Published on Web 02/02/2006
Mild Aerobic Oxidative Palladium (II) Catalyzed C-H Bond Functionalization: Regioselective and Switchable C-H Alkenylation and Annulation of Pyrroles Elizabeth M. Beck, Neil P. Grimster, Richard Hatley,† and Matthew J. Gaunt* Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom Received November 30, 2005; E-mail:
[email protected] The development of direct C-H bond functionalization strategies for the facile generation of compounds with useful molecular architecture remains of high interest to academic and industrial chemists.1 Such processes preclude the need for a prior functionalization step, making the overall chemical transformation highly efficient. We are particularly interested in the development of new methods for direct metal catalyzed oxidative C-H transformations of organic molecules under mild and operationally simple conditions. Catalytic reactions of this nature would be very useful for the elaboration of molecules that may be sensitive to the harsh conditions that can often be required for C-H functionalization processes. Recently, a number of groups,2 including ourselves,2e have reported C-H bond transformations of indole. In contrast, the use of pyrrole in similar processes is rare,3 and yet these heterocycles are ubiquitous in natural products4 and medicinal agents5 and are useful as intermediates in multistep synthesis.6 Despite their potential in chemical synthesis, the instability of pyrroles toward acidic and oxidative environments has limited their utility in metal catalyzed C-H transformations. Herein, we report an efficient aerobic palladium (II) oxidation system for C-H bond functionalization of sensitiVe molecules under ambient conditions.
This method can be used to directly generate a range of functionalized and annulated pyrrole architectures and it is possible to control the position of C-H bond functionalization via simple steric and electronically tuned N-pyrrole protecting groups to form products with either C2 or C3 elaboration. At the outset of our studies we were guided by our discovery that the solvent media could control positional selectivity during palladium catalyzed C-H bond functionalizations of indoles.2e Despite the success in the indole series the corresponding pyrrole systems suffered from unselective and polyalkenylation as well as significant polymerization. With this in mind we speculated that the reactivity of the pyrrole nucleus may enable a catalytic C-H bond functionalization at room temperature or under ambient conditions. To test this hypothesis, we focused our attention on oxidative alkenylations of simple pyrroles. After initial optimization studies we identified that 10 mol % Pd(OAc)2 in a dioxane-AcOHDMSO solvent system and tBuOOBz as oxidant provided an effective system for pyrrole functionalization.7 We found that N-Bn pyrrole reacted smoothly with benzyl acrylate at only 35 °C to form the alkenylated products. Although it was expected that the natural reactivity of pyrrole would direct reaction to the C2 position, we observed a 2:1 ratio of C2 to C3 isomers (Table 1, entry 1). A †
Present address: GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertsfordshire SG1 2NY, UK.
2528
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J. AM. CHEM. SOC. 2006, 128, 2528-2529
Table 1. Effect of N-Protecting Group on Pyrrole C-H Alkenylation
entry
catalyst loading (%)
R
yield of C2
yield of C3
ratio 2:3
1 2 3 4 5 6
10 10 10 10 10 10
Bn SEM Ac Boc Ts TIPS
48 48 65 73 70 -
23 21 78
2.1:1 2.3:1 >95:5 >95:5 >95:5
