OUTLINE 535 LECTURE 4 (2003) Page 31

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1 UTLINE 535 LECTURE 4 (2003) Page 31 Protecting Groups in rganic Chemistry for xygen-based functionality. References: 1.1. Comprehensive Synthetic rganic Chemistry, 6, Protective Groups in rganic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M 1.3. Synthetic rganic Chemistry Michael B. Smith, A very smart discussion Advanced rganic Chemistry part B: Reactions and Synthesis 3rd ed. Carey, F.A.; Sundberg, R.J. pp Some things to consider before you use protecting groups 2.1. Know why and when do you need to protect a functional group ne 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 3. 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. 4. Example of an oxygen-based functionality protecting scheme: Kitching J. rg. Chem. 1989, 54, TP 2 TP nex nex 3 TP 4 TP Starting from the 1,3-diol, what if we want to extend the chain by 6 carbon atoms.

2 UTLINE 535 LECTURE 4 (2003) Page 32 Remember the arrows above are retroarrows. We are thinking backwards. The numbers below refer to each retrosynthetic step Deprotect An annoying result of having put the thing on in the first place hexyl 4.2. Consider for example, nucleophilic addition of nexylli to a ketone followed by protonation If the functionality on the other end of the molecule were left as the ketone ( )nexyl would have also attacked this ketone in a 1,2 fashion xidation of the unprotected alcohol Without one of the R- groups protected they would have both oxidized to aldehydes TP addition to protect one alcohol from oxidation Protection of one alcohol functionality by stoichiometric control of reagent 5. The simplest protection of the group is the methyl ether 5.1. Protects alcohols and phenols from a variety of chemical conditions 5.2. Difficult to remove, removal is not as difficult with phenols 5.3. Protection: Williamson Ether synthesis Na/TF/R/MeX 5.4. Deprotect: B ften this reagent is compatible with Lewis acid-sensitive functionality B C3 B C3 C 3 B B + C 3 6. Benzyl ether protection of alcohol 6.1. Performs similarly to the methyl ether.

3 UTLINE 535 LECTURE 4 (2003) Page Protection: Williamson ether synthesis where the electrophile is something like Ph C Deprotection is much easier Deprotection is under hydrogenation conditions 7. Because ethers are difficult to remove other protection options are sought for alcohols MM: methoxymethyl = R-C2C3. Really an acetal! 7.2. Protection Installed by Williamson ether synthesis 7.3. Deprotection Sometimes a subtle balance of Lewis Acid and Base SEM Me LiBF 4 C 3 CN/ 2 70 C 100% Me MM SEM

4 UTLINE 535 LECTURE 4 (2003) Page above example is from: Protective Groups in rganic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M p SEM is trimethylsilyethoxymethyl ÿ R-C2--C2-C2-SiMe3 8. xidation state as a protecting Scheme 8.1. Remember adjustment of oxidation state is often easy 8.2. Never carry an aldehyde through multiple steps These air-oxidize undergo facile aldol condensation 9. Silyl ethers 9.1. are not as difficult to cleave as the methyl ether and can perform similar function 9.2. Ease of cleavage is as follows Me3Si- > Et3Si- ipr3si- > tbume2si- EtMe2Si- PhMe2Si For example TMS- can be deprotected in the presence of tbume2si- 10. Diols 1,2; 1,3; and 1,4 do not react like regular alcohols. The reactivity of the functionality is moderated by the presence of the other group These can be protected as their cyclic ketals C 2 Et C 2 Et C Driving force is the removal of water Dean Stark conditions

5 UTLINE 535 LECTURE 4 (2003) Page ften one of the above two reagents are used; one does not have to worry about the removal of water under these conditions... why not? Bn Bn C 2 Me TMSS 2 CF 3-78 C N Bn Bn C 2 Me 12. The reaction can be run under aprotic conditions; Me-C2-Me the reagent that produces 1,3-dioxane is also the solvent In the above example under protic conditions the methyl ester may have been hydrolyzed The reagent TMSS2CF3 [(C3)3Si--S2-CF3] is a source of (+)SiMe This reagent can be used catalytically similarly to the manner in which (+) is used. acetone, Ts + 1: 5 acetone, Ts + 1: 9 2-pentanone, Ts + 90% yield only the dioxolane at right was formed 13. The scheme above tells you that the formation of the cyclic acetals depends heavily on ring strain. 14. PRTECTIN F ALDEYDES AND KETNES Most often you want to protect ketones and aldehydes from strong nucleophiles ketones and aldehydes when treated with strong nucleophiles Ketones and aldehydes have π* orbitals as the lowest unoccupied molecular orbitals.

6 UTLINE 535 LECTURE 4 (2003) Page Nucleophiles interact with this orbital by doing 1,2 addition Bases interact with this orbital by deprotonation at the alpha position. 15 π base nuc Two things can happen to Addition Deprotonation / polymerization Both are governed by π* 16. ne can expect to protect the aldehyde selectively in the presence of ketones Me 1 Me Ac 2 Ac Me, dry Cl, 2 min, reflux, 12 min N 2S4, Me, 2, reflux J. Chem. Soc. 1953, The authors could have pushed the reaction to also make the ketal Note the conditions under which the acetal is unmasked Alkene and enol ethers are sensitive to acid don t expect to carry them through a deprotection of this sort Use your head ften milder conditions for deprotection are available oxalic acid, TF, 2 room temperature can undo some ketals

7 UTLINE 535 LECTURE 4 (2003) Page 37 (Me) 3 C Ts C 2 Cl 2 Me Me Me Me 18. Ketalization is not the only thing that can happen Epimerization can also occur. Why? The ketones can unmasked with (+)(cat), 2, acetone % 2, Silical gel, C2Cl2 18 h. 19. Cyclic acetals Nomenclature membered ring ether oxirane with two oxygen atoms dioxirane membered ring ether oxetane with two oxygen atoms dioxetane membered ring ether oxolane, tetrahydrofuran with two oxygen atoms dioxolane

8 UTLINE 535 LECTURE 4 (2003) Page membered ring ether oxane, tetrahydropyran with two oxygen atoms dioxane membered ring ether oxepin with two oxygen atoms dioxepin membered ring ether oxocane with two oxygen atoms dioxocane ,4-dioxane, 1,3-dioxane, 1,4-dioxepin The oxygen atoms are numbered relative to each other. 20. Rates of hydrolysis (deprotection) ,2-dimethyl-1,3-dioxolane: 2-methyl-1,3-dioxolane: dioxolane; 50,000: 5000: This means that you have a chance of selectively deprotecting ketones 21. The steric effect ethylene glycol + ethylene glycol Ts, Ph, reflux, 4h. TMS TMS TMSTf -78 C C2Cl2 27:1

9 UTLINE 535 LECTURE 4 (2003) Page In the last example the steric influence against ketalization wins over the electronic reason against ketalization With everything else equal α,β -unsaturated ketone are more difficult to ketalize than saturated dialkylketones. 25. Thioketals Can be deprotected in the presence of ketals and can survive ketal deprotection The two protecting schemes are orthogonal TMSSC3, ether 2. rt, 93% SMe SMe 27. Synthesis: thioketals are synthesized with oxophilic Lewis Acids RS (R = Et, Pr, Ph), Me3SiCl, CCl3, 20 C, 1 h. > 80%yield B(SR)3 (R=Et, Bu, C511), reflux, 2 h PhS, BF3 Et2, CCl3 0 C, 10 min, ZnCl2, Mg RS, TiCl4, CCl3 0 C RSSR (R=Me, Ph, Bu), Bu3P, rt, reagent also reacts with epoxides. 28. Deprotection: removed oxidatively or by thiophilic Lewis Acids (transition metals) These can be harmful to the environment SR oxidizes easier than -RC=CR- or R3C usually so often deprotection is compatible with alkenes, α,β-unsaturated enones and esters, Baeyer-Villiger and epoxidation reactions are possible under oxidative conditions with these functionalities Give an example of both AgCl4, 2, C66, gcl2, CdC3, aq. acetone I2, NaC3, dioxane, , 2, acetone 29. 1,3-dithianes and 1,3-dithiolanes are used as in their oxygen atoms cousins 30. The cyclic thioketals are prepared like their acyclic variants are prepared, with oxophilic Lewis acids a good reagent:

10 UTLINE 535 LECTURE 4 (2003) Page 40 S B R S R= Cl or Ph, conditions: CCl 3, 25 C, 2 h, 90%-quant yield. 31. A good reagent for the protection of the carboxyl ate functionality: R BF 3 Et 2, C 2 Cl 2 r.t. R The product is called an orthoester Like the ketals the orthoester function masks the carbonyl _ * from nucleophiles and bases