Enantioselective Friedel-Crafts alkylation of pyrroles catalyzed by PYBOX-DIPH-Zn(II) complexes

Article abstract of DOI:10.1021/ol902360b

Chemical Equation Presented A highly enantioselective Friedel-Crafts alkylation of pyrroles with 2-enoylpyridine 2-oxides catalyzed by chiral PYBOX-DIPH-Zn(II) complexes has been developed. The catalyst offers substantial substrate scope and furnished alkylated pyrroles in excellent yields (up to 99%) and enantioselectivities (up to >99% ee).

Full text of DOI:10.1021/ol902360b

ORGANIC
LETTERS
2010
Vol. 12, No. 1
80-83
Enantioselective Friedel-Crafts
Alkylation of Pyrroles Catalyzed by
PYBOX-DIPH-Zn(II) Complexes
Pradeep K. Singh† and Vinod K. Singh*,†,‡
Department of Chemistry, Indian Institute of Technology, Kanpur, India 208 016, and
Indian Institute of Science Education and Research, ITI Campus (Gas Rahat) Building,
GoVindpura, Bhopal, India 460 023
Vinodks@iitk.ac.in
Received October 13, 2009
ABSTRACT
A highly enantioselective Friedel-Crafts alkylation of pyrroles with 2-enoylpyridine N-oxides catalyzed by chiral PYBOX-DIPH-Zn(II) complexes
has been developed. The catalyst offers substantial substrate scope and furnished alkylated pyrroles in excellent yields (up to 99%) and
enantioselectivities (up to >99% ee).
The Friedel-Crafts (F-C) reaction, first reported in 1877,1
now 132 years later remains one of the most efficient
procedures in synthetic organic chemistry for the formation
of new C-C bonds. The asymmetric version of this reaction
provides access to important enantiomerically enriched
alkylated arene products and is a topic of ongoing research.
Recently, there have been several reports of asymmetric F-C
alkylation of indole derivatives for which excellent enanti-
oselectivities have been achieved.2 However, asymmetric
F-C alkylation of pyrroles is less explored despite their
prevalence in biologically active compounds.3 Perhaps the
tendency of dialkylation of pyrrole at both the 2- and
5-positions and instability toward acids have precluded the
intensive research in this area. The first enantioselective F-C
alkylation of pyrrole was reported by MacMillan using an
iminium-catalysis strategy by chiral imidazolidinone.4 After
this poineering work, successful catalysts reported for
enantioselective F-C alkylation of pyrrole include chiral
bisoxazoline-metal complexes,5 phosphoric acids,6 BINOL-
zirconium complex,7 dinuclear zinc complex,8 imidazoline-
(4) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370.
(5) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2001, 66, 1009. (b) Palomo, C.; Oiarbide, M.; Kardak, B. G.;
Garc´ıa, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (c) Evans,
D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249. (d) Evans, D. A.; Fandrick,
K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129,
10029. (e) Liu, H.; Lu, S.-F.; Xu, J.; Du, D.-M. Chem. Asian J. 2008, 3,
1111. (f) Yamazaki, S.; Kashima, S.; Kuriyama, T.; Iwata, Y.; Morimoto,
T.; Kakiuchi, K. Tetrahedron: Asymmetry 2009, 20, 1224. (g) Cao, C.-L.;
Zhou, Y.-Y.; Sun, X.-L.; Tang, Y. Tetrahedron 2008, 64, 10676.
(6) (a) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett.
2007, 9, 4065. (b) Nakamura, S.; Sakurai, Y.; Nakashima, H.; Shibata, N.;
Toru, T. Synlett 2009, 1639. (c) Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You,
S.-L. J. Org. Chem. 2009, 74, 6899. (d) Sheng, Y.-F.; Li, G.-Q.; Kang, Q.;
Zhang, A.-J.; You, S.-L. Chem.sEur. J. 2009, 15, 3351.
† Indian Institute of Technology.
‡ Indian Institute of Science Education and Research.
(1) (a) Friedel, C.; Crafts, J. M. C. R. Hebd. Seances Acad. Sci. 1877,
84, 1392. (b) Friedel, C.; Crafts, J. M. C. R. Hebd. Seances Acad. Sci.
1877, 84, 1450.
(2) For reviews, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550. (b) Poulsen, T. B.; Jørgensen, K. A.
Chem. ReV. 2008, 108, 2903. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc.
ReV. 2009, 38, 2190.
(3) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (b)
Hoffmann, H.; Lindel, T. Synthesis 2003, 1753. (c) Balme, G. Angew.
Chem., Int. Ed. 2004, 43, 6238. (d) Jolicoeur, B.; Chapman, E. E.;
Thompson, A.; Lubell, W. D. Tetrahedron 2006, 62, 11531.
(7) (a) Blay, G.; Ferna´ndez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9,
2601. (b) Blay, G.; Ferna´ndez, I.; Monleo´n, A.; Pedro, J. R.; Vila, C. Org.
Lett. 2009, 11, 441.
(8) Trost, B. M.; Mu¨ller, C. J. Am. Chem. Soc. 2008, 130, 2438.
10.1021/ol902360b  2010 American Chemical Society
Published on Web 11/30/2009

aminophenol-CuOTf complex,9 and secondary amine orga-
nocatalysts.10 Most of the literature known F-C pyrrole
alkylation methods lack substrate generality. Previous studies
identified chiral pyridine 2,6-bis(5′,5′-diphenyloxazoline)-
metal complexes as a potential catalyst for asymmetric
synthesis.11 We observed that the diphenyl groups at the C-5
of the oxazoline rings played a crucial role in enhancing the
enantioselectivity. Meanwhile, 2-enoylpyridine N-oxides12
proved to be a good template for enantioselective reactions.
This led to enantioselective F-C alkylation of indoles with
2-enoylpyridine N-oxides catalyzed by chiral ip-pybox-
diph-Cu(II) complexes.11m Herein, we report the application
of this method to catalytic enantioselective F-C alkylation
of pyrroles with 2-enoylpyridine N-oxides catalyzed by chiral
ip-pybox-diph-metal complexes. The initial study was carried
out by using a 1.5:1.0:0.1 mixture of pyrrole, benzylidene-
2-acetylpyridine N-oxide, and chiral Cu(II) complex of ligand
1a (Figure 1) in chloroform at -20 °C. The F-C reaction
Table 1. Enantioselective Friedel-Crafts Alkylation of Pyrrole
with Benzylidene-2-acetylpyridine N-Oxide Catalyzed by
1a-Cu(OTf)2
yield (%)a
entry pyrrole (equiv) temp (°C) time
3a
4
ee 3a (%)b
1
2
3
4
5
6
1.5
1.5
1.5
5
10
20
-20
-40
-60
-60
-60
-60
15 min 48 46
30 min 65 42
3 h
2 h
2 h
2 h
95
96
96
93
85
85
42 40c
69 17
75 12
90
a Isolated yields. b Determined by chiral HPLC, using a chiralcel OD-H
column (see the Supporting Information). c Dimer consisted of a 77:23
mixture of C2-symmetric (>99% ee):meso isomer.
acids, solvents, and chiral ligands were screened. To our
delight, a change in metal salt to Zn(OTf)2 furnished the
product in 96% enantioselectivity and 85% yield at -20 °C
(Table 2, entry 1). Lowering the temperature to -60 °C
Figure 1. C2 symmetric bisoxazoline ligands.
Table 2. Screening of Lewis Acids for Enantioselective
Friedel-Crafts Alkylation of Pyrrolea
of pyrrole with benzylidene-2-acetylpyridine N-oxide cata-
lyzed by 1a-Cu(OTf)2 was efficient and gave the product
3a with excellent enantioselectivity (95% ee). However, the
yield of the reaction was 48% and the monoalkylated product
3a was accompanied by dialkylated product 4 (46% yield,
Table 1, entry 1). We thought that lowering the temperature
may reduce the dialkylated product formation. However, it
was not the case, and the dialkylated product was obtained
with the same yield at -40 and -60 °C (Table 1, entries 2
and 3). The increase in the amount of pyrrole had a beneficial
effect on the suppression of dimer formation albeit at the
expense of enantioselectivity of the product (Table 1, entries
4-6). To optimize the reaction conditions, various Lewis
catalyst temp
yieldb eec
entry
Lewis acid
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Cu(ClO4)2·6H2O
Cu(BF4)2·xH2O
(CuOTf)2·PhCH3
(CuOTf)2·PhH
Cu(MeCN)4·PF6
Sc(OTf)3
In(OTf)3
Yb(OTf)3
Sn(OTf)2
(mol %) (°C)
time
(%)
(%)
1
2
3
4
5
6
7
8
10
10
10
5
-20 30 min
-40 1.5 h
-60 9 h
-60 24 h
-60 4 d
85
84
95
59
59
51
67
89
86
46
38
34
38
29
96
98
>99
99
85
96
95
95
94
51
0
2
10
10
10
10
10
10
10
10
10
-60 30 min
-60 30 min
-60 2.5 h
-60 1 h
-20 60 h
-60 3 h
-60 30 min
-60 30 min
-60 2 h
(9) Yokoyama, N.; Arai, T. Chem. Commun. 2009, 3285.
(10) (a) Bonini, B. F.; Capito`, E.; Comes-Franchini, M.; Fochi, M.; Ricci,
A.; Zwanenburg, B. Tetrahedron: Asymmetry 2006, 17, 3135. (b) Hong,
L.; Liu, C.; Sun, W.; Wang, L.; Wong, K.; Wang, R. Org. Lett. 2009, 11,
2177.
9
10
11
12
13
14
(11) (a) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994,
50, 13725. (b) DattaGupta, A.; Singh, V. K. Tetrahedron Lett. 1996, 37,
2633. (c) Sekar, G.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1998, 63,
2961. (d) Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159.
(e) Lu, J.; Ji, S.-J.; Loh, T.-P. Chem. Commun. 2005, 2345. (f) Lu, J.; Hong,
M.-L.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Chem. Commun. 2005, 4217. (g)
Lu, J.; Ji, S.-J.; Teo, Y.-C.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 7435.
(h) Ginotra, S. K.; Singh, V. K. Tetrahedron 2006, 62, 3573. (i) Ginotra,
S. K.; Singh, V. K. Org. Biomol. Chem. 2006, 4, 4370. (j) Bisai, A.; Singh,
V. K. Org. Lett. 2006, 8, 2405. (k) Chen, W.-Y.; Li, X.-S. Lett. Org. Chem.
2007, 4, 398. (l) Dodda, R.; Zhao, C.-G. Tetrahedron Lett. 2007, 48, 4339.
(m) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121.
6
37
2
a 1.5 equiv of pyrrole was used. b Isolated yields. c Determined by chiral
HPLC, using a chiralcel OD-H column (see the Supporting Information).
improved the enantioselectivity to >99% and yield to 95%
(Table 2, entry 3). Lowering the catalyst loading to 5 mol %
Org. Lett., Vol. 12, No. 1, 2010
81

gave the product with the same enantioselectivity but reduced
the reaction rate and yield of the product. So, the 10 mol %
catalyst loading and temperature of -60 °C were selected,
and various Lewis acids were screened. Cu(II) salt gave good
enantioselectivity, but the yield of product was low because
of the formation of dialkylated product (Table 2, entries 6
and 7). However, CuOTf gave good yields (86-89%, Table
2, entries 8 and 9). With other tested Lewis acids, the reaction
was fast but yields and enantioselectivities were poor (Table
2, entries 11-14). From the results of Table 2, ligand 1a-
Zn(OTf)2 was selected, and several solvents were evaluated.
The reaction was sensitive to solvents as shown in Table 3.
Table 4. Friedel-Crafts Alkylation of Pyrrole with Benzylidene-
2-acetylpyridine N-Oxide Catalyzed by Various Catalystsa
entry
ligand
time
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
9 h
3 h
24 h
3 h
5 d
24 h
36 h
3 d
24 h
24 h
40 h
95
75
82
92
61
69
72
31
75
67
79
>99
96
44
98
78
7
74
5
92
95
79
Table 3. Effect of Solvents on Enantioselective Friedel-Crafts
Alkylation of Pyrrolea
9
10
11
1j
1k
a 1.5 equiv of pyrrole was used. b Isolated yields. c Determined by chiral
HPLC, using a chiralcel OD-H column (see the Supporting Information).
entry
solvent
temp (°C)
time
yield (%)b
ee (%)c
1
2
3
4
5
6
7
CHCl3
CH2Cl2
THF
-60
-60
-60
-20
-60
-20
-60
9 h
9 h
3 d
10 h
3 d
6 h
3 d
95
77
nr
56
nr
72
nr
>99
97
nr
97
nr
After optimization of reaction conditions, the generality
of the F-C reaction was explored. First substitution on the
pyrrole ring was studied (Table 5, entries 1-3). N-Substitu-
THF
CH3CN
CH3CN
toluene
48
nr
a 1.5 equivalent pyrrole was used. b Isolated yields. c Determined by
chiral HPLC using a chiralcel OD-H column (see the Supporting Informa-
tion). nr ) no reaction.
Table 5. Enantioselective Friedel-Crafts Alkylation of Pyrroles
with Various 2-Enoylpyridine N-Oxidesa
Chloroform was optimal in terms of both enantioselectivity
and yield (Table 3, entry 1). Apart from chloroform,
dichloromethane gave comperable enanantioselectivity (Table
3, entry 2). There was no reaction in THF at -60 °C.
However, by increasing the temperature to -20 °C, the
product was obtained in 56% yield and 97% enantiomeric
excess (Table 3, entries 3 and 4). Not unexpectedly, the use
of strong coordinating solvent (acetonitrile) has a detrimental
effect on the asymmetric induction (Table 3, entries 5 and
6). To further investigate the reaction, various ligands were
screened. Pybox-diph ligands with different substituents at
the chiral center (1a-g) were used in the above reaction as
shown in Table 4. It was observed that ip-pybox-diph (1a)
gave the best results (Table 4, entry 1). The other ligands
such as tb-pybox-diph (1b) and sb-pybox-diph (1d) gave
comperable enantioselectivity (Table 4, entries 2 and 4). Poor
enantioselectivity (5%) with 1h indicated the importance of
pyridine nitrogen in chelation with Zn(II) (Table 4, entry
8). Ligand 1k gave the product with 79% ee (Table 4, entry
11), which clearly indicated the importance of gem-diphenyl
substitutions at C5 of the oxazoline rings.
entry
R1
R2
3
time yield (%)b ee (%)c
1
2
3
4
5
6
7
8
H
1-Me
Ph
Ph
3a 9 h
3b 3 d
3c 20 h
3d 3 h
95
87
97
90
54
96
99
98
86
96
88
71
82
76
74
>99
95d
2,4-diMe,3-Ac Ph
>99
98
99
85
98
97
>99
98
98
99
95
94
95
H
H
H
H
H
H
H
H
H
H
H
H
4-FC6H4
4-MeOC6H4 3e 18 h
4-NO2C6H4 3f 3 h
3-NO2C6H4 3g 3 h
2-NO2C6H4 3h 5 h
4-ClC6H4
3-ClC6H4
2-ClC6H4
1-naphthyl 3l 9 h
2-furyl 3m 18 h
cyclohexyl 3n 12 h
n-pentyl 3o 5 h
9
3i 3 h
3j 5 h
3k 5 h
10
11
12
13
14
15
a 1.5 equiv of pyrrole was used. b Isolated yields. c Determined by chiral
HPLC, using a chiral column (see the Supporting Information. d Reaction
was carried out at -30 °C.
tion of pyrrole reduced the reaction rate. In the case of
N-methylpyrrole, the reaction took 3 days to complete at -30
°C with 95% enantioselectivity. However, a substituted
pyrrole gave excellent enantioselectivity (>99%; Table 5,
(12) (a) Barroso, S.; Blay, G.; Pedro, J. R. Org. Lett. 2007, 9, 1983. (b)
Barroso, S.; Blay, G.; Mun˜oz, M. C.; Pedro, J. R. AdV. Synth. Catal. 2009,
351, 107.
82
Org. Lett., Vol. 12, No. 1, 2010

entry 3). The reaction was then extended to different
ꢀ-substituted 2-enoylpyridine N-oxides (Table 5, entries
4-15). Aromatic substituted substrates gave excellent enan-
tioselectivity, regardless of the electron density of the
aromatic ring. Even substrates having an electron-donating
group on the phenyl ring gave excellent enantioselectivity,
although the reaction rate was slow (Table 5, entry 5).
In the case of aliphatic substituted substrates, the catalyst
system was efficient, and good enantioselectivity was
obtained (Table 5, entries 14 and 15). The absolute stereo-
chemistry in the reaction was determined by converting the
product 3b into a known compound 5.4 The pyridine N-oxide
ring of 3b was cleaved with 20% aq KOH to give the
corresponding acid. The acid was esterified and reduced with
DIBAL-H to give an alcohol 5 without any loss in enanti-
oselectivity (Scheme 1). We have also evaluated the ip-
Scheme 2
.
Enantioselective Friedel-Crafts Alkylation Catalyzed
by Chiral ip-pybox-diph -Zn (II) Complex
Scheme 1. Determination of Absolute Stereochemistry
with 2-enoylpyridine N-oxides utilizing the ip-pybox-diph-
Zn(II) complex. Our catalytic system offers substantial
substrate scope and excellent enantioselectivities were ob-
tained in all cases. Even trisubstituted pyrrole underwent
Friedel-Crafts alkylation with excellent enantioselectivity.
Furthermore, the pyridine N-oxide ring of the product was
cleaved to give the corresponding acid, allowing further
transformations. The method also works well with 2-meth-
oxyfuran and benzene derivatives. Further studies to extend
the method to various phenols and related Friedel-Crafts
reaction are underway.
Acknowledgment. V.K.S. thanks the Department of
Science and Technology, Government of India for a research
grant through Ramanna and J. C. Bose Fellowships. P.K.S.
thanks the Council of Scientific and Industrial Research, New
Delhi for a Senior Research Fellowship.
pybox-diph-Zn(II) complex in enantioselective F-C alky-
lation of 2-methoxyfuran where the product was obtained
in 85% ee. Our catalytic system was also extended to simple
benzene derivatives, and to our delight, chiral F-C alkylated
benzene derivatives were obtained in 93% ee (Scheme 2).
The absolute stereochemistry of 6 and 7 is not known.
However, we assume that the major isomer would have the
same absolute stereochemistry as that observed with pyrrole
F-C alkylation product 3.
Supporting Information Available: General experimental
procedures and full characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient method for
highly enantioselective Friedel-Crafts alkylation of pyrrole
OL902360B
Org. Lett., Vol. 12, No. 1, 2010
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