Cyclic nitrones formation

Formation of functionalized cyclic nitrones via a new reaction intermediate, nitrosoketene, and its development for the synthesis of nonproteinogenic amino acids 99YGK116. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

The reduction of y-nitroketone acetals as in Eq. 6.50 v/ith ammonium formate in the presence of Pd/C gives the correspondmg amines in good yields. However, the reduction ofy-nitro ketones are reduced to cyclic nitrones fEq. 6.51. This reduction is far superior to the classical method using Zn/T4HlCl due to improved yield and simple workup. 

Intramolecular variations of a series of bifunctional derivatives lead to the formation of cyclic nitrones. Many pyrroline /V-oxide derivatives were obtained in the course of intramolecular interaction in situ between carbonyl and hydrox-ylamine groups, resulting from the reduction of a y-nitro group (Scheme 2.31) (Fig. 2.8) (238-253). 

As a result of Ag (I) catalyzed cyclization of allenic oximes (124) and (125), stable five- (126) and six-membered (127) cyclic nitrones were obtained (Scheme 2.46) (298a). Recently, a novel method of pyrroline-type nitrone formation via P-allenyl-oxime cyclization has been described (298b). 

Formation of nitrones can be achieved in the first stage of a Krohnke type reaction in which p-n trosodi methy 1 an dine reacts with 2-oo-bromoacetylphenoxathiin in alkaline medium (336). The synthesis of a series of cyclic nitrones of structure (182) has been achieved by regioselective, and by an unusual [3 + 2] cycloaddition of a-nitrosostyrenes (181) to 1,3-diazabuta-l,3-dienes (180) (Scheme 2.64) (337a). Theoretical studies of the substitution effect at the imine nitrogen on the competitive [3 + 2] and [4 + 2] mechanisms of cycloaddition of simple acyclic imines with nitrosoalkenes have been reported (337b). 

The formation of enantiopure tricyclic compounds takes place by intramolecular 1,3-dipolar cycloadditions of acyclic nitrones to cyclic olefinic fragments (Scheme 2.214a,b) (706, 707a), or of cyclic nitrones to acyclic olefins (Scheme 2.214c) (116). Recently (707),b intramolecular nitrone cycloaddition reactions (according to Scheme 2.211a) have been applied in the synthesis of... 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

It was demonstrated (83) that the reaction of dinitrostyrenes (28) with aryl diazo compounds RR CN2 afford nitronates (24 g) in good yields. These products contain the nitro group at the C-4 atom in the trans position with respect to the substituent at C-5 (if R =H). Since the reaction mechanism remains unknown, the direct formation of cyclic nitronates (24 g) from pyrazolines A without the intermediate formation of cyclopropanes also cannot be ruled out. 

This is responsible for the formation of /V-hydroxyiminium cations (350f-h) as by-products, which was established by silylation of six-membered cyclic nitronates (Scheme 3.205). 

The formation of five-membered cyclic nitronates (404) is explained in terms of ring-chain tautomerism of cationic intermediates A (A=A ). The presence of the alkoxy substituent (R4) at the C-6 atom could stabilize the open form (cation A7), which finally leads to the formation of functionalized five-membered cyclic nitronates (404) probably with the participation of water. 

The reaction of compounds 465 with an excess of aryl isocyanate in acetonitrile at reflux leads to the formation of imidazooxadiazolones 466, via a Beckmann fragmentation that affords a presumed cyclic nitrone intermediate 187 (Equation 107) <1999SC3889>. 

The formation of cyclic nitrones (150) from pericyclic mechanism. Kinetic and computational studies have provided evidence for the involvement of a novel pseudo-pericyclic electrocyclization in the conversion of o-vinylphenyl isocyanates into quinolin-2-ones. " Such reactions have also provided evidence of torquoselectivity in a 6jt system. Hash vacuum thermolysis of triazoles (151) has been found to afford dihydroquinolines (155), presumably by generation of a-oxoketenimines (152) which can undergo a [1,5]-hydrogen shift to the o-quinoid imines (153)7(154) and subsequent electrocyclization (see Scheme 57). 

For the alkynyUiydroxylamines 274 smdied by Holmes (309,311), initial intramolecular 1,3-azaprotiocyclotransfer affords the N-oxides 275 via a 5- or a 6-exo-dig process [Baldwin s terminology (312)], which then tautomerize to the cyclic nitrones (276) (Scheme 1.57). The 1-exo-dig cyclization required for the formation of a seven-membered nitrone (277) by this approach from 278 was found to be disfavored with respect to the alternative reaction of hydroxylamine and alkene 5-exo-trig process) to afford a mixture of the alkynylpyiTolidines 279... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

The intramolecular cycloadditions of cychc nitronates have received much more attention. The cyclic nitronate structure provides three basic modes of intramolecular cycloaddition (Fig. 2.15). Attachment of the tether to the C(3) position of the nitronate results in the formation of a sprro system (sprro mode). However, if the tether is appended to the C(4) position of the nitronate, the dipolar cycloaddition yields a fused ring system (fused mode). Finally, if the tether is attached at any other point of the cyclic nitronate, the cycloadducts obtained will consist of bicyclic structures (bridged mode). 

Perhydropyrrolo[l,2-fc]isoxazoles result from 1,3-dipolar cycloaddition of cyclic nitrones with alkenes. The high regio- and stereoselectivity of this cycloaddition has been used to control the stereochemistry in the synthesis of natural products. As one example, pyrroline N-oxide (70) and 3,4-dimethoxystyrene gave a diastereomeric mixture of pyrroloisoxazoles (71) and (72), in nearly quantitative yield with preferential formation of (71). 

Cyclic nitrones, which are commonly formed by cycloaddition of ketones to nitrosoketene, can also be obtained by pyrolysis of 5-isonitroso-2,2-dimethyl-l,3-dioxane-4,6-dione (73) (isonitroso Mcldrum s acid) in the presence of various ketones. Two possible reaction pathways (Scheme 8) have been proposed previously to account for formation of cyclic nitrones from (73), but the proposed nitrosoketene intermediate could not be observed. Spectroscopic evidence for generation of the nitrosoketene in the gas phase at > 80 °C has now been found and ab initio calculations in support of the vibrational frequencies observed have been reported.35... 

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