1,5-Diazabicyclo[3.1.0]hexanes and 1,6-diazabicyclo[4.1.0]heptanes: a new method for the synthesis,quantum-chemical calculations,and X-ray diffraction study

A new method was developed for the synthesis of 6-substituted 1,5-diazabicyclo[3.1.0]hexanes and 7-substituted 1,6-diazabicyclo[4.1.0]heptanes by condensation of N-monohalotrimethylene- and N-monohalotetramethylenediamines with carbonyl compounds in the presence of bases. X-ray diffraction studies and quantum-chemical B3LYP/6-31G* calculations demonstrated that the conformations of the resulting bicyclic systems are stabilized by stereoelectronic interactions. As a result, a boat conformation prevails in 1,5-diazabicyclo[3.1.0]hexanes, whereas the energies of chair, half-chair, and boat conformations of 1,6-diazabicyclo[4.1.0]heptanes are equalized.     

Palladium-Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio-, Diastereo-, and Enantioselective Construction of Benzofuro[3,2-b]azepine Skeletons

The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.     

Nitrogen is a requirement for the photochemical induced 3-azabicyclo[3.3.1]nonane skeletal rearrangement!

Specific 3-azabicyclo[3.3.1]nonane derivatives undergo skeletal cleavage when subjected to light or Lewis acidic conditions affording novel heterotricycles, which is in stark contrast to 3-oxabicyclo[3.3.1]nonanes.     

Lewis acid catalyzed reactions of methylenecyclopropylcarbinols with acetals for the construction of 3-oxabicyclo[3.1.0]hexane derivatives

Reactions of methylenecyclopropylcarbinols 1 with acetals 2 in the presence of Lewis acid Sc(OPf)₃ produce the ring-closure products 3-oxabicyclo[3.1.0]hexane in moderate to high total yields along with the products in trans-configuration as the sole or major one. The plausible reaction mechanism has been discussed, which is based on the Prins-type reaction mechanism.     

An efficient stereoselective synthesis of 1-iodo- or 1-phenyl selenenyl-2-aryl-3-azabicyclo[3.1.0]hexane via electrophilic cyclization of benzyl-2-arylmethylidenecyclopropylmethyl-amines

The reaction of benzyl-2-arylmethylidenecyclopropylmethyl-amine 1 with iodine in the presence of potassium carbonate or PhSeBr stereoselectively gives ring-closure product 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexane or 1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]hexane in good yields at room temperature. A plausible reaction mechanism has been proposed.     

One-pot assembly of 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes from alkyl aryl(hetaryl) ketoximes, acetylene, and aliphatic ketones: a new three-component reaction

A new three-component reaction between alkyl aryl(hetaryl)ketoximes, acetylene, and aliphatic ketones in the superbasic systems KOH/DMSO and LiOH/CsF/DMSO (70-90 °C, initial acetylene pressure 13-15 atm, 5-60 min) affords novel 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes in yields of up to 75%. Using KOH/DMSO, the side products of the reaction are O-vinylketoximes and 2-aryl(hetaryl)pyrroles, while with LiOH/CsF/DMSO, the reaction proves to be selective, only minor amounts of the corresponding alkyl aryl(hetaryl) ketones being detectable.     

苯酚(醌)与烯烃的不对称[3+2]环化反应: 手性二氢苯并呋喃的合成进展

二氢苯并呋喃结构单元广泛存在于具有良好生物活性和药用价值的天然产物之中, 因而引起了有机合成化学家和药物化学家们的关注. 针对该结构单元所包含的C2和C3邻二立体中心的对映选择性构建, 也是目前有机合成方法学研究的挑战性问题之一. 在众多解决方案中, 以苯酚(醌)与烯烃为底物, 具体采用催化不对称和手性辅剂诱导的[3+2]环化两种方式, 可以构建具有光学活性的二氢苯并呋喃结构单元. 本综述将不同类型的手性催化剂和手性辅剂进行分类梳理, 介绍了近年来不对称[3+2]环化反应的发展, 并重点剖析其中涉及的立体选择性控制. 同时, 简要介绍了该关键方法在二氢苯并呋喃天然产物合成中的应用. 为了启发更加高效和普适性的新催化体系出现, 最后总结和展望了不对称[3+2]环化反应的发展趋势.     

Azabicyclo[3.1.0]hexane-1-ols as frameworks for the asymmetric synthesis of biologically active compounds

Azabicyclo[3.1.0]hexane-1-ols, easily obtained by Ti(IV)-mediated cyclopropanation of amino acid derivatives, constitute versatile, and unprecedented intermediates for the asymmetric synthesis of pharmacologically active products. Indeed, through selective rearrangement, these compounds undergo unusual ring cleavage to lead to pyrrolidinones. Fe(III)-promoted ring opening followed by basic dehydrohalogenation furnishes optically active dihydropyridinones, while Ce(IV)-promoted ring opening provides chiral tricyclopiperidinones via a radical process.     

8-Azabicyclo[3.2.1]oct-3-en-2-ones via asymmetric 1,3-dipolar cycloaddition of a homochiral 3-oxidopyridinium betaine

8-Azabicyclo[3.2.1]oct-3-en-2-ones were prepared by asymmetric 1,3-dipolar cycloadditions of homochiral pyridinium betaine 4. Excellent diastereofacial selectivity was achieved for the major 6-exo cycloadducts. The absolute stereochemistry of cycloadduct 7 was confirmed by a single-crystal X-ray diffraction study.     

Cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from N-allyl enamines

An efficient iodine-mediated cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from easily prepared N-allyl enamines has been developed. The advantages of the reaction include facilitative preparation of substrates 3a–t, good functional group tolerance and transition-metal-free conditions.     

Development of Bicyclo[3.1.0]hexane-Based A3 Receptor Ligands: Closing the Gaps in the Structure–Affinity Relationships

The adenosine A₃ receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5′-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure–affinity relationships. The most potent derivative 30 displayed moderate A₃AR affinity (Ki of 0.38 μM) and high A₃R selectivity. A subset of compounds varied at 5′-position was further evaluated in functional P2Y₁R assays, displaying no off-target activity.     

Palladium-catalyzed one-pot synthesis of benzo[b][1,6]naphthyridines via Sonogashira coupling and annulation reactions from 2-chloroquinoline-3-carbonitriles

Palladium-catalyzed one-pot synthesis of 1,3-disubstituted benzo[b][1,6]naphthyridines and [1,6]naphthyridines has been described from easily accessible precursors, 2-chloroquinoline-3-carbonitriles and 2-chloropyrido-3-carbonitrile via sequential additions of palladium-catalyst for Sonogashira-coupling and the following annulations in good to excellent yields. A plausible mechanism for annulation is discussed.     

Studies toward the construction of substituted piperidine-2-ones and pyridine-2-ones from Baylis-Hillman adducts: discovery of a facile synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates

Studies toward the construction of functionalized piperidone derivatives from derivatives of Baylis-Hillman adducts are described. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthesis of 4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates.     

Construction and investigation of photo-switch property of azobenzene-bridged pillar[5]arene-based [3]rotaxanes

Series of azobenzene-bridged pillar[5]arene-based [3]rotaxanes with different alkyl chain length of guest molecules were constructed by threading-endcapping method with alkylenetriazole as axile and tetrahydrochromene as endcapping group.The encapsulation of pillar[5]arenes were proved by highresolution mass,¹ H NMR and NOESY spectra.The photo-responsive property were examined by irradiation of the synthesized [3]rotaxanes with 365 nm and blue light LED,which caused trans to cis and cis to trans isomerization,respectively.Irradiation of corresponding model guest compounds without pillar[5]arene encapsulation resulted in near completely trans to cis and cis to trans isomerization,indicating the existence of pillar[5]arenes is the determining factor for the comprised photo isomerization efficiency.     

Oxidative Cyclization of 5H-Chromeno[2,3-b]pyridines to Benzo[b]chromeno[4,3,2-de][1,6]naphthyridines,Their NMR Study and Computer Evaluation as Material for LED

Oxidative cyclization is one of the most significant reactions in organic synthesis. Naphthyridine derivatives are often used as luminescence materials in molecular recognition because of their rigid planar structure and as new drugs. Organic light-emitting diodes (OLEDs) have rapidly grown as one of the leading technologies for full-color display panels and eco-friendly lighting sources. In this work, we propose the synthesis of previously unknown benzo[b]chromeno[4,3,2-de][1,6]naphthyridines via intermolecular oxidative cyclization of 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines in formic acid. The investigation of the reaction mechanism using ¹H-NMR monitoring made it possible to confirm the proposed mechanism of the transformation. The structure of synthesized benzo[b]chromeno[4,3,2-de][1,6]naphthyridines was confirmed by 2D-NMR spectroscopy. Such a rigid geometry of synthesized compounds is desired to minimize non-radiative energy losses in OLEDs. The quantum chemical calculations are also presented in the study.     

Highly Concise Synthesis of 3'-"Up"-ethynyl-5'-methylbicyclo-[3.1.0]-hexyl Purine and Pyrimidine Nucleoside Derivatives Using Rhodium(II) Carbenoid Cycloaddition and Highly Diastereoselective Grignard Reaction

Synthesis of north‐5'‐methylbicyclo[3.1.0]hexyl purine and pyrimidine nucleosides with an ethynyl group at C‐3' position has been successfully accomplished by a facile method. Methylbicyclo[3.1.0]hexanone (±)‐ 5 having three contiguous chiral centers was remarkably simply constructed only by four steps containing a carbenoid insertion reaction in the presence of rhodium(II) acetate dimer and CuSO₄, giving a correct relative stereochemistry of the generated three chiral centers. Upon Grignard reaction of (±)‐ 5 with ethynylmagnesium bromide, exclusive diastereoselectivity was observed. Condensation of glycosyl donor (±)‐ 9 with purine nucleobase afforded only the desired N⁹‐alkylated nucleoside, while condensation with pyrimidine, N³‐benzoylated uracil gave the desired N¹‐alkylated nucleoside (±)‐ 13 with the undesired O²‐alkylated nucleoside (±)‐ 14 . Probably, (±)‐ 14 would be formed due to steric hindrance caused upon approaching for N¹‐alkylation.     

Synthesis and Photochromic Properties of New Heterocyclic Derivatives of 1,3‐Diazabicyclo[3.1.0]Hex‐3‐Ene

The facile synthesis of several 1,3‐diazabicyclo[3.1.0]hex‐3‐ene derivatives with varying substitutions such as 2‐methyl‐6‐(4‐nitrophenyl)‐2,4‐diphenyl‐( 1 ), 2‐methyl‐6‐(4‐nitrophenyl)‐4‐phenyl‐2‐(pyridin‐3‐yl)‐( 2 ), 2‐(furan‐2‐yl)‐6‐(4‐nitrophenyl)‐4‐phenyl‐( 3 ), 2‐(furan‐2‐yl)‐6‐(3‐nitrophenyl)‐4‐phenyl‐( 4 ), 6‐(3‐nitrophenyl)‐2,4‐diphenyl‐( 5 ) and 6‐(4‐chlorophenyl)‐4‐(3‐nitrophenyl)‐2‐phenyl‐( 6 ) that all behave as “intelligent materials” are reported.     

Palladium‐Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio‐, Diastereo‐, and Enantioselective Construction of Benzofuro[3,2‐b]azepine Skeletons

The palladium‐catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran‐derived azadienes furnishes chiral benzofuro[3,2‐b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd‐trimethylenemethane can enrich the arsenal of Pd‐TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition‐metal‐catalyzed asymmetric [4+3] cyclization.     

Simple synthesis of substituted 3-oxabicyclo[3.1.0]hexan-2-ones and their rearrangement in the presence of lithium iodide

2-Alkenylidenemalonic ester monoepoxides react with organolithium and organomagnesium compounds to give 1-ethoxycarbonyl-4-alkyl-6-alkenyl(alkyl, aryl, alkynyl)-3-oxabicyclo[3.1.0]hexan-2-ones in high yields. The latter, when an alkenyl fragment is present, undergo rearrangement in the presence of LiI to substituted 1-ethoxycarbonyl-3-oxabicyclo[3.3.0]-6-octen-2-ones or 3-(1,3-butadienyl)-4-butanolides.Institute of Chemistry, Bashkir Science Center, Ural Branch, Russian Academy of Sciences, Ufa 450054. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 4, pp. 946–954, April, 1992.