Enamines by elimination reactions

The stereospecific generation of enamines by -elimination reactions (187) and a vinylogous elimination, which leads to a dienamine (188), have been reported. The loss of an a substituent from a tertiary amine is seen in the generation of enamines by elimination of hydrogen cyanide from benzylic a-aminonitriles (189,190). 

This type of reaction with A N-disubstituted formamides, giving aldehydes, was an early application of Grignard reagents, sometimes known as the Bouveault reaction [A]. Dimethylformamide and N-methylformanilide, PhN(Me)CHO, have been most commonly used, but more recently iV-formylpiperidine and 2-(/V-formylmethylamino)pyridine have been recommended examples are listed in Table 6.5, and a recent example of the traditional procedure follows. It should be noted that these reactions are subject to a number of side-reactions [A]. One useful one is the formation of enamines by elimination from the initial adduct [9] ... 

Enamines derived from aldehydes can usually be obtained by the reaction of 2 equivalents of a secondary amine with the carbonyl compound, in the presence of anhydrous potassium carbonate, followed by pyrolytic distillation of the aminal with elimination of one of the amine groups (10,15, 30-36). Ketones are directly converted to enamines under the conditions of aminal formation. The azeotropic removal of water with excess aldehyde has also been described (32,37). 

Reactions of enamines with aluminum hydrogen dichloride (540,541) (UAIH4 and AICI3) or aluminum hydrogen dialkyl compounds (542) led to organoaluminum intermediates which could be hydrolyzed to tertiary amines or oxidized to aminoalcohols. The formation of olefins by elimination of the tertiary amine group has also been noted in these reactions. 

An approach to isobacteriochlorins1 ln-e makes use of Pd(II) or metal-free bilatrienes 1 as starting materials. Cyclization of the corresponding bilatriene derivatives is induced by base in the presence of palladium(II) or zinc(II) which exercise a template effect. Zinc can be readily removed from the cyclized macrotetracycles by acid whereas palladium forms very stable complexes which cannot be demetalated. Prior to the cyclization reaction, an enamine is formed by elimination of hydrogen cyanide from the 1-position. The nucleophilic enamine then attacks the electrophilic 19-position with loss of the leaving group present at the terminal pyrrole ring. 

Dialkyl esters of cystine (39) and lanthionine (40) undergo a surprising thermolysis reaction at between 25 C and 80 °C to afford cis and trans methyl 2-methylthiazolidine-2,4-dicarboxylates (43) in protic solvents. A two stage process is proposed for this transformation. An initial i-elimination reaction gives the thiol (41) and the enamine (42). Thiol addition to the imine tautomer of (42) is then followed by loss of ammonia and an intramolecular cyclisation to give (43) <96CC843>. 

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. 

Practically speaking, almost all syntheses of these systems are based on the enamine-sulfene cycloaddition reaction " . The thietane sulfone thus obtained yields, by elimination of R2NH, the desired unsaturated, four-membered sulfone... 

Scheme 33 illustrates the difference in reactivity between triazolines obtained from cyclohexanone and cyclo-pentanone enamines. Thus, the reactions of azidophosphonates 239 with cyclohexanone enamines produce unstable aminotriazolines 240 that cannot be isolated due to their spontaneous elimination of amines to provide triazoles 241. Contrary to that, triazolines 242, derived from cyclopentanone enamines, are isolated in good yield (76-88%) and cannot be converted to the corresponding triazoles even by thermolysis <1995H(40)543>. Probably, introduction of a double bond between two five-membered rings would involve too much molecular strain. 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

Benzothiazine ylides can be prepared by reaction of a sulfoxide with trifluoroacetic anhydride followed by an intramolecular nucleophilic attack of enamine and elimination of OAc from the sulfur (Equation 56) <1982J(P1)831, 1991J(P1)2249>. An interesting variation is the replacement of the enamine with an aniline (Equation 57) <1997JCM416>. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

The reaction of Dewar pyrimidinone 220 with water in 1 9 mixture of water and acetone at 20°C for 1 hour afforded 4//-pyrido[ 1,2-a]pyrimidin-4-one 108 and enamine 107 in 34% and 64% yields, respectively [89JCS(P1)1231]. Enamine 107 was formed by the cleavage of bond a of 4-hydroxyazetidin-2-one 221, and ring closure of enamine 107 by elimination of water gave 4//-pyrido[l, 2-a]pyrimidin-4-one 108 (Scheme 15). When the solvent polarity was increased, the cleavage of bond b of 4-hydroxyazetidin-2-one 221 also occurred. The reaction in aqueous acetoni-trile-d3 at 35°C for 37 hours gave 4//-pyrido[ 1,2-a]pyrimidin-4-one 109 and lactam 222 in 85% and 10% yields, respectively. The reaction of Dewar... 

In a manifestation of the reaction shown above, quinoline rings have also been formed by the cycloaddition of /V-arylketenimines 543 with 3,4-dihydro-2//-pyran 455 under high-pressure conditions (Scheme 100) <2001H(55)1971>. The reaction is proposed to proceed via the initial formation of 544 by attack of the enol ether on the protonated ketenimine subsequent electrophilic aromatic substitution gives 545. Protonation of the enamine to give 546 is followed by elimination to produce 547. Protection of the alcohol with 455 gives 548. 

Vinylcyclobutanones (51) can be prepared by cycloaddition of vinylketenes such as 49 (generated in situ by elimination of hydrogen chloride with triethylamine from a,/ -unsaturated acid chlorides) to / ,/ -dialkyl enamines such as 50 (equation 8)40. This type of reaction was originally reported by Hickmott and coworkers41. 

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction164 (equation 63). 

The 1,3-diazines have also been prepared by a reaction of enamines and S, S -dimethyl-A (A arylbenzimidoyl)sulfimides 360 in boiling tetraline220,221. The mechanism of the ring formation probably involves a thermal cleavage of the imidoylsulfimides 360 into imidoylnitrenes 361 and dimethyl sulfide. The nitrene can then react with the enamine to give an aziridine intermediate 362 which rearranges to a 3,4-dihydroquinazoline 363. Subsequent elimination of amine yields the quinazoline 364220. 

The presence of enamine intermediates is especially prominent in some of the elimination reactions catalyzed by the coenzyme, as exemplified by the reaction of serine dehydratase, an enzyme that performs a / -elimination process (Scheme 14). 

In contrast to the reaction of l,3-dithiole-2-thiones 406 (R = H or Ph) with pyrrolidi-nocyclohexene, which leads to thiophenes (see equation 23), the analogous reaction with the more reactive pyrrolidinocyclopentene results in l,3-dithionin-2-thiones 409. It is thought that the initial betaine 407 adds a second molecule of the enamine to give 408. Cyclization, followed by elimination of pyrrolidine, yields the product (equation 168)44. 

The driving force behind this reaction is the formation of an aromatic ring. The reactions in this problem are nucleophilic addition of a primary amine, followed by elimination of water to yield an imine or enamine. All of the other steps are protonations and deprotonations. 

Triethylamine is converted into thienopentathiepin 39 and heptathiocane 40 by the unprecedented cascade reaction with S2CI2 in the presence of DABCO. Oxidation of an A -ethyl group of EtsN by a complex of S2CI2 with l,4-diazabicyclo[2.2.2]octane (DABCO) (X-S-S-Cl) affords an enamine, which reacts with X-S-S-Cl to give a thioamide followed by elimination of X-SH. The condensation of this thioamide with the enamine followed by cyclization and oxidation affords the thiophene 39 (Scheme 9) <20030L1939>. 

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