INSECT CHEMOSTERILANTS. VI
Scptcnihcr 196s
studied by many workers.7 The deniethylation of octaniethylpyrophosphoramide to the heptaniethyl stage has been well established and the reaction sequence shown in Scheme I1 was suggested by Hartley.8 A
-s/CH3 \
ClI?
SCHEME I1 0 CHI CHiOH --f
+-s /
-s +'
\
H
/
9 59 SCHEME I11
RNCHJ
LiAIHI
RN(CHi)CHO
4
YH RN(CH3)Na
H C O V
3 , R = [(CHi)rN]iPO 7 , R = (CH i),XPONHCH3
4 , R = [(CH,),Nj,PO 6 , R = (CHa)?NPONHCH3
3
8 , R = (CH2)iNPON
+ -N
\
CI-I?
'CHI
CHI
similar sequence has been proposed for 17a3h913m but the intermediate S-oxides and S-methyl01 compounds in the oxidation of octaniethylpyrophosphoraniide or 1 were not isolated or identified. I n the 31n04- oxidation of 1 we found no evidence that an IS-oxide was fornied but circumstantial evidence indicated that the methylol compound 2 was indeed an important intermediate. Formaldehyde was detected in the oxidation mixture, and the isolation of the formyl compound 49 pointed to the methylol compound 2 as being its logical precursor. When only 1 eyuiv of A\InO,- was used in the oxidation of 1 (Table I) the only products in the chloroform-soluble fraction were 3 and 4. The possibility t h a t 3 was formed by oxidation of 4 cia the carbamic acid 5 can be eliminated. In it separate reaction, a n authentic sample of 4 yielded upon oxidation with ;\hod- 6 but not 3 (or 5 ) . During the oxidation, the diniethylariiino groups in 3 and 4 were apparently attacked preferentially because both compounds were oxidized to 6 in separate experiments. -4t higher ratios of ;\In04- to H E M P A the formyl compounds 4 and 6 were the major products but the appearance of S-iiiethylforniamide in the chloroform extract pointed to an increasing degree of cleavage of the 1'-S bond. The resulting phosphoramidates and phosphorodiamidates would not be expected to partition into chloroform. Only a sniall aniount of oxidation products wa5 obtained when a mixture of 1 and 30% hydrogen peroxide was kept a t 50' for 3 days. The products were analyzed by glpc and identified as 1, 4, and 6 . Synthesis of N-Formy1phosphoramides.-The formyl compounds 4,6 , and 9 were synthesized by a nev formylation procedure shown in Scheme 111. The monomethylamino compounds 3, 7, and 8 were converted ( i ) (a) G. S.Hartley and D. F. Heath, Nature, 167, 816 (1951); (b) D. F. Heath, D. R. J. Lane, and 11. Llewellyn. J . Sci. Food A g r . , 3, 69 (1952); (c) .J. E. Casida. T . C. Allen, and AI. A. Stahmann, J . A m . Chem. Soc., 74, 5548 (1952); (d) R. D. O'Brien a n d E. E'. Spencer, J . B g r . Food Chem., 1, 946 (1953); (e) J. E. Casida, T. C . .illen, and M. A . Stahmann, Nature, 170, 218 (1953); ( f ) J. E. Casida, T. C. Allen, and R l . A . Stahmann, J . Biol. Chem., 210, 607 (1954); (p) H. Tsuvuki. hI Stahmann, and J. E. Casida. . I . .4gr. Food Chem.. 3 , 922 (1Q55); (ti) E. Spencer, Chem. Can., 10,33 ( 1 9 5 5 ) ; (i) D. F. Heath, D. IV. J. Lane, and P. 0. Park, Trans. Roy. SOC. (London). 239B, 191 (1955): ( j ) R . D. O'Brien and E. T.Spencer, .J. 4 g r . F o o d Chem.. 3, 56 (1955); (k) H. Tsuyuki, bl. -1..Stahmann, and J. E. Casida, Biochem. .I., 59, I V (1955); (I) E. 1.Spencer, R. D. O'Brien, and R. tV. White, .I. .4gr. Food Chem., 5 , 123 (1957); ( m) B. IV. .4rthur and .J. E. Casida, d . Gcon. E'ntomol., 51, 49 (1958). ( 8 ) Reierence 7i refers t o a paper presented by G. S. Hartley a t the 12th International Chemical Congress, New Tork, N. Y.,1951. ( 9 ) Although t h e oxidation of phosphoramides to their K-formyl derivatives is unique, carboxylic amides a n d aromatic amines a r e known t o give this type of oxidation product; see, e . g . , (a) M . V. Loch a n d B. F. Sagar, .I. Chem. Soc., 690 (1966); ( b ) A . RI. Abdel-Wahab, R. J. Kuhr, a n d J. E. Casida. J . A g r . Food Chem., 14, 290 (1966); (c) 4.R l . Adbel-Wahab and .T. E. Casida. ibid., 1 5 , 479 (1967); (d) H. B. Henbest and A. Thomas. Chem. I n d . (London), 1097 (19.56); ( P ) H . R . Henllest a n d A . Thomas, J . Chem. S o r . . 3032 (1957).
t o their sodium derivatives and treated with formyl fluoride.In The formyl group in 4 was easily reduced with LiBlH, to 3 but, as mentioned earlier, the oxidation of the formyl group appears to be more difficult. Although neither 4 nor 6 were found among the metabolites of 1 in niale house flies4 and 4, 6 , and 9 were ineffective as house fly sterilants, 4 was metabolized by male flies to 3." The oxidation of S,S,T\",K'-tetramethyl-P-piperidinophosphonic diamide (10) yielded 9 but because the other products in the chloroform-soluble fraction were not identified the relative susceptibility of the methylene and methyl groups in 10 to l I n 0 , - oxidation could not be assessed. Experimental Section Boiling points are uncorrected. Where analyses12are indicated only by symbols of the elements, the analytical results obtained for those elements were within &0.4% of the theoretical values. The identity of all new compounds wm confirmed by ir, pmr, and mass spectra. Ir spectra were recorded with a Perkin-Elmer 521 spectrophotometer, pmr spectra with either a Varian A-60 or a Varian HA-100 spectrometer using T M S as an internal standard, and mass spectra with a CEC 21-llOD spectrometer. Analytical glpc determinations were performed with an F & 11 Model 720 dual-column chromatograph. Company and trade names are given for identification purposes only and do not constitute endorsement by the U. S. Department of Agricultnre. Oxidation of Hexamethylphosphoric Triamide (1). A. With KMn04.-In each of the experiments outlined in Table I, 1.79 g (0.01 mole) of 1 and a 0.3 ilf K l I n O l solution were allowed to react until all the K l I n 0 4 was decolorized (4-8 hr). T h e MnOl was filtered off; the clear filtrateb were freed of the H?O under vacuum. The resulting mixtures of liquid and solid materials were each extracted with two 50-ml portions of CHCL, the extracts were dried (lIgSO4), and the CHCI, was removed under vacuum. The CHCl,-soluble material was analyzed semiqiiaiititatively by glpc.13 In these small-scale oxidations 1 was oxidized completely when 0.02 mole of K l I n O l was used but when the reaction was repeated on a larger scale, larger ratios of K1InO4 were required for complete oxidation. The CHCla-insoluble solids were dried to constant weight over P20,. These solids evolved NH, (and perhaps other amines) on heating, gave off COa on acidification, and after acidification contained 2.10coC and 1.2670 H. B. With H202.-.4 mixture of 0.286 g (1.6 mmoles) of 1, 25 ml of H 2 0 , and 0.36 g (3.2 mmoles) of 30% H 2 0 2was kept at room temperature for 1 day, and then heated in a hot-air bath for 3 days a t 50". Removal of the H 2 0gave mostly unreacted 1 (glpc analysk), but a small amount of 4 and traces of 6 and Smethplfoimamide were detected. Compound 4 hay also been (10) Various amides, including 3, have lieen nculateil in this manner; see. E. Sasse, E d . , "Organische Phosphor\.erbindunoen," Vol. 2 , Part 2. Georg Thieme Verlag, Stuttgart, 1964, pp 968-971. (11) S. C. Chang, unpublished results. (12) Microanalyses were by Galbraith Lahoratories, Knoxville, Tenn. (13) T h e column used in all glpc analyses v a s a 6 1 X 0.636 cm a d stainless steel column containing 5% Carbowax 2011 on 60-80 mesh base-washed Chromosorb W. T h e conditions used routinely were column, injectionport, and detector-block temperatures 190°, 225', a n d 235", respectively. H e flow rate 60 ml/min, chart speed 2.54 cm/min, and attenuation 1. Under these conditions, compounds 1, 3, 4, a n d 6 eluted a t r a , 0.5, 1, 2, and 5.5 min, respertively. I n addition, compounds 8, 9 , and 10 eluted a t m . 3.25, 6.5, and 1.75 min. respect,ivel?;.
cy.,
September 19RS
INSECT CHEMOSTERTLANTR. VI1
the combined filtrates were dried (MgSOd). Removal of the drying agent and solvent left 28.24 g of a yellow liquid. Shortr path distillation gave 2456 g (77.5'5) of 11 (ea. 99% pure by glpc). A single redistillation gave the analytical sample, n% __ 1.4932, bp 7i' (0.005 nim). Anal. (C?H&lN;OP) C, H,-X, P. Isolation of N-Methylformamide from Oxidation Mixtures.I n various oxidations of 1 (Table I ) and in the oxidation of 3 to 6, a low-boiling product was noted in the initial distillations of
96 1
the criide products. The volatile material was identified as N-methylformamide by comparing its ir spectrum with that of the authentic compound.
Acknowledgments.-We thank A h . E. L. Gooden and Dr. John L. Ruth of this Division for the pmr and mass Spectra, respectively.
Insect Cheniosterilants. VII.' Oxidative Degradation of Hexamethylmelamine
The chloroform- and ether-soluble products of the oxidation of hexamei hylmelamine with potassiirm permanganate were identified as methylmelamines and mono- and diformylated methylmelamines. The formyl compounds were also synthesized by formylation of methyl me la mine^ wii h formamide o r wit h formyl fliioride.
I n conjuction with our study of the metabolism of hexaniethyliiielaniirie ( H E I I E L ) in male house flies, Sfusca domestzca L., we have investigated the oxidation of this chemosterilant with aqueous potassium permanganate. Our previous experiments with the cheinosterilant HEAIPA (hexamethylphosphoric triamide) showed that this dimethylamino coinpound was demethylated in uwo3 and in vztro' to the corresponding peritaniethyl derivative. The pentamethylphosphoric trianiide is a much less effective sterilant than HERIPA and its further oxidation or deniethylation does not yield active chemosterilants. On the other hand, a gradual demethylation of H E M E L leads to compounds of considerable activity that sonietimes surpasses t h a t of the initial c ~ i n p o u r i d . I~n~the ~ present study, we have isolated and identified the chloroform-soluble and ether-soluble products of the oxidation of H E J I E L : all were derivatives of s-triazine. The possibility that other s-triazines which were not extracted with chloroform or ether still remained in the mixture cannot be entirely eliininated but the solubility characteristics of most triazines which could be formed by oxidizing H E J I E L do not support it. The mildly exothermic oxidation of H E J I E L with aqueous KAIiiO~was carried out a t room temperature. dlthough the insoluble base was first dissolved in acid, the mixture became basic and heterogeneous as the reaction progressed. The solubility of methylnielamines in water increases with the decreasing number of nieth) 1 groups and the lower methylmelamines had to be extracted with ether from the aqueous phase. Higher methylmelamines and formylnielaniines were extracted with chloroform from the solid phase. The products obtained from a typical reaction are shown in Table I. All possible methylmelamines, with the exception of S*,S2-diniethylmelaniine mere detected aniong the products. About 11% of the initial quantity of 1 WVRSrecovered and about 39Yc of it was converted to ( 1 ) Prelious paper in t h e serie. P H. Terry and .A B Boikovec l l e d C l i e n , 11, 958 (1968) (2) h C Chano \ B DeAIilo C 11 V oods. and 4 B Boikoirc, .I. Eron Entomol , in preqq ( 3 ) S C. Chane, P H T e r n C 11 IVoods, and A B Boihovec, ahzd , 60, 1623 (1967) (4) (a) .i.B. R o i k o i e r and P H Trrr C 9 P a t m t 3 189,.521(l!lRA) [lij 1 13 Buihmer and 1 R I h h I i l o , .I Pi1 C h p n i , 10, 4 5 i ( l Q 6 i ) .
R" \v t SO.
1 2 3 4
R
N(CHB)? KHCH, SH, SHCH, .iS H 2 6 NHCH,
R'
R"
K(CH, 17
N(CH,), S (CH, 12 N(CH3)s ~ ( C H S ) ~ S(CH3)2 K(CHB)? NHCH, NHCH3 N(CH,), NHCH3 NHCH,
Yieldn Mole
%
55
10.ih 7.5' 0.3' 9.5'
10.7 7 9 0.3 11.0
O..ib
0.7
3.1h 1.7c 5.1' 4.1'
t3.8 2.1 7.0 6 1 4.5 :3.2 3.4
7 NH, S HC H, SHCHp 8 NHZ NH2 NHCH, 9 K(CH3)CHO S(CH3)2 N(CHa)2 4 . R h 10 N(CH3)CHO XHCH, N(CH,)% 3.2' 11 Ii(CH3)CHO X(CH3)CHO X(CH,), 3.9' 12 S(CH,)CHO N(CH,)CHO S H C H , Trace' The individiial yields refer to the initial amount of H E I I E L rised in the reaction. They were calciilated from glpc peak areas (CHCL fraction) or estimated by tlc (Et20 fraction). * I n CHCI, extract. I n Et20 extract.
lower methylnielamines. In analogy t o H E J I P A , the oxidation of 1 follows two routes which appear to have n H
.
I
-.\
I
CHO
\
CHa
common intermediate. Xone of the possible methylol intermediates was found in the oxidatiori mixture but some of them have been synthesized previously and were sufficiently stable to be used in confirmatory reactions. Thus, when { [4,6-bis(diniethylamino)-s-triazin-2-yl]niethylaniino 1 methanol4b was oxidized with aqueous permanganate, both expected products 2 and 9 wcrc isoh t ed.
