Esterification carbopalladation

A spectacular example of application of the cyclic carbopalladation-carbonylative esterification tandem process is the synthesis of a possible intermediate for the synthesis of perophoramidine [121] (Scheme 39). 

The feasibility of such a sequential process was accidentally discovered in 1989 in an unsuccessful attempt to achieve cyclic acylpalladation (Sect. VI.4) of la (Scheme 1) with 40 atm of CO, 1.5 equiv of NEtj, and 4 equiv of MeOH in the presence of 3 mol % of Pd(PPh3)4 at 100 °C. Whereas none of the desired cyclic acylpalladation product 2a was formed, the reaction gave an unexpected carbopalladation product 3a in 42% yield along with an uncyclized premature esterification product 4a formed in 28% yield. Similarly, lb provided 3b and 4b in 18% and 42% yields, respectively, rather than the desired 2b (Scheme 1). Since formation of seven-membered ketones via cyclic acylpalladation has never been observed, the results are perhaps not surprising. Later optimization of the reaction conditions including the use of 1 atm pressure of CO has... 

The catalytic cyclic carbopalladation of alkynes can proceed to produce five- and six-membered rings at 1.0-1.1 atm of CO without premature incorporation of CO, and in situ regeneration of Pd-phosphine catalysts can be achieved in high yields by termination of the cyclic carbopalladation via deferred carbonylative esterification and lactonization, as suggested by the results shown in Scheme 1. One key to observing the formation of the desired products in high yields is to employ 1.0-1.0 atm of CO. Some representative examples are summarized in Scheme 3. 

Cyclic carbopalladation producing five- and six-membered rings can proceed in good yields despite the fact that the expected carbonylative esterification does take... 

The relative rates of CO insertion and intramolecular carbopalladation producing five- and six-membered rings are more difficult to assess. However, the results summarized in Scheme 7 indicate that the CO insertion-lactonization tandem process of 5 producing 6 is competitive with the intramolecular C—Pd process producing a five-membered ring (7) and that their relative rates depend on CO pressure. One may conclude that CO insertion can be at least as fast as or possibly faster than favorable intramolecular carbopalladation. This, in turn, indicates that CO insertion must readily be reversible for favoring the cyclic C—Pd process over premature esterification. The ready reversibility of CO insertion is clearly indicated by the results shown in Scheme S. In summary, the relative rates of various processes in decreasing order of rates are as shown in Scheme 9. 

A detailed investigation with 10 summarized in Table 2 indicates that premature esterification and cyclopropanation (Type HI C— Pd process in Scheme 2) can occur as dominant side reactions but that, under the optimized conditions (entry 7), both can be suppressed to insignificant levels (<3%). It is also important to note that, in marked contrast with the cyclic acylpalladation (Type n Ac—Pd) discussed in Sect. VI.4.1.1, monosubstituted alkenes that can readily participate in dehydropalladation (e.g., 11) cannot undergo the cyclic carbopalladation-carbonylative esterification tandem process (Type II C-Pd) since they merely undergo the cyclic Heck reaction (Type I C— Pd process in Scheme 14). The contrasting behavior mentioned above may be attributable to a chelation effect exerted by the carbonyl group in the acylpalladation (Scheme 15), which is lacking in the carbopalladation shown in Scheme 14. 

C.ii. Diastereoselective Cyclic Carbopalladation of 1,1-Disubstituted Alkenes Terminated by Carbonylative Esterification... 

Cop6ret, C. and Negishi, E.-i. (1999) Palladium-catalyzed highly diastereoselective cyclic carbopalladation-carbonylative esterification tandem reaction of iododienes and iodoary-lalkenes. Org. Lett., 1,165-7. 

In fact, the preferential cyclic carbopalladation even in the presence of large excesses of CO and MeOH has been exploited in developing cyclic carbopalladation cascades terminated by carbonylative esterification, as discussed in Sect. IV.3.3. More recent attempts... 

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