Acylation of aliphatics

ACYLATION OF ALIPHATIC COMPOUNDS Similar to alkylation, not only aromatic but also aliphatic and cycloaliphatic compounds undergo Friedel-Crafts acylation reactions. 

In principle, the acylation of aliphatic compounds is analogous with the Friedel-Crafts acylation of aromatics in the sense that a hydrogen of the reacting alkanes, alkenes, or alkynes is replaced by an acyl group to yield ketones, unsaturated ketones, or conjugated acetylenic ketones, respectively. As discussed subsequently, however, the reactions are more complex. The acylation of aliphatics is an important but less frequently used and studied process.11-13... 

Of the acylation of aliphatics, the acylation of alkenes pioneered by Nenitzescu was mainly explored, because the resulting unsaturated ketones are intermediates in synthesis. This acylation of alkenes, however, has its difficulties. First, the product unsaturated ketones, which are reactive compounds themselves, can undergo various further transformations, such as addition, elimination, and isomerization, often resulting in complex product mixtures. The acylation of alkenes, therefore, is less selective and often yields products other than expected by a simple substitution of one of the vinylic hydrogens. 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

The direct interaction of benzyl carbonyl compounds 38 and 48 with aromatic aldehydes in the presence of PPA or AC2O + HC104(86KGS125 87TH1), or with acetals or acylals of aliphatic or aromatic aldehydes in the presence of triphenylmethyl perchlorate (73KGS881 75ZOR1962), gives rise to benzo[c]pyrylium salts 62 in yields of 15-70 %. 

Table 3.1 A selection of the results obtained for the acylation of aliphatic amines in a metal microreactor (under pressure-driven flow).

Hauser and co-workers have prepared a number of triketones by (1) acylation of benzoylacetone with aliphatic esters employing lithium amide, (2) by twofold aroylation of acetone with methyl esters using sodium hydride, (3) by aroylation and acylation of aliphatic diketones with potassium amide in liquid ammonia and (4) by aroylation of sodioacetoacetaldehyde in the presence of potassium amide. Disodio- and dipotassiobenzoylacetone are not acylated by ethyl acetate or by phenyl propionate. However, dilithiobenzoylacetone and dilithioacetylacetone with an excess of lithium amide are acylated by aliphatic esters. It is usually more convenient to synthesize 4-pyridones directly from these triketones by cyclization with ethanolic ammonia rather than by way of the intermediate Qpyrone. ... 

Acyl halides are intermediates of the carbonylations of alkenes and organic-halides. Decarbonylation of acyl halides as a reversible process of the carbo-nylation is possible with Pd catalyst. The decarbonylation of aliphatic acid chlorides proceeds with Pd(0) catalyst, such as Pd on carbon or PdC, at around 200 °C[109,753]. The product is a mixture of isomeric internal alkenes. For example, when decanoyl chloride is heated with PdCF at 200 C in a distillation flask, rapid evolution of CO and HCl stops after I h, during which time a mixture of nonene isomers was distilled off in a high yield. The decarbonylation of phenylpropionyl chloride (883) affords styrene (53%). In addition, l,5-diphenyl-l-penten-3-one (884) is obtained as a byproduct (10%). formed by the insertion of styrene into the acyl chloride. Formation of the latter supports the formation of acylpalladium species as an intermediate of the decarbonylation. Decarbonylation of the benzoyl chloride 885 can be carried out in good yields at 360 with Pd on carbon as a catalyst, yielding the aryl chloride 886[754]. 

V-Acylation of oxaziridine (54) is of more importance, yielding 2-acyloxaziridines which were unaccessible otherwise until recently. Oxaziridines (54) derived from cyclohexanone, butanone or benzaldehyde are acylated readily by acetic anhydride, acid chlorides or isocyanates. Oxaziridines from aliphatic aldehydes, too unstable to be isolated, may be trapped in situ by benzoylation (67CB2593). 

AcCl, NaOH, dioxane, Bu4N HSO, 25°, 30 min, 90% yield. Phase-transfer catalysis with tetra-n-butylammionium hydrogen sulfate effects acylation of sterically hindered phenols and selective acylation of a phenol in the presence of an aliphatic secondary alcohol. 

The results of more recent investigations by Blicke with Maxwell and with Kaplan covering a wide range of basic components and of acyl residues, do not lend themselves to a simple generalisation. The basic components were mainly dialkylamino-derivatives of aliphatic hydrocarbons from ethane to pentane, e.g.,. CHj. CHj. NMcj to. CHj. CMcj. CHj. NEtj, and similar but shorter series of derivatives of piperidine (CgHjoN), morpholine, e.g.,. CHj. CHj. NC HgO, and methylcj/clohexylamine... 

A very interesting steric effect is shown by the data in Table 7-12 on the rate of acid-catalyzed esterification of aliphatic carboxylic acids. The dissociation constants of these acids are all of the order 1(T, the small variations presumably being caused by minor differences in polar effects. The variations in esterification rates for these acids are quite large, however, so that polar effects are not responsible. Steric effects are, therefore, implicated indeed, this argument and these data were used to obtain the Es steric constants. Newman has drawn attention to the conformational role of the acyl group in limiting access to the carboxyl carbon. He represents maximum steric hindrance to attack as arising from a coiled conformation, shown for M-butyric acid in 5. 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

Since the rate of aliphatic acylation is higher than that of aromatic acylation, the olefin may possess aromatic substituents yields are lower, however, than with aliphatic olefins. Tlie types of olefins with aliphatic or aromatic substituents, undergoing diacylation, are shown in Table I. Systematic variation of the structure of the olefin... 

When applied to ketones, this is called Norrish Type / cleavage or often just Type I cleavage. In a secondary process, the acyl radical R —CO can then lose CO to give R radicals. Another example of a category 1 process is cleavage of CI2 to give two Cl atoms. Other bonds that are easily cleaved by photolysis are the 0—0 bonds of peroxy compounds and the C—N bonds of aliphatic azo compounds R—N=N—R. The latter is an important source of radicals R , since the other product is the very stable N2. 

Salts of aliphatic or aromatic carboxylic acids can be converted to the corresponding nitriles by heating with BrCN or CICN. Despite appearances, this is not a substitution reaction. When R COO was used, the label appeared in the nitrile, not in the C02, and optical activity in R was retained. The acyl isocyanate... 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

The positions, numbers, and types of sugars on the anthocyanin molecule influence its bioaccessibility. Indeed, a recent human study reported that the acylation of anthocyaifins resulted in a sigififlcant decrease of anthocyanin recoveries in plasma and urine. In addition, anthocyanins form linkages with aromatic acids, aliphatic acids, and methyl ester derivatives, which can also affect their passage through the intestinal barrier. 

Since anthocyaifins acylated with aliphatic acids are sensitive to acids, as verified, for example, in fruits of R suberosa when extracted with methanol containing 0.1% HCl," their occurrence in foods may be underestimated. Malonyl acylation in glucose at its position 6 was found in anthocyanins from blood... 

Harbome, J.B., The natural distribution in angiosperms of anthocyanins acylated with aliphatic dicarboxyhc acid. Phytochemistry, 25, 1887, 1986. 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

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