Sarcosine, azomethine ylides

The central five-membered ring of Manzamine A (315), a member of a family of antileukimic and antibacterial marine polycyclic alkaloids, has been constructed using intramolecular azomethine ylide technology (88). Model studies on the construction of the central ABC rings, by condensation of the aldehyde 316 prepared by standard chemistry with sarcosine ethyl ester, furnished the desired ABC ring system as a single diastereoisomer in 45% yield (Scheme 3.105). 

Confalone and Earl have reported a series of intramolecular azomethine ylide cyclizations employing a-dithiolanyl aldehydes (Scheme 35).60 Thus, reaction of the aldehydes (115a-b) with ethyl sarcosinate at 140 C provided the 5,6-fused bicyclic pyrrolidines (116a-b), presumably via cyclization of the singly stabilized azomethine ylides. The dithiolanyl group could be removed by standard reactions this route then provides bicyclic pyrrolidines which cannot be prepared directly from enolizable aldehydes. 

Spirooxindoles, such as, for example ( )-coerulescine (101) have been prepared employing a sequence starting from 2-fluoronitrobenzene, which was initially subjected to treatment with the anion of dimethyl malonate, followed by decarboxylation and concomitant installation of the methylene group using formaldehyde in the presence of potassium carbonate to produce the intermediate 102 in good yield. This material readily underwent dipolar cycloaddition with the azomethine ylide generated from sarcosine and formaldehyde, followed by a reductive cyclization of adduct 103 to furnish the natural product 101 <02TL9175>. 

Pyrrolo[3,4-c]quinolines are synthesized by 1,5-electrocyclisation of azomethine ylides. 2-Aryl-3-formylquinolines were reacted with sarcosine in refluxing xylene. The products were purified in fair yields. Trapping with iV-phenylmaleimide <03TL2343> showed presence of the azomethine ylide intermediate. 

According to Eq. (11), Confalone has presented a new method of generation of azomethine ylides through the condensation of N-substituted ot-amino esters with aldehydes (83JOC2994 84JA7175). Thus, 5-formylmethyldibenzo-[a.d]tropylidene or o-(allyloxy)benzaldehyde is heated with ethyl sarcosinate or methyl prolinate under reflux in toluene. The water formed is continuously driven off with the aid of a Dean-Stark trap. The ester-stabilized azomethine ylide 77 or 78 quantitatively generated is trapped in an intramolecular fashion. 

The only example has been reported by Achiwa (84TL1579). Thus, methyl Af-(phenylthiomethyl)sarcosinate is treated with sodium hydride (2 equivalents) in 1,2-dimethoxyethane (DME) and hexamethylphosphoric triamide (HMPA) to lead to azomethine ylide 91. A cyclic ylide, 92, is generated by a similar procedure using methyl Af-(phenylthiomethyl)prolinate and trapped with a dipolarophile to give the corresponding cycloadduct as a 1 1 regio-isomeric mixture. 

During investigations on the carbonyl-assisted decarboxylation of N-alkylated ot-amino acids, Rizzi found that azomethine ylide intermediates are involved in the decarboxylative condensation (70JOC2069). Heating sarcosine and benzophenone at 170°C (or benzaldehyde at 150-170°C) gave 3-methyl-2,2,5,5-tetraphenyloxazolidine, which corresponds to the cycloadduct of azomethine ylide 98 to the carbonyl compound. This sequence may involve the initial formation of iminium carboxylate betaines and subsequent decarboxylation to generate nonstabilized azomethine ylides [Eq. (15)]. This... 

The influence of water as a solvent on the rate of dipolar cycloadditions has been reported [76]. Thus the rate of the 1,3-dipolar cycloaddition of 2,6-dichloroben-zonitrile N-oxide with 2,5-dimethyl-p-benzoquinone in an ethanol/water mixture (60 40) is 14-fold that in chloroform [76b]. Furthermore the use of aqueous solvent facilitates the workup procedure owing to the low solubility of the cycloadduct [76b]. In water-rich solutions, acceleration should be even more important. Thus in water containing 1 mol% of l-cyclohexyl-2-pyrrolidinone an unprecedented increase in the rate of the 1,3-dipolar cycloaddition of phenyl azide to norbornene by a factor of 53 (relative to hexane) is observed [77]. Likewise, the 1,3-dipolar cycloaddition of C,Ar-diphenylnitrone with methyl acrylate is considerably faster in water than in benzene [78]. Similarly, azomethine ylides generated from sarcosine and aqueous formaldehyde can be trapped by dipola-rophiles such as N-ethylmaleimide to provide pyrrolidines in excellent yields... 

During investigations on the carbonyl-assisted decarboxylation of N-alkylated a-amino acids, Rizzi found that azomethine ylide intermediates are involved in the decarboxylative condensation (70JOC2069). Heating sarcosine and benzophenone at 170°C (or benzaldehyde at 150-170°C) gave... 

As already discussed (Section II,E), sarcosine undergoes a condensation with acetophenone or benzophenone to generate the corresponding azomethine ylide 98 (R = H or Ph), which is then trapped with the carbonyl compound giving rise to 3-methyl-2,5-diphenyl- or 3-methyl-2,2,5,5-tetra-phenyloxazolidine 211 (R = H or Ph) (70JOC2069). Similar condensation of... 

The densely functionalized dispiro species 157 has been stitched together by Mondal and coworkers who choreographed a three-component azomethine ylide strategy for spirocyclization [83]. In the event, isatin 154, amino add (sarcosine 155), and the exocyclic a,p-unsaturated lactone (andrographolide 156) were combined to afford the aza-spirooxindole 157 in 60% yield (Scheme 39). 

Novel dicyano-functionalized spiropyrrolizidine (166 and 167) and spiropyrro-lidine (168 and 169) were synthesized in a regio- and stereoselective manner from the reaction of various arylidenemalononitriles (163) with nonstabilized azomethine ylides generated from isatin (155)/acenaphthenequinone (159) and proline (160)/ sarcosine (164)/N-phenylglycine (165). The reactions were carried out under both conventional heating and ultrasonic irradiation conditions (Scheme 8.53). In general, improvement in rates and yields were observed when the reactions were carried out under sonication compared with classical conditions (Rezaei et al. 2011). 

A formal [3-I-3]-cycloaddition of azomethine ylide derived from sarcosine and formaldehyde with benzaldehydes has been reported to give 5-aryloxazolidines which rearrange to 2-methyl-l,2,3,4-tetrahydroisoquinolin-4-ols on heating with hydrochloric acid (Scheme 63). ... 

Another reaction type involving iminium salts led to pyrrolidines via the trapping of azomethine ylides generated from sarcosine and aqueous formaldehyde (Lubineau et al, 1995). The efficiency of [3+2] cycloaddition was related to the water content. Indeed, adding THF to the reaction medium decreased the rate of the Michael addition, which competed with the desired pyrrolidine synthesis ... 

There are several examples in literature on cycloaddition of alkenes to azomethine ylides, generated in situ by decarboxylative condensation of isatins with an a-amino acid, sarcosine (MeNHCH2C02H), for architecture of pyrrolidine ring in spiro-pyrrolidine-oxindoles [55]. The cycloaddition of ylide 62 from N-methylisatin 58 and sarcosine to 3,4-diphenylcyclobutene-l,2-dione 63 proceeded smoothly to afford the product 64 (Scheme 20) [56]. 

Kathiravan and Raghxmathan reported the synthesis of pyrrole-fused polycyclic heterocycles via intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides derived from pyrrole-2-carbaldehyde 28 and secondary amino acids in IL [BM1M][BF4]. The methodology involved the synthesis of N-alkenyl carboxaldehyde from 28 followed by freafment with sarcosine in [BM1M][BF4] as reaction medium at 85-95 C for about 3h to afford pyrrolo-pyrrolidines 29 in good yield (Scheme 3). The same reaction when carried out in organic solvents such as toluene, methanol, and acetonitrile, the reactions observed were slow, giving product in low yield [80]. 

An alternative transformation in this class involved the generation of azomethine ylides from the decarbojqrlative condensation of amino acids, specifically proline, thiazolidine-4-carbo grlic acid and sarcosine (not shown),... 

---