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Alkane Functionalization by Metal-Catalyzed Carbene Insertion from Diazo Reagents

María Álvarez Ana Caballero and Pedro J. Pérez

Universidad de Huelva, Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC - CIQSO-Centro de Investigación en Química Sostenible and Departamento de Química, 21007, Huelva, Spain

1.1 Introduction

The metal-catalyzed decomposition of diazo compounds, known from the beginning of the twentieth century [1], occurs through the formation of metal-carbene intermediates which display electrophilic nature, mainly located at the carbenic carbon atom (MC, Scheme 1.1) [2]. Such feature is the origin of the reactivity toward nucleophiles triggering the transfer of the carbene group and subsequent functionalization of the latter. A variety of powerful nucleophiles have been employed along the years, such as unsaturated molecules (olefins, alkynes, or arenes) or amines and alcohols, for which carbene incorporation, either added to an unsaturated bond or inserted into a saturated one, was favored. At variance with that, the functionalization of the less nucleophilic carbon-hydrogen bonds by this methodology has developed at a lower rate [3]. Intramolecular transformations were described with a substantial degree of success, albeit many examples took advantage of the existence of carbon-hydrogen bonds vicinal to heteroatoms (N, O), of being located at benzylic positions, and/or of the formation of very stable five- or six-member rings. But when facing the modification of non-activated carbon-hydrogen bonds, and under intermolecular conditions, this reaction becomes a challenge that only in the last decade has been significantly achieved and with some goals yet to be reached.

Scheme 1.1 General catalytic cycle for several nucleophiles functionalization by carbene transfer from diazo compounds.

In this chapter, an account of the state of the art on the functionalization of the carbon-hydrogen bonds of alkanes by carbene incorporation from diazo compounds is presented. In this sense, only saturated hydrocarbons CnH2n+2 as well as their cyclic partners CnH2n are considered. Other C-H bonds in substrates containing activating groups (heteroatoms, aryl, or olefin) are not considered herein, unless a substantial degree of novelty is implicit. As shown in Figure 1.1, the strengths of the C-H bonds of the alkanes are considerably higher than those of substrates containing activating groups [4]. As a representative comparison, the C-H bond of cyclohexane displays a bond dissociation energy (BDE) of 99.5?kcal?mol-1, whereas the methyl C-H bonds of toluene are nearly 10?kcal?mol-1 below. Interestingly, some literature reports refer to the latter as "alkane functionalization," although it is clearly far of being and behaving as an alkane.

Figure 1.1 Bond dissociation energies of representative carbon-hydrogen bonds. Values in kcal?mol-1.

Based on the low nucleophilicity of the targeted C-H bonds, the success of the carbene transfer depends on exerting a high electrophilicity in the metallocarbene intermediate (MC, Scheme 1.1) generated from the catalyst precursor and the diazo reagent. The carbenic carbon needs to be drained of electron density; therefore, reactivity toward the weak electrophile is increased. Several tactics can be employed to achieve such effect (Scheme 1.2). On one hand, electron donation from the ancillary ligand(s) bonded to the metal ion should be as low as possible while always ensuring that coordination is maintained. The use of a very poor coordinating ligand could be a problem if it is de-coordinated during catalysis. Additionally, the nature of the substituents at the diazo reagent may also help since electron withdrawing, electron donating, or the neutral H can be employed at those positions. It could be thought that using two electron-withdrawing groups could be the best option to enhance the reactivity. However, this is not the case since other side reactions can also occur (see Section 1.2), and very reactive metallocarbenes could enhance the formation of undesired products. A balance between the ancillary ligand, the metal center and the diazo substituent must be found to optimize the reaction outcome.

Scheme 1.2 Factors affecting the electrophilicity of the carbenic carbon atom.

1.2 Chemo- and Regioselectivity

1.2.1 Definitions

The metallocarbene intermediates are highly reactive and interact with available nucleophiles in the reaction mixture. In addition to the substrate employed, other side, non-desired reactions might occur, decreasing the selectivity of the process. Scheme 1.3 shows the most common byproducts derived from such behavior. Olefins derived from the catalytic coupling of two diazo molecules are the most frequent byproducts, in a process which usually is highly favored [5]. The use of slow addition techniques to maintain a low diazo concentration is a tactic to decrease their formation. Such olefins can also be transformed into cyclopropanes with a third diazo molecule, a reaction which may occur with highly active catalysts and high concentration of the olefins. When adventitious water is present, the O-H bond can also be modified upon incorporation of a carbene moiety. Because all these possible processes decrease the yields into the targeted alkane C-H bond functionalization product, the chemoselectivity is usually defined as the amount of the latter referred to the initial amount of the diazo reagent, which can also be transformed into the other byproducts. The formation of the olefins and cyclopropanes involve two and three, respectively, molecules of diazo reagent, a fact that needs to be accounted for the chemoselectivity value.

Scheme 1.3 Chemoselectivity in C-H bond functionalization by carbene insertion, with potential undesired side reactions.

Regioselectivity in the context of alkane functionalization by this methodology refers to the distinct reactivity shown by the different C-H bonds available in the alkane molecule employed as substrate. Considering n-hexane as an example, three distinct potential sites are present, i.e. the primary C-H bonds at C1 and the secondary sites at C2 and C2´ (Scheme 1.4). Once the reaction outcome is quantified, a distribution of the three products derived from the carbene insertion in such those three sites is obtained. Albeit those numbers can be employed to define the selectivity of the catalyst, it is more convenient to correct them employing the number of C-H bonds existing at each site, therefore eliminating statistic effects. In this manner, six C-H bonds are available at C1 sites, whereas C2 and C2´ contain four C-H bonds each. In the case of 2,3-dimethylbutane, there are 12 primary sites at C1 and 2 tertiary ones at C3. Scheme 1.4 shows a comparison with hypothetical values for the distributions of products and the regioselectivity defined as the latter corrected by the number of available C-H bonds. The selectivity toward C1 and C2 in hexane corresponds to a 1 : 9 ratio, which may be misinterpreted focusing only on the distribution of products (10 : 60). The case of 2,3-dimethylbutane is more pronounced: a 60 : 40 ratio for the distribution of products, which provides more of the primary site functionalized product, corresponds to a 1 : 4 regioselectivity favoring the tertiary site.

Scheme 1.4 Examples for the comparison of the distribution of products and the regioselectivity calculated employing the number of C-H bonds of each class in the substrate.

1.2.2 Catalysts

A number of catalysts have been described for the functionalization of the carbon-hydrogen bonds of alkanes and cycloalkanes through this methodology, many of them consisting of transition metal complexes bearing somewhat elaborated ligands. Scheme 1.5 displays all those commented along this chapter, either showing the structure of the catalyst or, in some cases, the ligand used as an additive along with a simple metal salt. Each catalyst is given a number which is later employed in the discussion of results.

Scheme 1.5 Catalysts employed for the functionalization of alkanes or cycloalkanes by carbene insertion from diazo compounds.

1.2.3 Chemoselectivity

Cyclohexane is very often employed as the probe substrate to evaluate the potential of a catalyst toward the carbene transfer from a diazo compound and subsequent alkane C-H bond functionalization. With a substantial BDE value (99?kcal?mol-1), it is an appropriate reactant since only one product is formed, at variance with linear alkanes, and thus provides a measure of the chemoselectivity induced by the catalyst chosen. In this section, an overview of the catalytic systems described for the conversion of cyclohexane into the corresponding derivatives upon carbene insertion is given. Table 1.1 contains a list of such...