JULY
1959
nlj/t 'C.
Dcriveti From
a
\l,7
/\
It0
I
Lib 70 60 56 59 63 62
1.4596/18
62
(3
Carbon. Calcd. Found
- Hydrogcn Calcd. Found
39.7 43.6 43.6 46.9 49.7 46.9 53.0 46.3
9.3 9.8 9.8 10.0 10.4 10.0
39.4 43.4 43.5 46.6 49.6 46.7 53.2 46 1
!1.8
8.7
9.0 9.6 9.7 !f .If 10.1 9.9 !I . 5 8.7
piperidine arid morpholine.
RO
0 COClr
v
CII$
Yicld,
1.4303/24 1.4320/25 1.4300/22 1.4341/26 1.4362/21 1.4360/21 1.4590/16
a riuinbcr of alkyl N,N-dialkyl ethylphosphonamidates. We h a w synthesized a number of similar compounds based on methylphosphonamidic acid by a difforcnt and apparently more convenient route. Dialkyl methylphosphonatcs (I) were treated with phosgene by the procedure of Coe et aL4 to give the alkyl methylphosphonochloridates (11). These compounds which are thermally unstable were obtained sufficiently pure by this method to be used without distillation. licaction of the chloridates with two equivalents of the appropriate amine gave the correspondirig alkyl N,N-dialkyl methylphosphonamidate (111) in yiclds ranging from 607070 after distillation. Similarly b y using piperidine and morpholiiie, with isopropyl methylphosphoiiochloridate, the isopropyl methyl phosphonopiperidate and morpholidate were obtained respectively. RO
1019
NOTES
RO
0
0
2ll2"ti
P7 '
_i)
/\
CI
CH3
I1
/\
cEr8
iim
I11
'I'hcsc coinpouiids, the dut:i for which arc givcii 'l'ablc I, w r c tested as insccticides and found to have proiiounoed systemic activity but very low mammalian toxicity.5
ill
KXPEI1IMENTAL
n-Propyl Ar,iV-climhh?j1 Inelhylphosphonantidate. I h y pliosgene was bubbled slowly through 60 g. (0.33 inole) of din-propyl mctliyl~~liosphoriatc for J 8 hr. with wntcr cooling during the first 3 hr. Vo1:ttilc prodiict)s were removed by degassing iLt 30' and 10 mm. On :mdysis it. was found that the chlorine content of thc residue was within 0.5% of thitt required for CH~PO(OCJH,)C~. The chloridate was dissolved in 250 ml. of dry ether, and into i t passed 30 g. (0.7 mole) of anhydrous dimethylamine, with continuous stirring (4) D. G. Coe, B. J. Perry, and R. K. Brown, J. Chem. Soc., 3604 (1957). ( 5 ) D. G. Coo, H. Hurtig, B. J. Perry, and E. S. Sherlock, J. Agr. Food Chem., 7, 251 (1959).
and i w cooling. Aftcr st,itrding for 3 lir. at, room tcmperature the mixture was filtered arid the cther rernovcd under reduced prcssure. The rcsidue was fractionally distilled to yield 33 g. (60%) of n-propyl N-dimothyl mcthylphosphonamidate, b.p. 62" a t 1 mm.; n:: 1.4:320. Anal. Cnlcd. for CJ1,~O~IiI':C, 4a.61; 1-1, 9.75. Fourid: C, 43.38; 11, 9.60. SITFIELD EXPICRIhIENTAL STATIOS
HALSTON,ALBERTA
Diosinetin Triacetate from 3-Bromohesperetin Triacetate and Silver Acetate-Acetic Anhydride1n2
Received January 16, 1059
In an investigation of hesperetin (I) as a potcritial synthetic precursor of qiiercctin 4'-monomcthyl cthcr, the reaction of the :~-broinohcsperctiiitriarctate (11) of Zemplcii and 130gn,zr4with silvcr acctate in acetic ahhydride, reported to give 3-ucetoxyhcspcrctiii t r i a c e t a t ~ was , ~ invcstig:itcd. The prcsciit notc reports th:it this reaction lcad5 to diosmctin triacctatc (111). 3-Bromohespcretiii triacetate (11) w:is prepared by the general method of Zemplrii and B ~ g r i a r . ~ The quality of the absolute chloroform used in thcir procedure w a h found to be extraordinarily critical. Repeated attempts were made to carry out the reported syrithcsis of 5-ncctoxyhespcrctiil triacetate by reaction of I1 with silver acetate 111 acetic arihyh i d e . Thcrc \\;as obtained, however, in yields up to 75%, 111, identical with il product obtained from ( 1 ) From the M.S.thesis (1956) of Myron James Holm. ( 2 ) This investigation was supported in part by a research
grant (E-1703) from the Iiational Institute of Allergic and Infectious Diseases, Public Health Service. (3) Du Pont Postgraduate Tcaching Assistant, 195657; Standard Oil of Indiana Foundation Fellow, 1957-58. (4) G. Zemplen rtnd R. Rognar, Ber., 76B, 454 (1943).
the action of NBS on hesperetin triacetates5Characterization of I11 involved both acidic and basic hydrolysis to give diosmetin (IV), in turn characterized by reacetylation to 111, and demethylation followed by acetylation to give luteolin tetraacetate. The I V thus obtaiiied had an uItraviolet absorption spectrum identical with that previously reported.6 Our observation is similar to that of Robertson, who attempted to prepare Cavill and co-~vorkers,~ 3-acetoxy-7-methoxyflavanone by reaction of silvcr acetate with 3-bromo-7-methoxyf?avanone. 7-Methoxyflavone was the sole reaction product.
\
RO
I. S = H; R = 13 11. X = Br; R = COCH,
111. R
COCI-13
IV. It = 13
EXPERIMENTAL
343romohMperetin triacetate. Numerous experiments proved the quality of the absolute chloroform to be critical. Reagent grade chloroform was washed twice with conc. sulfuric acid, and then five or six times with water (at Iwst twice after the chloroform layer becomes clear). The chloroform was shaken with anhydrous calcium chloride, decanted onto fresh calcium chloride, and alloivcd to stand for several hours. The chloroform was then distilled, arid the first distillate fraction te&d for phosgene by addit,ion of silvcr riitrate. If sriy cloudiness whiitsocvcr nppewcd, t ~ l lof the chloroform, both distillatc and rcsiduc, was discarded. I f no cloudiness appeared, approrimakly */q of the chloroform was dis1,illecl and discarded. The middle portion was then c:ollectcd, and usually distilled ovcr a 0.2' boiling rango. If the boiling range was greihter than 0.4", all of the chloroform was discarded. The chloroform thus purified \vas used within a few hours. A I-g. quantity of hcspcrcbin triacetate, m.p. 143.5144.5',* was broniinat,cd i n thsolut,e chloroform rrolution in a \'ycor flask uiider irradiation wi1.h a Hanovia Model 30600 quartz mercury vitpor lamp under the gcrieral coriditioris of Zcrnplen and BogntLr. A total quant.ity of 520 mg. of crude, c:rystalline bromination product (two c r o p , second by c-ryst,xllizat,ionof residuitl oil from ether) wits obt,ained. Recrystullization of the t n t d crude from 4 ml. of c,hloroform and 12 ml. of nhsolutr: cthnnol gave 510 mg. of prodiict,, m.p. 170-190'. Three additioual crystallizations from chloroforni-cthanol gave 270 mg. of 3-bromohesperetin txiticctat,e, m.p. 19G-198' (1it.d m.p. 190-191'). The high loss upon recryst,allizatiori necessitated reworking of the mother liquors. Ar~al.9Calcd for C2z€119BrO~: Br, 15.7. Found: Br, 15.6. ( 5 ) J. IT. Looker and 31. J. Tfolni, J . Org. Chem., 24, 567 (1959). ( 6 ) It. A I . HoroMitz, J. Org. Clwn., 21, 1185 (1956). ( 7 ) C,. W. K. Cavill, F. RI. Dean, A. McGooltin, H. M. Marshall, and A. Robertson, J . Chem. SOC.,4579 (1954). ( 8 ) This m.p. is in reasonable agreement with the value of 139-141 ' reported for racemic hesperetin triacetate by H. R. Arthur, W. H. Hui, and C. N. Ma, J . Chenz. Soc., 632 (1956). (9) Previoiis aiialytical chnrnctcrixation (ref. 4) was restricted to methoxyl debmiination.
,hi alcoholic solution of 3-bi omohespel etin triacetate gave no turbidity with aqueous silver nitrate at room temperature, but slowly became turbid a t thc boiling point. In acetonitrile, no silver bromide \vas obtained with silver nitrate in tn o weeks. Reactwn of 3-bromohesperetin traacelate m t h stlver acetcte. A 0.6 g. quantity of 3-bromohesperetin triacetate, 800 mg. of silver acetate, and 8 ml. of anhydrous acetic anhydride were heated on a steam bath for 2 hr.,then for 1hr. at 130' in an oil bath. The reaction mixture then was poured into water and allon ed to stand overnight. The resulting solid was collected, extracted aith three 20 ml. portions of chloroform, and the solvent subsequelitly evaporated. The residual oil was crystallized ta ice from acetonc-alcohol, to give 320 mg. (75'3,) (two crops), of diosmetin triacetate, m.p. 195197' (lit.10 m.p. 195-196'). The infrared spectrum (KBr pellet) was identical with that of diosmetin triacetate obtained by NBS dehydrogenation of hesperetin triacetate, and contained strong or medium absorption bands a t 1767, 1645, 1631, 1613, 1520, 1434, 1373, 1343, 1284, 1262, 1199, 1147, 1103, 1091,1038,1024,and 910 cm.-' In view of thc previous rcport4.11 that this sabstanct is 3-acetoxyhesperetin triacetate, additional characterization was carried out. Basic hydrolysis of 50 mg. of product (diosmetin triacetate) in 2.5 ml. of 95% ethanol mas effected by addition of 0.3 ml. of 3% aqueous sodium hydroxide, heating 5 min. on a steam bath, diluting with water, and acidifying to pH ca. 4.5. Further dilution gave a precipitate, m.p. 185-187' (positive test nith msgnesium-hydrochloric acid). This product was redissolved in 2.5 ml. of 95% ethanol and 0.3 ml. of 370 sodium hydroxide added. Immediate precipitation of yellow solid ensued, and sohtion was effected by addition of water. After warming 10 min., the solution was diluted and acidified to give diosmetin, m.p. 252' (1it.lOm.p. 253-254'). Acid hydrolysis was carricd out by dissolving 200 nig. of diosmetin triacetate in 16 ml. of 07.5% ethanol, adding 0.4 ml. of concentrated hydrochloric acid and heating the wsulting mixture under reflux 1 hr. under nitrogen. Dilution with 24 mi. of water, and cooling overnight gave a florrulwlt precipitate of diosmetin, which bccanic orange colored during collection by filtration, evrn undcr nitrogen; yield, 140 mg., m.p. 255-258'. Acetylation of 50 mg. of this product in 3 mi. of acetic anhydride containing 250 mg. of ~ J I hydrous sodium acetate by heating under reflux for 3 hr. gave diosmetin triacetate, m.p. 196-197'. Drmethylat~on of the crude diosmetin was effected by dispolving 50 mg. in 1 ml. of glacial acetic acid, adding 0.5 ml. of hydriodic acid (d. 1.7), and heating undcr reflux for 3 hr. The crude Iuleolin (ca 40 mg.) was isolated by pouring the reaction mixture into ice water, collccting the precipitate by fill riition and air drying; m.p. 326' (lit.'* m.p. 327-329'). The Inteolin thus obtaincd was acetylated by boiling 1 hr. with 40 mg. of anhydrous sodium acetate and 2 ml. of arctic anhydride. Thr mixture was poured into water, and the prrcipitated solid collected and rerrystnllizcd from 95% cthonol; m.p. 230' (lit.13 1n.p. 226-227').
AVERYTABORATORY THEUXIVERSITY OF K E B I U ~ K A Xm. LINCOLN,
(10) A. Lovery, It. Itobinuon, : ~ n dS. Sugnbiiun, J . Clrrnr. SOC.,817 (1930). (11) Zempleii and Bogliar (ref. 4) reported m.p. 19% 194", and observed OCHa = 6.84 for 3-acetoxyhruperetin triacetate (calcd. OCH, = 6.40). M.p. of diosmetin triacctate is 195-196', and theoretical OCH, = 7.28. (12) A. G. Perltin and L. M. Horsfall, J . Chem. Soc., 77, 1320 (1900). (13) 13. h'itkamiir:i, 1'.Otn, and C . I'iikuchi, J . I'harm. Soc. J a p u n , 56, 107 (1930); ('hem. %e7lh. 1936, 11, 3801.
