Article Cite This: J. Org. Chem. 2017, 82, 13003−13011
pubs.acs.org/joc
Regioselective C−H Bond Alkynylation of Carbonyl Compounds through Ir(III) Catalysis Xianwei Li,*,† Guocai Wu,† Xiaohang Liu,‡ Zhongzhi Zhu,§ Yanping Huo,*,† and Huanfeng Jiang*,§ †
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, P. R. China BASF Advanced Chemicals Co., Ltd., No. 300, Jiangxinsha Road, 200137 Shanghai, China § School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China ‡
S Supporting Information *
ABSTRACT: Selective C−H bond alkynylation toward modular access to material and pharmaceutical molecules is of great desire in modern organic synthesis. Reported herein is Ir(III)-catalyzed regioselective C−H alkynylation of ketones and esters, which is generally applicable for the rapid construction of molecular complexity. This protocol provides a complementary process for conventional alkyne synthesis. Further functionalization of carbonyl-derived material molecules and pharmaceuticals demonstrates the potential synthetic utility of this methodology.
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INTRODUCTION Alkynes are prevalent across a wide range of molecules from simple building blocks and synthetic intermediates to biomolecules, pharmaceuticals, and natural products. This ubiquity has inspired long-standing research interest for their synthesis both in academia and industry.1 Since the invention of the Sonogashira reaction using Pd/Cu synergistic catalysis,2 a variety of methods have been developed to broaden substrate scope and increase atom and step efficiency for alkyne synthesis.3 Direct C−H bond alkynylation,4 which provides a novel path to introduce and expand molecular complexity, has emerged as a powerful strategy for the construction of structurally diverse alkynes. However, to achieve regioselective C−H alkynylation, either specific substrates5 or introduction of directing groups6 are needed (Scheme 1). For example, Su5a developed oxidative cross-coupling of two C−H bonds for internal alkyne synthesis using polyfluoro-substituted aromatic compounds. As to directing strategy, the nitrogen functionality has been commonly utilized; Loh,6a Li,6b and Glorius6c have independently explored this field using nitrogen functionality-facilitated direct C−H bond alkynylation reactions. Chatani6d and Yu6e achieved amide-directed C(sp3)−H bond alkynylation with Pd(II) catalysis. Carbonyl compounds exist widely in nature as well as in functionalized molecules.7 Due to the weaker coordination ability of the carbonyl functionality (e.g., ester) compared to nitrogen groups, carbonyls are less explored as a directing group in transition metal-catalyzed reactions. The weak interaction between carbonyl group and transition metal makes simultaneous achievement of high activity and selectivity challenging. Direct introduction of a C−C triple bond into carbonyl molecules, which have more synthetic utility for expedient synthesis of materials and pharmaceutical molecules, remains unexplored.8,9 Significantly, the advantages of using carbonyl groups are as follows: (1) they are easily accessible; © 2017 American Chemical Society
Scheme 1. Regioselective C−H Bond Alkynylation via Transition-Metal Catalysis
(2) they allow quick construction of complex molecules directly from commercially available products.
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RESULTS AND DISCUSSION In our continuing research on the introduction of the alkynyl moiety into molecules using alkynyl bromide,10 we were Received: June 27, 2017 Published: November 27, 2017 13003
DOI: 10.1021/acs.joc.7b01489 J. Org. Chem. 2017, 82, 13003−13011
Article
The Journal of Organic Chemistry inspired by the weak coordination strategy11 developed by Yu, Chang, Ackermann, and others. We envisaged that by using a highly reactive metal catalyst (such as Cp*M catalyst,12 which leads to an effective concentration of C−H bonds at the metal center) in combination with a highly electrophilic alkynylation reagent, carbonyl compounds can serve as proper substrates for direct C−H alkynylation.13 To commence our study on direct C−H bond alkynylation, acetophenone 1a was selected as the model substrate, and alkynyl bromide 2 as the alkynylation reagent. As shown in Table 1, various metal catalysts, such as Pd(II), Ru(II), Rh(III),
process. A competition experiment showed that an electronrich aromatic ketone reacts more rapidly than an electron-poor substrate (see Supporting Information). Ortho-, meta-, and para-substituted fluoro and chloro groups were also compatible, furnishing the desired alkynylation products in slightly decreased yields. Halogen-substituted acetophenones (1e, 1f, 1g, 1l) were compatible, thus providing a complementary method for further diversification. Fused heterocyclic aromatic rings, such as pyrrole (1m)-, thiophene (1n)-, and benzofuran (1o)-derived ketones, were readily transformed into functionalized alkynes, which hold synthetic potential for highly conjugated molecules.15 This transformation was sensitive to steric hindrance; for instance, regioslective alkynylation took place at C3-H rather than C1-H in 1q. Notably, the alkenyl Csp2−H bond also unwent alkynlation efficiently, delivering conjugated enyne ketone 3r in good yield; such enyne ketones are versatile synthetic building blocks for the synthesis of functionalized heterocycles and can also serve as metal carbene precursors.16 Besides acetyl ketones, other types of aryl ketones were also good partners for direct C−H alkynylations (Table 3). Notably, halogen-substituted diaryl ketones, which are commonly utilized in materials chemistry, were also good substrates to deliver the alkynyl-functionalized molecules.14 Bioactive molecules, such as 2-phenyl-4H-chromen-4-one (4c), 4H-chromen4-one (4d), and 9H-xanthen-9-one (4e), underwent alkynylation while CC groups remained inert, which demonstrates that the carbonyl group competes with the electronic nature of the substrates. 5H-Dibenzo[a,d][7]annulen-5-one (4f) and diaryl ketones (4g), which can serve as versatile building blocks, also showed good reactivity toward catalytic alkynylation. Moderate regioselectivity was also observed using unasymmetric diaryl ketones. For instance, 5:1 regioselectivity was detected with substrate 4i, exhibiting better performance and reactivity at the position with higher electron density. Notably, substrate 4j, which is a precursor of the pharmaceutical fenofibrate17 (fibrate class of cholesterol-reducing drugs), also underwent dialkynylation in moderate yield. These results encouraged us to further investigate the synthetic utility of this catalytic system with esters substrates.18 As depicted in Table 4, aromatic esters can serve as suitable substrates through ester group-assisted C−H bond alkynylation. The compatibility of amine groups (7b, 7c), even with free N−H amines, allows for further synthetic evaluation. Notably, great efficiency was obtained when employing heterocyclic-substituted esters as substrates, such as 4-ester oxazole 6e; the desired C−H alkynylation proceeded well and provided the alkynylation product in quantitative yield. More significantly, impressive C4-H alkynylation with a C3-ester indole substrate was observed with regioselectivity and efficiency (7f), which demonstrates the synthetic potential of this catalytic alkynylation for quick access to complex molecules. To further demonstrate the effect of directing ability in this catalytic alkynylation reaction, we subjected substrates possessing two directing groups with two available C(sp2)−H bonds to the standard conditions. As summarized in Scheme 2, regioselective C−H alkynylation was observed; significantly, these results demonstrate that the coordination ability of the directing groups is as follows: nitrogen heterocycle > ketone > ester, and amide > ketone. Dialkynylation was observed in Nheterocycle 1zc.18g,19
Table 1. Optimization of Reaction Conditionsa
entry 1 2 3 4 5 6 7 8 9c 10d 11e 12 13f 14 15 16
metal catalyst (mol %) [IrCp*Cl2]2 (2)/AgNTf2 (8) [RhCp*Cl2]2 (2)/AgSbF6 (8) [RuCl2(p-ymene)2]2 (2) /AgSbF6 (8) Pd(OAc)2 (5)/NFSI (200) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (2)/AgNTf2 (8) [IrCp*Cl2]2 (4)/AgNTf2 (16) [IrCp*Cl2]2 (4)/AgNTf2 (16) [IrCp*Cl2]2 (4)/AgNTf2 (16) [IrCp*Cl2]2 (4)/AgNTf2 (16) [IrCp*Cl2]2 (4)/AgNTf2 (16)
additive (mol %/equiv)
yield (%)b
NaOAc (7.5) NaOAc (7.5) NaOAc (7.5)
12 n.d. 7
CsOAc (7.5) HOAc (7.5) HOAc/Li2CO3 NaOAc/AgOAc NaOAc/AgOAc NaOAc/AgOAc NaOAc/AgOAc NaOAc/AgOAc NaOAc/Cu(OAc)2 NaOAc/tBuOOtBu NaOAc/K2S2O8
n.d. n.d. 10 n.d. n.d. 25 46 72 78 86 (85) 6 n.d.
