Azoles in nature of cyclic organic compounds.pptx

Azole structure and positions in organic compounds

1. Bioactive 1,3-Azoles N O Me O N O -methylhalfordinol H 2 N N Me N N S H O vitamin B 1 (thiamin) MeH N N Me H N S C N Me cimetidine N N H • 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 • Cimetidine (Tagamet®, GSK) is an H 2 -receptor antagonist which reduces acid secretion in the stomach and is used to treat peptic ulcers and heartburn 91

2. Drugs Containing a 1,3-Azole N O 2 H N Name: Mirapex N S S N H 2 N N N Name: Azathioprine H N N N 2008 Sales: $0.34 billion 2008 Ranking: 108 branded Company: Boehringer Ingelheim Disease: Parkinson's disease S N Ph O O H N N N N H H O O H Ph Name: Norvir 2008 Sales: $0.31billion 2008 Ranking: 112 branded Company: Abbott Disease: HIV/AIDS 2008 Sales: $53 million 2008 Ranking: 178 generic Company: N/A Disease: Kidney transplant rejection Cl N N O H S N N N H N N O Name: Cozaar 2008 Sales: $0.69 billion 2008 Ranking: 54 branded Company: Merck 92 Disease: Hypertension

3. 1,3-Azoles - Synthesis The Hantzsch Synthesis (“3+2”) O δ + Me N H 2 δ + Me S Cl Me C 6 H 6 , heat S Me S O N H 2 Me N − H 2 O Me Me H O S Me H O S H N Me N Me 43% • 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 93

4. 1,3-Azoles - Synthesis Cyclodehydration of α-acylaminocarbonyl compounds H N Ph Ph O O H c-H 2 SO 4 , rt N Ph Ph O O H H H Ph H 2 O N O − H 2 O Ph Ph N O 72% Ph • 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 From Isocyanides H Ts Me K 2 CO 3 , MeOH N H N C t -Bu Ts = O 2 S H Me H Me Ts N C N t -Bu H Me H Ts N N t -Bu Me N N t -Bu 94% • Tos yl m ethyl i so c yanide (TOSMIC) is a readily available isocyanide • Route can be adapted to give oxazoles and thiazoles using an acid chloride or a 94 thiocarbonyl compound

5. 1,3-Azoles - Electrophilic Substitution Nitration N c-HNO 3 , 1% oleum, rt N H O 2 N N N S H 90% N Me N 2 O 4 /BF 3 rt → 70 °C O 2 N N S 59% O 2 N + Me N S 27% Me • Imidazoles are much more reactive to nitration than thiazoles (activation helps) • Imidazoles usually nitrate at the 4-position and thiazoles tend to react at the 5-position • Oxazoles do not generally undergo nitration Halogenation N H Br N Br 2 , AcOH, NaOAc, rt Br N N H 78% Br Na 2 SO 3 aq., heat Br N N H 58% • Imidazoles are brominated easily and bromination at multiple positions can occur • Thiazole does not brominate easily but 2-alkylthiazoles brominate at the 5-position 95

6. 1,3-Azoles - Electrophilic Substitution Acylation N PhCOCl, Et 3 N, MeCN, rt N Me O O O Ph Ph N N N N N N Me Me Me Ph H 2 O Ph O N N Me 71% Ph O • 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 96

7. 1,3-Azoles - Nucleophilic Substitution Displacement of Halogen N S PhSNa, MeOH, rt Cl N S 75% S Ph • 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 n -Pr n -Pr N O n -Pr PhNHMe, xylene, 155 °C Cl n -Pr N O 96% Ph N Me • 2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles 97

8. 1,3-Azoles - Metallation Direct Deprotonation N N n -BuLi, THF, − 78 °C N then ZnCl 2 N 1. N Br Pd(PPh 3 ) 4 Zn Cl 2. acid aq. N N N H S O 2 N Me 2 S O 2 N Me 2 90% • Direct deprotonation oxazoles, thiazoles and N -alkylimidazoles occurs preferentially at either the 2- or 5-position • Transmetallation of the lithiated intermediate is possible Metal-Halogen Exchange Br N N H Ph Ph 1. t -BuLi (2 equiv.) 2. Ph 2 CO O H N N H 64% • Metallation at the 4-position can be accomplished by metal-halogen exchange • In the case of imidazoles without substitution at the 1-position, two equivalents of base 98 are required

9. 1,2-Azoles - Bioactive 1,2-Azoles Me O N H N Me O C F 3 leflunomide C F 3 N N celecoxib S O 2 N H 2 • 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 • 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 99

10. 1,2-Azoles - Synthesis Synthesis of Pyrazoles/Isoxazoles from 1,3-Dicarbonyl Compounds and Hydrazines or Hydroxylamines (“3+2”) Me H 2 NNH 2 , Me O NaOH aq., rt Me O N H 2 H 2 N Me N Et O N H 75% O Et O Et O Et N H 2 H O H 2 NOH.HCl H 2 O, heat N O 84% • 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) • When a β-keto ester is used a pyrazolone/isoxazalone is formed 100

11. 1,2-Azoles - Synthesis Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to Alkynes or Enamines (“3+2”) Et Et O 2 C Et O 2 C EtCNO C N Me N Me N O H Et O 2 C Me N Et N O Et O 2 C Me Et N O 70% • Nitrile oxides react readily with alkenes and alkynes • Addition to an alkene generates an isoxazoline unless a leaving group is present Cl Ph Et 3 N, Et 2 O, rt N H O Ph PhCCH N Ph O Ph Ph N O 76% • 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 101

12. 1,2-Azoles - Electrophilic Substitution Nitration of Isoxazoles, Pyrazoles and Isothiazoles O 2 N c-HNO 3 , Ac 2 O, N AcOH, rt N N N H 70% c-H 2 SO 4 , 0 °C N O 2 N N H 80% • Pyrazoles and isothiazoles undergo straightforward nitration • 1-Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating reagent, acetyl nitrate • 1-Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at low temperature Me O 2 N Me f-H 2 SO 4 , N c-HNO 3 , N O → 70 °C O 40% • Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to undergo nitration at the 4-position 102

13. 1,2-Azoles - Electrophilic Substitution Halogenation of Isoxazoles, Pyrazoles and Isothiazoles H Br Br Br Br Br 2 , NaOAc N N N N H H Br N N H • Halogenation (iodination, bromination) of pyrazole leads to the 4-halopyrazole • 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 O Acylation Cl Me N N PhCOCl, AlCl 3 , 95 °C Me Ph Cl Me N N N Me Me O H Me 2 NCHO, POCl 3 , N 95 °C then H 2 O N N Me 33% • Only N -substituted pyrazoles can be C -acylated directly 103 • Vilsmeier formylation produces the 4-formylpyrazole in modest yield

14. 1,2-Azoles - Metallation Direct Metallation of Isoxazoles, Pyrazoles and Isothiazoles n -BuLi, MeI N N Ph Me N N S Ph Ph n -BuLi, THF, N − 78 °C then CO 2 H O 2 C Ph N S 88% • 1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position N H N CH 2 O, EtOH, heat N H 1. n -BuLi, THF, − 78 °C O N 2. PhNCO N 3. HCl aq. Ph N H N N N H 79% • It is possible to temporarily protect the 1-position of pyrazole and then perform sequential deprotonation and alkylation/acylation at the 5-position 104

15. 1,2-Azoles - Metallation Direct Metallation of 4-Bromopyrazoles Br n -BuLi, Et 2 O, N − 78 °C N S O 2 Ph Br Li CO 2 N N S O 2 Ph Br H O 2 C N N S O 2 Ph 65% • At low temperature, N -sulfonyl 4-bromopyrazoles can be lithiated at 5-position without undergoing metal-halogen exchange Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange H Br Li n -BuLi, THF, O N − 78 °C N N N H Li O H S S N N 39% H • Treatment of 4-bromopyrazole with two equivalents on n -butyllithium results in N -deprotonation and exchange of lithium for bromine • 2,5-Dilithiopyrazole reacts with carbon electrophiles to give the 4-substituted product 105

16. 1,2-Azoles - Side Chain Deprotonation Deprotonation of 5-methylisothiazole and 5-methylisoxazole Me 3-O 2 NC 6 H 4 CHO, N Ac 2 O, piperidine S 150 °C O 2 N N S 42% • 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 • Surprisingly, 3-methylisothiazole does not deprotonate as easily as 5-methylisothiazole and the same effect is found in isoxazoles Me Me n -BuLi, THF, N − 78 °C O Me Me CH 2 CHCH 2 Br N N O O Li 80% • Metal-halogen exchange can be used to avoid deprotonation of alkyl groups Me Me Br 2 N O Br Me Me N O 1. n -BuLi, THF, − 78 °C 2. CO 2 3. HCl aq. H O 2 C Me Me N O 106

17. 1,2-Azoles - Synthesis of a Drug Synthesis of Celecoxib (Celebrex®, Pfizer) C F 3 C F 3 N Me O N + Me N O Me N H 2 N H 2 S O 2 N H 2 F 3 C celecoxib S O 2 N H 2 N S O 2 N H 2 • A regioisomeric mixture is formed requiring separation and disposal of the side product Me C F 3 F 3 C O S O 2 Ph N H N Et 3 N, THF, EtOAc 5 → 10 °C S O 2 N H 2 N N N Me O S O 2 N H 2 C F 3 N N 72% S O 2 N H 2 107 • 1,3-Dipolar cycloaddition of a nitrile imine offers a regioselective alternative route

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