synthetic methods

Selected Synthetic Methods in Pharmaceutical Chemistry

Presenter Information

• Name: Abdulai Turay
• Qualifications: B.Pharm(Hons), MSc Drug Discovery and Development
• Department: Pharmaceutical Chemistry, B.Pharm II COMAHS, USL

Course Objective

• The objective of this course is for students to learn methods to synthesize simple organic molecules by the end of the course.

Course Content

• Introduction to Synthetic Methods:
  • Exposure to various classes of oxidizing and reducing reagents.
  • Understanding the factors governing the choice of method.

A. Oxidation

1. Types of Oxidation Reactions:
   • Oxidation of Olefinic Double Bonds
   • Cleavage of Double Bonds (Ozonolysis)
   • Oxidation of C-H Bonds
   • Oxidation of Alcohols
   • Oxidation of Nitrogen-containing Compounds
   • Oxidation of Ketones
   • Oxidation of Phenolic Compounds
   • Oxidation of Glycols

B. Reduction

1. Types of Reduction Reactions:
   • Reduction of Carbonyl Group to Phenol, Alcohol, Hydrocarbon
   • Reduction of Double or Triple Bond to Alcohol or Alkane
   • Catalytic Reduction
   • Methylation, Demethylation and Acylation
   • Reduction by Dissolving Metals

C. Redox Reactions

• Key Concepts:
  • In terms of Oxygen
  • In terms of Hydrogen
  • In terms of Electrons
  • In terms of Oxidation Number

D. Exercises

1. Calculate the oxidation state of carbon in:
   • $ext{CH}_3 ext{CH}_3$
   • $ext{CH}_2 ext{CH}_2$
   • $ext{CH} ext{CH}$
2. Calculate the oxidation number of carbon in the following reactions:
   • $ext{CH}_4 + ext{Cl}_2 <br /> ightarrow ext{CH}_3 ext{Cl} + ext{HCl}$
   • $ext{CH}_3 ext{Cl} + 2 ext{Li} <br /> ightarrow ext{CH}_3 ext{Li} + ext{LiCl}$

E. Oxidizing and Reducing Reagents

1. Oxidizing Agents:
   • Definition: An oxidizing agent, or oxidant, gains electrons and undergoes reduction. Known as the electron acceptor.
   • Examples:
     • Halogens
     • Potassium Nitrate
     • Nitric Acid
2. Reducing Agents:
   • Definition: A reducing agent, or reductant, loses electrons and undergoes oxidation. Known as the electron donor.
   • Typically present in one of its lower possible oxidation states.
   • Examples:
     • Earth Metals
     • Formic Acid
     • Sulfite Compounds

F. Oxidation of Olefinic Bonds

1. Oxidizing Agents Used:
   • Osmium Tetroxide (OsO4):
     • Specific for olefinic double bonds
     • Example Reaction: $ext{H}_3 ext{C}- ext{C}= ext{C}- ext{H} <br /> ightarrow ext{CH}_3 ext{CH(OH)CH(OH)CH}_3$ (cis-product, forming vicinal diols)
   • Potassium Permanganate (KMnO4):
     • Requires careful control of the reaction; produces cis-hydroxylated products
   • Iodine/Silver Acetate (Prevost Reagent):
     • Wet conditions yield a cis product; dry conditions yield a trans product
   • Peracids:
     • Example: Peracetic acid and perbenzoic acid
     • Reaction: $ext{RCOOH} + ext{H}_2 ext{O}_2 <br /> ightarrow ext{RCOOOH}$
   • Selenium Dioxide (SeO2):
     • Mild but toxic oxidizing agent, oxidizes olefinic double bonds to ketones

G. Ozonolysis

• The process of adding ozone to olefinic double bonds forming an ozonide that is then cleaved by boiling water or hydrogen to yield two carbonyl-containing fragments.
• Used for locating double bonds.

H. Oxidation of C-H Bonds

• Common Reagents:
  • Aqueous KMnO4
  • Chromic Acid in Aqueous Solution or Acetic Acid
  • Sodium Dichromate
  • Chromium Trioxide
  • Chromyl Chloride in $CCl_4$ or $CS_2$
• Example Reaction:
  • $ext{RCH}_3 <br /> ightarrow ext{RCOOH}$

I. Importance of C-H Bond Oxidation

• Side-chain oxidation of alkyl benzenes in the liver converts compounds into forms more easily excreted through urine.

J. Oxidation of Alcohols

1. Methods for Oxidation to Aldehydes and Ketones:
   • KMnO4
   • Sodium Dichromate in Aqueous Sulfuric Acid
   • Chromium Trioxide in Pyridine
   • Metal Oxides
   • Metal Alkoxides
   • Others
2. Specific Outcomes:
   • Primary alcohols oxidize to aldehydes; secondary to ketones; tertiary alcohols are generally unreactive.

K. Common Oxidizing Agents

1. Chromic Acid:
   • Reaction: $Na_2Cr_2O_7 ext{ in }H_2SO_4$
2. Jones Oxidation:
   • Solution of chromium trioxide in aqueous sulfuric acid, common in steroid oxidation reactions.
3. Metal Oxides:
   • Example: $ext{MnO}_2$ and $ext{Ag}_2 ext{O}$
   • Specific for allylic and benzylic hydroxyl groups
4. Metal Alkoxides (Oppenauer Oxidation):
   • Utilizes aluminium alkoxides for selective alcohol oxidation
5. Others:
   • Include Ruthenium Tetroxide (RuO4), Nickel Peroxide, and Concentrated HNO3.

L. Oxidation of N-Containing Compounds

1. Primary Amines:
   • Oxidized to aldoximes using hydrogen peroxide and peracids
2. Secondary Amines:
   • Oxidized to hydroxylamines
3. Tertiary Amines:
   • Oxidized to N-oxides

M. Oxidation of S-Containing Compounds

1. Thiol and Sulphide Oxidation:
   • Thiols oxidized to sulphonic acids.
   • Powerful oxidants convert thiols to derivatives including sulphonyl chlorides.

N. Oxidation of Phenols

• Generally more easily oxidized than alcohols; weak oxidants can be sufficient.

O. Reduction

1. Reduction Pathways:
   • Carbonyl group to phenol, alcohol, hydrocarbon
   • Double or triple bond to alcohol or alkane
   • Catalytic reduction methods
   • Methylation and demethylation
2. Reduction of Carbonyl Group:
   • Key reagents include lithium aluminum hydride (LiAlH4), lithium borohydride (LiBH4), and sodium borohydride (NaBH4).
   • These allow selective reductions without affecting other functionality in the vicinity.

P. Specific Reduction Reactions

1. Pinacol Reduction:
   • Electropositive metals reduce ketones to pinacols via dimerization of anion radicals.
2. MPV Reduction:
   • Utilizes aluminium alkoxides in a reductive environment.
3. Hydroboration:
   • Reduction of double or triple bonds to alcohols or alkanes using boranes or diboranes followed by hydrolysis.
4. Hydrogenation:
   • Catalytic reduction utilizing hydrogen, catalysts like Pt, Pd, and varying solvents depending on reaction pressure.

Q. Methylation and Acetylation

1. Methylation Reagents:
   • Methanol/Sulfuric Acid or Methyl Iodide with K2CO3.
2. Acetylation Reagents:
   • Acetyl Chloride or Acetic Anhydride under acidic conditions.
3. Detachment of Protecting Groups:
   • Can be achieved through demethylation or deacetylation to revert to the original functional structure.