Chapter 10 Protective groups Topics: The strategy Protection of alcohols, carboxylic acids, thiols, aldehydes and ketones, 1,2 and 1,3-diols, amines. Some examples

References: 1. Comprehensive Synthetic Organic Chemistry, 6, 631-701. 2. Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M 3. Synthetic Organic Chemistry Michael B. Smith, 629-672. A very smart discussion. 2.4. Advanced Organic Chemistry part B: Reactions and Synthesis 3rd ed. Carey, F.A.; Sundberg, R.J. pp. 677-92

Some things to consider before you use protecting groups Know why and when do you need to protect a functional group. Don’t just protect a group because you have to go through x number of steps. One must use protecting groups when the functionality (you wish to preserve) and the reaction conditions necessary to accomplish a desired transformation are incompatible (non-orthogonal). If you can avoid protection of a group in a synthesis, you should It is much better to plan ahead and avoid protection Protecting groups add extra steps to your synthesis more steps cost time and money.

‘Good’ protecting groups . . . Are small compared to the mass of what you are trying to make. Can be applied and removed in great yield. Allow the functionality to survive the reaction conditions necessary. Do not introduce stereocenters. Uncontrolled stereo centers in the protecting group complicate the manipulation and handling of the material because the amount of diastereomers increases. Allow selective deprotection under mild conditions.

Protection of alcohols The simplest protection of the OH group is the methyl ether Protects alcohols and phenols from a variety of chemical conditions Difficult to remove, removal is not as difficult with phenols Protection: Williamson Ether synthesis NaH/THF/ROH/MeX Deprotect: BBr3 Often this reagent is compatible with Lewis acid-sensitive functionality

Protection of alcohols (Formation of benzyl ether (OBn)) Performs similarly to the methyl ether. Protection: Williamson ether synthesis where the electrophile is something like Ph−CH2−Br. Deprotection is much easier. Deprotection is under hydrogenation conditions or Na/liq. NH3.

Protection of alcohols (Formation of methoxymethyl ether (MOM)) Installed by Williamson ether synthesis Deprotection Can be hydrolyzed in aqueous acid above example is from: Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M p. 20.

Protection of alcohols (Formation of silyl ethers) Are not as difficult to cleave as the methyl ether and can perform similar function Ease of cleavage is as follows Acidic condition TMS > TES > TBDMS > TIPS > TBDPS Basic condition TMS > TES > TBDMS = TBDPS > TIPS For example TMSO- can be deprotected in the presence of tBuMe2Si-O

Protection of alcohols (Formation of esters) Installed by treatment with the appropriate acyl chloride or anhydride in the presence of base. Deprotection by hydrolysis in basic media or by reduction with metal hydride.

Protection of carboxylic acids Formation of esters Methyl ester t-Butyl ester Ester of MOM, MEM, BOM, MTM and SEM Benzyl ester Allyl ester Silyl ester Formation of ortho esters

Protection of aldehydes and ketones Ketones and aldehydes have π* orbitals as the lowest unoccupied molecular orbitals. Nucleophiles interact with this orbital by doing 1,2 addition Bases interact with this orbital by deprotonation at the alpha position. Two things can happen to: Addition and Deprotonation / polymerization. Both are governed by π*.

Protect the aldehyde selectively in the presence of ketones 1 MeOH, dry HCl, 2 min, reflux, 12 min 2 deprotection 2N H2SO4, MeOH, H2O, reflux Reference: J. Chem. Soc. 1953, 3864.

Ketalization is not the only thing that can happen. Epimerization can also occur. Why?

Protection of aldehydes and ketones: Cyclic acetals Formation of O,O-acetals Inert with metal hydride reduction, organolithium reagents, basic solution of water or alcohol, catalytic hydrogenation(not including benzylidene), Li/NH3 reduction, oxidation in neutral or basic condition. Formation of S,S-acetals Formation of O,S-acetals

Protection of aldehydes and ketones: O,O-acetals Preparation: diol react with aldehydes or ketones in the presence of acid catalyst. Acetal is prepared easier than ketal. Cyclic is easier than acyclic. Bulky carbonyl compound react slower. Electron-withdrawing group of aromatic ring promotes the reaction. Nomenclature Deprotection by acidic hydrolysis, Lewis acids 1,3-dioxolane > 1,3-dioxane 1,3-dioxane of ketones > 1,3-dioxane of aldehyde

Nomenclature 3-membered ring ether: oxirane, with two oxygen atoms: dioxirane 4 membered ring ether: oxetane, with two oxygen atoms: dioxetane 5 membered ring ether: oxolane or tetrahydrofuran, with two oxygen atoms: dioxolane 6 membered ring ether: oxane or tetrahydropyran, with two oxygen atoms dioxane 7 membered ring ether: oxepin, with two oxygen atoms: dioxepin 8 membered ring ether: oxocane, with two oxygen atoms dioxocane 1,4-dioxane 1,3-dioxane 1,4-dioxepin

Protection of aldehydes and ketones: S,S-acetals RSH (R = Et, Pr, Ph), Me3SiCl, CHCl3, 20 °C, 1 h. > 80%yield B(SR)3 (R=Et, Bu, C5H11), reflux, 2 h PhSH, BF3•Et2O, CHCl3 0 °C, 10 min, ZnCl2, MgBr2 RSH, TiCl4, CHCl3 0 °C. RSSR (R=Me, Ph, Bu), Bu3P, rt, reagent also reacts with epoxides. Deprotection By transition metal salts By oxidation AgClO4, H2O, C6H6, HgCl2, CdCO3, aq. acetone I2, NaHCO3, dioxane, H2O H2O2 , H2O , acetone

Protection of 1,2- and 1,3-diols Driving force is the removal of water

The scheme above tells you that the formation of the cyclic acetals depends heavily on ring strain.

Protection of amines N-alkylation N-Acylation Formation of carbamates Not commonly used N-Acylation Converted to amide by acylation with acyl chloride or anhydride Formation of carbamates Most commonly used

Summary Alcohols are most commonly protected as ethers, especially where the ether function is in reality part of a (mixed) acetal or ketal; this enables the protecting group to be removed under relatively mild acidic conditions. Silyl ethers, especially where the silicon carries bulky substituents, offer acid-stable alternatives, deprotection being effected by reaction with fluoride ion. Alcohols may also be protected by esterification; removal of the protecting group then involves hydrolysis or reduction using lithium aluminium hydride. Carboxylic acids are ususlly lprotected as esters or ortho esters, deprotection again requiring hydrolysis,.

For aldehydes and ketones, protetion usually involves the formation of an acetal or ketal, the five- and six-membered cyclic derivatives (1, 3-dioxolanes and 1,3-dioxanes, respectively) being particularly important. Deprotection involves acid hydrolysys. The formation of these cyclic acetals and ketals is also used for the protection of 1,2- and 1,3-diols. Amines may be protected as N-alkyl (especially benzyl, trityl and allyl) or N-acyl derivatives (especially acetyl, trifluoroacetyl, benzoyl or phthaloyl) or as carbamates. Hydrolytic or reductive methods of deprotection are employed, according to the individual circumstances.