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
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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
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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)
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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
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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)
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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 H2O2oxidation
• 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
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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
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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-dimethylmethylenecyclohexane
– 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