Salicylaldehyde synthesis

Coumarin is usually prepared by heating salicylaldehyde with acetic anhydride and sodium acetate (i.e., the Perkin cinnamic acid synthesis, p. 23 6), whereby the 0" hydroxy-cinnamic acid (I) undergoes cyclisation to coumarin. Coumarins having substituents in the benzene ring can often be similarly prepared. 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

Complexes with chelating organic reagents such as salicylaldehyde and -diketonales were first prepared by N. V. Sidgwick and his students in 1925, and many more have since been characterized, Stability, as measured by equilibrium formation conslanis, is rather low and almost invariably decreases in the sequence Lj > Na > K. This situation changed drainalically in 1967 w hen C. J. Pedersen announced the synthesis of several macrocyclie polyethers which were shown to form stable complexes with... 

The only known example of this type of cyclization is the synthesis of dibenz[, /]azepines 457 from appropriate salicylaldehyde 454 and 2,4, 6-trinitrotoluene (455) via the corresponding intermediate 456 (Scheme 72) (62M766). 

Another CNS active agent in this structural class is the tranquilizer-antidepressant caroxazone (52). Its published synthesis begins by reductive aminatiwi of salicylaldehyde and glycinamide to give The synthesis is completed by reaction with phosgene and sodium bicarbonate. ... 

Dduzorme has reported a simple synthesis of flavanones by radical denitratiQn and dehalo-genadon of 3-chlQrQ-2,3-dihydrQ-3-nitrQ-2-aryl-4//-l-ben2Qpyran-4-ones, which are readily prepared by the reacdon of salicylaldehydes with l-chlQrQ-l-nltrQ-2-arylethenes fEq. 7.73. ... 

A structurally related tetrameric macroheterocycle is compound 13 that is prepared in a one-pot synthesis (yield 64%) from salicylaldehyde and (3-aminophenyl)boronic acid in methanol (Fig. 4). Due to its insolubility it has been characterized only by mass spectrometry. If a substitutent is introduced at the imine function (R = Me, Ph), trimeric structures (14 and 15) are... 

A neat stereoselective synthesis of trans-fused tetrahydropyrano[3,2-c][l]benzopyrans involves treating salicylaldehydes with alk-4-en-l-ols and triethyl orthoformate. The selectivity is attributed to steric repulsion in the endo transition state, the precursor of the cw-fused compound <96CL889>. 

A further example of the utility of the cyclobuta[ >]chroman system in synthesis (see 6.4.1.3) is provided by the conversion of the cyclobutenedione derivatives (19) into substituted xanthones. Compounds (19) are obtained in high yield from salicylaldehydes and squarate esters and their reaction with alkenyl, aryl and heteroaryl li compounds is both facile and high yielding <96JA12473>. 

Synthesis of complex 1. The pentadentate salen catalyst 1 was synthesized as described (9). In short, the tosylated 2-[2-(2-methoxyethoxy)-ethoxy]-ethanol 2 (10) was reacted with 2,4-dihydroxybenzaldehyde 3 to yield 4-alkoxy salicylaldehyde 4 after chromatographic purification (eq. 1). Subsequent condensation of 4 with 1,3-diaminopropanol yielded water-soluble salen ligand 5 in sufficient purity and 89% yield (11). The formation of an azomethine bond is indicated by a shift of the NMR signal for the carbonyl carbon from 194.4 ppm in aldehyde 4 to 166.4 ppm for the imino carbon in 5. The pentadentate ligand 5 was then treated with copper(ll) acetate in methanol to obtain the dinuclear copper(ll) complex 1 as a green solid (eq. 2) (11). 

Although thiosalicylaldehyde 46a (R2 = H) was first synthesized by Friedlander and Lenk (Scheme 23),95 it is an unstable intermediate and should be stored in solution below 0°C. Alternate synthetic procedures utilizing o-chlorobenzaldehyde or salicylaldehyde, as starting materials, are shown in Scheme 24.96 The preferred method for the synthesis of substituted thiosalicylaldehydes 46 is via salicylaldehyde. 

One method of solving the kinetics dilemma is well known in coordination chemistry that is, start with a labile metal ion and render it inert during the course of the synthetic reaction. We have accomplished this in the case of zirconium(IV) by starting with tetrakis(salicylaldehydo)zirconium(IV), which is quite labile, and polymerization with 1,2,4,5-tetraaminobenzene in a Schiff-base condensation reaction in situ (6). The polymeric product contains a "double-headed" quadridentate ligand, which is much more inert to substitution. However, 1,2,4,5-tetraaminobenzene has become very expensive. Therefore, the synthesis of a zirconium polymer with 3,3, 4,4 -tetraaminobiphenyl (commercially 3,3 -diami nobenzidine) with zirconium salicylaldehyde, Zr(sal)4 (7) has been undertaken as shown below ... 

Hallberg and coworkers [84] developed a synthesis of monoprotected 3-hydroxy-indan-l-ones 6/1-156 in moderate to good yields using salicylaldehyde triflates and... 

Condensation of salicylaldehyde and its derivatives with a variety of esters of chlo-roacetic acids in the presence of TBAB led to the synthesis of benzo[fo]furans by means of a solid-liquid PTC reaction under the action of microwave irradiation [33], This was a modification of one of the most popular routes to substituted benzo[fo]fu-... 

The pyrano[3,2-c][l]benzopyran system is available from the reaction between salicylaldehyde and 5-phenylthio-4-penten-l-ols which proceeds by an intramolecular cycloaddition of an o-quinone methide desulfurisation is facile (Scheme 29) <00TL2643>. Mild conditions have been established for the synthesis of (-)-hexahydrocannabinol 50 from the olivetol derivative 49 which also involves a quinone methide (Scheme 30) <00SC1431>. 

In the preparation described above we have an important means of making fi-arylacrylic acids, and from them, by hydrogenation, fi-arylpropionic acids. The method is used in the investigation of alkaloids and in the synthesis of coumarin from salicylaldehyde. 

THE REIMER-TIEMANN SYNTHESIS SALICYLALDEHYDE FROM PHENOL AND CHLOROFORM 1... 

From salicylaldehyde and sodium acetate by Perkin s synthesis coumarin is formed. (Formulate )... 

Using the tandem aza-Wittig/bir-electrocyclization strategy, an isoquinoline synthesis starts with salicylaldehyde, which is converted with azido-... 

I2 vapor is extremely corrosive while scandium compounds are moisture-sensitive and very expensive. In addition, these reactions are carried out in an environmentally unfriendly solvent, CH2CI2. We have reported the bismuth triflate-catalyzed synthesis of substituted dihydro-2//-1-benzopyrans by the condensation of substituted salicylaldehydes with 2,2-dimethoxypropane (Scheme 3) [22]. 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

Numerous methods for the synthesis of salicyl alcohol exist. These involve the reduction of salicylaldehyde or of salicylic acid and its derivatives. The alcohol can be prepared in almost theoretical yield by the reduction of salicylaldehyde with sodium amalgam, sodium borohydride, or lithium aluminum hydride by catalytic hydrogenation over platinum black or Raney nickel or by hydrogenation over platinum and ferrous chloride in alcohol. The electrolytic reduction of salicylaldehyde in sodium bicarbonate solution at a mercury cathode with carbon dioxide passed into the mixture also yields saligenin. It is formed by the electrolytic reduction at lead electrodes of salicylic acids in aqueous alcoholic solution or sodium salicylate in the presence of boric acid and sodium sulfate. Salicylamide in aqueous alcohol solution acidified with acetic acid is reduced to salicyl alcohol by sodium amalgam in 63% yield. Salicyl alcohol forms along with -hydroxybenzyl alcohol by the action of formaldehyde on phenol in the presence of sodium hydroxide or calcium oxide. High yields of salicyl alcohol from phenol and formaldehyde in the presence of a molar equivalent of ether additives have been reported (60). Phenyl metaborate prepared from phenol and boric acid yields salicyl alcohol after treatment with formaldehyde and hydrolysis (61). 

Production. Coumarin is currently produced by Perkin synthesis from salicyl-aldehyde. In the presence of sodium acetate, salicylaldehyde reacts with acetic anhydride to produce coumarin and acetic acid. The reaction is carried out in the liquid phase at elevated temperature. 

Phenylcoumarins are conveniently prepared by the Knoevenagel condensation of salicylaldehyde with a benzyl cyanide, in the presence of base such as sodium hydroxide or piperidine, followed by acid hydrolysis of the resultant imine. A second convenient synthesis is via condensation of 2-methoxybenzaldehyde with benzyl cyanide and cyclization of the 2-methoxy-a-phenylcinnamic nitrile in pyridine (Scheme 12). 

A series of papers by Schweizer s group222 224 has indicated the possibility of a general synthesis of chromencs in high yield by addition of the phenolate anion of salicylaldehyde to a vinylphosphoniuin salt, 0-... 

Salicylaldehyde is the starting material for the preparation (Scheme 12) of most spirobenzopyrans, which are important photochromic compounds. The reader interested in their synthesis and properties is referred to the recent excellent book by Bertelson.5... 

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