Search results
Search for "isothiazole" in Full Text gives 10 result(s) in Beilstein Journal of Organic Chemistry.
Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors
- Jens Frackenpohl,
- David M. Barber,
- Guido Bojack,
- Birgit Bollenbach-Wahl,
- Ralf Braun,
- Rahel Getachew,
- Sabine Hohmann,
- Kwang-Yoon Ko,
- Karoline Kurowski,
- Bernd Laber,
- Rebecca L. Mattison,
- Thomas Müller,
- Anna M. Reingruber,
- Dirk Schmutzler and
- Andrea Svejda
Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46
- 1,8-naphthyridine scaffold can also be formally substituted by an isothiazole group, as can be seen in isothiazolo[3,4-b]pyridine 6 [15]. Thus, several bicyclic heteroaromatic motifs containing two nitrogen atoms serve as structural surrogates of cinmethylin (1), bearing a substituted 7-oxabicyclo
Graphical Abstract
Scheme 1: Selected known inhibitors 1–3 of acyl-ACP thioesterases (belonging to the protein family of FATs) a...
Scheme 2: Preparation of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines 7a–c and 13a–c via iron-mediated sulfur rem...
Scheme 3: Evaluation of potential side reactions in the borane-mediated preparation of 2,3-dihydro[1,3]thiazo...
Figure 1: Preemergence efficacy of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine-based FAT inhibitors 7b, 7c, and 1...
Figure 2: Preemergence efficacy of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine-based FAT inhibitors 7b, 7c, and 1...
Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes
- Wenqing Hao,
- Long Wang,
- Jinlei Zhang,
- Dawei Teng and
- Guorui Cao
Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29
- benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes (Scheme 1). Results and Discussion To initiate our studies, 3-ethylbenzo[d]isothiazole 1,1-dioxide (1a) and α-halogeno hydrazone 2a were selected as the model substrates. Our aim was to explore the possibility of enamine–iminium tautomerism of N-sulfonyl
- reaction of 3-ethylbenzo[d]isothiazole 1,1-dioxide (1a, 1.0 g) and α-halogeno hydrazone 2a (2.1 g) afforded 3aa (2.0 g) in 91% yield (Scheme 3) [34]. Finally, we focused on the transformation of 3aa. When 3aa was treated with KOH and H2O in methanol at 60 °C, the 3,3-disubsitituted-1,2-benzothiazin-4-one
- bond under basic conditions. Finally, the ring expansion led to intermediate C which was then hydrolyzed to 4aa. Conclusion In conclusion, we have developed a [4 + 2] annulation reaction of 3-substituted benzo[d]isothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes for the efficient preparation of
Graphical Abstract
Scheme 1: Comparision of previous work with this work.
Scheme 2: The effects of substituent groups on the [4 + 2] annulation reaction. Reaction conditions: 1 (1.0 m...
Scheme 3: Gram-scale synthesis of 3aa.
Scheme 4: The transformation of 3aa.
Scheme 5: The reaction mechanism of the reaction from 3aa to 4aa.
Development of N-F fluorinating agents and their fluorinations: Historical perspective
- Teruo Umemoto,
- Yuhao Yang and
- Gerald B. Hammond
Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123
- reagent 27-2 in good to high yields [90]. In addition, Takeuchi et al. reported that optically active N-fluorosultams, (R)- and (S)-N-fluoro-3-cyclohexyl-3-methyl-2,3-dihydrobenzo[1,2-d]isothiazole 1,1-dioxides 27-6 (Scheme 61) were efficient reagents for the asymmetric fluorination of enolates [91]. To
Graphical Abstract
Scheme 1: Fluorination with N-F amine 1-1.
Scheme 2: Preparation of N-F amine 1-1.
Scheme 3: Reactions of N-F amine 1-1.
Scheme 4: Synthesis of N-F perfluoroimides 2-1 and 2-2.
Scheme 5: Synthesis of 1-fluoro-2-pyridone (3-1).
Scheme 6: Fluorination with 1-fluoro-2-pyridone (3-1).
Figure 1: Synthesis of N-F sulfonamides 4-1a–g.
Scheme 7: Fluorination with N-F reagent 4-1b,c,f.
Scheme 8: Fluorination of alkenyllithiums with N-F 4-1h.
Scheme 9: Synthesis of N-fluoropyridinium triflate (5-4a).
Scheme 10: Synthetic methods for N-F-pyridinium salts.
Figure 2: Synthesis of various N-fluoropyridinium salts. Note: athis yield was the one by the improved method...
Scheme 11: Fluorination power order of N-fluoropyridinium salts.
Scheme 12: Fluorinations with N-F salts 5-4.
Scheme 13: Fluorination of Corey lactone 5-7 with N-F-bis(methoxymethyl) salt 5-4l.
Scheme 14: Fluorination with NFPy.
Scheme 15: Synthesis of the N-F reagent, N-fluoroquinuclidinium fluoride (6-1).
Scheme 16: Fluorinations achieved with N-F fluoride 6-1.
Scheme 17: Synthesis of N-F imides 7-1a–g.
Scheme 18: Fluorination with (CF3SO2)2NF, 7-1a.
Scheme 19: Fluorination reactions of various substrates with 7-1a.
Scheme 20: Synthesis of N-F triflate 8-1.
Scheme 21: Synthesis of chiral N-fluoro sultams 9-1 and 9-2.
Scheme 22: Fluorination with chiral N-fluoro sultams 9-1 and 9-2.
Scheme 23: Synthesis of saccharin-derived N-fluorosultam 10-2.
Scheme 24: Fluorination with N-fluorosultam 10-2.
Scheme 25: Synthesis of N-F reagent 11-2.
Scheme 26: Fluorination with N-F reagent 11-2.
Scheme 27: Synthesis and reaction of N-fluorolactams 12-1.
Scheme 28: Synthesis of NFOBS 13-2.
Scheme 29: Fluorination with NFOBS 13-2.
Scheme 30: Synthesis of NFSI (14-2).
Scheme 31: Fluorination with NFSI 14-2.
Scheme 32: Synthesis of N-fluorosaccharin (15-1) and N-fluorophthalimide (15-2).
Scheme 33: Synthesis of N-F salts 16-3.
Scheme 34: Fluorination with N-F salts 16-3.
Figure 3: Monofluorination with Selectfluor (16-3a).
Figure 4: Difluorination with Selectfluor (16-3a).
Scheme 35: Transfer fluorination of Selectfluor (16-3a).
Scheme 36: Fluorination of substrates with Selectfluor (16-3a).
Scheme 37: Synthesis of chiral N-fluoro-sultam 17-2.
Scheme 38: Asymmetric fluorination with chiral 17-2.
Figure 5: Synthesis of Zwitterionic N-fluoropyridinium salts 18-2a–h.
Scheme 39: Fluorinating power order of zwitterionic N-fluoropyridinium salts.
Scheme 40: Fluorination with zwitterionic 18-2.
Scheme 41: Activation of salt 18-2h with TfOH.
Scheme 42: Synthesis of NFTh, 19-2.
Scheme 43: Fluorination with NFTh, 19-2.
Scheme 44: Synthesis of 3-fluorobenzo-1,2,3-oxathiazin-4-one 2,2-dioxide (20-2).
Scheme 45: Fluorination with 20-2.
Scheme 46: Synthesis of N-F amide 21-3.
Scheme 47: Fluorination with N-F amide 21-2.
Scheme 48: Synthesis of N,N’-difluorodiazoniabicyclo[2.2.2]octane salts 22-1.
Scheme 49: One-pot synthesis of N,N’-difluoro-1,4-diazoniabicyclo[2.2.2]octane bistetrafluoroborate salt (22-1d...
Figure 6: Fluorination of anisole with 22-1a, d, e.
Scheme 50: Fluorination with N,N’-diF bisBF4 22-1d.
Scheme 51: Synthesis of bis-N-F reagents 23-1–5.
Scheme 52: Fluorination with 23-2, 4, 5.
Figure 7: Synthesis of N,N’-difluorobipyridinium salts 24-2.
Figure 8: Controlled fluorination of N,N’-diF 24-2.
Scheme 53: Fluorinating power of N,N’-diF salts 24-2 and N-F salt 5-4a.
Scheme 54: Fluorination reactions with SynfluorTM (24-2b).
Scheme 55: Additional fluorination reactions with SynfluorTM (24-2b).
Scheme 56: Synthesis of N-F 25-1.
Scheme 57: Fluorination of polycyclic aromatics with 25-1.
Scheme 58: Synthesis of 26-1 and dimethyl analog 26-2.
Scheme 59: Fluorination with reagents 26-1, 26-2, 1-1, and 26-3.
Scheme 60: Synthesis of N-F reagent 27-2.
Scheme 61: Synthesis of chiral N-F reagents 27-6.
Scheme 62: Synthesis of chiral N-F 27-7–9.
Scheme 63: Asymmetric fluorination with 27-6.
Scheme 64: Synthesis of chiral N-F reagents 28-3.
Scheme 65: Asymmetric fluorination with 28-3.
Scheme 66: Synthesis of chiral N-F reagents 28-7.
Figure 9: Asymmetric fluorination with 28-7.
Scheme 67: In situ formation of N-fluorinated cinchona alkaloids with SelectfluorTM.
Scheme 68: Asymmetric fluorination with N-F alkaloids formed in situ.
Scheme 69: Synthesis of N-fluorocinchona alkaloids with Selectfluor.
Scheme 70: Asymmetric fluorination with 30-1–4.
Scheme 71: Transfer fluorination from various N-F reagents.
Figure 10: Asymmetric fluorination of silyl enol ethers.
Scheme 72: Synthesis of N-fluoro salt 32-2.
Scheme 73: Reactivity of N-fluorotriazinium salt 32-2.
Scheme 74: Synthesis of bulky N-fluorobenzenesulfonimide NFBSI 33-3.
Scheme 75: Comparison of NFSI and NFBSI.
Scheme 76: Synthesis of p-substituted N-fluorobenzenesulfonimides 34-3.
Figure 11: Asymmetric fluorination with 34-3 and a chiral catalyst 34-4.
Scheme 77: 1,4-Fluoroamination with Selecfluor and a chiral catalyst.
Figure 12: Asymmetric fluoroamination with 35-5a, b.
Scheme 78: Synthesis of Selectfluor analogs 35-5a, b.
Scheme 79: Synthesis of chiral dicationic DABCO-based N-F reagents 36-5.
Scheme 80: Asymmetric fluorocyclization with chiral 36-5b.
Scheme 81: Synthesis of chiral 37-2a,b.
Scheme 82: Asymmetric fluorination with chiral 37-2a,b.
Scheme 83: Asymmetric fluorination with chiral 37-2b.
Scheme 84: Reaction of indene with chiral 37-2a,b.
Scheme 85: Synthesis of Me-NFSI, 38-2.
Scheme 86: Fluorination of active methine compounds with Me-NFSI.
Scheme 87: Fluorination of malonates with Me-NFSI.
Scheme 88: Fluorination of keto esters with Me-NFSI.
Scheme 89: Synthesis of N-F 39-3 derived from the ethylene-bridged Tröger’s base.
Scheme 90: Fluorine transfer from N-F 39-3.
Scheme 91: Fluorination with N-F 39-3.
Scheme 92: Synthesis of SelectfluorCN.
Scheme 93: Bistrifluoromethoxylation of alkenes using SelectfluorCN.
Figure 13: Synthesis of NFAS 41-2.
Scheme 94: Radical fluorination with different N-F reagents.
Scheme 95: Radical fluorination of alkenes with NFAS 41-2.
Scheme 96: Radical fluorination of alkenes with NFAS 41-2f.
Scheme 97: Decarboxylative fluorination with NFAS 41-2a,f.
Scheme 98: Fluorine plus detachment (FPD).
Figure 14: FPD values of representative N-F reagents in CH2Cl2 and CH3CN (in parentheses). Adapted with permis...
Scheme 99: N-F homolytic bond dissociation energy (BDE).
Figure 15: BDE values of representative N-F reagents in CH3CN. Adapted with permission from ref. [127]. Copyright 2...
Figure 16: Quantitative reactivity scale for popular N-F reagents. Adapted with permission from ref. [138], publish...
Scheme 100: SET and SN2 mechanisms.
Scheme 101: Radical clock reactions.
Scheme 102: Reaction of potassium enolate of citronellic ester with N-F reagents, 10-1, NFSI, and 8-1.
Scheme 103: Reaction of compound IV with Selectfluor (OTf) and NFSI.
Scheme 104: Reaction of TEMPO with Selecfluor.
Synthesis of benzannelated sultams by intramolecular Pd-catalyzed arylation of tertiary sulfonamides
- Valentin A. Rassadin,
- Mirko Scholz,
- Anastasiia A. Klochkova,
- Armin de Meijere and
- Victor V. Sokolov
Beilstein J. Org. Chem. 2017, 13, 1932–1939, doi:10.3762/bjoc.13.187
- spectrometric data. The structure of the sultam 10c was unequivocally confirmed by a single-crystal X-ray diffraction study (Figure 1). While the intramolecular arylation of the C–H acidic CH2 group in sulfamoylacetates 8a–g to yield 1,3-dihydrobenzo[c]isothiazole-2,2-dioxide derivatives 10a–h works well, the
- (PMB) from the nitrogen, the methyl 1-(4-methoxybenzyl)-1,3-dihydrobenzo[c]isothiazole-3-carboxylate-2,2-dioxide (10a) was treated with cerium(IV) ammonium nitrate (CAN) according to a previously developed protocol [18][20]. Unexpectedly, this PMB resisted its removal, and the only formed product was
- methyl 5-chloro-1-(4-methoxybenzyl)-1,3-dihydrobenzo[c]isothiazole-3-carboxylate-2,2-dioxide (10c) in the crystal [CCDC: 1520988]. Structure of methyl 1-(4-methoxybenzyl)-3-(nitrooxy)-1,3-dihydrobenzo[c]isothiazole-3-carboxylate-2,2-dioxide (22) in the crystal [CCDC: 1520989]. A previous and a new
Graphical Abstract
Scheme 1: A previous and a new approach to arene-annelated sultams.
Scheme 2: Pd-catalyzed cyclization of (2-iodophenyl)sulfonamides 3 and 5.
Scheme 3: Preparation of 4-methoxybenzyl-protected methyl 2-(N-o-iodoarylsulfamoyl)acetates 8. Reagents and c...
Scheme 4: Synthesis of arene-annelated sultams 10 by Pd-catalyzed intramolecular arylation of a C–H acidic me...
Figure 1: Structure of methyl 5-chloro-1-(4-methoxybenzyl)-1,3-dihydrobenzo[c]isothiazole-3-carboxylate-2,2-d...
Scheme 5: Palladium-catalyzed transformation of N-(2-iodophenyl)-N-(4-methoxybenzyl-benzylsulfonamide 12. Ar ...
Scheme 6: Palladium-catalyzed intramolecular arylation to yield a benzannelated six-membered sultam 21. Ar = ...
Scheme 7: An attempted and a successful removal of the PMB group from the sultam 10a.
Figure 2: Structure of methyl 1-(4-methoxybenzyl)-3-(nitrooxy)-1,3-dihydrobenzo[c]isothiazole-3-carboxylate-2...
Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds
- M. Fernanda N. N. Carvalho,
- Rudolf Herrmann and
- Gabriele Wagner
Beilstein J. Org. Chem. 2017, 13, 1230–1238, doi:10.3762/bjoc.13.122
- positions. In addition, where taxol has the bridgehead hydroxy and its neighbouring benzoate groups, we find the heterocyclic reduced isothiazole ring in the product of the Pt(II) catalysis. Other camphor derivatives prepared as entrance to taxoid compounds have a carbocyclic ring at this place in the
Graphical Abstract
Scheme 1: Synthesis of 3-oxo-camphorsulfonylimine (3) [13,15] and its bis-alkynyl derivatives 4 from camphor-10-sulf...
Scheme 2: Reactions of bis-alkynyl camphor derivative 4a with TiCl4 and with Br2, respectively.
Scheme 3: Reactions of bis-alkynylcamphor derivatives 4a–e with catalytic amounts of PtCl2(PhCN)2.
Scheme 4: Attempted selective synthesis of 3-alkynyl derivatives via sulfonylimine reduction of oxoimide 3.
Scheme 5: Selective synthesis of 2-alkynyl derivatives by protection of the 3-oxo group as an acetal.
Scheme 6: Selective synthesis of 2-alkynyl derivatives by protection of the 3-oxo group as an imine.
Scheme 7: Synthesis of the bis-alkynyl derivatives bearing different alkyne substituents and their platinum-c...
Scheme 8: Proposed mechanism of the platinum-catalysed cycloisomerisation.
Strecker degradation of amino acids promoted by a camphor-derived sulfonamide
- M. Fernanda N. N. Carvalho,
- M. João Ferreira,
- Ana S. O. Knittel,
- Maria da Conceição Oliveira,
- João Costa Pessoa,
- Rudolf Herrmann and
- Gabriele Wagner
Beilstein J. Org. Chem. 2016, 12, 732–744, doi:10.3762/bjoc.12.73
- was stirred at 45 °C for ca. 10 h. Compound 2 ((3aS,6S,Z)-7-(((3aS,6S)-8,8-dimethyl-2,2-dioxido-4,5,6,7-tetrahydro-3H-3a,6-methanobenzo[c]isothiazol-7-yl)imino)-8,8-dimethyl-4,5,6,7-tetrahydro-3H-3a,6-methanobenzo[c]isothiazole 2,2-dioxide) was obtained as a pale yellow solid upon filtration and
Graphical Abstract
Figure 1: Camphor and some camphor derivatives.
Scheme 1: Formation of 2 from reaction of oxoimine 1 with amino acids (H2NCH(R)COOH: R = H, CH3, CH2Ph, CH2CH...
Figure 2: ESI mass spectrum of 2 (positive ion mode).
Figure 3: 1H NMR spectrum of 2 in CD3CN at T = −20 °C.
Figure 4: 13C NMR spectrum of 2 in CD3CN at T = −20 °C.
Figure 5: Optimized structure of 2 ((S)-3A isomer) with labeling scheme.
Figure 6: NOESY spectrum (detail) showing the cross peak between H3A and H10A (see Supporting Information File 1, Figure S6 for the full s...
Figure 7: Upper row: anion 3 and zwitterion 4 which are stable upon geometry optimization. Middle row: zwitte...
Figure 8: Intramolecular reactions of non-zwitterionic ground state 6g to 11 (top) or 8 (bottom). The activat...
Figure 9: Transition-state geometry and salient bond distances along the IRC path for the reaction of 6g → 11...
Figure 10: Transition-state geometry and salient bond distances along the IRC path for the reaction of 6g → 8....
Figure 11: Potential products 7–11 of the Strecker degradation together with the reaction of compound 10 to gi...
Figure 12: ESI(+) tandem mass spectrum of the intermediate 12 (m/z 229) and proposed fragment ions.
Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines
- Alexander F. Khlebnikov,
- Mikhail S. Novikov,
- Yelizaveta G. Gorbunova,
- Ekaterina E. Galenko,
- Kirill I. Mikhailov,
- Viktoriia V. Pakalnis and
- Margarita S. Avdontceva
Beilstein J. Org. Chem. 2014, 10, 1896–1905, doi:10.3762/bjoc.10.197
- Manning [4][5] discovered the Rh-catalyzed reaction of diazo esters with 3,5-dialkylisoxazoles, benzo[d]isoxazole and 3-chlorobenzo[d]isothiazole leading to the corresponding 2H-1,3-oxazines, 2H-benzo[e][1,3]oxazine and 2H-benzo[e][1,3]thiazine. The authors assumed that the reaction of isoxazoles A with
Graphical Abstract
Scheme 1: Mechanistic scheme of the formation of 2H-1,3-oxazine by the reaction of isoxazoles with a diazo co...
Scheme 2: Mechanistic scheme of the formation of 2H-1,3-oxazine by the reaction of azirine with a diazo compo...
Figure 1: Energy profiles for the transformations of ylides C, (3Z)-1-oxa-5-azahexa-1,3,5-triene D and oxazin...
Figure 2: Energy profiles for the transformations of (3Z)-1-oxa-5-azahexa-1,3,5-triene D and oxazines E deriv...
Scheme 3: Reaction of isoxazole 1a and diazo ester 2a.
Figure 3: Molecular structures of compounds 3a,k, displacement parameters are drawn at 50% probability level.
Figure 4: Molecular structures of compounds 4a,b, displacement parameters are drawn at 50% probability level.
Scheme 4: Isodesmic reactions for 1,3-oxazines 3d,e,n,o and 1-oxa-5-azahexa-1,3,5-trienes 4a,b,g,h.
Scheme 5: Reaction of complementary isoxazole 1a and azirine 5 with diazo esters.
An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
- Marcus Baumann and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265
- pyridine containing lead compounds is to commonly replace the ring with a bioisostere such as a methylisoxazole, isothiazole, oxadiazole [11][12] or various diazines [13][14]. This strategy is based mainly upon a desire to avoid potential late stage toxicology issues which as indicated have arisen in the
Graphical Abstract
Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
Scheme 3: Synthesis of 3-picoline and nicotinic acid.
Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
Scheme 8: Synthesis of rosiglitazone.
Scheme 9: Syntheses of 2-pyridones.
Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
Scheme 11: Polymer-assisted synthesis of rosiglitazone.
Scheme 12: Synthesis of pioglitazone.
Scheme 13: Meerwein arylation reaction towards pioglitazone.
Scheme 14: Route towards pioglitazone utilising tyrosine.
Scheme 15: Route towards pioglitazone via Darzens ester formation.
Scheme 16: Syntheses of the thiazolidinedione moiety.
Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
Scheme 19: Synthesis of moxifloxacin.
Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
Scheme 21: Synthesis of levofloxacin.
Scheme 22: Alternative approach to the levofloxacin core 1.125.
Figure 3: Structures of nifedipine, amlodipine and clevidipine.
Scheme 23: Mg3N2-mediated synthesis of nifedipine.
Scheme 24: Synthesis of rac-amlodipine as besylate salt.
Scheme 25: Aza Diels–Alder approach towards amlodipine.
Scheme 26: Routes towards clevidipine.
Figure 4: Examples of piperidine containing drugs.
Figure 5: Discovery of tiagabine based on early leads.
Scheme 27: Synthetic sequences to tiagabine.
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
Scheme 28: Enantioselective synthesis of solifenacin.
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
Scheme 30: Improved route to carmegliptin.
Figure 9: Structures of lamivudine and zidovudine.
Scheme 31: Typical routes accessing uracil, thymine and cytosine.
Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
Scheme 33: Synthesis of lamivudine.
Scheme 34: Synthesis of raltegravir.
Scheme 35: Mechanistic studies on the formation of 3.22.
Figure 10: Structures of selected pyrimidine containing drugs.
Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
Scheme 37: Synthesis of imatinib.
Scheme 38: Flow synthesis of imatinib.
Scheme 39: Syntheses of erlotinib.
Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
Scheme 41: Synthesis of lapatinib.
Scheme 42: Synthesis of rosuvastatin.
Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
Scheme 44: Syntheses of varenicline and its key building block 4.5.
Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
Scheme 46: Asymmetric synthesis of bortezomib.
Figure 13: Structures of some prominent piperazine containing drugs.
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
Scheme 48: Syntheses of azelastine (5.1).
Figure 15: Structures of captopril, enalapril and cilazapril.
Scheme 49: Synthesis of cilazapril.
Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
Scheme 50: Synthesis of lamotrigine.
Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
Scheme 52: Conventional synthesis of imiquimod (no yields reported).
Scheme 53: Synthesis of imiquimod.
Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
Figure 18: Structures of various anti HIV-medications.
Scheme 55: Synthesis of abacavir.
Figure 19: Structures of diazepam compared to modern replacements.
Scheme 56: Synthesis of ocinaplon.
Scheme 57: Access to zaleplon and indiplon.
Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
Scheme 60: Early synthetic route to sildenafil.
Scheme 61: Convergent preparations of sildenafil.
Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
Scheme 62: Short route to imidazotriazinones.
Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
Scheme 64: Bayer’s approach to the vardenafil core.
Scheme 65: Large scale synthesis of vardenafil.
Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
Scheme 67: Different routes to temozolomide.
Scheme 68: Safer route towards temozolomide.
Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
Chemistry of polyhalogenated nitrobutadienes, 10: Synthesis of highly functionalized heterocycles with a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety
- Viktor A. Zapol’skii,
- Jan C. Namyslo,
- Armin de Meijere and
- Dieter E. Kaufmann
Beilstein J. Org. Chem. 2012, 8, 621–628, doi:10.3762/bjoc.8.69
- feasible. Keywords: isothiazole; nitrochlorobutadiene; nitropyrazole; nucleophilic substitution; pyrimidine; small rings; Introduction Nitropolychlorobutadienes are potent precursors for a variety of highly functionalized acyclic and (hetero)cyclic compounds. The readily accessible 2-nitroperchloro-1,3
- nucleophilic substitution reactions as described above, it was of interest to incorporate a persubstituted diene unit as in 3 and 4 into a heterocycle. For example, the isothiazole 17 was obtained from the nitrodiene 3 upon treatment with elemental sulfur at 200 °C [23]. Subsequent reaction with fuming nitric
- , 12. Synthesis of the 4,4-bis(aminoazabicyclo[3.1.0]hexyl)-1-chloro-1,3-dinitrobutadiene 13. Synthesis of the highly substituted trisaminodichloronitrobutadiene 16. Syntheses of the perfunctionalized isothiazole derivatives 20, 21. Preparation of the pyrazoles 27, 28, the pyrimidine 26 and the
Graphical Abstract
Figure 1: Promising starting materials for biologically active compounds.
Figure 2: Pharmaceuticals bearing an azabicyclo[3.1.0]hexane unit.
Scheme 1: Synthesis of the azabicyclic hydrazone 6.
Scheme 2: Novel imidacloprid analogues 11, 12.
Figure 3: Stabilizing hydrogen bond in nitrobutadiene-derived imidacloprid analogues 9–12.
Scheme 3: Synthesis of the 4,4-bis(aminoazabicyclo[3.1.0]hexyl)-1-chloro-1,3-dinitrobutadiene 13.
Scheme 4: Synthesis of the highly substituted trisaminodichloronitrobutadiene 16.
Figure 4: Conceivable tautomeric structures of 16.
Scheme 5: Syntheses of the perfunctionalized isothiazole derivatives 20, 21.
Scheme 6: Preparation of the pyrazoles 27, 28, the pyrimidine 26 and the pyridopyrimidine 24.
Scheme 7: Proposed reaction mechanism for the formation of 27, 28.
Scheme 8: Attempted deprotection of the azabicyclic compounds 21,12, and 28.
Approaches towards the synthesis of 5-aminopyrazoles
- Ranjana Aggarwal,
- Vinod Kumar,
- Rajiv Kumar and
- Shiv P. Singh
Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25
- sodium ethoxide (Scheme 47). Ioannidou and Koutentis [91] investigated the conversion of isothiazoles into pyrazoles on treatment with hydrazine. The influence of various C-3, C-4 and C-5 isothiazole substituents and some limitations of this ring transformation were investigated. When a good nucleofugal
- group (e.g., Cl, Br and I) is present at C-3 in the isothiazole 165, it is replaced by an amino group and 5-aminopyrazoles 166 are obtained. However, when the 3-substituent is not a good leaving group it is retained in the pyrazole product 167. A series of 3-chloro-5-substituted isothiazole-4
- -carbonitriles 168 bearing steric and/or electronic constraints at C-5 were also treated with anhydrous hydrazine and the corresponding 3-aminopyrazoles 169 were obtained in varying yields. However, when the substituent at C-5 in isothiazole was a better nucleofuge (e.g., PhO, PhS and Cl), the 5
Graphical Abstract
Figure 1: Pharmacologically active 5-aminopyrazoles.
Scheme 1: General equation for the condensation of β-ketonitriles with hydrazines.
Scheme 2: Reaction of hydrazinoheterocycles with α-phenyl-β-cyanoketones (4).
Scheme 3: Condensation of cyanoacetaldehyde (7) with hydrazines.
Scheme 4: Synthesis of 5-aminopyrazoles and their sulfonamide derivatives.
Scheme 5: Synthesis of 5-aminopyrazoles, containing a cyclohexylmethyl- or phenylmethyl- sulfonamido group at...
Scheme 6: Regioselective synthesis of 3-amino-2-alkyl (or aryl) thieno[3,4-c]pyrazoles 19.
Scheme 7: Solid supported synthesis of 5-aminopyrazoles.
Scheme 8: Synthesis of 5-aminopyrazoles from resin supported enamine nitrile 25 as the starting material.
Scheme 9: Two-step “catch and release” solid-phase synthesis of 3,4,5-trisubstituted pyrazoles.
Scheme 10: Synthesis of pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones.
Scheme 11: Synthesis of the 5,5-ring system, imidazo[1,2-b]pyrazol-2-ones.
Scheme 12: Synthesis of 5-amino-3-(pyrrol-2-yl)pyrazole-4-carbonitrile.
Scheme 13: Synthesis of N-(1,3-diaryl-1H-pyrazol-5-yl)benzamide.
Scheme 14: Synthesis of 3,7-bis(arylazo)-6-methyl-2-phenyl-1H-imidazo[1,2-b]pyrazoles.
Scheme 15: Synthesis of 3,5-diaminopyrazole.
Scheme 16: Synthesis of 5-amino-4-cyanopyrazole and 5-amino-3-hydrazinopyrazole.
Scheme 17: Synthesis of 3,5-diaminopyrazoles with substituted malononitriles.
Scheme 18: Synthesis of 3,5-diamino-4-oximinopyrazole.
Scheme 19: Synthesis of 4-arylazo-3,5-diaminopyrazoles.
Scheme 20: Synthesis of 3- or 5-amino-4-cyanopyrazoles.
Scheme 21: Synthesis of triazenopyrazoles.
Scheme 22: Synthesis of 5(3)-aminopyrazoles.
Scheme 23: Synthesis of 3-substituted 5-amino-4-cyanopyrazoles.
Scheme 24: Synthesis of 2-{[(1-acetyl-4-cyano-1H-pyrazol-5-yl)amino]methylene}malononitrile.
Scheme 25: Synthesis of 5-aminopyrazole carbodithioates and 5-amino-3-arylamino-1-phenylpyrazole-4-carboxamide...
Scheme 26: Synthesis of 5-amino-4-cyanopyrazoles.
Scheme 27: Synthesis of thiazolylpyrazoles.
Scheme 28: Synthesis of 5-amino-1-heteroaryl-3-methyl/aryl-4-cyanopyrazoles.
Scheme 29: Synthesis of 5-amino-3-methylpyrazole-4-carboxamide.
Scheme 30: Synthesis of 4-acylamino-3(5)-amino-5(3)-arylsulfanylpyrazoles.
Scheme 31: Synthesis of 5-amino-1-aryl-4-diethoxyphosphoryl-3-halomethylpyrazoles.
Scheme 32: Synthesis of substituted 5-amino-3-trifluoromethylpyrazoles 114 and 118.
Scheme 33: Solid-support synthesis of 5-N-alkylamino and 5-N-arylaminopyrazoles.
Scheme 34: Synthesis of 5-amino-1-cyanoacetyl-3-phenyl-1H-pyrazole.
Scheme 35: Synthesis of 3-substituted 5-amino-1-aryl-4-(benzothiazol-2-yl)pyrazoles.
Scheme 36: Synthesis of 5-amino-4-carbethoxy-3-methyl-1-(4-sulfamoylphenyl)pyrazole.
Scheme 37: Synthesis of inhibitors of hsp27-phosphorylation and TNFa-release.
Scheme 38: Synthesis of the diglycylpyrazole 142.
Scheme 39: Synthesis of 5-amino-1-aryl-4-benzoylpyrazole derivatives.
Scheme 40: Synthesis of 4-benzoyl-3,5-diamino-1-(2-cyanoethyl)pyrazole.
Scheme 41: Synthesis of the 5-aminopyrazole derivative 150.
Scheme 42: Synthesis of 3,5-diaminopyrazoles 153.
Scheme 43: Synthesis of 5-aminopyrazoles derivatives 155 via lithiated intermediates.
Scheme 44: Synthesis of 5-amino-4-(1,2,4-oxadiazol-5-yl)-pyrazoles 157.
Scheme 45: Synthesis of a 5-aminopyrazole with anticonvulsant activity.
Scheme 46: Synthesis of tetrasubstituted 5-aminopyrazole derivatives.
Scheme 47: Synthesis of substituted 5-aminopyrazoles from hydrazonoyl halides.
Scheme 48: Synthesis of 3-amino-5-phenylpyrazoles from isothiazoles.
Scheme 49: Synthesis of 5-aminopyrazoles via ring transformation.
