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Synthetic studies on O-heterocycles via cycloadditions. Part 2. Adducts from styrene oxides
Abstract
The styrene oxides (14) and (15), bearing electron-withdrawing functions, readily undergo thermal and photochemical (triplet sensitised) dipolar cycloadditions with simple electron-deficient olefins, regioselectively in the case of methyl acrylate. However, cycloadditions with 5-arylbutenolides as dipolarophiles, required for lignan synthesis, could not be effected in significant yield. A new short route to 5-arylbut-2-enolides was devised. The dihydro- and tetrahydro-furan adducts (18d), (19d), and (20d) all fragment in base to the dienol nitrile (25).
... 20 Although there is sufficient literature evidence available for synthesis of R, -unsaturated keto esters, the present set of conditions afforded compounds 38, 39, and 75-84 in better yields and are scalable. [21][22][23][24][25][26][27][28] As dihydropyrazole analogues 4-24 contained a chiral center at position 5, the above synthesis provides a target compound in the form of racemic mixture. To further explore the stereochemical (chiral) requirements/consequences for binding to the CB1 receptor, the key compound 9 was synthesized as a chiraly pure moiety by introducing resolution at suitable stage. ...
A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.
of main observation and conclusion
The first LA‐catalyzed [3 + 2]IMCC of GDA‐epoxides with carbon‐carbon double bonds has been developed. This provides an efficient and general strategy for construction of bridged oxa‐[n.2.1] skeletons. A novel SN‐like mechanism through a carbon‐carbon bond cleavage of epoxide ring has been proposed.
The styrene oxides (III) and (IX), bearing electron-withdrawing functions, readily undergo thermal and photochemical (triplet sensitized) dipolar cycloadditions with simple electron-deficient compounds such as (II), (IV), (VI), (X).
The photoreactions of [60]fullerene (C60) with various epoxides have been investigated. Trans 2-aroyl-3-aryloxiranes reacted with [60]fullerene giving both the major cis products and the minor trans adducts. The influence of substituent group on aryl ring on the photoreaction is entirely different from that of preliminary reported thermal reaction. In addition, the photo condition could avoid the decomposition of some original epoxides compared to the thermal condition at high temperature. It provides a simple and efficient route to synthesize C60-fused tetrahydrofuran derivatives.
This document is part of Subvolume C2 `Chemical Shifts and Coupling
Constants for Hydrogen-1. Part 2: Heterocycles' of Volume 35 `Nuclear
Magnetic Resonance (NMR) Data' of Landolt-Börnstein - Group III
Condensed Matter.
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Reactions of tricarbonyl compounds with vinyl diazo compounds 2 were carried out. Reaction of 1,2,3-indanetrione with 2a,b,c gave the spiroindan-1,3-dione-2,2′-benzodihydrooxepin 7a,b,c, but not normal products oxirane and dihydrofuran derivatives expected from intermediate vinyl carbonyl ylides 4. Formation of 7 requires isomerization of vinyl carbonyl ylides 4 bearing a (Z)-cyanostyryl group to unstable (E)-form 5 and subsequent cyclization to oxepin 6 followed by a 1,5-hydrogen shift. However, reaction of 2 with six-membered cyclic tricarbonyl compounds 1,2,3-trioxo-2,3-dihydrophenalene 11 and dimethylalloxane 13 gave the dioxole 12 and the dihydrofuran 14, respectively, typical products expected from vinyl carbonyl ylides.
Imidazolophanes 3 bridged by short chains (n = 5, 6) are readily accessible by [3 + 2] cycloadditions of imines with 2, formed from the bicyclic azirines 1 under electron-transfer conditions. Other heterocyclophanes can also be prepared by this method. DCN = naphthalene dicarbonitrile.
Photoinduced electron-transfer conditions (the photoexcitation of the electron acceptor naphthalenedicarbonitrile (DCN)) are required for [3 + 2] cycloadditions of azirines (1) with imines, which afford N-substituted imidazoles (3). Probable intermediates are the radical cations 2, which were detected by the trapping reaction with trifluoroethanol.
This review covers synthetic routes to lignans belonging to the 2,6-disubstituted dioxabicyclo[3.3.0]octane subclass (also known as furofurans). The different approaches have been loosely categorised according to the synthetic strategies applied. The routes discussed range from the classical biomimetic oxidative coupling of cinnamyl derivatives to more recent asymmetric syntheses.
1 Introduction
2 Synthetic Routes to Furofurans
2.1 Oxidative Dimerisation of Cinnamyl Alcohols and Cinnamic Acids and Enolate Anions
2.2 Approaches Based on Conjugate Addition of Acyl Anion Equivalents
2.3 Approaches Based on Aldol Chemistry
2.4 Approaches Based on Cycloaddition/Rearrangement
2.5 Radical and Photochemical Strategies
2.6 Transition Metal Mediated Strategies
3 Concluding Remarks
Cycloadditions of aldehydes with carbonyl ylides to give dioxolanes have been carried out without solvent under microwave irradiation. The reactions proceeded in similar yields and stereoselectivities, but in shorter reaction times, than those obtained in toluene at reflux using an oil bath. Cycloadditions conducted between imines and carbonyl ylides using the same protocol were less efficient because the oxazolidines formed proved unstable under the reaction conditions.
Photocyclization of aryl vinyl ethers reportedly proceeds via carbonyl ylide intermediates. The photochemical behavior of several aryl vinyl ethers, which incorporate a pendant alkene side chain, was explored. Naphthyl vinyl ethers 1c and 1d provided products that are consistent with photocyclization and subsequent intramolecular ylide-alkene addition. Product distribution is influenced by solvent and temperature effects. Thus, irradiation of 1c in toluene provides 9a in 87% yield. However, irradiation of 1c in methanol/toluene (1:1) provides 3c (45%), 11 (24%), and 12 (23%). Product 12 results from photoinitiated intramolecular [2 + 2] cycloaddition of the butenoate ester side chain to the naphthalene system.
The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and alkynes (phenylacetylene, methyl propiolate, methyl but-2-ynoate and methyl 3-phenylpropiolate) to give substituted 2,5-dihydrofurans was investigated. The effect of indium(iii) chloride on the outcome of the reaction was studied in the case of phenylacetylene and methyl propiolate. The thermal reaction between the carbonyl ylide coming from 2,2-dicyano-3-phenyloxirane and both methyl propiolate and methyl but-2-ynoate was theoretically investigated using DFT methods in order to explain the reactivity and regioselectivity observed.
The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted dioxolanes and spirocyclic dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained.
A single method is never sufficient, which is why there is a great need for developing many diverse and creative approaches towards every chemical substrate class. This statement is supported by the contents of this perspective in addition to providing the reader with a helpful synthetic roadmap for selecting a suitable method for the building blocks being discussed. Detailed in this review are eight different synthetic approaches that provide access to valuable 2,5-dihydro- furan, thiophene and pyrrole building blocks. Each approach is briefly presented and its limits discussed. The strengths and weaknesses of each approach are further highlighted with a graphical table summary at the end. This summary clearly drives home the point that for every chemical substrate class we need many good methods in order to provide access to every member of each class.
Rh(2)(OAc)(4)-catalyzed reaction of vinyldiazo compound 1a in the presence of p-methoxybenz- 2a, mesit- 2b, and p-chlorobenzaldehyde 2c gave a mixture of isomeric vinyloxiranes 3a-c and 4a-c, and sterically unstable (E)-dihydrofurans 5a-c, but not stable (Z)-dihydrofurans 6. However, the reactions with p-nitro- 2d and 2,4-dinitrobenzaldehyde 2e gave (Z)-dihydrofurans 6d,e along with 3d, 4d, and 5d,e. The reaction in the presence of maleic anhydride and dimethyl fumarate gave single 1,3-dipolar cycloadducts 11 and 13, respectively, indicating that a single conformer, the sterically unstable endo-aryl-endo-cyanostyryl carbonyl ylide 14 (15), is initially formed in the reaction of 1 with 2. It was concluded that the endo-vinyl-exo-aryl vinylcarbonyl ylides 17a-c arising from 2a-c undergo disrotatory cylization to exclusively produce 5, whereas the ylides 17d,e arising from 2d,e undergo partly symmetry-forbidden conrotaory cyclization to sterically stable trans-diaryldihydrofurans 6d,e as well as the symmetry-allowed process to 5d,e.
The thermal reaction of [60]fullerene (C60) with the carbonyl ylides generated in situ from trans-epoxides to give C60-fused tetrahydrofuran derivatives has been investigated. The reaction of C60 with trans-2-benzoyl-3-aryloxiranes afforded only cis-products, while the reaction of C60 with 2-cyano-2-ethoxycarbonyl-3-aryloxiranes gave exclusively or predominantly cis isomers. The isomeric distributions of the latter reactions were drastically affected by the substituent on the phenyl ring.
Contrary to the established literature, 'isocubebinic ether', 'cubebinic ether', and 'cubebinol' are acid-catalysed cyclisation products, (IV), (VII; R = OAc), and (VII: R = H), respectively. Their formation from (-)-cubebin (I) is discussed. The first synthesis of cubebin is described. (±)-α-(3,4-Methylenedioxybenzyl)-β-(3,4- methylenedioxybenzylidene) succinic acid (XIII) is prepared by a double Stobbe approach and resolved with quinine. Reduction to the diol (XXI) and oxidation with manganese dioxide gives (+)-, (-)-, and (±)-hibalactone (XXII) [the first synthesis of the natural (-)-form]; selective oxidation with this reagent gives dehydrocubebin (XXIII). (+)-, (-)-, and (±)-Isohinokinin (XXV) are obtained by hydrogenation of the corresponding hibalactones; epimerisation of (+)-and (-)-isohinokinin gives (-) and (+)-hinokinin (XXVI) respectively. By selective reduction with sodium aluminium hydride the lactone (-)-hinokinin is converted into the hemiacetal (-)-cubebin (I).
A combination of the reaction of dianions of (phenylthio) acetic acid and its homologs with epoxides, the conjugate addition reaction of 3-phenylthio-2-(5H)-furanones with carbanion species, and the α-alkylation reaction of α-phenylthio-γ-butyrolactones is shown to provide a general method for the synthesis of a variety of substituted α-phenylthio-γ-butyrolactones. Oxidation of these α-phenylthiolactones to the corresponding sulfoxides, followed by pyrolysis furnishes all the types of substituted (3-, 4-, and 5-mono-; 3,4-, 3,5- 4,5-, and 5,5-di-; 3,4,5-tri-) 2(5H)-furanones in good overall yields.
Naturally occurring 4-hydroxy-2-vinylbut-2-en-4-olide (V), an allenic analogue [4-hydroxy-3,3-dimethyl-2-vinylidenebutan-4-olide (VII)], and the corresponding aldehyde ester [ethyl 2-(1-formyl-1-methylethyl)buta-2,3-dienoate (VIII)] have been synthesised by a Claisen-type sigmatropic rearrangement of 3-carboxyprop-2-ynyl vinyl ethers.
Die beiden Sultone (Ia) und (Ib) geben bei der unsensibilisierten Photolyse übe.