7-Hydroxymethyl-2-substituted

Several products resulted when 4-HMP was allowed to condense under the same conditions. These are provided in Scheme 6. These products indicate that a p-hydroxymethyl group can react with either an unsubstituted ortho position or through an ipso-attack on a hydroxymethyl-substituted para position. The two condensation products were formed at approximately equal rates. Since there were two unoccupied orthos, it seems that the specific reaction rate for the ortho site is about half that of the occupied para position in this situation. The condensation rate for 4-HMP was about 5 times the rate for 2-HMP overall. 

Blasius and coworkers have offered a somewhat different approach to systems of this general type. In the first of these, shown in Eq. (6.20), he utilizes a hydroxymethyl-substituted 15-crown-5 residue as the nucleophile. This essentially similar to the Mon-tanari method. The second approach is a variant also, but more different in the sense that covalent bond formation is effected by a Friedel-Crafts alkylation. In the reaction... 

More recently, the reaction advancement of resole syntheses (pH = 8 and 60°C) was monitored using high-performance liquid chromatography (HPLC), 13C NMR, and chemical assays.55,56 The disappearance of phenol and the appearances of various hydroxymethyl-substituted phenolic monomers and dimers have been measured. By assessing the residual monomer as a function of reaction time, this work also demonstrated the unusually high reactivity of 2,6-dihydroxymethyl-phenol. The rate constants for phenolic monomers toward formaldehyde substitution have been measured (Table 7.6). 

As the reactions proceed, the disappearance of phenol is delayed due to competition for reaction with formaldehyde between phenol and the faster reacting hydroxymethyl-substituted phenols. Competition also exists between formaldehyde substitution reactions and condensation reactions between rings. Condensation reactions between two ortho-hydroxymethyl substituents are the least favorable condensation pathway. Depending on the reaction conditions, substitutions occur... 

The mechanisms for model condensation reactions of para-hydroxymethyl-substituted phenol (and therefore para-quinone methide) with reactive ortho positions are described in Fig. 7.29. The phenolate derivatives react with para-quinone... 

The reaction conditions, formaldehyde-to-phenol ratios, and concentration and type of catalyst govern the mechanisms and kinetics of resole syntheses. Higher formaldehyde-to-phenol ratios accelerate the reaction rates. This is to be expected since phenol-formaldehyde reactions follow second-order kinetics. Increased hydroxymethyl substitution on phenols due to higher formaldehyde compositions also leads to more condensation products.55... 

Crosslinking resoles in the presence of sodium carbonate or potassium carbonate lead to preferential formation of ortho-ortho methylene linkages.63 Resole networks crosslinked under basic conditions showed that crosslink density depends on the degree of hydroxymethyl substitution, which is affected by the formaldehyde-to-phenol ratio, the reaction time, and the type and concentration of catalyst (uncatalyzed, with 2% NaOH, with 5% NaOH).64 As expected, NaOH accelerated the rates of both hydroxymethyl substitution and methylene ether formation. Significant rate increases were observed for ortho substitutions as die amount of NaOH increased. The para substitution, which does not occur in the absence of the catalyst, formed only in small amounts in the presence of NaOH. 

Cyclization of substituted phenylacetylene sequences afforded functionalized macrocycles that were amenable to subsequent manipulation. For example, transesterification of 42 with octanol in the presence of 18-crown-6 ether and potassium carbonate gave the corresponding ester in 85% yield (Scheme 13). The ester functionalities could be reduced by DIBALH to give the hydroxymethyl-substituted macrocycle (43) in 61 % yield. The low yield of this particular transformation is attributed to mechanical losses during purification, due to the highly polar nature of the product. Macrocycle 43 could then be treated with alkyl bromides to give a group of benzyl ether derivatized PAMs. 

Pd, or Ni (Scheme 5-3). First, P-H oxidative addition of PH3 or hydroxymethyl-substituted derivatives gives a phosphido hydride complex. P-C bond formation was then suggested to occur in two possible pathways. In one, formaldehyde insertion into the M-H bond gives a hydroxymethyl complex, which undergoes P-C reductive elimination to give the product. Alternatively, nucleophilic attack of the phosphido group on formaldehyde gives a zwitterionic species, followed by proton transfer to form the O-H bond [7]. 

According to the coordinatoclathrate predict, the Spiro compound 23 will not allow the formation of inclusion compounds with dimethylformamide and other polar solvents, but with benzene, tetrahydrofuran, and 1-bromopentane (Table 3). Due to the limited number of guest inclusions, a lattice cavity of rather restricted dimensions is suggested for 23 e.g. toluene, cyclohexane or dioxane are not suitable guest partners for 23, whereas lower homologues (cf. benzene, tetrahydrofuran) are readily included 37). The behavior of a reduced analogue of 23, the hydroxymethyl — substituted spiro compound 24, is in some way comparable since an inclusion compound with benzene is the only one known interestingly it is formed exclusively with optically resolved but not with racemic 24 49). 

The hydroxymethyl-substituted phenylsulfoxide 92, also as the optically active (R) enantiomer, added to cyclopentadiene (6) at 90 °C to give a mixture of two diastereoisomers 93 in 1.6 1 ratio (Scheme 18) [19]. 

Metalated cyclic aldo-nitrones are characterized by high reactivity toward electrophilic reagents. Reactions with aldehydes and ketones afford satisfactory yields of a-hydroxymethyl substituted derivatives of nitrones (551). The reactions were also carried out with a number of aliphatic, aromatic, and hetero-aromatic aldehydes and ketones (Schemes 2.124 and 2.125). 

Scheme 12 Synthesis of cis and trans 1-hydroxymethyl substituted C6-HSL and their carbamate derivatives... 

Despite these promising results, bis(oxazoline) ligands seem to perform better in the ATH of ketones when associated with Ru precursors. Pinel et al. [79] described a comparative study on the effect of the metal in ATH of acetophenone using the hydroxymethyl-substituted bis(oxazoline) 88 (Scheme 4.38). Whereas, Ru(ll) complexes gave 89% ee at 50% conversion, only 22% conversion was... 

Ring-Chain Equilibrium CoNSTANrs" por o-Hydroxymethyl-SuBSTiTUTED Arene Carbal.dehydes AND Arylketones (34-36)... 

To summarize the amides are most suitable for the formation, by ortholithiation, of condensed heterocycles and polycyclic aromatics (in which subsequent rings are formed by intramolecular attack on the amide group). In other cases the removal of the amide group may be problematic, though if carboxylic acids, aldehydes or hydroxymethyl-substituted compounds are required, alternative amide substituents may be used. 

Trollsas M, Lowenhiehn P, Lee VY, Mbller M, Miller RD, Hedrick JL (1999) New approach to hyperbranched polyesters self-condensing cyclic ester polymerization of bis (hydroxymethyl)-substituted e-caprolactone. Macromolecules 32 9062-9066... 

The hydroxymethyl-substituted methyl esters can then be transesterified with any number of different initiator types to tailor the structure of the polyol to the end-use application, and all from a single raw material source. The stoichiometry of the polyol is adjustable, to produce polyols of any molecular weight. This synthetic strategy was developed by The Dow Chemical Company as the Renuva polyols. 

Preparation of a-monofluoromethyl amino acids is not easy. Indeed, although the amino acids can easily be hydroxymethylated, substitution of the hydroxyl by a fluorine atom is not always easy (SF4, DAST). On the other hand, preparation of monofluoroketones (substrates of the Strecker reaction) involves the use of highly toxic fluoroacetonitrile. ° ... 

Dibenzothiophene carbamate 396 was converted to the corresponding l,3-oxazin-2-one derivatives 397 in a two-step, one-pot procedure. Lithiation of 396 gave a bis-anion intermediate, treatment of which with ketones led to cyclization to tetracyclic l,3-oxazin-2-ones 397 (Equation 43). In the similar reaction of the analogous dibenzofuran carbamate, a hydroxymethyl-substituted acylic compound was formed <1998J(P1)457>. 

Various 2-functionalized-l,3-oxathianes have been prepared from 1,3-thioalcohols by a combined SNV/Michael addition sequence using (Z)-l,2-bis-phenylsulfonylethylene (BPSE) as Michael acceptor. The yields were in the range of 72-90% for aliphatic 1,3-thioalcohols and somewhat lower for 2-hydroxymethyl-substituted aromatic thiols (33%) (Equation 90) <2003TL5723>. 

Among a number of other homochiral furanosyl- and isoxazolidinylthymine targets, these workers also applied an achiral cycloaddition approach with vinyl acetate to successfully prepare the antiviral agent d4T (11) and its 2-methyl analogue (Fig. 1.1) (45). In more recent work, similar nitrones [9, R = Me or benzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues. 

This method has been extended to heterocycles bearing a hydroxymethyl-substituted nitrogen. Thus, ethyl l-(hydroxymethyl)pyrazole-4-carboxylate (10) is converted into ethyl 1-(fluoromethyl)pyrazole-4-carboxylate (11) in 76% yield with cesium fluoride/methanesulfonyl fluoride/18-crown-6 system.167 Potassium fluoride did not react at all and tetrabutylammonium fluoride leads to decomposition and formation of coupling products. 

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

The structure of the phenylcoumarone (XXII) 26) was derived from analytical and spectral investigation and was confirmed by a synthesis 29) starting from dehydrodiconiferyl alcohol (XXVII). The latter compound (XXVII) was converted by monoperphthalic acid into an epoxide whose side chain was equivalent to that of an arylglycerol. By properly performed acidolysis, the epoxide side chain therefore was converted into the primary ketol structure, and at the same time the hydroxymethyl-substituted phenylcoumaran system see XXVII) was converted into the methyl-substituted phenylcoumarone system of XXII (Figure 8). 

The starting substrate, protected ot-vinylproline 187 was activated by HATU and coupled with glycine methyl ester hydrochloride to give protected peptide derivatives 188. Further, ozonolysis of these derivatives and subsequent reduction with excess of Na[BH(OAc)3] provided the hydroxymethyl-substituted derivative 189 in... 

In recent years, it has been shown that co-ordinated phosphines may also undergo reactions with carbonyl compounds. This is well exemplified in the reactions of [(MeHPCH2CH2PHMe)2Pd]2+ (Fig. 5-51). The reaction with formaldehyde yields a complex of an open-chain hydroxymethyl substituted ligand, the same species that is obtained from reaction of the free ligand. This is the phosphorus analogue of the aminol intermediate in imine formation. It is extremely unusual to obtain RP=CR2 systems in the absence of sterically demanding substituents. 

Kaufman, T. S. Extension of the Bobbitt acetal 364 cyclization to the elaboration of 1-hydroxymethyl substituted simple tetrahydroisoquino-... 

Hydroxymethyl-substituted tetrahydrofurans have been prepared with high diastere-oselectivity by reaction of the carbanion derived from 3,4-epoxybutyl phenyl sulfone (g) with aldehydes in the presence of a mixture of lithium and potassium /-buloxidcs (Scheme 8).48 Initial formation of aldol-type adducts is a non-diastereoselective but reversible process thus, subsequent formation of one main diastereoisomer is controlled by the relative rates of cyclization. The configuration of the carbon stereocentre at the oxirane ring is inverted in the course of the 5 2 process, and two new centres are created diastereoselectively (up to 87 13 0 0). 

Transformations of Epoxy Hydroperoxides to Hydroxymethyl-Substituted Dioxetanes 791... 

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