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
 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
 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
 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
 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
 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
 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
 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
 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
 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)
 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
 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