Imines direct cycloaddition reaction

Scheme 3.25 Direct cycloaddition reaction of imines with cyclohexenone.

The cycloaddition of nitrile oxide 235 to the 4-iminobenzopyran-2-one 236 gave the fully conjugated 1,2,4-oxadiazole 238 directly, a reaction that most likely proceeds via loss of methanol from the intermediate 237 (Scheme 36) <1996JHC967>. Similarly, nitrile oxide 239 reacted with imine 240 to give the 1,2,4-oxadiazole 242 via the nonisolable intermediate 241 <2002PJC1137>. 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Asymmetric 1,3-dipolar cycloaddition reactions have been reviewed, but ongoing research is still vigorous. The effectiveness of 138, a phosphine modified from serine, for synthesizing cyclopentenecarboxylic esters from 2,3-alkadienoic esters and electron-deficient alkenes has been validated.Phosphine-thiourea 139 is useful for directing enan-tioselective combination of allenes and imines. ... 

The same group [50] developed a remarkable enantioselective synthesis of chiral indenylamines 179 via domino Rh(I)-catalyzed C-H activation/cyclization of aryl ketimines 177 and internal alkynes 170 (a formal [3+2] cycloaddition) (Scheme 3.46). A major challenge of this transformation was the requirement of a catalyst that could accommodate the many different steps in the reaction sequence and show selectivity for instance, imine-directed ortho C-H activation/... 

We next turned our attention to l,3 diol2u cycloaddition reactions of nitrilium ylides as a direct approach towards the tetrasubstituted imidazole. Nitrilium ylides have been reported to undergo 1,3-dipolar cycloaddition with a number of dipolarophUes including imines.(/2-i6) Thus we reasoned that if the nitrilium yUde 14 could be formed, then reacted with the imine 4 derived from 2-cUoro-pyridinecarboxaldehyde 15, it might provide the desired imidazole (Scheme 3). 

Same reaction has also been carried out with methyl iodide in place of amine and in the presence of sodium hydride to yield N-methyl-3,4-dihydropyrazino[2,l-b] quinazolin-6-ones. The novel pyrimido[4,5-d]pyrimidine derivatives of biological significance from electron rich 6-[(dimethylamino)methylene]amino uracil undergoes [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides, after elimination of dimethylamine from the (1 1) cycloadducts and oxidative aromatization. This method provides a suitable method for the direct synthesis of pyrimido[4,5-d]pyrimidines in excellent yields, when reaction was carried out in the solid state and under microwave irradiations (Prajapati et al., 2006). 

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

The beta lactam moiety is formed by the 2-1-2 cycloaddition of a ketene with an imine. Thus reaction of the acid chloride (37-7) with the benzylimine from 3-fiirylacrolein (38-2) in the presence of triethylamine goes directly to the azetidone (38-3),... 

Two very elegant alkaloid syntheses basing on intramolecular cycloadditions of imino dienophiles have been published by Grieco and his coworkers. The preparation of ( )-eburnamonine 7-32 is very efficient since imine 7-31, available from (5-valerolactam in a straightforward sequence, is directly converted into the desired alkaloid 7-32 by aza Diels-Alder reaction and subsequent isomerisation of the newly formed double bond. (Fig. 7-8) [506],... 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

Annulation to carbonyl functions has also been achieved with Trost s bifunctional reagents. Whereas the parent silyl acetate (97) yields only simple alkylation products with aldehydes under normal conditions, addition of only a few mole % of trimethyltin acetate to the reaction mixture results in facile formation of methylenetetrahydrofurans Furthermore, excellent diastereoselectivity is observed in the cycloaddition to a galactose-derived aldehyde (125) (equation 136). The tin acetate co-catalyst also promotes addition to relatively unreactive ketone carbonyls, such as in the case of benzofuran (126) and the acetylenic ketone (127) (equations 137, 138). It is remarkable that even the sterically hindered enone (128) reacts preferentially at the ketone function (equation 139). A tributyltin analog (129) of (97) has been used in the stepwise formation of a methylenetetrahydrofuran from aldehydes. Similarly, pyrrolidines can be prepared from the corresponding imines in two steps via a Lewis acid-catalyzed 1,2-addition of the tin reagent, which is then followed by a Pd-catalyzed cyclization (equation 140). Direct formation of pyrrolidine from the imine is possible if one uses a mesylate analog of (97) and a nickel(O) catalyst (equation 141). ... 

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