AuCl₃ catalyzed [3 + 2 + 1] cycloaddition: first use of aldehyde as a carbon monoxide-like one carbon synthon for triple C–C coupling

Abstract

A new [3 + 2 + 1] cycloaddition strategy is demonstrated using an aldehyde, an aldimine of a glycine ester and a terminal triple bond with AuCl₃ catalyst. Aldehyde is exploited as the first alternative to the crucial partner CO for triple C–C coupled annulation for the synthesis of novel fused-tricyclic heterocycles.

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The cycloaddition reaction is an attractive synthetic tool in organic chemistry which is most frequently used for the direct construction of valuable ring structures.¹ Since the pioneering discovery of CO insertion reactions from carbene chromium carbonyls,² the formal [3 + 2 + 1] cycloaddition approach has found innovative applications in the direct synthesis of difficult-to-access functionalized cyclohexanone and other valuable compounds.³ Carbon monoxide is the crucial one carbon partner in the cycloaddition assembly for dual C–C coupling. Only a few examples are reported to date which may be due to the unavailability of alternative one carbon synthons. Less hazardous and readily available aldehydes (RCH=O) can be utilized as a one carbon synthon for the [3 + 2 + 1] strategy which has the advantage of a triple C–C coupling involving both C=O and C–H. This approach does not need the specially designed reaction set up required for CO which is undetectable to human senses and a “silent killer”.⁴ We used the aldehyde group of O-propargyl salicylaldehyde (1a, Scheme 1), its terminal alkyne residue and ethyl glycinate aldimine (3a) to undergo a [3 + 2 + 1] cycloaddition through the formation of a complex assembly (I, Scheme 1). The natural polycyclic and fused-chromone pyridines are used as traditional medicines and displayed anticancer, antimalarial, antiulcer, antiinflammatory, antihepatitis, protein kinase and acetylcholine esterase inhibition activities.⁵ In spite of the practical importance of the heterocyclic scaffolds, only a limited number of synthetic methods were developed such as the cycloaddition of nitriles and imines.⁶ Therefore, development of a conceptually different catalytic synthetic approach is desirable to afford a new class of 5H-benzopyrano[4,3-c]pyridines (4).

Scheme 1 [3 + 2 + 1] cycloaddition with one carbon aldehyde synthon.

In our initial experiments we were looking for a powerful metal catalyst for the triple C–C coupled intermolecular cycloaddition between the three, two and one units (I) of 1a and 3a.

To our embarrassment, the [3 + 2 + 1] intermolecular cycloaddition was unsuccessful during our survey with prospective rare-earth⁷ (CeCl₃, Yb(OTf)₃, La(OTf)₃ etc.) and transition metal⁸ catalysts (CuI, FeCl₃, PdCl₂, RuCl₃, RhCl₃, [Ir(COD)Cl]₂, AgOTf, PtBr₂ etc.) under refluxing conditions in toluene. Gold compounds are soft Lewis acids and have recently emerged as a powerful catalyst for alkyne, allene and C–H activated functionalization.⁹ We found AuCl₃ (3 mol%) to be an efficient catalyst to afford the desired compound 5-hydro-1-(2-prop-2-ynyloxyphenyl)-3-ethoxycarbonylbenzopyrano[4,3-c]pyridine (4a) in a 61% yield after refluxing in toluene for 9 h. The moderate yield was attributed to the formation of a small amount of the corresponding intramolecular [3 + 2] cycloaddition product 4-hydro-2-ethoxycarbonyl-1H-benzopyrano[4,3-b]pyrrole (5a) from 3a.

With this initial success we further optimized the [3 + 2 + 1] cycloaddition reaction to prepare the imine 3a in situ and the reaction proceeded smoothly by treatment of 2 mmol of aldehyde (1a) and 1 mmol of glycine ester (2a) to afford 4a with a slightly lower yield (55%, entry 1, Scheme 2). The scope of the reaction was explored with unsubstituted and activated phenyl rings which proceeded well with different glycine esters (4b–o, entries 1–14). The structure of this new class of fused-heterocyclic compounds was established by single crystal XRD. The structure of 4m (Scheme 2) and the spectroscopic data (FT-IR, NMR and ESI-MS) of all the new compounds are in the ESI.† The involvement of the C–H of the aldehyde in the cycloaddition was further confirmed by carrying out a reaction using the corresponding ketimine (3p) and ketone (1h) as the reactants (entry 16) which did not proceed at all. Herein, the terminal triple bond is a crucial partner in the assembly (I, Scheme 1) because the reactions were completely blocked on replacement of the propargyloxy group by allyloxy (1i, 3q, entry 17) and also the methylpropargyloxy group (R² = Me, 1j, 3r, entry 18). Moreover, the free triple bond in the imine (3) has a role during construction of the desired 5H-benzopyrano[4,3-c]pyridine skeleton because the corresponding benzyloxy substituted imine (3s) could not synthesize compound 6s on treatment of 1a in an unsymmetrical coupling reaction (entry 19). The possibility of the AuCl₃-catalyzed [3 + 2 + 1] cycloaddition reaction through formation of an allene-type intermediate¹⁰ was also nullified by executing the reaction with a dimethyl propargyl precursor (3o, entry 15) which afforded the desired tricyclic heterocycle 4o.

Scheme 2 Synthesized 5H-benzopyrano[4,3-c]pyridines (4).

To realize the electronic requirements of the [3 + 2 + 1] reaction in the transition state, crossover experiments were executed between two different imines [3t (R¹ = 3-OMe) and 3m (R¹ = 5-NO₂), Scheme 3] and unsubstituted O-propargyl salicylaldehyde (1a). Interestingly, we observed the occurrence of transimination under the catalytic conditions to form corresponding aldehydes 1A (1a,k) from imines 3 (3t,m), imine 3A from the aldehyde 1a and in situ generated ethyl glycinate (2a) from 3. The construction of the four possible 5H-benzopyrano[4,3-c]pyridines are depicted in Scheme 3. Surprisingly, out of the four possible products, the imine 3t bearing the NO₂ group produced 4a (entry 1, table in Scheme 2) as the sole product which was generated from the relatively electron rich transiminated imine 3a. However, in the second experiment with aldimine (3m) bearing the activated aromatic nucleus afforded the desired compound 4t as a major product along with 4m in 3 : 1 yield ratio. The other two possible compounds were not found in the post reaction mixture. These crossover experiments indicated that the transition state of the new [3 + 2 + 1] cycloaddition reaction is assisted by electron donating and un-favoured by electron withdrawing substituents present in the aromatic ring of the imines (3) and aldehydes (1).

Scheme 3 Cross coupling reaction with the transimination.

Interestingly, Grigg et al.^11a and Tsuge et al.^11b reported the classical [3 + 2] intramolecular 1,3-dipolar cycloaddition (DC) involving Grigg's dipole^11c (path c, II, Scheme 4) generated in situ through 1,2-prototropic shift under heating conditions (1–2 days) using phenyl glycinate and non-terminal alkyne derivatives of 3a to afford the corresponding cycloadduct of III along with dehydrogenated pyrrole (only 3%).¹¹ However, the glycine ester aldimine 3 bearing a non-terminal alkyne was never attempted for the 1,3-DC reaction. Our attempts for the conventional monocatalytic 1,3-dipolar cycloaddition (path c) of 3a under heating conditions to III or the valuable 5a ¹² was unsuccessful. The 1,3-DC reaction with AuCl₃ was also completely arrested on replacement of ≡C–H by ≡C–Me (path b) to afford the desired heterocycle 6. It indicates that the [3 + 2] cycloaddition (path a) is passing through a non-conventional pathway to construct 4a along with 5a. Thus, it is expected that the activation of ≡C–H by AuCl₃ is crucial for executing both the [3 + 2] and [3 + 2 + 1] cycloaddition reactions.

Scheme 4 Non-conventional [3 + 2] intramolecular cycloaddition.

Next, we sought to expand the scope of the C–H activation by the powerful AuCl₃ catalyst in other precursors towards the direct construction of new N-heterocycles. We used aldehyde 7 and imine 8 (Scheme 5) bearing no triple bond. To our delight, it responded well to construct a new class of benzofurano[3,2-c]pyridines (9) involving a new [3 + 2 + 1] strategy. The synthesis of this compound is unknown in the literature.¹³ Herein, the C₃–H bonds of the 3,3-dimethoxyethoxy group of the aldehyde (7) and CH₂ of imine (8) are expected to undergo activation with AuCl₃ and the subsequent elimination of MeOH to afford 9 through the [3 + 2 + 1] cycloaddition.

Scheme 5 A new [3 + 2 + 1] cycloaddition to synthesize benzofurano[3,2-c]pyridine.

In conclusion, we have demonstrated the first example to use aldehyde as a carbon monoxide-like one carbon synthon for a triple C–C coupled [3 + 2 + 1] cycloaddition strategy. AuCl₃ catalyzed multi C–H bond activated formal cycloaddition leads to the construction of valuable tricyclic N-heterocycles such as 5H-benzopyrano[4,3-c]pyridine and benzofurano[4,3-b]pyridine in a single operation. The new [3 + 2 + 1] cycloaddition approach, use of aldehyde for triple C–C coupling one carbon synthon and powerful C–H activation capability of AuCl₃ will find important applications in synthetic chemistry.

Financial support from DST (SR/S1/OC-05/2012 and SR/NM/NS-29/2010), CRNN and research fellowship from CSIR (SPM), India are gratefully acknowledged.

Notes and references

1. (a) A. M. Szpilman and E. M. Carreira, Cycloaddition Reactions, in Silver in Organic Chemistry, John Wiley & Sons, Inc., 2010; (b) K. V. Gothelf and K. A. Jørgensen, Chem. Rev., 1998, 98, 863–909; (c) G. Pandey, P. Banerjee and S. R. Gadre, Chem. Rev., 2006, 106, 4484–4517; (d) N. Chatterjee, P. Pandit, S. Halder, A. Patra and D. K. Maiti, J. Org. Chem., 2008, 73, 7775–7778; (e) F. López and J. L. Mascareñas, Chem.–Eur. J., 2011, 17, 418–428; (f) F. Heaney, Eur. J. Org. Chem., 2012, 3043–3058; (g) S. Diethelm and E. M. Carreira, J. Am. Chem. Soc., 2013, 135, 8500–8503.
2. (a) S. Chan and W. D. Wulff, J. Am. Chem. Soc., 1986, 108, 5229–5236; (b) S. R. Pulley, S. Sen, A. Vorogushin and E. Swanson, Org. Lett., 1999, 1, 1721–1723.
3. (a) S. I. Lee, J. H. Park, Y. K. Chung and S.-G. Lee, J. Am. Chem. Soc., 2004, 126, 2714–2715; (b) T. Fukuyama, Y. Higashibeppu, R. Yamaura and I. Ryu, Org. Lett., 2007, 9, 587–589; (c) L. Busetto, F. Marchetti, R. Mazzoni, M. Salmi, S. Zacchinia and V. Zanotti, Chem. Commun., 2010, 46, 3327–3329; (d) L. Jiao, M. Lin, L.-G. Zhuo and Z.-X. Yu, Org. Lett., 2010, 12, 2528–2531; (e) B.-L. Lu, Y. Wei and M. Shi, Organometallics, 2012, 31, 4601–4609.
4. http://www.redcross.org.
5. (a) J. W. Daly, H. M. Garraffo and T. F. Spande, in Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier, Pergamon, New York, 1999, vol. 13, pp. 1–161; (b) W. Lin, G. Brauers, R. Ebel, V. Wray, A. Berg, Sudarsono and P. Proksch, J. Nat. Prod., 2003, 66, 57–61; (c) Z.-M. Lu, Q.-J. Zhang, R.-Y. Chen and D.-Q. Yu, J. Asian Nat. Prod. Res., 2008, 10, 656–664; (d) P. W. Okanya, K. I. Mohr, K. Gerth, R. Jansen and R. Müller, J. Nat. Prod., 2011, 74, 603–608; (e) V. A. F. F. M. Santos, L. O. Regasini, C. R. Nogueira, G. D. Passerini, I. Martinez, V. S. Bolzani, M. A. S. Graminha, R. M. B. Cicarelli and M. Furlan, J. Nat. Prod., 2012, 75, 991–995.
6. (a) J. A. Varela and C. Saá, Chem. Rev., 2003, 103, 3787–3801; (b) K. Kumari, D. S. Raghuvanshi and K. N. Singh, Tetrahedron, 2013, 69, 82–88; (c) Y. Li, J. Zhu, L. Zhang, Y. Wu and Y. Gong, Chem.–Eur. J., 2013, 19, 8294–8299.
7. D. Dhara, K. S. Gayen, S. Khamarui, P. Pandit, S. Ghosh and D. K. Maiti, J. Org. Chem., 2012, 77, 10441–10449.
8. (a) V. Ritleng, C. Sirlin and M. Pfeffer, Chem. Rev., 2002, 102, 1731–1769; (b) C. Copéret, Chem. Rev., 2010, 110, 656–680; (c) D. Balcells, E. Clot and O. Eisenstein, Chem. Rev., 2010, 110, 749–823; (d) Y. Fujiwara and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 12293–12297; (e) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293–1314; (f) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879–5918; (g) T. Sengupta, K. S. Gayen, P. Pandit and D. K. Maiti, Chem.–Eur. J., 2012, 18, 1905–1909; (h) S. Ghosh, S. Khamarui, K. S. Gayen and D. K. Maiti, Sci. Rep., 2013, 3, 2987,  DOI:10.1038/srep02987.
9. (a) E. Jiménez-Núñez and A. M. Echavarren, Chem. Rev., 2008, 108, 3326–3350; (b) D. Benitez, N. D. Shapiro, E. Tkatchouk, Y. Wang, W. A. Goddard, III and F. D. Toste, Nat. Chem., 2009, 1, 482–486; (c) T. C. Boorman and I. Larrosa, Chem. Soc. Rev., 2011, 40, 1910–1925; (d) B. Biannic and A. Aponick, Eur. J. Org. Chem., 2011, 6605–6617; (e) W. Rao, M. J. Koh, P. Kothandaraman and P. W. H. Chan, J. Am. Chem. Soc., 2012, 134, 10811–10814; (f) R. B. Dateer, B. S. Shaibu and R.-S. Liu, Angew. Chem., Int. Ed., 2012, 51, 113–117.
10. N. Krause and S. K. Hashmi, Modern Allene Chemistry, Wiley-VCH Verlag Gmbh & Co KGaA, Weinheim, 2004, vol. 1.
11. (a) R. Grigg, M. Jordan and J. F. Malone, Tetrahedron Lett., 1979, 20, 3877–3878; (b) O. Tsuge, K. Ueno and K. Oe, Chem. Lett., 1979, 1407–1410; (c) P. Armstrong, R. Grigg, M. W. Jordan and J. F. Malone, Tetrahedron, 1985, 41, 3547–3558.
12. (a) H. E. Ortega, P. R. Graupner, Y. Asai, K. TenDyke, D. Qiu, Y. Y. Shen, N. Rios, A. E. Arnold, P. D. Coley, T. A. Kursar, W. H. Gerwick and L. Cubilla-Rios, J. Nat. Prod., 2013, 76, 741–744; (b) M. Takase, T. Narita, W. Fujita, M. S. Asano, T. Nishinaga, H. Benten, K. Yoza and K. Mullen, J. Am. Chem. Soc., 2013, 135, 8031–8040.
13. L. A. Aksanova, L. M. Sharkova, N. F. Kucherova and V. A. Zagorevskii, Chemistry of Heterocyclic Compounds, in Synthesis of some new condensed benzofuran systems, Springer, 1970, vol. 6, (11), pp. 1478–1479.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, NMR spectra, and CIF file. CCDC 938786. For ESI and crystallographic data in CIF see DOI: 10.1039/c3ra47093h

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