Reactive Dienophiles Research Articles

Light-Induced Generation and Cycloaddition Reactions of Benzyne: Synthesis of Naphthoxindoles E and Annulated Indolizines.

By virtue of their high electrophilic nature, benzynes serve as reactive dienophiles in numerous cycloaddition reactions. However, in situ generation of benzyne involves either base-mediated thermal reactions, low-temperature conditions, or metal-catalyzed reactions of substituted arenes. This limits the applicability of benzynes as suitable dipolarophiles in cycloaddition reactions. Herein, we have reported a UVA (365 nM)-induced in situ generation of benzynes (from triazenyl benzoic acid) and subsequently their [4 + 2] Diels-Alder and [3 + 2] cycloaddition reactions with appropriate reaction partners such as N-protected alkylidene oxindole carboxylates and pyridinium ylides to afford naphthoxindoles E and pyrido[2,1-a]isoindole, respectively, in moderate to excellent yield. The reactions occurred at room temperature and under reagent-free reaction conditions. Each of these building blocks is pharmaceutically relevant; hence, this highlights an interesting strategy to access these classes of compounds.

Boradigermaallyl: (4+3) Cycloaddition-Initiated Boron Insertion into Benzene.

The 2π electron 1,3-dipole boradigermaallyl, valence-isoelectronic to an allyl cation, is synthesized from a bis(germylene). It reacts with benzene at room temperature by insertion of a boron atom into the benzene ring. Computational investigation of the mechanism shows the boradigermaallyl reacting with a benzene molecule in a concerted (4+3) or [π4s+π2s] cycloaddition reaction. Thus, the boradigermaallyl acts as a highly reactive dienophile in this cycloaddition reaction with nonactivated benzene as diene unit. This type of reactivity provides a novel platform for ligand assisted borylene insertion chemistry.

Boradigermaallyl: (4+3) Cycloaddition‐Initiated Boron Insertion into Benzene

AbstractThe 2π electron 1,3‐dipole boradigermaallyl, valence‐isoelectronic to an allyl cation, is synthesized from a bis(germylene). It reacts with benzene at room temperature by insertion of a boron atom into the benzene ring. Computational investigation of the mechanism shows the boradigermaallyl reacting with a benzene molecule in a concerted (4+3) or [π4s+π2s] cycloaddition reaction. Thus, the boradigermaallyl acts as a highly reactive dienophile in this cycloaddition reaction with nonactivated benzene as diene unit. This type of reactivity provides a novel platform for ligand assisted borylene insertion chemistry.

Site selective gold(i)-catalysed benzylic C-H amination via an intermolecular hydride transfer to triazolinediones.

Triazolinediones are known as highly reactive dienophiles that can also act as electrophilic amination reagents towards enolisable C-H bonds (ionic pathway) or weak C-H bonds (free radical pathway). Here, we report that this C-H amination reactivity can be significantly extended and enhanced via gold(i)-catalysis. Under mild conditions, several alkyl-substituted aryls successfully undergo benzylic C-H aminations at room temperature. The remarkable site selectivity that is observed points towards strong electronic activation and deactivation effects, that go beyond a simple weakening of the C-H bond. The observed catalytic C-H aminations do not follow the expected trends for a free radical-type C-H amination and show complementarity to existing methods. Density functional theory (DFT) calculations and distinct experimental trends provide a clear mechanistic rationale for observed selectivity patterns, postulating a novel pathway for triazolinedione-induced aminations via a carbon-to-nitrogen hydride transfer.

Synthesis and Reactivity of a Stable Prototropic Isomer of 2-Acetyl-3-methylpyrrole

Abstract4-Isocyanobut-1-ene reacted rapidly with acetyl bromide to afford an unstable imidoyl bromide adduct. Subsequent in situ cyclization under Heck conditions generated a stable prototropic isomer of 2-acetyl-3-methylpyrrole. The reactivity of this molecule toward ­acids, bases, and oxidants was explored, and its conversion into an α-methylidene γ-lactam was demonstrated. In protonated form, the molecule functioned as a reactive dienophile in Diels–Alder reactions.

Microwave-assisted synthesis of 4,6-disubstituted isoindoline-1,3-diones by Diels-Alder reactions

The synthesis of 4,6-disubstituted isoindoline-1,3-diones through microwave-assisted Diels-Alder (DA) reactions is reported. Chromones bearing an α,β-unsaturated carbonyl system at C-3 were used as dienes and a scope of maleimides as dienophiles was investigated. The proposed mechanism involves a DA reaction of 3-benzoylvinylchromones with different maleimides, followed by chromanone ring opening and in situ oxidation. The observed aromatization of DA adducts was accomplished without employment of any oxidizing agent and can be explained by the presence of several acidic protons due to the electron-withdrawing groups (carbonyl groups), affording the 4,6-disubstituted isoindoline-1,3-diones in 15-59% yield. Among tested maleimides, N-phenylmaleimide revealed to be the most reactive dienophile, yielding the corresponding 2-phenylisoindoline-1,3-dione in 59% yield.

Dienophilic reactivity of 2-phosphaindolizines: a conceptual DFT investigation.

The >C=P– or –N=P– functionality in 1,3-azaphospholo[1,5-a]pyridine, named as 2-phosphaindolizine and its 1- and 3-aza derivatives act as dienophiles and undergo Diels–Alder reactions with 1,3-dienes. However, the dienophilic reactivity is affected by the nature of the substituent groups on the two sides of the σ2,λ3-P atom and also by the presence of more nitrogen atom(s) in the five-membered ring. The conceptual density functional theory (DFT) calculations have been used in recent years to predict the reactivity of organic molecules in reactions. We calculated global hardness (η), global softness (S), electronic chemical potential (μ), electrophilicity (ω), and nucleophilicity (N) indices of four classes of 2-phosphaindolizines, on the basis of which their observed relative dienophilic reactivities could be rationalized. Besides, the Fukui functions of the carbon/nitrogen and phosphorus atoms of the >C=P– and –N=P– functionalities were also computed which revealed their hard electrophilic character and accorded well with the dienophilic reactivities observed experimentally. Furthermore, energies and symmetries of the lowest unoccupied molecular orbitals (LUMO) of 2-phosphaindolizines were found to be in conformity with their dienophilic reactivities.

Diels-Alder Reaction of Photochemically Generated (E)-Cyclohept-2-enones: Diene Scope, Reaction Pathway, and Synthetic Application.

Upon irradiation at λ = 350 nm, cyclohept-2-enone undergoes an isomerization to the strained (E)-isomer. The process was studied by XMS-CASPT2 calculations and found to proceed by two competitive reaction channels on either the singlet or the triplet hypersurface. (E)-Cyclohept-2-enone is a reactive dienophile in thermal [4 + 2] cycloaddition reactions with various dienes. Ten different dienes were probed, most of which─except for 1,3-cyclohexadiene─underwent a clean Diels-Alder reaction and gave the respective trans-fused six-membered rings in good yields (68-98%). The reactions with furan were studied in detail, both experimentally and by DLPNO-CCSD(T) calculations. Two diastereoisomers were formed in a ratio of 63/35 with the exo-product prevailing, and the configuration of both diastereoisomers was corroborated by single crystal X-ray crystallography. The outcome of the photoinduced Diels-Alder reaction matched both qualitatively and quantitatively the calculated reaction pathway. Apart from cyclohept-2-enone, five additional cyclic hept-2-enones and cyclooct-2-enone were employed in their (E)-form as dienophiles in the Diels-Alder reaction with 1,3-cyclopentadiene (80-98% yield). The method was eventually applied to a concise total synthesis of racemic trans-α-himachalene (four steps, 14% overall yield).

Substituents effects in the Diels-Alder reaction of 1,1-difluoronaphthalen-2(1H)-ones with cyclopentadiene

1,1-difluoronaphthalen-2(1H)-ones are promising fluorine-containing building blocks due to the possibility of multiple-site functionalization. The Diels-Alder reaction is one of the powerful approaches to construction of complex saturated rigid three-dimensional structures or polyaromatic compounds. Being readily available through the electrophilic fluorodearomatization of substituted naphthalene-2-ols, the naphthalenones are good models to elucidate the structural effects on the rate and selectivity of the Diels-Alder reaction. Moderate reactivity and high diastereoselectivity of cycloaddition reaction of 1,1-difluoronaphthalen-2(1H)-ones allow careful investigation of the substituent effects. In this paper we determined the rate constants for the cycloaddition reaction to compare the reactivity of the dienophiles under study. We experimentally explored the substituents effects on the rate and the selectivity of [4+2]-cycloaddition. A quantum chemical approach was used to rationalize the results obtained and predict the substituents effect on the reactivity of dienophiles. Performed correlation analysis demonstrated a relation between the substituent's constants and the reactivity of corresponding dienophiles in the reaction with cyclopentadiene.

Discovery and Surprises with Cyclizations, Cycloadditions, Fragmentations, and Rearrangements in Complex Settings.

We discuss a number of synthesis routes to complex natural products recently reported from our group. Although the structures are quite varied, we demonstrate the research endeavor as a setting to examine the implementation of cyclizations, cycloadditions, rearrangements, and fragmentations. We showcase how the various transformations enabled access to key core structures and thereby allowed the rapid introduction of complexity. Two different routes to (-)-mitrephorone A, the first case discussed, led to the use of Koser's reagent to effect oxetane formation from diosphenol derivatives. Even though the Diels-Alder cycloaddition reaction represents one of the workhorses of complex molecule synthesis, there are opportunities provided by the complexity of secondary metabolites for discovery, study, and development. In our first approach to (-)-mitrephorone A, Diels-Alder cycloaddition provided access to fused cyclopropanes, while the second synthesis underscored the power of diastereoselective nitrile oxide cycloadditions to access hydroxy ketones. The successful implementation of the second approach required the rigorous stereocontrolled synthesis of tetrasubstituted olefins; this was accomplished by a highly stereoselective Cr-mediated reduction of dienes. The diterpenoid (+)-sarcophytin provided a stage for examining the Diels-Alder cycloaddition of two electron-deficient partners. The study revealed that in the system this unusual combination works optimally with the E,Z-dienoate and proceeds through an exo transition state to provide the desired cycloadduct. Our reported pallambin synthesis showcased the use of fulvene as a versatile building block for the core structure. Fulvene decomposition could be outcompeted by employing it as a diene and using a highly reactive dienophile, which affords a bicyclic product that can in turn be subjected to chemo- and stereoselective manipulations. The synthesis route proceeds with a C-H insertion providing the core structure en route to pallambin A and B. The studies resulting in our synthesis of gelsemoxonine highlight the use of the acid-catalyzed rearrangement/chelotropic extrusion of oxazaspiro[2.4]heptanes to access complex β-lactams, which are otherwise not readily prepared by extant methods in common use. Mechanistic investigations of the intriguing ring contraction supported by computational studies indicate that the reaction involves a concerted cleavage of the N-O bond and cyclopropane ring opening under the extrusion of ethylene. The synthesis of guanacastepenes focused on the use of cyclohexyne in [2+2]-cycloadditions with enolates. The resulting cyclobutene can be enticed to undergo ring opening to give a fused six-seven ring system. The cycloinsertion reaction of cyclohexyne developed for the first time proves useful as a general approach to complex fused ring systems.

3-(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels-Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions.

Cyclobutenone has been used as a highly reactive dienophile in Diels-Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine-aluminum bromide catalyzed enantioselective Diels-Alder reaction of 3-alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (-)-kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

3‐(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels–Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions

AbstractCyclobutenone has been used as a highly reactive dienophile in Diels–Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine‐aluminum bromide catalyzed enantioselective Diels–Alder reaction of 3‐alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (−)‐kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes.

3-Aryl-1-(trifluoromethyl)prop-2-yn-1-iminium triflate salts represent a novel, highly reactive class of acetylenic iminium salts. Herein we present several reactions which are based on the electron-poor acetylenic bond and on the high electrophilicity of the CF3-substituted iminium group. These salts were found to be highly reactive dienophiles in Diels–Alder reactions with cyclopentadiene, 2,3-dimethylbutadiene and even anthracene. At higher temperature, the cycloadducts undergo an intramolecular SE(Ar) reaction leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and some substituted styrenes, cascade reactions take place, which likely include cyclobutene and several cationic intermediates and mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene as the substrate.

1-Bromo-1,2-dicyanoethylene: A dicyanoacetylene synthon useful in tetraazaporphyrin synthesis

Dicyanoacetylene, a highly reactive dienophile, readily reacts to form substituted maleonitriles which serve as precursors to soluble tetraazaporphyrins. Unfortunately, dicyanoacetylene is difficult to synthesize in large quantities. We report here a new dicyanoacetylene synthon, 1-bromo-1,2-dicyanoethylene, which is easily made in high yield by reaction of elemental bromine with fumaronitrile and easily purified by vacuum distillation. The resulting 5:1 mixture of geometric isomers reacts with dienes via a Diels–Alder reaction followed by elimination of HBr to give substituted maleonitriles. We demonstrate the utility of these reactions by reporting the synthesis of a novel, soluble tetraazaporphyrin bearing four 1,4-fused cyclohexyl groups on the macrocycle periphery.

Reactivity Variation of Tetracyanoethylene and 4-Phenyl-1,2,4-Triazoline-3,5-Dione in Cycloaddition Reactions in Solutions

The reasons for the very high reactivity and variability of reactivity of two dienophiles, tetracyanoethylene (1) and 4-phenyl-1,2,4-triazoline-3,5-dione (2), in the Diels–Alder reactions were considered. The data on the rate of reactions with anthracene (3), benzanthracene (4) and dibenzanthracene (5) in 14 solvents over a range of temperatures and high pressures, data on the change in the enthalpy of solvation of reagents, transition state, and adducts in the forward and backward reactions, and the enthalpies of these reactions in solution were obtained. Strong π-acceptor dienophile 1 has sharply reduced reactivity in reactions in π-donor aromatic solvents. It was observed that the π-acceptor properties of dienophile 1 disappear upon passage to the transition state and adduct. Large solvent effects on the reaction rate can be predicted for all types of reactions involving tetracyanoethylene. Very high reactivity of dienophiles 1 and, especially, 2 can be useful to catch such carcinogenic impurities such as 3–5 and neutralize them by transformation into less dangerous adducts.

Terminal Acetylenic Iminium Salts – Synthesis and Reactivity

Various types of terminal acetylenic iminium triflates (propyne iminium salts) featuring a ketiminium or an aldiminium group have been prepared for the first time by protiodesilylation of the corresponding trimethylsilyl‐substituted acetylenic iminium salts using triflic acid and catalytic silver(I) triflate. The high reactivity of the terminal C,C‐triple bond is documented herein by the facile Michael addition of nucleophiles and the exceptionally high dienophilic reactivity in Diels‐Alder reactions.

Hetero‐Diels‐Alder Reactions of α‐Nitrosoalkenes with Ferrocenyl, Hetaryl and Cycloaliphatic Thioketones

AbstractThe in situ generated α‐nitrosoalkenes react with ferrocenyl, hetaryl and cycloaliphatic thioketones yielding 4H‐1,5,2‐oxathiazines as products of the hetero‐Diels‐Alder reaction. These products are formed in a perfect regioselective manner. A similar reactivity is displayed by a thiochalcone (1,3‐diphenylprop‐2‐ene‐1‐thione), and in that case, the [4+2]‐cycloaddition occurs also chemoselectively and regioselectively along the C=S bond acting as a heterodienophile. The stability of the 4H‐1,5,2‐oxathiazines depends on the type of substituents, and in the case of ferrocenylthioketones, the diferrocenyl representative is the reagent of choice. The replacement of one ferrocenyl group by an ethyl group leads to a dramatic decrease of the product stability. Sterically crowded cycloaliphatic thioketones derived from 2,2,4,4‐tetramethylcyclobutane‐1,3‐dione are exceptional dienophiles in reactions with trifluoromethyl‐substituted nitrosoalkenes, and in these cases, a remarkably stable 3‐trifluoromethyl‐4H‐1,5,2‐oxathiazine derivative was obtained. For the first time, perfectly stable and non‐odorous 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione was explored as an active heterodienophile for a two‐fold hetero‐Diels‐Alder reaction.

Design and Synthesis of Aza-Bicyclononene Dienophiles for Rapid Fluorogenic Ligations.

Fluorogenic bioorthogonal reactions enable visualization of biomolecules under native conditions with excellent signal-to-noise ratio. Here, we present the design and synthesis of conformationally-strained aziridine-fused trans-cyclooctene (aza-TCO) dienophiles, which lead to the formation of fluorescent products in tetrazine ligations without the need for attachment of an extra fluorophore moiety. The presented aza-TCOs adopt the highly strained "half-chair" conformation, which was predicted computationally and confirmed by NMR measurements and X-ray crystallography. Kinetic studies revealed that the aza-TCOs belong to the most reactive dienophiles known to date. The potential of the newly developed aza-TCO probes for bioimaging applications is demonstrated by protein labeling experiments, imaging of cellular glycoconjugates and peptidoglycan imaging of live bacteria.

A Bifunctional Fluorogenic Rhodamine Probe for Proximity-Induced Bioorthogonal Chemistry.

Bioorthogonal reactions have emerged as a versatile tool in life sciences. The inverse electron demand Diels-Alder reaction (DAinv ) stands out due to the availability of reactants with very fast kinetics. However, highly reactive dienophiles suffer the disadvantage of being less stable and prone to side reactions. Herein, we evaluate the extent of acceleration of rather unreactive but highly stable dienophiles by DNA-templated proximity. To this end, we developed a modular synthetic route for a novel bifunctional fluorogenic tetrazine rhodamine probe that we used to determine the reaction kinetics of various dienophiles in a fluorescence assay. Under proximity-driven conditions the reaction was found to be several orders of magnitude faster, and we observed almost no background reaction when proximity was not induced. This fundamental study identifies a minimally sized fluorogenic tetrazine dienophile reactant pair that has potential to be generally used for the visualization of biomolecular interactions with temporal and spatial resolution in living systems.

Reactions of thebaine derivatives with trifluoroacetyl acetylenes: [4+2]-addition solely

Abstract Trifluoroacetyl acetylenes, highly reactive dienophiles and electrophiles, were used as the probe for study competitive [4+2] vs nucleophilic addition reactions in thebaine series. Unlike thebaine itself that reacts with these electron deficient acetylenes giving rise to the adducts resulted from the nucleophilic attack of the nitrogen at the alkyne carbon, the reactions of N -acyl- N -northebaines with trifluoroacetyl acetylenes furnished the [4+2]-adducts solely. The last ones readily rearranged to the corresponding 3 H -furo[4,3,2-fg][3]benzazocine derivatives. So, the use of N -acyl- N -northebaines as the starting materials in the reactions with acetylenic dienophiles provides the general methodology to avoid a formation of the undesirable “nucleophilic” adducts typical for the reactions of the natural alkaloid thebaine.