Archive for November, 2013

No microwave today —- deep frying!

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Before I take a couple of days off with the Family, I got to thinking about all that stored reaction knowledge as an organic chemist, and terms that enter the field that influence how we develop our strategies. A quick glance at the bookshelf — Umpolung strategies, Retrosynthetic and Synthon Disconnection Approaches, Tandem Reactions, New Transition Metal Catalysed Processes. It does seem like a lot to develop a concise approach to one’s work. So let’s mix it up and not have a particular approach but include some terms and see if there is some work out there: allenes, umpolung, synthon and microwave — so I want to find allenes where there is going to be some reversal of reactivity — that piece will provide us a useful synthon and will be used in a microwave reaction……no, I haven’t moved from espresso to bourbon quite yet….one more day, :).

So it is pretty well established that electon-deficient allenes undergo nucleophilic attack the alpha, beta electron-deficient double-bond to the EWG.

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Normal addition to electron-deficient allene

However, these particular allenes can also undergo a reversal of reactivity in the presence of phosphines to provide attack at the gamma position.

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New reactivity pattern for electron-deficient allenes

In a recent paper, a group takes advantage of the pattern and recognizes that an intermediate formed from addition of phosphines to butadienoates can be used as a 3-carbon synthon [3+2 synthon] in a cycloaddition reaction with electron-deficient alkenes and imines.

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Formation of the 3-carbon synthon from allene

The scheme below illustrates the allene and N-Tosyl imine used for the method. If you read the through the method development, PPh3 was typically used for the formation of the intermediate for the cycloaddition — normal heating times were reduced from hours to minutes. A more nucleophilic PBu3 was used in place of Ph3 to obtain the desired reaction in one of the examples. Optimal conditions included 100C mw 5 min. It is possible that a different solvent could be used but overall a pretty good process. The cis selectivity was found in all of the examples utilizing this sequence.

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[3+2] cycloaddition with allene and N-Tosyl imine

Additional examples and the same process was used for the formation of subst. cyclopentenes as well as some preliminary work on the starting allene in a Lewis acid allenoate-Claisen rearrangment, opening up additional difficult substitution patterns in a simple process. Happy reading!

Went looking for something current that I thought would provide some reflection on the part of the reader. A nice report from a group looking into annulated (is it annelated or annulated — I think I know but the topic has come up when to use which term, lol, as funny as the infinitive to column) indole-based polyheterocycles.

Lots of action around azide-alkyne inter/intramolecular 1,3-dipolar cycloadditions in the current literature. In most cases, we now accept that these process can stand a little steam room (heat, that is) cranked up to satisfy ring closure. Ah, a soft spot for say, a microwave.

In this particular report (2013), this group is interested in a domino process where 3 distinct reactions can be combined for the final construction of the indolodiazepinotriazoles, alkylation of indole, epoxide opening with azide and finally an intramolecular 1,3-cycloaddition of the pending azide and alkyne.

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Strategy to set-up the 3-component domino reaction

I have included the table to illustrate the amount of work that went into finding best conditions from conventional heating, solvent study to choosing the best base for the sequence.

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Summarizing the table: #3 provided NR at 110C of the alkylation, #4 solvent switch to CH3CN provided alkylation, 5-9 DMF provided alkylation at an interim time followed extending time to eventually give the desired material in 18 h. 11-13 provided a similar profile in DMSO, 14-19 while maintaining Cs2CO3 in DMSO at 120C the procedure was switched to microwave 10 to reduce the time to 1.5 h, lastly switching base to KOt-Bu resulted in similar results to Cs2CO3 in DMSO.

There was a lot of work that went into the procedure and a clear advantage for the microwave conditions. Certainly I think there might be some addition modification of the temperature, but if the microwave is used to screen bases and solvents this would take more advantage of the technology. That said, I enjoyed the process to coming up with these compounds. Although not mentioned above, they did take the time to illustrate the stepwise process by indicating the transformation of each of the steps to the final compound through the intermediates.

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product through a)epoxide with N3 and b) azide

Happy Reading!

It’s much harder to write when the coffee hasn’t made it across the goal line, but since I went into the utility of microwaves for chiral endeavors, I thought I should probably add a few more reasons why:

Here is a recent example (Molecules 2011, download pdf) of an improved method for making Evans oxazolidinone auxiliaries, or even analogs to be tried. If you don’t care as much about the aldol part, remember these heterocycles are found in a healthy number of antibiotic drugs. So much better for me than writing about Felkin and anti-Felkin selectivity this morning.

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mw: Amino alcohol and diethyl carbonate, mild base

In case you want to compare with conventional methods (oh yea, the caffeine is kicking in):

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Conventional v. MW

Expanding the route to include oxazolidine-2-thiones and thiazolidine-2-thiones gives some other possibilities to look at additional routes (one example had an inversion of stereochemistry by the end of the conversion, interesting— I believe some of these have shown equal or better selectivities.

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MW: Oxazolidine-2-thiones and thiazolidine-2-thiones

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Table: mw v. conventional

Chiral diazaborolidine substrates have been used for asymmetric reduction of (pro)chiral ketones ( I always thought that was a funny term).

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Reported use of diazaborolidine in chrial reduction

However, this group could not reproduce the formation of a similar reagent (to 10) under classical reflux conditions. Modification to microwave conditions provided the reagent.

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mw formation of chiral diazaborolidine

That seems about an espresso’s worth of microwave action for this morning. Enjoy the day.

Enjoyed “Would I want my kids to study chemistry” and “Why I Love Medicinal Chemistry” so much that anyone who visits here should take a look at The Free Radical site. I have to say I smiled all the way through — and I remember listening to my oldest son when he transferred from an engineering major to turf and grass research. He had the chops for it, but said he had watched his poor old dad — haha, and mom (she is also a chemist) slog through it on days. FR gives a much more uplifting feeling why I always knew it was for me, more art than science and more science than politics…..and tomorrow you might discover something that will make you smile….I doubt that I would be saying that as a banker.

Enjoy the site!

So that everyone understands that I feel that microwave approaches are simply a tool at our disposal, I don’t want anyone to think I have a giant sign up in the air saying that microwave should be used every time we have a dry flask ready to go, far from it in fact. In general, however, direct microwave heating can reduce chemical reaction times from days or hours to minutes or even seconds, and therefore suppress undesired side reactions, increase chemical yields, and improve reproducibility. That said, most of the time this applies to reactions that have a thermal component to the process….or one where a catalyst or solvent can be heated and the reaction flows along as a happy participant. There are actually a tremendous number of reactions where this can be used to the advantage, but it requires some thought and willingness to give it a try—-and the last time I checked the cool thing about organic synthesis is that it is an experimental science with a fair amount of art form. SO let’s get the bad out of the way first then go to some positive….high reaction temperatures have been shown to lead to a loss of selectivity, and therefore the percentage of reports with high enantioselective in a microwave is low. That said, I think it also is incumbent on us to look deeper into said processed for areas to tweak and look for new opportunities. Most microwave reviews and books focus on the utility of microwave irradiation for methods, reducing times in complex reactions and generation of advanced products, etc, but have left little time spent for asymmetric processes. We should understand this isn’t to slight the technique or understanding (especially by these chemists) because if the microwave could help with every reaction, we probably wouldn’t be doing anything else, right? Take a look through some of the recent microwave books (Loupy and Kappe) to see what I mean. Below I have listed a few recent chapters in books where microwave approaches have been described in more detail. Also probably one of the more interesting articles talked about involves a careful study on microwave vs. conventional heating, temperature measurement (by it really illustrates how important that FO probe is in doing true temp measurements using a microwave) in an asymmetric approach.

Catalytic Methods in Asymmetric Synthesis 2011 (Ch. 10 Microwave-assisted Transition Metal-Catalysed Asymmetric Synthesis

Catalytic Asymmetric Synthesis 2010

Optimized Methodologies in Asymmetric Organic Synthesis Applying Microwaves (J Mex. Chem. Soc. 2009)

Finally, let’s look at enough examples to show that there is a place for a microwave approach to chiral compounds.

Here is a recent example of an intramolcular aldol condensation to a morphan scaffold under microwave conditions.

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mw: Intramolecular aldol condensation organocatalytic

Well known allylic substitutions:

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Some typical transformations moving from conventional to microwave (J Mex. Chem. Soc. above)

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Moving from Conventional to mw, then standard transformations esterification, saponification and formation of the amides

Total Synthesis of Strychnos Alkaloid (+)-Minfiensine 2008

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MW Intramolecular asymmetric Heck reaction/iminium cyclization followed by microwave promoted hydroboration

There are certainly some opportunities out there. Having re-read many of these examples it is interesting to note where there are examples of low catalyst turnover and therefore a need to drive the reaction might be a good place for some thought here. Also, it does seem that if there is some stereo-direction in the reaction itself, a microwave approach can be a good one. Let’s not write it off just yet. I bet I could come up with a course of examples where this approach would be suited and often better than what was originally done. Take a look through some of your old work in those 30 step natural product routes and see where you might be doing something a little bit different now. I know there are plenty of hydrogenation and gas addition reactions that should be re-examined under microwave irradiation — definitely some opportunity.

Happy Reading!






Always looking for reaction types which fit a thermal process, or the type which needs cooling to say -78C (gosh not everything I would do is a thermal process). We should have chart of reactions defined in categories by how often they are used and what kind of process is at work. I also tend to think there are starting materials that seem to fit a list where one can use them in a wide diversity of reactions or schemes to form multiple core molecules or advanced structures…, that’s my kind of combichem! Benzoylacetonitrile is just that, one of those materials which can be used in so many ways, condensation, anion formation, addition to ketone and more….and you would imagine is ready for the part in many thermal processes

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Using the following review article (Turk J Chem 2013) on this substrate for the formation of 5-membered heterocycles there are a number of products formed (as well as intermediates) which were made using microwave heating  and compared with conventional. Two nice things about the review — you can see the utility of the starting material, but also that several schemes show where a microwave can be used — and if you pay attention, there are many more examples where one probably would have provided a substantial benefit over the described process (that is a take home message reading any of the journal articles, not all reactions are thermally driven, but many can be performed much quicker in the microwave and with a better yield in most cases.

In the scheme below, substrate 44 has been shown to be fully aromatized under microwave conditions with MnO2 in toluene in minutes at 120C compared to long times conventionally (BMCL 2006).

2-aminothiophenes/amino subst thieno[2,3-c]pyridines

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benzoylacetonitrile condensations for amino thiophenes: Substrate 44 is aromatized under mw irradiation

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thieno[2,3-c]pyridine derivative


a-d are different conditions for the hydrazine addition and ring-closure: for the mw conditions see citation

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pTsOH, MW <1 hr

If you like to look at patents, here is an example — little surprised they didn’t go higher in temperature an cut the reaction time (For patents ESPACENET and USPTO patent pair sites are great for dissecting patent synthetic schemes)

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MeOH, 120C, MW 1 h vs. 2 step 13 h reflux

2 additional sources of mw conditions for aminopyrazoles: OBMC 2006 and Patent 2012 

Keep in mind reading the microwave conditions in patents that most have not been optimized and fewer reported in journal format — no reason why most of these wouldn’t be done in minutes.

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For MW conditions: MeOH 110C, 1h

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Nice formation of tricycle in 5 min

In the kinase arena, a number of amino pyrazoles were used to form advanced clinical candidates for Raf and p38 kinases from both Bayer and BI in the 1990s (example Future Medicinal Chemistry 2010). Here is an example of a two step process using microwave irradiation.

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2 steps: microwave assisted Knoevenagel condensation and ring closure


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1:1 mix of benzoylacetonitrile and o-aminothiophenol

OK that is just the glimpse into what I was thinking here. See if you can come up with few reagents or starting materials that would provide a wheel of reactions — and where would be the thermal reactions and the reactions which are not thermally driven…let me know what you are thinking…would be great to get some different perspectives on the site. Happy Reading!

Here is another cool little website specializing in name reactions….I like the platform. I want more reactions added but if they do that it will replace a number of those books that I have sitting on the shelves — and it’s easy to access on my iphone.

The Organic Chemistry Blog is a site indicating that they filter through most of the big journals and report — man, I have to tell you if we had a company that would give us the cliff notes of all the papers, sweet! Anyway check it out….always fun to get someone’s perspective of what some of the HOT articles are in the current literature….maybe my new blog site will be only on HOT ARTICLES in ORGANIC SYNTHESIS (HAOS)…..nah, nah you can’t have it…and if taken surely I can come up with a better acronym or title than that.

I am going to go to the left side of the ballpark on this one, because if you like this site, small bits and pieces from several posts will show up. A few hints on this one…..remember, I like indoles, cascades, rearrangements —

This indole construction has its’ bottom seated in the intramolecular diels alder of a furan approach (IMDAF). I tip my hat to start to Al Padwa and Peter Wipf for some elegant construction of indoles without some of our more popular transition-metal catalyzed approaches we know look to pull off the shelves (as Henry Rappaport once said to me, as an organic chemist you should never be seduced by commercial availability — a true test it to make it. OK I love that sort of stuff from the giants.

Indoles from this approach: 3,4 from amino furan IMDAF with appropriately position double bonds and 4,5,6- (but particularly the 5-hydroxy for obvious reasons) from the amino furan and IMDAF and a triple bond (remember above — a furan 2-carboxylic acid undergoes a nice Curtius rearrangement to provide 2-amino furans – now I have 2 microwave steps again, just a game I play).

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3,4-Substituted indoles IMADF

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Before moving to the microwave the IMDAF reaction was popularized in the 60s — Wasserman, Cram, Herz were doing these when the music was good. Move forward and Al Padwa put some unbelievable touches on the reaction by placing and amino group on the furan system….I have done some reactions with this pendant group and it really can help open what can be made….anyway I have digressed, and if you are interested in these cyclizations or [4+2] cycloadditions take a look at the monograph series Advances in Cycloadditions.

Chem Comm 2009 in this report, Wipf’s group uses the appropriately positioned allylic alcohol with the amino furan in a microwave.  The process shown below produced moderate to good yields of the 4-substituted indoles, but in comparison to straight thermal conditions which only produced decomposition of the starting material.

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Microwave conditions for IMDAF

You should stay tuned to the first 2 schemes with the alkyne and some development on the amino furan moiety (brief reports from the Wipf team indicate they have made tremendous progress in indole construction with some tandem processes that expand the approach). I can’t wait to read the papers Peter.



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