Preparation of Heterocyclic Enamines

Preparation of Heterocyclic Enamines from y- and h-Amino Ketones 

2-Alkyl-/l -pyrrolines (8, n = 1) and 2-alkyl-/l -piperideines (8, n = 2) are readily formed by the methods used to prepare y- and S-amino ketones (3-6). The reaction of corresponding halogeno ketones with ammonia belongs to the classical reactions of this type. 

By use of potassium phthalimide we can isolate the intermediate. a-Oxo-S-aminovaleric (9, = 1) and a-oxo-e-aminocaproic acids (9, = 2) readily yield 2l -pyrroline-2-carboxylic acid (10, =1) and. d -piperideine-2-carboxylic acids (10, n = 2), respectively (7-10). The equilibria of the acids with their cyclic forms was observed in water solutions (11,12). 

Phenols and phenol ethers can be acylated with y- or S-amino acids in the presence of polyphosphoric acid to form 2-aryl-2d -pyrrolines (11, = 1) or 2-aryl-/l -piperideines (11, n = 2), respectively (13). 

Zl -Pyrrolines have been isolated from the hydrogenation products of y-ketonitriles (23-26) and in a large number of reactions during which enamino ketones are formed as intermediates. The preparation of pyrrolines from anhydro-5-hydroxyoxazolinium hydroxides (13, R, R = Ph, R = Me) is also important (27). By the reaction of 13 with styrene, l-methyl-2,3,5-triphenyl-/l -pyrroline (14) is formed. 

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Preparation of Heterocyclic Enamines by Means of Organometallic Reagents... 

Preparation of heterocyclic enamines by the intramolecular condensation of A-(5-oxohexyl) nitrogen heterocycles [201]. 

The 1,2-, 1,2,5-, 1,3,4-, and 1,2,2,5-substituted pyrrolidines afford the corresponding pyrrolines very readily. In the case of 1,2,3-tri-methylpyrrolidine, the formation of a double bond involving the unsubstituted a-carbon atom is followed by dimerization of the intermediate to l,5,5-trimethyl-3-(l,5,5-trimethyl-2-pyrrolidyl)-J2-pyr-roline.175 The formation of oligomers is a frequent complication in the preparation of heterocyclic enamines. On dehydrogenation of... 

Reductions of pyridines, quinolines, isoquinolines and their quaternary salts is a useful approach for the preparation of heterocyclic enamines. 

Lukes and coworkers " developed a very simple and useful method for the preparation of heterocyclic enamines. A-M ethyl lactams with five- and six-membered rings (104, n = 1,2) give, with Grignard reagents, l-methyl-2-alkyI(aryl)-2-pyrrolines (105, n = 1) and l-methyl-2-alkyl(aryl)-2-piperideines (105, n = 2), respectively. 2,2-Dialky-lated bases (106, n = 1,2) are by-products of this reaction. Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors " ". Some authors who repeated the reactions isolated only pyrrolines or, in other cases, 2,2-dialkylated bases . This can be ascribed to the use of unsuitable isolation technique by the authors. The reaction was also carried out with various substituted and non-methylated lactams . ... 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

Alkylation of heterocyclic enamines proceeds similarly to the alkylation of Fischer s base discussed above. Lukes and Dedek223 obtained on methylation of l-methyl-2-ethylidenepyrrolidine (51) a C-alkylation product, i.e. 1 -methyl-2-isopropyl-A2-pyrroline (52). Alkylation of the same enamine with ethyl bromoacetate 224 was the first synthetic step in the preparation of DL-pseudoheliotridane. 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

The preparation of enamines by reduction of aromatic heterocyclic bases and their quaternary salts or of lactams is not the most useful approach (97). The lithium aluminum hydride reduction of N-acyl enamines has been used with both fruitful and unsuccessful results. A series of 3-N-acetyl -d -cholestenes (104) has been prepared by desulfurization of the appropriate thiazolidine (105) (98,99). Lithium aluminum hydride reduction of the... 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

From the preparative point of view, reactions of heterocyclic aromatic compounds with nucleophilic reagents are very important, especially the reactions of their quaternary salts containing a formal enamine grouping in the molecule. 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

The synthetic potential of such transformations for the preparation of medium-size heterocycles has been discussed elsewhere. It is generally accepted that the reaction between thiirene dioxides and enamines is a stepwise (nonconcerted) thermal [2 + 2] cycloaddition. However, a concerted [4 + 2] cycloaddition, in which the lone pair of the enamine nitrogen atom participates, cannot be excluded. 

For the preparation of the anticipated heterocyclic library compounds (Scheme 6.257), solutions of the prepared enamine synthons were split and diluted with an appropriate solvent, and 1.2 equivalents of a dinucleophile (hydrazine, hydroxylamine, amidines see Scheme 6.257 for more complex building blocks) was added. Subsequent exposure to microwave conditions in acetic acid/DMF mixtures... 

The imine 217, formed from acetophenone and the 1-aminoimidazole, has been transformed into the enamine 218 which is then cyclized to 219 in trifluoroacetic acid (TFA) (Equation 40) <1995SC3271 >. The diaminoimidazole 220 reacts with ynone 221 to form 222 (Equation 41) <1998CHE1189>. Bromochalcones and chalcone dibromides can also be used in place of the ynone. Similar reactions have been used to prepare the dihydro analogues of 222 <1999CHE1207>. The reaction between 1-aminoimidazoles and 1,3-diketones has been extended to prepare bis-heterocyclic compounds, for example, 223 as ligands for transition metals (Equation 42) <2005EJI4382>. 

The second method of preparing of 4,7-dichloroquinoline (37.1.1.1) consists of reacting 3-chloroaniline with the diethyl ester of oxaloacetic acid in the presence of acetic acid to give the corresponding enamine (37.1.1.8), which when heated to 250 °C undergoes heterocyclization to the ethyl ester of 7-chloro-4-hydrozyquinolin-2-carboxylic acid (37.1.1.9) accompanied with a small amount of 5-chloro-4-hydroxyquinolin-2-carboxylic acid... 

From a more synthetic perspective, reaction of the aUtenylmagnesium derivatives with electrophiles is very interesting. Indeed, if the intermediates could be trapped with electrophiles, the reaction would provide a novel route to the preparation of nitrogen-containing heterocycles having a fully substituted enamine structure. This expectation proved to be possible (Table... 

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

In a related piece of work, chemists at the Akad. Wissenschaft DDR claimed the preparation of perfluorodicyclicamines by the ECF of enamines incorporating alicyclic and heterocyclic rings [91]. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Aminoquinolines 62 have been prepared in a two-step, one-pot, three-component reaction of 2-azidobenzophenones, secondary amines and arylac-etaldehydes [110]. The microwave-assisted reaction proceeded via the initial formation of enamines 59. Subsequent addition of 2-azidobenzophenones 60 afforded the triazoline intermediates 61, which underwent thermal rearrangement and cyclocondensation to furnish 2-aminoquinolines 62 (Scheme 41). Direct comparison with conventional thermal conditions demonstrated the superiority of microwave dielectric heating in terms of yields (73% vs. 31% of heterocycle 63 after 10 min at 180 °C). Furthermore, the formation of by-products due to decomposition of azide 60 was diminished in the microwave-assisted synthesis. Purification of the products was achieved using solid-phase extraction techniques. 

Nitrogen heterocycles more electrophilic than benzene are susceptible to attack by hydride ion from a complex metal hydride anion. In protic solvents the intermediate cyclic enamines can undergo further reduction. The proper choice of reducing agent and reaction conditions thus allows the preparation of many partially reduced nitrogen heterocycles unavailable by other routes. These reduction procedures provide a valuable adjunct to catalytic hydrogenation155 for the syntheses of saturated nitrogen heterocycles. 

In this review, the properties, methods of preparation, and reactions of heterocyclic compounds possessing the so-called enamine grouping,... 

The M-heterocyclic quaternary salts of nonaromatic enamines, such as the tialkyl-3,4,5,6-tetrahydropyridines, A-l-pyrrolines, and 5.6-dihydro-2//-thiazincs. are very sensitive to water, and molecular sieves need to be used in conjunction with azeotroping to keep the reaction mixture anhydrous. Preparing and handling these intermediates and spiro compounds2 from them requires great care. 

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