New strategy for the synthesis of N-aryl pyrroles: Cu-catalyzed C–N cross-coupling reaction of trans-4-hydroxy-L-proline with aryl halides V. Prakash Reddy, A. Vijay Kumar, K. Rama Rao ⇑ Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India article info Article history: Received 21 September 2010 Revised 2 December 2010 Accepted 4 December 2010 Available online 9 December 2010 Keywords: Aryl halides trans-4-Hydroxy-L-proline N-Aryl pyrroles Cross-coupling Copper iodide abstract trans-4-Hydroxy-L-proline is used for the first time as an effective nucleophilic coupling partner with aryl halides mediated by copper iodide with Cs 2 CO 3 as the base and DMSO as the solvent. Utilizing this pro- tocol cross-coupling of trans-4-hydroxy-L-proline with a wide variety of substituted aryl halides to pro- duce N-aryl pyrroles in moderate to good yields. Ó 2010 Elsevier Ltd. All rights reserved. Pyrroles are an important class of organic compounds found in many natural products and bioactive molecules. 1 These com- pounds exhibit remarkable activities such as antitumor, immuno- suppressant, anti HIV, anti inflammatory, antioxidant etc. 2 They have also been widely used in material science and molecular rec- ognition studies. 3 In view of their significance, several useful strategies have been developed for construction of the pyrrole moiety. 4–6 Conventional, protocols for their preparation include the cyclocondensation of primary amines with 1,4-dicarbonyl compounds 5 (Pall–Knorr reac- tion) or 2,5-dimethoxy tetrahydrofuran 7 and transition metal cat- alyzed coupling of aryl halides with pyrroles. 8 Despite these huge developments, the transition metal catalyzed cross-coupling reac- tion is considered to be the most attractive method for the synthe- sis of pyrroles. Recently Che and co-workers reported ligand-free CuCl-catalyzed C–N bond formation in 40% n Bu 4 N + OH aqueous solution. 9 In these reactions, the coupling between pyrroles and aryl halides is commonly involved. Since pyrrole is not a biomass resource, we have explored trans-4-hydroxy-L-proline (obtained from collagen 10 ) as a sustainable replacement of pyrrole for syn- thesizing N-arylpyrroles. Our recent report on b-CD catalyzed synthesis of pyrrole-substi- tuted indolinones by using trans-4-hydroxy-L-proline 6c prompted us to attempt trans-4-hydroxy-L-proline as a nucleophilic coupling partner in Cu catalyzed C–N cross-coupling reaction. In the course of our continuing investigations in the field of cross-coupling reac- tions, 11 we report, herein, a new approach for the synthesis of N- aryl pyrroles via C–N cross coupling of trans-4-hydroxy-L-proline with aryl halides catalyzed by CuI/Cs 2 CO 3 /DMSO at 110 °C for 24 h via an one-pot procedure (Scheme 1). To the best of our knowledge, this is the first protocol explored for the synthesis of N-aryl pyrroles via C–N cross-coupling of trans-4-hydroxy-L-pro- line with aryl halides. Initially the reaction between trans-4-hydroxy-L-proline with iodo benzene was selected as a model reaction for optimizing the reaction conditions, such as various copper sources, bases, sol- vents, and temperature (Table 1). First, several copper catalysts were screened (Table 1, entries 1 and 10–14), and CuI was proven to be preeminent for this tandem reaction (Table 1, entry 5). Among various bases screened, KOH and Cs 2 CO 3 provided the N- aryl pyrrole in moderate to excellent yields (Table 1, entries 3 and 5). Other bases such as NaOMe and K 3 PO 4 gave lesser amount of the desired product (Table 1, entries 4 and 6). Among the sol- vents, DMSO yielded the best results whereas PEG gave the prod- ucts in moderate yields (Table 1, entry 8) while solvents like toluene, water, and DMF were ineffective (Table 1, entries, 6, 7, and 9). The coupling reaction did not occur in the absence of cata- lyst (Table 1, entry 15) as well as the base (Table 1, entry 16). When 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.12.016 ⇑ Corresponding author. Tel.: +91 40 27193164; fax: +91 40 27160512. E-mail address: kakulapatirama@gmail.com (K.R. Rao). N N H HO O OH I R R CuI (20 mol%) Cs 2 CO 3 (2.5 equiv) DMSO (3.0 mL) Scheme 1. CuI catalyzed synthesis of N-aryl pyrroles. Tetrahedron Letters 52 (2011) 777–780 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet