Isomerization amino ketones

The proton magnetic resonance spectrum of the product in trifluoroacetic acid shows that the isomeric purity is greater than 90%. The proton magnetic resonance spectral properties for the isomeric amino ketones in both trifluoroacetic acid and chloroform-d are as follows (solvent) 8 (multiplicity, number of protons, assignment, coupling constant J in Hz.) 1-... 

The ratio of the isomeric amino ketones in the crude product can be determined from the relative intensities of the signals for the (CH3)2C grouping in a proton magnetic resonance spectrum taken in trifluoroacetic acid (see Note 10). In chloroform-d these absorptions overlap. 

Cyclic enamines with an isomeric position of the double bond have been obtained by the addition of Grignard reagents to five- (78-81), six- (82-86), seven- (87-90), and thirteen- (89-91) membered lactams, whereas other medium-sized (92,93) lactams furnished amino ketones. The reaction has been extended to substituted lactams (94-98), and iminoethers (99,100). 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

Amino ketones 11 isomerize to 2-aminocyclobutanols 12. A geminal dimethyl group on C2 increases the cyclization vs. cleavage rate of the intermediate diradical.10... 

Reduction of ketones other than 48 to dimers has been examined. Ethyl pyridyl ketone (51) gave a poor yield of the corresponding pinacol (52).79 Pinacols can also be made from crossed coupling of ketones with 3-(48).80 Finally, a study of the radical anions formed from the isomeric benzoylpyr-idines (53) was done, and the rates of rotation of the pyridyl ring were determined.81 The mechanism of reduction of the oxime and thiosemicar-bazone derivatives of 53 was determined by voltammetry techniques.82 The monoimine derivative of the pyridil 54 was reduced to the a-amino ketone 55 (Scheme 18).83 Unsaturated pyridyl ketones and heteroaryl pyridyl ketones have also been studied by voltammetry.84,85... 

An extension of the above work to fV-BOC deprotection of the amino ketones 86 gave the optically active 277-azepines 87 (e.g., 87, R1 = Me, Rz = Me 56%). Ready isomerization of 87 by a [1,5]-H shift to the corresponding 377-azepines was observed when the former were left in solution in organic solvents at 25 °C or on warming in CHCI3 solution (Equation 10) <1996T10883>. 

Isomerization then gave a / -amino-ketone (144), whose methosulphate readily suffered / -elimination and loss of the protecting group, with formation of the unsaturated amino-ketone identified as macroline (136) (Scheme 22).706... 

Lithium aldimine (131), an acyl anion equivalent derived from an isocyanide and an organolithium reagent, adds to aldehydes giving, after quenching with water, a-amino ketones (134) via the Amadori rearrangement (Scheme 33)." The a-amino ketone (134) results from a double tautomerization of a-hydroxy imine (132), formed initially after quenching with water. Thus, the imine (132) isomerizes to enolamine (133), which in turn tautomerizes to the observed product (134). 

A key observation as a result of these revised stereochemical assignments is that the stereochemistry of the Ban amino ketone (373) is now different from that of the natural series of compounds in which the C/E ring junction (A/ in 373) is cis. Stork s amino ketone (393) therefore has the correct stereochemistry, and the elaborate mechanism proposed to account for the total synthesis of natural aspidospermidine (249) (which originally involved isomerization at C-21) is unnecessary. What became important, however, was the identity of the product from a Fischer indole synthesis of 373. If Stork was correct and epimerization at C-21 is possible, then aspidospermidine should still be the product. If epimerization is not possible a new stereoisomer of aspidospermidine should result in which the C-21 proton and the C-20 ethyl group are trans. 

A method was developed for the synthesis of quinoline derivatives from isatoic anhydrides and lactones. The amino ketones formed at the first stage were then converted into the desired products by cyclocondensation after isolation or by direct heating of the reaction mass. Thus, the reaction of the anhydride 2 with the butyrolactones 94 in the presence of lithium diisopropylamide gave the amino ketones (95) (yield 99%), which when boiled in toluene gave 4-hydroxy-3-R-l-methyl-2-quinolones 96 (yield 98% with R = H or 70% with R = Me). It was established that the latter exist in two isomeric forms 96a,b [57],... 

Regioselective synthesis of isomeric Mannich bases from unsymmetrical ketones has been achieved with dimethyl(methylene)ammoniam trifluoroacetate in trifluoroacetic acid to give mainly the more-substituted amino-ketone (13) [and lesser amounts... 

Polymers prepared by condensation of 4,4 -diacetylstiblene as the bis(ketomethylene)monomer with 4,4 -diamino-3,3 -dibenzoylstilbene, a bi(amino ketone), exhibit photo-viscosity effects in dilute solutions due to cis-trans isomerization [202]. The preparation of the polymers and the photorearrangements can be illustrated as follows ... 

In a comparative study of various catalysts (HCl, ZnCb and AlCb) in the Bischler cyclization of a-amino ketones (R = Me, Et, CH2Ph) to P-indoles, AICI3 was found to be the most active catalyst. Isomerization of P-to a-indoles was observed by raising the reaction temperature. 

The Amadori rearrangement is a reaction between a-hydroxy aldehydes and suitable amines leading to a-amino ketones. When applied to aldoses, for example, D-glucose (1), it allows the introduction of an amino group at position C-1 with concomitant isomerization leading to 1-amino-1-deoxyketoses such as 2 (Scheme 1). 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

---