Stobbe condensations

Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of a base. 

Stobbe, H. Ber. Dtsch. Chem. Ges. 1893, 26, 2312. Hans Stobbe (1860-1938) was bom in Tiehenhof, Germany. He earned his Ph.D. in 1889 at the University of Leipzig where he became a professor in 1894. 

Moldvai, 1. Temesvari-Major, E. Gacs-Baitz, E. Egyed, O. Gomory, A. Nyulaszi, L. Szantay, C. Heterocycles 2001, 53, 759. 

Jv -CHO. COjMe 1. t-BuOK, t-BuOH, reflux COjMe 2. AcjO, NaOAc, reflux 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 248, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 266, Springer International Publishing Switzerland 2014 

Condensation of diethyl sueeinate and its derivatives with earbonyl eompounds in the presenee of bases. 

The Stobbe Condensation. When succinic ester derivatives (such as diethyl succinate, 215) are condensed with non-enolizable ketones or aldehydes in the presence of base, the initial condensation product is 216. The alkoxide reacts with the distal ester via acyl substitution to give a lactone intermediate (217). In the original version of this reaction, saponification of 217 gave the a-alkylidene monoester, 218. The reaction is not completely general and is limited to those a, co-diesters for which the Dieckmann condensation is not a 

The synthesis of paraconic acids described above starts from succinic acid the Stobbe condensation uses succinic esters and their substitution products  

R2CO + ROOCCH2CH2COOR + NaOR----------- R2C=C(COOR)CH2CH2COONa+2ROH 

The carbonyl compounds that can undergo this condensation include aliphatic, aromatic, and %,/ -unsaturated aldehydes, aliphatic, saturated carbo-cyclic, and aromatic ketones, diketones, oxo esters, and cyano ketones. Sodium ethoxide and potassium terf-butoxide are the condensing agents generally used. 

3-(Ethoxycarbonyl)-4,4-diphenyl-3-butenoic acid 927 Benzophenone (9.11 g, 0.05 mole) and diethyl succinate (13.05 g, 0.075 mole) are added to a solution of potassium (2.15 g, 0.055 mole) in dry tert-butyl alcohol (45 ml) with cooling. The air is replaced by dry nitrogen, and the mixture is boiled gently for 0.5 h and then cooled and acidified with dilute hydrochloric acid. The terf-butyl alcohol and ethanol are then removed in a vacuum and the residue is treated with water and extracted with ether. The acid ester is extracted from the ethereal solution into 20% sodium hydroxide solution whence it is obtained (13.94 g, 90% m.p. 119-123°) by acidification. After recrystallization from benzene-light petroleum it melts at 125-126°. 

alkenyl, acyl, CH(R)C02alkyl, CH(R)CN R = alkyl, aryl R = H, alkyl, aryl, alkylidene base NaOR , 

KOf-Bu, NaH, NaOEt, Na metal, NaCPha solvent Et20, EtOH, f-BuOH 

The first step of the Stobbe condensation is the deprotonation of the succinate at the a-carbon to afford an ester enolate that in situ undergoes an aldol reaction with the carbonyl compound to form a 3-alkoxy ester intermediate. The following intramolecular acyl substitution gives rise to a y-lactone intermediate which undergoes ring-opening and concomittant double bond formation upon deprotonation by the alkoxide ion. Under certain conditions the lactone intermediate can be isolated. 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

NaOMe (4 equiv) MeOH, reflux, 6h HOOC C02Me H2/MeOH HOOC COoMg s steps. MeO 0  

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The condensation of aldehydes and ketones with succinic esters in the presence of sodium ethoxide is known as the Stobbe condensation. The reaction with sodium ethoxide is comparatively slow and a httlo reduction of the ketonic compound to the carbinol usually occurs a shorter reaction time and a better yield is generally obtained with the more powerful condensing agent potassium ieri.-butoxide or with sodium hydride. Thus benzophenone condenses with diethyl succinate in the presence of potassium [Pg.919]

The Stobbe condensation thus provides a method for introducing a propionic acid residue at the site of a carbonyl group. 

Stephen reaction Stobbe condensation UUmann reaction Willgerodt reaction. ... 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Succinic esters condense with aldehydes and ketones in the presence of bases, eg, sodium alkoxide or piperidine, to form monoesters of alkybdenesuccinic acids, eg, condensation of diethyl succinate with acetone yields ethyl 2-isopropyhdenesuccinate (eq. 3). This reaction, known as Stobbe condensation, is specific for succinic esters and substituted succinic esters (98,99). 

Aromatic aldehydes (100), eg, cinnamaldehyde, and ketones (101) react ia a similar manner (eq. 4). Ketones containing reactive methyl or methylene groups give with succiaates, ia the presence of sodium hydride, both the Stobbe condensation and the formation of diketones by a Claisen mechanism (102) (eq. 5). 

KNOEVENAGEL OOEBNER STOBBE Condensation Base catalyzed aldol condensation of aldehydes or ketones with an activated methylene group of a malonic ester (Knoevenagel Doebner) or a succinic ester (Stobbe)... 

The. synthesis starts with the Stobbe condensation of diethylsuccinate and 3,4-dichloroben-zophenone (13). The product (14) is hydrolyzed and decarboxylated to a cis-trans mixture of olefins (15). This last is reduced using a Pd/C catalyst and then undergoes unidirectional Friedel-Crafts intramolecular acylation into the more reactive ring to produce substituted tetralone 16. 

An intriguing rearrangement was reported by Yates (72) during an attempt to carry out the Stobbe condensation. It resulted in the formation of a cyclopropane derivative from 4-benzoyloxycyclohexanone by the (proposed) mechanism shown. 

The Stobbe condensation has been extended to di-rert-butyl esters of glutaric... 

Table 6 Stobbe condensation reaction of 22 and 23 in the solid state...

Stirrer, for caustic fusion, 30, 104, 105 seal for, 30, 54 Stobbe condensation, 30, 18 Styrene, 33, 72 Styrene dibromide, 30, 73 Styrene oxide, 31, 3 Succinic acid, cc-benzhydrylidene-,... 

Although some attention has been paid to the hydrogenation of / -substituted itaconates, that can be prepared by Stobbe condensation, this class of com-... 

Stilbenes, photocyclization of, 30, 1 StiUe reaction, 50, 1 Stobbe condensation, 6, 1 Substitution reactions using organocopper reagents, 22, 2 41, 2 Sugars, synthesis by glycosylation with sulfoxides and sulfinates, 64, 2 Sulfide reduction of nitroarenes, 20, 4 Sulfonation of aromatic hydrocarbons and aryl halides, 3, 4 Swem oxidation, 39, 3 53, 1... 

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