Design and synthesis of a bis-macrocyclic host and guests as building blocks for small molecular knots

• Elizabeth A. Margolis,
• Rebecca J. Keyes,
• Stephen D. Lockey IV and
• Edward E. Fenlon

Beilstein J. Org. Chem. 2020, 16, 2314–2321, doi:10.3762/bjoc.16.192

• bromide in 1-bromo-4-chlorobutane (16) with sodium azide to give azide 17 in 52% yield (Scheme 5). Treatment of 17 with potassium phthalimide and catalytic potassium iodide was followed by hydrazine unmasking to give the desired aminoazide 18 in 37% over the two steps. Reductive amination of 18 with dial

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• ferrocene–sumanene conjugates by employing reductive amination reaction for the formation of compounds 110 and 116. Whereas compounds 111, 113, and 117 were prepared by means of condensation reaction as depicted in Scheme 27. On the other hand, Lentz’s group has reported the synthesis of sumanenylferrocene

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• -methyl-3-buten-1-yl tosylate in the presence of Grubbs’ 2nd generation catalyst yielded 59, which, upon elimination with potassium tert-butoxide led to the diene 50. The reductive amination of 50 afforded an inseparable mixture of the C-14 amines (6:1 ratio). However, the amidation of this mixture with

• produced 46. The hydrozirconation of 46 with Schwartz’s reagent under equilibrating conditions, followed by the reaction with I2 gave the vinyl iodide 47. Finally, the activation of the C-14 hydroxy group and the SN2 displacement with azide gave the C-8–C-16 fragment 48. Ghosh relied on a reductive

• amination of the tetrahydropyranone 50 to generate the (all-cis)-tetrahydropyran fragment. This group reported multiple different routes to 50. In an abortive route, the addition of allyl-Grignard to 5-methylfurfural, followed by the resolution of the racemic homoallylic alcohol with Amano lipase gave

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• hand, Wade et al. reported that ester 138b (R = iPr) afforded the isopropyl 3-fluorophenylalaninate (139b) as racemate in 45–50% yield [70] under similar reaction conditions (Scheme 31). 2.6. Fluorination and reductive amination of phenylpyruvate A direct fluorination of the ester derivatives of

• phenylpyruvic acids 140a,b with F2 followed by hydrolysis of the resulting fluoropyruvates in 50% isopropanol in the presence of NaHCO3 gave 3-fluoro-3-phenylpyruvate 141 in 40–50% yields [68]. The direct reductive amination gave a partially racemized mixture of threo and erythro-136 with the erythro

• stereoisomer 136 as the major product (Scheme 32). The reductive amination of 3-fluoro-3-phenylpyruvic acid (144) obtained by the fluorodehydroxylation of the enol form of ethyl 3-phenylpyruvate 142, using DAST instead of SF4 followed by hydrolysis, produced both threo and erythro-diastereomers of 136 [68

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• acrylate aldehyde 9 in 61% yield. The next step involved the crucial reductive amination reaction between aldehyde 9 with indolamine 10, which had been obtained via Fischer indole synthesis – the reaction of phenylhydrazine with 5-chloro-2-pentanone [35]. Initial reduction attempts using sodium

• final two steps, the reductive amination reaction and the hydroxamic acid preparation. Using the same reaction conditions developed for TOI1, we proceeded with precursors 22 and 23, which were obtained in 61% and 68% yield, respectively. The desired hydroxamic acid TOI2 and TOI3-rev were obtained in 49

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• -position, was also tested since this atom type provides full agonist activity of parent 1d. The synthesis of the compounds 2a–e was performed according to the strategies depicted in Scheme 1. The intermediate 7 was prepared as described previously by us [28] and was used in a reductive amination with 4

• performed following the strategies shown in Scheme 1 as disclosed for compounds 2a–e. Briefly, a reductive amination of 7 and 8b gave nitro compound 9b, which after reduction to 10b, coupling with nitroso compounds 11a–e to 13a–e and methylation gave iodide salts 3a–e with purities of trans-isomers ≥99% and

• was selectively reduced with DIBAL-H to benzyl alcohols 23f–h, which were oxidized with Dess–Martin periodinane to the corresponding benzaldehyde 26f–h. Reductive amination of 26f–h with 7 gave the tertiary amines 13f–h. Methylation with iodomethane and subsequent precipitation gave 3f–h as orange

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• trifluoroacetate 60 by a known electrophilic substitution procedure that was developed by Tahara and co-workers [64]. Curtius rearrangement of 60 gave an isocyanate intermediate, which was reduced with LiAlH4 followed by reductive amination affording tertiary amine intermediate 61. Oxidation of 61 to its

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• inhibitors. When the aziridine-aldehyde (2R,1'R)-6 was subjected to the reductive amination with 4 dipeptides secondary amines 172 (a R' = iBu, R''= sec-Bu; b R' = R'' = iBu; c R' = sec-Bu, R'' = iBu; d R' = R'' = sec-Bu) were produced (Scheme 44) [101]. In the presence of triphosgene a series of imidazolin

• biological activities [106]. (−)-Dihydropinidine (2S,6R)-187a, isosolenopsin (2S,6R)-187b, and isosolenopsins A (2S,6R)-187c and B (2S,6R)-187d were synthesized as hydrochloride salts from the aldehyde (2S,1'R)-6 applying a reductive amination as a key step (Scheme 50) [33]. To this end the aldehyde (2S,1'R

• form a cis-2,6-disubstituted piperidine framework in (2S,3R,6S)-197. N-Methylation of (2S,3R,6S)-197 was accomplished by reductive amination while a selective deprotection provided the hydroxymethyl group in (2S,3R,6S)-198. Swern oxidation, Julia–Kocienski olefination and desilylation gave (−)-(2S,3R

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

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

• -alkylation of the heroin domain via reductive amination. For the remaining drug–haptens, the use of repeated amide bonds naturally led us to employ EDC-mediated coupling to join the heroin and fentanyl domains. For the sake of brevity, detailed synthetic procedures, and structures of all intermediates can be

• found in Supporting Information File 2. Heroin domain syntheses All nine haptens in the series were constructed from one of the three heroin intermediates shown in Figure 3. Haptens to be prepared via reductive amination (HF-1, HF-2, HF-4, Figure 2 yellow background) required the secondary amine form

• tert-butyl ester protected derivative 4 of the commercially available 4-(4-aminophenyl)butanoic acid was accessed via protection and deprotection of the amine with a phthaloyl group (intermediates 2, 3). Reductive amination of 4 with commercially available phenethylpiperidin-4-one furnished

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• by X-ray photoelectron spectroscopy (XPS). This residue was introduced by reductive amination of the DAT scaffold with the respective benzaldehyde derivative. In one compound (60% yield over three steps) the ALA unit is directly bound to the DAT as a relatively electron-withdrawing amide. In solution

• accessed in three steps from diethyl succinate according to Wu et al. [41]. Reductive amination with trifluoromethylated benzaldehyde was accomplished with a mixture of ZnCl2 and NaBH3CN [42] yielding the respective N-benzylated compound 2 in good yield. After subsequent N-Boc-deprotection with TFA

• electronically decoupled by introduction of a propylene spacer. Therefore, we started the synthesis with compound 5 (Scheme 2), which was accessed from compound 1 in two steps by reductive amination with N-Alloc-3-aminopropanal and subsequent N-Boc deprotection as reported recently [44]. Reductive amination with

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

• obtained as a diastereomeric mixture via an Ugi–Nenajdenko reaction using the 4-methyl-2,6,7-trioxabicyclo[2,2,2]octyl (OBO) ester 46 to avoid epimerization of the isocyanide, followed by a reductive amination and chromatographic separation of the isomers; a Passerini–Dömling IMCR led to the heterocyclic

Strong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of cis-2-halocyclohexylamines

• Camila B. Francisco,
• Cleverton S. Fernandes,
• Ulisses Z. de Melo,
• Roberto Rittner,
• Gisele F. Gauze and
• Ernani A. Basso

Beilstein J. Org. Chem. 2019, 15, 818–829, doi:10.3762/bjoc.15.79

• -Chloro- and 2-bromocyclohexanone were synthetized as previously described [38][39], to provide cis-2-chloro (Cl) and cis-2-bromocyclohexylamine (Br), respectively, by a reductive amination [40]. To a sealed tube were added the corresponding ketone (10 mmol), ammonium acetate (100 mmol) and sodium

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• % yield in 17 steps from 16. The pyrrolidine nitrogen was then further derivatized with several small substituents (Scheme 7). Reductive amination with several aldehydes resulted in 3a–c. The N-methyl analogue 3d was synthesized via methylation with MeI. The methanesulfonamide 3e and acetamide 3f, in

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• protected naturally occurring amines such as GABA and phenylethylamine as well as diamines with orthogonal protecting groups, cf. product 2c. The combination of this protocol with the diastereoselective reductive amination reported by Hughes and Devine [41], provides access to very high value chiral α

Rational design of boron-dipyrromethene (BODIPY) reporter dyes for cucurbit[7]uril

• Mohammad A. Alnajjar,
• Jürgen Bartelmeß,
• Robert Hein,
• Pichandi Ashokkumar,
• Mohamed Nilam,
• Werner M. Nau,
• Knut Rurack and
• Andreas Hennig

Beilstein J. Org. Chem. 2018, 14, 1961–1971, doi:10.3762/bjoc.14.171

• synthesized according to a reported literature procedure [32], and then converted into the desired BODIPY anchor dye by reductive amination with the respective aldehyde using sodium triacetoxyborohydride as a mild reducing agent (route B) [36]. 3 was also synthesized by reductive amination by reacting BDP-NH2

A hemicryptophane with a triple-stranded helical structure

• Augustin Long,
• Olivier Perraud,
• Erwann Jeanneau,
• Christophe Aronica,
• Jean-Pierre Dutasta and
• Alexandre Martinez

Beilstein J. Org. Chem. 2018, 14, 1885–1889, doi:10.3762/bjoc.14.162

• . Finally, a [1 + 1] macrocyclization between 4 and 5 was achieved by a reductive amination in a 1:1 CHCl3/MeOH mixture. A remarkable yield of 92% was obtained for this last step. As this kind of reductive amination has been proved to be under thermodynamic control, the resulting intermediate cage bearing

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• α,β-unsaturated aldehyde 71. A series of reductive amination and amidation reactions then led to the formation of the targeted substituted benzo[7]annulene 72 (Scheme 13). Moreover, the structure–activity study revealed that some of the compounds showed nano- to subnanomolar IC50 values on αvβ3 and

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

• to Vasellas' procedure [31][32] – with benzylamine under the reductive amination conditions afforded an inseparable mixture of two products differing in the configuration at the C2 center (12a and 12b; Scheme 2); such a phenomenon – epimerization under these conditions – is known [33]. The

• from the C6’-position gave alcohol 22 in 97% yield. Under the same "Swern oxidation–reductive amination–acetylation" conditions, alcohol 22 was converted into aldehyde 23, which reacted further with amine 18, furnishing diolefin 24 in 64% total yield. Cyclization of precursor 24 induced by the Hoveyda

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• prepare compound 6. It is well known that the direct one-step reductive amination of 6 to give 12 can be accomplished by simple heterogeneous reduction with H2/Raney-nickel [24]. However, THF is employed in all of our prior flow steps and is a poor choice as a solvent for the reductive amination step due

• to limited solubility of ammonia in THF. H2/Raney-nickel reductions are often carried out in alcoholic media where much higher concentrations of ammonia are achievable but would require a solvent exchange. There are many reports of continuous-flow chemistry methods for reductive amination of ketones

•  2, entries 1–6). Optimization of the flow rate with 1 M concentrations of each reactant (Table 2, entries 6–8) showed that a flow rate of 1.0 mL min−1 (tR = 20 min) was optimal, giving an isolated yield of 78% (Table 2, entry 7). The reductive amination of 11 performed in the first generation batch

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

• formed by addition from the less sterically hindered amino group. The free amino group was alkylated by reductive amination on reaction with substituted aldehyde or ketones to provide the corresponding pyrazolo[1,5-a]pyrimidine derivatives 139 (Scheme 39). The pyrazolo[1,5-a]pyrimidine derivatives 139

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• starting aldehyde 2 was subjected to a reductive amination with aminoacetaldehyde dimethyl acetal and NaBH4, followed by N-tosylation and hydrochloric acid-mediated cyclization under concomitant N-detosylation and aromatization. Direct ring metalation of 3 with TMPMgCl∙LiCl was performed as described by us

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• functionalized carbohydrates (Figure 1c). Various types of reaction, such as reductive amination [32], oxime formation [33], amidation [34], and perfluorophenyl azide (PFPA) photocoupling [35][36], have been used to functionalize the surface of AuNPs with carbohydrates. The detailed information regarding the

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• , oxidation of the secondary alcohol with pyridinium dichromate into the corresponding cyclopentanone derivative and subsequent olefination using CBr3F gave the monofluoroalkene 96 with a modest selectivity towards the (Z)-alkene. A Negishi coupling then gave alkene 98. Stereoselective reductive amination

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• propargylamines by nucleophilic addition. The synthesis of propargylamines by diastereoselective reductive amination requires alkynyl ketones, which are difficult to prepare and are unstable towards reductive conditions. In approach I, organometallic nucleophiles are added to N-sulfinyl propargylimines, derived