Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• , which was then opened by morpholine to afford amide 167. The primary alcohol was then oxidized to the aldehyde under Swern conditions and submitted to a diastereoselective Strecker synthesis to install the amino acid moiety. Thus, condensation of the aldehyde with (R)-α-phenylglycinol followed by

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• involving taurine, formaldehyde and 2',3'-O-isopropylideneuridine [61]. Watanabe et al. described the synthesis of 7-(morpholinomethyl)tubercidin 5 by heating tubercidin, 37% aq formaldehyde and morpholine at 90 °C overnight (Scheme 3) [62]. Compound 5 was converted into the natural nucleoside toyocamycin

•  38) [112]. The palladium-catalyzed reactions of 5-iodopyrimidines, various acyclic or cyclic dienes, and amines were optimized by Larock et al. [113]. Thus, coupling of 5-iodo-2'-deoxyuridine (94a) or 3',5'-di-O-acetyl-5-iodo-2'-deoxyuridine (94b) with 1,2-, 1,3- or 1,ω-dienes 95, and morpholine

• secondary amines. In some cases, protection of the hydroxy groups in 94a was also necessary. The reactions between 3',5'-di-O-acetyl-5-iodo-2'-deoxyuridine (94b), long-chain 1,ω-dienes (e.g., deca-1,9-diene or tetradeca-1,13-diene) and morpholine afforded products as mixtures of regioisomers resulting from

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Mimoza Gjikaj and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2014, 10, 1638–1644, doi:10.3762/bjoc.10.170

• addition to the anilines described above (Scheme 2), we applied 1-naphthylamine as a bulkier aromatic representative and morpholine as a secondary, more basic aliphatic amine. Conversion of 3 and 5 with morpholine and 1-naphthylamine afforded the open chain products 20 and 21 in 93% and 80% yield

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• -containing residue to the morpholine nitrogen in monomers 5a,d,e resulted in the appearance of duplicate signals of the nucleobases and morpholine protons in the NMR spectra (see Experimental) similar to morpholinooxalyl nucleosides [8]. After completion of the loading, the unreacted amino groups were capped

• and physicochemical data of intermediate compounds. 2-Aminomethyl-4-trityl-6-(thymin-1-yl)morpholine (3e): Thymine containing monomer 3e was synthesized similarly to uracil analogue 3d [8] starting from the corresponding 2-hydromethyl derivative (2.16 g, 4.24 mmol). Yield 1.05 g, (2.20 mmol, 52%). Rf

• . Physicochemical characteristics for intermediate compounds see in Supporting Information File 1. General procedure for the synthesis of Boc-protected 2-aminomethylmorpholino monomers 5a,d,e 2-[N-(tert-Butyloxycarbonyl)aminomethyl]-6-(N6-benzoyladenin-9-yl)morpholine (2a), 2-[N-(tert-butyloxycarbonyl)aminomethyl

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• respectively employing TMSCl, morpholine and mixed TMSCl/morpholine as catalysts have been conducted. It was found that the target product could be formed only when both morpholine and TMSCl were present (Table 1, entries 1–3). Extended experiments using different amounts and types of amine catalysts

Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate

• Hong Gao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 2934–2939, doi:10.3762/bjoc.9.330

• spiro compounds by using the in situ generated Huisgen 1,4-dipoles [17][18][19][20][21][22][23][24]. During these research works, we noticed that even through the cyclic secondary amines such as pyrrolidine, piperidine and morpholine also reacted with electron-deficient alkynes to give the Huisgen 1,4

• amine morpholine still gave a very low yield of the desired 3-morpholinyl-2-pyrrolidinone 1n (Table 1, entry 14). It is known that pyrrolidine (pKb = 2.73) and piperidine (pKb = 2.88) have near similar basicity, while morpholine has a relative weak basicity (pKb = 5.64). At present, the exact reason for

• the different reactivity of piperidine, pyrrolidine and morpholine in this reaction is not very clear. The structures of the prepared 2-pyrrolidinones 1a–1n were fully characterized by 1H and 13C NMR, HRMS, IR spectra, and were further confirmed by single crystal structure determination of compound 1f

Diastereoselectivity in the Staudinger reaction of pentafluorosulfanylaldimines and ketimines

• Alexander Penger,
• Cortney N. von Hahmann,
• Alexander S. Filatov and
• John T. Welch

Beilstein J. Org. Chem. 2013, 9, 2675–2680, doi:10.3762/bjoc.9.303

• at δ 65.5 ppm in contrast to those of 5b that appeared at δ 59.5 ppm. The tendency for the enamine resonances to appear downfield of imine resonances was confirmed by the preparation of the morpholine enamine of 1a for which the equatorial fluorine resonance is also shifted downfield [46]. As

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• fluoral and morpholine, following the procedure described by B. R. Langlois et al. [77] Moderate to good yields were observed when the reaction was carried out in diglyme with cesium fluoride as a base (Table 14). More recently, compounds derived from trifluoroacetic acid appeared to be a cheap and

Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

• Pier Alexandre Champagne,
• Alexandre Saint-Martin,
• Mélina Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2013, 9, 2451–2456, doi:10.3762/bjoc.9.283

• 4-phenylbenzyl fluoride (1) [24] as the substrate and morpholine (3 equiv) as the nucleophile at 60 °C for 24 h. Commercially available 1,1,1-tris(hydroxymethyl)propane (2) was selected as the triol and was used in a slight excess (1.1 equiv) [25] relative to the substrate. Solvent screening was

• all could be observed without the activating agent. It is important to mention for this entry that even if morpholine is the only liquid component at room temperature, a homogeneous solution is generated around 60 °C by the fusion of 1,1,1-tris(hydroxymethyl)propane (melting point 56–58 °C). Starting

• effected a full conversion. It was also possible to reduce the amount of morpholine used from 3 equiv (Table 2, entry 3) to 2 equiv (Table 2, entry 5) without any impact on the conversion. However, lower amounts (Table 2, entries 6 and 7) resulted in decreased conversions. While a reasonable explanation

Synthesis, characterization and luminescence studies of gold(I)–NHC amide complexes

• Adrián Gómez-Suárez,
• David J. Nelson,
• David G. Thompson,
• David B. Cordes,
• Duncan Graham,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2013, 9, 2216–2223, doi:10.3762/bjoc.9.260

• straightforward methodology for the synthesis of gold(I)–amide complexes. Results and Discussion Synthesis and characterization of gold(I)–amide complexes We began our studies by exposing hydroxide 1 to a series of alkyl- and arylamines. While no reaction was observed with either morpholine or isopropylamine, the

The first example of the Fischer–Hepp type rearrangement in pyrimidines

• Inga Cikotiene,
• Mantas Jonusis and
• Virginija Jakubkiene

Beilstein J. Org. Chem. 2013, 9, 1819–1825, doi:10.3762/bjoc.9.212

• be explained by the stronger activation of the pyrimidine ring by the tertiary amine moiety (morpholine is a better activator than methyl, methylthio or acetamido groups). The prepared requisite N-nitrosated compounds 2 easily undergo the subsequent nucleophilic substitution reaction with amines. The

• morpholine in DMF, and the subsequent quenching of the reaction mixture with 50% (v/v) sulfuric acid gave the desired N-benzyl-4,6-dimorpholino-5-nitrosopyrimidin-2-amine (8) in 92% yield (Scheme 6). In conclusion, the ability of N-substituted-6-chloropyrimidin-4-amines to undergo a N-nitrosation reaction

Re₂O₇-catalyzed reaction of hemiacetals and aldehydes with O-, S-, and C-nucleophiles

• Wantanee Sittiwong,
• Michael W. Richardson,
• Charles E. Schiaffo,
• Thomas J. Fisher and
• Patrick H. Dussault

Beilstein J. Org. Chem. 2013, 9, 1526–1532, doi:10.3762/bjoc.9.174

• poor results with N-nucleophiles led us to reinvestigate a proven reaction in the presence of amines. The previously successful condensation of 4a with phenethyl alcohol (see Table 2) failed completely in the presence of added morpholine or pyridine (not shown). Allylation of hemiacetals Re2O7 has been

A³-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS-functionalized cellulose nanocrystalline films

• Jian-Lin Huang,
• Derek G. Gray and
• Chao-Jun Li

Beilstein J. Org. Chem. 2013, 9, 1388–1396, doi:10.3762/bjoc.9.155

• yields (Table 2, entries 1–8). However, long chain aldehydes had a lower activity, giving lower yields (Table 1, entries 9, 10). We also observed good to moderate yields when the cyclic dialkylamines such as pyrrolidine, morpholine and azepane were used (Table 2, entries 11–19). Catalyst recycling In

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• ) to deliver o-nitroanilines 9. The hydroxy groups of 9 were activated as the p-nitrobenzenesulfonates 10 and displaced with morpholine to give o-nitroanilines 7b and 7c (Scheme 2). Hydrogenation was used to reduce o-nitroanilines 7 followed by cyclization using thiocarbonyldiimidazole to yield

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• Johannes W. Wehner Thisbe K. Lindhorst Otto Diels Institute of Organic Chemistry, Christiana Albertina University of Kiel, Otto-Hahn-Platz 3/4, 24098 Kiel, Germany 10.3762/bjoc.8.242 Abstract Deprotection of an Nα-Fmoc-protected glycocysteine derivative 7 with an excess of morpholine unexpectedly

• the corresponding protected cysteine derivative, Fmoc-Cys(Trt)-OH (Scheme 1). Fmoc-deprotection by using morpholine as the base gave the free amine 2, and then removal of the S-trityl protecting group under oxidative conditions (iodine in methanol) led to the cystine derivative 3-dimer after in situ

• , when the trityl group in 4 was removed first, thiol 7 was obtained as expected, but the following Fmoc deprotection under standard conditions [14], employing 6 equiv of morpholine in DMF, unexpectedly led to the S-fluorenylmethyl (Fm)-protected glycoamino acid 8 in 77% yield (Scheme 2). The anticipated

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• reaction of primary aromatic amines (Table 4, entries 3, 4 and 6) proceeded smoothly under the optimized conditions to provide excellent yields of the corresponding coupling products 5a, 5b and 5d, respectively. The reaction was also effective for cyclic amine morpholine (Table 4, entry 5) and Boc

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

• Kalicharan Chattopadhyay,
• Erik Fenster,
• Alexander J. Grenning and
• Jon A. Tunge

Beilstein J. Org. Chem. 2012, 8, 1200–1207, doi:10.3762/bjoc.8.133

• possess interesting biological activity, the scope of the amination was investigated in somewhat more detail. Regarding the scope of the amine and coumarinyl acetate coupling reaction, dialkyl (5a–c) and the cyclic amines pyrrolidine (5d–5f), pyrazine (5g), and morpholine (5h) were competent coupling

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• conditions, this time by using two equiv of AlCl3 in dichloromethane at room temperature. For monoester 20, only a single conjugate addition was possible, leaving the pendant terminal alkene groups as handles for further reactivity. This cyclisation proceeded to give the expected, functionalised morpholine

• speculate that the relative difficulty in the reaction is due to the reduced availability of the lone pair of the morpholine nitrogen compared to the piperidine nitrogen (pKa 8.36 versus 11.22) [31], retarding the rate of nucleophilic attack. Another possibility is that the oxygens in the pendant chains can

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• heterocycles (motif C) and the position of the nitrogen atom in pyridine. As shown in Scheme 6, para-substituted pyridine was first replaced with meta- and ortho-pyridine, and other heterocycles, including pyrimidines and five-membered heteroaryl rings, as well as nonaromatic heterocycles, such as morpholine

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• the morpholine derived enamine 245 was used the desired 1,3,5-substituted pyrazole was formed with 100% regioselectivity (Scheme 49). This high regioselectivity is only obtained when a 1,1-disubstituted enamine is used, the corresponding 1,2-disubstituted enamine yields mainly the other regioisomer

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• to good yields of 49 and 50. Secondary acyclic amines 48 were unreactive: A variety of different conditions were investigated including the variation of base, ligand and copper source. Scheme 10 shows the optimized conditions for coupling with morpholine (46) and 2-(2-methoxyethoxy)ethanamine (47

9,10-Dioxa-1,2-diaza-anthracene derivatives from tetrafluoropyridazine

• Graham Pattison,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• John A. Christopher and
• David D. Miller

Beilstein J. Org. Chem. 2010, 6, No. 45, doi:10.3762/bjoc.6.45

• (EI+) m/z: 222 ([M]+, 10%), 138 (43), 74 (66), 63 (67), 50 (100). Reaction of 3,4-difluoro-9,10-dioxa-1,2-diaza-anthracene (5) with morpholine 3-Fluoro-4-(morpholin-4-yl)-9,10-dioxa-1,2-diaza-anthracene (9a) A mixture of 3,4-difluoro-9,10-dioxa-1,2-diaza-anthracene (5) (0.20 g, 0.90 mmol), morpholine

Comparison of zwitterionic N-alkylaminomethanesulfonic acids to related compounds in the Good buffer series

• Robert D. Long,
• Newton P. Hilliard Jr,
• Suneel A. Chhatre,
• Tatiana V. Timofeeva,
• Andrey A. Yakovenko,
• Daniel K. Dei and
• Enoch A. Mensah

Beilstein J. Org. Chem. 2010, 6, No. 31, doi:10.3762/bjoc.6.31

• aminomethanesulfonates, so our initial efforts were to synthesize the initial target compound N-morpholinomethanesulfonic acid (MMS) (1) by the reaction of morpholine with chloromethanesulfonic acid (Scheme 2). In spite of numerous attempts, this route produced no product, however. A subsequent literature search

• ) is readily available from commercial sources and reacts in good yield with morpholine in aqueous solution over several days at room temperature, or in hours with moderate heating, to form the desired product 1 in a zwitterionic or salt form (depending on the workup conditions). We extended this

• . alcohols (i.e. methanol, ethanol), as the materials are insoluble in other solvents. N-Morpholinomethanesulfonic acid [MMS (or MoMS)] (1). This was prepared as the half sodium salt by the general procedure from 0.200 mol of morpholine (17.4 mL), yielding 31.6 g (0.164 mol) of 1 (82% isolated yield) as a

2-Phenyl- tetrahydropyrimidine- 4(1H)-ones – cyclic benzaldehyde aminals as precursors for functionalised β²-amino acids

• Markus Nahrwold,
• Arvydas Stončius,
• Anna Penner,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2009, 5, No. 43, doi:10.3762/bjoc.5.43

• ) Boc2O, DMAP, CH3CN, 16 h, rt; b) 1. n-BuLi, THF, −78 °C, 30 min; 2. Cbz-Cl, rt, 16 h; c) H2, 10% Pd/C, abs. THF, 4 h, rt. Synthesis of enantiopure 2-phenyl-tetrahydropyrimidine-4(1H)-ones. a) PhCH(OMe)2, BF3·Et2O (6.0 equiv), CH2Cl2, −30 °C → −15 °C, 16 h; b) 1. [Pd(PPh3)4], morpholine, THF, rt, 1 h; 2

The tert- amino effect in heterocyclic chemistry: Synthesis of new fused pyrazolinoquinolizine and 1,4-oxazinopyrazoline derivatives

• Dipak Prajapati and
• Kalyan Jyoti Borah

Beilstein J. Org. Chem. 2007, 3, No. 43, doi:10.1186/1860-5397-3-43

• pyrazolone 1 under Vilsmeier conditions.[28] The 5-chloro atom of 2 is readily displaced by nucleophiles [29][30][31] and hence the reaction with several cyclic sec-amines (viz pyrrolidine, piperidine and morpholine) resulted in smooth conversion to the 5-tert-amino derivatives 3. These were then used in the

• characterized fully by high resolution spectral analysis (see Supporting Information File 1 &Supporting Information File 2 for full experimental and spectral data). We then reacted chloroformyl pyrazoline 2 with pyrrolidine and morpholine to get the corresponding tert-amino derivatives 3. The olefinic products