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May 21, 2007
Volume 85, Number 21
p. 9

Organic Synthesis

Amine Synthesis Gains Utility

Reaction combines C???H functionalization of an amine with its addition to an olefin to form a new amine

Stephen K. Ritter

The catalytic reaction of an N-alkyl arylamine with an unactivated olefin to produce a β-branched alkyl arylamine has been carried out for the first time in high yield (J. Am. Chem. Soc. 2007,129, 6690). This reaction, which involves activation of a C???H bond adjacent to the amine nitrogen atom, is anticipated to complement existing strategies for synthesizing amines from olefins.

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DOUBLE DUTY In a tandem sequence, Ta[N(CH3)2]5 facilitates C???H activation of a methyl group and its addition across the double bond of 1-octene (R = n-hexyl) to form a β-branched alkyl arylamine.

The chemists reporting this advance???Seth B. Herzon and John F. Hartwig of the University of Illinois, Urbana-Champaign???have dubbed the reaction hydroaminoalkylation. This reaction has been reported in the literature before, but until now it hadn't been refined to make it useful to synthetic chemists, according to Herzon and Hartwig.

In one example, the Illinois team reacted N-methylaniline with 1-octene at 160 oC using a tantalum catalyst, Ta[N(CH3)2]5, to form N-(β-methyloctyl)aniline in greater than 95% yield.

The β-branched product is the sole detectable regioisomer in the reactions, Hartwig notes. That type of reaction selectivity is unusual, he says, because it means that a C???H bond of the methyl group of N-methylaniline is activated, rather than the typically more reactive N???H bond or unsaturated C???H aryl bonds.

Additional progress needs to be made before the reaction "is truly practical," Hartwig tells C&EN. For example, it will be important to reduce reaction temperatures and to develop catalysts and conditions for reactions involving internal olefins, including cyclic olefins, he says. Hartwig suggests that direct alkylation of saturated nitrogen heterocycles is the most obvious application for the new reaction.

The work "is a significant step forward in the functionalization of C???H bonds adjacent to a nitrogen atom," says Brandeis University's Jin-Quan Yu, who has devised several C???H activation processes. Besides building on C???H activation using early transition metals (groups 3???5), this chemistry complements the amination process developed by Hartwig and Stephen L. Buchwald of Massachusetts Institute of Technology, which is used broadly in the pharmaceutical industry for arylamine syntheses, Yu notes.

"I'm amazed at the novel and useful chemistry that continues to emerge from early-transition-metal amide complexes," adds Patrick J. Walsh of the University of Pennsylvania, who conducts research using those metal catalysts. The new reaction "is an impressive demonstration" of C???H activation followed by C???C bond formation with good selectivity, he says. "It's sure to inspire others to explore this area."

Chemical & Engineering News
ISSN 0009-2347
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