Enantioselective Friedel-Crafts alkylation of 4,7-dihydroindoles with enones catalyzed by primary-secondary diamines

Article abstract of DOI:10.1002/chem.200901635

A study was conducted to demonstrate the development of a new chiral primary-secondary diamine catalyst derived from amino acid and its application in the asymmetric Friedel-Crafts alkylation of 4,7-dihydroindoles with α-βunsaturated enones. A array of pr

Full text of DOI:10.1002/chem.200901635

COMMUNICATION
DOI: 10.1002/chem.200901635
Enantioselective Friedel–Crafts Alkylation of 4,7-Dihydroindoles with
Enones Catalyzed by Primary–Secondary Diamines
Liang Hong,[a] Wangsheng Sun,[a] Chunxia Liu,[a] Lei Wang,[a] Kwokyin Wong,[b] and
Rui Wang*[a, b]
Over the past few years, a number of chiral organocata-
lysts have been developed for different asymmetric transfor-
mations.[1] Among them, chiral secondary amines are proba-
bly the most intensively used organocatalysts. In contrast,
little progress has been made in the development of chiral
primary amine catalysts, probably due to unfavorable
imine–secondary enamine equilibria.[2] Nevertheless, the use
of chiral primary amines as organocatalysts possesses partic-
ular charm because of their known occurrence in the cata-
lytic sites of several enzymes, such as type I aldolases, dehy-
dratases, and decarboxylases.[3] Recently, primary amine cat-
alysts have emerged to be effective promoters for organic
processes including Michael addition, aldol, a-aminations
and cycloaddition reactions.[4] Despite the recent successful
applications of primary amine catalysts (mainly derived
from cinchona alkaloid or 1,2-diamino-cyclohexane) in the
iminium catalysis of enones, few examples have been report-
ed for the use of primary–secondary diamine catalysts in the
Michael addition reactions of enones.[5]
2-Substituted indoles are potential intermediates for many
alkaloids and pharmacologically important substances.[6]
While the methods for the preparation of 3-substituted in-
doles are well established,[7] the development of novel and
efficient catalytic asymmetric synthesis of 2-substituted in-
doles appears to be of great importance. 4,7-Dihydroindoles,
due to their easy aromatization, are good intermediates to
synthesize 2-substituted indoles. In this regard, the enantio-
selective Friedel–Crafts alkylation[8] of 4,7-dihydroindoles
provides direct and useful access to such valuable scaffolds,
and great efforts and progress have been made in this
field.[9] However, to our knowledge, a general and highly
enantioselective Friedel–Crafts alkylation of 4,7-dihydroin-
doles with enones is still lacking. Herein, we describe the
development of a new chiral primary–secondary diamine
catalyst derived from amino acid and its application in the
asymmetric Friedel–Crafts alkylation of 4,7-dihydroindoles
with a,b-unsaturated enones.
As part of our continuing interest in asymmetric organo-
catalytic Friedel–Crafts alkylation,[10] we recently found that
chiral secondary amines were efficient catalysts for the
asymmetric Friedel–Crafts reaction of 4,7-dihydroindoles
with a,b-unsaturated aldehydes. We sought to extend this or-
ganocatalytic strategy to a,b-unsaturated ketones; however,
our initial attempts led to unsatisfactory results probably
due to poor generation of the corresponding iminium cat-
ions.[11] Considering the inherent problems of congested imi-
nium ions from ketones, we questioned whether primary
amines, in comparison with secondary amines, owing to
their reduced steric requirements, might be more suitable
for enone activation.
Based on the above consideration, an array of primary
amines derived from amino acids were investigated in the
asymmetric Friedel–Crafts alkylation of 4,7-dihydroindole
(1a) with benzylideneacetone 2a in toluene. When a pri-
mary amine catalyst 3a or 3b (see Figure 1) derived from l-
phenylalanine was utilized, only low enantioselectivity was
achieved (Table 1, entries 1 and 2). Fortunately, its monome-
thylated analogue 3c catalyzed the reaction very efficiently
to afford 4aa in good yield and promising enantioselectivity
(Table 1, entry 3). Encouraged by these findings, we investi-
gated the effects of the substituent of the terminal amino
group on the catalytic activity of 3. We found that the
length of the alkyl chain influenced the catalytic activity of
3 and the n-propylated catalyst 3e gave the best result
(Table 1, entry 5). To our surprise, the primary–tertiary dia-
mine catalysts 3g or 3h, a general catalyst for the Michael
[a] Dr. L. Hong, W. Sun, C. Liu, L. Wang, Prof. Dr. R. Wang
State Key Laboratory of Applied Organic Chemistry
and Institute of Biochemistry and Molecular Biology
Lanzhou University, Lanzhou, 730000 (China)
Fax : (+86)931-891-2567
E-mail: wangrui@lzu.edu.cn
[b] Prof. Dr. K. Wong, Prof. Dr. R. Wang
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Kowloon (Hong Kong)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901635.
Chem. Eur. J. 2009, 15, 11105 – 11108
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11105

lents of acid apparently lowered the enantioselectivity
(Table 1, entries 9 vs 15). The general tendency was that
salts of amine 3 with stronger acids were more reactive and
gave better enantioselectivity. Trifluoroacetic acid turned
out to be the best co-catalyst in terms of yield and enantio-
selectivity (Table 1, entry 9). We also investigated a variety
of solvents, and CHCl3 turned out to be optimal (Table 1,
entry 22). When the reaction temperature was lowered to
08C, the enantioselectivity increased to 94% ee to isolate
4aa in 86% yield, although the reaction time had to be ex-
tended to 48 h (Table 1, entry 24). Further decrease of the
temperature to À608C did not have any positive effects on
the reaction results and the ee values decreased to 28%
(Table 1, entry 25).
Figure 1. Structures of various primary amine catalysts.
addition of a,b-unsaturated aldehyde, was not active in the
present reaction (Table 1, entries 7 and 8). Moreover, varia-
tion of the amino acid side chain yielded the optimum cata-
lyst 3i derived from leucine, which provided the desired
product 4aa with 90% ee (Table 1, entry 9).
The acid co-catalyst also had a great effect on the reac-
tion. Almost no reaction occurred when no acid was added
(Table 1, entry 14). The use of two rather than one equiva-
Having established optimal reaction conditions, we next
examined the scope and limitations of the method with
regard to the enone and 4,7-dihydroindole substrates. In all
cases, the reaction proceeded smoothly to furnish the de-
sired product 4 in high yields and excellent enantioselectivi-
ties. For enones carrying both aromatic and aliphatic sub-
stituents, almost optically pure products were obtained in
excellent yields, irrespective of steric and electronic de-
mands of the b-olefin substituent (Table 2, entries 1–10). No
decrease in yield and ee value was observed for the slightly
sterically hindered enone 2k (Table 2, entry 11). Interesting-
ly, chalcone 2l, a particularly challenging class of substrates
for iminium catalysis, afforded the expected products in
high optical purity (Table 2, entry 12). Unfortunately, when
cyclic enone 2m was used, only a moderate ee was obtained
Table 1. Catalyst screening and reaction optimization.[a]
Entry
Catalyst
Solvent
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3i
3i
3i
3i
3i
3i
3i
3i
3i
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
none
39
63
71
79
83
81
65
54
86
88
67
73
65
<10
91
70
78
83
63
84
81
90
80
86
59
8
Table 2. Scope of Friedel–Crafts alkylation catalyzed by primary amine
17
79
81
82
79
62
61
90
85
84
75
69
n.d.[d]
74
76
87
88
70
81
90
92
88
94
28
catalyst 3i.[a]
9
Entry
R1
R2
R3
4, Yield [%][b]
ee [%][c]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[f]
25 g]
1
2
3
4
5
6
7
8
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
H, 1a
Ph
Me, 2a
Me, 2b
Me, 2c
Me, 2d
Me, 2e
Me, 2 f
Me, 2g
Me, 2h
Me, 2i
Me, 2j
Et, 2k
Ph, 2l
4aa, 86
4ab, 69
4ac, 84
4ad, 87
4ae, 93
4af, 89
4ag, 91
4ah, 91
4ai, 83
4aj, 78
4ak, 81
4al, 75
4am, 97
4ba, 82
4bh, 85
4ca, 80
<10
94
95
95
94
92
96
97
95
91
90
96
85
66
93
95
96
n.d.[d]
2-MeOPh
2-ClPh
3-MeOPh
3-ClPh
4-FPh
4-ClPh
4-BrPh
n-C3H7
n-C5H11
Ph
CF3CO2H[e]
PhCO2H
p-TSA
d-CSA
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
9
ether
10
11
12
13
14
15
16
17
CH2Cl2
CHCl3
MTBE
CHCl3
CHCl3
Ph
3i
3i
3i
H, 1a
ACHTUGNRTNE(NUNG CH2)3, 2m
5-MeO, 1b
5-MeO, 1b
5-F, 1c
1-Me, 1d
Ph
4-BrPh
Ph
Me, 2a
Me, 2h
Me, 2a
Me, 2a
[a] Unless otherwise specified, the reaction was carried out with 1a
(0.30 mmol) and 2a (0.36 mmol) in the presence of an organocatalyst 3
(0.06 mmol), additive (0.06 mmol), and solvent (1.0 mL) for 24 h. [b] Iso-
lated yield. [c] Determined by chiral HPLC on a Chiralpak AD column.
[d] Not determined. [e] 40 mol% CF3CO2H was used. [f] The reaction
was performed at 08C for 48 h. [g] The reaction was performed at À608C
for 72 h.
Ph
[a] Unless otherwise specified, the reactions were carried out on
a
0.30 mmol scale of 2 with 1.2 equiv of 1 in CHCl3 at 08C for 48 h in the
presence of 20 mol% of 3i and CF3CO2H. [b] Isolated yield. [c] For anal-
ysis of the ee values of the products, see the Supporting Information.
[d] Not determined.
11106
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Chem. Eur. J. 2009, 15, 11105 – 11108

Enantioselective Friedel–Crafts Alkylation
COMMUNICATION
(Table 2, entry 13). Finally, substituted 4,7-dihydroindole 1b
and 1c were tested, also with good results (Table 2, en-
tries 14–16). However, as a limitation of the approach, the
substitution on the 4,7-dihydroindolic nitrogen had a detri-
mental effect on the reactivity (Table 2, entry 17). This phe-
nomenon has been observed in other organocatalytic Frie-
del–Crafts alkylations of indoles, which are assumed to pro-
ceed via a dual activation mechanism.[7j,10a,12]
To demonstrate the suitability of the current methodology
for the synthesis of 2-functionalized indoles, the oxidation of
2-substituted 4,7-dihydroindoles was tested. To our delight
the corresponding 2-substituted indole derivatives were ob-
tained smoothly in good overall yields without any loss of
enantioselectivies in all cases (Scheme 1).
Figure 2. X-ray structure of (R)-7.
Figure 3. Pretransition state A.
4,7-dihydroindoles with a,b-unsaturated enones in high
yields and excellent enantioselectivies. The corresponding
4,7-dihydroindole products could be subsequently trans-
formed to 2-functionalized indoles by the oxidation of p-
benzoquinone without any loss of enantioselectivies. Further
application of the current methodology and study of the re-
action mechanism are ongoing in our laboratory.
Scheme 1. Synthesis of 2-functionalized indoles.
To determine the absolute configuration of the product,
we tried to oxidize 4aa to the literature-known compound 6
in analogy to the oxidative cleavage of pyrroles upon treat-
ment with NaIO4 in the presence of RuCl3.[13] Unfortunately,
the oxidative cleavage product 6 was not observed. Instead,
the oxidation–iodination product 7, which is beneficial for
numerous further transformations at C3 of indole,[14] was
formed in high yield in one step from 4ah (Scheme 2). Fi-
nally, suitable crystals of compound 7 which enabled assign-
ment of the absolute configuration were obtained, and a
single-crystal analysis revealed the configuration to be R
(Figure 2).[15]
Experimental Section
General procedure for the catalytic asymmetric Friedel–Crafts reaction:
To a mixture of enone 2a (0.30 mmol), catalyst 3i (0.06 mmol) and TFA
(0.06 mmol) in CHCl3 (1.0 mL) was added 4,7-dihydroindole (1a;
0.36 mmol) at room temperature. After 48 h of stirring, the reaction mix-
ture was concentrated, and the residue was purified by flash chromatog-
raphy (petroleum ether/ethyl acetate 6:1) to afford product 4aa.
With regards to the mechanism, we envisioned that cata-
lyst 3i would act in a bifunctional fashion (Figure 3). The
primary amine moiety activates the enone 2 via the forma-
tion of an iminum A, while the secondary amine may inter-
act with the N-H of 4,7-dihydroindole through a weak hy-
drogen bond to direct the attack of 4,7-dihydroindole
toward one enantioface of the double bond. The fact that N-
methyl-4,7-dihydroindole gives no reaction supports the nec-
essary existence of the hydrogen bond between the N-H
atom and the secondary amine.
Acknowledgements
We gratefully acknowledge financial support from NSFC (20525206,
20772052, 90813012 and 20621091) and Chang Jiang Scholar Program of
the Ministry of Education of China for financial support.
Keywords: conjugate addition · enantioselectivity · enones ·
Friedel–Crafts reaction · organocatalysis
In summary, a primary–secondary diamine catalyst has
been successfully applied in the Friedel–Crafts alkylation of
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Received: June 15, 2009
Published online: September 15, 2009
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