Ab-initio electrostatic molecular potential contour maps for initiation step and Ab-Initio MRD-CI calculations for propagation step of cationic polymerization of oxetanes

The initiation step in the cationic polymerization of cyclic ethers is influenced by basicity and ring strain. We carried out ab-initio MODPOT/VRDDO/MERGE calculations on a variety of substituted oxetanes and generated electrostatic molecular potential contour (EMPC) maps in three-dimensions around the molecules. The size of the negative EMPC map region around the oxygen enabled us to predict the propensity to polymerize prior to the syntheses of the actual monomers themselves. We carried out ab-initio MODPOT/VRDDO/MERGE MRD-CI calculations for the propagation step of oxetane reacting with protonated oxetanes to cause ring opening of protonated oxetane. Similar MRD-CI calculations on variously substituted oxetanes will shed insight into relative copolymerization preferences.     

Cu(OTf)2/NBS Promoted Cyclization of 1-Cinnamyl Alcohol-o-Carboranes: An Efficient Approach for Synthesis of o-Carboranes Substituted Oxetanes

The Cu(OTf)₂/NBS promoted cyclization of 1-cinnamyl alcohol-o-carboranes for synthesis of o-carborane substituted oxetanes has been developed. A series of substituted oxetanes has been synthesized with moderate to good yields, which would be an important synthon for design novel reactions in oxetane chemistry as well as carborane chemistry.     

Synthetic Reactions Using Low‐valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O‐i‐Pr or Cl) in the Presence of Me3SiCl and Mg

In the presence of Me₃SiCl, Ti(OR)₄ or CpTiX₃ (X = O‐i‐Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low‐valent titanium (LVT) species that mediates several synthetic reactions. The LVT‐catalyzed C–O bond‐cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O‐allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N–S or O–S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra‐ and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT‐mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino‐pinacol coupling of imines is mediated by the LVT to provide 1,2‐diamines.     

Hydroxy-assisted catalyst-free Michael addition-dehydroxylation of Baylis-Hillman adducts in poly(ethylene glycol)

Intramolecular hydrogen bonding facilitates nucleophilic addition of sulfones to Baylis-Hillman adducts in a single step to realize the substituted allyl sulfones. The reaction is performed in PEG (400 MW) as solvent, which allows easy solvent recycling.     

A ring opening reaction of oxetanes with lithium acetylides promoted by boron trifluoride etherate

Several substituted oxetanes were treated with lithium acetylides in the presence of boron trifluoride etherate to give f-hydroxyacetylenes. The reaction conditions were varied and several synthetic features of the present reaction were revealed.     

Oxetanes as versatile elements in drug discovery and synthesis

Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.     

Synthesis of Di‐, Tri‐, and Tetrasubstituted Oxetanes by Rhodium‐Catalyzed OH Insertion and CC Bond‐Forming Cyclization

Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2‐dicarboxylates were accessed in high yields, including functionalized 3‐/4‐aryl‐ and alkyl‐substituted oxetanes and fused oxetane bicycles. Enantioenriched alcohols provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry.     

Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: potential scaffolds for peptide mimetics

The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to alpha- or beta-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.     

Synthesis of Di‐, Tri‐, and Tetrasubstituted Oxetanes by Rhodium‐Catalyzed O?H Insertion and C?C Bond‐Forming Cyclization

Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of oxetane rings incorporating pendant functional groups is described. A wide variety of oxetane 2,2‐dicarboxylates were accessed in high yields, including functionalized 3‐/4‐aryl‐ and alkyl‐substituted oxetanes and fused oxetane bicycles. Enantioenriched alcohols provided enantioenriched oxetanes with complete retention of configuration. The oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry.     

Directed ring-opening of 1,5-dioxaspiro[3.2]hexanes: selective formation of 2,2-disubstituted oxetanes

1,5-Dioxaspiro[3.2]hexanes undergo ring-opening reactions with many heteroatom nucleophiles to provide alpha-substituted-beta'-hydroxy ketones. However, certain Lewis acidic nucleophiles provide 2,2-disubstituted oxetanes. Herein, the results of reactions of 3-phenyl-1,5-dioxaspiro[3.2]hexane with a variety of nitrogen-containing heteroaromatic bases are reported. There appears to be a correlation between the pK(a) of the nucleophile and the reaction outcome with more acidic nucleophiles providing 2,2-disubstituted oxetanes. Moreover, the mode of ring opening can be directed toward the substituted oxetane by the addition of a Lewis acid. These results are rationalized by calculation of stationary points on the potential energy surfaces for the various possible reaction pathways using ab initio molecular orbital methods.     

Photochemical access to tetra- and pentacyclic terpene-like products from R-(+)-sclareolide

Fused tetracyclic oxetanes 4, highly substituted cyclobutenes 6, and the pentacyclic derivatives 7 and 8 were obtained by irradiation of derivatives 3 that were prepared from commercial R-(+)-sclareolide (1) in three steps. Compounds 4 are formed through a Paterno-Büchi reaction, while tricyclic derivatives 6 are the fragmentation products of the first formed oxetanes. In clear contrast, cyclopentenyl and 3-furyl derivatives, 3e and 3f, gave the [2+2] adducts, namely pentacyclic derivatives 7 and 8. All the reported reactions are totally regio- and stereoselective, with the exception of the cyclization of furyl derivative 3f, which gave the mixture of both the crossed (7b) and the right (8) isomers.     

“Kick‐Starting” oxetane photopolymerizations

In the presence of small amounts of 2,2‐dialkyl‐, 2,2,3‐trialkyl‐, or 2,2,3,3‐tetraalkyl substituted epoxides such as isobutylene oxide, 1,2‐limonene oxide, and 2,2,3,3,‐tetramethyl oxirane, the photoinitiated cationic ring‐opening polymerizations of 3,3‐disubstituted oxetanes are dramatically accelerated. The acceleration affect was attributed to an increase in the rate of the initiation step of these latter monomers. Both mono‐ and disubstituted oxetane monomers are similarly accelerated by the above‐mentioned epoxides to give crosslinked network polymers. The potential for the use of such “kick‐started” systems in applications such as coatings, adhesives, printing inks, dental composites and in three‐dimensional imaging is discussed. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2934–2946     

A new and practical PIFA-promoted olefin amidohydroxylation: six- versus five-membered ring formation

A novel access to the isoindolinone and isoquinolin-2-one skeletons from adequately substituted aromatic precursors is described. The key intramolecular cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the corresponding vinyl or allyl substituted N-(p-methoxyphenyl)benzamide derivatives leading to the heterocyclic compounds through 5-exo-trig and 6-exo-trig processes, respectively.     

Towards bis(acylsilanes) and cyclic unsaturated acylsilanes via metathesis: an exploratory study

New acyl(allyl)- and acyl(vinyl)silanes have been synthesized in order to explore cross metathesis or ring-closing metathesis as a new way towards bis(acyl)silanes or unsaturated cyclic acylsilanes, respectively. Metathesis from acylsilanes did not work but their precursors, in particular in benzotriazol series, proved to be good candidates. Two new benzotriazolyl substituted silacyclic compounds (tetrahydrosiline and dihydrosilol) were thus prepared by RCM. Their conversion into the corresponding acylsilane failed. In contrast, the preparation of a bis(acylsilane) bearing the silicon atoms in internal position was achieved by a two-step sequence: cross metathesis of an allyl(dimethylsilyl) benzotriazolyl intermediate-hydrolysis.     

The Paternò-Büchi reaction—Mechanisms and application to organic synthesis

The [2 + 2] photocycloaddition between an electronically excited carbonyl compound and an alkene leading to oxetanes (Paternò-Büchi reaction) is one of the most investigated organic photochemical reaction. Regio-, stereo- and site selectivities are discussed as a consequence of the reaction mechanism. Spin multiplicity and electron transfer have a significant impact on the outcome of the reaction. Typical carbonyl and alkene reaction partners are presented indicating scope and limitation of the reaction. The Paternò-Büchi reaction possesses particular interest for being applied to organic synthesis, considering the difficulty for non-photochemical reactions to obtain oxetanes, with or without stereoselectivity. Mechanistic details are particularly focused. It has been applied as key step in various multi-step syntheses.     

An isomerization—claisen rearrangement route to olefinic dicarbonyl starting materials for conjugate cyclization

Unsaturated dicarbonyl compounds which are useful in conjugate cyclization processes are synthesized by a route which makes use of a sequential isomerization and Claisen rearrangement of the allyl ether of a substituted allyl alcohol.     

Titanocene catalyzed opening of oxetanes

The reductive opening of oxetanes by Cp₂TiCl was investigated by a combined synthetic and computational study. The activation and reaction energies predict a more difficult reaction than the related epoxide opening. Synthetically, the γ-titanoxy radicals obtained behave like typical free radicals. Their reactions are not controlled by the metal and its ligands. This is highlighted by the dimerization of phenyl substituted oxetane derived radicals.     

A Convenient and Versatile Method for the Preparation of α‐Hydroxymethyl Ketone Derivatives from the Corresponding Allyl Silyl Ethers or Allyl Carboxylates

The ozonolysis of 1‐substituted allyl silyl ethers or 1‐substituted allyl carboxylates followed by treatment with bases gave the corresponding α‐silyloxymethyl‐ or α‐acyloxymethyl‐ketones in good yields. It is proposed to proceed via the corresponding α‐silyloxy‐ or α‐acyloxyaldehydes intermediates followed by 1,4‐group migration. The results of theoretical calculations are applicable to explain the experimental results.     

Addition of organochromium reagents to heteroaryl aldehydes. Synthesis of heteroaryl substituted bis-allyl ethers and homoallyl ethers

Heteroaryl substituted allyl and homoallyl alcohols were synthesised with two different method. Synthesis of bis-allyl ethers and homoallyl ethers were carried out via reaction of allyl bromide with allyl alcohols and homoallyl alcohols, respectively. [2.3]-Wittig Rearrangement reactions of heteroaryl substituted bis-allyl ethers were investigated using GC/MS techniques. In these reactions two unexpected products were isolated in high yield.     

Allylation of erythromycin derivatives: introduction of allyl substituents into highly hindered alcohols

Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using substituted allyl tert-butyl carbonates under palladium(0) catalysis. This allylation works well where traditional ether-forming protocols function poorly. Allyl tert-butyl carbonates provide higher yields in this reaction than lesser substituted carbonates such as ethyl or isopropyl. Aryl-substituted allyl carbonates or carbamates may be employed as well and, when used, produce trans-olefinic products.