Ir-catalyzed regio- And enantioselective Friedel-crafts-type allylic alkylation of indoles

Article abstract of DOI:10.1021/ol800409d

Highly regio- and enantioselective Ir-catalyzed Friedel-Crafts type allylic alkylation of indoles have been realized using [lr(COD)Cl]₂/ phosphoramidite ligand 1a, affording the branched products with up to >97/3 branched-linear ratio and 92% e

Full text of DOI:10.1021/ol800409d

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1815-1818
Ir-Catalyzed Regio- and Enantioselective
Friedel–Crafts-Type Allylic Alkylation of
Indoles
Wen-Bo Liu, Hu He, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
slyou@mail.sioc.ac.cn
Received February 21, 2008
ABSTRACT
Highly regio- and enantioselective Ir-catalyzed Friedel–Crafts type allylic alkylation of indoles have been realized using [Ir(COD)Cl]2/
phosphoramidite ligand 1a, affording the branched products with up to >97/3 branched-linear ratio and 92% ee.
Synthesis of enantiopure indole derivatives is of significant
importance because of the wide distribution of indole
moieties in biologically active natural products and phar-
maceutical compounds.1 The enantioselective Friedel–Crafts
reactions of indoles have attracted considerable interest and
witnessed significant progress in the past decade.2,3 Recently,
transition-metal-catalyzed allylic alkylation has been proven
suitable for direct indole functionalization.4–6
In 1999, Kocˇovský and co-workers reported the first allylic
alkylation of indole with allyl acetates in the presence of a
Mo(II) catalyst.5a Recently, Pd-catalyzed allylic alkylation
of indole with allylic carbonates and the related intramo-
lecular enantioselective alkylation have been carried out by
Bandini and co-workers.5b,c A recent study by Chan and co-
workers showed that high enantioselectivities were obtained
during the alkylation of indoles with 1,3-diphenyl-2-propenyl
acetate.5e Pd-catalyzed C-3 allylation of 3-substituted indole
using trialkylborane and allyl alcohol have also been realized
to afford 3,3-disubstituted indolenines and indolines.6 Nev-
(3) Selected examples: (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002,
124, 9030. (b) Palomo, C.; Oiarbide, M.; Kardak, B. G.; García, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (c) Evans, D. A.; Fandrick,
K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (d) Jia, Y.-X.; Xie,
J.-H.; Duan, H.-F.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 1621. (e)
Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115. (f) Li, H.; Wang,
Y. Q.; Deng, L. Org. Lett. 2006, 8, 4063. (g) Zhao, J.-L.; Liu, L.; Sui, Y.;
Liu, Y.-L.; Wang, D.; Chen, Y.-J. Org. Lett. 2006, 8, 6127. (h) Li, C.-F.;
Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9,
1847. (i) Yang, H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281. (j) Blay,
G.; Fernández, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601. (k) Raheem,
I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc.
2007, 129, 13404. (l) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt,
K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029. (m) Wanner, M. J.;
van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra,
H. Angew. Chem., Int. Ed. 2007, 46, 7485. (n) Rueping, M.; Nachtsheim,
B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593.
(4) Reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996,
96, 395. (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (c) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Science: Oxford, 2000. (b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1. (c)
Agarwal, S.; Caemmerer, S.; Filali, S.; Froehner, W.; Knoell, J.; Krahl,
M. P.; Reddy, K. R.; Knolker, H.-J. Curr. Org. Chem. 2005, 9, 1601. (d)
O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
(5) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
Kocˇovský, P. J. Org. Chem. 1999, 64, 2751. (b) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Org. Lett. 2004, 6, 3199. (c) Bandini, M.; Melloni, A.;
Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem.
Soc. 2006, 128, 1424. (d) Ma, S.; Yu, S.; Peng, Z.; Guo, H. J. Org. Chem.
2006, 71, 9865. (e) Cheung, H. Y.; Yu, W.-Y.; Lam, F. L.; Au-Yeung,
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10.1021/ol800409d CCC: $40.75
Published on Web 04/03/2008
2008 American Chemical Society

ertheless, transition-metal-catalyzed asymmetric allylic alky-
lation of indoles exhibit excellent potential for the synthesis
of optically pure indole derivatives but the studies in this
field remain quite limited. To the best of our knowledge,
iridium catalyst7,8 has not been utilized in this type of
reaction, and neither has the 1,3-unsymmetrical allylic
substrate.9 However, the preferred branched alkylation
product from the above reaction would lead to the product
bearing a terminal alkene which would highly increase the
utility of the alkylation product (eq 1).
Figure 1. Chiral ligands 1a-g.
reaction mixture. Examination of various bases such as
DBU, Proton Sponge, NaOMe, and Cs2CO3 disclosed that
Cs2CO3 was the optimal base, affording the branched
product 4aa in 60% yield with 93% ee (entries 1–6, Table
1). Changing the substrate ratio of 2a/3a to 1/1 or 2/1
resulted in decreases of yield and ee in both cases (entries
7–8, Table 1). Varying different solvents such as toluene,
dioxane, CH2Cl2, DMF, DME, CH3CN, and reaction
temperatures showed that reaction in refluxed dioxane gave
the best result, affording 4aa in 82% yield and 92% ee
(entries 9–15, Table 1). Notably, running the reaction in
toluene at 60 °C or in refluxed CH2Cl2 could also give
4aa with excellent ee (92%) in slightly lower yields, 57%
or 74%, respectively.
Due to our interest in both the Friedel–Crafts reaction of
indole10 and the Ir-catalyzed allylic alkylation reaction,11 we
envisaged that enantiopure indole derivatives bearing a
terminal alkene moiety might be achieved through an Ir-
catalyzed regio- and enantioselective Friedel–Crafts type
allylic alkylation of indole. In this paper, we will report our
preliminary results from the study on this subject.
At the outset, we utilized a well-developed Ir-catalytic
system including [Ir(COD)Cl]2 and a phosphoramidite 1a
(Figure 1) as the catalyst. In the presence of 2 mol % of
[Ir(COD)Cl]2, 4 mol % of 1a, and 1 equiv of DBU,
reaction of indole (3a, 200 mol %) and allyl carbonate
2a in THF for 60 h only gave alkylation product 4aa in
29% yield (entry 1, Table 1). To our delight, only branched
Next, we examined the effects of different chiral ligands,
and the results are summarized in Table 2. Phosphoramidite
ligands 1b and 1c, varying the substituents on the amine
1
alkylation product was detected by H NMR of the crude
Table 1. Optimization of the Reaction Conditions for Ir-Catalyzed Allylic Alkylation with Ligand 1aa
entry
solvent
base
time (h)
T (°C)
yieldb (%)
4aa/5aac
eed (%)
1
2
3
4
5
6
THF
THF
THF
THF
THF
THF
THF
THF
toluene
dioxane
dioxane
CH2Cl2
DMF
DBU
60
60
60
36
36
21
36
36
36
36
4
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
29
8
trace
46
NR
60
31
45
57
61
82
74
trace
33
46
>97/3
73/27
DABCO
Proton Sponge
NaOMe
Li2CO3
94/6
83
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
>97/3
>97/3
>97/3
>97/3
>97/3
>97/3
>97/3
93
88
69
92
93
92
92
7e
8f
9
10
11
12
13
14
15
100
reflux
reflux
60
60
60
20
72
84
36
DME
CH3CN
80/20
91/9
c
89
65
1
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of 1a, 100 mol % of base, 200 mol % of 3a. b Isolated yields. Determined by H NMR of
the crude reaction mixture. d ee of 4aa was determined by chiral HPLC analysis (Chiralcel OD-H). e 2a/3a 1/1. f 2a/3a 2/1.
1816
Org. Lett., Vol. 10, No. 9, 2008

Table 2. Screening of the Chiral Ligandsa
Table 3. Ir-Catalyzed Allylic Alkylation of Indolesa
entry
ligand
t (h)
yieldb (%)
4aa/5aac
eed (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4
8
82
81
75
trace
61
>97/3
>97/3
>97/3
92
90
86
17
24
16
21
21
>97/3
55/45
63
42
36
NR
1g
a Reactions were conducted under the conditions of entry 11, Table 1.
c
b Isolated yields. Determined by H NMR of the crude reaction mixture
1
d ee of 4aa was determined by chiral HPLC analysis (Chiralcel OD-H).
moiety, afforded the products in slightly lower yields and
enantioselectivities (entries 1–3, Table 2). Ligand 1d bearing
phenyl groups on the 3,3′-positions of the binaphthyl scaffold
was not effective for the reaction (entry 4, Table 2). The
catalyst derived from 1e, the diastereoisomer of 1a, could
catalyze the reaction in a lower yield and enantioselectivity
(61% yield, 63% ee, entry 5, Table 2). PHOX ligands such
as 1f and 1g were also tested, and 1f was capable of
catalyzing the reaction but in only 36% yield with 55/45
branched to linear ratio and 42% ee (entry 6, Table 2).
Unfortunately, no reaction occurred when 1g was employed
as the ligand (entry 7, Table 2).
In the presence of 2 mol % of [Ir(COD)Cl]2, 4 mol % of
1a, and 1 equiv of Cs2CO3 in refluxed dioxane, alkylation
of different indoles with various substituted allyl carbonates
was carried out to test the generality of the reaction. As
summarized in Table 3, alkylation of different indoles bearing
either an electron-donating group (5-OMe, 6-OBn) or
electron-withdrawing group (5-Br) with p-methoxyphenyl-
substituted allyl carbonate 2a all led to their corresponding
alkylation products in good yields with excellent ee (72–85%
yield, 85–92% ee, entries 1–4, Table 3). For the aryl allyl
carbonate substrates, substituents having different electronic
properties on the phenyl ring were well tolerated, and
excellent enantioselectivities (85–92% ee, entries 4–8, Table
(6) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc.
2006, 128, 6314.
(7) For reviews, see: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
(b) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (c) Helmchen, G.; Dahnz,
A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675.
(8) For recent examples, see: (a) López, F.; Ohmura, T.; Hartwig, J. F.
J. Am. Chem. Soc. 2003, 125, 3426. (b) Kiener, C. A.; Shu, C.; Incarvito,
C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. (c) Leitner, A.;
Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506.
(d) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K.
Chem. Eur. J. 2006, 12, 3596. (e) Schelwies, M.; Dübon, P.; Helmchen, G.
Angew. Chem., Int. Ed. 2006, 45, 2466. (f) Kazmaier, U.; Stolz, D. Angew.
Chem., Int. Ed. 2006, 45, 3072. (g) Weihofen, R.; Tverskoy, O.; Helmchen,
G. Angew. Chem., Int. Ed. 2006, 45, 5546. (h) Lyothier, I.; Defieber, C.;
Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 6204. (i) Nemoto, T.;
Sakamoto, T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 8737.
(j) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2007, 46, 3139.
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of 1a, 100 mol
% of Cs2CO3, 200 mol % of 3 in refluxed dioxane. b Isolated yields.
c Determined by 1H NMR of the crude reaction mixture. d ee of 4 was
determined by chiral HPLC analysis. e Determined by chiral HPLC of the
N-Cbz derivative of 4ca. f The yield was determined by 1H NMR after column
chromatography since the product is inseparable from the indole starting
material.
(9) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J. Am.
Chem. Soc. 2001, 123, 7471.
3) were obtained except for o-methoxyphenyl substrate 2f
(4fa, 84% yield, 70% ee, entry 9, Table 3).
The unfavorable ortho substituent effect can also be found
during the reaction of 1-naphthyl-substituted allyl carbonate
(10) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129,
1484.
(11) He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007,
9, 4339.
Org. Lett., Vol. 10, No. 9, 2008
1817

with 5-methoxy indole, and the product 4gb was only
obtained in 39% yield with 31% ee (entry 10, Table 3).
Notably, the reaction of 2-furyl-substituted allyl carbonate
with indole proceeded smoothly to afford the desired product
4ha in 80% yield with 89% ee (entry 11, Table 3). Under
these same conditions, two carbonate substrates 2i and 2j
derived from γ-alkylallyl alcohols have also been tested. Both
of the substrates were tolerated but gave the alkylation
products in slightly lower yields and regioselectivities (4ia,
43% yield, b/l 93/7, 88% ee; 4ja, 55% yield, b/l 87/13, 85%
ee; entries 11–12, Table 3).
In summary, we have found that [Ir(COD)Cl]2/phosphora-
midite ligand is an efficient catalytic system for the highly regio-
and enantioselective Friedel–Crafts allylic alkylation of indoles.
For various unsymmetrically allylic substrates and indoles, the
reaction proceeded smoothly with excellent regioselectivities
to afford the branched alkylation products with high ee. The
ready availability of the starting materials and the great
importance of the enantiopure products make the current
methodology particularly interesting in organic synthesis.
Further extending the reaction scope and developing more
efficient catalytic systems are currently underway in our
laboratory.
Acknowledgment. We gratefully acknowledge the Chi-
nese Academy of Sciences, the National Natural Science
Foundation of China, and the Science and Technology
CommissionofShanghaiMunicipality(07pj14106,07JC14063)
for generous financial support.
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800409D
1818
Org. Lett., Vol. 10, No. 9, 2008