Indium-catalyzed, novel route to β,β-disubstituted indanones via tandem Nakamura addition-hydroarylation-decarboxylation sequence

Article abstract of DOI:10.1039/c4cc09799h

A novel method for the construction of β,β-disubstituted indanones has been developed via tandem Nakamura addition-hydroarylation-decarboxylation process. Indium(iii) triflate was demonstrated as a versatile multitasking catalyst, which catalyzes three different chemical transformations under one-pot conditions. This journal is

Full text of DOI:10.1039/c4cc09799h

ChemComm
View Article Online
View Journal
COMMUNICATION
Indium-catalyzed, novel route to b,b-disubstituted
indanones via tandem Nakamura addition–
hydroarylation–decarboxylation sequence†
Cite this:DOI: 10.1039/c4cc09799h
Received 8th December 2014,
Accepted 12th January 2015
Nimmakuri Rajesh and Dipak Prajapati*
DOI: 10.1039/c4cc09799h
www.rsc.org/chemcomm
A novel method for the construction of b,b-disubstituted indanones mainly from readily available starting materials, to avoid multi-step
has been developed via tandem Nakamura addition–hydroarylation– substrate synthesis in the absence of any additives.
decarboxylation process. Indium(III) triflate was demonstrated as
The addition of 1,3-dicarbonyl compounds to unactivated
a versatile multitasking catalyst, which catalyzes three different alkynes is a versatile tool for the construction of C–C bonds.
chemical transformations under one-pot conditions.
Nakamura’s group6 has contributed enormously to this subject
by employing indium salts as an effective catalytic system.
In recent years, the design and development of one-pot, multi- Nakamura reaction involves the addition of indium enolates
tasking catalysis1 has gained much attention because of its to unactivated alkynes to generate a vinylic double bond at the
potential to conjugate multiple reactive centres via various a-position of the carbonyl compound (Scheme 1, path a).
fundamentally different chemical transformations in a tandem Further elaboration of Nakamura products6g is highly attractive
manner under one-pot reaction conditions. The evaluation of due to the presence of potential alkene functionality. The
such catalytic systems for the generation of complex and intramolecular hydroarylation of alkenes7 is a powerful, atom-
valuable molecules from simple starting materials is highly economic method for the construction of aromatic ring-fused
desirable. Indanone is a valuable molecule that serves as a cyclic systems. Various metal-catalyzed protocols were developed
synthetic intermediate2 and exists in numerous natural products to activate the intramolecular hydroarylation process, including
and pharmaceuticals.3 Intramolecular Friedel–Crafts acylation
of 3-arylpropionic acid derivatives4 is the basic approach that
has been studied extensively for the construction of indanone
derivatives. Though this method effectively accesses the target
indanones, it suffers some limitations, like the requirement of
strong acids, elevated temperatures and pre-requisite synthesis
of starting 3-arylproponic acid derivatives. In this regard, the
development of alternative novel approaches is the ongoing
challenging task, which has been addressed with few fruitful
results.5 In 2005, Iwasawa5a and Hayashi5b successfully reported
a novel, rhodium-catalyzed isomerization of a-arylpropargyl
alcohols to b-monosubstituted indanones. Another rhodium-
catalyzed, useful method for the synthesis of b,b-disubstituted
indanones was demonstrated by Hayashi’s group via addition of
arylzinc reagents to aryl alkynyl ketones.5c Recently, enantio-
selective synthesis of substituted indanones5d,e was also achieved.
These novel methods have encouraged us to explore new strategies,
Medicinal Chemistry Division, CSIR-North-East Institute of Science and Technology,
Jorhat, Assam 785006, India. E-mail: dr_dprajapati2003@yahoo.co.uk;
Fax: +91 376 2370011
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Indium-catalyzed tandem strategy.
c4cc09799h
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Substrate scope for indium-catalyzed tandem sequencea
indium salts to generate potential scaffolds (Scheme 1, path b).
In our continuous efforts on indium catalysis,8 we engaged in
monitoring the potential of indium salts in one-pot Nakamura
reaction and the intramolecular hydroarylation of alkenes by
providing the necessary environment to starting substrates. We
envisioned that the aromatic b-keto esters, like ethyl benzoyl-
acetate, would participate in Nakamura reaction with terminal
alkynes, which further undergo a hydroarylation step with the
available double bond functionality under one-pot, indium-
catalyzed conditions to generate b,b-disubstituted indanones.
With this idea, we initiated our work and disclose here a novel,
indium-catalyzed tandem route to b,b-disubstituted indanones
via Nakamura reaction–hydroarylation–decarboxylation sequence
(Scheme 1, path c).
To test our hypothesis, we initiated our study by choosing
ethyl benzoylacetate 1a and phenyl acetylene 2a as the model
substrates. In the preliminary experiment, a model reaction
between 1a and 2a was carried out by employing 10 mol%
indium(III) triflate as a catalyst in toluene at 100 1C for 24 h. To
our delight, the formation of b,b-disubstituted indanones in
51% yield was observed. It was quite exciting to note that, in
addition to our expected Nakamura addition–hydroarylation
sequence, decarboxylation also took place in the one-pot condi-
tion to generate b,b-disubstituted indanones. It is well known that
decarboxylation of b-keto esters9 can be achieved under metal-
catalyzed conditions. With this promising unexpected result, we
dedicated our attention to studying this novel tandem reaction in
detail. Increase in yield (62%) was observed when we carried out
the model reaction in refluxing toluene for 16 h. As the reaction is
believed to progress in a tandem manner, we predict that the
isolation of an intermediate (which may be the product of any one
chemical transformation) would provide a clear note about
the reaction pathway. In agreement with Zhang’s report,10 the
a
Reaction conditions: b-ketoester (1 mmol), terminal alkyne (1.2 mmol)
and 10 mol% In(OTf)3 were allowed to react in toluene (6 ml) at reflux
temperature until the reaction was complete. Reaction was carried
out in toluene for 24 h.
b
formation of isomerised Nakamura product 3a0 was observed gave the best result, and thus, it was considered as the
within 5 h in 80% yield (Scheme 2, step a) as E:Z isomeric optimised condition. With the established optimised reaction
mixture. In case of unsubstituted b-keto esters, after the formation conditions, we next initiated the substrate scope study by
of Nakamura product, they would isomerize to a Knoevenagel-type varying a wide range of terminal alkynes. As illustrated in
product.6h Next, a sequential reaction was tried by employing Table 1, several substrates bearing electron-donating and
isomerised Nakamura products under current indium-catalyzed withdrawing groups on the aromatic ring of terminal alkynes
conditions. Gratifyingly, the formation of b,b-disubstituted indanone were well tolerated and underwent the current tandem addition–
3a was observed in 60% yield (Scheme 2, step b).
hydroarylation–decarboxylation process to furnish the desired
In order to figure out the standard reaction conditions, we b,b-disubstituted indanones in low to good yields. It was quite
further carried out optimisation studies with different metal encouraging that in all the cases, complete conversion of pre-
catalysts and solvents (see ESI,† Table S1). These studies formed isomerised addition products was observed. Electron-
revealed that employing 10 mol% In(OTf)3 in refluxing toluene donating substituted terminal alkynes were well tolerated under
the present indium-catalyzed conditions and afforded the target
indanones in 24–62% yield (Table 1, entries 3b–3h). Moderate
yields were observed when an electron-withdrawing group like
halogen was present on the aromatic ring of terminal alkynes;
fluoro and bromo substituted phenyl acetylene produce 3i and 3j
with 45% and 42% yield, respectively. Sterically hindered
terminal alkynes, for example 1-ethnyl-2,4,6-trimethyl benzene,
were ineffective in the present study; even addition product
was also not observed (Table 1, entry 3bb). Dimethylamino-
substituted terminal alkyne was inhibited entirely, perhaps
Scheme 2 Sequential study.
because of the coordination of the amino group to the indium(III)
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
Table 2 Tandem Nakamura addition–hydroarylation of terminal alkynes
with 1-benzoylacetonea
a
Reaction conditions: 1-benzoylacetone (1 mmol), terminal alkyne
(1.2 mmol) and 10 mol% In(OTf)3 were refluxed in toluene (6 ml) until
the reaction was complete.
atom (Table 1, entry 3aa). In turn, variation in other substrates, e.g.
ethyl benzoylacetate, were tried (Table 1, entries 3k–3q). These
studies revealed that electron-rich ethyl benzoylacetates (4-Me and
3-Me) undergo the tandem sequence smoothly with various
terminal alkynes to afford the desired products in 38–65% yield
(Table 1, entries 3k–3n). Halogen-substituted ethyl benzoylacetates
significantly reduced the conversion and shifted the yield towards
the lesser side (Table 1, entries 3o–3q).
In order to enhance the versatility of the reaction, we next
monitored the feasibility of 1,3-diketones instead of b-keto
esters under the present standard conditions. Initially, a reac-
tion between 1-benzoylacetone 4 and phenyl acetylene 2a was
tried by employing 10 mol% indium triflate as a catalyst in
refluxing toluene for 12 h (Table 1, entry 5a). As we expected,
Scheme 3 Possible mechanism.
the reaction had progressed through tandem Nakamura addi- aspects of decarboxylative allylation (DcA) reactions11 and
tion–hydroarylation sequence to generate b,b-disubstituted p-toluenesulfonic acid-promoted elimination reactions of b-keto
indanone (enol form) 5a with acetyl group at a-position in esters.12 We predicted that the reaction had progressed through
75% yield. With this result, the scope of terminal alkynes was the decarboxylative generation of indium enolate, followed by
tested with respect to 1-benzoylacetone, and the results are elimination process. The reaction is initiated by the oxidative
summarized in Table 2. In all cases, tandem addition–hydro- addition of indium triflate with b-keto carboxylate E to generate
arylation process took place exclusively and furnished the indium b-keto carboxylate Fa, which then undergoes decarboxy-
target products within 6–14 h in good to moderate yields lation to produce indium enolate Fb. Finally, indium enolate
(Table 2, entries 5b–5e). However, exploration of benzoyl- undergoes the elimination process to furnish the final product
1,1,1-trifluoroacetone as a 1,3-diketone partner completely G, along with the removal of ethylene and regeneration of
failed under the current tandem conditions.
catalyst for the next cycle.
On the basis of our sequential study, a plausible mechanism
In summary, we have developed a novel route for the assembly
is proposed in Scheme 3. The reaction is initiated with the of b,b-disubstituted indanones through a tandem indium-catalyzed
generation of indium enolate6a Aa from In(OTf)3 and b-keto Nakamura addition–hydroarylation and decarboxylation sequence.
ester, which further adds across the terminal alkyne to form Indium(III) triflate has shown remarkable ability to catalyze three
alkenyl indium intermediate Ab. Protonation of alkenyl indium fundamentally different chemical reactions under one-pot condi-
Ab by b-keto ester results in the formation of addition product tions in the absence of any additives or co-catalysts to generate
B and regeneration of indium enolate for further cycle. Addition indanone derivatives in low to good yields. Exploration of the
product B0 tautomerizes to enol form B and undergoes isomer- Nakamura addition product for further synthetic elaboration was
ization to afford Knoevenagel type product C. In the next step, successfully demonstrated, and sequential studies were carried out
indium activates the double bond functionality in C, which with the isolated isomerized addition intermediate. Further studies
further hydroarylates to form alkylindium7a intermediate Da. are in progress to develop more novel tandem processes by utilizing
Later on, aromatization with concomitant acid release generates indium salts as a versatile multitasking catalyst.
the intermediate Db, and subsequent protonolysis of the carbon–
We thank CSIR New Delhi for financial support of this work
indium bond affords the product E. Finally, removal of the ester under Network Project ORIGIN (CSC0108). NR thanks UGC,
group from E can be explained on the basis of mechanistic New Delhi for the award of a research fellowship. We also thank
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
6 (a) M. Nakamura, K. Endo and E. Nakamura, J. Am. Chem. Soc., 2003,
125, 13002–13003; (b) K. Endo, T. Hatakeyama, M. Nakamura and
E. Nakamura, J. Am. Chem. Soc., 2007, 129, 5264–5371; (c) M. Nakamura,
K. Endo and E. Nakamura, Org. Lett., 2005, 7, 3279–3281; (d) H. Tsuji,
I. Tanaka, K. Endo, K.-i. Yamagata, M. Nakamura and E. Nakamura,
Org. Lett., 2009, 11, 1845–1847; (e) Y. Itoh, H. Tsuji, K.-i. Yamagata,
K. Endo, I. Tanaka, M. Nakamura and E. Nakamura, J. Am. Chem. Soc.,
2008, 130, 17161–17167; ( f ) T. Fujimoto, K. Endo, H. Tsuji,
M. Nakamura and E. Nakamura, J. Am. Chem. Soc., 2008, 130,
4492–4496; (g) M. Nakamura, K. Endo and E. Nakamura, Adv. Synth.
Catal., 2005, 347, 1681–1686; (h) H. Tsuji, K.-i. Yamagata, Y. Itoh,
K. Endo, M. Nakamura and E. Nakamura, Angew. Chem., Int. Ed.,
2007, 46, 8060–8062.
7 (a) K. Xie, S. Wang, P. Li, X. Li, Z. Yang, X. An, C.-C. Guo and Z. Tan,
Tetrahedron Lett., 2010, 51, 4466–4469; (b) B. Cacciuttolo, P. Ondet,
S. Poulain-Martini, G. Lemiere and E. Dunach, Org. Chem. Front.,
2014, 1, 765–769; (c) R. K. Thalji, K. A. Ahrendt, R. G. Bergman and
J. A. Ellman, J. Org. Chem., 2005, 70, 6775–6781; (d) H. Harada,
R. K. Thalji, R. G. Bergman and J. A. Ellman, J. Org. Chem., 2008, 73,
6772–6779; (e) B. Cacciuttolo, S. Poulain-Martini and E. Dunach,
Eur. J. Org. Chem., 2011, 3710–3714; ( f ) S. W. Youn, S. J. Pastine and
D. Sames, Org. Lett., 2004, 6, 781–784.
8 (a) R. Sarma and D. Prajapati, Chem. Commun., 2011, 47, 9525–9527;
(b) R. Sarma, N. Rajesh and D. Prajapati, Chem. Commun., 2012, 48,
4014–4016; (c) N. Rajesh and D. Prajapati, RSC Adv., 2014, 4,
32108–32112; (d) N. Rajesh, R. Sarma and D. Prajapati, Synlett,
2014, 1448–1452; (e) M. M. Sarmah, D. Bhuyan and D. Prajapati,
Synlett, 2013, 2245–2248; ( f ) D. Prajapati, R. Sarma, D. Bhuyan and
W. Hu, Synlett, 2011, 627–630; (g) K. C. Lekhok, D. Prajapati and
R. C. Boruah, Synlett, 2008, 655–658; (h) H. N. Borah, D. Prajapati
and R. C. Boruah, Synlett, 2005, 2823–2825.
the Director, NEIST, Jorhat, for his keen interest and constant
encouragement.
Notes and references
1 For review on multifunctional catalysis see: A. Ajamian and
J. L. Gleason, Angew. Chem., Int. Ed., 2004, 43, 3754–3760. For recent
examples see: (a) Y. Yamamoto, K. Matsui and M. Shibuya, Org. Lett.,
2014, 16, 1806–1809; (b) Y. Ma, S. Zhang, S. Yang, F. Song and J. You,
Angew. Chem., Int. Ed., 2014, 53, 7870–7874; (c) B. Gabriele, L. Veltri,
R. Mancuso and C. Carfagna, Adv. Synth. Catal., 2014, 356,
2547–2558; (d) A. R. Almeida, R. D. Dias, C. J. P. Monteiro,
A. R. Abreu, P. M. P. Gois, J. C. Bayon and M. M. Pereira, Adv. Synth.
Catal., 2014, 356, 1223–1228; (e) L. Guo, F. Zhang, W. Hu, L. Li and
Y. Jia, Chem. Commun., 2014, 50, 3299–3302; ( f ) Y. Liu, H. Wang and
J.-P. Wan, J. Org. Chem., 2014, 79, 10599–10604.
2 (a) D. L. J. Clive, M. Sannigrahi and S. Hisaindee, J. Org. Chem., 2001,
66, 954–961; (b) H. Sugimoto, Pure Appl. Chem., 1999, 71, 2031–2037;
(c) H. Schumann, O. Stenzel and F. Girgsdies, Organometallics, 2001,
20, 1743–1751.
3 (a) S. Jane DeSolms, O. W. Woltersdorf Jr, E. J. Cragoe Jr, L. S. Watson
and G. M. Fanelli Jr, J. Med. Chem., 1978, 21, 437–443; (b) H. Sugimoto,
Y. Iimura, Y. Yamanishi and K. Yamatsu, J. Med. Chem., 1995, 38,
4821–4829; (c) T. Ito, T. Tanaka, M. Iinuma, K.-i. Nakaya, Y. Takahashi,
R. Sawa, J. Murata and D. Darnaedi, J. Nat. Prod., 2004, 67, 932–937;
(d) D. G. Nagle, Y.-D. Zhou, P. U. Park, V. J. Paul, I. Rajbhandari,
C. J. G. Duncan and D. S. Pasco, J. Nat. Prod., 2000, 63, 1431–1433;
(e) M. Banerjee, R. Mukhopadhyay, B. Achari and A. K. Banerjee, J. Org.
Chem., 2006, 71, 2787–2796; ( f ) M. Banerjee, R. Mukhopadhyay,
B. Achari and A. K. Banerjee, Org. Lett., 2003, 5, 3931–3933.
4 (a) D.-M. Cui, C. Zhang, M. Kawamura and S. Shimada, Tetrahedron Lett.,
2004, 45, 1741–1745; (b) E. Fillion, D. Fishlock, A. Wilsily and J. M. Goll,
J. Org. Chem., 2005, 70, 1316–1327; (c) E. Fillion and D. Fishlock, Org.
Lett., 2003, 5, 4653–4656; (d) R. Rendy, Y. Zhang, A. McElrea, A. Gomez
and D. A. Klumpp, J. Org. Chem., 2004, 69, 2340–2347; (e) B. V. Ramulu,
9 (a) N. Chatani, H. Tatamidani, Y. Ie, F. Kakiuchi and S. Murai, J. Am.
Chem. Soc., 2001, 123, 4849–4850; (b) J.-F. Detalle, A. Riahi,
V. Steinmetz, F. Henin and J. Muzart, J. Org. Chem., 2004, 69,
6528–6532; (c) J. T. Mohr, T. Nishimata, D. C. Behenna and
B. M. Stoltz, J. Am. Chem. Soc., 2006, 128, 11348–11349.
A. G. K. Reddy and G. Satyanarayana, Synlett, 2013, 868–872; ( f ) S. El- 10 J. Zhang, P. G. Blazecka, P. Angell, M. Lovdahl and T. T. Curran,
Sayrafi and S. Rayyan, Molecules, 2001, 6, 279–286. Tetrahedron, 2005, 61, 7807–7813.
5 (a) H. Yamabe, A. Mizuno, H. Kusama and N. Iwasawa, J. Am. Chem. 11 For recent review see: J. D. Weaver, A. Recio, III, A. J. Grenning and
Soc., 2005, 127, 3248–3249; (b) R. Shintani, K. Okamoto and T. Hayashi,
J. Am. Chem. Soc., 2005, 127, 2872–2873; (c) R. Shintani and T. Hayashi,
Org. Lett., 2005, 7, 2071–2073; (d) T. Matsuda, M. Shigeno, M. Makino
and M. Murakami, Org. Lett., 2006, 8, 3379–3381; (e) J. A. Brekan,
J. A. Tunge, Chem. Rev., 2011, 111, 1846–1913. For clear discussion
on competitive substitution and elimination pattern see:
K. Chattopadhyay, R. Jana, V. W. Day, J. T. Douglas and
J. A. Tunge, Org. Lett., 2010, 12, 3042–3045.
T. E. Reynolds and K. A. Scheidt, J. Am. Chem. Soc., 2010, 132, 12 (a) S.-O. Lawessson, E. H. Larsen, G. Sundstrom and H. J. Jakobsen,
1472–1473; ( f ) P. Wessig, C. Glombitza, G. Muller and J. Teubner,
J. Org. Chem., 2004, 69, 7582–7591.
Acta Chem. Scand., 1963, 17, 2216–2220; (b) S.-O. Lawessson,
M. Dahlen and C. Frisell, Acta Chem. Scand., 1962, 16, 1191–1198.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015