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Beilstein Journal of Organic Chemistry logoLink to Beilstein Journal of Organic Chemistry
. 2013 Oct 14;9:2097–2102. doi: 10.3762/bjoc.9.246

Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines

Amit Kumar 1,2, Dipak D Vachhani 1, Sachin G Modha 1,3,, Sunil K Sharma 2, Virinder S Parmar 2, Erik V Van der Eycken 1,
Editor: Thomas J J Müller
PMCID: PMC3817510  PMID: 24204421

Abstract

An Ugi four-component reaction of propargylamine with 3-formylindole and various acids and isonitriles produces adducts which are subjected to a cationic gold-catalyzed diastereoselective domino cyclization to furnish diversely substituted spiroindolines. All the reactions run via an exo-dig attack in the hydroarylation step followed by an intramolecular diastereoselective trapping of the imminium ion. The whole sequence is atom economic and the application of a multicomponent reaction assures diversity.

Keywords: alkynes, gold, indoles, multicomponent, spiroindolines, Ugi

Introduction

The importance of nitrogen containing heterocyclic molecules in chemical biology is undisputed. The synthesis of such biologically interesting heterocycles is generally target-oriented, inspired by nature or randomly directed. In all these cases the design of a synthetic sequence to produce a library of diversely substituted molecules is the first and most important step. The basic concept of diversity-oriented synthesis (DOS) involves short reaction sequences, a strong focus on bond construction, and functional group compatibility [13]. Reactions that involve multiple bond formation, such as multicomponent reactions [49] and tandem reactions [1016], are very useful in this context.

As an efficient activator of alkynes, gold has recently attracted a lot of attention [1736]. Many tandem approaches have been reported which utilize this coinage metal for the construction of variously substituted complex molecules [3743]. We have recently reported a post-Ugi gold-catalyzed intramolecular domino cyclization sequence which produces spiroindolines (Scheme 1) [44]. The first step in this sequence is an Ugi four-component reaction (Ugi-4CR) [45] with 2-alkynoic acid as an alkyne source. The second step is a cationic gold-catalyzed intramolecular hydroarylation tandem cyclization to produce spiroindolines with complete diastereoselectivity. This synthetic sequence is atom economic and mild conditions are applied to generate a very complex molecular structure from readily available starting materials. Based on this work and our continuous interest in transition metal catalysis [4554], multicomponent reactions [5557] and the chemistry of the indole core [5860], we herein report a post-Ugi gold-catalyzed intramolecular domino cyclization sequence for the synthesis of spiroindolines with propargylamines as an alkyne source (Scheme 1).

Scheme 1.

Scheme 1

Gold-catalyzed approaches towards spiroindolines.

Results and Discussion

The use of benzoic acid as an acid component in the Ugi-4CR did not produce the Ugi-adduct in good yield even after a prolonged reaction time. Therefore, we switched to phenylacetic acid. The Ugi-4CR of indole-3-carboxaldehyde (1a), propargylamine (2a), phenylacetic acid (3a) and tert-butylisonitrile (4a) in methanol at 50 °C gave the Ugi-adduct 5a with an excellent yield of 94%. With compound 5a in hand we were keen to apply the previously developed conditions for intramolecular hydroarylation [44]. Reaction of 5a with 5 mol % of Au(PPh3)SbF6 in chloroform at room temperature produced the desired spiroindoline 6a in a moderate yield of 55% along with some unidentified byproducts (Table 1, entry 1). The use of a protic acid with a gold catalyst is known in the literature [6164]. To our delight, when the above reaction was carried out with 1 equivalent of trifluoroacetic acid (TFA) the yield was improved to 81% (Table 1, entry 2). Apart from being a good proton source TFA might be working as a coligand.

Table 1.

Optimization for the intramolecular hydroarylation.a

graphic file with name Beilstein_J_Org_Chem-09-2097-i001.jpg

Entry Catalyst (mol %) Acid (1 equiv) Time h % Yieldb

1 Au(PPh3)SbF6 (5) 2 55c
2 Au(PPh3)SbF6 (5) TFA 2 81
3 PtCl2 (5) 10 d
4 PtCl2 (5) TFA 10 d
5 TFA 10 d
6 Au(PPh3)SbF6 (5) PTSA 2 70

aAll the reactions were run on 0.1 mmol scale of 5a with chloroform (2 mL) as a solvent at rt. bIsolated yields. cUnidentified byproducts were formed. dNo conversion.

Experiments with PtCl2 as a catalyst did not show any conversion and the starting material was recovered quantitatively (Table 1, entries 3 and 4). In absence of the gold catalyst no product could be observed (Table 1, entry 5). The application of p-toluenesulfonic acid (PTSA) instead of TFA did not improve the outcome (Table 1, entry 6).

Having the optimized conditions in hand (Table 1, entry 2), various Ugi-adducts 5b–q were synthesized and subjected to this hydroarylation domino cyclization sequence (Table 2). Different substituents are well-tolerated and the sprioindolines were obtained in good to excellent yields. A methyl substituent on the indole nitrogen did not hamper the domino cyclization (Table 2, entries 4, 6, 11, 12, 14, 15). Substituents like tert-butyl, cyclohexyl and n-butyl on the isonitrile are well-tolerated for the domino cyclization on the second position of the indole (Table 2, entries 1–16). Regarding the substituents coming from the acid part, tert-butyl gave a decreased yield probably due to steric hindrance (Table 2, entry 5). It is noteworthy that the gold-catalyzed intramolecular hydroarylation exclusively gives the exo-dig product in all cases and with complete diastereoselectivity.

Table 2.

Scope and limitations of intramolecular domino cyclization.a

Entry Ugi adduct 5 Spiroindolines 6 (+/−) Entry Ugi adduct 5 Spiroindolines 6 (+/−)

1 Inline graphic
5b, 87%
Inline graphic
6b, 70%
9 Inline graphic
5j, 89%
Inline graphic
6j, 75%
2 Inline graphic
5c, 86%
Inline graphic
6c, 60%
10 Inline graphic
5k, 63%
Inline graphic
6k, 80%
3 Inline graphic
5d, 69%
Inline graphic
6d, 76%
11 Inline graphic
5l, 77%
Inline graphic
6l, 74%
4 Inline graphic
5e, 72%
Inline graphic
6e, 66%
12 Inline graphic
5m, 74%
Inline graphic
6m, 68%
5 Inline graphic
5f, 68%
Inline graphic
6f, 40%
13 Inline graphic
5n, 65%
Inline graphic
6n, 72%
6 Inline graphic
5g, 77%
Inline graphic
6g, 71%
14 Inline graphic
5o, 68%
Inline graphic
6o, 60%
7 Inline graphic
5h, 79%
Inline graphic
6h, 83%
15 Inline graphic
5p, 58%
Inline graphic
6p, 84%
8 Inline graphic
5i, 67%
Inline graphic
6i, 69%
16 Inline graphic
5q, 59%
Inline graphic
6q, 69%

aAll the reaction were run on a 0.2 mmol scale of 5 in a screw capped vial employing the optimal conditions of Table 1. Cy = cyclohexyl, Bn = benzyl, PMB = p-methoxybenzyl, Bu = n-butyl.

A plausible mechanism [30,44] is shown in Scheme 2 with only the R-isomer of the Ugi-adduct 5a to simplify the discussion. The cationic gold coordinates with the terminal alkyne which becomes activated for a nucleophilic attack. This can occur from both sides of the indole core. When the attack occurs from the back side of the indole core, spiro intermediate B will be formed. However, in this spiro intermediate the intramolecular trapping of the imminium ion by the amidic NH is sterically impossible and thus the intermediate reopens to intermediate A. If the attack takes place from the front side of the indole core, intermediate C is formed and trapping is possible. After deprotonation and protodeauration the desired spiroindoline 6a is formed with the stereochemistry of two new stereocenters S.

Scheme 2.

Scheme 2

Plausible mechanism for the domino sequence.

Conclusion

In conclusion we have developed a diversity-oriented post-Ugi gold-catalyzed intramolecular hydroarylation domino cyclization sequence for the diastereoselective synthesis of spiroindolines. The mild reaction conditions and short synthetic sequence are the merits of this method. The flexibility given by the multicomponent reaction assures the generation of diversity.

Experimental

General procedure for the synthesis of spiroindolines 6aq

To a screw capped vial Au(PPh3)Cl (5 mol %) and AgSbF6 (5 mol %) were loaded along with chloroform (2 mL). Ugi product 5 (0.2 mmol) was added followed by TFA (1 equiv), and the reaction mixture was stirred at rt. After completion, the reaction mixture was partitioned between EtOAc (100 mL) and 2 N K2CO3 solution (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% diethyl ether in dichloromethane) to afford compound 6aq.

Supporting Information

File 1

Experimental section.

Acknowledgments

The authors wish to thank the F.W.O [Fund for Scientific Research – Flanders (Belgium)] and the Research Fund of the University of Leuven (KU Leuven) for financial support. A.K. is thankful to EMA2experts (Erasmus Mundus Action 2, Lot 11 Asia: Experts) for providing a doctoral exchange scholarship, and D.D.V. is thankful to EMECW, lot 13 (Erasmus Mundus External Cooperation Window, Lot 13) for providing a doctoral scholarship. The authors thank Ir. B. Demarsin for HRMS measurements.

This article is part of the Thematic Series "Multicomponent reactions II".

Contributor Information

Sachin G Modha, Email: sachinmodha@gmail.com.

Erik V Van der Eycken, Email: erik.vandereycken@chem.kuleuven.be.

References

  • 1.Ruijter E, Scheffelaar R, Orru R V A. Angew Chem, Int Ed. 2011;50:6234–6246. doi: 10.1002/anie.201006515. [DOI] [PubMed] [Google Scholar]
  • 2.Ganem B. Acc Chem Res. 2009;42:463–472. doi: 10.1021/ar800214s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.El Kaïm L, Grimaud L. Mol Diversity. 2010;14:855–867. doi: 10.1007/s11030-009-9175-3. [DOI] [PubMed] [Google Scholar]
  • 4.Dömling A, Ugi I. Angew Chem, Int Ed. 2000;39:3168–3210. doi: 10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  • 5.Dömling A. Chem Rev. 2006;106:17–89. doi: 10.1021/cr0505728. [DOI] [PubMed] [Google Scholar]
  • 6.Ramón D J, Yus M. Angew Chem, Int Ed. 2005;44:1602–1634. doi: 10.1002/anie.200460548. [DOI] [PubMed] [Google Scholar]
  • 7.Dömling A, Wang W, Wang K. Chem Rev. 2012;112:3083–3135. doi: 10.1021/cr100233r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Shriri M. Chem Rev. 2012;112:3508–3549. doi: 10.1021/cr2003954. [DOI] [PubMed] [Google Scholar]
  • 9.Chen Z, Zheng D, Wu J. Org Lett. 2011;13:848–851. doi: 10.1021/ol102775s. [DOI] [PubMed] [Google Scholar]
  • 10.Tietze L F, Rackelmann N. Pure Appl Chem. 2004;76:1967–1983. doi: 10.1351/pac200476111967. [DOI] [Google Scholar]
  • 11.Yang J, Xie X, Wang Z, Mei R, Zheng H, Wang X, Zhang L, Qi J, She X. J Org Chem. 2013;78:1230–1235. doi: 10.1021/jo302404v. [DOI] [PubMed] [Google Scholar]
  • 12.Cheng H-G, Lu L-Q, Wang T, Yang Q-Q, Liu X-P, Li Y, Deng Q-H, Chen J-R, Xiao W-J. Angew Chem, Int Ed. 2013;52:3250–3254. doi: 10.1002/anie.201209998. [DOI] [PubMed] [Google Scholar]
  • 13.El Kaïm L, Grimaud L, Le Goff X-F, Menes-Arzate M, Miranda L D. Chem Commun. 2011;47:8145–8147. doi: 10.1039/c1cc12236c. [DOI] [PubMed] [Google Scholar]
  • 14.Bai B, Li D-S, Huang S-Z, Ren J, Zhu H-J. Nat Prod Bioprospect. 2012;2:53–58. doi: 10.1007/s13659-012-0003-6. [DOI] [Google Scholar]
  • 15.Lajiness J P, Jiang W, Boger D L. Org Lett. 2012;14:2078–2081. doi: 10.1021/ol300599p. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Fan F, Xie W, Ma D. Org Lett. 2012;14:1405–1407. doi: 10.1021/ol3003496. [DOI] [PubMed] [Google Scholar]
  • 17.Fürstner A. Chem Soc Rev. 2009;38:3208–3221. doi: 10.1039/b816696j. [DOI] [PubMed] [Google Scholar]
  • 18.Dyker G. Angew Chem, Int Ed. 2000;39:4237–4239. doi: 10.1002/1521-3773(20001201)39:23<4237::AID-ANIE4237>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  • 19.Hashmi A S K, Hutchings G. Angew Chem, Int Ed. 2006;45:7896–7936. doi: 10.1002/anie.200602454. [DOI] [PubMed] [Google Scholar]
  • 20.Fürstner A, Davies P W. Angew Chem, Int Ed. 2007;46:3410–3449. doi: 10.1002/anie.200604335. [DOI] [PubMed] [Google Scholar]
  • 21.Gorin D J, Sherry B D, Toste F D. Chem Rev. 2008;108:3351–3378. doi: 10.1021/cr068430g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Jiménez-Núñez E, Echavarren A M. Chem Rev. 2008;108:3326–3350. doi: 10.1021/cr0684319. [DOI] [PubMed] [Google Scholar]
  • 23.Li Z G, Brouwer C, He C. Chem Rev. 2008;108:3239–3265. doi: 10.1021/cr068434l. [DOI] [PubMed] [Google Scholar]
  • 24.Arcadi A. Chem Rev. 2008;108:3266–3325. doi: 10.1021/cr068435d. [DOI] [PubMed] [Google Scholar]
  • 25.Hashmi A S K, Rudolph M. Chem Soc Rev. 2008;37:1766–1775. doi: 10.1039/b615629k. [DOI] [PubMed] [Google Scholar]
  • 26.Rudolph M, Hashmi A S K. Chem Soc Rev. 2012;41:2448–2462. doi: 10.1039/c1cs15279c. [DOI] [PubMed] [Google Scholar]
  • 27.Echavarren A M. Nat Chem. 2009;1:431–433. doi: 10.1038/nchem.344. [DOI] [PubMed] [Google Scholar]
  • 28.Jiménez-Núñez E, Echavarren A M. Chem Commun. 2007:333–346. doi: 10.1039/b612008c. [DOI] [PubMed] [Google Scholar]
  • 29.Rudolph M, Hashmi A S K. Chem Commun. 2011;47:6536–6544. doi: 10.1039/c1cc10780a. [DOI] [PubMed] [Google Scholar]
  • 30.Hashmi A S K. Angew Chem, Int Ed. 2010;49:5232–5241. doi: 10.1002/anie.200907078. [DOI] [PubMed] [Google Scholar]
  • 31.Ferrer C, Echavarren A M. Angew Chem, Int Ed. 2006;45:1105–1109. doi: 10.1002/anie.200503484. [DOI] [PubMed] [Google Scholar]
  • 32.Ferrer C, Amijs C H M, Echavarren A M. Chem–Eur J. 2007;13:1358–1373. doi: 10.1002/chem.200601324. [DOI] [PubMed] [Google Scholar]
  • 33.Ferrer C, Escribano-Cuesta A, Echavarren A M. Tetrahedron. 2009;65:9015–9020. doi: 10.1016/j.tet.2009.08.067. [DOI] [Google Scholar]
  • 34.Hashmi A S K, Yang W, Rominger F. Angew Chem, Int Ed. 2011;50:5762–5765. doi: 10.1002/anie.201100989. [DOI] [PubMed] [Google Scholar]
  • 35.Hashmi A S K, Yang W, Rominger F. Chem–Eur J. 2012;18:6576–6580. doi: 10.1002/chem.201200314. [DOI] [PubMed] [Google Scholar]
  • 36.Chaładaj W, Corbet M, Fürstner A. Angew Chem, Int Ed. 2012;51:6929–6933. doi: 10.1002/anie.201203180. [DOI] [PubMed] [Google Scholar]
  • 37.Loh C C J, Badorrek J, Raabe G, Enders D. Chem–Eur J. 2011;17:13409–13414. doi: 10.1002/chem.201102793. [DOI] [PubMed] [Google Scholar]
  • 38.Lu Y, Du X, Jia X, Liu Y. Adv Synth Catal. 2009;351:1517–1522. doi: 10.1002/adsc.200900068. [DOI] [Google Scholar]
  • 39.Xie X, Du X, Chen Y, Liu Y. J Org Chem. 2011;76:9175–9181. doi: 10.1021/jo2017668. [DOI] [PubMed] [Google Scholar]
  • 40.Zhang L. J Am Chem Soc. 2005;127:16804–16805. doi: 10.1021/ja056419c. [DOI] [PubMed] [Google Scholar]
  • 41.Cera G, Crispino P, Monari M, Bandini M. Chem Commun. 2011;47:7803–7805. doi: 10.1039/c1cc12328a. [DOI] [PubMed] [Google Scholar]
  • 42.Cera G, Chiarucci M, Mazzanti A, Mancinelli M, Bandini M. Org Lett. 2012;14:1350–1353. doi: 10.1021/ol300297t. [DOI] [PubMed] [Google Scholar]
  • 43.Liu Y, Xu W, Wang W. Org Lett. 2010;12:1448–1451. doi: 10.1021/ol100153h. [DOI] [PubMed] [Google Scholar]
  • 44.Modha S G, Kumar A, Vachhani D D, Jacobs J, Sharma S K, Parmar V S, Van Meervelt L, Van der Eycken E V. Angew Chem, Int Ed. 2012;51:9572–9575. doi: 10.1002/anie.201205052. [DOI] [PubMed] [Google Scholar]
  • 45.Modha S G, Kumar A, Vachhani D D, Sharma S K, Parmar V S, Van der Eycken E V. Chem Commun. 2012;48:10916–10918. doi: 10.1039/c2cc35900f. [DOI] [PubMed] [Google Scholar]
  • 46.Vachhani D D, Galli M, Jacobs J, Van Meervelt L, Van der Eycken E V. Chem Commun. 2013;49:7171–7173. doi: 10.1039/c3cc43418d. [DOI] [PubMed] [Google Scholar]
  • 47.Modha S G, Mehta V P, Van der Eycken E V. Chem Soc Rev. 2013;42:5042–5055. doi: 10.1039/c3cs60041f. [DOI] [PubMed] [Google Scholar]
  • 48.Kumar A, Vachhani D D, Modha S G, Sharma S K, Parmar V S, Van der Eycken E V. Eur J Org Chem. 2013:2288–2292. doi: 10.1002/ejoc.201300132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Vachhani D D, Sharma A, Van der Eycken E. J Org Chem. 2012;77:8768–8774. doi: 10.1021/jo301401q. [DOI] [PubMed] [Google Scholar]
  • 50.Vachhani D D, Mehta V P, Modha S G, Van Hecke K, Van Meervelt L, Van der Eycken E V. Adv Synth Catal. 2012;354:1593–1599. doi: 10.1002/adsc.201100881. [DOI] [Google Scholar]
  • 51.Vachhani D D, Kumar A, Modha S G, Sharma S K, Parmar V S, Van der Eycken E V. Eur J Org Chem. 2013:1223–1227. doi: 10.1002/ejoc.201201587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Modha S G, Trivedi J C, Mehta V P, Ermolat’ev D S, Van der Eycken E V. J Org Chem. 2011;76:846–856. doi: 10.1021/jo102089h. [DOI] [PubMed] [Google Scholar]
  • 53.Modha S G, Mehta V P, Ermolat’ev D S, Balzarini J, Van Hecke K, Van Meervelt L, Van der Eycken E V. Mol Diversity. 2010;14:767–776. doi: 10.1007/s11030-009-9221-1. [DOI] [PubMed] [Google Scholar]
  • 54.Kumar A, Li Z, Sharma S K, Parmar V S, Van der Eycken E V. Org Lett. 2013;15:1874–1877. doi: 10.1021/ol400526a. [DOI] [PubMed] [Google Scholar]
  • 55.Mehta V P, Modha S G, Ruijter E, Van Hecke K, Van Meervelt L, Pannecouque C, Balzarini J, Orru R V A, Van der Eycken E V. J Org Chem. 2011;76:2828–2839. doi: 10.1021/jo200251q. [DOI] [PubMed] [Google Scholar]
  • 56.Peshkov V A, Pereshivko O P, Van der Eycken E V. Chem Soc Rev. 2012;41:3790–3807. doi: 10.1039/c2cs15356d. [DOI] [PubMed] [Google Scholar]
  • 57.Vachhani D D, Sharma A, Van der Eycken E V. Angew Chem, Int Ed. 2013;52:2547–2550. doi: 10.1002/anie.201209312. [DOI] [PubMed] [Google Scholar]
  • 58.Modha S G, Vachhani D D, Jacobs J, Van Meervelt L, Van der Eycken E V. Chem Commun. 2012;48:6550–6552. doi: 10.1039/c2cc32586a. [DOI] [PubMed] [Google Scholar]
  • 59.Donets P A, Van Hecke K, Van Meervelt L, Van der Eycken E V. Org Lett. 2009;11:3618–3621. doi: 10.1021/ol901356h. [DOI] [PubMed] [Google Scholar]
  • 60.Donets P A, Van der Eycken E V. Synthesis. 2011:2147–2153. doi: 10.1055/s-0030-1260057. [DOI] [Google Scholar]
  • 61.Zhou C-Y, Chan P W H, Che C-M. Org Lett. 2006;8:325–328. doi: 10.1021/ol052696c. [DOI] [PubMed] [Google Scholar]
  • 62.Brand J P, Waser J. Angew Chem, Int Ed. 2010;49:7304–7307. doi: 10.1002/anie.201003179. [DOI] [PubMed] [Google Scholar]
  • 63.Vachhani D D, Modha S G, Sharma A, Van der Eycken E V. Tetrahedron. 2013;69:359–365. doi: 10.1016/j.tet.2012.10.019. [DOI] [Google Scholar]
  • 64.Tubaro C, Baron M, Biffis A, Basato M. Beilstein J Org Chem. 2013;9:246–253. doi: 10.3762/bjoc.9.29. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

File 1

Experimental section.


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