Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• considerable number of pacidamycin analogues. 4. The multicomponent domino reactions initiated by the Knoevenagel condensation The Knoevenagel condensation can be considered as one of the most useful tools for the formation of C=C double bonds. The condensation products, i.e., electron-deficient alkenes

• , readily act in subsequent reactions as Michael acceptors, Diels–Alder (hetero)dienes or dienophiles, or dipolarophiles. Multicomponent domino reactions initiated by the Knoevenagel condensation are a valuable tool for the construction of many compounds with complex molecular structures [90]. The syntheses

• shown in Scheme 23 and Scheme 24 represent examples of the Knoevenagel condensation-initiated domino reactions where the nucleoside aldehyde (i.e., 5-formyl-3',5'-di-O-acetyl-2'-deoxyuridine (14) or 5-formyl-2'-deoxyuridine (27)) acted as the Knoevenagel acceptor. Compounds 61 to 65 were prepared by the

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Mimoza Gjikaj and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2014, 10, 1638–1644, doi:10.3762/bjoc.10.170

• out a Knoevenagel-type condensation with benzaldehyde and 3,4-dichlorobenzaldehyde in acetic acid at 118 °C in the presence of triethylamine. Thus, the 5-arylmethylidenethiazolidin-4-ones 22–26 were obtained in 68–94% yield. The presence of only one signal for the benzylidene proton at 7.83–7.98 ppm

• thiazolidinone atropisomers, due to hindered rotation between the trichlorovinyl and the arylamino groups. X-ray analysis proved the Z-configuration of the nitrovinylidene group of 11. Subsequent reactions of the thiazolidinones, such as the SNVin thiolation in 2-position of the allylidene backbone, Knoevenagel

Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

• Akshay Kumar and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91

• -component version of the reaction by a domino Knoevenagel–Michael sequence. The Michael adduct 4a was transformed into spirooxindole 6 by a reduction with sodium borohydride in a highly enantioselective manner. Keywords: 3,3'-disubstituted oxindoles; Michael reaction; organocatalysis; primary-tertiary

• involves the initial formation of isatylidenemalononitrile by Knoevenagel condensation of isatin with malononitrile followed by the addition of acetone to provide Michael adduct 4a. Thus, catalyst 1a also finds its successful application in the multicomponet version of this reaction without compromising

• component process involving a domino Knoevenagel–Michael sequence was developed. 3,3'-Disubstituted oxindole could be transformed into spirooxindoles by reduction with NaBH4. Oxindole based Michael acceptors. Primary-tertiary diamine organocatalysts. Diamine catalyzed Michael addition of acetone to

One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines

• Christian Muschelknautz,
• Robin Visse,
• Jan Nordmann and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 599–612, doi:10.3762/bjoc.10.51

• been accessed by Knoevenagel condensations [12][13][14] or substitution reactions [15][16][17][18]. Still the quest for new synthetic strategies, novel substitution patterns, and eventually unusual properties and effects has become an ongoing challenge for organic synthesis, physical organic chemistry

Substrate dependent reaction channels of the Wolff–Kishner reduction reaction: A theoretical study

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 259–270, doi:10.3762/bjoc.10.21

• (C=O → C=C, alkene) conversion reaction, the Knoevenagel condensation [12] was utilized. While the condensation is traditionally base-catalyzed, it was found to proceed readily in water even without any catalyst [13][14]. Not only can this synthesis be considered as clean (green chemistry), but also

• conversion? An investigation about the role of the proton transfers along the hydrogen bonds may be of interest. Is a base-free W-K reduction comparable to the Knoevenagel condensation possible? Which path (a) or (b) in Scheme 2 is more favorable? Is the carbanion R1(R2)HC− a probable intermediate? Is the

• uncatalyzed (without base) Knoevenagel condensation in water. Experimental conditions and yields are taken from a) ref. [13] and b) ref. [14], respectively. Reaction models of neutral (a) and anionic (b) systems. Water molecules are linked to oxygen lone-pair orbitals and to H–N bonds of hydrazine. In the

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• ozonolysis to give aldehyde 136 [123]. Knoevenagel condensation with 4-iodooxindole was achieved in the next step. Pfitzner–Moffatt oxidation [124] followed by elimination furnished trans-divinylcycloproane 137. Submission of this compound to elevated temperature initiated a very smooth DVCPR yielding

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process. Keywords: continuous; flow chemistry; HIV; Knoevenagel; nevirapine

• acetone and malononitrile (Scheme 3) using the Vapourtec R series reactor system [38]. The batch synthesis commences with a Knoevenagel reaction condensing malononitrile and acetone catalyzed by aluminum oxide producing isopropylidenemalononitrile (4) [39][40]. The penultimate enamine 5 results by

• complicate downstream operations. We immediately recognized the water formed in the Knoevenagel condensation would quench the DMF-DMA in the second step. In addition, our batch Knoevenagel condensation was base catalyzed and we discovered that base increased dimer byproducts in the enamine step. Therefore

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• readily prepared by chlorination of 2-pyridone (1.42) with phosphorous oxychloride (Scheme 8) [31][32]. The resulting primary alcohol 1.45 is then subjected to a second SNAr reaction with 4-fluorobenzaldehyde [33]. A Knoevenagel condensation of the aldehyde functionality in compound 1.47 with

• chromium(VI) oxide yielded the aldehyde 1.67 required for the previously described Knoevenagel condensation. The five membered heterocycle 2,4-thiazolidinedione (1.68) is readily available commercially, but can be easily prepared at scale via a simple cyclocondensation between thiourea and chloroacetic

• crude material in the subsequent Knoevenagel condensation with thiazolidinedione 1.68. In order to reduce the intermediate benzylidene double bond in this example sodium borohydride is used in the presence of cobalt chloride efficiently delivering pioglitazone in high purity. Other syntheses of

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen–Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by

• conversion using NMR spectroscopy. Comparison of the values shows a good correlation (Table 1). Expanding the technique to other reactions The Knovenagel condensation We turned our attention next to the Knoevenagel condensation of ethyl acetoacetate with a range of aromatic aldehydes (Scheme 2). Our

• procedure for monitoring the Knoevenagel reaction An analogous approach was used to prepare the Knoevenagel product as for the case of 1, benzaldehyde (5.306 g, 50 mmol, 1 equiv) being used in place of salicylaldehyde and there being no need for acetone interception of the product mixture. The Raman

Enhancement of efficiency in organic photovoltaic devices containing self-complementary hydrogen-bonding domains

• Rohan J. Kumar,
• Jegadesan Subbiah and
• Andrew B. Holmes

Beilstein J. Org. Chem. 2013, 9, 1102–1110, doi:10.3762/bjoc.9.122

• ] followed by a Knoevenagel condensation provided the target compound 2 in excellent yield. The solubilizing strategy of incorporating alkyl groups on the thiophene unit provided the compound with excellent solubility in a wide range of common solvents. Optoelectronic properties In chloroform solution the UV

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• imaging, particularly [18F]FDDNP (152), although this scaffold is also represented by only a few examples in the literature. Compound 152 was prepared starting from 1-(6-hydroxy-2-naphthyl)-1-ethanone (153) via a Bucherer reaction with 2-(methylamino)ethanol (154) followed by Knoevenagel reaction of 155

Synthesis of functionalized spiro[indoline-3,4’-pyridines] and spiro[indoline-3,4’-pyridinones] via one-pot four-component reactions

• Li-Juan Zhang,
• Qun Wu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 846–851, doi:10.3762/bjoc.9.97

• ester A from the addition of arylamine to methyl propiolate. The second reaction is a Knoevenagel condensation of isatin with malononitrile or ethyl cyanoacetate under the catalysis of triethylamine to give the isatylidene deriatives B. The third reaction is a Michael addition of β-enamino ester

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• a C-2 phenyl substituent. The synthesis of flavans and flavones generally involves treatment of acetophenone (7) with a base to give enolate 8, which undergoes a Knoevenagel condensation with salicylaldehyde (5) to yield a chalcone 9. These chalcone derivatives are then cyclized by using various

• cleavage of the MOM protected hydroxy group delivered the desired flavan 16 in good yield. On the basis of the above precedent by Xue and co-workers, our group accomplished the synthesis of an array of flavans of type 10 [19]. The synthesis begins with a Knoevenagel reaction of salicylaldehyde (5) and

• and co-workers achieved the synthesis of flavone 11 relying on the reaction of salicylaldehyde (5) and an enolate derived from acetophenone (7, Scheme 5) [20]. To begin, chalcone 9 was prepared in 85% yield by the Knoevenagel reaction of salicylaldehyde (5) and acetophenone (7) in the presence of KOH

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• synthesis of the para-trifluoromethyl substituted unit A started with a modified Knoevenagel condensation [23][31]. The required aldehyde 9 was obtained by DIBAL-H reduction of the corresponding methyl ester 8 and was found to decompose upon chromatographic purification (Scheme 1). However, it can usually

• be employed in the Knoevenagel condensation without purification. Reaction of 9 with malonic acid in the presence of piperidine/acetic acid gave the β,γ-unsaturated carboxylic acid 10. The latter compound was transformed into the methyl ester by treatment with SOCl2 in methanol. The resulting ester

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• (up to 98% de). Later on the same group [71] developed another hydrogen-bond-mediated catalysis for the synthesis of tetrasubstituted thiochromans having three continuous stereocenters 49 following domino thio-Michael–Knoevenagel reaction between 2-mercaptobenzaldehydes 34 and benzylidenemalonates 48

• Córdova and co-workers. Enantioselective tandem Michael–Henry reaction of 2-mercaptobenzaldehyde with β-nitrostyrenes reported by Zhao. Enantioselective tandem Michael–Knoevenagel reaction between 2-mercaptobenzaldehydes and benzylidenemalonates, as developed by the Zhao group. Cinchona alkaloid thiourea

Catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to nitroalkenes by a grinding method

• Zong-Bo Xie,
• Na Wang,
• Ming-Yu Wu,
• Ting He,
• Zhang-Gao Le and
• Xiao-Qi Yu

Beilstein J. Org. Chem. 2012, 8, 534–538, doi:10.3762/bjoc.8.61

• reactions occur more efficiently in the solid state than in solution due to a more tight and regular arrangement of the substrate molecules [14]. Thus, the grinding mode for solid-state reactions had been applied in the Reformatsky reaction [15], Dieckmann condensation [16], Knoevenagel condensation [17

Branching out at C-2 of septanosides. Synthesis of 2-deoxy-2-C-alkyl/aryl septanosides from a bromo-oxepine

• Supriya Dey and
• Narayanaswamy Jayaraman

Beilstein J. Org. Chem. 2012, 8, 522–527, doi:10.3762/bjoc.8.59

• been explored in many instances, for example, (i) hemiacetal or acetal formation from a linear precursor containing aldehyde and an appropriately positioned hydroxyl group [4][5][6][7][8]; (ii) Knoevenagel-type condensation of sugar aldehyde with active methylene compounds [9][10]; (iii) ring-closing

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• acceptor obtained from an initial Knoevenagel condensation (Scheme 5). In order to improve the overall yield as well as the convergency, the industrial route [7] introduced the fully elaborated side chain 34 by condensation with the previously described 1,4-diketone 31 (Scheme 5 and Scheme 6). The desired

The preparation of 3-substituted-1,5-dibromopentanes as precursors to heteracyclohexanes

• Bryan Ringstrand,
• Martin Oltmanns,
• Jeffrey A. Batt,
• Aleksandra Jankowiak,
• Richard P. Denicola and
• Piotr Kaszynski

Beilstein J. Org. Chem. 2011, 7, 386–393, doi:10.3762/bjoc.7.49

• ]. The second route (Method 1B) consists of a Knoevenagel condensation of malonate diester and an aldehyde followed by conjugate addition of a second equivalent of malonate diester. The tetraester is hydrolyzed, decarboxylated, esterified, and then reduced to give the diol. Yields for tetraesters are in

• % yield. Reduction of 4 gave diol 2a in nearly quantitative yield (Scheme 4). Reaction of hexanal with excess dimethyl malonate under Knoevenagel conditions gave dimethyl 3-pentylglutarate (5) in 57% yield after decarboxylation and esterification (Scheme 5). 3-Propylglutarate 4 was obtained in a similar

Chromo- and fluorophoric water-soluble polymers and silica particles by nucleophilic substitution reaction of poly(vinyl amine)

• Katja Hofmann,
• Ingolf Kahle,
• Frank Simon and
• Stefan Spange

Beilstein J. Org. Chem. 2010, 6, No. 79, doi:10.3762/bjoc.6.79

• material acenaphthylene-1,2-dione undergoes a Knoevenagel condensation with malononitrile to give mono-adduct 2. Compound 2 was originally synthesized by Junek et al. [38]. However, no detailed NMR data were reported. In a second step, cyclization with anhydrous K2CO3 converted 2 to 1 in a good yield. In

Synthesis of some novel annulated pyrido[2,3-d]pyrimidines via stereoselective intramolecular hetero Diels–Alder reactions of 1-oxa-1,3-butadienes

• Mohit L. Deb and
• Pulak J. Bhuyan

Beilstein J. Org. Chem. 2010, 6, No. 11, doi:10.3762/bjoc.6.11

• the mixtures of both the cis- and trans-isomers [52][53]. When N-methylallylamine (2b) or N-benzylallylamine (2c) was used for the reaction as shown in Scheme 1, the Knoevenagel condensation did not occur even after refluxing in the presence of piperidine. The reason might be the delocalization of the

• 3a as a yellow solid 568 mg (95%). Similarly, 3b–c were prepared from the reaction of 1 with 2b–c. Knoevenagel condensation of 3 with cyclic β-diamide/β-diketones 4 and synthesis of 5: Equimolar amounts of 3a (2 mmol, 598 mg) and 4a (2 mmol, 312 mg) were mixed thoroughly in a round-bottomed flask

• consideration of its spectroscopic data. In case of N-methylallylamine 2b and N-benzylallylamine 2c, N,N-diisopropylethylamine (DIPEA) was used as catalyst for the Knoevenagel condensation and reactions were performed under reflux in ethanol for 3 h. The method gave satisfactory yields of up to 90%. Compounds

Hydroxyapatite supported caesium carbonate as a new recyclable solid base catalyst for the Knoevenagel condensation in water

• Monika Gupta,
• Rajive Gupta and
• Medha Anand

Beilstein J. Org. Chem. 2009, 5, No. 68, doi:10.3762/bjoc.5.68

• Monika Gupta Rajive Gupta Medha Anand Department of Chemistry, University of Jammu, Jammu 180 006, India 10.3762/bjoc.5.68 Abstract The Knoevenagel condensation between aromatic aldehydes and malononitrile, ethyl cyanoacetate or malonic acid with hydroxyapatite supported caesium carbonate in

• water is described. HAP–Cs2CO3 was found to be a highly active, stable and recyclable catalyst under the reaction conditions. Keywords: ethyl cyanoacetate; hydroxyapatite supported caesium carbonate; Knoevenagel condensation; malonic acid; malononitrile; Introduction An area of recent intense

• across a diverse array of C–C bond forming reactions. Without doubt, an alternative strategy for the Knoevenagel condensation [7] by this approach is worthwhile since it produces an extended domain of useful products for use in the pharmaceutical and biomedical industries. Arylidenemalononitriles are

Zeolite catalyzed solvent- free one-pot synthesis of dihydropyrimidin- 2(1H)-ones – A practical synthesis of monastrol

• Mukund G. Kulkarni,
• Sanjay W. Chavhan,
• Mahadev P. Shinde,
• Dnyaneshwar D. Gaikwad,
• Ajit S. Borhade,
• Attrimuni P. Dhondge,
• Yunnus B. Shaikh,
• Vijay B. Ningdale,
• Mayur P. Desai and
• Deekshaputra R. Birhade

Beilstein J. Org. Chem. 2009, 5, No. 4, doi:10.3762/bjoc.5.4

• conditions, even on using excess of ethyl acetoacetate (2 mmol), no side product arising through Knoevenagel condensation [41] was observed. This methodology was effective for aliphatic as well as aromatic aldehydes in the preparation of dihydropyrimidones (4a–4l) with uniformly high yields (Table 1). This

Catalytic synthesis of (E)-α,β-unsaturated esters from aldehydes and 1,1-diethoxyethylene

• Rubén Manzano,
• Lidia Ozores,
• Andreas Job,
• Lars Rodefeld and
• Benjamin List

Beilstein J. Org. Chem. 2009, 5, No. 3, doi:10.3762/bjoc.5.3

• satisfactory with respect to the demand for atom economy is still needed [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. We have recently developed a new approach based on the Knoevenagel condensation of readily available and inexpensive malonate half esters with aldehydes which

Sordarin, an antifungal agent with a unique mode of action

• Huan Liang

Beilstein J. Org. Chem. 2008, 4, No. 31, doi:10.3762/bjoc.4.31

• (Scheme 9). The latter was directly converted to a β-ketoester by reaction with ethyl diazoacetate in the presence of SnCl2. A final Knoevenagel cyclization afforded substance 45. The enantioselective synthesis implemented an improved procedure that relied on alkylation of the metallohydrazone of 43 with

• dioxenone 47. This allowed the Knoevenagel condensation to be performed directly. In both the racemic and asymmetric syntheses, tricyclic compound 48 was prepared by Cu(I)-catalyzed conjugate addition of vinylmagnesium chloride to 45 in the presence of TMSCl, followed by enol acetylation (Scheme 10