Cycloaddition reactions of 1,3-diazabuta-1,3-dienes with alkynyl ketenes

The cycloaddition reactions of ‘all-carbon’ 1,3-diazabuta-1,3-dienes with a few conjugated and unconjugated alkynyl ketenes are described. The reactions provide some interesting azetidinones and dihydropyrimidinones bearing an alkynyl moiety. The regiochemistry of cycloadduct is related with the degree of conjugation of the alkynyl ketene. Moreover, two alternative approaches to ‘all-carbon’ 1,3-diazabuta-1,3-dienes are reported.     

Synthesis of novel heterocyclic fused 1,3-diazabuta-1,3-dienes and accompanying rearrangements in their cycloaddition reactions with ketenes: synthesis of heterocyclic fused pyrimidinone derivatives

The reactions of 1,3-diazabuta-1,3-dienes 1 with 2-aminothiophenol have been shown to result in excellent yields of N-benzothiazol-2-yl-N′-aryl benzamidines 2. Their regioselective [4+2] cycloadditions with various ketenes are shown to yield novel benzothiazolo pyrimidinones 4. A similar and convenient protocol for the synthesis of bisthiosubstituted 1,3-diazabuta-1,3-dienes 8 and 9 and interesting rearrangements accompanying their [4+2] cycloadditions with a number of ketenes are described.     

Reaktionen von 4,4-Bis(trifluormethyl)-1,3-diazabuta-1,3-dienen. Synthese trifluormethyl-substituierter Heterocyclenvia Baylis-Hillman-Reaktion

Summary 4,4-Bis(trifluoromethyl)-1,3-diazabuta-1,3-dienes and ,-unsaturated heteromultiple bond systems react to givebis(trifluoromethyl) substituted heterocycles. The first step of the formal [4+2] cycloaddition represents aBaylis-Hillman reaction.

Prof. Dr. Rolf Huisgen zum 75. Geburtstag gewidmet     

Palladium-Catalyzed [4+2] Cycloaddition of Vinyl Benzoxazinanones with 1,3-Indanedione: Approach to Spiro-Tetrahydroquinoline Scaffolds

A palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 2-arylidene indan-1,3-dione has been established, which afford a series of bioactive spiro-tetrahydroquinolines (27 examples) in moderate to good yield (up to 87 %) with high diastereoselectivities. The synthetic utility of this reaction was demonstrated by gram-scale synthesis. Compounds synthesized by this method potently inhibited proliferation in a panel of cancer cell lines. Particularly, the most potent compounds 3 ae , 3 ah , 3 aj and 3 fa displayed selective inhibition of MDA-MB-231 breast carcinoma cells with IC₅₀ values of 1.292, 0.6118, 0.6558, 1.656 and 2.215 μM, respectively.     

Catalytic asymmetric synthesis of polysubstituted cyclohexa-1,3-dienes from β-branched α,β-alkenals

3-Methyl- and 3-phenylbut-2-enal in the presence of (S)-prolinol (0.1 eq.) in benzene or THF react with the acidic monoesters of alkenylidene, and arylmethylidene-, and alkylidenemalonic acids at –10 to +22 °C to give optically active esters of 4,6-disubstituted cyclohexa-1,3-diene-l-carboxylic acids in moderate (10–43 %) yields. The enantiomeric purity of the products formed from the lint two types of acidic ylidenemalonates varies from 28 to 68 % and is higher than that observed in the case of related alkylidenemalonates. Under similar conditions cyclohexylideneacetaldehyde affords optically active derivatives of 1,5,6,7,8,8a-hexahydronaphthalene as mixtures ofcis andtrans isomers. The enantiomeric purity and absolute configuration of the cyclohexadienes thus obtained were determined using¹H NMR spectroscopy in combination with chiral solvating agents.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 663–669, March, 1996.     

Behavior ofZ- andE-s-cis-ferrocenyl-1,3-dienes in cycloaddition and dimerization reactions

Z-3-Ferrocenylmethylene-2-methylenecamphane andE-2-ferrocenylmethylene-3-methylenequinuclidine were synthesized by isomerization of the corresponding isomericE- andZ-1,3-dienes in an acidic medium. The dienes obtained form [4+2]-cycloadditionendo-adducts withN-phenylmaleimide, do not form cyclodimers upon thermal or acid-catalyzed [4+2]-cyclodimerization, and addZ-3-ferrocenylmethylene-1,2,7,7-tetramethylbicyclo[2.2.1]hept-2-ylium andE-2-ferrocenylmethylene-3-methyl-1-azoniabicyclo[2.2.1]oct-3-ylium salts, respectively, at the terminal methylene group to give linear addition products. The latter undergo fragmentation on treatment with HBF₄ to form the corresponding carbocation tetrafluroborates. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1223–1228, June, 1998.     

Cycloaddition of a 1,2-diaza-1,3-butadiene to phenylpropiolic acid: an efficient route to pyridazinoquinolone derivatives

Diazocoupling of dihydroquinolin-4-ones with aryldiazonium nitrates gave the corresponding diazo derivatives, which undergo facile (4+2) cycloaddition reactions with phenylpropiolic acid to afford 2-aryl-4a-methyl-10-oxo-4-phenyl-2,4a,5,10-tetrahydropyridazino[4,3-b]quinoline-3-carboxylic acid derivatives 3. However, with β-nitrostyrene a mixture of three isomeric products 4a-c was obtained.     

Synthesis of 1,3-dithiole-2-thiones and tetrathiafulvalenes using oligo-(1,3-dithiole-2,4,5-trithione). (Review)

Methods for the synthesis of 1,3-dithiole-2-thiones, based on [4+2] cycloaddition of the 1,3-dithiole-2,4,5-trithione oligomer to various unsaturated acyclic, carbocyclic, and heterocyclic compounds, are reviewed. Methods for the production of substituted tetrathiafulvalenes, which can be regarded as derivatives of bis(ethylenedithio)tetrathiafulvalene, from 1,3-dithiole-2-thiones synthesized by this method are described. Dedicated to the memory of Professor O. Neilands. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 483–502, April, 2006.     

One Stone for Three Birds‐Rhodium‐Catalyzed Highly Diastereoselective Intramolecular [4+2] Cycloaddition of Optically Active Allene‐1,3‐dienes

RhCl(PPh₃)₃‐catalyzed [4+2] intramolecular cycloaddition of optically active axially chiral allene‐dienes afforded cis‐fused [3.4.0]‐bicyclic products with three chiral centers in good yields with an excellent chemo‐ and diastereoselectivity. A pair of enantiomers of such products was generated highly selectively from both enantiomers of starting allene‐dienes, indicating that the axial chirality dictated the absolute configurations of the three in situ generated chiral centers with a very high efficiency of chirality transfer.     

Polyfluorobenzoyl chlorides and isothiocyanates in reactions with CH-reactive benzimidazoles

Reactions of 2-benzoylmethylbenzimidazole with tetra- and pentafluorobenzoyl chlorides afford fluorine-containing 6-benzoyl-7H-benzimidazo[3,2-a]quinolones. 2-Cyanomethyl- or 2-benzoylmethylbenzimidazole reacts with tetra(penta) fluorobenzoyl isothiocyanates to give fluorine containing 1,3-benzothiazinones, which differently behave in reactions with cycloalkylimines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 720–724, March, 2005.     

O-Isocyanates as Uncharged 1,3-Dipole Equivalents in [3+2] Cycloadditions

1,3-Dipoles are commonly used in [3+2] cycloadditions, whereas isoelectronic uncharged dipole variants remain underdeveloped. In contrast to conventional 1,3-dipoles, uncharged dipole equivalents form zwitterionic cycloadducts, which can be exploited to build further molecular complexity. In this work, the first cycloadditions of oxygen-substituted isocyanates (O-isocyanates) were studied experimentally and by DFT calculations. This unique cycloaddition strategy provides access to a novel class of heterocycle aza-oxonium ylides through intramolecular and intermolecular cycloadditions with alkenes. This allowed a systematic study of the reactivity of the transient aza-oxonium ylide intermediate, which can undergo N−O bond cleavage followed by nitrene C−H insertion, and the formation of β-lactams or isoxazolidinones upon varying the structure of the alkene or O-isocyanate reagents.     

Synthesis of Poly-Substituted Pyridines via Noble-Metal-Free Cycloaddition of Ketones and Imines

An eco-friendly and noble-metal-free formal [4+2] cycloaddition reaction was developed for the efficient synthesis of biologically interesting poly-substituted pyridines from easily available ketones and imines, whereby two sequential C−C bonds are formed. The given approach features a unique synthetic strategy of imines and ketones with wide substrate scope, good functional group tolerance, mild conditions and operational simplicity, which represents a more direct pathway to synthesize poly-substituted pyridines than traditional methods.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

A Novel Method to Construct 2-Aminobenzofurans via [4 + 1] Cycloaddition Reaction of In Situ Generated Ortho-Quinone Methides with Isocyanides

A new approach for the synthesis of 2-aminobenzofurans has been described via Sc(OTf)₃ mediated formal cycloaddition of isocyanides with the in situ generated ortho-quinone methides (o-QMs) from o-hydroxybenzhydryl alcohol. Notably, as a class of readily available and highly active intermediates, o-QMs were first used in the construction of benzofurans. This [4 + 1] cycloaddition reaction provides a straightforward and efficient methodology for the construction of 2-aminobenzofurans scaffold in good yield (up to 93% yield) under mild conditions.     

A Convenient Synthesis of 1,2,4-Triazolo-1,3,5-triazin-4-ones and 1,2,4-Triazolo-1,3,5-triazin-4-thiones

The imidates derived from 3-aminotriazole 1 react with isocyanates and isothiocyanates to give corresponding 1,2,4-triazolo-1,3,5-triazin-4-ones and 1,2,4-triazolo-1,3,5-triazin-4-thiones in a 60–75% overall yield. If the condensation is realized at r.t., then the intermediate 2 can be isolated.     

Rhodium(I)-Catalyzed Three-Component [4+2+1] Cycloaddition of Two Vinylallenes and CO

Transition metal-catalyzed [4+2+1] reactions of dienes (or diene derivatives such as vinylallenes), alkynes/alkenes, and CO (or carbenes) are expected to be the most straightforward approach to synthesize challenging seven-membered ring compounds, but so far only limited successes have been realized. Here, an unexpected three-component [4+2+1] reaction between two vinylallenes and CO was discovered to give highly functionalized tropone derivatives under mild conditions, where one vinylallene acts as a C₄ synthon, the other vinylallene as a C₂ synthon, and CO as a C₁ synthon. It was proposed that this reaction occurred via oxidative cyclization of the diene part of one vinylallene molecule, followed by insertion of the terminal alkene part of the allene moiety in another vinylallene, into the Rh−C bond of five-membered rhodacycle. Then, CO insertion and reductive elimination gave the [4+2+1] cycloadduct. Further experimental exploration of why ene/yne-vinylallenes and CO gave monocyclic tropone derivatives instead of 6/7-bicyclic ring products were reported here.     

6-Aryl-2,2-dimethyl-1,3-dioxin-4-ones: Synthesis and Chemical Characteristics. (Review)

Methods for the production of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones and their thermolysis in the presence of nucleophiles and dienophiles are discussed     

Thermally-Induced Intramolecular [4+2] Cycloaddition of Allylamino- or Allyloxy-Tethered Alkylidenecyclopropanes

A thermally-induced intramolecular [4+2] cycloaddition reaction of allylamino- or allyloxy-tethered alkylidenecyclopropanes has been reported in this paper, giving a new protocol for the rapid construction of polycyclic skeleton molecules in moderate to excellent yields with a broad substrate scope. On the basis of control experiments and DFT calculations, we disclosed that the reaction proceeded through a [4+2] cycloaddition and trace of water assisted 1,3-H shift process to give the target product.     

Synthesis of Novel Spiro Pyrrolidine and Pyrrolizine Derivatives by 1,3-Dipolar Cycloaddition

The 1,3‐dipolar cycloaddition of azomethine ylides derived from isatin and amino acids viz. sarcosine and proline to 2‐arylmethylidene‐5,6‐dihydroimidazo[2,1‐b]thiazol‐3(2H)‐ones afforded novel spiro pyrrolidines and pyrrolizidines regio‐ and stereoselectively in moderate yields. The products were characterized thoroughly by IR, MS, NMR together with elementary analysis.