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

Abstract

Dedicated to Professor Emerituspropenoate (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.

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

“…Compounds 5a − z , 9d , f , 10a − x , and 15a − j were characterized by spectroscopic (IR, EI-MS, EI-HRMS, 1 H and 13 C NMR) and elemental analyses. Spectral data for known compounds 5y and 15a , e , 10a , b , and 15j were in agreement with the literature data. Spectral data for all other products 5 , 10 , and 15 were in agreement with spectral data for closely related propenoates and fused pyrimidones. , …”

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

“…On the other hand, the HMBC correlation technique has been found to be the most reliable for the determination of the configuration around the CC double bond in α,β-unsaturated carbonyl compounds, because the ( Z )- and the ( E )-isomeric forms can be differentiated on the basis of the long-range heteronuclear 13 C− 1 H coupling constants. Generally, the magnitude of the coupling constants 3 J C - H for nuclei with ( Z )-orientation around the CC double bond are smaller (2−6 Hz) than those for the ( E )-oriented ones (8−12 Hz). − Similar coupling constants have also been observed in 3-(dimethylamino)propenoates and related compounds (Figure ). ,,,,,,

4 Determination of configuration and/or isomerization around the CC double bond in solution by NOESY, ROESY, and HMBC techniques.

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“…Typical reactive N -nucleophiles are primary and secondary aliphatic, aromatic, and heteroaromatic amines, whereas in the C -nucleophile series, treatment with active methylene compounds, such as 1,3-dicarbonyl compounds and their cyclic analogues, indole derivatives, heteroarylacetic acid derivatives, and hydrogen cyanide, gives the substitution products (see sections 5.1.1−5.1.3 and 5.3.1). Reactions are acid-catalyzed and, most probably, they proceed by an addition−elimination mechanism (Figure ). − ,,,,− ,− ,− ,− ,,

6 Dimethylamine substitution reactions of 3-(dimethylamino)propenoates with N - and C -nucleophiles.

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“…Also, these reactions are acid-catalyzed and are usually carried out in acetic acid. Selectivity is controlled by reaction conditions: under mild conditions (20−80 °C), the dimethylamine substitution products are formed, whereas upon heating at 90−120 °C further cyclization takes place to give pyrazoles, pyridones, pyrimidones, 2 H -pyran-2-ones, and their fused analogues (see sections 5.2.3, 5.2.4, 5.2.8, 5.2.9, 5.2.11, 5.2.12, and 5.3.2) (Figure ). − ,,,,,

7 Reactions of 3-(dimethylamino)propenoates with ambident nucleophiles.

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“…Alternatively, the amine hydrochloride can be used instead of an equimolar mixture of free amine and hydrochloric acid (method C). In this manner, a number of various types of α-substituted β-aminopropenoates and analogues have been prepared. ,− ,,,,,,− For example, the use of 2-(acylamino)-3-(dimethylamino)propenoates 3 and 2-(vinylamino)-3-(dimethylamino)propenoates 13 as reagents enables a one-step preparation of N -protected β-alkylamino, β-arylamino, and β-heteroarylamino-α,β-dehydroalanine esters 74 , usually in good yields (Scheme ; Table ). ,,,,,,,,,, …”