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.

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.


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

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.

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