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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron Lett. Author manuscript; available in PMC 2017 April 11.
Published in final edited form as:
Tetrahedron Lett. 2016 April 11; 57(19): 2097–2099.
doi:  10.1016/j.tetlet.2016.03.111
PMCID: PMC4838999
NIHMSID: NIHMS776905

Convenient synthesis of phosphonohydrazines from arylamines

Abstract

Phosphonohydrazines were prepared in good yield from corresponding arylamines by a one-pot reaction through diazotization with an organic nitrite and treatment with a trialkyl phosphite. The trialkyl phosphite is postulated to function as a nucleophile as well as a reducing agent.

Keywords: phosphonohydrazine, arylamine, alkyl nitrite, diazo compounds, trialkyl phosphite, reduction

Graphical Abstract

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1. Introduction

Arylamines react readily with inorganic nitrite in acid to form diazonium compounds, which can be transformed to halides and other derivatives through the Sandmeyer reaction.1 The reaction of aryl amines with organic nitrite is reported to form a series of diazo compounds as shown in Scheme 1. The formation and reaction of diazoamino compound 1 have been established and carefully investigated; whereas the formation of diazo intermediates 2 and 3 has not been fully established.29 The formation of aryl radical intermediates from the decomposition of these diazo intermediates has been utilized in aryl-aryl coupling reactions.59 The aryl radical intermediates were also implicated in the conversion of aryl amines to aryl halides in the presence of organic nitrite as an alternative method to the Sandmeyer reaction.4,10,11 In Meerwein and related reactions, cupric chloride was proposed to catalyze the direct decomposition of aryldiazonium to from aryl radicals in the arylation of α,β-unsaturated carbonyl compounds.12,13

2. Results and Discussion

We are interested in the synthesis of arylphosphonate esters. Dialkylphosphite has been reported to react with alkenes to form phosphonate and phosphite radical from the homo-cleavage of the P–H bond was proposed as the reactive intermediate.14 We thus sought to prepare aryl phosponate esters through radical coupling of the phosphite radical and aryl radicals derived from arylamines as depicted in Scheme 1. However, aryl-phosphorus coupling did not occur when arylamine was treated with alkyl nitrite in the presence of dialkyl or trialkyl phosphite. When trialkyl phosphite was used, phosphonohydrazines 4 were formed in good yield instead (Scheme 2). In this Letter, we report the one-pot reaction of arylamines with isoamyl nitrite in the presence of triisopropyl phosphite to form phosphonohydrazines in good yield.

Phosphonohydrazines have been proposed as potential candidates for novel insecticides.15 Simple phosphonohydrazines (without aryl groups) were synthesized by the reaction of monochlorophosphonate and hydrazine.1618 In a special case, 2,4-dinitrophenylated phosphonohydrazine has been isolated as a rearranged product from the reaction of bis(2,4-dinitrophenyl) phosphate with hydrazine.19 This reaction therefore presented a convenient method for the preparation of phosphoryl derivatives of aromatic hydrazines.

The reaction was conveniently carried out in one pot and works with mild electron-donating and electron-withdrawing substituting groups on the aromatic ring as shown in Table 1.20 Arylamines with strong electron-withdrawing or electron-donating groups such as nitro and methoxy groups, respectively, did not react very well. It may be difficult to form intermediates such as 3 from arylamines with strong electron-withdrawing groups. On the other hand, the reaction of diazo intermediates with phosphite (first step in the proposed mechanism shown in Scheme 3) may not proceed well when strong electron-donating group is present.

Table 1
Transformation of arylamines to phosphonohydrazines

The reaction progress was monitored by thin-layer chromatography (TLC). In most cases, the reaction was completed in three hours. However, reactions run overnight did not seem to decrease the yield. The products were characterized using NMR and HRMS and the yields were found to be generally moderate to very good (Table 1).20

The mechanism of the reaction is still under investigation. However, it is conceivable that the reaction involves nucleophilic attack by phosphite on intermediate such as 3 to form phosphonium intermediate 5 as shown in Scheme 3. Elimination of the isopropyl group leads to the formation of the phosphorus-oxygen double bond in phosphonodiazo intermediate 6. Subsequent reduction of the diazo moiety in 6 by phosphite generates the final product 4. Phosphites are known to be excellent reducing agents and the reduction of N–N bonds in diaziridinones and N–O bonds in nitro compounds has been reported.2123 Further mechanistic investigation is currently under way and focuses on the characterization of reaction intermediates.

3. Conclusion

In summary, arylamines can be converted to aromatic phosphonohydrazines in good yield by reacting with organic nitrite in the presence of trialkyl phosphite. The reaction is likely to involve diazo intermediates formed by the reaction of arylamines and alkyl nitrite. Trialkyl phosphite is postulated to be the nucleophile as well as reducing agent. Considering the convenient and efficient one-pot nature of the reaction, this mechanistically interesting transformation represents an excellent method for the preparation of some aromatic phosphonohydrazines.

Highlights

  • Phosphonohydrazines were prepared in good yield from corresponding arylamines.
  • The reaction involves nucleophilic addition of trialky lphosphite to a diazo intermediate.
  • The trialkyl phosphite functions as reducing agent as well.

Acknowledgments

This investigation was supported by the National Institutes of Health, Grant SC1 GM095419 (W.W.), Departmental Summer Research Fellowship and CSUPERB Presidents’ Commission Scholarship (D.J.B.), National Institutes of Health MARC (M.L.M.) and RISE (J.R.G.) Scholarships. We thank Dr. Robert Yen for obtaining the mass spectra. The Mass Spectrometry Facility was funded by the National Science Foundation (CHE-1228656). The NMR facility was funded by the National Science Foundation (DUE-9451624 and DBI 0521342). We also thank Professor Ihsan Erden for helpful discussions and Sam Weick for technical assistance.

Footnotes

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References and Notes

1. Smith MB, March J. March’s Advanced Organic Chemistry. Reactions, Mechanisms, and Structure. 5. Wiley; New York: 2001.
2. Muller E, Haiss H. Chem Ber. 1963;96:571–583.
3. Kidd HVJ. Org Chem. 1937;2:198–208.
4. Smith WB, Ho OC. J Org Chem. 1990;55:2543–2545.
5. Hardie RL, Thopson RH. J Chem Soc. 1958:1286–1290.
6. Dyall LK, Pausacker KH. J Chem Soc. 1961:18–23.
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8. Ruchardt C, Merz E. Tetrahedron Lett. 1964;5:2431–2436.
9. Friedman L, Chlebowski JF. J Org Chem. 1968;33:1633–1636.
10. Friedman L, Chlebowski JF. J Org Chem. 1968;33:1636–1638.
11. Nair V, Richardson SG. J Org Chem. 1980;45:3969–3974.
12. Meerwein H, Buchner E, van Emsterk K. J Prakt Chem. 1939;152:237–266.
13. Doyle MP, Siegfried B, Elliott RC, Dellaria JF., Jr J Org Chem. 1977;42:2431–2436.
14. Nifantev EE, Magdeeva RK, Dolidze AV, Ingorokva KV, Vasyyanina, Russ LK. J Gen Chem. 1993;63:1201–1205. Zh. Obshch. Khim. 1993, 63, 1718–1725.
15. Jacobson RM, Nguyen LT. 6147062. US Patent. 2000
16. Cao LH, Zhou CJ, Gao HY, Liu YT. J Chinese Chem Soc. 2001;48:207–210.
17. Tolkmith H. J Am Chem Soc. 1962;84:2097–2104.
18. Timperley C. Best Synthetic Methods: Organophosphorus (V) Chemistry. 1. Elsevier; London: 2015.
19. Domingos JB, Longhinotti E, Brandao TAS, Santos LS, Eberlin MN, Bunton CA, Nome F. J Org Chem. 2004;69:7898–7905. [PubMed]
20. Experimental details: All reagents were obtained from commercial sources and used without further purification. Typical experimental procedures are described below using the 4-bromophenyl derivative (4a) as an example.
Isopentyl nitrite (292 mg, 2.5 mmol) was added to a solution of 4-bromoaniline (172 mg, 1.0 mmol) in triisopropyl phosphite (1 mL). The solution was stirred for three hours (monitored by TLC). The excess triisopropyl phosphite was removed by vacuum and the residue was purified by column chromatography using 50:50 hexanes/methylene chloride as eluents. The product 4a was obtained as an off-white solid (182 mg, 52%). 1H NMR δ (ppm, CDCl3) 7.32 (2H, d, aromatic, J = 9.0); 6.82 (2H, d, aromatic, J = 9.0); 5.39 (1H, s, NH-Ar); 4.74-4.66 (3H, m, NH-P, 2 x CH); 1.34 (6H, d, 2 x CH3, J = 6.0); 1.27 (6H, d, 2 x CH3, J = 6.0). δ (ppm, DMSO-d6) 7.32 (1H, s, NH-Ar); 7.26 (2H, d, aromatic, J = 8.5); 6.93 (1H, d, NH-P, J = 33.9); 6.80 (2H, d, aromatic, J = 8.5); 4.50 (2 H, m, 2 x CH); 1.23 (6H, d, 2 x CH3, J = 6.0); 1.19 (6H, d, 2 x CH3, J = 6.0). 13C NMR δ (ppm, CDCl3) 147.61, 131.82, 114.84, 112.72, 72.26, 23.79. HRMS (Electrospray, negative mode) m/z calculated for C12H19BrN2O3P (M-H) 349.0317, found 349.0323.
21. Greene FD, Bergmark WR, Pazos JF. J Org Chem. 1970;35:2813–2814.
22. Cadogan JIG, Cameron-Wood M, Mackie K, Searle RJG. J Chem Soc. 1965:4831–4837.
23. Reactions between diazonium salts and trivalent phosphorus did not produce phosphonohydrazines as product. Reduction of diazoniums to arenes were observed instead, see: Yasui S, Fujii M, Kawano C, Nishimura Y, Shioji K, Ohno AJ. Chem Soc, Perkin Trans. 1994;2:177–183.