Single bifunctional ruthenium catalyst for one-pot cyclization and hydration giving functionalized indoles and benzofurans.

DOI: 10.1002/chem.201001075 Single Bifunctional Ruthenium Catalyst for One-Pot Cyclization and Hydration giving Functionalized Indoles and Benzofurans Reji N. Nair, [a] Paul J. Lee, [a] Arnold L. Rheingold, [b] and Douglas B. Grotjahn* [a] Indole [1] and benzofuran [1d, 2] heterocycles are key structur- al units in a variety of biologically active natural products and unnatural synthetic materials. Over the last few years, transition-metal catalysts have been extensively used in the cyclization of o-alkynylarylamines [3a–l] and phenols [3m–p] to construct benzoheterocycles through intramolecular [3] and intermolecular reactions. [4] Many of these reactions required the use of a nitrogen protecting group in the case of indo- les [3g,i,k] or stoichiometric amounts of the metal. [3l] McLory and Trost [3d] synthesized both unprotected indoles or N- benzyl analogues by using rhodium–phosphine complexes, but to optimize the benzofuran synthesis, large amounts of phosphine (0.6 equiv) were needed. Saa and co-workers [3q] recently reported the use of 10 mol % catalyst and amine solvents in benzofuran synthesis at 90 8C. Herein, we report that the bifunctional ruthenium catalyst 1 which has been used for anti-Markovnikov alkyne hydration [5] emerges as a versatile choice for both indole and benzofuran formation, with a number of unique advantages, including the use of only 2 mol % catalyst in most cases and the unprecedented ability of a cycloisomerization catalyst to perform hydration or deuteration in the same reaction. We envisioned that the use of alkyne hydration catalyst 1 on substrates, such as 2, (Scheme 1) would generate the al- dehyde 3, on which cyclization and dehydration would then enable facile synthesis of heterocycles. Indeed, 2 a cyclized to hemiaminal 4 a, [5a] with some equilibrium amount of 3 a, [a] R. N. Nair, P. J. Lee, Prof. D. B. Grotjahn Department of Chemistry and Biochemistry San Diego State University 5500 Campanile Drive, San Diego, CA 92182-1030 (USA) Fax: (+ 1) 619-594-4634 E-mail: grotjahn@chemistry.sdsu.edu [b] Prof. A. L. Rheingold Department of Chemistry and Biochemistry University of California–San Diego La Jolla, CA 92093-0358 (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001075. Scheme 1. The use of bifunctional catalyst 1 for hydration and cycliza- tion; Cp = cyclopentadienyl. but elimination of water from 4 a required heating in second step, forming 5 a in 46 % overall yield. The same two-step process could be used on the homologous substrate 2 b, to form 5 b in 56 % overall yield. Encouraged by these results, and because of the impor- tance of indoles, we shifted our attention to substrates de- rived from o-ethynylaniline. The first four entries of Table 1 demonstrate that 1 cyclizes a wide range of aniline deriva- tives; most significantly, the simplest, unprotected parent compound 6 cyclized to indole 17 in 99 % yield (Table 1, entry 1). Sulfonamide 7 (Table 1, entry 2) was cyclized to give the N-tosyl (Ts) protected indole in just 2 h. Entries 3 and 4 in Table 1 show the ability of the catalyst to form ni- trogen analogues with different alkyl substituents. Especially notable is the selectivity of 1: the N-allyl group (Table 1, entry 3) is fully tolerated without the decomposition by iso- merization seen when using a Rh-based catalyst. [3d] The fact that a wide variety of nucleophilic nitrogen cen- ters could be used in indole formation encouraged us to ex- plore the scope of 1 not only in making more complex indole derivatives, but also in cyclizing phenol derivatives to benzofurans. Gratifyingly, 1 forms both 7-aza- and 6-nitroin- doles (Table 1, entries 5 and 6), showing tolerance of various ring substituents, including those that might coordinate to the catalyst. Furthermore, entry 9 (Table 1) shows the ability of 1 to form the benzofuran nucleus in essentially quantita- 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 7992 – 7995