pyrroles with R,β-unsaturated carbonyl compounds,5
nitroolefins,6imines,7 and ketones,8 but there are no exam-
ples of analogous reactions with aldehydes. On the other
hand, application of acylpyrroles in asymmetric FꢀC
reactions is very limited.7c,8b
complex as the most efficient catalyst.12 An asymmetric
FꢀC reaction of indoles with ethyl glyoxylate catalyzed
by similar complexes was discovered by Xiao and co-
workers.13 In this case, the corresponding ethyl 3-indolyl-
(hydroxy)acetates were formed in good yields and with
high enantiomeric excess. Those results encouraged us to
study the reaction of pyrroles with activated aldehydes.
Table 1. Optimization of the Model Reaction of 1a with 2 and 3a
Figure 1. BINOLꢀTi catalysts 6aꢀc.
Herein we describe a highly enantioselective Friedelꢀ
Crafts reaction of acylpyrroles with alkyl glyoxylates catal-
yzed by BINOLꢀTi(IV) complexes (Figure 1). This reac-
tion allows for the synthesis of chiral pyrrolyl-hydroxya-
cetates, a structural motif that can be found in various
biologically active molecules.9 To date, compounds of this
type have been synthesized using different approaches.10,9a
In our investigation we focused on enantioselective FꢀC
reactions of pyrroles having one electron-withdrawing
group (EWG) at the R, β or N-positions with activated
aldehydes, e.g. alkyl glyoxylates. Pyrroles with other types
of substituents are more nucleophilic and usually easily
form racemic products with alkyl glyoxylates and aryl-
glyoxals without catalysts.11
catalyst
temp
yield
(%)b
ee
entry
product
(5 mol %)
(°C)
(%)c
1
2
3
4
5
6
4
6a
6b
6c
6c
6c
6c
0
0
0
0
65
64
77
85
80
90
79
91
91
93
89
93
4
4
5a
5a
5a
20
ꢀ40 to 0
a The reactions were carried out using 5 mol % of catalyst (6aꢀc), 1.5
mmol of alkyl glyoxylate (2 or 3) in 2 mL of toluene, and 1.0 mmol of
2-acetyl-1-methylpyrrole (1a), at appropriate temperature. b Isolated
yield. c Enantiomeric excess determined by HPLC using chiral columns.
We initially investigated the reaction of commercially
available 2-acetyl-1-methylpyrrole (1a) and ethyl glyoxy-
late (2) in the presence of BINOLꢀTi(IV) complexes 6aꢀc
in toluene (Figure 1, Table 1). The catalyst 6b derived from
(R)-6,60-dibromo-BINOL give higher enantioselectivity
(91% ee, entry 2) than catalyst 6a with unsubstituted
(R)-BINOL (79% ee, entry 1). Adjusting the molar ratio
of BINOL and Ti(OPri)4 led to a slight improvement in
yield, when a 2:1 complex (catalyst 6c) was employed
(entry 3). In further studies, we decided to use catalyst
6c, also because of the positive nonlinear effect which was
observed in our previous work.12a Changing ethyl glyoxy-
late (2) to the more stable n-butyl glyoxylate (3) brought a
slight increase in the enantiomeric excess (93% ee) and
yield (85%) of product 5a (entries 4ꢀ6).
Recently we reported a highly enantioselective FꢀC reac-
tion of furans and thiophenes with alkyl glyoxylates cata-
lyzed by the optically pure 6,60-dibromo-BINOLꢀTi(IV)
€
(6) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438.
€ €
(7) (a) Abid, M.; Teixeira, L.; Torok, B. Org. Lett. 2008, 10, 933. (b)
Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett. 2007, 9,
4065. (c) Johannsen, M. Chem. Commun. 1999, 2233. (d) He, Y.; Lin, M.;
Li, Z.; Liang, X.; Li, G.; Antilla, J. C. Org. Lett. 2011, 13, 4490.
ꢁ
ꢁ
(8) (a) Blay, G.; Fernandez, I.; Monleon, A.; Pedro, J. R.; Vila, C.
Org. Lett. 2009, 11, 441. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
ꢁ
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009. (c) Blay, G.; Fernandez,
~
I.; Munoz, M. C.; Pedro, J. R.; Recuenco, A.; Vila, C. J. Org. Chem.
2011, 76, 6286.
(9) (a) Biava, M.; Porretta, G. C.; Poce, G.; Supino, S.; Manetti, F.;
Forli, S.; Botta, M.; Sautebin, L.; Rossi, A.; Pergola, C.; Ghelardini, C.;
Norcini, M.; Makovec, F.; Giordani, A.; Anzellotti, P.; Cirilli, R.;
Ferretti, R.; Gallinella, B.; La Torre, F.; Anzini, M.; Patrignani, P.
Bioorg. Med. Chem. 2008, 16, 8072. (b) Santo, R. D.; Costi, R.; Roux, A.;
Artico, M.; Befani, O.; Meninno, T.; Agostinelli, E.; Palmegiani, P.;
Turini, P.; Cirilli, R.; Ferretti, R.; Gallinella, B.; Torre, F. L. J. Med.
After establishing the optimal conditions for the model
reaction we explored the scope and the generality of the
FꢀC reaction with other acylpyrroles. The various 2-acyl-
1-methylpyrroles 1bꢀg were reacted with n-butyl glyoxy-
late (3) in the presence of 5 mol % of the (R)-6,60-dibromo-
BINOL/Ti(IV) complex (6c) in toluene (Table 2). In all
the cases, the reaction provided regioselectively 2,4-sub-
stituted products 5bꢀg with good yields (75ꢀ96%) and
high enantiomeric excesses (89ꢀ96%). In most cases, the
Chem. 2005, 48, 4220. (c) Krajewska, D.; Dabrowska, M.; Jakoniuk, P.;
)
ꢁ_ ꢁ
Rozanski, A. Acta Pol. Pharm. 2000, 57, 213. (d) Carson, J. R.;
Carmosin, R. J.; Pitis, P. M.; Vaught, J. L.; Almond, H. R.; Stables,
J. P.; Wolf, H. H.; Swinyard, E. A.; White, H. S. J. Med. Chem. 1997, 40,
1578.
(10) (a) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667. (b)
Ichikawa, Y.; Hirata, K.; Ohbayashi, M.; Isobe, M. Chem.;Eur. J.
2004, 10, 3241.
(11) (a) Ivonin, S. P.;Lapandin, A. V.;Anishchenko, A. A.;Shtamburg,
V. G. Synth. Commun. 2004, 451. (b) Zhuang, W.; Jørgensen, K. A.
Chem. Commun. 2002, 1336.
(12) (a) Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2008, 10,
2955. (b) Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2009, 11,
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(13) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J.
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Org. Lett., Vol. 13, No. 22, 2011
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