Look who’s coming to the party….amino-subst imidazo[1,2- a ]pyridines

If you’ve looked at this blog for any length of time — then of course you know that multi-component reactions and cool heterocycles are dear to me….but reading through this article (ARKIVOC 2012) caught two things that interest me on a different level: solventless reactions (where is all the data) and replacements of reagents and metals that are always tried because we don’t think as much as we do. Maybe it is just because I made a coupla’ hundred of these — well to protect the innocent and guilty, I had a number of modifications on the aldehyde and isocyanide (several metals are used in this strategy as well — Groebke reaction).

AS a starter — it is not hard to come across an article that uses a clay or solid acidic resin to do some solventless microwave chemistry. There a place for it in a so many areas — the problem stems from the variability of the reactions — sometimes I read through these like I am being graded for my 6th grade writing assignment (you remember, who are they? skipping theme content? and on and on. Well, not this paper, but when I started to read it, that’s the thought that came to me because so many papers doing this repeat a theme: we are using the $100 microwave with a reaction in an open beaker with clay….and it goes to 180C in near quantitative yield — really? Come on, I bet if you moved it around the cavity it would give you a different yield — like I said I have learned to expect this….and it’s why when we try, we are sometimes off so much on something that it doesn’t repeat at all….thanks, right?

3-component amino pyridine, iscoyanide and aldhyde mw with clay

With some slight change in the stoichiometry and a few changes in solvent, we find that higher temperature and toluene provide about a 20% increase in yield (compared to a lower oil bath yield)— I am not surprised — stirring, who knows if the clay has a limit in heating or we simply haven’t gone to high enough temperature (maybe that is a function of the vessel, but I think we should have gone higher — OK well 7 min is a pretty short reaction — I give them kudos!

Moving from solventless to organic solvents

Now this really got me going — maybe there is some likemindedness here….moving from organic solvents to ionic liquids — higher heating capacity than the clay, and we can still agitate the reaction if needed. Well well, not all IL processes are proved true. Depending on which was used, decomposition and low yields are the story. But there were a couple of strong reactions to note — don’t you love the heating capacity of ILs — almost no power added provided pretty decent temperatures — but it is interesting that the times went up significantly — maybe there is competition between the clay and IL for the reactants?

Same reaction with ILs

You will have to dig into the article for yourself, because there wasn’t much of a transition from ILs to guanidinium sustrates to replace the ILs and then the clay itself. Ionic indeed, about the same or a little better than clay, Entry 5c as the best tested. Maybe there are some good salt substitutions for this reaction after all. This article made me think a bit on how I would use the information — plenty of things to try. Happy Reading!

again, with guanidinium salts

best from the list tried

Staudinger-aza-Wittig: MW methods

It’s not often I get an opportunity to talk about the formation of a urea, where I haven’t actually performed the reaction…see if you have. After spending the better part of 3 years making ureas as raf kinase and p38 target analogs, I never once ran this reaction — bummer. Don’t feel too bad for me — our team was able to make 2generations of drugs for cancer on the motif — so things didn’t end too badly.

So why make another isocyanate or the final urea for that matter. Well, the impact from these two materials is a high percent of chemical output per year so there is clearly an interest. So since I didn’t perform a Staudinger reaction you can bet that I used plenty of phosgene in my day….now you see why we need people to continue to develop alternatives to older ideas. Other alternatives including Curtius and Hoffmann rearrangements or an activation of an amine with CDI followed by a second amine are all excellent methods to get there….but the Staudinger, sign me up.First things first — Staudinger — azide to an amine –and Wikipedia’s pinwheel example shows us how:

Staudinger: Azide to amine

We know of course that to be an aza-wittig variant we have to through the in situ formation of a phospazide and iminophosporane (perhaps this where the next part will come into play). To form an isocyanate at this point would involve reaction with CO2 at the iminophosphorane stage plus triphenylphosphene oxide. And voila, out goes the isocyanate — with total functional group compatibility. So the “crux” is the CO2 — although common enough in balloon and cyclinder form, there are so few examples of microwave technology being used to describe gaseous reagents in closed-vessels. Now that I have laid the trail — a very recent paper (Beilstein JOC 2013) does just this — a microwave method for the Staudinger reaction for the production of RNCO and ureas.

MW Staudinger with azide, polymer resin phospine under CO2

Two things of note in the approach — moving away from PPh3 to a resin bound phosphine (of course everyone who is reading this will understand that polymer swelling will come into play– which could be regenerated and how much CO2 and pressure would be to get this to work in a mw– what solvent will end up the best.

Optimizing Conditions

OK — this group used the SRC mw approach so that they could control the amount of CO2 pressure needed and they could test a few solvents simultaneously — comparing solvent and pressure — 14.5 bar did the trick for conversion and yield — and MeCN produced good yield and good conversion THF was a bit of an outsider here.

MW RNCO formation then amine addition under mw

The next step was to form the RNCO under mw conditions, stop then add amine and react under mw conditions. Well I must have been a bit ahead of myself because my thinking was that you should be able to do this in one pot — because the azide should be tied up in the iminophosphorane/RNCO formation with the CO2 — should be fast….so doing this in the presence of an amine should work just fine. First thing is first — several different azides were used in a single chamber (forming multiple RNCOs then reacting with one amine following the first mw step with second one — nice, library library library — just kidding!

cu de gras — mw to make azide – then phosphine, CO2 and second amine in one pot

And now they got where I wanted — a bit more in fact — RBr with NaN3 in mw to give multiple RN3s — then each of these reacted with resin, CO2 and amine in one pot to give a set of ureas with varying groups on either side. Don’t you just love it when a plan comes together. It is interesting that a few modifications in the microwave produced a nice method for an under-used reaction. Last thing to note — it comes up a bunch is that they scaled the reaction up in a Parr to show that the technology could be transferred back to conventional systems — I like that: hope the naysayers are watching and reading. For me personally, I would have scaled this up in the SRC as well to show the side by side ( a 1L pot would have produced even more material) For those interested — there is a 4L version of this technology — method development and scale are not that out of reach.

Hope you enjoy reading this one!

Sonogashira and a bag of tricks

Came across some interesting observations in a recent publication (Akivoc, 2009) on the synthesis of some pyridyl-benzimidazoles through 2 Sonogashira coupling reactions. The scheme is shown below: cyclocondensation of an aromatic acid in PPA with  phenylenediamine to give the benzimidazole. While unprotected, the pyridyl halide was treated with bis(triphenylphosphine)palladium(II)dichloride and CuI and the requisite terminal acetylene under microwave conditions: key to note, only 100C in DMSO (5-10 minute reactions).

Full scheme for advanced benzimidazoles utilizing 2 Sonogashira coupling

Taking a look at the table — it is clear that the microwave conditions accelerated the reaction in a huge way….and postulated that the yields go up because the homocoupling of the terminal alkyne is reduced by the quick reaction time — I tend to agree — funny how it isn’t apparent in many cases why a yield is improved…this one helps clear both couplings. In addition, I am always struck by the use of DMSO in a microwave reaction, but particularly with a coupling reaction such as this. It is know that a number of Pd reagents decompose in DMSO with heat at an accelerated rate. It seems like there is a balance here between reactivity and the possibility of decomposition or the possibility of homocoupling with heat and time…..well I know I am hand waving, but after 1000s of my own reactions like this, I speculate a bit.

3 MW methods (cyclocondensation, 2 Sonogashiras — comparison to conventional heating)

Although not the crux of the article — the benzimidazole doesn’t need protection during the chemistry — and EDGs and EWGs on the aryl are acceptable partners in the final coupling so it should be easy to expand if needed. Happy Reading!

What would you do?..some nice furans

I have to imagine that when an organic chemist really digs into an article, he/she thinks what they could use it for, and how would they have done it differently…..I know I just can’t help myself, and it should be seen as a complement to the author. I recently read through a nice paper (Synlett 2011 pdf author reprint) on the preparation of tetra-substituted furans — cyclization (Mn and Cu accelerated) through a chalcone derivive with a pending fluorous linker ( a term that gets debated a bit). The cool thing is that the linker can be set up to help purification, aid in additional steps including cleavage or transformation to additional analogs.

The following scheme is shown to give you an overall idea of the strategy. The fluorous linker is now set up to undergo typical transformations such as Suzukis and Hartwig-Buchwald aminations (like a triflate would) or simply cleaved at some point following changes in the groups on the furan. There certainly is a lot of possiblities (aryl and subst alkyl boronates, slew of amines and anilines, etc).

Chalcone formation followed by mw mediated ring formation

Suzuki reaction under mw conditions

OK so now the part I found both interesting but also where I would want to do things differently….for the Suzuki, there are a limited number of aryl boronic acids used — sure there is a significant rate acceleration using the mw -hours to minutes, but not enough diversity to peak my interest in what can be done. So I always wonder why — if the compounds are so interesting, why not expand to alkyl, heteroayl, etc? Is it because they are using a single-mode microwave and therefore at the mercy of doing a reaction at a time sequentially? For me it’s like you want to take away the benefit you got by using the alternate technology in the first place….not for me at least. The second thing the group did was an optimization of reaction conditions for the Buchwald couplings — solvent — toluene, base, catalyst, ligand but kept the same temperature. I felt a little let down at the part of the movie……you have heard me talk about microwave SRC technology — this is where you could screen solvent, base catalyst, amines, ligands all at the same time [this is is saving weeks worth of work]– could even change the functionality into an ester or ketone under a CO atmosphere……I would go crazy to have a set up like that. Maybe that’s my former med chem days leaking into my reading.

template for Buchwald couplings under mw conditions

Look through the optmization — all makes sense, but at 30 min a pop, which to me is too valuable a timeline not to be done simultaneously, there is a point of no return or which one simply doesn’t do the next necessary reaction. At any rate, a really cool scheme to make some compounds of interest…and something I would jump at for these type of furans. Keep in mind when a choice is made to use mw for libraries or optimization, there is a strategy that comes into play as well. Just choosing the microwave doesn’t make it efficient unless you think about the entire goal. Enjoy the article. Happy Reading!

If you haven’t been to this link once or twice…you might not be an organic chemist

Having used this site (www.organiclinks.net) for years, I am a bit biased, but it is never too late to dive in. This is the most comprehensive listing of organic (and a link to organo-metallic) academics in the US. A much needed resource in my links on the site…thanks Matt – a great contribution to our community. And, if you haven’t watched their short documentary “Total Synthesis – From Chemistry to Medicine” you are missing out.

Some interesting ideas…see if you agree

While recently visiting an academic lab, we had some interesting conversations surrounding enzyme catalysis, proteins and carbohydrate chemistry under microwave irradiation. For each of these areas, high temperatures was the central theme as a drawback to utilizing this technology for these approaches, so it got me to searching a bit. It is true, a substantial amount written points to this drawback. Unfortunately this would paint a pretty ugly picture if one were reading this and hasn’t thought in depth about the possibilities. For example, most of the bad press for enzyme reactions have been studied in aqueous environments — and we are now learning that depending on the enzyme (or an enzyme stabilized on a surface) one can achieve higher thermal stability in organic solvents. That said, the rates of reaction in general are supposed to be slower. For sugar chemistry, the story is much the same — ” I can only heat my molecule to 80 or 90C before I get degradation….well, take a look at all of those reactions done at room temperature and add to that some of the solvents that are used with low boiling points. There is a large and accelerated window between RT and 90C…a huge amount of energy. I would argue that something taking place at room temperature overnight would be an excellent candidate for some heating that you can’t normally do at reflux — say methylene chloride (not a good microwave absorber). Sparing most of the detail, I have seen a number of these reactions accelerated from 12-24 hrs, even days to an hour or two under the right microwave conditions…we simply need some thinking out of the box in these areas to get a more in-depth view, even methylene chloride at 90C works under the right choice of microwave conditions.

To generate some thinking around this area I found a nice publication (Journal of Molecular Catalysis B: Enzymatic 2007) on a lipase immobilized on a polyacylic resin for the resolution of (R,S)-2-octanol through a transesterification. Long story short….they found a significant rate acceleration through microwave irradiation over conventional heating. In the paper, solvent, temperature, catalytic rate and decomposition were studied with some interesting results.

Enzymatic resolution with immobilized enzyme

Without going through the entire paper (solvent, enzyme stability, conversion are all in there), the microwave acceleration over conventional heating is shown in the graph below: at the 50% conversion rate the microwave conditions gave a 3 hr time point compared with 12 h conventionally (the octanol 50 mmol, enzyme 60 mg in n-heptane 50 mL with stirring at 40C).

MW – circles and conventional in squares

To keep you a little more enticed — I have also included the table on solvents studied and the activity of the enzymes for the the reaction (seems like the enzyme in a microwave environment does its’ work in a non-polar media as compared with a more polar environment, but not everything holds true)– the rest you will have to work at — there is more (in addition to rate enhancement the ee%s went up as well.

Solvent and catalytic activity

Hopefully this will get everyone to think a little bit more on their protein, enzyme and carbohydrate chemistry and see where there might be some rate enhancements. Happy reading!

 

OK it’s been awhile

No excuses like my computer went down or I went on vacation or I have been out doing microwave demonstrations…all of those are true, but I am back and ready to contribute again….stay tuned as I get going again my fellow chem brethren…Cheers!