Pyrazolo[1,5-a]pyridines as p38 Kinase Inhibitors (original) (raw)
New fluorinating reagents. Dialkylaminosulfur fluorides
The Journal of Organic Chemistry, 1975
Middleton 2 N NaOH, brine), dried (MgSOd), and concentrated in uacuo. The residue, a red oil (7.4 g), was chromatographed on neutral I11 alumina made up in pentane. Elution by pentane gave 2.11 g which was discarded. Elution by ether gave 2-bis(tert-buty1thio)methylpyridine (3.05 g, 0.0113 mol, 11%) which was distilled in a short path apparatus: bp 80' (0.1 mm); ir (film) 1588 (s), 1568 (m), 1470 (s), 1432 (s), 1364 (s), 1154 (s), 990 (m), 742 (m), 718 (m) cm-'; uv X max (MeOH) 271 mfi (6 4480); nmr (CDCl3) 6 8.42 (broad d, 1, J
Perfluorinated Trialkoxysilanol with Dramatically Increased Brønsted Acidity
Chemistry – A European Journal, 2021
The Brønsted acidity of the perfluorinated trialkoxysilanol {(F 3 C) 3 CO} 3 SiOH is more than 13 orders of magnitude higher than that of orthosilicic acid, Si(OH) 4 , and even more for most previously known silanols. It is easily deprotonated by simple amines and pyridines to give the conjugate silanolates [OSi{OC(CF 3) 3 } 3 ] À , which possess extremely short SiÀ O bonds, comparable to those of silanones. Orthosilicic acid, Si(OH) 4 , is a very weak Brønsted acid. [1] The same holds true for organosilanols, R n Si(OH) 4-n , and alkoxysilanols, (RO) n Si(OH) 4-n (n = 1-3; R = alkyl, aryl), which can be regarded as organic derivatives or partial esters of Si(OH) 4. [2] Like orthosilicic acid, most small organosilanols and alkoxysilanols are sensitive towards self-condensation to give siloxanes and silica consisting of 2D or 3D networks of Si-OÀ Si linkages, which is of technical relevance for the curing of silicone resins and the sol-gel process. [3] The self-condensation is accelerated by heat as well as traces of acid and base. However, selfcondensation can be prevented by the judicious choice of mild reaction conditions and bulky substituents R, which allows the preparation of kinetically stabilized silanols that can be used for synthetic purposes, such as the preparation of well-defined metallasiloxanes containing SiÀ OÀ M linkages. [4] A prominent example is (t-BuO) 3 SiOH, which reacts with a variety of metals to give rise to thermolytic molecular precursors (TMPs) that upon heating produce multicomponent oxide materials, not accessible by the sol-gel process. [5] We have now set out to prepare a perfluorinated derivative of (t-BuO) 3 SiOH, which was achieved by two simple synthetic steps starting from commercially available starting materials. Thus, the reaction of SiCl 4 with three equivalents of NaOC(CF 3) 3 afforded {(F 3 C) 3 CO} 3 SiCl (1), the hydrolysis of which gave the silanol {(F 3 C) 3 CO} 3 SiOH (2) as low-melting crystals (Scheme 1). [6] The key feature in the crystal structure of 2 is the isolated silanol group, which, unlike that of the parent (t-BuO) 3 SiOH, [7] is not involved in hydrogen bonding (Figure 1). [8] Due to the high charge separation in 2 associated with the large number of fluorine atoms, it possesses a dramatically increased Brønsted acidity, compared to orthosilicic acid Si(OH) 4 and all previously known silanol species (see below). [9] For this reason, 2 can be readily deprotonated by weak and strong bases. Thus, the reaction of 2 with triethylamine, pyridine, lutidine andnbutyllithium provided the silanolates [Et 3 NH][OSi{OC(CF 3) 3 } 3 ] (3), [C 5 H 5 NH][OSi{OC(CF 3) 3 } 3 ] (4), [2,6-Me 2 C 5 H 3 NH][OSi{OC(CF 3) 3 } 3 ] (5) and [Li(C 6 H 4 F 2)OSi{OC(CF 3) 3 } 3 ] 2 (6) that were isolated as crystalline solids (Scheme 2 and Figure 1). [6] The deprotonation of silanols by simple amines and pyridines is unprecedented. [10] Usually, Si(OH) 4 [11] and all silanols are only known to form hydrogen-bonded complexes of the type OÀ H•••N, [12] which, for instance, has been utilized to buildup extended supramolecular networks. [13] In 3 and 5, the silanolate [OSi{OC(CF 3) 3 } 3 ]is associated with the triethylammonium ion, [Et 3 NH] + , and the lutidinium ion, [2,6-Me 2 C 5 H 3 NH] + , respectively, via a reverse, bipolar hydrogen bond of the type À O•••HÀ N + (Figure 1). [14] The donor-acceptor distances in 3 (2.518(2) Å) and 5 (2.512(4) Å) are indicative of strong hydrogen bonding. [12,15] This observation suggests that the silanolate [OSi {OC(CF 3) 3 } 3 ] À is still rather basic, which is in clear contrast to [a
Journal of Chemical and Pharmaceutical Research, 2012, 4 (7): 3377-3382
Journal of Chemical and Pharmaceutical …, 2012
were synthesized by series of reactions such as cyclization, deprotation, coupling and condensation. Newly synthesized compounds were characterized by spectroscopic techniques like NMR, IR, Mass spectrometry and elemental analysis. The compounds were tested to emphasize their activity against the fungi and pathogenic strains of bacteria. The compounds bearing fluoro, cyano and difluoromethoxy groups at para position showed competitive antifungal activity, while the compounds carrying either halogen or methyl substituent at ortho position showed significant antibacterial activity.
Org. Biomol. Chem., 2009
General details of equipment and techniques used are the same as those we have reported previously. 1 All reactions were carried out under an argon atmosphere, glassware was either flame dried or dried in the oven prior to use. All reactions were set up outside of a glovebox, including the weighing of solid substrates. Pd(PPh) 3 Cl 2 was supplied from Vertellus Specialties UK Ltd or prepared in house, 2 Pd(OAc) 2 was purchased from Aldrich, Pd 2 (dba) 3 was purchased from Alfa Aesar. t-Bu 3 P and D-t-BPF were purchased from Strem, PCy 3 was purchased from Molekula. All other reagents employed were of standard reagent grade, purchased from either Aldrich or Alfa Aesar and used without further purification. Anhydrous solvents were dried through a HPLC column on an Innovative Technology Inc. solvent purification system. All other solvents in this work were used without prior purification. Column chromatography was carried out using 40-60 µm mesh silica (Fluorochem). Thin-layer chromatography (TLC) was performed on 20 mm precoated plates of silica gel (Merck, silica gel 60F 254), visualisation was made using ultraviolet light (254 nm). NMR spectra were recorded on Bruker Avance-400 [ 1 H NMR (400 MHz), 13 C NMR (100 MHz), 11 B NMR (128 MHz)], Varian 500 [ 13 C NMR (125 MHz)], Varian VNMRS 700 [ 13 C NMR (175 MHz)] or Varian 200 [ 19 F NMR (188 MHz)] instruments, using deuterated solvent as a lock. Chemical shifts are quoted in ppm, relative to tetramethylsilane (TMS), using TMS or the residual solvent as internal reference for 1 H and 13 C NMR, and CFCl 3 as internal reference for 19 F NMR. Melting points were determined on a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Electron Impact (EI) mass spectra were recorded on a Thermo-Finnigan Trace with positive ionisation mode. Electrospray (ES +) mass spectra were recorded on a Micromass LCT mass spectrometer. Elemental analyses were obtained on an Exeter analytical Inc. CE-440 elemental analyser. Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is (c) The Royal Society of Chemistry 2009 S3 6-(Trifluoromethyl)-3-pyridylboronic acid (3) n-Butyllithium (2.5 M in hexane, 19.5 cm 3 , 49 mmol) was added to a mixture of 5-bromo-2-(trifluoromethyl)pyridine 1 (10.0 g, 44 mmol) and triisopropylborate (12.3 cm 3 , 53 mmol) in anhydrous THF (80 cm 3) at-78 °C under argon. The reaction was stirred at-78 °C for 3 h before warming gradually to-10 °C when the reaction was quenched with deionised water (100 cm 3). The organic solvent was removed in vacuo. The resulting aqueous phase was treated with solid NaOH to obtain pH 10, then washed with diethyl ether (50 cm 3) and acidified to pH 5 using acetic acid. The solution was extracted with EtOAc (200 cm 3) and evaporated to dryness in vacuo to yield 3 as a white solid (8.04 g, 95%): mp
ACS Medicinal Chemistry Letters
The amide (1.5 eq.), Pd2(dba)3 (5 mol%), XantPhos (10 mol%), cesium carbonate (3 eq.) and the 2chloropyridinylimidazole derivative (1 eq.) were dissolved under an atmosphere of argon in DMF (0.3 M). The reaction mixture was then stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to rt and sat. aq. NH4Cl solution was added. It was extracted with EtOAc (3x) and the combined organic layers were washed with sat. aq. NH4Cl solution (2x) and brine. After drying over anhydrous Na2SO4 the solvent was removed under reduced pressure and the compound was purified by flash chromatography.