Reaction of 2-methoxy-3H-azepine with NBS: efficient synthesis of 2-substituted 2H-azepines

[reaction: see text] The reaction of 2-methoxy-3H-azepines, in the presence or absence of a nucleophile, with N-bromosuccinimide (NBS) gave a regioselective 1,4-adduct from which the corresponding 2H-azepine derivatives were formed via base-promoted hydrogen bromide elimination, generally in moderate to quantitative yield. Competitive formation of 4-bromo-2-methoxy-3H-azepine by electrophilic substitutuion or 3H-azepin-2-yl 2H-azepin-2-yl ether by transetherification was minimized at lower reaction temperatures. Quantitative substitution of 2-(2',4',6'-trichlorophenoxy)-2H-azepine derivatives, formed in moderate yield from the respective 3H-azepine and NBS in the presence of 2,4,6-trichlorophenol (TCP), by various nucleophiles gave the corresponding 2-substituted 2H-azepine. Among these nucleophiles were alkanethiol and alkylamine that are not tolerated in the reaction of 3H-azepine and NBS.     

IPy2BF4-mediated rearrangements of 1,2-difunctionalized compounds and olefins

Acetal derivatives are easily obtained from 1,2-difunctionalized compounds by a new reaction mediated by IPy2BF4 with a mechanism based on a 1,2-migration of aryl or alkyl groups. A new oxidative rearrangement reaction of olefins is also described. Moreover, when this metal-free protocol is applied to cyclic olefins, interesting ring-contraction reactions are observed. The new methodologies described here are a clean and efficient alternative to known strategies that make use of potentially toxic metallic complexes.     

Palladium-catalyzed carbocyclization of allene-diene derivatives. Exploring different nucleophiles

The palladium-catalyzed carbocyclization of allene-diene derivatives leading to the stereospecific formation of various 4-substituted [4.3.0] and [5.3.0] bicyclic systems is presented. Different functionalities were introduced at the C-4 position of the bicyclic systems by using a range of external nucleophiles such as carboxylic acids, alcohols, phenols, and thiophenols. In the previous protocol acetic acid was used as solvent and also served as nucleophile. In this new methodology, reactions were run in nonnucleophlic solvents such as CH(2)Cl(2) or acetone in the presence of the appropriate nucleophile, making this new protocol a more versatile tool in organic synthesis. It is noteworthy that the Pd(II)-catalyzed cyclization of cycloheptadiene-derivative 1b gave exclusively the trans-annulated bicycle 4. Depending on the nature of the nucleophile, the regioselectivity of the reaction could be tuned to afford exclusively 4b or 4c' (Scheme 1). The mechanistic pathway is discussed.     

Nucleophilic substitution studies on nitroimidazoles,and applications to the synthesis of biologically active compounds

The rationalization of the synthesis of substituted analogs of megazol, a biologically active 5‐nitroimidazole at position 4 of the imidazole ring, had led to the study of intermediate steps. The methylation by diazomethane of 2,4‐(5)dihalogeno‐5‐(4)nitroimidazole is regioselective leading to 2,4‐dihalogeno‐1‐methyl‐5‐nitroimidazole 2. On this compound 2 , hard nucleophiles such as cyanide, methoxide or hydride anions react only with the halogen at the 2 position; whereas soft nucleophiles such as amine, thiol or trifluoromethyl anion from an organocopper species react only with the halogen at postion 4 in the intermediate 3b or compound 4b.     

Stereoselective and regioselective reaction of cyclic ortho esters with phenols

Cyclic ortho esters undergo stereoselective and regioselective reaction with phenols when treated with BF(3) x OEt(2) at low temperatures. Attack of the phenol on the ortho ester occurs at an open carbon para to electron-donating groups on the phenol ("C-addition") or at the phenolic hydroxyl group ("O-addition") depending on the nature of the cation formed from reaction of the ortho ester and BF(3) x OEt(2). Products resulting from O-addition undergo reversion to a mixture of starting phenol, C-addition product, and O-addition product if treated with BF(3) x OEt(2) at room temperature, but C-addition products are stable under the same conditions. X-ray structural analysis of the C-addition compound indicates that its stereochemistry is opposite to that observed in reaction of similar ortho esters with chloride from TMSCl. However, the stereochemistry of the reaction can be rationalized by the ability of the ortho ester to isomerize via an intermediate benzylic cation and examination of the preferred trajectory of attack of the nucleophile on the intermediate oxonium ion.     

An iron catalyzed regioselective oxidation of terminal alkenes to aldehydes

Fe(BF(4))(2)·6H(2)O with pyridine-2,6-dicarboxylic acid and PhIO can efficiently catalyze the regioselective oxidation of terminal alkene derivatives to aldehydes under mild and benign reaction conditions.     

Observation and mechanistic study of facile C-O bond formation between a well-defined aryl-copper(III) complex and oxygen nucleophiles

A well-defined macrocyclic aryl–Cu(III) complex (2) reacts readily with a variety of oxygen nucleophiles, including carboxylic acids, phenols and alcohols, under mild conditions to form the corresponding aryl esters, biaryl ethers and alkyl aryl ethers. The relationship between these reactions and catalytic C-O coupling methods is demonstrated by the reaction of the macrocyclic aryl–Br species with acetic acid and p-fluorophenol in the presence of 10 mol% Cu(I). An aryl-Cu(III)-Br species 2(Br) was observed as an intermediate in the catalytic reaction. Investigation of the stoichiometric C-O bond-forming reactions revealed nucleophile-dependent changes in the mechanism. The reaction of 2 with carboxylic acids revealed a positive correlation between the log(k(obs)) and the pK(a) of the nucleophile (less-acidic nucleophiles react more rapidly), whereas a negative correlation was observed with most phenols (more-acidic phenols react more rapidly). The latter trend resembles previous observations with nitrogen nucleophiles. With carboxylic acids and acidic phenols, UV-visible spectroscopic data support the formation of a ground-state adduct between 2 and the oxygen nucleophile. Collectively, kinetic and spectroscopic data support a unified mechanism for aryl-O coupling from the Cu(III) complex, consisting of nucleophile coordination to the Cu(III) center, deprotonation of the coordinated nucleophile, and C-O (or C-N) reductive elimination from Cu(III).     

Efficient intramolecular general acid catalysis of nucleophilic attack on a phosphodiester

The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate 4 and its reactions with a representative range of nucleophiles are catalyzed by the dimethylammonium group at acidic pH with rate accelerations of the order of 106. The reaction persists up to pH 7 because the strong intramolecular hydrogen bond, which is the key to efficient general acid catalysis, is present also in the reactant. The sensitivity to the basicity of the nucleophile (Br?nsted beta(nuc) = 0.29) lies between values measured previously for mono- and triesters. The comparisons suggest that general acid catalyzed reactions of phosphate mono- or diesters with strongly basic oxyanion nucleophiles (like those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation. Reactions with NH2OH and its N-methylated derivatives show an apparent alpha-effect, but NH2OMe reacts no faster than a primary amine of similar basicity. It is suggested that the reaction involving NH2OH as an oxygen nucleophile proceeds through the pre-equilibrium formation of the tautomer H3N+-O- as the active nucleophile: ab initio calculations support this idea.     

A new domino reaction based on [4+2]-cycloadditions of pyrido[1,2-a]pyrazines with azadienophiles

The reaction of pyrido[1,2-a]pyrazines 1 with nitroso compounds 2 provides pyridyl substituted 1,2,4-triazinones 4 via a domino reaction which involves a cycloaddition and a ring transformation reaction. The intermediate and regioselective formed oxadiazines 4′ were trapped by complexation yielding the (CO)₄Mo-complex 5. Derivatives of diazene such as N-phenyltriazolindione 6a , phthalazinedione 6b or esters of azodicarboxylic acid 6c-6f reacted with 1 to give different derivatives of 1,2,4-triazine 7a-f . The use of oxygen gave oxadiazinones 8 .     

Thiazolidine-2,4-dicarboxylic acid and its esters: Synthesis,in solution behaviour and regioselective cyclocondensation

Thiazolidine-2,4-dicarboxylic acid 2 was obtained as a diastereoisomeric mixture from the condensation of glyoxylic acid with L(-)R-cysteine 1 . In solution behaviour studies suggested that the reaction proceeded through an acid catalyzed epimerization mechanism. The methyl esterification of 2 was stereoselective, which can be explained by an interconversion of 2a via a ring seco intermediate. Condensation of the dimethyl ester 3 or the dissymmetric diester 4 with phenyl isocyanate gave rise to the same hydantoin 5 . N-acylation of diesters 3 or 4 followed by the reaction with benzylamine was regioselective leading to bicyclic derivatives 8-10 .     

Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols

Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinone-mediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a. On the other hand, enantioselective reaction of trisubstituted acetal rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)[bond]C(27) ansa-chain of rifamycin S.     

Catalytic synthesis of tricyclic quinoline derivatives from the regioselective hydroamination and C-H bond activation reaction of benzocyclic amines and alkynes

The cationic ruthenium-hydride complex [(PCy3)2(CO)(CH3CN)2RuH]+BF4- (1) was found to be an effective catalyst for the regioselective coupling reaction of benzocyclic amines and terminal alkynes to form the tricyclic quinoline derivatives. The scope of the reaction was explored by using the catalytic system Ru3(CO)12/NH4PF6. The catalytically active cationic ruthenium-acetylide complex [(PCy3)2(CO)(CH3CN)2RuCCPh]+BF4- was isolated from the reaction of 1 with phenylacetylene.     

Stereo- and regioselectivity in dynamic gas-phase thermoisomerization (DGPTI): novel route to alpha-campholanic acid and derivatives

[reaction: see text] Dynamic gas-phase thermoisomerization (DGPTI) of (-)-2-phenylisoborneols effects stereo- and regioselective ring opening under formation of (+)-trans-alpha-campholanic acid derivatives. Similarly, (-)-alpha-2-phenylfenchol underwent under DGPTI conditions ring opening to (-)-fencholic acid derivatives. In both cases, DGPTI led to cleavage of the weakest bond in the isomeric bicyclic structures. A reaction mechanism involving a diradical intermediate is supported by a deuterium labeling study.     

Ring-opening reactions of 1,4-diazabicyclo[2.2.2]octane (DABCO) derived quaternary ammonium salts with phenols and related nucleophiles

1,4-Diazabicyclo[2.2.2]octane (DABCO) has been evaluated as a starting material for the synthesis of 1-alkyl-4-(2-phenoxyethyl)piperazines and related derivatives. We found that 1-alkyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, resulting from the alkylation of DABCO, efficiently react with a variety of nucleophiles in polyethyleneglycol (PEG) or diglyme at high temperatures to give piperazine products resulting from the nucleophilic ring-opening reaction. The benzylation side reaction was found to be relevant with softer nucleophiles when using 1-benzyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, while other types of alkylations were not observed. One-pot methodologies allow for the synthesis of piperazines directly from primary alcohols, alkyl halides or sulfonates, using phenols, or other nucleophile sources, and DABCO.     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

O6-(benzotriazol-1-yl)inosine derivatives: easily synthesized, reactive nucleosides

A novel class of O6-(benzotriazol-1-yl)inosine as well as the corresponding 2'-deoxy derivatives can be conveniently prepared by a reaction between sugar-protected or -unprotected inosine or 2'-deoxyinosine nucleosides and 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The reaction appears to proceed via a nucleoside phosphonium salt, and in the absence of any additional nucleophile, the released 1-hydroxybenzotriazole undergoes reaction with the formed phosphonium salt leading to the requisite O6-(benzotriazol-1-yl)inosine or 2'-deoxyinosine derivatives. Isolation and characterization of the phosphonium salt as well as analysis by 31P{1H} NMR appear to be consistent with this reaction pathway. The resulting O6-(benzotriazol-1-yl)inosine derivatives are effective as electrophilic nucleosides, undergoing facile reactions with a variety of nucleophiles such as alcohols, phenols, amines, and a thiol. Unusual and challenging nucleoside derivatives such as an aryl-bridged dimer, a nucleoside-amino acid conjugate, and a nucleoside-nucleoside dimer have also been synthesized from the O6-(benzotriazol-1-yl)-2'-deoxyinosine derivative. Finally, a fully protected DNA building block, the O6-(benzotriazol-1-yl)-2'-deoxyinosine 5'-O-DMT 3'-O-phosphoramidite, has been prepared and a preliminary evaluation of its use for DNA modification has been performed. Results from these studies indicate several important facts: A single, simple methodological approach provides a class of stable, isolable ribo and 2'-deoxyribonucleoside derivatives that possess excellent reactivity for SNAr chemistry with a wide range of nucleophiles. Also, a benzotriazolyl nucleoside phosphoramidite appears to be a suitable reagent for incorporation into DNA for purposes of site-specific DNA modification.     

Nucleophilic substitution reactions of N-chloramines: evidence for a change in mechanism with increasing nucleophile reactivity

Third-order rate constants (kNu)H (M-2 s-1) for the hydronium ion catalyzed reactions of a range of nucleophiles with N-chlorotaurine (1) in water at 25 degrees C and I=0.5 (NaClO4) are reported. The solvent deuterium isotope effects on hydronium ion catalysis of the reaction with 1 of bromide and iodide ion are (kBr)H/(kBr)D=0.30 and (kI)H/(kI)D=0.54, respectively. The inverse nature of these isotope effects and the absence of general acid catalysis are consistent with a stepwise mechanism involving protonation of 1 in a fast preequilibrium step. The appearance of strong catalysis by general acids for the reaction of the more nucleophilic SO(3)2- and HOCH2CH2S- with the chloramine indicates a change to a concerted mechanism, with protonation of the chloramine at nitrogen and chlorine transfer to the nucleophile occurring in a single step. A rough estimate of the lifetime of the protonated chloramine in the presence of the thiolate anion suggests that the concerted mechanism is enforced by the absence of a significant lifetime of the protonated substrate in contact with the nucleophile. Theoretical calculations provide evidence against an electron-transfer mechanism for chlorination of the nucleophiles by protonated 1.     

Electroorganic synthesis of new benzofuro[2,3-d]pyrimidine derivatives

Electrochemical oxidation of 3,4-dihydroxybenzoic acid (1) in the presence of 1,3-dimethylbarbituric acid (2) and 1,3-diethyl-2-thiobarbituric acid (3) as nucleophiles in aqueous solution has been studied using cyclic voltammetry and controlled-potential coulometry. The results indicate that 1 via Michael reaction under electro-decarboxylation reaction converts to benzofuro[2,3-d]pyrimidine derivatives (6a, 6b). The electrochemical synthesis of 6a, 6b has been successfully performed in an undivided cell in good yields and purity.     

Reactions of 2-Deoxy-4, 5-O-Isopropylidene-D-Erythro- and D-Threo-Pent-1-Enose Derivatives

ABSTRACT

The reactivity of the title compounds has been studied toward different nucleophiles and electrophiles. Unlike other ketene dithioacetals, compounds 3-5 did not add nucleophiles to the double bond. Instead, in the presence of Lewis acids they underwent substitution reaction at position 3. If the nucleophile was not strong enough, formation of 6 and 7 were observed. With 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (18), a 3:1 mixture of 11 and 12 was formed from 4. These observations may be interpreted in terms of easy formation of the allylic carbocation I which gives diastereomers with nucleophiles. However, this allylic ether-like behaviour was ruled out by the fact that compounds 9 and 10 did not undergo [2,3] sigmatropic rearrangement with lithium diisopropylamide. With N-bromosuccinimide compound 3 gave the 2-bromo derivative 8. Compounds 3 and 8 resisted common mercury salt assisted demercaptalization procedures.     

Organocatalytic asymmetric direct phosphonylation of alpha,beta-unsaturated aldehydes: mechanism, scope, and application in synthesis

The first direct organocatalytic enantioselective phosphonylation of alpha,beta-unsaturated aldehydes with phosphite, in combination with a Br?nsted acid and a nucleophile, is presented. Mechanistic investigations have revealed that the first step in the catalytic process, after the formation of the iminium intermediate, is the addition of phosphite to the beta-carbon atom, leading to the phosphonium ion-enamine intermediate. The rate-determining step for the reaction is the transformation of P(III) to P(V), which occurs via a nucleophilic SN2-type dealkylation, and a screening of various nucleophiles shows that soft nucleophiles in combination with a Br?nsted acid improve the reaction rate and enantioselectivity. The reaction conditions developed show that the use of 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanoxymethyl]pyrrolidine as the catalyst and tri-iso-propyl phosphite as the phosphonylation reagent, in the presence of stoichiometric amount of benzoic acid and sodium iodide, gave the beta-phosphonylation of aromatic and aliphatic alpha,beta-unsaturated aldehydes in good yields and enantioselectivities. The products formed by this new reaction have been used for the synthesis of a number of biologically important compounds, such as optically active hydroxyl phosphonate esters, phosphonic acids, and especially glutamic acid and fosmidomycin precursors, of which the two latter are showing important properties for the treatment of central nervous system diseases and as anti-malarial compounds, respectively. DFT calculations have been applied to explain the approach of the phosphite to the reactive carbon atom in the iminium intermediate in order to account for the observed absolute enantioselectivity in the reaction.