Intramolecular [2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications

The intramolecular [2+2] photocycloaddition of 3-alkenyl-2-cycloalkenones was performed in an enantioselective fashion (nine representative examples, 54–86 % yield, 76–96 % ee) upon irradiation at λ=366 nm in the presence of an AlBr₃-activated oxazaborolidine as the Lewis acid. An extensive screening of proline-derived oxazaborolidines showed that the enantioface differentiation depends strongly on the nature of the aryl group at the 3-position of the heterocycle. DFT calculations of the Lewis acid–substrate complex indicate that attractive dispersion forces may be responsible for a change of the binding mode. The catalytic [2+2] photocycloaddition was shown to proceed on the triplet hypersurface with a quantum yield of 0.05. The positive effect of Lewis acids on the outcome of a given intramolecular [2+2] photocycloaddition was illustrated by optimizing the key step in a concise total synthesis of the sesquiterpene (±)-italicene.     

Enantioselective Catalysis of the Intermolecular [2+2] Photocycloaddition between 2‐Pyridones and Acetylenedicarboxylates

Intermolecular [2+2] photocycloadditions represent the most versatile and widely applicable of photochemical reactions. For the first time, such intermolecular reactions have been carried out in a catalytic fashion using a chiral triplet sensitizer, with high enantioselectivity (up to 92 % ee). The low catalyst loading (2.5–5 mol %) underlines the high efficiency of the process both in terms of reaction acceleration and differentiation of the enantiotopic faces of the substrate. The substrate is anchored to the chiral catalyst through noncovalent interactions (hydrogen bonds), thus providing a chiral environment in which the enantioselective photocycloaddition proceeds. The densely functionalized products present numerous possibilities for further synthetic transformations.     

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.     

Regio- and stereochemistry of [2 + 2] photocycloadditions of imines to alkenes: a computational and experimental study

The [2 + 2] photocycloaddition of isoxazolines to alkenes has been studied by means of CASPT2/6-31G*//CASSCF/6-31G*. The reaction outcome is influenced by the relative ratio of imine deactivation and photocycloaddition. Analysis of the conical intersection points involved in the photoreaction shows that fast deactivation is prevented when an electron-withdrawing group is placed in any position that can affect the imine moiety. Computational data predict that the photoreaction will be regiospecific but without stereoselectivity. Furthermore, the favored regioisomer will be different for alkenes with electron-withdrawing or electron-releasing substituents. The results of a complementary experimental study correlate well with the computational data. Several conclusions included in the present work could prove useful for the generalization of the photocycloaddition of imines.     

Evidence for Triplet Sensitization in the Visible‐Light‐Induced [2+2] Photocycloaddition of Eniminium Ions

Εniminium ions were prepared from the corresponding α,β‐unsaturated carbonyl compounds (enones and enals), and were found to be promoted to their respective triplet states by energy transfer. The photoexcited intermediates underwent intra‐ or intermolecular [2+2] photocycloaddition in good yields (50–78 %) upon irradiation at λ=433 nm or λ=457 nm. Iridium or ruthenium complexes with a sufficiently high triplet energy were identified as efficient catalysts (2.5 mol % catalyst loading) for the reaction. The intermolecular [2+2] photocycloaddition of an eniminium ion derived from a chiral secondary amine proceeded with high enantioselectivity (88 % ee).     

Molecular dynamics and metadynamics simulations of [2 + 2] photocycloaddition

Triplet state mechanism of [2 + 2] photocycloaddition forming a cyclobutane ring from two ethylenes is investigated in the context of photocatalysis. High‐level ab initio calculations are combined with ab initio adiabatic molecular dynamics and ab initio metadynamics for rare events modeling. In a photocatalytic scheme, a reactant reaches the triplet state either via intersystem crossing (ISC) or triplet sensitization. The model system adopts a biradical structure, which represents energy intersection with the ground state. The system either completes cyclization or undergoes fragmentation into two olefinic units. The potential and free energy surfaces of the cyclobutane/ethylenes system are mapped with multireference approaches describing possible reaction pathways. To obtain a full picture of a double bond photoreactivity, ab initio adiabatic dynamical calculations were used to estimate reaction yields and to model the effects of excess energy. The potential use of density functional theory based approaches for [2 + 2] photocycloaddition was investigated for future simulations and design of realistic photocatalytic systems. Dynamical aspects of [2 + 2] photocycloaddition via a triplet state manifold are investigated by combining ab initio multireference methods and ab initio molecular dynamics and metadynamics. The reaction pathways are studied for a model system of two ethylenes forming a cyclobutane ring to provide a basis for further studies on design of photocatalytic systems.     

Visible‐Light‐Triggered Cross‐Linking of DNA Duplexes by Reversible [2+2] Photocycloaddition of Styrylpyrene

Reversible photo‐cross‐linking of a DNA duplex through the [2+2] photocycloaddition of styrylpyrene is reported. Styrylpyrene moieties on d ‐threoninol linkers were introduced into complementary positions on DNA strands. Irradiation of the styrylpyrene pair in the duplex with visible light at λ=455 nm induced a [2+2] photocycloaddition between styrylpyrenes that cross‐linked the two strands of the duplex. Two diastereomers were formed after [2+2] photocycloaddition as a result of rotation of the styrylpyrene residues. Also, the cycloreversion reaction was induced by UV light at λ=340 nm, which reversibly yielded the uncross‐linked strands.     

Diastereodifferentiating the [2+2] Photocycloaddition of Ethylene to Arylmenthyl Cyclohexenonecarboxylates: Stacking‐Driven Enhancement of the Product Diastereoselectivity That Is Correlated with the Reactant Ellipticity

Upon diastereodifferentiating the [2+2] photocycloaddition of ethylene to a series of p‐substituted (?)‐8‐phenylmenthyl cyclohexenonecarboxylates, the diastereoselectivity was critically controlled by the nature of the substituent introduced to the chiral auxiliary, and the p‐nitro‐substituted substrate afforded the cycloadducts in 90 % diastereomeric excess (de) and with 97 % isolated yield. Detailed experimental and theoretical conformation analyses revealed that the stacking interaction of the aromatic auxiliary with the cyclohexenone moiety plays the decisive role in determining the substrate conformation and is, therefore, responsible for the dramatic enhancement of the de. Of particular interest, the product de was directly related to the ellipticity of the substrate, enabling us to “predict” the de prior to photoirradiation.     

Photocycloaddition of Quinoxaline-2(1H)-thiones to Alkenes

A synthetically useful C? C bond formation involving the photochemical addition of quinoxaline-2(1H)-thiones to alkenes is described. Irradiation of the quinoxaline-2(1H)-thiones 1–4 in the presence of the alkenes 7 gave the 2-(2′-mercaptoalkyl)quinoxalines 8–11 in moderate-to-good yields via ring cleavage of an intermediate aminothietane with aromatization of the quinoxaline ring. The latter was formed by [2+2] photocycloaddition of the C?S bond of the quinoxaline-2(1H)-thione and the C?C bond of the alkene.     

Peri-selective photocycloadditions of methyl 2-pyrone-5-carboxylate with unsaturated cyclic ethers

Photosensitized cycloaddition reaction of methyl 2-pyrone-5-carboxylate ( 1 ) with 2,3-dihydrofuran gave cis- exo- and cis-endo-[2 + 2] cycloadducts across the C₃-C₄ double bond in 1 , and a [4 + 2] cycloadduct which was different in addition-orientation from the Diels-Alder adducts. Each [2 + 2] cycloadduct was obtained by the use of sensitizers having different triplet energies. Photosensitized reactions of 1 with 3,4-dihydro-2H-pyrans afforded cis-endo-[2 + 2] cycloadducts, respectively. The photocycloaddition mechanism was also explained from the excited state of 1 calculated by means of MNDO-Cl method.     

RELATIVE REACTIVITIES OF THE EXCITED STATES OF FUROCOUMARINS FOR [2+2] PHOTOCYCLOADDITION REACTION WITH TETRAMETHYLETHYLENE

Abstract— The Stern-Volmer constants for fluorescence quenching by tetramethylethylene decrease in the order DMC ≫ DHP > F-2 > 8-MOP. The same order was observed for the quantum yields of [2+2] cycloaddition reaction with tetramethylethylene on direct irradiation. In [2+2] photocycloaddition of F-2 with tetramethylethylene in ethanol, the ratio of quantum yields deduced from singlet and triplet states of F-2; φ₃⁰/φ₁⁰, is about 5. The excited triplet state is the reactive state for the [2+2] photocycloaddition of F-2 with tetramethylethylene in solution but the excited singlet state of F-2 becomes very important in biological conditions.     

Photocycloaddition of Benzothiazole-2-thiones to Alkenes

The photocycloaddition of benzothiazole-2-thiones to electron-rich and aryl-substituted alkenes are described. Irradiation of N-unsubstituted benzothiazole-2-thione ( 1 ) in the presence of alkenes 3 gave 2-(2′-mercaptoalkyl)benzothiazoles 4 , and 2-substituted benzothiazoles 5 and 6 (in the case of 3a and 3h , resp.) through the ring cleavage of an intermediate 2-aminothietane (Schemes 1 and 3 ). The latter was formed by [2+2] cycloaddition of the C?S bond of 1 and the C?C bond of 3 . Irradiation of N-methylbenzothiazole-2-thione ( 2 ) and 2-methylpropene ( 3a ) gave the spiro-1,3-dithiane 8 , 1,2,6-benzodithiazocin-5-one 9 , and disulfide 10 . The structure of 9 was established by X-ray crystal-structure analysis.     

Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 4‐Substituted Coumarins Catalyzed by a Chiral Lewis Acid

Eight coumarins, which carry a terminal alkene tethered by a CH₂XCH₂ group to their 4‐position (X=CH₂, CMe₂, O, S, NBoc, NZ, NTs, NBn), were synthesized in overall yields of 51–80 %. Starting materials for the syntheses were either commercially available 4‐hydroxycoumarin or 4‐formylcoumarin. The intramolecular [2+2] photocycloaddition of these coumarins gave diastereoselectively products with a tetracyclic 3,3a,4,4a‐tetrahydro‐1H‐cyclopenta[2,3]cyclobuta[1,2‐c]chromen‐5(2H)‐one skeleton. Direct irradiation at λ=300 nm in dichloromethane (c=10 mM ) led to product formation in good yields for most substrates, presumably via a singlet excited state intermediate. Due to the low coumarin absorption at λ >350 nm the photocycloaddition was slow upon irradiation at λ=366 nm. Addition of a chiral oxazaborolidine‐based Lewis acid (50 mol %) increased the reaction rate at λ=366 nm and induced a significant enantioselectivity in the [2+2] photocycloaddition. Six out of eight coumarin substrates (X=CH₂, CMe₂, O, NBoc, NZ, NTs) gave the respective products in yields of 72–96 % and with 74–90 % enantiomeric excess (ee) upon irradiation in dichloromethane (c=20 mM ) at ?75 °C. The Lewis acid presumably acts by coordination to the coumarin carbonyl oxygen atom, which leads to a bathochromic shift (redshift) of the UV absorption and which increases the singlet state lifetime. A second electrostatic interaction of the hydrogen atom at C3 with the oxygen atom of the oxazaborolidine is likely.     

Intermolecular Photocyclizations of N‐(ω‐Hydroxyalkyl)tetrachlorophthalimide with Alkenes Leading to Medium‐ and Large‐Ring Heterocycles—Reaction Modes and Regio‐ and Stereoselectivity of the 1,n‐Biradicals

A new photocyclization strategy by using intermolecular tandem reactions between N‐(ω‐hydroxyalkyl)‐4,5,6,7‐tetrachlorophthalimides ( 1 , 2 , and 3 ) and a series of acyclic and cyclic alkenes is reported. Electron transfer of the triplet‐excited phthalimide with the alkene and regioselective trapping of the alkene cation radical by the hydroxyl group at the phthalimide side chain gives a triplet 1,n‐biradical, which after intersystem crossing (ISC) leads to regio‐ and diastereoselective synthesis of polycyclic heterocycles with an N,O‐containing medium to large ring. Regio‐ and diastereoselectivity in the cyclizations are clarified by unambiguous steric structure assignments of the products by X‐ray diffraction or extensive 2D NMR measurements. The diastereoselectivity is decided by the stereochemical course of the ISC process of the triplet 1,n‐biradicals. These intermolecular photoreactions also furnish a new strategy to generate triplet 1,n‐biradicals. Therefore, in photoreactions of 1 and 2 with phenylcyclohexene, the unprecedented stereoselective formation of products by intramolecular hydrogen‐atom transfer in the 1,n‐biradical intermediate was found ( 9 and 23 ). These facts provide direct verification to the reaction pathways of the 1,n‐biradicals and give a new insight into the factors deciding reaction‐pathway partitioning and stereoselectivity.     

Triplet Energy Transfer from Ruthenium Complexes to Chiral Eniminium Ions: Enantioselective Synthesis of Cyclobutanecarbaldehydes by [2+2] Photocycloaddition

Chiral eniminium salts, prepared from α,β‐unsaturated aldehydes and a chiral proline derived secondary amine, underwent, upon irradiation with visible light, a ruthenium‐catalyzed (2.5 mol %) intermolecular [2+2] photocycloaddition to olefins, which after hydrolysis led to chiral cyclobutanecarbaldehydes (17 examples, 49–74 % yield), with high diastereo‐ and enantioselectivities. Ru(bpz)₃(PF₆)₂ was utilized as the ruthenium catalyst and laser flash photolysis studies show that the catalyst operates exclusively by triplet‐energy transfer (sensitization). A catalytic system was devised with a chiral secondary amine co‐catalyst. In the catalytic reactions, Ru(bpy)₃(PF₆)₂ was employed, and laser flash photolysis experiments suggest it undergoes both electron and energy transfer. However, experimental evidence supports the hypothesis that energy transfer is the only productive quenching mechanism. Control experiments using Ir(ppy)₃ showed no catalysis for the intermolecular [2+2] photocycloaddition of an eniminium ion.     

Catalytic Asymmetric Dearomatization by Visible‐Light‐Activated [2+2] Photocycloaddition

A novel method for the catalytic asymmetric dearomatization by visible‐light‐activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2‐position with a chelating N‐acylpyrazole moiety which permits the coordination of a visible‐light‐activatable chiral‐at‐rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Alkylprop‐2‐enenitriles

The outcome of the photocycloaddition of cyclohex‐2‐enones to 2‐alkylprop‐2‐enenitriles differs basically from that of the corresponding 2‐alkylbut‐1‐en‐3‐ynes. While the latter afford mainly products resulting from 1,6‐cyclization of the intermediate triplet alkyl‐(prop‐2‐ynyl) 1,4‐biradical, the former give only cyclobutanecarbonitriles resulting from 1,4‐cyclization of the singlet alkyl‐cyanoalkyl 1,4‐biradical.     

3(2H)isoquinolones. 2. Studies on the structure and formation of aminonaphthols obtained in the preparation of 3(2H)isoquinolones

The reaction of a 2-acylphenylacetic acid derivative (I) with primary amines in glacial acetic acid produces novel, colorless aminonaphthols (III) which are isomeric with the brilliant yellow 3(2H)isoquinolones (II) obtained in the same reaction. A combination of chemical and spectral techniques allowed identification of the isomers as derivatives of 4-amino-2-naphthol. A plausible mechanism of formation of aminonaphthols versus 3(2H)isoquinolones is discussed and supported by chemical synthesis of N-substituted 2-aeylphenylacetamides (VIII) and a 1,4-dihydro-1-hydroxy-3(2H)isoquinolone derivative (IX).     

A Chiral Thioxanthone as an Organocatalyst for Enantioselective [2+2] Photocycloaddition Reactions Induced by Visible Light

Thioxanthone 1 , which was synthesized in a concise fashion from methyl thiosalicylate, exhibits a significant absorption in the visible light region. It allows for an efficient enantioselective catalysis of intramolecular [2+2] photocycloaddition reactions presumably by triplet energy transfer.     

Microwave‐Assisted Synthesis of Heterocycles by Rhodium(III)‐Catalyzed Annulation of N‐Methoxyamides with α‐Chloroaldehydes

α‐Chloroaldehydes have been used as alkyne equivalents in rhodium‐catalyzed syntheses of isoquinolones and 3,4‐dihydroisoquinolins starting from N ‐methoxyamides. Compared to the existing technology, a complementary regioselectivity is achieved. Mechanistic investigations have been performed, and it was found that steric effects of both substrate and additive determine the product selectivity. Various other heterocycles, such as isoquinolines and lactones, can be prepared by transformation of the obtained products.