Cu(OTf)2-catalyzed synthesis of 2,3-disubstituted indoles and 2,4,5-trisubstituted pyrroles from α-diazoketones

Article abstract of DOI:10.1021/ol303206w

A novel method has been devised for the synthesis of 2,4,5-trisubstituted pyrrole derivatives through the coupling of α-diazoketones with β-enaminoketones and esters using 10 mol % of Cu(OTf)₂. A wide range of 2,3-disubstituted indole derivatives were also prepared from α-diazoketones and 2-aminoaryl or alkyl ketones. The synthetic versatility of this approach has been exemplified in the formal synthesis of homofascaplysin C.

Full text of DOI:10.1021/ol303206w

ORGANIC
LETTERS
2013
Vol. 15, No. 3
464–467
Cu(OTf)2‑Catalyzed Synthesis
of 2,3-Disubstituted Indoles and
2,4,5-Trisubstituted Pyrroles from
r‑Diazoketones
B. V. Subba Reddy,*,† M. Ramana Reddy,† Y. Gopal Rao,† J. S. Yadav,† and B. Sridhar‡
Natural Product Chemistry, Laboratory of X-ray Crystallography, CSIR-Indian
Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500 007, India
basireddy@iict.res.in
Received November 22, 2012
ABSTRACT
A novel method has been devised for the synthesis of 2,4,5-trisubstituted pyrrole derivatives through the coupling of R-diazoketones with
β-enaminoketones and esters using 10 mol % of Cu(OTf)2. A wide range of 2,3-disubstituted indole derivatives were also prepared from
r-diazoketones and 2-aminoaryl or alkyl ketones. The synthetic versatility of this approach has been exemplified in the formal synthesis
of homofascaplysin C.
The indole nucleus is often found in various natural
products and is known to exhibit a broad spectrum of
biological activities (Figure 1).1 They are being recognized
as privileged structures in medicinal chemistry because of
their affinity to bind with various receptors. Consequently,
several approaches have been developed for the synthesis
of indole derivatives, which include the Fisher indole
synthesis,2 the hydroamination of 2-alkynylanilines,3 metal-
catalyzed cascade reactions,4 an intramolecular CÀH
amination of azidoacrylates,5 and the coupling of N-aryl
amides with ethyl diazoacetate.6 Recently, the synthesis of
2,3-disubstituted indoles by the nucleophilic addition of
phenyldiazoacetate to the ortho-imino group7 has been
reported, which are well-known for indole synthesis. In
particular, 3-substituted indole derivatives have been pre-
pared through the condensation of 2-aminobenzaldehyde
with ethyl diazoacetate via a 1,2-aryl shift.8 Although
numerous methods have been reported for the preparation
of indoles, simple and expedient approaches still remain
scarce. Therefore, the development of efficient methods for
the synthesis of indoles from simple precursors continues
to be a challenging task. In particular, an annulated
pyrrole skeleton is an important structural motif for the
† Natural Product Chemistry.
‡ Laboratory of X-ray Crystallography.
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r
10.1021/ol303206w
Published on Web 01/16/2013
2013 American Chemical Society

of 2,3-disubstituted indoles through the coupling of
R-diazoketones with 2-aminoaryl ketones while the coupling
of R-diazoketones with β-enaminoketones or esters affords
the corresponding 2,4,5-trisubstituted pyrroles in good yields.
Initially, we attempted the coupling of aryl diazoketone
with 2-aminoaryl ketone in the presence of 10 mol % of
Cu(OTf)2. Although the reaction proceeds smoothly at
25 °C, it required a prolonged reaction time (12 h) to
achieve high conversion. But the rate of reaction was
enhanced remarkably by increasing the temperature from
25 to 80 °C. For instance, treatment of phenyldiazoketone
(1a) with 2-aminoacetophenone (2a) in the presence of
10 mol % Cu(OTf)2 in DCE at 80 °C over 2 h afforded the
corresponding 3-methyl-2-benzoylindole 3a in 90% yield.
Inspired by the above result, we turned our attention toward
investigating the scope of this methodology. To our delight,
various aryl diazoketones reacted well with 2-aminoaryl
Figure 1. Biologically active indole based molecules.
Table 1. Synthesis of Indoles from R-Diazoketones with
2-Aminoalkyl or arylketones
construction of several indole based heterocycles.9 Further-
more, a 4-oxo-4,5,6,7-tetrahydroindole core is often pre-
sent in many biologically important alkaloids such as
mitomycins and 7-methoxymitosene.10 Consequently, a
three-component process has been developed for the
synthesis of annulated pyrroles through the condensation
of R-haloketones with 1,3-cyclohexadiones and ammonia
or primary amines.11 More recently, an elegant approach
has been devised for the synthesis of annulated pyrroles
from the MoritaÀ BaylisÀHillman acetates which in turn
are derived from the 2-oxo-2-(phenyl)acetaldehyde and
cyclohexenone.12 We also explored the synthetic potential
of R-diazoketones for the synthesis of biologically active
heterocycles such as imidazo[1,2-a]pyridines, 2-aminothio-
zoles, quinoxalines, spirooxindoles, and cyclopropyl glycals.13
Here, wewish toreportanefficientmethodforthesynthesis
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a All tie products were characterized by NMR, IR and mass spectros-
copy. b Yield refers to pure product after chromatography.
Org. Lett., Vol. 15, No. 3, 2013
465

ketones to afford the respective 2,3-disubstituted indoles.
Both aryl and alkyl diazoketones participated well in this
reaction. Similarly, various 2-aminoacetophenones and
2-aminobenzophenones afforded the desired indole deriv-
atives in good yields (Table 1). A tentative reaction
mechanism is proposed in Scheme 1. During the indole
formation, the Lewis acid activates the carbonyl group of
the aryl ketone to facilitate the nucleophilic attack of the
diazo compound. This is followed by displacement of N2
by aryl amine with subsequent dehydration resulting in the
formation of 2,3-disubstituted indoles (Scheme 1).14 Next
Table 2. Synthesis of Pyrroles from R-Diazoketones with
2-Enaminoketones
Scheme 1. A Plausible Pathway for the Formation of Indoles
we extended this approach for the synthesis of trisubsti-
tuted pyrrole derivatives via the coupling of diazoketones
with β-enamino ketones or esters. Accordingly, treatment
of R-diazoketone with β-enamino ketone in the presence of
10 mol % Cu(OTf)2 in DCE at 80 °C gave the 2,4,5-
trisubstituted pyrrole. Several R-diazoketones underwent
smooth coupling with β-enamino ketones to provide the
corresponding trisubstituted pyrrole derivatives (Table 2).
This method also works well with β-enamino esters to
furnish the respectivepyrrole carboxylates (Table 2, entries
b, d, and j). Next we applied this process to the synthesis of
annulated pyrroles which are key precursors for many
indole based natural products. Thus the coupling of R-
diazoketones with β-enaminoketones derived from cyclic
1,3-diketones such as 1,3-cyclohexadione and dimedone
gave the corresponding annulated pyrrole scaffolds
(entries k and l, Table 2). In contrast, cyclic β-enaminoke-
tones gave the annulated pyrroles in lower yields than
acyclic counterparts (Table 2). In the case of enaminoke-
tone, the keto group is less reactive due to its vinylogous
amide nature. Therefore, the Lewis acid activates the
carbonyl group of the diazo compound which acts as an
electrophile and reacts with the amino group of the
enamine leading to the pyrrole (Scheme 2). In order to
know the effect of solvent and the catalyst, we reacted
phenyl diazoketone (1a) with 2-aminoacetophenone (2a)
and 2-enaminoketone (2) using various acid catalysts
(Table 3) in different solvents. As shown in Table 3, the
products 3a and 4a were obtained in low yields in THF.
Toluene was also found to be ineffective for this reaction.
Also, various catalysts such as Rh2(OAc)4, Cu(OTf)2,
a All the products were characterized by NMR, IR, and mass
spectroscopy. b Yield refers to pure products after chromatography.
Cu(hfacac)2, and Cu(acac)2 were used. Among them, Cu-
(OTf)2 gave the best results in terms of reaction time and
conversion (entry a, Table 3). The solid acid catalysts such
as clays, heteropolyacids, and ion-exchange resin were also
found to be ineffective in facilitating this reaction.
In both cases, no regioisomers were formed under the
reaction conditions as evidenced by the NMR spectra of
the crude products. The assigned structures of 3h and 4d
were further confirmed by X-ray crystallography.
CuOTf, Sc(OTf)3, In(OTf)3, InCl3, BF3 OEt2, InBr3,
3
(14) The authors wish to acknowledge the referee for his valuable
input on the reaction mechanism.
466
Org. Lett., Vol. 15, No. 3, 2013

fascaplysin selectively inhibits the cyclin-dependent kinase,
which regulates the G0ÀG1/S checkpoint of the cell
cycle.17 It also shows antimicrobial activity and cytotoxi-
city against L-1210 mouse leukemia. Owing to its fascinat-
ing biological profiles, fascaplysin can be used as a lead
compound for creating novel anticancer drugs. As a result,
several methods have been devised for the synthesis of
fascaplysin.18 To show the synthetic utility, we applied the
present protocol to the formal synthesis of homofascaply-
sin C. Accordingly, the coupling of 2-aminoacetophenone
(2) with diazoketone (5) in the presence of 10% Cu(OTf)2
gave the 2,3-disubstitued indole (6) in 60% yield. Subse-
quent base catalyzed intramolecular cyclization of 6 af-
forded the compound 7 in 95% yield. Further treatment of
7 withphenylhydrazine in the presenceofp-TSA inethanol
at 80 °C gave the pyridodiindole 8 in 90% yield with high
regioselectivity, as the keto group does not have methylene
protons at both R-positions. The oxidation of 8 under
known conditions affords the target molecule (Scheme 3).19
Scheme 2. A Plausible Pathway for the Formation of Pyrroles
Table 3. Effect of Catalyst and Solvent in the Formation of 3a
and 4a
Scheme 3. A New Approach to the Synthesis of Homofascaplysin C
a The reaction was performed at 0.5 mmol scale at reflux. b lsolated yield.
Finally, we attempted the synthesis of homofascaply-
sin C through the coupling of alkyl diazoketone with
2-aminoacetophenone. The pentacyclic pyrido[1,2-a:3,4-b]-
diindole core is found in various natural products such as
fascaplysin and homofascaplysin C which were isolated
from Fascaplysinopsis Bergquist sp. and Fijian sponge
F. reticulata,15 respectively. These compounds are found to
exhibit a wide range of biological activities.16 In particular,
In conclusion, we have demonstrated a novel protocol
for the synthesis of 2,3-disubstituted indoles and 2,4,5-
trisubstituted pyrrole derivatives in good yields via the
coupling of R-diazoketones with 2-aminoketones and
β-enaminoketones respectively. This is the first example
of the synthesis of pyrrole derivatives through the coupling
of diazoketones with enaminoketones. This method is also
illustrated by the formal synthesis of homofascaplysin C.
This approach is very useful for the synthesis of indole-
based natural products, especially, 7-methoxymitosene.20
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Acknowledgment. M.R.R. and Y.G.R. thank CSIR,
New Delhi for the award of fellowships.
Supporting Information Available. Experimental de-
tails, characterization data of products, 1H and 13C NMR
spectra of products, and X-ray crystallography data for
3h and 4d. This material is available free of charge via the
Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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