Catalytic enantioselective Friedel-Crafts alkylation of indoles with β,γ-unsaturated α-keto phosphonates in the presence of Chiral palladium complexes

Article abstract of DOI:10.1055/s-0030-1259932

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with β,γ-unsaturated α-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-Crafts alkylation adducts with excellent enantioselectivities (up to 99% ee). Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259932

LETTER
1125
Catalytic Enantioselective Friedel–Crafts Alkylation of Indoles with
b,g-Unsaturated a-Keto Phosphonates in the Presence of Chiral
Palladium Complexes
Catalytic
E
nantios
o
elective Fried
u
el–Crafts
A
l
kylation of
I
g
ndoles Ku Kang, Ki Hyung Suh, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax +82(41)5301247; E-mail: dyoung@sch.ac.kr
Received 18 February 2011
tive reactions catalyzed by chiral palladium complexes
were reported.8 To the best of our knowledge, FC reaction
of indoles with b,g-unsaturated a-keto phosphonates cat-
alyzed chiral palladium complexes has not been reported.
Abstract: The catalytic enantioselective Friedel–Crafts alkylation
reaction promoted by chiral palladium complexes is described. The
treatment of indoles with b,g-unsaturated a-keto phosphonates un-
der the mild reaction conditions afforded the corresponding
Friedel–Crafts alkylation adducts with excellent enantioselectivi-
ties (up to 99% ee).
2+
1a Ar = Ph, X = BF4
Ar2
P
1b Ar = Ph, X = OTf
Key words: Friedel–Crafts reaction, asymmetric catalysis, chiral
palladium catalysts, indoles, b,g-unsaturated a-keto phosphonates
OH2
1c Ar = Ph, X = PF6
1d Ar = Ph, X = SbF6
1e Ar = 4-MeC6H4, X = PF6
1f Ar = 3,5-Me2C6H3, X = BF4
1g Ar = 3,5-Me2C6H3, X = PF6
2X–
Pd
NCMe
P
Ar2
The Friedel–Crafts (FC) reaction is one of the most pow-
erful C–C bond-forming processes in organic chemistry.1
Indole derivatives are present in many substances com-
monly found in nature, as well as in many compounds that
show pharmacological and biological activities. Thus, the
development of FC reaction of indole derivatives is im-
portant in the synthesis of natural products2 and pharma-
cological and biological activities.3 Over the past decade,
tremendous effort has been devoted to the development of
catalytic enantioselective FC reaction of a,b-unsaturated
carbonyl compounds using chiral metal complexes4 as
well as organocatalysts.7 Simple alkenyl esters have prov-
en to be difficult substrates for effective chirality relay in
asymmetric catalysis because of essentially low reactivity
of a,b-unsaturated esters as Michael acceptors. a-Keto
phosphonates, which have the ability of the phosphorus to
function as a leaving group, were introduced as activated
ester surrogates. Recently, several groups presented cata-
lytic asymmetric FC reactions of indoles to b,g-unsaturat-
ed a-keto phosphonates. Evans and Yamamoto groups
have developed FC reaction catalyzed by chiral Sc(OTf)3-
pybox complexes5 and chiral aluminium complexes.6 Ak-
iyama and Jørgensen groups have reported FC reaction
using organocatalysts such as chiral phosphoric acid7c and
chiral H-bonding catalysts.7b There are still some draw-
backs in the previously reported procedures, such as low
temperatures for high enantioselectivity, high catalyst
loading, and unsatisfactory enantioselectivities. There-
fore, the development of alternative catalysts for enantio-
selective FC reactions between indoles and b,g-
unsaturated a-keto phosphonates would be highly desir-
able. Recently, the efficient examples of the enantioselec-
Figure 1 Structures of chiral palladium catalysts
Table 1 Optimization of the Reaction Conditions
O
P(OEt)2
O
1) catalyst 1 (5 mol%)
O
2a
solvent, r.t.
+
OMe
H
2) DBU, MeOH, 2 h
N
HN
4a
3a
Entry
1
Catalyst
1a
Time
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
1 h
1 h
7 d
7 d
7 d
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Yield (%)a ee (%)b
70
75
70
71
73
76
79
77
25
50
30
47
39
89
83
93
81
89
65
39
90
91
90
79
7
2
1b
1c
3
4
1d
1e
5
6
1f
7
1g
8
1c
9
1c
THF
10
11
12
13
1c
EtOAc
acetone
MeCN
toluene
1c
1c
1c
85
SYNLETT 2011, No. 8, pp 1125–1128
x
x.
x
x.
2
0
1
1
a Yield of isolated product.
Advanced online publication: 30.03.2011
DOI: 10.1055/s-0030-1259932; Art ID: U00811ST
© Georg Thieme Verlag Stuttgart · New York
b Enantiomeric excess is determined by HPLC analysis with chiralcel
OD-H.

1126
Y. K. Kang et al.
LETTER
As part of research program related to the development of
synthetic methods for the enantioselective construction of
stereogenic carbon centers,9 we recently reported the cat-
alytic electrophilic amination, fluorination, Mannich reac-
tion, and Michael reaction of active methines promoted by
chiral palladium complexes with excellent enantioselec-
tivities.10 Herein, we wish to describe the enantioselective
FC reaction of indoles with b,g-unsaturated a-keto phos-
phonates catalyzed by air- and moisture-stable chiral pal-
ladium complexes (Figure 1).
Table 2 Catalytic Enantioselective Friedel–Crafts Reaction of
Indoles with b,g-Unsaturated a-Keto Phosphonates
O
R1
P(OR2)2
R4
O
R1
O
1) catalyst 1c (5 mol%)
2
+
CH2Cl2, r.t.
OMe
2) DBU, MeOH, 2 h
R3
N
N
R3
4
R4
To determine suitable reaction conditions for the catalytic
enantioselective FC reaction of indoles, we first examined
the FC reaction of indole 3a with b,g-unsaturated a-keto
phosphonate 2a in the presence of 5 mol% of dicationic
palladium complexes 1 in CH2Cl2 at room temperature
(Table 1). The intermediate g-indolyl-a-keto phospho-
nate, which is unstable, was converted to the correspond-
ing methyl ester by direct addition of MeOH and DBU.
We surveyed the effect of the structures of palladium
complexes 1. High yields with moderate to high enanti-
oselectivities (39–93% ee) were observed for structurally
variable palladium catalysts (Table 1, entries 1–7). Under
the standard reaction conditions, catalyst 1c exhibited bet-
ter enantioselectivity (93% ee, Table 1, entry 3). Next, we
examined the reaction in various solvents (Table 1, entries
3 and 8–13). The use of CH2Cl2 gave the best results,
whereas the FC reaction in 1,2-dichloroethane, tetrahy-
drofuran, ethyl acetate, acetone, acetonitrile, and toluene
led to lower yields and enantioselectivities (Table 1, en-
tries 3 and 8–13). The absolute configuration of 4a was
established by comparison of the optical rotation and
chiral HPLC analysis with previously reported values.5
3
Entry 2
R1
R2
3
R3
R4
Time Yield
(h) (%)a
ee
(%)b
1
2
2a Me Et
2b Me Me
3a
3a
H
H
2
2
1
2
3
3
1
2
2
2
4a 70
4a 75
4a 82
93
89
90
H
H
3
2c
2c
2c
2c
Me
Me
Me
Me
i-Pr 3a
i-Pr 3b
i-Pr 3c
i-Pr 3d
i-Pr 3a
i-Pr 3e
i-Pr 3c
i-Pr 3d
H
H
4
Me
H
H
4b 65 83
4c 80 99
4d 75 93
5
Br
OMe
H
6
H
7
2d Et
2d Et
2d Et
2d Et
H
4e 74
4f 68
4g 79
97
85
97
8
Me
H
Br
Br
OMe
H
9
10
11
H
4h 71 97
31
2e
Ph
Et
3a
H
36 4i 67
a Yield of isolated product.
b Enantiometic excess is determined by HPLC analysis with Chiralcel
With optimal reaction conditions in hand, we studied the
generality of the enantioselective FC reaction of various
indoles 3 with b,g-unsaturated a-keto phosphonates 2.11
As shown in the results summarized in Table 2, the corre-
sponding alkylated products 4 were obtained in good to
high yields with enantioselectivities (up to 99% ee). In
most cases, the reaction gave the desired products in ex-
cellent enatioselectivities but the reactions of N-methyl
indole derivatives 3b and 3e with a-keto phosphonates
gave relatively low enantioselectivities (Table 2, entries 4
and 8). Unfortunately, FC reaction of g-phenyl-substitut-
ed a-keto phosphonate 2e with indole gave the desired
product 4i in moderate yield and low enantioselectivity
(31% ee, Table 2, entry 11).
OD-H (for 4a–b,f,g) and Chiralpak AD-H (for 4c–e,h–i).
*
P
P
Pd
O
O
OR2
OR2
P
R1
indole
Figure 2 Plausible transition-state model
Although the reason for the observed enantioselectivity is
still unclear, we believe that b,g-unsaturated a-keto phos-
phonate 2 is activated by the palladium catalyst 1 in a bi-
dentate fashion. Then, indole 3 attacks the double bond as
shown in Figure 2. Because the Re face of the double bond
of phosphonate 2 was blocked preferentially by one of the
phenyl group of (R)-BINAP, the addition of indole pro-
ceeded from the Si face in a highly enantioselective man-
ner (Figure 2).12
In conclusion, we have developed an efficient catalytic
FC reaction of indoles to b,g-unsaturated a-keto phospho-
nates using air- and moisture-stable chiral palladium com-
plexes at room temperature. The intermediate g-indolyl a-
keto phosphonates were easily converted into the desired
methyl esters and the alkylated products were obtained in
good yields (65–82%) with excellent enantioselectivities
(up to 99% ee).
Synlett 2011, No. 8, 1125–1128 © Thieme Stuttgart · New York

LETTER
Catalytic Enantioselective Friedel–Crafts Alkylation of Indoles
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Following are results of a study on the ‘Human Resource Develop-
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Synlett 2011, No. 8, 1125–1128 © Thieme Stuttgart · New York

1128
Y. K. Kang et al.
LETTER
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93% ee). 1H NMR (200 MHz, CDCl3): d = 7.99 (br s, 1 H),
7.63 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.23–7.05
(m, 2 H), 6.90 (d, J = 2.5 Hz, 1 H), 3.65–3.47 (m, 1 H), 3.62
(s, 3 H), 2.82 (dd, J = 14.8, 6.0 Hz, 1 H), 2.56 (dd, J = 14.7,
8.7 Hz, 1 H), 1.39 (d, J = 6.9 Hz, 3 H). 13C NMR (50 MHz,
CDCl3): d = 173.0, 136.1, 125.9, 121.5, 120.2, 119.7, 118.8,
118.7, 110.9, 51.1, 41.9, 27.6, 20.6. ESI-MS: m/z = 217.9
[M + H]+, 117.0, 120.9, 123.0 147.0, 176.9. HPLC (hexane–
i-PrOH = 90:10, 220 nm, 0.8 mL/min) Chiralcel OD-H
column, tR = 9.0 min(minor), tR = 13.8 (major).
(11) Typical Procedure
To a stirred solution of (E)-diethyl 1-oxobut-2-enylphos-
phonate (2a, 20.6 mg, 0.1 mmol), Pd catalyst 1c (5.4 mg,
0.005 mmol) in CH2Cl2 (1 mL) was added indole (3a, 14.0
mg, 0.12 mmol) at r.t. The reaction mixture was stirred for 2
h at r.t. Then MeOH (0.15 mL), followed by DBU (0.03
mL), was added directly to the reaction mixture. The
reaction was allowed to stir for 2 h at r.t. The reaction was
diluted with EtOAc (10 mL), then washed with sat. NH4Cl.
The organic layer was dried over anhyd MgSO4, filtered,
concentrated, and purified by flash column chromatography
(EtOAc–hexane, 1:5) to afford (S)-methyl 3-(1H-indol-3-
yl)butanoate (4a, 70%, 15.2 mg). [a]D28 7.3 (c 0.7, CHCl3,
(12) The two-site-binding interaction between substrate and
palladium catalyst is crucial to guarantee reactivity as well as
stereocontrol. In fact, when the monodentate ethyl (E)-but-
2-enoate was reacted with indole under the same reaction
conditions, no reaction occurred.
Synlett 2011, No. 8, 1125–1128 © Thieme Stuttgart · New York

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