Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• ester or hydrazine bonds, cathepsin-B labile spacers and oxime bonds [21][22][25]. Due to its structural properties, Dau cannot be attached to the homing device by an ester bond like Dox, because of the absence of the primary hydroxy group in position C-14. However, the C-13 carbonyl group of Dox/Dau

• decapeptide the Dde group of 4Lys was removed with 2% hydrazine in DMF (12 × 5 min) and the peptidyl-resin was washed with DMF (5 × 1 min). Afterwards, the ε-NH2 amino group was butyrylated with 3 equiv butyric anhydride and 3 equiv DIPEA in DMF (2 h). In the next step, 8Lys(Mtt) was deprotected with 2% TFA

• presence of superagonist triptorelin (125–1000 µM) by flow cytometry. Cells were treated simultaneously with K2 and triptorelin for 100 min. Syntheses of GnRH-III–[(4Lys(Bu)/4Ser, 6Aaa, 8Lys(Dau=Aoa)] bioconjugates. a) (1) 2% hydrazine

Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms"

• Karolina Tiara,
• Mykhaylo A. Potopnyk and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2018, 14, 634–641, doi:10.3762/bjoc.14.50

• , the deprotection of the amine function with hydrazine caused also reduction of the C5–C6 double bond; two peaks at 189 and 191 Da were observed in the MS spectrum of crude post-reaction mixture (for 13b and 13c, respectively). We reasoned, that the all these problems may be overcome by an elongation

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• %. Wolff–Kishner reduction The Wolff–Kishner reaction is widely used by chemists to remove carbonyl moieties yielding unsubstituted alkyl chains. The reaction requires two steps: the hydrazine first reacts with the ketone forming a hydrazone; The addition of a strong base and heat then promote a

• rearrangement with the elimination of N2 yielding the desired alkyl chain (Figure 3). This reaction is applied to the synthesis of UDCA in order to remove the carbonyl group at C12. The use of hydrazine is a disadvantage in terms of safety (explosive risk) and economic costs (it should be used in excess

• relative to substrate). Several modifications of the Wolff–Kishner reaction can be found in literature: i.e., the Huang–Minlon modification, that consists of removing the unreacted hydrazine after the first step by distillation [42]. This results in higher yield and partial recovery of the unreacted

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• acetic acid (Scheme 1). In the same report the other regioisomers 6-trifluoromethylpyrazolo[3,4-b]pyridines 20 were obtained under multicomponent solvent-free conditions by the reaction of hydrazine 14, β-ketonitrile 15 and β-diketone 17 as an exclusive product. The structures of both the regioisomers

• shape of compound 93 makes it chiral in nature. It was proposed that there is in situ oxidation of ethanol to ethanal by conc. HNO3 which turned the reaction into a multi-component domino assembly of reactants hydrazine 14, β-ketonitriles 15 and acetaldehyde. Rahmati [75] carried out a reaction of 5

• (147) with 3-oxo-3-arylpropanenitrile 15 under solvent-free grinding conditions. The reaction was proposed to proceed via formation of hydrazine by C–N bond cleavage which under reaction conditions provided 7-aminopyrazolo[1,5-a]pyrimidines 148 on coupling with 3-oxo-3-arylpropanenitrile 15 (Scheme 42

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• reductive opening of the benzylidene acetal to give the acceptor monosaccharide 63. NIS/TMSOTf-promoted glycosylation of 63 with glycosyl donor 64 furnished desired β(1→6) disaccharide which was subjected to treatment with hydrazine hydrate to remove the phthalimido group. Subsequent acylation of the

From dipivaloylketene to tetraoxaadamantanes

• Gert Kollenz and
• Curt Wentrup

Beilstein J. Org. Chem. 2018, 14, 1–10, doi:10.3762/bjoc.14.1

• [29]. It should be noted that both the bisdioxines [19] and the tetraoxaadamantanes [29] exhibit axial chirality as confirmed by 1H NMR spectroscopy with the Eu(hfc)3 chiral shift reagent. Bisdioxine oxime and hydrazine derivatives 26 and 27 (Scheme 8) are formed from 3 at room temperature without the

• ) derived from dipivaloylketene (2). Mechanisms of formation of bisdioxine acid derivatives from dimer 3. Recently reported synthesis of chromenobisdioxines. Formation of tetraoxaadamantanes. Decarboxylative hydrolysis and oxa-Michael-type ring closure. Oxime and hydrazine derivatives of bisdioxines and

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• -propynyltriphenylphosphonium bromide (24) involved propadienylphosphonium bromide (25) – the tautomeric form of the starting phosphonium salt. The same authors carried out a series of nucleophilic additions of amines and hydrazine derivatives to 24 to obtain products with the proposed structure of 2-aminovinylphosphonium

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• hydrazine, without disturbing the peptide bond structure, to give H-Gly-Pro-1. DPP-4 activity measurement The fluorescence spectra of 1 and H-Gly-Pro-1 were recorded to confirm their fluorescence profiles; the spectra are shown in Figure 3. As expected, H-Gly-Pro-1 was non-fluorescent because of the

• = 2.2, 6.4 Hz, 3F); MS m/z: M+ 565, 468, 285, 257, 188, 160; HRMS m/z: M+ calcd for C27H21F6N3O4, 565.1436; found, 595.1437. N-(S)-1-(2-Aminoacetyl)-N-(2,4-bis((E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)pyrrolidine-2-carboxamide (H-Gly-Pro-1): To solution of 7 (0.05 mmol) in ethanol was added hydrazine

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• , followed by a hydrazinolysis step and a second hydrazine-Ugi-azide reaction to provide the desired acylhydrazino bis(1,5-disubstituted tetrazoles). Recently we have reported the synthesis of acylhydrazino-peptomers by a similar strategy [31]. The hydrazides 2a–c were prepared by the reaction of esters 1, 4

• and 6 with hydrazine monohydrate, following a known procedure (Scheme 2) [31]. To access the acylhydrazino-tetrazoles, the hydrazides 2a–c were subjected to a multicomponent reaction comprising an aldehyde or ketone 7a–h, trimethylsilyl azide (TMSN3, 8), methyl isocyanoacetate (9) and ZnCl2 (10 mol

• chose hydrazine tetrazole 10j to continue the synthesis, as it was obtained in excellent yield, it shows distinct NMR spectra and offers the possibility of further functionalization after removal of the Boc protecting group. Therefore, compound 10j was subjected to hydrazinolysis with hydrazine

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• subjected to heterogeneous hydrogenation conditions to produce the indole product 12 through a reductive cyclisation sequence. From the corresponding ester functionalised indole 12 we anticipated that condensation with hydrazine would furnish the corresponding acyl hydrazine 13 which could be cyclised to

• looked at telescoping the final two steps of the process; substitution of the ethoxy group by hydrazine and then ring formation to the 3H-[1,3,4]oxadiazol-2-one unit [32][33]. In this procedure a 0.95 M THF solution of compound 12 was united with a solution of hydrazine (1.0 M in THF) and directed into a

• heated flow coil to be superheated at 100 °C (Scheme 6). A residence time of 40 min allowed full conversion to the corresponding acyl hydrazine 13 which was directly intercepted with a further input stream containing CDI (1.1 M in THF) and heated at 75 °C for an additional 26 min in a second flow coil

¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• -amino-1,2,4-triazole 16-15N2 was synthesized by the interaction of 15N2-hydrazine sulphate (98%, 15N) with S-methyl isothiourea sulphate and consecutive cyclization with formic acid (see the Supporting Information File 1). The use of 16-15N2 in a reaction with ethyl 4,4,4-trifluoroacetoacetate (22

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

• carboxylic acid (see Supporting Information File 1) in moderate yield. Finally, the pthalimide group was removed with hydrazine to give the target amino acid 6a (Scheme 4). The modest overall yield for this three-step sequence can be partially attributed to the challenge of purifying the penultimate and

Diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside: synthesis, derivatives and antimicrobial activity

• Henryk Myszka,
• Patrycja Sokołowska,
• Agnieszka Cieślińska,
• Andrzej Nowacki,
• Maciej Jaśkiewicz,
• Wojciech Kamysz and
• Beata Liberek

Beilstein J. Org. Chem. 2017, 13, 2310–2315, doi:10.3762/bjoc.13.227

• determined by 1H and 13C NMR supported by COSY and HSQC techniques. The β linkage in 3, as well as the 4C1 conformation of the pyranose ring were confirmed by the coupling constant of the anomeric proton (J1,2 = 8.4 Hz). The deprotection of 3 was achieved by using 98% hydrazine hydrate in refluxing ethanol

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

• amines, hydrazine, and carbohydrazides. In some of these reactions, the initially formed adducts, after subsequent elimination of HCN, undergo heterocyclization (see chapter Heterocyclization reactions). The reaction of E-1a with either aqueous ammonia or gaseous NH3 in acetonitrile leads to the enamines

• reactions with E-1b is hydrazine and its derivatives. The parent hydrazine used as the hydrate reacts with E-1 in ethanol at room temperature, and in the case of diisopropyl dicyanofumarate (E-1c), the crystalline enehydrazine was isolated in 82% yield [62]. In addition, the N-benzyl-protected (S)-proline

• products (tandem reactions). These reactions occur through an initial formation of the Michael-type adduct followed by a heterocyclization step upon involvement of either a cyano or an ester group as a second electrophilic center. Hydrazine is a powerful dinucleophile and reacts easily with E-1 in ethanol

Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds

• Alexey Yu. Dubovtsev,
• Maksim V. Dmitriev,
• Аndrey N. Maslivets and
• Michael Rubin

Beilstein J. Org. Chem. 2017, 13, 2179–2185, doi:10.3762/bjoc.13.218

• formation of the indoline ring was unambiguously confirmed by the crystal structure of compound 21ab (CCDC 1546063, Figure 2). It seems that the nucleophilicity of the hydrazine moiety prevailed, and the formation of the thermodynamically more favorable amide bond governed the overall direction of this

Solid-state studies and antioxidant properties of the γ-cyclodextrin·fisetin inclusion compound

• Joana M. Pais,
• Maria João Barroca,
• Maria Paula M. Marques,
• Filipe A. Almeida Paz and
• Susana S. Braga

Beilstein J. Org. Chem. 2017, 13, 2138–2145, doi:10.3762/bjoc.13.212

• corresponding hydrazine (pale yellow in color), a reaction which can be monitored by UV–vis spectroscopy. As the kinetics of the reaction varies from sample to sample, the stabilization time for a complete reduction of the DPPH· free radical was determined. For all samples studied, the steady-state

Transition-metal-free synthesis of 3-sulfenylated chromones via KIO₃-catalyzed radical C(sp²)–H sulfenylation

• Yanhui Guo,
• Shanshan Zhong,
• Li Wei and
• Jie-Ping Wan

Beilstein J. Org. Chem. 2017, 13, 2017–2022, doi:10.3762/bjoc.13.199

• Discussion Initially, the reaction of enaminone 1a and sulfonyl hydrazine 2a was tentatively subjected to different iodine reagents or catalyst-free conditions. The results indicated that no product was observed in the reaction without catalyst (entry 1, Table 1), and different types of iodine reagents such

• (reaction 1, Scheme 3). In addition, sulfonyl hydrazine 2b gave disulfide 6 under the same conditions (reaction 2, Scheme 3), suggesting that chromone 5 and disulfide 6 might be key intermediates in the domino reactions. Moreover, the same reaction in the presence of TEMPO gave no formation of 6, indicating

• ), further confirming that a radical intermediate was generated during the reaction process. According to the results obtained in the control experiments, the mechanism for this domino reaction is proposed (Scheme 4). As one of the key steps, the reductive coupling of two sulfonyl hydrazine molecules may

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• the hydrazine is slow, meaning that the nucleophilicity is greatly retarded compared to lower acid loadings. Nonetheless, considering that the subsequent fluorination step should proceed optimally under basic conditions [17], the lowest amount of acid which also provided a good yield was thus chosen

Mechanochemical N-alkylation of imides

• Anamarija Briš,
• Mateja Đud and
• Davor Margetić

Beilstein J. Org. Chem. 2017, 13, 1745–1752, doi:10.3762/bjoc.13.169

• hazardous hydrazine hydrate was replaced by 1,2-diaminoethane [39] and conversion to the corresponding benzylamines was quantitative within 1 h. As a proof of concept of reaction, p-methylbenzylamine was isolated in 41% yield in the form of acetamide 42. In this way, a three-step, two-pot (A and B, Scheme 5

Encaging palladium(0) in layered double hydroxide: A sustainable catalyst for solvent-free and ligand-free Heck reaction in a ball mill

• Wei Shi,
• Jingbo Yu,
• Zhijiang Jiang,
• Qiaoling Shao and
• Weike Su

Beilstein J. Org. Chem. 2017, 13, 1661–1668, doi:10.3762/bjoc.13.160

• hybrid LDHs were then reduced by hydrazine hydrate (N2H4·H2O) to obtain the Pd catalyst supported on MgAl-LDHs (Pd/MgAl-LDHs). The as-prepared Pd/MgAl-LDH catalyst was further applied in representative cross-coupling Heck reactions under HSBM conditions (Scheme 1) by using a planetary ball mill

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

• Işıl Yenice,
• Sinan Basceken and
• Metin Balci

Beilstein J. Org. Chem. 2017, 13, 825–834, doi:10.3762/bjoc.13.83

• by a copper-catalyzed cross-coupling reaction. Nucleophilic cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with hydrazine afforded the 6-exo-dig/6-endo-dig cyclization products depending on the electronic nature of the substituents attached to the alkyne. On the other hand

• the presence of an electron-donating group at the benzene ring. However, when the reaction was carried out at the reflux temperature of toluene, the conversion increased to 35%. Next, we conducted cyclization reactions of N-alkyne substituted carboxylate derivatives 7a–d via hydrazine monohydrate

• . Methyl 1-(phenylethynyl)-1H-pyrrole-2-carboxylate (7c) was treated with hydrazine monohydrate in MeOH under N2 atmosphere at reflux temperature. Pyrrolopyrazinone 12c and pyrrolotriazinone 13c skeletons were formed in 67% and 24% yields, respectively (Scheme 2). The structures of cyclization products 12c

Derivatives of the triaminoguanidinium ion, 5. Acylation of triaminoguanidines leading to symmetrical tris(acylamino)guanidines and mesoionic 1,2,4-triazolium-3-aminides

• Jan Szabo,
• Julian Greiner and
• Gerhard Maas

Beilstein J. Org. Chem. 2017, 13, 579–588, doi:10.3762/bjoc.13.57

• the reaction of guanidinium chloride with hydrazine [2], triaminoguanidinium chloride (TAG-Cl) offers the opportunity to serve as a C3-symmetrical platform for the synthesis of triaminoguanidines with multiple functionalization (see [3] and references cited there). In most studies reported so far

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• " for safety reasons, such as those involving diazo compounds, hydrazine, azides, phosgene, cyanides and other hazardous chemicals could be performed with relatively low risk using flow technology [72][73][74][75][76]. Several research groups investigated this aspect, as highlighted by several available

• in Scheme 16, diazo species 18 could be generated from simple carbonyls 15 and hydrazine (16). Intermediate hydrazones 17 can be converted into the corresponding diazo compounds by oxidation using a recyclable oxidant based on N-iodo-p-toluenesulfonamide potassium salt. The possibility to regenerate

• to handle hazardous components such as hydrazine and molecular oxygen, which represent alternative reagents for selective reduction of C=C double bonds. In fact, combination of hydrazine hydrate (N2H4·H2O) and O2 provide diimide (HN=NH) as reducing agent. Nevertheless, this strategy is rarely used in