New Reactions

Iron or Palladium: You Decide

ckellz — Tue, 21 Feb 2012 04:27:57 +0000

Prakash, G. K. S.; Krishnan, H. S.; Jog, P. V.; Iyer, A. P.; Olah, G. A. A Domino Approach of Heck Coupling for the Synthesis of β-Trifluoromethylstyrenes Org. Lett., 2012, 14, 1146.

Iron(II)-Catalyzed Trifluoromethylation of Potassium Vinyltrifluoroborates Parsons, A. T.; Senecal, T. D.; Buchwald, S. L. Angew. Chem. Int. Ed. Early View Feb 10th 2012

After a bout with a nasty cold and a presentation in front of the department, there is nothing better than returning to blogging. It has been a long while since my last post, which unfortunately (or fortunately?) has been due to all the stuff going on in the Leadbeater lab. While we don’t have any new papers to report on yet, we are certainly getting very close! Over the past couple of weeks we’ve made a lot of headway on our collaboration with Dr. Tilley. We’ve certainly hit a few roadblocks along the way but we’ve found some clever ways around them. DiAndra and I are wrapping up the project she has been focusing on for the past couple of months which we likely will be submitting to either JOC or Org. Lett. In fact, DiAndra also presented this work this week at a departmental seminar and did an excellent job! Both DiAndra and I presented on the same day though on different projects (I focused on some other work I’ve done along with our collaboration with Dr. Tilley). We (and the rest of the Leadbeater group) plan on giving more talks at the CGSS in Buffalo as well as at the fall ACS meeting in Philly. Other than that I don’t think there is much more to report so let’s get to the lit!
This week we have two interesting (if not somewhat related) articles disclosing methods to access trifluomethylated olefins. The first was a article released a few weeks ago by Prakash/Olah and co-workers detailing a clever way to access trifluoromethylated styrenes. Prakash and Olah are, in my opinion, the current leaders in organofluorine chemistry and have been featured before on New Reactions. Prakash is one of the pioneers of making trifluoromethylation practical thanks to his investigations with TMS-CF3. Prakash is a former student of Olah and hence they often work together on projects particularly ones involving fluorine or carbocations. This article is no exception. As part of a broad program to access trifluoromethylated synthons, Prakash and Olah became interested in accessing vinyl trifluoromethylated compounds.

The current methods available rely on two disconnects, at the CF3 group and at the C-C double bond. Neither is very effective for synthesizing these sorts of olefins and have many drawbacks (the former being complicated by the synthesizing the appropriate olefin precursor and the latter requiring the preparation of a trifluoromethylated ylide. Prakash decided to take a somewhat different approach. His disconnect was at the C-C=C of the olefin. Rather than forming the double bond or adding in the CF3 group, he wanted to attach 3,3,3-trifluoropropene to arenes in a Heck-like manner. Now Prakash was not the first to attempt this strategy. Fuchikami and co-workers used 3,3,3-trifluoropropene to prepare trifluoromethylstyrenes. However not only did this require one to work with 3,3,3-trifluoropropene (a gas at room temperature), a autoclave was also needed and the scope of the reaction was very limited. Prakash’s solution was rather simple but ingenious: generate 3,3,3-trifluoropropene in situ and couple it to a iodobenzene derivative via a Heck-reaction. In fact, his group had experience in these sort of domino elimination-heck reaction in the preparation of styrene sulfonate salts. The idea is that under the basic conditions of the reaction, a dehydrohalogenation occurs generating the olefin in situ which can subsequently be coupled by Pd(0).

Prakash and Olah therefore began their investigation using commercially available (and relatively inexpensive) 1-iodo-3,3,3-trifluoropropane as their 3,3,3-trifluoropropene precursor. Rather than using a autoclave for heating and pressure, they opted for something our group is familiar with: microwave irradiation. Prakash and Olah believed that this would dramatically shorten reaction times making this far more practical than Fuchikami approach. Unfortunately they hit a rough start. Their test substrate, 2-iodoanisole, proved to be slow to react under their initial conditions. The authors only got, at maximum, 40 % yield which they attributed to the steric bulk of the methoxy group. They then switched to 3-iodotoluene and were pleased to get far better yield and conversion (83% conversion, 63 % yield). They screened a variety of variables in the process: Pd source, base, solvent, and temperature.

After optimizing, they explored the scope (and it turned out to be quite wide). Many were pretty standard (iodonaphthalene, p-iodofluorobenzene, p-iodoanisole etc.). There were some odd balls though. Surprisingly, o-iodoaniline reacted quite well while o-iodobenzoic acid failed to react. They also screened heterocycles, though most attempts were meet with low yields or a complete lack of reactivity. While somewhat of a short article, it was very to the point and thorough and I really enjoyed it.

Only a couple of weeks later, Dr. Steven Buchwald at MIT published a article detailing a somewhat different approach to the synthesis of trifluoromethylated olefins. As with Prakash and Olah, Buchwald and his group have been

After a bit of screening, they found that Iron (II) chloride was the most effective catalyst for their desired transformation and gave excellent E/Z selectivity. They found that a variety of vinyltrifluoroborates could be transformed into vinyltrifluoromethylated olefins under their conditions, and most gave fair to excellent yields. In an effort to explain the selectivity of their reaction, they reacted both Z and E vinyltrifluoroborates and obtained near idential E:Z ratios. This seemed to indicate an alternative more traditional pathway (radical or carbocationic) rather than a organometallic reaction. With that in mind, they investigated whether a Lewis acid was a suitable alternative catalyst. Indeed, they found that tin triflate also successfully catalyzed their trifluoromethylation reaction, indicating the reaction is likely proceeding through a carbocation. And that’s exactly where Buchwald leaves you hanging. I bet we will be seeing more of this sort of reaction in the near future.

Well there you have it, two excellent articles detailing new methods to access trifluoromethylated olefins. Hats off to both Prakash’s group and Buchwald’s group for excellent, through jobs! That’s it for now, Ckellz…Signing off…

Filed under: Reviews

Organic Chemistry Memes

ckellz — Tue, 14 Feb 2012 00:19:56 +0000

Hi All,

Just made this facebook group today, hope you all like it. Feel free to like it and post some of your own memes…also new post coming soon!!!

Link:
http://www.facebook.com/pages/Organic-Chemistry-Memes/320354588001862

Filed under: Reviews

New Blog!

ckellz — Sat, 28 Jan 2012 15:32:51 +0000

Just ran across a new blog this morning by the Sussex Drug Discovery group over in the UK. It’s a bit more med chem oriented but it looks promising and will likely have a lot of useful information so go take a look!
Link:
http://sussexdrugdiscovery.wordpress.com/

Filed under: Reviews

In Soviet Russia, Catalyst Reacts You!

ckellz — Fri, 27 Jan 2012 11:45:23 +0000

Kuznetsov, A.; Gevorgyan, V. General and Practical One-Pot Synthesis of Dihydrobenzosiloles from Styrenes Org. Lett. ASAP January 24, 2012

No I’m not dead! Sorry it’s been so long since my last post but I have finally returned to New Reactions after a very very busy 4 weeks. But what a 4 weeks it’s been. So a quick update on the happenings in the Leadbeater lab starting with some bad news. We unfortunately did not get our flow paper into Organic Letters and have subsequently resubmitted to a more appropriate journal, Org. Proc. Res. Dev. where we believe it should get in. But really, that’s about it in terms of bad news. DiAndra and myself continue to make progress with the project we are working on (and its allowed me to get into all sorts of chemistry from making benzofuran to bromination of thiophenes). I’ve never worked with heterocycles as much as I have recent and I have greatly enjoyed it. We are a little behind where I would hope we would be but the reactions are progressing quite well and based on some recent findings, I think this one might be better suited in Organic Letters! As for other projects, we are in the midst of substrate screen for our collaboration with Dr. Tilley and it has been extremely successful! We hope to have that out by the middle of this year. I really am very excited to get that work out and a few other projects we have been working on that are near completion.
Last week was the start of the semester for UConn students meaning the the course that Mike is TAing (Adv. Org. Chem. Lab) has begun. I assisted him in preparing some of the labs as well as giving a joint lecture yesterday on ChemDraw. I think the students will really enjoy the reactions we have in store for them this semester (a RCM, a Sonogashira, Suzuki, Click, and Paal-Knorr to name a few)! I’m also giving a seminar next month on some of the work I’ve done thus far at UConn. I’m also looking into going to the ACS meeting in Philly in the fall to present there as well (hopefully with a bit more accomplished ). I do find it weird sometimes that I used to be so scared of public speaking but now I really enjoy it. I actually look forward to talks. I still get nervous right before the talk of course, but as soon as I get past that first slide, things just slip into autopilot. Plus I genuinely love just talking chemistry! And with that, let’s get to it.

I’ve had the chance to read a number of articles since my last post (many of them quite excellent) and I’d like to share with you a few that stood out to me as cool/interesting/useful:

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkynes and Aryl Boronic Acids Using (Trifluoromethyl)trimethylsilane: Describes a relatively effective way to synthesize trifluoromethylated alkynes and arenes. It’s an extension of some of the work done earlier by the Qing group which improves on yields by using a syringe pump and expands their reaction to include boronic acids as substrates.

Electron Transfer Reduction of Carboxylic Acids Using SmI2- H2O- Et3N: describes a general procedure for converting carboxylic acids directly to primarily alcohols in one step. I found this to be a very practical, easy approach to avoid using LiAlH4 or boron-based reductants and features a cool mechanism.

Fragmentation of β-Hydroxy Hydroperoxides: describes an investigation into the role of vitamins and transition metals (specifically Vitamin E and C in the presence of iron) in the oxidative cleavage of unsaturated fatty acids. While not really synthetically useful, it was a very well done investigation and gave plenty of mechanistic insight.

Oxidative Homologation of Aldehydes to α-Ketoaldehydes by using Iodoform,
o-Iodoxybenzoic Acid, and Dimethyl Sulfoxide: describes a convenient and very effective way to make highly reactive ketoaldehydes in situ and trap them as quinoxalines. What I like about this is the shear number of examples done by the authors and the potentially variable approach that can be used by simply switching the phenylene diamine or varying the starting aldehyde.

Efficient Palladium-Catalyzed Cross-Coupling of Highly Acidic Substrates, Nitroacetates: an article by the Koziowski group at UPenn which describes a very interesting coupling reaction between highly acidic nitroacetates with various aryl bromides. The article was great and I especially loved the colorful three dimensional graphs!

This week’s article comes from, you guessed it, Org. Lett. Its by a Dr. Vladimir Gevorgyan at the University of Illinois at Chicago, whose work I have been following for some time (this being the second article of his I will be featuring). Gevorgyan does chemistry that is near and dear to me, namely small ring synthesis, organosilyl work, C-H bond functionalization, and heterocycle synthesis. He’s sort of a jack of all trades when it comes to his chemistry, but he publishes very good work (in only the top named journals). In this new article, he focuses on a new (or arguably a very recently discovered) class of organosilyl compounds: dihydrobenzosiloles. Prior to the release of this article, no effective synthetic method was available to access these compounds. One example was given by Hartwig in a 2005 paper, but synthesis of these compounds was not the main focus (hence the article gives only one example under very harsh conditions). Dibenzosiloles and biarylbenzosiloles are far better known in the literature.

Seeking a route to these compounds, Gevorgyan decided to use a two-stage approach to their synthesis. The first step with be β-hydrosilylation of a styrene derivative using diphenylsilane as their hydrosilylation source. That would give the desired phenethyldiphenylsilane compound. With that in hand, a dehydrogenative cyclization could then be used to obtain the elusive dihydrobenzosilole. However, like most things in chemistry, nothing is as easy in practice as it is in theory. Their first step was, simply put, known put somewhat impractical. Hydrosilylation of stryenes using diphenylsilane was known using some late transition metals (gold, rhodium etc.) but none were inexpensive and easy. Hydrosilylation of simple olefins was known using much more affordable nickel based catalysts but it was unknown whether these systems were compatible with stryenes. So rather than finding a new route, Gevorgyan explored some nickel catalysts to mediate the desired hydrosilylation. He ultimately found that NiBr2(PPh3)2 worked best after screen a plethora of nickel catalyst. With the hydrosilylation problem addressed, Gevorgyan turned to the cyclization step. Using a bit of inspiration from some previous findings he was able to use a general method for silylating aromatics to induce his cyclization. Better yet, he found this two step process could be conducted in a single flask in excellent overall yield!

After screening a variety of styrene derivatives, he found that only meta styrene substrates proved problematic. They lead to regiochemical isomers (whose ratio was influenced by sterics). m-fluorostyrene was the worst offender of this giving a 2:1 regiochemical ratio. Gevorgyan then investigated α-phenyl and α-methyl stryenes to see if the alkene substitution patterned played any role and in fact it did. These substrates were far more difficult to hydrosilylate and hence the addition of a LA catalyst was necessary. By adding B(C6F5)3, 3-methylbenzosilole and 3-phenyldehydrobenzosilole could successfully be accessed.

Gevorgyan finally got to my favorite part of discovering new reactions: mechanism proposal. After some study, he was able to determine that electron-withdrawing groups on the styrene accelerated the reaction dramatically. Moreover, kinetic isotope studies showed that the second cyclization step was likely the rate-determining step. Bearing this information in mind, the following mechanism was proposed (and its cool!):

Finally all good methods papers end with an application. Gevorgyan used his dihydrobenzosiloles to not only synthesize benzosiloles by DDQ oxidation but also to access dihydrobenzofuran derivatives by peroxide oxidation of the silyl moiety followed by Mitsunobu-mediated cyclization.

Overall I found this to be a excellent article by Gevorgyan and co-workers. Dihydrobenzosiloles are very unusual and interesting compounds (though I’m a bit biased since I came from Dr. Tilley’s group and therefore I love silicon-related molecules). I look forward to future articles from the Gevorgyan group. That’s all for now…Ckellz…signing off…

Filed under: Reviews

2011 No More!

ckellz — Sun, 01 Jan 2012 22:39:33 +0000

HAPPY NEW YEARS!!!! Thank you all for making this year a wonderful year of blogging for me and I hope you continue to visit in 2012!

Filed under: Reviews

Moar Oxidation! MOAR!

ckellz — Fri, 30 Dec 2011 17:31:07 +0000

Eddy, N. A.; Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E.; Fenteany G. Access to Dienophilic Ene-Triketone Synthons by Oxidation of Diketones with an Oxoammonium Salt Org. Lett. ASAP December 29, 2011

So that moment that you all have been waiting for (well lets be real, mostly the moment I have been waiting for) has arrived. I can finally share with you the project we worked on with Dr. Fenteany’s group this past year. After our group became interested in green oxidations using, surprise surprise, Bobbitt’s salt, we found that a graduate student upstairs had discovered something very unique. If 2,2 dimethyl-1,3-cyclohexadione was exposed to Bobbitt’s salt for an extended period, very little of the α-oxidation product was obtained. The student, Nick Eddy, was really interested in obtaining this another project he was working.

However, he noticed that another unusual product was obtained because some of the starting material had been consumed. After careful NMR analysis, he determined that the product was in fact an overly oxidized derivative of his starting material, an ene-triketone. Now at that point, it was fundamentally interesting but was it useful? After doing a bit of reading, he soon found out that the compound he has prepared normally took four steps to make and at 15% overall yield. No other ene-triketone had been reported in the literature, likely because of the difficulty of their synthesis. After talking with us about it, we agreed that if we could optimize the reaction to give a high yield of the ene-triketone and turn this into a project, it would likely be of high interest to the organic community. So we spent some time optimizing the reaction, ultimately finding that reaction only occurred at slightly elevated temperatures in highly polar solvents (DMF, MeCN). Moreover, it required a large loading of salt (3.8 equiv)! On a large scale, this meant greater than 60 grams of salt. So we became experts at preparing Bobbitt’s salt (which, as I’ve said, is very easy).
We also found that the quality of the salt needed to the be the highest it possibly could be. It needed to be absolutely free from impurities and water (as did the solvent). We needed to not only recrystallize the salt from boiling water but also rigorously dry it using not a desiccator but with a Abderhalden over KOH and ethanol! This boosted our yield from 20-30% using the normal powder version of the salt to 60-80% using the highly purified salt. With that accomplished, we then prepared a range of 2,2 disubstituted cyclohexadiones. Now you may wonder why it was necessary to block that 2 position (in between the two ketones). That is to prevent enolization at that position (very stable enol) and oxidation to give the 1,2,3 triketone which has been reported. Therefore we tried a variety of substituents with mixed results. Most of the ones we tried worked (and the syntheses of these substrates were amazingly fun)! We also got some meaningful mechanistic information out of the substrates we tried. The following two results:

told us that the driving force of the reaction was that first ene-like reaction and sterics (which was said to be, in their system, disfavorable by the AZADO article I just reviewed) and subsequent oxidation to the triketone. From there, the triketone immediately enolizes and reacts again. Since there is a acid proton in the vicinity, it eliminates to generate the olefin of the ene-triketone. We need for excess salt, heating, and the polarity of the solvent all make sense with the mechanism (stabilizing enol form, 3 oxidations, steric repulsion). The mechanism is by far the best part of the article to me so here it is in all its glory:

At that point we could have stopped and submitted the work. But we weren’t satisfied with just the oxidation, we wanted to see what sort of reactions we could do with the ene-triketones (being the only people to have access to them at that time). We decided that an excellent application would be as dienophiles in Diels-Alder reactions. That olefin is very electron-withdrawn and therefore would likely react in a shot. And, as predicted it did at room temperature! We found that most of our ene-triketones reacted quite well with fair to excellent endo : exo ratios. The sheer complexity of the molecules were generating was what really impressed me though. Well I really hope you go take a look at our article for more details and enjoy it! It certainly made my day yesterday! Ckellz…Signing Off…

Filed under: My Publications

What the Heck is an AZADO?

ckellz — Thu, 29 Dec 2011 05:16:28 +0000

Hayashi, M.; Shibuya, M.; Iwabuchi, Y. Oxidative Conversion of Silyl Enol Ethers to α,β-Unsaturated Ketones Employing Oxoammonium Salts Org. Lett. ASAP December 19, 2011

Happy holidays to all my readers!!! I hope that the holidays treated you all well. Thankfully, I have the week off this week which has allowed me to catch up on much of the writing I have put off. As I mentioned in my last article, our work with Dr. Fenteany’s group was accepted into Org. Lett. and (should) be up on the ASAPs this week. We received the proofs on Friday of last week and they were resubmitted on Christmas Day with very minimal corrections. I plan on doing a special post on it when it comes out so check back over the next few days. As for chemistry in the Leadbeater lab, nothing really new to report. The lab has the week off for the holidays allowing all of us to recoup and get ready for a very busy January. In the meantime, I have been working on prepping DiAndra’s work for submission to JOC. I’m still debating personally on whether it belongs there or Org. Lett. Either way it’s shaping up to be a phenomenal paper worthy (in my opinion) of both journals. In other news, one of our methods papers is just about complete and should be in by mid-January. I’m really excited about that one as it relates quite closely to the work DiAndra has been doing and gives a good feel for the sort of chemistry we’ve become interested in the Leadbeater lab. Our flow paper has (FINALLY) been submitted to Org. Lett. and, as far as I know, it is already out for review. So with all our hard work coming to fruition, 2012 is looking to be an excellent year in terms of publications. I hope to have at least 10 publications before I graduate from UConn (hopefully allowing me to graduate in less than 5 years). So far, that looks to be a very real possibility!
Not that I enjoy politics, but I can’t help but comment on the UCLA incident and the current criminal charges being filed against Professor Patrick Harran. For those who do not know what I am talking about see the summary here and the latest news here. I think what’s happening to him is appalling and not justice but revenge for an act he didn’t have much responsibility for. Do I feel bad for Sheri Sangji, the research assistant who died from the burns she received? Absolutely, no one deserves the suffering she endured from the fire. However, that does not mean the PI is responsible. Much of the fault is in fact her own. She was wearing inappropriate lab attire, minimal eye protection, and working with a extraordinarily dangerous reagent that she had little familiarity with by herself. She was also using a syringe size that no experienced chemist would use for the particular reagent she was dealing with (t-BuLi). For those who haven’t worked with t-BuLi, it’s one of the few reagent that puts me a little on edge. It ignites in a beautiful but frightening purple flame on contact with air and is stored in pentane, adding to its volatile nature. So if a bottle were accidentally exposed to air, the bottle would explode into flames and that’s exactly what happened with Sangji. However, I don’t believe that Harran deserves to have his life destroyed (4.5 years in prison and basically he will have no chance of returning to chemistry) for an incident he is, at most, minimally responsible for. Some fines against the university are understandable but not jail time for the PI. What do you all think?
Now on to some lighter, more academic news, a new review! I had another tough time again this week choosing an article. Here’s a few of the runner ups (which are they themselves very interesting and good chemistry!):
1. CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic Oxidative Synthesis of 2-Substituted Quinazolines and 4H-3,1-Benzoxazines Yu, W. et al JOC ASAP December 14, 2011
2. A phosphine-free Pd catalyst for the selective double carbonylation of aryl iodides Castillón, S. et al Chem. Commun. Advanced Articles
3.[1,4]Dithiepino[2,3-b]furans from Oxiranecarbaldimines and Lithiated 1,3-Dithiane: A Series of Rearrangement Reactions in One Pot Würthwein, E.-U. et al EJOC Early View
4.Reaction of InCl3 with Various Reducing Agents: InCl3–NaBH4-Mediated Reduction of Aromatic and Aliphatic Nitriles to Primary Amines JOC ASAP

However, for the sake of a bit of foreshadowing (HINT!) of my own article and to stick with the theme of oxoammonium salts, I decided to go with an article detailing the oxidation of silyl-enol ethers to their corresponding α,β-unsaturated ketones. I had never heard of 2-azaadamantane N-oxyl (AZADO) before nor it’s the oxoammonium salt derived from it. In fact there are quite a few of these oxyl radicals derived ridged ring systems (9-azabicyclo-[3.3.1]nonane N-oxyl ABNO being another). According to this article, these bicyclic oxoammonium salts are far more effective oxidant than our friend TEMPO-BF4,a salt very similar to Bobbitt’s salt. However, if you dig a little bit, you soon realize that synthesizing AZADO is far more difficult than TEMPO-BF4 (9 steps to get to AZADO (of ten total) and only two (of three total) to get to TEMPO). I smiled a little bit when I saw the sheer number of references to Bobbitt on the first page alone. The first few paragraphs simply outline the advantages of oxoammonium salts and their use so I won’t bore you with that. The author’s goal of this article was to provide an alternative (possibly greener and safer) approach to performing α,β-dehydrogenation of ketones.

Their first attempts to utilize AZADO for this transformation were met with mixed results. They tried using a cyclohexyl derivative to accomplish oxidation and got a mixture of the desired α,β-unsaturated ketone as well as the α-aminooxy ketone. As with most good reactions, their was the minor product and therefore the authors needed to find a way to turn the side reaction into the major reaction. By switching to lower temperatures (-78 oC) and using a tert-butyldimethyl silyl enol ether instead of the trimethylsilyl, they were able to obtain a 93:7 ratio of the dehydrogenated product to the α-aminooxy product. They compared salts too, finding that their original candidate, AZADO, was the reagent of choice for this oxidation.
Next they did a comparison of counter-ions: BF4-, PF6-, ClO4-, SbF6-, Cl-, NO3-. They found that the less nucleophilic counter-ions (BF4-, PF6-, ClO4-, SbF6-) gave very similar ratios of dehydrogenation to addition of the α-aminooxy group with BF4- being the most selective. Cl- and NO3 gave far worse ratios. No explanation was given for this so I’d be very interested as to why there is a counter-ion effect.
What I liked most about this article was the detail they went into in their experiments. Rather than immediately jumping to substrate screening, they focused on isolating a transient intermediate species in their oxidation. It turns out that an intermediate (before queching the reaction with saturated bicarbonate) is a mixed acetal. This gave the authors a unique insight into the reaction mechanism. They proposed the following:

Also they used the same rational to explain why the TEMPO derived salt gave far more of the α-aminooxy product:

After giving a plausible mechanism for their transformation, they then explored the scope. They found their reaction to be quite broad. Moreover they found their reaction proceeded stereoselectively in that acyclic species gave only the less sterically demanding E-isomer. Finally they noted that AZADOH (the reduction product of the spent oxidant) was recovered and re-oxidized quite easily, suggesting that their method was “recyclable” in oxidant.
Overall this was a short but very practical article demonstrating the versatility of these salts for transformations other than simple carbinol oxidation. Hats off to Iwabuchi and co-workers for an excellent investigation and a useful method! Be on the lookout for another post within the next couple of days! Ckellz…Signing off…

Filed under: Reviews

Husky Pride

ckellz — Thu, 15 Dec 2011 16:25:42 +0000

Qui, J.; Pradhan, P.P.; Blanck, N. B.; Bobbitt, J. M.; Bailey, W. F. Org. Lett. ASAP December 8, 2011

Nothing makes me want to blog more than good news. And frankly, I’ve hit the jackpot with good news lately. First off, I am extraordinary happy to be done with my teaching responsibilities, final projects for my classes, and finals in general. Less time for studying equates to more time for lab work! Secondly, I’m am happy to report that our collaborative work with the Fenteany group has been accepted to Organic Letters pending minor revisions (I’ll be giving a hint of what the article is about at the end of this post). Needless to say, getting another publication in one of the best organic journals out there made my day. Next, we just finished a flow project which, in theory, should also be submitted by the end of the week (likely to the same journal). DiAndra’s project, which I have spent an increasing amount of time on lately, has continued to give us excellent results and my estimate is that it will be done (and submitted) by the middle of January. I’ve made some progress with a few avenues I’ve been exploring as well (though due to the amount of work I’ve had, progress is slow to say the least).
As part of the requirements at UConn, students are required to take a graduate seminar course in which speakers from other institutions are brought in to present on their work. This past week was a somewhat special occasion as the speaker was Dr. Brian Stoltz from Cal-Tech and he gave one of the best talks I’ve heard in some time. His talk detailed a recently methodology developed in his lab for the synthesis of enantioselective decarboxylative alkylation reactions of cyclohexyl rings.

The transformation relies on the principle of stereoablation: the reaction destroys a stereocenter as part of the reaction mechanism and, in the ensuing chiral transformation, a highly enantio-enriched product is obtained. In the reaction discussed by Stoltz, which was modified Tsuji–Trost allylation, a methyl-substituted cyclohexyl beta-keto ester (the ester being an allyl ester) would be decarboxylated in a Trost-like manner yielding an enolate. Since enolate formation is independent of the stereochemistry of the starting material, a enatioselective recombination of the freed allyl group with the enolate is possible. In the presence of the proper ligand, high e.e.s for one enantiomer can be obtained from a completely racemic starting material. After his seminar, we had time to talk with him in person and I showed him a bit of the work we have been doing in the Leadbeater Lab. He seemed to like it and over all he was a very interesting and down to earth person to talk to.
Continuing with the trend of good news (and on to a review), there have been many good articles the past couple of weeks so choosing one for this post was quite hard. The runners up include:
1. A Suzuki cross coupling with 1-iodo-2,2,2-trifluoroethane to effect 2,2,2-trifluoroethylation of arenes in Ang. Chem.
2.Using a relatively under explored element, bismuth, for very unusual transformation (under the framework of “Carbobismuthination“) involving alkynes and silyl enol ethers. This paper was also in Ang. Chem..
3. Using lithium trimethoxy(trifluorovinyl)borate for the preparation of trifluorostyrene derivatives via a Suzuki cross coupling with arenes.This paper was also in Ang. Chem..
4. Converting Acids to Amides in one shot using trimethylaluminum in Org. Lett.
5. A SeO2/BF3 based method for the synthesis of triarylethanones from aromatic ketones and arenes in J. Org. Chem.
All of these articles are excellent and if you get a chance, certainly check them out! As for this week though, we have a home town pick, an article published by Dr. James Bobbitt (a emeritus professor here at UConn) and Dr. William Bailey. Dr. Bailey’s primary interest is in organolithiums, however in recent years he has worked quite closely with Dr. Bobbitt on studying oxoammonium salts for the oxidations of various species. Specifically, the oxoammonium salt of study by Bailey and Bobbitt is 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate, affectionately dubbed “Bobbitt’s Salt” due to the vast amount of work done by Dr. Bobbitt involving this salt. I cannot more highly recommend it as a oxidant of choice. It will selectively take primary alcohols to aldehydes with a extraordinarily simple workup (filter through a plug of silica). Moreover, oxidations are colorimetric; the reaction mixture will start off yellow and, when complete, turn milky white. While currently a UConn specialty, many members of the department have been spreading the word about the salt (especially since it’s very easy to prepare!). However, until now, oxidations with Bobbitt’s salt were somewhat limited in that they could only effectively be used to make aldehydes. In this new article, Bailey and Bobbitt detail a method for using the oxoammonium salt for the preparation of carboxylic acids.

The article begins by details the general use, advantage, and some previously established trends in reactivity. Early on they essentially revise and expand up some trends observed in their previous articles. Based on relative rate studies and computation work (done in collaboration with Dr. Kenneth Wiberg at Yale), Bobbitt and Bailey suggest that the mechanism is involves a formal hydride transfer from the carbinol to the oxoammonium salt. They found that the rate of oxidation is proportional the ability of substrates to accomidate positive charge at the carbinol carbon. With these tenets in mind, we can easily understand why oxidization of benzyl carbinols proceed quite fast (especially with electron rich arenes).

After this brief digression, the authors begin to describe their new methodology, namely the oxidation of primary alcohols to carboxylic acids. The conditions are relatively simple: 2-2.2 equiv of Bobbitt’s salt and the alcohol to be oxidized in a MeCN:H20 (9:1) solvent system. As with the oxidation of alcohols in DCM to aldehydes, this reaction is also colorimetric (doing from a orange-brown to a yellow-orange.
To demonstrate the versatility of their oxidation, a wide range of primary alcohols were oxidized. The authors also note a peculiar trend when examining the reactivity of these various substrates. Aliphatic alcohols seemingly oxidized the fastest while benzyl alcohols are very sluggish. This is in stark contrast to oxidations conduct in DCM to obtain aldehydes. In the latter case, benzyl alcohols react in mere hours rather than the former case in which it make take days to obtain the acid. Not only do the author’s give an explanation for this change in reactivity, they also exploit it. To better explain the change, a mechanism is necessary:

The authors argue that the rate determining step is hydration of the intermediate aldehyde. This is in line with previous work (and a previous post by myself) using TPAP. They further support this finding by conducting a relative rate study, finding that electron-deficient arenes (p-nitro) react many times fast than electron-rich arenes (p-methoxy). Hydrate formation is typically a function of the electrophilicity of the carbonyl carbon of the aldehyde, hence this finding makes sense. Bobbitt and Bailey then exploit this by working with a mixed aliphatic/benzyl diol system. They first show that the benzyl alcohol can be selectively oxidized over the aliphatic alcohol using the classic DCM conditions to the corresponding aldehyde. They then oxidize the aliphatic alcohol to the aldehyde. Treatment under their new conditions affords sole oxidation of the aliphatic aldehyde to the corresponding acid, thus proving the selective nature of their oxidant.

This was excellent work done by Bailey and Bobbitt, though I cannot say I’m not a little biased . I recently needed to oxidize a propargylic alcohol to the corresponding acid and I am happy to report that, using the conditions developed by the authors, I was able to obtain it in excellent yield. Overall this is a very practical and useful paper!
Now, as promised, a preview for our work with Dr. Fenteany’s group:

We were able to take diones to the ene-triketones all in one pot! As soon as it’s out I will share the rest of the story!

Filed under: Reviews

Proline: Not Your Typical Amino Acid?

ckellz — Sun, 27 Nov 2011 21:23:38 +0000

It’s been far too long since my last post. Between designing a total synthesis proposal for one of my classes, preparing a manuscript (and supporting information) for a project we are wrapping up, and (in the past week) doing a number of reactions, I’ve barely had time to read the literature, let alone blog. Moreover, I spent a week house hopping thanks to the surprise winter storm on Halloween that left most of Connecticut (myself including) without power for seven days. However, thanksgiving break has offered me a reprieve and I’ve managed to catch up on a lot that I was behind on. Chemistry continues to go well in the Leadbeater lab. Our collaboration with Dr. Tilley has picked up pace quite a bit with the successful isolation of another key substrate (which I was quite pleased about). We actually have been focusing on pushing out a continuous-flow project first now that it’s finally giving us promising results. I expect that a paper corresponding to that project should go out by next month at the latest. We are currently putting some finishing touches on another paper as well which should also go out by the end of next month (which I can’t wait to tell you all about!). Our paper with Dr. Fenteany’s group did not get into Nature Chemistry but we just submitted to Organic Letters so I’ll be sure to let you know how that process goes. I’ve also developed a new project based off some stuff I encountered while at Columbia that has allowed me to try my hand at a number of named reactions. I’m still just making a test substrate right now, but this one substrate offers a number of avenues to pursue. I’ve also been assisting another one of our lab members (DiAndra) with her project and she has been getting some very interesting (and exciting) results on what shaping up to be a pretty useful reaction. Other than that, Mike and myself have begun preparing lab experiments for the upcoming advance organic laboratory class we will be TAing for next semester. We hope to give the students experience with a broad range of reactions from transition-metal catalyzed couplings to organocatalysis. Our hope is that they will leave the course with the preparation they will need to begin graduate-level or industrial-level research.
In other news, I wanted to extend a warm congratulations to my friend Ryan Carris on his most recent publication (in JACS no less)! Ryan is a graduate student in the Johnson Lab at the University of South Carolina whom I met during my REU at Columbia. He’s doing some pretty good work down there, focusing on the manipulation of cyclopropanes for the construction of rather elaborate molecules. In his JACS communication, he details the umpoling of donor-acceptor cyclopropanes (in his case 2-vinylcyclopropane-1,1-dicarboxylate and related species) via a π-allyliridium complex. Carris and his fellow authors then exploit this umpole species to allow for alcohol and carbonyl allylations with a high degree of enantioselectivity (or diastereoselectivity depending on the substrate).They then showed the application of their research by making highly substituted lactones (which could serve as useful materials for a total synthesis) with excellent %ees (>90%). It’s pretty intereting work that’s well written so go check it out!
Now it’s time for something I haven’t done in ages, a review! I spent a lot of time catching up on articles in various journals (from Chemical Science to the European Journal of Organic Chemistry) but ultimately the most interesting article I found was in my favorite journal Organic Letters. About half a year ago I posted on some work that the Seidel group over at Rutgers was doing, regarding the exploitation of hydroxyproline decarboxylation for elaborate synthetic transformations. In this most recent article, Seidel and co-workers exploit the decarboxylation of proline itself (which to me is still somewhat of a weird concept) for a Strecker-like reaction.

The article begins with a brief overview of the Strecker reaction (which was discovered quite a long time ago in 1850). The article then diverges into specifics about decarboxylative reactions of proline along with some information about the resulting azomethine ylides (specifically their stability and reactivity).

Based on their previous experience with azomethine ylides, they rationalized that if they added a cyanide anion source to their reaction mixture, they could affect a Strecker-like transformations. Conceptually, what they wanted was imine formation between an aldehyde and proline, followed by a decarboxylation to give a azomethine ylide. This ylide could is in resonance with an alternative ylide. Protonation of that ylide followed by attack by cyanide at the iminium carbon would affect the first step in a Strecker-like synthesis.

To test whether this reaction was feasible, they looked into the reaction of proline with benzaldehyde in the presence of various cyanide sources under thermal conditions. In order to facilitate decarboxylation, high temperatures are required and their group found that microwave irradiation gave them the best results (especially since it allowed them to reach temperatures normally not readily accessible using conventional means). While many cyanide sources were tried, they ultimately found that TMS-CN gave them the best results. In fact, the reaction worked so well that it gave near quantitative yield.

With a relatively short optimization study behind them, they then proceeded to examine the scope of the reaction by first varying the starting aldehyde. A very broad range of aldehydes (from aryl to alkyl) were tolerated with only a few giving a mixture of regioisomers. Ketones proved far less reactive and lower yielding. After varying the carbonyl species, they then started altering the starting amino acid. They initially went with a previously successful unnatural amino acid, pipecolic acid. This amino acid gave solely the expected regioisomer as did tetrahydroisoquinoline-3-carboxylic acid. However when acyclic amino acid derivatives were used (N-benzyl glycine and N-methyl glycine), the unexpected regioisomer was the sole product. The authors attributed this to the substrate-level preferences for azomethine protonation.

During their study they noticed that if more proline was added, they could shift the preference for the unexpected regioisomer to the correct expected regioisomer. They suggested (in words and figures) the following mechanism to explain this trend:

This mechanism was supported some control experiments involving doping of proline or pipecolic acid in the presence of the unexpected regioisomers and conducting a reaction under their optimized conditions. They wrap-up the article with a small application. In a lesser known named reaction, the Bruylants reaction, α-cyano amines react with organometallic reagents (in particular Grignard reagents) in a substitution-like manner. This reaction relies on the concept that α-cyano amines are in at least a small equilibrium with their corresponding ion pair. Addition of the organometallic reagents leads to irreversible C-C bond formation thus driving the equilibrium towards substitution. Seidel and co-workers take the proline-derived α-cyano amine and react it with both an aryl and alkyl Grignard reagent to successfully give the corresponding α-alkyl/aryl amine.

Overall, this was an excellent article by Seidel and his students. Hats off for a job well done!! That’s all for now, I should be posting more regularly now, barring no more freak snow storms! Ckellz…Signing off…

Filed under: Reviews

Carbon Monoxide, What the Heck Just Happened???

ckellz — Wed, 26 Oct 2011 12:13:39 +0000

Ye, S.; Wu, J. Org. Lett. ASAP Oct 20th 2011

With work coming back to a (slightly) more regular pace, I now actually have to blog on a more regular even (gasp) weekly basis! Not all too much new to report this week. We are pretty much at a standstill with all our pending publications. Even our research has been, at best, coming along slowly. I did manage to have some late-day success Friday synthesizing a particularly hard compound to make. While the yield wasn’t the best, I’m going to retry it and scale it up because it is somewhat critical to our project with Dr. Tilley. Meanwhile, I’ve come up with a couple of new ideas to try, in addition to searching for a molecule to synthesize (and developing an appropriate synthesis). Mike has been doing the same. We also have the exciting (and somewhat daunting) task of designing an undergraduate advanced organic chemistry lab. The goal of this course is to give the undergrads the tools necessary to begin conducting research and prepare them for graduate school. We want to teach how to run flash columns (and learn other more advanced forms of purification), get them to perform some more complicated reactions (and we are open to suggestions!) as well as teaching them how to write scientifically. Moreover, it’s useful for us in that we will be learning how to design a course (and for someone looking at academia like me, such a skill is quite useful). I still haven’t decided where exactly I’ll end up (industry or academia) but I will likely carry out a post-doc after I complete my Ph.D. at UConn. I’ve even had a few thoughts as to where I would like to go for my post-doc. But that’s a ways off; I still have my thesis, classes, teaching and all sorts of other things to get done first. On an unrelated note, I’d like to mention I’ve added quite a number of links (thanks to a very useful post on BRSM) I hope you find them as useful as I and some of my lab mates have! And now, on to the lit!

This weeks article is from, surprise surprise, Org. Lett. As promised the focus of this article isn’t fluorine. Rather, we have some useful and mechanistically interesting palladium chemistry developed by the Wu group. The article begins with a discussion of the history of palladium chemistry, in particular with respect to carbonylation. If you don’t already know, carbon monoxide is a very useful material for the functionalization of aryl halides under mild conditions. I’ve in fact conducted such reactions and, for the most part, they are pretty reliable. With the recent rise in popularity of gem-dihaloolefins in the literature, it was simply a matter of time before these substrates were explored for carbonylation procedures. In fact, Wu had just recently explored it for use in Suzuki coupling reactions (forming indenes). Not surprisingly, indenes are quite useful in material science and chemical biology, so more routes to access these sorts of structures is beneficial. Instead of simply continuing on with their Suzuki work, Wu and co-workers attempted to prepare functionalized indenes (e.g. 1-methylene-1H-indene-2-carboxylates) via carbonylation. They theorized that 1,2 disubstituted aryl systems (in which one substituent was a gem-dihaloolefin and the other was some sort of cross coupling partner such as another point of unsaturation) could undergo a tandem Heck-carbonylation reaction.

Starting with (E)-methyl 3-(2-(2,2-dibromovinyl)phenyl)acrylate (which is surprisingly easy to prepare), Wu and co-workers conducted an extensive optimization study, ultimately finding that the ideal solvent was toluene, and most effective catalyst was palladium(II) acetate with PPh3 added in as a ligand. As one would expect, the carbonylated intermediate was trapped with an alcohol (in their optimization study, n-butanol). They found that the ideal base was in fact KHCO3.

Once optimized, they then screened pretty much every alcohol under the sun, from trifluoroethanol to naphthol (to me this didn’t prove all too much, just that you could make different esters, but it did get them more substrates). They then switched over to the more important variable, the gem-dibromoolefin. Initially, they had little to no luck until they realized that 4 angstrom molecular sieves were a necessary additive in order to achieve adequate yields. Unfortunately this limited them to phenols (likely due to competitive dehydration reactions). Therefore, they used 3-methylphenol as their “alcohol” source. With these modifications in place, Wu and co-workers decided to switch the substitution pattern on the ring up a bit (both EWGs and EDGs were tolerated under their conditions). Next, they changed the substituent on the other olefin. While changing it to a ketone or phenyl ring proved unamendable to their reaction, esters modifications and nitriles were well- tolerated. Overall the yields on the reactions that worked were good and they provided a reasonable mechanism.

While I did like this article, I felt it wasn’t all that impactful. I was displeased with the fact that more of their substrates were simple alcohol swaps. However, the transformation (tandem heck-carbonylation) was very cool in itself so congratulations to the Wu group for a pretty good article. That’s all for this week. Ckellz…Signing off…

Filed under: Reviews