Synthesis and stereochemistry of some multi methyl-substituted 1,3-dioxanes

Several multimethyl-substituted 1,3-dioxanes [ trans -2,4,4,6-tetramethyl ( 1 ), r -2,4,4, c -5, t -6- pentamethyl-( 2 ), r -2,4,4, t -5, t -6-pentamethyl ( 3 ) and trans -2,4,4,5,5,6-hexamethyl-1,3-dioxanes ( 4 )] with 2,6-trans-disubstitution has been prepared via the Grignard reaction of the corresponding axial 2-methoxy-1,3-dioxanes. Inspection of their 13 C NMR chemical shifts in respect of different substituent effects showed that 1 and 3 attain exclusively the 1,4-twist form whereas 2 and 4 still favor clearly the chair form due to the very strong steric interaction caused by the pseudo axial methyl groups at position 5. We also manage to equilibrate 1 and its cis-epimer ( 5 ) although less than 1% of 4 was present at equilibrium. Thus only − G o = 12.9±0.5 kJ mol − 1 could be given and it compares well with some literature values. Since the conformational energy of 4-axial methyl group in 5 is 12.2 kJ mol − 1 the  H(1,4-CT) is equal to 25 kJ mol − 1 again in good agreement with an earlier estimate.


Introduction
A great number of methyl-substituted 1,3-dioxanes have been prepared earlier. 1 However, only after Eliel and Nader 2 developed their special method for preparing trans-2,4,4,6-tetramethyl-1,3-dioxane it became possible to synthesize also other trans-2,6-methyl-substituted 1,3dioxanes.−5 It was concluded quite some time ago that if there is no pseudo axial substituent in the twist form, the 2,4-syn-diaxially substituted derivatives attain a 2,5-or 1,4twist form (Figure 1) depending on the location of the geminal substitution in position 2 or 4, respectively. 3,6The 1,4-twist form appears to be ca.3 kJ mol −1 more stable than the 2,5-twist form [H(1,4-CT) 25.0 kJ mol −1 ; H(2,5-CT) 28.7 kJ mol −1 ]. 3,5 By applying the method of Eliel and Nader 2 we prepared a few trans-2,6-methyl-substituted derivatives where one or the other of these substituents occupies an axial orientation (if being in a chair form) to get further insight into the chair-twist problem.

Results and Discussion
The experimental 13 C NMR chemical shifts for the compounds 1−4 are given in Table 1 together with those estimated for 2, 3 and 4 using the shift increments reported earlier by Pihlaja et al. [3][4][5] C(x) = Cp(x) In this equation C(x) is the C-13 chemical shift of the xth carbon, Cp(x) the shift of this carbon in the parent compound and SE(x) the sum of substituent effects influencing on the xth carbon.
It has already been shown that 1 attains the 1,4-twist form 2,3 and by comparing its chemical shifts with those of 3 it is easy to believe that also 3 is predominantly in the 1,4-twist form (Fig. 2) since 2-Me, 6-Me and 5-Me attain there pseudo equatorial positions and both methyl groups at C-4 are isoclinal thus being able to avoid any major interactions.Table 1 lists the chemical shifts estimated for 3 by adding to the chemical shifts of 1 additional increments based on the orientation of the 5-methyl substituent (pseudo-equatorial) in the 1,4-twist form in relation to the other substituents.Despite the fact that the additional increments were originally derived for the chair form the very good agreement between the calculated and estimated chemical shifts (Table 1) proves that 3 favors greatly the 1,4-twist form.The JH-5,H-6 = 10.4Hz fits also very well for this 1,4-twist structure where both H-5 and H-6 are pseudoaxial.In fact the sum of JH-4,H-5 couplings in the 1,4-twist form of 1 is 15 Hz (2x7.5 Hz 8 ) corresponding roughly an average of 5 and 10 Hz.
The equilibration of 1 and 5 (Fig. 5) pointed out that cis-2,4,4,6-tetramethyl-1,3-dioxane 5 is clearly more stable than 1 which attains the 1,4-twist form. 2,3,5Although we carried out the equilibrations at three temperatures (Table 3) the amount of 1 at equilibrium with 5 was so small that the integration of its peak ought to be carried out manually which caused a substantial deviation (Table 3) and therefore we just accept the average −G o = 12.9 kJ mol −1 to represent the standard Gibbs energy difference between 5 (having a 4-axial methyl, the conformational energy 3 of which is 12.2 kJ mol −1 ) giving a value ca. 25 kJ mol −1 for H(1,4-CT).The former value (−12.9 kJ mol −1 ) is in good agreement with the calculations of Burkert 6 based on molecular mechanical computations but is far from the estimate −G o  22.8 kJ mol −1 given by Eliel and Nader. 2 The value 25 kJ mol −1 has been reported for H(1,4-CT) also earlier.

Preparation of 2-methoxy-1,3-dioxanes.
A 250 ml three-necked bottle was equipped with a magnetic stirrer, a heating mantel and a distillation system.0.3 mol of trimethyl orthoformate together with an equivalent amount of an 1,3-diol was placed in the bottle.60 ml of cyclohexane (Merck, reinst) was purified by distillation and added in the bottle together with a catalytic amount of p-toluenesulfonic acid (Merck, pa).Thereafter the mixture was heated whereupon the atseotropic mixture formed by the methanol product and cyclohexane was distilled off.The heating was continued until the vapor reached a 353 K temperature.At this stage the reaction mixture was allowed to cool to room temperature.Then 1-2 g of K 2 CO 3 was added and the mixing was continued for two hours to neutralize the catalytic acid.Then the mixture was filtrated with mild suction.The precipitate was washed three times with ether and the solvent was removed from the combined liquid phase by evaporation at ordinary pressure.The product was distilled under reduced pressure through a short Vigreux column.The raw product boiled within a range of 12-15 degrees.The isomeric products (when possible) were separated with a Perkin Elmer 251 Auto Annular Still precision distiller at reduced pressure.The distillate was collected on anhydrous K2CO3 to avoid epimerization.2-Methoxy-4,4,5,6-tetramethyl-1,3dioxane decomposed in the precision distiller.A 90 % pure product was obtained by distilling it through a Hemppel column equipped with a vacuum mantle.
13 C NMR spectra.The noise-decoupled spectra were recorded on a Jeol GX-400 spectrometer operating at 100.53 MHz for 13 C ( and 399.78 MHz for 1 H).All spectra were recorded in 5 mm o.d.tubes using the solvent (CDCl3) deuterium signal for field locking.Internal TMS was used as the reference.
The reflux was ceased when the color of the Grignard reagent vanished and a dark oily precipitate formed.The reaction mixture was allowed to cool to room temperature before ca.3.5 ml of ice cold saturated ammonium chloride solution was added with vigorous stirring.The white precipitate formed was separated with a mild suction and washed with six 50 ml portions of warm ether.The combined ether extracts were dried with anhydrous MgSO4 and excess ether evaporated with rotavapor and the rest by distillation under normal pressure.The product was fractionated at reduced pressure and collected on anhydrous K2CO3 to avoid epimerization.
It has been shown earlier that 1 attains the 1,4-twist form and 5 exists in the chair form. 3,4The peaks of both isomers were well separated in gas chromatogram and therefore this technique was applied for the analysis of their equilibrium mixtures (Fig. 5) at three different temperatures.The equilibration was carried out in ether solution which was 0.1 molar in respect of both the substrate and the catalyst, trifluoroacetic acid (EGA Chemie, purum).The samples were sealed in glass ampoules and equilibration was carried out at 298, 313 and 333 K.The equilibrium mixtures were analyzed on a Perkin Elmer Sigma 2 B gas chromatograph using a 30 m XE 60 capillary column.The samples were neutralized before analysis with triethyl amine (Fluka AG, purum).The results of equilibrations after 100 days are shown in Table 4.

Table 2 .
13C NMR shift effects caused by the 4a5e6a-Me 3 and 4a5a6a-Me 3 substitutions

Table 3 .
Equilibrium constants and standard Gibbs energy differences between cis-5 and trans-