Hypervalent organoiodine promoted IPSO transformations of boronic acids/esters

Abstract

The alcohols, amines and nitro compounds, both aromatic and aliphatic are ubiquitous in various pharmaceuticals, agrochemicals, natural products and dyes. They play a very significant role in constructing different drug molecules (Figure 1). The incorporation of these groups especially to the aromatic ring is of great research importance. Specifically in the presence of different functional groups, the syntheses of phenols, amines or nitro compounds under milder and green reaction conditions without affecting the other functional groups, are always a challenging task for the chemists. Both hypervalent organoidine compounds and boronic acids/esters, in this respect, are non toxic and considered as green reagents. Furthermore, the reactions with these reagents could be performed under mild reaction conditions. Therefore, our aim was to develop new methodologies for synthesizing diversely functionalized phenols, nitroarenes or amines utilizing these two important reagents under appropriate milder reaction conditions. O OH OH OH HO O OH Quercitin (anti-oxidant and anti-inflamatory) N NO2 H3C 7-Methyl-8-nitroquinoline (anticancer, antitumor, antiallergetic) EtO2C NH2 benzocaine (topical anesthetic) Figure 1 Selected biologically important phenol, ntroarene and amine compounds The thesis entitled “Hypervalent Organoiodine Promoted Ipso Transformations of Boronic Acids/Esters” covers discussions on five novel hypervalent organoiodine(III) mediated methodologies, developed by us for ipso functionalization of boronic acids/esters along with relevant literature review associated with it. The contents of the thesis are divided into five chapters. Among them, Chapter 2 and Chapter 4 contain two sections (Section A & Section B) in each. Chapter 1 describes general introduction to hypervalent organoiodine chemistry, whereas Chapter 2, Chapter 3 and Chapter 4 deal with the ipso hydroxylation, nitration and amination of boronic acids/esters, respectively, which are based on the experimental work, carried out by us. Chapter 5 includes the summary of the complete work as the conclusion. Chapter 1: General introduction to Hypervalent Organoiodine Chemistry Hypervalent organoiodine compound is one of the wonderful and important class of reagent having all-round applicability in the field organic synthesis. The upswing in the use of hypervalent organoiodine reagents is due to their profound versatility and considerable similarity with the metal based reagents like Hg(II), Ti(III), Pb(IV) compounds, but without metallic toxicities. The useful mild oxidizing property in combination with their envirionmentally benign character and commertial availability has made the hypervalent organoiodine reagents as more convenient alternatives to toxic heavy metal congeners. In this chapter, general reactivity principle of the hypervalent organoiodine molecules, arising out from their structural disposition has been concisely discussed. Furthermore, the general preparatory methods of commonly used hyprvalent organoiodine compounds and their applications for functionalization of the organic molecules have been briefly reviewed. Chapter 2: Ipso Hydroxylation of Boronic Acids/Esters Mediated by Hypervalent Organoiodine(III) Reagents The alcohols, both aromatic and aliphatic, are important structural constituents of numerous natral products, pharmaceuticals and polymers. The conventional approaches to prepare phenols were through activated nucleophilic substitution of aryl halides and via formation of benzynes from suitable precursors. In recent years, arylboronic acids or esters, owing to their commercial availability and remarkable stability, have been widely utilized for different functionalization including hydroxylations. In this respect, both metal promoted and metal free methods have been documented in literature on ipso hydroxylation of boronic compounds. In this chapter, we have described two methodologies, in two different sections, for ipso hydroxylation of boronic acids and esters promoted by organic hypervalent iodine(III) reagents. In section A, iodobenzene diacetate [PhI(OAc)2] (PIDA) mediated ipso hydroxylation of the boronic acids and in section B, orgnoiodine(III) catalyzed ipso hydroxylation of the boronic acds/esters have been discussed. Chapter 2: Section A: Ipso Hydroxylation of Boronic Acids/Esters Mediated by [(Diacetoxy)iodobenzene] (PIDA) In this section, a metal free, highly efficient methodology for ipso hydroxylation of diversely functionalized aryl- and alkylboronic acids/esters, mediated by iodobenzene diacetate (PIDA) has been elaborated (Scheme 1). This protocol is also applicable to N-heterocyclic boronic acids and esters. It is an open flask hydroxylation reaction. The reaction is very fast and quantitative, completing in less than 10 minutes at ambient temperature. A notable feature of this protocol is that among the two electron demanding species [arylboronic acid and PhI(OAc)2] involved in the reaction, arylboronic acid in spite of being a Lewis acid, can be predicted to act as a Lewis base in the presence of a more electron demanding species, PIDA. PhI(OAc)2 (1.5 equiv.) CH3CN-H2O, rt, 10 min B(OH)2 OH 1 2 Et3N (2.0 equiv.) R R Scheme 1 PIDA mediated ipso hydroxylation of boronic acids Chapter 2: Section B: Organoiodine(III) Catalyzed Ipso Hydroxylation of Boronic Acids/Esters In this section, we have described a novel methodology for hypervalent organoiodine(III) catalyzed ipso hydroxylation of aryl-, heteroaryl- and alkylboronicacids/esters to access functionalized aromatic, heteroaromatic and aliphatic alcohols. The ipso hydroxylations of the boronic acids and esters were achieved by using the catalytic combination of 10 mol% of PhI and 2.0 equiv. of NaIO4 as a co-oxidant at 80 0C in CH3CN (Scheme 2). The protocol exhibits wide range of functional group tolerance including the aldehydes which are prone to get over oxidised easily. It was the first report of a generalized route for hypervalent organoiodine(III) catalyzed ipso hydroxylation of boronic acids and esters. Scheme 2 Organoiodine(III) catalyzed ipso hydroxylation of boronic acids Chapter 3: [Bis-(trifluoroacetoxy)iodo]benzene (PIFA) and NBS Mediated Ipso Nitration of Boronic Acids Over the last century nitroarenes and nitroalkanes have been considered as versatile structural motifs because of their wide range of applications in pharmaceuticals, pesticides, dyes, agrochemicals and polymers. They also play a vital role in the development of mechanistic concepts. Nitroarenes are generally synthesized via direct electrophilic nitration of the arenes. Later on, some notable achievements have been documented in literature toward regioselective syntheses of nitroarenes under mild reaction conditions. In this chapter, we have presented a very useful methodology for ipso nitration of boronic acids using a combination of PIFA–NBS and NaNO2 as the nitro source, under milder reaction conditions (Scheme 3). The protocol is applicable for aryl-, heteroaryl-, and alkylboronic acids and provides nitro compounds at ambient temperature in a significantly less reaction time exhibiting a broad range of functional group compatibility. It is anticipated that the reaction proceeds through in situ generation of NO2 and O-centred boronic acid radicals followed by the formation of an O–N bond via combination of the said radicals. Finally transfer of the NO2 group to the aryl moiety occurs through 1,3-aryl migration to provide the nitroarenes. In this context, it could be mentioned that it was the first report to use the combination of PIFA and NBS which would act as an acidic hydrogen radical abstractor. The simplicity, high efficiency, use of easily available inexpensive reagents and also the chemistry associated with it are the salient features of this method. B(OH)2 NO2 PhI(OCOCF3 )2 CH3CN, rt, 3 h 1 2 NBS, NaNO2 R R Scheme 3 PIFA-NBS mediated ipso nitration of boronic acids Chapter 4: Ipso Amination of Boronic acids Mediated by [Bis- (trifluoroacetoxy)iodo]benzene (PIFA) and NBS Both aromatic and aliphatic amines are ubiquitous in various pharmaceuticals, agrochemicals, natural products and dyes. The aromatic primary amines are the most vital moieties to construct different N-heterocycles and thus play a significant role in the branch of medicinal chemistry. It is needless to say that over the recent decades, significant advancements have taken place in the field of synthesis of secondary and tertiary anilines. On the contrary, much less attention has been devoted for development of efficient methodologies to synthesize primary amines under mild reaction conditions. The long established approaches to prepare the primary amines are the metal mediated reductions of the nitro compounds and via treatment of metal amide to the benzynes in liquid ammonia. In addition to that, several metal-promoted and metal-free primary aminations of aryl halides and aryl boronic acids have been reported in the literature in recent years. In this chapter, we will elaborate two methodologies for synthesizing primary amines via ipso amination of boronic acids utilizing the reagent combination of PIFA and NBS. The chapter is divided in two sections: Section A and Section B. In section A, PIFA-NBS mediated synthesis of primary amines via ipso amination of boronic acids using methoxyamine hydrochloride as the amine source, will be described, whereas, in section B, PIFA-NBS promoted chemoselective synthesis of primary amines using cyanamide/arylcyanamide as the aminating agent has been presented. Chapter 4: Section A: Metal and Base-free Synthesis of Primary Amines via ipso Amination of Boronic Acids Mediated by [Bis(trifluoroacetoxy)iodo]benzene (PIFA) and NBS In this section, we have delineated a novel metal and base free methodology for preparing primary amines via ipso amination of boronic acids using a combination of PIFA-NBS and MeONH2.HCl as the aminating agent (Scheme 4). The method is applicable for aryl-, heteroaryl-, and alkylboronic acids and produces amino compounds at ambient temperature within 2 h. The amines were primarily obtained as their trifluoroacetate salts which on subsequent aqueous alkaline work up provided the corresponding free amines. The combination of PIFA–NBS is found to be the mildest choice compared to the commonly used strong bases (e.g. n-BuLi, Cs2CO3) for activating the aminating agent. The reaction is expected to proceed via activation of the aminating reagent followed by B–N 1,2-aryl migration. The reaction conditions employed in the protocol show a wide range of functional groups tolerance especially to the carbonyl, nitrile ester and halogen which are hard to synthesize through some of the previously reported methods in this field. The utilization of PIFA-NBS combination, as a milder alternative to a base, acting as an acidic hydrogen radical abstractor is one of the remarkable features of this method. B(OH)2 CH3CN, rt, 2 h 1 2 aq. NaOH Ph NH2 I(OCOCF3 )2 - NBS MeONH2.HCl R R Scheme 4 PIFA-NBS mediated ipso amination of boronic acids Chapter 4: Section B: Chemoselective Primary Amination of Boronic Acids Using Cyanamide/Arylcyanamides as Aminating Agent In this section, we have demonstrated a unique metal and base free method for chemoselective synthesis of primary amines via ipso amination of boronic acids using a combination of PIFA-NBS as acidic hydrogen radical abstractor and cyanamidyl/arylcyanamidyl radical as the aminating species (Scheme 5). The reaction conditions employed in the protocol exhibited a wide range of functional groups compatibility especially to the carbonyl, nitrile and ester. The method is applicable for aryl-, heteroaryl- and alkylboronic acids and produces corresponding amino compounds at ambient temperature within 1 h. Furthermore, computational studies utilizing Density Functional Theory (DFT) have been performed to understand the mechanism of the reaction in depth. The DFT study in combination with experimental observations validates that the ipso amination of substituted boronic acids involves the formation of cyanamidyl/arylcyanamidyl radical, followed by regiospecific interaction of its nitrile-N centre with boron atom of the boronic acids, culminating to chemoselective primary amination. The use of ambident cyanamidyl radical and its exclusive specificity to utilize the nitrile-N centre towards the arylboronic acids leading to specifically primary amines is no doubt a unique study in this field. NH2CN or ArNHCN PhI(OCOCF3)2, NBS CH3CN, rt, 1 h aq. NaOH B(OH)2 1 NH2 2 R R Scheme 5 Chemoselective ipso amination of boronic acids mediated by PIFA-NBS The aforementioned pieces of work on the ipso functionalization of boronic acids are shown below in a schematic diagram to have a quick look (Scheme 6). R B(OH)2 PhI(OAC)2, Et3N CH3CN, rt, 10 min R OH R OH PhI (10 mol%), NaIO4 (2.0 equiv.) CH3CN, 80 0C, 8 h PhI(OCOCF3)2, NBS NaNO2, CH3CN rt, 3 h R NO2 PhI(OCOCF3)2, NBS MeONH2.HCl CH3CN, rt, 2-3 h PhI(OCOCF3)2, NBS NH2CN or ArNHCN R NH2 R NH2 Scheme 1 Scheme 2 Scheme 5 Scheme 3 Scheme 6 Organoiodine(III) assisted ipso transformations of boronic acids Chapter 5: Conclusion In this chapter, the summary of the whole work has been described. In addition, potential future aspects of the thesis are indicated.