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Innovative industrial technology starts with iodine
Published in Tatsuo Kaiho, Iodine Made Simple, 2017
One compound formerly used as an organic iodinating agent is N-iodosuccinimide (NIS). 1,3-Diiodo-5,5′-dimethylhydantoin (DIH) is an iodinating agent synthesized from iodine monochloride and dimethylhydantoin.
Chemical Synthesis of Core Structures
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
A different approach to the synthesis of the heptose-Kdo region related to important epitopes of lipooligosaccharides from Neisseria meningitidis was developed by van Boom’s group on the basis of iodonium ion-promoted glycosidations of thioglycosides (51–53). A thioglycoside group may be maintained as a temporary protection for the anomeric center through multistep reaction sequences, yet it may be selectively activated to serve as a versatile anomeric leaving group for glycosidation (Fig. 6). Thus, an aglyconic spacer-arm unit was introduced via glycosylation of N-benzyloxycarbonyl (Z) protected 3-aminopropanol with methyl or ethyl 2-thioglycosides of Kdo in the presence of N-iodosuccinimide (NIS) and catalytic amounts of triflic acid (TfOH) in yields of 50–80%, albeit with low anomeric selectivity not exceeding a ratio of 3:1 in favor of the a-anomer (51). Transformation of the protecting groups gave the 4-O-benzyl-7,8-O-isopropylidene-protected Kdo acceptor 44, which was reacted with the ethyl 1-thioheptopyranosyl donor 43 under promotion with NIS/TfOH to furnish the α-(l-→5)-linked disaccharide 45 in excellent yield (87%) and anomeric stereo-control. Deprotection of 45 was effected in three steps, namely deacetonation in acetic acid, debenzoylation, and catalytic hydrogenolysis on palladium-carbon, which gave, after Sephadex S-100 chromatography, the homogeneous disaccharide l-α-d-Hepp-(l→5)-α-Kdo-2-O-(CH2)3NH2 46. Proceeding toward epitopes containing also outer core determinants, the 2,3-O-isopropylidene-protected heptosyl donor 47 allowing for selective chain extension at O-4 was obtained from the ethyl 1-thio heptopyranosyl donor 43 in a few steps. Subsequent trimethylsilyl triflate-mediated glycosylation of 47 with the benzoyl-protected lactosyl trichloroacetimidate 48 afforded the trisaccharide ethyl 1-thioglycoside 49 in 91% yield. Exchange of the 2,3-O-isopropylidene group for benzoates afforded the trisaccharide donor 50, which was coupled in the presence of the thiophilic promoter system NIS/TfOH with the Kdo acceptor 44 to give the a -(l→5)-linked tetrasaccharide derivative 51 in excellent yield (55%). Removal of the blocking groups and final purification of the product on Sephadex S-100 furnished the tetrasaccharide p-d-Galp-(1→4)-β-d-G1cp-(1 →4)-l-α-DHepp-(l→5)-α-Kdo-2-O-(CH2)3NH252 corresponding to inner core determinant from N. meningitidis immunotypes L1–L9, which was subsequently used for the preparation of a synthetic vaccine.
Synthesis, antibacterial and anticancer activity, and docking study of aminoguanidines containing an alkynyl moiety
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
The synthesis of two series of aminoguanidine-linked alkynyl derivatives followed the general pathway outlined in Scheme 1 using 4-ethynylbenzaldehyde as starting material. The reaction of 4-ethynylbenzaldehyde with substituted-iodobenzenes in the presence of triethylamine (TEA), CuI and Pd(PPh3)Cl2 in tetrahydrofuran (THF) produced 4-(substituted-phenylethynyl)benzaldehyde (2a–2j) under the protection of nitrogen. The reaction of 4-ethynylbenzaldehyde with N-iodosuccinimide in the presence of AgNO3 in acetone produced 4-(iodoethynyl)benzaldehyde (4). The obtained 4-(iodoethynyl)benzaldehyde reacted with ethynylbenzenes in the presence of TEA, CuI and Pd(PPh3)Cl2 in THF yielding 4-((substituted-phenyl)buta-1,3-diyn-1-yl)benzaldehyde (5a–5k) under the protection of nitrogen. The target compounds 3a–3j and 6a–6k were prepared by the condensation of 2a–2j or 5a–5k with hydrazinecarboximidamide carbonate, respectively. Finally, the structures of the target compounds were characterised by 1H-NMR, 13C-NMR, and high-resolution mass spectrometry.
Iodine-mediated one-pot intramolecular decarboxylation domino reaction for accessing functionalised 2-(1,3,4-oxadiazol-2-yl)anilines with carbonic anhydrase inhibitory action
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Srinivas Angapelly, P. V. Sri Ramya, Rohini Sodhi, Andrea Angeli, Krishnan Rangan, Narayana Nagesh, Claudiu T. Supuran, Mohammed Arifuddin
We commenced our investigation with a reaction using an equimolar ratio of isatin and 4-methyl benzohydrazide as model substrates using molecular iodine (100 mol%) and Cs2CO3 (1.0 equiv.) in DMSO at 100 °C (Table 1). The desired product was obtained in 71% yield (Table 1, entry 1). No product was obtained in the absence of either catalyst or base which suggests that an iodine/base combination is required for the reaction to occur (Table 1, entries 2–4). Exploring the possibility for improving the reaction efficiency, the effect of other alkali metal carbonates/other bases on the reaction efficiency was then examined. The transformation underwent smoothly in the presence of K2CO3 to afford the desired product 3a in 80% yield after 12 h (Table 1, entry 5),whereas other bases, such as Na2CO3, K3PO4, and NaHCO3 were found to be less effective (Table 1, entries 6–8). With an attempt to further optimise the yield of the product, we investigated the influence of various iodine reagents. TBAI, N-iodosuccinimide (NIS) and KI gave poor to moderate yields, i.e. of 18, 45, and 35%, respectively (Table 1, entries 9–11). However, phenyliodine(III) diacetate (PIDA), and hydroxy(tosyloxy)iodobenzene (HITB) did not at all lead to the formation of the desired product 3a (Table 1, entries 12–13). Furthermore, a series of experiments were also carried out in various other solvents, such as, DMF, MeCN, THF, 1,4-dioxane, EtOH, MeOH, and H2O. From the obtained results, it can be seen that the use of DMSO and DMF at 120 °C gave an almost identical result, albeit with a lower yield in the latter case (Table 1, entries 14–15), whereas, MeCN, THF, 1,4-dioxane, EtOH, MeOH, and H2O at reflux temperatures proved to be less effective (Table 1, entries 16–21). Furthermore, the iodine loading was also investigated in this reaction, and the yields were dropped to 59 and 52 at 0.75 and 0.5 equiv., respectively (Table 1, entries 22–23) of I2, and to a significantly lower value of 33% at 0.2 mol equiv. of I2 (Table 1, entry 24). We also conducted a control experiment under nitrogen atmosphere, but the yield under these conditions was diminished to 25%. This indicated that atmospheric O2 played an important role in the above transformation. Surprisingly, when the same reaction was performed under microwave irradiation gave better yield of 3a (91%) within a short span of time (40 min). Indeed, the use of microwave technology has never been mentioned in the literature for the synthesis of 2–(1,3,4-oxadiazol-2-yl)aniline derivatives up until now. Thus the foregoing experiments led to the conclusion that the conditions used under entry 25 of Table 1 are the optimal ones for the reaction and, therefore, the microwave conditions were employed subsequently for all further reactions to generate compounds 3a–3u/6a–6g/8a–o.
Benzofuran–appended 4-aminoquinazoline hybrids as epidermal growth factor receptor tyrosine kinase inhibitors: synthesis, biological evaluation and molecular docking studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Malose J. Mphahlele, Marole M. Maluleka, Abimbola Aro, Lyndy J. McGaw, Yee Siew Choong
The benzofuran-aminoquinazolines 10a–j and the corresponding intermediates were prepared following the reaction sequence outlined in Scheme 2 and their yields are listed in Table 1. The initial task of this investigation involved the preparation of 5-bromo-2-hydroxy-3-iodoacetophenone 5 to serve as a substrate for the tandem palladium catalyzed Sonogashira cross-coupling with arylacetylenes and subsequent endo-dig Csp–O cyclization to afford the requisite 7-acetyl–substituted 2-aryl-5-bromobenzofurans. Recourse to the literature revealed that 5-bromo-2-hydroxy-3-iodoacetophenone has been prepared before by treatment of the commercially available 5-bromo-2-hydroxyacetophenone with pyridinium iodochloride (1 equiv.) in methanol under reflux for 2 h19. We opted for the use of commercially available 2-hydroxyacetophenone 4 (purchased from Sigma-Aldrich) as a substrate for initial halogenation with 1 equivalent of N-bromosuccinimide (NBS) in acetic acid under reflux for 1.5 h to afford 5-bromo-2-hydroxyacetophenone in 59% yield (Scheme 2). The latter was, in turn, subjected to iodination with N-iodosuccinimide (NIS) in acetic acid under reflux for 1 h to afford 5-bromo-2-hydroxy-3-iodoacetophenone 5. Sonogashira cross-coupling of 5 with terminal acetylenes afforded the corresponding 1–(5-bromo-2-arylbenzofuran-7-yl)ethanones 6a–e in appreciable yields. Oximation of compounds 6a–e with hydroxylamine hydrochloride in pyridine under reflux for 1 h followed by aqueous work-up and recrystallization afforded the corresponding oximes 7a–e. The Beckmann rearrangement of these oximes with 20% mol equivalent of trifluoromethanesulfonic acid (triflic acid, TfOH) in acetonitrile under reflux for 4 h afforded compounds characterized using a combination of NMR, IR and mass spectrometric techniques as the 7-aminobenzofuran derivatives 8a–e. The latter are the result of the initial Beckmann rearrangement via aryl carbon migration followed by an in situ acid-mediated hydrolysis of the intermediate 7-acetamido-2-aryl-5-bromobenzofuran derivatives. Hitherto, Cacchi et al.23 had reported a method for the synthesis of the 7-aminobenzofuran derivatives which makes use of the Buchwald-Hartwig C–N bond formation of the intermediate 7-bromobenzofurans with the primary and secondary amines. Despite what looks like a simple molecular framework, we found that no attempts have been made before towards the synthesis of benzofuran-quinazoline hybrids in which the two pharmacophores are linked through a heteroatom bridge. Consequently, we reacted the nucleophilic 7-aminobenzofurans 8a–e with the electrophilic 6-bromo-4-chloro-2–(4-halogenophenyl)quinazoline 9a (X = F) or 9 b (X = Cl) in the presence of 5% HCl in isopropanol (iPrOH) under reflux for 4 h to afford the corresponding benzofuran-aminoquinazoline hybrids 10a–e or 10f–j, respectively. Dechloroamination was confirmed by the presence of increased number of proton and carbon signals in the aromatic region of the 1H- and 13C-NMR spectra of compounds 10a–j.