Subsequent Diels Research Articles

Synthesis of New Allocolchicinoids with Seven‐ and Eight‐Membered B‐Rings by Enyne Ring‐Closing Metathesis

AbstractTotal syntheses of allocolchicines 4 and 5, with the ester functionality in the C‐ring at the C10 or C11 positions, is reported. An asymmetric synthesis of (7S)‐allocolchicine 5 is also described. The main features included the elaboration of a common intermediate, the AB bicyclic ring system, in which the construction of the seven‐membered ring was achieved by an enyne ring‐closing metathesis (RCM) reaction. A subsequent Diels–Alder/aromatization sequence afforded the set of functionalized ring‐C allocolchicinoids with high regioselectivity. This strategy was also applied for the synthesis of allocolchicine 6, containing an eight‐membered B‐ring.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Palladium‐Catalysed Isomerisation of 2‐Vinylidenehydrofurans to 1,3‐Dienes and Some Aspects of Their Reactivity

AbstractThe transformation of easily accessible 2‐vinylidenehydrofurans into stable 1,3‐dienes has been achieved by using catalytic amounts of palladium(0). These valuable compounds were then engaged in subsequent Diels–Alder reactions giving access to complex heterocyclic cores found in numerous natural products. A rationale for the regioselectivity of the Diels–Alder reactions with vinylfurans has been provided by DFT calculations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Retro-Diels−Alder Reaction of 4H-1,2-Benzoxazines to Generate o-Quinone Methides: Involvement of Highly Polarized Transition States

Here, we describe mechanistic studies of the retro-Diels-Alder reaction of 4H-1,2-benzoxazines bearing various substituents on the benzene ring. 4H-1,2-Benzoxazines are very simple, but quite new, heterocyclic compounds that afford substituted o-quinone methides (o-QMs) through retro-Diels-Alder reaction under mild thermal conditions. The resultant o-QMs undergo Diels-Alder reaction in situ with dienophiles to give phenol and chroman derivatives. The mechanism of the generation of o-QMs has been little studied. Our experimental and density functional theory (DFT) studies have yielded the following results. (1) The generation of o-QMs, i.e., the retro-hetero-Diels-Alder reaction of 4H-1,2-benzoxazines, is rate determining, rather than the subsequent Diels-Alder reaction of the resultant o-QM with dienophiles. (2) The reaction rate is strongly influenced by the electronic features of substituents and the polarity of the solvent. The reaction proceeds faster in a polar solvent such as dimethyl sulfoxide, probably because of stabilization of the electronically polarized TS structure. (3) The reactions show characteristic positional effects of substitution on the benzene ring. While an electron-withdrawing group such as CF3 at C5, C6, or C7 positions decelerates the reaction, the same substituent at C8 accelerates the reaction, compared with the reaction of unsubstituted 4H-1,2-benzoxazine. In particular, substitution at C5 significantly decelerates the reaction as compared with the unsubstituted case. This is due to the difference in the inductive effect of CF3 at the different positions. Similar positional effects occur with a halogen (Cl) and a nitro group. All these data support the involvement of polarized TS structures, in which the O-N bond cleavage precedes the C-C bond cleavage.

An easy and general protocol for multicomponent coupling reactions of aldehydes, amides, and dienophiles

An improved procedure for the three-component coupling reaction of aldehydes, amides, and dienophiles (AAD-reaction) has been developed. The use of microwave technology enables the endo-selective synthesis of N-acyl cyclohexenylamines via condensation of readily available aldehydes and amides, and subsequent Diels–Alder reaction with electron-deficient dienophiles in significantly improved yields. Advantageously, there is no need of employing additional solvents and reaction times are drastically reduced compared to similar thermal reactions.

A two-step biomimetic synthesis of antimalarial robustadials A and B

The antimalarial robustadials A and B have been synthesized in two steps starting from commercially available phloroglucinol comprising a key biomimetic three-component reaction that involves in situ generation of an o-quinone methide via Knoevenagel condensation and subsequent Diels–Alder cycloaddition with (−)-β-pinene.

Efficient Blue‐Light‐Emitting Electroluminescent Devices with a Robust Fluorophore: 7,8,10‐Triphenylfluoranthene

Silicon semiconductor technology has driven the profusion of information technology into every aspect of modern life. An obvious example of this is the emergence of portable electronic devices, such as cellular phones (mobile phones), personal digital assistants, palmtop computers, etc., that are rapidly becoming essential. These share a common Achilles heel, namely, battery life. The most obvious way to attack this problem is through replacement of the power hungry back-lit liquid-crystal displays (LCDs) that reside in all lightweight devices. It is this impetus that has brought organic light-emitting devices (OLEDs) to the forefront of modern materials science. The ability to mass produce thin, efficient, bright displays from organic polymers and small molecules that can supplant modern LCDs depends almost entirely on the ability to create new materials that can undergo efficient electroluminescence at a variety of wavelengths. This has lead to many publications and patents but to date has failed to produce an efficient, cheap, and robust blue-light emitter. It is, of course, not an easy task to find a small molecule that possesses not only a very large bandgap but also stability to the harsh electrochemical environment of OLEDs and a very large quantum yield in the solid state. One class of molecules in particular, fluorenes—especially spirofluorenes—has received much attention because of the outstanding properties in this area, but lengthy syntheses and low-yielding steps, such as boronic acid/ester formations, are less than ideal for singlelayer/host materials. In an effort to redirect some of the explorations, we have investigated a close cousin of fluorenes—fluoranthenes—for applications as blue-light emitters in OLEDs (Scheme 1). In particular, we have studied 7,8,10triphenylfluoranthene (TPF), a highly luminescent solid-state blue-light-emitting small molecule, which can be obtained in two steps from commercial starting materials. After the elucidation of the structure of fluoranthene at the turn of the 20th century, the chemistry of fluoranthenes evolved rapidly. Studies of the interesting photophysical properties followed, but interest in fluoranthenes faded fast. Of particular note is the synthesis of fluoranthene derivatives by a double Knoevenagel condensation between 2-propanone and acenaphthenequinone, which allows functionalization at the carbon 7 and 10 positions. A subsequent Diels–Alder addition allows further functionalization at the 8 and 9 positions. Finally, starting from bromoacenapthenequinone, the carbon 3 position is open to functionalization. With these synthetic tools in hand, we set about finding a fluoranthene derivative that would not crystallize and would remain highly blue-luminescent in the solid state. The most obvious candidate was a perphenylated derivative, which, due to steric hindrance, would keep the phenyl rings out of plane, thus presenting a ball-like surface to resist crystallization and reduce facial contacts that can lead to excimer quenching and bathochromic shifts in emission. To our surprise, only the 7,8,10-triphenyl derivative (2, Scheme 2) exhibited strong luminescence; the 7,8,9,10-tetraphenyl derivative is essentially non-fluorescent (in the solid state), and the 3,7,8,9-tetraphenyl derivative suffers from a large bathochromic shift in the solid state. The introduction of other functionality (e.g., esters, carboxylic acids, and halides) led to green/yellow emission and/or solubility problems. As with the other derivatives, 7,8,10-triphenylfluoranthene was synthesized via the Knoevenagel/Diels–Alder method (Scheme 2) from acenapthenequinone, diphenylacetone, and phenylacetylene, using only ethanol (EtOH) and (optionally) xylenes for solvents; all are inexpensive and readily available. Purification is uncompliC O M M U N IC A IO N S

Regioselective electrophilic substitutions of fulvenes with ethyl glyoxylate and subsequent Diels–Alder reactions

Highly regioselective electrophilic substitution of fulvenes with ethyl glyoxylate, catalyzed by EtAlCl 2 or Yb(OTf) 3 was achieved. Subsequent Diels–Alder reaction of the adduct with various dienophiles provides an efficient protocol toward highly functionalized indane and tricyclo[5.2.1.0 2,6]dec-8-ene systems.

A facile and efficient synthesis of enyne-reaction precursors by multicomponent reactions

Using improved reaction protocols for three-component coupling reactions of aldehydes, dienophiles, and amides (AAD-reaction) or anhydrides (ANAD-reaction) or orthoesters (ALAD-reaction), a variety of functionalized hexahydroisoindolo derivatives were synthesized and fully characterized. Condensation of ubiquitous available aldehydes with unsaturated amides or anhydrides or orthoesters and subsequent Diels–Alder reactions with electron deficient dienophiles furnishes endo-selective enyne-reaction precursors in good to excellent yield.

In-Plane Enyne Metathesis and Subsequent Diels−Alder Reactions on Self-Assembled Monolayers

We report in-plane enyne metathesis and subsequent Diels-Alder reactions on self-assembled monolayers (SAMs) terminating in vinyl and acetylenyl groups on gold. After the formation of SAMs of vinyl and acetylenyl group-containing dithiols on gold, in-plane enyne metathesis of the vinyl and acetylenyl groups, leading to the formation of 1,3-diene, was achieved on the SAMs, and Diels-Alder reactions were then successfully performed with tetracyanoethylene, maleic anhydride, and maleimide. The reactions were confirmed by FT-IR spectroscopy, X-ray photoelectron spectroscopy, and time-of-flight secondary-ion mass spectrometry. In-plane enyne metathesis developed herein would offer a versatile platform for the functionalization of surfaces with mild reaction conditions and a high compatibility in functional groups.

Terminal Heck Vinylations of Chelating Vinyl Ethers

AbstractTerminal chelation‐controlled Heck vinylations of electron‐rich amino‐functionalized vinyl ethers were performed with high regioselectivity furnishing moderate to good isolated yields of the corresponding 1‐alkoxy‐1,3‐butadienes. DFT calculations support an amine‐palladium(II) coordination strength reactivity/selectivity rationale, where the dimethylamino group was the preferred metal presenting functionality. Controlled microwave heating effectively accelerated these palladium‐catalyzed reactions and full conversion could be achieved within 30 minutes. Subsequent Diels–Alder reactions with dimethyl acetylenedicarboxylate under microwave irradiation resulted exclusively in partly aromatized bi‐ and tricyclic compounds by elimination of the aminoalkoxy group. Thus, the selected dimethylamino auxiliary both controlled the regiochemistry in the palladium‐catalyzed vinylation and was easily displaced in the aromatization process.

Nonaflates from 8‐Oxabicyclo[3.2.1]oct‐6‐en‐3‐ones as Building Blocks for Diversity‐Orientated Synthesis: Preparation, Heck‐Couplings and Subsequent Diels–Alder Reactions

AbstractA series of bicyclic alkenyl nonaflates was prepared in good yields by deprotonation of the corresponding 8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐ones and a sulfur relative with LDA followed by trapping with nonafluorobutanesulfonyl fluoride (NfF). The resulting compounds undergo Heck couplings to methyl acrylate under standard conditions, generally providing bicyclic dienes in satisfactory yields. For nonaflates 2 and 12 a novel base‐promoted fragmentation reaction to substituted furan derivatives was observed. Several Diels–Alder reactions of the bicyclic dienes were conducted leading to polycyclic compounds. Whereas the diastereofacial selectivity with respect to the oxygen or sulfur bridge of the dienes is excellent, the exo/endo selectivity strongly depends on the substitution patterns of the bicyclic diene and the dienophile. The results presented demonstrate the potential of bicyclic nonaflates to serve as versatile building blocks in diversity‐orientated synthesis.

Second Generation Protocol for Multicomponent Coupling Reactions of Aldehydes, Amides and Dienophiles

AbstractAn improved one‐pot procedure for the three‐component coupling reaction of aldehydes, amides and dienophiles (AAD reaction) has been developed. Compared to known protocols for this type of reaction, the use of aromatic solvents in the presence of dehydrating reagents allows an efficient synthesis of previously not accessible products. Condensation of ubiquitous available aldehydes and amides and subsequent Diels–Alder reactions with dienophiles furnishes endo‐selective amino‐functionalized hexahydroisoindole‐1,3‐dione and tetrahydrophthalic acid derivatives in good yield.

Development of Novel Asymmetric Reactions Oriented to Next‐Generation Enzymatic Organic Syntheses

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tandem methodology for heterocyclic synthesis

AbstractTandem methodology for heterocyclic synthesis represents a powerful approach for the rapid buildup of molecular complexity from potentially simple starting materials. Work from our laboratory has shown that the rhodium(II)-catalyzed cyclization cascade of alpha-diazo imides represents an effective method for the synthesis of a variety of heterocyclic systems. As an extension of these studies, we became interested in using a linked Pummerer/N-acyliminium ion cyclization sequence since we felt that this combination offers unique opportunities for the assemblage of complex target molecules. A synthetic method that combines transformations of different reaction types significantly broadens the scope of such procedures in synthetic chemistry. Alpha-thiocarbocations generated from the Pummerer reaction of beta-phenylsulfinylmethyl-alpha, beta-unsaturated amides can be intercepted by the adjacent amido group to produce transient amino-substituted furans which undergo subsequent Diels–Alder cycloadditions. Using this domino amido Pummerer/Diels–Alder cascade, we were able to assemble novel polycyclic systems in a single operation. The key step in the process involves the generation of a reactiveN-acyliminium ion by fragmentation of an amino-substituted [4+2]-cycloadduct. The successful synthesis of a number of alkaloids by this sequence of reactions reveals the usefulness and importance of this unique domino cascade. Application of the process for the preparation of the stenoma alkaloid stenine was recently carried out in our laboratory.

Development of novel asymmetric reactions oriented to next-generation enzymatic organic syntheses

Enzyme-catalyzed organic syntheses have enormous potential in the development of environmentally benign processes. In the last two decades, increased efforts have been devoted to making this a reality. However, the utility of the enzymes is generally limited. For example, although the lipases are extensively used for the kinetic resolution or the desymmetrization of alcohols and carboxylic acid derivatives, little is known about their ability to catalyze carbon-carbon bond-forming reactions. In the past several years, we have been engaged in exploiting a next-generation enzymatic synthesis by using the lipases for the construction of carbon skeletons. This review article describes the results. First, the development of a new type of acyl donor, 1-ethoxyvinyl esters (EVEs), that have significant advantages over common acyl donors (e.g., vinyl esters) for lipase-catalyzed esterification reactions. Second, the highly enantioselective desymmetrization of prochiral 1,3-propanediols and meso 1,2-diols using 1-ethoxyvinyl 2-furoate. The application of this technology for the asymmetric syntheses of fredericamycin A analogues and the oxindoles with a chiral, nonracemic quaternary carbon center has been demonstrated. Third, the first lipase-catalyzed domino reaction using EVEs possessing a suitably functionalized acyl moiety is described. The acyl moiety installed during the enzymatic kinetic resolution was used as a part of the constituent structure for the subsequent Diels--Alder reaction to product optically pure tricyclic compounds with five chiral carbon centers via a one-pot operation. The potential influence of the lipase on the Diets--Alder reaction and the domino process accompanied by the dynamic kinetic resolution are also described.

Simple preparation of cobaloxime dienyl complexes and their exo selective Diels–Alder cycloadducts : Progress toward transition metal-mediated Diels–Alder reactions which are catalytic in metal dienyl complex

A new method for the synthesis of cobaloxime dienyl complexes (cobaloxime=pyridine(dimethylglyoxime) 2Co) which involves a zinc-mediated hydrocobaltation of enynes is reported. Use of this dienyl complex synthesis method allows subsequent Diels–Alder reactions of these complexes to be accomplished without isolation of the dienyl complexes. A new silane-based cobaloxime-substituted cycloadduct demetallation protocol is then reported which provides Diels–Alder cycloadducts and cobalt complexes which have been recycled into the zinc-mediated dienyl complex synthesis.

Allenylmethylsilanes as Nucleophiles in N‐Acyliminium Ion Chemistry.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Selection and amplification of a catalyst from a dynamic combinatorial library.

The development of catalysts that rival the efficiency andselectivityofenzymesisoneoftheholygrailsinchemistry.Todate,successinthedesignandsynthesisofsuchsystemsislimited by an imperfect understanding of the host–guestinteractions underlying efficient activity. As an alternative,severalselection-basedapproachestothediscoveryofnewcatalytic systems are being developed.

Organotransition metal modified sugars: Part 23. Synthesis of vinylcarbene chromium complexes containing a C-monosaccharide ligand

Organometallic C-glycosides containing a chromium carbene functionality have been synthesized from pentacarbonyl[(methoxy)methylcarbene]chromium ( 1) in a TiCl 4-assisted aldol condensation with formyl glycosides. The condensation is trans-selective to give a 54–82% yield of chromium vinylcarbene C-glycosides 5, 6 and 8 which are promising candidates for subsequent Diels–Alder, Michael addition, benzannulation and cyclopropanation reactions.

Mechanistic investigations in diastereoselective Diels–Alder additions of chiral 9-anthrylethanol derivatives

The preparation and subsequent Diels–Alder addition reactions of chiral 9-functionalised anthracene derivatives have been investigated. 9-(1-Methoxyethyl)anthracene undergoes highly diastereoselective (>95 ∶ 5) thermal and photoinduced Diels–Alder additions with maleic anhydride and N-methylmaleimide. The corresponding reactions of 1-anthracen-9-ylethanol occur with the reverse sense of selectivity for additions with maleic anhydride with a corresponding increase in the reaction rate. The origins of this selectivity have been proposed to lie in hydrogen-bonding effects. The stereochemical outcome of the Diels–Alder additions has been determined from single X-ray crystallography of adducts 5 and 7. Solvent effects on the diastereoselectivity of these reactions have also been observed.