Ruthenium-catalyzed intramolecular carbocyclization of alkynes with an sp³carbon involving an oxidative deprotonation process

Abstract

A novel RuCl₃-catalyzed intramolecular oxidative hydration–deprotonation–cyclization method was developed for the synthesis of substituted quinolinones. The method serves as the first example of direct carbocyclization of an alkyne with an sp³carbon at the α-position of an amide through an oxidative deprotonation process.

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Quinolinone and its derivatives are widely presented in numerous bioactive natural products, potent pharmaceutical drugs and various functional materials, making their efficient synthesis of great interest.^1–6 These efficient strategies include the effective C–H bond functionalization method.^4–6 However, a significantly more challenging task is to functionalize an sp³ C–H bond version of the reaction, since the reported examples involve only sp² C–H bond functionalization methods, such as arylation of N-arylpropiolamides⁴ or N-(2-haloaryl)-benzamides⁵ (path a in Scheme 1) and amidation of 3-arylacrylamides (path b).⁶ We envisioned that quinolinones could be prepared from the carbocyclization of alkynes with an active sp³carbon at the α-position of a monofunctional carbonyl compound (path c).

Scheme 1 The C–H olefination and cyclization routes.

Generally, activation of this α-position carbon in a monofunctional carbonyl system requires a strong base for deprotonation, leading to a carbon nucleophile or an enol intermediate for valuable organic targets.⁷ Here, we describe a base-free method for the synthesis of 3,4-disubstituted quinolin-2(1H)-one derivatives from ruthenium-catalyzed oxidative deprotonation and carbocyclization reactions of 2-acetamido-N-(2-ethynyl)aryl)acetamides (Scheme 1). To the best of our knowledge, it is the first example of direct carbocyclization of an alkyne with an sp³carbon at the α-position of an amide through an oxidative deprotonation process under neutral conditions.⁸

Ruthenium has proven to be highly efficient for the oxidative functionalization of sp³ C–H bonds in the presence of oxidants (often H₂O₂, t-BuOOH (TBHP) or O₂).^9,10 Thus, our investigation began with the reaction of 2-acetamido-N-methyl-N-(2-(phenylethynyl)phenyl)-acetamide (1a) under previously reported Ru/oxidant (TBHP or H₂O₂) conditions.^9a–f These conditions were inert for the target reaction with a mixture of the C–N bonds decomposition products, which were determined by GC-MS analysis. Gratifyingly, the desired product, 2a, was observed in 9% yield under 10 mol % RuCl₃ and 1 atm O₂ conditions (entry 1, Table 1). We were pleased to find that CuCl₂ could promote the reaction and the best results were observed at 20 mol % CuCl₂ (entries 2–5). While 14% yield of 2a was isolated using 100 mol % CuCl₂ oxidant alone (entry 2), 40 mol % CuCl₂ at 1 atm of O₂ enhanced the yield sharply to 55%, together with two other cyclization by-products 3a and 4a (entry 3). The yield increased slightly to 59% in the presence of 20 mol % CuCl₂ and 1 atm O₂ (entry 4). Notably, air was less effective (entry 6). Among the different reaction temperatures and amounts of RuCl₃ examined, it turned out that 10 mol % RuCl₃ at 120 °C afforded the best results (entries 7–11). It is noted that the reaction cannot take place without Ru catalysis (entry 9). Finally, another solvent, diglyme, was examined and the yield increased slightly (entry 12). The structure of 2a was unambiguously confirmed by the X-ray single-crystal diffraction analysis.†

Table 1 Screening for optimal conditions^a

Entry	RuCl3 (mol %)	[Cu] (mol %)	T/°C	Isolated yield (%)
				2a	3a	4a
a Reaction conditions: 1a (0.3 mmol), H2O (6 equiv.), [Ru], additive, O2 (1 atm) and THF (3 mL) for 10 h. b In argon. c Air (1 atm) instead of O2. d Diglyme (3 mL) instead of THF.
1	RuCl3 (10)	—	120	9	trace	trace
2^b	RuCl3 (10)	CuCl2 (100)	120	14	trace	trace
3	RuCl3 (10)	CuCl2 (40)	120	55	5	6
4	RuCl3 (10)	CuCl2 (20)	120	59	6	6
5	RuCl3 (10)	CuCl2 (10)	120	49	trace	trace
6^c	RuCl3 (10)	CuCl2 (20)	120	16	trace	trace
7	RuCl3 (10)	CuCl2 (20)	100	40	6	4
8	RuCl3 (10)	CuCl2 (20)	130	55	6	9
9	—	CuCl2 (20)	120	0	0	0
10	RuCl3 (5)	CuCl2 (20)	120	45	trace	trace
11	RuCl3 (20)	CuCl2 (20)	120	43	trace	trace
12^d	RuCl3 (10)	CuCl2 (20)	120	65	3	5

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With the optimal reaction conditions in hand, a series of substrates with different functional substituents were examined (Table 2). We found that the analogous amides with the N-methyl group replaced by either a benzyl or an allyl group also successfully underwent the reaction with RuCl₃, CuCl₂ and O₂ in moderate yields (2b–2c). However, substrates bearing an aliphatic n-propyl group in place of the acetyl group lost the activity dramatically (2d). Subsequently, several substituents with an R¹group moiety at the terminal alkyne were investigated under the optimal conditions (2e–2m). For substrates with a methyl-substituted aryl group, the order of activity is ortho > para > meta in terms of yields (2e–2i). Interestingly, the bulky substrate also provided the desired product 2j in 61% yield. It is noted that naphthalen-1-yl-, 4-MeOC₆H₄- or 4-ClC₆H₄-susbtituted substrates are compatible with the optimal conditions (2k–2m). Gratifyingly, cyclohexenylalkyne was also suitable for the reaction (2n), which makes this methodology more useful for the preparation of pharmaceuticals and natural products. However, aliphatic alkyne was unsuitable for the reaction (2o). Two substituents, methyl or fluoro groups, on the N-aryl ring were tolerated and produced the target products 2p–2q in 56% and 28% yields, respectively. It is noteworthy that the yields of 2 were enhanced using diglyme medium (2j, 2m, 2n and 2q).

Table 2 The RuCl3-catalyzed synthesis of quinolinones (2)^a

a Reaction conditions: 1 (0.3 mmol), H₂O (6 equiv.), RuCl₃ (10 mol %), CuCl₂ (20 mol %), O₂ (1 atm) and THF (3 mL) at 120 °C for 10 h. The yield in diglyme is given in parentheses. b For 16 h. c For 36 h.

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Some control experiments are summarized in Scheme 2. The treatment of substrate 1a with H₂¹⁸O, RuCl₃, CuCl₂ and O₂ afforded the corresponding ¹⁸O-containing products, which were determined by GC-MS analysis,† suggesting that the oxygen atom is from water through the hydration reaction (eqn (1) in Scheme 2). Interestingly, a monodeuterated product, 3a-D1D1, was isolated from the corresponding deuterated substrate 1a-D2D2. However, about 20% D was missed in the cyclization reaction (see supplementary information†). Surprisingly, product 3a could be dehydrogenated to product 2a under the standard conditions, even in the presence of CuCl₂ alone.^10,11 Notably, no product 4a was observed from either 2a or 3a under the same conditions. The results in eqns (2) and (3) disclose that the dehydrogenation and isomerization between 2a and 3a took place under the optimal conditions. The value of the intermolecular kinetic isotope effect (k_H/k_D = 2.3) implies that the C–H bond functionalization is the rate-limiting step.^10,12

Scheme 2 Control experiments.

The reaction profiles showed that substrate 1a was consumed completely in 0.5 h. However, the yields of products 2a, 3a and 4a still changed slightly with time after 0.5 h, from a decrease to an increase for 2a, a decrease throughout the reaction for 3a, and from an increase to a decrease for 4a between 0.5–1.5 h (Fig. 1). The yield of 3a has a maximal peak at 0.5 h because some 3a is converted to 2a. The profile of 2a is contrary to that of 4a between 0.5–1.5 h, suggesting that 4a may be from the same intermediate with 2a and this intermediate is stable to some extent between 0.5–1.5 h.† Interestingly, the in situFTIR analysis also indicated that the concentration of the two peaks, 1975 cm⁻¹ and 2128 cm⁻¹, increased in the time period 0–1.5 h during the reaction of 1a in diglyme.†¹³ However, they disappeared after quenching the reaction.

Fig. 1 Reaction profiles (in THF) and data for the in situFTIR analysis (in diglyme) during the reaction of 1a.

A possible mechanism, outlined in Scheme 3, was proposed on the basis of the present results.†^7–13 The oxidation of RuCl₃ produces the active Ru^VOCl₃ species.^9g,10 The complexation of Ru^VOCl₃ with an alkyne and a nitrogen atom affords intermediate A, followed by the addition of Ru^VOCl₃ and H₂O to intermediate A, which yields intermediate B. Isomerization/C–H functionalization of intermediate B gives intermediate C¹⁰ and intermediate D.¹⁴ Reductive elimination of intermediate C results in product 3a. Intermediate D may undergo reductive elimination by two pathways:†^10,13 (1) α-H elimination leading to 2a and (2) α-NHAc elimination to 4a. The conversion of 3a to 2a may proceed via a dehydrogenation of amide/isomerization process in the presence of Ru or/and Cu, which is supported by eqns (2) and (3).^10,11

Scheme 3 Possible mechanism.

In summary, we have developed a novel ruthenium-catalyzed intramolecular carbocyclization of alkynes with an sp³carbon in an amide, including an oxidative deprotonation process. This tandem method is valuable for preparing bioactive amino-substituted quinolinones^1,2 with high functional group compatibility through the oxidative hydration–deprotonation–carbocyclization tandem reaction. The mechanism was also discussed according to the ¹⁸O-labeled experiment, intermolecular kinetic isotope effect experiment and in situFTIR analysis.

This research was supported by the National Natural Science Foundation of China (No. 20872112), Fundamental Research Funds for the Central Universities (Hunan university) and Hunan Provincial Innovation Foundation For Postgraduate for financial support.

Notes and references

1. For selected papers, see: (a) P. Desos, J. M. Lepagnol, P. Morain, P. Lestage and A. A. Cordi, J. Med. Chem., 1996, 39, 197; (b) M. Patel, R. J. McHugh Jr., B. C. Cordova, R. M. Klabe, L. T. Bacheler, S. Erickson-Viitanen and J. D. Rodgers, Bioorg. Med. Chem. Lett., 2001, 11, 1943; (c) P. R. Angibaud, G. C. Sanz, M. G. Venet, P. Muller, Janssen Pharmaceutica NV, EP 1 162 201, 2001; (d) T. Fujioka, S. Teramoto, T. Mori, T. Hosokawa, T. Sumida, M. Tominaga and Y. Yabuuchi, J. Med. Chem., 1992, 35, 3607; (e) A. L. Hopkins, J. Ren, J. Milton, R. J. Hazen, J. H. Chan, D. I. Stuart and D. K. Stammers, J. Med. Chem., 2004, 47, 5912; (f) B. C. Capell, M. Olive, M. R. Erdos, K. Cao, D. A. Faddah, U. L. Tavarez, K. N. Conneely, X. Qu, H. San, S. K. Ganesh, X. Chen, H. Avallone, F. D. Kolodgie, R. Virmani, E. G. Nabel and F. S. Collins, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 15902; (g) P. Cheng, Q. Zhang, Y.-B. Ma, Z.-Y. Jiang, X.-M. Zhang, F.-X. Zhang and J.-J. Chen, Bioorg. Med. Chem. Lett., 2008, 18, 3787; (h) J. M. Kraus, C. L. M. J. Verlinde, M. Karimi, G. I. Lepesheva, M. H. Gelb and F. S. Buckner, J. Med. Chem., 2009, 52, 1639; (i) D. S. Hong, S. M. Sebti, R. A. Newman, M. A. Blaskovich, L. Ye, R. F. Gagel, S. Moulder, J. J. Wheler, A. Naing, N. M. Tannir, C. S. Ng, S. I. Sherman, A. K. E. Naggar, R. Khan, J. Trent, J. J. Wright and R. Kurzrock, Clin. Cancer Res., 2009, 15, 7061.
2. (a) P. Friedlander, Ber. Dtsch. Chem. Ges., 1882, 15, 2572; (b) L. Knorr, Ber. Dtsch. Chem. Ges., 1883, 16, 2593; (c) G. Jones, Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, New York, 1996, vol. 5, p. 167.
3. For papers on the synthesis of quinolinones by transition metal-catalyzed carbonylative annulation, see: (a) A. C. Tadd, A. Matsuno, M. R. Fielding and M. C. Willis, Org. Lett., 2009, 11, 583; (b) Z. Liu, C. Shi and Y. Chen, Synlett, 2008, 1734; (c) G. Battistuzzi, R. Bernini, S. Cacchi, I. De Salve and G. Fabrizi, Adv. Synth. Catal., 2007, 349, 297; (d) R. Bernini, S. Cacchi, G. Fabrizi and A. Sferrazza, Heterocycles, 2006, 69, 99; (e) D. V. Kadnikov and R. C. Larock, J. Org. Chem., 2004, 69, 6772.
4. (a) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633; Pd: (b) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura and Y. Fujiwara, Science, 2000, 287, 1992; (c) C. Jia, W. Lu, J. Oyamada, T. Kitamura, K. Matsuda, M. Irie and Y. Fujiwara, J. Am. Chem. Soc., 2000, 122, 7252; (d) C. Jia, D. Piao, T. Kitamura and Y. Fujiwara, J. Org. Chem., 2000, 65, 7516; (e) D.-J. Tang, B.-X. Tang and J.-H. Li, J. Org. Chem., 2009, 74, 6749; Pt: (f) C. Nevado and A. M. Echavarren, Chem.–Eur. J., 2005, 11, 3155; Au: (g) D. B. England and A. Padwa, Org. Lett., 2008, 10, 3631; Ru: (h) M. Y. Yoon, J. H. Kim, D. S. Choi, U. S. Shin, J. Y. Lee and C. E. Song, Adv. Synth. Catal., 2007, 349, 1725; Lewis acids: (i) C. E. Song, D.-U. Jung, S. Y. Choung, E. J. Roh and S.-G. Lee, Angew. Chem., Int. Ed., 2004, 43, 6183.
5. (a) L.-C. Campeau and K. Fagnou, Chem. Commun., 2006, 1253; (b) L.-C. Campeau, M. Parisien, A. Jean and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581.
6. (a) M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058; (b) K. Inamoto, T. Saito, K. Hiroya and T. Doi, J. Org. Chem., 2010, 75, 3900; (c) S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9585; (d) J. Wencel-Delord, T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011 10.1039/c1cs15083a.
7. (a) D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36, 234; (b) F. Bellina and R. Rossi, Chem. Rev., 2010, 110, 1082; (c) F. Dénès, A. Pérez-Luna and F. Chemla, Chem. Rev., 2010, 110, 2366.
8. For a paper on a Cu-catalyzed oxidative dehydrogenation reaction between an sp³carbon adjacent to a nitrogen atom at the α-position of an amide and an sp C–H bond of a terminal alkyne under neutral conditions, see: L. Zhao and C.-J. Li, Angew. Chem., Int. Ed., 2008, 47, 7075.
9. (a) S.-I. Murahashi, T. Naota and K. Yonemura, J. Am. Chem. Soc., 1988, 110, 8256; (b) S.-I. Murahashi, T. Naota, T. Kuwabara, T. Saito, H. Kumobayashi and S. Akutagawa, J. Am. Chem. Soc., 1990, 112, 7820; (c) S.-I. Murahashi, T. Naota and T. Nakato, Synlett, 1992, 835; (d) S.-I. Murahashi, N. Komiya, H. Terai and T. Nakae, J. Am. Chem. Soc., 2003, 125, 15312; (e) S.-I. Murahashi, T. Nakae, H. Terai and N. Komiya, J. Am. Chem. Soc., 2008, 130, 11005; (f) M.-Z. Wang, C.-Y. Zhou, M.-K. Wong and C.-M. Che, Chem.–Eur. J., 2010, 16, 5723; (g) J. T. Groves, M. Bonchio, T. Carofiglio and K. Shalyaev, J. Am. Chem. Soc., 1996, 118, 8961; For reviews, see: (h) S.-I. Murahashi and N. Komiya, in Modern Oxidation Methods, ed. J.-E. Bkckvall,Wiley-VCH: Weinheim, 2004, p. 165; (i) S.-I. Murahashi, Angew. Chem., Int. Ed. Engl., 1995, 34, 2443; (j) T. Naota, H. Takaya and S.-I. Murahashi, Chem. Rev., 1998, 98, 2599; (k) C.-J. Li, Acc. Chem. Res., 2009, 42, 335.
10. (a) K. Yamaguchi and N. Mizuno, Angew. Chem., Int. Ed., 2003, 42, 1480; (b) Ruthenium in Organic Synthesis, ed. S.-I. Murahashi,Wiley-VCH: Weinheim, 2004; (c) I. W. C. E. Arends, T. Kodama and R. A. Sheldon, in Ruthenium Catalysts in Fine Chemistry; Topics in Organometallic Chemistry, ed. C. Bruneau and P. H. Dixneuf, Springer-Verlag: Berlin, Heidelberg, 2004, vol. 11, p. 277.
11. CuCl₂/O₂ (a) M. Shimizu, H. Orita, T. Hayakawa, K. Suzuki and K. Takehira, Heterocycles, 1995, 41, 773; Ru(OH) x/Al₂O₃: (b) K. Kamata, J. Kasai, K. Yamaguchi and N. Mizuno, Org. Lett., 2004, 6, 3577.
12. (a) W. D. Jones, Acc. Chem. Res., 2003, 36, 140; (b) W. D. Jones and F. Feher, Acc. Chem. Res., 1989, 22, 91.
13. (a) Structure Determination of Organic Compounds, Tables of Spectral Data, 4 ed.; E. Pretsch, P. Bühlmannn, C. Affolter, ed.; Springer-Verlag: Berlin Heidelberg, 2009, p. 269; (b) Y. Hu, J. Liu, Z. Lü, X. Luo, H. Zhang, Y. Lan and A. Lei, J. Am. Chem. Soc., 2010, 132, 3153; (c) Q. Liu, Y. Lan, J. Liu, G. Li, Y.-D. Wu and A. Lei, J. Am. Chem. Soc., 2009, 131, 10201.
14. B. M. Trost and M. T. Rudd, J. Am. Chem. Soc., 2002, 124, 4178.

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Footnotes

† Electronic supplementary information (ESI) available: Table S1, Figs S1(GC-MS analysis), S2 (FTIR analysis) and S3 (the reaction profiles). CCDC reference numbers 832462. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00423a

‡ These authors contributed equally

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