NEWS OF TH E WEEK
NEW ROUTE TO DIFFICULT PRODUCTS ORGANIC SYNTHESIS: Radical reaction yields previously hardto-get alkene coupling products
C
HEMICAL GROUPS containing oxygen, nitro-
gen, silicon, and other heteroatoms often react during alkene coupling reactions, generating undesirable product mixtures. But a new, iron-catalyzed radical reaction, developed by Phil S. Baran and coworkers at Scripps Research Institute, La Jolla, Calif., couples heteroatom-containing alkenes without all the messy side products (Nature 2014, DOI: 10.1038/nature14006). The heteroatom group remains unmodified while a carbon-carbon linkage forms in a highly controlled and predictable way. About a year ago, Baran and coworkers developed a radical reaction in which an iron-based agent catalyzed the coupling of all-carbon alkene substrates (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja4117632). Although this method is useful and practical, the products it generates can also be obtained—albeit with difficulty, in some cases—from known reactions of nonalkene substrates such as alkyl halides, alcohols, and carboxylic acids. The researchers have now identified a new ironbased catalyst that extends the scope of the reaction to heteroatom-containing alkene substrates. The paper shows 60 products, “90% of which have never been made before,” Baran says. The extended reaction uses the new catalyst, a reducing agent, and a weak base to form C–C bonds that link heteroatom-substituted olefin “donor” substrates to “acceptor” alkenes bearing electron-withdrawing groups. The catalyst removes an electron from the donor, producing a radical that then combines with the acceptor.
A variety of readily available heteroatom-containing alkene donors can be used, including enol ethers, enamides, vinyl boronates, vinyl thioethers, vinyl silanes, and vinyl halides. The reactions work at ambient pressure, and no special precautions need to be taken to exclude air and moisture. To prove just how versatile the reactions are, Baran and coworkers showed that they could be run in a variety of commercial alcoholic beverages as solvents. “It is surprising that the substrate scope of the reaction can be extended to such a wide variety of heteroatom-substituted olefins,” comments senior synthetic chemist Jonas Brånalt of AstraZeneca R&D, in Mölndal, Sweden, who uses the Baran group’s original all-carbon alkene reaction in his lab. “The new methodology will allow synthetic chemists to acR2 R3
R1
Catalyst, reducing agent, weak base
R2 R1
X
3 • R +
X
Donor alkene
O O
O Fe O
O O
Radical
A new reaction uses an iron-based catalyst, a reducing agent, and a weak base to combine heteroatomcontaining alkene “donors” with “acceptor” alkenes bearing electronwithdrawing groups. R2
C–C bond formation
R4 EWG
R1
Acceptor alkene
R4 EWG 3
R X Product
R1–4 = various groups EWG = electron-withdrawing group X = functional group containing heteroatom (such as O, N, S, B, Si, F, Cl, Br, or I)
Catalyst
cess novel structures that would be either difficult or even impossible to make using traditional synthetic routes.” The approach “has the potential to shift the retrosynthetic paradigm,” says catalytic reaction specialist Michael J. Krische of the University of Texas, Austin. “It unlocks new possibilities for the construction of C–C bonds that are otherwise difficult to achieve, and its operational simplicity—the use of an inexpensive iron catalyst in ethanol solvent—makes it especially attractive.” According to Baran, his team has some exciting follow-up plans: “Let me just say that this is the tip of the iceberg. There’s much more to come.”—STU BORMAN
INVESTIGATION Feds cite safety lapses, mechanical failures in fatal DuPont accident in Texas Mechanical problems and ineffective safety practices were likely factors in the chemical leak that killed four workers last month at DuPont’s complex in La Porte, Texas, federal authorities say. The U.S. Chemical Safety & Hazard Investigation Board (CSB), which investigates chemical accidents, points to problems with the vent system in the building where the release of 23,000 lb of toxic methyl mercaptan originated on Nov. 15. In addition, DuPont “did not effectively implement good safety practices” that
require workers to wear air respirators and other protective equipment, CSB alleges in preliminary findings. On the basis of its internal review, DuPont says that CSB’s description of the circumstances “leading to the release of methyl mercaptan from the vent header system is the most likely scenario.” But the company adds that it “does not necessarily agree with other aspects of CSB’s statement.” According to CSB, the leak occurred after an unplanned shutdown of the
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methomyl production unit. Methomyl is the active ingredient in DuPont’s Lannate brand insecticide. The agency found that workers were unable to restart the unit because supply piping from a methyl mercaptan storage tank was plugged. “It is likely that methyl mercaptan inadvertently entered the interconnected process vent system inside the building,” CSB says. The release occurred through a valve that was opened as part of a routine effort to drain liquid from the vent system to relieve pressure.—GLENN HESS
