Knoevenagel intramolecular

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6 ... 

An a ,/3-epoxycarboxylic ester (also called glycidic ester) 3 is formed upon reaction of a a-halo ester 2 with an aldehyde or ketone 1 in the presence of a base such as sodium ethoxide or sodium amide. Mechanistically it is a Knoevenagel-type reaction of the aldehyde or ketone 1 with the deprotonated a-halo ester to the a-halo alkoxide 4, followed by an intramolecular nucleophilic substitution reaction to give the epoxide 3 ... 

An intramolecular variant of this cycloaddition process is combined with a Knoevenagel reaction in a total synthesis of the insectan leporin A, a pyrano[3,2-c]pyridine derivative <96JOC2839>. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The CDE rings of camptothecin were synthesized via an intramolecular Knoevenagel condensation of 124 (Equation 30) <2004TL7247>. The tricyclic dihydropyridone 125 was aromatized to the pyridone with NBS/ KHMDS (NBS - iV-bromosuccinimide, KHMDS - potassium hexamethyldisilazane). 

A Knoevenagel condensation followed by a double intramolecular cyclization provides a route from the ketohy-drazone 506 to the thienopyrimidopyridazine 507 (Equation 232) <2000JRM510, 2000PS(167)29>. 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

Scheme 1. Inter-intramolecular domino-Knoevenagel-hetero-Diels-Alder reaction...

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Scheme 33 Preparation of the substrate (220) for an intramolecular Knoevenagel condensation...

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... 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

Intramolecular cyclization. Knoevenagel condensation of diphenylacetaldehyde with diethyl malonate (piperidinium acetate catalysis) results in only a trace of the expected product when molecular sieves are present, the a-naphthol 1 is formed in 52% yield.2 A similar reaction is observed with ethyl acetoacetate and ethyl benzoylacetate. 

The selective nucleophilic displacement of one ortho nitro group from 2,4,6-trinitrotoluene by esters of mercap-toacetic acid followed by oxidation leads to 2-(alkoxycarbonyl)methylsulfonyl compounds. These sulfones react with aromatic aldehydes under Knoevenagel conditions to produce thiochroman 1,1-dioxides 477, probably via a stilbene and a subsequent intramolecular Michael addition. Activating groups other than nitro are compatible with the route (Scheme 167) <2003RJ0397>. 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

Quaternary ammonium hydroxides anchored on MCM-41 provide stronger base catalysts than amine analogues11731 and were able to catalyse the same reaction as previously reported namely for the intermolecular Michael reaction leading to flavanone.[181] Moreover, this catalyst induced the successive intramolecular olefinic attack of the phenolic group from the Knoevenagel condensation product of salicylaldehyde and diethyl glutaconate (Scheme 9.6). This fast cyclization leads to chromene derivatives (1) from which subsequent conversions induced by proton abstraction from the alpha position of the ester function gives coumarin... 

The domino reaction consists of a Knoevenagel condensation giving an intermediate that immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [31]. As aldehydes, rac-dtronellal, an aromatic aldehyde, and two commercially available 1,3-diketones, 1,3-dimethylbarbituric add and Meldrum s acid, were seleded. By combinations of these reactants, different cycloadducts were generated. 

Sulfinyl dienes and vinyl sulfoxides have rarely been used in asymmetric hete-ro-Diels-Alder reactions [145]. The first example was reported in 1992 and describes an intramolecular cycloaddition using a heterodiene bearing a chiral sulfinyl group [146a]. In this paper, the conversion of a-p-tolylsulfinyl a,ft-unsaturated ketone 176 (prepared by Knoevenagel reaction of 3-methylcitronellal and (S)-p-toluenesulfinylacetone) into the hetero-Diels-Alder adducts 177... 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

Tetrahydroalstonine 7-7, a heteroyohimboid alkaloid, has been synthesised in enantiopure form by Martin et al. by means of an oxa Diels-Alder reaction as key step. The trienic precursor 7-5 underwent a thermal intramolecular cycloaddition to form a 5 1 mixture of 7-6 and its 15/J-epimer. The main cycloadduct was then subjected to a straightforward sequence to yield the natural product 7-7 (Fig. 7-2) [483-485]. In earlier work, Ogasawara et al. have employed a con-ceptionally different domino Knoevenagel-hetero Diels-Alder approach to this alkaloid and other natural products [486-488]. 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

The reaction under these conditions is sometimes called the Knoevenagel reaction after its nine-leenth century inventor, and presumably uses the enolate anion of the monocarboxylate of the malonic acid. Though this enolate is dianion, its extensive delocalization and the intramolecular hydrogen bond make it really quite stable. 

One of the most common strategies for the preparation of thiophenes involves the intramolecular condensation of -thioglycolates with adjacent carbonyls (Knoevenagel synthesis) a representative example is shown in Scheme 103. 

Alkali-exchanged mesoporous molecular sieves are suitable solid base catalysts for the conversion of bulky molecules which cannot access the pores of zeolites. For example, Na- and Cs-exchanged MCM-41 were active catalysts for the Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate (pKa=10.7) but low conversions were observed with the less acidic diethyl malonate (pKa=13.3) [123]. Similarly, Na-MCM-41 catalyzed the aldol condensation of several bulky ketones with benzaldehyde, including the example depicted in Fig. 2.38, in which a flavonone is obtained by subsequent intramolecular Michael-type addition [123]. 

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