Triflic acid-catalyzed highly stereoselective friedel-crafts aminoalkylation of indoles and pyrroles

Article abstract of DOI:10.1021/ol703095d

A simple and efficient synthesis to both enantiomers of highly enantiomerically enriched α-trifluoromethyl-α-(heteroaryl)-glycine derivatives via highly stereoselective aminoalkylation of indoles and pyrroles is described. The triflic acid-catalyzed react

Full text of DOI:10.1021/ol703095d

ORGANIC
LETTERS
2008
Vol. 10, No. 5
933-935
Triflic Acid-Catalyzed Highly
Stereoselective Friedel Crafts
Aminoalkylation of Indoles and Pyrroles
−
Mohammed Abid, Liliana Teixeira, and Be´la To1ro1k*
Department of Chemistry, UniVersity of Massachusetts Boston, 100 Morrissey BlVd.
Boston, Massachusetts 02125-3393
bela.torok@umb.edu
Received December 23, 2007
ABSTRACT
A simple and efficient synthesis to both enantiomers of highly enantiomerically enriched
r
-trifluoromethyl-
r
-(heteroaryl)-glycine derivatives
via highly stereoselective aminoalkylation of indoles and pyrroles is described. The triflic acid-catalyzed reaction of enantiomeric 3,3,3-
trifluoro-pyruvate- -methylbenzyl imines with indoles and pyrroles and the subsequent Pd-catalyzed hydrogenolysis of the methylbenzyl group
r
provided the products in high yields and excellent enantioselectivities.
The discovery of the beneficial effects of fluorine incorpora-
tion into organic molecules1 has drawn extensive attention
to synthetic organofluorine chemistry.2 Among organofluo-
rine compounds, trifluoromethyl group-containing products
are especially important.3 Fluorinated amino acids represent
new prospects in the construction of hyperstable protein folds
and in the production of highly specific protein-protein
interfaces. The CF3 group also serves as a reporting group
in 19F NMR studies.4 The expansion of their applications,
however, is strongly hindered by the very limited number
of synthetic procedures.
The electrophilic aminoalkylation of aromatic compounds
with R-iminoesters, a type of the well-known Friedel-Crafts
reaction,5 is a viable approach for the synthesis of aminoac-
ids.6 Asymmetric Friedel-Crafts reactions have been de-
veloped using chiral electron-deficient metal complexes,7
organocatalysts,8 and most recently chiral Brønsted acid
catalysts.9 Despite these efforts, there is no direct asymmetric
(1) Fried, J.; Sabo, E. F. J. Am. Chem. Soc. 1954, 76, 1455.
(2) Soloshonok, V. A., Ed. Enantiocontrolled Synthesis of Fluoro-organic
Compounds: Stereochemical Challenges and Biomedicinal Targets;
Wiley: New York, 1999; Ramachandran, P. V., Ed. Asymmetric Fluoro-
organic Chemistry; ACS Symp. Series; American Chemical Society:
Washington, D.C., 2000; Hiyama, T., Ed. Organofluorine Compounds;
Springer: Berlin, 2001; Kirsch, P. Modern Fluoroorganic Chemistry:
Synthesis, ReactiVity, Applications; Wiley-VCH: New York, 2004; Solos-
honok, V. A., Ed. Fluorine-Containing Synthons; ACS Symp. Series;
American Chemical Society: Washington D.C., 2005; Prakash, G. K. S.;
Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172.
(4) Yoder, N. C.; Kumar, K. Chem. Soc. ReV. 2002, 31, 335; Lazzaro,
F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.; Malpezzi, L.; Volonterio,
A.; Zanda, M. Tetrahedron: Asymmetry 2004, 15, 889; Papeo, G.; Giordano,
P.; Brasca, M. G.; Buzzo, F.; Caronni, D.; Ciprandi, F.; Mongelli, N.;
Veronesi, M.; Vulpetti, A.; Dalvit, C. J. Am. Chem. Soc. 2007, 129, 5665.
(5) Olah, G. A., Ed. Friedel-Crafts and Related Reactions; Wiley: New
York, 1965; Sheldon, R. A., van Bekkum, H., Eds. Friedel-Crafts Alkylation;
Wiley-VCH: New York, 2001.
(6) Johannsen, M. Chem. Commun. 1999, 2233; Saaby, S.; Fang, X.;
Gartherhood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 4114;
Jiang, B.; Huang, Z.-G. Synthesis 2005, 2198.
(7) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 160; Bandini, M.; Melloni, A.; Umani-Ronchi,
R. Angew. Chem., Int. Ed. 2004, 43, 550; Evans, D. A.; Fandric, K. A.;
Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942.
(3) Prakash, G. K. S.; Yudin, A. Chem. ReV. 1997, 97, 757; Prakash, G.
K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40, 589;
To¨ro¨k, M.; Abid, M.; Mhadgut, S. C.; To¨ro¨k, B. Biochemistry 2006, 45,
5377.
10.1021/ol703095d CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

Friedel-Crafts method available for the synthesis of fluori-
nated aminoacid derivatives, although few racemic processes
have been reported.10 The sporadic asymmetric Friedel-
Crafts reactions of imines and enamines focus on electron-
rich imines and produce amines.9
Our success in enantioselective Friedel-Crafts hydroxy-
alkylations with ethyl trifluoropyruvate (ETFP),11 prompted
us to extend the use of this valuable synthon. Herein, we
describe the first superacid-catalyzed chiral Friedel-Crafts
aminoalkylation with chiral imines derived from ethyl
trifluoropyruvate. We demonstrate that, with the application
of enantiomeric 3,3,3-trifluoro-pyruvate-R-methylbenzyl imi-
nes in the reaction with substituted 5-membered N-heteroaro-
matics (indoles and pyrroles), the synthesis of both enanti-
omeric products is possible (Scheme 1).
to produce N-phenylethyl-R-trifluoromethyl-R-(N-heteroaryl)-
glycine esters. In the last step, the benzyl group is cleaved
by Pd-catalyzed hydrogenolysis to obtain the target com-
pounds (3-6).
Optimization of the reaction conditions with indole as the
aromatic starting material identified the nonoxidizing, su-
peracidic trifluoromethanesulfonic acid (TfOH, triflic acid)
as the catalyst of choice for the aminoalkylation.12 We have
found that the expected products could be synthesized under
mild conditions in high yields (usually 90-94%).
The removal of the benzylic group was executed by Pd-
catalyzed hydrogenolysis.13 In the hydrogenolysis step the
Pearlman’s catalyst (Pd(OH)2/C) provided the best yields
(usually >90%). After determination of the optimum condi-
tions, we carried out the reaction sequence (Scheme 1) using
both (R)- and (S)-enantiomers of 2, respectively, with several
indole and pyrrole derivatives. The results are tabulated in
Tables 1 and 2.
Scheme 1. Synthesis of Chiral 3,3,3-Trifluoro-2-
(Indol-3-yl)-2-Amino-Propionic Acid Esters via Stereoselective
Friedel-Crafts Aminoalkylation
Table 1. Synthesis of Chiral 3,3,3-Trifluoro-2-(Indol-3-yl)-
2-Amino-Propionic Acid Esters via Stereoselective
Friedel-Crafts Aminoalkylationa
entry R1
R2
R3
2
product yield [%]b ee [%]c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-OMe
5-OMe
5-CO2Me (R) 3c (S)
5-CO2Me (S) 4c (R)
5-Me
5-Me
H
H
H
H
6-iPr
6-iPr
7-Me
7-Me
H
(R) 3a (S)
(S) 4a (R)
(R) 3b (S)
(S) 4b (R)
83
82
83
73
75
85
82
75
85
84
86
73
86
90
85
84
75
79
92
90
93
90
93
90
93
94
85
86
87
93
97
97
96
96
80d
60
(R) 3d (S)
(S) 4d (R)
(R) 3e (S)
(S) 4e (R)
(R) 3f (S)
(S) 4f (R)
(R) 3g (S)
(S) 4g (R)
(R) 3h (S)
(S) 4h (R)
(R) 3i (S)
(S) 4i (R)
To synthesize chiral R-trifluoromethylated-R-(N-heteroaryl)-
glycines through a simple approach, we have chosen R-meth-
ylbenzylamine, which is commercially available in both
enantiomeric forms. The enantiomeric imines (2) were
synthesized by K-10 montmorillonite-catalyzed condensation
of the amines with ETFP. This convenient method made
possible the bulk preparation of the starting material (2) in
excellent yields (98%).
9
Me
Me
Me Me
Me Me
H
H
H
H
H
H
10
11
12
13
14
15
16
17
18
H
H
H
H
CO2Et
CO2Et
Our approach is based on the Friedel-Crafts aminoalkyl-
ation of 5-membered N-heteroaromatics with these imines
H
a Reactions were carried out with 1.1 mmol of 2, 1 mmol of indole, and
1.6% (w/v) triflic acid in 4.5 mL CH2Cl2 at -40 °C; the hydrogenolysis
took place on 10% Pd(OH)2/C in 5 mL EtOH at rt under 5 bar H2. b Isolated
overall yields. c Determined by chiral HPLC. d X-ray analysis
(8) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370; Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576; Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 8156; Kang, Q.; Zhao, Z.-A.; You, S.-L. J.
Am. Chem. Soc. 2007, 129, 1484.
(9) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292; Kang,
Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484; Jia, Y.-X.;
Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2007, 46, 5565.
(10) Onys’ko, P. P.; Rassukanaya, Yu. V.; Sinitsa, A. D. Z. Obsch. Knim.
2002, 72, 1699; Soloshonok, V. A.; Kukhar, V. P. Z. Org. Khim. 1990, 26,
419; Osipov, S. N.; Chkanikov, N. D.; Shklyaev, Yu. V.; Kolomiets, A. F.;
Fokin, A. V. IzV. Akad. Nauk, Ser. Khim. 1989, 2131; Osipov, S. N.;
Chkanikov, N. D.; Kolomiets, A. F.; Fokin, A. V. IzV. Akad. Nauk, Ser.
Khim. 1986, 1384.
The data in Tables 1-2 show that the aminoalkylation
took place in high yields with very high stereoselectivity.
(12) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids; Wiley: New
York, 1985.
(13) (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436. (b)
Bisel, P.; Breifling, E.; Frahm, A. W. Eur. J. Org. Chem. 1998, 729. (c)
To¨ro¨k, B.; Prakash, G. K. S. AdV. Synth. Catal. 2003, 345, 165.
(11) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut,
S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086.
934
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Synthesis of Chiral 3,3,3-Trifluoro-2-(Pyrrol-2-yl)-2-
Amino-Propionic Acid Esters via Stereoselective Friedel-Crafts
Aminoalkylationa
entry
R1
R2
2
product
yield [%]b
ee [%]c
1
2
3
4
5
6
H
H
Me
Me
H
H
H
H
H
Et
Et
(R)
(S)
(R)
(S)
(R)
(S)
5a (S)
6a (R)
5b (S)
6b (R)
5c (S)
6c (R)
82
75
77
72
81
74
97
94
84
98
91
84
H
a Reactions were carried out with 1.1 mmol of 2, 1 mmol of pyrrole,
and 1.6% (w/v) triflic acid in 4.5 mL CH2Cl2 at -40 °C; the hydrogenolysis
took place on 10% Pd(OH)2/C in 5 mL EtOH at rt under 5 bar H2. b Isolated
overall yields. c Determined by chiral HPLC.
Figure 1. X-ray crystal structure of 3i for determination of the
absolute configuration of the chiral center formed in the aminoalkyl-
ation.
The overall isolated yields after the two steps were in the
72-90% range, indicating that the individual steps occurred
in about 90% yield each. The diastereomeric excesses (de)
of the intermediates were usually excellent (>97%) except
when using 2-carbethoxyindole, where the bulky substituent
in the 2 position resulted in decline in the de. More
importantly, the final enantiomeric excesses (ee) after
hydrogenolysis were mostly excellent (up to 97% and 98%
ee for the enantiomeric products). Although the yields are
slightly lower with substituted pyrroles, the enantiomeric
excess values are very high with both indoles and pyrroles.
The lower yields are most likely due to the higher acid
sensitivity of pyrroles.
The stereoselective aminoalkylation showed practically no
limitation in using substituted indoles and pyrroles. However,
it is worth mentioning that although the Friedel-Crafts
aminoalkylation occurred with very high stereoselectivity
with 5-halo-indoles (Cl, Br, I), the use of Pd catalyst in the
hydrogenolysis step resulted in the complete loss of the
halogens from the carbocyclic ring. In these cases, 3a and
4a were isolated, respectively, rather then the desired
halogenated products. Further investigations are underway
to solve this problem.
premature. Preliminary theoretical calculations indicated that
steric factors generated by the chiral auxiliary are primarily
responsible for the almost exclusive product formation. In
the case of (R)-R-trifluoromethyl-R-ketimino-ester, the het-
eroaromatic compounds attack from the Re face, yielding a
new chiral center in the product with predominantly (S)-
configuration.
In conclusion, we have developed an efficient synthesis
to both enantiomers of highly enantiomerically enriched
R-trifluoromethyl-R-(heteroaryl)-glycine derivatives. Besides
the high yields and enantioselectivities, the major advantages
of the process are clean and fast reactions and the commercial
availability of the chiral auxiliaries and catalyst, allowing
selective synthesis of both enantiomers of the products. The
new trifluoromethylated aminoacid derivatives represent a
potentially important new class of compounds with possible
extension to the synthesis of fluorinated peptides and other
compounds.
Acknowledgment. Respectfully dedicated to my (B.T.)
mentor, Professor George A. Olah on the occasion of his
80th Birthday. Financial support provided by University of
Massachusetts Boston and NIH (R-15 AG025777-02) is
gratefully acknowledged.
To characterize the stereochemistry of the products, the
absolute configuration of the (indol-3-yl)-trifluoromethyl
glycine ester 3i has been determined by X-ray crystal-
lography. The optical purity of 3i was improved to 100% ee
via fractional crystallization. The X-ray crystal structure of
3i is shown in Figure 1. The analysis of the structure leads
to an assignment of the chiral center formed in the reaction
as (S) (Figure 1).
Supporting Information Available: Complete experi-
mental details along with spectroscopic data for all com-
pounds synthesized. This material is available free of charge
via the Internet at http://pubs.acs.org.
At this point in our studies, discussion of the detailed
mechanism leading to the observed enantioselectivity is
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Org. Lett., Vol. 10, No. 5, 2008
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