Rest In Peace, Professor Richard Heck

Rest in peace, Prof. Richard Heck. You have contributed so much to organic synthesis. With the cross-coupling reaction bears your name (and was awarded a Chemistry Nobel Prize in 2010), you have significantly enhanced the versatility of chemical synthesis.

A classic example of the Heck reaction.

By installing a double bond functionality to an aromatic substrate in a Heck reaction, the synthetic utility of the resulting compound can be greatly enhanced. The reactive double bond can serve as a handle for further manipulations, such as metathesis, epoxidation, difunctionalization, hydrogenation, hydroformylation and so on, and many of these reactions have their asymmetric versions.

As the Heck reaction is fascinating both in scope and also mechanism (and stereochemical aspect), one can easily see that many further developments and studies have been committed to put this reaction into its maximum potential. Cationic, oxidative, or even asymmetric Heck reactions are present in the arsenal, and I am sure more innovative variations will emerge. Without the wisdom of Prof. Heck, I suppose synthesis nowadays will have far more road blocks on the way.

Dedicated with respect and admiration.

by Ed Law
18/10/2015

Have Faith in Iodine

In the Como Fluorine Conference, a substantial number of lectures and presentations are on the methodology and applications of installing the trifluoromethyl (CF₃) groups into diverse organic structures. It should not be too hard to understand that, given the extent to which the incorporation of a single fluorine atom into an organic molecule with biological relevance, can drastically alter its chemical properties, metabolic stability or lipophilicity, the incorporation of more than 3 fluorine atoms will dramatically change the potential inhibitory profiles of the molecule, no matter in a  positive or negative manner. Indeed, with the interest in attaching even longer perfluoroalkyl chains of the type C_xF_y (which is something more related to my research work), and the introduction of a new sulfur-based functional group, SCF₃ , it should not be surprising to see a lot of research work has appeared in the literature in these fields. In this article, I will talk about some of the most important methods regarding electrophilic perfluoroalkylation, and the new developments I have heard in the Como Conference.

Many of the trifluoromethylation reactions involve either an iodine-based (iodonium salt / hypervalent iodine) or a Group 6-based -onium salt (O, S, Se, Te...). The preliminary investigations of these reagents will eventually lead to 2 of the most common reagents, Togni's reagent and Umemoto's reagent. I have talked about the use of these reagents in my blog before, and don't be thrilled that you will regularly see these reagents in many of the major journals from time to time. That only testifies how powerful these reagents can be. Anyway, let's start with the background.

Iodonium salts have been known to transfer CF₃ or longer perfluoroalkyl chains to organic substrates. For example, the phenyl iodonium salt can transfer different R_F groups to the organic molecules (Figure 1).

Figure 1

On the other hand, a sulfonium salt can also be a CF₃- carrier than leads to trifluoromethylation (Figure 2).

Figure 2

Togni's reagent

The hypervalent iodine-based Togni reagent has become a very useful trifluoromethylation agent, and from the keynote lecture and the recent publications (including a Chemical Review article) one can easily realize that this reagent works for some many different functional groups, almost a CF₃ can be incorporated into a differnt structure using the Togni reagent. Most of the common Togni-type reagents involve either one of these skeletons (Figure 3).

Figure 3

Other than CF₃ group, longer perfluoroalkyl chains (C_xF_y) can also be incorporated into diverse organic substrated by using Togni-type reagents (Figure 4).

Figure 4

There are numerous other lectures and poster presentations regarding the trifluoromethylation.

A variation of the Togni's reagent can be used to substitute a CF₃ group to the trimethylsilyl group in the allyl trimethylsilane substrate. The reaction is catalyzed by CuCl (20 mol%) at elevated temperature, using an excess of the trifluoromethylating agent (Figure 5).

Figure 5

Umemoto's reagent

The Umemoto reagent is a sulfur-based salt which can act as a nice source of CF₃ for numerous organic substrates. The Umemoto reagent has been employed to install CF₃ group into many important organic substrates and natural products. For example, Umemoto reagent has been used to react with a stabilized enolate, giving a trifluoromethyl group in between 2 carbonyl groups. When reacting with a conjugated silyl enol ether, the CF₃ group is incoroprated at the end of the original conjuated system (Figure 6).

Figure 6

There also exists asymmetric trifluoromethylation reactions involving copper catalysis.

By using a biphenyl substituted with 2 fluorine atoms, they made their novel fluorinated Umemoto's reagent in 3 steps. While the initial counteranion was OTf ^- , they were able to exchange the anion to BF₄^- and Cl^- by using NaBF₄ and Bu₄NCl respectively. They have discovered that the identity of the counteranion can affect the activity of their reagent, with the non-nucleophilic BF₄^- version being the most active.

Figure 7

When they increased the number of fluorine atoms to 4 in their core structure, the activity dramatically increased. With 4 fluorine atoms, even the reagent with a - OTf ^- anion is still way more active than the 2-fluorine substituted Umemoto reagent, with the BF₄^- in it. Upon systematic investigation, they have found that the fluorine atoms at the 2-position are strongly stabilizing, while the fluorine atoms on the 4-position are destabilizing. Thus, the activity of the reagent comes as a balance between these effects.

BF₄^- version being the most active.

Figure 8

Of course, I have also asked a question that has been fascinating me for quite some time - why are there non Umemoto reagents for longer perfluoroalkyl chains (where x = 2 - 8 for C_xF_y, for example)? Prof. Umemoto has answered it is possible, and another nice professor has commented there are already alternative reagents for doing those reactions.

Fluorination reagents involving hypervalent iodine reagents

Another interesting piece of research I have heard is from Dr. Stuart's group. They are doing fluorination reactions by using a hypervalent iodine-based reagent (Figure 9).

Figure 9

The reagent is easy to prepare, and quite stable. They have carried out fluorination reactions on substrates such as β- ketoesters, including cyclic versions, which are more common in natural product synthesis. This method should find a lot of use in future chemical synthesis.

They have also reported fluorocyclizations, where fluorinated lactones or pyran-type products (or their nitrogen counterparts) can be made, which has important biological significance. Szabo et. al. has also carried out similar reseach on these.

by Ed Law

03/10/2015 

Reference:

Modern Fluoroorganic Chemistry by P. Kirsch, Wiley VCH.

Synthesis, 1978, 835.

Chem. Rev., 2015, 115, 650.

Angew. Chem. 2012, 5, 8221.

Angew. Chem. Int. Ed., 2012, 51. 4577

Chem. Eur. J., 2012, 18, 1279.

Chem. Commun., 2013, 49, 9263

RSC Adv., 2015, 5, 16501.