ORGANIC LETTERS
Sterically Controlled Iodination of Arenes via Iridium-Catalyzed CH Borylation
XXXX Vol. XX, No. XX 000–000
Benjamin M. Partridge and John F. Hartwig* Department of Chemistry, University of California, Berkeley, California 94720, United States
[email protected] Received November 16, 2012
ABSTRACT
A mild method to prepare aryl and heteroaryl iodides by sequential CH borylation and iodination is reported. The regioselectivity of this process is controlled by steric effects on the CH borylation step and is complementary to existing methods to form aryl iodides. The iodination of boronic esters has potential for the synthesis of radiolabeled aryl iodides, as demonstrated by the concise synthesis of a potential tracer for SPECT imaging.
Aryl iodides are common intermediates in organic synthesis. The ease by which they undergo oxidative addition makes them valuable precursors to aryl organometallic reagents1 and the aryl halide of choice for many transition metal-catalyzed processes.2 Furthermore, the decay of the radioisotopes of iodine has allowed aryl iodides to be used as imaging agents for Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT).3 Compounds containing 131 I also have been used to treat tumors.4 Despite their utility, aryl iodides are more expensive, and fewer aryl iodides are commercially available than aryl bromides and aryl chlorides. Traditional methods to form aryl iodides include direct iodination,5 which requires oxidizing conditions, and the Sandmeyer reaction, which requires the generation of a diazonium salt (Scheme 1).6 Such methods are either intolerant of functional groups or involve multistep sequences to reach the aryl iodide. More (1) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302. (2) Hartwig, J. F. Organotransition Metal Chemistry; University Science Books: Sausalito, CA, 2010; (b) Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043. (3) Pimlott, S. L.; Sutherland, A. Chem. Soc. Rev. 2011, 40, 149. (4) Goldsby, R. E.; Fitzgerald, P. A. Nucl. Med. Biol. 2008, 35, S49. (5) (a) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 2008, 1487. (b) Hanson, J. R. J. Chem. Res. 2006, 2006, 277. (6) Hodgson, H. H. Chem. Rev. 1947, 40, 251.
recently, the aromatic Finkelstein reaction, developed by Buchwald and co-workers, has allowed the interconversion of aryl bromides to the corresponding iodide.7
Scheme 1. Traditional Methods to Synthesize Aryl Iodides
In all of these reactions, the position of the iodine in the product is determined by the electronic properties of the arene (from nitration in the case of the Sandmeyer reaction or bromination in the case of the aromatic Finkelstein reaction). In contrast to these reactions, directed CH iodination catalyzed by palladium8a,b and rhodium complexes8c (7) (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844. (b) Vigalok, A.; Kaspi, A. W. Top. Organomet. Chem. 2010, 31, 19. (8) (a) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (c) Schroeder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 8298. 10.1021/ol303164h
r XXXX American Chemical Society
reported recently occur ortho to the directing group. Herein, we report a mild copper-catalyzed iodination of aryl pinacol boronic esters. By combining this process with the iridium-catalyzed CH borylation of arenes9 the iodination of arenes occurs with selectivity based on steric effects, rather than electronic or directing effects. Previously, we reported the combination of borylation and bromination, and the combination of borylation and chlorination, by the conversion of arylboronic esters to aryl halides with stoichiometric amounts of CuBr2 and CuCl2 respectively.10 However, the corresponding reaction with CuI did not lead to iodination. Although the iododeboronation of arylboronic acids,11ad trifluoroborate salts11e,f and borates11g has been reported, the conversion of aryl pinacol boronic esters to aryl iodides has not;12 the iodination of pinacolboronate esters is needed for the conversion of arenes to aryl iodides via CH borylation. Thus, we sought conditions for the conversion of pinacolsubstituted arylboronates to aryl iodides. The effects of ligand, solvent, reaction time, and temperature on the conversion of the arylboronate ester and the yield of iodoarene are summarized in Table 1. The reaction of p-methoxyphenyl pinacol boronate ester (1) with CuI and a substoichiometric amount of phenanthroline in air led to 4-iodoanisole (2) in good yield (Table 1). By adding KI as the iodide source, the reaction occurred with a substoichiometric amount of CuI. In contrast, iodide 2 was not formed when elemental iodine was used in place of KI. CuBr and CuCl also catalyzed the reaction, but the product was contaminated in these cases with the corresponding aryl bromide and aryl chloride. The reactions conducted with other bidentate nitrogen ligands occurred to lower conversions, and increasing the reaction temperature above 100 °C led to catalyst decomposition and competing protodeboronation. We hypothesized that transmetalation of the boronic ester was the rate-determining step in the catalytic cycle. To increase the rate of transmetalation, we investigated reactions in protic solvents.13 Although the reactions in methanol occurred faster than those in DMF, the reactions in mixtures of methanol and water occurred much faster than those in one solvent, and complete conversion of the boronic ester occurred within 1 h. Anisole, formed by protodeboronation of 1, was the only side product observed. This side product was formed in greater amounts at higher temperatures and higher (9) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (10) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434. (11) (a) Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.; Somayaji, V. Org. Prep. Proced. Int. 1982, 14, 359. (b) Zhang, G.; Lv, G.; Li, L.; Chen, F.; Cheng, J. Tetrahedron Lett. 2011, 52, 1993. (c) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem.;Eur. J. 2011, 17, 5652. (d) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 1998, 141. (e) Kabalka, G. W.; Mereddy, A. R. Nucl. Med. Biol. 2004, 31, 935. (f) Yong, L.; Yao, M.-L.; Kelly, H.; Green, J. F.; Kabalka, G. W. J. Labelled Compd. Radiopharm. 2011, 54, 173. (g) Akula, M. R.; Yao, M.-L.; Kabalka, G. W. Tetrahedron Lett. 2010, 51, 1170. (12) The iodination of neopentyl glycol boronic esters has been reported: Kabalka, G. W.; Akula, M. R.; Zhang, J. Nucl. Med. Biol. 2002, 29, 841 However, these cannot be prepared by C-H borylation. (13) Use of KOtBu to enhance transmetalation led to competing formation of the homodimer of the boronic ester. B
Table 1. Effect of Reaction Conditions on the Yield of the Iodination of a Model Aryl Pinacol Boronate Ester
ligand
solvent
1b 2c 3 4 5 6 7d 8
phen phen phen bpy dtbpy Me4phen phen phen
9
phen
10e
phen
DMF DMF DMF DMF DMF DMF DMF MeOH/H2O (4:1) MeOH/H2O (1:1) MeOH/H2O (4:1)
time (h)
conversion (%)
yielda (%)
39 47 23 23 23 23 39 1
100 84 88
