Gold(I)-catalyzed domino cyclization for the synthesis of polyaromatic heterocycles

Article abstract of DOI:10.3762/bjoc.9.297

Gold(I) complexes have emerged as powerful and useful catalysts for the formation of new C-C, C-O and C-N bonds. Taking advantage of the specificity of [IPrAuNCMe][SbF6] complexes to favor the 5-exo-dig cyclization over the 6-endo-dig pathway, we report a high yielding and efficient method to generate substituted polyaromatic heterocycles under remarkably mild reaction conditions.

Full text of DOI:10.3762/bjoc.9.297

Gold(I)-catalyzed domino cyclization for the
synthesis of polyaromatic heterocycles
Mathieu Morin, Patrick Levesque and Louis Barriault*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2625–2628.
Center for Catalysis Research and Innovation, Department of
Chemistry, University of Ottawa, Ottawa, Canada K1T 1B5
doi:10.3762/bjoc.9.297
Received: 30 August 2013
Accepted: 08 November 2013
Published: 22 November 2013
Email:
Louis Barriault* - lbarriau@uottawa.ca
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Keywords:
catalysis; cyclization; gold(I); gold catalysis; heterocycles;
regioselectivity
Guest Editor: F. D. Toste
© 2013 Morin et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Gold(I) complexes have emerged as powerful and useful catalysts for the formation of new C–C, C–O and C–N bonds. Taking
advantage of the specificity of [IPrAuNCMe][SbF6] complexes to favor the 5-exo-dig cyclization over the 6-endo-dig pathway, we
report a high yielding and efficient method to generate substituted polyaromatic heterocycles under remarkably mild reaction condi-
tions.
Introduction
In the last decade, phosphino and NHC–gold complexes have after an initial bond formation [18]. Indeed, the cyclization of
become prominent catalysts for the addition of nucleophiles to cyclic enol ether 1 using σ-donor ligands such as IPr (L1) [19]
alkenes, alkynes and allenes [1-11]. Owing to the high affinity was exceptionally selective for the 5-exo-dig pathway (1→2)
of gold(I) complexes to C–C π-systems in the presence of other whereas bulky Me4XPhos (L2) [12] gave mainly 6-endo-dig-
functional groups combined by its predictable reactivity pattern, cyclized product 3.
the gold(I)-catalyzed reaction provides tremendous opportuni-
ties for the discovery of new and useful reactions [12]. Results and Discussion
Recently, we [13] and other groups [14-17] reported that diver- During the course of our investigation, we examined the
gent pathway can be obtained by modulating the steric and elec- cyclization of non-cyclic enol ethers. As expected, the cycliza-
tronic properties of the gold(I) catalyst (Scheme 1). The ancil- tion of enol ether 4 using [L2AuNCMe][SbF6] in
lary ligand plays a direct role in the regioselectivity for the first dichloromethane afforded the cyclohexene 5 in 79% yield
bond formation rather than via a common intermediate created (Scheme 2). However, the anticipated 5-exo-dig product 6 was
2625

Beilstein J. Org. Chem. 2013, 9, 2625–2628.
Scheme 1: Gold(I)-catalyzed carbocyclization.
not observed when the catalyst [L1AuNCMe][SbF6] was nitromethane helps to alleviate the charge build-up at the
utilized. Instead, the benzothiophene 7 was isolated in 89% cationic cyclization transition state.
yield. The formation of this unforeseen product can be
explained by the proposed mechanism illustrated in Scheme 2. Substituted aromatic compounds have a fundamental impor-
The gold(I) complexation of alkyne 4 triggers the 5-exo-dig tance in organic and medicinal chemistry as well as in materials.
cyclization to produce intermediate 9. At this point, a nucleo- Although there are many methods to functionalize aromatic
philic addition of the thiophene unit to the carboxonium rings, one can recognize that the above transformation repre-
provides the sulfonium 10 which upon protodeauration and sents an attractive and complementary approach for the syn-
aromatization gives 7 [20-25]. Other polar solvents such as thesis of substituted aromatic rings. Taking advantage of the
acetone and dichloromethane were employed without much high regiospecificity of [L1AuNCMe][SbF6] associated with
success. One might consider that the high polarity of alkyne activation, we examined the scope of the reaction using
Scheme 2: Proposed mechanism for the gold(I)-catalyzed cyclization.
2626

Beilstein J. Org. Chem. 2013, 9, 2625–2628.
various substituted alkynes (Scheme 3). Gold(I)-catalyzed tive for the 5-exo-dig pathway. This Au(I)-catalyzed cycliza-
cyclizations of the enol ether 11a (R1 = p-BrC6H4, R2 = H) tion occurring in cascade provides a direct access to syntheti-
gave the corresponding benzothiophene 12a in 83% yield. The cally useful motifs commonly found in natural products and
use of electron-poor silyl enol ether 11b (R1 = p-NO2C6H4, important medicinally compounds. The application of this
R2 = H) gave the desired product 12b, albeit in lower yield of method in the total syntheses of senaequidolide (13) [26] and
63%. Di- and trisubstituted silyl enol ethers 11c (R1 and ellipticine (14) [27,28] are currently underway and will be
R2 = H) and 11d (R1 = H and R2 = Me) were converted to reported in due course (Figure 1).
benzothiophenes 12c and 12d in 82% and 95% yield, respect-
ively. The synthesis of substituted hydrindene 12e was also
achieved in 85% yield from monosubstituted enyne 11e
(R1 = Ph, R2 = H). Substituted enynes bearing heterocycles
such as indole 11f (R1 and R2 = H) and furan 11g (R1 = Ph and
R2 = H) were effectively transformed to the desired carbazole
12f and benzofuran 12g in 95% yields. It can be noticed that
large substituents at R1 and R2 did not affect the efficiency of
Figure 1: Structure of senaequidolide (13) and ellipticine (14).
the reaction. The gold(I)-catalyzed cyclization of 11h
(R1 = R2 = Ph) and 11i (R1 = Ph and R2 = Me) provided the
corresponding benzothiophenes 12h and 12i in 91% and 87% Experimental
yield, respectively.
General experimental procedure for the Au(I)-catalyzed
cyclization: In a flask equipped with a magnetic stirrer was
added the silyl enol ether 11 (0.101 mmol) followed by
Conclusion
In summary, we have developed a mild and efficient gold(I)- nitromethane (1 mL) and [L1AuNCMe][SbF6] (0.005 mmol).
catalyzed 5-exo-dig polycyclization cascade to prepare an array After stirring overnight, the reaction mixture was concentrated
of substituted aromatic compounds such as benzofuran, in vacuo and the crude mixture was purified by flash chroma-
benzothiophene, carbazole and hydrindene in high yields. The tography (1–5% ethyl acetate/hexanes) to give the desired
use of σ-donor ligands such as IPr (L1) was exceptionally selec- cyclized product 12.
Scheme 3: Gold-catalyzed 5-exo-dig carbocyclization cascade.
2627

Beilstein J. Org. Chem. 2013, 9, 2625–2628.
21.Nieto-Oberhuber, C.; Pérez-Galán, P.; Herrero-Gómez, E.;
Supporting Information
Lauterbach, T.; Rodriguez, C.; López, S.; Bour, C.; Rosellón, A.;
Cárdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269.
doi:10.1021/ja075794x
Supporting Information File 1
Materials and methods, experimental procedures for 4 and
11a–i, characterization data for 5, 7 and 12a–i, 1H and 13C
NMR spectra for all cyclized compounds.
22.Yeh, M.-C. P.; Tsao, W.-C.; Lee, B.-J.; Lin, T.-L. Organometallics 2008,
27, 5326. doi:10.1021/om8005917
23.Pérez-Galán, P.; Martin, N. J. A.; Campaña, A.; Cárdenas, D. J.;
Echavarren, A. M. Chem.–Asian J. 2011, 6, 482.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-297-S1.pdf]
doi:10.1002/asia.201000557
24.Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem., Int. Ed. 2012,
51, 113. doi:10.1002/anie.201105921
25.Brazeau, J.-F.; Zhang, S.; Colomer, I.; Corkey, B. K.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 2742. doi:10.1021/ja210388g
26.Bohlmann, F.; Ziesche, J.; King, R. M.; Robinson, H. Phytochemistry
1980, 19, 2675. doi:10.1016/S0031-9422(00)83942-4
27.Goodwin, S.; Smith, A. F.; Horning, E. C. J. Am. Chem. Soc. 1959, 81,
1903. doi:10.1021/ja01517a031
Acknowledgements
We thank the Natural Sciences and Engineering Research
Council (for an Accelerator and Discovery grants to L.B. and
CREATE scholarship for P.L.), the University of Ottawa (for a
University Research Chair to L.B.) for support of this work.
28.Miller, M. C.; McCarthy, F. O. RSC Adv. 2012, 2, 8883.
doi:10.1039/c2ra20584j
References
1. Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
doi:10.1038/nature05592
2. Jiménez-Núñez, E.; Echavarren, A. M. Chem. Commun. 2007, 333.
doi:10.1039/B612008C
License and Terms
3. Fürtsner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
doi:10.1002/anie.200604335
This is an Open Access article under the terms of the
Creative Commons Attribution License
4. Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. doi:10.1021/cr000436x
5. Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
doi:10.1021/cr068430g
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
6. Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
doi:10.1021/cr068434l
7. Arcadi, A. Chem. Rev. 2008, 108, 3266. doi:10.1021/cr068435d
8. Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917.
doi:10.1016/j.tet.2008.03.083
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
9. Shapiro, N. D.; Toste, F. D. Synlett 2010, 5, 675.
doi:10.1055/s-0029-1219369
The definitive version of this article is the electronic one
which can be found at:
10.Wagner, W. A.; Auzias, M. Angew. Chem., Int. Ed. 2011, 50, 8236.
doi:10.1002/anie.201101603
11.Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3, 2899.
doi:10.1039/c2sc20542d
doi:10.3762/bjoc.9.297
12.Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766.
doi:10.1039/b615629k
13.Barabé, F.; Levesque, P.; Korobkov, I.; Barriault, L. Org. Lett. 2011, 13,
5580. doi:10.1021/ol202314q
14.Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 6348. doi:10.1021/ja901649s
15.Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.;
Goddard, W. A., III; Toste, F. D. Nat. Chem. 2009, 1, 482.
doi:10.1038/nchem.331
16.Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; Fürstner, A.
Angew. Chem., Int. Ed. 2010, 49, 2542. doi:10.1002/anie.200907194
17.Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A., III;
Toste, F. D. Org. Lett. 2009, 11, 4798. doi:10.1021/ol9018002
18.Barabé, F.; Levesque, P.; Sow, B.; Bellavance, G.; Bétournay, G.;
Barriault, L. Pure Appl. Chem. 2013, 85, 1161.
doi:10.1351/pac-con-13-01-02
19.de Frémont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411. doi:10.1021/om050111c
20.Nieto-Oberhuber, C.; López, S.; Echavarren, A. M. J. Am. Chem. Soc.
2005, 127, 6178. doi:10.1021/ja042257t
2628