Enantioselective Friedel-Crafts alkylation of indoles with alkylidene malonates catalyzed by N,N′-dioxide-scandium(III) complexes: Asymmetric synthesis of β-carbolines

Article abstract of DOI:10.1002/chem.200802210

Highly enentioselective Friedel-Crafts alkylation of indoles with alkylidene malonates catalyzed by chiral N,N'-dioxide-scandium (III) triflate complexes was described. Under the optimal reaction conditions, various indoles and alkylidene malonates were e

Full text of DOI:10.1002/chem.200802210

COMMUNICATION
DOI: 10.1002/chem.200802210
Enantioselective Friedel–Crafts Alkylation of Indoles with Alkylidene
Malonates Catalyzed by N,N’-Dioxide–ScandiumACTHUNRTGNEUNG(III) Complexes:
Asymmetric Synthesis of b-Carbolines
Yanling Liu,[a] Deju Shang,[a] Xin Zhou,[a] Xiaohua Liu,[a] and Xiaoming Feng*[a, b]
Optically active indole derivatives have attracted signifi-
cant attention in organic synthesis because they are impor-
tant building blocks in a variety of interesting natural prod-
ucts and potential medicinal agents.[1,2] The asymmetric Frie-
del–Crafts alkylation of indoles[3–5] with alkylidene malo-
nates has shown promise as a synthetic methodology to-
wards functionalized indoles. In 2001, the Jørgensenꢀs
group[6] reported the first example of this reaction using a
C2-symmetric chiral bis(oxazoline)–CuII complex as catalyst.
Subsequently, Tang and co-workers disclosed that the Frie-
del–Crafts alkylation of indoles with alkylidene malonates
was further promoted by a pseudo-C3-symmetric tris(oxazo-
line)–CuII complex.[7] Very recently, Reiser et al. described
that the ratio of oxazoline/copper had a significant influence
on the enantioselectivity.[8] Despite these impressive contri-
butions, the catalysts were limited to chiral CuII–oxazoline
complexes. Considering the high synthetic versatility of the
products, the development of new and efficient catalysts is
still an interesting demanding challenge.
Some representative screening results[11] for the catalytic
enantioselective alkylation of indole 2a with alkylidene mal-
onate 3a in the presence of the chiral N,N’-dioxide–
scandium
in Table 1. Initially, different chiral N,N’-dioxide ligands
(1a–1 f) complexed with Sc(OTf)3 were investigated. As
ACHTUNGTREN(NGNU III) triflate complexes as catalysts are presented
AHCTUNGTRENNUNG
As a bidentate substrate, alkylidene malonate can chelate
a series of Lewis acids in many asymmetric reactions.[7b,9]
On the other hand, N,N’-dioxide–scandiumACTHUNRTGNEUNG(III) complexes
have proven to be effective chiral Lewis acid catalysts that
exhibit good chelating potential.[10] Herein, we describe the
highly enantioselective Friedel–Crafts alkylation of indoles
with alkylidene malonates catalyzed by chiral N,N’-dioxide–
shown in Table 1, ligand 1a (derived from l-Ramiprol acid)
containing a diphenylmethyl group emerged as a promising
ligand to provide better yield and enantioselectivity, while li-
gands with smaller or bulkier groups such as benzyl, triphe-
nylmethyl, and ortho-isopropylphenyl groups gave lower
enantioselectivities (Table 1, entries 1–4). Further modifica-
tions to the ligand structure led to the observation that li-
gands 1e and 1 f (derived from l-proline) afforded worse re-
sults compared with 1a (Table 1, entries 5 and 6). All these
studies indicated the cooperative role of both amino acid
and amine in defining the enantioselectivity and reactivity
of the reaction. Moreover, when ligand 1g, which lacked a
N,N’-dioxide, was employed, the reaction gave the racemic
product 4a in 79% yield, which revealed that the N-oxide
group plays a crucial role in determining the enantioselectiv-
ity of the reaction (Table 1, entry 7). To our delight, the
enantioselectivity was increased when the catalyst 1a-Sc-
scandiumACHTUNGTRENNUNG(III) triflate complexes.
[a] Y. Liu, D. Shang, X. Zhou, Dr. X. Liu, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases
Sichuan University, Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802210.
Chem. Eur. J. 2009, 15, 2055 – 2058
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2055

Table 1. Catalytic enantioselective Friedel–Crafts alkylation of indole 2a
with alkylidene malonate 3a.[a]
Table 2. Catalytic enantioselective Friedel–Crafts reaction of indoles 2
with alkylidene malonates 3.[a]
Entry
Ligand
T [oC]
Yield [%][b]
ee [%][c]
Entry
R1
R2
Yield [%][b]
ee [%][c]
90(R)[g]
90
92
93
92
87
92
83
88
83
80
62
84
92
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
1g
1a
1a
1a
0
0
0
0
0
0
0
0
99
90
88
13
98
24
79
79
35
94
68
39
62
33
3
51
0
80
90
90
1
2
3
4
H
H
H
H
H
H
H
H
H
H
H
H
5-Br
5-Br
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
5-OMe
Ph
94 (4a)
84 (4b)
59 (4c)
90 (4d)
97 (4e)
84 (4 f)
90 (4g)
98 (4h)
77 (4i)
92 (4j)
72 (4k)
71 (4l)
98 (4m)
77 (4n)
95 (4o)
73 (4p)
99 (4q)
89 (4r)
75 (4s)
78 (4t)
74 (4u)
98 (4v)
3-MeC6H4
3-MeOC6H4
3-PhOC6H4
3-BrC6H4
3-ClC6H4
3-CF3C6H4
4-FC6H4
3-PhO-4-FC6H3
3,4-Cl2C6H3
2-naphthyl
2-ClC6H4
Ph
5
6[d]
7
8[d]
9[d]
10[d,e]
8[d]
9
À20
À20
10
11[e]
12
13[e]
14[f]
15
16
17
18
19
20
21
22
[a] Unless otherwise noted, reactions were carried out with ligand
(11 mol%), Sc(OTf)3 (10 mol%), 2a (0.15 mmol), and 3a (0.125 mmol)
in Et2O (0.1 mL) at indicated temperature for 84 h. [b] Isolated yield.
[c] Determined by chiral HPLC analysis. [d] The catalyst 1a-Sc
was prepared in tBuOH. [e] The ratio of 2a/3a was 2:1.
ACHTUNGTRENNUNG
ACHTUNGERTN(NUNG OTf)3
3-BrC6H4
Ph
92(R)[g]
86
92
92
95
88
4-PhC6H4
3-MeC6H4
3-BrC6H4
3-PhOC6H4
3-ClC6H4
3-PhO-4-FC6H3
2-thienyl
ACHTUNGTRENNUNG(OTf)3 was prepared in tBuOH (Table 1, entry 8). Lowering
the reaction temperature further enhanced the enantioselec-
tivity to 90% ee but led to obvious loss in reactivity
(Table 1, entry 9). Fortunately, the reactivity was dramatical-
ly improved by increasing the amount of indole,[12] while the
enantioselectivity was maintained (Table 1, entry 10).
92
80
[a] Unless otherwise noted, reactions were carried out with 1a
(11 mol%), Sc(OTf)3 (10 mol%), 2 (0. 25 mmol), and 3 (0.125 mmol) in
AHCTUNGTRENNUNG
Et2O (0.1 mL) at À208C. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] 0.5 mmol indole was used. [e] The reaction was car-
ried out at 08C. [f] 0.5 mmol 5-bromoindole was used. [g] The absolute
configuration was determined by comparing with literature data.[7,8]
Under the optimal reaction conditions (Table 2, entry 1),
various indoles and alkylidene malonates were evaluated,
giving corresponding products with good to excellent enan-
tioselectivities (up to 95% ee). As shown in Table 2, the
enantioselectivity of the reaction was found to be insensitive
to the steric and electronic properties of meta-substituents
on the phenyl in arylidene malonate (Table 2, entries 2–7
and 17–20), which was different from the catalytic systems
of chiral CuII–oxazoline.[13] The para-substituted arylidene
malonates were also efficient for the reaction, albeit the
ortho-substituted one showed a reduced enantioselectivity[14]
(Table 2, entries 8, 12, and 16). It was noteworthy that the
reaction could be extended to condensed-ring, heterocyclic,
and disubstituted arylidene malonates with good to excellent
enantioselectivities (Table 2, entries 9–11, 21, and 22).[15] In
addition, indoles with either electron-withdrawing or elec-
tron-donating substituents were also competent substrates
(Table 2, entries 13–22, up to 95% ee). Although a C(5) bro-
mine substituent lowered yield, a good level of enantioselec-
tivity was still observed (Table 2, entries 13 and 14).
To demonstrate the synthetic potential of this catalytic ap-
proach, the product 4a was converted into some useful in-
termediates for the synthesis of biologically active com-
pounds, such as tryptamines,[2a] indolepropionic acids,[2b] and
b-carbolines.[2c] As shown in Scheme 1,[16] through the Cur-
tius rearrangement[1h,17] and Pictet–Spengler cyclization,[5c,d]
six-membered ring b-carboline 7[2c,18] could be obtained
from the potent neuroprotective agent 5. Furthermore,
adduct 4a could also be transformed into serotonin ana-
logue 9.[2f] It was noteworthy that the seven-membered b-
carboline-like 10 was furnished for the first time when prod-
uct 9 was subjected to Pictet–Spengler reaction. The relative
stereochemistry of 10 was tentatively assigned as 1,5-trans
by means of NOE experiments. All reactions occurred in
good to excellent yield with no drop in enantiomeric excess.
To understand the structure of the catalyst, we tried to
grow a single crystal of 1a-Sc
successfully determined by X-ray crystallography the struc-
ture of the complex 1 f-Sc(OTf)3, which showed similar cata-
lytic behavior to 1a-Sc(OTf)3 (Table 1, entry 6 vs. entry 1),
as its monohydrate 1 f-Sc(OTf)3·A
(H2O).[19] As shown in
ACHTUNGRTEN(NUNG OTf)3 but failed. However, we
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
CHTUNGTRENNUNG
Figure 1, both carbonyl oxygens and oxygens of N-oxide
were coordinated with scandium in the complex. This may
help to explain the behavior that only the racemic product
with moderate yield was afforded when the ligand 1g (the
precursor of N,N’-dioxide 1a) was employed (Table 1,
entry 7). Moreover, the X-ray crystal structure of 1 f-Sc-
ACHUTNGREN(NUG OTf)3·ACHTUTGNREN(NUNG H2O) also indicated that both the amide moiety and
the chiral backbone of the amino acid were essential for the
generation of a good chiral environment in the reaction,
which rationalized the observed phenomena (Table 1, en-
tries 1–6) in the study to a certain extent.
2056
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Chem. Eur. J. 2009, 15, 2055 – 2058

Asymmetric Synthesis of b-Carbolines
COMMUNICATION
0.25 mmol) in tBuOH (0.1 mL) was
stirred at 358C for 1 h under a nitro-
gen atmosphere. After the solvent was
removed
under
vacuum,
Et2O
(0.1 mL) was added. The reaction mix-
ture was cooled to À208C and alkyli-
dene malonate 3a (0.125 mmol) was
added under stirring. The reaction
mixture was stirred at À208C for 84 h
and directly purified by flash chroma-
tography on silica gel to obtain the de-
sired product 4a in 94% yield with
90% ee.
Scheme 1. Derivatization of the Friedel–Crafts adduct. Conditions: a) NaCl, DMSO, H2O, reflux, 66%; b)
THF, EtOH, H2O, 2n NaOH, reflux, 97%; c) Curtius rearrangement, Et3N, DPPA, tBuOH, toluene, reflux;
TFA, CH2Cl2, RT, 28%; d) Pictet–Spengler cyclization, TFA , benzaldehyde, CH3CN, reflux, 88%; e) LiAlH4,
THF, RT, quantitative yield; f) TsCl, pyridine, CH2Cl2, 508C, 72%; g) DMF, NaN3, 508C, 97%; h) Pd/C
(10%), H2, MeOH, 64%; i) Pictet–Spengler cyclization, TFA, benzaldehyde, CH3CN, reflux, 44%. TFA=tri-
fluoroacetic acid, DPPA=diphenylphosphoryl azide.
Acknowledgements
We thank the National Natural Sci-
ence Foundation of China (No.
20732003) and the Ministry of Educa-
tion (No. 20070610019) for financial
support, Sichuan University Analytical
& Testing Centre for NMR analysis,
the State Key Laboratory of Biotherapy for HRMS analysis, and Prof.
Zhongyuan Zhou for X-ray diffraction.
Keywords: alkylidene malonates · asymmetric synthesis ·
Friedel-Crafts alkylation · indole derivatives · scandium
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In summary, we have developed an efficient catalytic
enantioselective Friedel–Crafts alkylation of different in-
doles with a series of alkylidene malonates using the chiral
1a-ScACHTUNGTRENNUNG(OTf)3 complex as catalyst. The reaction could tolerate
condensed-ring, heterocyclic, and different substituted aryli-
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A
(H2O) reveals the manner of the coordination be-
(OTf)3. Further investi-
AHCTUNGTRENNUNG
gations on the mechanism of this catalytic system are in
progress.
Experimental Section
General experimental procedure:
A mixture of ligand 1a (9.8 mg,
0.0138 mmol), Sc(OTf)3 (6.2 mg, 0.0125 mmol), and indole 2a (29.3 mg,
ACHTUNGTRENNUNG
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2057

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[12] Excess indole could be recycled by flash chromatography on silica
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[13] In the catalytic systems of chiral CuII–oxazoline, ortho-substituted
and para-substituted arylidene malonates gave very good results but
meta-substituted arylidene malonates were not tolerated (see refer-
ences [6–8] for details).
[14] It was probably attributed to the steric hindrance effect of the
ortho-substituent on phenyl in arylidene malonate.
[15] Alkylidene malonates were also investigated, but only moderate re-
sults were obtained (propylidene malonate: 32% yield, 66% ee; cy-
clohexylmethylene malonate: 57% yield, 43% ee).
[16] See Supporting Information for details.
[5] For catalytic asymmetric Michael additions of indoles catalyzed by
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[19] CCDC-704000 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
Received: October 25, 2008
Published online: January 28, 2009
2058
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