Magnesium-mediatedortho-specific formylation and formaldoximation of phenols

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1994 Magnesium-mediated ortho-Specific Formylation and Formaldoximation of Phenols Robert Aldred,a Robert Johnston,e Daniel Levin *re and James Neilan" a Zeneca Fine Chemicals Manufacturing Organisation, Process Technology Dept., Hexagon House, Blackley, Manchester M9 SZS, UK Zeneca lnc., Chemical Technology Group, Wilmington, Delaware, USA Deprotonation of phenols using magnesium methoxide, followed by distillative removal of free methanol and addition of paraformaldehyde results in ortho-specific magnesium-mediated formylation to give the corresponding salicylaldehyde magnesium salts, from which the salicylaldehydes can be isolated by acidic work-up. Addition of aq. hydroxylamine sulfate to the salicylaldehyde magnesium salts, in place of the acid work-up, gives the corresponding salicylaldoximes. Significant industrial demand exists for ortho-formyhted phenols and their derivatives (including the corresponding oximes), for example as intermediates for the synthesis of various pharmaceuticals, agrochemicals, fragrance chemicals, ' mining chemical ligands and other products.Whilst con- ventional aromatic formylation procedures (e.g.Duff,3Reimer-Tiemann,4 Vilsmeier or Gatterman reactions) can be effective when the phenol hydroxyl is derivatised (for example, as an ether'), attempted formylation of the free phenol by these procedures frequently gives rise to poor yields and/or poor regioselectivity, or a predominance of para-formylation. a,a-Dichloromethyl methyl ether can be used for efficient formylation of phenols,8 but use of this material on a large scale is unattractive owing to toxicity and cost.Phenols can be ortho-formylated by formaldehyde in the presence of one of a variety of metal salt catalysts (e.g.use of Sn,' Fe,' '*I2 Cr l3 and Zr lo salts) but such reactions generally require high pressure and can give rise to unattractive process-effluent implications. Formylation of aryloxymagnesium bromides by formaldehyde oximation of the derived formylated products by hydroxyl- amine sulfate, again catalysed by the magnesium cation. Results Reaction of phenols 1with magnesium methoxide in methanol (or a methanol-toluene azeotropic distillate recovered from a subsequent step of the reaction sequence) gives the correspond- ing phenol magnesium salts 3 (Scheme 2).These magnesium 1 L = sdvating ligand, e.g. MeOH 3 a R=H b R=o-Me c R=m-Me d R =p-Me has been reported by Casiraghi, Casnati and co-worker~.'~ 8 R=o-F f R=m-FThese authors, however, prepared their phenol magnesium g R=p-Fsalts by the reaction of the parent phenols with alkyl Grignard h R = o-Me and p-Me i R=o-OMe j R = p-OMe k R = p-CI I R =p-NO, m R = o-BuS n R =m-Bur o R = p-C,H,, (mixed isomers) p R = p-C,,H, (mixed isomers) EtMgBr (1 eq.)___t R Et20 R ii, H30* R CHO 1 2 Scheme 1 ence of stoichiometric amounts of hexamethylphosphoramide (HMPA). They subsequently dismissed this chemistry as having limited large-scale applicability due to the need for the considerable amount of toxic HMPA and for the troublesome preparation of the magnesium phenolates.Mindful of the potential environmental advantages associated with catalysis by magnesium salts, compared with use of many other formylation catalysts (magnesium already being distributed in its various salts as the 6th most abundant element on the earth's surface16), we undertook investigation of alternative conditions for the synthesis and reaction of phenol magnesium salts with the aim of avoiding the disadvantages of the conditions involving Grignard reagents and HMPA reported by Casiraghi and Casnati.I4 We now report the successful ortho-formyl- ation 'by paraformaldehyde of magnesium bis(phenoxides) prepared from phenols and magnesium methoxide, using methanol as the cosolvent instead of HMPA.We also report reagents (Scheme 1) and carried out formylation in the pres- Scheme 2 OMgBr i, paraformaldehyde benzenbHMPA0'' aoHsalts in methanol are not efficiently formylated by formalde- hyde, however, removal of the free methanol by distillation with the addition of toluene (or xylene) as a replacement solvent, followed by the addition of paraformaldehyde at around 95 "C (with removal of volatile reaction by-products by distillation) gives the corresponding salicylaldehyde magnesium salts 4 as a result of formylation at the position ortho to the parent phenol hydroxyl (Scheme 3). The ortho-formylated phenols 2 are 3 4 2 Scheme 3 obtained from their magnesium salts by acidic work-up.Formylation yields are summarised in Table 1. Methanol is produced as a formylation reaction by-product and, if it is not removed by distillation during the course of the reaction, the progress of formylation is inhibited, resulting in poorer conversion of starting material to products. The major by-products from the reaction (as seen by GCMS, size exclusion J. CHEM. SOC. PERKIN TRANS. 1 1994 Table 1 Formylation of phenols 1to give salicylaldehydes 2 Yield of Unchanged starting Starting phenol 1, Salicylaldehyde salicylaldehyde phenol 1 substituent R product 2 (7 (7 H a 83 c2 3-Me C 74a C1 2-F e 5b ca. 72 3-F f 72 b~c C1 4-F g 46 ca. 36 2-OMe i None detected 95 4-OMe j 94 I 4-c1 k 33 ca.38 4-NOZ I None detected 95 4-Nonyl (mixed isomers) o 78 C1 4-Nonyl (mixed isomers)b o 85 el 4-Nonyl (mixed o 81 b*e c2 a 80 : 20 Ratio of 2-hydroxy-4-methylbenzaldehyde: 2-hydroxy-6-methylbenzaldehydeisomers by 3CNMR. Formylation carried out under reduced pressure (other examples carried out at atmospheric pressure). 86 : 14 Ratio of 4-fluoro-2-hydroxybenzaldehyde: 2-fluoro-6-hydroxybenzaldehyde isomers by 'H NMR and GC. Size exclusion chromatography and mass spec. indicate presence of 9.4 diarylmethanes 5 and 2.9 trinuclear products 6. Xylene as reaction solvent (other examples carried out in toluene). Table 2 Formaldoximation of phenols 1to give salicylaldoximes 7 Yield of Yield of diarylmethane Unchanged Intermediate Starting phenol 1 substituent R Salicylaldoxime product 7 salicylaldoxime(I by-product 5 (I starting phenol 1 (I aldehyde 2 ( H a 88 24 1-2 ca.2 2-Me b 56 ca. 29 co.1 ca. 1.5 3-Me C 72 ca. 5 co.1 ca. 3b 4-Me d 74 ca. 1.5 1 ca. 4' 2-Me and 4-Me h 33 ca. 65 co.1 C1 2-Me and 4-Me' h 58 ca. 35 co.1 1 4-OMe 2-BuS m j 84 14 ca. 3 ca. 58 4.5 C1 C1 c2 3-Bu' n 63 ca. 5 c0.5 c 1.5 4-Nonyl (mixed 4-Dodecyl (mixed isomers) 0 P 83 87.3 ca. lod Not determined c 1.5 I C1 c2 isomers) a ca. 80 : 20 Ratio of 2-hydroxy-4-methylbenzaldoxime: 2-hydroxy-6-methylbenzaldoximeisomers, estimated by NMR. Aldehyde due mainly to oxime hydrolysis on protracted acid work-up.Formylation step carried out under reduced pressure (all other examples at atmospheric pressure). ca. 3 Yield of trinuclear by-products 6 also identified by size exclusion chromatography/mass spec. chromatography and mass spectroscopy) are the 2,2'-dihy- aldehyde detectable by GC analysis of the crude reaction droxydiarylmethanes 5 and, to a lesser extent, the trinuclear product. compounds 6 (in common with the formylation products Addition of aq. hydroxylamine sulfate to the product of the reported by Casiraghi and Casnati). l4 The reaction selectivity formylation reaction, present as its magnesium salt 4 (without in favour of formylation (as opposed to formation of by-acidic work-up), results in efficient oximation (Scheme 4). In the products 5 and 6)is enhanced in many cases by carrying out the case of the 5-nonylsalicylaldehyde magnesium salt 4 (R = p-C9HI9), oximation (to 395 conversion of salicylaldehyde into salicylaldoxime) was achieved in about one-fifth of the time OH OH OH OH required for oximation of 2-hydroxy-5-nonylbenzaldehyde2 (R = p-C9HI9) by hydroxylamine sulfate solution in the presence of sodium carbonate (1 equiv.on hydroxylamine sulfate) but in the absence of the magnesium cation, under 5 6 otherwise identical reaction conditions. Formaldoximation X = H, CHO, CH20Me, HC=NOH yields are summarised in Table 2. It should be noted that HCN can be generated on acidification and heating of the aqueous reaction at temperatures around 70-90deg;C (i.e. below the phase after oximation.atmospheric reflux temperature of ca. 95 "C) using reduced pressure (200-400 mmHg) so as to maintain removal of the methanol by distillation (cf:Table 1, formation of the aldehyde 20 and Table 2, formation of the oxime 7h at atmospheric and at reduced pressures). When (unsubstituted) phenol 1 (R = H) is formylated, the o-hydroxybenzaldehyde product 2 (R = H) is obtained containing less than 0.05 (w/w) p-hydroxybenz- Scheme 4 J. CHEM. SOC. PERKIN TRANS. 1 1994 Discussion It is likely that formylation is preceded by depolymerisation rsquo;O of paraformaldehyde to liberate monomeric formaldehyde (CH,Q), under the basic conditions of the formylation reaction. In the absence of the magnesium counter-ion, phenols with formaldehyde give phenol-formaldehyde resin polymerisation products under either acidic or basic conditions.rdquo; The high selectivity for phenol ortho-formylation in the presence of the magnesium counter-ion indicates coordination of phenoxide and formaldehyde to the magnesium counter-ion under the reaction conditions described in this paper.The lack of formylation on addition of paraformaldehyde to phenol magnesium salts in methanol is presumably due to competitive inhibition by methanol of the coordination of formaldehyde to the magnesium counter-ion. Methanol is, accordingly, removed by distillation and replaced by toluene prior to addition of paraformaldehyde; however, as the methanol-magnesium salt ratio is reduced below 2 : 1, the phenol magnesium salt must presumably undergo first dimeris- ation and then polymerisation to maintain magnesium tetra- coordination (Scheme 5).This is supported by the marked Me0H:Mg = 2:l MeOH:Mg = 1:1 A*bsol; /OAr -amp;OH - MeOH fM$ -+M~OH MeOH M H MeOH Ar 8 0 10 Scheme 5 increase in reaction mixture viscosity observed on removing methanol below ca. 2 mol per mol magnesium bis(phenoxide), by distillation from the toluene-soluble magnesium bis(phen- oxide) 8 (ArOH = p-nonylphenol) prepared from p-nonyl- phenol. Reactivity to formylation is enhanced with a methanol- magnesium salt ratio of between 1 and 2 mol per mol such that the magnesium cation is at least partially in the form of the dimeric species 9, due to methanol ligand depletion.Under these conditions, added formaldehyde is presumably coordin- ated to magnesium in the ligand-depleted dimer 9 to give the better solvated monomeric salt 8, but with a formaldehyde in place of one of the methanol molecules. A suggested mechanism for the formylation is outlined in Scheme6 whereby formaldehyde (coordinated to the magnesium cation acting as Lewis Acid) undergoes addition of phenoxide to give the hydroxymethylated phenol magnesium salt 11. Coordination of a second formaldehyde then results in redox conversion of the hydroxymethyl anion to formyl with reduction of formaldehyde to methoxide by hydride transfer through a chair-like 6-membered transition state (cf: 12). Proton transfer from phenol to the more basic methoxide then completes the reaction to give the formylated phenol magnesium salt along with an equivalent of methanol (from formaldehyde reduction) as a volatile by-product.Methyl formate is also produced as a volatile by-product, presumably as a result of Tischenko reaction rsquo;rsquo;of formaldehyde catalysed by the magnesium cation. Ar MeOHJ0bsol; /MgMg MeO$ lsquo;flsquo;OAr 9 11 ArOH CH@11 ArOH + R .:yP-,/lsquo; o Pr-/0 00 (MeOH)w o0g x // 00 R R 4 Scheme 6 Varying amounts of the diarylmethane by-products 5 (and lesser amounts of the trinuclear species 6)are also produced during the course of the reaction, presumably as a result of elimination of magnesium oxide from intermediate 11, followed by coupling of the quinone methide intermediate 13with phenoxide (Scheme 7).fYoH 11 13 drsquo; + X = H, CHO, MgO CH20Me=NOH Scheme 7 Casiraghi and Casnati l4 report a predominance of this latter pathway in the absence of stabilising ligand, and suppression of this elimination pathway in the presence of stoichiometric quantities of HMPA (which reduces Mg2 + Lewis-acidity) during reaction of formaldehyde with their Grignard-derived aryloxy- magnesium bromide system. Our results indicate the equivalent suppression of the unwanted elimination pathway in the presence of 1-2 equiv. ofmethanol as stabilising ligand in place of HMPA, thereby avoiding the cost and toxicity of HMPA and with the additional advantage that use of magnesium methoxide as base both introduces the methanol ligand into the reaction system by default and allows use of half the molar quantity of di- acidic and cheap magnesium methoxide, as compared with use of the mono-acidic and costly Grignard reagent.J. CHEM. SOC. PERKIN TRANS. 1 1994 In the same way that methanol must be removed prior to formylation, the methanol by-product of formylation is also removed by distillation during the course of the reaction so as to avoid yield penalties due to inhibition by methanol of amp;,OH ccoordination of formaldehyde to magnesium. The increased Intramolecular reaction selectivity observed on reducing the reaction Lewis Acid temperature (whilst maintaining removal of volatile reaction by- Catalysis products by distillation under reduced pressure) indicates greater differentiation of the formylation and elimination reaction pathways at the lower reaction temperature.There is no substantial build-up of hydroxymethylated intermediate evident during the course of the reaction. ACSL23 modelling of the reaction profile generated on addition of 2 equiv. of paraformaldehyde as a single charge to 4-nonylphenol magnesium salt in toluene at 95 "Csuggests approximate values for the rate constants for the addition step and the redox step of R ca. 0.035 and 0.10 dm3 mol-' s-' respectively,i.e. a redox-step rate constant approximately 3 times that for the addition to formaldehyde. Use of less tightly coordinating cations (e.g.Li+, Na+ or K') in place of the small highly charged Mg2+, does 9 PH 8#result in the first (addition) step (albeit without the ortho-a;specificity observed with Mg2+) but this is followed by elimination of hydroxyl and formation of phenol-formaldehyde 0/ bsol;+OH resins oia quinone methides (cf: 13;Scheme 7) in preference to the redox step (cf: 12;Scheme 6)giving salicylaldehydes, which @OH predominates in the presence of the methanol solvated Mg2+ /'counter-ion. If the methanol-magnesium salt ratio is decreased R much below 1: 1, then formylation efficiency deteriorates as reaction mixture viscosity becomes increasingly unmanageable and (as reported by Casiraghi and Casnati with decreasing HMPA usage 14) the generation of diarylmethane by-products (e.g.5) increases.R R para-Electron withdrawing substituents on the starting material phenols (e.g.1, R = p-F, p-C1 or p-NO,; Table 1) give rise to reduced reactivity and poorer formylation yield whilst Proton transfer the converse is true for electron-donating substituents (e.g. 1, from salicyhdehyde anion 0, 0 to more basicR = p-OMe; Tables 1 and 2). Bulky substituents in the ortho-salicylaldoxirne anion Dposition (e.g. 1, R = o-Bus; Table 2) give rise to increased t8 formation of by-products 5 and 6 due, presumably, to steric hindrance inhibiting coordination of formaldehyde to mag- nesium (necessary for formylation) resulting in increased base- catalysed (but not magnesium mediated) by-product generation R/'voH(Scheme 7). Bulky substituents meta to the starting material phenol hydroxyl (e.g.1,R = m-Bu'; Table 2) direct formylation to the position ortho to the hydroxyl and opposite the meta Similarly NH30Hsubstituent.Smaller meta substituents (e.g. 1, R = m-F or rn-Me; Tables 1 and 2) direct formylation to the less hindered I+position ortho to oxygen, but give rise to a mixture of products formylated in either the 2 or the 6 positions. Substituents in the R ortho position able to coordinate to the magnesium cation (e.g. 1, R = o-F or o-OMe; Table 1) result in partial or complete inhibition of formylation, presumably due to chelation of magnesium (e.g.in 2-methoxyphenol magnesium salt 14) which precludes the coordination of formaldehyde necessary for formylation. Formylation of 3-fluorophenol gives a higher yield of salicylaldehydes 2f than does formylation of either 2-fluorophenol or 4-fluorophenol, due presumably to n-electron donation by the fluoro substituent in 3-fluorophenol, (i) serving to activate the positions ortho and para to fluorine and ortho to R/'VHoxygen, to electrophilic attack, and (ii) offsetting to some extent the deactivating inductive electron withdrawal by the electro- Scheme 8 negative fluorine substituent.It is likely that the faster oximation observed on addition of hydroxylamine sulfate to the formylated phenol magnesium salt 4 (R =p-C9HI9) in toluene (compared with use of sodium cation in place of magnesium) is due to intramolecular Lewis 14 acid catalysis of oximation by Mg2+ (Scheme 8) whereby the J.CHEM. SOC. PERKIN TRANS. 1 1994 magnesium counter-ion enhances the reactivity of the co-ordinated formyl group carbonyl to nucleophilic attack by hydroxylamine. Catalysis by the Mg2 + counter-ion throughout oximation (despite the liberation of H2S04 on reaction of hydroxylamine) can be explained by protonation of the more basic salicylaldoxime magnesium salt, in preference to proton- ation of salicylaldehyde magnesium salt, during the course of the oximation reaction (Scheme 8). It is possible that the greater rate of oximation of magnesium salt 4 (R = pC9H19) (compared with sodium salt) could also be influenced by different surfactant effects of the amphipathic nonylsalicylaldehyde magnesium salt (compared with sodium salt) at the aqueous-organic interface during the heterogeneous oximation. It should be noted that although a catalytic role is ascribed to the magnesium cation in the chemistry described above (in that the magnesium cation facilitates both the formylation and oximation steps whilst itself remaining essentially chemically unchanged), it is used in a 'stoichiometric' amount (20.5 mol used per mol of phenol) and not in the much smaller amounts that are conventionally associated with use of the word 'catalytic'.Unchanged formaldehyde left over after the formylation step is likely to be converted into formaldoxime during the o~imation;~~this formaldoxime can then be dehydrated to give HCN in the presence of strong acid and/or when heated.Care should, therefore, be taken both to minimise the amount of formaldehyde used and to avoid strong acidic treatment of the aqueous phase after oximation in conversion of phenols 1 into salicylaldoximes 7. Conclusions Reaction of magnesium bis(ary1 oxides) (prepared from hydroxyaromatics and magnesium methoxide) with para-formaldehyde gives rise to ortho-formylation, without the need for HMPA or use of Grignard reagents for aryloxymagnesium salt preparation. Reaction of the salicylaldehyde magnesium salt products of formylation with hydroxylamine sulfate allows efficient conversion into the corresponding salicylaldoximes without the need for work-up and isolation of the intermediate salicylaldeh ydes. Experimental NMR coupling constants (J) are given in Hz.GC conditions comprise use of Chrompack UK Ltd CPSil5CB 25m capillary column (injector temperature: 250 "C, column temperature: 100 "C for 2 min, then 10 "C min-' to 250 "C). HPLC conditions comprise use of Whatman 10 cm C-18 ODS reverse phase column, with an eluent gradient of MeOH-buffer of 75 :25 to 90 :10 over 10 min; held at 90: 10 for 10 min and then increased to 100 MeOH over 10 min the buffer comprised NaOAc (0.56 g), AcOH (7 cm3) and HPLC grade water (1 dm3). 2-Hydroxybenzaldehyde 2a.-Phenol (37.6 g, 0.4 mol) was added to magnesium methoxide (259 g of 8 wt. solution in methanol; 20.7 g, 0.24 mol) and the mixture was heated to reflux. Approximately half the methanol was distilled off and toluene (300 g) was added to the residue.The azeotropic mixture of toluene and methanol was removed by fractional distillation, until the temperature of the reaction mixture rose to 95 "C. A slurry of paraformaldehyde powder (43.2 g, 1.44 mol) in toluene (75 g) was added in small portions over 1 h to the reaction mixture at 95 "C with concurrent removal of volatile materials by distillation. Stirring was continued at 95 "C for 1 h, after which mixture was cooled to 25 "C and added slowly to 10 sulfuric acid (450 g). The resulting mixture was stirred at 30-40 "C for 2 h, after which the aqueous layer was separated and extracted with toluene (2 x 100 g). The combined organic layers and extracts were washed with 10 sulfuric acid (50 g) and water (50 g) and evaporated under reduced pressure to give the aldehyde 2a as a pale yeHow oil (48.35 g, 84 w/w by GC and 'H NMR comparison against a reference standard and against a commercial sample2' of known purity; 83 yield); 6,(400 MHz; CDCl,; Me,Si) 6.99 (1 H, dd, J 1 and 7.5, 3-H), 7.02(1 H,dt,Jland7.5,5-H),7.52(1H,dt,J1.7and7.5,4-H), 7.55 (1 H, dd, J 1.7 and 7.5,6-H), 9.9 (1 H, s, CHO) and 1 1.05 (1 H, s, OH); 6,(100.6 MHz; CDCl,; Me,) 117.45 (3-C), 119.74 (5-C), 120.53 (1-C), 133.64(6-C), 136.88 (4-C), 161.45 (2-C) and 196.53 (CHO).2-Hydroxy-4-methylbenzaldehyde 2c and 2-Hydroxy-6-methylbenzaldehyde 2c.-In a similar way to that described above, 3-methylphenol (27.0 g, 0.25 mol), magnesium meth- oxide (0.15 mol) and paraformaldehyde powder (23.2 g, 0.77 mol) gave a pale yellow oil which solidified with time (31.5 g) and comprised 2-hydroxy-4-methylbenzaldehydel4 (64, w/w, by 'H NMR using 1,Zdiphenylethane as internal standard; 59 yield); dH(300 MHz; CDCl,; Me,Si) 2.35 (3 H, s, Me), 6.76 (1 H, s, 3-H), 6.80 (1 H, d, J7.8, 5-H), 7.39 (1 H, d, J 7.8, 6-H), 9.76 (1 H, s, CHO) and 11.1 (1 H, s, OH); 6,(75.4 MHz; CDCl,; Me,Si; broad band proton decoupled) 22.4 (Me), 118 (3-C), 119 (1-C), 121.5 (5-C), 134 (6-C), 149 (4-C), 162 (2-C) and 196 (CHO), 13C NMR data consistent with 13C reference spectral data for the expected product,26 and 2- hydroxy-6-methylbenzaldehyde (1 5.9, w/w; 15 yield); 6,(300 MHz; CDCl,; Me4Si) 2.57 (3 H, s, Me), 6.68 (1 H, d, J 7.8, 3-H), 6.75-6.88 (1 H, obscured by major isomer peaks, 5-H), 7.34 (1 H, t, J7.8, 4-H), 10.26 (1 H, s, CHO) and 11.9 (1 H, s, OH); 6,(75.4 MHz; CDCl,; Me4Si; broad band proton decoupled) 18.3 (Me), 116.5 (3-C), 119 (1-C), 122 (5-C), 137.5 (4-C), 142.5 (6-C), 163.5 (2-C) and 195.5 (CHO).The substitution pattern of the products obtained was confirmed by comparison of 13C NMR chemical shift data for the ring carbons against values predicted 27 for the possible product isomers. 3-Fluoro-2-hydroxybenzaldehyde2e.-Magnesium raspings (5.85 g, 0.24 mol), methanol (120 g) and magnesium methoxide (4 g of 8 solution in methanol) were heated under reflux until the magnesium had dissolved and hydrogen evolution had ceased. 2-Fluorophenol (44.8 g, 0.40 mol) was added to the solution, followed by toluene (260 g) to maintain fluidity of the resulting slurry.The azeotropic mixture of methanol and toluene were distilled off under reduced pressure (380 mmHg) until the temperature of the reaction mixture rose to 75 "C. A slurry of paraformaldehyde powder (36.0 g, 1.2 mol) in toluene (70 g) was added to the mixture over 1 h at 75deg;C with concurrent removal of volatile materials by distillation under reduced pressure (380-280 mmHg). Stirring was continued at 75 "C (280 mmHg) for 2 h, after which 10 sulfuric acid (250 g) was added to the mixture. After the mixture had been stirred for a further 10 min, the organic layer was separated, washed with water (2 x 150 g) and evaporated under reduced pressure to give a brown oil (35.7 g); 6,(400 MHz; CDCl,; Me,Si) 6.15 (1 H, br s, OH), 6.7-7.3 (m, 2-fluorophenol and 3-fluoro-2-hydroxy- benzaldehyde aromatic protons) and 9.75 (1 H, s, CHO).The oil comprised the aldehyde 2e28*29 (8.5, w/w, by 'H NMR against internal standard; 5.1 yield); GCMS m/z140 (loo, M'), 139 (95, M -H), 122 (15), 111 (17, M -CHO), 94 (21, M -CHO and OH) and 83 (25) along with unchanged 2- fluorophenol (go, w/w, by GC; 72 yield). 4-Fluoro-2-hydroxybenzaldehyde2f and 2-Fluoro-6-hydroxy-benzaldehyde 2f.-In a similar way to that described above, 3-fluorophenol(44.8 g, 0.40 mol), magnesium methoxide (0.24 mol) and paraformaldehyde powder (36 g, 1.2 mol) gave a partially crystalline pale brown gum (53.1 g) comprising 4-fluoro-2-hydroxybenzaldehyde30 (70.3 w/w by 'H NMR against 2,3,4,5-tetrachloronitrobenzene internal standard; 62.6 yield); 6,(250 MHz; CDCl,; Me,Si) 6.62 (1 H, dd, J 3 and 11,3-H),6.69(1 H.ddd, J3,8and 11,5-H),7.52(1 H,dd, J 7 and 8,6-H), 9.78 (1 H, s, CHO) and 11.38 (1 H, s, OH); GCMS m/z 140 (85, M'), 139 (100, M -H), 122 (7), 94 (15, M -CHO and OH) and 83 (28); and 2-fluoro-6-hydroxybenz- aldehyde (1 1, w/w, by 'H NMR and GC; 9.8 yield); 6,(250 MHz; CDCl,; Me,) 6.6 (2 H, obscured my 3-H and 5-H), 7.43 (1 H, m, 4-H), 10.2 (1 H, s, CHO) and 11.48 (1 H, s, OH); GCMS m/z 140 (96, M'), 139 (100, M -H), 122 (13), 94 (1 8, M -CHO and OH) and 83 (25).3-Fluoro-6-hydroxybenzaldehyde2g.--In a similar way to that described above, 4-fluorophenol (44.8 g, 0.40 mol), magnesium methoxide (0.24 mol) and paraformaldehyde powder (36 g, 1.2 mol) gave a brown gum (42.9 g) comprising the aldehyde 2g28*32(63.4 wjw by 'H NMR against 2,3,4,5- tetrachlorobenzene internal standard; 45.6 yield); 6,(250 MHz; 2H6DMSO; Me,Si) 7.13 (1 H, dd, J 4.3 and 9, 5-H), 7.37(1H,dd,J3.3and8.6,2-H),7.4(1H,ddd,J3.3,8.3and8.9, 4-H), 9.78 (1 H, s, CHO) and 10.8 (1 H, s, OH); with unchanged 4-fluorophenol(38 w/w; 36 yield).2-Hydroxy-5-methoxybenzaldehyde2j.--In a similar way to that for the aldehyde 2c, 4-methoxyphenol (31.0 g, 0.25 mol), magnesium methoxide (0.15 mol) and paraformaldehyde pow- der (23.2 g, 0.77 mol) gave the aldehyde 2j l4 as a pale yellow oil (36.0 g; 97 w/w measured by GC and HPLC; 92 yield); GCMS m/z 152 (loo, M'), 137 (86, M -Me), 123 (6, M -CHO), 109 (32), 81 (34) and 53 (49).3-Chloro-6-hydroxybenzaldehyde2k.--In a similar way to that described above, 4-chlorophenol (32.2 g, 0.25 mol), magnesium methoxide (0.15 mol) and paraformaldehyde pow- der (23.2 g, 0.77 mol) gave the aldehyde 2k ', as a dark brown oil (32.3 g; 40, w/w, measured by 'H NMR against 1,2- diphenylethane internal standard; 33 yield); S,(300 MHz; CDC1,; Me,Si) 6.5-7.6 (m, aromatic protons unresolved from impurities), 9.75 (1 H, s, CHO) and 10.93 (1 H, s, OH); GCMS m/z 158 (32, 37M+), 157 (39, 37M-H), 156 (98, 35M'), 155 (100, 35M -H), 140 (5, 37M -HZO), 138 (16, 35M -HZO), 129 (6.5, 37M -CHO), 127 (19, 35M -CHO), 112 (8), 110 (23), 101 (7), 99 (27), 75 (14), 73 (15), 65 (22), 63 (27), 38 (26) and 36 (48).2-Hydroxy-5-nonylbenzaldehyde(Mixed Side-chain Isomers) 20.-Prepared with toluene as solvent at atmospheric pressure. Magnesium raspings (7.3 g, 0.3 mol), methanol (1 12 g), toluene (48.5 g) and magnesium methoxide (1.6 g of 8 w/w solution in methanol; 1.5 mmol) were heated under reflux for 2 h until the magnesium had dissolved and hydrogen evolution had ceased. 4-Nonylphenol (mixed side-chain isomers, prepared by alkyl- ation of phenol by propylene trimer) (1 12 g, 0.5 mol), was added to the mixture which was then heated under reflux for a further hour. Toluene (104 g) was then added to the mixture and the methanol-toluene azeotrope removed by fractional distillation until the temperature of the reaction mixture rose to 94 "C.A slurry of paraformaldehyde powder (45 g, 1.5 mol) in toluene (65 g) was added over 50 min to the reaction mixture at 97- 104 "C with concurrent removal of volatile products of reaction by distillation. Stirring was continued at 100 "C for 2 h after which the mixture was cooled to 25 "Cand added slowly to cold 20 sulfuric acid (625 g, 1.28 mol). The resulting mixture was stirred at 50 "C for 2 h, after which the lower (aqueous) layer J. CHEM. SOC. PERKIN TRANS. 1 1994 was separated and extracted with toluene (2 x 100 8). The combined organic layer and extracts were washed with 10 sulfuric acid (50 g) and water (50 g) and then evaporated under reduced pressure to give the aldehyde 20 33 as a pale yellow oil (122.7 g; 78.8, w/w, measured by GC comparison against an authentic standard sample of known purity; 78.0 yield).The product was purified by short-path vacuum distillation; b.p. 150-160 "C at 5 mmHg; v,,,/cm-' 3200 (OH), 3000-2800 (aliphatic CH), 2720 (CHO) and 1665 (M);MHz;6,(250 CDC1,;Me,Si)0.6-1.8(19H,m,C9H,,),6.92(1H,d,J9,3-H), 7.35-7.6 (2 H, m, 4-H and 6-H), 9.9 (1 H, s, CHO) and 10.85 (1 H, s, OH); GCMS m/z 248 (7, M+),233 (3, M -Me), 219 (7, M -CHO and M -Et), 205 (9, M -C3H7), 191 (20, M -C4H9), 177 (38, M -C5Hll), 163 (100, M -C,H,3), 149 (29, M -C7H15), 135 (35, M -C8HI7). The crude aldehyde 20 was analysed by preparative size exclusion chromatography C0.5 x 30 cm PL Gel 5p (2 x 500 A, 2 x 100 A, 1 x 50 A); eluent: THF; flow rate 1 cm3 min-'; wavelength 225 mm, mass spec.analysis of SEC product peaks indicated presence of 2,2'- methylene bis(4-nonylphenols) (ca.9.4 w/w) molecular ions at nt/z 452 (5; X = H), 480 (5; X = CHO) and 482 (5; X = CH,OH) and the trinuclear species 6 (ca. 2.9 w/w) molecular ions at m/z 684 (6, X = H), 712 (6; X = CHO) and 714 (6; X = CH20H). Prepared with toluene as solvent under reduced pressure. Magnesium raspings (14.6 g, 0.6 mol) were added in portions over 1.5 h to a mixture of methanol (225 g), toluene (108 g) and magnesium bis(4-nonylphenoxide) (ca. 4 g) at reflux temper- ature. Dissolution of the magnesium occurred with evolution of hydrogen. After the mixture had been heated under reflux for a further hour to complete the dissolution, 4-nonylphenol (mixed side-chain isomers) (224 g, 1 mol) was added to it followed by toluene (208 g).The azeotropic mixture of methanol and toluene was removed by fractional distillation under reduced pressure (380 mmHg) until an increase in viscosity was noted and the temperature of the reaction mixture had risen to 75 "C. A slurry of paraformaldehyde powder (90 g, 3 mol) in toluene (1 30 g) was then added to the reaction mixture at 75 "C over 2 h, under reduced pressure (380-270 mmHg) so as to maintain removal of volatile materials by distillation. The mixture was stirred at 75 "C under reduced pressure (260 mmHg) for a further 1 h after which it was cooled to 35 "C and added slowly to cold 14 sulfuric acid (872.5 g, 1.25 mol).The resulting mixture was stirred for 2 h at 40 "C after which the organic layer was separated with water (2 x 250 g) and evaporated under reduced pressure to give the aldehyde 20 as a pale-yellow oil (253 g; 83.3, w/w, measured by GC comparison against an authentic sample of known purity; 85 yield); characterization as above. Prepared with xylene as solvent under reduced pressure. A mixture of magnesium raspings (7.3 g, 0.3 mol), methanol (1 12 g) and magnesium methoxide (8, w/w, solution in methanol; 1.6 g, 1.5 mmol) were heated under reflux until the magnesium had dissolved and hydrogen evolution had ceased (2 h). 4- Nonylphenol (112 g, 0.5 mol) was added to the solution followed by xylenes (mixed isomers) (129 g).Methanol was removed by fractional distillation under reduced pressure (2 10 mmHg) until the temperature of the reaction mixture rose to 75 "C and the viscosity of the mixture began to significantly increase. A slurry of paraformaldehyde powder (45 g, 1.5 mol) in xylene (65 g) was added over 2 h to the reaction mixture at 75 "C under reduced pressure (210-90 mmHg) so as to maintain removal of volatile materials by distillation. Stirring was continued at 75 "C under reduced pressure (90 mmHg) for 1 h after which the mixture was cooled to 35 "C and then added slowly to cold 20 sulfuric acid (625 8). The resulting mixture was stirred at 40 "C for 2 h after which the organic layer was separated, washed with water (2 x 250 g) and evaporated J.CHEM. SOC. PERKIN TRANS. 1 1994 under reduced pressure to give the aldehyde 20 as a pale yellow oil (126.25 g, 79.4 w/w measured by GCcomparison against an authentic sample of known purity; 81 yield); characteriz- ation as above. 2-Hydroxybenzaldehyde Oxime 7a.-Magnesium raspings (5.85 g, 0.24 mol), methanol (119 g), toluene (43.5 g) and magnesium methoxide (8 w/w solution in methanol; 4.08 g, 3.8 mmol) were heated under reflux until the magnesium had dissolved and evolution of hydrogen had ceased. Phenol (37.6 g, 0.4 mol) was added to the mixture which was then heated under reflux for 1 h. After this it was diluted with toluene (208 g) and the methanol-toluene azeotropic was removed by fractional distillation until the temperature of the reaction mixture rose to 95 "C.Toluene (43 g) was added to mobilise the resulting slurry and a slurry of paraformaldehyde powder (37.6 g, 1.25 mol) in toluene (70 g) was added over 1.5 h to the mixture at 95 "C with removal of volatiles from the reaction mixture by distillation. Stirring was continued at 95 "C for 30 min after which the mixture was cooled to 55 "C and treated with a solution of hydroxylamine sulfate (39.4 g, 0.24 mol) in water (120 g), added at 50-55 "C over 30 min with vigorous stirring. Stirring was continued at 55 "C for 1 h after which the reaction mixture was cooled to 20 "C and the organic layer separated, washed at 10 "C with 7 sulfuric acid (195 g) and water (2 x 150 g) and evaporated under reduced pressure to give the oxime 7a 34 as a white crystalline solid (52.3 g; 92.2, w/w, by 'H NMR against benzyl acetate internal standard and by GC against an authentic commercial sample 34 of known purity; 88 yield); 6,(250 MHz; CDCl,; Me,Si) 6.87 (1 H, dt, J 1 and 7.5, 5-H), 1829 described above, 3-methylphenol (43.2 g, 0.4 mol), magnesium methoxide (0.24 mol) and paraformaldehyde powder (36 g, 1.2 mol), followed by hydroxylamine sulfate (39.4 g, 0.24 mol) gave a pale yellow crystalline solid (60.1 g) comprising 2-hydroxy-4- methylbenzaldehyde oxime 36 (61.3, w/w, by 'H NMR against benzyl acetate internal standard; 61 yield); 6,(250 MHz; CDC1,; Me,) 2.3 (3 H, s, Me), 6.72 (1 H, dd, J7.5 and 1.5, 5-H),6.81(1H,d,J1.5,3-H),7.03(1H,d,J7.5,6-H),8.16(2H, br s, CH=N and ArOH) and 10.05 (1 H, s, NOH); GCMS m/z 151 (53, M'), 135 (39), 133 (76, M -H,O) and 104 (100) and 2-hydroxy-6-methylbenzaldehydeoxime (10.95, w/w, by GC peak area ratio to major product; 10.9 yield); 6,(250 MHz; CDCl,; Me,Si) 2.3 (3 H, s, Me), 6.71 (1 H, dd, J 7.5 and 1.5, 5-H), 6.77-6.87 (2 H, obscured, 3-H and 4-H), 8.15 (2 H, br s, ArOH and CH=N) and 10.1 (1 H, s, NOH); GCMS m/z 151 (36, M'), 135 (29), 134 (39, 133 (92) and 104 (100).2-Hydroxy- 5-meth y lbenzaldeh yde Oxime 7d .-In a similar way to that described above, 4-methylphenol (43.2 g, 0.4 mol), magnesium methoxide (0.24 mol) and paraformaldehyde pow- der (36 g, 1.2 mol), followed by hydroxylamine sulfate (39.4 g, 0.24 mol) gave a pale yellow crystalline solid (57.65 g) comprising the oxime 7d36 (77.3, w/w, by 'H NMR against benzyl acetate internal standard; 73.8 yield); 6,(250 MHz; CDC1,; Me,Si) 2.3 (3 H, s, Me), 6.9 (1 H, d, J9,3-H), 6.96 (1 H, d, J 1.8, 6-H), 7.09 (1 H, dd, J 9 and 1.8, 4-H), 8.0 (1 H, s, ArOH), 8.19 (1 H, s, CH=N) and 9.9 (1 H, s, NOH); GCMS m/z 151 (86, M'), 135 (38), 134 (44),133 (91, M -H,O), 132 (98, M -H and H20), 104 (loo), 78 (74) and 77 (73) and 2- 6.97(1H,dd,J7.5andl,3-H),7.ll(lH,dd,J7.5and1.6,6-H), hydroxy-4-methylbenzaldehyde(ca.4 yield by GC) (formed 7.24(1 H,dt,J1.6and7.5,4-H),7.85(1H7brs,Ar0H),8.2(1H,by partial hydrolysis of oxime during protracted acid washing s, CH=N) and 10.0 (1 H, s, NOH). 2-Hydroxy-3-methylbenzaldehyde Oxime 7b.-Magnesium raspings (5.85 g, 0.24mol), methanol (1 19 g), toluene (43.5 g) and magnesium methoxide (4.08 g of 8, w/w, solution in methanol, 3.8 mmol) were heated under reflux until the magnesium had dissolved and hydrogen evolution had ceased.2-Methylphenol (43.2g, 0.4 mol) was added to the mixture which was then heated under reflux for 1 h. After this, toluene (208 g) was added to the mixture and the methanol-toluene azeotrope was removed by fractional distillation until the temperature of the reaction mixture rose to 97 "C. A slurry of paraformaldehyde powder (36 g, 1.2 mol) in toluene (70 g) was added over 1 h at 95 "C with concurrent removal of volatile materials by distillation. Stirring was continued at 95 "C for 1.25 h after which the mixture was cooled to 55 "C and treated with a solution of hydroxylamine sulfate (39.4 g, 0.24 mol) in water (120 g), added over 30 min at 50-55 "C with vigorous stirring.Stirring was continued at 55 "C for 1 h after which the mixture was cooled to 10 "C and 1.5, w/w, sulfuric acid (254 g) was added with stirring. The organic layer was separated, washed with cold 10 sulfuric acid (280 g) and then water (2 x 250 g) and evaporated under reduced pressure to give the oxime 7b as a pale yellow crystalline solid (61.1g, 55.1, w/w, by 'H NMR against benzyl acetate internal standard; 56 yield); 6,(250 MHz; CDCl,; Me,Si) 2.3 (3 H, s, Me), 6.85 (I H, t, J7.5,5-H), 7.0 (1 H, dd, J7.5 and 1.4,4-H), 7.14 (1 H, obscured, 6-H), 8.15 (1 H, s, ArOH), 8.2 (1 H, s, CH=N) and 10.35 (1 H, s, NOH); GCMS indicates the crude reaction product contains 2-hydroxy -3 -methylbenzaldehyde oxime (GC area 64.4), GCMS m/z 151 (56, M+), 135 (52), 133 (100, M -H20) and 104 (98) and 6,6'-Methylene bis(2-methyl- phenol) (GC area 25.2), GCMS m/z 228 (43, M'), 121 (100, M -C7H70) and 108 (52, M -C,H,O).2-Hydroxy-4-methylbenzaldehydeOxime 7c and 2-Hydroxy- 6-methylbenzaldehyde Oxime 7c.--In a similar way to that overnight) GCMS m/z 136 (loo, M'), 135 (95, M -H), 118 (12), 107 (34, M -CHO) and 77 (32). 2-Hydroxy-3,5-dimethylbenzaldehydeOxime 7h.-Prepared at atmospheric pressure. In a similar way to that described above, 2,4-dimethylphenol (48.8 g, 0.4 mol), magnesium methoxide (0.24 mol) and paraformaldehyde powder (36 g, 1.2 mol), followed by hydroxylamine sulfate (39.4 g, 0.24 mol) gave a pale yellow crystalline solid (65.8 g) comprising the oxime 7h37 (32.9, w/w, by 'H NMR against benzyl acetate internal standard; 32.8 yield) and 6,6'-methylene bis(2,4-dimethyl- phenol) (ca.65 yield by GC). Crude product GCMS: oxime 7h m/z 165 (60, M'), 149 (39,148 (39), 147 (63, M -H,O), 146 (49), 132 (100, M -H20 and Me), 118 (35, M -CHO and H20), 91 (54) and 77 (32) and diarylmethane 5 (R = ortho and para Me,); m/z 256 (51, M+), 135 (96, M -C,H,Me,OH), 122 (loo), 107 (24) and 91 (34). The crude product was recrystallised from toluene to give a white crystalline solid (47.8 g) comprising the oxime 7h (36.9, w/w, by 'H NMR against benzyl acetate) and the diarylmethane 5 (R = ortho and para Me,) (57 w/w by GC); 6,(250 MHz; CDC1,; Me,) 2.15-2.45 (4 x s, Me groups in both products), 3.85 (2 H, s, ArCH,Ar).6.2 (2 H, s, HOArCH,ArOH), 6.78 (2 H, d, J 2, diarylmethane aromatic MeCCHCMe), 6.80 (1 H, d, J2, oxime 4-H), 6.92 (2 H, d, J 2, diarylmethane aromatic CH,CHCMe), 6.97 (1 H, d, J 2, oxime 6-H), 7.8 (1 H, s, oxime ArOH), 8.17 (1 H, s, oxime CH=N) and 10.0 (1 H, s, NOH). Prepared under reduced pressure. Magnesium raspings (5.85 g, 0.24 mol), methanol (120 g) and magnesium methoxide (8 solution in methanol, 4 g) were heated under reflux until the magnesium had dissolved and hydrogen evolution had ceased. 2,4-Dimethylphenol(48.8 g, 0.4 mol) was added to the mixture followed by toluene (44g) and the methanol-toluene azeotrope was removed by fractional distillation under reduced pressure (380 mmHg) until the temperature of the reaction mixture rose to 75 "C.A slurry of paraformaldehyde powder (36 g, 1.2 mol) in toluene (70 g) was then added over 1.5 h to the reaction mixture at 75 "C under reduced pressure (380-250 mmHg) so as to maintain removal of volatile materials by distillation. Stirring was continued at 75 "C for 30 min, after which the mixture was cooled to 50 "C and treated with a solution of hydroxylamine sulfate (39.4 g, 0.24 mol) in water (120 g), added over 30 min with vigorous stirring at 50-55 "C. The mixture was stirred for a further 3 h at 55 "C, after which 0.5 sulfuric acid (200 g) was added to dissolve solids.The organic layer was separated, washed with cold 10 sulfuric acid (260 g) and water (2 x 200 g) and evaporated under reduced pressure to give the oxime 7h as a white crystalline solid (68.4 g; 55, w/w, by 'H NMR and by GC against internal standards; 57.5 yield); characterization as above. 2-Hydroxy-5-methoxybenzaldehydeOxime 7j.-Magnesium raspings (5.85 g, 0.24 mol), methanol (120 g), toluene (44g) and magnesium methoxide (8 w/w solution in methanol; 4.1 g, 3.8 mmol) were heated under reflux until the magnesium had dissolved and hydrogen evolution had ceased. 4-Methoxy- phenol (49.6 g, 0.4 mol) and toluene (26 g) were added to the mixture and the methanol-toluene azeotrope was removed by fractional distillation until the temperature of the reaction mixture rose to 93 "C to give a white slurry of the 4- methoxyphenol magnesium salt.A slurry of paraformaldehyde powder (36 g, 1.2 mol) in toluene (63 g) was added to the mixture at 93-95deg;C over 1 h with concurrent removal of volatile materials by distillation. Stirring was continued at 93 "C for 1 h after which the mixture was cooled to 55 "C and a solution of hydroxylamine sulfate (39.4 g, 0.24 mol) in water (120 g) was added to it over 30 min at 55 "C with vigorous stirring. Stirring was continued at 55 "C for 3 h, after which the resulting slurry was cooled to 1O"C, treated with cold 5 sulfuric acid (200 g) and extracted with dichloromethane (3 x 250 g).The combined extracts were washed with water (2 x 100 g) and evaporated under reduced pressure to give the oxime 7j 38 as a pale yellow crystalline solid (57.9 g; 88, w/w, by 'H NMR against benzyl acetate internal standard; 84.3 yield); 6,(250 MHz; CDCl,; Me,Si) 3.78 (3 H, s, OMe), 6.72 (1 J. CHEM. SOC. PERKIN TRANS. 1 1994 mol) gave a pale yellow crystalline solid (16.7 g) comprising the oxime 7n (73, w/w, by 'H NMR against benzyl acetate internal standard; 63.2 yield); 6,(250 MHz; CDC1,; Me,Si) 1.3(9H,s,Buf),6.95(1 H,dd, J9and 1.5,5-H),7.0(1 H,d,J1.5, 3-H), 7.1 (1 H, d, J9,6-H), 8.15 (1 H, br s, ArOH), 8.2 (1 H, s, CH=N) and 10.05 (1 H, br s, NOH), GCMS m/z 193 (3 1 , M +), 178 (78, M -Me), 175 (28, M -H,O), 160 (100, M -H20 and Me), 132 (60) and 120 (28).Negligible product regioisomer was evident by GC or NMR. 2-Hydroxy-5-nonylbenzaldehyde0xime.-Mixed side-chain isomers 70. Magnesium raspings (29.2 g, 1.2 mol) were added over 2 h to methanol (450 g), toluene (195 g) and magnesium methoxide (20 g of 8, w/w, solution in methanol) under reflux. The mixture was heated under reflux for 1.5 h until the magnesium had dissolved and evolution of hydrogen had ceased after which 4-nonylphenol (mixed side-chain isomers) (440 g, 2.0 mol) was added to it. The methanol-toluene azeotrope was then removed by fractionation distillation further toluene (408 g) being added, until the temperature of the reaction mixture rose to 95 "C. A slurry of paraformaldehyde powder (170 g, 5.65 mol) in toluene (250 g) was added to the mixture over 1.5 h at 95 "C with concurrent removal of volatile materials by distillation. Stirring was continued at 95-100 "C for 1 h, after which the mixture was cooled to 45 "C and treated with a solution of hydroxylamine sulfate (197 g, 1.2 mol) in water (600 g), added over 1 h at 45-50 "C with vigorous stirring. Stirring was continued at 50 "C for 2 h, after which the lower (aqueous) layer was separated and extracted with toluene (170 g).The combined organic layer and extracts were washed with 7 sulfuric acid (537 g) and water (2 x 250 g) and then evaporated under reduced pressure to give the oxime 702 as a yellow oil (528 g, 82.5, w/w, measured by GC with internal standard against an authentic sample of known purity; 83 yield); b.p.185 "C 0.4 mmHg (thermally unstable); SH(400 MHz; CDCl,; Me,) 0.4-1.8 (19 H, m, C9Hl9), 6.95 (1 H, d, J 9,3-H), 7.1 (1 H,d, J1,6-H), 7.25(1 H,dd, J9and 1,4-H),8.25 (1 H, s, CH=N), 8.6 (1 H, br s, ArOH) and 10.1 (1 H, br s, NOH); 6,(100.6 MHz; CDC1,; Me,Si) 8.6-51.7 (CgHig), 115 H,d,J2.6,6-H),6.88(1H,dd,J2.6and9,4-H),6.93(1H,d,J9,(1-C), 116 (3-C), 129 (4-C and 6-C), 140 (5-C) and 153-154 3-H), 7.85 (1 H, s, ArOH), 8.19 (1 H, s, CH=N) and 9.55 (1 H, s, NOH); GCMS WZ/Z 167 (8, M'), 149 (76, M -HZO), 134 (100, M -H,O and Me), 106 (37, M -CHNOH and OH) and 79 (24). 3-sec-Butyl-2-hydroxybenzaldehydeOxime 7m.-In a similar way to that described for the oxime 7a, 2-sec-butylpheno1(30 g, 0.2 mol), magnesium methoxide (0.12 mol), paraformaldehyde powder (18 g, 0.6 mol) and then hydroxylamine sulfate (19.7 g, 0.12 mol) gave the crude oxime 7m as an orange oil (38.6 g); 6,(250 MHz; CDC1,; Me,Si) 0.9 (3 H, overlapped, CH,Me), 1.2 (3 H, overlapped, CHMe), 1.65 (2 H, overlapped, MeCH,CH), 3.1 (1 H, overlapped, MeCHCH,), 6.15 (1 H, s, ArOH), 6.8 (1 H, m, 5-H),7.0(1 H,m,4-H),7.1 (1 H,m, 6-H),8.2(1 H,s, CH=N) and 10.1 (1 H, s, NOH).Analysis of this crude product indicated the presence of the oxime 7m (14.4, w/w, by 'H NMR against benzyl acetate internal standard; 14.4 yield), GCMS m/z 193 (29, M+), 175 (22, M -HZO), 164 (96, M -CHO), 146 (loo), 132 (24), 118 (23), 103 (14) and 91 (47), with 6,6'- methylene bis(2-sec-butylphenol) 5 (R = ortho-BuS) (58 yield by GCMS), GCMS m/z 194 (23, M'), 162 (31, M -Me and OH), 147 (loo), 133 (69), 120 (32), 105 (43), 91 (35) and 77 (33).(CH=N and COH). 3-Dodecyl-6-hydroxybenzaldehyde 0xime.-Mixed side-chain isomers 7p. In a similar way to that described above, 4- dodecylphenol (mixed isomers) (46.8 g, 0.179 mol), magnesium methoxide (0.121 mol), paraformaldehyde powder (18 g, 0.6 mol) and then hydroxylamine sulfate (19.7 g, 0.12 mol) gave the oxime 7p3' as a pale yellow oil (53.25 g; 89.3, w/w, by 'H NMR and GC;87.3 yield); b.p. 232 "C 2 mmHg;6,(250 MHz; CDCl,; Me,Si)0.4-1.8 (25 H, m, C12H25), 6.9 (1 H, d, J9,5-H), 7.05(1H,dd,J9and1,4-H),7.2(1H,d,Jl,3-H),7.3(1H,brs, ArOH), 8.2 (1 H, s, CH=N) and 9.7 (1 H, s, NOH).Acknowledgements Thanks are due to Dr. B. G. Cox and Mr. J. A. Umbers for assistance with ACSL 23 modelling of reaction kinetics and again to Dr. B. G. Cox for many helpful discussions, to Mr. J. Nightingale for size exclusion chromatography and to Mr. T. Killick for determination of phenol formylation regio- selectivity. 4-tert-Butyl-2-hydroxybenzaldehydeOxime 7n.-In a similar Referencesway to that described above, 3-tert-butylphenol(l5 g, 0.1 mol), 1 e.g. I. Kirk, R. Eller, D. F. Othmer, M. Grayson and D. Eckroth,magnesium methoxide (0.06 mol), paraformaldehyde powder Kirk-Othmer Encyclopedia of Chemical Technology, Wiley, New (9.0 g, 0.3 mol) and then hydroxylamine sulfate (9.85 g, 0.06 York, 3rd edition, 1979, volume 7, pp.196-206. J. CHEM. SOC. PERKIN TRANS. 1 1994 2 e.g. GB 1 421 766, published 12/1/76; B. Townson and K. J. Severs, Mining Magazine, 1990, 162, 26; R. F. Dalton and G. W. Seward, Reagents in the Minerals Industry, Ed. M. J. Jones, Institute of Mining and Metallurgy, London, 1984, pp. 107-1 16. 3 e.g. L. N. Ferguson, Chem. Rev., 1946,38,230. 4 e.g. H. Wynberg, Chem. Rev., 1960,60, 169. 5 e.g. C. Jutz, Adv. Org. Chem., 1976,9, 225. 6 e.g. E. Baltazzi and L. 1. Krimen, Chem. Rev., 1963,63, 526. 7 e.g. D. St. C. Black, N. Kumar and L. C. H. Wong, Synthesis, 1986, 474; I. M. Godfrey, M. V. Sargent and J. A. Elix, J. Chem. SOC., Perkin Trans. 1, 1974, 1353. 8 e.g. H. Gross, A. Rieche and G. Matthey, Chem. Ber., 1963,96,308; J. 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Chem., 1986,29, 1982. 31 G. H. Krause and H. Hoyer, 2.Naturforsch., Ted B, 1972,27,663. 32 Y. Suzuki and H. Takahashi, Chem. Pharm. Bull., 1983,31,1751. 33 US 4 085 146,18th April 1978. 34 Aldrich Catalogue, Aldrich Chemical Company Ltd., Gillingham, England, 1992; catalogue number 22,307-7. 35 M. J. Bruce, A. Chaudhry and K. Dawes, J, Chem. Soc., Perkin Trans. 1, 1974,288. 36 A. M. Fahmy, S. A. Mahgoub, M. M. Aly and M. Z. A. Badr, Rev. Roum. Chim., 1985,30,749. 37 M. C. Aversa, P. Giannetto, C. Caristi and A. Ferlazzo, J. Chem. Soc., Chem. Commun., 1982,469. 38 DE 3 421 252, published 1984. 39 D. Stepniak-Biniakiewicz, Pol. J. Chem., 1980,54, 1567. Paper 4/00201F Received 13th January 1994 Accepted 28th February 1994