c-h activation zing flow chemistry and microwave conference 2013

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

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•  ThalesNano  is  a  chemistry  technology  company  that  provides  chemists  solu7ons  for  making  new  chemistry  possible,  dangerous  chemistry  safer,  and  slow  chemistry  faster.  

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ThalesNano  is  specialized  on  designing  reactors  around  specific  chemistries  where  reac7ons  in  flow  would  be  highly  beneficial  

Exothermic Reactions

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Endothermic Reactions

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Reactions with gases

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Scale up

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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

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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!!

ANY QUESTIONS