Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Dehydrogenative β‑Arylation of Saturated Aldehydes Using Transient Directing Groups Xing-Long Zhang,§ Gao-Fei Pan,§ Xue-Qing Zhu, Rui-Li Guo, Ya-Ru Gao, and Yong-Qiang Wang* Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, People’s Republic of China
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S Supporting Information *
ABSTRACT: An unprecedented cross-dehydrogenative-coupling (CDC) reaction of saturated aldehyde β-C−H with arenes to form cinnamaldehydes via the cleavages of four C− H bonds has been developed. The reaction possesses complete E-stereoselectivity for the CC double bond. The protocol is featured by atom and step economy, mild reaction conditions, and convenient operation.
S
Scheme 1. CDC Reaction of Propionaldehydes with Arenes To Synthesize Cinnamaldehydes
imple aldehydes, such as propionaldehyde, are very important bulk chemical materials.1 Insofar as reactivity is concerned, these aldehydes rely very heavily on their carbonyl moieties (e.g., Grignard reactions, Wittig olefinations, and Aldol condensation) or acidic α-hydrogens (e.g., α-CO oxidations, alkylations, and halogenations).2 Although the equal importance of β-position, the direct β-C−H functionalization of the saturated aldehydes remains difficult, because of the inertness of the β-C−H bonds.3 One potential solution would be a metal-catalyzed redox cascade strategy,4 namely, a metal-mediated oxidative α,β-desaturation, followed by the functionalization on the β-position. However, such a transformation is a challenge, because of the aldehyde’s susceptibility toward oxidation under oxidative conditions,5 and undesired metal insertion into an acyl C−H bond.6 Cross-dehydrogenative-coupling (CDC) reactions, which combine two C−H bonds to form new C−C bonds, represent one of the most ideal synthetic procedures, because it avoids the requirement of prefunctionalized starting materials (i.e., organohalides and/or organometallic species) to make synthetic schemes shorter and more efficient, as well as lower cost and less waste.7 β-Arylation of propionaldehydes is a very appealing transformation, because of the broad application of β-arylated products, particularly cinnamaldehydes,8 which are used as flavoring in ice cream and candy,9 as safe, effective fungicides and insecticides,10 and as corrosion inhibitors for steel and other ferrousalloys.11 Moreover, cinnamaldehydes are versatile building blocks in organic synthesis.12 However, to the best our knowledge, the CDC reaction of saturated aldehyde β-C−H with arene has not been reported to date. Apparently, the realization of such CDC reactions to form cinnamaldehyde must cleave four inert C−H bonds (Scheme 1); therefore, the method is very challenging. To make the process possible, we thought that two aspects should be implemented: (1) for the cleavage of four inert C−H bonds in one step, a more efficient catalytic system should be developed; and (2) to realize regioselective arylation of the βC−H bond of saturated aldehyde, a directing group should be introduced. The directing group could facilitate the carbon− © XXXX American Chemical Society
metalation of β-C−H bond of aldehyde, thereby allowing subsequent coupling readily, and simultaneously prevent susceptible aldehyde groups from being oxidized. In the field of the directing group, undoubtedly, the transient directing group (TDG) is more attractive, because it can be easily removed or detached after the reaction.13 Inspired by elegant and pioneering works of Yu13a and Ge3f,13b et al. on TDG, we started this research. The study commenced with 2-methyl propionaldehyde (1a) and anisol (2a) as model substrates. We initially chose Pd(OAc)2 (10 mol %) as a catalyst, glycine (50 mol %) as a transient directing group, and K2S2O8 (2.0 equiv) as an oxidant, and the reaction was performed in CH3CN at 60 °C for 24 h. Nevertheless, the reaction did not afford any desired product but propionaldehyde drained gradually (Table 1, entry 1). The experiment not only indicated the difficulty of the transformation, but also reminded us that susceptible aldehyde groups were compatible with palladium-catalyzed oxidative systems to an extent, which encouraged us to modify the current palladium catalytic system. Considering that trifluoroacetic acid (TFA) and Pd(OAc)2 can facilitate the generation of more active [Pd(II)O2CCF3]+ species in situ,14 the same reaction was set up again just with TFA (2.0 equiv) introduced in the reaction system. To our delight, the reaction gave the desired product 3a in 10% yield (Table 1, entry 2). Despite a low yield, the result verified the feasibility of our conception. Encouraged by this result, the amount of TFA was investigated, and the best result was gotten when 9.0 equiv Received: February 23, 2019
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DOI: 10.1021/acs.orglett.9b00695 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(10 mol %), amino acid A6 (50 mol %), TFA (9 equiv) at 60 °C. With the optimal reaction conditions in hand, the direct oxidative dehydrogenative arylation was applied to various arenes with 2-methyl propionaldehyde (1a) as the coupling partner (Scheme 2). Benzenes substituted by monoalkoxyl
Table 1. Optimization of Dehydrogenative Arylation of 2Methyl Propionaldehyde with Anisola
Scheme 2. Reactions of Various Arenes with 2-Methyl Propionaldehydea,b entry
Pd source
amino acid
temperature (°C)
TFA (equiv)
yieldb (%)
1 2 3 4 5 6 7 8c 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25d
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 Pd(dba)2 PdCl2 Pd(PPh3)4 Pd(OAc)2
A1 A1 A1 A1 A1 A1 A1 A1 A2 A3 A4 A5 A6 A7 A8 A6 A6 A6 A6 A6 A6 A6 A6 A6 A6
60 60 60 60 60 60 60 60 60 60 60 60 60 60 60 rt 40 80 100 120 60 60 60 60 60
0 2.0 5.0 7.0 9.0 15.0 30.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0 9.0
0 10 23 34 52 45
