Name: 5324-30-1|Diethyl (2-bromoethyl)phosphonate|98%
Brand: Ambeed
SKU: A560002
Price: 6.0 USD
Availability: InStock
Rating: 90 (40 reviews)

1
[ 5324-30-1 ]
[ 682-30-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine In benzene for 1h; Reflux;
90%	With potassium hydroxide In ethanol Reflux;	3.ii A 150 ml two-necked round bottom flask was filled with EtOH (85 ml). KOH pellets (2.52 g, 0.045 mol) were added. The mixture was stirred in an ice bath until complete KOH dissolution. Diethyl (2-bromoethyl)phosphonate (1) (8.1 ml, 0.045 mol) was added dropwise (30 minutes) by means of an equalizing pressure funnel. Meanwhile a white solid formed. The mixture was refluxed for 15 minutes, and, after cooling, was filtered using a frit. The white solid was washed with absolute EtOH and the filtrate was roto-evaporated, and finally dried under a vacuum pump for 15 minutes. The residue was distilled with a micro-distillator. The first fraction (43° C., 0.5 mmHg) corresponded to pure diethyl vinylphosphonate (3) (yield 90%).1H NMR (CDCl3): δ(ppm)=5.99-6.36 (3H), 4.09 (m, 4H), 1.33 (t, 6H).31P{1H} (CDCl3): δ(ppm)=18.1.
90%	With potassium hydroxide In ethanol for 0.25h; Heating / reflux;	3.ii (ii) Synthesis of diethyl vinylphosphonate (3); A 150 ml two-necked round bottom flask was filled with EtOH (85 ml). KOH pellets (2.52 g, 0.045 mol) were added. The mixture was stirred in an ice bath until complete KOH dissolution. Diethyl (2- bromoethyl) phosphonate (1) (8.1 ml, 0.045 mol) was added dropwise (30 minutes) by means of an equalizing pressure funnel. Meanwhile a white solid formed. The mixture was refluxed for 15 minutes, and, after cooling, was filtered using a frit. The white solid was washed with absolute EtOH and the filtrate was roto-evaporated, and finally dried under a vacuum pump for 15 minutes. The residue was distilled with a micro-distillator. The first fraction (43°C, 0.5 mmHg) corresponded to pure diethyl vinylphosphonate (3) (yield 90%) .IH NMR (CDC13) : δ(ppm) .= 5.99-6.36 (3H), 4.09 (m, 4H), 1.33 (t, 6H) . 31P{1H} (CDC13) : δ(ppm) = 18.1.

86%	With orthoformic acid triethyl ester for 2h; Heating;
86%	With potassium hydroxide In ethanol at 20℃; for 1.25h; Reflux;	4.1.3. Preparation of diethyl vinylphosphonate Diethyl 2-bromoethylphosphonate (24.5 g, 0.1 mol) was slowly added to a cold solution of KOH (5.6 g, 0.1 mol) in 150 ml of ethanol. The reaction mixture was stirred at room temperature for 1 h then heated to reflux for 15 min. The formed solid was filtered off and washed with ethanol. Ethanol was removed under vacuum and the remaining oil was distilled under reduced pressure.
83%	With triethylamine In water; acetone for 4h;
	With potassium hydroxide
	With triethylamine; benzene
	With diethylamine; toluene
10 g	With triethylamine In benzene for 1h; Reflux;

Reference： [1]Zhang, Xiaojuan; Zhang, Qian; Xie, Chao; Gao, Aiting; Chang, Zheng; Kwon Oh, Jung; Yang, Peng; Li, Pengfei [Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 10, p. 1396 - 1408]
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem); GENERAL ELECTRIC CO - US2010/160615, 2010, A1 Location in patent: Page/Page column 11-12
[3]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem); GENERAL ELECTRIC CO - WO2007/83395, 2007, A1 Location in patent: Page/Page column 41-42
[4]Kurdyumova; Ragulin; Tsvetkov [Russian Journal of General Chemistry, 1996, vol. 66, # 5, p. 750 - 752]
[5]Lukáč, Miloš; Garajová, Mária; Mrva, Martin; Devínsky, Ferdinand; Ondriska, František; Kubincová, Janka [Journal of Fluorine Chemistry, 2014, vol. 164, p. 10 - 17]
[6]Leslie, D. Ralph; Pantelidis, Sue [Australian Journal of Chemistry, 1994, vol. 47, # 3, p. 545 - 560]
[7]Kosolapoff [Journal of the American Chemical Society, 1948, vol. 70, p. 1971]
[8]Ford-Moore; Williams [Journal of the Chemical Society, 1947, p. 1467]
[9]Kosolapoff [Journal of the American Chemical Society, 1948, vol. 70, p. 1971]
[10]Li, Jing; Ni, Xufeng; Ling, Jun; Shen, Zhiquan [Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 11, p. 2409 - 2415]

2
[ 5324-30-1 ]
[ 124-40-3 ]
[ 41948-36-1 ]

Yield	Reaction Conditions	Operation in experiment
29%	In lithium hydroxide monohydrate at 20℃; Reflux;

Reference： [1]Chang, Wei-Chen; Guo, Yisong; Li, Xiaojun; Xue, Shan [Journal of the American Chemical Society, 2022]
[2]Myers; Jibril [Journal of Organic Chemistry, 1957, vol. 22, p. 180] Pudowik; Denisowa [Zhurnal Obshchei Khimii, 1953, vol. 23, p. 263,265; enlg.Ausg.S.273,274]

3
[ 106-93-4 ]
[ 122-52-1 ]
[ 5324-30-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	for 2h; Reflux;	1.i 1,2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1,2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70° C. The residue was distilled under reduced pressure (2 mmHg, 95-105° C. or 1 mmHg, 75° C.). Yield 95%.1H NMR (CDCl3), δ(ppm)=4.01 (m, 4H); 3.42 (q, 2H); 2.27 (m, 2H); 1.22 (t, 6H).31P{1H} (CDCl3): δ(ppm)=26.4.
95%	for 2h; Heating / reflux;	1.i Example 1; Synthesis of bis [ (dimethoxypropylphosphino) ethyl] ethoxyethylamine (PNP5) by the method of the present invention(i) Synthesis of diethyl (2-bromoethyl) phosphonate (1) 1, 2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1 , 2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70 °C. The residue was distilled under reduced pressure (2mmHg, 95-1050C or lmmHg, 75°C). Yield 95%.IH NMR (CDC13) , δ(ppm) = 4.01 (m, 4H); 3.42 (q, 2H); 2.27 (m, 2H) ; 1.22 (t, 6H) .31P{1H} (CDC13) : δ(ppm) = 26.4.
83%	at 160℃; for 3h;	Diethyl (2-bromoethyl)phosphonate. The mixture of1,2-dibromoethane (75.2 g, 0.4 mol) and triethylphosphite (16.6 g, 0.1 mol) wasplaced in a 100-ml three-necked flask, then heated at 160 oC for 3h. The resulted solution was distilled under reduced pressure to give diethyl(2-bromoethyl)phosphonate as a colorless liquid (18.6 g, 83%).

80%	at 160℃; for 4h; Inert atmosphere;
79%	at 160℃; for 4h;
74%	at 206℃;
70%	at 160℃; for 3.5h;
70%	at 160℃; for 1h;	Preparation of diethyl 2-bromoethylphosphonate (1) 1,2-dibromoethane(150 mL, 1.75 mol) was placed into a 250 mL three-neckedask, andthe solution was slowly heated to 160 °C withvigorous stirring. Triethylphosphite (60 mL, 0.35 mol) was added dropwise over the course of 1h, andthe reaction was monitored by 31P NMR spectrum.Whenthe peak at δ 137ppmdisappeared, the reaction wasfinished. The solution wascooled to roomtemperature and distilledat reducedpressure(1-5 mbar at 110-128 °C, ref.1 105-130°C) togivecolourlessoil1 (59.8 g, 70.0%). 1H NMR (CDCl3)d = 4.12 (m,4H), 3.54 (m, 2H), 2.39 (m, 2H), 1.34 (t, J = 14.4 Hz, 1H).13C NMR (CDCl3)d = 65.6, 48.2 (d, J =10.0 Hz), 29.3 (d, J =140.0 Hz), 19.2.31P NMR (CDCl3) d = 25.1.
68%	at 150 - 160℃; for 13h;
66.7%	at 160℃; for 3h;
65%	1.) 120 deg C; 2.) 160 deg C, 2 h;
64%	at 160℃; for 4h;
64%	at 140℃; for 0.5h;	1 Preparation Example 1: Preparation of DL-2-amino-4-phosphonobutanoic acid hydrate Triethyl phosphite (40.0 ml, 233 mmol) was added to 1,2-dibromoethane (80 ml, 928 mmol), the mixture was raised in temperature up to 140° C. with stirring on an oil bath, heated at the same temperature for 30 minutes, and naturally cooled. After cooling down to around 40° C., pressure reduction was started. The pressure reduction and heating were gradually intensified, to distill off excess dibromoethane and by-products such as ethyl bromide. The pressure reduction was then further intensified to a degree of vacuum of about 1 mmHg, and distillation was performed with heating at about 130° C. This gave colorless, odorless, oily diethyl 2-bromoethylphosphonate (36.3 g, yield: 64%).
62%	at 160℃; for 4h;	4.1.2. Preparation of diethyl 2-bromoethylphosphonate Triethylphosphite (35 ml, 0.2 mol) was mixed with 1,2-dibromoethane (69 ml, 0.8 mol) in a round-bottom flask equipped with a reflux condenser, heated at 160 °C and stirred for 4 h. The reaction mixture was cooled and purified by distillation at reduced pressure.
61%	at 160℃; for 4h;
58.5%	at 150℃;
	at 160℃;
	at 160℃; for 0.333333h; Microwave irradiation;	22.1 Example 22Table 1Compound 22Synthesis of 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid (22)Step 1: diethyl 2-bromoethylphosphonateCommercially available 1,2-dibromoethane (1.0 equiv.) and triethyl phosphite (1.0 equiv.) were heated with microwave irradiation at 160° C. for 20 minutes. The resulting residue was purified by reverse phase high performance liquid chromatography (HPLC) (0.035% TFA in ACN: 0.05% TFA in H2O, C18 column) to give diethyl 2-bromoethylphosphonate as a colorless liquid.
	for 5h; Reflux;
	at 140℃; for 5h;
	In neat (no solvent) for 0.5h; Reflux;
	at 160℃; for 4h;
	at 110℃;
	With trifluoroacetic acid at 160℃; for 0.333333h; Microwave irradiation;	22.1 Step 1: diethyl 2-bromoethylphosphonate Commercially available 1,2-dibromoethane (1.0 equiv.) and triethyl phosphite (1.0 equiv.) were heated with microwave irradiation at 160° C. for 20 minutes. The resulting residue was purified by reverse phase high performance liquid chromatography (HPLC) (0.035% TFA in ACN: 0.05% TFA in H2O, C18 column) to give diethyl 2-bromoethylphosphonate as a colorless liquid.
	at 140℃;	General procedure for synthesis of bromo-alkyl phosphonate (7c-7f) General procedure: Compounds 7c-7d were synthesized from corresponding dibromoalkane and triethylphosphite. 1 equivalent (20 mmol) of corresponding dibromoalkane and 1 equivalent (20 mmol) of triethyl phosphite was refluxed at 140°C overnight. The reaction mixture was cooled to room temperature and the compounds 7c-7f were purified by passing through a short column packed with silica gel and used immediately after removal of solvents. Compounds 7a, and 7b are commercially available compounds and 7c-7f are previously reported compounds 4-6.
36.3 g	at 140℃; for 0.5h;	3 Example 3 Triethyl phosphite (40.0 ml, 233 mmol) was added to 1,2-dibromoethane (80 ml, 928 mmol), heated to 140 ° C. in an oil bath under stirring, heated at the same temperature for 30 minutes, did. After cooling to around 40 ° C., pressure reduction was started. Gradual depressurization and heating were intensified, by-products such as ethyl bromide and excess dibromoethane were distilled off. Thereafter, the degree of vacuum was further raised (about 1 mmHg) and heated and distilled at about 130 ° C. to obtain diethyl 2-bromoethylphosphonate (36.3 g) in the form of colorless odorless oil.
	at 150 - 160℃;	Compounds 4a-4d (general procedure). General procedure: A mixtureof triethyl phosphite (0.41 mL, 2.5 mmol) and 1,2-dibromoethane(3a), oxalyl chloride (3b), chloroacetylchloride (3c), or ethyl chloroacetate (3d) (3.5 mmol)was heated under reflux at 150-160°C for 3-5 h.Excess reactants were removed under reduced pressure,a solution of pyranopyrimidine 2 (0.74 g, 2.5 mmol)in THF (25 mL) containing sodium hydride (0.07 g,3 mmol) was added to the residue, and the mixture wasfurther heated at 55-60°C for 10-15 h. After completionof the reaction, the solvent was removed underreduced pressure, and the residue was recrystallizedfrom an appropriate solvent.

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem); GENERAL ELECTRIC CO - US2010/160615, 2010, A1 Location in patent: Page/Page column 9
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem); GENERAL ELECTRIC CO - WO2007/83395, 2007, A1 Location in patent: Page/Page column 33-34
[3]Tang, Xiaoyan; Zhong, Qixuan; Xu, Ji; Li, Haiqing; Xu, Sinong; Cui, Xueyuan; Wei, Bo; Ma, Yunsheng; Yuan, Rongxin [Inorganica Chimica Acta, 2016, vol. 442, p. 195 - 199]
[4]Cichowicz, Nathan R.; Nagorny, Pavel [Organic Letters, 2012, vol. 14, # 4, p. 1058 - 1061]
[5]Ohashi, Kinji; Kosai, Shunji; Arizuka, Mitsuo; Watanabe, Takashi; Yamagiwa, Yoshiro; et al. [Tetrahedron, 1989, vol. 45, # 9, p. 2557 - 2570]
[6]Balczewski, Piotr; Pietrzykowski, Witold M. [Tetrahedron, 1996, vol. 52, # 43, p. 13681 - 13694]
[7]Leslie, D. Ralph; Pantelidis, Sue [Australian Journal of Chemistry, 1994, vol. 47, # 3, p. 545 - 560]
[8]Li, Xu; Chen, Xiaolan; Yuan, Jinwei; Liu, Yang; Li, Peipei; Qu, Lingbo; Zhao, Yufen [Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 7, p. 961 - 971]
[9]Zhang, Xiaojuan; Zhang, Qian; Xie, Chao; Gao, Aiting; Chang, Zheng; Kwon Oh, Jung; Yang, Peng; Li, Pengfei [Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 10, p. 1396 - 1408]
[10]Matoba; Yonemoto; Fukui; Yamazaki [Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 10, p. 3918 - 3925]
[11]Aboujaoude, E. Elia; Collignon, N.; Savignac, P.; Bensoam, J. [Phosphorus and Sulfur and the Related Elements, 1987, vol. 34, p. 93 - 104]
[12]Baber, Angharad; De Vries, Johannes G.; Orpen, A. Guy; Pringle, Paul G.; Von Der Luehe, Karl [Dalton Transactions, 2006, # 40, p. 4821 - 4828]
[13]Current Patent Assignee: NAHLS; KYOTO UNIVERSITY - US2020/131207, 2020, A1 Location in patent: Paragraph 0096; 0097
[14]Lukáč, Miloš; Garajová, Mária; Mrva, Martin; Devínsky, Ferdinand; Ondriska, František; Kubincová, Janka [Journal of Fluorine Chemistry, 2014, vol. 164, p. 10 - 17]
[15]Chang, Wei-Chen; Guo, Yisong; Li, Xiaojun; Xue, Shan [Journal of the American Chemical Society, 2022]
[16]Li, Jing; Ni, Xufeng; Ling, Jun; Shen, Zhiquan [Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 11, p. 2409 - 2415]
[17]Kosolapoff [Journal of the American Chemical Society, 1948, vol. 70, p. 1971] Ford-Moore; Williams [Journal of the Chemical Society, 1947, p. 1467]
[18]Rabinowitz,R. [Journal of Organic Chemistry, 1963, vol. 28, p. 2975 - 2978] Chun; Park; Oh; Hong; Kim [Synthesis, 1994, # 9, p. 909 - 910]
[19]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2011/53893, 2011, A1 Location in patent: Page/Page column 70
[20]Location in patent: experimental part Zhou, Liang [Asian Journal of Chemistry, 2012, vol. 24, # 10, p. 4821 - 4822]
[21]Zhou, Liang [Journal of Chemical Research, 2012, vol. 36, # 9, p. 512 - 515]
[22]Ragulin [Russian Journal of General Chemistry, 2012, vol. 82, # 12, p. 1928 - 1937][Zh. Obshch. Khim., 2012, vol. 82, # 12, p. 1973 - 1982,10]
[23]Tian, Yu; Wang, Yuanhao; Shang, Hai; Xu, Xudong; Tang, Yefeng [Organic and Biomolecular Chemistry, 2015, vol. 13, # 2, p. 612 - 619]
[24]Current Patent Assignee: USHIO CHEMIX CORP; UNIVERSITY OF YAMANASHI - JP2015/105241, 2015, A Location in patent: Paragraph 0117
[25]Current Patent Assignee: GLAXOSMITHKLINE PLC - US9950062, 2018, B2 Location in patent: Page/Page column 134
[26]Subedi, Yagya Prasad; Alfindee, Madher N.; Shrestha, Jaya P.; Becker, Greg; Grilley, Michelle; Takemoto, Jon Y.; Chang, Cheng-Wei Tom [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3034 - 3037]
[27]Current Patent Assignee: NAHLS; KYOTO UNIVERSITY; TOABO CORPORATION - JP2018/203682, 2018, A Location in patent: Paragraph 0084; 0085
[28]Ali; Assiri; Yahia; Zahran; Meselhy; Hussien [Russian Journal of Organic Chemistry, 2021, vol. 57, # 1, p. 79 - 84][Zh. Org. Khim., 2021, vol. 57, p. 79 - 84,6]

4
[ 5324-30-1 ]
[ 999-82-6 ]

Reference： [1]Synthesis,2001,p. 553 - 554
[2]Journal of the American Chemical Society,1965,vol. 87,p. 679 - 680
[3]Synthetic Communications,2003,vol. 33,p. 3781 - 3788

5
[ 54524-71-9 ]
[ 5324-30-1 ]
[ 80135-05-3 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium carbonate In N,N-dimethyl-formamide at 40℃;

Reference： [1]Krenitsky; Rideout; Koszalka; Inmon; Chao; Elion; Latter; Williams [Journal of Medicinal Chemistry, 1982, vol. 25, # 1, p. 32 - 35]

6
[ 2857-97-8 ]
[ 5324-30-1 ]
[ 69310-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃; for 24h;
	In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Shapiro, Gideon; Buechler, Dieter; Ojea, Vicente; Pombo-Villar, Esteban; Ruiz, Maria; Weber, Hans-Peter [Tetrahedron Letters, 1993, vol. 34, # 39, p. 6255 - 6258]
[2]Guenin, Erwann; Herve, Anne-Cecile; Floch, Virginie; Loisel, Severine; Yaouanc, Jean-Jacques; Clement, Jean-Claude; Ferec, Claude; Des Abbayes, Herve [Angewandte Chemie - International Edition, 2000, vol. 39, # 3, p. 629 - 631]
[3]Rigger, Lukas; Schmidt, Rachel L.; Holman, Kaitlyn M.; Simonovic, Miljan; Micura, Ronald [Chemistry - A European Journal, 2013, vol. 19, # 47, p. 15872 - 15878]

7
[ 5324-30-1 ]
[ 129365-25-9 ]
4-[2-(Diethoxy-phosphoryl)-ethyl]-piperazine-1,2-dicarboxylic acid 1-benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium carbonate In ethanol for 24h; Heating;

Reference： [1]Hays; Bigge; Novak; Drummond; Bobovski; Rice; Johnson; Brahce; Coughenour [Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2916 - 2924]

8
[ 5324-30-1 ]
[ 31166-44-6 ]
[ 81071-02-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine In benzene at 50 - 55℃; for 15h;

Reference： [1]Kametani, Tetsuji; Kigasawa, Kazuo; Hiiragi, Mineharu; Wakisaka, Kikuo; Haga, Seiji; et al. [Heterocycles, 1981, vol. 16, # 7, p. 1205 - 1242]

9
[ 5324-30-1 ]
[ 1068-90-2 ]
[ 107257-47-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydride; In toluene; at 110℃; for 24h;	Diethyl 2-bromoethylphosphonate (25.0 g, 102 mmol) was combined with toluene (70 mL), diethyl carbonate (40 mL), diethyl acetamidomalonate (16.9 g, 77.6 mmol), and 60% sodium hydride (4.40 g, 110 mmol) washed with hexane, followed by refluxing at 110 C. After being refluxed for 24 hours, the mixture was cooled down to room temperature, filtered through Celite to remove solids, and the filtrate was concentrated under vacuum. This gave brown, oily diethyl 2-acetamido-2-[2-(diethoxyphosphoryl)ethyl]malonate (33.3 g, in quantitative yield).
33.3 g	With sodium hydride; Diethyl carbonate; In hexane; toluene; mineral oil; at 110℃; for 24h;	To toluene (70 mL), diethyl carbonate (40 mL), diethyl acetamidomalonate (16.9 g, 77.6 mmol), and 60% sodium hydride (4.2 mL) were added to diethyl 2-bromoethylphosphonate (25.0 g, 40 g, 110 mmol) was washed with hexane was charged,And refluxed at 110 C.After refluxing for 24 hours,After cooling to room temperature,Filtration was carried out using celite,By concentrating the resulting filtrate under reduced pressure,Brown oilyTo obtain diethyl 2-acetamido-2- [2- (diethoxyphosphoryl) ethyl] malonate (33.3 g).

Reference： [1]Phosphorus and Sulfur and the Related Elements,1987,vol. 34,p. 93 - 104
[2]Patent: US2020/131207,2020,A1 .Location in patent: Paragraph 0098
[3]Patent: JP2018/203682,2018,A .Location in patent: Paragraph 0084; 0086; 0087

10
[ 5324-30-1 ]
[ 196302-98-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium azide In N,N-dimethyl-formamide; acetonitrile for 7h; Heating;
92%	With sodium azide In water; N,N-dimethyl-formamide for 48h; Reflux;	Preparationof diethyl 2-azidoethylphosphonate Asolution of sodium azide (1.3 g, 20.0 mmol) in water (5.0 mL) was added to avigorously stirred solution of diethyl 2-bromoethylphosphonate(2.4 g, 10.0 mmol) in DMF (20 mL) at roomtemperature.The mixture solution was stirred over 48 h at room temperature.The reaction course was monitored by 31PNMR. Thereaction was finished, and thesolution was extracted with dichloromethane (30 mL × 3), and the combined organic phase was dried over Na2SO4. Thesolvent was removed in vacuoand thecrude product was purified by flash column chromatography on silica gel usingEtOAc:hexane (1:1) as the eluent to afford the colorless oil2 (1.9 g, 92%).IR (KBr) ν (cm-1) =2103, 1248, 1028, 965. 1H NMR(CDCl3)d = 1.32 (t, J= 7.1 Hz, 6H, CH3), 2.04 (dt, J= 18.6 Hz, J = 7.7 Hz, 2H, PCH2), 3.52 (dt, J= 7.8 Hz, J = 7.7 Hz, 2H, NCH2), 4.07-4.11 (m, 4H, OCH2). 13C NMR(CDCl3) d = 61.7, 45.1 (d, J =10.0 Hz), 26.4 (d, J =140.0 Hz), 16.2. ESI MS: m/z = 208.0 [M+H]+.Spectroscopic data was in accordance with that reported literature.2
89%	With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water for 144h; Sealed tube;	i (i) Diethyl 2-azidoethylphosphonate 115 Diethyl 2-bromoethylphosphonate (500 mg, 2 mmol) was dissolved in DCM (10 mL) with tetrabutylammonium bisulfate (2.04 g, 6 mmol). A solution of sodium azide (1.30 g, 20 mmol) in distilled water was added (10 mL) and the resulting mixture was stirred vigorously in a sealed flask. The reaction progress was monitored by TLC. After 6 days, the product was extracted with diethyl ether (2×10 mL), dried over Na2SO4, filtered, and the solvent evaporated. The crude residue was purified via flash chromatography (1:1→3:1 EtOAc-hexanes) to afford the title compound (370 mg, 89%) as a white solid. Rf=0.225 (2:1 EtOAc-hexanes); IR vmax (neat) 2099, 1240, 1019, 957; 111 NMR (400 MHz, CDCl3) δ 1.34 (6H, t, J=6.9 Hz, CH3), 2.07 (2H, dt, J=18.6 Hz, J=7.8 Hz, CH2), 3.55 (2H, dt, J=12.6 Hz, J=7.5 Hz, CH2), 4.13 (4H, m, CH2); 13C NMR (400 MHz, D2O) δ 16.1, 24.72, 26.58, 45.13, 61.60; m/z (ESI) 208.08 [M+H]+, 230.07 [M+Na]+. The 1H and 13C NMR and MS data obtained were in agreement with that reported in the literature (Brunet, E. et al. Tetrahedron Lett. 2009, 50, 5361-5363).

87%	With sodium azide; tert-butylammonium hexafluorophosphate(V) In tetrahydrofuran at 60℃; for 48h;
85%	With sodium azide; tetrabutylammomium bromide In tetrahydrofuran for 48h; Reflux;
74%	With azide exchange resin on amberlite at 20℃; for 20h;
60%	With sodium azide In water at 100℃; for 0.5h; Microwave irradiation;	General procedure for the preparation of products 5a-e to 7a-e General procedure: Dialkyl ω-bromoalkylphosphonate (2.0 mmol) was added to the solution of NaN3 (3.0 mmol, 1.5 eq) in H2O (3 mL) placed in 10-mL pressure vial, equipped with magnetic stirrer. The reaction was carried under MW conditions. After that, reaction mixture was extracted with Et2O (4 10 mL). The combined organic layers were washed successively with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and evaporated under reduced pressure. The rest of the volatile material was removed at 35 °C / 27 Pa to give pure products 5-7. If necessary, products 5-7 were subjected to flash chromatography on silica gel.
46%	With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In toluene
	With sodium azide
	With Merrifield resin supported tetra-alkyl ammonium azide In dimethyl amine at 25℃; for 72h;
	With sodium azide; 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate at 80℃; for 2h;
	With sodium azide; tetrabutylammomium bromide In tetrahydrofuran for 48h; Reflux;	Diethyl (2-bromoethyl)phosphonate (2.5 g, 10 mmol) was dissolved in THF (50 mL).Tetrabutylammonium bromide (10 g, 30 mmol; TBAB) was added followed by sodium azide (6.5 g).The reaction mixture was refluxed for 2 days. The reaction mixture was poured in EtOAc (250 mL).Water (125 mL) was added. The slightly orange organic layer was separated and dried with Na2SO4.Evaporation under reduced pressure afforded the crude product as an oil (3.6 g). According to NMRanalysis ca. 25% product was present together with 75% TBAB. Mass only: M+1 208 found and 242(M+ Bu4N+). Diisopropyl ether (100 mL) was added to the crude oil. After mixing for 2 minutes the upper solution was decanted from the oily precipitate. Evaporation of the diisopropyl ether solventafforded diethyl (2-azidoethyl)phosphonate as a clear colorless oil, pure according to NMR analysis.
	With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In methanol at 65℃;	Synthesis of Diethyl (2-Azidoethyl)phosphonate (3) Diethyl (2-bromoethyl)phosphonate (2.00 mL, 11 mmol) and TBAHS (5.6 g, 16.5 mmol) were dissolved in methanol (MeOH; 50 mL). NaN3 (2.9 g, 44 mmol) was added and the reaction mixture was stirred at 65°C under a reflux condenser for 17 h. The solvent was evaporated to dryness and the residue diluted with Et2O (30 mL) and filtered through Celite. The filtrate was then washed with H2O (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.44 g, 63 %) as a yellow oil that was not purified further. Caution: azides are potentially explosive. δH (CDCl3, 400 MHz) 4.11 (4H, m), 3.53 (2H, dt, J 10.0, 6.4), 2.08 (2H, dt, J 10.4, 4.4), 1.33 (6H, t, J 7.9). δC (CDCl3, 75 MHz) 61.9, 45.2, 24.4, 16.2. The NMR data closely matched that previously reported.[26]
	With sodium azide In ethanol Inert atmosphere; Reflux;
	With sodium azide In N,N-dimethyl-formamide at 80℃; for 12h;
	With sodium azide In acetone at 60℃; Inert atmosphere;	General procedure for synthesis of azido-alkyl phosphonate (8a-8f) General procedure: 1-Bromoalkylphosphonate (3 mmol, 1 equiv.) was heated with sodium azide (9 mmol, 3 equiv.) in acetone and at 60°C overnight under nitrogen atmosphere for overnight. The reaction mixture was cool to room temperature and filtered through filter paper. The filtrate was concentrated, and the residue was re-dissolved in 30 mL dichloromethane and washed with 2x40 mL water. After evaporation of solvents, the azidoalkylphosphonate was obtained as an oil. Compound 8a-8c, and 8f are previously reported compounds 4, 7.

Reference： [1]Malakhov, D. V.; Semizarov, D. G.; Yas'ko, M. V. [Russian Journal of Bioorganic Chemistry, 1995, vol. 21, # 7, p. 464 - 469][Bioorganicheskaya Khimiya, 1995, vol. 21, # 7, p. 539 - 544]
[2]Li, Xu; Chen, Xiaolan; Yuan, Jinwei; Liu, Yang; Li, Peipei; Qu, Lingbo; Zhao, Yufen [Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 7, p. 961 - 971]
[3]Current Patent Assignee: Brimble, Margaret A.; Papst, Stefanie; Peltier, Raoul; Tilley, Richard D.; Williams, David E. - US2013/29920, 2013, A1 Location in patent: Paragraph 0711
[4]Location in patent: scheme or table Brunet, Ernesto; Juanes, Olga; Jiménez, Laura; Rodríguez-Ubis, Juan Carlos [Tetrahedron Letters, 2009, vol. 50, # 38, p. 5361 - 5363]
[5]Yang, Sung Hyun; Lee, Dong Jun; Brimble, Margaret A. [Organic Letters, 2011, vol. 13, # 20, p. 5604 - 5607]
[6]Location in patent: experimental part Dijkstra, Harmen P.; Sprong, Hein; Aerts, Bas N. H.; Kruithof, Cornelis A.; Egmond, Maarten R.; Klein Gebbink, Robertus J. M. [Organic and Biomolecular Chemistry, 2008, vol. 6, # 3, p. 523 - 531]
[7]Janczewski, Łukasz; Gajda, Anna; Braszczyńska, Julia; Gajda, Tadeusz [Synthetic Communications, 2016, vol. 46, # 19, p. 1625 - 1633]
[8]Yashunsky, Dmitry V.; Borodkin, Vladimir S.; Ferguson, Michael A. J.; Nikolaev, Andrei V. [Angewandte Chemie - International Edition, 2006, vol. 45, # 3, p. 468 - 474]
[9]Efimtseva; Mikhailov; Jasko; Malakhov; Semizarov; Fomicheva; Kern [Nucleosides and Nucleotides, 1995, vol. 14, # 3-5, p. 373 - 375]
[10]Blass, Benjamin E.; Coburn, Keith R.; Faulkner, Amy L.; Seibel, William L.; Srivastava, Anil [Tetrahedron Letters, 2003, vol. 44, # 10, p. 2153 - 2155]
[11]Artyushin, Oleg I.; Vorob'eva, Daria V.; Vasil'eva, Tamara P.; Osipov, Sergey N.; Roeschenthaler, Gerd-Volker; Odinets, Irina L. [Heteroatom Chemistry, 2008, vol. 19, # 3, p. 293 - 300]
[12]Seerden, Jean-Paul G.; Leusink-Ionescu, Gabriela; Woudenberg-Vrenken, Titia; Dros, Bas; Molema, Grietje; Kamps, Jan A.A.M.; Kellogg, Richard M. [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3412 - 3418]
[13]Dolan, Ciarán; Naysmith, Briar; Hinkley, Simon F. R.; Sims, Ian M.; Brimble, Margaret A.; Williams, David E.; Jin, Jianyong [Australian Journal of Chemistry, 2015, vol. 68, # 4, p. 680 - 686]
[14]Lam, Tina; Avti, Pramod K.; Pouliot, Philippe; Tardif, Jean-Claude; Rhéaume, Éric; Lesage, Frederic; Kakkar, Ashok [Journal of Materials Chemistry B, 2016, vol. 4, # 22, p. 3969 - 3981]
[15]Protasova, Irina; Bulat, Bekir; Jung, Nicole; Bräse, Stefan [Organic Letters, 2017, vol. 19, # 1, p. 34 - 37]
[16]Subedi, Yagya Prasad; Alfindee, Madher N.; Shrestha, Jaya P.; Becker, Greg; Grilley, Michelle; Takemoto, Jon Y.; Chang, Cheng-Wei Tom [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3034 - 3037]

11
[ 5324-30-1 ]
[ 109838-85-9 ]
[ 682-30-4 ]
[ 172342-72-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h;
26%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate; Diethyl vinylphosphonate In tetrahydrofuran; hexane at -78 - 20℃;	1a 1a) Diethyl {2-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]ethyl}phosphonate [Show Image] nBuLi (6.51 mL, 2.5 mol/L in hexanes, 16.3 mmol) was added at -78°C to a solution of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazin (2.91 mL, 16.3 mmol) in dry THF (30 mL). After 30 min a solution of diethyl (2-bromoethyl)phosphonate (2.84 mL, 15.5 mmol) and diethyl vinylphosphonate (0.13 mL, 0.81 mmol) in dry THF (20 mL) was added drop wise to the mixture. After further 10 min the mixture was warmed to r.t. and concentrated under reduced pressure. The residue was taken up in water (50 mL) and the solution was extracted with ethyl acetate (3 x 50 mL). The combines organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Hex/EE). Yield: m = 1.50 g, 4.31 mmol, 26%. MS (ESipos): m/z = 349 [M+H]+ 1H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 0.68 (d, 3H), 1.02 (d, 3H), 1.31 (td, 6H), 1.65 - 1.82 (m, 2H), 1.82 - 2.00 (m, 1H), 2.03 - 2.36 (m, 2H), 3.66 (s, 3H), 3.69 (s, 3H), 3.94 (t, 1H), 3.98 - 4.17 (m, 5H).

Reference： [1]Schick, Andreas; Kolter, Thomas; Giannis, Athanassios; Sandhoff, Konrad [Tetrahedron, 1995, vol. 51, # 41, p. 11207 - 11218]
[2]Current Patent Assignee: BAYER AG - EP2322514, 2011, A1 Location in patent: Page/Page column 26-27

12
[ 5324-30-1 ]
[ 142778-06-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium iodide In acetone at 75℃; for 24h; Inert atmosphere;
93%	With sodium iodide In acetone Heating;

Reference： [1]Kiyokawa, Kensuke; Suzuki, Itaru; Yasuda, Makoto; Baba, Akio [European Journal of Organic Chemistry, 2011, # 11, p. 2163 - 2171]
[2]Balczewski; Pietrzykowski [Tetrahedron, 1997, vol. 53, # 21, p. 7291 - 7304]

13
[ 5324-30-1 ]
[ 68076-36-8 ]
[ 144912-93-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium carbonate In ethanol Heating;
	With sodium carbonate In dichloromethane; chloroform	12 [2-(9,10-Dioxo-2,7-diazabicyclo[6.2.0]dec-1(8)-en-2-yl)ethyl]phosphonic acid A solution of (4-aminobutyl)carbamic acid 1,1-dimethylethyl ester (13.3 g, 71 mmol), sodium carbonate (11.25 g, 106 mmol) and diethyl 2-bromo-ethylphosphonate (20 mL, 104 mmol) in absolute ethanol (150 mL) was prepared under nitrogen. This mixture was refluxed overnight and was then concentrated in vacuo. The residue was dissolved in chloroform (150 mL) and then preadsorbed onto silica gel and purified by flash chromatography (7 cm diameter, gradient elution with 5-30% methanol in dichloromethane) to yield [4-[[2-(diethoxyphosphinyl)ethyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester as a colorless oil (13.7 g, 55%); MS (+FAB): 353 MH+, 100), 150 (68), 56 (83); 1 H NMR (CDCl3, 400 MHz): δ 5.01 (br s, NH), 4.17-4.03 (m, 4H),3.15-3.08 (m, 2H), 2.92 (d of t, J=15 and 7.5 Hz, 2H), 2.84 (br s, NH), 2.66 (br t, J=7 Hz, 2H), 2.02 (d of t, J=18 and 7.5 Hz, 2H), 1.56-1.52 (m, 4H), 1.43 (s, 9H), 1.33 (t, J=7 Hz, 6H).

Reference： [1]Kinney, William A.; Abou-Gharbia, Magid; Garrison, Deanna T.; Schmid, Jean; Kowal, Dianne M.; Bramlett, Donna R.; Miller, Tracy L.; Tasse, Rene P.; Zaleska, Margaret M.; Moyer, John A. [Journal of Medicinal Chemistry, 1998, vol. 41, # 2, p. 236 - 246]
[2]Current Patent Assignee: PFIZER INC - US5168103, 1992, A

14
[ 5324-30-1 ]
[ 292606-35-0 ]
[2-(3-tert-Butoxycarbonylamino-2,2-dimethyl-propylamino)-ethyl]-phosphonic acid diethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 236 - 246

15
[ 5324-30-1 ]
[ 144912-84-5 ]
[ 144912-85-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In dichloromethane; chloroform;	A solution of <strong>[144912-84-5](3-amino-2-hydroxypropyl)carbamic acid 1,1-dimethylethyl ester</strong> (7.73 g, 41 mmol), sodium carbonate (6.52 g, 62 mmol) and diethyl 2-bromoethylphosphonate (11.8 mL, 65 mmol) in absolute ethanol (150 mL) was prepared under nitrogen. This mixture was refluxed overnight and was then concentrated in vacuo. The residue was dissolved in chloroform (150 mL) and then preadsorbed onto silica gel and purified by flash chromatography (7 cm diameter, gradient elution with 2.5-20% methanol in dichloromethane) to yield [3-[[2-(diethoxyphosphinyl)ethyl]amino]-2-hydroxypropyl]carbamic acid 1,1-dimethylethyl ester as a colorless oil (11.16 g, 77%); IR (neat, cm-1): 3320, 1710, 1250, 1170, 1040; MS (+FAB): 355 (MH+, 68), 255 (90), 58 (100); 1 H NMR (CDCl3, 400 MHz): delta 5.23 (br s, NH), 4.16-4.05 (m, 4H), 3.77 (m, 1H), 3.32-2.90 (m, 4H), 2.73 (d of d, J=12 and 3.5 Hz, 1H), 2.58 (d of d, J=12 and 8.5 Hz, 1H), 2.00 (d of t, J=18 and 7 Hz, 2H), 1.43 (s, 9H), 1.32 (t, J=7 Hz, 6H).

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 236 - 246
[2]Patent: US5168103,1992,A

16
[ 553-26-4 ]
[ 5324-30-1 ]
C₂₂H₃₆N₂O₆P₂⁽²⁺⁾*2Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In acetonitrile at 65℃; for 120h;
	In water for 72h; Heating;
	at 20℃; for 12h;	2 Comparative Example 2 4,4'-bipyridinium-bis(diethyl phosphonic acid) Dichloride Salt (VIII) (PVP) 3.12 g of 4,4'-Dipyridyl was mixed with 10.1 g of diethyl-(2-bromoethyl) phosphonate and the mixture was reacted for 12 hours at room temperature. 500 ml of cold diethylether was added thereto, followed by stirring for additional 1 hour and filtration of precipitate. The precipitate was washed with 50 ml of diethylether three times and dried under vacuum to obtain 11.6 g of compound (VII). 11.6 g of compound (VII) obtained as described above was dissolved in 100 ml of 6N HCl and reacted under reflux for 24 hours. After evaporation of the solvent, recrystallization was performed by using H2O, MeOH and THF to obtain 6.85 g of compound (VIII).

Reference： [1]Felderhoff, Michael; Heinen, Susanne; Molisho, Ngongo; Webersinn, Simona; Walder, Lorenz [Helvetica Chimica Acta, 2000, vol. 83, # 1, p. 181 - 192]
[2]Cummins, David; Boschloo, Gerrit; Ryan, Michael; Corr, David; Rao, S. Nagaraja; Fitzmaurice, Donald [Journal of Physical Chemistry B, 2000, vol. 104, # 48, p. 11449 - 11459]
[3]Current Patent Assignee: LG CHEM CO.,LTD. - US2009/137807, 2009, A1 Location in patent: Page/Page column 9

17
[ 5324-30-1 ]
[ 56-40-6 ]
[ 210306-41-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In water at 80℃; for 3h;

Reference： [1]Yu, Peilin; Wang, Wei; Zhang, Hua; Yang, Xueyong; Liang; Gao, Xiaolian [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 1, p. 107 - 119]

18
[ 5324-30-1 ]
[(Z)-2-(Diphenyl-phosphinoyl)-1-methyl-vinyl]-p-tolyl-amine [ No CAS ]
[3-(diphenyl-phosphinoyl)-4-<i>p</i>-tolylamino-pentyl]-phosphonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: [(Z)-2-(Diphenyl-phosphinoyl)-1-methyl-vinyl]-p-tolyl-amine With methyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran; diethyl ether at 20℃; for 12h; Stage #3: With sodium cyanoborohydride; zinc(II) chloride In ethanol for 24h; Heating;