Recent Advances in Solution-PhaseMulticomponent Methodology for the Synthesis of HeterocyclicCompounds

Abstract

Following the increased interest from the pharmaceutical industry for the generation of diverse libraries of heterocyclic compounds, scientific efforts have become more and more focused on the development of novel multi-component procedures as a means of gaining rapid access to such compounds. Initially, the development of solid-phase procedures received considerable attention. However, current efforts are increasingly concerned with the development of solution-phase procedures. The latter will be the subject of discussion in this review, which aims to give an overview of the progress made in the past decade.After a general introduction, non-catalyzed, acid-catalyzed, and transition metal-catalyzed solution-phase multi-component procedures for the preparation of a wide range of heterocycles will be discussed. The last chapter discusses the role of cycloaddition reactions in the development of novel MCRs for the synthesis of heterocyclic compounds.In spite of their important role in the synthesis of heterocyclic compounds, MCRs involving isocyanides are not discussed in this review, since the topic has been exhaustively reviewed several times.

Syntheses of Spirocyclic Oxindole‐Butenolides by Using Three‐Component Cycloadditions of Isocyanides, Allenoates, and Isatins

“…Encouraged by this result, a series of aliphatic and aromatic isocyanides were successively employed to react with allenoate 2 a and isatin 3 a. As shown in Table 1, the present reactions proceeded smoothly in all cases and all compounds 4 were characterized by IR, 1 H NMR, 13 C NMR, and HRMS spectroscopic analyses. [15] Moreover, the structures of compounds 4 were unambiguously confirmed by single-crystal X-ray analysis.…”

Syntheses of Spirocyclic Oxindole‐Butenolides by Using Three‐Component Cycloadditions of Isocyanides, Allenoates, and Isatins

“…Encouraged by this result, a series of aliphatic and aromatic isocyanides were successively employed to react with allenoate 2 a and isatin 3 a. As shown in Table 1, the present reactions proceeded smoothly in all cases and all compounds 4 were characterized by IR, 1 H NMR, 13 C NMR, and HRMS spectroscopic analyses. [15] Moreover, the structures of compounds 4 were unambiguously confirmed by single-crystal X-ray analysis.…”

β‐Carbolinone Analogues from the Ugi Silver Mine

“…Isocyanide-based multicomponent reactions (IMCRs) have attracted a lot of attention, due to the fact that versatile functional groups can be introduced in the MCR adducts, which can undergo further condensations or cyclizations reactions leading to an array of structurally diverse scaffolds. [10] In this study, starting from the Ugi-4CR of propargylamine 1a as an amine source, benzaldehyde 2a , indole-2-carboxylic acid 3a and tert -butyl isocyanide 4a in methanol at room temperature resulted to the corresponding Ugi adduct 5a in a good yield of 83 % after 12 h. With compound 5a in hand, we were keen to investigate the intramolecular hydroarylation. The initial investigation with Al(OTf ) 3 (20 mol-%) in CH 3 CN at 75 °C gave the desired product 6a but in a low yield of 21 %, whereas no product was detected with CuI, PTSA, TfOH, KOTf, and NaOTf.…”

Green synthesis of pyrazole systems under solvent-free conditions

“…The protonation of this intermediate by compound (1) led to the formation of a positively charged ion (7) that acts as a Michael acceptor. Therefore, the adduct (7) immediately undergoes Michael-type addition with anion of the NH-acid (8) to generate the open-chain intermediate (9). Finally, the ketenimine intermediate (9) can be converted to target molecule by intramolecular N-cyclization reaction.…”

Syntheses of Spirocyclic Oxindole‐Butenolides by Using Three‐Component Cycloadditions of Isocyanides, Allenoates, and Isatins

“…Encouraged by this result, a series of aliphatic and aromatic isocyanides were successively employed to react with allenoate 2 a and isatin 3 a. As shown in Table 1, the present reactions proceeded smoothly in all cases and all compounds 4 were characterized by IR, 1 H NMR, 13 C NMR, and HRMS spectroscopic analyses. [15] Moreover, the structures of compounds 4 were unambiguously confirmed by single-crystal X-ray analysis.…”

β‐Carbolinone Analogues from the Ugi Silver Mine

“…Isocyanide-based multicomponent reactions (IMCRs) have attracted a lot of attention, due to the fact that versatile functional groups can be introduced in the MCR adducts, which can undergo further condensations or cyclizations reactions leading to an array of structurally diverse scaffolds. [10] In this study, starting from the Ugi-4CR of propargylamine 1a as an amine source, benzaldehyde 2a , indole-2-carboxylic acid 3a and tert -butyl isocyanide 4a in methanol at room temperature resulted to the corresponding Ugi adduct 5a in a good yield of 83 % after 12 h. With compound 5a in hand, we were keen to investigate the intramolecular hydroarylation. The initial investigation with Al(OTf ) 3 (20 mol-%) in CH 3 CN at 75 °C gave the desired product 6a but in a low yield of 21 %, whereas no product was detected with CuI, PTSA, TfOH, KOTf, and NaOTf.…”

Green synthesis of pyrazole systems under solvent-free conditions

“…The protonation of this intermediate by compound (1) led to the formation of a positively charged ion (7) that acts as a Michael acceptor. Therefore, the adduct (7) immediately undergoes Michael-type addition with anion of the NH-acid (8) to generate the open-chain intermediate (9). Finally, the ketenimine intermediate (9) can be converted to target molecule by intramolecular N-cyclization reaction.…”

Syntheses of Spirocyclic Oxindole‐Butenolides by Using Three‐Component Cycloadditions of Isocyanides, Allenoates, and Isatins

“…Encouraged by this result, a series of aliphatic and aromatic isocyanides were successively employed to react with allenoate 2 a and isatin 3 a. As shown in Table 1, the present reactions proceeded smoothly in all cases and all compounds 4 were characterized by IR, 1 H NMR, 13 C NMR, and HRMS spectroscopic analyses. [15] Moreover, the structures of compounds 4 were unambiguously confirmed by single-crystal X-ray analysis.…”

β‐Carbolinone Analogues from the Ugi Silver Mine

“…Isocyanide-based multicomponent reactions (IMCRs) have attracted a lot of attention, due to the fact that versatile functional groups can be introduced in the MCR adducts, which can undergo further condensations or cyclizations reactions leading to an array of structurally diverse scaffolds. [10] In this study, starting from the Ugi-4CR of propargylamine 1a as an amine source, benzaldehyde 2a , indole-2-carboxylic acid 3a and tert -butyl isocyanide 4a in methanol at room temperature resulted to the corresponding Ugi adduct 5a in a good yield of 83 % after 12 h. With compound 5a in hand, we were keen to investigate the intramolecular hydroarylation. The initial investigation with Al(OTf ) 3 (20 mol-%) in CH 3 CN at 75 °C gave the desired product 6a but in a low yield of 21 %, whereas no product was detected with CuI, PTSA, TfOH, KOTf, and NaOTf.…”

Green synthesis of pyrazole systems under solvent-free conditions

“…The protonation of this intermediate by compound (1) led to the formation of a positively charged ion (7) that acts as a Michael acceptor. Therefore, the adduct (7) immediately undergoes Michael-type addition with anion of the NH-acid (8) to generate the open-chain intermediate (9). Finally, the ketenimine intermediate (9) can be converted to target molecule by intramolecular N-cyclization reaction.…”