Nov., 1946
ORGANOMAGNESIUM COMPLEX IN CARBONYL BRIDGEINDENONES
CH3CCHs
V
The bimolecular products, 111, formed from monoalkylated anhydroacetonebenzils, likewise show one active hydrogen and one addition with methylmagnesium iodide. Four of these have been examined and all behaved alike. The product, after acidification, is a ketocarbinol, IV, which, in contrast to homologous Grignard produ c t ~does , ~ not lose carbon monoxide when heated, indicating that the Grignard reagent has attacked the bridge. Therefore they contam a car(1) Allen, Chcm. Rev., 31,235 (1945). (2) Allen. Jonesand VanAllan, THIS JOURNAL, 68,708 (1946). (3) Allen and Gates, ibid.. 64, 2123 (1942).
2387
These ketocarbinols evolve two equivalents of methane when treated quantitatively with meth-
VI
-
replacement of the hydroxyl by chlorine has repressed the enolization tendency of the angular hydrogen alpha to the carbonyl group. A dichloro compound, VIII, the structure of which has not been determined, obtained from the action of phosphorus pentachloride on 111, likewise shows one addition but no active hydrogen. The bimolecular product, IX, from cu,ar’-dimethylanhydroacetonebenzil’ reacts in two ways (4) Allen and VanAlhn, ;bid., 6S, 1384 (1943). (6) AUen and VanAllsn. Bid., 66, 8 (1944). (6) Allen,Jones and VanAllan, J . Org. C k m . , 11,268 (1946). (7) Allen and VanAllan. Tars JOURNAL, 64,1260 (1942).
2x58
Vol. 68
C. F. H. ALLENAND J. A. VANALLAN
I
CHa CsHs
R-C-OH
I
in XI, is isomerized, with a concomitant 1,3-shift of the phenyl group. Such a behavior appears to be characteristic of highly arylated cyclopentadienol^.'^^ It should also be recalled that the dimer, IX, cannot be decarbonylated readily by heat, because of its easy dissociation.6 On long refluxing, it I turns to a glass, which is probably the result of a XVII CH3 slow decarbonylation. with organometallic compounds. When examThe evidence for the structures of the Grignard ined quantitatively with methylmagnesium io- products, X and XI, is as follows: molecular dide, i t shows one addition. In ether, this reagent weight determinations show that they must be gives a product that has one active hydrogen, pre- derived from the monomolecular form, XIII. The sumably a carbinol (XI1 or XIIa-no attempt methoxylated substance is the carbinol, XI, has been made to distinguish between these struc- formed by 1,2-addition, for it shows one active hytures). Phenyllithium under forced conditions drogen, adds maleic anhydride to give XVII, and also gives a carbinol (incorrectly called a diol on gives a deep blue-violet color with concentrated p. 1267 of ref. 7). The dimer also reacts by addi- sulfuric acid. The substance, X, however, aptions with one equivalent of phenyl- or p-methoxy- pears to be an enol, formed by 1,4-addition; it phenylmagnesium bromide under forced condi- shows one active hydrogen, does not add maleic tions but, in this instance, the products, X and anhydride, gives a yellow color with concentrated XI, are derived from the monomeric cyclopenta- sulfuric acid, and furnishes benzophenone upon dienone formed by dissociation; thus, this be- oxidation. These properties parallel those of havior parallels that of the bimolecular product analogous substances.6 with other reagents.' From this behavior with organometallic comThe carbinols (XI1 or XIIa), formed by the ac- pounds it is thus possible to arrange the bimotion of methylmagnesium iodide and phenyllith- lecular products in three groups: (1) those deium, however, are unusual, in that when heated rived from symmetrical dialkylated anhydroacethey regenerate the bimolecular product, I X ; tonebenzils, (2) those from the monoalkylated the yield of the latter is about 20%. When the homologs, and (3) those from anhydroacetonephenylated carbinol (XII, R = CeH6) is employed, benzil itself. Members of the last two groups show a second product, the enol, X, can be isolated. one active hydrogen and one addition when treated This gives a clue as to the nature of the heat treat- quantitatively with methylmagnesium iodide, ment. The carbinol is dissociated into its compo- whereas with the first only addition can be denents, cleavage occurring in accordance with the tected. The Grignard products from the third double-bond rule' ; the dienone part, XIII, then group are indenols, still having a carbonyl bridge; dimerizes to IX. The second part, which would in those from the second group, the bridge has be expected to be the carbinol of the type shown been converted to a carbinol, while the indenone ( 8 ) The statement on p. 1267 of ref. 7 , that "the bimolecular prodcarbonyl is left free. Upon being heated, the caruct I V failed t o react" is incorrect; a t that time the reaction was binols of the third group form hydrocarbons in the attempted a t the boiling point of ether; reaction occurs when the indene series, that retain the radical introduced by ether is replaced by benzene and the temperature is raised.
Nov., 1916
ORCANOMAGNESIUM COMPLEX I N CARBONYL
BRIDGEI N D E N O N E S
2389
hours a mixture of 13.2 g. of 2,3,4-triphenylcyclopenten-30lonc,13 18 cc. of styrene, 70 cc. of acetic acid and two drops of concentrated sulfuric acid, and removing the solvent in vacuo until crystals appeared. The product was recrystallized from isopropyl alcohol; the yield was 9.5 g.; m. p. 155". Anal. Calcd. for C31H240: C, 90.3; H, 5.8. Found: C,90.6; H , 6 . 2 ; act. H,O; addn., 1.1. Proof of Structure.-Cleavage of the bridge by alkali was brought about by four hours' refluxing of 4.1 g. of the ketone, I, 3 g. of potassium hydroxide and 30 cc. of aldehyde-free absolute ethanol. The red solution was poured into water, acidified, and extracted with benzene. The liquid acid was dissolved in dilute potassium carbonate solution and stirred for one hour on the steam-bath during which titne 12 g. of potassium permanganate was gradually added. After acidification, the mixture was extracted with benzene, the extract shaken with sodium bicarbonate solution, and, after removal of the solvent, heated in vacuo as long as any distillate came over. The latter solidified in the receiver, and melted a t 125-132" after one recrystallization from ligroin. This crude dihydro compound was taken up in carbon tetrachloride and 0.5 cc. c€H54'I of bromine was added; hydrogen bromide was evolved copiously. After evaporation of the solvent, the residue C6H5Q ! J : K was crystallized from a benzene-methanol mixture. It was identified by comparison with an authentic specimen R I at hand; there was no deof 1,2,3,4-tetraphenylbenzene OMgX pression of melting point on admixture. A chlorinated xv product, thought to be 1,1-dichloro-8-keto-2,7-di-methyl3,3a,5,6- tetraphenyl-4,7 -methano-3a,4,7,7a tetrahydroindene, VIII, was produced on refluxing for two and one-half hours a mixture of 4.6 g. of the dimethylated bimolecular product,14 m. p. 230" (111, R = CH,), 6.2 g. of phosphorus pentachloride, and 20 cc. of benzene, pouring the mixture into water, and working up by suitable A manipulation; it was recrystallized from cymene, after R OMgX which it had the melting point of 290'. XVI Anal. Calcd. for C36H&120: C, 79.0; H, 5.1; C1, Such a structure cannot be applied to magne- 13.0. Found: C, 79.0; H, 5.4; C1, 12.7; act. H, 0 ; sium derivatives of the indenols which retain the addn., 0.9. The carbinols, IV, were all prepared in the same way; group introduced by the Grignard reagent. These, hot benzene solution of the carbonyl bridged compound however, ,are formed from a rearranged bimolec- awas added to the Grignard reagent as fast as the reaction ular product; in this instance it is believed'O that permitted, after which the mixture was refluxed one and the ring is opened under the influence of the Gri- one-half to two hours. A yellow solid slowly separated. gnard reagent, and that the magnesium complex This was cautiously decomposed by the addition, at 5has the structure shown in XVI. This accounts lo', of a solution of 35 cc. of acetic acid in 200 cc. of water. The insoluble carbinol was collected and recrystallized satisfactorily for the fact that both stereoisomeric from a large volume of solvent; there is a strong tendency forms of the bimolecular product give the same to retain solvent of crystallization. The phenylated carbinol, m. p. 229", was never obtained in an analytically carbinol with phenylmagnesium bromide." pure condition, but its derivatives all gave correct values. It now appears that in the indenones the neces- The were 90-98y0. Their properties are given in sary hydrogen atom for enolization is not the one Tableyields 1. alpha to the carbonyl bridge, but the one on the The chlorides, VI, were obtained by refluxing for one and angular carbon atom common to both rings, and one-half hours a mixture of 2 g. of the carbinol and 10 cc. of thionyl chloride, retnoving the unused solvent in vacuo, alpha to the indenone carbonyl group. and triturating the residue with ligroin (b. p. 90-120'); The proof of structure for the ketone, I, was ob- cymene was employed for recrystallization. Their propertained by reactions now known to be characteris- ties are collected in Table I. The acetates, VII, were prepared by dissolving 3 g. of the tic for carbonyl bridge compounds, cleavage of the bridge with alkali,z$6decarboxylation by per- carbinol in 25 cc. of hot acetic anhydride, cooling to 30°, adding one drop of concentrated sulfuric acid; the manganate,2-12and dehydrogenation with bro- and acetate (2.9 g.) separated quickly; cymene was used for mine.2 The known 1,2,3,4-tetraphenylbenzene13 recrystallization. With the methyl carbinol (IV, R' = produced showed the mode of addition of styrene. CHa), dioxane was added to the acetic anhydride to effect. solution. The properties of the acetates are given in Table Experimental I. 7-Keto-1,2,3,6-tetraphenyl-l,4-methano-1,4,S,d-tetra- The carbinols, XI1 (except where R = CHs), were obhydrobenzene, I, was obtained by refluxing for three tained under forced conditions. The bimolecular product, IX, was dissolved in hot benzene or butyl ether, and after (9) Bredt, Ami., 457, 1 (1924). it had been added to the ethereal solution of the organo(10) See ref. 1, pp. 236, 237. metallic compound, the ether was distilled, and the residual (11) Allen and Gates, THISJOURNAL, 64, 2439 (1942). mixture heated, with stirring, on the steam-bath for six to
the Grignard reagent. On the contrary, carbinols of the second group lose this radical, and give dihydroindenones. When carbinols of the first group are heated, the original bimolecular product from which the carbinols were prepared is always formed; the second product can be identified only in favorable instances. The structure of the organomagnesium derivatives of groups 2 and 3 would appear to be reprcsented by the structure XV, in view of the following facts: (a) the non-enolization of ketones I and I1 by Grignard reagents; (D) the formation of a series of ketocarbinols in the monoalkylated series which yield the same dihydroindenone on heating. -1previous assumption,' involving a supposed exception to Rredt's rule,q is no longer tenable. csFI5
-
(12) Allen and Gates, ibid., 64, 2120 (1942). (13) Dilthep and Hurtig. Bcr., 67, 2004 (1934).
(14) Japp and Meldrum, J. Chcm. SOL, 79, 1024 (1901).
2390
G. E. MCCASLAND, D. S. TARBELL, R. B. CARLINAND NANCY SHAKESPEARE Vol. 68 TABLE I PROPERTIES OF BRIDGED COMPOUNDS -Calcd.-
7
IV IV IV
IV VI VI VI1 VI1 VI1 XI1 XI1 XVII 0
No. R , R' = CHa R = CHa, R' = CsHi R = CH3, R' = 4-CH:OOH4 R = n-CrHn, RZ CsHi R, R' = CHI R = CHs, R' = CsHi R . R' = CHI R = CHI, R ' = CaHs R := CHa, R' = 4-CHsOCeH4 R = CHa R .= CaHs
-
a From xylene. From toluene.
Substance Methylated carbinol Phenylated carbinol Anisylated carbinol Phenylated carbinol Methylated chloride Phenylated chloride Methylated acetate Phenylated acetate Anisylated acetate Methylated carbinol Phenylated carbinol Anhydride
From n-octane.
e
M. P., OC. 286-288" 229) 258O 180-18 1 235 198-1994 199' 281' 2700 206 223 2 10- 2 12a
From butanol.
* One addition. * Insoluble in reagent.
C 87.4 88.5 86.0 88.0
H 6.3 6.0 6.0 7.3
C
Mol. Act. wt. H 2 2 6.3 640e 2 2 7.2 6 . 6 569' 1 6 . 0 50V Oh 6.2 543' 5.8 6.2 6.5 543' l i 6.4 5.6
H 87.5 6 . 5
600 8 6 . 1 87.6 6 . 8 527 6 . 0 588 85.0 6 . 2 550 8 5 . 1 86.3 5 . 9 86.7 84.3 5 . 9 84.3 87.3 6.7 536 8 7 . 0 88.3 6.4 88.2 77.2 5 . 6 77.1
From chloroform-methanol.
-
Analyses, % -Found-
Mol. C1 wt.
In benzene.
CI
From cymene.
338; act. H, 1; addn., 0. Found: C, 88.7; H, 6.5; act. H, 1; addn., 0.25; mol. wt., 304 (in CeHs). It was oxidized by chromic acid and the benzophenone 1-pMethoxyphenyl-2,S-dimethyl-3,4-diphenylcyclopen- formed was identified in the usual way.' tadienol, XI, resulted when p-methoxyphenylmagneWhen the phenylated carbinol, (XII, R =E CsHs),.wv sium bromide reacted with the dimer, IX, by the proce- distilled, there was some decomposition. The solid distildure just described; it crystallized well from benzene, late was triturated with methanol, followed by extractoluoene and butanol; and has the melting point of 193tion with hot ligroin (b. p. 90-100"). The latter removed 194 . I t gives a bluish-violet solution, tinged with red, the enol, X, which was identified by a mixed melting point. when dissolved in concentrated sulfuric acid. The insoluble portion was crystallized from benzeneAnal. Calcd. for C ~ ~ H H OC,~ 84.7; : H, 6.5; act. H , 1. ligroin, and identified *by comparison with an authentic specimen of the bimolecular product, IX, and also with Found: C,81.9; H,6.5; act.H, 1. its 2,4-dinitrophenylhydrazone. The dimer, IX, was also The anhydride, XVII, of 3,6-dimethyl-4,6-diphenyl-7-p-identified after the other carbinols in the series (XII) had methoxyphenyl- 7 - hydroxy-3,6-methano- 1,2,3,6-tetrahy- been heated, drobenzene-1,2-dicarboxylicacid was formed by the addi- crystallize. but the remainder of the material failed to tion of maleic anhydride to the carbinol, XI, equal weights Summary of the components being heated for two hours a t 200". I t was also obtained by two hours' refluxing a benzene soluAll three types of bimolecular products formed tion of the components; any acidic material was extracted by shaking with aqueous sodium carbonate. The proper- by the dehydration of anhydroacetonebenzils under acidic conditions have been compared with ties are given in Table I. The product from the action of phenylmagnesium bro- respect to their behavior with Grignard reagents. mide upon the dimer, IX, was distilled in vucuo, b. p. They fall into three groups, each having charac197-201 ' (2 mm.). After recrystallization from i-propyl teristic properties. alcohol or heptane, the white 2,5-dimethyl-3,3,4-triThe structures which are postulated for the orphenylcyclopentadienol-1,X, has a melting point of 137138'; nothing else could be obtained from the yellow solu- ganomagnesium complex of each group appear to tion. The enol gives a yellow solution, with a slight green- account satisfactorily for the behavior. ish fluorescence, in concentrated sulfuric acid. Anal. Calcd. for Cz5HaO: C, 88.7; H , 6.6; mol. wt., ROCHESTER 4, NEWYORK RECEIVED MAY17, 1946 eighteen hours. The products were handled by suitable operations. The properties of the two bridged -~ products are given in Table I.
[CONTRIBUTION FROM THE
DEPARTMENT OF CHEMISTRY OF THEUNIVERSITY
OF ROCHESTER]
Analogs of Pyridoxine. I. Some Hydroxymethylpyrimidine Derivatives' BY
G. E. MCCASLAND,~ D. S T A N L E Y
TARBELL,
The synthesis of analogs of pyridoxine (I) for testing as antimalarials was suggested by the work of Seeler16who found that large doses of pyridoxine counteracted the effects of atebrine or quinine on (1) The early work on this problem was conducted under a contract recommended by the Committee on Medical Research between the O 5 c e of Scientific Research and Development and the University of Rochester. (2) Present address: Department of Chemistry, University of Illinois. (3) Present address: Department of Chemistry, Carnegie Institute of Technology. (4) Present address: American Cyanamid Company, Stamford, Connecticut. (5) Seeler. Proc. Soc. Ex$. Biol. M e d . , 57, 113 (1944).
R. B.
CARLIN' AND
NANCY SHAKESPEARE*
P.Zophurae in ducks. This might mean that pyridoxine was necessary for growth of the parasites, and hence that its action might be antagonized by a compound differing slightly from it in structure. Accordingly, we attempted the preparation of compounds in which the characteristic groups of pyridoxine are attached to a different heterocyclic rings than the pyridine ring. There are seven different ways in which the four characteristic groups of pyridoxine might be attached to the four carbon atoms in the pyrimidine ring. The most promising route for any of (6) Work on thiazole analogs is now in progress in this Laboratory.
