Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water

Abstract

A general and one-pot synthesis of 2-alkyl/aryl substituted indoles via a tandem Pd/C mediated coupling/5-endo-dig cyclization of terminal alkynes (including acetylenic carbinols) with o-iodoanilides in water is reported. The reaction is carried out using PPh 3 and CuI as co-catalysts and 2-aminoethanol as a base. The reaction appears to tolerate a variety of functional groups present in the alkynes and does not require the use of any organic co-solvent.The indole nucleus is a frequently found unit in many natural products and diverse biologically active molecules. 2 Interesting pharmacological properties, such as antithrombotic, 3 anticancer, 4 histamine H 3 receptor antagonism 5 etc. exhibited by the various 2-substituted indoles have led to a continued interest in the practical synthesis of these compounds. Among the classical methods for the synthesis of indole ring, the Fischer indole synthesis, the Batcho-Leimgruber synthesis (from o-nitrotoluenes and dimethylformamide acetals), the Gassman synthesis (from N-haloanilines), the reductive cyclization of o-nitrobenzylketones and the Madelung cyclization of N-acyl-o-toluidines are often used. However, the introduction of an aryl group at the 2-position of an indole ring is usually achieved by de novo indole ring construction 6 either by Fischer indole synthesis or more popularly by transition metal mediated reactions, 7 especially by palladium catalyzed protocols. 8-10 Palladium-catalyzed annulation of o-haloanilines with terminal alkynes (under Sonogashira reaction conditions) or internal alkynes (under Larock's conditions) has been employed widely due to the versatile nature of these protocols, increased functional group tolerance and improved yields (Scheme 1). Despite being quite versatile, the synthesis of 2-substituted indoles employing terminal alkynes often involves a twostep process i.e. Sonogashira coupling of o-haloanilines with terminal alkynes followed by the cyclization of the resulting 2-alkynylanilines in the presence of various reagents (e.g. metal alkoxides, halides or Lewis acids). 11 Moreover, cyclization of anilides having an alkynol moiety at the 2-position yielded quinolines/2,3-dihydro-4(1H)-quinolones rather than indoles. 11d Very recently, a one-pot synthesis of 2-substituted indoles has been reported in the presence of Pd(II)-NaY zeolite catalysts. 8a However, the reaction was carried out in a sealed tube and appeared to be unsuitable for the preparation of these compounds in a large scale. Scheme 1 Palladium-catalyzed synthesis of indolesPalladium-promoted reactions in aqueous media are a focus of current research 12,13 because water-based synthetic processes are inherently safer as well as inexpensive (especially for industrial-scale processes). Therefore, the use of water-soluble catalysts 13g and water-soluble phosphine ligands 13f has been explored successfully. The use of Pd/ C-CuI-PPh 3 as a catalyst system for efficient Sonogashira coupling has also been reported. 14,15 All these Pdcatalyzed reactions are usually carried out i...

Practical synthesis of indoles and benzofurans in water using a heterogeneous bimetallic catalyst

“…With the aim of developing a heterogeneous bimetallic catalysis in water, we took inspiration from the work of Pal et al [34], who reported the preparation of indoles in a Pd/C-catalysed reaction in water with CuI as co-catalyst, Ph 3 P as ligand and 2-aminoethanol as base. To our great pleasure, the application of these conditions with our Pd–Cu/C catalyst, for the coupling of iodoaniline 1 with phenylacetylene ( 2 ) provided the expected indole 3 with an excellent 90% yield (Table 1, entry 1).…”

Design and synthesis of novel indole-quinoxaline hybrids to target phosphodiesterase 4 (PDE4)

“…It is worthy to mention that while chloro group of 3-chloroquinoxalin-2-amines is known to participate in the Pd/C-Cu mediated alkynylation reaction , the chloro group of 4 remained inert in the present reaction perhaps due to the higher reactivity of iodo group of 5 towards the Pd catalyst. Thus, the active Pd(0) species generated in situ (Pal, 2009;Layek et al, 2009;Pal et al, 2004) (Scheme 2) undergoes oxidative addition with 5 rather than 4 to give the organo-Pd(II) species E-1 which on trans organometallation with copper acetylide generated in situ from CuI and 4 affords E-2. The reductive elimination of Pd(0) from E-2 affords the internal alkyne E-3 which subsequently undergoes Cu-mediated intramolecular ring closure to give the desired product 6 via E-4.…”

“…In view of the promising in silico results obtained for B through docking studies we planned to synthesize molecules based on A including B. A Pd/C-catalyzed coupling-cyclization strategy leading to the formation of indole ring was used to prepare our target molecules (Scheme 1) (Pal 2009;Layek et al, 2009' Pal et al, 2004. We preferred this strategy as the concerned methodology involved the use of less expensive, stable, easy to handle and recyclable Pd/C which is advantageous over the other Pd-based methodologies.…”

Recent Uses of Palladium Chemistry in Indole Synthesis

“…The reaction of N-acyl 2-iodoaniline with alkyl, aryl, and heteroaryl substituted terminal alkynes using various reaction conditions like changing the concentration of base/additive/Pd-zeolite, solvent and temperature to get higher yields of the 2-substituted indoles (140) along with open chain compounds (141) was studied by Hong et al [112]. The optimal reaction condition for the higher yields was 5 mol % of Pdloaded zeolite, 1 equiv LiCl, 2 equiv Cs 2 CO 3 and DMF at 140 o C. Pal et al [111] have described a one-pot synthesis of 2-alkyl/arylsubstitued indoles (138) Botta and co-workers [113,114] reported the stereoselective synthesis of α-aryl-1H-indole-2-methanamines (144) by reacting racemic and enantiomerically pure arylpropargylamines (142) with o-halo aniline derivative via palladium and copper catalyzed heteroannulation. Yamanaka and co-workers [115] succeeded in synthesizing indoles (146) from terminal alkynes and N-(2-iodophenyl)methane sulfonamide (145) by employing a palladium and copper bimetallic catalyst.…”