The presentation "C-O, C-N and C-S Bond Formation Methods" delves into the pivotal role of carbon-heteroatom (C-O, C-N, C-S) bond formation in synthetic organic and medicinal chemistry, focusing on their significance in natural products and pharmaceuticals. It surveys key synthetic strategies, from historical methods like Williamson ether synthesis to advanced transition metal-catalyzed reactions such as Chan-Lam and Buchwald-Hartwig couplings, emphasizing their efficiency and practical applications. The discussion highlights the importance of these bonds in drug-receptor interactions and molecular synthesis, while addressing challenges and recent innovations in eco-friendly, cost-effective catalytic systems. The presentation concludes by affirming the enduring value of these reactions as essential tools for synthesizing diverse, critical compounds across agrochemical, pharmaceutical, and fine chemical industries.

1. Vinayak V Khairnar
Medicinal Chemistry
C-O, C-N and C-S
Bond
Formation
Methodologies
1

2. Content……….
❑ Introduction
❑ Background
❑ Importance of Carbon Heteroatom Bonds in Medicinal &
Organic chemistry
❑ Organic Chemistry Perspective
❑ Literature Review
❑ Conclusion
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3. Carbon-Heteroatombonds in drug receptor interactions
❑ Lead compounds are capable of fitting the binding site and have the functional groups
needed to interact with some of the important binding regions present.
❑ Adding another functional group to the lead structure enable extra binding interactions
with the target.
❑ For example, a lead compound may bind to three binding regions in the binding site
but fail to use a fourth. Extra functional groups may locate that fourth region.
❑ Introducing carbon-heteroatom bond helps to enhance physicochemical properties
of drug molecule.
Additional FG(C-O,C-
N & C-S bond improves
drug receptor
interactions
No additionalFGwith
( C-O,C-N & C-S bond)
Drug optimisation
3

4. Captopril: Importanceof C-N bond
❑ The C–C bond would have no double bond character (C has no lone pair) and free rotation
about the bond would be possible.
❑ Captoprilemerged from an extensive study of analogues featuring isosteric replacement.
❑ The proline nitrogen atom is fundamentally important in controlling the shape of the
molecule, as the C–N amide bond is rigid (partial double bond character).
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5. ❑ The carbon–heteroatom bond forming reactions are of much importance in academia as
well as pharmaceutical industry.
❑ Carbon-carbon / carbon-heteroatom bond-forming reactions are the backbone of synthetic
organic chemistry
❑ Today’s scientists are constantly trying to develop new methods for such bond forming
reactions as these are one of the valuable tools for the syntheses of structurally diverse
molecular entities.
❑ The hetero atoms and their bond formation play important role in synthesis of drug
molecules.
❑ Construction of C-C, C-O, C-N, and C-S bonds are reviewed with special emphasis on
their synthetic applications.
Organic Chemistry Perspective
5

6. Vancomycin Chloropeptin
C-O bond in Natural products
❑ Ethers are common structural features in numerous natural products and
biologically active Compounds.
6

7. Williamsons synthesis(1851)
The Williamson ether synthesis is forming
an ether from an organo- -halide and an alcohol.
Despite more than a century of immense
focus on finding efficient synthetic routes
for the
synthesis of ethers remain difficult .
Alexander Williamson
C-O bond Formation:Development
Ullmann coupling(1904)
Chan-Lam reaction (1998)
Buchwald-Hartwig couplings(1999)
✓ Efficient, experimentally simple and economically
attractive method
✓ Tolerates a variety of functionalgroups
✓ Ability to synthesize hindered and heteroaryl diaryl
synthesis 7

8. Metal Catalysis Vs Metal free synthesis of Diaryl Ethers
Metal Catalysis
Iodonium salt Mediated
C-O bond formationReactions
➢ Long reaction time
➢ High Temperature
➢ Excess reagents
➢ Sensitive to sterics
Metal Free
Org.Lett., 2011, 13, 6, 1552-1555
✓ Fast and mild
✓ Metal free
✓ Steric bulk ok
✓ No racemization
Easy synthesis of Iodonium salt
Chem. Commun. 2007, 2521;
Org. Synth. 2009, 86, 308-314.
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9. Mitsunobu reaction: (1967 )
More than 80% of reported Mitsunobu reactions
in the literature have been run with these two reagents
C-O bond FormationReactions
Macrocycle Lactonization
Oyo Mitsunobu(1967)
Main Issue: Unnecessary Waste
So, Need of avoiding/minimizing the Waste!
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10. Toy’sAzodicarboxylaterecycling
MitsunobuReaction
Azodicarboxylaterecycling
Taniguchi’scatalyticMitsunobu reaction
Substrate scope Substrate scope
50 % catalytic System Org. Biomol. Chem., 2018, 16, 7774–7781
10

11. Phosphine recycling
O’Brien’s phosphineRecycling
MitsunobuReaction
Aldrich “Fully Catalytic:System
50 % catalytic System
Substrate scope
Substrate scope
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12. C-N bond in Drugs
Amine & amides are common structural features in numerous natural products
and biologically active Compounds.
Ketoconazole
Aripiprazole
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13. C-N bond formationreactions
❑ Easily available starting materials
❑ Low cost catalytic system
❑ A valuable alternative for the construction of interesting heterocycles
Chan Lam reaction : Benzimidazoles synthesis by forming C-N bond formation
5
82%
6
77%
7
24%
8
68%
9
61%
Org. Lett., 2012, 14, 23, 5980-5983
First report in literature for Chan Lam reaction of unprotected amidines
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14. Copper catalyzed Chan-Lam coupling between sulfonyl azides /amides and Boronic acids
Previous wok:
In many of the cases reactions are completed in 2 h
using open flask conditions
Present wok:
TL, 2003, 44, 3385
Org.Lett.,2014, 16, 338
C-N bond formationreactions
JACS,2002, 124, 6043
❑ Anilines are Genotoxic Substrates
❑ Sulphonyl chlorides are Mutagenic in Nature
❑ Non mutagenic Substrates
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15. Direct catalytic N-alkylation of amines with carboxylic acids
C-N bond formation reactions
JACS, 2014, 136, 1431
One-pot catalytic synthesis of Cinacalcet HCl
JACS, 2014,136,14314
❑ Convenient and straight forward
catalytic reaction for N-alkylation of
amines with Easily available carboxylic
acids and silanes as reducing agents.
❑ Novel protocol demonstrated in the
preparation of valuable first one-pot
catalytic synthesis of
Cinacalcet hydrochloride
15

16. C-S bond in Natural products
Sulphidesare common structural features in numerous natural products and
biologically active Compounds.
Ceftaroline Cefotetan
The development of mild and general methods for C−S bond formation has received
significant attention because the C−S bond is indispensable in many important biological
and pharmaceutical compounds
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17. Previouswok:
▪ Use of 5 mol% of simple copper salt
▪ Inexpensive ligand 1,10-phen.H2O.
▪ Use of eco-friendly solvent(EtOH) and air as oxidant
C-S bond formationreactions
Present wok:
Org. Lett., 2000, 2, 2019
Org. Lett., 2002,4, 4309
J. Org. Chem., 2007, 72, 1241
J. Org. Chem., 2012, 77, 2878
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18. C-S bond formation reactions
C-H Activation
C−S bond formation via C−H functionalization are growing opportunitiespresent
to the construction of complex chemical scaffolds.
Inamoto’s Pd(II)-catalyzed synthesis of 2-arylbenzothiazoles
Chemical Society Reviews,2014
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19. Conclusion
❑ Research towards the design of reaction strategies, carbon-heteroatom bond formation
reactions, constitutes an exciting and never ending field in the arena of synthetic organic
chemistry.
❑ These bond forming reactions are considered as extremely powerful tools for the synthesis
of a wide range of essential compounds existing in the fields of agrochemicals,
pharmaceuticals, natural products and fine chemicals.
❑ Literature from the last few years has reveals mainly transition metal catalyzed cross-
coupling reactions which utilize copper, palladium, nickel, cobalt etc. as major transition
metals for their catalytic performance.
C-O, C-N and C-S Bond
Never
Ending
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20. Bibilography
Bibliography
1. Org. Biomol. Chem., 2018, 16, 7774–7781
2. Angew. Chem., 2015, 54, 5662-5665
3. Org. Lett., 2012, 14, 23, 5980-5983
4. J. Org. Chem., 2012, 77, 2878
5. JACS, 2014, 136, 14314
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