Florian Monnier

Catalytic C-C, C-N, and C-O Ullmann-type coupling reactions.

Copper-catalyzed Ullmann condensations are key reactions for the formation of carbon-heteroatom and carbon-carbon bonds in organic synthesis. These reactions can lead to structural moieties that are prevalent in building blocks of active molecules in the life sciences and in many material precursors. An increasing number of publications have appeared concerning Ullmann-type intermolecular reactions for the coupling of aryl and vinyl halides with N, O, and C nucleophiles, and this Minireview highlights recent and major developments in this topic since 2004.

Catalytic C-C, C-N, and C-O Ullmann-Type Coupling Reactions: Copper Makes a Difference

Copper-catalyzed arylations of nucleophiles (Ullmann, Ullmann-Goldberg and UllmannHurtley condensations) have been well known for more than a century for being one the most useful and practical methods in the formation of C(aryl)-N, C(aryl)-C and C(aryl)-O bonds.[1] These reactions are thus involved in numerous industrial applications such as the synthesis of intermediates as well as synthetic targets throughout the life science and polymer industries. However until 2000, Ullmann condensations have not been employed to their full potential. They indeed suffered from reduced synthetic scope as a result of the harsh reaction conditions often required, a limited substrate scope and the moderate yields obtained. Condensations were traditionally conducted at temperatures as high as 210 °C, often in the presence of stoichiometric amounts of copper reagents and preferentially with activated aryl halides.[1]. Early studies revealed rate enhancement when arylation were conducted in the presence of copper additive.[2] The additive compounds were thought to increase catalyst solubility and stability, but their exact role was not well established. Finally in 2001, important breakthroughs [3] were achieved by two groups with the discoveries of versatile and very efficiency new copper/ligand systems (C-C, C-N or C-O coupling) allowing the use of catalytic amount of metal under very mild conditions (90-110°C). Since 2001, these works and the potentially attractiveness of copper has led to a spectacular resurgence of interest in catalyzed Ullmann-type reactions. Many groups have thus been developing so far new Cu/Ligand systems to improve the variety and efficiency of the coupling reactions. We present here recent major developments in Cu-catalyzed C-C, C-O and C-N bond formation. The two selected contributions are of highly impact for cross coupling reaction, and deal with enantioselective and chemoselectivitive copper catalytic systems.

Copper-Catalyzed Sonogashira-Type Reactions Under Mild Palladium-Free Conditions

We have developed an inexpensive catalytic system using a readily available copper/ligand combination for the Sonogashira-type cross-coupling of aryl iodides and phenyl- and hexyl-acetylene which affords disubstituted alkynes in good to excellent yields.

Sol–gel immobilized and reusable copper-catalyst for arylation of phenols from aryl bromides

A simple β-diamide ligand was immobilized by the sol–gel process on hybrid silica for Cu-mediated O-arylation reactions. Combined with 5% of CuI, the latter can easily be recovered and reused to generate diarylethers under smooth conditions from cheap aryl bromides in an eco-friendly solvent (MIBK). Besides, negligible metal leaching occurred after reaction in solution from the supported catalyst.

A Simple Copper-Catalyzed Synthesis of Tertiary Acyclic Amides

The N-arylation of aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, has been accomplished using a simple and cheap copper catalytic system. The corresponding tertiary acyclic amides, which can be found in numerous biologically active compounds, have been obtained in good to excellent yields.

Ruthenium-Catalysed Synthesis of Fluorinated Bicyclic Amino Esters through Tandem Carbene Addition/Cyclopropanation of Enynes

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF(3))(CO(2)R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp*=C(5)Me(5) , PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N(2)CHSiMe(3), whereas N(2)CHCO(2)Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions.

Selective one-pot synthesis of symmetrical and unsymmetrical di- and triarylamines with a ligandless copper catalytic system

The one-pot synthesis of symmetrical or unsymmetrical di- or triarylamines using aryl iodides or bromides and LiNH(2) as ammonia source is reported. This highly selective method is based, for the first time, on a copper-catalyzed system, which does not require the presence of any additional ligand.

Copper-Catalyzed Hydroamination of Terminal Allenes.

The ligand-free copper-catalyzed hydroamination of allenes has been accomplished in the presence of cyclic secondary amines or anilines derivatives. This novel methodology undergoes the selective generation of (E)-allylamines under smooth conditions with total regio- and stereoselectivity.

Copper-Catalyzed Hydroamination of Alkynes with Aliphatic Amines: Regioselective Access to (1E,3E)-1,4-Disubstituted-1,3-dienes

Copper-catalyzed hydroamination of aromatic or heteroaromatic alkynes with cyclic secondary aliphatic amines undergoes generation of an enamine-type intermediate. The latter is transformed in situ via a coupling reaction with a second molecule of alkyne to afford regioselectively (1E,3E)-1,4-disubstituted-1,3-dienes with the formation of C-N, C-C, and C-H bonds.

Ruthenium catalyzed regioselective hydrophosphination of propargyl alcohols

Catalytic hydrophosphination of propargyl alcohols by ruthenium complexes RuCl(cod)(C5Me5) and RuCl(PPh3)2(C5Me5) leads to the formation of functionalized vinylphosphines, with linkage of the phosphorus atom to the terminal alkyne carbon, via a ruthenium vinylidene intermediate.