Enamine nucleophiles

Propiolactone is subject to attack by enolate ions to give propionic acid derivatives of ketones. It may likewise react with nucleophilic enamines to give carboxyethylation according to the reactions. The morpholide is easily hydrolyzed to the corresponding acid. 

After filtration of the reaction mixture, treatment of the toluene filtrate with ketene gas accomplishes a smooth mono-C-acetylation of the nucleophilic enamine function in 25, and provides keto enamine... 

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. 

In general, the most nucleophilic enamines are those where the nitrogen lone pair is most effectively delocalized. This requires effective overlap of the lone pair with the C = C 71 bond and maximum flattening (sp hybridization) of the enamine nitrogen. 

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

The plane of symmetry bisecting varenicline means that it is meso, rather than chiral. Nevertheless, in combination with a chiral additive such as tartaric acid or camphorsulfonic add (CSA), it may still be possible to achieve asymmetric induction via aminocatalysis. In such a scenario, a nucleophilic enamine formed from varenicline might be desymmetrized by selective protonation of one of the two heteroaromatic nitrogens. Alternatively, the enamine might effect asymmetric induction merely by virtue of the chiral environment resulting from the presence of either one or two chiral camphorsulfonate counterions. However, varenicline... 

Examine the electrostatic potential map of each nucleophile enamine, silyl enol ether, lithium enolate and enol) with emphasis on the face of the nucleophilic alkene carbon. Rank the nucleophiles from most electron rich to least electron rich. What factors are responsible for this order (Hint For each molecule, consider an alternative Lewis structure to that given above that places a negative charge on the nucleophilic carbon.)... 

In 30 (R3 = Aik), given that there is possibility of a competing formation of a-naphthylamines 153, the application of acetic acid catalysis, in some cases, leads to an adverse effect by increasing the yields of carbocycli-zation products 153. Such a marked influence of acid catalysis may be explained by the greater susceptibility of a substituted imino group in the ring-opened intermediate 150 toward exhibiting basic, but not nucleophilic, properties, in comparison with ammonium intermediate 136 (Scheme 8). This may lead to the formation of more nucleophilic enamines... 

For the proline- and proline congener-catalyzed aldol reaction [23, 24], a mechanism based on enamine formation is proposed [25], Scheme 7. The catalytic process starts with condensation of the secondary amino group of proline with a carbonyl substrate leading to a nucleophilic enamine intermediate, which mimics the condensation of the active-site lysine residue with a carbonyl substrate in type I aldolases. The adjacent carboxylic acid group of the enamine intermediate... 

The transformation of an electrophilic carbonyl group to a nucleophilic enamine group with the help of a secondary amine was also applied in coinage metal catalysis.34 The reaction often, in much the same way as do other enamine catalyses, requires quite high catalyst loadings of the secondary amine. A test substrate for catalyst optimization was the malonate shown in Scheme 12.17. 

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

Mechanistically, the antibody aldolases resemble natural class I aldolase enzymes (Scheme 4.7) [52]. In the first step of a condensation reaction, the s-amino group of the catalytic lysine reacts with a ketone to form a Schiffbase. Deprotonation of this species yields a nucleophilic enamine, which condenses with electrophilic aldehydes in a second step to form a new carbon-carbon bond. Subsequent hydrolysis of the Schiffbase releases product and regenerates the active catalyst. 

Thiazolium and triazolium salt-derived NHC, in particular, are well known catalysts for benzoin- and Stetter-type umpolung reactions. In the course of these reactions, the NHC catalyst adds to the electrophilic aldehyde, resulting in the formation of a nucleophilic enamine species. Subsequently, this enamine can react with a series of different electrophiles such as aldehydes (benzoin condensation) or a, )-unsaturalcd substrates (Stetter reaction) (Scheme 4). 

STEP 3 The nucleophilic enamine double bond attacks a sulfur atom of iipoamide and does an SM2-like displacement of the second sulfur atom. 

In Scheme 57, the nucleophilic enamine (135) adds to the strained cyclic vinyl sulfone (136) to give the bicydic sulfone (137) a similar [2+2] cydoaddition occurs between (138) and the ynamine (139) to form the cyclic phenyl sulfone (140). The regiospecific reactions probably involve stepwise attack of the nucleophilic enamine (or ynamine) on the electrophilic sulfone. The four-membered ring products (137) and (140) are obtained in good yields and can be readily hydrolysed by dilute acid to form the corresponding cyclobutanones. 

A .A -Dialkyl enamines yield alkyl 2-dialkylaminocyclopropane-l-carboxylates in low yield only, or, more typically, not at all. In contrast, less nucleophilic enamines, such as 77-acyl enamines (see Houben-Weyl, Vol. El9b, p 1153), A-acyl-2,3-dihydropyrroles, 77-acyl-l,2,3,4-tetrahydropyridines and A W-bis(trimethylsilyl) enamine 15, are cyclopropanated by diazoacetic esters without problems, e.g. formation of 16. In contrast to ( )-15, the Z-isomer and related trisubstituted enamines are cyclopropanated only in low yield (5-10%). ... 

On the other hand, 2,3-diphenyl-4,4-dicyanotriafulvene (1) is stable and inert to strong acids such as hydrobromic acid and tetrafluoroboric acid. Chlorine, however, adds to this triafulvene at the exocyclic C — C double bond to give a dichloride which regenerates the triafulvene upon zinc reduction. Although the dicyanotriafulvene 1 is also inert to most dienes, it undergoes [2 + 2] cycloadditions with nucleophilic enamines followed by ring opening. 

Unfortunately the nitrogen atom lowers the HOMO energy of the diene 24 and it is not a good match with the LUMO of maleic anhydride. Instead the imine 24 is in equilibrium with the enam-ine 27 and, in conformation 27b, this has a high energy HOMO and so the product2 of the reaction is 28. The tautomerism between 24 and 27 may be especially easy as it can be drawn as a [1,5]H sigmatropic shift. This conflict between weakly electrophilic imines and their tautomers, the nucleophilic enamines, is one of the themes of this chapter.1... 

These Fp-alkene complexes react with a variety of other nucleophiles,3 5 including water, alcohols, amines,3 6 phosphines, and thiols as well as carbon nucleophiles (enamines, organocuprates, enolates),3 2,3l8 and dialkyl cadmium reagents.3 9 Diene complexes such as 487 were converted to the corresponding cationic complexes (488), for example, and reaction with malonate gave 489. The iron complex was removed with trimethylamine N-oxide (Me N-O) to give 490.320... 

A second synthesis of elaeocarpine (15) and isoelaeocarpine (16), by a direct, two-stage procedure, has been reported." Reduction of 2,3-dihydro-1//-indolizinium bromide (17) with lithium aluminium hydride in the presence of 6-methylsalicylaldehyde afforded the condensation product (20), presumably via the dihydropyridine derivative (18) which, as a nucleophilic enamine, attacks the... 

One of the milestones in the development of organocatalysis is the intramolecular aldol reaction catalyzed by proline developed independently by two industrial research groups at Hoffmann-La Roche and Schering (Scheme 1.3). This reaction, also known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction, was reported in 1971 and is based on the foundations of stoichiometric enamine chemistry by Stork and the mechanistic conclusions driven by Langebeck himself on some enzymatic reactions, and outlines for the first time the reversible formation of a nucleophilic enamine as the key intermediate participating in the catalytic cycle. 

Chiral secondary amines have proven to be amongst the most dynamic and efficient of asymmetric catalysts. There are essentially two modes of activation by secondary amines whereby a nucleophilic enamine or an electrophilic imininm ion is generated. Figure 1.4 shows a generic scheme of these two modes of activation and how they would be used in asymmetric organocatalytic cyclizations. A third mode of catalysis, named Organo-SOMO catalysis is discussed in Sect 1.5.1.5. 

Proline (1) has showed to be a effective catalyst for both the homo-aldol and the cross-aldol reactions (Schane 4.12). Thus, the homo-aldol process using propi-onaldehyde (R =Me in 5a and R =Et in 2) afforded the expected a-hydroxyaldehyde in an excellent enantioselectivity for the major anti-29. Under similar reaction conditions, the cross-aldol reaction between propionaldehyde as source of nucleophile (5, R =Me) and other different aliphatic and aromatic aldehydes has been performed, giving the anti-29 isomer as the main diastereoisomer [71], This reaction course has been explained due to the steric hindrance as well as the kinetic inaccessibility of the hydrogen for some a,a-disubstimted aldehydes which leads, in both cases, to a very thermodynamic unstable corresponding nucleophilic enamine intermediate. 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

I rrolidine-thioxotetrahydropyrimidinone catalyst 57 in the presence of 4-nitrobenzoic acid cocatalyst effectively catalysed the asymmetric reaction of cyclic ketones with substituted benzhydrol to afford the a-alkylated products in moderate to quantitative yields and in low to high enantiomeric excesses (up to 80%) (Scheme 19.72). According to the authors, the stereochemical outcome of the reaction indicates some type of interactions between the generated carbocation and the thioxotetrahy-dropyrimidinone ring of the catalyst, in lieu of steric shielding, hence leading to a front-face attack from the nucleophilic enamine (see TS in Scheme 19.72). 

The vinylogous functionalization of conjugated aldehydes and ketones R CH2CH= CHCH=CHCR =0, using primary and secondary amines RR NH as catalysts, has been analysed from the point of view of the intermediate formation of nucleophilic enamines (with raised HOMO) and electrophilic iminiums (with lowered LUMO), in an attempt to rationalize the transmission of the stereochemical information. ... 

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