Hydroxy-ketones condensation

Hoesch synthesis A variation of the Gattermann synthesis of hydroxy-aldehydes, this reaction has been widely applied to the synthesis of anthocyanidins. It consists of the condensation of polyhydric phenols with nitriles by the action of hydrochloric acid (with or without ZnCl2 as a catalyst). This gives an iminehydrochloride which on hydrolysis with water gives the hydroxy-ketone. 

AJdoJ Condensation -Aldol condensation Initially give p-hydroxy ketones which under certain conditions readily eliminated to give a,p-unsaturated carbonyls. 

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

LAPWORTH (BENZOIN) Condensation Condensation of two molecules of aryl aldehydes fo an alpha-hydroxy ketone catalysed by CN (via cyanohydnns). 

Functionalized 5-alkoxymethyl- and 5-phenoxymethyl-2(5//)-furanones 44-46 were obtained starting from 3-alkoxy- and 3-phenoxy-2-hydroxy ketones 40 (98T1801). Condensation of the hydroxy ketones 40 with a slight excess of diethyl malonate 41 (Z = COOMe R = Me), ethyl cyanoacetate 42 (Z = CN R = Me),... 

Upon heating of a carboxylic ester 1 with sodium in an inert solvent, a condensation reaction can take place to yield a a-hydroxy ketone 2 after hydrolytic workup. " This reaction is called Acyloin condensation, named after the products thus obtained. It works well with alkanoic acid esters. For the synthesis of the corresponding products with aryl substituents (R = aryl), the Benzoin condensation of aromatic aldehydes is usually applied. 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

Aromatic aldehydes 1 can undergo a condensation reaction to form a-hydroxy ketones 2 (also called benzoins) upon treatment with cyanide anions.This reaction, which is called benzoin condensation, works by that particular procedure with certain aromatic aldehydes and with glyoxals (RCOCHO). 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Whereas condensation of a-hydroxy ketones such as benzoin and acetoin on heating with formamide [240] or ureas in acetic acid [239, 242] to form imidazoles such as 769 or 770 is a well known reaction, only two publications have yet discussed the amination of silylated enediols, prepared by Riihlmann-acyloin condensation of diesters [241], by sodium, in toluene, in the presence of TCS 14 [241, 242]. Thus the silylated acyloins 771 and higher homologues, derived from Riihl-... 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

Preparation and phytochemical reduction of 2,2 -thenoin and 2,2 -thenil have been studied in the authors laboratory (20a). It has been shown that 2,2 -thenoin gives a color reaction similar to that shown by benzoin and other acyloin condensation products in- the presence of alcoholic alkali. The hydroxy ketone may be oxidized by iodine in the presence of sodium methoxide to give the diketone, 2,2 -thenil, in excellent yields. Phytochemical reduction was shown also to be applicable to both compounds. It is significant that thenoin differs from benzoin, since reduction products were not obtained enzymatically from the latter. 

Stereoselective aldol condensation. 2-Butenyllilhium (1) reacts with aldehydes to form the threo- and erythro-fl-methyl alcohol in equal amounts. However, if a trialkylboranc is present, r/ireo-products predominate. Presumably an allylboronate complex (a) is involved.1 An example is formulated in equation (1). The products are converted into 0-hydroxy ketones (4) by a Wacker-type oxidation.2... 

Carbonyldiimidazole can also function as a carbonyl equivalent (79TL4517). Condensation of the dianion derived from an a-hydroxy ketone (545) with this reagent provides a general although modest yield approach to tetronic acids (546 equation 7). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Conjugate addition-aldol reactions. A novel synthesis of a-substituted a,(3-enones involves conjugate addition of 1 to an a,p-enone the resulting 0-phenyl-selenoboron enolate undergoes aldol condensation with aldehydes. The adduct on oxidative elimination furnishes unsaturated p-hydroxy ketones.1 Example ... 

HYDROXY KETONES (see also Aldol condensation) Raney nickel. 

Aromatic aldehydes form a condensation product when heated with a cyanide ion dissolved in an alcohol-water solution. This condensation leads to the formation of a hydroxy ketones. 

Apart from the large number of different a-keto acids which may be decarboxylated by PDC, only a few of the resulting aldehydes may be transferred to a second aldehyde molecule to form an a-hydroxy ketone [151]. Besides acetaldehyde, which is the best acylanion equivalent, propionaldehyde and butyraldehyde have been condensed to benzaldehyde by baker s yeast after decarboxylation of the corresponding a-keto acids [116,149]. 

In the benzoin condensation, a new stereogenic center is formed, as the product is an a-hydroxy ketone. Consequently, many chemists aspired to develop heterazolium-catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions [9]. For example, Sheehan et al. presented the first asymmetric benzoin condensation in 1966, with the chiral thiazolium salt 7 (Fig. 9.2) as catalyst precursor [10]. 

The precatalyst 17 produced (S)-benzoin (6, Ar = Ph) in very good yield (83%) and enantioselectivity (90% ee). The condensation of numerous other aromatic aldehydes 4 yielded the corresponding a-hydroxy ketones 6 with excellent ee-values of up to 95%. (For experimental details see Chapter 14.20.2). Electron-rich aromatic aldehydes gave consistently higher asymmetric inductions than electron-deficient (i.e., activated) aromatic aldehydes, with lower reaction temperatures or lower amounts of catalyst leading to slightly higher enantioselectivities coupled with lower yields. 

Carboxylic esters react with sodium metal to give a-hydroxy ketones (often referred to as acyloins). The reaction, known as the acyloin condensation, is thought to proceed by the mechanism shown in Figure Si3.13. 

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

CL—Hydroxy ketones take part in condensation reactions too. How would you make TM148 ... 

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