Chiral Bronsted acid-mediated enantioselective organocatalytic three-component reaction for the construction of trifluoromethyl-containing molecules

Article abstract of DOI:10.1002/adsc.200800239

In combination with the advantages of organocatalysis, we have developed a highly enantioselective Friedel-Crafts aminoalkylation of indoles with imines generated in situ from trifluoroacetaldehyde methyl hemiacetal and aniline. Novel chiral trifluoromethyl-containing compounds were obtained in high yields with excellent enantioselectivities. This methodology was further extended to difluoroacetaldehyde methyl hemiacetal to demonstrate the broad scope of substrates.

Full text of DOI:10.1002/adsc.200800239

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DOI: 10.1002/adsc.200800239
Chiral Brønsted Acid-Mediated Enantioselective Organocatalytic
Three-Component Reaction for the Construction of Trifluoro-
methyl-Containing Molecules
Guang-Wu Zhang,a Lian Wang,a Jing Nie,a and Jun-An Maa,b,*
a
Department of Chemsitry, Tianjin University, Tianjin 300072, Peopleꢀs Republic of China
Fax : (+86)-22-2740-3475; e-mail: majun_an68@tju.edu.cn
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: April 20, 2008; Published online: June 23, 2008
Dedicated to Prof. Manfred T. Reetz on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: In combination with the advantages of or-
ganocatalysis, we have developed a highly enantio-
selective Friedel–Crafts aminoalkylation of indoles
with imines generated in situ from trifluoroacetalde-
hyde methyl hemiacetal and aniline. Novel chiral
trifluoromethyl-containing compounds were ob-
tained in high yields with excellent enantioselectivi-
ties. This methodology was further extended to di-
fluoroacetaldehyde methyl hemiacetal to demon-
strate the broad scope of substrates.
catalytic asymmetric reactions with chiral metal com-
plexes and small organic molecules have been report-
ed.[4]
To the best of our knowledge, no enantioselective
catalytic three-component reaction for the synthesis
of chiral trifluoromethylated compounds has been re-
ported. More recently, chiral phosphoric acids were
found to have efficient asymmetric catalytic activi-
ties.[5] The applications have been extended to a large
range of asymmetric transformations,[6] among which
the Friedel–Crafts alkylation of aromatic compounds
with imines or enamides has attracted attention over
Keywords: Brønsted acids; enantioselectivity; Frie-
del–Crafts reaction; organocatalysis; organofluorine
compounds
À
the past several years as a versatile C C bond-form-
ing process.[7] While these publications are excellent,
troublesome imines or enamides have to be prepared
beforehand. Herein, we present the first highly enan-
tioselective, organocatalytic Friedel–Crafts aminoal-
kylation with imines generated in situ from trifluoro-
The incorporation of a CF3 group with its potent elec-
C
leads to significant changes in the physical, chemical,
As trifluoroacetaldehyde hemiacetal itself is an
and biological properties of the parent compounds. active electrophilic reagent, the reaction conditions
Thus, over the past decades trifluoromethylated com- must be chosen carefully in accordance with the fol-
pounds have attracted considerable attention in or- lowing terms: 1) the direct reaction of trifluoroacetal-
ganic synthesis, medicinal and agrochemical chemis- dehyde hemiacetal with an indole is likely; therefore,
try, and materials sciences.[1] In this context, structures the reaction of the imine or N,O-acetal generated in
in which the CF3 group is attached to a stereogenic situ from trifluoroacetaldehyde hemiacetal and amine
center are gaining increasing importance. Despite the with indole must be faster than the direct reaction. 2)
numerous methodologies available,[2] advances in the Undesired racemization and bisindole alkylation
synthesis of such compounds are still in great events must be rigorously avoided (Scheme 1). Taking
demand. The asymmetric transformation of prochiral these considerations into account, we initiated screen-
trifluoromethylated materials is one of the most im- ing experiments using chiral phosphoric acids 1 as or-
portant strategies as it provides a powerful route to ganocatalysts. The results are shown in Table 1.[10] The
structurally elaborated molecules.[3] However, previ- simplest catalyst 1a was able to catalyze this one-pot
ous asymmetric processes of the starting trifluoro- reaction smoothly to give the desired product in 90%
methyl-containing chemicals have mostly relied on a yield, but with almost no enantioselectivity (entry 1).
stoichiometric amount of chiral auxiliaries. Recently, Accordingly, a series of phosphoric acids with varying
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Scheme 1. Three-component reaction for the synthesis of trifluoromethyl-containing compounds.
Table 1. Screening of catalysts and reaction conditions for the three-component reaction.
Entry
Catalyst (mol%)
ArNH2 (4)
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (10)
1h (5)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ClCH2CH2Cl
toluene
CH2Cl2
ClCH2CH2Cl
CHCl3
90
72
62
93
93
80
66
97
97
99
99
99
83
85
85
42
63
92
À3
25
17
39
29
39
5
47
64
92
94
92
90
91
95
96
93
92
9
10
11
12
13
14
15
16[c]
17
18[d]
CCl4
Et2O
CH3CN
CH2Cl2
CH2Cl2
1h (10)
[a]
Isolated yield.
[b]
[c]
[d]
Enantiomeric excess was determined by chiral HPLC analysis.
Reaction time: 72 h.
At 08C for 48 h.
substituents at the 3,3’-positions of the binaphthyl gave both the best selectivity (47% ee) and highest
scaffold was prepared and tested in the model reac- chemical yield (97%). The enantioselectivity in-
tion (entries 2–8). The use of catalyst 1h with bulky creased to 64% ee when the reaction was carried out
2,4,6-triisopropylphenyl groups at the 3,3’-positions in dichloroethane (entry 9). The structure of the
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amine component has a considerable effect on the re- proceeded in toluene, chlorinated alkanes and ether
action (see Supporting Information). It was encourag- to afford the desired product in good to high yields
ing to find that high enantioselectivity and reactivity and with high enantioselectivity (entries 11–15). Ace-
could be obtained by means of 3,4,5-trimethoxylani- tonitrile gave a slight improvement in the enantiomer-
line (entry 10). Following this evaluation of chiral cat- ic excess, but a low conversion rate was obtained even
alysts, a solvent screen was undertaken. The reaction with a longer reaction time (entry 16). Among the sol-
Table 2. Scope of the enantioselective Brønsted acid catalyzed three-component reaction.
Entry
1
Product
Time [h]
24
Yield [%][a]
99
ee [%][b]
5a
5b
5c
5d
5e
94 (>99.9)[c]
2
3
4
5
72
24
72
72
83
99
99
90
95
92
94
92
6
7
8
5f
5g
5h
5i
48
48
48
96
95
97
99
80
90
96
98
79
9
[a]
Isolated yield.
[b]
[c]
Enantiomeric excess was determined by chiral HPLC analysis.
After recrystallization.
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vents tested, dichloromethane was found to be the reaction. A weak hydrogen-bonded complex could be
best with respect to catalytic activity and asymmetric formed between the phosphoric acid and the
induction. When lowering the reaction temperature indole.[11] On the other hand, the absolute configura-
or decreasing the amount of catalyst, a drop-off in tion of the desired adducts was determined to be R
both the reaction rate and ee value of the product was by X-ray measurements on a single crystal of product
observed (entries 17 and 18).
5a, as well as by comparison with the sign of optical
With these optimized conditions in hand, the gener- rotation of the deprotected compound reported in the
al scope of indole derivatives was examined in the literature (Figure 1).[8b,12] Regarding the mechanism of
asymmetric, organocatalytic, three-component reac- this one-pot three component reaction, we assume
tion in the presence of chiral phosphoric acid 1h. As that, in the first step, the reaction of trifluoroacetalde-
highlighted in Table 2, a wide range of functional hyde methyl hemiacetal with aniline readily provides
groups, including alkyl, methoxy, halogen, and ester the corresponding N,O-acetal and imine in the pres-
groups, can be readily tolerated on the indole ring. ence of phosphoric acid and molecular sieves at room
Excellent enantioselectivities of more than 90% ee temperature. Moreover, the N,O-acetal forms an equi-
were obtained, and the enantioenriched products librium with the imine, which is protonated and acti-
were formed in good yield (entries 1–8). However, by vated by the chrial phosphoric acid to shield the Si
contrast, the substituent at the 2-position of the face of the imine. Subsequently, the indole attacks
indole has a little effect on the reactivity and enantio- mainly from the Re face of the imine to give the cor-
selectivity. For example, the reaction of 2-methylin- responding product with an R configuration, and the
dole needed 96 h to give the desired product in 80% chiral catalyst is regenerated (Figure 2). Thus, the
yield with a 79% ee value (entry 9). To the best of our phosphoric acid provides a chiral environment, as
knowledge, this is the best enantioselective result re- well as positioning the reaction partners in close prox-
ported to date for the Friedel–Crafts reaction of a 2- imity and with the correct relative geometry to facili-
substituted indole.
tate this reaction in a synergistic manner.
It is very interesting that when both N-acetylindole
and N-benzylindole were employed as substrates, re-
This methodology was further extended to difluoro-
acetaldehyde methyl hemiacetal to demonstrate the
A
spectively, no reaction was observed, thereby demon- scope of this one-pot, three-component reaction. We
strating that the hydrogen on the N atom of the found that the solvent influenced the reaction rate
indole is crucial for the activation of the reactant by and selectivity. Dichloromethane did not lead to full
the phosphoric acid catalyst in this three-component conversion, and resulted in a less than 75% ee value.
Figure 1. X-ray structure of (R)-5a and deprotection of (R)-5a.
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Brønsted Acid-Mediated Enantioselective Organocatalytic Three-Component Reaction
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Figure 2. Proposed reaction mechanism.
Scheme 2. Organocatalytic enantioselective synthesis of difluoromethyl-containing compounds.
However, a considerable improvement was observed Experimental Section
with acetonitrile. The reactions performed in this sol-
vent exhibited improved quantitative yields and excel- Typical Pocedure
lent enantioselectivities (Scheme 2).
Brønsted acid catalyst 1h (18.8 mg, 0.025 mmol) was added
to a mixture of indole (43.8 mg, 0.37 mmol), trifluoroacetal-
dehyde methyl hemiacetal (48.8 mg, 0.37 mmol), 3,4,5-trime-
thoxyaniline (45.7 mg, 0.25 mmol) and powdered 4 Š molec-
ular sieves (50 mg) in dichloromethane (1.0 mL). The result-
ing mixture was stirred at room temperature for 24 h. Then,
the reaction solution was concentrated under vacuum, and
the residue was purified by silica gel flash column chroma-
tography (petroleum ether/AcOEt: 15:1) to give the desired
product 5a as a white solid; yield: 94.3 mg (99%, 94% ee).
In conclusion, we have developed an asymmetric,
catalytic, one-pot, three-component Friedel–Crafts-
type reaction by employing chiral phosphoric acids as
efficient catalysts. The use of trifluoroacetaldehyde
hemiacetal as a stable, easily handled, and commer-
cially available prochiral trifluoromethyl-containing
source, in combination with the advantages of organo-
catalysis, allows this simple protocol. A series of
indole derivatives can be aminoalkylated in high yield
with excellent enantioselectivity. High enantioselectiv-
ity is also achieved with difluoroacetaldehyde hemi-
acetal. Further studies on the application of these
chiral trifluoromethyl and difluoromethyl compounds
to other areas of chemistry and chemical synthesis are
currently underway in our laboratory.
Acknowledgements
We gratefully appreciate the National Natural Science Foun-
dation of China (No. 20772091), and the Ministry of Educa-
tion of China for generous financial support.
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Brønsted Acid-Mediated Enantioselective Organocatalytic Three-Component Reaction
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