Enamines strategy

Strategy A. The enamine strategy to asymmetric transformations of carbonyl compounds is also exploited for the construction of carbon-heteroatom bonds using proline as catalyst, dissolved in ionic liquid media. Thus, a highly enantioselective a-aminoxylation of aldehydes and ketones has been reported based on the use of nitrosobenzene as the aminoxylating agent and catalysed by proline in [bmim] and [pmim] [BF4] and The reaction reported in Figure 6 affords poorer values in terms of yield and reaction rate when carried out in molecular solvents. Conversely, proline dissolved in the IL is recovered up to 6 times without appreciable loss of activity. 

In 2009, Breit et al. [109d] have extended the enamine strategy to unactivated allyl alcohols as substrates for the allyhc substitution (Scheme 12.47). When (d/l)-proline is used as the amine component, the carboxylic acid moiety in situ activates the allylic alcohol for abstraction of water and formation of a tt-allylpalladium complex. Subsequent nucleophilic attack of the enamine leads to the a-allylated ketones or aldehydes. Interestingly, the use of enantiopure prohne has no effect on the stereochemical outcome of the reaction with prochiral substrates. 

Analysis The most suitable discoimection follows the strategy we originally used (b, in frames 335, and 171-175). But can we make the right enamine fi om the unsaturated ketone, and does it alkylate in the right place It turns out that it can and does. 

Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an cr,/3-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C—C bond made in the Michael addition step is the one between the a- carbon of the ketone donor and the /3 carbon of the unsaturated acceptor. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

It appears, however, that the most used strategy for the preparation of thietane dioxides is the [2 + 2] cycloaddition of enamines (202) with in situ-generated sulfenes (220)74,143,186 188,202,242 to give /(-aminothietane sulfones (equation 85). 

Asymmetric induction and the synthesis of optically active thietane and thiete dioxides can be achieved via the basic strategy depicted above (equation 87), by using optically active enamine in the first (2 + 2) cycloaddition187 (equation 90). [Pg.449]

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

Another application of this strategy is the construction of cyclic systems bearing 1,4-dissonant relationships. For example, the synthesis of the hasubanan alkaloid ring system 35. reported in 1972 by Evans [24], involves the Diels-Alder cycloaddition of a dienyl sulphoxide 32 with an endocyclic enamine 33, followed by a [2,3]-sigmatropic rearrangement of the resulting cycloadduct 34 (Scheme 5.21). 

Hong and co-workers have described a formal [3-t-3] cycloaddition of a,P-unsaturated aldehydes using L-proline as the catalyst (Scheme 72) [225], Although the precise mechanism of this reaction is unclear a plausible explanation involves both iminium ion and enamine activation of the substrates and was exploited in the asymmetric synthesis of (-)-isopulegol hydrate 180 and (-)-cubebaol 181. This strategy has also been extended to the trimerisation of acrolein in the synthesis of montiporyne F [226],... 

An interesting strategy for pyrrolidine a,/3-functionalization has been developed <2005T1221>, starting from readily available endocyclic enamine derivatives. A two-step heteroannulation procedure involving iodoetherification of A -acyl-2-pyrrolines 216 giving 217 followed by radical cyclization gave access to the bicyclic compounds 218 which can be used in further transformations to form substituted pyrrolidines 219 and 220 (Scheme 22). 

A series of special linkers and cleavage strategies has been developed for the release of amines from insoluble supports (Table 3.23). These include the attachment of amines as triazenes, enamines, aminals, amidines, sulfonamides, sulfinamides, hydrazines, or amides. 

Strategies that lead to the formation of isoxazoles during cleavage from an insoluble support include the oxidative cleavage of /V-(4-alkoxybenzyl)isoxazolidincs with DDQ to yield isoxazolines (Entry 14, Table 15.16), the nucleophilic cleavage of 2-acyl enamines with hydroxylamine (Entry 15, Table 15.16), and the acidolysis of 2-cyano-phenols etherified with an oxime resin (Entry 17, Table 15.16). The required oxime ethers for the latter synthesis were prepared by reaction of the corresponding 2-fluorobenzonitriles with Kaiser oxime resin [203],... 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

A conceptually different approach to dihydropyrimidine analogues was developed by Kishi and co-workers (Scheme 4.8) [137, 138], The trimolecular room-temperature condensation of an enamine, acetaldehyde, and isocyanic acid provides the bicyclic dihydropyrimidine derivative 21. With some modification, this strategy was initially employed toward a stereospecific [138, 139] and later an enan-tioselective [140] synthesis of the natural product saxitoxin. Recent investigations by Elliott and coworkers have shown that substituted isocyanates can also be employed in this method [141-146], but a more general modification of this trimolecular condensation towards monocyclic dihydropyrimidine derivatives of the Bigi-nelli type has not yet been reported. 

Rather surprisingly this strategy works.5 It was better to use the diketone 36 (rather than 33), made by acylation of the morpholine enamine 35 of 34 and reductive amination of with 3-aminopropanol to give 37 that is dehydrated in acid to the amine 38. A Mitsunobu-like treatment with Ph3P-Br2 converts the OH to Br whereupon cyclisation of 32 X = Br gives 31. 

In reaction with cyclic enamines, 1,2,4-triazines have been used to prepare 2,2 -bispyridines <2004T6021> with extensions of this strategy to include a tethered inime-enamine, facilitating the direct conversion of the triazine to the pyridine without the requirement of a separate aromatization step (Scheme 128) <2004CC508>. 

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