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Search for "six-membered ring" in Full Text gives 138 result(s) in Beilstein Journal of Organic Chemistry.
Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization
- Barry M. Trost,
- Michael C. Ryan and
- Meera Rao
Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110
- reaction for the synthesis of Tris-protected [3.1.0] pyrrolidines, it occurred to us that protecting groups other than Tris may be equally effective for the [3.1.0] system. The Tris group was chosen during our optimization of the six-membered ring system (Table 5), which may have significantly different
Graphical Abstract
Scheme 1: Divergent behavior of the palladium and ruthenium-catalyzed Alder–ene reaction.
Scheme 2: Some asymmetric enyne cycloisomerization reactions.
Figure 1: (a) Mechanism for the redox biscycloisomerization reaction. (b) Ruthenium catalyst containing a tet...
Scheme 3: Synthesis of p-anisyl catalyst 1.
Figure 2: Failed sulfinate ester syntheses.
Scheme 4: Using norephedrine-based oxathiazolidine-2-oxide 7 for chiral sulfoxide synthesis.
Scheme 5: (a) General synthetic sequence to access enyne bicycloisomerization substrates (b) Synthesis of 2-c...
Figure 3: Failed bicycloisomerization substrates. Reactions performed at 40 °C for 16 hours with 3 mol % of c...
Scheme 6: Deprotection of [3.1.0] bicycles and X-ray crystal structure of 76.
Scheme 7: ProPhenol-catalyzed addition of zinc acetylide to acetaldehyde for the synthesis of a chiral 1,6-en...
Figure 4: Diastereomeric metal complexes formed after alcohol coordination.
Scheme 8: Curtin–Hammitt scenario of redox bicycloisomerization in acetone.
Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies
- Takashi Nishikata,
- Alexander R. Abela,
- Shenlin Huang and
- Bruce H. Lipshutz
Beilstein J. Org. Chem. 2016, 12, 1040–1064, doi:10.3762/bjoc.12.99
- (Ph2PCH2CH2CH2PPh2)(dppp)) (angle of P–Pd–P: 90.58°) having a six-membered ring conformation [217], and palladacycles reported previously [73][206][215]. The length of the Pd–N4 bond, (2.126 Å), is slightly longer than those of Pd–N(3), Pd–C(5), Pd–O(2) bonds, likely due to a trans effect of the strong σ-donor aryl
Graphical Abstract
Figure 1: Road map to enhanced C–H activation reactivity.
Scheme 1: Concerted metalation–deprotonation and elelectrophilic palladation pathways for C–H activation.
Scheme 2: Routes for generation of cationic palladium(II) species.
Scheme 3: Optimized conditions for C–H arylations at room temperature.
Scheme 4: Biaryl formation catalyzed by Pd(OAc)2.
Figure 2: C–H arylation results. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water (1 mL) with 1...
Figure 3: Monoarylations in water at rt. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water with ...
Scheme 5: Selective arylation of a 1-naphthylurea derivative.
Figure 4: Fujiwara–Moritani coupling rreactions in water. Conditions A: 10 mol % [Pd(MeCN)4](BF4)2, 1 equiv B...
Figure 5: Optimization. Conducted at rt for 8 h or as otherwise noted in EtOAc with 10 mol % Pd catalyst, AgO...
Figure 6: Representative results in EtOAc. Conducted at rt in EtOAc with 10 mol % Pd(OAc)2, HBF4 (1 equiv), a...
Scheme 6: Previous syntheses of boscalid®.
Scheme 7: Synthesis of boscalid®. aConducted at rt for 20 h in EtOAc with 10 mol % [Pd(MeCN)4](BF4)2, BQ (5 e...
Scheme 8: Hypothetical reaction sequence for cationic Pd(II)-catalyzed aromatic C–H activation reactions.
Scheme 9: Palladacycle formation.
Figure 7: X-ray structure of palladacycle 6 with thermal ellipsoids at the 50% probability level. BF4 and hyd...
Figure 8: NMR studies. A: The reaction of [Pd(MeCN)4](BF4)2 and 3-MeOC6H4NHCONMe2 in acetone-d6. B: The react...
Scheme 10: The generation of cationic Pd(II) from Pd(OAc)2.
Scheme 11: Electrophilic substitution of aromatic hydrogen by cationic palladium(II) species.
Scheme 12: Attempted reactions of palladacycle 6.
Scheme 13: The impact of MeCN on C-H activation/coupling reactions.
Scheme 14: Stoichiometric MeCN-free reactions. a2% Brij 35 was used instead of EtOAc.
Scheme 15: The reactions of divalent palladacycles.
Scheme 16: Role of BQ in stoichiometric Fujiwara–Moritani and Suzuki–Miyaura coupling reactions. aYields based...
Scheme 17: Proposed role of BQ in Fujiwara–Moritani reactions.
Scheme 18: Proposed role of BQ in Suzuki–Miyaura coupling reactions.
Scheme 19: Stoichiometric C–H arylation of iodobenzene. aYields based on Pd.
Scheme 20: Impact of acetate on the cationicity of Pd.
Scheme 21: Roles of additives in C–H arylation.
Scheme 22: Cross-coupling in the presence of AgBF4.
Scheme 23: A proposed catalytic cycle for Fujiwara–Moritani reactions.
Scheme 24: Proposed catalytic cycle of C–H activation/Suzuki–Miyaura coupling reactions.
Scheme 25: A proposed catalytic cycle for C–H arylation involving a Pd(IV) intermediate.
Scheme 26: Selected reactions of divalent palladacycles.
Opportunities and challenges for direct C–H functionalization of piperazines
- Zhishi Ye,
- Kristen E. Gettys and
- Mingji Dai
Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70
- -substituted piperazines in regioselective and stereoselective manners. The common and traditional way to synthesize α-carbon-substituted piperazines is through de novo construction of the six-membered ring with starting materials such as amino acids and diamines followed by oxidation level adjustment (Figure
- six-membered ring [51]. As of yet only a few examples have been reported so far and are far from being general and practical; no enantioselective versions have been shown. Rhodium-catalyzed dehydrogenative carbonylation In 1997, Murai and co-workers reported a novel Rh-catalyzed α-C–H
Graphical Abstract
Figure 1: Selected piperazine-containing small-molecule pharmaceuticals.
Figure 2: Strategies for the synthesis of carbon-substituted piperazines.
Figure 3: The first α-lithiation of N-Boc-protected piperazines by van Maarseveen et al. in 2005 [37].
Figure 4: α-Lithiation of N-Boc-N’-tert-butyl piperazines by Coldham et al. in 2010 [38].
Figure 5: Diamine-free α-lithiation of N-Boc-piperazines by O’Brien, Campos, et al. in 2010 [40].
Figure 6: The first enantioselective α-lithiation of N-Boc-piperazines by McDermott et al. in 2008 [41].
Figure 7: Dynamic thermodynamic resolution of lithiated of N-Boc-piperazines by Coldham et al. in 2010 [38].
Figure 8: Enantioselective α-lithiation of N-Boc-N’-alkylpiperazines by O’Brien et al. in 2013 and 2016 [42,43].
Figure 9: Asymmetric α-functionalization of N-Boc-piperazines with Ph2CO by O’Brien et al. in 2016 [43].
Figure 10: A “chiral auxiliary” strategy toward enantiopure α-functionalized piperazines by O’Brien et al. 201...
Figure 11: Installation of methyl group at the α-position of piperazines by O’Brien et al. 2016 [43].
Figure 12: α-Lithiation trapping of C-substituted N-Boc-piperazines by O’Brien et al. 2016 [43].
Figure 13: Rh-catalyzed reactions of N-(2-pyridinyl)piperazines by Murai et al. in 1997 [52].
Figure 14: Ta-catalyzed hydroaminoalkylation of piperazines by Schafer et al. in 2013 [55].
Figure 15: Photoredox catalysis for α-C–H functionalization of piperazines by MacMillan et al. in 2011 and 201...
Figure 16: Copper-catalyzed aerobic C–H oxidation of piperazines by Touré, Sames, et al. in 2013 [67].
Figure 17: Free radical approach by Undheim et al. in 1994 [68].
Figure 18: Anodic oxidation approach by Nyberg et al. in 1976 [70].
(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
- main tools a synthetic chemist has to perform asymmetric catalysis. In this review the synthesis of six-membered rings, that contain multiple chiral centers, either by a ring closing process or by a functionalization reaction on an already existing six-membered ring, utilizing bifunctional (thio)ureas
- chiral centers; organocatalysis; six-membered ring; thiourea; urea; Introduction During the last 15 years, organocatalysis has flourished and has been established as one of the three major pillars of asymmetric synthesis [1][2][3]. Among the modes of activation of organic molecules that have been
- organocatalysts. Review Primary amine-thioureas as organocatalysts promoting asymmetric transformations that lead to a six-membered ring As discussed earlier, except from the activation of the substrates with the formation of the corresponding enamines or iminium ions, the synthesis of enantiopure products can be
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].
Enantioselective [3 + 2] annulation of α-substituted allenoates with β,γ-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine
- Huanzhen Ni,
- Weijun Yao and
- Yixin Lu
Beilstein J. Org. Chem. 2016, 12, 343–348, doi:10.3762/bjoc.12.37
- in different reaction modes and undergo [4 + 2] annulations with suitable reaction partners to afford six-membered ring structures [37][38][39][40][41][42][43][44][45][46][47]. Recently, He and co-workers disclosed that the reaction between α-substituted allenoates and β,γ-unsaturated N
Graphical Abstract
Scheme 1: The [3 + 2] annulation of α-substituted allenoates reported by He.
Scheme 2: Possible reaction mechanism.
Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst
- Minami Odagi,
- Yoshiharu Yamamoto and
- Kazuo Nagasawa
Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22
- the guanidine moiety (Table 1, entries 5 and 6). A catalyst bearing a six-membered ring at R1 and R2 (1e) gave excellent yield, but with only 27% ee (Table 1, entry 5). Interestingly, catalyst 1f bearing a pyrrolidine ring at R1 and R2 showed the highest selectivity, and 5a was obtained in 99% yield
Graphical Abstract
Figure 1: a) Asymmetric α-hydroxylation of 2 in the presence of 1a. b) Asymmetric α-amination of 4 explored i...
Scheme 1: Substrate scope of α-amination.
Figure 2: NLE study of α-amination.
Scheme 2: α-Amination of 4a using 9 or 10 as catalyst.
2-Hetaryl-1,3-tropolones based on five-membered nitrogen heterocycles: synthesis, structure and properties
- Yury A. Sayapin,
- Inna O. Tupaeva,
- Alexandra A. Kolodina,
- Eugeny A. Gusakov,
- Vitaly N. Komissarov,
- Igor V. Dorogan,
- Nadezhda I. Makarova,
- Anatoly V. Metelitsa,
- Valery V. Tkachev,
- Sergey M. Aldoshin and
- Vladimir I. Minkin
Beilstein J. Org. Chem. 2015, 11, 2179–2188, doi:10.3762/bjoc.11.236
- convenient approach to the construction of seven-membered rings of 1,3-tropolone derivatives has been afforded by the acid-catalyzed reaction of o-quinones with methylene active compounds that proceeds with the expansion of the quinone six-membered ring [17][18][19][20]. The study of the reaction had been
- three compounds of these series as well as quantum chemical DFT PBE0/6-311+G** calculations point to energy preference of the NH-tautomeric form of the obtained 1,3-tropolones with the very strong intramolecular N–H···O bond closing up the conjugate six-membered ring. The theoretically predicted
Graphical Abstract
Scheme 1: 1,3-Tropolones 2–4 prepared by the reaction of o-chloranil with methylene active compounds.
Scheme 2: General scheme of the synthesis of 2-(2-hetaryl)-5,6,7-trichloro-1,3-tropolones 5 and 2-(2-hetaryl)...
Scheme 3: The mechanism for the formation of 5,6,7-trichloro-1,3-tropolones 5 and 4,5,6,7-tetrachloro-1,3-tro...
Figure 1: Molecular structure of 2-(3,3-dimethylindolyl)-5,6,7-trichloro-1,3-tropolone 5g. Thermal ellipsoids...
Figure 2: Molecular structure of 2-(5-chlorobenzothiazolyl)-4,5,6,7-tetrachloro-1,3-tropolone 6e. Thermal ell...
Scheme 4:
The fast prototropic N–H···O ![[Graphic 3]](/bjoc/content/inline/1860-5397-11-236-i8.png?max-width=637&scale=1.18182)
N···H–O equilibrium in solutions of 2-hetaryl-5,6,7-trichloro- and 4,...
Scheme 5: Two reaction paths for coupling 2-hetaryl-1,3-tropolones 5 and 6 with alcohols.
Figure 3: Molecular structure of 2-(3,3-dimethylindolyl)-5,7-dichloro-6-ethoxy-1,3-tropolone 13. Selected bon...
Figure 4: Molecular structure of 2-(2-ethoxycarbonyl-6-hydroxy-3,4,5-trichlorophenyl)benzoxazole 11b. Selecte...
Figure 5: Electronic absorption (1, 2), fluorescence emission (λexc = 350 nm) (3, 4) and fluorescence excitat...
Synthesis of constrained analogues of tryptophan
- Elisabetta Rossi,
- Valentina Pirovano,
- Marco Negrato,
- Giorgio Abbiati and
- Monica Dell’Acqua
Beilstein J. Org. Chem. 2015, 11, 1997–2006, doi:10.3762/bjoc.11.216
- six-membered ring [8]. Moreover, fused bicyclic unnatural amino acids are present in the structures of two antiviral drugs, boceprevir (Merck) [9] and telaprevir (Vertex, Johnson & Johnson) [10] used against hepatitis C genotype 1 viral infections (Figure 1). In this research field, tryptophan
Graphical Abstract
Figure 1: Examples of drugs embodying unnatural amino acids.
Figure 2: Examples of biologically active compounds embodying constrained analogues of tryptophan.
Scheme 1: Planned Diels–Alder reactions for the synthesis of tetrahydrocarbazoles as constrained analogues of...
Figure 3: Structure elucidation of diastereoisomeric tetrahydrocarbazoles 3a and 3’a via NMR experiments.
Scheme 2: Synthesis of unprotected tryptophan derivatives 6a–e.
Scheme 3: Plausible reaction mechanism for the cycloaddition reactions of indoles 1a–h with 2 in toluene.
Scheme 4: Cycloaddition reaction of 2-vinylindole 1k and methyl 2-acetamidoacrylate (2).
Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction
- Cesar Garcias-Morales,
- David Ortegón-Reyna and
- Armando Ariza-Castolo
Beilstein J. Org. Chem. 2015, 11, 1973–1984, doi:10.3762/bjoc.11.213
- 7 are reported for the first time. Crystals of 1 were obtained by slow evaporation of a saturated toluene solution, and 1 crystallized in the P21/n space group. The six-membered ring in the crystal structure exhibits a chair–boat conformation. For 1, the crystal structure shows that the aromatic
- rings on the six-membered ring with the boat conformation are antiperiplanar to the aromatic ring on the six-membered ring with the chair conformation (Figure 7a). This geometry allowed a C–H∙∙∙π intramolecular interaction between the aromatic rings. There are also C–H∙∙∙π intermolecular interactions
Graphical Abstract
Figure 1: (a) Schematic representation of the vicinal σC−H→σ*C−X interaction by double-bond/no-bond resonance...
Figure 2: Schematic representation of stereoelectronic effects (a) hyperconjugation, (b) homohyperconjugation...
Figure 3: Schematic representation of possible homoanomeric interactions in six-membered saturated heterocycl...
Figure 4: Structure of compounds 1 to 8.
Scheme 1: Proposed reaction mechanism for the synthesis of piperidones by the Mannich reaction. The substitue...
Scheme 2: For 6, R1 = R2 = H, for 7, R1 = H, R2 = CH3, for 8, R1 = R2 = CH3.
Figure 5: (a) Favored conformation for compound 1, determined by nOe effect, (b) t-ROESY spectrum of 1 record...
Figure 6: (a) Preferred conformation of 4 determined by nOe, (b) t-ROESY spectrum of 4 recorded at 500 MHz in...
Figure 7: (a) ORTEP diagram of 1. The thermal ellipsoids are drawn at the 30% probability level for all atoms...
Figure 8: (a) ORTEP diagrams of 6 and 7. The thermal ellipsoids are drawn at the 30% probability level for al...
Figure 9: (a) 1JC,H coupling constant of 3, 5, 6, and 8. (b) Plot of the population analysis versus 1JC,H (sl...
Scheme 3: Representation of the nN→σ*C–H(7)eq interaction. The interaction energy is 0.55 kcal/mol at the ωB9...
Figure 10: Distances between N(3) and C(7) for 3, 5, 6, and 7 measured in the structures obtained by XRD.
Mechanism, kinetics and selectivity of selenocyclization of 5-alkenylhydantoins: an experimental and computational study
- Biljana M. Šmit,
- Radoslav Z. Pavlović,
- Dejan A. Milenković and
- Zoran S. Marković
Beilstein J. Org. Chem. 2015, 11, 1865–1875, doi:10.3762/bjoc.11.200
- five-membered ring (S,R)-TS-INT3 and (S,R)-TS-INT3, and two for the formation of the six-membered ring (S,R)-TS-INT3’ and (S,S)-TS-INT3’ (Figure 4). In (S,R)-TS-INT3 and (S,S)-TS-INT3 the N-C(5) bond is partially formed, the Se-C(5) bond is partially cleaved, whereas the Se-C(6) bond is becoming
- states for the formation of the five-membered ring (S,R)-TS-INT3 and (S,S)-TS-INT3 and six-membered ring (S,R)-TS-INT3’ and (S,S)-TS-INT3’. The crucial bond lengths are given in pm. Optimized geometries of intermediate bicyclic imidazolinium cations. The crucial bond lengths are given in pm. Optimized
Graphical Abstract
Scheme 1: Proposed mechanism for the selenocyclization of model substrate 1.
Scheme 2: 5-Exo pathway of the proposed mechanism with all possible intermediates and products.
Figure 1: 1H NMR monitoring of the cyclization of 5-alkenylhydantoin 1 with PhSeCl in acetonitrile-d3 solutio...
Figure 2: Optimized geometries of possible Markovnikov-type intermediates formed by the anti-stereospecific a...
Figure 3: Energy profile for the proposed mechanism of selenocyclization of model substrate 1. Relative energ...
Figure 4: Optimized geometries for seleniranium cations and corresponding transition states for the formation...
Figure 5: Optimized geometries of intermediate bicyclic imidazolinium cations. The crucial bond lengths are g...
Figure 6: Optimized geometries of possible products of the selenocyclization of 1, with relative free energy ...
Scheme 3: Proposed mechanism for selenocyclization of model substrate 3.
Figure 7: Optimized geometries of possible intermediates of the selenocyclization of model substrate 3, with ...
Figure 8: Optimized geometries of possible products of the selenocyclization of model substrate 3, with relat...
Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship
- Mohamed Yacine Ameur Messaoud,
- Ghenia Bentabed-Ababsa,
- Madani Hedidi,
- Aïcha Derdour,
- Floris Chevallier,
- Yury S. Halauko,
- Oleg A. Ivashkevich,
- Vadim E. Matulis,
- Laurent Picot,
- Valérie Thiéry,
- Thierry Roisnel,
- Vincent Dorcet and
- Florence Mongin
Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160
- hexane (thermodynamic conditions) [11][12] or (ii) with butyllithium activated by potassium tert-butoxide (LICKOR) in tetrahydrofuran (THF) at −75 °C [11][13]. N-Arylpyrroles substituted on their six-membered ring by methoxy [14], halogen [15][16], alkyl [17][18], or trifluoromethyl [19][20] groups have
Graphical Abstract
Figure 1: Substrates involved in deproto-metallation reaction.
Figure 2: ORTEP diagram (30% probability) of 2e.
Scheme 1: Synthesis of the azole substrates 1f and 2f.
Scheme 2: Deproto-metallation of 1c followed by iodolysis [33].
Scheme 3: Deproto-metallation of 1a and 2a followed by iodolysis.
Scheme 4: Deproto-metallation of 1b and 2b followed by iodolysis.
Scheme 5: Deproto-metallation of 1c and 2c followed by iodolysis.
Figure 3: ORTEP diagrams (30% probability) of 4c, 3d and 3e.
Scheme 6: Deproto-metallation of 1d and 2d followed by iodolysis.
Scheme 7: Deproto-metallation of 1e and 2e followed by iodolysis.
Scheme 8: N-arylation of the iodides 3b, 3d and 4d.
Figure 4: ORTEP diagram (30% probability) of 5d.
Figure 5: Calculated values of pKa(THF) of the compounds 1 and 2, and bromobenzene.
Figure 6: Antiproliferative activity (growth inhibition) of the tested compounds 1a,b,e,f, 2a,b and 5d at con...
Figure 7: Iodides previously formed as major products from the corresponding N-(4-methoxyphenyl)azoles using ...
Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition
- Zachary L. Palchak,
- Paula T. Nguyen and
- Catharine H. Larsen
Beilstein J. Org. Chem. 2015, 11, 1425–1433, doi:10.3762/bjoc.11.154
- release of torsional strain when the sp2 center in the six-membered ring is attacked, cyclohexanone represents a special case as this cyclic ketone is nearly as reactive as an aldehyde [24]. The resultant tetrasubstituted (red) cyclohexylamine is found in natural alkaloids such as (–)-lycodine (Figure 2
Graphical Abstract
Figure 1: A sampling of propargylamine-derived triazoles with therapeutic effects includes alpha-tetrasubstit...
Figure 2: A tetrasubstituted carbon bearing an amine (red) can provide 100-fold increase in activity compared...
Scheme 1: KA2 coupling followed by tandem silyl deprotection and triazole formation.
Scheme 2: Silyl deprotection/click conditions applied to tert-butylacetylene. An identical yield is observed ...
Scheme 3: High overall yield of 1,2,3-triazole fully-substituted at the 4-position.
Surprisingly facile CO2 insertion into cobalt alkoxide bonds: A theoretical investigation
- Willem K. Offermans,
- Claudia Bizzarri,
- Walter Leitner and
- Thomas E. Müller
Beilstein J. Org. Chem. 2015, 11, 1340–1351, doi:10.3762/bjoc.11.144
- -membered ring intermediate to a six-membered ring. Moreover, Wu et al. studied a) the cycloaddition of ethylene oxide and CO2, catalysed by Ni(PPh3)2 [39], b) the cycloaddition of chloromethyloxirane and CO2, catalysed by Re(CO)5Br [40] and c) the cycloaddition of 4-(phenoxymethyl)-1,3-dioxolan-2-one and
Graphical Abstract
Scheme 1: Reaction of carbon dioxide with epoxide to yield alternating polycarbonates, polyethercarbonates or...
Scheme 2: Epoxide and CO2 copolymerisation by homogeneous Cr(III)– and Al(III)–salen complexes.
Figure 1: The tri-coordinated di-iminate zinc–alkoxide complex [(BDI)ZnOCH3].
Scheme 3: Heterogeneous zinc dicarboxylates for the copolymerisation of CO2 and epoxides. (* = End group of p...
Scheme 4: Backbiting mechanism for the formation of cyclic carbonates.
Scheme 5: Two-step pathway for the cycloaddition of propylene oxide and CO2 in the ionic liquid 1-butyl-3-met...
Scheme 6: Formation of copper(I) cyanoacetate for the activation of CO2.
Scheme 7: Activation of CO2 by nucleophilic attack of bromide in the Re(I)-catalysed cycloaddition.
Scheme 8: Direct catalytic carboxylation of aliphatic compounds and arenes by rhodium(I)– and ruthenium(II)–p...
Scheme 9: Insertion of carbon dioxide into a metal–oxygen bond via a cyclic four-membered transition state. R...
Scheme 10: Facile CO2 uptake by zinc(II)–tetraazacycloalkanes.
Figure 2: The [(2-hydroxyethoxy)CoIII(salen)(L)] complex chosen as catalyst model for the calculations; 1: R1...
Figure 3: The two most relevant configurations of [(2-hydroxyethoxy)CoIII(salen)(L)] complexes. The left-hand...
Figure 4: Carbon dioxide insertion into the cobalt(III)–alkoxide bond of [(2-hydroxyethoxy)CoIII(salen)(L)] c...
Figure 5: Energy relationship between the activation barrier and the reaction energy of the CO2 incorporation...
Synthesis of γ-hydroxypropyl P-chirogenic (±)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors
- Iris Binyamin,
- Shoval Meidan-Shani and
- Nissan Ashkenazi
Beilstein J. Org. Chem. 2015, 11, 1332–1339, doi:10.3762/bjoc.11.143
- once binded to metals which favor a six-membered ring geometry. Moreover, these compounds could be advantageously used in organocatalysis and are commonly embedded in inorganic or organic matrix for various heterogeneous applications. Chemical structures of 2-methoxy-1,3,2-dioxaphospholane 2-oxide (1
Graphical Abstract
Figure 1: Chemical structures of 2-methoxy-1,3,2-dioxaphospholane 2-oxide (1), 2-ethoxy-1,3,2-dioxaphospholan...
Scheme 1: (A) Alkaline hydrolysis of dioxaphospholane: the phosphorane intermediate includes one endocyclic o...
Scheme 2: Reaction of 4 with various Grignard reagents.
Scheme 3: Synthesis of 2-phenyl-1,2-oxaphospholane 2-oxide (5).
Scheme 4: Formation of phosphinates and phosphine oxides bearing three different substituents from oxaphospho...
Scheme 5: Synthesis of acetylene and allene phosphine oxides.
The chemical behavior of terminally tert-butylated polyolefins
- Dagmar Klein,
- Henning Hopf,
- Peter G. Jones,
- Ina Dix and
- Ralf Hänel
Beilstein J. Org. Chem. 2015, 11, 1246–1258, doi:10.3762/bjoc.11.139
- for all non-H atoms. The angles at C2 and C7 are greatly widened (to 132–135°). The central six-membered ring displays a 1,2-diplanar ("sofa") conformation, whereby the atom N1 lies 0.5 Å out of the plane of the other five atoms. The next two higher vinylogs, pentaene 20 and hexaene 21, reacted
- shown in Figure 6. The O–O bond length is 1.4755(12) Å, which corresponds well to the mean value of 1.480 Å obtained from the Cambridge Crystallographic Database [17] for similar ring systems (69 hits, 81 values; one severe outlier omitted). The six-membered ring has an approximate “sofa” conformation
Graphical Abstract
Scheme 1: The polyenes 2 stabilized by terminal tert-butyl substituents.
Scheme 2: The catalytic hydrogenation of diene 3.
Figure 1: The structure of compound 4 in the crystal. Ellipsoids correspond to 30% probability levels.
Scheme 3: The catalytic hydrogenation of triene 7.
Scheme 4: Addition of bromine to model dienes.
Scheme 5: Bromine addition to diene 3 and triene 7.
Scheme 6: Bromine addition to the higher oligoenes 19–22.
Figure 2: (a) The structure of compound 24 in the crystal. Ellipsoids correspond to 50% probability levels. (...
Figure 3: The structure of compound 25 in the crystal. This was a structure of poor quality and served only t...
Scheme 7: Epoxidation of triene 7 with MCPBA and DMDO.
Scheme 8: Epoxidation of tetraene 19 with MCPBA and DMDO.
Scheme 9: Diels–Alder addition of PTAD (36) to triene 7 and tetraene 19.
Figure 4: The structure of compound 37 in the crystal. Only one of two independent molecules is shown. Ellips...
Scheme 10: Diels-Alder addition of oligoenes 20 and 21 with PTAD (36).
Scheme 11: Addition of excess PTAD (36) to hexaene 21 and heptaene 22.
Scheme 12: TCNE addition to oligoolefins: from tetraene 19 to nonaene 42.
Figure 5: The structure of compound 43 in the crystal. Only one of two independent molecules is shown. Ellips...
Scheme 13: Photochemical experiments with tetraene 19.
Figure 6: The structure of compound 52 in the crystal. Ellipsoids correspond to 50% probability levels.
Attempts to prepare an all-carbon indigoid system
- Şeref Yildizhan,
- Henning Hopf and
- Peter G. Jones
Beilstein J. Org. Chem. 2015, 11, 363–372, doi:10.3762/bjoc.11.42
- be obtained. The molecule 24 displays crystallographic inversion symmetry, although the true symmetry is close to C2h (rmsd 0.02 Å). The molecular packing involves herringbone layers, parallel to the bc plane, in which two C–H···π contacts to the centroid of the aromatic six-membered ring are
- the aromatic six-membered ring (seen side-on) can be recognized, but are not drawn explicitly. H atoms not involved in these contacts are omitted. One of the two independent molecules of compound 25 in the crystal. Ellipsoids represent 50% probability levels. a) The molecule of compound 30 in the
- crystal. Ellipsoids represent 50% probability levels. Only the asymmetric unit is numbered. b) Packing diagram of compound 30 viewed perpendicular to (102). C–H···π contacts to the centroid of the six-membered ring can be recognized, but are not drawn explicitly. H atoms not involved in these contacts are
Graphical Abstract
Scheme 1: From indigo to heteroindigo derivatives and all-carbon-indigo.
Scheme 2: Attempts to prepare the α-methylene ketones 12 and 13.
Figure 1: a) Both independent molecules of compound 13 in the crystal; ellipsoids represent 50% probability l...
Scheme 3: Dimerization of 13 under McMurry conditions.
Figure 2: a) The molecule of compound 17 in the crystal; ellipsoids represent 50% probability levels. Only th...
Scheme 4: Dimerization of indan-1-one (18) by a stepwise approach.
Scheme 5: Methylenation of 19 and bisalkylation of the product 23 with 1,2-dibromoethane.
Figure 3: The molecule of compound 23 in the crystal. Ellipsoids represent 50% probability levels. Only the a...
Figure 4: a) The molecule of compound 24 in the crystal. Ellipsoids represent 50% probability levels. Only th...
Figure 5: One of the two independent molecules of compound 25 in the crystal. Ellipsoids represent 50% probab...
Scheme 6: Cross-conjugated hydrocarbons by Thiele condensation.
Figure 6: a) The molecule of compound 30 in the crystal. Ellipsoids represent 50% probability levels. Only th...
Photovoltaic-driven organic electrosynthesis and efforts toward more sustainable oxidation reactions
- Bichlien H. Nguyen,
- Robert J. Perkins,
- Jake A. Smith and
- Kevin D. Moeller
Beilstein J. Org. Chem. 2015, 11, 280–287, doi:10.3762/bjoc.11.32
- barriers of quaternary carbon and six-membered ring formation. The use of the second nucleophile and a fast initial trapping reaction reduced the cation character of the radical cation intermediate, slowed competitive elimination reactions, and allowed for the desired quaternary carbon formation. In these
Graphical Abstract
Scheme 1: Electrochemical recycling of a chemical oxidant.
Figure 1: a) Electrolysis setup with a “suitcase” photovoltaic device. b) Electrolysis with a very simple, co...
Scheme 2: Examples of solar-driven direct electrochemical oxidations.
Scheme 3: Overoxidation of dithioketal.
Scheme 4: Examples of solar-driven, indirect electrochemical oxidations.
Scheme 5: Solar-driven synthesis of C-glycosides.
Scheme 6: Solar-driven oxidative condensation.
Scheme 7: Solar-driven oxidative cyclization with a second nucleophile.
Design and synthesis of novel bis-annulated caged polycycles via ring-closing metathesis: pushpakenediol
- Sambasivarao Kotha and
- Mirtunjay Kumar Dipak
Beilstein J. Org. Chem. 2014, 10, 2664–2670, doi:10.3762/bjoc.10.280
- allyl groups in PCUD can be converted to a six-membered ring by RCM [28]. Since the two allyl groups in the PCUD framework are far apart, they did not undergo a RCM reaction. Later, by introducing additional unsaturated fragments in the PCUD system one can generate multiple rings in the PCUD system by
Graphical Abstract
Figure 1: Selected theoretically interesting molecules.
Figure 2: Retrosynthetic approach toward bis-annulated PCUD.
Scheme 1: The synthesis of diallylated tricyclic diene 19.
Scheme 2: The synthesis of diallylated pentacyclic dione 20.
Scheme 3: The synthesis of heptacyclic diol 22.
Figure 3: (a) Optimized structure of 22 (b) Ancient flying machine “Pushpak Viman”.
Scheme 4: The synthesis of diallylated hexacyclic diols.
Scheme 5: The attempted synthesis of heptacyclic diol via ring-rearrangement metathesis.
Dimerisation, rhodium complex formation and rearrangements of N-heterocyclic carbenes of indazoles
- Zong Guan,
- Jan C. Namyslo,
- Martin H. H. Drafz,
- Martin Nieger and
- Andreas Schmidt
Beilstein J. Org. Chem. 2014, 10, 832–840, doi:10.3762/bjoc.10.79
- obtained by slow evaporation of a saturated solution in methanol. This compound crystallized monoclinic. A molecular structure is shown in Figure 4. In the single crystal the NH group of the aniline (N18–H) forms a hydrogen bond to the imine group (N25) so that an almost planar six-membered ring is formed
- . The dihedral angle C11–C12–C17–N18 (crystallographic numbering) was determined to be 0.5(2)°. This six-membered ring is almost perpendicularly twisted in relation to the quinazoline ring [N1–C10–C11–C12 = −92.65(17)°]. Conclusion The N-heterocyclic carbene of indazole, indazol-3-ylidene, displays a
Graphical Abstract
Scheme 1: Generation of indazol-3-ylidenes.
Scheme 2: Reaction products of indazol-3-ylidenes in heterocycle synthesis.
Scheme 3: Syntheses of acridines from indazol-3-ylidenes.
Scheme 4: Dimerisation of indazol-3-ylidenes to spiro compounds.
Figure 1: Diagnostic 1H and 13C NMR chemical shifts of the Z and E configuration isomer in CDCl3.
Figure 2: Molecular structure of 14c, displacement parameters are drawn at 50% probability level.
Scheme 5: Rhodium complex formation.
Figure 3: Structure of the cation of 15e, displacement parameters are drawn at 50% probability level.
Scheme 6: Rearrangement of the spiro compounds on heating.
Figure 4: Molecular structure of 16b, displacement parameters are drawn at 50% probability level.
Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics
- Gijs Koopmanschap,
- Eelco Ruijter and
- Romano V.A. Orru
Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50
- temperature and the final tetrazoles 158a–c were obtained in moderate to good yields. Six-membered ring constraints Pipecolic acid In the previous section we discussed some important conformational properties of proline derivatives playing an important role in controlling peptide and protein secondary
Graphical Abstract
Scheme 1: The proposed mechanism of the Passerini reaction.
Scheme 2: The PADAM-strategy to α-hydroxy-β-amino amide derivatives 7. An additional oxidation provides α-ket...
Scheme 3: The general accepted Ugi-mechanism.
Scheme 4: Three commonly applied Ugi/cyclization approaches. a) UDC-process, b) UAC-sequence, c) UDAC-combina...
Scheme 5: Ugi reaction that involves the condensation of Armstrong’s convertible isocyanide.
Scheme 6: Mechanism of the U-4C-3CR towards bicyclic β-lactams.
Scheme 7: The Ugi 4C-3CR towards oxabicyclo β-lactams.
Scheme 8: Ugi MCR between an enantiopure monoterpene based β-amino acid, aldehyde and isocyanide resulting in...
Scheme 9: General MCR for β-lactams in water.
Scheme 10: a) Ugi reaction for β-lactam-linked peptidomimetics. b) Varying the β-amino acid resulted in β-lact...
Scheme 11: Ugi-4CR followed by a Pd-catalyzed Sn2 cyclization.
Scheme 12: Ugi-3CR of dipeptide mimics from 2-substituted pyrrolines.
Scheme 13: Joullié–Ugi reaction towards 2,5-disubstituted pyrrolidines.
Scheme 14: Further elaboration of the Ugi-scaffold towards bicyclic systems.
Scheme 15: Dihydroxyproline derivatives from an Ugi reaction.
Scheme 16: Diastereoselective Ugi reaction described by Banfi and co-workers.
Scheme 17: Similar Ugi reaction as in Scheme 16 but with different acids and two chiral isocyanides.
Scheme 18: Highly diastereoselective synthesis of pyrrolidine-dipeptoids via a MAO-N/MCR-procedure.
Scheme 19: MAO-N/MCR-approach towards the hepatitis C drug telaprevir.
Scheme 20: Enantioselective MAO-U-3CR procedure starting from chiral pyrroline 64.
Scheme 21: Synthesis of γ-lactams via an UDC-sequence.
Scheme 22: Utilizing bifunctional groups to provide bicyclic γ-lactam-ketopiperazines.
Scheme 23: The Ugi reaction provided both γ- as δ-lactams depending on which inputs were used.
Scheme 24: The sequential Ugi/RCM with olefinic substrates provided bicyclic lactams.
Scheme 25: a) The structural and dipole similarities of the triazole unit with the amide bond. b) The copper-c...
Scheme 26: The Ugi/Click sequence provided triazole based peptidomimetics.
Scheme 27: The Ugi/Click reaction as described by Nanajdenko.
Scheme 28: The Ugi/Click-approach by Pramitha and Bahulayan.
Scheme 29: The Ugi/Click-combination by Niu et al.
Scheme 30: Triazole linked peptidomimetics obtained from two separate MCRs and a sequential Click reaction.
Scheme 31: Copper-free synthesis of triazoles via two MCRs in one-pot.
Scheme 32: The sequential Ugi/Paal–Knorr reaction to afford pyrazoles.
Scheme 33: An intramolecular Paal–Knorr condensation provided under basic conditions pyrazolones.
Scheme 34: Similar cyclization performed under acidic conditions provided pyrazolones without the trifluoroace...
Scheme 35: The Ugi-4CR towards 2,4-disubstituted thiazoles.
Scheme 36: Solid phase approach towards thiazoles.
Scheme 37: Reaction mechanism of formation of thiazole peptidomimetics containing an additional β-lactam moiet...
Scheme 38: The synthesis of the trisubstituted thiazoles could be either performed via an Ugi reaction with pr...
Scheme 39: Performing the Ugi reaction with DMB-protected isocyanide gave access to either oxazoles or thiazol...
Scheme 40: Ugi/cyclization-approach towards 2,5-disubstituted thiazoles. The Ugi reaction was performed with d...
Scheme 41: Further derivatization of the thiazole scaffold.
Scheme 42: Three-step procedure towards the natural product bacillamide C.
Scheme 43: Ugi-4CR to oxazoles reported by Zhu and co-workers.
Scheme 44: Ugi-based synthesis of oxazole-containing peptidomimetics.
Scheme 45: TMNS3 based Ugi reaction for peptidomimics containing a tetrazole.
Scheme 46: Catalytic cycle of the enantioselective Passerini reaction towards tetrazole-based peptidomimetics.
Scheme 47: Tetrazole-based peptidomimetics via an Ugi reaction and a subsequent sigmatropic rearrangement.
Scheme 48: Resin-bound Ugi-approach towards tetrazole-based peptidomimetics.
Scheme 49: Ugi/cyclization approach towards γ/δ/ε-lactam tetrazoles.
Scheme 50: Ugi-3CR to pipecolic acid-based peptidomimetics.
Scheme 51: Staudinger–Aza-Wittig/Ugi-approach towards pipecolic acid peptidomimetics.
Figure 1: The three structural isomers of diketopiperazines. The 2,5-DKP isomer is most common.
Scheme 52: UDC-approach to obtain 2,5-DKPs, either using Armstrong’s isocyanide or via ethylglyoxalate.
Scheme 53: a) Ugi reaction in water gave either 2,5-DKP structures or spiro compounds. b) The Ugi reaction in ...
Scheme 54: Solid-phase approach towards diketopiperazines.
Scheme 55: UDAC-approach towards DKPs.
Scheme 56: The intermediate amide is activated as leaving group by acid and microwave assisted organic synthes...
Scheme 57: UDC-procedure towards active oxytocin inhibitors.
Scheme 58: An improved stereoselective MCR-approach towards the oxytocin inhibitor.
Scheme 59: The less common Ugi reaction towards DKPs, involving a Sn2-substitution.
Figure 2: Spatial similarities between a natural β-turn conformation and a DKP based β-turn mimetic [158].
Scheme 60: Ugi-based syntheses of bicyclic DKPs. The amine component is derived from a coupling between (R)-N-...
Scheme 61: Ugi-based synthesis of β-turn and γ-turn mimetics.
Figure 3: Isocyanide substituted 3,4-dihydropyridin-2-ones, dihydropyridines and the Freidinger lactams. Bio-...
Scheme 62: The mechanism of the 4-CR towards 3,4-dihydropyridine-2-ones 212.
Scheme 63: a) Multiple MCR-approach to provide DHP-peptidomimetic in two-steps. b) A one-pot 6-CR providing th...
Scheme 64: The MCR–alkylation–MCR procedure to obtain either tetrapeptoids or depsipeptides.
Scheme 65: U-3CR/cyclization employing semicarbazone as imine component gave triazine based peptidomimetics.
Scheme 66: 4CR towards triazinane-diones.
Scheme 67: The MCR–alkylation–IMCR-sequence described by our group towards triazinane dione-based peptidomimet...
Scheme 68: Ugi-4CR approaches followed by a cyclization to thiomorpholin-ones (a) and pyrrolidines (b).
Scheme 69: UDC-approach for benzodiazepinones.
Scheme 70: Ugi/Mitsunobu sequence to BDPs.
Scheme 71: A UDAC-approach to BDPs with convertible isocyanides. The corresponding amide is cleaved by microwa...
Scheme 72: microwave assisted post condensation Ugi reaction.
Scheme 73: Benzodiazepinones synthesized via the post-condensation Ugi/ Staudinger–Aza-Wittig cyclization.
Scheme 74: Two Ugi/cyclization approaches utilizing chiral carboxylic acids. Reaction (a) provided the product...
Scheme 75: The mechanism of the Gewald-3CR includes three base-catalysed steps involving first a Knoevnagel–Co...
Scheme 76: Two structural 1,4-thienodiazepine-2,5-dione isomers by U-4CR/cyclization.
Scheme 77: Tetrazole-based diazepinones by UDC-procedure.
Scheme 78: Tetrazole-based BDPs via a sequential Ugi/hydrolysis/coupling.
Scheme 79: MCR synthesis of three different tricyclic BPDs.
Scheme 80: Two similar approaches both involving an Ugi reaction and a Mitsunobu cyclization.
Scheme 81: Mitsunobu–Ugi-approach towards dihydro-1,4-benzoxazepines.
Scheme 82: Ugi reaction towards hetero-aryl fused 5-oxo-1,4-oxazepines.
Scheme 83: a) Ugi/RCM-approach towards nine-membered peptidomimetics b) Sequential peptide-coupling, deprotect...
Scheme 84: Ugi-based synthesis towards cyclic RGD-pentapeptides.
Scheme 85: Ugi/MCR-approach towards 12–15 membered macrocycles.
Scheme 86: Stereoselective Ugi/RCM approach towards 16-membered macrocycles.
Scheme 87: Passerini/RCM-sequence to 22-membered macrocycles.
Scheme 88: UDAC-approach towards 12–18-membered depsipeptides.
Figure 4: Enopeptin A with its more active derivative ADEP-4.
Scheme 89: a) The Joullié–Ugi-approach towards ADEP-4 derivatives b) Ugi-approach for the α,α-dimethylated der...
Scheme 90: Ugi–Click-strategy for 15-membered macrocyclic glyco-peptidomimetics.
Scheme 91: Ugi/Click combinations provided macrocycles containing both a triazole and an oxazole moiety.
Scheme 92: a) A solution-phase procedure towards macrocycles. b) Alternative solid-phase synthesis as was repo...
Scheme 93: Ugi/cyclization towards cyclophane based macrocycles.
Scheme 94: PADAM-strategy towards eurystatin A.
Scheme 95: PADAM-approach for cyclotheanamide.
Scheme 96: A triple MCR-approach affording RGD-pentapeptoids.
Scheme 97: Ugi-MiBs-approach towards peptoid macrocycles.
Scheme 98: Passerini-based MiB approaches towards macrocycles 345 and 346.
Scheme 99: Macrocyclic peptide formation by the use of amphoteric aziridine-based aldehydes.
Synthesis of 3,4-dihydro-1,8-naphthyridin-2(1H)-ones via microwave-activated inverse electron-demand Diels–Alder reactions
- Salah Fadel,
- Youssef Hajbi,
- Mostafa Khouili,
- Said Lazar,
- Franck Suzenet and
- Gérald Guillaumet
Beilstein J. Org. Chem. 2014, 10, 282–286, doi:10.3762/bjoc.10.24
- optimal experimental conditions already reported with triazines [22][23][24]. In chlorobenzene at 220 °C (optimal reaction temperature for six-membered-ring formation), the corresponding cycloadducts 10–13 were obtained in high yields (Scheme 4, Table 3). We therefore developed an efficient method for the
Graphical Abstract
Scheme 1: (a) MeI, EtOH, reflux, 3 h (87%); (b) phenylglyoxal, Na2CO3, H2O, 5 °C, 6 h (96%); (c) MCPBA, CH2Cl2...
Scheme 2: Coupling of pent-4-ynoic acid with different amines. Conditions: (a) EDCI, DMAP, THF, rt, 36 h.
Scheme 3: Reaction of triazine 1 with different pent-4-ynamides. Conditions: n-BuLi, THF, −30 °C, 2 h.
Scheme 4: Reaction of triazines 6–9 under microwave irradiation. Conditions: Chorobenzene, 220 °C, 1 h.
Scheme 5: Preparation of aryl-N-triazinylpentynamides. Conditions: CuI (10 mol %), Pd(PPh3)2Cl2 (5 mol %), DM...
Scheme 6: Preparation of 3,4-dihydro-1,8-naphthridin-2(1H)-ones. Conditions: Chlorobenzene, 220 °C, 1 h.
Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition
- Regina Berg and
- Bernd F. Straub
Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308
Graphical Abstract
Scheme 1: Exemplary 1,3-dipolar cycloaddition of phenylacetylene with phenyl azide [6].
Scheme 2: CuAAC reaction of benzyl azide with (prop-2-yn-1-yloxy)benzene [12].
Scheme 3: Bioconjugation reaction of capsid-bound azide groups with alkynyl-functionalized dye molecules (cow...
Figure 1: Tris(triazolylmethyl)amine ligands for CuAAC applications in bioorganic chemistry: TBTA = tris[(1-b...
Figure 2: Derivatives of 2,2’-bipyridine and 1,10-phenanthroline, commonly used ligands in CuAAC reactions un...
Scheme 4: CuAAC reaction with copper(II) precursor salt and rate-accelerating monodentate phosphoramidite lig...
Scheme 5: Synthesis of 1-(adamant-1-yl)-1H-1,2,3-triazol-4-ylcarbonyl-Phe-Gly-OH by solid-supported Click cat...
Scheme 6: CuAAC reaction with re-usable copper(I)-tren catalyst [129].
Scheme 7: CuAAC test reaction with chlorido[tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol-κ3N3]copper(I) and a...
Scheme 8: CuAAC model reaction with [Cu2(μ-TBTA-κ4N2,N3,N3’,N3’’)2][BF4]2 [131].
Scheme 9: Application of a (2-aminoarenethiolato)copper(I) complex as homogeneous catalyst for the CuAAC test...
Scheme 10: Application of [CuBr(PPh3)3] as homogeneous catalyst for the CuAAC test reaction of benzyl azide wi...
Figure 3: Phosphinite and phosphonite copper(I) complexes presented by Díez-González [144].
Scheme 11: Effect of additives on the CuAAC test reaction with [(SIMes)CuCl] [149].
Scheme 12: Initiation of the catalytic cycle by formation of the copper acetylide intermediate from [(ICy)2Cu]...
Scheme 13: Early mechanistic proposal by Sharpless [12,42].
Scheme 14: Chemoselective synthesis of a 5-iodo-1,4-disubstituted 1,2,3-triazole [156].
Scheme 15: Mechanistic proposals for the copper-catalyzed azide–iodoalkyne cycloaddition [156].
Scheme 16: 1,3-Dipolar cycloaddition of 3-hexyne catalyzed by [(SIMes)CuBr] [146].
Scheme 17: Mechanistic picture for the cycloaddition of internal alkynes catalyzed by NHC-copper(I) complexes ...
Scheme 18: Catalytic cycle of the CuAAC reaction on the basis of the proposed mechanistic scheme by Fokin and ...
Figure 4: Schematic representation of the single crystal X-ray structures of copper(I) acetylide complexes [Cu...
Figure 5: Acetylide-bridged dicopper complexes with tris(heteroarylmethyl)amine ligand(s) as key intermediate...
Scheme 19: Off-cycle equilibrium between unreactive polymeric copper(I) acetylide species (right) and reactive...
Figure 6: Categories of tris(heteroarylmethyl)amine ligands regarding their binding ability to copper(I) ions ...
Scheme 20: Mechanistic scheme for ligand-accelerated catalysis with tripodal tris(heteroarylmethyl)amine ligan...
Scheme 21: Synthesis of supposed intermediates in the CuAAC’s catalytic cycle [164,187].
Figure 7: Tetranuclear copper acetylide complexes as reported by Weiss (left) [176] and Tasker (middle) [185] and model...
Figure 8: Gibbs free energy diagram for the computed mechanistic pathway of the CuAAC reaction starting from ...
Figure 9: Energy diagram by Ahlquist and Fokin [125].
Scheme 22: Mechanistic proposal for the CuAAC reaction based on DFT calculations by Fokin [125] and our group [186] ([Cu...
Figure 10: ORTEP plot [202,203] of the X-ray powder diffraction crystal structure of (phenylethynyl)copper(I) [(PhC≡CCu)...
Scheme 23: Synthesis of [(PhC≡CCu)2]n as co-product in the Glaser coupling of phenylacetylene in the presence ...
Scheme 24: Mechanistic explanation for the isotopic enrichment in the product triazolide in the presence of th...
Scheme 25: Homogeneous CuAAC catalysis with a bistriazolylidene dicopper complex (0.5 mol %) and comparison wi...
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.
Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring
- Marta Pérez-Torralba,
- Rosa M. Claramunt,
- M. Ángeles García,
- Concepción López,
- M. Carmen Torralba,
- M. Rosario Torres,
- Ibon Alkorta and
- José Elguero
Beilstein J. Org. Chem. 2013, 9, 2156–2167, doi:10.3762/bjoc.9.253
Graphical Abstract
Figure 1: The six 1,5-benzodiazepinones discussed in this paper together with clobazam.
Scheme 1: Synthesis of compounds 1 and 2.
Figure 2: The X-ray structures of 3a (TUPSAZ), 5a (EFARUA). In TUPSAZ there is a disordered water molecule.
Figure 3: ORTEP plot (30% probability) of 1, showing the X-ray labeling of the asymmetric unit.
Figure 4: View of the zigzag chain formed in 1, showing the H-bond and F–F interactions.
Figure 5: ORTEP plot (20% probability) of 2, showing the X-ray labeling of the asymmetric unit.
Figure 6: Packing of 2 showing the F–F contacts along the chain (orange) and the π–π interactions that form t...
Figure 7: The different tautomers in the 1H and 1-methyl series.
Figure 8: 2-Methoxy-4-methyl-3H-1,5-benzodiazepine (7).
Figure 9: 1H–19F coupling constant values either through-bond or through-space.
Figure 10: The optimized geometry of the TS of 2a inversion.
Figure 11: Equations used to transform absolute shieldings into chemical shifts [38,39].
Organocatalyzed enantioselective desymmetrization of aziridines and epoxides
- Ping-An Wang
Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192
- ). Interestingly, the aziridines with a six-membered ring were desymmetrized to give the corresponding thioethers in excellent yields and enantioselectivities when the molar ratio of aziridine/nucleophile/catalyst is 1.0:1.5:0.1. For the unreactive acyclic and seven-membered ring aziridines, the good
Graphical Abstract
Figure 1: The catalyzed enantioselective desymmetrization.
Figure 2: Cinchona alkaloid-derived catalysts OC-1 to OC-11.
Scheme 1: The enantioselective desymmetrization of meso-aziridines in the presence of selected Cinchona alkal...
Figure 3: Cinchona alkaloid-derived catalysts OC-12 to OC-19.
Scheme 2: The enantioselective ring-opening of aziridines in the presence of OC-16.
Scheme 3: OC-16 catalyzed enantioselective ring-opening of aziridines.
Figure 4: The chiral phosphoric acids catalysts OC-20 and OC-21.
Scheme 4: OC-20 and OC-21 catalyzed enantioselective desymmetrization of meso-aziridines.
Figure 5: The proposed mechanism for chiral phosphorous acid-induced enantioselctive desymmetrization of meso...
Scheme 5: OC-21 catalyzed enantioselective desymmetrization of meso-aziridines by Me3SiSPh.
Scheme 6: OC-21 catalyzed the enantioselective desymmetrization of meso-aziridines by Me3SiSePh/PhSeH.
Figure 6: L-Proline and its derivatives OC-22 to OC-27.
Scheme 7: OC-23 catalyzed enantioselective desymmetrization of meso-aziridines.
Figure 7: Proposed bifunctional mode of action of OC-23.
Figure 8: The chiral thioureas OC-28 to OC-44 for the desymmetrization of meso-aziridines.
Scheme 8: Desymmetrization of meso-aziridines with OC-41.
Figure 9: The chiral guanidines (OC-45 to OC-48).
Scheme 9: OC-46 catalyzed desymmetrization of meso-aziridines by arylthiols.
Scheme 10: Desymmetrization of cis-aziridine-2,3-dicarboxylate.
Figure 10: The proposed activation mode of OC-46.
Scheme 11: The enantioselective desymmetrization of meso-aziridines by amine/CS2 in the presence of OC-46.
Figure 11: The chiral 1,2,3-triazolium chlorides OC-49 to OC-55.
Scheme 12: The enantioselective desymmetrization of meso-aziridines by Me3SiX (X = Cl or Br) in the presence o...
Figure 12: Early organocatalysts for enantioselective desymmetrization of meso-epoxides.
Scheme 13: Attempts of enantioselective desymmetrization of meso-epoxides in the presence of OC-58 or OC-60.
Scheme 14: The enantioselective desymmetrization of a meso-epoxide containing one P atom.
Figure 13: Some chiral phosphoramide and chiral phosphine oxides.
Scheme 15: OC-62 catalyzed enantioselective desymmetrization of meso-epoxides by SiCl4.
Figure 14: The proposed mechanism of the chiral HMPA-catalyzed desymmetrization of meso-epoxides.
Scheme 16: The enantioselective desymmetrization of meso-epoxides in the presence of OC-63.
Figure 15: The Chiral phosphine oxides (OC-70 to OC-77) based on an allene backbone.
Scheme 17: OC-73 catalyzed enantioselective desymmetrization of meso-epoxides by SiCl4.
Figure 16: Chiral pyridine N-oxides used in enantioselective desymmetrization of meso-epoxides.
Scheme 18: Catalyzed enantioselective desymmetrization of meso-epoxides in the presence of OC-80 or OC-82.
Figure 17: Chiral pyridine N-oxides OC-85 to OC-94.
Scheme 19: Enantioselective desymmetrization of cis-stilbene oxide by using OC-85 to OC-92 as catalysts.
Figure 18: A novel family of helical chiral pyridine N-oxides OC-95 to OC-97.
Scheme 20: Desymmetrization of meso-epoxides catalyzed by OC-95 to OC-97.
Scheme 21: OC-98 catalyzed enantioselective desymmetrization of meso-epoxides by SiCl4.
