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Green Chemistry via Continuous Flow

“Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906” Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op200340c

“Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin.” Lévesque, F.; Seeberger, P. H. Angew. Chem. Int. Ed.. 2012, 51, 1706-1709. DOI: 10.1002/anie.201107446

“Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy” Cervera-Padrell, A. E.; Nielsen, J. P.; Pedersen, M. J.; Christensen, K. M.; Mortensen, A. R.; Skovby, Dam-Johansen, T. K.; Kiil, S.; Gernaey, K. V. Org. Proc. Res. Dev. 2012, ASAP. DOI: 10.1021/op2002563

A little while back I wrote about an aerobic oxidation which was greatly improved by switching from a traditional round bottom flask setup to a continuous flow reactor – basically, continuous flow reactors are much better at handling oxygen, especially on scale.  But most of the advantages of the flow reactor were specific to that reaction, and it wasn’t clear to me how a flow process would improve a reaction that doesn’t use oxygen, or some other gas.  Fortunately, a lot has been published since then to help me get a handle on how continuous flow reactions can contribute towards greener processes.  In particular, this review covers continuous processing within a green chemistry context, and Organic Process Research and Developement has a continuous flow themed issue in their ASAP section, including this process-oriented review (speaking of OPRD, check out this recent editorial concerning solvent selection and green chemistry).  It turns out that flow chemistry can improve processes in a bunch of different ways, and it’s hard to get a sense for how this can work by just looking at one reaction.  So I’ll cover a few different reactions that illustrate different green aspects of continuous flow reactors.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture.  This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale.  One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative.  The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

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Iron-Catalyzed C-H Amination

“Iron-Catalyzed Intramolecular Allylic C-H Amination” Paradine, S. M.; White, M. C. J. Am. Chem. Soc. 2012, 134, 2036-2039. DOI: 10.1021/ja211600g

In their recent communication, Christina White’s group at Illinois reports a new allylic C-H amination catalyzed by iron. This builds on previous work from their group in Pd sulfoxide catalyzed allylic amination and iron catalyzed C-H oxidation. In addition to showcasing an exciting reaction, this paper is a great contribution from a green chemistry perspective: they use a cheap, non-toxic metal catalyst to do a highly selective C-H oxidation reaction, one that streamlines the synthesis of C-N bonds directly from the (relatively) unreactive C-H bond. Interestingly, quantitative comparisons are made throughout the paper to the more commonly used Rh2(OAc)4 catalyst.

They start by screening Fe catalysts for intramolecular allylic amination reactivity of sulfamate substrates. Although the polypyridyl Fe complex they have used previously for hydroxylation and desaturation chemistry gave a low yield of product, the phthalocyanine Fe complex 1 gave a good yield (and better than a tetraphenylporphyrin iron complex) of allylic amination. Importantly, they obtained only trace quantities of the aziridination product, showing the high selectivity of the iron-catalyzed reaction (>20:1).

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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.

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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!

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. (more…)

Hydrogen-Mediated C-C Coupling to form Allylic Alcohols

“Direct Vinylation of Alcohols or Aldehydes Employing Alkynes as Vinyl Donors: A Ruthenium Catalyzed C-C Bond Forming Transfer Hydrogenation”  Patman, R. L.; Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009131, 2066-2067. DOI: 10.1021/ja809456u

In their 2007 JOC perspective on hydrogen-mediated C-C bond formation, Krische and co-workers point out that “upon consideration of the E-factor for various segments of the chemical industry, a strong inverse correlation between process volume and waste generation is observed.”(1) Given that the lower volume fine chemical and pharmaceutical sectors typically focus on the production of chemicals with higher degrees of molecular complexity then their bulk chemical counterparts, the authors propose that there is a persistent need for the development of selective, atom-economical reactions capable of producing these relatively specialized chemicals. As luck would have it, the Krische group has come to the rescue with a number of reactions that might fit the bill.

One such reaction is their recent report of the ruthenium-catalyzed vinylation of alcohols or aldehydes using alkynes as the vinyl donors (shown above).

I think this reaction is neat because it represents a departure from how people have typically gone about bringing alkynes and alcohols together to form allylic alcohols. In this early example from the Wipf group, (more…)

From Biomass to Commodity Chemicals

“An efficient didehydroxylation method for the biomass-derived polyols glycerol and erythritol.  Mechanistic studies of a formic acid-mediated deoxygenation” Arceo, E.; Marsden, P.; Bergman, R. G.; Ellman, J. A. Chemical Communications, 2009, 23, 3357. 10.1039/b907746d

Scheme 1, Proposed Conversion of Biomass Into Value Added Chemicals

A major focus in the area of “green” methods development is the mild and selective removal of functionality from readily available bio-derived feed stocks.  Unlike petrochemical derived starting materials, the majority of biomass is highly oxygenated (think carbohydrates or lignin), and before the carbon embedded within this framework can be used for all-purpose chemical manufacturing the oxygen must be removed. (more…)