Enamines aliphatic—

The next seven references are cited not because of the experimental procedures described but because they indicate diversification in the types of enamines prepared and studied. Both Paquette (25) and Kasper 26) have condensed 2,5-methylene-l,2,5,6-tetrahydrobenzaldehyde (5-nor-bornene-2-carboxyaldehyde) (2) with several cyclic and open-chain aliphatic secondary amines. Kasper studied the ratio of endo to exo aldehyde formed upon hydrolysis of these enamines and the dihydro enamines. Paquette investigated the addition of sulfene to the enamines. -Fluoro-... 

An interesting preparation of substituted o-aminophenols has been developed by Birkofer and Daum (30). 2-Acylfurans (8) plus an aliphatic secondary amine presumably condense to give the eorresponding enamine (9) (not isolated), which undergoes thermal isomerization to the o-amino-phenol (10). 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

The enamines of cyclic ketones, on reaction with aliphatic and aromatic aldehydes, give good yields of the 2-monoalkylidene derivative of the corresponding ketones (J28). The first step in the reaction appears to be the... 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

Thus, simple ketones or aliphatic aldehydes may be successfully used as starting materials in the CSIC (Carbanion mediated Sulfonate Intramolecular Cyclization) reaction. Ai-alkylsulfonamides could be also cyclized under CSIC conditions (99T(55)7625) affording the spiroisothiazoline 79. By treatment with TMSCl, Nal in acetonitrile at r.t., hydrolysis of the enamine and formation of the corresponding keto derivative 80 was obtained. 

Although catalytic hydrogenation is the method most often used, double bonds can be reduced by other reagents, as well. Among these are sodium in ethanol, sodium and rerr-butyl alcohol in HMPA, lithium and aliphatic amines (see also 15-14), " zinc and acids, sodium hypophosphate and Pd-C, (EtO)3SiH—Pd(OAc)2, trifluoroacetic acid and triethylsilane (EtsSiH), and hydroxylamine and ethyl acetate.However, metallic hydrides, such as lithium aluminum hydride and sodium borohydride, do not in general reduce carbon-carbon double bonds, although this can be done in special cases where the double bond is polar, as in 1,1-diarylethenes and in enamines. " °... 

Certain quaternary ammonium salts will alkylate [Co (DMG)2py] . The addition of PhCH2NMc3 I to a solution of the complex in methanol gives the PhCH2Co complex in 45% yield. The reaction works more slowly with dimethylpiperidinium iodide to give the CH3—Co complex 15). There is no alkylation with tertiary amines alone 164), but in the presence of equimolar amounts of dimethylacetylenedicarboxylate certain aliphatic tertiary amines can alkylate [Co (DMG)2py] in methanol solution. The reaction also produces the enamine derivative of a maleic ester, and the mechanism appears to involve addition of the amine to the triple bond to form an ammonium salt, which can then attack the Co(I) derivative (75). 

Aliphatic or aromatic aldehydes RCHO can be transformed, in situ, via their iminium iodides, on reaction with enamines of ketones, to give /9-aminoketones. Thus, 4-methoxybenzaldehyde reacts with dimethylammonium chloride, triethyla-... 

In a typical example of aliphatic cyclizations, already discussed in Section 5.2, the enamine 675 is alkylated by silylated methyl 4-chloroacetoacetate 747 a [2] to give, via 760 and subsequent ehmination of pyrrolidine, the unsaturated bicycHc /9-ke-toester 761 in, as yet, only 30-40% yield [1]. Analogously, the bicycHc system 1408 with an additional 6-keto group is silylated to 1409 and cyclized via 1410, in an overall yield of 42%, to the tricyclic capnellene intermediate 1411 [3] (Scheme 9.1). An alternative synthesis of bicyclic compounds Hke 761 is given elsewhere [3 a]. 

The synthesis of a variety of chiral aliphatic aldehydes of high optical purity through the enantioselective isomerization of allylamines found many applications in organic synthesis. The enantioselective isomerization of diethylgeranylamine, which was prepared from myrcene, furnished (R, )-diethylenamine in >98% yield with >98% ee. This enamine is converted to (—(-menthol stereospecifically in high chemical yield (yield of each step >92%, Scheme 4).9 11... 

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

Aliphatic c a -dibromo ketones, such as 2,4-dibromopentan-3-one (262), react with primary amines RNH2 (R = Me, Et, Pr, /-Pr or t-Bu) to give mixtures of imines 263 and lesser amounts of diimines 264. l,3-Dibromo-l-phenylpropan-2-one yields only the amide 265, the product of a Favorskii rearrangement. The nature of the products from aliphatic amines and cyclic a,a -dibromo ketones depends on ring size the cyclohexanone derivative 266 gave Favorskii amides 267 (R = Pr, /-Pr or t-Bu), while trans-2,5-dibromocyclopentanone afforded the enamines 268 (R = /-Pr or t-Bu) (equation 95)296. 

The Pd(PPh3)4-catalysed reaction of perfluoroalkyl iodides with tertiary aliphatic amines gives enamines in 40-50% yields, e.g. equation 98309. 

Also alkynylcarbene complexes can react as Michael acceptors with nucleophiles, forming 1,3-dien-l-ylcarbene complexes (Figure 2.17). Both carbon nucleophiles, such as, e.g., enamines [246-249], and non-carbon nucleophiles, such as imidates [250], amines [64,131,251], aliphatic alcohols [48,79,252], phenols [252], and thiols [252] can add to the C-C triple bond of alkynylcarbene complexes. Further reactions of the C-C triple bond of alkynylcarbene complexes include 1,3-dipolar [253,254], Diels-Alder [64,234,238,255-258] and [2 -i- 2] cycloadditions [259 -261], intramolecular Pauson-Khand reactions [43,262], and C-metallation of ethynylcarbene complexes [263]. 

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

Whilst the method described above appears very elegant, Weix and Hartwig expressed their discontent about the allylations of aliphatic silyl enol ethers and developed an alternative system using enamines as nucleophiles. Once the considerable initial difficulties had been overcome, these authors were able to present a procedure that gave excellent results (Scheme 9.16) [50]. 

A variety of aliphatic and aromatic ketones have been investigated (cyclohexanone, cyclopentanone, acetophenone, p-nitroacetophenone) and they all usually lead to 2-R -3-R"-5-nitropyridine in moderate to good yields. Better yields were recorded when enamines of the respective ketones were used. With aldehydes the yields are in general lower than with ketones. 

At present, most enamine-catalyzed aldol reactions are reliable only with electron-poor aromatic aldehyde acceptors, hi addition, a handful of aliphatic aldehydes (e.g. isobutyraldehyde or pivalaldehyde) are often used as acceptors. The use of unbranched aldehyde acceptors is difficult, and generally only modest yields have been obtained. In addition, unsaturated aldehydes are curiously absent from the list of commonly used acceptors. On a positive side, it should be noted that even potentially racemizing a-chiral aldehydes have been employed as acceptors. As an example, in the recent synthesis of caUipeltoside C, MacMillan and coworkers were able to employ protected Roche aldehyde 113 as a starting material (Scheme 22) [204]. 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

Based on the previous findings by Koomen [21], the Hiemstra group subsequently reported the Pictet-Spengler reaction of N-tritylsulfenyl tryptamines and various aliphatic and aromatic aldehydes by 11 (Scheme 5.11) [22]. Notably, the authors found that stabilization of the N-sulfenyliminium ion by the sulfenyl substituent facilitated preferential cyclization over enamine formation. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

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 reaction of aliphatic and aromatic ketone oximes 97 with a dialkyl carbonate 98 in the presence of K2CO3 at 180-190 °C yields 3-alkyl-4,5-disubstituted-2(3//)-oxazolones 104 in 22-48% yields. Mechanistically, it is proposed that N-alkylation of the initially formed oxime O-carbonate 99 yields 100, which affords the enamine 101 in the presence of base. A [3,3] sigmatropic rearrangement ensues to produce 102, which then cyclizes to 104. In cases where 97 contains two methylene groups in proximity to the C=N bond, one of which is benzylic, the above reaction sequence is regioselective for the benzylic methylene group (Fig. 5.25 Table 5.6, Fig. 5.26). ... 

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