The asymmetric Friedel-Crafts reaction of indoles with fluoroalkylated nitroalkenes catalyzed by chiral phosphoric acid

Article abstract of DOI:10.1002/ejoc.201100683

The enantioselective Friedel-Crafts fluoroalkylation of indoles with fluoroalkylated nitroalkenes, catalyzed by chiral phosphoric acid is described. The regioselectivity of fluoroalkylated nitroalkenes is a problem worth discussing, and it was found that the carbon atom adjacent to the fluoroalkyl group is more reactive than that adjacent to NO₂ group.

Full text of DOI:10.1002/ejoc.201100683

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100683
The Asymmetric Friedel–Crafts Reaction of Indoles with Fluoroalkylated
Nitroalkenes Catalyzed by Chiral Phosphoric Acid
Jin-Hong Lin[a] and Ji-Chang Xiao*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Friedel–Crafts reactions / Fluoroalkylation / Enantioselectivity
The enantioselective Friedel–Crafts fluoroalkylation of in-
doles with fluoroalkylated nitroalkenes, catalyzed by chiral
phosphoric acid is described. The regioselectivity of fluoro-
alkylated nitroalkenes is a problem worth discussing, and it
was found that the carbon atom adjacent to the fluoroalkyl
group is more reactive than that adjacent to NO2 group.
Introduction
The enantioselective Friedel–Crafts alkylation of indoles
with nitroalkenes has attracted considerable attention be-
cause it is recognized as one of the most efficient methods
for the preparation of biologically active compounds such
as indole alkaloids. Over the past several years, the reaction
has witnessed significant progress, and much effort has been
focused on the development of new catalyst systems for the
asymmetric alkylation.[1–4] But the design of novel nitro-
alkenes, which might lead to novel products with strong
bioactivities, is largely ignored. Within the realm of medici-
nal chemistry, the introduction of CF3– or –CF2– groups
is a powerful and widely employed tactic to improve the
biological properties of drugs.[5] Therefore, it would be
interesting to incorporate fluoroalkylated nitroalkenes into
the Friedel–Crafts reaction of indoles. Furthermore, the re-
gioselectivity of fluoroalkylated nitroalkenes might become
a problem worth discussing because of the strong electrone-
gativity and large steric hindrance of the fluoroalkylated
substituents[6] (Scheme 1), relative to the non-fluoroalkyl-
ated analogues.
Recently, chiral BINOL-derived phosphoric acid has
been found to be a versatile organocatalyst in a variety of
reactions.[7] The asymmetric nitroalkylation of indoles cata-
lyzed by phosphoric acid was realized by Akiyama et al. in
2008.[1e] To improve the yield and enantioselectivity of the
reaction, activated and powdered molecular sieves (MS)
must be added. Besides, low temperatures were necessary
for good enantioselectivity. However, the reaction becomes
retarded at low temperature. Especially for the aliphatic ni-
troalkenes, the reaction time had to be prolonged to 10 d
Scheme 1.
with 20 mol-% catalyst in order to achieve moderate yields.
Recently, You et al. also found that the reaction of 4,7-
dihydroindoles[8] or pyrroles[9] with nitroalkenes could be
catalyzed by chiral phosphoric acid. However, the reaction
did not work very well with aliphatic nitroalkenes either. It
seemed that the aliphatic nitroalkenes could not efficiently
be activated by chiral phosphoric acid. Fluoroalkylated ni-
troalkenes should possess a different reactivity to the usual
aliphatic ones because of the presence of fluorine. To ex-
plore the reactivity of the fluoroalkylated nitroalkenes and
to develop a practical synthetic method for the fluorinated
indole derivatives, we investigated the chiral phosphoric
acid catalyzed asymmetric reaction of indoles with fluoro-
alkylated nitroalkenes.
Results and Discussion
Under the catalysis of phosphoric acid 3a (10 mol-%),
the reaction of indole (1a) (1 equiv.) with 3,3,3-trifluoro-1-
nitroprop-1-ene (2a) (2 equiv.) in dichloromethane pro-
ceeded smoothly to give 4a in 85% yield (Table 1, Entry 1).
The CF3 group exhibits a comparable electronegativity with
that of the NO2 group and a higher steric hindrance. How-
ever, the reaction occurs exclusively at the carbon atom ad-
jacent to the CF3 group. Unfortunately, almost no enantio-
[a] Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China
Fax: +86-21-6416 6128
E-mail: jchxiao@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100683.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4536–4539

Friedel–Crafts Reaction of Indoles with Fluoroalkylated Nitroalkenes
selectivity was observed under the catalysis of 3a. After the ene. Therefore, a mixture of ClCH2CH2Cl/C6H6 was chosen
introduction of substituents at the 3,3Ј-positions of the bi- as the optimal solvent.
naphthyl scaffold, the enantioselectivity was still very poor
Both Akiyama[1e] and You[8,9] found that the addition of
(Entries 2–5). To our delight, the enantioselectivity could molecular sieves is of great importance in chiral phosphoric
be significantly improved with further increase in the size acid catalyzed Friedel–Crafts reactions. Therefore, we ex-
of the substituent at the 3,3Ј-positions. The reaction cata- amined the effect of molecular sieves on this fluoroalk-
lyzed by 3f with two triphenylsilyl substituents gave an ee ylation (Table 1, Entries 15–17). In contrast to their results,
value of 67% of 4a(Entry 6). However, the phosphoric acids we found that the presence of molecular sieves decreases
with other bulky substituents were not so efficient for the the ee substantially, even though the reaction time was
reaction (Entry 7 and 8). Catalyst 3i, derived from octahy- shortened.
dro-(R)-BINOL, could not induce good enantioselectivity
It was found that the reaction of 1a with 2a proceeded
either (Entry 9). These results showed that 3f is a suitable smoothly at room temperature without any catalyst or sol-
catalyst for this asymmetric fluoroalkylation.
Table 1. Screening of reaction conditions.[a]
vent. It might be probable to obtain a higher ee by lowering
the reaction temperature. The starting materials were mixed
at –35 °C. The reaction mixture was then warmed to –5 °C
and stirred at this temperature until completion of the reac-
tion (Entries 18 and 19). As expected, the ee increased (En-
try 18), but the reaction time became longer; therefore fur-
ther lowering of the temperature is not necessary. In an at-
tempt to shorten the reaction time, 20 mol-% catalyst was
used (Entry 19). As can be seen, the reaction time was
shortened and a higher ee was obtained. Therefore, 20 mol-
% of 3f as catalyst, ClCH2CH2Cl/C6H6 as the solvent, and
–5 °C were considered to be the most suitable reaction con-
ditions.
A series of indoles and fluoroalkyl nitroalkenes were then
subjected to these optimal reaction conditions. As summa-
rized in Table 2, the reactions of indole with fluoroalkylated
1-nitroprop-1-ene proceeded smoothly to give the desired
products with good yields and enantioselectivities (Entries
1–4). The introduction of bulky groups such as PhCF2 or
4-MeOPhCF2 into nitroalkene had no effect on the regio-
selectivities, but resulted in lower yields and ee values (En-
Time
Yield
[%][b]
ee
Entry Catalyst Solvent
[d]
[%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
2.5
1
3
2
85
93
83
89
89
93
81
78
94
78
85
93
93
trace
94
93
93
93
93
1
1
21
25
13
67
27
7
3.5
3
Table 2. Asymmetric Friedel–Crafts reactions of indoles with fluo-
roalkylated nitroalkenes, catalyzed by chiral phosphoric acid.[a]
4.5
2.5
2.5
2.5
1.5
2
2
1
1
1
9
CH2Cl2
9
10
11
12
13
14
15
16
17
18
19
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
CHCl3
46
71
73
73
–
50
51
39
83
85
ClCH2CH2Cl
ClCH2CH2Cl/C6H6
PhMe
[d]
THF
[d,e]
ClCH2CH2Cl/C6H6
PhMe[e]
Time
[d]
4, yield
ee [%][c]
[f]
Entry
R
Rf
CH2Cl2
ClCH2CH2Cl/C6H6
ClCH2CH2Cl/C6H6
[%][b]
[d,g]
6
5
[d,g,h]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
CF3
5
4a, 93
4b, 92
4c, 89
4d, 98
4e, 78
4f, 70
4g, trace
4h, 97
4i, 90
4j, 88
4k, 98
4l, 90
85
77
84
82
79
75
–
86
89
76
87
89
CF2Cl
CF2Br
CF2H
PhCF2
4-MeOC6H4CF2 10
CF3
3.5
4.5
6
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol) and catalyst
3 in solvent (1 mL) at room temperature. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] ClCH2CH2Cl/C6H6 (0.6 mL/
0.6 mL) were used. [e] 3-Å MS (10 mg) was used. [f] 4-Å MS
(10 mg) was used. [g] The starting materials were mixed at –35 °C,
and the reaction proceeded at –5 °C. [h] 20 mol-% catalyst was
used.
9
4-Cl
5-MeO CF3
6-Me CF3
4-MeO CF2Br
5-MeO CF2Br
6-Me
5
4
3
6
2.5
2.5
9
10
11
12
Suitable solvents were then also screened in the presence
of 3f (Table 1, Entries 10–14). The ee value was slightly im-
proved when the reaction was conducted in a mixture of
ClCH2CH2Cl/C6H6 or toluene. However, in ClCH2CH2Cl/
CF2Br
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol) and catalyst
3f (20 mol-%) in ClCH2CH2Cl/C6H6 (1.2 mL/1.2 mL) at –5 °C. [b]
C6H6, a shorter reaction time was needed than that in tolu- Isolated yield. [c] Determined by chiral HPLC analysis.
Eur. J. Org. Chem. 2011, 4536–4539
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J.-H. Lin, J.-C. Xiao
SHORT COMMUNICATION
tries 5 and 6). This indicates that the steric hindrance of
nitroalkene influences the yield and selectivity. In the case
of 4-chlorinated indole, only trace amounts of product were
detected by TLC (Entry 7). The presence of chlorine leads
to an electron deficiency of indole, which results in low re-
activity of indole toward nitroalkenes. When this procedure
was applied to other indoles with electron-donating groups,
good yields and enantioselectivities were obtained again
(Entries 8–12).
As shown in Figure 1, a transition state is proposed. Chi-
ral phosphoric acid acts as a bifunctional catalyst, which
activates both the nucleophile and electrophile by hydrogen
bonding. To support this hypothesis, further evidence has
been collected (Scheme 2). It was found that the absence of
a hydrogen atom on the nitrogen atom or the presence of a
methyl group at the 2-postion of indole decreases the
enantioselectivity greatly under the same reaction condi-
tions. Hence, the N–H moiety is responsible for the forma-
tion of hydrogen bonds. The presence of the methyl group
at the 2-position of indole might block the formation of
hydrogen bonding as a result of steric hindrance.
Experimental Section
1H NMR spectra were recorded with a Bruker AM-300 (300 MHz)
or Varian VXR (300 MHz) spectrometer. 19F NMR spectra were
recorded with a Bruker AM-300 (282 MHz) with CFCl3 as an ex-
ternal standard (negative for upfield). 13C NMR spectra were re-
corded with a Bruker AM-400 (100 MHz) spectrometer. MS was
recorded with a Hewlett–Packard HP-5989A spectrometer. Ele-
mental analyses were obtained with a Perkin–Elmer 2400 Series II
Elemental Analyzer. Infrared spectra were measured with a Perkin–
Elmer 983 spectrometer. Optical rotations were measured on a JA-
¯
SCO P1030 Polarimeter at λ = 589 nm. Analytical high perform-
ance liquid chromatography (HPLC) was carried out on a Waters
515 instrument (2487 dual λ absorbance detector and a 515 HPLC
pump) by using a chiral column. Unless otherwise noted, reagents
were commercially available and used as received.
Typical Procedure for the Asymmetric Friedel–Crafts Reactions:
Under N2 atmosphere, the solution of indole (23.4 mg, 0.2 mol)
and chiral phosphoric acid 3f (34.3 mg, 0.04 mmol) in
ClCH2CH2Cl/C6H6 (0.6 mL/0.6 mL) was cooled to 35 °C. The
solution of 3,3,3-trifluoro-1-nitroprop-1-ene (56 mg, 0.4 mmol) in
ClCH2CH2Cl/C6H6 (0.6 mL/0.6 mL) was then added slowly over
15 min. The resulting solution was warmed to –5 °C and stirred at
this temperature until the reaction was complete as monitored by
TLC.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis of the fluoroalkyl-
ated nitroalkenes and for the asymmetric Friedel–Crafts reactions
are presented. The 1H NMR, 19F NMR, 13C NMR and HPLC
spectra of the compounds are also given.
Figure 1. Proposed transition state.
Acknowledgments
We thank the Chinese Academy of Sciences and the National Natu-
ral Science Foundation (20972179, 21032006) for financial support.
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An enantioselective Friedel–Crafts fluoroalkylation of
indoles catalyzed by chiral phosphoric acid has been de-
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Received: May 15, 2011
Published Online: July 12, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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