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Based on new methodology for nitration of pyridine and pyridine derivatives developed at our department by Professor Jan Bakke and coworkers at NTNU, a whole range of substituted nitropyridines are now readily available. The method provides new possibilities in heterocyclic chemistry for the preparation of new materials. Due to the importance and useful properties of many pyridine-based compounds, the chemistry of nitropyridine derivatives is being investigated by our group at NTNU and results for nitropyridine carbamates, amides and carboxylates are presented in this thesis. These nitropyridine derivatives have been used as substrates for the formation of new bisheterocyclic compounds and pyridine derivatives. New synthetic routes to fused heterocycles have been developed.Chapter 2 and Paper I presents the preparation, stability and reactivity of nitropyridine isocyanates (13, 23), a new class of compounds in organic chemistry. The introduction of an electronegative substituent represented by the nitro group was expected to reduce the basisity of the pyridine nitrogen, hence decrease the rate of dimerisation and increase the reactivity of the isocyanate carbon towards a nucleophile. The preparation of nitropyridine isocyanates (13, 23) are reported.Isocyanates constitute an important class of compounds in organic chemistry and undergo a series of reactions to yield a variety of interesting products includingheterocyclic derivatives. Heterocyclic isocyanates, however, have not received the same attention as the respective aromatic compounds in synthesis and reactivity studies because of their instability and high reactivity. 2-Pyridine isocyanate dimerises while the 4-isomer trimerises to form the trimer.Chapter 3 and Paper I presents the preparation, stability and reactivity of the isocyanate dimer and trimer. The isocyanate dimer (28) was formed in high yield from the reactive 5-nitro-2-pyridine isocyanate (23) by a [2+4]-cycloaddition reaction. Another byproduct in the preparation of the isocyanate using oxalyl chloride was the tetrone (26).The isocyanate trimer was formed from the unstable 4-pyridine isocyanate for reference purposes. The trimer proved to be less stable than previously reported and afforded 4-aminopyridine and methyl 4-pyridine carbamate as decomposition products in the presence of moisture and alcohols, respectively. This demonstrates that the reactive trimer can be used as a protected version of the isocyanate for synthetic purposes.Chapter 4 and Paper II presents studies of the nitropyridine isocyanates in cycloaddition reactions. The reactivity of the nitropyridine isocyanates in 1,3-dipolar cycloaddition reactions with trimethylsilylazide and 3,5-dimethylpyridine N-oxide to afford tetrazolinones (41, 43) and substituted amines (52, 55) was investigated. A [2+4]-cycloaddition reaction of nitropyridine isocyanate with diphenylketene was also studied. The cycloadduct (59) was formed. These results demonstrate the potential of the nitropyridine isocyanates to undergo cycloaddition reactions.Application of nitropyridine carbamates, amides and carboxylates in the formation of new heterocyclic compounds have been investigated and discussed in Chapter 5-7.Chapter 5 and Paper III presents the aromatic nucleophilic substitution reaction of the nitro group of methyl 3-nitro-4-pyridine carboxylate. The nitro group was successfully replaced by nitrogen, oxygen and sulfur nucleophiles to afford the substitution products (16a-d) in moderate yields.Chapter 6 and Paper IV presents the cyclization reaction of nitropyridine carbamates for the formation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (79a-b), a biologically active compound. A facile acid-catalysed cyclization method for the preparation of the cyclic urea by traditional heating and the corresponding microwave-promoted reaction were developed. Both methods afforded the cyclic urea in high yield and represent a “green method” for the preparation of this compound.Chapter 7 and Paper V presents the preparation of 1H-1,2,3-triazol [4,5-c]pyridine (86) and N-acyl and N-alkoxycarbonyl triazolo[4,5-c]pyridine derivatives (96a-e, 98a-e). The triazolopyridine derivatives were readily formed by diazotization and cyclization of the respective nitropyridine carbamates and amides in high yields. The application of triazolo[4,5-c]pyridine derivatives (98a-e) in the acylation of amines and amino acids was investigated. They proved to be more effective than the commercially available benzotriazole and afforded the protected amines in high yields under mild conditions.

Based on new methodology for nitration of pyridine and pyridine derivatives developed at our department by Professor Jan Bakke and coworkers at NTNU, a whole range of substituted nitropyridines are now readily available. The method provides new possibilities in heterocyclic chemistry for the preparation of new materials. Due to the importance and useful properties of many pyridine-based compounds, the chemistry of nitropyridine derivatives is being investigated by our group at NTNU and results for nitropyridine carbamates, amides and carboxylates are presented in this thesis. These nitropyridine derivatives have been used as substrates for the formation of new bisheterocyclic compounds and pyridine derivatives. New synthetic routes to fused heterocycles have been developed.Chapter 2 and Paper I presents the preparation, stability and reactivity of nitropyridine isocyanates (13, 23), a new class of compounds in organic chemistry. The introduction of an electronegative substituent represented by the nitro group was expected to reduce the basisity of the pyridine nitrogen, hence decrease the rate of dimerisation and increase the reactivity of the isocyanate carbon towards a nucleophile. The preparation of nitropyridine isocyanates (13, 23) are reported.Isocyanates constitute an important class of compounds in organic chemistry and undergo a series of reactions to yield a variety of interesting products includingheterocyclic derivatives. Heterocyclic isocyanates, however, have not received the same attention as the respective aromatic compounds in synthesis and reactivity studies because of their instability and high reactivity. 2-Pyridine isocyanate dimerises while the 4-isomer trimerises to form the trimer.Chapter 3 and Paper I presents the preparation, stability and reactivity of the isocyanate dimer and trimer. The isocyanate dimer (28) was formed in high yield from the reactive 5-nitro-2-pyridine isocyanate (23) by a [2+4]-cycloaddition reaction. Another byproduct in the preparation of the isocyanate using oxalyl chloride was the tetrone (26).The isocyanate trimer was formed from the unstable 4-pyridine isocyanate for reference purposes. The trimer proved to be less stable than previously reported and afforded 4-aminopyridine and methyl 4-pyridine carbamate as decomposition products in the presence of moisture and alcohols, respectively. This demonstrates that the reactive trimer can be used as a protected version of the isocyanate for synthetic purposes.Chapter 4 and Paper II presents studies of the nitropyridine isocyanates in cycloaddition reactions. The reactivity of the nitropyridine isocyanates in 1,3-dipolar cycloaddition reactions with trimethylsilylazide and 3,5-dimethylpyridine N-oxide to afford tetrazolinones (41, 43) and substituted amines (52, 55) was investigated. A [2+4]-cycloaddition reaction of nitropyridine isocyanate with diphenylketene was also studied. The cycloadduct (59) was formed. These results demonstrate the potential of the nitropyridine isocyanates to undergo cycloaddition reactions.Application of nitropyridine carbamates, amides and carboxylates in the formation of new heterocyclic compounds have been investigated and discussed in Chapter 5-7.Chapter 5 and Paper III presents the aromatic nucleophilic substitution reaction of the nitro group of methyl 3-nitro-4-pyridine carboxylate. The nitro group was successfully replaced by nitrogen, oxygen and sulfur nucleophiles to afford the substitution products (16a-d) in moderate yields.Chapter 6 and Paper IV presents the cyclization reaction of nitropyridine carbamates for the formation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (79a-b), a biologically active compound. A facile acid-catalysed cyclization method for the preparation of the cyclic urea by traditional heating and the corresponding microwave-promoted reaction were developed. Both methods afforded the cyclic urea in high yield and represent a “green method” for the preparation of this compound.Chapter 7 and Paper V presents the preparation of 1H-1,2,3-triazol [4,5-c]pyridine (86) and N-acyl and N-alkoxycarbonyl triazolo[4,5-c]pyridine derivatives (96a-e, 98a-e). The triazolopyridine derivatives were readily formed by diazotization and cyclization of the respective nitropyridine carbamates and amides in high yields. The application of triazolo[4,5-c]pyridine derivatives (98a-e) in the acylation of amines and amino acids was investigated. They proved to be more effective than the commercially available benzotriazole and afforded the protected amines in high yields under mild conditions.

In this paper, we report an efficient one-pot synthesis of 1,2,3-triazole/quinoline-fused imidazo[1,2-a]pyridines starting from 2-(2-bromophenyl)imidazo[1,2-a]pyridines, alkynes, and sodium azide. This novel method involves a one-pot bimetallic relay-catalyzed cascade process combining azide–alkyne cycloaddition, C–N coupling between 1,2,3-triazole and aryl bromide, and intramolecular cross dehydrogenative C–C coupling between 1,2,3-triazole and imidazo[1,2-a]pyridine. Notable features of this protocol include simple starting materials, sustainable oxidants, reduced synthetic steps, and high efficiency.

This paper reports an efficient two-step method for synthesizing a series of new (5aS,10R)-10-aryl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines by a catalyst-free three-component Strecker reaction followed by an intramolecular [3+2] cycloaddition. The first step involved three-component coupling of aldehydes, (S)-2-(azidomethyl)pyrrolidine and potassium cyanide in presence of water to form (R)-2-((S)-2-(azidomethyl)pyrrolidin-1-yl)-2-phenylacetonitriles (3a–3v). In the next step products (3a–3v) underwent intramolecular [3+2] cycloaddition on heating to form (5aS,10R)-10-aryl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines (4a–4v). The present methodology is cost-effective, operationally simple, and applicable for various aromatic, aliphatic and heterocyclic aldehydes, and gives desired products in satisfactory yields and diastereoselectivities. A proposed mechanism for synthesis of 3a and 4a is reported.

N-Protected (S)-2-(diazoacetyl)pyrrolidines can be considered as a group of the N-protected (S)-proline derivatives. They can be conveniently prepared from the corresponding acyl chloride or mixed anhydride via Arndt–Eistert reaction.1 In recent years, the N-protected (S)-2-(diazoacetyl)-pyrrolidines have been widely explored as easily available, chiral building blocks bearing the reactive diazo function and have found numerous applications for the multistep synthesis of more complicated heterocycles including some natural products and their analogs. Some of them are reported to display biological activities, e.g., antifungal,2 α4β2 nicotinic acetylcholine receptor-binding,3 , 4 oxygen free radical scavenging,5 and selective antihistamine.6 Three types of key reactions performed with N-protected (S)-2-(diazoacetyl)pyrrolidines are a) halogenation via treatment with HX agents and N2 elimination, b) catalytic decomposition and generation of reactive ketenes via the Wolff rearrangement of the intermediate α-oxo carbenes, and c) (3+2) cycloaddition reactions of the diazo 1,3-dipole with C=S dipolarophiles. In this article, mainly the papers from the period after 2001 are reviewed.

This paper focuses on the use of natural sources for the preparation of efficient and low cost catalysts. CaCO3 is obtained from cuttlefish bone and was modified by the cation exchange of Ca2+ by Cu2+ in CaCO3 using solutions of copper (Cu(NO3)2) at different concentrations. The modification of the solids was investigated using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive spectrometry (EDS) and ultraviolet-visible (UV-vis) spectroscopy. The results show that the copper exchanged materials contain a CuCO3–CuO nanoparticle composite. The obtained solids were used as catalysts for the cycloaddition reaction of different azides with activated alkenes at room temperature under liquid phase conditions. The different parameters which affect the reaction were investigated such as reaction time, temperature of the reaction, effect of the copper content, catalyst mass, effect of the solvent and nature of the azide. High yields were obtained when the catalyst contained more copper. The best catalysts were calcined at different temperatures (200, 300, 400, 500 °C) in order to determine whether the active phase was CuCO3 or CuO in the catalytic reaction. The XRD analysis of the calcined composites shows that an increase in calcination temperature leads to the formation of the CuO phase. On the other hand, the use of these calcined materials as catalysts shows that the active phase is copper carbonate. Finally, a new method for preparing triazoles with short reaction times was developed by the use of a cheap environmentally friendly catalyst.

In this paper, an elegant synthesis of 1,2,3-triazole derivatives via domino [3 + 2] azide cycloaddition and denitration reaction sequence under catalyst free conditions has been described. Treatment of Baylis–Hillman adducts and their cyclic derivatives from nitroolefins with sodium azide in the absence of catalyst smoothly afforded the 1,2,3-triazole derivatives in excellent yields.

The pharmaceutically important tetrahydro-[1,2,3]triazolopyrazine heterocyclic architecture has been synthesized via a concise tandem “click”/6-exo-dig cyclization strategy in mixed aqueous–organic media. The generality of this mild method was expanded to various amino acid based substrates. The scopes and limitations of this method are discussed in the paper.

Reactions of α,β-unsaturated aldehydes and cyclic 1,3-dicarbonyl compounds proceed primarily by cascade Knoevenagel condensation/six-π-electron electrocyclization (K6EC, formal [3 + 3] cycloaddition), while α,β-unsaturated ketones usually react with cyclic 1,3-dicarbonyl compounds in a 1,4-addition manner. This paper discloses our findings that under acidic conditions, α,β-unsaturated carbonyl compounds (ketones and aldehydes) with a tethered alcohol react with cyclic 1,3-dicarbonyl compounds in a highly regioselective 1,4-addition fashion via in situ generation of a hypothetical α-methylene cyclic oxonium ion as the reactive Michael acceptor. Our studies uncovered the important effect of the tethered alcohol on the reaction rate and/or efficiency and some new mechanistic aspects of the cascade Michael addition/cycloketalization. Finally, the substrate scope was examined, and 43 analogues of penicipyrone and tenuipyrone were prepared in good to excellent yields.

Since its isolation in 1962, minovincine[1] (1) has garnered considerable interest within the chemical synthesis community due to its characteristic spiroindoline framework, a common structural feature found among a number of high-profile natural products derived from the Aspidosperma, Kopsia, and Catharanthus genre.[2] Indeed, this structural core has led to minovincine being described as a “biogenetic turntable” between the vindolinine and kopsinine classes of isolates,[3a,b] and has provided the impetus over several decades for a number of racemic total syntheses of this biosynthetic linchpin. At the present time, however, no asymmetric total synthesis of minovincine has been reported,[4] a surprising fact given the range of catalytic technologies that have been developed to forge this broadly represented spiroindoline framework. In this communication, we detail the first enantioselective total synthesis of (−)-minovincine in only nine chemical steps, using a novel organocascade[5] catalysis transformation that incorporates an enantioselective Diels–Alder cycloaddition/β-elimination/conjugate addition sequence.[6] Central to the development of this new catalysis cascade has been the identification of ketone substrates and amine catalysts which combine to provide direct access to the key functional and architectural elements found in minovincine. We were initially drawn to minovincine on the basis of its (i) benchmark spiroindoline framework, which is broadly represented across a large range of Aspidosperma, Kopsia, and Catharanthus isolates; and (ii) the exocyclic ketone substituent that is not common within these alkaloid families.[2] Previous studies conducted by our group have revealed that similar tetracycles are readily constructed via iminium-activated organocascade catalysis protocols that involve enantioselective [4 + 2] cycloaddition of 2-vinyl indoles with an unsaturated aldehyde partner.[6] We questioned whether this strategy might be extended to ketone dienophiles, such as 3-butyn-2-one, thereby providing direct access to the exocyclic ketone present in minovincine and several other natural alkaloids. Despite their apparent similarities on paper, aldehydes and ketones exhibit markedly different behavior in organocatalytic processes, and the latter have historically posed a significant challenge in amine-catalyzed Diels–Alder and cascade catalysis reactions (Figure 2).[7] More specifically, ketones typically exhibit (i) attenuated reactivity towards condensation with secondary amines in comparison to their formyl counterparts – a limitation that can dramatically impact overall reaction efficiency; and (ii) they are prone to non-selective iminium geometry formation with amine catalysts, a loss of organizational control that often leads to diminished enantioselectivity in the critical bond-forming step. As such, we were intrigued by the possibility of expanding the scope of organocascade catalysis to include this more challenging family of carbonyls while developing a concise route to minovincine. Figure 2 Issues with ketone substrates in organocatalytic cascades. The pathway for the proposed organocascade sequence involves a series of catalytic cycles outlined in Scheme 1. In the first cycle, condensation between 3-butyn-2-one (3, R = Me) and amine catalyst 4 would transiently generate a LUMO-lowered unsaturated iminium ion poised to undergo [4 + 2] cycloaddition with vinyl indole 2.[8] We hypothesized that incorporation of a suitable leaving group on the terminus of the diene would result in facile βelimination, delivering indolinium ion 6. At this stage, 5-exo-heterocyclization of the pendent amine onto the α,β-unsaturated iminium moiety would directly yield tetracycle 11 (Path A), which, after hydrolysis, would deliver spiroindoline 13 and regenerate the amine catalyst. Based on previous studies, we recognized the possibility of an alternative second cycle in which indolinium trapping by the pendent amine would furnish pyrroloindoline 8 (Path B), an isolable intermediate when propynal is utilized as the dienophile (R = H). Importantly, we have demonstrated that this aldehyde undergoes facile conversion to the desired spiroindoline 13 (R = H) in the presence of the tribromoacetic acid salt of N-methyl 4 (incapable of undergoing iminium ion formation), illustrating the feasibility of Bronsted acid catalysis as an operative pathway in this organocascade sequence.[6] As a key stereocontrol element, we hypothesized that condensation of 3-butyn-2-one with the imidazolidinone catalyst would lead to an iminium ion geometry wherein the acetylenic functionality of the conjugated system is projected towards the benzylic unit on the catalyst scaffold (enabling stabilizing cation-π interactions between the pendent arene and the terminal alkyne). In this geometry, the catalyst substituents effectively shield one π-face of the iminium ion, thereby ensuring that endo-selective Diels–Alder cycloaddition[8,9] occurs from the opposing trajectory (TS-A, Figure 3), a feature that should induce high levels of enantiocontrol. Figure 3 Proposed stereochemical model for cascade Diels–Alder. Scheme 1 Proposed mechanism for [4 + 2] cycloadddition/β-elimination/hetero-conjugate addition organocascade sequence. To evaluate the key organocascade sequence, a series of halide-or selenium-bearing vinyl indoles were prepared via a straightforward, three-step protocol (Scheme 2). More specifically, N-indole protection of commercially available tetrahydro-β-carboline derivative 18 was followed by selenium dioxide-mediated oxidation[10] and subsequent olefination to afford diene 16 as the vinyl bromide, iodide, or selenide. Scheme 2 Total synthesis of (−)-minovincine: a) NaH, PMB-Cl, DMF, 0 °C, 94%; b) SeO2, 95:5 dioxane:H2O, 100 °C, 87%; c) LG = Br: [(PPh3)CH2Br]Br, t-BuOK, THF, −78 °C, 21%; LG = I: CrCl2, CHI3, THF, 0 °C, 50%; LG ... As illustrated in Table 1, our initial attempts to construct spiroindoline 17 via our proposed organocascade sequence using the vinyl bromide derivative of 16 were unsuccessful (entry 1). However, employing the indole vinyl iodide derivative in conjunction with the camphorsulfonic acid salt of catalyst 14 (known to efficiently condense with cyclic ketones to form enamines)[11] produced the desired tetracycle, albeit with low yield and enantioselectivity (entry 2, 15% yield, 24% ee). To our delight, further investigation revealed that use of the vinyl selenide system afforded cascade product 17 in a promising 45% yield and 36% ee (entry 3). Reaction medium was also critical with respect to obtaining high levels of asymmetric induction, as demonstrated by the implementation of chloroform (entry 4, 79% ee). Further improvements in enantioselectivity were achieved by increasing the size of the pendent aromatic unit on the catalyst framework, presumably allowing for greater facial shielding of the transient iminium ion (entry 5, catalyst 15, 95% ee). Finally, a pronounced acid co-catalyst effect was identified, wherein changing from camphorsulfonic acid[12] to p-toluenesulfonic acid provided the desired spiroindoline in 72% yield while maintaining excellent levels of enantioselectivity (entry 6, 91% ee). Table 1 Evaluation of key organocascade step. Having established our optimal ketone activation cascade catalysis sequence, and with the enantioenriched tetracyclic core 17 in hand, we next focused upon completing the natural product synthesis in an expeditious fashion (Scheme 2). With the goal of installing the requisite minovincine ester group, we exposed spiroindoline 17 to a variety of traditional acylating agents (i.e. phosgene, methyl chloroformate, etc.), however, with little success. Fortunately, the palladium-catalyzed carbomethoxylation of the dienylogous amide in the presence of carbon monoxide and methanol proceeded smoothly to afford vinylogous carbamate 20 in excellent yield (92%).[13] Regioselective 1,4-conjugate reduction of the resulting α,β,γ,δ-unsaturated ketone was accomplished with the aid of the sterically demanding reducing agent L-Selectride,[14] followed by Lewis acid-mediated Boc-deprotection to deliver the βamino ketone 21 in 54% yield over two steps.[15] Closure of the final ring was achieved through N-alkylation with 1,3-diiodopropane and treatment with potassium tert-butoxide to provide the natural product in its protected form in 73% yield as a single diastereomer. Finally, removal of the para-methoxybenzyl group from the indoline nitrogen afforded (−)-minovincine in 77% yield for the final step, and in 13% overall yield for the nine-step sequence.[16] Synthetic (−)-minovincine was found to be identical in all spectroscopic respects to the natural isolate. In summary, the first enantioselective total synthesis of (−)-minovincine has been completed in nine chemical steps and 13% overall yield from commercial materials. A prominent feature of this synthesis involves an organocatalytic Diels–Alder/βelimination/conjugate addition cascade to rapidly construct the tetracyclic framework of minovincine in a highly enantioselective manner. This total synthesis exemplifies the capacity of ketone dienophiles to be viable substrates for iminium catalysis in the context of complex target settings.

The (4+2) cycloaddition or the Diels-Alder reaction is one of the most important reactions in the field of organic synthesis. The Diels-Alder reaction well known to all chemists is 100 years old. The Diels-Alder reaction during that period it has been studied intensively, where there are more papers, many books and reviews in the Diels-Alder reactions making the complete study of these works impossible, therefore in this article we concentrate on the review and generalization of the Diels-Alder reaction of 9-substituted anthracene with a variety of dienophiles.

In connection with the preceding paper dealing with the preparation of (Z)-β-sulfonyl enoates, the process is extended to the synthesis of bicyclic esters (IV) and (VI) via 1,3-dipolar cycloaddition of cyclopentadiene as a third step.

In this paper, we report our ongoing progress in the preparation of fullerene-azide or fullerene-alkyne building blocks, allowing their further chemical transformation under the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction conditions.

Direct transformation of five-membered zirconacycles to carbocyclic compounds is of great synthetic interest. The reaction of zirconacycles with electrophiles containing at least two reactive functional groups or an oxidant affords various carbocycles through cross coupling, addition, and/or oxidative coupling reactions. In this paper, we present our recent results on the zirconacycle-mediated formation of carbocycles, including: (1) 1,1-cycloaddition of oxalyl dichloride with zirconacycles; (2) benzoquinone-promoted coupling of zirconacyclopentadienes in the presence of CuCl; (3) cycloaddition of zirconacyclopentadienes to quinones; (4) cycloaddition of zirconacyclopentadiene with 2-bromoacrylate, 2-bromoacrylaldehyde and 3-bromofuran-2,5-dione in the presence of CuCl; (5) one-pot coupling of two alkynes and an alkene to form cyclohexene derivatives via zirconacyclopentadienes; and (6) dianionic cycloaddition of decatetraenes with esters or acyl chlorides to form nine-membered carbocycles.

The concept of 1,3-dipolar cycloaddition was developed, starting in the late 1950s, largely by Rolf Huisgen and his students in Munich, and it has led to one of the most versatile methods for the construction of five-membered ring heterocycles. Although first known only as transient intermediates, nitrile imines have been at the heart of mechanistic studies of this type of cycloaddition reactions. Hundreds of mechanistic papers appeared in 1960s and 1970s; reliable spectroscopic observations were achieved in the early 1980s both at low temperatures and in the gas phase; finally, the first crystalline nitrile imine was reported in 1988. The unusual structures found by X-ray analyses as well as the facile rearrangements observed experimentally have fostered a new interplay between experiment and theory. The story of nitrile imines, from matrix characterization to stable compounds, nicely illustrates the role that main group elements can play in organic chemistry.

This paper describes the first total syntheses of the diterpene quinones aegyptinones A and B via an extremely direct route which should easily accommodate the production of gram quantities of each compound. The key step in the synthetic strategy involves the application of a recently developed «second-generation» photochemical aromatic annulation method for the construction of highly substituted aromatic systems. The synthesis of one of the annulation components, the diazo ketone 6, was achieved using a Diels-Alder-based benzannulation strategy employing cyanoallene and the dienamine 13. Cyanoallene proved to be uniquely effective for this cycloaddition, which either failed or proceeded in poor yield using several substituted acetylenes as dienophiles. The pivotal aromatic annulation reaction was accomplished by irradiating a solution of the diazo ketone 5 and the readily available siloxyalkyne 4 in a Pyrex vessel with a 450-W medium-pressure Hanovia lamp at room temperature for 17-20h. The desired tricyclic phenol 3 was produced in 58-70% yield and was then converted to aegyptinone B (2) by treatment with tetra-n-butylammonium fluoride in the presence of oxygen. Finally, cyclization to generate aegyptinone A was accomplished in high yield by brief exposure of 2 to an ethanolic solution of concentrated sulfuric acid at room temperature. Overall, this strategy provides efficient routes (six and seven steps, respectively) to aegyptinones A and B which should facilitate the systematic investigation of the pharmacological activity of these novel diterpenes

This paper reports the synthesis of 3-substituted-1,2,3-triazolo[1,5-a]quinazolin-5-ones prepared by 1,3-dipolar cycloaddition reaction of 2-azidobenzoic acid to methylenic compounds activated by a cyano group. The new derivatives were submitted to benzodiazepine receptor binding assays: the results indicated an interesting receptorial affinity of the 1,2,3-triazolo[1,5-a]quinazoline ring. On the basis of the biological results, theoretical calculations were performed, which suggested useful structural modifications.

Fullerene functionalization with heterocycles is reviewed, focusing attention on cycloaddition methodology and oxidative heterocyclization. 1 1This paper was presented before the Symposium 3 on ‘Expanded Horizons of Fullerene Science and Technology’ organized by L. Y. Chiang, E.Osawa, H. Terrones and M. Saunders at the 4th International Conference on Advanced Materials (ICAM-IV), Aug. 27 to Sept. 1, 1995, Cancun, Mexico.

A comprehensive series of multiple adducts of C60 was prepared by tether-directed remote functionalization. When the tether-reactive-group conjugates 2 and 10 were attached to methano[60]fullerenecarboxylic acid ( = cyclopropafullerene-C60-Ih-carboxylic acid) and C60, respectively, the e-bis-adducts 4 and 9 (Schemes 1 and 2) were obtained with complete regioselectivity as predicted by semi-empirical PM3 calculations (Fig. 2). Attachment of the anchor-tether-reactive-group conjugate 13 to C60 by Bingel reaction, followed by double intramolecular Diels-Alder cycloaddition afforded the tris-adduct 12 (Scheme 3). Starting from 12, a series of selective e-additions led to the tetrakis-adducts 16 and 19 (Scheme 4), pentakis-adducts 20–23 (Scheme 5), and, ultimately, to hexakis-adducts 24 and 25 (Scheme 6), and 29 and 30 (Scheme 7) with a pseudo-octahedral addition pattern on the fullerene core. Oxidative cyclization of diethynylmethanofullerene 30 under Eglinton-Glaser conditions afforded the trimeric and tetrameric acetylenic macrocycles 26, with three, and 27, with four appended C60 moieties, respectively (Scheme 8). These multinanometer-sized compounds are the first soluble derivatives of C195 and C260, two members of a new class of fullerene-acetylene hybrid C-allotropes with the general formula Cn(60 + 5). The matrix-assisted laser-desorption time-of-flight mass spectra of 26 and 27 showed a remarkable fragmentation; the sequential loss of fullerene spheres led to the formation of ions corresponding to mono-fullerene adducts of the cyclocarbons cyclo-C15 and cyclo-C20 (Fig. 4). Large solvent effects were observed in the Bingel addition of 2-bromomalonates to higher adducts of C60, with the use of polar solvents enhancing the reaction rate without loss of regioselectivity. Experimental evidence for the enhanced reactivity of eface over eedge bonds was obtained, which had previously been predicted in computational studies. The correlated series of mono- to hexakis-adducts of C60 allowed identification of the changes in reactivity and physical properties that occur, when the conjugated π-electron chromophore of the fullerene is reduced as a result of increasing functionalization; this analysis is the subject of the directly following paper.

A new class of potential antiviral drugs is represented by isoxazolidine nucleosides. The paper reports on the synthesis of protected adenines useful as dipolarophiles in the preparation of analogues of dideoxyadenosine by 1,3-dipolar cycloaddition processes.

This paper have delineated the effectiveness of [3+2] cycloaddition process in the synthesis of multifunctional 6-membered rings. The novel synthesis of chiral A-ring fragment of 1α,25-dihydroxyvitamin D 3 and also a novel route to A-ring fragment of taxane diterpenoids have been established.

In this paper we report our recent results in the area of nitrile oxide cycloaddition to optically active vinylboronic esters to afford optically active boronic ester substituted Δ 2 -isoxazolines. In these studies, a number of optically active diols were investigated and TADDOLs have been found to afford the best diastereoselectivity. The mixture of diastereomers obtained in these reactions can be readily purified by formation of the diethanolamine–boron complexes and recrystallized to afford the pure enantiomers.

Department of Chemistry, UniVersity of California, Berkeley, California 94720 ReceiVed June 14, 1999 Since its discovery in 1912,1 the Claisen rearrangement has become one of the most powerful tools for carbon-carbon bond formation in chemical synthesis.2 This [3,3]-sigmatropic rearrangement, which involves the conversion of an allyl vinyl ether to an R,â-disubstituted γ,δ-unsaturated carbonyl, generally proceeds with high levels of stereocontrol, securing its widespread use in natural product and medicinal agent synthesis.2 Activation of this rearrangement has traditionally been accomplished under thermal control; however, significant rate acceleration can be achieved through the incorporation of cationic3 or anionic4 charge in the bond reorganization event. Despite its prolific use in chemical synthesis and disposition toward charge acceleration, only two examples of catalytic Claisen variants have been reported.5 In this paper we describe a broadly useful Lewis acidcatalyzed [3,3]-sigmatropic rearrangement that we expect will provide a new avenue for the development of an enantioselective catalytic Claisen process.6 In 1978, Bellus and Malherbe reported the conceptually novel ketene-Claisen reaction.7 In an attempt to perform a [2 + 2] cycloaddition, the authors discovered that treatment of an allyl ether with dichloroketene resulted instead in the formation of a 1,3-dipolar allyl vinyl ether, which subsequently underwent [3,3]bond reorganization (eq 1). Although the scope of this reaction

This thesis describes mechanistic studies, rational ligand design, and synthesis of asymmetric transition metal catalysts. The topics addressed concerned [Papers I-VII]:[I] The asymmetric addition of diethyl zinc to N-(diphenylphosphinoyl)benzalimine catalyzed by bicyclic 2-azanorbornyl-3-methanols was studied. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center was developed, in the best case 97% ee was obtained with these ligands. The experimental results were rationalized by a computational DFT-study.[II] An aza-Diels-Alder reaction of cyclopentadiene with chiral heterocyclic imines derived from (S)-1-phenylethylamine and different heteroaromatic aldehydes was developed. The cycloaddition proved to be highly diastereoselective and offers a very rapid access to possible biologically active compounds and interesting precursors for chiral (P,N)-ligands. [III] A convenient and high-yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantio-enriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. [IV] The reaction mechanism of the iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins has been studied by means of DFT-calculations (B3LYP) and kinetic experiments. The calculations suggest that the reaction involves an unexpected IrIII-IrV catalytic cycle facilitated by coordination of a second equivalent of dihydrogen. On the basis of the proposed catalytic cycle, calculations were performed on a full system with 88 atoms. These calculations were also used to explain the enantioselectivity displayed by the catalyst.[V and VI] A new class of chiral (P,N)-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes was developed. These new ligands proved to be highly efficient and tolerate a broad range of substrates. The enantiomeric excesses are, so far, the best reported and can be rationalized using the proposed selectivity model.[VII] The complex formed between the quincorine-amine, containing both a primary and a quinuclidine amino function, and [Cp*RuCl]4 catalyzes the hydrogenation of aromatic and aliphatic ketones in up to 90% ee approx. 24-times faster than previously reported Ru-diamine complexes. The reason for the lower but opposite stereoselectivity seen with the quincoridine-amine, as compared to the quincorine-amine, was rationalized by a kinetic and computational study of the mechanism. The theoretical calculations also revealed a significantly lower activation barrier for the alcohol mediated split of dihydrogen, as compared to the non-alchol mediated process. A finding of importance also for the diphosphine/diamine mediated enantioselective hydrogenation of ketones.

The aldehyde 2-formyl-2-(pent-4-enyl)-1,3-dithiane 1, containing both alkene and aldehyde functional groups, is a good substrate for intramolecular dipolar cycloaddition reactions after condensation with various N-alkyl α-amino-esters. This paper reports the optimization, scope and stereoselectivity of this reaction to give octahydroindoles (2-azabicyclo[4.3.0]nonanes).

[4.3.0]- and [5.3.0]Bicyclic ring systems containing a nitrogen atom at the bridgehead position were prepared by a [3+2] addition of acetylenic dipolarophiles to the conformationally locked cyclic α-alkoxycarbonylnitrones 1a–c and 18. Reaction proceeded with a high degree of diastereofacial selectivity with cycloaddition taking place to the face of the dipole opposite the C-5 methyl group. Reaction with the C-phenyl nitrones, 1b and 1c, was straightforward and the structure of 12b, arising from reaction of 1b with dimethyl acetylenedicarboxylate has been determined by single crystal X-ray diffraction. The identity of the product(s) from reaction of C-methyl nitrones, 1a or 18, with dimethyl acetylenedicarboxylate varies with reaction duration; 12a and 20 are the primary cycloaddition products and the pyrrolooxazinones 14 and 22 appear after prolonged reaction duration. A similar pattern of reactivity is observed when the same dipoles react with methyl propiolate. The structure of 14 has been confirmed following X-ray crystallographic analysis. The primary cycloadducts, 12a, 20, 24a and 30, bearing a C3a-methyl group had poor thermal stability and rearranged to the pyrrolooxazinones 13, 21, 25 and 31 respectively. A mechanistic proposal for the origin of the fused pyrroles is included. A C-6 methyl substituent on the dipole 18 had no determining influence on the stereochemical course or the rate of the cycloaddition reaction established by its unsubstituted analogues 1a and 1b. In addition to its mechanistic findings, this paper reports two significant synthetic advances: access to a range of unusually substituted hetero-fused pyrroles and to isoxazolooxazepinones, a rare bicyclic ring system.

This Paper is dedicated to Professor Sang Chul Shim on the occasion of his 65 th birthday. Abstract - The reactions involving one of the simplest imines, N-methyleneamine (monomeric formaldehyde imine), are very limited from the synthetic viewpoint because it is difficult to generate the N-methyleneamine. In this review are summarized a method and synthetic applications of N-methyleneamine equivalents generated from hexahydro-1,3,5-triazines or N-methoxymethylamines in the presence of a Lewis acid. Reactions with various nucleophiles yield aminomethylated products at the α -position of amines. Lewis acid-induced N- methyleneanilines can also serve as azadienes with electron rich diene for reverse electron demand (4π+2π) cycloaddition reactions.

In this paper, we report a novel sequential reaction sequence consisting of a series of processes including Sonogashira coupling, propargyl-allenyl isomerization, [3 + 2] cycloaddition, denitrogenation, and highly selective biradical coupling reaction, providing an efficient synthesis of fused polycyclic pyrrole derivatives. The reaction features one C-C bond and two C-N bonds formed to construct the pyrrole unit, together with two rings efficiently assembled in one stroke.

This paper describes carbonylative cycloaddition reactions catalyzed by Ru3(CO)12. Ru3(CO)12 was found to catalyze an intramolecular Pauson–Khand-type reaction. Carbonylative cycloaddition reactions involving a carbonyl group in aldehydes, ketones, and esters as a two-atom assembling unit were also achieved in the presence of Ru3(CO)12 as the catalyst. The reaction of 5-hexyn-1-al and 6-heptyn-1-al derivatives with CO in the presence of Ru3(CO)12 resulted in cyclocarbonylation from which bicyclic α, β-unsaturated lactones were obtained. Intermolecular [2 + 2 + 1] carbonylative cycloaddition of alkenes, ketones, and CO was also catalyzed by Ru3(CO)12 as the catalyst to give saturated γ-lactone derivatives. Simple ketones were not applicable, but ketones having a CO or CN group at the α-position served as a good substrate. These reactions could be extended to carbonylative cycloaddition of the corresponding imines leading to γ-butyrolactam derivatives. The [4 + 1] carbonylative addition of α,β-unsaturated imines leading to unsaturated γ-lactams was achieved with Ru3(CO)12. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 201–212; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20149

This paper describes a simple method for synthesizing a small library of 5-isoxazol-5-yl-2′-deoxyuridines from 5-iodo-2′-deoxyuridine. Nitrile oxides were generated in situ from oximes using a commercial bleaching agent; their cycloaddition with 5-ethynyl-2′-deoxyuridine yielded isoxazoles possessing activity against herpes simplex viruses 1 and 2, Encephalomyocarditis virus, Coxsackie B3, and vesicular stomatitis virus; these isoxazoles were, however, inactive against corona virus, influenza virus, and HIV.

This paper describes some approaches toward the templated synthesis of rotaxanes incorporating strapped metalloporphyrin moieties as the shuttle unit, with the thread component containing both a neutral diimide "station" and a functionalized pyridine moiety, the latter acting not only as a template but also as a second binding motif. In the first instance, the use of appropriately 3,5-difunctionalized pyridine esters and naphthoquinol-strapped rhodium(III) chloride porphyrins in a stoppering approach to rotaxanes produced only unlinked components: the flexibility of the strap allowed sufficient room for the potential thread unit to bind on the same face of the porphyrin as the strap, while not being interlocked through it. An alternative strategy involving a 1,3-dipolar cycloaddition reaction (a "click" reaction) between azides and alkynes, producing triazole linkers in the thread component of rotaxanes, was more successful. Both porphyrinic (zinc, free base, and rhodium(III) derivatives) and crown ether rotaxanes were successfully produced, with multifunctional (triazole and naphthodiimide) thread units. The potential for molecular motion through the use of stimuli such as acid, solvent, and competing ligands was investigated, with limited success. The same cycloaddition methodology was extended to pyridine-templated analogues of the thread components in the Rh(III)-strapped porphyrins, but again, only unlinked thread and porphyrin shuttle units were produced.

Here we report on our studies of the use of combinations of amino acids, amines, K2CO3 or Cs2CO3 and CuSO4/Cu for catalysing green cascade reactions. We aimed to prepare the highly reactive and substituted olefin species 7 and 8, under very mild and environmentally friendly conditions, thus giving the hydrogenated products 10 and 12 through the action of Hantzsch ester (4) by self-catalysis through decreasing the HOMO–LUMO energy gaps between olefins 7/8 and Hantzsch ester (4) through biomimetic reductions. Highly useful compounds 10 to 14 were assembled from simple substrates such as aldehydes 1, ketones 2, CH acids 3, Hantzsch ester (4) and alkyl halides 5 by diversity-oriented green synthesis involving cascade olefination/hydrogenation (O/H), olefination/hydrogenation/alkylation (O/H/A) and hydrogenation/olefination/hydrogenation (H/O/H) reaction sequences in one-pot fashion with stereospecific organo- and organo-/metal-carbonate catalysis. Highly functionalized diverse compounds such as 10 to 14 are biologically active products and have found wide applications as pharmaceutical drugs, drug intermediates and drug ingredients. For the first time in organocatalysis, we report the O/H/A/TE reaction to furnish high yields of transesterification products 11 by simply mixing the reactants under proline/K2CO3 catalysis conditions. Additionally, a novel organocatalytic H/O/H reaction sequence for the synthesis of alkyl-substituted aromatics has been developed. Furthermore, for the first time we have developed organocatalysed cascade olefination/hydrogenation/hydrolysis (O/H/H) reactions to furnish highly useful materials such as 2-oxochroman-3-carboxylic acid (14kc) and 2-amino-4H-chromene-3-carbonitrile (14kj) in good yields. Experimentally simple and environmentally friendly organocatalytic two-carbon homologation through cascade O/H/H reactions of aldehydes 1, Meldrum's acid (3c), Hantzsch ester (4) and acetic acid/triethylamine in ethanol has been demonstrated. Additionally, we have developed a green synthesis of the highly substituted 1,2,3-triazole 17 from simple substrates through a two-step combination of olefination/hydrogenation/alkylation and Huisgen cycloaddition reaction sequences under stereospecific organocopper catalysis conditions. In this paper we have found strong support for our hypothesis that, “decreasing the HOMO–LUMO energy gap between olefins 7/8 and Hantzsch ester (4) will drive the biomimetic hydrogenation reaction by self-catalysis”. This self-catalysis was further confirmed with many varieties of examples.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Multicomponent reactions (MCRs) generate multiple bonds in a single reaction process, which is highly efficient to construct relatively complex molecules. Conducting post-MCR modification reactions further increases the molecular complexity and diversity. MCR has become a powerful approach to make drug-like molecules in lead generation chemistry. In fluorous MCR (F-MCR), one of the starting materials is attached to a fluorous tag and used as the limiting agent. After the MCR, the fluorous component is fished out from the reaction mixture and used for post-MCR modifications. The fluorous tag can be finally removed in traceless fashion by displacement or cyclization reactions. Unique fluorous technology such as fluorous solid-phase extraction (F-SPE) facilitates the separation process. Other techniques such as microwave irradiation and plate-to-plate SPE can also be used to make the F-MCR even more efficient. Syntheses of unique heterocyclic and natural product-like library scaffolds using Ugi/de-Boc/cyclization, MCR/Suzuki coupling, and [3+2] cycloaddition/de-tag/cyclization protocols are described in this paper.

Since transition metal catalysis allows simultaneous formation of more than one bond in a single step operation with high selectivity, the exploitation of a model compound for nitrogen-containing polycyclic biologically active natural products has been a worthwhile contribution in synthetic and medicinal chemistry. Intramolecular hydroamidation of acetylenes, carbonylation of 2-alkylbenzenylamines, 1-aryl-3-hexen-1,5-diynes initiated by methoxide addition, fluoroarenes and nitriles via 1,2-arynes, nitroarylstannanes, radical dearomatization of benzene and hydrothermal reaction of o-phenylaniline, ullamann cross-coupling of 1-bromo-2-nitroarenes and 1,3dipolarcycloaddition of nonstabilized azomethine ylide and photocycloaddition of phthalimide anion to alkenes have been used to synthesize benzazepinone, phenanthridine and benzophenathridinone derivatives. However, these synthetic routes are often complicated and limited to only some substituents. Recently, we reported various cycloisomerization reactions with different unsaturated systems catalyzed by Au, Pt, Pd, and Rh. Our continued interest in the synthesis of polycyclic systems prompted us to develop the Rhcatalyzed cyclization of o-alkynylbenzaldehydes having a nitrile tether that produced tricyclic benzazepinones and benzophenanthridine derivatives via [3+2] and [4+2] cycloaddition via pyrylium intermediates as shown in Scheme 1. An initial study was tested with o-alkynylbenzaldehyde 1a in the presence of various late transition metal catalysts (Table 1). PtCl2 as a catalyst in refluxing 1,4-dioxane for 12 h converted 1a to give a mixture of products, which were separated by column chromatography to give 2,3-dihydrobenzo[e]cyclopenta[b]azepin-5(1H)-one (3a) in 50% yield along with the hydrated product 2a in 30% yield (entry 1). When this reaction was carried out in dry 1,4-dioxane in the presence of 4 A molecular sieves, the reaction was dramatically accelerated to give the product 3a in 59% yield still along with 2a in 10% yield (entry 2). We presumed that a trace amount of water in the reaction medium or in solvent might generate a nucleophile which could undergo hydration to the metal-activated triple bond followed by tautomerization to the corresponding ketoaldehyde 2a. It was observed that gold(III) bromide in 1,2-dichloroethane (EDC) hydrated 1a to afford 2a even at room temperature exclusively (entry 3). This might be understood by the high reactivity of gold catalyst or the poor reactivity of the nitrile group toward the pyrylium intermediate A. We tried the same reaction with different catalysts, such as AuCl3, AuCl(PPh3) with AgSbF6, and AgSbF6 itself, under dry reaction condtions, but led to hydration (entries 4-6). In fact, Zhu et al. reported that o-alkynylbenzaldehydes were hydrated in the presence of gold(+3) catalysts and trifluoroacetic acid to afford the corresponding ketoaldehyde. Finally, we found [Rh(COD)Cl]2 as an optimal catalyst for the present [3+2] cyclization of pyrylium intermediate, generated in situ with alkynophilic metal cations, with a pendent nitrile. Thus, when the substrate 1a in the presence of [Rh(COD)Cl]2 (10 mol%) in dry xylene containing 4 A molecular sieves was heated at 110 C for 12 h, the product 3a was isolated in 71% yield along with the ketoaldehyde 2a in 10% yield. With this promising result, we further examined this [3+2] cycloaddition with structural alteration in the tether (eq. 1-2). This paper is dedicated to Professor Sang Chul Shim at Kyungpook National University on the occasion of his honorable retirement. Scheme 1 Table 1. Optimization of intramolecular [3 + 2] cyclization-cycloaddition under various reaction conditions with 1a

The paper describes the course of cycloadditions of Diels-Alder dienophiles containing linked enyne sites, each substituted with activating groups. Consistently, it was found that in the enyne cases the Diels-Alder reaction occurred specifically at the acetylenic center. Furthermore, it was found that the regiochemical sense of the cycloaddition was apparently determined by the remote activating group bound to the olefinic site. This remote acrylyl group totally dominated the course of the cycloaddition, relative to the activating group bound directly on the acetylene site. Explanations for these findings at the computational level are provided. The computations also rationalize the strong preference for cycloaddition to occur at the acetylene linkage and encompass the otherwise surprising regiochemical dominance by the remote ester on the olefinic site. The high selectivities available through such reactions provide important new opportunities in the synthesis of orsenillate type substructures that are found in a variety of natural products of contemporary interest.

The conjugate acids (PHCH +s) of P-heterocyclic carbenes (PHCs) are prepared by formal [3+2] cycloaddition of a 1,3-diphosphaallyl or 1,3-phosphinophosphenium cation with various nitriles. The effect of the phosphorus substituent on the fate of the cyclization and on that of the counteranion and base in the subsequent deprotonation reaction are reported. Two PHCs that are indefinitely stable in the solid state are described. In solution, one of them, made from acetonitrile, undergoes a facile [3+2] cycloreversion, whereas the other, based on dimethyl cyanamide, is stable, presumably owing to its zwitterionic structure, which involves a tricoordinate pentavalent phosphorus atom. The reactivity of PHCs is strongly driven by the high electrophilicity of the phosphorus centers, as demonstrated by their reactivity with water and benzaldehyde. Although both PHCs reported in this paper are direct analogues of the least-basic NHCs, their basicity is comparable to those of the more strongly basic NHCs (as determined by comparison of the carbonyl stretching frequencies of their corresponding cis-[RhCl-(CO)2(L)] complexes).

This paper describes the optimization of the synthesis of pyridinium-substituted indolizines. Different conditions, solution and solid-phase synthesis were used for the key step of [3+2] cycloaddition. The best yields and shortest reaction time were obtained by microwave-assisted solid-phase synthesis.

This Letter has been retracted, as it was found that (a) spectra of the linear precursor, compound 14, differed when its synthesis was repeated and (b) spectra published for several compounds resulting from compound 14 (compounds 3, 4, and 20) were scanned from other papers. Compounds 3 and 20: Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone, D. J. Am. Chem. Soc. 1996, 118 (40), 9812−9813; Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D.; McPhail, A. T. J. Org. Chem. 1999, 64 (6), 1932−1940. Compound 4: Chackalamannil, S.; Davies, R.; McPhail, A. T. Org. Lett. 2001, 3 (10), 1427−1429.

The Pauson−Khand (PK) reaction is a formal [2+2+1] cycloaddition involving an alkene, an alkyne and carbon monoxide. The allene moiety represents a versatile and useful building block in organic synthesis. In place of the usual alkene, allene reagents are fascinating substrates in the Pauson−Khand-type reaction because of their unique reactivity and the synthetic utility of the final products. However, there are significant problems of selectivity. Several studies, most of them recent, have greatly enhanced the synthetic utility of this reaction by the use of allenes instead of alkenes. This paper presents recent advances in the less exploited allenic and dienic variants of the Pauson−Khand-type cycloaddition. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

In this paper the application of high pressure in multicomponent reactions is discussed. Using high pressure the scope of certain multicomponent reactions can be increased. Reactions are described that can only be performed in a multicomponent fashion when high pressure catalysis is applied. An overview of high pressure catalysed multicomponent reactions is presented with special attention to the domino [4 + 2]/[3 + 2] cycloaddition reaction.

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium−trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.

In this paper we report the development of a stereoselective IMDA approach to the phytotoxic polyketides (±)-solanapyrones A and B. The stereoselectivity of the key IMDA cycloaddition was optimized by investigating a range of 2,8,10-dodecatrienoic acid derivatives. This established that use of the Weinreb amide led to the desired exo -selectivity and also facilitated construction of the pyrone moiety. A novel approach to the installation of the C-3 formyl group in solanapyrone A is also described.

Introduction In a series of recent papers we were able to add further arguments to the opinion that thioketones are not only useful starting materials for syntheses of sulfur-containing organic compounds but can also be used as interesting models for studying mechanisms of organic reactions [1]. Due to a special ability of the thiocarbonyl group to enter cycloaddition reactions, thioketones were found to be extremely useful reagents in 1,3-dipolar cycloadditions and betero-Diels-Alder syntheses. Another interesting point concerns the application of thioketones and other thiocarbonyl compounds to the generation of sulfur-centered 1,3-dipolar species such as thiocarbonyl ylides, thiocarbonyl S-imides, thiocarbonyl S-sulfides (thiosulfines) and thiocarbonyl S-oxides (sulfines). A new topic in the studies which is directed towards the chemistry of thioketones, concerns their transformations induced by “naked” fluoride anions.

The paper describes three possible routes for the formation of 1-dethia-1-oxa-cephams. The first two routes: (a) [2+2]cycloaddition to chiral vinyl ethers and (b) condensation of 4-acetoxyazetidin-2-one to chiral alcohols, are followed by the ring closure step involving N-alkylation. The third route (c) consists of N-alkylation prior to the cyclization step. In order to compare routes (a), (b) and (c), diastereomeric 1-dethia-3-(4-methoxybenzyloxy)-1-oxacephams were synthesized using three possible strategies. While the comparison of stereoselectivities of the [2+2]cycloaddition method (a) and the condensation (b) shows unequivocally the advantage of the former, the route (c) leads to the reverse direction of asymmetric induction relative to the first two steps and offers the highest asymmetric induction.