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1980 1139 Bicyclic Heterocycles with Nitrogen at the Ring Junction. Part 2.l Application of the Dakin-West Reaction to the Synthesis of Imidazo- [5,1-f]-1,2,4-triazin -4(3H)-ones By Isabel Charles, David W. S. Latham, David Hartley," Alexander W. Oxford, and David 1. C. Scopes, Glaxo Group Research Ltd., Ware, Hertfordshire SG12 ODJ A series of novel acylamino cc-keto-esters (4) have been prepared via a Dakin-West reaction of acyiated cc-amino- acids and ethyl oxalyl chloride. Their use in a general synthesis of imidazo[5,1-f] -1,2,4-triazin-4(3H)-ones (7) is described. The conversion of the imidazotriazinones into the corresponding imidazo[5,1 -f]-1,2,4-triazines (20) and their 3,4-dihydro-derivatives (19) are also reported. RECENTLYwe described the synthesis and chemistry of 2-amino-5-methyl-7-propylimidazo[S,1-f]-1,2,4-t riazin- 4(3H)-one (1) and the corresponding imidazotriazine derivative (2).l We now report an improved procedure that allows a more flexible approach to the preparation of a wide range of compounds based on the imidazo[5,l-f]- 1,2,4-triazine ring system.0 The principal feature of this new metliod is tlie con- densation of an acylamino-cc-keto-ester (4) with an amidrazone or aminoguanidine derivative (5) to afford HO,CCHIR1 1 NHCOR2 i -iii (3) the key intermediate (6).l Although the formation of an acylaniino cc-keto-acid lias been reported,2 no general synthetic route to acylamino-a-keto-esters (4) had previously been described. However, we found that these compounds could be obtained from a-amino-acids and ethyl oxalyl chloride via the Dakin-West rea~tion.~ Treat men t of the ay propriat e acylamino- acid (3) with ethyl oxalyl chloride (2 equiv.), pyridine (3 equiv.), and a catalytic quantity of 4-dimethylaminopyridine (DMAP)? gave the enol esters (10)which were hydrolysed directly with base to tlie acylamino-a-keto-ester (4). In general the crude enol esters (10a-d) were isolated as oils but the benzamido-derivative (10e) was obtained as a stable crystalline solid.The azlactones (8) were shown to be intermediates in the reaction by the independent synthesis of (8b) and subsequent treatment with ethyl oxalyl chloride (1 Et O,CCOCH( R')NHCOR2 (4) Et0,C R' LJ -(4) Et O,CCO, (10) , a; R = M~,R*=BU' b; R' = Me, R2= Pr" c; R' = Me,R d; R'=Ph,R*=Pr" e; R ' Me, R2= Ph SCHEMEReagents: i, Et0,CCOCl-pyridine-DMAP; ii, H,O ; iii, base ; iv, polyphosphoric acid ; v, EtO,CCO,- equiv.), pyridine (2 equiv.), and monoethyl oxalate (1 equiv.) in refluxing tetrahydrofuran to give the enol ester (lob).This process presumably involves the C-acylated oxazolone (9b) but the latter could not be isolated under the conditions of the reaction. Support for this type of C-acylated intermediate is provided by the work of Steglich and Hofle who have reported the preparation of (9e) by acylation of 4-methyl-2-phenyloxazolin-5-one (8e)with ethyl oxalyl chloride in the presence of triethyl- amine at 0 "C. The enol ester (lob) was also shown to contain the N-acyloxazolone (11)as an impurity.The structure of this by-product was assigned on the basis of its n.ni.r. and mass spectra and by hydrogenation to give a mixture of oxazolidinones (12) and (13). The N-acyloxazolone (1 1) was the major product when reaction of the oxazolone (8b)with ethyl oxalyl chloride (1 equiv.) and pyridine (2 equiv.) was carried out in tetrahydro- furan at reflux in the absence of monoethyl oxdate. This implies that monoethyl oxalate is required in the reaction for the formation of the enol esters (10). The a-keto-esters ethyl 3-butyramido-2-oxobutyrate (4b) and ethyl 3-isovaleramido-2-oxobutyrate (4a) were characterised, after chromatography, as low melting crystalline solids but in most cases these intermediates were used in subsequent reactions without purification. Condensation of arninoguanidine (5; R3=NH2) with J.C.S.Perkin I the a-keto-ester (4b) afforded the triazinone (6; R1=Me, R2=Pr, R3 =NH,) in 50% yield which on cyclisation with polyphosphoric acid gave the irnidazotriazinone (1), previously described.l By employing amidrazones in place of amin

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