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

Maker Faire 2010 has brought me back from the dead

It's been a long time since I've posted. I admit it. I'm not happy about it, but my energies have been unbelievably sapped. I attended an event last weekend that revitalized my faith in science as something FUN, though. (Note: this is the same post that I've also put at Chemistry Blog.)

The Maker Faire is a "World Science Fair" event conceived and organized by those who produce Make magazine, which is described as "a do-it-yourself technology magazine written by makers."  It was held in three cities this year - NYC, Detroit, and the Bay Area.  The Faire happened in NYC at the New York Hall of Science in Queens last weekend and was a fantastic, energetic composite of things going on.  Well worth the trek to get out that far into Queens!

The event embodied the "do-it-yourself technology" theme, featuring exhibits with a heavy focus on science, cool demonstrations, and lots of do-it-yourself booths where "makers" hosted hands-on activities for children and adults alike.   Naturally, something like this was irresistible to me, and I was able to attend for free since I was volunteering at a booth (unrelated to science or technology - I was with a group of a different kind of maker).  I didn't get too much of a chance to spend time at many of the huge number of booths and exhibits, unfortunately, which was a huge bummer.

The schedule was overwhelmingly packed - definitely intended for people to spend an entire day there.  There was a demonstration stage, multiple craft tents, a huge food area, a beer tent tucked in there (which seemed to result in me getting security to throw out one guy who was harassing one of the women I was working with), and a large handmade craft sale section hosted by BUST magazine called BUST Craftacular.

Activities included "Cardboard Music," where instruments were made from cardboard and found objects, a live presentation called "Thinking Like a Scientist" (some demonstrations of which are 200 years old) given by Wizard IV (Steve Jacobs), who also happens to be the science consultant for MythBusters.   MakerBot Industries was there - they create 3D printers that you assemble and then can then function as a little factory to make things for you (see the company website for more awesomeness).  One of the biggest pulls for visitors was the "Reverse Geocache (TM) Puzzle" - unlike using GPS to locate boxes around the country/world, you are given the box, but it won't open unless you are at particular coordinates that've been programmed into it, and you have a limited number of clues to find that exact location.   Add this fun kind of intellectually stimulating product, activities and ideas, to children's rides, music shows, tasty paella, and handmade crafts, and you've got one heck of a good sciencey time.

Check out images of the event on their own website, as well as those on CNET, guaranteed to be focused on the super techie stuff.

Some science for raw foodists

I once lived with a woman who insisted that cooking food broke down the enzymes that we so desperately need from the food.

...

This same roommate also insisted that water kept at room temperature was more "alkaline" than when it was cold.  (Though this website insists that the water must have a pH = 10 to have this effect, and that if you drink it, it will clean toxins from your body. She insisted temperature alone achieved this desired effect.) 

...

She was taking general chemistry at my university at the time, in my very department.  Apparently equilibrium means nothing to her... would you trust her as your doctor?  Excuse me, as your holistic natural medicine doctor who seeks to legitimize the profession by attending medical school.  I have zero beef with natural medicine, don't get me wrong, but more alkaline at room temp??  Is there a temperature dependence constant missing from H₂O → H⁺ + OH^- ??  F, man.  I have a beef with momos who deny the fundamentals of general chemistry.  Or who doesn't realize that the person or book that told her that might've said the pH was higher...

So, I acknowledge the health benefits of restricting the amount of processed food that one consumes, and in many fruits and vegetables, cooking does cause vitamins to leach from the greens into water, sometimes to an alarming degree.  Freezing in many cases also causes nutrient-dense foods to lose their potency.  Thanks to an article that just came out in Journal of Agricultural and Food Chemistry, we can now argue that at least eggplants do not behave the same way.  

Sample preparation:  Eggplant (the "black bell" variety) was grown in a research facility in Lodi, Italy, selected by visual inspection to be homogenous in size, color, and free from diseases or pests.  The fruits were cut into 1 cm slices and treated one of three ways - 1) kept raw (freeze-dried and lyophilized); 2) grilled on a surface of 190-210C such that the inside reached and stayed at 100C; 3) boiled in 10 min in tap water at a 1:10 fruit:water ratio such that the inside of the slices reached and stayed at 100C.  The grilled and boiled fruits were cooled for 1 minute at room temperature, then immediately frozen and lyophilized until constant weight was reached.   From these samples, 2 g samples were taken from each treatment group, treated twice with 55 mL 75% EtOH at 60C then dried with 20 mL acetone until constant weight to produce ethanol-insoluble residue, EIR.  (I bet you never thought about food sample preparation in science before, eh?)

Analytical chemical analyses:  

• Total polyphenol index was measured with RP-HPLC and the quantity of chlorogenic acid determined, since chlorogenic acid is the predominant polyphenol found in eggplant.  Anthocyanins from the peels were quantified as well.  
• Glycoalkaloid content (solamargine & solasonine, which you really don't want to eat in gigantic quantities as they are toxic in high doses) was determined from 0.5 g tissue treated with 95% ethanol and analyzed by RP-HPLC.  

• Antiradical activity, signified by superoxide anions and hydroxide radicals, was determined using ESR (electron spin resonsance) spectroscopy 1 minute after generating these species via:    
• Superoxide anions were generated by treatment of eggplant extract with 6.4 mM KO₂-18-crown-6 1:1 in DMSO followed by spin trapping with 25 mM 5,5-dimethyl-1-pyrrolin-N-oxide (DMPO)
• Hydroxyl radicals were generated by treatment of extract with 2 mM Fenton system (?) in 0.1M phosphate buffer (pH=7.4) followed by spin trapping with 10 mM DMPO

Biological assay:  Human polymorphonuclear neutrophils, which are the most common type of white blood cells (shown at the left surrounded by red blood cells), polymorphonuclear because their nuclei are often lobed -  are a type of granulocytes (dubbed so because their cytoplasms are granular in appearance).  These cells were isolated from human blood samples and chosen because when under oxidative stress, they produce oxidative species (as a good white blood cell should!) including superoxide anions, peroxides, oxygen radicals, hydroxyl radicals, and HClO, which are all considered "reactive oxidative species" (ROS).  The assay involved viewing the cells under a fluoroscence microscope to visualize the chemiluminescence produced by luminol when luminol is reacted with one of these ROS; this "luminol-amplified chemiluminescence" (LACL) assay allowed the researchers to measure oxidative bursts given off by the cells in response to varying concentrations of the eggplant extract; the fewer the bursts, the more antioxidant species the extract contains as the cells are emitting fewer ROS.

The authors found that cooking didn't affect the glycoalkaloid content, but the phenolic content was increased threefold, most likely due to greater extractability of the compounds by cooking.  The effect of the extract on the neutrophils was very marked, and the researchers were able to extrapolate that approximately 40 - 80 g of eggplant, which can be obtained in one serving, may be able to react with all the neutrophils in the body.   The following TOC graphic (black & white in the paper) shows that at higher concentration of extract, the inhibition of ROS is greater - though the concentrations needed to cause this effect are quite low.  Hope you like eggplant!  Make sure you grill the heck out of it.

• Lo Scalzo, R., Fibiani, M., Mennella, G., Rotino, G., Dal Sasso, M., Culici, M., Spallino, A., & Braga, P. (2010). Thermal Treatment of Eggplant (L.) Increases the Antioxidant Content and the Inhibitory Effect on Human Neutrophil Burst. Journal of Agricultural and Food Chemistry DOI: 10.1021/jf903881s

Pinacol boronates from arylamines

Pinacol boronates are important synthetic building blocks used predominantly in the Suzuki-Miyura coupling reaction. Instead of a boronic acid, R-B(OH)<sub>2, the hydroxyls are substituted with a cyclic organic moiety, commonly pinacol. These compounds are often generated via iridium catalysis with alcohols and diboron starting materials; the use of metals in their synthesis complicates industry synthesis, however, as boronic acids and esters at time can be unstable and thus difficult to purify. Price is also an issue, as many of these molecules are pricey.

Fanyang Mo and authors from Peking University have published a method to convert arylamines to pinacol boronates without the use of metals at room temperature. This is great news. The approach uses a Sandmeyer-type reaction sequence to activate the amine, the diboron reagent B 2pin2, and a catalytic amount of a radical initiator, benzoyl peroxide (BPO). Unfortunately, there are some limitations on the substrate scope as the substitution - and hence, the electronics - of the aryl ring strongly affect the reactivity of the arylamines. For example, meta-substitued electron donating groups are not tolerated, and steric bulk via ortho substituents do result in low yields or even trace amounts of products. Halogen substituents are tolerated, though, which could potentially be useful further on in a synthesis for orthogonal reactivity. The optimized reaction conditions and a sampling from the substrate table are below.</sub> 

_{As the isolation of boronic acids and esters can sometimes be tricky, the researchers were able to establish that the crude material can be treated with activated charcoal and filtered through Celite to produce a compound that can undergo the Suzuki-Miyaura reaction (under standard conditions) well.  Those provided in the paper are below.  Cool, huh?}

• Mo, F., Jiang, Y., Qiu, D., Zhang, Y., & Wang, J. (2010). Direct Conversion of Arylamines to Pinacol Boronates: A Metal-Free Borylation Process Angewandte Chemie International Edition DOI: 10.1002/anie.200905824
  

Fabulous methylene functionalizations

M. Christina White from UIUC has again hit Science with her direct C-H functionalization chemistry in the January 29th issue (doi: 10.1126/science.1183602). As an alternate route to traditional functional group modification, White's group, and those of groups pursuing C-H functionalization (which I mentioned in my previous post) seek to "streamline" synthesis by cutting out unnecessary steps and going right in for the kill at the otherwise "inert" C-H bond.  Badass. 


In this paper, selective methylene C-H oxidation is achieved with substoichiometric amounts of peroxide, acetic acid, and the same catalyst as published in the same journal in 2007 for tertiary C-H bond activation, Fe(S,S-PDP) - nice environmentally friendly conditions.  This time the catalyst is selective for secondary C-H bonds when tertiary positions are unfavored due to additional sterics or a nearby electron withdrawing group (EWG).  This was indicated in one of the substrates in the 2007 Science paper, so it's not a huge surprise nor is it fishy that the selectivity is suddenly "different." 

Normally, tertiary C-H bonds (tertiary = 3 C's attached to the C) are the easiest for this catalyst to cleave as they are the most electron-rich C-H bonds of the molecule, but the catalyst is surprisingly - and predictably - selective for certain secondary C-H bonds, as demonstrated with a substrate scope table and a few complex molecules to boot.  The C-H bond that is oxidized:

• Is the furthest from any EWG, which would obviously deactivate the bond by reducing electron density
• Furthest from bulky carbon substituents (i.e. dimethylene)
• Next to an sp² hybridized substituent (including a cyclopropyl group) or an atom with lone pairs (i.e. ethereal oxygen)

These are all very intuitive factors to drive selectivity.  One of the tables neatly summed them up with examples, so I'm reproducing it here (crappily), complete with White's signature office-wall yellow:

Check out this exquisite example of applying the methodology to a more complex substrate - the method predicts the sites of oxidation well.  

Picky, skeptical scientist that I am, I'm a wee bit bothered by the lack of integrations on the ¹H NMR spectra and the obvious alteration of the HMQC spectra  in the Supporting Information (it looks like someone dragged around the big spraypainter in Paint - at least when I viewed it on a Macbook Pro).  I suppose beautification is important, but why don't I get to see the dirty specks??  Anyway, there are 2 different sets of conditions to perform this reaction, one of which is sometimes better than the other - either a slow addition with 25 mol% catalyst and the peroxide (~1h) via syringe pump, or 3 iterative additions with 5 mol% catalyst and the peroxide in each, dropwise.

There's been ANOTHER paper recently wherein the authors from Penn State, Y. Feng & G. Chen, report a direct functionalization of a methylene C-H bond in Angew. Chem. Int. Ed. (doi: 10.1002/anie.200905134), "Total Synthesis of Celogentin C by Stereoselective C H Activation."  Celogentin C is a bicyclic peptide active against tubulin polymerization isolated from Celosia argentea.  

The parts of the synthesis I'm summarizing install the part of the molecule that is dark green, and the methylene indolylation occurs at the bright green bond.   By using an iodoindole and a palladium catalyst with a temporary palladium-coordinating group to direct the reaction to the specific C-H bond, the reaction proceeds in good yield and excellent regio- and stereoselectivity.  The chemistry is inspired by the strong precedent (same substrate, same conditions) by Corey in Org Lett in 2006 (doi: 10.1021/ol061389j) where the same bond was either arylated or acetylated.  In this paper, the difference is the iodoindole, which is prepared from tryptophan.  Tryptophan is protected, nitrated, the nitro group reduced, and a Sandmeyer reaction applied to convert to iodine.  The C-C bond is then formed via palladium-catalyzed coupling at the methylene beta to the carbonyl.  The phthalate protecting group is used though azide is needed there later on in the synthesis because the indolylation shut down in the presence of the azide. 

Presumably, the above intermediate forms according to the authors, and it is this species that performs oxidative addition with the C-I bond and reductive elimination to produce the coupling.  I don't like the idea of the C-H insertion happening immediately, but perhaps the slowness of this step is why 2 equivalents of this coupling partner is optimal.  Oxidative addition into the iodide, especially considering the presence of the silver salt, SHOULD theoretically be first, but if Corey proposed the reverse order, then, well.

For more awesome chemistry like this, check out a recent review in Chemistry, doi:  10.1002/chem.200902374, published in memory of Keith Fagnou. 

• Chen, M., & White, M. (2010). Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation Science, 327 (5965), 566-571 DOI: 10.1126/science.1183602

• Chen, M., & White, M. (2007). A Predictably Selective Aliphatic C H Oxidation Reaction for Complex Molecule Synthesis Science, 318 (5851), 783-787 DOI: 10.1126/science.1148597

• Feng, Y., & Chen, G. (2009). Total Synthesis of Celogentin C by Stereoselective CH Activation Angewandte Chemie International Edition DOI: 10.1002/anie.200905134

cLicking hard-core sugar balls

Check out this post by Everyday Scientist alerting the audience to a rare gem of an article title in Chemical Communications, "Clicking hard core sugar balls".  He took out the C.  Amazing.

Real post coming tonight, just need to Chemdraw a bit.  Weather's been too shitty for me to care about anything other than sleeping!

Chaos!

Anyone check out asaps for J. Agric. Food Chem.?  There's actually some good stuff lurking in there.  Not just hilarious TOC graphics of chaotic olive oil.

A Novel Method To Quantify the Adulteration of Extra Virgin Olive Oil with Low-Grade Olive Oils by UV-Vis

J. Agric. Food Chem., Article ASAP

DOI: 10.1021/jf903308u

Nickel catalyzed aryl-X - alkyl-X coupling from a new group

Looking through current organic methodology literature, we all see tons of 'copper-catalyzed this' and 'ligandless palladium-catalyzed cross-coupling' that and even now the onset of 'direct C-H functionalization' blablabla.  Of course that stuff is important, and my own methodology involves this kind of chemistry, but it's just a matter of fine-tuning all of the reaction conditions to work with the electronics of your particular substrate.  We are continuously hard-pressed to find truly general reaction conditions that we can throw at any ol' aryl halide and get coupling to form a C-C bond.

One of the issues with traditional cross-coupling reactions is preparing the cross-coupling partners; usually we try to mix R-X, with X being Cl (ideally), Br, I or OTf, with a second molecule that has to have a transmetallating group or otherwise activating group (boronic acid/ester, organocuprate generated in situ, etc.; see Sonogashira, Suzuki, Negishi, Buchwald-Hartwig or Hartwig-Buchwald coupling depending on who you talk to, and Stille, to name a few of these cross-coupling named reactions with preformed coupling partners).  Toss in some ligand, base, and transition metal complex and you've got a catalytic system for C-C bond formation.

To circumvent the necessity of this group, direct functionalization of an sp² C-H bond is becoming quite popular and works well for some substrates (see work of Lautens, the late Fagnou, Daugulis, Sames, Cheng, Bellina/Rossi, and Mori, just to name a few of the many).  This requires intense screening and optimization, however, and possibly requires directing groups; a few examples (linked to references) are arylation (popular), alkylation, cyanation, hydroxylation, and allylation.

The glory of JACS has recently given us R-X / R-X coupling between aryl iodides and alkyl iodides catalyzed by nickel reported by the brand new Weix group at the University of Rochester, "Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides" (DOI: 10.1021/ja9093956).  The authors sought to find a system that minimized the common cross-coupling complications - homocoupling and/or reduction byproducts, having to use an excess of one of the coupling partners, and using a stoichiometric amount of a reagent required for the transmetallation.  Aryl and alkyl halides have been coupled before through organometallic intermediates like alkyl-ZnI or alkyl-MgBr, but the tolerance for acidic protons such as OH and the slow timescale of insertion by the Mn⁰ reductant provide evidence that the mechanism is more direct, without such an intermediate species.  Check out the paper for the decent substrate scope.

The reaction and conditions are as follows:

My favorite example?  The conditions tolerate a boronic ester which you DEFINITELY wouldn't get using palladium, so you can build your own reagent to be used in a future Suzuki.  Woohoo!  I look forward to the future publications of this group.

Reaction of the Week #2 - Strecker reaction & amino acid synthesis

I selected the Strecker synthesis based on a recent Nature paper by Jacobsen and coworkers using an asymmetric Strecker synthesis to create unnatural α-amino acids. The classical Strecker reaction, first reported in 1850 (!), involves the reaction of a carbonyl acompound (ketone or aldehyde) with ammonia (to create the free amine) or primary or secondary amines to form an α-amino nitrile, which can be followed by acidification to hydrolize the nitrile group to a carboxylic acid.  (The intermediate may also be reduced to produce 1,2-diamines or undergo α-substitution chemistry following deprotonation at the α-position, provided there is an available proton). The mechanism/sequence concluding with acid-catalyzed, sans the formation of the iminium and acid stepwise, is shown below.

The entire sequence can be achieved in one pot.  This reaction and the synthesis of amino acids can be easily rendered asymmetric using a chiral Lewis acid or an organocatalyst (in the latter, the additive would coordinate to the imine nitrogen...it would obviously have to be trisubstituted/neutral for this to occur) and another basic moiety at the appropriate distance would associate with the proton from HCN, pulling H away and direct the CN to whichever side of the imine it is closest to.  Anionic CN sources are generally a problem because of the toxicity of the CN anion, and so improvements and modifications to the reaction are continuously made.  Examples of reagents include Bu₃SnCN, TMSCN (which is expensive and difficult to handle), Et₂AlCN, and HCN; while KCN and NaCN are desirable as they are inexpensive and easily handled cyanide salts, they are not typically seen presumably due to their low solubility in organic solvents unless buffered aqueous medium is used, according to the authors of the Nature paper.

A neat caveat to α-amino nitriles is that if they are treated with a heavy metal salt (such as a Ag(I) salt), a Brönsted or Lewis acid, cyanide can be a leaving group to reform iminium which is trappable by a nucleophile - when the nucleophile is organometallic, the reaction is the Bruylants reaction.

Jacobsen and coworkers have developed a chiral catalyst derived from (S)-tert-leucine (read: inexpensive and accessible) to achieve asymmetric imine hydrocyanation.  Using 2 equivalents of TMSCN, 2 equivalents of MeOH, and 0.5 mol% of the catalyst in 0.2 M toluene at -30C for 20 hours, excellent yields were achieved with good to excellent ee with the exception of only a few of the reported substrates which were still in good yield.

A nice graphic that explains the enantioselectivity was presented in the paper:

Another example which is included in the entry in Kürti and Czakó text is in the synthesis of (-)-α-kainic acid, a neurotoxic compound that induces seizures (it is used in research commonly to induce seizures in rats).  It is a kainate receptor agonist (hence its name), and since the kainate receptor is one of the "ionotropic glutamate receptors" it is understandably a stimulant (glutamate is an excitatory neurotransmitter).  The Strecker reaction in this case is mediated by zirconium with the Schwartz reagent to form imine, which was not isolated but directly treated with cyanotrimethylsilane to produce the α-amino nitrile.  Hydrolysis to the acid and concomitant epimerization selectively led to (-)-α-kainic acid.

I hope you like the festive-colored kainic acid!

Starfruit visualied with SEM

Have you ever had starfruit (also called carambola)?  Personally, to me they taste like apple, without the grainy texture, and they're super cute.

The Talapin group at the University of Chicago has taken some SEM images that look JUST like them.  Yum!

Size-Dependent Multiple Twinning in Nanocrystal Superlattices 
J. Am. Chem. Soc., Article ASAP (doi: 10.1021/ja9074425)

 

Reaction of the Week #1 - Schmidt reaction

I intended this to come out at least a week ago, but with the holiday season seems to come family crises and deaths.

So. The Schmidt reaction.  Its seminal publication came in 1923 It's pretty commonly known, and very similar to the Curtius and the Hofmann rearrangements taught in undergraduate organic II.  It can transform a carboxylic acid into an amine one carbon shorter, an aldehyde into a nitrile (generally aromatic aldehydes), or a ketone into an amide or lactam (depending on the starting material) with the addition of HN₃, hydrazoic acid, in acidic conditions (the first few times I looked at it my brain saw NH₃, so watch out).  Other groups that may react with HN₃ are nitriles, imines, diimides, some alkenes, and alcohols, according to the Kürti and Czakó text, as well as any other acid-sensitive groups.

The intramolecular version appears in the literature frequently.  An alternative electrophile to those listed above (and the acid-to-carboxonium shown in the mechanism) is a leaving group, such as an iodide, triflate, tosylate or nosylate.  A recent JACS Communication by Kapat and coworkers at the University of Berne (Switzerland) used an acid-free version of this variation that produced great enantioselectivity of a natural product from tree frog skin, (-)-indolizidine 167B.  (This target is fairly attractive for the challenge of that particular stereocenter; a quick Google search will show you quite a few other approaches.) This is the TOC graphical abstract...to be honest the colors are what made me check it out.

The full synthesis is detailed below. There was a few interesting reactions so I wrote the synthesis out stepwise.  Copper-catalyzed asymmetric allylic substitution with a Grignard reagent enantioselectively installed a t-butoxypropyl group.  The terminal alkene then underwent carboazidation - which is a really neat reaction, though at first glance the reagents looked like some gen. chem. magic.  Reduction of the ester to the alcohol which was tosylated and then reduced resulted in the desired propyl side chain.  The t-butyl ether was cleaved under mild Lewis acidic conditions to produce the free primary alcohol.   Note the box with various deprotection conditions for t-butyl ethers (the group is generally installed with isobutene in the presence of acid).

The last few steps where the Schmidt comes in are as follows:

The free alcohol is converted to the triflate, which is nucleophilically attacked by the azide anion.  A 1,2-alkyl shift ejects nitrogen gas, and reduction of the iminium product results in 98% ee, 79% yield of the natural product.