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Search for "aza-Michael" in Full Text gives 42 result(s) in Beilstein Journal of Organic Chemistry.
Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines
- David R. Chisholm,
- Garr-Layy Zhou,
- Ehmke Pohl,
- Roy Valentine and
- Andrew Whiting
Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174
- [24]. Reports of aza-Michael additions occurring in water indicated that the desired 8 could be synthesised under mild conditions, and we therefore decided to adapt these published conditions to larger scale work [25][26]. Initial attempts involving a 1:1 molar mixture of o-toluidine (5) and methyl
- intermediate 7. Synthesis of THQ 10, by initial aza-Michael addition, followed by formation of the tertiary alcohol 9, which was then cyclised with H2SO4. Synthesis of THQ 14 by initial acylation, cyclisation with H2SO4 and reduction with borane·dimethyl sulphide complex. N-Alkylation of 13 and 14. Facile
Graphical Abstract
Figure 1: Tetrahydroquinoline (THQ) and dihydroquinoline (DHQ) scaffolds to be synthesised.
Scheme 1: Proposed retrosynthesis scheme to access N-isopropyl-THQ 2.
Scheme 2: Synthesis of THQ 3 by initial N-alkylations, followed by PPA-mediated cyclisation.
Scheme 3: Bromination of 3 and attempted halogen exchange of the intermediate 7.
Scheme 4: Synthesis of THQ 10, by initial aza-Michael addition, followed by formation of the tertiary alcohol ...
Scheme 5: Synthesis of THQ 14 by initial acylation, cyclisation with H2SO4 and reduction with borane·dimethyl...
Scheme 6: N-Alkylation of 13 and 14.
Scheme 7: Facile route for the synthesis of 20a.
Scheme 8: Synthesis of THQ 21 and DHQ 22 using borane·dimethyl sulphide complex or DIBAL, respectively.
Figure 2: Simulated structure of 22 indicates a flattened quinoline-like structure. Hartree–Fock calculations...
Scheme 9: Postulated mechanism for the formation of 22 using DIBAL.
Figure 3: Combined, normalised absorption and emission spectra of 28 in chloroform. Absorption spectrum was r...
Scheme 10: Miyaura borylation of 21 and 22 to give crystalline boronic esters 29 and 30.
Figure 4: Comparison of the crystal structures of 29 (left) and 30 (right) as viewed along the plane of the a...
Figure 5: Combined, normalised absorption and emission spectra of 30 in diethyl ether. Absorption spectrum wa...
Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents
- Daniel Wiegmann,
- Stefan Koppermann,
- Marius Wirth,
- Giuliana Niro,
- Kristin Leyerer and
- Christian Ducho
Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77
- this producing organism, L-arginine is diastereoselectively hydroxylated to afford (3S)-3-hydroxy-L-arginine. The ring-closure reaction then occurs with formal inversion of the β-stereocenter (but quite likely through an aza-Michael addition to the α,β-unsaturated intermediate) [119][120][121]. The
- studies [123][124]. It should also be noted that a biomimetic domino guanidinylation–aza-Michael-addition reaction for the synthesis of the capreomycidine scaffold has been developed, which only furnished the target structures as stereoisomeric mixtures though [125]. The epicapreomycidine-derived
Graphical Abstract
Figure 1: Structures of the naturally occurring muraymycins isolated by McDonald et al. [22].
Figure 2: Structures of selected classes of nucleoside antibiotics. Similarities to the muraymycins are highl...
Figure 3: Structure of peptidoglycan. Long chains of glycosides (alternating GlcNAc (green) and MurNAc (blue)...
Figure 4: Schematic representation of bacterial cell wall biosynthesis.
Figure 5: Translocase I (MraY) catalyses the reaction of UDP-MurNAc-pentapeptide with undecaprenyl phosphate ...
Figure 6: Proposed mechanisms for the MraY-catalysed reaction. A: Two-step mechanism postulated by Heydanek e...
Scheme 1: First synthetic access towards simplified muraymycin analogues as reported by Yamashita et al. [76].
Scheme 2: Synthesis of (+)-caprazol (19) reported by Ichikawa, Matsuda et al. [92].
Scheme 3: Synthesis of the epicapreomycidine-containing urea dipeptide via C–H activation [96,97].
Scheme 4: Synthesis of muraymycin D2 and its epimer reported by Ichikawa, Matsuda et al. [96,97].
Scheme 5: Synthesis of the urea tripeptide unit as a building block for muraymycins reported by Kurosu et al. ...
Scheme 6: Synthesis of the uridine-derived core structure of naturally occuring muraymycins reported by Ducho...
Scheme 7: Synthesis of the epicapreomycidine-containing urea dipeptide from Garner's aldehyde reported by Duc...
Scheme 8: Synthesis of a hydroxyleucine-derived aldehyde building block reported by Ducho et al. [107].
Scheme 9: Synthesis of 5'-deoxy muraymycin C4 (65) as a closely related natural product analogue [78,109,110].
Figure 7: Summary of modifications on semisynthetic muraymycin analogues tested by Lin et al. [86]. Most active c...
Figure 8: Bioactive muraymycin analogues identified by Yamashita et al. [76].
Figure 9: Muraymycin D2 and several non-natural lipidated analogues 91a–d [77,114].
Figure 10: Non-natural muraymycin analogues with varying peptide structures [77,114].
Figure 11: SAR results for several structural variations of the muraymycin scaffold.
Figure 12: Muraymycin analogues designed for potential anti-Pseudomonas activity (most active analogues are hi...
Scheme 10: Proposed outline pathway for muraymycin biosynthesis based on the analysis of the biosynthetic gene...
Scheme 11: Biosynthesis of the nucleoside core structure of A-90289 antibiotics (which is identical to the mur...
Scheme 12: Transaldolase-catalysed formation of the key intermediate GlyU 101 in the biosynthesis of muraymyci...
(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers
- Giorgos Koutoulogenis,
- Nikolaos Kaplaneris and
- Christoforos G. Kokotos
Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48
- it near the enolate. In 2011, You and co-workers described the intramolecular desymmetrization of cyclohexadienones 69 catalyzed by thiourea 71, derived from cinchonine to give a bicyclic system 70 containing two chiral centers, utilizing an aza-Michael reaction (Scheme 24) [34]. The reaction
- constructed via a desymmetrization aza-Michael reaction. That key intermediate 72 was afforded in 91% yield and 97% ee. (Scheme 25). In 2012, Cobb and co-workers developed a novel asymmetric Michael–Michael reaction between nitrohex-4-enoates 73 and nitroolefins 74 to construct a cyclohexene moiety, bearing
- excellent diastereoselectivities (1.2:1–57:1 dr). In 2011, Chen, Xiao and co-workers, based on their previous work [77], described the aza-Michael–Michael cascade between substituted anilines 178 and nitroolefin enoates 172, utilizing a bifunctional cinchonine-derived thiourea 57 (Scheme 58) [79]. The
Graphical Abstract
Scheme 1: Activation of carbonyl compounds via enamine and iminium intermediates [2].
Scheme 2: Electronic and steric interactions present in enamine activation mode [2].
Scheme 3: Electrophilic activation of carbonyl compounds by a thiourea moiety.
Scheme 4: Asymmetric synthesis of dihydro-2H-pyran-6-carboxylate 3 using organocatalyst 4 [16].
Scheme 5: Possible hydrogen-bonding for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate [16].
Scheme 6: Asymmetric desymmetrization of 4,4-cyclohexadienones using the Michael addition reaction with malon...
Scheme 7: The enantioselective synthesis of α,α-disubstituted cycloalkanones using catalyst 11 [18].
Scheme 8: The enantioselective synthesis of indolo- and benzoquinolidine compounds through aza-Diels–Alder re...
Scheme 9: Enantioselective [5 + 2] cycloaddition [20].
Scheme 10: Asymmetric synthesis of oxazine derivatives 26 [21].
Scheme 11: Asymmetric synthesis of bicyclo[3.3.1]nonadienone, core 30 present in (−)-huperzine [22].
Scheme 12: Asymmetric inverse electron-demand Diels-Alder reaction catalyzed by amine-thiourea 34 [23].
Scheme 13: Asymmetric entry to morphan skeletons, catalyzed by amine-thiourea 37 [24].
Scheme 14: Asymmetric transformation of (E)-2-nitroallyl acetate [25].
Scheme 15: Proposed way of activation.
Scheme 16: Asymmetric synthesis of nitrobicyclo[3.2.1]octan-2-one derivatives [26].
Scheme 17: Asymmetric tandem Michael–Henry reaction catalyzed by 50 [27].
Scheme 18: Asymmetric Diels–Alder reactions of 3-vinylindoles 51 [29].
Scheme 19: Proposed transition state and activation mode of the asymmetric Diels–Alder reactions of 3-vinylind...
Scheme 20: Desymmetrization of meso-anhydrides by Chin, Song and co-workers [30].
Scheme 21: Desymmetrization of meso-anhydrides by Connon and co-workers [31].
Scheme 22: Asymmetric intramolecular Michael reaction [32].
Scheme 23: Asymmetric addition of malonate to 3-nitro-2H-chromenes 67 [33].
Scheme 24: Intramolecular desymmetrization through an intramolecular aza-Michael reaction [34].
Scheme 25: Enantioselective synthesis of (−)-mesembrine [34].
Scheme 26: A novel asymmetric Michael–Michael reaction [35].
Scheme 27: Asymmetric three-component reaction catalyzed by Takemoto’s catalyst 77 [46].
Scheme 28: Asymmetric domino Michael–Henry reaction [47].
Scheme 29: Asymmetric domino Michael–Henry reaction [48].
Scheme 30: Enantioselective synthesis of derivatives of 3,4-dihydro-2H-pyran 89 [49].
Scheme 31: Asymmetric addition of α,α-dicyano olefins 90 to 3-nitro-2H-chromenes 91 [50].
Scheme 32: Asymmetric three-component reaction producing 2,6-diazabicyclo[2.2.2]octanones 95 [51].
Scheme 33: Asymmetric double Michael reaction producing substituted chromans 99 [52].
Scheme 34: Enantioselective synthesis of multi-functionalized spiro oxindole dienes 106 [53].
Scheme 35: Organocatalyzed Michael aldol cyclization [54].
Scheme 36: Asymmetric synthesis of dihydrocoumarins [55].
Scheme 37: Asymmetric double Michael reaction en route to tetrasubstituted cyclohexenols [56].
Scheme 38: Asymmetric synthesis of α-trifluoromethyl-dihydropyrans 121 [58].
Scheme 39: Tyrosine-derived tertiary amino-thiourea 123 catalyzed Michael hemiaketalization reaction [59].
Scheme 40: Enantioselective entry to bicyclo[3.2.1]octane unit [60].
Scheme 41: Asymmetric synthesis of spiro[4-cyclohexanone-1,3’-oxindoline] 126 [61].
Scheme 42: Kinetic resolution of 3-nitro-2H-chromene 130 [62].
Scheme 43: Asymmetric synthesis of chromanes 136 [63].
Scheme 44: Wang’s utilization of β-unsaturated α-ketoesters 87 [64,65].
Scheme 45: Asymmetric entry to trifluoromethyl-substituted dihydropyrans 144 [66].
Scheme 46: Phenylalanine-derived thiourea-catalyzed domino Michael hemiaketalization reaction [67].
Scheme 47: Asymmetric synthesis of α-trichloromethyldihydropyrans 149 [68].
Scheme 48: Takemoto’s thiourea-catalyzed domino Michael hemiaketalization reaction [69].
Scheme 49: Asymmetric synthesis of densely substituted cyclohexanes [70].
Scheme 50: Enantioselective synthesis of polysubstituted chromeno [4,3-b]pyrrolidine derivatines 157 [71].
Scheme 51: Enantioselective synthesis of spiro-fused cyclohexanone/5-oxazolone scaffolds 162 [72].
Scheme 52: Utilizing 2-mercaptobenzaldehydes 163 in cascade processes [73,74].
Scheme 53: Proposed transition state of the initial sulfa-Michael step [74].
Scheme 54: Asymmetric thiochroman synthesis via dynamic kinetic resolution [75].
Scheme 55: Enantioselective synthesis of thiochromans [76].
Scheme 56: Enantioselective synthesis of chromans and thiochromans synthesis [77].
Scheme 57: Enantioselective sulfa-Michael aldol reaction en route to spiro compounds [78].
Scheme 58: Enantioselective synthesis of 4-aminobenzo(thio)pyrans 179 [79].
Scheme 59: Asymmetric synthesis of tetrahydroquinolines [80].
Scheme 60: Novel asymmetric Mannich–Michael sequence producing tetrahydroquinolines 186 [81].
Scheme 61: Enantioselective synthesis of biologically interesting chromanes 190 and 191 [82].
Scheme 62: Asymmetric tandem Henry–Michael reaction [83].
Scheme 63: An asymmetric synthesis of substituted cyclohexanes via a dynamic kinetic resolution [84].
Scheme 64: Three component-organocascade initiated by Knoevenagel reaction [85].
Scheme 65: Asymmetric Michael reaction catalyzed by catalysts 57 and 211 [86].
Scheme 66: Proposed mechanism for the asymmetric Michael reaction catalyzed by catalysts 57 and 211 [86].
Scheme 67: Asymmetric facile synthesis of hexasubstituted cyclohexanes [87].
Scheme 68: Dual activation catalytic mechanism [87].
Scheme 69: Asymmetric Michael–Michael/aldol reaction catalyzed by catalysts 57, 219 and 214 [88].
Scheme 70: Asymmetric synthesis of substituted cyclohexane derivatives, using catalysts 57 and 223 [89].
Scheme 71: Asymmetric synthesis of substituted piperidine derivatives, using catalysts 223 and 228 [90].
Scheme 72: Asymmetric synthesis of endo-exo spiro-dihydropyran-oxindole derivatives catalyzed by catalyst 232 [91]....
Scheme 73: Asymmetric synthesis of carbazole spiroxindole derivatives, using catalyst 236 [92].
Scheme 74: Enantioselective formal [2 + 2] cycloaddition of enal 209 with nitroalkene 210, using catalysts 23 ...
Scheme 75: Asymmetric synthesis of polycyclized hydroxylactams derivatives, using catalyst 242 [94].
Scheme 76: Asymmetric synthesis of product 243, using catalyst 246 [95].
Scheme 77: Formation of the α-stereoselective acetals 248 from the corresponding enol ether 247, using catalys...
Scheme 78: Selective glycosidation, catalyzed by Shreiner’s catalyst 23 [97].
Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones
- Antonia Di Mola,
- Maximilian Tiffner,
- Francesco Scorzelli,
- Laura Palombi,
- Rosanna Filosa,
- Paolo De Caprariis,
- Mario Waser and
- Antonio Massa
Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279
- several methods to obtain rac-9 are available [32][33][34][35][36], it is worth noting that the asymmetric synthesis of 9 is one of the major obstacles when targeting the synthesis of chiral isoindolinones. The recently introduced intramolecular aza-Michael reactions of 2-substituted acrylates gave very
Graphical Abstract
Figure 1: Some chiral, bioactive isoindolinones.
Scheme 1: This work: 1) trans-1,2-cyclohexane diamine-based bifunctional ammonium salts 8 in the asymmetric s...
Scheme 2: Asymmetric cascade, crystallization and decarboxylation reaction.
Scheme 3: Proposed racemization pathways of isoindolinones 9 via retro-Michael process.
Scheme 4: Asymmetric synthesis of (S)-PD172938.
Scheme 5: Coupling of chiral acid 9 with p-tolylpiperazine and CuI arylation of chiral isoindolinones.
Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams
- Katherine M. Byrd
Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60
- )-(+)-pseudoephedrine has emerged as a chiral auxiliary for the use in DCA reactions of α,β-unsaturated amides [49][50][51][52][53][54]. Badía and co-workers published a report where they performed aza-Michael additions to various α,β-unsaturated amides attached to (S,S)-(+)-pseudoephedrine [51] (Scheme 5
- opposite face. Prior to the development of the diastereoselective aza-Michael reactions, (S,S)-(+)-pseudoephedrine had been used as a chiral auxiliary for the diastereoselective α-alkylation of amides [55][56][57]. This literature precedent aided in the development of the tandem conjugate addition–α
- environment for the reaction to occur. The first part of this section will focus on the asymmetric 1,4-addition of carbon nucleophiles and the next two parts will discuss the addition of amines (aza-Michael addition) and phosphorous compounds. 2.4.1 Asymmetric 1,4-addition of carbon nucleophiles: Since its
Graphical Abstract
Scheme 1: Generic mechanism for the conjugate addition reaction.
Figure 1: Methods to activate unsaturated amide/lactam systems.
Scheme 2: DCA of Grignard reagents to an L-ephedrine derived chiral α,β–unsaturated amide.
Figure 2: Chiral auxiliaries used in DCA reactions.
Scheme 3: Comparison between auxiliary 5 and the Oppolzer auxiliary in a DCA reaction.
Scheme 4: Use of Evans auxiliary in a DCA reaction.
Figure 3: Lewis acid complex of the Evans auxiliary [43].
Scheme 5: DCA reactions of α,β-unsaturated amides utilizing (S,S)-(+)-pseudoephedrine and the OTBS-derivative...
Figure 4: Proposed model accounting for the diastereoselectivity observed in the 1,4-addition of Bn2NLi to α,...
Scheme 6: An example of a tandem conjugate addition–α-alkylation reaction of an α,β-unsaturated amide utilizi...
Scheme 7: Conjugate addition to an α,β-unsaturated bicyclic lactam leading to (+)-paroxetine and (+)-femoxeti...
Scheme 8: Intramolecular conjugate addition reaction to α,β-unsaturated amide.
Scheme 9: Conjugate addition to an α,β-unsaturated pyroglutamate derivative.
Scheme 10: Cu(I)–NHC-catalyzed asymmetric silylation of α,β-unsaturated lactams and amides.
Scheme 11: Asymmetric copper-catalyzed 1,4-borylation of an α,β-unsaturated amide.
Scheme 12: Asymmetric cross-coupling 49 to phenyl chloride.
Scheme 13: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam.
Scheme 14: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide.
Scheme 15: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide using a chiral bicyclic dien...
Scheme 16: Synthesis of (R)-(−)-baclofen through a rhodium-catalyzed asymmetric 1,4-arylation of lactam 58.
Scheme 17: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide and lactam employing organo[...
Scheme 18: Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam employing benzofuran-2-ylzi...
Figure 5: Further chiral ligands that have been used in rhodium-catalyzed 1,4-additions of α,β-unsaturated am...
Scheme 19: Palladium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to a α,β-unsaturated lactam.
Scheme 20: SmI2-mediated cyclization of α,β-unsaturated Weinreb amides.
Figure 6: Chiral Lewis acid complexes used in the Mukaiyama–Michael addition of α,β-unsaturated amides.
Scheme 21: Mukaiyama–Michael addition of thioester silylketene acetal to α,β-unsaturated N-alkenoyloxazolidino...
Scheme 22: Asymmetric 1,4-addition of aryl acetylides to α,β-unsaturated thioamides.
Scheme 23: Asymmetric 1,4-addition of alkyl acetylides to α,β-unsaturated thioamides.
Scheme 24: Asymmetric vinylogous conjugate additions of unsaturated butyrolactones to α,β-unsaturated thioamid...
Scheme 25: Gd-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrroles [205].
Scheme 26: Lewis acid-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrazole 107.
Scheme 27: Lewis acid mediated 1,4-addition of dibenzyl malonate to α,β-unsaturated N-acylpyrroles.
Scheme 28: Chiral Lewis acid mediated 1,4-radical addition to α,β-unsaturated N-acyloxazolidinone [224].
Scheme 29: Aza-Michael addition of O-benzylhydroxylamine to an α,β-unsaturated N-acylpyrazole.
Scheme 30: An example of the aza-Michael addition of secondary aryl amines to an α,β-unsaturated N-acyloxazoli...
Scheme 31: Aza-Michael additions of anilines to a α,β-unsaturated N-alkenoyloxazolidinone catalyzed by palladi...
Scheme 32: Aza-Michael additions of aniline to an α,β-unsaturated N-alkenoylbenzamide and N-alkenoylcarbamate ...
Scheme 33: Difference between aza-Michael addition ran using the standard protocol versus the slow addition pr...
Scheme 34: Aza-Michael additions of aryl amines salts to an α,β-unsaturated N-alkenoyloxazolidinone catalyzed ...
Scheme 35: Aza-Michael addition of N-alkenoyloxazolidiniones catalyzed by samarium diiodide [244].
Scheme 36: Asymmetric aza-Michael addition of p-anisidine to α,β-unsaturated N-alkenoyloxazolidinones catalyze...
Scheme 37: Asymmetric aza-Michael addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones catalyzed by i...
Scheme 38: Asymmetric 1,4-addition of purine to an α,β-unsaturated N-alkenoylbenzamide catalyzed by (S,S)-(sal...
Scheme 39: Asymmetric 1,4-addition of phosphites to α,β-unsaturated N-acylpyrroles.
Scheme 40: Asymmetric 1,4-addition of phosphine oxides to α,β-unsaturated N-acylpyrroles.
Scheme 41: Tandem Michael-aldol reaction catalyzed by a hydrogen-bonding organocatalyst.
Scheme 42: Examples of the sulfa-Michael–aldol reaction employing α,β-unsaturated N-acylpyrazoles.
Scheme 43: Example of the sulfa-Michael addition of α,β-unsaturated N-alkenoyloxazolidinones.
Figure 7: Structure of cinchona alkaloid-based squaramide catalyst.
Scheme 44: Asymmetric intramolecular oxa-Michael addition of an α,β-unsaturated amide.
Scheme 45: Formal synthesis atorvastatin.
Chiral phosphines in nucleophilic organocatalysis
- Yumei Xiao,
- Zhanhu Sun,
- Hongchao Guo and
- Ohyun Kwon
Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218
- 2010, using the bifunctional chiral phosphine G1, bearing both Brønsted acid and Lewis base units, as the catalyst, asymmetric domino aza-MBH/aza-Michael reactions of activated alkenes and N-tosylimines with Michael acceptor moieties at their ortho positions were accomplished to give chiral 1,3
Graphical Abstract
Figure 1: Cyclic chiral phosphines based on bridged-ring skeletons.
Figure 2: Cyclic chiral phosphines based on binaphthyl skeletons.
Figure 3: Cyclic chiral phosphines based on ferrocene skeletons.
Figure 4: Cyclic chiral phosphines based on spirocyclic skeletons.
Figure 5: Cyclic chiral phosphines based on phospholane ring skeletons.
Figure 6: Acyclic chiral phosphines.
Figure 7: Multifunctional chiral phosphines based on binaphthyl skeletons.
Figure 8: Multifunctional chiral phosphines based on amino acid skeletons.
Scheme 1: Asymmetric [3 + 2] annulations of allenoates with electron-deficient olefins, catalyzed by the chir...
Scheme 2: Asymmetric [3 + 2] annulations of allenoate and enones, catalyzed by the chiral binaphthyl-based ph...
Scheme 3: Asymmetric [3 + 2] annulations of N-substituted olefins and allenoates, catalyzed by the chiral bin...
Scheme 4: Asymmetric [3 + 2] annulations of 2-aryl-1,1-dicyanoethylenes with ethyl allenoate, catalyzed by th...
Scheme 5: Asymmetric [3 + 2] annulations of 3-alkylideneindolin-2-ones with ethyl allenoate, catalyzed by the...
Scheme 6: Asymmetric [3 + 2] annulations of 2,6-diarylidenecyclohexanones with allenoates, catalyzed by the c...
Scheme 7: Asymmetric [3 + 2] annulations of allenoate with alkylidene azlactones, catalyzed by the chiral bin...
Scheme 8: Asymmetric [3 + 2] annulations of C60 with allenoates, catalyzed by the chiral phosphine B6.
Scheme 9: Asymmetric [3 + 2] annulations of α,β-unsaturated esters and ketones with an allenoate, catalyzed b...
Scheme 10: Asymmetric [3 + 2] annulations of exocyclic enones with allenoates, catalyzed by the ferrocene-modi...
Scheme 11: Asymmetric [3 + 2] annulations of enones with an allenylphosphonate, catalyzed by the ferrocene-mod...
Scheme 12: Asymmetric [3 + 2] annulations of 3-alkylidene-oxindoles with ethyl allenoate, catalyzed by the fer...
Scheme 13: Asymmetric [3 + 2] annulations of dibenzylideneacetones with ethyl allenoate, catalyzed by the ferr...
Scheme 14: Asymmetric [3 + 2] annulations of trisubstituted alkenes with ethyl allenoate, catalyzed by the fer...
Scheme 15: Asymmetric [3 + 2] annulations of 2,6-diarylidenecyclohexanones with allenoates, catalyzed by the f...
Scheme 16: Asymmetric [3 + 2] annulations of α,β-unsaturated ketones with ethyl allenoates, catalyzed by the f...
Scheme 17: Asymmetric [3 + 2] annulations of α,β-unsaturated esters with allenoates, catalyzed by the ferrocen...
Scheme 18: Asymmetric [3 + 2] annulations of alkylidene azlactones with allenoates, catalyzed by the chiral sp...
Scheme 19: Asymmetric [3 + 2] annulations of α-trimethylsilyl allenones and electron-deficient olefins, cataly...
Scheme 20: Asymmetric [3 + 2] annulations of α,β-unsaturated ketones with an allenone, catalyzed by the chiral...
Scheme 21: Asymmetric [3 + 2] annulations of cyclic enones with allenoates, catalyzed by the chiral α-amino ac...
Scheme 22: Asymmetric [3 + 2] annulations of arylidenemalononitriles and analogues with an allenoate, catalyze...
Scheme 23: Asymmetric [3 + 2] annulations of α,β-unsaturated esters with an allenoate, catalyzed by the chiral...
Scheme 24: Asymmetric [3 + 2] annulations of 3,5-dimethyl-1H-pyrazole-derived acrylamides with an allenoate, c...
Scheme 25: Asymmetric [3 + 2] annulations of maleimides with allenoates, catalyzed by the chiral phosphine H10....
Scheme 26: Asymmetric [3 + 2] annulations of α-substituted acrylates with allenoate, catalyzed by the chiral p...
Scheme 27: Asymmetric [3 + 2] annulation of an N-tosylimine with an allenoate, catalyzed by the chiral phosphi...
Scheme 28: Asymmetric [3 + 2] annulations of N-tosylimines with an allenoate, catalyzed by the chiral phosphin...
Scheme 29: Asymmetric [3 + 2] annulations of N-tosylimines with an allenoate, catalyzed by the chiral phosphin...
Scheme 30: Asymmetric [3 + 2] annulations of N-diphenylphosphinoyl aromatic imines with butynoates, catalyzed ...
Scheme 31: Asymmetric [3 + 2] annulations of N-tosylimines with allenylphosphonates, catalyzed by the chiral p...
Scheme 32: Asymmetric [3 + 2] annulation of an N-tosylimine with an allenoate, catalyzed by the chiral phosphi...
Scheme 33: Asymmetric [3 + 2] annulations of N-diphenylphosphinoyl aromatic imines with allenoates (top), cata...
Scheme 34: Asymmetric [3 + 2] annulation of N-diphenylphosphinoylimines with allenoates, catalyzed by the chir...
Scheme 35: Asymmetric [3 + 2] annulation of an azomethine imine with an allenoate, catalyzed by the chiral pho...
Scheme 36: Asymmetric [3 + 2] annulations between α,β-unsaturated esters/ketones and 3-butynoates, catalyzed b...
Scheme 37: Asymmetric intramolecular [3 + 2] annulations of electron-deficient alkenes and MBH carbonates, cat...
Scheme 38: Asymmetric [3 + 2] annulations of methyleneindolinone and methylenebenzofuranone derivatives with M...
Scheme 39: Asymmetric [3 + 2] annulations of activated isatin-based alkenes with MBH carbonates, catalyzed by ...
Scheme 40: Asymmetric [3 + 2] annulations of maleimides with MBH carbonates, catalyzed by the chiral phosphine ...
Scheme 41: A series of [3 + 2] annulations of various activated alkenes with MBH carbonates, catalyzed by the ...
Scheme 42: Asymmetric [3 + 2] annulations of an alkyne with isatins, catalyzed by the chiral phosphine F1.
Scheme 43: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine B1.
Scheme 44: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine H5.
Scheme 45: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphines H13 and H12.
Scheme 46: Asymmetric [4 + 2] annulations catalyzed by the chiral phosphine H6.
Scheme 47: Kerrigan’s [2 + 2] annulations of ketenes with imines, catalyzed by the chiral phosphine B7.
Scheme 48: Asymmetric [4 + 1] annulations, catalyzed by the chiral phosphine G6.
Scheme 49: Asymmetric homodimerization of ketenes, catalyzed by the chiral phosphine F5 and F6.
Scheme 50: Aza-MBH/Michael reactions, catalyzed by the chiral phosphine G1.
Scheme 51: Tandem RC/Michael additions, catalyzed by the chiral phosphine H14.
Scheme 52: Intramolecular tandem RC/Michael addition, catalyzed by the chiral phosphine H15.
Scheme 53: Double-Michael addition, catalyzed by the chiral aminophosphine G9.
Scheme 54: Tandem Michael addition/Wittig olefinations, mediated by the chiral phosphine BIPHEP.
Scheme 55: Asymmetric Michael additions, catalyzed by the chiral phosphines H7, H8, and H9.
Scheme 56: Asymmetric γ-umpolung additions, catalyzed by the chiral phosphine A1.
Scheme 57: Asymmetric γ-umpolung additions, catalyzed by the chiral phosphines E2 and E3.
Scheme 58: Intramolecular γ-additions of hydroxy-2-alkynoates, catalyzed by the chiral phosphine D2.
Scheme 59: Intra-/intermolecular γ-additions, catalyzed by the chiral phosphine D2.
Scheme 60: Intermolecular γ-additions, catalyzed by the chiral phosphines B5 and B3.
Scheme 61: Intermolecular γ-additions, catalyzed by the chiral phosphines E6 and B4.
Scheme 62: Asymmetric allylic substitution of MBH acetates, catalyzed by the chiral phosphine G2.
Scheme 63: Allylic substitutions between MBH acetates or carbonates and an array of nucleophiles, catalyzed by...
Scheme 64: Asymmetric acylation of diols, catalyzed by the chiral phosphines E4 and E5.
Scheme 65: Kinetic resolution of secondary alcohols, catalyzed by the chiral phosphine E8 and E9.
Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives
- Giordano Lesma,
- Fiorella Meneghetti,
- Alessandro Sacchetti,
- Mattia Stucchi and
- Alessandra Silvani
Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141
- post-Ugi cyclization, namely an intramolecular aza-Michael [24] reaction, which afforded compound 18 bearing the privileged spiro-diketopiperazine scaffold (Scheme 2). Spiro-diketopiperazines are present in many natural products [38][39][40] and have recently received much attention as
Graphical Abstract
Figure 1: Biologically active agents containing a 3-substituted-3-aminooxindole core.
Figure 2: ORTEP [37] view of one of the two independent molecules of 4a present in the asymmetric unit, showing t...
Figure 3: Proposed explanation of the stereochemical outcome of the Ugi 3CR.
Scheme 1: Post-Ugi transformation on compound 10a.
Scheme 2: Post-Ugi cyclization on compound 15a.
Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach
- Thi Thanh Huyen Trinh,
- Khanh Hung Nguyen,
- Patricia de Aguiar Amaral and
- Nicolas Gouault
Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242
- of (−)-epimyrtine have been described to date including the intramolecular allylsilane N-acyliminium ion cyclization [6], the organocatalytic aza-Michael reaction [7], the intramolecular Mannich reaction [8], and the iminium ion cascade reaction [9][10]. More efficient, convenient and highly
Graphical Abstract
Scheme 1: Previously reported approach from β-aminoynones for the synthesis of pyridones.
Scheme 2: Retrosynthetic analysis of (−)-epimyrtine.
Scheme 3: Synthesis of (−)-epimyrtine.
The chemistry of amine radical cations produced by visible light photoredox catalysis
- Jie Hu,
- Jiang Wang,
- Theresa H. Nguyen and
- Nan Zheng
Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234
- 15 by abstraction of a hydrogen atom directly. The addition of the enol form of α-ketoester 59 to 15 furnishes the Mannich adduct 60. A retro-aza-Michael reaction via enol 61 allows cleavage of the C–N bond to yield secondary aniline 62. Aniline 62 is first oxidized to imine 63, which is further
Graphical Abstract
Scheme 1: Amine radical cations’ mode of reactivity.
Scheme 2: Reductive quenching of photoexcited Ru complexes by Et3N.
Scheme 3: Photoredox aza-Henry reaction.
Scheme 4: Formation of iminium ions using BrCCl3 as stoichiometric oxidant.
Scheme 5: Oxidative functionalization of N-aryltetrahydroisoquinolines using Eosin Y.
Scheme 6: Synthetic and mechanistic studies of Eosin Y-catalyzed aza-Henry reaction.
Scheme 7: Oxidative functionalization of N-aryltetrahydroisoquinolines using RB and GO.
Scheme 8: Merging Ru-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
Scheme 9: Merging Au-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
Scheme 10: Merging Ru-based photoredox catalysis and Cu-catalyzed alkynylation reaction.
Scheme 11: Merging Ru-based photoredox catalysis and NHC catalysis.
Scheme 12: 1,3-Dipolar cycloaddition of photogenically formed azomethine ylides.
Scheme 13: Plausible mechanism for photoredox 1,3-dipolar cycloaddition.
Scheme 14: Photoredox-catalyzed cascade reaction for the synthesis of fused isoxazolidines.
Scheme 15: Plausible mechanism for the photoredox-catalyzed cascade reaction.
Scheme 16: Photoredox-catalyzed α-arylation of glycine derivatives.
Scheme 17: Photoredox-catalyzed α-arylation of amides.
Scheme 18: Intramolecular interception of iminium ions by sulfonamides.
Scheme 19: Intramolecular interception of iminium ions by alcohols and sulfonamides.
Scheme 20: Intermolecular interception of iminium ions by phosphites.
Scheme 21: Photoredox-catalyzed oxidative phosphonylation by Eosin Y.
Scheme 22: Conjugated addition of α-amino radicals to Michael acceptors.
Scheme 23: Conjugated addition of α-amino radicals to Michael acceptors assisted by a Brønsted acid.
Scheme 24: Conjugated addition of α-amino radicals derived from anilines to Michael acceptors.
Scheme 25: Oxygen switch between two pathways involving α-amino radicals.
Scheme 26: Interception of α-amino radicals by azodicarboxylates.
Scheme 27: α-Arylation of amines.
Scheme 28: Plausible mechanism for α-arylation of amines.
Scheme 29: Photoinduced C–C bond cleavage of tertiary amines.
Scheme 30: Photoredox cleavage of C–C bonds of 1,2-diamines.
Scheme 31: Proposed mechanism photoredox cleavage of C–C bonds.
Scheme 32: Intermolecular [3 + 2] annulation of cyclopropylamines with olefins.
Scheme 33: Proposed mechanism for intermolecular [3 + 2] annulation.
Scheme 34: Photoinduced clevage of N–N bonds of aromatic hydrazines and hydrazides.
Efficient synthesis of β’-amino-α,β-unsaturated ketones
- Isabelle Abrunhosa-Thomas,
- Aurélie Plas,
- Nishanth Kandepedu,
- Pierre Chalard and
- Yves Troin
Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52
- reaction of chiral imines with enolates derived from Weinreb amides [13][14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone
- devised for the asymmetric synthesis of β’-amino-protected-α,β enones, a valuable intermediate for the synthesis of trans 2,6-disubstituted piperidines. The scope and limitation of the aza-Michael reaction were studied with a range of substrates. We are currently working on the application of this
Graphical Abstract
Scheme 1: Asymmetric synthesis of 2-methyl-6-phenyl piperidine.
Scheme 2: (a) Davies amine, BuLi, THF, −78 °C; dr ≥ 94% ; (b) H2, Pd(OH)2, MeOH; (c) Na2CO3, PhCH2CO2Cl, CH2Cl...
Scheme 3: Modified synthetic route to15.
Scheme 4: Possible pathways to obtain phosphonate 13 (a) Davies amine, BuLi, THF, −78 °C; dr ≥ 95%; (b) H2, P...
Scheme 5: Synthesis of compound 14.
Scheme 6: General synthesis of compound 13 (a) Davies amine, BuLi, THF, −78 °C; (b) H2, Pd(OH)2/C, MeOH; (c) ...
Scheme 7: Optimization of conditions for the Horner–Wadsworth–Emmons reaction.
Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives
- Zhi-Cong Geng,
- Jian Chen,
- Ning Li,
- Xiao-Fei Huang,
- Yong Zhang,
- Ya-Wen Zhang and
- Xing-Wang Wang
Beilstein J. Org. Chem. 2012, 8, 1710–1720, doi:10.3762/bjoc.8.195
- 65880378 10.3762/bjoc.8.195 Abstract The catalytic synthesis of nitrogen-containing heterocycles is of great importance to medicinal and synthetic chemists, and also a challenge for modern chemical methodology. In this paper, we report the synthesis of pyrazolidine derivatives through a domino aza-Michael
- good results (up to 86% yield, >10/1 regioselectivity, >20:1 dr, 99% ee) in the presence of (S)-diphenylprolinol trimethylsilyl ether catalyst. Keywords: aza-Michael; domino; hydrazine; organocatalysis; pyrazolidine; Introduction Pyrazolidines are privileged and valuable heterocyclic compounds, which
- explored by several groups [72][73]. In 2007, Jørgensen et al. reported that the organocatalyzed asymmetric aza-Michael addition of hydrazones to cyclic enones had been achieved in good yield and stereoselectivity [74]. In 2011, the Deng group developed a highly enantioselective organocatalytic synthesis
Graphical Abstract
Figure 1: Important heterocycles containing pyrazolidine or pyrazoline structures.
Figure 2: X-ray crystal structure of racemic 4a (25% thermal ellipsoids).
Figure 3: X-ray crystal structure of racemic 4n (25% thermal ellipsoids).
Figure 4: The X-ray crystal structure of chiral compound 4s (40% thermal ellipsoids).
Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines
- Chittaranjan Bhanja,
- Satyaban Jena,
- Sabita Nayak and
- Seetaram Mohapatra
Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191
- thiochromenes; and (3) Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines, using chiral proline and its derivatives (Figure 2), chiral bifunctional thioureas, cinchona alkaloids and other organocatalysts (Figure 3). For each reaction, the initial screening result of various
- -unsaturated nitro compounds 27 in toluene afforded chiral thiochromans 51 bearing three continuous stereogenic centers with high diastereo- and enantioselectivities by this novel cascade process (Scheme 26). 3. Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines 3.1. Reaction
- alcohol. Córdova and co-workers [73] in 2007 first reported an asymmetric organocatalytic tandem aza-Michael–aldol reaction for the synthesis of 1,2-dihydroquinolines through the iminium activation strategy. Thus, the aza-Michael–aldol reaction between 2-aminobenzaldehydes 52 and enals 2 in the presence
Graphical Abstract
Figure 1: Some representative molecules having chromene, thiochromene or 1,2-dihydroquinolin structural motif...
Figure 2: Screened chiral proline and its derivatives as organocatalysts. Rb = rubidium.
Figure 3: Screened chiral bifunctional thiourea, its derivatives, cinchona alkaloids and other organocatalyst...
Scheme 1: Diarylprolinolether-catalyzed tandem oxa-Michael–aldol reaction reported by Arvidsson.
Scheme 2: Tandem oxa-Michael–aldol reaction developed by Córdova.
Scheme 3: Domino oxa-Michael-aldol reaction developed by Wei and Wang.
Scheme 4: Chiral amine/chiral acid catalyzed tandem oxa-Michael–aldol reaction developed by Xu et al.
Scheme 5: Modified diarylproline ether as amino catalyst in oxa-Michael–aldol reaction as reported by Xu and ...
Scheme 6: Chiral secondary amine promoted oxa-Michael–aldol cascade reactions as reported by Wang and co-work...
Scheme 7: Reaction of salicyl-N-tosylimine with aldehydes by domino oxa-Michael/aza-Baylis–Hillman reaction, ...
Scheme 8: Silyl prolinol ether-catalyzed oxa-Michael–aldol tandem reaction of alkynals with salicylaldehydes ...
Scheme 9: Oxa-Michael–aldol sequence for the synthesis of tetrahydroxanthones developed by Córdova.
Scheme 10: Synthesis of tetrahydroxanthones developed by Xu.
Scheme 11: Diphenylpyrrolinol trimethylsilyl ether catalyzed oxa-Michael–Michael–Michael–aldol reaction for th...
Scheme 12: Enantioselective cascade oxa-Michael–Michael reaction of alkynals with 2-(E)-(2-nitrovinyl)-phenols...
Scheme 13: Domino oxa-Michael–Michael–Michael–aldol reaction of 2-(2-nitrovinyl)-benzene-1,4-diol with α,β-uns...
Scheme 14: Tandem oxa-Michael–Henry reaction catalyzed by organocatalyst and salicylic acid, as reported by Xu....
Scheme 15: Asymmetric synthesis of nitrochromenes from salicylaldehydes and β-nitrostyrene, as reported by San...
Scheme 16: Domino Michael–aldol reaction between salicyaldehydes with β-nitrostyrene, as reported by Das and c...
Scheme 17: Enantioselective synthesis of 2-aryl-3-nitro-2H-chromenes, as reported by Schreiner.
Scheme 18: (S)-diphenylpyrrolinol silyl ether-promoted cascade thio-Michael–aldol reactions, as reported by Wa...
Scheme 19: Organocatalytic asymmetric domino Michael–aldol condensation of mercaptobenzaldehyde and α,β-unsatu...
Scheme 20: Organocatalytic asymmetric domino Michael–aldol condensation between mercaptobenzaldehyde and α,β-u...
Scheme 21: Hydrogen-bond-mediated Michael–aldol reaction of 2-mercaptobenzaldehyde with α,β-unsaturated oxazol...
Scheme 22: Domino Michael–aldol reaction of 2-mercaptobenzaldehydes with maleimides catalyzed by cinchona alka...
Scheme 23: Domino thio-Michael–aldol reaction between 2-mercaptoacetophenone and enals developed by Córdova an...
Scheme 24: Enantioselective tandem Michael–Henry reaction of 2-mercaptobenzaldehyde with β-nitrostyrenes repor...
Scheme 25: Enantioselective tandem Michael–Knoevenagel reaction between 2-mercaptobenzaldehydes and benzyliden...
Scheme 26: Cinchona alkaloid thiourea catalyzed Michael–Michael cascade reaction, as reported by Wang and co-w...
Scheme 27: Domino aza-Michael–aldol reaction between 2-aminobenzaldehydes and α,β-unsaturated aldehydes, as re...
Scheme 28: (S)-Diphenylprolinol TES ether-promoted aza-Michael–aldol cascade reaction, as developed by Wang’s ...
Scheme 29: Domino aza-Michael–aldol reaction reported by Hamada.
Scheme 30: Organocatalytic asymmetric synthesis of 3-nitro-1,2-dihydroquinolines by a dual activation protocol...
Scheme 31: Asymmetric synthesis of 3-nitro-1,2-dihydroquinolines by cascade aza-Michael–Henry–dehydration reac...
A quantitative approach to nucleophilic organocatalysis
- Herbert Mayr,
- Sami Lakhdar,
- Biplab Maji and
- Armin R. Ofial
Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166
- °C, silyl ketene acetal 7b in dichloromethane with c(3a-CF3CO2) = (1.7–2.5) × 10−5 M, kryptopyrrole 12a in acetonitrile with c(3a-CF3CO2) = 5.0 × 10−5 M). Comparison of calculated and experimental rate constants of electrophilic aromatic substitutions with iminium ions [56]. Aza-Michael additions of
Graphical Abstract
Figure 1: Second-order rate constants for reactions of electrophiles with nucleophiles.
Figure 2: Mechanism of amine-catalyzed conjugate additions of nucleophiles [23-28].
Figure 3: Kinetics of the reactions of the iminium ion 3a with the silylated ketene acetal 7a [35].
Figure 4: Laser flash photolytic generation of iminium ions 3a.
Figure 5: Correlations of the reactivities of the iminium ions 3a and 3b toward nucleophiles with the corresp...
Figure 6: Comparison of the electrophilicities of cinnamaldehyde-derived iminium ions 3a–3i.
Figure 7: Nucleophiles used in iminium activated reactions [35,42,44-52].
Figure 8: Counterion effects in electrophilic reactions of iminium ions 3a-X (at 20 °C, silyl ketene acetal 7b...
Figure 9: Comparison of calculated and experimental rate constants of electrophilic aromatic substitutions wi...
Figure 10: Aza-Michael additions of the imidazoles 15 with the iminium ion 3a [58].
Figure 11: Plots of log k2 for the reactions of enamides 17a–17e with the benzhydrylium ions 18a–d in CH3CN at...
Figure 12: Comparison of the nucleophilicities of enamides 17 with those of several other C nucleophiles (solv...
Figure 13: Experimental and calculated rate constants k2 for the reactions of 17b and 17g with 3a and 3b in th...
Figure 14: Comparison between experimental and calculated (Equation 1) cyclopropanation rate constants [64].
Figure 15: Electrostatic activation of iminium activated cyclopropanations with sulfur ylides.
Figure 16: Sulfur ylides inhibit the formation of iminium ions.
Figure 17: Enamine activation [65].
Figure 18: Electrophilicity parameters E for classes of compounds that have been used as electrophilic substra...
Figure 19: Quantification of the nucleophilic reactivities of the enamines 32a–e in acetonitrile (20 °C) [83]; a d...
Figure 20: Proposed transition states for the stereogenic step in proline-catalyzed reactions.
Figure 21: Kinetic evidence for the anchimeric assistance of the electrophilic attack by the carboxylate group....
Figure 22: Differentiation of nucleophilicity and Lewis basicity (in acetonitrile at 20 °C): Rate (left) and e...
Figure 23: NHCs 41, 42, and 43 are moderately active nucleophiles and exceptionally strong Lewis bases (methyl...
Figure 24: Nucleophilic reactivities of the deoxy Breslow intermediates 45 in THF at 20 °C [107].
Figure 25: Comparison of the proton affinities (PA, from [107]) of the diaminoethylenes 47a–c with the methyl catio...
Figure 26: Berkessel’s synthesis of a Breslow intermediate (51, keto tautomer) from carbene 43 [112].
Figure 27: Synthesis of O-methylated Breslow intermediates [114].
Figure 28: Relative reactivities of deoxy- and O-methylated Breslow intermediates [114].
Figure 29: Reactivity scales for electrophiles and nucleophiles relevant for organocatalytic reactions (refere...
Coupled chemo(enzymatic) reactions in continuous flow
- Ruslan Yuryev,
- Simon Strompen and
- Andreas Liese
Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169
- and solvent-free environment [38]. In the first noncatalyzed thermal aza-Michael addition performed at 80 °C, the racemic ester rac-46 is formed from cheap starting materials benzylamine (44) and trans-ethylcrotonate (45) (Scheme 14). Subsequently, Novozym 435 is applied for the kinetic resolution of
Graphical Abstract
Figure 1: Metabolic pathways in a living cell as an example of efficient coupled-reaction processes. A: Subst...
Figure 2: Four generations of biotransformations. I: Single-reaction processes; II: Single-reaction processes...
Scheme 1: Production of L-leucine (3) in a continuously operating enzyme membrane reactor (EMR). E1: L-Leucin...
Scheme 2: Production of D-mandelic acid (5) in a continuously operating enzyme membrane reactor. E1: D-(−)-Ma...
Scheme 3: Simultaneous synthesis of gluconic acid (9) and glutamic acid (8) in a continuously operated membra...
Scheme 4: Production of L-tert-leucine (11) in a continuously operated enzyme membrane reactor equipped with ...
Scheme 5: Continuous oxidation of lactose (12) to lactobionic acid (13) in a dynamic membrane-aerated reactor...
Scheme 6: Production of N-acetylneuraminic acid (17) in a continuously operated enzyme membrane reactor. E1: ...
Scheme 7: Chemo-enzymatic epoxidation of 1-methylcyclohexene (18) in a packed-bed reactor (PBR) containing No...
Scheme 8: Continuous production of (R)-1-phenylethyl propionate (24) by dynamic kinetic resolution of (rac)-1...
Scheme 9: Synthesis of D-xylulose (28) from D,L-serine (26) and D,L-glyceraldehyde (25) in a continuously ope...
Scheme 10: Continuous production of L-alanine (31) from fumarate (29) in a two-stage enzyme membrane reactor. ...
Scheme 11: Continuous synthesis of 1-phenyl-(1S,2S)-propanediol (35) in a cascade of two enzyme membrane react...
Scheme 12: Production of a dipeptide 39 in a cascade of two continuously operated membrane reactors. E1: Carbo...
Scheme 13: Continuous production of GDP-mannose (43) from mannose 1-phosphate (40) in a cascade of two enzyme ...
Scheme 14: Continuous solvent-free chemo-enzymatic synthesis of ethyl (S)-3-(benzylamino)butanoate (48) in a s...
Scheme 15: Continuous chemo-enzymatic synthesis of grossamide (52) in a cascade of packed-bed reactors. E: Per...
Scheme 16: Chemo-enzymatic synthesis of 2-aminophenoxazin-3-one (56) in a cascade of continuously operating pa...
Scheme 17: Continuous conversion of 3-phospho-D-glycerate (57) into D-ribulose 1,5-bisphosphate (58) in a casc...
Scheme 18: Continuous hydrolysis of 4-cyanopyridine (59) to isonicotinic acid (61) in a cascade of two packed-...
Scheme 19: Continuous fermentative production of ethanol (64) from hardwood lignocellulose (62) in a stirred-t...
Scheme 20: Production of hydrogen by anaerobic fermentation of glucose (7) using Clostridium acetobutylicum ce...
Scheme 21: Continuous production of (2R,5R)-hexanediol (67) in an enzyme membrane reactor containing whole cel...
Scheme 22: Synthesis of L-phenylalanine (69) in a continuously stirred tank reactor equipped with a hollow-fib...
Scheme 23: Continuous epoxidation of 1,7-octadiene (70) to (R)-7-epoxyoctene (72) by a strain of Pseudomonas o...
Scheme 24: Oxidation of styrene (73) to (S)-styrene oxide (74) in a continuously operated biofilm tube reactor...
Scheme 25: Reduction of estrone (75) to β-estradiol (76) by Saccharomyces cerevisiae in a cascade of two stirr...
Amines as key building blocks in Pd-assisted multicomponent processes
- Didier Bouyssi,
- Nuno Monteiro and
- Geneviève Balme
Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163
- used. A proper choice of catalyst and reaction conditions is also needed to improve the efficiency of each reaction (Scheme 18) [18]. Consecutive one-pot transformations initiated by Heck reaction and terminated by intramolecular aza–Michael addition were developed by Hanson and coworkers to access a
- , and catalytic Pd2(dba)3·CHCl3 led to the production of the desired sultams 42 upon heating at 110 °C. A series of sultam derivatives of bioactive, related isoindol-1-one amides 43 were also prepared by entering acrylic acid into the Heck–aza–Michael process and coupling a second amine derivative
- sulfur dioxide. However, this Pd-catalyzed aminosulfonylation process proved inefficient with primary amines (Scheme 20) [20]. Multicomponent synthesis of nitrogen-containing heterocycles may also be initiated by an aza-Michael addition and terminated by a palladium-catalyzed ring-closure process [21
Graphical Abstract
Scheme 1: Synthesis of substituted amides.
Scheme 2: Synthesis of ketocarbamates and imidazolones.
Scheme 3: Access to β-lactams.
Scheme 4: Access to β-lactams with increased structural diversity.
Scheme 5: Synthesis of imidazolinium salts.
Scheme 6: Access to the indenamine core.
Scheme 7: Synthesis of substituted tetrahydropyridines.
Scheme 8: Synthesis of more substituted tetrahydropyridines.
Scheme 9: Synthesis of chiral tetrahydropyridines.
Scheme 10: Preparation of α-aminonitrile by a catalyzed Strecker reaction.
Scheme 11: Synthesis of spiroacetals.
Scheme 12: Synthesis of masked 3-aminoindan-1-ones.
Scheme 13: Synthesis of homoallylic amines and α-aminoesters.
Scheme 14: Preparation of 1,2-dihydroisoquinolin-1-ylphosphonates.
Scheme 15: Pyrazole elaboration by cycloaddition of hydrazines with alkynones generated in situ.
Scheme 16: An alternative approach to pyrazoles involving hydrazine cycloaddition.
Scheme 17: Synthesis of pyrroles by cyclization of propargyl amines.
Scheme 18: Isoindolone and phthalazone synthesis by cyclization of acylhydrazides.
Scheme 19: Sultam synthesis by cyclization of sulfonamides.
Scheme 20: Synthesis of sulfonamides by aminosulfonylation of aryl iodides.
Scheme 21: Pyrrolidine synthesis by carbopalladation of allylamines.
Scheme 22: Synthesis of indoles through a sequential C–C coupling/desilylation–coupling/cyclization reaction.
Scheme 23: Synthesis of indoles by a site selective Pd/C catalyzed cross-coupling approach.
Scheme 24: Synthesis of isoindolin-1-one derivatives through a sequential Sonogashira coupling/carbonylation/h...
Scheme 25: Synthesis of pyrroles through an allylic amination/Sonogashira coupling/hydroamination reaction.
Scheme 26: Synthesis of indoles through a Sonogashira coupling/cyclofunctionalization reaction.
Scheme 27: Synthesis of indoles through a one-pot two-step Sonogashira coupling/cyclofunctionalization reactio...
Scheme 28: Synthesis of α-alkynylindoles through a Pd-catalyzed Sonogashira/double C–N coupling reaction.
Scheme 29: Synthesis of indoles through a Pd-catalyzed sequential alkenyl amination/C-arylation/N-arylation.
Scheme 30: Synthesis of N-aryl-2-benzylpyrrolidines through a sequential N-arylation/carboamination reaction.
Scheme 31: Synthesis of phenothiazine derivatives through a one-pot palladium-catalyzed double C–N arylation i...
Scheme 32: Synthesis of substituted imidazolidinones through a palladium-catalyzed three-component reaction of...
Scheme 33: Synthesis of 2,3-diarylated amines through a palladium-catalyzed four-component reaction involving ...
Scheme 34: Synthesis of rolipram involving a Pd-catalyzed three-component reaction.
Scheme 35: Synthesis of seven-membered ring lactams through a Pd-catalyzed amination/intramolecular cyclocarbo...
Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam
- Václav Jurčík,
- Alexandra M. Z. Slawin and
- David O'Hagan
Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86
- explored as the enantiomerically pure amine. In the event 4a was generated after aza-Michael addition as a mixture of two stereoisomers, without any obvious diastereoisomeric bias (1:1, 0% de) as judged by both 1H and 19F NMR. β-Lactam ring closure, using thionyl chloride and triethylamine gave the N
- explored for the hydrogenolysis of 5a, however cleavage of the C–N bond proved very difficult and a satisfactory method could not be found. Therefore, (S)-α-(p-methoxyphenyl)ethylamine (3b) was explored as an alternative amine for the aza-Michael reaction, as removal of this amine using ceric ammonium
- nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The
Graphical Abstract
Figure 1: Enantiomers of α-(trifluoromethyl)-β-lactam (1).
Scheme 1: Synthetic route involving a diastereoisomeric separation to α-(trifluoromethyl)-β-lactam ((S)-1) fr...
Figure 2: X-ray structures of (a) β-lactam (S)-1 and (b) (αR,3R)-5c. (a) Determination of the absolute stereo...
Scheme 2: Synthesis of stereoisomers 5c. The stereochemistry of the major isomer (αR,3R)-5c was solved by X-r...
Michael-type addition of azoles of broad-scale acidity to methyl acrylate
- Sławomir Boncel,
- Kinga Saletra,
- Barbara Hefczyc and
- Krzysztof Z. Walczak
Beilstein J. Org. Chem. 2011, 7, 173–178, doi:10.3762/bjoc.7.24
- reports on the synthesis of Michael-type adducts of azoles by the use of microwave irradiation [7][24]. The optimisation of aza-Michael reactions with N-methylimidazole as the base catalyst was published in 2007 by Liu et al [25]. However, when this catalyst was used with azoles of narrower-scale acidity
- important drugs, have seldomly been considered as aza-Michael donors due to their poor nucleophilicity and the possible tendency of adducts to undergo retro-Michael reactions [26]. Here, we present Michael-type addition of azoles, inter alia imidazole and 1,2,4-triazole derivatives of high acidity (pKa
Graphical Abstract
Figure 1: Examples of azole derivatives as important therapeutic agents.
Scheme 1: Michael-type addition of azoles of broad-scale acidity 1a–h to methyl acrylate (2) under basic cond...
Scheme 2: Chemical evidence for a regioselective Michael-type addition of 4(5)-nitroimidazole (1c) to methyl ...
