Alex J. Roche

Synthesis of new hypoxia markers EF1 and [18F]-EF1

We report on the preparation of a hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(3-fluoropropyl)acetamide (EF1) and its 18F analog, 2-(2-nitroimidazol-1[H]-yl)-N- (3-[18F]fluoropropyl)acetamide ([18F]-EF1). Two methods for the preparation of 3-fluoropropylamine, the EF1 side chain, are described. [18F]-EF1 was prepared with a radiochemical yield of 2% by nucleophilic substitution of bromine in 2-(2-nitroimidazol-1[H]-yl)-N-(3-bromopropyl)acetamide (EBr1) by carrier-added 18F in DMSO at 120 degrees C. Our results demonstrate the preparation of clinically relevant amounts of [18F]-EF1 for use as a non-invasive hypoxia marker with detection using positron emission tomography (PET).

New fluorination of organic compounds using thermodynamically unstable nickel fluorides

Replacement of hydrogen by fluorine in a variety of organic compounds is accomplished with high efficiency in liquid hydrogen fluoride (aHF), at or below 20 °C, using the thermodynamically unstable fluorides RNiF3 and NiF4 the latter prepared in situ from K2NiF6 with BF3.

Fluorinated di-enes

Abstract Fluorinated di-enes may be obtained by the defluorination of some oligomers of F -alkenes and -cycloalkenes using tetrakis(dimethylamino)ethene. These di-enes are very susceptible to nucleophilic attack. Nucleophilic epoxidation of ( 4 ) gives a new diepoxide which undergoes a novel ring-opening reaction. Di-ene ( 4 ) forms cyclopentadienylide derivatives with di-functional carbon nucleophiles and a cyclopentadienylide salt ( 17 ) is obtained in a remarkable ‘one-pot’ reaction from hexachlorobutadiene.

Investigation of the correlations between 19F and 1H NMR signals for various mono- and di-substituted octafluoro[2.2]paracyclophanes

A selection of mono‐ and pseudo ortho di‐substituted octafluoro[2.2]paracyclophane derivatives were analyzed using 19F‐1H HOESY, 1H COSY and 19F COSY techniques. This resulted in the unambiguous assignment of the 19F and 1H NMR resonances, and also revealed interesting solvent effects and noteworthy coupling patterns for various JHH, JHF, and JFF interactions, including observable through bond 7JFF and 8JFF couplings. For the four mono‐substituted derivatives, the assignments were achieved through the combination of 19F‐1H HOESY, 1H COSY and 19F COSY techniques. The C2 symmetry of the six pseudo ortho di‐substituted derivatives that were examined produced simplified spectra, and careful inspection of the characteristic 1H coupling patterns led to the assignment of 1H signals. Therefore only 19F‐1H HOESY experiments were required to complete the assignments for those molecules. Refinements and alternative strategies for previous protocols are presented for the molecules that were less responsive to nuclear Overhauser effect (nOe) experiments. Copyright

2h-heptafluorobut-2-ene as a synthon for hexafluorobut-2-yne

Abstract Reactions of heptafluorobut-2-ene with nucleophiles are described, in some cases giving products analogous to those previously obtained from hexafluorobut-2-yne. Depending on the conditions, hydrolysis can lead to 1,1,1,4,4,4-hexafluorobutan-2-one, or 1,1,1-trifluoroacetone. Reactions with diols, bis-phenols, ammonia and amines are also described.

Eliminations from 2h-heptafluorobut-2-ene

Abstract Various approaches are described for dehydrofluorination of heptafluorobut-2-ene ( 2 ) to give hexafluorobut-2-yne ( 1 ). Molecular sieve is particularly successful. Reaction of ( 2 ) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) surprisingly gave the novel heterocycle ( 8 ) via initial nucleophilic attack. Reactions of ( 2 ) with other bases are also described.

Discrimination of pseudo‐meta and pseudo‐para diamino‐octafluoro[2.2]paracyclophanes by 1H, 19F, and 13C NMR

Pseudo‐meta and pseudo‐para diamino‐octafluoro[2.2]paracyclophanes are challenging to separate either by chromatography or recrystallization, but through the use of a mixture of the two isomers, the 1H, 19F, and 13C NMR spectra of these compounds have been fully and unambiguously assigned using 1H COSY, 1H‐19F HOESY, 1H‐13C HSQC, 1H‐13C HMBC, and 19F‐13C HSQC techniques. This permits the easy identification of either of the individual isomers. In addition, the 13C spectrum of the pseudo‐ortho analogue is reported and assigned for the first time. The gem shift effect in this series of bridge‐fluorinated paracyclophanes serves to deshield 1H resonances and shield 13C. Copyright

The Unexpected Formation of 9,9,10,10-Tetrafluoro-1,2,4,12-tetraphenyl[2.2]paracyclophan-1-ene

An investigation of the palladium-catalyzed Kumada cross-coupling reaction between PhMgBr and (pseudo-ortho) 4,12-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane revealed that in addition to the expected cross-coupled product, an unintended major product was generated. The product was determined to be 9,9,10,10-tetrafluoro-1,2,4,12-tetraphenyl[2.2]paracyclophan-1-ene by X-ray crystallography and is proposed to be formed via the first reported example of reductive defluorination by a Grignard reagent.

Polyhalogenated heterocyclic compounds. Part 41. Cycloaddition reactions involving hexafluorobut-2-yne and 1,1,1,2,4,4,4-heptafluorobut-2-ene

Cycloadducts, formed by addition of hexafluorobut-2-yne, may be transformed into bis(trifluoromethyl)-benzene, -phenol and -furan derivatives. Tetrakis(trifluoromethyl)benzene may also be produced. Heptafluorobut-2-ene 2 is also a very efficient dienophile for reactions with cyclopentadiene and furan. Reaction of 2 with furan derivatives at elevated temperatures gives a very effective ‘one pot’ synthesis of 3,4-bis(trifluoromethyl)furan derivatives.

Direct syntheses of pentakis(trifluoromethyl)cyclopentadienide salts and related dienes

Direct routes for the synthesis of pentakis(trifluoromethyl)cyclopentadienide salts, hexakis(trifluoromethyl)cyclopentadiene and 5H pentakis(trifluoromethyl)cyclopentadiene are described.