Cyclobutenone Ethylenedithioacetals and Their Ready Electrocyclic Ring Opening

: Reported here is a general regiospecific synthesis of cyclobutenedione monoethylendithioacetals which readily undergo ring opening after addition of an organolithium reagent. The gener-ated acyclic enols either tautomerize to the corresponding carbonyl compounds or can be trapped as silylenol ethers, which serve as electron rich dienes in Diels - Alder additions with tetracyanoethylene or maleic anhydride.

Cyclobutenone derivatives have been efficiently used for the synthesis of highly substituted p-quinones and related annulated compounds over the last 15 years. [1][2][3] The thermal ring expansion is presumed to proceed via ring opening of the cyclobutenone to a vinyl ketene intermediate which then undergoes elecrocyclic ring closure to form the six-membered ring. Starting materials of particular note are cyclobutenedione monoketals. Such compounds having predictable regiochemistry are readily prepared and serve as useful precursors to asymmetrically substituted p-quinones. 4,5 Our interest in organosulfur derivatives of cyclobutenones 6 led us to investigate the chemistry of cyclobutenone dithioacetals. In particular, we were interested in 1,3-dithiolane derivatives because of their potential utility for the generation of cyclobutenediones via a base induced [3 + 2] cycloreversion reaction. 7 Reported herein is an efficient preparation of cyclobutenedione monodithioacetals involving the transthioacetalization of the corresponding dialkyl acetals. Firouzabadi and Iranpoor 8 have developed a method for a selective transthioacetalization of open chain acetals in the presence of cyclic acetals by the use of catalytic amounts of ZrCl 4 . This methodology could be extended to the transthioacetalization of cyclobutenedione monoacetals. Thus, the readily available dimethyl acetals 1 were converted to the corresponding 1,3-dithiolanes 2 in the presence of 1,2-ethanedithiol (1.05 equivalents) and ZrCl 4 (15 mol%) in very good yields and with complete control of chemoselectivity (Scheme 1).

Scheme 1
Bisthioacetalization or other by-products were not observed for any of the examples listed above. It is noted that even a vinylic methoxy group was tolerated under these conditions ( Table 1).
The symmetrically substituted cyclobutenedione monoethylendithioacetal 2i was prepared by a BF 3 ×OEt 2 catalyzed thioacetalization of 3,4-dimethylcyclobutenedione (3) (Scheme 2). The degree of the accompanying bisthioacetalation was reduced by a very slow addition of a CH 2 Cl 2 solution of ethanedithiol and BF 3 ×OEt 2 to a solution of the dione in CH 2 Cl 2 at 0°C. However, under these conditions, we obtained 8% of the bisthioacetal 4 and 73% of the desired monoethylenedithioacetal 2i. The cyclobutenedione monoethylendithioacetals 2 were treated with an organolithium reagent (R 3 Li) in THF at -78°C followed by an aqueous work up to furnish the ring opening products 6 (Scheme 3, Table 2). Thus, in contrast to the stable 4-hydroxy-cyclobutenone dialkyl acetals, 3,4 the dithiolane derivatives readily undergo ring opening and subsequent tautomerization of the primary enols to the ketones 6 under the reaction conditions.

Scheme 3
Quenching of the 1,2-adducts 5 with chlorotrimethylsilane led to the vinyl ketenethioacetals 7 (Scheme 3, Table 3). The 1-(hex-1-ynyl)-silylenol ether 7e was obtained by reversing the addition and adding a THF solution of the dithiolane to a solution of the acetylide at 0°C before quenching with chlorotrimethylsilane (method C).
Dienes 7 warrant further study as multifunctional synthetic building blocks; it is noted that they are thermally stable and do not cyclize even in refluxing p-xylene solution. Even more flexibility can be expected for sterically less hindered derivatives with R 3 = H, e.g., diene 11 (Scheme 4).
The synthesis of 11 started with the reduction of cyclobutenedione 2i with DIBALH in THF at 0°C to give alcohol 8 in 88% yield. Subsequent ring opening of the secondary alcohol to the acyclic aldehyde 9 was completed in 4 hours at 50°C. At room temperature, this ring opening is comparatively slow. Thus, isolation and subsequent silylation of the alcohol 8 by tert-butyldimethylsilyl triflate (TBSOTf), triethylamine and 4-DMAP in CH 2 Cl 2 at 0°C were possible and allowed clean conversion to the silylether 10 in 92% yield. The silylenol ether 11 was obtained in 99% yield by heating a solution of 10 in CHCl 3 at 50°C for 4 hours.
To illustrate the utility of diene 11 in Diels-Alder cycloaddition reactions, it was treated with tetracyanoethylene (TCNE) in CHCl 3 at room temperature to give the desired adduct 12 within 30 minutes in 97% yield. The cycloaddition with maleic anhydride required the higher reaction temperature of refluxing toluene and led to the cycloadduct 13 in 52% yield. The scope of these [4 + 2] cycloadditions is so far limited to reactive dienophiles.
NMR spectra were recorded on a Bruker ARX-400 or G.E. Omega 500 spectrometer using CDCl 3 or TMS as internal standard. IR spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer. MS were recorded on a VG Analytic 7070E instrument. THF was dried by passing through two 4 ´ 36 in. 2 columns of anhyd neutral A-2 alumina. CH 2 Cl 2 and toluene were distilled from CaH 2 . All reactions were followed by TLC using Merck precoated plates of silica gel 60 F 254 . Merck silica gel 60 (mesh 230-400) was used in   (1 mmol) and 1,2-ethanedithiol (87 mL, 1.05 mmol) in dry CH 2 Cl 2 (5 mL) was stirred at 0°C when ZrCl 4 (35 mg, 0.15 mmol) was added. After 2 h at 0°C, the reaction mixture was quenched with NaOH (10%, 5 mL). The aqueous layer was separated and extracted with CH 2 Cl 2 (2 5 mL). The combined organic layers were washed with H 2 O (10 mL), then with brine (10 mL), and dried. Removal of the solvent in vacuo followed by flash chromatography (hexanes-EtOAc) on silica gel provided the desired product.

Silylenolether 7e Method C:
To a solution of 1-hexyne (0.18 mL, 1.6 mmol) in dry THF (5 mL) at -78°C, n-BuLi (0.75 mL, 1.5 mmol, 2.0 M) was introduced dropwise via syringe. The resulting mixture was stirred at -78°C for 30 min, then allowed to warm up to 0 °C before a solution of the dithiolane 2f in THF (5 mL) was transferred under a positive pressure of N 2 , via cannula, to the reaction mixture. After stirring at 0°C for 30 min, chlorotrimethylsilane (0.25 mL, 2 mmol) was added. The solution was stirred at r.t. for 1 h, then worked up and purified as described in method B.
The combined organic layers were washed with brine (10 mL) and dried. Removal of solvent in vacuo followed by flash chromatography (hexanes-EtOAc, 50:1) provided the product as a colorless oil (278 mg, 92% yield).