Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• and di-tert-butyl azodicarboxylate (Scheme 22) [45]. An added benefit to these products is that they possess an intramolecular hydrogen bond acting as a stabilizing factor and products 68 were prepared in good to very good yields and excellent enantiomeric purities. Based on the authors’ design

• the azodicarboxylate as crucial to forming hydrogen bonds with the organocatalyst. Benzylation of this nitrogen or substitution of just one of the carboxylate groups led to no product being observed. A series of naphthylindoles 71 was tested for potential biological activity and showed promising

• azodicarboxylate catalyzed by CPA (R)-C23 provided axially chiral unprotected biaryls (S)-74a–r and axially chiral protected biaryls (R)-75a–r (Scheme 24) [48]. Consistently high enantioselectivities and yields were reported with various binaphthyl and biphenyl substrates. Control experiments revealed the

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• azodicarboxylate reagents. In the attempt to recycle catalyst 28 for the reaction between ethyl 2-oxocyclopentanecarboxylate (25) and di-tert-butyl azodicarboxylate (26) (Scheme 8), a decline in catalytic activity was initially noticed. While this could be attributed to the nucleophilic deactivation of thioureas

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• no products at room temperature (see Table 1) presumably due to the low solubility of Cs2CO3 in dioxane. They also provided a single example of a Mitsunobu reaction utilizing n-pentanol, dibutyl azodicarboxylate (DBAD), and PPh3. Therefore, there is still a great need to develop an operationally

• and mild Mitsunobu conditions for the preparation of N2-substituted indazole analogs 16a–q. By directly reacting compound 6 with alcohols 13a–q (2 equiv), diethyl azodicarboxylate (DEAD, 2 equiv), and triphenylphosphine (TPP, 2 equiv) in THF at 50 °C (conditions B), the corresponding N2-substituted

• under conditions A. Concerning conditions B, we began our calculations under the assumption that MeOPPh3+ was already present in THF at 50 °C. The deprotonation by the dimethyl azodicarboxylate (DMAD) anion (DMAD−) to form 6(N-H) and 17 was found favorable by 14.7 kcal/mol (Figure 6). DFT-calculated

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• -workers, and was accessed over 8 steps from diene 161 (Scheme 17A) [51]. Diels–Alder reaction of diene 161 and di-tert-butyl azodicarboxylate (160) followed by palladium-assisted elimination of acetic acid gave diene 162. A sequence of 4π-electrocyclisation and electrophilic transcarbamation (to 163

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• retention of configuration at C3 [17]. In 2008, a direct dehydroxyazidation of cholesterol by treatment of the steroid with a zinc azide–pyridine complex, diisopropyl azodicarboxylate (DIAD), and PPh3 was described [18]. This Mitsunobu-like reaction occurred with complete inversion at C3 to afford 3α

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• -hydroxybenzimidazole core has several modification sites that allow one to control the properties of the catalyst over a wide range. The authors demonstrated the high efficiency of N-hydroxybenzimidazole catalysts in the benzylic CH-amination with diethyl azodicarboxylate and the CH-fluorination of aldehydes with

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• asymmetric addition reaction of racemic naphthylindole 42 with azodicarboxylate 43 under chiral phosphoric acid catalysis. In the presence of CPA 2, 42 and 43 reacted and underwent dynamic kinetic resolution to afford naphthylindoles 44 with axial chirality in moderate to good yields (50–98%) and high

• afforded products 46 in moderate to good yields (50–97%), excellent diastereoselectivities (>95:5 dr), and high enantioselectivities (91:9 to 98:2 er, Scheme 15). The control experiments showed that the N–H group in naphthylindoles, the OH group in phenol, and the carboxylate group in azodicarboxylate play

• -naphthylamine and azodicarboxylate through a dual hydrogen bond activation mode and a π–π interaction strategy (Scheme 31) [2]. Diarylamines and related scaffolds are among the most common potentially atropisomeric chemotypes in medicinal chemistry. For example, the drugs binimetinib and bosutinib contain

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• mmol) in dry THF (10 mL) was cooled in an ice-water bath, and subsequently, diisopropyl azodicarboxylate (DIAD, 1.21 g, 6.0 mmol) and diphenylphosphoryl azide (DPPA, 1.65 g, 6.0 mmol) were added dropwise under argon atmosphere. The mixture was allowed to reach room temperature and stirred for 20 h. The

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• started to develop extensively only after 2010. The oxidation of β,γ- and γ,δ-unsaturated oximes (103 and 104, respectively) using the TEMPO/DEAD system or only DEAD (diethyl azodicarboxylate) afforded 5-exo-trig radical cyclization [124] with the formation of the corresponding isoxazolines 105 and 106 or

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• ] for a decarboxylative amination of indoline-2-carboxylic acids with azodicarboxylate esters. Another photocatalytic strategy for accessing C(sp3) radicals from carboxylic acids proceeds through a reductive decarboxylation pathway. This approach relies on the conversion of the acid into an easy

Chiral terpene auxiliaries V: Synthesis of new chiral γ-hydroxyphosphine oxides derived from α-pinene

• Anna Kmieciak and
• Marek P. Krzemiński

Beilstein J. Org. Chem. 2019, 15, 2493–2499, doi:10.3762/bjoc.15.242

• chromatography on silica gel. For the purpose of this study, (1R,4R,5R)-apopinenol (16) was subjected to the Mitsunobu reaction to obtain the product with inverted configuration at C4. Alcohol 16 was reacted with diisopropyl azodicarboxylate, triphenylphosphine, and p-nitrobenzoic acid in THF [30]. 1H NMR

Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP)

• Małgorzata Urbańczyk,
• Michał Jewgiński,
• Joanna Krzciuk-Gula,
• Jerzy Góra,
• Rafał Latajka and
• Norbert Sewald

Beilstein J. Org. Chem. 2019, 15, 1581–1591, doi:10.3762/bjoc.15.162

• the resin. After two minutes the diisopropyl azodicarboxylate (DIAD) solution was added dropwise to the reaction mixture. Once the reaction was complete, the o-NBS protecting group was removed by using 2-mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The Kaiser test did not reveal any

• diisopropyl azodicarboxylate (DIAD) in THF was introduced dropwise to the reaction vessel, in order to control exothermic reaction. The reaction was carried out for 2 hours and repeated. The resin was washed with THF and NMP. Finally, the o-NBS protecting group was removed by using 2-mercaptoethanol and 1,8

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

• mmol) and phthalimide (6.60 mmol) were dissolved in THF (40 mL). To this mixture was slowly added a solution of diisopropyl azodicarboxylate (DIAD, 40% in THF) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the reaction mixture was re

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• separate the diastereomers of product 13 by column chromatography. The use of DMEAD (di-2-methoxyethyl azodicarboxylate) [38] was inferior (33%). The PMP protecting group was envisioned to be stable during the following steps and to be selectively cleavable with ceric ammonium nitrate (CAN). Reduction of

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• reagents, mostly triphenylphosphine and a dialkyl azodicarboxylate. This reaction has been frequently used in carbohydrate chemistry for the modification of sugar hydroxy groups. Modification at the anomeric position, leading mainly to anomeric esters or glycosides, is of particular importance in the

• circumstances. Keywords: anomeric stereoselectivity; carbohydrates; glycoside synthesis; Mitsunobu reaction; Introduction Fifty years ago, Oyo Mitsunobu reported a preparation of esters from alcohols and carboxylic acids supported by two auxiliary reagents, diethyl azodicarboxylate (DEAD) and

• triphenylphosphine [1]. This reaction has ever since become known as the “Mitsunobu reaction”, being a frequently utilized tool in organic synthesis. In 1981, Mitsunobu published a first review about this reaction, entitled "The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• intermediate NSA16 generated from allenyl N-siloxysulfonamide 89 in the presence of TBAF and diisopropyl azodicarboxylate. Interestingly, the addition product 90 does not undergo cyclization (Scheme 33). At the same time, reactions of nitrosoallenes of type NSA16 with malodinitrile and ethyl cyanoacetic ester

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

• Bemba Sidi Mohamed,
• Christian Périgaud and
• Christophe Mathé

Beilstein J. Org. Chem. 2017, 13, 251–256, doi:10.3762/bjoc.13.28

• -Boc-adenine or 2-amino-6-chloropurine in the presence of diisopropyl azodicarboxylate (DIAD) and PPh3, provided the N9 carbocyclic nucleosides (+/−)-8 and (+/−)-9 as racemic mixtures. No concomitant formation of the N7 regioisomer was observed. The removal of Boc and acetyl groups from (+/−)-8

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

• Wiesława Perlikowska,
• Remigiusz Żurawiński and
• Marian Mikołajczyk

Beilstein J. Org. Chem. 2016, 12, 2234–2239, doi:10.3762/bjoc.12.215

• rosaprostol methyl esters (−)-9 and (+)-9 in yields higher than 90%. Then the esters 9 were subjected to a Mitsunobu esterification under standard conditions (THF, rt) using p-nitrobenzoic acid (PNBA), triphenylphosphine and diisopropyl azodicarboxylate (DIAD). The p-nitrobenzoic acid esters (+)-10 and (−)-10

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• . 2.2.2 α-Amination reactions. Thiazolones 2 have also been investigated in the α-amination reaction with tert-butyl azodicarboxylate in the presence of the ureidopeptide like catalysts C5 and C8 (Scheme 18) [85]. In these cases better enantioselectivity was observed with catalyst C8, and thiazolones

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• (diethyl azodicarboxylate, 2a) was selected as the model reaction for the evaluation of chiral phosphine catalysts (Table 1). Using bifunctional thiourea catalysts 4a and 4b, the reaction proceeded smoothly at room temperature to afford the product 3a in good yields, albeit with low enantiomeric excesses

• DEAD was obtained at −30 °C (Table 2, entry 13). Interestingly, the use of other azodicarboxylates with larger R group as amination reagent revealed different optimum reaction temperatures for the best enantioselectivity, and −78 °C was identified as optimal for di-tert-butyl azodicarboxylate (2d, DBAD

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

• Guozheng Huang,
• Simon Schramm,
• Jörg Heilmann,
• David Biedermann,
• Vladimír Křen and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 662–669, doi:10.3762/bjoc.12.66

• , triphenylphosphine (Ph3P) and diethyl azodicarboxylate (DEAD) [9], versus addition of diisopropyl azodicarboxylate (DIAD) to the mixture of silibinin, acid and Ph3P [10]. In both cases, the desired C-23 ester was obtained in moderate yields, and we observed a side reaction, which we expected to be a dehydration

• silybins [22]. Putative mechanism of dehydration of flavanonols under Mitsunobu conditions. Synthesis of ester derivatives of silibinin and conversion to hydnocarpin-type compounds. Reaction conditions: a) 7 or benzoic acid, Ph3P, diisopropyl azodicarboxylate (DIAD), THF, 10 °C to rt, 3 h.; b) LiOH·H2O

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• leads to an intermediate α-aminoperoxy structure, which quickly collapses to the oxaziridine 71. Formation of C–X bonds α-functionalisation In two separate reports, Zhou and co-workers demonstrate the use of di-tert-butyl azodicarboxylate 72 (DBAD) in the direct amination of several different substrates

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• Minami Odagi Yoshiharu Yamamoto Kazuo Nagasawa Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city, 184-8588, Tokyo, Japan 10.3762/bjoc.12.22 Abstract An asymmetric α-amination of β-keto esters with azodicarboxylate in the

• expected that guanidine–bisurea bifunctional organocatalyst 1 would be effective in promoting α-amination of β-keto esters as a result of interactions between guanidine and enolate of the β-keto ester, and between urea and azodicarboxylate (Figure 1b). Herein, we describe the catalytic asymmetric α

• -amination of β-keto esters with azodicarboxylates as a nitrogen source in the presence of 1. Results and Discussion The reaction conditions for α-amination of β-keto ester 4a in the presence of diethyl azodicarboxylate (DEAD) were optimized as follows. First, we focused on the catalyst structure (Table 1

Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines A, B and C and taste evaluation

• Marco G. Rigamonti and
• Francesco G. Gatti

Beilstein J. Org. Chem. 2015, 11, 2117–2124, doi:10.3762/bjoc.11.228

• ]. Indeed, the treatment of (–)-isopulegol with diisopropyl azodicarboxylate (DIAD) and p-nitrobenzoic acid in the presence of triphenylphosphine gave the corresponding ester in an almost quantitative yield. The latter was easily purified by crystallization from n-hexane, and then transesterificated with