Enamines with ketenes

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

The reactions of ketenes with enamines are apparently not concerted but take place by the diionic mechanism Otto, P. Feiler, L.A. Huisgen, R. Angew. Chem. Int. Ed. Engl, 1968. 7, 737. 

In the reaction of ketenes with enamines, the pathway is usually a stepwise one. Thus the regioselectivity of a reaction such as that between the enamine (248) and dimethyl ketene (249) is largely determined by the relative stability of the intermediate (250) and its regioisomer. The intermediate (250) is highly stabilized, and its regioisomer would not be. As in the case of the Diels-Alder reaction on p. 137, the formation of this inter-... 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

The reaction of ketene with the enamine (113) is reported (88) to give l-morpholino-2-acetyl-l-cyclohexene i.e., the enamino ketone expected from acylation of (113). The pyrrolidine enamine (28), however, has been shown to react (73) with excess ketene to give the a-pyrone (124). On the... 

Vinyl ethers undergo many cycloaddition reactions similar to those which take place with enamines. In general, however, these cycloaddition reactions with vinyl ethers take place less readily than those with enamines. These reactions include cycloaddition of vinyl ethers with ketene (200-205), phenyl isocyanate (206), sulfene (207,208), methyl acrylate (209), diethyl acetylenedicarboxylate (210), and diphenylnitrilimine (183). 

The facile formation of cyclobutane products is indeed another important contribution of enamine chemistry (302-306). The formation of cyclobutanes has also been found in the closely related reactions of amino acetal derivatives of ketenes with acrylic esters (307). 

The intermediacy of ketenes in some enamine acylation reactions using acid chlorides was described above (386,387). Direct addition of ketene to enamines was studied simultaneously by several groups (414-420). The initially formed aminocyclobutanone products could be isolated in some instances, depending on the substitution of the initial enamine. Opening to give either the acylated enamine or the alternative vinylogous amide was found to occur spontaneously or on heating, particularly in adducts derived from enamines with an olefinic proton. 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Hermann and colleagues218,219 found that treatment of ketene thioacetal monoxides 172 and 173, with enamines, sodium malonates, /J-dicarbonyl compounds and lithio-... 

Treatment of benzoylisocyanate 1562 with trimethylsilyl ketene 1563 gives the oxazine 1564 which reacts, e.g., with enamines 1565 to give pyridine-2-ones 1567,... 

The rather complex reactivity exhibited by cyclopropenones on interaction with enamines (see p. 74) is not re-found in the reactions of triafulvenes with enamines and ketene acetals. Instead of a (3 + 3) cycloaddition of enamine C=C—N sequence to the CI(2)/C3 bond of triafulvene (as represented by ylide 51 J) the addition of the enamine double bond to triafulvene C /C2 bond (operating with cyclopropenones only as a minor side-reaction) predominates in all reactions hitherto investigated. 

Ketene acetals show a pattern of product formation very similiar to enamines79 Diphenyl-4,4-diacetyl triafulvene is converted to diacetylmethyl cyclopentadiene 529 by S,N-acetals, whilst diphenyl-4,4-dicyano triafulvene undergoes C—C-inser-tion to S,N- and N,N-acetals, e.g. 530/531, resulting in cross-conjugated systems 533/534 by analogy with enamines. Cyclic S,N-acetals 532, however, yield exclusively the bicyclic fulvenes 535 due to additional loss of methyl mercaptan. 

The reactions of nitroalkenes (42) with various enols (43b) (vinyl ethers, silyl, and acyl enolates, ketene acetals) have been studied in most detail (110, 111, 125—154). As a mle, these reactions proceed smoothly to give the corresponding nitronates (35f) in yields from high to moderate. As in the reactions with enamines, the formation of compounds (44b) is attributed to the ambident character of the anionic centers in zwitterionic intermediates analogous to those shown in Scheme 3.43. 

With conjugated dienes, photocycloaddition of carbonyl compounds occurs at one of the double bonds to give vinyloxetanes. An interesting example is the reaction of acetone with 2-methyl-l,3-butadiene, which gave the two oxetanes (60) and (61) in a ratio of 3 1 and a total yield of about 20% (72JA8761). Other alkenes which have been used for photosynthesis of oxetanes include enol ethers, ketene acetals, enamines, allenes and diketene, with the reaction of the last compound with benzaldehyde illustrated in equation (105) (75CPB365). 

Ketene itself reacts with enamines and if in excess produces pyran-2-ones which are substituted in the 4-, 5- and 6-positions (65JOC2642). It seems likely that the acylated enamine undergoes a 1,4-addition with ketene to give an intermediate 4-amino-3,4-dihydropyranone, which eliminates the secondary amine on further reaction with ketene. 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

At low temperatures arylcyclopropenones condense with enamines by 1,2-addition to give the 2-azoniabicyclo[3.1.0]hex-3-en-3-olates 344, which isomerize on heating to penta-2,4-dienamides 348. In an overall sense these products arise from insertion of the cyclopropenone three carbon unit into the C-N bond of the enamine and at elevated temperatures compounds 344 are not isolated. In certain instances, -aminoenones 345, co-aminocyclopentenones 347 and cyclopentenones 346 (next page) also ensue . Ketene acetals behave in a similar manner to enamines . 

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