Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Pd(0)-Catalyzed Intermolecular Dearomatizing [3 + 2] Spiroannulation of Phenol-Based Biaryls and Allenes Wenjie Hu,‡ Hui Wang,‡ Lu Bai, Jingjing Liu, and Xinjun Luan* Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710127, China S Supporting Information *
ABSTRACT: Readily available phenol-derived biaryls reacted with allenes under palladium catalysis to provide a variety of highly valuable spiro[cyclohexane-1,1′-indene]-2,5-dien-4-ones. This new catalytic process, involving a key step of regioselective allylative dearomatization of phenol, proceeded efficiently through a [3 + 2] spiroannulation pathway by overcoming undesired β-hydride elimination. Preliminary asymmetric studies showed that high enantioselectivity could be realized by using a commercially available PHOX ligand. Moreover, the potential application of this method was exemplified by several further transformations.
S
Scheme 1. Reaction Design Plan
pirocyclohexadienones are key structural motifs in many biologically interesting natural products and pharmaceuticals.1 Moreover, their inherent characteristic with the spirocyclic skeleton and the enone functionality renders them to be a class of synthetically useful building blocks in organic syntheses.2 Thus, there is great interest in the development of practical methods for their rapid assembly from simple precursors. Notably, the use of synthetic protocols involving transition-metal-catalyzed dearomatization of phenols is especially appealing.3 Among them, elegant examples of intramolecular dearomative spirocyclizations,4−7 which were first discovered by the groups of Hamada,4 You,5 and Buchwald,6 were realized by using diversely functionalized phenols with a tethered electrophilic species. Recently, we,8 Gulı ́as,9 Lam,10 and You11 described the intermolecular dearomatizing [3 + 2] annulations of phenol-based biaryls with internal alkynes under oxidative conditions. However, further attempts to adapt allenes for such a potential [3 + 2] spiroannulation proved to be difficult, and the reactions took place via a formal [5 + 1]12 or [5 + 2]13 annulation, which was due to the facile consumption of π-allylmetal intermediate through β-hydride elimination12 or O-allylation.13 In this context, we envisaged using a Pd(0) catalysis strategy, which we recently developed,14 to promote the desired [3 + 2] annulation between halogenated substrates and allenes. Remarkably, allenes generally react with an aryl halide bearing an internal N- or O-nucleophile in the presence of a Pd(0) catalyst to deliver various heterocycles.15 Consequently, allenyl substrates tethered with a phenolic species, which need multistep synthesis, were utilized to facilitate the desired spirocyclization.16 The key challenge facing the development of an intermolecular [3 + 2] spiroannulation of allenes consists in identifying a system that would allow for a chemo- and regioselective attack of a phenolic carbon nucleophile at the πallylpalladium intermediate A (Scheme 1). Herein, we disclose © XXXX American Chemical Society
the successful execution of our design, which leads to the straightforward assembly of spiroindene cyclohexadienones, an attractive structural motif widely found in alkaloids and other bioactive compounds (Figure 1).17 We began the investigation by employing phenol-based biaryl 1a and alkyl-substituted allene 2a as the standard substrates to explore the reaction conditions, and the catalytic results are given in Table 1. With Pd(OAc)2 (5 mol %), PPh3
Figure 1. Representative examples of related natural occurring spiroindene cyclohexadienones. Received: January 3, 2018
A
DOI: 10.1021/acs.orglett.8b00014 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Survey the Scope of Phenol-Based Biaryls
yieldb (%) entry
ligand
solvent
3a
4a
1 2 3 4 5 6 7 8 9 10 11 12 13
PPh3 PCy3 Xphos P(2-furyl)3 BINAP dppm dppf P(2-furyl)3 P(2-furyl)3 P(2-furyl)3 P(2-furyl)3 P(2-furyl)3 P(2-furyl)3
DMF DMF DMF DMF DMF DMF DMF DMA DME toluene THF 1,4-dioxane MeCN
25 7 20 38 18 29 16 21 50 34 45 54 92
69 45 22 57 9 47 59 73 7
