June 5 , 1955
~-KETOPIIOSPHONIC ACIDS F R O M
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LABORATORY FOR CAXCER RESEARCH AYD UXIVERSITYOF CHICAGO]
THE
DEPARTMEY’T OF BIOCHEhIISTRV,
Phosphonic Acids. 11. Synthesis of 7-Ketophosphonic Acids from Methyl Ketones oia Mannich Bases’,’ BY TERRELL C. MYERS,RONALD G. HARVEY AND ELWOOD V.
JENSEN
RECEIVED NOVEMBER 29, 1954 Triethyl phosphite reacts smoothly with the methiodide or hydrochloride of the Mannich base, l-diethylaminobutan-3one, to yield diethylyketobutylphosphonate. This reaction provides a convenient synthesis of y-ketophosphonic acids The reaction of diethyl phosphite and sodium diethyl phosphite with the Mannich base and itq derivatives has been i r i vestigated
It is well known that 0-dialkylamino ketones, commonly known as Mannich bases and readily prepared by the treatment of ketones with fcrmaldehyde and a secondary amine3 (equation l ) , react with active methylene compounds in the presence of alkaline catalysts4 to replace the nitrogen function by the active methylene residue.3j The quaternary salts derived from Mannich bases (equation 2) undergo similar reactions, in many cases more readily than the free bases themselves. Analogous alkylations by certain quaternary amine salts have been observed with a number of other anionic species including cyanide, sulfide, mercaptide, thiocyanate and bisu1fite.j In a search for convenient synthetic routes to y-ketophosphonic acids,6 the possibility of alkylation of trivalent phosphorus compounds by Mannich bases or their salts was investigated. This paper describes the reaction of a typical Mannich base, 1-diethylaminobutan-3-one (I, R = CH3), its hydrochloride and its methiodide with triethyl phosphite, diethyl phosphite and the sodium salt of diethyl phosphite. The results obtained are summarized in Table I. In certain of the reactions, l-diethylamin0-3-phenylpropan-3-one(I, R = C6H5)was tried and found to react similarly. 385
RCOCH3
+ HCHO + ”Et2
+ RCOCH2CHrNEtZ (1) I
+ CH3I +RCOCH?CH&Et&fe TI + P ( O E t ) s + I1 I
I-
(2)
+
i
(3)
R C O C H ~ C H ~ P O ( O K ) Q2EtOH IT7
(4)
RCOCH2CH2PO(OEt)? Et3$Me IIT I11
HCl + HzO -+
+
(1) Paper I, THIS J O U R N A L , 7 6 , 4172 (1954).
(2) This investigation was supported in part by a grant from the Ameiican Cancer Society as recommended by the Committee on Growth of the National Research Council. (3) F. F. Blicke in “Organic Reactions,” Vol. 2 , R. Adams, Ed., John Wiley and Sons, Inc., New York, N. Y., 1942, p. 303. (4) Recently it has been shown that alkylation of ketones, thiols and nitroparaffins by Mannich bases can be effected in the absence of catalysts; N. S. Gill, K. B James, F. Lions and K T. Potts, THIS JOURNAL, 74, 4923 (1952). (5) J. H. Brewster and E. L. Eliel in “Organic Reactions,” Vol. 7, R. Adams, Ed., John Wiley and Sons,Inc., New York, h7,Y.,1953, p. 99. ( 6 ) Such compounds are of potential biochemical interest as phosphonate analogs of certain phosphorylated intermediates of carhohydrate metabolism, S. Preis, T. C. Myers and E. V. Jensen, to he published.
S U M M A R Y O F THE O N E WITH
Reagent
TABLE I REACTION OF DIE THY LA MI NO BUT AN-^VARIOUS PHOSPHORUS REAGESTS
Mannich base as:
P(OEt 1 3 P(OEt)3 1% S a O E t HPO( OEt )?
Yield4 of diethvl r-ketobutvlphosphonate, % . Meth- Hydroiodide chloride Free base
72
Noreacn.b Traceb 26 16 Traceb 15 HPO(OEt)? 10% S a P O ( O E t ) > . . .. 35b 9 NaPO(0Et)g 18b .. .. Yield of redistilled product calculated on the Mannich base in methiodide experiments but on the pure salt in hydrochloride experiments. I n these reactions equimolar quantities of the Mannich base and phosphorus reagent were employed; in other cases excess phosphorus reagent was used.
+
61
..
+
Triethyl phosphite was found to react smoothly upon heating with the Mannich base methiodide I1 to eliminate the nitrogen function and produce the y-ketophosphonate ester 111 which, by acid hydrolysis, is converted to the free y-ketophosphonic acid IV. Thus the sequence of reactions (1-4) provides a convenient and apparently general procedure for the synthesis of y-ketophosphonic acids. P(OEt)3
+ RCOCH2CH2XfEt2H El
----f
I11
+ Et3fSH Ci
(5)
The hydrochloride of the Mannich base reacts with triethyl phosphite in a manner similar to that of the methiodide to yield the same y-ketophosphonate (equation 5). Although the yield is slightly higher and the product somewhat cleaner when the methiodide is used, the reaction of the Mannich base hydrochloride with triethyl phosphite is satisfactory and could serve as an alternative synthetic procedure in cases where the use of the methiodide is not convenient. In contrast to the behavior with the quaternary salts, no reaction is observed between triethyl phosphite and the free Mannich base even a t 180” unless a catalytic amount of sodium ethoxide is present, in which case diethylamine is evolved, but little y-ketophosponate is obtained. The reaction of diethyl phosphite with Mannich bases and their salts follows a pattern somewhat different from that of triethyl phosphite. Diethyl phosphite reacts with both the methiodide and the hydrochloride, but the yield of y-ketophosphonate is rather low, and appreciable amounts of higher
TERRELT, C. MYERS,RONALD C . HARVEY AND I31,woo~I '. J ~ l r s ~ s
3 1 02
Vol.
TT
Reaction of Sodium Diethyl Phosphite with 3-Ketobutyldiethylmethylammonium Iodide .-The methiodide preparetl from 14.3 g. (0.1 mole) of l-diethylamiriobutan-:3-one Ira. dissolved in 20 ml. of dry tetrahydrofuran and treated with a tetrahydrofuran solution containing 0.1 mole of sodium diethyl phosphite. The mixture was stirred in an atmosphert of dry nitrogen a t room temperature for two hours a n d tl1c11 on the steam-bath for another liour. After most of thi. tetrahydrofuran had been removed in a stream of nitrogen. the residue ivas filtered to remove solid material; the filtrate, was evaporated and the product extracted from the viscou. residue by trituration with several portions of toluene. The toluene \\-as removed a t reduced pressure and the residue distilled. Diethyl y-ketobutylphosphonate (3.78 g. 187,) \vas collected a t 103-10io (0.3 m m . j , ?Z?$D 1.4353. A n a l . Calcd. for C,Hli04P: C, 46.13; H, 8.23; 1', 14.87. Found: C , 46.30; H, 8.50; P, 14.74. The infrared spectrum of this product indicated a carbonyl peak (1718 cm.-l) in addition t o the usual phosphonNaPO(OEt)? ate absorption" (peaks at 735, 1030, 1162 and 1245 cm.-'). HPO(OEt)* f RCOCH*CH?SEt? I t s identity was confirmed further by hydrolysis to the free 111 Et2SH ( 6 ) phosphonic acid (see below) and by conversion t o the 2,4dinitrophenylhydrazone derivative. For the latter reacThe sodium salt of diethyl phosphite reacts with tion, a solution of 0.42 g. of the y-ketophosphonate ester, 0.40 the hlannich base methiodide in tetrahydrofuran g. of 2,4-dinitrophenylhr-drazine and 0.3 ml. of concensolution to give a low yield of the y-ketophosphon- trated sulfuric acid in 10 ml. of absolute methanol was ate. The yield is not improved by carrying out the heated t o reflux for 15 minutes and allowed to stand at room temperature overnight. The reaction mixture was then reaction with sodium dibutyl phosphite in benzene poured through a column of Amberlite IR-4B (OH-) resiu solution. which previously had been well washed with ethanol. The The mechanism of the reaction of Mannich eluant from the column was concentrated under reduced bases and their salts with diethyl phosphite and pressure and the residual orange oil crystallized from ethanol at 0". After three recrystallizations from ethanol, the 2,4with triethyl phosphite bears an interesting rela- dinitrophenylhydrazone melted at 10j-107". tionship to the mechanism or mechanisms of the Anal. Calcd. for CI4HYLOiN4P: C , 43.30; H, 5.45; reaction of hlannich bases with nucleophilic re- S,14.40; P , 8.16. Fnuntl: C, 43.70; H, 3.62; N , 13.90; agents in general. Investigations of this problem P , 7.90. r-Ketobutylphosphonic Acid.---Diethyl y-ketobutylphosare currently in progress and will form the subject phonate (980 mg.) was heated under reflux for four hours of B subsequent paper. with 5 ml. of concentrated hydrochloric acid. The mixture was evaporated to dryness i n zjuczio, and the last traces of Experimental moisture were removed from the residual oil by distilling Reactants .-Commercial7 diethyl phosphite and triethyl off two 10-id. portions of dry benzene. After evacuation overnight with a n oil-pump, the resulting solid was recrysphosphite were redistilled before use. Sodium diethyl tallized from chloroform t o yield sa0 mg. (707c) of ?-ketophosphite was prepared by stirring a solution of diethyl butylphosphonic acid, m . p . 81-82 . phosphite in dry tetrahydrofuran with an excess of metallic sodium for 48 hours with subsequent renioval of the un.-lnal. Calcd. for C,H,O,P: C, 31.59; H , S.06; P, 20.37. dissolved sodium. The Mannich bases were prepared in the Found: C,31.44; H , 6.34; P , 2 0 . 2 6 . usual manner3 from diethylamine, formaldehyde and aceReaction of Triethyl Phosphite with 3-Ketobutyldiethyltone or acetophenone, respcctiT-ely. 1-Diethylaminobutanmethylammonium Iodide.-The triethiodide, prepared by one was isolated as the free base according to the procedure the reaction of 7.15 g. (0.03 mole) of l-diethylaminobutarlof n'ilds arid Shunk.8 The hydrochloride was prepared by 3-one with 7.15 g. of methyl iodide, was treated with p:tssing dry hydrogen chloride through a shaken solution of 4 1 2 g. (0.23 mole) of triethyl phosphite, and the mixture the freshly distilled amine in dry ether a t 0". After pre- x a s heated a t 130' for one hour. After cooling, the white cipitation was complete, the solid was filtered viith suction precipitate was removed by filtration and washed on the and washed with dry ether, always keeping the crystals filter with dry benzene. Thus was obtained 10.6 g. ( 8 7 ' , 'i covered with solvent on the filter. The solid was trans- of triethplmethylamnionium iodide, m.p. 283-28,j". ferred immediately to a vacuum desiccator and allowed to .-fnai. Calcd. for C7HlaKI: I, 52.20. Found: I , 32.25. stand several hours over KOH. 3-Ketobutyldiethylamthe filtrate a t reduced monium chloride thus Tvas ohtained in 54y0 yield, m.p. r oil distilled in v a r u o . ; ,-;7..j0, reported9 74-77". 1-Diethylamino-3-phenylprote (8.4 g., 81%) waq pan-3-one was isolated directly as the hydrochloride, m . p . collected a t 89-97" (0.08 m m . l and redistilled to yield the 108-11Oo, as described by Bliclie and l3urckhalter.lo purified product (7.:) g., 7 2 ( ( , b , p . 96-98' (0.14 min.), The preparation of ~3-ketobutyldiethyl1~ieth~lammonium n25g 1.43,52) 1%-hose infrared spectrum was similar to that of iodide was carried out 115- a slight modification of the procedure of li'ilds and Shunk.R l l e t h y l iodide was added slowly the previously analyzed sample of this ester. 1.0 g. of the product was hydrolyzed in hydrochloric with stirring to an equal weight of 1-diethylaminobutan-3; acid as described previously to yield 650 mg. (89%) of. y one held a t 0". Stirring n-as continued for a n hour a t 0 neut. equlv., and then another hour at room temperature until the meth- ketobutylphosphonic acid, 1n.p. 80-81'; iodide began t o crystallize. .4t this point stirring was dis- calcd. 132.1, found 152.4. Reaction of Triethvl Phosohite with 3-Ketobutyldiethylcontinued or else the reaction became too violent. The g. (0.034 mole) of the hydiosolid methiodide was thoroughly washed with dry benzene ammonium Chloride:-6.0 three times by decantation, and the diethyl phosphite or chloride of 1-diethylaminobutan-3-one was treated with 27.7 g . (0.167 mole) of triethyl phosphite and the mixture triethyl phosphite 'ivas added directly. heated under reflux t o 140" xvhereupon vigorous boiling ( 7 ) Generously supplied b y t h e 3 l o n s a n t o Chemical Co. and t h e took place. The reaction was maintained at this temperaVirginia--Carolina Co. ture for two hours and then a t room temperature overnight. (8) A I,. Wilds and C. 13. Shunk, THISJ O U R N A L , 66, 469 (1943). A small amount of white solid precipitate was removed by (9) K. T s u d a , S . Hukushima and A . Oguri, J . P h o ~ r nSOL. . J a $ a n , 61, filtration, and the pale yellow reaction mixture was distilled. 71 (1941) A product with the odor of diethylamine was collected a t
hoiling products are found. Diethyl phosphite
