Ti(II)-Mediated domino cyclization of 2-functionalized 1-halo-2,n-enynes (n = 7, 8) to bicyclic compounds

The reaction of 2-functionalized 1-halo-2,n-enynes (n = 7 or 8) with a divalent titanium reagent, Ti(O-i-Pr)4/2i-PrMgCl, proceeded in a domino fashion to afford bicyclic compounds in good yields. © 2011 Elsevier Science. All rights reserved ——— * Corresponding author. Tel.: +81-45-481-5661; fax: +81-45-413-9770; e-mail: [email protected] We have recently developed a divalent titanium reagent-mediated cyclization of 2,7and 2,8-enyn-1-ol derivatives. Thus, the reaction of enyn-1-ol derivatives 2 (G = H) with Ti(O-i-Pr)4/2i-PrMgCl (1) proceeded through β-elimination of the leaving group X from a titanacyclic intermediate 3 (G = H) to give alkenyltitanium compound 4 (Scheme 1). The resulting alkenyltitaniums 4 could act as a nucleophile and reacted with various electrophiles to give 5. With these results in hand, we thought that further intramolecular cyclization of the resulting alkenyltitaniums of the type 4 to bicyclic compounds might occur in a domino fashion when the starting enynes have a functional group (FG), which can react with the alkenyltitanium moiety, as a substituent G at a C-2 position (Scheme 1). Herein reported is the realization of this idea by introducing -CO2R’ or -CH2Cl as the FG at a C-2 position of 2,7and 2,8-enyn-1-ol derivatives, which might be expected to produce the corresponding bicyclic products 6 and 7, respectively. First, we investigated the 1-mediated reaction of 2a, which has a methoxycarbonyl group as the substituent G (Table 1). Thus, enynol derivative 2a was treated with 1.4 equiv of 1 at –40 to –20 C for 2 h and the mixture was quenched by addition of H2O. However, the expected dienone 6a was not produced but 29% of enone compound 8 was produced with 37% of the recovered 2a (Table 1, entry 1). Scheme 1. Plan for domino reaction. Tetrahedron Letters 2 Table 1. Reactions of 5 with 1. Therefore, we carried out the reaction using 2.3 equiv of 1 and found that the reaction provided 8 [diastereomeric ratio (d.r.) = 95:5] in 84% yield (Table 1, entry 2). Enynes 2 having a more sterically demanding ester group reacted smoothly with 1.4 equiv of 1 but afforded mono-cyclic compounds 9 as a major product (entries 3 and 4). The results can be explained by assuming that the reaction of 2a with 1 provided dienone 6a via 4’a as expected, however, the resulting 6a further reacted with 1 fast to afford the corresponding oxatitanacyclic compound 10, hydrolysis of which gave 8 (the order of reaction rates: k2, k3 > k1) (Scheme 2). Introduction of cyclohexyl group into an ester moiety relatively decreased the reaction rate from the corresponding 4’ to 6a (k2) and, therefore, the reaction provided a mixture of 8 and 9 (k1, k3 > k2). t-Bu group may be so bulky that intramolecular acyl substitution reaction of the corresponding 4’ could not undergo. Scheme 2. Possible explanation for formation of 8 and 9. The presence of an intermediate 10 was confirmed by iodolysis of the reaction mixture derived from 2a and 2.3 equiv of 1 (Scheme 3): The reaction mixture was treated with I2 to give 6a in 62% yield. Thus, Ti(II)-mediated domino cyclization could provide bicyclic compounds 6a and 8 having a cyclopentene and methylenecyclopenetene structures, respectively, from the acyclic enyne starting compound. Scheme 3. Formation of 6a by the reaction of 10 with I2. Next, we prepared enyne 2d as a substrate which has a chloromethyl moiety as the substituent G at the C-2 position, expecting that the corresponding titanium compound 4’d could undergo intramolecular allylic substitution giving 7d (Scheme 4). Treatment of 2d with 1.2 equiv of 1, however, resulted in production of mono-cyclic compound 11 after hydrolysis. The results indicate that generated alkenyltitanium 4’d could not undergo allylic substitution. It was found that addition of a catalytic amount of Li2Cu(CN)Cl2 to the reaction mixture of 4’d could effect intramolecular allylic substitution to produce 1,2-annulated fuluvenes 7d in 80% yield. Scheme 4. Reaction of 2d with 1 and the following Cu-catalyzed