Enamines, reaction with alkenes

C-Alkylations of hindered aldehyde enamines can be effected with a variety of alkylating agents, but only allylic and benzylic reagents are useful for alkylations of unhindered systems.Acyclic, homoan-nular and heteroannular dienamines undergo alkylation primarily at the a-positions. ° As discussed above, reactions of enamines with electrophiles containing sp -hybridized carbon atoms have numerous limitations. On the other hand, enamine reactions with electrophilic alkenes are highly useful and have received wide coverage in the literature. 

Methyl-1,2-dihydropyridine behaves as an enamine rather than as a diene at — 10°C in its primary cycloaddition reactions with alkenes and alkynes. At higher temperatures, the [2 -I- 2] cyclo-adducts, e.g. (79), are unstable, and the more thermodynamically stable Diels-Alder endo- and exo-adducts, e.g. (80) and (81), are formed. ... 

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. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Olefins conjugated with electron-withdrawing groups other than a carbonyl group undergo reactions with enamines in a manner similar to the carbonyl-conjugated electrophilic alkenes described above. Namely, they condense with an enamine to form a zwitterion intermediate from which either 1,2 cycloaddition to form a cyclobutane ring or simple alkylation can take place. 

The similarity between the reactions of alkenes and cyclopropanes is further demonstrated by the reactions of electrophilic cyclopropanes and cyclopropenes with enamines. Cyclopropylcyanoester74, when treated with the pyrrolidine enamine of cyclohexanone, undergoes what would be a 1,2 cycloaddition in the analogous alkene case, but is actually a 1,3 cycloaddition here, to form adduct 75 (90). A similar reaction between the... 

Enamines 1 are useful intermediates in organic synthesis. Their use for the synthesis of a-substituted aldehydes or ketones 3 by reaction with an electrophilic reactant—e.g. an alkyl halide 2, an acyl halide or an acceptor-substituted alkene—is named after Gilbert Stork. 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Reaction of a,/MJnsaturated Fischer Carbene Complexes with Alkenes, Butadienes, Enamines, and Imines... 

Alkenes with electron-withdrawing groups may form cyclobutanes with alkenes containing electron-donating groups. The enamine reactions, mentioned above, are examples of this, but it has also been accomplished with tetracyanoethylene and similar molecules, which give substituted cyclobutanes when treated with alkenes of the form C=C—A, where A may be... 

Apart from the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity norbornene, for example, is consistently more reactive than cyclohexene in 1,3-DCA reactions. Conjugated functional groups usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enol ethers, enamines, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with several 1,3-dipoles are given in Table 10.6 of Part A. Additional discussion of these reactivity trends can be found in Section 10.3.1 of Part A. 

Cyclobutanones (11, 560-561). Ketenimium salts are more reactive than ke-tenes in [2 + 2] cycloadditions with alkenes to prepare cyclobutanones. The salts are readily available by in situ reaction of tertiary amides with triflic anhydride and a base, generally 2,4,6-collidine. The cycloaddition proceeds satisfactorily with alkyl-substituted alkenes and alkynes, but not with enol ethers or enamines.1... 

Ruthenium complexes B also undergo fast reaction with terminal alkenes, but only slow or no reaction with internal alkenes. Sterically demanding olefins such as, e.g., 3,3-dimethyl-l-butene, or conjugated or cumulated dienes cannot be metathesized with complexes B. These catalysts generally have a higher tendency to form cyclic oligomers from dienes than do molybdenum-based catalysts. With enol ethers and enamines irreversible formation of catalytically inactive complexes occurs [582] (see Section 2.1.9). Isomerization of allyl ethers to enol ethers has been observed with complexes B [582]. 

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). 

Enamines represent nucleophilic alkenes which undergo cycloaddition reactions readily with electrophilic alkenes. For example, acrylonitrile (5) reacts with cyclic enamines 10 to give bicyclic aminocyclobutanenitrilcs 11, albeit in poor yields.29... 

For more reactive electrophilic alkenes possessing two or more electron-withdrawing groups, cycloadditions with enamines occur under mild conditions. The cycloadditions of A,A -dimethyl-2-methylprop-1-enamine (12) with a series of electrophilic alkenes 13 proceed at temperatures ranging from — 30 °C to room temperature in short reaction times to give good to very good yields of the aminocyclobutanes 14.30... 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

A wide range of alkenes may be used as substrates. The reaction is most commonly performed with alkenes of normal electronic nature, but electron deficient alkenes, such as a, 3-unsaturated carbonyl compounds, and very electron rich alkenes, such as enol ethers and enamines, have also been used successfully. Not surprisingly, the cyclopropylcarbinyl ethers and amines that are formed in the latter reactions (see Table S) are subject to facile rearrangements. 

The original Fischer-type caibene complexes react with electron deficient alkenes such as a,f3-unsatu-rated esters102 and especially electron rich alkenes such as enol ethers103 and enamines,104 but reactions with simple alkenes have been limited in their usefulness. Furthermore, because these particular caibene complexes most commonly contain heterosubstituted caibene units, they formally fall outside the scope of this chapter. A few nonheterosubstituted examples that have proven to be useful are benzylidene105 and diphenylcaibene106 complexes of tungsten. 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

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