Ruthenium(II)-Catalyzed Cyclization of Aromatic Acids with Allylic

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Ruthenium(II)-Catalyzed Cyclization of Aromatic Acids with Allylic Acetates via Redox-Free Two-Fold Aromatic/Allylic C−H Activations: Combined Experimental and DFT Studies Subramanian Jambu, Masilamani Tamizmani, and Masilamani Jeganmohan* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India S Supporting Information *

ABSTRACT: A Ru(II)-catalyzed, redox-free, two-fold aromatic/ allylic C−H bond activation of aromatic acids with allylic acetates to give (Z)-3-ylidenephthalides is described. In the reaction, H2 was formed as a side product. The detailed mechanistic investigation and DFT studies including the transition-state analysis support the postulate that the C−H allylation takes place at the ortho position of aromatic acids with allylic acetates followed by intramolecular cyclization at the allylic C(sp3)−H via a π-allylruthenium intermediate.

T

he transition-metal-catalyzed, chelation-assisted cyclization of substituted aromatics with carbon−carbon πcomponents is an efficient method for constructing carbocyclic and heterocyclic molecules in a highly selective manner from easily available starting materials.1 Alkynes, alkenes, and allenes are widely used as π-components in cyclization reactions.1 In this regard, allyl electrophiles are not well-utilized as a πcomponent for the cyclization reaction.2,3 Generally, allyl electrophiles such as allylic halides, acetates, or carbonates reacted with substituted aromatics, providing allylated or vinylated aromatics.2a Usually, an acetate or carbonate base is needed to activate the C−H bond of aromatics along with the metal catalyst via a chelation-assisted deprotonation pathway.2a Very recently, we observed that an acetate group of allyl acetate itself acts a base to deprotonate the C−H bond apart from the allylation (Figure 1).2f,g Thus, this type of allylation reaction can be performed in the redox-free version without any oxidant.

This type of reactivity was not observed with other allylating agents such as allylic halides or carbonates. Transition-metal-catalyzed selective allylic C−H functionalization of substituted α-olefins with nucleophiles via π-allyl metal intermediates is a powerful method for synthesizing γsubstituted alkene derivatives.4 Palladium, rhodium, and iridium complexes are widely used as a catalyst for this type of reaction. Herein, we report an unprecedented ruthenium(II)-catalyzed, redox-free, two-fold C−H activation such as aromatic C−H allylation of aromatic acids with allylic acetates followed by allylic C−H oxidation of ortho-allylated aromatic acids.5 The method provides 3-ylidenephthalide derivatives in good to excellent yields with easily available benzoic acids and allylic acetates. It is important to note that the 3-ylidenephthalide skeleton is found in various natural products and biologically active molecules.6 It is noteworthy to say that the ortho allylation of benzoic acids with allylic acetates is not known in the literature.7 Similarly, a ruthenium(II)-catalyzed allylic C−H oxidation of ortho-allylated benzoic acids via π-allylruthenium intermediate is also not known in the literature. The allylation and allylic C−H addition were performed in the ruthenium(II) oxidation state in the redox-free version. The proposed reaction mechanism was strongly supported by deuterium-labeling studies, mechanistic investigations, and DFT studies, including transition-state studies. When 2-methoxybenzoic acid (1a) was treated with allyl acetate (2a) in the presence of [{RuCl2(p-cymene)}2] (5 mol %) and K2CO3 (2 equiv) in DMF at 100 °C for 12 h, (Z)-3ylidenephthalides 3aa was observed in 86% isolated yield with

Figure 1. Redox-neutral aromatic/allylic C−H activations.

Received: February 13, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b00533 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 99% Z-stereoselectivity (Scheme 1). In the reaction, green and environmentally benign H2 was formed as a side product. The

3ma−oa in 70%, 55%, and 60% yields, respectively. Similarly, 2naphthoic acid (1p) yielded product 3pa in 86% yield in a highly regioselective manner. In these substrates 1m−p, C−H bond activation takes place at the less hindered C6 or C3 position. In the reaction of 3,5-dimethoxybenzoic acid 1q, ortho-allylated 3-ylidenephthalide 3qa was observed in 71% yield. The reaction of p-methoxybenzoic acid (1r), benzoic acid (1s), and 4-acetylbenzoic acid (1t) with 2a yielded the expected cyclized products 3ra−ta in 38%, 30%, and 35% yields, respectively. In addition, ortho-vinylated 3-ylidenephthalides 4ra−ta were also observed in 40%, 35%, and 40% yields, respectively. When the reaction of 1a with 2a was attempted in ClCH2CH2Cl solvent instead of DMF, ortho-vinylated benzoate 5aa was observed in 70% yield, in which the COOH group of benzoic acid alkylated with ClCH2CH2Cl (Scheme 3). Similarly, 1b, 1f, and 1h also successfully provided orthovinylated benzoates 5ba−da in 51%, 46%, and 53% yields, respectively.

Scheme 1. Cyclization of 2-Methoxybenzoic Acid

liberation of H2 gas was confirmed by gas chromatography with a TCD detector (for detailed optimization studies, see the Supporting Information). The scope of the cyclization reaction was examined with various substituted aromatic acids 1b−t (Scheme 2). The Scheme 2. Scope of Aromatic Acids

Scheme 3. Ortho Vinylation of Aromatic Acids

The scope of the reaction was further examined with substituted allylic acetates. The reaction was compatible with γsubstituted allylic acetates 2b−h (Scheme 4). However, αScheme 4. Ortho Allylation of Benzoic Acids

reaction of o-methyl (1b), phenyl (1c), bromo (1d), chloro (1e), fluoro (1f), and acetyl (1g) benzoic acids reacted with 2a, giving products 3ba−ga in 68%, 73%, 40%, 75%, 55%, and 72% yields, respectively. The Z-stereoselectivity of the product 3ca was confirmed by single-crystal X-ray crystallography. 2,3Dimethoxy (1h), 2,5-dimethoxy (1i), and 2,4-dimethoxy (1j) benzoic acids provided products 3ha−ja in 78%, 90%, and 86% yields, respectively. 2,4,5-Trimethoxy (1k) and 3,4,5-trimethoxy (1l) benzoic acids afforded products 3ka and 3la in moderate 52% and 33% yields, respectively. The cyclization reaction was also highly regioselective with unsymmetrical benzoic acids. The reaction of 3,4-dimethyl (1m), 3,4-dimethoxy (1n), and 3methyl (1o) benzoic acids with 2a provided cyclized products

methyl- and β-methyl-substituted allyl acetates were not suitable for the reaction. γ-Methyl (2b), ethyl (2c), n-butyl (2d), and n-pentyl (2e) substituted allyl acetates reacted with 1i in ClCH2CH2Cl, yielding ortho-allylated benzoates 6ab−ae in 77% 65%, 63%, and 55% yields, respectively, with 3:1 to 2:1 E/Z ratio. γ-Phenyl-substituted allyl acetates 2f−h were also effectively involved in the reaction with 1i, followed by alkylation with MeI in K2CO3, providing ortho-allylated B

DOI: 10.1021/acs.orglett.8b00533 Org. Lett. XXXX, XXX, XXX−XXX

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reaction of 1r with 2a provided cyclized product D-3ra in 32% yield with 25% deuterium incorporation at the ortho position. In addition, ortho-vinylated, cyclized product D-4ra was observed in 35% yield with 40% deuterium incorporation at the methyl group of the exo double bond as well as 18% and 40% deuterium incorporation at the vinyl and methyl positions. This result clearly reveals that the cyclization reaction proceeds via π-allylruthenium intermediate and that the C−H activation is a reversible process. Meanwhile, we have tried to isolate the key five-membered ruthenacycle intermediate in the reaction of 1j with a stoichiometric amount of [{RuCl2(p-cymene)}2]. However, we failed to isolate the key metalacycle intermediate. However, the preruthenium intermediate 9a was isolated in 95% yield. Later, 9a was converted into product 3ja in the presence of 2a and K2CO3. A possible reaction mechanism was proposed to account for the present redox-free cyclization reaction (Scheme 7). The

benzoates 6af−ah in 83%, 65%, and 80% yields, respectively, with high E-stereoselectivity. To understand the observation of various products such as cyclization of 3 vs vinylation of 5 vs allylation of 6 in Schemes 2−4, DFT calculations were carried out (Scheme 5). The orthoScheme 5. DFT Calculations

vinylated benzoate 5aa is stabilized by −4.7 kcal mol−1 over that of the ortho-allylated benzoate. This isomerization is found to be exergonic and thermodynamically feasible. Thus, this isomerization takes place nicely and is also crucial for the cyclization reaction. However, in the case of γ-substituted allylic acetates 2b−h, only ortho-allylated benzoates were observed. In particular, products 6aa and 6af are stabilized by −9.6 and −20.4 kcal mol−1, respectively, over the corresponding orthovinylated benzoates. Thus, this isomerization is found to be endergonic and may be thermodynamically unfeasible. The ester groups of substituted benzoates 5aa and 6aa were converted into substituted benzoic acids 7aa and 7ba in 85% and 81% yields, respectively, in the presence of LiOH in THF/ MeOH/H2O (4:1:1) at 80 °C for 48 h (eqs 1 and 2).

Scheme 7. Proposed Mechanism

reaction of aromatic acid 1 with [{RuCl2(p-cymene)}2] in the presence of K2CO3 provided a ruthenium carboxylate complex 9. Complex 9 undergoes ortho-metalation via a concerted deprotonation pathway, providing a five-membered ruthenacycle intermediate 10. Coordinative insertion of the alkene bond of 2 into the Ru−carbon bond of intermediate 10 followed by β-acetate elimination affords ortho-allylated benzoate−ruthenium adduct 13. Coordination of the double bond of the alkene with a ruthenium species followed by OAcmediated deprotonation at the allylic C(sp3)−H provides πallylruthenium intermediate 14. Protonation of the η1 C−Ru bond of intermediate 14 by RCO2H provides ortho-vinylated ruthenium species 15. Intramolecular Wacker-type addition of the oxygen atom of CO2−Ru at the double bond of intermediate 15 provides intermediate 16. β-Hydride elimination of intermediate 16 affords cyclized product 3 and a ruthenium hydride species 17. Later, intermediate 17 reacts with RCOOH, liberating H2 gas and regenerating the active catalyst 9. Product 3 can also be formed via intramolecular migratory insertion at the hindered η1 C−Ru bond of intermediate 18 followed by protonation to provide intermediate 16. To support the proposed mechanism, detailed DFT calculations were performed (Figure 2) at the BP86/6-

To understand the reaction mechanism, the following reactions were performed. Treatment of 4-methoxybenzoic acid (1r) with CD3COOD under the optimized reaction conditions gave D-1r in 96% yield with 15% deuterium incorporation at both ortho carbons (Scheme 6). Further, the Scheme 6. Mechanistic Studies

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DOI: 10.1021/acs.orglett.8b00533 Org. Lett. XXXX, XXX, XXX−XXX

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Figure 2. Gibbs free energy profile (kcal/mol) obtained at the BP86/6-31G*, SDD(Ru) level of theory in MeCN solvent.

mol−1. The overall energy barrier for transformation of intermediate 16 via pathway B is found to be 39.0 kcal mol−1. Thus, pathway B is disfavored in comparison with pathway A. The formation of a less the hindered η1 C−Ru type π-allylruthenium intermediate 14 is more favorable for the cyclization reaction as compared with hindered η1 C−Ru type π-allylruthenium intermediate 18. The observation of 76% deuterium incorporation at the methyl group of the exo double bond in product D-3ra strongly supports the formation of intermediate 14 (Scheme 6). In particular, the palladiumcatalyzed allylic C−H activation proceeds via intermediate 18.4a,b The present ruthenium-catalyzed allylic C−H activation prefers intermediate 14. In conclusion, we have described the facile synthesis of (Z)3-ylidenephthalides and ortho-allylated and vinylated benzoic acids via a Ru(II)-catalyzed redox-neutral reaction of aromatic acids with allylic acetates. The isomerization of the double bond of ortho-allylated benzoic acid into the vinylated benzoic acid plays a crucial role for the cyclization reaction. In the reaction, green and environmentally benign H2 was formed as a side product. The mechanism involving two-fold aromatic/allylic C−H bond activation for the cyclization was strongly supported by a detailed mechanistic investigation, deuteriumlabeling studies, and DFT studies, including the transition-state analysis.

31G(d), SDD(Ru) level of theory in acetonitrile (MeCN) as the continuum solvent.5e Concerted metalation−deprotonation of the ortho C−H bond of benzoic acid 1 takes place via TS-1, forming a five membered metalacycle intermediate 10 in the presence of LRu(OR)2 9 and K2CO3. The ortho C−H bond is activated by an acetate moiety of active intermediate 9′ via agostic interaction. The overall C−H activation barrier is found to be 12.8 kcal mol−1. The replacement of acetic acid by allyl acetate 2 in intermediate 10 forms intermediate 11 exothermically (−4.2 kcal mol−1). Insertion of the double bond of allyl acetate into the Ru−C bond takes place via TS-2, which forms intermediate 12. Intermediate 12 undergoes β-acetate elimination via TS-3 to afford ortho-allylated benzoate−ruthenium adduct 13 exothermically (−28.8 kcal mol−1). There are two possible pathways for product formation. In pathway A, protonation of intermediate 13 by acetic acid provides orthoallylated benzoic acid 8. Subsequently, product 8 undergoes isomerization in the presence of catalyst 9 and RCO2H, providing intermediate 7. This alkene isomerization proceeds via π-allylruthenium intermediate 14 (see Scheme 6) (2.9 kcal mol−1). Protonation of the η1 C−Ru bond of intermediate 14 by RCO2H is crucial for the isomerization. Later, intramolecular Wacker-type addition of the oxygen atom of CO2− Ru at the double bond of intermediate 15 provides intermediate 16. The overall energy barrier for Wacker-type addition is −3.3 kcal mol−1 exergonic. β-Hydride elimination of intermediate 16 affords cyclized product 3 via TS-5 and a ruthenium hydride species 17. TS-5 is crucial for the formation of product 3 with a high Z-selectivity in which the β-hydrogen of the intermediate 16 was activated by the ruthenium metal in a syn fashion where the corresponding hydrogen is trans to the methyl group. Later, intermediate 17 reacts with RCOOH to liberate H2 gas and regenerate the active catalyst 9 exothermically (−4.9 kcal mol−1). In pathway B, the acetate moiety deprotonates the allylic C−H bond to provide the hindered η1 C−Ru bond of intermediate 18 with 24.5 kcal mol−1. Subsequent intramolecular migratory insertion of oxygen into the Ru−C bond of intermediate 18 is endergonic by 14.5 kcal

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00533. General experimental procedure, characterization details, computational details, and Cartesian coordinate of all molecules (PDF) Accession Codes

CCDC 1823693 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge D

DOI: 10.1021/acs.orglett.8b00533 Org. Lett. XXXX, XXX, XXX−XXX

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Jeganmohan, M. Chem. Sci. 2017, 8, 4130. (h) Hu, F.; Szostak, M. Org. Lett. 2016, 18, 4186. (i) Nareddy, P.; Jordan, F.; Szostak, M. Chem. Sci. 2017, 8, 3204. (6) (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213. (b) Danoun, G.; Mamone, P.; Gooben, L. J. Chem. - Eur. J. 2013, 19, 17287. (c) Zhang, M.; Zhang, H. J.; Han, T.; Ruan, W.; Wen, T. B. J. Org. Chem. 2015, 80, 620. (d) Han, W. J.; Pu, F.; Fan, J.; Liu, Z. W.; Shi, X. Y. Adv. Synth. Catal. 2017, 359, 3520 and references cited therein. (7) Selected benzoic acid reviews and papers: (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (b) Ruiz, S.; Villuendas, P.; Urriolabeitia, E. P. Tetrahedron Lett. 2016, 57, 3413. (c) Manikandan, R.; Jeganmohan, M. Chem. Commun. 2017, 53, 8931. (d) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864. (e) Pichette Drapeau, M.; Gooßen, L. J. Chem. - Eur. J. 2016, 22, 18654. (f) Chinnagolla, R. K.; Jeganmohan, M. Chem. Commun. 2012, 48, 2030. (g) Mei, R.; Zhu, C.; Ackermann, L. Chem. Commun. 2016, 52, 13171. (h) Mei, R.; Zhang, S. K.; Ackermann, L. Org. Lett. 2017, 19, 3171. (i) Zhang, J.; Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144. (j) Mandal, A.; Sahoo, H.; Dana, S.; Baidya, M. Org. Lett. 2017, 19, 4138.

via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], mjeganmohan@iitm. ac.in. ORCID

Masilamani Tamizmani: 0000-0002-7168-6041 Masilamani Jeganmohan: 0000-0002-7835-3928 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the DST-SERB (EMR/2014/000978), India, for support of this research. S.J. thanks the CSIR for a fellowship. M.T. thanks the IITM for a postdoctoral fellowship.

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DOI: 10.1021/acs.orglett.8b00533 Org. Lett. XXXX, XXX, XXX−XXX