1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with Carbonyl Dipolarophiles Yielding Oxazolidine Derivatives

We provide a comprehensive account of the 1,3-dipolar cycloaddition reactions of azomethine ylides with carbonyl dipolarophiles. Many different azomethine ylides have been studied, including stabilized and non-stabilized ylides. Of the carbonyl dipolarophiles, aldehydes including formaldehyde are the most studied, although there are now examples of cycloadditions with ketones, ketenes and carboxyl systems, in particular isatoic anhydrides and phthalic anhydrides. Intramolecular cycloadditions with esters can also occur under certain circumstances. The oxazolidine cycloadducts undergo a range of reactions triggered by the ring-opening of the oxazolidine ring system.


Review of Reactions of Azomethine Ylides with Carbonyl Compounds
Each section of this review refers to different types of azomethine ylide and/or different synthetic methods used to form the azomethine ylide. Within each section, examples of carbonyl dipolarophiles such as formaldehyde, aldehydes, ketones and anhydrides are provided, in that order.

Reactions with Ylides Formed from Ring-Opening of Aziridines
It is fitting that Huisgen in 1967 disclosed the first 1,3-dipolar cycloaddition reaction between an azomethine ylide generated by thermal carbon-carbon bond cleavage of an aziridine ring and a carbonyl group. In this brief account, a trans-2,3-dimethoxycarbonyl-1-arylaziridine was heated in the presence of benzaldehyde to give a high yield of the corresponding oxazolidine as three stereoisomers [49]. A more detailed report of this work, published in 1971, described the reaction between trans-2,3-dimethoxycarbonyl-1-(4-methoxyphenyl)aziridine (15) and an excess of benzaldehyde (2a) to form three diasteromeric oxazolidines 17a-c. When heated, trans-aziridine 15 underwent a conrotatory ring-opening (according to Woodward-Hoffmann theory) to generate cis-azomethine ylide 16a, which primarily underwent a cycloaddition reaction with the carbonyl group of 2a to form cis-2,4-oxazolidine 17a, but also interconverted to the more stable trans-isomer 16b, which then reacted with 2a to form lesser amounts of the trans-2,4-oxazolidines 17b and 17c (Scheme 2). Aziridine 15 also underwent ring-opening and diastereoselective cycloaddition with the ketone group within diethyl ketomalonate, to predominantly form the corresponding cis-2,4-oxazolidine (not shown) [50].

Review of Reactions of Azomethine Ylides with Carbonyl Compounds
Each section of this review refers to different types of azomethine ylide and/or different synthetic methods used to form the azomethine ylide. Within each section, examples of carbonyl dipolarophiles such as formaldehyde, aldehydes, ketones and anhydrides are provided, in that order.
In 1970 Lown and co-workers disclosed that a variety of 2-benzoylaziridines 23 underwent thermal [3 + 2] cycloaddition reactions with a range of aromatic aldehydes 2 to give mixtures of the diastereomeric oxazolidines 25 and 26 (Scheme 4, Table 2).    When trichloroacetaldehyde (2g) was used as the dipolarophile, the corresponding trans-4,5oxazolidines 25k-o were obtained exclusively ( Table 2, . The orientation of the addition was confirmed by specific deuterium-labelling experiments, and the preference for the trans-4,5isomer was rationalized by considering that the intermediate cis-and trans-azomethine ylides had time to equilibrate to mostly the more stable trans-azomethine ylide 24 prior to addition (owing to the sluggish dipolarophilic activity of the carbonyl bond). The addition of the azomethine ylide 24 to the dipolarophiles 2 then occurred in such a manner so as to predominantly form the trans-4,5oxazolidines [54,55]. Two years prior, Lown's research group also reported that azomethine ylides, derived from 3-aroyl-and 3-acylaziridines 23, added to the carbonyl group of diphenylcyclopropenone (3a). This afforded intermediate oxazolidines 27 that were postulated to open to give azomethine ylides 28 and subsequently close onto the adjacent carbonyl group to afford 4-aroyl-and 4-acyl-4oxazolines 29 (Scheme 5, Table 3) [56,57].  6 3-NO2-C6H4 C6H11 Ph f (27) 1 7 4-NO2-C6H4 C6H11 Ph g (64) Scheme 4. Cycloaddition of trans-azomethine ylide 24, generated from 2-benzoylaziridines 23, to aldehydes 2. When trichloroacetaldehyde (2g) was used as the dipolarophile, the corresponding trans-4,5-oxazolidines 25k-o were obtained exclusively ( Table 2, . The orientation of the addition was confirmed by specific deuterium-labelling experiments, and the preference for the trans-4,5-isomer was rationalized by considering that the intermediate cisand trans-azomethine ylides had time to equilibrate to mostly the more stable trans-azomethine ylide 24 prior to addition (owing to the sluggish dipolarophilic activity of the carbonyl bond). The addition of the azomethine ylide 24 to the dipolarophiles 2 then occurred in such a manner so as to predominantly form the trans-4,5-oxazolidines [54,55]. Two years prior, Lown's research group also reported that azomethine ylides, derived from 3-aroyl-and 3-acylaziridines 23, added to the carbonyl group of diphenylcyclopropenone (3a). This afforded intermediate oxazolidines 27 that were postulated to open to give azomethine ylides 28 and subsequently close onto the adjacent carbonyl group to afford 4-aroyl-and 4-acyl-4-oxazolines 29 (Scheme 5, Table 3) [56,57]. oxazolines 29 (Scheme 5, Table 3) [56,57]. Lown and Akhtar went on to examine the thermolysis of cis-3-benzoylaziridine 30 in dry acetonitrile, which predominantly formed an 80:20 mixture of the corresponding stereoisomeric  Lown and Akhtar went on to examine the thermolysis of cis-3-benzoylaziridine 30 in dry acetonitrile, which predominantly formed an 80:20 mixture of the corresponding stereoisomeric oxazolidines 31 and 32, respectively, by an autocatalytic partial hydrolytic fragmentation of one molecule of aziridine 30 to give 3-nitrobenzaldehyde (2h) and subsequent 1,3-dipolar cycloaddition of 2h to the azomethine ylide formed from ring opening of another molecule of aziridine 30. A marked difference in reactivity was observed for the corresponding trans-aziridine isomer, which underwent mainly hydrolytic ring-cleavage processes, and only small amounts of each oxazolidine were isolated. In contrast, both cisand trans-3-carbomethoxyaziridines 33 formed the corresponding stereoisomeric oxazolidines 34 and 35 in identical ratios and yields by an analogous partial hydrolytic fragmentation/cycloaddition process (Scheme 6) [58]. The thermolysis of an N-unsubstituted aziridine, dimethyl 3-[(4-nitro)phenyl]aziridine-2,2-dicarboxylate, in toluene also lead to an oxazolidine, albeit in low yield, from a partial fragmentation/cycloaddition process [59]. molecule of aziridine 30 to give 3-nitrobenzaldehyde (2h) and subsequent 1,3-dipolar cycloaddition of 2h to the azomethine ylide formed from ring opening of another molecule of aziridine 30. A marked difference in reactivity was observed for the corresponding trans-aziridine isomer, which underwent mainly hydrolytic ring-cleavage processes, and only small amounts of each oxazolidine were isolated. In contrast, both cis-and trans-3-carbomethoxyaziridines 33 formed the corresponding stereoisomeric oxazolidines 34 and 35 in identical ratios and yields by an analogous partial hydrolytic fragmentation/cycloaddition process (Scheme 6) [58]. The thermolysis of an N-unsubstituted aziridine, dimethyl 3-[(4-nitro)phenyl]aziridine-2,2-dicarboxylate, in toluene also lead to an oxazolidine, albeit in low yield, from a partial fragmentation/cycloaddition process [59]. Scheme 6. The partial fragmentation/cycloaddition reactions of aziridines 30 and 33.

Reactions with Ylides Formed from Decarboxylative Condensation of Secondary α-Amino Acids and Carbonyl Compounds
The decarboxylative condensation reaction of secondary α-amino acids and carbonyl compounds is a convenient method to generate a wide variety of non-stabilized azomethine ylides. The first evidence for the generation of a non-stabilized azomethine ylide in this manner was reported by Rizzi in 1970. This work described the decarboxylation of sarcosine (47) in an excess of benzaldehyde (2a) to form the corresponding azomethine ylide 48, which underwent a 1,3-dipolar cycloaddition reaction with a second molecule of benzaldehyde (2a) to form the oxazolidine 49, albeit in low yield (Scheme 11). A similar reaction between sarcosine and excess benzophenone gave an array of products derived from both resonance forms of the corresponding azomethine ylide, which included a small isolable amount of an oxazolidine product (not shown) [65].

Reactions with Ylides Formed from Decarboxylative Condensation of Secondary α-Amino Acids and Carbonyl Compounds
The decarboxylative condensation reaction of secondary α-amino acids and carbonyl compounds is a convenient method to generate a wide variety of non-stabilized azomethine ylides. The first Molecules 2016, 21, 935 9 of 54 evidence for the generation of a non-stabilized azomethine ylide in this manner was reported by Rizzi in 1970. This work described the decarboxylation of sarcosine (47) in an excess of benzaldehyde (2a) to form the corresponding azomethine ylide 48, which underwent a 1,3-dipolar cycloaddition reaction with a second molecule of benzaldehyde (2a) to form the oxazolidine 49, albeit in low yield (Scheme 11). A similar reaction between sarcosine and excess benzophenone gave an array of products derived from both resonance forms of the corresponding azomethine ylide, which included a small isolable amount of an oxazolidine product (not shown) [65]. Scheme 10. Reaction of N-tosylaziridine 44a with (4-methoxyphenyl)propiolaldehyde (2j) to form 1,3-oxazolidine 46a.

Reactions with Ylides Formed from Decarboxylative Condensation of Secondary α-Amino Acids and Carbonyl Compounds
The decarboxylative condensation reaction of secondary α-amino acids and carbonyl compounds is a convenient method to generate a wide variety of non-stabilized azomethine ylides. The first evidence for the generation of a non-stabilized azomethine ylide in this manner was reported by Rizzi in 1970. This work described the decarboxylation of sarcosine (47) in an excess of benzaldehyde (2a) to form the corresponding azomethine ylide 48, which underwent a 1,3-dipolar cycloaddition reaction with a second molecule of benzaldehyde (2a) to form the oxazolidine 49, albeit in low yield (Scheme 11). A similar reaction between sarcosine and excess benzophenone gave an array of products derived from both resonance forms of the corresponding azomethine ylide, which included a small isolable amount of an oxazolidine product (not shown) [65]. Fifteen years later, Orsini and co-workers reported a study on the generation of azomethine ylides from an aldehyde-induced decarboxylation of secondary α-amino acids, and their subsequent 1,3-dipolar cycloadditions to a second mole of aldehyde to form oxazolidines [66]. A more detailed account of their work appeared in 1988, where proline (50) was reacted with various aromatic aldehydes 2 to afford, with complete regioselectivity, the hexahydropyrrolo[2,1-b]oxazoles 52 and 53, with the trans-2,3-oxazolidine 52 being either the exclusive or major stereoisomer formed [67][68][69]. The stereoselectivity of the cycloaddition was governed by both the ylide stereochemistry, with the anti-azomethine ylide 51 being favored, and the mutual orientation of the dipole and dipolarophile (Scheme 12, Table 7). The reaction of N-substituted glycine derivatives 47 or 54 with aldehydes 2a and 2i was also investigated, with complex mixtures of the respective 4,5-and 2,5-disubstituted-1,3oxazolidines 55 and 56 being isolated (Scheme 13, Table 8). When this method was applied to N-benzylalanine and aldehydes 2a or 2i, complex mixtures of regio-and stereoisomeric oxazolidines were also obtained. Scheme 12. Cycloaddition of azomethine ylides 51, generated from proline (50) and aromatic aldehydes 2, to a second mole of aldehyde. Fifteen years later, Orsini and co-workers reported a study on the generation of azomethine ylides from an aldehyde-induced decarboxylation of secondary α-amino acids, and their subsequent 1,3-dipolar cycloadditions to a second mole of aldehyde to form oxazolidines [66]. A more detailed account of their work appeared in 1988, where proline (50) was reacted with various aromatic aldehydes 2 to afford, with complete regioselectivity, the hexahydropyrrolo[2,1-b]oxazoles 52 and 53, with the trans-2,3-oxazolidine 52 being either the exclusive or major stereoisomer formed [67][68][69]. The stereoselectivity of the cycloaddition was governed by both the ylide stereochemistry, with the anti-azomethine ylide 51 being favored, and the mutual orientation of the dipole and dipolarophile (Scheme 12, Table 7). The reaction of N-substituted glycine derivatives 47 or 54 with aldehydes 2a and 2i was also investigated, with complex mixtures of the respective 4,5-and 2,5-disubstituted-1,3-oxazolidines 55 and 56 being isolated (Scheme 13, Table 8). When this method was applied to N-benzylalanine and aldehydes 2a or 2i, complex mixtures of regio-and stereoisomeric oxazolidines were also obtained. Scheme 10. Reaction of N-tosylaziridine 44a with (4-methoxyphenyl)propiolaldehyde (2j) to form 1,3-oxazolidine 46a.

Reactions with Ylides Formed from Decarboxylative Condensation of Secondary α-Amino Acids and Carbonyl Compounds
The decarboxylative condensation reaction of secondary α-amino acids and carbonyl compounds is a convenient method to generate a wide variety of non-stabilized azomethine ylides. The first evidence for the generation of a non-stabilized azomethine ylide in this manner was reported by Rizzi in 1970. This work described the decarboxylation of sarcosine (47) in an excess of benzaldehyde (2a) to form the corresponding azomethine ylide 48, which underwent a 1,3-dipolar cycloaddition reaction with a second molecule of benzaldehyde (2a) to form the oxazolidine 49, albeit in low yield (Scheme 11). A similar reaction between sarcosine and excess benzophenone gave an array of products derived from both resonance forms of the corresponding azomethine ylide, which included a small isolable amount of an oxazolidine product (not shown) [65]. Fifteen years later, Orsini and co-workers reported a study on the generation of azomethine ylides from an aldehyde-induced decarboxylation of secondary α-amino acids, and their subsequent 1,3-dipolar cycloadditions to a second mole of aldehyde to form oxazolidines [66]. A more detailed account of their work appeared in 1988, where proline (50) was reacted with various aromatic aldehydes 2 to afford, with complete regioselectivity, the hexahydropyrrolo[2,1-b]oxazoles 52 and 53, with the trans-2,3-oxazolidine 52 being either the exclusive or major stereoisomer formed [67][68][69]. The stereoselectivity of the cycloaddition was governed by both the ylide stereochemistry, with the anti-azomethine ylide 51 being favored, and the mutual orientation of the dipole and dipolarophile (Scheme 12, Table 7). The reaction of N-substituted glycine derivatives 47 or 54 with aldehydes 2a and 2i was also investigated, with complex mixtures of the respective 4,5-and 2,5-disubstituted-1,3oxazolidines 55 and 56 being isolated (Scheme 13, Table 8). When this method was applied to N-benzylalanine and aldehydes 2a or 2i, complex mixtures of regio-and stereoisomeric oxazolidines were also obtained. Scheme 12. Cycloaddition of azomethine ylides 51, generated from proline (50) and aromatic aldehydes 2, to a second mole of aldehyde. Scheme 12. Cycloaddition of azomethine ylides 51, generated from proline (50) and aromatic aldehydes 2, to a second mole of aldehyde.   Grigg and co-workers found that cyclic secondary amino acid 57 reacted regio-and stereo-specifically with 2-pyridylcarboxaldehyde (2k), via the anti-azomethine ylide 58, to give the corresponding oxazolidine 59 in good yield. In a similar manner, β-carboline 60 reacted with aldehyde 2k to give oxazolidine 61 (Scheme 14). In further examples, thiazolidine-4-carboxylic acid (62) reacted regiospecifically with 2k to give a 2:1 mixture of 63 and 64, and proline (50) reacted with phenylglyoxal (2l) to give a 5:1 mixture of 65 and 66 (Scheme 15) [70,71]. Proline (50) also reacted with 2-(allyloxy)benzaldehyde to afford an azomethine ylide that underwent intermolecular cycloaddition with the aldehyde moiety of another equivalent of 2-(allyloxy)benzaldehyde to give the corresponding hexahydropyrrolo[2,1-b]oxazole in 51% yield rather than intramolecular cycloaddition with the unactivated internal olefin [72]. Furthermore, proline underwent a step-wise decarboxylative condensation with 2-phenylbenzaldehyde followed by cycloaddition with the same aldehyde to give the corresponding oxazolidine as a single isomer in low yield [73]. L-Proline reacted with (a) ethyl pyruvate to give the corresponding hexahydropyrrolo[2,1-b]oxazole derivative as a mixture of diastereomers in high yield [74]; and (b) with 4-nitrobenzaldehyde in a Ce(IV) oxide catalyzed cycloaddition reaction [75]. The reaction of sarcosine or L-proline with heteroaryl-2-carboxaldehydes afforded inseparable diastereomeric mixtures of the corresponding decarboxylative condensationcycloaddition products [76].  Grigg and co-workers found that cyclic secondary amino acid 57 reacted regio-and stereo-specifically with 2-pyridylcarboxaldehyde (2k), via the anti-azomethine ylide 58, to give the corresponding oxazolidine 59 in good yield. In a similar manner, β-carboline 60 reacted with aldehyde 2k to give oxazolidine 61 (Scheme 14). In further examples, thiazolidine-4-carboxylic acid (62) reacted regiospecifically with 2k to give a 2:1 mixture of 63 and 64, and proline (50) reacted with phenylglyoxal (2l) to give a 5:1 mixture of 65 and 66 (Scheme 15) [70,71]. Proline (50) also reacted with 2-(allyloxy)benzaldehyde to afford an azomethine ylide that underwent intermolecular cycloaddition with the aldehyde moiety of another equivalent of 2-(allyloxy)benzaldehyde to give the corresponding hexahydropyrrolo[2,1-b]oxazole in 51% yield rather than intramolecular cycloaddition with the unactivated internal olefin [72]. Furthermore, proline underwent a step-wise decarboxylative condensation with 2-phenylbenzaldehyde followed by cycloaddition with the same aldehyde to give the corresponding oxazolidine as a single isomer in low yield [73]. L-Proline reacted with (a) ethyl pyruvate to give the corresponding hexahydropyrrolo[2,1-b]oxazole derivative as a mixture of diastereomers in high yield [74]; and (b) with 4-nitrobenzaldehyde in a Ce(IV) oxide catalyzed cycloaddition reaction [75]. The reaction of sarcosine or L-proline with heteroaryl-2-carboxaldehydes afforded inseparable diastereomeric mixtures of the corresponding decarboxylative condensation-cycloaddition products [76].
An intramolecular variant that involves the generation of non-stabilized azomethine ylides from the condensation of α-amino acids with aldehydes bearing a tethered carbonyl group has also been reported. Thus, the azomethine ylide generated from sarcosine (47) and 5-oxo-7-phenyl-6-heptenal (2q), reacted exclusively at the internal carbonyl moiety to produce regio-and stereoselectively cycloadduct 105 in 82% yield. Similarly, 2-phenyl-4-thiazolidinecarboxylic acid (106) reacted with 2q and 2r to produce 109a and 109b, respectively, as single stereoisomers in good yields. The trans-configuration between 4a-H and 8a-H was due to the selective participation of the Z,E-ylidic forms 108, which was presumably derived from the stereospecific decarboxylation of the more thermodynamically stable bicyclic lactones 107 (Scheme 26) [100].

Reactions of Ylides from the Condensation of Secondary Alpha Amino Acid Esters with Carbonyl Compounds
A simple approach to generate stabilized azomethine ylides is via the reaction of a secondary amine, bearing an α-carboxylic ester functionality, with an aldehyde, and the subsequent deprotonation of the resultant iminium ion. The first example of an azomethine ylide being generated in this manner Scheme 31. Cycloaddition of azomethine ylide 126, generated from pyrrolidine (124) and aromatic aldehydes 2, to a second molecule of aldehyde 2.

Reactions of Ylides from the Condensation of Secondary Alpha Amino Acid Esters with Carbonyl Compounds
A simple approach to generate stabilized azomethine ylides is via the reaction of a secondary amine, bearing an α-carboxylic ester functionality, with an aldehyde, and the subsequent deprotonation of the resultant iminium ion. The first example of an azomethine ylide being generated in this manner and participating in a 1,3-dipolar cycloaddition with a carbonyl bond to form an oxazolidine ring, was published by Joucla and co-workers in 1987 [108]. In this report, the condensation of allylic α-amino esters 128 with paraformaldehyde (2m) presumably gave rise to the corresponding azomethine ylides 129, which underwent intermolecular cycloadditions with a second equivalent of paraformaldehyde (2m) to afford oxazolidines 130 in good yields. When these oxazolidines were subjected to flash vacuum thermolysis (FVT), a cycloreversion process occurred to regenerate azomethine ylide 129, which underwent an intramolecular cycloaddition reaction with the adjacent alkene to furnish pyrrolidines 131 (Scheme 32, Table 18). and participating in a 1,3-dipolar cycloaddition with a carbonyl bond to form an oxazolidine ring, was published by Joucla and co-workers in 1987 [108]. In this report, the condensation of allylic α-amino esters 128 with paraformaldehyde (2m) presumably gave rise to the corresponding azomethine ylides 129, which underwent intermolecular cycloadditions with a second equivalent of paraformaldehyde (2m) to afford oxazolidines 130 in good yields. When these oxazolidines were subjected to flash vacuum thermolysis (FVT), a cycloreversion process occurred to regenerate azomethine ylide 129, which underwent an intramolecular cycloaddition reaction with the adjacent alkene to furnish pyrrolidines 131 (Scheme 32, Table 18).

Scheme 32.
Cycloaddition of azomethine ylide 129, generated from allylic α-amino esters 128 and paraformaldehyde (2m), to a second molecule of paraformaldehyde (2m), and subsequent FVT-induced cycloreversion-intramolecular cycloaddition. Scheme 32. Cycloaddition of azomethine ylide 129, generated from allylic α-amino esters 128 and paraformaldehyde (2m), to a second molecule of paraformaldehyde (2m), and subsequent FVT-induced cycloreversion-intramolecular cycloaddition. Around the same time, Joucla and co-workers reported that the azomethine ylide 133, prepared in situ from the condensation of pipecolic acid ethyl ester (132) and benzaldehyde (2a) underwent a 1,3-dipolar cycloaddition with a second molecule of benzaldehyde (2a) to form a 70:30 mixture of the oxaindolizidines 134a and 134b, respectively (Scheme 33) [109]. The stereoselectivity of the cycloaddition reaction was governed by both the conformation of the ylide, and the orientation at which the dipole and dipolarophile approached. Furthermore, the same workers disclosed the synthesis of a number of oxazolidines derived from reactions between proline, sarcosine and N-benzylglycinate methyl esters and two molar equivalents of formaldehyde or benzaldehyde [110]. Scheme 32. Cycloaddition of azomethine ylide 129, generated from allylic α-amino esters 128 and paraformaldehyde (2m), to a second molecule of paraformaldehyde (2m), and subsequent FVT-induced cycloreversion-intramolecular cycloaddition. Around the same time, Joucla and co-workers reported that the azomethine ylide 133, prepared in situ from the condensation of pipecolic acid ethyl ester (132) and benzaldehyde (2a) underwent a 1,3-dipolar cycloaddition with a second molecule of benzaldehyde (2a) to form a 70:30 mixture of the oxaindolizidines 134a and 134b, respectively (Scheme 33) [109]. The stereoselectivity of the cycloaddition reaction was governed by both the conformation of the ylide, and the orientation at which the dipole and dipolarophile approached. Furthermore, the same workers disclosed the synthesis of a number of oxazolidines derived from reactions between proline, sarcosine and N-benzylglycinate methyl esters and two molar equivalents of formaldehyde or benzaldehyde [110]. The reaction between L-proline alkyl esters 135 and aromatic aldehydes 2 generated the azomethine ylides 136, which were trapped by a second aldehyde molecule to give mostly mixtures of the oxapyrrolizidines 137a, 137b and 138 (Scheme 34, Table 19). The oxapyrrolizidines were prone to cycloreversion to regenerate azomethine ylides 136, and in the presence of a range of conjugated nitroolefins underwent cycloaddition to afford the corresponding pyrrolizidines [111]. A number of reactions of N-alkylated glycine ethyl esters and paraformaldehyde have also been reported, which were conducted neat and under microwave irradiation, to afford the corresponding oxazolidines in moderate The reaction between L-proline alkyl esters 135 and aromatic aldehydes 2 generated the azomethine ylides 136, which were trapped by a second aldehyde molecule to give mostly mixtures of the oxapyrrolizidines 137a, 137b and 138 (Scheme 34, Table 19). The oxapyrrolizidines were prone to cycloreversion to regenerate azomethine ylides 136, and in the presence of a range of conjugated nitroolefins underwent cycloaddition to afford the corresponding pyrrolizidines [111]. A number of reactions of N-alkylated glycine ethyl esters and paraformaldehyde have also been reported, which were conducted neat and under microwave irradiation, to afford the corresponding oxazolidines in moderate yield [112]. During a reaction involving sarcosine methyl ester, formaldehyde and N-ethyl maleimide, the azomethine ylide generated from sarcosine methyl ester and formaldehyde was trapped by a second molecule of formaldehyde to give very small amounts of the corresponding oxazolidine cycloadduct [98]. yield [112]. During a reaction involving sarcosine methyl ester, formaldehyde and N-ethyl maleimide, the azomethine ylide generated from sarcosine methyl ester and formaldehyde was trapped by a second molecule of formaldehyde to give very small amounts of the corresponding oxazolidine cycloadduct [98].   Harwood and co-workers have reported the diastereoselective synthesis of bicyclic oxazolidines via 1,3-dipolar cycloaddition reactions of azomethine ylides derived from the condensation of 5-(S)-phenylmorpholine-2-one (139) with aldehydes 2, and their subsequent trapping by the carbonyl bond of a second equivalent of the aldehyde 2. Thus, chiral morpholinone 139 reacted with aldehydes 2 to generate stabilized anti-azomethine ylides 140, which underwent highly diastereocontrolled cycloadditions with a second aldehyde 2 to afford cycloadducts 141. The high stereocontrol was rationalized by cycloaddition mode A involving the aldehyde dipolarophile approaching the least hindered side of the anti-azomethine ylide, and from the face opposite the 5-phenyl substituent (Scheme 35, Table 20). Subsequent hydrogenolysis of cycloadducts 141 formed the corresponding homochiral β-hydroxy-α-amino acids [113][114][115]. When morpholinone 139 was condensed with two equivalents of (S)-glyceraldehyde acetonide 142, a cycloaddition occurred that was diastereochemically 'matched' in both the ylide generation and trapping steps such that cycloadduct 143 was formed exclusively. Sequential hydrolysis and hydrogenolysis of cycloadduct 143 afforded polyoxamic acid 144 in an enantiomerically pure fashion (Scheme 35). In the same manner, the opposite enantiomer of polyoxamic acid was obtained by reacting (R)-139 with (R)-142, followed by sequential degradation of the cycloadduct [116]. Furthermore, a chiral azomethine ylide, derived from morpholinone 139 and acetophenone dimethyl acetal (145), underwent Lewis acid-promoted cycloaddition with 4-nitrobenzaldehyde (2i) to afford anti-exo 146a and syn-exo 146b cycloadducts in 42% and 18%, respectively. Hydrogenolysis of either cycloadduct afforded the same product, (2S,3R)-2-amino-3-hydroxy-3-(4-aminophenyl)propanoic acid (147) (Scheme 35), which confirmed that 146a and 146b were epimeric at C-9, the stereochemistry was retained at C-7, and that both synand anti-ylides were involved in the cycloaddition [115,117]. Having developed this methodology, Harwood's research group also prepared enantiopure long chain threo-2-amino-3-hydroxyesters via chiral azomethine ylides derived from the reaction of 5-(R)-phenylmorpholine-2-one with long chain aldehydes, and their subsequent trapping with a second equivalent of aldehyde [118].

Reactions with Ylides Formed from Silylmethylamines and Related Reagents
A wide range of azomethine ylides generated from silylmethylamine reagents have been explored in reactions with carbonyl dipolarophiles.

Desilylation of (Trimethylsilylmethyl)iminium Ions
Padwa demonstrated that non-stabilized azomethine ylides formed by desilylation of N-(trimethylsilylmethyl)-immonium ions, a process initially developed by Vedejs [121], react with aldehydes 2 [122]. The reaction of N-(trimethylsilylmethyl)benzamide 154 with methyl triflate afforded the trimethylsilylmethyl iminium ion 155, which on treatment with CsF produced azomethine ylide 156, and in the presence of 3-nitrobenzaldehyde (2h) afforded cycloadduct 157 as the exclusive product, indicating a highly regioselective process (Scheme 38). The regioselectivity was determined by a combination of spectroscopic analyses and chemical transformation into a known derivative, however, no comment was made about the stereoselectivity. The exclusive formation of the isolated regioisomer was rationalised to be the result of the union of the larger azomethine ylide HOMO coefficient on the unsubstituted carbon of the ylide 156 with that of the larger dipolarophile LUMO coefficient on the carbon atom of the carbonyl group of the aldehyde 2h. Scheme 38. Cycloaddition of an azomethine ylide, generated from desilylation of a N-(trimethylsilylmethyl)-immonium ion, with 3-nitrobenzaldehyde (2h) (Ar = 3-NO2-C6H3).
Dithiolane-isocyanate imminium methylides are interesting azomethine ylides that undergo efficient and regioselective cycloaddition to carbonyl compounds [123]. The azomethine ylide 160, produced from CsF-promoted desilylation of iminodithiolane salt 159 (in turn produced by the reaction of the readily available N-methylimino dithiolane (158) with trimethylsilylmethyl triflate), reacted with aldehydes 2 or benzophenone (3c) to give a mixture of regioisomeric cycloadducts 161 and 162 (Scheme 39, Table 21). While the minor adducts 162 could be isolated by silica chromatography, the major adducts 161 decomposed under these conditions, with loss of thiirane, to afford the isolated thiolactam 163. When the minor benzaldehyde cycloadduct 162a was heated in refluxing toluene for 48 h, it underwent an analogous decomposition to give thiolactam 164 in 48% yield. The preferred regioselectivity of the cycloaddition was thought to be a result of the union of the larger LUMO coefficient on the carbon of the carbonyl group with the larger HOMO coefficient on the unsaturated Scheme 37. Reaction of sarcosine esters 151a and 151b with paraformaldehyde (2m) to afford oxazolidines 152a and 152b, respectively.

Reactions with Ylides Formed from Silylmethylamines and Related Reagents
A wide range of azomethine ylides generated from silylmethylamine reagents have been explored in reactions with carbonyl dipolarophiles.

Desilylation of (Trimethylsilylmethyl)iminium Ions
Padwa demonstrated that non-stabilized azomethine ylides formed by desilylation of N-(trimethylsilylmethyl)-immonium ions, a process initially developed by Vedejs [121], react with aldehydes 2 [122]. The reaction of N-(trimethylsilylmethyl)benzamide 154 with methyl triflate afforded the trimethylsilylmethyl iminium ion 155, which on treatment with CsF produced azomethine ylide 156, and in the presence of 3-nitrobenzaldehyde (2h) afforded cycloadduct 157 as the exclusive product, indicating a highly regioselective process (Scheme 38). The regioselectivity was determined by a combination of spectroscopic analyses and chemical transformation into a known derivative, however, no comment was made about the stereoselectivity. The exclusive formation of the isolated regioisomer was rationalised to be the result of the union of the larger azomethine ylide HOMO coefficient on the unsubstituted carbon of the ylide 156 with that of the larger dipolarophile LUMO coefficient on the carbon atom of the carbonyl group of the aldehyde 2h. When sarcosine (−)-menthyl or (−)-8-phenylmenthyl esters, 151a and 151b respectively, were reacted with paraformaldehyde (2m) cycloaddition occurred in a diastereoselective fashion to give the respective oxazolidines 152a and 152b, which were exhaustively hydrolyzed to form predominantly N-methyl-D-serine (153) (Scheme 37) [120]. Scheme 37. Reaction of sarcosine esters 151a and 151b with paraformaldehyde (2m) to afford oxazolidines 152a and 152b, respectively.

Reactions with Ylides Formed from Silylmethylamines and Related Reagents
A wide range of azomethine ylides generated from silylmethylamine reagents have been explored in reactions with carbonyl dipolarophiles.

Desilylation of (Trimethylsilylmethyl)iminium Ions
Padwa demonstrated that non-stabilized azomethine ylides formed by desilylation of N-(trimethylsilylmethyl)-immonium ions, a process initially developed by Vedejs [121], react with aldehydes 2 [122]. The reaction of N-(trimethylsilylmethyl)benzamide 154 with methyl triflate afforded the trimethylsilylmethyl iminium ion 155, which on treatment with CsF produced azomethine ylide 156, and in the presence of 3-nitrobenzaldehyde (2h) afforded cycloadduct 157 as the exclusive product, indicating a highly regioselective process (Scheme 38). The regioselectivity was determined by a combination of spectroscopic analyses and chemical transformation into a known derivative, however, no comment was made about the stereoselectivity. The exclusive formation of the isolated regioisomer was rationalised to be the result of the union of the larger azomethine ylide HOMO coefficient on the unsubstituted carbon of the ylide 156 with that of the larger dipolarophile LUMO coefficient on the carbon atom of the carbonyl group of the aldehyde 2h. Scheme 38. Cycloaddition of an azomethine ylide, generated from desilylation of a N-(trimethylsilylmethyl)-immonium ion, with 3-nitrobenzaldehyde (2h) (Ar = 3-NO2-C6H3).
Dithiolane-isocyanate imminium methylides are interesting azomethine ylides that undergo efficient and regioselective cycloaddition to carbonyl compounds [123]. The azomethine ylide 160, produced from CsF-promoted desilylation of iminodithiolane salt 159 (in turn produced by the reaction of the readily available N-methylimino dithiolane (158) with trimethylsilylmethyl triflate), reacted with aldehydes 2 or benzophenone (3c) to give a mixture of regioisomeric cycloadducts 161 and 162 (Scheme 39, Table 21). While the minor adducts 162 could be isolated by silica chromatography, the major adducts 161 decomposed under these conditions, with loss of thiirane, to afford the isolated thiolactam 163. When the minor benzaldehyde cycloadduct 162a was heated in refluxing toluene for 48 h, it underwent an analogous decomposition to give thiolactam 164 in 48% yield. The preferred regioselectivity of the cycloaddition was thought to be a result of the union of the larger LUMO coefficient on the carbon of the carbonyl group with the larger HOMO coefficient on the unsaturated Scheme 38.
Dithiolane-isocyanate imminium methylides are interesting azomethine ylides that undergo efficient and regioselective cycloaddition to carbonyl compounds [123]. The azomethine ylide 160, produced from CsF-promoted desilylation of iminodithiolane salt 159 (in turn produced by the reaction of the readily available N-methylimino dithiolane (158) with trimethylsilylmethyl triflate), reacted with aldehydes 2 or benzophenone (3c) to give a mixture of regioisomeric cycloadducts 161 and 162 (Scheme 39, Table 21). While the minor adducts 162 could be isolated by silica chromatography, the major adducts 161 decomposed under these conditions, with loss of thiirane, to afford the isolated thiolactam 163. When the minor benzaldehyde cycloadduct 162a was heated in refluxing toluene for 48 h, it underwent an analogous decomposition to give thiolactam 164 in 48% yield. The preferred regioselectivity of the cycloaddition was thought to be a result of the union of the larger LUMO coefficient on the carbon of the carbonyl group with the larger HOMO coefficient on the unsaturated centre attached to the sulfur atoms of the dithiolane ring. Interestingly, it was noted that the cycloaddition only occurred with conjugated carbonyl compounds. For attempts at cycloaddition using simple non-conjugated aldehydes and ketones, e.g., acetone, cyclohexanone and butyraldehyde, no reaction was observed. centre attached to the sulfur atoms of the dithiolane ring. Interestingly, it was noted that the cycloaddition only occurred with conjugated carbonyl compounds. For attempts at cycloaddition using simple non-conjugated aldehydes and ketones, e.g., acetone, cyclohexanone and butyraldehyde, no reaction was observed.
In a related study, reaction of azomethine ylide 160 with α,β-unsaturated ketones produced mainly cycloadducts of the carbon-carbon double bond, with small quantities (5%) of the ketone cycloadduct also isolated [124].
In a related study, reaction of azomethine ylide 160 with α,β-unsaturated ketones produced mainly cycloadducts of the carbon-carbon double bond, with small quantities (5%) of the ketone cycloadduct also isolated [124].
In a related study, reaction of azomethine ylide 160 with α,β-unsaturated ketones produced mainly cycloadducts of the carbon-carbon double bond, with small quantities (5%) of the ketone cycloadduct also isolated [124].

Desilylation of α-Substituted Methyl(trimethylsilylmethyl)amines
A series of α-substituted methyl(trimethylsilylmethyl)amine reagents were developed and shown to act as azomethine ylide precursors, adding to a range of dipolarophiles including carbonyl compounds. The first of these reagents to be explored in carbonyl cycloadditions was the cyanomethylamine reagent 171 [127] which was efficiently prepared from benzylamine (169) by firstly reacting with (chloromethyl)trimethylsilane and then formaldehyde and KCN (Scheme 41). Treatment of reagent 171 with AgF produced the non-stabilized azomethine ylide 172, which was trapped with a range of dipolarophiles including benzaldehyde (2a) which produced oxazolidine 173a, isolated in 50% yield (Scheme 41). A series of α-substituted methyl(trimethylsilylmethyl)amine reagents were developed and shown to act as azomethine ylide precursors, adding to a range of dipolarophiles including carbonyl compounds. The first of these reagents to be explored in carbonyl cycloadditions was the cyanomethylamine reagent 171 [127] which was efficiently prepared from benzylamine (169) by firstly reacting with (chloromethyl)trimethylsilane and then formaldehyde and KCN (Scheme 41). Treatment of reagent 171 with AgF produced the non-stabilized azomethine ylide 172, which was trapped with a range of dipolarophiles including benzaldehyde (2a) which produced oxazolidine 173a, isolated in 50% yield (Scheme 41).
A series of chiral cyanoaminosilanes 174a-c were produced, using the same methods as used to prepare 171, to explore potential for asymmetric cycloaddition reactions [127]. Although cycloaddition reactions between the in situ produced ylides 175a-c and benzaldehyde (2a) did occur to give oxazolidines 176a-c respectively, little if any diastereoselectivity was observed for this carbonyl dipolarophile (Scheme 42). In contrast, improved and at times promising diastereoselectivity was observed for olefinic dipolarophiles. The related phenylthio-substituted amine 177 was produced from benzylamine by reacting with chloromethyltrimethylsilane followed by paraformaldehyde and thiophenol [128]. In a similar way to the cyanoaminosilane reagents 171 and 174, when treated with AgF, reagent 177 released nonstabilized azomethine ylide 172 and the ylide formed in this way showed utility in cycloaddition reactions with a range of dipolarophiles including benzaldehyde (2a), in which case oxazolidine 173a was produced in 52% yield (Scheme 43). A series of chiral cyanoaminosilanes 174a-c were produced, using the same methods as used to prepare 171, to explore potential for asymmetric cycloaddition reactions [127]. Although cycloaddition reactions between the in situ produced ylides 175a-c and benzaldehyde (2a) did occur to give oxazolidines 176a-c respectively, little if any diastereoselectivity was observed for this carbonyl dipolarophile (Scheme 42). In contrast, improved and at times promising diastereoselectivity was observed for olefinic dipolarophiles. A series of α-substituted methyl(trimethylsilylmethyl)amine reagents were developed and shown to act as azomethine ylide precursors, adding to a range of dipolarophiles including carbonyl compounds. The first of these reagents to be explored in carbonyl cycloadditions was the cyanomethylamine reagent 171 [127] which was efficiently prepared from benzylamine (169) by firstly reacting with (chloromethyl)trimethylsilane and then formaldehyde and KCN (Scheme 41). Treatment of reagent 171 with AgF produced the non-stabilized azomethine ylide 172, which was trapped with a range of dipolarophiles including benzaldehyde (2a) which produced oxazolidine 173a, isolated in 50% yield (Scheme 41). A series of chiral cyanoaminosilanes 174a-c were produced, using the same methods as used to prepare 171, to explore potential for asymmetric cycloaddition reactions [127]. Although cycloaddition reactions between the in situ produced ylides 175a-c and benzaldehyde (2a) did occur to give oxazolidines 176a-c respectively, little if any diastereoselectivity was observed for this carbonyl dipolarophile (Scheme 42). In contrast, improved and at times promising diastereoselectivity was observed for olefinic dipolarophiles. The related phenylthio-substituted amine 177 was produced from benzylamine by reacting with chloromethyltrimethylsilane followed by paraformaldehyde and thiophenol [128]. In a similar way to the cyanoaminosilane reagents 171 and 174, when treated with AgF, reagent 177 released nonstabilized azomethine ylide 172 and the ylide formed in this way showed utility in cycloaddition reactions with a range of dipolarophiles including benzaldehyde (2a), in which case oxazolidine 173a was produced in 52% yield (Scheme 43). The related phenylthio-substituted amine 177 was produced from benzylamine by reacting with chloromethyltrimethylsilane followed by paraformaldehyde and thiophenol [128]. In a similar way to the cyanoaminosilane reagents 171 and 174, when treated with AgF, reagent 177 released non-stabilized azomethine ylide 172 and the ylide formed in this way showed utility in cycloaddition reactions with a range of dipolarophiles including benzaldehyde (2a), in which case oxazolidine 173a was produced in 52% yield (Scheme 43).
By far the most studied and utilized of the α-substituted methyl(trimethylsilylmethyl)amine reagents is the N-methoxymethyl-substituted reagent 178 [129][130][131], readily produced from benzylamine by alkylation with chloromethyltrimethylsilane followed by reaction with formaldehyde in the presence of methanol [132]. The reagent is now commercially available from various vendors. The advantages of this reagent include that the ylide 172 can be produced by treatment with LiF, without the use of Ag salts, by sonication at 35˝C in acetonitrile and when reacted with benzaldehyde (2a), cycloadduct 173a was obtained in a higher yield than that obtained with the previous reagents. When 178 was reacted in this way with ketones, benzophenone (3c) or acetone (3d), moderate yields of the corresponding cycloadducts 179 or 180 were obtained (Scheme 44). By far the most studied and utilized of the α-substituted methyl(trimethylsilylmethyl)amine reagents is the N-methoxymethyl-substituted reagent 178 [129][130][131], readily produced from benzylamine by alkylation with chloromethyltrimethylsilane followed by reaction with formaldehyde in the presence of methanol [132]. The reagent is now commercially available from various vendors. The advantages of this reagent include that the ylide 172 can be produced by treatment with LiF, without the use of Ag salts, by sonication at 35 °C in acetonitrile and when reacted with benzaldehyde (2a), cycloadduct 173a was obtained in a higher yield than that obtained with the previous reagents. When 178 was reacted in this way with ketones, benzophenone (3c) or acetone (3d), moderate yields of the corresponding cycloadducts 179 or 180 were obtained (Scheme 44). Recently, a thorough exploration of the reactions of reagent 178 with aromatic and heteroaromatic aldehydes 2 was reported [133]. Firstly, it was found that generating the ylide by trifluoroacetic acid catalysis [131] in CH2Cl2 at 25 °C in the presence of benzaldehyde (2a) afforded a 95% yield of the oxazolidine cycloadduct 173a (Scheme 45) (Table 23, entry 1), a higher yield than that reported using LiF to generate the ylide from reagent 178 [129]. The trifluoroacetic acid catalysis method was then applied to a range of aromatic aldehydes 2 (Table 23). High yields of cycloadducts 173 were obtained in the cases of benzaldehydes substituted with electron-withdrawing (entries 2-7), electron-donating (entries [8][9][10][11]14), sterically demanding (entries 5 and 12), basic (entry 8) and acidic (entry 13) groups. Chemoselectivity was seen in the case of the 4-cyano example (entry 7) with only the product from cycloaddition to the aldehyde moiety being obtained. There were some limitations, in that 3-hydroxybenzaldehyde (2s) afforded complex mixtures and oxazolidine 173o could not be detected. Additionally, for 4-hydroxybenzaldehyde (2t), the main product was the bis adduct 174, isolated in 53% yield (Figure 2). Recently, a thorough exploration of the reactions of reagent 178 with aromatic and heteroaromatic aldehydes 2 was reported [133]. Firstly, it was found that generating the ylide by trifluoroacetic acid catalysis [131] in CH 2 Cl 2 at 25˝C in the presence of benzaldehyde (2a) afforded a 95% yield of the oxazolidine cycloadduct 173a (Scheme 45) (Table 23, entry 1), a higher yield than that reported using LiF to generate the ylide from reagent 178 [129]. The trifluoroacetic acid catalysis method was then applied to a range of aromatic aldehydes 2 (Table 23). High yields of cycloadducts 173 were obtained in the cases of benzaldehydes substituted with electron-withdrawing (entries 2-7), electron-donating (entries [8][9][10][11]14), sterically demanding (entries 5 and 12), basic (entry 8) and acidic (entry 13) groups. Chemoselectivity was seen in the case of the 4-cyano example (entry 7) with only the product from cycloaddition to the aldehyde moiety being obtained. There were some limitations, in that 3-hydroxybenzaldehyde (2s) afforded complex mixtures and oxazolidine 173o could not be detected. Additionally, for 4-hydroxybenzaldehyde (2t), the main product was the bis adduct 174, isolated in 53% yield (Figure 2). By far the most studied and utilized of the α-substituted methyl(trimethylsilylmethyl)amine reagents is the N-methoxymethyl-substituted reagent 178 [129][130][131], readily produced from benzylamine by alkylation with chloromethyltrimethylsilane followed by reaction with formaldehyde in the presence of methanol [132]. The reagent is now commercially available from various vendors. The advantages of this reagent include that the ylide 172 can be produced by treatment with LiF, without the use of Ag salts, by sonication at 35 °C in acetonitrile and when reacted with benzaldehyde (2a), cycloadduct 173a was obtained in a higher yield than that obtained with the previous reagents. When 178 was reacted in this way with ketones, benzophenone (3c) or acetone (3d), moderate yields of the corresponding cycloadducts 179 or 180 were obtained (Scheme 44). Recently, a thorough exploration of the reactions of reagent 178 with aromatic and heteroaromatic aldehydes 2 was reported [133]. Firstly, it was found that generating the ylide by trifluoroacetic acid catalysis [131] in CH2Cl2 at 25 °C in the presence of benzaldehyde (2a) afforded a 95% yield of the oxazolidine cycloadduct 173a (Scheme 45) (Table 23, entry 1), a higher yield than that reported using LiF to generate the ylide from reagent 178 [129]. The trifluoroacetic acid catalysis method was then applied to a range of aromatic aldehydes 2 (Table 23). High yields of cycloadducts 173 were obtained in the cases of benzaldehydes substituted with electron-withdrawing (entries 2-7), electron-donating (entries [8][9][10][11]14), sterically demanding (entries 5 and 12), basic (entry 8) and acidic (entry 13) groups. Chemoselectivity was seen in the case of the 4-cyano example (entry 7) with only the product from cycloaddition to the aldehyde moiety being obtained. There were some limitations, in that 3-hydroxybenzaldehyde (2s) afforded complex mixtures and oxazolidine 173o could not be detected. Additionally, for 4-hydroxybenzaldehyde (2t), the main product was the bis adduct 174, isolated in 53% yield (Figure 2). Scheme 45. Cycloaddition of non-stabilized ylide 172, generated by CF3CO2H-catalyzed decomposition of methoxymethylamine reagent 178, with aromatic aldehydes 2.

Scheme 45.
Cycloaddition of non-stabilized ylide 172, generated by CF 3 CO 2 H-catalyzed decomposition of methoxymethylamine reagent 178, with aromatic aldehydes 2. 11 4-NHAc-C6H4 173k 78 12 2,4,6-(Me)3-C6H2 173l 80 13 4-CO2H-CC6H4 173m 59 14 2-OH-C6H4 173n 54 15 3-OH-C6H4 173o - The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.   The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiophene-and 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2-carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.   The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.   The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.  The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.  The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.  The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.  The cycloaddition of ylide 172, generated by trifluoroacetic acid catalyzed decomposition of silylamine reagent 178, to a range of heteroaromatic aldehydes 2 was also explored with the only limitation appearing to be electron-rich aromatic aldehydes (Table 24) [133]. 2-Furan-, 2-thiopheneand 3-pyridine carboxaldehydes (2u-w) all underwent efficient cycloaddition under these conditions (Entries 1-3). In contrast, experiments with pyrrole-2-carboxaldehyde (2x) and N-methylpyrrole-2carboxaldehyde (2y) afforded complex intractable product mixtures with no sign of oxazolidine products (Entries 4 and 5). The lack of effective cycloaddition under these conditions was thought to be due to the electron-rich nature of the pyrrole leading to deactivation of the pyrrole via increasing the carbonyl LUMO energy with concomitant increase in the carbonyl LUMO-azomethine ylide HOMO energy gap. Consistent with this rationale, when the pyrrole contained the electron-withdrawing N-benzenesulfonyl group (compound 2z), which was expected to lower the carbonyl LUMO energy, a high yield of the oxazolidine product 173v was obtained.  Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems.  90 Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems.   During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3 1 -dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3 1 -dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems. Recently, 5-aryloxazolidines 173, formed under the above conditions, were applied to the synthesis of β-hydroxy-β-arylethylamines [87]. The oxazolidines 173j and 173r underwent hydrazinolysis leading to the trimethoxyphenyl-and thiophenyl derivatives 175a and 175b, isolated in 68% and 71%, respectively ( Figure 3). During a recent study into the dearomatization of electron-deficient arenes and heteroarenes by azomethine ylide cycloadditions, competing cycloadditions to aldehydes and ketones were occasionally observed [134]. The reaction of N-triflylindole-3-carboxaldehyde (2aa) with azomethine ylide 172, formed by trifluoroacetic acid-catalyzed decomposition of reagent 178, afforded a mixture of three products in a 6:2:2 ratio. The major product produced was the mono aldehyde adduct 173x (isolated in 41% yield) with the balance of the product being an inseparable mixture of mono indole C2-C3 adduct 181a and a bis-adduct 182a formed by addition to both carbonyl and indole C2-C3 double bonds (Scheme 46). Similarly, methyl N-acetyl-indole-3-pyruvate (3e) afforded a similar distribution of a mono ketone adduct 183 (70% of crude product, 20% isolated yield) along with a mixture of C2-C3 double bond adduct 181b and bis-adduct 182b (~30% of crude product) (Scheme 47). The reaction of the same ylide with 4-nitro-and 3,3′-dinitrobenzophenones (3f) and (3g) resulted in exclusively ketone adducts 184a and 184b both isolated in 77% yield (Scheme 48). In a further example, 3,3′-dinitroanthroquinone (3h) afforded bis ketone adduct 185 isolated in 66% yield as a 9:1 mixture of diastereoisomers (Scheme 49). These studies indicate the relatively greater reactivity of such aldehyde and ketone groups over the nitroarene in these particular systems.  Using modified conditions (LiF, DMF, reflux), reagent 178 has been employed in azomethine ylide cycloadditions to benzophenone (3c) and acetophenone (3i), to produce good yields of the corresponding oxazolidines 186a and 186b, respectively (Scheme 50) [90]. Acid catalyzed hydrolysis of 186a provided access to 2-amino-1,1-diphenylethylalcohol derivative 187. Scheme 50. Cycloaddition of azomethine ylide 172, formed from silylamine reagent 178, with aromatic ketones 3c and 3i.
This alkylaminomethylation chemistry was applied to aryl aldehyde and aryl ketone derivatives to produce alkylaminomethylated species that could undergo further transformations to produce alkylaminomethylphthalides (Scheme 51) [91]. Methyl 2-formyl benzoate (2p) underwent cycloaddition reaction with azomethine ylide 172 generated by trifluoroacetic acid catalyzed decomposition of reagent 178 to give a quantitative yield of oxazolidine 188a which underwent hydrolysis and cyclization under acidic conditions at 70 °C to give phthalide 189a. The less reactive dipolarophile methyl ester of 2-acetylbenzoic acid (3j) gave low yields of the oxazoldine 188b under conditions involving trifluoroacetic acid catalysis; however, with the use of excess LiF in refluxing DMF a 74% yield of This alkylaminomethylation chemistry was applied to aryl aldehyde and aryl ketone derivatives to produce alkylaminomethylated species that could undergo further transformations to produce alkylaminomethylphthalides (Scheme 51) [91]. Methyl 2-formyl benzoate (2p) underwent cycloaddition reaction with azomethine ylide 172 generated by trifluoroacetic acid catalyzed decomposition of reagent 178 to give a quantitative yield of oxazolidine 188a which underwent hydrolysis and cyclization under acidic conditions at 70˝C to give phthalide 189a. The less reactive dipolarophile methyl ester of 2-acetylbenzoic acid (3j) gave low yields of the oxazoldine 188b under conditions involving trifluoroacetic acid catalysis; however, with the use of excess LiF in refluxing DMF a 74% yield of oxazoldine 188b was obtained. Acidic hydrolysis and heating at 90˝C afforded phthalide 189b in 35% yield from the ketone starting material. Similar treatment of the methyl ester of 2-benzoylbenzoic acid (3k) afforded phthalide 189c in 57% yield. In the case of the methyl ester of 8-formyl-naphthalene-1-carboxylic acid (2ab), the alkylaminomethyl lactone 191 was obtained in 40% yield (Scheme 52). Neutralisation of phthalide 189c followed by heating in refluxing butanol gave a 60% yield of the corresponding cyclized dihydroisoquinolinone 192 (Scheme 53). In related cycloaddition-hydrolysis-cyclization processes, the aryl ketone derivatives 3l and m were elaborated into the respective 4-aryl-4-hydroxypiperidone derivatives 194a and b (Scheme 54). Recently it was reported that activated carboxyl systems can undergo 1,3-dipolar cycloaddition reactions [40]. A range of isatoic anhydrides 5a reacted with the azomethine ylide 172, generated from Recently it was reported that activated carboxyl systems can undergo 1,3-dipolar cycloaddition reactions [40]. A range of isatoic anhydrides 5a reacted with the azomethine ylide 172, generated from Recently it was reported that activated carboxyl systems can undergo 1,3-dipolar cycloaddition reactions [40]. A range of isatoic anhydrides 5a reacted with the azomethine ylide 172, generated from Recently it was reported that activated carboxyl systems can undergo 1,3-dipolar cycloaddition reactions [40]. A range of isatoic anhydrides 5a reacted with the azomethine ylide 172, generated from Recently it was reported that activated carboxyl systems can undergo 1,3-dipolar cycloaddition reactions [40]. A range of isatoic anhydrides 5a reacted with the azomethine ylide 172, generated from reagent 178 by trifluoroacetic acid-mediated catalysis or by treatment with LiF, to afford spiro-oxazolidine cycloadducts 195, that spontaneously extruded CO 2 with structural rearrangement to give the isolated 1,3-benzodiazepin-5-one products 196 (Scheme 55). High yields of the benzodiazepinones 196 were obtained for a wide range of Nand benzo-substituted isatoic anhydrides except for cases with electron-releasing substituents ortho-or para-related to the dipolarophilic carboxyl group, in which case, starting material was returned (Tables 25 and 26). The lack of reaction in these cases was thought to be due to stereoelectronic effects which resulted in raising the energy of the carbonyl LUMO energy and concomitant raising of the energy of the cycloaddition transition state. A plausible mechanism for the transformation of the isatoic anhydrides into the benzodiazepines was proposed involving a complex reaction cascade (Scheme 56). The initial cycloaddition gives the oxazolidine product (observable by NMR and IR spectroscopies) which undergoes step-wise oxazolidine ring-opening, decarboxylation and ring-closure. reagent 178 by trifluoroacetic acid-mediated catalysis or by treatment with LiF, to afford spiro-oxazolidine cycloadducts 195, that spontaneously extruded CO2 with structural rearrangement to give the isolated 1,3-benzodiazepin-5-one products 196 (Scheme 55). High yields of the benzodiazepinones 196 were obtained for a wide range of N-and benzo-substituted isatoic anhydrides except for cases with electron-releasing substituents ortho-or para-related to the dipolarophilic carboxyl group, in which case, starting material was returned (Tables 25 and 26). The lack of reaction in these cases was thought to be due to stereoelectronic effects which resulted in raising the energy of the carbonyl LUMO energy and concomitant raising of the energy of the cycloaddition transition state. A plausible mechanism for the transformation of the isatoic anhydrides into the benzodiazepines was proposed involving a complex reaction cascade (Scheme 56). The initial cycloaddition gives the oxazolidine product (observable by NMR and IR spectroscopies) which undergoes step-wise oxazolidine ring-opening, decarboxylation and ring-closure.
Molecules 2016, 21, 935 33 of 53 reagent 178 by trifluoroacetic acid-mediated catalysis or by treatment with LiF, to afford spiro-oxazolidine cycloadducts 195, that spontaneously extruded CO2 with structural rearrangement to give the isolated 1,3-benzodiazepin-5-one products 196 (Scheme 55). High yields of the benzodiazepinones 196 were obtained for a wide range of N-and benzo-substituted isatoic anhydrides except for cases with electron-releasing substituents ortho-or para-related to the dipolarophilic carboxyl group, in which case, starting material was returned (Tables 25 and 26). The lack of reaction in these cases was thought to be due to stereoelectronic effects which resulted in raising the energy of the carbonyl LUMO energy and concomitant raising of the energy of the cycloaddition transition state. A plausible mechanism for the transformation of the isatoic anhydrides into the benzodiazepines was proposed involving a complex reaction cascade (Scheme 56). The initial cycloaddition gives the oxazolidine product (observable by NMR and IR spectroscopies) which undergoes step-wise oxazolidine ring-opening, decarboxylation and ring-closure.
Scheme 55. Cycloaddition of azomethine ylide 172, formed from silylamine reagent 178, with isatoic anhydrides 5a, followed by conversion of the oxazolidines 195 to 1,3-benzodiazepin-5-ones 196. In a recent development, phthalic anhydrides 5b were reported to undergo cycloaddition with the azomethine ylide 172, formed from reagent 178 under conditions of trifluoroacetic acid catalysis [41]. The generated spiro-oxazolidine cycloadducts 200 proved to be more stable than the analogous cycloadducts generated from isatoic anhydrides 5a. Although the cycloadducts 200 decomposed during attempted purification on silica, they could be isolated in pure form after chromatography on Florosil™. The reaction appeared to be general with a range of substituted phthalic anhydrides reacting under these conditions and high yields of the cycloadduct products 200 were obtained (Table 27). In all cases only mono cycloaddition products were isolated. In the cases of the unsymmetrical phthalic anhydrides (Entries 4-6), inseparable mixtures of the two possible mono adducts were obtained, with varying degrees of regioselectivity. In the case, of 3-methoxyphthalic anhydride (Entry 6), a 70:30 ratio of the regioisomeric products were obtained, with the major product being that where the ylide adds to the carboxyl group distal to the methoxy group. This result was explained to be a combination of steric Scheme 56. Proposed mechanism for the conversion of isatoic anhydrides 5a into benzodiazepinones 196. Table 26.
In a recent development, phthalic anhydrides 5b were reported to undergo cycloaddition with the azomethine ylide 172, formed from reagent 178 under conditions of trifluoroacetic acid catalysis [41]. The generated spiro-oxazolidine cycloadducts 200 proved to be more stable than the analogous cycloadducts generated from isatoic anhydrides 5a. Although the cycloadducts 200 decomposed during attempted purification on silica, they could be isolated in pure form after chromatography on Florosil™. The reaction appeared to be general with a range of substituted phthalic anhydrides reacting under these conditions and high yields of the cycloadduct products 200 were obtained (Table 27). In all cases only mono cycloaddition products were isolated. In the cases of the unsymmetrical phthalic anhydrides (Entries 4-6), inseparable mixtures of the two possible mono adducts were obtained, with varying degrees of regioselectivity. In the case, of 3-methoxyphthalic anhydride (Entry 6), a 70:30 ratio of the regioisomeric products were obtained, with the major product being that where the ylide adds to the carboxyl group distal to the methoxy group. This result was explained to be a combination of steric and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, and electronic effects of the methoxy group on the adjacent carboxyl group having the effect of raising the transition state energy and lowering the rate of reactivity of the adjacent carboxyl group. The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH4 in methanol led to conversion, in reasonable yields, to 3-hydroxyisobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, The reductive ring-opening of the spiro-oxazolidines 200 was also investigated [41]. Treatment of the oxazolidines with NaBH 4 in methanol led to conversion, in reasonable yields, to 3-hydroxy-isobenzofuran-1-ones 201 ( Table 28). The products were stable to chromatographic purification on silica which allowed for separation and characterization of the isomers (Entries 4 and 5). Additionally, the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions. the products appear to be mainly present as the depicted ring-closed form (rather than the tautomeric ring-opened keto-carboxylic acid form) in solution state, as assessed by NMR analyses and in solid state as shown by X-ray crystallographic analysis of a representative example. Lower yields obtained for two examples (Entries 7 and 8) were thought to be due to the electron-deficient nature of these systems resulting in over reduction side-reactions.

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from hydrolysis of the cycloadduct in the reaction mixture and indeed the cycloadduct 204 could be

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from hydrolysis of the cycloadduct in the reaction mixture and indeed the cycloadduct 204 could be

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield 12

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from hydrolysis of the cycloadduct in the reaction mixture and indeed the cycloadduct 204 could be transformed into the alcohol 205 by treatment with aqueous HCl.

Photochemistry of N-(silylmethyl)phthalimides and Related Reagents
An investigation of the photochemistry of N-trimethylsilylmethyl-substituted phthalimides revealed a C-to O-trimethylsilyl transfer process that produced azomethine ylide intermediates [135,136]. Irradiation of an acetonitrile solution of N-trimethylsilylmethylphthalimide (202) with Pyrex-filtered light led to migration of the silyl group from carbon to oxygen to form azomethine ylide 203 (Scheme 57). When performed in the presence of dipolarophiles, cycloadditions proceeded, and in the case where the reaction was performed in acetone (3d), a single cycloadduct 204 was obtained in 84% yield together with an alcohol side-product 205. The alcohol side-product was presumed to be formed from hydrolysis of the cycloadduct in the reaction mixture and indeed the cycloadduct 204 could be transformed into the alcohol 205 by treatment with aqueous HCl.

Electrochemical Oxidation of bis(silylmethyl)amines
Double desilylation of bis(silylmethyl)amines using either photoelectron induced transfer (PET) or AgF were developed as processes for generating non-stabilised azomethine ylides [137]. In the case of bis(trimethylsilylmethyl)benzylamine (206) this process is an alternative method for generating ylide 172. Whilst most of the examples involved the use of alkene dipolarophiles, benzophenone (3c) was also studied resulting in cycloadduct 186a being isolated in 80% and 62% yields from PET and AgF processes, respectively (Scheme 58).

Electrochemical Oxidation of bis(silylmethyl)amines
Double desilylation of bis(silylmethyl)amines using either photoelectron induced transfer (PET) or AgF were developed as processes for generating non-stabilised azomethine ylides [137]. In the case of bis(trimethylsilylmethyl)benzylamine (206) this process is an alternative method for generating ylide 172. Whilst most of the examples involved the use of alkene dipolarophiles, benzophenone (3c) was also studied resulting in cycloadduct 186a being isolated in 80% and 62% yields from PET and AgF processes, respectively (Scheme 58).

Reactions of Ylides Formed from Addition of Carbenes and Carbenoids to Schiff Bases
The reaction of carbenes or carbenoid species with imines is a convenient way to generate azomethine ylides and has been applied to cycloadditions with a range of carbonyl dipolarophiles.

Diazoalkanes
The catalytic decomposition of diazoalkanes in the presence of a Schiff's base is a convenient source of azomethine ylides (Scheme 59) [138]. The copper(I) bromide-catalyzed decomposition of phenyldiazomethane 207 produces a carbene-Cu(I) complex 209. In the presence of a large excess of imine 210 a trans-azomethine ylide 211 is formed and this intermediate reacts with dipolarophiles to product five-membered heterocycles. With benzaldehyde (2a) or anisaldehyde (2c) as the dipolarophile, oxazolidines 212 were formed, however they proved to be unstable and on standing at room temperature for a few days transformed into the more thermodynamically stable isomers 213. Competition experiments were performed that indicated dimethyl maleate was a more reactive dipolarophile than benzaldehyde (2a).

Reactions of Ylides Formed from Addition of Carbenes and Carbenoids to Schiff Bases
The reaction of carbenes or carbenoid species with imines is a convenient way to generate azomethine ylides and has been applied to cycloadditions with a range of carbonyl dipolarophiles.

Diazoalkanes
The catalytic decomposition of diazoalkanes in the presence of a Schiff's base is a convenient source of azomethine ylides (Scheme 59) [138]. The copper(I) bromide-catalyzed decomposition of phenyldiazomethane 207 produces a carbene-Cu(I) complex 209. In the presence of a large excess of imine 210 a trans-azomethine ylide 211 is formed and this intermediate reacts with dipolarophiles to product five-membered heterocycles. With benzaldehyde (2a) or anisaldehyde (2c) as the dipolarophile, oxazolidines 212 were formed, however they proved to be unstable and on standing at room temperature for a few days transformed into the more thermodynamically stable isomers 213. Competition experiments were performed that indicated dimethyl maleate was a more reactive dipolarophile than benzaldehyde (2a).

Diazoalkanes
The catalytic decomposition of diazoalkanes in the presence of a Schiff's base is a convenient source of azomethine ylides (Scheme 59) [138]. The copper(I) bromide-catalyzed decomposition of phenyldiazomethane 207 produces a carbene-Cu(I) complex 209. In the presence of a large excess of imine 210 a trans-azomethine ylide 211 is formed and this intermediate reacts with dipolarophiles to product five-membered heterocycles. With benzaldehyde (2a) or anisaldehyde (2c) as the dipolarophile, oxazolidines 212 were formed, however they proved to be unstable and on standing at room temperature for a few days transformed into the more thermodynamically stable isomers 213. Competition experiments were performed that indicated dimethyl maleate was a more reactive dipolarophile than benzaldehyde (2a). The Rh(II)-catalyzed decomposition of α-diazocarbonyls in the presence of imino π-bonds is also an elegant way to produce functionalized azomethine ylides [139]. Many variations of this process were explored, including the use of benzaldehyde (2a) as a dipolarophile. The Rh(I)-catalyzed decomposition of diazomalonate 214 in the presence of imine 210a provided stabilized azomethine ylide 215 which underwent cycloaddition to benzaldehyde (2a) to provide cycloadduct 216, isolated as a single diastereoisomer in 68% yield (Scheme 60). The Rh(II)-catalyzed decomposition of α-diazocarbonyls in the presence of imino π-bonds is also an elegant way to produce functionalized azomethine ylides [139]. Many variations of this process were explored, including the use of benzaldehyde (2a) as a dipolarophile. The Rh(I)-catalyzed decomposition of diazomalonate 214 in the presence of imine 210a provided stabilized azomethine ylide 215 which underwent cycloaddition to benzaldehyde (2a) to provide cycloadduct 216, isolated as a single diastereoisomer in 68% yield (Scheme 60). As an extension to studies on the intramolecular addition of azomethine ylides derived from imines to ester carbonyl moieties (see Section 2.6.2), the intramolecular reaction of imines of O-acylsalicylic aldehydes with metallocarbenes generated from diazocarbonyl compounds was recently investigated experimentally and computationally [140]. A range of Rh-and Cu-catalysts were tested with copper(II)trifluoroacetoacetate (Cu(tfacac)2) providing the highest yields (Scheme 61). The reaction of imine 217 with ethyl diazoacetate (218) catalyzed by 10 mol % of Cu(tfacac)2, in refluxing benzene, led to formation of azomethine ylide intermediate 5c which underwent intramolecular cycloaddition onto the ester carbonyl to produce both endo and exo isomers of 219, isolated in 13% and 14% yield, respectively. In refluxing CH2Cl2, endo-219 was obtained in 36% yield, whereas with the use of a stoichiometric amount of Cu(tfacac)2, a 41% yield of endo-219 resulted. The latter conditions were applied to a wide range of imines (Table 29). In order for cycloaddition to occur, an electron-withdrawing substituent was required on the imine aryl group (Entries 1-8). In these cases, where an electronwithdrawing substituent was also present on the benzoyl group, both endo-and exo-cycloadduct isomers were produced (Entries 6-8). For the subset of cases with an electron-donating substituent on the benzoyl group, exclusive endo stereochemistry resulted (Entries 1-5). A range of experimental and theoretical (DFT) calculations were performed that indicated that the change in stereochemistry of cycloaddition was due to a decrease in the barrier to cycloaddition and an increase in the barrier of U-to S-ylide interconversion with an electron-withdrawing group on the benzoyl group. The U-ylide leads to the endo-cycloadduct, whereas the S-ylide leads to the exo-cycloadduct (Scheme 62). Scheme 60. Cycloaddition of azomethine ylide 215, generated from Rh(II)-catalyzed decomposition of diazomalonate 214 in the presence of imine 210a, and benzaldehyde (2c).
As an extension to studies on the intramolecular addition of azomethine ylides derived from imines to ester carbonyl moieties (see Section 2.6.2), the intramolecular reaction of imines of O-acylsalicylic aldehydes with metallocarbenes generated from diazocarbonyl compounds was recently investigated experimentally and computationally [140]. A range of Rh-and Cu-catalysts were tested with copper(II)trifluoroacetoacetate (Cu(tfacac) 2 ) providing the highest yields (Scheme 61). The reaction of imine 217 with ethyl diazoacetate (218) catalyzed by 10 mol % of Cu(tfacac) 2 , in refluxing benzene, led to formation of azomethine ylide intermediate 5c which underwent intramolecular cycloaddition onto the ester carbonyl to produce both endo and exo isomers of 219, isolated in 13% and 14% yield, respectively. In refluxing CH 2 Cl 2 , endo-219 was obtained in 36% yield, whereas with the use of a stoichiometric amount of Cu(tfacac) 2 , a 41% yield of endo-219 resulted. The latter conditions were applied to a wide range of imines (Table 29). In order for cycloaddition to occur, an electron-withdrawing substituent was required on the imine aryl group (Entries 1-8). In these cases, where an electron-withdrawing substituent was also present on the benzoyl group, both endoand exo-cycloadduct isomers were produced (Entries 6-8). For the subset of cases with an electron-donating substituent on the benzoyl group, exclusive endo stereochemistry resulted (Entries 1-5). A range of experimental and theoretical (DFT) calculations were performed that indicated that the change in stereochemistry of cycloaddition was due to a decrease in the barrier to cycloaddition and an increase in the barrier of U-to S-ylide interconversion with an electron-withdrawing group on the benzoyl group. The U-ylide leads to the endo-cycloadduct, whereas the S-ylide leads to the exo-cycloadduct (Scheme 62).
led to formation of azomethine ylide intermediate 5c which underwent intramolecular cycloaddition onto the ester carbonyl to produce both endo and exo isomers of 219, isolated in 13% and 14% yield, respectively. In refluxing CH2Cl2, endo-219 was obtained in 36% yield, whereas with the use of a stoichiometric amount of Cu(tfacac)2, a 41% yield of endo-219 resulted. The latter conditions were applied to a wide range of imines (Table 29). In order for cycloaddition to occur, an electron-withdrawing substituent was required on the imine aryl group (Entries 1-8). In these cases, where an electronwithdrawing substituent was also present on the benzoyl group, both endo-and exo-cycloadduct isomers were produced (Entries 6-8). For the subset of cases with an electron-donating substituent on the benzoyl group, exclusive endo stereochemistry resulted (Entries 1-5). A range of experimental and theoretical (DFT) calculations were performed that indicated that the change in stereochemistry of cycloaddition was due to a decrease in the barrier to cycloaddition and an increase in the barrier of U-to S-ylide interconversion with an electron-withdrawing group on the benzoyl group. The U-ylide leads to the endo-cycloadduct, whereas the S-ylide leads to the exo-cycloadduct (Scheme 62).

Reaction with Ylides Formed by Interaction of Imines with Dihalocarbenes
Azomethine ylides derived from the reaction of imines with difluoro-or dichlorocarbene also undergo cycloaddition with a range of carbonyl dipolarophiles. The first report of these processes demonstrated that ylides derived from difluorocarbene undergo regioselective cycloaddition with aldehydes and ketones to give oxazolidinone derivatives (Scheme 63, Table 30) [141]. Heating a mixture of the imine 210 (R 1 = Ph), dibromodifluoromethane, Pb powder, tetrabutylammonium bromide and a twofold excess of benzaldehyde (2a) gave the oxazolidinone 222a in 39% as a ca. 5:3 mixture of diastereoisomers (Entry 1). Presumably, the oxazolidinone 222a was formed by hydrolysis of the cycloadduct 221a during silica chromatography. The reaction with other aldehydes provided moderate yields of oxazolidinones 222 (Entries 2-5), however, the experiments with acetone (3d) or acetophenone (3i) gave low or no yield of product (Entries 6 and 7).   Azomethine ylides derived from the reaction of imines with difluoro-or dichlorocarbene also undergo cycloaddition with a range of carbonyl dipolarophiles. The first report of these processes demonstrated that ylides derived from difluorocarbene undergo regioselective cycloaddition with aldehydes and ketones to give oxazolidinone derivatives (Scheme 63, Table 30) [141]. Heating a mixture of the imine 210 (R 1 = Ph), dibromodifluoromethane, Pb powder, tetrabutylammonium bromide and a twofold excess of benzaldehyde (2a) gave the oxazolidinone 222a in 39% as a ca. 5:3 mixture of diastereoisomers (Entry 1). Presumably, the oxazolidinone 222a was formed by hydrolysis of the cycloadduct 221a during silica chromatography. The reaction with other aldehydes provided moderate yields of oxazolidinones 222 (Entries 2-5), however, the experiments with acetone (3d) or acetophenone (3i) gave low or no yield of product (Entries 6 and 7). Scheme 62. Mechanistic rationale for the formation of endo-and exo-cycloadducts 219.

Reaction with Ylides Formed by Interaction of Imines with Dihalocarbenes
Azomethine ylides derived from the reaction of imines with difluoro-or dichlorocarbene also undergo cycloaddition with a range of carbonyl dipolarophiles. The first report of these processes demonstrated that ylides derived from difluorocarbene undergo regioselective cycloaddition with aldehydes and ketones to give oxazolidinone derivatives (Scheme 63, Table 30) [141]. Heating a mixture of the imine 210 (R 1 = Ph), dibromodifluoromethane, Pb powder, tetrabutylammonium bromide and a twofold excess of benzaldehyde (2a) gave the oxazolidinone 222a in 39% as a ca. 5:3 mixture of diastereoisomers (Entry 1). Presumably, the oxazolidinone 222a was formed by hydrolysis of the cycloadduct 221a during silica chromatography. The reaction with other aldehydes provided moderate yields of oxazolidinones 222 (Entries 2-5), however, the experiments with acetone (3d) or acetophenone (3i) gave low or no yield of product (Entries 6 and 7).   Dipolar cycloaddition reactions starting with benzophenone imines 223 and difluorocarbene were also studied [141]. Under the same conditions as above, imine 223a added to difluorocarbene to generate the azomethine ylide intermediate 224a, which underwent efficient cycloaddition to benzaldehyde (2a) to afford the cycloadduct 225a. The oxazolidine 225a hydrolysed on silica to give the oxazolidinone 226a which was isolated in 75% yield (Scheme 64). The reaction with the N-carboxymethyl ester 223b under these conditions with benzaldehyde (2a) as the dipolarophile resulted in formation of oxazolidinone 226b via ylide cycloaddition and hydrolysis along with aziridine side-products 228 and 231 (Scheme 65). The mechanism proposed for the formation of 228 involved a 1,3-H shift of the ylide intermediate 224a to give an alternative ylide 227 which ring-closed to afford the isolated aziridine 228. Alternatively, addition of benzaldehyde (2a) to the ylide 224b could give ring-opened adduct 229 which could undergo a rapid 1,5 H-shift to give another alternative ylide 230 which on ring closure would afford aziridine 231. The authors propose that ring-opened adduct 229 could ring-close to give oxazolidine 225b which when exposed to silica, underwent hydrolysis to afford the isolated oxazolidinone 226b. An alternative pathway whereby 224b undergoes 1,3-dipolar cycloaddition to afford oxazolidine 225b which then ring-opens to provide 229 eventually leading to 231, was not mentioned.
to afford the isolated aziridine 228. Alternatively, addition of benzaldehyde (2a) to the ylide 224b could give ring-opened adduct 229 which could undergo a rapid 1,5 H-shift to give another alternative ylide 230 which on ring closure would afford aziridine 231. The authors propose that ring-opened adduct 229 could ring-close to give oxazolidine 225b which when exposed to silica, underwent hydrolysis to afford the isolated oxazolidinone 226b. An alternative pathway whereby 224b undergoes 1,3-dipolar cycloaddition to afford oxazolidine 225b which then ring-opens to provide 229 eventually leading to 231, was not mentioned.
involved a 1,3-H shift of the ylide intermediate 224a to give an alternative ylide 227 which ring-closed to afford the isolated aziridine 228. Alternatively, addition of benzaldehyde (2a) to the ylide 224b could give ring-opened adduct 229 which could undergo a rapid 1,5 H-shift to give another alternative ylide 230 which on ring closure would afford aziridine 231. The authors propose that ring-opened adduct 229 could ring-close to give oxazolidine 225b which when exposed to silica, underwent hydrolysis to afford the isolated oxazolidinone 226b. An alternative pathway whereby 224b undergoes 1,3-dipolar cycloaddition to afford oxazolidine 225b which then ring-opens to provide 229 eventually leading to 231, was not mentioned. A later study of addition of the ylides formed by imines and difluorocarbene with alkynes revealed side reactions involving addition to alkynyl aldehydes [142]. The ylide 233, formed from N-phenylbenzaldehyde imine (232) and difluorocarbene, reacted with alkynyl aldehyde 2ac to form the cycloadduct 234. On silica chromatography, hydrolysis occurred and a mixture of oxazolidinones 235 was isolated in 25% yield as a 5:1 mixture of diastereoisomers (Scheme 66). In contrast, the corresponding alkynyl esters and alkynyl ketones resulted in selective addition to the alkyne triple bond. A later study of addition of the ylides formed by imines and difluorocarbene with alkynes revealed side reactions involving addition to alkynyl aldehydes [142]. The ylide 233, formed from N-phenylbenzaldehyde imine (232) and difluorocarbene, reacted with alkynyl aldehyde 2ac to form the cycloadduct 234. On silica chromatography, hydrolysis occurred and a mixture of oxazolidinones 235 was isolated in 25% yield as a 5:1 mixture of diastereoisomers (Scheme 66). In contrast, the corresponding alkynyl esters and alkynyl ketones resulted in selective addition to the alkyne triple bond. The cycloaddition of gem-difluorosubstituted NH-azomethine ylides with α,α,α-trifluoroacetophenones has been reported to form 4-fluorooxazolidines [143]. The optimized procedure involved stirring a mixture of the imine 223c, with an excess of trifluoroacetophenone (3o), CBr2F2, Pb filings and tetrabutylammonium bromide, and resulted in isolation of the fluoro-oxazolines 238 after chromatography on silica (Scheme 67, Table 31). Presumably the imine 223c reacts with liberated difluorocarbene to afford the azomethine ylide 236 which undergoes cycloaddition with The cycloaddition of gem-difluorosubstituted NH-azomethine ylides with α,α,α-trifluoro-acetophenones has been reported to form 4-fluorooxazolidines [143]. The optimized procedure involved stirring a mixture of the imine 223c, with an excess of trifluoroacetophenone (3o), CBr 2 F 2 , Pb filings and tetrabutylammonium bromide, and resulted in isolation of the fluoro-oxazolines 238 after chromatography on silica (Scheme 67, Table 31). Presumably the imine 223c reacts with liberated difluorocarbene to afford the azomethine ylide 236 which undergoes cycloaddition with trifluoroacetophenones 3 to afford the cycloadducts 237. On exposure to silica, the cycloadducts 237 lose HF to afford the 2-fluorooxazolidine products 238. A side-product 239 was at times isolated, that was thought to be formed by the isomerization of the ylide 236. The optimized method was applicable to a range of substituted benzophenone imines 223c and substituted trifluoroacetophenones 3 (Table 31). Additionally the products appear to have potential utility, with 238 undergoing displacement of the fluoride with a range of Nand O-centred nucleophiles. The cycloaddition of gem-difluorosubstituted NH-azomethine ylides with α,α,α-trifluoroacetophenones has been reported to form 4-fluorooxazolidines [143]. The optimized procedure involved stirring a mixture of the imine 223c, with an excess of trifluoroacetophenone (3o), CBr2F2, Pb filings and tetrabutylammonium bromide, and resulted in isolation of the fluoro-oxazolines 238 after chromatography on silica (Scheme 67, Table 31). Presumably the imine 223c reacts with liberated difluorocarbene to afford the azomethine ylide 236 which undergoes cycloaddition with trifluoroacetophenones 3 to afford the cycloadducts 237. On exposure to silica, the cycloadducts 237 lose HF to afford the 2-fluorooxazolidine products 238. A side-product 239 was at times isolated, that was thought to be formed by the isomerization of the ylide 236. The optimized method was applicable to a range of substituted benzophenone imines 223c and substituted trifluoroacetophenones 3 (Table 31). Additionally the products appear to have potential utility, with 238 undergoing displacement of the fluoride with a range of N-and O-centred nucleophiles.  In 2002, the first 1,3-dipolar cycloaddition of an azomethine ylide to an ester carbonyl was reported [144,145]. Azomethine ylides 5d, generated by the reaction of difluorocarbene with aryl and alkyl imines of O-acylated salicylaldehydes 217, underwent intramolecular 1,3-dipolar cycloaddition onto the ester carbonyl to give cycloadducts 240 (Scheme 68). This process proved to be quite general for a range of N-aryl substituted imines as well as N-alkylimines (Table 32). The cycloadducts 240a-m were stable enough to be isolated and characterized whereas the cycloadduct 240n, from the N-(trimethylsilylmethyl) imine, underwent rapid hydrolysis during chromatographic purification on silica, affording lactam 241 in 67% yield. Interestingly, the cycloadducts 240 degraded on longer term storage in chloroform, yielding, for example, from 240k after 3.5 months, salicylaldehyde (242) and phenylglyoxamide 243 (Scheme 69). In the cases of imines 217f-i there is an internal competition between cycloaddition of the ylide to the ester carbonyl and cycloaddition to the olefin. Only cycloaddition to the ester carbonyl was observed indicating a much faster rate of cycloaddition to the ester than these types of olefins. An external competition reaction was performed by running the reaction of 217k in the presence of a reactive dipolarophile, dimethyl acetylenedicarboxylate, and resulted in roughly equimolar amounts of intramolecular cycloadduct 240k and the pyrrole 244 resulting from intermolecular cycloaddition of the ylide with the alkyne (Scheme 70). Additionally the ylide 245 (Figure 4) did not undergo intramolecular cycloaddition, indicating the requirement of the close proximity of the ester group to the ylide for efficient ester carbonyl cycloaddition to occur.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241.  The reaction of analogous ylides derived from imines and dichlorocarbene has also been explored [146]. Although N-benzylidene anilines generally react with dichlorocarbene to give aziridines, the salicylaldehyde imines 217 reacted with dichlorocarbene, generated under a number of different conditions, to produce 2,5-epoxy-1,4-benzoxepin-3-ones 241, isolated in high yields (Scheme 71, Table 33). The proposed mechanism involves addition of the dichlorocarbene to the imine 217 to produce 5e which undergoes intramolecular cycloaddition of the ylide onto the ester carbonyl to give adduct 246 which then hydrolyses on work up or chromatographic purification, providing the isolated lactams 241. Scheme 71. Intramolecular cycloadditions of the azomethine ylide 5e. Scheme 71. Intramolecular cycloadditions of the azomethine ylide 5e. The chemistry of the bicyclic systems was also briefly explored. Reduction of 241b, o or i with LiAlH 4 in refluxing ether afforded the respective aminoalcohols 247b, o or i (Scheme 72). The analogous reduction of the difluorinated cycloadducts 240a and m, required more forcing conditions and was achieved in refluxing dioxane (Scheme 72, Table 34). The chemistry of the bicyclic systems was also briefly explored. Reduction of 241b, o or i with LiAlH4 in refluxing ether afforded the respective aminoalcohols 247b, o or i (Scheme 72). The analogous reduction of the difluorinated cycloadducts 240a and m, required more forcing conditions and was achieved in refluxing dioxane (Scheme 72, Table 34).

Reactions with Ylides Formed by Reaction of Isocyanides, Alkylboranes and Aldehydes
A multicomponent reaction of aldehydes 2, isocyanides 248 and trialkylboron reagents 249 resulted in formation of azomethine ylides 250 which underwent further reaction with aldehydes 2 to yield oxazolidines 251 in an efficient manner, with the aldehyde group playing dual roles in the formation of the ylide as well as the dipolarophile (Scheme 73) [147]. The reaction generally worked for aryl isocyanides and aryl carboxaldehydes, however failed in the case of alkyl and alkenyl isocyanides and sterically hindered aldehydes (Table 35).

Reactions with Ylides Formed by Reaction of Isocyanides, Alkylboranes and Aldehydes
A multicomponent reaction of aldehydes 2, isocyanides 248 and trialkylboron reagents 249 resulted in formation of azomethine ylides 250 which underwent further reaction with aldehydes 2 to yield oxazolidines 251 in an efficient manner, with the aldehyde group playing dual roles in the formation of the ylide as well as the dipolarophile (Scheme 73) [147]. The reaction generally worked for aryl isocyanides and aryl carboxaldehydes, however failed in the case of alkyl and alkenyl isocyanides and sterically hindered aldehydes (Table 35). The chemistry of the bicyclic systems was also briefly explored. Reduction of 241b, o or i with LiAlH4 in refluxing ether afforded the respective aminoalcohols 247b, o or i (Scheme 72). The analogous reduction of the difluorinated cycloadducts 240a and m, required more forcing conditions and was achieved in refluxing dioxane (Scheme 72, Table 34).

Reactions with Ylides Formed by Reaction of Isocyanides, Alkylboranes and Aldehydes
A multicomponent reaction of aldehydes 2, isocyanides 248 and trialkylboron reagents 249 resulted in formation of azomethine ylides 250 which underwent further reaction with aldehydes 2 to yield oxazolidines 251 in an efficient manner, with the aldehyde group playing dual roles in the formation of the ylide as well as the dipolarophile (Scheme 73) [147]. The reaction generally worked for aryl isocyanides and aryl carboxaldehydes, however failed in the case of alkyl and alkenyl isocyanides and sterically hindered aldehydes (Table 35). The mechanism that was proposed for this transformation involves a complex series of steps (Scheme 74). The process is initiated by addition of the isocyanide 248 to the trialkylborane 249 to give adduct 252. Alkyl migration would then give iminoborane 253. Further interaction of 253 with benzaldehyde 2a with concomitant alkyl migration gives an oxazaborolidine intermediate 254.
Electrocyclic ring-opening of 254 affords the non-stabilized azomethine ylide 250. Dipolar cycloaddition with further aldehyde 2a would then provide for the trans-oxazolidine 251.  The mechanism that was proposed for this transformation involves a complex series of steps (Scheme 74). The process is initiated by addition of the isocyanide 248 to the trialkylborane 249 to give adduct 252. Alkyl migration would then give iminoborane 253. Further interaction of 253 with benzaldehyde 2a with concomitant alkyl migration gives an oxazaborolidine intermediate 254.
Electrocyclic ring-opening of 254 affords the non-stabilized azomethine ylide 250. Dipolar cycloaddition with further aldehyde 2a would then provide for the trans-oxazolidine 251. Scheme 74. Proposed mechanism for the formation of oxazolidines 251.

Reactions of Dicyanoazomethine Ylides
The stable dicyanoazomethine ylides 257, derived from reaction of 3,4-diazanorcaradienes 255 with tetracyanoethylene oxide 256 [148], undergo reaction with a range of dipolarophiles [149]. The carbonyl dipolarophile trichloroacetaldehyde (2g) undergoes efficient cycloaddition with ylide 257 to give cycloadduct 258 isolated as a single endo stereoisomer in 40% yield (Scheme 75). The mechanism that was proposed for this transformation involves a complex series of steps (Scheme 74). The process is initiated by addition of the isocyanide 248 to the trialkylborane 249 to give adduct 252. Alkyl migration would then give iminoborane 253. Further interaction of 253 with benzaldehyde 2a with concomitant alkyl migration gives an oxazaborolidine intermediate 254.
Electrocyclic ring-opening of 254 affords the non-stabilized azomethine ylide 250. Dipolar cycloaddition with further aldehyde 2a would then provide for the trans-oxazolidine 251. Scheme 74. Proposed mechanism for the formation of oxazolidines 251.

Conclusions
The 1,3-dipolar cycloaddition reaction of azomethine ylides and carbonyl dipolarophiles is a general method for producing oxazolidines. In terms of scope, many ylides have been demonstrated to react with carbonyl groups including an array of stabilized and non-stabilized ylides and many more ylide systems could be explored. Aldehydes including formaldehyde are the most studied group of carbonyl dipolarophiles studied, with ketones are also being well represented. There are few examples of ketenes, even though these systems appear quite reactive. Activated carboxyl systems such as isataoic anhydrides and phthalic anhydrides have been shown to react with non-stabilized azomethine ylides and the interesting reactivity of the spiro-fused oxazolidine products deserves further exploration. An intramolecular cycloaddition of azomethine ylides and esters (the latter group is typically unreactive in dipolar cycloadditions) provides for bicyclic systems and also warrants further exploration.