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Green C-Alkylation of N-Heterocycles with Direct C-H Activation in Continuous Flow Heather Graehl, MS, MBA Director of Sales North America [email protected]
Who we are?
• ThalesNano is a chemistry technology company that provides chemists solu7ons for making new chemistry possible, dangerous chemistry safer, and slow chemistry faster.
• >700 customer install base on 6 con7nents.
• 33 employees with own chemistry team. • 11 years old-‐most established flow reactor company. • R&D 100 Award Winner
What are our drivers?
ThalesNano is specialized on designing reactors around specific chemistries where reac7ons in flow would be highly beneficial
Exothermic Reactions
• Safety • New chemistry • Simplicity
Endothermic Reactions
• New chemistry • Speed • Green
Reactions with gases
• Safety • Simplicity • Speed • Green
Scale up
• Safety • Selectivity • Reproducibility • Speed
Reaction Line
150°C, 100 bar (1450 psi) H2, CO, O2, CO/H2, C2H4, CO2. Reactions in minutes. Minimal work-up.
-70 - +80°C O3, Li, -N3, -NO2, F
Safe and simple to use. Multistep synthesis. 2 step independent T control.
450°C, 100 bar (1450 psi) New chemistry capabilities. Chemistry in seconds. Milligram-kilo scale Solve Dead-end chemistry.
H-Cube Pro & Gas Module: Reagent gases
Phoenix Flow Reactor: Endothermic chemistry
IceCube: Exothermic Chemistry
5
H-Cube Pro and Phoenix Flow Reactors
H-Cube Pro™ • Available pressure: 0-100 bar • Flow rate: 0.3-3 mL/min • Temperature: 10-150 °C
Phoenix Flow Reactor • Can be used as an external heater
module with the H-Cube or H-Cube Pro. • Temperature: RT-450 °C • Work with:
-Catalyst filled cartridges -Loops 4-8-16 mL SS, teflon or
Hastelloy
• Standard benzannulation reaction • Good source of:
• Quinolines • Pyridopyrimidones • Naphthyridines
→ Important structural drug motifs
Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity
W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895
High T Chemistries – in Batch
Replacement of diphenyl ether (b.p: 259 °C) with THF (b.p.: 66 °C)
Cyclization conditions: a: 360 °C, 130 bar, 1.1 min b: 300 °C, 100 bar, 1.5 min c: 350 °C, 100 bar, 0.75 min
Pyridopyrimidinone Quinoline
No THF polymerization!
Batch conditions: 2 hours
Gould-Jacobs Reaction – in Flow
New Scaffold Generation
5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
Phoenix Flow Reactor: N-Alkylation
RaNi 70mm 200C, 80bar 0.5ml/min
51%
60% 54%
55% 300C,
130bar
47%
64% 300C,
130bar
Phoenix
Variety of anilines and alcohols tested
Green: atom efficient, alcohol is solvent, avoid using alkyl halides
RaNi CatCart
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Today’s Presentation’s Chemistry Focus
• Objectives: to find a cheap and green alternative of performing 1 step
alkylation reaction via C-H activation.
• Relevance: used for generation of novel compounds, via C-H activation
untouched positions on rings can be activated.
• Main problems: • strong bond between carbon and hydrogen atoms
• Multistep reaction
• Require expensive metal catalysts (Pd, Pt)
• Selectivity is an issue
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Reaction pathway using Raney-Ni catalyst
Advantages of Raney-Nickel: • Cheaper than Pd, Pt containing catalytic systems • Differently preactivated Raney-Ni catalyst can give more
flexibility – selectivity issues
But: Pyrophoric!
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Optimizing the reaction conditions:
• 0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results
Reach higher selectivity: Protect the N-atom with
TMS-Cl Result: 90% conversion with 80%
selectivity (300 °C, 100 bar, 0.5 mL/min,
isolated yield: 76.5%)
RaNi +
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Alkylation of other heterocycles:
88.5%
Without N-protection, 300 °C, 100 bar, 0.5mL/min, 0.1 M, ethanol
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Reaction with additional alcohols:
With secondary alcohols the main products were the fully reduced heterocycles.
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Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is coupled with hydrogenation of double bond
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Summary
1) We identified a cheap catalyst for C-H activation reactions (activated nickel catalysts)
2) We developed a new route for ring closing of 2-methyl-indole via C-H activation
3) As the solvent also acts as a reagent, we found a new alkylation method with high atom economy using greener reagents
THANK YOU FOR YOUR ATTENTION!!
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