Ammonia Knoevenagel reaction

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

The Knoevenagel reaction [3] is one of the most important C-C bond-forming reactions available to synthetic chemists. It is widely used in the synthesis of important intermediates or end-products for perfumes [4], pharmaceuticals [5], e. g. antihypertensive and calcium antagonists [6], and polymers [7]. The reaction is catalyzed by bases, acids, or catalysts containing acid-base sites [8], e. g. bases such as ammonia, primary and secondary amines and their salts [1], and Lewis acids such as CUCI2 [9], ZnCl2 [10], and Sml3 [11]. 

The Knoevenagel reaction is one of the oldest C-C bond forming reactions (see also Section 7.1) [36]. It involves the condensation of a carbonyl component (typically benzaldehyde) with a C-acid (typically ethyl cyanoacetate)-Figure 5. This classical reaction is usually catalyzed by organic bases (primary, secondary, and tertiary amines), ammonia, and ammonium salts [37]. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

In contrast to alkylation in liquid ammonia/sodamide, only the mono-alkylated product is formed. A variety of carbanion reactions can be carried out. Ketones undergo the Knoevenagel reaction. The Wittig reaction is successful with aldehydes, and olefines can be transformed into halocyclopropanes via carbene addition (e.g. equation 12.14). 

The condensation of aldehydes or ketones, with active methylene compounds (especially malonic ester) in presence of a weak base like ammonia or amine (primary or secondary) is known as Knoevenagel reaction. However, when condensation is carried out in presence of pyridine as a base, decarboxylation usually occurs during the condensation. This is known as Doebner modification. Some examples are given (Scheme 37). 

Knoevenagel condensation is a classic C-C bond formation reaction. It occurs between aldehydes or ketones and active methylene compounds with ammonia or another amine as a catalyst in organic solvents. The Knoevenagel reaction is considered to be a modification of the aldol reaction. The main difference between these approaches is the higher acidity of the active methylene hydrogen as compared to a carbonyl hydrogen. 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

A novel basic support and catalyst have been prepared by activation of aluminium phosphate with ammonia. Fine control of time and temperature allows to adjust the 0/N ratio of these oxynitride solids and thus to tune the acid-base properties. The aluminophosphate oxynitrides are active in Knoevenagel condensation, but a basicity range can not yet determined. Supporting Pt or Pt/Sn on AlPONs allows to prepare catalysts that are highly active and selective in dehydrogenation reactions. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

Compound 85 was dehydrogenated at 300° over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86) was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92) was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-cinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol 94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53). 

A series of tetrasubstituted thiazole derivatives 28 has been prepared via a multi-component tandem protocol <07T10054>. Reaction of bis(aroylmethyl)sulfides 23 with aryl aldehydes and ammonium acetate in 1 2 1 ratio under solvent-free microwave irradiation affords 28 in good yields. This reaction presumably starts with Knoevenagel condensation of sulfide with 2 equiv. of aryl aldehydes to give 24. Michael addition with ammonia and concomitant cyclocondensation lead to 26. Base-catalyzed ring opening of 26 to 27 and ring... 

Selenophene-2-aldehyde takes part in the Hantzsch synthesis [Eq. (I)]108 and reacts readily with ammonia, aromatic amines and diamines,109 hippuric, barbituric, and malonic acids, malononitrile,70 and rhodanine.109 /3-(Selenien-2-yl)acrylic acid has been obtained from selenophene-2-aldehyde by the Perkin reaction and by Knoevenagel condensation with malonic acid.70 Esters of /9-(selenien-2-yl)acrylic acid are easily formed by condensation of the aldehyde... 

Sonochemistry has been applied to acceleration of the Reformatsky reaction, Diels-Alder reactions, the arylation of active methylene compounds nucleophilic aromatic substitution of haloarenes, and to hydrostannation and tin hydride reduction. " Other sonochemical applications involve the reaction of benzyl chloride and nitrobenzene, a Sr I reaction in liquid ammonia at room temperature, and Knoevenagel condensation of aromatic aldehydes. lodination of aliphatic hydrocarbons can be accelerated, and oxyallyl cations have been prepared from ot,ot -diiodoketones using sonochemistry. Sonochemistry has been applied to the preparation of carbohydrate compounds.When sonochemistry is an important feature of a chemical reaction, this fact will be noted in the reactions presented in Chapters 10-19. 

The Knoevenagel condensation with 1,3-dicaibonyls followed by a Michael reaction of a second molecule of the methylene compound, with or without addition of an amine or ammonia, may be used for the qualitative and quantitative determination of aldehydes even in the presence of ketones. Thus, cyclic 3-diketones such as dimedone (59) react with aldehydes but not with ketones in the absence of a catalyst. For the characterization the bis(2,6-dioxo-4,4-dimethylcyclohexyl)methanes (67) or the 4,6-dioxo-2,2,8,8-tetramethyl-l,2,3,4,5,6,7,8-octahydro-9F/-xanthene (68) may used. ... 

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