DOI: 10.1002/chem.

201404354 Communication

& Asymmetric Synthesis

Highly Enantioselective Ring-Opening Reactions of Aziridines with

Indole and Its Application in the Building of C3-Halogenated
Pyrroloindolines
Dongxu Yang,[a] Linqing Wang,[a] Fengxia Han,[a] Dan Li,[a] Depeng Zhao,[a] Yiming Cao,[a]
Yunxia Ma,[a] Weidong Kong,[a] Quantao Sun,[a] and Rui Wang*[a, b]
reactions is still in high demand. In 2004, Cozzi and the
Abstract: A magnesium-catalyzed asymmetric ring-open- Umani–Ronchi group reported an elegant [Cr(salen)]-catalyzed
ing reaction of aziridine with indole has been realized by asymmetric ring-opening reactions of meso aromatic epoxides
employing commercially available chiral ligands. Both of with indoles.[6a] Kobayashi and co-workers also realized the de-
the enantiomers of the ring-opening product could be ob- symmetrization reactions of meso epoxides proceeded
tained with good yields and a high level of enantioselec- smoothly in water (Figure 1, Eq. (1)).[6b–d] In 2012, A highly inter-
tivity. The corresponding ring-opening product could be
further transformed to various types of enantioenriched
C3-halogenated-pyrroloindolines.

Optically active indole skeletons are highly attractive frame-

works in synthetic targets and the application of indoles in
Friedel–Crafts alkylation constitutes one of the fundamental
and thoroughly investigated reactions in synthetic chemistry.[1]
Consequently, significant progress has been described on the
development of extensive methods for the asymmetric 1,4-
Friedel–Crafts conjugate reactions and 1,2- Friedel–Crafts alky-
lations over the past decade.[2, 3] On the other hand, asymmet-
ric allylic alkylation (AAA, Tsuji–Trost reaction) employing
indole as a nucleophile has proven to be a powerful strategy
for the synthesis of chiral indole architectures that are usually
found in biologically important natural skeletons and useful
pharmaceutical agents.[4] Very recently, Hu and co-workers re-
ported a rhodium and chiral phosphoric acid co-catalyzed
asymmetric multicomponent facile access to form polyfunc-
tional indole derivatives with contiguous chiral centers through Figure 1. Asymmetric ring-opening reactions of indoles.
the reactions of imines, diazo compounds, and indoles.[5] These
well-established works highlight the importance of enantiose- esting enantioselective ring-opening reaction of episulfonium
lective Friedel–Crafts alkylation that could furnish indole-con- ions by indole was achieved through an anion-binding catalyt-
taining organic skeletons that are playing important roles both ic strategy by the Jacobsen group[6e] and very recently, the
in synthetic and medicinal chemistry. At the same time, the de- enantioconvergent Friedel–Crafts reactions of indoles with cy-
velopment of other novel asymmetric Friedel–Crafts alkylation clopropanes have also been successfully developed by Tang
and Johnson independently (Figure 1, Eq. (2));[7] this type of re-
[a] D. Yang,+ L. Wang,+ F. Han, D. Li, Dr. D. Zhao, Dr. Y. Cao, Y. Ma, W. Kong,
action could provide rapid access to enantioenriched cyclopen-
Q. Sun, Prof. Dr. R. Wang
School of Life Sciences, Lanzhou University ta-fused indoline frameworks and can be further extended to
Lanzhou, 730000 (P. R. China) build tetracyclic pyrroloindolines.[7a] Given these well-devel-
E-mail: [email protected] oped methods in this context, we found that there is still no
[b] Prof. Dr. R. Wang successful example in asymmetric ring-opening reactions of
State Key Laboratory of Chiroscience, Department of Applied
aziridines with indoles that could provide an easy access to in-
Biology and Chemical Technology, The Hong Kong Polytechnic University
Kowloon, Hong Kong (P. R. China) dolethylamine scaffolds and that could be further transformed
[+] These authors contribute equally on this work. to chiral pyrroloindoline architectures.[8]
Supporting information for this article is available on the WWW under To date, there are several examples of Lewis acid promoted
http://dx.doi.org/10.1002/chem.201404354. ring-opening reactions of aziridines with indoles;[9] however,

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Communication

the catalytic asymmetric version of this approach has

not been realized. We postulated that the blankness
of literature reports on this enantioselective transfor-
mation was related to the difficulty in controlling the
enantiotopic center with an effective chiral catalyst.
In the course of our ongoing efforts in asymmetric
Friedel–Crafts reactions and our recent exploration
on the catalytic asymmetric ring-opening reaction of
meso-aziridines by cinchona alkaloid type catalysts,[10,
11c]
herein we report the first example of a highly
enantioselective desymmetrization of meso aziridines
with indoles catalyzed by a MgII bifunctional catalyst
employing quinine as a commercially available chiral
ligand.
Our study began by evaluating the reaction of
indole with various aziridines[11] bearing different pro-
tecting groups. The choice of Bu2Mg as catalyst was
based on our previous work[12] for there are many po-
tential chiral ligands that could be employed to real-
ize this enantioselective reaction. After the prelimina-
ry screening of various types of N-tosylated and N-
benzoylated aziridines, we found the intermolecular
ring-opening reaction could proceed well while using
N-(2-picolinoyl)-aziridine (2 a) as the substrate.[13] This
type of aziridine has also been proven to be nice
substrate in metal–alkyl reagent catalyzed ring-open-
ing reactions in previous studies.[13b] Our next stage
of investigations was then to focus on the examina-
tion of different chiral ligands. As illustrated in
Table 1, the ligands bearing a monohydroxyl group
were proven to be feasible leading to formation of
the desired ring-opening product (3 a), which might
as a result of the existence of an alkyl–metal bond
remain after the neutralization process of the ligand
and MgBu2, whereas the use of ligands bearing
double-OH groups failed to afford product 3 a (en-
tries 1, 2). The experiments showed that chiral amino-
alcohols were potential ligands to introduce enantio-
selectivities in the present transformation, and fortu-
nately, we have identified that the commercially
available aminoalcohols, such as quinine (L6) and
quinidine (L7) could act as effective chiral ligands
with respect to both of the chemical yields and enan-
tioselectivities (entries 6, 7). Changing of reaction sol-
vents showed p-xylene could enhance the experi-
mental result, which might be due to the polarity
effect of solvents (entries 8–12).
The substrate scope of the enantioselective desym-
metrization of meso aziridines with indoles is illustrat-
ed in Scheme 1. In general, the reactions could pro-
ceed smoothly to give the desired ring-opening Scheme 1. Substrate scope of the ring-opening reactions of indoles. Reactions were per-
products in high chemical yields and enantioselectivi- formed with aziridine (0.20 mmol) and indole (0.40 mmol) in p-xylene (0.5 mL) in the
presence of L6 (20 mol %) and MgBu2 (20 mol %) at 30 8C for 36 h. [a] achiral ligand L9
ties with respect to indoles bearing different elec-
(20 mol %) was added. [b] The reaction was conducted for 48 h.
tronic substituents on the C4-, C5-, or the C6-position
of the aromatic ring (Scheme 1, 3 a–j). But C7-substi-
tuted indole was an inefficient nucleophile in the reaction might coordinate to the metal center of the catalyst (3 k).
owing to the steric hindrance affect to the N1-position, which More importantly, we found part of the product’s enantioselec-

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Communication

a dramatic decrease in the ee

Table 1. Screening of the reaction conditions.
value of the product was ob-
served, which might be owing
to its hindrance effect on the co-
ordination result of the pyridine
group (3 s–w). Subsequently, we
Entry[a] Ligand Solvent Yield [%][b] ee [%][c] have also tested the ring-open-
ing reaction with quinidine as
1 L1 tol – –
2 L2 tol trace – a chiral ligand and the enantio-
3 L3 tol 25 3 mers were obtained with similar
4 L4 tol 23 33 results as expected (Scheme 2).
5 L5 tol 37 14
Furthermore, when the reac-
6 L6 tol 89 87
7 L7 tol 90 85 tion of indole with aziridine 2 a
8 L6 THF 32 69 was performed on a gram scale
9 L6 benzene 76 86 employing 10 % mol in-situ gen-
10 L6 o-xylene 91 91
erated catalysis, the product 3 a
11 L6 m-xylene 84 84
12 L6 p-xylene 91 92 was obtained in 94 % yield
(1.50 g) with a slightly lower ee
[a] Reactions were performed with 0.20 mmol of 2 a and 0.40 mmol of 1 a in solvent (0.5 mL) in the presence
of L (20 mol %) and MgBu2 (20 mol %) at 30 8C for 36 h. [b] Isolated yield. [c] Enantiomeric excesses were ana-
value (88 % ee). The chiral ligand
lyzed by chiral stationary phase HPLC. could also be recovered in
almost quantitative yield by
single column chromatography
(Scheme 3). Given the fact that
C3-halogenated-pyrroloindolines
have played an important role in
synthetic and medicinal chemis-
try in recent years and the high
level of demand for the enantio-
selective building of this key
skeleton, we wish to utilize our
aforementioned catalytic asym-
metric approach to construct
various halogenated-pyrroloin-
tivies could be increased in the presence of the achi-
ral ligand L9. We speculated it might be due to the
coordination ability of ligand L9 to the metal center
during the reaction process which could create
a more beneficial chiral environment for some spe-
cially substituted indoles.[14, 15] We then investigated
the scope of various aziridines with indoles under the
optimized reaction conditions. Two types of other
six-membered aziridines were applied to the reaction
and could deliver highly optically active ring-opening
products 3 l and 3 r in good yields. The correspond-
ing five-membered aziridine also reacted with indoles
smoothly and afforded the product 3 m with excel-
lent enantioselectivity. However, seven-membered
aziridines showed reduced reactivity and gave mod-
erate yields due to their cyclic nature. Furthermore,
acyclic aryl- and aliphatic-aziridines were also good
substituents in the ring-opening reactions, and the
favorable effect of achiral ligand L9 was also ob-
served with respect to the transformation employing
diphenyl-substituted aziridine (3 q). Different substitu-
tions on the pyridine ring were also investigated and
Scheme 2. Ring-opening reaction with quinidine as a chiral ligand. Reactions were per-
the substituted sites have obvious effects on the re- formed with aziridine (0.20 mmol) and indole (0.40 mmol) in p-xylene (0.5 mL) in the
sults. When using a 5-brominated protecting group, presence of L7 (20 mol %) and MgBu2 (20 mol %) at 30 8C for 36 h.

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Communication

ditions,[17] we eventually obtained the C3-fluorinated, chlorinat-

ed, and brominated-pyrroloindolines with a high level of enan-
tioselectivity. (Scheme 4).
Although the detailed mechanism of this ring-opening reac-
tion is not completely clear yet, based on previous reports on
metal–alkyl reagents in asymmetric catalysis,[18, 12, 13c] we pro-
Scheme 3. The ring-opening reaction was performed on a gram scale. posed a catalytic cycle that is shown in Figure 2. After a depro-
tonation process of indole by
the precatalyst generated from
quinine (L6) and MgBu2, the azir-
idine coordinates to the magne-
sium center from a favored di-
rection that might be deter-
mined by the steric hindrance
effects of the catalyst. Then the
activated indole could attack
aziridine and finish the ring-
opening step. Still, a clear-cut
understanding of the reaction
mechanism and the origin of
enantioselectivities in the cur-
rent ring-opening reaction of
meso-aziridines needs further in-
vestigation.[19]
Scheme 4. Applications of the ring-opening reaction towards C3-halogenated-pyrroloindolines. Boc = tert-butoxy- In summary, we have devel-
carbonyl; DMAP = 4-dimethylaminopyridine; NBS = N-bromosuccinimide; NFSI = N-fluorobenzenesulfonimide). oped the first example of an
asymmetric ring-opening reac-
tion of aziridines with indoles by
using a magnesium catalyst em-
ploying a commercially available
chiral ligand. Both of the enan-
tiomers could be obtained with
good yields and with a high
level of enantioselectivity. The
corresponding ring-opening
products could be smoothly
transferred to various types of
enantioenriched C3-halogenated-
pyrroloindolines. Further investi-
gation of the ring-opening reac-
tions of aziridines and the utiliza-
tion of the current method to
building other types of pyrro-
loindolines are currently under-
way in our laboratory.

Acknowledgements

This work was supported by

NSFC (21432003, 81473095,
Figure 2. Proposed possible catalytic cycle of the ring-opening reaction.
21202071); National S&T Major
Project of China
(2012ZX09504001-003).
dolines, which could act as an alternative route to build opti-
cally active halogenated heterocycles.[16] As depicted in Keywords: asymmetric synthesis · cyclization · magnesium ·
Scheme 4, after a screening process of the halocyclization con- ring-opening reactions

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Communication

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