Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: benzyl versus o-tolyl rearrangement

Summary The Grignard reaction of 2,3-O-isopropylidene-α-D-lyxo-pentodialdo-1,4-furanoside and benzylmagnesium chloride (or bromide) afforded a non-separable mixture of diastereomeric benzyl carbinols and diastereomeric o-tolyl carbinols. The latter resulted from an unexpected benzyl to o-tolyl rearrangement. The proportion of benzyl versus o-tolyl derivatives depended on the reaction conditions. Benzylmagnesium chloride afforded predominantly o-tolyl carbinols while the application of benzylmagnesium bromide led preferably to the o-tolyl carbinols only when used in excess or at higher temperatures. The structures of the benzyl and o-tolyl derivatives were confirmed unambiguously by NMR spectral data and X-ray crystallographic analysis of their 5-ketone analogues obtained by oxidation of the corresponding mixture of diastereomeric carbinols. A possible mechanism for the Grignard reaction leading to the benzyl→o-tolyl rearrangement is also proposed.


Introduction
One of the most popular synthetic routes leading to the formation of simple alkyl or aryl branched-chain sugars involves the addition of Grignard reagents. In this regard, a wide variety of Grignard reagents have been added to the free or masked (as hemiacetal) carbonyl functionalities present in the molecule of a suitable fully O-protected saccharide, thereby making possible the preparation of a series of useful carbohydrate derivatives [1][2][3][4][5][6][7][8]. Despite the demonstrable advantages of the Grignard reaction, there remain, in addition to the recognised drawbacks, some new unexpected impediments limiting its application in the synthesis of branched carbohydrates.
In the context of our studies on the synthesis of sugar amino acids structurally related to iminosugar mannojirimycin (a strong inhibitor of α-mannosidase), we have recently prepared, by applying the Grignard reaction, several branched sugar carbinols as intermediates for subsequent oxidation to ketones affording the corresponding hydantoins (precursors of amino

Results and Discussion
Although 1 and 2 have frequently been used for the introduction of the benzyl group into a carbohydrate molecule [12][13][14][15][16][17][18], the benzyl→o-tolyl rearrangement has, to the best of our knowledge, only been reported once. In this regard, Panigot and Curley [19] showed that the reaction of 1 with 2,3,4,6-tetra-Oacetyl-α-D-glucopyranosyl bromide (or chloride) produced a 3:1 mixture of 2-(β-D-glucopyranosyl)toluene and (β-Dglucopyranosyl)phenylmethane isolated as the corresponding 2,3,4,6-tetra-O-acetates. However, this is not a case of the typical Grignard reaction where the Grignard reagent is coupled with a carbonyl compound. Moreover, the anomeric position was involved in the reaction and there was an important limitation: the formation of the unexpected o-tolyl rearrangement product entailed the participation of both of the equatorially disposed 2-and 6-acetoxy groups present in the substrate. The non-acetylated substrates (like O-benzyl) afforded solely nonrearranged benzyl derivatives. Our results represent the situation where the benzyl→o-tolyl rearrangement occurs during the Grignard reaction between 1 or 2 and the non-anomeric free aldehyde function (C-5 position of the furanose) of an O-alkyl (methyl and isopropylidene)-protected carbohydrate.
First, the addition reaction of aldehyde 3 with 1 under the standard Grignard reaction conditions (method A, see Experimental part) was examined. Based on the NMR spectral data of the isolated product, a mixture of 5-(R) and 5-(S) o-tolyl derivatives 4 and 5 together with a mixture of 5-(R) and 5-(S) benzyl derivatives 6 and 7 (Scheme 1) in the ratio of approximately 3:1 was confirmed, indicating the substantial predominance of the benzyl→o-tolyl rearrangement. In the subsequent experiments (methods B-E), the influence of the reaction conditions (temperature, reactants ratio, solvent, sequence of reactants addition) was examined, with the aim of suppressing the formation of the rearranged products 4 and 5. As the preliminary experiments revealed that the addition of a solution of Grignard reagent 2 into a solution of the carbohydrate aldehyde 3 (i.e., reverse addition of reactants) in the mole ratio of 1.3:1 had some positive effect in respect of the yield (but not of the proportion of isomers) of the Grignard reaction products, we applied these parameters in subsequent experiments. It was found that the application of 2 instead of 1 also afforded a mixture of o-tolyl and benzyl carbinols but their proportion was dependent on the reaction conditions (see Table 1 and Table 2). The mixture of diastereomeric carbinols 6 and 7 resulted as a main product of the "normal" Grignard reaction only at lower temperature without excess of 2. Only a minor positive effect on the formation of "normal" addition products 6 and 7 was observed using 2-methyltetrahydrofuran as a solvent as well as the addition of an equivalent of CeCl 3 ·2LiCl in THF to the reaction mixture, although it is known that the application of these reagents favours the addition of Grignard reagents to carbonyl compounds to afford higher yields [20][21][22]. Since all attempts to separate and purify carbinols 4-7 using column chromatography were unsuccessful even after acetylation, their physical and spectral data are not given here in detail. In this regard, the ratio of the R and S isomers thus formed has not been studied. However, based on the NMR data (signals for methyl and methylene group of o-tolyl and benzyl group, respectively) of the isolated crude mixture of products 4-7, it was possible to determine the relative ratio of o-tolyl and benzyl isomers. Finally, for the separation of o-tolyl isomer from benzyl isomer, a mixture of all four chromatographically nonseparable isomeric alcohols 4-7 was oxidised using PDC, thereby destroying the chiral center at C-5 position of the saccharide moiety, to afford a mixture of the two corresponding crystalline ketones 8 and 9. These were successfully separated and purified using column chromatography and recrystallisation. Their structures were established on the basis of 1 H and 13 C NMR spectral data. The EI mass spectra and the data of elemental analysis were also confirmative. The singlet signal observed for the H1 atom strongly supports the α-configuration at the anomeric atom C1 with the equatorially positioned H1 and H2. A singlet (three protons) at δ = 3.91 and a singlet (two protons) at δ = 2.48 clearly indicate the methyl (in o-tolyl) and methylene (in benzyl) groups, respectively. Finally, the o-tolyl structure and benzyl structure of the moieties at C-5 atom of ketone 8 ( Figure 1) and ketone 9 ( Figure 2), respectively, (the numbering of the atoms is in accordance with the numbering recommended by the IUPAC Nomenclature of Carbohydrates [23]) was unambiguously confirmed by singlecrystal X-ray analysis.
The formation of o-tolyl isomers 4 and 5 can be explained by the possible reaction sequence (path 1) depicted in Scheme 2. The first step involves an addition of the Grignard reagent to the saccharide aldehyde, producing a trienic magnesium alkoxide  [24,25] for the reaction of 1-naphthylmethylmagnesium chloride (10) with some aldehydes and ketones (Scheme 3). However, in this case, a trienic magnesium alkoxide intermediate E (magnesium salt of 2-hydroxymethyl-1methylene-1,2-dihydronaphthalene, an analogue of intermediate A in Scheme 2, path 1), produced by an addition of the Grignard reagent 10 to the monomeric formaldehyde (11, R 1 = R 2 = H), was unstable and decomposed by a reversible process into the Grignard reagent and aldehyde. The latter underwent a Prins-type reaction with the magnesium alkoxide intermediate E in the presence of MgCl 2 , to give magnesium salt G which, upon quenching with aqueous NH 4 Cl, affords 1-(2-hydroxyethyl)-2-hydroxymethylnaphthalene H (an analogue of diol D in  Scheme 2, path 2) and 1-methylnaphthalene (12). On the other hand, the reaction of 10 with ketones produced either normal benzylic alcohols, rearranged alcohols or a mixture of both, depending on the steric hindrance. However, the rearranged alcohols representing 1-methylene-2-substituted-1,2-dihydronaphthalenes F (analogues of intermediate B in Scheme 2) were unstable and decomposed to 1-methylnaphthalene (12)  To extend and confirm these observations, the analogous addition of 1 as well as 2 to another two representative carbohydrate aldehydes -3-O-benzyl-1,2-O-isopropylidene-α-D-xylopentodialdo-1,4-furanose and 1,2:3,4-di-O-isopropylidene-α-Dgalacto-hexodialdo-1,5-pyranose were investigated next. Unfortunately, only very complex reaction mixtures (including diatereomeric carbinols, biphenyl, polymeric impurities, etc.) resulted under the above reaction conditions. However, analysis of the NMR spectral data of these mixtures showed the absence of CH 3 protons of the o-tolyl moiety, indicating that the benzyl→o-tolyl rearrangement did not occur in these cases; accordingly, no further detailed inspections of the reaction mixtures were performed.

X-ray analysis
Single crystals (stable at ambient temperature) suitable for X-ray diffraction were obtained by the slow crystallisation of 8 and 9 from MeOH by cooling in a refrigerator. The preliminary orientation matrices and final cell parameters were obtained using Siemens SMART and Siemens SAINT software [26]. The data were empirically corrected for absorption and other effects using the SADABS program [27] based on the method of Blessing [28]. The crystal and experimental data for 8 and 9 are summarised in Table 3 and Table 4. The structure was solved by direct methods and refined by full-matrix least-squares on all F 2 data using Bruker SHELXTL [29]. The non-H atoms were refined anisotropically. All the hydrogen atoms were constrained to the geometrically idealised positions using an appropriate riding model. Molecular graphics were obtained using the program DIAMOND [30].  Based on the calculated values of the ring-puckering parameters (Q, Φ, θ) [31] (Table 5) and relevant torsion angles (Table 6)

Ring
Torsion angle Compound