Mono enamines

The term enaminone is used to indicate any compound containing the conjugated system N—C=C—c=0582,583. It may be a mono-enamine of 1,3-diketone or of a 3-keto ester. A general method for the preparation of enaminones involves reaction between ammonia or primary or secondary amine and a 1,3-diketone (3-chloro(bromo)-2-alkenone) or a 3-ketoester584"590. An improved procedure employed ammonium and amine acetates591 (equation 38). 

Die Mono-enamine von / -Dicarbonyl-Verbindungen sind so stabil, da6 zusatzlich im Molekiil befindliche C=N-Doppelbindungen selektiv mit Palladium hydriert werden kon-nen5. 

Enaminones are compounds containing the system N—C=C—C=0. They are mono enamines of 1,3-diketones (vinylogous amides) or enamines of 3-keto esters (vinylogous urethanes). Their unique properties and the versatility of their applications in organic synthesis follow from the system Na Cb=Cc—Cd=Oe, which is tridentate (sites a, c, and e) toward electrophiles and bidentate (sites b and d) toward nucleophiles. This makes possible a wide variety of reactions, but with such a multiplicity of sites vulnerable to attack, reactions are sometimes unpredictable and can be unexpectedly complex. 

A new pyridone synthesis was developed to form the basis of the second synthesis (Scheme 27) to be announced. This new heterocyclic method involves, in essence, the interaction of a 1,3-dialkoxycarbonylallene with a P-aminocrotonate [in the present context, (95)] or mono-enamine of a 1,3-dicarbonyl... 

The opposite result may be obtained by preparing the mono-enamine, followed by catalytic reduction and jS-climina-tion [258] (Fig. 9.16). 

Methyl-cyclopentane-1,2-dione, which exists mainly in the enolic form (33), has been studied in connection with the synthesis of compounds related to Jasmone. Its acetylation gave the mono-enol acetate (34) which by subsequent ketalization and alkaline hydrolysis gave the monoketal (35), which reacted normally with Grignard reagents [26]. On the other hand, the mono-enamine formed from (33) with pyrrolidine has the structure (36) [261, 262] (Fig. 9.17). 

The pyrrolidine enamine of cyclohexanone (28) has been shown to react with 0-, m-, and p-nitrobenzenesulfenyl chlorides (105). A mixture of the 2-mono- and 2,6-bis(o-, m-, and p-nitrophenylsulfenyl)cyclohexanones is obtained on hydrolysis. Only the monosubstituted derivative (155) is... 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The Nenitzescu reaction generally occurs under relatively mild reaction conditions. Moreover mono-, di-, and tri-substituted quinones react with equal facility. Many enamines including p-aminoacrylonitriles, p-aminoacrylamides, and p-amino-a,p-unsaturated ketones react with quinones to form indole nuclei as well. The mild reaction conditions and the availability of the starting material render it attractive even in those instances where the yield of the product is low. ... 

Extension of this work by reacting 5-nitropyrimidine with 0,0-ketene acetals and with other cyclic and non-cyclic enamines showed that also with these electron-rich dienophiles the addition is regioselective and gives rise to the formation of 2-mono- or 2,3-disubstituted 5-nitropyridines (Scheme 30). Thus, reaction of 5-nitropyrimidine with the cyclic N,S-ketene acetals 4,5-dihydro-1 -methyl-2-methylthiopyrrole and 4,5,6,7-tetrahydro-1 -methyl-2-methylthioazepine gives in low yields 2,3-dihydro-1-methyl-5-nitropyr-olo[2,3-h]pyridine and the 5,6,7,8-tetrahydro-9-methyl-3-nitropyrido [2,3-Z)]azepine, respectively (89T2693) (Scheme 30). 

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... 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

An enamine was trifluoromethylated with 5-salt 17 (1 equivalent) in the presence of an equimolar amount of 4-(dimethylamino)pyridine to give mono(trifluoromethyl) and di(trifluoromethyl) ketones (Eq. 23). 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

Vinylamines (enamines) are reduced by alane, mono- and dichloroalane to saturated amines, and hydrogenolyzed to amines and alkenes [710]. Reduction is favored by dichloroalane while hydrogenolysis is favored by alane. Alane, chloroalane and dichloroalane gave the following results with -N-pyrrolidinylcyclohexene V-pyrrolidinylcyclohexane in 13, 15 and 22% yield, and pyrrolidine and cyclohexene in 80, 75 and 75% yields, respectively [710]. Saturated amines were also obtained by treatment of enamines with sodium borohydride [711], with sodium cyanoborohydride [103, 712] (Procedure 22, p. 210) and by heating for 1-2 hours at 50-70° with 87% or 9S% formic acid (yields 37-89%) [320]. 

Enamine 106 (derived from Meldrum s acid), in a process of mono-decarboxylating transesterification and subsequent intramolecular alkylation, is cyclized to form enamino ester 107 (90H(31)1251). The direct route by flash vacuum thermolysis does not work in the case of 6/7 bicyclic 107. Methylene compound 109 originates (analogously to bicyclic 40b) from... 

To suppress enamine-derived side products, we explored addition of benzotriazole (BtH) to the reaction mixture. The premise behind these experiments was the ability of BtH to form stable adducts with imines,23,24 thereby blocking tautomerization of 19 to 20 through in situ formation of the benzotriazolyl derivative 21. It was hoped that subsequent hydride displacement of the Bt moiety would afford the desired mono alkylated products 23. Indeed, analytical high-performance liquid chromatography (HPLC) revealed a remarkable improvement in terms of product purity, especially for reactions carried out at room temperature, with the desired secondary anilines 23 being essentially the only products detected. In... 

P-amino acid derivatives, the problems associated with obtaining just one isomer of 17 thwarted high ee s. It is now possible to prepare just one isomer of the enamine.94 In addition, the MonoPhos family of ligands have been shown to provide good ee s with either isomer of 17 (Scheme 2.26).95 The ability to prepare ligand libraries and screen them for asymmetric hydrogenations, such as to prepare P-amino acids,96-98 makes this approach a powerful one. For a full discussion on mono-dentate ligands see Chapter 14. 

We have also examined the use of cyclodextrin-derived artificial enzymes in promoting bimolecular aldol reactions, specifically those of m-nitrobenzaldehyde (57) and ofp-t-butylbenzaldehyde (58) with acetone [141]. Here, we examined a group of mono-substituted cyclodextrins as catalysts (e.g. 59), as well as two disubstituted (3-cyclodextrins (e.g. 60) (10 catalysts in all). They all bound the aldehyde components in the cyclodextrin cavity and used amino groups of the substituents to convert the acetone into its enamine. An intracomplex reaction with 58 and hydrolysis of the enamine product then afforded hydroxyketone 61 (cf. 62). These catalysts imitate natural enzymes classified as Class I aldolases. 

Some synthetic lapachol derivatives have also showed cytotoxic activity. Burton et al have prepared mono(arylimino) derivatives of P-lapachone. Some of these derivatives had good scores with net cell kills in preliminary in vivo testing hollow fiber assays against a standard panel of 12 human tumor cell lines [160].Twelve substituted 1,4-naphthoquinones were tested against the ascitic form of sarcoma 180 in Swiss mice. Statistical analysis showed that the most important molecular parameter determining their effectiveness in prolonging the life of mice bearing this tumor is their redox potentials [161]. Zalkow et al have synthesized a monoimine quinone, namely 2-methyl-(Z)-4-phenylimino)naphth[2,3-d]oxazol-9-one, which in in vitro tests showed a selective activity for some solid cancer tumors [162]. Enamine derivatives of lapachol were... 

Tris(organoamino)boranes have been utilized to prepare, in reasonable yields,4,5 mono- and dihalo(organoamino)boranes which are often difficult to obtain by direct amination of the boron trihalides. Carboxylic acids, 1,3-diketones, ketones, and /3-ketoesters have been converted into carboxamides, enamino-ketones, enamines, and j -enamino-amides, respectively, by reaction with an appropriate tris(organoamino)borane under very mild conditions.6 Sulfenamides (R2NSC6H5) have also been prepared in high yield from selected tris(organoamino)boranes and sulfenic esters under relatively mild conditions.7... 

Some special enamines, such as ethyl / -aminocrotonate and its alkylation and acetylation products, have already been known since the last century4. The general preparation of enamines was first reported by Mannich and Davidsen5 in 1936. However, this class of compounds found widespread synthetic applications only in the fifties due to the pioneering work of Stork and his coworkers6-8 and for a long period of time enamines have been studied mainly as synthetic intermediates and as tools for specific mono-substitution of ketones or aldehydes. 

An attractive alternative to the direct preparation of enamines from mono-substituted phosphonate reagents is the use of dimethyl diazomethylphosphonate (Me0)2P(0)CH= N2. Treatment of this diazo compound with t-BuOK (or with LiOH or K2C03), followed by various ketones in the presence of secondary amines, delivered the corresponding enamines251-253 (equation 17). In the presence of amines, (MeO)2P(0)CH= N2 and RCHO afforded the terminal acetylenes RC=CH. 

An interesting recent development is the synthesis of protected primary enamines475. iV-Mono(trimethylsilyl)enamines have been prepared by trimethylsilylation of metalloenamines476. The stereoselective synthesis of ( )- V, V-bis(trimethylsilyl)enamines PhCH2CH=CHN(SiMe3)2 has been described477. 

Considerable work has been carried out by Risaliti and coworkers on the re-gioselectivity and stereoselectivity of the alkylation of enamines with vinyl sul-phones100-105 and nitro alkenes106-116. A surprising result was observed in the reaction of phenyl vinyl sulphone with 1-iV-morpholinocyclohexene in that the more substituted mono-alkylated enamine (51) was the main product. Its isomer 52 was formed only in 25% yield (Scheme 35). 

Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the / -nitro-a-phenylethyl ketone on hydrolysis117. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-7V-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers107 (Scheme 39). 

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