Cyclohexane acylation

Even saturated hydrocarbons give ketones with acyl chlorides (20). For example, cyclohexane and acetyl chloride react in the presence of aluminum chloride to give l-acetyl-2-methylcyclopentane. 

A central core of benzene rings is linked by a fuactioaal group X. The most common end groups at the para sites, and R2, are alkyl (—C H2 ) or alkoxy (—OC H2 + ), or acyl chains C SI NO2 cinnamate (—CH=CHCOOC H2 ) or halogens. Cyclohexane rings can sometimes replace one or more of the benzene rings without loss of Hquid crystallinity. 

Enzymatic hydrolysis is also used for the preparation of L-amino acids. Racemic D- and L-amino acids and their acyl-derivatives obtained chemically can be resolved enzymatically to yield their natural L-forms. Aminoacylases such as that from Pispergillus OTj e specifically hydrolyze L-enantiomers of acyl-DL-amino acids. The resulting L-amino acid can be separated readily from the unchanged acyl-D form which is racemized and subjected to further hydrolysis. Several L-amino acids, eg, methionine [63-68-3], phenylalanine [63-91-2], tryptophan [73-22-3], and valine [72-18-4] have been manufactured by this process in Japan and production costs have been reduced by 40% through the appHcation of immobilized cell technology (75). Cyclohexane chloride, which is a by-product in nylon manufacture, is chemically converted to DL-amino-S-caprolactam [105-60-2] (23) which is resolved and/or racemized to (24)... 

It has been found that the fusion of the pyrazole with the pyrrole ring is difficult, probably for steric reasons. All attempts to cyclize 3-amino- and 5-amino-4-acetylenylpyrazole have failed. For example, upon prolonged heating of 5-amino-4-acetylenylpyrazole 68 in DMF in the presence of Cul and (or) CuC=CPh, side transformations andresinification occurred. The side processes were suppressed by acylation of the amino group and substitution of DMF by inert cyclohexane. However, 80-90% of the starting compounds was recovered after heating acylamine... 

The chemoenzymatic synthesis of the analgesic U-(—)-50,488 [41] and new C2-symmetric bisaminoamide ligands derived from N,N-disubstituted trans-cyclohexane, ,2-diamine [41] has been possible by a CALB-catalyzed resolution using ethyl acetate as solvent and acyl donor [42]. 

Other important derivatives for the preparation of (i-aminoacids are the corresponding P-aminonitriles. Lipase-catalyzed N-acylations of racemic cis-2-aminocyclopentane and cyclohexane carbonitriles with 2,2,2-trifluoroethyl butanoate have been successfully carried out in organic solvents and ionic liquids [53], PSL yielding better results than CALB (Scheme 7.29). 

Nitration of ketones or enol ethers provides a useful method for the preparation of a-nitro ketones. Direct nitration of ketones with HN03 suffers from the formation of a variety of oxidative by-products. Alternatively, the conversion of ketones into their enolates, enol acetates, or enol ethers, followed by nitration with conventional nitrating agents such as acyl nitrates, gives a-nitro ketones (see Ref. 79, a 1980 review). The nitration of enol acetates of alkylated cyclohexanones with concentrated nitric acid in acetic anhydride at 15-22 °C leads to mixtures of cis- and rrans-substituted 2-nitrocyclohexanones in 75-92% yield. 4-Monoalkylated acetoxy-cyclohexanes give mainly m-compounds, and 3-monoalkylated ones yield fra/w-compounds (Eq. 2.40).80... 

Photolysis of the methylidyne cluster HRu3(CO)] (/1, 71"COCH3) (A) (14) in cyclohexane solution leads to an unprecedented oxygen-to-carbon alkyl migration to form the bridging acyl complex HRu3(CO)10( i-> 2-C(O)CH3) (B) ... 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

In fluorosulfonic acid the anodic oxidation of cyclohexane in the presence of different acids (RCO2H) leads to a single product with a rearranged carbon skeleton, a 1-acyl-2-methyl-1-cyclopentene (1) in 50 to 60% yield (Eq. 2) [7, 8]. Also other alkanes have been converted at a smooth platinum anode into the corresponding a,-unsaturated ketones in 42 to 71% yield (Table 1) [8, 9]. Product formation is proposed to occur by oxidation of the hydrocarbon to a carbocation (Eq. 1 and Scheme 1) that rearranges and gets deprotonated to an alkene, which subsequently reacts with an acylium cation from the carboxylic acid to afford the a-unsaturated ketone (1) (Eq. 2) [8-10]. In the absence of acetic acid, for example, in fluorosulfonic acid/sodium... 

The solvent present in biphasic reactions can still have an effect on the enzyme even though the enzyme functions primarily in an aqueous microenvironment. A particularly dramatic example is the lipase AH (lipase from Burkholderia cepac/fl)-catalysed desym-metrization of prochiral 1,4-dihydropyridine dicarboxylic esters, where either enantiomer can be accessed in high enantioselectivity by using either water-saturated cyclohexane or diisopropyl ether (DIPE) respectively (Scheme 1.60). The acyl group used in acylation and deacylation can also have a dramatic effect on enantioselectivity. " ... 

The other phospholipids can be derived from phosphatidates (residue = phosphatidyl). Their phosphate residues are esterified with the hydroxyl group of an amino alcohol choline, ethanolamine, or serine) or with the cyclohexane derivative myo-inositol. Phosphatidylcholine is shown here as an example of this type of compound. When two phosphatidyl residues are linked with one glycerol, the result is cardiolipin (not shown), a phospholipid that is characteristic of the inner mitochondrial membrane. Lysophospholipids arise from phospholipids by enzymatic cleavage of an acyl residue. The hemolytic effect of bee and snake venoms is due in part to this reaction. 

The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

Electron paramagnetic resonance studies have shown that the biacetyl ketyl radical (3) and the radical derived from dioxane are formed when biacetyl is irradiated in dioxane solution.51 Nonphotochemically generated radicals derived from dioxane and cyclohexane add to biacetyl to yield acylated product.56 If cleavage were occurring in addition to or instead of hydrogen abstraction, one would expect to find at least moderate yields of acylated products in all solvents instead of just those which produce the least stable solvent radical. 

In contrast to pyridine derivatives, aryl- and alkyl-substituted A -phosphorins cannot be protonated by strong, non-oxidizing acids such as trifluoroacetic acid. Addition of trifluoroacetic acid to cyclohexane solutions of various A -phosphorins fails to produce any change in the UV spectra Similarly, alkylation by such strong agents as oxonium salts or acylation by acylchlorides cannot be induced at the P atom or any ring C atom. This behavior has also been discussed theoretically 55a)... 

Cyclohexane can be acylated with acetyl chloride and AICI3 to yield l-acetyl-2-methylcyclopentene in 37% yield.127 Alkanes, such as 2-methylbutane, cyclohexane, methylcyclopentane, and methylcyclohexane, are easily acylated with a,p-unsaturated acyl chlorides in the presence of A1C13 and a hydride acceptor to afford mono- or bicyclic products after secondary transformations.128 Isoalkanes (isopentane, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane) undergo diacylation and eventually form pyrilium salts under Friedel-Crafts acylation conditions with acetyl chloride or acetic anhydride.129... 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (41 X = NH) the a carbon signal is shifted by about 20 ppm, to ca. 8 47.7, while in yV-methylpiperidine (41 X=NMe) it appears at 8 56.7. Quatemization at nitrogen produces further effects similar to replacement of NH by Aralkyl, but simple protonation has only a small effect. W-Acylpiperidines (41, X = NCOR) show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 ppm, and the mean shift is close to that of the unsubstituted amine (41 X = NH). The nitroso compound (41 X = N-NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 ppm). The (3 and y carbon atoms of piperidines, W acyl piperidines and piperidinium salts are all upheld of the cyclohexane resonance, by 0-7 ppm. 

NEN1TZESCIJ INDOLE SYNTHESIS. Hydrogenanve acylation of cycloolefins with acid chlorides in the presence of aluminum chloride with five- and six-membered rings, no change in ring size occurs, but with seven-membered rings, rearrangement takes place with formation of a cyclohexane derivative. 

Dialkyl peroxydicarbonates (17) are produced by reaction of alkyl chlo-roformates with sodium peroxide. OO-Acyl O-alkyl monoperoxycarbon-ates i 8 i are obtained from tine reaction of alky] chloroformates with perox-ycarbnxylic acids in the presence of a hase. Symmetrical di (organosulfonyl) peroxides (20, R = R2l) have been prepared by the reaction of organosul-fonyl chlorides with sodium peroxide or hydrogen peroxide in the presence of a base. Acyl organosullbnyl peroxides (19) are prepared from Ihe, organosulfonyl chlorides and a metal salt of a peroxycarboxylic acid. Acetyl cyclohexanesulfonyl peroxide has been produced commercially by the sulfoxidation of cyclohexane. QjH. in the presence of acetic anhydride. 

Groves et al. found that a simple heme-iodosobenzene system mimics the enzymic reactions.127 Cyclohexane and cyclohexene are oxidized to cyclohexanol and a mixture of cyclohexene oxide and cyclohexenol respectively by this system. Using meso-tetrakis-a,/J,a,/J-(o-acylamidophenyl)por-phinatoiron(III) chloride where the acyl group is (i )-2-phenylpropionyl or (S)-2 -methoxy-carbonyl-l,T-binaphthyl-2-carbonyl, optically active styrene oxides are obtained in 51% e.e. The Fe(TPP)Cl-PhIO system can also oxygenate arenes to arene oxides.128 Based on the following observations, mechanisms involving O—Felv(Por) t as the active species have been proposed (Scheme 30).127... 

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