Parallel solution phase synthesis of benzyl (3S,4E)-4-[(arylamino)methylidene]-5-oxotetrahydrofuran-3-ylcarbamates

Abstract

Benzyl (3S,4E)-4-[(dimethylamino)methylidene]-5-oxotetrahydrofuran-3-ylcarbamate 5 was prepared in 4 steps from L-aspartic acid 1. Acid-catalysed treatment of 5 with amines 6 gave the dimethylamine substitution products 7. Benzyl (3S,4E)-4-[(arylamino)methylidene]-5-oxotetrahydrofuran-3-ylcarbamates 7c-n were prepared by parallel solution phase synthesis from 5 and anilines 6c-n in 45-94% yields. Enaminone 5 reacted with potassium cyanide in the presence of 18-crown-6 to afford benzyl 4-cyanomethyl-5-oxo-2,5-dihydrofuran-3-ylcarbamate 9. Upon reaction of 9 with nitrile oxide 10 the 1,2,4-oxadiazole derivative 11 was isolated in poor yield, while treatment of 9 with diazomethane 12 furnished the methylation products 13 and 14.

Parallel Solution-Phase Synthesis of (Z)-3-(Arylamino)-2,3-dehydroalanine Derivatives and Solid-Phase Synthesis of Fused Pyrimidones

“…For the preparation of libraries of fused pyrimidones, the solid-phase approach could be advantageous to the classical solutionphase approach, since isolation is easier and no purification of the products is necessary. In conclusion, the results of this and other recent studies 29,30 indicate that alkyl 2-substituted 3-(dimethylamino)prop-2-enoates and their analogues can also be employed in combinatorial synthetic applications.…”

“…28 Just recently, the use 3-(dimethylamino)prop-2-enoates in combinatoral synthesis of heterocycles has also been reported. 29,30 Previously, we reported syntheses of various N-protected 3-(hetero)arylamino-2,3-dehydroalanine esters and fused pyrimidones with a bridgehead nitrogen atom from a series of alkyl 2-substituted 3-(dimethylamino)prop-2-enoates and their analogues. [18][19][20][21][22][23][24] As an extension of our studies toward applications of 3-(dimethylamino)prop-2-enoates and related enaminones in combinatorial chemistry, we now report a one step solution-phase parallel synthesis of N-acyl-3-arylamino-2,3-dehydroalanine esters 5a-z and 10a-x and a three-step solid-phase parallel synthesis of fused 3-acetylamino-4Hpyrimidin-4-ones 15a-j as functionalized heterocycles with incorporated R-amino acid structural element.…”

“…To date, several reviews on utilization of 3-(dimethylamino)prop-2-enoates and analogous reagents in heterocyclic synthesis have been published. − Various types of biologically active compounds are available from 3-(dimethylamino)prop-2-enoates and related enaminones: 3-arylamino-2,3-dehydroalanine esters have been used as intermediates in the synthesis of 3-(arylamino)alanine derivatives with anticancer activity, and some aplysinopsins have been found to be cytotoxic and affecting neurotransmission, whereas 4 H -pyridino[1,2- a ]pyrimidin-4-one derivatives exhibit various biological activities . Just recently, the use 3-(dimethylamino)prop-2-enoates in combinatoral synthesis of heterocycles has also been reported. , …”

Synthesis of Heterocycles from Alkyl 3-(Dimethylamino)propenoates and Related Enaminones

“…186 In the same manner, a library of 12 R-arylaminomethylidene-β-benzyloxycarbonylamino-γ-butyrolactones 253a-j,l,m was synthesized from propenoate 25c in 45-94% yields (Scheme 68; Table 42). 61 In the case of dimethylamine substitution products, the solution phase synthesis is advantageous to the solid phase approach, because the products precipitate from the reaction mixtures and can be isolated, mostly in analytically pure form, simply upon filtration, washing, and thorough drying. Due to its simplicity, this method was extended on preparation of the combinatorial library of 24 2-(aroylamino)-3arylaminopropenoates 254a-x in 70-91% yields by varying four anilines and six propenoates (Scheme 68; Table 43).…”

Parallel Synthesis of 3-Amino-4H-Quinolizin-4-ones, Fused 3-Amino-4H-Pyrimidin-4-ones, and Fused 3-Amino-2H-Pyran-2-ones

“…Until now, several reviews on utilization of 3-(dimethylamino)prop-2-enoates and analogous reagents in heterocyclic synthesis have been published. [34][35][36][37][38][39][40][41][42] Recently, the use of 3-(dimethylamino)prop-2-enoates in combinatorial synthesis of heterocycles [43][44][45] and protected 3-(arylamino)alanines 45 has also been reported.…”