Ammonium acetate, reaction with ketones

The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

In articles like this one, the scientists don t have the time nor the space to write out the details and amounts of reactants used for every single substrate they tried things on. So they pick just a few of the precursors they tried and use their numbers as an example of how the reaction typically goes. All one does is just substitute an equal amount of their favorite phenylacetone for the one in the example while keeping everything else the same. This will not be too big of a stretch of the old imagination with the first example below. The example ketone is just phenylbutanone. One little carbon more than phenylacetone, but a methyl ketone nonetheless (don t ask). They react exactly the same. As it so happens this first example is also the one using ammonium acetate to make MDA. Sweet ... 

Carbonyl Compounds. Cychc ketals and acetals (dioxolanes) are produced from reaction of propylene oxide with ketones and aldehydes, respectively. Suitable catalysts iaclude stannic chloride, quaternary ammonium salts, glycol sulphites, and molybdenum acetyl acetonate or naphthenate (89—91). Lactones come from Ph4Sbl-cataly2ed reaction with ketenes (92). 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

In a similar manner, 2,4,6-trisubstituted 3-pyridinecarboxylic acid esters have been prepared using a mixture of a, 3-ketoesters, propargylic alcohols, ammonium acetate and Mn02. The reaction proceeds by oxidation of the propargylic alcohol to the corresponding ketone, which reacts with the enamine being formed from the like loos lor and ammonium acetate. For this domino process, normal heating at 70 °C was used. 

The reaction of y-nitrobutenoate with aldehydes and ketones in the presence of ammonium acetate gives 3-nitropiperidines.130 This reaction is used for synthesis of CP-99,994, a highly potent substance P antagonist (Scheme 10.23).131... 

Azolo[1,5]naphthyridines. Imidazonaphthyridines can be prepared by the reaction of ammonium acetate with appropriately substituted naphthyridinium salts. For example, reaction of the ketone 236 in acetic acid with iron(m) chloride produces the tetracycle 237 <2001AJC105> (Equation 64). 

In contrast to these vapour-phase reactions, it has been reported that ketones and aqueous ammonia (or ammonium acetate) in an autoclave give less complex mixtures of pyridines. Crotonaldehyde gives 5-ethyl-2-methylpyridine (570) in up to 59% yield, methyl vinyl ketone gives 2,3,4-trimethylpyridine (571) rather than 2,3,6-trimethylpyridine 1,3,3-trimethoxybutane has been used in place of methyl vinyl ketone (49JA2629). In some cases reverse aldol reactions occur (for example with benzalacetophenone) giving unwanted products. A similar reverse aldol is responsible for the production of triarylpyridines (572) when benzalacetophenones are treated with formamide and ammonium formate (73JA4891). 

The same may be said of an amine function adjacent to a ketone, although with a 4-substituted pyrrolo[2,3-r/ -pyrimidine 166 as the end product. Equation (62) illustrates this type of reaction, where 165 is heated with ammonium acetate <1996IZV1720>. 

This synthetic procedure, using the hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems to be quite general for ketone compounds related to 3,4-methylenedioxyphenylacetone. Not only were most of the MD-group of compounds discussed here made in this manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P) itself appears to be equally effective. The reaction of butylamine hydrochloride in methanol, with phenyl-2-propanone and sodium cyanoborohydride at pH of 6, after distillation at 70-75 °C at 0.3 mm/ Hg, producedN-butylamphetamine hydrochloride (23.4 g from 16.3 g P-2-P). And, in the same manner with ethylamine hydrochloride there was produced N-ethyl-amphetamine (22.4 g from 22.1 g P-2-P) and with methy lamine hydrochloride there was produced N-methylamphetamine hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple ammonia (as ammonium acetate) gives consistently poor yields in these reactions. 

Aldehyde or ketone (3 mmol), ammonium acetate (3 mmol, 231 mg), basic alumina (3 g) and active methylene compound 2 (3 mmol) were mixed thoroughly in a mortar. The reaction mixture was placed in a beaker and irradiated under the conditions shown in Table. The progress of reaction was monitored by TLC using petroleum ether-CH2Cl2 (30 70) as eluent. The mixture was extracted into CH2C12 then filtered and washed with water. The solvent was removed under reduced pressure by rotatory evaporator. Further purification by column chromatography on silica gel gave the desired product. 

A mixture of arylidenemalanonitrile 1 (3 mmol), ketone 2 or 4 (3 mmol), ammonium acetate (24 mmol) and o-dichlorobenzene (0.5 mL) was placed in a borosil beaker (100 mL) and mixed thoroughly with the help of a glass rod. The mixture was then subjected to microwave irradiation for an optimized time at a power output of 275 W. After completion of the reaction (monitored by TLC), ethanol... 

Most of the publications on the reactions of malonic acid derivatives are devoted to the reaction of a,(3-unsaturated carbonyls with malononitrile 107. In this book we do not describe the results of all known publications but only the most characteristic or interesting ones in our opinion. The reactions of unsaturated ketones with malononitrile are usually carried out in methanol or ethanol in the presence of ammonium acetate [102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117]. Treatment of malononitrile 107 with chalcone 5 [115] and its heterocyclic analogue 109 [104] yielded 3-cyanopyri-dines 108 and 110 (Scheme 3.33). 

Substitution of the acetate group at the C-3 position of the /3-sultam 105 can occur by reaction with silyl enol ethers in the presence of zinc iodide or zinc chloride. When the diazo compound is used, after desilylation with tetrabutyl-ammonium fluoride (TBAF), photochemical cyclization gives the bicyclic /3-sultam 106 as a mixture of two cis/ fra -diastereoisomers. When silyl enol ethers derived from cyclic ketones are used, the substitution product is stabilized by a retro-Michael-type reaction leading to open-chained sulfonamides 107 (Scheme 31) <1997LA1261>. 

To a mixture of anhydrous dimethyl sulfoxide (4 mL) and ketone donor (1 mL) was added the corresponding aldehyde (0.5 mmol) followed by L-proline (20-30mol%) and the resulting mixture was stirred at room temperature for 4—72 h. The reaction mixture was treated with saturated ammonium chloride solution, the layers were separated, and the aqueous layer was extracted several times with ethyl acetate, dried with anhydrous MgS04, and evaporated. The pure aldol products were obtained by flash column chromatography (silica gel, mixture of hexanes and ethyl acetate). 

C—C—O—C+N. The formation of oxazoles from a-acyloxy ketones and ammonium salts was discovered in 1937 when it was found that treatment of benzoin benzoate with ammonium acetate in hot acetic acid gave triphenyloxazole in excellent yield. It has been shown that the reaction proceeds by way of intermediate enamines (equation 113). The synthesis is quite general and it is only.limited by the difficulty of obtaining the starting keto esters, particularly formates. The latter are probably intermediates in the preparation of cycloalkenooxazoles from acyloins and formamide in hot sulfuric acid (equation 114). Another variation is to heat a mixture of an a-bromo ketone, the sodium salt of a carboxylic acid and ammonium acetate in acetic acid (equation 115). 

The first reported synthesis of MDMA was from safrole by converting it to its bromo derivative followed by reaction with meth-ylamine (Biniecki et al., 1960). Bailey et al. describe the synthesis of MDMA from 3,4-methylenedioxyphenylacetone using a Leuckart reaction with N-methylformamide and hydrolysis of the N-formyl derivative (Bailey et al., 1975). A third synthesis for MDMA described in the literature starts with peperonal which is reacted with nitroethane, ammonium acetate, and acetic acid to form a nitrostyrene derivative that is reduced to the ketone and then reacted with methylamine to form MDMA (Rabjohns, 1963). Using the method of Borch et al., MDMA can be synthesized by the reductive amination of the appropriate ketone in the presence of sodium cyanoborohydride (Borch et al., 1971). The MDMA syntheses used in clandestine laboratories are analogous. 

Acylamino ketones on heating with ammonium acetate are converted into imidazoles. 2,4,5-Triarylimidazoles 235 were prepared in this way from the amides 234 (Scheme 113) <1973CB2415>, and numerous variations are possible for this reaction. 

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