Diels−Alder Reactions of 4-Alkenylthiazoles:  A New Approach to Thiazole Functionalization

Abstract

Somewhat unexpectedly, the computed highest occupied molecular orbital (HOMO) energies of some 4-alkenylthiazoles afforded values close to those calculated for the Danishefsky-Kitahara and Rawal dienes. In fact, 4-alkenylthiazoles behave as all-carbon dienes in Diels-Alder reactions with the participation of the formal C-C double bond of the thiazole ring and the side-chain double bond. The reactions with N-substituted maleimides, maleic anhydride, and naphthoquinone take place with high levels of stereocontrol to give the corresponding endo-cycloadducts in good to excellent yields. Depending on the dienophile, the cycloadduct further transforms under the reaction conditions through either a 1,3-hydrogen shift, dehydrogenation, or an ene reaction or Michael addition with another molecule of dienophile. These unprecedented results open new synthetic perspectives for the functionalization of the thiazole ring.

4‐Alkenyl‐2‐aminothiazoles: Smart Dienes for Polar [4 + 2] Cycloadditions

“…According to the FMO theory, dienes with substituents capable of donating electron density into the conjugated πsystem show higher reactivity in normal-electron-demand Diels-Alder reactions. [18] The data shown in Table 3 show that the HOMO energy is slightly enhanced by the presence of a phenyl group at C-1 ( Figure 1 and Table 3, entry 1), as was also found for the analogous 2phenyl-substituted thiazole. Contrary to our expectations, the presence of an amino group induces only a slight increase in the HOMO energies of 2-aminothiazoles 1i-k compared to those of their 2-methyl-and 2-phenyl-substituted counterparts.…”

“…In Table 3 we summarize the HOMO energies and the 2p z eigenvectors of the HOMOs of dienes 1i-m. [18] Thus, the HOMO value of 2-amino-4-vinylthiazole 1j is -7.98 eV (Table 3, entry 2), whereas the previously reported values for 2-phenyl-and 2-methyl-4-vinylthiazoles are -8.01 eV and -8.41 eV, respectively. [21,24] Thus, we used the computed HOMO values of thiazoles 1i-m to predict their relative reactivities.…”

“…Thiourea 3d was prepared following a previously reported method. [19] The synthesis of α-chloro ketone 2d is described in the Supporting Information. Synthesis of 4-alkenyl-2-aminothiazoles 1a-e (2a: R 1 = 4-MeC 6 H 4 , 2b: R 1 = 4-MeOC 6 H 4 , 3a: R 2 = NH 2 , 3b: R 2 = NHPh, 3c: R 2 = NHMe, 3d: R 2 = NMe 2 ).…”

“…[15] In fact, only reactions with highly reactive dienophiles have been described to date. [17] Recently, we have demonstrated that 4-alkenyl-2-methyland 4-alkenyl-2-phenylthiazoles react with classical dienophiles such as maleimides, [18] maleic anhydride, [18] or 4phenyl-1,2,4-triazoline-3,5-dione (PTAD), [19] which opens a new route to polyheterocyclic derivatives. [17] Recently, we have demonstrated that 4-alkenyl-2-methyland 4-alkenyl-2-phenylthiazoles react with classical dienophiles such as maleimides, [18] maleic anhydride, [18] or 4phenyl-1,2,4-triazoline-3,5-dione (PTAD), [19] which opens a new route to polyheterocyclic derivatives.…”

Synthesis and biological evaluation of (E)-cinnamic acid, (E)-2-styrylthiazole and (E)-2-[2-(naphthalen-1-yl)vinyl]thiazole derivatives

“…4 Cinnamic acid analogues act as precursors of many commercially important synthetic cinnamic esters 5 and as reactants in the preparation of chalcones and stilbenes. 6 Cinnamic acid derivatives have also been reported to possess antidiabetic, 7 hepato-protective, 8 antioxidant, 9 antimicrobial, 10 anti-tuberculosis 11 and anti-cancer properties. 12 On the other hand, compounds containing the thiazole nucleus have also been reported to exhibit various biological activities, the specificity of action often being dictated by the attached functionalities.…”