Reactions of Heterocyclic Enamines

The double bonds of either enamines or their salts readily undergo many reactions. We shall divide the reactions of heterocyclic enamines on the basis of the mechanism involved. 

Reactions of Electrophilic Reagents with the Double Bond OF Enamines 

Since there are two available sites for electrophilic attack in an enamine, the electrophile can add to the nitrogen atom to form an ammonium salt, or it can add to the position to form an immonium salt. 

The first reported alkylations at the /3-carbon atom of a heterocyclic enamine were observed with the alkylations of dihydroberberine (102) (190,191) and l,3,3-trimethyl-2-2-methyleneindoline (192,193) (104) to yield monomethylated products 103 and l,3,-trimethyl-2-isopropylidene-indoline (105), respectively. 

C alkylation was used in the corydaline synthesis 194). LukeS and Dedek 195) obtained on methylation of l-methyl-2-ethylidenepyrrolidine a C-alkylation product, i.e., l-methyl-2-isopropyl-/l -pyrroline (106). Alkylation of the same enamine with ethyl bromoacetate was the first synthetic step in the preparation of D,L-pseudoheliotridane 196). 

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V. Aldol Reactions of Heterocyclic Enamines and Their Importance for the... 

Reactions of Heterocyclic Enamines with Other Electrophilic Reagents... 

In the Michael reaction of HC=C-COMe with primary amines having an a-substituent containing impaired electrons (methoxylamine, ethyl glycinate, hydrazine, etc.), an unexpectedly small influence of this substituent (the a-effect) was observed. The reaction of heterocyclic enamines with HC C-COaEt and Et02C-C=C-C02Et has been systematically studied. In contrast to their heterocyclic ketene aminai analogues, heterocyclic enamines (178) reacted with electrophilic alkynes via the Michael addition pathway (178) -> (179) rather than via the aza-ene reaction mechanism (181). In the presence of a strong base, such as EtONa and NaH,... 

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. 

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

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... 

The conjugated double bond of enamines readily undergoes many reactions. The reactions of imines with a double bond between the nitrogen and carbon atoms are also discussed to allow comparison. Some reactions of heterocyclic compounds containing the enamine grouping as a part of the aromatic ring are also considered. The reactions of these compounds can be divided on a mechanistic basis into three groups ... 

Leonard and coworkers " have developed the mercuric acetate oxidation of cyclic tertiary amines into a eneral method for the synthesis of heterocyclic enamines. This method has been used by other authors , A solution of the amine with a four-molar excess of mercuric acetate in 95% aqueous acetic add was refluxed on a steam bath and, after 1.5 hours, the mercurous acetate had precipitated and the amine obtained in 60-80% yield. It was assumed that 1,2-elimination, which requires an antiperiplanar arrangement of the nitrogen-electron pair and the eliminated hydrogen atom, took place, and that elimination of the hydrogen atom on the tertiary carbon atom is preferred, Oyeroxidation can be avoided by adding disodium ethylenediamine-tetraacetate to the reaction mixture . 

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 . ... 

Endocyclic enamines, such as pyrrolines and tetrahydropyridines are useful for the synthesis of complex heterocyclic compounds, as found in many alkaloids. Thus, reaction of the enamine 27 with methyl vinyl ketone gave the alkaloid mesem-brine(1.41). 

J With enamines. l-Oxa-2-azulenones (as tethered heptafulvenes) with enamines undergo [8+2] cycloaddition as well (85HOU(5/2c)127, p. 218 98SL950). This way, in the case of heterocyclic enamines (such as 40), azuleno[l,2]-fused azoles and azines are formed (Schemes 13 and 14) The reactions of oxaazulenone 37 with the isomer mixtures of enamines 40a or 40b yield mixtures of isomeric dihydrothiophenes 41 and 42 that are dehydrogenated by 2,3-dichloro-5,6-dicyano-p-benzoqui-none (DDQ) to yield thiophenes 43 and 44, respectively (83CL1721). Whereas the latter [l,2-c]-fused compound is unstable because of its o-quinonoid structure, thiophenes 43a and b are demethoxycarbonylated to yield substances 45a and b. 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

The formation of heterocycles derived from quinones is an important synthetic technique. The reaction may be intramolecular, eg, the reaction of (92). Either nitrogen products, eg (93) (yields of 85—91% for R = H, CH, and C H ) or oxygen products (94) are obtained (92,93). Reactions with enamines have been especially important. 

Reaction with vatious nucleophilic reagents provides several types of dyes. Those with simple chromophores include the hernicyanine iodide [16384-23-9] (20) in which one of the terminal nitrogens is nonheterocyclic enamine triearbocyanine iodide [16384-24-0] (21) useful as a laser dye and the merocyanine [32634-47-2] (22). More complex polynuclear dyes from reagents with more than one reactive site include the trinuclear BAB (Basic-Acidic-Basic) dye [66037-42-1] (23) containing basic-acidic-basic heterocycles. Indolizinium quaternary salts (24), derived from reaction of diphenylcyclopropenone [886-38-4] and 4-picoline [108-89-4] provide trimethine dyes such as (25), which absorb near 950 nm in the infrared (23). 

A similar sequence of reactions takes place with the enamlnes of cyclic ketones (55-57) the initially formed unstable cyclobutene rearranges with insertion of two carbon atoms into the ring. A wide variety of cyclic ketones have been allowed to react in this way. For instance, the enamine (75) gave 76 on reaction with dimethyl acetylenedicarboxylate in refluxing toluene (55) and the heterocyclic enamine (77) obtained from dihydro-3-(2H)-... 

The pyrrolidine enamine of 2-tetralone (177) was converted to l-cyano-2-tetralone, which exists almost entirely in the enolic form (178), by reaction with cyanogen chloride (J23). Reaction of 177 with cyanogen bromide gave N-naphthylpyrrolidine (179), presumably via the unstable bromoenamine (180). The latter observation is in accord with the mode of reaction of the heterocyclic enamine (126) with cyanogen bromide, which resulted in the... 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

All heterocyclic enamines readily undergo condensation with o-amino-benzaldehyde. The quinoxaline derivatives thus formed have a characteristic yellow color. Therefore, this reaction can serve as evidence of the presence of an enamine in plants (295,309). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

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. 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

Synthetic use can be made of the potent electrophilic properties of ADC compounds by transforming the initial adducts into heterocyclic products. For example, reaction of DEAZD with enamine 92 gives the substitution product 93 in quantitative yield. Further treatment of this initial adduct with acid, followed by base hydrolysis leads to benzoxazol-2-ones. The dimethyl substituted enamine (92, R = Me) gives the rare, but isolable 6//-benzoxazol-2-one ring system (Scheme 13).147... 

The glutamic moiety of TNP-351, a pyrrolo[2,3-d]pyrimidine glutamic acid derivative, and related compounds have been transformed into their A-co-masked ornithine analogs which show remarkable antifolate activity <00CPB1270>. The reaction of the heterocyclic enamine 77 with tosyl azide leads to the tosylimino derivative of 1,2,4-triazolo[l, 5-a]pyrimidine 79. Extrusion of nitrogen from the primary adduct 78 is followed by a 1,2-shift of a methyl group to yield 79 <00JHC195>. 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

The enamine adducts formed in the reaction of aromatic amines with DMAD have been found to undergo cyclization leading to heterocyclic compounds, and the mode of these reactions is to a considerable extent influenced by the reaction conditions, the catalyst employed, and also the nature of the functional groups present in the starting amine. The reaction of aniline with methyl propiolate in presence of cuprous acetate, for example, is reported to give a mixture of 2(lH)-quinolone (1) and 4(l//)-quinolone (2) [Eq. (1)]." On the other hand, dimethyl anilinofumarate (3), formed from aniline with DMAD, undergoes... 

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