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Article

Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity

by
Anna Brol
and
Tomasz K. Olszewski
*
Department of Physical and Quantum Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, ul. Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(24), 8849; https://doi.org/10.3390/molecules27248849
Submission received: 18 November 2022 / Revised: 3 December 2022 / Accepted: 5 December 2022 / Published: 13 December 2022
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
Browse Figures
Versions Notes

Abstract

:
Deamination of 1-aminoalkylphosphonic acids in the reaction with HNO2 (generated “in situ” from NaNO2) yields a mixture of substitution products (1-hydroxyalkylphosphonic acids), elimination products (vinylphosphonic acid derivatives), rearrangement and substitution products (2-hydroxylkylphosphonic acids) as well as H3PO4. The variety of formed reaction products suggests that 1-phosphonoalkylium ions may be intermediates in such deamination reactions.

Graphical Abstract

1. Introduction

Organophosphorus compounds are a very interesting class of molecules well known to exist in nature, exhibit very intriguing activity, and have already found broad applications in various sectors of industry, such as in agrochemistry [1], pharmacy [2], catalysis [3], materials [4], as flame retardants [5], or chemical reagents [6]. Particular interest is devoted to substituted 1-aminoalkylphosphonic acids that can be considered structural analogs of natural 2-aminoalkanoic acids [7,8,9]. In that regard, the use of 1-aminoalkylphosphonic acids in drug discovery has proven successful in many cases, with prominent examples being potential drugs for the treatment of diabetes [10,11], asthma [12], inflammation [13], heart failure [14], cancer [15], malaria [16], and HIV [17]. Due to the importance of the 1-aminoalkylphosphonic acids, several synthetic methods for their preparation have been designed over the years [18,19,20,21,22,23,24,25,26].
Surprisingly, further transformations of 1-aminoalkylphosphonic acids and their reactivity as reaction substrates in organic synthesis are scarcely described in the literature [27,28,29,30,31,32,33]. Those described include among others alkaline deacylation of 1-(acylamino)alkylphosphonic acids, ref. [31] oxidative dephosphorylation of 1-aminoalkylphosphonic acids [32], oxidation of 1-(N,N-dialkylamino)-alkylphosphonic acids leading to corresponding N,N-dialkyl-N-oxide derivatives [30], or recently effective preparation of 1-aminoalkylphosphonic acid quaternary ammonium salts from simple 1-aminoalkylphosphonic acid [27]. On the other hand, the use of analogous 2-aminoalkanoic acids as substrates, particularly in diazotization reaction, is a well-known methodology that yields 2-hydroxyalkanoic acids or 2-chloroalkanoic acids (Scheme 1a) [34,35,36,37], useful building blocks in medicinal chemistry [38,39,40], total synthesis of natural products [41,42,43], and polymer chemistry [44,45,46]. Inspired by the activity and utility of 2-amino acids in diazotization reactions we decided to study the reactivity of 1-aminoalkylphosphonic acids in deamination by the diazotization reaction (Scheme 1d). It is well known that the amine group reacts with nitrous acid (HNO2) generated by the acidification of aqueous solutions of sodium nitrite (NaNO2) with a mineral acid to yield diazonium salts, followed by reaction with various nucleophiles [47]. However, aliphatic diazonium salts are commonly unstable, and the formation of carbenium ion intermediate is inevitable, which causes complications with controlling the selectivity of such reaction [47,48].
While the deamination of 2-aminoalkanoic acids as substrates has been described in a great number of articles, reactions of structurally similar 1-aminoalkylphosphonic acids are scarcely described in the literature. In 1950 [49] and 1954 [50], Kabachnik and Medved described the analytical applications of the deamination reaction of aminomethylphosphonic acid and 1-amino-1-phenylethylphosphonic acid with nitrous oxides in which hydroxymethylphosphonic acid and 1-hydroxy-1-phenylethylphosphonic acids were formed respectively (Scheme 1b). Much later, reactions of related aminoalkylidene-1,1-diphosphonic acids with nitrous acid were described by Blum and Worms [51,52,53]. The authors concluded that carbenium ions with two phosphonic groups are formed and the reaction products are hydroxyalkylidene-1,1-diphosphonic acids, chloroalkylidene-1,1-diphosphonic acids, and derivatives of vinylphosphonic acid (Scheme 1c). It is worth mentioning that 1-phosphonoalkylium ions 9, which may be intermediates in the deamination reaction of 1-aminoalkylphosphonic acids 1, have also not been extensively studied in the literature. Only theoretical calculations for the simplest phosphonomethylium ion (9h) (which exist in the cyclic form 10h) have been described by Pasto (Scheme 2a) [54]. On the other hand, Creary et al. studied the formation of carbenium ions substituted with phosphonic ester group 11 in the solvolysis reactions of mesylates 12 [55,56,57,58]. Experiments on the α-deuterium isotope effect proved that intermediates have an open form 11 and that no cyclic compounds 13 are formed (Scheme 2b). Intrigued by the very scarce literature reports on the deamination of 1-aminoalkylphosphonic acids, and interested in revealing the reactivity of the 1-phosphonoalkylium ions, possible intermediates in deamination of 1-aminoalkylphosphonic acids, we decided to study this interesting reaction in greater detail (Scheme 1d).
Herein we present the results of our detailed study on the deamination reaction of structurally diverse 1-aminoalkylphosphonic acids carried out with nitrous acid. The presented results show the potential application of this transformation in organic synthesis and shed light on the possible reaction mechanism and reaction intermediates.

2. Results

For our study, we selected a representative and structurally diverse palette of 1-aminoalkylphosphonic acids (Figure 1, 17 examples). The selected examples include phosphorus analogs of such amino acids as alanine 1a, valine 1b, leucine 1d, glycine 1h, phenylalanine 1g, and phenylglycine 1f.

2.1. Diazotization of 2-Aminoalkanoic Acids vs. 1-Aminoalkylphosphonic Acids—Preliminary Experiments

We started our preliminary experiments using the conditions applied for the diazotization of 2-aminoalkanoic acids (NaNO2, 5M HCl) (Scheme 3) [59]. Preliminary experiments clearly showed that 1-aminoalkylphosphonic acids reacted with nitrous acid (HNO2), generated in situ from sodium nitrite (NaNO2), differently than the tested amino acids. The degree of conversion in the case of 1-aminoalkylphosphonic was slightly higher than in the case of classical amino acids. No other products than the ones depicted on Scheme 3 were observed and they were additionally accompanied by unreacted starting material. Under the examined conditions, no selectivity towards chloride ions was observed and 1-hydroxyalkylphosphonic acids were the main reaction products.
Moreover, in the case of amino acids 2, as expected, the main reaction products were 1-hydroxy or 1-chloroalkanoic acids, while in the case of 1-aminoalkylphosphonic 1 a greater number of reaction products, including rearrangement and fragmentation products, were observed (Scheme 3).
Due to the complex composition of post-reaction mixtures, we decided to modify the original reaction conditions used for the diazotization of amino acids. Expecting to obtain complex reaction mixtures, we wanted to focus first on generating the carbenium ions and then observe their reactivity with just a limited number of nucleophiles to simplify the analysis of the results. Based on the literature data describing the diazotization of amino acids, we envisaged that the most important parameter is the initial pH of the reaction mixture [60,61,62,63]. Lowering the pH should increase the concentration of the electrophilic nitrosating agent, but at the same time causes the protonation of the amino group in the starting 1-aminoalkylphosphonic acids, which lowers the nucleophile concentration. Additionally, we have assumed that 1-aminoalkylphosphonic acids are strong enough acids to generate the nitrosating agent in situ from sodium nitrite in water, therefore there is no need to use hydrochloric acid in the reaction. After this simplification, the only nucleophiles in the reaction mixture were nitrite ions and water.

2.2. Diazotization of 1-Aminoalkylphosphonic Acids—Optimized Reaction Conditions

When 1-aminoalkylphosphonic acid 1 (1 equiv.) was added to the solution of NaNO2 (2 equiv.), nitrogen evolution was observed, which proved that diazonium salts 8 were generated. The post-reaction mixtures contained products of substitution reaction (1-hydroxyalkylphosphonic acids 5), elimination reaction (vinylphosphonic acid derivatives 7), and additionally 2-hydroxyalkylphosphonic acids 5′ and phosphoric acid (H3PO4).
We have observed that the product distribution in these reactions depended strongly on the structure of the starting 1-aminoalkylphosphonic acid 1, therefore the reaction results are outlined in Table 1, Table 2, Table 3 and Table 4, according to the structure of the substrates used.
To avoid the formation of secondary products, the crude post-reaction mixtures were analyzed directly by NMR spectroscopy without isolation of the reaction products, and thus the results are given in the form of conversion. In all cases, the structures of reaction products were confirmed by NMR spectroscopy (especially 31P NMR and 1H NMR) by the addition of known reference compounds (synthesized separately) or by analysis and comparison of the NMR spectra of the crude reaction mixture with spectra of products known from the literature (see Supplementary Materials for more details).
Substitution was generally the main reaction for most of the investigated 1-aminoalkylphosphonic acids 1 (Table 1 and Table 2), especially for those that do not have protons in the β-position (1f, 1n, 1h). For example, in the reaction of amino(phenyl)methylphosphonic acid (1f) the conversion of substrate to hydroxy(phenyl)phosphonic acid (5f) was 97% (Table 2, entry 1).
In turn, elimination was the major reaction for 1-aminoalkylphosphonic acids 1q, 1l, and 1i which have bulky substituents (Table 3). For substrates 1l and 1i, two isomers of vinylphosphonic acid derivatives were formed: 7l, 7′l for 1l and 7i, 7′i for 1i. We assume that in this case the steric hindrance impedes the access of nucleophiles and, as a result, the elimination reaction is favored.
Furthermore, for substrates 1j, 1b, and 1k that have β-position migrating groups, the major reaction product was phosphoric acid (H3PO4), accompanied by various amounts of substitution products 5 and rearrangement products 5′.
While direct substitution on the diazonium group in 1-phosphonoalkenediazonium salts 8 cannot be excluded (Scheme 4a), the complex composition of the post-reaction mixtures suggests that 1-phosphonoaklylium ions 9 may be intermediates in the diazotization reaction of 1-aminoalkylphosphonic acids 1. This assumption is supported by the fact that all typical products of carbenium ion reactions, especially rearrangement products 5′, were observed simultaneously in the crude post-reaction mixtures (Scheme 4b). It has to be mentioned that the accepted mechanism of deamination of analogous aliphatic 2-aminoalkanoic acids assumes the presence of α-lactones as reaction intermediates (Scheme 1a). As postulated, their formation is the reason for the high enantioselectivity of these reactions. By analogy, in the reaction of 1-aminoalkylphosphonic acids similar cyclic intermediates, namely 2-hydroxy-2-oxa-1,2-oxaphosphiranes 10, could also be postulated (Scheme 4c). However, there is no experimental information about intermediate 10 described thus far in the literature. In addition, our results indicate that the formation of 10 is unlikely. For example, the reaction products of 3-amino-3-phosphonopropanoic acid (1e) with nitrous acid may be explained by the assumption that 1-phosphonoalkylium ion 9e is formed (Scheme 5). The 3-hydroxy-3-phosphonopropanoic acid (5e) is formed in the reaction of nucleophile (water) addition to 1-phosphonoalkylium ion 9e, while (E)-3-phosphonoacrylic acid (7e) is formed as the result of proton elimination from 9e. Carbenium ion 9e also undergoes fragmentation and as a result, vinylphosphonic acid (7a) and carbon dioxide are formed.
An interesting example illustrating the complexity of the deamination reaction of 1-aminoalkylphosphonic acid 1 is the reaction of 1-amino-2-phenylethylphosphonic acid (1g) with HNO2 (Scheme 6). Among the expected products of substitution 5g, elimination 7g, and phosphoric acid, in the post-reaction mixture, the rearranged 2-hydroxy-1-phenylethylphosphonic acid (5″g) was identified. Considering the formation of carbenium ion 9g we expected the rearrangement of this carbenium ion to 9′g, which should be more stable due to the stabilizing effect of the phenyl group. Subsequent addition of nucleophile (H2O) to both carbenium ions should lead to the corresponding hydroxyalkylphosphonic acids 5g and 5′g respectively (Scheme 6). However, analysis of the NMR spectra of the crude reaction mixture revealed that the second product of the reaction is not the 5′g but 5″g (see Supplementary Materials for more details).
Formation of 2-hydroxy-1-phenylphosphonic acid (5″g), as well as unrearranged 5g and phosphoric acid may be explained by the formation of cyclic intermediate 9″g (Scheme 6a). The nucleophilic attack of water on the less crowded side (pink arrow on Scheme 6a) of intermediate 9″g yields rearranged 2-hydroxyalkylphosphonic acid 5″g, while fragmentation of 9″g (Scheme 6b) yields styrene and metaphosphoric acid which hydrolyses to phosphoric acid. Finally, when examining the reactivity of 1-aminoalkylphosphonic acids 1 in a deamination reaction with HNO2, in every reaction we have always observed the presence of various amounts of phosphoric acid (H3PO4). We postulate that the formation of H3PO4 could be explained by two reaction mechanisms which depend on the structure of the used 1-aminoalkylphosphonic acids 1 (Scheme 7 and Scheme 8). According to the first reaction mechanism (Scheme 7a), if the structure of the formed 1-phosphonoalkylium ion 9 enables its rearrangement to the more stable 2-phosphonoalkylium ion 9′ (compounds 1j, 1b, 1k, 1g), then ion 9′ can further undergo fragmentation with cleavage of the C–P bond resulting in the formation of alkene and metaphosphoric acid (that undergo hydrolysis to phosphoric acid in the presence of water). A similar mechanism was proposed by Mastalerz and Richtarski for the deamination of 2-aminoethylphosphonic acid and related compounds, where the main reaction products were ethylene and phosphoric acid (Scheme 7b) [64,65,66].
The second reaction mechanism should explain the formation of H3PO4 in the case where there is no possibility of rearrangement of the formed carbenium ion 9 (Scheme 8), especially for the reaction of substrates 1a, 1f, 1n, and 1h. By analogy to reactions of 2-aminoalkanoic acids with HNO2 [67], the reaction of 1-phosphonoalkylium ion 9 with biphilic nitrite ion (NO2-) gives 1-nitroalkylphosphonic acid 14 (Scheme 8a) or nitrite ester of 1-hydroxyalkylphosphonic acids 15 (Scheme 8b). Compounds 14 and 15 may undergo secondary reactions which ultimately produce phosphoric acid.

3. Materials and Methods

3.1. General Information

The 1H, 13C{1H}, 31P NMR, and DEPT-135 spectra were collected on a Jeol 400yh instrument (Jeol, Ltd., Tokio, Japan) (400 MHz for 1H NMR, 162 MHz for 31P NMR, and 100 MHz for 13C NMR) and were processed with dedicated software (Delta 5.0.5). NMR experiments recorded in D2O were referenced to the respective residual 1H signal of the solvent. Multiplicities were reported using the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). The reported coupling constants (J) values were those observed from the splitting patterns in the spectrum and may not reflect the true coupling constant values. The composition of post-reaction mixtures (as the conversion of substrate to the given product) was calculated based on 31P NMR (recorded in D2O) of the crude reaction mixture. Structural assignments of 5″g were made with additional information from gCOSY, gHSQC, and gHMBC experiments.

3.2. Reagents

Aminomethylphosphonic acid (1h) was obtained in the reaction of benzamide, formaldehyde, and phosphorous trichloride [68]. 3-Amino-3-phosphonopropanoic acid (1e) was synthesized from diethyl acetamidomethylenemalonate [69]. The remaining 1-aminoalkylphosphonic acids 1 were obtained in the reaction of an appropriate carbonyl compound with acetamide, acetyl chloride, and PCl3 in acetic acid, using Soroka’s protocol [70]. 1-Hydroxyalkylphosphonic acids 5, which were used as reference materials for confirmation of reaction products structures, were synthesized by dealkylation of diethyl 1-hydroxyalkylphosphonates, which were obtained in the reaction of triethyl phosphite with suitable aldehyde or ketone and hydrogen chloride [71].

3.3. Deamination of 1-Aminoalkylphosphonic Acids 1 and 2-Aminoalkanoic Acids 2 in 5M HCl

The deamination experiments were conducted in a three-necked flask equipped with a reflux condenser, thermometer, dropping funnel, and magnetic stirrer, as described in the original protocol [40]. The solution of 1-aminoalkylphosphonic acid 1 or 2-aminoalkanoic acid 2 (10 mmol) in 5M HCl (65 mmol, 13 mL) was cooled in an ice/NaCl cooling bath to a temperature of −12 °C. Subsequently, 4 M NaNO2 solution in water (16 mmol, 4.0 mL) was added dropwise for 2 min. The temperature of the reaction mixture was maintained under 0 °C for 5 h, and then at 25 °C for 12 h. The samples for 1H and 31P NMR spectra were prepared by diluting post-reaction mixtures (0.10 mL) in D2O (0.40 mL). The samples were re-measured after the addition of reference materials. The composition of the mixture was calculated based on the integration of signals on the 31P NMR spectra (for phosphorous substrates) or on the 1H NMR spectra (for 2-aminoalkanoic acids).

3.4. Deamination of 1-Aminoalkylphosphonic Acids 1 in Water

The deamination reactions of 1-aminoalkylphosphonic acids 1 were conducted in a round-bottom flask equipped with a magnetic stirrer and calibrated gas burette (Figure S11 in Supplementary Materials). The flask was placed in a water bath at a temperature of about 20 °C. 1-Aminoalkylphosphonic acid 1 (3.0 mmol) was added to a 0.67 M solution of NaNO2 (6.0 mmol, 9.0 mL). The solution or suspension was stirred by the means of a magnetic stirrer until the stoichiometric volume of gas was evolved, and additionally for 12 h. The 1H and 31P NMR spectra were recorded after that time and additionally after a few days. The composition of the mixture was calculated based on the integration of signals on the 31P NMR spectra.

4. Conclusions

We have studied the deamination of 17 1-aminoalkylphosphonic acids 1 in the reaction with nitrous acid. We have postulated that 1-phosphonoalkylium ions 9 are plausible reactive intermediates in these reactions. Depending on the structure of 1-aminoalkylphosphonic acid 1 used, these ions 9 react with a nucleophile (H2O or NO2¯), undergo elimination of protons, or a rearrangement/fragmentation reaction (Scheme 9). Furthermore, we explained the formation of the phosphoric acid (H3PO4), present in every reaction mixture, through two mechanisms (Scheme 6 and Scheme 7). We have experimentally demonstrated that the selectivity of the reaction of 1-phosphonoalkylium ions 9 is not easy to control but, in some cases, the addition of nucleophile (H2O) is the major reaction and the starting 1-aminoalkylphosphonic acids 1 could be transformed into 1-hydroxyphosphonic acids 5 (Scheme 9). In turn, the derivatives of vinylphosphonic acid 7 resulting from proton elimination from 1-phosphonoalkylium ions 9 (Scheme 9) could be major products in the case of 1-aminoalkylphosphonic acids having a positive charge positioned at the tertiary carbon atom and surrounded by bulky substituents, such as compounds 1q, 1l, and 1i (Scheme 9, Table 3). Finally, if the generated 1-phosphonoalkylium ions 9 have migrating groups in the β-position, such as in compounds 9j, 9b, 9k, and 9g, they can further rearrange to more stable 2-phosphonoalkylium ions 9′ and either react with a nucleophile to form 2-hydroxyalkylphosphonic acid 5′ or undergo fragmentation to alkene and H3PO4 (Scheme 9, Table 4). Although the reported procedure of the deamination of 1-aminoalkylphosphonic 1 generally may have limited synthetic application, in specific cases, it may be an irreplaceable synthetic method leading to the desired products.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27248849/s1, The material includes detailed procedures and NMR spectra for all reactions and compounds [72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88].

Author Contributions

Conceptualization, AB. and T.K.O.; methodology, A.B.; formal analysis, A.B. and T.K.O.; investigation, A.B.; writing—original draft preparation, A.B. and T.K.O.; writing—review and editing, A.B. and T.K.O.; supervision, T.K.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhou, C.; Luo, X.; Chen, N.; Zhang, L.; Gao, J. C–P natural products as next-generation herbicides: Chemistry and biology of glufosinate. J. Agric. Food Chem. 2020, 68, 3344–3353. [Google Scholar] [CrossRef] [PubMed]
  2. Demmer, C.S.; Krogsgaard-Larsen, N.; Bunch, L. Review on modern advances of chemical methods for the introduction of a phosphonic acid group. Chem. Rev. 2011, 111, 7981–8006. [Google Scholar] [CrossRef] [PubMed]
  3. Guo, H.; Fan, Y.C.; Sun, Z.; Wu, Y.; Kwon, O. Phosphine organocatalysis. Chem. Rev. 2018, 118, 10049–10293. [Google Scholar] [CrossRef] [PubMed]
  4. Wehbi, M.; Mehdi, A.; Negrell, C.; David, G.; Alaaeddine, A.; Ameduri, B. Phosphorus-containing fluoropolymers: State of the art and applications. ACS Appl. Mater. Interfaces 2020, 12, 38–59. [Google Scholar] [CrossRef] [PubMed]
  5. Wendels, S.; Chavez, T.; Bonnet, M.; Salmeia, K.A.; Gaan, S. Recent developments in organophosphorus flame retardants containing P-C bond and their applications. Materials 2017, 10, 784. [Google Scholar] [CrossRef] [Green Version]
  6. Cabre, A.; Riera, A.; Verdaguer, X. P-Stereogenic amino-phosphines as chiral ligands: From privileged intermediates to asymmetric catalysis. Acc. Chem. Res. 2020, 53, 676–689. [Google Scholar] [CrossRef]
  7. Abdou, M.M. Synopsis of recent synthetic methods and biological applications of phosphinic acid derivatives. Tetrahedron 2020, 76, 131251. [Google Scholar] [CrossRef]
  8. Rodriguez, J.B.; Gallo-Rodriguez, C. The role of the phosphorus atom in drug design. ChemMedChem 2019, 14, 190–216. [Google Scholar] [CrossRef] [Green Version]
  9. Sevrain, C.M.; Berchel, M.; Couthon, H.; Jaffres, P.-A. Phosphonic acid: Preparation and applications. Beilstein J. Org. Chem. 2017, 13, 2186–2213. [Google Scholar] [CrossRef]
  10. Combs, A.P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 2010, 53, 2333–2344. [Google Scholar] [CrossRef]
  11. Dang, Q.; Kasibhatla, S.R.; Xiao, W.; Liu, Y.; DaRe, J.; Taplin, F.; Reddy, K.R.; Scarlato, G.R.; Gibson, T.; van Poelje, P.D.; et al. Fructose-1, 6-bisphosphatase inhibitors. 2. Design, synthesis, and structure—Activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5′-adenosinemonophosphate (AMP) mimics. Med. Chem. 2010, 53, 441–451. [Google Scholar] [CrossRef] [PubMed]
  12. Maryanoff, B.E. Inhibitors of serine proteases as potential therapeutic agents: The road from thrombin to tryptase to cathepsin G. J. Med. Chem. 2004, 47, 769–787. [Google Scholar] [CrossRef] [PubMed]
  13. Lassaux, P.; Hamel, M.; Gulea, M.; Delbruck, H.; Mercuri, P.S.; Horsfall, L.; Dehareng, D.; Kupper, M.; Frere, J.-M.; Hoffmann, K.; et al. Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases. J. Med. Chem. 2010, 53, 4862–4876. [Google Scholar] [CrossRef] [PubMed]
  14. Kumar, T.S.; Zhou, S.-Y.; Joshi, B.V.; Balasubramanian, R.; Yang, T.; Liang, B.T.; Jacobson, K.A. Structure−activity relationship of (N)-methanocarba phosphonate analogues of 5′-AMP as cardioprotective agents acting through a cardiac P2X receptor. J. Med. Chem. 2010, 53, 2562–2576. [Google Scholar] [CrossRef] [Green Version]
  15. Kang, S.-U.; Shi, Z.-D.; Worthy, K.M.; Bindu, L.K.; Dharmawardana, P.G.; Choyke, S.J.; Bottaro, D.P.; Fisher, R.J.; Burke, T.R., Jr. Examination of Phosphoryl-Mimicking Functionalities within a Macrocyclic Grb2 SH2 Domain-Binding Platform. J. Med. Chem. 2005, 48, 3945–3948. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Haemers, T.; Wiesner, J.; Van Poecke, S.; Goeman, J.; Henschker, D.; Beck, E.; Jomaa, H.; Van Calenbergh, S. Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 1888–1891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Robbins, B.L.; Srinivas, R.V.; Kim, C.; Bischofberger, N.; Fridland, A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob. Agents Chemother. 1998, 42, 612–617. [Google Scholar] [CrossRef] [Green Version]
  18. Maestro, A.; del Corte, X.; López-Francés, A.; Martínez de Marigorta, E.; Palacios, F.; Vicario, J. Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives. Molecules 2021, 26, 3202. [Google Scholar] [CrossRef]
  19. Varga, P.; Keglevich, G. Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction. Molecules 2021, 26, 2511. [Google Scholar] [CrossRef]
  20. Keglevich, G. Microwaves as “Co-Catalysts” or as Substitute for Catalysts in Organophosphorus Chemistry. Molecules 2021, 26, 1196. [Google Scholar] [CrossRef]
  21. Rádai, Z.; Keglevich, G. Synthesis and Reactions of α-Hydroxyphosphonates. Molecules 2018, 23, 1493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Keglevich, G.; Bálint, E. The Kabachnik–Fields Reaction: Mechanism and Synthetic Use. Molecules 2012, 17, 12821–12835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Chen, L.; Liu, X.-Y.; Zou, Y.-X. Recent Advances in the Construction of Phosphorus-Substituted Heterocycles, 2009–2019. Adv. Synth. Catal. 2020, 362, 1724–1818. [Google Scholar] [CrossRef]
  24. Maestro, A.; Martinez de Marigorta, E.; Palacios, F.; Vicario, J. α-Iminophosphonates: Useful Intermediates for Enantioselective Synthesis of α-Aminophosphonates. Asian J. Org. Chem. 2020, 9, 538–548. [Google Scholar] [CrossRef]
  25. Chen, L. Recent Advances in the Catalytic Asymmetric Construction of Phosphorus-Substituted Quaternary Carbon Stereocenters. Synthesis 2018, 50, 440–469. [Google Scholar] [CrossRef]
  26. Ordonez, M.; Viveros-Ceballos, J.L.; Cativiela, C.; Sayago, F.J. An update on the stereoselective synthesis of α-aminophosphonic acids and derivatives. Tetrahedron 2015, 71, 1745–1784. [Google Scholar] [CrossRef]
  27. Brol, A.; Olszewski, T.K. Synthesis and stability of 1-aminoalkylphosphonic acid quaternary ammonium salts. Org. Biomol. Chem. 2021, 19, 6422–6430. [Google Scholar] [CrossRef]
  28. Acha, A.; Zineb, A.; Hacene, K.; Yasmine, C.; Racha, G.; Rachida, Z.; Nour-Eddine, A. Recent advances in the synthesis of α-aminophosphonates: A review. Chem. Select 2021, 6, 6137–6149. [Google Scholar]
  29. Kudzin, M.H.; Drabowicz, J.; Jordan, F.; Kudzin, Z.H.; Urbaniak, P. Reactivity of aminophosphonic acids. 2. Stability in solutions of acids and bases. Phosphorus Sulfur Silicon Relat. Elem. 2019, 194, 326–328. [Google Scholar] [CrossRef]
  30. Kudzin, M.H.; Drabowicz, J.; Jordan, F.; Kudzin, Z.H.; Urbaniak, P. Reactivity of aminophosphonic acids. 3. Reaction with hydrogen peroxide. Phosphorus Sulfur Silicon Relat. Elem. 2019, 194, 297–299. [Google Scholar] [CrossRef]
  31. Cypryk, M.; Drabowicz, J.; Gostynski, B.; Kudzin, M.H.; Kudzin, Z.H.; Urbaniak, P. 1-(Acylamino)alkylphosphonic acids-alkaline deacylation. Molecules 2018, 23, 859. [Google Scholar] [CrossRef] [PubMed]
  32. Drabowicz, J.; Jordan, F.; Kudzin, M.H.; Kudzin, Z.H.; Stevens, C.V.; Urbaniak, P. Reactivity of aminophosphonic acids. Oxidative dephosphonylation of 1-aminoalkylphosphonic acids by aqueous halogens. Dalton Trans. 2016, 45, 2308–2317. [Google Scholar] [CrossRef] [PubMed]
  33. Kudzin, Z.H.; Kudzin, M.H.; Drabowicz, J.; Stevens, C.V. Aminophosphonic acids—phosphorus analogues of natural amino acids. Part 1: Syntheses of α-aminophosphonic acids. Curr. Org. Chem. 2011, 15, 2015–2071. [Google Scholar] [CrossRef]
  34. Mear, S.J.; Jamison, T.F. Diazotization of S-sulfonyl-cysteines. J. Org. Chem. 2019, 84, 15001–15007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Hu, D.X.; O’Brien, M.; Ley, S.V. Continuous multiple liquid-liquid separation: Diazotization of amino acids in flow. Org. Lett. 2012, 14, 4246–4249. [Google Scholar] [CrossRef] [PubMed]
  36. Stuhr-Hansen, N.; Padrah, S.; Strømgaard, K. Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids. Tetrahedron Lett. 2014, 55, 4149–4151. [Google Scholar] [CrossRef]
  37. Deechongkit, S.; You, S.-L.; Kelly, J.W. Synthesis of all nineteen appropriately protected chiral α-hydroxy acid equivalents of the α-amino acids for Boc-Solid-Phase Depsi-peptide Synthesis. Org. Lett. 2004, 6, 497–500. [Google Scholar] [CrossRef]
  38. Humber, D.C.; Jones, M.F.; Payne, J.J.; Ramsay, M.V.J.; Zacharie, B.; Jin, H.; Siddiqui, A.; Evans, C.A.; Tse, H.L.A.; Mansour, T.S. Expeditious preparation of (−)-2′-deoxy-3′-thiacytidine. Tetrahedron Lett. 1992, 33, 4625–4628. [Google Scholar] [CrossRef]
  39. Biel, M.; Deck, P.; Giannis, A.; Waldmann, H. Synthesis and evaluation of acyl protein thioesterase 1 (APTI) inhibitors. Chem.-Eur. J. 2006, 12, 4121–4143. [Google Scholar] [CrossRef]
  40. Raza, A.R.; Saddiqa, A.; Çakmak, O. Chiral pool-based synthesis of naptho-fused isocoumarins. Chirality 2015, 27, 951–957. [Google Scholar] [CrossRef]
  41. Hu, D.X.; Bielitza, M.; Koos, P.; Ley, S.V.A. Total synthesis of the ammonium ionophore, (−)-enniatin B. Tetrahedron Lett. 2012, 53, 4077–4079. [Google Scholar] [CrossRef]
  42. Lücke, D.; Dalton, T.; Ley, S.V.; Wilson, Z.E. Synthesis of natural and unnatural cyclooligomeric depsipeptides enabled by flow chemistry. Chem. -Eur. J. 2016, 22, 4206–4217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Matthes, D.; Richter, L.; Müller, J.; Denisiuk, A.; Feifel, S.C.; Xu, Y.; Espinosa-Artiles, P.; Sussmuth, R.D.; Molnar, I. In vitro chemoenzymatic and in vivo biocatalytic synthesis of new beauvericin analogues. Chem. Commun. 2012, 48, 5674–5676. [Google Scholar] [CrossRef] [Green Version]
  44. Sokolsky-Papkov, M.; Agashi, K.; Olaye, A.; Shakesheff, K.; Domb, A.J. Polymer carriers for drug delivery in tissue engineering. Adv. Drug Deliv. Rev. 2007, 59, 187–206. [Google Scholar] [CrossRef] [PubMed]
  45. Rasal, R.M.; Janorkar, A.V.; Hirt, D.E. Poly(lactic acid) modifications. Prog. Polym. Sci. 2010, 35, 338–356. [Google Scholar] [CrossRef]
  46. Lu, Y.; Yin, L.; Zhang, Y.; Zhang, Z.; Xu, Y.; Tong, R.; Cheng, J. Synthesis of water-soluble poly(α-hydroxy acids) from living ring opening polymerization of O-benzyl-L-serine carboxyanhydrides. ACS Macro Lett. 2012, 1, 441–444. [Google Scholar] [CrossRef] [Green Version]
  47. Cupido, T.; Spengler, J.; Burger, K.; Albericio, F. NO as temporary guanidino-protecting group provides efficient access to Pbf-protected argininic acid. Tetrahedron Lett. 2005, 46, 6733–6735. [Google Scholar] [CrossRef]
  48. Shin, I.; Lee, M.-T.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. Synthesis of optically active phthaloyl D-aminooxy acids from L-amino acids or l-hydroxy acids as building blocks for the preparation of aminooxy peptides. J. Org. Chem. 2000, 65, 7667–7675. [Google Scholar] [CrossRef]
  49. Kabachnik, M.I.; Medved, T.Y. Organophosphorus compounds. XIV. Synthesis of aminophosphonic acids. Izv. Akad. Nauk. SSSR Seriya Khimicheskaya 1950, 635–640. [Google Scholar]
  50. Medved, T.Y.; Kabachnik, M.I. New method of synthesis of aminophosphonic acids. II. Reaction of ketones with dialkyl phosphites and ammonia. Izv. Akad. Nauk. SSSR 1954, 314–322. [Google Scholar]
  51. Blum, H.; Worms, K.H. (1-Hydroxyalkylidene)diphosphonic Acids. Patent DE 2165833, 4 September 1980. [Google Scholar]
  52. Blum, H.; Worms, K.H. Arylchloromethanediphosphonic Acids. Patent DE 2601644, 5 January 1984. [Google Scholar]
  53. Worms, K.H.; Blum, H. Reactions of 1-aminoalkane-1,1-diphosphonic acids with nitrous acid. Z. Fuer Anorg. Und Allg. Chem. 1979, 457, 209–213. [Google Scholar] [CrossRef]
  54. Pasto, D.J. A theoretical analysis of the interaction of the phosphonate and sulfonyl groups with a carbocationic center. J. Org. Chem. 1985, 50, 1014–1018. [Google Scholar] [CrossRef]
  55. Creary, X. Electronegatively substituted carbocations. Chem. Rev. 1991, 91, 1625–1678. [Google Scholar] [CrossRef]
  56. Creary, X. Carbocationic and related processes in reactions of α-keto mesylates and triflates. Acc. Chem. Res. 1985, 18, 3–8. [Google Scholar] [CrossRef]
  57. Creary, X.; Geiger, C.C.; Hilton, K. Mesylate derivatives of α-hydroxy phosphonates. Formation of carbocations adjacent to the diethyl phosphonate group. J. Am. Chem. Soc. 1983, 105, 2851–2858. [Google Scholar] [CrossRef]
  58. Creary, X.; Underiner, T.L. Underiner Stabilization demands of diethyl phosphonate substituted carbocations as revealed by substituent effects. J. Org. Chem. 1985, 50, 2165–2170. [Google Scholar] [CrossRef]
  59. Koppenhoefer, B.; Schuring, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-2-amino acids: (S)-2-Chloropropanoic acid. Org. Synth. 1988, 66, 151. [Google Scholar] [CrossRef]
  60. del Pilar Garcıa-Santos, M.; Gonzalez-Mancebo, S.; Hernandez-Benito, J.; Calle, E.; Casado, J. Reactivity of amino acids in nitrosation reactions and its relation to the alkylating potential of their products. J. Am. Chem. Soc. 2002, 124, 2177–2182. [Google Scholar] [CrossRef]
  61. Weston, T.; Taylor, J. The action of nitrous acid on amino-compounds. Part II. Aliphatic amino-acids. J. Chem. Soc. 1928, 1897–1906. [Google Scholar] [CrossRef]
  62. Erlenmeyer, E.; Lipp, A. Synthesis of tyrosine. Justus Liebigs Ann. Chem. 1883, 219, 161–178. [Google Scholar] [CrossRef] [Green Version]
  63. Kowalik, J.; Zygmunt, J.; Mastalerz, P. Determination of absolute configuration of optically active 1-aminoalkanephosphonic acids by chemical correlations. Phosphorus Sulfur Relat. Elem. 1983, 18, 393–396. [Google Scholar] [CrossRef]
  64. Mastalerz, P.; Richtarski, G. Ethylene formation by fragmentation of 2-aminoethylphosphonic and 2- aminoethylphenylphosphinic acid. Rocz. Chem. 1971, 45, 763–768. [Google Scholar]
  65. Richtarski, G.; Mastalerz, P. Deamination and rearrangement of (1-phenyl-1-hydroxy-2- aminoethyl)phosphonic acid. Tetrahedron Lett. 1973, 5, 4069–4070. [Google Scholar] [CrossRef]
  66. Richtarski, G.; Soroka, M.; Mastalerz, P.; Starzemska, H. Deamination and rearrangement of 1-hydroxy-1- phenyl-2-aminoethylphosphonic acid. Rocz. Chem. 1975, 49, 2001–2005. [Google Scholar] [CrossRef]
  67. Austin, A.T. Deamination of amino acids by nitrous acid with particular reference to glycine. The chemistry underlying the Van Slyke determination of α-amino acids. J. Chem. Soc. 1950, 149–157. [Google Scholar] [CrossRef]
  68. Soroka, M. Comments on the synthesis of aminomethylphosphonic acid. Synthesis 1989, 7, 547–548. [Google Scholar] [CrossRef]
  69. Soroka, M.; Mastalerz, P. The synthesis of phosphonic and phosphinic analogs of aspartic acid and asparagine. Rocz. Chem. 1976, 50, 661–666. [Google Scholar]
  70. Soroka, M. The synthesis of 1-aminoalkylphosphonic acids. A revised mechanism of the reaction of phosphorus trichloride, amides and aldehydes or ketones in acetic acid (Oleksyszyn reaction). Liebigs Ann. Chem. 1990, 1990, 331–334. [Google Scholar] [CrossRef]
  71. Goldeman, W.; Soroka, M. The preparation of dialkyl 1-hydroxyalkylphosphonates in the reaction of trialkyl phosphites with oxonium salts derived from aldehydes or ketones. Synthesis 2006, 2006, 3019–3024. [Google Scholar] [CrossRef]
  72. Baltser, A.E.; Zaitsev, D.A.; Ivanova, T.V.; Babenko, T.G.; Barskova, E.N. Addition of morpholine and pyrrolidine to isopropenylphosphonic acid in situ. Russ. J. Org. Chem. 2013, 49, 627–628. [Google Scholar] [CrossRef]
  73. Blazis, V.J.; Koeller, K.J.; Spilling, C.D. Reactions of Chiral Phosphorous Acid Diamides: The Asymmetric Synthesis of Chiral α-Hydroxy Phosphonamides, Phosphonates, and Phosphonic Acids. J. Org. Chem. 1995, 60, 931–940. [Google Scholar] [CrossRef]
  74. Zhou, S.; Pan, J.; Davis, K.M.; Schaperdoth, I.; Wang, B.; Boal, A.K.; Krebs, C.; Bollinger, J.M. Steric enforcement of cis-epoxide formation in the radical C–O-coupling reaction by which (S)-2-hydroxypropyl-phosphonate epoxidase (HppE) produces Fosfomycin. J. Am. Chem. Soc. 2019, 141, 20397–20406. [Google Scholar] [CrossRef] [PubMed]
  75. Hudson, H.R.; Ismail, F.; Pianka, M.; Wan, C.-W. The formation of α-amino- and α-hydroxyalkanephosphonic acids in the reactions of phosphite esters with aldehydes and alkyl carbamates. Phosphorus Sulfur Silicon Relat. Elem. 2000, 164, 245–257. [Google Scholar] [CrossRef]
  76. Oehler, E.; Kanzler, S. Synthesis of phosphonic acids related to the antibiotic fosmidomycin from allylic α- and γ-hydroxyphosphonates. Phosphorus Sulfur Silicon Relat. Elem. 1996, 112, 71–90. [Google Scholar] [CrossRef]
  77. Quast, H.; Heuschmann, M. Three-membered heterocycles. 12. Synthesis of a phosphirane oxide. Liebigs Ann. Der Chem. 1981, 5, 977–992. [Google Scholar] [CrossRef]
  78. Kenyon, G.L.; Westheimer, F.H. Stereochemistry of unsaturated phosphonic acids. J. Am. Chem. Soc. 1966, 88, 3557–3561. [Google Scholar] [CrossRef]
  79. Prishchenko, A.A.; Livantsov, M.V.; Novikova, O.P.; Livantsova, L.I.; Petrosyan, V.S. Synthesis of new functionalized aryl-substituted methylphosphonic and methylenediphosphonic acids and their derivatives. Heteroat. Chem. 2016, 27, 381–388. [Google Scholar] [CrossRef]
  80. Rueppel, M.L.; Marvel, J.T. Proton and phosphorus-31P NMR spectra of substituted methylphosphonic acids with indirect determination of phosphorus-31P shifts. Org. Magn. Reson. 1976, 8, 19–20. [Google Scholar] [CrossRef]
  81. Yan, F.; Moon, S.-J.; Liu, P.; Zhao, Z.; Lipscomb, J.D.; Liu, A.; Liu, H.-W. Determination of the Substrate Binding Mode to the Active Site Iron of (S)-2-Hydroxypropylphosphonic Acid Epoxidase Using 17O-Enriched Substrates and Substrate Analogues. Biochemistry 2007, 46, 12628–12638. [Google Scholar] [CrossRef] [Green Version]
  82. Chen, R.; Breuer, E. Direct Approach to α-Hydroxyphosphonic and α,ω-Dihydroxyalkane-α,ω-bisphosphonic Acids by the Reduction of (Bis)acylphosphonic Acids. J. Org. Chem. 1998, 63, 5107–5109. [Google Scholar] [CrossRef]
  83. Saha, U.; Helvig, C.F.; Petkovich, P.M. Phosphate Management with Small Molecules. U.S. Patent US 9198923; (Granted 2015-12.01),
  84. De Macedo Puyau, P.; Perie, J.J. Synthesis Of Substrate Analogues And Inhibitors For The Phosphoglycerate Mutase Enzyme. Phosphorus Sulfur Silicon Relat. Elem. 1997, 129, 13–45. [Google Scholar] [CrossRef]
  85. Sainz-Diaz, C.I.; Galvez-Ruano, E.; Hernandez-Laguna, A.; Bellanato, J. Synthesis, Molecular Structure, and Spectroscopical Properties of Alkenylphosphonic Derivatives. 1. Vinyl-, Propenyl-, (Bromoalkenyl)-, and (Cyanoalkenyl)phosphonic Compounds. J. Org. Chem. 1995, 60, 74–83. [Google Scholar] [CrossRef]
  86. Fitch, S.J.; Moedritzer, K. Nuclear magnetic resonance study of the P-C(OH)-P to P-CO-P rearrangement: Tetraethyl-1-hydroxyalkylidenediphosphonates. J. Am. Chem. Soc. 1962, 84, 1876–1879. [Google Scholar] [CrossRef]
  87. Chang, W.-C.; Mansoorabadi, S.O.; Liu, H.-W. Reaction of HppE with Substrate Analogues: Evidence for Carbon-Phosphorus Bond Cleavage by a Carbocation Rearrangement. J. Am. Chem. Soc. 2013, 135, 8153–8156. [Google Scholar] [CrossRef] [Green Version]
  88. Liu, P.; Murakami, K.; Seki, T.; He, X.; Yeung, S.M.; Kuzuyama, T.; Seto, H.; Liu, H.W. Protein Purification and Function Assignment of the Epoxidase Catalyzing the Formation of Fosfomycin. J. Am. Chem. Soc. 2001, 123, 4619–4620. [Google Scholar] [CrossRef] [PubMed]
Molecules 27 08849 sch001 550
Scheme 1. General presentation of deamination reaction carried out on 2-aminoalkanoic acids and their phosphorus analogs [34,35,36,37,49,50,51,52,53].
Scheme 1. General presentation of deamination reaction carried out on 2-aminoalkanoic acids and their phosphorus analogs [34,35,36,37,49,50,51,52,53].
Molecules 27 08849 sch001
Molecules 27 08849 sch002 550
Scheme 2. Possible structures of the 1-phosphonoalkylium ions known from the literature [54,55,56,57,58].
Scheme 2. Possible structures of the 1-phosphonoalkylium ions known from the literature [54,55,56,57,58].
Molecules 27 08849 sch002
Molecules 27 08849 g001 550
Figure 1. Structures of 1-aminoalkylphosphonic acids used in this study.
Figure 1. Structures of 1-aminoalkylphosphonic acids used in this study.
Molecules 27 08849 g001
Molecules 27 08849 sch003 550
Scheme 3. Preliminary experiments on the diazotization of alanine (2a) and valine (2b) and their corresponding phosphorus analogs 1a and 1b.
Scheme 3. Preliminary experiments on the diazotization of alanine (2a) and valine (2b) and their corresponding phosphorus analogs 1a and 1b.
Molecules 27 08849 sch003
Molecules 27 08849 sch004 550
Scheme 4. Possible mechanism of the reaction of 1-aminoalkylphosphonic acids 1 with HNO2.
Scheme 4. Possible mechanism of the reaction of 1-aminoalkylphosphonic acids 1 with HNO2.
Molecules 27 08849 sch004
Molecules 27 08849 sch005 550
Scheme 5. Deamination reaction of 3-amino-3-phosphonopropanoic acid (1e) with HNO2.
Scheme 5. Deamination reaction of 3-amino-3-phosphonopropanoic acid (1e) with HNO2.
Molecules 27 08849 sch005
Molecules 27 08849 sch006 550
Scheme 6. (a) Deamination of 1-amino-2-phenylethylphosphonic acid (1g) with HNO2 and analysis of the reaction products. (b) Mechanism of phosphoric acid formation from cyclic intermediate 9″g.
Scheme 6. (a) Deamination of 1-amino-2-phenylethylphosphonic acid (1g) with HNO2 and analysis of the reaction products. (b) Mechanism of phosphoric acid formation from cyclic intermediate 9″g.
Molecules 27 08849 sch006
Molecules 27 08849 sch007 550
Scheme 7. Mechanism of H3PO4 formation in rearrangement and fragmentation reaction [64,65,66].
Scheme 7. Mechanism of H3PO4 formation in rearrangement and fragmentation reaction [64,65,66].
Molecules 27 08849 sch007
Molecules 27 08849 sch008 550
Scheme 8. Proposed mechanisms of H3PO4 formation in the reactions of 1-phosphonoalkylium ion with nitrite ion.
Scheme 8. Proposed mechanisms of H3PO4 formation in the reactions of 1-phosphonoalkylium ion with nitrite ion.
Molecules 27 08849 sch008
Molecules 27 08849 sch009 550
Scheme 9. Possible transformations of 1-phosphonoalkylium ions 9 discussed in this study.
Scheme 9. Possible transformations of 1-phosphonoalkylium ions 9 discussed in this study.
Molecules 27 08849 sch009
Table
Table 1. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that are stabilized by substituents in 1-position or those that cannot rearrange a.
Table 1. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that are stabilized by substituents in 1-position or those that cannot rearrange a.
Molecules 27 08849 i001
Entry SubstrateR1R1Conversion of 1 to 5 bConversion of 1 to 7 bConversion of 1 to H3PO4 b
1 Molecules 27 08849 i002HPhMolecules 27 08849 i003-2%
2Molecules 27 08849 i004PhMeMolecules 27 08849 i005Molecules 27 08849 i0063%
3Molecules 27 08849 i007HMeMolecules 27 08849 i008Molecules 27 08849 i0092%
4Molecules 27 08849 i010HHMolecules 27 08849 i011Molecules 27 08849 i01210%
5Molecules 27 08849 i013MeHMolecules 27 08849 i014Molecules 27 08849 i01526%
6Molecules 27 08849 i016iPrHMolecules 27 08849 i017Molecules 27 08849 i01827%
7Molecules 27 08849 i019COOHHMolecules 27 08849 i020Molecules 27 08849 i0214%
a Reaction conditions: 1-aminoalkylphosphonic acid (1.0 mmol), NaNO2 (2.0 mmol), evolution of N2 occurs, 21 °C, and NMR analysis of crude reaction mixture; b Conversions calculated based on 31P NMR (recorded in D2O) of the crude reaction mixture.
Table
Table 2. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that do not have protons in the β-position a.
Table 2. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that do not have protons in the β-position a.
Molecules 27 08849 i022
Entry SubstrateRConversion of 1 to 5 bConversion of 1 to H3PO4 b
1 Molecules 27 08849 i023PhMolecules 27 08849 i0243%
2Molecules 27 08849 i0254-MeOPhMolecules 27 08849 i02625%
3Molecules 27 08849 i027HMolecules 27 08849 i0289%
a Reaction conditions: 1-aminoalkylphosphonic acid (1.0 mmol), NaNO2 (2.0 mmol), evolution of N2 occurs, 21 °C, and NMR analysis of crude reaction mixture; b Conversions calculated based on 31P NMR (recorded in D2O) of the crude reaction mixture.
Table
Table 3. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 having sterically hindered tertiary carbon atom a.
Table 3. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 having sterically hindered tertiary carbon atom a.
Molecules 27 08849 i029
Entry SubstrateR1R1Conversion of 1 to 5 bConversion of 1 to 7 bConversion of 1 to H3PO4 b
1 Molecules 27 08849 i030C3H6Molecules 27 08849 i031 7%
2Molecules 27 08849 i032iPrHMolecules 27 08849 i033Molecules 27 08849 i034Molecules 27 08849 i0357%
3Molecules 27 08849 i036MeHMolecules 27 08849 i037Molecules 27 08849 i038Molecules 27 08849 i0398%
a Reaction conditions: 1-aminoalkylphosphonic acid (1.0 mmol), NaNO2 (2.0 mmol), evolution of N2 occurs, 21 °C, and NMR analysis of crude reaction mixture; b Conversions calculated based on 31P NMR (recorded in D2O) of the crude reaction mixture.
Table
Table 4. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that have a migrating group in the β-position a.
Table 4. Reaction of HNO2 with 1-aminoalkylphosphonic acids 1 that have a migrating group in the β-position a.
Molecules 27 08849 i040
Entry SubstrateR1R1Conversion of 1 to 5 bConversion of 1 to 7 bConversion of 1 to 5′ bConversion of 1 to H3PO4 b
1 Molecules 27 08849 i041MeHMolecules 27 08849 i042-Molecules 27 08849 i04386%
2Molecules 27 08849 i044HHMolecules 27 08849 i045-Molecules 27 08849 i04659%
3Molecules 27 08849 i047HMeMolecules 27 08849 i048Molecules 27 08849 i049Molecules 27 08849 i05040%
a Reaction conditions: 1-aminoalkylphosphonic acid (1.0 mmol), NaNO2 (2.0 mmol), evolution of N2 occurs, 21 °C, and NMR analysis of crude reaction mixture; b Conversions calculated based on 31P NMR (recorded in D2O) of the crude reaction mixture.
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Brol, A.; Olszewski, T.K. Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity. Molecules 2022, 27, 8849. https://doi.org/10.3390/molecules27248849

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Brol A, Olszewski TK. Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity. Molecules. 2022; 27(24):8849. https://doi.org/10.3390/molecules27248849

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Brol, Anna, and Tomasz K. Olszewski. 2022. "Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity" Molecules 27, no. 24: 8849. https://doi.org/10.3390/molecules27248849

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Brol, A., & Olszewski, T. K. (2022). Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity. Molecules, 27(24), 8849. https://doi.org/10.3390/molecules27248849

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