Advances in Heterocyclic Chemistry

1. Auflage 2015
ISBN: 978-0-12-802874-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 116, 386 Seiten

Reihe: Advances in Heterocyclic Chemistry

Advances in Heterocyclic Chemistry is the definitive series in the field-one of great importance to organic chemists, polymer chemists, and many biological scientists. Because biology and organic chemistry increasingly intersect, the associated nomenclature also is being used more frequently in explanations. Written by established authorities in the field from around the world, this comprehensive review combines descriptive synthetic chemistry and mechanistic insight to yield an understanding of how chemistry drives the preparation and useful properties of heterocyclic compounds. - Considered the definitive serial in the field of heterocyclic chemistry - Serves as the go-to reference for organic chemists, polymer chemists, and many biological scientists - Provides the latest comprehensive reviews written by established authorities in the field - Combines descriptive synthetic chemistry and mechanistic insight to enhance understanding of how chemistry drives the preparation and useful properties of heterocyclic compounds

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Chapter One The Larock Reaction in the Synthesis of Heterocyclic Compounds
Jesús Herraiz-Cobo1,2, Fernando Albericio1,2,3 and Mercedes Álvarez1,2,4,*     1Institute for Research in Biomedicine, Barcelona Science Park–University of Barcelona, Barcelona, Spain     2CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Barcelona, Spain     3Department of Chemistry, University of Barcelona, Barcelona, Spain     4Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
* Corresponding author: E-mail: [e-mail] 
Abstract
The indole ring is one of the most common features in natural products and small molecules with important bioactivity. Larock reported a new methodology for the synthesis of the indole ring system based on the palladium-catalyzed heteroannulation of 2-iodoaniline and substituted alkyne moieties. This procedure was subsequently extended to the preparation of other nitrogen- and oxygen-containing heterocycles. This is the process of choice for the synthesis of a large number of heterocyclic derivatives, as it provides outstanding regioselectivity and good to excellent yields. Keywords
Alkynes; Heteroannulation; Heterocycles; Natural compounds; Palladium catalyst 1. Introduction
The Larock indole synthesis, also known as the Larock heteroannulation, is a one-pot palladium-catalyzed heteroannulation of o-iodoaniline and internal alkynes for the synthesis of 2,3-disubstituted indoles. The original Larock reaction was performed with Pd(OAc)2 using carbonate or acetate bases with or without catalytic amounts of triphenyl phosphine and n-Bu4NCI. However, it was subsequently observed that LiCl is often more effective and reproducible (Scheme 1; 1991JA6689). The reaction was shown to be a high regioselective process giving the bulky substituent of the alkyne in position two of the resulting indole ring.
Scheme 1 Palladium-catalyzed heteroannulation of alkynes. Larock modified the annulation process to access 3-substituted indoles by employing silyl-substituted alkynes. In this case, the bulky silyl group dominates the regioselectivity of the annulation and thus serves as a phantom-directing group in the heteroannulation step. Silylated alkynes provide 2-silyl-3-substituted indoles with excellent regioselectivity. Subsequent desilylation affords 3-substituted indoles in good yield. In 1995, Larock and coworkers reported that this chemistry also provides a valuable route for the synthesis of benzofurans, benzopyrans, and isocoumarins in good to excellent yields (Figure 1; 1995JOC3270). Several reviews about the synthesis of heterocycles via palladium-catalyzed reactions containing revisions of Larock procedures have been made until the end of 2014 (2005CR2873, 2006CR2875, 2006CR4644). This chapter provides a review and update of the Larock reaction. It will be implemented not only for the preparation of indole and its derivatives but also for other heterocyclic systems, natural compounds, and derivatives. 2. Mechanism of Larock Heteroannulation
The scope and mechanism of palladium-catalyzed annulation of internal alkynes to give 2,3-disubstituted indoles, the effect of substituents on the aniline nitrogen or on the alkynes, as well as the effect of the salts such as LiCl or n-Bu4NCl were studied by Larock and coworkers (1998JOC7652). The mechanism they propose for indole synthesis proceeds as follows: (a) reduction of the Pd(OAc)2 to Pd(0); (b) coordination of the chloride to form a chloride-ligated zerovalent palladium species; (c) oxidative addition of the aryl iodide to Pd(0); (d) coordination of the alkyne to the palladium atom of the resulting arylpalladium intermediate and subsequent regioselective syn-insertion into the arylpalladium bond; (e) nitrogen displacement of the halide in the resulting vinyl palladium intermediate to form a six-membered, heteroatom-containing palladacycle; and (f) reductive elimination to form the indole and to regenerate Pd(0) (Scheme 2; 1993JA9531).
Figure 1 Benzoheterocycles synthesized by Larock heteroannulation. The first and third steps are well known and integral to a wide variety of Pd(0)-catalyzed processes. Less hindered alkynes are known to insert more readily than more hindered alkynes (1993T5471). Syn-addition of the arylpalladium compound to the alkyne has been established for the analogous palladium-catalyzed hydroarylation process (1986G725, 2004JOM4642) and implemented in many other alkyne insertion processes (1989JA3454, 1989JOC2507, 1990JA8590, 1990TL4393, 1991JOC6487, 1991SL777, 1991TL4167, 1992JA791, 1992JA10091, 1992CC390, 1992PAC3323, 1992TL3253, 1992TL8039, 1993JOC560, 1993T5471, 1994JA7923, 1995TL1771).
Scheme 2 Proposed mechanism for Larock heteroannulation. The Larock annulation process is highly regioselective, and, generally, significantly higher in selectivity than the related palladium-catalyzed hydroarylation process, which often produces regioisomeric mixtures (1984TL3137, 1985T5121, 1986G725, 1986TL6397, 1988T481, 1989TL3465). The regioselectivity is perhaps due to chelation of the palladium in the arylpalladium intermediates by the neighboring nitrogen, which reduces the overall reactivity and increases the steric hindrance of these intermediates towards alkyne insertion. The controlling factor in the insertion processes may be the steric hindrance present in the developing carbon–carbon bond or the orientation of the alkyne immediately prior to syn-insertion of the alkyne into the aryl palladium bond. Alkyne insertion occurs to generate the least steric strain near the developing carbon–carbon bond rather than the longer carbon–palladium bond. The alkyne may adopt an orientation in which the more steric demanding group is located away from the sterically encumbered aryl group. The result of that orientation is the regioselectivity of the reaction in which the aryl group of the aniline is located at the less sterically hindered end of the triple bond and the nitrogen moiety at the more sterically hindered end. The regioselectivity of Larock indole annulation with 2-alkynylpyridines and o-iodoaniline to give 3-substituted-2-pyridin-2-ylindoles has also been rationalized by a combination of steric and electronic coordinative effects (2008TL363; Scheme 3). A coordination of the pyridine nitrogen during the catalytic cycle was postulated to justify the different regioisomeric ratios 94:6, 68:32, and 72:28 of the Larock reaction obtained with cyclopentyl 2-, 3- and 4-pyridyl acetylenes, respectively.
Scheme 3 Proposed coordinative effect in Larock indolization with 2-alkynylpyridines.
Figure 2 Structures of indole derivatives 1 and 2. The same work but using tert-butyl-2-pyridylacetylene showed the importance of steric factors in the regioselectivity of the Larock indolization. The large steric bulk of the tert-butyl group overrides the electronic effect of the pyridin-2-yl group favoring production of the 2-(tert-butyl)indole 1 over the 3-(tert-butyl)indole 2, in a ratio of 69:31 (Figure 2). Reversed regioselectivity has been described by Isobe and coworkers in the reaction between an N-protected iodoaniline and the a-C-glucosylpropargyl glycine 3 (2002MI2273). An excellent yield of the 3-substituted isotryptophan 4 was obtained using an N-tosyl protecting group. Isobe and coworkers could not identify the motif of reversed regioselectivity after systematic studies on the Larock reaction using N-tosyliodoaniline (2008MI2092; Scheme 4). 2.1. Homogeneous Catalyst
The ligand-free conditions of the Larock reaction work well with iodoanilines but not with the more economic and accessible 2-bromo or 2-chloroanilines. Lu, Senanayake, and coworkers were the first group to test the preparation of indole from chloroaniline or bromoanilines in combination with highly active phosphine ligands such as trialkylphosphines (Cy3P, t-Bu3P) (2004OL4129). Ferrocenyl phosphines (5–7) and biaryl phosphines (8–11) were examined (Figure 3). Among these phosphines, 1,1'-bis(di-tert-butylphosphino)ferrocene (7) was found to be the most active. Several bases were also tested to ascertain their effect on the reaction rate and regioselectivity.
Scheme 4 Reversed regioselectivity in the Larock...