Synthesis of racemic nicotine

Question

In my advanced organic chemistry course, we were asked to fill the following scheme for the synthesis of racemic nicotine, starting with ethyl nicotinate:

Exercise 6: Complete the following scheme showing the synthesis of racemic nicotine.

I believe, that the first step is a Claisen condensation reaction, forming the 1,3-dicarbonyl compound.

The next step is the amide hydrolysis step, forming a carboxylic acid and the amine functionality.

The third step is the decarboxylation. However, the next step is a hydrogenation; has the compound to cyclize first? Then we would have an enamine that would be reduced, however we would have formed the product by then, making the last two steps unnecessary..

Does anyone have any tips?

Answer 1

You are correct about the Claisen condensation and the decarboxylation. You can't solve the synthesis as shown because there are too many steps. Ethyl nicotinate (1) and the lactam 2 condense to form the sodium salt of 3 in a reaction stoichiometric in base. That is to say, the reaction is not catalytic in base. Vigorous treatment with aq. HCl will neutralize the sodium salt 3, hydrolyse the lactam, and effect decarboxylation of the intermediate β-ketocarboxylic acid forming the salt 4. In my experience in a related case, neutralization of the salt with aqueous alkali, extraction with ether, and drying the extract over anhydrous $\ce{MgSO4}$ will afford dehydronicotine 5 via enamine formation. Hydrogenation produces racemic nicotine 6. The last two steps of the scheme are unnecessary. This said, I believe the scheme is made up. See the reference below and citations therein.

1. C. J. Dunsmore, R. Carr, T. Fleming, and N. J. Turner, J. Am. Chem. Soc., 2006, 128, 2224.

Answer 2

It seems you are in right track. I also wasn't sure why that last two steps are necessary. I have filled the necessary structures of your scheme since you have shown your understanding of the procedure:

This method of synthesis is a useful older method (Ref.1 & 2), still used to synthesize substituted nicotine starting with substituted nicotinate esters (e.g., Ref.3). In usual method, most researchers have used N-vinyl pyrrolidinone instead of N-methyl pyrrolidinone as in given question (Ref.2 has used this starting material). Thus, I put usual structures given in literature in the given boxes and put expected structures outside them in blue boxes. The structures in given boxes are consistence with those in literature where they have used N-vinyl pyrrolidinone (e.g., Ref.1 & 3). The flow of the process is described in Ref.1 by stating:

[...] base-catalyzed condensation of ethyl 5-bromonicotinate(3) with vinyl pyrrolidinone, followed by acid-catalyzed hydrolysis, decarboxylation, and cyclization to 4 during basic workup.

It is important that basic workup with concentrated $\ce{NaOH}$ after acid hydrolysis is important process that course the cyclization (as OP questioned), which is missing in the given flow chart. I put it in here in red letters. It is also note that decarboxylation happens during hydrolysis, not in separate step as shown in the chart. As OP questioned, the last two steps is a mystery. There is no mentioned of acid workup in any literature I have conducted (see recent review Ref.4). It is known fact that use of chiral acids here to enhance enantiomeric purity but given question is about synthesis of racemic mixture.

References:

1. Peyton Jacob III, "Resolution of ($\pm$)-5-bromonornicotine. Synthesis of (R)- and (S)-nornicotine of high enantiomeric purity," J. Org. Chem. 1982, 47(21), 4165−4167 (https://doi.org/10.1021/jo00142a032).
2. Akio Ide, Kunihiko Matsumori, and Hiroyasu Watanabe, "Synthesis of 3-(1-Methyl-2-pyrrolidinyl)quinoline," Nippon kagaku zassi 1970, 91(6), 578-580 (https://doi.org/10.1246/nikkashi1948.91.6_578).
3. Leo S. Bleicher, Nicholas D. P. Cosford, Audrey Herbaut, J. Stuart McCallum, and Ian A. McDonald, "A Practical and Efficient Synthesis of the Selective Neuronal Acetylcholine-Gated Ion Channel Agonist (S)-(−)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y)," J. Org. Chem. 1998, 63(4), 1109–1118 (https://doi.org/10.1021/jo971572d).
4. Florence F. Wagner, and Daniel L. Comins, "Recent advances in the synthesis of nicotine and its derivatives," Tetrahedron 2007, 63(34), 8065-8082 (https://doi.org/10.1016/j.tet.2007.04.100).

Answer 3

I got the answer key. Problem is, I didn't think it would be possible to hydrogenate the ketone functionality to the alcohol using Pd/C. Never seen it. Rest makes sense, SN1 reaction for the iodine subsitution, and subsequent cyclization and removal of ammonium proton by potassium carbonate.