Roy V. Davies

ORGANOCERIUM REACTIONS OF BENZAMIDES AND THIOBENZAMIDES : A DIRECT SYNTHESIS OF TERTIARY CARBINAMINES

Abstract A simple and efficient process has been developed for the direct conversion of benzamides and thiobenzamides into tertiary carbinamines. A synthesis of benzonitriles from simple benzamides and a thiobenzamide is also described.

Structural studies on bioactive compounds. Part 29 ☆: Palladium catalysed arylations and alkynylations of sterically hindered immunomodulatory 2-amino-5-halo-4,6-(disubstituted)pyrimidines

The immunological agent bropirimine 5 is a tetra-substituted pyrimidine with anticancer and interferon-inducing properties. Synthetic routes to novel 5-aryl analogues of bropirimine have been developed and their potential molecular recognition properties analysed by molecular modelling methods. Sterically challenged 2-amino-5-halo-6-phenylpyrimidin-4-ones (halo = Br or I) are poor substrates for palladium catalysed Suzuki cross-coupling reactions with benzeneboronic acid because the basic conditions of the reaction converts the amphoteric pyrimidinones to their unreactive enolic forms. Palladium-mediated reductive dehalogenation of the pyrimidinone substrates effectively competes with cross-coupling. 2-Amino-5-halo-4-methoxy-6-phenylpyrimidines can be converted to a range of 5-aryl derivatives with the 5-iodopyrimidines being the most efficient substrates. Hydrolysis of the 2-amino-5-aryl-4-methoxy-6-phenylpyrimidines affords the required pyrimidin-4-ones in high yields. Semi-empirical quantum mechanical calculations show how the nature of the 5-substituent influences the equilibrium between the 1H- and 3H-tautomeric forms, and the rotational freedom about the bond connecting the 6-phenyl group and the pyrimidine ring. Both of these factors may influence the biological properties of these compounds.

A new synthesis of isocyanates

The isocyanates (3)–(7) were prepared from the corresponding amine, carbonyl sulphide, and S-ethyl chlorothioformate by a procedure analogous to the Andreasch–Kaluza synthesis of isothiocyanates.

Syntheses of flosequinan: a novel 4-quinolone shown to be useful in congestive heart failure

Two synthetic routes to flosequinan 1 and flosequinoxan 2 are described in which either ring closure of the β-keto sulfoxides 12 or 13 with ortho esters or cyclisation of the anilinoacrylates 23, 28 or 29 are the key steps.

Condensed thiophen ring systems. Part XIX. Synthesis of 6,7-dihydrothieno[3,2-c]pyridines and 4,5-dihydrothieno[2,3-c]pyridines by intramolecular cyclisation of 2-(2- or 3-thienyl)ethyl isothiocyanate

Cyclisation of 2-(2-thienyl)ethyl isothiocyanate (8) with methyl fluorosulphate or triethyloxonium tetrafluoroborate gave 1-methylthio-(1) or 1-ethylthio-6,7-dihydrothieno[3,2-c]pyridine (2), respectively. Compound (1) was prepared also by cyclisation of the isothiocyanate (8) with polyphosphoric acid and subsequent alkylation of the 6,7-dihydrothieno[3,2-c]pyridine-4(5H)-thione (6) produced with methyl fluorosulphate. Compounds (5) and (7) were prepared similarly from 2-(3-thienyl)ethyl isothiocyanate (9). The amines (3) and (4) were prepared by reaction of compound (1) or (2) with the appropriate aliphatic amine.

4-quinolones as potential cardiovascular agents.

Publisher Summary This chapter focuses on 4-Quinolones as potential cardiovascular agents. Cardiovascular diseases continue to be the focus of considerable attention from the pharmaceutical industry. Prevalence of the disease is high in Western society and, despite publicity surrounding healthier lifestyles, is likely to continue to be a problem. The promising profile of activity shown by certain 4-quinolone-3-sulphoxides, including, in animal models established the true lead potential of 4-quinolone analogues and prompted a major research effort to find other related compounds with potential for development. The strategy for the next phase of the work involved the synthesis of 4-quinolone analogues bearing as 3-substituents groups whose size approximated to those already described above. As physico-chemical parameters were not available for other groups of interest, it was decided to investigate bridged versions of previously identified 3-substituents. The dose-response relationship for antihypertensive effects in renal hypertensive dogs for a range of 4-quinolones is shown in the chapter. Certain 4-quinolones have been shown to possess antihypertensive or hypotensive activity in SH rats, RH dogs and normotensive cats.

Intramolecular cyclisation of 2-phenylethyl isocyanates

Cyclisations of 2-phenylethyl isocyanate (2), (+)-1-methyl-2-phenylethyl isocyanate (3), and 2,2-diphenylethyl isocyanate (4) have been studied using polyphosphoric acid, aluminium chloride, boron trifluoride–diethyl ether, and triethyloxonium tetrafluoroborate. Depending on the reaction conditions, triethyloxonium tetrafluoroborate, for example, not only gave the expected isoquinolones (14)–(16) and other expected products, but in two cases, also gave the 2-N-(2-phenylethyl)formamidyl-3,4-dihydroisoquinolin-1 (2H)-ones (9) and (10). The isoquinolone (15) was alkylated with triethyloxonium tetrafluoroborate or methyl fluorosulphonate to give 1-ethoxy-(7) or 1-methoxy-3-methyl-3,4-dihydroisoquinoline (8), respectively.

Intramolecular cyclisation of arylalkyl isothiocyanates. Part 3. Synthesis of 4,5-dihydro-3H-2-benzazepines and 7,8-dihydro-6H-thieno[3,2-c]-azepines

The 4,5-dihydro-3H-benzazepine-1-thiones (6) and (7), prepared by cyclisation of 3-phenylpropyl isothiocyanate (2) and its 3,4-dimethoxy-derivative (3) with polyphosphoric acid or aluminium chloride, were alkylated with tri-ethyloxonium tetrafluoroborate, dimethyl sulphate, or methyl fluorosulphate to yield the 1-alkylthio-compounds (8)–(10). 3-(2-Thienyl)propyl isothiocyanate (12) reacted with polyphosphoric acid to give a thione (13) which was prepared also from the corresponding lactam (14) and phosphorus pentasulphide. The thione (13) and the lactam (14) were ethylated with triethyloxonium tetrafluoroborate and each of the products. (15) and (16), respectively, was converted into 4-cyclopropylamino-7,8-dihydro-6H-thieno[3,2-c]azepine (17) by reaction with cyclopropylamine. With aluminium chloride 3-(2-thienyl)propyl isothiocyanate (12) gave a product (18) arising from intermolecular condensation. Attempts to cyclise the isothiocyanates (1)–(5), (12), (26), and (29) with triethyloxonium tetrafluoroborate succeeded only in the case of compound (3), which gave 1-ethylthio-4,5-dihydro-7,8-dimethoxy-3H-2-benzazepine (10).

Intramolecular cyclisation of arylalkyl isothiocyanates. Part I. Synthesis of 1-substituted 3,4-dihydroisoquinolines

With triethyloxonium tetrafluoroborate or ethyl or methyl fluorosulphonate, 2-arylethyl isothiocyanates cyclised to give a 1-ethylthio- or 1-methylthio-3,4-dihydroisoquinoline, respectively. These compounds were prepared also by successive cyclisation of the isothiocyanates with aluminium chloride or polyphosphoric acid and alkylation of the resultant 3,4-dihydroisoquinoline-1(2H)-thione. They are useful starting materials for the synthesis of other 1-substituted 3,4-dihydroisoquinolines, e.g. 1-amino-compounds.

Experiments Towards the Synthesis of the Ergot Alkaloids and Related Structures. Part 8.17 The Total Synthesis of 4-Methyl-2,3,4,4a,5,6-hexahydro-benzo[f]quinoline-2-carbonitrile Hydrochloride Hemihydrate, an Immediate Precursor of the Despyrrole Analogues of Lysergic Acid and Its Amides

Exposure of the N -methoxycarbonyl-bicyclic-keto-acid 5 (improved preparation) to the Barnick β -keto-acid synthesis 1 yielded an aqueous solution of the sodium salts of the β -keto-acids 26 and 27 which on heating at 60-65°C furnished the N -methoxycarbonyl-tricyclic-ketone 9 (55%) plus the hydroxy-ketone 28 which on acid treatment raised the yield of 9 to 68%. Reduction (NaBH 4) of 9 yielded the alcohol 32 (94%) which was treated with thionyl chloride followed by copper (I) cyanide and sodium iodide in acetonitrile to give the tricyclic- N -methoxycarbonyl nitrile 35 whose relative configuration was obtained by X-ray analysis. Attempts to remove the N -methoxycarbonyl group from 35 were unsuccessful. Conversion of the alcohol 32 to its methoxypropyl ether 41 followed by reaction with ethereal MeLi-LiBr yielded the amino-alcohol 39 (75%) converted to the N -formyl-tricyclic alcohol 42 with formic-acetic anhydride (70%). The alcohol 42 was then converted into the N -formyl nitrile 44 via the chloride 43 as employed in the earlier synthesis of the nitrile 35. Removal of the N -formyl group from the nitrile 44 was achieved by refluxing methanolic hydrochloric acid to give the required amino-nitrile hydrochloride 46 (91%) whose structure was confirmed by X-ray analysis. Reaction of the free base with methyl iodide in ethyl acetate in the presence of calcium carbonate furnished the N -methyl base 48 isolated as its hydrochloride, hemihydrate 49 (59%). The overall yield of 49 via this eleven-step synthesis was 3.4%.