N-Heterocyclic Carbene Ligands in Cobalt-Catalyzed Sequential Cyclization/Cross-Coupling Reactions of 6-Halo-1-hexene Derivatives with Grignard Reagen

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070392f.html

From Prof. Koichiro Oshima's group at Kyoto University, Japan

Another paper utilizing NHCs as ligands appeared in this month's Org Lett ASAP. This is the paper describing intramolecular cyclization of alkyl iodide and tethered alkene, followed by cross-coupling with Grignard reagents. The reaction is catalyzed by Co-catalyst.

Several NHC ligands were excamined. These are shown below.

In the initial studies, NHC ligand 1 and allyldimethylsilylmethylmagnesium chloride were subjected to react with alkene 5 to give coupling product 6 in good yield. The allyldimethylsilyl group in the product could be oxidized smoothly via Tamao-Flemming oxidation to alcohol 7. This initial result showed that the method could be used in a sequential operation to obtain a cyclic alcohol of type 7.

A number of imidazolium salts other than 1 were screened. Salts 2 and 3 showed moderate reactivity giving product 6 36% and 54% yields, respectively. The use of phosphine and diamine ligands resulted in much lower yield. The scope of the reaction is as shown below.

In a related example, secondary iodide 18 could be subjected to the reaction conditions to give 19, followed by Tamao-Flemming oxidation to give diol 20 in good overall yield.

In addition, the authors also found that the reaction conditions could be used in a normal cross-coupling reaction (without cyclization) of primary alkyl iodide and Grignard reagent. For example, treatment of isobutyl iodide (0.5 mmol) with allyldimethylsilylmethylmagnesium chloride (1.5 mmol, 1 M ether solution) in dioxane (2 mL) in the presence of 1 (0.025 mmol) and CoCl2 (0.025 mmol) for 30 min at 25 °C afforded the corresponding coupling product in 79% yield.

Next, the cyclization-coupling process was examined for the cross-coupling reaction with alkynyl Grignard. Recently, the authors obtained promising result with trimethylsilyl-substituted alkynyl Grignard, but not with alkyl-substituted ones. However, for the cyclization-cross coupling process it was discovered that NHC ligand 2 proved to be effective. As shown in Scheme 3, cyclization-cross coupling sequence of various alkyl-substituted alkynyl Grignard reagents (21a-c) proceeded smoothly with CoCl2 in the presence of ligand 2 to give the coupling products 22a-c in good yields.

21a also underwent cyclization-cross coupling process with 9, and after Jones oxidation, provided lactone 23 in good yield over two steps.

The mechanism of this process is proposed to be:

1) generation of primary radical of the iodide via single electron transfer (SET) process
2) radical cyclization to give Co-carbocycle
3) transmetallation of Grignard reagent with Co species
4) reductive cyclization