Azomethine ylide, cycloadditions nitroalkenes

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Dipolar cycloaddition reaction of azomethine ylides to alkynes or alkenes followed by oxidation is one of the standard methods for the preparation of pyrroles.54 Recently, this strategy has been used for the preparation of pyrroles with CF3 or Me3Si groups at the (3-positions.55 Addition of azomethine ylides to nitroalkenes followed by elimination of HN02 with base gives pyrroles in 96% yield (Eq. 10.48).56... 

The first chiral thiourea-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes 210 was reported by Gong, et. al., Scheme 3.68 [85], This reaction afforded highly substituted pyrrolidines 212 with high diastereo-selectivities and moderate enantioselectivities. 

Vivanco et queried the origin of the loss of concertedness in pericyclic reactions. They studied several [3+2] thermal cycloadditions between azomethine ylides and nitroalkenes both computationally and experimentally. An analysis of the energy density H at relevant BCPs reveals that the lithium-heteroatom interactions are electrostatic. 

Scheme 6.16 1,3-DipoIar cycloadditions of azomethine ylide to nitroalkenes.

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Shortly after, Waldmann and co-workers reported the first efficient Cu(I)-catalyzed highly diastereoselective and enantioselective[3-1-2] cycloaddition reaction of S-shaped 1,3-fused cyclic azomethine ylides with nitroalkenes, providing an unprecedented and general access to functionalized tropane scaffolds bearing quaternary and tertiary stereocenters in a stereoselective manner (Scheme 16) [28], Furthermore, subjecting a collection of these tropane derivatives to a cell-based screen revealed a novel class of hedgehog signaling inhibitors. 

When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole moiety) is applied, product 134 was selectively formed by a highly diastereo- and enantioselective 1,3-dipolar cycloaddition (11 examples, 56-90%, 60-91% ee). This reaction most likely involves activation of the nitroalkene by the thiourea, via the earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted attack of the in situ formed azomethine ylide (this ylide is not activated by nor coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but is most likely formed via a 1,2-prototropic rearrangement [92]). 

The employment of bifunctional urea-tertiary amine 104 or monothiourea 105 catalysts selectively promotes either the Michael addition or cycloaddition process, respectively, [60]. As depicted in Scheme 2.30, the tertiary amine group would activate the in situ formed a-amino esters to produce azomethine ylides A (or enolates), whereas the nitroalkene counterparts would be activated by the thiourea (urea) moiety through a double H bonding interaction (B). 

Hou and coworkers have developed a remarkable methodology for highly enantioselective cycloaddition of azomethine ylides (349) with nitroalkenes (353) [109]. CuC104/ligand (354) or (357) complexes both provide the desired pyrrolidine cycloadducts (355) or (358) excellent enantioselectivities. However, CuCl04/(354)... 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utilized to obtain highly substituted pyrrolidines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine ylides 100,... 

Hou and co-workers disclosed the asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides with fluoromethyl-substituted nitroalkenes using Cu(MeCN)4C104/Walphos as the catalyst, affording the corresponding optically active 3-(fluoromethyl)-4-nitroproline derivatives in good yield with excellent exoselectivity and enantiocontrol (Scheme 7) [18]. 

Scheme 7 Asymmetric [3-1-2] cycloaddition of azomethine ylides with fluoromethyl-substituted nitroalkenes...

CuOTf-catalyzed synthesis of polysubstituted pyrroles from a-diazoketones, nitroalkenes, and amines was reported by Lu, Wang, and coworkers. The corresponding polysubstituted pyrroles could be obtained in moderate yields using air as the oxidant. This cascade process of the polysubstituted pyrrole formation involves an NH insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide [21] (Scheme 8.9). 

Cinchona alkaloid thiourea catalyst 17 (Figure 37.2) was later employed by Gong el al. to induce the enantio- and diastereoselective 1,3-dipolar cycloaddition of azomethine ylides generated from Schiffbases and nitroalkenes [31]. This process provided straightforward access to chiral highly substituted pyrrolidines with good yields, moderate enantioselectivities (<63% ee), and excellent diastereoselectivities... 

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