Methyl salicylate, reactions

Canosa-Mas, C.E., J.M. Duffy, M.D. King, K.C. Thompson, and R.P. Wayne (2002), The atmospheric chemistry of methyl salicylate-reactions with atomic chlorine and with ozone, Atmos. Environ., 36, 2201-2205. 

An improved route to fluorinated 4-hydroxycoumarins has been reported, based on a facile decarboxylation-deacetylation of their 3-(3-oxopropanoic acid) derivatives <96TL15S1>. The reaction of methyl salicylates with triphenylphosphoranylidene ketene, Ph3P=C=C=0, affords 4-methoxycoumarins <96JCS(P1)2799> and the formation of coumarin 3-phosphonates from salicylaldehydes and phosphonoacetates, Et02CCH2P(0)(0R)2, has been investigated <96T12597>. 

Reaction of n-butylamine with methyl salicylate in dioxane is second-order in amine (Snell et al., 1967), but reaction with methyl p-hydroxybenzoate could not be detected. The aminolysis of phenyl... 

Note that in nature, these are all enzyme-catalysed reactions. This makes the reactions totally specific. It means possible competing Sn2 reactions involving attack at either of the two methylene carbons in SAM are not encountered. It also means that where the substrate contains two or more potential nucleophiles, reaction occurs at only one site, dictated by the enzyme. The enzymes are usually termed methyltransferases. Thus, in animals an A-methyltransferase is responsible for SAM-dependent A-methylation of noradrenaline (norepinephrine) to adrenaline (epinephrine), whereas an O-methyltransferase in plants catalyses esterification of salicylic acid to methyl salicylate. 

The reaction of methyl salicylate with DMAD in presence of triethylamine yields a mixture of o-carbomethoxyphenoxymaleate (315) and fumarate (316) lEq. (45)]. Similarly, s cylamide (317a) and... 

Early Synthesis. Reported by Kolbe in 1859, the synthetic route for preparing the acid was by treating phenol with carbon dioxide in the presence of metallic sodium (6). During this early period, the only practical route for large quantities of salicylic acid was the saponification of methyl salicylate obtained from the leaves of wintergreen or the bark of sweet birch. The first suitable commercial synthetic process was introduced by Kolbe 15 years later in 1874 and is the route most commonly used in the 1990s. In this process, dry sodium phenate reacts with carbon dioxide under pressure at elevated (180—200°C) temperature (7). There were limitations, however not only was the reaction reversible, but the best possible yield of salicylic acid was 50%. An improvement by Schmitt was the control of temperature, and the separation of the reaction into two parts. At lower (120—140°C) temperatures and under pressures of 500—700 kPa (5—7 atm), the absorption of carbon dioxide forms the intermediate phenyl carbonate almost quantitatively (8,9). The sodium phenyl carbonate rearranges predominately to the 07 0-isomer, sodium salicylate (eq. 8). 

The esters of salicylic acid account for an increasing fraction of the salicylic acid produced, about 15% in the 1990s. Typically, the esters are commercially produced by esterification of salicylic acid with the appropriate alcohol using a strong mineral acid such as sulfuric as a catalyst. To complete the esterification, the excess alcohol and water are distilled away and recovered. The cmde product is further purified, generally by distillation. For the manufacture of higher esters of salicylic acid, transesterification of methyl salicylate with the appropriate alcohol is the usual route of choice. However, another reaction method uses sodium salicylate and the corresponding alkyl halide to form the desired ester. 

Benzyl salicylate can be prepared by the reaction of benzyl chloride with an alkali salt of salicylic acid at 130—140°C or by the transesterification of methyl salicylate with benzyl alcohol. It is used as a fixative and solvent for nitro musks and as a fragrance for deteigents. Benzyl salicylate was priced at... 

Salicylamide [65-45-2] is prepared by the reaction of methyl salicylate with ammonia. Salicylamide has mild analgesic, antiinflammatory, and antipyretic properties. Salicylamide is unlike other salicylates in that it causes sedation and central nervous system depression. Salicylamide is not hydrolyzed to salicylate and its action depends on the entire molecule. Salicylamide has been useful for protection against mildew and fungus in a variety of soaps, salves, lotions, and oils. The May 1996 price was 8.00/kg (18). 

Cycloaromatization.1 The diene can be used as the equivalent of the dianion of methyl acctoacctate for a novel synthesis of methyl salicylates. In the presence of titanium(IV) chloride (1 equivalent) 1 reacts with /3-dicarbonyl equivalents to form methyl salicylates. Various reactions of 1 indicate that CA is more nucleophilic than C2. The examples formulated in equations (1) and (II) show that the reaction is... 

Oxidative cyclization of unsaturated /3-dicarbonyl compounds with two a-hydro-gen atoms will give products that still have one a-hydrogen and can be oxidized further. If the product is oxidized at a rate competitive with that of the starting material, mixtures of products will be obtained. For instance, oxidative cyclization of 26 affords 36 % of 27 and 10 % of dienone 28 formed by further oxidation of 27, as shown in Scheme 6 [7]. The product is occasionally oxidized much more readily than the starting material so that none of the initial product is isolated. These reactions may still be synthetically useful if the products of further oxidation are monomeric. For example, oxidative cyclization of methyl 3-oxo-6-heptenoate provides 78% of methyl salicylate [29]. The overall reaction consumes 4equiv. Mn(OAc)3. Competitive oxidation of the product is not usually a problem in inter-molecular addition reactions, because a vast excess of the oxidizable substrate, for example acetone or acetic acid, is usually used as solvent. Use of excess substrate is not possible in oxidative cyclizations. 

On excitation the phenolic group becomes more strongly acidic while the carboxylic acid group becomes a stronger base and proton exchange then occurs between the two. In confirmation of this explanation, methyl salicylate was found to behave similarly, but methyl 2-methoxybenzoate, with no transferable proton, showed a normal Stokes shift. Quenching experiments demonstrated that at room temperature the proton transfer reaction reached equilibrium within the lifetime of the excited state. 

Salicylic acid and its methylated derivatives have been reexamined recently (Schulman and Gerson, 1968 Kovi et al., 1972b) and the pH-dependence of the intramolecular proton transfer reaction has been investigated. In both chloroform and aqueous media, salicylic acid both in the uncharged and carboxylate forms undergoes intramolecular proton transfer in the excited state. In the case of methyl salicylate, the proton transfer occurs intramolecularly in chloroform but intermolecularly in aqueous media. By comparison with the behaviour of 2-methoxybenzoic acid and methyl salicylate,... 

The epoxide can now rearrange with the whole side chain migrating in a reaction very similar to the laboratory rearrangement to give methyl salicylate that you saw on p. 1409. 

Now the last chain extension Occurs and the completed Z-tetraketide cyclizes to 6-methyl salicylic acid. Chemically, we would prefer not to carry the unstable Z-enone through several steps, but Nature controls these reactions very precisely. 

C/HgOsts) + CH3OHw -> C8H803W + H2Ow A chemist reacts 3.50 g of salicylic acid with excess methanol. She calculates the theoretical yield of methyl salicylate to be 3.86 g. If 2.84 g of methyl salicylate are recovered, what is the percentage yield of the reaction ... 

These pyrones undergo Diels-Alder reactions with electron-deficient alkenes with loss of COj and formation of an aromatic ring. Thus reaction with 1,1-dimethoxyethylene (11, 279-281) provides a regiospecific route to methyl salicylates (e.g., 3), which are convertible in several steps into catechol derivatives (4) or by decarbomethoxylation into phenol ethers (5). Similar reactions with vinylene carbonate or 1, 1,2-trimethoxyethylene provide regiospecific routes to phenols, differentially protected derivatives of catechol, resorcinol, or pyrogallol (equation II). 

Since salicylic acid has both an alcohol functional group and a carboxylic acid functional group, it can undergo two different esterification reactions depending on which functional group reacts. For example, when treated with ethanoic acid (acetic acid), salicylic acid behaves as an alcohol and the ester produced is acetylsalicylic acid (aspirin). On the other hand, when reacted with methanol, salicylic acid behaves as an acid and the ester methyl salicylate (oil of wintergreen) is produced. Methyl salicylate is also an analgesic and part of the formulation of many liniments for sore muscles. What are the structures of acetylsalicylic acid and methyl salicylate ... 

Methyl salicylate in topical analgesic preparations can cause irritant or allergic contact dermatitis and anaphylactic reactions (6). 

---