synth for pyridine n-oxide?
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0828 (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0828)
are you thinking about reducing the pyridine ring also?
What a great post, Ritter. Thank you very much. But mabey it isn't even necessary to reduce the intermediate 4-nitropyridine-N-oxide before reducing the nitro group. In the following article, they do the two reactions in one step.
SYNTHESIS OF 4-AMINOPYRIDINE AND 4-ACETYLAMINOPYRIDINE BY REDUCTION OF 4-NITROPYRIDINE-N-OXIDE WITH IRON AND MINERAL ACIDS
Vladimir N. Bulavka*, Igor I. Boiko
“Technologist Co. Ltd.”, 2 Mendeleev sq., Pereslavl-Zalessky, Yaroslavl reg., 152020, Russian Federation
E-mail: main@tech.users.botik.ru
*at present time: “Slavich Company”, 2 Mendeleev sq., Pereslavl-Zalessky, Yaroslavl reg.,152020, Russian Federation. E-mail: nifti@slavich.ru
Received: 9 August 2000 / Uploaded: 16 August
The usual way of commercial 4-aminopyridine preparation is a two-stage synthesis starting from pyridine and including 1-(4-pyridyl)pyridinium chloride hydrochloride as an intermediate. The total yield is 36-40% [1, 2, 3].
A semipreparative scale three-stage synthesis including pyridine-N-oxide and 4-nitropyridine-N-oxide as an intermediates is preferable. At the third stage 4-nitro-pyridine-N-oxide was reduced with iron and acetic acid at reflux temperature to produce 4-aminopyridine in quantitative yield. The reaction demands continuous extraction with diethyl ether of the title compound. The total yield is 65% [4].
In order to avoid the use of special equipment for continuous extraction with diethyl ether (or a large amount of diethyl ether for ordinary extraction) we tried to minimize the acid excess. All our attempts to minimize the amount of acetic acid or replace its excess with water failed. The precipitation of basic ferric acetates and/or extensive 4-aminopyridine hydrolysis to 4-pyridone were observed.
We studied the reduction of 4-nitropyridine-N-oxide with iron and aqueous mineral acids. The reduction with iron and hydrochloric acid gives mainly 4-aminopyridine (80-85%), and as by-products 4-aminopyridine-N-oxide, 4-pyridone, and 4,4’-azopyridine. The reduction with iron and 25-30% sulphuric acid proceeds slowly, but the yield of the desired 4-aminopyridine is better. The isolation of the reaction product after reduction, subsequent neutralization with sodium carbonate, and filtration was carried out by two methods. The first method was extraction with ethyl acetate. After removal of the solvent 4-aminopyridine was obtained in 85-90% yield. The second method was the concentration of the filtrate on the rotatory evaporator, extraction with ethanol, and after evaporation of ethanol reextraction with hot benzene to give a title compound after cooling (85%).
After evaporation of the solvent, crude 4-aminopyridine, if desired, was acetylated with acetic anhydride to produce 4-acetylaminopyridine in 80-85% yield [5].
When the neutral or basic aqueous solutions containing of 4-aminopyridine were heated for concentration, partial hydrolysis to 4-pyridone was observed. It caused some decreased yields of desired compound.
References
1. Koenigs, E., Greiner, H. 4-Pyridylpyridinium dichloride and the synthesis of g-derivatives of pyridine. Ber. 1931, 64B, 1049.
2. Koenigs, E., Greiner, H. Verfahren zur Darstellung von Pyridinderivaten. DRP 536891 (12p 1/01), 28.10.1931, appl. K115847 (IVa/12p), 24.07.1929.
3. Wibaut, J. P., Herzberg, S., Schlatmann, J. Note on the preparation of 4-amino-pyridine. Rec. trav. chim., 1954, 73, 140-142.
4. den Hertog, H. J., Overhoff, J. Pyridine and quinoline derivatives. LXXXII. Pyridine-N-oxide as an intermediate for the preparation of 2- and 4-substituted pyridines. Rec. trav. chim., 1950, 69, 468-473.
5. 4-Acetylaminopyridine monohydrate, m. p. 145-147oC (from 96% ethanol);
MS (“Selmi” TOF-spectrometer, +25kV), (m/z): M+ 136,8.
PMR (Bruker AC-300), (CCl4 and (D3C)2SO) (p. p. m.): 3,02 (3H, s, CH3);
7,52 (2H, d, 3- and 4-H); 8,33 (2H, d, 2- and 5-H); 10.05 (1H, bs, NH).
Further details about the reduction can be found here:
ONE-POT SYNTHESIS OF 4-PYRIDONE FROM 4-NITROPYRIDINE-N-OXIDE
Vladimir N. Bulavka1, Igor’ I. Boiko2
1) "Slavich Company", Mendeleev sq. 2, Pereslavl-Zalesskiy, Yaroslavl reg., 152025, Russian Federation. E-mail: nifti@slavich.botik.ru
2) "Technologist Co., Ltd.", Mendeleev sq. 2, Pereslavl-Zalesskiy, Yaroslavl reg., 152025, Russian Federation. E-mail: main@tech.users.botik.ru
Received: 20 August 2001 / Uploaded 21 August 2001
4-Pyridone (4-hydroxypyridine) is a convenient synthon for obtaining plurality of biologically active pyridine derivatives. For our opinion, elaboration of one more method for its synthesis proved to be useful.
Earlier we have described formation of 4-pyridone as by-product in the synthesis of 4-aminopyridine at reduction of 4-nitropyridine-N-oxide with iron and mineral acids. We also have assumed that the process can to be modified for 4-pyridone synthesis [1]. Here we present the procedure elaborated for one-pot synthesis of 4-pyridone from 4-nitropyridine-N-oxide.
Experimental part
In the 100 ml round-bottom flask were placed 1,4 g (0,01 mol) of 4-nitropyridine-N-oxide, 2,23 g (0, 04 mol) of iron powder, and 18 ml of water. During 1 hr 6,8 ml (0,08 mol) of 36% hydrochloric acid was added to the reaction mixture with stirring. The reaction mixture became warm. After the addition complete, the reaction mixture was gentle refluxed for 3 hr. After cooling, the solution 3,6 g (0,09 mol) of sodium hydroxide in 8 ml of water was added and reaction mixture was refluxed again for 2 hr (until the formation of ammonia ceased). Then the reaction mixture was neutralised with ca.0,85 ml (0,01 mol) of 36% hydrochloric acid to pH 7. The solvent was evaporated in vacuo (rotatory evaporator) almost to dryness. Ethanol (20 ml) was added to the residue, mixture was warmed, filtered with suction and precipitate washed twice with additional 5 ml portions of hot ethanol. The filtrate was evaporated to dryness and the residue exstracted with 6 ml of hot ethanol in 1,5-2 ml portions. The extract was evaporated, 2 ml benzene added, the crystals filtered, washed 1 ml of bezene and dried. Crude 4-pyridone 0,86 g (0,009 mol, 90%) was obtained. M. p. 148-150oC. 1H NMR (CD3OD): 6,5 (d., 2H), 7,8 (d., 2H). MS (m/z): (M+1)+ 96 (20%); 40 (60%), 38 (100%), 23 (40%).
References
1. V. N. Bulavka, I. I. Boiko. Formation of 4-pyridone at obtaining of 4-aminopyridine. IX All-Russian conference "Carbonyl compounds in the synthesis of heterocycles". (Russian Federation, Saratov, September 25-28, 2000). (In the scientific book: "The new achivements in the chemistry of carbonyl and heterocyclic compounds" Edited by Prof. A. P. Kriven’ko. Saratov university edition, 2000. P. 28-30). (Russian).
A procedure for the nitration of of 3-methylpyridine-N-oxide can be found at:
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?rxntypeid=181&prep=CV4P0654 (http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?rxntypeid=181&prep=CV4P0654)
I 've also found a little review about the chemistry of pyridine-N-oxide:
http://www.arkat-usa.org/ark/journal/Volume2/Part3/General/1-180B/180.htm (http://www.arkat-usa.org/ark/journal/Volume2/Part3/General/1-180B/180.htm)
http://abc.net.au/beasts/evidence/prog5/page4.htm (http://abc.net.au/beasts/evidence/prog5/page4.htm)
Patent DE536891 (http://l2.espacenet.com/dips/viewer?PN=DE536891&CY=gb&LG=en&DB=EPD)