An example of the experimental procedure of the Dieckmann condensation is exemplified by the synthesis of 3-quinuclidone hydrochloride. This preparation involves two steps. In the first step, 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine is treated with potassium ethoxide in refluxing toluene leading to the formation of the bridgehead bicyclic system via the Dieckmann condensation. In the second step, the intermediate is decarboxylated via treatment with concentrated hydrochloric acid.

Experimental:

3-Quinuclidone hydrochloride

1. Dieckmann Condensation:

Freshly cut potassium (40 g, 1.03 mol) is added to 165 mL of dry toluene under inert atmosphere. The mixture is heated at reflux until the potassium has melted. Absolute ethanol (63 mL, 49.3 g, 1.07 mol) is then added over 30 minutes to the rapidly stirred solution at reflux. Upon the disappearance of the potassium metal, the temperature of the reaction mixture is raised to 130 °C and 1-((ethoxycarbonyl)methyl)-4-carbethoxypiperidine (100 g, 0.411 mol) in 250 mL of dry toluene is added dropwise over 2 hours.

After heating at 130 °C for an additional 3 hours, the reaction mixture is cooled to 0 °C followed by slow addition of 250 mL 10M hydrochloric acid. The resulting mixture is then extracted with 10M hydrochloric acid (2X125 mL).

2. Decarboxylation:

The combined aqueous fractions are heated at reflux for 15 hours followed by the addition of 5 g of activated charcoal. The resulting mixture is then filtered and evaporated to dryness in vacuo. The crude product is then dissolved in 150 mL of water and saturated aqueous potassium carbonate is added very slowly to avoid foaming until the solution has become basic. The resulting solution is then treated with solid potassium carbonate until a slurry is obtained, followed by extraction with diethyl ether (4X200 mL). The combined organic fractions are then treated with calcined potassium carbonate. After 60 minutes the mixture is filtered and concentrated in vacuo. The resulting solid is then treated with 75 g of ice and 10M hydrochloric acid (65 mL, 75 g) followed by evaporation to dryness. The resulting material is then purified via recrystallization from hot water and boiling isopropanol.

The Dieckmann Condensation is an intramolecular variant of the Claisen Condensation. The reaction is most commonly used to prepare 5 or 6 membered ring ß-keto esters. The formation of 5 membered rings tends to be faster than 6 membered rings, although the 6 membered ring products are generally more thermodynamically stable. Ring formation becomes progressively more difficult to accomplish as the ring size of the desired product increases.

The reaction typically employs the sodium alkoxide of the alcohol that corresponds to the alcoholic moiety of the ester functional groups. The reaction can also be promoted by the use of one equivalent of sodium hydride and a catalytic amount of the corresponding alcohol.

The Dieckmann Condensation generally cannot be used to prepare small, highly strained ring systems. Rather than form a three membered ring, diethyl succinate undergoes an intermolecular Claisen Condensation followed by a Dieckmann Condensation to afford the six membered ring compound instead of reacting to form the three membered ring ß-keto ester as shown below.

See 3-quinuclidone hydrochloride for an example of a laboratory procedure for the Dieckmann condensation.

References:
Dieckmann, W. Ber., 1894, 27, 102, 965.
Dieckmann, W. Ber., 1900, 33, 595, 2670.
Dieckmann, W. Ann., 1901, 317, 51, 93.
Schaefer, J.P.; Bloomfield, J.J. Org. React., 1967, 15, 1-203.
J. Org. Chem., 1998, 63, 4069-4078.
T. R. Hoye, V. Dvornikovs, E. Sizova, Org. Lett., 2006, 8, 5089-5091.
Davis, B. R.; Garrett, P. J. Comp. Org. Syn. 1991, 2, 806-829. (Review)
Janice Gorzynski Smith. Organic Chemistry: Second Ed. 2008. pp 932-933.

The Claisen Condensation is an important carbon-carbon bond forming reaction that produces a 1,3-dicarbonyl compound from an ester and another carbonyl compound. The intramolecular variant of the reaction is known as the Dieckmann Condensation. The reaction is performed under basic conditions, usually using the alkoxide form of the alcohol component of the ester to avoid transesterification.

The reaction usually involves the reaction of two molecules of the same ester to avoid forming a mixture of different condensation products. An ester and a different carbonyl compound can be used however, particularly when the ester does not possess an enolizable hydrogen atom α to the carbonyl. This variant is known as the Crossed Claisen Condensation.

The mechanism involves formation of the enolate of the compound that will react with the ester as a nucleophile. The enolate is formed via deprotonation of a hydrogen atom α to the carbonyl. The enolate then attacks the carbonyl carbon of the ester, and the tetrahedral intermediate undergoes elimination of alkoxide.

The driving force of the reaction is the deprotonation of the resulting 1,3-dicarbonyl compound condensation product. Hydrogen atoms that are α to two carbonyl carbon atoms are significantly more acidic than either the alcohol or the starting materials and essentially all of the 1,3-dicarbonyl product will be deprotonated in solution. For example, the pKa of ethyl acetoacetate (shown above) is 11, whereas the pKa of ethanol is 16.

The Claisen Condensation differs from the Aldol Condensation because the Aldol Condensation forms an intermediate β-hydroxy carbonyl compound which undergoes elimination to form an α,β-unsaturated carbonyl compound. In the Claisen Condensation however, the resulting tetrahedral intermediate is a hemiketal which can eliminate alkoxide to form the ketone.

The Aldol Condensation is one of the most fundamental carbon-carbon-bond forming reactions in organic synthesis. Two carbonyl compounds, each of which may be either an aldehyde or a ketone, undergo a base-promoted condensation to afford an α,β-unsaturated carbonyl compound.

The reaction takes place in two stages. First, the enol form of one of the carbonyl compounds attacks the non-enolized carbonyl carbon atom of the second compound. This results in the formation of a β-hydroxy carbonyl compound. In the second stage, the intermediate tautomerizes to the enol form and a molecule of water is eliminated. This second step is possible only if the first enolizable compound possesses two hydrogen atoms on a carbon adjacent to the carbonyl because it must be able to tautomerize to the enol form twice. If only one such hydrogen atom is present, the reaction can proceed no farther than the β-hydroxy carbonyl compound.

Scheme:

The Mannich Reaction is an important carbon-carbon-bond forming reaction that is commonly employed in the synthesis of alkaloid natural products and is involved in a number of biosynthetic pathways. The reaction uses three components: an amine, a non-enolizable aldehyde or ketone, and a compound containing an enolizable carbonyl moiety. The final product of the reaction is a β-amino-carbonyl compound.

Mechanism:

The amine and non-enolizable aldehyde or ketone react to form an iminium ion or “Schiff base”. The second carbonyl compound tautomerizes to the enol form and attacks the iminium ion at the electrophilic carbon atom. The reaction typically requires long reaction times and elevated temperature under acidic conditions.

The reaction has continued to enjoy frequent use by synthetic chemists and has been employed in a several of the most important accomplishments in organic synthesis including strychnine, quinine, and atropine. The reaction has been extended by the discovery that a catalytic amount of (S)-proline, an inexpensive and naturally occurring amino acid, can be used to control the stereoselectivity of the reaction and provide products with high ee (enantiomeric excess).

Experimental Procedure:

For an example of the laboratory procedure for the Mannich reaction, see the synthesis of 4-(diethylamino)butan-2-one.

References:

Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III (2002). “A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives”. Journal of the American Chemical Society 124 (9): 1866–1867. doi:10.1021/ja017833p.

Mannich, C.; Krosche, W. (1912). “Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin”. Archiv der Pharmazie 250: 647–667. doi:10.1002/ardp.19122500151.

Mitsumori S., Zhang H., Ha-Yeon Cheong P., Houk K. N.,Tanaka F., Barbas III C. F. (2006). “Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid”. Journal of the American Chemical Society 128 (4): 1040–1041. doi:10.1021/ja056984f.