Università degli Studi del Piemonte Orientale “Amedeo Avogadro” Dipartimento di Scienze del Farmaco Dottorato di Ricerca in Chemistry & Biology Curriculum Drug discovery and development (SSD CHIM/08) XXIX ciclo a.a. 2015-2016 Nitrile N-oxides and nitrile imines as electrophilic partners for the discovery of novel isocyanide multicomponent reactions: an innovative strategy for the synthesis of molecular scaffolds useful in medicinal chemistry Valentina Mercalli Supervised by Prof. Gian Cesare Tron PhD program coordinator Prof. Domenico Osella Contents Contents Chapter 1 . Introduction 1 1.1 Introduction 3 1.2 Multicomponent reactions (MCRs) 4 1.3 Isocyanides 9 1.4 Isocyanide based multicomponent reactions (IMCRs) 14 1.5 References 23 Chapter 2 . Outline of the thesis 29 2.1 Outline of the thesis 30 2.2 References 33 Chapter 3 . Prologue (I): Nitrile N-oxides as electrophilic 35 partners in IMCRs 3.1 Introduction 37 3.2 Reaction between Z-chlorooximes, isocyanides and 41 carboxylic acids 3.3 References 44 Chapter 4 . Isocyanide -mediated multicomponent synthesis of 47 C-oximinoamidines 4.1 Results and discussion 49 4.2 Conclusions 55 4.3 Experimental section 56 4.4 References 66 Chapter 5 . Reaction between Z‑arylchlorooximes and α‑isocyanoacetamides: a procedure for the 69 synthesis of aryl-α-ketoamide amides 5.1 Results and discussion 71 5.2 Conclusions 79 5.3 Experimental section 80 5.4 References 95 iii Contents Chapter 6 . Solution -phase parallel synthesis of aryloxyimino amides via a novel multicomponent reaction among aromatic Z‑chlorooximes, isocyanides, and 97 electron-deficient phenols 6.1 Results and discussion 99 6.2 Conclusions 109 6.3 Experimental section 110 6.4 References 133 Chapter 7 . A multicomponent reaction among Z-chlorooximes, isocyanides and hydroxylamines as hypernucleophilic traps. A one-pot route to aminodioximes and their transformation into 135 5‑amino-1,2,4-oxadiazoles by Mitsunobu−Beckmann rearrangement 7.1 Results and discussion 137 7.2 Conclusions 147 7.3 Experimental section 148 7.4 References 164 Chapter 8 . General mechanism of the reaction between nitrile N-oxides and isocyanides 167 8.1 General mechanism 169 8.2 Conclusions 176 8.3 References 177 Chapter 9 . Prologue (II): Nitrile imines as electrophilic partners in IMCRs 179 9.1 Introduction 181 9.2 References 188 iv Contents Chapter 10 . Synthesis of aminocarbonyl N‑acylhydrazones by a three- component reaction of isocyanides, 191 hydrazonoyl chlorides, and carboxylic acids 10.1 Results and discussion 193 10.2 Conclusions 205 10.3 Experimental section 206 10.4 References 222 Chapter 11 . Exploiting the electrophilic and nucleophilic dual role of nitrile imines: one-pot, three- component synthesis of furo[2,3 ‑d]pyridazin- 225 4(5 H)‑ones 11.1 Results and discussion 227 11.2 Conclusions 233 11.3 Experimental section 234 11.4 References 247 Chapter 12 . An efficient synthesis of 1 -arylindazole -3- carboxamides using nitrile imines, isocyanides and 2-hydroxymethylbenzoic acid, followed by a 249 chemoselective Buchwald–Hartwig intramolecular cyclization 12.1 Results and discussion 251 12.2 Conclusions 260 12.3 Experimental section 262 12.4 References 276 Chapter 13. Conclusions 279 Chapter 14. Publications 285 Chapter 15. Synopsis 291 Chapter 16. Curriculum Vitae 303 v Chapter 1 Introduction 1 Introduction 1.1 Introduction Modern drug discovery is facing with the challenge of designing chemical reactions that are capable of providing most of different structural molecules with a minimum number of synthetic steps. 1–5 Classical chemical reactions correspond to equilibria between one or two reagents and their products. In theory, the perfect chemical reactions form their products irreversibly, without the competing formation of by-products, affording the desired products in quantitative yield. This ideal situation is anyway very far from the reality. Finally, using the two-component chemistry to form complex products, requires usually sequences of chemical reactions leading to reduced overall yield.6 On the contrary, in the multicomponent reactions (MCRs) three or more different starting materials are combined, in one step, to give a product that incorporates substantial portions of all the components, reducing the number of synthetic steps necessary to form the desired molecules.7,8 Indeed, over the last decades, multicomponent reactions have demonstrated their ability and efficiency in the generation of chemical diversity, being an extremely powerful synthetic tool for medicinal chemists and pharmaceutical industry.9–12 3 Chapter 1 1.2 Multicomponent reactions (MCRs) Reaction in which more than two starting compounds react to form a product in such a way that the majority of the atoms of the starting materials can be found in the product are called multicomponent reactions. 8 To note that MCRs do not directly convert their educts into the products, but they are sequences of subreactions that proceed stepwise. Ideally, all reaction equilibria in the MCR mixture are reversible, except one, thus providing the driving force to shift all intermediates and starting materials towards a single final product. Figure 1. Schematic presentation of a one component reaction, a two component reaction, and a three and four component (adapted from reference 5). Compared to conventional multistep organic syntheses, MCRs are advantageous due to their greater efficiency and the accessibility to a large number of molecules with broad structural diversity. The experimental simplicity of one-pot procedures is also a major benefit, they are easier to carry out than multistep syntheses and require a single final purification. Finally, the structure of the reaction product can be modified by systematic variation of each input. 5 A selection of the most important named MCR discovered starting from 1850 are reported herein (Figure 2). 4 Introduction Name of the Year of Example reaction discovery Strecker synthesis 13 1850 Hantzsch dihydropyridine 1882 synthesis 14 Radziszewski imidazole 1882 synthesis 15 Willgerodt-Kindler reaction 16,17 1887 NH O 2 COOR 2 OR 2 Döebner R1 R1 18,19 reaction 1887 O CHO N R3 R3 O O H R1 N R1 OR 2 Hantzsch pirrole 1890 O NH 3 O synthesis 20,21 R3 Ph O R3 R X 2 Figure 2. Named MCRs. 5 Chapter 1 Name of the Year of Example reaction discovery Biginelli reaction 22–25 1891 Guareschi reaction 26,27 1896 Betti reaction 28,29 1900 Reissert reaction 30 1905 Bargellini reaction 31 1906 Figure 2. Named MCRs ( continued). 6 Introduction Name of the Year of Example reaction discovery Mannich reaction 32 1912 Bucherer-Bergs hydantoin 1929 synthesis 33,34 Kabachnik-Fields synthesis 35,36 1952 1956 Asinger reaction 37 OR Povarov reaction 38 1963 NH 2 RO CHO N H Figure 2. Named MCRs ( continued). 7 Chapter 1 Name of the Year of Example reaction discovery Gewald reaction 39 1966 Pauson-Khand reaction 40 1977 Yonemitsu synthesis 41 1978 Petasis reaction 42 1993 Figure 2. Named MCRs ( continued). As shows in Figure 2, a vast number of MCRs have been reported in the literature, but special subclasses isocyanide based MCRs (IMCRs) are probably the most documented ones.1,5,10,43–46 8 Introduction 1.3 Isocyanides Isocyanides (or isonitriles or carbylamine) represent a class of stable organic compounds with the functional group -N≡C.47 Isocyanides are considered as highly “unpleasant” compounds, due to their vile odor. However, higher molecular weight isocyanides are often solid and odorless. Isocyanides are considered resonance forms between divalent carbon forms 1a and zwitterions 1b (Scheme 1). The carbon atom of the isocyano group can exhibit a carbene-like reactivity that is reflected in the resonance structure 1a, conversely, the linear structure of isocyanides is well represented by the dipolar resonance structure 1b , which has a nucleophilic character. 48,49 Scheme 1. Resonance structures of isocyanides. Isocyanides are stable under basic treatment (they are often made under basic conditions), but they are quite sensitive to acids. In the presence of aqueous acidic solutions, isocyanides react to give the corresponding formamides by an acidic hydrolysis and this is a generally convenient method for removing the horrible smell of isocyanides. 50,51 The chemistry of isocyanide is characterized by three properties: the α-acidity, the easy formation of radicals and the α-addition. The α-acidity of the isocyanides is further increased by electron-withdrawing substituents in the α-position such as carboxylic ester, nitriles and phosphonic ester 9 Chapter 1 or sulfonyl group. In certain cases, a weak base is sufficient to alkylate the isonitrile. This property has been widely studied for the synthesis of oxazoles 51,52 pyrroles, 53 triazoles. 30 For instant, Van Leusen reported an oxazole synthesis to oxazoles from toluenesulfonylmethyl isocyanide (TosMIC) and an aldehyde (Scheme 2).53 Scheme 2. Synthesis of oxazole starting from TosMIC. In the radical reaction of isocyanides, radicals are able to add on isonitriles to form an imidoyl radical species, which can then fragment into a nitrile and an alkyl radical 55 or can react intramolecularly with an unsaturated system to give cyclic compounds 56 (Scheme 3). Scheme 3. Addition of a radical on an isonitrile. 10 Introduction Finally, isocyanides are able to react with nucleophiles and electrophiles at the same isocyanide carbon-atom through an “α-addition”, to give an “α-adducts” 5 (Scheme 4). Scheme 4. Formation of α-adducts. This characteristic is unique in organic chemistry, both nucleophile and electrophile attacks will occur on the terminal carbon atom. After the attack of the isocyanide on an electrophile, the divalent carbon becomes electrophilic and can be attacked by a nucleophile, and conversely although rarer it can react first with a nucleophile and then with an electrophile. Only a few isocyanides are commercially available, but they can be easily prepared in one or two steps. The first isocyanide compound, allyl isocyanide, was obtained by Lieke in 1859, from the reaction of allyl iodide and silver cyanide.57 In 1867, Hofman described a new approach via the condensation of a primary amine with a dichlorocarbene, generated in situ by reacting chloroform with potassium hydroxide 58 (Scheme 5).