Facile Access to Versatile Polyaromatic Building Blocks: Selectively Protected Benzocyclobutenedione Derivatives via Regioselective [2+2] Cycloaddition of α‐Alkoxybenzyne and Ketene Silyl Acetal

A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the regioselective [2+2] cycloaddition of α‐alkoxybenzynes and ketene silyl acetals. The cycloadducts could be converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.     

The Photochemical Reaction of Vinylaziridines and Vinylazetidines with Chromium(0) and Molybdenum(0) (Fischer) Carbene Complexes

The [5+2] and [6+2] cycloaddition reactions of vinylaziridines and vinylazetidines with ketenes generated photochemically from chromium(0) and molybdenum(0) Fischer carbene complexes have been investigated. These processes constitute a straightforward and efficient route to azepanones and azocinones, respectively. The peculiar electronic properties of the metalated ketenes allow for the introduction of electron‐rich substituents in the final cycloadducts, a difficult task using conventional organic chemistry procedures. The versatility of the process is demonstrated by using Cr⁰ Fischer bis(carbene) complexes as metalated bis(ketene) precursors. These species produce tethered bis(azepanone)s in a single step under mild reaction conditions. Density functional theory calculations point to a stepwise reaction pathway through the initial nucleophilic attack of the nitrogen atom of the aziridine on the metalated ketene, followed by ring closure of the zwitterionic intermediate formed.     

[2+2] Cycloaddition Reactions of Imines with Cyclic Ketenes: Synthesis of 1,3‐Thiazolidine Derived Spiro‐β‐lactams and Their Transformations

Unsymmetric cyclic ketenes were generated from N‐acyl‐1,3‐thiazolidine‐2‐carboxylic acids 1a – c by means of Mukaiyama's reagent, and then reacted with imines 2a – c to the new, isomeric spiro‐β‐lactams 3 and 4 via [2+2] cycloaddition (Staudinger ketene–imine reaction; Scheme 1). The reactions were stereoselective (Table 1) and mainly afforded the spiro‐β‐lactams with a relative trans configuration. The spiro‐β‐lactams could be transformed into the corresponding monocyclic β‐lactams by means of thiazolidine ring opening or into substituted thiazolidines via hydrolysis of the β‐lactam ring.     

1,3‐cycloadditions of pyridinium N‐arylimides

The title compounds (5a: Ar = C₆H5, 5b: Ar = 2‐pyridyl) are 1,3‐dipoles of the azomethine imine type; their 1,3‐cycloadditions are accompanied by the loss of the pyridinium resonance energy. As a consequence, the interaction with electron‐deficient ethylenes gives rise to cycloaddition/cycloreversion equilibria, in contrast to the cycloadditions of isoquinolinium N‐arylimides; enamines do not react with 5. The cycloadducts of 5a to dimethyl maleate, fumaronitrile, and acrylonitrile are N^β‐dienyl‐phenylhydrazines, which undergo a hydrazo rearrangement affording aminals derived from a tetracyclic system. Like enamines, the dienehydrazine system of the cycloadducts reacts with dimethyl acetylenedicarboxylate by [2 + 2] cycloaddition and electrocyclic ring opening furnishing tetrahydropyrrolo[3,2‐a]azocine derivatives. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 79–88, 1999     

Asymmetric Synthesis of Diazepino-β-lactams by [2 + 2] Cycloaddition of an ‘Evans-Sjogven’ Ketene with 1H-1,2-Diazepines

The ketene derivative of the chiral oxazolidinone 1 underwent non-concerted stereo specific [2 + 2] cycloadditions with the (Z)-imine moiety of diazepines 2 , leading thereby with good diastereoselection to the trans-β-lactam adducts 3 (major) and 4 (minor). The absolute configuration of the major cycloadduct 3a was determined by an X-ray analysis. Its formation is discussed in terms of minimisation of steric interaction in the two transition states which give sequencially the zwitterionic intermediates and the final cycloadducts.     

1,3‐Dipolar Cycloaddition Reactions of Indan‐1‐one Enamines across Arylnitrile Oxides Leading to Novel Cyclic Isoxazoline Derivatives

Synthesis of a series of cyclic fused‐isoxazolines has been accomplished by regioselective and diastereoselective 1,3‐dipolar cycloaddition of 3‐methylindan‐1‐one enamines ( 1a , 1b , 1c ) and 3‐phenylindan‐1‐one enamines ( 2a , 2b , 2c ) to arylnitrile oxides ( 3d , 3e , 3f , 3g , 3h ). The structure of the cycloadducts was elucidated by ¹H and ¹³C NMR spectroscopy. The proposed regio‐ and stereochemistry of fused‐compounds ( 4 ) and ( 5 ) has also been corroborated by two single‐crystal X‐ray diffraction studies carried out on 4‐methyl‐8b‐morpholinyl‐3‐(p‐tolyl)‐4H‐3a,8b‐dihydroindeno[2,3‐d]isoxazoline ( 4be ) and 3‐(p‐anisyl)‐4‐phenyl‐8b‐pyrrolidinyl‐4H‐3a,8b‐dihydroindeno[2,3‐d]isoxazoline ( 5af ) and by means of density functional theory calculations.     

Site-selective photocycloadditions of 2-pyrones with electron-poor olefins and the derivation from the cycloadducts

Photosensitized cycloaddition of 4,6-dimethyl-2-pyrone ( 1 ) with methacrylonitrile ( 3b ) afforded two types of [2 + 2]cycloadducts, 4b and 6b , across the C₅-C₆ and C₃-C₄ double bonds in 1 , respectively. Photosensitized reactions of 1 with dimethyl maleate and dimethyl cyclobutene-1,2-dicarboxylate gave [2 + 2]cycload-ducts 4d, 4e across the C₅-C₆ double bond, in addition to [4 + 2]cycloadduct 9d or bicyclo[4.2.0]octadiene 10e . The photoreactions of methyl 2-pyrone-5-carboxylate ( 2 ) with 3b and 2-chloroacrylonitrile ( 3c ) gave [4 + 2]cycloadducts 5b, 5c in addition to [2 + 2]cycloadducts 11b and 11c across the C₅-C₆ double bond in 2 . The photocycloaddition mechanism was explained from results calculated by means of PM3-CI method. Namely, the site- and/or regio-selective products, 4, 5, 8, 9 and 10 were thought to come from the same site-selective radical intermediates in the case of electron-poor olefins. Pyrolysis and/or hydrolysis of the cycload-ducts 4e, 5b, 5c gave 5,6-dihydro-2-pyrone 12 or benzene derivatives.     

An Efficient Synthesis of Optically Active trans‐(3R,4R)‐3‐Acetoxy‐4‐aryl‐1‐(chrysen‐6‐yl)azetidin‐2‐ones Using (+)‐Car‐3‐ene as a Chiral Auxiliary

An efficient enantioselective synthesis of 3‐acetoxy trans‐β‐lactams 7a and 7b via [2+2] cycloaddition reactions of imines 4a and 4b , derived from a polycyclic aromatic amine and bicyclic chiral acid obtained from (+)‐car‐3‐ene, is described. The cycloaddition was found to be highly enantioselective, producing only trans‐(3R,4R)‐N‐azetidin‐2‐one in very good yields. This is the first report of the synthesis of enantiomerically pure trans‐β‐lactams 7a and 7b with a polycyclic aromatic substituent at N(1) of the azetidin ring.     

Rapidly and Highly Yielded Synthesis of Pyrimidine,Dihydropyrimidinone, and Triazino[2,1‐b]quinazolin‐6‐ones Derivatives

The reaction of 4‐oxo‐3,4‐dihydroquinazolinyl‐2‐guanidine 1 with several active methylene compounds has revealed formation of the corresponding hydropyrimidine and dihydropyrimidnone (DHPMs) derivatives via cycloaddition reaction mechanism. Satisfactory results were obtained with good yields, short time, and simplicity in the experimental procedure. Reaction with ketones in DMF proceeded via (5+1) heterocyclization and resulted in the formation of 2‐amino‐4‐(het)aryl‐4,6‐dihydro‐1(3)(11)H‐[1,3,5]triazino[2,1‐b]quinazolin‐6‐ones 8 , 9 , 10 , 11 , 12 , 13 , respectively. All compounds have been characterized based on IR, ¹H‐NMR, and mass spectrum.     

Photocycloisomerization of Boc‐Protected 5‐Alkenyl‐2,5‐dihydro‐1H‐ pyrrol‐2‐ones

On irradiation (254 nm), the newly synthesized Boc‐protected 5‐alkenyl‐2,5‐dihydro‐1H‐pyrrol‐2‐ones 13 undergo regioselective intramolecular [2+2] photocycloadditions. While the allyl derivatives 13a – 13c afford mainly azatricyclo[3.3.0.0^2,7]octanones, i.e., crossed cycloadducts, the butenyl‐ and pentenyl‐substituted compounds 13d and 13e isomerize preferentially to straight cycloadducts.     

Synthesis and Antifungal Activities of Some New 5,7‐Disubstituted[1,2,4]Triazolo[1,5‐a]Pyrimidin‐6‐one Derivatives

Synthesis of a new series of [1,2,4]triazolo[1,5‐a]pyrimidin‐6‐one by [4 + 2]cycloaddition reaction of 3‐benzylidineamino[1,2,4]triazole with monophenyl ketene and diphenyl ketene generated in situ from phenylacetyl chloride and diphenylacetyl chloride in the presence of triethylamine is described. The newly synthesized compounds were also tested for antifungal activities against Rhizoctonia solani and Trichoderma sp.     

Stereoselective Rhodium‐Catalysed [2+2+2] Cycloaddition of Linear Allene–Ene/Yne–Allene Substrates: Reactivity and Theoretical Mechanistic Studies

Allene–ene–allene ( 2 and 5 ) and allene–yne–allene ( 3 and 7 ) N‐tosyl and O‐linked substrates were satisfactorily synthesised. The [2+2+2] cycloaddition reaction catalysed by the Wilkinson catalyst [RhCl(PPh₃)₃] was evaluated. Substrates 2 and 5 , which bear a double bond in the central position, gave a tricyclic structure in a reaction in which four contiguous stereogenic centres were formed as a single diastereomer. The reaction of substrates 3 and 7 , which bear a triple bond in the central position, gave a tricyclic structure with a cyclohexenic ring core, again in a diastereoselective manner. All cycloadducts were formed by a regioselective reaction of the inner allene double bond and, therefore, feature an exocyclic diene motif. A Diels–Alder reaction on N‐tosyl linked cycloadducts 8 and 10 allowed pentacyclic scaffolds to be diastereoselectively constructed. The reactivity of the allenes on [2+2+2] cycloaddition reactions was studied for the first time by density functional theory calculations. This mechanistic study rationalizes the order in which the unsaturations take part in the catalytic cycle, the reactivity of the two double bonds of the allene towards the [2+2+2] cycloaddition reaction, and the diastereoselectivity of the reaction.     

Synthesis of some mono- and bis-spiro-β-lactams of benzylisatin

Some new mono- and bis-spiro-β-lactams of benzylisatin were prepared by Staudinger’s ketene-imine [2+2] cycloaddition reaction. The cycloadducts were characterized by spectral data including ¹H NMR, ¹³C NMR, IR and mass spectra. The configuration of benzylisatin and one of mono-spiro-β-lactams (5a) was established by X-ray crystal analysis.     

Chiral nitrone reagents for cycloaddition reactions

The preparation and cycloaddition reactions of new imidazoline nitrones are described. The imidazo[1,2‐b]isoxazole alkene cycloadducts are formed via an exo approach. An example has been tranformed into a pyrrolo[1,2‐a]imidazole as a prelude to a new pyrrolidine synthesis.     

[4+2]-Cycloadditionen von α,β-ungesättigten Hydrazonen. Teil 2. Pyridin-2,3-dicarboximide aus 1,4-Dihydropyridin-Derivaten

[4+2] Cycloaddition of α,β-Unsaturated Hydrazones to Pyridine-2,3-dicarboximides via 1,4-Dihydropyridine Derivatives The [4 + 2] cycloaddition of α,β-unsaturated hydrazones of type 1 (1-aza-1,2-butadienes) with maleimides (e.g. 2b ) affords the tetrahydropyridines of type 8. Elimination of dimethylamine to 9 is easily achieved by treatment of 8 with silica gel at elevated temperature. Oxidation of the dihydropyridines 9 leads to highly substituted pyridine-2,3-dicarboxylic-acid dervatives 4 .     

Photochemistry of 6,6-Dimethyl- and 2,2,6,6-Tetramethyl-2H,6H-pyran-3-one

The title compounds 1a and 1b have been synthesized in two steps from the saturated pyran-3-ones 2a and 2b , respectively. Upon irradiation (254 nm or 350 nm) in dilute solutions (10^?3?10^?2M ), compounds 1 undergo a formal [4 + 2] cycloreversion from the excited triplet state to give (2-methylprop-1-enyl)ketene ( 11 ) and either formaldehyde or acetone, ketene 11 being trapped by H₂O or MeOH to afford 4-methylpent-3-enoic acid ( 5 ) or its methyl ester 4 in 75–85% isolated yield. In this (monomolecular) photoreaction, heterocycles 1 differ from their alicyclic counterparts, i.e., 4,4-dimethylcyclohex-2-enone ( 10a ) and 4,4,6,6-tetramethylcyclohex-2-enone ( 10b ), as no rearrangement to a 4-oxabicyclo[3.1.0]hexan-2-one occurs. On the other hand, the photochemical behavior of pyranone 1a in bimolecular reactions (cyclodimerization, [2 + 2] cycloaddition to 2,3-dimethylbut-2-ene) resembles that of enone 10a .     

Diastereoselective 1,3‐Dipolar Cycloadditions of Chiral Derivatives of 2‐Oxoethanenitrile Oxide to Noncyclic Conjugated Symmetrical Alkenes

Asymmetric 1,3‐dipolar cycloadditions of chiral derivatives of the nitrile oxides 3a – 3c derived from (2R)‐bornane‐10,2‐sultam, (2R)‐10‐(dicyclohexylsulfamoyl)isoborneol, and (1R)‐8‐phenylmenthol, to either (E)‐stilbene 4 or dimethyl fumarate 5 , leading to the corresponding 4,5‐dihydroisoxazoles 6a – 6c and 7a – 7c in both moderate yields and diastereoselectivities, are presented. All cycloadducts were converted into the corresponding methyl esters 8 and 9 , which were used for determination of their enantiomeric purities via chiral HPLC analyses. In the case of both stilbene cycloadducts 6a and 6b , their absolute configurations were determined by X‐ray crystal‐structure analyses. These [3+2] cycloadditions suggest the participation of the thermodynamically less stable SO₂/CO syn‐conformer in the π_y approach along the C?O bond of the linear nitrile oxide 3a .     

Organocatalytic Enantioselective Higher‐Order Cycloadditions of In Situ Generated Amino Isobenzofulvenes

The [8+2] cycloaddition of indene‐2‐carbaldehydes and nitro olefins is described to provide benzonorbornene scaffolds in a highly peri‐, diastereo‐, and enantioselective fashion in the presence of a C₂‐symmetric aminocatalyst. This reaction, which proceeds through a transient semi‐aromatic amino isobenzofulvene, represents the first example of catalytic formation and transformation of these species. Quantum chemical calculations suggest a kinetically controlled stepwise mechanism where the stereochemistry is determined in the first bond‐forming event. Beyond the useful [8+2] cycloadducts, [10+4] cycloadducts have been identified in silico as potential off‐pathway intermediates.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.