C-H Activation Zing Flow Chemistry and Microwave Conference 2013
Green C-Alkylation of
N-Heterocycles with Direct
C-H Activation in Continuous
Heather Graehl, MS, MBA
Director of Sales North America
• New chemistry
• New chemistry
Reactions with gases
150°C, 100 bar (1450 psi)
H2, CO, O2, CO/H2, C2H4, CO2.
Reactions in minutes.
-70 - +80°C
O3, Li, -N3, -NO2, F
Safe and simple to use.
2 step independent T
450°C, 100 bar (1450 psi)
New chemistry capabilities.
Chemistry in seconds.
Solve Dead-end chemistry.
H-Cube Pro & Gas Module:
Phoenix Flow Reactor:
H-Cube Pro and Phoenix Flow Reactors
• 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
• Standard benzannulation reaction
• Good source of:
→ Important structural drug motifs
• Harsh conditions
• High b.p. solvents
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)
a: 360 °C, 130 bar, 1.1 min
b: 300 °C, 100 bar, 1.5 min
c: 350 °C, 100 bar, 0.75 min
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
Variety of anilines and alcohols tested
Green: atom efficient, alcohol is solvent,
avoid using alkyl halides
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
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
Optimizing the reaction conditions:
• 0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results
Reach higher selectivity:
Protect the N-atom with
90% conversion with 80%
(300 °C, 100 bar, 0.5 mL/min,
isolated yield: 76.5%)
Alkylation of other heterocycles:
Without N-protection, 300 °C, 100 bar, 0.5mL/min, 0.1 M, ethanol
Reaction with additional alcohols:
With secondary alcohols the main products were the fully reduced
Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is
1) We identified a cheap catalyst for C-H activation reactions (activated
2) We developed a new route for ring closing of 2-methyl-indole via C-H
3) As the solvent also acts as a reagent, we found a new alkylation
method with high atom economy using greener reagents