A Flexible and Catalytic One‐Pot Procedure for the Synthesis of Indoles (2003)

One pot, two bonds, three rings: A clever combination of a [Cp2TiMe2]-catalyzed hydroamination of alkynes with a Pd-catalyzed N-arylation of imines results in a new and general method for the synthesis of indoles. Impressively, two new CN bonds are formed during the one-pot procedure (see scheme). Initiated by improved screening methods, a steadily increasing demand for highly flexible synthetic procedures has evolved during the last couple of years. The major purpose of these synthetic methods is the fast generation of various derivatives of a certain class of substances. In the past, we have repeatedly shown that the titanium-catalyzed hydroamination of alkynes1 is a versatile tool for the highly flexible synthesis of biologically interesting compounds.2 Expanding these studies, we now present a highly flexible and catalytic one-pot procedure for the synthesis of indoles3 employing ortho-chloro-substituted 1-phenyl-2-alkyl alkynes or phenyl(aminoalkyl)alkynes as starting materials. The general principle of the one-pot procedure is shown in Scheme 1. The major expectation is that under basic conditions, the imines, which are regioselectively formed during the hydroamination in the presence of the Ti catalyst [Cp2TiMe2] (Cp=C5H5)4, will be in equilibrium with the corresponding enamines. In addition, an ortho-chloro-substituent in the benzene ring, should offer the possibility to convert the enamines into indoles by a Pd-catalyzed N-arylation/cyclization (Buchwald–Hartwig reaction).5 Since the enamines are removed from the equilibrium during this cyclization step it should be possible to convert the imines completely into indoles. However, to our knowledge, corresponding N-arylations of N-substituted imines under basic conditions in the presence of Pd-catalysts have not been reported.6 Outline of a flexible and catalytic one-pot procedure for the synthesis of indoles. Entry Alkyne Product Yield [%][a] 1 0 0 65[b] 2 0 0 78 3 0 0 77 4 0 0 39 5 0 0 70 6 0 0 65 7 0 0 81 8 0 0 68 9 0 0 75 10 0 0 64 The products 11, 12, 17, and 20 have potentially removable protecting groups at the indole N atom. In addition, the O groups located in the side chains of 15 and 17 offer various possibilities for further synthetic transformations (e.g. cyclization to the carbazole skeleton). Entry Aminoalkyne Product Yield [%][a] 1 0 0 68 2 0 0 53[b] 3 0 0 75 4 0 0 77 5 0 0 –[c] 6 0 0 53 7 0 0 –[c] 8 0 0 –[c] In summary, we have shown that a clever combination of a [Cp2TiMe2]-catalyzed hydroamination of alkynes with a Pd-catalyzed N-arylation of imines results in a new and general method for the synthesis of indoles, in which two new CN bonds are formed during the one-pot procedure. Since the starting materials employed are easily accessible from 1-chloro-2-iodobenzenes and terminal alkynes by Sonogashira coupling reactions this procedure offers a great deal of synthetic flexibility. A Schlenk tube equipped with a Teflon stopcock and a magnetic stirring bar was charged with amine (2.0 mmol), alkyne (2.0 mmol), and a solution of [Cp2TiMe2] (0.21 mL, 0.48 M in toluene, 0.1 mmol, 5.0 mol %). The mixture was heated under argon to 110 °C for 24 h (thin-layer chromatography (TLC) monitoring). After the resulting brown liquid had cooled to room temperature, [Pd2(dba)3] (92 mg, 0.1 mmol, 5.0 mol %), 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (68 mg, 0.2 mmol, 10.0 mol %), KOtBu (337 mg, 3.0 mmol), and 1,4-dioxane (5.0 mL) were added. The mixture was heated to 110 °C for further 12 h (TLC monitoring) and then filtered through SiO2. After the SiO2 had been washed with CH2Cl2, the organic layer was concentrated under vacuum. The residue was purified by flash chromatography (SiO2). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z51345_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.