Palladium complexes of anionic N-heterocyclic carbenes derived from sydnones in catalysis

1 Introduction

Sydnones presumably are the most prominent of all mesomeric betaines. They not only are versatile 1,3-dipoles in cycloaddition reactions, but they also constitute a class of compounds of considerable pharmacological interest [1–3]. Sydnones have an interesting history. The parent compound N-phenylsydnone was first prepared in 1935 by Earl and Mackney [4] in Sydney by reaction of N-nitroso-N-phenyl-glycine (1) with acetic anhydride. Although structure I was allotted to the reaction product, Eade and Earl [5] stated in 1946 that “the originally prepared structure is still in doubt and that they are therefore referred to as ‘sydnones’”. Sydnones were later shown not to have the originally proposed bicyclic structure I, but the structure of 1,2,3-oxadiazolium-5-olates 2, in which all resonance forms are dipolar or tetrapolar [6–8] (Scheme 1). The adjective “mesoionic” was suggested as a consequence. As early as 1955, Katritzky [9] pointed out inconsistencies found in the literature concerning representations and suggested that the ± representation as shown in structures II and III, as well as the description “mesoionic” should be discontinued. He suggested the term “mesomeric betaine” as general term, which has indeed been accepted as the name of the entire compound class today. Among the numerous dipolar and tetrapolar resonance forms of sydnones, representation 2A is the most common, although it does neither reflect the spectroscopic properties nor the calculated or experimentally determined bond lengths [10]. With respect to this, the canonical form 2B seems to be more appropriate, whereas representation IV emphasizes single-, double-, and partial double-bond characters of sydnones [11]. Concerning the spectroscopic properties, carbonyl stretching frequencies of sydnones that correspond to an exocyclic C=O double bond are also in agreement with canonical form 2B [10].

Scheme 1:

Synthesis of N-phenylsydnone and some representations, among them the historic structure proposal I.

As an extension of an earlier system, Ramsden [12] published a new classification system for mesomeric betaines in 2013 that is based on a matrix-connectivity approach and is supported by calculations [13, 14]. As a consequence, the originally proposed classes of conjugated (CMB), cross-conjugated (CCMB), and pseudo-cross-conjugated heterocyclic mesomeric betaines (PCCMB) [15–17] have been expanded by the classes of semi-conjugated and pseudo-semi-conjugated mesomeric betaines [12] (Fig. 1). Sydnones belong to type A mesoionic compounds that form the subgroup of several five-membered systems of conjugated heterocyclic mesomeric betaines (CMB) [18, 19] or to class 1B of the new classification [12].

Fig. 1:

Classification system of heterocyclic mesomeric betaines according to Ramsden (2013/1985) and categorization of mesoionic compounds.

The definition of CMB is as follows: “Conjugated heterocyclic mesomeric betaines are cyclic mesomeric betaines in which the positive and negative charges are not restricted to separate parts of the π-electron system of the molecule. The positive and negative charges are in mutual conjugation and both are associated with the common conjugated π-electron system of the molecule” [15]. The following are the characteristic features: Sydnones are constructed of the 1,3-dipole azomethin-imine (V) and carbon dioxide (Fig. 2). In the dipolar resonance forms, sites for positive and negative charges exist (VI). They are isoconjugated to even, non-alternant hydrocarbon dianions VII. Mesoionic compounds of type A are constructed of atoms a–f, which contribute electrons to the system as indicated by the superscripts (VIII).

Fig. 2:

Characteristic features of sydnones.

The chemistry of sydnones has not been associated with the chemistry of N-heterocyclic carbenes so far, although their lithium adducts have been used for years in the synthesis of heterocycles and in metal-organic chemistry [20–23]. In fact, sydnones form highly moisture sensitive anions on deprotonation, which can be represented by tripolar resonance forms such as IX and X and as anionic heterocyclic carbenes XI [10] (Scheme 2). We have found that cyanomethyllithium is a suitable base to generate sydnone anions without decomposition [10].

Scheme 2:

Generation of sydnone anionic N-heterocyclic carbenes.

Heteroaromatic tripoles are not necessarily carbenes [24–26], but sydnone anions supplement the relatively new family of anionic N-heterocyclic carbenes such as imidazol-2-yliden-4-olate 4 [27–29], imidazol-2-yliden-4-aminide 5 [30], and imidazol-2-yliden-1-indolate 6 [31–33], all of which are derivatives of conjugated mesomeric betaines (Scheme 3). The anionic N-heterocyclic carbene 7 was formed on deprotonation of a cross-conjugated heterocyclic mesomeric betaine [34, 35]. In addition, some formal trapping products of anionic N-heterocyclic carbenes have been described [36, 37]. Among the anionic NHCs shown in Scheme 3, the sydnone anion has the strongest negative partial charge on the carbene center [10]. The first review dealing with the interesting area of overlap between the classes of N-heterocyclic carbenes and mesomeric betaines summarizes the results achieved thus far [38].

Scheme 3:

Some members of the family of anionic N-heterocyclic carbenes.

We report here on a palladium complex of the N-phenylsydnone anion that is catalytically active in transition metal catalyzed cross-coupling reactions.

2 Results and discussion

The palladium complexes of N-phenylsydnone and 5-ethoxy-3-phenyl-1,2,3-oxadiazolium tetrafluoroborate (O-ethylsydnone) were prepared starting from 4-bromo-3-phenylsydnone (8) and 4-bromo-5-ethoxy-3-phenyl-1,2,3-oxadiazolium tetrafluoroborate (10) and tetrakis(triphenylphosphine)palladium in THF at room temperature, respectively, according to own procedures [10] and those of others [39] (Scheme 4). ³¹P NMR spectra showed that the sydnone palladium complex 9 and the O-ethylsydnone palladium complex 11 were formed as 93.5:6.5 and 100:16 mixtures of trans- and cis-isomers under these conditions, respectively. Upon warming to 90°C, the cis-isomer of 9 is transformed to the trans-isomer, so that only one ³¹P NMR signal could be observed at δ = 21.3 ppm.

Scheme 4:

Synthesis of the palladium complexes 9 and 11.

To test the catalytical properties, we first performed Suzuki-Miyaura reactions on 2,5-dibromo-3,4-dinitrothiophene with phenylboronic acid and compared four catalyst systems (Scheme 5). Reactions under catalysis of tetrakis(triphenylphosphine)palladium (catalyst I) as well as a mixture of N-phenylsydnone and tetrakis(triphenylphosphine)palladium (catalyst II) gave high yields of 2,5-dibromo-3,4-diphenylthiophene (Scheme 5). The palladium complex of N-phenylsydnone (catalyst III), which we used as a mixture of trans- and cis-isomers as described above, gave even better yields under analogous reaction conditions. We also tested this reaction under catalysis of the pure trans-isomer of the palladium complex 9 and obtained identical yields of the coupling product, i.e. 96% of 13. The palladium complex of O-ethylsydnone (catalyst IV) resulted in the formation of very similar yields under identical reaction conditions. Thiophene 13 has been prepared before as starting material for the preparation of dyes for organic light-emitting diodes [40]. It was synthesized by cross-coupling tetrakis(triphenylphosphine)palladium and potassium carbonate in a mixture of methanol and toluene over a period of 8 h at reflux temperature in 37% yield [41]. An alternative procedure was published that uses 1,2-dimethoxyethane as solvent to give 80% yield of 13 [42].

Scheme 5:

A catalyst screening for Suzuki-Miyaura cross-couplings.

Next, we tested the cross-coupling reactions starting from 2,5-dibromo-3,4-dinitrothiophene (12) to prepare the sterically more hindered thiophene 14 [10] and the usage of more deactivated boronic acids as reaction partners such as (4-(trifluoromethoxy)phenyl)boronic acid, which yielded thiophene 15 (Fig. 3). It becomes obvious that the sydnone catalysts (catalysts III and IV) gave better yields than Pd(PPh₃)₄ (catalyst I) under the conditions outlined in Scheme 5. As catalysts III and IV proved to have a similar activity, we decided to pursue our investigations with catalysts I and III to synthesize thiophenes 16 and 17, respectively. To the best of our knowledge, thiophenes 15–17 are new compounds.

Fig. 3:

Preparation of thiophenes by cross-coupling reactions: spectroscopic numberings.

The electron-poor 3-chlorophenylboronic acid converted the thiophene 12 into the corresponding cross-coupled product 18, which is also, to the best of our knowledge, a new compound. In this reaction, we reduced the amount of catalyst to 5 mol%, but we applied a longer reaction time (Scheme 6).

Scheme 6:

A cross-coupling of two electron-poor substrates: spectroscopic numbering.

In the next series of reactions, we reduced the catalyst concentrations successively and chose the cross-coupling of 3-bromoquinoline with phenanthren-9-yl boronic acid as model reaction. We started from a catalyst concentration of 5.0 mol% of the palladium complex of sydnone (catalyst III), which resulted in the formation of 3-(phenanthren-9-yl)quinolone (21) in 90% yield, which decreased slightly with decreasing catalyst concentration as shown in Scheme 7.

Scheme 7:

Variation of the catalyst concentration: spectroscopic numbering.

In continuation of our project, we applied the sydnone palladium complex catalyst to the electron-poor substrate 1-chloro-2,4-dinitrobenzene 22, which was reacted with three different boronic acids. Phenylboronic acid, 1-naphthylboronic acid, and 9-phenanthrylboronic acid were used to prepare the aromatics 23a–c in 80%–99% yield as slightly yellowish solids (Scheme 8). The phenyl derivative 23a was described before as reaction product of the Suzuki-Miyaura reaction with 1-iodo-2,4-dinitrobenzene in a yield of 99% [43]. To the best of our knowledge, the compounds 23b, c are new.

Scheme 8:

Preparation of aromatics by cross-coupling reactions employing a sydnone-palladium complex: spectroscopic numberings.

Finally, we tested the coupling of an aliphatic boronic acid with 2,5-dibromo-3,4-dinitrothiophene 12 and chose isopropylboronic acid as reaction partner. However, under the conditions applied no reaction took place. By contrast, 4-bromobenzylic alcohol 24 gave the cross-coupled product in almost quantitative yield (Scheme 9). Numerous synthetic procedures for the preparation of (4-isopropylphenyl)methanol 25 exist, among those reductions of the corresponding aldehyde in the presence of iron catalysts [44–47] or ruthenium catalysts [48], or by enzymatic oxidation of p-cymene [49, 50]. To the best of our knowledge, this is the first synthesis of 25 by a cross-coupling reaction.

Scheme 9:

Coupling with an alkylboronic acid.

In summary, we show that the palladium complex of the N-phenylsydnone anion, which can be represented as anionic N-heterocyclic carbene, is catalytically active in cross-coupling reactions.

3 Experimental section

Bruker Avance 400 MHz and Bruker Avance III 600 MHz instruments were employed to measure the nuclear magnetic resonance (NMR) spectra. The ¹H NMR spectra were recorded at 400 or 600 MHz, and the ¹³C NMR spectra were recorded at 100 or 150 MHz. The solvent peaks or tetramethylsilane were used as the internal references. Multiplicities are described using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Peak assignments were accomplished using H,H-COSY, HSQC, and HBMC measurements. FT-IR spectra were measured with a Bruker ALPHA spectrometer. A Varian 320 MS Triple Quad GC/MS/MS spectrometer with a Varian 450-GC gas chromatograph was employed to measure the mass spectra, whereas the electrospray ionization mass spectra (ESIMS) were measured with an Agilent LCMSD series HP 1100 with APIES. Samples for ESIMS were dissolved in methanol and sprayed from acetonitrile at 30-V fragmentor voltage unless otherwise noted. Melting points are uncorrected and were determined in an apparatus according to Dr. Tottoli (Büchi). Yields are not optimized.