Isoquinoline, pyrrole-fused

The cycloaddition reactions of isoquinolinium species produce fused isoquinoline products. The Af-ylide of 53, formed with base addition, couples with alkenes <99S51> or imines <99T7279> to afford tricyclic products, such as 54. Pyrrole-fused isoquinolines result from the reaction between mUnchnone imine intermediates and a,yff-ethylenic esters <99EJOC297>. N-Arylimides undergo 1,3-dipolar cycloaddition with strained frani-cyclooctenes, as opposed to common cycloalkenes, to tdford the pyrazolidine-fused ring system <99H(50)353>. 

The precursor 514 has been shown to undergo anodic oxidation to produce the 5-amino-l,2-thiazolium salt 515, which rearranged to the pyrrole 516 upon treatment with triethylamine (Scheme 68) <1995JPR310>. The mechanistic aspects of this approach have also been discussed <1996J(P1)2339>. Cycloaddition of nitrones with acetylenes has been used to generate A -isoxazolines, which underwent thermal rearrangement to pyrroles fused to the isoquinoline framework <1996T12049>. 

Using a dipole precursor as the amine component in imine formation, the iso-quinolinium intermediate undergoes [3 + 2] cycloaddition to form fused isoquinoline derivatives. Su and Porco found that treatment of alkynylimines 175 with AgOTf (10 mol %) affords azomethine ylides 178, which undergo dipolar cycloaddition in the presence of appropriate alkynes to give pyrrole-fused isoquinolines 176 (Scheme 19.44) [80]. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

We move from benzo-fused pyrroles to benzo-fused pyridines and meet quinoline and isoquinolinc. Isoquinolines will feature as benzyl isoquinoline alkaloids in Chapter 51 and their synthesis will mostly be discussed there. In this section we shall concentrate on the quinolines. 

Azomethine ylide cycloadditions have been utilized to prepare a number of novel fused pyrroles including pyrrolo[2,l-u]isoquinolines <06CHJC279, 06TL1469> and pyrrolo[l,2-i>]pyridazines <06SL804>. Fused hydroxypyrroles were obtained in cycloaddition reactions with trimethylsilylketenes (TMS ketene) <06TL1469>. 

Arndtsen and co-workers developed an isocyanide-mediated three-component synthesis ofthe polysubstituted pyrroles 97, wherein an acyclic imine was activated in situ by acylation [54]. Thus, reaction of an imine, an acyl chloride, an alkyne, and an isocyanide in the presence of PrNEt2 afforded 97 in good to excellent yields (Scheme 5.29). A complex reaction sequence involving formation ofthe N-acyliminium by [4 + 1] followed by [3 + 2] cycloadditions and a retro-cycloaddition was proposed to account the formation of 97. The isocyanide participated actively in this reaction sequence however, it was not incorporated in the final adduct since it was lost as isocyanate by a retro-D-A reaction. The aliphatic imine was shown to be an appropriate substrate, at least in one case, leading to the corresponding pyrrole (R2 = isopropyl) in 72% yield. Azenes participated in this reaction in a similar manner. Thus, the isoquinoline 94 was converted to the benzo-fused pyrrole 98 in 50% yield. 

The quaternization of a j8-carboline, followed by the generation of an azomethine ylid, enables cycloaddition of diethyl acetylenedicarboxylate to yield the fused pyrrole product (357) (Scheme 115) <89TL3423>. Similar systems, namely the pyrrolo[2,l-a]isoquinolines, have been formed by an intramolecular electrophilic substitution on the 2-aryl ring of a suitably substituted pyrrole (358) (Equation (104)) <93JCS(Pi)276i>. 

Two bicyclic aromatic compounds contain one nitrogen quinoline (N at position 1) and isoquinoline (N at position 2). Indole has a pyrrole unit fused to a benzene ring to give a bicyclic aromatic system with N at position 1. 

R =aryl) in aprotic solvents, for example, xylene at 140 °C, is more important and has been applied very frequently to prepare indoles of type 176 via intermediate 172. This method is connected with the names of Hemetsberger and Knittel and can be transferred to the synthesis of azaindoles, fused indoles, and fused pyrrol derivatives. Quite recently, reactions like 171 (R =Ph) —> 176 have been conducted in a rhodium(II)-catalyzed way, which allows to decrease the necessary temperature into a range of 25-60 C. The transformation of 171 into isoquinolines is also possible if one or both ortho positions of the aryl group R are substituted appropriately. ... 

Transition-metal-mediated C—X bond formation by intramolecular reactions with alkynes is a powerful strategy for the construction of heteroarene rings such as pyridines, pyrroles, and furans. Because of the wide availability of Sonogashira coupling of various haloarenes with terminal alkynes, these transformations provide efficient routes to synthesize fused heteroarenes, including isoquinolines, indoles, and benzofurans. In this chapter the construction of aromatic rings by transition-metal-catalyzed or transition-metal-mediated intramolecular C—X bond formation between C—X or X—H and alkynes is described. As shown in Scheme 19.1, Section... 

As described in this chapter, transition-metal catalysts promote various types of cyclization reactions between C=N, C=0, N—H, O—H, and S—H bonds and alkynes in 5/6-endo/exo-dig manners. These reaction modes provide facile and atom-economical pathways to aromatic compounds such as pyrroles, indoles, isoquinolines, quinolines, furans, thiophenes, oxazoles, pyrones, and isoquinolones and their aza analogs and fused-ring congeners. Particularly notable is their utility in cascade reactions, which are step-economical approaches to target molecules, which increase rapidly in structural complexity. Therefore, these reactions can help provide solutions to meet the increasing demands of environmentally benign synthesis in modern organic chemistry. 

Larocket fl/. in 2000 developed the fluoren-9-one synthesis by the cyclocarbonyla-tion of ort/zo-halobiarys with a commercially available Pd(PCy3)2 catalyst [17] This procedure was initiated by the palladium(0) and could be utilized to the synthesis of polycyclic and heterocyclic fluorenones containing the fused isoquinoline, indole, pyrrole, thiophene, benzothiophene, and benzofuran rings (Table 15.12). 

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