines 1b-d, as illustrated in Figure 1. Herein, I would like to report my recent
results on their synthesis and application in asymmetric Friedel-Crafts alkylation of indole
derivatives with nitroalkenes.
2. Experimental

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2.1 Materials and methods
1,2,4,5-Benzenetetracarboxylic acid, anhydrous zinc chloride, D-valinol, D-phenylalaninol
and (R)-2-amino-1-propanol were purchased from Alfa Aesar Co. 1,2,4,5-Tetra[(4'S)-isopro-
pyloxazolin-2'-yl]benzene (1a) and 1,3-bis[(4'S)-isopropyloxazolin-2'-yl]benzene (2) were
prepared according to the literatures’ approaches [15, 16]. Other reagents were of all
analytical grade. Melting points were measured on an X-6 precision melting point apparatus.
1
13
H and C NMR spectra were recorded on Bruker DRX-500, Bruker DRX-400, Bruker
DRX-300 or DRX-100 NMR spectrometers, using TMS as an internal standard；chemical
shift, multiplicity (s = single, d = doublet, t = triplet, m = multiplet) are given in parts per
million and are referenced to residual solvent peaks. Mass spectra were measured on a LCQ
DECA XP LC/MS system. Optical rotation values were recorded on a Polartronic HNQW 5
polarimeter. The enantiomeric excesses were carried out using chiral HPLC with a Daicel
Chiracel OD-H column on Waters with a 996 UV-detector.
2.2 General procedure for the synthesis of tetraoxazolines 1b-d
1,2,4,5-benzenetetracarboxylic acid (0.63 g, 2.5 mmol), chiral -amino alcohol (D-valinol,
D-phenylalaninol or (R)-2-amino-1-propanol) (10.0 mmol) and DMF (20 mL) were added to
a three-neck flask equipped with a water segregator, a reflux condenser and a magnetic
stirring bar. The mixture was refluxed with continuous removal of water for 10 h. After
cooling to room temperature, DMF was removed under reduced pressure and the residue was

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purified by silica gel column chromatography with trichloromethane as eluant to obtain the
pure 1b-d.
2.3 General procedure for asymmetric Friedel-Crafts reactions
The ligand 1 (0.01 mmol) and anhydrous zinc chloride (0.02 mmol) were added to a
three-neck flask under the protect of a nitrogen atmosphere, followed by addition of solvent
(5.0 mL). The mixture was refluxed for 0.5 h and cooled to room temperature, then
nitroalkene 4 (0.5 mmol) was added. The mixture was stirred for 10 min at the same
temperature and then cooled to -10 ℃. Indole derivative 3 (0.5 mmol) was added at -10 ℃.
After completion of the addition, the mixture was stirred at the same temperature until indole
derivative 3 had disappeared. The reaction solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography with petroleum ether-ethyl
acetate 4:1 to 2:1 (V/V) as eluant to obtain the desired product 5. The configuration of the
product was determined by optical rotation and the enantiomeric excess was determined by
HPLC analysis using a Daicel Chiracel OD-H column.
3. Results and discussion
Previously, we reported a facile and efficient synthesis of the tetraoxazoline 1a [15]. Here
the tetraoxazolines 1b-d could be prepared conveniently in good yields from

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1,2,4,5-benzenetetracarboxylic acid and the corresponding -amino alcohols using a similar
strategy for the preparation of tetraoxazoline 1a (Scheme 1) [15].
O
O
H2N
R
O
O
O
O
R
R
R
R
N
N
N
N
HO
HO
OH
OH
OH
DMF/Reflux
10 h, 90-93%
O
O
1
1b:R=CH(CH3)2
1c:R=Bn
1d:R=CH3
Scheme 1. Synthesis of chiral tetraoxazolines.
The development of efficient Friedel-Crafts alkylations of arenes and heteroarenes using
only catalytic amounts of a Lewis acid has gained much attention over the last decade [17-21].
Indole derivatives as heteroarenes represent a class of biologically active compounds [22-24],
and they often have chiral carbon chains attached to indole rings. The asymmetric
Friedel-Crafts alkylation to indoles is a versatile method for preparing such chiral indole
derivatives. Up to now, a number of Friedel-Crafts alkylations by either metal catalysts or
organocatalysts have been reported [25-30]. In particular, the metal catalysts with chiral
oxazoline-based ligands have been demonstrated to possess a high feasibility for preparing
chiral indole derivatives through asymmetric Friedel-Crafts alkylation reactions [31-35].
However, to date, most of these reactions were routinely conducted by the metal catalysts
with mono- or bisoxazoline ligands. Herein, I investigated the asymmetric Friedel-Crafts

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alkylation of indole derivatives with nitroalkenes using the zinc catalysts with tetraoxazolines
1a-d.
Table 1
Optimizations for enantioselective Friedel-Crafts alkylation of indole with -nitrostyrene.a
NO2
Ligand 1, ZnCl2
*
NO2
+
N
N
H
H
4a
5a
3a
Entry Ligand Loading
Solvent
Time Temp Yield ee
(h)
(%) c (%) d
Abs. config e
(mol%) b
(℃)
1
2
3
4
5
6
7
2.0
2.0
2.0
2.0
2.0
2.0
2.0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
14 -10
14 -10
14 -10
14 -10
14 -10
89
88
98
87
76
98
98
83
82
95
85
64
87
92
S
1a
1b
1c
1d
2
R
R
R
S
8
10
R
R
1c
1c
10 -5

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8
2.0
2.0
2.0
2.0
2.0
1.0
1.5
2.5
toluene
CH2Cl2
CHCl3
THF
22 -20
14 -10
14 -10
14 -10
14 -10
14 -10
14 -10
14 -10
91
90
89
82
92
74
90
99
96
80
77
74
90
83
88
96
R
S
1c
1c
1c
1c
1c
1c
1c
1c
9
10
11
12
13
14
15
R
R
R
R
R
R
benzene
toluene
toluene
toluene
a The catalyst was prepared in situ by refluxing ligand 1 and anhydrous zinc chloride in 5 mL
of solvent.
b Loading: catalyst/indole (molar ratio).
c
Conditons: indole (0.5 mmol), -nitrostyrene (0.5 mmol) and solvent (5.0 mL). The
reactions were carried out under the protect of a nitrogen atmosphere.
d Enantiomeric excesses were determined by HPLC using a Daicel Chiracel OD-H column.
e All absolute configurations were determined by optical rotation measurements.
With the desired tetraoxazolines 1a-d in hand, I first examined their catalytic reactivities in
the asymmetric Friedel-Crafts alkylation of indole 3a with -nitrostyrene 4a. The results are
presented in Table 1. Compared with the bisoxazoline 2/ZnCl2 complex, the catalytic activity

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and enantioselectivity of the ligand 1a/ZnCl2 complex were greatly increased (Table 1, entry
1 vs. entry 5). For the ligands 1a-d, their reactivities and enantioselectivities are sensitive to
the substituents on oxazoline ring. 1c with benzyl group on the 4-position of oxazoline ring
obtained good yield and enantioselectivity (Table 1, entry 3), while the yields and
enantioselectivities decreased dramatically with the bulkier isopropyl group and relatively
smaller methyl group (Table 1, entries 1, 2 and 4). Next, for ligand 1c, I investigated the
effect of temperature on the catalytic reaction. Longer reaction times were necessary and the
enantioselectivity increased when the reaction temperature was decreased (Table 1, entries 3
and 6-8). When the reaction was operated at -10 ℃, the enantioselectivity can be improved to
95% ee (Table 1, entry 3). As for solvent effects, the reaction gave a preference for toluene as
solvent (Table 1, entry 3 vs. entries 9-12). The use of aprotic solvents such as
dichloromethane, chloroform and tetrahydrofuran gave 5a in good yield with low
enantioselectivity (Table 1, entries 9-11). Catalyst concentrations have a significant effect on
both the yield and enantioselectivity. Increasing the catalyst loading not only obtained good
yield but also increased the enantioselectivity (Table 1, entries 3 and 13-15). Enhancing the
catalyst loading to 2.5 mol% to give 99% yield and 96% ee, but it showed no significant
improvement. The optimized loading of the catalyst employed at 2.0 mol%, relative to indole.
After the reaction conditions were optimized, this asymmetric catalytic reaction was
further explored using more indole derivatives and nitroalkenes (Table 2). A few indole
derivatives 3a-d bearing different substitutes were first examined in the reaction. An
electron-donating substitute such as methyl or methoxy in the 5-position of the indole ring
caused a slight increase in enantioselectivity (Table 2, entries 2-3 vs. entry 1), while lower

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yield and enantiomeric excess were obtained for electron-deficient 5-chloroindole (Table 2,
entry 4). Then the generality of this reaction was further evaluated by a variety of structurally
different nitroalkenes. The ortho-substitution on the phenyl in nitrostyrenes, either
electron-donating or electron-withdrawing groups decreased the enantiomeric excesses of
products, perhaps due to the steric effect of ortho-substitutes (Table 2, entries 5 and 6). Good
yields and high enantioselectivities could be achieved for the nitrostyrenes with both
electron-donating and electron-withdrawing groups on the meta or para positions of the
phenyl ring and the aliphatic-substituted nitroalkenes (Table 2, entries 7-10 and 12). The
nitroalkene containing furan gave 89% yield and 83% ee (Table 2, entry 11).
Table 2
Asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes.
R2
R1
R1
NO2
Ligand 1c, ZnCl2
NO2
R2
+
N
N
H
H
4a-i
5a-l
3a-d
Entry Product
R1
R2
Yield (%) a ee (%) b
1
2
H
Ph
Ph
98
96
95
97
5a
5b
Me

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3
MeO
Cl
H
Ph
Ph
95
89
98
82
78
75
96
94
90
95
83
92
5c
5d
5e
5f
4
5
2-MeOC6H4 98
6
H
2-ClC6H4
3-BrC6H4
85
87
7
H
5g
5h
5i
8
H
3-NO2C6H4 95
4-MeOC6H4 91
9
H
10
11
12
H
4-ClC6H4
2-furyl
94
89
91
5j
H
5k
5l
H
CH3(CH2)3
a Conditions: catalyst/indole derivative = 2.0 mol%, indole derivative (0.5 mmol), nitroalkene
(0.5 mmol), toluene (5.0 mL), -10 ℃, 14 h.
b
Enantiomeric excesses were determined by HPLC using a Daicel Chiracel OD-H column.
All absolute configurations were determined as R by optical rotation measurements.
In the asymmetric Friedel-Crafts alkylation of indole derivatives with nitroalkenes
catalyzed by the complexes of tetraoxazolines 1a-d with anhydrous zinc chloride, their
catalytic mechanisms are still not clear at this stage. As shown in Table 1, the absolute
configurations of the resulting products were in good agreement with those of the

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corresponding chiral -amino alcohols. This result indicates that the enantioselectivities may
be determined by the chirality of oxazoline rings derived from the chiral amino alcohols.
In conclusion, the novel chiral benzene-based tetraoxazolines 1b-d have been synthesized
in high yields from 1,2,4,5-benzenetetracarboxylic acid and chiral -amino alcohols. In most
cases, the catalytic system with the tetraoxazoline 1c and anhydrous zinc chloride gave good
yields (up to 99%) and high enantioselectivities (up to 98% ee) in the asymmetric
Friedel-Crafts alkylation of indole derivatives with nitroalkenes. Further applications in other
asymmetric catalytic reactions catalyzed by the new benzene-based tetraoxazolines are in
progress in my laboratory.
Acknowledgments
The author gratefully acknowledges the financial support of the National Natural Science
Foundation of China (81371612) and the Natural Science Foundation of Hanshan Normal
University (DQ20110616).
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Graphical abstract
R2
NO2
R1
R1
Ligand 1, ZnCl2
NO2
R
+
R2
N
N
O
O
H
H
R
up to 99% yield
N
N
N
N
up to 98% ee
R
R
O
O
1

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Highlights




A series of new chiral benzene-based tetraoxazoline ligands were prepared.
The catalytic system is composed of the synthesized tetraoxazoline and ZnCl2.
The catalytic system was tested in asymmetric Friedel-Crafts alkylations.
The catalytic system presented excellent activities and enantioselectivities.