1
Diazo-Mediated Homologation Reactions

Nuno R. Candeias1,2 and Hélio M.T. Albuquerque1

1University of Aveiro, LAQV-REQUIMTE, Department of Chemistry, Campus de Santiago, 3810-193 Aveiro, Portugal

2Tampere University, Faculty of Engineering and Natural Sciences, Korkeakoulunkatu 3, 33101 Tampere, Finland

1.1 Introduction

Diazo compounds are highly energetic compounds. This feature, as with many other compounds, makes such molecules very attractive in chemical synthesis but imposes several hurdles to their use. The high reactivity of diazo compounds makes them very versatile compounds as the diazo functionality can undergo innumerable transformations. The palette of reactions that paint the reactivity spectrum of diazo compounds is greatly expanded when considering dediazotization reactions and their ability to form carbenes. The synthetic community has paved a long way in controlling the high reactivity of diazo compounds since the first report on the preparation of diazomethane more than 125?years ago. Nevertheless, many of the uses of diazo compounds in organic synthesis continue to be very much linked to the seminal works on their reactivity, reported in the first half of the twentieth century.

This chapter intends to compile the most relevant works on the field of homologations with diazo compounds, contextualizing the different transformations within a historical perspective and keeping a bibliographic record of the seminal works while not aiming to be a full comprehensive compilation of the literature on the field. The chapter is divided in two main sections; the first is devoted to the most used strategies for preparation of diazo reagents, and the second is devoted to its use in homologation reactions. The former section is then subdivided according to the functional groups to be homologated, namely, aldehydes and ketones; carboxylic acids and other classes are not included in the first section. The reader is nevertheless directed to the many excellent reviews on the preparation [1] and use [2] of diazo compounds in organic synthesis.

1.2 Diazo Reagents for Homologations

Diazo compounds constitute a very important class of reactive species, which finds a wide range of applicability in a variety of chemical transformations. This kind of nitrogen compounds, though, have serious safety handling concerns since they are highly toxic and sometimes explosive. Despite the high safety and health risks, diazo compounds have become a versatile class of chemicals for organic synthesis, comprising several classes of compounds depending on the nature of the substituents (electron-withdrawing group [EWG] or electron-donating group [EDG]) at the diazo carbon atom (Figure 1.1). Compounds having one or two EWG groups at the diazo carbon are considered "stabilized diazo compounds," while species with alkyl or dialkyl substituents are thought "non-stabilized diazo compounds," and therefore more difficult to prepare and isolate. Compounds having either an aryl or vinyl group adjacent to the diazo function can be recognized as "semi-stabilized" diazo compounds [1, 3].

There are several possible well-documented routes for the preparation of diazo compounds, basically divided into typical protocols such as (i) diazotization of amines, (ii) basic decomposition of nitroso derivatives, (iii) oxidation of hydrazones, (iv) Bamford-Stevens reactions, and (v) diazo-transfer reactions to activated methylene group (Scheme 1.1) [4].

Aryl or alkyl diazo compounds can be prepared from N-sulfonylhydrazones in basic reaction conditions, while unsubstituted hydrazones can be dehydrogenated using oxidizers. For diazo compounds with at least one EWG, the diazo-transfer reaction, commonly from a sulfonyl azide to an activated methylene compound, is the preferred method. p-Acetamidobenzenesulfonyl azide (p-ABSA) is a "safer" diazo transfer agent and generally is the chosen azide over less safer ones as mesyl (MsN3) or tosyl azide (TsN3) for batch diazo preparation. In recent years, a myriad of new types of azides were developed as safer and easy to handle diazo transfer agents, with imidazole sulfonyl azides arising as the most noteworthy examples [4]. The method of choice to prepare diazo compounds is closely dependent on the substituents at the diazo carbon, which confers more or less stability toward temperature, acids, or bases.

Figure 1.1 Examples of different families of diazo compounds based on their stability.

Scheme 1.1 Typical methods for the synthesis of diazo compounds.

Source: Based on Refs. [4].

1.2.1 Diazoalkanes

1.2.1.1 Diazomethane

Diazomethane, firstly described in 1894 by von Pechmann, represents the shortest entirely aliphatic homologs of alkyl diazo compounds [5]. It is one of the most flexible and useful reagents in organic chemistry, especially for its application in the construction of C-C and C-heteroatom bonds, as depicted in Scheme 1.2. The conversion of carboxylic acids into the corresponding methyl esters is perhaps the most well-known example of the utility of diazomethane in organic synthesis. Nevertheless, diazomethane also has other important applications, namely, as methylating agent of phenols, enols, and other C-N and C-S nucleophiles. Ahead of this, one can always find diazomethane in the synthesis of diazo ketones, in the homologation of ketones and carboxylic acids (Arndt-Eistert homologation), in the transition metal-catalyzed cyclopropanations, and as a 1,3-dipole in [3+2] cycloadditions to generate N-heterocycles (Scheme 1.2) [2, 6].

Scheme 1.2 Synthetic effectiveness of diazomethane.

Source: Based on Refs. [2, 6].

Most chemical reactions involving diazomethane proceed in a fast, clean manner, producing only nitrogen as by-product. Despite these interesting features, the very same reactions where diazomethane is involved are often accompanied with some hazards (it is a highly toxic and explosive gas), and, therefore, it should be handled with extreme caution. To deal with these safety concerns, diazomethane is usually generated in situ from benign precursors, which are subsequently converted into more advanced, nonhazardous products. In this sense, the most common way to produce diazomethane is through base-mediated decomposition of N-methyl-N-nitrosoamines possessing electron-withdrawing substituents such as sulfonyl or carboxyl groups, in the presence of diethyl ether (Scheme 1.3) [2, 6, 7].

Scheme 1.3 Preparation of diazomethane from N-methyl-N-nitrosoamine precursors.

Source: Based on Refs. [2, 6, 7].

Nowadays, the typically used N-nitroso precursor is N-methyl-N-nitroso-p-toluenesulfonamide (Diazald®). Regrettably, Diazald is also very irritant and its synthesis from N-methyl-N-nitrosoamines via nitrosation of the corresponding N-methyl compounds in acidic medium is preferred for safety concerns (Scheme 1.3). The other two diazomethane precursors, N-nitroso-N-methylurea (NMU) and N-methyl-N´-nitro-N-nitrosoguanidine (MNNG) (Scheme 1.3), are no longer available in the market from chemical suppliers due to carcinogen, mutagen, and teratogen issues. In batch methodologies, distillation techniques have been used in the synthesis of anhydrous diazomethane, which is isolated as a solution in an organic solvent (typically anhydrous ether) (Scheme 1.3) [2]. These traditional approaches for diazomethane generation are still being employed nowadays, with the major improvements being focused on minimizing the risk of exposure to the user, by generating and reacting diazomethane in situ. Considering this, lots of research have been focused on continuous flow, which will be discussed elsewhere in this book. Nevertheless, in seminal report, Carreira and coworker described the in situ batch preparation of diazomethane using a biphasic system and a water-soluble Diazald derivative developed by Almac Sciences Ltd. (Scheme 1.4). The diazomethane molecules are generated in aqueous basic conditions and then moved into an organic layer to be trapped by a cyclopropanation reaction catalyzed by an iron porphyrin (Scheme 1.4) [8].

Scheme 1.4 In situ diazomethane generation, phase transfer, and cyclopropanation.

Source: Based on Morandi and Carreira [8].

Even though this method does not require any purification of diazomethane, the biphasic reaction imposes a water-soluble Diazald derivative in which the 4-tolyl moiety is exchanged with a 3-sodium benzoate residue. Furthermore, it is limited to...