1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Chapter 15
Review Table 15.1,

8. 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

9. 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

10. 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

11. 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

12. 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

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