Counter-ion-dependent alkyne iminium ion cyclization for divergent synthesis of n -fused indolylidine, indole, and indoline derivatives promoted by the lewis/bronsted acid

Article abstract of DOI:10.1021/acs.orglett.5b00615

Divergent synthesis of N-fused indolylidine, indole, and indoline derivatives using alkyne iminium ion cyclization is described. Trapping of vinyl cation intermediate generated after alkyne iminium ion cyclization was found to be dependent on the Lewis/Br

Full text of DOI:10.1021/acs.orglett.5b00615

Letter
pubs.acs.org/OrgLett
Counter-Ion-Dependent Alkyne Iminium Ion Cyclization for
Divergent Synthesis of N‑Fused Indolylidine, Indole, and Indoline
Derivatives Promoted by the Lewis/Bronsted Acid
Santosh J. Gharpure,* Yogesh G. Shelke, and Dasari Praveen Kumar
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
S
* Supporting Information
ABSTRACT: Divergent synthesis of N-fused indolylidine,
indole, and indoline derivatives using alkyne iminium ion
cyclization is described. Trapping of vinyl cation intermediate
generated after alkyne iminium ion cyclization was found to be
dependent on the Lewis/Bronsted acid and solvent used. N-
Fused indolylidine triflate could be used in the divergent
synthesis of N-fused indole derivatives.
he indole framework is a “privileged” structure and is a
pyrroloindoles and pyrroloindolines starting from a common
intermediate using alkyne-N-acyliminium ion cyclization is not
reported in the literature. In continuation of our interest in
stereoselective synthesis of fused indole derivatives, we disclose
herein a divergent approach for the construction of pyrrolo[1,2-
a]indole derivatives using alkyne N-acyliminium ion cyclization.7
Recently, we developed a novel and efficient protocol for the
stereoselective synthesis of dihydrobenzofurans by using alkynyl
Prins reaction on vinylogous carbonates.8 Based on this
approach, we envisioned that intramolecular trapping of the N-
acyliminium ion intermediate generated from the γ-hydroxy
lactam 7 with alkyne, which is a π-nucleophile, could assemble
the pyrroloindoline derivative 8 (Scheme 1). The γ-hydroxy
T
constituent of many pharmaceuticals and natural products.1
N-Fused indoles in general and pyrrolo[1,2-a]indoles in
particular are primary targets as they are found to be important
pharmacophores (Figure 1). Mitomycin C (1) and mitomycins
Scheme 1. Retrosynthetic Analysis for N-Fused Indole
Derivatives Using Alkyne Iminium Ion Cyclization
Figure 1. Natural products bearing the pyrrolo[1,2-a]indole core.
G, H, and K (2−4) are some of the most prominent members of
this class of natural products, which exhibit a strong ability to
bind DNA and show antitumor activity.2 Yuremamine (5), which
is isolated from the stem bark of Mimosa hostilis, shows
hallucinogenic and psychoactive effects, whereas isatisine A (6)
is an antiviral agent.3,4 Biological activity of many of these N-
fused indole derivatives coupled with structural diversity has
attracted considerable attention from synthetic chemists, and
many strategies for their synthesis have been reported.5 Iminium
ion cyclization is one of the most powerful methods for
construction of nitrogen-containing heterocycles. The use of N-
acyliminium ions in these cyclizations is particularly preferred, as
they are more electrophilic (and hence more reactive toward
various range of nucleophiles) and can be easily generated.6
However, to the best of our knowledge, a divergent synthesis of
lactam 7 can be readily prepared from the imide 9 by reduction.
We also anticipated that pyrroloindole 10 could be obtained by
the oxidation of pyrroloindoline moiety 8. Further, there was a
possibility that intermediate vinyl cation generated by attack of
the alkyne on the iminium ion may get trapped by the
counteranion of the Lewis/Bronsted acid used for its
generation.9
Our studies began with the synthesis of the requisite substrate
γ-hydroxy lactam 7a. Thus, the known iodide 11 was subjected to
Sonogashira coupling reaction with phenyl acetylene (12) to
Received: February 28, 2015
Published: March 27, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00615
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Organic Letters
Letter
furnish the imide 9a in excellent yield.10 Selective reduction of
the imide 9a using DIBAL-H gave the requisite γ-hydroxy lactam
7a in 62% yield (Scheme 2).
Table 1. Synthesis of N-Fused Indole Derivatives
Scheme 2. Synthesis of the γ-Hydroxy Lactam 7a
Having the γ-hydroxy lactam 7a in hand, attention was turned
toward using it in the synthesis of N-fused indole derivatives
under various reaction conditions. The results are summarized in
Table 1. When γ-hydroxy lactam 7a was treated with 1 equiv of
TMSOTf in CH2Cl2 at 0 °C, N-fused indolylidine triflate 13a was
obtained in 65% yield as a mixture of geometrical isomers by the
trapping of intermediate vinyl cation with counteranion of the
Lewis acid, and none of indoline 8a or indole 10a was formed.
After some optimization, it was found that when 2 equiv of
TMSOTf was used the reaction time was reduced significantly
(to 1.5 h vs 8 h) with an increase in yield (75%) and selectivity
(Table 1, entry 1). In order to study the effect of solvent, the
reaction was carried out in diethyl ether. However, rather than
the cyclization, the intermediate acyl iminium ion underwent loss
of proton followed by isomerization to yield the lactam 14a
(Table 1, entry 2). Similarly, in MeOH, the reaction led to aminal
15 in excellent yield, and none of alkyne iminium ion cyclization
was observed. Interestingly, when CH3CN was used as a solvent,
cascade N-acyliminum cyclization/Ritter reaction ensued and N-
fused indolylidine amide derivative 16 was obtained in good yield
(Table 1, entry 4). It is pertinent to mention here that this type of
Ritter reaction involving vinyl cation is very uncommon.11 As
expected, the product 16 was found to be unstable, and
elimination of all possible sources of acid during purification was
essential. In order to test whether counteranions other than
triflate could trap the vinyl cation, the reaction was carried out
with other Lewis acids. Thus, when TiCl4 was used as the Lewis
acid, the vinyl chloride derivative 17 was obtained in good yield,
and bromide 18 was the product when BiBr3 was used (Table 1,
entries 5 and 6). Fluorinated compounds are the least abundant
organohalides and have been widely utilized in pharmaceutical
drugs and agrochemicals. Synthesis of vinyl fluorides in general is
particularly challenging.12 Keeping this in mind, we attempted
reaction of γ-hydroxy lactam 7a with BF3·OEt2. Gratifyingly, N-
fused indolylidine fluoride 19 was indeed obtained in good yield
and selectivity (Table 1, entry 7). Again, the synthesis of vinyl
fluorides under metal free conditions using a simple, inexpensive
Lewis acid is very rarely encountered.13 When a Bronsted acid like
triflic acid was used, triflate 13a was obtained in moderate yield.
When a milder acid like BINOL-phosphoric acid was used, only
starting material was recovered. On the other hand, H2SO4 in
acetone gave the N-fused indoline derivative 8a as the sole
product (Table 1, entry 8). Interestingly, when formic acid was
used to effect the cyclization, pyrrolo[1,2-a]indole derivative 10a
was obtained in 88% yield (Table 1, entry 9). Given the stability
of the triflate derivatives 13, the possibility of using triflates in
further transformations and, keeping in mind importance of
indoline scaffold, these reactions were explored further to study
the substrate scope.14
a
b
Isolated yield of Z-isomer unless otherwise noted. The numbers in
c
parentheses refer to Z/E ratio or dr. 52% (Z/E = 82:18) with TfOH
as the catalyst. Isolated yield of mixture of isomer.
d
substituted γ-hydroxy lactams 7b−j (Scheme 3). Initially, the
effect of substitution, which is in conjugation with the nitrogen
atom on the iminium ion, was studied. The reactions were found
to be generally efficient with the electron-releasing as well as
electron-withdrawing group working efficiently, and the
corresponding triflates 13b−d were obtained in good yield
with moderate Z/E selectivities. On the other hand, changing the
aryl groups bearing a mildly electron-releasing methyl group on
the alkyne part worked more efficiently and furnished the
indolylidine triflates 13e,f in excellent yield and diastereose-
lectivity. When a stronger electron-releasing methoxy group was
used as the substituent, formation of the corresponding triflate
13g was observed in the crude sample along with indoline 8g (ca.
1:1). However, the triflate 13g was found to be rather labile and
underwent complete hydrolysis during silica gel column
chromatography to furnish exclusively the indoline 8g.
The scope of the alkyne iminium ion cyclization using
TMSOTf as the Lewis acid was studied with a variety of
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Letter
Scheme 3. Scope of Synthesis of N-Fused Indolylidine Triflate
a b
,
Derivatives
Figure 2. Proposed mechanism and explanation for stereochemical
outcome.
Scheme 4. Scope of Synthesis of N-Fused Indole Derivatives
a
b
Isolated yields of major isomer, Numbers in parentheses refer to Z/
E ratio or dr.
Interestingly, in the nitro group substituted γ-hydroxy lactam 7h,
the indolylidine triflate 13h was formed in poor yield. The major
product was lactam 14b formed by elimination of water (similar
to 14a, cf. Table 1, entry 2). Alkyl group substituted alkynes were
found to react sluggishly, and the corresponding product 13i was
obtained in poor yields albeit with excellent diastereoselectivity.
Indolylidine triflate derivative 13j having a tetracyclic core was
also synthesized in moderate yield and diastereoselectivity from
γ-hydroxy lactam 7j. To further expand the scope of the reaction,
we also investigated the synthesis of pyrido[1,2-a]indolylidine
triflate derivatives. When δ-hydroxylactams 20a−c were
subjected to optimized reaction conditions, the corresponding
pyrido[1,2-a]indolylidine triflate derivatives 21a−c were ob-
tained in excellent yield with good diastereoselectivities. The
geometry of the double bond was assigned as Z on the basis of
NOE experiments. These were further confirmed by single-
crystal X-ray diffraction studies on the triflate derivatives 13a,
13c, 21a−c, and indoline 8g.15
the indole derivative 10f in 22% yield. The structures of the
indoles 10a−f were confirmed based on the spectroscopic data as
well as single-crystal X-ray diffraction studies on the indole
derivative 10a.15 Further efforts are underway to probe this
reaction mechanistically.
Attention was next turned toward exploring the generality of
the indoline derivatives using Bronsted acidic conditions. Thus,
γ-hydroxy lactam derivatives 7 were subjected to reaction with 10
M H2SO4 in acetone at 40 °C to furnish N-fused indoline
derivatives 8 in good yield and selectivity (Scheme 5). The
Scheme 5. Scope of Stereoselective Synthesis of N-Fused
a b
,
Indoline Derivatives 8.
Formation of the Z-isomer can be explained as a result of an
attack of triflate counterion from Lewis acid on vinyl cation 22
generated from the N-acyliminium ion 23 during the course of
reaction. Since the vinyl cation intermediate 22 is planar, there
are two possible paths for attack as shown in Figure 2. Transition-
state structure A formed during attack by path “a” is more
favorable than transition-state structure B as it is comparatively
free from steric interaction between the aromatic ring and
hydrogen present in the pyrrolo[1,2-a]indolylidine framework.
Thus, the Z-isomer formed through transition-state structure A is
the major product.
a
b
Isolated yield of trans-isomer. Isolated yield of the mixture of
isomers.
During this study, we attempted this alkyne iminium ion
cyclization reaction on the γ-hydroxy lactams 7k−p bearing an
olefin. To our surprise, rather than the expected triflates 13k−p,
this reaction furnished exclusively the indolyl ketone derivatives
10a−f in excellent yield (Scheme 4). This reaction was found to
be quite general, and a variety of substrates bearing different aryl
substituents furnished the indole derivatives 10a−e in excellent
yields. However, the reaction with alkyl-substituted alkyne 7p
was sluggish, and the reaction proceeded only at reflux furnishing
substrates 7b,d,f,g bearing electron-releasing as well as mildly
electron-withdrawing groups were found to work efficiently
furnishing the indolines 8b,d,f,g, respectively, in excellent yield
albeit with moderate diastereoselectivity. In all the cases, the trans
isomer was the major isomer, which was unambiguously
confirmed by single-crystal X-ray diffraction studies on indolines
8f,g.15 Formation of trans isomer as the major product can be
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Organic Letters
Letter
explained on the basis of trapping of the vinyl cation with water
resulting in enol, which upon tautomerization gives the ketone.
During tautomerization, the substituents on C9 and C9a prefer
to be trans to each other to minimize steric interaction.
We decided to exploit the potential of N-fused indolylidine
triflates to generate various N-fused pyrroloindole derivatives
(Scheme 6). Thus, indolylidine triflate 13a could be converted
ment of Chemistry, IIT Bombay, for collecting single-crystal X-
ray diffraction data.
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cyclization reaction for the synthesis of N-fused indole
derivatives. The reaction gives diversely substituted indolylidine
derivatives depending on the counterion of the Lewis/Bronsted
acid. The indolylidine triflates and indolines could be synthesized
in good yield and diastereoselectivity. Reaction of γ-hydroxy
lactam bearing olefin led to indole derivatives. We have also
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ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures, spectroscopic data of products, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(14) Chassaing, S.; Specklin, S.; Weibel, J.-M.; Pale, P. Tetrahedron
2012, 68, 7245.
(15) CCDC 1049514−1049522, 1050948 (8a,f,g, 10a, Z-13a, E-13a,
13c, 21a−c) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sjgharpure@iitb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank BRNS, Mumbai, and the Council of Scientific and
Industrial Research (CSIR), New Delhi, for financial support.
We are grateful to CSIR, New Delhi, for the award of a research
fellowships to Y.G.S. We thank Mr. Darshan Mhatre, Depart-
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DOI: 10.1021/acs.orglett.5b00615
Org. Lett. 2015, 17, 1926−1929