Categories: C-P Bond Formation >

Synthesis of phosphonates

Synthesis of
α-Hydroxy phosphonates		α-Amino phosphonates

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Name Reactions

Arbuzov Reaction

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Recent Literature

Using a prevalent palladium catalyst, Pd(PPh₃)₄, a quantitative cross-coupling of various H-phosphonate diesters with aryl and vinyl halides was achieved in less than 10 min under microwave irradiation. The reactions occurred with retention of configuration at the phosphorus center and in the vinyl moiety.
M. Kalek, A. Ziadi, J. Stawinski, Org. Lett., 2008, 10, 4637-4640.

The reaction of diaryliodonium salts with phosphites in the presence of a base under visible-light illumination provides a large variety of aryl phosphonates. The reaction proceeds smoothly, tolerates various functionalities, and was applied for the synthesis of pharmaceutically relevant compounds.
W. Lecroq, P. Bazille, F. Morlet-Savary, M. Breugst, J. Lalevée, A.-C. Gaumont, S. Lakhdar, Org. Lett., 2018, 20, 4164-4167.

A carbonate anion assisted photochemical protocol for the C-X bond activation generates aryl radicals from easily accessible aryl halides that are further utilized in C-P and C-B bond formation reactions with excellent reactivity and broad functional group tolerance. This inexpensive method alleviates the use of a photocatalyst and the need of preactivation of the substrate.
V. J. Roy, S. R. Roy, Org. Lett., 2023, 25, 923-927.

A Pd-catalyzed Michaelis-Arbuzov reaction of triaryl phosphites and aryl iodides provides aryl phosphonates. A water-mediated phosphonium intermediate rearrangement process makes the reaction conditions rather mild. This mild and general reaction exhibits excellent functional group tolerance and can be extended to aryl phosphonites and phosphinites.
J. Zhang, W. Hu, Z. Chen, N. Wu, C. Li, T. Chen, L.-B. Han, Org. Lett., 2024, 26, 3386-3390.

A copper-catalyzed reaction of phosphorus nucleophiles with diaryliodonium salts at room temperature delivers products of a P-C bond formation in high yields within a short reaction time of 10 min. The method can be easily adapted to large-scale preparations. With unsymmetrical iodonium salts, nucleophilic substitution occurs preferentially on the sterically hindered aromatic ring or the more electron-deficient ring.
J. Xu, P. Zhang, Y. Gao, Y. Chen, G. Tang, Y. Zhauo, J. Org. Chem., 2013, 78, 8176-8183.

A broad range of aryl iodides are efficiently coupled with secondary phosphine oxides using low loadings of a catalyst formed in situ from tris(dibenzylideneacetone)dipalladium and Xantphos.
A. J. Bloomfield, S. B. Herzon, Org. Lett., 2012, 14, 4370-4373.

A mild and efficient copper-catalyzed addition of H-phosphonate dialkyl esters to boronic acids gives aryl phosphonates using Cu₂O/1,10-phenanthroline as catalytic system.
R. Zhuang, J. Xu, Z. Cai, G. Tang, M. Fang, Y. Zhao, Org. Lett., 2011, 13, 2110-2113.

A nickel-catalyzed electrochemical cross-coupling reaction of aryl bromides with dialkyl phosphites, ethyl phenylphosphinate, and diphenylphosphine oxide provides aryl phosphonates, aryl phosphinates, and arylphosphine oxides at room temperature using a simple undivided cell with inexpensive carbon electrodes.
Y. Bai, N. Liu, S. Wang, S. Wang, S. Ning, L. Shi, L. Cui, Z. Zhang, J. Xiang, Org. Lett., 2019, 21, 6795-6799.

The energetic limitations of visible light can be circumvented by electrochemically priming a photocatalyst prior to excitation. This method enables the use of aryl chlorides with reduction potentials hundreds of millivolts beyond the potential of Na⁰ in carbon-carbon and carbon-heteroatom bond-forming reactions.
N. G. W. Cowper, C. P. Chernowsky, O. P. Williams, Z. K. Wickens, J. Am. Chem. Soc., 2020, 142, 2093-2099.

In an efficient nickel-catalyzed phosphorylation, various phenyl pivalates coupled readily with hydrogen phosphoryl compounds to afford the corresponding aryl phosphonates and aryl phosphine oxides in very good yields.
J. Yang, J. Xiao, T. Chen, L.-B. Han, J. Org. Chem., 2016, 81, 3911-3916.

A decarbonylative palladium catalysis enables the synthesis of organophosphorus compounds from ubiquitous aryl and vinyl carboxylic acids. The catalytic system olerates a wide range of functional groups.
C. Liu, C.-L. Ji, T. Zhou, X. Hong, M. Szostak, Org. Lett., 2019, 21, 9256-9261.

A catalytic amount of inexpensive salicylic acid promotes a straightforward and scalable synthesis of diphenyl arylphosphonates from anilines and triphenyl phosphite at 20°C within 1-2 h. The reaction proceeds via radical-radical coupling and tolerates a wide range of functional groups.
M. Estruch-Blasco, D. Felipe-Blanco, I. Bosque, J. C. González-Gómez, J. Org. Chem., 2020, 85, 14473-14485.

An efficient metal-free phosphorylation process based on a Sandmeyer-type transformation of arylamines proceeds smoothly at room temperature without the exclusion of moisture or air. This reaction tolerates a wide range of functional groups and affords the phosphorylation products in good yields.
S. Wang, D. Qiu, F. Mo, Y. Zhang, J. Wang, J. Org. Chem., 2016, 81, 11603-11611.

A palladium-catalyzed phosphorylation of aryl mesylates and tosylates exhibits excellent functional group compatibility - including free amino, keto, ester, and amido groups. The mesylated derivatives of biologically active compounds such as 17β-estradiol and 6-hydroxyflavone are applicable substrates too.
W. C. Fu, C. M. So, F. Y. Kwong, Org. Lett., 2015, 17, 5906-5909.

A novel and highly efficient Pd-catalyzed cross-coupling of triarylbismuths with various P(O)-H compounds proceeds smoothly without exclusion of moisture or air and provides valuable arylphosphonates, arylphosphinates, and arylphosphine oxides, with high atom-economy, operational simplicity of the procedure, and good to high yield.
T. Wang, S. Sang, L. Liu, H. Qiao, Y. Gao, Y. Zhao, J. Org. Chem., 2014, 79, 608-617.

An efficient use of arynes for C-P bond construction enables a mild process for the synthesis of aryl-phosphonates, -phosphinates, and -phosphine oxides. The reaction circumvents the relatively harsh reaction conditions using transition-metal-catalyzed P-arylation (Arbuzov/Hirao reaction).
R. A. Dhokale, S. B. Mhaske, Org. Lett., 2013, 15, 2218-2221.

Diacyl peroxides, generated in situ from aliphatic acids and H₂O₂, serve as a source for alkyl radicals and also an initiator for the generation of phosphorus radicals from H-P(O) compounds. A subsequent CuI-catalyzed cross-coupling of alkyl- and phosphorus-centered radicals provides alkylated phosphorous compounds in good yields.
C.-K. Li, Z.-K. Tao, A. Shoberu, W. Zhang, J.-P. Zou, Org. Lett., 2022, 24, 6083-6087.

Triflic anhydride promotes a phosphorylation of ketones to provide vinylphosphorus compounds under solvent- and metal-free conditions. Both aryl and alkyl ketones give vinyl phosphonates in high to excellent yields. This convenient and mild reaction can easily be scaled up.
N. Xin, Y. Lv, Y. Lian, Z. Lin, X.-Q. Huang, C.-Q. Zhao, Y. Wang, J. Org. Chem., 2023, 88, 2898-2907.

A convenient and practical method for the one-pot, three-component synthesis of terminal vinylphosphonates from aldehydes, nitromethane and trialkylphosphites through a tandem Henry-Michael reaction followed by nitro elimination in the presence of 5-hydroxypentylammonium acetate (5-HPAA) as a task-specific ionic liquid offers good yields of the products under mild reaction conditions.
S. Sobhani, M. Honarmand, Synlett, 2013, 24, 236-240.

A two step procedure involving a transesterification between a diol and diethyl phosphite followed by a palladium-catalyzed coupling of the so-obtained cyclic phosphite with vinyl bromide gave vinyl phosphonates in good yields.
M. Maffei, G. Buono, Tetrahedron, 2003, 59, 8821-8825.

An efficient method allows the synthesis of benzylphosphonate diesters via a palladium(0)-catalyzed cross-coupling reaction between benzyl halides and H-phosphonate diesters, using Pd(OAc)₂ as a palladium source and Xantphos as a supporting ligand.
G. Lavéna, J. Stawinski, Synlett, 2009, 225-228.

A Lewis acid-mediated Michaelis-Arbuzov reaction of arylmethyl halides and alcohols with triethyl phosphite at room temperature enables a facile preparation of arylmethyl and heteroarylmethyl phosphonate esters in good yields.
G. G. Rajeshwaran, M. Nandakumar, R. Sureshbabu, A. K. Mohanakrishnan, Org. Lett., 2011, 13, 1270-1273.

A convenient and efficient copper-catalyzed approach for P-arylation of organophosphorus compounds containing P-H uses the commercially available and inexpensive proline and pipecolinic acid as ligands. The method can provide an entry to arylphosphonates, arylphosphinates and arylphosphine oxides.
C. Huang, X. Tang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem., 2006, 71, 4951-4955.

A visible-light-driven redox-neutral phosphonoalkylation of alkene-bearing alkyl sulfonates provides a variety of organophosphorus-containing three-membered carbocyclic scaffolds. The transition-metal-free protocol displays good functional group tolerance, broad substrate scope, high yields, and mild reaction conditions.
Y.-M. Jiang, J. Liu, Q. Fu, Y.-M. Yu, D.-G. Yu, Synlett, 2021, 32, 378-382.

A palladium-catalyzed hydrophosphorylation of alkynes with P(O)-H compounds (i.e., H-phosphonates, H-phosphinates, secondary phosphine oxides, and hypophosphinic acid) provides Markovnikov adducts in high yields with high regioselectivity for both aromatic and aliphatic alkynes. The reaction tolerates a wide variety of functional groups.
T. Chen, C.-Q. Zhao, L.-B. Han, J. Am. Chem. Soc., 2018, 140, 3139-3155.

A low-ligated palladium/triphenylphosphane catalytic system in the presence of a catalytic amount of trifluoroacetic acid allows a hydrophosphorylation of terminal and internal alkynes with high isolated yields and excellent regio- and stereoselectivity. The catalytic system permits the formation of diverse alkenylphosphonates utilizing various available H-phosphonates and alkynes.
V. P. Ananikov, L. L. Khemchyan, I. P. Beletskaya, Synlett, 2009, 2375-2381.

Copper-catalyzed aerobic oxidative coupling of terminal alkynes with H-phosphonates affords alkynylphosphonates in high yields.
Y. Gao, G. Wang, L. Chen, P. Xu, Y. Zhao, Y. Zhou, L.-B. Han, J. Am. Chem. Soc., 2009, 131, 7956-7957.

The reaction of various terminal alkynes with dialkyl phosphites in the presence of a catalytic amount of Cu₂O provides alkynylphosphonates in very good yields. Reactions are performed under air, in acetonitrile as solvent, and in the absence of base or ligand additives. This simple and mild methodology is compatible with a broad range of functional groups on the starting alkynes and can be scaled up to a gram scale.
Y. Moglie, E. Mascaró, V. Gutierrez, F. Alonso, G. Radivoy, J. Org. Chem., 2016, 81, 1813-1818.

Efficient Cs₂CO₃-promoted phosphorylations or phosphinylations of various 1,1-dibromo-1-alkenes with readily available trialkyl phosphites, ethyl diphenylphosphinite, or diethyl phenylphosphonite under metal-free conditions provide valuable alkynylphosphonates, -phosphinates, and -phosphine oxides in very good yields.
Y. Wang, J. Gan, L. Liu, H. Yuan, Y. Gao, Y. Liu, Y. Zhao, J. Org. Chem., 2014, 79, 3678-3683.

Stable copper acetylides can be easily activated by oxidation with oxygen in the presence of simple nitrogen ligands such as TMEDA or imidazole derivatives. Upon activation, these nucleophilic species undergo a formal umpolung and can transfer their alkyne subunit to a wide range of heteronucleophiles under especially mild conditions providing ynamides, ynimines, and alkynylphosphonates on a multigram scale.
C. Theunissen, M. Lecomte, K. Jouvin, A. Laouiti, C. Guissart, J. Heimburger, E. Loire, G. Evano, Synthesis, 2014, 46, 1157-1166.

A new, efficient method based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles produces allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety.
M. Kalek, T. Johansson, M. Jezowska, J. Stawinski, Org. Lett., 2010, 12, 4702-4704.

When treated with a radical initiator selenophosphates, selenophosphorodithioates, selenophosphorothioates and selenophosphorotrithioates undergo homolytic cleavage of the P-Se bond to generate radicals. Addition onto electron-rich and electron-poor alkenes in the presence of a hydrogen donor delivers the expected adducts in good yields.
C. Lopin, G. Gouhier, A. Gautier, S. R. Piettre, J. Org. Chem., 2003, 68, 9916-9923.

Chiral dinuclear rare-earth metal complexes stabilized by Trost ligands displayed high reactivity in the asymmetric hydrophosphonylation of α,β-unsaturated ketones in the presence of (1S,2S)-1,2-cyclohexanediamine as additive. Various hydrophosphonylation products with excellent yields and very high ee values were obtained.
H. Song, Y. Sun, C. Lu, B. Zhao, J. Org. Chem., 2022, 87, 7749-7762.

A diaminomethylenemalononitrile catalyzes an asymmetric 1,4-addition of phosphonates to trans-crotonophenone and chalcone derivatives to provide chiral γ-ketophosphonates in high yields with excellent enantioselectivities.
R. Arai, S.-i. Hirashima, T. Nakano, M. Kawada, H. Akutsu, K. Nakashima, T. Miura, J. Org. Chem., 2020, 85, 3872-3878.

A Mn(OAc)₃-promoted oxidative phosphonylation of N,N-dimethylenaminones with H-phosphonates provides functionalized β-ketophosphonates in very good yields under mild reaction conditions. This method offers operational simplicity, broad substrate scope, and large-scale preparation.
P. Zhou, B. Hu, L. Li, K. Rao, J. Yang, F. Yu, J. Org. Chem., 2017, 82, 13268-13276.

A copper-catalyzed aerobic oxidative/decarboxylative phosphorylation of aryl acrylic acids with P(III)-nucleophiles via the Michaelis-Arbuzov rearrangement provides β-ketophosphine oxides, β-ketophosphinates, and β-ketophosphonates in very good yields. The present reaction could be conducted effectively without the use of a ligand and a base.
B. Xiong, L. Si, L. Zhu, Y. Liu, W. Xu, K.-W. Tang, S.-F. Yin, P.-C. Qian, W.-Y. Wong, J. Org. Chem., 2023, 88, 12502-12518.

A direct enaminone C-N bond coupling with dialkyl phosphonate enables a stereoselective synthesis of (E)-alkenylphosphonates with a broad scope.
T. Liu, L. Wei, B. Zhao, Y. Liu, J.-P. Wan, J. Org. Chem., 2021, 86, 9861-9868.

Related

A deprotonative cross-coupling process (DCCP) enables a new synthetic route to access diarylmethyl phosphonates via introduction of aromatic groups on benzylic phosphonates. A catalytic system based on Pd(OAc)₂/CataCXium A allows a reaction between benzyl diisopropyl phosphonate derivatives and aryl bromides in very good isolated yields.
S. Montel, L. Raffier, Y. He, P. J. Walsh, Org. Lett., 2014, 16, 1446-1449.

An efficient O-H insertion of hydrogenphosphate derivatives and α-diazo compounds provides α-phosphoryloxy scaffolds under mild and catalyst-free conditions in good yields. The control experiments suggest a protonation and nucleophilic addition process of α-diazo compounds via a diazonium ion pair.
F. Tan, W. Wang, X. Huang, Y. Zhong, T. Song, J. Wang, L. Mei, J. Org. Chem., 2024, 89, 2588-2598.

The N-heterocyclic carbene derived from N-mesitylimidazolium chloride was an effective catalyst for a Stetter reaction of aromatic aldehydes with vinylphosphonates providing γ-ketophosphonates in good yields.
A. Patra, A. Bhunia, A. T. Biju, Org. Lett., 2014, 16, 4798-4801.

The use of lithiated methyl α-(trimethylsilyl)methylphosphonate as mild lithiated phosphonate reagent enables a highly chemoselective synthesis of β-ketophosphonates from pentafluorophenyl esters in high yield. The reaction tolerates for example the presence of unactivated esters.
S. Specklin, J. Cossy, J. Org. Chem., 2015, 80, 3302-3308.

The use of a palladium(II) acetate-organophosphine catalyst system enables an efficient coupling of (1-bromovinyl)phosphonates with aryl boronic acids. A wide range of (1-arylvinyl)phosphonates were prepared in very good yields. The protocol can be effectively scaled up and even allows the use of a (1-chloro­vinyl)phosphonate as the electrophilic coupling partner.
Y. Fang, L. Zhang, X. Jin, J. Li, M. Yuan, R. Li, H. Gao, J. Fang, Y. Liu, Synlett, 2015, 26, 980-984.

α-Phosphonovinyl tosylates can be coupled efficiently with a range of arylboronic acids to provide α-arylethenylphosphonates. The unprecedented procedure exhibits excellent functional group tolerance, giving the terminal vinylphosphonates in good to excellent isolated yields under mild reaction conditions.
Y. Fang, L. Zhang, J. Li, X. Jin, M. Yuan, R. Li, R. Wu, J. Fang, Org. Lett., 2015, 17, 798-801.

Various vinyl phosphonates were prepared by the regioselective addition reaction of monoesters of phosphonic acid to alkynes in the presence of Hg(OAc)₂/BF₃·OEt₂.
A. Y. Peng, Y. X. Ding, Synthesis, 2003, 205-208.

An efficient Cu(I)-catalyzed coupling of diazophosphonates with terminal alkynes provides allenylphosphonates using inexpensive CuI as the catalyst under mild conditions.
C. Wu, F. Ye, G. Wu, S. Xu, G. Deng, Y. Zhang, J. Wang, Synthesis, 2016, 48, 751-760.

A mild, high-yielding and general procedure for the preparation of β-ketophosphonates by condensation of esters and phosphonates provides products in high yields within minutes at 0°C. The reaction procedure is operationally simple and amenable to large-scale preparations.
K. M. Maloney, J. Y. L. Chung, J. Org. Chem., 2009, 74, 7574-7576.