Grignard Synthesis of Bifunctional Diols

The Grignard reaction

Preparation of protected 6-bromohexan-1-ol

The Grignard reagent is widely used in synthetic organic chemistry to form carbon-carbon single bonds. Nucleophilic additions of a Grignard regent to an epoxide give a stereoselective product. This addition is one of the key steps for the preparation of the ꙍ- methoxy mycolic acid. Bifunctional diols, HO–(CH2)n–OH, were used in this work to extend chain lengths as they are inexpensive, are available in a variety of different chain length and they can be easily regioselectively modified. A Grignard reagent was needed for the reaction of the epoxide (x) and six carbon chain length 1,6-hexanediol (1) was chosen. 1,6-Hexanediol was mono-brominated with 48 % HBr by refluxing in toluene to give 6-bromo-hexan-1-ol (2). The presence of six proton signals in the 1H NMR and six carbon signals in the 13C NMR spectrum of compound 2 indicated that that the starting material (hexane 1,6- diol) had been transformed to a product. This is because the 1H NMR of the diol is only expected to show 4 proton signals and 3 carbon signals due to the presence of symmetry in the molecule. The 1H NMR spectrum of (2) showed a total of 6 proton signals and a singlet at δH 7.26 for the solvent peak, a triplet at δH 3.65 (J = 6.5 Hz) (CH2OH) and a triplet at δH 3.4 (J= 6.8 Hz) (CH2Br). The significant reduction of the coupling constants is due to the effect of electronegativity of the two electronegative elements bromine and oxygen. The rest of the signals were two proton pentets at δH 1.88 and δH1.60 with coupling constants (J=6.8Hz and J=6.7Hz) respectively, integrating for two protons each, and a multiplet at δH 1.52 – 1.36 integrating for four protons. The 13C NMR spectrum of structure (2) showed six carbon signals and a solvent peak at δC 77 ; an oxy-methylene (CH2OH) signal at δC 62.7 assigned to (C-1), a signal at δC 33.74 (C-5), a signal at δC 32.50 (C-6), a signal at δC 32.19 assigned to (C-2), δC 27.72 assigned to C-4 and δC 24.73 assigned to C-3. The 1H NMR and the 13C NMR spectrum displayed and confirmed the formation of the targeted product 6-bromohexan-1-ol.

The hydroxyl group of the 6-bromo-hexan-1-ol (2) was protected with 3,4-dihydro-2H-pyran to give 2-(6-bromo-hexyloxy)-tetrahydro-2H-pyran (3). The protection of the alcohol functional group is a necessary step in the synthetic pathway, although it increases the number of steps in the synthetic pathway. This is because it prevents side reactions involving the alcohol functional group and thus increases the yield of the desired product. It also successfully masks the alcohol functional group and provides a way of maintaining it. This is achieved by the cleavage of the pyran ring in the final step of the synthesis. 1 3,4-dihydro-2H-pyran is chosen as the protecting group is known to be widely used for its use a protecting group for thiols (R-SH), amines (N-H) and carboxylic acids (R-COOH). 2 The advantages of using THP as a protecting group include ease of introduction, suitability to most non-acidic reagents and this is because it is cleaved through acid hydrolysis and hence it cannot be used if the subsequent steps involve aqueous, acidic media.3 This reagent is also cheap and confers good solubility.1Pyridinium-p-toluene-sulfonate was used as a catalyst and dry dichloromethane as solvent. This chemical reaction results into the formation an of ether .The 1H NMR spectrum of structure 3 showed a broad one proton doublet at δH 4.52 for the acetal proton (H-5’), proving the attachment of the 2,3-dihydro-2H-pyran moiety on the 6-bromohexan-1-ol. There were also additional proton signals for the tetrahydro-2H-pyran ring protons; two one proton triplet of a doublet at δH 3.8 (J= 6; 9.4 Hz) and δH 3.48 (J =6.7, 9.4 Hz) which were assigned to (O-CH2) together with multiplets δH (1.5 to 2.0) for the other ring protons. In addition to these the 1H NMR spectrum showed a triplets at δH 3.7 (J= 6.7Hz) for the oxymethylene protons of the straight chain and a two proton triplet δH 3.35 (J= 6.7 Hz)for the methylene protons next to bromine as was seen in the 1H NMR spectrum of 6-bromohexan-1-ol . The multiplet signals δH (1.2-1.6) are due to the aliphatic methylenes as seen in the 1H NMR spectrum of compound 2. The 13C NMR spectrum of structure 3 showed a signal at δC 98.5 for the acetal carbon (C-5’), this was further confirmed by the DEPT spectrum which indicated it was a C-H. The spectrum also showed two signals at δC 67.0 (C-1’) and δC 61.9 (C-1) for the methylene carbons bonded to oxygen, one of which is for the tetrahydro-2H-pyran and the other for the oxy-bromohexyl. In addition to these eight carbon signals were also seen in the spectrum in the 13C NMR. These signals are for the methylene carbons of the aliphatic region (6-bromohexyl) and those of the tetrahydro-2H-pyran assigned as follows: δC 33.4 (C-6), δC 32.5 (C-5), δC 30.5 (C-4’), δC 29.3 (C-2), δC 27.7 (C-3), δC 25.2 (C-4), δC 25.2 (C-2’) and δC 19.4 (C-3’). Structure 3 is therefore confirmed to be 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran.The total number of carbon signals in structure 2 were only six while those of structure three were 9. This together with the structure elucidation of compound 3 showed the transformation of structure 2 to structure 3.

Addition of the Grignard reagent to the epoxide

6-(Tetrahydropyran-2-oxy)hexyl bromide (3) in dry THF was added slowly to metallic magnesium in dry THF then refluxed for one hour to generate the Grignard reagent. 4 This reagent then added to copper (I) iodide in dry THF and at – 30 oC and stirred for 30 minutes. The epoxide (4) was then added and stirred at first – 30 oC and then at room temperature to give (5). The 1H NMR spectrum of (5) showed; a one proton doublet resonating at δH 4.6 assigned to the acetal proton (H-10), two one proton triplet of doublets resonating at δH 3.9 and δH 3.8 assigned to the oxymethylene protons of the tetrahydro-2H-pyran ring (H-14), a two proton multiplet resonating at δH 3.76 assigned to the oxymethylene protons of the aliphatic chain (H-9), a one proton multiplet resonating at δH 3.4 assigned to the oxymethine (H-2), a three proton doublet resonating at δH 1.19 assigned to the methyl protons (H-1). The other proton signals similar to those for (2) and (3) explained above. The 13C NMR and the DEPT spectrum 5 showed two methine carbon peaks resonating at δC 98.8 for the acetal carbon (C-10) and δC 69.0 for the carbon attached to the hydroxyl group (C-2). The spectrum also showed the presence of a methyl carbon resonating at δC 23.5 assigned to (C-I). In addition to these the spectrum showed two oxymethylene signals resonating at δC 67.6 (OCH2-) and δC62.3 (OCH2-) and nine other methylene carbon peaks similar to those discussed earlier Structure (2) and (3). Structure (5) was thus confirmed to be (2S-9-((tetrahydro-2H-pyran-2-yl) oxynonan-2-ol. The presence of an additional oxymethine peak δC 69.0 and a methyl carbon in the spectrum of compound (5), confirmed structure (3) had been transformed to compound 5.