The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• efforts and investments in the research and development of new membranes that might be able to surpass the actual limitations. Our studies started with the synthesis of phosphonate and phosphonic acid compounds to be used as membrane dopants [24][25]. These studies were followed by the incorporation of

• of phosphonic acid derivatives into commercial Nafion polymers increment their proton conduction properties. The synthesized compounds (TP1–TP6) were attempted to be applied as dopants in the preparation of new proton exchange membranes. With this in mind, new doped membranes were prepared by

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• )butyl)phosphonic acid (28) in 45% yield as a byproduct, which was generated from the Pd-catalyzed arylmethylic cleavage under hydrogenolysis conditions (Scheme 5) [22]. To avoid the formation of the acyclic byproduct, the same research group designed a new inhibitor with a reverse phosphonate bond

An alternative C–P cross-coupling route for the synthesis of novel V-shaped aryldiphosphonic acids

• Stephen J. I. Shearan,
• Enrico Andreoli and
• Marco Taddei

Beilstein J. Org. Chem. 2022, 18, 1518–1523, doi:10.3762/bjoc.18.160

• commercially available and can often be difficult to prepare. Most often, the challenge is, in fact, not the synthesis of the phosphonic acid itself, but that of the phosphonic ester precursor [21]. Perhaps the most well-known C–P coupling procedure is the Michaelis–Arbuzov rearrangement involving a reaction

• hydrolysis using the method put forward by McKenna et al. (1977), which involves the use of trimethylbromosilane (TMSiBr) in a transesterification of the dialkyl phosphonate to bis(trimethylsilyl) phosphonate, followed by treatment in water or short-chain alcohols to obtain a phosphonic acid, as shown in

• method employing TMSiBr, which most often led to achieve overall yields above 70% for the phosphonic acid, based on the initial Br-substrate. Conclusion Presented in this article is the synthesis of three novel phosphonate esters and their corresponding phosphonic acids. While the phosphonic acids are

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• , Ali’s group performed the reaction of (E)-2-cyano-N'-((4-oxo-4H-chromen-3-yl)methylene)acetohydrazide (220) and phosphonic acid in the presence of 4-toluenesulfonic acid in dioxane, affording (E)-2,3-dihydroxy-1-(((4-oxo-4H-chromen-3-yl)methylene)amino)-1-hydro-1,2-azaphosphol-5-one 2-oxide (223) in 38

• -fused 1,2-azaphospholine 2-oxides from 2-azidoquinoline-3-carbaldehydes and tris(dimethylamino)phosphine. Synthesis of 1-hydro-1,2-azaphosphol-5-one 2-oxide from cyanoacetohydrazide with phosphonic acid and phosphorus tribromide. Synthesis of chromene-fused 5-oxo-1,2-azaphospolidine 2-oxides. Synthesis

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• desired triazole derivatives were not obtained. Furthermore, the hydrolysis of the dialkyl ester groups were performed with TMSI [29][30], and phosphonic acid 10 was obtained. The latter was inert to the SNAr reaction with NaN3 at C2 (Scheme 4). SNAr–Arbuzov reaction between 2,6-bistriazolylpurines and P

• purinylphosphonates 4. Synthesis of phosphonates 2, 7, and 8. Synthesis of phosphonic acid monoesters 3 and 7–9 as well as phosphonic acid 10. Synthesis of 2,6-bistriazolylpurine derivatives 6a–i. SNAr–Arbuzov reaction between the bistriazolylpurines 6a–i and P(OEt)3. Synthesis of 2,6-bistriazolylpurines 6a–i (5→6a–i

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• Micromonospora [5]. Dipeptide analogs with phosphonoproline 2 and piperidine-2-phosphonic acid 3 are potent inhibitors of dipeptidyl peptidase IV [6][7]. Oxygen-containing heterocycles containing a phosphoryl group are also of interest in the development of new drugs. It is known that phosphorylated carbohydrate

The McKenna reaction – avoiding side reactions in phosphonate deprotection

• Katarzyna Justyna,
• Joanna Małolepsza,
• Damian Kusy,
• Waldemar Maniukiewicz and
• Katarzyna M. Błażewska

Beilstein J. Org. Chem. 2020, 16, 1436–1446, doi:10.3762/bjoc.16.119

• subjected an equimolar mixture of the easily available propargylamide 10 [22] and triethyl phosphonoacetate (8a) to BTMS (Scheme 2). Besides the target product of the McKenna reaction, phosphonic acid 14a, we also isolated a mixture of three compounds 15–17, derived from propargylamide 10, the compound

• products of the McKenna reaction was not the topic of this investigation, and most model substrates that were used in the study did not contain organophosphorus ester/acid. If required (compounds 20 and 21), the product was purified by HPLC. Additionally, the free phosphonic acid could be easily removed

Copper-catalyzed O-alkenylation of phosphonates

• Nuria Vázquez-Galiñanes,
• Mariña Andón-Rodríguez,
• Patricia Gómez-Roibás and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2020, 16, 611–615, doi:10.3762/bjoc.16.56

• counterparts has received less attention. Current methodologies for the synthesis of acyclic mixed enol phosphonates include the Perkow-type reaction between phosphonites and α-halocarbonyl compounds [11], the mercury-catalyzed addition of phosphonic acid monoesters to terminal alkynes [12][13] and multistep

• procedures involving a Mitsunobu reaction between 2-hydroxyalkyl phenyl selenides and phosphonic acid monoesters followed by an oxidation/elimination step [14] or reaction of an enolate with a phosphonic dichloride and subsequent treatment with an alcohol [15] (Scheme 1a). However, these procedures are

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• was also isolated in 16% yield, which was readily separable from 6 by column chromatography. The synthesis of 20 has been reported only once before and the resulting phosphonic acid also possesses antiviral activity [54]. The authors report that 20 was prepared in four steps while our three step route

• whether a similar strategy could be exploited to access adefovir dipivoxil (2) directly. Although we were able to successfully prepare novel phosphonate 33 via phosphonic acid 31, subsequent attempts at converting 33 to the corresponding iodide 34, or alkylation of salt 21 were unsuccessful and hence we

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• exhibited the best result. Aza-Diels–Alder and epoxide ring-opening reaction Manoury et al. have very recently reported facile synthesis of an enantiomerically pure inherently chiral calix[4]arene phosphonic acid (cR,pR)-121 from the readily available (cS)-enantiomer of calix[4]arene acetic acid 119 or its

• ). The corresponding tetrahydropyridine derivatives 124 were obtained in good to excellent yields but the enantioselectivity remained moderate. Calixarene phosphonic acid (cR,pR)-121 was also tested in the asymmetric ring opening of several cyclic meso epoxides 125 with benzoic acid (Scheme 41). Good

• . Chiral AlIII–calixarene complexes bearing distally positioned chiral substituents. Asymmetric MPV reduction in the presence of chiral calix[4]arene diphosphites. Synthesis of enantiomerically pure inherently chiral calix[4]arene phosphonic acid. Asymmetric aza-Diels–Alder reactions catalyzed by (cR,pR

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• Charlotte M. Sevrain Mathieu Berchel Helene Couthon Paul-Alain Jaffres CEMCA UMR CNRS 6521, Université de Brest, IBSAM. 6 Avenue Victor Le Gorgeu, 29238 Brest, France 10.3762/bjoc.13.219 Abstract The phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three

• that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional

• the best methods to prepare phosphonic acids. Keywords: bromotrimethylsilane; hydrolysis; McKenna’s reaction; phosphonate; phosphonic acid; Review 1. Introduction Phosphonic acid is a functional group featuring two hydroxy moieties, one P=O double bond and one P–C bond. This functional group was

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• /v/v). Then, the reaction was stopped by adding triethylammonium bicarbonate buffer (TEAB 1 M, pH 7) and concentrated to dryness under high vacuum. Column chromatography of the crude materials on reverse phase (gradient: water to methanol 100%) gave the expected phosphonic acid (as triethylammonium

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• biologically active scaffolds as well as some industrial compounds [1][2][3]. On the other hand, phosphonic acid and its related derivatives are considered as potential bioisosters of the corresponding carboxylic acids [4]. Thus, the incorporation of phosphonyl groups into the heterocyclic systems has led to

• -oxazolopiperidines 52 with 58% yield and 79:21 dr. Further reduction and hydrogenolysis of 52 in the presence of Pd/C led to aminoester 53 which was converted to (S)-piperidin-2-phosphonic acid (54) through acidic hydrolysis and subsequent treatment with propylene oxide in 42% overall yield and 58% ee (Scheme 13

• reaction followed by an intramolecular ring-closing reaction for the synthesis of diethyl (2-methyl-2-pyrrolidinyl)phosphonate. Synthesis of (S)-piperidin-2-phosphonic acid through an asymmetric Kabachnik–Fields reaction. A modified diastereoselective Kabachnik–Fields reaction for the synthesis of

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene–derived aminophosphonates

• Jarosław Lewkowski,
• Maria Rodriguez Moya,
• Anna Wrona-Piotrowicz,
• Janusz Zakrzewski,
• Renata Kontek and
• Gabriela Gajek

Beilstein J. Org. Chem. 2016, 12, 1229–1235, doi:10.3762/bjoc.12.117

• derivatives, e.g., amino(pyrene-1-yl)methyl phosphonic acid derivatives have been described only twice in the chemical literature. Firstly, Harry Hudson’s team [8] published the synthesis of diethyl N-benzhydrylamino(pyrene-1-yl)methylphosphonate in a series of N-benzhydryl substituted aminomethyl

Friedel–Crafts-type reaction of pyrene with diethyl 1-(isothiocyanato)alkylphosphonates. Efficient synthesis of highly fluorescent diethyl 1-(pyrene-1-carboxamido)alkylphosphonates and 1-(pyrene-1-carboxamido)methylphosphonic acid

• Anna Wrona-Piotrowicz,
• Janusz Zakrzewski,
• Anna Gajda,
• Tadeusz Gajda,
• Anna Makal,
• Arnaud Brosseau and
• Rémi Métivier

Beilstein J. Org. Chem. 2015, 11, 2451–2458, doi:10.3762/bjoc.11.266

• amide groups. The synthesized phosphonic acid was soluble in a biological aqueous buffer (PBS, 0.01 M, pH 7.35) and was strongly emissive under these conditions (λem = 383, 400 nm, τ = 18.7 ns, ΦF > 0.98). Solid-state emission of diethyl 1-(pyrene-1-carboxamido)methylphosphonate (λmax = 485 nm; ΦF

• synthesize and unstable [29]. Moreover, in our recent work we observed that reaction of pyrene with isothiocyanates proceeds more efficiently than an analogous reaction with isocyanates [7]. Additionally, compound 3a was transformed, using a standard procedure [30], to the corresponding phosphonic acid 4

• -carboxamides. Solid-state emission assigned to the aggregates was also observed. Finally, a pyrenecarboxamide phosphonic acid was synthesized, showing very efficient emission in a biological buffer and promising possible biological applications. Structure of amide 5. Normalized electronic absorption (a) and

Pyrrolidine nucleotide analogs with a tunable conformation

• Lenka Poštová Slavětínská,
• Dominik Rejman and
• Radek Pohl

Beilstein J. Org. Chem. 2014, 10, 1967–1980, doi:10.3762/bjoc.10.205

• of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle. Keywords: conformation; NMR; nucleic acids; nucleotide analog; phosphonic acid; pseudorotation; pyrrolidine; Introduction Nucleotides

• fundamental differences in the NMR spectra of phosphonomethyl and phosphonoformyl derivatives, which will be commented on in detail in the following paragraphs. NMR study of phosphonomethyl derivatives Phosphonomethyl derivatives 7–10 contain both basic (pyrrolidine) and acidic (phosphonic acid

• ), exist at a very low pD value (<3) as free phosphonic acids with a deuterated pyrrolidine nitrogen atom (Figure 6). The phosphonic acid moiety goes through a two-stage deuteration/dedeuteration transition at pD ~ 3 and 5 and the pyrrolidine nitrogen atom stays deuterated until pD ~ 9. This suggests that

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• phosphonamides: (A) Arbuzov reaction, (B) condensation of diamines with phosphonic acid dichlorides, (C) nucleophilic displacement, and (D) alkylation of 2-oxo-1,3,2-diazaphospholidine (Scheme 9). All of these methods were employed to prepare the phosphonamide reagents used in the synthesis of the natural

• exist as a single pair of enantiomers. An example for the synthesis of a complex phosphonamide by the Arbuzov reaction can be found in the total synthesis of estrone (12) [44], as discussed later in this review. Phosphonamides by condensation of diamines with phosphonic acid dichlorides The most

• commonly applied method for the synthesis of simple phosphonamides is the condensation of phosphonic acid dichlorides with a diamine. Thus, treatment of acid dichloride 62 with (R,R)-N,N’-dimethyl-1,2-diaminocyclohexane (58) afforded cyclopropanation reagent 47a [28][51]. The required phosphonic acid

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• City, Iowa 52242-1294, USA 10.3762/bjoc.10.171 Abstract A set of bisphosphonate ethers has been prepared through sequential phosphonylation and alkylation of monophosphonate ethers. After formation of the corresponding phosphonic acid salts, these compounds were tested for their ability to inhibit the

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• transcarbamoylase (ATCase). 5-Membered 26 was completely inactive, whereas 6-membered 29 showed modest activity (Ki = 1 μM, 63 times less active than phosphonic acid N-phosphonacetyl-L-aspartate PALA, Ki = 16 nM). 1,3-Azaphosphorines and 1,3-azaphospholidines Several 1,3-azaphosphorines and 1,3-azaphospholidines

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• formaldehyde, forming (α-hydroxymethyl)phosphinate 8. Its further irreversible rearrangement [28] to the corresponding phosphonate 9 was accompanied with hydrolysis of the ester function and formation of (trifluoromethyl)phosphonic acid (10) [29] as the main product. Analogous results were obtained, when CHF2

• . This resulted in the preparation of the analogues of glycine 14a and phenylglycine 14b (Scheme 3). The three-component reaction with formaldehyde gave the best results and N-protected aminophosphinic acid 13a was isolated in a moderate yield, alongside phosphonic acid 10. The analogous reaction with

• 24 in satisfactory yields (Scheme 5). Attempts to convert ester 23 to the free acid failed. Removal of the ester group from 23 by acidolysis with HCl or HI was accompanied by cleavage of the P–C bond to give only (trifluoromethyl)phosphonic acid (10) after an ion-exchange chromatography. Attempts to

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• et al. reported the syntheses of an α-halodiazomethyl phosphonic acid dimethyl ester and an α-halodiazomethyl diphenyl phosphoxide, starting from the silver salts of the respective diazo compounds [10]. More recently, two novel protocols for the halogenation of diazoesters and -phosphonates have been

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

• stage was now set for a two-step modification of the phosphonate moiety. Reaction of 8 with lithium azide in hot DMF, under conditions developed for the monodealkylation of phosphonic acid dialkyl esters of nucleosides [19], provided the novel monoethyl ester 9 in 87% yield following purification by a