The Formation of Organocopper Reagents Via Activated Copper

Nearly all organocuprates are formed by treating organolithium or Grignard reagents with a cuprous salt at low temperatures in an ethereal solvent under an inert atmosphere. However, very little functionality can be incorporated into these organocopper compounds due to the highly reactive lithium and Grignard precursors.

To alleviate these and other difficulties associated with traditional organocuprate formation, the our research group has helped develop a method for producing a highly activated zero-valent copper of sufficient reactivity which allows the direct oxidative addition to many organic halides to produce organocopper reagents. The active copper is formed by mixing, under argon, an ethereal solution of CuI•PR₃ with an equivalent of a cooled, preformed, ethereal solution of lithium naphthalenide as shown below. This synthetic route by-passes the highly reactive organolithium and Grignard precursors commonly used to form cuprates.

To date, the thrust of our research has been the development of functionalized organocopper reagents. In earlier work we demonstrated that -NO₂, -CN, ester, and ketone functionality could be incorporated into organocopper compounds. In our most recent work we have shown that o-halophenylcopper reagents can be directly produced and utilized as o-halophenyl nucleophiles at room temperature without undergoing elimination to form benzyne.

The two primary objectives of our current efforts are: (1) to examine the incorporation of halogen into organocopper compounds by developing halovinylcopper reagents, and (2) to produce functionalized benzoic acids and esters by studying the carboxylation and subsequent esterification of various functionalized arylcopper compounds.

(1) Examine the Formation and Substitution Reactions of Halovinylcopper Reagents

We intend to explore the preparation of halovinylcopper reagents via activated copper and determine the scope of the cross-coupling reaction with these compounds.

Cu^o R'X'

By varying the temperature, concentration of reactants, solvent polarity, and rates of addition we will optimize the formation of the 1-halovinylcopper compounds and then examine the cross-coupling reaction with a variety of alkyl and acyl halides. These compounds are apt to be somewhat labile due to their ability to undergo a-elimination. Indeed, the 1-bromovinylcopper species may be too unstable to be useful.

(2) Examine the Carboxylation and Esterification of Functionalized Arylcopper

We propose to explore the carboxylation and subsequentesterification of functionalized arylcopper reagents prepared from the corresponding functionalized aryl halides and active copper as illustrated below.

Cu^o CO₂ RX'

The successful development of halovinylcopper reagents would permit the incorporation of the halovinyl species into target molecules without the necessity of masking or protecting the halogen which would likely be required if these reagents were formed by traditional cuprate procedures. The successful carboxylation and esterification of functionalized arylcopper compounds produced from activated copper would permit the formation of certain functionalized benzoic acids and esters which would be very difficult to synthesize by other methods. The development of both of these methodologies would be extremely useful in organic synthesis.

• "Halogen Functionalized Organocopper Compounds", Greg W. Ebert, Deborah R. Pfennig, Scott D. Suchan, Thomas A. Donovan Jr., Safa S. Tehrani, Emmanuel Aouad, and James N. Gunnersen., (in preparation).
• "Remarkably Stable ortho-Halophenylcopper Reagents", Greg W. Ebert, Deborah R. Pfennig, Scott D. Suchan, and Thomas A. Donovan Jr., Tetrahedron Lett. 1993, 34, 2279.
• "The Formation and Substitution of Remote Ester Functionalized Organocopper Reagents", Greg W. Ebert, James W. Cheasty, Safa S. Tehrani, and Emmanuel Aouad, Organometallics 1992, 11, 1560.
• "A Two-Step Synthesis of the 'Queen Substance' of the Honey Bee", Greg W. Ebert, Synth. Commun. 1991, 21, 1527.
• "Direct Formation and Subsequent Substitution of Remote Ketone-Functionalized Organocopper Reagents", Greg W. Ebert and Walter R. Klein, J. Org. Chem. 1991, 56, 4744.