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

(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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Anodic coupling of carboxylic acids to electron-rich double bonds: A surprising non-Kolbe pathway to lactones

• Robert J. Perkins,
• Hai-Chao Xu,
• John M. Campbell and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2013, 9, 1630–1636, doi:10.3762/bjoc.9.186

• trapping of a ketene dithioacetal derived radical cation by an amine was shown to lower the oxidation potential measured for the ketene dithioacetal by 460 mV [21], a value consistent with the potential measured here for 14a. The oxidation of 14b to afford the six-membered ring product also proceeded well

Structures of the reaction products of the AZADO radical with TCNQF₄ or thiourea

• Hideto Suzuki,
• Yuta Kawahara,
• Hiroki Akutsu,
• Jun-ichi Yamada and
• Shin’ichi Nakatsuji

Beilstein J. Org. Chem. 2013, 9, 1487–1491, doi:10.3762/bjoc.9.169

• AZADO molecule in the next step to give an addition product (a salt) resulting from the addition to one of the double bonds in the six-membered ring. Finally, the oxoammonium cation in the adduct will react with the counter anion from the less hindered site to afford the final product 5 with trans

• -membered ring in a trans-manner, as seen from its molecular structure (Scheme 1) (Figure 2). Therefore, a plausible mechanism of the reaction could be considered as shown in Scheme 2. First, a transient CT complex would be formed between 2 and 3 but it would be unstable enough to be attacked by another

• amount of TCNQF4 (3) did not give dark blue crystals but gave an orange solid. After purification, the orange crystals obtained were proved to be the addition product 5 and not a CT complex as seen from the X-ray analysis. Furthermore, the addition was found to take place to a double bond of the six