(1R,3R,5S,Z)-2-Ethylidene-6,6-dimethyl-3-vinylbicyclo[3.1.1]-heptane

Abstract

(1R,3R,5S,Z)-2-ethylidene-6,6-dimethyl-3-vinylbicyclo[3.1.1]heptane was prepared by hydrovinylation of nopadiene catalyzed by a cationic Ru complex. The structure was fully characterized by ¹H- and ¹³C-NMR spectroscopy, including 2D-COSY and 2D-NOESY spectra, optical rotation, and combustion analysis. In contrast to the previously reported 1,2-hydrovinylation of 1-vinylcycloalkenes by this catalyst, the reaction with nopadiene proceeds by 1,4-addition of ethylene.

1. Introduction

Transition metal catalyzed hydrovinylation is an atom economical C–C bond forming reaction [1,2], which has seen increasing utility in natural product synthesis [3,4]. Complexes of nickel [4,5,6], cobalt [6,7,8,9,10], iron [11], palladium [12], and ruthenium [13,14,15,16,17] have been reported as catalysts for this reaction. In general, for 1-vinylcycloalkene substrates Ni- and Ru-based catalysts proceed with 1,2-selectivity (Scheme 1). In contrast, Co-catalysis proceeds with 1,4-regioselectivity, with the cis-stereoisomer predominating. We herein report that the hydrovinylation of nopadiene (1), utilizing cationic Ru-complex 2, proceeds with unanticipated 1,4-regioselectivity with trans-stereoselectivity.

2. Results

The reaction of nopadiene (1) with excess ethylene, catalyzed by cationic Ru-complex 2, produced a mixture of a hydrovinylation product (3) along with unreacted 1 (Equation (1)). To separate the two hydrocarbons, the mixture was titrated with a solution of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), which reacted rapidly with nopadiene via a hetero-Diels–Alder reaction, until the red color of PTAD persisted. Chromatographic purification of this mixture gave 3.

The structure of 3 was assigned based on its ¹H NMR spectral data (see Supplementary Materials). In particular, the signals at δ 5.24 (dq, J = 1.5, 6.9 Hz, 1H), 3.04 (br t, J = 8.0 Hz, 1H), 2.87 (t, J = 5.7 Hz, 1H), and 1.57 (dd, J = 1.5, 6.9 Hz, 3H) were assigned to H(10), H(3), H(1), and the allylic methyl group. The absence of any ³J_H-H coupling between the diallylic proton H(3) and any of the methyl signals excluded a 1,2-hydrovinylation structure. A small cross-peak in the NOESY NMR spectrum of 3 was observed between the allylic methyl group and H(1), suggesting a (Z)-stereochemical assignment. However, this stereochemical assignment must be considered tentative, as a cross-peak on the opposite side of the diagonal could not be observed, in spite of extensive attempts at manual phase correction along F2. Notably, no cross-peak between H(10) and H(1) was evident. The vinyl group at C(3) was tentatively assigned an orientation opposite the gem-dimethyls of the bicyclo[3.1.1]heptane system. These tentative assignments were eventually corroborated by X-ray diffraction analysis of a crystalline derivative [18].

(1)

(2)

3. Discussion

The hydrovinylation of 1 is anticipated to involve coordination of the less substituted olefin of nopadiene to a ruthenium–hydride species (i.e., 4, Scheme 2). Reversible insertion of the coordinated olefin into the Ru–H bond generates the π-allyl-Ru intermediate 5, which has the allylic methyl group in a syn-orientation. Notably, the π-allyl-Pd complex generated by the reaction of ethylidenenorpinane with PdCl₂ was assigned a similar structure based on its ¹H NMR spectral data, as well as an X-ray crystal structure [19]. Coordination of ethylene to 5 affords a σ-allyl intermediate 6. Insertion of the coordinated ethylene occurs with retention of the configuration to generate 7. The product that (+)-3 produced by β-hydride elimination from 7 resulted in ligand exchange. The formation of the 1,4-addition product, in contrast to the 1,2-addition product which we have observed for all other 1-vinylcycloalkenes [13], may be rationalized on the lower energy of σ-allyl intermediate 6 compared to 8. Intermediate 6 should be lower in energy due to the additional strain in 8 from the C2–C3 olefin within the strained bicyclo[3.1.1]heptane ring system.

4. Materials and Methods

4.1. General

All ¹H NMR and ¹³C NMR spectra were recorded using a Varian 300 MHz spectrometer in CDCl₃. ¹H spectra were calibrated according to the residual signal of CHCl₃ (δ 7.26 ppm) and ¹³C spectra were calibrated to the central peak for CDCl₃ (δ 77.0 ppm). Optical rotations were recorded on a Perkin Elmer 341 optical polarimeter at a 589 nm wavelength (20 °C). Elemental analysis was obtained from Midwest Microlabs, Ltd. (Indianapolis, IN, USA). Nopadiene (1) [20] and catalyst 2 [21] were prepared following the literature procedures.

4.2. Synthesis of (1R,3R,5S,Z)-2-Ethylidene-6,6-dimethyl-3-vinylbicyclo[3.1.1]heptane (3)

Inside a nitrogen-filled glovebox, a 25 mL medium-walled vacuum Schlenk tube equipped with stirring bar and Teflon stopcock was charged with nopadiene (0.2 mL, 1.07 mmol), cationic catalyst 2 (1.0 mol%), and methylene chloride (3 mL). The tube was removed from the glove box, cooled in a liquid N₂ bath, and excess ethylene (ca. 6.4 mmol) was condensed into the tube. The tube was stoppered, removed from the liquid N₂ bath, warmed to room temperature, and immersed in an oil bath at 75 °C for 15 h [NOTE: an explosion safety shield should be used between the heating reaction mixture and the fume hood sash]. After this time, the reaction mixture was cooled to room temperature and the tube opened to the air. The reaction mixture was concentrated, and the residue was dissolved in hexanes/dichloromethane and passed through a short column of silica gel in a disposable pipet to remove the catalyst. The crude product was dissolved in CH₂Cl₂ and small amounts of a solution of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in CH₂Cl₂ were added to the stirred solution until the red color of the PTAD persisted. The mixture was concentrated and the residue purified by column chromatography (SiO₂, hexanes) to afford 3 as a colorless oil (0.142 g, 75%): [α]_D²⁰ = +4.70 (c = 4.4, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ = 5.85 (ddd, J = 8.0, 9.9, 16.8 Hz, 1H), 5.24 (dq, J = 1.5, 6.9 Hz, 1H), 4.92 (ddd, J = 1.5, 2.1, 16.8 Hz, 1H), 4.85 (ddd, J = 1.0, 2.1, 9.9 Hz, 1H), 3.04 (br t, J = 8.0 Hz, 1H), 2.87 (t, J = 5.7 Hz, 1H), 2.33 (dtd, J = 2.1, 6.0, 9.9 Hz, 1H), 2.22 (tdd, J = 2.1, 10.2, 13.8 Hz, 1H), 2.05–1.96 (m, 1H), 1.72 (ddd, J = 2.7, 3.9, 13.8 Hz, 1H), 1.57 (dd & m, J = 1.5, 6.9 Hz, 4H), 1.29 (s, 3H), 0.78 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ = 146.8 (CH), 1.42 (C), 118.5 (CH), 110.9 (CH₂), 44.4 (CH), 41.4 (CH), 40.8 (C), 40.7 (CH), 32.0 (CH₂), 28.2 (CH₂), 26.6 (CH₃), 22.1 (CH₃), 13.1 (CH₃). Anal. calcd for C₁₃H₂₀ (176.30): C, 88.57; H, 11.43. Found: C, 88.63; H, 11.47.