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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Addressing a dynamic aspect of organic chemistry, this book describes synthetic strategies and applications for multicomponent reactions - including key routes for synthesizing complex molecules. * Illustrates the crucial role and the important utility of multicomponent reactions (MCRs) to organic syntheses * Compiles novel and efficient synthetic multicomponent procedures to give readers a complete picture of this class of organic reactions * Helps readers to design efficient and practical transformations using multicomponent reaction strategies * Describes reaction background, applications to synthesize complex molecules and drugs, and reaction mechanisms
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Seitenzahl: 958
Veröffentlichungsjahr: 2015
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CONTENTS
COVER
TITLE PAGE
LIST OF CONTRIBUTORS
PREFACE
LIST OF ABBREVIATIONS
1 INTRODUCTION
GENERAL INTRODUCTION
1.1 BASIC CONCEPTS
1.2 CATALYSIS IN MCRs AND VARIOUS SYNTHETIC APPROACHES
1.3 GREEN CHEMISTRY
1.4 IMPORTANCE AND EVOLUTION
REFERENCES
2 ORGANOCATALYTIC ASYMMETRIC MULTICOMPONENT REACTIONS
2.1 INTRODUCTION
2.2 THREE-COMPONENT MANNICH REACTION
2.3 CYCLOADDITION REACTION
2.4 ORGANOCATALYTIC MULTICOMPONENT DOMINO ASYMMETRIC REACTIONS
2.5 DEVELOPMENT OF DRUG INTERMEDIATES
2.6 MISCELLANEOUS REACTION
2.7 CONCLUSIONS
REFERENCES
3 METAL-CATALYZED MULTICOMPONENT REACTIONS
3.1 INTRODUCTION
3.2 PALLADIUM-CATALYZED MCRs
3.3 NICKEL-CATALYZED MCRs
3.4 GROUP 11 METAL-CATALYZED MCRs
3.5 RHODIUM-CATALYZED MCRs
3.6 GROUP 8 METAL-CATALYZED MCRs
3.7 CONCLUSIONS
REFERENCES
4 MULTICOMPONENT REACTIONS WITH ORGANOBORON COMPOUNDS
4.1 INTRODUCTION
4.2 CATALYTIC MCRs WITH ORGANOBORON COMPOUNDS
4.3 MULTICOMPONENT ASSEMBLY OF ORGANOBORON COMPOUNDS: EFFICIENT APPROACH TO SUPRAMOLECULAR CHEMISTRY
4.4 MULTICOMPONENT PETASIS-BORONO–MANNICH REACTION
4.5 ALLENYLBORATES IN MCRs
4.6 MULTICOMPONENT HETERO-DIELS–ALDER/ALLYLBORATION
4.7 PALLADIUM-CATALYZED ASYMMETRIC ALLENE DIBORATION/α-AMINOALLYLATION
4.8 SYNTHETIC APPLICATIONS OF BORON-BASED MCRs
4.9 CONCLUSION
REFERENCES
5 CARBENE-PROMOTED MULTICOMPONENT REACTIONS
5.1 INTRODUCTION
5.2 MCRs INVOLVING CARBENES AS KEY COMPONENTS
5.3 MCRs INVOLVING CARBENES AS CATALYSTS
5.4 SYNTHETIC UTILITY
5.5 CONCLUSION
REFERENCES
6 MULTICOMPONENT REACTIONS IN THE SYNTHESIS OF TARGET MOLECULES
6.1 INTRODUCTION
6.2 MCRs IN DRUG DISCOVERY AND FOR THE SYNTHESIS OF BIOLOGICALLY IMPORTANT MOLECULES
6.3 SYNTHESIS OF NATURAL PRODUCTS IN AN EFFICIENT MANNER
6.4 HETEROCYCLES AS KEY SUBSTRATES IN MCRs
6.5 AMINO ACID DERIVATIVES BY MCRs
6.6 INDUSTRIAL APPLICATIONS
6.7 CONCLUSION
REFERENCES
7 RECENT ADVANCES IN THE UGI MULTICOMPONENT REACTIONS
7.1 INTRODUCTION
7.2 UGI THREE-COMPONENT REACTIONS
7.3 UGI FOUR-COMPONENT REACTIONS
7.4 FIVE-, SIX-, SEVEN-, AND EIGHT-COMPONENT REACTIONS BASED ON THE UGI REACTION
7.5 UGI POSTMODIFICATION PROCESSES
7.6 UGI–SMILES APPROACH
7.7 UGI–SMILES POSTMODIFICATION PROCESSES
7.8 CONCLUSION
REFERENCES
8 PASSERINI MULTICOMPONENT REACTIONS
8.1 INTRODUCTION
8.2
O
-ALKYLATIVE AND SILYLATIVE PASSERINI THREE-COMPONENT REACTIONS
8.3 PASSERINI 3CR UNDER OXIDATIVE CONDITIONS
8.4 SYNTHESIS OF MACROCYCLES BY A PASSERINI REACTION
8.5 ENANTIOSELECTIVE METAL-CATALYZED PASSERINI REACTION
8.6 SYNTHESIS OF PHARMACOLOGICALLY IMPORTANT PEPTIDOMIMETICS
8.7 MULTICOMPONENT PASSERINI APPROACH TO IMPORTANT TARGETS
8.8 α-HYDROXYCARBOXAMIDE, AN IMPORTANT INTERMEDIATE FOR CHEMICAL SYNTHESIS
8.9 PASSERINI 3CR UNDER ECO-FRIENDLY REACTION CONDITIONS
8.10 CONCLUSIONS
REFERENCES
9 BIGINELLI MULTICOMPONENT REACTIONS
9.1 INTRODUCTION
9.2 MECHANISM
9.3 CHIRAL LEWIS- AND BRØNSTED ACID-CATALYZED BIGINELLI REACTIONS
9.4 BRØNSTED BASE-CATALYZED ONE-POT THREE-COMPONENT BIGINELLI-TYPE REACTIONS
9.5 ORGANOCATALYTIC ENANTIOSELECTIVE BIGINELLI REACTIONS
9.6 VARIATIONS OF THE TRADITIONAL BIGINELLI CONDENSATION
9.7 HETEROCYCLES BEYOND THE DHPMs
9.8 IMPORTANT TARGETS
9.9 CONCLUSION
REFERENCES
10 BUCHERER–BERGS AND STRECKER MULTICOMPONENT REACTIONS
10.1 BUCHERER–BERGS REACTION
10.2 MC STRECKER REACTION
10.3 CONCLUSIONS
REFERENCES
11 UNUSUAL APPROACH FOR MULTICOMPONENT REACTIONS
11.1 ZEOLITE-CATALYZED MCRs
11.2 MW-ASSISTED THREE-COMPONENT REACTIONS
11.3 IONIC LIQUID-PROMOTED MCRs
11.4 MCRs UNDER SOLVENT-FREE CONDITIONS
11.5 MCRs IN AQUEOUS MEDIA
11.6 HIGH-PRESSURE PROMOTED MCRs
11.7 THREE-COMPONENT REACTIONS USING SUPPORTED REAGENTS
11.8 CONCLUSION
REFERENCES
12 ESSENTIAL MULTICOMPONENT REACTIONS I
12.1 RADZISZEWSKI REACTIONS (IMIDAZOLE SYNTHESIS)
12.2 SAKURAI MCRs
12.3 GEWALD MCRs
12.4 KABACHNIK–FIELDS REACTIONS
12.5 CONCLUSION
REFERENCES
13 ESSENTIAL MULTICOMPONENT REACTIONS II
13.1 KNOEVENAGEL REACTIONS IN MULTICOMPONENT SYNTHESES
13.2 YONEMITSU-TYPE TRIMOLECULAR CONDENSATIONS
13.3 MCRs INVOLVING MELDRUM’S ACID
13.4 POVAROV MCRs
13.5 HANTZSCH MULTICOMPONENT SYNTHESIS OF HETEROCYCLES
13.6 CONCLUSIONS
REFERENCES
INDEX
END USER LICENSE AGREEMENT
List of Tables
Chapter 01
TABLE 1.1 Some historically significant MCRs
Chapter 02
TABLE 2.1 Several proline-catalyzed multicomponent Mannich reactions
Chapter 04
TABLE 4.1 Thiourea organocatalyzed Petasis reaction
TABLE 4.2 Four-component synthesis of α-amino acids from allyl alcohols
via
PBM
Chapter 05
Table 5.1 Synthesis of oxa-bridged adduct 31 and aromatized
N
-containing heterocyclic 32 by coupling of FCC VI with an
o
-alkynyl carbonyl heteroaryl 28–30 and a dienophile
Table 5.2 Ligand-controlled regioselectivity reversal
Chapter 09
TABLE 9.1 Inhibition of chorismate mutase (CM)
Chapter 11
TABLE 11.1 Synthesis of spiroheterocycles
via
the one-pot Mannich reaction of ketone, amine, and formaldehyde
List of Illustrations
Chapter 01
FIGURE 1.1 Examples of drugs synthesized with MCRs: factor Xa inhibitors [3], praziquantel [4], farnesoid X receptor agonists [5], and (–)-oseltamivir [6].
FIGURE 1.2 Fogg’s simple classification of one-pot processes involving multiple catalytic transformations.
FIGURE 1.3 Single reactant replacement method for MCRs.
FIGURE 1.4 Example of a reaction-operator strategy carried out by changing two substrates.
FIGURE 1.5 Modular reaction sequence approach in MCRs.
FIGURE 1.6 Divergence in MCRs achieved through changing reaction conditions.
FIGURE 1.7 Combination of two MCRs.
SCHEME 1.1 Biocatalyzed synthesis of isoindolo[2,1-
a
]quinazolines carried out by Raval and coworkers using baker’s yeast as the catalyst [45a].
SCHEME 1.2 Cocatalyzed MCR using a metal catalyst and an organocatalyst along with the proposed mechanism [46].
SCHEME 1.3 MCR using either conventional heating or microwave irradiation and the results observed by Hasaninejad and coworkers [48].
SCHEME 1.4 Synthesis of dihydropyrano[2,3-
c
]pyrazoles under ultrasound irradiation [49].
SCHEME 1.5 Syntheses of a large number of compounds having the same base structure through Ugi four-component condensations carried out by Armstrong and coworkers [51b].
SCHEME 1.6 MCR using reusable magnetic particles as the catalyst [63a].
Chapter 02
SCHEME 2.1 First three-component Mannich reaction by List et al.
SCHEME 2.2 Plausible mechanism for the proline-catalyzed Mannich reaction.
SCHEME 2.3 Reversal regioselectivity using fluoroacetone.
SCHEME 2.4 Selected examples of proline derivative catalysis in Mannich reaction.
SCHEME 2.5
N-p
-dodecylphenylsulfonamide-based proline catalysis.
SCHEME 2.6 Asymmetric Mannich reaction under wet conditions.
SCHEME 2.7 Anthracene-fused proline catalysis.
SCHEME 2.8 Isosteviol–amino acids organocatalysis by Tao’s group.
SCHEME 2.9
Anti
-Mannich product by threonine derivative catalysis.
SCHEME 2.10 Siloxy serine catalysis in water and ionic liquid.
SCHEME 2.11 (a) (
S
)-Proline (
1
) catalysis in ionic liquid. (b) Ionic liquid
41
as organocatalyst.
SCHEME 2.12 Asymmetric organocatalytic MCR developed by Córdova.
SCHEME 2.13 Bifunctional thiourea catalysis.
SCHEME 2.14 Mannich reaction catalyzed by a proline–thiourea host–guest complex.
SCHEME 2.15 Phosphoric acid catalysis.
SCHEME 2.16 Proposed mechanistic pathway for a Brønsted acid-catalyzed synthesis of 1,3-diamine.
SCHEME 2.17 Axially chiral phosphoric acid catalysis of vinylogous Mannich reaction.
SCHEME 2.18 Biphosphorylimides as novel Brønsted acid catalysts.
SCHEME 2.19 Proline-mediated three-component enantioselective aza-Diels–Alder reaction.
SCHEME 2.20 Organocatalytic trienamine–enamine multicomponent tandem reaction.
SCHEME 2.21 Organocatalytic one-pot three-component synthesis of polysubstituted pyrrolidines
78
.
SCHEME 2.22 Biomimetic asymmetric three-component 1,3-dipolar cycloaddition.
SCHEME 2.23 Asymmetric synthesis of spiro[5,5]undecane-1,5,9-trione derivatives
87
.
SCHEME 2.24 Three-component synthesis of 3-amino-δ-lactams via a formal [4 + 2] cycloaddition reaction.
SCHEME 2.25 Cyclization reaction of cinnamaldehydes
75
and anilines
51
with 1,3-dicarbonyl compounds
91
.
SCHEME 2.26 Proposed mechanism for the cyclization reaction α,β-unsaturated aldehydes
75
and aniline
51
with 1,3-dicarbonyl compounds
91
under chiral Brønsted acid catalysis.
SCHEME 2.27 Organocatalyzed conjugated addition/amination reaction of α,β-unsaturated aldehydes.
SCHEME 2.28 Combination of enamine and iminium ion activation for the enantioselective conjugated addition/amination reaction of α,β-unsaturated aldehydes.
SCHEME 2.29 Organocascade catalysis with combination of azodicarboxylate and either indole or thiol derivatives.
SCHEME 2.30 Reaction control in the organocatalytic asymmetric one-pot, three-component reaction of aldehyde, diethyl α-aminomanolate, and nitroalkenes.
SCHEME 2.31 Proposed cascade iminium–enamine activation.
SCHEME 2.32 Examples of enantioselective organocascade catalysis.
SCHEME 2.33 Asymmetric synthesis of hexahydropyrrolo[2,1-
a
]isoquinolines
115
by organocatalytic MCRs.
SCHEME 2.34 Asymmetric synthesis of spiro[4
H
-pyran-3,3′-oxindoles]
117
via three-component reactions.
SCHEME 2.35 Working hypothesis for the formation of spiro[4
H
-pyran-3,3′-oxindoles]
117
.
SCHEME 2.36 One-pot three-component synthesis of indoloquinolizidines
122
.
SCHEME 2.37 One-pot Michael/Pictet–Spengler sequence.
SCHEME 2.38 Enantioselective three- and four-component reactions for the synthesis of pyranopyrazoles
128
.
SCHEME 2.39 Enantioselective organocatalytic multicomponent synthesis of 2,6-diazabicyclo[2.2.2]octanones.
SCHEME 2.40 Asymmetric organocatalytic three-component cascade reaction.
SCHEME 2.41 Proposed catalytic cycle of the triple cascade with the stereocontrolled formation of four new stereogenic centers.
SCHEME 2.42 One-pot procedure for the synthesis of the tricyclic carbaldehyde
144
and
145
.
SCHEME 2.43 Melchiorre’s approach to complex cyclohexyl carbaldehydes.
SCHEME 2.44 Asymmetric synthesis of pyrazolones
150
.
SCHEME 2.45 Multicomponent domino organocatalytic reactions toward cyclohexane derivatives
152
.
SCHEME 2.46 Proposed iminium–iminium–enamine sequential activation of α,β-unsaturated aldehyde
95
.
SCHEME 2.47 Organocatalytic asymmetric triple domino reaction of nitromethane (
153
).
SCHEME 2.48 Preparation of spirocyclic benzofuranones
156
by aminocatalytic cascade reaction with enals.
SCHEME 2.49 Asymmetric organocatalytic relay cascade (AORC) approach to functionalized cyclohexanes
159
.
SCHEME 2.50 Organocatalytic domino Michael/α-alkylation reaction.
SCHEME 2.51 Postulated mechanism for the one-pot combination of AHCC.
SCHEME 2.52 Synthesis of tetrahydropyridines via Michael/Mannich/cyclization MCR.
SCHEME 2.53 Synthesis of tetrahydro-6
H
-benzo[
c
]chromenes
168
via quadruple cascade reaction.
SCHEME 2.54 Trisubstituted cyclohexane derivatives
170
via quadruple cascade reaction.
SCHEME 2.55 Enders’s Friedel–Crafts-type/Michael/Michael/Aldol condensation domino sequence.
SCHEME 2.56 Postulated mechanism for the Friedel–Crafts-type/Michael/Michael/Aldol domino sequence.
SCHEME 2.57 Asymmetric aza-Michael/Michael/Michael/Aldol sequence toward tetracyclic indole structures.
SCHEME 2.58 Quadruple iminium–enamine–iminium–enamine catalysis toward spirooxindole derivatives
177
.
SCHEME 2.59 Heterodomino Knoevenagel/Diels–Alder/epimerization and its postulated mechanism.
SCHEME 2.60 Synthesis of spiro[5,5]undecane-1,5,9-triones
181
via domino Knoevenagel/Diels–Alder.
SCHEME 2.61 Three-component domino Knoevenagel/Diels–Alder/epimerization.
SCHEME 2.62 Synthesis of Wieland–Miescher ketone via Knoevenagel/hydrogenation/Robinson annulation sequence.
SCHEME 2.63 Jørgensen’s approach to optically active propargylic
192
and allylic
194
fluorides.
SCHEME 2.64 Proposed reaction pathway toward the preparation of propargylic and allylic fluorides.
SCHEME 2.65 Enantioselective reduction/alkylation of cinnamaldehyde derivatives
196
.
SCHEME 2.66 Proposed mechanistic pathway for the reduction/alkylation sequence.
SCHEME 2.67 Preparation of enantioenriched tetrahydropyridines
202
via organocatalytic MCRs.
SCHEME 2.68 Kinetic resolution of nitroallylic acetates
203
with stereoselective formation of 3-alkylated indoles
204
.
SCHEME 2.69 Asymmetric synthesis of (–)-oseltamivir
205
and ABT-341
206
.
SCHEME 2.70 One-pot synthesis of tetrahydropyranols
207
via Michael/Henry/acetalization/isomerization sequence.
SCHEME 2.71 Organocatalytic one-pot strategy to octahydroacridines
210
.
SCHEME 2.72 Organocatalytic one-pot strategy to bicyclo[3.3.1]non-2-ene compounds
212
.
SCHEME 2.73 Asymmetric one-pot strategy for the synthesis of imidazoles, oxazoles, and thiazoles.
SCHEME 2.74 Double cascade proline-catalyzed five-component O–DA–E–O–H reaction.
SCHEME 2.75 Thiourea-catalyzed three-component reaction for preparing dihydropyrryl-spirooxindoles.
SCHEME 2.76 Application of a three-component 1,3-dipolar cycloaddition reaction.
SCHEME 2.77 Formal double arylation of azomethines for the synthesis of isoindolines.
SCHEME 2.78 Formal [3 + 3] cycloadditions for the synthesis of piperidine frameworks
228
.
SCHEME 2.79 Oxa-Michael/Michael/Michael/aldol condensation on the first total synthesis of (+)-conicol
232
.
FIGURE 2.1 Selected organocatalyzed MCRs for structure–diversity on APIs.
SCHEME 2.80 Multicomponent aza-Henry reaction via water-compatible H bond activation.
SCHEME 2.81 Ma’s approach to α-aminophosphonates
243
via organocatalytic MCRs.
SCHEME 2.82 Bhusare’s approach to α-aminophosphonates
245
via organocatalytic MCRs.
Chapter 03
SCHEME 3.1 Palladium-catalyzed aminocarbonylation of aryl chlorides.
SCHEME 3.2 Carbonylative coupling of heteroarenes and aryl iodides
via
C
─
H activation.
SCHEME 3.3 Palladium-catalyzed carbonylative coupling of aryl bromides and alkynes.
SCHEME 3.4 Synthesis of nitrogenated heterocycles
via
Münchnone intermediate.
SCHEME 3.5 Synthesis of π-conjugated oligomers
via
carbonylative coupling of dialdehydes, di(acyl chloride)s, and imines.
SCHEME 3.6 Palladium-catalyzed coupling of aryl halides, isocyanide, and amines.
SCHEME 3.7 Proposed mechanism for the palladium-catalyzed isocyanide reactions.
SCHEME 3.8 Synthesis of benzoxazoles and oxazolines by palladium-catalyzed isocyanide reactions.
SCHEME 3.9 Synthesis of quinazolin-4(3
H
)-imines by palladium-catalyzed isocyanide reactions.
SCHEME 3.10 Synthesis of 4-aminophthalazin-1(2
H
)-ones by palladium-catalyzed isocyanide reactions.
SCHEME 3.11 Proposed mechanism for the synthesis of 4-amine-benzo[
b
][1,4]oxazepines by palladium-catalyzed isocyanide reactions.
SCHEME 3.12 Synthesis of 1,3-dienes and trienes by palladium-catalyzed cross-coupling of aryl halides, internal alkynes, and arylboronic acids.
SCHEME 3.13 Synthesis of 1,3-butadienes by palladium-catalyzed cross-coupling of iodobenzene, diphenylacetylene, and arylboronic acids.
SCHEME 3.14 Synthesis of 1,3-butadienes and 1,3,5-hexatrienes by palladium-catalyzed cross-coupling of aryl iodides, diarylacetylenes, and monosubstituted alkenes.
SCHEME 3.15 Synthesis of 1,3,5-hexatrienes by palladium-catalyzed cross-coupling of β-bromostyrenes, diarylacetylenes, and monosubstituted alkenes.
SCHEME 3.16 Palladium-catalyzed arylalkynylation of aryl iodides, internal alkynes, and alkynylsilanes. Synthesis of 1,1,2-trisubstituted enynes.
SCHEME 3.17 Palladium-catalyzed synthesis of 1-allyl-2-alkynylbenzenes and
o
-allylbiaryls.
SCHEME 3.18 Palladium-catalyzed carbocyclization of aryl iodides, bicyclic alkenes, and arynes. Synthesis of annulated 9,10-dihydrophenanthrenes.
SCHEME 3.19 Synthesis of phenanthrenes
via
palladium-catalyzed cross-coupling of aryl halides, acetylenes, and arynes.
SCHEME 3.20 Palladium-catalyzed Heck-type benzyne three-component coupling.
SCHEME 3.21 Palladium-catalyzed aminosulfonylation of aryl and vinyl iodides.
SCHEME 3.22 Palladium-catalyzed aminosulfonylation of boronic acids. Proposed mechanism.
SCHEME 3.23 Palladium-catalyzed multicomponent reaction
via
Buchwald–Hartwig amination process.
SCHEME 3.24 Sonogashira/Buchwald–Hartwig amination processes in Pd-catalyzed MCR.
SCHEME 3.25 Synthesis of phenothiazines
via
Pd-catalyzed Buchwald–Hartwig amination and thiolation processes.
SCHEME 3.26 Synthesis of spiroacetals
via
palladium-catalyzed alkynol cyclization/Mannich-type processes.
SCHEME 3.27 Palladium-catalyzed synthesis of 1,2,4-trisubstituted and 1,3-disubstituted pyrroles.
SCHEME 3.28 Ni-catalyzed 1:1:1 cross-trimerization of alkynes.
SCHEME 3.29 Proposed mechanism for Ni-catalyzed 1:1:1 cross-trimerization of alkynes.
SCHEME 3.30 Ni-catalyzed synthesis of 1,3-dien-5-ynes and 1,5-enynes.
SCHEME 3.31 Ni-catalyzed coupling between arynes, enones, or α,β-unsaturated esters and boronic acids.
SCHEME 3.32 Ni-catalyzed synthesis of allylic and homoallylic
O
-silyl ethers by reductive coupling between alkenes and aldehydes.
SCHEME 3.33 Ni-catalyzed synthesis of allylic
O
-silyl ethers by reductive coupling between alkynes and aldehydes.
SCHEME 3.34 Synthesis of 1,3-diketones by Ni-catalyzed redox coupling of enones, aldehydes, and alkynes.
SCHEME 3.35 Synthesis of enol silyl ethers by Ni-catalyzed reductive coupling of aryl/alkyl halides, enones, and trialkylchlorosilane.
SCHEME 3.36 β-Hydroxi-1,2,3-triazoles synthesis
via
CuAAC.
SCHEME 3.37 1,4-Substituted 1,2,3-triazoles synthesis using a silica-immobilized copper-based catalyst.
SCHEME 3.38 Synthesis of 1,4-substituted 1,2,3-triazoles by CuAAC in ionic liquid media.
SCHEME 3.39 Synthesis of
N
-sulfonylamidines by CuAAC reactions.
SCHEME 3.40 Propargylamine synthesis by metal-catalyzed A
3
-coupling reactions.
SCHEME 3.41 Synthesis of propargylamines by Cu-catalyzed KA
2
-coupling reaction.
SCHEME 3.42 A
3
-coupling synthesis of propargylamines using a supported silver-based catalyst.
SCHEME 3.43 Synthesis of polycyclic pyrrole-2-carboxylates
via
CuAAC/cycloisomerization/Diels–Alder cycloaddition/dehydrogenation sequence.
SCHEME 3.44 CuAAC in the synthesis of triazolodibenzo[1,5-
a
]azocines.
SCHEME 3.45 Synthesis of 2-dialkylaminoimidazoles and 2-thio- and 2-oxoimidazoles from propargylcyanamides.
SCHEME 3.46 Proposed mechanism for the gold(III)-catalyzed A
3
-coupling/cycloisomerization reaction.
SCHEME 3.47 Proposed mechanism for the Cu(I)-catalyzed synthesis of 2-(aminomethyl)indoles.
SCHEME 3.48 Synthesis of butenolides
via
gold(III)-catalyzed A
3
-coupling/cyclization sequence.
SCHEME 3.49 Cu-catalyzed A
3
-coupling synthesis of oxazolidinones.
SCHEME 3.50 Asymmetric synthesis of propargylamines by Cu-catalyzed A
3
-couplings.
FIGURE 3.1 Chiral P,N-ligands used in asymmetric A
3
-coupling.
SCHEME 3.51 PINAP ligand in the Cu-catalyzed asymmetric A
3
-coupling reaction.
SCHEME 3.52 Cu-catalyzed amine–alkyne–alkyne coupling reaction.
SCHEME 3.53 The use of dihaloalkanes in the Cu-catalyzed A
3
-coupling reaction.
SCHEME 3.54 The use of carbamates in the Cu-catalyzed A
3
-coupling reaction.
SCHEME 3.55 C
─
H alkylation of azoles
via
Cu-catalyzed A
3
-coupling reaction.
SCHEME 3.56 Synthesis of benzothiazoles
via
Cu-catalyzed coupling of 2-iodoanilines, carbon disulfide, and secondary amines.
SCHEME 3.57 Au(I)-catalyzed oxidative oxyarylation of alkenes.
SCHEME 3.58 Rh-catalyzed insertion of carbene species into X
─
H bonds.
SCHEME 3.59 Rh-catalyzed reaction of oxonium ylides with aldehydes and imines.
SCHEME 3.60 Asymmetric version of the reaction of oxonium ylides with aldehydes and imines.
SCHEME 3.61 Rh-catalyzed four-component reactions of oxonium ylides with imines.
SCHEME 3.62 Rh-catalyzed addition of oxonium ylides to Michael acceptors.
SCHEME 3.63 Synthesis of indanols by 1,4-addition/aldol-type intramolecular cascade reaction.
SCHEME 3.64 Rh-catalyzed 1,2- and 1,4-addition of ammonium ylides.
SCHEME 3.65 Asymmetric addition of ammonium ylides to imines.
SCHEME 3.66 Rh-catalyzed asymmetric addition of zwitterionic intermediates to imines.
SCHEME 3.67 Rh-catalyzed 1,3-cycloaddition reactions of carbonyl and azomethine ylides.
SCHEME 3.68 Rh-catalyzed three-component cross-addition reactions.
SCHEME 3.69 Synthesis of isoquinolines and pyridines by Rh-catalyzed annulation reactions.
SCHEME 3.70 Iron(III)-catalyzed A
3
-coupling reactions.
SCHEME 3.71 Fe(III)-catalyzed synthesis of quinoline-2,4-dicarboxylates and quinazolines
via
A
3
-type coupling reactions.
SCHEME 3.72 Four-component iron(III)-catalyzed synthesis of pyrroles.
SCHEME 3.73 Four-component Fe(II)-catalyzed synthesis of branched amines.
SCHEME 3.74 Iron-catalyzed 1,2-addition of ammonium ylides to β,γ-unsaturated α-ketoesters.
SCHEME 3.75 Ru(II)-catalyzed intermolecular cyclotrimerization of alkynes.
SCHEME 3.76 Proposed mechanism for the Ru(II)-catalyzed intermolecular cyclotrimerization of alkynes.
SCHEME 3.77 Ru-catalyzed three-component synthesis of pyrroles.
SCHEME 3.78 Ru-catalyzed cross-enyne metathesis/Diels–Alder multicomponent reactions.
Chapter 04
SCHEME 4.1 Cobalt(I)-catalyzed Diels–Alder reaction for the synthesis of polycyclic multifunctionalized products.
SCHEME 4.2 Multicomponent cobalt-catalyzed 1,4-hydrovinylation/allylboration. dppe, 1,2-bis(diphenylphosphino)ethane.
SCHEME 4.3 Four-component one-pot reaction
via
two cobalt-catalyzed 1,4-hydrovinylations and allylboration. dppp, 1,2-bis(diphenylphosphino)propane.
SCHEME 4.4 Five-component one-pot reaction
via
triple-cobalt-catalyzed reaction sequences. py-imine, 2,4,6-trimethylphenyl-
N
-(pyridin-2-ylmethylene)aniline.
SCHEME 4.5 Scope of the cycloisomerization/Diels–Alder cycloaddition/allylboration multicomponent process.
SCHEME 4.6 Synthesis of macrocyclic boron containing compounds.
SCHEME 4.7 Use of amines or aldehydes in the macrocyclization reaction.
SCHEME 4.8 Formation of dendritic nanostructures based on [4 + 4 + 4]-type self-assembly.
SCHEME 4.9 Synthesis of macrocycles through a [4 + 2 + 2] condensation reaction.
SCHEME 4.10 Multicomponent synthesis of macrobicycle
9l
.
SCHEME 4.11 Metal–ligand coordination assisted boronic acid-based macrocycle
15
, from 12 molecular building blocks.
SCHEME 4.12 Synthesis of rotaxane
20
by multicomponent self-assembly.
SCHEME 4.13 Multicomponent synthesis of trigonal prismatic cages
24
.
SCHEME 4.14 Petasis reaction using α-hydroxy aldehydes.
SCHEME 4.15 Thiourea organocatalyzed Petasis reaction.
FIGURE 4.1 Mode of dual activation in the Petasis reaction.
SCHEME 4.16 Organocatalyzed Petasis multicomponent reaction.
SCHEME 4.17 One-pot synthesis of α-amino acids
via
catalytic generation of allyl boronates.
SCHEME 4.18 Plausible mechanism for 4-component PBM reaction.
SCHEME 4.19 Synthesis of active NN703 derivatives through PMB protocol.
SCHEME 4.20 Synthesis of the antiplatelet agent clopidogrel
42
through PBM strategy.
SCHEME 4.21 Synthesis of maraviroc
43
via
PMB protocol.
SCHEME 4.22 Synthesis of uniflorine A
45
.
FIGURE 4.2 Target compounds synthesized through a PMB protocol.
SCHEME 4.23 Yoshida multicomponent reaction: (a) (Ar
1
=
p
-tolyl) Pd(OAc)
2
, PPh
3
, Cs
2
CO
3
, H
2
O, toluene, 90 °C, under air. (b) Ethyl
cis
-3-iodoacrylate, Cs
2
CO
3
, H
2
O, 90 °C. (c) Ar
2
I, Cs
2
CO
3
, H
2
O. (d) Pd(OAc)
2
, PPh
3
,
p
-benzoquinone, CO (1 atm), MeOH, 50 °C (amine is benzylamine). (e) Pd(OAc)
2
, PPh
3
,
p
-benzoquinone, CO (1 atm), MeOH, 50 °C (amine is morpholine).
SCHEME 4.24 Synthesis of rolipram: (a) Pd
2
(dba)
3
, P(2-furyl)
3
,
i
Pr
2
NEt, toluene, 80 °C; (b) Pd(OAc)
2
, PPh
3
,
p
-benzoquinone, CO (1 atm), MeOH, 50 °C; (c) Pd/C, H
2
(60 atm), EtOH, 60 °C; (d) Li, liq. NH
3
, –40 °C.
SCHEME 4.25 Chiral cycloaddition [4 + 2]/allylboration using aldehydes.
SCHEME 4.26 Retrosynthetic analysis for the preparation of compound
58
.
SCHEME 4.27 Retrosynthetic analysis for the preparation of compound
59
.
SCHEME 4.28 Synthesis of intermediate
60
.
SCHEME 4.29 Solid-phase synthesis approach with a supported aldehyde or the maleimide component.
SCHEME 4.30 Palladium-catalyzed enantioselective diboration/allylation.
SCHEME 4.31 Synthesis of allylic amines
64
.
SCHEME 4.32 Total synthesis of (+)-strictifolione
65
.
Chapter 05
SCHEME 5.1 Different carbene-promoted multicomponent reactions.
FIGURE 5.1 Nucleophilic carbenes as 1,1-dipole equivalents.
SCHEME 5.2 MCRs: carbenes as components.
SCHEME 5.3 Oxadiazoline
1
as precursor of dimethoxycarbene
I
.
SCHEME 5.4 General mechanism of MCR to obtain dihydrofuran derivatives starting from
1
.
SCHEME 5.5 Synthesis of substituted dihydrofuran derivatives by MCR of dimethoxycarbene
I
.
SCHEME 5.6 Synthesis of spirodihydrofurans
6–8
and cyclopentene acetals
9
by MCR.
SCHEME 5.7 Solvent effect on dimethoxycarbene addition to aryl isocyanates.
SCHEME 5.8 Thiazolium-mediated MCR for the synthesis of 3-aminofuran derivatives
13
.
SCHEME 5.9 Synthesis of polysubstituted furan-fused 1,4-thiazepine derivatives
14
.
SCHEME 5.10 Plausible mechanism of the synthesis of 1,4-thiazepines.
SCHEME 5.11 MCRs involving imidazol/imidazolin-2-ylidenes.
SCHEME 5.12 Plausible mechanism for MCR of imidazol-2-ylidenes
III
and imidazolin-2-ylidenes
IV
.
SCHEME 5.13 MCR involving
N
,
N
-di-
tert
-butyl imidazol/imidazolin-2-ylidenes.
SCHEME 5.14 Multicomponent reaction involving imidazo[1,5-
a
]pyridin-3-ylidenes, aldehydes, and allenoates.
SCHEME 5.15 Mechanism of the reaction of imidazo[1,5-
a
]pyridin-3-ylidenes with aldehydes and allenoates.
SCHEME 5.16 Multicomponent reaction involving imidazo[1,5-
a
]pyridin-3-ylidenes, aldehydes, and DMAD.
SCHEME 5.17 MCR of imidazo[1,5-
a
]pyridin-3-ylidenes with
ortho
-dialdehydes and DMAD.
SCHEME 5.18 Mechanism of MCR of imidazo[1,5-
a
]pyridin-3-ylidenes with
ortho
-dialdehydes and activated alkynes.
SCHEME 5.19 MCR involving triazol-5-ylidene
V
, DMAD, and aldehydes.
SCHEME 5.20 MCR of triazol-5-ylidene
V
, MMA, and PhNCO.
SCHEME 5.21 MCR of
V
, MMA, and PhNCO across the equilibrium between
V
and
I13
.
SCHEME 5.22 Synthesis of Fischer carbene complex
VI
.
SCHEME 5.23 Fischer carbene complexes in MCRs.
SCHEME 5.24 Synthesis of
N
-containing heterocyclic ring systems by coupling of FCC
VI
with an
o
-alkynyl carbonyl heteroaryl
28–30
and a dienophile.
SCHEME 5.25 Coupling of α,β-unsaturated carbene
VIIa/b
with alkynyl heteroaryl ketone
33
and DMAD.
SCHEME 5.26 Synthesis of furoquinoline/furoisoquinoline derivatives
37
and
38
from FCC
VI
.
SCHEME 5.27 Coupling of carbene
VIII
with carbonyl derivatives
41a
,
b
.
SCHEME 5.28 Synthesis of chromenes
46
from FCC
IX
.
SCHEME 5.29 Synthesis of 4-allenyl-4-hydroxy-2-cyclohexenones
49
.
SCHEME 5.30 (a) Mechanistic pathway for the synthesis of cyclohexenone
49
. (b) Stereochemical models.
SCHEME 5.31 MCRs: NHCs as organocatalysts/ligands.
SCHEME 5.32 Basic modes of substrate activation by NHCs in organocatalysis.
SCHEME 5.33 Proposed amidation of carbonyls using nitrosoarenes.
SCHEME 5.34 NHC-catalyzed 3CR of enals, nitrosoarenes, and enones.
SCHEME 5.35 Base promoted oxo-Michael addition of
51
to enones.
SCHEME 5.36 Proposed domino amidation–redox amination of acrolein with nitrosobenzene.
SCHEME 5.37 3CR for the synthesis of
N
-arylaziridines
56
.
SCHEME 5.38 General strategy for MCR design through homoenolates.
SCHEME 5.39 NHC-catalyzed 3CR of enals, chalcones, and methanol for the synthesis of
58
.
SCHEME 5.40 Proposed annulation of
I41
to access cyclopentanes
58
.
SCHEME 5.41 Different reaction pathways in NHC-catalyzed 3CR of enals, chalcones, and alcohols.
SCHEME 5.42 Plausible mechanism for the formation of
62
.
SCHEME 5.43 NHC-catalyzed 3CR of enals, nitroalkenes, and methanol for the synthesis of
63
.
SCHEME 5.44 NHC-catalyzed 4CR or 3CR of enals and
p
-tolylsulfonamide for the synthesis of
64
and
65
.
SCHEME 5.45 Postulated catalytic cycle.
SCHEME 5.46 Catalytic generation of α,β-unsaturated acyl azolium
I51
.
SCHEME 5.47 NHC-catalyzed 3CR of alkynyl aldehydes with oxindoles.
SCHEME 5.48 Proposed mechanism for NHC-catalyzed 3CR of alkynyl aldehydes with oxindoles.
SCHEME 5.49 NHC-catalyzed 3CR for the synthesis of furans
68
.
SCHEME 5.50 A plausible mechanism for NHC-catalyzed 3CR for the synthesis of
68
.
FIGURE 5.2 Features of M-NHC in organometallic catalysis.
SCHEME 5.51 One-pot Strecker reaction using Pd–NHC catalysts
XVIII
and
XIX
.
SCHEME 5.52 Pd–NHC-catalyzed carbonylative Suzuki reaction.
SCHEME 5.53 Pd–NHC-catalyzed carbonylative Suzuki reaction using
XX–XXII
as catalyst.
SCHEME 5.54 Synthesis of acyl pyrroles via Pd–NHC-catalyzed carbonylative amination.
SCHEME 5.55 Aminocarbonylation of aryl iodides with primary/secondary amines using PS-Pd–NHC
XXIV
(PS denotes poly(imidazoliummethyl styrene)-surface grafted polystyrene resin).
FIGURE 5.3 Robust allylic Pd–NHC catalysts
XXV
.
SCHEME 5.56 Double carbonylation using SILP–Pd catalysts
XXVI
.
FIGURE 5.4 Grubbs catalysts.
SCHEME 5.57 One-pot multicomponent synthesis of 2,3-dihydropyrans
80
.
SCHEME 5.58 Multicomponent synthesis of
81
.
SCHEME 5.59 Mechanism of ene–yne metathesis/Diels–Alder multicomponent reaction.
SCHEME 5.60 Reaction pathways in reductive couplings of 1,3-dienes, aldehydes, and silanes.
SCHEME 5.61 Asymmetric Ni–NHC-catalyzed reductive coupling of 1,3-dienes, aldehydes, and silanes.
SCHEME 5.62 Asymmetric Ni–
XXXIII
-catalyzed reductive coupling of 1,3-dienes, aldehydes, and silanes.
SCHEME 5.63 Ni(COD)–
IMes
-catalyzed reductive coupling of alkynes, aldehydes, and triethylsilanes.
SCHEME 5.64 Ni(COD)–
NHC
-catalyzed reductive coupling of alkynes, aldehydes, and silanes.
SCHEME 5.65 Proposed mechanism in reductive couplings of alkynes, aldehydes, and silanes.
SCHEME 5.66 Predictive model for regiocontrol.
SCHEME 5.67 Synthesis of oxasilacyclopentanes
87
.
SCHEME 5.68 Synthesis of
anti
-1,2-diols
88
.
SCHEME 5.69 Asymmetric 3-C reductive coupling employing chiral imidazolium salt
XXXVI
as ligand precursor.
SCHEME 5.70 Ni–NHC-catalyzed 3-C couplings.
SCHEME 5.71 Ni–NHC-catalyzed 3-C coupling between aryl aldehydes, norbornenes, and silanes.
SCHEME 5.72 Ni–
IMes
-catalyzed alkylative 3-C couplings of 1,3-dienes, aldehydes, and tetraorganosilicon reagent
91
.
SCHEME 5.73 Ag(I)–NHC-catalyzed A
3
-coupling reaction.
SCHEME 5.74 Tentative mechanism for the Ag(I)-catalyzed A
3
-coupling.
FIGURE 5.5 Ag(I)–NHC systems for A
3
-coupling.
FIGURE 5.6 Ag(I)–NHC catalysts for A
3
-coupling.
FIGURE 5.7 Silica-immobilized Cu(I)–NHC complex
XLVII
.
FIGURE 5.8 Neutral Cu(I)–NHC complex
XLVIII
.
SCHEME 5.75 3-C CuAAC catalyzed by
XLIX/L
.
FIGURE 5.9 Silica-immobilized Cu(I)–NHC heterogeneous catalyst
LI
.
SCHEME 5.76 Synthesis of bicyclic lactones
95
starting from a MCR.
SCHEME 5.77 Synthesis of vitamin E following a MCR with FCC
LII
.
SCHEME 5.78 Transformation of
δ
-nitroester
63a
into
δ
-lactam
101
.
SCHEME 5.79 Synthesis of tamibarotene
105
using robust Pd–NHC complex
XXV
.
SCHEME 5.80 Application of
XXVIII
for the preparation of biologically interesting building blocks in carbohydrate chemistry.
Chapter 06
FIGURE 6.1 Examples of heterocycles and complex natural products synthesized by MCR chemistry [4, 5].
FIGURE 6.2 Biologically active products synthesized by a multicomponent Ugi approach [8–14].
SCHEME 6.1 U-3CR reaction in the synthesis of FVIIa inhibitor
23
.
SCHEME 6.2 Stereoselective intermolecular U-4CR in the synthesis of omuralide.
SCHEME 6.3 Combined MCRs in the synthesis of tubulysin analogues
38
.
SCHEME 6.4 MCR chemistry combined with biocatalysis in the synthesis of telaprevir
47
.
FIGURE 6.3 MCRs as powerful tool for natural products synthesis [22–26].
SCHEME 6.5 Synthesis of key fragment
60
in the total synthesis of ecteinascidin 743
48
, using the Ugi multicomponent reaction.
SCHEME 6.6 Mannich-type 4CR in the synthesis of (±)-roelactamine
65
.
SCHEME 6.7 [3 + 2]-Dipolar cycloaddition in the synthesis of spirotryprostatin B
50
.
SCHEME 6.8 Three-component [4 + 2]/[2 + 2] cycloaddition cascade in the total synthesis of paesslerin A
52
.
SCHEME 6.9 Povarov multicomponent reaction applied in the total synthesis of (±)-martinelline
51
.
SCHEME 6.10 Synthesis of cannabinol
83
in a multicomponent domino reaction.
SCHEME 6.11 Organocatalytic oxa-Michael–Michael–Michael–aldol as the key step in the synthesis of (+)-conicol
89
.
FIGURE 6.4 Indole-containing medicinal compounds
90–96
.
SCHEME 6.12 Cascade reaction through iminium–enamine catalysis.
SCHEME 6.13 Catalytic cascade cycle.
SCHEME 6.14 One-pot cascade catalysis with star polymer catalysts.
SCHEME 6.15 Phosphoric acid
121
-catalyzed three-component reaction.
FIGURE 6.5 Activated transition state
TS-1
.
SCHEME 6.16 Primary amine
128
-catalyzed multicomponent reaction, to give chiral indole derivatives
129
[43].
SCHEME 6.17 Enantioselective three-component Michael addition/Pictet–Spengler reaction sequence to synthesize highly substituted indoloquinolizidines
135
.
SCHEME 6.18 Transition state (
TS-2
and
TS-3
) of the Pictet–Spengler cyclization.
SCHEME 6.19 Three-component aza-Diels–Alder reaction to create indoles derivatives
140
.
a
Catalyst (
S
)-
139
was used.
FIGURE 6.6 Indoles
140k-m
, which were tested against different cell lines.
SCHEME 6.20 Three-component tandem reaction to synthesize acyclic products—indole derivatives
146
—with three contiguous stereocenters.
FIGURE 6.7 Natural products
149–156
, containing fused heterocycles.
SCHEME 6.21 Pd-catalyzed multicomponent reaction in the synthesis of (±)-frondosin B
49
[23].
SCHEME 6.22 Efficient one-pot synthesis of chromene-5-ones
171
or
172
.
SCHEME 6.23 Synthesis of nuevamine aza-analogues
178
.
SCHEME 6.24 Four-component reaction to create
N
-fused polycycles
182
.
a
PPTS (5 mol%) and MW were used.
SCHEME 6.25 Multicomponent Pictet–Spengler cyclizations to obtain fused polycycles
186–188
.
SCHEME 6.26 Noyori-type three-component reaction in the total synthesis of dendrobatid 251 F
192
.
SCHEME 6.27 Noyori-type three-component reaction in the total synthesis of garsubellin A
195
.
SCHEME 6.28 Asymmetric inverse electron demand aza-Diels–Alder (IEDDA) reaction to yield fused heterocycles
200
.
SCHEME 6.29 Phosphoric acid-catalyzed Povarov reaction.
FIGURE 6.8 Rationale for the
endo
-selectivity of reaction depicted in Scheme 6.29.
SCHEME 6.30 Synthesis of multifunctionalized tetracyclic indeno[1,2-
b
]indole derivatives
207
and
209
.
SCHEME 6.31 Proposed mechanism for the synthesis of the multifunctionalized tetracyclic indeno[1,2-
b
]indole derivatives
207
and
209
.
FIGURE 6.9 Representative spirocycles
219–225
with biological properties.
SCHEME 6.32 MCR strategy used in the synthesis of spirooxindole pyrans
231
.
SCHEME 6.33 CAN-catalyzed synthesis of spirooxindole derivatives
235
via
three-component reaction in aqueous media.
SCHEME 6.34 First enantioselective synthesis of spiropyrrolidine oxindoles
240
using BINOL-derived phosphoric acid
239
.
FIGURE 6.10 Proposed transition state
TS-6
for the reaction depicted in Scheme 6.34.
SCHEME 6.35 Triethylamine-catalyzed multicomponent reaction to synthesize spiroheterocycles
243
.
SCHEME 6.36 One-pot four-component [3 + 2]-cycloaddition.
SCHEME 6.37 Synthesis of dispirooxindoles
via
multicomponent reaction.
SCHEME 6.38 Isocyanide-based multicomponent reaction to build polycyclic spiroindolines
253
and natural products tabersonine and akuammicine.
FIGURE 6.11 Naturally derived bioactive spiro-morpholines
255
and
256
.
SCHEME 6.39 Electrophilic multicomponent approach for the synthesis of spiro-morpholine
260
.
SCHEME 6.40 Synthesis of ferrocene-grafted pyrrolidine spiroheterocycles.
SCHEME 6.41 Synthesis of highly functionalized novel dispiropyrrolidines
267–271
.
SCHEME 6.42 Synthesis of polycyclic alkaloids using an Ugi/Michael/aza-Michael cascade reaction.
FIGURE 6.12 Synthesis of pentacyclic indeno[2,1-
c
]quinolones
279
and pyrano[4,3-
b
]oxepines
280
.
FIGURE 6.13 Interesting natural compounds containing dihydropyrimidines or thiazines [83–85].
SCHEME 6.43 Two asymmetric routes to the synthesis of MCH inhibitor SNAP-7941
293
[90].
SCHEME 6.44 Multicomponent approach to the core of crambescidin 800
10
.
SCHEME 6.45 Synthesis of biologically interesting dihydropyrimidines
306
.
SCHEME 6.46 Synthesis of dihydropyrimidinones
310
by the use of ionic liquid. Gram-scale synthesis of monastrol
310a
.
SCHEME 6.47 Synthesis of 3,6-dihydro-2
H
-1,3-thiazine-2-thiones
313
and 3,4-dihydro-2
H
-1,4-benzo[
b
]thiazine derivatives
317
.
FIGURE 6.14 Interesting pyrrole-derived natural products
318–326
[101].
FIGURE 6.15 Selected pyrrole structures synthesized through a multicomponent reaction:
327
[104],
328
[105], and
329
[106].
SCHEME 6.48 Synthesizing pentasubstituted pyrroles
331–334
.
SCHEME 6.49 BDMS-catalyzed MCR for the obtainment of pyrroles
339
.
SCHEME 6.50
N
-Methylimidazole-catalyzed synthesis of tetrasubstituted pyrroles
343
in water.
SCHEME 6.51 FeCl
3
-catalyzed four-component coupling synthesis of functionalized pyrroles
348
.
SCHEME 6.52 Silica gel-supported tungstic acid as catalyst for the synthesis of pyrroles
356
.
SCHEME 6.53 Catalyst-free synthesis of polysubstituted pyrroles
360
and proposed mechanism.
SCHEME 6.54 Asymmetric synthesis of
syn
-4,5-dihydropyrroles
370
in water and proposed mechanism.
SCHEME 6.55 Synthesis of 3
H
-pyrroles
376
.
SCHEME 6.56 Large-scale synthesis of unnatural amino acids
380
using an Ugi reaction.
SCHEME 6.57 Ugi reaction in the synthesis of α,α-disubstituted amino acids
386
.
SCHEME 6.58
anti
-Selective synthesis of β-amino acid derivatives
391
and catalytic cycle.
SCHEME 6.59 Three-component reaction to synthesize β-amino acids
399
.
SCHEME 6.60 Asymmetric multicomponent reaction of chiral β,γ-alkynyl α-amino acid derivatives
404
.
SCHEME 6.61 Solid-phase Ugi reaction for the synthesis of
N
-acylated α,α-dialkylglycines
409
.
SCHEME 6.62 Synthesis of γ,δ-alkynyl β-amino acid derivatives.
SCHEME 6.63 Ugi four-component reaction allows the synthesis of seleno amino acid derivatives
418
.
SCHEME 6.64 Four-component Ugi reaction followed by Pictet–Spengler cyclization to obtain praziquantel
424
.
SCHEME 6.65 Multicomponent reaction of
rac
-clopidogrel
430
.
SCHEME 6.66 Four-component Ugi reaction in the synthesis of key intermediate
435
in the synthesis of Crixivan
436
.
SCHEME 6.67 Multicomponent reaction to synthesize fingolimod FTY 720
440
.
SCHEME 6.68 Seebach’s variation of the Passerini reaction to synthesize fungicide mandipropamid
444
.
Chapter 07
FIGURE 7.1 Different Ugi reactions and variations highlighted in this chapter.
SCHEME 7.1 Synthesis of α-amino amides
2
using aminoborane
1
as catalyst.
SCHEME 7.2 Mechanism for the Ugi-3CR catalyzed by aminoborane.
SCHEME 7.3 Synthesis of α-amino amides
2
using phenyl phosphinic acid
6
.
SCHEME 7.4 Synthesis of α-amino amidines
10
by using BDMS
9
as catalyst.
SCHEME 7.5 Reaction mechanism for the synthesis of α-amino amidines by using BDMS.
SCHEME 7.6 Synthesis of nonnaturally occurring dipeptides by using Novozym 435.
SCHEME 7.7 The first oxidative Ugi-3CR for the synthesis of tetrahydroisoquinolines
15
.
SCHEME 7.8 Synthesis of substituted prolyl peptides
17
by MAO-N oxidation–Ugi sequence.
SCHEME 7.9 Enantioselective synthesis of 2-(1-aminoalkyl)-5-aminoxazoles
20
.
SCHEME 7.10 Mechanism proposal for the asymmetric synthesis of aminoxazoles
20
.
SCHEME 7.11 Synthesis of enantiomerically enriched heterocyclic compounds
28
.
SCHEME 7.12 The three-component Ugi reaction based on BOROX catalyst
30
.
SCHEME 7.13 Synthesis of dibenzo[
c
,
e
]azepinones
35
by an Ugi-4C-3CR.
SCHEME 7.14 Classical Ugi four-component reaction.
SCHEME 7.15 Proposed mechanism of the Ugi-4CR.
SCHEME 7.16 Synthesis of iminodicarboxamides
40
by an Ugi-5C-4CR.
SCHEME 7.17 Synthesis of functionalized peptoids.
SCHEME 7.18 Split-Ugi reaction and selected examples.
SCHEME 7.19 Sequential four-component synthesis of diamides
45
from organolithium and Grignard reagents.
SCHEME 7.20 Sequential five-component synthesis of diamides
47
from organolithium or Grignard compounds.
SCHEME 7.21 Sequential five-component synthesis of spiropyrrolidinochromanones
51
.
SCHEME 7.22 Access to chiral lactams
55
via Friedel–Crafts and Ugi reaction.
SCHEME 7.23 Multicomponent synthesis of
E
-enaminones
58
via 5-component reaction.
SCHEME 7.24 Mechanism proposal for the 5-component synthesis of
E
-enaminones
58
.
SCHEME 7.25 6-MCR for the synthesis of
Z
-dithiocarbamates
61
.
SCHEME 7.26 Mechanism proposal for the 6-MCR synthesis of
Z
-dithiocarbamates.
SCHEME 7.27 Synthesis of piperazine derivatives
65
by a 5-MCR.
SCHEME 7.28 [4 + 1]-Cycloaddition (Groebke–Blackburn reaction) and Ugi reaction.
FIGURE 7.2 Different starting imines used in the Groebke–Blackburn/Ugi reaction.
SCHEME 7.29 Synthesis of coumarin-3-carboxamides
73
based on a six-component reaction.
SCHEME 7.30 Six-multicomponent reaction involving an Ugi-4CR.
SCHEME 7.31 Use of diisocyanide and synthesis of intermediate
77
.
SCHEME 7.32 One-pot 8MCR based on the intermediates
74
and
77
.
SCHEME 7.33 Synthesis of nitrogen heterocycles by Ugi/aldol sequence.
SCHEME 7.34 Synthesis of oxindoles
84
using a one-pot Ugi/Heck carbocyclization/Sonogashira/nucleophilic addition.
SCHEME 7.35 Synthesis of fused azaspiro tricycles
87
.
SCHEME 7.36 Synthesis of benzo-1,4-diazepin-2,5-diones
88
under Ugi and reductive conditions.
SCHEME 7.37 Synthesis of pyroglutamic acid derivatives by convertible indole-isonitrile methodology.
SCHEME 7.38 Synthesis of azepinoindolones
95
under In(I) catalysis (right) or azocinoindolones
96
under Au(I) catalysis (left).
SCHEME 7.39 Postmodification of the Ugi products using Diels–Alder reaction.
SCHEME 7.40 Synthesis of nitrogen-enriched polycyclic scaffolds by sequential postcondensation intramolecular U-4C-3CR strategy.
SCHEME 7.41 Comparison of the mechanism of Ugi-4CR and Ugi–Smiles-4CR.
SCHEME 7.42 First Ugi–Smiles-4CR reaction described by El Kaïm and Grimaud.
SCHEME 7.43 Heterocyclic products obtained using the Ugi–Smiles coupling.
SCHEME 7.44 Pyrazine synthesis by Ugi–Smiles coupling.
SCHEME 7.45 Mercapto-heterocycles in the Ugi–Smiles coupling.
SCHEME 7.46 Piperidines and pyrrolidines via Ugi–Smiles coupling.
SCHEME 7.47 First asymmetric Ugi–Smiles coupling.
SCHEME 7.48 Seven-component reactions by sequential chemoselective Ugi–Mumm/Ugi–Smiles reactions.
SCHEME 7.49 Ugi–Smiles combined with an olefin ring-closure metathesis.
SCHEME 7.50 One-pot Ugi–Smiles reaction and Heck cyclization.
SCHEME 7.51 One-pot Ugi–Smiles reaction and Sonogashira cyclization.
SCHEME 7.52 Ugi–Smiles reaction and palladium-catalyzed opening of furans.
SCHEME 7.53 Combination of Ugi–Smiles coupling and a reduction process.
SCHEME 7.54 Combination of Ugi-Smiles coupling, reduction process, and nitration.
FIGURE 7.3 Different heterocycles obtained by combination of the Ugi–Smiles coupling and other one-pot transformations.
Chapter 08
SCHEME 8.1 The classical Passerini three-component reaction.
SCHEME 8.2 Generally accepted Passerini mechanism.
FIGURE 8.1 Acyloxyamides prepared by a Passerini MCR:
7
[6],
8
[7],
9
[8],
10
[9],
11
[10],
12
[11], and
13
[12].
SCHEME 8.3 Modified nitrophenol (ArOH) and heteroaromatic phenol (HetOH) Passerini–Smiles coupling.
SCHEME 8.4 Mechanistic proposal for the
O
-arylative Passerini MCR.
SCHEME 8.5 In(OTf)
3
-catalyzed O-alkylative multicomponent P-3CR.
SCHEME 8.6 Proposed reaction mechanism.
SCHEME 8.7 Scope of the O-silylative P-3CR.
SCHEME 8.8 Mechanism for the
O
-silylative P-3CR.
SCHEME 8.9 General reaction to give access to α-(phosphinyloxy)amides
28
.
SCHEME 8.10 IBX-promoted oxidation/P-3CR reaction.
SCHEME 8.11 CuCl
2
·TEMPO-catalyzed oxidative P-3CR.
SCHEME 8.12 Mechanistic hypothesis.
FIGURE 8.2 Depsipeptide-like macrocycles synthesized through a multicomponent P-3CR.
SCHEME 8.13 First catalytic enantioselective Passerini-type reaction.
SCHEME 8.14 Ti-catalyzed asymmetric Passerini 3CR.
SCHEME 8.15 Cu-catalyzed asymmetric Passerini 3CR.
FIGURE 8.3 Scope of the [(salen)Al
III
Cl]
41
-catalyzed enantioselective Passerini reaction.
SCHEME 8.16 Enantioselective synthesis of tetrazole derivatives
44
.
SCHEME 8.17 Mechanistic proposal for the formation of tetrazole derivatives
44
.
FIGURE 8.4 General structure of norstatines
46
[44],
cis
-constrained norstatine analogues
47
[40a], benzimidazole analogues
48
[45], and peptidic kinase inhibitors
49
[46].
SCHEME 8.18 General mechanism for a PADAM strategy.
SCHEME 8.19 Retrosynthesis for formal synthesis of cyclotheonamide C (CtC)
54
.
SCHEME 8.20 Synthesis of intermediate
59
in the synthesis of CtC
54
, using a PADAM sequence.
FIGURE 8.5 Synthesis of di-, tri-, and tetrafunctional redox agents containing multiple chalcogen and quinone redox sites.
SCHEME 8.21 Synthesis of target compounds
60
via
Passerine reaction.
SCHEME 8.22 Retrosynthetic route of telaprevir
61
.
FIGURE 8.6 Preparation of complex molecules following a postcondensation transformation after an initial Passerini MCR:
62
[52],
63
[53], and
64
[54].
SCHEME 8.23 Passerini-Zhu/Staudinger–aza-Wittig protocol: (a) IBX, THF, MW (150 W), 100 °C; (b) polymer supported triphenylphosphine, CH
2
Cl
2
, MW (150 W), 100 °C.
SCHEME 8.24 Passerini-Zhu/cycloaddition protocol: (a) IBX, THF, 100 °C (MW, 150 W), then R
3
NC and R
4
C≡CCO
2
H, THF, r.t.; (b) R
3
NC, R
4
C≡CCO
2
H, IBX, THF, 100 °C (MW, 150 W); (c) DMF, 150 °C (MW, 150 W).
SCHEME 8.25 Competition mechanism between the reactions performed in water and “on water.”
FIGURE 8.7 Passerini adducts under greener conditions.
SCHEME 8.26 Passerini 3CR under solvent-free conditions.
SCHEME 8.27 Isatin derivatives synthesized following a Passerini 3CR.
SCHEME 8.28 MW-promoted Passerini 3CR.
Chapter 09
FIGURE 9.1 Biologically active DHPM structures:
1
[8],
2
[9],
3
[10],
4
[11],
5
[8],
6
[12],
7
[13],
8
[14], and
9
[15].
SCHEME 9.1 Original Biginelli reaction.
SCHEME 9.2 Currently accepted Biginelli mechanism.
SCHEME 9.3 Sweet and Fissekis’ Biginelli mechanism.
SCHEME 9.4 Yb-catalyzed enantioselective three-component Biginelli.
SCHEME 9.5 Base-catalyzed synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1
H
)-ones/thiones
25
and
26
.
SCHEME 9.6 Proposed Biginelli reaction mechanism using thiourea
24
as substrate.
SCHEME 9.7 Proposed Biginelli reaction mechanism using urea
10
as substrate.
SCHEME 9.8 Phosphoric acid-catalyzed Biginelli reaction.
SCHEME 9.9 Proposed organocatalytic mechanism.
SCHEME 9.10 Use of cyclic ketones
33
in the enantioselective Biginelli-like reaction.
FIGURE 9.2 Use of cyclic
33
and acyclic ketones
35
in the enantioselective Biginelli-like reaction.
a
Same reaction conditions with those shown in Scheme 9.10.
b
Same reaction conditions with those shown in Scheme 9.10 but at 65°C instead of 50°C.
SCHEME 9.11 Mechanistic hypothesis.
SCHEME 9.12 Biginelli reaction catalyzed by amine
36
.
SCHEME 9.13 Proposed organocatalytic mechanism.
SCHEME 9.14 Biginelli reaction catalyzed by amine
38
.
FIGURE 9.3 Proposed organocatalytic mechanism.
FIGURE 9.4 Proposed organocatalytic mechanism using catalyst
42
.
SCHEME 9.15 Biginelli reaction catalyzed by primary amine-thiourea
43
.
SCHEME 9.16 Mechanism to explain the formation of the
R
absolute configuration observed using catalyst
45
.
SCHEME 9.17 Enantioselective Biginelli reaction using catalyst
47
.
SCHEME 9.18 Ionic liquid-catalyzed Biginelli reaction.
SCHEME 9.19 Invoked mechanism for one-pot oxidative multicomponent Biginelli reaction.
SCHEME 9.20 SnCl
2
-catalyzed Biginelli reaction using
β
-oxodithioesters as dicarbonyl compound.
SCHEME 9.21 Mechanistic hypothesis for the synthesis of 5-methylmercaptothiocarbonyl-4-aryl-3,4-dihydropyrimidin-2(1
H
)-ones
53
and substituted 2
H
-chromen-2-thiones
55
.
SCHEME 9.22 Synthesis of important heterocycles compounds.
FIGURE 9.5 Selection of active DHPMs:
56
[67],
57
[68],
58
[69], and
59
[70].
SCHEME 9.23 Enantioselective synthesis of the SNAP-7941
62
through a key Biginelli reaction.
SCHEME 9.24 Collection of 3,4-dihydropyrimidin-2(1
H
)-one structures
63
and
64
as A
2B
receptor antagonists.
SCHEME 9.25 Synthesis of
o
-alkynylphenyl-substituted dihydropyrimidin-2(1
H
)-one derivatives
65
via
Biginelli MCR.
FIGURE 9.6 Cylindrospermopsin alkaloids
66–68
.
SCHEME 9.26 Reagents and conditions: (a) AcOH, 24 h. (b) Morpholine acetate,
69
, Na
2
SO
4
, CF
3
CH
2
OH, 70°C, 12 d, 43%. (c) Pd(PPh
3
)
4
, pyrrolidine, THF/MeOH, 1 h 30 min. (d) NaBH
3
CN, AcOH/MeOH, 16 h, 57% (two steps from
70
).
Chapter 10
SCHEME 10.1 General Bucherer–Bergs reaction and mechanism.
SCHEME 10.2 Relative stereochemistry of final amino acids through a Strecker and Bucherer–Bergs synthesis.
FIGURE 10.1 Hydantoins with biological activities: nilutamide
4
[10], phenytoin
5
[11], (+)-hydantocidin
6
[12], iprodione
7
[13], fosphenytoin
8
[14], ethotoin
9
[15], and mephenytoin
10
[16].
FIGURE 10.2 Synthesis of interesting hydantoins through a Bucherer–Bergs reaction:
11
[21],
12
[22],
13
[23],
14
[24], and
15
[25].
SCHEME 10.3 Synthesis of active spirobicycloimidazolidine-2,4-diones
17
.
SCHEME 10.4 Synthesis of spirocyclic acyl guanidine derivatives
19
: (a) morpholine, toluene, reflux, Dean–Stark trap. (b) Toluene, r.t. (c) Oxalyl chloride, DMSO, Et
3
N, CH
2
Cl
2
, −78 °C. (d) HOAc, r.t. (e) L-Selectride, THF, −78 °C. (f) KCN, (NH
4
)
2
CO
3
, NaHSO
3
, EtOH, 130 °C. (g) MeI, K
2
CO
3
, DMF, r.t. (h) Lawesson’s reagent, toluene, 90 °C. (i)
t
BuOOH, NH
4
OH
(aq.)
, MeOH, 50 °C. (j) RB(OH)
2
, Pd[P(Ph)
3
]
4
, Na
2
CO
3(aq.)
, dioxane, 90 °C.
SCHEME 10.5 Synthesis of polyheterocyclic systems
25
and
26
.
SCHEME 10.6 Pd-catalyzed one-pot synthesis of hydantoins.
SCHEME 10.7 Ga(III)-catalyzed Bucherer–Bergs one-pot reaction.
SCHEME 10.8 Modified Bucherer–Bergs reaction.
SCHEME 10.9 Synthesis of hydantoins
2
using organolithium compound and Grignard reagents.
SCHEME 10.10 Synthesis of amide-functionalized monothiohydantoin
34
.
FIGURE 10.3 Representative α-amino acid derivatives:
35
[36],
36a
and
36b
[37],
37
[38],
38
and
39
[39], and
40
[40].
SCHEME 10.11 Synthesis of PHA·399733E
42
through Bucherer–Bergs hydantoin.
SCHEME 10.12 First-generation synthesis of LY2140023
46
through Bucherer–Bergs hydantoin.
FIGURE 10.4 Diaminodicarboxylic acids biologically active:
47
[43],
48
[43],
49
[44], and
50
[44].
FIGURE 10.5 Diaminodicarboxylic acid derivatives:
51
[46]and
52
[47].
SCHEME 10.13 Synthesis of dimers
53
and
54
from
cis
-
55
and
trans
-
56
spirocyclic linkers, respectively.
SCHEME 10.14 Synthesis of intermediates
52
and
57
.
SCHEME 10.15 Strecker synthesis of α-amino acid
via
α-aminonitriles.
SCHEME 10.16 Synthesis of α-aminonitriles
59
using Lewis base catalyst
58
.
SCHEME 10.17 Multicomponent Strecker synthesis for the obtainment of α-iminonitriles
60
.
SCHEME 10.18 Synthetic application of α-iminonitriles for the preparation of indolizidines
61
.
SCHEME 10.19 Postulated mechanism for IBX-mediated oxidation of aminonitrile.
SCHEME 10.20 One-pot synthesis of amides from aldehydes, amines, and cyanide.
SCHEME 10.21 One-pot synthesis of amides
67
from alcohols, amines, and cyanide.
SCHEME 10.22 Synthesis of functionalized α-aminonitriles
68
via
multicomponent tandem SAA reaction.
SCHEME 10.23 Synthesis of α-methylene-γ-butyrolactam
69a
via
SAAC strategy.
SCHEME 10.24 Mechanism proposal.
SCHEME 10.25 Ga(OTf)
3
-catalyzed Strecker reaction using ketones.
SCHEME 10.26 Multicomponent Strecker synthesis of ketones catalyzed by Fe(Cp)
2
PF
6
.
SCHEME 10.27 Plausible Strecker one-pot mechanism.
SCHEME 10.28 Strecker-type reaction in pure water.
SCHEME 10.29 Plausible reaction mechanism.
SCHEME 10.30 Strecker reaction using acetone cyanohydrin as cyanide source.
SCHEME 10.31 Strecker reaction under solvent-free conditions.
SCHEME 10.32 Palladium-catalyzed one-pot Strecker reaction.
SCHEME 10.33 Thiourea-organocatalyzed asymmetric Strecker 3CR.
SCHEME 10.34 Organocatalytic asymmetric Strecker 3CR.
FIGURE 10.6 Proposed transition states for the hydrocyanation catalyzed by bisformamide
78
.
SCHEME 10.35 Chiral phosphoric acid-catalyzed three-component Strecker reaction of ketones.
SCHEME 10.36 Plausible catalytic mechanism.
SCHEME 10.37 Synthesis of
83
through α-aminonitrile intermediate
81
.
SCHEME 10.38 Sequential MCR/[4 + 1] cycloaddition strategy for the preparation of
85
.
Chapter 11
FIGURE 11.1 Interesting syntheses of functionalized structures:
1
[5],
2
[6],
3
[7],
4
[8],
5
[9],
6
[10], and
7
[11].
SCHEME 11.1 Mannich multicomponent reaction for the synthesis of spirocyclic compounds.
SCHEME 11.2 Mannich-type mechanism through enamine activation.
FIGURE 11.2 Representative heterocycles synthesized by MW-assisted MCRs.
SCHEME 11.3 MW-assisted three-component synthesis of
28a
,
b
, and
d
.
FIGURE 11.3 Biological active compounds containing the pyrazino[2,1-
b
]quinazoline-3,6-dione core
27
.
SCHEME 11.4 MW-assisted three-component synthesis of
40
and
43
.
SCHEME 11.5 Microwave-assisted diastereoselective multicomponent reaction to access dibenzo[
c
,
e
]azepinones
46
.
FIGURE 11.4 Ionic liquid-assisted synthesis of interesting molecules:
48
[47],
49
[48],
50
[49],
51
[50], and
52
[51].
SCHEME 11.6 Synthesis of substituted cyclohexa-1,3-diene.
SCHEME 11.7 Synthesis of polyhydroindenes and polyhydronaphthalenes
63
.
SCHEME 11.8 Synthesis of isochromene and isothiochromene derivatives
65
.
SCHEME 11.9 Synthesis of isoquinoline derivatives
67
.
SCHEME 11.10 Synthesis of amidoalkyl naphthols
70
.
SCHEME 11.11 Synthesis of 3-amino-2-arylimidazo[1,2-
a
]pyridines
79
reported by Adib.
SCHEME 11.12 Solvent-free multicomponent synthesis of pyridines
83
reported by Romanelli.
SCHEME 11.13 Synthesis of 2
H
-indazolo[2,1-
b
]phthalazine-1,6,11-triones
86
.
SCHEME 11.14 Synthesis of pyrazoles
89
.
SCHEME 11.15 Three-component solvent-free Mannich reaction developed by Nayak.
SCHEME 11.16 Multicomponent oxidative coupling reported by Nguyen.
SCHEME 11.17 Multicomponent synthesis reported by Ponnuswamy.
SCHEME 11.18 Proposed mechanism for the synthesis of pyrano[2,3-
a
]carbazoles
106
.
SCHEME 11.19 Synthesis of pyrano[2,3-
a
]carbazoles
107
and
108
.
SCHEME 11.20 Synthesis of benzofurans
111
.
SCHEME 11.21 Synthesis of amides
112
.
SCHEME 11.22 Synthesis of benzo[
γ
]imidazo[1,2-
a
]quinolinediones reported by Li.
SCHEME 11.23 Enhancement of Passerini reaction in water.
SCHEME 11.24 Synthesis of seleno cysteines
126
reported by Wessjohann.
SCHEME 11.25 Synthesis of highly functionalized thiophenes
130
.
SCHEME 11.26 Proposed mechanism.
SCHEME 11.27 Synthesis of spirooxindoles reported by Dandia.
SCHEME 11.28 Synthesis of 2-azapyrrolidines
141
.
SCHEME 11.29 Multicomponent synthesis of phosphonates on water.
SCHEME 11.30 Synthesis of β-functionalized 5-methyl-1
H
-pyrazol-3-ol derivatives
147
.
SCHEME 11.31 One-pot synthesis of 5-methoxyseselin and alloxanthoxyletin skeletons.
SCHEME 11.32 [4 + 2]/[3 + 2] sequential cycloaddition.
SCHEME 11.33 [4 + 2]/[3 + 2] sequential cycloaddition using 2 molecules of nitrostyrene
157a
.
SCHEME 11.34 [4 + 2]/[3 + 2] sequential cycloaddition using simple styrenes.
SCHEME 11.35 [4 + 2]/[3 + 2] sequential cycloaddition using 3-nitroindole.
SCHEME 11.36 Strecker reaction.
SCHEME 11.37 Supported [4 + 2]/[3 + 2] sequential cycloaddition.
SCHEME 11.38 Supported Ugi reaction.
SCHEME 11.39 Supported Grieco’s reaction.
Chapter 12
SCHEME 12.1 General Radziszewski reaction.
SCHEME 12.2 General mechanistic hypothesis for Radziszewski reaction.
SCHEME 12.3 An example of application of Radziszewski reaction in the preparation of a pyrimidine–imidazole-based library.
FIGURE 12.1 Imidazole-based drugs.
SCHEME 12.4 Synthesis of 2,4-diarylimidazoles.
SCHEME 12.5 Mechanistic hypothesis for the condensation of aromatic aldehyde, 1,2-diketone (a) (or α-hydroxy ketone (b)), and ammonium, using ionic liquid: [Hbim]BF
4
.
SCHEME 12.6 Synthesis of biologically active compounds, lepidiline B
25
and trifenagrel
28
,
via
Wolkenberg method.
SCHEME 12.7 Modified Radziszewski reaction performed under microreactor conditions.
SCHEME 12.8 Mechanistic proposal for the Radziszewski synthesis of imidazoles given by Orru and Stevens.
SCHEME 12.9 General Weidenhagen reaction.
SCHEME 12.10 Synthesis of 2-phenyl-4(5)-(2′-hetaryl)imidazoles
38
by Weidenhagen reaction.
SCHEME 12.11 The first described Hosomi–Sakurai reactions.
SCHEME 12.12 General mechanism for Hosomi–Sakurai reaction.
SCHEME 12.13 Multicomponent (aza-)Hosomi–Sakurai reactions: synthesis of homoallylic ethers (Eq. 1) and synthesis of homoallylic amines (Eq. 2).
SCHEME 12.14 The first chiral aldehyde-based Sakurai MCR reported by Markó et al.
SCHEME 12.15 Proposed mechanism.
FIGURE 12.2 Antifungal agents: (+)-ambruticin (
54
) [75]and jerangolid D (
55
) [76].
SCHEME 12.16 Domino multicomponent allylation reaction (MCAR) for the stereoselective synthesis of homoallylic ethers and alcohols, a proposed mechanism.
SCHEME 12.17 MCAR for the stereoselective synthesis of natural products.
SCHEME 12.18 Brønsted acid-catalyzed three-component Sakurai reaction using either silyl ether (
path I
) or the corresponding alcohol (
path II
).
SCHEME 12.19 Four-component aza-Sakurai reaction catalyzed by FeSO
4
∙7H
2
O.
SCHEME 12.20 Mechanistic proposal for the four-component aza-Sakurai reaction.
SCHEME 12.21 Four-component aza-Sakurai reaction catalyzed by Fe
3
O
4
.
SCHEME 12.22 Three-component one-pot, two-step transformation aza-Sakurai reaction catalyzed by Pd(OAc)
2
.
SCHEME 12.23 The first (Eq. 1), second (Eq. 2), third (Eq. 3), and fourth (Eq. 4) versions of Gewald reaction.
SCHEME 12.24 Proposed mechanism for the three-component Gewald reaction (G-3CR).
FIGURE 12.3 Biologically active compounds containing 2-aminothiophenes. PD81723 [110], olanzapine [111], AX20017 [112], and TPCA-1 [113].
FIGURE 12.4 Cyanoacetamides used as a nitrile component in the G-3CR.
SCHEME 12.25 G-3CR catalyzed by amine-functional polysiloxane
76
.
FIGURE 12.5 Thiophenes synthesized by G-3CR as a precursor of biologically active compounds.
SCHEME 12.26 General scheme and mechanistic pathways for Kabachnik–Fields reaction.
SCHEME 12.27 One-pot synthesis of poly(aminophosphonate)s through K-F–RAFT system.
FIGURE 12.6 Catalysts
80–83
used in enantioselective versions of Kabachnik–Fields reaction.
SCHEME 12.28 Enantioselective Kabachnik–Fields reaction catalyzed by chiral binol-derived phosphoric acid
80
.
SCHEME 12.29 Enantioselective Kabachnik–Fields reaction catalyzed by chiral Sc(III) complex
82
.
SCHEME 12.30 Enantioselective Kabachnik–Fields reaction catalyzed by chiral bis(imidazoline)-zinc(II) complex
83
.
FIGURE 12.7 Proposed transition state for Zn(II)-bis(imidazoline) complex
83
catalyzed Kabachnik–Fields reaction.
SCHEME 12.31 General scheme for the reactions compiled in this chapter: Radziszewski, Sakurai, Gewald, and Kabachnik–Fields reactions.
Chapter 13
SCHEME 13.1 Proposed mechanism of the base-mediated Knoevenagel condensation.
SCHEME 13.2 Proposed mechanism of the Knoevenagel condensation mediated by secondary amines.
SCHEME 13.3 Proposed mechanism of the acid-mediated Knoevenagel condensation.
SCHEME 13.4 Proposed mechanism of the base-mediated MCR completion for nitrile-
5
and carbonyl-
6
bearing CH-acids.
SCHEME 13.5 Proposed mechanism of the enamine MCR.
SCHEME 13.6 (a) General concerted mechanism for the IEDHDA reaction to generate dihydropyran derivatives
12
; (b) stepwise alternative for certain substrates such as
2a
[3, 8, 9].
SCHEME 13.7 Diammonium hydrogenphosphate-catalyzed synthesis of 4
H
-pyrans
18
.
SCHEME 13.8 Mixed metal oxides (MMO) catalyze the formation of 4
H
-pyran derivatives
22
.
SCHEME 13.9 Iron nanoparticles in the synthesis of 2-amino-4
H
-pyrans
25
.
SCHEME 13.10 Indium(III) chloride-catalyzed 2-amino-4
H
-pyran
28
formation [6].
SCHEME 13.11 Synthesis of a tetracyclic 4
H
-pyran derivative
33
using [bmim]Br ionic liquid
32
.
SCHEME 13.12
N
-Methylmorpholine (NMM)-catalyzed 4
H
-pyran
36
formation.
SCHEME 13.13 Sodium carbonate-catalyzed formation of a tricyclic pyran
39
.
SCHEME 13.14 Indium(III) chloride-catalyzed four-component reaction.
SCHEME 13.15 Cupreine
45
-catalyzed enantioselective synthesis of spiropyrans
46
.
SCHEME 13.16 Piperidine-catalyzed Knoevenagel/enamine–Michael addition/cyclization sequence.
SCHEME 13.17 Pyrazolo[3,4-
b
]quinoline
54
and chromeno[2,3-
c
]pyrazole
55
syntheses.
SCHEME 13.18 Application of a three-component Knoevenagel-induced six-step domino process in the synthesis of cannabinol
60
.
SCHEME 13.19 Indium(III) chloride (or scandium(III) triflate)-catalyzed Knoevenagel/IEDHDA reaction.
SCHEME 13.20 Knoevenagel/IEDHDA reaction in aqueous suspension.
SCHEME 13.21 Formaldehyde
72
in the synthesis of 4-unsubstituted 3,4-dihydro-2
H
-pyrans
73
[33–36].
SCHEME 13.22 Formaldehyde
72
in the multicomponent synthesis of substituted porphyrins
77
.
SCHEME 13.23 Application of a Knoevenagel/hetero-Diels–Alder MCR in the synthesis of new furowarfarins.
SCHEME 13.24 MCR synthesis of new potential antitubercular agents.
SCHEME 13.25 Assumed transition states for the dehydration step of the initial Knoevenagel addition product and the corresponding Gibbs free energies based on DFT calculations of monohydrated compounds [44].
SCHEME 13.26 Pseudo-5CR provides a tricyclic product
88
.
SCHEME 13.27 (a) Multicomponent Knoevenagel/IEDHDA reaction in Tietze’s forosamine synthesis (2009) [8]; (b) key step in the improved synthesis of the forosamine- and ossamine-type sugars (2011) [9].
SCHEME 13.28 Organocatalyst-mediated construction of 2-hydroxy-3,4-dihydro-2
H
-pyrans
96
followed by lactol oxidation.
SCHEME 13.29 Ammonium acetate-/acetic acid-catalyzed synthesis of 2-hydroxy-2,3-dihydro-4
H
-pyran
99
.
SCHEME 13.30 Ionic liquid synthesis of tricyclic dihydropyridines
102
by Wang et al.
SCHEME 13.31 Synthesis of spirodihydropyridine derivatives
105
by Ji et al.
SCHEME 13.32 Indium(III) chloride-catalyzed synthesis of dihydropyrido[2,3-
d
]pyrimidines
108
.
SCHEME 13.33 Dihydropyridone
111
synthesis mediated by lithium perchlorate and triphenyl phosphine by Georg and Gu.
SCHEME 13.34 Direct cyclization of Knoevenagel/enamine–Michael addition products to the corresponding pyridone derivatives
115
,
118
, and
122
[53–55].
SCHEME 13.35 Synthesis of a tetracyclic 1,4-dihydropyridine derivative
126
by Pashkovskii et al.
SCHEME 13.36 Four-component syntheses of pyridone derivatives
129
,
132
,
135
,
138
, and
140
[57–61].
SCHEME 13.37 Four-component 1,4-dihydropyridine
145
synthesis by Jiang et al.
SCHEME 13.38 Synthesis of tetracyclic 1,4-dihydropyridine derivatives
150
and
153
by Li et al.
SCHEME 13.39 Thio-substituted 1,4-dihydropyridines
156
and
159
/
160
synthesis, reported by Altuğ et al. [65, 66].
SCHEME 13.40 Tricyclic 2-amino-1,4-dihydropyridines
163
and 1,4-dihydropyridones
166
cyclized by nucleophilic aromatic substitution [68, 69].
SCHEME 13.41 Knoevenagel/hetero-Diels–Alder approach to pyrido[2,3-
d
]pyrimidines
171
.
SCHEME 13.42 Base-mediated pyrimidine and pyrimidinone formation under thermal and MWI conditions [11, 74, 75].
SCHEME 13.43 Spiro-2-aminopyrimidinone
184
synthesis.
SCHEME 13.44 5-Unsubstituted pyrimidinones
186
by Balalaie et al.
SCHEME 13.45 Biginelli reaction for the synthesis of ferrocenyl-dihydro-1,3-pyrimidine-2-thiones
190
.
SCHEME 13.46 Kaolin-catalyzed Biginelli-type reaction.
SCHEME 13.47 Iodine-catalyzed Biginelli-type reaction of an implemented guanidine moiety.
SCHEME 13.48 5-Hydroxy-2
H
-pyrrol-2-one
202
synthesis by Liang et al. [85].
SCHEME 13.49 Proposed mechanism for the formation of 5-hydroxy-2
H
-pyrrol-2-ones
202
by Quai et al. [86].
SCHEME 13.50 (a) Three-component thiazole
209
synthesis by Renuga et al. and (b) the proposed mechanism for its formation [87].
SCHEME 13.51 (a) Four-component dispiropyrrolidine
218
synthesis by Li et al. and (b) the proposed mechanism for its formation [88].
SCHEME 13.52 Three-component spiropyrrolidine
226
synthesis by Dandia et al. [89].
SCHEME 13.53 MCR to afford 5-substituted thiazoles
228
and
230
as reported by Bazgir et al. [90].
SCHEME 13.54 Knoevenagel condensation/1,3-dipolar cycloaddition to afford spiro-isoxazolines
234
[91].
SCHEME 13.55 Synthesis of 1
H
-pyrazolo[1,2-
b
]phthalazine-5,10-dione derivatives
238
by Bazgir et al. [92].
SCHEME 13.56 Synthesis of 1
H
-pyrazolo[1,2-
b
]phthalazine-5,10-dione derivatives
240
by Rostamnia et al. [73].
SCHEME 13.57 Syntheses of tetracyclic derivatives of 1,10-phenanthroline
243
and phenanthridine
247
[93, 94].
SCHEME 13.58 Silica tungstic acid (STA)-catalyzed dispiro-compound
249
formation [96].
SCHEME 13.59 NHC umpolung to deliver fully substituted furan derivatives
252
[97].
SCHEME 13.60 Knoevenagel condensation/phospha-Michael addition/double cyclization sequence for the synthesis of tetracyclic 2,3,4,11
b
-tetrahydro-1
H
,6
H
-6λ
5
-[1, 2]benzoxaphospholo[2,3-
b
][1,2]benzoxa-phosphol-1-ones
254
[98].
SCHEME 13.61 Variably substituted 2-aminothiophenes by modified Gewald reactions [99–101].
SCHEME 13.62 2-Aminothiopyran
268
and
272
syntheses [102, 103].
SCHEME 13.63 Two-carbon homologation by Ramachary et al. [104–109].
SCHEME 13.64 Five-component Knoevenagel condensation/Diels–Alder reaction/epimerization/Knoevenagel condensation/hydrogenation sequence [110].
SCHEME 13.65 Syntheses of β-acetamido ketones
287
and
291
[111, 112].
SCHEME 13.66 Knoevenagel condensation/nucleophilic aromatic substitution by Wang et al. [113].
SCHEME 13.67 Functionalization of 2-thioxothiazolidin-2-one derivatives [114–117].
SCHEME 13.68 Tetrahydroisoquinoline
311
synthesis by Wang et al. [119].
SCHEME 13.69 Model reaction for the multicomponent synthesis of stilbene derivatives
315
[122].
SCHEME 13.70 Knoevenagel condensation/asymmetric Michael addition by Wang et al. [123].
SCHEME 13.71 Knoevenagel condensation/Diels–Alder cycloaddition by Delgado et al. [124].
SCHEME 13.72 Multicomponent reaction of Meldrum’s acid
112
and indole
327
with several aldehydes
328
by Yonemitsu et al.
SCHEME 13.73 Proposed mechanism of the Yonemitsu reaction.
SCHEME 13.74 Yonemitsu reaction for the synthesis of 3,4-furanone annulated tetrahydro-β-carbolines
336
.
SCHEME 13.75 Proline-catalyzed construction of compounds
338
and
341
.
SCHEME 13.76 One-pot Yonemitsu reaction/aminolysis to 3-substituted 3-indolepropionic amides
345
.
SCHEME 13.77 Proline-catalyzed Yonemitsu reaction with subsequent nucleophilic substitution of the Meldrum’s acid moiety and its proposed mechanism.
SCHEME 13.78 Base-mediated Yonemitsu-type reaction and its proposed mechanism.
SCHEME 13.79 Lewis acid-catalyzed Yonemitsu-type reactions [135–137].
SCHEME 13.80 A small insight into the synthesis of dihydropyridine derivatives by exchange of the heterocyclic component in the Yonemitsu reaction [138–143].
SCHEME 13.81 Yonemitsu-type trimolecular condensation with
in situ
generation of unstable heterocyclic compounds
385
from stable precursors by Krayushkin et al. [153–158].
SCHEME 13.82 Prevention of the decarboxylative cyclization [139, 159].
SCHEME 13.83 Preparation of tricyclic dihydropyridine derivatives by amino-heterocycles and various cyclic CH acids different from Meldrum’s acid [140, 143, 160, 161].
SCHEME 13.84 Yonemitsu-type reaction under electrolytic reaction conditions.
SCHEME 13.85 Four-component Yonemitsu-type reactions [163, 164].
SCHEME 13.86 Proposed structures
421
and
112
of Meldrum’s acid and its acidic, nucleophilic, and electrophilic properties.
SCHEME 13.87 Synthesis of benzo[
f
]quinolin-3-ones
423
with spirocyclic by-product
424
by Wang et al. Three-component reaction for the generation of dispiro[4.2.5.2]pentadecanes
427
by Tu et al. [170, 171].
SCHEME 13.88 Synthesis of diazaspiro[5.5]undecanes
430
by Jetti et al.
SCHEME 13.89
trans
-Cyclopropane spiro compounds
433
from the reaction of Meldrum’s acid
112
with aromatic aldehydes
432
and α-thiocyanato ketones
431
.
SCHEME 13.90 An example of zwitterionic salts
436
with Meldrum’s acid as the anionic structural element.
SCHEME 13.91 Synthesis of novel pentacyclic quinoline derivatives
439
under solvent-free conditions.
SCHEME 13.92 Synthesis of quinoline derivatives
442
by AgNO
3
catalysis.
SCHEME 13.93 Tributylphosphine-catalyzed synthesis of highly substituted tetrahydrofuran derivatives
445
.
SCHEME 13.94 Synthesis of 4(1
H
)-quinolones
449
and 4
H
-pyrimido[2,1-
b
]benzothiazol-4-ones
452
in a two-step fashion introduced by a three-component reaction step.
SCHEME 13.95 Synthesis of 3,4-dihydropyranones
454
/
458
starting from 1,3-dicarbonyl compounds
15
/
47
/
455
/
456
.
SCHEME 13.96 Synthesis of 3,4-dihydropyranones
460
/
463
starting from stable enols
37
/
461
.
SCHEME 13.97 Synthesis of 3,4-dihydropyranones
466
starting from barbituric acids
61
/
464
.
SCHEME 13.98 Synthesis of C4-amide-substituted 3,4-dihydropyranones
469
/
472
.
SCHEME 13.99 Synthesis of 3,4-dihydropyridinones
474
/
477
using ammonium acetate or primary amines
475
[57, 190].
SCHEME 13.100 Synthesis of tetrahydropyridinones
480
[190a].
SCHEME 13.101 Synthesis of 3,4-dihydropyridinones
482
/
484
/
487
starting from
125
/
104
/
485
, respectively [191, 192].
SCHEME 13.102 Meldrum’s acid as malonic acid equivalent—I.
SCHEME 13.103 Meldrum’s acid as malonic acid equivalent—II.
SCHEME 13.104 Synthesis of benzodiazepinedions and benzooxazepinedions (
495
,
498
) [194, 195].
SCHEME 13.105 1,2,3,4-Tetrahydroquinoline synthesis reported by Povarov in 1963.
SCHEME 13.106 Use of Povarov reaction in total synthesis of luotonin A
502
.
SCHEME 13.107 Use of the Povarov reaction in total synthesis of martinellic acid
504
.
SCHEME 13.108 Mechanism of the Povarov reaction—part I.
SCHEME 13.109 Mechanism of the Povarov reaction—part II.
SCHEME 13.110 Mechanism of the Povarov reaction—part III.
SCHEME 13.111 Synthesis of 2,4-
cis
1,2,3,4-tetrahydroquinolines
506
[203b, 204, 205].
SCHEME 13.112 Synthesis of 2,4-
trans
1,2,3,4-tetrahydroquinolines
509
.
SCHEME 13.113 Synthesis of 2,3,4-substituted 1,2,3,4-tetrahydroquinolines
511
.
SCHEME 13.114 Synthesis of 1,2,3,4-tetrahydroquinolines
514
starting from 2,3-dihydrofurans and 3,4-dihydro-2
H
-pyrans
512
[206, 209b].
SCHEME 13.115 Synthesis of 1,2,3,4-tetrahydroquinolines
517
starting from 3-aminocoumarins
515
[207d].
SCHEME 13.116
Endo
-selective synthesis of 1,2,3,4-tetrahydroquinolines
518
.
SCHEME 13.117 Synthesis of 1,2,3,4-tetrahydroquinolines
521
starting from norbornene
519
.
SCHEME 13.118 Synthesis of 1,2,3,4-tetrahydroquinolines
525
starting from dihydropyrrole
523
.
SCHEME 13.119 Enantioselective synthesis of octahydroacridines
527
.
SCHEME 13.120 One-pot synthesis of quinolines
531
by a Povarov reaction and subsequent oxidation with DDQ.
SCHEME 13.121 Domino one-pot synthesis of quinolines
533
by Povarov reaction and subsequent oxidation by O
2
or air [202a, 212].
SCHEME 13.122 Synthesis of 1,10-phenantrolines
536
by a Povarov reaction.
SCHEME 13.123 Synthesis of quinolines
539
using terminal alkynes
537
[200, 207b].
SCHEME 13.124 Synthesis of benzoquinolines
542
using acetylenedicarboxylates
540
and 2-aminonaphthalene
125
.
SCHEME 13.125 Synthesis of chromenopyridinones
544
using 3-aminocoumarins
515
.
SCHEME 13.126 Hantzsch 1,4-dihydropyridine synthesis from 1881.
SCHEME 13.127 Hantzsch pyrrole synthesis from 1890.
FIGURE 13.1 Pharmaceutically active 1,4-dihydropyridines.
FIGURE 13.2 Pharmaceutically active pyrroles.
SCHEME 13.128 Mechanism of the Hantzsch 1,4-dihydropyridine synthesis—part I.
SCHEME 13.129 Mechanism of the Hantzsch 1,4-dihydropyridine synthesis—part II.
SCHEME 13.130 Mechanism of the Hantzsch pyrrole synthesis.
SCHEME 13.131 Synthesis of symmetric 1,4-dihydropyridines
563
under solvent-free conditions [220–224, 232, 235, 237, 238].
SCHEME 13.132 Synthesis of resin-bound symmetric 1,4-dihydropyridines
567
.
SCHEME 13.133 Synthesis of symmetric 1,4-dihydropyridines
563
in water, methanol, and ethanol.
SCHEME 13.134 Synthesis of symmetric 1,4-dihydropyridines
563
in acetonitrile and 1,4-dioxane [221e, 227, 228, 242].
SCHEME 13.135 Synthesis of symmetric 1,4-dihydropyridines
563
in ionic liquids [239b–d].
SCHEME 13.136 Synthesis of bridged bis-1,4-dihydropyridines
572
/
574
.
SCHEME 13.137 Synthesis of asymmetric 1,4-dihydropyridines
579
using dimedone
15
or cyclohexane-1,3-dione
578
.
SCHEME 13.138 Synthesis of asymmetric 1,4-dihydropyridines
581
starting from 1
H
-indene-1,3(2
H
)-dione
217
[219a, 230d, 245].
SCHEME 13.139 Synthesis of asymmetric 1,4-dihydropyridines
583
with preformed α,β-unsaturated carbonyls
582
[219b].
SCHEME 13.140 Synthesis of asymmetric 1,4-dihydropyridines
586
with preformed enamines
167
.
SCHEME 13.141 Catalytic oxidation of 1,4-dihydropyridines
587
by molecular oxygen.
SCHEME 13.142 Catalytic oxidation of 1,4-dihydropyridines
563
by hydrogen peroxide [221a, 248].
SCHEME 13.143 Catalytic oxidation of 1,4-dihydropyridines
587
by sodium periodate [249].
SCHEME 13.144 Stoichiometric oxidation of 1,4-dihydropyridines
563
by halogen-based oxidants [251–257].
SCHEME 13.145 Stoichiometric oxidation of 1,4-dihydropyridines
563
by metal, metalloid, and nonmetal-based oxidants [258–260].
SCHEME 13.146 Stoichiometric oxidation of 1,4-dihydropyridines
563
by nitrates and nitrites [262, 263].
SCHEME 13.147 Domino Hantzsch synthesis and subsequent oxidation—I [267].
SCHEME 13.148 Domino Hantzsch synthesis and subsequent oxidation—II [266, 268].
SCHEME 13.149 Hantzsch pyrrole synthesis under HSVM conditions.
SCHEME 13.150 Hantzsch synthesis of pyrrol-2-carbaldehydes
598
/
600
.
Guide
Cover
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