Synthesis of polysubstituted cyclopenta[b]indoles via relay gold(i)/Bronsted acid catalysis

Article abstract of DOI:10.1039/c4cc08174a

An efficient relay catalytic process involving Au(i)/Bronsted acid to access various polysubstituted cyclopentannulated indoles from easily accessible 1-(2-aminophenyl)prop-2-ynols and readily available 1,3-dicarbonyls has been developed. In an unprecedented event, the intermediate 2-indolylmethyl cations undergo the cation-Ene reaction with various 1,3-dicarbonyls followed by an intramolecular Friedel-Crafts-type reaction generating functionalized cyclopenta[b]indoles. This journal is

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Polysubstituted Cyclopenta[b]indoles via Relay
Gold(I)/Brønsted Acid Catalysis
Cite this: DOI: 10.1039/x0xx00000x
Seema Dhiman and S. S. V. Ramasastry*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
On the other hand, activation of -systems of alkynes and
alkenes via gold catalysis for the synthesis of a wide range of natural
products and complex molecules in an efficient and predictable
manner has received significant attention during the past decade.4
Especially, relay catalytic processes involving gold were
demonstrated to have great potential to rapidly assemble complex
chemical structures often associated with pot, step and atom
economy.5 Motivated by the pioneering works of Chan6 for the
synthesis of indole derivatives starting from propargylic tert-
alcohols of the type A, and with our experience in the chemistry of
heteroaryl carbinols,7 we initiated a program to develop an efficient
and general methodology towards the synthesis of a novel series of
cyclopentannulated indoles and to evaluate their biological efficacy,
Scheme 1. Prior to commencing our investigation, a detailed
literature survey revealed that the prevailing 2-indolylmethyl cation
intermediate B was routinely trapped by nucleophiles such as
alcohols, aryls, heteroaryls, etc.8 However, to our surprise, no
attempt was ever made to employ readily available 1,3-dicarbonyl
compounds as nucleophiles.9
An efficient relay catalytic process involving Au(I)/Brønsted
acid to access various polysubstituted cyclopentannulated
indoles from easily accessible 1-(2-aminophenyl)prop-2-ynols
and readily available 1,3-dicarbonyls has been developed. In
an unprecedented event, the intermediate 2-indolylmethyl
cations undergo cation-Ene reaction with various 1,3-
dicarbonyls followed by an intramolecular Friedel-Crafts-
type reaction generating functionalized cyclopenta[b]indoles.
Indoles and indolines are considered to be privileged structures due
to their wide spread occurrence in nature with intricate structural
diversity often associated impressive bioactivities, and in
pharmaceutical sense due to their durg-like properties.1 Among
indole derivatives, cyclopenta[b]indoles are especially attractive due
to their presence in numerous biologically active natural products,
for example, paspalines, terpendoles, emindoles, polyveolines,
spiroindimicins, fischerindoles, yeuhchukene, etc., in addition to
medicinally important compounds such as MK-0524, Fig. 1.2
Presence of complex molecular architectures coupled with
impressive pharmacological properties prompted several research
groups contribute significantly to the construction of
cyclopentannulated indole derivatives.3 However, the quest for the
development of simple and efficient access to this class from readily
available starting materials still remains an area of active research.
Fig. 1 Representative examples of bioactive cyclopenta[b]indoles.
Scheme 1 Our strategy for the synthesis of cyclopentannulated indoles.
Chem. Commun., 2014, 00, 1-4 | 1
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Herein, we delineate our efforts towards the generation of especially because, as per our hypothesis, the intervening
indolylmethyl cations from 2-aminophenyl propargylic secondary indolylmethyl cation formed under Lewis acidic conditions
alcohols C,10 their reactions with a variety of 1,3-dicarbonyl successfully underwent cation-Ene reaction with acetylacetone 2a
compounds and subsequent intramolecular aldol-type reaction for and furthermore the 1,3-dicarbonyl adduct 4a via intramolecular
the synthesis of 1,2,3-trisubstituted cyclopenta[b]indoles. aldol-type reaction furnished 1,2,3-trisubstituted cyclopenta[b]indole
Accordingly, we have initiated optimization studies towards 5a. It is worth mentioning that the current method also constitutes a
identifying effective catalytic system and other reaction parameters. potential alternative to the traditionally employed methods for indole
Towards this, the amino alcohol 1a6b,11 and acetylacetone 2a were cyclopentannulations such as [3+2]-cycloadditions, Nazarov
chosen as substrates for the model reaction. The screening results are cyclizations, etc.14 Further, synthesis of cyclopentannulated indoles
compiled in Table 1.
via 2-indolylmethyl cation intermediates is underexplored.3h
Table 2 Substrate scope with 1-(2-aminophenyl)prop-2-ynols and 1,3-
dicarbonyls in the relay Au(I)/Brønsted acid catalyzed tandem processa,b
Table 1 Optimization of reaction parametersa
Co-
catalyst
Time
(h)
48
48
48
48
48
48
48
26
20
13
16
15
18
13
24
Yieldb
(%)








82

51
72
70
83
74
80

53
72
90




Entry Catalyst
Acid
Solvent
1
AuCl
DCE
DCE
DCE
DCE






2
3
PPh3AuCl
AuCl
AgOTf
4
PPh3AuCl AgOTf
5c
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
Na2CO3
Et3N
Sc(OTf)3 MeNO2
In(OTf)3
AgOTf
Bi(OTf)3 MeNO2
TMSOTf DCE
TFA
H3PO4
HClO4
H2SO4
TfOH
TfOH
TfOH

TfOH
TfOH
TfOH
TfOH
TfOH
6c
MeNO2
MeNO2
7c
8
9
10
11
12
13
14
15
16
17
18
19
20d
21c,e
22d
23d
24d
DCE
DCE
DCE
DCE
DCE
MeNO2
Toluene 13
DCE
DCE
DEC
DCE
DCE
DCE
40
35
27
18
48
42
36
34
K2CO3
K2CO3
PPh3AuCl K2CO3
AuCl
AgOTf
K2CO3

TMSOTf DCE
TfOH MeNO2
a Reaction conditions: A 5 mL glass vial was charged with 1a (0.1 mmol),
catalyst (2 mol%), co-catalyst (2 mol%) in an appropriate solvent (1 mL) and
stirred at 60 oC, upon disappearance of starting compound (1a), acetylacetone
2a (0.11 mmol) and an acid (20 mol%) were introduced and continued
stirring at 60 C until indoline 3a and acetylacetone adduct 4a disappeared. b
o
c
Isolated yields after silica gel column chromatography. Intermediate 3a
formed and only the acetylacetone adduct 4a was isolated. d 10 mol% TfOH
was employed. e Step-II was done at room temperature.
To begin with, cyclization of amino alcohol 1a to indoline 3a
was explored. Reaction of 1a in the presence of Au(I) or Ag(I) salts
alone or a combination of Au(I) and silver based Lewis acids failed
to deliver the indoline 3a (Table 1, entries 1-4). Interestingly, the
amino alcohol 1a generated indoline 3a when a combination of
Au(I) and base was employed,12 however, subsequent transformation
of the indoline 3a to the desired indole 5a was not observed upon
treatment with a variety of Lewis acids, only the acetylacetone
adduct 4a was isolated (Table 1, entries 5-7). Nevertheless, an
approach for indoline 3a via a catalytic sequence involving Au(I)
and a base could be established for the first time.13
a Reaction conditions: A mixture of the amino alcohol 1 (0.1 mmol), AuCl (2
mol%), K2CO3 (2 mol%) and DCE (1 mL) in a 5 mL glass vial were stirred at
60 oC. After complete consumption of the starting compound (1), 1,3-
dicarbonyl 2 (0.11 mmol) and TfOH (10 mol%) were added successively and
o
Upon further screening, Lewis acids such as Bi(OTf)3 and continued stirring at 60 C until the complete disappearance of the respective
TMSOTf gratifyingly generated the cyclopentannulated indole 5a in
very good yields (Table 1, entries 8 and 9). We were delighted
b
1,3-dicarbonyl adduct (4).
Isolated yields after silica gel column
chromatography.
2 | Chem. Commun., 2014, 00, 1-4
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In order to further improve the efficiency of the reaction, we
On the other hand, reaction of the amino tert-alcohol 1m even in
opted to investigate the influence of Brønsted acids in place of Lewis the presence of 2a generated only the indole 5w in 84% yield via a
acids in step-II. Among several Brønsted acids explored, trifilic acid Nazarov electrocyclization (Table 2).6a Thus, indoles of the type 5w
mediated reaction in DCE delivered the cyclopentannulated indole could now be accessed in excellent yields with less Au(I) catalyst
5a in very good yield (Table 1, entries 10-16). Subsequently, loading and milder reaction conditions over the existing method.6a
influence of co-catalyst (base) in step-I was also studied. While no
Since the alcohol 6 and the cationic intermediate 7 are believed
desired product was observed when sodium bicarbonate was to be the intermediates in the transformation of 1a to 5a, we planned
employed as co-catalyst, sodium carbonate and an organic base such to undertake a comparative study between the reactions of the amino
as triethylamine furnished 5a only in moderate yields (Table 1, alcohol 1a and the 2-indolyl carbinol 6 under the optimized
entries 17-19). Gratifyingly, further enhancement in the yield was conditions, Scheme 2. It can be noted that the reaction of the amino
observed when TfOH loading was reduced from 20 mol% to 10 alcohol 1a with 2a or 2e is found to be efficient in generating 5a or
mol% (Table 1, entry 20). Striking temperature dependence was 5e, respectively, when compared to the reaction of the alcohol 6 in
realized when TfOH reaction at room temperature failed to generate forming 5a and 5e, thereby clearly demonstrating the advantage of
the desired product 5a and only the acetylacetone adduct 4a was the one-pot tandem process. It is worth mentioning that the direct
isolated (Table 1, entry 21). Further attempts to enhance the yield Friedel-Crafts-type alkylation of unmodified 2-indolyl carbinols and
were not encouraging (Table 1, entries 22-24).
In order to validate the generality of the unprecedented method subsequent cyclization cascade as well.
for polysubstituted cyclopenta[b]indoles, variety of 1-(2-
1,3-dicarbonyls as such is unprecedented17 and of course the
a
aminophenyl)prop-2-ynols 1a-1m were synthesized according to
literature methods6,8 and subjected to the optimized conditions,
Table 2. It is noteworthy that the relay Au(I)/Brønsted acid catalyzed
tandem transformation is quite general, and a diverse library of
annulated indoles can be rapidly accessed in good to excellent yields
(Table 2, 5a-5w). The reaction displays significant tolerance towards
various alkynols bearing electron-donating as well as electron-
withdrawing aryl groups (for example, p-tolyl and p-fluorophenyl),
heteroaryls such as 2-thienyl, and the alkyl groups. Further, alkyl
and aryl-bearing 1,3-diketones, 1,3,5-triketones, -ketoesters and -
ketoamides are also well-tolerated under the reaction conditions.
Scheme 2 Comparison between the efficiency of amino alcohol 1a and
indolyl carbinol 6 in forming the same end product. First demonstration of
direct reaction between 2-indolyl carbinols and 1,3-dicarbonyls.
To further illustrate the generality and synthetic utility of this
Evidently from Table 2, the amino alcohol 1a upon reaction with methodology, we considered an elaboration as in Scheme 3. Thus,
di- and triketones 2a-2d, and ketoamide 2e generated the respective reaction of 1a with ketoester 2i under the optimized conditions
1,2,3-trisubstituted cyclopentannulated indoles 5a-5e in excellent furnished the adduct 8, which underwent smooth in situ
yields. Similarly, the analogous aryl and heteroaryl amino alcohols decarboxylation to form β-branched 4-(2-indolyl)-2-butanone 9 in
1b-1d upon reaction with a variety of diketones, ketoesters and 76% yield, synthesis of which otherwise would require a multistep
ketoamides generated functionalized cyclopenta[b]indoles (Table 2, sequence. Indole 9 upon reaction with excess Mg in methanol
5f-5l). Significantly, reaction of 1e having a pendant alkyl group on generated alcohol 10 by undergoing simultaneous tosyl deprotection
the acetylenic carbon centre with diketones 2a and 2e also furnished and ketone reduction. Selective O-mesylation and subsequent
the respective annulated indoles 5m and 5n though in moderate intramolecular N-alkylation18 conveniently generated 1,3-
yields,15 but enhanced the scope of this method. Even 1,2- disubstituted dihydropyrroloindole 11, an important motif prevalent
disubstituted cyclopentannulated indoles (such as 5o) could be in a number of pharmaceutically important compounds and natural
efficiently generated by the reaction of unsubstituted alkynol 1f with products.19
the diketone 2a. But reaction of 1f with the triketone 2d,
unexpectedly formed the pyranone indole 5p. Complex indole
derivatives bearing electron-withdrawing as well as electron-
donating substitutions (such asCF3, OTsOMe) on the indole
moiety could also be accessed easily in high yields (Table 2, 5q-5u).
However, contrary to our expectation, the amino alcohols 1g and 1h
failed to deliver the desired products under the reaction conditions.
Presumably, the presence of acid sensitive cyclopropyl system and a
2-butyne-1,4-oxygenated system would have triggered unwanted
side reactions. The molecular structure of a representative example
5v, obtained by the reaction of 1a and 2h, was unambiguously
Scheme 3 Elaboration to an advanced intermediate.
In conclusion, we have developed a general and efficient
relay Au(I)/Br nsted acid catalyzed one-pot tandem process for
the synthesis of medicinally significant 1,2-di- and 1,2,3-
trisubstituted cyclopentannulated indoles from 1-(2-
confirmed by single crystal X-ray diffraction analysis (see
Supporting Information for details), Fig. 2.16
ø
aminophenyl)prop-2-ynols and 1,3-dicarbonyls. Key features of
this method are its readily accessible starting compounds and,
atom, step and pot economy. During the course of our
investigation, we have also developed novel Au(I)/base
mediated conditions for the synthesis of indolines starting from
1-(2-aminophenyl)prop-2-ynols. In addition, we have
demonstrated for the first time, Friedel-Crafts-type alkylation of
unmodified 2-indolyl carbinols and 1,3-dicarbonyls.
Application of this methodology for the synthesis of
Fig. 2 ORTEP diagram of 5v.
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We are grateful to the DST, Govt. of India for financial
support through Fast Track Scheme (SR/FT/CS-156/2011). We
thank IISER Mohali for funding and for NMR, mass, and X-ray
facilities. S.D. thanks IISER Mohali for a research fellowship.
5
6
Notes and references
a Department of Chemical Sciences, Indian Institute of Science Education
and Research (IISER) Mohali, Sector 81, S. A. S. Nagar, Manuali PO,
Punjab 140306, India. E-mail: ramsastry@iisermohali.ac.in
† Electronic Supplementary Information (ESI) available: Complete
experimental procedures and characterization data of all new compounds.
CCDC 1029309. For ESI and crystallographic data in CIF or other
electronic format, see DOI: 10.1039/c000000x
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2
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As such, reactions of 1,3-dicarbonyls and 2-indolylmethyl cations
generated by any method were never studied.
10 While reactions of 2-indolylmethyl cations originating from
propargylic tertiary alcohols ( ) with different nucleophiles is well-
established,6,8 but generation of 2-indolylmethyl cations from
propargylic secondary alcohols ( ) and their reactions with any
nucleophile is not reported thus far.
A
C
11 Other NH-protecting groups (Ms, Boc, Ac) were also evaluated prior
to proceeding to optimization. Only N-sulfonyl propargyl alcohols
generated desired product (see Supporting Information for details).
12 Step-I was found to proceed very slowly at room temperature. After
o
several attempts, the reaction temperature was optimized to 60 C.
3
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16 The crystal structure of 5v has been deposited at the Cambridge
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4
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4 | Chem. Commun., 2014, 00, 1-4
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