Thermally induced [3+2] cyclization of aniline-tethered alkylidenecyclopropanes: A facile synthetic protocol of pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1039/c2cc33269h

A facile synthetic method of functionalized pyrrolo[1,2-a]indoles has been developed via a thermally-induced ring-opening and cyclization reaction from aniline-tethered alkylidenecyclopropanes with aldehydes.

Full text of DOI:10.1039/c2cc33269h

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Thermally induced [3+2] cyclization of aniline-tethered
alkylidenecyclopropanes: a facile synthetic protocol
of pyrrolo[1,2-a]indolesw
Kai Chen,a Zhen Zhang,a Yin Weib and Min Shi*ab
Received 7th May 2012, Accepted 11th June 2012
DOI: 10.1039/c2cc33269h
A facile synthetic method of functionalized pyrrolo[1,2-a]indoles
has been developed via a thermally-induced ring-opening and
cyclization reaction from aniline-tethered alkylidenecyclopropanes
with aldehydes.
The indole ring system is probably the most ubiquitous heterocycle
in nature.1 Their importance in medicinal chemistry has encouraged
the development of new synthetic strategies to prepare these
compounds.2 The pyrrolo[1,2-a]indoles, tricyclic indole derivatives,
are common cores found in a number of natural products.3 For
example, the alkaloid Mitomycin C has attracted considerable
attention due to its potent antitumoral and antibacterial
activity (Scheme 1).4 Moreover, another member of the alkaloids,
Yuremamine, is a new phytoindole isolated from the stem bark
of Mimosa hostilis (Scheme 1).5 These previous findings have
stimulated our interest to develop facile synthetic approaches
to access the pyrrolo[1,2-a]indole structure motif owing to its
biological profile and fascinating molecular architecture.
Scheme 2 Previous studies on the formation of heterocyclic com-
pounds from MCPs.
thermodynamic driving force.6,7 These ring-opening processes can
trigger various reactions of MCPs with other substrates, giving
efficient access to enhanced molecular complexity in organic
syntheses.8 For example, in 2003, Yamamoto and co-workers
have disclosed palladium-catalyzed intermolecular [3+2]
cycloaddition of alkylidenecyclopropanes with imines to give
3-methylenepyrrolidines in good yields (Scheme 2, eq. 1).9 In 2004,
we reported that MCPs could undergo [3+2] cycloaddition with
aldimines to give the corresponding pyrrolidine skeletons in the
presence of BF3.OEt2 under mild reaction conditions (Scheme 2,
eq. 2).10 More recently, we have also found an efficient route to
2-substituted N-(1-amino-3-methylpyrrol)amides by ring-opening
cyclization of benzylidene- and alkylidenecyclopropylcarbalde-
hydes with hydrazides (Scheme 2, eq. 3).11 It should be noted that
Yamamoto and co-workers have reported the only transfor-
mation using aniline-tethered alkylidenecyclopropanes to the
six-membered exo-methylene nitrogen heterocyclic compounds
in the presence of palladium catalysts (Scheme 2, eq. 4).12 These
interesting findings have encouraged us to continue to discover
more useful transformations with these special MCPs tethered
by an aniline moiety.
Methylenecyclopropanes (MCPs), as highly strained but
readily accessible molecules, can undergo a variety of ring-
opening reactions in the presence of transition metals or Lewis
acids because the relief of ring strain can provide a potent
Scheme 1 Mitomycin C and Yuremamine, highlighting the common
pyrrolo[1,2-a]indole core.
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 MeiLong Road, Shanghai, 200237, P. R. China.
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai, 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of new compounds, and CCDC
826603 and 869056. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc33269h
These aniline-tethered alkylidenecyclopropanes were prepared
according to the previous literature.13 With these aniline-tethered
alkylidenecyclopropanes in hand, we initially attempted to trans-
form them to the corresponding imine derivatives. We found
that the corresponding imine could be indeed obtained at room
c
7696 Chem. Commun., 2012, 48, 7696–7698
This journal is The Royal Society of Chemistry 2012

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Table 2 Substrate scope of the [3+2] cyclization reaction of aniline-
tethered alkylidenecyclopropanes 1 to pyrrolo[1,2-a]indoles 2a
Scheme 3 Unexpected formation of pyrrolo[1,2-a]indoles upon heat-
Entry Substrate (R1/R2) R3
Product 2 Yieldb (%)
ing of aniline-tethered MCPs and aldehydes.
1
2
3
4
5
6
7
8
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1a (Ph/H)
1b (Ph/Cl)
1b (Ph/Cl)
1c (Me/H)
4-MeC6H4
4-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
3-thienyl
2-furyl
1-naphthyl
H
CH3CHQCH 2k
2b
2c
2d
2e
2f
2g
2h
2i
93
86
91
89
92
88
91
Table 1 Optimization of the reaction conditions of 1a with benzaldehyde
81
Yielda (%)
9
2j
92c
88d
86
10
11
12
13
2a
3a
Entry
Amount of PhCHO
T/1C
Time/h
C6H5
H
C6H5
2l
2m
2n
1
2
3
4
5
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
2.0 equiv.
20
80
100
110
110
24
24
72
48
24
0
42
89
91
93
88
54
0
0
0
85c
70e
a
Reaction conditions: aldehyde (2.0 equiv.), anhydrous magnesium sulfate
(10.0 equiv.), toluene (2.0 mL), 110 1C, 24 h. b Isolated yield. c Paraform-
aldehyde (10.0 equiv.). d Product mixtures were obtained as trans-and cis-
isomeric mixtures, major : minor = 3 : 1. e ortho-Xylene (1.0 mL), 140 1C.
a
Isolated yield.
temperature in toluene in the presence of MgSO4. To our delight,
when the reaction was carried out at 110 1C, tricyclic indole
derivatives could be formed in good yields rather than the imine
derivatives, affording a novel synthetic approach to the useful
pyrrolo[1,2-a]indole derivatives (Scheme 3). In this paper, we wish
to report the details of this interesting transformation.
and the results are shown in Table 2. As for various aryl
aldehydes (R3 = Ar), the reactions with substrate 1a proceeded
smoothly to furnish the desired products 2b–2f in 86–93% yields,
regardless of whether they have electron-rich or electron-poor
aromatic rings (Table 2, entries 1–5). Heteroaromatic aldehydes
and naphthyl aldehyde were also tolerable, giving the desired
products 2g–2i in 81–91% yields (Table 2, entries 6–8). When R3
is a hydrogen atom or an alkenyl group, the reactions still
proceeded efficiently to afford the desired products 2j–2k
in 88–92% yields (Table 2, entries 9–10). Changing the R2
substituent to chlorine, the reactions proceeded smoothly,
furnishing the desired products 2l and 2m in 85–86% yields
(Table 2, entries 11–12). When R1 is a methyl group, the reaction
still proceeded very well to afford the desired product 2n in 70%
yield at 140 1C in ortho-xylene (Table 2, entry 13).
To gain more insight into this cascade cyclization reaction
mechanism, a control experiment was performed as shown in
Scheme 4. We first investigated the thermal induced reaction
of imine 3a and found that upon heating at 110 1C for 24 h, 3a
could be easily transformed to 2a in > 99% yield on the basis
of 1H NMR analysis, suggesting that imine 3a is the real
intermediate of this [3+2] intramolecular cyclization reaction.
Moreover, the control experiment has confirmed that
this cyclization reaction under the optimized conditions was
unaffected by the addition of the radical inhibitors such as
TEMPO (2.0 equiv.) and 2,6-di-tert-butyl-4-methylphenol
(BHT) (2.0 equiv.), rendering unlikely the intervention of a
radical pathway (Scheme 5).
We initially investigated the [3+2] cyclization reaction of aniline-
tethered alkylidenecyclopropane 1a with benzaldehyde in toluene at
different temperature and the results are summarized in Table 1.
The reaction of 1a with 1.2 equiv. benzaldehyde in the presence of
10.0 equiv. anhydrous magnesium sulfate afforded imine 3a in 88%
yield at room temperature after 24 h (Table 1, entry 1). Raising the
reaction temperature to 80 1C produced the [3+2] cyclization
product 2a in 42% yield along with the formation of imine 3a in
54% yield (Table 1, entry 2). Upon heating the reaction mixture at
100 1C for 72 h, 2a was obtained in 89% yield as a sole product
(Table 1, entry 3). Its structure has been unambiguously determined
by X-ray diffraction. Its ORTEP drawing is indicated in Fig. 1 and
the corresponding CIF data have been presented in the ESI.w14
Carrying out the reaction at 110 1C (under reflux) led to the
formation of 2a in 91% yield (Table 1, entry 4). Increasing the
employed amounts of benzaldehyde to 2.0 equiv. delivered 2a in
93% yield within 24 h (Table 1, entry 5).
Under the optimized conditions (2.0 equiv. of aldehyde and
10.0 equiv. anhydrous magnesium sulfate in toluene at 110 1C
for 24 h), we next examined the substrate scope of this reaction
Fig. 1 ORTEP drawing of 2a.
Scheme 4 Control experiment for the formation of 2a from 3a.
Chem. Commun., 2012, 48, 7696–7698 7697
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Scheme 6 A plausible reaction mechanism.
Based on above control experiments and the reported
literature,15 a plausible mechanism for this reaction is outlined
in Scheme 6. The aniline-tethered alkylidenecyclopropane 1a
reacts with benzaldehyde to give imine 3a. Then, the thermal
induced [3+2] cyclization takes place leading to the formation
of 2a through a three-membered ring opening pathway.
In summary, a facile synthetic method for the synthesis of
functionalized pyrrolo[1,2-a]indoles has been developed from the
thermal-induced [3+2] cyclization of easily available aniline-
tethered alkylidenecyclopropanes with aldehydes via a cyclo-
propane ring-opening process. The product 2 has an important
structural motif in organic and medicinal chemistry. The
potential utilization and extension of the scope of this synthetic
methodology are currently under investigation.
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We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), National Basic Research Program
of China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20732008 and 21121062).
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c
7698 Chem. Commun., 2012, 48, 7696–7698
This journal is The Royal Society of Chemistry 2012