DOI: 10.1002/chem.201501094

Communication

& C H Activation

Radical-Induced Metal-Free Alkynylation of Aldehydes by Direct C H Activation Xuesong Liu,[a] Linqian Yu,[a] Mupeng Luo,[a] Jidong Zhu,*[b] and Wanguo Wei*[a] efficient method to prepare ynones with readily available materials. Recently, direct C H alkynylation reactions have gained a lot of success for the functionalization of a broad range of substrates.[19] Great efforts on this subject have led to the discovery of various transition-metal-catalyzed reactions, as well as metal-free conditions. Although much progress has been made in the development of direct C H alkynylation of aromatic C(sp2) H bonds,[19] as well as C(sp3) H bonds,[20] direct C(sp2) H alkynylation of aldehyde C(O) H, to our knowledge, has not been well documented. This could be ascribed to the high reactivity of the carbonyl group but poor activity of the formyl C H. On the basis of recent advances in metal-catalyzed or metal-free oxidative cross-coupling reactions involving alkynes, we envision that the development of an oxidative alkynylation of the aldehyde C(O) H bonds with alkynyl sources derived from terminal alkynes would provide more efficient and straightforward routes to ynones. Aldehydes have been known to easily generate corresponding acyl radicals in the presence of peroxides.[21] The acyl radical can be used for a variety of direct C C bond-formation reactions.[22] We were thus interested in whether the generated acyl radicals could be efficiently trapped by a suitable alkynylating agent to provide a direct synthesis of ynones from readily available aldehydes. With tert-butyl hydroperoxide (TBHP) as the oxidant, we began our study with benzaldehyde (1 a) as our model substrate while investigating different alkynylation reagents in the absence of transition metal salts (Scheme 1). However, the reaction of benzaldehyde with phenylacetylene

Abstract: A direct C(sp2) H alkynylation of aldehyde C(O) H bonds with hypervalent iodine alkynylation reagents provides ynones under metal-free conditions. In this method, 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol3(1H)-one (TIPS-EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and a,b-unsaturated aldehydes.

Ynones are important structural motifs in organic chemistry, as they serve as key intermediates in the synthesis of various bioactive molecules.[1] More importantly, they represent a basic scaffold for the synthesis of various heterocyclic structures, such as furans,[2] flavones,[3] chromenes,[4] pyrazoles,[5] pyridines,[6] pyrimidines,[7] indenones,[8] and benzodiazepines[9] for numerous applications. Classical methods for synthesizing ynones involve the addition of an acetylide anion to carbonyl electrophiles,[10] Sonogashira coupling of terminal alkynes with acyl halides,[11] or carbonylative Sonogashira of terminal alkynes with aryl halides,[12] aryl triflates,[13] or aryl anilines[14] in the presence of gaseous CO. Other methods, including gold-catalyzed dehydrogenative Meyer–Schuster-like rearrangement, have also been reported.[15] Huang and co-workers reported the direct synthesis of ynones from aldehydes by oxidative C C bond cleavage under aerobic conditions.[16] Very recently, Lei and co-workers disclosed a one-pot synthesis of ynones by direct coupling of terminal alkynes with aldehydes by a nucleophilic addition/Oppenauer oxidation.[17] During the preparation of this report, Li and co-workers reported an IrIII- and RhIII-catalyzed C H alkynylation of benzaldehydes under chelation assistance.[18] These methods, however, often have limitations with respect to functional group tolerance, substrate scope, and practical convenience. Given the recent demand for highly efficient and environmentally friendly processes, there has been growing interest in the development of a direct, simple, and [a] X. Liu, L. Yu, M. Luo, Prof. W. Wei Shanghai Advanced Research Institute, Chinese Academy of Sciences 99 Haike Road, Shanghai 201210 (P. R. China) E-mail: [email protected] [b] Prof. J. Zhu Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 354 Lingling Road, Shanghai 200032 (P. R. China) E-mail: [email protected]

Scheme 1. Oxidative C H alkynylation of benzaldehyde. Reaction conditions: Benzaldehyde 1 a (0.50 mmol), alkyne (0.60 mmol), TBHP (0.75 mmol), 1,2-dichloroethane (5.0 mL), 110 8C, N2, 12 h, in Schlenk tubes. [a] Yield of product isolated by column chromatography. TBHP = tert-butyl hydroperoxide (70 % aqueous solution).

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501094. Chem. Eur. J. 2015, 21, 1 – 6

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Communication conducted in 1,2-dichloroethane at 110 8C in the presence of TBHP under N2 atmosphere did not form the desired cross-coupling product in any detectable amount. Other terminal alkynes, such as 1-heptyne, also failed to give any coupling products. Considering the undesired terminal alkyne homocoupling under oxidative conditions,[23] we investigated various preactivated alkynylating reagents, such as alkynyl halides[24] and benziodoxolone-based hypervalent iodine reagents[25] as coupling partners. After considerable efforts, benziodoxolonederived hypervalent iodine reagents were found to be optimal and furnished desired coupling products. Gratifyingly, when 1[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPSEBX)[26] was employed, the desired ynone 2 a was obtained in 63 % isolated yield (Scheme 1; G = TIPS). While further optimizing the reaction conditions, we discovered that the right choices of solvent, reaction temperature, and oxidant were crucial to minimizing formation of the undesired side product. The reaction worked in a broad range of solvents (Table 1, entries 1–5), with toluene giving the best re-

yield of 2 a was obtained (Table 1, entry 12). During our studies, we found that metal catalysts, such as [{RhCp*Cl2}2], Pd(OAc)2, Cu(OAc)2, AuCl3, had adverse effects on the reaction and only trace amounts of the desired product were formed (Table 1, entries 13–16). Similarly, when AgNO3 (Table 1, entry 17) was employed, the reaction process was also dramatically affected and only 36 % of alkynylation adduct was obtained. This observation suggests that the reaction may proceed through a different mechanism from conventional metalcatalyzed C H alkynylations.[18, 27] Encouraged by this result, we initiated an attempt to synthesize ynones directly from aldehydes and alkynyl source derived from terminal alkynes under metal-free conditions. With the optimized reaction conditions in hand, we converted a variety of commercially aromatic aldehydes into the corresponding ynones to examine the scope of the direct alkynylation protocol (Table 2). Simple alkyl- and alkoxy-substituted aromatic aldehydes were successfully coupled with TIPS-EBX to afford the corresponding ynones in good to excellent yields (2 a–c, 52–91 % yield). Unfortunately, when electron-withdraw-

Table 1. Optimization of the direct C H alkynylation.[a] Table 2. Scope of the alkynylation of (hetero)aryl aldehydes.[a,b]

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Solvent

Oxidant

DCE dioxane THF CH3CN toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene

TBHP TBHP TBHP TBHP TBHP TBHP BPO MnO2 H2O2 K2S2O8 TBPB DTBP DTBP DTBP DTBP DTBP DTBP

Catalyst – – – – – – – – – – – – [{RhCp*Cl2}2] Pd(OAc)2 Cu(OAc)2 AuCl3 AgNO3

T [8C]

Yield [%][b]

110 110 85 85 110 130 130 130 130 130 130 130 130 130 130 130 130

72(63) 34