Noteworthy Chemistry

May 9, 2011

Metal- and halogen-free Friedel–Crafts acylations are a big step for green chemistry. The Friedel–Crafts acylation is a basic transformation in organic synthesis, but it generates large amounts of metal- and halogen-containing waste. Environmentally friendly optimization of conditions for this reaction would be valuable to the chemical industry. Two defining goals of green chemistry are atom economy (waste minimization) and benign waste streams.

M. C. Wilkinson at GlaxoSmithKline (Stevenage, UK) reports a metal- and halogen-free Friedel–Crafts acylation that generates small waste streams. A key to his reaction strategy is the use of (MeSO2)2O as the activating agent and MeSO3H as the strong acid catalyst.

The reaction typically proceeds with only 2 equiv of aromatic nucleophile and no additional solvent to form Friedel–Crafts product 1, as illustrated in the figure. Despite the obvious steric hindrance to the acylation, the reaction proceeds with an 87% yield of 1. Yields in the series of reactions in the study ranged from 53 to 87%. A methyl ester substituent on the carboxylic acid substrate survives the reaction conditions, demonstrating the chemoselectivity of the acylation. Reactions are also possible with electron-poor chlorinated aromatics, although the yields are lower with these substrates.

Because MeSO3H is a reaction product of (MeSO2)2O with the substrate acid, it is important that it can be derived from biomass. MeSO3H can be biodegraded using suitable industrial processes. The absence of halogenated reagents is an advantage in waste treatment.

The author reports further reduction of the required amount of nucleophile to 1.3 equiv, as illustrated by the formation of benzophenone derivative 2. In this case, 2 is crystallized directly from the reaction mixture with n-PrOH–H2O, minimizing reagents and waste. The author estimates that only 50 g of waste is formed for every 10 g of product. He notes that, with one exception, all products in the study can be isolated by crystallization from the reaction mixture to provide a scalable one-pot process. (Org. Lett. 2011, 13, 2232–2235; W. Jerry Patterson)

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This polymeric N-heterocyclic carbene catalyst supports itself. Led by A. H. Cowley, researchers at the University of Texas at Austin and the Tokyo Institute of Technology synthesized an organocatalyst derived from N-heterocyclic carbene (NHC) polymers. They prepared the “self-supported” catalyst in five steps in high yield. The catalyst is recyclable with minimal loss in activity (from 67% yield in the first cycle to 64% in the third).

The authors demonstrated the performance of the organocatalyst in the dimerization of benzaldehyde derivatives. The polymeric version of the catalyst generates yields similar to those obtained with the monomeric catalyst; and it has higher yields of benzoin products obtained from electron-rich or electron-deficient benzaldehydes. Unlike the monomer, the polymeric catalyst is almost completely recoverable. (J. Am. Chem. Soc. 2011, 133, 5218–5220; LaShanda Korley)

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Xenon dioxide has been synthesized—and it may solve a mystery. Xenon exists in levels ≈20 times lower than those of the lighter noble gases neon, argon, and krypton in the atmospheres of the Earth and Mars. It also appears that >99% of primordial xenon has degassed from the Earth’s mantle. Several theories have been proposed to explain the disappearance of xenon, such as entrapment in ice, clathrates, or sediments; or escape from the planets’ atmospheres.

D. S. Brock and G. J. Schrobilgen* at McMaster University (Hamilton, ON) prepared the “missing” xenon oxide, XeO2. They hydrolyzed XeF4 at 0 °C in the presence of pure water or 2 M H2SO4 and then warmed the mixture to ≈20 °C to produce a yellow suspension that is stable for ≈2 min at 0 °C and for longer periods at –78 °C. By using Raman spectroscopy with isotopic enrichment at –150 °C, they found that the product does not contain Xe–F bonds, nor is it a hydroxy compound. It also does not have bent geometry as expected for XeO2, but instead has an extended chain or network structure consistent with local square planar geometry for the XeO4 unit, as shown in the figure.

The presence of two valence-electron lone pairs in the valence shell of Xe(IV) in XeO2 indicates that xenon may be incorporated into interstitial spaces of SiO2 lattices. A recent computational study (Probert, M. I. J. J. Phys.: Condens. Matter 2010, 22, 025501) indicates that xenon could be incorporated into the lattices at high pressure via the following equations:

(Si–O–)2–Si–(–O–Si)2(quartz) → 2Si–O–O–Si(s) + Si(s)

2Si–O–O–Si(s) + Xe(g) → (Si–O–)2–Xe–(–O–Si)2(s)

The authors suggest that the existence of XeO2 as the only covalent network structure for a noble gas near ambient temperature may explain the depleted amount of xenon in the atmosphere. (J. Am. Chem. Soc. 2011, 133, 6265–6269, José C. Barros)

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Tetrazole-modified polymers absorb carbon dioxide efficiently. Polymers of intrinsic microporosity (PIMs) are a series of macromolecules with rigid molecular structures. These polymer chains contain few backbone single bonds around which rotation occurs. They have large amounts of free volume inside their 3-D architectures. These properties make PIMs promising materials for gas transport and liquid purification.

PIMs’ ability to separate gases, however, could be improved. M. D. Guiver and coauthors at the National Research Council of Canada (Ottawa, ON), Hanyang University (Seoul), and Vaperma (Québec, QU) developed a method for preparing PIM membranes for efficient CO2 absorption and separation from other gases.

The authors’ strategy uses the functional groups in the repeat PIM units. They designed the polymeric framework to contain nitrile and ether groups (1), and after polymerization, they treated them with NaN3. A click reaction produces polymer-bound tetrazoles (2), which have basic nitrogen atoms and acidic hydrogen atoms.

The tetrazoles have high affinity to CO2 molecules; and interchain hydrogen bonding among the tetrazole and ether groups enhances the stability of the bulk membrane. CO2 is preferentially absorbed, and the gas molecules that occupy the 3-D structure hinder the containment of other gases such as nitrogen and methane. (Nat. Mater. 2011, 10, 372–375; Sally Peng Li)

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Which is the best intermediate in a drug synthesis? During the development of a second-generation route to the migraine drug eletriptan, C. P. Ashcroft and co-workers at Pfizer (Sandwich, UK, and Loughbeg, Ireland) used the acetal of bromoacetaldehyde as a starting material to produce the acetal of 3-(N-methylpyrrolidin-2-yl)propionaldehyde, a substrate for a Fischer indole synthesis. In the first route, N-methylpyrrole was lithiated and treated with 2-bromoethyl-1,3-dioxolane. An improved route proceeded via the Grignard reagent of the bromo acetal, which reacted with the Weinreb amide of N-CBz-N-methyl-4-amonibutyric acid and was then cyclized to a 1,3-dioxan. (CBz is carbobenzoxy.)

The authors found that the 1,3-dioxan acetal was a better, more stable substrate for this chemistry than the 1,3-dioxolane. A third route used the Wittig reaction; the Wittig reagent was generated from 2-(2-bromomethyl)-5,5-dimethyl-1,3-dioxan and treated with N-methylpyrrole-2-carboxaldehyde. The 5,5-dimethyl-1,3-dioxan was chosen because it gave a crystalline intermediate and was less prone to hydrolysis than the 1,3-dioxolane or the 1,3-dioxan. (Org. Process Res. Dev. 2011, 15, 98–103; Will Watson)

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Convert chiral β-lactams to diverse fused bicyclic systems. The β-lactam ring system is recognized as a highly reactive scaffold for elaboration to more complex structures. G. I. Georg, S. V. Malhotra, and coauthors at the National Cancer Institute at Frederick (MD) and the University of Minnesota (Minneapolis) devised a strategy that begins with ring expansion of β-lactams such as 1 to dihydropyridones 2. Structure 2 is functionalized to serve as a common precursor of indolizidine, quinolizidine, and pyridoazepine fused bicyclic systems. Each features nitrogen at a bridgehead position. (PMP is p-methoxyphenyl; TBS is tert-butyldimethylsilyl; Boc is tert-butoxycarbonyl.)

β-Lactam scaffold 1 with the desired structural features is prepared from β-lactam esters as racemic mixtures. Ring opening 1 with an alkynyl Grignard reagent forms an intermediate ynone, which is cyclized to dihydropyridone 2. N-Functionalization of 2 with various alkene derivatives yields 3, 4, and 5. Alternatively, the silyl-protected dihydropyridones can be treated with HF–pyridine to prepare the corresponding alcohols.

Fused ring structures were formed by a ring-closing metathesis (RCM) reaction to give the desired bicyclic products 6, 7,and 8, which contain five-, six-, and seven-membered rings, respectively. The more reactive second-generation Grubbs catalyst efficiently mediates the RCM reaction under mild conditions in each case. (J. Org. Chem. 2011, 76, 3527–3530; W. Jerry Patterson)

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