Pyrrolo pyrrolidine derivative

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

The precursor of (+ )-anthramycin, pyrrolo-benzodiazepine 196, can be synthesized by deprotection, acylation and reductive cyclization of pyrrolidine derivative 195, obtained by enyne metathesis (Scheme 40 (2004T9649)). 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

The most general synthesis of substituted 6,7-dihydro-5/f-pyrrolo[l,2-a]imidazoles has been described in several patents. The starting materials are pyrrolidine derivatives such as the 2-iminopyrrolidine or 2-pyrrolidone (Scheme 8) <89EUP306300, 92MI 802-01 >. In the first case, the 2-iminopyrrolidine reacts with the chloroketone (57) at 40°C to give the dihydro pyrrolo[l,2-a]im-idazole (58). In the second case the 2-pyrrolidone was A -acylated by 4-picolyl chloride and the product (59) cyclocondensed with a nitrile to give the 2,3-diaryl-6,7-dihydro-5//-pyrrolo[l,2-a]im-idazole (60). 

Monteiro and coworkers [97] reported the synthesis of pyrrolo[2, l,c]pyrrolidine derivate 126, which was again the sole isolated product under optimized conditions no traces of the endo-cychc double-bond isomer could be detected (Scheme 6.34). 

Rodgers JD, Shepard SA, Argyrios G, Wang H, Storace L, Folmer B, Shao L, Zhu W, Glenn J (2010) N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[23-d]pyrimidines and pyrrol-3-ylpyrrolo[2,3-d]pyrimidines as janus kinase inhibitors. US2010/298334(A1)... 

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]. 

According to a recent report, however, the carbonyl ylides formed under these conditions may isomerize and lead to adducts different from those normally expected87. Thus, (5)-l-acetyl-2-(diazoacetyl)pyrrolidine (8). derived from /V-acetyl-i.-proline, upon treatment with dimethyl butynedioate in the presence of a catalytic amount of rhodium(II) acetate dimer at 25 °C affords only 10% of the expected adduct dimethyl 5,8-epoxy-2,3,5,8,9,9a-hexahydro-5-methyl-9-oxo-lH-pyrrolo[l, 2-o]azepine-6,7-dicarboxylate (9). Instead, dimethyl 1,2,8,9-tetrahydro-5-methyl-l-oxo-3a//,7//-furo[3,2-g]pyrrolizine-3a,4-dicarboxylate (10) is obtained in 87% yield. The formation of this product is explained via an isomeric ylide87 and thus occurs with complete loss of chiral information. 

Monsal and coworkers have achieved the construction of pyrrolidine nucleus in the synthesis of tetrahy-dropyrrolo[3, 4 3.4]pyrrolo[2.1-fl]isoquinoline-9,ll-diones 57 derivatives in an aqueous micellar medium [53]. The S5mthesis involves a one-pot three-component reaction of variously substituted isoquinolines 54, 2-bromoacetophenone 55, and N-arylmaleimide derivatives 56 in the presence of triethylamine as a base (Scheme 18). The preliminary investigation indicated that the presence of surfactant was essential for the success of reaction. Accordingly, the reactions were carried out in cationic, anionic, and nonionic surfactants well above their critical micelle concentrations (CMC). The maximum yields were obtained in cetyltrimethylammonium bromide (CTAB) (CTABiCMC value 0.29 mM at 80mM concentration). The mechanism of formation involves an in situ generation of isoquinolinium ylides followed by [2 -h3] cycloaddition of N-aryl maleimides. 

---