Friedel-Crafts alkylation of natural amino acid-derived pyrroles with CF3-substituted cyclic imines

Article abstract of DOI:10.1016/j.mencom.2013.03.013

Natural amino acid-derived ethyl 2-(1-pyrrolyl)alkanoates react with 2-trifluoromethyl-1-azacycloalkenes selectivity at the β-position of the pyrrole moiety to afford ethyl 2-[3-(1-trifluoromethyl-2-azacycloalkyl)pyrrol-1- yl]alkanoates.

Full text of DOI:10.1016/j.mencom.2013.03.013

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 92–93
Friedel–Crafts alkylation of natural amino acid-derived
pyrroles with CF3-substituted cyclic imines
Olga I. Shmatova,a Nikolay E. Shevchenko,a Elizabeth S. Balenkova,a
Gerd-Volker Röschenthaler*b and Valentine G. Nenajdenko*a
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
b School of Engineering and Science, Jacobs University Bremen GmbH, 28759 Bremen, Germany.
E-mail: g.roeschenthaler@jacobs-university.de
DOI: 10.1016/j.mencom.2013.03.013
Natural amino acid-derived ethyl 2-(1-pyrrolyl)alkanoates react with 2-trifluoromethyl-1-azacycloalkenes selectivity at the b-position
of the pyrrole moiety to afford ethyl 2-[3-(1-trifluoromethyl-2-azacycloalkyl)pyrrol-1-yl]alkanoates.
Recently we have elaborated the synthesis of perfluoroalkylated
(CF3- and C2F5-substituted) cyclic imines1,2 and started inves-
tigation of their use as promising fluorine-containing building
blocks.3 It worth noting that both nitrogen heterocyclic core and
fluorine-contaning fragment are very important structural units of
many biological active compounds comprising modern pharma-
ceutical and crop protection products.4
leucine and isoleucine.8 Early diastereoselective aminoalkyla-
tion of indoles and pyrroles with chiral imines was studied.6(e),(d)
Pyrroles with a chiral moiety derived from the natural amino
acids have never been studied in such kind of reactions. This
situation motivated us to investigate the aminoalkylation of various
CF3-cyclic imines 1 with chiral pyrroles 4 and its diastereo-
selectivity.
Having these considerations in mind, we decided to investigate
the a-CF3 substituted cyclic imines in Friedel–Crafts type amino-
alkylation of (hetero)aromatics. This study is focused on the reac-
tion of such imines with easy accessible chiral pyrroles derived
from natural amino acids. Pyrrole moiety is presented in many
natural compounds5 and chiral fragment may affect stereo outcome
of the reaction. Investigation of diastereoselectivity in these reac-
tions seemed of special interest.
H2N
COOEt
SOCl2 /EtOH
100%
H2N
COOH
R
R
6
5
R
COOEt
OMe
O
MeO
N
In literature, only several examples of the aromatic substitu-
tion with fluorine-containing imines have been reported to date.6
Highly active fluorinated imines bearing additional electron-with-
drawing groups both on nitrogen and imine carbon atoms are able
to react with electron-rich aromatics without any activators or in
the presence of Brønsted acids. Other fluorinated imines require
promoting by stronger Lewis acid, e.g. BF3·Et2O. In addition,
reaction of cyclic imines with heteroaromatics is known only for
non-fluorinated aldimines (pyrroline and tetrahydropyridine).7
The starting CF3-cyclic imines 1a–c were prepared from
N-protected lactams 2 using our previously published two-step
method (Scheme 1).1 First step of the synthetic sequence is Claisen
condensation of N-protected lactams 2 with ethyl trifluoroacetate
followed by deprotection. Subsequent decarboxylation of per-
fluoroacyl lactams 3 in acidic media afforded CF3-cyclic imines
after treatment with sodium hydroxyde.
AcOH, AcONa
58–69%
4a R = H
4d R = Bn
4b R = Me 4e R = Bui
4c R = Ph 4f R = Busec
Scheme 2
Using glycine derived pyrrole 4a and 2-trifluoromethylpyr-
roline 1a, we performed optimization of the reaction conditions
and screening of the Lewis and Brønsted acids as activators.
We examined equimolar amounts of TfOH, BF3·Et2O and TiCl4
as imine activators. In a typical experiment, imine 1a was mixed
with 1 equiv. of the catalyst in dichloromethane at 0°C. Then,
pyrrole 4a was added at the same temperature and progress of
the reaction was monitored by 19F NMR. No reaction was observed
at all for TfOH. In the case of TiCl4 reaction was complete within
2 h giving the product 7a in 81% yield (Scheme 3). The reaction
promoted by BF3·Et2O required longer but reasonable reaction
time (5 days) and provided the slightly lower yield (75%). Never-
theless, there were no side products in the latter case, so the
isolation of product 7a was easier. The structure of product 7a
Starting chiral pyrroles 4 were synthesized in good yields by
condensation of 1,4-dimethoxytetrahydrofurane with ethyl esters
of amino acids 5 (Scheme 2), which were prepared from natural
amino acids 6: glycine, alanine, phenylglycine, phenylalanine,
i, CF3CO2Et,
O
i, 6 M HCl
ii, 50% NaOH
NaH
CF3
O
ii, H+
n
n
CF3
O
COOEt
H
CF3
CF3
n
BF3·Et2O
(75%)
N
N
COOEt
N
+
N
NH
PG
N
N
1a n = 1
1b n = 2
1c n = 3
or TiCl4
(81%)
2
3
1a
4a
7a
Scheme 1
© 2013 Mendeleev Communications. All rights reserved.
Scheme 3
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Mendeleev Commun., 2013, 23, 92–93
Table 1 Aminoalkylation reaction of pyrroles 4a–f with imines 1a–c.
was quite unusual. We expected to obtain a-substituted pyrrole,7
however, in fact b-substitution product was formed regardless BF3
or TiCl4 were used as a catalyst. Apparently, such a regioselec-
tivity could occur due to steric hindrance of bulky intermediate
iminium species. The structure of compound 7a was undoubtedly
proved using HMBC experiment (for details of HMBC correla-
tions, see Online Supplementary Materials).
The transformations were carried out in the similar manner
for other N-substituted pyrroles 4† with BF3·Et2O and/or TiCl4 as
activators (Scheme 4). No restrictions on the structure of pyrroles
4 or trifluoromethylated imines 1 were found. b-Substituted pyr-
roles 7a–j bearing both pyrrolidine moiety and its homologues
were synthesized in good yields (Table 1). However, according
to NMR data, no diastereoinduction was observed and 1:1 mixture
of diastereomers was formed in cases of chiral substrates 4b–f
since newly formed stereocentres are too distant from starting
chirality.
R
n
Product
Yield (%)
H
Me
Ph
Bn
Bui
Busec
H
Me
H
1
1
1
1
1
1
2
2
3
3
7a
7b
7c
7d
7e
7f
7g
7h
7i
75 (81)a
69 (73)
(81)
74
87
(68)
62
75
65
Me
7j
60
aYields with TiCl4 are given in parentheses.
This work was supported by the Russian Foundation for Basic
Research (grant no. 11-03-01167-a) and the Deutsche Forschungs-
gemeinschaft (RO 362/42-1).
BF3·Et2O
H
CF3
CF3
or TiCl4
CO2Et
R
N
N
CO2Et
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.03.013.
+
N
N
n
n
R
1a–c
4a–f
7a–j
References
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Scheme 4
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successfully involved in the Friedel–Crafts aminoalkylation with
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s
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†
General procedure for preparation of 7. Freshly distilled BF3·Et2O
(0.126 ml, 1 mmol) or TiCl4 (0.11 ml, 1 mmol) was added slowly under
vigorous stirring and cooling to a solution of imine 1 (1 mmol) in dry
dichloromethane (10 ml). After 5 min a solution of the corresponding
pyrrole (1 mmol) in dichloromethane (3–4 ml) was added dropwise. The
mixture was stirred for 2 h at 0°C in the case of TiCl4 and 5 days at room
temperature for BF3·Et2O. After that the reaction mixture was quenched with
saturated aqueous solution of NaHCO3 (15 ml), extracted with dichloro-
methane (2×10 ml), the combined organic extracts were dried over Na2SO4,
concentrated under reduce pressure and the residue was purified by column
chromatography on silica gel eluting with dichloromethane affording target
amine to give after solvent evaporation products 7.
Ethyl {3-[2-(trifluoromethyl)pyrrolidin-2-yl]-1H-pyrrol-1-yl}acetate 7a:
1
71%, yellow oil. H NMR (400 MHz, CDCl3) d: 1.29 (t, 3H, CH2Me,
J 7.13 Hz), 1.81–1.99 (m, 3H), 2.12–2.19 (m, 1H), 2.32–2.39 (m, 1H),
3.04–3.17 (m, 2H, CH2N), 4.23 (q, 2H, CO2CH2Me, J 7.13 Hz), 4.58 (s,
2H, CH2CO2Et), 6.19–6.22 (m, 1H, HAr), 6.62–6.63 (t, 1H, HAr, J 2.52 Hz),
6.68–6.69 (m, 1H, HAr). 13C NMR (100 MHz, CDCl3) d: 13.9 (Me), 26.0,
34.0 (CH2Cq), 47.3 (CH2N), 50.8 (CH2CO2Et), 61.6 (CO2CH2Me), 66.3
(q, CCF3, JCF 27.3 Hz), 107.8 (Ar), 119.7 (Ar), 122.1 (Ar), 124.4 (Cq, Ar),
127.5 (q, CF3, JCF 282.7 Hz), 168.4 (CO). 19F NMR (280 MHz, CDCl3)
d: –78.6 (CF3). IR (KBr, n/cm–1): 3367, 1753, 1155. Found (%): C, 53.85;
H, 5.99; N, 9.58. Calc. for C13H17F3N2O2 (%): C, 53.79; H, 5.90; N, 9.65.
For characteristics of compounds 7b–j, see Online Supplementary
Materials.
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Received: 3rd December 2012; Com. 12/4027
– 93 –