David S. Ennis

Synthesis of 3-substituted furans by directed lithiation and palladium catalysed coupling

Abstract The 5-position of the furan ring of 4,4-dimethyl-2-(2-furyl)oxazoline ( 1a ) was protected by a trimethylsityl group. The product, compound ( 2a ), was then lithiated at the 3-position with sec-butyllithium and converted to the bromozinc species ( 2d ) with zinc bromide. Coupling reactions with a range cf aryl-, acyl-, and vinyl halides were performed with Pd(PPh3) 4 as catalyst. The reaction with (l-bromoethenyl)- trimethylsilane is abnormal in that it gives a mixture of two products ( 2l ) and ( 2m ). The origin of the abnormal product ( 2l ) is discussed. The coupling reactions of this silane with 2-thienyl-, 2-furyl-, and phenyl-zinc bromide have also been carried out: in each case, a mixture of the expected coupling product and an isomer, the ethen-2-yltrimethylsilane, was obtained. The ratio of products is shown to depend upon the temperature at which the coupling is carried out. 4,4-Dimethyl-2-(2-thienyl)oxazoline ( 1b ) was lithiated at the 3-position of the thiophene ring and coupled to iodobenzene without protection of the 5 -position.

OBSERVATIONS ON THE SYNTHESIS OF FUNCTIONALISED METHYLENEAZIRIDINES

Abstract N-Triphenylmethyl-2-methyleneaziridine 8 was synthesised from N-(2-bromo-2-propenyl)-amine7 by treatment with sodium amide in liquid ammonia and its structure established using x-ray crystallography. Using modified conditions, (S)-N-(1-phenylethyl)-2-methyleneaziridine 9 was prepared in enantiomerically enriched form. Studies directed towards the synthesis of N-tosyl and N-Boc methyleneaziridines 14 and 15 respectively reveal limitations with this methodology.

Abnormal products of palladium catalysed coupling reactions of (1-bromovinyl)trimethylsilane

Abstract Coupling reactions of (1-bromovinyl)trimethylsilane ( 1 ) with organozinc bromides catalyzed by tetrakis(triphenylphosphine)palladium(0) give not only the expected 1-substituted vinylsilanes ( 2 ) but also the isomeric 2-substituted vinylsilanes ( 3 ).

Novel ring opening reactions of methyleneaziridines

Abstract Treatment of 2-methyleneaziridines with chloroformates (MeO 2 CCl, PhCH 2 O 2 CCl) or acid chlorides (AcCl, p -NO 2 C 6 H 4 COCl) at room temperature in a variety of nonpolar solvents (CH 2 Cl 2 , THF, toluene) produces ring opened enamine products in moderate to good yields.

Directed metallation studies on 2-(2-heteroaryl)imidazolines: Synthesis of some 2,3-disubstituted thiophenes and furans

Abstract A general method for the synthesis of 2-(2-heteroaryl)imidazolines ( 1a-c ) has been developed and subsequent metallation studies have shown the imidazoline group to be a strong director of ortho -metallation. The synthetic utility of lithio intermediates ( 5 ) and ( 7 ) has been shown by reaction with a series of electrophiles.

ONE STEP SYNTHESIS OF AZETIDINONE DITHIOCARBOXYLIC ESTERS, INTERMEDIATES IN THE PREPARATION OF 2-SUBSTITUTED PENEMS

Organocuprate reagents react with CS2 and 4-acetoxyazetidinone to form azetidinone dithiocarboxylic esters, which can be converted to the corresponding penems in good yields.

Synthesis of chiral, nonracemic methyleneaziridines derived from β-amino alcohols

Abstract An efficient three step process for the synthesis of chiral, nonracemic methyleneaziridines derived from homochiral β-amino alcohols is described. Methyleneaziridines 4a-e produced using this chemistry have been shown to possess high enantiomeric purities (≥ 95%ee).

Pyridinium ylides in syntheses of naphthopyrandiones and in regioselective syntheses of acylated anthraquinones related to fungal and bacterial metabolites

Improvements have been made in the use of acylated pyridinium ylides for the transformation of 2-methyl-1,4-naphthoquinone into derivatives (15) and (16) of naphtho[2,3-c]pyran-5,10-dione, containing furan and thiophene groups. The substitution and cyclisation steps can be combined effectively by using 2-phenoxymethyl- instead of 2-methyl-naphthoquinone. The use of better leaving groups than phenoxy (especially 4-nitrophenoxy) allows the quinone to react with two proportions of ylide and leads regiospecifically to 1-aroyl-2-arylanthracene-9,10-diones such as (20a). If the leaving group is nuclear bromine as in 2-bromo-3-methyl-1,4-naphthoquinone, another reaction with 2 mol equiv. of ylide leads to complex red intermediates of type (31) which in contact with alumina are quantitatively converted into the regioisomeric 2-aroyl-3-aryianthracene-9,10-diones such as (22a).The structures have been determined by standard methods but special features of the NMR spectra are reported including a case of extreme line broadening by traces of iron. Mechanisms are suggested for the diverse reactions between the quinones and the ylides.

CHAPTER 23:The Chemical Development and Medicinal Chemistry Interface

As a molecule progresses from discovery into clinical development, drug discovery chemists will hand over their development candidate and its synthetic route to a chemical development group. The quality of that handover can have a big influence on the speed of the early development program and therefore the commercial value of the target or new chemical entity. This chapter will try and convey the considerations and thoughts that go through the minds of the chemical development scientists when confronted with a new molecule, and how medicinal chemistry can ease this transition at little or no extra cost with a little thinking ahead. The chapter will highlight how efficient chemistry is the single biggest success factor, and tell-tale signs of potential issues with synthetic routes are highlighted, and an ongoing dialog between medicinal chemistry and chemical development scientists is encouraged.

Observations on the ring opening reactions of 2-methyleneaziridines with acid chlorides and alkyl chloroformates

A variety of 1-alkyl-2-methyleneaziridines react with alkyl chloroformates (MeO2CCl, PhCH2O2CCl) or acid chlorides (AcCl, p-NO2C6H4COCl) at room temperature in nonpolar solvents (CH2Cl2, THF, toluene) to produce ring opened enamide products in moderate to good yields. Mechanistic studies using 3-deuterio-N-(1-phenylethyl)-2-methyleneaziridine suggest the reactions proceed by initial N-acylation to form the corresponding aziridinium cation (e.g.27) which subsequently undergoes regiospecific ring opening by chloride ion at the sp3 hybridised aziridine carbon atom to produce the observed products.