Green C-Alkylation of
N-Heterocycles with Direct
C-H Activation in Continuous
Flow
Heather Graehl, MS, MBA
Director of Sal...
Who	
  we	
  are?	
  
•  ThalesNano	
  is	
  a	
  chemistry	
  technology	
  company	
  that
	
  provides	
  chemists	
  s...
What	
  are	
  our	
  drivers?	
  
ThalesNano	
  is	
  specialized	
  on	
  designing	
  reactors	
  around	
  specific
	
 ...
Reaction Line
150°C, 100 bar (1450 psi)
H2, CO, O2, CO/H2, C2H4, CO2.
Reactions in minutes.
Minimal work-up.
-70 - +80°C
O...
5
H-Cube Pro and Phoenix Flow Reactors
H-Cube Pro™
•  Available pressure: 0-100 bar
•  Flow rate: 0.3-3 mL/min
•  Temperat...
•  Standard benzannulation reaction
•  Good source of:
•  Quinolines
•  Pyridopyrimidones
•  Naphthyridines
→ Important st...
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: ...
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
Phoen...
10
Today’s Presentation’s Chemistry Focus
•  Objectives: to find a cheap and green alternative of performing 1 step
alkyla...
11
Reaction pathway using Raney-Ni catalyst
Advantages of Raney-Nickel:
•  Cheaper than Pd, Pt containing catalytic system...
12
Optimizing the reaction conditions:
•  0.1M Indole solution in ethanol, RaNi 4200 Catalyst, GC-MS results
Reach higher ...
13
Alkylation of other heterocycles:
88.5%
Without N-protection, 300 °C, 100 bar, 0.5mL/min, 0.1 M, ethanol
14
Reaction with additional alcohols:
With secondary alcohols the main products were the fully reduced
heterocycles.
15
Ring closuring of 2-methyl-indole with 1,3-butanediol
Ring closure is
coupled with
hydrogenation of
double bond
16
Summary
1)  We identified a cheap catalyst for C-H activation reactions (activated
nickel catalysts)
2)  We developed a...
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS
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C-H Activation Zing Flow Chemistry and Microwave Conference 2013

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C-H Activation Zing Flow Chemistry and Microwave Conference 2013

  1. 1. Green C-Alkylation of N-Heterocycles with Direct C-H Activation in Continuous Flow Heather Graehl, MS, MBA Director of Sales North America heather.graehl@thalesnano.com
  2. 2. 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  
  3. 3. 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
  4. 4. 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. 5. 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
  6. 6. •  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
  7. 7. 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
  8. 8. New Scaffold Generation 5 novel bicyclic scaffolds generated-fully characterized. Many more to follow
  9. 9. 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
  10. 10. 10 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
  11. 11. 11 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!
  12. 12. 12 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 +
  13. 13. 13 Alkylation of other heterocycles: 88.5% Without N-protection, 300 °C, 100 bar, 0.5mL/min, 0.1 M, ethanol
  14. 14. 14 Reaction with additional alcohols: With secondary alcohols the main products were the fully reduced heterocycles.
  15. 15. 15 Ring closuring of 2-methyl-indole with 1,3-butanediol Ring closure is coupled with hydrogenation of double bond
  16. 16. 16 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
  17. 17. THANK YOU FOR YOUR ATTENTION!! ANY QUESTIONS

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