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Search for "chloroacetic acid" in Full Text gives 22 result(s) in Beilstein Journal of Organic Chemistry.
Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates
- Péter Kisszékelyi,
- Tibor Peňaška,
- Klára Stankovianska,
- Mária Mečiarová and
- Radovan Šebesta
Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124
- as a catalyst [19]. The reactions of 2-aminobenzenethioles with ethyl 2-bromoalkanoates [20], 2-chloroacetic acid [21][22], or diethyl 2-bromo-2-methylmalonate [23] gave 2H-benzo[b][1,4]thiazin-3(4H)-one derivatives 3 (Figure 1), which also have interesting biological properties. 2H-Benzo-1,4-thiazin
Synthetic strategies toward 1,3-oxathiolane nucleoside analogues
- Umesh P. Aher,
- Dhananjai Srivastava,
- Girij P. Singh and
- Jayashree B. S
Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182
- the oxathiolane precursor 56a from acyclic precursors. The method used chloroacetic acid (53), vinyl acetate, sodium thiosulfate, and water to construct the oxathiolane moiety. The use of sulfenyl chloride provided a new method to access such oxathiolanes (Scheme 16). Thioglycolic acid (3o), upon
Graphical Abstract
Figure 1: Representative modified 1,3-oxathiolane nucleoside analogues.
Figure 2: Mechanism of antiviral action of 1,3-oxathiolane nucleosides, 3TC (1) and FTC (2), as chain termina...
Figure 3: Synthetic strategies for the construction of the 1,3-oxathiolane sugar ring.
Scheme 1: Synthesis of 4 from benzoyloxyacetaldehyde (3a) and 2-mercapto-substituted dimethyl acetal 3na.
Scheme 2: Synthesis of 8 from protected glycolic aldehyde 3b and 2-mercaptoacetic acid (3o).
Scheme 3: Synthesis of 20 from ᴅ-mannose (3c).
Scheme 4: Synthesis of 20 from 1,6-thioanhydro-ᴅ-galactose (3d).
Scheme 5: Synthesis of 8 from 2-(tert-butyldiphenylsilyloxy)methyl-5-oxo-1,2-oxathiolane (3m).
Scheme 6: Synthesis of 20a from ʟ-gulose derivative 3f.
Scheme 7: Synthesis of 31 from (+)-thiolactic acid 3p and 2-benzoyloxyacetaldehyde (3a).
Scheme 8: Synthesis of 35a from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g) hydrate.
Scheme 9: Synthetic routes toward 41 through Pummerer reaction from methyl 2-mercaptoacetate (3j) and bromoac...
Scheme 10: Strategy for the synthesis of 2,5-substituted 1,3-oxathiolane 41a using 4-nitrobenzyl glyoxylate an...
Scheme 11: Synthesis of 44 by a resolution method using Mucor miehei lipase.
Scheme 12: Synthesis of 45 from benzoyloxyacetaldehyde (3a) and 2-mercaptoacetaldehyde bis(2-methoxyethyl) ace...
Scheme 13: Synthesis of 46 from 2-mercaptoacetaldehyde bis(2-methoxyethyl) acetal (3nc) and diethyl 3-phosphon...
Scheme 14: Synthesis of 48 from 1,3-dihydroxyacetone dimer 3l.
Scheme 15: Approach toward 52 from protected alkene 3rb and lactic acid derivative 51 developed by Snead et al....
Scheme 16: Recent approach toward 56a developed by Kashinath et al.
Scheme 17: Synthesis of 56a from ʟ-menthyl glyoxylate (3h) hydrate by DKR.
Scheme 18: Possible mechanism with catalytic TEA for rapid interconversion of isomers.
Scheme 19: Synthesis of 35a by a classical resolution method through norephedrine salt 58 formation.
Scheme 20: Synthesis of 63 via [1,2]-Brook rearrangement from silyl glyoxylate 61 and thiol 3nb.
Scheme 21: Combined use of STS and CAL-B as catalysts to synthesize an enantiopure oxathiolane precursor 65.
Scheme 22: Synthesis of 1 and 1a from glycolaldehyde dimer 64 and 1,4-dithiane-2,5-diol (3q) using STS and CAL...
Scheme 23: Synthesis of 68 by using Klebsiella oxytoca.
Scheme 24: Synthesis of 71 and 72 using Trichosporon taibachii lipase and kinetic resolution.
Scheme 25: Synthesis of 1,3-oxathiolan-5-ones 77 and 78 via dynamic covalent kinetic resolution.
Figure 4: Pathway for glycosidic bond formation.
Scheme 26: First synthesis of (±)-BCH-189 (1c) by Belleau et al.
Scheme 27: Enantioselective synthesis of 3TC (1).
Scheme 28: Synthesis of cis-diastereomer 3TC (1) from oxathiolane propionate 44.
Scheme 29: Synthesis of (±)-BCH-189 (1c) via SnCl4-mediated N-glycosylation of 8.
Scheme 30: Synthesis of (+)-BCH-189 (1a) via TMSOTf-mediated N-glycosylation of 20.
Scheme 31: Synthesis of 3TC (1) from oxathiolane precursor 20a.
Scheme 32: Synthesis of 83 via N-glycosylation of 20 with pyrimidine bases.
Scheme 33: Synthesis of 85 via N-glycosylation of 20 with purine bases.
Scheme 34: Synthesis of 86 and 87 via N-glycosylation using TMSOTf and pyrimidines.
Scheme 35: Synthesis of 90 and 91 via N-glycosylation using TMSOTf and purines.
Scheme 36: Synthesis of 3TC (1) via TMSI-mediated N-glycosylation.
Scheme 37: Stereoselective N-glycosylation for the synthesis of 1 by anchimeric assistance of a chiral auxilia...
Scheme 38: Whitehead and co-workers’ approach for the synthesis of 1 via direct N-glycosylation without an act...
Scheme 39: ZrCl4-mediated stereoselective N-glycosylation.
Scheme 40: Plausible reaction mechanism for stereoselective N-glycosylation using ZrCl4.
Scheme 41: Synthesis of enantiomerically pure oxathiolane nucleosides 1 and 2.
Scheme 42: Synthesis of tetrazole analogues of 1,3-oxathiolane nucleosides 97.
Scheme 43: Synthetic approach toward 99 from 1,3-oxathiolane 45 by Camplo et al.
Scheme 44: Synthesis of 100 from oxathiolane phosphonate analogue 46.
Scheme 45: Synthetic approach toward 102 and the corresponding cyclic thianucleoside monophosphate 102a by Cha...
Scheme 46: Synthesis of emtricitabine (2) from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g).
Scheme 47: Synthesis of 1 and 2, respectively, from 56a–d using iodine-mediated N-glycosylation.
Scheme 48: Plausible mechanism for silane- and I2-mediated N-glycosylation.
Scheme 49: Pyridinium triflate-mediated N-glycosylation of 35a.
Scheme 50: Possible pathway for stereoselective N-glycosylation via in situ chelation with a metal ligand.
Scheme 51: Synthesis of novel 1,3-oxathiolane nucleoside 108 from oxathiolane precursor 8 and 3-benzyloxy-2-me...
Scheme 52: Synthesis of 110 using T-705 as a nucleobase and 1,3-oxathiolane derivative 8 via N-glycosylation.
Scheme 53: Synthesis of 1 using an asymmetric leaving group and N-glycosylation with bromine and mesitylene.
Scheme 54: Cytidine deaminase for enzymatic separation of 1c.
Scheme 55: Enzymatic resolution of the monophosphate derivative 116 for the synthesis of (−)-BCH-189 (1) and (...
Scheme 56: Enantioselective resolution by PLE-mediated hydrolysis to obtain FTC (2).
Scheme 57: (+)-Menthyl chloroformate as a resolving agent to separate a racemic mixture 120.
Scheme 58: Separation of racemic mixture 1c by cocrystal 123 formation with (S)-(−)-BINOL.
Transition-metal-free intramolecular Friedel–Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives
- Tülay Yıldız,
- İrem Baştaş and
- Hatice Başpınar Küçük
Beilstein J. Org. Chem. 2021, 17, 2203–2208, doi:10.3762/bjoc.17.142
- , iron(III) chloride hexahydrate, trifluoroacetic acid (TFA), N-trifylphosphoramide (NTPA), benzoic acid, diphenyl phosphate (DPP), malonic acid, chloroacetic acid, copper(II) triflate, acetic acid, and p-toluenesulfonic acid (p-TSA) were used as catalysts. TFA gave the best yield of these catalysts with
Graphical Abstract
Scheme 1: Synthesis of 4a: (i) phenol, K2CO3, DMF, reflux, 2 h, 91%; (ii) PhMgBr, dry THF, 0 °C, 2 h, 86%; (i...
Figure 1: Scope of substrates for intramolecular FCA by activation of 4a–l and their isolated yields. aCondit...
Scheme 2: Plausible reaction mechanism for the cyclization reaction of alkene 4a.
Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid
- Dong Cai,
- ZhiHua Zhang,
- Yufan Meng,
- KaiLi Zhu,
- LiYi Chen,
- ChangXiang Yu,
- ChangWei Yu,
- ZiYi Fu,
- DianShen Yang and
- YiXia Gong
Beilstein J. Org. Chem. 2020, 16, 798–808, doi:10.3762/bjoc.16.73
- give compound 8 and acetic acid. At the reaction temperature, the acetic acid (boiling point 117–118 °C) boiled and vapors escaped from the reaction mixture during the reaction process. However, in the reaction of compound 9 with chloroacetic anhydride (Scheme 3), the chloroacetic acid (boiling point
- factor is that the acidity of chloroacetic acid (pKa = 2.87) was stronger than that of acetic acid (pKa = 4.76). The procedure for the generation of byproduct 11 was similar to N-Boc-deprotection using trifluoroacetic acid. The effective synthesis of compound 10 was then explored (Table 3). In our
- initial attempt, compound 9 was reacted with chloroacetic anhydride (Table 3, entry 1) at 130 °C, whereas the reaction was complicated by the side formation of byproduct 11, which was obviously due to the presence of chloroacetic acid. Next, the reactions were performed with organic or inorganic bases to
Graphical Abstract
Figure 1: Chemical structure of 18β-glycyrrhetinic acid and known derivatives.
Scheme 1: Synthesis of compound 4. Reagents and conditions: (a) Ac2O, NEt3, DMF (cat.), DCM, 25 °C, 1 day; (b...
Scheme 2: Synthesis of compound 4. Reagents and conditions: (a) Ac2O, 130 °C, 1 h; (b) 1-Boc-piperazine, CH3C...
Figure 2: a) Estimated structure of the intermediate 6; b) Possible aminolysis process.
Scheme 3: Synthesis of byproduct 11. Reagents and conditions: (a) chloroacetic anhydride, 130 °C, 1 h.
Scheme 4: Synthesis of compound 17. Reagents and conditions: (a) chloroacetic anhydride, 130 °C, 1 h; (b) mor...
Figure 3: Crystal structure of conpound 18.
Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid
- Kaj M. van Vliet,
- Nicole S. van Leeuwen,
- Albert M. Brouwer and
- Bas de Bruin
Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38
- catalysts used in this reaction. In an attempt to trap one of the radical intermediates with TEMPO, we observed a compound indicating the generation of a chloromethyl radical. Keywords: ATRA; catalysis; chloroacetic acid; lactone; photoredox; Introduction Monochloroacetic acid is an industrially important
Graphical Abstract
Figure 1: A part of the industry around monochloroacetic acid.
Scheme 1: Redox based activation of haloacetic acid.
Figure 2: Cyclic voltammogram of monochloroacetic acid and ferrocene with 0.1 M [TBA][PF6] in MeCN. The poten...
Scheme 2: Initial attempts for lactone formation by photoredox catalysis.
Scheme 3: The photoredox reaction of TEMPO with monochloroacetic acid catalyzed by fac-[Ir(ppy)3].
Figure 3: EPR spectra measured (black) and simulated (red) based on the structure of the oxidized photoredox ...
Scheme 4: Two possible acid-assisted, reductive activation pathways of monochloroacetic acid (A–H = acid).
Figure 4: Reaction mixtures after overnight irradiation of (A) 4-chloro-4-phenylbutanoic acid (3) and fac-[Ir...
Scheme 5: Substrate scope of styrene derivatives in the photoredox reaction with monochloroacetic acid. Yield...
Scheme 6: Proposed reaction mechanism.
Scheme 7: The photoredox formation of 1-(chloromethoxy)-2,2,6,6-tetramethylpiperidine.
Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo
- Alexander Sailer,
- Franziska Ermer,
- Yvonne Kraus,
- Rebekkah Bingham,
- Ferdinand H. Lutter,
- Julia Ahlfeld and
- Oliver Thorn-Seshold
Beilstein J. Org. Chem. 2020, 16, 125–134, doi:10.3762/bjoc.16.14
- , so it was sought to minimise their exposure to these conditions during synthesis. In the end, we used two routes to the thioindoxyls: either Friedel–Crafts acylation of α-phenylthioacetic acids (which are easily accessible from thiophenols by alkylation using 2-chloroacetic acid, Figure 1b) or else
Graphical Abstract
Figure 1: a) The potent tubulin inhibitor colchicine as a lead scaffold led to the development of the HOTub g...
Figure 2: Chemical structures of HITubs. Key variations with respect to HITub-4 are highlighted in dashed box...
Figure 3: Photocharacterisation of HITub-4. a) Photochemical and thermal isomerisation. b) UV–vis spectra aft...
Figure 4: a) Resazurin reduction assay for HITub-4 and nocodazole in HeLa cells (n = 3), demonstrating the di...
Figure 5: Confocal microscopy images of immunofluorescently labelled MT networks after treatment with HITubs ...
Figure 6: Cell cycle analysis of HITub-4-treated cells. a) and b) (Z)-HITub-4 caused significant G2/M arrest ...
Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation
- Sambasivarao Kotha,
- Gaddamedi Sreevani,
- Lilya U. Dzhemileva,
- Milyausha M. Yunusbaeva,
- Usein M. Dzhemilev and
- Vladimir A. D’yakonov
Beilstein J. Org. Chem. 2019, 15, 2774–2781, doi:10.3762/bjoc.15.269
- synthesis of thiazolidinedione derivatives is refluxing chloroacetic acid (2) with thiourea (1), followed by a Knoevenagel condensation with an aldehyde (Scheme 1) [25]. Results and Discussion Limited reports are available dealing with the synthesis of spiro derivatives of thiazolidine-2,4-diones [26][27
Graphical Abstract
Scheme 1: Conventional method of synthesis of thiazolidine-2,4-dione derivatives.
Scheme 2: [2 + 2 + 2] Cyclotrimerization of N-methylthiazolidinedione.
Scheme 3: Unexpected product 5b obtained in the attempted NH-protection of thiazolidinedione with (Boc)2O.
Figure 1: Comparison of 13C NMR values of 9 and 5b.
Scheme 4: [2 + 2 + 2] Cyclotrimerization of dipropargylthiazolidinediones with propargyl halides.
Scheme 5: Formation of sultine 13 from compound 8b followed by DA reaction.
Scheme 6: Dipropargylation of 2,4-thiazolidinedione derivatives.
Scheme 7: [2 + 2 + 2] Cycloaddition in the presence of Wilkinson’s catalyst.
Scheme 8: N-Ester derivative 18 hydrolysis to N-acid derivative 22.
Scheme 9: Synthesis of triazolo derivative 24 via click reaction.
Steroid diversification by multicomponent reactions
- Leslie Reguera,
- Cecilia I. Attorresi,
- Javier A. Ramírez and
- Daniel G. Rivera
Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121
- previously proposed by Marcaccini and co-workers [17]. Here, the route included the Ugi-4CR reaction of varied amines and isocyanides with the androstanic aldehyde 4 and chloroacetic acid followed by a post-cyclization reaction by treating the Ugi products 5 with ethanolic KOH under ultrasonication. This
Graphical Abstract
Figure 1: Structures of natural steroids of A) animal and B) plant origin.
Scheme 1: Synthesis of a steroidal β-lactam by Ugi reaction of a cholanic aldehyde [14].
Scheme 2: Synthetic route to steroidal 2,5-diketopiperazines based on a diastereoselective Ugi-4CR with an an...
Scheme 3: Multicomponent synthesis of a heterocycle–steroid hybrid using a ketosteroid as carbonyl component [18]....
Scheme 4: Synthesis of peptidomimetic–steroid hybrids using the Ugi-4CR with spirostanic amines and carboxyli...
Scheme 5: Synthesis of azasteroids using the Ugi-4CR with androstanic and pregnanic carboxylic acids [22].
Figure 2: Ugi-4CR-derived library of androstanic azasteroids with diverse substitution patterns at the phenyl...
Scheme 6: Synthesis of 4-azacholestanes by an intramolecular Ugi-4C-3R [26].
Scheme 7: Synthesis of amino acid–steroid hybrid by multiple Ugi-4CR using steroidal isocyanides [29].
Scheme 8: Synthesis of ecdysteroid derivatives by Ugi-4CR using a steroidal isocyanide [30].
Scheme 9: Stereoselective multicomponent synthesis of a steroid–tetrahydropyridine hybrid using a chiral bifu...
Scheme 10: Pd(II)-catalyzed three-component reaction with an alkynyl seco-cholestane [34].
Scheme 11: Multicomponent synthesis of steroid–thiazole hybrids from a steroidal ketone [36].
Scheme 12: Synthesis of cholanic pseudo-peptide derivatives by novel MCRs based on the reactivity of ynamide [37,38].
Scheme 13: Synthesis of steroid-fused pyrimidines and pyrimidones using the Biginelli-3CR [39,42,43].
Scheme 14: Synthesis of steroidal pyridopyrimidines by a reaction sequence comprising a 4CR followed by a post...
Scheme 15: Synthesis of steroid-fused pyrimidines by MCR of 2-hydroxymethylene-3-ketosteroids [46].
Scheme 16: Synthesis of steroid-fused naphthoquinolines by the Kozlov–Wang MCR using ketosteroids [50,51].
Scheme 17: Conjugation of steroids to carbohydrates and peptides by the Ugi-4CR [62,63].
Scheme 18: Solid-phase multicomponent conjugation of peptides to steroids by the Ugi-4CR [64].
Scheme 19: Solid-phase multicomponent conjugation of peptides to steroids by the Petasis-3CR [68].
Scheme 20: Synthesis of steroidal macrobicycles (cages) by multiple multicomponent macrocyclizations based on ...
Scheme 21: One-pot synthesis of steroidal cages by double Ugi-4CR-based macrocyclizations [76].
A hemicryptophane with a triple-stranded helical structure
- Augustin Long,
- Olivier Perraud,
- Erwann Jeanneau,
- Christophe Aronica,
- Jean-Pierre Dutasta and
- Alexandre Martinez
Beilstein J. Org. Chem. 2018, 14, 1885–1889, doi:10.3762/bjoc.14.162
- Discussion Synthesis of cage 1 According to the synthetic pathway shown in Scheme 1, hemicryptophane host 1 was obtained in five steps [14][15]. Alkylation of vanillyl alcohol by chloroacetic acid in ethanol under reflux afforded 2 in 73% yield. The CTV triester was obtained by adding first one equivalent of
Graphical Abstract
Scheme 1: Synthesis of 1.
Figure 1: 1H NMR spectrum of 1 (400 MHz, CDCl3).
Figure 2: X-ray molecular structure of 1. Hydrogen atoms are omitted for clarity; dashed lines represent hydr...
Figure 3: (a) Structure of compound 6. (b) 1H NMR of 6 (CDCl3, 400 MHz). (c) 1H NMR of 1 (CDCl3, 400 MHz).
Recent applications of chiral calixarenes in asymmetric catalysis
- Mustafa Durmaz,
- Erkan Halay and
- Selahattin Bozkurt
Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117
- aldol reaction between 21 and 70 and offered superior diastereo- and enantioselectivities in the presence of chloroacetic acid (96% conversion, 86:14 anti diastereoselectivity and 73% ee) (Scheme 25). Under the optimum reaction media, a series of diverse benzaldehydes bearing electron withdrawing groups
Graphical Abstract
Figure 1: Inherently chiral calix[4]arene-based phase-transfer catalysts.
Scheme 1: Asymmetric alkylations of 3 catalyzed by (±)-1 and (±)-2 under phase-transfer conditions.
Scheme 2: Synthesis of chiral calix[4]arene-based phase-transfer catalyst 7 and structure of O’Donnell’s N-be...
Scheme 3: Asymmetric alkylation of glycine derivative 3 catalyzed by calixarene-based phase-transfer catalyst ...
Figure 2: Calix[4]arene-amides used as phase-transfer catalysts.
Scheme 4: Phase-transfer alkylation of 3 catalyzed by calixarene-triamide 12.
Scheme 5: Synthesis of inherently chiral calix[4]arenes 20a/20b substituted at the lower rim. Reaction condit...
Scheme 6: Asymmetric Henry reaction between 21 and 22 catalyzed by 20a/20b.
Figure 3: Proposed transition state model of asymmetric Henry reaction.
Scheme 7: Synthesis of enantiomerically pure phosphinoferrocenyl-substituted calixarene ligands 27–29.
Scheme 8: Asymmetric coupling reaction of aryl boronates and aryl halides in the presence of calixarene mono ...
Scheme 9: Asymmetric allylic alkylation in the presence of calix[4]arene ligand (S,S)-29.
Figure 4: Structure of inherently chiral oxazoline calix[4]arenes applied in the palladium-catalyzed Tsuji–Tr...
Scheme 10: Asymmetric Tsuji–Trost reaction in the presence of calix[4]arene ligands 36–39.
Figure 5: BINOL-derived calix[4]arene-diphosphite ligands.
Scheme 11: Asymmetric hydrogenation of 41a and 41b catalyzed by in situ-generated catalysts comprised of [Rh(C...
Figure 6: Inherently chiral calix[4]arene 43 containing a diarylmethanol structure.
Scheme 12: Asymmetric Michael addition reaction of 44 with 45 catalyzed by 43.
Figure 7: Calix[4]arene-based chiral primary amine–thiourea catalysts.
Scheme 13: Asymmetric Michael addition of 48 with 49 catalyzed by 47a and 47b.
Scheme 14: Enantioselective Michael addition of 51 to 52 catalyzed by calix[4]arene thioureas.
Scheme 15: Synthesis of calix[4]arene-based tertiary amine–thioureas 54–56.
Scheme 16: Asymmetric Michael addition of 34 and 57 to nitroalkenes 49 catalyzed by 54b.
Scheme 17: Synthesis of p-tert-butylcalix[4]arene bis-squaramide derivative 64.
Scheme 18: Asymmetric Michael addition catalyzed by 64.
Scheme 19: Synthesis of chiral p-tert-butylphenol analogue 68.
Figure 8: Novel prolinamide organocatalysts based on the calix[4]arene scaffold.
Scheme 20: Asymmetric aldol reactions of 72 with 70 and 71 catalyzed by 69b.
Scheme 21: Synthesis of p-tert-butylcalix[4]arene-based chiral organocatalysts 75 and 78 derived from L-prolin...
Scheme 22: Synthesis of upper rim-functionalized calix[4]arene-based L-proline derivative 83.
Scheme 23: Synthesis and proposed structure of Calix-Pro-MN (86).
Figure 9: Calix[4]arene-based L-proline catalysts containing ester, amide and acid units.
Scheme 24: Synthesis of calix[4]arene-based prolinamide 92.
Scheme 25: Calixarene-based catalysts for the aldol reaction of 21 with 70.
Scheme 26: Asymmetric aldol reactions of 72 with cyclic ketones catalyzed by calix[4]arene-based chiral organo...
Figure 10: A proposed structure for catalyst 92 in H2O.
Scheme 27: Synthetic route for organocatalyst 98.
Scheme 28: Asymmetric aldol reactions catalyzed by 99.
Figure 11: Proposed catalytic environment for catalyst 99 in the presence of water.
Scheme 29: Asymmetric aldol reactions between 94 and 72 catalyzed by 55a.
Scheme 30: Enantioselective Biginelli reactions catalyzed by 69f.
Scheme 31: Synthesis of calix[4]arene–(salen) complexes.
Scheme 32: Enantioselective epoxidation of 108 catalyzed by 107a/107b.
Scheme 33: Synthesis of inherently chiral calix[4]arene catalysts 111 and 112.
Scheme 34: Enantioselective MPV reduction.
Scheme 35: Synthesis of chiral calix[4]arene ligands 116a–c.
Scheme 36: Asymmetric MPV reduction with chiral calix[4]arene ligands.
Scheme 37: Chiral AlIII–calixarene complexes bearing distally positioned chiral substituents.
Scheme 38: Asymmetric MPV reduction in the presence of chiral calix[4]arene diphosphites.
Scheme 39: Synthesis of enantiomerically pure inherently chiral calix[4]arene phosphonic acid.
Scheme 40: Asymmetric aza-Diels–Alder reactions catalyzed by (cR,pR)-121.
Scheme 41: Asymmetric ring opening of epoxides catalyzed by (cR,pR)-121.
Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins
- Robby Vroemans,
- Fante Bamba,
- Jonas Winters,
- Joice Thomas,
- Jeroen Jacobs,
- Luc Van Meervelt,
- Jubi John and
- Wim Dehaen
Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49
- -azidobenzaldehyde (1a), propargylamine (2a), 2-chloroacetic acid (3a) and benzyl isocyanide (4a, Scheme 2). Initially, the condensation of the aldehyde and the amine was effected in MeOH in the presence of 4 Å MS. This was followed by the sequential addition of chloroacetic acid and the isocyanide which, after 24
- conformational restrictions prevent the side chains on the benzodiazepine bearing the amide and halogen to be in close proximity, which is needed for the reaction to proceed. The generality of the developed fused-heterocycle synthesis was studied with substituted azidoaldehyde, isocyanides and chloroacetic acid
- ), chloroacetic acid 3 (1.85 mmol), benzyl isocyanide 4 (1.85 mmol), 4 Å MS (100 mg), EtOH (7 mL), 20 h, rt; 2. Ugi adduct 5 (0.26 mmol), KOH (0.28 mmol), ethanol (1.5 mL), sonication for 30 minutes, rt; 3. neutralization with 1 M HCl, EtOH (20 mL) reflux, 3 h. Overall yields for 3 steps are given for all the
Graphical Abstract
Figure 1: Triazolobenzodiazepine drugs.
Scheme 1: Retrosynthetic analysis towards 2,5-diketopiperazine fused triazolobenzodiazepine.
Scheme 2: Ugi 4-CR reaction.
Scheme 3: Synthesis of diketopiperazine-fused triazolobenzodiazepine 7a.
Figure 2: Generality in the synthesis of diketopiperazine-fused triazolobenzodiazepine 7. Reaction conditions...
Scheme 4: ‘One-pot’ synthesis of diketopiperazine-fused triazolobenzodiazepines 7a and 7b.
Scheme 5: Synthesis of hydantoin-fused triazolobenzodiazepine 10. Reaction conditions: 1. 2-azidobenzaldehyde ...
Figure 3: X-ray crystal structure of hydantoin-fused triazolobenzodiazepine 10a. (Displacement ellipsoids are...
Scheme 6: Mechanism of formation of diketopiperazine and hydantoin-fused triazolobenzodiazepines.
Mechanochemical synthesis of small organic molecules
- Tapas Kumar Achar,
- Anima Bose and
- Prasenjit Mal
Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186
- 2016 Juaristi and co-workers have reported Ugi 4-component reactions (4-CR) by liquid-assisted grinding (LAG) using MeOH. Equimolar amounts of benzaldehyde, chloroacetic acid, tert-butyl isocyanide, and propargylamine in the presence of 2 mol % InCl3, under ball-mill yielded the desired Ugi product in
Graphical Abstract
Scheme 1: Mechanochemical aldol condensation reactions [48].
Scheme 2: Enantioselective organocatalyzed aldol reactions under mechanomilling. a) Based on binam-(S)-prolin...
Scheme 3: Mechanochemical Michael reaction [51].
Scheme 4: Mechanochemical organocatalytic asymmetric Michael reaction [52].
Scheme 5: Mechanochemical Morita–Baylis–Hillman (MBH) reaction [53].
Scheme 6: Mechanochemical Wittig reactions [55].
Scheme 7: Mechanochemical Suzuki reaction [56].
Scheme 8: Mechanochemical Suzuki–Miyaura coupling by LAG [57].
Scheme 9: Mechanochemical Heck reaction [59].
Scheme 10: a) Sonogashira coupling under milling conditions. b) The representative example of a double Sonogas...
Scheme 11: Copper-catalyzed CDC reaction under mechanomilling [67].
Scheme 12: Asymmetric alkynylation of prochiral sp3 C–H bonds via CDC [68].
Scheme 13: Fe(III)-catalyzed CDC coupling of 3-benzylindoles [69].
Scheme 14: Mechanochemical synthesis of 3-vinylindoles and β,β-diindolylpropionates [70].
Scheme 15: Mechanochemical C–N bond construction using anilines and arylboronic acids [78].
Scheme 16: Mechanochemical amidation reaction from aromatic aldehydes and N-chloramine [79].
Scheme 17: Mechanochemical CDC between benzaldehydes and benzyl amines [81].
Scheme 18: Mechanochemical protection of -NH2 and -COOH group of amino acids [85].
Scheme 19: Mechanochemical Ritter reaction [87].
Scheme 20: Mechanochemical synthesis of dialkyl carbonates [90].
Scheme 21: Mechanochemical transesterification reaction using basic Al2O3 [91].
Scheme 22: Mechanochemical carbamate synthesis [92].
Scheme 23: Mechanochemical bromination reaction using NaBr and oxone [96].
Scheme 24: Mechanochemical aryl halogenation reactions using NaX and oxone [97].
Scheme 25: Mechanochemical halogenation reaction of electron-rich arenes [88,98].
Scheme 26: Mechanochemical aryl halogenation reaction using trihaloisocyanuric acids [100].
Scheme 27: Mechanochemical fluorination reaction by LAG method [102].
Scheme 28: Mechanochemical Ugi reaction [116].
Scheme 29: Mechanochemical Passerine reaction [116].
Scheme 30: Mechanochemical synthesis of α-aminonitriles [120].
Scheme 31: Mechanochemical Hantzsch pyrrole synthesis [121].
Scheme 32: Mechanochemical Biginelli reaction by subcomponent synthesis approach [133].
Scheme 33: Mechanochemical asymmetric multicomponent reaction[134].
Scheme 34: Mechanochemical Paal–Knorr pyrrole synthesis [142].
Scheme 35: Mechanochemical synthesis of benzothiazole using ZnO nano particles [146].
Scheme 36: Mechanochemical synthesis of 1,2-di-substituted benzimidazoles [149].
Scheme 37: Mechanochemical click reaction using an alumina-supported Cu-catalyst [152].
Scheme 38: Mechanochemical click reaction using copper vial [155].
Scheme 39: Mechanochemical indole synthesis [157].
Scheme 40: Mechanochemical synthesis of chromene [158].
Scheme 41: Mechanochemical synthesis of azacenes [169].
Scheme 42: Mechanochemical oxidative C-P bond formation [170].
Scheme 43: Mechanochemical C–chalcogen bond formation [171].
Scheme 44: Solvent-free synthesis of an organometallic complex.
Scheme 45: Selective examples of mechano-synthesis of organometallic complexes. a) Halogenation reaction of Re...
Scheme 46: Mechanochemical activation of C–H bond of unsymmetrical azobenzene [178].
Scheme 47: Mechanochemical synthesis of organometallic pincer complex [179].
Scheme 48: Mechanochemical synthesis of tris(allyl)aluminum complex [180].
Scheme 49: Mechanochemical Ru-catalyzed olefin metathesis reaction [181].
Scheme 50: Rhodium(III)-catalyzed C–H bond functionalization under mechanochemical conditions [182].
Scheme 51: Mechanochemical Csp2–H bond amidation using Ir(III) catalyst [183].
Scheme 52: Mechanochemical Rh-catalyzed Csp2–X bond formation [184].
Scheme 53: Mechanochemical Pd-catalyzed C–H activation [185].
Scheme 54: Mechanochemical Csp2–H bond amidation using Rh catalyst.
Scheme 55: Mechanochemical synthesis of indoles using Rh catalyst [187].
Scheme 56: Mizoroki–Heck reaction of aminoacrylates with aryl halide in a ball-mill [58].
Scheme 57: IBX under mechanomilling conditions [8].
Scheme 58: Thiocarbamoylation of anilines; trapping of reactive aryl-N-thiocarbamoylbenzotriazole intermediate...
Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis
- Elisabeth Mairhofer,
- Elisabeth Fuchs and
- Ronald Micura
Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250
- (121 MHz, CDCl3) δ 149.52, 153.84 ppm; HRMS [M + H+]: calcd for C59H87N7O7PSi+, 1064.6168; found, 1064.6192. Synthesis of c3A described by Rousseau et al. in 1966 [22]. a) 1,2,3,5-Tetraacetyl-ß-D-ribofuranose, chloroacetic acid (cat.), 175 °C (melting until clear solution). b) NH3 in CH3OH, 0 °C, 14 h
Graphical Abstract
Scheme 1: Synthesis of c3A described by Rousseau et al. in 1966 [22]. a) 1,2,3,5-Tetraacetyl-ß-D-ribofuranose, ch...
Scheme 2: Synthesis of c3A described by Montgomery et al. in 1977 [23]. The final step, displacement of the 2-chl...
Scheme 3: Synthesis of tribenzoylated 6-azido-3-deazapurine nucleoside 2. a) LiN3 (1.3 equiv), N,N-dimethylfo...
Scheme 4: Efficient 5-step synthesis of 3-deazaadenosine phosphoramidite 8 from commercially available, affor...
Investigation on the reactivity of α-azidochalcones with carboxylic acids: Formation of α-amido-1,3-diketones and highly substituted 2-(trifluoromethyl)oxazoles
- Kandasamy Rajaguru,
- Arumugam Mariappan,
- Rajendran Suresh,
- Periasamy Manivannan and
- Shanmugam Muthusubramanian
Beilstein J. Org. Chem. 2015, 11, 2021–2028, doi:10.3762/bjoc.11.219
- ). With this optimised protocol, we subsequently extended the scope of this transformation with other carboxylic acids as well. The reaction works well with different acids including acetic acid (2b) (3c–h) and chloroacetic acid (2c) (3i and 3j). It should be mentioned that the reaction goes well with
Graphical Abstract
Figure 1: Formation of substituted aziridine.
Figure 2: Various strategies for the formation of 2H-azirine.
Scheme 1: Attempted reaction for the synthesis of 3a.
Figure 3: Synthesis of α-amido-1,3-diketone (3a–o). Reaction conditions: α-azidochalcone 1 (1.0 equiv) and ca...
Scheme 2: Plausible mechanism.
Scheme 3: Attempted reaction with acid derivatives.
Scheme 4: Oxazole formation from 3.
Figure 4: Possible isomers for 7.
Scheme 5: Oxazole formation.
Figure 5: Synthesis of highly substituted 2-(trifluoromethyl)oxazoles (8a–e). Reaction conditions: α-azidocha...
Scheme 6: Mechanism for the formation of 8.
Synthetic strategies for the fluorescent labeling of epichlorohydrin-branched cyclodextrin polymers
- Milo Malanga,
- Mihály Bálint,
- István Puskás,
- Kata Tuza,
- Tamás Sohajda,
- László Jicsinszky,
- Lajos Szente and
- Éva Fenyvesi
Beilstein J. Org. Chem. 2014, 10, 3007–3018, doi:10.3762/bjoc.10.319
- review has been recently published [11]. Cationic and anionic cyclodextrin polymers were synthesized by simultaneous modification and branching from β-CD, epichlorohydrin and choline chloride (for cationic polymer) or chloroacetic acid (for anionic polymer) in an one-step polycondensation process and
Graphical Abstract
Scheme 1: Schematic representation of the various synthetic routes for the introduction of an anchoring group...
Scheme 2: Synthetic strategy for the rhodaminylation of β-CD polymer.
Figure 1: TLC study of β-CD iodination showing the proceeding of 6-monoiodination with increasing reaction ti...
Figure 2: HSQC-DEPT spectrum of compound 1 with partial assignment.
Figure 3: IR spectra of compound 1 (black line) and compound 2 (red line) showing the disappearance of the az...
Scheme 3: Schematic representation for the coumarinylation of methylated β-CD-polymer, n, m, p and q mean the...
Figure 4: HSQC-DEPT spectra of compound 4 with partial assignment; in the upper part the full spectrum is sho...
Scheme 4: Schematic representation for the introduction of NBF in a cationic β-CD-polymer.
Scheme 5: Schematic representation for the introduction of fluorescein into a β-CD-polymer.
Electrocarboxylation: towards sustainable and efficient synthesis of valuable carboxylic acids
- Roman Matthessen,
- Jan Fransaer,
- Koen Binnemans and
- Dirk E. De Vos
Beilstein J. Org. Chem. 2014, 10, 2484–2500, doi:10.3762/bjoc.10.260
- alternative for the conventional synthesis of cyanoacetic acid, which is carried out by the reaction of chloroacetic acid and alkaline cyanides [147][148][149]. The electrocarboxylation of acetonitrile to cyanoacetic acid is an example of a convergent paired electrosynthesis, meaning that two different
Graphical Abstract
Scheme 1: Synthesis of salicylic acid and p-hydroxybenzoic acid via Kolbe–Schmidt reaction [16-20].
Scheme 2: Electroreduction of carbon dioxide to formic acid, methanol or methane.
Scheme 3: Electrochemical fixation of CO2 in olefins.
Scheme 4: Electrohydrodimerisation of acrylonitrile to adiponitrile [32].
Scheme 5: Parallel paired electrosynthesis of phthalide and tert-butylbenzaldehyde dimethylacetal [34].
Scheme 6: Overview of electrocarboxylation setups using (a) a sacrificial anode, (b) an inert anode, generati...
Scheme 7: General mechanism of the electrochemical dicarboxylation of conjugated dienes [49].
Scheme 8: Reported anodic reactions for the electrocarboxylation of 1,3-butadiene.
Scheme 9: General mechanism for electrocarboxylation of alkynes.
Scheme 10: Electrocarboxylation of ethyl cinnamate [70].
Scheme 11: General electrocarboxylation mechanism for carbonyl compounds (Y = O) and imines (Y = NH) [75-77].
Scheme 12: Electrocarboxylation mechanism of butyraldehyde proposed by Doherty [78].
Scheme 13: Electrocarboxylation of AMN to HN using a sacrificial aluminum anode [86].
Scheme 14: Electrocarboxylation of benzalaniline using a sacrificial aluminum anode [105].
Scheme 15: Electrocarboxylation of p-isobutylacetophenone with stable electrodes [94,95].
Scheme 16: Electrochemical carboxylation of MMP to MHA [110,111].
Scheme 17: General mechanism for electrocarboxylation of alkyl halides [122,124-126,128].
Scheme 18: Electrocarboxylation of benzylic chlorides as synthesis route for NSAIDs.
Scheme 19: Electrocarboxylation of 1,4-dibromo-2-butene [144].
Scheme 20: Convergent paired electrosynthesis of cyanoacetic acid, with X− = F4B−, ClO4−, HSO4−, Cl−, Br− [147].
Scheme 21: General scheme of carboxylation of weak acidic hydrocarbons with electrogenerated bases. RH: weakly...
Scheme 22: Electrocarboxylation of N-methyldiglycolimide to methoxymethane-1,1,1’-tricarboxylate precursors. R1...
Scheme 23: Electrochemical dimerization of CO2 with stable electrodes [153].
Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives
- Akshay Kumar and
- Swapandeep Singh Chimni
Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91
- a highly enantioselective transformation, the effect of different acid additives on the enantioselectivity of 4a was studied (Table 3). The reaction was performed with 3,5-dinitrobenzoic acid and chloroacetic acid afforded 4a in good yield of 91% and 90%; and moderate enantioselectivity of 58% ee
Graphical Abstract
Figure 1: Oxindole based Michael acceptors.
Figure 2: Primary-tertiary diamine organocatalysts.
Scheme 1: Diamine catalyzed Michael addition of acetone to isatylidenemalononitrile.
Scheme 2: Substrate scope of the addition of 2 with 3 catalyzed by 1a D-CSA.
Scheme 3: One-pot, three-component Knoevenagel condensation–Michael addition.
Scheme 4: Cascade reduction–cyclization for the synthesis of spirooxindole.
Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics
- Gijs Koopmanschap,
- Eelco Ruijter and
- Romano V.A. Orru
Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50
- yields (57–97%). A less common approach was reported by Pramitha and Bahulayan [91]. Herein, the Ugi reaction was performed with chloroacetic acid, tert-butyl isocyanide and different aldehydes and amines yielding chloro-Ugi products 89 (Scheme 28). A subsequent substitution with sodium azide followed by
Graphical Abstract
Scheme 1: The proposed mechanism of the Passerini reaction.
Scheme 2: The PADAM-strategy to α-hydroxy-β-amino amide derivatives 7. An additional oxidation provides α-ket...
Scheme 3: The general accepted Ugi-mechanism.
Scheme 4: Three commonly applied Ugi/cyclization approaches. a) UDC-process, b) UAC-sequence, c) UDAC-combina...
Scheme 5: Ugi reaction that involves the condensation of Armstrong’s convertible isocyanide.
Scheme 6: Mechanism of the U-4C-3CR towards bicyclic β-lactams.
Scheme 7: The Ugi 4C-3CR towards oxabicyclo β-lactams.
Scheme 8: Ugi MCR between an enantiopure monoterpene based β-amino acid, aldehyde and isocyanide resulting in...
Scheme 9: General MCR for β-lactams in water.
Scheme 10: a) Ugi reaction for β-lactam-linked peptidomimetics. b) Varying the β-amino acid resulted in β-lact...
Scheme 11: Ugi-4CR followed by a Pd-catalyzed Sn2 cyclization.
Scheme 12: Ugi-3CR of dipeptide mimics from 2-substituted pyrrolines.
Scheme 13: Joullié–Ugi reaction towards 2,5-disubstituted pyrrolidines.
Scheme 14: Further elaboration of the Ugi-scaffold towards bicyclic systems.
Scheme 15: Dihydroxyproline derivatives from an Ugi reaction.
Scheme 16: Diastereoselective Ugi reaction described by Banfi and co-workers.
Scheme 17: Similar Ugi reaction as in Scheme 16 but with different acids and two chiral isocyanides.
Scheme 18: Highly diastereoselective synthesis of pyrrolidine-dipeptoids via a MAO-N/MCR-procedure.
Scheme 19: MAO-N/MCR-approach towards the hepatitis C drug telaprevir.
Scheme 20: Enantioselective MAO-U-3CR procedure starting from chiral pyrroline 64.
Scheme 21: Synthesis of γ-lactams via an UDC-sequence.
Scheme 22: Utilizing bifunctional groups to provide bicyclic γ-lactam-ketopiperazines.
Scheme 23: The Ugi reaction provided both γ- as δ-lactams depending on which inputs were used.
Scheme 24: The sequential Ugi/RCM with olefinic substrates provided bicyclic lactams.
Scheme 25: a) The structural and dipole similarities of the triazole unit with the amide bond. b) The copper-c...
Scheme 26: The Ugi/Click sequence provided triazole based peptidomimetics.
Scheme 27: The Ugi/Click reaction as described by Nanajdenko.
Scheme 28: The Ugi/Click-approach by Pramitha and Bahulayan.
Scheme 29: The Ugi/Click-combination by Niu et al.
Scheme 30: Triazole linked peptidomimetics obtained from two separate MCRs and a sequential Click reaction.
Scheme 31: Copper-free synthesis of triazoles via two MCRs in one-pot.
Scheme 32: The sequential Ugi/Paal–Knorr reaction to afford pyrazoles.
Scheme 33: An intramolecular Paal–Knorr condensation provided under basic conditions pyrazolones.
Scheme 34: Similar cyclization performed under acidic conditions provided pyrazolones without the trifluoroace...
Scheme 35: The Ugi-4CR towards 2,4-disubstituted thiazoles.
Scheme 36: Solid phase approach towards thiazoles.
Scheme 37: Reaction mechanism of formation of thiazole peptidomimetics containing an additional β-lactam moiet...
Scheme 38: The synthesis of the trisubstituted thiazoles could be either performed via an Ugi reaction with pr...
Scheme 39: Performing the Ugi reaction with DMB-protected isocyanide gave access to either oxazoles or thiazol...
Scheme 40: Ugi/cyclization-approach towards 2,5-disubstituted thiazoles. The Ugi reaction was performed with d...
Scheme 41: Further derivatization of the thiazole scaffold.
Scheme 42: Three-step procedure towards the natural product bacillamide C.
Scheme 43: Ugi-4CR to oxazoles reported by Zhu and co-workers.
Scheme 44: Ugi-based synthesis of oxazole-containing peptidomimetics.
Scheme 45: TMNS3 based Ugi reaction for peptidomimics containing a tetrazole.
Scheme 46: Catalytic cycle of the enantioselective Passerini reaction towards tetrazole-based peptidomimetics.
Scheme 47: Tetrazole-based peptidomimetics via an Ugi reaction and a subsequent sigmatropic rearrangement.
Scheme 48: Resin-bound Ugi-approach towards tetrazole-based peptidomimetics.
Scheme 49: Ugi/cyclization approach towards γ/δ/ε-lactam tetrazoles.
Scheme 50: Ugi-3CR to pipecolic acid-based peptidomimetics.
Scheme 51: Staudinger–Aza-Wittig/Ugi-approach towards pipecolic acid peptidomimetics.
Figure 1: The three structural isomers of diketopiperazines. The 2,5-DKP isomer is most common.
Scheme 52: UDC-approach to obtain 2,5-DKPs, either using Armstrong’s isocyanide or via ethylglyoxalate.
Scheme 53: a) Ugi reaction in water gave either 2,5-DKP structures or spiro compounds. b) The Ugi reaction in ...
Scheme 54: Solid-phase approach towards diketopiperazines.
Scheme 55: UDAC-approach towards DKPs.
Scheme 56: The intermediate amide is activated as leaving group by acid and microwave assisted organic synthes...
Scheme 57: UDC-procedure towards active oxytocin inhibitors.
Scheme 58: An improved stereoselective MCR-approach towards the oxytocin inhibitor.
Scheme 59: The less common Ugi reaction towards DKPs, involving a Sn2-substitution.
Figure 2: Spatial similarities between a natural β-turn conformation and a DKP based β-turn mimetic [158].
Scheme 60: Ugi-based syntheses of bicyclic DKPs. The amine component is derived from a coupling between (R)-N-...
Scheme 61: Ugi-based synthesis of β-turn and γ-turn mimetics.
Figure 3: Isocyanide substituted 3,4-dihydropyridin-2-ones, dihydropyridines and the Freidinger lactams. Bio-...
Scheme 62: The mechanism of the 4-CR towards 3,4-dihydropyridine-2-ones 212.
Scheme 63: a) Multiple MCR-approach to provide DHP-peptidomimetic in two-steps. b) A one-pot 6-CR providing th...
Scheme 64: The MCR–alkylation–MCR procedure to obtain either tetrapeptoids or depsipeptides.
Scheme 65: U-3CR/cyclization employing semicarbazone as imine component gave triazine based peptidomimetics.
Scheme 66: 4CR towards triazinane-diones.
Scheme 67: The MCR–alkylation–IMCR-sequence described by our group towards triazinane dione-based peptidomimet...
Scheme 68: Ugi-4CR approaches followed by a cyclization to thiomorpholin-ones (a) and pyrrolidines (b).
Scheme 69: UDC-approach for benzodiazepinones.
Scheme 70: Ugi/Mitsunobu sequence to BDPs.
Scheme 71: A UDAC-approach to BDPs with convertible isocyanides. The corresponding amide is cleaved by microwa...
Scheme 72: microwave assisted post condensation Ugi reaction.
Scheme 73: Benzodiazepinones synthesized via the post-condensation Ugi/ Staudinger–Aza-Wittig cyclization.
Scheme 74: Two Ugi/cyclization approaches utilizing chiral carboxylic acids. Reaction (a) provided the product...
Scheme 75: The mechanism of the Gewald-3CR includes three base-catalysed steps involving first a Knoevnagel–Co...
Scheme 76: Two structural 1,4-thienodiazepine-2,5-dione isomers by U-4CR/cyclization.
Scheme 77: Tetrazole-based diazepinones by UDC-procedure.
Scheme 78: Tetrazole-based BDPs via a sequential Ugi/hydrolysis/coupling.
Scheme 79: MCR synthesis of three different tricyclic BPDs.
Scheme 80: Two similar approaches both involving an Ugi reaction and a Mitsunobu cyclization.
Scheme 81: Mitsunobu–Ugi-approach towards dihydro-1,4-benzoxazepines.
Scheme 82: Ugi reaction towards hetero-aryl fused 5-oxo-1,4-oxazepines.
Scheme 83: a) Ugi/RCM-approach towards nine-membered peptidomimetics b) Sequential peptide-coupling, deprotect...
Scheme 84: Ugi-based synthesis towards cyclic RGD-pentapeptides.
Scheme 85: Ugi/MCR-approach towards 12–15 membered macrocycles.
Scheme 86: Stereoselective Ugi/RCM approach towards 16-membered macrocycles.
Scheme 87: Passerini/RCM-sequence to 22-membered macrocycles.
Scheme 88: UDAC-approach towards 12–18-membered depsipeptides.
Figure 4: Enopeptin A with its more active derivative ADEP-4.
Scheme 89: a) The Joullié–Ugi-approach towards ADEP-4 derivatives b) Ugi-approach for the α,α-dimethylated der...
Scheme 90: Ugi–Click-strategy for 15-membered macrocyclic glyco-peptidomimetics.
Scheme 91: Ugi/Click combinations provided macrocycles containing both a triazole and an oxazole moiety.
Scheme 92: a) A solution-phase procedure towards macrocycles. b) Alternative solid-phase synthesis as was repo...
Scheme 93: Ugi/cyclization towards cyclophane based macrocycles.
Scheme 94: PADAM-strategy towards eurystatin A.
Scheme 95: PADAM-approach for cyclotheanamide.
Scheme 96: A triple MCR-approach affording RGD-pentapeptoids.
Scheme 97: Ugi-MiBs-approach towards peptoid macrocycles.
Scheme 98: Passerini-based MiB approaches towards macrocycles 345 and 346.
Scheme 99: Macrocyclic peptide formation by the use of amphoteric aziridine-based aldehydes.
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
- chromium(VI) oxide yielded the aldehyde 1.67 required for the previously described Knoevenagel condensation. The five membered heterocycle 2,4-thiazolidinedione (1.68) is readily available commercially, but can be easily prepared at scale via a simple cyclocondensation between thiourea and chloroacetic
- acid [42]. Finally, hydrogenation of the double bond using Pearlmans catalyst furnishes rosiglitazone (1.40). In addition to the illustrated syntheses of rosiglitazone several routes towards pioglitazone (1.41) and its key intermediates have been reported. Pioglitazone is clearly related to
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.
A facile, rapid, one-pot regio/stereoselective synthesis of 2-iminothiazolidin-4-ones under solvent/scavenger-free conditions
- Murugan Sathishkumar,
- Sangaraiah Nagarajan,
- Poovan Shanmugavelan,
- Murugan Dinesh and
- Alagusundaram Ponnuswamy
Beilstein J. Org. Chem. 2013, 9, 689–697, doi:10.3762/bjoc.9.78
- the formation of the carboxylate anion of one the starting materials viz. chloroacetic acid or the thiourea-chloroacetic acid coupled product. This may retard the direct amine–carboxylic acid coupling, thus decreasing the yield of the product. In view of the above perception, the solvent-free protocol
- was screened with one equivalent or in the absence of acid scavenger and varying equivalents of chloroacetic acid at 100 °C (Table 2). The optimum conditions were found to be with 3 equivalents of chloroacetic acid in the absence of acid scavenger affording a good yield of 2-iminothiazolidin-4-one 4f
- . Optimization of solution-phase and solvent-free synthesis of 2-iminothiazolidin-4-one 4f. Screening of base and equivalents of chloroacetic acid in the solvent-free synthesis of 2-iminothiazolidin-4-one 4f. Solvent/scavenger-free synthesis of 2-iminothiazolidin-4-ones 4a–n. Solvent/scavenger-free synthesis of
Graphical Abstract
Figure 1: Medicinally relevant 2-iminothiazolidin-4-ones.
Scheme 1: Plausible mechanism.
Figure 2: Retardation of the nucleophilic attack of amines on the isothiocyanate due to the steric effect.
Figure 3: Possible regio/stereoisomeric products.
Scheme 2: Regioselective cyclization in 2-iminothiazolidin-4-one synthesis directed by allylic strains.
Figure 4: Stereoselectivity of the reaction directed by A1,3 strain.
Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity
- Krzysztof M. Borys,
- Maciej D. Korzyński and
- Zbigniew Ochal
Beilstein J. Org. Chem. 2012, 8, 259–265, doi:10.3762/bjoc.8.27
- ). Reaction of 4-chlorothiophenol (2) with sodium hydroxide and sodium chloroacetate (obtained in situ by neutralization of chloroacetic acid with NaOH solution) afforded 2-(4-chlorophenylthio)acetic acid (3). Oxidative bromination of 3 with sodium hypobromite gave sulfone 1 in moderate (57%) overall yield
Graphical Abstract
Scheme 1: Retrosynthetic analysis of the designed target molecules.
Scheme 2: Synthetic routes for 4-chlorophenyl tribromomethyl sulfone (1).
Scheme 3: Halogenation/nitration sequence for 4-halogenphenyl methyl sulfones 4 and 4'.
Scheme 4: SNAr transformations of sulfone 6.
Scheme 5: Preparation of phenylhydrazones 8a–8l.
Scheme 6: Products of the nitro group reduction of sulfone 7a.
Scheme 7: Synthesis of benzimidazole derivatives 11a–11g.
Scheme 8: Preparation and further transformation of 2-mercaptobenzimidazole 11h.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
- Marcus Baumann,
- Ian R. Baxendale,
- Steven V. Ley and
- Nikzad Nikbin
Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57
Graphical Abstract
Figure 1: Structures of atorvastatin and other commercial statins.
Figure 2: Structure of compactin.
Scheme 1: Synthesis of pentasubstituted pyrroles.
Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
Scheme 6: Convergent synthesis towards atorvastatin.
Figure 3: Binding pocket of sunitinib in the TRK KIT.
Scheme 7: Synthesis of sunitinib.
Scheme 8: Alternative synthesis of sunitinib.
Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
Scheme 13: Alternative introduction of the sulfonamide.
Scheme 14: Negishi-type coupling to benzylic sulfonamides.
Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
Scheme 18: Improved synthesis of rizatriptan.
Scheme 19: Larock-type synthesis of rizatriptan.
Scheme 20: Synthesis of eletriptan.
Scheme 21: Heck coupling for the indole system in eletriptan.
Scheme 22: Attempted Fischer indole synthesis of elatriptan.
Scheme 23: Successful Fischer indole synthesis for eletriptan.
Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
Scheme 26: Palladium-mediated synthesis of ondansetron.
Scheme 27: Fischer indole synthesis of ondansetron.
Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
Figure 4: Structures of carvedilol 136 and propranolol 137.
Scheme 29: Synthesis of the carbazole core of carvedilol.
Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
Scheme 31: Convergent synthesis of etodolac.
Scheme 32: Alternative synthesis of etodolac.
Figure 5: Structures of imidazole-containing drugs.
Scheme 33: Synthesis of functionalised imidazoles towards losartan.
Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
Scheme 35: Synthesis of trisubstituted imidazoles.
Scheme 36: Preparation of the imidazole ring in olmesartan.
Scheme 37: Synthesis of ondansetron.
Scheme 38: Alternative route to ondansetron and its analogues.
Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
Scheme 40: Synthesis of benzimidazole core pantoprazole.
Figure 6: Structure of rabeprazole 194.
Scheme 41: Synthesis of candesartan.
Scheme 42: Alternative access to the candesartan key intermediate 216.
Scheme 43: .Medicinal chemistry route to telmisartan.
Scheme 44: Improved synthesis of telmisartan.
Scheme 45: Synthesis of zolpidem.
Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
Figure 7: Structure of celecoxib.
Scheme 47: Preparation of celecoxib.
Scheme 48: Alternative synthesis of celecoxib.
Scheme 49: Regioselective access to celecoxib.
Scheme 50: Synthesis of pazopanib.
Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
Scheme 52: Regioselective synthesis of anastrozole.
Scheme 53: Triazine-mediated triazole formation towards anastrozole.
Scheme 54: Alternative routes to 1,2,4-triazoles.
Scheme 55: Initial synthetic route to sitagliptin.
Figure 8: Binding of sitagliptin within DPP-IV.
Scheme 56: The process route to sitagliptin key intermediate 280.
Scheme 57: Synthesis of maraviroc.
Scheme 58: Synthesis of alprazolam.
Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
Scheme 60: Synthesis of itraconazole.
Scheme 61: Synthesis of rufinamide.
Scheme 62: Representative tetrazole formation in valsartan.
Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
Scheme 63: Early stage introduction of the tetrazole in losartan.
Scheme 64: Synthesis of cilostazol.
Figure 11: Structure of cefdinir.
Scheme 65: Semi-synthesis of cefdinir.
Scheme 66: Thiazole syntheses towards ritonavir.
Scheme 67: Synthesis towards pramipexole.
Scheme 68: Alternative route to pramipexole.
Scheme 69: Synthesis of famotidine.
Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
Scheme 71: Synthesis of ziprasidone.
Figure 12: Structure of mometasone.
Scheme 72: Industrial access to 2-furoic acid present in mometasone.
Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
Scheme 74: Synthesis of nitrofurantoin.
Scheme 75: Synthesis of benzofuran.
Scheme 76: Synthesis of amiodarone.
Scheme 77: Synthesis of raloxifene.
Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
Scheme 79: Gewald reaction in the synthesis of olanzapine.
Scheme 80: Alternative synthesis of olanzapine.
Figure 13: Access to simple thiophene-containing drugs.
Scheme 81: Synthesis of clopidogrel.
Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
Scheme 83: Alternative synthesis of key intermediate 422.
Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
Scheme 84: Synthesis of timolol.
Scheme 85: Synthesis of tizanidine 440.
Scheme 86: Synthesis of leflunomide.
Scheme 87: Synthesis of sulfamethoxazole.
Scheme 88: Synthesis of risperidone.
Figure 15: Relative abundance of selected transformations.
Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
