(1S,5R)-6,6-Dimethyl-4-(((1S,2S,5S)-2,6,6-trimethyl-4- oxobicyclo[3.1.1]heptan-2-yl)methyl)bicyclo[3.1.1]hept-3- en-2-one

A simple and convenient procedure for the γ, β-dimerization of verbenone was developed. The dimer was obtained during aging with KOH without a solvent. The process proceeds as the formation of the extended enolate of verbenone and its Michael addition to other molecules of verbenone. The product yield was 82% after purification by column chromatography and recrystallization.


Introduction
Verbenone is a natural monoterpenoid with pinene framework and plays an important role in the relationships between different species in some ecosystems. On the one hand, it is found in plants: large quantities of verbenone were observed in some rosemary oils (27.0-28.9%) [1] and it was found as major component in flowers of different chrysanthemum cultivars and their wild relatives [2]. On the other hand, verbenone is a purported anti-aggregation pheromone of several economically significant bark beetle species [3]. Moreover, the mycangial symbiotic fungus of Dendroctonus frontalis produces verbenone, thus, the development of fungus in the plant host may play a role in influencing the behavior of the beetle to a success fully colonized tree [4]. The most important way to obtain verbenone is the allylic oxidation of widespread-and available in large amountsmonoterpene α-pinene [5,6]. Verbenone as a component of essential oil can be used in aromatherapy [7]. Finally, one of the most important directions for the use of verbenone is fine chemistry. Verbenone, being a chiral compound, is used in the asymmetric synthesis of complex biologically active compounds, for example, a diol with a para-menthane skeleton with high antiparkinsonian activity [8] or the antitumor agent, taxol [9].
It is known that the extended enolate of verbenone can act as a d 4 -synthon, in particular, it reacts with aldehydes at the methyl group in the presence of a base [10][11][12]. At the same time, verbenone itself is a Michael acceptor, thus, is an a 3 -synthon. However, in the case of simple C-nucleophiles, this obvious approach does not work, and to obtain the corresponding products, the following detours are used: through cyclopropanation, followed by the opening of the cyclopropane ring [13]; or on the basis of nopinone, which temporarily introduces an additional SO 2 Ph acceptor into the α-positions, and is subsequently removed with Li/NH 3 (liquid) [14]. However, verbenone can react with a strong delocalized conjugated C-nucleophile, such as a structurally similar dianion of crotonic acid. [15]. Moreover, the nucleophile, corresponding to an extended enolate, is attached at its γ-position. Therefore, verbenone can be potentially dimerized, and since in the case of verbenone dianion, it does not need to be created, the reaction should proceed under mild conditions. The resulting γ, β-dimer is promising for further modification, 2 of 4 including the separate modification of each fragment with a pinane framework due to their structural difference. Importantly, to the best of our knowledge there are no data on the γ, β-dimerization of (−)-verbenone. Dimers of different structures obtained by the oxidation of the extended enolate of verbenone are described [16]. In particular, the γ, γ-attachment at methyl groups was observed when using CuCl 2 , but α, γ-joint occurred in the case of FeCl 3 .

Results and Discussion
We found that the dimerization of verbenone actually proceeds when it interacts for a week at room temperature without a solvent with KOH ground in a mortar. The yield of product 1 (Scheme 1) after purification by column chromatography on SiO 2 and recrystallization was 82%.
Molbank 2022, 2022, x FOR PEER REVIEW 2 of 5 the case of verbenone dianion, it does not need to be created, the reaction should proceed under mild conditions. The resulting γ, β-dimer is promising for further modification, including the separate modification of each fragment with a pinane framework due to their structural difference. Importantly, to the best of our knowledge there are no data on the γ, β-dimerization of (−)-verbenone. Dimers of different structures obtained by the oxidation of the extended enolate of verbenone are described [16]. In particular, the γ, γ-attachment at methyl groups was observed when using CuCl2, but α, γ-joint occurred in the case of FeCl3.

Results and Discussion
We found that the dimerization of verbenone actually proceeds when it interacts for a week at room temperature without a solvent with KOH ground in a mortar. The yield of product 1 (Scheme 1) after purification by column chromatography on SiO2 and recrystallization was 82%. The molecular structure of the compound is illustrated in Figure 1 according to the X-ray diffraction data. The bond lengths and bond angles are the same as the statistical means [17]. In the crystal packing, the short H19A...O2 2.58 Å contact leads to the formation of 1D infinite chains of molecules.

General
All reagents and solvents are commercially available and used as supplied. NMR spectra Spectral and analytical measurements were obtained at the Multi-Access Chemical Research Center SB RAS (Moscow, Russia) for spectral and analytical measurements. NMR spectra were registered on Bruker AV-600 spectrometer (resonance frequency for 1H 600.3 MHz) (Moscow, Russia) Chemical shifts for 1 H and 13 C were Scheme 1. γ, β-Dimerization of (−)-verbenone.
The molecular structure of the compound is illustrated in Figure 1 according to the X-ray diffraction data. The bond lengths and bond angles are the same as the statistical means [17]. In the crystal packing, the short H19A...O2 2.58 Å contact leads to the formation of 1D infinite chains of molecules.
under mild conditions. The resulting γ, β-dimer is promising for further modif including the separate modification of each fragment with a pinane framework their structural difference. Importantly, to the best of our knowledge there are no the γ, β-dimerization of (−)-verbenone. Dimers of different structures obtained oxidation of the extended enolate of verbenone are described [16]. In particular γ-attachment at methyl groups was observed when using CuCl2, but α, γ-joint o in the case of FeCl3.

Results and Discussion
We found that the dimerization of verbenone actually proceeds when it inter a week at room temperature without a solvent with KOH ground in a mortar. Th of product 1 (Scheme 1) after purification by column chromatography on Si recrystallization was 82%. The molecular structure of the compound is illustrated in Figure 1 accordin X-ray diffraction data. The bond lengths and bond angles are the same as the st means [17]. In the crystal packing, the short H19A...O2 2.58 Å contact leads formation of 1D infinite chains of molecules.

General
All reagents and solvents are commercially available and used as supplied spectra Spectral and analytical measurements were obtained at the Multi Chemical Research Center SB RAS (Moscow, Russia) for spectral and an measurements. NMR spectra were registered on Bruker AV-600 spectrometer (res frequency for 1H 600.3 MHz) (Moscow, Russia) Chemical shifts for 1 H and 13

General
All reagents and solvents are commercially available and used as supplied. NMR spectra Spectral and analytical measurements were obtained at the Multi-Access Chemical Research Center SB RAS (Moscow, Russia) for spectral and analytical measurements. NMR spectra were registered on Bruker AV-600 spectrometer (resonance frequency for 1H 600.3 MHz) (Moscow, Russia) Chemical shifts for 1 H and 13 C were measured relative to the internal standard CDCl 3 (δ 7.24 ppm for 1 H, 76.9 ppm for 13 C). For structure determination and NMR signal assignment in 1 2D correlation spectra, 1 H-1 H (COSY, NOESY) and 1 H-13 C (HSQC, HMBC) were used. Optical rotation: polAAr 3005 spectrometer, CHCl 3 solution. HR-MS: DFS-Thermo-Scientific spectrometer (Thermo Fisher Scientific, Moscow, Russia) in a full scan mode (15-500 m/z, 70eVelectron-impact ionization, direct sample introduction).

Conclusions
The interaction of verbenone with KOH without solvent led to the Michael addition of verbenone-extended enolate and provided its γ,β-dimer with an 82% preparative yield.