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Search for "diene" in Full Text gives 323 result(s) in Beilstein Journal of Organic Chemistry. Showing first 200.
Vicinal ketoesters – key intermediates in the total synthesis of natural products
- Marc Paul Beller and
- Ulrich Koert
Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129
- cycloaddition delivered the advanced intermediate 43 in an efficient and elegant way. Jatropha-5,12-diene Towards the total synthesis of natural and unnatural jatrophane diterpenes, Hiersemann et al. used a highly efficient, intramolecular carbonyl-ene reaction of α-ketoester 49 (Scheme 8) [22]. The ketoester
Graphical Abstract
Scheme 1: Structures of vicinal ketoesters and examples for their typical reactivity.
Scheme 2: Doyle’s diastereoselective intramolecular aldol addition of α,β-diketoester.
Scheme 3: Synthesis of euphorikanin A (16) by intramolecular, nucleophilic addition [6].
Scheme 4: Ketoester cycloisomerization for the synthesis of preussochromone A (24) [10].
Scheme 5: Diastereoselective, intramolecular aldol reaction of an α-ketoester 28 in the synthesis of (−)-preu...
Scheme 6: Synthesis of an α-ketoester through Riley oxidation and its use in an α-ketol rearrangement in the ...
Scheme 7: Azomethine imine cycloaddition towards the synthesis of the proposed structure of palau’amine (44) [19]....
Scheme 8: Intramolecular diastereoselective carbonyl-ene reaction of an α-ketoester in the synthesis of jatro...
Scheme 9: Grignard addition to an α-ketoester and subsequent Friedel–Crafts cyclization in the synthesis of (...
Scheme 10: Diastereoselective addition to an auxiliary modified α-ketoester in the formal synthesis of (+)-cam...
Scheme 11: Intramolecular photoreduction of an α-ketoester in the synthesis of (rac)-isoretronecanol (69) [26].
Scheme 12: α-Ketoester as nucleophile in a Tsuji–Trost reaction in the synthesis of (rac)-corynoxine (76) [27].
Scheme 13: Mannich reaction of an α-ketoester in the synthesis of (+)-gracilamine (83) [28].
Scheme 14: Enantioselective aldol reaction using an α-ketoester in the synthesis of (−)-irofulven (87) [29].
Scheme 15: Allylboration of a mesoxalic acid ester in the synthesis of (+)-awajanomycin (92) [30,31].
Scheme 16: Condensation of a diamine with mesoxolate in the synthesis of (−)-aplaminal (96) [32].
Scheme 17: Synthesis of mesoxalic ester amide 102 and its use in the synthesis of (rac)-cladoniamide G (103) [33].
Scheme 18: The thermodynamically controlled, intramolecular aldol addition of a vic-tricarbonyl compound in th...
Dienophilic reactivity of 2-phosphaindolizines: a conceptual DFT investigation
- Nosheen Beig,
- Aarti Peswani and
- Raj Kumar Bansal
Beilstein J. Org. Chem. 2022, 18, 1217–1224, doi:10.3762/bjoc.18.127
- reaction with an electron-rich diene such as DMB. However, in the case of compound 1 (R1 = R2 = CO2Me), the EWG at the 1-position functions as electron-sink between the nitrogen lone-pair and the >C=P– functionality. As a result, the latter retains its electron-deficient character and undergoes DA reaction
Graphical Abstract
Figure 1: Structures of 2-phosphaindolizine (1) and indolizine (2).
Figure 2: Structures of 1-aza-2-phosphaindolizines 3, 3-aza-2-phosphaindolizines 4, and 1,3-diaza-2-phosphain...
Figure 3: Transfer of the nitrogen lone-pair in 2-phosphaindolizines.
Figure 4: Energy gap (ΔE) between HOMO of 1,3-butadiene and LUMO of 2-phosphaindolizine.
Figure 5: Kohn–Shan HOMO of 1,3-butadiene and LUMOs of 2-phosphaindolizines computed at the B3LYP/6-31+G(d) l...
Radical cation Diels–Alder reactions of arylidene cycloalkanes
- Kaii Nakayama,
- Hidehiro Kamiya and
- Yohei Okada
Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112
- reaction is a typical example of this activation mode since both the original diene and dienophile are electron-rich and thus not an effective combination of reactants [1][2][3][4][5][6][7][8][9][10][11]. Single-electron transfer makes the construction of six-membered ring systems possible. In general
- , single-electron oxidation of an electron-rich dienophile generates its radical cation which is then trapped by the diene (Figure 1). Since the forming cyclohexene remains in the radical cation state as well, one electron reduction is required to complete the net redox neutral transformation. Therefore, a
- there is some correlation between these arylidene cycloalkane cycloadditions. Control studies are summarized in Table 1. LiClO4, TiO2, and light were crucial for the reaction (Table 1, entries 1–4) and the equivalents of the diene 2 was also key (entries 5 and 6 in Table 1). The reaction was sensitive
Graphical Abstract
Figure 1: Plausible mechanism of the radical cation Diels–Alder reaction (EDG: electron-donating group).
Figure 2: Landscape of the radical cation Diels–Alder reaction.
Scheme 1: Radical cation Diels–Alder reaction of β-methylstyrene.
Scheme 2: Radical cation Diels–Alder reaction of β-methylanethole (1). Recovered starting material is reporte...
Figure 3: Formal expression of radical cations.
Scheme 3: Radical cation Diels–Alder reactions of the arylidene cycloalkanes (4–7). Recovered starting materi...
Scheme 4: Scope of the radical cation Diels–Alder reaction of arylidene cycloalkanes (recovered starting mate...
Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates
- Hui Zheng,
- Ying Han,
- Jing Sun and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99
- -hydroxy-4-(4-methoxyphenyl)cyclopent-2-ene-1-carboxamido)-5-(4-methoxyphenyl)cyclopenta-2,4-diene-1,2-dicarboxylate (4a): yellow solid, 62%; mp 182–184 °C; 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H, NH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 6.90 (s, 1H, CH), 6.88–6.84 (m, 4H, ArH
Graphical Abstract
Scheme 1: Representative cycloaddition reactions of phenacylmalononitriles.
Figure 1: Single crystal structure of compound 3k.
Figure 2: Single crystal structure of compound 4a.
Figure 3: Single crystal structure of compound 4c.
Scheme 2: Proposed reaction mechanism for compounds 3, 4, and 5.
Figure 4: Single crystal structure of compound 5.
Scheme 3: Control experiment.
Understanding the competing pathways leading to hydropyrene and isoelisabethatriene
- Shani Zev,
- Marion Ringel,
- Ronja Driller,
- Bernhard Loll,
- Thomas Brück and
- Dan T. Major
Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97
- ) precursor erogorgiaene and (1R)-epoxyelisabetha-5,14-diene (EED), respectively [6][7]. Ps, marine amphilectane-type diterpenoids from the gorgonian coral Antillogorgia elisabethae, feature superior anti-inflammatory properties which render them innovative target compounds for drug development [8][9]. Hence
Graphical Abstract
Figure 1: Summary of yields of HP and IE products in hydropyrene synthase.
Scheme 1: Proposed mechanism for HP and IE routes.
Figure 2: Free energy profile of hydropyrene cation (a), and IE cation (b) formation in the gas phase. The fr...
Figure 3: Structures of intermediates C‘ and C. The distance between the double bond and the cation in interm...
Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa
- Shou-Mao Shen,
- Qing Yang,
- Yi Zang,
- Jia Li,
- Xueting Liu and
- Yue-Wei Guo
Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91
- isomerized to nerolidyl diphosphate (NPP), followed by the 6,7-bond formation to generate carbocation intermediate I (Scheme 1, II) [31]. Sequential 1,3-hydride shift and 1,6-cyclization occurred to afford cadinyl cation (J). Further 1,3-hydride shift and deprotonation on J resulted in cadina-1(6),4-diene (L
Graphical Abstract
Figure 1: Chemical structures of compounds 1–8.
Figure 2: ORTEP drawing of 2 (displacement ellipsoids are drawn at the 50% probability level).
Figure 3: Experimental and calculated ECD curves of (+)-1.
Figure 4: 1H-1H COSY, key HMBC correlations, and NOESY correlations of compound 5.
Figure 5: Experimental ECD curves of compounds (+)-4, (−)-4 (top), (+)-5, and (−)-5 (bottom).
Scheme 1: Proposed cyclization pathway of terpene intermediates and plausible post-modifications of compounds ...
Figure 6: Compound 3 reduced the mRNA levels of TNF-α (left) and CCL2 (right) in LPS-stimulated RAW264.7 macr...
Synthesis of odorants in flow and their applications in perfumery
- Merlin Kleoff,
- Paul Kiler and
- Philipp Heretsch
Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76
- ]. Therefore, Roberge, Fogg, and co-workers investigated the advantages of continuously stirred tank reactors (CSTR) and tube reactors in comparison to the corresponding batch reaction for the ring-closing metathesis of diene 58, producing macrocyclic olefin 60 (Scheme 14) [52]. Although, macrocycle 60 is not
- min. When diene 58 and catalyst 59 are pre-mixed and pumped through a tube reactor, the ethylene released from the reaction results in a segmented flow. Therefore, the formed ethylene is not released from the tube reactor, hampering the reaction to reach full conversion as observed under batch
- and with a Z-selectivity of >98% [54]. In contrast, Amorelli, Collins, and co-workers performed a ring-closing metathesis for the synthesis of macrocycle 72 from diene 70 at high temperatures of 150 °C in only 5 min without removal of formed ethylene (Scheme 17) [55]. Under these conditions, the
Graphical Abstract
Figure 1: The olfactory spectrum wheel ordering different types of odorants from fruity to musky.
Figure 2: Classification of odorants as “top note”, “middle note” and “base note” depending on their substant...
Scheme 1: Synthesis of raspberry ketone (5) and raspberry ketone methyl ether (6) in two steps in flow.
Scheme 2: Autoxidation of (+)-valencene (7) to (+)-nootkatone (8) under catalyst and solvent-free conditions ...
Scheme 3: Enzyme-catalyzed acetylation of isoamyl alcohol (9) in a biphasic n-heptane/water mixture utilizing...
Scheme 4: Esterification of alcohols by transesterification, catalyzed by immobilized acyltransferase in a pa...
Scheme 5: Synthesis of homologated alcohols 20 by iterative homologation of terpenyl boronate esters 17 follo...
Scheme 6: Sequential three-step synthesis of (S)-α-phellandrene (30) from (R)-carvone (25) via selective hydr...
Scheme 7: Selective hydrogenation of alkyne 31 to “leaf alcohol” 32 employing a solid-supported palladium cat...
Scheme 8: A) Synthesis of jasmonal (35) by crossed aldol condensation of benzaldehyde (33) and heptanal (34) ...
Scheme 9: Synthesis of thymol (41) from m-cresol (39) and isopropyl alcohol via Fries-type rearrangement of e...
Scheme 10: Preparation of coumarin (46) by reaction of salicylaldehyde (44) with potassium acetate, acetic aci...
Scheme 11: Synthesis of phthalide (50) by photoinduced decatungstate catalysis.
Scheme 12: Synthesis of woody acetate (54) by reduction of cyclohexanone 51 and subsequent acetylation; ADH200...
Scheme 13: Synthesis of juniper lactone (56) by pyrolysis of triperoxide 55 generated by oxidation of cyclohex...
Scheme 14: Synthesis of macrocyclic olefine 60 by ring-closing metathesis of diene 58 in a continuously stirre...
Scheme 15: Synthesis of macrocycles 65 and 66 by ring-closing metathesis of dienes 62 or 63, respectively, in ...
Scheme 16: Z-Selective synthesis of civetone (69) enabled by metathesis catalyst 68 in a tube-in-tube reactor.
Scheme 17: Synthesis of macrocyclic olefine 72 by ring-closing metathesis of diene 70.
Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities
- Viktor A. Zapol’skii,
- Isabell Berneburg,
- Ursula Bilitewski,
- Melissa Dillenberger,
- Katja Becker,
- Stefan Jungwirth,
- Aditya Shekhar,
- Bastian Krueger and
- Dieter E. Kaufmann
Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54
- reported on the syntheses of a wide range of diverse substance classes applying this useful starting material. In the course of our studies concerning polyhalogenated nitrodienes, in many cases 2-nitroperchlorobuta-1,3-diene (1) [8][9][10] or nitrotrichloroethylene [11][12][13] have proved as appropriate
- precursors for a diverse variety of synthetically and/or physiologically interesting chemical compounds. Recently, we have developed an efficient method for the synthesis of persubstituted nitropyrazoles from diene 1 [14]. In this paper we are describing the formation of uniquely persubstituted 1H-pyrazoles
- -bisazolylbutadienes 2a–c with up to 98% yield (Scheme 1). The regiospecificity is caused by the fact that the LUMO of diene 1 is located preferentially at the dichloronitrovinyl fragment, and to an extent of 67% (by using MINDO/3 as semi-empirical method for the quantum calculation of the molecular electronic
Graphical Abstract
Figure 1: The structures of chloroquine, hydroxychloroquine, and amodiaquine.
Scheme 1: Synthesis of 3-azolylpyrazoles 3a–c.
Scheme 2: Assumed mechanism for the formation of 1H-pyrazoles 3a–c.
Scheme 3: Synthesis of 3-aminopyrazoles 5b–k and 5-aminopyrazoles 5a and 5l–o.
Scheme 4: Orientation of nucleophilic attack of 7-chloro-4-hydrazinylquinoline on nitrobutadienes 4.
Scheme 5: Synthesis of oxazolidine 6 and pyrazole 7.
Scheme 6: A plausible mechanism for the formation of pyrazole 7.
Scheme 7: Synthesis of pyrazoles 9 and sulfoxide 10d.
Scheme 8: Synthesis of pyrazole 11.
Menadione: a platform and a target to valuable compounds synthesis
- Acácio S. de Souza,
- Ruan Carlos B. Ribeiro,
- Dora C. S. Costa,
- Fernanda P. Pauli,
- David R. Pinho,
- Matheus G. de Moraes,
- Fernando de C. da Silva,
- Luana da S. M. Forezi and
- Vitor F. Ferreira
Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43
- 2002, an interesting methodology for menadione synthesis was reported by Kacan and Karabulut (Scheme 5). The authors studied a Diels–Alder reaction, using LiClO4-diethyl ether (LPDE) as a catalyst, 1-ketoxy-1,3-butadiene 28 as a diene and 2-methyl-1,4-benzoquinone (29) as dienophile. By this method
- demethoxycarbonylating annulation of methyl methacrylate (33) with 3-cyanophthalide (32), in the presence of lithium tert-butoxide as catalyst (64% yield) (Scheme 7) [91]. Recently, Dissanayake and co-workers tested the stability of furans to be used as a diene in Diels–Alder reactions for the synthesis of p
- -benzoquinones and p-hydroquinones or the synthesis of menadione (10). The furan derivative 34 was used as a diene and 2-iodophenyltrifluoromethanesulfonate (35) as a dienophile, in the presence of n-butyllithium, forming 10 in 55% yield (Scheme 8) [92]. In the same year, Gogin and and co-workers developed a
Graphical Abstract
Figure 1: Natural bioactive naphthoquinones.
Figure 2: Chemical structures of vitamins K.
Figure 3: Redox cycle of menadione.
Scheme 1: Selected approaches for menadione synthesis using silver(I) as a catalyst.
Scheme 2: Methylation approaches for the preparation of menadione from 1,4-naphthoquinone using tert-butyl hy...
Scheme 3: Methylation approach of 1,4-naphthoquinone using i) rhodium complexes/methylboronic acid and ii) bi...
Scheme 4: Synthesis of menadione (10) from itaconic acid.
Scheme 5: Menadione synthesis via Diels–Alder reaction.
Scheme 6: Synthesis of menadione (10) using p-cresol as a synthetic precursor.
Scheme 7: Synthesis of menadione (10) via demethoxycarbonylating annulation of methyl methacrylate.
Scheme 8: Furan 34 used as a diene in a Diels–Alder reaction for the synthesis of menadione (10).
Scheme 9: o-Toluidine as a dienophile in a Diels–Alder reaction for the synthesis of menadione (10).
Scheme 10: Representation of electrochemical synthesis of menadione.
Figure 4: Reaction sites and reaction types of menadione as substrate.
Scheme 11: DBU-catalyzed epoxidation of menadione (10).
Scheme 12: Phase-transfer catalysis for the epoxidation of menadione.
Scheme 13: Menadione epoxidation using a hydroperoxide derived from (+)-norcamphor.
Scheme 14: Enantioselective Diels–Alder reaction for the synthesis of asymmetric quinone 50 catalyzed by a chi...
Scheme 15: Optimized reaction conditions for the synthesis of anthra[9,1-bc]pyranone.
Scheme 16: Synthesis of anthra[9,1-bc]furanone, anthra[9,1-bc]pyridine, and anthra[9,1-bc]pyrrole derivatives.
Scheme 17: Synthesis of derivatives employing protected trienes.
Scheme 18: Synthesis of cyclobutene derivatives of menadione.
Scheme 19: Menadione reduction reactions using sodium hydrosulfite.
Scheme 20: Green methodology for menadiol synthesis and pegylation.
Scheme 21: Menadione reduction by 5,6-O-isopropylidene-ʟ-ascorbic acid under UV light irradiation.
Scheme 22: Selected approaches of menadione hydroacetylation to diacetylated menadiol.
Scheme 23: Thiele–Winter reaction catalyzed by Bi(OTf)3.
Scheme 24: Carbonyl condensation of menadione using resorcinol and a hydrazone derivative.
Scheme 25: Condensation reaction of menadione with thiosemicarbazide.
Scheme 26: Condensation reaction of menadione with acylhydrazides.
Scheme 27: Menadione derivatives functionalized with organochalcogens.
Scheme 28: Synthesis of selenium-menadione conjugates derived from chloromethylated menadione 84.
Scheme 29: Menadione alkylation by the Kochi–Anderson method.
Scheme 30: Menadione alkylation by diacids.
Scheme 31: Menadione alkylation by heterocycles-substituted carboxylic acids.
Scheme 32: Menadione alkylation by bromoalkyl-substituted carboxylic acids.
Scheme 33: Menadione alkylation by complex carboxylic acids.
Scheme 34: Kochi–Anderson method variations for the menadione alkylation via oxidative decarboxylation of carb...
Scheme 35: Copper-catalyzed menadione alkylation via free radicals.
Scheme 36: Nickel-catalyzed menadione cyanoalkylation.
Scheme 37: Iron-catalyzed alkylation of menadione.
Scheme 38: Selected approaches to menadione alkylation.
Scheme 39: Menadione acylation by photo-Friedel–Crafts acylation reported by Waske and co-workers.
Scheme 40: Menadione acylation by Westwood procedure.
Scheme 41: Synthesis of 3-benzoylmenadione via metal-free TBAI/TBHP system.
Scheme 42: Michael-type addition of amines to menadione reported by Kallmayer.
Scheme 43: Synthesis of amino-menadione derivatives using polyalkylamines.
Scheme 44: Selected examples for the synthesis of different amino-substituted menadione derivatives.
Scheme 45: Selected examples of Michael-type addition of complex amines to menadione (10).
Scheme 46: Addition of different natural α-amino acids to menadione.
Scheme 47: Michael-type addition of amines to menadione using silica-supported perchloric acid.
Scheme 48: Indolylnaphthoquinone or indolylnaphthalene-1,4-diol synthesis reported by Yadav et al.
Scheme 49: Indolylnaphthoquinone synthesis reported by Tanoue and co-workers.
Scheme 50: Indolylnaphthoquinone synthesis from menadione by Escobeto-González and co-workers.
Scheme 51: Synthesis of menadione analogues functionalized with thiols.
Scheme 52: Synthesis of menadione-derived symmetrical derivatives through reaction with dithiols.
Scheme 53: Mercaptoalkyl acids as nucleophiles in Michael-type addition reaction to menadione.
Scheme 54: Reactions of menadione (10) with cysteine derivatives for the synthesis of quinoproteins.
Scheme 55: Synthesis of menadione-glutathione conjugate 152 by Michael-type addition.
Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study
- Angel Ho,
- Austin Pounder,
- Krish Valluru,
- Leanne D. Chen and
- William Tam
Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30
- catalyzed by rhodium/diene to afford the 1,2,4-trisubstituted naphthalene framework 8 with complete regio- and stereocontrol (Scheme 1) [62][63]. In 2015, the Nishimura group reported the first iridium-catalyzed addition of salicylaldehydes 14 to bicyclic alkenes 11 (Scheme 1) [64]. Although a variety of
- this field. Potential energy profile of the PCM solvation model for the hydrometalation/reductive elimination pathway of the Ir/diene-catalyzed hydroacylation of MeOBD with salicylaldehyde (14) in 1,4-dioxane, as evaluated by DFT calculation (M06 [69]/def2SVP [70]/PCM [72]//M06 [69]/def2TZVP [70]/PCM
- PCM solvation model for the carbometalation/reductive elimination pathway of the Ir/diene-catalyzed hydroacylation of MeOBD with salicylaldehyde (14) in 1,4-dioxane, as evaluated by DFT calculation (M06 [69]/def2SVP [70]/PCM [72]//M06 [69]/def2TZVP [70]/PCM [72]). Calculated Gibbs free energies (in
Graphical Abstract
Scheme 1: Previously reported metal-catalyzed reactions of heterobicyclic alkenes and applications towards th...
Scheme 2: Iridium-catalyzed hydroacylation of C1-substituted OBDs 13a–k with salicylaldehyde 14.
Scheme 3: Competition reaction of different C1-substituted OBDs.
Figure 1: Potential energy profile of the PCM solvation model for the hydrometalation/reductive elimination p...
Figure 2: Potential energy profile of the PCM solvation model for the carbometalation/reductive elimination p...
Figure 3: Potential energy profile of the PCM solvation model for the endo hydrometalation/reductive eliminat...
Figure 4: Potential energy profile of the PCM solvation model for the Ir/diene-catalyzed hydroacylation of Me...
Diametric calix[6]arene-based phosphine gold(I) cavitands
- Gabriele Giovanardi,
- Andrea Secchi,
- Arturo Arduini and
- Gianpiero Cera
Beilstein J. Org. Chem. 2022, 18, 190–196, doi:10.3762/bjoc.18.21
- scavenger [37]. After 4 h, NMR analysis of the crude reaction mixture revealed high conversion of the starting material with the formation of the 6-endo-dig rearranged diene 2a and the parental regioisomer 2b in a 1:1 ratio. Noteworthy, this latter is formed by an initial 5-exo-dig cyclization step (entry 1
Graphical Abstract
Figure 1: Selected examples of: a) calix[4]arene-; b) resorcin[4]arene-; c) calix[6]arene-gold(I) macrocyclic...
Scheme 1: i) NH2NH2∙H2O, Pd/C in EtOH, 80 °C (quant.); ii) diphenylphosphinobenzoic acid, EDC∙HCl, DMAP (cat....
Figure 2: Stacked-plot, mid-field expanded region of the 1H NMR spectrum (400 MHz, 298 K) of A(AuCl)2, B(AuCl)...
Figure 3: Stacked plot 1H NMR (tetrachloroethane-d2) of A(AuCl)2 at variable temperature.
Scheme 2: Synthesis of the monomeric gold catalyst analogues A’,B’,C’(AuCl). Conditions: i) diphenylphosphino...
Iron-catalyzed domino coupling reactions of π-systems
- Austin Pounder and
- William Tam
Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196
- Cheng investigated the cascade cyclization of dienes 119 with alkyl carbazates 117 for the synthesis of fused nitrogen heterocyclic compounds 120 (Scheme 25) [117]. Diene substrates possessing EDGs reacted smoothly under the optimized conditions while their electron-deficient counterparts delivered the
Graphical Abstract
Figure 1: Price comparison among iron and other transition metals used in catalysis.
Scheme 1: Typical modes of C–C bond formation.
Scheme 2: The components of an iron-catalyzed domino reaction.
Scheme 3: Iron-catalyzed tandem cyclization and cross-coupling reactions of iodoalkanes 1 with aryl Grignard ...
Scheme 4: Three component iron-catalyzed dicarbofunctionalization of vinyl cyclopropanes 14.
Scheme 5: Three-component iron-catalyzed dicarbofunctionalization of alkenes 21.
Scheme 6: Double carbomagnesiation of internal alkynes 31 with alkyl Grignard reagents 32.
Scheme 7: Iron-catalyzed cycloisomerization/cross-coupling of enyne derivatives 35 with alkyl Grignard reagen...
Scheme 8: Iron-catalyzed spirocyclization/cross-coupling cascade.
Scheme 9: Iron-catalyzed alkenylboration of alkenes 50.
Scheme 10: N-Alkyl–N-aryl acrylamide 60 CDC cyclization with C(sp3)–H bonds adjacent to a heteroatom.
Scheme 11: 1,2-Carboacylation of activated alkenes 60 with aldehydes 65 and alcohols 67.
Scheme 12: Iron-catalyzed dicarbonylation of activated alkenes 68 with alcohols 67.
Scheme 13: Iron-catalyzed cyanoalkylation/radical dearomatization of acrylamides 75.
Scheme 14: Synergistic photoredox/iron-catalyzed 1,2-dialkylation of alkenes 82 with common alkanes 83 and 1,3...
Scheme 15: Iron-catalyzed oxidative coupling/cyclization of phenol derivatives 86 and alkenes 87.
Scheme 16: Iron-catalyzed carbosulfonylation of activated alkenes 60.
Scheme 17: Iron-catalyzed oxidative spirocyclization of N-arylpropiolamides 91 with silanes 92 and tert-butyl ...
Scheme 18: Iron-catalyzed free radical cascade difunctionalization of unsaturated benzamides 94 with silanes 92...
Scheme 19: Iron-catalyzed cyclization of olefinic dicarbonyl compounds 97 and 100 with C(sp3)–H bonds.
Scheme 20: Radical difunctionalization of o-vinylanilides 102 with ketones and esters 103.
Scheme 21: Dehydrogenative 1,2-carboamination of alkenes 82 with alkyl nitriles 76 and amines 105.
Scheme 22: Iron-catalyzed intermolecular 1,2-difunctionalization of conjugated alkenes 107 with silanes 92 and...
Scheme 23: Four-component radical difunctionalization of chemically distinct alkenes 114/115 with aldehydes 65...
Scheme 24: Iron-catalyzed carbocarbonylation of activated alkenes 60 with carbazates 117.
Scheme 25: Iron-catalyzed radical 6-endo cyclization of dienes 119 with carbazates 117.
Scheme 26: Iron-catalyzed decarboxylative synthesis of functionalized oxindoles 130 with tert-butyl peresters ...
Scheme 27: Iron‑catalyzed decarboxylative alkylation/cyclization of cinnamamides 131/134.
Scheme 28: Iron-catalyzed carbochloromethylation of activated alkenes 60.
Scheme 29: Iron-catalyzed trifluoromethylation of dienes 142.
Scheme 30: Iron-catalyzed, silver-mediated arylalkylation of conjugated alkenes 115.
Scheme 31: Iron-catalyzed three-component carboazidation of conjugated alkenes 115 with alkanes 101/139b and t...
Scheme 32: Iron-catalyzed carboazidation of alkenes 82 and alkynes 160 with iodoalkanes 20 and trimethylsilyl ...
Scheme 33: Iron-catalyzed asymmetric carboazidation of styrene derivatives 115.
Scheme 34: Iron-catalyzed carboamination of conjugated alkenes 115 with alkyl diacyl peroxides 163 and acetoni...
Scheme 35: Iron-catalyzed carboamination using oxime esters 165 and arenes 166.
Scheme 36: Iron-catalyzed iminyl radical-triggered [5 + 2] and [5 + 1] annulation reactions with oxime esters ...
Scheme 37: Iron-catalyzed decarboxylative alkyl etherification of alkenes 108 with alcohols 67 and aliphatic a...
Scheme 38: Iron-catalyzed inter-/intramolecular alkylative cyclization of carboxylic acid and alcohol-tethered...
Scheme 39: Iron-catalyzed intermolecular trifluoromethyl-acyloxylation of styrene derivatives 115.
Scheme 40: Iron-catalyzed carboiodination of terminal alkenes and alkynes 180.
Scheme 41: Copper/iron-cocatalyzed cascade perfluoroalkylation/cyclization of 1,6-enynes 183/185.
Scheme 42: Iron-catalyzed stereoselective carbosilylation of internal alkynes 187.
Scheme 43: Synergistic photoredox/iron catalyzed difluoroalkylation–thiolation of alkenes 82.
Scheme 44: Iron-catalyzed three-component aminoazidation of alkenes 82.
Scheme 45: Iron-catalyzed intra-/intermolecular aminoazidation of alkenes 194.
Scheme 46: Stereoselective iron-catalyzed oxyazidation of enamides 196 using hypervalent iodine reagents 197.
Scheme 47: Iron-catalyzed aminooxygenation for the synthesis of unprotected amino alcohols 200.
Scheme 48: Iron-catalyzed intramolecular aminofluorination of alkenes 209.
Scheme 49: Iron-catalyzed intramolecular aminochlorination and aminobromination of alkenes 209.
Scheme 50: Iron-catalyzed intermolecular aminofluorination of alkenes 82.
Scheme 51: Iron-catalyzed aminochlorination of alkenes 82.
Scheme 52: Iron-catalyzed phosphinoylazidation of alkenes 108.
Scheme 53: Synergistic photoredox/iron-catalyzed three-component aminoselenation of trisubstituted alkenes 82.
Targeting active site residues and structural anchoring positions in terpene synthases
- Anwei Hou and
- Jeroen S. Dickschat
Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161
- ionised substrate [9]. The structure of bacterial selina-4(15),7(11)-diene synthase (SdS) and its comparison to other TPS structures revealed that this helix break motif is a general feature of type I TPSs [11]. Furthermore, hydrogen bondings of the substrate’s diphosphate to a highly conserved Arg
Graphical Abstract
Figure 1: Highly conserved residues in the active site of SdS for Mg2+ complexation, substrate recognition an...
Figure 2: The products of SmTS1. A) Structures of sestermobaraenes A–F (1–6) and sestermobaraol (7). B) The t...
Figure 3: Swiss homology modelling of SmTS1. A) Superimposition of the SdS crystal structure (green) with the...
Figure 4: Products and relative activities of SmTS1 and its variants. Bars left of the dashed line show relat...
Figure 5: Total ion chromatogram of an extract from an incubation of GGPP with the SmTS1 A222V variant.
Figure 6: Relative activities of SmTS1 and its variants towards GFPP (blue bars) and GGPP (yellow bars), and ...
Scheme 1: Determination of the enantiomeric composition of 8 and 9 obtained from GGPP with SmTS1 enzyme varia...
Figure 7: Determination of the absolute configuration of compounds 8 and 9. Partial HSQC spectra of A) unlabe...
Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction
- Ren-Jie Fang,
- Chen Yan,
- Jing Sun,
- Ying Han and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159
- active diene, indole-substituted chalcones. Then, the p-TsOH-catalyzed Diels–Alder reaction of indole-chalcones with second chalcones and sequential aromatization through DDQ dehydrogenation resulted in the polyfunctionalized carbazoles 6a–l in good yields (Table 2). Additionally, the similar reaction
- 3-(indol-3-yl)-1,3-diphenylpropan-1-one gave the expected indole-substituted chalcone A, which comprises the desired 3-vinylindole scaffold as the reactive diene. In the meantime, the carbonyl group of the chalcone is protonated to give the activated dienophile in the presence of p-toluenesulfonic
Graphical Abstract
Figure 1: Representative bioactive carbazole derivatives.
Scheme 1: Synthesis of tetrahydropyrrolo[3,4-c]carbazoles 3a and 3b.
Figure 2: Single crystal structure of the isomer 3a.
Figure 3: Single crystal structure of the isomer 3b.
Figure 4: Single crystal structure of the isomer 4g.
Scheme 2: Proposed domino reaction mechanism for the formation of carbazoles 6.
Strategies for the synthesis of brevipolides
- Yudhi D. Kurniawan and
- A'liyatur Rosyidah
Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157
- -promoted double bond migration. The cyclopropyl functionality in 46 can be assembled from the reaction of sulfur ylide and the α,β-unsaturated ketone 47, which in turn can be realized from the cross metathesis between commercially available ethyl vinyl ketone (48) and the C2-symmetrical diene-diol 49. The
- synthesis commenced with the monoprotection of the known diene-diol ent-49 as TBS ether affording compound 50 in 76% yield, which served as an excellent strategy to direct the later cross metathesis reaction to one site of the olefin over another (Scheme 5). Thus, the desired α,β-unsaturated ester 51 was
- route, the alcohol product 75 was isolated in 81% yield (dr 85:15). Esterification of this molecule with acryloyl chloride (76) went smoothly providing the diene 77 (85%), which, after the sequential ring-closing metathesis with Grubbs I catalyst and TBS removal, gave the 5,6-dihydro-α-pyrone 78 in 71
Graphical Abstract
Figure 1: Structures of brevipolides A–O (1 – 15).
Scheme 1: Retrosynthetic analysis of brevipolide H (8) by Kumaraswamy.
Scheme 2: Attempt to synthesize brevipolide H (8) by Kumaraswamy. (R,R)-Noyori cat. = RuCl[N-(tosyl)-1,2-diph...
Scheme 3: Attempt to synthesize brevipolide H (8) by Kumaraswamy (continued).
Scheme 4: Retrosynthetic analysis of brevipolide H (8) by Hou.
Scheme 5: Synthesis ent-brevipolide H (ent-8) by Hou.
Scheme 6: Retrosynthetic analysis of brevipolide H (8) by Mohapatra.
Scheme 7: Attempt to synthesize brevipolide H (8) by Mohapatra.
Scheme 8: Attempt to synthesize brevipolide H (8) by Mohapatra (continued). (+)-(IPC)2-BCl = (+)-B-chloro-dii...
Scheme 9: Retrosynthetic analysis of brevipolide H (8) by Hou.
Scheme 10: Synthesis of brevipolide H (8) by Hou.
Scheme 11: Retrosynthetic analysis of brevipolide M (13) by Sabitha.
Scheme 12: Synthesis of brevipolide M (13) by Sabitha.
Scheme 13: Retrosynthetic analysis of brevipolides M (13) and N (14) by Sabitha.
Scheme 14: Synthesis of brevipolides M (13) and N (14) by Sabitha.
Nomimicins B–D, new tetronate-class polyketides from a marine-derived actinomycete of the genus Actinomadura
- Zhiwei Zhang,
- Tao Zhou,
- Taehui Yang,
- Keisuke Fukaya,
- Enjuro Harunari,
- Shun Saito,
- Katsuhisa Yamada,
- Chiaki Imada,
- Daisuke Urabe and
- Yasuhiro Igarashi
Beilstein J. Org. Chem. 2021, 17, 2194–2202, doi:10.3762/bjoc.17.141
- -cis configuration of the diene moiety was indicated by a NOESY correlation between H21 and H27. The absolute configuration of the dehydrodecalin moiety of 3 was tentatively assigned to be identical with 4 because 3 was considered as a biosynthetic precursor of 4 [20]. Compounds 1‒3 showed
Graphical Abstract
Figure 1: Structures of nomimicins A–D (4 and 1–3).
Figure 2: COSY and key HMBC correlations for 1.
Figure 3: Relative configuration of 1 determined by ROESY analysis.
Figure 4: Experimental ECD spectra of 1, 2, and 4 and calculated ECD spectrum of 4.
Figure 5: Four tautomers 4a–4d of the tetronic acid moiety of 4 and calculated ECD spectra.
Figure 6: COSY and key HMBC correlations for 3.
Figure 7: Relative configuration of 3 determined by NOESY analysis.
On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets
- Renato L. Carvalho,
- Amanda S. de Miranda,
- Mateus P. Nunes,
- Roberto S. Gomes,
- Guilherme A. M. Jardim and
- Eufrânio N. da Silva Júnior
Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126
- ligands but also to the diene R5 and R6 substituents. With this innovative method in hands, the authors explored the synthetic applicability in the preparation of a core unit from lasalocid A (124), a known antibiotic drug [194] that, along with its four analogues 120–123 (Scheme 37A), were extracted from
Graphical Abstract
Scheme 1: Schematic overview of transition metals studied in C–H activation processes.
Scheme 2: (A) Known biological activities related to benzimidazole-based compounds; (B and C) an example of a...
Scheme 3: (A) Known biological activities related to quinoline-based compounds; (B and C) an example of a sca...
Scheme 4: (A) Known biological activities related to sulfur-containing compounds; (B and C) an example of a s...
Scheme 5: (A) Known biological activities related to aminoindane derivatives; (B and C) an example of a scand...
Scheme 6: (A) Known biological activities related to norbornane derivatives; (B and C) an example of a scandi...
Scheme 7: (A) Known biological activities related to aniline derivatives; (B and C) an example of a titanium-...
Scheme 8: (A) Known biological activities related to cyclohexylamine derivatives; (B) an example of an intram...
Scheme 9: (A) Known biologically active benzophenone derivatives; (B and C) photocatalytic oxidation of benzy...
Scheme 10: (A) Known bioactive fluorine-containing compounds; (B and C) vanadium-mediated C(sp3)–H fluorinatio...
Scheme 11: (A) Known biologically active Lythraceae alkaloids; (B) synthesis of (±)-decinine (30).
Scheme 12: (A) Synthesis of (R)- and (S)-boehmeriasin (31); (B) synthesis of phenanthroindolizidines by vanadi...
Scheme 13: (A) Known bioactive BINOL derivatives; (B and C) vanadium-mediated oxidative coupling of 2-naphthol...
Scheme 14: (A) Known antiplasmodial imidazopyridazines; (B) practical synthesis of 41.
Scheme 15: (A) Gold-catalyzed drug-release mechanism using 2-alkynylbenzamides; (B and C) chromium-mediated al...
Scheme 16: (A) Examples of anti-inflammatory benzaldehyde derivatives; (B and C) chromium-mediated difunctiona...
Scheme 17: (A and B) Manganese-catalyzed chemoselective intramolecular C(sp3)–H amination; (C) late-stage modi...
Scheme 18: (A and B) Manganese-catalyzed C(sp3)–H amination; (C) late-stage modification of a leelamine deriva...
Scheme 19: (A) Known bioactive compounds containing substituted N-heterocycles; (B and C) manganese-catalyzed ...
Scheme 20: (A) Known indoles that present GPR40 full agonist activity; (B and C) manganese-catalyzed C–H alkyl...
Scheme 21: (A) Examples of known biaryl-containing drugs; (B and C) manganese-catalyzed C–H arylation through ...
Scheme 22: (A) Known zidovudine derivatives with potent anti-HIV properties; (B and C) manganese-catalyzed C–H...
Scheme 23: (A and B) Manganese-catalyzed C–H organic photo-electrosynthesis; (C) late-stage modification.
Scheme 24: (A) Example of a known antibacterial silylated dendrimer; (B and C) manganese-catalyzed C–H silylat...
Scheme 25: (A and B) Fe-based small molecule catalyst applied for selective aliphatic C–H oxidations; (C) late...
Scheme 26: (A) Examples of naturally occurring gracilioethers; (B) the first total synthesis of gracilioether ...
Scheme 27: (A and B) Selective aliphatic C–H oxidation of amino acids; (C) late-stage modification of proline-...
Scheme 28: (A) Examples of Illicium sesquiterpenes; (B) first chemical synthesis of (+)-pseudoanisatin (80) in...
Scheme 29: (A and B) Fe-catalyzed deuteration; (C) late-stage modification of pharmaceuticals.
Scheme 30: (A and B) Biomimetic Fe-catalyzed aerobic oxidation of methylarenes to benzaldehydes (PMHS, polymet...
Scheme 31: (A) Known tetrahydroquinolines with potential biological activities; (B and C) redox-selective Fe c...
Scheme 32: (A) Known drugs containing a benzofuran unit; (B and C) Fe/Cu-catalyzed tandem O-arylation to acces...
Scheme 33: (A) Known azaindolines that act as M4 muscarinic acetylcholine receptor agonists; (B and C) intramo...
Scheme 34: (A) Known indolinones with anticholinesterase activity; (B and C) oxidative C(sp3)–H cross coupling...
Scheme 35: (A and B) Cobalt-catalyzed C–H alkenylation of C-3-peptide-containing indoles; (C) derivatization b...
Scheme 36: (A) Cobalt-Cp*-catalyzed C–H methylation of known drugs; (B and C) scope of the o-methylated deriva...
Scheme 37: (A) Known lasalocid A analogues; (B and C) three-component cobalt-catalyzed C–H bond addition; (D) ...
Scheme 38: (A and B) Cobalt-catalyzed C(sp2)–H amidation of thiostrepton.
Scheme 39: (A) Known 4H-benzo[d][1,3]oxazin-4-one derivatives with hypolipidemic activity; (B and C) cobalt-ca...
Scheme 40: (A and B) Cobalt-catalyzed C–H arylation of pyrrole derivatives; (C) application for the synthesis ...
Scheme 41: (A) Known 2-phenoxypyridine derivatives with potent herbicidal activity; (B and C) cobalt-catalyzed...
Scheme 42: (A) Natural cinnamic acid derivatives; (B and C) cobalt-catalyzed C–H carboxylation of terminal alk...
Scheme 43: (A and B) Cobalt-catalyzed C–H borylation; (C) application to the synthesis of flurbiprofen.
Scheme 44: (A) Benzothiazoles known to present anticonvulsant activities; (B and C) cobalt/ruthenium-catalyzed...
Scheme 45: (A and B) Cobalt-catalyzed oxygenation of methylene groups towards ketone synthesis; (C) synthesis ...
Scheme 46: (A) Known anticancer tetralone derivatives; (B and C) cobalt-catalyzed C–H difluoroalkylation of ar...
Scheme 47: (A and B) Cobalt-catalyzed C–H thiolation; (C) application in the synthesis of quetiapine (153).
Scheme 48: (A) Known benzoxazole derivatives with anticancer, antifungal, and antibacterial activities; (B and...
Scheme 49: (A and B) Cobalt-catalyzed C–H carbonylation of naphthylamides; (C) BET inhibitors 158 and 159 tota...
Scheme 50: (A) Known bioactive pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives; (B and C) cobalt-catalyzed C–H ...
Scheme 51: (A) Known antibacterial cyclic sulfonamides; (B and C) cobalt-catalyzed C–H amination of propargyli...
Scheme 52: (A and B) Cobalt-catalyzed intramolecular 1,5-C(sp3)–H amination; (C) late-stage functionalization ...
Scheme 53: (A and B) Cobalt-catalyzed C–H/C–H cross-coupling between benzamides and oximes; (C) late-state syn...
Scheme 54: (A) Known anticancer natural isoquinoline derivatives; (B and C) cobalt-catalyzed C(sp2)–H annulati...
Scheme 55: (A) Enantioselective intramolecular nickel-catalyzed C–H activation; (B) bioactive obtained motifs;...
Scheme 56: (A and B) Nickel-catalyzed α-C(sp3)–H arylation of ketones; (C) application of the method using kno...
Scheme 57: (A and B) Nickel-catalyzed C(sp3)–H acylation of pyrrolidine derivatives; (C) exploring the use of ...
Scheme 58: (A) Nickel-catalyzed C(sp3)–H arylation of dioxolane; (B) library of products obtained from biologi...
Scheme 59: (A) Intramolecular enantioselective nickel-catalyzed C–H cycloalkylation; (B) product examples, inc...
Scheme 60: (A and B) Nickel-catalyzed C–H deoxy-arylation of azole derivatives; (C) late-stage functionalizati...
Scheme 61: (A and B) Nickel-catalyzed decarbonylative C–H arylation of azole derivatives; (C) application of t...
Scheme 62: (A and B) Another important example of nickel-catalyzed C–H arylation of azole derivatives; (C) app...
Scheme 63: (A and B) Another notable example of a nickel-catalyzed C–H arylation of azole derivatives; (C) lat...
Scheme 64: (A and B) Nickel-based metalorganic framework (MOF-74-Ni)-catalyzed C–H arylation of azole derivati...
Scheme 65: (A) Known commercially available benzothiophene-based drugs; (B and C) nickel-catalyzed C–H arylati...
Scheme 66: (A) Known natural tetrahydrofuran-containing substances; (B and C) nickel-catalyzed photoredox C(sp3...
Scheme 67: (A and B) Another notable example of a nickel-catalyzed photoredox C(sp3)–H alkylation/arylation; (...
Scheme 68: (A) Electrochemical/nickel-catalyzed C–H alkoxylation; (B) achieved scope, including three using na...
Scheme 69: (A) Enantioselective photoredox/nickel catalyzed C(sp3)–H arylation; (B) achieved scope, including ...
Scheme 70: (A) Known commercially available trifluoromethylated drugs; (B and C) nickel-catalyzed C–H trifluor...
Scheme 71: (A and B) Stereoselective nickel-catalyzed C–H difluoroalkylation; (C) late-stage functionalization...
Scheme 72: (A) Cu-mediated ortho-amination of oxalamides; (B) achieved scope, including derivatives obtained f...
Scheme 73: (A) Electro-oxidative copper-mediated amination of 8-aminoquinoline-derived amides; (B) achieved sc...
Scheme 74: (A and B) Cu(I)-mediated C–H amination with oximes; (C) derivatization using telmisartan (241) as s...
Scheme 75: (A and B) Cu-mediated amination of aryl amides using ammonia; (C) late-stage modification of proben...
Scheme 76: (A and B) Synthesis of purine nucleoside analogues using copper-mediated C(sp2)–H activation.
Scheme 77: (A) Copper-mediated annulation of acrylamide; (B) achieved scope, including the synthesis of the co...
Scheme 78: (A) Known bioactive compounds containing a naphthyl aryl ether motif; (B and C) copper-mediated eth...
Scheme 79: (A and B) Cu-mediated alkylation of N-oxide-heteroarenes; (C) late-stage modification.
Scheme 80: (A) Cu-mediated cross-dehydrogenative coupling of polyfluoroarenes and alkanes; (B) scope from know...
Scheme 81: (A) Known anticancer acrylonitrile compounds; (B and C) Copper-mediated cyanation of unactivated al...
Scheme 82: (A) Cu-mediated radiofluorination of 8-aminoquinoline-derived aryl amides; (B) achieved scope, incl...
Scheme 83: (A) Examples of natural β-carbolines; (B and C) an example of a zinc-catalyzed C–H functionalizatio...
Scheme 84: (A) Examples of anticancer α-aminophosphonic acid derivatives; (B and C) an example of a zinc-catal...
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
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.
A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries
- Guido Gambacorta,
- James S. Sharley and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90
- quenched aldol outlet stream was directed into a cooled receiver vessel, to which trifluoroacetic anhydride (TFAA) was simultaneously added, creating a net semi-continuous process. Subsequent ammonia-mediated cyclisation of the resultant diene followed by alkylation with the chlorotriazolinone 48 yielded
Graphical Abstract
Figure 1: Representative shares of the global F&F market (2018) segmented on their applications [1].
Figure 2: General structure of an international fragrance company [2].
Figure 3: The Michael Edwards fragrance wheel.
Figure 4: Examples of oriental (1–3), woody (4–7), fresh (8–10), and floral (11 and 12) notes.
Figure 5: A basic depiction of batch vs flow.
Scheme 1: Examples of reactions for which flow processing outperforms batch.
Scheme 2: Some industrially important aldol-based transformations.
Scheme 3: Biphasic continuous aldol reactions of acetone and various aldehydes.
Scheme 4: Aldol synthesis of 43 in flow using LiHMDS as the base.
Scheme 5: A semi-continuous synthesis of doravirine (49) involving a key aldol reaction.
Scheme 6: Enantioselective aldol reaction using 5-(pyrrolidin-2-yl)tetrazole (51) as catalyst in a microreact...
Scheme 7: Gröger's example of asymmetric aldol reaction in aqueous media.
Figure 6: Immobilised reagent column reactor types.
Scheme 8: Photoinduced thiol–ene coupling preparation of silica-supported 5-(pyrrolidin-2-yl)tetrazole 63 and...
Scheme 9: Continuous-flow approach for enantioselective aldol reactions using the supported catalyst 67.
Scheme 10: Ötvös’ employment of a solid-supported peptide aldol catalyst in flow.
Scheme 11: The use of proline tetrazole packed in a column for aldol reaction between cyclohexanone (65) and 2...
Scheme 12: Schematic diagram of an aminosilane-grafted Si-Zr-Ti/PAI-HF reactor for continuous-flow aldol and n...
Scheme 13: Continuous-flow condensation for the synthesis of the intermediate 76 to nabumetone (77) and Microi...
Scheme 14: Synthesis of ψ-Ionone (80) in continuous-flow via aldol condensation between citral (79) and aceton...
Scheme 15: Synthesis of β-methyl-ionones (83) from citral (79) in flow. The steps are separately described, an...
Scheme 16: Continuous-flow synthesis of 85 from 84 described by Gavriilidis et al.
Scheme 17: Continuous-flow scCO2 apparatus for the synthesis of 2-methylpentanal (87) and the self-condensed u...
Scheme 18: Chen’s two-step flow synthesis of coumarin (90).
Scheme 19: Pechmann condensation for the synthesis of 7-hydroxyxcoumarin (93) in flow. The setup extended to c...
Scheme 20: Synthesis of the dihydrojasmonate 35 exploiting nitro derivative proposed by Ballini et al.
Scheme 21: Silica-supported amines as heterogeneous catalyst for nitroaldol condensation in flow.
Scheme 22: Flow apparatus for the nitroaldol condensation of p-hydroxybenzaldehyde (102) to nitrostyrene 103 a...
Scheme 23: Nitroaldol reaction of 64 to 105 employing a quaternary ammonium functionalised PANF.
Scheme 24: Enantioselective nitroaldol condensation for the synthesis of 108 under flow conditions.
Scheme 25: Enatioselective synthesis of 1,2-aminoalcohol 110 via a copper-catalysed nitroaldol condensation.
Scheme 26: Examples of Knoevenagel condensations applied for fragrance components.
Scheme 27: Flow apparatus for Knoevenagel condensation described in 1989 by Venturello et al.
Scheme 28: Knoevenagel reaction using a coated multichannel membrane microreactor.
Scheme 29: Continuous-flow apparatus for Knoevenagel condensation employing sugar cane bagasse as support deve...
Scheme 30: Knoevenagel reaction for the synthesis of 131–135 in flow using an amine-functionalised silica gel. ...
Scheme 31: Continuous-flow synthesis of compound 137, a key intermediate for the synthesis of pregabalin (138)...
Scheme 32: Continuous solvent-free apparatus applied for the synthesis of compounds 140–143 using a TSE. Throu...
Scheme 33: Lewis et al. developed a spinning disc reactor for Darzens condensation of 144 and a ketone to furn...
Scheme 34: Some key industrial applications of conjugate additions in the F&F industry.
Scheme 35: Continuous-flow synthesis of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (156) via double conjugat...
Scheme 36: Continuous-flow system for Michael addition using CsF on alumina as the catalyst.
Scheme 37: Calcium chloride-catalysed asymmetric Michael addition using an immobilised chiral ligand.
Scheme 38: Continuous multistep synthesis for the preparation of (R)-rolipram (173). Si-NH2: primary amine-fun...
Scheme 39: Continuous-flow Michael addition using ion exchange resin Amberlyst® A26.
Scheme 40: Preparation of the heterogeneous catalyst 181 developed by Paixão et al. exploiting Ugi multicompon...
Scheme 41: Continuous-flow system developed by the Paixão’s group for the preparation of Michael asymmetric ad...
Scheme 42: Continuous-flow synthesis of nitroaldols catalysed by supported catalyst 184 developed by Wennemers...
Scheme 43: Heterogenous polystyrene-supported catalysts developed by Pericàs and co-workers.
Scheme 44: PANF-supported pyrrolidine catalyst for the conjugate addition of cyclohexanone (65) and trans-β-ni...
Scheme 45: Synthesis of (−)-paroxetine precursor 195 developed by Ötvös, Pericàs, and Kappe.
Scheme 46: Continuous-flow approach for the 5-step synthesis of (−)-oseltamivir (201) as devised by Hayashi an...
Scheme 47: Continuous-flow enzyme-catalysed Michael addition.
Scheme 48: Continuous-flow copper-catalysed 1,4 conjugate addition of Grignard reagents to enones. Reprinted w...
Scheme 49: A collection of commonly encountered hydrogenation reactions.
Figure 7: The ThalesNano H-Cube® continuous-flow hydrogenator.
Scheme 50: Chemoselective reduction of an α,β-unsaturated ketone using the H-Cube® reactor.
Scheme 51: Incorporation of Lindlar’s catalyst into the H-Cube® reactor for the reduction of an alkyne.
Scheme 52: Continuous-flow semi-hydrogenation of alkyne 208 to 209 using SACs with H-Cube® system.
Figure 8: The standard setups for tube-in-tube gas–liquid reactor units.
Scheme 53: Homogeneous hydrogenation of olefins using a tube-in-tube reactor setup.
Scheme 54: Recyclable heterogeneous flow hydrogenation system.
Scheme 55: Leadbeater’s reverse tube-in-tube hydrogenation system for olefin reductions.
Scheme 56: a) Hydrogenation using a Pd-immobilised microchannel reactor (MCR) and b) a representation of the i...
Scheme 57: Hydrogenation of alkyne 238 exploiting segmented flow in a Pd-immobilised capillary reactor.
Scheme 58: Continuous hydrogenation system for the preparation of cyrene (241) from (−)-levoglucosenone (240).
Scheme 59: Continuous hydrogenation system based on CSMs developed by Hornung et al.
Scheme 60: Chemoselective reduction of carbonyls (ketones over aldehydes) in flow.
Scheme 61: Continuous system for the semi-hydrogenation of 256 and 258, developed by Galarneau et al.
Scheme 62: Continuous synthesis of biodiesel fuel 261 from lignin-derived furfural acetone (260).
Scheme 63: Continuous synthesis of γ-valerolacetone (263) via CTH developed by Pineda et al.
Scheme 64: Continuous hydrogenation of lignin-derived biomass (products 265, 266, and 267) using a sustainable...
Scheme 65: Ru/C or Rh/C-catalysed hydrogenation of arene in flow as developed by Sajiki et al.
Scheme 66: Polysilane-immobilized Rh–Pt-catalysed hydrogenation of arenes in flow by Kobayashi et al.
Scheme 67: High-pressure in-line mixing of H2 for the asymmetric reduction of 278 at pilot scale with a 73 L p...
Figure 9: Picture of the PFR employed at Eli Lilly & Co. for the continuous hydrogenation of 278 [287]. Reprinted ...
Scheme 68: Continuous-flow asymmetric hydrogenation using Oppolzer's sultam 280 as chiral auxiliary.
Scheme 69: Some examples of industrially important oxidation reactions in the F&F industry. CFL: compact fluor...
Scheme 70: Gold-catalysed heterogeneous oxidation of alcohols in flow.
Scheme 71: Uozumi’s ARP-Pt flow oxidation protocol.
Scheme 72: High-throughput screening of aldehyde oxidation in flow using an in-line GC.
Scheme 73: Permanganate-mediated Nef oxidation of nitroalkanes in flow with the use of in-line sonication to p...
Scheme 74: Continuous-flow aerobic anti-Markovnikov Wacker oxidation.
Scheme 75: Continuous-flow oxidation of 2-benzylpyridine (312) using air as the oxidant.
Scheme 76: Continuous-flow photo-oxygenation of monoterpenes.
Scheme 77: A tubular reactor design for flow photo-oxygenation.
Scheme 78: Glucose oxidase (GOx)-mediated continuous oxidation of glucose using compressed air and the FFMR re...
Scheme 79: Schematic continuous-flow sodium hypochlorite/TEMPO oxidation of alcohols.
Scheme 80: Oxidation using immobilised TEMPO (344) was developed by McQuade et al.
Scheme 81: General protocol for the bleach/catalytic TBAB oxidation of aldehydes and alcohols.
Scheme 82: Continuous-flow PTC-assisted oxidation using hydrogen peroxide. The process was easily scaled up by...
Scheme 83: Continuous-flow epoxidation of cyclohexene (348) and in situ preparation of m-CPBA.
Scheme 84: Continuous-flow epoxidation using DMDO as oxidant.
Scheme 85: Mukayama aerobic epoxidation optimised in flow mode by the Favre-Réguillon group.
Scheme 86: Continuous-flow asymmetric epoxidation of derivatives of 359 exploiting a biomimetic iron catalyst.
Scheme 87: Continuous-flow enzymatic epoxidation of alkenes developed by Watts et al.
Scheme 88: Engineered multichannel microreactor for continuous-flow ozonolysis of 366.
Scheme 89: Continuous-flow synthesis of the vitamin D precursor 368 using multichannel microreactors. MFC: mas...
Scheme 90: Continuous ozonolysis setup used by Kappe et al. for the synthesis of various substrates employing ...
Scheme 91: Continuous-flow apparatus for ozonolysis as developed by Ley et al.
Scheme 92: Continuous-flow ozonolysis for synthesis of vanillin (2) using a film-shear flow reactor.
Scheme 93: Examples of preparative methods for ajoene (386) and allicin (388).
Scheme 94: Continuous-flow oxidation of thioanisole (389) using styrene-based polymer-supported peroxytungstat...
Scheme 95: Continuous oxidation of thiosulfinates using Oxone®-packed reactor.
Scheme 96: Continuous-flow electrochemical oxidation of thioethers.
Scheme 97: Continuous-flow oxidation of 400 to cinnamophenone (235).
Scheme 98: Continuous-flow synthesis of dehydrated material 401 via oxidation of methyl dihydrojasmonate (33).
Scheme 99: Some industrially important transformations involving Grignard reagents.
Scheme 100: Grachev et al. apparatus for continuous preparation of Grignard reagents.
Scheme 101: Example of fluidized Mg bed reactor with NMR spectrometer as on-line monitoring system.
Scheme 102: Continuous-flow synthesis of Grignard reagents and subsequent quenching reaction.
Figure 10: Membrane-based, liquid–liquid separator with integrated pressure control [52]. Adapted with permission ...
Scheme 103: Continuous-flow synthesis of 458, an intermediate to fluconazole (459).
Scheme 104: Continuous-flow synthesis of ketones starting from benzoyl chlorides.
Scheme 105: A Grignard alkylation combining CSTR and PFR technologies with in-line infrared reaction monitoring....
Scheme 106: Continuous-flow preparation of 469 from Grignard addition of methylmagnesium bromide.
Scheme 107: Continuous-flow synthesis of Grignard reagents 471.
Scheme 108: Preparation of the Grignard reagent 471 using CSTR and the continuous process for synthesis of the ...
Scheme 109: Continuous process for carboxylation of Grignard reagents in flow using tube-in-tube technology.
Scheme 110: Continuous synthesis of propargylic alcohols via ethynyl-Grignard reagent.
Scheme 111: Silica-supported catalysed enantioselective arylation of aldehydes using Grignard reagents in flow ...
Scheme 112: Acid-catalysed rearrangement of citral and dehydrolinalool derivatives.
Scheme 113: Continuous stilbene isomerisation with continuous recycling of photoredox catalyst.
Scheme 114: Continuous-flow synthesis of compound 494 as developed by Ley et al.
Scheme 115: Selected industrial applications of DA reaction.
Scheme 116: Multistep flow synthesis of the spirocyclic structure 505 via employing DA cycloaddition.
Scheme 117: Continuous-flow DA reaction developed in a plater flow reactor for the preparation of the adduct 508...
Scheme 118: Continuous-flow DA reaction using a silica-supported imidazolidinone organocatalyst.
Scheme 119: Batch vs flow for the DA reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane (513) with acrylon...
Scheme 120: Continuous-flow DA reaction between 510 and 515 using a shell-core droplet system.
Scheme 121: Continuous-flow synthesis of bicyclic systems from benzyne precursors.
Scheme 122: Continuous-flow synthesis of bicyclic scaffolds 527 and 528 for further development of potential ph...
Scheme 123: Continuous-flow inverse-electron hetero-DA reaction to pyridine derivatives such as 531.
Scheme 124: Comparison between batch and flow for the synthesis of pyrimidinones 532–536 via retro-DA reaction ...
Scheme 125: Continuous-flow coupled with ultrasonic system for preparation of ʟ-ascorbic acid derivatives 539 d...
Scheme 126: Two-step continuous-flow synthesis of triazole 543.
Scheme 127: Continuous-flow preparation of triazoles via CuAAC employing 546-based heterogeneous catalyst.
Scheme 128: Continuous-flow synthesis of compounds 558 through A3-coupling and 560 via AgAAC both employing the...
Scheme 129: Continuous-flow photoinduced [2 + 2] cycloaddition for the preparation of bicyclic derivatives of 5...
Scheme 130: Continuous-flow [2 + 2] and [5 + 2] cycloaddition on large scale employing a flow reactor developed...
Scheme 131: Continuous-flow preparation of the tricyclic structures 573 and 574 starting from pyrrole 570 via [...
Scheme 132: Continuous-flow [2 + 2] photocyclization of cinnamates.
Scheme 133: Continuous-flow preparation of cyclobutane 580 on a 5-plates photoreactor.
Scheme 134: Continuous-flow [2 + 2] photocycloaddition under white LED lamp using heterogeneous PCN as photocat...
Figure 11: Picture of the parallel tube flow reactor (PTFR) "The Firefly" developed by Booker-Milburn et al. a...
Scheme 135: Continuous-flow acid-catalysed [2 + 2] cycloaddition between silyl enol ethers and acrylic esters.
Scheme 136: Continuous synthesis of lactam 602 using glass column reactors.
Scheme 137: In situ generation of ketenes for the Staudinger lactam synthesis developed by Ley and Hafner.
Scheme 138: Application of [2 + 2 + 2] cycloadditions in flow employed by Ley et al.
Scheme 139: Examples of FC reactions applied in F&F industry.
Scheme 140: Continuous-flow synthesis of ibuprofen developed by McQuade et al.
Scheme 141: The FC acylation step of Jamison’s three-step ibuprofen synthesis.
Scheme 142: Synthesis of naphthalene derivative 629 via FC acylation in microreactors.
Scheme 143: Flow system for rapid screening of catalysts and reaction conditions developed by Weber et al.
Scheme 144: Continuous-flow system developed by Buorne, Muller et al. for DSD optimisation of the FC acylation ...
Scheme 145: Continuous-flow FC acylation of alkynes to yield β-chlorovinyl ketones such as 638.
Scheme 146: Continuous-flow synthesis of tonalide (619) developed by Wang et al.
Scheme 147: Continuous-flow preparation of acylated arene such as 290 employing Zr4+-β-zeolite developed by Kob...
Scheme 148: Flow system applied on an Aza-FC reaction catalysed by the thiourea catalyst 648.
Scheme 149: Continuous hydroformylation in scCO2.
Scheme 150: Two-step flow synthesis of aldehyde 655 through a sequential Heck reaction and subsequent hydroform...
Scheme 151: Single-droplet (above) and continuous (below) flow reactors developed by Abolhasani et al. for the ...
Scheme 152: Continuous hydroformylation of 1-dodecene (655) using a PFR-CSTR system developed by Sundmacher et ...
Scheme 153: Continuous-flow synthesis of the aldehyde 660 developed by Eli Lilly & Co. [32]. Adapted with permissio...
Scheme 154: Continuous asymmetric hydroformylation employing heterogenous catalst supported on carbon-based sup...
Scheme 155: Examples of acetylation in F&F industry: synthesis of bornyl (S,R,S-664) and isobornyl (S,S,S-664) ...
Scheme 156: Continuous-flow preparation of bornyl acetate (S,R,S-664) employing the oscillating flow reactor.
Scheme 157: Continuous-flow synthesis of geranyl acetate (666) from acetylation of geraniol (343) developed by ...
Scheme 158: 12-Ttungstosilicic acid-supported silica monolith-catalysed acetylation in flow.
Scheme 159: Continuous-flow preparation of cyclopentenone 676.
Scheme 160: Two-stage synthesis of coumarin (90) via acetylation of salicylaldehyde (88).
Scheme 161: Intensification process for acetylation of 5-methoxytryptamine (677) to melatonin (678) developed b...
Scheme 162: Examples of macrocyclic musky odorants both natural (679–681) and synthetic (682 and 683).
Scheme 163: Flow setup combined with microwave for the synthesis of macrocycle 686 via RCM.
Scheme 164: Continuous synthesis of 2,5-dihydro-1H-pyrroles via ring-closing metathesis.
Scheme 165: Continuous-flow metathesis of 485 developed by Leadbeater et al.
Figure 12: Comparison between RCM performed using different routes for the preparation of 696. On the left the...
Scheme 166: Continuous-flow RCM of 697 employed the solid-supported catalyst 698 developed by Grela, Kirschning...
Scheme 167: Continuous-flow RORCM of cyclooctene employing the silica-absorbed catalyst 700.
Scheme 168: Continuous-flow self-metathesis of methyl oleate (703) employing SILP catalyst 704.
Scheme 169: Flow apparatus for the RCM of 697 using a nanofiltration membrane for the recovery and reuse of the...
Scheme 170: Comparison of loadings between RCMs performed with different routes for the synthesis of 709.
Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years
- Asha Budakoti,
- Pradip Kumar Mondal,
- Prachi Verma and
- Jagadish Khamrai
Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77
- was thermodynamically favored in the presence of a phenyl group (Scheme 65). Matsumoto and co-workers reported a Lewis acid-mediated Prins cyclization between an alcohol 278 bearing a nonconjugated diene moiety and an aldehyde 277 with alkyl or aryl substituent in presence of BF3·Et2O and TMSCl at −40
Graphical Abstract
Scheme 1: General strategy for the synthesis of THPs.
Scheme 2: Developments towards the Prins cyclization.
Scheme 3: General stereochemical outcome of the Prins cyclization.
Scheme 4: Regioselectivity in the Prins cyclization.
Scheme 5: Mechanism of the oxonia-Cope reaction in the Prins cyclization.
Scheme 6: Cyclization of electron-deficient enantioenriched alcohol 27.
Scheme 7: Partial racemization through 2-oxonia-Cope allyl transfer.
Scheme 8: Partial racemization by reversible 2-oxonia-Cope rearrangement.
Scheme 9: Rychnovsky modification of the Prins cyclization.
Scheme 10: Synthesis of (−)-centrolobine and the C22–C26 unit of phorboxazole A.
Scheme 11: Axially selective Prins cyclization by Rychnovsky et al.
Scheme 12: Mechanism for the axially selectivity Prins cyclization.
Scheme 13: Mukaiyama aldol–Prins cyclization reaction.
Scheme 14: Application of the aldol–Prins reaction.
Scheme 15: Hart and Bennet's acid-promoted Prins cyclization.
Scheme 16: Tetrahydropyran core of polycarvernoside A as well as (−)-clavoslide A and D.
Scheme 17: Scheidt and co-workers’ route to tetrahydropyran-4-one.
Scheme 18: Mechanism for the Lewis acid-catalyzed synthesis of tetrahydropyran-4-one.
Scheme 19: Hoveyda and co-workers’ strategy for 2,6-disubstituted 4-methylenetetrahydropyran.
Scheme 20: Funk and Cossey’s ene-carbamates strategy.
Scheme 21: Yadav and Kumar’s cyclopropane strategy for THP synthesis.
Scheme 22: 2-Arylcylopropylmethanolin in centrolobine synthesis.
Scheme 23: Yadav and co-workers’ strategy for the synthesis of THP.
Scheme 24: Yadav and co-workers’ Prins–Ritter reaction sequence for 4-amidotetrahydropyran.
Scheme 25: Yadav and co-workers’ strategy to prelactones B, C, and V.
Scheme 26: Yadav and co-workers’ strategy for the synthesis of (±)-centrolobine.
Scheme 27: Loh and co-workers’ strategy for the synthesis of zampanolide and dactylolide.
Scheme 28: Loh and Chan’s strategy for THP synthesis.
Scheme 29: Prins cyclization of cyclohexanecarboxaldehyde.
Scheme 30: Prins cyclization of methyl ricinoleate (127) and benzaldehyde (88).
Scheme 31: AlCl3-catalyzed cyclization of homoallylic alcohol 129 and aldehyde 130.
Scheme 32: Martín and co-workers’ stereoselective approach for the synthesis of highly substituted tetrahydrop...
Scheme 33: Ene-IMSC strategy by Marko and Leroy for the synthesis of tetrahydropyran.
Scheme 34: Marko and Leroy’s strategy for the synthesis of tetrahydropyrans 146.
Scheme 35: Sakurai dimerization/macrolactonization reaction for the synthesis of cyanolide A.
Scheme 36: Hoye and Hu’s synthesis of (−)-dactyloide by intramolecular Sakurai cyclization.
Scheme 37: Minehan and co-workers’ strategy for the synthesis of THPs 157.
Scheme 38: Yu and co-workers’ allylic transfer strategy for the construction of tetrahydropyran 161.
Scheme 39: Reactivity enhancement in intramolecular Prins cyclization.
Scheme 40: Floreancig and co-workers’ Prins cyclization strategy to (+)-dactyloide.
Scheme 41: Panek and Huang’s DHP synthesis from crotylsilanes: a general strategy.
Scheme 42: Panek and Huang’s DHP synthesis from syn-crotylsilanes.
Scheme 43: Panek and Huang’s DHP synthesis from anti-crotylsilanes.
Scheme 44: Roush and co-workers’ [4 + 2]-annulation strategy for DHP synthesis [82].
Scheme 45: TMSOTf-promoted annulation reaction.
Scheme 46: Dobb and co-workers’ synthesis of DHP.
Scheme 47: BiBr3-promoted tandem silyl-Prins reaction by Hinkle et al.
Scheme 48: Substrate scope of Hinkle and co-workers’ strategy.
Scheme 49: Cho and co-workers’ strategy for 2,6 disubstituted 3,4-dimethylene-THP.
Scheme 50: Furman and co-workers’ THP synthesis from propargylsilane.
Scheme 51: THP synthesis from silyl enol ethers.
Scheme 52: Rychnovsky and co-workers’ strategy for THP synthesis from hydroxy-substituted silyl enol ethers.
Scheme 53: Li and co-workers’ germinal bissilyl Prins cyclization strategy to (−)-exiguolide.
Scheme 54: Xu and co-workers’ hydroiodination strategy for THP.
Scheme 55: Wang and co-workers’ strategy for tetrahydropyran synthesis.
Scheme 56: FeCl3-catalyzed synthesis of DHP from alkynylsilane alcohol.
Scheme 57: Martín, Padrón, and co-workers’ proposed mechanism of alkynylsilane Prins cyclization for the synth...
Scheme 58: Marko and co-workers’ synthesis of 2,6-anti-configured tetrahydropyran.
Scheme 59: Loh and co-workers’ strategy for 2,6-syn-tetrahydropyrans.
Scheme 60: Loh and co-workers’ strategy for anti-THP synthesis.
Scheme 61: Cha and co-workers’ strategy for trans-2,6-tetrahydropyran.
Scheme 62: Mechanism proposed by Cha et al.
Scheme 63: TiCl4-mediated cyclization to trans-THP.
Scheme 64: Feng and co-workers’ FeCl3-catalyzed Prins cyclization strategy to 4-hydroxy-substituted THP.
Scheme 65: Selectivity profile of the Prins cyclization under participation of an iron ligand.
Scheme 66: Sequential reactions involving Prins cyclization.
Scheme 67: Banerjee and co-workers’ strategy of Prins cyclization from cyclopropane carbaldehydes and propargy...
Scheme 68: Mullen and Gagné's (R)-[(tolBINAP)Pt(NC6F5)2][SbF6]2-catalyzed asymmetric Prins cyclization strateg...
Scheme 69: Yu and co-workers’ DDQ-catalyzed asymmetric Prins cyclization strategy to trisubstituted THPs.
Scheme 70: Lalli and Weghe’s chiral-Brønsted-acid- and achiral-Lewis-acid-promoted asymmetric Prins cyclizatio...
Scheme 71: List and co-workers’ iIDP Brønsted acid-promoted asymmetric Prins cyclization strategy.
Scheme 72: Zhou and co-workers’ strategy for chiral phosphoric acid (CPA)-catalyzed cascade Prins cyclization.
Scheme 73: List and co-workers’ approach for asymmetric Prins cyclization using chiral imidodiphosphoric acid ...
Synthetic reactions driven by electron-donor–acceptor (EDA) complexes
- Zhonglie Yang,
- Yutong Liu,
- Kun Cao,
- Xiaobin Zhang,
- Hezhong Jiang and
- Jiahong Li
Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67
- hydrogen atoms from thiophenol to produce the final product 47 (Scheme 17). In 2020, Alemán and colleagues [53] proposed an approach in which ketene 48 and diene 49 condense with the help of diamine 51 to afford cyclobutane product 50 (Scheme 18). The reaction could be catalyzed by a simple diamine due to
- ; moreover, 53 and 54 can be mutually transformed. Excited state 53 reacts with diene 49, forming a double radical intermediate 55 that subsequently evolves to cyclobutyliminium ion 56, and then product 50 is provided after hydrolysis, along with the release of diamine 51. In 2020, Zhang and colleagues [25
Graphical Abstract
Scheme 1: The electron transfer process in EDA complexes.
Scheme 2: Synthesis of benzo[b]phosphorus oxide 3 initiated by an EDA complex.
Scheme 3: Mechanism of the synthesis of quinoxaline derivative 7.
Scheme 4: Synthesis of imidazole derivative 10 initiated by an EDA complex.
Scheme 5: Synthesis of sulfamoylation product 12 initiated by an EDA complex.
Scheme 6: Mechanism of the synthesis of sulfamoylation product 12.
Scheme 7: Synthesis of indole derivative 22 initiated by an EDA complex.
Scheme 8: Synthesis of perfluoroalkylated pyrimidines 26 initiated by an EDA complex.
Scheme 9: Synthesis of phenanthridine derivative 29 initiated by an EDA complex.
Scheme 10: Synthesis of cis-tetrahydroquinoline derivative 32 initiated by an EDA complex.
Scheme 11: Mechanism of the synthesis of cis-tetrahydroquinoline derivative 32.
Scheme 12: Synthesis of phenanthridine derivative 38 initiated by an EDA complex.
Scheme 13: Synthesis of spiropyrroline derivative 40 initiated by an EDA complex.
Scheme 14: Synthesis of benzothiazole derivative 43 initiated by an EDA complex.
Scheme 15: Synthesis of perfluoroalkyl-s-triazine derivative 45 initiated by an EDA complex.
Scheme 16: Synthesis of indoline derivative 47 initiated by an EDA complex.
Scheme 17: Mechanism of the synthesis of spirocyclic indoline derivative 47.
Scheme 18: Synthesis of cyclobutane product 50 initiated by an EDA complex.
Scheme 19: Mechanism of the synthesis of spirocyclic indoline derivative 50.
Scheme 20: Synthesis of 1,3-oxazolidine compound 59 initiated by an EDA complex.
Scheme 21: Synthesis of trifluoromethylated product 61 initiated by an EDA complex.
Scheme 22: Synthesis of indole alkylation product 64 initiated by an EDA complex.
Scheme 23: Synthesis of perfluoroalkylation product 67 initiated by an EDA complex.
Scheme 24: Synthesis of hydrotrifluoromethylated product 70 initiated by an EDA complex.
Scheme 25: Synthesis of β-trifluoromethylated alkyne product 71 initiated by an EDA complex.
Scheme 26: Mechanism of the synthesis of 2-phenylthiophene derivative 74.
Scheme 27: Synthesis of allylated product 80 initiated by an EDA complex.
Scheme 28: Synthesis of trifluoromethyl-substituted alkynyl product 84 initiated by an EDA complex.
Scheme 29: Synthesis of dearomatized fluoroalkylation product 86 initiated by an EDA complex.
Scheme 30: Mechanism of the synthesis of dearomatized fluoroalkylation product 86.
Scheme 31: Synthesis of C(sp3)–H allylation product 91 initiated by an EDA complex.
Scheme 32: Synthesis of perfluoroalkylation product 93 initiated by an EDA complex.
Scheme 33: Synthesis of spirocyclic indolene derivative 95 initiated by an EDA complex.
Scheme 34: Synthesis of perfluoroalkylation product 97 initiated by an EDA complex.
Scheme 35: Synthesis of alkylated indole derivative 100 initiated by an EDA complex.
Scheme 36: Mechanism of the synthesis of alkylated indole derivative 100.
Scheme 37: Synthesis of arylated oxidized indole derivative 108 initiated by an EDA complex.
Scheme 38: Synthesis of 4-ketoaldehyde derivative 111 initiated by an EDA complex.
Scheme 39: Mechanism of the synthesis of 4-ketoaldehyde derivative 111.
Scheme 40: Synthesis of perfluoroalkylated olefin 118 initiated by an EDA complex.
Scheme 41: Synthesis of alkylation product 121 initiated by an EDA complex.
Scheme 42: Synthesis of acylation product 123 initiated by an EDA complex.
Scheme 43: Mechanism of the synthesis of acylation product 123.
Scheme 44: Synthesis of trifluoromethylation product 126 initiated by an EDA complex.
Scheme 45: Synthesis of unnatural α-amino acid 129 initiated by an EDA complex.
Scheme 46: Synthesis of thioether derivative 132 initiated by an EDA complex.
Scheme 47: Synthesis of S-aryl dithiocarbamate product 135 initiated by an EDA complex.
Scheme 48: Mechanism of the synthesis of S-aryl dithiocarbamate product 135.
Scheme 49: Synthesis of thioether product 141 initiated by an EDA complex.
Scheme 50: Mechanism of the synthesis of borate product 144.
Scheme 51: Synthesis of boronation product 148 initiated by an EDA complex.
Scheme 52: Synthesis of boration product 151 initiated by an EDA complex.
Scheme 53: Synthesis of boronic acid ester derivative 154 initiated by an EDA complex.
Scheme 54: Synthesis of β-azide product 157 initiated by an EDA complex.
Scheme 55: Decarboxylation reaction initiated by an EDA complex.
Scheme 56: Synthesis of amidated product 162 initiated by an EDA complex.
Scheme 57: Synthesis of diethyl phenylphosphonate 165 initiated by an EDA complex.
Scheme 58: Mechanism of the synthesis of diethyl phenylphosphonate derivative 165.
Scheme 59: Synthesis of (Z)-2-iodovinyl phenyl ether 168 initiated by an EDA complex.
Scheme 60: Mechanism of the synthesis of (Z)-2-iodovinyl phenyl ether derivative 168.
Scheme 61: Dehalogenation reaction initiated by an EDA complex.
Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles
- Ramazan Koçak and
- Arif Daştan
Beilstein J. Org. Chem. 2021, 17, 719–729, doi:10.3762/bjoc.17.61
- the tetrazine ring is an electron-poor diene, the dibenzosuberenone (1) dienophile is not electron-rich enough. Therefore, for such cycloaddition reactions, the tetrazine must be substituted by EWGs to decrease the electron density of the diene. Consequently, our results confirm that EDGs and EWGs
- –Alder reactions, depending on the structure of the diene and the reaction conditions [64]. A proposed reaction mechanism for the formation of the dibenzosuberenone derivatives 3 and 4 is illustrated in Scheme 3. Although 3k was isolated, 3l could not be detected in the reaction mixture due to its
Graphical Abstract
Figure 1: Structures of dibenzosuberenone 1 and pyridazine and pyrrole derivatives.
Figure 2: Structures of s-tetrazines 2a–l.
Scheme 1: Inverse electron-demand Diels–Alder reactions of dibenzosuberenone (1) with tetrazines 2a–l.
Scheme 2: Inverse electron-demand Diels–Alder reactions between dibenzosuberenone 1 and tetrazines 2ka and 2lb...
Scheme 3: Proposed reaction mechanism for the formation of dibenzosuberenone derivatives 3 and 4.
Scheme 4: Proposed mechanism for the formation of 5l.
Scheme 5: Oxidation of dihydropyridazines 3a–f. All reactions were carried in CH2Cl2 at room temperature (4e:...
Scheme 6: Synthesis of pyrrole 10a. a1.34 mmol 4a, Zinc (for 10aa: 6.68 mmol, for 10ab: 13.36 mmol), 10 mL gl...
Scheme 7: Synthesis of pyrrole 10b. a1.21 mmol 4b, 12.10 mmol Zinc, 118 °C, 2 h. b1.13 mmol 10ba, 1.69 mmol K...
Scheme 8: Synthesis of p-quinone methides 13–16. a1.77 mmol 11, 1.77 mmol 2, 5 mL toluene, 80 °C (13a: overni...
Scheme 9: Proposed mechanism for the formation of 13.
Figure 3: UV–vis spectra of 3c–f and 3k in CH3CN at rt (c = 5 μM).
Figure 4: Fluorescence spectra of 3c–f and 3k in CH3CN at rt (c = 5 μM).
Figure 5: Ambient (top) and fluorescence (bottom, under 365 nm UV light) images of 3c–f and 3k in CH3CN.
A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles
- Lucía Rossi-Fernández,
- Viviana Dorn and
- Gabriel Radivoy
Beilstein J. Org. Chem. 2021, 17, 519–526, doi:10.3762/bjoc.17.46
- the diene (±)-limonene (1k, Table 2, entry 11) took place mainly on the endocyclic C=C double bond with good selectivity, although with a relatively modest conversion. On the contrary, for cyclohexene (1l, Table 2, entry 12) the main oxidation product was found to be the corresponding allylic ketone
Graphical Abstract
Figure 1: TEM micrograph and size distribution graphic for CoNPs@MgO catalyst (scale bar = 20 nm).
Scheme 1: Plausible mechanistic pathway for olefin epoxidation catalyzed by CoNPs/MgO in the presence of t-Bu...
Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes
- Savva A. Ponomarev,
- Roman V. Larkovich,
- Alexander S. Aldoshin,
- Andrey A. Tabolin,
- Sema L. Ioffe,
- Jonathan Groß,
- Till Opatz and
- Valentine G. Nenajdenko
Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27
- powerful tool for assembling a variety of fluorinated carbo- and heterocycles using either the diene [24][25][26][27][28][29][30] or the dienophile component [31][32][33][34][35][36][37][38][39] as fluorine-containing building blocks. The application of [4 + 2] cycloadditions for the preparation of
- conducted in screw-top vials in o-xylene at 110 °C using a fivefold excess of the diene (Scheme 1). The reaction proceeded smoothly under these conditions to give the target cycloadducts 2 as a mixture of exo and endo-isomers in high isolated yield (up to 97%). It should be noted that in the present work we
- dispersion effects are not included, whereas M062X includes nonlocal effects of electronic dispersion [70][75]. We also demonstrate the preparation of norbornene structures substituted at the methylene bridge. The reaction of model nitrostyrene 1h with spiro[2.4]hepta-4,6-diene was carried out (Scheme 2). As
Graphical Abstract
Scheme 1: Scope of the nitrostyrenes 1 in the Diels–Alder reaction with CPD (dr = exo:endo).
Figure 1: The structure assignment of norbornenes 2 by 1H (a) and NOE (b) NMR spectroscopy.
Figure 2: 13C NMR spectrum of the mixture of exo- and endo-isomers of norbornene 2l.
Figure 3: The predicted reaction pathway for the Diels–Alder reaction of nitrostyrene 1h with CPD is displaye...
Scheme 2: The Diels–Alder reaction of nitrostyrene 1h with spiro[2.4]hepta-4,6-diene.
Scheme 3: Diels–Alder reaction of nitrostyrenes 1 with CHD (dr = exo:endo). (а) Reaction under microwave acti...
Scheme 4: Kinetic study of reactions of 1h with CPD and CHD.
Figure 4: Kinetic curves for the reactions of nitrostyrene 1h with CPD (50–130 °C) and CHD at 110 °C.
Scheme 5: The Diels–Alder reaction of the nitrostyrene 1h with 1-methoxy-1,3-cyclohexadiene.
Scheme 6: Selected chemical transformations of norbornenes 2 (dr = exo:endo).
The preparation and properties of 1,1-difluorocyclopropane derivatives
- Kymbat S. Adekenova,
- Peter B. Wyatt and
- Sergazy M. Adekenov
Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25
- isomerization [36]. Several nitrogen nucleophiles have been evaluated as catalysts to promote the difluorocarbene formation from TFDA in order to bring about the cyclopropanation of a 2-siloxybuta-1,3-diene derivative; 1,8-bis(dimethylamino)naphthalene (proton sponge) was found to be particularly effective [37
Graphical Abstract
Scheme 1: Synthesis of 1,1-difluoro-2,3-dimethylcyclopropane (2).
Scheme 2: Cyclopropanation via dehydrohalogenation of chlorodifluoromethane.
Scheme 3: Difluorocyclopropanation of methylstyrene 7 using dibromodifluoromethane and zinc.
Scheme 4: Synthesis of difluorocyclopropanes from the reaction of dibromodifluoromethane and triphenylphosphi...
Scheme 5: Generation of difluorocarbene in a catalytic two-phase system and its addition to tetramethylethyle...
Scheme 6: The reaction of methylstyrene 7 with chlorodifluoromethane (11) in the presence of a tetraarylarson...
Scheme 7: Pyrolysis of sodium chlorodifluoroacetate (12) in refluxing diglyme in the presence of alkene 13.
Scheme 8: Synthesis of boron-substituted gem-difluorocyclopropanes 16.
Scheme 9: Addition of sodium bromodifluoroacetate (17) to alkenes.
Scheme 10: Addition of sodium bromodifluoroacetate (17) to silyloxy-substituted cyclopropanes 20.
Scheme 11: Synthesis of difluorinated nucleosides.
Scheme 12: Addition of butyl acrylate (26) to difluorocarbene generated from TFDA (25).
Scheme 13: Addition of difluorocarbene to propargyl esters 27 and conversion of the difluorocyclopropenes 28 t...
Scheme 14: The generation of difluorocyclopropanes using MDFA 30.
Scheme 15: gem-Difluorocyclopropanation of styrene (32) using difluorocarbene generated from TMSCF3 (31) under...
Scheme 16: Synthesis of a gem-difluorocyclopropane derivative using HFPO (41) as a source of difluorocarbene.
Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).
Scheme 18: The cyclopropanation of 1-octene (46) using Seyferth's reagent (45) as a source of difluorocarbene.
Scheme 19: Alternative approaches for the difluorocarbene synthesis from trimethyl(trifluoromethyl)tin (48).
Scheme 20: Difluorocyclopropanation of cyclohexene (49).
Scheme 21: Synthesis of difluorocyclopropane derivative 53 using bis(trifluoromethyl)cadmium (51) as the diflu...
Scheme 22: Addition of difluorocarbene generated from tris(trifluoromethyl)bismuth (54).
Scheme 23: Addition of a stable (trifluoromethyl)zinc reagent to styrenes.
Scheme 24: The preparation of 2,2-difluorocyclopropanecarboxylic acids of type 58.
Scheme 25: Difluorocyclopropanation via Michael cyclization.
Scheme 26: Difluorocyclopropanation using N-acylimidazolidinone 60.
Scheme 27: Difluorocyclopropanation through the cyclization of phenylacetonitrile (61) and 1,2-dibromo-1,1-dif...
Scheme 28: gem-Difluoroolefins 64 for the synthesis of functionalized cyclopropanes 65.
Scheme 29: Preparation of aminocyclopropanes 70.
Scheme 30: Synthesis of fluorinated methylenecyclopropane 74 via selenoxide elimination.
Scheme 31: Reductive dehalogenation of (1R,3R)-75.
Scheme 32: Synthesis of chiral monoacetates by lipase catalysis.
Scheme 33: Transformation of (±)-trans-81 using Rhodococcus sp. AJ270.
Scheme 34: Transformation of (±)-trans-83 using Rhodococcus sp. AJ270.
Scheme 35: Hydrogenation of difluorocyclopropenes through enantioselective hydrocupration.
Scheme 36: Enantioselective transfer hydrogenation of difluorocyclopropenes with a Ru-based catalyst.
Scheme 37: The thermal transformation of trans-1,2-dichloro-3,3-difluorocyclopropane (84).
Scheme 38: cis–trans-Epimerization of 1,1-difluoro-2,3-dimethylcyclopropane.
Scheme 39: 2,2-Difluorotrimethylene diradical intermediate.
Scheme 40: Ring opening of stereoisomers 88 and 89.
Scheme 41: [1,3]-Rearrangement of alkenylcyclopropanes 90–92.
Scheme 42: Thermolytic rearrangement of 2,2-difluoro-1-vinylcyclopropane (90).
Scheme 43: Thermal rearrangement for ethyl 3-(2,2-difluoro)-3-phenylcyclopropyl)acrylates 93 and 95.
Scheme 44: Possible pathways of the ring opening of 1,1-difluoro-2-vinylcyclopropane.
Scheme 45: Equilibrium between 1,1-difluoro-2-methylenecyclopropane (96) and (difluoromethylene)cyclopropane 97...
Scheme 46: Ring opening of substituted 1,1-difluoro-2,2-dimethyl-3-methylenecyclopropane 98.
Scheme 47: 1,1-Difluorospiropentane rearrangement.
Scheme 48: Acetolysis of (2,2-difluorocyclopropyl)methyl tosylate (104) and (1,1-difluoro-2-methylcyclopropyl)...
Scheme 49: Ring opening of gem-difluorocyclopropyl ketones 106 and 108 by thiolate nucleophiles.
Scheme 50: Hydrolysis of gem-difluorocyclopropyl acetals 110.
Scheme 51: Ring-opening reaction of 2,2-difluorocyclopropyl ketones 113 in the presence of ionic liquid as a s...
Scheme 52: Ring opening of gem-difluorocyclopropyl ketones 113a by MgI2-initiated reaction with diarylimines 1...
Scheme 53: Ring-opening reaction of gem-difluorocyclopropylstannanes 117.
Scheme 54: Preparation of 1-fluorovinyl vinyl ketone 123 and the synthesis of 2-fluorocyclopentenone 124. TBAT...
Scheme 55: Iodine atom-transfer ring opening of 1,1-difluoro-2-(1-iodoalkyl)cyclopropanes 125a–c.
Scheme 56: Ring opening of bromomethyl gem-difluorocyclopropanes 130 and formation of gem-difluoromethylene-co...
Scheme 57: Ring-opening aerobic oxidation reaction of gem-difluorocyclopropanes 132.
Scheme 58: Dibrominative ring-opening functionalization of gem-difluorocyclopropanes 134.
Scheme 59: The selective formation of (E,E)- and (E,Z)-fluorodienals 136 and 137 from difluorocyclopropyl acet...
Scheme 60: Proposed mechanism for the reaction of difluoro(methylene)cyclopropane 139 with Br2.
Scheme 61: Thermal rearrangement of F2MCP 139 and iodine by CuI catalysis.
Scheme 62: Synthesis of 2-fluoropyrroles 142.
Scheme 63: Ring opening of gem-difluorocyclopropyl ketones 143 mediated by BX3.
Scheme 64: Lewis acid-promoted ring-opening reaction of 2,2-difluorocyclopropanecarbonyl chloride (148).
Scheme 65: Ring-opening reaction of the gem-difluorocyclopropyl ketone 106 by methanolic KOH.
Scheme 66: Hydrogenolysis of 1,1-difluoro-3-methyl-2-phenylcyclopropane (151).
Scheme 67: Synthesis of monofluoroalkenes 157.
Scheme 68: The stereoselective Ag-catalyzed defluorinative ring-opening diarylation of 1-trimethylsiloxy-2,2-d...
Scheme 69: Synthesis of 2-fluorinated allylic compounds 162.
Scheme 70: Pd-catalyzed cross-coupling reactions of gem-difluorinated cyclopropanes 161.
Scheme 71: The (Z)-selective Pd-catalyzed ring-opening sulfonylation of 2-(2,2-difluorocyclopropyl)naphthalene...
Figure 1: Structures of zosuquidar hydrochloride and PF-06700841.
Scheme 72: Synthesis of methylene-gem-difluorocyclopropane analogs of nucleosides.
Figure 2: Anthracene-difluorocyclopropane hybrid derivatives.
Figure 3: Further examples of difluorcyclopropanes in modern drug discovery.
