Chem 634 Fall 2013 Introduction to Protecting Groups Prof. Donald Watson " Assistant Professor" " " Protecting Groups Protecting groups are groups of atoms that are attached to (and later removed from) a functional group to mask it from competitive undesired reactions. Without Protection: R FG Chemistry to modify R R FG P Chemistry to modify R R' Y With Protection: R FG R' FG P R' FG Advantages: Allows reactions that otherwise would not be possible. Disadvantages: extra steps (at least 2 - protection and deprotection), lowered yield, low atom economy, added mass of PG on substrate. Considerations: protecting group and both protection / deprotection sequences must be compatible with all other desired steps and other functional groups. Protecting Groups Bible of protecting groups: Protective Groups in Organic Synthesis by Theodora Green & Peter Wuts Published by Wiley Make sure you have access to this book Note From Don This lecture has a lot of different reactions, most of the mechanism are very simple, or will be once we have covered a little more material in the class. For the sake of time, I have not included many mechanisms in this lecture. However, do not mistake this for me thinking that they are not important. You need to be able to draw out every mechanism for every reaction in this lecture. Not only will this help you understand the material more deeply, but by knowing what each reaction is doing, it will help you remember the reagents needed for it. ROH Protecting Groups Silyl Protecting Groups R O SiR3 Most Common: SiR3 Name Abbrevia.on SiMe3 trimethylsilyl "TMS" SiEt3 triethylsilyl "TES" SitBuMe2 tertbutyldimethylsilyl "TBDMS" or "TBS" Si(iPr)3 triisopropylsilyl "TIPS" SitBuPh2 tert-­‐butyldiphenylsilyl "TBDPS" ROH Protecting Groups Silyl Ether Formation R OH R'3SiCl R OSiR'3 imid or Et3N R OH R'3SiOTf 2,6-lutidine R OSiR'3 N imid = imidazole = HN Corey, JACS, 1972, 94, 6190 2,6-lutidine = Me N Me Corey, TL, 1981, 22, 3455 Note: Formation becomes harder as substitution of alcohol increases, and size of silyl group increases. For example, TMS ethers are difficult with form on 3° alcohols, others are nearly impossible. ROH Protecting Groups Stability of Silyl Ethers Basic: OH (5% NaOH/MeOH) T1/2: TMS < TES < TBS < TIPS < TBDPS ≤ 1 min 24 h Acidic: H (1% HCl/MeOH) T1/2: TMS < TES < TBS < TIPS < TBDPS <1 min <1 min ~1 h ~4 h R OSiR3' R OH (1°) • Note: This data is for silyl ethers of primary alcohols, gives relative stabilities. • Also note: TMS is not a protecting group for 1° alcohols. Too unstable! ROH Protecting Groups Deprotection of Silyl Ethers With Fluoride: Fluoride: F- (TBAF 0.06 M) R OSiR3' TBAF = Bu4NF R OH (1°) R OSiR3' F R OH2 + F SiR3' Driven by strength of Si-F bond – strongest σ bond known. T1/2: TMS < TES < TBS < TIPS < TBDPS 2.5 h 6.5 h Other F- Sources: Protic: TBAF (contains water), HF·Py, Et3N·HF, HF(aq), HOAc/CsF Aprotic: (anhydrous) TSAF= Ph3SiF2 S(NMe)3 TBAT= Bu4N Ph3SiF2 ROH Protecting Groups Esters: O O = RO CF3 (TFA) R' O Ph (Bz) why ? Formation: Deprotection: O O X R' base O RO Me Me (Piv) Me Me (Ac) Increasing Stability ROH O O NaOH R' RO R' O RO or H LiAlH4 R' ROH ROH ROH Protecting Groups Carbonates: O RO OR' Me CH3 R'= Me methyl carbonate Me tBu tert-butyl carbonate (Boc) allyl (alloc) 9-Fluorenyl methyl carbonate (Fmoc) Cl Cl benzyl (Cbz) Cl 2,2,2-trichloroethyl (Troc) OTMS (TEOC) ROH Protecting Groups Carbonate Formation: O R OH Cl or O O OR' O R'O O OR' base, (DMAP) RO OR' ROH Protecting Groups Carbonate Deprotection: O RO K2CO3/MeOH R OH OMe R O(Fmoc) R O(Troc) R O(Teoc) R O(alloc) R O(Cbz) R O(Boc) Et3N or Py Zn/AcOH F Pd0‚ Et2NH Pd/C, H2 H or Δ R OH R OH R OH R OH R OH R OH Carbonates (like many classes of protecting groups) have different conditions for deprotection depending on the exact carbonate involved. This is advantageous because many of the conditions are orthogonal, meaning you can remove one without effecting the others. You need to learn the conditions for removing all of these procecting groups. By the end of the course, you should be able to draw mechanisms for each. ROH Protecting Groups Acetals: RO OMe methoxy methyl ether (MOM) RO O Benzyoxy methyl ether (BOM) Me RO O β-Methoxyethoxymethyl ether (MEM) RO O TMS 2-trimethyl silyl ethoxy methyl ether (SEM) ROH Protecting Groups Acetals: Formation: R OH R'O Cl NaH, etc RO O R' Cleavage: HCl R OMOM R OBOM R OSEM or Lewis acid Na/NH3 or H2, Pd/C F R OH R OH R OH ROH Protecting Groups Cyclic Acetals: tetrahydropyran Formation: O R OH H+ RO H O tetrahydropyran "THP" Note! mixture of epimers Cleavage: dilute H R OTHP H2O R OH ROH Protecting Groups Ethers: RO RO allyl benzyl (Bn) RO OMe p-methoxyl benzyl "PMB" Formation: R OH R'X NaH, etc RO R' RO CPh3 trityl (Tr) ROH Protecting Groups Ethers: Cleavage: R O L4Pd0 HCO2Na R OBn R OPMB R OH or other reductant H2, Pd/C or Na/NH3 or DDQ (hard to do) DDQ R OH R OH O DDQ= 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone = (mild oxidant) NC Cl NC Cl O Protecting Groups for Diols All ROH protecting groups work, but 1,2- or 1,3- can be protected in unique ways. Acetals: O OH OH n=1 or 2 n R R' cat. H+ can also use: n O R O R' R=R'=Me "acetonide" What is the mechanism? MeO MeO OMe R or R R OMe Me Common: O Ph Me O O R R acetonide R O R benzylidine acetal O R O R p-methoxybenzyidine acetal ROH Protecting Groups Acetal Cleavage: Me Me O O H MeOH HO OH n n Ph O O Pd/C or Na/NH3 HO OH n n OMe DDQ HO OH n O O Protecting Groups for Carbonyls O R O R' R H Common: MeO OMe R O R' dimethyl acetal MeS SMe R R' R R' 1,3 dioxane S O O S O R R' 1,3 dioxalane S S Me Me R R' 1,3 dithiane 1,3 dithiolane Protecting Groups for Carbonyls Acetal Formation: MeOH O R MeO OMe or R' R n O O Me Me or R' n HO OH anhydrous HCl or Lewis acid TMSOMe O R MeO OMe cat TMSOTf R' R' R Acetal Cleavage: MeO OMe R R' TsOH, acetone or HCl, H2O O R R' Protecting Groups for Carbonyls Thioacetals: Formation : R'SH O R SR' SR' R R' or R n S S Me Me or n HS SH HCl or Lewis acid Cleavage: SR' SR' R R' O cond. R R' (Generally Oxidative) Difficult! Conditions: Hg(ClO4)2, CuCO3; NBS, AgNO3; CuCl2, CuO, Δ; H2O2, NaOH; DDQ, BF3 No not worry about these mechanisms. Thioacetals are robust protecting groups, but often very hard to remove. The oxidative conditions for removal often destroy complex molecules. Use only with proper planning and foresight. Note about Thioacetals SR' SR' R H useful nucleophile, synthetic equiv for SR' nBuLi R O SR' R mildy acidic Li SR' R1 X R2 SR' SR' SR' R2 R1 O R2 R1 Note: As carbonyls are normally electrophilic, this is known as an “umpolung” strategy (from German verb “umpolen” meaning “reversed polarity”). Protecting Groups for Amines RNH2, R2NH Carbamates (very common): O R2'N R'= Me, tBu, etc. OR' formation and removal same as for corresponding with carbonates Protecting Groups for Amines Alkyl Protecting Groups Formation: RNH2 P X , base or 1° and 2°: R2NH P= Bn, allyl, Tr RNHP or R2NP note: over alkylation is a probelm with primary amines O 1°: RNH2 H PG RHN NaBH4 prevents over alkylation OAc RR'NH Pd(0) RR'N Removal is the same as with the alkyl ether PG's. Protecting Groups for Amines Amides O R' N R Most common (others hard to remove) CF3 trifluoroacetomide Formation: O R' N R H F3C O O CF3 O R' Et3N N R 1° or 2 ° Removal: O R' N R NaOH CF3 R' N R H CF3 Protecting Groups for Amines Sulfonamides (Avoid where possible) O N S R O R' Me Tosyl- "Ts' Formation (easy): R' N H R TsCl py R' N Ts R Removal (typically very hard with destroying substrate): R' Li/NH3 or SmI3 N Ts R strong reducing conditions R' N H R Protecting Groups for Amides (not a lot of options) Alkyl Protecting Groups Formation: O Cl O R R NHR N R NaH or C2CO3 O BnBr or PMBCl O R NHR NaH or C2CO3 R N R R' R' = H or OMe Protecting Groups for Amides Removal of Alkyl Protecting Groups from Amides O R Pd (0) N R red. O R NHR usually best option O R N R H2, Pd/C O ΔΔ or tBuLi, O2 R NHR (Hard to remove from amides) O R N R CAN O R NHR OMe CAN = ceric ammonium nitrate = strong oxidant Protecting Groups for Amides Indirect Methods: formation Me Me Me O R removal NH2 O R Cl O TfOH N H tBu R NH2 NHR' O R MeO Cl OMe O R N R' O CAN R N H R' para-methoxyphenyl (PMP) Note: these protecting groups are hard to install from an existing amide