Enantioselective [4+2] cycloadditions of 2-vinyl-1 H-indoles with 3-nitro-2 H-chromenes catalyzed by a Zn(OTf)2/bis(oxazoline) complex: An efficient approach to fused heterocycles with a quaternary stereocenter

Article abstract of DOI:10.1002/asia.201100820

There's a ringer: The asymmetric [4+2] cycloaddition reaction of 3-nitro-2H-chromenes with 1-benzyl-2-vinyl-1H-indoles catalyzed by Zn(OTf) ₂ with bis(oxazoline) ligands offers a practical and efficient method to synthesize a variety of fused h

Full text of DOI:10.1002/asia.201100820

DOI: 10.1002/asia.201100820
Enantioselective [4+2] Cycloadditions of 2-Vinyl-1H-indoles with 3-Nitro-
2H-chromenes Catalyzed by a ZnACTHNUTRGNE(UNG OTf)2/Bis(oxazoline) Complex: An
Efficient Approach to Fused Heterocycles with a Quaternary Stereocenter
Fen Tan,[a] Cong Xiao,[b] Hong-Gang Cheng,[a] Wei Wu,[a] Ke-Rong Ding,*[a] and
Wen-Jing Xiao*[a]
Highly functionalized fused heterocycles are of great sig-
nificance, with prevalence in many natural alkaloids and
bioactive compounds.[1] In particular, diversely substituted
carbazoles and tetrahydrocarbazoles (THCs) have become
prime targets for drug development.[2] As shown in
Scheme 1, clausamine A and B are typical carbazole alka-
tetrahydropyranoACTHNGUTERNNU[G 3,4-b]indoles (THPIs) and tetrahydro-b-
carbolines (THBCs).[3g]
Chromans are another important type of heterocycles that
exhibit remarkable biological activities.[4,5] For example,
(À)-siccanin (4), isolated from the culture broth of Helemin-
thosposium siccans, was found to possess antifungal activity
against the pathogenic fungi Trichophyton interdigitale, Tri-
chophyton asteroids, Mycosporum, and Epidermophyton
(Scheme 1).[6] Because of the interesting biological profiles
of tetrahydrocarbazole and chroman derivatives, we envis-
aged that combinatorial assembly of these two “privileged”
structural motifs into one molecule in an enantioselective
manner would lead to a new type of fused heterocycle for
drug discovery.
During the past decades, asymmetric [4+2] cycloaddition
reactions have been widely applied for the construction of
diversely functionalized complex molecules, with up to four
stereogenic centers created in a single step.[7,8] Among the
different reaction components of this methodology, vinylin-
doles have recently been actively investigated for the enan-
tioselective synthesis of biologically interesting polycyclic
indole derivatives.[9,10] For example, the MacMillan group re-
ported an enantioselective total synthesis of the Strychnos
alkaloid (+)-minfiensine based on an organocatalytic Diels–
Alder/amine cyclization sequence from 2-vinylindole.[10a]
Meanwhile, Ricci and co-workers disclosed an asymmetric
Diels–Alder reaction to afford a variety of enantiomerically
pure tetrahydrocarbazoles.[10b,c] In the context of our ongoing
interest in the synthesis of biological important carbon- and
heterocycles,[11] we have also developed several examples of
enantioselective cycloaddition reactions of 2-vinylindoles
with nitroolefins[12a] and enals.[12b] Herein, we further ad-
vance the use of 2-vinylindoles[12c,d] to develop a chiral
Lewis acid complex-catalyzed enantioselective [4+2] cyclo-
addition with 3-nitro-2H-chromenes [Equation (1)].[13,14]
Scheme 1. Representative biologically active carbazole, tetrahydrocarba-
zole, and chroman derivatives.
loids isolated from Clausena anisata (Rutaceae) collected in
Thailand.[2d] Pharmacological screening identified substitut-
ed tetrahydrocarbazole 3 as a new NPY-1 antagonist.[2e]
Consequently, these compounds represent particularly ap-
pealing targets for synthetic efforts.[3] In this regard, Bandini
and Eichholzer reported an elegant allylic alkylation of in-
doles in the presence of a gold complex, providing an effi-
cient synthesis of 1-vinyl- and 4-vinyl-THCs in a highly
enantioselective manner.[3f] Furthermore, You and co-work-
ers described an olefin cross metathesis (CM)/intramolecu-
lar asymmetric Friedel–Crafts alkylation sequence, which of-
fered a powerful platform to construct enantioenriched
[a] F. Tan, H.-G. Cheng, W. Wu, K.-R. Ding, 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)
Fax : (+86)27-67862041
E-mail: wxiao@mail.ccnu.edu.cn
[b] C. Xiao
College of Chemistry, Peking University
Beijing 100871 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100820.
Chem. Asian J. 2012, 7, 493 – 497
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
493

COMMUNICATION
This protocol provides an efficient and convenient ap-
proach to fused heterocycles bearing a quaternary stereo-
center[15] with excellent reaction efficiency (up to 94%
yield), high enantioselectivities (up to 96% ee), and great
diastereoselectivities (>95:5 d.r.).
At the outset of the studies, 3-nitro-2H-chromene 1a and
1-benzyl-2-vinyl-1H-indole 2a were chosen as model sub-
strates for this asymmetric [4+2] cycloaddition reaction. A
variety of Lewis acids and the chiral ligands were investigat-
ed, and the representative results are summarized in
Table 1. In the presence of chiral ligand I, the screening of
triflates were used, no desired product was observed
(Table 1, entries 8 and 9). To improve the enantioselectivity
of this process, we further examined chiral ligands.[16] The
tabulated results showed that tridentate bis(oxazoline)
ligand I was the most promising ligand, and it was found to
be more active than ligands III–V (Table 1, entry 1 vs. en-
tries 11–13). Ligand II, which is otherwise identical to ligand
I but has the opposite configuration, gave comparable re-
sults (Table 1, entry 10). Other C2-symmetric bis(oxazoline)
ligands VI–VIII had detrimental effects on the enantioselec-
tivity, albeit with good yields (Table 1, entries 14–16).
With the optimal chiral Zn-
AHCTUNGERTG(NNUN OTf)2/I complex identified, we
Table 1. Effects of various metal sources and chiral ligands.[a]
continued to examine the reac-
tion media and other parame-
ters to further improve the
chemical yield and stereoselec-
tivity. It was found that the re-
actions in toluene and xylenes
gave almost identical results
(Table 2, entries 1 and 2). The
use of halogenated solvents re-
sulted in a substantial decrease
in enantioselectivities, although
high diastereoselectivities were
obtained (Table 2, entries 3 and
4). Notably, the reaction could
also proceed efficiently in ethe-
real solvents, such as Et2O,
MeOtBu, PhOMe, and 1,4-diox-
ane, and generally good results
were achieved, except for in
THF (Table 2, entries 7–10 vs.
entry 6). Variation of the ratio
of metal to ligand I revealed
Entry
Lewis acid
Ligand
t [h]
Yield[b]
[%]
ee[c]
[%]
d.r.[c]
1
2
3
4
5
6
7
8
Zn
ZnCl2
Cu(OTf)2
In(OTf)3
Sc(OTf)3
Sm(OTf)3
La(OTf)3
Mg(OTf)2
AgOTf
A
I
I
I
I
I
I
I
I
23
108
58
21
19
13
41
130
130
26
48
28
40
45
64
64
88
62
79
80
80
95
91
<5
<5
87
93
94
94
74
93
83
89
7
13
À5
0
0
0
–
–
À86
À71
À80
À63
À5
7
>95:5
>95:5
>95:5
N
R
>95:5 that a 1:1.1 ratio of Zn
>95:5
ACHTUNGRTEN(NUNG OTf)2 to
E
I increased the ee from 89 to
92% (Table 2, entry 11 vs. 1).
Optimizations of the concentra-
tion did not improve the reac-
tion efficiency. The desired cy-
E
>95:5
>95:5
–
G
E
9
I
–
10
11
12
13
14
15
16
Zn
Zn
Zn
Zn
Zn
Zn
Zn
N
II
III
IV
V
VI
VII
VIII
>95:5
>95:5
>95:5
>95:5
>95:5
cloaddition
worked well even with 5 mol%
catalyst loading, although
reaction
also
a
>95:5 slight decrease in enantioselec-
À4
>95:5
tivity was found for these con-
ditions (Table 2, entry 16). Fi-
nally, we determined that the
[a] Conditions: 1a (0.30 mmol), 2a (0.45 mmol), Lewis acid (10 mol%), ligand (10 mol%), toluene (2.0 mL).
[b] Yield of isolated product after chromatography. [c] Determined by HPLC analysis on a chiral stationary
phase.
use of 10 mol% ZnACHTUNRGTNEUNG(OTf)2 and
11 mol% I in toluene (2.0 mL)
at room temperature were the
metal catalysts demonstrated that Zn
CF3SO3)was the best choice (Table 1, entry 1). ZnCl2 and
Cu(OTf)2 led to moderate yields and low enantioselectivities
(Table 1, entries 2 and 3). In(OTf)3 gave reversed enantiose-
(OTf)2 (OTf=
optimal reaction conditions for this asymmetric [4+2] cyclo-
addition reaction (Table 2, entry 11).
Having established the optimal reaction conditions, we
next explored the scope of this asymmetric [4+2] cycloaddi-
tion reaction. As highlighted in Table 3, a wide range of 3-
nitro-2H-chromenes with electron-donating and -withdraw-
E
AHCTUNGTRENNUNG
lectivity, while other rare-earth triflates gave no enantiose-
lectivities (Table 1, entries 4 and 5–7). When MgII and AgI
494
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 493 – 497

Enantioselective [4+2] Cycloadditions of 2-Vinyl-1H-indoles
Table 2. Reaction conditions optimization.[a]
ing groups at 6-, 7-, and 8-positions reacted well with 1-
benzyl-2-vinyl-1H-indole 2a, giving the corresponding prod-
ucts in generally good yields (82–94%) with high stereose-
lectivities (86–96% ee, >95:5 d.r.). The reaction with disub-
stituted 3-nitro-2H-chromenes, such as 1i, also exhibited
high efficiency and stereoselectivity (94% yield, 90% ee,
>95:5 d.r.) (Table 3, entry 9). Moreover, 2-naphthyl-substi-
tuted 3-nitro-2H-chromene 1j could efficiently participate in
the cycloaddition reaction to afford the desired product 3j
in 91% yield with 70% ee and >95:5 d.r. (Table 3,
entry 10). Interestingly, simple filtration gave the cyclized
product 3j in acceptable yield (63%) with more than 99%
ee when the reaction was completed. For the less reactive 5-
nitro-3,4-dihydro-2H-pyran 1k,[17] the cycloaddition reaction
also occurred efficiently with excellent d.r. (>95:5), albeit
with low ee (Table 3, entry 11). Then, the generality of the
reaction was further probed by variation of 2-vinylindole
partner with 3-nitro-2H-chromene 1a. Substrates with elec-
tron-rich substituents on the indole ring (2d and 2e) proved
to be more effective than the electron-poor ones (2b and
2c; Table 3, entries 14–15 vs. 12–13).
Entry
Solvent
t [h]
Yield[b] [%]
ee[c] [%]
d.r.[c]
1
2
3
4
5
6
7
8
toluene
xylenes
CH2Cl2
ClCH2CH2Cl
CH3CN
THF
23
22
33
41
26
136
45
36
18
23
20
21
22
17
18
24
88
87
87
76
88
63
76
76
88
75
92
90
93
91
93
90
89
89
72
50
26
50
88
78
77
86
92
92
90
87
88
89
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
Et2O
MeOtBu
PhOMe
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11[d]
12[e]
13[d,f]
14[d,g]
15[d,h]
16[i]
[a] Conditions: 1a (0.30 mmol), 2a (0.45 mmol), ZnACTHNUGTRENUNG(OTf)2 (10 mol%), I
(10 mol%), solvent (2.0 mL). [b] Yield of isolated product after chroma-
tography. [c] Determined by HPLC analysis on a chiral stationary phase.
To demonstrate the synthetic utility of the current meth-
odology, we performed the reaction of 3-nitro-2H-chromene
1a with 1-benzyl-2-vinyl-1H-indole 2a on a gram scale with
5 mol% catalyst (Scheme 2). To our delight, the desired
fused heterocycle derivative 3a could be isolated in 77%
yield with >99% ee and >95:5 d.r. by simple filtration of
the reaction mixture.
[d] Zn
used. [g] Toluene (1.5 mL) was used. [h] Toluene (1.0 mL) was used.
[i] Zn(OTf)2 (5 mol%), I (5.5 mol%) were used.
ACHTUNGTRENNUNG(OTf)2/I=1:1.1. [e] ZnAHCUTTGNREN(NUNG OTf)2/I=1:1.2. [f] Toluene (3.0 mL) was
ACHTUNGTRENNUNG
Table 3. Asymmetric [4+2] cycloaddition reaction of 3-nitro-2H-chro-
mene 1 with 1-benzyl-2-vinyl-1H-indole 2 catalyzed by ZnACHTNUTRGNEUNG(OTf)2-I com-
plex[a]
Scheme 2. Gram-scale preparation of 3a.
Entry R1
R2
Yield[b] [%] ee[c] [%] d.r.[c]
1
2
3
4
5
6
7
H (1a)
6-F (1b)
6-Cl (1c)
6-Br (1d)
6-Me (1e)
6-MeO (1 f)
7-MeO (1g)
8-MeO (1h)
6,8-Br2 (1i)
2-naphthyl (1j)
H (2a)
H
H
H
H
H
H
H
H
92 (3a)
90 (3b)
91 (3c)
90 (3d)
91 (3e)
93 (3 f)
91 (3g)
82 (3h)
94 (3i)
91 (3j)
(63)[d]
92
89
86
86
94
96
75
92
90
70
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
Finally, the absolute stereochemistry of 3i was elucidated
by X-ray crystallographic analysis.[18] To account for the ste-
reochemical course of this reaction, a possible transition
state was shown in Figure 1. According to Du and Xuꢁs acti-
vation model[19] of reactions catalyzed by metal bis(oxazo-
line) complexes, we proposed a bifunctional activation form,
wherein zinc(II) acted as a Lewis acid to activate the nitro
moiety of 3-nitro-2H-chromene, while the NH group of
ligand I worked as a donor for the NH···p (2-vinylindole) in-
teraction.[20] Such an endo-selective cycloaddition process
provided the corresponding product with (7S,8R) configura-
tion exclusively.
In conclusion, we have developed a practical and conven-
ient catalytic asymmetric [4+2] cycloaddition of 3-nitro-2H-
chromenes to 1-benzyl-2-vinyl-1H-indoles in the presence of
chiral ZnACHTUNGRTENNG(U OTf)2/bis(oxazoline) complex. High reaction effi-
ciency (up to 94% yield) and excellent stereoselectivities
8[d]
9
10
H
AHCTUNGTRENNUNG
(>99)[d]
11
12
H
67 (3k)
24
>95:5
>95:5
H
5-F (2b)
93 (3l)
(65)[d]
93 (3m)
92 (3n)
78
A
13
14
15
H
H
H
5-Cl (2c)
5-Me (2d)
5-MeO (2e) 91 (3o)
78
92
94
>95:5
>95:5
>95:5
[a] Conditions: 1 (0.30 mmol), 2 (0.45 mmol), ZnACTHNURGTNEUNG(OTf)2 (10 mol%), I
(11 mol%), toluene (2.0 mL). [b] Yield of isolated product after chroma-
tography. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] The result was based on direct filtration of the reaction mixture.
(up to 96% ee, >95:5 d.r.) have been obtained for a variety
Chem. Asian J. 2012, 7, 493 – 497
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
495

K.-R. Ding, W.-J. Xiao et al.
COMMUNICATION
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Figure 1. X-ray crystal structure of 3i and the proposed transition state
for the asymmetric [4+2] cycloaddition reaction.
of biologically important fused heterocycles bearing a qua-
ternary stereocenter. Further efforts will focus on the appli-
cations of this asymmetric transformation, and the studies
are currently in progress.
[6] a) K. J. Ishibashi, J. Antibiot. Ser. A. 1962, 15, 161–167; b) M. G.
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5406.
Experimental Section
General procedure: The metal catalyst ZnACTHNUTRGENUN(G OTf)2 (10 mol%) and chiral
ligand I (11 mol%) were stirred in toluene (2.0 mL) at room temperature
for 30 min in a 10 mL Schlenk tube. 3-Nitro-2H-chromene 1 (0.30 mmol)
was then added. After 20 min, 1-benzyl-2-vinyl-1H-indole 2 (0.45 mmol)
was added quickly. The reaction mixture was stirring until the completion
of the reaction as determined by TLC. Then the reaction mixture was pu-
rified directly by flash column chromatography on silica gel (petroleum
ether/acetone (65:1 to 60:1)) to give the corresponding product as a
solid.
[8] For reviews on the applications of [4+2] cycloaddition reactions,
see: a) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassiliko-
giannakis, Angew. Chem. 2002, 114, 1742–1773; Angew. Chem. Int.
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[9] For an early example of a non-asymmetric version with vinylindole,
see: W. E. Noland, G.-M. Xia, K. R. Gee, M. J. Konkel, M. J. Wahl-
strom, J. J. Condoluci, D. L. Rieger, Tetrahedron 1996, 52, 4555–
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Acknowledgements
We are grateful to the National Science Foundation of China (No.
20872043, 21072069, and 21002036), the National Basic Research Pro-
gram of China (2011CB868603), and the Program for Changjiang Schol-
ars and Innovative Research Team in University (IRT0953) for support
of this research.
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Keywords: cycloaddition · enantioselectivity · heterocycles ·
indoles · Lewis acid catalysis
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Received: September 30, 2011
Published online: January 20, 2012
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