Knovenagel reaction

Functionalizing C-5 of 2,4-oxazolidinediones is generally accomplished by alkylation or Knovenagel reaction (Schemes 6.66-6.69). For example, treating 251 (R = H, Ri = Me) with 3 equiv of LDA followed by two equivalents of a protected bromo alcohol and deprotection with dilute hydrochloric acid gave the... 

A. C. Cope, H. L. Holmes, and H. O. House, Org. Reactions, 9, 107 (1957) House, p. 510. c Commonly catalyzed by ammonia or an amine, the Knovenagel reaction. Amine may in some cases act as proton acceptor, in other cases as nucleophilic catalyst. Dehydration usually occurs and shifts equilibrium in favor of product. 

While the DCJTB series replaced the active methyl group with tert-butyl or iso-propyl substituents to avoid bis-Knovenagel condensation reactions during the synthesis of DCM or DCJ series, Zhang et al. came up with the idea of using substituted cyclohexane rings to block the reactive site of the pyran ring. They then synthesized a series of 4H-benzopyran-based red emitters (158-160) as shown in Scheme 3.49 [210]. 

Otherwise, the same products can be obtained by a Knovenagel-type reaction between )3-cyanosulphones and aromatic aldehydes in the presence of sodium telluride (behaving as a base). This result is consistent with the above-formulated desulphonylation of an intermediate a-alkylidene )3-cyanosulphone at the expense of the sodium hydrogen telluride formed during the reaction. 

The Knovenagel condensation under basic conditions was first investigated with D-glucosamine chlorhydrate (28.HC1) as the sugar. The condensation of this reducing amino sugar with pentane-2,4-dione 1 in aqueous acetone in the presence of sodium carbonate afforded the pyrrole derivative 29 in 85% yield [99] (Scheme 5). The reaction was extended to other 2-amino-2-deoxy-aldose and carbon nucleophiles [100-104]. 

An important issue with respect to the Knovenagel condensation is that a mixture of isomeric disubstituted 3-methyleneoxindoles can be obtained. NMR measurements, including nOe experiments, and quantum chemical calculations have also shown that 3-[cyano(ethoxycarbonyl)methylene]-2-oxindoles, which are obtained from the reaction of isatin or from 1-methylisatin with ethyl cyanoacetate, exist as a mixture of the E and Z isomers, and that the E isomer exists in an equilibrium between two conformers, trans-s-cis and (rans-s-/ram431 (Scheme 100). 

Aldol and Knoevenagel condensations. The aldol reaction between 1,4-cyclo-hexanedione and aldehydes to give 2-substituted hydroquinones is conducted with LiCl in refluxing p)nidine. Microwave irradiation facilitates Knovenagel condensation using LiCl as catalyst, otherwise NMP is employed as solvent. 

A microwave-promoted solvent-free Knovenagel condensation has been used as a tool for exposing students to new preparative chemistry techniques, identification of a product using analytical methods, and use of the Karplus rule for identification of stereoisomers by H-NMR spectroscopy. The experiment was designed for and tested in a second-year organic chemistry laboratory. It involved the reaction of methyl... 

It is assumed that the reaction proceeded by Knovenagel condensation of 1,3-dione and aldehyde, followed by Michael addition of the phthalhydrazide (11), and subsequent cyclization to afford the product 25 or 27. 

The Knovenagel condensation reactions are very often used as a test reaction for characterizing the basic properties of solid bases, especially, the condensation of benzaldehyde [reaction (12)] and ethyl cyanoacetae, and malonitrile are often used as favorite test reactions. Table 5 lists the results of the reaction of benzaldehyde and ethyl cyanoacetate over typical solid-base catalysts. 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

Scheme 9.84. A representation of the Knovenagel condensation. The reaction shown is the reaction between benzenecarboxaldehyde (benzaldehyde, QH5CHO) and diethyl propanedi-carboxylate (diethyl malonate [CH2(C02CH2CH3)2]) in the presence of azacyclohexane (piperidine, QHuN) and azabenzene (pyridine, QH5N).The early work was reported by Japp, F. R. Streatfield, F. W. J. Chem. Soc., 1883,43,27, and only later by Knovenagel, who developed the reaction further. See Knovenagel, E. Chem. Ber., 1898,31,735 and references therein.

The entire manifold of aldol-type condensation reactions. The aldol condensation itself (Equation 9.45, el seq) and all of those in Table 9.5 (viz. the Claisen, Stobbe, Perkin, and Knovenagel condensation reactions and the Robinson annulation). 

When using acetoacetic esters as 1,3-dicarhonyl compounds in the presence of tertiary amine and 2-hydro g yridine as a dual catalyst, aldolisation adducts were obtained giving a simple access to carbon-elongated branched carbohydrates. This reaction was conducted at room temperature in DMSO no competitive Knovenagel condensation (Lubineau reaction) products were deteeted. 

Matyus et al. described a cascade Knovenagel/1,5-hydride transfer/cyclization reactions of 4-aryl-2-phenyl-1,4-benzoxazepine derivatives 19, which furnished fused 0,A -heterocycles 20 containing tetrahydro-l,4-benzoxazepine and tetrahydroquinoline moieties with high yields and diastereoselectivity (Scheme 9) [92]. Basically, under thermal conditions, the benzylidene intermediate I generated in situ... 

Figure 17.4 Representation of the crystal structures accompanying the formation of desolvated 20 (catalyst for Knovenagel condensation) from 20 (catalyst for cyanosilylation reaction).

Scheme 17.7 (a) Cyanosilylation reaction of aromatic aldehydes to cyanohydrins (b) Knovenagel condensation of aromatic aldehydes to... 

Another method has been shown using the Knovenagel condensation reaction with a ketone precursor (127). This process is shown in Figure 2.37. 

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