Oligomeric epoxide–amine adducts based on 2-amino-N-isopropylacetamide and α-amino-ε-caprolactam: Solubility in presence of cyclodextrin and curing properties

• Julian Fischer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 2803–2811, doi:10.3762/bjoc.9.315

• for the formation of corresponding oligomers [16]. Inspired by the molecular structure of N-isopropylacrylamide, we synthesized a primary amine 2-amino-N-isopropylacetamide (5) that is based on the amino acid glycine (Scheme 1). This was achieved in a three-step reaction through protection of the

• primary amino function of glycine methyl ester hydrochloride (1) with di-tert-butyl dicarbonate [21], further amidation with isopropylamine (3), and finally deprotection in acidic solution. We also synthesized as a further monomer the lysine based primary amine α-amino-ε-caprolactam (7) through

• reactivity of the primary amine group towards epoxides due to the formation of activating hydrogen bonds. The subsequent epoxide–amine polyaddition was carried out with glycerol diglycidyl ether (8), which was directly used as a mixture of the structural isomers 8a and 8b. To facilitate the following

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• % overall yield from 3. Alternatively, the use of previously devised conditions for benzyl deprotection (DDQ, DCE/pH 7 phosphate buffer, 45 °C, 78%) and then sodium borohydride-mediated reduction of the azide (EtOH, 65 °C, 62%) cleanly furnished primary amine 9, an exo-cyclopamine derivative with no F-ring

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

• phenylalanine residue as well as through several H-bonds facilitated by the adjacent polar substituents (Figure 8). The reported synthesis of carmegliptin enlists a Bischler-Napieralski reaction utilising the primary amine 2.76 and methyl formate to yield the initial dihydroquinoline 2.77 as its HCl salt

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

• James C. Anderson,
• Andreas S. Kalogirou,
• Michael J. Porter and
• Graham J. Tizzard

Beilstein J. Org. Chem. 2013, 9, 1737–1744, doi:10.3762/bjoc.9.200

• single diastereoisomer in 50% yield (Scheme 4). With diamine 17 in hand, the reaction with a suitable keto acid derivative was investigated. We presumed that the nitrogen of the primary amine would be the more nucleophilic and hence should react with the more electrophilic carbonyl group – i.e. the

• [56]. Further stereochemical proof was provided by a single crystal X-ray structure determination of 2·HCl (vide infra). We presumed again that the primary amine of 21 would be more nucleophilic towards a keto acid derivative 5. In order to obtain a piperazinone of the desired connectivity (23) a keto

Palladium-catalyzed synthesis of N-arylated carbazoles using anilines and cyclic diaryliodonium salts

• Stefan Riedmüller and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2013, 9, 1202–1209, doi:10.3762/bjoc.9.136

• structurally assigned. x-Axis = retention time. Substrate scope. All reactions were performed using iodonium salt 1 (0.35 mmol), 1.2 equiv of primary amine 2, 2.7 equiv of Cs2CO3, 5 mol % Pd(OAc)2, 10 mol % Xantphos, and 5–8 mL p-xylene at 125 °C. Reaction times 2–4 h. Isolated yields are given in parentheses

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• amine with concomitant reduction of the alkyne revealing the olefin functionality; and (b) dehydrative condensation of this primary amine with 1,3-cyclohexanedione. Oxidation of the secondary allylic alcohol in 9 with MnO2 at ambient temperature provided enone 10 in 85% yield. We were poised to

• onto 1,4-dibromobutane afforded bromide 6 in 81% overall yield. Acid-mediated removal of THP followed by azide formation using NaN3 afforded alkyl azide 7 in 94% overall yield. Preparation of vinylogous amide 9 was then achieved by a two-step sequence: (a) LAH-mediated azide reduction to give a primary

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• primary amine analogues [16]. Also as with chalcones, the degree of pegylation had only minor effects on binding properties. Compounds 29a–c showed uptake rates indicative of high to sufficient levels for brain imaging (2.89–4.17% ID/g at 2 min) and moderate clearance rates [16]. The flavone backbone of

• (98) were prepared and studied for Aβ imaging [73][74][75]. The simple two-step synthesis of 97 used polyphosphoric acid trimethylsilyl ester (PPSE) catalyzed condensation of 4-fluoro-2-aminophenol (112) with a cinnamic acid 113 to give the benzoxazole core followed by conversion to the primary amine

3D-printed devices for continuous-flow organic chemistry

• Vincenza Dragone,
• Victor Sans,
• Mali H. Rosnes,
• Philip J. Kitson and
• Leroy Cronin

Beilstein J. Org. Chem. 2013, 9, 951–959, doi:10.3762/bjoc.9.109

• , each of them connected to one of the inlets of the 3D-printed reactionware device R1. The syringe pumps were filled with the starting materials with a carbonyl compound (1a–c) being placed in syringe pump no. 1 and with a primary amine (2a–d) being placed in syringe pump no. 2 (Figure 3). The

• the primary amine 2b (see Supporting Information File 1). (a) IR spectra of benzaldehyde at different concentrations. The solvent peak at 1022 cm−1 remains constant while the aldehyde peak at 1704 cm−1 increases with the concentration of benzaldehyde. (b) Calibration curve of the different molar

End-labeled amino terminated monotelechelic glycopolymers generated by ROMP and Cu(I)-catalyzed azide–alkyne cycloaddition

• Ronald Okoth and
• Amit Basu

Beilstein J. Org. Chem. 2013, 9, 608–612, doi:10.3762/bjoc.9.66

• used to terminate polymers prepared by ring-opening metathesis polymerization of norbornenes bearing an activated ester. The terminating agent is a cis-butene derivative bearing a Teoc (2-trimethylsilylethyl carbamate) protected primary amine. Post-polymerization modification of the polymer was

• (Teoc) protected primary amine. The Teoc group is tolerant of subsequent polymer-side-functionalization chemistries, such as amidation and azide–alkyne click reactions. The upfield TMS 1H NMR resonances of the Teoc group are a useful signal for assessing the efficiency and success of post-ROMP

• modifications. Teoc deprotection under mildly basic conditions with tetrabutylammonium fluoride (TBAF) reveals the terminal primary amine, which can be subsequently coupled with a reporter molecule such as a dye. The terminating agent 3 was obtained by conjugation of 4-nitrophenyl (2-(trimethylsilyl)ethyl

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• –cyclisation leading to indoline 97 with an intramolecular Friedel–Crafts reaction to afford a tricyclic derivative 98 substituted by a trifluoromethyl group [44]. The second exploits the presence of both a protected primary amine and an easily substitutable chlorine on the pyrimidine ring in 99a,b to afford

• bonds are created, and the product now contains two electrophilic centres, a ketone and an unsaturated ester. Treatment with a primary amine or ammonia and in situ reduction of the intermediate imine 127 with sodium cyanoborohydride furnishes arylpiperidine 128 in good overall yield. Ammonia may be

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• , and after optimization of the reaction conditions, we found that the transformation of 7a to 10a could be done without purification. Hence, the addition of enantiopure lithium N-benzyl-N-α-methylbenzylamide to α,β-unsaturated ester 7 followed by hydrogenation to the corresponding primary amine and

Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions

• Matthias Leven,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2013, 9, 155–165, doi:10.3762/bjoc.9.18

• of 4-hydroxycoumarin in an efficient way since conversions are often in the quantitative range. Furthermore, the catalysts provide very mild pH conditions, since the pH values are in the range of 9. This is very unusual, since ordinary primary amine catalysts require strong acids as additives, which

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• assembly of the 2-nitrobenzenesulfonyl-(Nosyl, further abbreviated with Ns)-protected spermine backbone 8 on a solid phase via Fukuyama Ns strategy [51]. The next step was the Ns protection of the residual primary amine with 6.00 equiv of Ns-chloride and 12.0 equiv 2,4,6-collidine in CH2Cl2 followed by N

• (amination) a primary amine is used to substitute the bromine to give the peptoid residue. This approach avoids the use of N-terminally protected monomers, which have to be synthesized in advance. For the incorporation of the alkyne side chains we chose propargylamine as building block. A sixfold repetitive

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• phthalimide in DMF at 90 °C, affording the corresponding N-allylphthalimide. Deprotection of the phthalimide by hydrazinolysis followed by protection of the resulting primary amine as a tert-butyl-carbamate gave the Boc-protected amine 13 required for the synthesis of the substrate of the anionic cyclization

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• ester). Thus, the activated ester end of excess SPDP was reacted with the primary amine group in aminophalloidin to form an amide linkage. In general, 63 µmol aminophalloidin were dissolved in 3.4 mL H2O and 1.7 equiv SPDP, dissolved in 900 µL dimethylformamide, were added. The solution was adjusted to

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

• -protected piperazine (Table 4, entry 8). The reaction works equally well for aliphatic primary amine too (Table 4, entry 7) resulting in 90% isolated yield. There was a feeble change in yield by varying the substitution on the 7-azaindole nitrogen (N1) from a methyl to an ethyl group (Table 4, entries 6–8

Facile synthesis of functionalized tetrahydroquinolines via domino Povarov reactions of arylamines, methyl propiolate and aromatic aldehydes

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

Beilstein J. Org. Chem. 2012, 8, 1839–1843, doi:10.3762/bjoc.8.211

• dienophiles, vinyl enol ethers, vinyl enamides, vinyl sulfides, cyclopentadienes, indenes, alkynes and enamines have been mostly used in this method [12][13][14][15][16][17][18][19][20][21][22]. β-Enamino esters [23][24][25][26], which may be readily generated in situ by the addition of a primary amine to

Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro-Michael reaction: Theoretical studies on mechanism and enantioselectivity

• Tatyana E. Shubina,
• Matthias Freund,
• Sebastian Schenker,
• Timothy Clark and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2012, 8, 1485–1498, doi:10.3762/bjoc.8.168

• group and that of Jacobsen reported the first successful application of primary amine-thiourea organocatalysts with the synchronous dual activation of a nucleophile and an electrophile in nitro-Michael addition reactions [36][37][38][39][40][41][42]. Bifunctional organocatalysts that contain both a

• -Diaminocyclohexane (1) and (R)-1-phenylethyl isothiocyanate (2) were employed for the synthesis of primary amine-thiourea 3 [36][38][40][54]. Subsequent treatment of 3 with a guanidinylation reagent, N,N′-di-Boc-N″-triflylguanidine (4) [54][55], gave the intermediate 5 in 98% yield. The next step involved cleavage

• , 57.00, 125.39, 128.18, 128.88, 140.11 ppm. Primary amine-thiourea 3: To a solution of (S,S)-1,2-diaminocyclohexane (1) (1.273 g, 11.15 mmol, 1.0 equiv) in anhydrous dichloromethane (100 mL), at ambient temperature and under a nitrogen atmosphere, a solution of 2 (1.820 g, 11.15 mmol, 1.0 equiv) in

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• bicyclic guanidines [7][9][12]. Xiao et al. reported the addition of nitroalkanes to 4-oxo-enoates, using chiral urea derivatives [7]. Miura et al. achieved an asymmetric addition of α,α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea organocatalyst [13]. Wang et al. reported the

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• aqueous work-up followed by the addition of 3,5-bis(trifluoromethyl)phenyl isothiocyanate to each crude primary amine completed the syntheses of ethylene-linked sulfonimidoyl-containing thioureas (SS,SC)-18 and (RS,SC)-19 providing them in very good yields (98% and 87%, respectively) over two steps. One

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

• Kim A. Fredriksen,
• Tor E. Kristensen and
• Tore Hansen

Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125

• 4–9, thereby adjusting the degree of cross-linking. As for the Cinchona organocatalysts, we wanted to incorporate either unmodified quinine (1), the primary amine organocatalyst 2, or thiourea organocatalyst 3 into the thiol–ene network (Figure 1). While quinine is available directly, primary amine

• 23% ee), and probably not very useful for benchmarking, the supported catalysts 10a–d were obviously catalytically active, albeit modestly selective compared to the free catalyst, giving quantitative yields and a selectivity of 11–14% ee. Of greater interest was the performance of the primary amine

• organocatalysts 11. Polymer-supported catalysts 11a,b were tried out in the asymmetric preparation of the anticoagulant warfarin from benzylideneacetone and 4-hydroxycoumarin, a transformation that we have investigated in our group as part of developmental work in primary amine organocatalysis on a previous

Enaminones in a multicomponent synthesis of 4-aryldihydropyridines for potential applications in photoinduced intramolecular electron-transfer systems

• Nouria A. Al-Awadi,
• Maher R. Ibrahim,
• Mohamed H. Elnagdi,
• Elizabeth John and
• Yehia A. Ibrahim

Beilstein J. Org. Chem. 2012, 8, 441–447, doi:10.3762/bjoc.8.50

• -piperidinoacrylonitrile (13) with the appropriate aldehyde and primary amine under the same reaction conditions (A, B) (Scheme 4). Compounds 2a–c and 6a were readily oxidized to the corresponding pyridine derivatives 15a–d by stirring in aqueous nitric acid (70%) at 5 °C to room temperature (Scheme 5). The X-ray

• . This is a one-pot three-component reaction; on the other hand, the reported method involves two steps starting with the reaction of phenylpropynone with a primary amine, followed by reaction with different aldehydes. The synthesis of suitable substituted derivatives, such as 6 and 7, possessing

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• product. The initiation module of curacin biosynthesis contains a GCN5-related N-acetyltransferase (GNAT) domain. These enzymes typically catalyze acyl transfer to a primary amine. The curacin GNAT, however, was shown to be bifunctional and to exhibit decarboxylase/S-acetyltransferase activities [45]. The

Synthesis of dye/fluorescent functionalized dendrons based on cyclotriphosphazene

• Aurélien Hameau,
• Sabine Fuchs,
• Régis Laurent,
• Jean-Pierre Majoral and
• Anne-Marie Caminade

Beilstein J. Org. Chem. 2011, 7, 1577–1583, doi:10.3762/bjoc.7.186

• [15]. The method elaborated is also useful for the grafting of dyes, as will be illustrated with the dabsyl dye. We also paid particular attention to the nature of the remaining function (usable for the grafting of the dendron). We choose an aldehyde and a primary amine, both being well-known for

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• , giving good to excellent yields (Scheme 10) [9]. Barluenga and coworkers reported a synthesis of spiroacetals 22, through a Pd(II)-catalyzed three-component cascade reaction, starting from an alkynol, an aldehyde and a primary amine. The authors suggested that the first step of the reaction was the

• reported by Wu and coworkers. Initial Sonogashira coupling was effected between a 2-bromobenzaldehyde and an alkyne in the presence of catalytic amounts of PdCl2(PPh3)2 and CuI. After complete conversion of the aldehyde into the coupling product 25 (TLC control), a primary amine and diethylphosphite were

• substituted pyrroles involving a dihalogeno substrate and a sequential Sonogashira coupling followed by an hydroamination was developed by Duchêne and Parrain [32]. In this one-pot sequence, the first reaction is an allylic amination between the 3,4-diiodobut-2-enoic acid (54) and a primary amine, which can