Cation Triggered Domino Aza-Piancatelli Rearrangement/Friedel-Crafts Alkylation of Indole-Tethered Furfuyl Alcohols to Access Cycloocta[ b]indole Core of Alkaloids

Article abstract of DOI:10.1021/acs.orglett.0c03155

A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel-Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel-Crafts alkylation to access bridged tetracyclic frameworks in one pot.

Full text of DOI:10.1021/acs.orglett.0c03155

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Letter
Cation Triggered Domino Aza-Piancatelli Rearrangement/Friedel−
Crafts Alkylation of Indole-Tethered Furfuyl Alcohols to Access
Cycloocta[b]indole Core of Alkaloids
Nagarjuna Reddy Vonteddu, Pooja R. Solanke,∥ Kiranmai Nayani,∥ and Srivari Chandrasekhar*
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ABSTRACT: A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel−
Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted
aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel−Crafts
alkylation to access bridged tetracyclic frameworks in one pot.
atalytic domino reactions represent important advances
in synthetic organic chemistry by providing atom- and
C
step-economical method for the construction of complex
frameworks. Synthetic organic chemists always pursue new
catalytic transformations to construct complex moieties
preferably in a single pot. In this regard, great efforts have
been made to develop efficient single step transformations
which results in the formation of multiple bonds and
stereocenters with selectivity.1
The cycloocta[b]indole core is a common scaffold in many
bioactive alkaloids like macroline, lochnerine, sarpagine,
ajmaline, macrocapramine, and dispegatrine with a broad
spectrum of activities like antiamoebic, antiplasmodic,
antihypertensive, anticancer, and antibiotic properties (Figure
1).2 A recent study by Waldmann et al. showed analogues of
cycloocta[b]indole frameworks as promising targets for the
development of novel class of potent and selective
Mycobacterium protein tyrosine phosphatase B (MptpB)
inhibitors against Mycobacterium tuberculosis.3 In addition,
Waldmann et al. have presented an analysis of selected pseudo-
natural product (NP) libraries using chemoinformatic tools
that provide access to unprecedented pseudo-NPs to offer
opportunities for the discovery of bioactive small-molecule
scaffolds.4 Reports of synthetic approaches to construct
sarpagine and macroline group of alkaloids consist of multiple
steps.3,5 Few reports are available for the construction of
indoles fused to 8-membered rings through cascade or
sequential reactions.6 The scaffold poses a challenge to
Figure 1. Representative naturally occurring bioactive cycloocta[b]-
indole alkaloids.
synthetic organic and medicinal chemists to construct the
functionalized cycloocta[b]indole core efficiently using one-pot
reaction sequences.
2-Furylcarbinols have emerged as important building blocks
for the construction of cyclic systems. Under Lewis acid or
Brønsted acid catalysis, the furylcarbinols converts into a highly
reactive electron-deficient furfuryl cation intermediate, pre-
Received: September 19, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03155
© XXXX American Chemical Society
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cursor to a variety of cyclic systems.7 Piancatelli reaction is one
of the most efficient method for the conversion of 2-
furylcarbinol to 4-hydroxy-2-cyclopentenones which served as
valuable building block for a variety of biologically important
molecules.8 This reaction was scarcely used for more than 30
years but of late has been the focus of interest and has been
explored to construct a variety of skeletons in the past few
years. Developments have been achieved in reaction
conditions, catalytic systems, and use of different nucleophiles
in the process.9,10 In addition, cascade and sequential reactions
involving Piancatelli rearrangement have also been reported.11
We have earlier reported a domino aza-Piancatelli rearrange-
ment/aza-Michael reaction where 2-furfurylcarbinol reacted
with 2-aminobenzamide to give 1,4-benzodiazepin-5-one in
one pot.12 Recently, Leboeuf and co-workers reported
synthesis of bridged tetrahydrobenzo[b]azepines via Piancatelli
cyclization/Michael addition in sequence.13 Our continued
interest in the development of novel cascade strategies for the
synthesis of biologically relavent molecules has resulted in the
design and synthesis of bridged nitrogen rich tetracyclic
frameworks. Here in, we report for the first time, a simple and
efficient approach for the construction of bridged cycloocta-
[b]indolone, an aza tetracyclic core using a novel domino
strategy based on aza-Piancatelli rearrangement coupled with
Friedel−Crafts alkylation in single pot.
Scheme 2. Synthesis of Cycloocta[b]indolone Tetracycle in
Sequence
that proper selection of Lewis or Brønsted acid and solvent
may lead to the conversion of the aza-Piancatelli product 9a to
bridged tetracyclic derivative 10a via an in situ intramolecular
Friedel−Crafts reaction in one pot (Table 1). Our initial
experiment was performed with 2-furylcarbinol 7a and aniline
a
Table 1. Optimization of the Reaction Conditions
We anticipated that indole-tethered 2-furylcarbinol 7 in the
presence of aniline 8 could serve as a substrate for aza-
Piancatelli rearrangement and form 4-arylamino cyclopente-
none 9, which in turn could undergo a Friedel−Crafts
alkylation from C-2 position of indole moiety to give bridged
cycloocta[b]indolone derivative 10 (Scheme 1).
b
yield (%)
Scheme 1. Proposed Strategy for Bridged Tetracyclic
Cycloocta[b]indolone core
entry
catalyst
Dy(OTf)3
Dy(OTf)3
Sc(OTf)3
ZnCl2
solvent
time (h) 9a
10a
9b
10
1
2
3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
24
48
48
48
48
48
24
24
24
24
48
24
36
48
48
48
24
02
36
72
36
36
70
10
05
20
15
30
−
−
−
−
10
30
05
50
65
30
−
<5
60
50
<5
50
<5
−
10
10
25
05
08
−
c
4
5
Cu(OTf)2
Ba(OTf)2
Bi(OTf)3
La(OTf)2
In(OTf)3
Yb(OTf)3
Dy(OTf)3, 4 Å MS
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
TFA
c
6
d
7
8
e
−
−
e
9
−
trace
e
10
−
−
11
12
13
50
50
70
08
05
05
−
10
10
10
05
10
10
−
82
10
20
10
10
DCE
c
14
toluene
dioxane
THF
HFIP
DCE
DCE
DCE
DCE
DCE
To test our hypothesis, indole-tethered furfuryl alcohol 7a
was prepared from 3-indole propanoic acid (see Supporting
Information).14,15 To check the feasibility of the bridged
cycloocta[b]indolone formation, we initially carried out an aza-
Piancatelli rearrangement of furfuryl alcohol 7a with aniline 8a
using Dy(OTf)3 in acetonitrile at 90 °C (Scheme 2). We
obtained the corresponding rearrangement product 9a, in 70%
yield, after purification. This product was treated with
Dy(OTf)3 in acetonitrile at 90 °C (with the assumption that
the cyclopentenone 9a will undergo intramolecular Friedel−
Crafts reaction at C2 position of indole moiety), where the
proposed cycloocta[b]indolone derivative 10a was obtained in
72% yield.
15
c
16
d
17
18
−
−
f
19
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
05
05
04
05
68
50
65
66
g
20
21
h
i
22
a
The reactions were performed with 7a (0.4 mmol), 8a (0.4 mmol),
and catalyst (5 mol %) in solvent (1.5 mL) at 90 °C, unless otherwise
b
c
noted. Yields of purified products. Starting material was not
d
e
consumed completely. Starting material was decomposed. Multiple
f
After confirmation of the bridged cycloocta[b]indolone
compound 10a, we focused on optimization of reaction
conditions to get the target molecule in one pot. We assumed
spots observed in TLC. 10 mol % of catalyst was used in the reaction.
Reaction was performed at 70 °C. Reaction was performed at 120
°C. 2,2′-Bipyridine (10 mol %) was used as an additive.
g
h
i
B
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a,b
8a in the presence of Dy(OTf)3 in CH3CN at 90 °C for 24 h.
The aza-Piancatelli product 9a and domino product 10a were
obtained in 70% and <5% yields, respectively (Table 1, entry
1). In this reaction, substitution product of furfuryl cation 9b
(10%) was also observed. When the reaction time was
increased to 48 h, the domino product 10a has increased to
60% (Table 1, entry 2). Various Lewis acids were screened to
choose the best suited for the reaction (Table 1, entries 3−10).
The Lewis acids Sc(OTf)3and Cu(OTf)2 were found to be
comparatively good catalysts for the reaction (Table 1, entries
3 and 5) whereas the reaction was found to be slow with ZnCl2
and Ba(OTf)2 (Table 1, entries 4 and 6). The formation of
substitution product 9b was observed in the reactions. Other
Lewis acids were not found to be suitable for the domino
reaction (Table 1, entries 7−10). The Dy(OTf)3 was found to
be the better catalyst for the domino aza-Piancatelli−Friedel−
Crafts alkylation to get the required bridged tetracycle (Table
1, entry 2). When the reaction was performed in the presence
of molecular sieves, the yield of domino product did not
increase further (Table 1, entry 11). Then, we moved to
solvent screening where the domino reaction was conducted in
solvents such as DCE, toluene, dioxane, THF, and HFIP
(Table 1, entries 12−17). It was observed that DCE was found
to be the best solvent for the domino reaction (Table 1, entries
12 and 13). When the reaction was conducted in the presence
of strong acid such as TFA, the formation of domino product
was significantly inhibited and we observed the formation of
substitution product of furfuryl cation 9b alone (Table 1, entry
18). When the catalyst loading was increased to 10 mol %,
there was no considerable change in the reaction time and
yield (Table 1, entry 19). When the reaction was carried out at
70 °C, reaction became slow and yield was decreased (Table 1,
entry 20). There was no improvement in the yield observed by
increasing the reaction temperature to 120 °C (Table 1, entry
21). One reaction was performed with ligand 2,2′-bipyridine
(10 mol %) as an additive (Table 1, entry 22). No chiral
induction was observed as confirmed by HPLC (see the
Supporting Information).
Scheme 3. Substrate Scope
We then turned our attention to examine the substrate scope
of domino reaction, and the results are summarized in Scheme
3. The furfuryl alcohol with methyl protected indole 7a was
reacted with different substituted anilines and the correspond-
ing domino products were obtained in good yields (60−70%,
10a, 10c−10f). The structure and configuration of bridged
tetracycle 10a were confirmed by X-ray crystallography (Figure
2, CCDC 1999110). Here, the aza-Piancatelli reaction is trans-
selective and Friedel−Crafts reaction is diastereoselective and
cis-fused ring was obtained in 10a. In the case of p-anisidine,
the reaction stopped after aza-Piancatelli rearrangement 9g
(65%) where the corresponding domino product 10g was not
obtained even after increasing the reaction time and catalyst.
Reaction of 2-furylcarbinol 7a with meta-substituted anilines
also gave corresponding domino products 10h and 10i in 65−
70% yields. We have carried out one reaction using
unprotected indole substrate 7b and aniline 8a. To our
delight, the domino reaction proceeded smoothly to give
corresponding domino product 10b in 62% yield. Similarly,
unprotected indole substrate 7b was also reacted with
substituted anilines and the corresponding domino products
were obtained in 58−65% yields (10j−10l). Another two
indole-tethered 2-furfuryl alcohols were prepared to see the
substituent effect of indole ring on the domino reaction. The
furfuryl alcohol 7c was obtained from 5-methoxyindole, and 7d
a
Reaction conditions: 7 (0.75−0.83 mmol), 8 (0.75−0.83 mmol),
b
and Dy(OTf)3 (5 mol %), DCE (3 mL), 90 °C, 18−48 h. Isolated
yields after chromatographic purification. nd, not detected.
Figure 2. ORTEP diagram of compound 10a.
was obtained from 5-bromoindole. The substrate 7c was
reacted with 4-bromoaniline and m-chloroaniline to give the
C
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corresponding domino products 10m and 10n in good yields,
70 and 72%, respectively. The substrate 7d was also reacted
with m-chloroaniline to give the corresponding domino
product 10o smoothly in 68% yield. In the case of N-
methylaniline, the corresponding aza-Piancatelli product 9p
was obtained in 70% yield and failed to give domino product
10p. The substrates 7a and 7b, when treated with 2-ethyl 6-
methylaniline, failed to give corresponding products 10q and
10r, respectively. In this case, aniline was added on to furfuryl
cation and deoxyamination products (10q′ and 10r′) were
formed, hence no aza-Piancatelli rearrangement was observed.
Then, we turned our attention to see the possibility of making
other fused indole tetracycles such as indoles fused to 7- and 9-
membered rings using different indole-tethered furfuryl
alcohols. The furfuryl alcohol 7e was prepared from 3-indole
acetic acid. Another furfuryl alcohol 7f was prepared from 3-
indole butyric acid (see Supporting Information). When
furfuryl alcohol 7e was treated with m-chloroaniline, the
corresponding Piancatelli product 9s was obtained in 70%
yield and failed to undergo Friedel−Crafts alkylation to give
bridged cyclohepta[b]indolone derivative. Another attempt
was made, wherein furfuryl alcohol 7e was reacted with
tBuOH/H2O in the presence of Dy(OTf)3 to get Piancatelli
product 9t in 63% yield but failed to give cyclohepta[b]-
indolone derivative. The furfuryl alcohol 7f was treated with m-
chloroaniline in the presence of Dy(OTf)3 and the substitution
product of furfuryl cation 9u was formed exclusively in 2 h only
and no Piancatelli rearrangement product as well as domino
product was detected. This confirms that under Lewis acid
conditions indole moiety is more reactive to add on furfuryl
cation to form cyclized byproduct 9u. Hence, the furfuryl
cation was not available for aniline to undergo Piancatelli
rearrangement.
acceptor, activated by Dy(OTf)3 and undergoes diastereose-
lective Friedel−Craft’s alkylation from C2 position of indole
moiety followed by protonation/aromatization to afford
bridged tetracycle 10a.
After successfully obtaining a library of domino aza-
Piancatelli/FC alkylation products, we turned our attention
to see the feasibility of other nucleophile such as H2O for the
domino process (Scheme 5). The furfuryl alcohol 7a was
Scheme 5. Domino Reaction with O-Nucleophile
t
treated with Dy(OTf)3 in BuOH/H2O (3:1) at 90 °C. The
Piancatelli product 11 was obtained along with 9b. The crude
hydroxy cyclopentenone 11 after solvent evaporation, was
subjected to Friedel−Crafts alkylation conditions in acetoni-
trile at 90 °C to get required bridged hydroxy cycloocta[b]-
indolone tetracycle 12 in 48% yield over two steps.
In summary, we have developed a simple and highly efficient
domino aza-Piancatelli rearrangement/intramolecular Friedel−
Crafts alkylation reaction to access a series of novel complex
bridged cycloocta[b]indolone derivatives. This domino proto-
col is found to be general, and the corresponding nitrogen-rich
bridged tetracyclic adducts are isolated in good yields. The
synthesized products were looked using Tanimoto index and
3D overlap with the Waldmann’s pseudo-NP 1 and alkaloids
thus giving a clue that these new skeletons could be considered
as novel pseudo-NPs for further evaluation.
Based on the observations, we propose a plausible reaction
pathway of the domino process which is shown in Scheme 4.
The furfuyl alcohol 7a on treatment with Lewis acid converts
into reactive furyl cation A. Then aniline 8a attacks on the
cation A to form intermediate B which rearranges to key
intermediate trans-cyclopentenone 9a via aza-Piancatelli
rearrangement. Cyclopentenone part of 9a acts as a Michael
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 4. Plausible Reaction Pathway of Domino Aza-
Piancatelli/Friedel−Crafts Alkylation
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03155.
Experimental procedures, characterization details, and
1H and 13C NMR spectra of related compounds, HPLC
and X-ray crystal structure of 10a (PDF)
Accession Codes
CCDC 1999110 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Srivari Chandrasekhar − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India; Academy of Scientific
and Innovative Research (AcSIR), Ghaziabad 201002, India;
D
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orcid.org/0000-0003-3695-4343; Email: srivaric@
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iict.res.in
Authors
Nagarjuna Reddy Vonteddu − Academy of Scientific and
Innovative Research (AcSIR), Ghaziabad 201002, India; Cipla
Ltd, MIDC Patalganga, Rasayani, Maharashtra 410220, India
Pooja R. Solanke − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India; Academy of Scientific
and Innovative Research (AcSIR), Ghaziabad 201002, India
Kiranmai Nayani − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India; orcid.org/0000-
0001-5407-3799
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03155
Author Contributions
∥P.R.S. and K.N. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Council of Scientific and Industrial
Research (CSIR), Ministry of Science and Technology,
Government of India for research facilities. N. R. thanks
Cipla Ltd. and AcSIR for doctoral studies. P. R. S. thanks the
CSIR for research fellowship. K. N. thanks the CSIR-Indian
Institute of Chemical Technology (IICT) for fellowship and
research facilities under the National Laboratories Scheme of
CSIR (No.11/3/Rectt.-2020). S. C. thanks the Science and
Engineering Research Board (SERB), Government of India for
J C Bose fellowship (SB/S2/JCB-002/2015). We gratefully
acknowledge Dr Balasubramanian Sridhar, Laboratory of X-ray
Crystallography, CSIR-IICT, for X-ray analysis.
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