Design and synthesis of a chiral N-tethered bis(imidazoline) ligand

Article abstract of DOI:10.1055/s-2005-917101

A chiral nitrogen-tethered bis (imidazoline) ligand (Nb-imidazoline) was newly designed and synthesized in a divergent strategy. Thus, a single coupling reaction of primary amine with two molecules of chloromethylated imidazoline provided the Nb-imidazoline. The copper(II) triflate complex of Nb-imidazoline catalyzed a trans-selective cyclopropanation of styrene with ethyl diazoacetate to give the adduct in high chemical yield with good enantiomeric excess up to 83%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917101

2670
LETTER
Design and Synthesis of a Chiral N-Tethered Bis(imidazoline) Ligand
Synthesis of
a
C
a
hiral
N
-Te
k
thered
B
is(im
a
idazoline)
y
Ligand oshi Arai,*a Tomoe Mizukami,a Naota Yokoyama,b Daisuke Nakazato,b Akira Yanagisawaa
a
Department of Chemistry, Faculty of Science, Chiba University, Inage 263-8522, Japan
Fax +81(43)2902889; E-mail: tarai@faculty.chiba-u.jp
b
Graduate School of Science and Technology, Chiba University, Inage 263-8522, Japan
Received 1 August 2005
similar to the oxazoline ligands, they have not received as
much attention.3
Abstract: A chiral nitrogen-tethered bis (imidazoline) ligand (Nb-
imidazoline) was newly designed and synthesized in a divergent
strategy. Thus, a single coupling reaction of primary amine with
two molecules of chloromethylated imidazoline provided the Nb-
imidazoline. The copper(II) triflate complex of Nb-imidazoline cat-
alyzed a trans-selective cyclopropanation of styrene with ethyl di-
azoacetate to give the adduct in high chemical yield with good
enantiomeric excess up to 83%.
Herein, we report the design and efficient synthesis of the
bis(imidazoline) ligand. In the design of the bis(imidazo-
line) ligand, two molecules of chiral imidazoline are teth-
ered by the appropriate length of a linker including a
pendant element (X) as depicted in Figure 1.4 A divergent
synthetic route was adopted for making possible utiliza-
tion of various tethering groups for accessing the general
structure.
Key word: asymmetric catalysis, ligands, imidazoline, copper,
cyclopropanation
R2
R2
The synthesis of chiral molecules in catalytic asymmetric
manner is a fascinating methodology in fine chemistry to
supply fundamentally valuable organic compounds, and
has now become a driving force for the promotion of sus-
tainable chemistry.1 The important research topic of
asymmetric catalysis has stimulated worldwide chemists
to develop numerous chiral ligands for the various types
R1
R1
N
M
N
N
N
( )n
( )n
R3
R3
X
R4
Figure 1 X-tethered bis(imidazoline)-metal complex
of metal-catalyzed reactions. A representative example of The first synthesis of the bis(imidazoline) ligand tethered
the chiral ligand chemistry can be seen in the famous
by primary amine is shown in Scheme 1. Starting from
bis(oxazoline) ligands, in which the nitrogen atom of the enantiomerically pure diphenyl ethylenediamine (1),
N,O-containing five-membered ring of the oxazoline co- chloromethylated imidazoline 2 was readily prepared by
ordinates to the metal cation to form the complex.1,2 The the reaction with 2-chloromethyl-1,1,1-triethoxyethane5
oxazoline ring formation using commercially available, in acetic acid. Further tosylation using TsCl furnished the
optically active amino alcohols makes it possible to adjust corresponding derivative 3. Using 2 equivalents of 3, the
the sterical hindrance of the coordination sphere. More- double alkylation of benzylamine proceeded smoothly to
over, the C2-symmetry concept for the design of efficient give the desired N-tethered bis(imidazoline) 4 as the sole
chiral ligands has been employed to make the bis(oxa-
zoline) by tethering two molecules of the oxazoline ring.
Ph
Ph
Combination of the substituent on the oxazoline ring with
the tethering groups has enlarged the size of a diverse
bis(oxazoline) family.
Ph
Ph
(EtO)3CCH2Cl
AcOH
HN
N
H2N
NH2
Cl
1
However, even in the beautiful success of bis(oxazoline)
ligands in asymmetric catalysis, regulating the electron
density of the oxazoline ring has been remained an un-
solved problem. One way to overcome the limitation of
electronic variation on the oxazoline ring would be by a
rational design of a chemical analogue (e.g. imidazoline)
of oxazoline. Imidazoline, the N,N-analogue of N,O-con-
sisting oxazoline, would be reasonably considered to suf-
ficiently meet such an electronically tunable demand.
Ligands carrying an imidazoline motif are structurally
2
Ph
Ph
TsCl, DMAP,
Et3N
BnNH2, NaI
DMF
TsN
N
CH2Cl2
Cl
N
3
Ph
Ph
Ph
TsN
Ph
N
NTs
N
Bn
SYNLETT 2005, No. 17, pp 2670–2672
1
7
.1
0
.2
0
0
5
4
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917101; Art ID: U26105ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

LETTER
Synthesis of a Chiral N-Tethered Bis(imidazoline) Ligand
2671
product. The newly obtained Nb-imidazoline6 (4) is stable
to moisture at ambient temperature, and can be kept under
air.
Table 1 Cyclopropanation of Styrene Catalyzed by 4–Cu(OTf)2 in
CH2Cl2
4 (6.5 mol%)
Cu(OTf)2 ( 5 mol%)
R
O
N2
+
Ph
With the newly developed Nb-imidazoline (4) in hand, the
coordination ability of 4 to various metal salts was briefly
examined by the characteristic change in color. For an ex-
ample, spontaneous formation of a blue color metal com-
plex was observed by a mixing of Cu(OTf)2 and 4 in
CH2Cl2. The formation of 4–Cu(II) complex was strongly
suggested by FAB mass spectrometry by the observation
of an ion peak [4 + Cu(OTf)]+ at m/z = 1095. Using the 4–
Cu(II) complex, we started to explore a suitable asymmet-
ric reaction for demonstrating an efficient asymmetric re-
action sphere produced by bis(imidazoline) ligand. A
preliminary result was obtained in an asymmetric
benzoylation7 of 1,2-diols as shown in Scheme 2. The re-
action of racemic hydrobenzoin and 0.5 mol equivalents
of benzoyl chloride was smoothly promoted by a catalytic
amount of 4–Cu(OTf)2 in CH2Cl2 at room temperature to
provide the mono-benzoylated product in 28% yield (in
50% maximum yield) with 48% ee. Although the enanti-
omeric excess of the product is moderate, this is the first
reported use of Nb-imidazoline in Lewis acid catalysis.
OEt
CH2Cl2, r.t.
R
CO2Et
H
Ph
CO2Et
H
+
Ph
R
trans
R
cis
Entry
1a
Time (h) Yield (%)c trans/cis ee (trans/cis)
H
20
7
51
96
42
39
80:20
84:16
49:51
–
83:36
75:35
80:70
75
2b
H
3b
Me
Ph
17
18
4b
a Ethyl diazoacetate was added in one portion.
b Ethyl diazoacetate was slowly added over 4 h.
c Isolated yield.
high chemical yield with good enantiomeric excess in the
cyclopropanation. Due to the fascinating, short synthetic
route of the tethered bis(imidazoline) ligand, further study
on the development of diverse tethering bis(imidazoline)
ligands is in progress.
4 (5.5 mol%)
Cu(OTf)2 ( 5 mol%)
Ph
Ph
+
PhCOCl (0.5 equiv)
CH2Cl2, r.t., 2.5 h
HO
OH
rac.
Experimental Procedure for the Synthesis of Nb-Imidazoline
and for the Catalytic Asymmetric Cyclopropanation
[(4S,5S)-2-(Chloromethyl)-4,5-dihydro-4,5-diphenyl-1H-imida-
zole] (2)
Ph
Ph
Ph
Ph
OH
+
HO
OBz
HO
28%, 48% ee
67%
To the solution of (1S,2S)-1,2-diphenylethane-1,2-diamine(1 g,
4.71 mmol) in AcOH (23.5 mL) was added 2-chloromethyl-1,1,1-
triethoxyethane (1.17 mL, 6.12 mmol), and the mixture was stirred
for 15 h at r.t. After diluting by adding CHCl3 (100 mL), the reaction
mixture was neutralized by 2 N NaOH aq, and the aqueous layer
was extracted with CHCl3. The combined organic extracts were
Scheme 2
This result stimulated us to undertake further experiments
using the same complex. In the next trial, copper-cata-
lyzed cyclopropanation using ethyl diazoacetate was ex- dried over anhyd Na2SO4, and concentrated in vacuo after filtration.
The residual crude product was purified by silica gel column chro-
amined. Fortunately, the cyclopropanation of styrene was
matography to give the chloromethylated imidazoline 2 (1.01 g
also smoothly catalyzed by 4–Cu(OTf)2 in CH2Cl2 as
80% yield) as a colorless amorphous solid.
shown in Table 1.
Spectral data of 2: 1H NMR (400 MHz, CDCl3): d = 4.38 (s, 2 H),
When the ethyl diazoacetate was added in one portion, the
4.82 (s, 2 H), 5.35 (br s, 1 H, NH), 7.24–7.38 (m, 10 H, aromatic).
reaction proceeded trans-selectively, and 83% ee of the
trans-adduct was obtained (entry 1). The chemical yield
was improved up to 96% by a slow addition of diazoace-
tate with maintaining similar diastereo- and enantioselec-
tivities (entry 2). Furthermore, the cyclopropanation of
1,1-diphenyl ethylene was also catalyzed by 4–Cu(OTf)2
to give the desired adduct in 39% yield with 75% ee (entry
4). Although the preliminary results using Nb-imidazoline
(4) as a chiral ligand presented herein are at a level of
moderate enantioselectivity, the potential of imidazoline
ligands would be predicted by considering electronic and
sterical variations.8
[(4S,5S)-2-(Chloromethyl)-4,5-dihydro-4,5-diphenyl-1-tosyl-
1H-imidazole] (3)
To the solution of 2 (255 mg, 0.94 mmol), Et3N (172 mL, 1.22 mol),
and DMAP (5.7 mg, 0.047 mmol) in dry CH2Cl2 (4.7 mL) was add-
ed TsCl (216 mg, 1.13 mmol) at 0 °C, and the mixture was stirred
for 24 h at r.t. The reaction was quenched by sat. NaHCO3, and the
aqueous layer was extracted by CHCl3. The combined organic ex-
tracts were dried over anhyd Na2SO4, and concentrated in vacuo af-
ter filtration. The residual crude product was purified by silica gel
column chromatography to give the tosylated imidazoline 3 (226
mg 57% yield) as a white solid.
1
Spectral data of 3: H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H,
Ts-CH3), 4.69 (d, 1 H, J = 12.5 Hz, CH2Cl), 4.92–4.99 (m, 3 H),
6.88–7.50 (m, 14 H, aromatic). 13C NMR (125 MHz, CDCl3): d =
21.3, 38.6, 71.9, 77.7, 126.0, 126.3, 127.5, 127.7, 128.1, 128.6,
128.8, 129.4, 134.9, 140.5, 140.5, 144.6, 155.7. MS: m/z = 425 [M
+ H]+.
In summary, we have succeeded in developing a novel
chiral N-tethered bis(imidazoline) ligand. The Nb-imida-
zoline 4–Cu(OTf)2 complex smoothly catalyzed different
types of reactions, and the desired product was obtained in
Synlett 2005, No. 17, 2670–2672 © Thieme Stuttgart · New York

2672
T. Arai et al.
LETTER
{N-benzyl[(4S,5S)-4,5-dihydro-4,5-diphenyl-1-tosyl-1H-imida-
zol-2-yl]-N-{[(4S,5S)-4,5-dihydro-4,5-diphenyl-1-tosyl-1H-imi-
dazol-2-yl]methyl}methanamine} (4)
References
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Ed.; Wiley: New York, 1994. (b) Comprehensive
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(3) Recent progress on chiral ligands containing imidazoline
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To the solution of 3 (353 mg, 0.83 mmol) in DMF was added Et3N
(171 mL, 1.22 mmol ), NaI (184 mg, 1.23 mmol), and benzyl amine
(48 mL, 0.41 mmol), and the mixture was stirred for 8 h at r.t. The
reaction was quenched by sat. NaHCO3, and the aqueous layer was
extracted by Et2O. After washing the combined organic extracts
with H2O three times, the organic layer was dried over anhyd
Na2SO4, and concentrated in vacuo after filtration. The residual
crude product was purified by silica gel column chromatography to
give the N-tethered bis(imidazoline) 4 (178 mg, 49% yield) as a pale
yellow amorphous solid.
Spectral data of 4: 1H NMR (400 MHz, CDCl3): d = 2.32 (s, 6 H),
4.29 (s, 2 H), 4.31–4.36 (dd, J = 1.7, 17.1 Hz, 2 H, CH2), 4.39–4.43
(d, J = 17.1 Hz, 2 H, CH2), 4.83 (d, J = 5.1 Hz, 2 H, CH), 4.98 (d,
J = 5.1 Hz, 2 H, CH), 6.90 (dd, J = 1.7, 8.0 Hz, 4 H, aromatic), 6.98
(d, J = 8.0 Hz, 4 H, aromatic), 7.18–7.40 (m, 25 H, aromatic). 13
C
NMR (100 MHz, CDCl3): d = 21.5, 51.2, 57.0, 71.5, 78.0, 126.2,
126.5, 127.2, 127.4, 127.5, 128.0, 128.3, 128.6, 128.9, 129.4, 129.6,
135.6, 138.7, 141.5, 141.6, 144.1, 157.0. HRMS (FAB+): m/z calcd
for C53H50N5O4S2 [M+ + H]: 884.3304; found: 884.3252.
Catalytic Asymmetric Cyclopropanation (Table 1, Entry 2)
Nb-imidazoline (4, 23.0 mg, 0.026 mmol) and Cu(OTf)2 (7.2 mg,
0.02 mmol) were dissolved in dry CH2Cl2 under Ar atmosphere, and
the resulting blue color solution was stirred for 12 h. To the solution
was added styrene (230 mL, 2 mmol), and 0.4 M solution of ethyl
diazoacetate in CH2Cl2 (1.0 mL) was slowly added over 4 h at r.t.
After being stirred for further 3 h at the same temperature, the reac-
tion was quenched by H2O, and the aqueous layer was extracted by
CHCl3. The combined organic extracts were dried over anhyd
Na2SO4, and concentrated in vacuo after filtration. The residual
crude product was purified by silica gel column chromatography to
give the trans-adduct (62 mg 81% yield) and cis-adduct (11 mg
15% yield). The ee of the adducts were determined by chiral station-
ary phase HPLC analysis (DAICEL CHIRALCEL OJ-H, flow
rate = 0.5 mL/min, hexane–2-PrOH = 9:1).
(4) Zhang et al. reported the N-tethered bis(oxazoline) as
ambox: Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc.
1998, 120, 3817.
(5) Mylari, B. L.; Scott, P. J.; Zembrowski, W. J. Synth.
Commun. 1989, 19, 2921.
(6) Nb-imidazoline is an abbreviation of N-tethered
bis(imidazoline).
(7) Recent progress in Cu-bis(oxazoline)-catalyzed asymmetric
benzoylation of 1,2-diol: (a) Matsumura, Y.; Maki, T.;
Murakami, S.; Onomura, O. J. Am. Chem. Soc. 2003, 125,
2052. (b) Matsumura, Y.; Maki, T.; Tsurumaki, K.;
Onomura, O. Tetrahedron Lett. 2004, 45, 9131. (c) Gissibl,
A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325.
(8) During the preparation of this manuscript, Beller et al.
reported a similar type of pyridinebisimidazoline ligand for
a Ru-catalyzed asymmetric epoxidation: Bhor, S.;
Anilkumar, G.; Tse, M. K.; Klawonn, M.; Döbler, C.;
Bitterlich, B.; Grotevendt, A.; Beller, M. Org. Lett. 2005, 7,
3393.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, Culture and
Technology of Japanese Government. We thank Mr. Masahiko
Watanabe and Mr. Akitsugu Fujiwara for their kind technical
support and helpful discussion.
Synlett 2005, No. 17, 2670–2672 © Thieme Stuttgart · New York