Intramolecular cycloadditions azomethine ylides

Mono- and disubstituted N-alkyl and N-arylaziridines are reported to undergo a photoinduced electron transfer [3+2] cycloaddition to dipolarophiles to produce five-membered heterocycles, and it is suggested that in this process the radical cation intermediate behaves differently from the corresponding classical azomethine ylide. Intramolecular [4+4] photocycloaddition of the dipyridyl-propane (73) followed by Li/NHa reduction is a useful route to the eleven-membered ring system (74), and on irradiation of benzene solutions of 2,3-dicyano-5,6-dimethylpyrazine in the presence of allylic silanes a [2+2] cyclisation is induced followed by rearrangement to give 2,8-diazatricyclo[3.2.1.0 ]oct-2-ene (75 R = H, Me). ... 

Cycloaddition reactions also provide a very straightforward means for the preparation of the quinoline scaffold. Hexahydropyrrolo[3,2-c]quinolines, the core structure of the Martinella alkaloids, were prepared through an intramolecular 3 + 2] azomethine ylide-alkene cycloaddition. Condensation of an aldehyde such as 51 and W-alkyl amino acids followed by decarboxylation and cycloaddition afforded quinoline derivatives such as 52 <01T4095>. The... 

Scheme 4.20 Synthesis of fused tricyclic amine by intramolecular 1,3-dipolar azomethine ylide-alkene cycloaddition.

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

The feasibility of azomethine ylide generation from 7 and intramolecular dipolar cycloaddition was examined under a variety of conditions. For example, activation of vinylogous amide 71 with BzOTf [41] followed by desilylation with TBAT led to complex mixtures of products. Likewise, using MeOTf as the activating agent yielded similar results. Significantly, none of these protocols furnished the desired pyrrolidine 73. Only decomposition of the silylpyridinone to form unidentified products was observed, despite the fact that quantitative O-methylation of the... 

Scheme 6.186 Intramolecular azomethine ylide-alkene/alkyne [3+2] cycloadditions.

Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted azomethine ylides have been conducted under microwave irradiation. Oritani reported that a mixture of the aldehyde 137 and N-methyl- or N-benzylglycine ethyl ester (138) on the surface of silica gel, irradiated under microwaves for 15 min, generated azomethine ylides 139 that subsequently underwent in situ intramolecular cycloadditions to afford the corresponding tricyclic compounds 140 in 79 and 81% yield, respectively (Scheme 9.42) [93],... 

The photocycloaddition of aliphatic and aromatic aldehydes with 2,4,5-trimethyloxazole (131) gave bicyclic oxetanes 132 in almost quantitative yields hydrolitic cleavage led selectively to erytro a-amino-P-hydroxy methyl ketones 133 <00CC589>. The oxazolium salt 134 was converted to the azomethine ylide 136 via electrocyclic ring opening of the oxazoline 135. Intramolecular cycloaddition afforded 137 in 66% overall yield which was transformed into the aziridinomitosene derivative 138 . 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

The addition to alkenes normally leads to unstable adducts that lose carbon dioxide under the reaction conditions. The intramolecular cycloaddition of the sydnone (30) takes place at room temperature, however (Equation (5)) and the cycloadduct (31) has been characterized <86HCA927>. The unstable species formed by the loss of carbon dioxide are also azomethine ylides. It is therefore possible for a second 1,3-dipolar addition to take place, as illustrated in Scheme 6 for the reaction of 3-phenylsydnone with Al-phenylmaleimide <86TL317,92JA8414>. This 2 1 addition has been used as the basis of a synthesis of polyimides. Imides of the type (32) were used as the dipolarophiles and their reaction with 3-phenylsydnone gave linear polymers <87MM726>. 

Azomethine ylide generation from oxazolidines has also been achieved by flash vacuum thermolysis (20,21). During synthetic efforts toward alkaloid central skeletal cores, Joucla and co-workers (22) revealed that flash vacuum thermolysis of oxazolidine (84) led to an intramolecular [3 + 2] cycloaddition furnishing pyrrolidine 85 in 82% as a single regio- and stereoisomer. Subsequent Dieckmann... 

The proposed reaction pathway invokes initial formation of carbonyl ylide 100 by intramolecular cyclization of the intermediate keto carbenoid onto the oxygen atom of the amide. Subsequent isomerization to the azomethine ylide is followed by 1,3-dipolar cycloaddition to DMAD to furnish the intermediate cycloadduct 101, which undergoes in situ alkoxy 1,3-shift to the final drhydropyrrolizine 102 (Scheme 3.28). 

In this section, those reactions in which the ylide is attached by a tether to the dipolaraphile resulting in an intramolecular cycloaddition will be discussed. To date, such a strategy has proved to be one of the less investigated aspects of azomethine ylide chemistry. However, intramolecular azomethine ylide technology, when combined with the excellent stereocontrol offered by cycloaddition reactions, allows for the rapid construction of complex polycyclic systems from relatively simple precursors. Consequently, it represents a highly attractive synthetic protocol that makes it a candidate for further investigation in the coming years. 

At about the same time, Wenkert and c-workers (75) reported a similar smdy into the intramolecular 1,3-dipolar cycloaddition of 2-alkenoyl-aziridine derived azomethine ylides. Thermolysis of 231 at moderate temperature (85 °C) produced 232 as a single isomer in 58% yield. Similarly, 233 furnished 234 in 67% yield. In each case, the same stereoisomers were produced regardless of the initial stereochemistry of the initial aziridine precursors. However, the reaction proved to be sensitive to both the substituents of the aziridine and tether length, as aziridines 235 and 236 furnished no cycloadducts, even at 200 °C (Scheme 3.79). 

During the synthetic efforts of Heathcock and co-workers toward the complex marine alkaloid sarain-A (Scheme 3.80), he outlined an elegant intramolecular, azomethine ylide cycloaddition, as one of the key stages in the construction of the central core (76). Of the generation methods known for azomethine ylides, thermolysis of aziridines was selected in this instance. The azomethine ylide... 

In a similar approach, Garner et al. (78) made use of silicon-based tethers between ylide and dipolarophile during their program of research into the application of azomethine ylides in the total asymmetric synthesis of complex natural products. In order to form advanced synthetic intermediates of type 248 during the asymmetric synthesis of bioxalomycins (249), an intramolecular azomethine ylide reaction from aziridine ylide precursors was deemed the best strategy (Scheme 3.84). Under photochemically induced ylide formation and subsequent cycloaddition, the desired endo-re products 250 were formed exclusively. However, due to unacceptably low synthetic yields, this approach was abandoned in favor of a longer tether (Scheme 3.85). 

A novel application of phosphate-stabilized ylides in intramolecular reactions has been reported by Martin and Cheavens (87). Thus, condensation of aldehydes of the type 293 with the amine 294 furnished the intermediate azomethine ylide, which then underwent a cycloaddition process, leading to pyrrolidines 295, where... 

Harwood and Lilley (87) reported the tandem generation and intramolecular trapping of a stabilized azomethine ylide, derived from the enantiopure template examined in detail in Section 3.2.3. Condensation of 5-hexenal with template 205 under standard conditions led to in situ ylide generation and subsequent cycloaddition of the tethered alkene to furnish 296 as a single enantiomer in 95% yield after purification and this despite the fact that the dipolarophile is unactivated. Hydro-genolytic destruction of the template revealed the bicyclic amino acid 297 in 75% yield (Scheme 3.97). 

In a similar study to that outlined by Grigg, Kanemasa et al. (68) has demonstrated the intramolecular cycloaddition of azomethine ylides derived from either amino acids or esters. Treatment of the amino methyl ester 302 with... 

Treatment of proline derivative 154 with rhodium acetate (57) originally led to ylide 155. However, this ylide (155) quickly rearranges to the more stable azomethine ylide 156, which undergoes cycloaddition with DMAD to give the unusual adduct 157. Intramolecular trapping experiments (58,59) have also been conducted (Scheme 4.35). 

---