Practice Problems December, 000 ) Propose sequences of reactions that could accomplish each of the following transformations. Starting from N a) C Starting from Starting from c) ) Propose detailed, stepwise mechanisms to explain the following transformations. + C a) S N + ) What is the product from the following Birch-type reduction? C Na N (l) Et Mass Spectrum shows m/z = 8.9 N C +
Answers to Practice Problems December, 000 ) Propose sequences of reactions that could accomplish each of the following transformations. This type of question is one that we have not really addressed in class because we need to have a large repertoire of reactions to make it work. You should go over these carefully, considering not only your own answer, but also the basic logic of the questions. There are also several other sets of synthesis problems on the course web site, taken from the 999 session. There are two strategies to use in solving problems of this kind. The first is to work backwards from the product to the starting material. Don t worry about the specific reagents and conditions, just look at the kinds of transformations you require. Draw in the intermediate compounds along the pathway going back to the starting compound. Then when you have a complete chain of compounds, go back and fill in the reagents and solvents needed to accomplish the transformations in the forward direction. This approach is called retrosynthetic analysis. The second strategy, which to some extent complements the first, is to identify a key reaction that can unlock some latent functionality in the starting material. You then try to link the starting material to this reaction going forwards, and you link the product to the reaction going backwards. Problem b is of this type. n the exam, bear in mind that there is a lot of room for variation and partial credit. There is not necessarily one right answer to these problems. Don t get hung up fussing over the specific reaction conditions for one transformation get a complete pathway and fill in the reaction conditions as much as possible. There are more marks for a valid sequence than for getting one or two reactions exactly right. nce you have a sequence, you can work on the details at your leisure. owever, please note that for full credit you must specify the reagent(s), the solvent(s), the temperature (if it is different from room temperature), and any special workup conditions. You should not use generic R-groups or X-groups although I will give partial credit for such generic answers if the basic idea is correct.
Starting from N a) N N Cl Na (to p. -.0) + N NaI s (cat.) N-methylmorpholine N- oxide (NM) NaB CN acetone/ s (cat.), NaI ( equiv.) acetone/, C Cl, -78 o C then S workup Notice that the amine in the product must be inserted at the site of the alkene in the starting material. All C atoms in the starting material are present in the product, so we simply want to clip the alkene open and then close it back on the N group. We know of two reactions that insert N into a structure: the Beckmann Rearrangement and Reductive Amination. Beckmann chemistry leads to amides, and requires a ketone as starting material. This approach would require us to install unnecessary functionality, and remove it later. Reductive amination is better, because we know of several ways to convert an alkene into a pair of carbonyls. You can see one of the conventions of retrosynthetic analysis in this answer as well. The analysis is written from left to right in the retrosynthetic direction, using block arrows to show that these are not reactions, but logical backwards connections. You can then write the synthetic process in several ways. ne is to put the forward arrows and reagents etc. above the retrosynthetic arrows. You could also re-write the sequence in the forward direction. I have used a schematic approach, because I want to show that there are several alternative ways of accomplishing the same thing.
C Starting from C C This problem is quite tricky. I won't use quite such a difficult one on the exam. You need to see that the extended chain drawing of the product can be re-written in a more useful way that emphasizes its connection with the starting material. This is an example of an analysis driven by the need to use a particular reaction - the Birch Reduction. We only know of this one way to break open an aromatic ring. nce this is accomplished, we know that the resulting enol ether can be hydrolyzed to a ketone, and if we use a strong acid, the other double bond will move into conjugation. This is important, because the problem also requires the addition of a group, and the only chemistry we have discussed in this course that can form a C-C bond is a dissolving metal reduction of an enone, trapping the intermediate dianion with one equivalent of + followed by R-X. C C C C In the forward (synthetic) direction: Na (s) N (l) Cl, Li (s) N (l) C Et equiv. Et then I C C LiAl mcpba C Cl TF C
Starting from c) NaB acetone s (cat.) Ts NM acetone/ This was a much simpler problem. The formation of an acetal from a diol is not something we did in class, but it has come up in some of the problem sets. You could choose several different conditions for this reaction; I have only indicated the simplest. The final synthetic step could employ one of several reducing agents. Notice that it is important to form the acetal before reducing the ketone. If you formed a triol you would encounter serious problems of regioselectivity in subsequent acetal formation. ) Propose detailed, stepwise mechanisms to explain the following transformations. + C C C a) This is a sequence of Wagner-Meerwein rearrangements, followed by elimination.
S + N N N C + This is a Beckmann rearrangement gone bad. Notice that instead of migrating, the tertiary benzylic centre forms a highly stabilized cation by an elimination process. Further elimination forms the alkene. ) What is the product from the following Birch-type reduction? C Na N (l) C Et Mass Spectrum shows m/z = 8.9 C C C C C C N C