Novel enantiocomplementary C2-symmetric chiral bis(imidazoline) ligands: Highly enantioselective Friedel-Crafts alkylation of indoles with ethyl 3,3,3-trifluoropyruvate

Article abstract of DOI:10.1002/adsc.200800189

Enantioselective Friedel-Crafts alkylations of a variety of indoles with ethyl 3,3,3-trifluoropyruvate catalyzed by novel chiral m-phenylene- bis(imidazoline)-copper(II) complexes or the bis-(imidazoline)-achiral acid combination afforded products with high enantioselectivity. Both enantiomers of indole derivatives can be prepared with high enantioselectivities by tuning the N-substituents of the imidazoline.

Full text of DOI:10.1002/adsc.200800189

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DOI: 10.1002/adsc.200800189
Novel Enantiocomplementary C2-Symmetric Chiral
Bis(imidazoline) Ligands: Highly Enantioselective Friedel–Crafts
Alkylation of Indoles withEthyl 3,3,3-Trifluoropyruvate
Shuichi Nakamura,a,* Kengo Hyodo,a Yuko Nakamura,a Norio Shibata,a
and Takeshi Torua,*
a
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-5442; e-mail: snakamur@nitech.ac.jp or toru@nitech.ac.jp
Received: March 30, 2008; Published online: June 9, 2008
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Enantioselective Friedel–Crafts alkyla-
tions of a variety of indoles with ethyl 3,3,3-trifluo-
ACHTREUNG
ACHTREUNG
ACHTRE(UNG F-C) alkylation of indole derivatives with ethyl 3,3,3-
trifluoropyruvate (1). Outstanding aspects of these li-
gands are also described: (i) a new dual activation
mechanism for the chiral induction is proposed, (ii)
both enantiomers can be obtained with phebim by
changing the substituents on the nitrogen atom and
the counter ion of the cupric salt, and (iii) phebim
acts as a chiral Brønsted acid by the action of an achi-
ral acid without using a Lewis acid. The F-C alkyla-
tion of indole derivatives was chosen as a benchmark
reaction for using phebim, since the synthesis of
indole derivatives has captured much attention in or-
ganic chemistry for many decades.[4,5] Catalytic enan-
tioselective F-C alkylation reactions of indole deriva-
tives using chiral Lewis acids[6] and organocatalysts[7]
have been reported.
ACHTREUNG
products with high enantioselectivity. Both enantio-
mers of indole derivatives can be prepared with
high enantioselectivities by tuning the N-substitu-
ents of the imidazoline.
Keywords: asymmetric catalysis; Friedel–Crafts re-
action; imidazolines; Lewis acids
The development of asymmetric catalysts has been
Various novel bis(imidazoline) ligands 2c–p were
extensively studied over the last decade. Certainly, prepared by the reaction of benzene-1,3-dicarbalde-
one of the privileged classes of chiral ligands is the hyde, chiral 1,2-diphenylethylenediamine, and NBS as
bis(oxazoline) framework, which consists of two N,O- an oxidant[8] giving phenylenebis(imidazoline), fol-
containing five-membered rings coordinating to a lowed by sulfonylation and acylation.[9,10]
metal cation.[1] Fine tuning of the electron density and
The results of the F-C alkylation of indole with 1
the steric bulkiness of the oxazoline ring remain to be using imidazoline catalysts are shown in Table 1. The
solved. The highly tuneable construction of bis(imida- reaction using chiral Lewis acids prepared from Cu-
[11]
zoline) ligands would overcome this limitation and re-
alize better matching of chiral ligands, metal ions, and
N
and mono-imidazoline 2a or pyridine-bis-
(imidazoline) (pybim) 2b[2d,f,j] in CH2Cl2 at À788C af-
substrates other than bis(oxazoline)s, and thus forded the product (R)-3a with low enantioselectivity
ACHTREUNGachieve excellent catalytic performance. We started to (entries 1 and 2). On the other hand, the reaction
explore bis(imidazoline) catalytic reactions several using N-p-toluenesulfonyl-substituted phebim 2c gave
years ago. During our study, a number of studies of (R)-3a in high yield with 94% ee (entry 3). As we ex-
asymmetric synthesis using Lewis acid-bis(imidazo- pected, the enantioselectivity of 3a depended on the
line) catalysts have appeared.[2,3] Herein we report substituents on the imidazolyl nitrogen atoms. The re-
new excellent bis(imidazoline) ligands, “phebims”, action using various N-arenesulfonyl- or N-alkanesul-
having various substituents, in the asymmetric Frie- fonyl-substituted phebims 2d–k with CuACHTREUNG
del–Crafts
Adv. Synth. Catal. 2008, 350, 1443 – 1448
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Shuichi Nakamura et al.
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Table 1. Enantioselective reaction of indole with 1 using various chiral imidazoline ligands with CuACHTREU(GN OTf)2 or CF3SO2H in
CH2Cl2.
Run
Ligand
Lewis Acid
Cu(OTf)2
Solvent
Yield [%] of 3a
ee [%][a]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2n
2q
2c
2c
2c
2c
2q
N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
81
88
93
86
53
78
42
75
58
77
84
47
79
87
95
97
91
83
96
0
1
Cu
Cu
U
94 (R)
93 (R)
74 (R)
84 (R)
80 (R)
88 (R)
46 (R)
6 (R)
20 (R)
23 (R)
18 (R)
77 (R)
95 (R)
93 (R)
87 (R)
82 (R)
48 (R)
Cu
Cu
Cu
Cu
Cu
Cu
Cu
ACHTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
ACHTREUNG
9
10
11
12
13
14
15[b]
16[c]
17[d]
18
19
Cu
A
Cu
Cu
Cu
ACHTREUNG
ACHTREUNG
AHCTREUNG
Cu
Cu
Cu
ACHTREUNG
AHCTREUNG
AHCTREUNG
TfOH
TfOH
[a]
Determined by chiral HPLC analysis.
Catalyst loading is 5 mol%.
Catalyst loading is 0.5 mol%.
Catalyst loading is 0.2 mol%.
[b]
[c]
[d]
than that from the reaction using 2c (entries 4–11). lectivity (entries 16 and 17). Thus, the turnover num-
N,N’-Dibenzolylbis(imidazoline) 2l also afforded (R)- bers (TONs) reached to almost 200 together with
3a but with low enantioselectivity (entry 12). On the high enantioselectivity. Phebim 2c was found to work
other hand, the reaction using the phebox ligand 2q as a chiral Brønsted acid catalyst in combination with
as a bis(oxazoline)-type ligand gave (R)-3a with lower CF3SO3H to give (R)-3a with a good level of enantio-
enantioselectivity than when using 2c (entry 14). We selectivity (entry 18), whereas the combination of
next attempted to decrease the catalyst loading. Even phebox 2q with CF3SO3H activated the reaction to
0.5 mol% of 2c worked efficiently, and the reaction give (R)-3a with lower enantioselectivity than that ob-
using 0.2 mol% of 2c showed slightly lower enantiose- tained by the 2c-CF3SO3H combination. The absolute
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Novel Enantiocomplementary C2-Symmetric Chiral Bis(imidazoline) Ligands
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Table 2. Enantioselective reaction of indole with 1 using various chiral bis(imidazoline) ligands with CuCAHTREU(GN NTf2)2 or Tf2NH.
Run
Ligand
Acid
Solvent
Yield [%] of 3a
ee [%][a]
1
2
2l
Cu
Cu
Cu
Cu
Cu
Cu
Cu
C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
93
27
99
53
61
95
95
90
62 (S)
56 (S)
90 (S)
83 (S)
12 (S)
88 (S)
80 (S)
73 (S)
2m
2n
2o
2p
2n
2n
2n
3[b]
4[b]
5[b]
6[b,c]
7[b,d]
8
Tf2NH
[a]
Determined by chiral HPLC analysis.
Molecular sieves 4 Š were added.
Catalyst loading is 5 mol%.
[b]
[c]
[d]
Catalyst loading is 0.5 mol%.
stereochemistry of product 3a was assigned to be R in tion, N-methylindole drastically changed the chiral in-
comparison with the value of the specific rotation re- duction giving the racemic 3a and decreased the reac-
ported in the literature.[6c]
tivity in comparison with the reaction of the unpro-
Interestingly, the reaction using N-benzoyl-substi- tected indole (Table 3, entry 1 vs. 19). These results
tuted phebim 2l and Cu(NTf2)2 in toluene afforded suggest that hydrogen bonding of the indole N-H to
(S)-3a having a stereochemistry opposite to that ob- the imidazoline nitrogen plays an important role in
tained in the reaction using phebims and Cu(OTf)2 enhancing the reactivity and, hence, enantioselectivity.
(Table 2, entry 1).[12,13] Optimization experiments for Avoiding bidentate chelation of phebim with Cu2+,[16]
the fine tuning of the substitution of phebim 2 were phebim 2c would form a complex with Cu(OTf)2 that
AHCTREUNG
AHCTREUNG
AHCTREUNG
carried out to improve the enantioselectivity of (S)- in turn activates pyruvate 1 as a chelating Lewis acid
3a. Electron-withdrawing substituents on the bis(imi- (Figure 1),[17] where the triflate is placed at the
dazoline) showed high enantioselectivity, i.e., N-p-ni- upward position avoiding the steric interaction with
trobenzoyl-substituted phebim 2n was found to be the phenyl group on the imidazoline ring. Through
very efficient (entry 3). The catalyst loading of 2n can this dual activation transition state, indole approaches
be reduced to 5 mol% without loss of enantioselectiv- the Si face of the carbonyl attached to the trifluoro-
ity, although the reaction using 0.5 mol% of 2n result- methyl group. It is known that the nitrogen of N-sul-
ed in slightly lower enantioselectivity (entries 6 and fonylimidazoline takes the pyramidal structure, while
7). It should be noted that the 2n-Tf2NH combination N-benzoyl- and N-alkylimidazolines have planar ni-
gave (S)-3a with good enantioselectivity (entry 8), trogens.[2h] It is possibly due to the drastic change in
showing that phebim 2n acts as a chiral Brønsted acid the nitrogen structure of bis(imidazoline) that the re-
in combination with Tf2NH.
actions using 2c and 2n gave 3 with opposite stereo-
We next examined the reaction of 1 with various in- chemistry. Further experiments are needed to prove
doles using two catalytic systems, method A; the above assumed transition state.
2c-Cu
A
and
method
B;
2n-Cu
A
In conclusion, we have developed novel m-pheny-
AHCTRElUNG enebis(imidazoline)-Lewis acid systems for the F-C
(Table 3).[14] The results indicate that (R)- and (S)-3a–
j can be obtained in high yield with good to high alkylation of indoles. With our new phebim ligands,
enantioselectivity by the respective method (en- catalyst loading can be successfully minimized up to
tries 5–18) and that enantiocomplementary synthesis 0.5 mol% without a significant decrease in yield and
is generally quite applicable.[15]
enantioselectivity. The efficient enantioflexible stereo-
We propose the dual activation transition state for control can be achieved by changing the substituents
the reaction of indole and trifluoropyruvate in the on imidazoline, the counter anion of the Lewis acid,
presence of phebim-Cu
lowing results. Reactions of indole with 1 in the pres- Brønsted acid in combination with an achiral acid.
ence of 5 mol% of 2a-Cu(OTf)2 or 2c-Cu(OTf)2 and The above outstanding aspects in the reactivity of
ACHTREU(NG OTf)2 on the basis of the fol- and the solvent. In addition, phebim works as a
A
ACHTREUNG
in the absence of the catalyst were carried out in phebim are possibly due to the dual activation of
CD2Cl2 at À788C for 1 min, and then the mixture was indole and pyruvate by two imidazoline rings, thus, ef-
quenched with CD3OD. The reaction with fecting the chiral induction. Further experiments are
2c-Cu
reactions using 2a-Cu
gave 3a in 13% and 19% yield, respectively. In addi-
ACHTREUNG
AHCTREUNG
Adv. Synth. Catal. 2008, 350, 1443 – 1448
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shuichi Nakamura et al.
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Table 3. Enantioselective reaction of various indoles with 1.
Entry
R
Method
Time [h]
Product
Yield [%]
ee [%]
1
2
3
4
H
H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
3
4
2
4
1
4
4
4
19
17
17
17
17
17
50
34
2
(R)-3a
(S)-3a
(R)-3b
(S)-3b
(R)-3c
(S)-3c
(R)-3d
(S)-3d
(R)-3e
(S)-3e
(R)-3f
(S)-3f
(R)-3g
(S)-3g
(R)-3h
(S)-3h
(R)-3i
(S)-3i
3j
95
99
91
81
85
94
95
99
95
99
99
96
92
99
75
80
92
99
79
95
90
60
67
90
93
86
91
93
97
87
93
87
96
51
80
57
80
1
2-Me
2-Me
5-Me
5-Me
5-F
5-F
5-Cl
5-Cl
5-Br
5-Br
5-I
5-I
5-CO2Me
5-CO2Me
5-OMe
5-OMe
N-Me
5
6
7[a]
8
9
10
11
12
13
14
15[b]
16[b]
17
18
19
5
17
[a]
2c (10 mol%) and CuACHTREU(NG OTf)2 (11 mo%) were used.
Warmed to À608C.
[b]
Figure 1. Proposed reaction mechanism of the reaction of indole with 1 using the 2c-CuCAHTRE(UGN OTf)2 combination
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Novel Enantiocomplementary C2-Symmetric Chiral Bis(imidazoline) Ligands
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Experimental Section
Typical Procedure for the Friedel–Crafts Reaction
using the Phebim Ligand: (2R)-Ethyl 3,3,3-Trifluoro-
2-hydroxy-2-(indol-3-yl)propionate [(R)-3a]
To a mixture of CuACHTRE(UNG OTf)2 (2.5 mg, 6.91 mmol), 2c (6.3 mg,
7.60 mmol) and molecular sieves 4 Š (24 mg) in CH2Cl2
(1.0 mL) was added 1 (20.2 mL, 0.152 mmol) at À788C.
After stirring for 30 min, a solution of indole (16.2 mg,
0.138 mmol) in CH2Cl2 (1.0 mL) was slowly added. After
disappearance of indole in the reaction mixture on TLC, the
solvent was removed under reduced pressure to give a resi-
due which was purified by column chromatography (hexane/
Et2O=55:45) giving 3a as a white solid; yield: 37.6 mg
(95%).
Acknowledgements
[5] The products are known to act as an inhibitor of amy-
loid fibrillogenesis for Alzheimerꢁs disease; see: M.
Tçrçk, M. Abid, S. C. Mhadgut, B. Tçrçk, Biochemistry
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This work was supported by the Mitsubishi Chemical Corpo-
ration Fund. We are grateful to Central Glass Co. for a gift of
1.
[6] For a recent review on asymmetric F-C alkylations
using chiral Lewis acids, see: a) M. Bandini, A. Mello-
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[13] The reaction using 2c with Cu
53% yield with 3% ee.
ACHTRE(UNG NTf2)2 afforded (S)-3a in
[14] Molecular sieves 4 Š improved reproducibility of the
reaction.
[15] Enantioselective reactions of pyrroles and N,N-dialk-
[8] H. Fujioka, K. Murai, Y. Ohba, A. Hiramatsu, Y. Kita,
Tetrahedron Lett. 2005, 46, 2197–2199.
AHCTREUNG
[9] Recently, preparations of similar m-phebims from
chiral amino alcohols have been reported, see: a) X.
Hao, J. Gong, C. Du, L. Wu, Y. Wu, M. Song, Tetrahe-
dron Lett. 2006, 47, 5033–5036; b) M. Ishihara, H.
Togo, Synthesis 2007, 1939–1942; see also refs.[2b,h]
ACHTREUNG
tivity.
[16] Bidentate chelation of phebim with Cu2+ could be
ruled out because of the significant repulsive effect of
the phenyl proton and Cu2+.
[10] For recent reviews of bis
A
[17] A similar dual activation mechanism in the oxidation
of tryptophan by human tryptophan dioxygenase has
been reported, in which the activations by hydrogen
bonding of indole to the imidazole nitrogen in histidine
and by coordination of oxygen to Fe2+ are involved,
see: D. Batabyal, S.-R. Yeh, J. Am. Chem. Soc. 2007,
129, 15690–15701.
(Phebox), see: a) H. Nishiyama, Chem. Soc. Rev. 2007,
36, 1133–1141; b) H. Nishiyama, J. Ito, Chem. Rec.
2007, 7, 159–166.
[11] With various other Lewis acids such as CuOTf,
A
ACHTREUNG(OTf)2, ZnACHTREUNG(OTf)2 , and ScACHTRE(UGN OTf)3, the enantioselec-
1448
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Adv. Synth. Catal. 2008, 350, 1443 – 1448