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Chapter 3. Functional Group Interconversion

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1 Chapter 3. Functional Group Interconversion
Advanced Org Chem-Carey B Fall 2002 Chapter 3. Functional Group Interconversion Conversion of alcohols to alkylating agents Alcohols to sulfonates: R-OH  R-O-SO2-R’ R-OH + ClSO2R’/O(SO2R’)2 + R”3N  R-OSO2R’ R’: Me (mesylate, Ms), p-MePh (tosylate, Ts), CF3 (triflate, Tf) RO-Li: more reactive;  216 middle no rearrangement or racemization with 1o & 2o alcohols reversible ionization possible with allylic/benzylic alcohols elimination with 3o alcohols to alkenes Carey B-Chap3-5ed Chapter 3

2 Conversion of Alcohols to Sulfonates
Advanced Org Chem-Carey B Fall 2002 Conversion of Alcohols to Sulfonates Carey B-Chap3-5ed Chapter 3

3 Conversion of Alcohols (I)
Advanced Org Chem-Carey B Fall 2002 Conversion of Alcohols (I) Alcohols to halides: R-OH  R-X simple 1o alcohols: R-OH + HBr/HCl-ZnCl2  R-Br/Cl SOCl2: inversion/retention,  217 middle; PCl3 ready transformation with Bt(z) [pKa 8.37]:  218 top PBr3: racemization & rearrangement;  top Ph3P+–X Y- for acid-labile compounds:  219 middle X=Br: inversion via R’3P+–OR;  219 bot &  220 top X=Cl: Y=Cl/CCl3/CCl2C(O)CCl3;  220 middle X=I/Br, imidazole & Y=I/Br: for R–I/Br Carey B-Chap3-5ed Chapter 3

4 Chlorination with SOCl2: Inversion/Retention
Advanced Org Chem-Carey B Fall 2002 Chlorination with SOCl2: Inversion/Retention inversion retention Carey B-Chap3-5ed Chapter 3

5 Halogenation with R3P+–X•Y-: Milder
Advanced Org Chem-Carey B Fall 2002 Halogenation with R3P+–X•Y-: Milder Carey B-Chap3-5ed Chapter 3

6 Halogenation with R3P+–X•Y-: Cl / I
Advanced Org Chem-Carey B Fall 2002 Halogenation with R3P+–X•Y-: Cl / I Carey B-Chap3-5ed Chapter 3

7 Chlorination of Alcohols: Xanthate Esters
Advanced Org Chem-Carey B Fall 2002 Chlorination of Alcohols: Xanthate Esters March’s Advanced Organic Chemistry (5th ed), p. 760 Carey B-Chap3-5ed Chapter 3

8 Conversion of Alcohols (II)
Advanced Org Chem-Carey B Fall 2002 Conversion of Alcohols (II) Alcohols to halides:  222 Scheme 3.1 Ph2PCl, imidazole & I2: reactive;  220 bottom Ph2P(O)H: removable with basic workup Mitsunobu reaction: mild conditions;  221 top activation of Ph3P with DEAD & iodination with MeI allylic alcohols: R–OH  R–OMs  R–X;  221 mid mild & basic conditions (SN2 type): no rearrangement oxazolium ions as activators: R–Cl;  221 bottom for R–Br/I: use of RN+Br-/I- Carey B-Chap3-5ed Chapter 3

9 Introduction of FGs at sp3-Carbons: SN2
Advanced Org Chem-Carey B Fall 2002 Introduction of FGs at sp3-Carbons: SN2 Reactivity of electrophiles (E+): R-L leaving groups (L); R’SO3  I > Br > Cl structure of R: O=C-C-L > PhCH2/allylic > 1o > 2o >> 3o Reactivity of nucleophiles (Nu): Nu-M solvents: polar aprotic solvents;  Chapter 1 additives: crown ethers as a catalyst:  225 top phase-transfer catalysts (PTC): R4N+(R4P+)X- PTC transfers Nu in aqueous solvent to E+ in organic solvent & enhanced reactivity of Nu due to poor solvation Carey B-Chap3-5ed Chapter 3

10 Nitriles & Azides:  235 Scheme 3.2 A & B
Advanced Org Chem-Carey B Fall 2002 Nitriles & Azides:  235 Scheme 3.2 A & B Nitriles: R-CN  -CO2R, -CHO, -CH2NH2 Na-/KCN: reactive in DMSO / with PTC:  226 top Azides: R-N=N+=N-  R-NH2, N-intermediates NaN3: usually in DMSO/DMF;  231 bottom top direct preparation from alcohols: R-OH  R-N3 2-fluoropyridinium salt & LiN3:  232 middle HN3/Ph2P(O)N3, Ph3P & DEAD:  232 middle Ph2P(O)N3/(p-NO2-Ph)2P(O)N3 & DBU:  232 bottom tetrametylguanidinium azide: soluble in CHCl3/CH2Cl2 Carey B-Chap3-5ed Chapter 3

11 Formation of C-O Bonds:  Scheme 3.2 D & E
Advanced Org Chem-Carey B Fall 2002 Formation of C-O Bonds:  Scheme 3.2 D & E Oxygen nucleophiles: HO-, RO- & RCO2- substitution vs elimination: alcohols/ethers;  227 top MeI & BnX as alkylating agents: no elimination AcO-: equivalent to HO- after hydrolysis esterification under non-acidic conditions use of CH2N2 or Ar-N=N-NHR’:  227 mid & section F SN2 reactions: RCO2M + R’-X in polar aprotic solvents reactivity of M: Cs > Rb > K > Na; section G inversion of alcohols: Mitsunobu reactions;  228 top sulfates & mixed phosphites:  228 bottom & 229 top Carey B-Chap3-5ed Chapter 3

12 Advanced Org Chem-Carey B
Fall 2002 Formation of C-N Bonds Nitrogen nucleophiles:  236 section C aryl/alkyl amines: multiple alkylation;  229 middle selective alkylation of amines Gabriel synthesis: phthalimide;  229 bot &  230 top amide alkylation:  230 middle (1st) O-alkylation: hard E+ (Me3O+BF4-);  230 mid (2nd) amides under Mitsunobu conditions:  230 bottom mild C-N bond formation:  231 reductive amination with carbonyls:  Carey B-Chap3-5ed Chapter 3

13 Nitrogen Nucleophiles (I)
Advanced Org Chem-Carey B Fall 2002 Nitrogen Nucleophiles (I) Carey B-Chap3-5ed Chapter 3

14 Advanced Org Chem-Carey B
Fall 2002 Formation of C-S Bonds Sulfur nucleophiles:  237 section J RS-: better Nu than RO-;  233 top R2S & thioamides: good Nu;  233 top alkylation of R2S=O:  233 middle Formation of C-P Bonds phosphorus nucleophiles:  237 section I R3P & R2P-: good Nu;  233 bottom Michaelis-Arbuzov reaction: mechanism Carey B-Chap3-5ed Chapter 3

15 Phosphorus Nucleophiles
Advanced Org Chem-Carey B Fall 2002 Phosphorus Nucleophiles Carey B-Chap3-5ed Chapter 3

16 Cleavage of C-O Bonds in Ethers & Esters
Advanced Org Chem-Carey B Fall 2002 Cleavage of C-O Bonds in Ethers & Esters Reagents for mild cleavage:  241 Scheme 3.3 Lewis acids: BX3;  239 top BX3 & Me2S: effective for cleaving aryl methyl ethers SN2 mechanism for Me, Bn; SN1 for tBu Me3SiI: more reactive;  239 middle in-situ generation of Me3SiI:  239 bottom H2SiI2: effective for cleaving 2o alkyls cleavage of esters:  240 middle Ac2O & Lewis acids (BF3, FeCl3, MgBr2):  240 mid Carey B-Chap3-5ed Chapter 3

17 C-O Bond Cleavage: BBr3 & Me3SiI
Advanced Org Chem-Carey B Fall 2002 C-O Bond Cleavage: BBr3 & Me3SiI Carey B-Chap3-5ed Chapter 3

18 Carboxylic Acid Derivatives (I)
Advanced Org Chem-Carey B Fall 2002 Carboxylic Acid Derivatives (I) Active acylating agents:  250 Scheme 3.4 acyl (acid) chlorides/bromides: R-C(O)-Cl/Br SOCl2 or PCl5:for acid-stable carboxylic acids (COCl)2 & Ph3P+Br:  243 middle &  244 top catalyzed by pyridine or DMAP:  244 middle acid anhydride & MgBr2, i-Pr2NEt: 3o/hindered R-OH ScTf3, Sc[TFSI]3, BiTf3, TMS-Tf:   246 R-C(O)-imid.: stable & produced with CDI;  247 top less N-C=O delocalization & activated by protonation Carey B-Chap3-5ed Chapter 3

19 Esters & Anhydrides with Acid Halides
Advanced Org Chem-Carey B Fall 2002 Esters & Anhydrides with Acid Halides Carey B-Chap3-5ed Chapter 3

20 Activation of Acid Chlorides/Anhydrides (I)
Advanced Org Chem-Carey B Fall 2002 Activation of Acid Chlorides/Anhydrides (I) Carey B-Chap3-5ed Chapter 3

21 Activation of Acid Chlorides/Anhydrides (IV)
Advanced Org Chem-Carey B Fall 2002 Activation of Acid Chlorides/Anhydrides (IV) Carey B-Chap3-5ed Chapter 3

22 Carboxylic Acid Derivatives (II)
Advanced Org Chem-Carey B Fall 2002 Carboxylic Acid Derivatives (II) In situ activation of HO-C(O)-R:  250 Scheme 3.4 DCC activation: catalyzed by DMAP;  247 middle 2-Chloropyridinium ion:  248 top (cf.  232 middle) 2,2’-dipyridyl disulfide: reactive thioesters;  248 middle useful for macrolactonization:  248 bottom &  249 top Yamaguchi method: 2,4,6-trichloro-PhCOCl;  249 middle Acid-catalyzed activation:  253 Scheme 3.5 Fischer esterification: RCO2H+R’OH RCO2R’+H2O equilibrium-controlled: excess R’OH, removal of H2O Carey B-Chap3-5ed Chapter 3

23 Activation of Carboxylic Acid (I)
Advanced Org Chem-Carey B Fall 2002 Activation of Carboxylic Acid (I) Carey B-Chap3-5ed Chapter 3

24 Advanced Org Chem-Carey B
Fall 2002 Preparation of Amides Amides: RCO-Y + R’R”NH  RCONR’R” + HY acyl halides (Y=Cl/Br): amines or NaOH (Schotten-Bauman process,  252 bottom);  257 Scheme 3.6 active esters: Y = O-succinimide ( 253), O-Ph-p-NO2 in situ activation: DCC & HOBt ( 254 bottom), (PhO)2P(O)N3 ( 255 top), BOP-Cl ( 255 middle) activation of esters with Lewis acids:  255 bottom from nitriles: acidic/basic conditions;  256 middle Carey B-Chap3-5ed Chapter 3

25 In Situ Synthesis of Amides from Acids (I)
Advanced Org Chem-Carey B Fall 2002 In Situ Synthesis of Amides from Acids (I) Carey B-Chap3-5ed Chapter 3

26 In Situ Synthesis of Amides from Acids (II)
Advanced Org Chem-Carey B Fall 2002 In Situ Synthesis of Amides from Acids (II) BOP-Cl [N,N’-bis(2-oxo-3-oxazolidinyl)- phosphinic chloride] BOP [benzotriazol-1-yloxytris(dimethylamino)- phosphonium hexafluorophosphate] (S.-Y. Han Tetrahedron 2004, 60, ) Carey B-Chap3-5ed Chapter 3

27 Advanced Org Chem-Carey B
Fall 2002 Amides from Nitriles Carey B-Chap3-5ed Chapter 3

28 Protecting Groups & Deprotection
Advanced Org Chem-Carey B Fall 2002 Protecting Groups & Deprotection strategy of using protecting groups Carey B-Chap3-5ed Chapter 3

29 Requirements for Ideal Protecting Groups
Advanced Org Chem-Carey B Fall 2002 Requirements for Ideal Protecting Groups Quantitative protection under mild conditions Stable under the reaction conditions Quantitative deprotection under mild conditions Orthogonal protection: inert to deprotection conditions of other protecting groups references: (1) P. G. M. Wuts & T. W. Greene, ‘Greene’s Protective Groups in Organic Synthesis’ 4th ed., Wiley, (2) P. J. Kocienski, ‘Protecting Groups’, Thieme, 3rd ed Carey B-Chap3-5ed Chapter 3

30 Alcohols (I): R-OH R-O-P
Advanced Org Chem-Carey B Fall 2002 Alcohols (I): R-OH R-O-P Acetals: R-O-C-O-R’; stable to bases, oxidants THP: mild acidic hydrolysis, new chiral center;  259 mid EE & MOP (x 20): faster deprotection;  260 top MOM: rather stable, ready protection;  260 middle MEM: cleaved with Lewis acids; orthogonality,  260 bot MTM: quite stable with H+, removed with Hg2+, Ag+ & MeI in moist acetone;  261 top ROCH2OCH2CCl3: labile with Zn, SmI2, Na(Hg);  261 mid SEM: deprotected with F-, MgBr2;  261 bottom Carey B-Chap3-5ed Chapter 3

31 Hydroxy-Protecting Groups (I): THP
Advanced Org Chem-Carey B Fall 2002 Hydroxy-Protecting Groups (I): THP DHP (dihydropyran) Carey B-Chap3-5ed Chapter 3

32 Hydroxy-Protecting Groups (II): EE & MOP
Advanced Org Chem-Carey B Fall 2002 Hydroxy-Protecting Groups (II): EE & MOP EE (ethoxyethyl) MOP (methoxypropyl) Carey B-Chap3-5ed Chapter 3

33 Hydroxy-Protecting Groups (III): MOM & MEM
Advanced Org Chem-Carey B Fall 2002 Hydroxy-Protecting Groups (III): MOM & MEM (methoxymethyl) (methoxyethoxymethyl) Carey B-Chap3-5ed Chapter 3

34 Hydroxy-Protection (IV): Cl3CH2OCH2-OR
Advanced Org Chem-Carey B Fall 2002 Hydroxy-Protection (IV): Cl3CH2OCH2-OR Carey B-Chap3-5ed Chapter 3

35 Alcohols (II): R-OH R-O-P
Advanced Org Chem-Carey B Fall 2002 Alcohols (II): R-OH R-O-P Ethers: R-O-R’; stable to bases, oxidants R (alkyl): very stable but hard to remove Me, allyl, benzyl (Bn), p-methoxybenzyl (PMB) t-Bu: TFA, acidic hydrolysis;  262 middle Tr: faster deprotection than t-Bu; < MMTr < DMTr < TMT SiR3: versatile & orthogonal protection;  264 – 265 Esters: R-O-C(O)-R’;  265 – 266 Common OH protecting groups:  267 Table 3.2 Carey B-Chap3-5ed Chapter 3

36 Protection of Alcohols (R-OH) (I)
Advanced Org Chem-Carey B Fall 2002 Protection of Alcohols (R-OH) (I) ether formation: R-O-R’ stable under neutral/basic conditions & to oxidations 1. RO-CH3 / RO-CH2CH3: alkyl ethers 2. RO-CH2CH=CH2: allyl ethers Carey B-Chap3-5ed Chapter 3

37 Protection of Alcohols (R-OH) (II)
Advanced Org Chem-Carey B Fall 2002 Protection of Alcohols (R-OH) (II) ether formation: R-O-R’ 3. RO-CH2Ph (Bn): benzyl ethers; RO-CH2Ph-p-OMe (PMB) Carey B-Chap3-5ed Chapter 3

38 Protection of Alcohols (R-OH) (III)
Advanced Org Chem-Carey B Fall 2002 Protection of Alcohols (R-OH) (III) ether formation: R-O-R’ 4. RO-CPh3 (Tr): trityl ethers, selective for 1o alcohols 5. RO-CMe3 (RO-tBu): tert-butyl ethers, stable & bulky Carey B-Chap3-5ed Chapter 3

39 Protection of Alcohols (R-OH) (IV)
Advanced Org Chem-Carey B Fall 2002 Protection of Alcohols (R-OH) (IV) ether formation: R-O-R’; 6. RO-SiR’3 (RO-TMS): trimethylsilyl ether TMS: unstable in acid, TBDMS: rather stable, TBDPS & TPS: bulky & very stable, TIPS: bulky & stable, SEM: orthogonal deprotection Carey B-Chap3-5ed Chapter 3

40 Protection of Alcohols (R-OH) (V)
Advanced Org Chem-Carey B Fall 2002 Protection of Alcohols (R-OH) (V) ester formation: R-O-CO-R’;  265 stable under mild acidic conditions & to oxidations Carey B-Chap3-5ed Chapter 3

41 Protection of 1,2- / 1,3-Diols
Advanced Org Chem-Carey B Fall 2002 Protection of 1,2- / 1,3-Diols acetals: stable under basic conditions;  266 reagents: ArCHO / ketones or PhCH(OMe)2 / Me2C(OMe)2 carbonates: stable under mild acidic conditions; R=R’=O reagents: COCl2, (RO)2C=O, (Cl3CO)2C=O, CDI Carey B-Chap3-5ed Chapter 3

42 Protection of Aldehydes & Ketones (I)
Advanced Org Chem-Carey B Fall 2002 Protection of Aldehydes & Ketones (I) acetals / thioacetals:  273 – 275 Y = W = O; stable to bases, deprotection with acids (TMSOCH2)2 & cat. TMS-triflate: under neutral conditions by Noyori Y = W = S; stable to acids & bases, deprotection with HgO, F3B•OEt2 Y =O, W = S; intermediate between acetals & thioacetals Carey B-Chap3-5ed Chapter 3

43 Protection of Aldehydes & Ketones (II)
Advanced Org Chem-Carey B Fall 2002 Protection of Aldehydes & Ketones (II) Carey B-Chap3-5ed Chapter 3

44 Deprotection of Aldehydes & Ketones (III)
Advanced Org Chem-Carey B Fall 2002 Deprotection of Aldehydes & Ketones (III) Carey B-Chap3-5ed Chapter 3

45 Protection of Amines (I)
Advanced Org Chem-Carey B Fall 2002 Protection of Amines (I) alkylamines: similar to alcohols (Bn, SEM, allyl);  269 Carey B-Chap3-5ed Chapter 3

46 Protection of Amines (II)
Advanced Org Chem-Carey B Fall 2002 Protection of Amines (II) amides/imides: rather stable;  270 – 271 less basic/nucleophilic N & more acidic H Carey B-Chap3-5ed Chapter 3

47 Protection of Amines (III)
Advanced Org Chem-Carey B Fall 2002 Protection of Amines (III) Imides: Gabriel synthesis;  270 less basic/nucleophilic N (more acidic H) Carey B-Chap3-5ed Chapter 3

48 Protection of Amines (IV)
Advanced Org Chem-Carey B Fall 2002 Protection of Amines (IV) disilylimides/sulfonamides:  271 less basic/nucleophilic N (more acidic H) Carey B-Chap3-5ed Chapter 3

49 Protection of Amines (V)
Advanced Org Chem-Carey B Fall 2002 Protection of Amines (V) Carbamates:  272 Table 3.2 R-NH-Troc R-NH-Boc R-NH-Fmoc R-NH-Teoc Carey B-Chap3-5ed Chapter 3

50 Protection of Carboxylic Acids (RCO2H) (I)
Advanced Org Chem-Carey B Fall 2002 Protection of Carboxylic Acids (RCO2H) (I) ester formation: RC(O)-O-R’; similar to alcohols esterification with alcohols, CH2N2, or SN2 reaction orthoester formation: RC(OR’)3, acid labile;  276 Carey B-Chap3-5ed Chapter 3

51 Protection of Carboxylic Acids (RCO2H) (II)
Advanced Org Chem-Carey B Fall 2002 Protection of Carboxylic Acids (RCO2H) (II) dithioorthoester formation:  276 oxazoline formation:  275 Carey B-Chap3-5ed Chapter 3

52 Deprotection of Carboxylic Esters
Advanced Org Chem-Carey B Fall 2002 Deprotection of Carboxylic Esters Carey B-Chap3-5ed Chapter 3


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