3-Amino-5- -2-methyl- -iodid

The amino group activates the thiazole ring toward electrophilic centers. This point is illustrated by the rate constants of the reaction between 2-dialkylaminothiazoles (32) and methyl iodide in nitromethane at 25 C (Scheme 23) (158). The steric effects of substituents on nitrogen are... 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

However, these authentic cyclic compounds are converted by acetic anhydride or methyl iodide into derivatives of the hypothetical amino-aldehyde form. Methylation gives first the cyclic methiodides (23a-b) and (24) which occur by the addition of a single molecule of methyl iodide in the presence of sodium hydroxide and excess methyl iodide these are converted into the open-chain quaternary methiodides (25a-b) and (26). Similar examples have been given by Garden and by Gensler and co-workers. ... 

Aminopyrimidine is the only monosubstituted derivative studied in which the position of quaternization is ambiguous. Methyl iodide and the 4-amino compound react slowly in 2-ethoxyethanol at 100° to give the N-1 salt (42 R = H), whereas 5-aminopyrimidine and... 

It is also interesting to note that quatemization of a chloropyrimi-dine at the nitrogen atom adjacent to the chloro group with methyl iodide results in the easy replacement of the chlorine by iodine, whereas similar salt formation on the remote nitrogen either leaves the chlorine unaffected or replacement occurs only at higher temperatures. A similar reaction occurs between 2-amino-6-chloro-4-methylpyrimidine and dimethyl sulfate in nitrobenzene to give the salt 45 and betaine 46. ... 

Atkinson and Taylor summarized the evidence in support of the earlier assumption, arising from the evidence discussed above, that quatemization occurs on N-1 and also showed that 4-amino-, 4-amino-6-nitro-, and 4-amino-7-chloro-cinnoline gave two salts with methyl iodide, while 4-amino-8-nitrocinnoline gave only one salt and the... 

The structure of only one 1,2,4-thiadiazole salt has been determined. Unambiguous synthesis of the imino compound obtained on alkali treatment of the salt formed by the reactions of methyl iodide with 5-amino-1,2,4-thiadiazole established that the salt possesses structure 7 136 pjjjg quatemization exactly parallels the reaction occurring in... 

When 2-amino-4-methylimidazo[4,5-/]quinoline (R = Me, R = H) was alkylated with methyl iodide in K2CO3-DMSO, a mixture of both 1//-1,4-dimethyl- and 3//-3,4-dimethyl derivatives was obtained (80CL1391). In the case of DMF-DMA or its bis-trideuterio analogue, methylation in the ratio 8 1 in favor of the 3//-isomer is preferred (88SC973). 

The reaction of 3-amino-1,2,4-triazine 1-oxide 1 with methyl iodide in the presence of sodium bicarbonate leads to the methylation of the amino group to afford 3-methylamino-l,2,4-tiiazine 1-oxide 123. This iV-oxide 123, under neutral conditions in the presence of Mel, undergoes methyl group migration to the N(2) atom of the 1,2,4-triazine ring, yielding 3-imino-2-methyl-1,2,4-triazine 1-oxide 124. The same product 124 was obtained by direct methylation of compound 1 under neutral conditions (84TL1677). 

Bischler-Napieralski reaction of 139 to a 3,4-dihydroisoquinoline, oxidation, dehydrogenation and reduction of the nitro to the amino function gave 140 which was subjected to a Pschorr reaction (Scheme 49). Quaternization was accomplished by methyl iodide to furnish the isoquinolininium salt 141 which underwent an ether cleavage on heating a solid sample or benzene or DMF solution to Corunnine (127) (73TL3617). 

The ultraviolet and infrared spectra of 2-aminothiazole and the methyl derivatives of both the imino and the amino forms have been compared and discussed by Sheinker, Kushkin, and Postovskii ° who showed that the amino form predominates in the solid state and in various solvents. The reaction of 2-aminothiazoles with methyl iodide in the presence or in the absence of sodium ethoxide has been considered to give information concerning the proportion of the amino and imino forms present under these conditions, ... 

It has been prepared synthetically by Ewins in the following manner Meta-oxybenzoic acid is converted with the aid of dimethyl sulphate into m-methoxybenzoic acid, which is then nitrated, and from the nitration products 2-nitro-3-methoxybenzoic acid is separated. This is reduced to 2-amino-3-methoxybenzoic acid which on heating with methyl iodide, yields 2-methylamino-3-methoxybenzoic acid. On warming this with freshly precipitated silver chloride it yields damascenine hydrochloride. 

The synthesis of 987 from 985 via 986 has been reported (83S759) by reaction of 985 with aryl isothiocyanates under neutral conditions. The reaction of 4-amino-6-anilino[l,2,4]triazine 988 with methyl iodide and then carbon disulfide gave 989 (90MI3, 90MI9). 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

WIN 64821 (10) and (—)-ditryptophenaline (11) syntheses [7], not only effectively differentiated the two amide moieties but also most importantly marked the first in a series of stereochemical transfer steps in which the stereochemistry of the constituent L-amino acids was relayed to ultimately define each of the relative and absolute stereochemical configurations at all eight stereogenic centers found in the target compound. Finally, /V-methylation of the base-sensitive amide in 77 % yield using methyl iodide and potassium carbonate in acetone completed the 5-step synthesis of our key tetracyclic bromide monomer starting from commercially available amino acid derivatives. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Thiadiazoles are weak bases. They form salts with mineral acids and addition compounds with heavy-metal salts. Methylation of 5-amino-l,2,4-thiadiazoles 17 leads to the product of methylation at the 4-position 18 (Equation 2) <1996CHEC-II(4)307>. More recently, the reaction of the 3-methylthio derivative 19 with methyl iodide led to methylation at N-4 to afford product 20 (Equation 3) <2001CHE1005>. 

FIGURE 8.16 Preparation of Cbz/Boc-/V-methylamino acids by methylation of Cbz/Boc-amino acids. [Benoiton et al., 1972]. Sodium hydride is added to substrate and methyl iodide in tetrahydrofuran, producing the sodium salt of the /V-methylated derivative. 

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