Phosphine-free thiopseudourea-Pd(II) complex catalyzed Larock heteroannulation of 2-haloamines with internal alkynes Keesara Srinivas, Parvathaneni Saiprathima, Kodicherla Balaswamy, Mandapati Mohan Rao * I & PC Division, Indian Institute of Chemical Technology, Hyderabad 500607, India article info Article history: Received 10 April 2013 Received in revised form 29 May 2013 Accepted 30 May 2013 Keywords: Thiopseudourea Larock indolization Phosphine free Palladium abstract We examined the Pd-catalyzed heteroannulation of 2-haloamines with internal alkynes under phosphine- free conditions. The thiopseudourea palladium(II) complex (5) found to be an efficient catalyst for the Pd induced heteroannulation. Achieved high turnover number for the heteroannulation reactions of internal alkynes with 2-iodoaniline. A variety of 2-bromoanilines and N-tosyl substituted 2-bromoanilines effec- tively reacted with different substituted internal alkynes to give the corresponding indoles in good to high yields (1:1 ratio of regioisomers). Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction The phosphine-free palladium catalyzed heteroannulation of internal alkynes with 2-haloamines is an important synthetic method for 2,3-disubstituted indole formation [1e3]. The indole nucleus is an important compound, found in numerous natural products and biological active materials [4,5]. Widespread use of indole nucleus in pharmaceutical studies [6,7], aimed to develop efficient synthetic methods. Compared to many reported methods for the indole synthesis [8e14], the palladium-catalyzed indoliza- tion is emerged as a powerful synthetic method (Larock indole synthesis) (Scheme 1) [1]. This reaction is normally performed with 5 mol% of Pd(OAc) 2 for 2-iodoanilines and the same is not possible for 2-bromo or 2-chloroanilines. A number of heterogeneous [15e 20] and homogeneous [21e25] Pd catalysts were reported for Larock indolization. Among them N-phenylurea [21] and 1,1 0 - bis(di-tert-butylphosphino)ferrocene [22] ligands based high loading Pd catalysts have shown better results. Few reports are available for the synthesis of 2,3-diphenyl-1-tosyl indole from N- tosyl-2-haloanilines with diphenylacetylene [1,19]. Herein, we report heteroannulation of 2-haloamines with in- ternal alkynes using an efficient thiopseudourea Pd(II) complex (5) (Fig. 1). Recently, we have reported the synthesis (1) and its application for SuzukieMiyaura, Sonogashira, Heck and Hiyama cross coupling reaction [26]. 2. Results and discussion Initially, we studied the catalytic activity of thiopseudourea Pd(II) complex (5) for the heteroannulation reaction between 2- iodoaniline and diphenylacetylene using 0.01 mol% of catalyst with various bases in DMF (N,N-dimethylformamide) at 130  C (Table 1). Among the studied bases, LiOH$H 2 O found to be the best (entry 4). Furthermore, the reaction efficiently proceeded with 4.0 equiv of LiOH$H 2 O (with respect to 2-iodoaniline) to afford 2,3- diphenylindole in an excellent yield (entry 4). With the optimized base (4.0 equiv of LiOH$H 2 O), apart from DMF, the role of various solvents was studied (entries 8e10). The best results achieved with DMF solvent. Under the similar experimental conditions with 0.01 mol% Pd(OAc) 2 very low yield was observed (entry 11). In order to study the effect of temperature, we have conducted the experi- ment at 100  C for 48 h and observed very low yield (entry 12). Further, the activity of different phosphine-free ligands 1aec (Fig. 2) with Pd(OAc) 2 was studied under the same reaction con- ditions that resulted in moderate to good yields (entries 13e15). We confirm that thiopseudourea-Pd(II) complex is an efficient catalyst for heteroannulation of 2-haloamine with diphenylacetylene. From the above optimized reaction conditions (0.01 mol% of 5, DMF 2 mL, LiOH$H 2 O 4 equiv at 130  C), reactions of 2-iodoaniline * Corresponding author. Tel.: þ91 40 27193181; fax: þ91 40 27160921. E-mail addresses: mandapati@iict.res.in, mandapatirao@yahoo.co.in (M.M. Rao). Contents lists available at SciVerse ScienceDirect Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem 0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jorganchem.2013.05.049 Journal of Organometallic Chemistry 741-742 (2013) 162e167