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Cu(I)-catalyzed tandem decarboxylative/C–H

activation coupling of cyclic diketones, proline and
alkynes: synthesis of a-alkynylated pyrrolidine-
Cite this: RSC Adv., 2014, 4, 9412

Received 3rd December 2013 oxyindoles†

Accepted 14th January 2014
Atul Kumar,* Mukesh Kumar, Lalit Prakash Gupta and Maneesh Kumar Gupta
DOI: 10.1039/c3ra47238h

[Link]/advances

An efficient ligand/base and oxidant-free copper(I) catalyzed inter- worker reported C–C bond-forming reaction using copper- or
molecular direct alkynylation (IDA) strategy has been developed for iron-catalyzed oxidative decarboxylative coupling of sp3-
the synthesis of a-alkynylated pyrrolidine-oxindole derivatives using hybridized carbons with N-benzylproline.5a Concurrently,
cyclic diketones, amino acids and alkynes via tandem decarboxylative/ Seidel6 and Li's group5b,c also reported new methods involving
C–H activation and reductive-amination strategy. aldehyde-induced intermolecular tandam decarboxylative
coupling reaction of amino acids and alkynes to afford prop-
argylic amino acids derivatives (Fig. 1). These new reactions
The carbon–carbon bond formation by transition-metal-cata- increases the scope and synthetic utility of the catalytic decar-
lyzed coupling has reinvigorateded the science of synthesis boxylative coupling reactions. However, these decarboxylative
due to its inventive contribution to the synthetic organic coupling protocols requiring complex ligands, long reaction
chemistry. Generally, these synthetic methodologies involve time, harsh reaction conditions, and superstoichiometric
expensive metal catalysts, and preformed “organo-metallic amount of oxidants or transition metals besides copper to
reagents” that produce unwanted, oen toxic, stoichiometric facilitate the reaction. However, to the best of our knowledge,
side-products.1 there are no literature examples describing the synthesis of
With increasing environmental concerns and waste a-alkynylated pyrrolidine-oxyindole via tandam decarboxylative
management, especially in the area of pharmaceuticals, devel- coupling reaction using isatin and cyclic aromatic diketones.
opment of methods that avoid preformed “organo-metallic The oxindole skeleton has been widely known as a privileged
reagents” and organic solvents are very important because the scaffold in naturally occurring alkaloids and biologically active
removal of metallic impurities from nal pharmaceutical enti- molecules.7 Furthermore, Pyrrolidine-oxyindoles also forms the
ties increases the cost considerably. Construction of new C–C core unit of several medicinal and natural spiropyrrolidine-
bond by decarboxylative coupling reaction is also a powerful oxindole alkaloids like nelivaptan, spirotyrpstatin and
and attractive alternative synthetic method because of their compound I etc.8 (Fig. 2)
high efficiency, selectivity and convenience.2 Further, extrusion
of CO2 as the waste product during the reaction is considered to
be environmentally benign and requires no special separation
procedures.
Transition-metal catalyzed decarboxylative coupling reaction
of amino acids provides new synthetic route for the construc-
tion of C–C or C–N bond. For examples, Cohen et al. reported a
decarboxylative reaction of proline with sterically congested
2-hydroxyacetophenones in 1979.3 In 2008, Seidel
et [Link] the synthesis of aminals by the coupling reaction
of proline with 2-aminobenzaldehyde.4 Recently, Li's and co-

Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow, India. E-mail: dratulsax@[Link]; Fax: +91-522-26234051; Tel: +91-
522-2612411
† Electronic supplementary information (ESI) available. See DOI: Fig. 1 Comparison of different intermolecular decarboxylative cross
10.1039/c3ra47238h coupling protocols.

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Table 1 Optimization of reaction conditionsa

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Fig. 2 Important biologically active compounds possessing pyrroli-

dine-oxindoles motif.
Entry Catalyst (mol%) Solvent t (h) Yieldb (%)

1 — CH3CN 8 0
The direct and straightforward approach for the synthesis of 2 CuBr (15) CH3CN 6 20
a-phenyl-ethynyl pyrrolidine-oxyindole via tandem decarbox- 3 CuI (15) CH3CN 6 65
ylative/C–H activation in one-pot remains a challenging task. 4 CuI (20) CH3CN 6 82
Herein, we wish to describe, the highly efficient Cu(I)-catalyzed 5 CuI (10) CH3CN 7 47
6 CuI (5) CH3CN 7 35
intermolecular direct alkynylation (IDA) of in situ generated
7 CuI (20) Toluene 6 40
oxindoles-pyrrolidine ylide via tandem decarboxylative/Csp3- 8c CuI (20) DMSO 6 25
Csp C–H activation coupling reaction using aromatic cyclic 9c CuI (20) DMF 6 27
ketones, a-amino acid and alkyne for the synthesis of a-alky- 10 CuI (20) THF 6 30
nylated pyrrolidine-oxyindole without use of any ligant and 11 CuI (20) Dioxane 6 20
12 CuI (20) Ethanol 6 12
oxidants outlined in Scheme 1.
13 CuI (20) Methanol 6 10
As illustrated in Table 1, our initial investigation were initi- 14 CuCl2 (20) CH3CN 6 12
ated employing isatin (1a), proline (2a) and phenylacetylene (3a) 15 Cu(OTf)2(20) CH3CN 8 15
as model substrate to nd the optimal reaction conditions. Our 16 Cu(OAc)2(20) CH3CN 8 <10
rst attempts was focused on to carry out the reaction in the 17 Cu2O (20) CH3CN 6 <5
18 CuBr2 (20) CH3CN 6 <5
absence of any catalysts in 5 mL of acetonitrile at 100
C for
19 PdCl2 (15) CH3CN 8 n.r.
8 hours, unfortunately the desired coupling product 4a was not 20 Pd(OAc)2 (15) CH3CN 8 n.r.
observed (Table 1, entry 1). The desired 4a was obtained in 20% a
Reaction conditions: Isatin 1a (1 mmol), proline 2a (1.5 mmol), and
yield when reaction was carried out in 15 mol% of CuBr alkyne 3a (2 mmol), in 5 mL of solvent in the presence of catalysts at
(Table 1, entry 2). Delightfully, 65% yield of 4a was achieved reuxed condition under nitrogen atmosphere. b Yield of the isolated
when 15 mol% of CuI was employed as catalyst (Table 1, entry product. c Reuxed at 110
C. Nr ¼ not reacted. DMSO ¼
dimethylsulfoxide; DMF ¼ N,N-dimethylformamide; THF ¼
3). To further improve the yield, we used different amount of tetrahydrofuran.
CuI, and the best yield (82%) of coupling product 4a was
obtained with 20 mol% of CuI in 6 hours (Table 1, entries 4, 5,
and 6). Among the copper catalysts examined, CuI was the most
successful catalyst for this reaction compared to CuCl2, various isatin derivatives reacted with proline and alkyne under
Cu(OTf)2, Cu(OAc)2, Cu2O, and CuBr2 (Table 1, entries 14–18). optimized conditions, and the results are illustrated in Fig. 3. A
We attempts to use other catalyst like PdCl2 and Pd(OAc)2, but wide range of isatin bearing chloro, bromo, nitro, ouro, and
the trials were also unsuccessful (Table 1, entries 19 and 20). iodo at the 5th position along with electron-neutal isatin 1a
The reaction was explored in different solvents as well. Preem- could be employed as coupling partner with proline 2a which
inent result was found when reaction was performed in aceti- were smoothly transformed to the corresponding a-substituted
nitrile as reaction medium, the coupling product 4a could be pyrrolidine-oxindole 4a with phenylacetylene 3a in good to
isolated in 82% yield, whereas no observable improvement was excellent yield by NMR (Fig. 3 entries 4a–4f). N-substituted isatin
achieved in other solvents like toluene, DMSO, DMF, THF, like methyl, ethyl, propyl, butyl, and benzyl also furnished
dioxane, ethanol, and methanol (Table 1, entries 4, and 7–13). desired product in good to moderate yield (Fig. 3, entries 4g–4k).
With the optimized reaction conditions established, we then Subsequently, we also explored the use of various alkynes
examined the scope of decarboxylative coupling reaction, reacted under the same conditions in Fig. 3. Aromatic alkynes
bearing methyl group at para and meta position afforded good
yields (Fig. 3, entries 4l–4m). However, aliphatic alkyne like
pentyne and hexyne did not react well and gave an inseparable
complex mixture (Fig. 3, entries 4o–4p), whereas methyl-
propiolate furnished desired product in better yields (Fig. 3, 4n).
All the synthesized product of the reaction was fully character-
ized by 1H and 13C NMR methods and mass spectroscopic data.
A proposed mechanism for the Cu(I) catalyzed decarboxylation/
Scheme 1 Synthesis of a-alkynylated pyrrolidine-oxyindole. C–H activation for the synthesis of a-substituted pyrolidine

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Scheme 2 Proposed mechanism.

Fig. 3 Synthesized a-alkynylated pyrollidine-oxindoles.

oxindoles in one-pot is illustrated in Scheme 2. Condensation of

Fig. 4 Proposed rationalization of regioselectivity.
proline with isatin in the presence of CuI to gave imine-type
intermediate A which converted into reactive intermediate spiro
[indoline-3,30 -pyrrolo[1,2-c]oxazole]-10 ,2-dione B. B immediately
undergoes decarboxylation by CuI to afforded C which subse-
quently gave intermediate D. Intermediate D (pyrrolidine-type
ylide) will be in equilibrium with D0 . D or D0 further co-ordinated
with copper and reacted with 3a to generated organo-copper
complex intermediate E, which undergoes intramolecular
nucleophilic addition to give desired coupling products and
regenerates the copper catalyst for additional reaction.
This proposed mechanism readily illuminates the formation
of the two regioisomers and suggest that the regioselectivity Scheme 3 Synthesis of a-phenylethynyl pyrrolidine acenaphthylnone.
depends on the charge distribution in between intermediate D
and D0 in addition to potential steric factor. The negative charge
on intermediate D appear to stabilize with amidic oxygen of
isatin that favours the protonation at 3-position of isatin and
ultimately leads to the predominantly formation of regioisomer
4 whereas in case of intermediate D0 the protonation at
2-position of pyrrolidine ring is not favour since negative charge
is not more stabilize at that position, resulted no formation of
regioisomer 5. Steric factor also inhibit the formation of 5 Fig. 4.
Using same reaction conditions we have also synthesized
several pharmacologically valuable 2-(2-(phenylethynyl)-
pyrrolidin-1-yl)acenaphthylen-1(2H)-one,2-(2-(phenylethynyl) Scheme 4 Synthesis of a-phenylethynyl pyrrolidine aceanthrylenone.

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