Letter pubs.acs.org/OrgLett
Construction of Complex 1,3-Cyclohexadienes via PhosphineCatalyzed (4 + 2) Annulations of δ‑Acetoxy Allenoates and Ketones Yuwen Zhang and Xiaofeng Tong* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, 1 Gehu Road, Changzhou, 213164, China S Supporting Information *
ABSTRACT: The phosphine-catalyzed substrate-dependent (4 + 2) annulations of δ-acetoxy allenoates with ketones is described. Allenoates 1 with an alkyl substituent at δC are able to react with cyclic 1,3-diketones 2, wherein the δC is attacked by the methenyl carbon of 2 while the αC attacks the ketone of 2. Allenoates 5 with an aryl group at δC is poised to react with cyclic β-carbonyl amides 6, in which the αC is attacked by the methenyl carbon of 6 and the δC undergoes 1,2-addition to the ketone of 6.
C
Scheme 1. Overview of Phosphine-Catalysed Construction of Cyclic Compounds and Design Plan of This Work
atalytic annulation reactions are actively pursued due to the importance of these processes for rapidly assembling complexity. In this context, phosphine-catalyzed annulations of allenoates have emerged as one of the most powerful strategies for quickly preparing structurally complex molecules.1 Such methods for the construction of various heterocycles and carbocycles are numerous, which include several elegant processes with Lu’s (3 + 2) cycloaddition,2 Kwon’s (4 + 2) annulation,3 and the annulation of γ-alkyl substituted allenoate4 serving as benchmarks (Scheme 1a). Despite these contributions, construction of cyclic 1,3-diene via the phosphine catalysis is unprecedented. Due to our continuous efforts on the phosphine-catalyzed annulations of β′/δ-acetoxy allenoates,5,6 we were attracted to the potential utility of 3-phosphonium-2,4-dienoate A given the presence of multiple reactive sites that might be harnessed subtly to induce disparate bond-forming events (Scheme 1b).6 Cationic intermediate A is generated via the addition− elimination reaction of phosphine and allenoate 1, which has been proven to be a good bis-electrophile toward annulations with bisnucleophiles. By contrast, zwitterionic intermediates are prevailing within the phosphine catalysis, which have proven exceedingly useful for dipole-type annulations with various dipolarophiles (Scheme 1a).1 Obviously, this underlying reaction mechanism cannot be applicable to cyclic diene synthesis. However, we anticipated that cyclic diene would arise from a reaction of A when an appropriate compound, such as anionic ketone 2, was elected as the other annulation partner (Scheme 1b). Following 1,4-addition of 2 to A, phosphonium enolate B would be formed, allowing for α-addition to the attached ketone to deliver C.7 Deprotonation of the activated allylic δH would facilitate the conversion of C into D. Fortunately, D is analogous to the key intermediate of phosphine-catalyzed 1,3-diene isomerization,8 which would ultimately produce 1,3-cyclohexadiene following the same mechanism (Scheme 1b). © 2017 American Chemical Society
1,3-Cyclohexadiene is a common motif in bioactive compounds and natural products (Figure 1).9 They also are useful intermediates in organic synthesis and good ligands for transition metals.10 While several efficient strategies exist for their synthesis, including microbial arene oxidation,11 metalcatalyzed [2 + 2 + 2] cycloaddition,12 Heck reaction,13 and a Michael−Aldol tandem sequence,14 methods with a wider Received: September 6, 2017 Published: September 27, 2017 5462
DOI: 10.1021/acs.orglett.7b02787 Org. Lett. 2017, 19, 5462−5465
Letter
Organic Letters
Scheme 2. Reaction Scope of the (4 + 2) Annulations
Figure 1. Representative bioactive compounds and natural products containing the 1,3-cyclohexadiene motif.
scope and operational simplicity are still needed. With these considerations in mind, we sought to develop a phosphinecatalyzed (4 + 2) annulation that could efficiently assemble 1,3cyclohexadienes from readily available starting materials. This process may represent a new catalytic mode for the phosphinecatalyzed annulation. To confirm the feasibility of the proposed (4 + 2) annulation, we chose 2-methyl-1,3-cyclopentanedione 2a as the required anionic ketone. When the reaction of allenoate 1a and 2a was conducted in toluene at room temperature with the use of PPh3 (20 mol %) as the catalyst and K2CO3 (1.2 equiv) as the base, the desired (4 + 2) annulation product 3aa was isolated only in 7% yield while compound 4 was obtained in 68% yield (Table 1, entry 1). Compound 4 is the product of a competing Table 1. Optimization of Reaction Conditionsa
yield (%)b entry
PR3
base
solvent
temp (°C)
3aa
4
1 2 3 4 5 6
PPh3 PPh3 PBu3 PPh2Me PPh2Me PPh2Me
K2CO3 K2CO3 K2CO3 K2CO3 (iPr)2NEt (iPr)2NEt
PhMe PhMe PhMe PhMe PhMe MeTHF
rt 80 80 80 80 80
7 31
