Ring methylation

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

The reactivity of sulfathiazoles has been reviewed (65). Methylation in alkaline solution with dimethyl sulfate gives only the ring methylated derivative (85). Mixtures of products are obtained with diazomethane as alkylating agent (see p. 37). Other alkyl halides in aqueous alkali lead also to ring-alkylated products (85. 251, 650. 669-671). 

Ring-methylated 1-ethynylpyrazoles were similarly obtained as minor produets in the pyrolysis of 3,5-dimethyl- and a mixture of 3- and 5-methyl- 1-propynoylpyrazoles. Pyrolysis of the 3-methyl derivative gave only pyrazolo[l,5-a]pyridin-5-ol... 

The selectivity 3,0 is strongly dependent on the Mg content (Fig. 4). It increases with Mg concentrations up to 7 5%, passing through a maximum of S3.0 = 0.65. 3-methyl catechol becomes the main product at low conversion. It is worthwhile to note that only the relative formation of guaiacol and 3-methyl catechol are affected by the percentage of Mg added to alumina, 0-alkylation is reduced in favour of C-alkylation, but the ring methylation stays preferentially ortho-selective. 

Raddeanamine (360) is an unusual spirobenzylisoquinoline alkaloid having a tertiary methyl group in five-membered ring. Methylation of the corresponding ketone gave the methyl carbinol with the reverse stereochemistry, namely, the methyl carbinol 361 was obtained from the reaction of the ketone 294 with methyllithium (Scheme 64). Stereoselective synthesis of ( )-raddeanamine was accomplished by an intramolecular oxyfunctionalization via the 8-methyl-8,14-cycloberbine 364 (175). 

In view of the activity of 13, but the lack of activity for the alpha-ethyl homolog of DOM, the two isomeric ring-methylated derivatives Structures 16a and 16b were recently prepared (114). Neither isomer showed significant activity, either as an agonist in the rat fundus preparation or in a mouse assay, when compared with 13. It would appear that little bulk can be tolerated near the alpha-carbon, other than a methyl or methylene. 

Jacob, J. N., and Nichols, D. E. (1982) Isomeric cyclopropyl ring-methylated homologues of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, an hallucinogen analogue. J. Med. Chem., 25 526-530. 

The dopamine D2 agonist SAR area has been reviewed by Hacksell and coworkers from the perspective of stereochemistry and pharmacological profiles of the enantiomers of the compounds synthesized by that research group during a period of 10 years. The structural classes surveyed were 3-phenylpiperidines, 2-aminotetralins and their ring-methylated analogues and octahydrobenzo[/]quinolines (OHB[f]Qs) [60]. 

S-Values of the Ring Methyl Singlet in Isomer 149 and the Amidine Methyl Singlet in Isomer 150 the Ratio 150/149... 

Fig. 17 Variation of reaction free energy (kcal/mol) with temperature (K) for alkyl C—H hydrogen atom loss in (a) five-membered ring methyl-substituted heteroaromatic rings and (b) six-membered ring methyl-substituted heteroaromatic rings.

Ring protons of 1,2,5-selenadiazoles (29) resonate at low field (Table 4). The chemical shifts of ring methyl groups lie at ca. 6 2.6 (79S979, 87H(26)2153>. The chemical shifts of the ring protons of three 1,2,5-telluradiazoles, (30a)-(30c), in DMSO-dg appear between S 10.7 and 11.5. The 3-methyl... 

Table 4 Proton NMR chemical shifts ( ) of ring hydrogens and ring methyl groups in 1,2,5-selenadiazoles (29) and 1,2,5-telluradiazoles (30) .

The HNMR spectra of the diaqua and aqua (hydroxo) hemin complexes encapsulated in micelles have been reported [20] (Fig. 5). The heme methyl resonances in the diaqua species lie in the same region as those of the high-spin bis(dimethyl sulphoxide) iron (III) porphyrin complex [37-39], while those of the aqua (hydroxo) complex appear in a more upheld region. The positions and linewidths of the heme methyl resonances in these complexes are similar to those observed in the aqua and hydroxo hemoproteins [19,40]. The broadness of the ring methyl resonances of both the diaqua and aqua (hydroxo) species in micelles has been ascribed to arise from the hindered rotational tumbling motion of the heme inside the micelles. The spread and linewidth of these resonances are much larger than those of similar high-spin model heme complexes in simple solution [3]. 

Fig. 6a, b. Temperature variation of the paramagnetic shift of ring methyl proton resonances of (a) diaqua hemin, and (b) aqua hydroxo hemin complexes, in 5% aqueous SDS micelles. (Taken from Ref. 20)... 

The temperature dependence (296-330 K) of the ring methyl proton resonances of these monomeric heme complexes in the hydrophobic micellar cavity shows [22] a small deviation from the Curie law as in the low-spin complexes in organic and simple aqueous solvents [1, 52]. The origin of such deviation has been variously ascribed [3, 1, 53] either to aggregation or second order Zeeman (SOZ) effect or presence of low-lying spin-quartet state. Since these low-spin hemes in micellar solutions are in deaggregated form, the deviation may be due to the SOZ and/or presence of low-lying excited state. 

Dialkyl ketones 10 (Scheme 4) react with ammonia and excess sulfur at low temperature to give moderate yields of 2//-imidazoles 11. The method complements those above in allowing the introduction of alkyl substituents into the 4- and 5-positions of the ring. Methyl ketones (10 = H), in... 

---