Nitroalkenes with enamines

Reactions of nitroalkenes with enamines (43a) were studied in-depth (112-125). These reactions can produce Michael adducts (when nitroalkenes... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

The reactions of nitroalkenes (42) with various enols (43b) (vinyl ethers, silyl, and acyl enolates, ketene acetals) have been studied in most detail (110, 111, 125—154). As a mle, these reactions proceed smoothly to give the corresponding nitronates (35f) in yields from high to moderate. As in the reactions with enamines, the formation of compounds (44b) is attributed to the ambident character of the anionic centers in zwitterionic intermediates analogous to those shown in Scheme 3.43. 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

A reaction forming enamine adducts between nitroalkenes and enamines takes place with excellent diastereoselectivity572,573 and enantioselectivity. Seebach and coworkers574-577 have proposed a topological rule for the carbon-carbon bond-forming process between prochiral centres in enamines and nitroalkenes. This reaction is very important in the synthesis of enantiomerically pure organic compounds. 

A reaction forming enamine adducts between nitroalkenes and enamines takes place with excellent diastereoselectivity and enantioselectivity. Seebach and cowork-... 

Reactions of nitroalkenes and enamines take place not only in good chemical yields but also in excellent diastereomeric yields (>W%) . A topological rule has been formulated for carbon-carbon bond-forming processes between prochiral centres in enamines and nitroalkenes as well as other systems The reaction of enamines and imines with acrylamide results in aza-annulation ° . Other electrophilic alkenes which have been us to alkylate enamines and the products used in hetero- or carbocyclic synthesis include ethyl /5-nitroacrylate, where reaction occurs beta to the nitro not the ester group, 2- phenylseleno)prop-2-enenitrile [CH2 = C(SePh)CN] , phenyl a-phenylselenovinyl sulphone [CH2 = C(SePh)-S02Ph] and phenyl a-bromovinyl sulphone. An electrophilic allene, phenylsulpho-nylpropadiene, has also been used to alkylate enamines (Scheme 44). 

If an unsaturated aldehyde was combined with a 1,3-dinitro compound, chiral cyclohexanes were formed by a nitro-Michael/Heniy reaction sequence. Miehael addition followed by double Heniy reaction also led to ehiral eyelohexane derivatives. In another application of the Henry re-aetion, Hayashi used nitroalkenes with pentane-l,5-dial (generated in situ) to form ehiral eyelohexane carboxaldehydes. Chiral cyclopentanes were also eonstrueted in another manner. Enamine-mediated Michael addition of aldehydes to 5-iodo-l-nitropent-l-ene led to an intermediate enamine, which underwent intramoleeular cyclisation via iodide displacement. ... 

Different groups reported in 2007 on the use of C9 amino cinchona alkaloids as catalysts for the stereoselective functionaUzation of branched carbonyl compounds. Connon and coworkers demonstrated that the C9 amino derivative of epidihydro-quinine (40) and epidihydroquinidine (41) were effective catalysts for the conjugate addition of aldehydes and (cyclic) ketones to nitroalkenes via enamine catalysis [99] (Scheme 6.46). The catalysts with the same configuration at C9 as in the natural cinchona alkaloid gave poor results, in line with the results obtained for... 

The earliest examples of this process involve thermal cycloadditions with enamines as the 2jt-components in which the cycfic nitronates could be isolated [65]. Subsequently, silyl enol ethers were shown to react with nitroalkenes in the presence of Lewis acids, such as TiCl2(0-i-Pr)2 [66f]. In this same smdy, Seebach showed that the nitronates... 

The strongly nucleophilic enamines are among the first reported dienophiles for nitroalkene cycloadditions [85]. Thus, nitroalkene 51 undergoes thermal [4 + 2] cycloaddition with enamine 52 to provide nitronate 53 (Scheme 16.11) [86]. 

Nitroalkene acceptors in reactions with enamines Dihydrooxazine oxides (406) have now been identified as stable, key intermediates in the Michael addition of aldehydes to nitroalkenes, catalysed by pyrrolidines (405) (Scheme 15). Theoretical calculations suggest that these intermediates are protonated directly (e.g. by p-nitrophenol), without the formation of the zwitterion species. The latter protonation accounts for both the role of the acid cocatalyst and the stereochemistry.257 Theoretical studies of the proline-catalysed Michael addition of aldehydes and ketones to 0-nitrostyrene (MP2/6-311-l-G //M06-2X/6-31G ) suggest that, contrary to the... 

The Michael addition of enamines to nitroalkenes proceeds with high Yyn selectivity. The Yyn selectivity is explained by an acyclic synclinal model, in which there is some favorable interaction between the nitro group and the nitrogen lone pair of the enamine group CEq. 4.67i. Both Z- and E-nitrostyrenes afford the same product in over 90% diastereoselecdvity. 

The chiral enamines provide the opportunity for the enandoselecdve Michael addidon to nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with anee>90%. ... 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

High syn selectivity can be obtained from the addition of enamines to nitroalkenes. The reaction of 4-(1-cyclohexenyl)morpholine with ( )-l-bromo-4-(2-nitroethenyl)benzene gives, after acid hydrolysis, exclusively the. ryw-adduct, the relative configuration of which was unequivocally... 

Valentin and coworkers have studied extensively the reaction of enamines with nitroalkenes. The reaction proceeds under mild conditions to give y-nitroketones, which are converted into 1,4-diketones by the Nef reaction (Eq. 4.65).M... 

The reaction of enaminones with nitroalkenes gives a pentalenone system via the Michael addition and aldol reaction (Eq. 4.66).85a Linear a-keto enamines react with nitroalkenes to afford [3 + 2] carbocyclized products.8515... 

Nitroalkenes can also be converted to nitronates by direct combination with an alkene. The nitronate is formed as a result of a [4 + 2] cycloaddition of the electron-deficient nitroalkene, wherein one of the N—O bonds of the nitro group participates as part of the 4n fragment (Eq. 2.19) (89). Because of the electron-deficient nature of the heterodiene, alkenes react in the order electron rich > electroneutral > electron poor. Therefore, the majority of dienophiles investigated are enamines (52,71,199-207) and vinyl ethers (99,208-213). 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

Bronsted acid (Scheme 2.42) [26-28]. (For experimental details see Chapter 14.9.4). These catalysts mediate the addition of ketones to nitroalkenes at room temperature in the presence of a weak acid co-catalyst, such as benzoic acid or n-butyric acid or acetic acid. The acid additive allows double alkylation to be avoided, and also increases the reaction kinetic. The Jacobsen catalyst 24 showed better enantio- and diastereoselectivity with higher n-alkyl-ethyl ketones or with branched substrates (66 = 86-99% dr = 6/1 to 15/1), and forms preferentially the anti isomer (Scheme 2.42). The selectivity is the consequence of the preferred Z-enamine formation in the transition state the catalyst also activates the acceptor, and orientates in the space. The regioselectively of the alkylation of non-symmetric ketones is the consequence of this orientation. Whilst with small substrates the regioselectivity of the alkylation follows similar patterns (as described in the preceding section), leading to products of thermodynamic control, this selectivity can also be biased by steric factors. 

Beak used this method in a synthesis of (-)-paroxetine 97 (Paxil or Seroxat), a selective serotonin reuptake inhibitor.9 Lithiation of 92 with n-BuLi-(-)-sparteine and addition of the product 93 to the nitroalkene 94 yields the protected Z-enamine 95, as usual for reactions of lithiated allylamides, in >94% ee. Hydrolysis and reduction of the product, followed by mesylation and cyclisation gave the fnms-substituted piperidine 96. Displacement of the hydroxyl group by sesamol yielded (-)-paroxetine 97. 

Chiral dienophiles, e.g. enol ethers and enamines, allow to conduct these hetero Diels-Alder reactions in a highly stereoselective manner. In an exemplary transformation described by Backvall et al. the nitrone 4-50 was formed as a single diastereomer upon treatment of the chiral enamine 4-48 with the nitroalkene 4-49 which was generated in situ from the seleno compound 4-47 [387]. Interestingly, the enamine 4-48 did not only act as dienophile, it also catalysed the initial base induced elimination of PhSeH from 4-47 (Fig. 4-11). 

The 13C-, 15N- and -NMR spectral data for a series of simple l-amino-2-nitroalkenes are collected in Table 30. The greater electron-withdrawing character of the nitro group as compared with carbonyl results in downfield shifts of the resonances of C(2) ( + 10 to +14 ppm), the enaminic nitrogen ( + 23.2 to + 27.4 ppm) and the olefinic protons [ + 0.8 to +1.0 ppm for H(l) +1.5 to = 1.8 ppm for H(2)] of 2-nitroenamines with respect to enaminones. This deshielding does not affect C(l), which has in fact a lower chemical shift ( — 5.5 to — 10.2 ppm) in 2-nitroenamines. The NMR spectra show that 2-nitroenamines with a primary or a secondary amino groups exist in solution as solvent-dependent equilibrium mixtures of E- and Z-isomers. The... 

Reaction of a-ketoenamines with a series of cyclic and acyclic nitroolefins gave aminocyclopentene derivatives with high diastereoselectivity, as products of kinetic control instead of the expected 1,2-oxazine N-oxides (see Section III.D.2)45,46. For example, ketoenamine 62 when reacted with cyclic nitroalkene 61 afforded 65 as a single diastereoisomer46, first through the dipolar intermediate 63 and later through the betaine-type intermediate 64. Hydrolysis of this enamine furnished the cyclopentanone derivative 66, also as a single diastereoisomer (equation 11). 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

SMP enamines have a very broad range of applications as d synthons. Cyclohexanone SMP enamine can be used for efficient Michael additions to nitroalkenes, Knoevenagel acceptors, and to a nitroallylic ester in a [3 + 3] carbocyclization with excellent stereoselectivities (eq 1). The synthesis of y-oxo-a-amino acids using SMP enamines has been developed (eq 2). ... 

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