Enantioselective Friedel-Crafts reaction of acylpyrroles with glyoxylates catalyzed by BINOL-Ti(IV) complexes

Article abstract of DOI:10.1021/ol202244u

We report the first efficient enantioselective Friedel-Crafts hydroxyalkylation of pyrroles having one electron-withdrawing group at the α, β or N-positions with alkyl glyoxylates catalyzed by readily available chiral BINOL-Ti(IV) complexes (1-5 mol %). The reaction regioselectively led to the desired pyrrole-hydroxyacetic acid derivatives with good yields (70-96%) and enantiomeric excesses up to 96%, and is applicable in multigram scale with low loading of the catalyst (1 mol %).

Full text of DOI:10.1021/ol202244u

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5944–5947
Enantioselective FriedelꢀCrafts
Reaction of Acylpyrroles with Glyoxylates
Catalyzed by BINOLꢀTi(IV) Complexes
Jakub Majer,† Piotr Kwiatkowski,†,‡ and Janusz Jurczak*,†,‡
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland,
and Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
jurczak@icho.edu.pl
Received August 18, 2011
ABSTRACT
We report the first efficient enantioselective FriedelꢀCrafts hydroxyalkylation of pyrroles having one electron-withdrawing group at the R, β or
N-positions with alkyl glyoxylates catalyzed by readily available chiral BINOLꢀTi(IV) complexes (1ꢀ5 mol %). The reaction regioselectively led
to the desired pyrrole-hydroxyacetic acid derivatives with good yields (70ꢀ96%) and enantiomeric excesses up to 96%, and is applicable in
multigram scale with low loading of the catalyst (1 mol %).
Chiral pyrrole derivatives are important compounds for
the synthesis of many interesting biologically active mole-
cules, chiral catalysts, and receptors.1 Of special interest
are derivatives with a sterogenic center in the R-position to
the pyrrole ring. Acylpyrrole systems, on the other hand,
are abundant in natural products2 and other biologically
active molecules, including synthetic drugs, e.g., ketorolac,
tolmetin, atorvastatin, indanomycin, calcimycin, and pyr-
role C-nucleosides.3 The FriedelꢀCrafts (FꢀC) reaction is
one of the most useful and straightforward approaches to
aromatic system synthesis with a stereogenic carbon center
in the benzylic position. In the literature there are many
examples of enatioselective FꢀC reactions of aromatic
and heteroaromatic compounds with a wide range of
electrophiles in the presence of various chiral catalysts.4
The literature describes enantioselective FꢀC reactions of
(4) (a) Bandini, M.; Umani-Ronchi, A. Catalytic Asymmetric Friedel-
Crafts Alkylations; Wiley-VCH: Weinheim, Germany, 2009. (b) Terrasson,
V.; Figueiredo, R. M.; Campagne, J. M. Eur. J. Org. Chem. 2010, 2635.
(c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190.
(d) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
(e) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550.
(5) (a) Singh, P. K.; Singh, V. S. Org. Lett. 2010, 12, 80. (b) Wang, W.;
Liu, X.; Cao, W.; Wang, J.; Lin, L.; Feng, X. Chem.;Eur. J. 2010, 16,
1664. (c) Hong, L.; Liu, C.; Sun, W.; Wang, L.; Wong, K.; Wang, R. Org.
Lett. 2009, 11, 2177. (d) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wong, K.;
Wang, R. Chem.;Eur. J. 2009, 15, 11105. (e) Sibi, M. P.; Coulomb, J.;
Stanley, L. M. Angew. Chem., Int. Ed. 2008, 47, 9913. (f) Cao, C.-L.;
Zhou, Y.-Y.; Sun, X.-L.; Tang, Y. Tetrahedron 2008, 64, 10676. (g) Blay,
† Polish Academy of Sciences.
‡ University of Warsaw.
(1) Thirumalairajan, S.; Pearce, B. M.; Thompson, A. Chem. Com-
mun. 2010, 46, 1797–1812.
(2) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008,
108, 264. (b) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931. (c) Macherla,
V. R.; Liu, J.; Bellows, C.; Teisan, S.; Nicholson, B.; Lam, K. S.; Potts,
B. C. M. J. Nat. Prod. 2005, 68, 780.
(3) Joshi, U.; Josse, S.; Pipelier, M.; Chevallier, F.; Pradere, J.-P.;
Hazard, R.; Legoupy, S.; Huet, F.; Dubreuil, D. Tetrahedron Lett. 2004,
45, 1031.
ꢁ
G.; Fernandez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601. (h)
Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am.
Chem. Soc. 2007, 129, 10029. (i) Evans, D. A.; Fandrick, K. R. Org. Lett.
2006, 8, 2249. (j) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (k) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370.
ꢀ
r
10.1021/ol202244u
Published on Web 10/19/2011
2011 American Chemical Society

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,
4636.
(13) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J.
Adv. Synth. Catal. 2007, 349, 1597.
Org. Lett., Vol. 13, No. 22, 2011
5945

products containing unprotected pyrroles provide an op-
portunity for further functionalization on the nitrogen
atom.14
Table 2. Scope of the FriedelꢀCrafts Reaction of N-Me Pyrroles
with Glyoxylate 3 Catalyzed by 6ca
Scheme 1. FriedelꢀCrafts Reaction of 3-Acylpyrroles (1l, 1m)
with Glyoxylate 3 Catalyzed by 6c
mol % of yield ee
entry
R1
substrate product cat. 6c
(%)b (%)c
1
2
3
4
5
6
But
Bn
Ph
1b
1c
1d
1e
1f
5b
5c
5d
5e
5f
5
5
5
2
2
5
89
85
75
94
96
90
96
93
96
96
96
89
m-NO2C6H4
p-NO2C6H4
MeO
We also examined two examples of the FꢀC reaction of
3-acylpyrroles (1l, 1m) with n-butyl glyoxylate (Scheme 1).
The reaction provides products with high yields and enan-
tioselectivity but different regioselectivity, which depends on
the position of the EWG in the pyrrole ring. In general,
pyrroles bearing EWGs (e.g., Ac, ArCO, MeO2C) in posi-
tion 2 lead to electrophilic substitution in position 4 (Tables 2
and 3), whereas an EWG in position 3 directs glyoxylate on
position 5 (Scheme 1). The observed regioselectivity is in
agreement with the literature,15 and the structures of pro-
ducts were confirmed by NOE experiments.16
Use of more activated pyrroles (without an EWG, e.g.,
1-methylpyrrole or 2-styryl-1-methylpyrrole) and our re-
action conditions give practically racemic products. This
problem could be circumvented by introducing a protect-
ing EWG on the nitrogen atom (e.g., Boc or Cbz). The
FriedelꢀCrafts reaction of 1-Boc-pyrrole (1n) and 1-Cbz-
pyrrole (1o) with n-butyl glyoxylate (3) give desired chiral
products (respectively 5n and 5o, Scheme 2), slightly con-
taminated with a difficult to separate byproduct.17
1g
5g
a The reactions were carried out using 2 or 5 mol % of catalyst 6c, 1.5
mmol of n-butyl glyoxylate (3) in 2 mL of toluene, and 1.0 mmol of
2-acyl-1-methylpyrrole (1bꢀg), at lowered temperature (from ꢀ40 to
0 °C). b Isolated yield. c Enantiomeric excess determined by HPLC using
chiral columns.
regioisomeric 2,5-substituted products were not observed.
The reaction can be carried out with excellent yield and
enantioselectivity also using a lower amount of catalyst
(2 mol %) (see products 5e and 5f).
Table 3. Scope of the FriedelꢀCrafts Reaction of N-H Pyrroles
with Glyoxylate 3 Catalyzed by 6ca
Another applicable substrate for this reaction is 1-Boc-
2,5-dimethylpyrrole (1p), which with n-butyl glyoxylate (3)
gives only 3-substituted product 5p with high yield (91%)
and acceptable enantiomeric excesses (75% ee, Figure 2).
Pyrrole derivatives containing two electron-withdrawing
groups (e.g., N-Boc or N-Cbz 2-acetylpyrrole) are not
reactive enough in this reaction.
With a practical procedure in hand for synthesis of
pyrrolyl-hydroxy acetates 5, we turned our attention to
scale-up (Table 4). A few products were prepared on the
6c
time yield
ee
entry
R1
substrate product (mol %)
(h)
(%)b (%)c
1
2
3
4
Me
1h
1i
5h
5i
5
5
5
2
10
5
71
80
70
82
81
95
77
94
But
Ph
1j
5j
10
5
MeO
1k
5k
a The reactions were carried out using 2 or 5 mol % of catalyst 6c, 1.5
mmol of n-butyl glyoxylate (3) in 2 mL of toluene, and 1.0 mmol of
2-acylpyrrole (1hꢀk), at 0 °C. b Isolated yield. c Enantiomeric excess
determined by HPLC using chiral columns.
(15) (a) Mai, A.; Massa, S.; Ragno, R.; Cerbara, I.; Jesacher, F.;
Loidl, P.; Brosch, G. J. Med. Chem. 2003, 46, 512. (b) Harsanyi, M. C.;
Norris, R. K. J. Org. Chem. 1987, 52, 2209.
(16) For details see Supporting Information.
(17) We suppose that corresponding regioisomers substituted on the
3-position were obtained as byproducts.
It is also noteworthy that the FꢀC reactions carried out
with N-unprotected acylpyrroles 1hꢀk give the desired
products 5hꢀk (Table 3). Methyl group absence at the
nitrogen does not have a negative influence on the yield
(70ꢀ91%) and enantiomeric excesses (74ꢀ95%). Moreover,
(18) Reaction of 2-pivaloyl-1-methylpyrrole (1b) with n-butyl glyox-
ylate (3) provides two isomers, a mainly obtained product substituted on
position four (5b) on the pyrrole ring and a byproduct 5r substituted on
position five.
(14) Jolicoeur, B.; Chapman, E. E.; Thompson, A.; Lubell, W. D.
Tetrahedron 2006, 62, 11531.
5946
Org. Lett., Vol. 13, No. 22, 2011

Table 4. Scaled-Up Synthesis of Pyrrolyl-hydroxy Acetatesa
Scheme 2. FriedelꢀCrafts Reaction of N-Boc and N-Cbz Pyr-
roles with Glyoxylate 3 Catalyzed by 6c
mol % of
yield
(%)b
ee
entry
substrate
product
cat. 6c
(%)c
1
2
3
1b
1f
5b
5f
1
1
1
78
90
72
9618
96
1h
5h
79
a The reactions were carried out using 1 mol % of catalyst 6c, 12.0
mmol of n-butyl glyoxylate (3) in 4 mL of toluene, and 10.0 mmol of
pyrrole (1b, 1f, 1h), at 0 °C. b Isolated yield. c Enantiomeric excess
determined by HPLC using chiral columns.
In summary, we have demonstrated the first efficient
regioselective and highly enantioselective FriedelꢀCrafts
reaction of pyrroles with alkyl glyoxylates catalyzed by
readily available chiral BINOLꢀTi(IV) complexes. Among
various tested substrates, pyrroles having one electron-
withdrawing group at R, β or N-positions were the best
substrates for this reaction. The products of this reaction
provide easy access to important synthons in chemical
synthesis which are commonly found in biologically active
molecules, chiral catalysts, and receptors.
Figure 2. Product of reaction of 1-Boc-2,5-dimethylpyrrole (1p)
with glyoxylate 3.
Supporting Information Available. Experimental pro-
cedures and analytical data for all the FꢀC products (4,
5aꢀr) with reprints of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.
org.
10.0 mmol scale, using a low loading of the catalyst 6c
(1 mol %) and higher concentration of reagents (2.5 M).
The results are comparable to 1.0 mmol scale reactions in
terms of yield and enantioselectivity.
Org. Lett., Vol. 13, No. 22, 2011
5947