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

Article abstract of DOI:10.3762/bjoc.9.246

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.

Full text of DOI:10.3762/bjoc.9.246

Post-Ugi gold-catalyzed diastereoselective
domino cyclization for the synthesis of diversely
substituted spiroindolines
Amit Kumar1,2, Dipak D. Vachhani1, Sachin G. Modha*1,3, Sunil K. Sharma2,
Virinder S. Parmar2 and Erik V. Van der Eycken*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2097–2102.
1Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, 3001, Leuven, Belgium, 2Bioorganic
Laboratory, Department of Chemistry, University of Delhi, Delhi-110
007, India and 3Chemistry Building-4.20b, School of Chemistry, The
University of Manchester, Manchester M13 9PL, UK
doi:10.3762/bjoc.9.246
Received: 22 July 2013
Accepted: 13 September 2013
Published: 14 October 2013
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
Email:
Sachin G. Modha* - sachinmodha@gmail.com;
Erik V. Van der Eycken* - erik.vandereycken@chem.kuleuven.be
© 2013 Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
alkynes; gold; indoles; multicomponent; spiroindolines; Ugi
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.
Introduction
The importance of nitrogen containing heterocyclic molecules multiple bond formation, such as multicomponent reactions
in chemical biology is undisputed. The synthesis of such bio- [4-9] and tandem reactions [10-16], are very useful in this
logically interesting heterocycles is generally target-oriented, context.
inspired by nature or randomly directed. In all these cases the
design of a synthetic sequence to produce a library of diversely As an efficient activator of alkynes, gold has recently attracted a
substituted molecules is the first and most important step. The lot of attention [17-36]. Many tandem approaches have been
basic concept of diversity-oriented synthesis (DOS) involves reported which utilize this coinage metal for the construction of
short reaction sequences, a strong focus on bond construction, variously substituted complex molecules [37-43]. We have
and functional group compatibility [1-3]. Reactions that involve recently reported a post-Ugi gold-catalyzed intramolecular
2097

Beilstein J. Org. Chem. 2013, 9, 2097–2102.
domino cyclization sequence which produces spiroindolines with 1 equivalent of trifluoroacetic acid (TFA) the yield was
(Scheme 1) [44]. The first step in this sequence is an Ugi four- improved to 81% (Table 1, entry 2). Apart from being a good
component reaction (Ugi-4CR) [4,5] with 2-alkynoic acid as an proton source TFA might be working as a coligand.
alkyne source. The second step is a cationic gold-catalyzed
intramolecular hydroarylation tandem cyclization to produce Experiments with PtCl2 as a catalyst did not show any conver-
spiroindolines with complete diastereoselectivity. This syn- sion and the starting material was recovered quantitatively
thetic sequence is atom economic and mild conditions are (Table 1, entries 3 and 4). In absence of the gold catalyst no
applied to generate a very complex molecular structure from product could be observed (Table 1, entry 5). The application of
readily available starting materials. Based on this work and our p-toluenesulfonic acid (PTSA) instead of TFA did not improve
continuous interest in transition metal catalysis [45-54], multi- the outcome (Table 1, entry 6).
component reactions [55-57] and the chemistry of the indole
core [58-60], we herein report a post-Ugi gold-catalyzed intra-
Table 1: Optimization for the intramolecular hydroarylation.a
molecular domino cyclization sequence for the synthesis of
spiroindolines with propargylamines as an alkyne source
(Scheme 1).
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 phenyl-
acetic acid. The Ugi-4CR of indole-3-carboxaldehyde (1a),
Entry Catalyst (mol %)
Acid (1 equiv) Time h % Yieldb
propargylamine (2a), phenylacetic acid (3a) and tert-butylisoni-
trile (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 intramo-
lecular 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 [61-
64]. To our delight, when the above reaction was carried out
1
2
3
4
5
6
Au(PPh3)SbF6 (5)
—
2
55c
81
Au(PPh3)SbF6 (5) TFA
2
PtCl2 (5)
PtCl2 (5)
—
—
10
10
10
2
—d
—d
—d
70
TFA
TFA
Au(PPh3)SbF6 (5) PTSA
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.
Scheme 1: Gold-catalyzed approaches towards spiroindolines.
2098

Beilstein J. Org. Chem. 2013, 9, 2097–2102.
Having the optimized conditions in hand (Table 1, entry 2), probably due to steric hindrance (Table 2, entry 5). It is note-
various Ugi-adducts 5b–q were synthesized and subjected to worthy that the gold-catalyzed intramolecular hydroarylation
this hydroarylation domino cyclization sequence (Table 2). exclusively gives the exo-dig product in all cases and with
Different substituents are well-tolerated and the sprioindolines complete diastereoselectivity.
were obtained in good to excellent yields. A methyl substituent
on the indole nitrogen did not hamper the domino cyclization A plausible mechanism [30,44] is shown in Scheme 2 with only
(Table 2, entries 4, 6, 11, 12, 14, 15). Substituents like tert- the R-isomer of the Ugi-adduct 5a to simplify the discussion.
butyl, cyclohexyl and n-butyl on the isonitrile are well-toler- The cationic gold coordinates with the terminal alkyne which
ated for the domino cyclization on the second position of the becomes activated for a nucleophilic attack. This can occur
indole (Table 2, entries 1–16). Regarding the substituents from both sides of the indole core. When the attack occurs
coming from the acid part, tert-butyl gave a decreased yield from the back side of the indole core, spiro intermediate B
Table 2: Scope and limitations of intramolecular domino cyclization.a
Entry
Ugi adduct 5
Spiroindolines 6 (+/−)
Entry
Ugi adduct 5
Spiroindolines 6 (+/−)
1
9
5j, 89%
5b, 87%
6b, 70%
6j, 75%
2
3
4
5
10
11
12
13
5k, 63%
6k, 80%
5c, 86%
6c, 60%
5l, 77%
6d, 76%
5d, 69%
6l, 74%
5m, 74%
5e, 72%
6m, 68%
6e, 66%
5n, 65%
5f, 68%
6f, 40%
6n, 72%
2099

Beilstein J. Org. Chem. 2013, 9, 2097–2102.
Table 2: Scope and limitations of intramolecular domino cyclization.a (continued)
6
7
8
14
15
16
5o, 68%
5g, 77%
6g, 71%
6h, 83%
6i, 69%
6o, 60%
6p, 84%
6q, 69%
5p, 58%
5h, 79%
5q, 59%
5i, 67%
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.
Scheme 2: Plausible mechanism for the domino sequence.
will be formed. However, in this spiro intermediate the intramo- mediate A. If the attack takes place from the front side of the
lecular trapping of the imminium ion by the amidic NH is indole core, intermediate C is formed and trapping is possible.
sterically impossible and thus the intermediate reopens to inter- After deprotonation and protodeauration the desired spiro-
2100

Beilstein J. Org. Chem. 2013, 9, 2097–2102.
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
indoline 6a is formed with the stereochemistry of two new
stereocenters S.
5. Dömling, A. Chem. Rev. 2006, 106, 17–89. doi:10.1021/cr0505728
6. Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
doi:10.1002/anie.200460548
Conclusion
In conclusion we have developed a diversity-oriented post-Ugi
gold-catalyzed intramolecular hydroarylation domino cycliza-
tion sequence for the diastereoselective synthesis of spiroindo-
lines. The mild reaction conditions and short synthetic sequence
are the merits of this method. The flexibility given by the multi-
component reaction assures the generation of diversity.
7. Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
doi:10.1021/cr100233r
8. Shriri, M. Chem. Rev. 2012, 112, 3508–3549. doi:10.1021/cr2003954
9. Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848–851.
doi:10.1021/ol102775s
10.Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983.
doi:10.1351/pac200476111967
Experimental
General procedure for the synthesis of
spiroindolines 6a–q
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
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
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 6a–q.
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
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
15.Lajiness, J. P.; Jiang, W.; Boger, D. L. Org. Lett. 2012, 14, 2078–2081.
doi:10.1021/ol300599p
16.Fan, F.; Xie, W.; Ma, D. Org. Lett. 2012, 14, 1405–1407.
doi:10.1021/ol3003496
17.Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221.
doi:10.1039/b816696j
Supporting Information
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
Supporting Information File 1
Experimental section.
19.Hashmi, A. S. K.; Hutchings, G. Angew. Chem., Int. Ed. 2006, 45,
7896–7936. doi:10.1002/anie.200602454
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-246-S1.pdf]
20.Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410–3449. doi:10.1002/anie.200604335
21.Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108,
3351–3378. doi:10.1021/cr068430g
Acknowledgements
22.Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
3326–3350. doi:10.1021/cr0684319
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.
23.Li, Z. G.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265.
doi:10.1021/cr068434l
24.Arcadi, A. Chem. Rev. 2008, 108, 3266–3325. doi:10.1021/cr068435d
25.Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775.
doi:10.1039/b615629k
26.Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448–2462.
doi:10.1039/c1cs15279c
27.Echavarren, A. M. Nat. Chem. 2009, 1, 431–433.
doi:10.1038/nchem.344
28.Jiménez-Núñez, E.; Echavarren, A. M. Chem. Commun. 2007,
333–346. doi:10.1039/b612008c
References
29.Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536–6544.
doi:10.1039/c1cc10780a
1. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011,
50, 6234–6246. doi:10.1002/anie.201006515
2. Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
doi:10.1021/ar800214s
30.Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232–5241.
doi:10.1002/anie.200907078
31.Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45,
1105–1109. doi:10.1002/anie.200503484
3. El Kaïm, L.; Grimaud, L. Mol. Diversity 2010, 14, 855–867.
doi:10.1007/s11030-009-9175-3
2101

Beilstein J. Org. Chem. 2013, 9, 2097–2102.
32.Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.–Eur. J. 2007, 13,
1358–1373. doi:10.1002/chem.200601324
56.Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.
Chem. Soc. Rev. 2012, 41, 3790–3807. doi:10.1039/c2cs15356d
57.Vachhani, D. D.; Sharma, A.; Van der Eycken, E. V.
Angew. Chem., Int. Ed. 2013, 52, 2547–2550.
33.Ferrer, C.; Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009,
65, 9015–9020. doi:10.1016/j.tet.2009.08.067
34.Hashmi, A. S. K.; Yang, W.; Rominger, F. Angew. Chem., Int. Ed.
2011, 50, 5762–5765. doi:10.1002/anie.201100989
35.Hashmi, A. S. K.; Yang, W.; Rominger, F. Chem.–Eur. J. 2012, 18,
6576–6580. doi:10.1002/chem.201200314
doi:10.1002/anie.201209312
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
36.Chaładaj, W.; Corbet, M.; Fürstner, A. Angew. Chem., Int. Ed. 2012,
51, 6929–6933. doi:10.1002/anie.201203180
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
60.Donets, P. A.; Van der Eycken, E. V. Synthesis 2011, 2147–2153.
doi:10.1055/s-0030-1260057
37.Loh, C. C. J.; Badorrek, J.; Raabe, G.; Enders, D. Chem.–Eur. J. 2011,
17, 13409–13414. doi:10.1002/chem.201102793
38.Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 1517–1522.
doi:10.1002/adsc.200900068
61.Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325–328.
doi:10.1021/ol052696c
39.Xie, X.; Du, X.; Chen, Y.; Liu, Y. J. Org. Chem. 2011, 76, 9175–9181.
doi:10.1021/jo2017668
62.Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 7304–7307.
doi:10.1002/anie.201003179
40.Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804–16805.
doi:10.1021/ja056419c
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
64.Tubaro, C.; Baron, M.; Biffis, A.; Basato, M. Beilstein J. Org. Chem.
2013, 9, 246–253. doi:10.3762/bjoc.9.29
41.Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Chem. Commun. 2011,
47, 7803–7805. doi:10.1039/c1cc12328a
42.Cera, G.; Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M.
Org. Lett. 2012, 14, 1350–1353. doi:10.1021/ol300297t
43.Liu, Y.; Xu, W.; Wang, W. Org. Lett. 2010, 12, 1448–1451.
doi:10.1021/ol100153h
License and Terms
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.
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
doi:10.1002/anie.201205052
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
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
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
47.Modha, S. G.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev.
2013, 42, 5042–5055. doi:10.1039/c3cs60041f
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
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.246
49.Vachhani, D. D.; Sharma, A.; Van der Eycken, E. J. Org. Chem. 2012,
77, 8768–8774. doi:10.1021/jo301401q
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
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
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
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
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
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
2102