Pd-catalyzed asymmetric allylic alkylation of indoles and pyrroles by chiral alkene-phosphine ligands

Article abstract of DOI:10.1021/ol200602x

Chemical equations presented. A variety of chiral binaphthyl-based terminal-alkene-phosphine hybrid ligands were synthesized in four steps with (S)-BINOL as a starting material and utilized for the Pd-catalyzed enantioselective allylic alkylations of indo

Full text of DOI:10.1021/ol200602x

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2164–2167
Pd-Catalyzed Asymmetric Allylic
Alkylation of Indoles and Pyrroles by
Chiral Alkene-Phosphine Ligands
Ziping Cao, Yilin Liu, Zhaoqun Liu, Xiangqing Feng, Minyang Zhuang, and
Haifeng Du*
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
haifengdu@iccas.ac.cn
Received January 17, 2011
ABSTRACT
A variety of chiral binaphthyl-based terminal-alkene-phosphine hybrid ligands were synthesized in four steps with (S)-BINOL as a starting material
and utilized for the Pd-catalyzed enantioselective allylic alkylations of indoles and pyrroles to afford the desired products in high yields with good
to excellent ee’s.
Indole moieties are present in a broad range of
biologically and medically important compounds.1
Regio- and enantioselective alkylations of indoles at
the C-3 position through Lewis or Brønsted acids
promoted FriedelÀCrafts reactions2 and transition-
metal-catalyzed allylic alkylations3 provide an efficient
approach to afford optically active indole derivatives.
As one of the most important methodologies to con-
struct CÀC bonds, great success has been achieved for
TsujiÀTrost reactions.4 However, Pd-catalyzed asym-
metric allylic alkylation of indoles with 1,3-diphenyl-2-
propenyl acetate was not realized until 2007 by Chan
and co-workers with the use of chiral ferrocenyl P/S
ligands to give the desired products in high ee’s.3h In
their study, various well-known bisphosphine or P/N
ligands were also examined and found not suitable for
this transformation. Hence, exploring other types of
chiral ligands for this reaction is of great interest.
(1) (a) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559. (b) Agarwal, S.;
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r
10.1021/ol200602x
Published on Web 04/04/2011
2011 American Chemical Society

Chiral alkenes as one novel type of ligands have received
considerable attention and witnessed significant progress
since Hayashi’s group reported the first chiral diene ligand
for transition-metal-catalyzed highly enantioselective re-
actions in 2003.5,6 In addition to the rapid growth of chiral
diene ligands,7 some hybrid ligands combined alkenes with
heteroatoms, such as phosphorus8 or nitrogen9 to improve
the coordination ability to the metal, have also been
developed for asymmetric conjugated addition or allylic
substitution. As part of our ongoing efforts in exploring
new, effective, and accessible chiral alkene ligands, we have
discovered several flexible acyclic dienes possessing two
terminal olefins as coordinating moieties which were effec-
tive for Rh-catalyzed asymmetric conjugated additions or
arylations.10 However, the coordination ofanalkene tothe
metal was not observed in the NMR study in some cases,
which may partially be attributed to the relatively weak
coordination ability of the flexible dienes. Therefore, a
strategywas adopted in ourgroup for the development of a
novel alkene-phosphine hybrid ligand by installing the
terminal alkene and phosphorus atom on suitable chiral
backbones (Figure 1). Ligand 1 was then developed and
synthetic route using (S)-BINOL (3) as a starting material
(Scheme 1). Wherein, the coupling reaction between com-
pounds 6 and potassium alkenyltrifluoroboroates was the
key step and Pd(PPh3)4 was found to be the most suitable
catalyst for this transformation giving pure ligands 2
without inseparable impurities. Ligand 2e bearing a partially
reduced binaphthyl backbone was also obtained under the
same procedure.
Scheme 1. Synthesis of Alkene-Phosphine Hybrid Ligands
Subsequently, chiral ligands 1 (Ar = 3,5-Me2C6H3) and
2a were subjected to the asymmetric allylic alkylation of
indole (7a) with 1,3-diphenyl-2-propenyl acetate (8a) in the
presence of [Pd(C3H5)Cl]2 and K2CO3 in CH2Cl2 at room
temperature. We were pleased to find that both of them
were effective for this reaction to give the desired product
9a accompanied with a small amount of C,N-dialkylation
byproduct in high conversions and promising ee’s, and
ligand 2a gave a relatively better result (Table 1, entries 1
and 2). In order to further improve the enantioselectivity
and reduce the amount of byproducts, various reaction
conditions including base, solvent, and temperature were
then optimized (Table 1, entries 3À11). When this reaction
was carried out under the catalysis of a Pd/2a complex
(3.0 mol % Pd) in CH2Cl2 at0 °C using Na2CO3 (2.0 equiv)
as base, the corresponding product 9a can be obtained in
92% ee with only a little amount of byproduct (Table 1,
entry 11). Under the same condition, ligands 2bÀe were
examined. It was found that all of these chiral ligands
modified Pd catalysts can promote this reaction to give the
corresponding product in 44À99% conversions and
79À90% ee (Table 1. entries 12À15). It was noteworthy
that ligand 2d containing an internal CÀC double bond
gave the product with a reverse absolute configuration in
moderate conversion (Table 1, entry 14). Overall, ligand 2a
gave the highest conversion and ee. When the catalyst
Figure 1. Strategy for exploring alkene-phosphine ligands.
found to be highly effective for palladium-catalyzed asym-
metric allylic substitutions.11 In this work, we wish to
report our efforts on the development of binaphthyl-based
chiral alkene-phosphine hybrid ligands for Pd-catalyzed
enantioselective allylic alkylations of indoles and pyrroles.
Initially, chiral alkene-phosphine ligands 2 were obtained
in reasonable yields through a straightforward four-step
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see: (a) Deblon, S.; Grutzmacher, H.; Schonberg, H. WO 03/048175 A1,
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metallics 2005, 24, 3207. (b) Hahn, B. T.; Tewes, F.; Frohlich, R.;
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see: (a) Maire, P.; Breher, F.; Schonberg, H.; Grutzmacher, H. Organo-
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Chem., Int. Ed. 2005, 44, 4611. (d) Duan, W.-L.; Iwamura, H.; Shintani,
R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130. (e) Kasak, P.; Arion,
V. B.; Widhalm, M. Tetrahedron: Asymmetry 2006, 17, 3084. (f) Defieber,
C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007,
46, 3139. (g) Mariz, R.; Briceno, A.; Dorta, R.; Dorta, R. Organometallics
2008, 27, 6605. (h) Stepnicka, P.; Cısarova, I. Inorg. Chem. 2006, 45, 8785.
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Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 1143.
(10) (a) Hu, X.; Zhuang, M.; Cao, Z.; Du, H. Org. Lett. 2009, 11,
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~
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Org. Lett., Vol. 13, No. 9, 2011
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Table 1. Evaluation of Ligands and Optimization of Reaction
Conditionsa
Table 2. Pd/2a-Catalyzed Asymmetric Alkylation of Indolesa
temp time
conv
(%)b
ee
(%)c
entry
L
base
solvent
(°C)
(h)
1d
2
1
K2CO3
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
12
6
95 (19/1)
99 (5/1)
99 (6/1)
80
80
88
85
85
87
87
87
77
86
87
92
87
90
À79
83
90
2a K2CO3
3
2a Cs2CO3 CH2Cl2
2a Et3N CH2Cl2
11
11
11
11
11
11
9
4
5
2a Na2CO3 CH2Cl2
2a Na2CO3 MeCN
2a Na2CO3 THF
99 (10/1)
74
6
7
77 (8/1)
82 (4/1)
76
8
2a Na2CO3 toluene
2a Na2CO3 CH2Cl2
2a Na2CO3 CH2Cl2
2a Na2CO3 CH2Cl2
2b Na2CO3 CH2Cl2
2c Na2CO3 CH2Cl2
2d Na2CO3 CH2Cl2
2e Na2CO3 CH2Cl2
2a Na2CO3 CH2Cl2
9e
10f
11
12
13
14
15
16g
9
98 (11/1)
97 (19/1)
99 (13/1)
99 (10/1)
44
24
24
24
24
24
48
0
0
0
0
79
0
97 (10/1)
a All reactions were carried out with 7a (0.20 mmol), 8a (0.24 mmol),
Pd/L = 1/1 (3 mol % Pd), base (0.40 mmol), and solvent (1.0 mL) unless
otherwise stated. b The conversion was determined by crude 1H NMR.
The ratios of 9a and C,N-dialkylation product were noted in parenth-
eses. c The ee values were determined by chiral HPLC with the N-Boc-
protected derivative of 9a. d 5.0 mol % Pd was used. e Na2CO3 (1.0 equiv)
was used. f Na2CO3 (3.0 equiv) was used. g 1.0 mol % Pd was used.
loading was further decreased to 1.0 mol %, the reaction
still went smoothly with only a slightly lower ee (Table 1,
entry 16).
To evaluate the effect of alkene moieties of 2a, ligand 10
bearing an ethyl group instead of a vinyl group and a well-
known MOP ligand 11 were subjected to this reaction
respectively (Scheme 2).12 However, no desired product at
all was observed, which strongly suggests that the vinyl
group of ligand 2a played a crucial role in both reactivity
a All reactions were carried out with 7 (0.20 mmol), 8 (0.24 mmol),
[Pd(C3H5)Cl]2 (0.003 mmol), 2a (0.006 mmol), Na2CO3 (0.40 mmol),
and CH2Cl2 (1.0 mL) at 0 °C for 24 h. b The absolute configuration was
tentatively assigned by analogy with 9j. c Isolated yield. d The ee values
were determined by chiral HPLC with the N-Boc-protected derivatives
of 9aÀn (see Supporting Information).
Scheme 2. Palladium-Catalyzed Asymmetric Allylic Alkylation
of Indole 7a
and enantioselectivity. Importantly, the ratio of Pd/2a was
found to be another factor to affect this reaction. The
conversion and ee dropped sharply when the ratio of Pd
and 2a was tuned to 1/2 and 1/3 (Scheme 2). The reasoning
was related to the phosphorus atom’s strong coordination
ability to palladium resulting in some amount of ligand 2a
to only act as ineffective monophosphine ligands.11
(12) For leading references on ligands 10 and 11, see: (a) Hattori, T.;
Shijo, M.; Kumagai, S.; Miyano, S. Chem. Express 1991, 6, 335.
(b) Uozumi, Y.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 9887.
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Org. Lett., Vol. 13, No. 9, 2011

With the best ligand 2a and optimal reaction conditions
in hand, Pd-catalyzed asymmetric allylic alkylations of a
variety of indoles 7 with 1,3-diaryl-2-propenyl acetate (8)
were subsequently investigated. As shown in Table 2, all of
the alkylation reactions proceeded efficiently to give the
corresponding products 9 in 72À99% yields with 75À94%
ee (Table 2, entries 1À14). The alkylations of 2-substituted
and 7-substituted indoles gave high yields but with rela-
tively lower ee’s (Table 2, entries 2 and 11). Moreover, the
substituents of 1,3-diaryl-2-propenyl acetate (8) were
found to have some impact on both reactivities and
enantioselectivities (Table 2, entries 1 vs 12À14). The
absolute configuration of product 9j was determined to
be S by an X-ray structure of its derivatives (Figure 2), and
the configurations of other products were tentatively
assigned by analogy.
Other N-heterocycles, such as 1-methylpyrrole, 7-azain-
dole, and benzimidazole, were not suitable for this reaction
(Scheme 3). Although the substrate scope still awaits
further expansion, to the best of our knowledge, the
present work represents the first successful example of
asymmetric allylic alkylation of pyrroles catalyzed by Pd
complexes.13
Scheme 3. Palladium-Catalyzed Asymmetric Allylic Alkylation
of Other N-Heterocycles
In summary, a variety of binaphthyl-based chiral
alkene-phosphine hybrid ligands were successfully prepared
through a straightforward four-step synthesis. Ligand 2a
was found to be highly effective for the Pd-catalyzed
asymmetric allylic alkylation of indoles with 1,3-diaryl-2-
propenyl acetate (8) to give the corresponding products in
high yields with good to excellent ee’s. Interestingly, the
enantioselective alkylations of pyrroles catalyzed by Pd/2a
were also realized with up to 98% ee. Expanding the sub-
strate scope, searching for other effective terminal-alkene-
phosphine hybrid ligands, and exploring their applications
in asymmetric catalysis are currently underway in our lab.
Figure 2. X-ray structure of N-Boc-protected (S)-9j.
To further expand the substrate scope, several N-hetero-
cycles including pyrroles, 7-azaindole, and benzimidazole
were subjected to this reaction. We were pleased to find
thatthe reactionbetween pyrrole (12a) and 1,3-diphenyl-2-
propenyl acetate (8a) under the catalysis of Pd/2a (5.0mol%)
proceeded smoothly to give a 2,5-dialkylation product 13a
in excellent yield with 8.5/1 dr and 98% ee (Scheme 3).
When 2-ethylpyrrole was employed as a substrate, the
alkylation reaction occurred at the 5-position to give the
desired product 13b in 95% yield with 86% ee (Scheme 3).
Acknowledgment. The authors are thankful for finan-
cial support from the National Science Foundation of
China (20802079, 21072194), the National Basic Research
Program of China (973 program, 2010CB833300), and the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars.
Supporting Information Available. The procedure for
the synthesis of chiral ligands 2; Pd-catalyzed asymmetric
allylic alkylation; characterization of 9aÀn, their Boc-
protected derivatives, and 13aÀb; and data for the deter-
mination of enantiomeric excesses of 9aÀn and 13aÀb
along with NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) For selected examples on asymmetric FriedelÀCrafts alkylation
of pyrroles, see: (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009. (c) Palomo, C.; Oiarbide,
M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005,
127, 4154. (d) Li, G.; Rowland, G. B.; Antilla, J. C. Org. Lett. 2007, 9,
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4065. (e) Trost, B. M.; Muller, C. J. Am. Chem. Soc. 2008, 130, 2438. (f)
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