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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
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.
Synthesis of spirocyclic scaffolds using hypervalent iodine reagents
- Fateh V. Singh,
- Priyanka B. Kole,
- Saeesh R. Mangaonkar and
- Samata E. Shetgaonkar
Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152
- acid and 4-iodophenylacetic acid in two steps (Figure 2). Both polymer-supported reagents 17a and 17b were used in similar spirocyclizations of tyrosine 14. Both tyrosine 14a and N-protected tyrosine derivatives 14b,c were used as starting material and results of their spirolactonization are summarized
- 13, respectively. PIDA-mediated spirolactonization of N-protected tyrosine 14 to spirolactone 16. Spirolactonization of substrates 14 to spirolactones 16 using polymer-supported reagents 17a and 17b. PIDA-mediated spirolactonization of 1-(p-hydroxyaryl)cyclobutanols 18 to spirolactones 19. Iodine(III
- electrophilic species PIDA (15). Iodine(III)-catalyzed oxidative spirocyclization of ortho-substituted phenols 158 to spirocyclic ketals 159. Spirolactonization of substrates 14 to spirolactones 16 using polymer-supported reagents 17a and 17b. Acknowledgements Fateh V Singh is thankful to the DST New Delhi for
Graphical Abstract
Figure 1: The structures of biologically active natural and synthetic products having spirocyclic moiety.
Scheme 1: Iodine(III)-mediated spirocyclization of substituted phenols 7 and 11 to 10 and 13, respectively.
Scheme 2: PIDA-mediated spirolactonization of N-protected tyrosine 14 to spirolactone 16.
Figure 2: The structures of polymer-supported iodine(III) reagents 17a and 17b.
Scheme 3: Spirolactonization of substrates 14 to spirolactones 16 using polymer-supported reagents 17a and 17b...
Scheme 4: PIDA-mediated spirolactonization of 1-(p-hydroxyaryl)cyclobutanols 18 to spirolactones 19.
Scheme 5: Iodine(III)-mediated spirocyclization of aryl alkynes 24 to spirolactones 26 by the reaction with b...
Scheme 6: Bridged iodine(III)-mediated spirocyclization of phenols 27 to spirodienones 29.
Scheme 7: Iodine(III)-mediated spirocyclization of arnottin I (30) to its spirocyclic analogue arnottin II (32...
Scheme 8: Iodine(III)-catalyzed spirolactonization of p-substituted phenols 27 to spirolactones 29 using iodo...
Scheme 9: Iodine(III)-catalyzed oxylactonization of ketocarboxylic acid 34 to spirolactone 36 using iodobenze...
Scheme 10: Iodine(III)-mediated asymmetric oxidative spirocyclization of naphthyl acids 37 to naphthyl spirola...
Scheme 11: Oxidative cyclization of L-tyrosine 14 to spirocyclic lactone 16 using PIDA (15).
Scheme 12: Oxidative cyclization of oxazoline derivatives 41 to spirolactams 42 using PIDA (15).
Scheme 13: Oxidative cyclization of oxazoline 43 to spirolactam 44 using PIDA 15 as oxidant.
Scheme 14: PIFA-mediated spirocyclization of amides 46 to N-spirolactams 47 using PIFA (31) as an electrophile....
Scheme 15: Synthesis of spirolactam 49 from phenolic enamide 48 using PIDA (15).
Scheme 16: Iodine(III)-mediated spirocyclization of alkyl hydroxamates 50 to spirolactams 51 using stoichiomet...
Scheme 17: PIFA-mediated cyclization of substrate 52 to spirocyclic product 54.
Scheme 18: Synthesis of spiro β-lactams 56 by oxidative coupling reaction of p-substituted phenols 55 using PI...
Scheme 19: Iodine(III)-mediated spirocyclization of para-substituted amide 58 to spirolactam 59 by the reactio...
Scheme 20: Iodine(III)-mediated synthesis of spirolactams 61 from anilide derivatives 60.
Scheme 21: PIFA-mediated oxidative cyclization of anilide 60 to bis-spirobisoxindole 61.
Scheme 22: PIDA-mediated spirocyclization of phenylacetamides 65 to spirocyclic lactams 66.
Scheme 23: Oxidative dearomatization of arylamines 67 with PIFA (31) to give dieniminium salts 68.
Scheme 24: PIFA-mediated oxidative spirocarbocyclization of 4-methoxybenzamide 69 with diphenylacetylene (70) ...
Scheme 25: Synthesis of spiroxyindole 75 using I2O5/TBHP oxidative system.
Scheme 26: Iodine(III)-catalyzed spirolactonization of functionalized amides 76 to spirolactones 77 using iodo...
Scheme 27: Intramolecular cyclization of alkenes 78 to spirolactams 80 using Pd(II) 79 and PIDA (15) as the ox...
Scheme 28: Iodine(III)-catalyzed spiroaminocyclization of amides 76 to spirolactam 77 using bis(iodoarene) 81 ...
Scheme 29: Iodine(III)-catalyzed spirolactonization of N-phenyl benzamides 82 to spirolactams 83 using iodoben...
Scheme 30: Iodine(III)-mediated asymmetric oxidative spirocyclization of phenols 84 to spirolactams 86 using c...
Scheme 31: Iodine(III)-catalyzed asymmetric oxidative spirocyclization of N-aryl naphthamides 87 to spirocycli...
Scheme 32: Cyclization of p-substituted phenolic compound 89 to spirolactam 90 using PIDA (15) in TFE.
Scheme 33: Iodine(III)-mediated synthesis of spirocyclic compound 93 from substrates 92 using PIDA (15) as an ...
Scheme 34: Iodine(III)-mediated spirocyclization of p-substituted phenol 48 to spirocyclic compound 49 using P...
Scheme 35: Bridged iodine(III)-mediated spirocyclization of O-silylated phenolic compound 96 in the synthesis ...
Scheme 36: PIFA-mediated approach for the spirocyclization of ortho-substituted phenols 98 to aza-spirocarbocy...
Scheme 37: Oxidative cyclization of para-substituted phenols 102 to spirocarbocyclic compounds 104 using Koser...
Scheme 38: Iodine(III)-mediated spirocyclization of aryl alkynes 105 to spirocarbocyclic compound 106 by the r...
Scheme 39: Iodine(III)-mediated spirocarbocyclization of ortho-substituted phenols 107 to spirocarbocyclic com...
Scheme 40: PIFA-mediated oxidative cyclization of substrates 110 to spirocarbocyclic compounds 111.
Scheme 41: Iodine(III)-mediated cyclization of substrate 113 to spirocyclic compound 114.
Scheme 42: Iodine(III)-mediated spirocyclization of phenolic substrate 116 to the spirocarbocyclic natural pro...
Scheme 43: Iodine(III)-catalyzed spirocyclization of phenols 117 to spirocarbocyclic products 119 using iodoar...
Scheme 44: PIFA-mediated spirocyclization of 110 to spirocyclic compound 111 using PIFA (31) as electrophile.
Scheme 45: PIDA-mediated spirocyclization of phenolic sulfonamide 122 to spiroketones 123.
Scheme 46: Iodine(III)-mediated oxidative spirocyclization of 2-naphthol derivatives 124 to spiropyrrolidines ...
Scheme 47: PIDA-mediated oxidative spirocyclization of m-substituted phenols 126 to tricyclic spiroketals 127.
Figure 3: The structures of chiral organoiodine(III) catalysts 129a and 129b.
Scheme 48: Iodine(III)-catalyzed oxidative spirocyclization of substituted phenols 128 to spirocyclic ketals 1...
Scheme 49: Oxidative spirocyclization of para-substituted phenol 131 to spirodienone 133 using polymer support...
Scheme 50: Oxidative cyclization of bis-hydroxynaphthyl ether 135 to spiroketal 136 using PIDA (15) as an elec...
Scheme 51: Oxidative spirocyclization of phenolic compound 139 to spirodienone 140 using polymer-supported PID...
Scheme 52: PIFA-mediated oxidative cyclization of catechol derived substrate 142 to spirocyclic product 143.
Scheme 53: Oxidative spirocyclization of p-substituted phenolic substrate 145 to aculeatin A (146a) and aculea...
Scheme 54: Oxidative spirocyclization of p-substituted phenolic substrate 147 to aculeatin A (146a) and aculea...
Scheme 55: Oxidative spirocyclization of p-substituted phenolic substrate 148 to aculeatin D (149) using elect...
Scheme 56: Cyclization of phenolic substrate 131 to spirocyclic product 133 using polymer-supported PIFA 150.
Scheme 57: Iodine(III)-mediated oxidative intermolecular spirocyclization of 7-methoxy-α-naphthol (152) to spi...
Scheme 58: Oxidative cyclization of phenols 155 to spiro-ketals 156 using electrophilic species PIDA (15).
Scheme 59: Iodine(III)-catalyzed oxidative spirocyclization of ortho-substituted phenols 158 to spirocyclic ke...
Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries
- Ruth Suchsland,
- Bettina Appel and
- Sabine Müller
Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28
- strategy and syntheses will be described elsewhere. 3. Preparation of trinucleotides by inverse solid-phase synthesis Interestingly, also the use of polymer-supported reagents for H-phosphonate or phosphoramidite activation and phosphite oxidation has been described [34][39], thereby combining the
Graphical Abstract
Figure 1: Preparation of fully protected trinucleotides in solution (A), on solid phase (B) and on soluble po...
Figure 2: Strategies for trinucleotide synthesis using different pairs of orthogonal groups for protection of...
Figure 3: Strategy for the synthesis of nucleotide dimers and extension to the trimer in either 5'- or 3'-dir...
Figure 4: Removal of the 3'-O-protecting group under conditions that leave all other protecting groups at 5'-...
Figure 5: Release of trinucleotide blocks from the solid support by cleavage of an oxalyl anchor (A) and by a...
Figure 6: Release of the trinucleotide from the support under reductive conditions.
Figure 7: Phosphitylation of trimers. Reaction conditions, in particular the choice of the phosphitylation re...
An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
- Marcus Baumann and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265
Graphical Abstract
Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
Scheme 3: Synthesis of 3-picoline and nicotinic acid.
Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
Scheme 8: Synthesis of rosiglitazone.
Scheme 9: Syntheses of 2-pyridones.
Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
Scheme 11: Polymer-assisted synthesis of rosiglitazone.
Scheme 12: Synthesis of pioglitazone.
Scheme 13: Meerwein arylation reaction towards pioglitazone.
Scheme 14: Route towards pioglitazone utilising tyrosine.
Scheme 15: Route towards pioglitazone via Darzens ester formation.
Scheme 16: Syntheses of the thiazolidinedione moiety.
Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
Scheme 19: Synthesis of moxifloxacin.
Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
Scheme 21: Synthesis of levofloxacin.
Scheme 22: Alternative approach to the levofloxacin core 1.125.
Figure 3: Structures of nifedipine, amlodipine and clevidipine.
Scheme 23: Mg3N2-mediated synthesis of nifedipine.
Scheme 24: Synthesis of rac-amlodipine as besylate salt.
Scheme 25: Aza Diels–Alder approach towards amlodipine.
Scheme 26: Routes towards clevidipine.
Figure 4: Examples of piperidine containing drugs.
Figure 5: Discovery of tiagabine based on early leads.
Scheme 27: Synthetic sequences to tiagabine.
Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
Scheme 28: Enantioselective synthesis of solifenacin.
Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
Scheme 30: Improved route to carmegliptin.
Figure 9: Structures of lamivudine and zidovudine.
Scheme 31: Typical routes accessing uracil, thymine and cytosine.
Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
Scheme 33: Synthesis of lamivudine.
Scheme 34: Synthesis of raltegravir.
Scheme 35: Mechanistic studies on the formation of 3.22.
Figure 10: Structures of selected pyrimidine containing drugs.
Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
Scheme 37: Synthesis of imatinib.
Scheme 38: Flow synthesis of imatinib.
Scheme 39: Syntheses of erlotinib.
Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
Scheme 41: Synthesis of lapatinib.
Scheme 42: Synthesis of rosuvastatin.
Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
Scheme 44: Syntheses of varenicline and its key building block 4.5.
Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
Scheme 46: Asymmetric synthesis of bortezomib.
Figure 13: Structures of some prominent piperazine containing drugs.
Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
Scheme 48: Syntheses of azelastine (5.1).
Figure 15: Structures of captopril, enalapril and cilazapril.
Scheme 49: Synthesis of cilazapril.
Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
Scheme 50: Synthesis of lamotrigine.
Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
Scheme 52: Conventional synthesis of imiquimod (no yields reported).
Scheme 53: Synthesis of imiquimod.
Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
Figure 18: Structures of various anti HIV-medications.
Scheme 55: Synthesis of abacavir.
Figure 19: Structures of diazepam compared to modern replacements.
Scheme 56: Synthesis of ocinaplon.
Scheme 57: Access to zaleplon and indiplon.
Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
Scheme 60: Early synthetic route to sildenafil.
Scheme 61: Convergent preparations of sildenafil.
Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
Scheme 62: Short route to imidazotriazinones.
Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
Scheme 64: Bayer’s approach to the vardenafil core.
Scheme 65: Large scale synthesis of vardenafil.
Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
Scheme 67: Different routes to temozolomide.
Scheme 68: Safer route towards temozolomide.
Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow
- Kimberley A. Roper,
- Malcolm B. Berry and
- Steven V. Ley
Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207
- chemist [1][2][3][4][5][6][7]. Combining this enabling technology with solid-supported reagents and scavengers offers synergistic benefits over using the two technologies independently. Utilising polymer-supported reagents and scavengers to purify the flow stream permits telescoping of reaction sequences
Graphical Abstract
Scheme 1: Formation of gem-dibromoolefin 3 from the reaction of carbon tetrabromide and triphenylphosphine as...
Scheme 2: Formation of the triphenylphosphine monoliths.
Figure 1: a. An unfunctionalised triphenylphosphine monolith; b. Monolith after functionalisation with carbon...
Scheme 3: Functionalising the triphenylphosphine monolith to give the active Ramirez monolith using carbon te...
Scheme 4: Flow synthesis of gem-dibromoolefins using the functionalised triphenylphosphine monolith.
Scheme 5: Flow synthesis of bromides from the corresponding alcohols using the functionalised triphenylphosph...
Scheme 6: Mechanisms for the Ramirez and Appel reactions [41,59].
Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition
- Kim A. Fredriksen,
- Tor E. Kristensen and
- Tore Hansen
Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125
- ]. Regrettably, cost issues linger over the field as a whole, due to the lengthy and laborious syntheses involved in the preparation of these polymer-supported entities, hampering the more widespread utilization of polymer-supported reagents or catalysts as part of conventional chemical synthesis. Consequently
Graphical Abstract
Figure 1: Thiol, alkene and organocatalyst building blocks for combined bead polymerization and Cinchona orga...
Scheme 1: Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition.
Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions
- Lukas Kupracz,
- Jan Hartwig,
- Jens Wegner,
- Sascha Ceylan and
- Andreas Kirschning
Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168
- reactor. Keywords: flow reactor; inductive heating; iodine azide; polymer-supported reagents; vinyl azides; Introduction Azides are highly versatile organic functional groups and their preparation and their reactivity are well explored [1]. In contrast, the synthesis of vinyl azides is far away from
Graphical Abstract
Scheme 1: Hassner's synthesis of vinyl azides and a stable, nonexplosive analogue 5 of iodine azide (1).
Scheme 2: Preparation of polymer-bound bisazido iodate(I) 5 and polymer-bound 1,8-diaza-[5.4.0]bicyclo-7-unde...
Scheme 3: Two-step protocol for the preparation of vinyl azides 4a–e and 4g–i under flow conditions.
Scheme 4: Regeneration of functionalized polymers 5 and 8.
Scheme 5: Preparation of triazoles 12a–l by using inductively heated copper turnings as a packed-bed material...
Continuous flow based catch and release protocol for the synthesis of α-ketoesters
- Alessandro Palmieri,
- Steven V. Ley,
- Anastasios Polyzos,
- Mark Ladlow and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2009, 5, No. 23, doi:10.3762/bjoc.5.23
- and release; flow synthesis; α-ketoesters; mesoreactor; polymer supported reagents; Introduction Organic synthesis is changing rapidly owing to the discovery of processes that challenge current dogma and lead to the invention of new chemical reactions [1][2]. Likewise, new synthesis tools are
Graphical Abstract
Figure 1: The Uniqsis FlowSyn™ continuous flow reactor comprising of a column holder and heating unit (A) and...
Scheme 1: General procedure for the flow synthesis of α-ketoester products 4a–j.
Scheme 2: General procedure for the batch synthesis of nitroolefinic esters 1a–j.
Scheme 3: General procedure for the flow synthesis of nitroolefinic esters 1a,c.
Figure 2: α-Ketoesters prepared and isolated yields.
