Synthesis and transformations of methyl (Z)-2-[(tert-butoxycarbonyl)amino]-3-(dimethylamino)propenoate

Janez Baš,Branko Stanovnik,Jurij Svete,Simona Golic-Grdadolnik,Simon Recnik,Joachim Schantl

doi:10.3998/ark.5550190.0002.208

Janez Baš, Branko Stanovnik + Show 4 more

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https://doi.org/10.3998/ark.5550190.0002.208

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Abstract

Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(dimethylamino)propenoate (3) was prepared in 2 steps from glycine methyl ester hydrochloride (1). Acid catalysed reactions of 3 with various alkyl-, aryl-, and heteroarylamines 4a-g, performed at 20-80 °C, proceeded by substitution of the dimethylamino group giving the corresponding substitution products, 3-N-substituted methyl (Z)-2-((tert-butoxycarbonyl)-amino)amino)propenoates 5a-g. Treatment of 3 with ambident 1,3- nucleophiles, such as 2-pyridineacetonitrile (6), 2-aminothiazole (4d), 2-aminopyridine (4f), and 4-hydroxy-6-methyl-2H-pyran-3-one (7) in acetic acid at 85-120 °C afforded fused pyridones 8 and 12, pyrimidones 9 and 10 and pyranones 11 and 13.

Highlights

Quinolizines, pyridinopyrimidines, and related systems with a bridgehead nitrogen atom are the constituents of many naturally occurring compounds and exhibit like their synthetic derivatives various biological activities.1,2 3-Aminopyridino[1,2–a]pyrimidines have been prepared in the past by reduction of the corresponding 3-nitro derivatives using either titanium(III) chloride or Pd–C in the presence of hydrogen[3] or by hydrolysis of 3-benzoyl-amino derivatives in concentrated hydrochloric acid in yields below 40%
Reviews on this topic have been published. 5-9 Alkyl 2-acylamino-3-(dimethylamino)propenoates are an important subclass of 2-substituted alkyl 3-(dimethylamino)propenoates and were employed as reagents in one step syntheses of 3-N-substituted alkyl 2-acylamino-3aminopropenoates and heterocycles with an incorporated α-amino acid structural element
In continuation of our work in this field, we report the preparation of methyl (Z)-2-[(tert-butoxycarbonyl)amino]-3(dimethylamino)propenoate (3) and its transformations with amines and ambident 1,3dinucleophiles with the intention to prepare acylamino derivatives, which can be deprotected under milder conditions

Summary

Introduction

Quinolizines, pyridinopyrimidines, and related systems with a bridgehead nitrogen atom are the constituents of many naturally occurring compounds and exhibit like their synthetic derivatives various biological activities.1,2 3-Aminopyridino[1,2–a]pyrimidines have been prepared in the past by reduction of the corresponding 3-nitro derivatives using either titanium(III) chloride or Pd–C in the presence of hydrogen[3] or by hydrolysis of 3-benzoyl-amino derivatives in concentrated hydrochloric acid in yields below 40%. Treatment of methyl (Z)-2-[(tert-butoxycarbonyl)amino]-3(dimethylamino)propenoate (3) in acetic acid at 90–120 °C with the following ambident nucleophiles: 2-pyridineacetonitrile (6), 2-aminothiazole (4d), 2-aminopyridine (4f), and 4hydroxy-6-methyl-2H-pyran-2-one (7), gave the corresponding 3-acetylamino substituted fused pyridone (8), pyrimidones (9, 10), and pyranone (11), respectively.

Results

Conclusion