Benzaldehyde addition

A completely different product class, a-amido, (3-hydroxy carboxylic acids, can be obtained from the [2+2]-photocycloaddition of aldehydes to 5-methoxyoxazoles and subsequent hydrolysis of the bicyclic oxetanes [3]. Compound 3 is available from the triplet benzaldehyde addition to dimethyl 5-methoxyoxazole in diastereomerically pure (erythro-selective) form. 

The benzaldehyde addition which was most intensively investigated gave a 88 12 mixture of endo and exo diastereoisomers 118. Thus, the thermodynamically less stable stereoisomers (>1.5kcal/mol, from ab initio calculation) were formed preferentially. To further enlarge the phenyl substituent, ortho-tolyl and mesitaldehyde as well as... 

The conversion of 34 into BIRT 377 is rather efficient and very atom-economical. Treatment with 1.1 eq. MeOLi in methanol at rt provides the methyl ester of the protected amino acid along with 4-phenyl benzaldehyde. Addition of aqueous sodium bisulfite precipitates the aldehyde as the bisulfite adduct which can be removed by filtration. The crude methyl ester is then refluxed in toluene with the sodium salt of 3,5-dichloroaniline to afford hydantoin 35, which is then iV-methylated using LiHMDS/Mel in DMF to provide the final product. This sequence provides BIRT 377 in excellent purity in 40% overall yield over 5 steps, starting in this case from readily available (L)-A -/-butoxycarbonylalanine. 

Scheme 75 Synthesis of oxazoles via benzaldehyde addition to sulfones 10.4...

A 1500 ml. flask is fitted (preferably by means of a three-necked adaptor) with a rubber-sleeved or mercury-sealed stirrer (Fig. 20, p. 39), a reflux water-condenser, and a dropping-funnel cf. Fig. 23(c), p. 45, in which only a two-necked adaptor is shown or Fig. 23(G)). The dried zinc powder (20 g.) is placed in the flask, and a solution of 28 ml. of ethyl bromoacetate and 32 ml. of benzaldehyde in 40 ml. of dry benzene containing 5 ml. of dry ether is placed in the dropping-funnel. Approximately 10 ml. of this solution is run on to the zinc powder, and the mixture allowed to remain unstirred until (usually within a few minutes) a vigorous reaction occurs. (If no reaction occurs, warm the mixture on the water-bath until the reaction starts.) The stirrer is now started, and the rest of the solution allowed to run in drop-wise over a period of about 30 minutes so that the initial reaction is steadily maintained. The flask is then heated on a water-bath for 30 minutes with continuous stirring, and is then cooled in an ice-water bath. The well-stirred product is then hydrolysed by the addition of 120 ml. of 10% sulphuric acid. The mixture is transferred to a separating-funnel, the lower aqueous layer discarded, and the upper benzene layer then... 

Bisulphite addition compound. Shake 1 ml. of benzaldehyde with about 0 5 ml. of saturated NaHSOj solution. The mixture becomes warm, and the white addition product separates (rapidly on cooling). 

Atophan. In a 1 litre round-bottomed flask, equipped with a reflux condenser, place 25 g. (24 ml.) of purified benzaldehyde (Section IV,115), 22 g. of freshly-distilled P3 ruvic acid and 200 ml. of absolute ethyl alcohol. Heat the mixture to tlie boiling point on a water bath and add slowly, with frequent shaking, a solution of 23 g. (22 -5 ml.) of pure aniline in 100 ml. of absolute ethyl alcohol. The addition usually occupies about 1 hour. Reflux the mixture on a water bath for 3 hours, and allow to stand overnight. Filter off the crude atophan (1) at the pump and wash the crystals with a little ether. Recrystallise from ethyl alcohol (about 20 ml. per gram). The yield of pure 2-phenvlquinoUne-4-carboxvUc acid, m.p. 210°, is 30 g. 

After the air in the flask had been completely replaced with nitrogen, it was cooled in a liquid nitrogen bath and a solution of 25 g of acetylene in 160 ml of dry THF was introduced. The solution had been prepared by dissolving acetylene (freed from acetone by means of a cold trap) in THF cooled at -80 to -90°C. A solution of 0.21 mol of butyl lithium in about 150 ml of hexane was added in 5 min to the vigorously stirred solution. During this addition the temperature of the mixture was kept between -80 and -100°C by occasionally dipping the flask into the liquid nitrogen. To the white suspension were successively added at -80°C a solution of 10 g. of anhydrous lithium bromide (note 1) in 30 ml of THF and 0.20 mol of freshly distilled benzaldehyde. The reaction mixture was kept for 3 h at -69°C, after which the temperature was allowed to rise to +10°C over a period of 2 h. 

Hove 1. The procedure described in Ref. 1 was modified. To a solution of 2.0 mol of lithium acetylide in 1.2 1 of liquid ammonia in a 4-1 round-bottomed, three-necked flask (see Fig. 2) was added 1.5 mol of freshly distilled benzaldehyde with cooling at about -45°C. After an additional 30 min finely powdered ammonium chloride (2 mol) was introduced in 15 min. The ammonia was allowed to evaporate, then water (1.1 1) was added and the product was extracted with diethyl ether. After drying over magnesium sulfate the extract was concentrated in a water-pump vacuum. High-vacuum distillation,... 

Indol-3-ylcarbinols can also be reduced using Et3SiH-TFA. Aryl indolyl-3-ylcarbinols can be formed in situ from 2-alkylindoles and benzaldehydes. These reactions, when run in tandem, provide a versatile route to 3-benzylin-doles[l 1]. Indole itself undergoes reduction to indoline under these conditions. lndol-3-ylcarbinols can also be generated by organomelallic additions to 3-acylindoles[12]. 

The mechanism for formation of benzaldehyde diethyl acetal which proceeds m two stages is presented m Figure 17 9 The first stage (steps 1-3) involves formation of a hemiacetal m the second stage (steps 4-7) the hemiacetal is converted to the acetal Nucleophilic addition to the carbonyl group characterizes the first stage carbocation chemistry the second The key carbocation intermediate is stabilized by electron release from oxygen... 

Aldol additions of benzaldehyde with active methylene groups produce other aldehydes. 

In stepwise additions, ketenes are usually the nucleophilic component, so that such additions can be catalyzed by Lewis acids, such as the additions of trimethylsilylketenes to aldehydes, catalyzed by BF3 (Scheme 14) (79JOC733). However, the roles can be reversed, such as in the addition of chlorocyanoketene to benzaldehyde (79JA5435). 

Compound (253) is formed from benzaldehyde and methylhydroxylamine-O-sulfonic acid in 35% yield. With ethyl-substituted chloramine or hydroxylamine-O-sulfonic acid yields do not exceed 10%, which is assumed to be due to steric hindrance and is foreseeable for both carbonyl addition and O —N bond formation. 

Mandelic acid is best prepared by the hydrolysis of mandeloni-trile with hydrochloric acid. The mandelonitrile has been prepared from amygdalin, by the action of hydrocyanic acid on benzaldehyde, and by the action of sodium or potassium cyanide on the sodium bisulfite addition product of benzaldehyde. ... 

B. Preparation of B- and Z-Cirmamonitrile. A 1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, reflux condenser, and addition funnel is charged with potassium hydroxide pellets (33 g, 0.5 mol. Note 1) and acetonitrile (400 mL, Note 2), The mixture is brought to reflux under nitrogen and a solution of benzaldehyde (53 g, 0.5 mol. Note 4) in acetonitrile (100 mL) is added in a stream (1-2 min). After addition. 

The crude product (Note 2) is transferred to a 2-I. flask and mixed thoroughly with 200 g. of powdered calcium carbonate. About 300 cc. of water is added and the mixture is heated cautiously (Note 3) and then refluxed for fifteen hours to effect hydrolysis. The product is then distilled in a rapid current of steam (Note 4), and the distillate is collected in soo-cc. portions, cooled, and the />-bromobenzaldehyde is collected and dried in a desiccator. From the first liter of distillate 50-60 g. of -bromo-benzaldehyde melting at 55-57° is obtained. An additional... 

The dehydration reactions have somewhat higher activation energies than the addition step and are not usually observed under strictly controlled kinetic conditions. Detailed kinetic studies have provided rate and equilibrium constants for the individual steps in some cases. The results for the acetone-benzaldehyde system in the presence of hydroxide ion are given below. Note that is sufficiently large to drive the first equilibrium forward. 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

Carbocations can also be generated during the electrolysis, and they give rise to alcohols and alkenes. The carbocations are presumably formed by an oxidation of the radical at the electrode before it reacts or diffuses into solution. For example, an investigation of the electrolysis of phenylacetic acid in methanol has led to the identification of benzyl methyl ether (30%), toluene (1%), benzaldehyde dimethylacetal (1%), methyl phenylacetate (6%), and benzyl alcohol (5%), in addition to the coupling product bibenzyl (26%). ... 

Adolph Baeyer is credited with the first recognition of the general nature of the reaction between phenols and aldehydes in 1872 ([2,5-7] [18], Table 5.1). He reported formation of colorless resins when acidic solutions of pyrogallic acid or resorcinol were mixed with oil of bitter almonds, which consists primarily benzaldehyde. Baeyer also saw resin formation with acidic and basic solutions of phenol and acetaldehyde or chloral. Michael and Comey furthered Baeyer s work with additional studies on the behavior of benzaldehyde and phenols [2,19]. They studied a variety of acidic and basic catalysts and noted that reaction vigor followed the acid or base strength of the catalyst. Michael et al. also reported rapid oxidation and darkening of phenolic resins when catalyzed by alkaline materials. 

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