7. On cyclopropane C-H activation.

If there is a topic of catalysis that has been restlessly growing these past ten years, it is without much doubt the field of C-H activation. In it, C-H activation on Csp3 positions proves difficult, though more and more methods are developed. In particular, the C-H bonds borne by cyclopropane moieties seem to be activated reasonably easily by palladium complexes.

In 2012, the group of Prof. Nicolai Cramer of EPFL (Lausanne, Switzerland) reported a new enantioselective method for the synthesis of cyclopropane-fused tetrahydroquinolines via palladium-catalysed cyclopropane Csp3-H activation.

7.b

The only downside of the method is the mandatory substitution on the R position. In the case where R = H, the favoured product is the corresponding spiro dihydroindole compound.

7.a

This is easily understandable as the 6-membered ring product must come from a 7-membered ring intermediate whereas the 6-membered intermediate would be favoured, affording the 5-membered product.

7.c

Reference:
Angew. Chem. Int. Ed. 2012, 51, 12842-12845. link

6. A new way to make methyl esters.

If you are planning to convert a carboxylic acid into the corresponding methyl ester, chances are your two main plans will be the Fischer esterification or the reaction with a methyl electrophile. While the esterification is one of the easiest reactions to perform, you will need strong acidic conditions, and not many organic functionalities will stand it. Otherwise, if you do not mind to use slightly basic reaction conditions, the use of methyl iodide or dimethyl sulfate (or even worse, diazomethane) generally does the job and does it well. The downside, of course, is the notorious toxicity of these bad boys. If not acute, they will methylate anything they find, and if you are not cautious, it may well be your lungs or your DNA (remember these are very volatile species, and dimethyl sulfate was once considered as a chemical weapon, but as I remember it, it was not deadly enough).

6.aA new way to get around this whole toxicity issue is described in one of the last papers from the team of Dr. David J. Gorin (from Smith College, Northampton, MA). Here dimethyl carbonate plays the role of the methylating agent, and the good news are, it is cheap, readily available, the boiling point is quite high (90 °C) and it is fairly harmless compared with methyl iodide and dimethyl sulfate.

6.bThe yields are good to excellent (75-99%) and the method is chemoselective. In fact, this methylation does not affect unprotected phenols, so there is no point in worrying about having a product mixture or struggling with protecting group manipulation.

Reference:
J. Org. Chem. 2013, 78, 11606-11611. link

5. Mechanism Monday: the acid-promoted cascade cyclisations of N-Cinnamoyl-1-naphtylamines

A recent paper of Dr. Frank D. King and co-workers (from University College London) was dealing with the acid-mediated cyclisation patterns of N-cinnamoyl-1-naphtylamines.1 While most results were matching what one would expect, the authors observed two new products appearing when the nitrogen atom was bearing a benzyl group. They proposed structures for these unexpected products, so the question is, what would you propose for the mechanism?

5.aNot too difficult, I agree, but a nice warm-up exercise to start a group meeting.

Reference:
1. J. Org. Chem. 2013, 78, 10938-10946 link

4. Electrochemical chlorination of 1,3-dicarbonyls

A recent paper of Prof. Fumitoshi Kakiuchi et al. (from Keio University in Yokohama, Japan) deals with the copper-catalysed α-chlorination of 1,3-dicarbonyl compounds.

You might be thinking that it is just another paper on an overused method, but there is a twist here that I particularly liked. The source of chlorine here is nothing but hydrochloric acid, probably the cheapest and simplest source of chlorine atoms, without the issue of handling a toxic gas like Cl2. I guess there is no point in mentioning N-chlorosuccinimide. The trick for the transformation of a fairly inert Cl into a formal Cl+ is the use of electrochemistry. A mild current at the appropriate intensity provides just enough oxidation to provide monochlorinated 1,3-dicarbonyls in ok-to-high yields.

4.a

While I doubt I will ever use this method in a lab (I am not too experienced with organic electrochemistry), I can see the potential of it on an industrial scale: reducing costs of reagents, reducing waste, and perhaps you could even use the H2 produced by the reaction to power an auxiliary generator or something.

Asian J. Org. Chem. 2013, 2, 935-937 link

3. On azirines. 2/2

In the last post I concluded on the fact that you could obtain 4-phenyloxazole by a Lewis acid-mediated rearrangement from a phenyl-substituted azirine-carbaldehyde. It seems at first like trying to establish a synthesis from an intermediate more convoluted than the final product is. When seeing the azirine structure for the first time, I figured how to call it referring to nomenclature rules, but I was only vaguely aware of their existence, I thought azirines would be reaction intermediates at best. I was surprised to discover that you could actually isolate some of these compounds, and even more surprised to find that their synthesis was not that dreadful. Actually, you can synthesise 3-phenyl-2H-azirine-2-carbaldehyde in two steps from easily accessible and dirt cheap starting materials. The first step is a Vilsmeier-Haack-type reaction on acetophenone that generally delivers the β,β-disubstitued acrolein in pleasingly high yields.1 Then, reaction of said acrolein with sodium azide affords the azirine in moderate-to-high yield (typically around 60-70%).2

3.a Azirine synth

I found this second reaction quite intriguing. Guessing that azide, as a good nucleophile, would add in a Michael fashion to the acrolein, leading eventually to the bromide being kicked out, an then something else would happen to the newly formed vinyl azide en route to the azirine. The only way out I could imagine was the elimination of a nitrogen molecule, leaving a highly unstable vinyl nitrene that would rearrange to the more stable azirine form, Curtius rearrangement-style.

 3.b vinyl azide rearr

It seems that I wasn’t too unrealistic here because, according to Wikipedia, the rearrangement of vinyl azides is the most popular way to synthesise azirines directly. This led me to discover that azirines are also reliable precursors for the in situ formation of nitrile ylides, which can be involved in dipolar cycloadditions, e.g. with an alkyne to form a 3,4-substituted pyrrole after tautomerisation.

 3.c nitrile ylide

Azirines apparently also play a role as an intermediate in the Neber rearrangement (to be honest I had never heard of it before) that converts oximes to α-aminoketones.

 3.d Neber rearr

References:
1. J. Org. Chem. 2013, 78, 6223-6232 link
2. J. Heterocycl. Chem. 2008, 45, 311-317. link

2. On Auxofuran Total Synthesis, Oxazoles and Azirines. 1/2

I have recently come across the total synthesis of (–)-auxofuran by Boukouvalas and Loach (from Université Laval in Québec) and it is really the kind of synthesis I like: short, efficient, well thought.1 The central feature, namely the construction of a 3,4-disubstituted furan, is particularly interesting.

 Furans are notoriously difficult to functionalise on other positions than 2 and 5, whether you try a classic SEAr or a directed lithiation. Here the authors got around the synthetic difficulty by a de novo construction of the furan core from a disubstituted alkyne.

2.a DArDAI like the way a pretty standard molecule such as 4-phenyloxazole can be used as a synthetic equivalent of “dimethine ether” or as a super-carbonyl ylide.

2.b synthetic equivalentThis is all fine and dandy, but I wondered how accessible 4-phenyloxazole was. I could not find it in the catalogues of common suppliers, so I guess you would have to make it yourself.

I guess I can already rule out the van Leusen oxazole synthesis since this reaction affords 5-substituted oxazoles.

2.c TosMICI was thinking of using oxazole directly and start from there, but with a cost of £229 for only 10 g of starting material (price found in the Sigma-Aldrich catalogue), I turned to a less risky plan. It seems that the strategy of Rickborn et al.2 is somehow the most reasonable. One step from cheap commercially available starting materials (2-bromoacetophenone and ammonium formate are not particularly expensive stuff…), the yield is the only drawback.

2.d AcetophenoneWhilst fathoming the literature for interesting strategies, I came across some very interesting photochemical rearrangements from 4-phenylisoxazole3 (94% yield in 5 min!) and 2-phenyloxazole4 leading to 4-phenyloxazole. Agreed, it would lengthen the synthesis but, to me at least, it seems so much more interesting (mechanism-wise). On the same topic, the photo-mediated addition of 1,3-dioxole to benzonitrile seems to give an original access to 4-phenyloxazole, albeit in low yield.5

2.e Photochemistry

One last interesting way to synthesise 4-phenyloxazole I found was the Lewis acid-mediated rearrangement of 3-phenyl-2H-azirine-2-carbaldehyde.6 Oddly enough, this compound rearranges into two different isomers depending on the type of species it is treated with. In presence of transition metal complexes (of Rh and Ru, here TM) 3-phenylisoxazole is produced while main group Lewis acids (BF3.OEt2, AlCl3, InCl3, here LA) tend to favor 4-phenyloxazole.

2.f Azirine rearr

The second part or this article, a focus on the chemistry of azirines is to come for next time.

References:
1. Org. Lett. 2013, 15, 4912-4915. link
2. J. Org. Chem. 1990, 55, 929-935. link
3. J. Heterocycl. Chem. 2005, 42, 273-281. link
4. J. Chem. Soc., Perkin Trans. 1 1977, 239-247. link
5. Tetrahedron 1987, 43, 5781-5790. link
6. J. Heterocycl. Chem. 2008, 45, 311-317. link

1. About this blog, about me…

To anyone  reading this, I would like to thank you first for visiting my blog. Comments on articles are very welcome.

A the moment I am still a postgraduate researcher, at least on paper, as I am between my thesis submission and my Ph.D. viva.

I have often considered the opening of a chemistry-based blog to give my views, tips and thoughts on general organic chemistry, past and recent literature, etc. but I never found the time to do it. Now that I am out of the lab, not yet an actual doctor, I have time on my hands to start my own blog. I hope this will help me to practise my scientific English writing (as you might have noticed, I am not a native speaker). Please feel free to correct my grammar, I do not notice my mistakes sometimes .

 

Make yourself comfortable, and be welcome to Organic Chemistry Periodically!