Reactions of Enamines

Both of these reactions result in the alkylation of 4-t-butylcyclohexanone, but the selectivity obtained is very different. The lithium enolate produced on reaction with LDA is sterically undemanding, and hence approach of the methyl iodide is possible either axially or equatorially there is a marginal preference for the more stable equatorial product. However, the pyrrolidine ring of the enamine is much bulkier and inhibits approach to the equatorial position more than it does to the axial position. 

FIGURE 17.53 Reformatskii reagent considered as an ester enolate. 

Reactions of Enamines.—Hydroboronation of the 2-enamine (397) gave a product (amine-borane adduct ) from which the 3a- and 3 -pyrrolidino-derivatives (398 3a 3)5 = 82 18) were liberated by refluxing methanol. The stereochemistry of this reduction is quite unusual, and not fully explained. Reaction of the 3,5-dienamine (399) with dichlorocarbene led to ring expansion, giving the A-homo-4-chloro-dienone (400). Condensations of the enamine 

The conjugated double bond of enamines readily undergoes many reactions. The reactions of imines with a double bond between the nitrogen and carbon atoms are also discussed to allow comparison. Some reactions of heterocyclic compounds containing the enamine grouping as a part of the aromatic ring are also considered. The reactions of these compounds can be divided on a mechanistic basis into three groups  

Reactions of electrophilic reagents with the double bond of enamines. 

Reactions of enamine salts with nucleophilic reagents. 

Aldolization reactions of enamines (a special case combining classes A and B). 

Reactions of Electrophilic Reagents with the Double Bond of Enamines 

Both aldehydes (R = H) and ketones (R = alkyl or aryl) can be used as the carbonyl compound. 

Acyl groups are introduced by reaction of the enamine with an acid chloride (R = acyl).465 467 The products of hydrolysis are then / -diketones or, if R = H, j8-oxo aldehydes.469 

Reaction of the enamines with ethyl chloroformate gives good yields of ethyl j8-oxo carboxylates (R = COOC2H5),465,467 and cyanogen chloride affords / -oxo nitriles (R = CN) smoothly.470 

Further, enamines can be formylated by treatment with formic acid and acetic anhydride467 or with dimethylformamide and carbonyl chloride, the latter process being analogous to the Vilsmeier reaction and sometimes giving very good yields.471 

Some of the / -dicarbonyl compounds and substituted ketones obtained in the above-mentioned ways can be used without isolation for a wide variety of further reactions. For instance, Hiinig and his co-workers472 used such compounds for preparation of long-chain acids the 2-acylcyclohexanones obtained from A,A-dialkyl-l-cyclohexenylamine and an acyl chloride were cleaved by acid to co-acyl hexanoic acids, whose oxo groups were then reduced by the Wolff-Kishner method  

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The addition of 1,3-dicarbonyl compounds to /3-chloroazoalkenes is the basis of a pyrrole synthesis (Scheme 70a) 81TL1059). Pyrroles are also obtained by the reaction of enamines with azoalkenes (Scheme 70b) (79TL2969,81TL1475), and the copper(II) chloride catalyzed addition of 1,3-dicarbonyl compounds to arylazoalkenes (Scheme 70c) (82JOC684). 

C. Reaction of Enamines of 3-Ketones with Cyanogen Azide... 

The reaction of enamines with perfluoro olefins has also been reported (62). Dienamines have been reported to react with ethyl acrylate at C2 to give the alkylated a,j8-unsaturated ketone derivative. Thus the dienamine (44) gave 71 in 50 % yield on reaction with ethyl acrylate in dioxane for 40 hr (63). 

Arylation of enamines with p-benzoquinones takes a somewhat different course (70). The enamine (16) reacts exothermally with p-benzoquinone in benzene solution to give 2-(dimethylamino)-2,3-dihydro-3,3-dimethyl-5-benzofuranol (92). The reaction of enamines with quinone dibenzenesul-fonimide proceeds similarly (68). The product from the enamine (28) is the tetrahydrocarbazole derivative (93). 

Stable )3-chloro and bromo enamines have recently been obtained by reaction of enamines with the corresponding N-halosuccinimides (118a). 

The intermediacy of dipolar species such as 186 has been demonstrated by reaction of enamines with 2-hydroxy-1-aldehydes of the aromatic series (129). The enamine (113) reacts in benzene solution at room temperature with 2-hydroxy-1-naphthaldehyde to give the crystalline adduct (188) in 91 % yield. Oxidation with chromium trioxide-pyridine of 188 gave 189 with p elimination of the morpholine moiety. Palladium on charcoal dehydrogenation of 189 gave the known 1,2-benzoxanthone (129). 

The reaction of enamines derived from cyclohexanone with dichlorocarbene to give the 1 1 adducts is now well established (137-139). The morpholine enamine (113) reacted with dichlorocarbene at —10 to —20° in tetrahydrofuran to give the stable crystalline adduct (201). Thermal decomposition followed by an aqueous work-up gave an a,)3-unsaturated ketone identified as 2-chloromethylene-cyclohexan-l-one (202) (139). 

The reaction of enamines with ketene (146) and sulfene (147) are presumed to proceed by a two-step process involving an iminium intermediate such as 99. In fact, reaction with all electrophilic olefins such as acrylonitrile and related reagents could be thought of as going through an iminium intermediate similar to 99. Another example is given by addition to an enamine... 

This is illustrated by the reaction of enamine, 113 with sulfene to produce adduct 114 in an 80 % yield (146). The product 114 was also observed in an 18% yield from the reaction of diazomethane, sulfur dioxide, and enamine 113 (153). It was demonstrated that this cyclization reaction must involve sulfene adding to the enamine directly and not acylation of the enamine by... 

Enaminoketones undergo 1,4 cycloadditions with sulfene (162a). This is illustrated by the reaction of enamine 120 with sulfene to form sulfone 121 in an 80 % yield (162,163). 

B. Reactions of Enamine Salts with Nucleophilic Reagents. . 286... 

Reactions of Enamine Salts with OrganometalUc Compounds Organolithium and organomagnesium compounds react with enamine salts to give amines substituted on the ix-carbon atoms. The treatment of. -dehydroquinolizidinium perchlorate (163) with alkylmagnesium halides gives 9-alkylated quinolizidines (164) (252,256). Formation of... 

The aldol reactions of enamines may be formally considered to proceed via acyclic amino aldehyde or amino ketone forms, in spite of the fact that the cyclic enamine forms can also take part in aldol reactions. 

D. Reactions of Enamines with Divalent Carbon and Related Reactions. ... 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

The reactions of enamines with a,/3-unsaturated acid chlorides have provided bridged bicyclic diketones 312,313). 

A reaction related to the Michael addition reactions of enamines to unsaturated esters, which leads to S-ketoesters, is the reaction with 1-carb-ethoxy-l-cyanocyclopropane (318). This gives access to ketones substituted with the next higher homologous acid chain. 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

The reactions of enamines with aldehydes (329,350) are noteworthy in that they provide a route to the monobenzylidene derivatives of five- to seven-membered eyclic ketones as well as a method for the formation of other a, 9-unsaturated carbonyl compounds, in fair to good yields. The condensation of benzaldehyde with enamines is also involved in the formation of 3,5-dibenzylpyridine from piperidine and benzaldehyde (191-193). 

The long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

The reactions of enamines with positively activated olefins have been extended to arylations with />-quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

Closely related is the reaction of enamines with O-sulfonyl lactams (411-413), which has extended the versatility of Hiinig s carboxylic acid extension sequence to compounds with a terminal amine function. 

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