Photocycloaddition of Conjugated Cyclohex‐2‐enones to 2,3‐Dimethylbuta‐1,3‐diene

On irradiation, in the presence of 2,3‐dimethylbuta‐1,3‐diene, naphthalen‐2‐ones 1 are quantitatively and regioselectively converted to mixtures of diastereoisomeric cyclobutane adducts 3 and 4 , whereas, under these conditions, 3‐(alk‐1‐ynyl)cyclohex‐2‐enones 5 give only one cyclobutane adduct 6 regio‐ and diastereoselectively. In contrast, 3‐(alk‐1‐ynyl)‐2‐methylcyclohex‐2‐enones 10 undergo [2+2]‐cycloaddition to the same diene exclusively at the C≡C bond to afford hitherto unknown 3‐cyclobutenylcyclohex‐2‐enones 11 .     

Photocycloaddition Reactions of 5,5‐Dimethyl‐3‐(3‐methylbut‐3‐en‐1‐ynyl)cyclohex‐2‐en‐1‐one

The title cyclohexenone 1d undergoes photodimerization selectively at the exocyclic C?C bond to give a 1 : 1 mixture of 1,2‐dialkynyl‐1,2‐dimethylcyclobutanes 6 and 7 . On irradiation in the presence of 2,3‐dimethylbuta‐1,3‐diene, 1d affords bicyclo[8.4.0]tetradeca‐1,2,3,7‐tetraen‐11‐one 9 . This – formal – (6+4)‐cycloadduct undergoes quantitative isomerization to 3‐cycloheptadienyl‐2,5,5‐trimethylcyclohex‐2‐enone 11 on treatment with basic silica gel.     

Multiple Cycloaddition Reactions of Ketones with a β‐Diketiminate Al Compound

A β‐diketiminate Al compound ( 1 ) with an exocyclic double bond reacts with two equivalents each of benzophenone and 2‐benzoylpyridine in a [4+2] cycloaddition to generate bicyclic and tricyclic compounds 2 and 3, respectively. Compound 2 consists of six‐ and eight‐membered aluminium rings, whereas 3 has two five‐ and one eight‐membered ring. Compounds 2 and 3 were characterized by a number of analytical tools including single‐crystal X‐ray diffraction. The quantum mechanical calculations suggest that the dissociation of the solvent molecule from 1 would lead to an active species 1A having two 1,4‐dipolar 4π electron moieties, in which the electrophilic site is the Al atom and the nucleophilic positions are polarized exocyclic and endocyclic C?C π bonds. The detailed mechanistic study shows that the dipolarophiles, benzophenone, and 2‐benzoylpyridine undergo double cycloaddition with two 1,4‐dipolar 4π electron moieties of 1A . Herein, the addition of one molecule of the dipolarophile promotes the addition of the second one.     

Photocycloaddition of Six‐Membered Cyclic Enones to Propen‐2‐yl Isocyanate

On irradiation in the presence of propen‐2‐yl isocyanate ( 4 ), six‐membered cyclic enones 3 are converted into regio‐ and stereoisomeric mixtures of [2+2] cycloadducts 5 – 10 ; the preferentially formed HT products, 5 – 8 , can be converted into the corresponding bicyclic amines by acid hydrolysis, whereas, under these conditions, the regioisomeric HH‐isocyanato derivatives undergo a retro‐Mannich reaction.     

Photocycloaddition of Cyclohex‐2‐enones to Penta‐1,2,4‐triene

Dihydrothiinone 9a undergoes photocycloaddition regioselectively to all three C?C bonds of penta‐1,2,4‐triene ( 10 ), the relative stabilities of the biradical intermediates determining the product distribution. In contrast, cyclohexenone 9b and dihydropyranone 9c afford more complex mixtures of bicyclo[4.2.0]octanones, which also turn out to be less stable on chromatographic workup, reflecting the higher strain due to the shorter bond lengths (C? O and C? C vs. C? S) in the six‐membered rings, respectively.     

Chemoselectivity of the Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine

The reactions of 5‐benzylidene‐3‐phenylrhodanine ( 2 ; rhodanine=2‐thioxo‐1,3‐thiazolidin‐4‐one) with diazomethane ( 7a ) and phenyldiazomethane ( 7b ) occurred chemoselectively at the exocyclic C?C bond to give the spirocyclopropane derivatives 9 and, in the case of 7a , also the C‐methylated products 8 (Scheme 1). In contrast, diphenyldiazomethane ( 7c ) reacted exclusively with the C?S group leading to the 2‐(diphenylmethylidene)‐1,3‐thiazolidine 11 via [2+3] cycloaddition and a ‘two‐fold extrusion reaction’. Treatment of 8 or 9b with an excess of 7a in refluxing CH₂Cl₂ and in THF at room temperature in the presence of [Rh₂(OAc)₄], respectively, led to the 1,3‐thiazolidine‐2,4‐diones 15 and 20 , respectively, i.e., the products of the hydrolysis of the intermediate thiocarbonyl ylide. On the other hand, the reactions with 7b and 7c in boiling toluene yielded the corresponding 2‐methylidene derivatives 16, 21a , and 21b . Finally, the reaction of 11 with 7a occurred exclusively at the electron‐poor C?C bond, which is conjugated with the C?O group. In addition to the spirocyclopropane 23 , the C‐methylated 22 was formed as a minor product. The structures of the products (Z)‐ 8, 9a, 9b, 11 , and 23 were established by X‐ray crystallography.     

Photocycloaddition of 2H‐1‐Benzopyran‐3‐carbonitriles and 2H‐1‐Benzothiopyran‐3‐carbonitriles to Alkenes and Alkenynes

Both (intermolecular) photocycloadditions of 2H‐1‐benzopyran‐ and 2H‐1‐benzothiopyran‐3‐carbonitriles to 2,3‐dimethylbut‐2‐ene and 2‐methylbut‐1‐en‐3‐yne, and (intramolecular) photoisomerization of 4‐(alkenyl)benzopyran‐3‐carbonitriles were investigated. In contrast to 2H‐1‐benzopyran‐3‐carbonitrile ( 1 ), its thia analog 4 reacts with 2,3‐dimethylbut‐2‐ene selectively, to afford only cyclobuta derivative 7 . In the presence of 2‐methylbut‐1‐en‐3‐yne, both 1 and 4 behave alike to afford the all‐cis‐cyclobuta diastereoisomers, 15 and 8 , respectively, as main products, as well as minor amounts of cyclobutenes 17 and 10 , respectively, which result from the addition of the terminal C‐atom of the acetylenic bond to C(3) of the heterocycle. 4‐Methyl‐2H‐1‐benzopyran‐3‐carbonitrile ( 5 ) does not undergo photoaddition to the alkene or the alkenyne mentioned above, whereas the corresponding intramolecular [2+2] photocycloaddition of 4‐(pent‐4‐enyl)benzopyran‐3‐carbonitrile ( 6b ) to tetracycle 20 proceeds quantitatively.     

Nickel(0)‐Catalyzed Enantioselective [3+2] Annulation of Cyclopropenones and α,β‐Unsaturated Ketones/Imines

Ni⁰‐catalyzed chemo‐ and enantioselective [3+2] cycloaddition of cyclopropenones and α,β‐unsaturated ketones/imines is described. This reaction integrates C?C bond cleavage of cyclopropenones and enantioselective functionalization by carbonyl/imine group, offering a mild approach to γ‐alkenyl butenolides and lactams in excellent enantioselectivity (88–98 % ee) through intermolecular C?C activation.     

Zirconium‐Mediated Multicomponent Reactions of 1,3‐Butadiynes with Ylidenemalononitriles to Form Functionalized 1,8‐Naphthyridine and Cyclopenta[b]pyridine Derivatives

Zirconocene‐mediated multicomponent reactions of 1,3‐butadiynes with ylidenemalononitriles in the absence or presence of CuCl have been developed. In the absence of CuCl, 1,3‐butadiyne couples with three molecules of ylidenemalononitriles to yield azazirconacycles bearing a hexahydro‐1,8‐naphthyridine skeleton with high stereoselectivity. In the presence of CuCl, cyclopenta[b]pyridine or cyclopenta[b]quinolin‐1‐one derivatives are obtained via transmetalation of Zr?C bond to Cu?C bond as the key reaction step. These domino‐type reactions proceed with high chemo‐, regio‐ and/or stereoselectivities, and allowing the formation of multiple C?N and C?C bonds in a single operation.     

Regio‐ and Stereoselective Reductive Coupling of Bicyclic Alkenes with Propiolates Catalyzed by Nickel Complexes: A Novel Route to Functionalized 1,2‐Dihydroarenes and γ‐Lactones

7‐Oxabenzonorbornadienes derivatives 1 a – d underwent reductive coupling with alkyl propiolates CH₃C?CCO₂CH₃ ( 2 a ), PhC?CCO₂Et ( 2 b ), CH₃(CH₂)₃C?CCO₂CH₃ ( 2 c ), CH₃(CH₂)₄C?CCO₂CH₃ ( 2 d ), TMSC?CCO₂Et ( 2 e ), (CH₃)₃C?CCO₂CH₃ ( 2 f ) and HC?CCO₂Et ( 2 g ) in the presence of [NiBr₂(dppe)] (dppe=Ph₂PCH₂CH₂PPh₂), H₂O and zinc powder in acetonitrile at room temperature to afford the corresponding 2alkenyl‐1,2‐dihydronapthalen‐1‐ol derivatives 3 a – n with remarkable regio‐ and diastereoselectivity in good to excellent yields. Similarly, the reaction of 7azabenzonorbornadienes derivative 1 e with propiolates 2 a, b and d proceeded smoothly to afford reductive coupling products 2alkenyl‐1,2‐dihydronapthalene carbamates 3 o – p in good yields with high regio‐ and stereoselectivity. This nickel‐catalyzed reductive coupling can be further extended to the reaction of 7oxabenzonorbornene derivatives. Thus, 5,6‐di(methoxymethyl)‐7‐oxabicyclo[2.2.1]hept‐2‐ene ( 4 ) reacted with 2 a and 2 d to furnish cyclohexenol derivatives bearing four cis substituents 5 a and b in 81 and 84 % yield, respectively. In contrast to the results of 4 with 2 , the reaction of dimethyl 7oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboxylate ( 6 ) with propiolates 2 a – d afforded the corresponding reductive coupling/cyclization products, bicyclo[3.2.1]γ‐lactones 7 a – d in good yields. The reaction provides a convenient one‐pot synthesis of γ‐lactones with remarkably high regio‐ and stereoselectivity.     

Intramolecular [2+2] Photocycloaddition of 3‐ and 4‐(But‐3‐enyl)oxyquinolones: Influence of the Alkene Substitution Pattern,Photophysical Studies,and Enantioselective Catalysis by a Chiral Sensitizer

The intramolecular [2+2] photocycloaddition of four 4‐(but‐3‐enyl)oxyquinolones (substitution pattern at the terminal alkene carbon atom: CH₂, Z‐CHEt, E‐CHEt, CMe₂) and two 3‐(but‐3‐enyl)oxyquinolones (substitution pattern: CH₂, CMe₂) was studied. Upon direct irradiation at λ=300 nm, the respective cyclobutane products were formed in high yields (83–95 %) and for symmetrically substituted substrates with complete diastereoselectivity. Substrates with a Z‐ or E‐substituted terminal double bond showed a stereoconvergent reaction course leading to mixtures of regio‐ and diastereomers with almost identical composition. The mechanistic course of the photocycloaddition was elucidated by transient absorption spectroscopy. A triplet intermediate was detected for the title compounds, which–in contrast to simple alkoxyquinolones such as 3‐butyloxyquinolone and 4‐methoxyquinolone–decayed rapidly (τ≈1 ns) through cyclization to a triplet 1,4‐diradical. The diradical can evolve through two reaction channels, one leading to the photoproduct and the other leading back to the starting material. When the photocycloaddition was performed in the presence of a chiral sensitizer (10 mol %) upon irradiation at λ=366 nm in trifluorotoluene as the solvent, moderate to high enantioselectivities were achieved. The two 3‐(but‐3‐enyl)oxyquinolones gave enantiomeric excesses (ees) of 60 and 64 % at ?25 °C, presumably because a significant racemic background reaction occurred. The 4‐substituted quinolones showed higher enantioselectivities (92–96 % ee at ?25 °C) and, for the terminally Z‐ and E‐substituted substrates, an improved regio‐ and diastereoselectivity.     

A New Type of Donor–Acceptor Cyclopropane Reactivity: The Generation of Formal 1,2‐ and 1,4‐Dipoles

A new type of donor–acceptor cyclopropane reactivity has been discovered. On treatment with anhydrous GaCl₃, they react as sources of even‐numbered 1,2‐ and 1,4‐dipoles instead of the classical odd‐numbered 1,3‐dipoles due to migration of positive charge from the benzyl center. This type of reactivity has been demonstrated for new reactions, namely, cyclodimerizations of donor–acceptor cyclopropanes that occur as [2+2]‐, [3+2]‐, [4+2]‐, [5+2]‐, [4+3]‐, and [5+4]‐annulations. The [4+2]‐annulation of 2‐arylcyclopropane‐1,1‐dicarboxylates to give polysubstituted 2‐aryltetralins has been developed in a preparative version that provides exceedingly high regio‐ and diastereoselectivity and high yields. The strategy for selective hetero‐combination of donor–acceptor cyclopropanes was also been developed. The mechanisms of the discovered reactions involving the formation of a comparatively stable 1,2‐ylide intermediate have been studied.     

Stereoselective Synthesis of 1,3‐Diaminotruxillic Acid Derivatives: An Advantageous Combination of CH‐ortho‐Palladation and On‐Flow [2+2]‐Photocycloaddition in Microreactors

The stereoselective synthesis of ε‐isomers of dimethyl esters of 1,3‐diaminotruxillic acid in three steps is reported. The first step is the ortho‐palladation of (Z)‐2‐aryl‐4‐aryliden‐5(4H)‐oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho‐C?H bond of the 4‐arylidene ring in carboxylic acids. The second step is the [2+2]‐photocycloaddition of the C?C exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho‐palladated cyclobutanes 3 . This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε‐1,3‐diaminotruxillic acid derivatives as single isomers.     

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil,Synthesis and Transformation into Annulated Pyrimidinediones

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil ( 5 ) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7a and 7b . Rh₂(OAc)₄ catalyzed the transformation of 5 into to a 2 : 1 (Z)/(E) mixture of 1,2‐diuracilylethenes 9 (67%). Heating (Z)‐ 9 in 12n HCl at 95° led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4‐f]quinazolinetetraone 12 . The Rh₂(OAc)₄‐catalyzed reaction of 5 with 3,4‐dihydro‐2H‐pyran and 2,3‐dihydrofuran gave endo/exo‐mixtures of the 2‐oxabicyclo[4.1.0]heptane 13 (78%) and the 2‐oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl₃ or Me₂AlCl promoted a vinylcyclopropane–cyclopentene rearrangement, leading to the pyrano‐ and furanocyclopenta[1,2‐d]pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2‐methoxypropene was transformed into the 5‐methylcyclopenta‐pyrimidinedione 18 (55%). The Rh₂(OAc)₄‐catalyzed reaction of 5 with thiophene gave the exo‐configured 2‐thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8‐oxabicyclo[3.2.1]oct‐2‐ene 20 (73%), and the reaction with (E)‐2‐styrylfuran yielded a diastereoisomeric mixture of hepta‐1,4,6‐trien‐3‐ones 21 (75%) that was transformed into the (1E,4E,6E)‐configured hepta‐1,4,6‐trien‐3‐one 21 (60%) at ambient temperature.     

Photocycloaddition Reactions of Alkyl and Aryl 2‐Thioxo‐3H‐benzoxazole‐ 3‐carboxylates to Alkenes

The photochemical reactions of alkyl and aryl 2‐thioxo‐3H‐benzoxazole‐3‐carboxylates 1 have been examined. Irradiation of 1 in the presence of tetra‐ and trisubstituted alkenes 2a and 2b , 2‐methylprop‐2‐ene nitrile 2e , and dienes 2f and 2g gave [2+2] cycloadducts of the CS bond of 2‐thioxobenzoxazoles and the CC bond of alkenes, spiro[benzoxazole‐thietanes] 3, 4, 8 – 13, 15, 18, 20, 23 – 26 in moderate‐to‐good yields. The photoaddition reactions proceed in a regiospecific manner. The spirocyclic compounds obtained are indefinitely stable at room temperature. Irradiation of 1a in the presence of 1,1‐ and 1,2‐disubstituted alkenes 2c and 2d yielded the products 5 – 7 of oxazole‐ring cleavage. Compound 1d also underwent photoaddition with alkenes to yield spiro[benzoxazole‐thietanes] and/or 2‐substituted benzoxazoles and/or iminothietanes, depending on the nature of the substituents present in the alkenes. On intramolecular [2+2] photoadduct, tetracyclic 27 , was obtained, when ethenyl 2‐thioxobenzoxazole‐3‐carboxylate 1e was irradiated.     

One Stone for Three Birds‐Rhodium‐Catalyzed Highly Diastereoselective Intramolecular [4+2] Cycloaddition of Optically Active Allene‐1,3‐dienes

RhCl(PPh₃)₃‐catalyzed [4+2] intramolecular cycloaddition of optically active axially chiral allene‐dienes afforded cis‐fused [3.4.0]‐bicyclic products with three chiral centers in good yields with an excellent chemo‐ and diastereoselectivity. A pair of enantiomers of such products was generated highly selectively from both enantiomers of starting allene‐dienes, indicating that the axial chirality dictated the absolute configurations of the three in situ generated chiral centers with a very high efficiency of chirality transfer.     

[8+2] and [8+3] Cyclization Reactions of Alkenyl Carbenes and 8‐Azaheptafulvenes: Direct Access to Tetrahydro‐1‐azaazulene and Cyclohepta[b]pyridinone Derivatives

The reactivity of Fischer alkenyl carbenes toward 8‐azaheptafulvenes is examined. Alkenyl carbenes react with 8‐azaheptafulvenes with complete regio‐ and stereoselectivity through formal [8+3] and [8+2] heterocyclization reactions, which show an unprecedented dependence on the C_β substituent at the alkenyl carbene complex. Thus, the formal [8+3] heterocyclization reaction is completely favored in carbene complexes that bear a coordinating moiety to give tetrahydrocyclohepta[b]pyridin‐2‐ones. Otherwise, alkenyl carbenes that lack appropriate coordinating groups undergo a formal [8+2] cyclization with 8‐azaheptafulvenes to give compounds that bear a tetrahydroazaazulene structure. A likely mechanism for these reactions would follow well‐established models and would involve a 1,4‐addition/cyclization in the case of the [8+2] cyclization or a 1,2‐addition/[1,2] shift–metal‐promoted cyclization for the [8+3] reaction. The presence of a coordinating moiety in the carbene would favor the [1,2] metal shift through transition‐state stabilization to lead to the [8+3] product. All these processes provide an entry into the tetrahydroazaazulene and cycloheptapyridone frameworks present in the structure of biologically active molecules.     

Facile Chemoselective synthesis of 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids and 3H,3’H‐Spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives

Oxidation of some derivatives of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐one have been investigated in detail using lead(IV) acetate in acetic acid under reflux conditions and periodic acid in aqueous ethanol at room temperature. We realized that during the first 5–15 minutes of the oxidation reactions in lead(IV) acetate/acetic acid system, 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives have been synthesized chemo selectively, while, if the reaction mixtures stirred for additional 3 hours, the main products would be 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids. Moreover, room temperature oxidation of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐ones by periodic acid (H₅IO₆), leads to the formation of 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives in good to excellent yields.     

Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine – A Computational Study

It has been shown previously that the reaction of diazomethane with 5‐benzylidene‐3‐phenylrhodanine ( 1 ) in THF at ?20° occurs at the exocyclic C?C bond via cyclopropanation to give 3a and methylation to yield 4 , respectively, whereas the corresponding reaction with phenyldiazomethane in toluene at 0° leads to the cyclopropane derivative 3b exclusively. Surprisingly, under similar conditions, no reaction was observed between 1 and diphenyldiazomethane, but the 2‐diphenylmethylidene derivative 5 was formed in boiling toluene. In the present study, these results have been rationalized by calculations at the DFT B3LYP/6‐31G(d) level using PCM solvent model. In the case of diazomethane, the formation of 3a occurs via initial Michael addition, whereas 4 is formed via [3+2] cycloaddition followed by N₂ elimination and H‐migration. The preferred pathway of the reaction of 1 with phenyldiazomethane is a [3+2] cycloaddition, subsequent N₂ elimination and ring closure of an intermediate zwitterion to give 3b . Finally, the calculations show that the energetically most favorable reaction of 1 with diphenyldiazomethane is the initial formation of diphenylcarbene, which adds to the S‐atom to give a thiocarbonyl ylide, followed by 1,3‐dipolar electrocyclization and S‐elimination.     

Visible‐Light‐Mediated 1,2‐Acyl Migration: The Reaction of Secondary Enamino Ketones with Singlet Oxygen

Secondary enaminones were oxidized by photochemically generated singlet oxygen, followed by nucleophilic addition of alcohol and an unexpected 1,2‐acyl migration to afford quaternary amino acid derivatives. An ene‐type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C?C bond pathway.