Chapter 15 Multistep Syntheses

1. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Retrosynthetic Analysis • Reactions Requiring Both Functional-Group Transformation and Skeletal Construction • Extending the Retrosynthetic Approach: Alternative Routes for Synthesizing more Complex Molecules • Selecting the Best synthetic Route • Criteria for Evaluating Synthetic Efficiency • Real-World Synthetic Objectives • Protecting Groups • Practical Examples of Multistep Syntheses

2. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Carbon-Carbon bond formation processes • R-MgBr with ketone forms alcohol • R-MgBr with epoxides form alcohols • Enolates with R-I • Enolates with ketones form -hydroxy ketones and ,-unsaturated ketones • Cyanide with RCH2X • Cyanide with ketones forms Cyanohydrin • Ylide and ketone forms alkene • Diene and Dienophile undergoes Diels-Alder cyclization • Alkyne and base with Alkylhalide forms alkylated alkyne

3. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Oxidation-Reduction Reactions • Secondary alcohol to ketone with Cr-VI • primary alcohol to aldehyde with Cr-VI in Pyridine • Primary alcohol to aldehyde with Cr-VI in water • Alkene to 2 carbonyls with ozone followed by Zn/HOAc • Alkane to halo alkane with light and chlorine or bromine • Carbonyl -hydrogen with bromine to -bromo carbonyl • Alkene and OsO4 to vicinal di-alcohol • Alkene a per-acid to epoxide • Aldehyde and ketone to sec-alcohol with NaBH4 • Ester to pri-alcohol with LiAlH4

4. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Oxidation-Reduction Reactions (continued) • Alkene to alkane with H2/Pt • Alkyne to cis-alkene with H2/Pd and Quinoline • Imine to amine with H2/Pt • Ketone to alkane with Zn(Hg), HCl or with NH2NH2, base • Amide to Amine with LiAlH4 • Alkyne with R2B-H followed by oxidation forms aldehyde • Alcohol to Alkene with sulfuric acid

5. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Functional group transformation • Alcohol to alkyl halide with PX3 (x=Br, Cl, I) • alkyl halide to alcohol with NaOH Ketone to Ketal with acid/ROH • Ketal to Keone with acid/H2O • Ester to Acid with NaOH followed by acidification • Acid to Ester with acid and ROH • Nitrile to Amide with NaOH/H2O • Amide to Nitrile with POCl3 • Acid chloride to Acid with water • Acid to acid chloride with thionyl chloride • Acid Chloride to substituted amide or amide with HNR2 or NH3 • Acid chloride to Ester with ROH

6. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Functional group transformation (continued) • Ketone to imine with pri-amine • Imine to ketone with acid/water • Ketone to enamine with sec-amine (needs alpha H on carbonyl • Alkene to Alcohol withBH3-hydroboration followed by H2O2-oxidation • Aryl-H to Aryl-Br with bromine/FeBr3

7. Chapter 15 • Review Table 15.1, 15.2 15.3

8. Chapter 15Multistep Syntheses • Retrosynthetic Analysis • Designing a synthesis by Working Backward • Synthesis requires analysis, insight, intuition and a sound knowledge of the reactivity of organic compounds • Many correct answers, the only incorrect one is one that fails to produce the desired compound • Need to have reactions and reagent combinations at your finger tips • Rational for Retrosynthetic Analysis • Basic changes during a synthesis • molecular skeleton: extend, connect, rearrange • functional groups: interchange or transpose • stereocenters: invert or transfer

9. Chapter 15Multistep Syntheses • Extending the Retrosynthetic Approach: Alternative Routes for Synthesizing more Complex Molecules • Analyzing Individual Reactions in a Sequence • look for patterns or structures you have seen before • Order of Chemical Transformations • Order is important • May have to use protecting groups

10. Chapter 15Multistep Syntheses • Selecting the Best synthetic Route • Number of Steps • Yield of each step • Reaction conditions • Ease of isolation and purification • Cost and availability of raw materials • Criteria for Evaluating Synthetic Efficiency • Linear synthesis • Convergent Synthesis • Logistical Factors

11. Chapter 15Multistep Syntheses • Competing Reactions • Review Fox and Whitesell exercise 15.8 page 767 • good practice and problems for competing reactions • Protecting Groups • Protection of Aldehydes and Ketones • via acetal/ketal, regenerate with acid/water • Protection of Alcohols • via benzyl ether, regenerate with acid/water • via dihydropyran, regenerate with acid/water • via dimethyl-t-butyl-silylchloride, regenerate with fluoride • Protection of Carboxylates • with isobutylene to form t-butylester, regenerate with acid/water • Protection of Amines • via a urethane, regenerate with acid (decarboxylates)

12. Chapter 15Multistep Syntheses • Practical Examples of Multistep Syntheses • 1.) cis-3-hexene • 2.) 2-heptanone • 3.) heptanal • 4.) 4-(3-ol-butyl)cyclohexanone from 4-vinylcyclohexanone • 5.) 2-methyl-6-one-heptanal from 2,6-dimethyl-methylenecyclohexane • 6.) heptane from cyclohexanol

13. Chapter 15 Summary • Reactions classified as • Carbon-Carbon-bond-forming • Oxidation-Reduction • Functional group transformations • Analyze carefully by working backwards, develop an overall strategy • Utilize convergent synthesis to shorten overall sequence • Utilize protecting groups to control the order of the reactions • Study, Study, Study • Table 14.1 • Table 15.1, 15.2, 15.3 • Appendix: Summary of Synthetic Methods • Practice, Practice, Practice