Bi(OTf)(3)-Catalyzed 5-Exo-Trig Cyclization via Halide Activation.

The formation of carbocations1 from a variety of organohalogen compounds2 by Lewis acid activation is an important process in the field of organic chemistry. The trapping of in situ generated cations by nucleophiles (Scheme 1) is a useful synthetic strategy if the reactions can be well controlled.3 Weak nucleophiles can readily take part in such processes. Scheme 1 There are a number of examples of halide activation by Lewis or Bronsted acids to generate carbocations. Typically Lewis acids such as Ag(I), B(III), Ti(IV), Al(III), and Sn(IV) are used to cleave carbon-halide bonds.4 However, major limitations for this chemistry are that the conditions are often severe and the use of stoichiometric amount of Lewis acids is often required. Strongly acidic byproducts (e.g. HCl, HBr) can poison Lewis acids and perturb their catalytic turnover. Thus, reactions driven by catalytic halide activation by Lewis acids are rare. Recently, Hua and coworkers reported that catalytic amounts of BiCl3 catalyzed the Friedel-Crafts reaction of acyl or vinyl chlorides with arenes.5 We recently reported the In(III)-catalyzed atom transfer cyclization6 and ring-closing Friedel-Craft reaction7 proceeding via efficient and mild activation of allylic bromides. During our investigation of these cationic processes we discovered that Bi(OTf)3 was also able to activate allylic halides catalytically with high efficiency. Bismuth Lewis acids are intriguing and have been known to catalyze a variety of reactions8 including an interesting BiBr3-catalyzed silyl-Prins reaction. Herein, we disclose another application driven by Lewis acid catalyzed halide activation.9 Similar to our atom transfer cyclization of alkynes and allyl bromides, we envisioned that the dimethyl substituted alkene-allylic bromide substrate 1a (Scheme 2) would also undergo a similar process.6 However, in the presence of 20 mol% of InCl3 in CH2Cl2 1a decomposed. Interestingly, in the presence of 4A molecular sieves, the diene product 2 was obtained via proton elimination cleanly in 68% isolated yield. We believe that molecular sieves in this reaction play the role of a neutral base to trap HBr after the reaction takes place. Scheme 2 We next turned our attention to screening a variety of metals for the cyclization to determine which catalysts would be capable of effecting the reaction in substoichiometric amounts (Table 1). Thus 1a was treated with 20 mol% of Lewis acids in CH2Cl2 (0.5M) at room temperature for 16 hours. Most of the Lewis acids failed to catalyze the reaction. Surprisingly, Lewis acids known to cleave carbon-halide bonds including AlCl3, AgSbF6, and AgOTf yielded less than 20% (entries 3, 21, 22). From this study, we found Fe(ClO4)3, ZnBr2, ZnI2, Bi(OTf)3, InBr, InI, In(OTf)3, InBr3, and InCl3 (entries 5, 8, 9, 14, 23, 24, 25, 26 and 27) demonstrated promising catalytic ability for this reaction. Table 1 Lewis Acid Screen We next examined the phenyl-substituted substrate 1b utilizing several of the most promising Lewis acid catalysts (Table 2). Again, we were surprised to find that none of the catalysts tested resulted in success with the exception of Bi(OTf)3 (entry 15). ZnBr2, ZnI2, and Fe(ClO4)3 decomposed the starting material (entries 1, 2, 3). In the presence of 20 mol% InI mostly starting material was observed along with some decomposition (entry 4). When In(III) salts were employed (InCl3, InBr3, and In(OTf)3) in the presence of 4A molecular sieves, trace amounts of the cyclized product 2b were seen, however, yields were very poor and mostly decomposition was observed (entries 5, 6, 9). In the absence of molecular sieves the starting material also decomposed (entry 7). The combination of InCl3 with other types of molecular sieves was also tested, however, all of them (3A, 13X, Na+13Y, or NH4+13Y) interfered with catalysis and the starting material was recovered quantitatively (entries 8, 10, 11, 12). On the other hand, employing only 10 mol% of Bi(OTf)3 with 4A molecular sieves resulted in successful catalysis of cyclization to yield 2b in 78% isolated yield. The combination of Bi(OTf)3 with other types of molecular sieves in this reaction were found to be ineffective (entries 14, 16, 17, 18). Table 2 Phenyl-substituted Substrates A variety of substrates were tested in the exo-trig cyclization catalyzed by Bi(OTf)3 and the results are shown in Table 3. In the presence of 10 mol% of Bi(OTf)3 and 4A molecular sieves in 0.05M CH2Cl2, the carbocycle 2a, where both R1 and R2 were methyl, was synthesized in 58% isolated yield (entry 1). Nitrogen heterocycle 3a was produced in 60% yield (entry 2). If X was oxygen, the starting material decomposed (entry 3). Alkene substitution was also varied with mixed results. In the case of phenyl substituted alkene, 2b was obtained in 78% yield (entry 4). However, with alkyl disubstituted alkene or terminal alkene, the substrate was recovered unreacted (entries 5, 6). Table 3 Substrate Modifcation A proposed mechanism is shown in Scheme 3. When treated with a catalytic amount of Bi(OTf)3 to activate the allylic bromide, substrate A undergoes ionization to generate an allyl carbocation. Attack of the nucleophilic alkene produces carbocation intermediate B and Br-Bi(OTf)3-. Importantly the stabilization of the carbocation in B is critical for this reaction. Stabilization is optimal with gem-dimethyl or phenyl substitution. Elimination of proton then yields the 1,3-diene product C and HBr as a byproduct. Molecular sieves serve to trap the HBr and prevent decomposition of substrate and/or product.7 Scheme 3 Proposed Mechanism In conclusion, a Bi(OTf)3 catalyzed exo-trig cyclization via halide activation was demonstrated. The choice of molecular sieves was critical as only 4A molecular sieves were effective in this particular reaction. Screening of Lewis acis showed that Zn(II), Fe(III), In(I), In(III), and Bi(III) catalysts were capable of activating the allylic halide, however, Bi(OTf)3 was optimal for the phenyl substituted alkene. Further investigation into the unique role of bismuth Lewis acids is currently underway.