Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ⁶-sulfanyl)acetic acid esters with aldehydes

• Anna-Lena Dreier,
• Andrej V. Matsnev,
• Joseph S. Thrasher and
• Günter Haufe

Beilstein J. Org. Chem. 2018, 14, 373–380, doi:10.3762/bjoc.14.25

• -substituted acetamides into aldol additions with the intension of applying amides in Evans-type substrate directed asymmetric C–C-bond forming reactions. Therefore, 2-(pentafluoro-λ6-sulfanyl)acetic morpholide (8) was prepared by reaction of SF5-CH2C(O)Cl (7) [36][37] with morpholine (Scheme 5). According to

• two multiplets of the morpholine ring for four protons each at δ = 3.37 ppm and δ = 3.28 ppm, one can reason the formation of an aldol addition product 9. This assignment is supported by a multiplet for one axial fluorine atom at δ = 75.39 ppm (J = 147 Hz) and a doublet (of multiplets) for four

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• corresponding benzyl fluoride (1) using a modification of Bio’s method [13][14] to promote the SN2 reaction exclusively, using TMS-morpholine and DAST, in moderate yield (51%) and high ee (94%). The isotopically enriched [2H1]-benzyl fluoride ((R)-1, 95% ee) was then subjected to a range of C–F activation

• that some nucleophiles (such as N-methylbenzylamine and morpholine [not shown]) were unsuitable for this study, as the resulting products 7 could not be resolved in the 2H NMR with PBLG assay. Two different activator systems were investigated for the nucleophilic substitution of 1: a mixture of water

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• it was found that the inclusion of the additive TMS-morpholine [36][37] was also required to ensure a high diastereoisomeric excess of 38a. The epoxide 38a was then ring-opened using Et3N·3HF to deliver the difluorodiol 39a as a mixture of regioisomers. This mixture subsequently converged during the

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• and ester groups. The reactions of E-1 with morpholine performed in the presence of equimolar amounts of strained 1-azabicyclo[1.1.0]butanes 55 afforded enamines 56 containing both amine units [58] (Scheme 19). Their structures evidence that the first reaction step is the Michael-type reaction of 55

• leading to a zwitterionic intermediate 57, which is trapped by morpholine to give the adduct 58. The latter eliminates HCN and converts to enamine 56. The postulated pathway was supported by a similar experiment, in which methanol replaced morpholine as a trapping reagent [58][59]. An interesting

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• , respectively. On the other hand, two nucleophilic substitution reactions using phenol and morpholine gave the expected heterocycles 10 and 11 in 73% and 23% yields, respectively. Conclusion In summary, we developed a short and completely regioselective method for the synthesis of imidazo[1,2-a]-N-heterocycles

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• 4-(benzenesulfinyl)morpholine (BSM)/Tf2O [53]. The combination of BSP/Tf2O [19][49] has been utilized as the promoter for iterative oligosaccharide synthesis including oligoglucosamine library [20], oligomannan [54] and Lewisa trisaccharide [55]. During their synthesis, van der Marel and co-workers

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• the sole products. Contrastingly, in the solution of acetonitrile imines of benzaldehyde and amines were formed preferably. Different aromatic or heteroaromatic aldehydes including thiophene carboxaldehyde, pyridine carboxaldehyde and cyclohexyl carboxaldehyde as well as various amines like morpholine

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• -type amine–isothiocyanate coupling reaction (Scheme 4). In the case of secondary amines (piperidine, morpholine and thiomorpholine) and sterically hindered amines (2,4- and 2,6-dimethylanilines), ball milling again resulted in ≥99% yields in 10 minutes, except for the reactions involving 4

Substitution of fluorine in M[C₆F₅BF₃] with organolithium compounds: distinctions between O- and N-nucleophiles

• Anton Yu. Shabalin,
• Nicolay Yu. Adonin and
• Vadim V. Bardin

Beilstein J. Org. Chem. 2017, 13, 703–713, doi:10.3762/bjoc.13.69

• benzimidazolyl) with 74–93% isolated yield. In contrast, sodium morpholinide and sodium diethylamide did not react with K[C6F5BF3] under the same conditions. The attempted preparation of K[4-R2NC6F4BF3] (R2N = morpholinyl, Et2N) using an excess of dialkylamine as well as morpholine and K2CO3 leads to C6F5H and

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• in developing new organic reaction methodologies as well as to synthesize propargylamine, we performed one reaction of salicylaldehyde, morpholine and phenylacetylene at 80 °C in the presence of a Cu(I) dithiane-based complex as the catalyst that gave rise to the formation of 3a in good yield (89

• achieved in the first two solvents (85–88%), the use of ethanol resulted in a low yield (47%). Thus the A3 coupling of salicylaldehyde, phenylacetylene and morpholine can be achieved under solvent-free conditions as well as in solvents like toluene or acetonitrile with the formation of the coupled product

• in 85–90% isolated yields. We also conducted similar reactions with cyclohexylamine and benzylamine instead of morpholine. In both cases, we ended up with the formation of corresponding imines (Table 1, entries 12 and 13). After the successful optimization, further extension of the reaction protocol

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• isomeric mixture, followed by filtration. (1RS,4'RS)-2,2'-Dibenzyl-4'-(morpholine-4-carbonyl)spiro[isoindoline-1,5'-isoxazolidin]-3-one (6a): White solid; mp 197–199 °C (Yield: 71 mg, 51%); IR (KBr) νmax: 1685, 1638 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.82–7.78 (m, 1H), 7.62–7.47 (m, 5H), 7.43 (d, J = 7.1 Hz

• , 484.2262. (1RS,4'SR)-2,2'-Dibenzyl-4'-(morpholine-4-carbonyl)spiro[isoindoline-1,5'-isoxazolidin]-3-one (7a): White crystals, mp 185–187 °C (Yield: 12 mg, 9%); IR (KBr) νmax: 1680, 1642 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 6.7 Hz, 1H), 7.62–7.46 (m, 4H), 7.45–7.20 (m, 10H), 5.05 (d, J = 11.6 Hz, 1H

• , 53.9, 46.1, 46.0, 40.6, 31.4, 25.9, 23.8, 20.7, 13.9; HRMS–ESI (m/z): [M + H]+ calcd for C26H32N3O3, 434.2444; found, 434.2471. (1RS,4'RS)-2'-Benzyl-2-butyl-4'-(morpholine-4-carbonyl)spiro[isoindoline-1,5'-isoxazolidin]-3-one (6c): White solid, mp 122–124 °C (Yield: 54 mg, 38%); IR (KBr) νmax: 1687

Construction of bis-, tris- and tetrahydrazones by addition of azoalkenes to amines and ammonia

• Artem N. Semakin,
• Aleksandr O. Kokuev,
• Yulia V. Nelyubina,
• Alexey Yu. Sukhorukov,
• Petr A. Zhmurov,
• Sema L. Ioffe and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2016, 12, 2471–2477, doi:10.3762/bjoc.12.241

• ). Similarly, the reaction with a secondary amine (morpholine) according to this procedure provided the monoalkylated adduct 6 in good yield. Importantly, secondary polyamines could be exhaustively alkylated with chloroacetone hydrazone 1a demonstrating the efficiency of our approach for the synthesis of

Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation

• Erika Bálint,
• Ádám Tajti,
• Anna Dzielak,
• Gerhard Hägele and
• György Keglevich

Beilstein J. Org. Chem. 2016, 12, 1493–1502, doi:10.3762/bjoc.12.146

• column chromatography, the new amino-methylenebisphosphine oxides 1a–d were obtained in yields of 72–82% (Table 1, entries 1–4). The condensation of simple secondary amines (diethyl-, dibutyl-, N-butylmethyl-, N-cyclohexylmethyl-, N-benzylmethylamine, N-methylaniline and morpholine) was also investigated

Antibacterial structure–activity relationship studies of several tricyclic sulfur-containing flavonoids

• Lucian G. Bahrin,
• Henning Hopf,
• Peter G. Jones,
• Laura G. Sarbu,
• Cornelia Babii,
• Alina C. Mihai,
• Marius Stefan and
• Lucian M. Birsa

Beilstein J. Org. Chem. 2016, 12, 1065–1071, doi:10.3762/bjoc.12.100

• , synthesized by reacting morpholine with halogenated benzaldehydes [21][22], are collected in Table 1. The individual substitution patterns and yields for flavonoids 4a–m and 5a–m are presented in Table 2. The reaction between brominated and iodinated phenacyl carbodithioates 2a–f and halogenated aminals 3a–e

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

• -amine radical followed by trapping with acrylate, to functionalize the α-position of amines [68]. The strategy works for morpholine and piperazine substrates, but the yields for the latter are generally low, ranging from 12% to 41% (Figure 17). Anodic oxidation strategy Another uncommon way to perform α

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• throughout) is present in all conformers. 3) The equilibrium H-bond length of 1.70 Å and the calculated relaxed force constant [40] of 0.31 N/cm point to a strong interaction [41], which is decisive for the recognition process. According to experimental results [11], the morpholine ring is not directly

• involved in the molecular recognition process. Our simulation could reproduce this high flexibility of the morpholine moiety, too (see Figure 6). Turning to the conformational changes in the receptor, they seem to be localized at the nucleobases G2540 and U2620 as well at the CCA-N-Phe unit. The

• flexibility of the U2620 (U2585 in Escherichia coli) moiety has already been discussed elsewhere [20]. Nevertheless, due to our simulation, there is no hydrogen bond between this nucleobase and the morpholine ring. The absence of a second hydrogen bond in our simulations (which is indeed observed for

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• ] (Scheme 15). Hemiaminal derivative 1 is readily prepared from commercially available CF3CH(OH)(OEt), which is a fluoral equivalent, and morpholine [52]. The substrate scope of the catalytic trifluoromethylation is shown in Scheme 16. Nitro, cyano, and ester groups in iodoarenes were tolerable under the

Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

• A. John Blacker and
• Katherine E. Jolley

Beilstein J. Org. Chem. 2015, 11, 2408–2417, doi:10.3762/bjoc.11.262

• NaOCl (aq) into a 1 M morpholine (aq) at a rate of 1 g/min. The calorimeter jacket temperature was set at −15 °C, and power compensation used to maintain the reactor at 5 °C. 20 mL of the NaOCl solution were added to 20 mmol of morpholine over 20 min, and after subtracting the feed solution temperature

• phase with KD [organic]/[aqueous] = 28.8, causing the reaction to be limited by the mass transfer rate. For example mixing in the T-piece alone gives 11% conversion with N-benzylmethanamine, but 46% with 1,4-morpholine; also 65% conversion is seen with 0.8 min of intense mixing of N-benzylmethanamine

• with NaOCl, whilst 68% is seen with 1,4-morpholine mixed for half this time, because it partitions more favourably into the aqueous phase with KD = 0.01. Substrates The formation of a range of N-chloro-N,N-dialkylamines was investigated. Some were found to react relatively slowly, partly for the mass

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• by focusing on amine-mediated degradation of GII and they highlighted various plausible decomposition pathways depending on the nature of the amine [45]. At first, the reaction between GII and various amines such as n-butylamine (a), pyrrolidine (b), morpholine (c) and DBU (d) were examined by 1H NMR

• NMR experiments [45]. The steric hindrance of the amine appeared to be a critical parameter. The non-bulky primary amine n-butylamine (a) induced a fast decomposition of the methylidene 2 (Table 1, entry 1) whereas secondary amines such as pyrrolidine (b) and morpholine (c) are less detrimental to the

• , the addition of amino additives such as pyridine, morpholine, Et3N or DBU was shown to be detrimental to the G-HII-catalyzed dimerization of styrene (Table 2). Moderate to poor yields in stilbene 7’ were obtained and the value of the yields was correlated with the pKa of the couple ammonium/amine. An

[2.2]Paracyclophane derivatives containing tetrathiafulvalene moieties

• Laura G. Sarbu,
• Lucian G. Bahrin,
• Peter G. Jones,
• Lucian M. Birsa and
• Henning Hopf

Beilstein J. Org. Chem. 2015, 11, 1917–1921, doi:10.3762/bjoc.11.207

• (3b) and morpholinium morpholine-4-carbodithioate (3c), respectively. These compounds were obtained as colorless crystals in 80% isolated yields. The structures of dithiocarbamates 4a–c were inferred from their analytical and spectral data; thus the 1H NMR spectra include the expected signals for the

Azobenzene-based inhibitors of human carbonic anhydrase II

• Leander Simon Runtsch,
• David Michael Barber,
• Peter Mayer,
• Michael Groll,
• Dirk Trauner and
• Johannes Broichhagen

Beilstein J. Org. Chem. 2015, 11, 1129–1135, doi:10.3762/bjoc.11.127

• 1c offers the second-lowest affinity (Ki = 55.4 nM), which seems counter-intuitive, as the only difference with respect to 1b is the connection of the ethyl chains by an oxygen atom to a morpholine ring. This does not only affect the binding properties, but also the π–π* band, which is 46 nm blue

• wavelength versus the IC50 (Figure 4c and d, respectively), no clear correlation can be found. In both cases morpholine 1c, azide 1e, methyl 1f and unsubstituted azobenzene sulfonamide 1h lie in the same region (50 µM), while all other inhibitors (hydroxy 1a, alkyl amine 1b, amine 1d, nitro 1h and ethyl

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• intramolecular cyclization of a chiral alkenylated pyrrolidinone, followed by hydroxylation [32], or by the intramolecular ring closure of chiral pyrrolidine diesters followed by ester and oxo group reduction [33], while the syntheses of (+)-epitashiromine starts from a chiral morpholine derivative, with nitrone

• (Z-Cl) afforded protected amino ester (±)-3 in 78% yield. In agreement with our earlier observations [40][41][42] C–C double bond functionalization of the cyclooctene β-amino ester via dihydroxylation with N-methyl morpholine N-oxide (NMO) in the presence of OsO4 afforded the corresponding all-cis

Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

• Hongnan Sun,
• Binbin Huang,
• Run Lin,
• Chao Yang and
• Wujiong Xia

Beilstein J. Org. Chem. 2015, 11, 524–529, doi:10.3762/bjoc.11.59

• : ammonium persulfate; aziridine; metal free; morpholine; Introduction Morpholines are common structural cores of a broad range of biological and pharmacological natural or synthetically important organic molecules [1]. In particular, a number of 2-substituted and 2,3-disubstituted morpholines are

• clinically available drugs (Figure 1). For example, the trans-2,3-disubstituted morpholine, phendimetrazine (bontril), is a clinically available appetite suppressant [2], the 2-substituted morpholine, reboxetine, is a clinically active, efficacious, and well-tolerated antidepressant drug [3][4][5], and the

• cis-2,3-disubstituted morpholine, aprepitant, is approved for the use in the prevention of chemotherapy-induced nausea and vomiting [6]. In addition to pharmacological properties, morpholines are also used in organic synthesis as bases, catalysts, and chiral auxiliaries [7][8][9][10][11][12][13]. Thus

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• , 12 was dissolved in an aqueous 2-(N-morpholine)ethanesulfonic acid (MES buffer) at pH 4.5 (enzyme activity optimum) and incubated with the enzyme in the presence of solubilizing 2,6-di-O-methyl-ß-cyclodextrin at 25 °C [51]. By virtue of analytical HPLC (UV detection based on Fmoc) and mass

Regio- and stereoselective synthesis of new diaminocyclopentanols

• Evgeni A. Larin,
• Valeri S. Kochubei and
• Yuri M. Atroshchenko

Beilstein J. Org. Chem. 2014, 10, 2513–2520, doi:10.3762/bjoc.10.262

• [29]. The treatment of the corresponding acetates 4 with mesyl chloride and subsequent transesterification of mesylated substrates 5 resulted in the formation of 6a,b. Epoxides 3 and 6 were identified by 1H NMR data [28]. Morpholine (7a), 2-methyl-1H-imidazole (7b), N-acetylpiperazine (7c) and 9H

• experiments was performed under solvent-free conditions at 100 °C. In case of morpholine (7a), the best catalytic effect was observed with LiClO4 [36] and Zn(ClO4)2·6H2O [37] affording 56 and 76% yield of 8a after isolation and purification, therefore the absence of the solvent seems crucial for the reaction

• displayed poor regioselectivity. In fact, a mixture of the separable regioisomers 9a–d and 10a–d were obtained, where the major products 9a–d were formed due to the attack of the nucleophile at the C1-oxirane carbon atom. In case of aliphatic cyclic amines (morpholine (7a) and N-acetylpiperazine (7c)), the