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Org. Synth. 2024, 100, 295-308
DOI: 10.15227/orgsyn.101.0295
Discussion Addendum for: Palladium-Catalyzed Dehydrative Allylation of Hypophosphorous Acid with Allylic Alcohols. Preparation of Cinnamyl-H-Phosphinic acid
Karla Bravo-Altamirano and Jean-Luc Montchamp*1
Original Article: Org. Synth. 2008, 85, 96
Discussion
A review on the dehydrative functionalization of various phosphorus species with alcohols was published in 2019.2 Various methods exist for the preparation of allylic H-phosphinates, including allylation of a hypophosphorous acid (H3PO2) equivalent with allylic halides.3 However, this approach is not atom-economical, requires a base, and the yields are generally moderate. In 2006, we introduced the palladium-catalyzed direct dehydrative allylation of hypophosphorous acid with allylic alcohols,4 on which was based the 2008 Organic Syntheses article.5 Also in 2008 was published a full paper, which dealt in part with this reaction.6 A great feature of the original reaction is since the product is an acid, a simple extractive work-up can be employed to give products of generally high purity. However, in many instances the H-phosphinate ester product may be more desirable for subsequent reactions. Whereas the Dean-Stark esterification of H-phosphinic acids proceeds well,7 it is limited in terms of the ester moiety and is less convenient on small scales. On the other hand, we showed that H-phosphinic acids can be esterified with alkoxysilanes.8 Thus, direct treatment of the crude allylation reaction mixtures in DMF with tetrabutoxysilane for 10-16 h at 85 ℃ gave the corresponding butyl esters, which were isolated by chromatography over silica gel in good to excellent yields. Nonetheless, the yields of the allylation/esterification sequence6 are a little lower than with the direct extraction.5 In the simplest case of allyl alcohol, a 43% yield of allyl H-phosphinic acid was isolated after extractive work-up. This is likely due to the more difficult handling and lower hydrolytic stability of the more polar, low molecular weight product. In this case, DBU-promoted alkylation of alkyl phosphinates with allyl bromide was superior.3g
The 2008 full paper also examined the mechanism of the reaction and the related allylation with allylic acetates, benzoates, and carbonates.6 It is interesting to note that these substrates performed well, and that DMF could be substituted with CH3CN.
In this addendum to our original article, we summarize recent extensions in the scope of the methodology, which include replacing hypophosphorous acid with H-phosphinic acids and their esters, using allylic amines or benzylic alcohols instead of allylic alcohols. Some synthetic applications are also included.
Extension to the Synthesis of Disubstituted Phosphinic Acids
The Pd-catalyzed allylation of hypophosphorous acid (H3PO2) with allylic alcohols4,5,6 was subsequently extended to the less reactive H-phosphinic acids (RPO2H2) as shown in Scheme 1.10 The reactivity of phosphinylidene compounds R1R2P(=O)H correlates with the ease of - or rather the less difficult - tautomerization to R1R2P-OH, and this can be experimentally determined by measuring the rate of deuteration of R1R2P(=O)H into R1R2P(=O)D.10
Reactivity/rate of tautomerization increases from electron-donating to less electron-donating, to electron-withdrawing substituents.11 For example, the half-life of deuteration of H3PO3, OctPO2H2, PhPO2H2, and H3PO2, are: 49 h, 5.4 h, 55 min, and 3 min, respectively. Thus, the Pd-catalyzed allylation of H-phosphinic acids is intrinsically more difficult than of hypophosphorous acid and requires more forcing conditions.9 First, the reaction solvent and temperature were changed from DMF4 at 85℃ to t-AmOH at reflux (102 ℃) in the presence of molecular sieves (3Å, 1 g/mmol) or a Dean-Stark trap. Part of the success of t-amyl alcohol is attributed to the stabilization of the RP(OH)2 tautomer via hydrogen-bonding. Second, the catalyst loading required was generally 2 mol% Pd/xantphos (versus 0.5 mol% when H3PO2 was the reaction partner). With these modifications, a variety of disubstituted phosphinic acids could be obtained in good to moderate yield after esterification (BnBr/Ag2O).9 Again, cinnamyl alcohol proved to be a superb allylating agent.
v101p0295-2.gif
Scheme 1. Palladium-catalyzed allylation of H-phosphinic acids.

Extension to Allylic Amines
In 2014, Tian and coworkers published the analogous allylation of hypophosphorous acid and H-phosphinic acids with (protonated) allylic amines.12 As in our reactions, H3PO2 is much more reactive than RPO2H2, so Pd/xantphos loadings of 0.2 mol% in CH3CN and 2 mol% in t-AmOH were used respectively. Scheme 2 shows some of the results.
v101p0295-3.gif
Scheme 2. Palladium-catalyzed allylation of hypophosphorous acid and H-phosphinic acids with primary allylic amines (22 examples, 68-98 %).

Extension to Benzylation
Having developed the successful allylation of the less reactive H-phosphinic acids, we then turned our attention to replacing allylic alcohols with benzylic ones. Since the palladium insertion into a benzylic electrophile is significantly more difficult than into an allylic one, more demanding reaction conditions were expected. Higher loadings were necessary as well as higher reaction temperature (Scheme 3).13
Two examples of benzylation of H-phosphinic acid were also provided. Finally, the benzylation of (R)-1-(2-naphthyl)ethanol (97% ee) proceeded in good yield but with significant erosion of the ee to 77%.
v101p0295-4.gif
Scheme 3. Direct, palladium-catalyzed benzylation of hypophosphorous acid with benzylic and heterobenzylic alcohols.

Extension to H-Phosphinate Esters and Related Compounds
Exactly ten years after the publication of our original reaction,4 we decided to investigate the reaction of H-phosphinate esters. Based on mechanistic studies and the resulting postulated mechanism of the allylation/benzylation, esterification of hypophosphorous acid or H-phosphinic acid is the first step of the transformation. Thus, we did not think that H-phosphinate esters could give the desired product. However, this assumption was wrong and both allylation and benzylation were accomplished with somewhat narrower scope than those described above.14 This could be explained by the generally more electron donating nature of the R ester group compared to R=H in the acid, and therefore the ester is less reactive than the acid. Indeed, the half-life of deuteration of n-OctP(O)(OEt)H, OctPO2H2, PhP(O)(OEt)H and PhPO2H2, are: 8.2 h, 5.4 h, 1.4 h, and 55 min, respectively.10 With cinnamyl alcohol, even rather unreactive phosphorus compounds like diethyl H-phosphonate gave good results (Scheme 4).14
v101p0295-5.gif
Scheme 4. Palladium-catalyzed reaction of various phosphorus compounds with cinnamyl alcohol.

Additional results with different allylic and benzylic alcohols are summarized in Scheme 5.14 Not shown in Scheme 5 is the reaction between diethyl H-phosphonate and benzyl alcohol, which gives only 23% of product (31P-NMR yield). Fortunately, Arbuzov-type reactions have been described to prepare phosphonate diesters from the corresponding benzylic and allylic alcohols.15,16
v101p0295-6.gif
Scheme 5. Palladium-catalyzed reaction of various H-phosphinate esters with allylic and benzylic alcohols.

Synthetic Applications
If the original conditions are followed by heating in air at 110 ℃, the product can be directly converted into the corresponding phosphonic acid (Scheme 6).17
v101p0295-7.gif
Scheme 6. One-pot allylation/oxidation preparation of cinnamyl phosphonic acid.

The reaction can also be used to prepare various P-heterocycles (Scheme 7). In 2008, butyl cinnamyl-H-phosphinate 1 was allylated through a sila-Arbuzov reaction to 2 or esterified using the Atherton-Todd reaction to produce 3. Both intermediates were cyclized via Grubbs' ring-closing metathesis using catalyst 4, to P-heterocycles 5 and 6, respectively.6
The same year, the allylation of H-phosphinic acids became available and symmetrical bis(cinnamyl)phosphinic acid 7 could be synthesized directly in quantitative yield.9 Silver-promoted esterification gave 8, which was submitted to ring-closing metathesis. Because of the alkene substitution, the reaction required a higher catalyst loading and the yield was lower. From intermediate 8, a different type of heterocycle 10 could be prepared via ozonolysis and double reductive amination.
Later on, once we discovered that H-phosphinate esters could also be allylated, an improved synthesis of heterocycle 5 became possible (Scheme 7, Montchamp 2016).14 Monoallylation of hypophosphorous acid to prepare 11 proceeded in excellent yield.4,5 Because H-phosphinic acids like 11 can be esterified via azeotropic distillation but disubstituted phosphinic acids like 7 cannot, this allows an inexpensive and efficient access to 1. Allylation of 1 with allylic alcohol produces intermediate 2, this time in a very efficient sequence with only water as a byproduct in each step. Ring closing metathesis forms heterocycle 5 and the yield was improved over the initial cyclization of 2. This streamlined synthesis produces 5 in 4 steps and 70% overall yield.
v101p0295-8.gif
Scheme 7. Preparation of P-heterocycles using the synthesis of allylic precursors.

In connection with studies aiming at the preparation of aspartate transcarbamoylase (ATCase) inhibitors, ozonolysis of allylated precursors was a key step (Scheme 8). Ozonolysis of 8 as in Scheme 7, but this time using benzylated aspartic acid in the reductive amination step, gave heterocycle 12. Straightforward debenzylation gave 13, which unfortunately showed no inhibition.18
Cinnamyl-H-phosphinic acid 11 was protected with triethylorthoacetate and the resulting 14 was ozonolyzed and oxidized to carboxylic acid 15. Simple carbodiimide amidation gave 16, which was subsequently deprotected to give 17. Compound 17 is a competitive inhibitor with an inhibition constant of 420 nM, which is approximately 25 times less potent than the known phosphonic acid and anticancer agent PALA.19
v101p0295-9.gif
Scheme 8. Preparation of potential inhibitors of aspartate transcarbamoylase.

In another application, menthyl (hydroxymethyl)-H-phosphinate 18 of high diastereoisomeric excess20 was elaborated into chiral heterocycle 22 (Scheme 9). Dehydrative allylation of 18 under the usual conditions proceeded stereospecifically and gave 19 in nearly quantitative yield. It should be noted that the half-life of deuteration for 18 is remarkably short at only 7 min,21 thus indicating an unusual reactivity. Reduction of the double-bond to 20 followed by Corey-Kim oxidation delivered menthyl H-phosphinate 21 in excellent yield and very slight erosion of the diastereoselectivity. Cyclization then gave heterocycle 22, stereospecifically and in excellent yield.
v101p0295-10.gif
Scheme 9. Preparation of a chiral P-heterocycle.

Additionally, the reaction below has been used for the preparation of a corrosion inhibitor.22 Palladium-catalyzed allylation of geraniol and oxidation gave geranylphosphonic acid in 60% overall yield (Scheme 10).
v101p0295-11.gif
Scheme 10. Preparation of geranylphosphonic acid.


References and Notes
  1. Department of Chemistry and Biochemistry, TCU Box 298860, Texas Christian University, Fort Worth, Texas 76129 (USA). Email: j.montchamp@tcu.edu; orcid.org/0000-0002-7327-1800.
  2. Chen, L.; Zou, Y.-X.; Liu, X.-Y Gou, X.-J. "Dehydrative Cross-Coupling and Related Reactions between Alcohols (C-OH) and P(O)-H Compounds for C-P Bond Formation" Adv. Synth. Catal. 2019, 361, 3490 - 3513. DOI: 10.1002/adsc.201900332.
  3. a) Boyd, E. A.; Regan, A. C.; James, K. "Synthesis of Alkyl Phosphinic Acids from Silyl Phosphonites and Alkyl Halides" Tetrahedron Lett. 1994, 35, 4223-4226. DOI: 10.1016/S0040-4039(00)73157-1. b) Baylis, E. K. "1,1-Diethoxyethylphosphinates and Phosphonites. Intermediates for the Synthesis of Functional Phosphorus Acids", Tetrahedron Lett. 1995, 36, 9385-9388. DOI: 10.1016/0040-4039(95)01992-Q. c) Gallagher, M. J.; Ranasinghe, M. G.; Jenkins, I. D. "Mono- and Dialkylation of Isopropyl Phosphinate - A Simple Preparation of Alkylphosphinate Esters", Phosphorus, Sulfur, and Silicon 1996, 115, 255-259. DOI: 10.1080/10426509608037971. d) Gallagher, M. J.; Ranasinghe, M. G. "Stereoselective Route to a New Class of Phosphasugars. Novel Analogues of 2-Deoxyglucose and 2-Deoxyallose", J. Org. Chem. 1996, 61, 436-437. DOI: 10.1021/jo951479u. e) Ravaschino, E., L.; Docampo, R.; Rodriguez, J. B. "Design, Synthesis, and Biological Evaluation of Phosphinopeptides against Trypanosoma cruzi Targeting Trypanothione Biosynthesis", J. Med. Chem. 2006, 49, 426-435. DOI: 10.1021/jm050922i. f) Abrunhosa-Thomas, I.; Ribière, P.; Adcock, A. C.; Montchamp, J.-L. "Direct Monoalkylation of Alkyl Phosphinates to Access H-Phosphinic Acid Esters" Synthesis 2006, 325-331. DOI: 10.1055/s-2005-924768. g) Gavara, L.; Petit, C.; Montchamp, J.-L. "DBU-Promoted Alkylation of Alkyl Phosphinates and H-Phosphonates" Tetrahedron Lett. 2012, 53, 5000-5003. DOI: 10.1016/j.tetleth+.2012.07.019. h) Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.; Ludmila I. Livantsova, L. I.; and Valery S. Petrosyan, V. S. "Synthesis and Reactivity of Alkoxy(trimethylsiloxy)phosphines and Their Derivatives" Heteroatom Chemistry 2012, 23, 138-145. DOI: 10.1002/hc.20762.
  4. Bravo-Altamirano, K.; Montchamp, J.-L. "Palladium-Catalyzed Dehydrative Allylation of Hypophosphorous Acid with Allylic Alcohols" Org. Lett. 2006, 8, 4169-4171. DOI: 10.1021/ol061828e.
  5. Bravo-Altamirano, K.; Montchamp, J.-L. "Palladium-Catalyzed Dehydrative Allylation of Hypophosphorous Acid with Allylic Alcohols. Preparation of Cinnamyl-H-Phosphinic Acid" Org. Synth. 2008, 85, 96-105. DOI: 10.15227/orgsyn.085.0096.
  6. Bravo-Altamirano, K.; Abrunhosa-Thomas, I.; Montchamp, J.-L. "Palladium-Catalyzed Reactions of Hypophosphorous Compounds with Allenes, Dienes and Allylic Electrophiles: Methodology for the Synthesis of Allylic-H-Phosphinates" J. Org. Chem. 2008, 73, 2292-2301. DOI: 10.1021/jo702542a.
  7. For example: a) Sasaki, M. "Optical Resolution of 1-Hydroxyethylphosphinic Acid and Its Esters", Agric. Biol. Chem. 1986, 50, 741-745. DOI: 10.1080/00021369.1986.10867432. b)Tran, G.; Pardo, D. G.; Tsuchiya, T.; Hillebrand, S.; Vors, J.-P.; Cossy, J. "Palladium-Catalyzed Phosphonylation: Synthesis of C3‑, C4‑, and C5-Phosphonylated Pyrazoles" Org. Lett. 2013, 15, 5550-5553. DOI: 10.1021/ol402717b. c) Berger, O.; Montchamp, J.-L. 1"Manganese-Catalyzed and Mediated Synthesis of Arylphosphinates and Related Compounds" J. Org. Chem. 2019, 84, 9239-9256. DOI: 10.1021/acs.joc.9b01239.
  8. Dumond, Y. R.; Baker, R. L.; Montchamp, J.-L. "Orthosilicate-Mediated Esterification of Monosubstituted Phosphinic Acids" Org. Lett. 2000, 2, 3341-3344. DOI: 10.1021/ol006434g.
  9. Coudray, L.; Bravo-Altamirano, K.; Montchamp, J.-L. "Allylic Phosphinates via Palladium-Catalyzed Allylation of H-Phosphinic Acids with Allylic Alcohols" Org. Lett. 2008, 10, 1123-1126. DOI: 10.1021/ol8000415.
  10. Janesko, B. J.; Fisher, H. C.; Bridle, M. J.; Montchamp, J.-L. "P(=O)H to P-OH Tautomerism: A Theoretical and Experimental Study" J. Org. Chem. 2015, 80, 10025-10032. DOI: 10.1021/acs.joc.5b01618.
  11. a) Montchamp, J.-L. "Phosphinate Chemistry in the 21st Century: A Viable Alternative to the Use of Phosphorus Trichloride in Organophosphorus Synthesis" Acc. Chem. Res. 2014, 47, 77-87. DOI: 10.1021/ar400071v. b) Montchamp, J.-L. "Challenges and solutions in phosphinate chemistry" Pure Appl. Chem. 2019, 91, 113-120. DOI: 10.1515/pac-2018-0922.
  12. Wu, X.-S.; Zhou, M.-G.; Chen, Y.; Tian, S.-K. "Catalytic Allylation of Hypophosphorous Acid and H-Phosphinic Acids with Primary Allylic Amines" Asian J. Org. Chem. 2014, 3, 711-714. DOI: 10.1002/ajoc.201402050.
  13. Coudray, L.; Montchamp, J.-L. "Green, Palladium-Catalyzed Synthesis of Benzylic H-Phosphinates from Hypophosphorous Acid and Benzylic Alcohols" Eur. J. Org. Chem. 2008, 4101-4103. DOI: 10.1002/ejoc.200800581.
  14. Fers-Lidou, A.; Berger, O.; Montchamp, J.-L. "Palladium-Catalyzed Allylation/Benzylation of H-Phosphinate Esters with Alcohols" Molecules 2016, 21, 1295-1309. DOI: 10.3390/molecules21101295.
  15. Barney, R. J.; Richardson, R. M.; Wiemer, D. F. "Direct Conversion of Benzylic and Allylic Alcohols to Phosphonates" J. Org. Chem. 2011, 76, 2875-2879. DOI: 10.1021/jo200137k.
  16. Ma, X.; Xu, Q.; Li, H.; Su, C.; Yu, L.; Zhang, X.; Caob, H.; Han, L.-B. "Alcohol-based Michaelis-Arbuzov reaction: an efficient and environmentally-benign method for C-P(O) bond formation" Green Chem. 2018, 20, 3408-3413. DOI: 10.1039/c8gc00931g.
  17. Bravo-Altamirano, K., Montchamp, J.-L. "A Novel Approach to Phosphonic Acids from Hypophosphorous acid" Tetrahedron Lett. 2007, 48, 5755-5759. DOI: 10.1016/j.tetlet.2007.06.090.
  18. Coudray, L.; Pennebaker, A. F.; Montchamp, J.-L. "Synthesis and In Vitro Evaluation of Aspartate Transcarbamoylase Inhibitors" Bioorg. Med. Chem. 2009, 17, 7680-7689. DOI: 10.1016/j.bmc.2009.09.045.
  19. Coudray, L.; Kantrowitz, E. R.; Montchamp, J.-L. "Submicromolar Phosphinic Inhibitors of E. coli Aspartate Transcarbamoylase" Bioorg. Med. Chem. Lett. 2009, 19, 900-902. DOI: 10.1016/j.bmcl.2008.11.115.
  20. Berger, O.; Montchamp, J.-L. "A General Strategy for the Synthesis of P-Stereogenic Compounds" Angew. Chem. Int. Ed. 2013, 52, 11377-11380. DOI: 10.1002/anie.201306628.
  21. Unpublished result.
  22. a) Ruf, E.; Naundorf, T.; Seddig, T.; Kipphardt, H.; Maison, W. "Natural Product-Derived Phosphonic Acids as Corrosion Inhibitors for Iron and Steel" Molecules 2022, 27, 1778 (17 pages). DOI: 10.3390/molecules27061778. b) Ruf, E.; Naundorf, T.; Kipphardt, H.; Maison, W. "Natural Material-Based Phosphonic Acids as Corrosion Inhibitors", World Patent WO 2021/165313 Al.

Karla Bravo-Altamirano was born in Oaxaca, Mexico. She received her B.S. in Chemistry from Universidad de las Américas Puebla, Mexico. She obtained her Ph.D. from Texas Christian University under the supervision of Prof. Jean-Luc Montchamp in 2007. She conducted postdoctoral research with Prof. Peter Wipf at the University of Pittsburgh and with Prof. Uttam K. Tambar at UT Southwestern Medical Center. In 2010, Karla joined Corteva Agriscience, where she worked in Crop Protection Discovery Chemistry until March 2022. She then moved to Pfizer, where she was part of the Inflammation & Immunology Department for about two years. In April 2024, she returned to Corteva Agriscience as a Principal Investigator.
Jean-Luc Montchamp was born in Lyon, France. He completed his undergraduate studies at the Ecole Superieure de Chimie Industrielle de Lyon (ESCIL), now known as CPE. He obtained his Ph.D. from Purdue University in 1992, under the direction of Professor John W. Frost. After postdoctoral experiences at the Scripps Research Institute and Michigan State University, he returned to Purdue University for a postdoctoral stay with Professor Ei-ichi Negishi. He started at Texas Christian University in 1998, where he is now Full Professor. His research interests include the development of methodology for the synthesis of organophosphorus compounds; and the bioactivity of phosphorus-containing analogs of natural products.