With Ketonic Side Chain

These intermediates have been used mainly to make quinazolines. Thus, 6-acetyl-3-methylcyclohex-2-enone (38), when boiled with guanidine carbonate in ethanol, gave 2-amino-4,7-dimethyl-5,6-dihydroquinazoline (yield not given).25 2-Oxocyclohexylglycolic acid (39), when boiled with guanidine 

---

Modification of the ketonic side chain is also consistent with retention of analgesic activity. Thus, reduction of methadone with lithium aluminum hydride affords the alcohol, 128 (apparently as a single diastereomer). Acetylation gives acetyl-methadol (129). ... 

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

As might be expected, a complex mixture of lactones corresponding to abstraction of a hydrogen atom from various sites along the methylene chain was obtained from the photolysis. The mixture of lactones was converted by dehydration, ozonolysis, and hydrolysis to a mixture of ketones. It was found that no functionalization occurs with ester side chains of less than nine carbon atoms. This is probably due to the inability of the carbonyl to approach any methylene closely enough to abstract a hydrogen. The data for side chains of nine carbons or greater is presented in Table 3.11. 

An Indian team carried out the transformation of mercaptotriazole 320 using an oxazolone reagent <2001IJB252> and found that a series of triazolothiazines with the substitution pattern 321 can be obtained in high yields. Treatment of the mercaptotriazole with an unsaturated ketone side chain 322 under basic conditions gave rise to ring closure to 323 <1998JRM2056>. 

Cyclic mixed acetals with pendant diazo ketone side-chains undergo rearrangement to ether-bridged cycloheptane ring systems on treatment with Cu(hfacac)2.118 A Stevens [1,2]-shift of an oxonium ylide gives the major product (62), in some cases accompanied by minor amounts of a product (63) resulting from a [l,2]-shift of a sulfonium ylide. 

Acid-catalyzed removal of a TMS protecting group from a bicyclic lactone in methanol solution proceeded with intramolecular acetylation after conjugate addition of methanol to an a,/ -unsatu-rated ketone side chain. By this route the 6-5-5 tricyclic acetal (27) is obtained in excellent yield (Equation (7)) <90JCS(Pl)75i>. Hemiacetal derivatives of the acetals were also prepared, and were found to exist in equilibrium with their open hydroxy-ketone forms by H NMR. 

The dianions of /S-enamino ketones react with a wide range of electrophiles such as alkyl halides, oxiranes, nitriles, esters, aldehydes and ketones37. Dalpozzo and coworkers reported the generation of the dianion derived from /S-enamino ketones with lithium 2,2,6,6-tetramethylpiperidide and the reaction of the dianion with nitroalkene (Scheme 24)38. The dianion underwent exclusive alkylation at the y-carbon atom to give the monoalkylated product in high yield. This reaction is useful for the introduction of a nitro group into a ketone side chain. 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

Ketones can be homologated to unsaturated ketones or aldehydes by addition of the appropriate vinyl nucleophile followed by oxidative rearrangement, as shown in Scheme 9. The use of this traiisformation in a synthetic approach to steroids with unsaturated side chains is shown in equation (16). ... 

Cyclopropyl-substituted ketones are suitable substrates for generating distonic radical anions from ketyl radical anions. A series of cycloalkanone substrates with unsaturated side-chains, to trap the primary radical formed after cyclopropylcar-binyl ring opening, has been investigated (Scheme 31) [118, 119]. For the first electron-transfer step triethylamine is used as electron donor. The reaction sequence is terminated by proton or hydrogen transfer from the solvent or the a-amino radical formed after deprotonation of the amine radical cation. 

Actually, the reaction is a bit more complex than shown above because it does not take place on the free ketone. Instead, fructose 1,6-bisphosphate undergoes reaction with the side-chain -NH2 group of a lysine residue on the aldolase enzyme to yield an imine (Section 19.9), sometimes called a Schiff base. Protonation of the imine makes it more reactive a retro aldol-like reaction ensues, giving glyceraldehyde 3-phosphate and the imine of dihydroxyacetone phosphate and the imine is then hydrolyzed to yield dihy-droxyacetone phosphate. 

As was true in step 4 of glycolysis (Figure 29.4), this aldol reaction actually takes place not on the free ketone but on an imine (Schiff base) formed by reaction of dihydroxyacetone phosphate with a side-chain -NH2 group on the enzyme. Loss of a proton from the neighboring carbon then generates an enamine (Section 19.9), an aldol-like reaction ensues, and the product is hydrolyzed. 

---