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Organic Chemistry-III CH-423 Krishna P. Kaliappan Department of Chemistry Indian Institute of Technology-Bombay Mumbai 400 076 INDIA http://www.chem.iitb.ac.in/~kpk [email protected] 9/3/14 Syllabus CH-423 (2013)/Chem/IIT-B Dr. Kaliappan, Krishna P. Organic Chemistry III Classification of reactions: A brief introduction to substitution, elimination, addition, oxidation, reduction, rearrangement and pericyclic reactions. Functional group transformations: alcohols to alkylating agents, Mitsunobu and related reactions, introduction of functional groups by nucleophilic substitution at saturated carbon, nucleophilic cleavage of C-O bonds in ethers and esters and inter-conversion of carboxylic acid derivatives. Oxidation: Metal based oxidizing reagents: A review and detailed discussion of chromium, manganese, ruthenium, silver and other metalbased reagents. Non-metal based oxidizing reagents: DMSO, peroxide, peracid and oxygen based oxidation. Miscellaneous oxidizing reagents like IBX, DMP, CAN, DDQ, periodate etc. CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Syllabus CH-423 (2013)/Chem/IIT-B Organic Chemistry III Dr. Kaliappan, Krishna P. Reduction: Homogeneous and heterogeneous hydrogenations; Discussion on borane based racemic and chiral reagents, aluminum, tin, silicon based reducing agents. Dissolving metal reductions. Selectivity and protecting groups: Illustration of chemoselectivity, regioselectivity and stereoselectivity with examples; protecting groups for alcohols, amines, acids, ketones and aldehydes. Cycloaddition reactions: Diels-Alder reaction; general features, dienes, dienophiles, selectivity, intramolecular and intermolecular reactions, hetero-Diels Alder reaction. 1,3-dipolar cycloaddition reactions; general features, dipoles, dipolarophiles. [2+2] cycloaddition reactions; general features, selected examples. Molecular rearrangements: Illustration of electron deficient and electron rich skeletal rearrangements with examples; Sigmatropic rearrangements-Claisen and related rearrangements, Cope and oxy-Cope rearrangements; 2,3-sigmatropic rearrangements and ene reaction. CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Syllabus Suggested Books/Reviews: Jerry March, “Advanced Organic Chemistry”, Fifth Ed., Wiley, 2007. F. A. Carey and R. J. Sundburg, “Advanced Organic Chemistry, Part B”, Fifth Ed., Springer, 2007. J. Clayden, N. Greeves, S. Warren and P. Wothers, “Organic Chemistry”, First Ed., Oxford University Press, 2001. W. Carruthers, I. Coldham , “Modern Methods of Organic Synthesis”, Cambridge University Press K. Peter C. Vollhardt and Neil E. Schore “Organic Chemistry” W. H. Freeman and Company, 1999. Evaluation Pattern Mid-Semester 30% End Semester + Assignment 50% Quiz (2) 20% -There will be a total of 36 (1h) lectures, and 7 tutorials CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups Only With Carbon and Hydrogen C C C C With Heteroatoms With One Oxygen Atom: 1. Alcohol: R OH Primary alcohol R OH R secondary alcohol R R R OH tertiary alcohol 2. Ether: O O Diethyl ether anisole O diphenyl ether CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With One Oxygen Atom: 3. Ketone: O O Acetone Acetophenone 4. Aldehyde: O O H Acetaldehyde H Benzaldehyde 5. Epoxide, Cyclic Ethers: O Epoxide 9/3/14 O Oxetane CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 6 Functional Groups With Heteroatoms With Two Oxygen Atoms: 1. Acid: O O OH OH Acetic acid 2. Ketal: OR' R Benzoic acid OR' R 3. Acetal: OR' OR' R 4. Ester: H O O OEt Ethyl acetate O Ethyl benzoate CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With heteroatoms With Two Oxygen Atoms: 5. Lactones (Cyclic Esters): O O O O γ-lactone δ-lactone 6. Peroxides: R O O R With Three Oxygen Atoms: 1. Anhydrides: O O O Acetic anhydride CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With Heteroatoms With Three Oxygen Atoms: 2. Hydroxy acids: O O O OH OH OH β-hydroxy acid OH α-hydroxy acid OH OH γ-hydroxy acid 3. Peracids: O Cl O OH meta-chloro perbenzoic acid CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With Heteroatoms With One Nitrogen Atom 1) Amines: NH2 H3C Methyl amine (primary amine) H N CH3 H3C Dimethyl amine (secondary amine) N Triethyl amine (tertiary amine) 2) Aromatic Amines: NH2 Aniline 3) Nitriles: CN H3C Acetonitrile CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With Heteroatoms With One Nitrogen Atom 4) Aziridines: H N aziridine 5) Aromatic Amines: N H Pyrrole N Pyridine 6) Imines: N R H H Primary aldimine N R R H Secondary aldimine N R H N R R Primary Ketimine R R Secondary Ketimine CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Groups With Heteroatoms With Two Nitrogen Atoms With Three Nitrogen Atoms 1) Diazo: 1) Azides: H2C N2 R Diazomethane N N N 2) Triazole: 2) Azo: R N N R 3) Diazonium: N N Benzenediazonium cation H N H N N N N N 1,2,4-triazole 1,2,3-triazole With Four Nitrogen atoms 1) Tetrazole: H N N N N 1-triatrazole CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group With Heteroatoms With One Nitrogen Atom and One Oxygen Atom 1) Amides: 3) Oximes: O R N NH2 R NH β−lactam N R H aldoxime 2) Lactams: O OH O NH N O γ−lactam 5) Nitrile Oxides: R R ketoxime 4) Nitroso: R OH N O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group With Heteroatoms With One Nitrogen Atom and Two Oxygen Atoms 1) Nitro: R 2) Nitrones: R NO2 R N O With Two Nitrogen Atom and One Oxygen Atom 1) Urea: O H2N NH2 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group With Heteroatoms (Sulfur) 1) Thiols: SH Thiophenol 2) Thio Ethers: R S SH Ethanethiol 4) Thiirane: S R 3) Thio carbonyl: 5) Heterocycles: S R R S Thiophene CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Functional Group With Heteroatoms (Halogens) 1) Halides: I H3C Br Ethyl bromide Methyl iodide 4) Acid Chloride: O 2) Halohydrin: Cl Acetyl chloride I R R HO OH Cl 5) Halolactones: 3) Dihalides: Cl O Cl 1,2-dichloroethane CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O I Functional Group Transformations Organic Synthesis and Music: What is Common Between Them? Reactions Can be Classified into Seven Types Oxida'on Pericyclic Elimina'on CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 17 Functional Group Transformations 1. Addition Reaction: a. Nucleophilic Addition O R O R' E R' R Nu Nu OE R Nu R' Reaction is categorized by first step and not by second step b. Electrophilic Addition Br Br Br2 Br Br X . c. Radical Addition X . Y . X Y CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 18 Functional Group Transformations 2. Elimination Reactions E1, E2, E1CB, syn, anti, pyrolytic Syn Elimination: OAc OAc H AcOH AcOH Syn elimination O H OH O O NaH CS2, MeI H SMe S O + HS COS + MeSH SMe Xanthate ester OH H Side reactions like Wagner-Meerwein rearrangement can take place CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 19 Functional Group Transformations 3. Substitution Reactions a. Aromatic Substitution b. Aliphatic Substitution 1. Nucleophilic Substitution NO2 OR NO2 OR F 2. Addition- Elimination Br 1. Nucleophilic Substitution SN1, SN2, SNi 2. Electrophilic E1, E2, E1CB, syn, anti, pyrolytic CN CN NaNH2 via Benzyne CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 20 Functional Group Transformations Esters Ways to make esters RCO2H + R'OH RCO2H + R'OH O R O R O H+ Base RCO2R' RCO2R' O R'OH Base R OR' Base must be non nucleophilic HO AcO Ac2O O N HO Morphine (Acute pain killer) H+ O N AcO Heroin CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 21 Functional Group Transformations Ways to Make Esters O R O CH2N2 R OH O R OMe O O H H2C N2 R O H3C N2 If compound containing nitrogen having more nitrogen content (more than 50%), then compound may be explosive (CH2N2 is explosive) OH OMe CH2N2 R OH CH2N2 OH OH CH2N2 R OMe OH OMe Proton must be acidic enough to pick by CH2N2 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 22 Functional Group Transformations Ways to Make Esters RCO2H RCO2H + + R'-I R'OH base RCO2R' DCC RCO2R' N C N N,N'-Dicyclohexylcarbodiimide (DCC) N C N H R H N C N RCO2R' O + R O O H O R' O O N H N H Dicyclohexyl urea Sometimes its difficult to separate product from DCU, in that case, use EDCI instead of DCC CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 23 Functional Group Transformations Ways to Make Esters Baeyer-Villiger Oxidation Favorskii Rearrangement O O NaOEt/EtOH O mCPBA CO2Et Br O Mitsunobu Reaction RCO2H Ph3P EtO2C N N CO2Et + DEAD, PPh3 R'OH RCO2R' R Ph3P EtO2C N N CO2Et H Ph3P N N H EtO2C O O H O R CO2Et + RCO2 R O PPh3 CO2Et H O PPh3 + N N H EtO2C O + RCO2R' R O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 24 Functional Group Transformations Mitsunobu Reaction iPr, R= DIAD N N Diisopropyl azodicarboxylate RO2C OH R R1 CO2R O R2CO 2H PPh3, DIAD R PPh3 DEAD OH R2 O R = Et, DEAD Diethyl azodicarboxylate R R1 R R1 OH R1 O OPh O ? O O O OBn O OBn H+, H2O O PPh3, DEAD BnO HO HO O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 25 Functional Group Transformations Mitsunobu Reaction Nitrogen Nucleophile: H3C OH OBn N Ts OBn PPh3, DEAD TsNHCH3 OH O O PPh3 HN DEAD N Weak Nitrogen Nucleophile: O BnO BnO OH OBn N N R PPh3, DEAD R O BnO BnO N OBn N H Intramolecular Mitsunobu Reaction: HO Ph HN CO2Et CO2Et PPh3 DEAD Ph N CO2Et CO2Et CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 26 Functional Group Transformations Mitsunobu Reaction Azides: HN3 ROH + PPh3 + DEAD O (PhO)2P N3 RN3 H H RO PPh3 + EtO2C N N CO2Et Can be used instead of HN3 O PhO P OPh O ROH + (PhO)2P N3 + PPh3 + DEAD RN3 + Ph3PO EtO2C N N CO2Et H O (PhO)2P N3 EtO2C N N CO2Et PPh3 O O PhO P OPh PhO P OPh EtO2C N N CO2Et R O PPh3 + EtO2C N N CO2Et H PPh3 R OH N N N R N3 + PhP O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 27 Functional Group Transformations Alcohols Reduction: RCHO RCO2R RCO2H NaBH4 LiAlH4 LiAlH4 BH3 NaOH, H2O2 R HCHO Primary alcohols RMgX OH R RCH2OH CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 28 Functional Group Transformations Alcohols O reduction R' R RMgX RCHO Secondary Alcohols Oxymercuration R RMgX HCO2R symmetrical 2o alcohol formate ester O R RMgX R' Oxymercuration R RCO2R Tertiary Alcohols RMgX CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 29 Functional Group Transformations Activation of Hydroxyl Group Alcohols are important class of compounds but they are not good leaving group −OH is not a reactive alkylating agent. Reactivity can be enhanced by converting into a better leaving group like sulfonate esters or halides Preparation of Sulfonate Esters: ROH ROH ROH ROH ROH R OTs Pyridine, Mscl Pyridine, Tscl Pyridine, Brcl Pyridine, Nscl Pyridine, Tf2O NaBr Acetone R OMs Mesylate R OTs Tosylate R OBs Brosylate R ONs Nosylate R OTf Triflate R Br Most reactive Finkelstein reaction CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 30 Functional Group Transformations Activation of Hydroxyl Group Alkyl halides are involved in the formation of C−C bond by nucleophilic substitution Preparation of Alkyl Halides: Reaction with SOCl2 O O R O H Cl S R Cl O S Cl Cl R Cl + SO2 + Cl Inversion of configuration But, if reaction is taking place in solvent like 1,4-dioxane O R O O S Cl O O R Cl R Cl Retention of configuration O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 31 Functional Group Transformations Activation of Hydroxyl Group Reaction with Phosphorous Halides R Cl O H Cl P RO - HCl Cl P Cl 2ROH RO P OR OR Cl The reaction will stop at this stage if it is carried out in presence of an amine When amine is not present RO P OR OR R O H+ P R Cl + H OR Cl O O O O OR H P OH + 2RCl H P OR OR Inversion of configuration ? OH O O OH Br Drawbacks: Not suitable for acid sensitive compounds Amines can not be used CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 32 Functional Group Transformations Activation of Hydroxyl Group Reaction with Alkoxyphosphonium Salts Br Ph3P Br + Ph3P Br Br - HBr R O PPh3 R Br O PPh3 Br R O H Formation of strong phosphoryl double bond is the driving force Ph3P Br2 Br HO Br R OH + PPh3 + Br Br O R Br Br Bromide source CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 33 Functional Group Transformations Activation of Hydroxyl Group PPh3/ CCl4 Cl Ph3P Cl CCl3 + C Cl Ph3P Cl Cl Cl R O PPh3 R O H CCl3 R Cl Hexachloroacetone can be used as chloride source PPh3 R OH R Cl O Cl3C C CCl3 PPh3/ I2/ Imidazole N PPh3 Ph3P I N H I I2 Ph3P R R OH I -HI Imidazole HO R R O I PPh3 I CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan R I 34 Functional Group Transformations Activation of Hydroxyl Group Reaction with 2-Halo-3-alkylbenzoxazolium Cation Cl Addition N Cl HO R N O O Elimination O R N R Cl O O Mitsunobu Reaction R Ph3P CO2Et Ph3P Me I H I R I H CO2Et N N Me EtO2C N N EtO2C O R O PPh3 + I CO2Et N N Me EtO2C CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 35 Functional Group Transformations Activation of Hydroxyl Group Mild Method OH MsCl OMs Cl LiCl MsOLi Py Some Other Methods HBr HBr Br O O Br HBr Br O O Br Br HO H Br Br HBr Br H2O Br Br CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 36 Functional Group Transformations Nitriles RCONH2 De RCH2NH2 hy dra t H -C LA Pd / 2 + H O H3 ion N R OH Abnormal Beckmann Rearrangement RCO2H R'MgBr R CN DIB A AL -H y lk RCHO n io t la RX + NaCN RCOR' R' R' CN CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 37 Functional Group Transformations Preparation of Nitriles R X NaCN O R CN Reaction proceed faster in polar aprotic solvents N NH2 R CN OH p-TsCl, Py R H aldoxime HO R P2O5 R CN AcCl, Py H2O N Beckmann rearrangenment can also occur N N H+ H2O H N O NC H+ N OH -H+ N OH2 N tertiary carbocation CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 38 Functional Group Transformations Preparation of Nitriles 18-Crown-6 RCH2CN RCH2Br + KCN R CHO CH3CN 83oC OH KCN H+ R CN stable under mild acidic condition unstable under basic condition OH- R CHO + CN- OTMS TMSCN R CHO ZnBr2 R CN CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 39 Functional Group Transformations Utility of Nitriles R CN LAH or H/Pd-C R CH2 NH2 partial hydrolysis R CN O R R CN H3O+ Reflux NH2 R CO2H O SnCl2/HCl R CN DIBAL-H R H Stephen reaction R R CN CN R'MgBr H+/H2O O R' LDA R'I R' R R CN CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 40 Functional Group Transformations Azides 3, DM RNH2 SO Pd -C NaN 3, PTC H R'CH2Br N 2/ Na R'CH2Br PPh3, H2O R N3 r la n po tio Di di 3- d 1, loa c cy F N AD DE h 3, HN 3 N3 PP ROH RNH2 R N N N ROH O ROH N3 P(OPh)2 DBU CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 41 Functional Group Transformations Preparation of Azides R X NaN3, DMF R N3 At room temperature & phase transfer condition: NaN3 RCH2N3 RCH2Br TBAB 25oC From alcohols: RN3 + N Me F N HO R O R Me N N3 O Me Mitsunobu Reaction R OH R OH PPh3, DEAD HN3 O (PhO)2 P N3 DBU R N3 N DBU N R N3 1,8-Diazabicycloundec-7-ene CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 42 Functional Group Transformations Utility of Azides H2/Pd-C R N3 R N3 PPh3, H2O R NH2 R NH2 N2 Ph3P O Staudinger Reaction R N N N R N N N -N2 R N PPh3 H2O R NH2 PPh3 PPh3 R N PPh3 N R N N N PPh3 R N N N PPh3 R R NH2 H2O R N PPh3 N N PPh3 R N PPh3 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 43 Functional Group Transformations Amines Preparation of Amines With same number of carbon atom RCH2NH2 RCN N R RNH2 RN3 RNH2 RNO2 R N OH R NH2 O OH NH2 R R' R R' N R' N R R' R" R" Gabriel amine synthesis N O O O O K + R X N R NH2NH2 O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan NH NH + RNH2 O 44 Functional Group Transformations Preparation of Amines With One Carbon Atom More R X R X R CHO + R CN CN CH3NO2 R CH2NO2 Base CH3NO2 Base R NO2 reduction reduction reduction R CH2NH2 R CH2NH2 R NH2 With One Carbon Atom Less O O R NH2 R NH2 R Hoffmann Rearrangement N3 O R NH2 R Curtius Rearrangement R NH2 Lossen Rearrangement O R N OH H OH R NH2 Schmidt Rearrangement CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 45 Functional Group Transformations Reduction: R NO2 R CN R N3 N R Preparation of Amines R NH2 H2/ Pd-C LAH Zn/ HCl RH2C NH2 H2/ Pd-C BH3 NaBH4 LAH Li/ NH3 R NH2 H2/ Pd-C B 2H 6 NaBH4 PPh3, H2O OH R' H2/ Pd-C LAH Raney Ni NH2 R R' R N Can be achieved by using either one of the reagents O R N R" R' R" R' H2/ Pd-C B 2H 6 LAH CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 46 Functional Group Transformations How to Get Secondary and Tertiary Amine ? reduction R NC R O R''NH2 O R'' R N Schiff base O R' R NaBH4 R N H R' R' R R' R N Schiff base R'NH2 Reaction is not facile R NH CH3 N H R' Secondary amine R' NaBH4 R N H R'' R'' R N R' R'' NaCNBH3 R N R'' R' CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan One pot 47 Functional Group Transformations Synthetic Utility of Amines R NH2 Ar NaNO2 HCl R N2 Ar X X= Br, CN, I N2 CN CN R NH2 Sandmeyer reaction R N CN R NH2 R'CHO R' RN CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 48 Functional Group Transformations Amides Preparation of Amides Reaction of an Activated Acid or Acid Derivative with Amine: O R OH + R' O DCC NH2 O R R + R' HN O N3 NH2 R' N R Me R N H O OMe Me Weinreb amide O P(OPh)2 R OMe O O R + Cl R' O Cl O N H R O O O P(OPh)2 R O R'NH2 N3 R NHR' N3 CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 49 Functional Group Transformations Preparation of Amides Schimdt type Rearrangement: O R O HN3 R' R NHR' Reaction with N-hydroxysuccinimide: O R O O O O O O N HO N OH R R O R' NH2 HO N NHR' O O 1-Hydroxybenzotriazole: Boc H N O COOH H2N CO2Me Ph NH DCC N N HN Boc N OH CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan CO2Me Ph 50 Functional Group Transformations Preparation of Amides Alkaline Hydroperoxide: R CN H O O O H2O2, NaOH R NH2 O R O OH H NH R C N H O O O O O H2O2 H R NH2 O2 + H2O H O O O CH2N2 Bayer-Villiger Oxidation HN3 NH or Beckmann rearrangement O O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 51 Functional Group Transformations Preparation of Amides O H H N N N O O H N N2 NH -N2 HN3 N3 O Beckmann Rearrangement: N R OH O PCl5 R' R' NHR Interconversion of Carboxylic Acid Derivatives RCOOR RCONH2 RCOOH RCOCl Synthetic Utilities of Amides O O N R PPh3, DEAD O NH NaH, MeI N Me ROH CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 52 Functional Group Transformations Synthetic Utilities of Amides O Al OMe DIBAL-H N Me R R O R O R H O Me N Me O OMe N Me R'MgBr R' MgBr N O Me O H2O R O H+, H2O O N HN O OH HN R' R O Br H O PPh3, DEAD CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan N 53 Functional Group Transformations Ethers Preparation: H+ R OH Ar OH CH2N2 OH R OR R OH Ar OMe Ar OH OH NaH, R'I NaOH Me2SO4 R OR' Ar OMe O PPh3, DEAD Basic condition R OH COCH3 OH HO NaH BnBr R OBn COCH3 MeI K2CO3 OH MeO CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 54 Functional Group Transformations Preparation of Ethers Acidic Condition NH R OH Cl3C CN Cl3C OBn R OBn CSA NH BnOH, DBU Cl3C OBn O SO3H Camphor sulphonic acid CSA NH2 Cl3C Bn NH2 O Cl3C O NH2 + R OBn Cl3C O Bn trichloro acetamide R CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O H 55 Functional Group Transformations Cleavage of C-O Bonds in Ethers & Esters Nu R O CH3 O Nu R C O CH3 R O R BBr3 R OH H3C Nu R O O H3C Nu R C O R Br B(OH)3 2 HBr Mechanism in next slide R O R TMS-I I R O R R O SiMe3 O R C O R' TMS-I O I SiMe3 SiMe3 R C O R' R I O R C O SiMe3 R' I H2O O R C OH CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 56 Functional Group Transformations Synthetic Utility of Ethers R OR HX O ROH Me + RX mix of products OH HBr CH3Br + H O Me Br Br O Me BBr3 Br B O Br BBr2 O Me OH Me MeBr Br O Me TMSI OH TMSCl, NaI CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 57 Functional Group Transformations Interconversion of Carboxylic Acid Derivatives O R C O CH3 O SOCl2 R C OH O R C Cl O OH R'2NH H3C OH R C O O SO2 R C Cl HCl O HCl R C NR'2 O O Cl C C Cl O R C OH O O R - Cl O C C O Cl Cl O R C Cl CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 58 Functional Group Transformations Iodolactonization: O Epoxylactonization: O O KI3 HO HO O O NaHCO3 I CH2CO2H I2 I NaH HO O NaHCO3 O PhSe N O O OH Selenoetherification: HO O OH O O Mild base Selenolactonization: O O HO SePh O PhSeCl O Base O CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan SePh 59 Functional Group Transformations I OH CO2H O O O HO O O CO2Me CO2Me OMe MeO NaOMe I O O O O MeO CO2Me OH OMe CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 60