A novel and safe strategy for carbonylation reaction which generates insitu carbon monoxide followed by insertion to give carbonyl product.

1. SEMINAR PRESENTATION ON
COtab: Expedient and Safe Setup for Pd-Catalyzed
Carbonylation Chemistry
Presented by:
Abdul Kalam
Process Chemistry
PTPC/2019/501

2. Introduction
Design of COware and CO-releasing Molecules
Comparison of Conventional and COware technique and
Advantages
Olaparib and its scale up using COtab techniques
Optimization of reaction condition
Application of COtab in Carbonylation reactions
Contents

3. Introduction
 Carbon monoxide (CO) in combination with transition metal catalysis, become a versatile reagent in organic
synthesis
 Not only it introduce CO into a complex molecule but also add an extra carbon to the growing molecule, it
simultaneously introduces a carbonyl group, one of the most common functionalities in bioactive compounds
 The bulk chemical industry also takes advantage of CO as a cost efficient C1 building block, transforming
olefins into aldehydes, carboxylic acid derivatives, or alcohols by way of carbonylation reactions
 Since the first reports by Heck and co-workers in the 1970s on palladium catalyzed carbonylation reactions, the
scope of CO chemistry has expanded considerably
Classical
examples of
Pd-catalyzed
Carbonylative
couplings
In oxidation
states 0 and II
CO is a high
affinity ligand
for palladium

4.  Despite all the above-mentioned advantages of CO gas as a reagent, some lack of academic interest toward
this field is still eminent
 This reluctance is due to
 High toxicicity
 Leads to exclusion of oxygen from binding to hemoglobin and cause asphyxiation
 Flammable
 To overcome the dangers involved using CO gas, several groups have developed CO-equivalents, One
special class of solid in situ CO-releasing molecules is the metal carbonyls, such as Fe(CO)5, Cr(CO)6,
Co2(CO)8, and especially Mo(CO)6, which have been extensively studied by the group of Larhed et al.
 Pressurized cylinders are the primary source for CO, and hence their use in a research laboratory setting
necessitates CO detectors as a safety measure for the operator
 in situ decarbonylation protocols lead to byproducts from the CO surrogate in the reaction mixture with the
desired product, complicating reaction workup and product purification.
Introduction

5. Design of COware and CO-releasing Molecules
Safe Versatile
Convenient
Solid CO
Precursor
Carbonylation
reactions
CO CO
CO
With this technology, an array of low-pressure carbonylations were developed
applying only near stoichiometric amounts of carbon monoxide

6. CO
9-Methyl-9H-fluorene COgen SilaCOgen
Cogen: 99%
SilaCOgen: 96%
Synthesis of COgen and SilaCOgen

7. Comparison of Conventional and COware Technique
CO Generation from Cogen

8. Advantages
• Handling Solid and Liquid reagents are safe but same is not the case with gases.
• Reluctance in academic laboratory research regarding Carbonylation can be avoided
• Chemist routinely handle solids and liquids reagents, but same is not the case with gaseous reagents.
• In situ decarbonylation of CO surrogate adds additional steps of workup and purification
• Synthetic transformation employing such reagents are commonly conducted under pressure(Autoclave) or
other which necessitates specialised equipment or other hazardous non recommended installations.
• Other safety concerns include toxicity of these reagents, even though industrial processes apply gaseous
building blocks regularly due to their low cost and ready availability but nevertheless under a strictly
controlled manner.
• Reaction can be carried out safely without Glovebox in academic laboratory.

9. General Mechanism Of Carbonylation Reaction

10. Olaparib
• It is a PARP (poly ADP ribose ploymerase) inhibitor Drugs
• An enzyme involved in DNA repair
• Was developed and first dosed into patients by the UK-based biotechnology
company, KuDOS Pharmaceuticals
• It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations,
which include some ovarian, breast, and prostate cancers

11. Scaleup Of Olaparib To Gram Scale

12. Optimization of Reaction Conditions for the Amino-
carbonylation of 4-iodoanisole with Mo(CO)6 and
DBU in the CO-Producing Vial (COware)

13. Mechanistic Demonstration of reaction using
Mo(CO)6 as CO source

14. n Time (h) Pd(PPh3)4
(mol %)
Mo(CO)6 (equiv) Yield (%)
1 15 5 1 94
2 15 5 0.5 95
3 5 3 0.5 61
4 15 5 0.3 88
5 5 5 0.3 52
6 5 5 0.5 69
7 15 3 1 75
8 15 1 0.5 14
9 15 5 0.5 92

15. Two-Step Synthesis of Clenbuterol, with a Double
Carbonylation as the Key Step

16. Use of COtabs in Carbonylative reactions
Method B
(COtab)
Method A
(Glovebox)

17. Method B
(Cotab)
Method A
(Glovebox)
Use of COtabs in Aminocarbonylative Reactions

18. Other drugs that were synthesized:
Chemical Yield: 72% Chemical Yield: 74%
Chemical Yield:87 % Chemical Yield: 83%

19. Conclusion
A COware is a competent tool for conducting safe reactions with gaseous
reagents on a laboratory scale.
We anticipate that this glovebox-free carbonylation protocol will be of great
utility for chemists without access to specialized equipment.
It is utilized for a wide number of both well known and new transition metal
catalyzed carbonylative transformations.
The two-chamber system has also proven to be valuable for other gases than CO.

20. References
1. Menear, K. A., et al. (2008). "4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-
fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-
ribose) Polymerase-1." Journal of Medicinal Chemistry 51(20): 6581-6591.
2. Collin, H. P., et al. (2019). "COtab: Expedient and Safe Setup for Pd-Catalyzed
Carbonylation Chemistry." Organic Letters 21(15): 5775-5778.
3. Nordeman, P., et al. (2012). "Aminocarbonylations Employing Mo(CO)6 and a Bridged
Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl
Bromides." The Journal of Organic Chemistry 77(24): 11393-11398.
4. Hughes, D. L. (2017). "Patent Review of Manufacturing Routes to Recently Approved
PARP Inhibitors: Olaparib, Rucaparib, and Niraparib." Organic Process Research &
Development 21(9): 1227-1244.

21. THANK
YOU