Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• amidation (2→5) due to competitive formation of the corresponding benzyl esters. Depending on the NaBH4 batch the dibenzyl-protected derivatives 4 formed as side products (<10% referred to 2). The residual impurities (BnOH and 4) were separated either through work up (of amide 5a) or chromatographic

• purification (of amides 5b–d) after the following amidation (2→5). Importantly, through this procedure not only one isolation step was avoided, but also the overall yield was improved significantly: For the transformation from 1a to 2a (I isolated as free acid) under (optimized) literature conditions we

• desired amide 5c was isolated with a very good ee of 95% (entry 6) [64]. The high racemisation sensitivity of 2c is further underlined by a T3P/pyridine (n-propylphosphonic acid anhydride) [65][66] mediated amidation, which has been reported to suppress racemisation [67]. With substrate 2c the

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• pharmacophore was synthesized in two steps by the oxidation of alcohol 156 with H5IO6/RuCl3 followed by amidation of the acid 157 (Scheme 39) [88]. It was shown that compound 158 exhibits antimalarial activity comparable with that of artemisinin [88]. Plakinic acids belong to a large family of natural products

• -methyloxime (192) and 4-carbomethoxycyclohexanone 193 to form cis-adamantane-2-spiro-3’-8’-methoxycarbonylmethyl-1’,2’,4’-trioxaspiro[4.5]decane 194. The latter is hydrolyzed to cis-adamantane-2-spiro-3’-8’-carboxymethyl-1’,2’,4’-trioxaspiro[4.5]decane 195, followed by mild amidation with the formation of the

• compounds was synthesized by the following series of steps: reduction of the double bond in the presence of the peroxide group (transformation of ethyl 2-(6,6-dimethyl-1,2-dioxan-3-yl)acrylate (272d) into ethyl 2-((S)-6,6-dimethyl-1,2-dioxan-3-yl)propanoate (293)), alkaline hydrolysis, and amidation (Scheme

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

• 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

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

• strong P1 base polymer-supported BEMP gave the corresponding ether adduct which was then converted to the desired secondary amine 1.64 via direct amidation and borane-mediated reduction. Next an SNAr reaction on 2-fluoropyridine (1.66) followed by oxidation of the benzylic alcohol using immobilised

A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand

• Hideki Shimizu,
• Jeffrey C. Holder and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2013, 9, 1637–1642, doi:10.3762/bjoc.9.187

• reaction sequence to be highly variable, and the purification by silica gel chromatography to be tedious. In the revised retrosynthesis, picolinic acid (5) was identified as a comparably priced, commonly available surrogate for cyanopyridine 2. Amidation of (S)-tert-leucinol (6) and picolinic acid (5

• ) would generate amide 4, which upon cyclization would generate the ligand framework. Initial efforts focused on the amidation reaction between (S)-tert-leucinol and picolinic acid (5) via acid chloride 7 (Table 1), which was generated in situ by treatment of acid 5 with a number of chlorinating agents

• synthesis and revised plan. Scale-up synthesis of (S)-t-BuPyOx. Amidation reactions of picolinic acid. Cyclization screen. Supporting Information Materials and methods, auxiliary experimental details, and relevant NMR spectra are provided. Supporting Information File 382: Experimental details

Design and synthesis of tag-free photoprobes for the identification of the molecular target for CCG-1423, a novel inhibitor of the Rho/MKL1/SRF signaling pathway

• Jessica L. Bell,
• Andrew J. Haak,
• Susan M. Wade,
• Yihan Sun,
• Richard R. Neubig and
• Scott D. Larsen

Beilstein J. Org. Chem. 2013, 9, 966–973, doi:10.3762/bjoc.9.111

• acid (4) was reacted with substituted anilines 5 under standard EDC-mediated amidation conditions, followed by TFA-catalyzed deprotection to afford amides 6. A subsequent second amidation with benzoic acids 7 afforded final bis(amide) analogues 8. We also synthesized a model azide (Scheme 2). Synthesis

• coupled with 4 and deprotected to give amine 13. Final amidation with 3-methoxy-5-trifluoromethylbenzoic acid provided model probe 14. Table 1 presents biological activity data for all of the new model probes. These include: potency at inhibiting the Rho/MKL1/SRF-driven expression of a luciferase reporter

• -benzoylbenzoic acid afforded the final probe 19. Synthesis of a photoprobe based on the most active model 8c is shown in Scheme 4. Acid 20 was esterified prior to alkylation with propargyl bromide, affording ester 22. Saponification, followed by amidation with the previously prepared piperidine 6c, provided the

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• condensed with succinic anhydride to provide the oxadiazole acid 7. Conversion of 7 to the corresponding acid chloride and subsequent amidation with excess methylamine afforded 8 in excellent yield after normal phase chromatography. This route was employed to make a variety of analogues and was generally

• coupled to cyclopropylamine to give 12 using a standard amidation protocol. The compound was purified by normal phase chromatography and was recovered as a white solid with a sharply defined melting point. The route was also amenable toward the preparation of related analogues. Generally, 9 was used

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

• accomplished by amidation with an azido-amine linker followed by Cu(I)-catalyzed azide–alkyne cycloaddition with propargyl sugars. Subsequent Teoc deprotection and conjugation with pyrenyl isothiocyanates afforded well-defined end-labeled glycopolymers. Keywords: capping agent; carbohydrate; glycan; olefin

• (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

Facile synthesis of benzothiadiazine 1,1-dioxides, a precursor of RSV inhibitors, by tandem amidation/intramolecular aza-Wittig reaction

• Krishna C. Majumdar and
• Sintu Ganai

Beilstein J. Org. Chem. 2013, 9, 503–509, doi:10.3762/bjoc.9.54

• reactions of all the substrates having electron-deficient R-substituents at the 2-position proceeded smoothly, providing excellent yields, whereas the substrates having electron-donating R-substituents gave lower yields. The proposed mechanism for the formation of the products 13 may involve amidation of

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• . Instead, 53 had a propensity to convert to the diketopiperazine 54. Also, the methyl ester of 52 resisted direct amidation under a variety of standard conditions. Rather, 52 had to be hydrolyzed to the acid and then coupled to NH3 with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium

An improved synthesis of a fluorophosphonate–polyethylene glycol–biotin probe and its use against competitive substrates

• Hao Xu,
• Hairat Sabit,
• Gordon L. Amidon and
• H. D. Hollis Showalter

Beilstein J. Org. Chem. 2013, 9, 89–96, doi:10.3762/bjoc.9.12

• of fluoridation and amidation reactions such that the reactive FP moiety can be introduced in the last step. Overall, these modifications make for a more scalable, higher yielding sequence and importantly isolate the handling of reactive and potentially toxic FP compounds to a single step, namely the

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

• (OAc)2 and Xantphos (L1) as a ligand provided good yield in 4 to 3 h (Table 1, entries 8 and 9). It is worth mentioning that Xantphos (L1) as a supporting ligand finds wide popularity in palladium-mediated amidation reactions by various research groups [54][55][56], which prompted us to evaluate the

Rh(III)-catalyzed directed C–H bond amidation of ferrocenes with isocyanates

• Satoshi Takebayashi,
• Tsubasa Shizuno,
• Takashi Otani and
• Takanori Shibata

Beilstein J. Org. Chem. 2012, 8, 1844–1848, doi:10.3762/bjoc.8.212

• ] catalyzed the C–H bond amidation of ferrocenes possessing directing groups with isocyanates in the presence of 2 equiv/Rh of HBF4·OEt2. A variety of disubstituted ferrocenes were prepared in high yields, or excellent diastereoselectivities. Keywords: amidation; C–H activation; C–H functionalization

Imidazolinium and amidinium salts as Lewis acid organocatalysts

• Oksana Sereda,
• Nicole Clemens,
• Tatjana Heckel and
• René Wilhelm

Beilstein J. Org. Chem. 2012, 8, 1798–1803, doi:10.3762/bjoc.8.205

• amidation under neat conditions and reduction with LAH, furnishing the product in 98% yield over two steps. Next, the aminal formation under neat conditions was performed. The aminal was further oxidized to a bromide salt by N-bromoacetamide in dimethoxyethane. The bromide counter anion was further

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

• Gianluigi Broggini,
• Egle M. Beccalli,
• Andrea Fasana and
• Silvia Gazzola

Beilstein J. Org. Chem. 2012, 8, 1730–1746, doi:10.3762/bjoc.8.198

• triggered after the initial amidation step. Conclusion Palladium-catalyzed reactions to construct bonds by coupling of C–H/C–H or C–H/N–H bonds have been widely investigated in recent years. This interest arises from the need for unfunctionalized starting materials and from the presence of waste products

• -indolyl allenamides. Amidation reaction of 1-allyl-2-indolecarboxamides. Intramolecular cyclization of N-benzoylindole. Intramolecular alkenylation/carboxylation of alkenylindoles. Intermolecular alkenylation/carboxylation of 2-substituted indoles. Mechanistic investigation of the cyclization

Influence of cyclodextrin on the solubility of a classically prepared 2-vinylcyclopropane macromonomer in aqueous solution

• Helmut Ritter,
• Jia Cheng and
• Monir Tabatabai

Beilstein J. Org. Chem. 2012, 8, 1528–1535, doi:10.3762/bjoc.8.173

• vinylcyclopropane end group and a poly(N-isopropylacrylamide) (poly(NiPAAm)) chain was obtained from amidation of 1-ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) with an amino-terminated poly(NiPAAm) 3 as an example. This macromonomer 5 showed an LCST effect after complexation of the vinyl end group with

• uncharged nucleophilic 2-aminoethanethiol. After treating with triethylamine, amino-terminated polymer 3 was obtained. The amidation of the amino group of 3 with 1-ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) in the presence of N,N′-dicyclohexylcarbodiimide (DCC) as condensation agent led to the

• with DI equal to 2.2. Altogether, the successful ozonolytic degradation is proved. Conclusion A new macromonomer 5 was synthesized via amidation of 1-ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) with an amino-terminated poly(NiPAAm) 3 as an example. Thanks to its relative hydrophobic

Synthesis and anion recognition properties of shape-persistent binaphthyl-containing chiral macrocyclic amides

• Marco Caricato,
• Nerea Jordana Leza,
• Claudia Gargiulli,
• Giuseppe Gattuso,
• Daniele Dondi and
• Dario Pasini

Beilstein J. Org. Chem. 2012, 8, 967–976, doi:10.3762/bjoc.8.109

• chiral binol scaffolds, which incorporate either methoxy or acetoxy functionalities in the 2,2' positions and carboxylic functionalities in the external 3,3' positions, were used as the source of chirality. Two of these binaphthyls are joined through amidation reactions using rigid diaryl amines of

• , we set out to exploit two orthogonal synthetic strategies (Figure 1, bottom): (1) A direct amidation of the carboxylic acids in the 3,3' positions, in the presence of the free phenolic oxygens in the 2,2' positions. Literature precedents for such amidation using aromatic amines in the presence of

• presence of Et3N as the acid scavenger gave compound 5a in excellent yields (93%) after purification by column chromatography (Scheme 1). The yield was higher in our hands than the one previously reported [35]. Alternative one-pot amidation procedures, performed directly with the aromatic carboxylic acid

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• , further confirming the importance of the proposed intramolecular strategy for preparing α-carbolines. Lewis acid catalyzed amidation of 8a with methyl propargyl amine (12) gave the cycloaddition precursor 13a in excellent yield when Al(Me)3 was used as catalyst (Scheme 3, Table 2) [81][82][83][84

• ]. However, the most convenient procedure for library protocols employed 1.2 equiv of Zr(Ot-Bu)4 [85]. Weinreb amidation with Al(Me)3 also gave excellent yields, but required the extra step of first mixing Al(Me)3 and the amine, then cannulating this amine–AlMe3 complex into the triazine solution in order to

• avoid ketonization of the ester [86]. Other Lewis acids, MgCl2, Mg(OTf)2, Zn(OTf)2, Yb(OTf)3 and Sc(OTf)3, were not successful in catalyzing the amidation. Stoichiometric amounts of catalyst were required for the amidation, presumably due to the product itself sequestering the catalyst and preventing

Liquid-crystalline nanoparticles: Hybrid design and mesophase structures

• Gareth L. Nealon,
• Romain Greget,
• Cristina Dominguez,
• Zsuzsanna T. Nagy,
• Daniel Guillon,
• Jean-Louis Gallani and
• Bertrand Donnio

Beilstein J. Org. Chem. 2012, 8, 349–370, doi:10.3762/bjoc.8.39

• the grafting of dendrons 221–3 (Figure 24) to carboxylic acid functionalised Au NPs of diameters 5.9 ± 0.6, 6.8 ± 0.7 and 6.8 ± 0.8 nm through a surface amidation reaction. Interestingly, the hybrids only displayed 2-D hexagonal organisation (TEM) when coated with the second generation dendron 222

Carbamate derivatives and sesquiterpenoids from the South China Sea gorgonian Melitodes squamata

• Li-Si Huang,
• Fei He,
• Hui Huang,
• Xiao-Yong Zhang and
• Shu-Hua Qi

Beilstein J. Org. Chem. 2012, 8, 170–176, doi:10.3762/bjoc.8.18

• were very similar to those of compounds 3–5 [5][6]. Compound 3 is a symmetric urea derivative that was formed from the amidation of two molecules of 4 [6]. Comparison of the NMR data of 1 with 3–5 suggested that 1 was an asymmetric urea derivative that was formed from the amidation of 4 and 5 [5][6

• = 8.0 Hz, 1H). The 1H and 13C NMR spectral data of 2 show similarities to those of 3 [5] (Table 1). Comparison of the NMR data of 2 and 3 suggests that 2 is an asymmetric urea derivative that was formed from the amidation of two molecules of 4 [5][6], and the only difference between 2 and 3 is the

• amidation position of the two molecules of 4. Based on the 1H NMR, 13C NMR HSQC, HMBC and 1H–1H COSY spectral data analysis, the structure of 2 was elucidated to be as shown above and named as obtucarbamate D. Urea derivatives are closely related in structure to carbamates. Urea is synthesized in the body

Hyperbranched polyethylenimine bearing cyclodextrin moieties showing temperature and pH controlled dye release

• Indra Böhm,
• Susanne Katharina Kreth and
• Helmut Ritter

Beilstein J. Org. Chem. 2011, 7, 1130–1134, doi:10.3762/bjoc.7.130

• , Scheme S1). Briefly, compound 3 can be obtained through polymer-analogous amidation with 5-hexynoic acid and subsequent reaction with mono-(6-azido-6-desoxy)-β-cyclodextrin by click reaction under microwave assisted conditions. Synthesis of 1,4-di-N-adamantylaminoanthraquinone (2): 2 was synthesized

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• amino acids or their corresponding commercially available N-hydroxysuccinimide esters. The method involved the in situ formation of selenocarboxylate intermediate of protected amino acids and the subsequent non-nucleophilic amidation with an azide. Common protecting groups used in amino acid/peptide

• -amino-4-methylcoumarin; p-nitroaniline; proteolytic substrate; selenocarboxylate/azide amidation; synthon; Introduction Chromogenic and fluorogenic amino acid/peptide conjugates are widely used as substrates in enzyme assays for protease activity and specificity [1]. Proteolytic cleavage of the amino

• solvent to suppress the potential removal of the Boc protecting group of amino acids. To increase nucleophilicity of the aromatic amino group and hence improve the acylation yield, p-(Boc-amino)aniline was used in place of p-nitroaniline as the starting material for amidation, followed by selective

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

• María Martín-Rodríguez,
• Carmen Nájera,
• José M. Sansano,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2011, 7, 988–996, doi:10.3762/bjoc.7.111

• )-13/AgClO4 complex is also valuable. With the most enantiomerically enriched cycloadduct 5b, the synthesis of the antiviral agent 2a could be accomplished in two conventional steps involving an amidation reaction and a double ester hydrolysis. The latter step consisted of a first stage TFA-mediated

Application of the diastereoselective photodeconjugation of α,β-unsaturated esters to the synthesis of gymnastatin H

• Ludovic Raffier and
• Olivier Piva

Beilstein J. Org. Chem. 2011, 7, 151–155, doi:10.3762/bjoc.7.21

• ) configuration at the C-6 carbon. By saponification under mild conditions, 24 was converted into carboxylic acid 25 which was implicated into a free-epimerising amidation procedure with HOBt [22] and the readily available O-protected tyrosine derivative 26. Finally, the TBS group of the amino ester moiety was

A new and facile synthetic approach to substituted 2-thioxoquinazolin-4-ones by the annulation of a pyrimidine derivative

• Nimalini D. Moirangthem and
• Warjeet S. Laitonjam

Beilstein J. Org. Chem. 2010, 6, 1056–1060, doi:10.3762/bjoc.6.120

• common synthetic route involves the amidation of 2-aminobenzoic acid or its derivatives, i.e., 2-aminobenzonitrile, 2-aminobenzoates, and 2-arylnitrilium salts, followed by oxidative ring closure [10][11][12][13]. Other synthetic pathways include the cyclization of anthranilamides with aldehydes [14