Michael and Aldol Condensation Reactions

Crystallization Devising a procedure Critical thinking application 

In Experiment 37 ( The Aldol Condensation Reaction Preparation of Benzalacetophenones ), substituted benzaldehydes are reacted with acetophenone in a crossed aldol condensation to prepare benzalacetophenones (chalcones). This is illustrated in the following reaction, where Ar and Ph are used as abbreviations for a substituted benzene ring and the phenyl group, respectively.  

Experiment 38 involves the reaction between ethyl acetoacetate and trans-chalcone in the presence of base. Under the conditions of this experiment, a sequence of three reactions takes place a Michael addition followed by an internal aldol reaction and a dehydration. 

You will be assigned one of the aromatic aldehydes shown in the following list. For each aldehyde, the melting points of the corresponding chalcone and the Michael/aldol product are given  

If your starting compound is 4-chlorobenzaldehyde, all filtrates should be poured into a waste container designated for halogenated organic wastes. If you use one of the other three aldehydes, dispose of all filtrates in the container designated for nonhalogenated organic wastes. 

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Preparation of an a,IB-Unsaturated Ketone via Michael and Aldol Condensation Reactions... 

There is some similarity between the cracking of petroleum and the cracking of biomass. However, biomass is more complex chemically both in terms of structrual types and functional groups. In petrochemistry, hydrocarbons are fractionated and they are then functionalized by oxidation, halogenation, nitration and other chemical processes so as to add value. The commodity chemicals are then built up into more complex molecules using such popular synthetic methods as Friedel Craft reactions, Michael and aldol condensations, and Heck and Suzuki couplings. The speciality products of these reactions are then further elaborated into formulations for use in everyday applications ranging from personal care... 

New and continuing efforts towards the total synthesis of dendrobine (59 R = H) have been reported.In one sequence (Scheme 8), the butyric acid (85) was readily transformed into the ketal (86), which was submitted to a Birch reduction and hydrolysis to yield the cyclohexenone (87) as the single diastereomeric product. Acid treatment of (87) gave a stereoisomeric mixture of products (88) which were not separated but subjected to reaction with base to give compound (89). The same compound was obtained directly by treatment of (87) with strong base (Michael and aldol condensations combined). After some discouraging results, the tricyclic compound (89) was transformed into the desired keto-acid (90) via an abnormal ozonolysis reaction. Compound (90) possesses the correct stereochemistry at three asymmetric centres required for elaboration of dendrobine (59 R = H). 

The inexpensive and readily available diisopropylamine was used in the iminium-ion-forming process for domino Michael addition/aldol condensation reaction to N-hydroxypyrrole 232 (Scheme 7.49). When a variety of different functional groups at R3 of the a,P-unsaturated aldehydes 231 were tried (phenylethyl, benzoxypropyl, and 2-(tert-butoxycarbonylamino)ethyl), the process was efficient in forming the highly substituted hydroxypyrroles 232. However, aromatic groups in this position were unsuccessful. The regioselectivity of the domino reaction in water and methods for the later synthesis of liT-pyrrole were also reported [116]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

During 1989-93 lithium perchlorate iethyl ether (LiC104 EtiO, LP-DE) was studied as a reaction medium in organic synthesis when it was observed that cycloadditions, sigmatropic rearrangements, Michael additions and aldol condensations carried out in LP-DE occurred quickly and selectively under mild reaction conditions [33]. In addition, LP-DE allowed the reaction and subsequent work-up to be carried out under essentially neutral conditions. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

The reaction is very slow in acetic acid alone, and accelerated as acetate by the addition of bases [59]. These two isomers undergo Pd-catalysed allylic rearrangement with each other. 3-Acetoxy-l,7-octadiene (139) is converted to the allylic alcohol 157 and to the enone 158, which is used as a bisannulation reagent [60], Thus Michael addition of 158 to 2-methylcyclopentanedione (159) and aldol condensation give 160. The terminal alkene is oxidized using PdCl2/CuCl/02 to the methyl ketone 161. After reduction of the double bond in 161, aldol condensation affords the tricyclic system 162. 

Fig. 13.72. Tandem reaction II, consisting of Michael addition and aldol condensation.

Since both oxidative splitting of the double bond and aldol condensation represent reliable and general reactions, their sequence serves as an efficient route for the transformation of readily available cyclohexene systems e.g. formed via the Diels-Alder reaction or Robinson annulation) into functionalized cyclopentene derivatives. This standard operational mode is extensively used in total syntheses. One of the numerous examples, the synthesis of helminthosporal 463, the sesquiterpenoid toxin of fungi, is shown in Scheme 2.150. In the initial phases of the synthesis, commercially available (—)-carvomenthone 464 was transformed into 465 via Michael reaction with methyl vinyl ketone to give 466 and subsequent intramolecular aldol condensation. 

In particular, we have described selected examples of the application of monofunctional supported catalysts in reactions of considerable synthetic interest such as aldol, Michael and Knoevenagel condensations. In general. 

At high-temperature conditions, the product distributions of typical decar-boxylative and aldol condensations vary with temperature, time on stream, and catalyst age. Several ketone isomers can be produced. With acetic acid, e.g., C5-C7 (e.g., methylhexanone, pentan-2-one, 3,3 -dimethylbutan-2-one) ketones and alkylphenols arise from acetone aldolization. An important cyclic product in low temperature acetone aldolization is isophorone (2-cyclohexen-l-one, 3,5,5 -trimethyl), formed by the aldol condensation of acetone with mesityl oxide, followed by 1,6-Michael addition. In reactions with acetic acid, we have observed 2-cyclohexen-l-one, 3,5-dimethyl, which is probably a cracking product of isophorone, and small amounts of isophorone itself. Cracking to produce... 

Robinson annulation reactions involve two steps Michael addition and aldol condensation. Assume that Michael addition leads to the following intermediate. What would be produced when this intermediate undergoes aldol condensation ... 

Use as a Base. TBAF has been widely used for a variety of base-catalyzed reactions such as alkylation, elimination, halogenation, Michael addition, " aldol condensation, and intramolecular cycUzations. " It is especially useful when other inorganic bases face solubility problems in organic solvents. The reactions are usually carried out below 100 °C due to the low thermal stability of TBAF. ... 

The horizontal approach for the DEF synthon was more rewarding due to its simplicity and more importantly due to its straightforwardness. The easily obtainable acetylene precursor 107 underwent synchronous Michael-aldol condensation reaction with dimethyl acetone dicarboxylate to give 108 which was smoothly transformed into 86a (Scheme 22). 

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

Through a domino oxa-Michael-aldol condensation reaction, a range of 2-substituted 3-formyl-2E/-chromenes were prepared from salicylaldehydes and a,p unsaturated aldehydes catalyzed by a diphenylperhydro indoUnol... 

Fukumoto and coworkers [45, 46] have observed a threefold domino SN/Michael/aldol condensation reaction on treatment of an acetylcyclopropane... 

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

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