Enamine-like

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Ultraviolet spectra of A-4-thiazoline-2-thione in 10 A HCl show that protonation occurs on the exocyclic sulfur rather than on the cyclic nitrogen or on the enamine-like Co-position (56). 

The rearrangement discovered by Kolosova et al. probably involves such reactivit (159). This reaction provides a good preparative method for various 5-amino-methylthiazoles (Scheme 43). No mechanism is proposed in the report, and it is not easy to understand how the C-5 enamine-like position competes with the very nucleophilic thiocarbonyl group of the formed A-4-thiazoline-2-thione. An alternative mechanism could start with ethanol addition at C-2. leading to the A-4-thiazoline (90) (Scheme 44). In this intermediate, C-5 nucleophilic reactivity would be favored bv the true enaminic structure. After alkylation on C-5,... 

It was found, during a study of synthetic routes leading to quinine analogues, that oxidation of a specific bicydic pyrazoline derivative with mercuric acetate gives an enamine-like pyrazole (87b). 

Aqueous acid has been utilized to cleave the enamine-like C—N bond of the 9-alkenylcarbazoles 94 and 95 ° and the products 82 of alkylation of the anions of 9-allyIcarbazoles hydrated ferric nitrate was used to remove the vinyl group from 3-halo-9-vinylcarbazoles, Strong base... 

The orf/io-methoxy group of 2-(o-methoxyphenyl)oxazolines has been displaced with organometallic reagents in a similar fashion (75JA7383). The excellent activating effect of the oxazoline combined with its ability to form a chelated enamine-like intermediate on addition of the organometallic is responsible for the success of this process. 

Two types of such [2 + 2] cycloadditions are known. In the first, Lewis acid catalyzes the cycloaddition in the second type, one of the reactants is enamine-like. 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

There has been extensive research into electrophilic additions to 3-substituted-l,4-dihydropyridines, such as N-methyl-3-cyano-l,4-dihydropyridine 138, which readily undergoes addition across the more reactive enamine-like 5,6-alkene to give 2,3,5-trisubstituted-l,2,3,4-tetrahydropyridines (Scheme 38) <1998JOC2728, 2000CEJ1763, 2003TL8449>. In an unusual example, the reaction with sulfinyl chlorides and triethylamine results in the formation of the 1,4-dihydropyridine sulfoxide 139, where in the absence of an additional nucleophile, the iminium intermediate is deprotonated to yield the monosubstituted 1,4-dihydropyridine product 139. 

Cycloadditions on 1,2,3,4-tetrahydropyridines are usually limited to those bearing an electron-withdrawing group at the 5-position or with a 4-oxo group to activate the enamine-like alkene. For example, di-l,2,3,4-tetrahydropyridine 220 in which one of the two 1,2,3,4-tetrahydropyridine units has a 4-oxo group undergoes [2+2] photocycloaddition... 

Now consider condensation of ammonia with ketoester 1.18. The isolated product is not imine 1.19 but the thermodynamically more stable enamine tautomer 1.20 which has a conjugated double bond system and a strong intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20 illustrates that an enamine-like linkage, as in generalised heterocycle 1.21, is also accessible by a condensation reaction. 

Unlike our initial imine disconnection which is restricted to nitrogen heterocycles (with one or two specific exceptions such as pyrylium salts, see Chapter 9), the heteroatom in the enamine or enamine-like disconnection could be divalent. Therefore this disconnection is also applicable to oxygen-and sulphur-containing heterocycles, typified by 1.24 and 1.25. 

Hint. Start by acetylating the pyridine to give a quaternary cationic species. How can deprotonation afford a nucleophilic enamine-like system ... 

The intramolecular McMurry coupling between the C=0 group of an amide and the C=0 double bond of a ketone leads to the formation of a heterocycle with an enamine-like substructure. The most important heterocycle of this type is the indole skeleton ... 

Intermediates in acylation reactions, 47 carbinolamine as, 41 in diazonium coupling, 77 enamine-like, 85... 

The mechanism consists of the same steps as those that take place when imincs form from primary amines, up to formation of the iminium ion. This iminium ion has no N-H proton to lose, so it loses one of the C-H protons next to the C=N to give the enamine. Enamines, like imines, are unstable to aqueous acid. We shall return to them in Chapter 21. 

The stereochemical data discussed for the protonation/deprotonation at C-fi catalyzed by the above enzymes are consistent with the results of trapping experiments with JV-ethylmaleimide carried out by Flavin and Slaughter [160]. This reagent will react with enamines, like the PLP-aminocrotonate intermediate, with formation of an adduct, a-keto-3-[3 -(A"-ethyl-2, 5 -diketopyrrolidyl)]butyric add (KEDB) This compound has two chiral centers which are generated during the reaction. 

In the first naive attempt a search for structures of compounds containing N—C—C grouping without any constraints on bond types or number of substituents at N and C atoms gave a huge amount of 7481 structures. This result prompted us to eliminate such formally enamine-like compounds as porphyrines, phthalocyanines, tetraazamacrocyclic compounds, purine and pyrimidine derivatives, as well as to formulate more precise conditions for selection of proper enamine groupings. To this end a new structural data retrieval from CSDS was performed in four stages. 

Chromenes (342) were prepared, via 0-quinone methides, from 0-phenolic Mannich bases and enamines202, but have also been obtained by reaction of functionalized enamines like 340, with an electron-withdrawing substituent in the -position, and substituted 0-hydroxybenzyl alcohols 341 in boiling acetic acid203 (equation 74). 

That there is an enamine-like intermediate in all thiamin diphosphate-dependent enzymatic pathways has been suggested for many years, although the issue is still sometimes clouded by the observation that the C2a-protonated form, the C2a-hydro-xyethylThDP when added to oxidases such as pyruvate oxidase (POX) and the pyruvate dehydrogenase multienzyme complex (PDHc), will undergo oxidation. 

Particularly interesting was the case of 3-methylpyrrole in addition to the expected hydroxy- and methoxylactams, compounds 97 and 98 were found.124 This fact was presented as the first evidence for the formation of a cyclic dioxetane intermediate (99) arising from 1,2-cycloaddition of singlet oxygen to the enamine-like 2,3 bond of the pyrrole. 

Enamines like enolates are alkylated when treated with reactive alkylating agent, a-Substituted enamines can be converted into aldehydes and ketones by acid-catalyzed hydrolysis. Thus, in the three-step process, alkylation of aldehydes and ketones may be carried out via enamines (Stork enamine synthesis) (Scheme 3.19). 

An unlikely step is the addition of hydroxide to the double bond. Double bonds of enamines, like this one, tend to be nucleophilic rather than electrophilic. That is, the resonance interaction of the lone pair of electrons on nitrogen with the double bond is more important than the... 

Pyridines by Enamines. Like 6-aminouracil (243) 3-aminocrotonitrile (245a) and 3-aminocrotonic acid esters (245 b, c), vinylogues of cyanamide or urethane represent stable but acyclic members of enamines with a free amino group. Vinamidinium salts (7) in the presence of sodium methoxide or the related 3,3-diethoxy-... 

Cross-conjugated enamines like 2-morpholinobutadienes (319) react with benzylide-neaniline (320) in the presence of ZnClj to give tetrahydropyridine (322) with a high degree of stereoselectivity . The high stereoselectivity was explained by assuming that the reaction takes place in a concerted manner via coordination of diene and dienophile to the Lewis acid (equation 69). 

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