Back again, 2 years after last post

Well, I am back here to post some stuff about chemistry. I have a new job (Ok, been here for over 1 year now) at Cambrex as Process/Synthetic chemist and I love it.

Well, what has happened now is that we have been having a problem with a quench. We are using Dess-Martin Periodinane (DMP) for an oxidation and Sodium Thiosulfate for quenching DMP and its bi-products (IBA and possibly IBX).

We found a big problem in the process. Some of the batches that were produced contained elementary sulfur and first we though it could be alleviated by decreasing the amount of thiosulfate used for the quench. It did not work too well.

Second, we found a paper (DOI: 10.1021/op700227p) were they described a similar problem, and the recommendation was to add the quench solution to basified reaction mixture. We used Sodium bicarbonate to basify our solution and then started the addition of Sodium Thiosulfate. Sometimes it did work, sometimes it did not.

Further work demonstrated that the pH first increased upon addition of Sodium thiosulfate, but started to decrease over time. Experiment showed that longer quenching times increased the amount of sulfur formed in the reaction.

That is when I found this very useful paper (for me at this moment it is very useful at least). It is written by Takei et al,, DOI 10.1246/bcsj.49.70.

In this paper they make a series of experiments in acidic media, in which they observe and measure the disproportionation of thiosulfate and other sulfur containing species, at high temperatures (>70 °C). Although their reaction conditions do not match the ones in the oxidation I am performing, an interesting detail can be found in page 73. First some background.

Sodium thiosulfate is used to typically reduce idodine and bromine. In the reaction I am interesting to quench, I am using Sodium Thiosulfate to reduce Dess-Martin Periodinane (DMP) and its related bi-products (IBA and possibly IBX). 

If the reduction of DMP follows the same electronic pattern as the reduction of iodine (and is quite likely), Sodium Thiosulfate should oxidize to tetrathionate. Now, check page 73 in the publication from the 70's.Tetrahionate can disproportionate to sulfur, sulfate and acid. This would explain why, I am obtaining sulfur even though I am using alkaline solvents. 

This assumptions seems very likely, as when I measure the pH of my quenching, the pH first increases to 9-10, but then starts to decrease to 8 over time, and more sulfur is formed.

3SO4O62- + 2H2O --> 7S + 5SO42- + 4H+

Well, hope if someone encounters this problem this can be of help. If I am mistaking me hugely, please correct me.

Peace

/ Alejandro

I am trying to plan a reaction in which I incorporate a sulfonamide in the last step of the reaction. I need the conditions to be mild and the yields to be good. I found a paper by Mayer et al. in which the reaction conditions I want may be used:

Sulfonamide/aniline, KOt-Bu, NMP, allylchloro{1,3-bis(2,6-di-propylphenyl)imidazol-2- yilidine]
palladium(II) (IPr•HCl•Pd), Pd(dppf)Cl2•CHCl2,

What I see as a problem is the imidazol Pd(II) salt that is used. Is actually the first time I see it and they use it in 20% amounts along with Pd(dppf)Cl2•CHCl2 and I have a hard time understanding why. I have to find something more general or an explanation for this...

On the other hand, there are many other methods to go. Wang et al recently (2012) published a paper were mild reaction conditions were used. This method is very similar to an older paper by Wei et al (2005) in which they use an aminoacid as a ligand stabilizing the copper reagent.

Of course, the group of Buchwald et al. have Pd-methods that can be used, and in an earlier paper, they stress the importance of using a bulky P-ligand for the reaction to work (here are some examples with amides, and one example with sulfonamide working with chlorides).


An update. Tried out all these reactions, but the one that worked best was an old protocol using Pd(OAc)2 and the ligand Xantphos and Cs2CO3 (s) as the base in THF:Toluene (1:1) at 120 °C. Got almost 80 % product after a very easy purification procedure.

Synthesis of Cyanthiwigin U

Cyanthiwigin U is a challenging molecule to synthesize, and is the topic of tomorrow's synthesis seminar. Cyanthiwigin U is a diterpenoid which is isolated from both fungal and marine sources. It contains a cyclohepta[e]indene ring system, and has no less than 5 stereocenters, a real synthetic challenge.

In this paper, Phillips and Pfeiffer shows a very beautiful approach to synthesize Cyanthiwigin U. It all begins with the synthesis of an endo-acrylisoborneol. The authors used a synthetic strategy presented by Palomo et al. Lithiated methoxyallene is reacted with (1R)-(+)-camphor (1) using THF as solvent at -30 °C and TMEDA as metal ligand. The intermediate (2) is then hydrolyzed in 1M HCl, yielding the desired enones (3, 4 or 5 in the scheme 1 below).

Scheme 1. Taken from Palomo's publication

Through

In  Phillips and Pfeiffer's paper, the endo-acrylisoborneol is then reacted with alkene 6 via a metathesis using Grubb's catalyst (7). The product is a substrate (8) which is next used as a Diels-Alder precursor.

Conditions: (1) 5 mol % Grubbs catalyst (7), 93%

The precursor 8 was then reacted with 1,4-dimethylcyclohexadiene in acidic media (2 equiv TfOH) at -78 °C provided the Diels-Alder product (9, a bicyclo[2.2.2]octene).

Conditions: (2) 1,4-dimethylcyclohexadiene, TfOH (2 equiv), -78 °C, 70%

The cyclization between 8 and 1,4-dimethylcyclohexadiene occurs through a Diels-Alder cyclization. 

Reacting product 9 with CAN (Cerium Ammonium Nitrate), removes the borneol group through a radical reaction. This procedure is also described by Palomo et al. in an earlier publication.

Conditions: (3) CAN, aqueous MeCN, 82%.

The carboxylic acid and pivalic ester are thereafter reduced to the alcohols using LiAlH4. The product is then  subjected to a Swern oxidation to yield the corresponding aldehydes.

Conditions: (4) a) LiAlH4, THF, reflux, 16h, 99%. b) (COCl)2, DMSO, Et3N, 84% 

The dialdehyde 11 is trated with vinylmagnesium bromide. The formed alcohols were re-oxidized
using Dess-Martin periodinane, providing the bis-enone 12. The bis-enone 12 was then exposed to Grubb's catalyst 7, under an atmosphere of ethylene, providing 13.

Conditions: (5) a) Vinylmagnesium bromide, CeCl3. b) Dess-Martin Periodinane. (6) 20 mol% 7, ethylene, Toluene

So, I did not quite get it at the beginning what was going on between 12 and 13, but I tried to make a drawing to understand it better. Here it is:

So the Grubbs catalyst open up the ring's alkene, and from there, it could either make the 7-membered ring first and then the 5-membered ring right after. It could also be the other way around. The important thing is that the alkene in the ring is opened first.

And it is very late right now so I will pause here and continue tomorrow or when I have some more time to write.

Peace & Luv

Chemistry Problem Set #1

At work, every Wednesday we have a problem set to solve. I will try to solve them and write down the solution here (I will loose my papers if I write them down on a paper-block, here I can always go back and look).

So, the target molecule for this week is (1)

(1)

It did not look like something difficult, especially if you think about the parent scaffold (2)

(2)

So, I started to think how to make the parent scaffold (2) and then go back to the target. So, retro-synthetically I was thinking that you would need to have 2-(aminomethyl)aniline and react it with some kind of carbonyl with good leaving groups (like L1-CO-L2). Some brainstorming and google search gives me CDI (carbonyldimidazole)

Anyway. They usually are not happy with one-step answers, but want you to go further back. So, how to make the 2-(aminomethyl)aniline? Well. I guess you could do something like having a bromide where the aminomethylgroup is (i.e. having a bromomethyl instead of amino, and yea, the aniline should be a nitro group which can be reduced with iron dust). Well, they say one image says more than 1000 words and it is very truth in chemistry. This is the route I would choose:

a) AIBN, NBS in CHCl3. b) NH3 in... something aprotic. Maybe neat NH3 (?). c) Reduce the NO2, Fe-dust in ethanol and NH4Cl is quite normal to use here. Or  Zn(Hg) in HCl

Well, I guess there are other routes. I found this papers (here and here) in which other routes are conducted (and the molecule looks a bit different).

Do not have much more time now so I will have to do the rest later :).

And here is the rest of the exercise. So, the target molecule can be synthesized in a different way. Here is a short retrosynthetic analysis

And the mechanism for this is a one-pot reaction (click on the image to see it clearly), but you can also isolate the imidine and then react it with the nitromethane

One thing I was wondering for my self... why does the methoxi do not attack the imidine carbon? I have to check the paper and see what they say about it (do not have the paper with me at the moment)

Eschenmoser's Salt

On monday, just gonna start easy on the lab. Going to make some kind of alkylation using Eschenmoser's salt (N,N-Dimethylmethyleneiminium iodide), which is a hygroscopic crystalline substance having a melting point of 240 °C (although I have seen everything from 117 °C and 147 °C as melting points, but this is the one you find at Sigma and other serious producers).

Safety Information

Symbol	GHS07
Signal word	Warning
Hazard statements	H315-H319-H335
Precautionary statements	P261-P305 + P351 + P338
Personal Protective Equipment	dust mask type N95 (US), Eyeshields, Gloves
Hazard Codes	Xi
Risk Statements (Europe)	36/37/38
Safety Statements (Europe)	26-36

It is used to prepare compounds of the type RCH2N(CH3)2, and is very compatible with enolates, enolsilyl ethers and ketones. The mechanism of reaction is quite simple, and I have seen many different solvents and bases being used (like Et3N and Dichloromethane, or Et3N in acetonitrile).

Lägg till bildtext

Now, the salt we have at the lab is quite old and dirty, so I have some different alternatives:

• Buy a new bottle
• Recrystallize the dirty compound
• Synthesize new salt
• Use it as it is

Of coure, I'll go for re-crystallization of the outdated compound. But, to synthesize some more should be quite easy:

Well, so I guess I will have to recrystallize then....

Uppdate,

So, I said I was planning to recrystallize the salt. I did not manage to find a proper solvent for recrystallization so I opted to test the salt as it was, since I supposed I would get some product and then I could purify it. I was quite wrong. I did run the reaction (in dry Acetonitrile, reflux) and got a by-product in HUGE amounts. This by-product had a molecular mass of 12 a.u. higher than the expected compound. So, of course, a carbon was added to my molecule somehow.  

I got curious to know what this was and started to purify the stuff and run NMR (H, C, COSY, HSQC, HMBC) to see what the hell was happening. It turned out that there was a big amount of decomposed Eschenmoser's salt (i.e., it had decomposed to formaldehyde). So what was happening was that the formed product was subjected to a second enolization, which resulting in the attack of formaldehyde present in the mixture. Apparently, there is a publication about this reaction and would I have come around this problem 15 years ago, I would have invented a new methodology 8-)).

Reaction of arylketone with Eschemoser's salt

So, I really had to purify the salt, and the best way was actually to run a bulb-to-bulb. I crushed the salt (with a mortar) and put the temperature at 80 °C and the pressure at 8 mbar. It did the trick. All paraformaldehyde sublimated. Raising the temperature to 95 °C resulted in slow sublimation of the Eschenmoser salt. I did this quite quickly and I do not think those temperatures are optimal, but the product was pure enough for my purposes. Now the reaction is running and I hope I can get some pure product by tomorrow :))

Design of Experiments (DoE)

Well, there is a lot of discussion whether to use DoE on method development when working in organic chemistry or not. According to me, you should use it as fast as you can. I mean, the industry has adapted to this quite well and it is now a standard procedure so I do not understand the reluctance from academics to adapt to this powerful tool. There is an excellent article by Torbjörn Lundstedt et al. about DoE (here).

One major reason I like DoE is, I guess, doe to my engineering background. As an engineer, you like graphs, you like correlations and you like computers. DoE offers all of this and assist you in your work. In the paper to which I linked (see above), they address some of the common objections from people reluctant to use DoE. Here is a summary of the normal arguments people use to avoid using DoE (that I have heard my self, there are many more for sure)

“Why Bother When the Results Are Blindingly Obvious?”

Personally I think there is a lot of ego in this kind of statements. Of course you have to have an idea of what will work and what wont work, but given the fact that chemistry is affected by so many parameters (temperature, time, pressure, reagents, rate of addition, catalyst, solvent, concentration, pH, etc), it is worthwhile to try a small screening design at the beginning of any project. At the end, all information might be used and the effect of a given variable can be calculated .

Many people expect DoE to provide miracle results. But, visualize that one-factor-at the time is the counterpart of running with boots, DoE is the counterpart of running with proper running shoes. Having to run is a pain in the *ss no matter the shoes you choose, but you cannot deny that is h*ll more easy to run with Asics Gel-Scout than using a pair of gothic boots.

What If We Miss a Factor? Will My DOE Work Not Be Wasted?

If you miss a factor using DoE, you will probably miss it using the usual approach (one factor at a time). With DoE you can actually use Lack of Fit tests and residual analysis  which may help you find that missing variable (with a little bit of thinking and analysis).

Other stuff you may hear are that the resources are limited. But, using this argument just proves that you have missed the whole point of DoE, it is designed to minimize costs and the amount of experiment that have to be performed in order to find optimal responses. The thing is that you see in beforehand the amount of material that will be "wasted". Changing one-factor-at-the time, you waste while you progress and at the end, you do not realize that the amount of material used just surpassed the amount of material that would be needed to make a screening design and an optimization.

So, I do not have so much more time to use here. I may be wrong in some points, but my advice for them who are new at DoE in method development are (besides reading the papers above)

• Search the literature. Remember, four weeks in the lab will save you four hours in front of the computer (or library).
• Start with a screening design. What parameters are important? (usually, temperature and solvent have to be included...)
• Do not forget to try to minimize the number of variables used. Sometimes using A, B and C (three variables) is just as meaningful as using ratios of these factors (i.e. A/B and C/B, which give you two variables instead of three)
• When you are done with the screening design and have found the most important variables, is time to optimize. Response surface design is usually the way to go.

Well, the reason I posted this is because of a little bit of frustration I feel due to the almost non-existent use of DoE at academic organic chemistry labs, while this is a method that is a must out in industry. I have been striving to work with it as much as I possibly can, and one day, I hope it will be a tool as frequently used as an analytical HPLC.