Nucleophilic substitution enamines

The essential feature of enamines is that they are nitrogen analogues of enols and behave as enolate anions. They effectively mask a carbonyl function while activating the compound towards nucleophilic substitution. 

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]. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Intramolecular nucleophilic displacements are sometimes better suited to difficult cyclizations than additions to C-C multiple bonds, because nucleophilic substitutions are usually irreversible. Some metalated 4-halobutyl imines cydize to yield cydobutanes rather than six-membered cydic enamines (Scheme 9.22). If alkoxides are used as bases, however, exclusive N-alkylation is observed. No examples could be found of the cydization of 4-halobutyl ketones to cyclobutyl ketones, but 5-halopen-... 

Two other nucleophilic substitution reactions of pyridine iV-oxides deserve mention and further study to determine the effects of substituents. Pyridine N-oxide, benzoyl chloride, and the piperidine enamine of cyclohexanone give a good yield of 2-(2 -pyridyl)cyclo-hexanone (155) (63%).360 When W-methoxy-4-picolinium methyl... 

Interestingly, furan ring annelation is also found in the reaction of 3-bromo-4-nitroquinoline with enamines. Due to hydrolysis of the iminium intermediate, the keto group is formed, which after enolization is able to act in the intramolecular cyclization with expulsion of bromide ion (Scheme 17) (76H453). The nucleophilic substitution of hydrogen at C-2 is preferred to that of the nitro group at C-4. 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

Electrophilic and nucleophilic substitution and addition reactions of enamines... 

Scheme 7. Enamine catalysis of nucleophilic substitution reactions...

Unexpected chiral adducts were formed in the thermal reaction of Cgo with enamines such as (V-cyclopent- l-cnylpipcridinc and N--cyclohex- 1-enylpyr-rolidine.402 Fullerene derivatives with chiral side chains can also be obtained in nucleophilic substitution reactions between fullerenide ions and electrophiles such as halides having the leaving group attached to a stereogenic center.403... 

Prior to 2001, when the first serious computational approaches to the problem appeared in print, four mechanistic proposals had been offered for understanding the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.8). Hajos and Parrish proposed the first two mechanisms Mechanisms A and B. Mechanism A is a nucleophilic substitution reaction where the terminal enol attacks the carbinolamine center, displacing proUne. The other three mechanisms start from an enamine intermediate. Mechanism B invokes an enaminium intermediate, which undergoes C-C formation with proton transfer from the aminium group. Mechanism C, proposed by Agamii to account for the nonlinear proline result, has the proton transfer assisted by the second proline molecule. Lastly, Mechanism D, proffered by Jung, proposed that the proton transfer that accompanies C-C bond formation is facilitated by the carboxylic acid group of proline. 

IG and added in the free energy of solvation in DMSO computed with PCM at HF/6-31-l-G(d,p). The lowest energy TS is for the carboxyhc-acid-catalyzed enamine route (Scheme 6.8 D). This barrier is 10.7 kcal mol smaller than that for the barrier without proline acting as a catalyst. The transition state for the enaminium-catalyzed route (Scheme 6.8 B) is 29.0 kcal mol higher than the TS for Scheme 6.8 D. All attempts to locate a TS for the nucleophilic substitution route (Scheme 6.8 A) failed. However, the carbinolamine intermediate that proceeds the TS on path A lies 12.7 kcal mol above the TS for Scheme 6.8... 

The author believes that students are well aware of the basic reaction pathways such as substitutions, additions, eliminations, aromatic substitutions, aliphatic nucleophilic substitutions and electrophilic substitutions. Students may follow undergraduate books on reaction mechanisms for basic knowledge of reactive intermediates and oxidation and reduction processes. Reaction Mechanisms in Organic Synthesis provides extensive coverage of various carbon-carbon bond forming reactions such as transition metal catalyzed reactions use of stabilized carbanions, ylides and enamines for the carbon-carbon bond forming reactions and advance level use of oxidation and reduction reagents in synthesis. 

The cyano group in position 4 of quinazolines behaves like a halogen towards nucleophilic reagents and can be displaced by a hydroxide anion, alkoxides, amines, hydrazines, and various carbon nucleophiles, o.g. ketones, a-keto esters, dialkyl malonates, nitroalkanes, Gri-gnard reagents, and enamines, to give 4-substituted quinazolines 1. The cyano group of quin-azoline-2-carbonitriles is less reactive for nucleophilic substitution but its displacement has not been intensively studied. Alkaline or acid hydrolysis of quinazoline-4-carbonitriles affords quinazolin-4(3// )-oncs. ... 

The method is quite useful for particularly active alkyl hahdes, such as allylic, benzyhc, and propargyhc halides, and for a-halo ethers and esters. Other primary and secondary halides can show sluggish reactivity. The react of enamines with benzotriazole derivatives has been reported. Tertiary hahdes do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and ehmination predominates. The reaction can also be applied to activated aryl halides (e.g., 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, and to activated alkenes, such as acrylonitrile. The latter is a Michael-type reaction (15-24) with respect to the alkene. 

Nucleophilic substitution and addition reactions of olefins are possible with Pd2 salts. A typical example is the formation of acetaldehyde by the reaction of ethylene with water (Wacker reaction). As nucleophiles, water, alcohols, phenols, carboxylic acids, amines, enamines, carbanions derived from active methylene compounds, and carbon monoxide react with olefins with stoichiometric consumption of Pd2 salts. 

Thus the stabilization of the benzylic positive charge in a dibenzotropylium species 2 may be the reason for the favored formation of the substituted enamines 4 from the chloroenamine 1 by action of nucleophiles such as hydroxide anion, dimethylamine and silver(I) nitrate or thiolate. So far only treatment of the chloroenamine 1 with sodium borohydride has given the aminocyclopropane derivative 5 with Nu = H. 

Quinolone antibiotics such as ofloxacin 200 are totally different from P-lactams, tetracyclines and so on and work in a different way. They offer some hope that resistance may be slow to appear. They all contain the quinolone core a benzene ring fused to a y-pyridone. Most have various amine substituents and ofloxacin has a fluorine atom. Disconnection of the enamine reveals a benzene ring with a series of heteroatom substituents (N, N, O, F) and the one fluorine suggests that a series of nucleophilic substitutions might provide a synthesis. 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

Nucleophilic substitution by halide, cyanide, carbon nucleophiles, such as enamines, and acetate (by reaction with acetic anhydride), with concomitant loss of the oxide function, occur smoothly in all three systems, though the site of introduction of the nucleophile is not always that predicted by analogy with pyridine chemistry (a to the AT-oxide), as illustrated by two of the examples below. 

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