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Intramolecular dipolar cycloaddition reactions with azomethine ylides
Abstract
The intramolecular 1,3-dipolar cycloaddition reactions of several aziridine carboxylates containing a neighboring π bond were studied. The only reaction found to occur on thermolysis of cis- and trans-allyl 1-isopropyl-2-(p-biphenyl)-3-aziridinecarboxylate corresponds to isomerization about the three-membered ring. With this system, equilibration of the ring-opened azomethine ylides occurs at a faster rate than internal cycloaddition. Attachment of an electron-withdrawing carbomethoxy substituent to the double bond was found to significantly enhance the intramolecular dipolar cycloaddition rate. Isomerization of the less reactive cis-azomethine ylide to the trans form was still found to compete with the cycloaddition reaction. An additional system which was also studied involved the thermal chemistry of cis- and trans-methyl N-(4-carbomethoxy-3-butenyl)-2-(p-biphenyl)-3-aziridinecarboxylate. The azomethine ylides derived from these aziridines undergo regioselective cycloadditions which are compatible with the principles of frontier MO theory.
... The 1,3-dipolar cycloaddition of azomethine ylides with olefinic dipolarophile is identified as one of the most attractive strategy for the construction of isolated as well as fused pyrrolidine ring systems. 2,3 Taking the advantage of the regio-and stereoselectivity of such cycloadditions, compounds possessing complex molecular framework such as eserethole, 4 erythramine, 5 α-lycorane, 6 allokainic acid, 7 acromelic acid, 8 (-)-kainic acid, 9 sceletium alkaloid A4, 10 menzamine alkaloids, 11 martinelline alkaloids 12 and various other bicyclic [13][14][15][16] and polycyclic [17][18][19] fused pyrrolidine ring systems such as 2-azatricyclo[5.2.1.0 4,10 ]decanes, 20 and 2,5diazatricyclo [5.2.1.0 ...
... The color of the reaction mixture gradually turned dark brown and the reaction was completed within 46 h with the concomitant formation of silver mirror on the surface of the reaction flask. The reaction mixture was passed through a Celite pad and the residue was purified by silica gel column chromatography using chloroform / methanol (7:3) to afford a single product 15a in 61 % yield, characterized by 1 H NMR, 13 C NMR and mass spectral data (Scheme 5). ...
Various new structural entities related to X-azatricyclo[m.n.0.0. a,b]alkanes 15a-d are constructed employing the intramolecular [3+2]-dipolar cycloaddition of nonstabilized cyclic azomethine ylides. The ylides are generated by the sequential double desilylation of N-alkyl-α,α′-bis(trimethylsilyl)cyclic amines 14a-d using Ag(I)F as a one-electron oxidant. More rigid azatetracyclo compounds of type 23, in which benzene ring is attached as a tether unit in the N-alkyl chain moiety, are also synthesized by the cyclization of 22. These rigid azatricyclo compounds 15 and 23 possess structural resemblance to the rigid azatricyclo analogues 8-10, which are reported to exhibit selective and high binding affinity at dopamine transporter (DAT).
... In [3 + 2] 1,3 dipolar cycloaddition reactions, a 1,3 dipole (or ylide) and a dipolarophile react leading to the regioand stereo-selective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives [5]. A 1,3 dipole can either be an allyl-type or a allenyl-type with both type sharing four electrons in the pi system over three atoms, and they usually have a nitrogen, carbon, oxygen, or sulphur atom [6,7]. The dipolarophile in a 1,3 dipolar cycloaddtion is a reactive moiety containing two π-electrons and the most commonly used ones are alkenes and alkynes. ...
This work investigated computationally the regio-, stereo-, and enantio-selectivity of the reactions of azomethine imines with olefins, maleimides, and benzynes, important reactions towards the synthesis of heteropolycyclic, N,N′-fused, spirocyclic systems, which serve as building blocks for the synthesis of many pharmaceuticals, agrochemicals, and biologically active compounds. The results show that the thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imide and methyl acrylate provides two regio-isomers: 1,4-regioisomer (N-C1, C-C2) and 1,3-regioisomer (N-C2, C-C1). The 1,4-regioisomer has cis and trans-stereoisomers while the 1,3-regioisomer has R-enantiomer and S-enantiomer, and the barriers for the formation of these isomers are 5.1, 19.1, 10.7, and 10.5 kcal/mol, respectively. The reaction between quinolinium imide and maleimide leads to the formation of two stereoisomers; cis-isomer and trans-isomer in which the cis-isomer is kinetically and thermodynamically favoured by 6.1 kcal/mol and 8.7 kcal/mol, respectively. The reaction between quinolinium imide and benzyne also leads to the formation of two stereoisomers through one transition state, with a barrier of 3.0 kcal/mol. Global electrophilicity index calculations show that the dipole acts as a good electrophile in the reaction and decreasing or increasing electrophilicity index has no correlation with the activation barriers.
Pathways of the 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes for the synthesis of fused N,N′-heterocycles
... As well known, 1,3-dipolar cycloaddition has been widely employed in construction of 5-membered heterocyclic systems. 6) In the present work, we devoted to developing an efficient synthetic route for the synthesis of ODM-201's diastereomers through intramolecular 1,3-dipolar cycloaddition. ...
An efficient synthesis of ODM-201's diastereomers has been developed from (R)-methyl 3-hydroxybutanoate or (S)-methyl 3-hydroxybutanoate, respectively, with high overall yield and excellent diastereomeric purity. The key step in this synthesis is the preparation of the key intermediate (R)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid or (S)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid through intramolecular 1,3-dipolar cycloaddition of the vinyl diazo carbonyl compounds.
... Owing to its facility of constructing two rings simultaneously, intramolecular 1,3dipolar cycloaddition strategies have emerged as an important tool for the synthesis of structurally complex fused heterocyclic ring systems [37,38]. Particularly several bicyclic [39][40][41][42] and polycyclic [43][44][45] fused pyrrolidine ring systems are synthesized by the intermolecular cycloadditions of stabilized acyclic azomethine ylides with tethered dipolarophiles. Pandey et al. [46] reported an efficient strategy for the construction of x-azatricyclo [m.n.0.0 a,b ]alkanes by intramolecular cycloaddition of cyclic azomethine ylide. ...
Fourier-transform-Raman and infrared spectrum of 4-azatricyclo [5.2.2.0(2,6)] undecane-3,5,8-trione were recorded and analyzed. The vibrational wavenumbers were examined theoretically using the Gaussian03 set of quantum chemistry codes, and the normal modes were assigned by potential energy distribution (PED) calculations. The first hyperpolarizability, predicted infrared intensities and Raman activities are reported. The calculated first hyperpolarizability is comparable with reported values of similar structures which makes this compound an attractive object for future studies of nonlinear optics. Optimized geometrical parameters of the compound are in agreement with similar reported structures. The red shift of the NH stretching wavenumber in the infrared spectrum from the computational wavenumber indicates the weakening of NH bond.
... Owing to its facility of constructing two rings simultaneously, intramolecular 1,3dipolar cycloaddition strategies have emerged as an important tool for the synthesis of structurally complex fused heterocyclic ring systems [37,38]. Particularly several bicyclic [39][40][41][42] and polycyclic [43][44][45] fused pyrrolidine ring systems are synthesized by the intermolecular cycloadditions of stabilized acyclic azomethine ylides with tethered dipolarophiles. Pandey et al. [46] reported an efficient strategy for the construction of x-azatricyclo [m.n.0.0 a,b ]alkanes by intramolecular cycloaddition of cyclic azomethine ylide. ...
Fourier-transform (FT)-Raman and FT-infrared spectrum of 4-(3-bromopropyl)-4-azatricyclo [5.2.2.0(2,6)]undecane-3,5,8-trione were recorded and analyzed. The vibrational wavenumbers were examined theoretically using the Gaussian03 set of quantum chemistry codes, and the normal modes were assigned by potential energy distribution (PED) calculations. The first hyperpolarizability, predicted infrared intensities and Raman activities are reported. The calculated first hyperpolarizability is comparable with reported values of similar structures which makes this compound an attractive object for future studies of nonlinear optics. The calculated first hyperpolarizability was found to be very high and it is due to the pi-electron cloud movement from donor to acceptor which makes the molecule highly polarized and the intermolecular charge transfer interaction which is justified by the FT-IR spectrum due to the presence of strong broad bands in the region 2873-2000cm(-1). Optimized geometrical parameters of the compound are in agreement with similar reported structures.
An efficient metal‐free, additive‐free synthetic method was developed to access benzooxepino‐fused pyrrole derivatives from alkynyl substituted aziridines. In this organic transformation, two new C−C bonds were formed via initial cleavage of C−C bond of aziridine ring by in situ generated azomethine ylides. Moderate to excellent yields of benzooxepino‐fused pyrroles were obtained atom economically in the presence of t‐BuOH in one‐pot. image
This chapter starts with an overview of the light–matter interaction models needed for the comprehension of compounds’ photochemistry and photophysics. The second section is dedicated to heterocyclic photoactive compounds (three-membered and larger ring systems), discussed in terms of their synthetic methods and photochemical properties, which are useful characteristics providing the understanding of their reactivity. The final section describes the main applications of promising photoactive compounds with a focus on conjugated heterocyclic backbones for efficient organic photovoltaics.
A study of the reactivity and regio- and stereo-selectivity of Diels-Alder reactions of 2-methyl- 3-propionylcycloprop-2-ene carboxylic acid methyl ester with cyclohexa-1,3-diene derivatives and furan, in the gas phase, has been carried out using density functional theory (DFT)-based reactivity indices and activation energies. Four reaction channels associated with ortho (or meta), meta (or para), endo and exo pathways have been explored and characterised. The activation energies indicate that the endo pathways are preferred and DFT-based reactivity indices clearly predict the stereochemistry of the isolated cycloadducts.
Ethyl 4‐hydroxycrotonate product: ethyl 4‐hydroxycrotonate
Ring expansions promoted by ring strain in aziridines and azetidines are reviewed in this chapter, putting emphasis on recent applications from the last decade. This vast subject cannot be surveyed here exhaustively, and the reader will be guided to relevant precedent reviews or key reports. Rather, special attention will be put on selected examples and their mechanistic details, aiming to demonstrate that high selectivity can be reached in these reactions. In this issue, this fast-growing topic has been divided into two distinct chapters, this one dealing with “nonactivated” aziridines and azetidines. Therefore, the reader will only find here examples involving NH- or N-alkylaziridines and N-azetidines as substrates for ring expansions, while N-acyl, N-carbamoyl, or N-tosyl compounds, defined as “activated” substrates, will be presented in the next chapter. This distinction can appear quite arbitrary at first sight but is amply justified by the great difference in reactivity of these distinct substrates. The first part focuses on the ring expansions of nonactivated aziridines into up to seven-membered rings and is further divided into expansions involving the incorporation of one (or more) heteroatoms, followed by ring expansions involving only incorporation of carbon atoms. The same model is then followed for azetidines.
Three-membered heterocycles are strained molecules because of the bond angle distortion. These heterocycles have high energy contents relative to their acyclic isomers. Three-membered heterocycles generally have shorter C-C bonds than in cyclopropane (thiirane being an exception). The C-X-C bond angles (X = hetero-atom) in oxiranes and aziridines are very close to 60° and the peripheral H-C-H bond angles are near to 118°. In unsaturated three-membered heterocycles, the introduction of the double bond further enhances angle distortion and this inevitably increases the ring strain.
Azomethine ylides, generated from imine-derived O-cinnamyl or O-crotonyl salicylaldeyde and α-amino acids, undergo intramolecular 1,3-dipolar cycloaddition, leading to chromene[4,3-b]pyrrolidines. Two reaction conditions are used: (a) microwave-assisted heating (200 W, 185 °C) of a neat mixture of reagents, and (b) conventional heating (170 °C) in PEG-400 as solvent. In both cases, a mixture of two epimers at the α-position of the nitrogen atom in the pyrrolidine nucleus was formed through the less energetic endo-approach (B/C ring fusion). In many cases, the formation of the stereoisomer bearing a trans-arrangement into the B/C ring fusion was observed in high proportions. Comprehensive computational and kinetic simulation studies are detailed. An analysis of the stability of transient 1,3-dipoles, followed by an assessment of the intramolecular pathways and kinetics are also reported. The two-component synthesis of chromene[4,3-b]pyrrolidines has been achieved under two different conditions. The strategy was used to obtain N-sulfonylated adducts with interesting biological activity. Calculations show that formation of W and S′ 1,3-dipoles determines the stereochemical outcome of the reaction, which involves asynchronous transition structures.
Aziridines derived from 2-(prop-2-yn-1-yloxy)- and 2-(buta-2,3-dien-1-yloxy)chalcones and from benzyl 2-(prop-2-yn-1-yloxy)- and 2-(buta-2,3-dien-1-yloxy)phenylacrylates were prepared in a stereoselective fashion. Their reactivity as azomethine ylide precursors was examined, leading to the synthesis of 1,4-dihydrochromeno[4,3-b]pyrrole and 3-methylenechromano[4,3-b]pyrrole derivatives through intramolecular 1,3-dipolar cycloaddition reactions.
Azomethine ylides are planar molecules composed of one nitrogen and two terminal sp2 carbons. At most, four geometrical isomers are possible for these transient molecules. Their cycloadditions to olefin or acetylene dipolarophiles give rise to the formation of two sets of carbon-carbon bonds in a single step. Because of the structural complexity of azomethine ylide itself compared to other dipoles and the stereochemical selectivity in the cycloadditions, a number of stereoisomers are possible for the cycloadducts. These two points make azomethine ylides one of the most attractive 1,3-dipoles, both in the fields of ylide chemistry and synthetic organic chemistry. Azomethine ylides can be classified in groups according to their structure. This chapter concentrates on the most basic ylides, acyclic azomethine ylides, in order to catch the generalized concepts involved in the azomethine ylide chemistry. Accordingly, it also deals with the recent advances of the chemistry of acyclic azomethine ylides covering its preparation, cycloadditions, intramolecular cycloadditions, and synthetic applications.
Domino reactions of difluorocarbene with Schiff bases containing a tethered olefinic or acetylenic dipolarophile moiety involve intramolecular 1,3-dipolar cycloaddition of iminiodifluoromethanides and yield chromeno[4,3-b]pyrrole derivatives.
On thermal treatment of the aziridines - intramolecular cycloaddition reactions of the intermediate azomethine ylides result in the formation of the metacyclophanes - . For and the conformational barriers areestimated to be approximately 20 and 12 kcal/mol, respectively.
Difluoro(iminio)methanides generated by the action of difluorocarbene on Schiff bases react with derivatives of maleic and fumaric acids, following the 1,3-dipolar cycloaddition pattern to give 2,2-difluoropyrrolidines which were detected by gas chromatography-mass spectrometry. The final products are stereo-isomeric substituted 2-pyrrolidinones formed by hydrolysis of difluoropyrrolidines and their dehydrofluorination products, 2-fluoro-4,5-dihydropyrroles. The observed stereoselectivity of the cycloaddition suggests Z configuration of intermediate ylide and both endo- and exo-approach to the dipolarophile in the transition state corresponding to cycloaddition.
Stereoselektive Synthesen von Heterocyclen sind ein wichtiges Anwendungsgebiet der intramolekularen 1,3‐dipolaren Cycloaddition. Am Beispiel der Modellverbindungen (1) , n = 1, 2, wird gezeigt, daß auch Carbonyl‐ylide wie (2) und (3) derart reagieren können. Aus (3) , n = 1, entsteht (4) ; aus (2) , n = 1, 2, bilden sich die (4) entsprechenden trans ‐verknüpften Verbindungen. magnified image
We describe here effective epimerization of trans to cis isomer of 1-benzyl-3-arylaziridine-2-carboxylates. The combination of samarium metal, iodine and N,N-dimethylaminoethanol promoted the epimerization of trans isomer to a ca. 1 : 1 mixture of cis and trans ones. Investigating more effective catalyst, indium chloride was found to afford a ca. 2 : 1 mixture of cis and trans isomers. Epimerization at benzylic position in the aziridines is suggested from the result with optically active ones. Preparation of cis-2-indolylaziridine towards construction of aziridinomitosene skeleton was achieved in this epimerization reaction. © 2008 The Japan Institute of Heterocyclic Chemistry All rights reserved.
Stereochemistry of the cycloadditions of twenty-four heteroaromatic N-ylides with several symmetrically substituted cis and trans olefins has been investigated. Cyclic and acyclic cis olefins cycloadd to the and form of the ylides in a highly endo-selective manner giving almost quantitative yields of stereospecific endo 3+2 cycloadducts. N-Ylides stabilized with a substituent of carbonyl type react with trans olefins to form mostly two stereoisomeric 3+2 cycloadducts to the anti form of the ylides. In most cases, they undergo the stereospecific interconversion through a retro cycloaddition process, the isomer ratios and the easiness of transformation depending upon the nature and size of substituents on the five-membered ring which has been built up in the cycloaddition step. On the other hand, N-ylides stabilized with a substituent of noncarbonyl type react with trans olefins to give stereospecific and stereoselective 3+2 cycloadducts as single isomers which are assigned as the cycloadducts to the syn form of the ylides.
Azomethinylides generated by reaction of difluorocarbene with N-alkyl- and N-arylimines of O-acylated salycilaldehyde undergo intramolecular 1,3-dipolar cycloaddition to the ester carbonyl group forming regioselectively 2,5-epoxy-1,4-benzoxazepine derivatives.
The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5-unsubstituted-1-aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3-butadienes and aldehydes is presented. These domino reactions offer the advantage of executing multistep transformation without intermediate workup procedures. The stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic acid derivatives are also studied.
Die 1,3-dipolaren Cycloadditionen der Azomethin-ylide 2 und 9 mit Schiffschen Basen wurden untersucht. Es bilden sich Cycloaddukte vom “exo”-und/oder “endo”-Typ in Abhängigkeit von der Struktur des Dipolarophils und des Dipols.
1,3-Dipolar Cycloadditions of Azomethine Ylides
1,3-Dipolar cycloadditions of the azomethine ylides 2 and 9 with Schiff′s bases have been investigated. Depending on the structures of both the dipolarophiles and the dipoles, cycloadducts of “exo” and/or “endo” type were formed.
Carbonyl Ylides as Cycloaddition Components: Intramolecular Transfer of a DMAD Unit
On heating the specifically designed ene‐oxirane 6 is cleanly transformed into the 2,5‐dihydrofuran derivative 7 As mechanism of this conversion ring opening to carbonyl ylide 8 is proposed followed by formation of the intramolecular cycloadduct 9 which suffers rapid cycloreversion leading to 7 . The latter process is precluded in the case of the dihydro derivative 10 which, in fact, reacts under comparable conditions and with equally good yield to give 11 as a thermally stable and sterically pure compound. In the presence of dimethyl acetylene dicarboxylate (DMAD) as external dipolarophile bimolecular cycloadditions do not compete with the intramolecular reaction mode.
Stereoselective syntheses of heterocycles represent an important area of application of intramolecular 1,3-dipolar cycloaddition. With the aid of model compounds (1), n = 1, 2, it is demonstrated that also carbonyl ylides such as (2) and (3) can undergo this type of reaction. Reaction of (3), n = 1, affords (4) while reaction of (2), n = 1, 2, leads to the trans-coupled compounds corresponding to (4).
Der Substituenteneinfluß auf die einzelnen Schritte der 3σ → 3π‐Route zu 1H‐Azepinen wird an Hand mehrerer neu synthetisierter Edukte näher definiert: Das C‐unsubstituierte 7‐Azanorbornadien 2a, das 2,3‐Dichlorderivat 2b, der 5,6‐Dichlor‐2,3‐dicarbonester 2c und die an C‐1/N‐7 mit einem dipolarophilen Rest versehenen 2,3‐Dicarbonester 2d,e lassen sich durch sensibilisierte/direkte Lichtanregung mehr oder weniger einheitlich in die zum Teil hochlabilen Azaquadricyclane 29a – e isomerisieren. Für die thermische Umwandlung des Grundgerüstes (N‐Tos) 29a werden die kinetischen Parameter bestimmt (Benzol): Ea = 28.0 ± 0.2 kcal/mol, lg A = 15.7; ΔH≠ = 27.3 ± 0.2 kcal/mol, ΔS≠ = 11.1 ± 0.7 e.u. Diese Barriere wird durch die Halogenreste in 29b(c) noch stärker als durch die Esterreste (29f) herabgesetzt – wobei die +M‐ im Gegensatz zu den – M‐Resten ausschließlich die Spaltung der gegenüberliegenden Cyclopropanbindungen bewirken. Die intermediären Azomethinylide können je nach Substitution mit dipolarophilen Reagentien unterschiedlich gut abgefangen werden. Im Fall von 29d(28d) ist die intramolekulare Addition der nichtaktivierten In‐Seitenkette (37) bei −30°C so rasch, daß Azepinbildung fast vollständig unterdrückt wird ([π2 + σ2 + σ2], 36?). Das Azepin/Benzolimin‐Gleichgewichtsgemisch 31c⇄32c (ca. 90:10) kristallisiert als 31c (Röntgenstrukturanalyse).
The reaction of nitrones, derived from benzaldehydes having an olefinic dipolarophile at the o-position, with DMAD provides the first example for the inter- and intramolecular double 1,3-dipolar cycloaddition.
N-(Cyanomethyl)- and N-(α-cyanobenzyl)imines derived from a variety of aldehydes and ketones can tautomerize into N-protonated azomethine ylides which undergo cycloadditions with olefinic dipolarophiles. These cycloadditions are often accompanied by the elimination of HCN, mostly in a stereospecific manner, showing these imines to be synthetic equivalents of nonstabilized nitrile ylides. Stereoselectivity of the cycloadditions is discussed.
The use of dithiane chemistry to synthesize functionalized azomethine ylides which are then employed in [3+2] cycloaddition chemistry is described. The advantages of this methodology as well as an approach to the lycorenine alkaloid system are presented.The synthesis and chemistry of functionalized azomethine ylide-olefins and their cycloadducts are described
N-[(Trimethylsilyl)methyl]amino ethers have been found to act as azomethine ylide equivalents. Treatment of these compounds with lithium fluoride in the presence of a reactive dipolarophile afforded dipolar cycloadducts in high yield. The cycloaddition proceeded with complete stereospecificity with dimethyl fumarate and maleate. This result is consistent with the intermediacy of an azomethine ylide. The reaction of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine afforded several silylated diamines when treated with zinc chloride or cesium fluoride in the absence of a trapping agent. This can be attributed to an initial loss of the methoxy group to give a transient iminium ion. This species reacts further with the azomethine ylide or undergoes hydrolysis to give a silylated amine. The cycloaddition behavior of several unsymmetrically substituted azomethine ylide precursors was also examined. Competitive rate studies showed that the cycloaddition is compatible with a HOMO-controlled process. The regiochemistry of the cycloaddition, however, is not easily rationalized by simple FMO considerations and may instead be related to the charge transfer interaction energy of the reaction.
The 1,3-dipolar cycloaddition of a number of N-[(trimethylsilyl)methyl]-substituted indoles with several dipolarophiles has been investigated. The reaction requires the use of an equivalent amount of silver fluoride and provides a direct and efficient synthesis of the pyrrolo[1,2-a]indole ring system. The structures of the cycloadducts were established by high-field NMR spectroscopy as well as by several X-ray crystal structures. The cycloaddition reactions show all the characteristics of a concerted reaction, including complete stereospecificity and regioselectivity. The results are consistent with a mechanism that involves the intermediacy of an azomethine ylide. Formation of the dipole is rationalized by assuming that silver ion behaves as a very specific Lewis acid that attacks the indole ring to give a silver bonded carbonium ion. This is followed by a rapid desilylation reaction to give the azomethine ylide. After the cycloaddition step, the resulting silver-bonded intermediate undergoes consecutive loss of silver and a hydrogen to give the observed product. Attempts to extend the cycloaddition methodology to N-[(trimethylsilyl)methyl]-substituted enamines and pyrroles are also described.
Pyrolysis of aziridines 6 or 7 affords azomethine ylides, which can also be generated from 3-methyl-2,5-diphenyl-4-oxazoline (1a) at room temperature. Attempts to trap the thermally generated ylide with dimethyl acetylenedicarboxylate afford increasing amounts of the unusual enamine product 9 as the temperature decreases. The aziridine-derived dipoles (2a or 3a vs 4a or 5a) cannot be trapped prior to equilibration. Similar results are obtained from the aziridines 16/17, but in this case, dipole isomers can be intercepted by N-phenylmaleimide in xylene solution. The 2,3-dimethyl-5-methoxy-4-oxazoline derived dipole 2b probably does not equilibrate, but its 2 + 3 cycloadducts correspond to the major products formed by aziridine pyrolysis under equilibrating conditions.
Treatment of oxazolium salts with cyanide generates 4-oxazolines 2 in situ. Ring opening to azomethine ylides 3 occurs spontaneously and 2 + 3 cycloadducts are obtained in the presence of acrylate, propiolate, or acetylenedicarboxylate dipolarophiles. In the case of acetylenic dipolarophiles, loss of HCN occurs under the reaction conditions and leads directly to pyrroles 5. The propiolate experiments are complicated by the formation of six-membered adducts 17 in some cases. This reaction pathway is explained by the addition of the acetylide anion derived from propiolate to the dipole, followed by cyclization. Sulfide nucleophiles can also be used to generate 4-oxazolines, but the yields of cycloadducts are lower.
3-Phenyl- and 3-unsubstituted-2-alkenoyl-1-methylaziridines have been synthesized via Grignard reactions with the corresponding 2-cyanoaziridines. The 3-phenylated-2-alkenoylaziridines have been thermally transformed into ring-fused pyrrolidine compounds. The configurations and conformations of the aziridine and pyrrolidine compounds have been determined by 1H and 13C NMR spectroscopy and X-ray crystallography.
The scope and limitations of the intramolecular 1,3-dipolar cycloaddition of doubly-stabilized azomethine ylides to unactivated olefinic, acetylenic, and aromatic dipolarophiles is reported. The azomethine ylides studied were generated by flash vacuum pyrolysis of their corresponding aziridines and were found to add stereospecifically in good to excellent yields to a variety of unactivated dipolarophiles. Generation of the diazabicyclo[3.3.0]octane (e.g., 15a,b), diazabicyclo[4.3.0]nonane (e.g., 4,13), and diazabicyclo[5.3.0]decane (e.g., 15c) ring systems are possible using this technology. In addition, the first examples of cycloaddition of a stabilized azomethine ylide to benzene dipolarophiles are reported. Cycloadditions of this type generate highly functionalized triciclic systems with complete relative stereocontrol at the newly formed stereocenters (e.g., 24-26). Finally, it has been shown that cycloadducts 31 and 32 are in equilibrium, presumably by way of the intermediate azomethine ylide 33, under conditions of flash vacuum pyrolysis.
The rapidly expanding field of combinatorial chemistry has stimulated the development of new methods and synthetic strategies for assembly of compound libraries. We propose four criteria that are desirable for synthetic routes to such libraries: (1) the sequence involves a small number of steps; (2) no more than one variable is introduced in any step; (3) starting materials are readily obtained with a diverse selection of substituents, and (4) cyclic, nonoligomeric structures represent the most interesting targets. Guided by these criteria, we have explored an intramolecular version of the azomethine ylide cycloaddition reaction which utilizes readily available amino acids, aldehydes, and 2° amines as inputs. We prepared a number of cycloadducts in solution to optimize conditions and examine the scope of the process and to identify a synthetic strategy that would be amenable to solid-phase synthesis of these compounds. Transfer of the sequence to solid phase was demonstrated by the synthesis of a number of representative compounds, indicating that the chemistry is suitable for construction of a combinatorial library.
Treatment of oxazolium salts with phenylsilane/CsF generates 4-oxazolines 14 in situ. Provided that R4 = H or alkoxy, ring opening to azomethine ylides 15 occurs spontaneously and [2 + 3] cycloadducts are obtained in the presence of acrylate, N-phenylmaleimide, propiolate, or dimethyl acetylenedicarboxylate (DMAD) dipolarophiles. If R5 = alkyl or aryl, the initially formed 4-oxazoline resists ring opening, probably due to steric interactions in the dipole, and affords products 30 derived from 2 + 2 trapping with DMAD. In typical cases, the [2 + 3] cycloadducts are formed with geometry corresponding to the trapping of the S-dipole 15 to the exclusion of other dipole isomers. Pyrolysis of analogous N-methylaziridines results in an equilibrated dipole, although the major adduct also corresponds to the trapping of 15. Dipole trapping with phenyl vinyl sulfone is also possible, and reductive desulfonylation with sodium amalgam affords the adduct 41, which corresponds to the adduct of the stabilized azomethine ylide with ethylene. Overall, the oxazolium salt reduction provides access to a large variety of azomethine ylides stabilized by acyl, ester, benzoyl, and formyl substituents. The dipoles can be generated and trapped at room temperature or below.
IntroductionPhysical PropertiesSynthesis of AziridinesReactions of AziridinesAziridines with Biological ActivityAziridinium Saltsα-Lactams (Azirinones)Aziridine IminesMethylene Aziridines
Esters of N-benzhydrylideneglycin and -alanine undergo prototropic isomerization to yield azomethine ylides that react stereoselectively with N-substituted maleimides and fumaronitrile affording pyrrole derivatives.
Synthesis of a series of novel hexahydrochromenopyrrole analogues has been accomplished through an intramolecular 1,3-dipolar cycloaddition (1,3-DC reaction) of azomethine ylides, generated by the aldehyde induced decarboxylation of secondary amino acids. These compounds were screened for antibacterial and antifungal activities against six human pathogenic bacteria and three human pathogenic fungi and found to have good antimicrobial properties against most of the microorganisms.
Enamines, silyl enol ethers, and beta-keto ester anions derived from bicyclo[3.3.0]octan-2-one efficiently underwent a formal [2 + 2] cycloaddition reaction with DMAD and ethyl propynoate leading to a large variety of electrophilic cyclobutenes. The latter were transformed into polyfunctionalized bicyclo[5.3.0]decane (or hydroazulene) ring systems in high yields by fragmentation of the cyclobutene moiety. These two-carbon ring-enlargement reactions were utilized as a synthetic tool for the construction of a polyfunctionalized hydroazulene derivative that represents a potential precursor of the tricyclic framework of ingenol.
An efficient catalytic (2 + 2)-cycloaddition reaction leading to the formation of cyclobutane rings has been devised. The process transforms silyl enol ethers and alpha,beta-unsaturated esters into polysubstituted cyclobutanes with a high degree of trans-stereoselectivity. Both the rate and stereoselectivity of the process can be controlled by the choice of the ester group and silyl substituents. The results of stereochemical studies show that the cycloaddition step in this reaction proceeds in a nonstereospecific manner and, thus, by a pathway involving sequential nucleophilic additions via a short-lived zwitterionic intermediate.
We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 degrees C, this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopyrrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino and ester groups. We discuss the plausible mechanisms of the ring closure and opening.
Since the first intramolecular 1,3-dipolar cycloaddition reaction of an azomethine ylide was reported in 1976, various useful methods for the formation of azomethine ylides and the determination of the requirements for a successful intramolecular cycloaddition reaction have been developed. This review describes the background and mechanisms of azomethine ylide formation and intramolecular cycloaddition, giving a critical account including the very first example and covering the early 2005. The review is intended to be a useful resource for chemists interested in cycloaddition reactions and will inspire further exciting developments in this area.
Enantioselective [2+2]-cycloaddition pathways to chiral cyclobutanes are rare and not generally utilized for synthesis. A new cycloaddition reaction of vinyl ethers with trifluoroethyl acrylate in the presence of a catalytic amount of chiral oxazaborolidine-AlBr3 complex is described which affords [2+2]-adducts with excellent yields and enantioselectivities. Applications of these adducts to the synthesis of synthetically valuable intermediates are also presented.
The intramolecular 1,3-dipolar cycloaddition reaction of suitably functionalized 1,3-dipoles represents a general scheme for the synthesis of novel fused ring heterocycles. Such reactions of a number of 1,3-dipoles are summarized and the general outline and potential analogies for these reactions noted. While the immediate aim of this review is to survey and correlate published work, it is hoped that general and specific points in need of study will be revealed and will stimulate further work in this fertile field.
Orbital symmetry controls in an easily discernible manner the feasibility and stereochemical consequences of every concerted reaction.
The concerted mechanism of 1,3-dipolar cycloadditions was challenged recently by Firestone, who proposed a diradical alternative on thermochemical and regiochemical grounds. His arguments are critically disproved here. The retention of configuration of 1,3-dipole and dipolarophile in the cycloaddition is incompatible with a diradical intermediate. 1,3-Dipoles are "heteroallyl anions" which lose the allylic resonance energy in forming a diradical intermediate; taking this into consideration, the energies of diradical formation exceed the experimental activation energies of cycloadditions. Following the symmetry-allowed scheme [π48 + π28], 1,3-dipoles undergo only cycloadditions of the ring size classification 3 + 2 → 5 while allyl cations are only amenable to 1,4 additions of the type 3 + 4 → 7. The activity sequences of dipolarophiles are 1,3-dipole specific; the diradical hypothesis fails to explain this phenomenon while recent MO perturbation treatments provide elegant interpretations for dipolarophile activities as well as for directions of addition. The frequently found "bidirectionality", i.e., different orientations of dipolarophiles with electron-releasing and electron-attracting substituents, is at variance with diradical intermediates. The regioselectivity is connected with the ambident nucleophilic and electrophilic properties of 1,3-dipoles. An independently synthesized 1,5-diradical does not show the reactivity postulated by Firestone.
The cis-trans isomer ratios of 1-benzyl- and 1-cyclohexyl-2,3-dibenzoylaziridines and 1-cyclohexyl-2-phenyl-3-benzoylaziridine, when equilibrated by base catalysis in seven alcohols and the aprotic solvent dimethyl sulfoxide, have been determined. These equilibria are expressed as constants, K, which range from 5.25 in DMSO to 0.32 in t-butyl alcohol and which approximately parallel the dielectric constants of the solvents used. The effects on K of amounts of base and of added salt used are delineated.
The syntheses and reactions of the 1,4-diaza[4.1.0]hept-4-enes (2) and the 1,1a-dihydro-1,2-diarylazirino-[1,2-a]quinoxalines (3) are described. These compounds are prepared by the reaction of 1-phenyl-2,3-dibromo-3-aryl-1-propanones with ethylenediamine and o-phenylenediamine, respectively. Compounds 3 undergo carbon-carbon bond fission of the aziridine ring in refluxing toluene and form adducts with diethyl azodicarboxylate, dimethylacetylene dicarboxylate, dibenzoylacetylene, aromatic aldehydes and acenaphthylene. Compounds such as 3 also react with nitrosobenzene to form nitrones and 2-phenylquinoxaline and pyrolyze to stilbenes and 2-phenylquinoxaline. Compounds 3 isomerize in the presence of acid to 2-benzyl-3-arylquinoxalines. Compounds 2 are converted in concentrated sulfuric acid into benzyl phenyl diketones.
The products of the thermal decomposition of the title compounds were investigated. In the case of the cycloheptenecarboxaldehyde and the cyclopentenylacetaldehyde derivatives intramolecular carbene addition to the double bond took place to a minor extent, with formation of tricyclo[5.1.0.04,8]octane (II) and nortricyclene (VII), respectively. No intramolecular carbene-addition product could be detected in the decomposition product of the cyclohexenylacetaldehyde tosylhydrazone anion. The major product of the decomposition reaction of the cycloheptenecarboxaldehyde derivative was found to be 2,3-diazatricyclo[3.3.2.02,6]dec-2-ene (III) formed by intramolecular 1,3-addition. The decomposition of the cycloheptenecarboxaldehyde and the cyclohexenylacetaldehyde derivatives took place at low temperatures indicating double-bond participation.
Belichtung von 2-Allyloxy-phenyldiazomethan (2) ergibt 3 (Produkt einer intramolekularen Einschiebung) und 4 (Produkt einer intramolekularen Addition) im Verhältnis 2.5 : 1. Im Dunkeln geht 2 in das Pyrazolin 5 über, dessen Zersetzung ausschließlich 4 liefert. Bei Belichtung von 2 in Äthanol entsteht hauptsächlich der Äther 9 neben wenig 3 und 4.
Numerous examples of intramolecular cycloaddition of 1,3-dienes, nitrones, and azomethine imines attest the preparative value of this variant for regioselective and stereoselective synthesis of annelated and bridged ring systems. The common features, differences, and limitations of these types of reaction are systematically reviewed.
1,2,3-Triphenylaziridine and 1-p-bromophenyl-2,3-diphenylaziridine react with ethynes and ethenes in refluxing toluene or xylene to form 3-pyrrolines and pyrrolidines, respectively. A novel decarboxylative elimination of 3,4,5-triphenyl-1,2-dicarbethoxy-1,2,4-triazolidine into benzalazine and aniline is described.
Displacement of the p-toluenesulfonate function of pseudodiosgenin 27-p-toluenesulfonate with potassium azide in dimethylformamide was followed by a 1,3-dipolar cycloaddition to the enol ether olefinic bond of ring E to furnish a triazoline derivative. Protonation of the triazoline in methanol solution led to abrupt evolution of nitrogen with genesis of a secondary amino methyl ketal. Transformation products of the methyl ketal include the hemiketal, the ethyl ketal, an enol ether tertiary amide originating from hemiketal dehydration, and a 16β-hydroxy acetylamino ketone resulting from opening of the ketal ring system.
Adducts of 2,2-dimethyl-4-phenyl-6-p-nitrophenyl-1,3-diazabicyclo[3.1.0]hex-3-ene with diethylacetylene dicarboxylate, diethyl fumarate, cis- or trans-dibenzoylethene, diethyl azodicarboxylate, and N-phenylmaleimide are formed in refluxing p-xylene. The reaction proceeds by carbon-carbon bond scission of the aziridine ring of the 1,3-diazabicyclo[3.1.0]hex-3-ene.
1,2-Benzocarbazole(III) has been prepared in high yield from both 2-(2′-azidophenyl)naphthalene(IV) and 1-azido-2-phenylnaphthalene(V). The isomeric 2,4-benzocarbazole has been prepared from 1-(2′-azidophenyl)naphthalene. 1,4-Dimethoxycarbazole has been prepared from (o-azidophenyl)hydroquinone dimethyl ether, and 2-methoxy-, 2-hydroxy-, and 3-chloro-carbazole have been prepared from o-azidobiphenyls. 2-Azido-2′-cyanobiphenyl has been found to cyclize to tetrazolophenanthridine instead of to 4-cyanocarbazole, and 4-azidofluorene and 4-azidofluorenone to decompose on heating without apparent cyclization, to give intractable products. o-Azidobiphenyl has been prepared from o-hydrazinobiphenyl and N15-labeled potassium nitrite. Thermal decomposition gave carbazole with normal isotope content, while all the excess N15 was found in the evolved nitrogen.
Azido compounds 1 containing dipolarophile groups, such as C=C, C≡C, and C≡N bonds, were synthesized from the corresponding anilines and thermally decomposed in aromatic hydrocarbon solvents. Bridgehead nitrogen aziridines 3 were obtained from 1a-c, probably through an intramolecular cycloaddition leading to unstable Δ2-1,2,3-triazolines. From 1d-g, the corresponding 1,3-cycloaddition products, namely the fused-ring triazoles 7 and tetrazoles 8, were isolated in good yields.
The stereochemistry of the intramolecular, 1,3-dipolar cycloaddition of several methyl-substituted N-methyl-C-6-heptenylnitrones was studied. The major product isoxazolidines were confirmed to have the 7-aza-8-oxabicyclo[4.3.0]nonane (3a,4,5,6,7,7a-hexahydro-2,1-benzisoxazoline, hydrindan) skeleton. The stereochemistry at the ring fusion was assigned primarily on the basis of nmr spectral evidence. It was found that cyclization of the nitrones at 76° gave primarily the trans-fused isomers in all cases, and the ratio between cis and trans isomers was influenced mainly by substitution in the five-membered isoxazolidine ring. Interconversion of the isoxazolidines in the temperature range 180-300° occurred by retro-1,3-dipolar cycloaddition. At these temperatures the thermodynamically more stable cis-fused isomers predominated. These results correlate well with what is known concerning the relative stabilities of cis- and trans-hydrindan. The retro-1,3-dipolar cycloaddition of bicyclic isoxazolidines promises to be a valuable method for relative stability studies of fused heterobicyclo[n.3.0] derivatives.
The isotopic analysis of the cyclopropylcarbinol and cyclobutanol formed in the reaction of allylcarbinylamine-α-14C with nitrous acid has indicated that all of the possible methylene-labeled, isotope-position isomers are formed but not quite to the extent expected for statistical equilibrium. The compositions of the alcohols resulting from treatment of cyclopropylcarbinyl-, cyclobutyl- and allylcarbitiylamines with nitrous acid have been measured accurately and correlated with the degree of isotope-position rearrangement obtained with 14C-labeled amines. The results are in agreement with the previously postulated interpretation of these reactions as involving rapid but not instantaneous equilibration of unsymmetrical non-classical cations.
The synthesis of olefinic azides and their thermal decomposition in a solvent to give 1-azabicyclo[3.1.0]-hexanes and cyclic imines is described. Evidence is presented to show that the azide functionality adds intramolecularly to the double bond to give an isolable triazoline VII, which opens up in the rate-determining step to a diazonium ion type intermediate VIII, followed by evolution of nitrogen and formation of products.
The oxidation of N-methyl-N-5-hexenylhydroxylamine with mercuric oxide and the condensation between 5-hexenal and N-methylhydroxylamine afforded cis-N-methyl-3-oxa-2-azabicyclo[3.3.0]octane (2). Other bicyclic isoxazolidines have been synthesized by the condensation reaction employing unsaturated aldehydes and unsaturated ketones. The structures of these compounds were proved by hydrogenolysis and, in some cases, independent synthesis of the amino alcohols. The mechanism of the cyclization reactions are postulated as intramolecular 1,3-additions of an unsaturated nitrone intermediate. The scope of this preparative route to fused bicyclic isoxazolidines is discussed in terms of reactivity, orientation, and stereochemistry.
Eight 3-diazoalkenes have been prepared from the related ethyl alkenylnitrosocarbamates and methanolic sodium methoxide. All of these unsaturated diazo compounds spontaneously cyclized at room temperature to form pyrazoles in essentially quantitative yields. The cyclizations were cleanly unimolecular. The first-order rate constants for the reactions of four substituted trans-3-diazo-1-phenylpropenes fit the Hammett equation (ρ = -0.40). The relative insensitivity of the cyclization rates to the electronic nature of substituents suggests that the reaction is an intramolecular 1,3-dipolar cycloaddition.
Die Bestrahlung des Azirins (II) in Cyclohexan liefert das Azabicyclohexen (I).
Alkylation of sodium cyclopentadienide with N-(bromomethyl)benzamide followed by Diets- Alder addition of dimethyl azodicarboxylate generated dimethyl 7-anti-benzamidomethyl-2,3-diazabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate. Nitrosation followed by base converted the benzamido group to a diazo grouping. Quenching of this diazo compound with acetic acid produced the 7-anti-acetoxymethyl-2,3-diazabicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylate also available by an analogous alkylation Diels-Alder route using bromomethyl acetate. This quench served to allow assignment of stereochemistry at C-7. Carbene generation by photolysis of the diazo compound led by double bond insertion to dimethyl 7,8-diazatetracyclo[3.3.0.02,4.0 3,6]octane-7,8-dicarboxylate. Hydrolysis, decarboxylation, and oxidation by cupric chloride generated the title compound. The flexibility of the approach should permit applicability to the all carbon system as well.
Perturbation theory is applied to 1,3-dipolar cycloaddition phenomena. The generalizations made in the previous paper concerning 1,3 dipole and dipolarophile frontier orbital energies and coefficients allow a specific qualitative treatment of reactivity of individual 1,3 dipoles. The explanation of regioselectivity and periselectivity phenomena also follows from this treatment. Extensions of the frontier orbital method to other cycloaddition reactions are outlined.
Molecular orbital calculations have been performed by CNDO/2 and EH methods for parent and some substituted nitrilium betaines, diazonium betaines, azomethinium betaines, and carbonyl betaines and for a series of substituted alkenes. Experimental values for ionization potentials and electron affinities, calculations performed here, and calculations in the literature have been used to generate a set of frontier orbital energies and coefficients for 1,3 dipoles and dipolarophiles. The effects of substituents on orbital energies and coefficients are deduced. These frontier orbitals are of general utility in the rationalization and prediction of relative rates and regioselectivity of 1,3-dipolar cycloadditions, as well as other cycloadditions and "frontier-controlled" organic reactions.
The rate of decomposition of 4′-substituted-2-azidobenzophenones to give 4′-substituted-3-phenylanthranils has been studied in decalin over a 45° temperature range. The reaction was found to be accelerated by electron-withdrawing groups and retarded by electron-donating groups. The enthalpy of activation was found to be considerably less than reported for phenyl azide decompositions. The entropy of activation was moderately large and negative (-6 to -21 cal deg-1 mol-1). A plot of ΔH≠ vs. ΔS≠ was linear. An isokinetic temperature of 163° was calculated. The reaction was accelerated only slightly in changing the solvent from decalin to anisole to dimethylformamide. A 1,3-dipolar addition mechanism is proposed to account for these results.
Der Mechanismus der intramolekularen Photocycloadditionsreaktionen zahlreicher alkenylphenyl-substituierte Aziridine wird untersucht.
Intramolekulare dipolare Cycloaddition der aus den Azirinen (I) intermediär gebildeten Nitrilylide (II) gibt die Heterocyclen (III), von denen (IIIb) und (IIIc) beim Stehen an der Luft oder bei der Chromatographie in die Oxidationsprodukte (IVa) bzw. (IVb) übergehen.
The intramolecular photocycloaddition reaction of a number of 3-phenyl-2-methyl-2-allyl substituted 2H-azirines has been examined in mechanistic detail. Upon irradiation with ultraviolet light, these systems undergo rearrangement to azabicyclo[3.1.0]hex-2-enes via transient nitrite ylides. These reactive 1,3-dipoles can be intercepted with added dipolarophiles to give five-membered heterocyclic rings. Irradiation of the isomeric 3-methyl-2-phenyl-2-allyl-2H-azirine system gave similar results. Inspection of molecular models of these 2-allyl substituted nitrile ylides indicates that the normal "two-plane orientation approach" is impossible as a result of the geometric restrictions imposed on the system. With these nitrile ylides, attack by the alkene is constrained to occur perpendicular to the CNC plane of a bent nitrile ylide. The second LUMO, which is perpendicular to the CNC plane, is low lying and presents a large vacancy at C-1 for attack by the more nucleophilic terminus of the alkene, without the possibility of simultaneous bonding at the C-3 carbon atom. Attack by the carbene carbon on the terminal position of the neighboring double bond generates a trimethylene derivative which subsequently collapses to a mixture of azabicyclohexenes. This cycloaddition sequence proceeds in a nonconcerted manner and bears a strong resemblance to the stepwise diradical mechanism suggested by Firestone to account for bimolecular 1,3-dipolar cycloadditions.
Aus dem Oxazolin (I) wird das (o-Allyl-phenyl)-imidoylchlorid (II) synthetisiert, das in Gegenwart von Triäthylamin in Benzol das instabile Nitrilylid (III) gibt; dieses reagiert mit dem Acylat (IV) unter 1,3-Cycloaddition zu einem Gemisch (hohe Ausbeute) zweier Diastereoisomerer des Pyrrolins (V); in Abwesenheit des Dipolarophils (IV) geht das Ylid (III) eine intramolekulare 1,1-Cycloaddition zu dem Bicyclohexen (VI) ein . Eine analoge 1,1-Cycloaddition wird auch bei der Photolyse der Azirine (VIII) - die aus (I) über die Benzaldehyde (VII) zugänglich sind - beobachtet.
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