science of synthesis : houben-weyl methods of molecular transformations. hetarenes and related ring...

Science of synthesis : Houben-Weyl methods of molecular transformations. Hetarenes and Related Ring Systems. Fully unsaturated small ring heterocycles and monocyclic five-membered hetarenes with one heteroatom - PDFDrive.comVolume 9: Fully Unsaturated Small Ring Heterocycles and Monocyclic Five-Membered Hetarenes with One Heteroatom
1. Product Class 1: Oxirenes
1. Synthesis by Ring-Closure Reactions
1. By Formation of Two O—C Bonds
1. Fragments C—C and O
1. Method 1: Oxidation of Alkynes
1. Variation 1: With Peroxy Acids
2. Variation 2: With Dioxiranes
3. Variation 3: With Atomic and Molecular Oxygen
4. Variation 4: Enzymatic Oxidation
2. By Formation of One O—C Bond
1. Fragment O—C—C
1. Method 1: Isomerization of α-Oxo Carbenes
2. Method 2: Isomerization of Ketene
2. Synthesis by Ring Transformation
1. Method 1: From Larger Heterocycles by Extrusion Reactions
3. Aromatization
2. Method 2: β-Elimination Reactions of Oxiranes
3. Method 3: Cycloreversion Reactions of Fused Oxiranes
2. Product Class 2: Thiirenes and Their Derivatives
1. Product Subclass 1: Thiirenes
1. Method 1: From 1,2,3-Thiadiazoles
1. Variation 1: Photochemical Decomposition in Matrixes
2. Variation 2: Photochemical Decomposition in Solution
2. Product Subclass 2: Thiirene 1,1-Dioxides
1. Method 1: From α,α′-Dihalo-Substituted Sulfones
2. Aromatization
1. Method 1: From α,α′-Dihalo-Substituted Sulfoxides
2. Aromatization
1. Method 1: Fused Thiirene 1-Oxides from Diels–Alder Reactions of 2,3-Bis(alkylidene)thiirane 1-Oxides
4. Product Subclass 4: Thiirenium Ions
1. Method 1: Addition of a Sulfonium Ion to Alkynes
2. Method 2: From 1-Halo-2-sulfanylethenes
3. Product Class 3: Selenirenes
1. Method 1: From 1,2,3-Selenadiazoles
1. Variation 1: Photochemical Decomposition in a Matrix
2. Variation 2: Photochemical Decomposition in Solution
4. Product Class 4: Tellurirenes
5. Product Class 5: 1H-Azirines
1. By Formation of Two N—C Bonds
1. Fragments C—C and N
1. Method 1: Reactions of Alkynes with Nitrenes or Nitrene Equivalents
1. Variation 1: Generation of Nitrene (NH) from Hydrazoic Acid
2. Variation 2: Generation of Nitrenes from Organic Azides
3. Variation 3: Oxidation of N-Aminophthalimides in the Presence of Alkynes
2. By Formation of One N—C Bond
1. Fragment N—C—C
1. Method 1: Cyclization of α-Imino Carbenes
1. Variation 1: Generation of α-Imino Carbenes from 1H-1,2,3-Triazoles
2. Variation 2: Generation of α-Imino Carbenes from α-Diazo Imines
3. Variation 3: Generation of Cyclic α-Imino Carbenes from 1H-1,2,3-Benzotriazoles
(Formation of 1H-Benzo[b]azirines)
4. Variation 4: Generation of Cyclic α-Imino Carbenes from Isatin and Its Derivatives (Formation of 1H- Benzo[b]azirines)
2. Method 2: Cyclization of Vinylnitrenes
3. By Formation of One C—C Bond
1. Method 1: Fragment C—N—C
1. Method 1: Extrusion Reactions of Larger Heterocycles
3. Aromatization
2. Method 2: β-Elimination from Aziridines
3. Method 3: Cycloreversion Reactions of Fused Aziridines
6. Product Class 6: Phosphirenes
1. Product Subclass 1: λ5-1H-Phosphirenes
1. Synthesis by Substituent Modification
1. Method 1: Reaction of λ3-1H-Phosphirenes with Benzo-1,2-quinones
2. Method 2: Reaction of λ3-1H-Phosphirenes with Azodicarboxylates
3. Method 3: Modification of an Existing λ5-1H-Phosphirene
2. Product Subclass 2: λ5-1H-Phosphirene Imides, Oxides, and Homologues
1. By Formation of Two P—C Bonds
1. Method 1: Cycloaddition of Iminophosphines to Alkynes
1. Method 1: Oxidative Addition to λ3-1H-Phosphirenes
3. Product Subclass 3: λ5-1H-Phosphirenium Salts
1. Method 1: Cycloaddition of Electrophilic Phosphorus Compounds to Alkynes
1. Variation 1: Cycloaddition with Phosphenium Cations
2. Variation 2: Cycloaddition with Halophosphines
3. Variation 3: Reaction with Dichlorophosphines
4. Variation 4: Reaction with Phosphiranium Cations
1. Method 1: Alkylation of λ3-1H-Phosphirenes
1. Variation 1: Alkylation with Alkyl Triflates
2. Variation 2: Alkylation with Trimethyloxonium Tetrafluoroborate
2. Method 2: Protonation of λ5-1H-Phosphirene Imides
4. Product Subclass 4: η1-1H-Phosphirene–Metal Complexes
1. Method 1: Cycloaddition of Phosphinidene Complexes to Alkynes
1. Variation 1: With Phosphinidene Complexes Generated from 7-Phosphabicyclo[2.2.1]hepta-2,5-diene Complexes
2. Variation 2: With Phosphinidene Complexes Generated from λ3-1H-Phosphirane Complexes
3. Variation 3: With Phosphinidene Complexes Generated from λ3-2H-1,2-Azaphosphirene Complexes
4. Variation 4: With Phosphinidene Complexes Generated from Secondary λ3-Phosphine Complexes
5. Variation 5: With Phosphinidene Complexes Generated from Disodium Tetracarbonylferrate (Collman's Reagent) and an Aminodichlorophosphine
1. Method 1: Exchange Reactions with the Substituent at Phosphorus
2. Method 2: Modification of the Metal Fragment
3. Method 3: Formation of η1-1H-Phosphirene–Metal Complexes by Complexation of λ3-1H-Phosphirenes
5. Product Subclass 5: λ3-1H-Phosphirenes
1. Method 1: Cycloaddition of Phosphinidenes to Alkynes
2. Method 2: λ3-1H-Phosphirenes from Metallacyclopropenes
3. Method 3: λ3-1H-Phosphirenes from a Vinylcarbene–Cobalt Complex
2. By Formation of One P—C and One C—C Bond
1. Method 1: Cycloaddition of Carbenes to Phosphaalkynes
1. Variation 1: Cycloaddition with Halocarbenes
2. Variation 2: Cycloaddition with Chloro(vinyl)carbenes
3. Variation 3: Cycloaddition with a Stable Phosphino(silyl)carbene
2. Synthesis by "Aromatization"
1. Elimination Reactions with λ3-Phosphiranes
1. Method 1: Cycloaddition of Halocarbenes to Phosphaalkenes Followed by HX Elimination
2. Method 2: Cyclization of Bis(methylene)phosphoranes Followed by 1,2-Elimination
1. Method 1: Decomplexation of η1-1H-Phosphirene–Metal Complexes
1. Variation 1: Decomplexation with Iodine and 1-Methyl-1H-imidazole
2. Variation 2: Decomplexation with 1,2-Bis(diphenylphosphino)ethane
2. Method 2: Reduction of 1-Halo-λ5-1H-phosphirenium Salts with Tertiary Phosphines
3. Method 3: Substitution of Hydrogen at the λ3-1H-Phosphirene Double Bond
4. Method 4: Substitution of Chlorine in 1-Chloro-λ3-1H-phosphirenes
1. Variation 1: Substitution by Hydrogen with Complex Hydrides
2. Variation 2: Substitution by Lithium and Grignard Nucleophiles
3. Variation 3: Substitution by Boron Functionalities with Lithium, Sodium, or Silver Borates
4. Variation 4: Substitution with Silylated and Stannylated Nucleophiles
6. Product Subclass 6: λ3-1H-Phosphirenylium Salts
7. Product Class 7: Three-Membered Rings with Phosphorus and One or More Heteroatoms
1. Product Subclass 1: 2λ3-2H-1,2-Azaphosphirenes
1. By Formation of One P—N and One P—C Bond
1. Method 1: From Amino(aryl)carbene Complexes and a P1 Reagent
1. Variation 1: Reactions of Amino(aryl)carbene Complexes with Chlorophosphaalkenes
2. Variation 2: Reactions of Amino(aryl)carbene Complexes with Dichlorophosphines
2. Product Subclass 2: 1λ3,2λ3-1H-Diphosphirenes
1. By Formation of One P—P and One P—C Bond
1. Method 1: Cycloaddition of Phosphinidenes or Phosphinidene Equivalents to Phosphaalkynes
1. Variation 1: Cycloaddition with Iminophosphines
2. Variation 2: Cycloaddition with Phosphinidene Complexes
3. Variation 3: Cycloaddition with Halo(silyl)phosphines
2. Method 2: Cyclooligomerization of Phosphaalkynes under the Influence of Lewis Acids
2. By Formation of One P—P Bond
1. Method 1: Cyclization of Aminophosphino-Substituted Phosphaalkenes
2. Method 2: Synthesis by Substituent Modification
3. Product Subclass 3: 1H-Triphosphirenes
8. Product Class 8: Four-Membered Rings with One or More Heteroatoms
1. Product Subclass 1: Azetes
1. Method 1: Ring Enlargement of Azidocyclopropenes
2. Product Subclass 2: λ5-Phosphetes
1. By Formation of One P—C Bond
1. Method 1: From (Arylmethylene)phosphoranes
3. Product Subclass 3: λ3-Phosphetes
1. By Formation of One P—C and One C—C Bond
1. Method 1: From Phosphaalkynes and Alkynes in the Coordination Sphere
of Transition Metals
1. By Formation of Two S—C Bonds
1. Method 1: From Alkynes and Sulfur
1. Variation 1: From Alkynes and Molten Sulfur
2. Variation 2: From Alkynes and Sulfur in Solution
2. By Formation of One S—S Bond
1. Method 1: From an α-Thioxo Ketone and Lawesson's Reagent
1. Synthesis by Ring Contraction
1. Method 1: From 1,3-Dithiol-2-ones
2. Method 2: Dimethyl 1,2-Dithiete-3,4-dicarboxylate by Oxidative Ring Contraction
of a 2-Titana-1,3-dithiole
1. Method 1: From a 1,3,2-Diselenazolylium Salt
6. Product Subclass 6: 1,2λ5-Azaphosphetes
1. Synthesis by Ring Contraction
1. Method 1: From 1,2,3,4λ5-Triazaphosphinines
2. Synthesis by Ring Enlargement
1. Method 1: From 2-[Bis(dialkylamino)phosphino]-2H-azirines
7. Product Subclass 7: 1λ5,3λ5-Diphosphetes
1. Method 1: From Alkylidenephosphoranes
1. Variation 1: From [Chloro(phosphino)methylene]phosphoranes
2. Variation 2: From (Alkylidene)fluorophosphoranes
2. Method 2: From Diazo(phosphino)(phosphoryl)methanes
3. Method 3: From Diazo(phosphino)(trimethylsilyl)methanes
4. Method 4: From [Bis(trimethylsilyl)methyl]dichlorophosphine
1. Method 1: From 1,1,3,3-Tetrakis(dimethylamino)-1λ5,3λ5-diphosphete
by Substitution at Ring Carbon Atoms
1. Synthesis by Ring Enlargement
1. Method 1: From a 2-Phosphino-2H-phosphirene
1. Method 1: From Phosphaalkynes in the Coordination Sphere of Titanium
2. Aromatization
1. Method 1: From Phosphaalkynes in the Coordination Sphere of Transition Metals
1. Variation 1: From Phosphaalkynes and Transition-Metal–Alkene Complexes
2. Variation 2: From Phosphaalkynes and Transition-Metal Carbonyls
3. Variation 3: From Phosphaalkynes and Transition-Metal–Arene Complexes
4. Variation 4: From Phosphaalkynes and Metal Vapor
5. Variation 5: Additional Variations
11. Product Subclass 11: 1,3,2λ5-Diazaphosphetes
1. By Formation of Two N—P Bonds
1. Method 1: From 3-Bromo-3-phenyl-3H-diazirine and a Stannylphosphine
12. Product Subclass 12: 1λ5,2λ3,3λ5-Triphosphetes
1. By Formation of Two P—P Bonds
1. Method 1: From Lithium Bis(diphenylphosphino)(trimethylsilyl)methanide
and Phosphorus Trichloride
1. By Ring Contraction
1. By Formation of Two N—P Bonds
1. Method 1: From Azidobis(diisopropylamino)phosphine
2. Method 2: From N-[Bis(diisopropylamino)phosphino]-C-[bis(diisopropylamino)thiophosphoryl]nitrilimine
15. Product Subclass 15: 1λ5,3λ5,2λ3,4λ3-Tetraphosphetes
1. By Formation of Four P—P Bonds
1. Method 1: From Cyclic Bis(amino)chlorophosphines
16. Product Subclass 16: 1,2,3,4-Tetraphosphetes
1. By Formation of Four P—P Bonds
1. Method 1: From White Phosphorus in the Coordination Sphere of Transition Metals
9. Product Class 9: Furans
1. By Formation of One O—C and One C—C Bond
1. Fragments O—C—C and C—C
1. From α-Heterofunctionalized Ketones
1. Method 1: Transition-Metal-Catalyzed Reaction of α-Diazoalkanones with Alkynes
2. Method 2: From α-Halo Ketones and 3-Oxoalkanoates (Feist–Benary Reaction)
3. Method 3: From 1,1-Dialkoxy-2-bromoalkanes and Dicarbonyl Compounds
or 1-(Trimethylsiloxy)alk-1-enes
4. Method 4: From α-Hydroxy Ketones and Dialkyl But-2-ynedioate
5. Method 5: From α-Hydroxy Ketones and Dicarbonyl Compounds and Derivatives
6. Method 6: From α-Haloalkanones and α-Trimethylstannyl Ketones
2. From 1,3-Dicarbonyl Compounds
2. Method 2: Palladium-Catalyzed Reaction of Alkyl 3-Oxoalkanoates with 2-(Alk-1-ynyl)oxiranes
3. Method 3: Manganese-Mediated Reaction of Alkyl 3-Oxoalkanoates with Enol Ethers
4. Method 4: Knoevenagel Condensation of 1,3-Dicarbonyl Compounds and Aldehydes Followed by Bromination and Cyclization
5. Method 5: From 1,3-Dicarbonyl Compounds and 1-Nitroalk-1-enes
6. Method 6: Palladium-Catalyzed Reaction of 1,3-Dicarbonyl Compounds with Prop-2-ynyl Carbonate
3. From Functionalized Alkenes and Alkynes with C,C,O Building Blocks
1. Method 1: From 1-Haloalk-1-enes and Methylene Ketones
2. Method 2: From Alk-2-ynylsulfonium Salts and Carbonyl Compounds
3. Method 3: From 1-Aminoalk-1-ynes and Sulfonylalk-1-ynes
2. Fragments C—C—C and O—C
1. Method 1: From 3-Bromopropenal Acetals and Alkanals
2. Method 2: From Silylallenes and Acid Chlorides
3. Fragments O—C—C—C and C
1. Method 1: From α,β-Unsaturated Carbonyl Compounds and Sulfonium Ylides
2. Method 2: From 1-Aryl-3-chloroalkan-1-ones and Potassium Cyanide
3. Method 3: From Selectively Protected 1,3-Dicarbonyl Compounds
4. Method 4: 2,3-Disubstituted Furans from 1-(Benzyloxy)-3-tosylalkenes and Aldehydes
2. By Formation of Two C—C Bonds
1. Fragments C—O—C and C—C
1. Method 1: From Dialkyl Oxalate and Bis(alkoxycarbonylmethyl) Ethers
3. By Formation of One O—C Bond
1. Fragment O—C—C—C—C
1. By Cyclization of 1,4-Diheterofunctional C4 Compounds
1. Method 1: Cyclization of 4-Oxobutanamides or 4-Oxobutanenitriles to Furan-2-amines
2. Method 2: Cyclization of 4-Hydroxybut-2-enenitriles
3. Method 3: Reductive Cyclization of Alkene-1,4-diones and Cyclization of 4-Hydroxyalk-2-en-1-ones
4. Method 4: Cyclization of 4-Diazoalk-2-en-1-ones
5. Method 5: Cyclization of 4,4-Dialkoxyalkan-1-ones
6. Method 6: Cyclization of Alkane-1,4-diones (The Paal–Knorr Synthesis)
7. Method 7: Cyclization of γ-Hydroxy Ketone or Their Derivatives
8. Method 8: Cyclization of 1,4-Dihydroxyalk-2-ynes
9. Method 9: Oxidative Cyclization of 1,4-Dihydroxyalk-2-enes
2. By Cyclization of Monofunctionalized C4 Compounds
1. Method 1: Palladium-Catalyzed Cyclization of Alk-1(2)-yn-4-ones
2. Method 2: Cyclization of Alka-1,2-dien-4-ones
3. Method 3: Cyclization of α-Substituted β,γ-Unsaturated Ketones with Diphenyl Diselenide
4. Method 4: Cyclization of 5-Hydroxyalk-3-en-1-ynes
5. Method 5: Base-Assisted Cyclization of 1-(4-Hydroxyalk-2-ynyl)benzotriazoles
6. Method 6: Cyclization of Alkynyloxiranes
7. Method 7: Cyclization of 4-Hydroxyalk-1-ynes and Substituted 4-Hydroxyalk-1-enes
8. Method 8: Oxidative Cyclization of Alk-1-en-4-ones
1. Fragment C—O—C—C—C
1. Method 1: McMurry-type Cyclization of 1-Acyloxyalk-1-en-3-ones
2. Fragment C—C—O—C—C
1. Method 1: Cyclization of 1-(Alk-2-ynyloxy)-2-bromo-1-(organooxy)alkanes via a Radical Mechanism
1. Ring Enlargement
2. From Five-Membered Heterocycles
1. Method 1: Cycloaddition of Alkynes to Furans Followed by Retro-Diels–Alder Reaction
2. Method 2: Cycloaddition of Alkynes to Oxazoles Followed by Retro-Diels–Alder Reaction
3. Method 3: Cycloaddition of Alkynes to Mesoionic Heterocycles Followed by Retro-Diels–Alder Reaction
4. Method 4: Decomposition of 4-(Benzoyloxy)-1,3-dioxolanes
5. Method 5: Reduction and Rearrangement of 4,5-Dihydroisoxazoles
3. Ring Contraction
2. Method 2: Synthesis from 2H-Pyrans and Pyrylium Salts
3. Method 3: Synthesis from 3,6-Dihydro-1,2-dioxins
4. Method 4: Synthesis from Sugar Derivatives
3. Aromatization
1. Method 1: Reduction and Elimination of Water from Furan-2(5H)-ones
2. Method 2: Oxidation of Dihydro-and Tetrahydrofurans
1. Substitution of Hydrogen
2. Method 2: Metalation
2. Variation 2: Replacement of a Halogen by Lithium
3. Method 3: Introduction of Formyl Groups
4. Method 4: Introduction of Acyl Groups
5. Method 5: Introduction of Chloromethyl and Hydroxymethyl Groups
6. Method 6: Introduction of Aminoalkyl Groups (Mannich Reaction)
7. Method 7: Introduction of Allyl Groups
8. Method 8: Introduction of Alk-1-enyl Groups
9. Method 9: Introduction of Aryl Groups
10. Method 10: Introduction of Alkyl Groups by Reaction with Alkyl Halides (Friedel–Crafts Reaction)
11. Method 11: Introduction of Alkyl Groups by Reaction with α,β-Unsaturated Carbonyl Compounds
12. Method 12: Introduction of Halogen Substituents
13. Method 13: Sulfonation
14. Method 14: Nitration
2. Substitution of Metals
1. Method 1: Replacement of Lithium by Hydrogen or Deuterium
2. Method 2: Replacement of Lithium by a Silyl Group
3. Method 3: Replacement of Lithium by a Carboxy Group
4. Method 4: Replacement of Lithium by an Acyl Group
5. Method 5: Replacement of Lithium by a Hydroxymethyl Group
6. Method 6: Replacement of Lithium by an Aryl Group via Intermediate Boronates (Suzuki Coupling)
7. Method 7: Replacement of Lithium by an Aryl or Alkenyl Group via Intermediate Stannanes (Stille Coupling)
8. Method 8: Replacement of Lithium by an Acyl Group via Intermediate Furylcopper Compounds (Including Ullmann Coupling)
9. Method 9: Replacement of Lithium by Aryl, Alkenyl, or Alkynyl Groups via Intermediate Furylzinc Compounds
10. Method 10: Replacement of Lithium by an Alkyl Group
11. Method 11: Replacement of Lithium by a Halogen
12. Method 12: Replacement of Lithium by an Alkylsulfanyl or Arylsulfanyl Group
3. Substitution of Carbon Functionalities
1. Method 1: Decarboxylation of Furoic Acids
4. Substitution of Heteroatoms
2. Method 2: Reaction of Halo-or Nitrofurans with Carbon Nucleophiles
3. Method 3: Metal-Catalyzed Cross Coupling of Halofurans with Alkenes, Arenes,
and Alkynes
4. Method 4: Reaction of Halo-or Nitrofurans with Hetero Nucleophiles
5. Modification of α-Substituents
2. Method 2: Ene Reaction of 3-Methylene-2,3-dihydrofurans
3. Method 3: Wittig Rearrangement of Alkyl 3-Furylmethyl Ether
4. Method 4: Anionic Oxy-Cope Reaction of a 2-But-3-enylfuran
10. Product Class 10: Thiophenes, Thiophene 1,1-Dioxides, and Thiophene 1-Oxides
1. Product Subclass 1: Thiophenes
1. By Formation of Two S—C Bonds and One C—C Bond
1. Fragment S and Two C—C Fragments
1. Method 1: Oxidative Coupling of Aryl Methyl and Related Ketones and a Source of Sulfur
2. Method 2: Reaction of Alkenes or Alkynes with a Source of Sulfur
1. Variation 1: Reaction of Alkynes with a Source of Sulfur
2. Variation 2: Reaction of Alkenes with a Source of Sulfur
3. Method 3: Thionation of N-(Phenylacetyl)thiobenzamides
2. By Formation of Two S—C Bonds
1. Fragments C—C—C—C and S
1. Method 1: Reaction of Buta-1,3-diynes with Sulfuration Reagents
1. Variation 1: Reaction of Buta-1,3-diynes with Sulfides
2. Variation 2: Reaction of Buta-1,3-diynes with Sulfur Dichloride
2. Method 2: Reaction of Buta-1,3-dienes with a Source of Sulfur
3. Method 3: Reaction of But-2-enes or Butanes with Sulfur
4. Method 4: Cyclization of Sulfinylalkenes
1. Variation 1: Reaction of Buta-1,2-dienes with Sulfur Dioxide
2. Variation 2: Reaction of 1-Siloxypenta-1,4-dienes with Thionyl Chloride
5. Method 5: Reaction of 1,4-Diketones with Sulfur Reagents and Cyclization (The Paal Synthesis)
6. Method 6: Reaction of α,β-Unsaturated Nitriles with Sulfur (The Gewald Synthesis)
3. By Formation of One S—C and One C—C Bond
1. Fragments S—C—C—C and C
1. Method 1: S-Alkylation of β-Thioxo Carbonyl Compounds or β-Thioxonitriles Followed by Ring Closure
1. Variation 1: S-Alkylation of Enolizable β-Thioxo Carbonyl Compounds or β-Thioxonitriles
2. Variation 2: Reaction of β-Oxo Dithioesters and β-Oxothioamides
with a 4-Bromobut-2-enoate
3. Variation 3: Reaction of Active Methylene Compounds with Carbon Disulfide Followed
by S-Alkylation and Ring Closure
2. Method 2: Carbene Addition to α-Oxoketene Dithioacetals and α-Oxoketene Monothioacetals
2. Fragments S—C—C and C—C
1. Method 1: From α-Sulfanyl Ketones
1. Variation 1: Reaction of α-Sulfanyl Ketones with 2-(Diethoxyphosphoryl)-Substituted Alk-2-enoates
2. Variation 2: From α-Sulfanyl Ketones and Cyanoacetates
2. Method 2: Reaction of α-Alkylsulfanyl Ketones with Grignard Reagents
3. Method 3: From Vinyl Sulfides and Alkynes
4. Method 4: From 1,2,3-Thiadiazoles and Alkynes
3. Fragments S—C and C—C—C
1. Method 1: Reaction of Dithioesters with Alk-1-ynes
2. Method 2: Reaction of Isothiocyanates with Allyl or Alkynyl Compounds
1. Variation 1: Reaction of Isothiocyanates with (Cyanomethyl)ketene Dithioacetals
2. Variation 2: Reaction of Isothiocyanates with Alk-1-ynyllithium Compounds
3. Method 3: Reaction of Thioglycolates with β-Electrophilic Carbonyl Compounds
or Equivalents
1. Variation 1: Reaction of Thioglycolates with β,β-Dihalo or α,β-Dihalo Carbonyl Compounds
2. Variation 2: Reaction of Thioglycolates with β-Chlorovinyl Carbonyl Compounds
and Equivalents (The Fiesselmann Synthesis)
3. Variation 3: Reaction of Thioglycolates with β-Chloro-Substituted Cinnamonitriles
4. Variation 4: Reaction of Thioglycolates with α-Oxoalkynes
5. Variation 5: Reaction of Thioglycolates or α-Sulfanyl Ketones with Acetylenic Esters
6. Variation 6: Reaction of Thioglycolic Acid or Esters with β-Oxo Esters
4. Method 4: Reaction of Benzyl Thiols with Butadiynes
5. Method 5: Reaction of Thiocarboxylic Acids with a Cyclopropyl(triphenyl)phosphonium Salt
6. Method 6: Reaction of Dithiocarbonates or Equivalents and Cyclopropenylium Salts
1. Fragments C—S—C—C and C
1. Method 1: S-Alkylation of Thioamides and Reaction with a Chloromethaniminium Salt
2. Fragments C—S—C and C—C
1. Method 1: Reaction of 3-Thia-1,5-dicarbonyl Compounds or Equivalents with 1,2-Dicarbonyl Compounds (The Hinsberg Synthesis)
2. Method 2: 1,3-Dipolar Cycloaddition of Thiocarbonyl Ylides with Alkynes
1. Variation 1: Reaction of 1,3-Dithiolylium-4-olates with Alkynes
2. Variation 2: Reaction of Bis[(trimethylsilyl)methyl] Sulfoxides with Alkynes
3. Method 3: From 1,3-Thiazoles and Alkynes
5. By Formation of One S—C Bond
1. Fragment S—C—C—C—C
1. Method 1: From ω-Sulfanyl Carbonyl Compounds by Ring Closure
1. Variation 1: Cyclization of γ-Sulfanyl Ketones
2. Variation 2: Oxidative Cyclization of 2-Sulfanylpenta-2,4-dienoic Acids
2. Method 2: Cyclization of 3-Sulfanylprop-1-ynyl Ketones
3. Method 3: From γ,δ-Unsaturated Thioamides
1. Fragment C—S—C—C—C
1. Method 1: Cyclization of Aroylketene S,N-Acetals
2. Fragment C—C—S—C—C
1. Method 1: From β,β′-Dioxo Sulfides by Reductive Coupling
1. From Five-Membered Heterocycles
2. Method 2: From 1,2-Thiazolium Salts
3. Method 3: From 3-Amino-1,2-dithiolium Salts
4. Method 4: From 1,3-Oxathiolium Salts
5. Method 5: From Furans
2. Ring Contraction
1. Method 1: From 1,2-or 1,4-Dithiins
1. Variation 1: From 1,2-Dithiins by Thermal or Photochemical Ring Contraction, or by Use of Thiophilic Phosphorus Reagents
2. Variation 2: From 1,4-Dithiins by Thermal Ring Contraction
3. Variation 3: From 1,4-Dithiins via their S-Oxides
2. Method 2: From 4H-Thiopyrans and Thiopyrylium Salts
3. Ring Expansion
1. Variation 1: From 2-(1-Hydroxyalk-2-ynyl)thiiranes by Electrophile-Induced Ring Expansion
2. Variation 2: From 2-(2-Oxoalkyl)thiiranes
3. Variation 3: From 2-(2-Oxoalkyl)oxiranes
3. Aromatization
1. Variation 1: Generation of Organometallic Compounds by Hydrogen–Lithium Exchange
3. Method 3: Introduction of Formyl Groups
4. Method 4: Introduction of Acyl Groups
5. Method 5: Introduction of Chloromethyl and Hydroxymethyl Groups
6. Method 6: Introduction of Alkylamino Groups (The Mannich Reaction)
7. Method 7: Introduction of Allyl, Alk-1-enyl, or Alk-1-ynyl Groups
8. Method 8: Introduction of Aryl Groups
9. Method 9: Introduction of Alkyl Groups
10. Method 10: Halogenation
11. Method 11: Sulfonation
12. Method 12: Nitration
2. Method 2: Substitution Reactions Involving Organocopper or
Organozinc Derivatives
4. Method 4: Substitution Reactions Involving Organolithium Derivatives
1. Variation 1: Replacement of Lithium by Hydrogen or Deuterium
2. Variation 2: Replacement of Lithium by a Silyl Group
3. Variation 3: Replacement of Lithium by a Carboxy Group
4. Variation 4: Replacement of Lithium by a Formyl or Acyl Group
5. Variation 5: Replacement of Lithium by a Hydroxymethyl or an Aminomethyl Group
6. Variation 6: Replacement of Lithium by an Alkyl, Alkenyl, Alkynyl, or Aryl Group
7. Variation 7: Replacement of Lithium by a Halogen
8. Variation 8: Replacement of Lithium by a Sulfanyl or Sulfonyl Group
1. Method 1: Decarboxylation
1. Method 1: Substitution of Halogen by Hydrogen
2. Method 2: Substitution of Halogen by Lithium
3. Method 3: Substitution of Halogen by Alkoxy or Sulfanyl Groups
4. Method 4: Metal-Assisted Cross Coupling of Halothiophenes
with Alkenes, Arenes, and Alkynes
1. Variation 1: Manganese-Assisted Coupling Reactions
2. Variation 2: Zinc-Assisted Coupling Reactions
3. Variation 3: Palladium-Assisted Coupling Reactions
5. Modification of α-Substituents
3. Method 3: Side-Chain Bromination of Alkylthiophenes
2. Product Subclass 2: Thiophene 1,1-Dioxides
1. Oxidation of Thiophenes
2. Aromatization
2. Variation 2: From Dihydro-or Tetrahydrothiophene 1,1-Dioxides by Nitrous Acid Elimination
3. Product Subclass 3: Thiophene 1-Oxides
1. Formal Exchange of Ring Members
1. Method 1: From Zirconocenes
2. Oxidation of Thiophenes
11. Product Class 11: Selenophenes
1. By Formation of Two Se—C Bonds
1. Fragments C—C—C—C and Se
1. Method 1: Reaction of C4 Building Blocks with Sources of Selenium
1. Variation 1: Reaction of 1,4-Dilithio- or 1,4-Diiodobutadienes with a Selenium Source
2. Variation 2: Reaction of Butadiynes with Selenides
3. Variation 3: Reaction of 1-Alkynyl-2-bromobenzenes with Elemental Selenium
4. Variation 4: Reaction of Chloroalkynols or Alkynyloxiranes with Selenides
1. Fragments C—Se—C and C—C
1. Method 1: From 1,2-Diketones and a Selenodiacetate (Hinsberg Synthesis)
1. Fragment C—C—Se—C—C
1. Method 1: Reductive Cyclization of Diphenacyl Selenides
2. Synthesis by Formal Exchange of Ring Members
1. Method 1: Exchange of Zirconium by Selenium
12. Product Class 12: Tellurophenes
1. By Formation of Two Te—C Bonds
1. Fragments C—C—C—C and Te
1. Method 1: Reaction of C4 Building Blocks with Sources of Tellurium
1. Variation 1: Reaction of 1,4-Dilithio- or 1,4-Diiodobutadienes with a Tellurium Source
2. Variation 2: Reaction of Butadiynes with Tellurides
3. Variation 3: Reaction of 1-Alkynyl-2-bromobenzenes or But-1-en-3-ynes with Elemental Tellurium
4. Variation 4: Reaction of Chloroalkynols with Tellurides
1. Fragment C—Te—C—C—C
1. Method 1: Cyclization of 3-(Alkyltellanyl)propenals
13. Product Class 13: 1H-Pyrroles
1. By Formation of Two N—C Bonds and One C—C Bond
1. Fragment N and Two C—C Fragments
1. Method 1: Condensation Reaction of β-Dicarbonyl Compounds, α-Halo Carbonyl Compounds and Amines (The Hantzsch Synthesis)
2. Method 2: Condensation Reaction of Benzyl Ketones, Benzoins, and Ammonia
3. Method 3: Condensation Reaction of Aliphatic Aldehydes or Ketones and Hydrazines (The Piloty Synthesis)
2. By Formation of One N—C Bond and Two C—C Bonds
1. Fragments N—C, C—C, and C
1. Method 1: Reaction of Trimethylsilyl Cyanide with Alkynes, Catalyzed by Palladium(II) or Nickel(II) Chloride
2. Method 2: Reaction of Zirconium and Titanium Complexes with Alkynes and Carbonyl Compounds
1. Variation 1: Reaction of Zirconocene Derivatives of Alkylamines with Alkynes and Carbon Monoxide
2. Variation 2: Reaction of Zirconocene Derivatives of C-Silyl Imine Compounds with Alkynes and Acyl Chlorides
3. Variation 3: Reaction of Titanium Alkyne Complexes with Imines and Carbon Monoxide
3. Method 3: Reaction of Terminal Alkynes with Imines and Tungsten–Carbene Complexes
4. Method 4: Reaction of Imines with α-Haloacetals and 1-Benzylbenzotriazoles
3. By Formation of Three C—C Bonds
1. Fragment C—N—C and Two C Fragments
1. Method 1: Reaction of Alkyl Isocyanoacetates with Aldehydes
4. By Formation of Two N—C Bonds
1. Fragments C—C—C—C and N
1. Method 1: Condensation Reactions of 1,4-Dicarbonyl Compounds or Equivalents with Amines (The Paal– Knorr Synthesis)
2. Method 2: Reaction of 4-Substituted Carbonyl Compounds or Equivalents with Amines
3. Method 3: Reaction of Alk-2-enyl Carbonyl Compounds or Equivalents with Amines
4. Method 4: Reaction of Alk-3-ynyl Carbonyl Compounds with Amines
5. Method 5: Reaction of Buta-1,3-dienes and Related Compounds with Amines
6. Method 6: Reaction of Buta-1,3-diynes with Amines
7. Method 7: Pyrrol-2-amines from the Reaction of Functionalized Nitriles with Amines
8. Method 8: 2-(Benzotriazolylmethyl)pyrroles from the Reaction of Alkynyloxiranes with Amines
5. By Formation of One N—C and One C—C Bond
1. Fragments N—C—C—C and C
1. Method 1: Reaction of α,β-Unsaturated Imines with Esters and Niobium(III) Chloride
2. Method 2: Reaction of α,β-Unsaturated Imine Iron–Tricarbonyl Complexes with Methyllithium
3. Method 3: Hydroformylation and a Related Reaction of Propargylamines
4. Method 4: Reaction of β-Amino Ketones with Diazo(trimethylsilyl)methane
5. Method 5: 3-Aminopyrrole-2,4-dicarbonitriles from the Reaction of Alkylidenemalononitriles with Aminoacetonitriles
2. Fragments N—C—C and C—C
1. Method 1: Condensation Reaction of α-Amino Ketones with Methylene-Active Carbonyl Compounds (The Knorr Pyrrole Synthesis)
2. Method 2: Condensation Reaction of Enamino Esters with α-Electrophilic Carbonyl Compounds and their Synthetic Equivalents
3. Method 3: Reaction of Enamino Esters with α-Diazo Ketones
4. Method 4: Reaction of Oximes (and Hydrazones) with Alkynes
5. Method 5: Reaction of Azoalkenes with Methylene Ketones
6. Method 6: Combination of α-Amino Carbonyl Compounds and Enolates via Aldol Reactions
7. Method 7: Reaction of α-Metalated Imines with α-Halo Ketones or α-Diketones
3. Fragments N—C and C—C—C
1. Method 1: Reaction of α-Aminoacyl or α-Iminoacyl Compounds with 1,3-Diketones or Equivalents
2. Method 2: Reaction of Benzotriazole Enamines with Imines
3. Method 3: Reaction of Allenes with Tosylimines
1. Fragments C—N—C—C and C
1. Method 1: Reaction of 2-Arylvinyl Isocyanides with Carbon Nucleophiles
2. Fragments C—N—C and C—C
1. Method 1: Aldol Reaction of α-Diketones with Bis(acceptor-substituted methyl)amines
2. Method 2: Reaction of α-Amidonitriles with Vinylphosphonium Salts
3. Method 3: Reaction of Isocyano-Substituted Acetates, Acetonitriles, or Methylphosphonates with Nitroalkenes
4. Method 4: Reaction of Tosylmethyl Isocyanide with Electrophilic Alkenes
5. Method 5: Reaction of N-(Tosylmethyl)- or N-(Benzotriazolylmethyl)-Substituted Imidothioates with Electrophilic Alkenes
6. Method 6: Reaction of Azomethine Ylides or Related Systems with Alkynes or Alkenes
7. Method 7: Reaction of Chromium–(Alkylidenamino)carbene Complexes with Alkynes
7. By Formation of One N—C Bond
1. Fragment N—C—C—C—C
1. Method 1: Cyclizative Condensations
2. Method 2: Cyclization of Alk-4-yn-1-amines
3. Method 3: Cyclization of Dienyl Azides
1. Fragment C—N—C—C—C
1. Method 1: Reactions Involving Typical C—C Bond Construction
2. Fragment C—C—N—C—C
1. Method 1: Reactions Involving Typical C—C Bond Construction
1. By Ring Enlargement
2. Method 2: Rearrangement of 2-Vinyl-2H-azirines
2. By Ring Contraction
3. Synthesis by Aromatization
2. By Elimination
3. By Isomerization
4. By Dehydrogenation
1. Substitution of Existing Substituents
2. Method 2: C-Acylation
3. Method 3: C-Alkylation
1. Variation 1: C-Alkylation by Typical Electrophiles
2. Variation 2: C-Alkylation (and Arylation) by Carbenes and Free Radicals
3. Variation 3: C-Alkylation by Various Electrophiles
4. Method 4: C-Halogenation
5. Method 5: C-Thiolation
7. Method 7: N-Substitution
1. Method 1: Substitution Reactions Involving Mercury and Thallium Derivatives
2. Method 2: Substitution Reactions Involving Organocopper and Organozinc Derivatives
3. Method 3: Substitution Reactions Involving Organopalladium Derivatives
4. Method 4: Substitution Reactions Involving Organolithium Derivatives
1. Method 1: Reactions Involving Decarboxylation from a Ring Carbon
2. Method 2: Reactions Involving Dealkylation from the Ring Nitrogen
3. Method 3: Reactions Involving Detritylation from the Ring Nitrogen
1. Method 1: Replacement of Tosyl by Trialkylstannyl Groups on a Ring Carbon
2. Method 2: Replacement of Sulfur and Silyl Groups on the Ring Nitrogen
2. Modification of Substituents
1. Method 1: Reduction of Acyl Groups to Alkyls
2. Method 2: Addition and Condensation Reactions of Acyl Groups
3. Method 3: Rearrangement of Acyl Groups
2. Modification of Alkyl Substituents
1. Method 1: Substitution Reactions of Mannich Bases
2. Method 2: Alkylation of α-Methylene Substituents
3. Method 3: Halogenation of α-Methylene Substituents
4. Method 4: Oxidation of α-Methylene Substituents
14. Product Class 14: Phospholes
1. Product Subclass 1: λ3-1H-Phospholes
1. By Formation of Two P—C Bonds and One C—C Bond
1. Fragment P and Two C—C Fragments
1. Method 1: Reaction of Dihalophosphines with Enamines
1. Fragments C—C—C—C and P
1. Method 1: Reaction of Dilithiophosphines with 1,4-Dihalo-Substituted 1,3-Dienes
2. Method 2: Reaction of Dihalophosphines with 1,4-Dilithio-Substituted 1,3-Dienes
3. Method 3: Reaction of Primary Phosphines with 1,3-Diynes
4. Method 4: Thermal Reaction of Dihalophosphines with 1,3-Dienes
1. Method 1: Reaction of Dihalophosphines with Metallacyclopentadienes
2. Method 2: Insertion of Alkynes into Phosphirenes
3. Aromatization
2. Method 2: Dehydrohalogenation of 1-Halodihydrophospholium Halides
1. Variation 1: P-Bromination of 2,5-Dihydro-λ3-1H-phospholes Followed by Dehydrobromination
2. Variation 2: Quaternization of 1-Bromo-2,5-dihydro-1H-phospholes Followed
by Dehydrobromination
1. Addition Reactions
2. Method 2: α-Functionalization of 1H-Phosphol-2-yllithiums
2. Substitution of Existing Substituents
1. Method 1: Reaction of Nucleophiles with Phospholes
2. Method 2: Transformation of α-Substituents
3. Method 3: Reduction of λ5-Phospholes
3. Decomplexation and Thermolysis
2. Method 2: Thermolysis of λ3-Phospholes
2. Product Subclass 2: Phospholide Ions
1. Aromatization
1. Method 1: Cleavage of the Exocyclic P—R Bond of λ3-1H-Phospholes
1. Variation 1: By Alkali Metals
2. Variation 2: By Base
2. Method 2: Deprotonation of Transient 2H-Phospholes
3. Product Subclass 3: η5-Phospholyl Complexes
1. Method 1: Assembly of a Phospholyl Ring
2. Synthesis by Complexation
1. Variation 1: Via Intermediate 1-Stannyl-1H-phospholes or 1,1′-Bi-1H-phospholes
2. Method 2: From λ3-1H-Phospholes
3. Method 3: From λ3-2H-Phospholes
1. Method 1: Electrophilic Substitution
2. Method 2: Modification of α-Substituents
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and Monocyclic Five-Membered Hetarenes with One Heteroatom
G. Maas, December 2000, Vol. 9, Page 1
Introductory Text This volume covers the synthesis of three-and four-membered heterocycles with maximum unsaturation and five-membered hetarenes with one oxygen, sulfur, selenium, tellurium, nitrogen, or phosphorus atom. The parent ring systems treated in this volume are shown in Table 1 together with the sections in which they appear. Obviously, this collection does not include ring systems incorporating heteroatoms of elements with metallic character such as arsenic, lead, or silicon and its higher homologues. Such heterocycles will appear in volumes devoted to organoelement compounds.
Table 1 Structures and Numbering Schemes of the Heterocycles Covered in Volume 9
Product Class Ring System
three- membered rings with P and one or more heteroatoms
four- membered rings with one or more heteroatoms
furans
thiophenes
selenophenes
tellurophenes
pyrroles
phospholes
Table 1 also illustrates how the individual product classes are further divided into product subclasses. While the subclasses associated with thiirenes, phosphirenes, thiophenes, and phospholes all embrace a group of chemically closely related molecules, this is not always so for the ring systems registered in Sections 9.7 and 9.8. In these cases, practical considerations, such as the low number of different synthetic pathways to these systems and the avoidance of having too many product classes with only a couple of members, have led to the chosen system.
This volume deals mostly with the synthesis of the heterocyclic ring systems shown in Table 1. For furans, thiophenes, and pyrroles, in contrast to all other systems, the wealth of available methods does not allow a comprehensive coverage to be given here, and only selected methods are presented. The chemistry of these heterocycles is only discussed insofar as it is relevant to their synthesis (examples: subsequent reactions of oxirenes and azirines, formed only as reactive intermediates; generation of some of the three-and four-membered phosphorus-containing heterocycles in the coordination sphere of transition metals or trapping by metal complexation); for the five-
membered hetarenes, reactions of substituents at the α-position of the ring are also addressed briefly.
The synthesis of furans, thiophenes, and pyrroles was discussed in a comprehensive manner in Houben–Weyl, Vol. E 6. Azetes have been
covered in Houben–Weyl, Vol. E 16c, and 1,2-dithietes in Houben– Weyl, Vol. E 11/2. The structure, synthesis, chemistry, and applications
of many heterocyclic ring systems covered in this volume have also collectively been reviewed. References to reviews on specific
heterocyclic systems are given in each article. The major part of this volume is devoted to the synthesis of furans, thiophenes, and pyrroles. Readers who wish to obtain the most important facts on the synthesis, reactivity, and properties in particular of these three product classes in condensed form are recommended to consult some recent textbooks on heterocyclic chemistry.
The synthetic methods for each ring system are arranged in general according to the following scheme, which applies strictly only for the five- membered hetarenes, although not all subheadings are relevant in all cases. For the three-and four-membered rings, this scheme is applied appropriately.
x: volume number=9; y: product class; z: product subclass x.y.z.1 Synthesis by Ring-Closure Reactions x.y.z.1.1 By Formation of Two Heteroatom—Carbon Bonds and One C—C Bond x.y.z.1.1.1 Fragment X and Two C—C Fragments x.y.z.1.1.2 Fragments C—C—C, X, and C Although this is a possible disconnection, no associated methods are given in this volume.
x.y.z.1.2 By Formation of One Heteroatom—Carbon and Two C—C Bonds x.y.z.1.2.1 Fragments X—C, C—C, and C
[1]
[2]
[3]
[4,5]
[6-9]
x.y.z.1.2.2 Fragments X—C—C and Two C Fragments Although this is a possible disconnection, no associated methods are given in this volume.
x.y.z.1.3 By Formation of Three C—C Bonds x.y.z.1.3.1 Fragment C—X —C and Two C Fragments x.y.z.1.4 By Formation of Two Heteroatom— Carbon Bonds x.y.z.1.4.1 Fragments C—C—C—C and X
x.y.z.1.5 By Formation of One Heteroatom—Carbon and One C—C Bond x.y.z.1.5.1 Fragments X—C—C and C—C
x.y.z.1.5.2 Fragments X—C and C—C—C
x.y.z.1.5.3 Fragments X—C—C—C and C
x.y.z.1.6 By Formation of Two C—C Bonds x.y.z.1.6.1 Fragments C—X —C and C—C
x.y.z.1.6.2 Fragments C—X—C—C and C
x.y.z.1.7 By Formation of One Heteroatom—Carbon Bond x.y.z.1.7.1 Fragment X—C—C—C—C
x.y.z.1.8 By Formation of One C—C Bond x.y.z.1.8.1 Fragment C—X— C—C—C
x.y.z.1.8.2 Fragment C—C—X—C—C
x.y.z.2 Synthesis by Ring Transformation x.y.z.3 Aromatization (e.g., by Oxidation of Dehydro Compounds or Elimination Reactions) In this volume, the term "aromatization" should be interpreted as "introduction of maximum unsaturation", since the target ring systems can be aromatic, antiaromatic, or nonaromatic.
x.y.z.4 Synthesis by Substituent Modification The fragment headings in the list given above are a useful categorization scheme whenever a chosen strategy to assemble a ring system by formation of one or more heteroatom—carbon or C—C bonds can be achieved with different building blocks. For example, assembly of a thiophene ring by formation of one S—C and one C—C bond can be effected by three different combinations of building blocks or fragments as shown in Scheme 1. In cases where a ring is assembled from two or more fragments, the fragment headings which include fragments of similar size and contain the heteroatom in the larger fragment are mentioned first. However, some minor deviations from this general rule of Science of Synthesis can be found in this volume. Thus, the author of Sections 9.13.1.5 and 9.13.1.6 arrived at a different order by "working around the ring" with one C—C disconnection, which is, of course, another reasonable approach.
Scheme 1 Three Ways To Construct a Thiophene Ring by Formation of One S—C and One C—C Bond
While fragment headings are especially useful for the five-membered rings (see Sections 9.10 and 9.13 for graphical representations of the fragment approach to the synthesis of thiophenes and pyrroles, respectively), they are applied for systematic reasons throughout this volume, even in cases where this is redundant information, as for example in the cases of ring closure by formation of two heteroatom— carbon bonds or of one heteroatom—carbon bond.
After the fragment headings, a further subdivision into methods is given. In the sections on furans, thiophenes, and pyrroles, selected methods are presented which are considered the most useful and versatile ones to obtain the respective ring system with a certain substituent pattern. For
obtain the respective ring system with a certain substituent pattern. For all other ring systems, only a small number of different methods exist, partly because the chemistry of particular ring systems is still under active development, and therefore the given list of methods is more or less complete. In selected cases, methods are further subdivided into variations on a method. The presentation of methods and variations is generally given to include: 1.An introduction, in which some (historical) background information is given, the scope of the method/variation is described, and a comparison with other methods/variations is eventually made; safety information is given when necessary, and mechanistic information is provided where relevant to the use of the method in synthesis.
2.Reaction schemes associated with a short list of representative examples.
3.Representative experimental procedures.
Within each article, the organizational principle is based on the synthetic methods used, not on the functional groups or substitution patterns of the heterocyclic product. Related methods, e.g. those involving the simultaneous formation of two C—C bonds, are grouped together, not necessarily the methods of synthesis of similarly substituted hetarenes. However, the index can be used to locate methods recommended for the synthesis of a particular type of hetarene with specific substituents.
The term "fully unsaturated ring systems" in the title of this volume also deserves a short comment. It is applied here to heterocycles with the maximum possible number of double bonds, or of C=C bonds in the ring, or of other double bonds, depending on which criterion is applicable. It follows from this definition that 1H-azirines 1 and 1H-phosphirenes 3
(Scheme 2) are covered in this volume while the respective isomers, 2H- azirines 2 and 2H-phosphirenes 4, are not. By the same principle, 2H- and 3H-pyrroles and 2H-phospholes do not appear as product subclasses in this volume.
Scheme 2 1H- and 2H-Isomers of Azirines and Phosphirenes
From a structural point of view, three-membered and some of the four- membered heterocyclic ring systems reach the level of full unsaturation when they carry heteroatoms with an unshared pair of electrons that can eventually conjugate with the π-orbitals of the ring double bond. For the sake of completeness, however, it was decided to also include some subclasses of unsaturated heterocycles where this unshared pair of electrons was involved in further bonding. Thus, thiirene 1,1-dioxides were included as a subclass of thiirenes; as subclasses of phosphirenes, not only derivatives of tervalent phosphorus (λ -1H-phosphirenes) but also of quinquevalent phosphorus (λ -1H-phosphirenes) as well as the η -metal complexes of λ -1H-phosphirenes are given. As the only exception in the group of five-membered hetarenes, the thiophene 1,1- dioxides were included as a subclass of thiophenes although they are clearly not heteroaromatic compounds. This was done because of their close relationship to thiophenes and in order to complete the presentation of their syntheses, which is addressed in part already in the preceding section on substituent modification of thiophenes.
The ring systems covered in this volume embrace a wide range of stabilities as well as physical and chemical properties. This is in part
3
5
1 3
connected to the question of whether or not cyclic π-conjugation exists in these heterocycles and, if so, whether it leads to an antiaromatic destabilization or aromatic stabilization of the molecule. Oxirenes, 1H- azirines, thiirenes, and selenirenes (see Table 1) are prototypes of Huckel-type antiaromatic compounds with a 4π-electron system. In fact, no stable representatives of these systems have been isolated so far, but low-temperature matrix-isolation studies gave spectroscopic evidence of their formation in a few cases, including the parent thiirene and
selenirene. Thus, these species represent, in general, highly reactive
intermediates and their participation in a reaction must be concluded from product analysis and isotope labelling studies [for this reason, the style of the articles on oxirenes (Section 9.1), thiirenes (Section 9.2), selenirenes (Section 9.3), and 1H-azirines (Section 9.5) is different from the others; since the synthetic approach does not give these species as stable products but rather leads to other products formed subsequently, detailed arguments supporting the intermediacy of the reactive species are also described]. For example, oxirenes may be involved in the enzymatic or chemical oxidation of alkynes with sources of oxygen atoms (Section 9.1.1), and there are indications that they interconvert with α-oxo carbenes. Azirines and thiirenes are assumed to take part in a similar rearrangement (Scheme 3).
Scheme 3 Oxirenes, Azirines, and Thiirenes as Intermediates in Carbene–Carbene Rearrangements
The S-oxides of thiirenes, the thiirene 1-oxides and thiirene 1,1-dioxides, are both more stable than thiirene itself. Several compounds of this type
[10] [11]
[12]
have been synthesized, and 2,3-diphenylthiirene 1-oxide (5) has been found to be more stable thermally than the 1,1-dioxide 6. It is assumed that this difference is due to the fact that sulfur dioxide is a better leaving group than sulfur monoxide, which is also reflected in the different thermolysis pathways of both compounds (Scheme 4). The chemistry of thiirene 1-oxides and 1,1-dioxides is characterized by nucleophilic opening of the strained ring and cycloaddition reactions across the C=C bond.
Scheme 4 Thermolysis Pathways of 2,3-Diphenylthiirene 1-Oxide (5) and 1,1-Dioxide 6
Thiirenium ions are sulfur analogues of the Huckel-aromatic cyclopropenylium ions, and it is therefore not surprising that several dialkyl-and alkyl-aryl-substituted derivatives of this ring system could be isolated as stable salts with non-nucleophilic counterions (Section 9.2.4).
The synthesis of the first λ -1H-phosphirene was reported in 1982; since then, the chemistry of these systems and of the related λ -1H- phosphirenes, and λ -1H-phosphirenylium and λ -1H-phosphirenium
[13]
[14]
3
5
3 5
[15,16] 3
salts as well, has been under intense investigation. λ -1H- Phosphirenes, in contrast to 1H-azirines, are not antiaromatic compounds since the phosphorus atom has a distorted pyramidal configuration which prevents the unshared pair of electrons from conjugation with the π-bond in the ring, also, the large barrier to inversion at phosphorus prevents a planar C transition state which would
generate an antiaromatic situation. λ -Phosphirenes can occur as 1H- or 2H-tautomers. Ab initio calculations show that, for the parent compound, the 2H-tautomer is more stable, while substitution at phosphorus with a halogen, especially fluorine, reverses the stabilities (Scheme 5).
Scheme 5 1H- and 2H-Tautomers of λ -Phosphirenes
In practice, the parent 1H-phosphirene is not known, and a 1- unsubstituted phosphirene, 2-tert-butyl-3-phenyl-λ -1H-phosphirene, readily decomposes in solution to give the alkyne and presumably a phosphinidene (PH) (Section 9.6.5.3.4.1). On the other hand, a good number of λ -1H-phosphirenes are known which are substituted at phosphorus not only with halogen but also with various other groups. 1- Chloro-λ -1H-phosphirenes 7 are key compounds to generate other phosphirenes by nucleophilic substitution of the chlorine atom (Scheme 6).
Scheme 6 Substitution Reactions with 1-Chloro-λ -1H- Phosphirenes
[15,16] 3
2v 3
3
3
3
3
[17-19]
3
[18,19]
λ -1H-Phosphirenium ions 8 (Scheme 7) are stabilized energetically by σ* aromaticity according to ab initio calculations, and the parent λ -1H- phosphirenylium ion 9 is an aromatic 2π-delocalized system with a resonance energy of 34–38 kcal·mol . In practice, the ions 8 are much easier to prepare than 9 as stable salts. A number of phosphirenium salts 8 have been isolated in the form of their tetrachloroaluminate and triflate salts, whereas the presence of chloride ions (as well as of bettter nucleophiles such as water) tends to induce ring opening. λ -1H- Phosphirenylium ions have been postulated as intermediates in various nucleophilic substitution reactions of 1-halo-λ -1H-phosphirenes. However, no stable salt of type 9 has been isolated so far, and the first species to be characterized by NMR in solution [9, R =t-Bu; R =Ph;
X=B(OTf) ; generated in liquid sulfur dioxide] was only reported in 1994.
Scheme 7 λ -1H-Phosphirenium 8 and λ -1H-Phosphorenylium Salts 9
5
Among the fully unsaturated four-membered heterocycles, azetes (azacyclobutadienes) have probably attracted most attention from both a synthetic and a theoretical point of view. According to theory, they are antiaromatic compounds similar to cyclobutadienes. While the parent azete is still unknown, thermodynamic stabilization (by amino substituents or benzannulation) and kinetic stabilization (by bulky substituents) leads to isolable azetes. By far the best investigated azete so far is tri-tert-butylazete (10), which is readily obtained by thermolysis of tri-tert-butylcyclopropenyl azide. In spite of its kinetic stabilization, it
is a highly reactive compound which is easily oxidized and hydrolyzed and undergoes a broad range of addition and cycloaddition reactions (Scheme 8).
Scheme 8 Generation and Selected Transformations of Tri-tert- butylazete (10)
[22]
[2,23]
[23]
In contrast to azetes, derivatives of λ -phosphete and λ -phosphete are
much less known. λ -Phosphetes have been isolated so far only in benz-
or naphthannulated form 11 and λ -phosphetes have been obtained
only as η -ligands of transition-metal complexes. For the whole set of
fully unsaturated four-membered phosphorus heterocycles (see Table 1), it appears that the presence of a λ -phosphorus rather than a λ -
phosphorus atom gives a better chance of isolating such a ring system. Thus, compounds 11–18 (Scheme 9), all of which contain at least one λ -phosphorus atom, have been isolated, whereas all other phosphetes
of Table 1, containing only λ -phosphorus, have so far been generated
only in the coordination sphere of transition metals. It should be mentioned that, for some of the compounds shown in Scheme 9, crystal structure analyses, spectroscopic data, and chemical behavior suggest
5 3
5
3
that the ring double bonds are highly polarized and that an ylide description is more appropriate. In contrast to the other compounds in
Scheme 9, 1λ ,3λ -diphosphetes constitute a well-investigated subclass
with many compounds, the chemistry of which is dominated by the strong carbanionic nature of the ring carbon atoms and the ability to form six- membered ring systems by insertion of π-systems such as alkynes and isocyanates (see Section 9.8.7).
Scheme 9 Fully Unsaturated Four-Membered Phosphorus Heterocycles Which Have Been Isolated
1,2-Dithietes 19 and the less-studied 1,2-diselenetes are π-isoelectronic with benzene. The parent 1,2-dithiete has been generated by pyrolysis of 1,3-dithiol-2-one and was shown to exist at 620°C in the gas phase.
1,2-Diselenete has been generated analogously and was characterized by photoelectron spectroscopy in the gas phase and by IR spectroscopy
[38]
in an argon matrix. A variety of 3,4-disubstituted 1,2-dithietes have
also been isolated and were shown to have an interesting chemistry. A typical feature of these compounds is the valence equilibrium with 1,2- dithiones (Scheme 10); electron-attracting or sterically demanding substituents stabilize the cyclic form whereas electron-donating substituents favor the 1,2-dithione form.
Scheme 10 The Valence Equilibrium between 1,2-Dithietes 19 and 1,2- Dithiones 20
Furan, thiophene, selenophene, tellurophene, and pyrrole are five- membered heteroaromatic compounds; they are also called π-excessive hetarenes since their π-electron density at each atom is higher than in benzene. Although quantification of their relative aromaticities is difficult owing to the variety of different criteria to define and to evaluate aromaticity, most of the presently available criteria point to an order of decreasing aromaticity of benzene>thiophene>selenophene≈pyrrole>tellurophene>furan.
Furans, thiophenes, and pyrroles occupy a major role among heteroaromatic compounds. They are both synthetic targets and building blocks for further transformations which do not leave the heteroaromatic ring intact. Only a few aspects of their synthesis and reactivity will be mentioned here.
The majority of substituted furans, thiophenes, and pyrroles are synthesized from acyclic precursors, and it is therefore helpful to know
[40]
[6]
which particular pattern of substituents and functionalities can be achieved with a certain synthetic method. For the major ring-closure procedures, readily accessible starting materials can be used in many cases, and the same general strategy can often be applied to synthesize all three ring systems. Some selected examples are shown in Scheme 11 together with the sections in which they appear. Additional flexibility of a certain synthetic method often results from the replacement of a functional group by a similar one, e.g. a carbonyl function may be replaced by an imine function or a cyano group, and α-halo ketones may be replaced by other α-electrophilic carbonyl compounds and their synthetic equivalents.
Scheme 11 Some General Methods for the Synthesis of Furans, Thiophenes, and Pyrroles from Acyclic Precursors Fragments C—C—C—C and X, or Fragment X—C—C—C—C (a ) From 1,4-diketones: Paal–Knorr (X=O, NR) or Paal (X=S) synthesis
(a ) From buta-1,3-diynes
1
2
Fragments X—C—C and C—C (b ) From 3-oxocarboxylic esters and α-halocarbonyl compounds
(b ) From α-hydroxy (-sulfanyl, -amino) ketones and activated alkynes
(b ) From α-hydroxy (-sulfanyl, -amino) ketones and active methylene
compounds
1
2
3
Fragments C—X—C and C—C (c ) From bis(acceptor-substituted methyl)amines (ethers, sulfides) and
1,2-diketones (Hinsberg synthesis)
Electrophilic-substitution reactions are typical for the introduction of substituents at preformed furan, thiophene, and pyrrole rings. Because of the π-excessive character of these hetarenes, the reaction rates are higher than in the case of benzene. For the electrophilic bromination of the α-position, relative rates of 3?10 (pyrrole), 6?10 (furan), 5?10
(thiophene), and 1 (benzene) have been calculated from rate and isomer distribution data, but the differences are not always so expressed. It
is interesting to note that pyrrole reacts substantially faster than furan in spite of its higher degree of aromaticity, mainly because of better stabilization of the intermediate σ-complex. As will be discussed in the respective articles, electrophilic substitution reactions, such as halogenation, nitration, acylation, and alkylation, can be carried out under much milder conditions than in the case of benzene, and less- electrophilic reagents can often be used. The latter possibility sometimes turns into a necessity, for example in order to avoid unselective and multiple halogenation reactions of pyrroles or to circumvent the sensitivity of the most electron-rich hetarenes, pyrroles and furans, towards strong proton Lewis acids, from which ring opening and polymerization often results.
In solution reactions, electrophiles preferentially attack the α-rather than the β-position, the α-directing effect being highest for furan and lowest for
1
pyrrole. General trends for the directing effect of substituents are
also known. Five-membered hetarenes with 2-and 2,5-substitution are
readily obtained by direct electrophilic-substitution reactions, but selective introduction of substituents in the 3-and 4-position requires blocking of the α-position(s) and eventually removal of these substituents after manipulation of the β-position(s), as illustrated in the synthesis of 3- bromothiophene (21) (Scheme 12). In pyrroles, strongly electron-
withdrawing or sterically demanding removable substituents at nitrogen favor 3-substitution. Thus, pyrroles 23 and 24 could be
synthesized from 1-phenylsulfonyl- and 1-(triisopropylsilyl)pyrrole, respectively. It must be mentioned, however, that in contrast to the Friedel–Crafts acylation of 1-(phenylsulfonyl)pyrrole, softer electrophiles still react almost exclusively by 2-substitution (e.g., Vilsmeier formylation with N,N-dimethylformamide/phosphoryl chloride, cyanation with cyanogen bromide/aluminum trichloride ).
Scheme 12 Directed Synthesis of 3-Substituted Thiophenes 21 and
22 and Pyrroles 23, 24, and 25
[6,41]
[6]
[42]
Highly regioselective and efficient substitution reactions are possible when a metalated furan, thiophene, or Nsubstituted pyrrole is exposed to electrophilic reagents. If no other substituent is present, metalation at the α-position is usually achieved by hydrogen–lithium exchange. A bromine–lithium exchange using butyllithium or tert-butyllithium allows selective metalation at the corresponding ring position. The syntheses of 3-acetylthiophene (22) and of 3-substituted pyrroles 25 (Scheme 12) illustrate these selective transformations.
The ring systems of furan, thiophene, and pyrrole occur in many compounds of natural or synthetic origin. Since it is not in the scope of this volume to give an overview on these compounds, it may suffice to single out two compounds, lamellarin L (26) and ningalin B (27), from two closely related classes of marine natural products which are currently under active investigation as new antitumor agents and as nontoxic modulators of the multidrug-resistant phenotype. Both 26 and 27 (Scheme 13) are highly substituted and functionalized pyrrole derivatives and, in both cases, the pyrrole ring was constructed with most of the functionality already present in the precursors. The total synthesis of 26 used two different arylpyruvic acid units with a Paal–Knorr-type ring-
[46]
[47]
closure step (i.e., two C—C fragments and an N fragment), and the
pyrrole ring of 27 was generated by a reductive ring-contraction of a tetrasubstituted 1,2-diazine. Another approach to the lamellarin class
of alkaloids used an intramolecular azomethine ylide cycloaddition reaction (i.e., fragments C—N—C and C—C).
Scheme 13 Lamellarin L (26) and Ningalin B (27)
Derivatives of furan, thiophene, and pyrrole can also be found in a number of pharmaceuticals. The thiophene ring is often introduced because it is considered to be bioisosteric with the benzene ring; however, this does not prevent the synthesis of a compound with modified biological activity. The following pharmacologically active compounds are listed in Scheme 14: ranitidine (28), one of the most successful drugs ever developed (histamine H -receptor antagonist;
treatment of gastrointestinal disorders and of gastric and duodenal cancer), furosemide (29; diuretic), nitrofural (30; bacteriostatic and bactericide; used for wound treatment), nitrofurantoin (31; treatment of infections of the urinary tract), articain or carticain (32; local anesthetic), pyrantel (33; anthelmintic), thenalidin (34; histamine H -receptor
antagonist), tiagabine (35; anticonvulsant), tiaprofenic acid (36; anti- inflammatory), tioconazol (37; local antimykotic), ketorolac (38; analgesic, anti-inflammatory; alleviation of postoperative pain), atorvastatin (39; lowering of cholesterol levels), and zomepirac (40; analgesic, anti-
[47]
[48]
[49]
2
1
inflammatory).
Scheme 14 Selected Examples of Pharmacologically Active Compounds with Furan, Thiophene, and Pyrrole Units
Some agrochemicals also contain furan and pyrrole rings as the central structural unit. Formecyclox (41) and related furancarboxamides are components of formulations of seed-disinfectant fungicides and wood preservatives. Several 5-substituted 2-nitrofurans are known for their fungicidal, insecticidal, or plant growth-regulatory activities (Scheme 15). The 4-aryl-1H-pyrrole-3-carbonitriles 42 and 43 (fempiclonil) are fungicides used in cereal seed treatment. The fully substituted pyrrole
44 (Pirate) has recently been registered in the US and in Japan as an agricultural insecticide and miticide; it is interesting to note that
this compound was developed from the lead structure of dioxapyrrolomycin (45), which was isolated from fermentation broths of streptomyces fungi and displayed a moderate broad-band insecticidal activity.
Scheme 15 Selected Examples of Agrochemicals with Furan, Thiophene, and Pyrrole Units
[50]
[51,52,66]
In materials science, oligo-and polythiophenes have met considerable interest due to their conductivity, electroactivity, and long-term chemical stability, and they play an important role in the design of functional conducting polymers with a broad range of possible applications.
Polypyrroles, including simple substituted ones, and polypyrrole copolymers have also been evaluated as conducting polymers for many applications, for instance as solid electrolytes in capacitors, in
electrocatalysis on modified electrodes, and as electrodes in
chemical sensor and biosensor devices.
λ -1H-Phospholes are only weakly aromatic because the high intrinsic inversion barrier of the pyramidal phosphorus cannot be overcome by the substantial stabilization by π-electron delocalization in the planar form. Since the unshared pair of electrons at phosphorus cannot overlap efficiently with the π-orbitals of the diene system, 1H-pyrroles behave like a combination of a 1,3-diene and a phosphine, and they resemble cyclopentadienes more than 1H-pyrroles. Typical for the reactivity of
1H-phospholes 46 is the easy cleavage of the exocyclic P—R bond with alkali metals leading to phospholide ions 47, and the rearrangement into 2H-phospholes by an initial [1,5]-sigmatropic shift of the P-substituent, e.g. 48→49 (Scheme 16). The 2H-phospholes undergo dimerization but can be trapped in a Diels–Alder reaction with dienophiles, e.g. 49→50, and 1,3-dienes. P—H phospholes undergo the [1,5]-H shift readily at low temperature and therefore the parent compound was
[53,54]
[56,57]
[58]
3
[16,59]
[60,61]
[60]
[61]
observed in solution only at 173K. Heating of 1H-phospholes in the presence of potassium tert-butoxide is another route to generate phospholide ions (e.g., 48→51, via deprotonation of intermediate 2H- phospholes), and the latter can be alkylated to give other 1-substituted phospholes (51→52). Furthermore, the 1H-phosphole system can act as a 1,3-diene in Diels–Alder reactions and as a 2π-component in photochemical [2+2]-cycloaddition reactions.
Scheme 16 Reactivity Patterns of λ -1H-Phospholes
In contrast to 1H-phospholes, phospholides are without doubt aromatic planar rings with a fully delocalized 6π-electron system. Their chemistry seems to take place exclusively at phosphorus, but this is no longer the case with the η -phospholyl metal complexes; for example,
phosphaferrocenes undergo Friedel–Crafts acylation and Vilsmeier formylation at the phospholyl ligand (see Section 9.14.3).
Some phosphole derivatives have recently emerged as promising
[61]
[62]
phosphine-type ligands in transition metal-catalyzed organic transformations (Scheme 17). Palladium complex 53, containing a tetraphosphole macrocycle as ligand, was found to be a robust catalyst in cross-coupling reactions of the Stille and Heck type. Starting from 1H- phospholes, 1-phosphanorbornadienephosphonates 54 and 2,2′-bis(1-
phosphanorbornadienyl) 55, as well as some related compounds, were synthesized. The water-soluble compounds 54 can serve as ligands for the biphasic rhodium-catalyzed hydroformylation of alkenes, and enantiopure 55 (BIPNOR) displays high efficiency in the rhodium-or ruthenium-catalyzed asymmetric hydrogenation of C=C and C=O bonds.
Scheme 17 Novel Phosphole Derivatives Used in Homogeneous Catalysis
[63]
[64]
[65]
[63-65]
References
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9.1 Product Class 1: Oxirenes
K.-P. Zeller, December 2000, Vol. 9, Page 19
General Introduction The heterocyclic oxirene system 1 is formally obtained by replacing the methylene group of cyclopropene with an oxygen atom. Like thiirene (2) and 1H-azirine (3), oxirene can be considered as a heterocyclic analogue of the 4π-antiaromatic cyclopropenyl anion 4 (Scheme 1).
Scheme 1 Oxirene and Related Compounds
A cautionary note on the practice of naming oxiranes fused to a polycyclic aromatic system is in order. These compounds, which are really arene oxides, are generally considered by both CAS and IUPAC nomenclature as derivatives of arenooxirenes; for example, compound 5 (Scheme 2) would be named 1a,11b-dihydrobenzo[3,4]anthra[1,2- b]oxirene.
Scheme 2 Structure of Arene Oxide 5
The potential antiaromatic character of 1, the strain of the fully unsaturated three-membered ring, and the possible involvement of oxirenes in important reactions (e.g., oxidation of alkynes, Wolff rearrangement) have made these species outstanding objects of study, of both theoretical and experimental interest. The extreme
elusiveness of oxirenes 6 is mainly based on the ease with which they rearrange to α-oxo carbenes 7 and 8, followed by further isomerization to ketenes 9 or to α,β-unsaturated carbonyl compounds (Scheme 3).
Scheme 3 Oxireneα-Oxo Carbene Isomerization
From computational studies it is difficult to decide whether oxirenes are relative minima on the potential-energy surface or merely transition states. A high-level ab initio treatment of the C H O energy
surface led to the conclusion that there is little or no barrier separating
[1-3]
[4,5]
formylmethylene from the parent oxirene, the potential-energy surface linking these two species being extremely flat; however, a more significant barrier (21–23 kJ·mol ) separates formylmethylene or oxirene
from ketene. This supports the intermediacy of the parent oxirene. Similarly, dimethyloxirene is predicted to be a genuine minimum. In
contrast, substituted oxirenes C X O, where X=BH , NH , OH, and F, are
characterized as transition states. From a naive point of view, push-pull
substitution of oxirene should diminish its antiaromaticity and thus lead to stabilization. AM1 and ab initio calculations on 3-aminooxirene-2-
carbaldehyde (10), however, demonstrate that 10 is merely a transition state linking the two isomeric α-oxo carbenes 11 and 12 (Scheme 4).
Scheme 4 Push–Pull Substitution of Oxirene
As a result of ab initio calculations on benzooxirene (13) and the associated α-oxo carbene 14 (Scheme 5), it seems that benzoannulation has a stabilizing effect, placing 13 in a relative minimum on the potential- energy surface.
Scheme 5 Structure of Benzooxirene and the Related α-Oxo Carbene
−1
[6]
[7]
[7]
[8]
If theory is taken as a guide, there is no doubt that oxirenes are, at the outmost, extremely unstable intermediates which cannot exist under "normal" conditions. In this section, approaches to detect oxirenes indirectly (labeling studies, product analysis) or spectroscopically are summarized. These attempts have led, inter alia, to the synthesis of interesting compounds as the final products, clearly marking oxirenes as reaction intermediates.
The chemistry of oxirenes has been partly covered in an earlier review article in Houben–Weyl, Vol. E19b/2, p 1219. Due to their character as reactive intermediates, oxirenes have evoked less interest in preparative and synthetic organic chemistry, and have limited themselves to being postulated intermediates in certain reactions. The entire chemistry of oxirenes is covered in this section, with special attention being paid to synthetic aspects and the elaboration of techniques used for their detection as intermediates.
References
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[4] Scott, A. P.; Nobes, R. H.; Schaefer, H. F., III; Radom, L., J. Am. Chem. Soc., (1994) 116, 10159; and references cited therein.
[5] Vacek, G.; Galbraith, J. M.; Yamaguchi, Y.; Schaefer, H. F., III; Nobes, R. H.; Scott, A. P.; Radom, L., J. Phys. Chem., (1994) 98, 8660.
[6] Fowler, J. E.; Galbraith, J. M.; Vacek, G.; Schaefer, H. F., III, J. Am. Chem. Soc., (1994) 116, 9113, and references cited therein.
[7] Lewars, E., J. Mol. Struct. (THEOCHEM), (1997) 391, 39. [8] Lewars, E., J. Mol. Struct. (THEOCHEM), (1996) 360, 67.
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure Reactions
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure Reactions 9.1.1.1 By Formation of Two O—C Bonds
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure Reactions 9.1.1.1 By Formation of Two O—C Bonds 9.1.1.1.1 Fragments C—C and O
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure Reactions 9.1.1.1 By Formation of Two O—C Bonds 9.1.1.1.1 Fragments C—C and O 9.1.1.1.1.1 Method 1: Oxidation of Alkynes
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure Reactions 9.1.1.1 By Formation of Two O—C Bonds 9.1.1.1.1 Fragments C—C and O 9.1.1.1.1.1 Method 1: Oxidation of Alkynes 9.1.1.1.1.1.1 Variation 1: With Peroxy Acids
See also: Science of Synthesis Electronic Backfile Information.
Introductory Text In 1952 Schubach and Franzen claimed to have oxidized dec-5-yne with peroxyacetic acid to form 2,3-dibutyloxirene. Subsequently, it was shown that this was in fact incorrect. The products formed in the oxidation of acetylenic compounds 15 with peroxy acids are α,β-unsaturated ketones 19, their further oxidation products, and products derived from ketenes 20. A plausible mechanistic rationalization of this product distribution consists of a sequence involving oxirenes 16 and α-oxo carbenes 17 and 18 as intermediates (Scheme 6; see also Section 9.1.1.2.1.1).
Scheme 6 Peroxy Acid Oxidation of Alkynes
[9]
[10,11]
Thus, peroxy acid treatment of hept-3-yne (21) gives products 22–25, the ratio of products being dependent on the solvent employed, and
cyclooctyne (26) results in compounds 27–29 (Scheme 7). Since α- oxo carbenes can also be generated from α-diazo ketones, similar product ratios are expected for the two methods. This is the case for hept-3-yne (21), but not for cyclooctyne (26). To account for these observations, it has been suggested inter alia that α-oxo carbenes may be formed from oxirenes and α-diazo ketones in two different reactive conformations.
Scheme 7 Peroxy Acid Oxidation of Hept-3-yne and Cycloo

science of synthesis : houben-weyl methods of molecular transformations. hetarenes and related ring...

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