Enamine hydrochlorides

In fact, the morpholino enamine of cyclohexanone is not reduced by hydride reagents, whereas the enamine hydrochloride is easily and quantitatively reduced within 15 minutes. If the enamine is conjugated with the carbonyl group, reduction becomes more difficult and the pH must be decreased to 4. Enamines from jS-diketones are resistant to reduction. 

Heating 1,3,5-triazine (1) with an enamine hydrochloride bearing clcctron-acccpting substituents on Cl, i.e. 14, gives 4,5-disubstituted pyrimidines 15.28 This class of reactions is proposed to proceed by a Diels-Alder mechanism and is discussed further in Section 2.3.2.3. 

Ethyl 2-oxocyclohexanecarboxylate Ethyl chloroformate (7.2 g, 0.066 mole) is added to a well stirred solution of 4-(l-cyclohexenyl)morphoIine (20.0 g, 0.12 mole) in anhydrous benzene (100 ml) under nitrogen, and the mixture is boiled under reflux for 10 h, then cooled and filtered. The precipitate of enamine hydrochloride is washed with anhydrous ether. The united filtrates are treated with 10% aqueous hydrochloric acid (22 ml) and the mixture is stirred vigorously for 15-30 min. The layers are separated, the aqueous phase is extracted with benzene, the organic phases are united, and the solvent is distilled off under reduced pressure. Fractionation of the residue gives 62% (6.2 g) of the /S-oxo ester, b.p. 112-115°/ 10 mm. 

The reaction of the enamine (96) with acetyl chloride was reported (72) to afford no acyl derivative but the aminocyclobutanone (97) and the hydrochloride of the enamine. 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

The chiral a-cyano allylamines prepared from ( )-3-phenylpropenal, potassium cyanide and (L)-ephcdrinc [(17 ,2S )-2-methylamino-l-phenylpropanol] hydrochloride as a mixture (1 1) of C-l epimers, were deprotonated using 2 equivalents of LDA in THF to give the dilithio compound37. Alkylation at C-3 afforded regioselectively a mixture of (E)- and (Z)-enamines in variable amounts depending on reaction conditions. Diastereoselectivity varied from moderate to excellent. Addition of HMPA and especially lithium iodide improved the diastereoselectivity. De-aggregation is proposed to be the reason for the effect of these additives. 

Triazines on reaction with enamines followed by loss of a nitrogen from the intermediates give pyridine derivatives (85H2789) (Scheme 56). The reaction of 1,3,5-triazine with enamine and enaminoester hydrochlorides in acetonitrile leads to mixtures containing pyrimidines and pyridines... 

Apart from the reaction of diazomethane with benzoyl chloride,5-6 diazoacetophenone has been prepared by the reaction of 2-aminoacetophenone hydrochloride with sodium nitrite,7 from the mixed anhydride of benzoic acid and ethyl carbonate with diazomethane,8 from benzoyl chloride and potassium methyldiazotate,9 by treating the enamine formed from 2-formylacetophenone and N-methylaniline with p-toluenesulfonyl azide,10 and from the reaction of the sodium enolate of 2-formylacetophenone with p-toluenesulfonyl azide.11... 

The formation of a-naphthols of type 189 from 1-alkyl-substituted salts 30, on heating with dimethylamine hydrochloride in ethanol, occurs by another mechanism and will be explained in Section III,C,4,b,i. The interaction of l-aryl-3-carboxy-substituted salts 62 with secondary amines in benzene is initiated probably as in the reaction of these salts with primary amines, and the attack by the secondary amine on position 3 is the primary step of this reaction. However, since protonation of the intermediate anion 190, a masked acyl anion, becomes difficult, an interaction of this anion with the carbonyl group of the benzophenone fragment occurs (86KGS125). The enamines 191 thus formed are usually hydrolyzed on purification, yielding five-membered cyclic acyloins 192. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

The Sceletium alkaloid ( )-A4 (36) has been synthesized as shown in Scheme 5, using previously developed enamine-vinyl ketone ring annulation methodology (see Vol. 7 of these Reports).12 Treatment of the hydrochloride of the 2-pyrroline (32) with the acetal enone (33) gave a mixture of epimeric keto-acetals (34) in 85%... 

Amide should be first transformed to its hydrochloride in order to cut down the formation of a-chloro-jf(-chlorocarbonyl enamines 72,73). The method is very general but the choice of experimental conditions and of the base is critical and yields may vary strongly depending on the case (39). There is also one side-reaction which can hardly be avoided the ynamine already formed reacts with the yet unreacted amide chloride, the a-chloroenamine 70) or even with the tert-amine hydrochloride to form the very stable cyclobutene cyanines and/or allenamidinium salts. These by-products have an interest of their own and will be discussed later. Formation of these salts may strikingly lower the yield of ynamines, but because of their salt character they are not harmfull during the work-up72). 

If DAMN is mono-N-alkylated before reaction with the carbonyl reagent the method gives 1-alkylimidazoles [15]. For example, 4,5-dicyano-l-(2, 3, 5 -tri-0-benzoyl-)S-D-ribofuranosyl)imidazole (57%) has been made by treatment of the ribosylamino-DAMN with triethyl orthoformate at 90°C in anisole under nitrogen for 5h. The intermediate enamine is not isolated in this case [42]. When DAMN is treated with AyV-dialkylamides in the presence of phosphoryl chloride, the Schiff base (14) (R = NR R ) cyclizes to give 2-dialkylaminoimidazoles (15) (R = NR R ), including 4,5-dicyanoimidazole (15) (R = H) when DMF is used [15], Imidazoles (15) (R = OR, NR R ) can be made in one step when DAMN reacts with orthoesters or iminoether hydrochlorides. Under mild reaction conditions the intermediate alkoxyimines (14) (R = OR" ) or amidines (14) (R = NR R ) can be isolated before oxidation to (15) [46, 47, 49], Table 2.1.4 lists some examples. 

Mannich bases. The preparation is a simple mixture of enamines, aldehydes, dimethylamine hydrochloride, MejSiCl, Nal, and EtjN. 

The chloroform/base/phase-transfer catalyst method is generally used for the preparation of 2-amino-l,l-dichlorocyclopropanes 1 from enamines. Morpholine enamines form stable products, often with high yields. 1,1-Dichlorocyclopropanes derived from other enamines are less stable, nevertheless they are conveniently isolated in the form of stable hydrochlorides. Typical examples of these cyclopropanes are collected in Table 21. 

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