3825
HENRYE. BAUMGARTEN AND HELEXCHIEX-FAN Sv
3,4-Epo~-2,5-dimethoxytatrahydofur~ (X).-To a suspension of 60.7 g. (1.1 moles) of powdered potassium hydroxide in 250 ml. of dry ether was added slowly with stirring a solution of 62.5 g. (0.34 mole) of the chlorohydrin in 275 ml. of dry ether, whereupon an orange coloration rapidly developed. After the heat of reaction had subsided, the mixture was shaken mechanically for 9 hours. The precipitated salts were removed by filtratiori and \rashed thoroughly with ether. After drying the combined filtrates over magnesium sulfate, the solvent was removed and the crude epoxide (43.3 g . ) w'is distilled through a 15-cm. vacuum-jacketed Vigreux column. The colorless distillate, b.p. 48-53' (0.5 mm.), 35.1 g. (TO%), partially crystallized to yield 17.1 g. of needles, 1tr.p. 42.5-45'. A sample mas evaporatively distilled to give long needles, m.p. 43-46". Anal. Calcd. for CsHlnOl: C, 4 Y 31; I€, 6.90. Found: C, 48.99; H, 6.84. The oil remaining after separation of crystalline (X) contained a small amount of impurity which prevented the further crystallization of the low-melting material. However, this oil was sufficiently pure for use in subsequent reactions. 3-Hydroxy-2,5-dimethoxytetrahydrofuran(XI).-.% solution of 17.1 g. (0.117 mole) of X in 175 ml. of dry ether was added dropwise over a 40-minute period t o a suspension of 2.24 g. (0.059 mole) of lithium aluminum hydride in 100 ml. of dry ether. During the addition period, the heat of reaction maintained the ether a t reflux. Stirring w a s cotitinued for 2 hours, and then the excess hydride was decomposed with 10 ml. of water followed by 30 ml. of 6 LV sodium hydroxide solution. After separating the ether layer, the aqueous layer was extracted with three 200-nil. portions of
[CONTRIBUTION FRUX AVERY
Vol. i 4
ether, and the combined extracts were dried over magnesium sulfate. The other was removed and the residue was distilled through a short Vigreux column. The yield of colorless 3-hydroxp-2,5dimethoxytetrahydrof~ranamounted to 15.0 g. (87%); b.p. 48-51' (0.9 mm.), ~ S 1.4382. D Anal. Calcd. for CsH120,: C,48.64; H, 8.17. Found: C, 48.73; H, 7.98. 6-Hydroxytropinone (XIV).-A solution of 15.0 g. (0.10 mole) of XI in 75 ml. of N hydrochloric acid was heated on a steam-cone for 8 minutes. The resulting orange solutioii was freed of methanol by concentration. Acetonedicarboxylic acid (29.2 g., 0.20 mole) and methylamine hydrochloride (8.78 g., 0.13 mole) were dissolved in 400 ml. of citrate buffer solution (PH 5). The aqueous solution of malicaldehyde was then added, and the acidity adjusted t o pH 5.0 with 6 Nsodinm hydroxidesolution The resultant orange solution (700 ml.) evolved carbon dioxide vigorously After 32 hours the red-orange reaction mixture (PH 6.1 ) M ,I saturated with potassium carbonate and coutinuously extracted with ether for 4 days. Removal of the ether gave 8.1 g. of a clear orange oil which partially crystallized on standing at room temperature. Trituration with ether containing a sinal1 amount of ethanol gave 1.67 g. of colorless lleCdk5, m.p. 121.5123'. The residual oil, oil similar treatmerit, yielded additional crops amounting to 1.45 g., bringing the total yield t o 3.12 g. (20%). A sample sublimed at 70' (0.2 mm.) gave tiny prisms, m.p. 122.5-123.5". Anal. Calcd. for CSHI&TOt: C, 61.91; H, 8.44; N, 9.03. Found: C, 62.12; H, 8.57; N,8.91.
-
C ~ R I D G39, E MASSACHUSETTS
LABORATORY, UNIVERSITY
OF XEBRASKA]
Synthesis of 3- and 5-Nitro-2-picoline and Derivatives BY HENRY E. BAUMGARTEN AND HELEN CHIEN-FAN Su IIBCE~VED FEBRUARY 25. 1952
6-Amino-5-nitro-2-picoline has been converted successively into 6-hydroxy-, B-chloro- and 6-hydrazino-5-nitro-2-picoline and the latter has been oxidized to 5-nitro-2-picoline. By a similar sequence, 6-amino-3-nitro-2-picolinehas been converted into 3-nitro-2-picoline. Several derivatives of the intermediate and final products have been prepared and characterized.
Investigations concerning the synthesis of polynuclear heterocyclic bases required the preparation of 5-nitro-%picoline (V), 3-nitro-2-picoline (XIIIj , and some of their ring-substituted derivatives. Plazekl has reported the formation of V (and possibly XIII) in trace amounts through the direct nitration of 2-picoline, but the method was stated not to be of preparative value. The only other reported syntheses of derivatives of V and XI11 are those of Parker and Shive,2who nitrated 6-amino-2picoline to obtain the readily separable isomers, 6amino-5-nitro-2-picoline (I) and 6-amino-3-nitro-2picoline (VI), and converted these substances into a number of 2-picoline derivatives. This communication reports the preparation of V, XI11 and several of their derivatives through the modification and extension of the procedures of Parker and Shive as outlined in the flow sheet. Parker and Shive2 converted I and VI directly into 6-chloro-5-nitro-2-picoline (111) and 6-chloro-3nitro-2-picoline (VIII), respectively, by diazotization of the amino compounds with sodium nitrite and concentrated hydrochloric acid in sealed tubes. As is the usual experience in such procedure^,^
yields of less than SOY0 were obtained (38y0for 111 and 29% for VIII) and a considerable portion of the product consisted of the corresponding 6-hydroxy compounds, I1 (30%) and VI1 (49%). A two-step conversion4 of 2-amino-substituted pyridines to the 2-chloro compounds has given, in general, more satisfactory results, Thus, in this work I was converted into I1 in 92y0 yield by diazotization in cold sulfuric acid solution and then I1 was transformed into 111in 86% yield by treatment with a mixture of phosphorus pentachloride and phosphorus oxychloride. Similarly, VI was converted successively into VI1 (98% yield) and VIII (80% yield). I n the work described below it became increasingly apparent that there was a pronounced difference in reactivity between the halogen atoms of compounds 111 and VIII, the compound with the chlorine atom and nitro group ortho to each other (111) being the more reactive. A similar compasiSon has been drawn previously between 4chloro-3the nitropyridine and 2-chlor0-5-nitropyridine,~ former being more reactive. Thus, when VI11 was treated with a rnethanolic solution of sodium methoxide, an 82y0 yield of 6-methoxy-3-nitro-2-pico-
( 1 ) E. Plazck, Bar., 7BB, 577 (1039) 12) E. D. Parker and W. Shive, THISJOURNAL, 69, 03 (1847) (3) H S . Mosher in R. C. Elderfield's "1Ieterocyclic Compomds," Vol. I, John Wiley and Sons Inc , X e w YorL, 1*: Y , 1950, p 512
(4; For a recent example of the utility of the two-step procedure. see: A i . A. Phillips, J. Chcm. Sac., 9 (1941). (5) 11. Maier-Bode and J. Altpeter, "Das Pyridin iind seine Derivat
