Ruthenium-catalyzed aerobic oxidative coupling of alkynes with 2-aryl-substituted pyrroles

Abstract

Ruthenium-catalyzed aerobic oxidative annulations of alkynes were accomplished with co-catalytic amounts of Cu(OAc)₂·H₂O under ambient air. The C–H/N–H bond functionalization occurred with unparalleled selectivities and ample scope to deliver structural analogs of bioactive marine alkaloids.

---

Introduction

Substituted pyrroles are indispensable structural motifs of, among others, bioactive compounds and functional materials, and therefore their site-selective preparation is of continued strong interest.^1–3 Particularly, oxidative annulation reactions of alkynes by C–H⁴ bond cleavages have lately set the stage for economically attractive, ecologically benign syntheses of fused polycyclic heteroarenes,⁵ the vast majority of which has thus far been accomplished by rhodium catalysis.^6–8 On the contrary, oxidative annulations of alkynes⁹ by benzamides employing significantly less expensive ruthenium catalysts were only very recently disclosed.^10,11 Unfortunately, these ruthenium-catalyzed transformations were as of yet restricted to the use of superstoichiometric amounts of copper(II) or silver(I) salts as the sacrificial oxidants, thereby leading to the formation of stoichiometric amounts of undesired heavy metal by-products. During studies on ruthenium-catalyzed oxidative C–H bond functionalizations with substituted pyrroles, we developed ruthenium-catalyzed oxidative annulations with air as an ideal oxidant, on which we wish to report herein. Thereby, we established a novel access to pyrrolo[2,1-a]isoquinolines, which are indispensable structural motifs of inter alia bioactive lamellarine alkaloids.¹² An additional asset of our ruthenium-catalyzed process is represented by its complementary scope and chemoselectivity as compared to the previously reported rhodium-catalyzed^7,8 transformation that was found by Miura and coworkers.¹³

Results and discussion

At the outset of our studies, we explored representative oxidants and additives for the envisioned ruthenium-catalyzed annulation of alkyne 2a by indole 1a (Table 1). Thus, the C–H/N–H bond functionalization was achieved with the commercially available, inexpensive complex [RuCl₂(p-cymene)]₂ and stoichiometric amounts of Cu(OAc)₂·H₂O as the terminal oxidant (entries 1–3). Interestingly, catalytic amounts of Cu(OAc)₂·H₂O were found to be sufficient, provided that reactions were conducted under an atmosphere of air (entries 4, and 5). While CuBr₂ turned out to be unsuitable as a co-catalyst (entry 6), acetate additives restored the catalytic activity (entries 7–10), thereby highlighting carboxylate assistance¹⁴ to be of crucial importance for the C–H bond functionalization. A noteworthy feature of the optimized aerobic annulation is represented by the use of either distilled or even reagent grade solvent t-AmOH under ambient air, rendering the overall process operationally-simple, and further illustrating the robust nature of the new ruthenium-based catalytic system.

Table 1 Optimization of oxidative annulation with indole 1a^a

Entry	Co-catalyst (mol %)	Additive (mol %)	Yield (%)
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), co-catalyst, t-AmOH (2.0 mL), 100 °C, 22 h; isolated yields. b GC-conversion. c Under N2.
1	---	---	<5%^b
2	Cu(OAc)2·H2O (200)	---	84%^c
3	Cu(OAc)2·H2O (200)	K2CO3 (300)	70%^c
4	Cu(OAc)2·H2O (10)	---	21%^c
5	Cu(OAc)2·H2O (10)	---	82%
6	CuBr2 (10)	---	<5%^b
7	CuBr2 (10)	KPF6 (20)	<5%^b
8	CuBr2 (10)	LiOAc·H2O (20)	16%^b
9	CuBr2 (10)	CsOAc (20)	50%
10	CuBr2 (10)	NaOAc (20)	51%

---

With an optimized catalytic system in hand, we explored its scope in the ruthenium-catalyzed aerobic oxidative annulation of tolane (2a) (Scheme 1). Notably, the aerobic annulation proved to be broadly applicable, and occurred chemoselectively at the N–H functionality of indoles 1. Electron-rich as well as electron-deficient heteroarenes 1 were efficiently converted, with the latter generally furnishing higher isolated yields. Valuable functional groups, such as fluoro, nitro, ester, ketone or aldehyde substituents, were well tolerated by the catalytic system, as were more sterically demanding indoles 1e–1h bearing C–3 substituents.

Scheme 1 Aerobic oxidative annulation with indoles 1.

Moreover, the scope of the novel aerobic annulation included diversely-decorated tolane derivatives 2 as well (Scheme 2).

Scheme 2 Scope of aerobic oxidative annulations of alkynes 2.

Importantly, the ruthenium catalysis was not restricted to the use of 2-aryl-substituted indoles 1, but also allowed for first metal-catalyzed oxidative annulations with pyrroles 4 (Scheme 3). The remarkable chemoselectivity of the catalytic system thereby enabled the preparation of substituted pyrrolo[2,1-a]isoquinolines 5 in a highly regioselective fashion, a structural motif found among others in the biologically active marine lamellarine alkaloids.^3,12,15 Notably, the ruthenium catalyst proved tolerant of valuable electrophilic functional groups, such as esters or enolizable ketones.

Scheme 3 Aerobic oxidative annulation with pyrroles 4.

Further, the aerobic ruthenium-catalyzed annulation displayed an improved chemoselectivity as compared to a recently reported rhodium-catalyzed process.^7,13 For instance, challenging n-alkyl-substituted alkynes 2 gave access to the desired products without the formation of structural isomers (Scheme 4). Hence, the annulated heteroarenes 3 and 5 were isolated in high yields, while a related rhodium-catalyzed transformation was shown to deliver a mixture of products.¹³ The selective transformation of n-alkyl-substituted alkynes 2 also enabled aerobic oxidative annulations with unsymmetrically-substituted alkynes 2i and 2j, which proceeded with synthetically useful regiocontrol.

Scheme 4 Aerobic annulation of n-alkyl-substituted alkynes 2.

Considering the unique selectivity and outstanding efficacy of our ruthenium catalyst, we became interested in understanding its mode of action. To this end, intermolecular competition experiments with an excess of differently substituted indoles 1j and 1n selectively yielded the fluoro-substituted indole 3ja as the sole product (Scheme 5a). Furthermore, electron-deficient alkyne 2e was preferentially converted under the optimized reaction conditions (Scheme 5b).

Scheme 5 Intermolecular competition experiments.

Additionally, an intramolecular competition experiment with meta-fluoro-substituted indole 1o predominantly gave isomer 3oa′ (Scheme 6), which can be rationalized with a deprotonative ruthenation manifold.^14,16,17 Based on our experimental mechanistic studies we hence propose the ruthenium-catalyzed aerobic annulation reaction to take place by concerted, acetate-assisted ruthenation as a key step.¹⁸

Scheme 6 Annulation with meta-fluorophenyl-substituted indole 1o.

Conclusions

In summary, we have reported on the first ruthenium-catalyzed oxidative annulation of alkynes with ambient air as the ideal sacrificial oxidant. The aerobic annulation reactions were accomplished with co-catalytic amounts of Cu(OAc)₂·H₂O employing differently substituted 2-arylindoles. Moreover, the remarkably broad scope of the ruthenium catalyst was exploited for unprecedented oxidative annulations with 2-arylpyrroles to deliver pyrrolo[2,1-a]isoquinolines, structural analogs of bioactive marine alkaloids. The highly selective conversion of n-alkyl-substituted alkynes is a strong testament to the beneficial features which can be achieved in ruthenium-catalyzed annulation processes as compared to previously developed rhodium-catalyzed transformations. Experimental mechanistic studies provided strong evidence for a concerted deprotonative metalation through acetate assistance.

Acknowledgements

Support by the DFG, and the Chinese Scholarship Council (fellowship to L.W.) is gratefully acknowledged.

Notes and references

1. T. Eicher and S. Hauptmann, The Chemistry of Heterocycles, 2nd ed., Wiley-VCH, Weinheim, 2003.
2. Selected recent reviews: (a) R. Vicente, Org. Biomol. Chem., 2011, 9, 6469–6480; (b) S. Cacchi, G. Fabrizi and A. Goggiamani, Org. Biomol. Chem., 2011, 9, 641–652; (c) K. Krüger, A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153–2167; (d) L. Ackermann, Synlett, 2007, 507–526; (e) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875–2911; (f) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873–2920 , and references cited therein.
3. H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264–287.
4. Select recent reviews on metal-catalyzed C–H bond functionalizations: (a) M. C. Willis, Chem. Rev., 2010, 110, 725–748; (b) L. Ackermann and H. K. Potukuchi, Org. Biomol. Chem., 2010, 8, 4503–4513; (c) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Commun., 2010, 46, 677–685; (d) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624–655; (e) K. Fagnou, Top. Curr. Chem., 2010, 292, 35–56; (f) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169; (g) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242–3272; (h) L. Ackermann, R. Vicente and A. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (i) P. Thansandote and M. Lautens, Chem.–Eur. J., 2009, 15, 5874–5883; (j) F. Kakiuchi and T. Kochi, Synthesis, 2008, 3013–3039; (k) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200–205; (l) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238 , and references cited therein.
5. Representative recent reviews: (a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068–5083; (b) S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215–1292; (c) C. Liu, H. Zhang, H. W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780–1824; (d) W.-J. Yoo and C.-J. Li, Top. Curr. Chem., 2010, 292, 281–302 , and references cited therein.
6. For early reports on rhodium-catalyzed oxidative annulations, see: (a) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2007, 9, 1407–1409; (b) D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess and K. Fagnou, J. Am. Chem. Soc., 2008, 130, 16474–16475.
7. A recent review: T. Satoh and M. Miura, Chem.–Eur. J., 2010, 16, 11212–11222.
8. For representative examples illustrating recent progress, see: [Rh] (a) K. Muralirajan, K. Parthasarathy and C.-H. Cheng, Angew. Chem., Int. Ed., 2011, 50, 4169–4172; (b) T. K. Hyster and T. Rovis, Chem. Sci., 2011, 2, 1606–1610; (c) M. P. Huestis, L. Chan, D. R. Stuart and K. Fagnou, Angew. Chem., Int. Ed., 2011, 50, 1338–1341; (d) D. R. Stuart, P. Alsabeh, M. Kuhn and K. Fagnou, J. Am. Chem. Soc., 2010, 132, 18326–18339; (e) F. W. Patureau, T. Besset, N. Kuhl and F. Glorius, J. Am. Chem. Soc., 2011, 133, 2154–2156; (f) T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565–10569; (g) J. Chen, G. Song, C.-L. Pan and X. Li, Org. Lett., 2010, 12, 5426–5429; (h) N. Umeda, H. Tsurugi, T. Satoh and M. Miura, Angew. Chem., Int. Ed., 2008, 47, 4019–4022; [Cu] (i) R. Bernini, G. Fabrizi, A. Sferrazza and S. Cacchi, Angew. Chem., Int. Ed., 2009, 48, 8078–8081; [Pd] (j) J. Wu, X. Cui, X. Mi, Y. Li and Y. Wu, Chem. Commun., 2010, 46, 6771–6773; (k) Z. Shi, S. Ding, Y. Cui and N. Jiao, Angew. Chem., Int. Ed., 2009, 48, 7895–7898 , and references cited therein.
9. For examples of ruthenium-catalyzed cross-dehydrogenative alkenylations, see: (a) L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153–4155; (b) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2011, 13, 706–708; (c) H. Weissman, X. Song and D. Milstein, J. Am. Chem. Soc., 2001, 123, 337–338.
10. (a) L. Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem., Int. Ed., 2011, 50, 6379–6382; see also: (b) L. Ackermann, A. V. Lygin and N. Hofmann, Org. Lett., 2011, 13, 3278–3281.
11. Recent reviews on ruthenium-catalyzed direct C–H bond arylations and alkylations: (a) L. Ackermann and R. Vicente, Top. Curr. Chem., 2010, 292, 211–229; (b) L. Ackermann, Chem. Commun., 2010, 46, 4866–4877.
12. T. Fukuda, F. Ishibashi and M. Iwao, Heterocycles, 2011, 83, 491–529.
13. K. Morimoto, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2010, 12, 2068–2071.
14. L. Ackermann, Chem. Rev., 2011, 111, 1315–1345.
15. For selected references on the synthesis and antitumor activities of lamellarines, see: (a) Q. Li, J. Jiang, A. Fan, Y. Cui and Y. Jia, Org. Lett., 2011, 13, 312–315; (b) C. Ballot, J. Kluza, S. Lancel, A. Martoriati, S. M. Hassoun, L. Mortier, J.-C. Vienne, G. Briand, P. Formstecher, C. Bailly, R. Neviere and P. Marchetti, Apoptosis, 2010, 15, 769–781; (c) S. Su and J. A. Porco, J. Am. Chem. Soc., 2007, 129, 7744–7745; (d) J. Kluza, M.-A. Gallego, A. Loyens, J.-C. Beauvillain, J.-M. Fernandez Sousa-Faro, C. Cuevas, P. Marchetti and C. Bailly, Cancer Res., 2006, 66, 3177–3187; (e) C. Peschko, C. Winklhofer and W. Steglich, Chem. Eur. J., 2000, 6, 1147–1152 , and references cited therein.
16. D. Balcells, E. Clot and O. Eisenstein, Chem. Rev., 2010, 110, 749–823.
17. 2-Aryl-substituted indoles bearing electron-donating groups on the aryl moiety provided less satisfactory results.
18. For studies on the kinetic isotope effect in ruthenium-catalyzed oxidative annulations of alkynes, see ref. [10a].

---

Footnote

† Electronic supplementary information (ESI) available: experimental procedures, characterization data, and ¹H and ¹³C NMR spectra for products. See DOI: 10.1039/c1sc00619c

---