Download as PDF, PPTX
![13
General Strategies for Heterocycle Synthesis
Ring Construction
Manipulation of Oxidation State
Y
X
Y
X
X, Y = O, S, NR
conjugate addition
δ+ δ+
δ+
δ− δ−
• Cyclisation – 5- and 6-membered rings are the easiest to form
• C−X bond formation requires a heteroatom nucleophile to react with a C electrophile
• Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation
X
[O]
−H2
X
−H2
[O]
X X
−H2
[O]
X
or
aromatic
dihydro
tetrahydro
hexahydro](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-13-2048.jpg)
![14
General Strategies for Heterocycle Synthesis
O O
NH3
N
H
NH3
N
N
H
O O
N
H
−2H2O −2H2O
X X
Common Strategies
“4+1” Strategy
• Strategy can be adapted to incorporate more than one heteroatom
X X
“5+1” Strategy
• 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones
O O
NH3
N
H
H
−H2
[O]
N
−2H2O](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-14-2048.jpg)
![50
Quinolines – Synthesis
Skraup Synthesis (“3+3”)
• Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid
NH2
Me
Me
O
N
Me
Me
65%
1.
ZnCl2 or FeCl3,
EtOH, reflux
2. [O]
• A mild oxidant is required to form the fully aromatic system from the dihydroquinoline
N
H
H
O
H
N
H
OH
H
−
−
−
−H2O
N
H
H
O
N
H
130 °
C, H2SO4
H
OH
N
NH2
85%
[O] (e.g. I2)](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-50-2048.jpg)
![53
Isoquinolines – Synthesis
Pictet Spengler Synthesis (“5+1”)
• An electron-donating substituent on the carboaromatic ring is required
NH2
MeO
HCHO 20% aq.
N
MeO
heat
[O]
N
MeO
NH
MeO
20% HCl aq.
100 °
C
NH
MeO
H
N
MeO
H
80%
• A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the
fully aromatic isoquinoline](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-53-2048.jpg)
![56
Quinolines/Isoquinolines –
Nucleophilic Reactions
Regiochemistry
Carbon Nucleophiles
N
N
N
2-MeOC6H4Li
Et2O, rt
N
H
Li
OMe
H2O
[O]
N
MeO
N
H
H OMe
• Attack occurs at hetero- rather than benzo-ring
• They are enerally more reactive than pyridines to nucleophilic attack](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-56-2048.jpg)
![57
Quinolines/Isoquinolines –
Nucleophilic Reactions
N
n-BuLi
N
H n-Bu
benzene, rt
H2O
N
n-Bu
NH
H n-Bu
[O]
Li
• Oxidation is required to regenerate aromaticity
Amination
N
KNH2, NH3 (l)
N
NH2
H
K
>−45 °
C
−65 °
C
KMnO4, −65 °
C
N NH2 N
NH2
N
NH2
H
K
50% 60%
thermodynamic product
KMnO4, −40 °
C](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-57-2048.jpg)
![85
Indoles – Synthesis
Fischer Synthesis
N
H
NH2
N
H
N
R
2
R
1
N
R1
H
R
2
R
1
O
R
2
−
−
−
−NH3
H or
Lewis acid
−
−
−
−H2O
N
H
N
Ph
N
H
NH
Ph
N
H
NH2
Ph
NH
NH2
Ph
H
H
N
H
Ph
N
H
Ph
H
H
NH3
NH2
NH2
Ph
ZnCl2, 170 °
C
76%
[3,3]
• A protic acid or a Lewis acid can be used to promote the reaction](https://image.slidesharecdn.com/heterocyclelectures20112c12-221226143513-7d15a73e/75/HeterocycleLectures2011_2C12-pdf-85-2048.jpg)
More Related Content
Similar to HeterocycleLectures2011_2C12.pdf
HeterocycleLectures2011_2C12.pdf
- 1. 1 Heterocyclic Chemistry Heterocyclic Chemistry ProfessorJ. Stephen Clark Room C4-04 Email: [email protected] http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html 2011–2012
- 2. 2 Recommended Reading • HeterocyclicChemistry – J. A. Joule, K. Mills and G. F. Smith • Heterocyclic Chemistry (Oxford Primer Series) – T. Gilchrist • Aromatic Heterocyclic Chemistry – D. T. Davies
- 3. 3 Course Summary • Definitionof terms and classification of heterocycles • Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups • Synthesis of pyridines Introduction Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • Examples of commonly used strategies for heterocycle synthesis • Carbon–heteroatom bond formation and choice of oxidation state Pyridines • General properties, electronic structure • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines Pyridine derivatives • Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines • General methods used for the synthesis of quinolines and isoquinolines
- 4. 4 Course Summary (cont) •General properties, structure and reactivity of pyrroles, furans and thiophenes • Methods and strategies for the synthesis of five-membered heteroaromatics • Fisher and Bischler indole syntheses Five-membered aromatic heterocycles • Electrophilic substitution reactions of pyrroles, furans and thiophenes • Metallation of five-membered heteroaromatics and use the of directing groups • Strategies for accomplishing regiocontrol during electrophilic substitution Indoles • Comparison of electronic structure and reactivity of indoles to that of pyrroles • Reactions of indoles with electrophiles • Mannich reaction of indoles to give 3-substituted indoles (gramines) • Modification of Mannich products to give various 3-substituted indoles 1,2 and 1,3-Azoles • Structure and reactivity of 1,2- and 1,3-azoles • Synthesis and reactions of imidazoles, oxazoles and thiazoles • Synthesis and reactions of pyrazoles, isoxazoles and isothiazoles
- 5. 5 Introduction • Heterocycles containone or more heteroatoms in a ring • Aromatic, or partially or fully saturated – this course will focus on aromatic systems • Heterocycles are important and a large proportion of natural products contain them X Y X Y X Z carbocycle heterocycles − − − − X, Y, Z are usually O, N or S • Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit • Heterocyclic systems are important building-blocks for new materials possessing interesting electronic, mechanical or biological properties
- 6. 6 Classification – AromaticSix-Membered Isoelectronic carbocycle Heterocycles N 1 O isoquinoline pyrylium pyridazine pyrimidine pyrazine 2 N 3 N 4 5 6 7 8 N N 1 2 3 4 5 6 N N 2 3 4 5 6 7 1 N N 2 3 4 5 6 1 8 2 3 4 5 6 1 1 2 3 4 5 6 1 2 3 4 5 6 pyridine quinoline X
- 7. 7 Classification – AromaticFive-Membered Isoelectronic carbocycle Heterocycles O 1 2 pyrrole furan thiophene thiazole oxazole imidazole pyrazole indole isothiazole 3 4 5 isoxazole N H S 1 2 3 4 5 1 N H 2 3 4 N O 5 1 2 3 4 N O 1 2 3 4 5 5 6 N S 2 5 1 2 3 4 7 N S 5 1 2 3 4 3 4 N N H 1 5 1 N N 2 H 3 4 5 1 2 3 4 5
- 8. 8 Classification – Unsaturated/ Saturated O O O N H O O O N H OH N 4(γ γ γ γ)-pyrone aromatic dipolar resonance form 2-pyridone Unsaturated Saturated O O O O THF N H O ethylene oxide 1,4-dioxan pyrrolidine dihydropyran
- 9. 9 Functional Group Chemistry ImineFormation • Removal of water is usually required to drive the reaction to completion • If a dialkylamine is used, the iminium ion that is formed can’t lose a proton and an enamine is formed R1 R2 O R1 R2 N R3 R1 R2 N R3 R1 R2 O H R1 R2 OH N R3 H H R1 R2 OH2 N R3 H R1 R2 N R3 H − − − −H H R3 NH2 H H3O
- 10. 10 Functional Group Chemistry Enolsand Enolates R 1 O R 1 OH keto form enol form E R 2 R 2 R1 O R 2 H H B R 1 O R 2 R1 O R 2 enolate • Avoid confusing enols (generated under neutral/acidic conditions) with enolates (generated under basic conditions) • The enol form is favoured by a conjugating group R2 e.g. CO2R, COR, CN, NO2 etc. • Enolates are nucleophilic through C or O but react with C electrophiles through C R 1 OR 3 enol ether H R 1 O R 3 R2 R1 O R 2 R 1 R 2 OR 3 R 3 O acetal R 3 OH H2O R 2 Enol Ethers
- 11. 11 Functional Group Chemistry Enamines R1 O R2 N H R3 R3 H R1 N R2 R3 R3 ER1 N R3 R3 R2 E R1 N R3 R3 R2 H H H2O R1 O R2 E R1 N R 3 R 3 R2 enamine iminium ion (Schiff base) • Analogues of enols but are more nucleophilic and can function as enolate equivalents • Removal of water (e.g. by distillation or trapping) drives reaction to completion • Enamines react readily with carbon nucleophiles at carbon • Reaction at N is possible but usually reverses
- 12. 12 Functional Group Chemistry CommonBuilding-Blocks Building-Blocks for Sulfur-Containing Heterocycles • During heterocycle synthesis, equilibrium is driven to the product side because of removal of water, crystallisation of product and product stability (aromaticity) • Heterocycle synthesis requires: C−O or C−N bond formation using imines, enamines, acetals, enols, enol ethers C−C bond formation using enols, enolates, enamines R1 R2 O P2S5 R1 R2 S R SH R1 S R2 thioketones thiols thioethers OH O R H2N O NH2 H2N NH NH2 NH2 O R O O R2 R1 NH2 NH R O O OR2 R1 amidines amides carboxylic acids urea guanidine β-diketones β-keto esters
- 13. 13 General Strategies forHeterocycle Synthesis Ring Construction Manipulation of Oxidation State Y X Y X X, Y = O, S, NR conjugate addition δ+ δ+ δ+ δ− δ− • Cyclisation – 5- and 6-membered rings are the easiest to form • C−X bond formation requires a heteroatom nucleophile to react with a C electrophile • Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation X [O] −H2 X −H2 [O] X X −H2 [O] X or aromatic dihydro tetrahydro hexahydro
- 14. 14 General Strategies forHeterocycle Synthesis O O NH3 N H NH3 N N H O O N H −2H2O −2H2O X X Common Strategies “4+1” Strategy • Strategy can be adapted to incorporate more than one heteroatom X X “5+1” Strategy • 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones O O NH3 N H H −H2 [O] N −2H2O
- 15. 15 General Strategies forHeterocycle Synthesis X X or X X X or X “3+2” Strategy “3+3” Strategy Examples X X H2N H2N OH H2N O H2N O δ+ δ− δ− δ− δ− δ− O O δ+ δ+ NH2 NH2 OH OH E E OH O δ− δ+ O Hal δ+ δ+ Hal = Cl, Br, I
- 16. 16 Bioactive Pyridines N N H H nicotine N N S O O H NH2 sulphapyridine • Nicotineis pharmacologically active constituent of tobacco – toxic and addictive • Paraquat is one of the oldest herbicides – toxic and non-selective N NH O NH2 isoniazide • Sulphapyridine is a sulfonamide anti-bacterial agent – one of the oldest antibiotics • Isoniazide has been an important agent to treat tuberculosis – still used, but resistance is a significant and growing problem N Me N Me paraquat
- 17. 17 Drugs Containing aPyridine 2008 Ranking: 2 branded Disease: Acid reflux 2008 Sales: $4.79 billion Company: AstraZeneca N O NH S O O Name: Nexium 2008 Ranking: 87 branded Disease: Chronic myeloid leukemia 2008 Sales: $0.45 billion Company: Novartis Name: Gleevec 2008 Ranking: 10 branded Disease: Type 2 diabetes 2008 Sales: $2.45 billion Company: Eli Lilly Name: Actos 2008 Ranking: 34 branded Disease: Duodenal ulcers and acid reflux 2008 Sales: $1.05 billion Company: Eisai Name: Aciphex N H N S O N O OMe N N N H N HN O N N N H N S O N OMe MeO
- 18. 18 Pyridines – Structure N 1.39Å 1.40 Å 1.34 Å N < < 2.2 D N H < < 1.17 D .. N N N N N δ+ δ+ δ− δ+ • Isoelectronic with and analogous to benzene • Stable, not easily oxidised at C, undergoes substitution rather than addition • −I Effect (inductive electron withdrawal) • −M Effect N N N H H H etc. • Weakly basic – pKa ~5.2 in H2O (lone pair is not in aromatic sextet) • Pyridinium salts are also aromatic – ring carbons are more δ+ than in parent pyridine
- 19. 19 Pyridines – Synthesis TheHantzsch synthesis (“5+1”) • The reaction is useful for the synthesis of symmetrical pyridines • The 1,5-diketone intermediate can be isolated in certain circumstances • A separate oxidation reaction is required to aromatise the dihydropyridine Me Me Me Me O O O O Ph H Me Me O O Me Me O O Ph Me Me O O Ph H O Me Me O O NH3 pH 8.5 Michael addition aldol condensation and dehydration Me Me Me Me O O N H Ph H HNO3 Me Me Me Me O Ph O N oxidation Me O Me Me O O H2N Ph H Me
- 20. 20 Pyridines – Synthesis FromEnamines or Enamine Equivalents – the Guareschi synthesis (“3+3”) Using Cycloaddition Reactions (“4+2”) • The β-cyano amide can exist in the ‘enol’ form CO2H N CO2H Me Me O N CO2H Me Me O H H H N O Me Me Me Me CO2H N Me N CO2H H HO Me −H2O Diels-Alder cycloaddition 70% H+ • Oxazoles are sufficiently low in aromatic character to react in the Diels-Alder reaction EtO2C Me CN Me N Me CN H2N O O CO2Et Me O CN H2N K2CO3 K2CO3 Me O CN CO2Et N H 73%
- 21. 21 Pyridines – ElectrophilicReactions N α α α α β β β β γ γ γ γ N E N E E N E E E E −E Pathways for the Electrophilic Aromatic Substitution of Pyridines • The position of the equilibrium between the pyridine and pyridinium salt depends on the substitution pattern and nature of the substituents, but usually favours the salt
- 22. 22 Pyridines – ElectrophilicReactions Regiochemical Outcome of Electrophilic Substitution of Pyridines • The β-substituted intermediate, and the transition state leading to this product, have more stable resonance forms than the intermediates/transition states leading to the α /γ products α α α α β β β β γ γ γ γ N N N N N N N N H E H E H E H E H E H E H E H E N H E • Resonance forms with a positive charge on N (i.e. 6 electrons) are very unfavourable
- 23. 23 Pyridines – ElectrophilicReactions • Regiochemical control is even more pronounced in the case of pyridinium ions Regiochemical Outcome of Electrophilic Substitution of Pyridinium Ions α α α α β β β β γ γ γ γ N N N N N N N N H E H E H E H E H E H E H E H E N H E E E E E E E E E E N δ+ δ+ δ+ • In both pyridine and pyridinium systems, β substitution is favoured but the reaction is slower than that of benzene • Reaction will usually proceed through the small amount of the free pyridine available
- 24. 24 Pyridines – ElectrophilicReactions N Substitution C Substitution N Me MeI N N SO3 NO2 BF4 R O Cl N NO2 BF4 Cl N O R SO3, CH2Cl2 • Reaction at C is usually difficult and slow, requiring forcing conditions • Friedel-Crafts reactions are not usually possible on free pyridines
- 25. 25 Pyridines – ElectrophilicReactions Nitration of Pyridine Use of Activating Groups N c-H2SO4, c-HNO3 N NO2 6% ! 300 ° C, 24 h • Multiple electron-donating groups accelerate the reaction • Both reactions proceed at similar rates which indicates that the protonation at N occurs prior to nitration in the first case N Me Me Me c-HNO3, oleum N Me Me Me H N Me Me Me MeI N Me Me Me Me c-HNO3, oleum I I N Me Me Me NO2 N Me Me Me Me NO2 100 ° C 100 ° C 70% 90%
- 26. 26 Pyridines – ElectrophilicReactions Sulfonation of Pyridine Halogenation of Pyridine N Cl N Br2, oleum N Br 130 ° C 86% Cl2, AlCl3, 100 ° C 33% • Low yield from direct nitration but good yield via a mercury intermediate • Forcing reaction conditions are required for direct halogenation N H2SO4, SO3 N HgSO3 N SO3H 70% HgSO4, H2SO4, 220 ° C (low yield)
- 27. 27 Pyridines – Reduction Fullor Partial Reduction of Pyridines • Pyridines generally resist oxidation at ring carbon atoms and will often undergo side-chain oxidation in preference to oxidation of the ring N H R H2, Pt, N N H R R EtOH Na-NH3, N H R AcOH, rt Na, EtOH • Full or partial reduction of the ring is usually easier than in the case of benzene
- 28. 28 Pyridines – NucleophilicReactions Regiochemical Outcome of Nucleophilic Addition to Pyridines • Nitrogen acts as an electron sink N N N Nu Nu Nu N H Nu N H Nu N H Nu N H Nu N H Nu N H Nu N H Nu N H Nu N H Nu β β β β α α α α γ γ γ γ • β Substitution is less favoured because there are no stable resonance forms with the negative charge on N • Aromaticity will is regained by loss of hydride or a leaving group, or by oxidation
- 29. 29 Pyridines – NucleophilicReactions N Cl NaOEt N OEt NO2 Cl N Cl N Cl N Cl Nucleophilic Substitution • The position of the leaving group influences reaction rate (γ > α >> β) N X Nu N Nu X Nu = MeO , NH3, PhSH etc. X = Cl, Br, I, (NO2) • Favoured by electron-withdrawing substituents that are also good leaving groups Relative rate 80 40 1 3 × 10−4
- 30. 30 Pyridinium Ions –Nucleophilic Reactions N Me Cl O O2N N Me O NO2 Nucleophilic Substitution • Conversion of a pyridine into the pyridinium salt greatly accelerates substitution Relative rate 5 × 107 1.5 × 104 1 10−4 • Substituent effects remain the same (α, γ >> β) but now α > γ N X Nu N Nu X Nu = MeO , NH3, PhSH etc. X = Cl, Br, I, (NO2) R R N Me Cl N Me Cl N Me Cl N Cl
- 31. 31 Pyridines – PyridyneFormation Substitution via an Intermediate Pyridyne • When very basic nucleophiles are used, a pyridyne intermediate intervenes NH2 N Cl H N Cl H NH2 NaNH2 NaNH2 N NH2 H H2N N N NH2 H NH2 N H2N N NH2 44% 27% benzyne • Pyridynes are similar to benzynes and are very reactive (not isolable)
- 32. 32 Pyridines – NucleophilicReactions Nucleophilic Attack with Transfer of Hydride • A hydride acceptor or oxidising agent is required to regenerate aromaticity N Ph N HN H2O O2 (air) Li LiNH2 Li N Ph H N H2N PhLi, Et2O, 0 ° C − − − −H2 Li N NHX H N H2N H X = H (NH3) / 2-aminopyridine LiNH2 • The reaction with LiNH2 is referred to as the Chichibabin reaction
- 33. 33 Pyridines – Metal-HalogenExchange N X n-BuLi N Li n-Bu X X = Cl, Br, I Direct Exchange of Metal and a Halogen • Metallated pyridines behave like conventional Grignard reagents • Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl lithium or alkyl magnesium reagents N Br n-BuLi, N Li N O Ph PhC N H2O N Ph N N Ph NH Li Et2O, − − − −78 ° C
- 34. 34 Pyridines – DirectedMetallation Use of Directing Groups • Directing groups allow direct lithiation at an adjacent position N O OMe t-BuLi, N O Ni-Pr2 N O Li Me O N O Li Ni-Pr2 Ph NMe2 O N O OMe I N O Ni-Pr2 O Ph N Me Me Me Me Li Et2O, − − − −78 ° C LiTMP, − − − −78 ° C LiTMP I(CH2)2Cl 90% • A Lewis basic group is required to complex the Lewis acidic metal of the base
- 35. 35 Oxy-Pyridines – Structure Oxy-Pyridines/Pyridones •Subject to tautomerism • The α, γ systems differ from the β systems in terms of reactivity and structure • In the α case, the equilibrium is highly solvent dependent, but the keto form is favoured in polar solvents γ γ γ γ α α α α β β β β N H N H N N H N H N N N H N H OH OH OH O O O O O zwitterion zwitterion zwitterion O N H O N H O N H O 1,3-dipole
- 36. 36 Amino Pyridines –Structure Amino Pyridine Systems • Contrast with oxy-pyridines • Amino pyridines are polarised in the opposite direction to oxy-pyridines N H NH N NH2 N NH2 etc.
- 37. 37 Oxy-Pyridines – Reactions N H O N OH Br2,H2O, rt c-H2SO4, c-HNO3 N OH Br Br Br N H O NO2 100 ° C, 2 days 38% Electrophilic Substitution • N is much less basic than that in a simple pyridine • Substitution occurs ortho or para to the oxygen substituent (cf. phenols) • Reactions such as halogenation, nitration, sulfonation etc. are possible
- 38. 38 Oxy-Pyridines – Reactions NucleophilicSubstitution • Replacement of the oxygen substituent is possible N O H Cl PCl4 PCl5 O PCl3 N Cl H Cl N O H PCl3 Cl Cl N O H PCl3 Cl Cl N O H PCl3 Cl Cl • In this case, the reaction is driven by the formation of the very strong P=O bond
- 39. 39 Oxy-Pyridines – Reactions Cycloaddition •Oxy-pyridines have sufficiently low aromatic character that they are able to participate as dienes in Diels-Alder reactions with highly reactive dienophiles N O Me Me Me CO2Me CO2Me N O CO2Me CO2Me Me Me
- 40. 40 Alkyl Pyridines –Deprotonation Deprotonation with a Strong Base • Deprotonation of α and γ alkyl groups proceeds at a similar rate, but β alkyl groups are much more difficult to deprotonate • Bases are also potential nucleophiles for attack of the ring PhLi N CH3 N CH2 N CH etc. N R2 R1 OH O R2 R1
- 41. 41 Pyridinium Salts –Reactions N Me H BH3 H BH3 EtOH NaBH4, N Me N Me H H3B N Me N Me H BH3 N Me N Me Nucleophilic Attack with Reducing Agents • Nucleophilic attack is much easier (already seen this) • Deprotonation of alkyl substituents is easier (weak bases are suitable) • Ring opening is possible by attack of hydroxide N O2N NO2 N O2N NO2 O H OH N O2N NO2 O etc. OH
- 42. 42 Pyridine N-Oxides N-Oxide Formation •The reactivity N-oxides differs considerably from that of pyridines or pyridinium salts N RCO3H N O N O N O O O H O Cl meta-chloroperoxybenzoic acid (m-CPBA) • A variety of peracids can be used to oxidise N but m-CPBA is used most commonly • N-Oxide formation can be used to temporarily activate the pyridine ring to both nucleophilic and electrophilic attack
- 43. 43 Pyridine N-Oxides N O c-H2SO4, N O NO2 H N O NO2 H c-HNO3, N O NO2 100 °C ElectrophilicSubstitution • The N-oxide is activated to attack by electrophiles at both the α and γ positions N O NO2 PPh3 N NO2 O PPh3 N NO2 PPh3 O PPh3 • Nitration of an N-oxide is easier than nitration of the parent pyridine • Reactivity is similar to that of a pyridinium salt in many cases e.g. nucleophilic attack, deprotonation of alkyl groups etc. Removal of O • Deoxgenation is driven by the formation of the very strong P=O bond
- 44. 44 Pyridines – Synthesisof a Natural Product Synthesis of Pyridoxine (Vitamin B6) Using the Guareschi Synthesis • The final sequence of steps involves formation of a bis-diazonium salt from a diamine • Pyridoxine performs a key role as the coenzyme in transaminases N H O O Me O Me CN O CN H2N piperidine, EtOH, heat c-HNO3, Ac2O, 0 ° C 90% N H O Me CN O2N H2, Pd/Pt, AcOH N Cl Me CN O2N 32% PCl5, POCl3, 150 ° C 40% N Me H2N 40% 2. 48% HBr (neat) N Me HO 1. NaNO2, HCl, 90 ° C 3. AgCl, H2O, heat NH2 EtO EtO EtO EtO EtO HO OH
- 45. 45 Bioactive Quinolines/Isoquinolines • Quinineis an anti-malarial natural product isolated from the bark of the Cinchona tree • Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle relaxant and a coronary vasodilator • Chloroquine is a completely synthetic anti-malarial drug that has the quinoline system found in quinine – parasite resistance is now a problem N N HO H MeO H N MeO MeO OMe OMe quinine papaverine N HN Me MeO NEt2 chloroquine
- 46. 46 Drugs Containing aQuinoline/Isoquinoline 2008 Ranking: 146 generic Disease: Malaria, lupus erythematosus, rheumatoid arthritis 2008 Sales: $74 million Company: N/A Name: Hydroxychloroquine 2008 Ranking: 7 branded Disease: Asthma and allergies 2008 Sales: $2.90 billion Company: Merck Name: Singulair 2008 Ranking: 84 generic Disease: Hypertension and heart failure 2008 Sales: $133 million Company: N/A Name: Quinapril N Cl HO S CO2H N HO2C CO2Et N H O Ph N Cl HN N OH
- 47. 47 Malaria Cinchona pubescens • Diseaseis caused by protazoan parasites of the genus Plasmodium (falciparum, vivax, ovale and malariae) • Approximately 500 million cases of malaria each year and 1–3 million deaths • Disease spread by the Anopheles mosquito (female) Plasmodium monocyte Anopheles mosquito
- 48. 48 Quinolines – Synthesis Structure CombesSynthesis (“3+3”) N N MeO MeO NH2 O O Me Me MeO N Me MeO Me O MeO N H Me MeO OH Me MeO N Me MeO Me −H2O MeO N H Me MeO Me O MeO N H Me MeO Me O H c-H2SO4, 23% −H2O • pKa values (4.9 and 5.4) are similar to that of pyridine • Possess aspects of pyridine and naphthalene reactivity e.g. form N-oxides and ammonium salts
- 49. 49 Quinolines – Synthesis Conrad-Limpach-KnorrSynthesis (“3+3”) • Very similar to the Combes synthesis by a β-keto ester is used instead of a β-diketone • Altering the reaction conditions can completely alter the regiochemical outcome NH2 O O OEt Me rt, − − − −H2O N H Me OEt O N Me OH N H Me O 70% 270 ° C N OH Me N H O Me 250 ° C, − − − −H2O N H O Me O O O OEt Me 140 ° C, − − − −H2O NH2 50%
- 50. 50 Quinolines – Synthesis SkraupSynthesis (“3+3”) • Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid NH2 Me Me O N Me Me 65% 1. ZnCl2 or FeCl3, EtOH, reflux 2. [O] • A mild oxidant is required to form the fully aromatic system from the dihydroquinoline N H H O H N H OH H − − − −H2O N H H O N H 130 ° C, H2SO4 H OH N NH2 85% [O] (e.g. I2)
- 51. 51 Quinolines – Synthesis FriedlanderSynthesis (“4+2”) • The starting acyl aniline can be difficult to prepare NH2 Ph O Me O Me N H O Me Me H Ph − − − −H2O NH2 Ph O N Ph O Me H OH Me O Me − − − −H2O N Ph Me Me N Ph Me c-H2SO4, AcOH heat KOH aq., EtOH 0 ° C 71% 88% • Acidic and basic conditions deliver regioisomeric products in good yields
- 52. 52 Isoquinolines – Synthesis O H EtOOEt H2N − − − −H2O N OEt OEt H , EtOH N Pomeranz-Fritsch Synthesis (“3+3”) Bischler-Napieralski Synthesis (“5+1”) NH2 MeCOCl NH Me O P4O10, heat N Me Pd-C, 190 ° C N Me 93% • Cyclisation can be accomplished using POCl3 or PCl5 • Oxidation of the dihydroisoquinoline can be performed using a mild oxidant
- 53. 53 Isoquinolines – Synthesis PictetSpengler Synthesis (“5+1”) • An electron-donating substituent on the carboaromatic ring is required NH2 MeO HCHO 20% aq. N MeO heat [O] N MeO NH MeO 20% HCl aq. 100 ° C NH MeO H N MeO H 80% • A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the fully aromatic isoquinoline
- 54. 54 Quinolines/Isoquinolines – Electrophilic Reactions N H N H * * Regiochemistry •Under strongly acidic conditions, reaction occurs via the ammonium salt • Attack occurs at the benzo- rather than hetero-ring • Reactions are faster than those of pyridine but slower than those of naphthalene Nitration N fuming HNO3, cH2SO4, 0 ° C N NO2 N NO2 72% 8% • In the case of quinoline, equal amounts of the 5- and 8-isomer are produced
- 55. 55 Quinolines/Isoquinolines – Electrophilic Reactions Sulfonation •Halogenation is also possible but product distribution is highly dependent on conditions • It is possible to introduce halogens into the hetero-ring under the correct conditions • Friedel-Crafts alkylation/acylation is not usually possible N 30% oleum3, 90 ° C N SO3H >250 ° C N HO3S 54% thermodynamic product
- 56. 56 Quinolines/Isoquinolines – Nucleophilic Reactions Regiochemistry CarbonNucleophiles N N N 2-MeOC6H4Li Et2O, rt N H Li OMe H2O [O] N MeO N H H OMe • Attack occurs at hetero- rather than benzo-ring • They are enerally more reactive than pyridines to nucleophilic attack
- 57. 57 Quinolines/Isoquinolines – Nucleophilic Reactions N n-BuLi N Hn-Bu benzene, rt H2O N n-Bu NH H n-Bu [O] Li • Oxidation is required to regenerate aromaticity Amination N KNH2, NH3 (l) N NH2 H K >−45 ° C −65 ° C KMnO4, −65 ° C N NH2 N NH2 N NH2 H K 50% 60% thermodynamic product KMnO4, −40 ° C
- 58. 58 Quinolines/Isoquinolines – Nucleophilic Substitution Displacementof Halogen N Cl N Cl reflux NaOEt, EtOH NaOMe, MeOH N OEt Cl N Cl OMe DMSO 100 ° C N OEt N OMe 87%
- 59. 59 Quinolines/Isoquinolines – The ReissertReaction • The reaction works best with highly reactive alkyl halides • The proton adjacent to the cyano group is extremely acidic N PhCOCl N O Ph KCN N Me CN N CN H O Ph N CN Me base, MeI NaOH aq. N CN Me HO Ph O O Ph
- 60. 60 Isoquinolines – Synthesisof a Natural Product • Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski reaction Synthesis of Papaverine Me ZnCl2, HCl, rt N N NH2 NH Na-Hg, H2O, 50 ° C MeO MeO O MeO MeO OH MeO MeO O MeO MeO O MeO OMe O NH MeO MeO MeO OMe O OH H MeO OMe MeO MeO O Me2CH(CH2)2ONO, NaOEt, EtOH, rt 75% OMe OMe O Cl KOH aq., rt P4H10, xylene, heat 60% 30%
- 61. 61 Bioactive Furans, Pyrrolesand Thiophenes O S Me2N N NHMe NO2 H ranitidine N CO2H O Ph ketorolac • Ranitidine (Zantac®, GSK) is one of the biggest selling drugs in history. It is an H2-receptor antagonist and lowers stomach acid levels – used to treat stomach ulcers • Ketorolac (Toradol®, Roche) is an analgesic and anti-inflammatory drug • Pyrantel (Banminth®, Phibro) is an anthelminthic agent and is used to treat worms in livestock S N Me N banminth
- 62. 62 Drugs Containing aFuran/Thiophene/Pyrrole 2008 Ranking: 14 branded Disease: Depression 2008 Sales: $2.17 billion Company: Eli Lilly Name: Cymbalta 2008 Ranking: 1 branded Disease: Lowers LDL levels 2008 Sales: $5.88 billion Company: Pfizer Name: Lipitor 2008 Ranking: 3 branded Disease: Stroke and heart attack risk 2008 Sales: $3.80 billion Company: Bristol-Myers Squibb Name: Plavix 2008 Ranking: 119 and 149 generic Disease: Antibiotic for urinary tract infections 2008 Sales: $92 + 72 million Company: N/A Name: Nitrofurantoin N S Cl MeO2C O N H S N Ph O NHPh F HO HO HO2C O O2N N N NH O O
- 63. 63 Furans, Pyrroles andThiophenes – Structure O N H S α α α α β β β β X .. X X X X etc. δ− δ+ δ− δ− δ− .. • 6 π electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion • Electron donation into the ring by resonance but inductive electron withdrawal Structure Resonance Structures • O and S are more electronegative than N and so inductive effects dominate O N H S 1.37 Å 1.35 Å 1.44 Å 1.57 D O N H S 1.55 D 0.52 D 1.87 D 0.71 D 1.68 D 1.38 Å 1.37 Å 1.43 Å 1.71 Å 1.37 Å 1.42 Å
- 64. 64 Furans – Synthesis PaalKnorr Synthesis • The reaction is usually reversible and can be used to convert furans into 1,4-diketones H O O R1 R2 O R2 R1 O O R1 R2 H H O R2 R1 H H O R2 R1 OH H O R2 R1 OH2 heat • A trace of acid is required – usually TsOH (p-MeC6H4SO3H)
- 65. 65 Furans – Synthesis Feist-BenarySynthesis (“3+2”) • Reaction can be tuned by changing the reaction conditions Me EtO2C O Cl Me O O Me Me EtO2C NaOH aq., rt Me EtO2C O O Me EtO2C OH Me Cl Me O OH O Cl EtO2C Me O Me O EtO2C Me OH Me H Cl −H2O δ+ δ+ isolable • The product prior to dehydration can be isolated under certain circumstances
- 66. 66 Furans – Synthesis ModifiedFeist-Benary • Iodide is a better leaving group than Cl and the carbon becomes more electrophilic Me EtO2C O Cl Me O O Me EtO2C Me −H2O NaI, NaOEt, EtOH Me EtO2C O O Me EtO2C OH Me O Me I EtO O O EtO2C Me Me O EtO2C Me H Me O δ+ δ+ I • The Paal Knorr sequence is followed from the 1,4-diketone onwards • The regiochemical outcome of the reaction is completely altered by addition of iodide
- 67. 67 Thiophenes – Synthesis Synthesisof Thiophenes by Paal Knorr type reaction (“4+1”) • Reaction might occur via the 1,4-bis-thioketone O O Me Ph Me P4S10 S O Me Ph Me O S Me Ph Me S Me Me Ph
- 68. 68 Pyrroles – Synthesis PaalKnorr Synthesis (“4+1”) • Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole O O Me Me N H Me Me N H R2 R1 H H O HN Me Me N H R2 R1 OH O H2N Me Me NH3, C6H6, heat
- 69. 69 Pyrroles – Synthesis MeO2C EtO2C ONH2 Me O KOH aq. N H HO2C Me EtO2C 53% Me H2N O NH2 Me O N N Me Me Knorr Pyrrole Synthesis (“3+2”) • Use of a free amino ketone is problematic – dimerisation gives a dihydropyrazine EtO2C EtO2C O NH3 Cl Me O NaOH aq. N H EtO2C Me EtO2C O NH2 EtO2C EtO2C Me HO N H O Me EtO2C EtO2C via or • Problem can be overcome by storing amino carbonyl compound in a protected form • Reactive methylene partner required so that pyrrole formation occurs more rapidly than dimer formation
- 70. 70 Pyrroles – Synthesis Liberationof an Amino Ketone in situ by Oxime Reduction Preparation of α-Keto Oximes from β-Dicarbonyl Compounds Me EtO2C O N Me O OH Zn, AcOH or Na2S2O4 aq. N H Me Me EtO2C (sodium dithionite) OEt O O N OEt O O OH (HNO2) NaNO2, H OEt O O H N OEt O O O H H2O N O
- 71. 71 Pyrroles – Synthesis One-PotOxime Reduction and Pyrrole Formation Hantzsch Synthesis of Pyrroles (“3+2”) N OEt O O OH EtO2C CO2Et O Zn, AcOH N H EtO2C CO2Et CO2Et Me EtO2C O rt to 60 ° C NH3 aq. N H Me EtO2C Me Cl Me O −H2O Me EtO2C NH2 N H Me EtO2C OH Me O Me Cl NH O EtO2C Me Me H NH2 EtO2C Me Me O δ+ δ+ 41% • A modified version of the Feist-Benary synthesis and using the same starting materials: an α-halo carbonyl compound and a β-keto ester
- 72. 72 Furans, Pyrroles Thiophenes– Electrophilic Substitution Electrophilic Substitution – Regioselectivity • Pyrrole > furan > thiophene > benzene X X E E X H E X H E X H E X H E −H X E X H E −H X E α α α α β β β β • Thiophene is the most aromatic in character and undergoes the slowest reaction • Pyrrole and furan react under very mild conditions • α-Substitution favoured over β-substitution more resonance forms for intermediate and so the charge is less localised (also applies to the transition state) • Some β-substitution usually observed – depends on X and substituents X AcONO2 X = O X = NH X NO2 X NO2 4:1 6:1
- 73. 73 Furans – ElectrophilicSubstitution O Br2, dioxan, O H Br Br Br Br O H Br H Br −HBr O Br 80% 0 ° C O AcONO2, O H NO2 NO2 AcO O H NO2 O H NO2 H AcO O NO2 −AcOH N <0 ° C pyridine, heat isolable (Ac2O, HNO3) Bromination of Furans Nitration of Furans • Nitration can occur by an addition-elimination process • When NO2BF4 is used as a nitrating agent, the reaction follows usual mechanism • Furan reacts vigorously with Br2 or Cl2 at room temp. to give polyhalogenated products • It is possible to obtain 2-bromofuran by careful control of temperature
- 74. 74 Furans – ElectrophilicSubstitution O NMe2 O H NMe2 CH2 NMe2 O Me2NH.HCl CH2O, O 66% Friedel-Crafts Acylation of Furan Mannich Reaction of Furans O Me Me2NCO, POCl3, O H O Me 76% 0 to 100 ° C Vilsmeier Formylation of Furan • Blocking groups at the α positions and high temperatures required to give β acylation O Ac2O, SnCl4, O Me O O Me Me Ac2O, SnCl4, O Me Me Me O α α α α:β β β β 6800:1 H3PO4 cat., 20 ° C 150 ° C 77%
- 75. 75 Thiophenes – ElectrophilicSubstitution S NO2 S NO2 AcONO2 S Nitration of Thiophenes Halogenation of Thiophenes • Reagent AcONO2 generated in situ from c-HNO3 and Ac2O • Occurs readily at room temperature and even at −30 ° C • Careful control or reaction conditions is required to ensure mono-bromination S Br Br2, Et2O, S Br2, Et2O, 48% HBr, 48% HBr, S Br Br −10 → → → → 10 ° C −25 → → → → −5 ° C
- 76. 76 Pyrroles – ElectrophilicSubstitution Nitration of Pyrroles • Mild conditions are required (c-HNO3 and c-H2SO4 gives decomposition) POCl3 N Me Me H OPCl2 N Me Me H Cl N H NMe2 H Cl N H NMe2 H N H O H N Me Me H O N Me Me H Cl N H K2CO3 aq. 83% N H AcONO2 N H NO2 N H NO2 AcOH, −10 ° C 51% 13% Vilsmeier Formylation of Pyrroles
- 77. 77 Pyrroles – PorphyrinFormation • The extended aromatic 18 π-electron system is more stable than that having four isolated aromatic pyrroles N H OH2 R 2 R 1 N H R 2 R1 N H OH R 2 R 1 N H N H R 1 R 2 H N H HN NH NH HN R 1 OH R 2 N H N H R 1 R 2 HN NH NH HN N H R 1 , R 2 = H N NH N HN 18 π-electron system no extended aromaticity
- 78. 78 Porphyrin Natural Products •Chlorophyll-a is responsible for photosynthesis in plants • The pigment haem is found in the oxygen carrier haemoglobin • Both haem and chlorophyll-a are synthesised in cells from porphobilinogen N N N N Fe N N N N Mg HO2C CO2H O MeO2C O C20H39 O haem chlorophyll-a N H H2N CO2H HO2C porphobilinogen
- 79. 79 Furans, Pyrroles Thiophenes– Deprotonation Metallation Deprotonation of Pyrroles X H n-BuLi Bu X Li α α α α>>β β β β X = O pKa (THF) 35.6 X = NR X = S pKa (THF) pKa (THF) 33.0 39.5 N H H R M N M M N N M pKa (THF) 39.5 pKa (THF) 17.5 • Free pyrroles can undergo N or C deprotonation • Large cations and polar solvents favour N substitution • A temporary blocking group on N can be used to obtain the C-substituted compound
- 80. 80 Furans, Pyrroles Thiophenes– Directed Metallation X Y n-BuLi X H Y Li Bu X Y Li Common directing groups: CO2H(Li), CH2OMe, CONR2, CH(OR)2 Control of Regioselectivity in Deprotonation Synthesis of α,α’-Disubstituted Systems X Y n-BuLi X Y E 1 n-BuLi X Y E 1 E2 E1 E2 X Y n-BuLi X Y SiMe3 n-BuLi Me3SiCl X Y SiMe3 E F X Y E E Use of a Trialkylsilyl Blocking Group
- 81. 81 Furans – Synthesisof a Drug Preparation of Ranitidine (Zantac®) Using a Mannich Reaction O S Me2N N NHMe NO2 H ranitidine O OH O Me2N OH O O furfural O S Me2N NH2 Me2NH.HCl, CH2O, rt HS(CH2)2NH2, c-HCl, heat MeS NHMe NO2 • Furfural is produced very cheaply from waste vegetable matter and can be reduced to give the commercially available compound furfuryl alcohol • The final step involves conjugate addition of the amine to the α,β-unsaturated nitro compound and then elimination of methane thiol • The second chain is introduced using a Mannich reaction which allows selective substitution at the 5-position
- 82. 82 Indoles – BioactiveIndoles • Sumatriptan (Imigran®, GSK) is a drug used to treat migraine and works as an agonist for 5-HT receptors for in the CNS • Tryptophan is one of the essential amino acids and a constituent of most proteins • LSD is a potent psychoactive compound which is prepared from lysergic acid, an alkaloid natural product of the ergot fungus N H 5-hydroxytryptamine (serotonin) NH2 HO N H CO2H NH2 H N H NMe2 S MeNH O O N H N H Me X O lysergic acid diethyamide (LSD) sumatriptan tryptophan X = NEt2 X = OH lysergic acid H
- 83. 83 Indoles – LysergicAcid Louvre Museum, Paris “The Beggars” (“The Cripples”) by Pieter Breugel the Elder (1568)
- 84. 84 Drugs Containing anIndole 2008 Ranking: 35 branded Disease: Migraine 2008 Sales: $0.97 billion Company: GlaxoSmithKline Name: Imitrex 2008 Ranking: 151 branded Disease: Migraine 2008 Sales: $0.21 billion Company: Pfizer Name: Relpax 2008 Ranking: 148 branded Disease: Migraine 2008 Sales: $0.22 billion Company: Merck Name: Maxalt 2008 Ranking: 66 branded Disease: Erectile disfunction 2008 Sales: $0.56 billion Company: Eli Lilly Name: Cialis N H NMe2 N H N N N N H O O N H NMe2 O O N N N S Ph O O S H N O O H
- 85. 85 Indoles – Synthesis FischerSynthesis N H NH2 N H N R 2 R 1 N R1 H R 2 R 1 O R 2 − − − −NH3 H or Lewis acid − − − −H2O N H N Ph N H NH Ph N H NH2 Ph NH NH2 Ph H H N H Ph N H Ph H H NH3 NH2 NH2 Ph ZnCl2, 170 ° C 76% [3,3] • A protic acid or a Lewis acid can be used to promote the reaction
- 86. 86 Indoles – Synthesis BischlerSynthesis • An α-arylaminoketone is cyclised under acidic conditions • The reaction also works with acetals of aldehydes N O CF3 O Me polyphosphoric acid (PPA), 120 ° C N H Me 64% N O CF3 O Me H − − − −H2O KOH aq. N EtO CF3 O OEt CF3CO2H, heat Me (CF3CO)2O, N 93% Me CF3 O
- 87. 87 Indoles – ElectrophilicSubstitution Nitration of Indoles Acylation of Indoles • Polymerisation occurs when there is no substituent at the 2-position • Halogenation is possible, but the products tend to be unstable • Acylation occurs at C before N because the N-acylated product does not react N H NO2 35% PhCO2NO2, 0 ° C Me c-H2SO4, c-HNO3 0 ° C N H Me N H Me O2N 84% N H N Ac2O, AcOH, heat Me O O Me N O Me Ac2O, AcOH, heat Ac2O, AcONa NaOH aq., rt N H Me O β β β β-product! 60%
- 88. 88 Indoles – ElectrophilicSubstitution Mannich Reaction Synthesis of Tryptophan from Gramine • A very useful reaction for the synthesis of 3-substituted indoles • The product (gramine) can be used to access a variety of other 3-substituted indoles N H NMe2 N H NHAc CO2Et EtO2C N H NH2 CO2H NaOH aq. then H2SO4, heat PhMe, heat EtO2C CO2Et NHAc Na 90% 80% N H H2C NMe2 N NMe2 N H NMe2 CH2O, Me2NH, H2O, heat 93% (preformed) 95% H2O, 0 °C or AcOH, rt 68%
- 89. 89 Indoles – ElectrophilicSubstitution Synthesis of Other 3-Substituted Indoles from Gramine • The nitrile group can be modified to give other useful functionality N H NMe3 N N H CN NaCN aq., 70 ° C MeSO4 CN H2O H2O H 100% N H CN N H NH2 N H CO2H LiAlH4 acid/base hydrolysis
- 90. 90 Indoles – Synthesisof a Drug Synthesis of Ondansetron (Zofran®, GSK) using the Fischer Indole Synthesis • Ondansetron is a selective 5-HT antagonist used as an antiemetic in cancer chemotherapy and radiotherapy N H O N Me O N Me O Me3N I N Me O N N Me NHNH2 O O N H NH O − − − −H2O MeI, K2CO3 ZnCl2, heat N N H Me Me2NH.HCl, CH2O then MeI • Introduction of the imidazole occurs via the α,β-unsaturated ketone resulting from elimination of the ammonium salt
- 91. 91 1,3-Azoles – Bioactive1,3-Azoles • O-Methylhalfordinol is a plant-derived alkaloid • Vitamin B1 (thiamin) is essential for carbohydrate metabolism. Deficiency leads to beriberi, a disease which is characterised by nerve, heart and brain abnormalities N N H Me S H N N CN MeHN cimetidine N S Me vitamin B1 (thiamin) N N Me H2N N O N MeO O-methylhalfordinol HO • Cimetidine (Tagamet®, GSK) is an H2-receptor antagonist which reduces acid secretion in the stomach and is used to treat peptic ulcers and heartburn
- 92. 92 Drugs Containing a1,3-Azole 2008 Ranking: 112 branded Disease: HIV/AIDS 2008 Sales: $0.31billion Company: Abbott Name: Norvir 2008 Ranking: 54 branded Disease: Hypertension 2008 Sales: $0.69 billion Company: Merck Name: Cozaar 2008 Ranking: 108 branded Disease: Parkinson's disease 2008 Sales: $0.34 billion Company: Boehringer Ingelheim Name: Mirapex 2008 Ranking: 178 generic Disease: Kidney transplant rejection 2008 Sales: $53 million Company: N/A Name: Azathioprine N S H N NH2 N N H H N Ph N H O O O O Ph OH S N S N N N N NH N N Cl OH N N S N N N H N NO2
- 93. 93 1,3-Azoles – Synthesis •The reaction is particularly important for the synthesis of thiazoles • A thiourea can be used in place of a thioamide leading to a 2-aminothiazole Me NH2 S Cl Me O C6H6, heat O S Me Me NH2 N S Me Me −H2O N S Me Me HO H N S Me Me HO δ+ 43% δ+ The Hantzsch Synthesis (“3+2”)
- 94. 94 1,3-Azoles – Synthesis OO N Ph Ph H N O Ph Ph H2O H H O O N Ph Ph H H c-H2SO4, rt −H2O N O Ph Ph 72% • A particularly important strategy for the synthesis of oxazoles which is known as the Robinson-Gabriel Synthesis • The starting α-acylaminocarbonyl compounds are easily prepared • Tosylmethylisocyanide (TOSMIC) is a readily available isocyanide Cyclodehydration of α-acylaminocarbonyl compounds From Isocyanides • Route can be adapted to give oxazoles and thiazoles using an acid chloride or a thiocarbonyl compound H Me N N Ts H K2CO3, MeOH N N Ts H t-Bu C t-Bu Me H N N Ts H t-Bu Me H C N N Me 94% Ts = Me O2S t-Bu
- 95. 95 1,3-Azoles – ElectrophilicSubstitution • Imidazoles are much more reactive to nitration than thiazoles (activation helps) • Oxazoles do not generally undergo nitration • Imidazoles usually nitrate at the 4-position and thiazoles tend to react at the 5-position N N H Br2, AcOH, N N H Br Br Br Na2SO3 aq., N N H Br NaOAc, rt 78% heat 58% N N H c-HNO3, N N H O2N N S Me N2O4/BF3 N S Me O2N N S Me O2N 27% 59% 1% oleum, rt 90% + rt → → → → 70 ° C Nitration Halogenation • Imidazoles are brominated easily and bromination at multiple positions can occur • Thiazole does not brominate easily but 2-alkylthiazoles brominate at the 5-position
- 96. 96 1,3-Azoles – ElectrophilicSubstitution • 1,3-Azoles do not undergo Friedel-Crafts acylation because complexation between the Lewis acidic catalyst and N deactivates the ring • Acylation can be accomplished under mild conditions via the N-acylimidazolium ylide Acylation N N Me PhCOCl, Et3N, N N Me O Ph N N Me O Ph N N Me O Ph O Ph N N Me O Ph MeCN, rt 71% H2O
- 97. 97 1,3-Azoles – NucleophilicSubstitution N S Cl PhSNa, MeOH, rt N S SPh 75% • There are many examples of displacement of halogen at the 2-position • 2-Halothiazoles react rapidly with sulfur nucleophiles, and are even more reactive than 2-halopyridines Displacement of Halogen N O n-Pr Cl n-Pr PhNHMe, N O n-Pr N n-Pr Me Ph xylene, 155 ° C 96% • 2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles
- 98. 98 1,3-Azoles – Metallation •Direct deprotonation oxazoles, thiazoles and N-alkylimidazoles occurs preferentially at either the 2- or 5-position • Metallation at the 4-position can be accomplished by metal-halogen exchange Metal-Halogen Exchange Direct Deprotonation N N H Br 1. t-BuLi (2 equiv.) N N H OH Ph Ph 2. Ph2CO 64% N N SO2NMe2 n-BuLi, THF, − − − −78 ° C N N ZnCl SO2NMe2 Pd(PPh3)4 N Br N N H N then ZnCl2 90% 1. 2. acid aq. • In the case of imidazoles without substitution at the 1-position, two equivalents of base are required • Transmetallation of the lithiated intermediate is possible
- 99. 99 1,2-Azoles – Bioactive1,2-Azoles • Leflunomide (Arava®, Sanofi-Aventis) inhibits pyrimidine synthesis in the body and is used for the treatment of rheumatoid arthritis and psoriatic arthritis • Celecoxib (Celebrex®, Pfizer) is a non-steroidal anti-inflamatory (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms N O Me NH O CF3 leflunomide N N CF3 celecoxib Me SO2NH2 • Celecoxib is a COX-2 inhibitor, blocking the cyclooxygenase-2 enzyme responsible for the production of prostaglandins. It is supposed to avoid gastrointestinal problems associated with other NSAIDs, but side effects (heart attack, stroke) have emerged
- 100. 100 1,2-Azoles – Synthesis H2NNH2, N N H Me Me 75% O O Me Me H2N NH2OEt OEt EtO OEt H2NOH.HCl HO NH2 N O 84% H2O, heat NaOH aq., rt • This is the most widely used route to pyrazoles and isoxazoles • The dicarbonyl component can be a β-keto ester or a β-keto aldehyde (masked) Synthesis of Pyrazoles/Isoxazoles from 1,3-Dicarbonyl Compounds and Hydrazines or Hydroxylamines (“3+2”) • When a β-keto ester is used a pyrazolone/isoxazalone is formed
- 101. 101 1,2-Azoles – Synthesis •Nitrile oxides react readily with alkenes and alkynes • Addition to an alkene generates an isoxazoline unless a leaving group is present Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to Alkynes or Enamines (“3+2”) • Mono-alkyl/-aryl alkynes react to give 3,5-disubstituted isoxazoles but when the alkyne possesses two substituents mixtures of 3,4- and 3,5-disubstituted isoxazoles are usually produced Me EtO2C N EtCNO Me EtO2C N O N C Et N O Et Me EtO2C N O Et N EtO2C Me H 70% O N Ph Et3N, Et2O, rt PhCCH Ph Cl Ph N HO N O Ph Ph 76%
- 102. 102 1,2-Azoles – ElectrophilicSubstitution • Pyrazoles and isothiazoles undergo straightforward nitration • Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to undergo nitration at the 4-position Nitration of Isoxazoles, Pyrazoles and Isothiazoles N N N N H 80% O2N NO2 N N H c-HNO3, Ac2O, AcOH, rt c-H2SO4, 0 ° C 70% • 1-Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating reagent, acetyl nitrate N O 40% O2N f-H2SO4, N O Me Me c-HNO3, 0 → → → → 70 ° C • 1-Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at low temperature
- 103. 103 1,2-Azoles – ElectrophilicSubstitution • Halogenation (iodination, bromination) of pyrazole leads to the 4-halopyrazole • Only N-substituted pyrazoles can be C-acylated directly Halogenation of Isoxazoles, Pyrazoles and Isothiazoles • Poor yields are obtained when attempting to halogenate isoxazole or isothiazole, but bromination can be accomplished when an activating group is present as a substituent Acylation N N H N N H Br2, NaOAc N N H Br Br H Br Br Br N N Me Cl Me N N Me Cl Me Ph O N N Me N N H O Me PhCOCl, AlCl3, 95 ° C Me2NCHO, POCl3, 95 ° C then H 2O 33% • Vilsmeier formylation produces the 4-formylpyrazole in modest yield
- 104. 104 1,2-Azoles – Metallation •1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position • It is possible to temporarily protect the 1-position of pyrazole and then perform sequential deprotonation and alkylation/acylation at the 5-position Direct Metallation of Isoxazoles, Pyrazoles and Isothiazoles 88% n-BuLi, MeI N S Ph HO2C N S Ph N N Me N N Ph Ph n-BuLi, THF, − − − −78 ° C then CO 2 N N N N H 79% N N H CH2O, EtOH, heat N H N 1. n-BuLi, THF, − − − −78 ° C 2. PhNCO PhNH O 3. HCl aq.
- 105. 105 1,2-Azoles – Metallation •At low temperature, N-sulfonyl 4-bromopyrazoles can be lithiated at 5-position without undergoing metal-halogen exchange • Treatment of 4-bromopyrazole with two equivalents on n-butyllithium results in N-deprotonation and exchange of lithium for bromine Direct Metallation of 4-Bromopyrazoles N N SO2Ph Br 65% − − − −78 ° C CO2 N N Li SO2Ph Br N N HO2C SO2Ph Br n-BuLi, Et2O, N N H Br 39% − − − −78 ° C N N Li Li N N H n-BuLi, THF, OH S S O H Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange • 2,5-Dilithiopyrazole reacts with carbon electrophiles to give the 4-substituted product
- 106. 106 1,2-Azoles – SideChain Deprotonation CH2CHCH2Br − − − −78 ° C n-BuLi, THF, N O Me Me N O Me N O Me Li 80% N S Me N S O2N 3-O2NC6H4CHO, Ac2O, piperidine 150 ° C 42% • Surprisingly, 3-methylisothiazole does not deprotonate as easily as 5-methylisothiazole and the same effect is found in isoxazoles Deprotonation of 5-methylisothiazole and 5-methylisoxazole • Metal-halogen exchange can be used to avoid deprotonation of alkyl groups • A weak base can be used to deprotonate 5-methylisothiazole and 5-methylisoxazole • In this case above, dehydration of the initial product occurs in situ 2. CO2 Br2 N O Me Me N O Me Me Br N O Me Me HO2C − − − −78 ° C 1. n-BuLi, THF, 3. HCl aq.
- 107. 107 1,2-Azoles – Synthesisof a Drug • A regioisomeric mixture is formed requiring separation and disposal of the side product • 1,3-Dipolar cycloaddition of a nitrile imine offers a regioselective alternative route Synthesis of Celecoxib (Celebrex®, Pfizer) O O CF3 NH2NH2 N N CF3 celecoxib Me SO2NH2 SO2NH2 Me + N N F3C SO2NH2 Me HN SO2NH2 N F3C OSO2Ph Et3N, THF, EtOAc 5 → → → → 10 ° C O N N N CF3 Me SO2NH2 N SO2NH2 N CF3 Me 72%