[17508-17-7]  · C6H5N3O5  · O-2,4-Dinitrophenylhydroxylamine  · (MW 199.14)

(widely applicable electrophilic amination reagent; converts aldoximes to cyanides and benzofurans)

Alternate Names: DNPHA; NH2ODNP.

Physical Data: pale yellow needles, mp 112-113 °C. A rapid active-site-directed inhibitor of D-amino acid oxidase.1

Preparative Methods: can be generated economically from the reaction of 2,4-dinitrochlorobenzene and ethyl N-hydroxyacetimidate with subsequent hydrolysis.2 t-Butyl N-hydroxycarbamate3 and N-hydroxy-5-norbornene-2,3-dicarboximide4 can be used in place of ethyl N-hydroxyacetimidate.

Handling, Storage, and Precautions: an otherwise stable, crystalline solid, DNPHA has been known to detonate when combined with Potassium Hydride and therefore direct combination of these two reagents should be avoided.5 2,4-Dinitrophenol, a byproduct of amination reactions involving DNPHA, is a highly toxic, flammable solid. Use in a fume hood.

Conversion of Aldoximes to Cyanides and Benzofurans.

The title compound has been used in a convenient, high-yield conversion of aldehydes to nitriles via oximes.6 Oximes derived from a variety of aldehydes and ketones have also been used in the formation of 5,7-dinitrobenzofurans via the Fischer reaction (eq 1).7

Preparation of Dialkylamines.

A number of reagents exist for the preparation of primary,8 secondary,9 and tertiary amines10 from organoboranes; a common feature of all these reagents is the lone leaving group on nitrogen. Consequently, these reagents are suitable for transferring only one alkyl group from the organoborane; transfer of two alkyl groups from the organoborane to the same nitrogen requires two leaving groups on the nitrogen. This dual transfer can be achieved with the use of N-chloro-O-(2,4-dinitrophenyl)hydroxylamine generated in situ from DNPHA. In the following example, reaction of DNPHA with t-Butyl Hypochlorite followed by addition of perhydroboraphenalene and subsequent peroxide oxidation gives the amino alcohol (eq 2).11

Amination Reactions.

Electrophilic amination constitutes the major use of DNPHA in synthesis; attack on the amine nitrogen of DNPHA readily occurs in an SN2 fashion. The stability of DNPHA relative to the corresponding O-arylsulfonylhydroxylamines,7c which also have been used for these transformations, and the good leaving-group ability of the 2,4-dinitrophenolate anion both enhance its usefulness. The primary substrates for amination by DNPHA are nitrogen-containing compounds in the form of heterocycles or disubstituted amino derivatives. Many species have been N-aminated, including pyrroles,3 pyridines,12 nucleosides,13-16 carbamates,17-19 amides,18 phthalimides,3,20 sulfonamides,3 thiazolidines,21 and triazin-5(2H)-ones;22-24 an example of a sulfonamide is given in eq 3.3 In the case of guanine14 and 2-amido- and 2-carbamoylthiophenes,18 however, other amination reagents have proven more efficacious; furthermore, nucleosides are aminated at the most basic endo nitrogen position.13 Primary25 and tertiary26 amines have also been N-aminated by this method.

DNPHA has been used to aminate other heteroatoms as well. Phenol derivatives27 (including hydroxycoumarins),28 thiophenol derivatives,11 and phosphines11 have all been successfully converted to their O- S-, and P-amino derivatives by this reagent. In addition, aliphatic compounds such as malonates5 and aromatic compounds such as fluorene derivatives3 have been aminated at the active carbon center. An interesting reaction involving a boraalkane has also been reported.29

The kinetics of DNPHA addition are first-order with respect to both substrate and nucleophile and are second-order overall.11

1. (a) D'Silva, C.; Williams, C. H., Jr.; Massey, V. B 1986, 25, 5602. (b) D'Silva, C.; Williams, C. H., Jr.; Massey, V. B 1987, 26, 1717.
2. Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M. JOC 1973, 38, 1239.
3. Sheradsky, T.; Salemnick, G.; Nir, Z. T 1972, 28, 3833.
4. Rougny, A.; Daudon, M. BSF 1976, 833.
5. Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. JOC 1979, 44, 4836.
6. Miller, M. J.; Loudon, G. M. JOC 1975, 40, 126.
7. Sheradsky, T. JHC 1967, 4, 413.
8. (a) Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S. JACS 1964, 86, 3565. (b) Rathke, M. W.; Inoue, N.; Varma, K. R.; Brown, H. C. JACS 1966, 88, 2870. (c) Tamura, Y.; Minamikawa, J.; Fujii, S.; Ikeda, M. S 1974, 196.
9. (a) Suzuki, A.; Sono, S.; Itoh, M.; Brown, H. C.; Midland, M. M. JACS 1971, 93, 4329. (b) Brown, H. C.; Midland, M. M.; Levy, A. B. JACS 1972, 94, 2114. (c) Brown, H. C.; Midland, M. M.; Levy, A. B. JACS 1973, 95, 2394.
10. Davies, A. G.; Hook, S. C. W.; Roberts, B. P. JOM 1970, 23, C11.
11. (a) Mueller, R. H. TL 1976, 2925. (b) Mueller, R. H.; Thompson, M. E.; DiPardo, R. M. JOC 1984, 49, 2217.
12. Oae, S.; Yamamoto, F. TL 1973, 5143.
13. Huang, G.-F.; Okamoto, T.; Maeda, M.; Kawazoe, Y. TL 1973, 4541.
14. Maeda, M.; Abiko, N.; Uchida, H.; Sasaki, T. JMC 1984, 27, 444.
15. Kohda, K.; Baba, K.; Kawazoe, Y. T 1990, 46, 1531.
16. Kohda, K.; Baba, K.; Kawazoe, Y. CPB 1986, 34, 2298.
17. Kim, M.; White, J. D. JACS 1975, 97, 451.
18. Kim, M.; White, J. D. JACS 1977, 99, 1172.
19. Binder, D.; Habison, G.; Noe, C. R. S 1977, 487.
20. Fuchigami, T.; Sato, T.; Nonaka, T. Electrochim. Acta 1986, 31, 365.
21. Iwata, C.; Watanabe, M.; Okamoto, S.; Fujimoto, M.; Sakae, M.; Katsurada, M.; Imanishi, T. S 1988, 261.
22. Rees, C. W.; Sale, A. A. JCS(P1) 1973, 545.
23. Sanemitsu, Y.; Nakayama, Y.; Shiroshita, M. JHC 1982, 19, 1583.
24. Sanemitsu, Y.; Nakayama, Y.; Shiroshita, M. JHC 1983, 20, 1671.
25. Gálvez, C.; García, F. JHC 1984, 21, 393.
26. Schmidhammer, H.; Obendorf, D.; Pirkner, G.-F.; Sams, T. JOC 1991, 56, 3457.
27. Castellino, A. J.; Rapoport, H. JOC 1984, 49, 1348.
28. Bender, D. R.; Hearst, J. E.; Rapoport, H. JOC 1979, 44, 2176.
29. Mikhailov, B. M.; Shagova, E. A.; Etinger, M. Yu. JOM 1981, 220, 1.

John R. Bellettini, Erik R. Olson, Min Teng & Marvin J. Miller

University of Notre Dame, IN, USA

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