Platinum-Catalyzed Hydrative Cyclization of 1,6-Diynes for the Synthesis of 3,5-Substituted Conjugated Cyclohexenones

We have developed a Pt(COD)Cl2-catalyzed hydrative cyclization of 1,6-diynes leading to the formation of functionalized cyclohexenones in good yields.


OPEN ACCESS
we succeeded in synthesizing conjugate cyclohexenone ring systems using the hydrative cyclization of 1,6-diynes with (PPh 3 )AuMe as a catalyst [24,25]. Herein, we report our studies on the use of Pt(COD)Cl 2 as a catalyst in this cyclization.

Results and Discussion
Initial hydrative cyclization experiments of 1,6-diyne 1a (0.5 mmol) with H 2 O (0.5 mmol) at 70 ºC for 4 h in a sealed-tube were performed to screen catalysts. Pt(COD)Cl 2 (COD = cyclooctadiene) combined with methanesulfonic acid (CH 3 SO 3 H) showed good catalytic activity in this reaction, furnishing cyclohexenone 2a in 75% yield without the formation of the corresponding hydration or methanol adducts (Table 1, entry 1), while the reaction conducted in the absence of CH 3 SO 3 H did not yield the cyclic product ( In order to demonstrate the efficiency and scope of the present method, we applied the optimum conditions of entry 1 in Table 1 to the hydrative cyclization of several 1,6-diyne substrates bearing a variety of functionalities at their 4-positions. The results are summarized in Table 2. Terminal malonate derivatives 1a and 1b were found to be good substrates ( Table 2, entries 1 and 2). This is quite similar to the results of Au (I)-catalyzed reactions [24,25]. To our delight, the presence of two hydroxyl groups as in compound 1c was tolerated, thus providing cyclohexenone 2c bearing hydroxyl groups with no intramolecular alcohol addition products ( Table 2, entry 3) [26,27]. Protecting groups such as the single methyl ether in 1d or the double methyl ether in 1e were also compatible with the present method ( Table 2, entries 4 and 5). Cyclic products with different substituent group pairs, such as the diphenylphosphoryl and ethoxycarbonyl in 2f, or the phenyl and methoxycarbonyl in 2h, were also obtained in good yields (Table 2, entries 6 and 8). The acetylacetone derivative 1i and its reduced derivative 1j were transformed into cyclic products 2i and 2j (Table 2, entries 9 and 10). In our hands the spirocyclic compound 2k bearing a fluorene moiety was successfully obtained from diyne 1k in 48% yield (Table 2, entry 11).  Presumably, the mechanism in this reaction could be similar to that of the PtCl 2 -catalyzed hydrative cyclization of trialkyne functionalities [7]. We thus propose a mechanism (Scheme 1) involving an initial coordination of the diyne to Pt(II) to afford the intermediate A. The addition of H 2 O takes place to form the -carbonyl platinum species C. After a second hydration at the remaining alkyne of species C, the resulting diketone species D undergoes a subsequent aldol condensation to form a product 2. Alternatively, cyclohexenone 2 could result from an alkyne insertion into intermediate E, followed by hydrodemetalation of intermediate F. The reason behind the catalytic activity of acid as an additive is unclear, although acid is proposed to exert a tuning effect on the activity of Pt catalysts.
Under otherwise noted, materials were obtained from commercial suppliers and used without further purification. Diynes were prepared by the procedures in the literature [29,30]. Thin layer chromatography (TLC) was performed using silica gel 60 F 254 and visualized using UV light. Column chromatography was performed with silica gel (mesh 300-400). 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz spectrometer in CDCl 3 with Me 4 Si as an internal standard. Data are reported as follows: chemical shifts in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad and m = multiplet, coupling constant (Hz) and integration. Infrared spectra (IR) were obtained on a 370 FT-IR spectrometer; absorptions are reported in cm -1 . Mass spectra (MS) and high resolution mass spectra (HRMS) were obtained at the Zhejiang University of Technology Mass Spectrometry Facility.

General procedure for the hydrative cyclization of diynes
To a reactor containing diyne (0.5 mmol), methanol (2 mL), and H 2 O (10 μL) under nitrogen Pt(COD)Cl 2 (9.0 mg, 0.025 mmol, 5 mol%) and CH 3 SO 3 H (20 μL) were added. The resulting yellow solution was then sealed and stirred at 70 ºC for 3-13 hours until the starting diyne was consumed, as judged by TLC. The mixture was quenched with a saturated solution of NaHCO 3 and then extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel) (Eluent: hexane/ethyl acetate) to yield the corresponding cyclized product in an analytically pure form. [24]. A pale yellow oil; 1   Methyl 3-methyl-5-oxocyclohex-3-enecarboxylate (2g) [24]. A pale yellow oil; 1

Conclusions
In summary, various 3,5-substituted conjugated cyclohexenones were synthesized by Pt(II)-catalyzed hydrative cyclization of 1,6-diynes. Advantages of the present method are the easily accessible starting materials, mild conditions, lack of coproducts and the fact that several types of functional groups were tolerated. Further studies are underway to expand the scope of the present method and are directed toward further method development on these cyclohexenone scaffolds as well as applications in natural product and the bioactive molecule synthesis.