Imines, with carboxylic acids 2 + 2 -cycloaddition

An example of 1,3-dipolar cycloaddition involving a thiazole dioxide derivative was described (99T(55)201). A-Benzoyl-(R)-thiazolidin-4-carboxylic acid 5,5-dioxide 120 was cyclized to the bicylic mesoionic thiazolo-oxazolium 5,5-dioxide with Ac O and reacted with the imine 121 in DMF... 

Nowadays, it is an accepted mechanistic model [5, 6] that the photolysis step (which proceeds under thermo-reversible CO insertion) leads to species best described as chromium ketene complexes of type 7 (Scheme 2). Indeed, these intermediates exhibit a ketene-like reactivity they undergo [2 + 2] cycloaddition reactions with olefins, imines and enol ethers, whereas reaction with nucleophiles leads to carboxylic acid derivatives. 

A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-benzyl-3,5-dimethyl-l/f-pyrazole-l-carboxamidine 90 and its polymer-bound variant were described <06S461>. 1,3-Dipolar cycloaddition of polymer-bound alkynes to azomethine imines generated in situ from N-aminopyridine iodides followed by aromatization of the cycloadducts gave polymer-bound pyrazolopyridines that were released from the resin as carboxylic acids with trifluoroacetic acid or as methyl esters with sodium methoxide <06JCO344>. 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

This imidazoline-carboxylate synthesis involves the coupling of four separate cont5)onents (two imines, an acid chloride and carbon monoxide), and the generation of at least five separate bonds, all via a one-pot, palladium catalyzed process. From an analysis of the structure of the imidazoline carboxylate, the individual constituents can be seen (Figure 3). This stmcture might be considered to arise from the dipolar cycloaddition of an imine with a mesoionic l,3-oxazolium-5-oxide (5) intermediate, which itself could be generated from imine, acid chloride and carbon monoxide. Consistent with this potential formulation, performing the catalytic reaction with CO leads to the incorporation of the carbon-13 label into the carboxylate position of 4. 

In the very first application of the tetrazole-based cycloaddition chemistry to proteins [39], a carboxylic acid functionalized tetrazole was coupled to a tripeptide (RGG) and the kinetics of the cycloaddition reaction between the tetrazole-modilied peptide and acrylamide was investigated under the 302-nm photoirradiation condition. The photolysis of the tetrazole-modilied peptide to its corresponding nitrile imine was extremely rapid with a first-order rate constant to be 0.14 s the subsequent cycloaddition with acrylamide proceeded with a second-order rate constant, 2, of 11.0 s . In the next step, the surface Lys residues of lysozyme... 

In a recent example of p-lactam formation dehydration ofphenoxyacetic acid with 2-fluoro-l-methylpyridinium p-toluenesulfbnate in the presence of diaryhmines is proposed to proceed thorough the pyridinium intermediate 142 which leads to phenoxyketene, which reacts by [2 + 2] cycloaddition with the imine forming the product ds-P-lactam (Eqn (4.87)). Similahly propylphosphonic anhydride (T3P) was also successful in carboxylic acid activation (Eqn (4.88)). 

The lactam is an important class of heterocycles and has been investigated due to its potent anti-bacterial activity. Among the multiple synthetic approaches, a [2 -i- 2] cycloaddition of a ketene with an imine, is one method to provide quick access to cis P lactams. The typical prerequisite for these protocols involves the generation of the ketene from an activated carboxylic acid derivative (often an acyl chloride), which limits the scope of this pathway. Lee and coworkers developed a rhodium-catalyzed oxygenative addition reaction that furnishes the acyl chloride equivalent from a more stable terminal alkyne 41. An intermediate rhodium vinylidene then undergoes a [2 -i- 2] cyclization with imines (42) to provide the P-lactam 4. This reaction pathway enables more easily accessible alkynes to be employed as substrates for tran -P-lactam formation. 

Cycloaddition of diverse types of ketenes and imines leading to the formation of P-lactams is reported. The reactions of chiral ketenes with achiral imines, chiral imines with achiral ketenes, chiral imines with chiral ketenes, and catalytic asymmetrical Staudinger reactions have been investigated. In general, a higher level of asymmetric induction is achieved using either chiral ketenes or chiral imines derived from chiral aldehydes in comparison to the use of a chiral imine derived from an achiral aldehyde with an achiral ketene. Both carboxylic acid chlorides and carboxylic acids themselves have been used as ketene precursors. 

SCHEME 7.5 (S)-Indoline-2-carboxylic acid-catalyzed cycloadditions of IV.lV -cyclic azomethine imines with acrolein. 

The role of acid in influencing the cyclization of 14 with imines towards imidazolines products is at present unclear. One possibility is suggested by the work of Ferraccioli and Croce (16), who have shown that the electronic nature of the imine can have a significant influence upon its reactivity with Munchnone. In particular, while N-alkyl substituted imines react with Munchnones to form (3-lactams, more electron poor imines, such as the N-tosyl substituted substrates, have been found to undergo a 1,3-dipolar cyclization with 14 to form imidazoles. (16) In our case, the role of acid may be in protonation of the imine substrate, thereby creating a more electrophilic C=N which can undergo a dipolar cycloaddition with 14 (path A, Scheme 2). Subsequent heterolysis of the C-0 bond in 18, would yield the observed imidazoline-carboxylate 17. 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

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