Direct experimental evidence for the priority of flexible ligand skeleton in asymmetric friedel-crafts alkylation of indole with nitroalkenes

Article abstract of DOI:10.2174/157017810790796354

Direct experimental evidence for the priority of flexible ligand skeleton in asymmetric Friedel-Crafts alkylation was obtained through XRD analysis of flexible ligand/ZnCl₂ complex, as well as synthesis of dihydroacridine-linked bis(oxazoline) ligands with planar rigid scaffold. A transition state model without NH φ interaction was proposed for the rigid ligands to interpret the inversion of absolute configuration.

Full text of DOI:10.2174/157017810790796354

114
Letters in Organic Chemistry, 2010, 7, 114-120
Direct Experimental Evidence for the Priority of Flexible Ligand Skeleton
in Asymmetric Friedel-Crafts Alkylation of Indole with Nitroalkenes
Han Liua, Neng-Dong Wanga and Da-Ming Du*,a,b
aBeijing National Laboratory for Molecular Sciences (BNLMS), College of Chemistry and Molecular Engineering,
Peking University, Beijing 100871, P. R. China
bSchool of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, P. R. China
Received November 26, 2009: Revised December 18, 2009: Accepted December 23, 2009
Abstract: Direct experimental evidence for the priority of flexible ligand skeleton in asymmetric Friedel-Crafts alkylation
was obtained through XRD analysis of flexible ligand/ZnCl2 complex, as well as synthesis of dihydroacridine-linked
bis(oxazoline) ligands with planar rigid scaffold. A transition state model without NH…ꢀ interaction was proposed for
the rigid ligands to interpret the inversion of absolute configuration.
Keywords: Rigid scaffold, flexible scaffold, diphenylamine, dihydroacridine, bis(oxazoline), Friedel-Crafts alkylation.
INTRODUCTION
like to document our recent results on the priority of flexible
ligand scaffold in asymmetric Friedel-Crafts alkylation.
Since the pioneering reports on oxazolines [1], chiral
bis(oxazoline) ligands have been extensively developed by
chemists in the fields of coordination chemistry, synthetic
chemistry, and catalysis [2]. Large number of ligands with
diverse scaffolds have been synthesized from commercially
available amino alcohols and carboxylic acids/aldehydes
through facile procedures, which illustrates their great
potency in application. Some ligand scaffolds stand out from
vast reports and gain broad applications in different
asymmetric transformations [3], while most ligand scaffolds
give satisfying results only in specific cases. Such a situation
makes the design of novel ligands for designated reactions a
difficult and unprofitable work. In recent years, some groups
dedicated to the research on the relationship of ligand
structure and enantioselectivity, especially the tuning of
electronic effect and rigidity of ligand scaffold. Compared
with the encouraging results achieved in the former case [4],
much less attention has been paid on the tuning of rigidity
[5]. Herein, we would like to document our recent progress
on this subject.
N
N
H
H
O
N
N
O
O
N
N
O
Lit. 5b
R1
3a-d
Rigid/distorted scaffold
R2
R1
R2
R1
1a-d
Flexible scaffold
R1
R2
R2
This work
Me
Me
N
H
Diphenylamine-linked bis(oxazoline) ligands 1a-d (Fig.
1), which were developed by Guiry et al. [6] and us [7], have
been successfully used in the asymmetric Henry reaction of
ꢁ -ketoesters [7a, b], asymmetric Micheal addition of
nitroalkanes to nitroalkenes [7c], asymmetric Nozaki-
Hiyama-Kishi reaction of aldehydes [6b], asymmetric
hydrosilylation of prochiral ketones [8], and asymmetric
Friedel-Crafts alkylation of electron-rich aromatic systems
with nitroalkenes [7d-f]. As a ‘privileged’ ligand scaffold,
more attention should be paid on the origin of its priority in
these asymmetric transformations, which may provide
meaningful information for ligand design. Herein, we would
O
N
N
O
R2
R1
R1
R2
2a-d
Rigid/planar scaffold
(a R1 = Ph, R2 = H; b R1 = Bn, R2 = H ; c R1 = i-Pr, R2 = H ; d R1 = R2 = Ph)
Fig. (1). Designed ligand for the tuning of ligand scaffold rigidity.
RESULT AND DISCUSSION
During our research on the asymmetric Friedel-Crafts
alkylation of electron-rich aromatic systems, good reactivity
and excellent enantioselectivity were obtained with
diphenylamine-linked bis(oxazoline)-Zn(OTf)2 complexes.
*Address correspondence to this author at the School of Chemical
Engineering and Environment, Beijing Institute of Technology, Beijing
100081, P. R. China; Fax: 86-10-68914985; E-mail: dudm@bit.edu.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Direct Experimental Evidence for the Priority of Flexible Ligand Skeleton
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
115
In order to interpret the better behaviour and inversed
absolute configuration than the systems developed by Zhou
et al. [9] and Singh et al. [10], a transition state model
containing bent ligand scaffold and NH…ꢀ interaction was
proposed, as illustrated in Fig. (2). Though the critical role of
NH moiety for the reactivity and enantioselectivity was
proved through comparison with diphenylether [7f] and
diphenylmethane-linked [7d] bis(oxazoline) ligands, the
XRD structure of the complex had not been obtained.
Recently, a single crystal of complex containing ligand 2a
and ZnCl2 was obtained from petroleum ether/CH2Cl2. As
illustrated in Fig. (3), the diphenylamine shows nonplanar
conformation, similar to our proposed model.
Synthesis of the designed ligands 2a-d was shown in
Scheme 1. The 4,4’-dimethyldiphenylamine 6 was prepared
through Buchwald-Hartwig coupling of 4 and 5 using a
modified procedure. Compared with literature condition
o
using 5 mol% catalyst at 100 C in THF [11], the catalyst
loading was reduced to 1 mol% and the solvent was changed
to toluene. Excellent yield can be achieved when the reaction
time was prolonged to 24 h. The methyl groups are critical
for the regioselective dibromination. A methoxycarbonyl
group was introduced through isatin formation, oxidative
cleavage, and esterification, similar to our former report [5b].
The dihydroacridine ring was formed via tertiary alcohol
formation and acid mediated intramolecular Friedel-Crafts
alkylation [12]. The preparation of the dicarboxylic acid 12
was facilitated through dibromination, lithium/bromine
exchange, and CO2 insertion. The product can be collected
conveniently via filtration in pure form. Though one
carboxyl group can be introduced via isatin formation and
oxidative cleavage similar to the preparation of 8, we failed
in the introduction of the second carboxyl group in this way
for the high strain of the ring system. The desired
bis(oxazoline) ligands 2a-d were obtained in one step from
acid 12.
O
Ph
Si
N
O
N
Zn
N
O
H
N
Ph
NH
O
With the designed ligands in hand, their reactivity was
tested in the model Friedel-Crafts alkylation (Scheme 2).
The results are summarized in Table 1. Compared with
diphenylamine-linked ligands 1a-d (entries 1-4), the ligands
2a-d with planar rigid scaffold gave much lower yields and
enantioselectivities (entries 5-8). To our surprise, the
absolute configuration of the products in the cases of
catalyzed by ligands 2a-c complex catalyst was inversed.
The results indicate that two types of ligands catalyze the
reaction through different transition state structure. On the
basis of our knowledge obtained in former research of this
system, a novel transition state was proposed, as illustrated
in Fig. (4). The absence of NH…ꢀ interaction led to a
relaxant transition state with weaker differentiation between
Re and Si face attack. Without the direction of NH moiety,
the indole comes close to the coordinated nitroalkene from
the less hindered Re face and forms the S product, similar to
the case of other bis(oxazoline) ligands without NH moiety
[9]. The enough flexibility of diphenylamine scaffold is
critical for the participation of NH…ꢀ interaction, while the
Fig. (2). Proposed transition state model.
highly rigid scaffold cannot accommodate
conformation for this interaction.
a proper
CONCLUSION
Fig. (3). XRD structure of complex 2a-ZnCl2.
In conclusion, we have provided the direct evidence for
the bent conformation of diphenylamine-linked bis(oxazo-
line) ligands in the transition state of Friedel-Crafts reaction
through XRD analysis of the ligand/ZnCl2 complex. The
priority of the flexible ligand scaffold was confirmed by
synthesis of dihydroacridine-linked bis(oxazoline) ligands
with planar rigid scaffold and comparison of the catalytic
reactivity/enantioselectivity. The information obtained in this
research will be useful for the expansion of the application of
diphenylamine-linked bis(oxazoline) ligands and novel
ligand design.
To get further information about the priority of the
flexible ligand scaffold, we designed two kinds of
bis(oxazoline) ligands containing NH moiety with different
scaffolds. As shown in Fig. (1), the iminodibenzyl-linked
ligands 3a-d with rigid but distorted scaffold were
investigated in our former work. These ligands gave much
lower reactivity and nearly no enantioselectivity in the model
Friedel-Crafts alkylation of indole with ꢁ-nitrostyrene. As a
natural extension, we designed the dihydroacridine-linked
ligands 2a-d with rigid and planar scaffold.

116 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Liu et al.
Me
1 mol% DPPF-PdCl2
3 mol%DPPF
Me
1. (COCl)2, benzene
reflux, 5 h
Me
Me
+
t-BuONa, toluene
110 oC, 24 h
96%
2. CS2, AlCl3
reflux, 16 h
I
NH2
N
H
4
5
6
Me
Me
Me
Me
Me
Me
CH2N2
NaOH, H2O, 4 h
Et2O
97%
N
then H2O2, 2 h
99%
N
H
N
H
COOH
CO2Me
O
O
9
8
7
1. n-BuLi, Et2O
-40 oC, 0.5 h
then r.t., 3 h
Me
Me
Me
Me
1. MeMgBr, THF
Br2, HOAc
2. H3PO4,120 oC, 2 h
91% for 2 steps
0 oC to r.t.
98%
2. CO2(g)
N
H
N
H
-40 oC, 1 h
Br
Br
then r.t., 2 h
11
10
79%
Me
Me
H2N
R1
OH
R2
Me
Me
2a R1 = Ph, R2 = H
2b R1 = Bn, R2 = H
2c R1 = i-Pr, R2 = H
2d R1 = R2 = Ph
34%
47%
37%
65%
N
H
N
H
CCl4, PPh3, Et3N
CH3CN, r.t., 48 h
O
N
N
O
CO2H
CO2H
R2
R1 R1
R2
12
Scheme 1. Synthesis of dihydroacridine-linked bis(oxazoline) ligands.
Ph
5 mol% Zn(OTf)2
6 mol% ligand
NO2
*
NO2
+
Ph
toluene, 20oC
N
N
H
H
13
14
15
Scheme 2. Asymmetric Friedel-Crafts alkylation of indole with ꢀ-nitrostyrene.
Table 1. Comparison Between Diphenylamine and Dihydroacridine-Linked Bis(oxazoline) Ligands in Asymmetric Friedel-Crafts
Alkylationa
Entry
Ligand
Yield (%)b
ee (%)c
Config.d
1
2
3
4
5
6
7
8
1a (R1 = Ph, R2 = H)
1b (R1 = Bn, R2 = H)
1c (R1 = i-Pr, R2 = H)
1d (R1 = R2 = Ph)
2a (R1 = Ph, R2 = H)
2b (R1 = Bn, R2 = H)
2c (R1 = i-Pr, R2 = H)
2d (R1 = R2 = Ph)
99
99
94
99
40
68
26
36
83e
66e
30e
88e
7
R
R
R
R
S
22
53
12
S
S
R
aThe reactions were conducted at 0.5 mmol scale under the catalysis of 5 mol% catalyst in 3 mL toluene at room temperature for 24 h. bIsolated yield. cDetermined by HPLC on
Daicel Chiracel OD-H column using n-hexaneꢀisopropanol 70 : 30 V/V as eluent. dDetermined by comparison of retension time with standard sample. edata from reference [7d].

Direct Experimental Evidence for the Priority of Flexible Ligand Skeleton
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
117
solution of (COCl)2 was added dropwise during 1 h. After
the addition, the mixture was stirred under reflux for another
5 h. All the solvents and unreacted (COCl)2 were removed
under vacuum. The residue was dissolved in CS2 (40 mL)
and added to a dropping funnel. The mixture of AlCl3 (8.6 g,
64 mmol) and CS2 (120 mL) was heated to reflux, and the
aforementioned solution was added dropwise during 1 h. The
mixture was stirred under reflux for 16 h. After being cooled
N
O
H
N
o
N
Zn
O
O
N
to 0 C, the reaction mixture was quenched by concentrated
Re
HCl (aq) (50 mL) and water (100 mL). The mixture was
extracted with CHCl3 (ꢁꢂꢀ 200 mL), and the organic phase
was dried with anhydrous Na2SO4. The solvent was removed
under vacuum, and the residue was purified by
recrystallization in toluene. The desired product was
O
NH
o
obtained as red solid (6.197 g, 66% yield). m.p.178–180 C.
1H NMR (300 MHz, CDCl3): ꢀ = 7.48 (s, 1H), 7.29–7.35
(m, 5H), 6.78 (d, J = 7.8 Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H).
13C NMR (75 MHz, CDCl3): ꢀ = 183.2, 157.5, 149.6, 138.7,
134.0, 130.4, 130.3, 125.7, 125.6, 117.4, 111.0, 21.2, 20.6.
IR (neat): 3033, 1732, 1621, 1599, 1515, 1488, 1353, 1298,
1192, 1163, 828, 814 cm-1. HR-ESIMS: m/z cacld for
C16H14NO2 (M+H): 252.10245. Found: 252.10173.
Fig. (4). Proposed transition state model for the dihydroacridine-
linked bis(oxazoline) ligand.
EXPERIMENTAL
Commercially available compounds were used without
further purification. Solvents were dried according to
standard procedures. Column chromatography was carried
out using silica gel (200-300 mesh). Melting points were
measured on a XT-4 melting point apparatus without
2-(N-(4-Methylphenyl)amino)-5-methylbenzoic acid (8)
To a round-bottom flask were added 1-(4-methylphenyl)-
5-methyloxindole (6.197 g, 24.7 mmol), NaOH (7.0 g, 175
mmol), and water (900 mL). The mixtrue was stirred at room
temperature for 4 h to generate a orange solution. A solution
of 30% H2O2 (7.0 mL, 62 mmol) in water (50 mL) was
added slowly to the mixture, and the color of the solution
turned to light yellow. The mixture was stirred for another 2
h. After removing the insoluable residue through filtration,
the mixture was acidified with concentrated HCl (aq), and
the solid was collected through filtration and washed
throughly with water. The desired product was obatined as
yellow solid (5.806 g, 97% yield). m.p.180–183 oC. 1H NMR
(300 MHz, d6-DMSO): ꢀ = 12.96 (s, 1H), 9.38 (s, 1H), 7.69
(s, 1H), 7.06–7.20 (m, 6H), 2.27 (s, 3H), 2.21 (s, 3H). 13C
NMR (75 MHz, d6-DMSO): ꢀ = 169.8, 145.2, 138.1, 134.9,
131.8, 131.5, 129.8, 125.5, 121.4, 113.7, 112.0, 20.3, 19.8.
1
correction. The H NMR spectra were recorded on Mercury
300 MHz spectrometers, while 13C NMR spectra were
recorded at 75 MHz, respectively. Infrared spectra were
obtained on a Nicolet AVATAR 330 FTIR spectrometer.
The ESI-MS spectra were obtained on Thermo Firrnigan
LCQ Deca XP Plus mass spectrometer. Optical rotations
were measured on Perkin-Elmer 341 LC spectrometer. The
enantiomeric excesses of the products were determined by
chiral HPLC using Agilent 1200 LC instrument on Daicel
Chiracel OD-H column.
4,4’-Dimethyl-1,1’-diphenylamine (6)
To a Schlenk tube were added 4-methylaniline (2.14 g,
20 mmol), 4-iodotoluene (4.36 g, 20 mmol), DPPF-PdCl2
(164 mg, 0.2 mmol), DPPF (332 mg, 0.6 mmol). The tube
was filled with argon and anhydrous toluene (12 mL) was
added, followed by t-BuONa (2.40 g, 25 mmol). The mixture
turned red immediately after the addition of t-BuONa, and
Methyl 2-(N-(4-methylphenyl)amino)-5-methylbenzoate
(9)
o
was stirred at 110 C for 24 h. After being cooled to room
To
a
round-bottom flask was added 2-(N-(4-
temperature, the mixture was filtered through celite to
remove the inorganic salts, and the crude product was
purified by silica gel flash chromatography using petroleum
ether-ethyl acetate 100: 1 V/V as eluent. The desired product
was obtained as white solid (3.783 g, 96% yield). m.p. 78–80
methylphenyl)amino)-5-methylbenzoic acid (4.40 g, 18.3
mmol) and Et2O (300 mL). A solution of excess amount of
CH2N2 (about 32 mmol) in Et2O (150 mL) was added to a
dropping funnel. The solution of CH2N2 was added to the
solution of acid slowly at room temperature, and the mixture
was stirred for another 1 h after the addition. The solvent
was removed under vacuum and the residue was purified by
silica gel column chromatography using petroleum ether and
petroleum ether-ethyl acetate 100 : 1 V/V as eluent. The
desired product was obtained as yellow oil (4.302 g, 92%
1
oC. H NMR (300 MHz, CDCl3): ꢀ = 7.05 (d, J = 8.4 Hz,
4H), 6.93 (d, J = 8.4 Hz, 4H), 5.47 (s, 1H), 2.28 (s, 6H). 13C
NMR (75 MHz, CDCl3): ꢀ = 141.1, 130.1, 129.8, 117.9,
20.6.
1
yield). H NMR (300 MHz, CDCl3): ꢀ = 9.21 (s, 1H), 7.75
1-(4-Methylphenyl)-5-methyloxindole (7)
(s, 1H), 7.12 (br, 6H), 3.88 (s, 3H), 2.33 (s, 3H), 2.25 (s,
3H). 13C NMR (75 MHz, CDCl3): ꢀ = 168.9, 146.2, 138.4,
135.1, 132.9, 131.2, 129.8, 125.8, 122.6, 114.0, 111.4, 51.6,
20.8, 20.3. IR (neat): 3328, 2950, 1682, 1591, 1517, 1436,
1318, 1261, 1206, 1083, 805 cm-1. HR-ESIMS: m/z cacld for
A dried round-bottom flask containing 4,4’-dimethyl-
1,1’-diphenylamine (7.312 g, 37.1 mmol) and anhydrous
benzene (100 mL) was equipped with a dropping funnel
containing a solution of (COCl)2 (5.1 mL, 58 mmol) in
benzene (40 mL). The flask was heated to reflux, and the

118 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Liu et al.
C16H18NO2 (M+H): 256.13375. Found: 256.13304. A by
product with higher retension on the column was obtained as
yellow oil (365 mg, 7% yield), which was determined to be
O,N-bismethylated product methyl 2-(N-methyl-N-(4-
methylphenyl)amino)-5-methylbenzoate. 1H NMR (300
MHz, CDCl3): ꢀ = 7.48 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H),
7.01 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.5 Hz, 2H), 6.42 (d, J
= 7.2 Hz, 2H), 3.46 (s, 3H), 3.10 (s, 3H), 2.23 (s, 3H), 2.10
(s, 3H). 13C NMR (75 MHz, CDCl3): ꢀ = 167.5, 147.1,
145.7, 134.5, 133.7, 131.4, 129.2, 128.7, 128.5, 126.6, 114.0,
51.8, 40.2, 20.6, 20.2. IR (neat): 2948, 1730, 1617, 1573,
1516, 1498, 1435, 1345, 1297, 1243, 1205, 1090, 806 cm-1.
HR-ESIMS: m/z cacld for C17H20NO2 (M+H): 270.14940.
Found: 270.14868.
3,6,9,9-Tetramethyl-9,10-dihydroacridine-1,8-dicarboxy-
lic acid (12)
1,8-Dibromo-3,6,9,9-tetramethyl-9,10-dihydroacridine
(790 mg, 2 mmol) and Et2O (25 mL) were added to a flamed
dried three necked flask equipped with a dropping funnel
containing n-BuLi (8.8 mmoL). The mixture was cooled to –
40 oC and the n-BuLi was added dropwise. The mixture
became clear and turned yellow. After the additon, the
mixture was stirred at room temperature for 3 h. Then the
solution was cooled to –40 oC again and dry CO2 was bulbed
into the solution for 1 h. The mixtrue was treated with 2 N
HCl (aq), and the solid was collected through filtration. After
being washed with petroleum ether, the desired product was
obtained as yellow solid (511 mg, 79% yield). m.p. > 250 oC.
1H NMR (300 MHz, d6-DMSO): ꢀ = 12.93 (br, 2H), 12.13
(s, 1H), 7.60 (s, 2H), 7.46 (s, 2H), 2.27 (s, 6H), 1.50 (s, 6H).
13C NMR (75 MHz, d6-DMSO): ꢀ = 168.6, 137.2, 131.0,
130.0, 129.4, 127.8, 112.0, 35.8, 31.0, 20.3. IR (neat): 3298,
2954, 2563, 1665, 1593, 1497, 1463, 1289, 1242, 956, 794,
720 cm-1. Anal. cacld for C19H19NO4ꢁ0.5H2O: C, 68.25; H,
6.03; N, 4.19. Found: C, 68.89; H, 6.01; N, 4.23.
3,6,9,9-Tetramethyl-9,10-dihydroacridine (10)
A solution of methyl 2-(N-(4-methylphenyl)amino)-5-
methylbenzoate (4.795 g, 18.8 mmol) in THF (60 mL) was
adde to a dried flask under argon, which was equipped with a
dropping funnel containing a solution of MeMgCl (75 mmol)
o
in THF (40 mL). The mixture was cooled to 0 C and the
Grignard reagent was added slowly during 0.5 h, and the
mixture was stirred for another 2 h at 0 C. After being
o
1,8-Bis((4S)-4-phenyloxazolin-2-yl)-3,6,9,9-tetramethyl-
9,10-dihydroacridine (2a)
quenched by water, the mixture was extracted with Et2O (3ꢁ
ꢀ 100 mL), and the combined organic phase was dried over
anhydrous Na2SO4. The solvent was removed under vacuum
and the desired product was directly used in the next step
without further purification. To a round-bottom flask were
added 85% H3PO4 (30 mL) and tertiary alcohol obtained in
To a round-bottom flask was added 3,6,9,9-tetramethyl-
9,10-dihydroacridine-1,8-dicarboxylic acid (650 mg,
2
mmol), (S)-phenylglycinol (548 mg, 4 mmol), CCl4 (6.7 mL,
154 mmol), Et3N (5.0 mL, 35 mmol), triphenylphosphine
(3.86 g, 14.7 mmol), and acetonitrile (40 mL). The mixture
was stirred at room temperature for 48 h. The solvent was
removed under vacuum, and the residue was treated with
water and extracted with CH2Cl2 (2ꢁ ꢀ 50 mL). The
combined organic phase was dired over anhydrous Na2SO4.
The solvent was removed under vacuum, and the residue was
purified by silica gel column chromatography using
petroleum ether–ethyl acetate 20 : 1 V/V as eluent. The
desired product was obtained as yellow solid (364 mg, 34%
o
the former step. The mixture was stirred at 120 C for 2 h
and cooled to room temperature. After being diluted with
water (200 mL), the mixture was basified with NaHCO3 and
extracted with CH2Cl2 (2ꢁꢀ 100 mL). The combined organic
phase was dried over anhydrous Na2SO4, and the solvent was
removed under vacuum. The residue was purified by silica
gel flash chromatography using petroleum ether–ethyl
acetate 40 : 1 V/V as eluent. The desired product was
obtained as colorless solid (4.069 g, 91% yield). m.p. 99–100
o
yield). m.p. 85–87 C. [ꢂ]D20 = +477.3 (c 0.86 g/100 mL,
1
oC. H NMR (300 MHz, d6-DMSO): ꢀ = 8.56 (s, 1H), 7.13
1
CH2Cl2). H NMR (300 MHz, CDCl3): ꢀ = 12.30 (s, 1H),
(s, 2H), 6.84 (d, J = 7.8 Hz, 2H), 6.67 (d, J = 7.8 Hz, 2H),
2.22 (s, 6H), 1.46 (s, 6H). 13C NMR (75 MHz, d6-DMSO):
ꢀ = 136.7, 127.8, 127.5, 127.0, 125.7, 113.1, 35.5, 31.0,
20.7.
7.55 (s, 2H), 7.24–7.32 (m, 8H), 7.14 (d, J = 7.2 Hz, 4H),
4.90 (t, J = 9.0 Hz, 2H), 4.39 (t, J = 9.1 Hz, 2H), 3.90 (t, J =
8.1 Hz, 2H), 2.33 (s, 6H), 1.58 (s, 6H). 13C NMR (75 MHz,
CDCl3): ꢀ = 163.9, 143.0, 136.9, 130.1, 129.0, 128.5,
128.1, 128.0, 127.3, 126.7, 110.3, 73.5, 70.2, 36.4, 30.6,
20.8. IR (neat): 3062, 2971, 1649, 1593, 1492, 1454, 1427,
1358, 1263, 1193, 1094, 994, 757, 698 cm-1. HR-ESIMS:
m/z cacld for C35H34N3O2 (M+H): 528.26510. Found:
528.26362.
1,8-Dibromo-3,6,9,9-tetramethyl-9,10-dihydroacridine (11)
To a solution of 3,6,9,9-tetramethyl-9,10-dihydroacridine
(4.069 g, 17.2 mmol) in acetic acid (35 mL), was added Br2
o
(5.60 g, 35 mmol) dropwise at 0 C. After the additon, the
o
mixture was stirred at 0 C for 0.5 h, and then at room
1,8-Bis((4S)-4-benzyloxazolin-2-yl)-3,6,9,9-tetramethyl-
9,10-dihydroacridine (2b)
temperature for 2 h. The reaction was quenched with a
solution NaHSO3, and the desired product was obtained
through filtration as light greenish solid (6.661 g, 98%
Prepared in similar procedure using 3,6,9,9-tetramethyl-
9,10-dihydroacridine-1,8-dicarboxylic acid (650 mg,
o
1
yield). m.p.167–168 C. H NMR (300 MHz, CDCl3): ꢀ =
7.38 (s, 1H), 7.20 (s, 2H), 7.09 (s, 2H), 2.28 (s, 6H), 1.53 (s,
6H). 13C NMR (75 MHz, CDCl3): ꢀ = 133.6, 130.9, 130.5,
130.3, 125.1, 108.9, 37.5, 30.3, 20.7. IR (neat): 3374, 2976,
2952, 1633, 1610, 1589, 1490, 1403, 1338, 1308, 1254,
1185, 1073, 1010, 967, 848, 812 cm-1. Anal. cacld for
C17H17Br2N: C, 51.67; H, 4.34; N, 3.54. Found: C, 51.65; H,
4.39; N, 3.69.
2
mmol) and (S)-valinol (412 mg, 4 mmol). The desired
product was obtained as yellow oil (338 mg, 37% yield). [ꢂ
20
D
1
]
= +266.4 (c 0.76 g/100 mL, CH2Cl2). H NMR (300
MHz, CDCl3): ꢀ = 12.01 (s, 1H), 7.52 (s, 2H), 7.20–7.29
(m, 12H), 4.54 (t, J = 5.9 Hz, 2H), 4.22 (t, J = 8.6 Hz, 2H),
4.05 (t, J = 7.5 Hz, 2H), 3.31 (dd, J1 = 13.5 Hz, J2 = 4.5 Hz,

Direct Experimental Evidence for the Priority of Flexible Ligand Skeleton
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
119
2H), 2.74 (dd, J1 = 13.5 Hz, J2 = 9.0 Hz, 2H), 2.31 (s, 6H),
1.58 (s, 6H). 13C NMR (75 MHz, CDCl3): ꢀ = 163.2, 138.1,
136.5, 129.9, 129.3, 129.1, 128.5, 128.1, 128.0, 126.5, 110.4,
70.5, 68.3, 42.2, 36.3, 31.2, 20.7. IR (neat): 3061, 3027,
2966, 2923, 1648, 1595, 1496, 1453, 1430, 1384, 1362,
1264, 1198, 1091, 991, 737, 702 cm-1. HR-ESIMS: m/z cacld
for C37H38N3O2 (M+H): 556.29640. Found: 556.29459.
ACKNOWLEDGEMENTS
We thank the National Science Foundation of China
(Grant No.20772006), the Development Program for
Distinguished Young and Middle-aged Teachers of Beijing
Institute of Technology and the Program for New Century
Excellent Talents in University (NCET-07-0011) for
financial support.
1,8-Bis((4S)-4-isopropyloxazolin-2-yl)-3,6,9,9-tetra-
methyl-9,10-dihydroacridine (2c)
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher's
Web site along with the published article.
Prepared in similar procedure using 3,6,9,9-tetramethyl-
9,10-dihydroacridine-1,8-dicarboxylic acid (487 mg, 1.5
mmol) and (S)-phenylalaninol (453 mg, 3 mmol). The
desired product was obtained as yellow solid (394 mg, 47%
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CH2Cl2). H NMR (300 MHz, CDCl3): ꢀ =11.62 (s, 1H),
7.45 (s, 2H), 7.20 (s, 2H), 4.19–4.23 (m, 4H), 4.07–4.16 (m,
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methyl-9,10-dihydroacridine (2d)
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9,10-dihydroacridine-1,8-dicarboxylic acid (650 mg,
2
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o
(889 mg, 65% yield). m.p. 143–145 C. [ꢁ]D20 = +159.2 (c
0.96 g/100 mL, CH2Cl2). 1H NMR (300 MHz, CDCl3): ꢀ =
12.56 (s, 1H), 7.69 (s, 2H), 7.29–7.37 (m, 8H), 7.06–7.16
(m, 10H), 6.98–7.04 (m, 4H), 5.01 (d, J = 7.5 Hz, 2H), 4.55
(d, J = 7.8 Hz, 2H), 2.33 (s, 6H), 1.63 (s, 6H). 13C NMR (75
MHz, CDCl3): ꢀ = 162.9, 142.4, 140.4, 137.0, 130.2, 129.3,
128.6, 128.41, 128.36, 128.2, 128.0, 127.3, 126.5, 125.8,
110.1, 87.2, 78.8, 36.4, 31.1, 20.8. IR (neat): 3061, 3028,
2921, 1651, 1591, 1493, 1454, 1427, 1347, 1294, 1254,
1190, 1158, 1091, 983, 762, 696 cm-1. HR-ESIMS: m/z cacld
for C47H42N3O2 (M+H): 680.32770. Found: 680.32533.
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Reaction
[3]
To a flame dried Schlenk tube were added Zn(OTf)2 (9
mg, 0.025 mmol) and ligand 1a-d or 2a-d (0.05 mmol) under
argon, followed by addition of toluene (3 mL). The mixture
was stirred at room temperature for 2 h and ꢂ-nitrostyrene
14 (74.5 mg, 0.5 mmol) was added. Then the mixture was
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