2,3-Disubstituted pyrrolo

Several 2,3-disubstituted pyrrolo[2,3-fe]pyridines (7-azaindoles) 24 have been obtained with high regioselectivity by Pd-catalyzed heteroannulation of alkynes with 2-amino-3-iodopyridine derivatives under the experimental conditions shown in Scheme 14 (1998TL627). The easy manipulation of substituents was also demonstrated. 

Several new 2,4-disubstituted pyrrolo[2,l- [l,2,4]triazines, which can be further elaborated, and pyrrolo[5,1 -c]pyrimido[4,5-e] [ 1,2,4]triazines have been made by the reaction of iV,Af-dimethyl-dichloromethyleniminium chloride with l-aminopyrrole-2-carbonitrile and ethyl 4-aniino-3-cyanopyrazolo 5,l-c][l,2,4]triazine-8-carboxylate respectively (Scheme 7) <9613037 >. 

Condensed quinoxalines have been synthesized using 2-chloro-3-alkynylquinoxalines as common intermediates. 2-Chloro-3-phenylethynylquinoxaline 98 was prepared from 2,3-dichloroquinoxaline (97). Action of methylamine on 98 gave 1,2-disubstituted pyrrolo[2,3-fcjquinoxaline 99. Similarly, 2-phenylthieno[2,3-fc]quinoxaline 100 was synthesized by treating 98 with ethanolic sodium sulfide. 

Photolytic cleavage of 2,3-disubstituted 2H-azirines or monoaryl-2H-azirines provides access to nitrile yiides with the structure 280.1,3-Dipolar cycloaddition of the in situ generated yiides to Cjq affords mono- or disubstituted pyrrolo fullerenes such as 281 (Scheme 4.50) [319, 320]. Aliphatic 2H-azirines are not reactive, as they have shorter excitation wavelengths than the phenylic substituted 2-azirines. 

Dipole moments for several mono- and disubstituted pyrrolo[2,3-3]pyridines, 26, have been calculated using the PM3 method <1997JFA2345>. The values range from approximately 1 D for 3-halo-substituted compounds to 5.14 D for the 3-nitro deriv ative (see Table 1, Section 10.06.2.2). 

Reaction of 4-thiazolones (236) with N-arylmaleimides gives 5,8-disubstituted pyrrolo[2,3 4, 5 ]pyrrolo[2, I -6]thiazol-3,6-(2//,7//)-diones (237) (83H1021) (Scheme 58). 

Disubstituted pyrrolo[2,l-Z ]thiazoles (296) have been obtained by treatment of the lithio derivative (293) of 2,4-dimethylthiazole (292) with a-haloketones at — 55 °C giving (294). Cyclization to (295) and dehydration under mild conditions afforded the corresponding pyrrolothiazole (296) in good yield (63-65%) (Scheme 53) <86JCS(P1)1255>. 

Pal and collaborators designed a ligand- and phase-transfer-catalyst-free intramolecular Heck reaction which they applied to the synthesis of 1,3-disubstituted pyrrolo[2,3-f)]quinoxalines 158, some of which were... 

A. Keivanloo, M. Bakherad, A. Rahimi, S.A.N. Taheri, One-pot s)mthesis of 1,2-disubstituted pyrrolo[2,3-i>]quinoxalines via palladium-catalyzed heteroannulation in water. Tetrahedron Lett. 51 (2010) 2409-2412. 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

In the search of new methodologies for the asymmetric synthesis of nonproteinogenic amino acids, 8-methyl-4,8a-diphenyltetrahydro-17/-pyrrolo[2.1 -r l, 4 oxazinc-l, 6(7//)-dionc 62, obtained as described in Scheme 24 (Section 11.11.7.3), was selectively reduced at the lactam carbonyl with BH3 and further opened by hydrogenolysis to give syn-disubstituted proline derivative 64 in 95% yield <1997SL935> (Scheme 6). It is noteworthy that hydrogenolysis did not affect the benzylic position of bicyclic compound 63. 

The /V-acyl compounds are very suitable for the synthesis of pyrrolo[3,4-b]pyridines (10). As a rule, these compounds are synthesized starting from 2,3-disubstituted pyridines (69BCJ2996 75CB1003 77CCC283). Only a... 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

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