More copper, please - Part 2 of 4

The next focus on copper-catalyzed reactions is direct C-H functionalization.  You may be able to tell from past posts that I have a special place in my heart for direct functionalization of C-H bonds.  A few recent papers use copper to achieve these kinds of reactions; I'm going over 2 here, bulleting the key points so that there aren't paragraphs upon paragraphs to read.

The first, "Copper-Catalyzed Direct Oxidative C-H Amination of Benzoxazole with Formamides or Secondary Amines under Mild Conditions" recently in JOC (doi: dx.doi.org/10.1021/jo200447x) features:

• The authors developed a catalytic system to form C-N bonds of azoles by decarboxylative coupling with formamides or direct C-H amination with secondary amines using Cu(OAc)₂.H₂O, 2 equivalents benzoic acid, and oxygen as the oxidant [to oxidize Cu(I) back to Cu(II)].  
• No base needed - only multiple equivalents of an acid additive. 

• Lower temperature allows direct coupling of amines to the azole core instead of decarbonylation of a formamide.  
• Conversion of benzoxazoles best, with drastically lowered yield for benzothiazoles and no reaction with benzimidazoles (we just can't get general methods in C-H activation can we?!). 
• Tolerates various aliphatic and methyl benzyl amines, including morpholine (55%) and diallyl amine (20%), with higher yields for less sterically hindered, electron-rich amines. 

• Is 20% really "catalytic"? 
• I'm sure the yields and scope suffer because of all the HX that's getting churned out - should use two equivalents of acid AND a base, since using both works for recent direct functionalization in palladium chemistry (substoichiometric HOPiv with multiple equivalents of a carbonate base, for example). 
• Authors they claim it's not protonating the azole in order to make it more electrophilic for the amine, or the Cu-amine complex, to attack.  The jury's still out on this mechanism, in my opinion. 

The next copper-loving paper is brought to you by the Daugulis group at the University of Houston (JACS 2011, 133, 9286-9289 doi: dx.doi.org/10.1021/ja2041942).

• Perfluoroalkylation of aryl iodides using 1H-perfluoroalkanes catalyzed by 10% CuI with 20% phenanthroline, whereas the group previous published perfluoroarylation conditions.
• Existing methods rely on either stoichiometric copper or suffer in substrate scope; also usually require R_FSiR₃ reagents, which are limited in the number that are available.
• Scope and conditions:

I particularly like the Daugulis paper because one doesn't normally think of polyfluorinated alkyl chains as being staple functionality to include in small molecule libraries in biologically active molecule discovery; this chemistry makes it highly accessible.   Early mechanistic studies support the following as the mechanism. 

Anyone have a favorite reaction with copper in it? 

• Yaming Li, Yusheng Xie, Rong Zhang, Kun Jin, Xiuna Wang, & Chunying Duan (2011). Copper-Catalyzed Direct Oxidative C–H Amination of Benzoxazoles with Formamides or Secondary Amines under Mild Conditions Journal of Organic Chemistry : 10.1021/jo200447x

• Popov I, Lindeman S, & Daugulis O (2011). Copper-Catalyzed Arylation of 1H-Perfluoroalkanes. Journal of the American Chemical Society, 133 (24), 9286-9 PMID: 21627068

More copper, please - Part 1 of 4

Lu and coworkers from the Tsinghua University in Shenzhen, China have just published a method in Org. Lett. to create a combined isoindolinone and 1,4-dihydropyrazine core by copper-catalyzed direct C-H amination, with the goal of creating a new scaffold for potentially biologically active heterocycles.

Screening of copper catalysts with acid additives resulted in the following set of conditions in 8-48 hours, which allow for fluoro, chloro, bromo, and ether groups appended to the aryl rings... I'd like to have seen a broader substrate scope at least addressed in the paper.

The inclusion of a potential mechanism was obviously included just out of necessity in a methods paper, and the arrows are pretty much what I could make of it.  The pyridinium nitrogen draws copper in close, bites it,  and isomerizes allowing the Cu-N bond to do some acrobatics and add across the double bond, followed by rearomatization and elimination of the barely-catalytic copper (I am of the school that views 20% as sub-stoichiometric, NOT catalytic).  But! My purpose in including this paper in this post was to demonstrate the cool stuff that copper can do that we'd normally just assume palladium would be used for, and to comment that I'd be interested to see what, if any, biological activity these structures offer.  Each day this week (or over the next 2 weeks) I will address a different transformation via copper catalysis. 

• Lu J, Jin Y, Liu H, Jiang Y, & Fu H (2011). Copper-Catalyzed Aerobic Oxidative Intramolecular Alkene C-H Amination Leading to N-Heterocycles. Organic letters PMID: 21696194

Phenols from cyclohexanones!

A Science Express paper (doi: 10.1126/science.1204183) just came out by Shannon Stahl's group (Wisconsin-Madison) featuring chemistry that can aromatize substituted cyclohexanones or cyclohexenones to phenols using a palladium catalyst.  This type of double dehydrogenation reaction has previously been difficult to achieve under reasonable reaction conditions, typically requiring complex catalysts, continuous-flow reactors, and/or extremely high temperatures.  No side products are produced in this reaction other than water.  The only downside to me is the DMSO solvent... I hate that stuff.  The conditions seem relatively straightforward - I can't believe someone hasn't found - or at rather, explored (see below) - this sooner!

1 atm O₂ and the relatively low temperature (compared to ~200-550 typically reported in the literature) make this an easily achievable benchtop reaction. The conditions were developed with the reasoning that the catalyst should be relatively electrophilic, since the key steps in the presumed reaction pathway were C-H activation (to nab the electron density you'd need an electrophilic catalyst) and β-hydride elimination.   The tosylic acid protonates the dimethyl amino group, rendering the ligand even more electron-deficient, thus the need for it in the reaction to improve the yield.

Figure 1A is the rationale for the transformation:

Electron donating and withdrawing groups are tolerated on aryl substituents, as are aryl ethers and esters, and halogens with the exception of para-bromide (28%) and iodide (16%), conveniently left out of the substrate table.  I'm sure the literature will reveal applications of this method to even more complex and highly functionalized systems, and hopefully the group continues mechanistic investigations so more reactions like this can be rationally developed.

It should be added that this is not the first time this type of reaction has been achieved at a reasonable reaction temperature with a palladium catalyst, but a previous (uncited!) Org. Lett. paper in 1998 saw phenol produced as a side product in selective dehydrogenation of ketones to produce allyl phenyl ethers, as in the following example from the screening table that produced undesired formation of phenol.

• Yusuke Izawa, Doris Pun, & Shannon S. Stahl (2011). Palladium-Catalyzed Aerobic Dehydrogenation of Substituted Cyclohexanones to Phenols Science : 10.1126/science.1204183

Do Not Publish

Is someone at Nature trying to send us a message?  The following showed up in the RSS feed that I pick up with Google Reader.

Christmas Lights Catalyze Oxygen Transfer Reactions

Some chemists and biochemists at the Simon Fraser University in British Columbia have published some neat biochemistry that isn't quite represented by their TOC graphic, which is a bit fuzzy and might be Christmas lights.   The graphic within the paper is much clearer.

Guanine-Rich RNAs and DNAs That Bind Heme Robustly Catalyze Oxygen Transfer Reactions

J. Am. Chem. Soc., Article ASAP (doi: 10.1021/ja108571a)

 

Kudos to the Fagnou Group

I am continuously impressed by the publications that have appeared since Prof. Keith Fagnou's shocking passing a little over a year ago. The chemical community still mourns; it is clear from these post-mortem publications that Fagnou's - and his clearly dedicated and talented graduate students and post-docs - brilliance lives on.

The chemistry that Fagnou has truly spearheaded, direct C-H functionalization, is a method of forming C-C, C-N, C-B, etc bonds without having to prepare one of the coupling partners, as in traditional transition-metal catalyzed cross-coupling reactions. Palladium, rhodium and ruthenium are commonly used catalysts in direct C-H functionalization reactions. Fagnou has published a great deal on arylation reactions of a wide variety of substrates and even a bit on direct benzylation reactions. Some fairly recent reviews are linked in a previous post.

A recent publication in Journal of Organic Chemistry (doi: 10.1021/jo102081a), "Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis," published by David Lapointe and coworkers, explores the development of two approaches to selectively functionalizing multi-ring systems - 1) using site-selective reaction conditions, and 2) a pathway with a particular order of reactivity according to a concerted metalation-deprotonation (CMD) mechanism. It is well-known in the field that a great many (hetero)arenes can be functionalized with (painfully) rigorous fine-tuning of the catalyst, ligand, additives, and other reaction conditions. Some substrates have been more difficult to functionalize than others, and selectivity of particular positions on these rings is always an issue - this publication tackles both issues.

To explore site-selective functionalization, the group used compounds with more than one available C-H bond for direct functionalization, and using multiple protocols specific for specific C-H bonds (Larossa's conditions for C2 arylation of indoles, Gaunt's Cu-catalyzed C3 arylation of indoles which is actually selective for meta to amido groups, and their own protocols for arylation of perfluorobenzenes and aromatic N-oxides) were able to successfully and selectively functionalize targeted C-H bonds in moderate yields. Here is an example with some decent yields, with reaction times ranging from 16 - 24 hours:

The alternative approach relies upon the CMD pathway as the operative mechanism, which favors electron-deficient substrates.  Several years ago, Echavarren published support of this mechanism by finding a preference for the most acidic C-H bond and requirement for a carbonate base, and Fagnou established the use of a pivalate additive, which was speculated to play a crucial role via CMD.   A recent mechanistic paper with aromatic N-oxides as the substrates strongly supports this mechanism.   The metal first inserts into the aryl-X bond, as expected, and in the key transition state, the pivalate coordinated to the metal deprotonates the C-H bond while the palladium forms a bond to the same C.  Reductive elimination (not shown) releases the arylated product.

In the current paper DFT calculations were found to agree quite well compared to competition reaction results of a series of heterocycles to elucidate the order of reactivity of the substrates.  Those presented in the paper are as follows, in order of reactivity - this is extremely convenient for the synthetic chemist who would like to utilize this chemistry.  And it's just plain neat - the kind of thing that will hopefully end up in a textbook someday. (Note: the last two substrates are either switched in the text or switched in the image - they don't agree in the paper and I haven't looked at the supporting information closely.)

Reaction conditions: 0.5 eq. of each of two heteroarenes in the competition experiment, 0.125 eq. 4-bromotrifluorobenzene, Pd(OAc)₂ 5 mol%, PCy₃.HBF₄ (10 mol%), PivOH (30 mol%), K₂CO₃ (1.5 eq.), DMA (0.3M), 100ºC.

And finally, for an example of the method in action - note that the difference between using this method and the previously described is that here, there aren't necessarily general optimized conditions available for each of the substrate classes here.  Examples of a few of these are peppered throughout the arylation literature but they aren't like indoles, pyridines, N-oxides, perfluorobenzenes, imidazoles, and pyrazoles and don't have their own special set of conditions (that I'm aware of at the moment).  Yields of included substrates range from 65-80%. Instead of optimizing conditions for each, the site of reactivity can be predicted with good specificity - here the indolizine C-H bond over the more electron-rich thiophene's:

Instead of an aryl bromide, benzyl chloride can be used as the coupling partner as well, with published yields from 55-84%.

• Lapointe, D., Markiewicz, T., Whipp, C. J., Toderian, A., Fagnou, K. (2011). Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis Journal of Organic Chemistry : 10.1021/jo102081a