Thiazole Diels-Alder reactions

The generation and Diels Alder reaction of 4,5-bis(bromomethylene)-4,5-dihydrothiazole 39 has been investigated. 39 is a heterocyclic analogue of ortho-quinodimethanes and is generated by treating 4,5-bis(dibromomethyl)thiazole 38 with sodium iodide in dimethylformamide. 39 can be trapped in situ with symmetrical dienophiles to give substituted benzothiazoles such as 40 <98EJOC2047>. 

Thiazoles have a low reactivity in cycloaddition reactions. However, it has been possible to achieve intramolecular Diels-Alder reactions in some cases (e.g. 362 — 363). 

An interesting approach to directly linked C-disaccharides 2-191 was developed by Dondoni et al. [171] via a hetero Diels-Alder reaction of sugar derived 1-oxa-1,3-butadienes as 2-190 bearing a thiazole moiety at position 2 as activating group (Fig. 2-54). 

Due to the high reactivity and high sensitivity of thioaldehydes, Lewis acid catalysis has not been applied to thia Diels-Alder reactions. However, Heim-garten et al. clearly demonstrated the suitability of Lewis acids to make less reactive thiocarbonyl compounds, e. g. thiazole thiones, react as heterodieno-philes in hetero Diels-Alder reactions [412]. 

Five-membered heteroaromatic systems that possess an electron-deficient azadiene substructure, e.g., oxazoles and thiazoles, are suitable for participation in Diels-Alder reactions with inverse electron-demand [49JA3062 59JA4342 62AG(E)329]. The introduction of strongly electron-donating substituents in many cases is sufficient to overcome the electron-deficient nature of the azadiene moiety and permits normal HOMO diene/ LUMO dienophile controlled Diels-Alder reactions (87MI6). 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

As thiazoles have significant aromatic character, they display poor reactivity in cycloaddition reactions. However, a theoretical study of the Diels-Alder reactions of a thiazole o-quinodimethane 83 with 2- and 3-bromo-5-hydroxy-naphthoquinones 84 and 85 has been carried out (Scheme 24) <2000T1701>. The findings from the PM3, molecular hardness, and ab initio (3-2 Gp) calculations of this study agree with the experimental results and support the statement that hydrogen bonding plays a crucial role on the regiocontrol of the cycloadditions. 

Thiazoles have a low reactivity in cycloaddition reactions due to their high aromatic character. However, it has been possible to achieve intramolecular Diels-Alder reactions in some cases. The reaction of the acetylenic thiazole (66) in decalin at 350 °C affords, after loss of acetonitrile, the thiophene derivative (67) in 75% yield (Equation (16)). The reaction is also applicable to other thiazoles although with some limitations <88T3327>. 

Alkoxythiazoles (68) give an abnormal Diels-Alder reaction with highly reactive dienophiles such as 4-phenyl-3//-l,2,4-triazole-3,5(4/0-dione (PTAD), diethyl azodicarboxylate (dead), or diethyl oxomalonate. As an example, the reaction of (68) with PTAD (69) is illustrated in Equation (17). The product of the reaction (70) is the formal [3-1-2] cycloadduct between (69) and the corresponding nitrile ylide derived by the opening of thiazole ring system. For this abnormal Diels-Alder reaction of thiazoles a stepwise mechanism has been proposed <92BCJ3315>. 

Thiazoles have been shown to be much more reluctant than oxazoles to participate in Diels-Alder reactions, and only two successful intermolec-ular Diels-Alder reactions have been described. Like oxazoles, olefinic dienophiles provide pyridine products via a Kondrat eva dehydration [Eq. (9)].60... 

A selected intramolecular Diels-Alder reaction of an acetylenic thiazole provided the expected thiophene product [Eq. (10)].59g... 

Unlike the case of oxazoles, the attempted intramolecular Diels-Alder reactions of thiazoles bearing electron-deficient alkynes have proved unsuccessful.59 ... 

Oxazole itself, in contrast to isoxazole, thiazole, and imidazole has been found to undergo Diels-Alder reaction with dienophiles.340 341 Isonicotinic acid esters (182, R = COOR ) and isonicotinonitriles (182, R = CN) are... 

Another static approach that can give us the relative reactivity of heterocycles as dienes for Diels-Alder reactions is evaluation of their aromatic stability through the ring bond order uniformity. If, for a moment, we examine reactivity of the heterocycle on the basis of FMO energy gap with cyclopropene as a dienophile, it is obvious that the most reactive heterocycle is 1,3-thiazole. It had a FMO energy gap of only 9.609 eV (Table 26). That finding is almost... 

Oxidation of a sulfur atom a way to activate 1,3-thiazole and 1,3,4-thiadiazole as dienes for the Diels-Alder reaction... 

Elimination of the ring s x-orbital delocalization in five-membered heterocycles is a most efficient chemical manipulation used to synthesize highly reactive dienes for Diels-Alder reactions from heterocycles that would otherwise not readily participate in the Diels-Alder reaction. One way to accomplish this goal using heterocycles that contain sulfur atoms is through their oxidation to sulfone derivatives. We will demonstrate the usefulness of this approach by studying the reactivity of 1,3-thiazole 1,1-dioxide and 1,3,4-thiadiazole 1,1,-dioxide as dienes for Diels-Alder reactions with acetylene, ethylene, and cyclopropene. 

Unlike oxazoles, thiazoles do not react as 1,3-dienes, i.e. they do not undergo a Diels-Alder reaction. This is further evidence for the greater aromaticity of thiazole as compared with oxazole. 

Under solvent-free conditions with microwave irradiation. Moody et al. have improved the hetero Diels-Alder reaction of eneacylamines with l-alkoxy-2-aza-1,3-dienes [67]. A mixture of l-(2-thiazolyl)-l-acetylaminoethylene 54 and the starting 2-aza-l,3-diene 55, irradiated in a GEM Focused Synthesizer at 180 °C for 15 min produced a 64% yield of adduct 56 (Scheme 11.16). Carboxylic acid esters and thiazole rings are tolerated under these reaction conditions (Scheme 11.16). Without microwave irradiation yields were in the range 25 to 42% [67]. 

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