6,12-Dimethyl-substituted

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

It is for this reason that not only the various Sulfur-containing groups present, but also the mono- and dimethyl-substituted species of benzothiophenes and dibenzoth-iophenes have to be separated and quantified individually. As the number of sulfur compounds present in (heavy) middle distillate fractions may easily exceed 10 000 species, a single high resolution GC capillary column is unable to perform such a separation. 

The pronounced acidity of the bridgehead hydrogen atoms in 4 (R = H) facilitates the regio-selective introduction of electrophiles. Rearrangements of 4 (R = H, Me, CHO, C02Me) catalyzed by dicarbonyldichlororhodium(I) lead to 4-substituted 1-benzothiepins 5,10 except in the case of R = Me where a mixture (1 1.3) of 3- and 4-methyl-l-benzothiepin is obtained (total yield 98 %). In the case of the dimethyl-substituted derivative 8 (R1 = R2 = Me), however, the rhodium(I)-catalyzed isomerization reaction leads to the thiophene isomer. 

When /V-arenesulfonyl-a-amino acid derived boranes 13 and 14 are used in substoichiometric amounts in order to mediate enantioselective aldol additions of a,a-dimethyl substituted ketcnc acetal 15, /J-hydroxycarboxylic esters 16 are obtained in enantiomeric excess of 84 to > 99 %3fi. 

Preliminary experiments prove that the substitution pattern of the /V-aryl moiety of imine 1 is crucial for the stereoselectivity of this reaction. The 2-substituent on the aryl group is of special importance. Namely, introduction of a methoxy group leads to a considerable decrease of enantioselectivity compared to the corresponding 2-H derivative, probably due to disfavor-able coordination with the organolithium complex. In contrast, alkyl groups show the reverse effect along with increased bulkiness (e.g., Tabic 1, entries l-3a) but 2,6-dimethyl substitution provides lower ee values. Furthermore, the 4-substituent of the TV-aryl moiety is of minor importance for the stereoselectivity of the reaction [the Ar-phcnyl and the /V-(4-methoxyphenyl) derivatives give similar results], whereas a substituent in the 3-position results in lower stereoselectivities (e.g., Et, Cl, OCHj)41. 

This methodology has been used in the synthesis of aspidosperma alkaloids220,221, the construction of an ABC ring precursor for steroids 222 and the preparation of an optically active phenanthronc in 93% ee 223. / -Substituted Michael acceptors such as methyl ( )-2-butenoate are generally unreactive with A-cycloalkylidene-l-phenylethanamines, however ( )-2-butenoyl cyanide is a useful alternative. This is shown in the synthesis of enantiomerically pure cis-dimethyl substituted bicyclic lactams224. 

The rate-acidity profile for pyrimidin-2-one indicated reaction on the free base but since the derived second-order rate coefficient is 104 times greater than that for 2-pyridone, and the acidity dependence in the H0 region was also greater, the slope of log kt versus —H0 plot being 0.45, cf. 0.15 for 2-pyridone reaction was, therefore, postulated as occurring via a covalent hydrate, hydration taking place at the 4 position. Methyl substitution increased the rate as expected and N-methyl substitution produced a larger effect than 4,6-dimethyl substitution and this may be due to alteration of the amount of covalent hydration at equilibrium. The data... 

Other workers have used the fused ring system (104) and 4,5-dimethyl substitutions (105) to simplify n.m.r. studies by restriction to one chair form. In each case the stable configuration had an axial alkoxy-group at phosphorus. 

The oxidation behavior of 3-oxa-chromanols was mainly studied by means of the 2,4-dimethyl-substituted compound 2,4,5,7,8-pentamethylM /-benzo[ 1,3]dioxin-6-ol (59) applied as mixture of isomers 27a it showed an extreme dependence on the amount of coreacting water present. In aqueous media, 59 was oxidized by one oxidation equivalent to 2,5-dihydroxy-3,4,6-trimethyl-acetophenone (61) via 2-(l-hydroxyethyl)-3,5,6-trimethylbenzo-l,4-quinone (60) that could be isolated at low temperatures (Fig. 6.41). This detour explained why the seemingly quite inert benzyl ether position was oxidized while the labile hydroquinone structure remained intact. Two oxidation equivalents gave directly the corresponding para-quinone 62. Upon oxidation, C-2 of the 3-oxa-chroman system carrying the methyl substituent was always lost in the form of acetaldehyde. 

During the course of modeling copper dioxygen chemistry, Kitajima et al. reported the synthesis of a yu-peroxo dinuclear complex with a 3,5-dimethyl-substituted tris(pyrazolyl)borate ligand, which showed remarkable physicochemical similarities to oxy-Hc and oxy-Tyr. Using a 3,5-di-isopropyl-substituted terminal ligand, they provided the first structural proof of the existence of peroxo dicopper(II) core (108) (copper geometry distorted square pyrami-... 

As a typical example, Fig. 1 shows the H NMR NOE difference spectra of the monomer 3, 1-phenyl-7,7-dihexyl-8,8-dimethyl-7,8-disilabicyclo[2.2.2]octa-2,5-diene. Irradiation of the methyl peak on silicon of the major isomer enhanced the peak intensities of the methyne (H and two vinylic hydrogens (Hb). The fact clearly indicates that the major isomer has the structure 3a. The isomer ration (7.8/1) was calculated from the relative area of methyl peaks. In a similar way, structures and isomer ratios were determined for all the monomers. Table 1 lists the results. Apparently, the ratio of the isomers a/b increased with increasing steric bulkiness of the alkyl substituents on the dichlorodisilanes, reaching to 96/4 for the di(2-methylpropyl)dimethyl-substituted derivative 5. 

Synthetic use can be made of the potent electrophilic properties of ADC compounds by transforming the initial adducts into heterocyclic products. For example, reaction of DEAZD with enamine 92 gives the substitution product 93 in quantitative yield. Further treatment of this initial adduct with acid, followed by base hydrolysis leads to benzoxazol-2-ones. The dimethyl substituted enamine (92, R = Me) gives the rare, but isolable 6//-benzoxazol-2-one ring system (Scheme 13).147... 

The dimethyl substituted triafulvenes 21 la-e (Table 11) show methyl resonances considerably shifted downfield from dimethyl cyclopropenone. The same... 

Table 11. Comparison of CH3 chemical shift and difference to reference 200 of several dimethyl-substituted triafulvenes to pKa of the corresponding H2X compounds...

The moderate specificity for forming m-2-butene initially (see Fig. 1) is again consistent with equatorial orientation of isopropyl the rather low cis specificity indicates only a moderate preference for equatorial orientation of the a-methyl, probably because of the offsetting weak repulsions caused by cis- 1,2-dimethyl-substitution. This effect is absent in the metathesis of tra i-4-methyl-2-pentene, and trans specificity for... 

The angle 6 is defined according to Scheme 2, the exact definitions of the angles in the last column, describing the double bond torsion, being given in Reference 38. Here we note only that 0 ° torsion means a planar olefin. The values are reported only for dimethyl-substituted double bonds. 

Rearrangement of the 3,5-dimethylated carbene Id would yield the destabilized cyclopropene 3d with a methyl group in the bridgehead position 1, and consequently no detectable amount of cyclopropene 3d is formed during irradiation of Id. Indeed, whereas the 3,5-dimethyl substituted carbene Id is 3.4 kcal mol-1 more stable than the 2,6-dimethyl isomer lb, the stability is reversed for the cyclopropenes, as 3d is found to be 6.5 kcal mol-1 higher in energy than 3b at the B3LYP/6-31G(d) level of theory (Table 3). 

Table 3. B3LYP/6-31 G(d) Energies (E i/kcal mol-1) of the 2,6-Dimethyl-substituted Species 1 b, 3b and the Transition State Relative to the 3,5-Dimethyl-substituted Species 1 d, 3d...

The addition of a beta-methyl to the side chain dramatically attenuates activity in animal models (1,155). An a,/3- or /3,/3-dimethyl substitution also abolished hallucinogen-like activity in animal models (1). 

---