Science of Synthesis Houben-Weyl Methods of Molecular Transformations Volume 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 1. Method 1: Isomerization of Oxiranylidenes 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. Synthesis by Ring Transformation 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. Synthesis by Ring-Closure Reactions 1. Method 1: From α,α′-Dihalo-Substituted Sulfones 2. Aromatization 1. Method 1: Dehydrohalogenation of 2-Halothiiranes 3. Product Subclass 3: Thiirene 1-Oxides 1. Synthesis by Ring-Closure Reactions 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. Synthesis by Ring-Closure Reactions 1. Method 1: Addition of a Sulfonium Ion to Alkynes 2. Method 2: From 1-Halo-2-sulfanylethenes 3. Product Class 3: Selenirenes
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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. Synthesis by Ring Transformation
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. Synthesis by Ring-Closure Reactions
1. Method 1: From α,α′-Dihalo-Substituted Sulfones
2. Aromatization
1. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
1. Method 1: Addition of a Sulfonium Ion to Alkynes
2. Method 2: From 1-Halo-2-sulfanylethenes
3. Product Class 3: Selenirenes
1. Synthesis by Ring Transformation
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. Synthesis by Ring-Closure Reactions
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
2. Synthesis by Ring Transformation
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. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
1. Method 1: Cycloaddition of Iminophosphines to Alkynes
2. Synthesis by Substituent Modification
1. Method 1: Oxidative Addition to λ3-1H-Phosphirenes
3. Product Subclass 3: λ5-1H-Phosphirenium Salts
1. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
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
2. Synthesis by Substituent Modification
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. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
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
2. Synthesis by Substituent Modification
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. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
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
3. Synthesis by Substituent Modification
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring Transformation
1. Method 1: Ring Enlargement of Azidocyclopropenes
2. Product Subclass 2: λ5-Phosphetes
1. Synthesis by Ring-Closure Reactions
1. By Formation of One P—C Bond
1. Method 1: From (Arylmethylene)phosphoranes
3. Product Subclass 3: λ3-Phosphetes
1. Synthesis by Ring-Closure Reactions
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
2. Synthesis by Ring Transformation
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 Transformation
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. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
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
2. Synthesis by Substituent Modification
1. Method 1: From
1,1,3,3-Tetrakis(dimethylamino)-1λ5,3λ5-diphosphete
by Substitution at Ring Carbon Atoms
8. Product Subclass 8: 1λ5,2λ3-Diphosphetes
1. Synthesis by Ring Transformation
1. Synthesis by Ring Enlargement
1. Method 1: From a 2-Phosphino-2H-phosphirene
9. Product Subclass 9: 1λ3,2λ3-Diphosphetes
1. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
1. Method 1: From Phosphaalkynes in the Coordination Sphere of
Titanium
2. Aromatization
10. Product Subclass 10: 1λ3,3λ3-Diphosphetes
1. Synthesis by Ring-Closure Reactions
1. By Formation of Two P—C Bonds
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
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. Synthesis by Ring-Closure Reactions
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
4. By Formation of One C—C Bond
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
2. Synthesis by Ring Transformation
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
4. Synthesis by Substituent Modification
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. Synthesis by Ring-Closure Reactions
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
4. By Formation of Two C—C Bonds
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
6. By Formation of One C—C Bond
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
2. Synthesis by Ring Transformation
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
4. Synthesis by Substituent Modification
1. Substitution of Hydrogen
2. Method 2: Metalation
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. Substitution of Metals
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
3. Substitution of Carbon Functionalities
1. Method 1: Decarboxylation
4. Substitution of Heteroatoms
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. Synthesis by Ring Transformation
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. Synthesis by Ring Transformation
1. Formal Exchange of Ring Members
1. Method 1: From Zirconocenes
2. Oxidation of Thiophenes
11. Product Class 11: Selenophenes
1. Synthesis by Ring-Closure Reactions
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
2. By Formation of Two C—C Bonds
1. Fragments C—Se—C and C—C
1. Method 1: From 1,2-Diketones and a Selenodiacetate (Hinsberg
Synthesis)
3. By Formation of One C—C Bond
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
3. Method 3: Synthesis by Substituent Modification
12. Product Class 12: Tellurophenes
1. Synthesis by Ring-Closure Reactions
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
2. By Formation of One C—C Bond
1. Fragment C—Te—C—C—C
1. Method 1: Cyclization of 3-(Alkyltellanyl)propenals
2. Method 2: Synthesis by Substituent Modification
13. Product Class 13: 1H-Pyrroles
1. Synthesis by Ring-Closure Reactions
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
6. By Formation of Two C—C Bonds
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
8. By Formation of One C—C Bond
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
2. Synthesis by Ring Transformation
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
4. Synthesis by Substituent Modification
1. Substitution of Existing Substituents
1. Substitution of Hydrogen
1. Method 1: Metalation
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
2. Substitution of Metals
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
3. Substitution of Carbon Functionalities
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
4. Substitution of Heteroatoms
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. Synthesis by Ring-Closure Reactions
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
2. By Formation of Two P—C Bonds
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
2. Synthesis by Ring Transformation
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
4. Synthesis by Substituent Modification
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. Synthesis by Ring-Closure Reactions
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
3. Synthesis by Substituent Modification
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
[1] Houben–Weyl, (1994); Vol. E 6. [2] Houben–Weyl, (1992); Vol. E
16c, pp 936–940. [3] Houben–Weyl, (1985); Vol. E 11/2, pp
1581–1583. [4] Comprehensive Heterocyclic Chemistry, Katritzky, A.
R.; Rees, C. W.; Bird, C. W.; Cheeseman, G. W. H.,
Eds.; Pergamon: Oxford, (1984); Vol. 4.
[5] Comprehensive Heterocyclic Chemistry II, Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V.; Bird, C. W., Eds.; Pergamon:
Oxford, (1996); Vol. 2.
[6] Katritzky, A. R., Handbook of Heterocyclic Chemistry, 2nd ed.
(with Pozharskii, A. F.), Pergamon: Oxford, (2000).
[7] Joule, J. A.; Mills, K., Heterocyclic Chemistry, 4th ed.,
Blackwell Science: Oxford, (2000). [8] Gilchrist, T. L.,
Heterocyclic Chemistry, 2nd ed., Longman: Harlow, (1993). [9]
Eicher, T.; Hauptmann, S., The Chemistry of Heterocycles, Thieme:
Stuttgart, (1995). [10] Sander, W.; Bucher, G.; Wierlacher, S.,
Chem. Rev., (1993) 93, 1583. [11] Torres, M.; Clement, A.; Bertie,
J. E.; Gunning, H. E.; Strausz, O. P., J. Org. Chem., (1978) 43,
2490. [12] Krantz, A.; Laureni, J., J. Am. Chem. Soc., (1977) 99,
4842. [13] Carpino, L. A.; Chen, H.-W., J. Am. Chem. Soc., (1979)
101, 390. [14] Carpino, L. A.; McAdams, L.V., III; Rynbrandt, R.
H.; Spiewak, J. W., J. Am. Chem. Soc., (1971) 93, 476. [15] Mathey,
F., Chem. Rev., (1990) 90, 997. [16] Dillon, K. B.; Mathey, F.;
Nixon, J. F., Phosphorus: The Carbon Copy, Wiley: Chichester,
(1998); p 181.
[17] Wagner, O.; Ehle, M.; Regitz, M., Angew. Chem., (1989) 101,
227; Angew. Chem. Int. Ed. Engl., (1989) 28, 225.
[18] Heydt, H.; Ehle, M.; Haber, S.; Hoffmann, J.; Wagner, O.;
Goller, A.; Clark, T.; Regitz, M., Chem. Ber./Recl., (1997) 130,
711.
[19] Wagner, O.; Ehle, M.; Birkel, M.; Hoffmann, J.; Regitz, M.,
Chem. Ber., (1991) 124, 1207. [20] Goller, A.; Heydt, H.; Clark,
T., J. Org. Chem., (1996) 61, 5840. [21] Laali, K. K.; Geissler,
B.; Wagner, O.; Hoffmann, J.; Armbrust, R.; Eisfeld, W.; Regitz,
M., J. Am. Chem.
Soc., (1994) 116, 9407. [22] Vogelbacher, U. J.; Regitz, M.;
Mynott, R., Angew. Chem., (1986) 98, 835; Angew. Chem. Int. Ed.
Engl.,
(1986) 25, 842. [23] Vogelbacher, U. J.; Ledermann, M.; Schach, T.;
Michels, G., Hees, U.; Regitz, M., Angew. Chem., (1988)
100, 304; Angew. Chem. Int. Ed. Engl., (1988) 27, 272. [24] Heim,
U.; Pritzkow, H.; Fleischer, U.; Grutzmacher, H.; Sanchez, M.;
Reau, R.; Bertrand, G., Chem. –Eur.
J., (1996) 2, 68. [25] Tejeda, J.; Reau, R.; Dahan, F.; Bertrand,
G., J. Am. Chem. Soc., (1993) 115, 7880. [26] Bieger, K.; Tejeda,
J.; Reau, R.; Dahan, F.; Bertrand, G., J. Am. Chem. Soc., (1994)
116, 8087. [27] Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.;
Bertrand, G., Angew. Chem., (1995) 107, 1358; Angew.
Chem. Int. Ed. Engl., (1995) 34, 1246. [28] Heckmann, G.; Fluck,
E., Rev. Heteroat. Chem., (1994) 11, 65. [29] Fluck, E.; Heckmann,
G., Rev. Heteroat. Chem., (1995) 12, 121. [30] Armbrust, R.;
Sanchez, M.; Reau, R.; Bergstrasser, U.; Regitz, M.; Bertrand, G.,
J. Am. Chem. Soc., (1995)
117, 10785. [31] Sanchez, M.; Reau, R.; Gornitzka, H.; Dahan, F.;
Regitz, M.; Bertrand, G., J. Am. Chem. Soc., (1997) 119,
9720.
[32] Alcaraz, G.; Baceiredo, A.; Nieger, M.; Bertrand, G., J. Am.
Chem. Soc., (1994) 116, 2159. [33] Alcaraz, G.; Baceiredo, A.;
Nieger, M.; Schoeller, W. W.; Bertrand, G., Inorg. Chem., (1996)
35, 2458. [34] Karsch, H. H.; Witt, E.; Hahn, F. E., Angew. Chem.,
(1996) 108, 2380; Angew. Chem. Int. Ed. Engl., (1996)
35, 2242. [35] Baceiredo, A.; Bertrand, G.; Majoral, J.-P.; Sicard,
G.; Jaud, J.; Galy, J., J. Am. Chem. Soc., (1984) 106,
6088.
[36] Baceiredo, A.; Bertrand, G.; Majoral, J.-P.; El Anba, F.;
Manuel, G., J. Am. Chem. Soc., (1985) 107, 3945. [37] Frank, W.;
Petry, V.; Gerwalin, E.; Reiss, G. J., Angew. Chem., (1996) 108,
1616; Angew. Chem. Int. Ed.
Engl., (1996) 35, 1512. [38] Bertrand, G., Angew. Chem., (1998)
110, 282; Angew. Chem. Int. Ed., (1998) 37, 271. [39] Schulz, R.;
Schweig, A.; Hartke, K.; Koster, J., J. Am. Chem. Soc., (1983) 105,
4519. [40] Diehl, F.; Schweig, A., Angew. Chem., (1987) 99, 348;
Angew. Chem. Int. Ed. Engl., (1987) 26, 343. [41] Marino, G., Adv.
Heterocycl. Chem., (1971) 13, 235. [42] Gronowitz, S.;
Raznikiewicz, T., Org. Synth., Coll. Vol. V, (1973), 549. [43] Xu,
R. X.; Anderson, H. J.; Gogan, N, J.; Loader, C. E.; McDonald, R.,
Tetrahedron Lett., (1981) 22, 4899. [44] Rokach, J.; Hamel, P.;
Kakushima, M.; Smith, G. M., Tetrahedron Lett., (1981) 22, 4900.
[45] Bray, B. L.; Mathies, P. H.; Nef, R.; Solas, D. R.; Tidwell,
T. T.; Artis, D. R.; Muchowski, J. M., J. Org.
Chem., (1990) 55, 6317. [46] Gronowitz, S., Ark. Kemi, (1958) 12,
533; Chem. Abstr., (1959) 53, 7133. [47] Peschko, C.; Winklhofer,
C.; Steglich, W., Chem. –Eur. J., (2000) 6, 1147. [48] Boger, D.
L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.; Jin, Q., J. Org.
Chem., (2000) 65, 2479. [49] Bannwell, M.; Flynn, B.; Hockless, D.,
Chem. Commun., (1997), 2259. [50] Nyfeler, R.; Ackermann, P., In
Synthesis and Chemistry of Agrochemicals III, Baker, D. R.; Fenyes,
J. S.;
Steffens, J. J., Eds., ACS Symposium Series 504, American Chemical
Society: Washington, (1992); p 395.
[51] Kuhn, D. G.; Kamhi, V. M.; Furch, J. A.; Diehl, R. E.; Trotto,
S. H.; Lowen, G. T.; Babcock, J. T., In Synthesis and Chemistry of
Agrochemicals III, Baker, D. R.; Fenyes, J. S.; Steffens, J. J.,
Eds., ACS Symposium Series 504, American Chemical Society:
Washington, (1992); p 298.
[52] Brown, D. G.; Siddens, J. K.; Diehl, R. E.; Wright, D. P., BR
8803788, (1989); Chem. Abstr., (1989) 111, 194576.
[53] Roncalli, J., Chem. Rev., (1992) 92, 711. [54] Skotheim, T.
A.; Elsenbaumer, R. E.; Reynolds, J. R., Eds., Handbook of
Conducting Polymers, 2nd ed.,
Dekker: New York, (1998).
[55] Fukuyama, M.; Kudoh, Y.; Nanai, N.; Yoshimura, S., Mol. Cryst.
Liq. Cryst. Sci. Technol., Sect. A, (1993) 224, 61.
[56] Deronzier, A.; Moutet, J.-C., Acc. Chem. Res., (1989) 22, 249.
[57] Curran, D.; Grimshaw, J.; Perera, S. D., Chem. Soc. Rev.,
(1991) 20, 391. [58] Bartlett, P. N.; Birkin, P. R., Synth. Met.,
(1993) 61, 15. [59] Mathey, F., Chem. Rev., (1988) 88, 429. [60]
Mathey, F.; Mercier, F.; Charrier, C.; Fischer, J.; Mitschler, A.,
J. Am. Chem. Soc., (1981) 103, 4595. [61] Charrier, C.; Bonnard,
H.; de Lauzon, G.; Mathey, F., J. Am. Chem. Soc., (1983) 105, 6871.
[62] Holand, S.; Jeanjean, M.; Mathey, F.; Angew. Chem., (1997)
109, 118; Angew. Chem. Int. Ed. Engl., (1987)
36, 98. [63] Mercier, F.; Laporte, F.; Ricard, L.; Mathey, F.;
Schroder, M.; Regitz, M., Angew. Chem., (1997) 109, 2460;
Angew. Chem. Int. Ed. Engl., (1997) 36, 2364. [64] Lelievre, S.;
Mercier, F.; Mathey, F., J. Org. Chem., (1996) 61, 3531. [65]
Mathey, F.; Mercier, F.; Robin, F.; Ricard, L., J. Organomet.
Chem., (1998) 557, 117.
[66] Brown, D. G.; Siddens, J. K.; Diehl, R. E.; Wright, D. P., JP
0495068 (US 5010098), (1992); Chem. Abstr.,
(1994) 121, 101980.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
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
[1] Lewars, E. G., Chem. Rev., (1983) 83, 519. [2] Lewars, E. G.,
In Comprehensive Heterocyclic Chemistry, Katritzky, A. R.; Rees, C.
W.; Lwowski, W., Eds.;
Pergamon: New York, (1984); Vol. 7, p 120.
[3] Erden, I., In Comprehensive Heterocyclic Chemistry II,
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Padwa, A., Eds.;
Pergamon: New York, (1996); Vol. 1A, p 98.
[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.
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
9.1 Product Class 1: Oxirenes 9.1.1 Synthesis by Ring-Closure
Reactions
K.-P. Zeller, December 2000, Vol. 9, Page 21
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
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
K.-P. Zeller, December 2000, Vol. 9, Page 21
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
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
K.-P. Zeller, December 2000, Vol. 9, Page 21
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
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
K.-P. Zeller, December 2000, Vol. 9, Page 21
Science of Synthesis. Volume 9.
9 Volume 9: Fully Unsaturated Small Ring Heterocycles and
Monocyclic Five-Membered Hetarenes with One Heteroatom
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
K.-P. Zeller, December 2000, Vol. 9, Page 21
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