Cycloaddition of imines

In 2007, a novel C2-symmetric diphenylthiophosphoramide ligand was found to be a fairly efficient chiral ligand for the Cu(I)-promoted 1,3-dipolar cycloaddition of imines and pyrrole-2,5-dione derivatives to give the corresponding adducts in moderate to good enantioselectivities and good yields (Scheme 10.14). ... 

The synthesis of nitrogen containing heterocyclic systems by photocylo-addition processes is virtually limited to examples involving [ 2 + 2] cycloaddition of imines, nitriles, and azo compounds. Successful additions are few in number and the requirements for success uncertain. The reactions do not proceed with the facility with which carbonyl containing compounds undergo photocycloaddition to alkenes to give oxetans, and various explanations have been advanced to account for this observed lack of reactivity.226... 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

A number of cycloadditions of imines or imino compounds with a variety of alkenes, including allenes (88HCA1025), vinyl ethers (88TL547), methyl acrylate (86ZOR636), ketene acetals (87JOC365) and electrophilic alkenes (85T1953), afford functionalized azetidines. 

In 2004, Troisi and coworkers have reported the palladium-catalyzed [2+2] carbo-nylative cycloaddition of imines to allyl halides of different structures to give (3-lactams (Scheme 65), [159]. 

The formal [2+2]-cycloaddition of imines to ketenes forms P-lactams. 

The formation of tetrahydropyridines by reaction of a suitable diene with an imino dienophile is a reaction known since more than half a century [177] and has been intensively studied. In general, the imines react as the electron-deficient component and their reactivity strongly depends on the electron density which may be tuned by activating or deactivating moieties. However, exceptions from this rule are possible as found by Padwa et al. [178]. They described cycloadditions of imines to bis(phenylsulfonyl)-1,3-butadienes. 

Another common method for the synthesis of 2-azetidinones is the cycloaddition of imines with ketenes, which is known as the Staudinger reaction . Although commonly described as a [2 + 2]... 

Thiazetidine 1,1-dioxides (-sultams) are prepared by cyclization of appropriate precursors (e.g., Scheme 20) <1975BSF(2)807> or via [Z + Z cycloaddition of imines with sulfenes 32, generated in situ from the corresponding sulfonyl chloride and an organic base (Scheme 21) . 

Hetero-Diels-Alder reactions have been extensively used in organic synthesis. Cycloadditions of imines 184 with maleimide 185 (Scheme 34) generated pyrazo-lopyridines 186 [71]. These compounds were further elaborated as shown in Scheme 34 to provide pyrazolopyridopyridazines 187 which were potent and selective PDE5 inhibitors [72]. Compound 188 was selected for further evaluation. This compound had superior selectivity towards other PDE isoenzymes and was found to be efficacious in an anesthetized rabbit model of erectile function. 

While cycloadditions of imines with ketenes or their precursors often produce cis P-lactams, the corresponding reactions of keteniminium salts are trans stereoselective (equations 70 and 71). 0 222 It is not clear whether the trans stereoselectivity is kinetic or results from an equilibration of 2-azetidiniminium salts under the basic conditions used in both cycloaddition and hydrolysis steps. 

Some results described by Holmes and coworkers are consistent with the stereochemical outcome of equation (3). Cycloaddition of imine (10) with 2-trimethylsiloxy-l,3-cyclohexadiene afforded a mixture of adducts (11) and (12) with the exo isomer predominating (equation 4). In this example, only a single regioisomer was detected. 

Immmium salts constitute a class of generally reactive hetero dienophiles. During the past several years a number of examples have been describe of [4 + 2] cycloadditions of imines with oxygenated dienes under Lewis acid catalysis. - These reactions probably involve intermediate immonium salts which react regio- and often stereo-selectively with these electron-rich 1,3-dienes. Danishefsky and coworkers have provided several instances of this type of process. Equation (18) shows an approach to... 

The cycloaddition of imines to the metal-carbon triple bond in the cationic rhenium carbyne complex 263 was reported by Geoffroy and... 

Apart from numerous similar 3-lactam syntheses,the very promising photolytic [2 + 2] cycloaddition of imines (or the corresponding hexahydro-l,3,5-triazenes respectively)to chromium carbene complexes that leads to norcardicin precursors merits special interest. 

A stereoselective synthesis of aminoalkyl-substituted P-lactams (41) has been developed, the key step of which is [2+2] cycloaddition of imines to ketenes generated photochemically from diazoketones (42), which are derived from protected a-amino acids. A number of steroidal diazoketones related to progesterone have been synthesized as potential photoaffinity labelling reagents for the mineralocorticoid receptor. ... 

Among the cycloaddition reactions which lead to imidazole products is the [3 + 2] cycloaddition of imines to 2-azaallenyl radical cations (derived from azirines by photolysis) which yields 1-substituted imidazoles <91AG(E)1336,93CB543). Similar addition of 2-azallyl anions (made by deprotonation of A-alkylated Schilf bases) to aromatic nitriles can give rise to either 3-imidazolines or imidazoles depending on the substitution pattern in the azaallyl species (229) <83CB492>. These reactions have been reviewed (Scheme 164) <90CHE1>. 

The stereoselectivity in the cycloadditions of imines 176 and 179 is only modest, and is probably controlled more by steric than by electronic effects [63 b, 65]. Examples of the kinetic stereochemical outcome of cycloaddition with chloral- and fluoral-derived N-sulfonyl imines and cyclic dienes are shown in Eq. (37)-(39) [65]. 

Lower levels of asymmetric induction are typically seen in the cycloadditions of ketenes with imines bearing chiral substituents on the nitrogen, although in exceptional cases excellent results are obtained. Cycloaddition of imine 23 (X = F), obtained from fluoroacetaldehyde and 1-phenylethylamine with phthalimidoketene, gives a 59% yield of m-/Mactam 24 in 81 19 d.r.68. Imine 23 (X = Cl) gives a 74% yield of cw-/f-lactam 24 in 90 10 d.r.69. 

In a similar fashion, resin-bound imines 109 were employed to prepare a library of structurally diverse P-lactams by [2+2] cycloaddition reactions with different ketenes. Thus, as shown in Scheme 4.1.22, amino acids tethered to the acid labile Sasrin resin (103) were condensed quantitatively to imines 109 by using a large excess of alkyl, aryl, or a,P-unsaturated aldehydes in a mixture of trimethylorthoformate and dichloromethane. Optimisation studies of the [2+2] cycloaddition step, showed that conversion to P-lactams 110 could only take place by slow addition of acid chlorides to a suspension of the imine resin at 0°C in the presence of triethylamine. By using a large excess of ketene at high concentration, the cycloaddition of imines derived from even sterically hindered amino acids [e.g. valine) could be carried out with full conversion. After mild TFA cleavage from the resin and preparative HPLC purification, the p-lactams 111, 112 were isolated in yields of 55-97%. 

Scheme 4.11 BTMG (2) catalysed 1,3-cycloaddition of imine with 2(5ff)-furanone...

Similarly, the planar chiral tricarbonylchromium complexes of ortho substituted benzaldimines are useful for a variety of stereoselective cycloaddition reactions. For example, the benzaldimine chromium complexes gave aza-Diels-Alder product, 2,3-dihydro-4-pyridinone chromium complexes with high diastereoselectivity by reaction with Danishefsky s diene (Eq. 18) [11,17,18]. The high diastereoselectivity of the cycloadducts is also based on the preferred antz-conformation of the starting benzaldimine chromium complexes as well as the planar chiral benzaldehyde chromium complexes. The cycloaddition of imines having arene chromium complex at the remote position with Danishefsky s diene underwent smoothly in good yields, but the diastereoselectivity was low (Eq. 19) [17]. 

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