Thermal equilibrium between “isoxazolidine” and “enamine”

Nitrones formed from the reaction of $\text{N}$-phenylhydroxylamine and aldehydes dimerized to isoxazolidines. A new thermal equilibrium between isoxazolidine and $\text{N}$-hydroxyenamine in DMSO was studied by ¹H and ¹³C NMR.     

The Effect of Acid Strength on the Mitsunobu Esterification Reaction: Carboxyl vs Hydroxyl Reactivity

In the presence of carboxylic acids, the adduct formed between triphenylphosphine and diisopropyl azodicarboxylate reacts to form mono- and bis-acylated hydrazides and the carboxylic acid anhydrides. These products are formed via attack of the carboxylate on the triphenylphosphonium group of the adduct, with weaker acids reacting much faster than stronger acids. This provides an explanation for the observation in the literature that acids stronger than acetic acid, such as 4-nitrobenzoic acid and chloroacetic acid, provide better yields in esterification reactions, since reaction of the alcohol with the phosphonium group of the adduct is more rapid than the competing reaction of the carboxylate for the phosphonium group.     

On-line delta(18)O measurement of organic and inorganic substances

A method for the automated sample conversion and on-line oxygen isotope ratio (delta(18)O) determination for organic and inorganic substances is presented. The samples are pyrolytically decomposed at 1400 degrees C in the presence of nickelized graphite. With the system presented organic as well as inorganic samples such as nitrates, sulphates and phosphates of 50-100 &mgr;g O can be analyzed for their delta(18)O values with a standard deviation usually better than 0.5 per thousand. Additionally, carbon isotope ratios of organic substances and nitrogen isotope ratios of inorganic nitrogenous compounds are available in the same sample run. Data for international and some inter-laboratory reference materials are presented to show the accuracy and reliability of the method. The effect of some additives on the CO yield was checked for substances which do not pyrolyze completely. Copyright 1999 John Wiley & Sons, Ltd.     

Synthesis of functionalized 3-chloro-1-naphthols via Friedel–Crafts acylation of vinyl chlorides

Friedel–Crafts type cyclization of vinyl chlorides was developed into a general method for the synthesis of functionalized naphthols. The chloro functional group contained within these products allowed for further elaboration via cross-coupling reactions, leading to increased structural complexity.     

Development of chromatographic methods to monitor the synthesis of (tributylstannyl)methanol through unstable lithiated intermediates

Simple and robust derivatization methods for monitoring the formation of (tributylstannyl)methanol from tributyltin hydride via unstable lithiated intermediates have been developed and validated. These analytes present both chromatographic and detection difficulties in their native states due to low volatility, poor aqueous solubility/stability, and lack of a chromophore. Derivatization of these analytes to trimethylsilyl analogues for gas chromatographic analysis or to benzenesulfonyl urethane analogues for reversed-phase liquid chromatographic analysis was evaluated. The derivatization/gas chromatographic methods developed were demonstrated to be more specific and sensitive for impurity monitoring during (tributylstannyl)methanol preparation.     

Phase-transfer catalysis in the N-benzylation of adenine

A convenient phase-transfer catalysis in the N-benzylation of adenine is described. The benzylation of adenine with benzyl halides in a two-phase system containing phase-transfer catalyst gave 9-benzylated adenines as a major product accompanied with 3-benzylated adenines.     

Identification of a trace colored impurity in drug substance by preparative liquid chromatography and mass spectrometry

6-(Nitrooxy)hexyl-(2z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoate (enoate 1) was investigated as a novel therapy for pain relief. In a recent manufacturing run at the pilot plant scale, the enoate drug substance was found to have a yellowish color not observed previously. An unknown impurity at trace level was detected by high-performance liquid chromatographic (HPLC) analysis and found to be the primary cause for the color of the drug substance. The colored impurity was enriched by preparative HPLC and structurally elucidated by liquid chromatography/tandem mass spectrometry (LC/MS/MS). It was found that the colored impurity was derived from the product of oxidative dimerization of rofecoxib, an impurity present in the enoic acid intermediate. It was further revealed by the photodiode array and LC/MS/MS data that the colored impurity exists in the drug substance as a pair of double-bond isomers with one isomer at majority. These findings were also confirmed by synthesizing the colored impurity through the proposed pathway.     

The synthesis of 3-(1′-hydroxyethyl)-2-azetidinone-4-yl acetic acid via dianion chemistry - an important intermediate in thienamycin total synthesis

A convenient synthesis of 3-(1′-hydroxyethyl)-2-azetidinone-4-yl acetic acid, one of the key intermediates in the thienamycin total synthesis, based on the chemistry of the dianion derived from readily available 2-azetidinone-4-yl acetic acid is described.     

A facile transformation of bicyclic keto esters to bisprotected (±)-8-epithienamycin via enol activation

A facile “one-pot” transformation of bicyclic keto ester (2) to bisprotected (±)-8-epithienamycin $\text{via}$ enol phosphate activation followed by the addition-elimination reaction of $\text{N}$-protected cysteamine derivative is described.