Highly enantioselective synthesis of β-heteroaryl-substituted dihydrochalcones through friedel-crafts alkylation of indoles and pyrrole

Article abstract of DOI:10.1002/chem.200902355

A highly enantioselective Friedel-Crafts (F-C) alkylation of indoles and pyrrole with chalcone derivatives catalyzed by a chiral N,N' -dioxide-Sc(OTf)₃ complex has been developed that tolerates a wide range of substrates. The reaction proceeds

Full text of DOI:10.1002/chem.200902355

DOI: 10.1002/chem.200902355
Highly Enantioselective Synthesis of b-Heteroaryl-Substituted
Dihydrochalcones Through Friedel–Crafts Alkylation of Indoles and Pyrrole
Wentao Wang, Xiaohua Liu, Weidi Cao, Jun Wang, Lili Lin, and Xiaoming Feng*[a]
Abstract:
A
highly enantioselective
enantioselectivities (85–92% enantio-
meric excess) using 2 mol% (for
indole) or 0.5 mol% (for pyrrole) cata-
lyst loading, which showed the poten-
tial value of the catalyst system. Mean-
while, a strong positive nonlinear effect
was observed. On the basis of the ex-
perimental results and previous reports,
a possible working model is proposed
to explain the origin of the activation
and asymmetric induction.
Friedel–Crafts (F–C) alkylation of in-
doles and pyrrole with chalcone deriva-
tives catalyzed by a chiral N,N’-diox-
ide–ScACHTUNGTRENNUNG(OTf)3 complex has been devel-
Keywords: alkylation · asymmetric
catalysis · dioxides · chalcones ·
scandium
oped that tolerates a wide range of
substrates. The reaction proceeds in
moderate to excellent yields and high
Introduction
many asymmetric procedures.[7–8] Herein, we describe a
readily
available
chiral
N,N’-dioxide–scandiumACHTUNGTRENNUNG(III)
The catalytic asymmetric Friedel–Crafts (F–C) alkylation is
trifluoroACTHNGUETRNNUmG ethanesulfonate complex system for the enantio-
À
one of the most powerful tools for C C bond formation;
selective conjugate addition of indoles and pyrrole to a
broad range of chalcones, giving a series of b-heteroaryl-
substituted DHCs in moderate to excellent yields (up to
99%) and high enantioselectivities (up to 92% ee) using
0.5–10 mol% catalyst loading under mild conditions.
this enables access to a variety of optically active building
blocks for organic transformations.[1] Since the pioneering
work of Paras and MacMillan,[2a] and Bandini and co-work-
ers,[3a] there have been several reports of highly enantiose-
lective asymmetric F–C alkylation of indole/pyrrole with
simple a,b-unsaturated aldehydes[2] and ketones.[3–4] Howev-
er, when chalcone derivatives were used, few examples were
documented and only moderate enantioselectivities (8–58%
enantiomeric excess (ee))[5] were achieved, probably owing
to the low reactivity of chalcone derivatives and the difficul-
ty in enantiofacial differentiation. In addition, the asymmet-
ric F–C alkylation of pyrrole using chalcones has not been
developed. Because b-heteroaryl-substituted dihydrochal-
cones (DHCs) exhibit biological activities, such as anti-
Results and Discussion
Our initial investigation began with screening several chiral
Lewis acid catalysts that were generated in situ from metal
salts and N,N’-dioxide L1 to evaluate their ability to pro-
mote the addition of indole 1a to chalcone 2a. As shown in
Table 1, ScACHTNUTRGNENG(U OTf)3 gave the best results (Table 1, entries 1–5).
As for the chiral backbone moiety, when N,N’-dioxide L3
(derived from l-pipecolic acid) was used instead of the l-
proline- and l-ramipril-derived ligands, the enantioselectivi-
ty increased to 87% ee (Table 1, entry 7 compared with en-
tries 1 and 6). Further optimization of the reaction condi-
tions was then aimed at exploring the effectiveness of Sc-
ACHTUNGTRENNUNG
mycotic and antibacterial properties,[6] it would be highly de-
sirable to develop effective protocols for the enantioselec-
tive synthesis of these optically pure compounds.
On the other hand, with a tunable electronic and steric
chiral environment, N,N’-dioxides have been applied to
AHCTUNGRTEG(NNUN OTf)3 with other N,N’-dioxide ligands. We found that the
amide moiety in the N,N’-dioxide ligands had a significant
effect on the enantioselectivity (Table 1, entries 8–15).
When R was replaced by an aromatic ring, the enantioselec-
tivity as well as the yield decreased dramatically (Table 1,
entries 8–9). Pleasingly, when N,N’-dioxide L10 (derived
from 9-anthracenylmethylamine) was used, the desired
product 3aa was obtained in 92% ee and 78% yield
[a] W. Wang, Dr. X. Liu, W. Cao, J. Wang, Dr. L. Lin, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902355.
1664
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Chem. Eur. J. 2010, 16, 1664 – 1669

FULL PAPER
Table 1. Central metal and ligand effects on catalytic asymmetric F–C re-
Table 2. Solvent and concentration effects on catalytic asymmetric F–C
action of indole 1a and chalcone 2a under indicated conditions.[a]
reaction of indole 1a and chalcone 2a.[a]
Entry
Solvent
t [h]
Yield [%][b]
ee [%][c]
Entry
Ligand
Metal
Sc(OTf)3
(OTf)3
La(OTf)3
In(OTf)3
ZrCl4
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
THF
EtOH
CH3CN
toluene
CH2Cl2
24
36
24
24
40
32
36
72
28
17
n.r.[d]
n.r.[d]
trace
n.r.[d]
78
26
40
53
99
–
–
60
–
92
72
90
83
92
89
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
A
48
40
36
24
24
48
40
50
72
36
24
40
40
40
44
48
n.r.[d]
n.r.[d]
7
18
54
65
26
17
83
45
–
–
0
0
82
87
21[e]
19
86
70
88
85
92
86
YACHTUNGTRENNUNG
G
G
CHCl3
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
G
Cl2CHCHCl2
ClCH2CH2Cl
CH2Cl2
E
E
9[e]
10[f]
R
CH2Cl2
>99
R
N
19
47
49
78
[a] Unless otherwise noted, reactions were carried out with 1a
(0.12 mmol) and 2a (0.1 mmol) in solvent (0.5 mL) with L10–Sc(OTf)3
complex (10 mol%; 1/1) catalyst under Ar atmosphere at 358C. [b] Iso-
lated yield. [c] Determined by HPLC analysis. Unless noted, the absolute
configuration was R by comparison with the reported optical rotation.[3c]
[d] No reaction. [e] CH2Cl2 (0.2 mL). [f] CH2Cl2 (0.1 mL).
G
ACHTUNGTRENNUNG
T
T
A
77
[a] Unless otherwise noted, reactions were carried out with 1a
(0.12 mmol) and 2a (0.1 mmol) in CH2Cl2 (0.5 mL) with L/metal complex
(10 mol%; 1/1) catalyst under Ar atmosphere at 358C. [b] Isolated yield.
[c] Determined by HPLC analysis. Unless noted, the absolute configura-
tion was R by comparison with the reported optical rotation.[3c] [d] No re-
action. [e] The absolute configuration of the major isomer was S.
to 0.5m, the product was obtained in excellent yield (99%)
and the enantioselectivity was maintained (Table 2, entry 9).
Further increases in concentration led to a slight decrease in
enantioselectivity although the reaction time was shortened
to 17 h (Table 2, entry 10).
(Table 1, entry 14). Therefore, the L10–ScACTHNURTGNENG(U OTf)3 system was
chosen to assess other reaction parameters.
Subsequently, the reaction temperature and catalyst load-
ing were examined and the results are presented in Table 3.
Decreasing the reaction temperature led to lower reactivity
although the enantioselectivity was maintained (Table 3, en-
tries 1–3). When the temperature was increased from 35 to
458C, the enantioselectivity was somewhat reduced (Table 3,
Table 3. Effect of temperature and catalyst loading on the catalytic asym-
metric F–C reaction of indole 1a and chalcone 2a.[a]
Entry
T
[8C]
Catalyst loading
[x mol%]
t
Yield
[%][b]
ee
G
[h]
[%][c]
Encouraged by the initial results, various solvents were
tested in the presence of L10–ScACHTNUTRGNEUNG(OTf)3 (10 mol%). The re-
1
2
3
4
5
6
À20
0
10
10
10
10
10
15
5
72
36
36
28
16
22
28
28
9
24
99
99
92
91
79
11
92
92
92
92
89
92
89
90
sults indicated that the reaction solvent plays an important
role in governing the rate and enantioselectivity of the reac-
tion. Coordinating and highly polar solvents such as THF,
EtOH, and CH3CN shut down the catalytic activity of the
25
35
45
35
35
35
L10–ScACHTUNGTRENNUNG(OTf)3 complex, presumably because of coordination
7
8[d]
1
to the central metal (Table 2, entries 1–3). No reaction took
place in toluene (Table 2, entry 4). Because CH2Cl2 was ini-
tially found to be the optimal solvent, other chlorinated al-
kanes were then investigated, but no superior result was ob-
tained (Table 2, entry 5 compared with entries 6–8). The
substrate concentration was also a key factor. To our de-
light, when the concentration of chalcone 2a was increased
[a] Unless otherwise noted, reactions were carried out with 1a
(0.12 mmol) and 2a (0.1 mmol) in CH2Cl2 (0.2 mL) with L10–Sc(OTf)3
(10 mol%; 1/1) under Ar atmosphere at 358C. [b] Isolated yield. [c] De-
termined by HPLC analysis. Unless noted, the absolute configuration
was R by comparison with the reported optical rotation.[3c] [d] The reac-
ACHTUNGTRENNUNG
tion was carried out with L10–Sc
and 2a (0.2 mmol) in CH2Cl2 (0.4 mL) under Ar atmosphere at 358C.
ACHTUNGERTN(NUNG OTf)3 (1 mol%; 1/1), 1a (0.24 mmol),
Chem. Eur. J. 2010, 16, 1664 – 1669
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1665

X. Feng et al.
Table 5. Catalytic asymmetric F–C reaction of indole 1a and enone de-
rivatives 2 under the optimal conditions.[a]
entry 5). The catalyst loading was then evaluated. Upon in-
creasing the catalyst loading from 10 to 15 mol%, neither
the yield nor the enantioselectivity were changed (Table 3,
entry 6). Reducing the catalyst loading caused a notable
drop in reactivity (Table 3, entry 7 and 8). Some additives
(for details see the Supporting Information) were also
screened, but no better results were obtained. Extensive
screening showed that the optimal conditions were as fol-
Entry R1
R2
Adduct Yield
[%][b]
ee
[%][c]
lows: L10–Sc
ACHTUNGTRENNUNG(OTf)3 complex (10 mol%; molar ratio L10/Sc-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
Ph
Ph
Ph
4-MeC6H4
Ph
Ph
4-MeOC6H4
Ph
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
99
84
87
77
91
68
57
99
92[d]
91
91
91
90
92
92
92
ACHTUNGTRENNUNG(OTf)3 1/1), chalcone (0.1 mmol), and indole (0.12 mmol) in
CH2Cl2 (0.2 mL) at 358C.
To investigate the scope of the reaction, we examined the
reactions of a range of indoles with chalcone 2a under the
optimized conditions and the results are listed in Table 4. In-
3-MeC6H4
4-MeC6H4
Ph
3-MeOC6H4
4-MeOC6H4
Ph
4-ClC6H4
Ph
99 (88) 90 (90)[e]
99 (85) 92 (92)[f]
99 (75) 92 (92)[f]
95 (88) 89 (89)[e]
Table 4. Catalytic asymmetric F–C reaction of indole derivatives and
chalcone 2a under the optimal conditions.[a]
3-CF3C6H4
3-NO2C6H4
4-CNC6H4
4-PhC6H4
3-PhOC6H4
95
91
75
99
99
92
90
92
90
92
3,4-OCH2OC6H3 Ph
Ph
2-naphthyl
4-FC6H4
4-BrC6H4
Ph
3-ClC6H4
Ph
Ph
Ph
À
Entry Indole
Product t [h]
Yield [%][b] ee [%][c]
99 (95) 90 (91)[f]
77 90
99 (82) 89 (89)[e]
71
99
74
43
66
75
46
1
2
3
4
5
6
7
8
9
1a, X: H, R: H
3aa
3ba
3ca
3da
28
40
44
99
99
92
92[d]
90
CH=CHC6H5 3as
1b, X: 7-Me, R: H
1c, X: 7-Et, R: H
1d, X: 5-Me, R: H
1e, X: 5-MeO, R: H 3ea
1 f, X: 6-MeO, R: H 3 fa
1g, X: 2-Me, R: H
1h, X: 5-Br, R: H
1i, X: 5-Cl, R: H
1j, X: 5-F, R: H
1k, X: H, R: Me
Ph
3at
92
4-FC6H4
3-ClC6H4
Ph
Ph
Ph
3au
3av
3aw
3ax
3ay
3az
3aaa
88
87
83
90
44 (60) 99 (89)
44 94
40 (53) 99 (81)
44 (48) 99 (80)
40
40
44
44
89 (88)[e]
Ph
90
2-MeOC6H4
2-furyl
2-thienyl
Ph
85 (85)[f]
3ga
3ha
3ia
3ja
3ka
81 (81)[e]
91
50
78
79
74
90
90
86
74
2-furyl
Ph
88
Me
58[g]
10
11
[a] Unless noted, reactions were carried out with 1a (0.12 mmol) and 2
(0.1 mmol) in CH2Cl2 (0.2 mL) with L10–Sc(OTf)3 complex (10 mol%)
AHCTUNGTRENNUNG
[a] Unless noted, reactions were carried out with 2a (0.1 mmol) and 1
(0.12 mmol) in CH2Cl2 (0.2 mL) with L10–Sc(OTf)3 complex (10 mol%)
under Ar atmosphere at 358C for 20–60 h (for details see the Supporting
Information). [b] Isolated yield. [c] Determined by HPLC analysis.
[d] The absolute configuration was R by comparison with the reported
optical rotation.[3c] [e] The results in parentheses were obtained with
AHCTUNGTRENNUNG
under Ar atmosphere at 358C. [b] Isolated yield. [c] Determined by
HPLC analysis. [d] The absolute configuration was R by comparison with
the reported optical rotation.[3c] [e] The results in parentheses were ob-
5 mol% L10–ScACHTNUGRTENUNG(OTf)3. [f] The results in parentheses were obtained with
tained with 2 mol% L10–Sc
ACHTUNGTRENNUNG
2 mol% L10–ScACHTNUGRTENUNG(OTf)3. [g] The absolute configuration was S by compari-
son with the reported optical rotation.[3e]
obtained with 5 mol% L10–Sc
AHCTUNGTRENNUNG
doles with an electron-donating group could be converted
into the desired products in high yields and ee values
(Table 4, entries 2–7). In the case of halogen-substituted in-
doles, the catalyst was also efficient (Table 4, entries 8–10).
Notably, for some indoles, good results were still maintained
using as low as 2 mol% catalyst loading (Table 4, entries 4,
6, and 7). When 1-methylindole (1k) was used, a moderate
result was obtained (Table 4, entry 11).
With these results in hand, various a,b-unsaturated ke-
tones were then examined (Table 5).[9] Good to excellent
yields and high enantioselectivities were obtained, regard-
less of the electronic nature or positions of the substituents
on the phenyl ring (Table 5, entries 1–23). A condensed-ring
chalcone reacted smoothly with indole, giving the product
3ap with 90% ee (Table 5, entry 16). When dibenzalacetone
was used, the single F–C alkylation product 3as was ob-
served, which can thus be further functionalized at the re-
maining double bond (Table 5, entry 19). Importantly, the
catalyst loading could be decreased to 5 or 2 mol% without
affecting the efficiency of the catalyst (Table 5, entries 9–12,
18, and 20). In addition, substrates bearing heteroaryl units
also proved to be competent candidates for the alkylation of
indole (Table 5, entries 24–26). For trans-1-phenylbut-2-en-
1-one, the desired product 3aaa was obtained with a moder-
ate ee value (Table 5, entry 27). It is noteworthy that some
b-indole-substituted DHCs could act as promising anti-
AHCTUNGTRENNUNG
with chalcones, we also investigated pyrrole as a nucleo-
phile.[10] Under the same reaction conditions, the desired
product 5a was obtained in 45% yield and 90% ee after 7 h.
To our delight, after a slight modification of the catalyst
system, by altering the ligand L10 to L6, the ee value of 5a
1666
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Chem. Eur. J. 2010, 16, 1664 – 1669

Friedel–Crafts Alkylation of Indoles and Pyrrole
FULL PAPER
increased to 92% using 2 mol% L6–Sc
G
tically pure 3aa was obtained after a single recrystallization.
entry 1). The substrate scope was then surveyed. Various
chalcones with electron-withdrawing or -donating groups on
Most notably, the reaction could be performed with pyrrole
in the presence of 0.5 mol% of L6–ScACTHNUTRGNEUNG(OTf)3, giving the de-
sired product 5a with 92% ee. In addition, reduction of the
adduct 3aa gave a diastereomeric mixture of alcohol 6 (dia-
stereomeric ratio (dr) 53:47). The product 3aa can also be
easily transformed into oxime 7 (92% yield, 91% ee), which
is a versatile building block.
Table 6. Catalytic asymmetric F–C reaction of pyrrole 4 and enones 2
under the indicated conditions.[a]
To gain insight into the reaction mechanism, a C2-symmet-
ric amide, compound 8 (Figure 1), which was the precursor
of the chiral N,N’-dioxide L10, was synthesized. Several ex-
periments were carried out and the results are summarized
in Table 7. No adducts were obtained by employing 8 or L10
as an organocatalyst (Table 7, entries 1 and 2). When 8–Sc-
AHCTUNGRTEG(NNUN OTf)3 was employed as the catalyst, the reaction did not
take place (Table 7, entry 3), which confirmed that the N-
oxide and the central metal play a key role in this reaction.
Entry
R1
R2
Adduct
Yield [%][b]
ee[%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5 f
5g
5h
73
78
55
48
80
75
46
46
92
92
92
92
90
92
92
74[d]
4-BrC6H4
4-MeC6H4
4-Cl
3-ClC6H4
Ph
Ph
4-FC6H4
4-MeC6H4
Ph
Ph
Me
In addition, the ratio of ligand L10 to Sc
cial. The reaction did not occur when the ratio of L10/Sc-
(OTf)3 was 1.5/1 or 2/1 (Table 7, entries 4 and 5), which sug-
ACHTUNGRTEN(NGNU OTf)3 was also cru-
[a] Unless otherwise noted, reactions were carried out with 4 (0.6 mmol)
and 2 (0.2 mmol) in CH2Cl2 (0.4 mL) with L6–Sc(OTf)3 (2 mol%; 1/1)
complex under Ar atmosphere at 358C for 15 h. [b] Isolated yield. [c] De-
termined by HPLC analysis. [d] When using 5 mol% L6–Sc(OTf)3 (1/1)
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
gested that the catalyst was poisoned by excess N,N’-dioxide
L10. The enantioselectivity decreased remarkably when a 2/
AHCTUNGTRENNUNG
complex for 20 h, the absolute configuration was S by comparison with
1 molar ratio of Sc
ACHTUNGTRENNUNG
the reported optical rotation.[3e]
strong background reaction of ScAHCNUTGTRENNUNG
the phenyl ring reacted with pyrrole smoothly using 2 mol%
L6–ScACHTUNGTRENNUNG(OTf)3 under mild conditions, giving the correspond-
ing products in good yields and high enantioselectivities
(90–92% ee) (Table 6, entries 2–7). When trans-1-phenylbut-
2-en-1-one was employed, the corresponding 2-alkylated
pyrrole 5h was obtained with 74% ee (Table 6, entry 8).
To show the synthetic application of the current system, a
large-scale synthesis of 3aa/5a was tested. As shown in
Scheme 1, catalytic asymmetric F–C reaction of indole with
chalcone 2a was accomplished with good results (90%
yield, 87% ee) by using only 2 mol% of L10–ScACTHNUGTRENUNG(OTf)3. Op-
Scheme 1. Catalytic asymmetric F–C reaction of indole and pyrrole to
chalcone 2a on a 1.0 mmol scale and the transformations of 3aa to 6 and
to 7. Conditions: a) NaBH4, CH3OH, 08C, 1 h, 91% yield, dr 53:47,
92% ee; b) pyridine, NH2OH·HCl, EtOH, 358C, 2 h, 85% yield, 91% ee.
Figure 1. a) Chiral amplification in the F–C alkylation of 1a with 2a cata-
~
&
lyzed by L10–Sc
ACHTUNGRTENUN(NG OTf)3 complex ( : ee value of 3aa, : yield of 3aa);
b) Proposed transition-state model.
Chem. Eur. J. 2010, 16, 1664 – 1669
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1667

X. Feng et al.
Table 7. Control experiments for mechanistic studies.[a]
posed transition-state model was put forward to explain the
origin of the asymmetric induction. Further application of
the current method is currently underway.
Experimental Section
Entry Ligand [mol%] ScACTHNUTRGNEUNG
(OTf)3 [mol%] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
8 (10)
L10 (10)
8 (10)
L10 (20)
L10 (15)
L10 (11)
L10 (10)
L10 (5)
–
–
40
48
24
28
28
28
28
24
n.r.[d]
n.r.[d]
n.r.[d]
trace
trace
92
–
–
–
–
Typical experimental procedure for indole: A solution of N,N’-dioxide
L10 (7.1 mg, 0.01 mmol), scandium triflate (4.9 mg, 0.01 mmol), and chal-
cone 2a (0.10 mmol) in CH2Cl2 (0.2 mL) was stirred under argon atmos-
phere at 358C for 0.5 h, then indole 1a (50 mL, 2.4m in CH2Cl2) was
added. The reaction mixture was stirred at 358C for 28 h and then puri-
fied by flash chromatography (petroleum ether/ethyl acetate/CH2Cl2 =
5:1:0.1) on silica gel to afford the desired product 3aa as a white solid
(99% yield, 92% ee). M.p. 139–1408C; [a]2D6 =À49.2 (c=0.39 in CHCl3)
(99% ee); 1H NMR (400 MHz, CDCl3): d=7.98 (brs, 1H), 7.97–7.94 (m,
2H), 7.58–7.54 (m, 1H), 7.47–7.43 (m, 3H), 7.39–7.34 (m, 3H), 7.30–7.26
(m, 2H), 7.20–7.15 (m, 2H), 7.06–7.02 (m, 2H), 5.09 (t, J=7.2 Hz, 1H),
3.84 (dd, J=6.8, 16.8 Hz, 1H), 3.75 ppm (dd, J=7.6, 16.8 Hz, 1H);
HPLC analysis using a chiral AD-H column (iPrOH/hexane=20/80,
1.0 mLminÀ1, 254 nm), tr (major)=13.267 min, tr (minor)=15.368 min,
92% ee.
10
10
10
10
10
10
–
92
92
57
99
99
[a] Unless noted, reactions were carried out with 1a (0.12 mmol) and 2
(0.1 mmol) in CH2Cl2 (0.2 mL) under Ar atmosphere at 358C . [b] Isolat-
ed yield. [c] Determined by HPLC analysis. Unless noted, the absolute
configuration was R by comparison with the reported optical rotation.[3c]
[d] No reaction.
Typical experimental procedure for pyrrole: A solution of N,N’-dioxide
L6 (2.2 mg, 0.004 mmol), scandium triflate (2.0 mg, 0.004 mmol), and
chalcone 2a (0.2 mmol) in CH2Cl2 (0.4 mL) was stirred under argon at-
mosphere at 358C for 0.5 h, then pyrrole 4 (42.0 mL, 0.6 mmol) was
added. The reaction mixture was stirred at 358C for 15 h and then puri-
fied by flash chromatography (petroleum ether/ethyl acetate=10:1) on
silica gel to afford the desired product 5aa as a colorless oil (73%,
92% ee). [a]2D7 =À3.5 (c=0.80 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=8.31 (s, 1H), 7.98–7.95 (m, 2H), 7.59–7.55 (m, 1H), 7.48–7.44 (m,
2H), 7.36–7.26 (m, 4H), 7.25–7.23 (m, 1H), 6.67–6.66 (m, 1H), 6.11–6.09
(m, 1H), 5.87–5.85 (m, 1H), 4.81–4.78 (m, 1H), 3.86–3.79 (dd, J=8.0,
17.2 Hz, 1H), 3.64–3.58 ppm (dd, J=6.8, 17.6 Hz, 1H); HPLC analysis
Next, the relationship between the ee value of ligand L10
and the product 3aa was investigated under the optimal
conditions shown in Table 4. A strong positive nonlinear
effect[11] was observed (Figure 1a), suggesting that two or
more monomeric catalyst species form catalytically inactive
oligomeric aggregates, thereby enhancing the proportion of
one catalytically active scandium N,N’-dioxide enantio-
mer.[12] In the light of the X-ray structure of the N,N’-diox-
ide–ScIII complex recently reported by us,[8h] and the above
experimental results, a proposed transition state that ration-
alizes the observed sense of asymmetric induction is provid-
ed in Figure 1b. In this transition state, the N-oxides and
amide oxygen atoms of L10 coordinate to scandium in a tet-
radentate manner to form two six-membered chelate rings,
and the chalcone can coordinate to scandium from the more
accessible side. The incoming indole prefers to attack the Re
face rather than Si face of the chalcone because the latter is
strongly shielded by the nearby anthracenyl ring, which re-
sults in the R-configured product.
using
a ,
chiral OD-H column (iPrOH/hexane=10/90, 1.0 mLminÀ1
254 nm), tr (minor)=10.949 min, tr (major)=11.757 min, 92% ee.
Acknowledgements
We appreciate the National Natural Science Foundation of China (Nos.
20732003 and 20602025) and the Ministry of Education (No.
20070610019) for financial support, the Sichuan University Analytical &
Testing Centre for NMR analysis, and the State Key Laboratory of Bio-
therapy for HRMS analysis.
Conclusion
[1] This reaction is also regarded as Michael-type reaction, for some re-
views, see: a) N. Saracoglua, Bioactive Heterocycles V, Springer,
Berlin, 2007, pp. 1–61; b) M. Bandini, A. Melloni, A. Umani-
Ronchi, Angew. Chem. 2004, 116, 560; Angew. Chem. Int. Ed. 2004,
43, 550; c) K. A. Jørgensen, Synthesis 2003, 1117; d) M. Bandini, A.
Melloni, S. Tommasi, A. Umani-Ronchi, Synlett 2005, 1199; e) T. B.
Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903; f) S. L. You,
Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190, and references
therein.
[2] a) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123,
4370; b) J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 1172; c) J. F. Austin, S. G. Kim, C. J. Sinz, W. J. Xiao, D. W. C.
MacMillan, Proc. Natl. Acad. Sci. USA 2004, 101, 5482; d) H. D.
King, Z. Meng, D. Denhart, R. Mattson, R. Kimura, D. Wu, Q. Gao,
J. E. Macor, Org. Lett. 2005, 7, 3437; e) C. F. Li, H. Liu, J. Liao, Y. J.
Cao, X. P. Liu, W. J. Xiao, Org. Lett. 2007, 9, 1847; f) L. Hong, L.
Wang, C. Chen, B. Z. Zhang, R. Wang, Adv. Synth. Catal. 2009, 351,
772; g) L. Hong, C. X. Liu, W. S. Sun, L. Wang, K. Wong, R. Wang,
Org. Lett. 2009, 11, 2177.
We have developed a catalytic asymmetric Friedel–Crafts al-
kylation of indoles and pyrrole with a number of chalcones
promoted by a N,N’-dioxide–ScACHTNUGTRENUNG(OTf)3 complex. This type of
electrophilic compound is challenging for F–C reactions on
account of the nonchelating character of chalcones. A series
of b-heteroaryl-substituted dihydrochalcones was obtained
with high enantioselectivities (up to 92% ee) and moderate
to excellent yields (up to 99%) under mild conditions. This
method also expanded considerably the range of optically
active indole/pyrrole derivatives that can be directly gener-
ated from readily available prochiral precursors. Good re-
sults were still maintained when using 2 (for indole) or
0.5 mol% (for pyrrole) catalyst loading, which showed the
potential value of the catalyst system. Meanwhile, a pro-
1668
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Chem. Eur. J. 2010, 16, 1664 – 1669

Friedel–Crafts Alkylation of Indoles and Pyrrole
FULL PAPER
[3] For simple a,b-unsaturated ketones see: a) M. Bandini, M. Fagioli,
P. Melchiorre, A. Melloni, A. Umani-Ronchi, Tetrahedron Lett.
2003, 44, 5843; b) M. Bandini, M. Fagioli, M. Garavelli, A. Melloni,
V. Trigari, A. Umani-Ronchi, J. Org. Chem. 2004, 69, 7511; c) G.
Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P. Mel-
chiorre, Org. Lett. 2007, 9, 1403; d) W. Chen, W. Du, L. Yue, R. Li,
Y. Wu, L. S. Ding, Y. C. Chen, Org. Biomol. Chem. 2007, 5, 816;
e) G. Blay, I. Fernꢁndez, J. R. Pedro, C. Vila, Org. Lett. 2007, 9,
2601; f) G. Blay, I. Fernꢁndez, J. R. Pedro, C. Vila, Tetrahedron Lett.
2007, 48, 6731.
[4] For other types of enones, see: a) K. B. Jensen, J. Thorhauge, R. G.
Hazell, K. A. Jørgensen, Angew. Chem. 2001, 113, 164; Angew.
Chem. Int. Ed. 2001, 40, 160; b) D. A. Evans, K. A. Scheidt, K. R.
Fandrick, H. W. Lam, J. Wu, J. Am. Chem. Soc. 2003, 125, 10780;
c) D. A. Evans, K. R. Fandrick, H. J. Song, J. Am. Chem. Soc. 2005,
127, 8942; d) C. Palomo, M. Oiarbide, B. G. Kardak, J. M. Garcia,
A. Linden, J. Am. Chem. Soc. 2005, 127, 4154; e) D. A. Evans, K. R.
Fandrick, Org. Lett. 2006, 8, 2249; f) D. A. Evans, K. R. Fandrick,
H. J. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129,
10029; g) H. Y. Yang, Y. T. Hong, S. Kim, Org. Lett. 2007, 9, 2281;
h) P. K. Singh, V. K. Singh, Org. Lett. 2008, 10, 4121; i) M. P. Sibi, J.
Coulomb, L. M. Stanley, Angew. Chem. 2008, 120, 10061; Angew.
Chem. Int. Ed. 2008, 47, 9913; j) A. J. Boersma, B. L. Feringa, G.
Roelfes, Angew. Chem. 2009, 121, 3396; Angew. Chem. Int. Ed.
2009, 48, 3346; k) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M.
Bolte, Angew. Chem. 2008, 120, 603; Angew. Chem. Int. Ed. 2008,
47, 593; l) M. Zeng, Q. Kang, Q. L. He, S. L. You, Adv. Synth. Catal.
2008, 350, 2169; m) G. Desimoni, G. Faita, M. Toscanini, M. Boioc-
chi, Chem. Eur. J. 2008, 14, 3630.
1985, 13, 307; d) M. M. Said, A. A. E. Ahmed, A. T. El-Alfy, Arch.
Pharmacal Res. 2004, 27, 1194.
[7] For reviews on chiral N-oxides in asymmetric catalysis, see: a) A. V.
ˇ
´
Malkov, P. Kocovsky, Eur. J. Org. Chem. 2007, 29; b) A. V. Malkov,
ˇ
´
P. Kocovsky, Curr. Org. Chem. 2003, 7, 1737; c) G. Chelucci, G. Mur-
ineddu, G. A. Pinna, Tetrahedron: Asymmetry 2004, 15, 1373, and
references therein.
[8] For our own work in this field, see: a) Z. P. Yu, X. H. Liu, Z. H.
Dong, M. S. Xie, X. M. Feng, Angew. Chem. 2008, 120, 1328; Angew.
Chem. Int. Ed. 2008, 47, 1308; b) D. J. Shang, J. G. Xin, Y. L. Liu, X.
Zhou, X. H. Liu, X. M. Feng, J. Org. Chem. 2008, 73, 630; c) X.
Yang, X. Zhou, L. L. Lin, L. Chang, X. H. Liu, X. M. Feng, Angew.
Chem. 2008, 120, 7187; Angew. Chem. Int. Ed. 2008, 47, 7079;
d) L. J. Wang, X. H. Liu, Z. H. Dong, X. Fu, X. M. Feng, Angew.
Chem. 2008, 120, 8798; Angew. Chem. Int. Ed. 2008, 47, 8670; e) C.
Tan, X. H. Liu, L. W. Wang, J. Wang, X. M. Feng, Org. Lett. 2008,
10, 5305; f) K. Zheng, J. Shi, X. H. Liu, X. M. Feng, J. Am. Chem.
Soc. 2008, 130, 15770; g) D. J. Shang, Y. L. Liu, X. Zhou, X. H. Liu,
X. M. Feng, Chem. Eur. J. 2009, 15, 3678; h) Y. L. Liu. D. J. Shang,
X, Zhou, X. H. Liu, X. M. Feng, Chem. Eur. J. 2009, 15, 2055;
i) S. K. Chen, Z. R. Hou, Y. Zhu, J. Wang, L. L. Lin, X. H. Liu,
X. M. Feng, Chem. Eur. J. 2009, 15, 5884.
[9] Benzalacetone (48 h, 76% yield, 15% ee); cyclohex-2-enone (36 h,
56% yield, 0% ee) under the optimal conditions shown in Table 4.
[10] Other nucleophiles such as furan, thiophene, and anisole were also
tested; no adducts were obtained under the standard conditions
shown in Table 4.
[11] a) D. Guillaneux, S. H. Zhao, O. Samuel, D. Rainford, H. B. Kagan,
J. Am. Chem. Soc. 1994, 116, 9430; b) C. Girard, H. Kagan, Angew.
Chem. 1998, 110, 3088; Angew. Chem. Int. Ed. 1998, 37, 2922; c) T.
Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. 2009, 121,
464; Angew. Chem. Int. Ed. 2009, 48, 456.
[5] a) W. Zhou, L. W. Xu, L. Li, L. Yang, C. G. Xia, Eur. J. Org. Chem.
2006, 5225; b) H. Y. Tang, A. D. Lu, Z. H. Zhou, G. F. Zhao, L. N.
He, C. C. Tang, Eur. J. Org. Chem. 2008, 1406. In addition, there
was only one substrate mentioned in references [3c,e], 78% yield
(82% ee) and 25% yield (96% ee) were obtained after 4 d under
20 mol% catalyst loading, respectively.
[12] a) By using optically pure L10 as the chiral ligand, the catalyst L10–
ScACHTNURGTNEUG(N OTf)3 complex prepared in situ in CH2Cl2 was soluble, however,
when nonenantiopure L10 was used, a large amount of deposition
was observed during the catalyst preparation; b) attempts to grow a
[6] a) M. Damodiran, R. S. Kumar, P. M. Sivakumar, M. Doble, P. T. Pe-
rumal, J. Chem. Sci. 2009, 121, 65; b) L. Sartor, E. Pezzato, I. Del-
lꢂAica, R. Caniato, S. Biggin, S. Garbisa, Biochem. Pharmacol. 2002,
64, 229; c) S. P. Sachchar, S. C. Bahel, A. K. Singh, Bokin Bobai
single crystal of L10–ScACHTNUTRGNENG(U OTf)3 were unsuccessful.
Received: August 26, 2009
Published online: December 10, 2009
Chem. Eur. J. 2010, 16, 1664 – 1669
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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