Synthesis of Known and Previously Inaccessible Poly(pyrazolyl)Borates under Mild Conditions

Poly(pyrazolyl)borate ligands have been obtained through the reaction of highly reactive haloboranes with in situ formed pyrazolides under very mild conditions. This versatile synthetic method allows the selective synthesis of bis-, tris-, or tetrakis(pyrazolyl)borates. Furthermore, the method is compatible with the use of functional groups on the heterocyclic moieties of the poly(pyrazolyl)borates that were not accessible to date. Strongly encumbered sodium and thallium(I) poly(pyrazolyl)borates with a reduced donating ability have been obtained for the first time.


General information.
Haloboranes are reagents sensitive to hydrolysis. All transformations implying these reagents have been performed using common Schlenk techniques or in a glove box. Dichloroborane dimethylsulfide complex is obtained from Merck. A careful manipulation of this reagent is advised since while recently opened commercial reagent presents < 4 % of BCl 3 ꞏSMe 2 and < 4 % of BH 2 ClꞏSMe 2 , as checked by 1 H and 11 B-NMR, when handling the reagent, small amounts of auxiliary SMe 2 are lost through evaporation and a very slow decomposition through H/Cl exchange is observed. After a period of three months ca. 10 % of BCl 3 ꞏSMe 2 and 10 % of BH 2 ClꞏSMe 2 was quantified. This contamination must be inhibited to avoid the loss of selectivity on the borate formation reaction. This decomposition can be prevented storing the reagent in the fridge and adding small amounts of anhydrous SMe 2 periodically. BH 2 ClꞏSMe 2 reagent, also purchased from Merck, presented the same exchange process, and received identical treatment. Dimethylsulfide has an unpleasant odor and manipulation of its derivatives should be manipulated on a fuming hood. Solutions containing SMe 2 should be treated with sodium hypochlorite before their disposal. CAUTION! Thallium salts and their derivatives are highly toxic. All thallium containing compounds must be handled with care and disposed conveniently. Pyrazole 1j was obtained from VWR and used as received. Anhydrous toluene was dried with sodium, anhydrous Et 2 O and THF were dried with sodium using benzophenone as indicator prior to use. DMF was achieved anhydrous and used as received. Poly(pyrazolyl)borates are stable compounds against moisture. Deuterated chloroform, deuterated acetone and deuterated dimethylsulfoxide have been used as received. Siligel 60 (40-63 mm) from Merck was used for column chromatography purification. NMR analysis have been performed in a Bruker AvanceIII 300, a Bruker AV400 or a Bruker Neo500 spectrometer. NMR data have been processed using MestReNova TM and are expressed in ppm. Residual signals of deuterated solvents have been used as internal reference (CHCl 3 at 7.26 ppm in 1 H-NMR and CDCl 3 77.2 ppm in 13 C-NMR, CHDCl 2 at 5.32 ppm in 1 H-NMR and CD 2 Cl 2 53.8 ppm in 13 C-NMR, DMSO-d 5 at 2.50 ppm and DMSO-d 6 39.5 ppm in 1 H-NMR and 13 C-NMR respectively, acetone-d 5 at 2.05 ppm and acetone-d 6 at 29.8 ppm in 1 H-NMR and 13 C-NMR respectively, C 6 HD 5 at 7.16 pp in 1H-NMR and C6D6 at 128.1 ppm in 13 C-NMR). Internal equipment calibration was used for 11 B-NMR. IR spectra have been recorded on a Thermo Scientific Nicolet iS10 and processed with Omnic TM . IR frequencies have been rounded to 1 cm -1 . HRMS (+ESI) analysis have been performed in AB SCIEX TripleTOF™ 5600 LC/MS/MS System and data have been processed using PeakView TM . Acidic methanolic conditions used during HRMS analysis yielded the identification of protonated borates as [Tp x H+H] + , [Bp x H+H] + or [Tkp x H+H] + . MALDI-QTOF analyses were performed in a TIMS-TOFF Flex (Bruker) in MALDI operation, in reflector positive mode at 200-3500 m/z rang and a laser intensity of 40 % The analysis was performed in the proteomics facility of SCSIE University of Valencia. Elemental analyses have been performed in a Thermofisher Flashmart Eager 200. X ray single crystal structures have been measured on Oxford Diffraction Supernova or D8 Venture Diffractometers. The structures were solved through dual space methods using SHELXT S1 and SHELXL-2018 S2 .

3-adamantyl-4-nitro-1-H-pyrazole (1d).
3-adamantyl-4-nitro-1-H-pyrazole (1d). To a solution of 1-adamantanecarboxylic acid (1.8 g, 10 mmol, 1 eq.) in 10 mL anhydrous diethyl ether at -20 o C was added under argon 21 mL of a 1M solution of methyllithium in diethyl ether (21 mmol, 2.1 eq.). After 10 min stirring at that temperature, the reaction mixture is allowed to reach room temperature and stirred for additional 2 hours. The solution was carefully hydrolyzed with water (20 mL) and the phases separated. The aqueous phase was additionally extracted with diethyl ether (2 x 20 mL). Crude adamantyl methyl ketone was obtained in 1.73 g (9.7 mmol, 97 % yield) as a white solid and used without purification. A mixture of adamantyl methyl ketone (2.7 g, 15 mmol, 1 eq.) and ethyl formate (2.4 mL, 30 mmol, 2 eq.) was slowly added over a suspension of potassium hydride (0.7 g, 18 mmol, 1.2 eq.), previously washed with n-hexane, on 10 mL of anhydrous diethyl ether under argon. The mixture was gently refluxed for 30 minutes in an oil bath and stirred at room temperature for additional 1.5 hours. The reaction crude was carefully hydrolyzed with 1 mL of isopropyl ether and diluted with 50 mL of water. The aqueous phase was washed with diethyl ether (2 x 15 mL) and acidified with concentrated aqueous hydrochloric acid until pH 1-2. The product was the extracted with diethyl ether (3 x 20 mL). The acidic extracts were combined, washed with brine, dried over anhydrous MgSO 4 and concentrated to provide 1.53 g (7.4 mmol, 49 % yield) of crude 3-adamantyl-3-oxopropanal as a yellowish oil. The crude product was directly solved in SI-6 25 mL of ethanol and monohydrated hydrazine as added (0.36 mL, 7.4 mmol, 1 eq.). The yellow solution was refluxed for 4 hours in an oil bath. Once at room temperature, the solvent was evaporated and 1.42 g of crude 3-adamantyl-1-H-pyrazole were obtained as a yellowish solid (7 mmol, 94 % yield). Crude 3-adamantyl-1-H-pyrazole (810 mg, 4 mmol, 1 eq.) was solved in 4 mL of cold sulfuric acid. The solution was warmed to 60 o C in an oil bath and 65% aqueous nitric acid (0.45 mL, 4.4 mmol, 1.1 eq.) was added. After 4 h stirring at that temperature the mixture was allowed to cool down and poured onto 40 mL of iced water. Aqueous phase was extracted with AcOEt (5 x 25 mL). The organic phases were combined, washed with brine, dried over anhydrous MgSO 4 and concentrated. Crude 1d was purified through column chromatography using n-hexane:AcOEt 2:1 as eluent. Pure 3adamantyl-4-nitro-1-H-pyrazole (1d) was obtained in 67 % yield as a pale-yellow solid (662 mg, 2.56 mmol  ,7.22;N,15.84. Found: C,58.59;H,7.22;N,15.84.

4-carboxaldehyde-3-phenyl-1-H-pyrazole (1g).
4-carboxaldehyde-3-phenyl-1-H-pyrazole (1g) was prepared according to a described procedure. S8 To a solution of sodium acetate (0.53 g, 6.25 mmol, 1.3 eq.) and acetophenone (0.55 mL, 4.8 mmol, 1.eq.) in 90 mL of ethanol is added semicarbazide hydrochloride (0.56 g, 5 mmol, 1.05 eq.) in 90 mL of water. The resulting suspension is warmed to 100 o C in an oil bath for 6 h and stirred at room temperature for additional 18 h. Solvent is evaporated to yield crude semicarbazone as a white crystalline solid. Crude product is directly solved in 4.5 mL of anhydrous DMF and cooled to 0 o C. Phosphorous(V) oxychloride (1 mL, 10.7 mmol, 2.2 eq.) is added dropwise. After 30 min stirring at 0 o C the solution is warmed to 65 o C in an oil bath for 6 h. Once at room temperature, the mixture Is poured onto 30 mL of iced water and neutralized with aqueous 2M NaOH solution. The aqueous solution is extracted with AcOEt (3 x 20 mL). Organic phases were combined, washed with brine, dried over anhydrous MgSO 4 , and concentrated. Crude 1g is purified through crystallization from chloroform. Pure 4-carboxaldehyde-3-phenyl-1-H-pyrazole (1g) is obtained as a colorless crystalline solid (0.51 g, 2.97 mol, 51 % yield). mp:139-141 o C (described mp:145 o C) Its NMR data were consistent with literature values.

Optimization of 3a Na formation.
Table S1 summarizes the conditions assayed during the optimization of 3a Na synthesis. Dichloroborane was preferred over dibromoborane to facilitate the resulting salt removal through filtration due to the lower solubility of chloride salts in organic solvents compared to their bromide counterparts. Among commercially available dichloroboranes, the dimethyl sulfide complex was chosen as starting boron source due to its higher stability compared to the tetrahydrofuran complex. We selected 3-tertbutylpyrazole as standard heterocycle for reaction optimization. Preparation of 3a Na was firstly attempted in dichloromethane. In the absence of a base (entry 1) the reaction did not complete due to starting pyrazole protonation with the HCl evolved from the reaction between 1a and dichloroborane. Addition of triethylamine or CsOAc (entries 2 and 6) increased the reaction performance, but yield was still low. Furthermore, in the first case ammonium salt formed was difficult to remove from the reaction mixture. Use of DBU, DMAP or K 2 CO 3 (entries 3, 4, and 5) as base yielded complex mixtures due to the reaction between the boron source and the base. We explored then the formation in situ of sodium pyrazolide with NaH and its direct reaction with the haloborane. This alternative presented as an advantage the formation of NaCl as concomitant product, easy to filter off from the reaction media. Use of THF resulted in the reaction of the solvent with the haloborane under the reaction conditions providing an unidentified mixture of products (entries 7 and 12). Less coordinating toluene gave better results than donating diethyl ether able to form complexes with the starting borane reducing its reactivity (entries 10 and 11 vs entries 9). Extension of the reaction time from 2 hours to 24 hours gave the best result (entry 11). Equivalents of pyrazole and base were not further explored due to the good results obtained with the ideal ca. stoichiometric amounts. Conditions of entry 11 were chosen as standard conditions for all poly(pyrazolyl)borates prepared. These optimized conditions were used with small adaptations for the synthesis of bis-and tetrakis(pyrazolyl)borates. For Bp x (2) ligands pyrazole and base equivalents were reduced to 2.05 equivalents and BH 2 ClꞏSMe 2 used as boron source. Preparation of Tkp x (4) ligands was performed using 4.1 equivalents of pyrazole and base and BCl 3 ꞏSMe 2 .Satisfactory results were obtained in both cases.

General synthesis of thallium(I) hydrotris(pyrazolyl)borates (3 Tl )
Pyrazole 1a-j (12.1 mmol, 3.02 eq.) was solved in 40 mL of anhydrous toluene and cooled to 0 o C on an ice bath. Sodium hydride (60% dispersion in mineral oil, 484 mg, 12.1 mmol, 3.02 eq.) was added at once. After 10 min stirring at that temperature, dichloroborane dimethyl sulfide complex (0.46 mL, 4 mmol, 1 eq.) was quickly added. The resulting suspension was stirred at room temperature for 24 h. Toluene was evaporated and replaced with 30 mL tetrahydrofuran. Thallium(I) acetate (1.58 g, 6 mmol, 1.5 eq.) was added and the suspension stirred at room temperature for 2.5 h. Precipitate was removed through filtration and washed twice with 10 mL THF. The filtrates were combined and evaporated, and the white solid obtained washed with n-hexane (3 x 10 mL), and methanol (3 x 15 mL), and dried under vacuum on a rotatory pump to yield pure thallium(I) hydrotris(pyrazolyl)borate 3a Tl , 3b Tl , 3c Tl , 3d Tl , 3e Tl , and 3f Tl . Sodium complexes were isolated for 3g Na and 3h Na .  Single crystals susceptible for its study through X ray diffraction were obtained through slow evaporation of a solution of 3b Na (OH 2 ) in AcOEt/n-hexane.

Caracterization of pyrazabole derivatives from 1e-f
For pyrazoles 1e-f the preparation of the corresponding 2e-f Tl complexes under standard conditions provided the expected complexes in low yields mixed with the corresponding pyrazabole compounds already described by S. Trofimenko with other substituents. 13 Enriched samples of pyrazaboles susceptible for NMR identification were obtained through column chromatography using n-hexane:DCM 10:1 to 1:1 as eluent.  9,139.8,138.0,135.6,128.4,124.9,95.3,21.4,20.2;

General synthesis of sodium tetrakis(pyrazolyl)borates (4 Na )
Pyrazole 1a-f (4.1 mmol, 4.1 eq.) was solved in 15 mL of anhydrous toluene and cooled to 0 o C on an ice bath. Sodium hydride (60% dispersion in mineral oil, 164 mg, 4.1 mmol, 4.1 eq.) was added at once. After 10 min stirring at that temperature, trichloroborane dimethyl sulfide complex (180 mg, 1 mmol, 1 eq.) was added at once. The resulting suspension was stirred at room temperature for 24 h. Toluene was evaporated. Crude 4 Na was washed with n-hexane (3 x 10 mL). Non reacted pyrazole was removed by heating at 100 o C under vacuum. Pure sodium tetrakis(pyrazolyl)borates 4a-f Na were obtained as white solids. NMR analysis shows the inequivalence of the four pyrazole rings. Elemental analysis indicates that these anions often act as doubly bidentated ligands. Single crystals susceptible for its study through X ray diffraction were obtained through slow evaporation of a solution of 4f Tl in AcOEt/n-hexane.

9.
Single crystal X ray structure determination for 2c Tl , 3b Na (OH 2 ), and 4f Tl 9.1 X-ray crystal structure of 2c Tl The molecular structure shows a symmetric Bp ligand 2c chelated to the thallium atom. The thallium centre adopts an angular dicoordinated geometry with a N-Tl-N angle of 74.66(9) o ( Figure S1). The six member metallacycle formed adopts a boat conformation with a Tl(1)ꞏꞏꞏB(1) distance of 3.3006(48) Å. This metallacycle boat conformation is present in all eleven BpTl X-ray structures deposited in CCDC showing a TlꞏꞏꞏB distance range of 3.12-3.83 Å. 14 The presence of a weak intramolecular [TlꞏꞏꞏH-B] agostic interaction [TlꞏꞏꞏH 2.67(5) Å and TlꞏꞏꞏH-B 115(3) o ] could favor the metallacycle boat conformation. This [TlꞏꞏꞏH-B] interaction has been previously described and is present in all the reported BpTl structures, with TlꞏꞏꞏH distance and TlꞏꞏꞏH-B angle ranges of 2.25-3.58 Å and 97.0-127.6 o , respectively (Table S2). 4, T = 120(2) K,  = 0.71073 Å, Dcalc = 1.889 g/cm 3 ,  = 8.330 cm -1 , 33523 reflections measured, 7680 unique (Rint = 0.0406), colourless prism of 0.18 x 0.14 x 0.12 mm size, crystal structure solved by dual space methods with all non-hydrogen atoms refined anisotropically on F 2 using the programs SHELXT-2018 and SHELXL-2019. 1,2 Hydrogen atoms were included using a riding model or as rigid methyl groups. GOF = 1.127, R (F o , I > 2(I)) = 0.0345, Rw (F o 2 , all data) = 0.0877. The molecular structure shows the sodium atom coordinated to a symmetric  3 -Tp ligand 3b and a water molecule ( Figure S2). The sodium centre adopts a distorted tetrahedral geometry. The molecule presents a plane of symmetry containing the O-NaꞏꞏꞏB axis and one of the pyrazol moieties [N(11)-C (15)