SILICON-SUBSTITUTED SPIROBARBITURATES
November, 1964
695
Silicon Heterocyclic Compounds. 111. Silicon- Substituted Spirobarbiturates’ RALPHJ. FESSEYDES, JAMES G.
LARSEN, > T A R V I E
D.
COOK, AKD JOAK
S. FESSESDES
Departnient of Chemistry, Sun Jose State College, Sun Jose, California
Received April l Y , 1964 A group of silicon-containing spirobarbiturates of the general structures I1 and I11 have been prepared by the and a urea or thiourea. classical reaction between a substituted malonic ester, 3,3-dicarbethosy-l-silacycloalkane, The tosicities and the EDsofor the loss of the righting reflex have been evaluated for these compounds.
Spirobarbiturates* have attracted the at tent ion of investigators since the first report in 1921.3 Studies of these interesting compounds have been limited by the relative unavailability of the starting dicarbethoxycycloalkanes and by the poor yields in the preparation of the spiranes. As medicinal agents, spirobarbiturates show activity similar to that of the 5,5-dialkylbarbiturates. -Although the parent cyclohexyl ring systein (I, R = H ; I- = 0 or S) does not show “narcotic activity,”l the alkyl-substituted rings (I, R = alkyl; T = 0 or Sj do shorn activity, “therapeutic ratios”j up t o 5.18 having been reported (I, R = nC3Hi) .6
CH, I
Q+Y
SH
CkLH, 0
’\ 0 C H ~CH,
I1
I11
Siiicc. in our study of sjlicon heterocyclic
(1) (:I> This investigation was supported in p a r t by Public Health Service Researcli Grant G l I 10122, from the Institute of General Medical Sciences. (b) Taken in part from the 11.9.Thesis of James G. Larsen, San Jose State College, 1963. (2) The term, spirobarbiturate, is used in this report t o emphasize the relationship of these compounds t o t h e 5,6-dialkylbarbiturates, as well as for simplicity. T h e numbering system and the generic name for this group of compounds are as fol1oa.s.
R O
2,i-di~za-ll-alkyl-8,8-dimethyl-8-silaspiro [6,6]undecane-1,3.5-trione (3) ( a j A. W. Dox and L. Yoder. J . .4m. Chem. Soc., 43, 1366 (1921): (b) A. C. Cope, P. Ilovacic, and AI. Burg, ibid., 71, 3658 (1949); (e) 0. IVichterle and 0. Semeck, Chem. L i s t y , 37, 381 (1943); Chem. Abstr.. 46, 561 (195lj: (d) E. van Heyningen, J . Am. Chem. Soc., 76, 2241 (1954): re) R. T a Lerina, S.S.Godovikor, and F. K. Yelichko, Z h . Obshch. Khim., 25, 2522 (1955); Chem. Abstr., 6 0 , 9430 11956): (f) R. Y a Levina and h-.X. Godovikov. Z h . Obshch. Khim.. 25, 986 (195.5); Chem. Abstr., 60, 3458 (1966); (g! R. T a Levina, S. hi. Nezentsova, and 0. V. Lebedev, Zh. Obshch. K h i m . , 25, 1097 (1955): Chem. Abstr., 60, 3267 (1956). (4) T h e term “narcotic activity” has been used by previous workers in this area3b to describe the dose a t which 50% of the test animals failed t o right themselves when struck on the tail by a. forefinger. This study used the righting reflex as the sub-lethal test of activity and t h e values are reported as effective dose for 50% of the group (EDro) (see Table 111). (6) The term “therapeutic ratio” has been defined b y previous workers in this area3b as t h e ratio of “narcotic dose” t o the toxic dose (NDlo/LDbo). When the term is used in connection with the compounds prepared in this study, the value refers to the ratio of the effective dose for the loss of the righting reflex to the toxic dose (EDho/LDao). (6) See ref. 3b. (7) (a) R. J. Fessenden and 11. C. Coon, J . 0 ~ 8 .C h m . . 29, 1069 (1964); (b) ihid., 29, 2499 (1964).
CH rCOOC.H,!
COOC2HS
XCH2SiCH2CH,CHX
I R
H 3 !(
IV
&@ 0
a synthetic route was developed allowing the preparation of silicon-substituted dicarbethoxycycloalkanes (V), it seemed opportune to synthesize these diesters and convert thein to silicon-substituted spirobarbiturates. Synthesis.-The dicarbethoxysilacycloalkanes used in this study were prepared by the ring closure of a dihalosilaalkane (IV) and malonic ester. The dihalo-
hCOOC2H
/ \ CHj CH3
v
silaalkanes used for the preparation of silacyclohexanes and silacycloheptanes have been previously r e p ~ r t e d . ~ The yields in the ring closure reactions varied from 25% (dicarbethoxysilacycloheptane) to 50% (dicarbethoxysilacyclohexanes) . The silicon-substituted spirobarbiturates and spirothiobarbiturates were prepared using the classical reaction between a urea and a substituted malonic ester.* The reaction of urea or thiourea with 3,3dicarbethoxy-1,l-dimethyl-1-silacyclohexane(V, R = H) gave reasonable yields (4570) of the spirobarbiturate I1 (R = H; IT= 0 or S). I n agreement 11-ith the observations of other investigators, the yields were substantially lower (0-187G) when the 4-alkyl-substituted silacyclohexanes (V, R = alkyl) were used in the reaction (see Table I). None of the alkyl-substituted spirothiobarbiturates could be isolated. The only cycloheptane diester available was 3,3dicarbethoxy-1,l-diniethylsilacycloheptane, which was converted to the spirobarbiturate (111, T = 0) and to the spirothiobarbiturate (111,IT= S) in 53 and 28y0 yields, respectively. It was also of interest to include in this study the X-substituted spirobarbiturates. Using the method of B ~ s e ,the ~ reaction of dicyclohexylcarbodiiniide with cyclohexane-1,l-dicarboxylic acid gave the expected K,N’-dicyclohexylspirobarbituratein 38y0 yield. However, when the reaction was attenipted using 1,ldiniethyl-l-silacyclohexane-3,3-dicarboxylic acid, a mixture of products was obtained. The ultraviolet spectra of the silaspirobarbiturates in ethanol both iii neutral and in basic solution were recorded. As has been noted with the 5,5-dialkylbarbiturates,’O the spectra of these spirobarbiturates (8) J. B. Dickey and A. R. Gray, “Organic Syntheses.” Coll. Vol. 11, John %ley and Sons, Inc.. New York, N. Y . , 1943, p. 60. (9) A. K. Bose and S. Garratt. J . A m . Chem. Soc.. 84, 1310 (1962).
696
R.,J. FESSENDEN, J. C:. LARSES,11. D. COOK,.4su .I.
in iicutral solut io115 showed oiily (wd absorptioii, while those ill basic soluli9iis (0.01 Ar SaOH) exhibited abhorptioii in the 2400-A. regioii (see Table 11). Pharmacology.-The results of' the pharmacological studies are summarized in Table 111. The cyclo1ir:sylspirobarbiturate (I, R = H : 1- = 0) and the sulfur analog (I, Ib = H ; Y = S ) were syuthesized and included in this portion of the study. The desirable high "therapeutic ratios" (2.4 t o 5.18) rrported for the cyclohexylspirobarbiturates (I, R = alkyl; J7 = 0) were not observed with the silacyclohexylspirobarbiturates (11), in which cases the range was 1.0 to 1.8. The sulfur analog of the silaspirotmhiturate (11, K = H; Y = S) showed a greatly iiicreased toxicity, an effect not observed with I (R = H ; 1- = S). These differences between the cycloliexylspirobarbit urates (I) a i d the corresponding silicoii compounds (11) may bc due to the yerra-dimethyl group in the silicon coinpounds, distortion of the cyclohexyl ring by the substitution of a silicon atom in the ring, or a conibinat ion of these effects. Cnfortunately, the direct carbon analogs of I1 are not readily available for comparison. Special note of the silacycloheptanespirobarbiturate (111) should be taken. Conipound I11 (Y = 0), which showed the most rapid onset of action of the coinpourids studied, also exhibited the highest "therapeutic ratio" (3.0) of the group (see Table 111). Con&IO) I-. K . Goldbaum, Anal. Chem., 24, 1604 (1952).
d. I' EhF-ESDES
1'01. 7
vcrsely, I11 (Y = S) sho\\-cd a hclatcd oirsc,t airti exhibited tlic greatebt toxicity of aiiy of tlic ( + O I I I pounds studied. Experimental
-
3,3-L)icarbethoxy-l-silacycloalkanes. Halomethyl-(i ha1oalkyl)dimethylsilanes.--The general procedure used t i , obtain the starting dihalogen intermediates has been publishetl
elsewhere.' The compounds used w r e purified prior to riiig (,losure h u t were not, completely charact.erized. T h r i i w v ( t i chlorosilaalkanes prepared in this study are: chloroi~iethyl[ ;-c.hlorobut?.l)diniethylsilane, 39-77' 1, h.p. 88" ( S nini. J . 7 1 2 0 ~ 1.4660; chloromethyl(~-chloropeiit~l)diinethylsilaiie, 14.56(,1, b.p. 60-64" (1.5 mni.), nZ41) 1.4630: chloroniethvl( -,chlorohexyl)dimethylsilane, 19(,-;, h.p. SI)-SO" (2.0 mni. 1, f t ?)I) 1.4632. Ring Closure.--The following general procedure WBS used t i ) obtain the cyclic diesters. In a three-iieck round-bottom flnsk uiere placed 200 ml. of absolute ethanol (freshly distilled frorii sodium), 0.15 mole of the dihalogen compound, and 0.15 riiiile of malonic ester. The mixture was heated to reflux and 0.3:; mole of sodium ethoxide in 200 ml. of ethanol was added in nile portion followed by 0.05 mole of sodium iodide. The niistuw was refluxed for 20 hr. At the end of the reflux period, the mixture was cooled, filtered, then concentrated to ca. 200 n i l . and diluted with an equal volume of water and extracted with
(11) All melting points are corrected and were taken on a Fislier-Juhs melting point stage. Analyses were performed by the Berkeley Microanalytical Laboratory except for t h e silicon analyses, which were performed in this laboratory. Infrared spectra were run using a Beckman IR-1 sperrrophotometer and the ultraviolet spectra were obtained using a ('nr) spectrophotometer.
November, 1964
PHARMACOLOGICSL
Spir0barbiturates.-The following general procedure was employed for the preparation of the compounds which are summarized in Table I. In a 50-ml. round-bottom flask were placed 0.02 mole of the appropriate diester, 0.02 mole of urea (or thiourea), and 0.02 mole of sodium ethoxide dissolved in 15 ml. of absolute ethanol. The mixture was heated a t reflux for 12 hr., cooled to room temperature, and acidified with 12 ml. of 2 HC1. It was then filtered and the solid material was washed with two 25-m1. portions of water. The product was crystallized from 95% ethanol and, in general, a recrystallized sample was used for analysis. The following exceptions and observations were made using this procedure. The reflux period for 4 was 24 hr.; for 5, 17 hr. The starting diest,er was recovered (46-47%) from the reactions leading to compounds 4 and 5. The procedure failed to yield solid material in the attempted reactions of 3,3-dicarbethoxy-4-propy1-1,l-dimethyl-l-silacyclohexane with urea and with thioof 3,3-dicarbethoxy-l,1,4-trimethyl-l-silacyclohexane urea. 2,4-Dicyclohexyl-2,4-diazaspiro [5.5]undecane-l,3,5-trione (IV).-A solution of 1.65 g. (8.0 mmoles) of dicyclohexylcarbodiimide in 20 ml. of tetrahydrofuran (dist,illed from lithium aluminum hydride) was mixed with a solution of 0.70 g. (4.0 mmoles) of cyclohexane-1,l-dicarboxylic acid12 in 20 ml. of tetrahydrofuran. The mixture was allowed to stand at room temperature for 1 hr. and was then filtered, yielding 0.90 g. (10070) of S,S'-dicyclohexylurea, m.p. 227-230" (lit.'3 231-232"). The tetrahydrofuran was removed from the filtrate using a roto evaporator and the solid residue was crystallized from ether-petroleum ether (b.p. 30-60°), yielding 0.55 g. (39%) of the product, m.p. 134134.5" ; infrared spectrum 5.59, 5.95, and 5.85 (sh) p . Anal. Calcd. for CY1H3?X?04: C, 69.95: H, 8.96; S , 7.77. Found: C, 70.18; H, 8.81; S , 7.80. In one run, the product was crystallized from ethanol. Initial crystallization occurred : however, after the m:sture was allowed to stand overnight, an oil was obtained. The infrared spectrum showed bands a t 3.0 (K-H)j 5.90, and 6.10 p (C=O), an indication that' cleavage had occurred. Attempted Synthesis of 2,4-Dicyclohexyl-2,4-diaza-S,S-dimethyl-S-silaspiro~Ci.Ci]undecane-l,3,5-trione.1,l-Dimethyl-lsilacyclohexane-3,3-dicarboxylic Acid.-In a 100-nil. roundbottom flask were placed 13.6 g. (0.05 mole) of 3,3-dicarbethoxy-1,l-dimethyl-1-silacyclohexane,40 g. (0.70 mole) of KOH, and 30 ml. of water. Upon warming, a vigorous, exothermic react,ion ensued, which required an ice bath for control. -4fter the react,ion had subsided, the reaction mixture was cooled to room temperature and added slowly to a sulfuric arid-ice mixture The M-hite preripit,a,te was extracted with three 100-nil. portion
TABLEI11 ACTIONO F SIL.%BdRBITUR.kTESAND RELATED COMPOVKDS"
Loss of the righting reflex
Toxicity LD60 (95% confidence levels), nig./kg.
ED30
(95%
Compd.
confidence levels), m d k .
1 2
...
. . .d
3
670 (500 to 880)
4
...
5
240 (185 to 320) 140 (100 to 200) 230 (165 to 320)
6 r
I
h
f
8
697
SILICON-SUBSTITUTED SPIROBARBITURATES
A \ -
Induction period,b hr.
1000" BOOQ (440 to 830) 1000 230 (165 to 320) 450 (330 to 530'1 230 (165 to 320) 670 (500 to 880) 140 (100 to 200)
Duration of activity,c hr.
6
..
2
1
1
..
2
6
1
2
0.2
3
6
..
a Female Webster Swiss white mice, 15-20 g., were used. The compounds were introduced intraperitoneally as corn oil suspensions using 25 animals per compound. The values reported were calculated by the method of J. T. Litchfield and F. Wilcoxon [ J . Pharmacol. Exptl. Therap., 96, 99 (1949)]. The induction period is defined as the time elapsed from injection to the loss of the righting reflex. The duration of activity is defined as the time in which the surviving animals were without the righting No activity was noted at 1000 mg./kg. e Lit,.abLDjo reflex. 800 nig./kg. (i.p. as the sodium salt). All animals who lost the righting reflex died. 0 Lit.3b LDjo, 1200 mg./kg. (i.p. as t'he sodium salt). The value obtained, 190 (135 to 270) mg./kg., is not considered to differ significantly from the toxicity.
'
three 100-ml. portions of ether. The ethereal extracts were washed with water, dried ( hIgS04), then fractionally distilled to obtain the cyclic diester. The analytical samples of the diesters were obtained using gas phase chromatography. The data for the diesters are summarized in Table IT. T'4BLE
11.
I)IC.kRBETHOXYSIL.4CYCI~OHEX.4SES
dCOOC!Hj COOC,H,
CH,j / \CHI Yield,
R
%
H CH3 CY& CIH,
50 34 50 21
B.P., O C . (n1111.)
115 ( 3 . 2 ) 114 ( 1 . 8 ) 117 ( 1 . 5 ) 130 ( 2 . 0 )
--Carbon. Calcd.
nD
("C.)
1,4567 (26) 1.4584 (26) 1.4589 (27) 1,4607(27)
Formula
C13H2404Si C14H2604Si C16H?~04Si ClsH3,04Si
An analytical sample of the 4-ethyldicarbethoxysilacyclohexane was not obtained. Gas phase chromatography of the dist'illation fractions indicated the presence of a close-boiling impurity (not identified) and gas chromatographic purification of this compound was not successful due to thermal decomposition on the column. The impure diester was used for the preparation of the spirobarbiturate. The only silacycloheptane diester prepared was 3,3-dicarbethoxy-1,l-dimethyl-1-silacycloheptane,b.p. 113" (0.8 mm.), n 2 j ~ 1.4621, which was obtained in 25% yield using bromomethyl(8-bromobutyl)dimethyl~~~ane as the starting dihalogen compound. '4nal. Calcd. for ClrHzsOaSi: c, 58.34; H, 9.71. Found: C, 58.70; H , 9.89.
57.33 58.34 ... 61.09
5-.
-Hydrogen,
R--
8.82 9.71
8.73 9.6s ... 9.55
Found
57 26 58.47 , . .
...
60.98
9.63
, . .
. . .
11.73
9 89
...
...
8 93
9 04
of ether. The ether was removed using a roto evaporator, and the diacid, 9.7 g. (goyo), was crystallized from petroleum ether (b.p. 30-60"), m.p. 156.5-158" dec. Anal. Calcd. for CgH1604Si: C, 50.00; H, 7.40; neut. equiv., 108.1. Found: C, 49.96; H, 7.53; neut. equiv., 107.9. Reaction with Dicyclohexy1carbodiimide.-Repeated at tempts to prepare the N-substituted silaspirobarbiturate using the pro-
(12) The diacid, m.p. 184-188', was obtained from the saponification of d i o a r b e t h o x y c y c l o h e x a ~b.p. ~ , 1020 (3 mm.), ~ U D1.4472: V. P. Gollmov [ Z h . Obrhch. Khim., 22, 1944 (1952): Chem. Abstr., 47, 9267 (1963)] reports b.p. 1000 (2 mm.), n 2 0 D 1.4482. (13) A. K. Bose, S. Garratt, and J. J. Pelois. J . 0 7 0 . Chem.. 28, 730 (1963).
