Metal-free, Organocatalytic Intramolecular C-H Amination

“Organocatalytic, Oxidative, Intramolecular C-H Bond Amination and Metal-free Cross-Amination of Unactivated Arenes at Ambient Temperature” Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem. Int. Ed. 2011, 50, 8605-8608. DOI: 10.1002/anie.201102984

For constructing aryl C-N bonds, the traditional synthetic sequence (i.e., what we teach undergrads) involves nitration followed by reduction, the nitration requiring harsh conditions and the reduction generating a stoichiometric amount of Sn waste.


More recently, Buchwald and Hartwig have improved on this through the use of catalytic Pd. This reaction, however, requires a pre-oxidized aryl halide, which must be prepared prior to coupling.

C-H bond amination has been highlighted recently as a method to streamline the synthesis of aryl C-N bonds (see the work of White or Dubois for examples of allylic and aliphatic C-H amination reactions, respectively). Fewer synthetic steps means less waste and an overall greener reaction. Most catalytic C-H aminations, however, require the use of Rh, an expensive heavy metal. The Antonchick group recently reported the metal-free, organocatalytic synthesis of carbazoles by aryl C-H amination. This chemistry is novel and complements the work others are doing to use earth-abundant metal complexes as C-H amination catalysts (esp. Fe and Cu).

The Antonchick group starts by optimizing the conditions for the synthesis of N-protected carbazole 2a from the precursor 2-aminobiphenyl 1a in 81 % isolated yield from a 12 hr reaction in hexafluoro-2-propanol (HFIP) at room temperature.

They then improve their conditions by using catalytic amounts of iodoarene in the presence of peracetic acid as their oxidant avoiding the generation of a stoichiometric amount of iodobenzene waste from their initial conditions. Note that their optimized conditions require a mixed solvent system consisting of HFIP and methylene chloride.

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More Stahl Aerobics

“Highly Practical Copper(I)/TEMPO Catalyst System for Chemoselective Aerobic Oxidation of Primary Alcohols” Hoover, J. M.,; Stahl, S. S.  J. Am. Chem. Soc. 2011. ASAP. DOI: 10.1021/ja206230h

To quickly follow up yesterday’s post on aerobic alcohol oxidation, I thought that this new paper from the Stahl lab on the same topic was worth mentioning.  While their continuous flow process for alcohol oxidation was a pretty big improvement over many existing methods, the reagents necessary were not ideal.  Toluene and pyridine are both toxic, and palladium is not extremely abundant, especially compared to 1st row transition metals.  So there was plenty of room for improvement, which is why I was really psyched to see this new catalyst system for primary alcohol oxidation that was published a few days ago. Virtually all of the reaction components have been replaced by greener reagents:  acetonitrile instead of toluene, N-methylimidazole instead of pyridine, and catalytic TEMPO/(bpy)Cu(I) instead of palladium acetate.  Unlike most aerobic alcohol oxidations, an atmosphere of pure oxygen was not necessary – the oxygen present in ambient air was enough for the reaction to run efficiently.  And the reaction is run at room temperature to boot.  It’s hard to imagine that this reaction would be more difficult to scale up using their flow reactor than the Pd-catalyzed version, although you never know I suppose.

There’s loads more in the paper on their catalyst development studies, and on the chemoselectivity of this process for primary alcohols versus secondary ones – definitely worth reading!

Engineering, Synthesis

The Problem with Oxygen

“Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions” Ye, X.; Johnson, M. D.; Diao, T.; Yates, M. S.; Stahl, S. SGreen Chemistry, 2010, 12, 1180-1186.  DOI: 10.1039/c0gc00106f

We’ve had a pair of posts recently about using oxygen as an terminal oxidant in cross-coupling and biomass degradation, and as a green oxidant, it’s pretty hard to beat.  So I was a little surprised to learn that of the many cool aerobic synthetic methods that have been developed in the last decade, very few are used in industry.  The big drawback, especially on large scale, is safety – oxygen is usually the limiting reagent in the combustion reaction, and things can get pretty crazy when you have an oxygen-enriched atmosphere (and much crazier with liquid oxygen – check out this awesome video, and this one that Marty had in his last post).  So while stirring 100 mL of toluene under a balloon of pure oxygen might be fine, doing the same thing with 100 L is problematic.

This setup doesn't scale up very well

Safety aside, these reactions suffer because proper gas-liquid mixing is more difficult to achieve as you scale up.  All of this prompted a collaboration between Eli Lilly and Shannon Stahl‘s lab to develop a scalable continuous-flow method for aerobic alcohol oxidation, which avoids these problems. Continue reading