Determination of Alkylphenols Originated from Alkylphenol Ethoxylates by Cleavage Treatment Combined with GC-MS

A chemical cleavage technique was developed for the determination of alkylphenol ethoxylates (APEOs) in environmental samples involving the conversion of APEOs to alkylphenols (APs). Aluminum triiodide (AlI₃) and trimethylsilyl iodide were selected as cleavage reagents and the former was found to be highly reactive and suitable. With AlI₃ as cleavage reagent, nonylphenol ethoxylates (NPEOs) and octylphenol ethoxylates (OPEOs) were equivalently converted to the corresponding origins—nonylphenol (NP) and octylphenol (OP), which were detected by gas chromatography—mass spectrometry (GC-MS). The cleavage process was completed under refluxing condition. Water and methanol influenced the cleavage reaction significantly and should be removed prior to the cleavage reaction. The analytical approach was applied for the estimation of APEOs contents in wastewater by normalizing to APs and presented satisfactory recovery and reproducibility. This cleavage technique provides a common and reliable means to assess the environmental significance of samples contaminated by APEOs based on the presence of APs.     

2-Trimethylsilylethyl sulfides in the von Braun cyanogen bromide reaction: selective preparation of thiocyanates and application to nucleoside chemistry

Mixed 2-(trimethylsilyl)ethyl sulfides were synthesized and used in the von Braun cyanogen bromide reaction for preparing selectively thiocyanates in high yield. We show here that this cleavage reaction is highly selective in methanol in comparison with the reaction of the corresponding non-silyl sulfide analogues. This reaction was applied to the synthesis of nucleosidic thiocyanates such as the new nucleosides 14 and 18 in the search for mechanism-based inhibitors of ribonucleoside diphosphate reductase and bioactive molecules. The selective cleavage is possible for sulfides bearing hydroxyl functions and aromatic rings. The reactions of cyanogen bromide as cyanating and brominating agent were observed for the first time under the same conditions with the naphthoxyhexyl 2-trimethylsilylethyl sulfide 7, which, treated with cyanogen bromide in dichloromethane, led selectively to the p-bromonaphthoxyhexyl thiocyanate 10 in 89% yield. Another reaction induced by cyanogen bromide was observed in dichloromethane with the 2-(trimethylsilylethyl)thio nucleoside 13, which gives the corresponding symmetrical disulfide 21 in good yield.     

Direct lactonization of alkenols via osmium tetroxide-mediated oxidative cleavage

[reaction: see text] A highly efficient, mild, and simple protocol is presented for the tandem OsO(4)-mediated oxidative cleavage/oxidative lactonization of alkenols to lactones. The protocol couples the OsO(4)-catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of aldehydes in alcoholic solvents to their corresponding esters.     

Autoxidation of 4-amorphen-11-ol and the biogenesis of nor- and seco-amorphane sesquiterpenes from fabiana imbricata

Photooxidation of 4-amorphen-11-ol (1), recently reported as one of the major sesquiterpene natural products from the medicinal plant Fabiana imbricata, results in three allylic hydroperoxides 6, 9 and 10, which are expected from the “ene-type” reaction of molecular oxygen with the tri-substituted double bond in 1. The tertiary allylic hydroperoxide 6 undergoes carbon-carbon bond cleavage and a second autoxidation reaction to yield the more highly oxygenated seco-amorphane 11 under very mild conditions. In acid, this compound may then undergo either a second carbon-carbon bond cleavage reaction to yield nor-sesquiterpenes 2 and 3 (reported as bona fide natural products from F. imbricata, or cyclize to the sesquiterpene peroxofabianane (5), which is a presumed precursor to the natural product fabianane (4). Some mechanistic investigations concerning the two chemical processes: viz:- carbon-carbon bond cleavage and autoxidation which would account for the formation of natural products 2, 3 and 4 from 1 are reported. Tertiary allylic hydroperoxide 32, which lacks the 11-hydroxyl functional group present in 1 undergoes only C-4/C-5 carbon-carbon bond cleavage under more forcing conditions, suggesting a role for this functional group in assisting the autoxidation reactions of 4-amorphen-11-ol.     

Acid/base-regulated reversible electron transfer disproportionation of N–N linked bicarbazole and biacridine derivatives

Regulation of electron transfer on organic substances by external stimuli is a fundamental issue in science and technology, which affects organic materials, chemical synthesis, and biological metabolism. Nevertheless, acid/base-responsive organic materials that exhibit reversible electron transfer have not been well studied and developed, owing to the difficulty in inventing a mechanism to associate acid/base stimuli and electron transfer. We discovered a new phenomenon in which N–N linked bicarbazole (BC) and tetramethylbiacridine (TBA) derivatives undergo electron transfer disproportionation by acid stimulus, forming their stable radical cations and reduced species. The reaction occurs through a biradical intermediate generated by the acid-triggered N–N bond cleavage reaction of BC or TBA, which acts as a two electron acceptor to undergo electron transfer reactions with two equivalents of BC or TBA. In addition, in the case of TBA the disproportionation reaction is highly reversible through neutralization with NEt₃, which recovers TBA through back electron transfer and N–N bond formation reactions. This highly reversible electron transfer reaction is possible due to the association between the acid stimulus and electron transfer via the acid-regulated N–N bond cleavage/formation reactions which provide an efficient switching mechanism, the ability of the organic molecules to act as multi-electron donors and acceptors, the extraordinary stability of the radical species, the highly selective reactivity, and the balance of the redox potentials. This discovery provides new design concepts for acid/base-regulated organic electron transfer systems, chemical reagents, or organic materials.     

A kinetic and thermodynamic study of the glycosidic bond cleavage in deoxyuridine

Density functional theory was used to study the thermodynamics and kinetics for the glycosidic bond cleavage in deoxyuridine. Two reaction pathways were characterized for the unimolecular decomposition in vacuo. However, these processes are associated with large reaction barriers and highly endothermic reaction energies, which is in agreement with experiments that suggest a (water) nucleophile is required for the nonenzymatic glycosidic bond cleavage. Two (S(N)1 and S(N)2) reaction pathways were characterized for direct hydrolysis of the glycosidic bond by a single water molecule; however, both pathways also involve very large barriers. Activation of the water nucleophile via partial proton abstraction steadily decreases the barrier and leads to a more exothermic reaction energy as the proton affinity of the molecule interacting with water increases. Indeed, our data suggests that the barrier heights and reaction energies range from that for hydrolysis by water to that for hydrolysis by the hydroxyl anion, which represents the extreme of (full) water activation (deprotonation). Hydrogen bonds between small molecules (hydrogen fluoride, water, or ammonia) and the nucleobase were found to further decrease the barrier and overall reaction energy but not to the extent that the same hydrogen-bonding interactions increase the acidity of the nucleobase. Our results suggest that the nature of the nucleophile plays a more important role in reducing the barrier to glycosidic bond cleavage than the nature of the small molecule bound, and models with more than one hydrogen fluoride molecule interacting with the nucleobase provide further support for this conclusion. Our results lead to a greater fundamental understanding of the effects of the nucleophile, activation of the nucleophile, and interactions with the nucleobase for this important biological reaction.     

Bi(III) halides as efficient catalysts for the O-acylative cleavage of tetrahydrofurans: an expeditious entry to tetralins

The mild (DCM/20 °C), quantitative, regioselective, O-acylative cleavage of tetrahydrofurans using organic acid halides with catalytic Bi(III) halides is reported. X-ray crystallography is used to rationalise the failure of the reaction in the case of certain crowded acid chlorides, and a useful aspect of chemoselectivity is revealed. The synthetic potential of this reaction is illustrated with a highly efficient O-acylative cleavage/intramolecular alkylation approach to tetralins.     

RuBisCO‐Inspired CO2 Activation and Transformation by an Iridium(I) Complex

The synthesis of a new iridium(I) complex containing an enamido phosphine anion (dbuP^?) and its unique reactivity with CO₂ is reported. The complex binds two equivalents of CO₂ and initiates a highly selective reaction cascade. The reaction leads to the reversible cleavage of CO₂ and the enamido ligand as well. Computational analysis points to the existence of a relatively stable Ir‐CO₂ complex as a reaction intermediate prior to CO₂ cleavage, which was confirmed experimentally. The observed transformation resembles several aspects of enzymatic CO₂ fixation by RuBisCO.     

A solvolytic C-C cleavage reaction of 6-acetoxycyclohexa-2,4-dienones: mechanistic implications for the intradiol catechol dioxygenases

6-Acetoxycyclohexa-2,4-dienones are found to undergo a rapid reaction in methanol/water under mildly basic conditions to give an acyclic ketoester as the major product for 6-phenyl and 6-methyl substrates. Reaction monitoring by UV spectroscopy indicates the formation of an unsaturated ketone reaction intermediate (lambda(max) 275 nm, R = Ph) and the transient appearance of a highly conjugated species. Reaction of the 6-phenyl substrate (4.95 x 10(-6) s(-1)) is 2-fold faster than the 6-methyl substrate (2.47 x 10(-6) s(-1)). The reaction rate is first order with respect to substrate concentration, and the final step in the reaction is pH-dependent. No cleavage was observed for a substrate lacking an acetyl substituent. A reaction mechanism for C-C cleavage is proposed involving a benzene oxide-oxepin interconversion. The possible relevance to the catalytic mechanism of the intradiol catechol dioxygenases is discussed.     

Synthesis of enantiomerically enriched tertiary 2-cyclohexene-1-thiols via configurationally stable alpha-thio-substituted allyllithium compounds

[reaction: see text] (S)-S-(2-Cyclohexenyl) N,N-diisopropylmonothiocarbamate [(-)-(S)-8] was deprotonated by sec-butyllithium/TMEDA to form a configurationally stable lithium compound (S)-9, which is the first example of a new class of alpha-thio-substituted organolithium compounds with improved properties. It is regioselectively alkylated by alkyl halides with complete stereoinversion to form the monothiocarbamates (+)-10 which afford highly enantioenriched tertiary 2-cyclohexene-1-thiols (+)-6 on reductive cleavage.     

Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan

A new asymmetric entry of the 1,2-aza-Friedel-Crafts reaction catalyzed by a chiral phosphoric acid is described. The present reaction has provided an atom-economical route to furan-2-ylamine derivatives in a highly enantioselective fashion. The synthetic utility of these products was displayed by oxidative cleavage of the furan ring (aza-Achmatowicz reaction) to form a 1,4-dicarbonyl compound that could be further derivatized to a chiral gamma-butenolid.     

Palladium-Catalyzed Enantio- and Regioselective Ring-Opening Hydrophosphinylation of Methylenecyclopropanes

Transition metal-catalyzed hydrofunctionalization of methylenecyclopropanes (MCPs) has presented a considerable challenge due to the difficult manipulation of regioselectivity and complicated reaction patterns. Herein, we report a straightforward Pd-catalyzed ring-opening hydrophosphinylation reaction of MCPs via highly selective C−C bond cleavage. This method allows for rapid and efficient access to a wide range of chiral allylic phosphine oxides in good yields and high enantioselectivities. Additionally, density functional theory (DFT) calculations were performed to elucidate the reaction mechanism and the origin of enantioselectivity.     

Synthesis of methyl epijasmonate and cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one

A novel and efficient synthesis of both (±)-methyl epijasmonate and (±)-cis-3-(2-oxopropyl)-2-(pent-2Z-enyl)-cyclopentan-1-one is described. The key step to establish the cis-stereochemistry on the 5-membered ring is an ionic Diels–Alder reaction, which is high yielding and highly regioselective. Subsequent key steps include oxidative cleavage of the six-membered ring, Wittig coupling and for the synthesis of epijasmonate, the haloform reaction.     

Synthesis of 4a-carba-alpha-D-lyxofuranose from 2,3-O-isopropylidene-L-erythruronolactone via Tebbe-mediated cascade reaction

A new, efficient and highly diastereoselective approach for the synthesis of 1,2,3,5-tetraacetylcarba-alpha-D-lyxofuranose from D-ribose is reported via one-pot conversion of to using Tebbe reagent which involves a cascade reaction sequence of methylenation, cleavage of isopropyl group, carbocyclization and again methylenation.     

A synthetic approach toward nitiol: construction of two 1,22-dihydroxynitianes

Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric hydroxylated derivatives, the 1,22-dihydroxynitianes. Key stereodefining steps in the construction of the A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction, a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps. The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural products, nitiol and variculanol, was completed.     

Solid-phase intramolecular N-acyliminium Pictet-Spengler reactions as crossroads to scaffold diversity

A novel solid-phase intramolecular Pictet-Spengler reaction is presented. The approach utilizes masked aldehyde building blocks protected as their N-Boc-1,3-oxazinanes for the clean generation of solid-supported aldehydes. When exposed to simple acidic treatment, the aldehyde functionality is rapidly released and becomes susceptible to nucleophilic attack from an amide nitrogen of the peptide backbone, which results in the formation of a highly reactive cyclic N-acyliminium ion. Subsequently, a quantitative and highly stereoselective Pictet-Spengler reaction takes place by attack of the indole from a neighboring tryptophan, thus appending two new N-fused rings to the indole moiety. Extension of this intramolecular reaction to substituted indoles, and other reactive heterocycles, such as furane and thiophenes, provides a convenient and rapid access to a range of pharmacologically interesting tri- and tetracyclic scaffolds. Finally, the reaction products may conveniently be released from the solid support (PEGA) by cleavage of the base-labile linker (HMBA).     

Stereoselective cycloadditions of chiral acyl-nitroso compounds; selective reactions of ring-cleaved cycloadducts leading to a new approach to polyoxamic acid

Diesters obtained from diacids produced by oxidative ring cleavage of cycloadducts derived from acyl-nitroso compounds and cyclic 1,3-dienes undergo highly regioselective hydrolysis on reaction with lithium hydroperoxide, which allows for easy differentiation of the carboxyl groups leading to a new approach to polyoxamic acid.     

Cleavage of a P=P Double Bond Mediated by N-Heterocyclic Carbenes

The reaction of the bulky diphosphenes (Rind)P=P(Rind) ( 1 ; Rind=1,1,3,3,5,5,7,7-octa-R-substituted s-hydrindacen-4-yl) with two molecules of N-heterocyclic carbene (NHC; 1,3,4,5-tetramethylimidazol-2-ylidene) resulted in the quantitative formation of the NHC-bound phosphinidenes NHC→P(Rind) ( 2 ), along with the cleavage of the P=P double bond. The reaction times are dependent on the steric size of the Rind groups (11 days for 2 a (R=Et) and 2 h for 2 b (R=Et, Me) at room temperature). The mechanism for the double bond-breaking is proposed to proceed via the formation of the NHC-coordinated, highly polarized diphospehenes 3 as an intermediate. Approach of a second NHC to 3 induces P−P bond cleavage and P−C bond formation, which proceeds through a transition state with a large negative Gibbs energy change to afford the two molecules of 2 , thus being the rate-determining step of the overall reaction with the activation barriers of 80.4 for 2 a and 29.1 kJ mol⁻¹ for 2 b .     

A Novel and Efficient Approach for the Combinatorial Synthesis of Structurally Diverse Pyrimidines on solid support

We describe a versatile novel approach for the synthesis of 2, 4, 6-trisubstituted pyrimidines on solid support. Thus, polymer-boun J thiouronium salt 2 reacted in high yield in a cyclocondensation reaction with the acetylenic ketones 3 to form, after tert-butyl-ester cleavage, the polymer-bound carboxylic acids 4 , which were cleaved by oxidation with 3-chloroperbenzoic acid and pyrrolidine to form the 2-pyrrolidinylpyrimidine-4-carboxylic acids 6a-c in high yields and purities without further purification (Scheme 1). Alternatively, acid 4a was subjected to an Ugi four-component condensation which gave the polymer-bound Ugi products 9a-e in good yields (Scheme 2). Multidirectional cleavage reaction of sulfone 8a with different nucleophiles resulted in the clean formation of pyrimidine-4-carboxamides 10–13 (Scheme 3). This strategy combines efficiently solid-phase chemistry with a multicomponent reaction and a multidirectional cleavage step to form highly diverse pyrimidines in a parallel array.     

Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives

A 2,3,4-tri-O-pivaloylated beta-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated alpha-amino acid amides. The reaction of the immobilized galactosylamine with aldehydes gave rise to the corresponding aldimines, which underwent a domino Mannich-Michael condensation reaction with Danishefsky's diene at ambient temperature to yield 2-substituted 5,6-didehydropiperidin-4-ones on the solid phase. Subsequent cleavage with tetra-n-butylammonium fluoride delivered the N-glycosylated products in high yields, purities, and diastereoselectivities. A chemoselective 1,4-hydride addition to the polymer-bound dehydropiperidinones was achieved in the presence of the bulky oxygenophilic Lewis acid methylaluminum [bis(2,6-di-tert-butyl-4-methylphenoxide)]. The conjugate addition of cyano-modified Gilman reagents to the immobilized dehydropiperidinones furnished 2,6-cis-substituted piperidine derivatives as the major diastereomers that were isolated after cleavage from the support.