Regiochemistry of Carbenoid Insertion into Zirconacycles

For application in organic synthesis, the regiochemistry of insertion of carbenoids into un-symmetrical zirconacydes needs to be predictable. In the case of insertion into mono- and bicydic zirconacydopentenes where there is an x-substituent on the alkenyl but not on the alkyl side, we have already seen that a wide variety of metal carbenoids insert selectively into the zirconium—alkyl bond [48,59,86], For more complex systems, the regiocon-trol has only been studied for the insertion of lithium chloroallylides (as in Section 3.3.2) [60]. Representative examples of regiocontrol relating to the insertion of lithium chloroal-lylide are shown in Fig. 3.2. 

It is observed that insertion into a zirconacyclopentene 163, which is not a-substituted on either the alkyl and alkenyl side of the zirconium, shows only a 2.2 1 selectivity in favor of the alkyl side. Further steric hindrance of approach to the alkyl side by the use of a terminally substituted trans-alkene in the co-cyclization to form 164 leads to complete selectivity in favor of insertion into the alkenyl side. However, insertion into the zirconacycle 165 derived from a cyclic alkene surprisingly gives complete selectivity in favor of insertion into the alkyl side. In the proposed mechanism of insertion, attack of a carbenoid on the zirconium atom to form an ate complex must occur in the same plane as the C—Zr—C atoms (lateral attack 171 Fig. 3.3) [87,88]. It is not surprising that an a-alkenyl substituent, which lies precisely in that plane, has such a pronounced effect. The difference between 164 and 165 may also have a steric basis (Fig. 3.3). The alkyl substituent in 164 lies in the lateral attack plane (as illustrated by 172), whereas in 165 it lies well out of the plane (as illustrated by 173). However, the difference between 165 and 163 cannot be attributed to steric factors 165 is more hindered on the alkyl side. A similar pattern is observed for insertion into zirconacyclopentanes 167 and 168, where insertion into the more hindered side is observed for the former. In the zirconacycles 169 and 170, where the extra substituent is (3 to the zirconium, insertion is remarkably selective in favor of the somewhat more hindered side. 

We thank the students and postdoctoral fellows whose efforts and enthusiasm led to the work from our group described herein. We also thank the organizations that generously support our work in this area (EPSRC, Pfizer, GlaxoWelcome (now GSK), and Zeneca (now AstraZeneca)). 

6-tetramethylpiperidine (TMP, 0.305 g, 2.16 mmol) and BuLi (0.86 mL, 2.5 m in hexane, 2.16 mmol) in THF (2.0 mL)]. The reaction mixture was stirred at —90 °C for 15 min., then hydrolyzed by the addition of 2 m aq. HC1 (8.0 mL). After extraction with diethyl ether (12 mL), the organic layer was washed with 2 m aq. HC1 (2 Xx 10 mL), dried over MgS04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica 40—60 petroleum ether) to afford (3Z,5E)-l,3,5-dodecatriene (0.104 g, 76% yield) [38], 

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