Enamines hydrides

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

Cationic rings are readily reduced by complex hydrides under relatively mild conditions. Thus isoxazolium salts with sodium borohydride give the 2,5-dihydro derivatives (217) in ethanol, but yield the 2,3-dihydro compound (218) in MeCN/H20 (74CPB70). Pyrazolyl anions are reduced by borohydride to pyrazolines and pyrazolidines. Thiazolyl ions are reduced to 1,2-dihydrothiazoles by lithium aluminum hydride and to tetrahydrothiazoles by sodium borohydride. The tetrahydro compound is probably formed via (219), which results from proton addition to the dihydro derivative (220) containing an enamine function. 1,3-Dithiolylium salts easily add hydride ion from sodium borohydride (Scheme 20) (80AHC(27)151). 

Enamines are stable to Grignard reagents, methyl iodide and lithium aluminum hydride. 

Enamines of A" -3-ketones (45) are stable to lithium aluminum hydride, but lithium borohydride reduces the 3,4-double bond of the enamine system." In the presence of acetic acid the enamine (45) is reduced by sodium borohydride to the A -3-amine (47) via the iminium cation (46). ... 

To overcome this, the A -acetyl group is reduced with lithium aluminum hydride. The resulting basic enamine then reacts extremely rapidly and selectively with peracid. The derived epoxide is hydrolyzed very easily with alkali during the workup. 

A solution of 10 g of this compound in 80 ml of tetrahydrofuran is added, with cooling, during 5 min, to a solution of 4.8 g of lithium aluminum hydride in 60 ml of tetrahydrofuran, and the mixture refluxed for 2.25 hr then cooled in an ice bath and treated with 60 ml of acetone, followed by 200 ml of ether and 72 ml of 2 A sodium hydroxide. The mixture is filtered, the cake washed with 50 ml of acetone, and the combined filtrate washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized from acetone to give 6.05 g (68 %) of the enamine. 

Johnson and Whitehead have further shown that the reductive elimination of the pyrrolidine group from the pyrrolidine enamine of 2,4-dimethyl-cyclohexanone (16), which involved treating it with a mixture of lithium aluminum hydride and aluminum chloride (9), gave the trans isomer of 3,5-dimethyl-/l -cyclohexene (17) which on subsequent hydrogenation on a platinum catalyst led to the // onr-3,5-dimethylcyclohexane (18). 

The preparation of enamines by reduction of aromatic heterocyclic bases and their quaternary salts or of lactams is not the most useful approach (97). The lithium aluminum hydride reduction of N-acyl enamines has been used with both fruitful and unsuccessful results. A series of 3-N-acetyl -d -cholestenes (104) has been prepared by desulfurization of the appropriate thiazolidine (105) (98,99). Lithium aluminum hydride reduction of the... 

N-acyl enaminc (104, R = CHjCHj) gave an unstable enamine (106) which decomposed readily to 3-cholestanone. The steroidal N-acetyl enamines (107 and 108, R = C HjCHj) can be reduced by lithium aluminum hydride in tctrahydrofuran to the corresponding enamines (109, R = CJH5CH2) in 90 and 68% yield, respectively 100). Attempts to reduce the enamide (107, R = CH3) led to the formation of the impure enamine (109, R = CHj), which decomposed to the hydroxy ketone (110). 

The reaction has been applied to more complex enamines 13) and to dienamines 19). The reduction may be rationalized by initial protonation at the enamine carbon and subsequent decarboxylation of formate ion and addition of the hydride ion to the iminium cation. This mechanism has been given support by the reaction of the enamine (205) with deuterated formic acid 143) to give the corresponding amines. The formation of 206 on reaction with DCOOH clearly indicates that protonation at the enamine carbon is the initial step. 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

The determination of position of protonation by reaction with diazomethane was performed as follows The enamine was treated at —70° with ethereal hydrogen chloride and the suspension of precipitated salt was treated with diazomethane and allowed to warm slowly to —40°, at which temperature nitrogen was liberated. The reaction with lithium aluminum hydride (LAH) was carried out similarly except that an ether solution of LAH was added in place of diazomethane. The results from reaction of diazomethane and LAH 16) are summarized in Table 1. 

Tertiary heterocyclic enamines are reduced with metals in acidic media 142) or electrolytically (237,238) and their salts are reduced with lithium aluminum hydride or sodium borohydride (239,240) to the corresponding saturated amines. 

This method has been used for the reduction of l-methyl-2-alkyl-.d -pyrrolinium and l-methyl-2-alkyl-.d -piperideinium salts by Lukes et al. (42,249-251) and for the reduction of more complex bases containing the dehydroquinolizidine skeleton by Leonard et al. (252). The formic add reduction may be satisfactorily explained by addition of a hydride ion, or an equivalent particle formed from the formate anion, to the -carbon atom of the enamine (253), as shown in Scheme 13. 

While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

The reduction (136) of pyridinium compounds to 1,2- or 1,4-dihydro products with complex metal hydrides or dithionite leads to cyclic di-enamines of synthetic and biochemical interest. 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

Cyclic enamines can also be obtained by the reduction of pyridine and isoquinoline with lithium aluminum hydride (163-165), and the latter reduction has also been accomplished with sodium in liquid ammonia (166). 

An enamine was obtained in the synthesis of coronaridine (648) by aluminum hydride reduction of a bridged lactam, followed by dehydration on alumina. Additional examples of enamine formation by reduction of enamides (649) and thioenamides (650) were reported. 

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

The stereochemical course of reduction of imonium salts by Grignard reagents was found to depend on the structure of the reagent 714). Hydro-boration of enamines and oxidation with hydrogen peroxide led to amino-alcohols (7/5). While aluminum hydrogen dichloride reacted with enamines to yield mostly saturated amines and some olefins on hydrolysis, aluminum hydride gave predominantly the unsaturated products 716). 

The familiar alkylation of -ketoesters followed by decarboxylation is still a useful route to a-alkyl ketones, although the alkylation of enamines is frequently the preferred route. Given below are two examples of alkylation of 2-carbethoxycycloalkanones (prepared in Chapter 10, Section I). In the first case, sodium ethoxide is the base employed to generate the enolate ion of 2-carbethoxycyclohexanone. In the second case, the less acidic 2-carbethoxycyclooctanone requires sodium hydride for the generation of the enolate ion. 

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