Facile N9-Alkylation of Xanthine Derivatives and Their Use as Precursors for N-Heterocyclic Carbene Complexes

The xanthine-derivatives 1,3,7-trimethylxanthine, 1,3-dimethyl-7-benzylxanthine and 1,3-dimethyl-7-(4-chlorobenzyl)xanthine are readily ethylated at N9 using the cheap alkylating agents ethyl tosylate or diethyl sulfate. The resulting xanthinium tosylate or ethyl sulfate salts can be converted into the corresponding PF6− and chloride salts. The reaction of these xanthinium salts with silver(I) oxide results in the formation of different silver(I) carbene-complexes. In the presence of ammonia, ammine complexes [Ag(NHC)(NH3)]PF6 are formed, whilst with Et2NH, the bis(carbene) salts [Ag(NHC)2]PF6 were isolated. Using the xanthinium chloride salts neutral silver(I) carbenes [Ag(NHC)Cl] were prepared. These silver complexes were used in a variety of transmetallation reactions to give the corresponding gold(I), ruthenium(II) as well as rhodium(I) and rhodium(III) complexes. The compounds were characterized by various spectroscopic methods as well as X-ray diffraction.


Introduction
Metal complexes containing N-heterocyclic carbenes (NHCs) are today considered a common class of ligands in organometallic chemistry. Their seemingly endless structural variety combined with a very stable metal-carbon-bond makes carbene complexes so important in homogeneous catalysis and also for biomedical applications [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Typically, most N-heterocyclic carbenes are derived from substituted imidazolium, benzimidazolium or triazolium salts. Related to this class of compounds are the xanthinium salts, which may also be used as precursors for N-heterocyclic carbenes. Especially xanthinium salts derived from caffeine or theophylline have been studied to some extent. The first reported xanthine-derived NHC complex was the mercury(II) bis(NHC) salt [Hg(NHC) 2 ]ClO 4 (NHC = 1,3,7,9-tetramethylxanthin-8-ylidene), prepared by Beck in 1976 [15]. After lying dormant for more than a quarter of a century, the groups of Youngs and Herrmann independently began to reinvestigate NHC-complexes derived from caffeine and its derivatives with rhodium(I), iridium(I) and silver(I) [16][17][18]. Especially the silver(I) complexes developed and patented by Youngs were found to be highly active against various pathogens [19][20][21][22][23][24]. Other groups have examined xanthine-derived carbene complexes with metals including Pt(II) [25][26][27], Pd(II) [28][29][30][31][32], Au(I) [33], Ir(I) [34] and Ag(I) [35,36]. Focus of these studies was their activity against cancer cells (Pt, Pd, Au, Ir and Ag) or homogeneous catalysis (Pd, Rh). There is also a publication on copper complexes containing a caffeine-derived NHC, but the results must be considered doubtful [37]. The compounds are referred to as being blue copper(II) species, but an alleged X-ray structure (data neither shown in the publication nor deposited with the CCDC) and NMR spectroscopic data are clearly consistent with the presence of copper(I). A short review from 2018 Work-up merely involves washing the product with diethyl ether and drying. This result encouraged us to try the even cheaper diethyl sulfate. Indeed, reacting 1,3-dimethyl-7-benzylxanthine in neat diethyl sulfate at 130 • C for two hours afforded the desired product as the ethyl sulfate salt in 87% yield (Scheme 1). Using the same procedure, the corresponding 4-chlorobenzyl-and caffeine-derivatives were also isolated as colorless solids in high yields (Scheme 1). In the case of caffeine, the ethyl sulfate anion evidently hydrolyzes during the reaction, forming the hydrogen sulfate salt instead. These xanthinium salts were characterized by NMR spectroscopy and electrospray mass spectrometry, the latter (in positive ion mode) shows only one signal corresponding to the respective xanthinium cations and, in negative ion mode, only the signals for the anions (EtSO 4 − , TsO − or PF 6 − ). The positive-ion mass spectra of the caffeine derivatives also feature one signal, which can be assigned to the fragment [M-Me+H] + , formed by loss of one methyl group.
The tosylate, ethyl sulfate or hydrogen sulfate anions in these salts could readily be exchanged in water to give the corresponding PF 6 − salts 1PF 6 , 2PF 6 and 3PF 6 (Scheme 1). Since halide salts are however the most convenient precursors for N-heterocyclic carbene metal complexes, we investigated the possibility of converting the PF 6 − salts into the corresponding chlorides. The group of Visentin reported that a xanthinium tetrafluoroborate could be converted into the chloride salt by anion exchange with [Ph 4 As]Cl [31]. Given the toxicity and high cost of [Ph 4 As]Cl, we sought alternative reagents to accomplish this anion exchange. Gratifyingly, we found that mixing THF solutions of the xanthinium PF 6 − salts with [ n Bu 4 N]Cl results in precipitation of the chloride salts 1Cl, 2Cl and 3Cl, which could be isolated almost quantitatively (Scheme 1). Based on mass spectrometry, the samples are free of PF 6 − anions and the presence of a chloride anion was confirmed by a sharp singlet in their 35 Cl-NMR spectra. Unfortunately, it was not possible to access the chloride salts directly from the ethyl sulfate of hydrogen sulfate salts.
With these xanthinium salts in hand, we examined their use as precursors for N-heterocyclic carbene complexes of silver. The reaction of the respective PF 6 − salts with Ag 2 O in a mixture of ethanol and aqueous ammonia afforded the corresponding cationic silver(I) carbene complexes [Ag(NHC)(NH 3 )]PF 6 , (NHC = 1,3-dimethyl-7-benzyl-9-ethylxanthine-8ylidene (4), 1,3-dimethyl-7-(4-chlorobenzyl)-9-ethylxanthine-8-ylidene (5) and 1,3,7-trimethyl-9-ethylxanthine-8-ylidene (6)) containing ammonia as co-ligand (Scheme 2) [49]. When using Et 2 NH instead of ammonia, we isolated the bis(carbene) silver(I) salts [Ag(NHC) 2 ]PF 6 (NHC = 1,3-dimethyl-7-benzyl-9-ethylxanthine-8-ylidene (7) and 1,3dimethyl-7-(4-chlorobenzyl)-9-ethylxanthine-8-ylidene (8)) (Scheme 2). The silver carbene compounds were characterized by NMR spectroscopy, mass spectrometry and single crystal X-ray diffraction. The proton spectra of the compounds lack the signal for the proton at position 8, consistent with carbene formation. This is further confirmed by a significant shift of the resonance of the carbon atom at position 8. In the xanthinium salts, these are observed between 138 and 139 ppm, whilst in the silver carbene complexes they fall in the range of 185 to 187 ppm. The chemical shifts of metal-bound carbene-carbon resonances can often vary, depending on the other ligands bound to the metal. In this series of silver compounds, the nature of the second ligand (NH 3 , carbene or Cl − ) does not appear to have a significant effect on the chemical shift of the carbene-carbon resonance. In the case of the bis(carbene) complexes 7 and 8, coupling between the 13 C and the 107/109 Ag isotopes with coupling constants of 192 and 217 Hz could be observed. These values are typical for silver(I) NHC-complexes, which have been observed in several other bis(carbene) complexes [50]. In the case of the ammonia complexes 4-6, broad signals due to the ammine can be observed in their proton NMR spectra at about 3 ppm. Furthermore, bands between 3300 and 3400 cm −1 due to the NH 3 stretching frequency are seen in their IR spectra. The molecular structures of compounds 5 and 7 are shown in Figures 1 and 2.
For compound 9 the two Ag-Cl bond lengths of 2.44 Å and 2.72 Å are unequal, resulting in an Ag 2 Cl 2 parallelogram. This structural motif is observed in several other silver NHC complexes [51,52]. Crystals of complex 10 were very small and thin, therefore diffraction data was collected at beamline P11 at the PETRA III synchrotron located at DESY in Hamburg, Germany. The trimeric structure of 10 is unique and, so far, has no precedence in the literature. The molecule consists of a planar Ag 3 -triangle with two shorter (3.11 and 3.21 Å) one much longer (3.89 Å) Ag-Ag distances. Above and below this Ag 3 -plane there is a µ 3 -bridging chloride ligand. The third chloride acts as µ 2 -ligand between two silver atoms in the plane of the triangle. Each silver atom is also C-bound to the carbene ligand (Figure 3 bottom). As can be seen, the C-Ag-Cl angles are not linear, resulting in a distorted tetrahedral coordination environment about each silver atom. Silver NHC complexes are commonly used in transmetallation reactions to transfer the NHC ligand to a different metal. We therefore examined the reaction of the silver chloride complexes 9-11 with various other metal salts including [AuCl(tht)] (tht = tetrahydrothiophene), [Ru(p-cym)Cl 2 ] 2 , [Rh(Cp*)Cl 2 ] 2 and [Rh(cod)Cl] 2 . In each case the corresponding metal xanthine-8-ylidene-derivatives were formed in good yields as air-and moisturestable solids (Scheme 4).
Complexes 12-23 were characterized by various spectroscopic methods and, in several cases, by X-ray diffraction. In all these compounds, the chemical shifts of the carbene-carbon resonances in the 13 C-NMR spectra are most diagnostic. Compared to the silver-precursors, the resonances are shifted either slightly upfield or downfield, depending on the metal. In case of the Rh-complexes, coupling between the 13 C and 103 Rh nuclei can be observed.      There is only one other reported X-ray structure of a xanthine-derived NHC Au(I) halide complex, namely that of the iodo-complex [Au(NHC)I] (NHC = 1,3,7,9-tetramethylxanthine-8-ylidene) [33]. The Au-C bond lengths in 12-13 are with around 1.9 Å, similar to those observed in the 1,3,7,9-tetramethylxanthine-8-ylidene derivative.
The structure of the ruthenium(II) complex 15 ( Figure 5) features one C-bound carbene and two chloride ligands at the arene-Ru center. This piano-stool type arrangement is typical for this class of compounds. While the preparation and biological properties of the 1,3,7,9-tetramethylxanthine-8-ylidene-analogue of 15 have been published [53], this is the first X-ray structure of an arene ruthenium complex containing a xanthine-derived carbene ligand.
The Rh(III) complexes 18 and 19 ( Figure 6) feature a similar piano-stool geometry, with the xanthine-derivative C8-bound to the metal. The only other structurally characterized examples of Cp*Rh(III) complexes with xanthine-derived carbene ligands are those reported by Hahn containing 7-picolyl-or 7-imidazoly-substituted theobromine-derivatives [54].

1,3,7-Trimethyl-9-ethylxanthinium hydrogen sulfate (3HSO 4 )
A mixture of caffeine (3) (0.287 g, 1.480 mmol) and diethyl sulfate (388 µL, 2.96 mmol) was heated in an open vial to 130 • C for 2 h. After cooling to room temperature, a 3:7 mixture of acetone and toluene (ca. 10 mL) was added. Upon standing over night, a colorless solid deposited, which was isolated by filtration and was washed with a small amount of acetone. After drying in vacuum, 0.435 g (91%) of the product was obtained. 1

[Ag(NHC)Cl] (9)
A solution of 1Cl (0.05 g, 0.149 mmol) in CH 2 Cl 2 (7.5 mL) was treated with Ag 2 O (0.0174 g, 0.0751 mmol). After 4 h at room temperature most of the silver oxide had dissolved. The mixture was passed through Celite, and the filtrate was concentrated in vacuum. Addition of Et 2 O precipitated a colorless solid, which was isolated by filtration and was washed with Et 2 O. A colorless solid was obtained in 67% yield (0.0445 g). 1  This was prepared as described above using 3Cl (0.0387 g, 0.150 mmol) and Ag 2 O (0.0174 g, 0.0751 mmol). As a result, 0.0285 g (52%) of a colorless solid was obtained. 1

Conclusions
We present, herein, a simple method to ethylate various xanthine derivatives at position N9 using ethyl tosylate or diethyl sulfate. High yields of the pure xanthinium salts were obtained in short times with minimal work-up. The anions could be exchanged to give the corresponding PF 6 − and Cl − salts. The xanthinium PF 6 − salts reacted with Ag 2 O in the presence of NH 3 or Et 2 NH to furnish either silver carbene complexes with ammonia co-ligands or bis(carbene) silver compounds, respectively. The xanthinium chloride salts gave the corresponding neutral Ag-carbene complexes. These silver compounds were used successfully to transfer the carbene ligands to a variety of other metals including Au(I), Ru(II), Rh(I) and Rh(III). Work is ongoing to incorporate other groups into the xanthinebackbone by this approach and to examine possible applications of these metal-carbenes.
Supplementary Materials: The following are available online, Table S1: Crystallographic and refinement details for all X-ray structures reported herein. Figures S1-S70: NMR spectra of the compounds.