Highly enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles

Article abstract of DOI:10.1002/anie.201209998

A new ring for your indole: An unprecedented copper-catalyzed enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles and β,γ-unsaturated α-ketoesters is reported. This mild strategy provides new access to various synthetically and biologically important 2,3-dihydro-1H-pyrrolo[1,2-a]indoles in a highly enantioselective manner.

Full text of DOI:10.1002/anie.201209998

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Angewandte
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DOI: 10.1002/anie.201209998
Indole Chemistry
Highly Enantioselective Friedel–Crafts Alkylation/N-
Hemiacetalization Cascade Reaction with Indoles**
Hong-Gang Cheng, Liang-Qiu Lu, Tao Wang, Qing-Qing Yang, Xiao-Peng Liu, Yang Li, Qiao-
Hui Deng, Jia-Rong Chen,* and Wen-Jing Xiao*
Chiral polycyclic indoles are ubiquitous and important ring
systems found in many bioactive alkaloids and pharmaceut-
icals.[1] As a result, extensive effort has been devoted to the
development of efficient methods for their synthesis. Most
approaches developed to date are based on the direct
functionalization of the “privileged” indole core.[2] Represen-
tative strategies include asymmetric intramolecular alkylation
of the C3, C2, or N1 positions of indoles, these reactions are
exemplified by allylic alkylation,[3] Friedel–Crafts alkyla-
tion,[4] the Pictet–Spengler reaction,[5] and N-alkylation.[6]
Scheme 1. Representative natural products based on 1H-pyrrolo[1,2-
a]indole.
Most of these processes are governed by the nucleophilic
character of the C3, C2, or N1 positions in the indole ring and
require the substrates to be carefully designed. The latter
requirement often limits the substrate scope of these reac-
tions. Recently, indole-based cascade reactions driven by the
nucleophilicity of the indole C3 position and the electro-
philicity of the iminium species generated in situ, have served
as the basis for alternative and robust methods of polycyclic
indole synthesis.[7] Despite these recent advances, the devel-
opment of new approaches to the construction of polycyclic
indole derivatives, which take advantage of the unique
reactivity profile of indoles, remains an important goal.
The [a]-annelated indole system, particularly the pyrrolo-
[1,2-a]indole scaffold, is present in a diverse family of
structurally complex polycyclic indoles and has consequently
become a primary target of synthetic efforts (Scheme 1).[8–10]
In 2009, the groups of Chen[9c] and Hartwig[9b] uncovered
regio and enantioselective N-allylation reactions of indoles
that employed a cinchona alkaloid and an iridium/phosphor-
amidite complex, respectively. Routine elaboration of the
products of these processes afforded highly substituted
dihydropyrrolo[1,2-a]indoles in good overall yields. Recently,
You and co-workers described another highly enantioselec-
tive N-allylation reaction of indoles that involved an iridium-
catalyzed allylic alkylation/oxidation cascade.[9a] The products
of the reactions were also readily transformed, in this case
into a diastereoisomer of naturally occurring methylyurem-
amine. Furthermore, Enders[6a] and Wang[6d] have also made
significant contributions to the construction of these alkaloids
by designing organocatalytic tandem N-alkylation/intramo-
lecular cyclization reactions of modified indoles. However, to
our knowledge, methods for the direct catalytic enantiose-
lective assembly of structurally diverse and stereochemically
complex pyrrolo[1,2-a]indole derivatives remain rare and, as
a result, a challenging goal in the area of organic synthesis.
In our recent research into the efficient asymmetric
functionalization of indoles,[11] we envisaged that simple
3-substituted 1H-indoles might serve as N1 and C2 dinucleo-
philes in cascade reactions with suitable dielectrophiles to
generate polycyclic indoles (Scheme 2). In elaborating this
scenario, several issues had to be considered, including: 1) the
possibility of competitive single reactions at either N1, C2, or
C3, 2) the occurrence of tandem reactions involving the C3
and C2 positions, and 3) the control of diastereo- and
[*] H.-G. Cheng, Dr. L.-Q. Lu, T. Wang, Q.-Q. Yang, X.-P. Liu, Y. Li,
Q.-H. Deng, Prof. Dr. J.-R. Chen, Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: jiarongchen2003@yahoo.com.cn
wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Prof. Dr. W.-J. Xiao
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, Gansu 730000 (China)
[**] We are grateful to the National Science Foundation of China
(21072069, 21002036, 21232003 and 21202053) and the National
Basic Research Program of China (2011CB808600) for support of
this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209998.
Scheme 2. Conceptual basis for the enantioselective Friedel–Crafts
alkylation/N-hemiacetalization cascade reaction with indoles.
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Table 2: Scope of the b,g-unsaturated a-ketoesters.[a]
enantioselectivity. The ensuing effort to probe these issues led
to the development of an unprecedented, copper-catalyzed
C2 Friedel–Crafts alkylation/N-hemiacetalization cascade
process that transformed 3-substituted indoles and b,g-
unsaturated a-ketoesters[12] into a wide range of functionally
diverse, enantioenriched 2,3-dihydro-1H-pyrrolo[1,2-a]-
indoles in a single step.
Entry R1, R2
3
Yield [%][b] d.r.[c]
ee [%][c]
In an initial investigation aimed at examining the feasi-
bility of the strategy described above, we observed that
treatment of 3-methylindole 1a with the b,g-unsaturated
a-ketoester 2a in the presence of copper(II) triflate
(10 mol%) promoted a cascade reaction that afforded the
2,3-dihydro-1H-pyrrolo[1,2-a]indole 3aa in 85% yield and 3:2
d.r. (Table 1, entry 1). Next, a series of commercially available
1
2
3
4
5
6
7
8
Ph, Me (2a)
Ph, Et (2b)
Ph, Bn (2c)
Ph, iPr (2d)
4-MeC6H4, Me (2e)
4-MeOC6H4, Me (2 f) 3af
4-FC6H4, Me (2g)
4-ClC6H4, Me (2h)
4-BrC6H4, Me (2i)
3-BrC6H4, Me (2j)
2-FC6H4, Me (2k)
3aa
3ab
3ac
3ad
3ae
95
93
92
93
96
95
95
94
93
93
96
92
95:5
96:4
95:5
96:4
95:5
96:4
95:5
93:7
92:8
92:8
88:12
95:5
89:11
85:15
97:3
>99
>99
>99
>99
>99
>99
>99
98
96
97
94
>99
99
3ag
3ah
3ai
3aj
3ak
9
Table 1: Optimization of reaction conditions.[a]
10
11
12
13
14[d]
15[e]
16[f]
17[e]
2-thiophenyl, Me (2l) 3al
=
PhCH CH, Me (2m) 3am 90
CO2Et, Me (2n)
Cy, Et (2o)
(MeO)2CH, Et (2p)
propyl, Et (2q)
3an
3ao
3rp
3aq
92
90
91
67
98
91
73 (98)
27 (76)
x [mol%] Solvent t [h] Yield [%][b] d.r.[c]
ee [%][c]
56:44
67:33
Entry
L
–
1
2
3
4
5
6
7
8
10
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
36
36
12
12
12
12
48
85
95
95
92
96
94
70
93
95
96
95
94
3:2
–
46
91
96
97
98
88
93
>99
>99
>99
>99
[a] Reaction conditions: 1a (0.42 mmol, 1.05 equiv), 2 (0.4 mmol,
1.0 equiv) in 4.0 mL toluene at 08C. [b] Yield of the isolated diastereo-
meric mixture. [c] Determined by HPLC analysis on a chiral stationary
phase. Data in parentheses are the ee values of the minor diastereomers.
[d] Performed at À208C. [e] 1a (0.48 mmol, 1.2 equiv) was used. [f] 1r
(0.48 mmol, 1.2 equiv) was used.
L1 10
L2 10
L3 10
L4 10
L5 10
L5 10
L5 10
L5 10
L5 10
70:30
80:20
80:20
85:15
91:9
75:25
83:17
94:6
95:5
95:5
CH2Cl2 12
toluene 12
toluene 12
toluene 12
toluene 32
9
10[d]
11[d]
12[d]
obvious effect on the reaction (Table 2, entries 1–4). More-
over, substrates containing a range of electron-donating and
-withdrawing substituents on the g-aryl ring react with
3-methylindole 1a to afford the corresponding 2,3-dihydro-
1H-pyrrolo[1,2-a]indoles 3ae–3ak in high yields (93–96%)
and with high diastereo- and enantioselectivities (up to 96:4
d.r. and > 99% ee; Table 2, entries 5–11). Heteroaromatic
and vinyl-substituted b,g-unsaturated a-ketoesters, such as 2l
and 2m, also participate in this transformation (Table 2,
entries 12 and 13). Moreover, reactions of 1a with g-ester- and
g-alkyl-substituted b,g-unsaturated a-ketoesters (2n and 2o)
also proceed smoothly to give the corresponding products
(3an and 3ao) in a highly enantioselective manner (Table 2,
entries 14 and 15). Note that the straight-chain aliphatic
substrates (2p and 2q) could also participate in the reaction to
afford the corresponding products 3rp and 3aq in good yields,
albeit with decreased diastereoselectivities (Table 2,
entries 16 and 17).
The 3-substituted indole substrate scope of the cascade
reactions was also investigated. As seen by inspection of the
data displayed in Table 3, a variety of substituted indoles
participate in reactions that produce 2,3-dihydro-1H-pyrrolo-
[1,2-a]indoles in high yields (89–97%) and excellent levels of
stereoselectivity (92:8–96:4 d.r., 98– > 99% ee; Table 3,
entries 1–11). The 3-substituted indoles containing C3 ethyl,
iso-propyl, cyclohexyl, and benzyl groups were also observed
to react with b,g-unsaturated a-ketoester 2a to afford the
expected products 3la–3oa in good yields (85–94%) and with
excellent diastereo- and enantioselectivities (Table 3,
L5
L5
5
1
94:6
[a] Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol,
1.0 equiv) in 2.0 mL solvent at 08C. [b] Yield of the isolated diastereo-
meric mixture. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] 1a (0.21 mmol, 1.05 equiv) was used.
chiral bis(oxazoline) ligands[13] were screened to uncover an
asymmetric variant of this process. As the data summarized in
Table 1 show, reactions with most of the ligands probed
produced 3aa with modest to high levels of enantioselectivity,
with ligand L5 providing the highest yield (94%) and most
stereoselective (91:9 d.r. and 98% ee) results (Table 1,
entry 6). A simple survey of solvents showed that toluene
was optimal in terms of diastereo- and enantioselectivity
(Table 1, entries 6–9). Further investigations, such as probing
substrate ratios and catalyst loadings, led to the optimized
conditions (3aa, 95%, 95:5 d.r., > 99% ee, Table 1, entry 11):
Cu(OTf)2/L5 (5 mol%) at 08C in 2.0 mL of toluene.
The scope of b,g-unsaturated a-ketoesters 2 that partic-
ipate in the cascade reaction carried out under the optimized
conditions was explored next (Table 2). Changing the ester
group in 2 from methyl to ethyl, benzyl, or iso-propyl had no
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Table 3: Scope of the 3-substituted indoles.[a]
Entry R3, R4
3
Yield [%][b] d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
H, Me (1a)
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
95
93
96
97
93
96
91
96
89
93
95
85
95:5
93:7
95:5
96:4
92:8
95:5
94:6
96:4
96:4
96:4
96:4
95:5
95:5
93:7
91:9
86:14
90:10
94:6
92:8
>99
98
>99
>99
99
>99
99
98
4-Me, Me (1b)
5-Me, Me (1c)
6-Me, Me (1d)
5-MeO, Me (1e)
5-BnO, Me (1 f)
5-F, Me (1g)
5-Cl, Me (1h)
5-Br, Me (1i)
6-Cl, Me (1j)
6-F, Me (1k)
H, Et (1l)
H, iPr (1m)
H, Cy (1n)
H, Bn (1o)
H, Ph (1p)
H, CH2CO2CH3 (1q)
H, (CH2)2OTBS (1r)
H, (CH2)2NPhth (1s) 3sa
Figure 1. X-ray crystal structure of compound 3ah.[14] Thermal ellip-
soids set at 30% probability.
This method can be applied in the formal total synthesis of
natural products, such as flinderoles B and C, which have
been found to exhibit impressive selective antimalarial
activities.[8a] As shown in Scheme 3, indole 1r reacted well
9
99
10
11
12
13
14
15
16
17
18
19
3ja
3ka
3la
>99
>99
99
98
96
98
80 (93)
98
>99
98
3ma 89
3na
3oa
3pa
3qa
3ra
92
94
90
92
95
90
[a] Reaction conditions: 1 (0.42–0.60 mmol, 1.05–1.50 equiv), 2a
(0.4 mmol, 1.0 equiv) in 4 mL toluene at 08C; Cu(OTf)2/L5 (5 mol%)
was used for entries 1–12 and 10 mol% for entries 13–19. [b] Yield of the
isolated diastereomeric mixture. [c] Determined by HPLC analysis on
a chiral stationary phase. Data in parentheses are the ee values of minor
diastereomers. TBS=tert-butyldimethylsilyl; NPhth=phthalimide.
Scheme 3. Formal total synthesis of analogues of flinderoles B and C.
with vinyl-substituted b,g-unsaturated a-ketoester 2m under
the standard reaction conditions to give the corresponding
product 3rm in 74% yield with 97% ee and 79:21 d.r. Next,
entries 12–15, 91:9–95:5 d.r., 96–99% ee). In the reaction of
3-phenylindole 1p with 2a, the product was formed in high
yield, but with a somewhat decreased level of stereoselectivity
(Table 3, entry 16). Notably, indoles bearing ester (1q), tert-
butyldimethylsiloxyethyl (1r), and protected aminoethyl (1s)
substituents also undergo reaction with 2a to produce the
corresponding products with high enantioselectivities
(Table 3, entries 17–19). These products are deserving of
special note, because such functional groups at the 3-position
of indole would facilitate further modification.
À
reduction of 3rm with Et3SiH BF3·Et2O at À508C provided
key intermediate 4 in good yield. Further transformations of
4, according to the procedure reported by the groups of
Dethe[15a] and Toste,[15b] could give the analogues 5 of
flinderoles B and C.
In conclusion, the studies described above have led to the
development of a new copper-catalyzed, enantioselective
Friedel–Crafts alkylation/N-hemiacetalization cascade reac-
tion between substituted indoles and b,g-unsaturated
a-ketoesters. The process enables the efficient construction
of diversely functionalized 2,3-dihydro-1H-pyrrolo[1,2-a]-
indoles in a highly enantioselective manner. We expect that
this and related strategies will have broad application in the
synthesis of bioactive natural alkaloids, such as those high-
lighted in Scheme 1, a proposal that is currently being
explored in our laboratory.
To demonstrate the synthetic potential of this new cascade
process, we explored a gram scale reaction of 3-methylindole
1a and b,g-unsaturated a-ketoester 2a. As shown in Equa-
tion (1), the use of only 0.5 mol% Cu(OTf)2/L5 promotes the
Experimental Section
Representative procedure: The metal catalyst Cu(OTf)2 (7.23 mg,
0.02 mmol; 5 mol%) and ligand L5 (6.61 mg, 0.02 mmol; 5 mol%)
were stirred in 4.0 mL of toluene at room temperature for 1 h in
a 10 mL schlenk tube under Ar. Then, b,g-unsaturated a-ketoester 2a
(76 mg, 0.40 mmol) was added and the reaction mixture was stirred
for a further 10 min. The mixture was placed in a 08C cooling bath
formation of 2,3-dihydro-1H-pyrrolo[1,2-a]indole 3aa in 92%
yield with 91:9 d.r. and 99% ee. The absolute configuration of
2,3-dihydro-1H-pyrrolo[1,2-a]indole 3ah was determined to
be 1R, 3S through X-ray crystallographic analysis
(Figure 1).[14]
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and stirred for 20 min. Then, 3-methyl indole 1a (55 mg, 0.42 mmol)
was added quickly to the mixture. Upon reaction completion
(determined by TLC), the crude reaction mixture was directly
subjected to column chromatograpy (petroleum ether/ethyl ace-
tate = 15:1 to 7:1) to afford the desired product 3aa as a yellowish
solid in 95% yield with 95:5 d.r. and > 99% ee.
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Received: December 14, 2012
Published online: February 10, 2013
Keywords: alkylation · asymmetric catalysis · chiral Lewis acids ·
.
heterocycles · indoles
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