Microwave‐assisted Regioselective Synthesis of Novel Bis(azoles) and Bis(azoloazines)

We introduce efficient regioselective synthesis of a series of novel bis(pyrazoles) and bis(isoxazoles) via 1,3‐dipolar cycloaddition reaction under microwave irradiation. Unequivocal structural assignment of the obtained regioisomers was determined utilizing ¹H‐¹³C HMBC NMR techniques as a valuable tool. A comparative study of the aforementioned reactions was carried out under conventional method as well as under microwave irradiation conditions.     

Mechanochemical synthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions and potential antimicrobial activities of the cycloadducts

Synthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions using ball‐milling technique have been reported. Significant change in rate and yields of the cycloadducts have been noticed compared with solvent‐free microwave‐induced reactions of fluoro nitrones. The present study reports synthesis of N‐benzyl fluoro nitrone and its cycloaddition reactions with maleimides and few electron deficient alkynes under solvent‐free conditions. The synthesized fluoro cycloadducts were found to exhibit potential antimicrobial activities.     

Asymmetric Brønsted Base Catalyzed and Directed [3+2] Cycloaddition of 2‐Acyl Cycloheptatrienes with Azomethine Ylides

Conjugated cyclic trienes have the potential for different types of cycloaddition reactions. In the present work, we will, in a novel asymmetric cycloaddition reaction, demonstrate that the organocatalytic reaction of 2‐acyl cycloheptatrienes with azomethine ylides proceeds as a [3+2] cycloaddition, which is in contrast to the Lewis acid‐catalyzed reaction, in which a [3+6] cycloaddition takes place. In the presence of a chiral organosuperbase, 2‐acyl cycloheptatrienes react in a highly enantioselective manner in the [3+2] cycloaddition with azomethine ylides, providing the 1,3‐dipolar cycloaddition product in high yields and up to 99 % ee. It is also shown that the diene formed by the reaction can undergo stereoselective dihydroxylation, bromination, and cycloaddition reactions. Finally, based on experimental observations, some mechanistic considerations are discussed.     

Microwave‐Assisted Aqueous Synthesis: A Rapid Approach to Poly‐functionalized Indoline‐Spiro Benzofurodiazepines

New cycloaddition has been established for the synthesis of indoline‐spiro benzofurodiazepine derivatives. Those reactions were conducted by reacting readily available and inexpensive starting materials, such as benzene‐1,2‐diamines, tetronic acid and indoline‐2,3‐diones, in aqueous solution under microwave irradiation. When mono‐substituted benzene‐1,2‐diamines as an amine component was employed, the reaction regioselectively resulted in the poly‐functionalized indoline‐spiro benzofurodiazepine with good yields. The present green synthesis shows attractive characteristics such as the use of water as reaction media, concise one‐pot conditions, short reaction periods, easy work‐up/purification and reduced waste production without the use of any strong acids or metal promoters.     

Strain‐Promoted Reaction of 1,2,4‐Triazines with Bicyclononynes

Strain‐promoted inverse electron‐demand Diels–Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5‐tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5‐tetrazines is complex and can involve volatile reagents. 1,2,4‐Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4‐triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4‐triazin‐3‐ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37 °C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late‐stage functionalization of other probe molecules, and the 1,2,4‐triazine‐SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.     

High-speed microwave-promoted hetero-Diels-Alder reactions of 2(1H)-pyrazinones in ionic liquid doped solvents

Inter- and intramolecular hetero-Diels-Alder reactions in a series of functionalized 2(1H)-pyrazinones were investigated under controlled microwave irradiation. The cycloaddition reactions were efficiently performed in sealed tubes, utilizing either a combination of 1,2-dichloroethane and a thermally stable ionic liquid, or 1,2-dichlorobenzene as reaction medium. In all cases, a significant rate-enhancement using microwave flash heating as compared to thermal heating was observed.     

Microwave-assisted regioselective cycloaddition reactions between 9-substituted anthracenes and levoglucosenone

The cycloaddition reactions of 9-substituted anthracenes and levoglucosenone were investigated under microwave irradiation and conventional heating conditions. Considering time, yields, and regioselectivity, microwave technology has proven to be an ideal tool to achieve this chemical transformation. [reaction: see text].     

Computational design of S‐nitrosothiol “click” reactions

To address a long‐standing problem of finding efficient reactions for chemical labeling of protein‐based S‐nitrosothiols (RSNOs), we computationally explored hitherto unknown (3+2) cycloaddition RSNO reactions with alkynes and alkenes. Nonactivated RSNO cycloaddition reactions have high activation enthalpy (>20 kcal/mol at the CBS‐QB3 level) and compete with alternative S—N bond insertion pathway. However, the (3+2) cycloaddition reaction barriers can be dramatically lowered by coordination of a Lewis acid to the N atom of the —SNO group. To exploit this effect, we propose to use reagents with Lewis acid and a strain‐activated carbon–carbon multiple bond linked by a rigid scaffold, which can react with RSNOs with small activation enthalpies (～5 kcal/mol) and high reaction exothermicities (～40 kcal/mol). The proposed efficient RSNO cycloaddition reactions can be used for future development of practical RSNO labeling reactions. © 2013 Wiley Periodicals, Inc.     

[8+3]‐Cycloaddition of Tropones with Azaoxyallyl Cations

Although azaoxyallyl cations are widely used as 1,3‐dipoles for various cycloaddition reactions leading to nitrogen‐containing heterocycles, their application in higher‐order cycloaddition reaction remains scarce. Herein, we present the [8+3]‐cycloaddition reaction of tropones with in situ generated azaoxyallyl cations allowing the one‐step construction of cycloheptatriene‐fused 1,4‐oxazinones in moderate to good yields. This base‐promoted new carbon‐oxygen and carbon‐nitrogen bond‐forming reaction takes place under mild conditions in the absence of transition metal catalysts.     

Microwave‐assisted One‐pot,Three‐component Regiospecific and Sterospecific Synthesis of Spiro Indanone Pyrrolidine/Piperidine Fused Nitrochromene Derivatives Through 1,3‐Dipolar Cycloaddition Reactions

A simple, straightforward, and versatile protocol for the synthesis of spiro indanone pyrrolidine/piperidine fused nitrochromene derivatives is described. The synthesis of a new series of spirocyclic molecules has been expediently accomplished via a one‐pot, three component 1,3‐dipolar cycloaddition reaction. 2‐Phenyl‐nitrochromene dipolarophiles were reacted with azomethine ylides, generated in situ by the condensation of dicarbonyl compound indane‐1,3‐dione and secondary amino acid (L‐proline/pipecolic acid), to produce the corresponding cycloadducts in good yields (85–90%) under classical as well as under microwave irradiation. The cycloaddition reaction was found to be highly regiospecific and diasterospecific. The regiochemical and sterochemical outcome of the cycloaddition reaction is ascertained by 2D NMR (COSY and NOESY) studies.     

Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations

We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.     

Microwave Assisted Neat Synthesis of Spiropyrrolidine Library

A new class of functionalized nitrothiophene containing spirropyrrolidines has been synthesized with high regioselectivity in moderate to excellent yields via microwave assisted solvent‐free‐three component 1,3‐dipolar cycloaddition reaction of in situ generated azomethineylides with various substituted chalcones as dipolarophiles. The structures of the newly synthesized compounds were established by analytical and spectral analysis. The product yields were slightly improved and reaction times were reduced to a great extent under microwave condition.     

Fluorous Synthesis of Biaryl-Substituted Proline Analogs by 1,3-Dipolar Cycloaddition and Suzuki Coupling Reactions

A solution-phase synthesis of bicyclic prolines containing four points of diversity has been developed by a two-step synthesis involving 1,3-dipolar cycloaddition of perfluoroalkylsulfonyl-protected hydroxybenzaldehydes followed by Pd-catalyzed Suzuki coupling reaction of fluorous sulfonates with boronic acids. Both reactions are conducted under microwave irradiation and reaction mixtures are purified by solid-phase extractions without performing chromatography.     

An Efficient Synthesis of Benzazocines by Gold(I)‐Catalyzed Tandem 1,2‐Acyloxy Shift/[3+2] Cycloaddition of Terminal 1,9‐Enynyl Esters

An effective synthesis of structurally diverse benzazocines was accomplished in good to excellent chemical yields (55–82 %) through a gold(I)‐catalyzed cascade reaction involving tandem 1,2‐acyloxy shift/[3+2] cycloaddition of terminal 1,9‐enynyl esters. The reaction proceeds under extremely mild conditions and represents one of the relatively few transition‐metal‐catalyzed intramolecular cycloaddition reactions for the synthesis of benzazocines.     

Unprecedented microwave effects on the cycloaddition of fulvenes. A new approach to the construction of polycyclic ring systems

[reaction: see text] Novel cycloaddition reactions between fulvenes and various alkenes and alkynes are promoted by the use of microwave irradiation. These processes result in the formation of intriguing polycyclic ring systems such as those found in isobarbatene, alcyopterosin, and enokipodin A. Importantly, these reactions do not occur under conventional thermolytic conditions.     

Synthesis of Fluorine‐Containing Multisubstituted Phenanthridines by Rhodium‐Catalyzed Alkyne [2+2+2] Cycloaddition and Tandem sp2 C?H Difluoromethylenation

A highly efficient method for the synthesis of fluorine‐containing multisubstituted phenanthridines through Rh‐catalyzed alkyne [2+2+2] cycloaddition reactions has been developed. This method exhibits excellent functional‐group compatibility. When a bromodifluoromethyl group, rather than a trifluoromethyl group, was employed in the cycloaddition reaction, more‐complicated polycyclic compounds were obtained through tandem Rh‐catalyzed cycloaddition/C? H difluoromethylenation. This route provides convenient access to fluorine‐containing polycyclic compounds.     

Microwave-Accelerated Organic Reactions

The use of microwave technology in accelerating organic reactions has received intense attention leading to immense growth recently. Accordingly, we have been interested in improving the efficacy of organic processes by microwave irradiation. Here we report our results on the microwave assisted 1,3-dipolar cycloaddition reaction of nitrile oxides with allylic alcohols, the cleavage reaction of 1,3-diketones under alkaline conditions, and the formation of carbamates from isocyanates with alcohols. The reactions carried out under microwave irradiation, in general, required considerably less reaction time and afforded the desired products in higher yields than those under classical conditions. In all the cases we have studied, the procedures are simplified, the purity of the products are higher, and the cost of reaction is greatly reduced employing microwave.     

Control of N‐Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole‐γ‐Amino Acid Derivatives

A strategy to control the switch between a non‐cycloaddition reaction and a cycloaddition reaction of enals, using N‐heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ‐amino‐acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo‐Mannich reactions of enals and isatin‐derived ketimines. By simply changing the N‐ketimine substituent to an ortho‐hydroxy phenyl group, the corresponding spirocyclic oxindolo‐γ‐lactams are obtained.     

(5,6‐Dihydro‐1,4‐dithiin‐2‐yl)methanol as a Versatile Allyl‐Cation Equivalent in (3+2) Cycloaddition Reactions

The title heterocyclic alcohol readily generates a sulfur‐substituted allylic cation upon simple treatment with a protic acid, thus facilitating a synthetically useful stepwise (3+2) cycloaddition reaction pathway with a range of conjugated‐olefin‐type substrates. The introduction of an allyl fragment in this way provided rapid access to a variety of cyclopentanoid scaffolds. The cyclic nature of the cation precursor alcohol was shown to be instrumental for efficient cycloaddition reactions to take place, thus indicating an attractive strategy for controlling the reactivity of heteroatom‐substituted allyl cations. The formal cycloaddition reaction is highly regio‐ and stereoselective and was also used for a short total synthesis of the natural product cuparene in racemic form through a cycloaddition–hydrodesulfurization sequence.     

[2 + 2] Cycloaddition Reactions of Butadienyl Ketene with 1,4‐Diazabuta‐1,3‐dienes: Synthesis of Functionalized Butadienyl‐4‐iminomethyl‐azetidin‐2‐ones and Butenylidene‐butadienyl‐[2,2′‐biazetidine]‐4,4′‐diones

The reactions of butadienylketene with variety of 1,4‐diazabuta‐1,3‐dienes are studied. The reactions resulted in the formation of previously unknown functionalized cis butadienyl‐4‐iminomethyl‐azetidin‐2‐ones and butenylidene‐butadienyl‐[2,2′‐biazetidine]‐4,4′‐ diones. Butadienyl ketene reacts in [2+2] cycloaddition fashion with both iminic portion of 1,4‐ diazabuta‐1,3‐dienes and competitive [4+2] cycloaddition reaction of 1,4‐diazabuta‐1,3‐dienes as 4π component with butadienyl ketene as 2π component are not observed.