Reactivity toward Nucleophilic Reagents

The recently reported rearrangement (1581) of 2-allylamino-4-carboxamido-5-aminothiazoIes to 4-aminoimidazole-5-carboxamide in presence of sodium bicarbonate probably involves the electrophilic reactivity of C-2, which allows the ring opening. 

2-Amino-4-phenylthiazole when heated with Raney Ni is reported to yield acetophenone (469). In the course of a general study on reductive cleavage in heterocyclic systems Hoff et al. studied the reaction of 2-amino-4-methylthiazole with Na in liquid ammonia. Two equivalents of Na are necessary to obtain a mixture of 4-methyl-3-thiazoline (240) and 

General trends in the reactivity of aminothiazoles and derivatives may be tentatively outlined. 

Reactivity of the conjugate acid of 2-aminothiazoles seems more clearly defined. The 5-carbon is the most reactive toward electrophilic 

In this section, only salient features of the synthesis, physicochemical properties, and reactivity of major derivatives of 2-aminothiazole and 2-imino-4-thiazoline are summarized. Further details on each compound are found in associated references collected in Section VII. The synthetic methods reported in this section exclude heterocydization methods treated in Chapter II but given in specific references found in Section VII. 

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The most striking chemical property of epoxides is their far- greater reactivity toward nucleophilic reagents compared with that of simple ethers. Epoxides react rapidly with nucleophiles under conditions in which other ethers are inert. This enhanced reactivity results from the angle strain of epoxides. Reactions that open the ring relieve this strain. 

The A1-piperideines, in contrast to the A2- and A3-isomers, are usually very reactive toward nucleophilic reagents. Depending upon the nature of the nucleophile, two reaction pathways are possible (equation 48). The nucleophile can add to the inline carbon or the nucleophile can abstract the a-hydrogen. Since both of the resulting anions can undergo further reactions, A1-piperideines have potential for the synthesis of complex six-membered ring heterocycles. 

The 7r-systems of the A2- and A3-piperideines are not reactive toward nucleophilic reagents. The A3-piperideine contains an isolated double bond whereas the A2-piperideine contains the electron-rich enamine functional group. However, treatment of either piperideine (10) or (11) with strong base (potassium t-butoxide) apparently does generate a small equilibrium concentration of the anion (217), as is evidenced by the equilibration of the A3-piperideine (10) to the more stable A2-isomer (11) (78T3027). The A2-piperideine is favored to such an extent that this reaction can be used preparatively (80JOC1336). 

The 2,3-, 2,5- and 3,4-dihydropyridines all contain a highly polarized carbon-nitrogen double bond and should be reactive toward nucleophilic reagents. From the limited information in the literature, this appears to be the situation. The 2,3-dihydropyridine is readily reduced by sodium borohydride (equation 58) (64JHC13). Hydride addition occurs in a 1,2 rather than 1,4 sense. 

Of particular interest as catalysts are the incompletely coordinated metal chelate compounds, which are sufficiently stabilized by the ligand to be stable in solution at pH values much higher than that at which the aquo metal ion would precipitate as the hydroxide and thus to become unavailable for homogeneous catalysis. Such a metal chelate would be particularly effective as a catalyst for the activation of a substrate which can coordinate to the metal ion in the chelate compound. The interaction of the substrate with the metal ion would increase its reactivity toward nucleophilic reagents such as solvent molecules or hydroxyl ions, in accordance with the following scheme ... 

A well understood case is that of quinoline reaction at position 2 is kinetically favored as compared with reaction at position 4, but the adduct from the latter is thermodynamically more stable. This situation, where the site of attack leading to the more stable adduct is the y position, is analogous with those regarding the formation of Meisenheimer adducts from benzene and pyridine derivatives and RCT nucleophiles. Presumably, with quinoline kinetic control favors the position that is more strongly influenced by the inductive effect of the heteroatom. The fact that position 2 of quinoline is the most reactive toward nucleophilic reagents is probably related to the lower 71-electron density at that position.123 However, the predominance of the C-4 adduct at equilibrium can be better justified by the atom localization energies for nucleophilic attachment at the different positions of quinoline. Moreover, both 7t-electron densities and atom localization energies indicate position 1 of isoquinoline to be the most favored one for nucleophilic addition. 

These cations undergo electrophilic substitution only reluctantly, being positively charged on the other hand, they are very reactive towards nucleophilic reagents. 

Protonated 1,4-diazines are certainly more reactive toward nucleophilic reagents than the corresponding uncharged substrates. The formation of diadducts in reactions of protonated pyridopyrazines (63JCS5737 66JCS(C)999 75AG(E)354 79JHC301), pyrazino [2,3-h] pyrazine... 

Due to their two electron-withdrawing groups, / ,/ -diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 

Among the most useful of these azolides is l,l -carbonyldiimidazole (253). This compound is extremely reactive towards nucleophilic reagents because the carbonyl group is subject to electron withdrawal from both sides. Also, although it is very rapidly hydrolyzed by water at room temperature with vigorous carbon dioxide evolution, tihe compound is crystalline, and much more easily handled than phosgene which has similar reactivity. In the formation of 1-acylimidazoles compound (253) reacts in equimolar proportions with a carboxylic acid in an inert solvent to give practically quantitative yields. This reaction comprises a two-step mechanism (Scheme 145) in which the carboxylic acid reacts initially... 

Diphenyl phosphorochloridite hydrolyzes slowly in air and more rapidly in water, but it is less reactive toward nucleophilic reagents than most chlorine derivatives of phosphorus(III). The reaction with alcohols in the presence of a tertiary base is used to prepare diphenyl alkyl phosphites. Addition of sulfur occur.s on reaction with thiophosphoryl chloride. 

The carbon atoms in cyclic sulfates and sulfites are highly reactive towards nucleophilic reagents [50], which allows us to use such functionalities as the epoxide substitutes in many reactions. The 3,5-sulfites having the neighboring free hydroxyl group were used for preparation of anhydronucleosides. Thus, D-xy/o-furanoside nucleoside 66 reacted with SOCI2 in p)Tidine to afford the cyclic sulfite 67, which upon treatment with sodium bicarbonate furnished the 2,3-anhydro-nucleoside 68 (O Scheme 21). 

Quaternary N-alkyl-1,2,4-triazinium salts are undoubtedly more reactive toward nucleophilic reagents than uncharged 1,2,4-triazines and are, therefore, attractive substrates. Only a few reports on the synthesis and reactions of N-alkyl-1,2,4-triazinium cations have been published (71CC1636 78HC(33)189 84LA283 86KGS1535 88KGS525). 

An allyl phosphate is sufficiently reactive toward nucleophilic reagents that even pyridine can be used to cleave the phosphate, albeit slowly. In this case, stronger bases could not be used because of elimination of phosphate to form a dehydroamino acid. " ... 

The 4-chloromethyl isothiazole 86, which could be obtained from the isothiazolyl carbinol by treatment with thionyl chloride, was very reactive towards nucleophilic reagents. Thus 4-chloromethylisothiazole 86 underwent a self-quaternization to form the 4-chloromethyl-3-methyl-2-(3-methylisothiazol-4-ylmethyl)isothiazolium chloride 87 (68JCS(C)611, Scheme 27). 

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