Unexpected polymorphism during a catalyzed mechanochemical Knoevenagel condensation

• Sebastian Haferkamp,
• Andrea Paul,
• Adam A. L. Michalchuk and
• Franziska Emmerling

Beilstein J. Org. Chem. 2019, 15, 1141–1148, doi:10.3762/bjoc.15.110

• condensation in detail. Results and Discussion The catalyzed Knoevenagel condensations of mono-fluorinated benzaldehydes 1a–c with malonodinitrile (2) are depicted in Scheme 1. In contrast to previous work, which reported the uncatalyzed reaction [19], piperidine was used as a basic catalyst. This was done as

• performed (Figure 3). The relative intensity of the peak corresponding to piperidine (Figure 3 red box) decreases systematically with respect to that of 3a (Figure 3 blue box). Hence, this suggests that the catalyst is indeed present in the solid product. Further analysis is required to understand the

• (1a) contain spectral properties belonging to PMMA (shaded areas in Figure S3, Supporting Information File 1). The mechanochemical catalyzed reactions of 1b and 1c with 2 performed with 2 µL piperidine did not exhibit the same polymorphic transformations as with 1a. Instead, reactions using 1b and 1c

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• ]. Considering that the widely used Fmoc protecting group, of which the H-9 has a pKa of ≈22 [42], can be readily removed with a weak base such as piperidine, we hypothesized that the oxidized Dmoc groups and linkers could be cleaved under weakly basic and non-nucleophilic conditions via β-elimination. Indeed

Precious metal-free molecular machines for solar thermal energy storage

• Meglena I. Kandinska,
• Snejana M. Kitova,
• Vladimira S. Videva,
• Stanimir S. Stoyanov,
• Stanislava B. Yordanova,
• Stanislav B. Baluschev,
• Silvia E. Angelova and
• Aleksey A. Vasilev

Beilstein J. Org. Chem. 2019, 15, 1096–1106, doi:10.3762/bjoc.15.106

• excess of crown ether 3 was easily removed. In general the zwitterionic salts 2a–d reacted to complete depletion in ethanol and in the presence of piperidine as catalyst with the crown ether benzaldehyde 3 (TLC monitoring, ethyl acetate/ethanol 4.5:0.5). After the addition of ethyl acetate the

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• most of the cases, the Z-isomer as the sole or main product, while tert-butyl derivatives gave the E-isomer selectively. On the secondary amine side, morpholine, piperidine, pyrrolidine and dibutylamine all rendered the reaction efficiently. A plausible explanation for the mechanism of this

A chemically contiguous hapten approach for a heroin–fentanyl vaccine

• Yoshihiro Natori,
• Candy S. Hwang,
• Lucy Lin,
• Lauren C. Smith,
• Bin Zhou and
• Kim D. Janda

Beilstein J. Org. Chem. 2019, 15, 1020–1031, doi:10.3762/bjoc.15.100

• obtain an aldehyde that could then be used in a reductive amination. Beginning with the commercially available 4-(4-bromophenyl)butanoic acid, an alkene was installed with a Suzuki reaction, which in turn underwent ozonolysis to give 21, shown in Scheme 4. In parallel, a commercially available piperidine

• the same linker as HF-4, its lengthy epitope actually required a different, but parallel synthetic strategy. The same commercially available piperidine used to obtain 24 was instead acylated with phthaloyl-protected aminopropanoyl chloride, deprotected, and reductively aminated with 21 to give 33

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• of polystyrene resin 3 as the amine component. After resin removal with piperidine in DMF, a combinatorial strategy of replacing the carboxylic acid component with trimethylsilyl azide (TMSN3) (azido-Ugi reaction) or cyanic acid, followed by Fmoc removal (TFA), allowed the formation of the tetrazole

Photochemical generation of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical from caged nitroxides by near-infrared two-photon irradiation and its cytocidal effect on lung cancer cells

• Ayato Yamada,
• Manabu Abe,
• Yoshinobu Nishimura,
• Shoji Ishizaka,
• Masashi Namba,
• Taku Nakashima,
• Kiyofumi Shimoji and
• Noboru Hattori

Beilstein J. Org. Chem. 2019, 15, 863–873, doi:10.3762/bjoc.15.84

• character, 2,2,6,6-tetramethyl-1-(1-(2-(4-nitrophenyl)benzofuran-6-yl)ethoxy)piperidine (2a) and its regioisomer 2b, were designed and synthesized. The one-photon (OP) (365 ± 10 nm) and TP (710–760 nm) triggered release (i.e., uncaging) of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical under air

• ), 126.43 (C), 125.01 (CH), 124.33 (CH), 124.07 (CH), 121.22 (CH), 110.42 (CH), 105.12 (CH), 29.25 (CH2), 15.84 (CH3); HRMS–ESI (m/z): [M−] calcd. for C16H13NO3, 267.09009; found, 267.09064. 2,2,6,6-Tetramethyl-1-(1-(2-(4-nitrophenyl)benzofuran-6-yl)ethoxy)piperidine (2a). Under air, TEMPO (0.23 g, 1.5 mmol

• -(1-(2-(4-nitrophenyl)benzofuran-5-yl)ethoxy)piperidine (2b). Under air, TEMPO (46.8 mg, 0.3 mmol), 5-ethyl-2-(4-nitrophenyl)benzofuran (5b, 267 mg, 1 mmol), Cu(OAc)2 (3.6 mg, 0.02 mmol), bpy (3.1 mg, 0.02 mmol), TBHP (aqueous 70%, 0.086 mL, 0.6 mmol) were added into a Schlenk tube in the dark. The

Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• Fmoc group removal and coupling steps. The Fmoc group was removed using piperidine/DMF (3:7). The coupling of amino acids was mediated by N,N’-diisopropylcarbodiimide (DIPCDI) and ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) in DMF, except for Fmoc-Glu-OpNB and Fmoc-Phe(4-I)-OH, which were coupled

• biaryl bicyclic peptide 1. Synthesis of the biaryl bicyclic peptide 1 incorporating a Phe-Phe linkage. Reagents and conditions: (i) Piperidine/DMF (3:7). (ii) Fmoc-βAla-OH, DIPCDI, Oxyma, DMF. (iii) Fmoc-Phe(4-I)-OH, COMU, Oxyma, DIPEA, DMF, overnight. (iv) Fmoc-Gln(Tmob)-OH, DIPCDI, Oxyma, DMF. (v) Fmoc

• . Synthesis of the biaryl bicyclic peptide 2 incorporating a Phe-Tyr linkage. Reagents and conditions: (i) Piperidine/DMF (3:7). (ii) Fmoc-βAla-OH, DIPCDI, Oxyma, DMF. (iii) Fmoc-Phe(4-I)-OH, COMU, Oxyma, DIPEA, DMF, overnight. (iv) Fmoc-Gln(Tmob)-OH, DIPCDI, Oxyma, DMF. (v) Fmoc-Gly-OH, DIPCDI, Oxyma, DMF

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• reported that 2,6-diazidopurine nucleosides exhibit opposite regioselectivity with aliphatic thiols, which do SNAr reactions at C(2) position of purines [50][51]. Taking this information into account, we performed an SNAr reaction between 2,6-diazidopurine 2a and piperidine and obtained the C(2

• or piperidine were more regioselective than in the purine series. In the latter case the purine products 6a–c had to be chromatographically separated to remove the 2-azido-6-amino isomer as the purification at the stage of final products was not effective. The observed C(2)-selectivity in the 7

• (piperidine or pyrrolidine) substituents did not significantly influence fluorescent properties. The preliminary study showed that introduction of other aliphatic amines at C(2) does not significantly affect the photophysical properties of the target substances either. On the other hand, the present synthetic

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• and in particular compounds with an amino functional group such as 3-aminopiperidine are valuable intermediates for the production of a large number of bioactive compounds with pharmacological properties. In this paper, the synthesis of both enantiomers of 3-amino-1-Boc-piperidine by amination of the

• intermediates for the synthesis of a large number of biologically active compounds used for the treatment of obesity, type-I and II diabetes mellitus or as psychotropic drugs against depression and schizophrenia [15][16][17][18][19]. In particular (R)-3-amino-1-Boc-piperidine is a useful precursor of compounds

• reaction parameters were studied to optimize the protocol for further scaling-up purposes. Results and Discussion In order to obtain enantiomerically pure (R)- and (S)-3-amino-1-Boc-piperidine (2), the transamination reaction was studied by using commercially available immobilized TAs (TAs-IMB) and

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• –al led to the substituted malonates 3a–al. A simple and general procedure was adopted for the condensation using fairly concentrated ethanolic solutions of diethyl malonate (4) and aldehydes 5a–al along with catalytic amounts of piperidine and acetic acid as well as some 4 Å molecular sieves to trap

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• has been adapted from an earlier work reported by Moroder et al. in which trifluoroacetyl (Tfa) moiety was deprotected during a peptide synthesis [44] using 1 M aqueous piperidine at ice cold temperature. The polypeptide chain 10 was thus subjected to 1 M aqueous piperidine at 0 °C to deprotect the ε

• -amino trifluoroacetyl moiety. The literature reported conditions, however, failed to deprotect the Tfa group from polypeptide chain 10. We have tested few reaction conditions and after optimization, we have successfully deprotected ε-amino Tfa protecting group from the side chain using 2 M aq piperidine

• -(trifluoroacetyl) group does not give positive Kaiser test (see Experimental section). Using 2 M aqueous piperidine we successfully cleaved the Tfa protecting group from the side chain of 15 to give a polypeptide chain 16 that is still intact with the resin. The successful cleavage of the Tfa group from the lysine

Synthesis of aryl sulfides via radical–radical cross coupling of electron-rich arenes using visible light photoredox catalysis

• Amrita Das,
• Mitasree Maity,
• Simon Malcherek,
• Burkhard König and
• Julia Rehbein

Beilstein J. Org. Chem. 2018, 14, 2520–2528, doi:10.3762/bjoc.14.228

• )piperidine was obtained in both cases. See Supporting Information File 1 for the HRMS analysis of the TEMPO adduct. These radical trapping experiments show that initially a radical cation of the arene is formed by the excited photocatalyst, which then is trapped by the radical scavenger TEMPO. S–S bond

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• higher hydrazine concentration (4% in DMF) and longer treatment (12 × 5 min) for the complete removal of the protecting group. However, ivDde is more stable in circumstances (2% DBU, 2% piperidine in DMF) used for the Fmoc removal. To avoid the unwanted Dde removal during the synthesis ivDde was applied

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• , 3-methylpiperidine 11 was isolated as a byproduct in 32% yield. A formation of the piperidine 11 proceeds via opening of aziridinium intermediate 10 (Scheme 1) [32]. Interestingly, a product of a ring expansion was not observed during the tosylate substitution with LiBHEt3. Simple acidic hydrolysis

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• followed by a ring-expansion rearrangement. In the rearrangement reaction, the phenyl substituent in the initially formed spiro-triazolium adducts 16 underwent a [1,2]-migration from C(3) to the electron-deficient N(2). This led to the ring expansion from 6-membered piperidine to 7-membered diazepine

• has a strong proclivity for ring expansion to occur. Accordingly, the 6-membered piperidine ring was enlarged to the 7-membered diazepine ring giving the isolated benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 via [1,2]-shift. It is noteworthy that the intermediate products 16 bear a

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• of 0.2 M. Reactions were run at 50 W at a temperature of 75 °C for 8 minutes, followed by 2 × 3 min deprotection with 20% piperidine in DMF. Peptide purification. Crude peptides were purified with RP-HPLC. The crude peptide was dissolved in ACN/H2O (1:4) and purified in 2.0–2.4 mL portions on either

An amine protecting group deprotectable under nearly neutral oxidative conditions

• Shahien Shahsavari,
• Chase McNamara,
• Mark Sylvester,
• Emily Bromley,
• Savannah Joslin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2018, 14, 1750–1757, doi:10.3762/bjoc.14.149

• and Fmoc protected diamine 9. We found that selective removal of Fmoc from 9 to give 8 could be achieved under typical Fmoc deprotection conditions involving piperidine. Selective removal of dM-Dmoc was also simple; treating 9 under the standard dM-Dmoc deprotection conditions gave the Fmoc protected

• equiv) in dry DCM (10 mL) was reacted with piperidine (2 mL) at rt under argon for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified with flash column chromatography (SiO2, 9:0.5:0.5 DCM/MeOH/Et3N; TLC Rf = 0.3, 9:1 DCM/MeOH) to give 8 as a light

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• with 10% piperidine in DMF providing the conjugates AN-152 and 1. It is worth mentioning that an O–N acyl shift (from the aglycone OH group to the daunosamine NH2 group ca. in 10–20%) was observed during the synthesis of conjugates containing an ester bond. This could be detected by the MS

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• rt as described previously [20]. CF-polymers were cleaved by treatment with 20% piperidine for 45 min. The successful coupling was verified by a Kaiser test [43]. To cleave the peptides from the resin, a mixture of triisopropylsilane (TIS), H2O and concentrated trifluoroacetic acid (TFA) (1:1:38 v/v

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• and A succeeded as previously described in the literature; unit A (15) and C–D (16) were connected by Yamaguchi esterification to give 17 (Scheme 2) [45]. Then, Fmoc was cleaved from the N-terminus of unit C–D–A (17) using piperidine and the resulting crude amine was coupled to the corresponding

• , 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C, 3 h; (b) 1) piperidine, DMF, rt, 2 h; 2) 13 or 14, HOAt, EDC·HCl, Et3N, CH2Cl2, 0 °C → rt, overnight; (c) 1) TFA/CH2Cl2/H2O, rt, 2 h; 2) HATU, HOAt, DIPEA, DMF, rt, slow addition + 2 h; (d) 1) (CH3O)3CH, PPTS, CH2Cl2, rt, 2 h; 2) AcBr, CH2Cl2, rt, 4 h; 3

Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

• Koichi Mitsudo,
• Junya Yamamoto,
• Tomoya Akagi,
• Atsuhiro Yamashita,
• Masahiro Haisa,
• Kazuki Yoshioka,
• Hiroki Mandai,
• Koji Ueoka,
• Christian Hempel,
• Jun-ichi Yoshida and
• Seiji Suga

Beilstein J. Org. Chem. 2018, 14, 1192–1202, doi:10.3762/bjoc.14.100

• reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be

• consistent with the Steven’s hypothesis. Keywords: cation pool; conformation; electroorganic synthesis; N-acyliminium ion; NMR analysis; piperidine; Introduction Cyclic amines are significant key motifs in pharmaceutical and natural products because a variety of compounds bearing those moieties exhibit

• give the disubstituted piperidine derivatives in an excellent diastereoselective manner (Scheme 1). This result inspired us to investigate the stereochemistry of the N-acyliminium ions by means of NMR spectroscopy, which is challenging to achieve without using cation pool methods. The current report

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• shown in Scheme 2. The C-terminal amino acid was immobilized onto the 2-Cl-Trt-Cl resin in the presence of 3.0 equiv of DIPEA in DCM/DMF (v:v 1:1). Subsequent peptide chain elongation was completed via Fmoc-SPPS protocol, which includes deprotection with 20% piperidine/DMF and peptide coupling with 3.0

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• GmbH, Marktredwitz, Germany) were used for the synthesis except Fmoc-Lys(Mtt)-OH that was applied for the development of branching in the peptide. The protocol of the SPPS was similarly as described in [17] as follows: (i) DMF washing (4 × 0.5 min), (ii) Fmoc deprotection with 2% DBU, 2% piperidine

• (Biolegend, San Diego CA). Samples were detected and analyzed by using an Attitude® Acoustic Focusing Cytometer (ThermoFischer Scientific). Schematic synthesis of cyclic KNGRE (A) and XNGRE (B) drug conjugates. a) Mtt-cleavage: 2% TFA/DCM; b) Fmoc-Aaa(X)-OH coupling; c) Fmoc-cleavage 2% piperidine/2% DBU/DMF

Anodic oxidation of bisamides from diaminoalkanes by constant current electrolysis

• Tatiana Golub and
• James Y. Becker

Beilstein J. Org. Chem. 2018, 14, 861–868, doi:10.3762/bjoc.14.72

• group attached to the N atom in various piperidine derivatives (Scheme 6) on the anodic oxidation of 'cyclic amides' was explored in methanol under different experimental conditions [17]. The results indicate that this type of amides mostly undergo mono- and dimethoxylation at the α and α'-positions to