C3-Symmetric chiral trisimidazoline-catalyzed Friedel-Crafts (FC)-type reaction

Article abstract of DOI:10.1039/c4ob00925h

Imidazoline-catalyzed enantioselective Friedel-Crafts (FC)-type reactions were established using C₃-symmetric chiral trisimidazolines. The imidazoline catalysts promoted the FC-type reaction of aldimines with 2-naphthols to produce the correspo

Full text of DOI:10.1039/c4ob00925h

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C3-Symmetric chiral trisimidazoline-catalyzed
Friedel–Crafts (FC)-type reaction†
Cite this: Org. Biomol. Chem., 2014,
12, 5827
Shinobu Takizawa,*a Shuichi Hirata,a Kenichi Murai,*b Hiromichi Fujiokab and
Received 6th May 2014,
Accepted 19th June 2014
Hiroaki Sasaia
DOI: 10.1039/c4ob00925h
www.rsc.org/obc
Imidazoline-catalyzed enantioselective Friedel–Crafts (FC)-type tion producing the adduct in high yields with high
reactions were established using C3-symmetric chiral trisimid- enantioselectivity.
azolines. The imidazoline catalysts promoted the FC-type reaction
An asymmetric FC-type reaction between phenols and aldi-
of aldimines with 2-naphthols to produce the corresponding mines is an important preparation route for the optically
adducts in high yields with up to 99% ee.
active α-aminomethylphenol unit,7,8 which is often found in
pharmaceutically important compounds9 and is widely uti-
lized in asymmetric transformations.10 The first enantio-
selective FC-type reaction of 2-naphthol and aldimines was
presented by Hui7a in 2010 using a stoichiometric amount of a
chiral zinc complex. In 2011, Wang7b and Chimni7c indepen-
dently reported catalytic enantioselective processes using
chiral organocatalysts derived from Cinchona alkaloids. We11e
also developed chiral dinuclear vanadium complexes for
the enantioselective FC-type reaction via a dual activation
mechanism.11
Our group previously reported the organocatalytic enantio-
selective Michael reaction and bromolactonization with tris-
imidazoline 1a.6 We assumed that in the trisimidazoline-
catalyzed reaction of aldimines with 2-naphthols, one imidazo-
line could function as a Brønsted base and other imidazoline
as a proton donor, leading to a straightforward coupling to
produce the adducts in high enantioselectivity (Fig. 2). As the
first step in the development of the FC-type process, the reac-
tion of aldimines 2 and 2-naphthol (3a) was attempted using a
5 mol % of the chiral trisimidazoline 1a (Table 1). Among the
substituent R imine groups we tested, the aryl sulfonyl groups
Asymmetric organocatalysis is one of the most attractive
approaches to synthesize optically pure compounds without
using any precious or toxic metals.1 In particular, chiral
organocatalysts with two or more reaction-promoting func-
tional groups are of current interest in recent enantioselective
synthesis.2 The functionalities on the catalyst activate the sub-
strates by a synergistic cooperation,3 creating the products
efficiently. Imidazolines have great potential as reaction-pro-
moting units because of their basicity and nucleophilicity, and
the Brønsted acidity of their salts.4 However, chiral imid-
azolines as organocatalysts have not been adequately studied
until now.5,6 Herein, we report the first chiral imidazoline-cata-
lyzed Friedel–Crafts (FC)-type reaction of aldimines with
2-naphthols. The C3-symmetric chiral trisimidazolines
(Fig. 1) work as powerful organocatalysts for the FC-type reac-
1
Fig. 1 Chiral trisimidazoline catalysts 1.
aThe Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihoga-
oka, Ibaraki-shi, Osaka 567-0047, Japan. E-mail: taki@sanken.osaka-u.ac.jp
bGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita-shi, Osaka 565-0871, Japan. E-mail: murai@phs.osaka-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00925h
Fig. 2 A plausible transition state for the FC-type reaction of aldimines
with 2-naphthols.
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The optimal result was obtained when the reaction of 2h with
3a was performed in toluene at −5 °C for 36 h (Table 2, entry 1).
When N-4-nosyl imines 2h–j containing an electron with-
drawing group (R1 = 4-, 3- or 2-Cl-C6H4) were utilized as sub-
strates under the optimal conditions, the organocatalyst 1a
efficiently promoted the reactions with 3a producing the
adducts 4h–j in high yields and high enantioselectivities
(Table 2, entries 1–3). The catalyst 1a mediated the reaction of
aldimine 2k, which possesses an electron rich aromatic ring
(R1 = 4-Me-C6H4), to afford the FC product 4k in 77% ee (entry
5). However, the use of the newly designed trisimidazoline 1b
which was derived from (1S,2S)-1,2-bis(4-methoxyphenyl)-
ethane-1,2-diamine improved the ee value of 4k (90% ee, entry
6) while maintaining the high chemical yield. The organocata-
lyst 1b also successfully activates the various substrates to
afford 4 in high yields with high enantioselectivity (entries 4
and 7–11). 2-Furyl N-4-nosylimine (2q), 6-methoxy-2-naphthol
(3b), and sesamol (3c) were applicable substrates for the reac-
tion (entries 12–14).15 The highest enantiomeric excess value
was obtained from the reaction of 3-methylphenyl N-4-nosyl-
Table 1 Coupling reaction of imines 2 with 2-naphthol (3a) mediated
by the chiral trisimidazoline catalyst 1aa
Temp.
(°C)
Time
(h)
Yieldb
(%)
eec
(%)
Entry
R
1
2
3
4
5
6
7
8
9
4-Br-C6H4 (2a)
Boc (2b)
PhSO2 (2c)
25
25
25
25
25
25
−5
−5
−5
24
24
24
24
24
12
24
24
24
82 (4a)
17 (4b)
88 (4c)
70 (4d)
65 (4e)
100 (4f)
100 (4f)
72 (4g)
70 (4h)
rac
17
22
27
30
40
48
63
96
4-Ts (2d)
4-MeO-C6H4SO2 (2e)
4-Cl-C6H4SO2 (2f)
2f
4-Br-C6H4SO2 (2g)
4-Ns (2h)
a Reaction conditions: 2 (0.1 mmol), 3a (0.15 mmol), 1a (5 mol %),
toluene (0.4 mL), N2. b Isolated yield. c Determined by HPLC (Chiralpak
AS-H for 4a; Chiralpak IB for 4b; Chiralcel OD-3 for 4c and 4h;
Chiralpak IC for 4d; Chiralpak IA for 4e; Chiralcel OD-H for 4f and 4g). imine (2l) with 3a to give the corresponding adduct 4l with
99% ee (entry 7).
The ability of the hydrogen atom attached to the nitrogen
resulted in products with relatively good yields and moderate
enantioselectivities (Table 1, entries 1–6); the reaction of 2f
(R = 4-Cl-C6H4SO2) with 3a gave the FC adduct 4f in 40% ee
quantitatively (entry 6).12 Using more electron deficient aryl
sulfonyl groups on the aldimines and lowering the reaction
temperature had positive effects on the enantioselectivities
(entries 7–9); the reaction of N-4-nosyl imine 2h (R = 4-NO2-
C6H4SO2) produced the FC adduct 4h in 96% ee (entry 9).13,14
in the catalyst 1 to play an important role in the promotion of
the high enantiocontrol reaction was suggested by the alkyl-
ation of N-methyl trisimidazoline 5, where no hydrogen bond-
interaction that was depicted in Fig. 2 could be formed and
therefore a low yield and a reduced enantioselectivity were
observed (Scheme 1). Since lower enantioselectivity and cata-
lytic activity were observed when using bisimidazoline 6 and
monoimidazoline 7 (Scheme 2), the three chiral imidazoline
Table 2 Chiral trisimidazoline-catalyzed Friedel–Crafts (FC)-type reactiona
Entry
1
R1
R2
3
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1a
1b
1b
1b
1b
1b
1b
1b
1b
2h
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
36
48
24
24
36
36
24
36
48
24
96
24
48
89 (4h)
92 (4i)
97 (4j)
96
98
83
88
77
90
99
85
90
73
73
72
77
3-Cl-C6H4
2-Cl-C6H4
4-Ns (2i)
4-Ns (2j)
2j
4-Ns (2k)
2k
4-Ns (2l)
4-Ns (2m)
4-Ns (2n)
4-Ts (2o)
4-Ns (2p)
4-Ns (2q)
2h
90 (4j)
4-Me-C6H4
100 (4k)
100 (4k)
95 (4l)
98 (4m)
90 (4n)
80 (4o)
100 (4p)
100 (4q)
90 (4r)
3-Me-C6H4
3-F-C6H4
4-Br-C6H4
3-NO2-C6H4
Ph
9
10
11d
12
13
2-Furyl
6-MeO-2-naphthol (3b)
14d
1b
2h
96
96 (4s)
84
a Reaction conditions: 2 (0.1 mmol), 3 (0.15 mmol), 1 (5 mol %), toluene (0.4 mL), −5 °C, N2. b Isolated yield. c Determined by HPLC (Chiralcel OD-3
for 4h and 4s; Chiralpak AD-H for 4i, 4k and 4p–q; Chiralpak IC-3 for 4l, 4j, 4o and 4r; Chiralpak IE for 4m; Chiralcel OD-H for 4n). d At −35 °C.
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Scheme 1 An FC-type reaction catalyzed by N-methyl trisimidazoline 5.
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Scheme 2 An FC-type reaction catalyzed by bisimidazoline
monoimidazoline 7.
6 and
units on the catalyst 1 were essential. These units construct
three equally-aligned reaction sites, to enable an efficient cata-
lytic activity and highly asymmetric induction ability.
Conclusions
We have discovered the first imidazoline-mediated highly
enantioselective FC-type reaction between aldimines 2 and
2-naphthols 3. Various aryl imine substrates bearing either
electron-withdrawing or electron-donating groups could be
successfully employed with 5 mol % of the C3-symmetric chiral
trisimidazolines 1. An investigation into the reaction mechan-
ism and the scope, as well as its application to enantioselective
synthesis of biologically active compounds, is currently
underway.
Acknowledgements
This study was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas – Advanced Molecular Trans-
formations by Organocatalysis – from The Ministry of Edu-
cation, Culture, Sports, Science and Technology (MEXT),
Japan, the CREST project of the Japan Science and Technology
Corporation (JST), and JST Advance Catalytic Transformation
Program for Carbon Utilization (ACT-C). We acknowledge the
technical staff of the Comprehensive Analysis Center of ISIR,
Osaka University (Japan).
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5830 | Org. Biomol. Chem., 2014, 12, 5827–5830
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