Chapter 15 Multistep 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 1

Chapter 15 Multistep 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 2

Chapter 15 Multistep 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 2

Chapter 15 Multistep 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 2

Chapter 15 Multistep 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 2

Chapter 15 Multistep 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 2

Chapter 15 Review Table 15.1, 15.2 15.3

Chapter 15 Multistep 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 3

Chapter 15 Multistep 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 5

Chapter 15 Multistep 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 7

Chapter 15 Multistep 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) 9

Chapter 15 Multistep 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 10

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