Enamines enaminones

Triazines are generally more reactive in [2 + 4] cycloaddition in comparison with 1,2,3-tria-zines. The wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene jV,O-acetals, /V-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cychc ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes like ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene and bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene,... 

For recent reviews on step-wise [3 + 3] formal cycloadditions leading to bridged carbocycles, pyridines or pyridones using enamines, enaminones, enol ethers, or (J-... 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

In addition to alkenes or compounds with strained double bonds, 1,2,4-triazines react readily with electron-rich dienophiles such as enol ethers, enamines, enaminones, vinyl silyl ethers, vinyl sulfides, vinyl acetate, and ketene derivatives (see also Ilouben-Weyl, Vol. E7b, p 471 ff). It has been shown195,403,404 that oxo compounds and catalytic amounts of amines can be used instead of enamines however, water formed in the reaction can result in the formation of side products.403... 

A 3,4,8,9-tetrahydropyrido[2,l-c][l,4]thiazine 336 and a benzo(A)-l,4-thiazine 335 was isolated from the reaction mixture of enaminone 334 and 2-(3-chlorobenzylidene)acetylacetate (99T7915). Reactions of enamines 334 and 337 with DMAD in MeOH yielded addition products 338 and 339 and bi- and tricyclic derivatives 340 and 341, respectively. The latters could be obtained in quantitative yields when the addition products 338 and 339 were heated in refluxing MeOH. 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

The reaction of enaminones with nitroalkenes gives a pentalenone system via the Michael addition and aldol reaction (Eq. 4.66).85a Linear a-keto enamines react with nitroalkenes to afford [3 + 2] carbocyclized products.8515... 

Another example of halogen-atom transfer by CPO is the vinylic halogenation of cyclic enaminones and enamines (Eq. 10, Table 11). 

The reaction of several a-amino acid esters with 0-lactones in chloroform solution gave hydroxyamide esters (equation 50), said to be useful fungicides (74JAP(K)74127918>. Enamines derived from cyclohexanone react smoothly with 0-propiolactone to give 3-(2-cyclo-hexanonyl)propionamides in reasonable yields (equation 51). No acylation of the enamine is observed. This reaction has been used as a key step in a new synthesis of 8-aza steroids (75JOC50). Cyclohexanone imines react in the same manner, except that the expected initial product cyclizes to give bicyclic lactams and enaminones (equation 52) (80T3047). 

When pyrimidinone 3 is treated with ethyl 3-oxobutanoate 19a in the presence of ammonium acetate, a different type of TCRT proceeds, giving ethyl 4-aminopyridine-3-carboxylate 41a (Table 10) [59]. In this reaction, pyrimidinone 3 behaves as the synthetic equivalent of activated diformylamine 5, and the amino group at the 4-position is derived from ammonium acetate. Since 3-ethoxycarbonyl-4-pyridone 14a prepared in Sect. 5.2 is intact under the same conditions, aminopyridine 41a is not formed via pyridone 14a. Furthermore, ammonium ion also causes no change on ethyl 3-oxobutanoate 19a, which indicates enamine is not dinucleophilic reagent in the present reaction. Hence, the keto ester moiety is converted to the enaminone after the addition of 19a to pyrimidinone 3. 

The behaviour of compounds 49 where R = H and CH3 from is even more complicated. For example, 4-methylamino-3-(4-X-phenylazo)pent-3-ene-2-one (49) contains two isomers. The tautomeric form of both isomers was confirmed with the help of 2D H-15N GHMQC spectra. The minor isomer is very similar to the tautomeric form of azo-enamine ( j(15N, H) = 89.6 Hz) the major isomer possesses a somewhat stronger character of hydrazono-ketimine form ( /(15N,1H) = 74.5 Hz about 80% azo and 20% hydrazone). These conclusions are confirmed by the values of <5(15NH2) in the minor isomer it is 6(15N) = —269.0 ppm (i.e. almost the same as in the starting enaminone with... 

X-ray determinations of the molecular structures of thirteen / -enaminones 84 to 96 with the formal possibility of push-pull conjugation and the formulae shown in Scheme 3 cover the range of tertiary 84 to 86, and 89 to 92, secondary 87,88 and 93, and primary 94 to 96 / -keto enamines. Relevant distances are given in Table 1 and angles in Table 2. 

The term enaminones is used in this section to designate enamines having at C(2) a carbonyl function conjugated with the carbon-carbon double bond. The two main groups of these compounds, 2-acylenamines (enaminoketones) and 2-alkoxycarbonyle-namines (enaminoesters), are discussed in the following subsections. 

The 13C-, 15N- and -NMR spectral data for a series of simple l-amino-2-nitroalkenes are collected in Table 30. The greater electron-withdrawing character of the nitro group as compared with carbonyl results in downfield shifts of the resonances of C(2) ( + 10 to +14 ppm), the enaminic nitrogen ( + 23.2 to + 27.4 ppm) and the olefinic protons [ + 0.8 to +1.0 ppm for H(l) +1.5 to = 1.8 ppm for H(2)] of 2-nitroenamines with respect to enaminones. This deshielding does not affect C(l), which has in fact a lower chemical shift ( — 5.5 to — 10.2 ppm) in 2-nitroenamines. The NMR spectra show that 2-nitroenamines with a primary or a secondary amino groups exist in solution as solvent-dependent equilibrium mixtures of E- and Z-isomers. The... 

There are few 15N-NMR spectral data for nitroenamines33,177. As already mentioned, the enaminic nitrogen resonates at a lower field than in enaminones, and exhibits the same dependence on the double-bond configuration (see Section III.A). The 15N resonance of the nitro group appears at 0.6-3.3 ppm for the compounds included in the Table. 

Although the reactivity of enaminones is not always the same as that of typical enamines due to the additional conjugative interaction with the carbonyl group, the anodic oxidation of enaminones seems useful in organic synthesis since they yield dimerized or cyclized products upon anodic oxidation. In anodic oxidation of the enaminones or enaminoesters in methanol containing sodium perchlorate, for instance, derivatives of pyrrole are formed via initial dimerization (equation 4)5. 

The term enaminone is used to indicate any compound containing the conjugated system N—C=C—c=0582,583. It may be a mono-enamine of 1,3-diketone or of a 3-keto ester. A general method for the preparation of enaminones involves reaction between ammonia or primary or secondary amine and a 1,3-diketone (3-chloro(bromo)-2-alkenone) or a 3-ketoester584"590. An improved procedure employed ammonium and amine acetates591 (equation 38). 

Ring closure of enamines and acid chlorides39, esters601 or nitriles (equation 40) or intramolecular alkylation of enaminone602,603 (equation 41) are general methods for the preparation of cyclic enaminones. 

The term enaminone is given and defined by Greenhill1 as a monoenamine of a 1,3-diketone or 3-ketoester. Because of their special chemical properties enaminones represent a class of organic compounds in its own right . In our opinion enamines from 3-ketonitriles exhibiting a similar reactivity may also be included in this definition. 

In order to define the scope, it seems useful to distinguish between / -ketoenamines (the term for enaminones resulting from 1,3-dicarbonyls, according to Greenhill) and a-ketoenamines (the term for the enamines derived from 1,2-dicarbonyls). 

The Mannich reaction of enaminones was examined intensively. Enamines derived from dimedone are aminoalkylated in the -position in good yield if the nitrogen is unsubstituted or monosubstituted31,34. Primary amines and formaldehyde react with enaminones to yield tetrahydropyrimidines34 (equation 21). A similar reaction is observed for acyclic enaminones. With primary amines and formaldehyde, tetrahydropyrimidines are formed35 (equation 22). 

Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equation 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 2]-cycloadducts, followed by retro-Diels-Alder reaction or rearrangement under thermodynamic control which leads diastereo-selectively to aminocyclopentenes. The reaction is called [3 + 2]-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration325 (equation 243). 

The photochemical behavior of enamines and their derivatives has been the subject of extensive mechanistic and synthetic investigations. The goal of this chapter is to summarize the photochemistry of enamines as well as enamides, enaminones, en-amidones and enaminonitriles, with particular emphasis on the application of the photochemistry of these chromophores in the synthesis of natural products. 

---