Chemists Adding Arynes to the Hunt for Cures

September 2014

Pharmaceutical companies, at the forefront of the fight against disease, rely on organic chemists to synthesize the new molecules that might provide the weapons we need to beat cancer and viruses.

There are hundreds of ways of making new compounds, but when it comes to duplicating those which nature can produce and which appear to have beneficial effects, chemists’ skills are tested to the limit, because such molecules are necessarily complex. Often they contain benzene rings as part of their structure, and these entities are not the easiest to manipulate. However, there is a way to boost their chemical reactivity and that is to convert them to an aryne. The simplest aryne is that of benzene itself: so-called benzyne.

Chemists have been fascinated by benzyne for almost a century. The molecule is benzene (C6H6) with two of its adjacent hydrogens removed (C6H4). In effect this turns a double bond in the ring into a triple bond, with the ring still intact, and yet this seems to be inconsistent with the normal chemistry of triple bonds which must perforce be linear.

Clearly such a molecule must be intrinsically unstable and highly reactive, as it seeks to resolve this dilemma; organic synthesis exploits these qualities. Chemists have found ways of temporarily forming benzyne, of which the best method is that devised by Himeshima, Sonoda and Kobayashi in 1983 (see table below, paper #1) and improved upon by Pena et al. in 2002 (table, paper #3). These papers have been much cited because they offer a relatively mild process for generating benzyne, whereas older methods involved either high temperatures or aggressive reagents as ways of stripping off the requisite hydrogen atoms from the benzene ring.

There has been a growing interest in arynes of late, as shown below by the number of papers that invoke them. As the graph shows, the number of papers mentioning “arynes” in their title, abstract, or keywords has nearly tripled since 2004. A 2012 review of the subject by Brian Stoltz of Caltech has already garnered 92 citations (#2).

One of Stoltz’s latest papers uses benzyne to make acridone (this type of molecule consists of two benzene rings joined through nitrogen and oxygen links). The synthesis involves its reaction with the C-N bond of a ß-lactam resulting in a ring expansion to form dihydroquinolinone which then reacts with a further benzyne unit to give the acridone. (See “A C-N insertion of ß-lactam to benzyne; unusual formation of acridone,” Tetrahedron Lett., 53 [37]: 4994-6, 2012.)

Arynes are an established part of the methods used to synthesize natural products because they have the ability to attach other groups to the benzene ring, in a single step reaction, in a selective manner. So far, more than 70 natural products have been made using arynes as intermediates.

Benzyne can react in various ways. It can simply add one or two other groups to replace the missing hydrogens, with sometimes both sections coming from the same molecule (known as a σ-bond insertion reaction). It can attach atoms of the reagent molecule to both active carbons to form another ring system (aka cycloaddition), or it can react with itself and produce molecules with fused benzene rings, given the right metal catalyst.

ARYNES IN ACTION

So what are the most-cited papers in this field at the present time? A search of the Web of Science for the most-recent, complete years, 2012 and 2013, revealed several papers (excluding standard reviews) that had already gathered 15 or more citations. These are listed in the table (#4 to #11).

Highly Cited Arynes Papers

(Listed by citations)

 

# Paper Citations
1 Y. Himeshima, et al., “Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions,” Chem. Lett., 8: 1211-4, 1983. [Kyushu U., Fukuoka, Japan] 363
2 P.M. Tadross, B.M. Stoltz, “A comprehensive history of arynes in natural product total synthesis,” Chem. Rev., 112 (6): 3550-7, 2012. [Caltech, Pasadena] 92
3 D. Pena, et al., “An efficient procedure for the synthesis of orth-trialkylsilyl triflates: easy access to precursors of functionalized arynes,” Synthesis, 10: 1454-8, 2002. [U. Santiago, Santiago De Compostela, Spain.] 75
4 S.S. Bhojgude, A.T. Biju, “Arynes in transition-metal-free multicomponent coupling reactions,” Angew. Chemie Int.. Ed., 51 (7): 1520-2, 2012. [CSIR, Pune, Maharashta, India.] 41
5 T.R. Hoye, et al., “The hexahydro-Diels-Alder reaction,” Nature, 490 (7419): 206-12. [U. Minnesota, Minneapolis] 40
6 H. Yoshida, K. Takaki, “Aryne insertion reactions into carbon-carbon sigma-bonds,” Synlett, 12: 1725-32, 2012. [Hiroshima U., Higashi-Hiroshima, Japan] 30
7 S.M. Bronner, et al., “Steric effects compete with are distortion to control regioselectivities of nucleophilic additions to 3-silylarynes,” J. Am. Chem. Soc., 134 (34): 13966-9, 2012.  [U. California, Los Angeles] 22
8 S.Y. Yun, et al., “Alkene C-H insertion by aryne intermediates with a silver catalyst,”  J. Am. Chem. Soc., 135 (12): 4668-71, 2013. [U. Illinois, Chicago] 20
9 Z. Jingjing, et al., “Aryne [3+2] cycloaddition with N-sulfonylpyridinium imides and in situ generated N-sulfonylisoquinolinium imides: a potential route to pyridol[1,2-b]indazoles and indazolo[3,2-a]isoquinolines,” Org. Biomol. Chem., 10 (9): 1922-30, 2012. [Henan U., China] 19
10 A.E. Goetz, N.K. Garg, “Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model,” Nature Chem., 5 (1): 54-60, 2013. [U. California, Los Angeles] 19
11 D.C. Rogness, et al., “Synthesis of pyridol[1,2-a]indole malonates and amines through aryne annulation,”  J. Org. Chem., 77 (6): 2743-55, 2012. [Iowa State U., Ames] 15

Source: Thomson Reuters Web of Science

The first of these is a mini-review and comes from Akkattu Biju of the CSIR National Chemical Laboratory of India. It concerns reactions of arynes in which it is not necessary to use transition metals to accomplish the desired outcome. The Biju group has since published ten papers on the arynes—see http://academic.ncl.res.in/at.biju/publications. One of their most recent publication is about the synthesis of benzobicyclo[3.2.2]nonatrienones  (see S.R. Yetra, et al., J. Org. Chem., 79 [9]: 4245-51, 2014).

Paper #5, from the group led by Thomas Hoye of the University of Minnesota, reports a reaction involving two substituents attached to a benzene ring—one with a single triple bond, the other with two adjacent triple bonds. These interact at room temperature over a period of 46 hours to give a 93% yield of product that involves the construction of two new rings, in the process of which there is formation of aryne intermediate by one of them. The same type of reaction is the subject of paper #8 where, in the presence of a silver catalyst, it is possible to activate a C-H bond in a way that requires much milder conditions than normally required for this process. Paper #8 is from a group led by Daesung Lee of the University of Illinois at Chicago.

Paper #6, from Hiroto Yoshida of Hiroshima University, concerns reactions which involve arynes and without the need for transition metal catalysts. Four kinds of reaction are described with the following types of reagents: ß-dicarbonyls, α-cyanocarbonyls, sulfonylacetonitrile, and trifluoromethyl ketones. In addition, the group also reports the total synthesis of two natural products: cytosporone B and phomopsin C. The former can be extracted from fungi and has potential as a possible cancer treatment. The latter interfere with the microtubules which support and shape living cells and again may have potential in anticancer treatment.

The group of Neil Garg, at the University of California, Los Angeles, merits two entries into the list of most-cited: #7 and #10. The first of these concerns the reactivity of triethylsilylbenzene and shows how the presence of this bulky substituent will affect the reactivity when this involves an aryne intermediate. If the nature of the aryne determines the outcome of a reaction then the incoming group should attach itself to the carbon that is ortho (i.e. adjacent) to the silyl group, but if the incoming group itself is bulky then it will end up attached to the meta position which is one carbon removed from the nitrogen. Garg’s paper shows that computational predictions of what will happen are borne out in reality.

Garg’s other paper (#10) concerns a different kind of aromatic system: pyridine, and indeed this is the target molecule for three papers in the list, i.e. #9, #10, and #11.

The pyridine molecular unit is part of more than 100 pharmaceutical drugs. In pyridine the C-C aryne bond can form in one of two different locations with respect to the nitrogen atom in the ring. In particular it allows the formation of 3,4-pyridines, in which the other groups are two and three carbons removed from the nitrogen, and which hitherto where difficult to obtain (#10).

Paper #9 is also concerned with pyridine and offers a route to potential anticancer agents. The team at Henan University in China, led by Jingjing Zhao, generated benzyne in situ so that it would attach the benzene ring to a pyridine derivative and in a one-pot reaction involving two separate steps.

Finally on the list is paper #11 from Richard Larock of Iowa State University and colleagues, in which an aryne is used to form an indole by reacting a pyridine with a substituted benzyne.

ARYNE APPRECIATION AND ANTICIPATION

So what have arynes got that is so special? I posed this question to a leading aryne chemist, Michael Greaney of Manchester University. He has been using arynes in synthesis for many years; his most-cited paper has gathered a notable 63 citations. (“Three-component coupling of benzyne: domino intermolecular carbopalladation,”  J. Amer. Chem. Soc., 128 [23]: 7426-7, 2008.)

Greaney: “Mild methods of aryne generation have dramatically expanded the repertoire of chemistry that is possible with the strained benzyne triple bond, but much remains to be discovered. Aryne carbon-oxygen bond formation, for example, is significantly under-developed relative to carbon-nitrogen transformations, and would open up new routes to oxygenated heterocycles and natural products. Capturing the inherent reactivity of arynes in C-arylation chemistry also presents opportunities, with some exciting examples of bi-aryl synthesis being reported in both metal-catalyzed and metal-free regimes.”

Greaney continues to be active in aryne chemistry, as shown by two recent papers. The first of these concerns new aryne precursors that involve reaction intermediates with the triple bond linked to a transition metal catalyst (“Use of 2-bromophenylboronic esters as benzyne precursors in the Pd-catalyzed synthesis of triphenylenes,” Org. Lett. 16 [9]: 2338-41, 2014). In the second paper he uses the technique of flow technology which was highlighted in ScienceWatchin early 2013. In this research, aryne formation was one of the steps (“Continuous-flow synthesis of trimethylsilylphenyl perfluorosulfonate benzyne precursors,” Org. Lett. 16 [10]: 2684-7, 2014).

Benzyne may never be isolated as such but it continues to guide chemists to some remarkable reactions and products, and maybe one day will be instrumental in creating a drug that will cure a disease that still afflicts humanity.


Dr. John Emsley is based at the Department of Chemistry, Cambridge University, UK.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.