A New Rapid and Speciﬁc Iodination Reagent for Phenolic Compounds

: A new rapid iodination reagent, N 1 ,N 3 ,N 5 - tris[(2,4,6-trimethylpyridine)iodo(I)]-2,4,6- triphenyl-s -triazine trihexaﬂuorophosphate, was synthesized in a modiﬁcation of the established synthesis of 2,4,6-triiodo-3,5-dimethylphenol in the presence of bis(2,4,6-trimethylpyridine)iodo(I) hexaﬂuorophosphate and used for the precise post-modiﬁcation of mono-and trisubstituted phenyl compounds. We performed triple iodinations with our new phenyl-based compounds as a proof of principle of selected types of phenols, ß-sympatholytic agents and their spin-labeled derivatives, which can be employed in electron paramagnetic resonance (EPR) spectroscopy. The new rapid iodination reagent can be employed with high reactivity and regioselectivity.


Introduction
Multistep reactions of the Sandmeyer type using diazonium salt formation are a wellestablished method of achieving some 'hard to access' substitution patterns of iodoarenes that are not achievable via direct substitution [1- 6]. Beyond these reactions, a broad variety of metal-based and metal-free one-pot (or two-step) syntheses to form arene C-I bonds with appropriate regioselectivity have been developed in the past few decades .
Derived from the established iodination reagent 2 (see Figure 1) [35], 1 serves as tripleiodonium-ion (I + ) donor and at identical iodine turnover, three activated I + are available per used mole of reagent 1 instead of one I + (as is the case for 2), and we can achieve very high yields, as shown below (95-99%). In 1, both reactants used for its synthesis, 2,4,6-trimethylpyridine as a water-soluble liquid and 2,4,6-triphenyl-s-triazine as a waterinsoluble solid, are recyclable after completion of the iodination process. The recyclability of both reactants is an important environmental advantage and it reduces the follow-up costs in the recovery of 1. A further reason for the choice of the water-insoluble 2,4,6-triphenyl-striazine instead of the water-soluble 2,4,6-trimethyl-s-triazine as a reactant is that the phenyl groups around the basic triazine compound have experimentally been shown to stabilize each I + better than the corresponding methyl groups in 2. We ascribe this stabilization to the interactions between iodonium ions and the aromatic phenyl group π-electron system Scheme 1. Synthetic strategy for the s-triazine-based iodination reagent, N 1 ,N 3 ,N 5 -tris[(2, 4,6-tr thylpyridine)iodo(I)]-2,4,6-triphenyl-s-triazine trihexafluorophosphate (1) via its precu N 1 ,N 3 ,N 5 -tris[(2,4,6-trimethylpyridine)silver(I)]-2,4,6-triphenyl-s-tri-azine trihexafluorophosp Yields of each reaction step are given in brackets.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.

Materials and Methods
Materials. All commercial chemicals were purchased from Sigma-Aldrich Chemie GmbH (St. Louis, MO, USA), TCI Deutschland GmbH (Eschborn, Germany), AppliChem GmbH (Darmstadt, Germany), Carl Roth GmbH + Co. KG (Karlsruhe, Germany), VWR International GmbH (Radnor, PA, USA) and ACROS Organics (Verona, Italy) in their highest purity grade and were used without further purification unless otherwise noted.
Instrumental techniques. (a) NMR spectroscopy. The 1 H-and 13 C(APT)-NMR spectra were measured at 27 • C with an Agilent Technologies VNMRS 400 MHz NMR spectrometer or Agilent Technologies DD2 500 MHz NMR spectrometer, in which the referencing was carried out to the signal of the deuterated solvent (CDCl 3 , DMSO-d6 or THF-d8). The chemical shifts (δ-values) of the NMR data are given in ppm relative to the internal standard tetramethylsilane (TMS). All 13 C(APT)-NMR experiments were always measured under proton decoupling. The measured values were indicated as follows: Experiment. NMR (measuring frequency, solvent): δ [ppm] = δ-value (spin multiplicity, coupling constant(s), number of nuclei, if necessary). The coupling constants ( x J a,b ) are given in Hertz (Hz), in which the superscript number x gives the estimated number of bonds between the coupling nuclei a and b. The spin multiplicity was classified by the following symbols: s = singlet, d = doublet, dd = doublet of doublet, ddd = doublet of doublet of doublet, t = triplet, tt = triplet of triplet, td = triplet of doublet, q = quartet, quin = quintet, sext = sextet, sept = septet, m = multiplet. (b) FD mass spectrometry (MS). The field desorption (FD) mass spectra were recorded on a Fisons Instruments Field Sector Mass Spectrometer Instruments VG ZAB 2-SE-FPD at an applied voltage of 8 kV. In addition to the measured m/z-values, the respective associated signal intensities are given in % in parentheses and the type of positively charged molecular ions. Furthermore, the FD method is particularly well suited for the characterization of non-polar molecules, since fragmentation of the molecular ions does not occur. Prior to each measurement,~2 mg of the sample was dissolved in 200 µL of the respective solvent (DCM or THF). Three equal drops of the resulting homogeneous solution were fixed on a freshly drawn, slightly roughened tungsten (W-) wire that was attached on an appropriate guide tube. Before transfer of the guide tube into the high-vacuum measuring cell, the solvent residues on the W-wire were removed by applying a fore-vacuum. After the transfer of the guide tube in the high-vacuum measuring cell and application of an accelerating voltage (8 kV), the now-ionized sample was measured. The signal intensities of the generated analyte ions could be detected using a preset acetone signal. (c) Elemental analysis (EA). The elemental composition of all synthesized compounds was mainly investigated in terms of their content of carbon (C), hydrogen (H), nitrogen (N) and, if available, sulfur (S) using a CHNS 932 elemental analyzer (Leco Corporation). CHNS determination of all anhydrous substances (each~5 mg) was carried out in triplicate, with respect to all isolated solid in a finely pulverized state. All analysis results are arithmetic averages of all triply determined analysis values of the respective examined substance. (d) FTIR spectroscopy. The Fourier transform (FT) infrared (IR) spectra were recorded at RT and 256 scans with a Bruker Vector 22 FTIR spectrometer. For the production of 13 mm KBr pellets was used a hydraulic pump and an associated pressing tool from the company Perkin-Elmer. During the measurement, the KBr pellet was permanently flushed with a stream of dry air, in order to counteract an air moisture influence that could interfere with the sample measurement. Exclusively dry KBr was used for sample preparation. The KBr pellets were pressed using a sample concentration of~1.5 mg sample per 150 mg KBr. The FTIR spectra were interpreted using OMNIC Spectra Software. The evaluation of the recorded FTIR spectra was performed according Synthetic strategy of 1 and its precursor. Synthesis of N 1 ,N 3 ,N 5 -tris[(2,4,6-trimethylpyridine)silver(I)]-2,4,6-triphenyl-s-triazine trihexafluorophosphate. A total of 10.2 g (0.06 mol, 3 eq.) of silver nitrate and 11.1 g of potassium hexafluorophosphate (~0.06 mol, 3 eq.) were dissolved (partly suspended) in~200 mL of absolute EtOH at RT under continuous stirring. Subsequently, a solution of 2,4,6-triphenyl-s-triazine (6.2 g, 0.02 mol, 1 eq.) dissolved in~80 mL of absolute EtOH and a solution of 2,4,6-trimethylpyridine (8 mL, 0.06 mol, 3 eq.) also dissolved in~80 mL of absolute EtOH were simultaneously and slowly added dropwise to the stirred reaction mixture over a period of about 15 min. After stirring of the resulting exothermic reaction mixture for 1 h at RT, the precipitated solid was filtered using a Buchner funnel, washed with plenty of H 2 O dd and freeze-dried for 24 h.
All reactions (see entries 1-6) give one main product with triple iodination (see entries 1-6) in a short amount of time (5-10 min) with high yields (95-99%) and a specific regioselectivity of each attached (o-, p-, m-) iodine atom under mild reaction conditions (RT). Again, all six products are characterized in detail (see the SM).
Finally, we could show that one eq. of 1 works quickly (5-10 min) at RT in the presence of all the selected substrates using dry CH 2 Cl 2 and in a regioselective manner since the use of one eq. of 1 leads to only one o-, m-and p-triiodinated main product (see Table 1) with very good yields (95-99%). In the previous work of Brunei et al. [35], 2,4,6-triiodo-3,5dime-thylphenol was easily synthesized with an excellent yield (95%) using three eq. of 2 and dry CH 2 Cl 2 as a solvent under mild reaction conditions (RT, 10 min). Our synthesis of the same modified phenol was achieved in the presence of one eq. of 1 using the same dry solvent under mild reaction conditions (see Table 1, entry 2), with a 99% yield. Yet, we refrain from interpreting the small difference in overall yield as significant, as it could also be due to differences in purification efficiency.

Supplementary Materials:
The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/org4020011/s1. Detailed synthetic descriptions including appropriate characterizations of 1 and its argentiferous precursor as well as all compounds synthesized with 1 (Table 1)