Acylation Reactions of Organoborons - ACS Symposium Series (ACS

Chapter 14

Acylation Reactions of Organoborons

Downloaded by MONASH UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch014

Manoj Mondal1 and Utpal Bora*,2 1Department

of Chemistry, Dibrugarh University, Dibrugarh 786004, Assam, India 2Department of Chemical Sciences, Tezpur University, Napaam, Tezpur 784028, Assam, India *E-mail: [email protected]

Organoborons are structurally diverse, relatively stable, readily prepared and environmentally benign with the potential to undergo rapid transmetalation with transition metal complexes. These characteristics have made them the most versatile organometallic species for frequent use in numerous well known cross-coupling reactions. The Ullmann and Suzuki-Miyaura couplings are prominent examples of such approaches, which have played decisive roles just over half a century, in many of chemistry’s most complex synthetic approaches. During the last quarter of the 20th century, acylation reactions have undergone tremendous development, largely driven by the implementations of organometalic reagents. Among them, the strategy involving couplings of organoborons in the presence of palladium catalysts are the most prominent. In this chapter, highlights of a number of important strategies are discussed.

Introduction Ketones are ubiquitous structural motifs found across various natural products, pharmaceuticals and agrochemicals (1–3). For example, as shown in Figure 1, (S)-ketoprofen is an anti-inflammatory drug with approximately 160 times the potency of aspirin (4). Rottlerin (ROT) is commonly used as an inhibitor of protein kinase C-delta (5). Sofalcone, a chalcone derivative, is used as an anti-ulcer drug with mucosa protective effect and commonly isolated from the root of the Chinese medicinal plant Sophora subprostrata (6). Sulisobenzone is used as a UV absorber in various sunscreens (1). © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 1. Examples of Representative Diaryl Ketones. Apart from this, ketones also represent a wide range of ideal starting material for the synthesis of cyanohydrins, oximes, hydrazones, carbazones, acetals, pinacols, etc. The synthetic and pharmaceutical significances of ketone derivatives have attracted substantial interest from the scientific community for the development of industrial processes under simple, safe, economical and environmentally benign conditions. Traditionally, one potential approach to introduce acyl functionalities is the Friedel-Crafts acylation of aromatic compounds with acyl halides (Equation 1) (7, 8).

However, the reaction is incompatible with many functional groups (9), and delivers limited para-regioselectivity, and a large amount of by-products. Organometallic species, such as organotin (10), zinc (11), Grignard and organolithium reagents also promote the synthesis of ketones from acid chlorides or esters (12–15), but strong affinity of these reagents towards the ketone product produces tertiary alcohols as side-products (16). Recently, the strategy involving the use of organoboron based cross-coupling reactions for the introduction of acyl functionality have received widespread application due to their non-toxicity, thermal and air stability (17–20).

446 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The chemical stability of boron compounds in water and alcohols makes them highly attractive compared to other organometallic counterparts. This unique property was previously considered insignificant for synthetic approaches. However, recently organoborons have been utilized in Green Chemistry approaches, as one can easily use them in the presence of water without any special care. Organoborons are structurally diverse, relatively stable, readily prepared and generally environmentally benign with the ability to undergo rapid transmetalation with palladium complexes. These characteristics have made them the most versatile organometallic species and have seen frequent use in numerous well known cross-coupling reactions. During the last four decades tremendous developments have been made in the application of organoborons for complex molecular synthesis under exceptionally mild and functional group tolerant reaction conditions. The outer shell in the neutral boron atom is sp2 hybridized in which the p-orbital is devoid of any electron. Thus, organoborons are trivalent boron-containing organic compounds with a trigonal planar geometry and a non-bonding vacant p-orbital orthogonal to the plane. This low-energy empty p-orbital is responsible for the chemical and physical characteristics of all neutral boron compounds and makes them reactive towards electron donating Lewis bases. The use of widely functionalized and diverse organoboron reagents allows the selective introduction of the acyl function into complex and unique structures under mild and efficient reaction conditions. In general there are two significant methods that have been developed to introduce acyl functionality onto a specific organoboron substrate with high regioselectivity. The first of them includes an extraordinarily useful transformation involving the palladium-catalyzed coupling of organic electrophiles, such as aryl halides with organoboron compounds in presence of carbon monoxide (21), a process known today as the carbonylative Suzuki-Miyaura Coupling reaction (Scheme 1). First published in 1986 by Kojima et al. (22) this coupling reaction relies on a palladium-based catalyst and a base to effect part of the catalytic transformation. Further efforts from the group of Suzuki (23) and other have modified this method into versatile and efficient protocols (24). The palladium-catalyzed cross-coupling of carboxylic acid derivatives with arylboronic acid under mild reaction conditions represent another powerful synthetic tool to prepare biaryl ketones (Scheme 1) (25, 26). Considering the cleavage of the C-O bond of the carboxylic acid derivative in the presence of a palladium catalyst, Bumagin introduced this imperative method for the synthesis of biaryl ketones in 1997 (25, 26). This method is superior to the previous one in terms of environmental significance, reaction conditions, efficiency, and functional group tolerance. Predominant advancements include numerous modifications, primarily involving homogeneous Pd(II)- or Pd(0)-based catalysts, and use of both conventional organic and biphasic media (21).

447 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 1. Synthetic Methods for Ketones

Carbonylation of Organoborons with Aryl Halides and Carbon Monoxide Conventionally, the introduction of acyl functionalities is achieved by the transition-metal-based, three-component, catalytic carbonylative cross-coupling reaction between aryl-X (X=Br, I, OTf, N2+), organometalic reagent and carbon monoxide. Numerous organometallic reagents including silicon (27), magnesium (28), tin (29–31) and aluminum (32) reagents have been reported. However, many of these methods suffer the drawback of the formation of biaryl side products without carbon monoxide insertion, particularly when electron-withdrawing groups are present on the aryl ring. Electron-deficient aryl halide accelerate the rate of transmetalation to form the aryl-Pd-aryl intermediate and block the insertion of carbon monoxide into the aryl-Pd-X species. In 1986, Kojima and co-workers reported a potent methodology for the synthesis of alkyl aryl ketones using palladium-catalyzed cross-coupling of aryl iodides or benzyl halides with organoboranes under a carbon monoxide atmosphere (Scheme 2) (22). This was the first report of the use organoboranes in carbonylative coupling reactions. The reaction relies on the use of 1.1 equivalents 448 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


of Zn(acac)2, which assist in the formation of the RCOPdII(acac) species for the transmetalation in the absence of base.

Scheme 2. First Pd-catalyzed Carbonylative Coupling of 9-borabicyclo-[3.3.1] nonane Thereafter, in 1991, Suzuki and co-workers developed another protocol for the Pd(PPh3)4-catalyzed carbonylative coupling of organoboranes with vinyl halides to synthesize vinyl ketones in benzene/dioxane and using K3PO4 as the base (Scheme 3) (33). However, the chemoselectivity of the reaction decreased when iodoalkenes bearing electron withdrawing substituents were used, and a mixture of both carbonylated and non-carbonylated products were observed.

Scheme 3. Pd-catalyzed carbonylative coupling of 9-borabicyclo-[3.3.1] nonane with vinyl halides. In 1993, Suzuki and Miyaura reported the synthesis of biaryl ketones using palladium-mediated cross-coupling of aryl iodides and benzyl bromide with arylboronic acids under a carbon monoxide atmosphere (Scheme 4) (23). Arylboronic acids have wide functionality, high selectivity, stability and non-toxicity, which make them a favorite candidate in coupling reactions. However, there are certain side-reactions associated with arylboronic acids that arise during the course of a palladium-based reaction (34–37). Hence, the proper 449 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


choice of catalyst, base and solvent is essential to obtain the desired ketones without by-products.

Scheme 4. Pd-catalyzed Carbonylative Coupling of Aryl and Benzyl Halides with Arylboronic Acids. The general mechanism for this carbonylative coupling reaction is analogous to the direct cross-coupling except the insertion of carbon monoxide, which takes place after the oxidative addition step and prior to the transmetalation step (Scheme 5).

Scheme 5. Mechanism for Carbonylative Cross-Coupling The method was further developed by employing various aryl electrophiles (Ar-I, Ar-Br and Ar-OTf) in the presence of a palladium catalyst and K2CO3 450 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


under an atmosphere of carbon monoxide (38). Although, PdCl2(PPh3)2 (3 mol %) provides efficient yields with aryl iodides, the use of the dppf ligand for the palladium catalyst and KI or NaI (3 equiv) are requisite to achieve selective coupling for aryl bromides or triflates. Moreover, the rate of carbon monoxide insertion and the selectivity of the ketone synthesis increases in the order of dppe

Acylation Reactions of Organoborons - ACS Symposium Series (ACS

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